JP2013177316A - Novel quinazoline compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a quinazoline compound having GPR119 receptor agonistic activity and being useful as a medicine.SOLUTION: There is provided a compound represented by general formula [I] or a pharmacologically acceptable salt thereof. (In formula [I], Rrepresents hydrogen or a halogen; ring A represents a 6-membered aryl ring which may contain nitrogen; Rrepresents hydrogen, a halogen, alkylthio or the like; Rrepresents hydroxy or the like; Rrepresents (a) cyano, or (b) 5 to 6-membered heteroaryl which contains one to three heteroatoms selected from oxygen and nitrogen, and which may be substituted with alkyl or the like which may be substituted with one to three halogens).

Description

  The present invention relates to a novel quinazoline compound or a pharmacologically acceptable salt thereof which has an excellent GPR119 receptor agonistic activity and is useful as a medicine.

  GPR119, a G protein-coupled receptor (GPCR), is a receptor that is highly expressed in pancreatic insulin-producing β-cells and intestinal cells, and is a natural long-chain fatty acid amide that is a natural long-chain fatty acid amide. It was activated by compounds such as oil ethanolamide (OEA) and low molecular weight synthetic ligand PSN632408, and activation of the receptor was observed to suppress feeding and weight gain in high-fat diet rats. (Non-Patent Document 1).

  Furthermore, a recent study on the physiological role of GPR119 using a selective small molecule agonist (AR231453) represented by the following formula revealed that pancreatic pancreatic pancreatic pancreatic pancreas was mediated by increased cAMP (adenylate cyclase activation) by activation of the receptor. It has been clarified that glucose-dependent insulin release in β-cells is enhanced, and that glucose homeostasis can be improved (Non-Patent Document 2).

  In addition, this receptor regulates glucose homeostasis through enhanced release of incretins (glucagon-like peptide-1 / GLP-1 and glucose-dependent insulin peptide / GIP), which can be referred to as endogenous antidiabetic hormones. (Non-patent Document 3). Furthermore, the low molecular weight GPR119 agonist can be expected to have an effect of directly and / or indirectly protecting the pancreas via an incretin hormone (an anti-apoptotic action and / or a proliferation promoting action on islet cells). From the above findings, GPR119 has attracted attention as an attractive therapeutic target in metabolic related diseases including diabetes and obesity.

  Currently, as GPR119 agonists, in addition to OEA, PSN632408 and AR231453 described above, bipiperidinyl compounds (Patent Document 1), 1H-pyrazolo [3,4-d] pyrimidin-4-yloxypiperidine compounds (Patent Document 2) 6,7 -Dihydro-5H-pyrrolo [2,3-d] pyrimidin-4-yloxy-1-piperidine compound, 2,3-dihydro-1-indol-4-yloxy-1-piperidine compound (Patent Document 3), 4- (Benzo [b] [1,4] oxazin4 (3H) -yl) piperidine compounds (Patent Document 4) and the like are known, but compounds such as the present invention (piperidine or piperazine is bonded to the 4-position of the quinazoline ring) It has been reported so far that a compound having a structure has an agonistic effect on GPR119. There.

WO2008 / 076243 WO2005 / 007658 WO2008 / 008895 WO2008 / 137435 Cell Metabolism 3: 167-175 (2006) Endocrinology 149 (5): 2035-2037 (2008) Endocrinology 149 (5): 2038-2047 (2008)

  An object of the present invention is to provide a novel quinazoline compound having an excellent GPR119 receptor agonistic activity and useful as a medicament.

  The present invention relates to the following general formula [I]:

[Where,
R ¹ is a hydrogen atom or a halogen atom,
Ring A is a 6-membered aromatic cyclic group which may contain a nitrogen atom as a hetero atom,
R ⁰¹ is a hydrogen atom, a halogen atom, a cyano group, an alkyl group or an alkylthio group,
R ⁰² is 1) a hydroxyl group;
2) a group represented by the formula: R ⁰⁴ — (CHR ⁰³ ) — [where,
R ⁰³ is a hydrogen atom or a group represented by the formula: R ^a R ^b N— (R ^a and R ^b are the same or different and are a hydrogen atom or an alkyl group),
R ⁰⁴ is a) a cyano group, b) a hydroxyl group, c) a hydroxymethyl group, d) a carboxyl group, e) a group represented by the formula: R ^c —S (═O) _m — (R ^c is a hydroxyl group and a formula: R ^d R ^e NCO-- at indicated are chosen alkyl group which may be substituted with a group from group, m represents an integer of 0 to 2, R ^d and R ^e are the same or different and each represents a hydrogen atom or an alkyl group; provided that And R ⁰³ is a hydrogen atom, R ^c is not an alkylsulfonyl group), f) a group represented by the formula: HO—Alk—O— (Alk represents an alkylene group), and g) a formula: A group represented by R ^f R ^g NCO— (R ^f and R ^g are the same or different and each represents a hydrogen atom, an alkyl group, a monohydroxyalkyl group or a dihydroxyalkyl group, or both are bonded to each other together with an adjacent nitrogen atom; 5-6 membered aliphatic Nitrogen heteromonocyclic group (said group may be substituted by a hydroxyl group or a carbamoyl group) to form a), h) formula: R h ^R i ^N-a group represented (R ^h and R ⁱ Are the same or different and each represents a hydrogen atom, an alkyl group, an alkanoyl group, a hydroxyalkanoyl group, an alkoxycarbonyl group or an alkanoyloxyalkanoyl group); or i) a 5- to 6-membered aliphatic nitrogen-containing heterocyclic group (the heterocyclic group) The group may be substituted with a group selected from a hydroxyl group, an oxo group, an alkanoyl group and a carbamoyl group)];
3) An alkoxy group substituted with a group selected from a hydroxyl group, an alkoxycarbonyl group, a carbamoyl group (the amino group portion of the group may be substituted with 1 to 2 alkyl groups) and a phenyl group;
4) a group ^{represented by the} formula: R ^k —S (═O) _n — (R ^k is an alkyl group substituted with a hydroxyl group or an alkoxy group, n represents an integer of 0 to 2);
5) a group represented by the formula: R ^m R ⁿ NC (═O) — (R ^m and R ⁿ are: (a) one is a hydrogen atom or an alkyl group and the other is a cycloalkyl group (the group is a hydroxyalkyl group) An alkoxycarbonylbenzyl group, a carboxyphenylalkyl group, or a 5- to 6-membered aliphatic sulfur-containing heterocyclic group (the group may be substituted with 1 to 2 oxo groups). Or (b) both R ^m and R ⁿ are bonded together at the end, together with the adjacent nitrogen atom, a hydroxyl group, a cyano group, an oxo group, a hydroxyalkyl group, and a carbamoyl group (the group is one or two alkyl groups). Represents a 4- to 6-membered aliphatic nitrogen-containing heterocyclic group substituted with a group selected from (which may be substituted with a group);
6) an amino group substituted with a group selected from an alkanoyloxyalkanoyl group and a hydroxyalkanoyl group;
7) containing 1 to 4 nitrogen atoms as a hetero atom and selected from a hydroxyl group, an oxo group, a hydroxyalkyl group and a carbamoyl group (this group may be substituted with 1 to 2 alkyl groups) A saturated or unsaturated 5- to 6-membered nitrogen-containing heterocyclic group substituted with 1 to 2 groups, which may further contain a heteroatom selected from an oxygen atom and a sulfur atom, and Or optionally substituted with a group selected from a group, a hydroxyalkyl group, an alkanoyl group, a hydroxyalkanoyl group and a carbamoyl group); or 8)

[Wherein, ring B represents a nitrogen-containing 5-membered aliphatic heterocyclic ring which may be substituted with an oxo group. ]
A group represented by
R ² contains (a) a cyano group, or (b) the same or different 1 to 4 heteroatoms selected from an oxygen atom and a nitrogen atom, and may be substituted with 1 to 3 halogen atoms. 5- to 6-membered heteroaryl group optionally substituted with 1 to 2 groups selected from an alkyl group, a hydroxyalkyl group, an amino group optionally substituted with 1 to 2 alkyl groups, and a cycloalkyl group Represents. ]
Or a pharmaceutically acceptable salt thereof.

  The present invention also relates to a pharmaceutical composition comprising the compound [I] or a pharmacologically acceptable salt thereof as an active ingredient. Furthermore, the present invention relates to a GPR119 modulator (in particular, a GPR119 agonist) comprising the compound [I] or a pharmacologically acceptable salt thereof as an active ingredient.

  The compound of the present invention is a compound that exerts an excellent regulatory action (agonist action, etc.) on GPR119 activity, has few side effects, and has high medicinal safety. For example, as shown in the experimental examples described below, the compound of the present invention was useful as a GPR119 agonist because it exhibited an excellent cAMP production enhancing action against the same cells in an assay system using human GPR119-expressing CHO cells. is there.

  In the compound [I] of the present invention, the ring A is a 6-membered aromatic ring which may contain a nitrogen atom as a hetero atom, and examples of such an aromatic ring include a benzene ring, a pyridine ring, and a pyrimidine ring. Among these, a benzene ring or a pyridine ring is preferable.

When R ⁰⁴ is a group represented by the formula: R ^f R ^g NCO— and R ^f and R ^g are bonded to each other to form a 5- to 6-membered aliphatic nitrogen-containing heterocyclic group, Examples of the nitrogen heterocyclic group include a pyrrolidinyl group, a piperidinyl group, an imidazolidinyl group, a piperazinyl group, and the like, and the heterocyclic group may be substituted with a hydroxyl group or a carbamoyl group.

When R ⁰⁴ is a 5- to 6-membered aliphatic nitrogen-containing heterocyclic group, examples of such a heterocyclic group include a pyrrolidinyl group, a piperidinyl group, an imidazolidinyl group, a piperazinyl group, and the like. The formula group may be substituted with a group selected from a hydroxyl group, an oxo group and an alkanoyl group.

When R ⁰² is a group containing a 5- to 6-membered aliphatic sulfur-containing heterocyclic group, examples of such a heterocyclic group include a tetrahydrothienyl group, a tetrahydrothiopyranyl group, and the like. The group may be substituted with 1 to 2 oxo groups.

R ⁰² is a group represented by the formula: R ^m R ⁿ NC (═O) —, wherein both R ^m and R ⁿ are bonded to each other and substituted with a group selected from a hydroxyl group, a hydroxyalkyl group and a carbamoyl group In the case of forming the 4- to 6-membered aliphatic nitrogen-containing heterocyclic group, examples of the heterocyclic group include an azetidyl group, a pyrrolidinyl group, a piperidinyl group, and a piperazinyl group.

R ⁰² contains 1 to 4 nitrogen atoms as heteroatoms and is a hydroxyl group, oxo group, hydroxyalkyl group or carbamoyl group (the carbamoyl group may be substituted with 1 to 2 alkyl groups). In the case of a saturated or unsaturated 5- to 6-membered nitrogen-containing heterocyclic group substituted with 1 to 2 groups selected, the nitrogen-containing heterocyclic group further comprises a heteroatom selected from an oxygen atom and a sulfur atom. You may contain. Examples of such a nitrogen-containing heterocyclic group include pyrrolidinyl group, imidazolidinyl group, thiazolidinyl, isothiazolidinyl group, oxazolidinyl group, piperidyl group, piperazinyl group, tetrahydropyrimidinyl group, morpholinyl group, tetrahydro-1,3-oxazinyl group , Triazolyl group, tetrazolyl group and the like. These heterocyclic groups may be further substituted with a group selected from an alkyl group, a hydroxyalkyl group, an alkanoyl group, a hydroxyalkanoyl group and a carbamoyl group.

R ⁰² is the formula:

Ring B (5-membered nitrogen-containing aliphatic heterocycle) includes, for example, a pyrrolidine ring, an imidazolidine ring, etc., and the aliphatic heterocycle is substituted with an oxo group. Also good.

The 5- to 6-membered heteroaryl group in R ² is a heteroaryl group containing the same or different 1 to 4 heteroatoms selected from an oxygen atom and a nitrogen atom. Specific examples of such heteroaryl groups include Oxazolyl group, oxadiazolyl group, tetrazolyl group, imidazolyl group, triazolyl group, pyridyl group and the like. The saturated or unsaturated 5- to 6-membered heteromonocyclic group is an alkyl group which may be substituted with 1 to 3 halogen atoms, and an amino group which may be substituted with 1 to 2 alkyl groups. And may be substituted with 1 to 2 groups selected from cycloalkyl groups.

  In one embodiment, the present invention provides the following formula in the above formula [I]:

The partial structure represented by the following formula:

[Wherein, one of a and b represents a carbon atom and the other represents a carbon atom or a nitrogen atom, and the other symbols have the same meaning as described above]
A substituted 6-membered aromatic cyclic group represented by formula (Ia):

[Wherein the symbols have the same meaning as described above]
Or a pharmaceutically acceptable salt thereof.

Among the compounds of the present invention, preferred compounds include, for example, in the general formula [I] or [Ia]
Ring A is a benzene ring,
R ⁰¹ is a halogen atom, a cyano group or an alkyl group,
R ⁰² is 1) a group represented by the formula: R ⁰⁴ — (CHR ⁰³ ) — [wherein R ⁰³ is a hydrogen atom, R ⁰⁴ is a) a hydroxymethyl group or b) a formula: R ^f R ^g NCO— Wherein R ^f and R ^g are the same or different and each represents a hydrogen atom or an alkyl group (the alkyl group may be substituted with a hydroxyl group), or both are bonded to each other to form a hydroxyl group and a cyano group. A 5-membered nitrogen-containing aliphatic heterocyclic ring substituted with 1 to 2 groups selected from:
2) a group ^{represented by the} formula: R ^k —S (═O) _n — wherein R ^k is an alkyl group substituted with a hydroxyl group or an alkoxy group, and n represents an integer of 0 to 2;
3) a group represented by the formula: R ^m R ⁿ NC (═O) — [wherein R ^m and R ⁿ are selected from a hydroxyl group, a cyano group, and a carbamoyl group together with an adjacent nitrogen atom bonded together at the terminal Represents a 4- to 6-membered aliphatic nitrogen-containing heterocyclic group substituted with 1 to 2 groups]; or 4) contains 1 to 2 nitrogen atoms as a heteroatom, and Saturated or unsaturated 5- to 6-membered nitrogen-containing heterocyclic group substituted with 1 to 2 groups selected from an oxo group and a hydroxyalkyl group [wherein the cyclic group is selected from an oxygen atom and a sulfur atom And may further contain a heteroatom and may be further substituted with a hydroxyl group, an alkyl group, a carbamoylalkyl group or a dialkylcarbamoylalkyl group], and R ² is the same selected from an oxygen atom and a nitrogen atom Or 5 member (s) containing 1 to 3 heteroatoms and substituted with an alkyl group (which may be substituted with 1 to 3 halogen atoms), a cycloalkyl group or an alkanoyloxyalkyl group Examples thereof include compounds that are heteroaryl groups.

Among the compounds of the present invention, as a more preferred compound, for example, in the general formula [I] or [Ia],
Ring A is a benzene ring,
R ⁰¹ is a halogen atom or a C _1-4 alkyl group,
R ⁰² is 1) a group represented by the formula: R ^f R ^g NCO—CH ₂ — (wherein R ^f and R ^g are the same or different and each represents a hydrogen atom or a C _1-4 alkyl group, or both are And represents a 5-membered nitrogen-containing aliphatic heterocyclic ring substituted with 1 to 2 groups selected from a hydroxyl group, a cyano group, and an oxo group together with adjacent nitrogen atoms).
2) a group ^{represented by the} formula: R ^k —S (═O) ₂ — (R ^k represents a C _1-4 alkyl group substituted with a group selected from a hydroxyl group and a C _1-4 alkoxy group);
3) a group represented by the formula: R ^m R ⁿ NC (═O) — (R ^m and R ⁿ are bonded to each other at the terminal and are selected from a hydroxyl group, a cyano group, and a carbamoyl group together with an adjacent nitrogen atom. Represents the formation of a 5-membered aliphatic nitrogen-containing heterocyclic group substituted with two groups); or 4) contains 1 to 2 nitrogen atoms as heteroatoms, and an oxo group and hydroxy- A saturated or unsaturated 5- or 6-membered nitrogen-containing heterocyclic group substituted with 1 to 2 groups selected from C _1-4 alkyl groups (the cyclic group further contains an oxygen atom as a hetero atom) And may be further substituted with a hydroxyl group, a carbamoyl-C _1-4 alkyl group or a di (C _1-4 alkyl) carbamoyl-C _1-4 alkyl group), and R ² is an oxygen atom. And the same or different selected from nitrogen atoms 5 containing 1 to 3 heteroatoms and substituted with a C _1-4 alkyl group (which group may be substituted with 1 to 3 halogen atoms) or a C _3-6 cycloalkyl group And compounds that are membered heteroaryl groups.

Among the compounds of the present invention, more preferable compounds include, for example, in the general formula [I] or [Ia]
Ring A is a benzene ring,
R ⁰² is 1) a group represented by the formula: R ^f R ^g NCO—CH ₂ — (where R ^f represents a hydrogen atom, R ^g represents a C _1-4 alkyl group, or both are bonded at the end) And forming a pyrrolidinyl group substituted with a hydroxyl group together with the adjacent nitrogen atom)
2) a hydroxy- _C1-4 alkylsulfonyl group,
3) The following formula:

(In the formula, one of R ^a3 and R ^a4 represents a hydrogen atom or a hydroxyl group, and the other represents a cyano group or a carbamoyl group)
Or 4) the following formula:

(Wherein R ^a1 is a hydrogen atom, a hydroxyl group or a hydroxy-C _1-4 alkyl group, R ^a2 is a hydroxy-C _1-4 alkyl group, a carbamoyl-C _1-4 alkyl group or di (C _1-4 alkyl). Represents a carbamoyl-C _1-4 alkyl group)
And R ² contains the same or different 1 to 3 heteroatoms selected from an oxygen atom and a nitrogen atom, and is substituted with 1 to 3 fluorine atoms Examples thereof include a compound having a 5-membered heteroaryl group substituted with a good C _1-4 alkyl group or C _3-6 cycloalkyl group.

Among the compounds of the present invention, particularly preferred compounds include, for example,
2- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] Phenyl] -N-methylacetamide;
6-Fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] -8- [3-fluoro-4- (2-hydroxyethyl) Sulfonyl) phenyl] quinazoline;
[2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenyl ] (3-hydroxypyrrolidin-1-yl) methanone;
1- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl] -3- (2-hydroxyethyl) imidazolidin-2-one;
6-Fluoro-4- [4- (5-n-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] -8- [3-fluoro-4-[(3 -Hydroxypyrrolidin-1-yl) carbonyl] phenyl] quinazoline;
1- [2-Fluoro-4- [6-fluoro-4- [4- (5-cyclopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline-8- Yl] phenyl] -3- (2-hydroxyethyl) imidazolidin-2-one;
1- [2-Fluoro-4- [6-fluoro-4- [4- (5-n-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline-8 -Yl] phenyl] -3- (2-hydroxyethyl) imidazolidin-2-one;
1- [2-Fluoro-4- [6-fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl] -3- (2-hydroxyethyl) imidazolidin-2-one;
1- [2-Fluoro-4- [5-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl] -3- (2-hydroxyethyl) imidazolidin-2-one;
1- [4- [6-Fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] -2- Fluorophenyl] -4-hydroxypyrrolidin-2-one;
[2-Fluoro-4- [6-fluoro-4- [4- (5-trifluoromethyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl] (3-hydroxypyrrolidin-1-yl) methanone;
1- [4- [6-Fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] -3- Methylphenyl] pyrrolidin-2-one;
2- [2-Fluoro-4- [6-fluoro-4- [4- (5-n-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline-8 -Yl] phenyl] -1- (3-hydroxypyrrolidin-1-yl) ethanone;
1- [2-Fluoro-4- [4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenyl]- 3- (2-hydroxyethyl) imidazolidin-2-one;
1- [2-Methyl-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl] -3- (2-hydroxyethyl) imidazolidin-2-one;
1- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl] piperazin-2-one;
1- [2-Fluoro-4- [5-fluoro-4- [4- (5-n-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline-8 -Yl] phenyl] -3- (2-hydroxyethyl) imidazolidin-2-one;
1- [2-Fluoro-4- [5-fluoro-4- [4- (5-cyclopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline-8- Yl] phenyl] -3- (2-hydroxyethyl) imidazolidin-2-one;
1- [2-Fluoro-4- [5-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl] -4-hydroxypyrrolidin-2-one;
1- [2-Fluoro-4- [5-fluoro-4- [4- (5-n-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline-8 -Yl] phenyl] -4-hydroxypyrrolidin-2-one;
1- [2-Fluoro-4- [5-fluoro-4- [4- (5-cyclopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline-8- Yl] phenyl] -4-hydroxypyrrolidin-2-one;
1- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl] -3- (2-hydroxy-2-methylpropyl) imidazolidin-2-one;
1- [4- [6-Fluoro-4- [4- (5-cyclopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] -3 -Methylphenyl] pyrrolidin-2-one;
4- [4- [6-Fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] -3- Methylphenyl] morpholin-3-one;
1- (2-Fluoro-4- {6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl } Phenyl) imidazolidin-5-one;
3- [2-Fluoro-4- [4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenyl]- 3-hydroxypyrrolidin-4-one;
1- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl] -5-hydroxymethylpyrrolidin-2-one;
2- [1- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline- 8-yl] phenyl] -2-oxoimidazolidin-3-yl] -N, N-dimethylacetamide;
[2-Fluoro-4- [6-fluoro-4- [4- (5-trifluoromethyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl] (2-carbamoylpyrrolidin-1-yl) methanone;
1- [2-Fluoro-4- [4- [4- [5- (1,1-difluoroethyl)-[1,2,4] oxadiazol-3-yl] piperidin-1-yl] quinazoline- 8-yl] phenyl] -3- (2-hydroxyethyl) imidazolidin-2-one;
[2-Fluoro-4- [6-fluoro-4- [4- (5-trifluoromethyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl] (2-cyano-4-hydroxypyrrolidin-1-yl) methanone;
[2-Fluoro-4- [5-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenyl ] (2-cyano-4-hydroxypyrrolidin-1-yl) methanone;
[2-Fluoro-4- [5-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenyl ] (3-hydroxypyrrolidin-1-yl) methanone;
[2-Fluoro-4- [5-fluoro-4- [4- [5- (1,1-difluoroethyl)-[1,2,4] oxadiazol-3-yl] piperidin-1-yl] Quinazolin-8-yl] phenyl] (3-hydroxypyrrolidin-1-yl) methanone;
[2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenyl ] (2-carbamoylpyrrolidin-1-yl) methanone;
1- [2-Methyl-4- [5-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl] -3- (2-hydroxyethyl) imidazolidin-2-one;
1- [2-Methyl-4- [6-fluoro-4- [4- (5-trifluoromethyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline-8 -Yl] phenyl] -3- (2-hydroxyethyl) imidazolidin-2-one; and 1- [2-methyl-4- [6-fluoro-4- [4- (5-cyclopropyl- [1, 2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenyl] -3- (2-hydroxyethyl) imidazolidin-2-one;
Or a pharmacologically acceptable salt thereof selected from the group consisting of:

  When the compound [I] of the present invention has an asymmetric carbon atom in the molecule, it can exist as a plurality of stereoisomers (diastereoisomers, optical isomers) based on the asymmetric carbon atom. The invention includes any one of these stereoisomers or mixtures thereof.

  Since the compound [I] of the present invention has an excellent agonistic effect on the GPR119 receptor, various diseases or conditions that can be expected to be improved by regulating the receptor activity, such as obesity, hyperglycemia, diabetes (Including insulin-dependent diabetes, non-insulin-dependent type 2 diabetes, or their intermediate type diabetes) and complications thereof, metabolic syndrome, impaired glucose tolerance, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, It is useful for the prevention and treatment of metabolic diseases including diseases such as hypertriglyceridemia and abnormal lipid metabolism, or cardiovascular diseases such as arteriosclerosis, hypertension, coronary disease, and myocardial infarction.

  The compound [I] of the present invention or a pharmacologically acceptable salt thereof has a feature of low toxicity and high safety as a medicine.

  The compound [I] of the present invention can be used for pharmaceutical use either in a free form or in the form of a pharmaceutically acceptable salt thereof. Examples of pharmaceutically acceptable salts include inorganic acid salts such as hydrochloride, sulfate, phosphate or hydrobromide, acetate, trifluoroacetate, fumarate, oxalate, citric acid, and the like. And organic acid salts such as acid salts, methanesulfonate, benzenesulfonate, tosylate, and maleate.

  The compound [I] of the present invention or a pharmacologically acceptable salt thereof includes any of its internal salts and adducts, solvates or hydrates thereof.

  The compound [I] of the present invention or a pharmacologically acceptable salt thereof can be administered orally or parenterally, and tablets, granules, capsules, powders, injections, inhalants, etc. It can be used as a conventional pharmaceutical preparation.

  The dose of the compound [I] of the present invention or a pharmacologically acceptable salt thereof varies depending on the administration method, patient age, body weight, and condition. 100 mg / kg, especially about 0.01 to 10 mg / kg, and oral preparations are usually about 0.01 to 1000 mg / kg per day, especially about 0.1 to 100 mg / kg.

  The compound [I] of the present invention or a pharmacologically acceptable salt thereof can be used alone or in combination with one or more other drugs depending on the disease to be treated. Examples of such drugs include the following.

(A) Antihypertensive agents: angiotensin converting enzyme inhibitors (enalapril maleate, imidapril hydrochloride, etc.), angiotensin II receptor antagonists (losartan potassium, candesartan cilexetil, etc.), β-blockers (atenolol, bisoprolol fumarate, etc.), alpha / beta blockers (carvedilol, hydrochloric labetalol, etc.), calcium antagonists (amlodipine besylate, diltiazem hydrochloride, etc.), alpha _1-blockers (doxazosin mesylate, prazosin hydrochloride, etc.), central alpha ₂ agonist or other centrally acting Drugs (clonidine hydrochloride, reserpine, etc.), vasodilators (hydralazine hydrochloride, minoxidil, etc.), etc .;
(B) Diuretics: thiazide diuretics (chlorothiazide, hydrochlorothiazide, etc.), loop diuretics (bumetanide, furosemide, etc.), potassium-sparing diuretics (amiloride hydrochloride, triamterene, etc.);
(C) Heart failure treatment drugs: nitrate drugs (nitroglycerin, etc.), digitalis preparations (digoxin, digitoxin, etc.), catecholamines (dobutamine hydrochloride, denopamine, etc.), endothelin antagonists (bosentan, etc.), phosphodiesterase inhibitors (milrinone lactate, amrinone) Etc.), neutral endopeptidase inhibitors (such as fascytril), atrial diuretic peptide, etc .;
(D) Antiarrhythmic drugs: Na channel blockers (procainamide hydrochloride, flecainide acetate, etc.), K channel blockers (amiodarone hydrochloride, etc.), Ca channel blockers (verapamil hydrochloride, etc.) and the like;
(E) Hyperlipidemic drugs: HMG-CoA reductase inhibitors (pravastatin sodium, atorvastatin calcium, fluvastatin sodium, etc.), fibrate derivatives (bezafibrate, clofibrate, etc.), squalene synthase inhibitors, etc .;
(F) Antithrombotic drugs: blood coagulation inhibitors (warfarin sodium, heparin sodium, etc.), thrombolytic drugs (urokinase, t-PA, etc.), antiplatelet drugs (aspirin, ticlopidine hydrochloride, etc.);
(G) Diabetes / diabetic complication therapeutic agent: insulin, DPP4 inhibitor (such as vildagliptin, sitagliptin), α-glucosidase inhibitor (such as voglibose, acarbose, miglitol, emiglitate), biguanide (such as metformin hydrochloride, buformin, phenformin) , Insulin resistance improvers (pioglitazone, troglitazone, rosiglitazone, etc.), insulin secretagogues (tolbutamide, glibenclamide, gliclazide, glyclopyramide, chlorpropamide, glimepiride, glybide, sulfonylurea compounds such as glybazole, tolazamide, acetohexamide ), Amylin antagonists (pramlintide, etc.), aldose reductase inhibitors (epalrestat, tolrestat, zenarestat, fidarestat, Naruresutatto, zopolrestat, etc.), neurotrophic factors (NGF, etc.), AGE inhibitors (pimagedine, pyratoxathine, etc.), neurotrophic factor production promoter agent, and the like;
(H) antiobesity agents: central antiobesity agent (mazindol, fenfluramine, sibutramine, etc.), pancreatic lipase inhibitors (orlistat, etc.), beta ₃ agonists (SB-226552, BMS-196085, etc.), peptidic appetite Inhibitors (such as leptin), cholecystokinin receptor agonists (such as lynchtrypto), etc .;
(I) Nonsteroidal anti-inflammatory drugs: acetaminophen, ibuprofen, etc. (j) Chemotherapeutic agents: antimetabolites (5-fluorouracil, methotrexate, etc.), anticancer drugs (vincristine, taxol, cisplatin, etc.);
(K) Immunomodulators: immunosuppressants (cyclosporine, tacrolimus, etc.), immunopotentiators (crestin, lentinan, etc.), cytokines (interleukin 1, interferon, etc.), cyclooxygenase inhibitors (indomethacin, celecoxib, etc.), anti-TNFα Antibodies (such as infliximab).

  When the compound [I] of the present invention is used in combination with another drug, the administration form includes (1) administration of a single preparation (mixture) containing the compound [I] and another drug, and (2) The combined administration of a preparation containing compound [I] and a preparation containing other drugs can be mentioned. In the case of the combined administration of (2), the administration route and administration time of each preparation may be different.

Compound [I] of the present invention can be produced, for example, according to the following synthesis method 1 (reaction scheme A).
Synthesis Method 1 (Reaction Scheme A):

[In the above scheme, X ¹ is a leaving group, R ′ and R ″ are a hydrogen atom or an alkyl group, or both are bonded to each other to form an alkylene group, and other symbols are the same as above] Has meaning.]
The reaction of compound [1a] and boronic acid compound [2a] in the above reaction scheme A is carried out in the presence of a transition metal catalyst and a base in a solvent at room temperature to the reflux temperature of the solvent, preferably 50 ° C. to the reflux temperature of the solvent. Can be implemented. The halogen atom shown by X ^1, a bromine atom, a chlorine atom or iodine atom. The solvent is not particularly limited as long as it does not interfere with the reaction. For example, alcohols such as ethanol, amides such as N, N-dimethylformamide, ethers such as dioxane, 1,2-dimethoxyethane or tetrahydrofuran, Aromatic hydrocarbons such as toluene, water and the like. Examples of the transition metal catalyst include tetrakis (triphenylphosphine) palladium (0), palladium (II) acetate, bis (dibenzylideneacetone) palladium (0), bis (triphenylphosphine) palladium (II) dichloride, bis ( Palladium catalysts such as tri-o-tolylphosphine) palladium (II) dichloride, bis (tricyclohexylphosphine) palladium (II) dichloride or [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride; Examples thereof include nickel catalysts such as 1,3-bis (diphenylphosphino) propane nickel (II) dichloride or bis (triphenylphosphine) nickel (II) dichloride. Examples of the base include potassium phosphate, sodium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium fluoride, triethylamine, dicyclohexylamine, lithium chloride and the like. The amount of boronic acid compound [2a] used in this reaction can be 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to compound [1a]. The usage-amount of a catalyst can be 0.01-0.3 equivalent with respect to compound [1a], Preferably it can be 0.03-0.06 equivalent. The amount of the base to be used can be 1 to 10 equivalents, preferably 2 to 7 equivalents, relative to compound [1a].

In addition, when R ⁰² in the target compound [I] is a group containing a hydroxyl group, the above reaction is carried out as a compound [2a] by protecting the hydroxyl group in the corresponding substituent with a suitable protecting group (such as a tert-butyldimethylsilyl group). A compound into which an alkylsilyl group, a tetrahydropyranyl group or the like is introduced can also be used. In addition, when R ⁰² in the target compound [I] is a group containing an amino (or imino) group, the above reaction can be carried out as appropriate protection for the amino (or imino) group in the corresponding substituent as the compound [2a]. A compound into which a group (an aralkyl group such as benzyl group or 2,4-dimethoxybenzyl group) has been introduced can also be used.
(Synthesis method 2)
Of the compounds [I] of the present invention, compounds in which R ⁰² is a group represented by the formula: R ^m R ⁿ NC (═O) —, that is, the following formula [Ia]:

[Wherein the symbols have the same meaning as described above. ]
For example, the compound represented by the following formula [1b]:

[Wherein the symbols have the same meaning as described above. ]
And a compound of the following formula [III-i]:
^{R n R m NH [III-} i]
[Wherein the symbols have the same meaning as described above. ]
Or a salt thereof (such as a mineral salt such as hydrochloride) in a solvent in the presence of a condensing agent and in the presence or absence of a base and an activator. . The solvent may be any inert solvent that does not interfere with the reaction. Examples of such solvents include halogenated aliphatic hydrocarbons such as dichloromethane, amides such as N, N-dimethylformamide, and tetrahydrofuran. Such ethers, water and the like. Examples of the condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC · HCl), N, N′-dicyclohexylcarbodiimide, diethyl cyanophosphonate, 4- (4,6-dimethoxy). -1,3,5-triazin-2-yl) -4-methylmorpholinium chloride n hydrate (DMT-MM). Examples of the activator include N-hydroxybenzotriazole monohydrate, N-hydroxysuccinimide and the like. Examples of the base include triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine and the like. The amount of compound [III-i] to be used is 1.0 to 5.0 equivalents, preferably 1.0 to 1.5 equivalents, relative to compound [II-d]. The usage-amount of a condensing agent and an activator is 1.0-5.0 equivalent with respect to compound [II-d] or compound [III-i], respectively, Preferably it is 1.0-1.5 equivalent. The amount of the base to be used is 1.0 to 2.0 equivalents, preferably 1.0 to 1.2 equivalents, relative to compound [II-d] or compound [III-i]. This reaction can be carried out at 0 to 100 ° C, preferably 0 to 40 ° C.
(Synthesis method 3)
Among the compounds [I] of the present invention, a compound in which R ⁰² is a hydroxyl group (or a group containing a hydroxyl group) or an amino group includes, for example, a hydroxyl group (or a protected group) in which the substituent corresponding to R ⁰² is protected. A corresponding compound which is a group containing a protected amino group) or a protected amino group, and the protecting group (acetyl group, tetrahydropyranyl group, benzyl group, 2,4-dimethoxybenzyl group, tert-butyldimethylsilyl group) , Tert-butoxycarbonyl group, etc.) can be prepared by subjecting to a conventional deprotection reaction. When the protecting group is an acetyl group, the protecting group can be removed by base treatment using sodium hydroxide or the like. When the protecting group is a tetrahydropyranyl group or a tert-butoxycarbonyl group, the protecting group can be removed by acid treatment using hydrochloric acid or the like. When the protecting group is a benzyl group, the protecting group can be removed by acid treatment using hydrobromic acid / acetic acid or the like. When the protecting group is a tert-butyldimethylsilyl group, the protecting group can be removed by treatment with tetra n-butylammonium fluoride (TBAF).
(Synthesis Method 4)
Among the compounds [I] of the present invention, a compound having a group containing an alkylsulfinyl group or an alkylsulfonyl group as a substituent on the ring A is prepared by replacing the corresponding compound [I] having a group containing an alkylthio group as a substituent with a solvent. In the presence of an acid (methanesulfonic acid, trifluoroacetic acid, etc.) in (halogenated aliphatic hydrocarbons such as dichloromethane, alcohols such as ethanol, ketones such as acetone, water, etc.), an oxidizing agent (m-chloroperoxide). It can also be produced by treatment with benzoic acid or the like.
(Synthesis Method 5)
Compound R ⁰² is an alkoxycarbonyl alkoxy group [I], the corresponding compound substituents corresponding to R ⁰² is a hydroxyl group and the formula:
X ¹ -Alk ¹ -COOR ^aa [1aa]
[Wherein, X ¹ represents a halogen atom, Alk ¹ represents an alkylene group, and R ^aa represents an alkyl group. ]
In a solvent (dimethylsulfoxide, amides such as N, N-dimethylformamide, ethers such as tetrahydrofuran, etc.), a base (an alkali metal carbonate such as potassium carbonate, an alkali metal hydride such as sodium hydride, etc.) ) In the presence of.
(Synthesis Method 6)
Compound R ⁰² is an amino group substituted with alkanoyloxy alkanoyl group [I], the corresponding compound substituents corresponding to R ⁰² is an amino group and the formula:
R ^bb -X ² [1bb]
[Wherein, X ² represents a halogen atom, and R ^bb represents an alkanoyloxyalkanoyl group or a hydroxyalkanoyl group. ]
In the presence of a base (a tertiary amine such as triethylamine, an alkali metal carbonate such as potassium carbonate) in a solvent (halogenated aliphatic hydrocarbons such as dichloromethane, ethers such as tetrahydrofuran). Can be manufactured.
(Synthesis Method 7)
Compound [I], wherein R ⁰² is a carbamoylmethyloxy group, is prepared by using a corresponding compound in which the substituent corresponding to R ⁰² is an alkoxycarbonylmethyloxy group and ammonia as a solvent (alcohols such as methanol, ethers such as dioxane, etc.) It can be made by reacting in the medium.
(Synthesis Method 8)
Compound R ⁰² contains a carboxyl group and a hydroxy alkanoyl group [I] is such alcohols corresponding compound solvent (methanol substituents corresponding to R ⁰² is a group containing an alkoxycarbonyl group, ethers such as tetrahydrofuran, It can be produced by treatment with a base (such as an alkali metal hydroxide such as sodium hydroxide) or an acid (such as hydrochloric acid) in water or a mixture thereof.
(Synthesis Method 9)
The compound [I] in which R ⁰² is a hydroxyethyl group is obtained by subjecting a corresponding compound in which the substituent corresponding to R ⁰² is a vinyl group to 9-borabicyclo [3.3.1] in a solvent (such as ethers such as tetrahydrofuran). After reacting with nonane (9-BBN), the reaction product can be produced by treatment with hydrogen peroxide in the presence of a base (such as an alkali metal hydroxide such as sodium hydroxide).
(Synthesis Method 10)
R ⁰² is the following formula:

[Wherein, ring B ¹ represents a 5- to 6-membered aliphatic nitrogen-containing heterocyclic group substituted with an oxo group (the heterocyclic group may further contain an oxygen atom as a hetero atom). ]
Compound [I], which is a group represented by formula (I), is obtained by subjecting a corresponding compound in which the substituent corresponding to R ⁰² is an amino group to a base in a solvent (ethers such as tetrahydrofuran, halogenated aliphatic hydrocarbons such as dichloromethane, etc.) In the presence of (a tertiary amine such as triethylamine, pyridine, etc.)
_{^{X a - (CH 2) p}} -CO-X b [1cc] or _{^{X a - (CH 2) q}} -O-CO-X b [1dd]
[In formula, ^Xa and ^Xb represent a halogen atom, p is an integer of 3-4, q represents the integer of 2-3. ]
Then, the reaction product can be prepared by treating with a base (an alkali metal hydride such as sodium hydride, an alkali metal carbonate such as potassium carbonate, etc.) in the solvent.
(Synthesis Method 11)
R ⁰² is the following formula:

[Wherein the symbols have the same meaning as described above]
Compound [I], which is a group represented by the following formula, represents a corresponding compound in which the substituent corresponding to R ⁰² is an amino group:
_{^{X aa -CH 2 -CO-X bb}} [1ii]
[In formula, ^Xaa and ^Xbb represent a halogen atom. ]
Then, the reaction product and the following formula:
^{_{HO- (CH 2) 2 -X cc}} [1jj]
[ ^Wherein X ^cc represents a halogen atom. ]
Can be produced by reacting in the presence of a base (an alkali metal hydride such as sodium hydride, an alkali metal carbonate such as potassium carbonate, etc.) in the solvent.
(Synthesis Method 12)
Among the compounds [I] of the present invention, the following formula [Ib]:

[Wherein the symbols have the same meaning as described above. ]
For example, the compound represented by the following formula [1c]:

[Wherein the symbols have the same meaning as described above. ]
And a compound represented by the following formula [1ee]:
^{_{X c - (CH 2) 2}} -N = C = O [1ee]
[Wherein, ^Xc represents a halogen atom. ]
A reaction product is produced by reacting the compound represented by the above in a solvent (ethers such as tetrahydrofuran, aromatic hydrocarbons such as toluene) in the presence or absence of a base (such as a tertiary amine such as triethylamine). The product can be prepared by treating with a base (an alkali metal hydride such as sodium hydride, an alkali metal carbonate such as potassium carbonate, etc.) in the solvent.
(Synthesis Method 13)
Among the compounds [I] of the present invention, the following formula [Ic]:

[Wherein R ^dd represents an alkyl group or a hydroxyalkyl group, and other symbols have the same meaning as described above. ]
For example, the compound represented by the above formula [Ib] and the following formula [1ff]:
R ^d1 −X ^d [1ff]
[Wherein, R ^d1 represents an alkyl group or a hydroxyalkyl group (the hydroxyl portion of the group may be protected), and X ^d represents a halogen atom. ]
In a solvent (an amide such as dimethylformamide, an ether such as tetrahydrofuran) in a solvent (an alkali metal hydride such as sodium hydride, potassium carbonate) In the presence of an alkali metal carbonate or the like, and then, if necessary, it can be prepared by removing the protecting group of the hydroxyl group from the reaction product. The hydroxyl-protecting group is not particularly limited as long as it does not hinder the progress of this reaction, but an alkylsilyl group such as tert-butyldimethylsilyl group, a tetrahydropyranyl group, and the like are preferable.
(Synthesis Method 14)
Among the compounds [I] of the present invention, the following formula [Id]:

[Wherein R ^ee represents a hydroxyalkyl group, and other symbols have the same meaning as described above. ]
For example, the compound represented by the above formula [Ib] and the following formula [1gg]:
^{ZO-Alk 2 -X e [1gg} ]
[Wherein, ZO represents a protected hydroxyl group, Alk ² represents a C _1-6 alkylene group, and X ^e represents a halogen atom. ]
Was reacted in the presence of a base (an alkali metal hydride such as sodium hydride, an alkali metal carbonate such as potassium carbonate, etc.) in a solvent (an ether such as tetrahydrofuran, an amide such as dimethylformamide). Thereafter, it can be produced by removing the protecting group (Z) from the reaction product. Examples of the hydroxyl protecting group include groups such as a tert-butyldimethylsilyl group, a trimethylsilyl group, and a tetrahydropyranyl group. Removal of the protecting group can be carried out by a conventional method depending on the type. For example, removal of the protecting group from a compound having a hydroxyl group protected with a tert-butyldimethylsilyl group (TBDMS) can be carried out by removing the compound in a solvent (ethers such as tetrahydrofuran) with tetra n-butylammonium fluoride ( It can be carried out by treatment with a quaternary ammonium salt such as TBAF).
(Synthesis Method 15)
Compound R ⁰² is an alkoxy group substituted with a hydroxyl group [I] is such amides corresponding compound solvent (dimethylacetamide substituents corresponding to R ⁰² is a halogen atom (a fluorine atom, etc.), dimethyl sulfoxide ) In the presence of a base (sodium hydride, alkali metal carbonates such as potassium carbonate, tertiary amines such as triethylamine, etc.), the following formula [1hh]:
^HO-Alk 3 -OH [1hh]
[Wherein Alk ³ represents an alkylene group]
It can manufacture by making it react with the alkanediol compound shown by these.
(Synthesis Method 16)
R ⁰² is the following formula:

[Wherein, ring B ² represents a 5- to 6-membered aliphatic nitrogen-containing heterocyclic group-substituted group which may be substituted with a group selected from a hydroxyl group, an oxo group and an alkanoyl group. ]
Compound [I], which is a group represented by formula (I), is a corresponding compound in which the substituent corresponding to R ⁰² is a halogenomethyl group (such as a chloromethyl group) in a solvent (such as amides such as dimethylformamide) or without solvent, In the presence of a base (an alkali metal hydride such as sodium hydride, an alkali metal carbonate such as potassium carbonate, a tertiary amine such as triethylamine, etc.), the following formula [1ff]:

[Wherein the symbols have the same meaning as described above. ]
It can manufacture by making it react with the cyclic amine compound shown by these.
(Synthesis Method 17)
R ⁰² is the following formula:

[Wherein, ring B ² has the same meaning as described above. ]
Compound [I], which is a group represented by formula (1), is a solvent (amides such as dimethylacetamide) obtained by using a corresponding compound in which the substituent corresponding to R ⁰² is a halogen atom (fluorine atom or the like) and the cyclic amine compound [1ff]. The reaction can be carried out in the presence of a base (a tertiary amine such as triethylamine, an alkali metal hydride such as sodium hydride, an alkali metal carbonate such as cesium carbonate, etc.) in the presence or absence of a solvent.

  The intermediate compound [1a] in the present invention can be produced, for example, according to the following reaction scheme.

[In the above scheme, the symbols have the same meaning as described above. ]
Conversion of compound [11a] to compound [12a] can be accomplished, for example, by treating compound [11a] with an alkali metal sulfate (such as sodium sulfate), chloral hydrate and an acid (such as concentrated hydrochloric acid), It can be carried out by reacting hydroxylamine or a salt thereof (such as sulfate). Any solvent may be used as long as it does not interfere with the reaction. Examples of such a solvent include alcohols such as ethanol or a mixture thereof with water. This reaction can be carried out at 50 ° C. to the reflux temperature of the solvent, preferably 80 ° C. to the reflux temperature of the solvent.

  Conversion of compound [12a] to compound [13a] can be carried out, for example, by treating compound [12a] with concentrated sulfuric acid. This reaction can be carried out at 40 ° C to 100 ° C, preferably 60 ° C to 80 ° C.

  Conversion of compound [13a] to compound [14a] can be carried out, for example, by treating compound [13a] with hydrogen peroxide in the presence of a base (such as sodium hydroxide) in a solvent (such as water). it can. This reaction can be carried out at 0 ° C to 100 ° C, preferably 50 ° C to 70 ° C.

  Conversion of compound [14a] to compound [15a] can be carried out, for example, by treating compound [14a] with methanamide (formamide). This reaction can be carried out at 100 ° C. to the reflux temperature of the solvent (methanamide), preferably 150 ° C. to 190 ° C.

  Conversion of compound [15a] to compound [16a] can be carried out, for example, by treating compound [15a] with thionyl chloride in the presence of dimethylformamide in a solvent or without solvent. Any solvent may be used as long as it does not interfere with the reaction. Examples of such solvents include amides such as dimethylformamide, aromatic hydrocarbons such as toluene or benzene, ethers such as tetrahydrofuran, dichloromethane, dichloroethane, or the like. And halogenated aliphatic hydrocarbons such as chloroform. This reaction can be carried out at 40 ° C. to the reflux temperature of the solvent, preferably 60 ° C. to the reflux temperature of the solvent.

  The reaction of compound [16a] and compound [2b] can be carried out in the same manner as in the reaction of compound [1b] and compound [2b] described above (synthesis method 2).

  Among the intermediate compounds in the present invention, the following general formula [1b]:

[Wherein the symbols have the same meaning as described above. ]
The compound represented by, for example, the compound [1a] and the following general formula [2a-1]:

[Wherein the symbols have the same meaning as described above. ]
It can manufacture by making the boronic acid compound shown by react. This reaction can be carried out in the same manner as in Synthesis Method 1 (Reaction Scheme A).

  The raw material compound [2a] or [2b] in the present invention is a known compound per se, or from a commercially available known compound, using a conventional method of organic chemistry such as the method described in the Reference Example of the present application. Can be manufactured.

  In the present invention, “halogen atom” means fluorine atom, chlorine atom, iodine atom or bromine atom, and “alkyl” or “alkoxy” means 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. Linear or branched alkyl or alkoxy is meant, and “cycloalkyl” means cycloalkyl having 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. “Alkylene” means linear or branched alkylene having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, and “alkanoyl” means 2 to 8 carbon atoms, preferably 2 carbon atoms. Means ~ 6 linear or branched alkanoyl.

  The abbreviations used in this specification have the following meanings unless otherwise defined.

Boc: tert-butoxycarbonyl DMF: dimethylformamide DMSO: dimethyl sulfoxide Me: methyl Et: ethyl i-Pr: isopropyl i-Bu: isobutyl Ph: phenyl Ac: acetyl TBS (or TBDMS): tert-butyldimethylsilyl pyran-2-yl TFA: trifluoroacetic acid CDI: 1,1'-carbonyldiimidazole HOBt: 1-hydroxybenzotriazole DIAD: diisopropyl azodicarboxylate dppf: diphenylphosphino ferrocene PPh _3: triphenylphosphine HPLC: High performance liquid chromatography Graphic

Example 1
6-Fluoro-8- [3-fluoro-4- (2-methoxyethylsulfanyl) phenyl] -4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidine- 1-Il] quinazoline production

8-Bromo-6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline (compound obtained in Reference Example 12) To 100 mg of 1,4-dioxane 4 mL solution, 1 mL of water, 2- [3-fluoro-4- (2-methoxyethylsulfanyl) phenyl] -4,4,5,5, -tetramethyl- [1,3,2 148.6 mg of dioxaborolane (the compound obtained in Reference Example 19), 27.5 mg of tetrakis (triphenylphosphine) palladium and 155 mg of cesium carbonate were added, and the mixture was stirred at 90 ° C. for 16 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by NH-silica gel column chromatography (Chromatorex; Fuji Silysia Chemical, solvent; hexane / ethyl acetate = 95/5 to 75/25) to give 62.7 mg of the title compound. Was obtained as a colorless solid (yield: 50%).
MS (APCI) m / z; 526 [M + H] +.

Example 2
[2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenyl Production of ((R) -3-hydroxypyrrolidin-1-yl) methanone

2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] benzoic acid (Compound obtained in Reference Example 29) 45 mg and (R)-(+)-3-pyrrolidinol 9.8 mg, 27 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzo Triazole monohydrate was added to 0.9 mL of a chloroform solution of 19 mg and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was subjected to NH-silica gel column chromatography (Chromatorex; Fuji Silysia Chemical, solvent; chloroform / methanol = 100/0 to 97/3) and gel permeation chromatography (JAIGEL-1H, 2H: purified by Nippon Analytical Industrial Co., Ltd., 20 mm × 600 mm, mobile phase: chloroform, flow rate 4 mL / min) and crystallized from ethyl acetate and diisopropyl ether to obtain 41 mg of the title compound as a colorless solid (yield 80 %).
MS (APCI) m / z; 549 [M + H] +.

Example 3
6-Fluoro-8- [3-fluoro-4- (2-hydroxyethylsulfanyl) phenyl] -4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidine- 1-Il] quinazoline production

6-Fluoro-8- [3-fluoro-4- [2- (tetrahydropyran-2-yloxy) ethylsulfanyl] phenyl] -4- [4- (5-isopropyl- [1,2,4] oxadiazole -3-yl) piperidin-1-yl] quinazoline (compound obtained in Reference Example 38) 109 mg of 1,4-dioxane 5 mL solution was added 4N hydrochloric acid-dioxane solution 0.5 mL, and the mixture was added at room temperature. Stir for 5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by NH-silica gel column chromatography (Chromatorex; Fuji Silysia Chemical, solvent; hexane / ethyl acetate = 67/33 to 20/80) to give 86 mg of the title compound. Obtained as a colorless solid (yield 92%).
MS (APCI) m / z; 512 [M + H] +.

Example 4
6-Fluoro-8- [3-fluoro-4- (2-hydroxyethylsulfonyl) phenyl] -4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidine- 1-Il] quinazoline production

Under ice cooling, 57 μL of methanesulfonic acid and 101 mg of m-chloroperbenzoic acid were added to a solution of 75 mg of the compound obtained in Example 3 in 2 mL of dichloromethane, and the mixture was stirred at room temperature for 40 minutes. A sodium thiosulfate aqueous solution and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated, and the obtained residue was purified by NH-silica gel column chromatography (Chromatorex; Fuji Silysia Chemical, solvent; hexane / ethyl acetate = 50/50 to 0/100) to give 39 mg of the title compound as colorless. Obtained as a powder (yield: 49%).
MS (APCI) m / z; 544 [M + H] +.

Example 5
6-Fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] -8- (3-methylsulfanyl-4-methylsulfanylmethylphenyl) ) Manufacture of quinazoline

The compound (252 mg) obtained in Reference Example 12 and the compound (203 mg) obtained in Reference Example 26 were treated in the same manner as in Example 1 to obtain 179 mg of the title compound as a viscous oil (yield: 57 %).
MS (APCI) m / z; 524 [M + H] +.

Example 6
6-Fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) -piperidin-1-yl] -8- (4-methylsulfinylmethyl-3-methylsulfanyl Of phenyl) quinazoline

6-Fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] -8- (3-methylsulfanyl-4-methylsulfanylmethylphenyl) ) 88 mg of metachloroperbenzoic acid (containing 25% water) was added to a solution of 149 mg of quinazoline (the compound obtained in Example 5) in 6 mL of trifluoroacetic acid, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (solvent; chloroform / methanol = 100/0 to 95/5) to give 62.9 mg of the title compound as a yellow solid (yield). Rate: 39%).
MS (APCI) m / z; 540 [M + H] +.

Example 7
2-Fluoro-4- {6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl} phenol odor Production of hydride

8- (4-Benzyloxy-3-fluorophenyl) -6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline (Compound obtained in Example 23) To 25 mg, 2 mL of a 25% odorous acid-acetic acid solution was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, toluene was added to the residue and azeotroped. The residue was washed with ethyl acetate and collected by filtration to give 30 mg of the title compound as a solid (yield: 56%).
MS (APCI) m / z; 452 [M + H] +.

Example 8
[2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenoxy ] Production of acetic acid ethyl ester

2-fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenol ( Compound obtained in Example 7) To a solution of 532 mg of dimethylformamide in 5 mL were added 250.5 mg of ethyl bromoacetate and 1382.1 mg of potassium carbonate, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by NH-silica gel column chromatography (Chromatorex; Fuji Silysia Chemical, solvent; hexane / ethyl acetate = 90/10 to 70/30) to obtain 380 mg of the title compound. Obtained as a colorless solid (yield: 71%).
MS (APCI) m / z; 538 [M + H] +.

Example 9
N- (2-fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Preparation of phenyl) -2-acetoxyacetamide

2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenylamine (Free form of the compound obtained in Reference Example 49) To a solution of 110 mg of dichloromethane in 4 mL were added acetoxyacetyl chloride 0.68 mg and triethylamine 0.07 mL, and the mixture was stirred at room temperature for 16 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by NH-silica gel column chromatography (Chromatorex; Fuji Silysia Chemical, solvent; hexane / ethyl acetate = 90 / 10-50 / 50) to give 83 mg of the title compound. Obtained as a colorless solid (yield: 60%).
MS (APCI) m / z; 551 [M + H] +.

Example 10
2- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Production of phenoxy] acetamide

A solution of 108 mg of the compound obtained in Example 8 in 4 mL of 2N ammonia-methanol was stirred at 50 ° C. for 16 hours. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (solvent; chloroform / methanol = 100/0 to 90/10) to give 47 mg of the title compound as a colorless powder (yield: 46 %).
MS (APCI) m / z; 509 [M + H] +.

Example 11
N- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl Production of phenyl] -2-hydroxyacetamide

N- (2-fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl) -2-acetoxyacetamide (compound obtained in Example 9) 75 mg of 2N sodium hydroxide 2 mL, tetrahydrofuran 2 mL and methanol 2 mL were stirred at room temperature for 2 hours. To the reaction mixture was added 10 mL of an aqueous solution of 1.36 g of potassium dihydrogen phosphate, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was washed with diethyl ether and dried under reduced pressure to give 55 mg of the title compound as a powder (yield: 79%).
MS (APCI) m / z; 509 [M + H] +.

Example 12
[2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenyl ] Production of acetic acid

[2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenyl A solution of 750 mg of 2N sodium hydroxide, 10 mL of tetrahydrofuran, 10 mL of tetrahydrofuran and 10 mL of methanol was stirred overnight at room temperature. A 2N aqueous hydrochloric acid solution and an aqueous potassium dihydrogen phosphate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was dried under reduced pressure to give 700 mg of the title compound as a powder (yield: 99%).
MS (APCI) m / z; 494 [M + H] +.

Example 13
2- [2-Fluoro-4- [6-fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl] ethanol production

6-Fluoro-8- (3-fluoro-4-vinylphenyl) -4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazoline ( Compound obtained in Reference Example 51) To a 2 mL solution of 95 mg of tetrahydrofuran was added 0.82 mL of a 0.5 mol / L solution of 9-borabicyclo [3,3,1] nonane (9-BBN) in tetrahydrofuran under a nitrogen atmosphere. The mixture was stirred at room temperature for 3.5 hours. The reaction mixture was cooled to 0 ° C., 0.2 mL of 2N aqueous sodium hydroxide solution and 0.1 mL of 30% aqueous hydrogen peroxide were added, and the mixture was stirred at 50 ° C. for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was concentrated, and the obtained residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 65 / 35-20 / 80) to give 30 mg of the title compound as a colorless powder (yield: 30%).
MS (APCI) m / z; 480 [M + H] +.

Example 14
3- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl] Oxazolidin-2-one

2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenylamine To a suspension of 80 mg of dihydrochloride (compound obtained in Reference Example 49) in 3 mL of tetrahydrofuran were added 32 μL of 2-chloroethyl chloroformate and 107 μL of triethylamine, and the mixture was stirred at room temperature for 3 days. To the reaction mixture was added 32 μL of 2-chloroethyl chloroformate, and the mixture was further stirred at room temperature for 1 day, and further stirred at 50 ° C. for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was concentrated, and the resulting residue was dissolved in 3 mL of tetrahydrofuran. After adding 10 mg of sodium hydride to the solution, the mixture was stirred at room temperature for 4.5 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was concentrated, and the obtained residue was purified by silica gel column chromatography (solvent; chloroform / methanol = 100/0 to 95/5) to give 68.6 mg of the title compound as a colorless powder (yield) : 86%).
MS (APCI) m / z; 521 [M + H] +.

Example 15
1- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl Production of phenyl] imidazolidin-2-one

2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenylamine To a suspension of dihydrochloride (the compound obtained in Reference Example 49) in 160 mg of tetrahydrofuran (3 mL) were added 2-chloroethyl isocyanate (53 μL) and triethylamine (214 μL), and the mixture was stirred at room temperature for 3 days. To the reaction mixture, 53 μL of 2-chloroethyl isocyanate was added, and the mixture was stirred at room temperature for 1 day, and further stirred at 50 ° C. for 5 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was concentrated, and the resulting residue was dissolved in 3 mL of tetrahydrofuran. Then, 20 mg of sodium hydride was added to the solution, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was concentrated, and the resulting residue was purified by silica gel column chromatography (solvent; chloroform / methanol = 100/0 to 95/5) to give 146.5 mg of the title compound as a colorless powder (yield) : 92%).
MS (APCI) m / z; 520 [M + H] +.

Example 16
1- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl Production of phenyl] -3-methylimidazolidin-2-one

1- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl] imidazolidin-2-one (compound obtained in Example 15) 45 mg of dimethylformamide in 1 mL was added with 4 mg of sodium hydride, and the mixture was stirred at room temperature for 10 minutes. 11 μL of methyl iodide was added to the reaction mixture, and the mixture was further stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was purified by silica gel column chromatography (solvent; chloroform / methanol = 100/0 to 95/5) to give 24.9 mg of the title compound as a colorless powder (yield: 54%).
MS (APCI) m / z; 534 [M + H] +.

Example 17
1- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl Preparation of phenyl] -3- (2-hydroxyethyl) imidazolidin-2-one

1- [2- (tert-Butyldimethylsilyloxy) ethyl] -3- (2-fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazole) -3-yl) piperidin-1-yl] quinazolin-8-yl] phenyl] imidazolidin-2-one (compound obtained in Reference Example 52) 35 mg of tetrabutylammonium fluoride was added to 38 mL of tetrahydrofuran, The mixture was stirred at room temperature for 3 hours, and the reaction mixture was purified by silica gel column chromatography (solvent; chloroform / methanol = 100/0 to 92/8) to give 26.7 mg of the title compound as a colorless powder. (Yield: 85%).
MS (APCI) m / z; 564 [M + H] +.

Example 18
2- [5- [6-Fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] pyridine-2 -Iloxy] ethanol production

6-Fluoro-8- (6-fluoropyridin-3-yl) -4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline ( Compound obtained in Reference Example 54) To 50 mg of dimethylacetamide 0.5 mL and ethylene glycol 1 mL was added 6 mg of sodium hydride, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was heated at 100 ° C. for 30 minutes in a microwave reactor (Initiator, Biotage). 6 mg of sodium hydride was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes, and further heated at 100 ° C. for 1 hour in a microwave reactor (Initiator, manufactured by Biotage). Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was purified by silica gel column chromatography (solvent; chloroform / methanol = 100/0 to 93/7) to give 13.7 mg of the title compound as a colorless powder (yield: 25%).
MS (APCI) m / z; 479 [M + H] +.

Example 19
1- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl Benzyl] pyrrolidin-2-one production

8- (4-Chloromethyl-3-fluorophenyl) -6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline (Compound obtained in Reference Example 53) 12 mg of sodium hydride was added to 95 mg of a pyrrolidone 1 mL solution, and the mixture was stirred at room temperature for 3.5 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was purified by silica gel column chromatography (solvent; chloroform / methanol = 100/0 to 95/5) to obtain 78.1 mg of the title compound as a colorless powder (yield: 75%).
MS (APCI) m / z; 533 [M + H] +.

Examples 20-27
The corresponding raw material compounds were treated in the same manner as in Example 1 to obtain the compounds described in Tables 1 and 2 below.

Examples 28-66
The corresponding starting materials were treated in the same manner as in Example 2 to obtain the compounds shown in Tables 3 to 9 below.

Examples 67-74
The corresponding starting materials were treated in the same manner as in Example 3 to obtain the compounds shown in Table 10 below.

Examples 75-83
The corresponding starting materials were treated in the same manner as in Example 4 to obtain the compounds described in Tables 11-12 below.

Example 84
5-Fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) -piperidin-1-yl] -8- (4-methylsulfinylmethyl-3-methylsulfanyl Of phenyl) quinazoline

The corresponding starting material compound was treated in the same manner as in Example 6 to give the title compound as a solid (yield: 39%).
MS (APCI) m / z: 540 [M + H] ^< +>.

Example 85
The corresponding starting material compounds were treated in the same manner as in Example 11 to obtain the compounds shown in Table 13 below.

Example 86
4-[[2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline-8- Yl] benzoyl] aminomethyl] benzoic acid

The corresponding starting material compound was treated in the same manner as in Example 12 to give the title compound as a powder (yield: 65%).
MS (APCI) m / z: 613 [M + H] ^< +>.

Example 87
1- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Production of phenyl] pyrrolidin-2-one

2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenylamine The title compound (50.4 mg) was obtained as a colorless powder by treating 80 mg of the dihydrochloride (compound obtained in Reference Example 49) and 42 μL of 4-chlorobutyric chloride in the same manner as in Example 14. (Yield: 64 %).
MS (APCI) m / z: 519 [M + H] ^< +>.

Example 88
6-Fluoro-4- [5- (1-hydroxy-1-methylethyl)-[1,2,4] oxadiazol-3-yl] piperidin-1-yl] -8- [3-fluoro-4 Preparation of-(2-oxopyrrolidin-1-yl) phenyl] quinazoline

The corresponding starting material compound was treated in the same manner as in Example 11 to give the title compound (54.1 mg) as a powder (yield: 90.8%).
MS (APCI) m / z: 535 [M + H] ^< +>.

Example 89
(R) -1- [5- [6-Fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Preparation of pyridin-2-yl] pyrrolidin-3-ol

6-Fluoro-8- (6-fluoropyridin-3-yl) -4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline ( 179 mg of cesium carbonate was added to a solution of 80 mg of the compound obtained in Reference Example 54 and 32 mg of (R) -3-hydroxypyrrolidine in 2 mL of dimethylacetamide, and the mixture was placed in a microwave reactor (Initiator, manufactured by Biotage) in 150 ml. Heated at 0 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was purified by silica gel column chromatography (solvent; chloroform / methanol = 100/0 to 93/7) to obtain 57.6 mg of the title compound as a yellow powder (yield: 63%).
MS (APCI) m / z; 504 [M + H] +.

Example 90
4- [4- [6-Fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] -3- Preparation of methylphenyl] morpholin-3-one

4- [6-Fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] -3-methylaniline 100 mg of dihydrochloride (compound obtained in Reference Example 58) and 32 μL of bromoacetic acid chloride were treated in the same manner as in Example 9. To a 4 mL tetrahydrofuran solution of the obtained crude product, 39 μL of 2-chloroethanol and 23 mg of sodium hydride were added at −78 ° C., and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 23 mg of sodium hydride and the mixture was stirred at room temperature for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and purified twice by silica gel column chromatography (solvent: chloroform / methanol = 100/0 to 94/6). As a result, 33.1 mg of the title compound was obtained as a colorless powder (yield: 35%).
MS (APCI) m / z; 531 [M + H] +.

Example 91
4-ethyl-1- [2-fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline -8-yl] phenyl] piperazin-2-one

1- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] To a suspension of 80 mg of dihydrochloride of phenyl] piperazin-2-one (compound obtained in Example 94) in 2 mL of acetonitrile were added 43 μL of iodoethane and 115 μL of ethyldiisopropylamine, and the mixture was added to a microwave reactor (Initiator, (Manufactured by Biotage Corporation) at 120 ° C. for 4 hours. The reaction mixture was subjected to silica gel column chromatography (solvent; chloroform / methanol = 100/0 to 93/7) and NH silica gel chromatography (Chromatorex; Fuji Silysia Chemical, solvent: hexane / ethyl acetate = 40/60 to 10/90). In this manner, 7.6 mg of the title compound was obtained as a colorless powder (yield: 10%).
MS (APCI) m / z: 562 [M + H] ⁺
Example 92
1- [4- [6-Fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] -2- Preparation of methylphenyl] -3- (2-hydroxyethyl) imidazolidin-2-one

1- [4- [6-Fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] -2- 100 mg of methylphenyl] imidazolidin-2-one (compound obtained in Reference Example 60) and 125 μL of 2- (tert-butyldimethylsilyloxy) ethyl bromide were treated in the same manner as in Example 16, and then obtained. The crude product was treated in the same manner as in Example 17 to obtain 27.3 mg of the title compound as a colorless powder (yield: 26%).
MS (APCI) m / z: 560 [M + H] ⁺
Example 93
1- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl Preparation of phenyl] -3- (3-hydroxypropyl) imidazolidin-2-one

1- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl] imidazolidin-2-one (compound obtained in Example 15) 100 mg and 2- (3-bromopropoxy) tetrahydropyran 98 μL were treated in the same manner as in Example 16, and then the resulting crude product Was treated in the same manner as in Example 3 to obtain 46.9 mg of the title compound as a colorless powder (yield: 42%).
MS (APCI) m / z: 578 [M + H] ^< +>.

Example 94
1- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl Production of phenyl] piperazin-2-one

4- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl] -3-oxopiperazine-1-carboxylic acid tert-butyl ester (compound obtained in Reference Example 57) (420 mg) in dichloromethane (2 mL) was added with trifluoroacetic acid (2 mL), and the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated, and the resulting residue was dissolved in 3 mL of dichloromethane and 3 mL of ethanol. To this was added 3 mL of 4N hydrochloric acid-dioxane solution, and the mixture was stirred overnight. The reaction mixture was concentrated to obtain 350.7 mg of the title compound (dihydrochloride). To 80 mg of the compound (dihydrochloride) were added 2 mL of dichloromethane and 0.5 mL of triethylamine, and the mixture was stirred for 10 minutes. The reaction mixture was subjected to silica gel column chromatography (solvent; chloroform / methanol = 100/0 to 91/9), and NH silica gel chromatography (Chromatorex; Fuji Silysia Chemical, solvent: chloroform / methanol = 100/0 to 97/3). By successive purification, 7.6 mg of the title compound was obtained as a colorless powder (yield: 73%).
MS (APCI) m / z: 534 [M + H] ^< +>.

Example 95
(R) -1- (4- {4- [4- (5-Cyclopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] -5-fluoroquinazoline-8- Yl} -2-fluorophenyl) -4-hydroxypyrrolidin-2-one

8-Bromo-4- [4- (5-cyclopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] -5-fluoroquinazoline (the compound obtained in Reference Example 122) ) 96.2 mg, (R) -4- (tert-butyldimethylsilyloxy) -1- [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane- 2-yl) phenyl] pyrrolidin-2-one (the compound obtained in Reference Example 89) 120.6 mg, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride-dichloromethane complex 9.4 mg A solution of 187 mg of cesium carbonate and 1,4-dioxane / water (3.6 mL / 0.4 mL) was stirred at 90 ° C. for 15 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH-silica gel column chromatography (Chromatorex; Fuji Silysia Chemical, solvent; hexane / ethyl acetate: 80/20 to 55/45). The obtained crude product was treated in the same manner as in Example 17 to obtain 83.2 mg of the title compound as a colorless solid (yield: 67.7%).
MS (APCI) m / z; 533 [M + H] ^< +>.

Example 96
1- [4- [6-Fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] -2- Preparation of methylphenyl] -3- (3-hydroxypropyl) imidazolidin-2-one

8-Bromo-6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline (the compound obtained in Reference Example 12) 150 mg and 1- [2-methyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -3- [3- (tetrahydropyran-2 -Iloxy) propyl] imidazolidin-2-one 190 mg was treated in the same manner as in Example 1, and then the resulting crude product was treated in the same manner as in Example 3 to obtain 153.6 mg of the title compound as a colorless powder. (Yield: 75%).
MS (APCI) m / z: 574 [M + H] ^< +>.

Example 97
3- (2-Fluoro-4- {6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl } Production of phenyl) imidazolidin-4-one

8-Bromo-6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline (compound obtained in Reference Example 12) 210 mg, 1- (2,4-dimethoxybenzyl) -3- [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] imidazo 342 mg of lysine-4-one (compound obtained in Reference Example 149), 20.4 mg of [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride-dichloromethane complex and 407 mg of cesium carbonate 1,4 The dioxane / water (9 mL / 1 mL) solution was stirred at 90 ° C. for 1 hour under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH-silica gel column chromatography (Chromatorex; Fuji Silysia Chemical, solvent; hexane / ethyl acetate: 68/32 to 41/59). To the obtained crude product was added 3 mL of trifluoroacetic acid, and the mixture was stirred at room temperature for 22 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Diisopropyl ether was added to the residue, and the mixture was filtered to obtain 77.2 mg of the title compound as a colorless solid (yield 59.4%).
MS (APCI) m / z; 520 [M + H] ^< +>.

Example 98
1- [2-Fluoro-4- (6-fluoro-4- {4- [5- (1-hydroxy-1-methylethyl)-[1,2,4] oxadiazol-3-yl] piperidine- 1-yl} quinazolin-8-yl) phenyl] -3- (2-hydroxyethyl) imidazolidin-2-one

1- {3- [1- (8-Bromo-6-fluoroquinazolin-4-yl) piperidin-4-yl]-[1,2,4] oxadiazol-5-yl) -1-methylethyl acetate Ester (the compound obtained in Reference Example 113) 95.7 mg, 1- [2- (tert-butyldimethylsilyloxy) ethyl] -3- [2-fluoro-4- (4,4,5,5-tetra Methyl- [1,3,2] dioxaborolan-2-yl) phenyl] imidazolidin-2-one (compound obtained in Reference Example 85) 112 mg, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) A solution of 8.2 mg of dichloride-dichloromethane complex and 163 mg of cesium carbonate in 1,4-dioxane / water (3.6 mL / 0.4 mL) was stirred at 90 ° C. for 3.5 hours under a nitrogen atmosphere. . The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (Chromatorex; Fuji Silysia Chemical, solvent; hexane / ethyl acetate: 72/28 to 50/50). The obtained crude product was treated in the same manner as in Example 11 to give 1- [2- (tert-butyldimethylsilyloxy) ethyl] -3- [2-fluoro-4- (6-fluoro-4- {4- [5- (1-Hydroxy-1-methylethyl)-[1,2,4] oxadiazol-3-yl] piperidin-1-yl} quinazolin-8-yl) phenyl] imidazolidine-2 -81.4 mg (yield: 58.7%) of the title compound and 18.3 mg of the title compound were obtained as a colorless solid (yield: 15.8%).
MS (APCI) m / z; 533 [M + H] ^< +>.

Example 99
1- (4- {4- [4- (5-Cyclopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] -6-fluoroquinazolin-8-yl} -2 -Fluorophenyl) pyrrolidin-2-one production

4- {4- [4- (5-Cyclopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] -6-fluoroquinazolin-8-yl} -2-fluorophenyl To a suspension of 67 mg of the amine (compound obtained in Reference Example 134) in 1.5 mL of tetrahydrofuran, 51 μL of 4-chlorobutyryl chloride and 84 μL of triethylamine were added, and the mixture was stirred at room temperature for 15 hours. Tetrabutylammonium iodide (3 mg) and 6N sodium hydroxide (1 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 22.5 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated, and the obtained residue was purified by NH-silica gel column chromatography (Chromatorex; Fuji Silysia Chemical, solvent; hexane / ethyl acetate: 70/30 to 50/50) to give 61.7 mg of the title compound. Was obtained as a colorless powder (yield: 79.9%).
MS (APCI) m / z; 517 [M + H] ^< +>.

Example 100
1- [2-Fluoro-4- (6-fluoro-4- {4- [5- (1-fluoro-1-methylethyl)-[1,2,4] oxadiazol-3-yl] piperidine- Preparation of 1-yl] quinazolin-8-yl) phenyl] pyrrolidin-2-one

1- [2-Fluoro-4- (6-fluoro-4- {4- [5- (1-hydroxy-1-methylethyl)-[1,2,4] oxadiazol-3-yl] piperidine- 1-yl] quinazolin-8-yl) phenyl] pyrrolidin-2-one (compound obtained in Example 88) 67 mg of methylene chloride in 0.7 mL solution under ice-cooling (diethylamino) sulfur trifluoride (DAST) 18 0.5 μL was added and stirred at 0-5 ° C. for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated, and the resulting residue was subjected to NH-silica gel column chromatography (Chromatorex; Fuji Silysia Chemical, solvent; hexane / ethyl acetate: 67/33 to 33/67) and reverse phase HPLC [column: CAPCELL PAK C18 MG. 5 μm, 20 mm × 50 mm, Shiseido; mobile phase A: methanol; mobile phase B: 10 mM ammonium carbonate aqueous solution, flow rate 40 mL / min (mobile phase B 60% → 75% / 5 min). .1 mg was obtained as a colorless powder (yield: 40.1%).
MS (APCI) m / z; 537 [M + H] ^< +>.

Example 101
1- [2-Fluoro-4- (6-fluoro-4- {4- [5- (1-fluoro-1-methylethyl)-[1,2,4] oxadiazol-3-yl] piperidine- Preparation of 1-yl] quinazolin-8-yl) phenyl] pyrrolidin-2-one

1- [2- (tert-Butyldimethylsilyloxy) ethyl] -3- [2-fluoro-4- (6-fluoro-4- {4- [5- (1-hydroxy-1-methylethyl)-[ 1,2,4] oxadiazol-3-yl] piperidin-1-yl} quinazolin-8-yl) phenyl] imidazolidin-2-one 81.4 mg (the compound obtained in Example 98) 81 mg of chloride 30.8 μL of (diethylamino) sulfur trifluoride (DAST) was added to 1.2 mL of methylene solution under ice cooling, and the mixture was stirred at 0 to 5 ° C. for 40 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated, and the resulting residue was purified by NH-silica gel column chromatography (Chromatorex; Fuji Silysia Chemical, solvent; hexane / ethyl acetate: 76/24 to 55/45). The obtained crude product was treated in the same manner as in Example 17. Reversed phase HPLC [column: CAPCELL PAK C18 MG, 5 μm, 20 mm × 50 mm, Shiseido; mobile phase A: methanol; mobile phase B: 10 mM ammonium carbonate aqueous solution, Purification at a flow rate of 40 mL / min (mobile phase B 60% → 75% / 5 min) gave 34 mg of the title compound as a colorless powder (yield: 50.1%).
MS (APCI) m / z; 582 [M + H] ^< +>.

Example 102
1-ethyl-3- (2-fluoro-4- {6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline -8-yl} phenyl) imidazolidin-4-one

3- (2-Fluoro-4- {6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl } Phenyl) imidazolidin-4-one 81.4 mg (compound obtained in Example 97) 36.4 mg of dichloroethane 1.4 mg solution at room temperature with 7.9 μL acetaldehyde, 6 μL acetic acid and 29. sodium triacetoxyborohydride 29. 7 mg was added and the mixture was stirred at room temperature for 5 hours. Acetaldehyde (7.9 μL) and sodium triacetoxyborohydride (29.7 mg) were further added to the reaction mixture, and the mixture was stirred at room temperature for 19 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated, and the resulting residue was purified by silica gel column chromatography (solvent; chloroform / methanol: 100/0 to 97/3) to give 21.3 mg of the title compound as a colorless powder (yield) : 55.5%).
MS (APCI) m / z; 548 [M + H] ^< +>.

Example 103
3- (2-Fluoro-4- {6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl } Phenyl) -1- (2-hydroxyethyl) imidazolidin-4-one

3- (2-Fluoro-4- {6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl } Phenyl) imidazolidin-4-one 81.4 mg (compound obtained in Example 97) 47.5 mg of dichloroethane 1.8 mg solution at room temperature with (tert-butyldimethylsilyloxy) acetaldehyde 69 μL, acetic acid 11 μL and triacetoxy 58 mg of sodium borohydride was added and the mixture was stirred at room temperature for 18.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated, and the resulting residue was purified by silica gel column chromatography (solvent; chloroform / methanol: 100/0 to 97/3). The obtained crude product was treated in the same manner as in Example 17 to obtain 14.3 mg of the title compound as a colorless powder (yield: 27.8%).
MS (APCI) m / z; 564 [M + H] ^< +>.

Example 104
1-ethyl-3- (2-fluoro-4- {6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline -8-yl} phenyl) tetrahydro-pyrimidin-4-one

1- (2,4-Dimethoxybenzyl) -3- (2-fluoro-4- {6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) Piperidine-1-yl] quinazolin-8-yl} phenyl) tetrahydropyrimidin-4-one (compound obtained in Reference Example 161) (278.8 mg) was added with 14 mL of trifluoroacetic acid, and the mixture was stirred at room temperature for 5 hours. . A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: chloroform / methanol: 100/0 to 96/4). The obtained crude product was treated in the same manner as in Example 102 to obtain 12.8 mg of the title compound as a colorless powder (yield: 5.6%).
MS (APCI) m / z; 562 [M + H] +.

Examples 105-138
The corresponding raw material compounds were treated in the same manner as in Example 1 to obtain the compounds shown in Tables 14 to 18 below.

Examples 139-176
The corresponding starting compounds were treated in the same manner as in Example 2 to obtain the compounds described in Tables 19-24 below.

Examples 177-251
The corresponding starting materials were treated in the same manner as in Example 95 to give the compounds shown in Tables 25 to 34 below.

Example 252
The corresponding starting material compound was treated in the same manner as in Example 17 to obtain the compound shown in Table 35 below (15.4 mg) (yield: 65%).

Examples 253-260
The corresponding starting material compound was treated in the same manner as in Example 96, to give compounds as shown in Table 36 below.

Examples 261-262
The corresponding starting material compounds were treated in the same manner as in Example 2 to give the compounds listed in Table 37 below.

Examples 263-265
The corresponding starting materials were treated in the same manner as in Example 9 to give the compounds as shown in Table 38 below.

Examples 266-272
The corresponding starting materials were treated in the same manner as in Example 11 to give the compounds as shown in Table 39 below.

Examples 273-276
The corresponding starting material compounds were treated in the same manner as in Example 14 to give the compounds listed in Table 40 below.

Examples 277-278
The corresponding starting compounds were treated in the same manner as in Example 15 to give the compounds as shown in Table 41 below.

Examples 279-280
The corresponding starting materials were treated in the same manner as in Example 16 to give the compounds as shown in Table 42 below.

Example 281
The corresponding starting materials were treated in the same manner as in Example 89 to give the compounds as shown in Table 43 below.

Examples 282 to 284
The corresponding starting materials were treated in the same manner as in Example 89 to give the compounds as shown in Table 44 below.

Example 285
The corresponding starting compounds were treated in the same manner as in Example 90 to give the compounds as shown in Table 45 below.

Example 286
The corresponding starting material compound was treated in the same manner as in Example 91, to give compounds as shown in Table 46 below.

Examples 287-289
The corresponding starting material compound was treated in the same manner as in Example 92, to give compounds as shown in Table 47 below.

Example 290
The corresponding starting compounds were treated in the same manner as in Example 98 to give the compounds as shown in Table 48 below.

Examples 291-295
The corresponding starting materials were treated in the same manner as in Example 99 to give the compounds as shown in Table 49 below.

Example 296
The corresponding starting material compound was treated in the same manner as in Example 103, to give compounds as shown in Table 50 below.

Example 297
[2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenyl ] Methanol production

8-Bromo-6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline (the compound obtained in Reference Example 12) To a solution of 210 mg of 1,4-dioxane in 10 mL, water 2.5 mL, acetic acid 2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzyl ester ( 294 mg of the compound obtained in Reference Example 188), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex 41 mg and cesium carbonate 650 mg were added, and the mixture was stirred at 90 ° C. under a nitrogen atmosphere. Stir for 16 hours. After returning the reaction solution to room temperature, 2N aqueous sodium hydroxide solution was added and stirred for 1 hour. The reaction solution was extracted with diethyl ether, and the organic layer was concentrated. The obtained residue was purified by NH-silica gel column chromatography (Chromatorex; Fuji Silysia Chemical, solvent; hexane / ethyl acetate: 90/10 to 50/50) to obtain the title compound as a powder (yield: 69%).
MS (APCI) m / z; 466 [M + H] ^< +>.

Examples 298-299
The corresponding starting materials were treated in the same manner as in Example 297 to give the compounds as shown in Table 51 below.

Reference example 1
Preparation of 8-bromo-5-fluoro-3H-quinazolin-4-one

(1) 26.1 g of chloral hydrate, 5.6 mL of concentrated hydrochloric acid, and 2-bromo-5-fluoroaniline (25 g) were added to a solution of 18.7 g of sodium sulfate in 500 mL of water, and the mixture was stirred at room temperature. Hydroxylamine disulfate (32.4 g) and ethanol (190 mL) were added to the reaction mixture, and the mixture was stirred at 80 ° C. for 5 hours. The reaction mixture was cooled to room temperature, 2000 mL of water was added and the mixture was stirred for 1 hour. The precipitate was collected by filtration and washed with water to obtain 28.0 g of N- (5-bromo-2-fluorophenyl) -2-hydroxyiminoacetamide. (Yield: 81%)
MS (APCI) m / z: 261/263 [M + H] ^< +>.

(2) 163 mL of concentrated sulfuric acid was added to 28.0 g of the compound obtained in (1), and the mixture was stirred at 75 ° C. for 1 hour. The reaction mixture was poured into ice (about 0.5 L) and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 24.9 g of 7-bromo-4-fluoro-1H-indole-2,3-dione. (Yield: 95%)
MS (APCI) m / z: 244/246 [M + H] ^< +>.

(3) 24.9 g of the compound obtained in (2) above was added to a solution of 24.5 g of sodium hydroxide in 195 mL of water, and 24 mL of 30% aqueous hydrogen peroxide was added dropwise to the solution under ice cooling. And stirred overnight. After adding 300 mL of water to the reaction mixture, 104 mL of 6N hydrochloric acid was added to the mixture under ice cooling, and the precipitate was collected by filtration and dried to give 23.0 g of 2-amino-3-bromo-5-fluorobenzoic acid. (Yield: 96%) was obtained.
MS (APCI) m / z: 234/236 [M + H] ^< +>.

(4) 115 mL of formamide was added to 23.0 g of the compound obtained in (3) above, and the mixture was stirred at 150 ° C. for 5 hours. The reaction mixture was cooled to room temperature, 640 mL of water was added, the precipitate was collected by filtration, washed with water, and dried at 50 ° C., thereby obtaining 13.0 g of 8-bromo-5-fluoro-3H-quinazolin-4-one. Obtained (yield: 54.4%).
MS (APCI) m / z: 243/245 [M + H] ^< +>.

Reference example 2
Preparation of 7-bromo-5-fluoro-1H-indole-2,3-dione

A solution of 5-fluoroisatin 20.6 g in ethanol 240 mL was heated to 80 ° C., and bromine 14 mL was added dropwise over 20 minutes, followed by stirring for 1 hour. 3 mL of bromine was added and stirred for another 20 minutes. The reaction mixture was cooled to room temperature, 200 mL of chloroform was added, and the precipitate was collected by filtration to obtain 23.1 g of 7-bromo-5-fluoro-1H-indole-2,3-dione. (Yield: 75.7%)
MS (APCI) m / z: 242/244 [M + H] ^< +>.

Reference example 3
Preparation of 8-bromo-6-fluoro-3H-quinazolin-4-one

49.2 g of 8-bromo-6-fluoro-3H-quinazolin-4-one was obtained by treating 55.4 g of the corresponding starting material compound in the same manner as in Reference Examples 1 (3) to (4).
MS (APCI) m / z: 243/245 [M + H] ^< +>.

Reference example 4
Preparation of 8-bromo-4-chloro-6-fluoroquinazoline

One drop of dimethylformamide was added to 100 mL of thionyl chloride in 10.1 g of 8-bromo-6-fluoro-3H-quinazolin-4-one, and the mixture was stirred at 80 ° C. for 4 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate and methylene chloride. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was triturated with hexane to obtain 10.1 g of the title compound. (Yield 93%)
MS (APCI) m / z: 261/263 [M + H] ^< +>.

Reference Example 5
Preparation of 4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidine hydrochloride

(1) 245 mL of 50% hydroxylamine aqueous solution was added to 440 mL of ethanol in 61.17 g of isobutyronitrile, and the mixture was stirred for 7 hours under reflux. The reaction mixture was concentrated under reduced pressure, and 300 mL of toluene was added to the residue, followed by azeotropic dehydration, followed by concentration under reduced pressure to obtain 82.98 g of N′-hydroxy-2-methylpropanimidamide as an oil (yield 91. 8%).
MS (APCI) m / z: 103 [M + H] ^< +>.

(2) N-tert-Butoxycarbonylisonipecotinic acid 56.9 g of dimethylformamide in 500 mL solution, 1,1′-carbonyldiimidazole 45 g of dimethylformamide in 275 mL were added dropwise over 30 minutes, and the mixture was stirred at room temperature. Stir for 30 minutes. To the reaction mixture, a solution of 32.4 g of the compound obtained in (1) above in 500 mL of dimethylformamide was added dropwise over 30 minutes, and the mixture was stirred at room temperature for 12 hours. To the reaction mixture was added dropwise 275 mL of dimethylformamide in 45 g of 1,1′-carbonyldiimidazole over 30 minutes, and the mixture was stirred at 100 to 105 ° C. for 13 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (solvent: hexane / ethyl acetate = 2/1) to give 4- (3-isopropyl-1,2,4-oxadiazol-5-yl. ) 21.75 g of piperidine-1-carboxylic acid tert-butyl ester was obtained as an oil (yield: 29.5%).
MS (APCI) m / z: 296 [M + H] ^< +>.

(3) To a solution of 10.44 g of the compound obtained in (2) above in 50 mL of ethyl acetate was added 44 mL of 4N hydrochloric acid / ethyl acetate, and the mixture was stirred at 60 to 70 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the precipitate was collected, washed with ethyl ether, and dried under reduced pressure to give 7.62 g of the title compound (yield: 93.1%).
MS (APCI) m / z: 196 [M + H] ^< +>.

Reference Examples 6-7
By treating the corresponding starting material compound in the same manner as in Reference Example 5, the following compound was obtained.
Reference Example 6 4- (3-n-propyl-1,2,4-oxadiazol-5-yl) piperidine hydrochloride

MS (APCI) m / z: 196 [M + H] ^< +>.
Reference Example 7 4- [3- (2,2,2-trifluoroethyl) -1,2,4-oxadiazol-5-yl] piperidine hydrochloride

MS (APCI) m / z: 236 [M + H] ^< +>.

Reference Example 8
Preparation of 4- (5-isopropyl-1,2,4-oxadiazol-3-yl) piperidine hydrochloride

(1) To a solution of 1.27 g of 4-cyanopiperidine-1-carboxylic acid tert-butyl ester in 6.0 mL of 2-propanol, 400 mg of a 50% aqueous hydroxylamine solution was added dropwise, and the mixture was stirred at 80 ° C. overnight. The reaction mixture was cooled to room temperature, ethyl acetate was added, and the organic layer was washed successively with water and saturated brine. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain 1.34 g of 4- (N-hydroxycarbamimidoyl) piperidine-1-carboxylic acid tert-butyl ester as a colorless solid. (Yield: 91%).
MS (APCI) m / z; 244 [M + H] ^< +>.

(2) To a mixture of 1.01 mL of isobutyric acid, 1.52 mL of triethylamine and 66 mL of toluene, 1.41 mL of isobutyl chlorocarbonate was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, 2.65 g of the compound obtained in the above (1) was added, and the mixture was stirred at 120 ° C. for 4 hours. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 91: 9-80: 20) to give 4- (5-isopropyl-1,2,4-oxadiazole-3- Yl) 2.18 g of piperidine-1-carboxylic acid tert-butyl ester was obtained as a colorless solid (yield: 68%).
MS (APCI) m / z; 296 [M + H] ^< +>.

(3) 25N of 4N hydrochloric acid-dioxane was added to 13 mL of 1,4-dioxane in 2.50 g of the compound obtained in (2), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was washed with diethyl ether and dried under reduced pressure to give 1.71 g of the title compound as a colorless solid (yield: 87%).
MS (APCI) m / z; 196 [M + H] ^< +>.

Reference Examples 9-11
By treating the corresponding starting material compound in the same manner as in Reference Example 8, the following compound was obtained.
Reference Example 9 4- (5-n-propyl-1,2,4-oxadiazol-3-yl) piperidine hydrochloride

MS (APCI) m / z: 196 [M + H] ^< +>.
Reference Example 10 4- (5-Cyclopropyl-1,2,4-oxadiazol-3-yl) piperidine hydrochloride

MS (APCI) m / z: 194 [M + H] ^< +>.
Reference Example 11 4- (5-Trifluoromethyl-1,2,4-oxadiazol-3-yl) piperidine hydrochloride

MS (APCI) m / z: 222 [M + H] ^< +>.

Reference Example 12
Preparation of 8-bromo-6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline

4- (5-Isopropyl-1,2,4-oxadiazol-3-yl) piperidine hydrochloride (compound obtained in Reference Example 8) 1.78 g of dichloromethane solution 30 mL of saturated aqueous sodium bicarbonate solution 30 mL and 8 1.80 g of bromo-4-chloro-6-fluoro-quinazoline (the compound obtained in Reference Example 4) was sequentially added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was separated into an organic layer and an aqueous layer, and the aqueous layer was extracted with dichloromethane. The obtained two organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (Chromatorex; Fuji Silysia Chemical, solvent; hexane / ethyl acetate: 100/0 to 75/25) to obtain a pale yellow solid. The crude crystals were further washed with hexane, collected by filtration, and dried under reduced pressure to give 2.75 g of the title compound as a colorless powder (yield: 94%).
MS (APCI) m / z; 420/422 [M + H] ^< +>.

Reference Examples 13-18
The following compounds were obtained by treating the corresponding raw material compounds in the same manner as in Reference Example 12.
Reference Example 13 8-Bromo-6-fluoro-4- [4- (5-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline

MS (APCI) m / z: 420/422 [M + H] ^< +>.
Reference Example 14 8-Bromo-6-fluoro-4- [4- (5-cyclopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline

MS (APCI) m / z: 418/420 [M + H] ^< +>.
Reference Example 15 8-Bromo-6-fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazoline

MS (APCI) m / z: 420/422 [M + H] ^< +>.
Reference Example 16 8-Bromo-6-fluoro-4- [4- (3-propyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazoline

MS (APCI) m / z: 420/422 [M + H] ^< +>.
Reference Example 17 8-Bromo-6-fluoro-4- [4- [3- (2,2,2-trifluoroethyl)-[1,2,4] oxadiazol-5-yl] piperidine- 1-yl] quinazoline

MS (APCI) m / z: 460/462 [M + H] ^< +>.

Reference Example 18
Preparation of 8-bromo-5-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl} quinazoline

One drop of dimethylformamide was added to a solution of 2.43 g of thionyl chloride in 2.43 g of 8-bromo-5-fluoro-3H-quinazolin-4-one (compound obtained in Reference Example 1), and the mixture was stirred at reflux for 4 hours. . After cooling to room temperature, the solvent was distilled off under reduced pressure. A solution of the residue suspended in 32 ml of methylene chloride was saturated with 2317 mg of 4- (5-isopropyl-1,2,4-oxadiazol-3-yl) piperidine hydrochloride (the compound obtained in Reference Example 8). 25 ml of aqueous sodium hydrogen carbonate solution was slowly added to the stirred reaction solution at room temperature. Furthermore, after stirring at room temperature for 50 minutes, water was added and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate: 80/20 to 65/35) to give 4.0 g of the title compound as a pale yellow solid (yield: 95. 2%).
MS (APCI) m / z; 420/422 [M + H] +.

Reference Example 19
Preparation of 2- [3-fluoro-4- (2-methoxyethylsulfanyl) phenyl] -4,4,5,5-tetramethyl- [1,3,2] dioxaborolane

  (1) To a solution of 4-bromo-2-fluoro-benzenethiol (1.00 g) in N-methylpyrrolidone (10 mL) were added 2-methoxyethane bromide (0.68 mL) and potassium carbonate (1.34 g), and the mixture was stirred at 85 ° C. for 1 hour. . The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH-silica gel column chromatography (Chromatorex; Fuji Silysia Chemical, solvent; hexane / ethyl acetate = 99/1 to 95/5) to give 4-bromo-2 1.13 g of fluoro-1- (2-methoxyethylsulfanyl) benzene was obtained as a colorless liquid (yield 88%).

(2) 1.13 g of the compound obtained in (1) above was added to 1.40 g of bis (pinacolato) diboron, 1.37 g of potassium acetate, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II ) 173 mg of dichloride / dichloromethane complex and 15 mL of dimethyl sulfoxide were added, and the mixture was deaerated and then stirred at 80 ° C. for 6 hours under a nitrogen atmosphere. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (solvent: hexane / ethyl acetate = 91 / 9-80 / 20) to give 1.14 g of the title compound as a colorless liquid (yield). Rate: 86%).
MS (APCI) m / z: No ion detection. ← Delete?
Reference Examples 20-24
By treating the corresponding starting material compound in the same manner as in Reference Example 19, the following compound was obtained.
Reference Example 20 2- [3-Fluoro-4- (3-methoxypropylsulfanyl) phenyl] -4,4,5,5-tetramethyl- [1,3,2] dioxaborolane

MS (APCI) m / z: 327 [M + H] ^< +>.
Reference Example 21 2- [3-Fluoro-4- [2- (2-tetrahydropyranyloxy) ethylsulfanyl] phenyl] -4,4,5,5-tetramethyl- [1,3,2] dioxaborolane

MS (APCI) m / z: 400 [M + NH 4] +.
Reference Example 22 2- [2-Fluoro-4- [2- (2-tetrahydropyranyloxy) ethylsulfanyl] phenyl] -4,4,5,5-tetramethyl- [1,3,2] dioxaborolane

MS (APCI) m / z: 400 [M + NH 4] +.
Reference Example 23 2- [4- [2- (2-Tetrahydropyranyloxy) ethylsulfanyl] phenyl] -4,4,5,5-tetramethyl- [1,3,2] dioxaborolane

MS (APCI) m / z: 382 [M + NH 4] +.
Reference Example 24 2- [2-Fluoro-4- (2-benzyloxyethyl) oxyphenyl] -4,4,5,5-tetramethyl- [1,3,2] dioxaborolane

Reference Example 25
Preparation of [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] acetonitrile

  (1) To a solution of 8.04 g of 4-bromo-2-fluorobenzyl bromide in 50 mL of dimethyl sulfoxide was added 1.68 g of sodium cyanide at room temperature, and the mixture was stirred at 90 ° C. overnight. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 90 / 10-80 / 20) to give 3.61 g of (4-bromo-2-fluorophenyl) acetonitrile. Was obtained as a yellow liquid (yield: 56%).

  (2) 1.84 g of the compound obtained in (1) above, 2.62 g of bis (pinacolato) diboron, 1.68 g of potassium acetate, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride -351 mg of a dichloromethane complex, 10 mL of dimethyl sulfoxide and 1 mL of water were added, and the mixture was deaerated and then stirred at 80 ° C. overnight under a nitrogen atmosphere. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (solvent: hexane / ethyl acetate = 90 / 10-70 / 30) to give 2.30 g of the title compound as a colorless viscous oil. (Yield: 99%).

Reference Example 26
Preparation of 4,4,5,5-tetramethyl-2- (3-methylsulfanyl-4-methylsulfanylmethylphenyl)-[1,3,2] dioxaborolane

  (1) To a solution of 13.40 g of 4-bromo-2-fluorobenzyl bromide in 100 mL of dimethyl sulfoxide, 14.21 g of sodium methanethiolate was added at room temperature and stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 100/0 to 90/10) to give 4-bromo-2-methylsulfanyl-1-methylsulfanylmethyl. -12.32 g of benzene was obtained as a yellow liquid (yield: 94%).

  (2) To 2.35 g of the compound obtained in the above (1), 3.05 g of bis (pinacolato) diboron, 1.96 g of potassium acetate, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II ) 408 mg of dichloride / dichloromethane complex, 5 mL of dimethyl sulfoxide and 0.5 mL of water were added, and the mixture was degassed and then stirred at 80 ° C. overnight under a nitrogen atmosphere. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (solvent: hexane / ethyl acetate = 100/0 to 90/10) to give 3.32 g of the title compound as a colorless viscous oil. (Yield: 99%).

Reference Example 27
Preparation of 1- [4- [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzyl] piperazin-1-yl] ethanone

(1) To a solution of 2.68 g of 4-bromo-2-fluorobenzyl bromide and 1.28 g of acetylpiperazine in 40 mL of dimethyl sulfoxide, 1.5 mL of triethylamine was added at room temperature and stirred for 1 hour. To this reaction solution was added 3.80 g of bis (pinacolato) diboron, 2.00 g of potassium acetate, and 410 mg of [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride / dichloromethane complex, and the mixture After degassing, the mixture was stirred at 70 ° C. overnight under a nitrogen atmosphere. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by NH silica gel chromatography (Chromatorex; Fuji Silysia Chemical, solvent: hexane / ethyl acetate = 80/20 to 40/60) to give 262 mg of the title compound as a viscous oil. (Yield: 7%).
MS (APCI) m / z: 363
Reference Example 28
Preparation of 2- [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] isothiazolidine-1,1-dioxide

  (1) To a solution of 1.90 g of 4-bromo-2-fluoroaniline in 20 mL of dichloromethane were added 2 mL of pyridine and 10 mL of dichloromethane in 1.77 g of 3-chloropropane-1-sulfonyl chloride, and the mixture was stirred at room temperature for 3 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with 1N hydrochloric acid, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was triturated with dichloromethane / diisopropyl ether to give 1.27 g of 2- (4-bromo-2-fluorophenyl) isothiazolidine-1,1-dioxide as a dark purple powder. Obtained (yield: 43%).

(2) By treating 1.20 g of the compound obtained in the above (1) in the same manner as in Reference Example 19 (2), 1.40 g of the title compound was obtained as a colorless powder (yield: 100%).
MS (APCI) m / z: 359 [M + NH4] ^< +>.

Reference Example 29
2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] benzoic acid Manufacturing of

  (1) 8-Bromo-6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline (obtained in Reference Example 12) 1.36 g, 0.961 g of 3-fluoro-4-methoxycarbonylphenylboronic acid, 0.374 g of tetrakistriphenylphosphine palladium, 2.11 g of cesium carbonate were dissolved in 54 mL of 1,4-dioxane and 13 mL of water, The mixture was heated and stirred at 90 ° C. for 7 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was subjected to NH silica gel column chromatography (Chromatorex; Fuji Silysia Chemical, solvent; hexane / ethyl acetate: 86/14 to 75/25, and solvent; hexane / ethyl acetate: 91/9. -75/25) twice to give 2-fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidine. -1-yl] quinazolin-8-yl] benzoic acid methyl ester (0.767 g) was obtained as colorless crystals (yield: 48%).

(2) 760 mg of the compound obtained in the preceding item (1) was dissolved in a mixed solution of 13 mL of tetrahydrofuran and 13 mL of methanol, 3.1 mL of 2N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized with 2N aqueous hydrochloric acid solution, water was added, and the mixture was stirred for 30 min. The precipitated crystals were collected by filtration and dried under reduced pressure to give 695 mg of the title compound as a colorless solid (yield: 94%).
MS (APCI) m / z: 480 [M + H] ^< +>.

Reference Examples 30-35
By treating the corresponding starting material compound in the same manner as in Reference Example 29, the following compound was obtained.
Reference Example 30 2-Fluoro-4- [6-fluoro-4- [4- (5-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline-8 -Il] benzoic acid

MS (APCI) m / z: 480 [M + H] ^< +>.
Reference Example 31 4- [4- [4- (5-Cyclopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] -6-fluoroquinazolin-8-yl] -2-Fluorobenzoic acid

MS (APCI) m / z: 478 [M + H] ^< +>.
Reference Example 32 2-Fluoro-4- [6-fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazoline-8 -Il] benzoic acid

MS (APCI) m / z: 480 [M + H] ^< +>.
Reference Example 33 2-Fluoro-4- [6-fluoro-4- [4- (3-propyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazoline-8 -Il] benzoic acid

MS (APCI) m / z: 480 [M + H] ^< +>.
Reference Example 34 (2-Fluoro-4- [6-fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazoline- 8-yl] phenyl) acetic acid

MS (APCI) m / z: 494 [M + H] ^< +>.
Reference Example 35 (2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) quinazolin-8-yl] benzylsulfanyl ] Acetic acid

  MS (APCI) m / z: 540 [M + H] +.

Reference Example 36
2-Fluoro-4- [6-fluoro-4- [4- [3- (2,2,2-trifluoroethyl)-[1,2,4] oxadiazol-5-yl] piperidine-1- Yl] quinazolin-8-yl] benzoic acid

8-Bromo-6-fluoro-4- [4- [3- (2,2,2-trifluoro-ethyl)-[1,2,4] oxadiazol-5-yl] piperidin-1-yl] By treating 1.00 g of quinazoline (the compound obtained in Reference Example 17) and 798 mg of 4-carboxy-3-fluorophenylboronic acid in the same manner as in Example 1, 265 mg of the title compound was obtained as a colorless powder (yield) : 24%).
MS (APCI) m / z: 520 [M + H] ^< +>.

Reference Example 37
Preparation of [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzylsulfanyl] acetic acid methyl ester

  (1) 50 mL of DMF solution of 2.7 g of methyl thioglycolate and 13.8 g of potassium carbonate and 6.7 g of 4-bromo-2-fluorobenzyl bromide were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 7.5 g of (4-bromo-2-fluorobenzylsulfanyl) acetic acid methyl ester as a colorless viscous oil (yield:> 99%).

(2) The title compound was obtained as a colorless viscous oil by treating 3.0 g of the compound obtained in (1) above in the same manner as in Reference Example 19 (yield: 32%).
MS (APCI) m / z: 358 [M + NH4] ^< +>.

Reference Example 38
6-Fluoro-8- [3-fluoro-4- [2- (tetrahydropyran-2-yloxy) ethylsulfanyl] phenyl] -4- [4- (5-isopropyl- [1,2,4] oxadiazole Preparation of -3-yl] piperidin-1-yl] quinazoline

8-Bromo-6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline (the compound obtained in Reference Example 12) By treating 200 mg in the same manner as in Example 1, 109 mg of the title compound was obtained as a colorless powder (yield: 38%).
MS (APCI) m / z: 596 [M + H] ^< +>.

Reference Examples 39-44
By treating the corresponding starting material compound in the same manner as in Reference Example 38, the following compound was obtained.
Reference Example 39 6-Fluoro-8- [4- [2- (tetrahydropyran-2-yloxy) ethylsulfanyl] phenyl] -4- [4- (5-isopropyl- [1,2,4] oxadi Azol-3-yl] piperidin-1-yl] quinazoline

MS (APCI) m / z: 578 [M + H] ^< +>.
Reference Example 40 6-Fluoro-8- [2-fluoro-4- [2- (tetrahydropyran-2-yloxy) ethylsulfanyl] phenyl] -4- [4- (5-isopropyl- [1,2, 4] oxadiazol-3-yl] piperidin-1-yl] quinazoline

MS (APCI) m / z: 596 [M + H] ^< +>.
Reference Example 41 6-Fluoro-8- [3-fluoro-4-[[2- (tetrahydropyran-2-yloxy) ethylsulfanyl] methyl] phenyl] -4- [4- (5-isopropyl- [1 , 2,4] oxadiazol-3-yl] piperidin-1-yl] quinazoline

MS (APCI) m / z: 610 [M + H] ^< +>.
Reference Example 42 6-Fluoro-8- [3-fluoro-4-[[3- (tetrahydropyran-2-yloxy) propylsulfanyl] methyl] phenyl] -4- [4- (5-isopropyl- [1 , 2,4] oxadiazol-3-yl] piperidin-1-yl] quinazoline

MS (APCI) m / z: 624 [M + H] ^< +>.
Reference Example 43 6-Fluoro-8- [3-fluoro-4-[[2- (tetrahydropyran-2-yloxy) ethylsulfanyl] methyl] phenyl] -4- [4- (3-isopropyl- [1 , 2,4] oxadiazol-5-yl] piperidin-1-yl] quinazoline

Reference Example 44 6-Fluoro-8- [3-fluoro-4-[[3- (tetrahydropyran-2-yloxy) propylsulfanyl] methyl] phenyl] -4- [4- (3-isopropyl- [1 , 2,4] oxadiazol-5-yl] piperidin-1-yl] quinazoline

MS (APCI) m / z: 624 [M + H] ^< +>.

Reference Example 45
2-tert-Butoxycarbonylamino-2- [4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl]- Preparation of quinazolin-8-yl] phenyl] -N, N-dimethylacetamide

(1) 8-Bromo-6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline (obtained in Reference Example 12) The compound 780 mg was treated in the same manner as in Reference Example 29 to give 2-tert-butoxycarbonylamino-2- [4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4]. ] 450 mg of oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenyl] acetic acid was obtained as a colorless powder (yield: 35%).
MS (APCI) m / z: 591 [M + H] ^< +>.

(2) By treating 150 mg of the compound obtained in (1) in the same manner as in Example 2, 96 mg of the title compound was obtained as a colorless powder (yield: 73%).
MS (APCI) m / z: 618 [M + H] ^< +>.

Reference Example 46
6-Fluoro-8- [3-fluoro-4- [2- [2- (tetrahydropyran-2-yloxy) ethyl] -2H-tetrazol-5-yl] phenyl] -4- [4-5-isopropyl- Preparation of [1,2,4] oxadiazol-3-yl] piperidin-1-yl] quinazoline

(1) 8-Bromo-6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline (obtained in Reference Example 12) Compound (420) and 250 mg of 4-cyano-3-fluorophenylboric acid were treated in the same manner as in Example 1 to give 2-fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [ There were obtained 334 mg of 1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] benzonitrile as a colorless powder (yield: 73%).
MS (APCI) m / z: 461 [M + H] ^< +>.

  (2) 200 mg of sodium azide and 400 mg of triethylamine hydrochloride were added to a solution of the compound 138 mg obtained in (1) above in 6 mL of toluene and stirred at 100 ° C. for 20 hours. The reaction mixture was cooled to room temperature, water was added, and the precipitate was collected by filtration. Water was added to the filtrate and extracted three times with methylene chloride. The organic layer was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (solvent; chloroform / methanol = 100/0 to 80/20) to give 6-fluoro-8- [3-fluoro-4- 113 mg of (2H tetrazol-5-yl) phenyl] -4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline was obtained as a colorless solid. (Yield: 74%).

  (3) 8 mg of sodium hydride and 33 mg of 2- (2-chloroethoxy) tetrahydropyran were added to a dimethylformamide solution of 90 mg of the compound obtained in (2) above, and the mixture was stirred at room temperature for 16 hours. 138 mg of potassium carbonate was added to the reaction mixture, and the mixture was stirred at 100 ° C. for 16 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and filtered, and the filtrate is concentrated under reduced pressure. The resulting residue is subjected to NH-silica gel column chromatography (Chromatorex; Fuji Silysia Chemical, solvent; hexane / ethyl acetate = 90 / 10-50 / 50) to give 56 mg of the title compound as a colorless solid (yield: 49%).

Reference Example 47
Preparation of 2- [2- [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzylsulfanyl] ethoxy] tetrahydropyran

  (1) To a solution of 5.34 g of 4-bromo-2-fluorobenzyl bromide in 50 mL of dimethylformamide was added 2.28 g of potassium thioacetate and stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and 3.29 g of 2- (2-chloroethoxy) tetrahydro-2H-pyran was added to 50 mL of a methanol solution of 5.5 g of the obtained residue, and the mixture was stirred at room temperature overnight. did. Water and saturated brine were added to the reaction mixture, and the mixture was extracted 3 times with methylene chloride. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: chloroform / methanol = 100/0 to 90/10) to give 2- [2- (4-bromo-2-fluorobenzylsulfanyl) ethoxy] -tetrahydro 3.62 g of pyran was obtained as a colorless solid (yield: 50%).

(2) The title compound (2.6 g) was obtained as an oil by treating 3.5 g of the compound obtained in (1) in the same manner as in Reference Example 19 (2) (yield: 66%).
MS (APCI) m / z: 414 [M + NH4] ^< +>.

Reference Example 48
Preparation of 2- [3- [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzylsulfanyl] propoxy] tetrahydropyran

  The corresponding starting material compound was treated in the same manner as in Reference Example 47 to give the title compound.

MS (APCI) m / z: 428 [M + NH 4] +.

Reference Example 49
2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenylamine Production of dihydrochloride

(1) 8-Bromo-6-fluoro-4- [4- (5-isopropyl- [1,2,4] -oxadiazol-3-yl) piperidin-1-yl] quinazoline (obtained in Reference Example 12) Compound 2) and 1.456 g of 4-tert-butoxycarbonylamino-3-fluorophenylboronic acid were treated in the same manner as in Example 1 to give 2-fluoro-4- [6-fluoro-4- [4. -(5-Isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenylcarbamic acid tert-butyl ester 1.9845 g was obtained as a colorless powder. (Yield: 76%)
(2) 15 mL of 4N hydrochloric acid-dioxane solution was added to 15 mL of dichloromethane and 15 mL of ethanol of 1.98 g of the compound obtained in (1) above, and the mixture was stirred at room temperature for 3 hours and 30 minutes. The reaction mixture was concentrated, the residue was crystallized from ethanol and ethyl acetate, and the precipitate was collected by filtration to give 1.74 g of the title compound as a pale yellow powder. (Yield: 93%)
MS (APCI) m / z: 451 [M + H] ^< +>.

Reference Example 50
Preparation of acetic acid 2- [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzyloxy] ethyl ester

  (1) After adding 2.1 g of acetic acid 2-hydroxyethyl ester to a solution of 0.8 g of sodium hydride in 100 mL of dimethylformamide at 0 ° C., 5.36 g of dimethylformamide of 4-bromo-1-bromomethyl-2-fluorobenzene 100 mL solution was added and stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 90 / 10-40 / 60) to give acetic acid 2- (4-bromo-2-fluorobenzyloxy). ) 1.50 g of ethyl ester was obtained as a colorless liquid (yield: 28%).

(2) By treating 1.50 g of the compound obtained in the above (1) in the same manner as in Reference Example 19 (2), 0.86 g of the title compound was obtained as a colorless viscous oily substance (yield: 51% ).
MS (APCI) m / z: 356 [M + NH4] ^< +>.

Reference Example 51
Of 6-fluoro-8- (3-fluoro-4-vinylphenyl) -4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazoline Manufacturing

(1) 8-Bromo-6-fluoro-4- [4- (3-isopropyl- [1,2,4] -oxadiazol-5-yl) piperidin-1-yl] quinazoline (Reference Example 15) The obtained compound) 0.5 g and 3-fluoro-4-formylphenylboronic acid were treated in the same manner as in Example 1 to give 2-fluoro-4- [6-fluoro-4- [4- (3- 0.34 g of isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl] benzaldehyde was obtained. (Yield: 62%)
(2) To a suspension of 174 mg of methyltriphenylphosphonium bromide in 5 mL of tetrahydrofuran was added dropwise 0.32 mL of a 1.54 mol / L solution of n-butyllithium in hexane at −78 ° C., and the mixture was stirred at −78 ° C. for 10 minutes. did. To the reaction mixture was added 150 mL of the compound obtained in (1) above in 5 mL of tetrahydrofuran, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated, water was poured into the residue, and the mixture was extracted with ethyl acetate. The organic layer was purified by silica gel chromatography (solvent: hexane / ethyl acetate = 85/15 to 65/35) to give 96 mg of the title compound as a colorless solid (yield: 64%).
MS (APCI) m / z: 462 [M + H] ^< +>.

Reference Example 52
1- [2- (tert-Butyldimethylsilyloxy) ethyl] -3- [2-fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazole) -3-yl) piperidin-1-yl] quinazolin-8-yl] phenyl] imidazolidin-2-one

1- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl The title compound 550 was treated by treating 848 mg of phenyl] imidazolidin-2-one (compound obtained in Example 15) and 700 μL of 2- (tert-butyldimethylsilyloxy) ethyl bromide in the same manner as in Example 16. 0.7 mg was obtained as a pale yellow powder (yield: 50%).
MS (APCI) m / z: 678 [M + H] ^< +>.

Reference Example 53
8- (4-Chloromethyl-3-fluorophenyl) -6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline Manufacturing of

[2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenyl ] To a solution of methanol (compound obtained in Example 297) 130 mg in dichloromethane 3 mL were added thionyl chloride 98 μL and dimethylformamide 1 drop, and the mixture was stirred at room temperature for 2 hours and 20 minutes. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with dichloromethane. The organic layer was concentrated, and the residue was purified by silica gel chromatography (solvent: hexane / ethyl acetate = 90 / 10-70 / 30) to give 118.6 mg of the title compound as a colorless powder (yield: 88% ).
MS (APCI) m / z: 484/486 [M + H] ^< +>.

Reference Example 54
Of 6-fluoro-8- (6-fluoropyridin-3-yl) -4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline Manufacturing

8-Bromo-6-fluoro-4- [4- (5-isopropyl- [1,2,4] -oxadiazol-3-yl) piperidin-1-yl] quinazoline (the compound obtained in Reference Example 12) The title compound was treated by treating 500 mg and 345 mg of 2-fluoro-5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) pyridine in the same manner as in Example 1. 426 mg was obtained as a colorless solid (yield: 82%).
MS (APCI) m / z: 437 [M + H] ^< +>.

Reference Example 55
[2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenyl ] Production of acetic acid ethyl ester

8-Bromo-6-fluoro-4- [4- (5-isopropyl- [1,2,4] -oxadiazol-3-yl) piperidin-1-yl] quinazoline (Reference Example 12 (A-1) (Compound obtained in 1) and [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] acetic acid ethyl ester (Reference Example 56). 610 mg of the compound obtained in the above was treated in the same manner as in Example 1 to obtain 750 mg of the title compound as a colorless viscous oil (yield: 100%).
MS (APCI) m / z: 522 [M + H] ^< +>.

Reference Example 56
Preparation of [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] acetic acid ethyl ester

  (1) (4-Bromo-2-fluorophenyl) acetonitrile (compound obtained in Reference Example 25 (2)) To a solution of 15.0 g of ethanol 150 mL and water 45 mL, 23.59 g of potassium hydroxide was added at room temperature. The mixture was stirred at 85 ° C. for 9 hours and 30 minutes. The reaction mixture was cooled to room temperature, adjusted to pH 3-4 with 6N aqueous hydrochloric acid solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 15.41 g of (4-bromo-2-fluorophenyl) acetic acid as a brown solid (yield: 94%).

(2) 2 mL of sulfuric acid was added to a solution of 16.94 g of the compound obtained in (1) above in 350 mL of ethanol, and the mixture was heated to reflux overnight. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was triturated with diisopropyl ether / hexane to give 14.3-g (4-bromo-2-fluorophenyl) acetic acid ethyl ester as a colorless solid (yield: 58 %).
MS (APCI) m / z: 261/263 [M + H] ^< +>.

(3) The title compound was obtained as a colorless solid by treating 2.00 g of the compound obtained in (2) above in the same manner as in Reference Example 19 (2) (yield: 66%).
MS (APCI) m / z: 309 [M + H] ^< +>.

Reference Example 57
4- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl Preparation of phenyl] -3-oxopiperazine-1-carboxylic acid tert-butyl ester

The corresponding starting material compound was treated in the same manner as in Reference Example 38 to give the title compound (423.3 mg) as a colorless solid (yield: 64%).
MS (APCI) m / z: 634 [M + H] ^< +>.

Reference Example 58
4- [6-Fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] -3-methylaniline Dihydrochloride

The corresponding starting material compound was treated in the same manner as in Reference Example 49 to give the title compound (819.8 mg) as a colorless powder (yield: 85%).
MS (APCI) m / z: 447 [M + H] ^< +>.

Reference Example 59
4- [6-Fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] -2-methylaniline

The corresponding starting material compound was treated in the same manner as in Reference Example 49, and then the reaction product was treated with a saturated aqueous sodium hydrogen carbonate solution to give the title compound (458.7 mg) as a pale yellow powder (yield: 100% ).
MS (APCI) m / z: 447 [M + H] ^< +>.

Reference Example 60
1- [4- [6-Fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] -2- Methylphenyl] imidazolidin-2-one

4- [6-Fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] -2-methylaniline ( Compound obtained in Reference Example 59) 172 μL of 2-chloroethyl isocyanate was added to a solution of 300 mg of 6 mL of tetrahydrofuran at room temperature and stirred for 19 hours. To the reaction mixture were added tetra n-butylammonium iodide (12.4 mg) and 6N aqueous sodium hydroxide solution (6 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by silica gel column chromatography (solvent; chloroform / methanol = 100/0 to 92/8) to give 272.9 mg of the title compound as a colorless powder (yield: 79%).
MS (APCI) m / z; 516 [M + H] ^< +>.

Reference Example 61
1- [4- [6-Fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] -3- Methylphenyl] imidazolidin-2-one

The corresponding starting material compound was treated in the same manner as in Reference Example 60 to give the title compound (136.6 mg) as a colorless powder (yield: 69%).
MS (APCI) m / z; 516 [M + H] ^< +>.

Reference Example 62
1- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl Preparation of phenyl] -4- (2-acetoxyacetyl) piperazin-2-one

1- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] By treating 80 mg of dihydrochloride of phenyl] piperazin-2-one (compound obtained in Example 94) and 29 μL of acetoxyacetyl chloride in the same manner as in Example 9, 89.1 mg of the title compound was obtained as a colorless powder. (Yield: 100%).
MS (APCI) m / z; 634 [M + H] ^< +>.

Reference Examples 63-64
The following compounds were obtained by treating the corresponding raw material compounds in the same manner as in Reference Example 12.
Reference Example 63 8-Bromo-4- [4- (5-trifluoromethyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline

MS (APCI) m / z; 428/430 [M + H] ^< +>.
Reference Example 64 8-Bromo-4- [4- (5-cyclopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline

MS (APCI) m / z; 400/402 [M + H] ^< +>.

Reference Example 65
Preparation of 1- (4-bromo-2-fluorophenyl) -3- [2- (tert-butyldimethylsilyloxy) ethyl] imidazolidin-2-one

(1) By treating 10 g of 4-bromo-2-fluoroaniline in the same manner as in Reference Example 60, 13.57 g of 1- (4-bromo-2-fluorophenyl) imidazolidin-2-one was obtained as a colorless powder. It was. (Yield 99%)
MS (APCI) m / z; 259/261 [M + H] ^< +>.

(2) By treating 7 g of the compound obtained in the above (1) and 11.6 mL of 2- (tert-butyldimethylsilyloxy) ethyl bromide in the same manner as in Example 16, 5.80 g of the title compound was colorless and viscous. Obtained as an oil (yield: 51%).
MS (APCI) m / z: 417/419 [M + H] ^< +>.

Reference Examples 66-68
By treating the corresponding starting material compound in the same manner as in Reference Example 65, the following compound was obtained.
Reference Example 66 1- (4-Bromophenyl) -3- [2- (tert-butyldimethylsilyloxy) ethyl] imidazolidin-2-one

MS (APCI) m / z: 399/401 [M + H] ^< +>.
Reference Example 67 1- (4-Bromo-2-methylphenyl) -3- [2- (tert-butyldimethylsilyloxy) ethyl] imidazolidin-2-one

MS (APCI) m / z: 413/415 [M + H] ^< +>.
Reference Example 68 1- (4-Bromo-2-methylphenyl) -3- [3- (tetrahydropyran-2-yloxy) propyl] imidazolidin-2-one

MS (APCI) m / z: 397/399 [M + H] ^< +>.

Reference Example 69
Production of (S) -4- (tert-butyldimethylsilyloxy) pyrrolidin-2-one

A suspension of 2.02 g of (S) -4-hydroxypyrrolidin-2-one, 3.16 g of tert-butyldimethylsilane chloride and 2.04 g of imidazole in 20 mL of dimethylformamide was stirred overnight at room temperature. Water was added to the reaction mixture at 0 ° C., and the precipitated solid was collected by filtration and dried to give 3.90 g of the title compound as a colorless powder. (Yield: 90%).
MS (APCI) m / z: 216 [M + H] ^< +>.

Reference examples 70-71
By treating the corresponding starting material compound in the same manner as in Reference Example 69, the following compound was obtained.
Reference Example 70 (R) -4- (tert-Butyldimethylsilyloxy) pyrrolidin-2-one

MS (APCI) m / z: 216 [M + H] ^< +>.
Reference Example 71 (S) -5- (tert-butyldimethylsilyloxymethyl) pyrrolidin-2-one

MS (APCI) m / z: 230 [M + H] ^< +>.

Reference Example 72
Production of (S) -1- (4-bromo-2-fluorophenyl) -4- (tert-butyldimethylsilyloxy) pyrrolidin-2-one

(S) -4- (tert-butyldimethylsilyloxy) pyrrolidin-2-one (the compound obtained in Reference Example 69) 859 mg, 4-bromo-2-fluoro-1-iodobenzene 1 g, copper chloride 32 mg, N A suspension of N′-dimethylethylenediamine (36 μL) and potassium phosphate (1.41 g) in 15 mL of toluene was stirred at 80 ° C. for 15 hours in a nitrogen atmosphere. The reaction mixture was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 100 / 0-80 / 20) to give 1.06 g of the title compound as a colorless solid (yield: 83%).
MS (APCI) m / z; 388/390 [M + H] ^< +>.

Reference Examples 73-76
By treating the corresponding starting material compound in the same manner as in Reference Example 72, the following compound was obtained.
Reference Example 73 (R) -1- (4-Bromo-2-fluorophenyl) -4- (tert-butyldimethylsilyloxy) pyrrolidin-2-one

MS (APCI) m / z; 388/390 [M + H] ^< +>.
Reference Example 74 (R) -1- (4-Bromo-2-methylphenyl) -4- (tert-butyldimethylsilyloxy) pyrrolidin-2-one

MS (APCI) m / z; 384/386 [M + H] ^< +>.
Reference Example 75 (R) -1- (4-Bromo-3-methylphenyl) -4- (tert-butyldimethylsilyloxy) pyrrolidin-2-one

MS (APCI) m / z; 384/386 [M + H] ^< +>.
Reference Example 76 4- (4-Bromo-2-fluorophenyl) -3-oxopiperazine-1-carboxylic acid tert-butyl ester

MS (APCI) m / z; 373/375 [M + H] ^< +>.

Reference Example 77
Production of (S) -1- (4-bromo-2-fluorophenyl) -5- (tert-butyldimethylsilyloxymethyl) pyrrolidin-2-one

(S) -5- (tert-Butyldimethylsilyloxymethyl) pyrrolidin-2-one (compound obtained in Reference Example 71) 8 g, 4-bromo-2-fluoro-1-iodobenzene 10 g, copper chloride 316 mg, A suspension of 758 mg of trans-cyclohexane-1,2-diamine and 17.6 g of potassium phosphate in 150 mL of toluene was stirred at 110 ° C. for 11 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 70 / 30-50 / 50) to give 6.09 g of the title compound as a yellow viscous oil (yield: 46%) ).
MS (APCI) m / z; 402/404 [M + H] ^< +>.

Reference Example 78
Preparation of (4-bromo-3-methylphenyl) carbamic acid tert-butyl ester

6 mL of triethylamine was added to a 160 mL methanol solution of 4 g of 4-bromo-3-methylaniline and 4.7 g of ditert-butyl dicarbonate, and the mixture was stirred at room temperature for 1 day. To the reaction mixture, 4.7 g of ditert-butyl dicarbonate and 6 mL of triethylamine were further added, and the mixture was stirred at room temperature for 17 hours. To the reaction mixture, 4.7 g of ditert-butyl dicarbonate and 6 mL of triethylamine were further added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 100/0 to 90/10) to give 4.57 g of the title compound as a colorless powder (yield). (Rate: 74%).
MS (APCI) m / z; 286/288 [M + H] ^< +>.

Reference Example 79
Preparation of (4-bromo-2-methylphenyl) carbamic acid tert-butyl ester

The corresponding starting material compound was treated in the same manner as in Reference Example 78 to give the title compound.
MS (APCI) m / z; 286/288 [M + H] ^< +>.

Reference Example 80
Preparation of 1- (4-bromo-2-fluorophenyl) -3- [2-methyl-2- (tetrahydropyran-2-yloxy) propyl] imidazolidin-2-one

(1) Treat 1 g of 1- (4-bromo-2-fluorophenyl) imidazolidin-2-one (compound obtained in Reference Example 65 (1)) and 232 mg of ethyl bromoacetate in the same manner as in Example 16. Gave 814.3 mg of 1- (4-bromo-2-fluorophenyl) -3-ethoxycarbonylmethylimidazolidin-2-one as a colorless solid (61% yield).
MS (APCI) m / z; 345/347 [M + H] ^< +>.

(2) To a solution of 810 mg of the compound obtained in (1) above in 20 mL of tetrahydrofuran was added dropwise 7.6 mL of a tetrahydrofuran solution of methylmagnesium bromide (0.93 mol / L) at −40 ° C. in a nitrogen atmosphere over 5 minutes. The mixture was stirred at room temperature for 100 minutes. To the reaction mixture, 7.6 mL of a methylmagnesium bromide tetrahydrofuran solution (0.93 mol / L) was added dropwise, and the mixture was stirred at room temperature for 2 hours. A saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 65/35 to 35/65). The obtained crude product was dissolved in 5 mL of dichloromethane, and 430 μL of 3,4-dihydro-2H-pyran and 59 mg of toluene-4-sulfonic acid pyridine salt were added thereto, and the mixture was stirred at room temperature for 5 hours. To the reaction mixture, 430 μL of 3,4-dihydro-2H-pyran and 59 mg of toluene-4-sulfonic acid pyridine salt were further added, and the mixture was stirred at room temperature overnight. The reaction mixture was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 85/15 to 65/35) to give 206.1 mg of the title compound as a colorless powder (yield: 21%).
MS (APCI) m / z; 286/288 [M + H] ^< +>.

Reference Example 81
Production of (R) -3- (4-bromo-2-fluorophenyl) -5- (tert-butyldimethylsilyloxymethyl) oxazolidine-2-one

(1) 20 mL of water and 4.66 g of sodium hydrogen carbonate were added to a 100 mL acetone solution of 5 g of 4-bromo-2-fluoroaniline at room temperature, and 16.5 g of a 30% toluene solution of benzyl chloroformate was added dropwise to the solution. The mixture was stirred at room temperature for 19 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated. Cold hexane (0 ° C.) is added to the resulting residue, and the precipitated solid is collected by filtration and dried to give 4-benzyl-2-fluorocarbamic acid benzyl ester 8 0.06 g was obtained as a colorless powder. (Yield 94%)
MS (APCI) m / z; 341/343 [M + H] ^< +>.

(2) To a 70 mL tetrahydrofuran solution of 3 g of the compound obtained in (1) above, 6.6 mL of a hexane solution (1.54 mol / L) of n-butyllithium was added dropwise at −78 ° C. in a nitrogen atmosphere over 15 minutes. And the mixture was stirred for 1 hour. To the reaction mixture, 1.57 mL of butanoic acid (R) -1-oxiranylmethyl ester was added dropwise at −78 ° C., and the mixture was stirred at room temperature for 22 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is dried over sodium sulfate and concentrated, and the obtained residue is purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 55/45 to 25/75) to give (R) -3- ( 1.27 g of 4-bromo-2-fluorophenyl) -5-hydroxymethyloxazolidine-2-one was obtained as a colorless solid (yield: 47%).
MS (APCI) m / z; 290/292 [M + H] +.

(3) 443 mg of imidazole and 0.72 g of tert-butyldimethylsilane chloride were added to 12 mL of dimethylformamide in 1.26 g of the compound obtained in (2), and the mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 90 / 10-75 / 25) to give 1.42 g of the title compound as a colorless solid (yield: 81%).
MS (APCI) m / z; 404/406 [M + H] ^< +>.

Reference Example 82
Preparation of 5-bromo-2- (2-oxopyrrolidin-1-yl) benzonitrile

The title compound (1.14 g) was obtained as a yellow solid by treating 2 g of 2-amino-5-bromobenzonitrile and 1.36 g of 4-chlorobutanoic acid chloride in the same manner as in Example 14. (Yield 42%)
MS (APCI) m / z; 265/267 [M + H] ^< +>.

Reference Example 83
Preparation of 4- [3- [2- (tert-butyldimethylsilyloxy) ethyl] -2-oxoimidazolidin] -1-yl] -3-fluorophenylboronic acid

1- (4-Bromo-2-fluorophenyl) -3- [2- (tert-butyldimethylsilyloxy) ethyl] imidazolidin-2-one (compound obtained in Reference Example 65) 2 g of tetrahydrofuran / toluene ( To the 15 mL / 15 mL) solution, 3.92 mL of n-butyllithium hexane solution (1.59 mol / L) was added dropwise at −80 ° C. over 10 minutes, and the mixture was stirred for 90 minutes. To the reaction mixture, 752 μL of trimethoxyborane was added and the mixture was stirred for 2 hours. To the reaction mixture was added 10 mL of saturated ammonium chloride solution, 1 mL of water and 0.5 mL of 85% aqueous phosphoric acid solution at 0 ° C., and the mixture was stirred for 90 minutes. The reaction mixture is extracted with ethyl acetate, the organic layer is dried over magnesium sulfate and concentrated. The resulting residue is purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 95/5 to 35/65). This gave 206.2 mg of the title compound as a colorless powder (yield: 11%).
MS (APCI) m / z; 383 [M + H] ^< +>.

Reference Example 84
1- [2- (tert-Butyldimethylsilyloxy) ethyl] -3- [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) Of phenyl] imidazolidin-2-one

2 g of 1- (4-bromo-2-fluorophenyl) -3- [2- (tert-butyldimethylsilyloxy) ethyl] imidazolidin-2-one (compound obtained in Reference Example 65) was referred to Reference Example 19 ( By treating in the same manner as in 2), 1.10 g of the title compound was obtained as a pale red solid (yield: 49%).
MS (APCI) m / z: 465 [M + H] ^< +>.

Reference Examples 85-98
By treating the corresponding starting material compound in the same manner as in Reference Example 84, the following compound was obtained.
Reference Example 85 1- [2- (tert-butyldimethylsilyloxy) ethyl] -3- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl ) Phenyl] imidazolidin-2-one

MS (APCI) m / z: 447 [M + H] ^< +>.
Reference Example 86 1- [2- (tert-Butyldimethylsilyloxy) ethyl] -3- [2-methyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane -2-yl) phenyl] imidazolidin-2-one

MS (APCI) m / z: 461 [M + H] ^< +>.
Reference Example 87 1- [2-Methyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] -3- [3- (tetrahydropyran) -2-yloxy) propyl] imidazolidin-2-one

MS (APCI) m / z: 445 [M + H] ^< +>.
Reference Example 88 (S) -4- (tert-butyldimethylsilyloxy) -1- [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane- 2-yl) phenyl] pyrrolidin-2-one

MS (APCI) m / z: 436 [M + H] ^< +>.
Reference Example 89 (R) -4- (tert-butyldimethylsilyloxy) -1- [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane- 2-yl) phenyl] pyrrolidin-2-one

MS (APCI) m / z: 436 [M + H] ^< +>.
Reference Example 90 (R) -4- (tert-butyldimethylsilyloxy) -1- [2-methyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane- 2-yl) phenyl] pyrrolidin-2-one

MS (APCI) m / z: 432 [M + H] ^< +>.
Reference Example 91 (R) -4- (tert-Butyldimethylsilyloxy) -1- [3-methyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane- 2-yl) phenyl] pyrrolidin-2-one

MS (APCI) m / z: 432 [M + H] ^< +>.
Reference Example 92 4- [2-Fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] -3-oxopiperazine-1-carvone Acid tert-butyl ester

MS (APCI) m / z: 421 [M + H] ^< +>.
Reference Example 93 (S) -5- (tert-Butyldimethylsilyloxymethyl) -1- [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane -2-yl) phenyl] pyrrolidin-2-one

MS (APCI) m / z: 450 [M + H] ^< +>.
Reference Example 94 [3-Methyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] carbamic acid tert-butyl ester

MS (APCI) m / z: 351 [M + H] ^< +>.
Reference Example 95 [2-Methyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] carbamic acid tert-butyl ester

MS (APCI) m / z: 351 [M + H] ^< +>.
Reference Example 96 1- [2-Fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] -3- [2-methyl-2 -(Tetrahydropyran-2-yloxy) propyl] imidazolidin-2-one

Reference Example 97 (R) -5- (tert-Butyldimethylsilyloxymethyl) -3- [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane -2-yl) phenyl] oxazolidin-2-one

MS (APCI) m / z: 452 [M + H] ^< +>.
Reference Example 98 2- (2-Oxopyrrolidin-1-yl) -5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzonitrile

MS (APCI) m / z: 313 [M + H] ^< +>.

Reference Example 99
Preparation of 8-iodo-3H-quinazolin-4-one

(1) To a solution of 25.4 g of sodium sulfate in 680 mL of water were added 35.5 g of chloral hydrate and 39.2 g of 2-iodoaniline, 44.06 g of hydroxylamine sulfate, 7.6 mL of concentrated hydrochloric acid, and 260 mL of ethanol, and the mixture Was stirred at 80 ° C. for 2 hours. The reaction mixture is cooled to room temperature and further stirred under ice-cooling, and the precipitated crystals are collected by filtration, washed with water and dried to give 27.7 g of 2- (hydroxyimino) -N- (2-iodophenyl) acetamide. Was obtained as a tan powder (yield 53%).
MS (APCI) m / z; 291 [M + H] ⁺
(2) A solution of 27.7 g of the compound obtained in (1) above in 150 mL of concentrated sulfuric acid was stirred at 75 ° C. for 1 hour. The reaction mixture was poured into 500 mL of ice water, stirred for 1 hour under ice cooling, the precipitated crystals were collected by filtration, washed with water and dried to give a crude product of 7-iodo-1H-indole-2,3-dione. 27.1 g was obtained as a reddish brown powder.
MS (APCI) m / z; 274 [M + H] +, 306 [M + MeOH] ⁺
(3) 27.1 g of the compound obtained in (2) above was added to a solution of 22.9 g of sodium hydroxide in 180 mL of water, and 22.5 mL of 30% hydrogen peroxide was slowly added dropwise to the mixture under ice cooling. Stir at room temperature for 1 hour. After slowly adding 97 mL of 6N hydrochloric acid to the reaction mixture under ice cooling, the mixture was stirred for 1 hour. 150 mL of water was added to the mixed solution, and the mixture was stirred at room temperature. The precipitated crystals were collected by filtration, washed with water, and dried at 50 ° C., whereby 20.8 g of 2-amino-3-iodo-benzoic acid was obtained as a light brown powder. (Yield 83% (total of two stages from (2))).
MS (APCI) m / z; 264 [M + H] ⁺
(4) To 20.7 g of the compound obtained in (3) above, 100 mL of formamide was added, and the mixture was stirred at 150 ° C. for 6 hours. The reaction mixture was cooled to room temperature, 400 mL of water was added, and the mixture was stirred for 30 minutes. The precipitated crystals were collected by filtration and washed successively with water and diethyl ether to give 8-iodo-3H-quinazolin-4-one. 2 g was obtained as a brown powder (yield 85%).
MS (APCI) m / z; 273 [M + H] ^< +>.

Reference Example 100
Preparation of 8-bromo-3H-quinazolin-4-one

The corresponding starting material compound (20.13 g) was treated in the same manner as in Reference Example 1 (4) to obtain 18.97 g of 8-bromo-3H-quinazolin-4-one (yield 90%).
MS (APCI) m / z: 225/227 [M + H] ^< +>.

Reference Example 101
Preparation of 4-chloro-8-iodo-quinazoline

1 drop of DMF was added to 4.5 mL of a solution of 8-iodo-3H-quinazolin-4-one (the compound obtained in Reference Example 99) in 450 mg of thionyl chloride, and the mixture was refluxed at 80 ° C. overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated, and the resulting crystals were washed with diisopropyl ether and collected by filtration to give 329 mg of the title compound as a light brown solid (yield 69%).
MS (APCI) m / z; 291, 293 [M + H] ^< +>.

Reference Example 102
Preparation of 8-bromo-4-chloro-quinazoline

The corresponding starting compound 5g was treated in the same manner as in Reference Example 4 to obtain 4.85 g of 8-bromo-4-chloro-quinazoline (yield 90%).
MS (APCI) m / z: 243/245 [M + H] ^< +>.

Reference Example 103
Preparation of 4- (5-difluoromethyl- [1,2,4] oxadiazol-3-yl) piperidine-1-carboxylic acid tert-butyl ester

4- (N-hydroxycarbamimidoyl) piperidine-1-carboxylic acid tert-butyl ester (compound obtained in Reference Example 8 (1)) 973 mg and difluoroacetic acid ethyl ester 4 ml were stirred at 100 ° C. for 14 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate: 90 / 10-80 / 20) to give 757 mg of the title compound as a colorless oil ( Yield: 62.4%).
MS (APCI) m / z; 204 [M + H-Boc] ^<+> .

Reference Example 104
Preparation of 4- [5- (1-acetyl-1-methylethyl)-[1,2,4] oxadiazol-3-yl] piperidine-1-carboxylic acid tert-butyl ester

4- (N-hydroxycarbamimidoyl) piperidine-1-carboxylic acid tert-butyl ester (compound obtained in Reference Example 8 (1)) 973 mg, triethylamine 669 μL in 10 ml toluene solution under ice-cooling, 2-acetoxy A solution of 630 μL of 2-methylpropionic acid in 2 ml of toluene was slowly added dropwise. The mixture was stirred at room temperature for 20 minutes and then stirred at 120 ° C. for 5.5 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (solvent; hexane / ethyl acetate: 80/20 to 65/35) to give 1183 mg of the title compound as a pale yellow oil ( Yield: 83.7%).
MS (APCI) m / z; 354 [M + H] +.

Reference Example 105
Preparation of 4- [5- (1,1-difluoroethyl)-[1,2,4] oxadiazol-3-yl] piperidine-1-carboxylic acid tert-butyl ester

To a solution of 500 mg of 2,2-difluoropropionic acid in 15 mL of dimethylformamide, [dimethylamino-([1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methylene] dimethylammonium hexafluorophosphate (HATU ) 1711 mg and 1.31 mL of diisopropylethylamine were sequentially added, and the mixture was stirred for 25 minutes. To the reaction mixture, 730 mg of 4- (N-hydroxycarbamimidoyl) piperidine-1-carboxylic acid tert-butyl ester (the compound obtained in Reference Example 8- (1)) was added, and the mixture was stirred at room temperature for 21 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate: 90 / 10-80 / 20) to give 592.5 mg of the title compound as a pale yellow oil (yield: 62. 2%).
MS (APCI) m / z; 318 [M + H] +.

Reference Example 106
4- [5- (1,1-difluoroethyl)-[1,2,4] oxadiazol-3-yl] piperidine-1-carboxylic acid tert-butyl ester, and 4- [5-dimethylamino- [ 1,2,4] Oxadiazol-3-yl] piperidine-1-carboxylic acid tert-butyl ester

To a solution of 920 mg of 4- (N-hydroxycarbamimidoyl) piperidine-1-carboxylic acid tert-butyl ester (compound obtained in Reference Example 8 (1)) in 23 mL of methylene chloride was added [dimethylamino-([1, 2,3] triazolo [4,5-b] pyridin-3-yloxy) methylene] dimethylammonium hexafluorophosphate (HATU) 1725 mg, 2,2-difluoro-propionic acid 500 mg, and diisopropylethylamine 1.32 mL were sequentially added at room temperature. And stirred for 26.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate: 95/5 to 40/60) to give 4- [5- (1,1-difluoroethyl)-[1,2, 4] oxadiazol-3-yl] piperidine-1-carboxylic acid tert-butyl ester (Compound R106A) (193 mg, yield: 16.1%) as a colorless oil, 4- [5-dimethylamino- [1 , 2,4] oxadiazol-3-yl] piperidine-1-carboxylic acid tert-butyl ester (Compound R106B) (489 mg, yield: 43.6%) was obtained as a pale yellow solid.
(Compound R106A): MS (APCI) m / z; 318 [M + H] ⁺
(Compound R106B): MS (APCI) m / z; 297 [M + H] ⁺ .

Reference Examples 107-110
The following compounds were obtained by treating the corresponding raw material compounds in the same manner as in Reference Example 8 (3).
Reference Example 107 4- (5-Difluoromethyl- [1,2,4] oxadiazol-3-yl) piperidine hydrochloride

MS (APCI) m / z; 204 [M + H] +.
Reference Example 108 4- [5- (1-Acetyl-1-methylethyl)-[1,2,4] oxadiazol-3-yl] piperidine hydrochloride

MS (APCI) m / z; 254 [M + H] +.
Reference Example 109 4- [5- (1,1-difluoroethyl)-[1,2,4] oxadiazol-3-yl] piperidine hydrochloride

MS (APCI) m / z; 218 [M + H] +.
Reference Example 110 4- [5-Dimethylamino- [1,2,4] oxadiazol-3-yl] piperidine dihydrochloride

MS (APCI) m / z; 197 [M + H] +.

Reference Examples 111-119
The following compounds were obtained by treating the corresponding raw material compounds in the same manner as in Reference Example 12.
Reference Example 111 8-Bromo-4- [4- (5-difluoromethyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] -6-fluoroquinazoline

MS (APCI) m / z; 428/430 [M + H] +.
Reference Example 112 Acetic acid 1- {3- [1- (8-bromo-6-fluoroquinazolin-4-yl) piperidin-4-yl]-[1,2,4] oxadiazol-5-yl} -1-methyl ethyl ester

MS (APCI) m / z; 478/480 [M + H] +.
Reference Example 113 8-Bromo-6-fluoro-4- [4- (2-propyl-2H-tetrazol-5-yl) piperidin-1-yl] quinazoline

MS (APCI) m / z; 420/422 [M + H] +.
Reference Example 114 8-Bromo-6-fluoro-4- [4- (2-isopropyl-2H-tetrazol-5-yl) piperidin-1-yl] quinazoline

MS (APCI) m / z; 420/422 [M + H] +.
Reference Example 115 8-iodo-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline

MS (APCI) m / z; 450 [M + H] +.
Reference Example 116 8-Bromo-4- [4- (5-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline

MS (APCI) m / z; 402/404 [M + H] +.
Reference Example 117 8-Bromo-4- {4- [5- (1,1-difluoroethyl)-[1,2,4] oxadiazol-3-yl] piperidin-1-yl} quinazoline

MS (APCI) m / z; 424/426 [M + H] +.
(Reference Example 118)
{3- [1- (8-Bromo-quinazolin-4-yl) piperidin-4-yl]-[1,2,4] oxadiazol-5-yl} dimethylamine

MS (APCI) m / z; 403/405 [M + H] +.
Reference Example 119 8-Iodo-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazoline

MS (APCI) m / z; 450 [M + H] +.

Reference Example 120
Preparation of 8-bromo-5-fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazoline

  The corresponding starting material compound was treated in the same manner as in Reference Example 18 to give the title compound (2662 mg) as a pale yellow solid (yield: 77%).

MS (APCI) m / z: 420/422 [M + H] ^< +>.

Reference Examples 121-124
By treating the corresponding starting material compound in the same manner as in Reference Example 25, the following compound was obtained.
Reference Example 121 8-Bromo-5-fluoro-4- [4- (5-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline

MS (APCI) m / z; 420/422 [M + H] +.
Reference Example 122 8-Bromo-4- [4- (5-cyclopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] -5-fluoroquinazoline

MS (APCI) m / z; 418/420 [M + H] +.
Reference Example 123 8-Bromo-5-fluoro-4- [4- (5-trifluoromethyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline

MS (APCI) m / z; 446/448 [M + H] +.
Reference Example 124 8-bromo-4- {4- [5- (1,1-difluoroethyl)-[1,2,4] oxadiazol-3-yl] piperidin-1-yl} -5- Fluoroquinazoline

MS (APCI) m / z; 442/444 [M + H] +.

Reference Example 125
Of 2- {3- [1- (8-Bromo-6-fluoroquinazolin-4-yl) piperidin-4-yl]-[1,2,4] oxadiazol-5-yl} propan-2-ol Manufacturing

1- {3- [1- (8-Bromo-6-fluoroquinazolin-4-yl) piperidin-4-yl]-[1,2,4] oxadiazol-5-yl} -1-methylethyl acetate 345 mg of the ester (compound obtained in Reference Example 112) was treated in the same manner as in Example 11 to obtain 282 mg of the title compound as a colorless solid (yield: 89.6%).
MS (APCI) m / z; 436/438 [M + H] +.

Reference Example 126
8-bromo-6-fluoro-4- {4- [5- (1-fluoro-1-methylethyl)-[1,2,4] oxadiazol-3-yl] piperidin-1-yl} quinazoline Manufacturing

2- {3- [1- (8-Bromo-6-fluoroquinazolin-4-yl) piperidin-4-yl]-[1,2,4] oxadiazol-5-yl} propan-2-ol ( The title compound (125 mg) was obtained as a colorless solid by treating 201 mg of the compound obtained in Reference Example 125 in the same manner as in Example 100 (yield: 61.9%).
MS (APCI) m / z; 438/440 [M + H] +.

Reference Example 127
Preparation of 2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzoic acid tert-butyl ester

  (1) To a solution of 5.00 g of 4-bromo-2-fluorobenzoic acid in 80 mL of methylene chloride, 8.75 mL of tert-butanol, 418 mg of 4-dimethylaminopyridine and 1-ethyl-3- (3-dimethyl) were cooled with ice. 5.25 g of aminopropyl) carbodiimide hydrochloride was added and the mixture was stirred at room temperature for 19 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (solvent; hexane / ethyl acetate = 100/0 to 93/7) to give 2-fluoro-4-bromobenzoic acid tert-butyl ester. 2.00 g was obtained as a colorless liquid (yield 32%).

(2) By treating 2.00 g of the compound obtained in (1) above in the same manner as in Reference Example 19 (2), 1.71 g of the title compound was obtained as a colorless liquid (yield: 73%).
MS (APCI) m / z: 323 [M + H] ^< +>.

Reference Example 128
2-Fluoro-4- [6-fluoro-4- [4- (5-trifluoromethyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] Production of benzoic acid and hydrochloride

(1) 8-Bromo-6-fluoro-4- [4- (5-trifluoromethyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline (in Reference Example 165) 680 mg of the obtained compound), 2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzoic acid tert-butyl ester (obtained in Reference Example 127) Compound) 638 mg, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride-dichloromethane complex 125 mg and cesium carbonate 2993 mg in 1,4-dioxane / water (24 mL / 6 mL) in a nitrogen atmosphere The mixture was stirred at 80 ° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (solvent; hexane / ethyl acetate: 90/10 to 75/25) to give 2-fluoro-4- [6-fluoro-4. There was obtained 545 mg of-[4- (5-trifluoromethyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] benzoic acid tert-butyl ester. (Rate: 64%).
MS (APCI) m / z: 562 [M + H] ^< +>.

(2) 14N of 4N hydrochloric acid-dioxane solution was added to 5 mL of 1,4-dioxane in 545 mg of the compound obtained in (1) above and stirred at room temperature for 19 hours. The reaction mixture was concentrated under reduced pressure, and the residue was triturated with diethyl ether to give 530 mg of the title compound as a colorless powder (yield: 100%).
MS (APCI) m / z: 506 [M + H] ^< +>.

Reference Examples 129 to 132
By treating the corresponding starting material compound in the same manner as in Reference Example 128, the following compound was obtained.
Reference Example 129 2-Fluoro-4- {5-fluoro-4- [4- (5-trifluoromethyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline -8-yl] benzoic acid hydrochloride

MS (APCI) m / z; 506 [M + H] ^< +>.
Reference Example 130 2-Fluoro-4- [5-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline-8 -Il] benzoic acid hydrochloride

MS (APCI) m / z; 480 [M + H] ^< +>.
Reference Example 131 4- (4- {4- [5- (1,1-difluoroethyl)-[1,2,4] oxadiazol-3-yl] piperidin-1-yl} -5-fluoro Quinazolin-8-yl] -2-fluorobenzoic acid hydrochloride

MS (APCI) m / z; 502 [M + H] ^< +>.
Reference Example 132 4- [5-Fluoro-4- [4- (5-trifluoromethyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] -2-Methylbenzoic acid hydrochloride

MS (APCI) m / z; 502 [M + H] ^< +>.

Reference Examples 133-134
The following compound was obtained by treating the compound obtained by treating the corresponding starting material compound in the same manner as in Reference Example 49 with a saturated aqueous sodium hydrogen carbonate solution.
Reference Example 133 4- {4- [4- (5-Cyclopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] -6-fluoroquinazolin-8-yl} -2-Fluorophenylamine

MS (APCI) m / z; 449 [M + H] +.
Reference Example 134 3-Fluoro-4- {6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline-8 -Yl} phenylamine

MS (APCI) m / z; 451 [M + H] ^< +>.

Reference Example 135
3- (4-Bromo-2-fluorophenyl) -1- (2,4-dimethoxybenzyl) tetrahydropyrimidin-4-one

(1) To a solution of 3.8 g of 4-bromo-2-fluorophenylamine in 12 mL of methylene chloride was added 1.7 mL of acrylic acid chloride at room temperature, 12 mL of methylene chloride was added, and the mixture was stirred at room temperature for 2 hours. Further, 12 mL of methylene chloride was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. Then, 325 μL of acrylic acid chloride was added thereto, and the mixture was stirred at room temperature for 23.5 hours. Water was added to the reaction mixture under ice cooling, and the mixture was stirred for 5 minutes and then concentrated under reduced pressure. The obtained residue was extracted with ethyl acetate, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was washed with diethyl ether and then dried under reduced pressure to obtain 3797 mg of N- (4-bromo-2-fluorophenyl) acrylamide as a colorless powder (yield: 77. 8%).
MS (APCI) m / z; 244/246 [M + H] ^< +>.

(2) A solution of 244 mg of the compound obtained in (1) above and 451 μL of 2,4-dimethoxybenzylamine in 1 mL of toluene was stirred at 80 ° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the obtained residue was purified by NH-silica gel column chromatography (Chromatorex; Fuji Silysia Chemical, solvent; hexane / ethyl acetate: 70/30 to 50/50) to give N- (4- 413 mg of bromo-2-fluorophenyl) -3- (2,4-dimethoxybenzylamino) propionamide was obtained as a colorless powder (yield: 100%).
MS (APCI) m / z; 411/413 [M + H] ^< +>.

(3) A mixture of 393 mg of the compound obtained in (2) above, 2 mL of a 37% formalin aqueous solution and 3 mL of tetrahydrofuran was stirred at room temperature for 9 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the obtained residue was purified by NH-silica gel column chromatography (Chromatorex; Fuji Silysia Chemical, solvent; hexane / ethyl acetate: 75/25 to 43/57) to give 351.6 mg of the title compound. Was obtained as a colorless powder (yield: 86.9%).
MS (APCI) m / z; 423/425 [M + H] ^< +>.

Reference Example 136
Preparation of 3- (4-bromo-2-fluorophenyl) -1- (2,4-dimethoxybenzyl) imidazolidin-4-one

(1) To a solution of 3.8 g of 4-bromo-2-fluorophenylamine and 4.18 mL of triethylamine in 100 mL of tetrahydrofuran was added 2.16 mL of bromoacetic acid chloride under ice cooling, followed by stirring for 1 hour under ice cooling. The reaction mixture was further stirred at room temperature for 3 days and concentrated under reduced pressure. To the obtained residue, 100 mL of 0.5N hydrochloric acid was added and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. To a 200 mL solution of the obtained residue in methylene chloride, 5.24 mL of diisopropylethylamine and 6.0 mL of 2,4-dimethoxybenzylamine were sequentially added at room temperature, and the mixture was stirred at room temperature for 18 hours. To the reaction mixture was added 300 mg of sodium iodide, and the mixture was stirred at room temperature for 21 hours and then stirred under reflux for 5.5 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate: 75 / 25-25 / 75) to give N- (4-bromo-2-fluorophenyl) -2- (2,4 -Dimethoxybenzylamino) acetamide 5.68 g was obtained as a brown oil (yield: 71.5%).
MS (APCI) m / z; 397/399 [M + H] ^< +>.

(2) A mixture of the compound obtained in (1) (1.53 g), 37% formalin aqueous solution (6.2 mL), and tetrahydrofuran (11.8 mL) was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with diisopropyl ether and dried under reduced pressure to give 1.21 g of the title compound as a colorless powder (yield: 76.8%).
MS (APCI) m / z; 409/411 [M + H] ^< +>.

Reference Example 137
Preparation of 3- (4-bromo-2-fluorophenyl) -1- [2- (tert-butyldimethylsilyloxy) ethyl] imidazolidin-4-one

(1) To a solution of 3.8 g of 4-bromo-2-fluorophenylamine and 4.18 ml of triethylamine in 100 mL of tetrahydrofuran was added 2.16 mL of bromoacetic acid chloride under ice cooling, and the mixture was stirred for 1 hour under ice cooling. The mixture was further stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, 100 mL of 0.5N hydrochloric acid was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. To a solution of the obtained residue in tetrahydrofuran (60 mL) was added diisopropylethylamine (6.99 mL), 2-aminoethanol (3.62 mL) and sodium iodide (300 mg) at room temperature, and the mixture was stirred with heating under reflux for 20 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: chloroform / methanol: 100/0 to 85/15) to give N- (4-bromo-2-fluorophenyl) -2- (2-hydroxyethyl). 2.02 g of amino) acetamide was obtained as a brown solid (yield: 69.5%).
MS (APCI) m / z; 291/293 [M + H] ^< +>.

(2) By treating 1.75 g of the compound obtained in (1) in the same manner as in Reference Example 135 (3), 3- (4-bromo-2-fluorophenyl) -1- [2-hydroxyethyl ] 1.75 g of imidazolidin-4-one was obtained as a yellow oil (yield: 95.9%).
MS (APCI) m / z; 303/305 [M + H] ^< +>.

(3) By treating 1.82 g of the compound obtained in the above (2) in the same manner as in Reference Example 69, 2.3 g of the title compound was obtained as a pale yellow oil (yield: 92.1%).
MS (APCI) m / z; 417/419 [M + H] ^< +>.

Reference Examples 138 to 139
By treating the corresponding starting material compound in the same manner as in Reference Example 69, the following compound was obtained.
Reference Example 138 (S) -3- (tert-Butyldimethylsilyloxy) pyrrolidin-2-one

MS (APCI) m / z; 216 [M + H] ^< +>.
Reference Example 139 (R) -3- (tert-Butyldimethylsilyloxy) pyrrolidin-2-one

MS (APCI) m / z; 216 [M + H] ^< +>.

Reference examples 140-142
By treating the corresponding starting material compound in the same manner as in Reference Example 72, the following compound was obtained.
Reference Example 140 (S) -1- (4-Bromo-2-fluorophenyl) -3- (tert-butyldimethylsilyloxy) pyrrolidin-2-one

MS (APCI) m / z; 388/390 [M + H] ^< +>.
Reference Example 141 (R) -1- (4-Bromo-2-fluorophenyl) -3- (tert-butyldimethylsilyloxy) pyrrolidin-2-one

MS (APCI) m / z; 388/390 [M + H] ^< +>.
Reference Example 142 (S) -1- (4-Bromo-2-methylphenyl) -3- (tert-butyldimethylsilyloxy) pyrrolidin-2-one

MS (APCI) m / z; 384/386 [M + H] ^< +>.

Reference Example 143
Preparation of 1- (4-bromo-2-fluorophenyl) -3- [2- (tert-butyldimethylsilyloxy) ethyl] tetrahydropyrimidin-2-one

The corresponding starting material compound was treated in the same manner as in Reference Example 65 to give the title compound (2358 mg) as a pale yellow solid (yield: 38.7%).
MS (APCI) m / z; 431/433 [M + H] ^< +>.

Reference examples 144-145
The corresponding compound was treated in the same manner as in Example 99 to obtain the following compound.
Reference Example 144 1- (4-Bromo-2-fluorophenyl) pyrrolidin-2-one

MS (APCI) m / z; 258/260 [M + H] ^< +>.
Reference Example 145 1- (4-Bromo-3-methylphenyl) pyrrolidin-2-one

MS (APCI) m / z; 254/256 [M + H] ^< +>.

Reference Example 146
Preparation of 4-bromo-2-methylbenzoic acid tert-butyl ester

The corresponding starting material compound was treated in the same manner as in Reference Example 127 (1) to give the title compound (5585 mg) as a pale yellow viscous oil (yield: 51.5%).
MS (APCI) m / z; 271/273 [M + H] ^< +>.

Reference Example 147
Preparation of (4-bromo-3-fluorophenyl) carbamic acid tert-butyl ester

The corresponding starting material compound was treated in the same manner as in Reference Example 78 to give the title compound (12.19 g) as a colorless solid (yield: 73.8%).
MS (APCI) m / z; 290/292 [M + H] ^< +>.

Reference Examples 148-159
The following compounds were obtained by treating the corresponding starting compounds in the same manner as in Reference Example 19 (2).
Reference Example 148 1- (2,4-dimethoxybenzyl) -3- [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) Phenyl] tetrahydro-pyrimidin-4-one

MS (APCI) m / z; 471 [M + H] ^< +>.
Reference Example 149 1- (2,4-Dimethoxybenzyl) -3- [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) Phenyl] imidazolidin-4-one

MS (APCI) m / z; 457 [M + H] ^< +>.
Reference Example 150 1- [2- (tert-butyldimethylsilyloxy) ethyl] -3- [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane -2-yl) phenyl] imidazolidin-4-one

MS (APCI) m / z; 465 [M + H] ^< +>.
Reference Example 151 (S) -3- (tert-butyldimethylsilyloxy) -1- [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane- 2-yl) phenyl] pyrrolidin-2-one

MS (APCI) m / z; 436 [M + H] ^< +>.
Reference Example 152 (R) -3- (tert-butyldimethylsilyloxy) -1- [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane- 2-yl) phenyl] pyrrolidin-2-one

MS (APCI) m / z; 436 [M + H] ^< +>.
Reference Example 153 (S) -3- (tert-Butyldimethylsilyloxy) -1- [2-methyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane- 2-yl) phenyl] pyrrolidin-2-one

MS (APCI) m / z; 432 [M + H] ^< +>.
Reference Example 154 1- [2- (tert-butyldimethylsilyloxy) ethyl] 3- [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane- 2-yl) phenyl] tetrahydro-pyrimidin-2-one

MS (APCI) m / z; 479 [M + H] ^< +>.
Reference Example 155 1- [2-Fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] pyrrolidin-2-one

MS (APCI) m / z; 306 [M + H] ^< +>.
Reference Example 156 1- [3-Methyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] pyrrolidin-2-one

MS (APCI) m / z; 302 [M + H] ^< +>.
Reference Example 157 2-Methyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzoic acid tert-butyl ester

MS (APCI) m / z; 336 [M + NH4] ^< +>.
Reference Example 158 [3-Fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] carbamic acid tert-butyl ester

MS (APCI) m / z; 338 [M + H] ^< +>.

Reference Example 159
Production of (2S, 4R) -4-hydroxypiperidine-2-carbonitrile hydrochloride

  (1) (2S, 4R) -4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 1.0 g of triethylamine 663 μL and ethyl chloroformate 455 μL were added under ice cooling to a tetrahydrofuran 17 mL solution, and the mixture Was stirred for 30 minutes. To the reaction mixture, 28% aqueous ammonia was added at the same temperature, and the mixture was stirred at room temperature for 18 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated, and the obtained residue was purified by silica gel column chromatography (solvent: chloroform / methanol = 95/5 → 80/20) to give (2S, 4R) -2-carbamoyl-4-hydroxy- 216 mg of pyrrolidine-1-carboxylic acid tert-butyl ester was obtained (22% yield).

(2) To a solution of 1.15 g of the compound obtained in (1) above in 12 mL of pyridine, 1.77 mL of trifluoroacetic anhydride was added at −20 ° C., and the mixture was stirred at room temperature for 21 hours. Water and ethyl acetate were added to the reaction mixture, which was then washed successively with 2N hydrochloric acid, 2N aqueous sodium hydroxide solution and saturated brine, and the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain (2S, 4R) -2-cyano-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as a crude product. To a 9 mL dichloromethane solution of the compound was added 4N hydrochloric acid-dioxane solution (8.9 mL), and the mixture was stirred at room temperature for 1 hour. Hexane was added to the reaction mixture, and the precipitated crystals were collected by filtration and dried under reduced pressure to give 460 mg of the title compound (yield 62%).
MS (APCI) m / z; 113 [M + H] ^< +>.

Reference Example 160
Preparation of 1- (8-bromo-6-fluoroquinazolin-4-yl) piperidine-4-carbonitrile

The corresponding starting material compound was treated in the same manner as in Reference Example 12 to give the title compound (2396 mg) as a colorless solid (yield: 89.4%).
MS (APCI) m / z; 335/337 [M + H] ^< +>.

Reference Example 161
1- (2,4-Dimethoxybenzyl) -3- (2-fluoro-4- {6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) Piperidin-1-yl] quinazolin-8-yl} phenyl) tetrahydropyrimidin-4-one

The corresponding starting material compound was treated in the same manner as in Example 1 to obtain the title compound (301.7 mg) as a brown solid (yield: 95.1%).
MS (APCI) m / z; 684 [M + H] ^< +>.

Reference Examples 162-163
By treating the corresponding starting material compound in the same manner as in Reference Example 38, the following compound was obtained.
Reference Example 162 6-Fluoro-8- [3-fluoro-4- [2- (tetrahydropyran-2-yloxy) ethoxy] phenyl] -4- [4- (5-isopropyl- [1,2,4] ] Oxadiazol-3-yl] piperidin-1-yl] quinazoline

MS (APCI) m / z: 580 [M + H] ^< +>.
Reference Example 163 6-Fluoro-8- [3-fluoro-4- [2- (tetrahydropyran-2-yloxy) ethoxy] phenyl] -4- [4- (5-cyclopropyl- [1,2, 4] Preparation of oxadiazol-3-yl] piperidin-1-yl] quinazoline

MS (APCI) m / z: 578 [M + H] ^< +>.

Reference Example 164
Preparation of 2- [3-fluoro-4- [2- (2-tetrahydropyranyloxy) ethoxy] phenyl] -4,4,5,5-tetramethyl- [1,3,2] dioxaborolane

The corresponding starting material compound was treated in the same manner as in Reference Example 19 to give the title compound (1.02 g) as an oil (yield: 53%).
MS (APCI) m / z: 384 [M + H] ^< +>.

Reference Example 165
Preparation of 8-bromo-6-fluoro-4- [4- (5-trifluoromethyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline

The corresponding starting material compound was treated in the same manner as in Reference Example 12 to give the title compound (2.26 g) as a powder (yield: 95%).
MS (APCI) m / z: 446/448 [M + H] ^< +>.

Reference Example 166
Preparation of 4- (2-propyl-2H-tetrazol-5-yl) piperidine hydrochloride

(1) To a solution of 5.00 g of 4-cyanopiperidine-1-carboxylic acid in 30 mL of dimethylformamide, 3.86 g of sodium azide and 3.45 g of ammonium chloride were added, and the mixture was stirred at 100 ° C. for 18 hours. A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (solvent: chloroform / methanol = 99 / 1-80 / 20) to give 4- (2H-tetrazol-5-yl) piperidine-1-carboxylic acid tert-butyl ester 4.75 g was obtained as a colorless powder (yield 79%).
MS (APCI) m / z: 254 [M + H] ^< +>.

(2) To a solution of the compound 2.20 g obtained in the above (1) in 22 mL of dimethylformamide, 2.40 g of potassium carbonate and 1.27 mL of propyl iodide were added, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (solvent: hexane / ethyl acetate = 75 / 25-35 / 65) to give 4- (2-propyl-2H-tetrazol-5-yl) piperidine-1-carboxyl 2.04 g of acid tert-butyl ester was obtained as a colorless liquid (yield 80%).
MS (APCI) m / z: 296 [M + H] ^< +>.

(3) By treating 2.04 g of the compound obtained in the above (2) in the same manner as in Reference Example 5 (3), 1.55 g of the title compound was obtained as a colorless powder (yield: 97%).
MS (APCI) m / z: 196 [M + H] ^< +>.

Reference Example 167
Preparation of 1- [2-methyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl] -pyrrolidin-2-one

(1) By treating 3.00 g of 4-bromo-2-methyl-phenylamine and 4-chlorobutyryl chloride (2.71 mL) in the same manner as in Example 99, 1- (4-bromo-2-methyl) -Phenyl) -pyrrolidin-2-one 3.75 g was obtained as a colorless solid (yield 92%).
MS (APCI) m / z; 254, 256 [M + H] ⁺
(2) By treating 2.70 g of the compound obtained in the above (1) in the same manner as in Reference Example 19 (2), 1.21 g of the title compound was obtained as a colorless solid (yield 38%).
MS (APCI) m / z; 302 [M + H] ⁺
Reference Example 168
Of 1- [2- [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] -2-oxoethyl] pyrrolidin-2-one Manufacturing

  (1) To a solution of 1.50 g of 4-bromo-2-fluoroacetophenone in 90 mL of dichloromethane / methanol (2/1) was added 3.33 g of tetra-N-butylammonium tribromide, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was produced by silica gel column chromatography (hexane / ethyl acetate = 95/5 to 85/15) to give 2-bromo-1- (4-bromo-2-fluoro). 1.88 g of phenyl) ethanone was obtained as a crude product.

(2) 400 mg of the compound obtained in (1) above and 4 mL of DMF solution of 147 mg of 2-methoxy-1-pyrroline were stirred at 60 ° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 50 / 50-0 / 100) to give 1- [2- (4-bromo-2-fluorophenyl). ) -2-oxoethyl] pyrrolidin-2-one 281 mg was obtained as a colorless solid (total yield from step (1) 63%).
MS (APCI) m / z; 300/302 [M + H] ⁺
(3) 280 mg of the compound obtained in the above (2) was treated in the same manner as in Reference Example 19 (2) to give 222 mg of the title compound as a brown oil (yield 68%).
MS (APCI) m / z; 348 [M + H] ⁺
Reference Example 169
Preparation of (S) -1- [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzyl] pyrrolidine-2-carboxylic acid amide

(1) To 18 mL of acetonitrile solution of 502 mg of (S) -pyrrolidine-2-carboxamide, 1.07 g of 4-bromo-2-fluorobenzyl bromide and 613 μL of triethylamine were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 60 / 40-20 / 80) to give (S) -1- (4-bromo-2-fluorobenzyl) pyrrolidine-2-carboxamide. 995 mg was obtained as a colorless solid (yield 83%).
MS (APCI) m / z; 348 [M + H] ⁺
(2) By treating 990 mg of the compound obtained in the above (1) in the same manner as in Reference Example 19 (2), 285 mg of the title compound was obtained as a colorless solid (yield 25%).
MS (APCI) m / z; 349 [M + H] ⁺
Reference Example 170
Preparation of [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzyl] carbamic acid tert-butyl ester

(1) To 120 mL of a dichloromethane solution of 7.7 g of dicarboxylic acid ditert-butyl ester, 6 g of 4-bromo-2-fluorobenzylamine and 10.2 mL of diisopropylethylamine were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. By purifying the obtained residue by silica gel column chromatography (hexane / ethyl acetate = 95/5 to 85/15), 8.32 g of (4-bromo-2-fluorobenzyl) carbamic acid tert-butyl ester was colorless. Obtained as a solid (93% yield).
MS (APCI) m / z; 304,306 [M + H] ⁺
(2) By treating 1000 mg of the compound obtained in (1) in the same manner as in Reference Example 19 (2), 852 mg of the title compound was obtained as a colorless viscous oil (yield 74%).
MS (APCI) m / z; 252 [M + 2H-Boc] ⁺
Reference Example 171
Preparation of [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzyl] methylcarbamic acid tert-butyl ester

(1) 15 mL of a dimethyl sulfoxide solution of sodium hydride was cooled to 0 ° C., and (4-bromo-2-fluorobenzyl) carbamic acid tert-butyl ester (compound obtained in Reference Example 170 (1)) 1 0.5 g was added and the mixture was stirred for 15 minutes. To the reaction mixture, 0.34 mL of methyl iodide was added dropwise, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. By purifying the obtained residue by silica gel column chromatography (chloroform / ethyl acetate = 0/100 to 1/99), 1.46 g of (4-bromo-2-fluorobenzyl) methylcarbamic acid tert-ester was colorless. Obtained as a viscous oil (93% yield).
MS (APCI) m / z; 318,320 [M + H] ⁺
(2) By treating 1000 mg of the compound obtained in (1) in the same manner as in Reference Example 19 (2), 649 mg of the title compound was obtained as a colorless viscous oil (yield 59%).
MS (APCI) m / z; 366 [M + H] ⁺
Reference Example 172
Preparation of [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] acetic acid ethyl ester

By treating 2.00 g of ethyl (4-bromo-2-fluorophenyl) acetate in the same manner as in Reference Example 19 (2), 1.56 g of the title compound was obtained as a colorless solid (yield 66%).
MS (APCI) m / z; 309 [M + H] ⁺
Reference Example 173
Preparation of [2-Fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] acetic acid tert-butyl ester

(1) 3.5 mL of concentrated sulfuric acid was added to 200 mL of a dichloromethane solution of 31.5 g of magnesium sulfate, and the mixture was stirred for 15 minutes. To the reaction mixture were added 60 mL of a dichloromethane solution of 15.2 g of 4-bromo-2-fluorophenylacetic acid and 31.2 mL of tert-butyl alcohol, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, ice and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was stirred for 15 min. After separating the organic layer, the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 95/5 to 90/9) to give 16.6 g of (4-bromo-2-fluorophenyl) acetic acid tert-butyl ester as a colorless solid. (Yield 88%).
MS (APCI) m / z; 289,291 [M + H] ⁺
(2) By treating 580 mg of the compound obtained in the above (1) in the same manner as in Reference Example 19 (2), 358.7 mg of the title compound was obtained as a colorless solid (yield 53%).
MS (APCI) m / z; 354 [M + H] ⁺
Reference Example 174
Preparation of [3-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] acetic acid tert-butyl ester

  (1) 600 mg of 4-bromo-3-fluorophenylacetic acid and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride n hydrate (DMT- (MM) To 12 mL of 855 mg of tert-butyl alcohol was added 340 μL of N-methylmorpholine (NMM), and the mixture was stirred at 50 ° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added, extracted with ethyl acetate, washed successively with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 97 / 3-85 / 15) to give 509 mg of (4-bromo-3-fluorophenyl) acetic acid tert-butyl ester as a pale yellow viscous oil. (Yield 68%).

(2) By treating 500 mg of the compound obtained in (1) above in the same manner as in Reference Example 19 (2), 146 mg of the title compound was obtained as a pale yellow viscous oil (yield 25%).
MS (APCI) m / z; 436 [M + H] ⁺
Reference Example 175
(2-Fluoro-4- [6-fluoro-4- [4- (5-propyl- [1,2,4] oxadiazol-3-yl) -piperidin-1-yl] quinazolin-8-yl] Of phenyl) acetic acid

(1) 8-Bromo-6-fluoro-4- [4- (5-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline (obtained in Reference Example 13) Compound) 450 mg and [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] acetic acid ethyl ester (obtained in Reference Example 172) Compound) 396 mg was treated in the same manner as in Example 29 (1) to give 2-fluoro-4- [6-fluoro-4- [4- (5-propyl- [1,2,4] oxadiazole- 476 mg of ethyl 3-yl) piperidin-1-yl] quinazolin-8-yl] phenyl) acetate was obtained as a colorless solid (yield 85%).
MS (APCI) m / z; 522 [M + H] ⁺
(2) By treating 450 mg of the compound obtained in the preceding item (1) in the same manner as in Reference Example 29 (2), 361 mg of the title compound was obtained as a colorless solid (yield 85%).
MS (APCI) m / z; 494 [M + H] ⁺
Reference Example 176
(3-Fluoro-4- [6-fluoro-4- [4- (5-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenyl ) Production of acetic acid

(1) 8-Bromo-6-fluoro-4- [4- (5-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline (obtained in Reference Example 13) 150 mg) and [3-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] acetic acid tert-butyl ester (obtained in Reference Example 174) The obtained compound) was treated in the same manner as in Example 29 (1) to give 3-fluoro-4- [6-fluoro-4- [4- (5-propyl- [1,2,4] oxadi Azol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenyl) tert-butyl acetate 115 mg was obtained as a colorless solid (yield 59%).
MS (APCI) m / z; 550 [M + H] ⁺
(2) By treating 100 mg of the compound obtained in the preceding item (1) in the same manner as in Reference Example 128 (2), 95 mg of the title compound was obtained as a colorless powder (yield 100%).
MS (APCI) m / z; 494 [M + H] ⁺
Reference Example 177
(4- [4 [4- (5-Cyclopropyl- [1,2,4] oxadiazol-3-yl)] piperidin-1-yl] -6-fluoroquinazolin-8-yl] -2-fluoro Of phenyl) acetic acid

(1) 8-Bromo-4- [4-4- (5-cyclopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] -6-fluoroquinazoline (Reference Example 14) Compound) and 500 mg of [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] acetic acid ethyl ester (in Reference Example 172) The obtained compound) (553 mg) was treated in the same manner as in Reference Example 29 (1) to give (4- [4 [4- (5-cyclopropyl- [1,2,4] oxadiazol-3-yl). ] Piperidin-1-yl] -6-fluoro-quinazolin-8-yl] -2-fluorophenyl) ethyl acetate (276 mg) was obtained as a colorless solid (44% yield).
MS (APCI) m / z; 520 [M + H] ⁺
(2) By treating 220 mg of the compound obtained in the preceding item (1) in the same manner as in Reference Example 29 (2), 198 mg of the title compound was obtained as a colorless solid (yield 95%).
MS (APCI) m / z; 492 [M + H] ⁺
Reference Example 178
[2-Fluoro-4- (6-fluoro-4- [4- [3- (2,2,2-trifluoroethyl)-[1,2,4] oxadiazol-5-yl] piperidine-1 -Il] quinazolin-8-yl) phenyl] acetic acid

(1) 8-Bromo-6-fluoro-4- [4- [3- (2,2,2-trifluoroethyl)-[1,2,4] oxadiazol-5-yl] piperidine-1- Yl] quinazoline (the compound obtained in Reference Example 17) and [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] acetic acid By treating 553 mg of tert-butyl ester (compound obtained in Reference Example 173) in the same manner as in Reference Example 128 (1), [2-fluoro-4- (6-fluoro-4- [4- [3- ( 2,2,2-trifluoroethyl)-[1,2,4] oxadiazol-5-yl] piperidin-1-yl] quinazolin-8-yl) phenyl] acetate 336 mg is obtained as a colorless solid. (Yield 79%).
MS (APCI) m / z; 590 [M + H] ⁺
(2) The compound obtained in (1) above was treated in the same manner as in Reference Example 128 (2) to give 77 mg of the title compound as a colorless solid (yield 23%).
MS (APCI) m / z; 534 [M + H] ⁺
Reference Example 179
(2-Fluoro-4- [6-fluoro-4- [4- (5-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] benzyl ) Production of tert-butyl methylcarbamate

8-Bromo-6-fluoro-4- [4- (5-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline (the compound obtained in Reference Example 13) 600 mg and [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzyl] methylcarbamic acid tert-butyl ester (obtained in Reference Example 171) Compound (626 mg) was treated in the same manner as in Example 1 to give the title compound (682 mg) as a colorless solid (yield 83%).
MS (APCI) m / z; 579 [M + H] ⁺
Reference Example 180
2-Fluoro-4- [6-fluoro-4- [4- (5-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] benzylamine Manufacturing of

(2-Fluoro-4- [6-fluoro-4- (5-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl) benzyl) carbamic acid To 12.2 mL of 610 mg of tert-butyl (the compound obtained in Example 133) in dichloromethane was added 6.1 mL of trifluoroacetic acid, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and water, dichloromethane and 1N aqueous sodium hydroxide solution were added to the resulting residue and stirred. The mixture was extracted with dichloromethane, and the organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by NH silica gel column chromatography (Fuji Silysia; hexane / ethyl acetate = 55 / 45-0 / 100) to give 410 mg of the title compound as a colorless solid ( Yield 82%).
MS (APCI) m / z; 465 [M + H] ⁺
Reference Example 181
(2-Fluoro-4- [6-fluoro-4- [4- (5-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] benzyl ) Production of methylamine

(2-Fluoro-4- [6-fluoro-4- [4- (5-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] benzyl ) Tert-butyl methylcarbamate (the compound obtained in Reference Example 179) was treated in the same manner as in Reference Example 180 to give 343 mg of the title compound as a colorless solid (yield 64%).
MS (APCI) m / z; 479 [M + H] ⁺
Reference Example 182
Acetic acid 1- (2-fluoro-4- [6-fluoro-4- [4- (5-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline-8- Yl] benzylcarbamoyl) -1-methylethyl ester

2-Fluoro-4- [6-fluoro-4- [4- (5-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] benzylamine (Compound obtained in Reference Example 180) and 27.1 μL of acetic acid 1-chlorocarbamoyl-1-methylethyl ester were treated in the same manner as in Example 9 to obtain 78.1 mg of the title compound as a colorless solid ( Yield 80%).
MS (APCI) m / z; 593 [M + H] ⁺
Reference Example 183
Acetic acid [(2-fluoro-4- [6-fluoro-4- [4- (5-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl) ] Benzyl) methylcarbamoyl] methyl ester production

(2-Fluoro-4- [6-fluoro-4- [4- (5-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] benzyl ) 80 mg of the methylamine (compound obtained in Reference Example 181) was treated in the same manner as in Example 9 to obtain 83 mg of the title compound as a colorless solid (yield 86%).
MS (APCI) m / z; 579 [M + H] ⁺
Reference Example 184
Acetic acid 1-[(2-fluoro-4- [6-fluoro-4- [4- (5-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline-8 Preparation of -yl] benzyl) methylcarbamoyl] -1-methylethyl ester

(2-Fluoro-4- [6-fluoro-4- [4- (5-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] benzyl ) 80 mg of the methylamine (compound obtained in Reference Example 181) was treated in the same manner as in Example 9 to obtain 80 mg of the title compound as a colorless solid (yield 79%).
MS (APCI) m / z; 607 [M + H] ⁺
Reference Example 185
8- (6-Chloro-2-methylpyridin-3-yl) -6-fluoro-4- [4- (5-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1- Ill] Manufacture of quinazoline

8-Bromo-6-fluoro-4- [4- (5-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline (the compound obtained in Reference Example 13) By treating 600 mg in the same manner as in Example 1, 442 mg of the title compound was obtained as a colorless solid (yield 66%).
MS (APCI) m / z; 467, 469 [M + H] ⁺
Reference Example 186
Preparation of 1- [2-methyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl] pyrrolidin-2-one

(1) To 40 mL of a dichloromethane solution of 1.29 g of aminoacetic acid ethyl ester, 2.00 g of 4-bromo-2-fluorophenyl isocyanate and 1.29 mL of triethylamine were added at room temperature, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in 20 mL of ethanol, 1.52 g of sodium methoxide (28% methanol solution) was added thereto, and the mixture was stirred at 80 ° C. for 6 hours. Further 1.52 g of sodium methoxide (28% methanol solution) was added to the reaction mixture, and the mixture was stirred at 80 ° C. for 1 day. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, 32 mL of 6N hydrochloric acid was added to the resulting residue, and the mixture was stirred at 100 ° C. for 3.5 hours. The reaction mixture was cooled to room temperature, poured into a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in a small amount of dichloromethane and methanol mixed solution and recrystallized from diethyl ether, whereby 1.19 g of 3- (4-bromo-2-fluorophenyl) imidazolidine-2,4-dione was colorless. Obtained as a solid (47% yield).
MS (APCI) m / z; 273,275 [M + H] ⁺
(2) By treating 500 mg of the compound obtained in (1) in the same manner as in Reference Example 65 (2), 3- (4-bromo-2-fluorophenyl) -1- [2- (tert-butyl) Dimethylsilyloxy) ethyl] imidazolidine-2,4-dione (466 mg) was obtained as a colorless solid (yield 59%).
MS (APCI) m / z; 431, 433 [M + H] ⁺
(3) 460 mg of the compound obtained in (2) above was treated in the same manner as in Reference Example 19 (2) to give 266 mg of the title compound as a colorless solid.
MS (APCI) m / z; 479 [M + H] ⁺
Reference Example 187
1- [2- (tert-Butyldimethylsilyloxy) ethyl] -3- (2-fluoro-4- [6-fluoro-4- [4- (5-propyl- [1,2,4] oxadiazole) -3-yl) piperidin-1-yl] quinazolin-8-yl] phenyl) imidazolidine-2,4-dione

By treating 70 mg of the compound obtained in Reference Example 16 and 95.6 mg of the compound obtained in Reference Example 186 in the same manner as in Reference Example 19 (2), 70.9 mg of the title compound was obtained as a colorless solid (yield) 62%).
MS (APCI) m / z; 692 [M + H] ⁺
Reference Example 188
Preparation of acetic acid 2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzyl ester

22.5 mL of a dimethyl sulfoxide solution of 1.50 g of 4-bromo-2-fluorobenzyl bromide and 2.74 g of potassium acetate was stirred overnight at room temperature. To the reaction mixture, 1.71 g of bis (pinacolato) diboron and 229 mg of 1,1-bis (diphenylphosphino) ferrocenepalladium (II) dichloride-dichloromethane complex were added, and the mixture was stirred at 80 ° C. for 7 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 95 / 5-83 / 17) to give 417 mg of the title compound as a pale green solid (yield 25%).
MS (APCI) m / z; 348 [M + H] ⁺
Reference Example 189
(S) -4- (tert-Butyldimethylsilyloxy) -1- (2-fluoro-4- [6-fluoro-4- [4- (5-propyl- [1,2,4] oxadiazolo-3- Yl) -piperidin-1-yl] quinazolin-8-yl] benzyl) pyrrolidin-2-one

(1) By treating 600 mg of the compound obtained in Reference Example 16 and 504 mg of the compound obtained in Reference Example 188 in the same manner as in Reference Example 19 (2), acetic acid 2-fluoro-4- [6-fluoro- 595 mg of 4- [4- (5-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] benzyl was obtained as a colorless solid (82% yield). ).
MS (APCI) m / z; 508 [M + H] ⁺
(2) By treating 590 mg of the compound obtained in the above (1) in the same manner as in Example 11, (2-fluoro-4- [6-fluoro-4- [4- (5-propyl- [1, 2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenyl) methanol (528 mg) was obtained as a colorless solid (yield 98%).
MS (APCI) m / z; 466 [M + H] ⁺
(3) A dichloromethane solution (10.5 mL) of the compound (525 mg) obtained in (2) and phosphorus tribromide (153 mg) was stirred at room temperature for 2.5 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 75 / 25-40 / 60) to give 8- (4-bromomethyl-3-fluorophenyl) -6-fluoro-4- [ There was obtained 427 mg of 4- (5-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline as a colorless solid (yield 72%).
MS (APCI) m / z; 528/530 [M + H] ⁺
(4) By treating 80 mg of the compound obtained in the above (3) in the same manner as in Example 19, 30.8 mg of the title compound was obtained as a colorless viscous oil (yield 31%).
MS (APCI) m / z; 663 [M + H] ⁺
Reference Examples 190-192
The following compounds were obtained by treating the corresponding starting compounds in the same manner as in Reference Example 177.
Reference Example 190 (3-Fluoro-4- [5-fluoro-4- (5-trifluoromethyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline-8 Yl) phenyl] acetic acid

MS (APCI) m / z; 520 [M + H] ⁺
Reference Example 191 (3-Fluoro-4- [5-fluoro-4- (6-trifluoromethyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline-8 -Yl) phenyl] acetic acid

MS (APCI) m / z; 520 [M + H] ^< +>.

Reference Example 192
Preparation of 4- (2-isopropyl-2H-tetrazol-5-yl) -piperidine hydrochloride

ＭＳ（ＡＰＣＩ）ｍ／ｚ：１９６［Ｍ＋Ｈ］^＋。

MS (APCI) m / z: 196 [M + H] ^< +>.

Reference Example 193
1- (2-acetoxyethoxy)-[3-fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidine-1- Yl] quinazolin-8-yl] benzene hydrobromide

8-Bromo-6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline (the compound obtained in Reference Example 12) To 168 mg of 1,4-dioxane 8 mL solution, water 2 mL, acetic acid 2- [2-fluoro-4- (2-benzyloxyethyl) oxyphenyl] -4,4,5,5-tetramethyl- [1,3, 2] 373 mg of dioxaborolane (the compound obtained in Reference Example 24), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride, dichloromethane complex 35 mg and cesium carbonate 650 mg were added, and the mixture was added under a nitrogen atmosphere. Was stirred at 90 ° C. for 16 hours. Ethyl acetate, water, and saturated brine were added to the reaction mixture, the mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The obtained residue was purified by NH-silica gel column chromatography (Chromatorex; Fuji Silysia Chemical, solvent; hexane / ethyl acetate: 90/10 to 70/30). To the crude product, 2 mL of a 25% acetic acid solution of hydrogen bromide was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was azeotroped with toluene and concentrated under reduced pressure to give 43 mg of the title compound as a viscous oil (yield: 17%).
MS (APCI) m / z; 538 [M + H] ^< +>.

Experimental example 1
(Purpose of this experiment)
The purpose of this experiment is to evaluate the GPR119 agonist activity (in vitro) of these compounds by adding a sample compound to human GPR119-expressing CHO cells and measuring the amount of cAMP produced by the cells.
(Preparation of human GPR119-expressing CHO cells)
CHO cells expressing human GPR119 (L8-18) are luciferase expression vector pLG3-CRE6-CRE-VIP according to a known technique described in The Journal of Biological Chemistry Vol. 274 (34), pp. 23940-23947. It was prepared by introducing the expression vector pMSF1-GPR119 (Geneticin resistance) carrying the human GPR119 gene into CHO cells (LM-3; Mock cells) into which (Hygromycin B resistance) was introduced.
(Test method)
The cryopreserved L8-18 cells were thawed, suspended in 9 times the assay buffer, and centrifuged (1000 rpm, 5 minutes) at room temperature. After removing the supernatant, the precipitated cells were resuspended in 4 mL of assay buffer, and IBMX (Sigma, # 17018-1G) -containing assay buffer was added thereto to add 0.75 × 10 ⁵ cells / mL. Cell suspension was prepared. The cell suspension was allowed to stand at room temperature for 15 minutes, and then 20 μL of the cell suspension and 5 μl of the sample compound solution or AR231453 solution were added to each well of a 96 half well white plate (Corning, # 3693) ( Final concentration: 1500 cells / well, 500 μM IBMX, 1% dimethyl sulfoxide). After incubating the mixture at 37 ° C. for 30 minutes, a 20-fold diluted solution (12.5 μL / well each) of cAMP-d2 and Anti cAMP-Cryptate from the HTRF cAMP kit (Cisbio, # 62AM4PEC) was added to each well. did. The mixture was stirred and allowed to stand for 1 hour in the dark, and fluorescence intensity was measured in a time-resolved fluorescence mode (Ex: 320 nm, Em: 665 nm, 620 nm) of a microplate reader (ARVO or SpectraMax M5e). . In the case of ARVO, the ratio of cAMP-d2 with respect to Anti cAMP-Cryptate [Ratio = (665 nm / 620 nm) × 10 ⁴ )] was calculated from the obtained fluorescence intensity, and cAMP prepared using the Ratio value and GraphPad Prism. From the standard curve, the cAMP concentration in each well was calculated. In the case of SpectraMax M5e, the cAMP concentration in each well was calculated based on the obtained fluorescence intensity and the standard curve prepared by Sofmax pro.
The EC ₅₀ value of the sample compound was calculated by setting the value of the dimethyl sulfoxide addition group as 0% and the maximum reaction value of AR231453 (cAMP concentration at the time of addition of 1 μM) as 100%.

(result)
The results of this experiment (EC ₅₀ values for each analyte compound) are as shown in Table 52 below. In the table, “++” and “++++” have the following meanings.
++: 3 μM> EC ₅₀ > 1 μM
+++: 1 μM> EC ₅₀

Experimental example 2
(Inhibition of blood glucose elevation of the compound of the present invention)
experimental method:
C57BL / 6N male mice were fasted for 21 hours (18 hours until grouping) and then stratified randomized allocation using SAS 9.1.3 (SAS Institute, Inc.) based on body weight (n = 8). The vehicle was orally administered with a vehicle (solvent: 0.1% Tween 80 / 0.5% hydroxypropylmethylcellulose) (control group) or a solution in which the sample compound was suspended in the vehicle (sample administration group), and the sample was administered for 1 hour. Later glucose loading (3 g / kg, po) was performed. Blood sampling from the test mice is performed at each time point immediately before drug administration (-60 min), immediately before glucose load (0 min), 30 minutes after glucose load (30 min), 60 minutes (60 min), and 120 minutes (120 min). It was. The blood glucose level at each time point was measured using Glucose CII-Test Wako (manufactured by Wako Pure Chemical Industries), AUC (0-120 min) in each administration group was calculated based on the measured value, and SAS 9.1. Tested with Student's t-Test using 3 (SAS Institute, Inc.).

result:
Table 53 below shows the blood glucose elevation-inhibiting action of each sample compound (value of the ratio of AUC (0-120 min) in the sample administration group when the AUC (0-120 min) in the control group is 100).
In the table, “*” and “**” have the following meanings.
*: P <0.05
**: P <0.01

Experimental Example 3
(Inhibition of blood glucose increase by the compound of the present invention 2)
experimental method:
Zucker Fatty male rats were fasted for 21 hours (18 hours until grouping) and then stratified randomized assignment using SAS 9.1.3 (SAS Institute, Inc.) based on body weight (n = 7). A vehicle (solvent: 0.1% Tween 80 / 0.5% hydroxypropylmethylcellulose) (control group) or a solution in which a sample compound is suspended in the vehicle (sample administration group) is orally administered to the rat, and the sample is administered for 1 hour. Later, mixed sugar solution loading (3.5 g / kg, po) was carried out. Blood sampling from the test mice is performed at each time point immediately before drug administration (-60 min), immediately before glucose load (0 min), 30 minutes after glucose load (30 min), 60 minutes (60 min), and 120 minutes (120 min). It was. The blood glucose level at each time point was measured using Glucose CII-Test Wako (manufactured by Wako Pure Chemical Industries), AUC (0-120 min) in each administration group was calculated based on the measured value, and SAS 9.1. 3 (SAS Institute, Inc.) was used for Student's t-test.

result:
The blood glucose elevation inhibitory action (value of the ratio of AUC (0-120 min) of the sample-administered group when the control group is 100 for AUC (0-120 min) based on the -60 min value) of each sample compound is shown below. Shown in the table.
In the table, “*” and “**” have the following meanings.
*: P <0.05
**: P <0.01

  Since the compound [I] of the present invention or a pharmacologically acceptable salt thereof has an agonistic action on the GPR119 receptor, various diseases or conditions that can be expected to be improved by regulating the receptor activity, such as obesity Metabolic diseases including diseases such as hyperglycemia, diabetes and its complications, metabolic syndrome, impaired glucose tolerance, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia and dyslipidemia, or It is useful as a medicament for the prevention and treatment of cardiovascular diseases such as arteriosclerosis, hypertension, coronary disease, myocardial infarction.

Claims (11)

The following general formula [I]:

[Where,
R ¹ is a hydrogen atom or a halogen atom,
Ring A is a 6-membered aromatic cyclic group which may contain a nitrogen atom as a hetero atom,
R ⁰¹ is a hydrogen atom, a halogen atom, a cyano group, an alkyl group or an alkylthio group,
R ⁰² is 1) a hydroxyl group;
2) a group represented by the formula: R ⁰⁴ — (CHR ⁰³ ) — [where,
R ⁰³ is a hydrogen atom or a group represented by the formula: R ^a R ^b N— (R ^a and R ^b are the same or different and are a hydrogen atom or an alkyl group),
R ⁰⁴ is a) a cyano group,
b) a hydroxyl group,
c) a hydroxymethyl group,
d) a carboxyl group,
e) a group represented by the formula: R ^c —S (═O) _m — (R ^c is a hydroxyl group and an alkyl group optionally substituted by a group selected from the group represented by the formula: R ^d R ^e NCO—; m is an integer of 0 to 2, R ^d and R ^e are the same or different and each represents a hydrogen atom or an alkyl group; provided that when R ⁰³ is a hydrogen atom, R ^c is not an alkylsulfonyl group),
f) a group represented by the formula: HO-Alk-O- (Alk represents an alkylene group);
g) a group ^{represented by the} formula: R ^f R ^g NCO— (R ^f and R ^g are the same or different and are a hydrogen atom, an alkyl group, a monohydroxyalkyl group or a dihydroxyalkyl group, or both are bonded to each other; A 5- or 6-membered aliphatic nitrogen-containing heteromonocyclic group together with the adjacent nitrogen atom (which represents that the group may be substituted with a hydroxyl group or a carbamoyl group),
h) a group represented by the formula: R ^h R ⁱ N— (R ^h and R ⁱ are the same or different and each represents a hydrogen atom, an alkyl group, an alkanoyl group, a hydroxyalkanoyl group, an alkoxycarbonyl group or an alkanoyloxyalkanoyl group); Or i) a 5- to 6-membered aliphatic nitrogen-containing heterocyclic group (the heterocyclic group may be substituted with a group selected from a hydroxyl group, an oxo group, an alkanoyl group, and a carbamoyl group)
Represents]];
3) An alkoxy group substituted with a group selected from a hydroxyl group, an alkoxycarbonyl group, a carbamoyl group (the amino group portion of the group may be substituted with 1 to 2 alkyl groups) and a phenyl group;
4) a group ^{represented by the} formula: R ^k —S (═O) _n — (R ^k is an alkyl group substituted with a hydroxyl group or an alkoxy group, n represents an integer of 0 to 2);
5) a group represented by the formula: R ^m R ⁿ NC (═O) — (R ^m and R ⁿ are: (a) one is a hydrogen atom or an alkyl group and the other is a cycloalkyl group (the group is a hydroxyalkyl group) An alkoxycarbonylbenzyl group, a carboxyphenylalkyl group, or a 5- to 6-membered aliphatic sulfur-containing heterocyclic group (the group may be substituted with 1 to 2 oxo groups). Or (b) both R ^m and R ⁿ are bonded together at the end, together with the adjacent nitrogen atom, a hydroxyl group, a cyano group, an oxo group, a hydroxyalkyl group, and a carbamoyl group (the group is one or two alkyl groups). Represents a 4- to 6-membered aliphatic nitrogen-containing heterocyclic group substituted with a group selected from (which may be substituted with a group);
6) an amino group substituted with a group selected from an alkanoyloxyalkanoyl group and a hydroxyalkanoyl group;
7) containing 1 to 4 nitrogen atoms as a hetero atom and selected from a hydroxyl group, an oxo group, a hydroxyalkyl group and a carbamoyl group (this group may be substituted with 1 to 2 alkyl groups) Saturated or unsaturated 5- to 6-membered nitrogen-containing heterocyclic group substituted with 1 to 2 groups (this heterocyclic group may further contain a heteroatom selected from an oxygen atom and a sulfur atom) And may be further substituted with a group selected from an alkyl group, a hydroxyalkyl group, an alkanoyl group, a hydroxyalkanoyl group and a carbamoyl group); or 8)

(In the formula, ring B represents a nitrogen-containing 5-membered aliphatic heterocyclic ring which may be substituted with an oxo group.)
A group represented by
R ² contains (a) a cyano group, or (b) the same or different 1 to 4 heteroatoms selected from an oxygen atom and a nitrogen atom, and may be substituted with 1 to 3 halogen atoms. 5- to 6-membered heteroaryl group optionally substituted with 1 to 2 groups selected from an alkyl group, a hydroxyalkyl group, an amino group optionally substituted with 1 to 2 alkyl groups, and a cycloalkyl group Represents)
Or a pharmaceutically acceptable salt thereof. The following formula in formula [I]:

The partial structure represented by the following formula:

[Wherein, one of a and b represents a carbon atom and the other represents a carbon atom or a nitrogen atom, and the other symbols have the same meaning as described above]
The compound according to claim 1, which is a substituted 6-membered aromatic cyclic group represented by the formula: Ring A is a benzene ring,
R ⁰¹ is a halogen atom, a cyano group or an alkyl group,
R ⁰² is 1) a group represented by the formula: R ⁰⁴ — (CHR ⁰³ ) — [wherein R ⁰³ is a hydrogen atom, R ⁰⁴ is a) a hydroxymethyl group or b) a formula: R ^f R ^g NCO— Wherein R ^f and R ^g are the same or different and each represents a hydrogen atom or an alkyl group (the alkyl group may be substituted with a hydroxyl group), or both are bonded to each other to form a hydroxyl group and a cyano group. A 5-membered nitrogen-containing aliphatic heterocyclic ring substituted with 1 to 2 groups selected from:
2) a group ^{represented by the} formula: R ^k —S (═O) _n — wherein R ^k is an alkyl group substituted with a hydroxyl group or an alkoxy group, and n represents an integer of 0 to 2;
3) a group represented by the formula: R ^m R ⁿ NC (═O) — [wherein R ^m and R ⁿ are selected from a hydroxyl group, a cyano group, and a carbamoyl group together with an adjacent nitrogen atom bonded together at the terminal Represents a 4- to 6-membered aliphatic nitrogen-containing heterocyclic group substituted with 1 to 2 groups]; or 4) contains 1 to 2 nitrogen atoms as a heteroatom, and Saturated or unsaturated 5- to 6-membered nitrogen-containing heterocyclic group substituted with 1 to 2 groups selected from an oxo group and a hydroxyalkyl group [wherein the cyclic group is selected from an oxygen atom and a sulfur atom And may further contain a heteroatom and may be further substituted with a hydroxyl group, an alkyl group, a carbamoylalkyl group or a dialkylcarbamoylalkyl group], and R ² is the same selected from an oxygen atom and a nitrogen atom Or 5 member (s) containing 1 to 3 heteroatoms and substituted with an alkyl group (which may be substituted with 1 to 3 halogen atoms), a cycloalkyl group or an alkanoyloxyalkyl group The compound according to claim 1, which is a heteroaryl group. Ring A is a benzene ring,
R ⁰¹ is a halogen atom or a C _1-4 alkyl group,
R ⁰² is 1) a group represented by the formula: R ^f R ^g NCO—CH ₂ — (wherein R ^f and R ^g are the same or different and each represents a hydrogen atom or a C _1-4 alkyl group, or both are And represents a 5-membered nitrogen-containing aliphatic heterocyclic ring substituted with 1 to 2 groups selected from a hydroxyl group, a cyano group, and an oxo group together with adjacent nitrogen atoms).
2) a group ^{represented by the} formula: R ^k —S (═O) ₂ — (R ^k represents a C _1-4 alkyl group substituted with a group selected from a hydroxyl group and a C _1-4 alkoxy group);
3) a group represented by the formula: R ^m R ⁿ NC (═O) — (R ^m and R ⁿ are bonded to each other at the terminal and are selected from a hydroxyl group, a cyano group, and a carbamoyl group together with an adjacent nitrogen atom. Represents the formation of a 5-membered aliphatic nitrogen-containing heterocyclic group substituted with two groups); or 4) contains 1 to 2 nitrogen atoms as heteroatoms, and an oxo group and hydroxy- A saturated or unsaturated 5- or 6-membered nitrogen-containing heterocyclic group substituted with 1 to 2 groups selected from C _1-4 alkyl groups (the cyclic group further contains an oxygen atom as a hetero atom) And may be further substituted with a hydroxyl group, a carbamoyl-C _1-4 alkyl group or a di (C _1-4 alkyl) carbamoyl-C _1-4 alkyl group), and R ² is an oxygen atom. And the same or different selected from nitrogen atoms 5 containing 1 to 3 heteroatoms and substituted with a C _1-4 alkyl group (which group may be substituted with 1 to 3 halogen atoms) or a C _3-6 cycloalkyl group The compound according to claim 1, which is a membered heteroaryl group. Ring A is a benzene ring,
R ⁰² is 1) a group represented by the formula: R ^f R ^g NCO—CH ₂ — (where R ^f represents a hydrogen atom, R ^g represents a C _1-4 alkyl group, or both are bonded at the end) And forming a pyrrolidinyl group substituted with a hydroxyl group together with the adjacent nitrogen atom)
2) a hydroxy- _C1-4 alkylsulfonyl group,
3) The following formula:

(In the formula, one of R ^a3 and R ^a4 represents a hydrogen atom or a hydroxyl group, and the other represents a cyano group or a carbamoyl group)
Or 4) the following formula:

(Wherein R ^a1 is a hydrogen atom, a hydroxyl group or a hydroxy-C _1-4 alkyl group, R ^a2 is a hydroxy-C _1-4 alkyl group, a carbamoyl-C _1-4 alkyl group or di (C _1-4 alkyl). Represents a carbamoyl-C _1-4 alkyl group)
And R ² contains the same or different 1 to 3 heteroatoms selected from an oxygen atom and a nitrogen atom, and is substituted with 1 to 3 fluorine atoms The compound according to claim 1, which is a 5-membered heteroaryl group substituted with a good C _1-4 alkyl group or a C _3-6 cycloalkyl group. 2- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl] -N-methylacetamide;
6-Fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] -8- [3-fluoro-4- (2-hydroxyethyl) Sulfonyl) phenyl] quinazoline;
[2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenyl ] (3-hydroxypyrrolidin-1-yl) methanone;
1- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl] -3- (2-hydroxyethyl) imidazolidin-2-one;
6-Fluoro-4- [4- (5-n-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] -8- [3-fluoro-4-[(3 -Hydroxypyrrolidin-1-yl) carbonyl] phenyl] quinazoline;
1- [2-Fluoro-4- [6-fluoro-4- [4- (5-cyclopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline-8- Yl] phenyl] -3- (2-hydroxyethyl) imidazolidin-2-one;
1- [2-Fluoro-4- [6-fluoro-4- [4- (5-n-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline-8 -Yl] phenyl] -3- (2-hydroxyethyl) imidazolidin-2-one;
1- [2-Fluoro-4- [6-fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl] -3- (2-hydroxyethyl) imidazolidin-2-one;
1- [2-Fluoro-4- [5-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl] -3- (2-hydroxyethyl) imidazolidin-2-one;
1- [4- [6-Fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] -2- Fluorophenyl] -4-hydroxypyrrolidin-2-one;
[2-Fluoro-4- [6-fluoro-4- [4- (5-trifluoromethyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl] (3-hydroxypyrrolidin-1-yl) methanone;
1- [4- [6-Fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] -3- Methylphenyl] pyrrolidin-2-one;
2- [2-Fluoro-4- [6-fluoro-4- [4- (5-n-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline-8 -Yl] phenyl] -1- (3-hydroxypyrrolidin-1-yl) ethanone;
1- [2-Fluoro-4- [4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenyl]- 3- (2-hydroxyethyl) imidazolidin-2-one;
1- [2-Methyl-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl] -3- (2-hydroxyethyl) imidazolidin-2-one;
1- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl] piperazin-2-one;
1- [2-Fluoro-4- [5-fluoro-4- [4- (5-n-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline-8 -Yl] phenyl] -3- (2-hydroxyethyl) imidazolidin-2-one;
1- [2-Fluoro-4- [5-fluoro-4- [4- (5-cyclopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline-8- Yl] phenyl] -3- (2-hydroxyethyl) imidazolidin-2-one;
1- [2-Fluoro-4- [5-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl] -4-hydroxypyrrolidin-2-one;
1- [2-Fluoro-4- [5-fluoro-4- [4- (5-n-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline-8 -Yl] phenyl] -4-hydroxypyrrolidin-2-one;
1- [2-Fluoro-4- [5-fluoro-4- [4- (5-cyclopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline-8- Yl] phenyl] -4-hydroxypyrrolidin-2-one;
1- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl] -3- (2-hydroxy-2-methylpropyl) imidazolidin-2-one;
1- [4- [6-Fluoro-4- [4- (5-cyclopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] -3 -Methylphenyl] pyrrolidin-2-one;
4- [4- [6-Fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] -3- Methylphenyl] -morpholin-3-one;
1- (2-Fluoro-4- {6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl } Phenyl) imidazolidin-5-one;
3- [2-Fluoro-4- [4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenyl]- 3-hydroxypyrrolidin-4-one;
1- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl] -5-hydroxymethylpyrrolidin-2-one;
2- [1- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline- 8-yl] phenyl] -2-oxoimidazolidin-3-yl] -N, N-dimethylacetamide;
[2-Fluoro-4- [6-fluoro-4- [4- (5-trifluoromethyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl] (2-carbamoylpyrrolidin-1-yl) methanone;
1- [2-Fluoro-4- [4- [4- [5- (1,1-difluoroethyl)-[1,2,4] oxadiazol-3-yl] piperidin-1-yl] quinazoline- 8-yl] phenyl] -3- (2-hydroxyethyl) imidazolidin-2-one;
[2-Fluoro-4- [6-fluoro-4- [4- (5-trifluoromethyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl] (2-cyano-4-hydroxypyrrolidin-1-yl) methanone;
[2-Fluoro-4- [5-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenyl ] (2-cyano-4-hydroxypyrrolidin-1-yl) methanone;
[2-Fluoro-4- [5-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenyl ] (3-hydroxypyrrolidin-1-yl) methanone;
[2-Fluoro-4- [5-fluoro-4- [4- [5- (1,1-difluoroethyl)-[1,2,4] oxadiazol-3-yl] piperidin-1-yl] Quinazolin-8-yl] phenyl] (3-hydroxypyrrolidin-1-yl) methanone [2-fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadi) Azol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenyl] (2-carbamoylpyrrolidin-1-yl) methanone;
1- [2-Methyl-4- [5-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl ] Phenyl] -3- (2-hydroxyethyl) imidazolidin-2-one;
1- [2-Methyl-4- [6-fluoro-4- [4- (5-trifluoromethyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline-8 -Yl] phenyl] -3- (2-hydroxyethyl) imidazolidin-2-one; and 1- [2-methyl-4- [6-fluoro-4- [4- (5-cyclopropyl- [1, 2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenyl] -3- (2-hydroxyethyl) imidazolidin-2-one or a compound thereof Pharmacologically acceptable salt.     A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.     The pharmaceutical composition according to claim 7, which is a prophylactic / therapeutic agent for metabolic diseases or cardiovascular diseases that can be treated by activation of GPR119.     The metabolic disease is obesity, hyperglycemia, diabetes and / or its complications, metabolic syndrome, impaired glucose tolerance, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia or dyslipidemia The pharmaceutical composition according to claim 8.     The pharmaceutical composition according to claim 8, wherein the cardiovascular disease is arteriosclerosis, hypertension, coronary disease or myocardial infarction.     A modulator of GPR119 activity comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.