JP2013177321A - New quinazoline compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a quinazoline compound having a GPR119 receptor agonistic activity and being useful as a medicine.SOLUTION: A compound expressed by general formula [I] or a pharmacologically acceptable salt thereof is provided. [In formula, Rrepresents hydrogen or halogen; ring A represents a 5- or 6-membered aryl ring (the aryl ring may contain one to four heteroatoms which are selected from O, S and N, and are the same or different); Rand Reach independently represents a halogen atom, a cyano group or the like; ring B represents a 6- or 7-membered aliphatic nitrogen-containing heterocyclic group; Rrepresents hydrogen or alkyl; Rrepresents hydrogen or a hydroxy group; and Rrepresents a hydroxy group, a cyano group or the like].

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, recent studies on the physiological role of GPR119 using a selective small molecule agonist (AR231453) have shown that glucose dependence in pancreatic β cells via cAMP increase (adenylate cyclase activation) by activation of the receptor. It has been clarified that the release of endogenous insulin and glucose homeostasis can be improved thereby (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 5- to 6-membered aryl group which may contain the same or different 1-4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom,
R ^A1 and R ^A2 are independently
1) a halogen atom;
2) a cyano group;
3) hydroxyl group;
4) an alkyl group (the alkyl group is a) a halogen atom, b) a hydroxyl group, c) a cyano group, d) a 5- to 6-membered nitrogen-containing heteroaryl group, e) a group represented by the formula: R ^a R ^b N— (R ^a and R ^b are the same or different and each represents a hydrogen atom or an alkyl group), f) a carboxyl group, g) a group represented by the formula: R ^c —S (═O) _m — (where R ^c is a hydroxyl group) And an alkyl group which may be substituted with a group selected from the group represented by the formula: R ^d R ^e NCO—, m is an integer of 0 to 2, and R ^d and R ^e are the same or different and are a hydrogen atom or an alkyl group. H) a group represented by the formula: HO-Alk-O- (where Alk represents an alkylene group), i) a group represented by the formula: R ^f R ^g NCO- (R ^f and R ^g are The same or different hydrogen atom, alkyl group, monohydroxyalkyl group or di- It is a droxyalkyl group, or both are bonded to each other and together with an adjacent nitrogen atom, a 5- to 6-membered aliphatic nitrogen-containing heteromonocyclic group (the cyclic group may be substituted with a hydroxyl group or a carbamoyl group) J) 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 Represents an alkanoyloxyalkanoyl group); and k) 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) It may be substituted with 1 to 3 groups selected from:
5) An alkoxy group (the alkoxy group is 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) May be);
6) a group ^{represented by the} formula: R ^k —S (═O) _n — (wherein R ^k is an alkyl group optionally substituted with a hydroxyl group or an alkoxy group, n represents an integer of 0 to 2);
7) an alkanoyl group;
8) a group represented by the formula: R ^m R ⁿ NC (═O) — (wherein R ^m and R ⁿ are the same or different, a) a hydrogen atom, an alkyl group, a mono- or dihydroxyalkyl group, mono- or di- A halogenoalkyl group, an alkoxycarbonylalkyl group, a cycloalkyl group (the group may be substituted with a hydroxyalkyl group), an alkoxycarbonylphenylalkyl group, a carboxyphenylalkyl group, or a 5- to 6-membered aliphatic sulfur-containing heterocyclic group A group (the hetero group may be substituted with 1 to 2 oxo groups), or b) both R ^m and R ⁿ are bonded together at the terminal, together with the adjacent nitrogen atom, a hydroxyl group, a cyano group , An oxo group, a hydroxyalkyl group and a carbamoyl group (the carbamoyl group may be substituted with 1 to 2 alkyl groups). It is expressed to form an even or 4-6 membered aliphatic nitrogen-containing heterocyclic group optionally);
9) an amino group (the amino group may be substituted with 1 to 2 groups selected from an alkyl group, an alkanoyl group, an alkoxycarbonyl group, an alkylsulfonyl group, an alkanoyloxyalkanoyl group and a hydroxyalkanoyl group);
10) A sulfamoyl group (the amino part of the group may be substituted with 1 to 2 alkyl groups);
11) The following formula:

(Here, ring A ⁰ represents a nitrogen-containing 5-membered aliphatic heterocyclic ring which may be substituted with an oxo group)
Or 12) a saturated or unsaturated 5- to 6-membered heterocyclic group (the heterocyclic group is the same or different 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom) And is substituted with one or two groups selected from the group consisting of a hydroxyl group, an oxo group, an alkyl group, a hydroxyalkyl group, an alkanoyl group, a hydroxyalkanoyl group, a carbamoyl group, a monoalkylcarbamoyl group, and a dialkylcarbamoyl group. You may)
Ring B is a 6 to 7-membered aliphatic nitrogen-containing heterocyclic group,
R ^B1 represents a hydrogen atom or an alkyl group,
R ^B2 is a hydrogen atom or a hydroxyl group,
R ^B3 is
1) hydroxyl group;
2) a cyano group;
3) an alkyl group;
4) a cycloalkylalkyl group;
5) an alkoxycarbonyl group;
6) a saturated or unsaturated 5- to 6-membered monocyclic heterocyclic group (the heterocyclic group contains 1 to 4 heteroatoms identical or different selected from an oxygen atom, a sulfur atom and a nitrogen atom, and An alkyl group which may be substituted with 1 to 3 halogen atoms; a hydroxyalkyl group; an alkoxyalkyl group (the alkoxyalkyl group may be substituted with 1 to 3 halogen atoms); a carboxyalkyl group; An amino group optionally substituted by 1 to 2 alkyl groups; an aminoalkyl group (the amino part of the aminoalkyl group may be substituted by 1 to 2 groups selected from an alkyl group and an alkoxycarbonyl group); good); and optionally substituted with one to two groups selected from cycloalkyl group); or 7): groups represented by -W-R ³ (where, W is oxygen Hara Represents a sulfur atom or a carbonyl group, R ³ is a) a phenyl group and alkoxyalkyl which may be an alkyl group substituted with a group selected from phenyl group, b) a cycloalkyl group, or c) an oxygen atom, a sulfur atom and a nitrogen atom The same or different 1 to 3 heteroatoms selected from: 1) a halogen atom, 2) an alkyl group, 3) an alkoxy group, 4) a cycloalkyl group, and 5) 1 to 2 (Represents a 5- to 6-membered monocyclic aryl group optionally substituted with 1 to 2 groups selected from an amino group optionally substituted with an alkyl group)
(Represents that)
Or a pharmaceutically acceptable salt thereof.

  The present invention also relates to a pharmaceutical composition comprising the above 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 pharmaceutically acceptable salt thereof as an active ingredient.

  In the compound [I] of the present invention, ring A is a 5- to 6-membered aryl group which may contain the same or different 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom. Examples of such aryl groups include phenyl, oxazolyl, thiazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyrimidinyl and the like.

When the substituent (R ^A1 or R ^A2 ) on ring A is an unsubstituted alkyl group, examples of such an alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and an n-butyl group. And an unsubstituted C _1-6 alkyl group such as

When the substituent (R ^A1 or R ^A2 ) on ring A is an alkyl group substituted with 1 to 3 halogen atoms, examples of such a substituted alkyl group include a trifluoromethyl group and a monofluoroethyl group. Mono, di or trihalogeno-C _1-6 alkyl group such as difluoroethyl group or trifluoroethyl group.

When the substituent (R ^A1 or R ^A2 ) on the ring A is an alkyl group substituted with a hydroxyl group, examples of such a substituted alkyl group include a hydroxy group such as a hydroxymethyl group, a hydroxyethyl group or a hydroxypropyl group. C _1-6 alkyl group.

When the substituent (R ^A1 or R ^A2 ) on ring A is an alkyl group substituted with a cyano group, examples of such a substituted alkyl group include a cyano-C _1-6 alkyl group such as a cyanomethyl group. It is done.

When the substituent (R ^A1 or R ^A2 ) on ring A is an alkyl group substituted with a nitrogen-containing 5-membered heteroaryl group, examples of such a substituted alkyl group include a triazolylmethyl group or tetrazolyl Examples thereof include a C _1-6 alkyl group substituted with a nitrogen-containing 5-membered heteroaryl such as a methyl group.

When the substituent (R ^A1 or R ^A2 ) on the ring A is an alkyl group substituted with a group represented by the formula: R ^c —S (═O) _m —, such a substituted alkyl group includes, for example, (A) Hydroxy-C _1-6 alkylthio-C _1-6 alkyl group such as hydroxyethylthiomethyl group or hydroxypropylthiomethyl group; (b) Di (C _1-6 alkyl) carbamoyl such as dimethylcarbamoylmethylthiomethyl group -C _1-6 alkylthio-C _1-6 alkyl group; (c) a C _1-6 alkylsulfinyl-C _1-6 alkyl group such as a methylsulfinylmethyl group; (d) a C _{1-6 such as a} methylsulfonylmethyl group. Alkylsulfonyl-C _1-6 alkyl group; (e) hydroxyethylsulfonylmethyl group or hydroxypropylsulfonylmethyl group Such hydroxy _{-C 1-6} alkylsulfonyl _{-C 1-6} alkyl group; or (f) such di _{(C 1-6} alkyl) of dimethylcarbamoyl methylsulfonylmethyl carbamoyl _{-C 1-6} alkylsulfonyl _{-C 1-6} And an alkyl group.

When the substituent (R ^A1 or R ^A2 ) on ring A is an alkyl group substituted with a carboxyl group, examples of such a substituted alkyl group include a carboxy-C _1-6 alkyl group such as a carboxymethyl group. can give.

When the substituent (R ^A1 or R ^A2 ) on ring A is an alkyl group substituted with a substituted or unsubstituted 5- to 6-membered aliphatic nitrogen-containing heterocyclic group, examples of such a substituted alkyl group include: (A) An unsubstituted or alkanoyl-substituted 5- to 6-membered aliphatic nitrogen-containing heterocyclic-substituted -C _1-6 alkyl group such as a piperazinyl group or an acetyl piperazinyl group is exemplified.

When the substituent (R ^A1 or R ^A2 ) on ring A is an alkyl group substituted with a group represented by the formula: R ^f R ^g NCO—, examples of such a substituted alkyl group include (a) N - methylcarbamoyl methyl or N, N-dimethylcarbamoyl-methyl group such as _{N-C 1-6} alkylcarbamoyl _{-C 1-6} alkyl or N, N-di _{(C 1-6} alkyl) carbamoyl _{-C 1-6} (B) N- (hydroxy-C _1-6 alkyl) carbamoyl-C _1-6 alkyl group such as N-hydroxyethylcarbamoylmethyl group or N-hydroxypropylcarbamoylmethyl group; (c) N-hydroxymethyl; N—C _1-6 alkyl-N- (hydroxy-C _1-6 alkyl) carbamoyl-C such as —N-methylcarbamoyl-methyl group _1-6 alkyl group; (d) N- (dihydroxy-C _1-6 alkyl) carbamoyl-C _1-6 alkyl group such as N-dihydroxypropylcarbamoylmethyl group; (e) (amino) (dimethylcarbamoyl) methyl group Or a C _1-6 alkyl group substituted with a di (C _1-6 alkyl) carbamoyl group; or (g) a pyrrolidinylcarbonylmethyl group, a hydroxypyrrolidinylcarbonylmethyl group or a carbamoylpyrrolidinylcarbonyl Examples thereof include an unsubstituted, hydroxy-substituted or carbamoyl-substituted pyrrolidinylcarbonyl-C _1-6 alkyl group such as a methyl group.

When the substituent (R ^A1 or R ^A2 ) on ring A is an alkyl group substituted with a group represented by the formula: HO—Alk—O—, such an alkyl group includes, for example, a hydroxyethoxymethyl group Examples thereof include a hydroxy-C _1-6 alkoxy-C _1-6 alkyl group.

When the substituent (R ^A1 or R ^A2 ) on the ring A is an alkyl group substituted with a group represented by the formula: R ^h R ⁱ N—, examples of such a substituted alkyl group include (a) methoxy An N—C _1-6 alkoxy-carbonylamino-C _1-6 alkyl group such as a carbonylaminomethyl group; (b) an N-acetoxyacetylaminomethyl group or an N- (2-hydroxyisobutyryl) aminomethyl group; N—C _2-7 alkanoyloxy-C _2-7 alkanoylamino-C _1-6 alkyl group; (c) N- (hydroxy-C _2-7 alkanoyl) amino-C _{1 such as} N-hydroxyacetylaminomethyl group; _-6 alkyl group; or (d) N- (hydroxy-C _2-7 alkanoyl-NC _{1-6 such as} N-hydroxyacetyl-N-methylaminomethyl group; An alkylamino-C1-6 alkyl group is mention _| raise | _lifted .

When the substituent (R ^A1 or R ^A2 ) on the ring A is an alkyl group substituted with a 5- to 6-membered aliphatic nitrogen-containing heteromonocyclic group, examples of such a substituted alkyl group include (a) Unsubstituted, hydroxy substituted, oxo substituted, carbamoyl substituted or hydroxy and oxo substituted pyrrolidinyl-C _1-6 alkyl groups such as pyrrolidinylmethyl, oxopyrrolidinylmethyl or carbamoylpyrrolidinylmethyl; or (b) Examples thereof include an unsubstituted or C _2-7 alkanoyl-substituted piperazinyl-C _1-6 alkyl group such as a piperazinyl group or an acetyl piperazinyl group.

When the substituent (R ^A1 or R ^A2 ) on ring A is an unsubstituted or substituted alkoxy group, examples of such an unsubstituted or substituted alkoxy group include a hydroxyl group, a C _1-6 alkoxy-carbonyl group, and a carbamoyl group. group (the amino group portion of the group is one to two C _1-6 alkyl which may be substituted with a group) exemplified and a C _1-6 alkoxy group optionally substituted by a group selected from a phenyl group It is done. More specifically, the alkoxy group includes a methoxy group, an ethoxy group, an n-propyloxy group or an isopropyloxy group, a hydroxymethoxy group, a hydroxyethoxy group, a methoxycarbonylmethoxy group, a methoxycarbonylethoxy group, a carbamoylmethoxy group, Examples thereof include N-methylcarbamoylmethoxy group, N, N-dimethylcarbamoylmethoxy group, benzyloxy group, phenethyloxy group and the like.

When the substituent (R ^A1 or R ^A2 ) on the ring A is a group represented by the formula: R ^k —S (═O) _n —, examples of such a substituent include (a) methylthio group, ethylthio A C _1-6 alkylthio group such as an n-propylthio group or an isopropylthio group; (b) a hydroxy-C _1-6 alkylthio group such as a hydroxyethylthio group; (c) a methoxyethylthio group or a methoxypropylthio group; A C _1-6 alkoxy-C _1-6 alkylthio group such as: (d) a C _1-6 alkylsulfinyl group such as a methylsulfinyl group or an ethylsulfinyl group; (e) a C _1-6 alkylsulfonyl group such as a methylsulfonyl group; (f) such hydroxyalkyl _{-C 1-6} alkylsulfonyl group hydroxyethyl sulfonyl group; or (g) methoxy ethylsulfonyl Or such _{a C 1-6} alkoxy _{-C 1-6} such alkylsulfonyl group methoxypropyl sulfonyl group.

When the substituent on the ring A (R ^A1 or R ^A2 ) is an alkanoyl group, examples of the substituent include a C _2-7 alkanoyl group such as an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, or a propionyl group. can give.

When the substituent (R ^A1 or R ^A2 ) on the ring A is a group represented by the formula: R ^m R ⁿ NC (═O) —, examples of the substituent include (a) a carbamoyl group, N-methyl Unsubstituted, such as carbamoyl group, N-ethylcarbamoyl group, N-propylcarbamoyl group, N- (hydroxybutyl) carbamoyl group, N, N-dimethylcarbamoyl group, N-ethyl-N-methylcarbamoyl group, mono C _{1- 6-} alkyl-substituted or di-C _1-6 alkyl-substituted carbamoyl groups; (b) N- (mono- or mono- or carbamoyl groups, N- (hydroxypropyl) carbamoyl groups, N- (dihydroxypropyl) carbamoyl groups, Dihydroxy-C _1-6 alkyl) carbamoyl group; (c) N-hydroxyethyl-N-methylcarbamoyl group, N- (mono or dihydroxy C _1-6 such as N- (hydroxypropyl) -N-methylcarbamoyl group, N- (dihydroxypropyl) -N-methylcarbamoyl group or N- (hydroxybutyl) -N-methylcarbamoyl group Alkyl) -N-C _1-6 alkylcarbamoyl group; (d) N- (mono or dihalogeno C _1-6 alkyl) carbamoyl group such as N- (difluoroethyl) carbamoyl group; (e) N- (ethoxycarbonylethyl) ) N- (C _1-6 alkoxy-carbonyl-C _1-6 alkyl) carbamoyl group such as carbamoyl group; (f) N- (unsubstituted) such as N- (unsubstituted or 1-hydroxymethyl-substituted cyclopentyl) carbamoyl group. Or hydroxy C _1-6 alkyl substituted-C _3-8 cycloalkyl) cal (G) unsubstituted or oxo (or dioxo) substituted tetrahydrothiopyranyl-carbamoyl group; (h) 1-pyrrolidinylcarbonyl group, hydroxy substituted 1-pyrrolidinylcarbonyl group, hydroxymethyl substituted 1-pyrrole An unsubstituted or substituted pyrrolidinylcarbonyl group such as a dinylcarbonyl group or a carbamoyl-substituted 1-pyrrolidinylcarbonyl group; (i) an unsubstituted or hydroxy-substituted pi (J) a morpholinocarbonyl group; (k) an N- (C _1-6 alkoxy-carbonyl-benzyl) carbamoyl group such as an N-methoxycarbonylbenzylcarbamoyl group; or (l) an N-carboxybenzylcarbamoyl group. N- (carboxy (Benzyl) carbamoyl group and the like.

When the substituent (R ^A1 or R ^A2 ) on ring A is a substituted amino group: the substituted amino group includes a C _1-6 alkyl group, a C _2-7 alkanoyl group, a C _1-6 alkoxy-carbonyl group And an amino group substituted with 1 to 2 groups selected from a group and a C _1-6 alkylsulfonyl group. More specifically, (a) mono-C _1-6 alkyl or di-C _{1 such as} N-methylamino group, N-ethylamino group, N, N-dimethylamino group or N-ethyl-N-methylamino group. _-6 alkylamino group; (b) such _{N-C 2-7} alkanoylamino group N- acetylamino group; (c) N- methoxycarbonylamino group, N- isopropyl-butyloxycarbonylamino group or an N-tert-butoxycarbonyl N—C _1-6 alkoxy-carbonylamino group such as amino group; (c) N—C _1-6 alkylsulfonylamino group such as N-methylsulfonylamino group; (d) N-methyl-N- (methylsulfonyl) ) N—C _1-6 alkyl-N— (C _1-6 alkylsulfonyl) amino group such as amino group; (e) N such as N-hydroxyacetylamino group; - (hydroxy _{-C 2-7} alkanoyl) amino group; (f) N-acetoxy-acetylamino group, such as _{N-(C 2-7} alkanoyloxy _{-C 2-7} alkanoyl) amino group; (g) N-acetyl - N- (C _2-7 alkanoyl) -N- (C _1-6 alkyl) amino group such as N-methylamino group; (h) N- (hydroxy C _{2 such as} N-hydroxyacetyl-N-methylamino group; _-7 alkanoyl) -N- (C _1-6 alkyl) amino group; (i) N- (C _2-7 alkanoyloxy-C _2-7 alkanoyl) -N such as N-acetoxyacetyl-N-methylamino group - _{(C 1-6} alkyl) amino group, and the like.

When the substituent (R ^A1 or R ^A2 ) on the ring A is a sulfamoyl group substituted with 1 to 2 alkyl groups, examples of the substituent include an N-methylsulfamoyl group or N, N— Examples thereof include mono- or di-C _1-6 alkylsulfamoyl groups such as dimethylsulfamoyl group.

The substituent (R ^A1 or R ^A2 ) on ring A is represented by the following formula:

In the case of a group represented by the formula, examples of such a substituent include a pyrrolidinylacetyl group and an oxopyrrolidinylacetyl group.

When the substituent (R ^A1 or R ^A2 ) on ring A is a saturated or unsaturated 5- to 6-membered heterocyclic group, the heterocyclic group is the same or selected from an oxygen atom, a sulfur atom and a nitrogen atom Containing 1 to 4 different heteroatoms and having a hydroxyl group, an oxo group, a C _1-6 alkyl group, a hydroxy-C _1-6 alkyl group, a halogeno-C _1-6 alkyl group, a C _2-7 alkanoyl group, It may be substituted with 1 to 2 groups selected from the group consisting of a hydroxy-C _2-7 alkanoyl group, a carbamoyl group and a mono- or di-C _1-6 alkylcarbamoyl group. More specifically, examples of such a substituent include a) a hydroxy group, an oxo group, a hydroxy C _1-6 alkyl group (such as a hydroxymethyl group), and a halogeno-C _1-6 alkyl group (a monofluoromethyl group). Etc.) and a pyrrolidinyl group optionally substituted with one or two groups selected from a carbamoyl group, b) a piperidyl group optionally substituted with an oxo group, c) an oxo group, a C _1-6 alkyl group ( Methyl group etc.), hydroxy C _1-6 alkyl group (hydroxymethyl group, hydroxyethyl group, hydroxypropyl group, hydroxybutyl group etc.), halogeno-C _1-6 alkyl group (monofluoroethyl group etc.), C _{2− 7} alkanoyl group (acetyl group, etc.), unsubstituted carbamoyl _{-C 1-6} alkyl group (carbamoylmethyl group) and mono or di _{C 1-} An alkyl-substituted carbamoyl -C _1-6 alkyl group 1 to 3 substituents which may be imidazolidinyl group with a group selected from (dimethylcarbamoylmethyl group), optionally substituted with d) 1 to 2 oxo groups A thiazolidinyl group, e) an oxazolyl group, f) an oxazolidinyl group optionally substituted by 1 to 2 groups selected from an oxo group and a hydroxy C _1-6 alkyl group (hydroxymethyl group, etc.), g) C _1-6 alkyl group (methyl group, ethyl group, n-propyl group, isopropyl group, etc.) optionally substituted oxadiazolyl group, h) triazolyl group, i) hydroxy C _1-6 alkyl group (hydroxyethyl group, etc.) ) in good tetrazolyl group which may be substituted, j) optionally a piperidyl group optionally substituted by an oxo group, k) C _1-6 alkyl (Methyl group, ethyl group, etc.), substituted with an oxo group, 1-2 groups selected from hydroxy _{C 1-6} alkyl group (hydroxyethyl group, etc.) and hydroxy _{C 2-7} alkanoyl group (hydroxyacetyl group) Piperazinyl group which may be substituted, l) morpholinyl group which may be substituted with oxo group, m) pyridyl group, n) pyrimidinyl group, o) oxo group, C _1-6 alkyl group (methyl group, ethyl group, etc.) And a tetrahydropyrimidinyl group substituted with 1 to 2 groups selected from a hydroxy C _1-6 alkyl group (such as a hydroxyethyl group), or p) dihydro-1,3-optionally substituted with an oxo group And oxazinyl group.

Preferred examples of ring A (including substituents R ^A1 and R ^A2 ) include
(A) The following formula:

[Where,
R ^A1 is (1) a hydrogen atom,
(2) a halogen atom,
(3) an alkyl group optionally substituted by 1 to 3 halogen atoms,
(4) an alkoxy group,
(5) an alkanoyl group,
(6) an amino group optionally substituted with a group selected from an alkanoyl group and an alkylsulfonyl group,
(7) an alkoxycarbonyl group, and R ^A2 is (1) a hydrogen atom,
(2) a halogen atom,
(3) a cyano group,
(4) an alkyl group,
(5) an alkyl group substituted with a saturated or unsaturated 5- to 6-membered heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom and a nitrogen atom,
(6) an alkylthio group (the alkyl part may be substituted with a hydroxyl group),
(7) an alkylsulfonyl group (the alkyl moiety may be substituted with a hydroxyl group),
(8) an alkylthioalkyl group (the alkyl part may be substituted with a hydroxyl group),
(9) an alkylsulfonylalkyl group (the alkyl moiety may be substituted with a hydroxyl group),
(10) a) 1 to 2 groups selected from a) an alkyl group optionally substituted with 1 to 3 halogen atoms, b) a monohydroxyalkyl group and c) an alkyl group substituted with a hydroxyl group and an alkoxy group A carbamoyl group optionally substituted by
(11) a sulfamoyl group optionally substituted by 1 to 2 alkyl groups,
(12) an amino group optionally substituted by 1 to 2 groups selected from an alkyl group, an alkanoyl group, an alkoxycarbonyl group, an alkanoyloxyalkanoyl group, a hydroxyalkanoyl group and an alkylsulfonyl group;
(13) an alkanoyl group,
(14) an alkoxy group,
(15) a nitro group,
(16) an alkoxycarbonyl group,
(17) Formula: R ¹¹ R ¹² NC (=) O— group (where R ¹¹ and R ¹² are (a) independently a hydrogen atom, an alkyl group, or (b) both are bonded to each other at the end. And a nitrogen-containing 5- to 6-membered aliphatic heterocyclic group which may be substituted with one or two groups selected from a hydroxyl group, an oxo group and a hydroxyalkyl group together with the adjacent nitrogen atom (the heterocyclic group is hetero Represents an oxygen atom as an atom)),
(18) represents a saturated or unsaturated 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from an oxygen atom and a nitrogen atom and optionally substituted with an alkyl group]
Or (B) the following formula:

Wherein R ^A11 is (1) a hydrogen atom, (2) a cyano group, (3) an alkyl group, (4) an alkoxy group, (5) a morpholino group, (6) an alkyl group, or (7) 1-2. R ^A12 is a hydrogen atom or a halogen atom, R ^A13 is a hydrogen atom or an alkoxy group, and R ^A14 and R ^A15 independently represent a hydrogen atom or an alkyl group.
And a substituted 5- or 6-membered heteroaryl group represented by the formula:

  Examples of the 6- to 7-membered aliphatic nitrogen-containing heterocyclic ring represented by ring B include a piperidine ring, a piperazine ring, a homopiperazine ring (1,4-diazacycloheptane ring) and the like.

When the substituent (R ^B3 ) on ring B is a saturated or unsaturated 5- to 6-membered monocyclic heterocyclic group, examples of such a heterocyclic group include a dihydrooxazolyl group and a thiazolyl group. Unsaturated oxygen-containing groups such as oxadiazolyl group, triazolyl group and tetrazolyl group, sulfur-containing or nitrogen-containing 5-membered monocyclic heterocyclic groups, or unsaturated nitrogen-containing 6-membered heterocyclic groups such as pyridyl groups and pyrimidinyl groups, etc. Can be given. Examples of the substituent on the saturated or unsaturated 5- to 6-membered monocyclic heterocyclic group include a) an alkyl such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, or a tert-butyl group. B) a cycloalkyl group such as a cyclopentyl group or a cyclobutyl group, c) substituted with 1 to 3 halogen atoms such as a difluoromethyl group, a difluoroethyl group, a trifluoromethyl group, a trifluoroethyl group or a monofluoropropyl group D) hydroxyalkyl group such as hydroxypropyl group, e) alkoxyalkyl group such as methoxyethyl group, f) alkoxyalkyl group substituted with 1 to 3 halogen atoms such as trifluoroethoxyethyl group G) an alkanoyl oxya such as an acetoxymethyl group or an acetoxypropyl group Kill group, h) substituted or mono- or dialkyl-substituted amino group such as dimethylamino group, i) aminoalkyl group such as aminomethyl group or aminoethyl group (the amino part of the group is an alkyl group (methyl group etc.) and j) The same or different 1 or 2 group chosen from an alkoxycarbonyl group (tert-butoxycarbonyl group etc.) is mention | raise | lifted.

When the substituent (R ^B3 ) on ring B is a group represented by the formula: —W—R ³ , and R ³ is a 5- to 6-membered monocyclic aryl group, the 5- to 6-membered monocyclic group The aryl group may contain the same or different 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and specific examples of such a 5-6 membered monocyclic aryl group include: Examples thereof include a phenyl group, a thiazolyl group, a thiadiazolyl group, an oxazolyl group, an oxadiazolyl group, a triazolyl group, a pyridyl group, and a pyrimidinyl group. The 5- to 6-membered monocyclic aryl (or heteroaryl) group includes 1) a halogen atom (for example, a chlorine atom, a fluorine atom, a bromine atom, and an iodine atom), 2) an alkyl group (for example, a methyl group, Ethyl group, isopropyl group, etc.) 3) alkoxy group (methoxy group, ethoxy group, propyloxy group, butyloxy group, etc.) 4) cycloalkyl group (for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, etc.) And 5) may be substituted with 1 to 2 groups selected from amino groups (for example, amino group, methylamino group, dimethylamino group, etc.) optionally substituted with 1 to 2 alkyl groups. .

Preferred examples of ring B (including R ^B1 , R ^B2 and R ^B3 ) include
(A) The following formula (i):

[Wherein R ² contains (a) a cyano group, or (b) 1 to 4 heteroatoms selected from the oxygen atom, sulfur atom and nitrogen atom, or 1 to 3 halogen atoms. Substituted with 1 to 2 groups selected from alkyl group, hydroxyalkyl group, alkoxyalkyl group, amino group optionally substituted with 1 to 2 alkyl groups and cycloalkyl group optionally substituted with Represents a saturated or unsaturated 5-6 membered monocyclic heterocyclic group which may optionally have
R ²⁰ represents a hydrogen atom or an alkyl group.
Or (B) the following formula (ii):

[Wherein W ¹ represents an oxygen atom, a sulfur atom or a carbonyl group, R ³¹ represents a) an alkyl group (the alkyl group may be substituted with a group selected from a phenyl group and an alkoxyphenyl group); b ) A cycloalkyl group; or c) a 5- to 6-membered monocyclic aryl group (the aryl group may contain 1 to 3 heteroatoms which are the same or different and are selected from an oxygen atom, a sulfur atom and a nitrogen atom) And 1) a halogen atom, 2) an alkyl group, 3) an alkoxy group, 4) a cycloalkyl group, and 5) 1-2 groups selected from amino groups optionally substituted by 1-2 alkyl groups. Which may be substituted with
Or (C) the following formula (iii):

[Wherein, R ⁴ represents an alkyl group, a cycloalkylalkyl group, an alkoxycarbonyl group, or a nitrogen-containing or oxygen-containing 5- to 6-membered heteroaryl group (the heteroaryl group may be substituted with an alkyl group); R ⁴⁰ represents a hydrogen atom or an alkyl group.
Or (D) the following formula (iv):

[Wherein R ⁴ has the same meaning as described above]
Or (E) the following formula (v):

[Wherein, R ^4A represents a nitrogen-containing or oxygen-containing 5- to 6-membered heteroaryl group (the heteroaryl group may be substituted with an alkyl group)]
The substituted 6-membered or 7-membered aliphatic nitrogen-containing heterocyclic group shown by these is mention | raise | lifted.

Among the compounds [I] of the present invention, preferred compounds include, for example,
Ring A is represented by the following formula:

[Where,
Ring A ¹ is a benzene ring or a pyridine ring,
R ^A is 1) a cyano group;
2) a mono- or dihydroxyalkyl group;
3) (a) a hydroxyl group, (b) an alkyl group substituted with a group selected from the formula: R ^p R ^q NC (═O) — and (c) an alkylsulfonyl group (where R ^p and R ^q independently represents a hydrogen atom, an alkyl group or a hydroxyalkyl group which may be substituted with 1 to 3 halogen atoms, or both are bonded to each other at the terminal and together with the adjacent nitrogen atom, a halogen atom, Representing the formation of a 5-membered nitrogen-containing aliphatic heterocyclic group optionally substituted with 1 to 2 groups selected from a hydroxyl group, a cyano group and a carbamoyl group);
4) an alkoxy group;
5) a group represented by the formula: R ^r —S (═O) _n — (wherein R ^r is an alkyl group optionally substituted with a hydroxyl group or an alkoxy group, n represents an integer of 0 to 2);
6) an alkyl group substituted with a 5-membered heteroaryl group containing 1-3 nitrogen atoms as heteroatoms;
7) an alkoxycarbonylalkyl group;
8) a group represented by the formula: R ^s R ^t N (C═O) — (wherein R ^s and R ^t independently represent a hydrogen atom, an alkyl group, a hydroxyalkyl group or a dihalogenoalkyl group) Or a 4- to 6-membered nitrogen-containing aliphatic heterocyclic group which may be substituted with one or two groups selected from a halogen atom, a hydroxyl group, a cyano group, and a carbamoyl group together with the adjacent nitrogen atom. Represents the formation of
9) a sulfamoyl group optionally substituted by 1 to 2 alkyl groups;
10) an alkanoyl group;
11) an alkoxycarbonylamino group;
12) an alkanoylamino group;
13) an alkylsulfonylamino group;
14) The following formula:

(Here, ring A ⁰¹ represents a nitrogen-containing 5-membered aliphatic heterocyclic ring substituted with an oxo group)
Or 15) the same or different 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, and an oxo group, a hydroxyl group, an alkyl group, a hydroxyalkyl group, a carbamoylalkyl group, A saturated or unsaturated 5- to 6-membered heterocyclic group which may be substituted with 1 to 2 groups selected from a monoalkylcarbamoylalkyl group and a dialkylcarbamoylalkyl group;
R ^B represents a hydrogen atom, a halogen atom, a cyano group, an alkyl group or a trihalogenoalkyl group.
A group represented by
Ring B is represented by the following formula:

[Wherein R ^2A contains the same or different 1 to 3 heteroatoms selected from a nitrogen atom and an oxygen atom, and an alkyl group (the alkyl group may be substituted with 1 to 3 halogen atoms) A saturated or unsaturated 5-membered heterocyclic group substituted with a cycloalkyl group, an alkoxyalkyl group or an alkanoyloxyalkyl group, and R ²¹ represents a hydrogen atom or an alkyl group.
A compound represented by the formula:

Among the above-mentioned compounds, as a more preferable compound, for example,
Ring A ¹ is a benzene ring,
R ^A is 1) a group represented by the formula: R ^u R ^v NCO—CH ₂ — (wherein R ^u and R ^v 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): R w -S (= O)}} 2 - group represented by ^{(R w} represents a substituted _{C 1-4} optionally alkyl with a group selected from hydroxyl and _{C 1-4} alkoxy) ;
3) A group represented by the formula: R ^x R ^y NC (═O) — (R ^x and R ^y are each independently an alkyl group or a monohydroxyalkyl group, or both are bonded at the end, together with the adjacent nitrogen atom, Representing the formation of a 5-membered aliphatic nitrogen-containing heterocyclic group substituted with 1 to 2 groups selected from a hydroxyl group, a cyano group and a carbamoyl group);
4) C _1-4 alkylsulfonylmethyl group; or 5) 1 to 2 containing 1 to 2 nitrogen atoms as heteroatoms and selected from an oxo group, a hydroxyl group and a hydroxy-C _1-4 alkyl group A saturated or unsaturated 5- or 6-membered nitrogen-containing heterocyclic group substituted with a group of the above (the cyclic group may further contain an oxygen atom as a hetero atom, and is a hydroxyl group, carbamoyl-C _1-4). An alkyl group or a di (C _1-4 alkyl) carbamoyl-C _1-4 alkyl group, which may be further substituted),
R ^B is a halogen atom, a cyano group or a C _1-4 alkyl group,
R ^2A contains the same or different 1 to 3 heteroatoms selected from an oxygen atom and a nitrogen atom, and a C _1-4 alkyl group (this group may be substituted with 1 to 3 halogen atoms) ) Or a saturated or unsaturated 5-membered heterocyclic group substituted with a C _3-6 cycloalkyl group, and a compound wherein R ²¹ is a hydrogen atom.

Among the above compounds, more preferable compounds include, for example,
Ring A ¹ is a benzene ring,
R ^A is 1) a group represented by the formula: R ^aa R ^bb NCO—CH ₂ — (where R ^aa represents a hydrogen atom, R ^bb represents a C _1-4 alkyl group, or both are bonded at the ends) A pyrrolidinyl group optionally substituted with a hydroxyl group together with the adjacent nitrogen atom));
2) a hydroxy- _C1-4 alkylsulfonyl group;
3) a carbamoyl group optionally substituted by 1 to 2 _C1-4 alkyl groups;
4) The following formula:

[Wherein, R ^a3 and R ^a4 are the same or different and each represents a hydrogen atom, a hydroxyl group, a cyano group, or a carbamoyl group]
Or a group represented by the following formula:

[Wherein, R ^a1 is a hydrogen atom, a hydroxyl group or a hydroxy-C _1-4 alkyl group, and 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]
A cyclic group represented by
Contain identical or different 1 to 3 heteroatoms R ^2A is selected from oxygen atom and nitrogen atom, and optionally substituted with 1-3 fluorine atoms C _1-4 alkyl group or a C _3- Examples thereof include a 5-membered heteroaryl group substituted with a _6- cycloalkyl group, and R ²¹ is a hydrogen atom.

Among the compounds [I] of the present invention, other preferable compounds include, for example,
Ring A is represented by the following formula:

[Wherein, ring A ² is a benzene ring, ^RC is 1) an alkylsulfonyl group; 2) a carbamoyl group optionally substituted with 1 to 2 alkyl groups; or 3) a morpholinocarbonyl group, and ^RD is hydrogen. (Represents an atom or a halogen atom)
A ring B is represented by the following formula:

[Wherein, W ¹ is an oxygen atom or a sulfur atom, R ³¹ is an alkyl group (the alkyl group may be substituted with an alkoxyphenyl group), a cycloalkyl group, a phenyl group (the phenyl group is a halogen atom, an alkyl group) A group, an alkoxy group and an amino group (the amino group may be substituted with 1 to 2 groups selected from 1 to 2 alkyl groups), or A sulfur 5- to 6-membered heteroaryl group (the heteroaryl group may be substituted with an alkyl group)]
A compound represented by the formula:

Among the compounds [I] of the present invention, other preferable compounds other than those described above include, for example,
Ring A is represented by the following formula:

[Wherein ring A ³ is a benzene ring, R ^E is (a) an alkylsulfonyl group, (b) an alkylsulfonylalkyl group, (c) a carbamoylalkyl group (the amino moiety of the carbamoyl group is an alkyl group and a hydroxyalkyl group) (Which may be substituted with 1 to 2 groups selected) , (d) a nitrogen-containing 5-membered aliphatic heterocyclic group substituted with 1 to 2 groups selected from an oxo group and a hydroxyalkyl group, or (E) The following formula:

(Here, ring A ⁰² represents a nitrogen-containing 5-membered aliphatic heterocyclic ring substituted with a hydroxyl group)
And R ^F represents a hydrogen atom or a halogen atom.]
A ring B is represented by the following formula:

[Wherein, R ⁴¹ is (a) an alkoxycarbonyl group or (b) a 5-membered heteroaryl containing 1 to 3 heteroatoms which are the same or different and selected from an oxygen atom and a nitrogen atom, and substituted with an alkyl group Group, R ⁴² represents a hydrogen atom or an alkyl group]
Among these, more preferred compounds are those in which R ^E is a C _1-4 alkylsulfonylmethyl group, a carbamoylalkyl group (the amino group portion of the carbamoyl group is 1 to 2 alkyl groups). Optionally substituted with a group) or

(Here, the symbols have the same meaning as described above.)
And a compound in which ^R42 is a hydrogen atom.

Among the compounds [I] of the present invention, particularly preferable compounds include, for example,
4- [5-Fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl] -N, N-dimethyl Benzamide;
3-Fluoro-4- [4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl] -N, N-dimethyl Benzamide;
3-Fluoro-4- [5-fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl] -N , N-dimethylbenzamide;
5-fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] -8- (4-mesylphenyl) quinazoline;
4- [6-Fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl] -N, N-dimethyl Benzamide;
2-Fluoro-4- [5-fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl] -N , N-dimethylbenzamide;
3-Fluoro-4- [6-fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl] -N , N-dimethylbenzamide;
2-Fluoro-4- [5-fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl] -N -Methylbenzamide;
N-ethyl-2-fluoro-4- [5-fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazoline-8- Il] benzamide;
2-Fluoro-4- [6-fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl] -N , N-dimethylbenzamide;
2-Fluoro-4- [6-fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl] -N -Methylbenzamide;
6-Fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] -8- [3-fluoro-4-[(pyrrolidine-1 -Yl) carbonyl] phenyl] quinazoline;
2-fluoro-4- [6-fluoro-4- (3-n-propyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl] -N, N-dimethylbenzamide;
6-Fluoro-4- [4- (3-n-propyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] -8- [3-fluoro-4-[(pyrrolidine -1-yl) carbonyl] phenyl] quinazoline;
2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] -N -Methylbenzamide;
4- [4- (3-Isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] -8- (4-mesylphenyl) quinazoline;
4- [4- [4- (3-Isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl] -N, N-dimethylbenzamide 3-fluoro -4- [6-fluoro-4- [4- (5-n-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] -N, N-dimethylbenzamide;
2-Fluoro-4- [6-fluoro-4- [4- [3- (2,2,2-trifluoroethyl)-[1,2,4] oxadiazol-5-yl] piperidine-1- Yl] quinazolin-8-yl] -N, N-dimethylbenzamide;
2-Fluoro-4- [6-fluoro-4- [4- [5-cyclopropyl- [1,2,4] oxadiazol-3-yl] piperidin-1-yl] quinazolin-8-yl]- N- (2-hydroxyethyl) -N-methylbenzamide;
6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] -8- (3-fluoro-4-mesylphenyl) quinazoline; And 6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] -8- (3-fluoro-4-methylsulfonylmethylphenyl) ) A compound selected from the group consisting of quinazoline or a pharmacologically acceptable salt thereof.

Among the compounds [I] of the present invention, other particularly preferable 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;
1- [2-Methyl-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 6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperazine- 1-yl] -8- (3-fluoro-4-methylsulfonylmethylphenyl) quinazoline,
[2-Fluoro-4- [5-fluoro-4- [4- [5- (1-fluoro-1-methylethyl)-[1,2,4] oxadiazol-3-yl] piperidine-1- Yl] quinazolin-8-yl] phenyl] (2-cyano-4-hydroxypyrrolidin-1-yl) methanone;
[2-Fluoro-4- [5-fluoro-4- [4- [5- (1-fluoro-1-methylethyl)-[1,2,4] oxadiazol-3-yl] piperidine-1- Yl] quinazolin-8-yl] phenyl] (3-hydroxypyrrolidin-1-yl) methanone;
[2-Fluoro-4- [5-fluoro-4- [4- [5- (1-fluoro-1-methylethyl)-[1,2,4] oxadiazol-3-yl] piperidine-1- Yl] quinazolin-8-yl] phenyl] (2-carbamoylpyrrolidin-1-yl) methanone;
1- [4- [5-Fluoro-4- [4- [5- (1,1-difluoroethyl)-[1,2,4] oxadiazol-3-yl] piperidin-1-yl] quinazoline- 8-yl] -2-methylphenyl] -4-hydroxypyrrolidin-2-one;
1- [4- [6-Fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] -2- Cyanophenyl] -4-hydroxypyrrolidin-2-one;
1- [2-Fluoro-4- [4- [4- [5- (1-fluoro-1-methylethyl)-[1,2,4] oxadiazol-3-yl] piperidin-1-yl] Quinazolin-8-yl] phenyl] -3- (2-hydroxyethyl) imidazolidin-2-one;
1- [2-Fluoro-4- [4- [4- [5-n-propyl- [1,2,4] oxadiazol-3-yl] piperidin-1-yl] quinazolin-8-yl] phenyl ] -3- (2-hydroxyethyl) imidazolidin-2-one; and [2-fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazole) -3-yl) piperazin-1-yl] quinazolin-8-yl] benzyl] (2-hydroxypyrrolidin-1-yl) methanone or a pharmaceutically acceptable salt thereof.

  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, but in the case of an injection, it is about 0.001 to 100 mg per day. / Kg, especially about 0.01 to 10 mg / kg, and in the case of an oral preparation, usually about 0.01 to 1000 mg / kg, especially about 0.1 to 100 mg / kg per day is preferable.

  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 (such as amiodarone hydrochloride), Ca channel blockers (such as verapamil hydrochloride), etc .;
(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 methods 1 to 28.
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 represent an alkylene group, and other symbols have the same meaning as described above]. ]
Synthesis Method 2) (Reaction Scheme B):

[In the above scheme, X ² represents a halogen atom, ring Ba represents a 6-membered nitrogen-containing aliphatic heterocyclic ring, and other symbols have the same meaning as described above. ]
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. Any solvent may be used 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, and toluene. Aromatic hydrocarbons, 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, 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].

The reaction of compound [1b] and cyclic amine compound [2b] in the above reaction scheme B is carried out in a solvent in the presence or absence of a base at −20 ° C. to the solvent reflux temperature, preferably −10 to 40 ° C. can do. The halogen atom represented by X ² is preferably a bromine atom, a chlorine atom or an iodine atom. Any solvent may be used as long as it does not interfere with the reaction. Examples thereof include halogenated aliphatic hydrocarbons such as dichloromethane, chloroform or 1,2-dichloroethane, amides such as 1-methylpyrrolidinone, dimethylformamide or dimethylacetamide. 1, 2-dimethoxyethane, dimethyl sulfoxide, ethers such as tetrahydrofuran or dioxane, aromatic hydrocarbons such as toluene or benzene, ketones such as acetone, and the like. Examples of the base include sodium hydride, potassium carbonate, pyridine, triethylamine, diisopropylethylamine, 4-methylmorpholine, 1,8-diazabicyclo [5,4,0] undecene (DBU) and the like. In the above reaction, the amount of compound [2b] to be used can be 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to compound [1b]. The amount of the base to be used can be 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to compound [1b] or compound [2b].

Among the compounds [I] of the present invention, a compound having an alkylsulfonyl group (or a group containing an alkylsulfonyl group) as a substituent on the ring A is prepared by subjecting the corresponding compound [I] having an alkylthio group as a substituent to a solvent ( Halogenated hydrocarbons such as dichloromethane, alcohols such as ethanol, ketones such as acetone, water, etc., in the presence of acids (methanesulfonic acid, trifluoroacetic acid, etc.), oxidizing agents (m-chloroperbenzoic acid, etc.) ) Can also be manufactured.
Synthesis method 3-1)
Among the compounds [I] of the present invention, the following general formula [IC]:

[Wherein the symbols have the same meaning as described above. ]
The compound represented by the general formula [1c]:

[Wherein the symbols have the same meaning as described above. ]
And a compound of the general formula [2c]:
R ³ —OH [2c]
[Wherein the symbols have the same meaning as described above. ]
In the presence of a azodicarboxylic acid dialkyl ester (diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc.) and trisubstituted phosphines (triphenylphosphine, tributylphosphine, etc.) in a solvent, Preferably, it can also be produced by reacting at room temperature to 50 ° C. Any solvent may be used as long as it does not interfere with the reaction. Examples thereof include halogenated aliphatic hydrocarbons such as dichloromethane, chloroform or 1,2-dichloroethane, amides such as 1-methylpyrrolidinone, dimethylformamide or dimethylacetamide. And ethers such as 1,2-dimethoxyethane, dimethyl sulfoxide, tetrahydrofuran or dioxane, and aromatic hydrocarbons such as toluene or benzene. In this reaction, the amount of compound [2c] to be used can be 1.0 to 3.0 equivalents, preferably 1.0 to 1.5 equivalents, relative to compound [1c]. The amount of azodicarboxylic acid dialkyl ester to be used can be 1.0 to 3.0 equivalents, preferably 1.0 to 1.5 equivalents, relative to compound [1c]. The usage-amount of tri-substituted phosphine can be 1.0-3.0 equivalent with respect to compound [1c], Preferably it can be 1.0-1.5 equivalent.
Synthesis Method 3-2)
Further, among the compounds [IC] of the present invention, the following formula:

[Wherein, R ³² represents an alkyl group which may be substituted with a group selected from a phenyl group and an alkoxyphenyl group. ]
For example, the compound represented by the above formula [1c] and the following formula:
R ³² -X ¹¹ [a]
[Wherein, X ¹¹ represents a halogen atom, and other symbols have the same meaning as described above. ]
In the presence of a base (an alkali metal hydride such as sodium hydride, an alkyl lithium such as n-butyllithium) in a solvent (ethers such as tetrahydrofuran, amides such as dimethylformamide) in the solvent (-10) The reaction can also be carried out by reacting at a temperature of from ℃ to the reflux temperature of the solvent, preferably from room temperature to 50 ℃. The halogen atom represented by X ^11, a chlorine atom or a bromine atom. In this reaction, the amount of compound [a] to be used can be 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to compound [1c]. The usage-amount of a base can be 1-10 equivalent with respect to compound [1c] or compound [a], Preferably it can be 1-3 equivalent.
Synthesis method 4)
Among the compounds [I] of the present invention, the following general formula [ID]:

[Wherein the symbols have the same meaning as described above. ]
The compound represented by general formula [1d]:

[Wherein X ³ represents a leaving group, and other symbols have the same meaning as described above. ]
And a compound represented by the general formula [2d]:
R ³ —SH [2d]
[Wherein the symbols have the same meaning as described above. ]
Can also be produced by reacting in a solvent in the presence of a base at room temperature to the reflux temperature of the solvent, preferably 50 ° C. to the reflux temperature of the solvent. Examples of the leaving group represented by X ³ include a methanesulfonyloxy group and a trifluoromethanesulfonyloxy group. Any solvent may be used as long as it does not interfere with the reaction. Examples thereof include alcohols such as methanol. Examples of the base include alkali metal alkoxides such as sodium methoxide, alkali metal hydrides, and the like. The amount of compound [2d] used in this reaction can be 1 to 10 equivalents, preferably 2 to 4 equivalents, relative to compound [1d]. The amount of the base to be used can be 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound [1d] or compound [2d].
Synthesis method 5)
Among the compounds [I] of the present invention, the following general formula [IE]:

[Wherein, ring Bb represents a 6-membered or 7-membered nitrogen-containing aliphatic heterocyclic ring, and other symbols have the same meaning as described above. ]
The compound represented by the general formula [1e]:

[Wherein the symbols have the same meaning as described above. ]
And a compound represented by the following general formula [2e]:
R ⁴¹ -X ⁴ [2e]
[Wherein, R ⁴¹ represents an alkyl group, a cycloalkyl group, or a nitrogen-containing or oxygen-containing 5- to 6-membered heteroaryl group (the heteroaryl group may be substituted with an alkyl group), and X ⁴ represents a halogen atom. . ]
Or the compound [1e] and the following general formula [2e-2]:
R ⁴² -COOH [2e-2]
[Wherein R ⁴² represents an alkoxy group. ]
It can manufacture by making the reactive derivative of the compound shown by reacting.

  The reaction of compound [1e] and compound [2e] is carried out in a solvent in the presence of a base and an activator (catalytic amount of potassium iodide, etc.) at room temperature to the reflux temperature of the solvent, preferably 50 to 100 ° C. Can do. Any solvent may be used as long as it does not interfere with the reaction. Examples thereof include amides such as dimethylformamide and ethers such as dioxane. Examples of the base include alkali metal carbonates such as potassium carbonate. The amount of compound [2e] used in this reaction can be 1.0 to 3.0 equivalents, preferably 1.0 to 2.0 equivalents, relative to compound [1e]. The usage-amount of a base can be 1.0-5.0 equivalent with respect to compound [1e] or compound [2e], Preferably it can be 1.0-3.0 equivalent.

The reaction of the reactive derivative of compound [1e] (corresponding acid chloride) and compound [2e-2] is carried out in the presence of a base (such as triethylamine) in a solvent (such as dichloromethane) at 0 to 40 ° C., preferably 0 to 30 It can be carried out at ° C.
Synthesis method 6)
Among the compounds [I] of the present invention, the following general formula [IF]:

[Wherein, A ^a represents a benzene ring or a pyridine ring (the benzene ring or pyridine ring may be substituted with a halogen atom or an alkyl group), and other symbols have the same meaning as described above. ]
The compound represented by the following general formula [1f]:

[Wherein the symbols have the same meaning as described above. ]
And the following general formula R ^a R ^b NH [2f]
[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 [2f] used in this reaction can be 1.0 to 5.0 equivalents, preferably 1.0 to 1.5 equivalents, relative to compound [1f]. The amount of the condensing agent to be used can be 1.0 to 3.0 equivalents, preferably 1.0 to 1.5 equivalents, relative to compound [2f] or compound [1f].
Synthesis method 7)
Among the compounds [I] of the present invention, the following general formula [IG]:

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

[Wherein the symbols have the same meaning as described above. ]
Is converted to the corresponding acid chloride, and then the acid chloride and the following formula [2g]:

In a solvent (halogenated aliphatic hydrocarbons such as chloroform, ethers such as tetrahydrofuran, aromatic hydrocarbons such as toluene, etc.)-10 ° C. to the reflux temperature of the solvent, preferably 40 ° C. to The reaction product is reacted at the reflux temperature of the solvent, and then the reaction product is azodicarboxylic acid ester (azodicarboxylic acid) in a solvent (halogenated hydrocarbons such as dichloromethane, ethers such as tetrahydrofuran, aromatic hydrocarbons such as toluene). It can also be produced by treatment with diisopropyl acid, diethyl azodicarboxylate, etc.) and tri-substituted phosphines (triphenylphosphine, tributylphosphine, etc.).
Synthesis method 8)
Among the compounds [I] of the present invention, the following general formula [IH]:

[Wherein, R ⁰⁰ represents an alkyl group, an alkoxyalkyl group or a cycloalkyl group, and other symbols have the same meanings as described above. ]
For example, the compound represented by the formula [1g] is prepared by using a base (triethylamine, diisopropyl, etc.) in a solvent (aromatic hydrocarbons such as toluene, ethers such as tetrahydrofuran, halogenated aliphatic hydrocarbons such as chloroform, etc.). In the presence of ethylamine, etc., after treatment with chloroformate (isobutyl chloroformate, isopropyl chloroformate, etc.) to convert to the corresponding mixed acid anhydride, the mixed acid anhydride and the following general formula [1h]:

[Wherein the symbols have the same meaning as described above. ]
In a solvent (aromatic hydrocarbons such as toluene, ethers such as tetrahydrofuran, halogenated aliphatic hydrocarbons such as chloroform, etc.), 0 ° C. to the reflux temperature of the solvent, preferably 40 ° C. to the solvent It can also be made by reacting at the reflux temperature of.
Synthesis method 9)
Among the compounds [I] of the present invention, the compound in which the substituent on the ring A is a hydroxyl group (or a group containing a hydroxyl group) or an amino group (or a group containing an amino group) is protected, for example, by the corresponding substituent. The corresponding compound [I], which is a hydroxyl group (or a group containing a protected hydroxyl group) or a protected amino group (or a group containing a protected amino group), is converted into the protecting group (acetyl group, tetrahydropyranyl group, Depending on the kind of benzyl group, 2,4-dimethoxybenzyl group, tert-butyldimethylsilyl group, tert-butoxycarbonyl group, etc., it 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, tert-butoxycarbonyl or 2,4-dimethoxybenzyl group, the protecting group can be removed by acid treatment using hydrochloric acid, trifluoroacetic 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) or sodium hydroxide.
Synthesis method 10)
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 11)
The compound [I] in which the substituent on the ring A is an alkoxycarbonylalkoxy group is the same as the corresponding compound [I] in which the corresponding substituent is a hydroxyl group:
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 12)
The compound [I] in which the substituent on the ring A is an amino group substituted with an alkanoyloxyalkanoyl group includes the corresponding compound [I] in which the corresponding substituent is an amino group and the following 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 13)
The compound [I] in which the substituent on the ring A is a carbamoylmethyloxy group is obtained by reacting the corresponding compound [I] in which the corresponding substituent is an alkoxycarbonylmethyloxy group with ammonia (an alcohol such as methanol or a dioxane). It can be produced by reacting in ethers).
Synthesis method 14)
The compound [I] in which the substituent on the ring A contains a carboxyl group and a hydroxyalkyl group is obtained by reacting the corresponding compound [I] in which the corresponding substituent contains an alkoxycarbonyl group with a solvent (alcohol such as methanol, tetrahydrofuran Such as ethers, water, or a mixture thereof) or the like, or by treatment with a base (such as an alkali metal hydroxide such as sodium hydroxide) or an acid (such as hydrochloric acid).
Synthesis method 15)
The compound [I] in which the substituent on the ring A is a hydroxyethyl group is obtained by subjecting the corresponding compound [I] in which the corresponding substituent is a vinyl group to 9-borabicyclo [3. 3.1] After reacting with nonane (9-BBN), the reaction product can be produced by treating with hydrogen peroxide in the presence of a base (such as an alkali metal hydroxide such as sodium hydroxide). .
Synthesis method 16)
The substituent on ring A has the following formula:

Wherein Ring A ^b represents a 5-6 membered aliphatic nitrogen-containing heterocyclic group substituted by an oxo group (said heterocyclic group may further contain an oxygen atom as a hetero atom). ]
In the compound [I], which is a group represented by the following formula, the corresponding compound [I] in which the corresponding substituent is an amino group is dissolved 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 the same or different 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 17)
The substituent on ring A has the following formula:

Compound [I], which is a group represented by formula (I), is a compound represented by the following formula:
_{^{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 also be produced by reacting the compound represented by formula (I) 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 18)
Among the compounds [I] of the present invention, the following formula [Ib]:

Wherein Ring A ^c represents a benzene ring or pyridine ring, and other symbols have the same meaning. ]
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. ]
The reaction product is reacted in the presence or absence of a base (such as a tertiary amine such as triethylamine) in a solvent (ethers such as tetrahydrofuran, aromatic hydrocarbons such as toluene) in a solvent. 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 19)
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. ]
The compound represented by, for example, (a) the above compound [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) Or (b) the above compound [Ib] and the following formula [1ff-2]:
^{Z b O-Alk b -CHO [} 1ff-2]
[Wherein, Z ^b O represents a protected hydroxyl group, and Alk ^b represents a linear or branched alkylene group having 4 to 5 carbon atoms]
Is reacted in a suitable solvent (halogenated hydrocarbons such as dichloroethane) in the presence of a reducing agent (alkali metal borohydride such as sodium triacetoxyborohydride), and if necessary, It can be produced by removing a hydroxyl-protecting 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 20)
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 2-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 21)
The compound [I] in which the substituent on the ring A is an alkoxy group substituted with a hydroxyl group is obtained by reacting the corresponding compound [I] in which the corresponding substituent is a halogen atom (fluorine atom etc.) with a solvent (amides such as dimethylacetamide). In the presence of a base (sodium hydride, alkali metal carbonate such as potassium carbonate, tertiary amine such as triethylamine, etc.) in the presence of 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 22)
The substituent on ring A has the following formula:

Wherein Ring A ^d represents a hydroxyl group, an oxo group and a group optionally substituted 5-6 membered aliphatic nitrogen-containing heterocyclic selected from alkanoyl group radical substituted radicals. ]
The compound [I], which is a group represented by the formula (1), is obtained by subjecting the corresponding compound [I] whose corresponding substituent is a halogenomethyl group (such as a chloromethyl group) in a solvent (such as an amide 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 23)
The substituent on ring A has the following formula:

[Wherein, ring B ² has the same meaning as described above. ]
Compound [I], which is a group represented by formula (I), is prepared by using a corresponding compound [I] in which the substituent corresponding to R ⁰² is a halogen atom (fluorine atom or the like) and the cyclic amine compound [1ff] as a solvent (an amide such as dimethylacetamide). Etc.) or in the absence of a solvent 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.). it can.
Synthesis method 24)
The compound [I] in which the substituent on the ring A is a carbamoyloxy optionally substituted with an alkyl group is obtained by reacting the compound [I] in which the corresponding substituent is a hydroxyl group in an appropriate solvent (such as pyridine) with the following formula: :
R ^jj R ^kk N-COOH
(In the formula, R ^jj and R ^kk represent the same or different alkyl groups.)
It can manufacture by making it react with the carbamic acid compound or its reactive derivative (corresponding acid halide etc.) shown by these.
Synthesis method 25)
The substituent on ring A has the following formula:

[Wherein, ring ^Ae is a 5- or 6-membered aliphatic heteromonocyclic group optionally substituted with 1 to 2 groups selected from a hydroxyl group and an oxo group, R ^mm represents an alkyl group, The symbols have the same meaning as above. ]
In the compound [I], which is a group represented by the formula:

[Wherein the symbols have the same meaning as described above. ]
Compound [I] which is a group represented by formula (I) and an alkylating agent (alkyl halide such as methyl iodide) in a suitable solvent (nitriles such as acetonitrile), base (tertiary amine such as diisopropylethylamine, etc.) It can manufacture by making it react in presence.
Synthesis method 26)
The substituent on ring A has the following formula:

[Wherein the symbols have the same meaning as described above. ]
In the compound [I], which is a group represented by the formula:

[Wherein, R ⁿⁿ represents an amino-protecting group, and other symbols have the same meaning as described above. ]
The compound can be prepared by removing the amino-protecting group from the compound [I], which is a group represented by the formula: Examples of the protecting group for the amino group include a tert-butoxycarbonyl group. The protecting group can be removed by removing the protecting group-containing compound [I] in an appropriate solvent (halogenated hydrocarbons such as dichloromethane). It can be carried out by acid treatment (such as trifluoroacetic acid treatment).
Synthesis method 27)
The substituent on ring B is represented by the following formula:

[Wherein R ^ff represents an alkyl group which may be substituted with 1 to 3 halogen atoms. ]
Compound [I], which is a group represented by
(A) the corresponding substituent on ring B has the following formula:

Compound [I] which is a group represented by the following formula [1gg]:
R ^ff -COX ⁶ [1 gg]
[Wherein, X ⁶ represents a halogen atom, and other symbols have the same meaning as described above. ]
Or a base (such as a tertiary amine such as triethylamine) in a suitable solvent (such as an aromatic hydrocarbon such as toluene), or (B) the corresponding substituent on ring B is a cyano group A certain compound [I] and hydroxylamine are reacted in a suitable solvent (alcohol such as isopropanol), and then the reaction product and the compound [1 gg] are reacted with a suitable solvent (aromatic hydrocarbons such as toluene). ) In the presence of a base (such as a tertiary amine such as triethylamine).
Synthesis method 28)
The compound [I] in which the substituent on the ring A or the substituent on the ring B is a group containing a halogenoalkyl group is, for example, suitable for the compound [I] in which the corresponding substituent is a group containing a hydroxyalkyl group. It can be produced by treating with a halogenating agent (such as diethylaminosulfur trifluoride (DAST)) in a solvent (halogenated hydrocarbons such as dichloromethane).

  Of the intermediate compound [1a] in the present invention, the following general formula [1a-1]:

[Wherein the symbols have the same meaning as described above. ]
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 (reaction scheme B).

  Among the intermediate compounds [1a] in the present invention, the following general formula [1a-2]:

[Wherein the symbols have the same meaning as described above. ]
For example, the compound represented by the above formula [16a] and the following formula:

[Wherein, Me represents a methyl group, and other symbols have the same meaning as described above. ]
Is reacted in an appropriate solvent (such as ethers such as 1,4-dioxane) in the presence of a base (such as an alkali metal carbonate such as cesium carbonate), and then the reaction product is reacted with a catalyst (palladium). -By reducing in the presence of carbon or the like).

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

[In the above scheme, X ² represents a halogen atom, and other symbols have the same meaning as described above. ]
The reaction between compound [11b] and compound [2a] can be carried out in the same manner as in the reaction between compound [1a] and compound [2a] described above (Reaction Scheme A).

  Conversion of compound [13b] to compound [1b] can be carried out by treating compound [13b] with a halogenating agent (thionyl chloride / dimethylformamide, etc.) in a 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 intermediate compound [1c] in the present invention is produced, for example, by reacting the compound [1b] with 4-hydroxypiperidine in a solvent (such as ethers such as tetrahydrofuran) in the presence of a base (such as diisopropylethylamine). be able to.

The intermediate compound [1d] in the present invention can be produced, for example, by converting the hydroxyl group in the compound [1c] to a desired leaving group. For example, the compound [1d] in which X ³ is a methanesulfonyl group or a trifluoromethanesulfonyl group is obtained by reacting the compound [1c] in the presence of a base (such as triethylamine) in a solvent (such as a halogenated hydrocarbon such as dichloromethane). :
X ³¹ -Cl [b]
[Wherein, X ³¹ represents a methanesulfonyl group or a trifluoromethanesulfonyl group. ]
It can manufacture by making it react with the compound shown by these. This reaction can be carried out at −10 ° C. to the reflux temperature of the solvent, preferably 0 ° C. to room temperature.

  The intermediate compound [1e] in the present invention includes, for example, the following formula [I-E1]:

[Wherein Boc represents a tert-butoxycarbonyl group, and other symbols have the same meanings as described above. ]
Can be produced by acid treatment in a solvent. Any solvent may be used as long as it does not interfere with the reaction. Examples of such solvents include halogenated aliphatic hydrocarbons such as dichloromethane and chloroform, esters such as ethyl acetate, ethers such as dioxane, and the like. Examples thereof include a mixture. Examples of the acid include hydrochloric acid and trifluoroacetic acid. This reaction can be carried out at −10 ° C. to the reflux temperature of the solvent, preferably from room temperature to the reflux temperature of the solvent.

Among the intermediate compounds in the present invention, the following general formula [1f]:
For example, the following formula [I-F1]:

[Wherein, the ring Ab is a 5- or 6-membered aryl group optionally substituted with a group selected from a halogen atom, a cyano group and an alkyl group (the aryl group is the same or selected from an oxygen atom, a sulfur atom and a nitrogen atom) May represent 1 to 2 different heteroatoms), and other 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 Me: methyl Et: ethyl i-Pr: isopropyl i-Bu: isobutyl Ph: phenyl Ac: acetyl TBDMS (or TBDS): tert-butyldimethylsilyl DMF: dimethylformamide DMSO: dimethyl sulfoxide THF TFA: trifluoroacetic acid DAST: (diethylamino) sulfur trifluoride CDI: 1,1′-carbonyldiimidazole HOBt: 1-hydroxybenzotriazole DIAD: diisopropyl azodicarboxylate BOP: hexafluorophosphoric acid benzotriazol-1-yloxytris (Dimethylamino) phosphonium dppf: Diphenylphosphinoferrocene PPh ₃ : Triphenylphos Fin HPLC: High performance liquid chromatography

Example A1
2-Fluoro-4- {5-fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl} -N -Production of methylbenzamide hydrochloride

8-Bromo-5-fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazoline in 200 mg 2-fluoro-N-methyl- 4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzamide 150 mg, 2M aqueous sodium carbonate 1.66 mL, tetrakis (triphenylphosphine) palladium (0) 30 mg and 30 mL of dioxane was added, and the mixture was reacted at 110 ° C. for 30 minutes in a microwave reactor (Emrys Optimizer, Biotage). The reaction mixture was extracted with dichloromethane, and the organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMSO and purified by reverse phase HPLC. [Column: Capcelpack C18 UG80, Shiseido, 5 μm, 20 mm × 250 mm, mobile phase A: 0.05% trifluoroacetic acid / water, mobile phase B: 0.05% Trifluoroacetic acid / acetonitrile, flow rate 15 mL / min (mobile phase B 35% → 80%) Fractions containing the reaction product were collected and concentrated, and the residue was dissolved in methanol.The solution was added to MT-Carbonate (Biotage). After removing the trifluoroacetic acid and concentrating under reduced pressure, the residue was dissolved in an ethyl acetate / ethyl ether mixture, 4N hydrochloric acid / ethyl acetate (150 μL) was added, and the precipitate was collected by filtration at 40 ° C. By drying under reduced pressure, 57.9 mg of the title compound was obtained (yield 22.6%).
MS (ESI) m / z: 493.3 [M + H] ^+
1 H-NMR (CDCl ₃ ) δ: 1.24-1.26 (6H, d, J = 6.95 Hz), 1.89-1.93 (2H, m), 2.21-2.25 ( 2H, m), 2.82-2.83 (3H, m), 3.01-3.10 (1H, m), 3.50-4.35 (6H, m), 7.45-7. 59 (3H, m), 7.74-7.80 (1H, t), 7.96-8.00 (1H, m), 8.33-8.37 (1H, m), 8.58 ( 1H, s).

Example A2
2-Fluoro-4- {4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl} -N, N-dimethyl Production of benzamide hydrochloride

(1) Thionyl chloride 1.8 mL and DMF 0.1 mL were added to 273.1 mg of 2-fluoro-N, N-dimethyl-4- (4-oxo-3,4-dihydroquinazolin-8-yl) benzamide, and the mixture Was stirred under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane. The solution was poured into ice water, washed with water, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 260 mg of 4- (4-chloroquinazolin-8-yl) -2-fluoro-N, N-dimethylbenzamide. Obtained. After adding 3 mL of THF to 46.2 mg of the compound and stirring the mixture at room temperature, 27.4 mg of 4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidine and diisopropylethylamine were added to the solution. 0.05 mL was added and the mixture was stirred at room temperature overnight. The reaction mixture was extracted with dichloromethane, and the organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (solvent: chloroform) to give 2-fluoro-4- {4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidine- 41.5 mg of 1-yl] quinazolin-8-yl} -N, N-dimethylbenzamide was obtained as an oil (yield 60.7%).
¹ H-NMR (CDCl ₃ ) δ: 1.35-1.37 (6H, d, J = 7 Hz), 2.20-2.34 (4H, m), 3.06-3.17 (7H, m), 3.31-3.41 (3H, m), 4.32-4.35 (2H, m), 7.46-7.56 (4H, m,), 7.76-7.78. (1H, d, J = 6.92 Hz), 7.93-7.95 (1H, t), 8.80 (1H, s).

(2) To a solution of the compound (41.5 mg) obtained in (1) above in 3 mL of ethyl ether was added 4N hydrochloric acid / ethyl acetate (0.05 mL) and the mixture was stirred overnight. The precipitate was collected by filtration, washed with ethyl ether, and dried under reduced pressure at 60 ° C. to give 36.8 mg of the title compound (yield 82.5%).
¹ H-NMR (CDCl ₃ ) δ: 1.35 to 1.36 (6H, d), 2.22-2.29 (2H, m), 2.42-2.45 (2H, m), 3 .08-3.14 (1H, m), 3.16 (3H, s), 3.26 (3H, s), 3.49-3.54 (1H, m), 3.94-3.98 (2H, t), 4.76 (2H, brs), 7.18-7.20 (1H, d, J = 8.99 Hz), 7.30-7.31 (1H, d, J = 7. 70 Hz), 7.61-7.64 (1H, t, J = 7.22), 7.71-7.64 (1H, t, J = 7.86), 7.85-7.86 (1H) , D, J = 7.06), 7.97-7.99 (1H, d, J = 8.34), 8.92 (1H, s)
MS (ESI) m / z: 389.3 [M + H] < ⁺ >.

Example A3
Of 6-fluoro-8- (2-fluoro-4-mesylphenyl) -4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazoline Manufacturing

6-Fluoro-8- (2-fluoro-4-methylsulfanylphenyl) -4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazoline (Compound obtained in Example A31) To a solution of 27.0 mg of dichloromethane in 1 mL were added 22 μL of methanesulfonic acid and 29 mg of m-chloroperbenzoic acid, and the mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in 1.5 mL of dichloromethane. 44 μL of methanesulfonic acid and 58 mg of m-chloroperbenzoic acid were added to the solution, and the mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and 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 chromatography (solvent: chloroform / methanol = 19/1) to give 5.2 mg of the title compound as a powder (yield 18.1%). .
MS (APCI) m / z; 514 [M + H] ^< +>.

Example A4
Preparation of N, N-dimethyl-4- {4- [4- (3-methylbutylsulfanyl) piperidin-1-yl] quinazolin-8-yl} benzamide

After adding 50 μl of 1- [8- (4-dimethylcarbamoylphenyl) quinazolin-4-yl] piperidin-4-yl ester of methanesulfonic acid to 42 mg of 3-methylbutane-1-thiol and 70 μL of 5M sodium methoxide-methanol solution And heated in a microwave reactor (Emmys Optimizer, Biotage) at 110 ° C. for 1 hour. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC [column: Capcelpack C18 UG80, 5 μm, 20 mm × 100 mm, manufactured by Shiseido; mobile phase A: 0.05% trifluoroacetic acid / water; mobile phase B: 0.05% trifluoroacetic acid / acetonitrile, flow rate 15 mL / min (mobile phase B 35% → 80%)]. Fractions containing the reaction product were collected and concentrated. A saturated aqueous sodium hydrogen carbonate solution and dichloromethane were added to the residue, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 25.4 mg of the title compound (yield). Rate 49.9%).
MS (ESI) m / z; 463.1 [M + H] ^< +>.

Example A5
Preparation of 2-fluoro-4- {5-fluoro-4- [4- (4-fluorophenoxy) piperidin-1-yl] quinazolin-8-yl} -N, N-dimethylbenzamide

2-fluoro-4- [5-fluoro-4- (4-hydroxypiperidin-1-yl) quinazolin-8-yl] -N, N-dimethylbenzamide 100 mg, 4-fluorophenol 32.6 mg and triphenylphosphine 76 62 μL of diisopropyl azodicarboxylate was added to 3 mg of THF 2.5 mL solution, and the mixture was stirred at 50 ° C. for 3 hours. The reaction mixture was concentrated, and the residue was dissolved in 2.4 mL of dimethyl sulfoxide and then purified by reverse phase HPLC [Column: XBridge ODS C18, 5 μm, 19 mm × 100 mm, Waters; mobile phase A: 10 mM ammonium carbonate / water; mobile phase B: acetonitrile, flow rate 15 mL / min (mobile phase B 60% → 90% / 6 min) The fraction containing the reaction product (RT = 3.92 to 4.23 min) is collected and concentrated to give the title compound 59.0 mg was obtained (48% yield).
MS (ESI) m / z: 507.2 [M + H] &lt; ⁺ &gt;.
¹ H-NMR (CDCl ₃ ) δ: 1.97-2.06 (2H, m), 2.08-2.17 (2H, m), 3.05 (3H, s), 3.16 (3H , S), 3.62-3.68 (2H, m), 3.88-3.95 (2H, m), 4.52-4.56 (1H, m), 6.88-6.94. (2H, m), 6.96-7.03 (2H, m), 7.14-7.20 (1H, dd, J = 8.3 Hz, 10.9 Hz), 7.41-7.52 ( 3H, m), 7.67-7.72 (1H, dd, J = 5.8 Hz, 8.2 Hz), 8.65 (1H, s).

Example A6
Preparation of 2-fluoro-N, N-dimethyl-4- {4- [4- (4-methylpentyl) piperazin-1-yl] quinazolin-8-yl} benzamide

2-Fluoro-N, N-dimethyl-4- [4- (piperazin-1-yl) quinazolin-8-yl] benzamide dihydrochloride 100 mg in DMF 3 mL solution in 122 mg potassium carbonate, catalytic amount of potassium iodide and 1- Bromo-4-methylpentane (38 μL) was added and the mixture was stirred at 50 ° C. for 10 hours. The reaction mixture was heated to 90 ° C. and further stirred for 6 hours. The reaction mixture was concentrated, water was added to the residue, pH was adjusted to 7 with 1N hydrochloric acid, and the mixture was extracted with dichloromethane. The organic layer was dried over a diatomaceous earth column and magnesium sulfate and then concentrated. The residue was dissolved in DMSO and purified by reverse phase HPLC [Column: XBridge ODS, C18, 5 μm, 19 mm × 100 mm, manufactured by Waters; mobile phase A: 10 mM ammonium carbonate / water; mobile phase B: acetonitrile, flow rate 15 mL / min. (Mobile phase B 60% → 90% / 6 minutes)]. By concentrating the fraction containing the reaction product (RT = 3.84 to 4.38 min), 33.2 mg of the title compound was obtained as a white powder (yield 32%).
MS (ESI) m / z: 464.3 [M + H] &lt; ⁺ &gt;.
¹ H-NMR (CDCl ₃ ) δ: 0.89-0.92 (6H, d, J = 6.6 Hz), 1.18-1.26 (2H, m), 1.53-1.64 ( 3H, m), 2.48-2.53 (2H, m), 2.78 (4H, brs), 3.05 (3H, s), 3.25 (3H, s), 3.89 (4H) , Brs), 7.45-7.55 (4H, m), 7.74-7.77 (1H, dd, J = 1.3 Hz, 7.2 Hz), 7.91-7.94 (1H, dd, J = 1.3 Hz, 8.3 Hz), 8.77 (1H, s).

Example A7
Preparation of 4- [4- (4-cyclohexylmethylpiperazin-1-yl) -5-fluoroquinazolin-8-yl] -2-fluoro-N, N-dimethylbenzamide

2-fluoro-4- [5-fluoro-4- (piperazin-1-yl) quinazolin-8-yl] -N, N-dimethylbenzamide dihydrochloride 100 mg in DMF 2 mL solution in potassium carbonate 117 mg, potassium iodide 3. 5 mg and 45 μL of bromomethylcyclohexane were added and the mixture was stirred at 90 ° C. for 6 hours. To the reaction mixture were added potassium iodide and 135 μL of bromomethylcyclohexane, and the mixture was further stirred at 90 ° C. for 14 hours. The reaction mixture was concentrated, water was added, and the pH was adjusted to 7 with 1N hydrochloric acid. The mixture was extracted with dichloromethane, and the organic layer was dried over a diatomaceous earth column and magnesium sulfate and then concentrated. The residue was dissolved in dimethyl sulfoxide and purified by reverse phase HPLC [column: XBridge ODS column, C18, 5 μm, 19 mm × 100 mm, Waters; mobile phase A: 10 mM ammonium carbonate / water; mobile phase B: acetonitrile, flow rate 15 mL / Min (mobile phase B 80% → 100% / 6 min)]. Fractions containing the reaction product (RT = 3.60-4.21 min) were collected and concentrated to give 15.3 mg of the title compound as a pale yellow powder (yield 15%).
MS (ESI) m / z: 494.3 [M + H] &lt; ⁺ &gt;.
¹ H-NMR (CDCl ₃ ) δ: 0.87-0.95 (2H, m), 1.19-1.27 (2H, m), 1.49-1.56 (1H, m), 1 .64-1.83 (6H, m), 2.18-2.21 (2H, d, J = 7.1 Hz), 2.54-2.57 (4H, brs), 3.05 (3H, s), 3.16 (3H, s), 3.73 (4H, brs), 7.11-7.18 (1H, dd, J = 8.3 Hz, 10.8 Hz), 7.41-7. 52 (3H, m), 7.65-7.70 (1H, dd, J = 5.7 Hz, 8.3 Hz), 8.62 (1H, s).

Example A8
4- {4- [4- (4-Methoxybenzyloxy) piperidin-1-yl] quinazolin-8-yl} -N, N dimethylbenzamide Preparation of trifluoroacetate

4- [4- (4-Hydroxypiperidin-1-yl) quinazolin-8-yl] -N, N-dimethylbenzamide 6.4 mg of 60% sodium hydride was added to a solution of 30 mg of THF and the mixture was added at room temperature. Stir for hours. To the reaction mixture, 22 μL of 4-methoxybenzyl chloride was added and further stirred for 15 hours. The reaction mixture was extracted with chloroform, the organic layer was washed with water, dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified by reverse phase HPLC [column: Capcelpack C18 UG80, 5 μm, 20 mm × 100 mm, manufactured by Shiseido; mobile phase; A: 0.05% trifluoroacetic acid / water; mobile phase B: 0.05% trifluoroacetic acid / acetonitrile, flow rate 15 mL / min (mobile phase B 35% → 80%)]. Fractions containing the reaction product were collected and concentrated under reduced pressure to give 18.7 mg of the title compound (yield 38.3%).
MS (ESI) m / z: 497 [M + H] ^< +>.

Examples A9 to A147
The corresponding starting material compounds were treated in the same manner as in Example A1 to give the compounds described in Tables 1 to 16 below.

Examples A148-A166
The corresponding starting material compounds were treated in the same manner as in Example A2 to obtain the compounds described in Tables 17-19 below.

Examples A167-A174
The corresponding starting material compounds were treated in the same manner as in Example A4 to obtain the compounds shown in Table 20 below.

Examples A175-A187
The corresponding starting materials were treated in the same manner as in Example A5 to obtain the compounds described in Tables 21-22 below.

Example A188
The corresponding starting compounds were treated in the same manner as in Example A6 to give the compounds shown in Table 23 below.

Example A189
The corresponding starting material compounds were treated in the same manner as in Example A7 to obtain the compounds shown in Table 24 below.

Example A190
2-Fluoro-4- {6-fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl} -N Preparation of-(3-hydroxypropyl) -N-methylbenzamide

(1) 8-Bromo-6-fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazoline (obtained in Reference Example B12) Compound (500 mg) and 4-carboxy-3-fluorophenylboronic acid (328 mg) were treated in the same manner as in Example A1 to give 2-fluoro-4- {6-fluoro-4- [4- (3-isopropyl- [ 280 mg of 1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl} benzoic acid was obtained as a colorless solid (49% yield).
MS (APCI) m / z; 480 [M + H] ^< +>.

(2) 50 mg of the compound obtained in (1) above, 37.4 mg of chloroform solution of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 47.4 mg and N-hydroxybenzotriazole 33.4 mg -(Methylamino) -1-propanol 23.4 μL was added dropwise and the mixture was stirred overnight. Water was added to the reaction mixture and the mixture was extracted with dichloromethane. 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 (Chromatorex; Fuji Silysia Chemical, solvent: hexane / ethyl acetate = 60/40 → 10/90) to give 39.6 mg of the title compound. Was obtained as a colorless solid (44% yield).
MS (APCI) m / z; 551 [M + H] ^< +>.

Example A191
3-Fluoro-4- {6-fluoro-4- [4-((S) -4-isopropyl-4,5-dihydrooxazol-2-yl) piperidin-1-yl] quinazolin-8-yl} -N Of N, N-dimethylbenzamide

(1) Thionyl chloride (29.8 μL) was added dropwise to 900 μL of a chloroform solution of 90 mg of 1- [8- (4-dimethylcarbamoyl-2-fluorophenyl) -6-fluoroquinazolin-4-yl)] piperidine-4-carboxylic acid. The mixture was stirred at 65 ° C. for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the corresponding acid chloride as a yellow solid. To a 900 μL solution of the acid chloride in chloroform, 4 mL of a 52.7 mg chloroform solution of L-valinol was added dropwise at 0 ° C. over 20 minutes. The mixture was stirred for 2 hours, water was added, and the mixture was extracted with chloroform. 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, solvent; chloroform / methanol = 100/0 → 91/9) to give N- (S) -1-hydroxymethyl. There was obtained 47.8 mg of 2-methylpropyl-1- [8- (4-dimethylcarbamoyl-2-fluorophenyl) -6-fluoroquinazolin-4-yl] piperidine-4-carboxamide as a colorless solid (yield 45 %).
MS (APCI) m / z; 526 [M + H] ^< +>.

(2) 35.5 μL of diisopropyl azodicarboxylate was added dropwise to 5.6 mL of a dichloromethane solution of 47.0 mg of the compound obtained in (1) above and 58.6 mg of triphenylphosphine, and the mixture was stirred overnight. Water was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was washed 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 (chloroform / methanol = 100/0 → 95/5) to give 46 mg of the title compound as a colorless solid (yield 99%).
MS (APCI) m / z; 508 [M + H] ^< +>.

Example A192
3-Fluoro-4- [6-fluoro-4- [4- [3- (2-methoxyethyl)-[1,2,4] oxadiazol-5-yl] piperidin-1-yl] quinazoline-8 -Il] -N, N-dimethylbenzamide production

(1) 80 mg of 1- [8- (4-dimethylcarbamoyl-2-fluorophenyl) -6-fluoroquinazolin-4-yl)] piperidine-4-carboxylic acid (the compound obtained in Reference Example A43) and triethylamine 25 23.6 μL of isobutyl chloroformate was added dropwise to a 3 μL toluene (1.6 mL) solution at 0 ° C., and the mixture was stirred at room temperature for 1.5 hours. 21.5 mg of N-hydroxy-3-methoxypropanimidamide was added dropwise to the reaction mixture, and the mixture was stirred at 120 ° C. for 6 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, and the obtained residue was purified by NH-silica gel column chromatography (Chromatorex, solvent; hexane / ethyl acetate = 95/5 → 25/75) to give 67.7 mg of the title compound as a colorless solid. Obtained (yield 71%).
MS (APCI) m / z; 523 [M + H] ^< +>.

Examples A193 to A196
The corresponding starting compounds were treated in the same manner as in Example A1 to give the compounds shown in Table 25 below.

Examples A197 to A198
The corresponding starting material compound was treated in the same manner as in Example A3 to give the compounds shown in Table 26 below.

Examples A199-A202
The corresponding starting material compounds were treated in the same manner as in Example A190 to give the compounds as shown in Table 27 below.

Example B1
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 B9) 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 B16), 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. 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, solvent; hexane / ethyl acetate = 95/5 to 75/25) to give 62.7 mg of the title compound as a colorless solid. Obtained (yield: 50%).
MS (APCI) m / z; 526 [M + H] +.

Example B2
[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 B26) 45 mg and (R)-(+)-3-pyrrolidinol 9.8 mg, 27 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzo Triazole monohydrate (19 mg) in chloroform (0.9 mL) was 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 concentrated under reduced pressure, and the resulting residue was subjected to NH-silica gel column chromatography (Chromatorex, solvent; chloroform / methanol = 100/0 to 97/3) and gel permeation chromatography (JAIGEL-1H, 2H: Japan analysis). Purification by Kogyo Co., Ltd., 20 mm × 600 mm, mobile phase: chloroform, flow rate 4 mL / min) and crystallization from ethyl acetate and diisopropyl ether gave 41 mg of the title compound as a colorless solid (yield 80%).
MS (APCI) m / z; 549 [M + H] +.

Example B3
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 B35) 109 mg of 1,4-dioxane 5 mL was added with 4 N 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, solvent; hexane / ethyl acetate = 67 / 33-20 / 80) to give 86 mg of the title compound as a colorless solid. (Yield 92%).
MS (APCI) m / z; 512 [M + H] +.

Example B4
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 B3 in 2 mL of dichloromethane under ice cooling, 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, solvent; hexane / ethyl acetate = 50 / 50-0 / 100) to give 39 mg of the title compound as a colorless powder. (Yield: 49%).
MS (APCI) m / z; 544 [M + H] +.

Example B5
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 B9 and the compound (203 mg) obtained in Reference Example B23 were treated in the same manner as in Example B1 to obtain 179 mg of the title compound as a viscous oil (yield: 57 %).
MS (APCI) m / z; 524 [M + H] +.

Example B6
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 B5) 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 B7
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 B23) To 55 mg was added 2 mL of a 25% odorous acid-acetic acid solution, and the mixture was 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 filtered to give 30 mg of the title compound as a solid (yield: 56%).
MS (APCI) m / z; 452 [M + H] +.

Example B8
[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 B7) 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, solvent; hexane / ethyl acetate = 90/10 to 70/30) to give 380 mg of the title compound as a colorless solid. (Yield: 71%).
MS (APCI) m / z; 538 [M + H] +.

Example B9
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 Compound Obtained in Reference Example B46) 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, solvent; hexane / ethyl acetate = 90 / 10-50 / 50) to give 83 mg of the title compound as a colorless solid. (Yield: 60%).
MS (APCI) m / z; 551 [M + H] +.

Example B10
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 B8 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 B11
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 B9) 75 mg of 2N sodium hydroxide 2 mL, THF 2 mL and methanol 2 mL were stirred at room temperature for 2 hours. 10 mL of an aqueous solution of 1.36 g of potassium dihydrogen phosphate 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 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 B12
[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 Ethyl acetate (compound obtained in Reference Example B52) 750 mg of 2N sodium hydroxide 20 mL, THF 10 mL and methanol 10 mL were 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 B13
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 B48) To 95 mg of THF 2 mL solution, 9-borabicyclo [3,3,1] nonane (9-BBN) THF 0.5 mol / L solution 0.82 mL was added under nitrogen atmosphere, and the mixture was added. Stir 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 B14
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 B46) 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 THF. 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 B15
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 (compound obtained in Reference Example B46) 160 mg in 3 mL of THF, 53 μL of 2-chloroethyl isocyanate and 214 μL of triethylamine were added, 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 THF, and then 20 mg of sodium hydride was added to the solution, followed by stirring 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 B16
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 B15) 4 mg of sodium hydride was added to 45 mg of 1 mL of dimethylformamide, 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 B17
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 B49) 38 mg of THF 3 mL solution was added 35 mg of tetrabutylammonium fluoride, 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 B18
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 B51) 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). To the reaction mixture was added 6 mg of sodium hydride, and the mixture was stirred at room temperature for 30 minutes and further heated at 100 ° C. for 1 hour in the same microwave reactor. 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 B19
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 B50) 12 mg of sodium hydride was added to a solution of 95 mg of pyrrolidone in 1 mL, 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 B20 to B27
The corresponding starting materials were treated in the same manner as in Example B1 to give the compounds shown in Table 28 below.

Examples B28-B66
The corresponding starting materials were treated in the same manner as in Example B2 to give the compounds shown in Tables 29 to 34 below.

Examples B67-B74
The corresponding starting material compound was treated in the same manner as in Example B3 to give the compounds shown in Table 35 below.

Examples B75-B83
The corresponding starting materials were treated in the same manner as in Example B4 to give the compounds described in Tables 36 to 37 below.

Example B84
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 B6 to give the title compound as a solid (yield: 39%).
MS (APCI) m / z: 540 [M + H] ^< +>.

Example B85
The corresponding starting materials were treated in the same manner as in Example B11 to give the compounds as shown in Table 38 below.

Example B86
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 B12 to give the title compound as a powder (yield: 65%).
MS (APCI) m / z: 613 [M + H] ^< +>.

Example B87
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 B46) and 42 μL of 4-chlorobutyric chloride in the same manner as in Example B14 (yield: 64 %).
MS (APCI) m / z: 519 [M + H] ^< +>.

Example B88
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 B11 to give the title compound (54.1 mg) as a powder (yield: 90.8%).
MS (APCI) m / z: 535 [M + H] ^< +>.

Example B89
(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 B51 and 32 mg of (R) -3-hydroxypyrrolidine in 2 mL of dimethylacetamide, and the mixture was heated at 150 ° C. for 1 hour in a microwave reactor (Initiator). did. 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 B90
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 B55) and 32 μL of bromoacetic acid chloride were treated in the same manner as in Example B9. To a 4 mL THF 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 B91
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 B94) in 2 mL of acetonitrile, 43 μL of iodoethane and 115 μL of ethyldiisopropylamine were added, and the mixture was added to a microwave reactor (Initiator). The mixture was heated at 120 ° C. for 4 hours. The reaction mixture is sequentially purified by silica gel column chromatography (solvent; chloroform / methanol = 100/0 to 93/7) and NH silica gel chromatography (Chromatorex, solvent: hexane / ethyl acetate = 40/60 to 10/90). As a result, 7.6 mg of the title compound was obtained as a colorless powder (yield: 10%).
MS (APCI) m / z: 562 [M + H] ⁺
Example B92
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 B57) and 125 μL of 2- (tert-butyldimethylsilyloxy) ethyl bromide were treated in the same manner as in Example B16, and then obtained. The crude product was treated in the same manner as in Example B17 to obtain 27.3 mg of the title compound as a colorless powder (yield: 26%).
MS (APCI) m / z: 560 [M + H] ⁺
Example B93
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 B15) 100 mg and 2- (3-bromopropoxy) tetrahydropyran 98 μL were treated in the same manner as in Example B16, and then the crude product obtained. Was treated in the same manner as in Example B3 to obtain 46.9 mg of the title compound as a colorless powder (yield: 42%).
MS (APCI) m / z: 578 [M + H] ^< +>.

Example B94
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 B54) was added to 2 mL of dichloromethane in 2 mL of trifluoroacetic acid, 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), 2 mL of dichloromethane and 0.5 mL of triethylamine were added, and the mixture was stirred for 10 minutes. The reaction mixture is sequentially purified by silica gel column chromatography (solvent; chloroform / methanol = 100/0 to 91/9) and NH-silica gel chromatography (Chromatorex, solvent: chloroform / methanol = 100/0 to 97/3). As a result, 7.6 mg of the title compound was obtained as a colorless powder (yield: 73%).
MS (APCI) m / z: 534 [M + H] ^< +>.

Example B95
(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 B119) ) 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 (compound obtained in Reference Example B86) 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, solvent; hexane / ethyl acetate: 80/20 to 55/45). The obtained crude product was treated in the same manner as in Example B17 to obtain 83.2 mg of the title compound as a colorless solid (yield: 67.7%).
MS (APCI) m / z; 533 [M + H] ^< +>.

Example B96
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 (compound obtained in Reference Example B9) 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 B1, and then the resulting crude product was treated in the same manner as in Example B3 to obtain 153.6 mg of the title compound as a colorless powder. (Yield: 75%).
MS (APCI) m / z: 574 [M + H] ^< +>.

Example B97
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 B9) 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 B146), 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, 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 B98
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 (Compound obtained in Reference Example B109) 95.7 mg, 1- [2- (tert-butyldimethylsilyloxy) ethyl] -3- [2-fluoro-4- (4,4,5,5-tetra 112 mg of methyl- [1,3,2] dioxaborolan-2-yl) phenyl] imidazolidin-2-one (compound obtained in Reference Example B81), [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. It was. 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, solvent; hexane / ethyl acetate: 72/28 to 50/50). The obtained crude product was treated in the same manner as in Example B11 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 B99
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 amine (compound obtained in Reference Example B130) 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, solvent; hexane / ethyl acetate: 70 / 30-50 / 50) to give 61.7 mg of the title compound as a colorless powder. Obtained (yield: 79.9%).
MS (APCI) m / z; 517 [M + H] ^< +>.

Example B100
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 B88) DAST 18.5 μL was added to a solution of 67 mg of dichloromethane 0.7 mL under ice-cooling, and the temperature was 0 to 5 ° C. Stir 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, 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 aqueous ammonium carbonate solution, purified sequentially at a flow rate of 40 mL / min (mobile phase B 60% → 75% / 5 min) to give 15.1 mg of the title compound colorless. Obtained as a powder (yield: 40.1%).
MS (APCI) m / z; 537 [M + H] ^< +>.

Example B101
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 (compound obtained in Example B98) 81 mg dichloromethane To the 1.2 mL solution, 30.8 μL of DAST was added under ice cooling, and the mixture was stirred at 0-5 ° 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, solvent; hexane / ethyl acetate: 76/24 to 55/45). The obtained crude product was treated in the same manner as in Example B17, and 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 B102
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 B97) 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 B103
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 B97) 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 B17 to obtain 14.3 mg of the title compound as a colorless powder (yield: 27.8%).
MS (APCI) m / z; 564 [M + H] ^< +>.

Example B104
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 B158) (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 B102 to give 12.8 mg of the title compound as a colorless powder (yield: 5.6%).
MS (APCI) m / z; 562 [M + H] +.

Examples B105-138
The corresponding starting materials were treated in the same manner as in Example B1, to give the compounds shown in Tables 39 to 43 below.

Examples B139-B176
The corresponding starting material compounds were treated in the same manner as in Example B2 to give the compounds listed in Tables 44 to 48 below.

Examples B177 to B251
The corresponding starting materials were treated in the same manner as in Example B95 to give the compounds shown in Tables 49 to 58 below.

Example B252
The corresponding starting material compound was treated in the same manner as in Example B17 to obtain the compound shown in Table 59 below (15.4 mg) (yield: 65%).

Examples B253 to B260
The corresponding starting materials were treated in the same manner as in Example B96 to give the compounds as shown in Table 60 below.

Examples B261 to B262
The corresponding starting compounds were treated in the same manner as in Example B2 to give the compounds shown in Table 61 below.

Examples B263 to B265
The corresponding starting material compound was treated in the same manner as in Example B9, to give compounds as shown in Table 62 below.

Examples B266-B272
The corresponding starting material compound was treated in the same manner as in Example B11, to give compounds as shown in Table 63 below.

Examples B273 to B276
The corresponding starting compounds were treated in the same manner as in Example B14 to give the compounds shown in Table 64 below.

Examples B277 to B278
The corresponding starting material compound was treated in the same manner as in Example B15, to give compounds as shown in Table 65 below.

Examples B279-B280
The corresponding starting compounds were treated in the same manner as in Example B16 to give the compounds as shown in Table 66 below.

Example B281
The corresponding starting compounds were treated in the same manner as in Example B89 to give the compounds as shown in Table 67 below.

Examples B282 to B284
The corresponding starting materials were treated in the same manner as in Example B89 to give the compounds as shown in Table 68 below.

Example B285
The corresponding starting compounds were treated in the same manner as in Example B90 to give the compounds as shown in Table 69 below.

Example B286
The corresponding starting materials were treated in the same manner as in Example B91 to give the compounds as shown in Table 70 below.

Examples B287-B289
The corresponding starting material compound was treated in the same manner as in Example B92, to give compounds as shown in Table 71 below.

Example B290
The corresponding starting material compound was treated in the same manner as in Example B98 to give the compounds shown in Table 72 below.

Examples B291-B295
The corresponding starting compounds were treated in the same manner as in Example B99 to give the compounds as shown in Table 73 below.

Example B296
The corresponding starting material compound was treated in the same manner as in Example B103, to give compounds as shown in Table 74 below.

Example B297
[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 (compound obtained in Reference Example B9) 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 B185), [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. 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, solvent; hexane / ethyl acetate: 90 / 10-50 / 50) to give the title compound as a powder (yield: 69%).
MS (APCI) m / z; 466 [M + H] ^< +>.

Examples B298 to B299
The corresponding starting material compound was treated in the same manner as in Example B297 to obtain the compound shown in Table 75 below.

Example B300
Preparation of 2-fluoro-4- [5-fluoro-4- [4- (5-methylpyrimidin-2-yl) piperazin-1-yl] quinazolin-8-yl] -N, N-dimethylbenzamide

2-Fluoro-N, N-dimethyl-4- [4- [4- (4-methylpentyl) piperazin-1-yl] quinazolin-8-yl] benzamide dihydrochloride (compound obtained in Reference Example A34) 1 mL of a DMSO solution containing 50 mg and 2-chloro-5-methylpyrimidine 20.5 mg was stirred at 80 ° C. overnight. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated, and the resulting crude product was purified by NH-silica gel chromatography (Chromatorex, solvent: hexane / ethyl acetate = 75 / 25-40 / 60) to give 15.3 mg of the title compound as a colorless powder. (Yield: 62).
MS (APCI) m / z; 490 [M + H] ⁺
Example B301
3-Fluoro-4- [6-fluoro-4- [1- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-4-yl] quinazolin-8-yl] -N Of N, N-dimethylbenzamide

3-Fluoro-4- [6-fluoro-4- [1- (N-hydroxycarbamimidoyl) piperidin-4-yl] quinazolin-8-yl] -N, N-dimethylbenzamide (obtained in Reference Example B191) The resulting compound was added to a solution of 87 mg of toluene in 1.5 mL of toluene under ice-cooling, and 27 μL of triethylamine and 20 μL of isobutyric chloride were added, and the mixture was stirred at 130 ° C. for 2.5 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 with saturated brine and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent; chloroform / methanol = 100/0 to 95/5), and then gel permeation chromatography (JAIGEL). Purification by -1H, 2H; Nippon Analytical Industry, mobile phase; chloroform) gave 26 mg of the title compound as a colorless powder (yield: 26%).
MS (APCI) m / z; 507 [M + H] ^< +>.

Example B302
2-Fluoro-4- [6-fluoro-4- [4- [5- (2,2,2-trifluoroethyl)-[1,2,4] oxadiazol-3-yl) piperidine-1- [Ill] quinazolin-8-yl] -N, N-dimethylbenzamide

4- [4- (4-cyanopiperidin-1-yl) -6-fluoroquinazolin-8-yl] -2-fluoro-N, N-dimethylbenzamide (compound obtained in Reference Example B192) 90 mg of isopropanol 1 mL To the solution was added 28 μL of 50% aqueous hydroxyamine solution and the mixture was stirred at 90 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, 1 mL of toluene was added to the resulting residue, 36 μL of triethylamine and 35 mg of 3,3,3-trifluoropropionyl chloride were added under ice cooling, and the mixture was stirred at 110 ° 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 under reduced pressure, and the obtained residue was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 20 / 80-0 / 100) to give 27 mg of the title compound as a colorless powder (yield) : 23%).
MS (APCI) m / z; 547 [M + H] ^< +>.

Example B303
6- [6-Fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl] -N, N-dimethyl Production of nicotinamide

6- [6-Fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl] nicotinic acid ethyl ester (reference Compound obtained in Example B225) To a solution of 45 mg in 3 mL of THF was added 0.5 mL of 2N aqueous sodium hydroxide solution, and the mixture was stirred overnight. After neutralizing the reaction mixture with 2N hydrochloric acid, the reaction mixture was concentrated, and 2 mL of dimethylformamide and 73 mg of BOP were added to a mixture of the obtained crude product and a solution of dimethylamine in THF (2 mol / L, 69 μL), followed by diisopropyl Ethylamine 48 μL was added and stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. 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 92/8) to give 26 mg of the title compound as a colorless solid (yield: 58%).
MS (APCI) m / z; 490 [M + H] ^< +>.

Example B304
(S) -1- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline -8-yl] phenyl-3-dimethylcarbamoyloxypyrrolidin-2-one

(S) -1- [2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline To a solution of -8-yl] phenyl-3-hydroxypyrrolidin-2-one (the compound obtained in Example B191) in 50 mg of pyridine was added 90 μL of dimethylcarbamoyl chloride, and the mixture was stirred at 80 ° C. for 4 hours. After adding 90 μL of dimethylcarbamoyl chloride to the reaction mixture, the mixture was stirred at 80 ° C. for 9 hours. After further adding 90 μL of dimethylcarbamoyl chloride to the reaction mixture, the mixture was stirred at 80 ° C. for 5 hours. 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 by silica gel column chromatography (solvent: chloroform / methanol = 100/0 to 95/5). By refining twice, 25.2 mg of the title compound was obtained as a colorless powder (yield: 45%).
MS (APCI) m / z; 606 [M + H] +.

Examples B305-B338
The corresponding starting material compounds were treated in the same manner as in Example B1, to obtain the compounds described in Tables 76 to 79 below.

Examples B339 to B380
The corresponding starting material compounds were treated in the same manner as in Example B2 to obtain the compounds described in Tables 80 to 85 below.

Example B381
The corresponding starting material compound was treated in the same manner as in Example B3 to give the compounds shown in Table 86 below.

Examples B382 to B391
The corresponding starting compounds were treated in the same manner as in Example B4 to obtain the compounds described in Tables 87 to 88 below.

Examples B392 to B395
The corresponding starting material compound was treated in the same manner as in Example B9, to give compounds as shown in Table 89 below.

Examples B396-B397
The corresponding starting material compound was treated in the same manner as in Example B11 to give the compounds shown in Table 90 below.

Examples B398 to B402
The corresponding starting material compound was treated in the same manner as in Example B16 to give the compounds shown in Table 91 below.

Example B403
The corresponding starting materials were treated in the same manner as in Example B17 to give the compounds as shown in Table 92 below.

Example B404
The corresponding starting material compound was treated in the same manner as in Example B94, to give compounds as shown in Table 93 below.

Examples B405 to B436
The corresponding starting materials were treated in the same manner as in Example B95, to give compounds as shown in Tables 94 to 97 below.

Example B437
The corresponding starting materials were treated in the same manner as in Example B96 to give the compounds as shown in Table 98 below.

Examples B438 to B441
The corresponding starting material compounds were treated in the same manner as in Example B100 to give the compounds listed in Table 99 below.

Examples B442 to B443
The corresponding starting material compounds were treated in the same manner as in Example B301 to give the compounds listed in Table 100 below.

Examples B444 to B447
The corresponding starting materials were treated in the same manner as in Example A192 to give the compounds as shown in Table 101 below.

Examples B448 to B450
The corresponding starting compounds were treated in the same manner as in Example A192 to give the compounds as shown in Table 102 below.

Example B451
6-Fluoro-8- (3-fluoro-4-methylsulfanylmethylphenyl) -4-[(R) -4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) -3 -Methylpiperazin-1-yl] quinazoline

The corresponding starting material compound was treated in the same manner as in Example B1 to give the title compound.
MS (APCI) m / z; 511 [M + H] ^< +>.

Example B452
5-Fluoro-8- (3-fluoro-4-methylsulfanylphenyl) -4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline Manufacturing of

The corresponding starting material compound was treated in the same manner as in Example B1 to give the title compound.
MS (APCI) m / z; 482 [M + H] ^< +>.

Example B453
6-Fluoro-8- (3-fluoro-4-methylsulfanylphenyl) -4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline Manufacturing of

The corresponding starting material compound was treated in the same manner as in Example B1 to give the title compound.
MS (APCI) m / z; 482 [M + H] ^< +>.

Reference Example A1
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%).
¹ H-NMR (CDCl ₃ ) δ: 1.16-1.20 (6H, d, J = 6.9 Hz), 2.40-2.50 (1H, q), 4.52 (2H, brs) .

(2) To a solution of 56.9 g of N-tert-butoxycarbonylisonipecotinic acid in 500 mL of DMF was added dropwise a solution of 45 g of 1,1′-carbonyldiimidazole in 275 mL of DMF over 30 minutes, and the mixture was stirred at room temperature for 30 minutes. . A solution of 32.4 g of the compound obtained in (1) above in 500 mL of DMF was added dropwise to the reaction mixture over 30 minutes, and the mixture was stirred at room temperature for 12 hours. A solution of 45 g of 1,1′-carbonyldiimidazole in 275 mL of DMF was added dropwise to the reaction mixture over 30 minutes, and then 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] oxadiazole-5- Yl) 21.75 g of piperidine-1-carboxylic acid tert-butyl ester was obtained as an oil (yield 29.5%).
¹ H-NMR (CDCl ₃ ) δ: 1.32-1.34 (6H, d), 1.47 (9H, s), 1.79-1.88 (2H, m), 2.03-2 0.08 (2H, m), 2.94 (2H, t), 3.03-3.10 (2H, m), 4.09-4.13 (2H, m).

(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 precipitates were collected, washed with ethyl ether, and dried under reduced pressure to give 7.62 g of the title compound (yield 93.1%).
¹ H-NMR (DMSO-d ₆ ) δ: 1.25-1.26 (6H, d, J = 6.74 Hz), 1.90-1.98 (2H, m), 2.16-2. 20 (2H, m), 3.01-3.08 (3H, m), 3.28-3.31 (2H, m), 3.36-3.42 (1H, m), 9.01- 9.15 (2H, brb).

Reference examples A2 to A4
The corresponding starting compounds were treated in the same manner as in Reference Example A1 to give the compounds listed in Table 103 below.

Reference Example A5
Preparation of 4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidine

4- (3-Isopropyl- [1,2,4] oxadiazol-5-yl) piperidine-1-carboxylic acid tert-butyl ester was added to a solution of 5.94 g of dichloromethane in 30 mL of dichloromethane and 10 mL of trifluoroacetic acid was added. After stirring at 40 ° C. for 4 hours, the mixture was further left overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane. A 30% aqueous potassium carbonate solution was added to the solution, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 2.73 g of the title compound (yield 69.6%).
¹ H-NMR (CDCl ₃ ) δ: 1.32-1.35 (6H, d, J = 6.9 Hz), 1.96-2.01 (2H, m), 2.16-2.22 ( 2H, m), 2.86-2.95 (2H, m), 3.05-3.14 (2H, m), 3.24-3.30 (2H, m).

Reference Example A6
Preparation of 8-bromo-4- [4- (3-cyclopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] -5-fluoroquinazoline

(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 was poured into ice (ca. 0.5 L) and the mixture was 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] ^< +>.

(5) To 2.0 g of the compound obtained in (4) above, 8 mL of thionyl chloride and 0.733 mL of dimethylformamide were added and stirred for 4 hours under reflux. The reaction mixture was concentrated under reduced pressure, and the solution in residual dichloromethane was cooled with ice, and 2.84 g of 4- (3-cyclopropyl- [1,2,4] oxadiazol-5-yl) piperidine hydrochloride, 12 g of potassium carbonate. , 30 mL of water and 30 mL of dichloromethane. The mixture was stirred at room temperature overnight and then extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (solvent: hexane / ethyl acetate = 3/1) to give 2.49 g of the title compound (yield 72.3). %).
¹ H-NMR (CDCl ₃ ) δ: 1.02-1.07 (4H, m), 2.03-2.13 (3H, m), 2.19-2.24 (2H, m), 3 .17-3.25 (1H, m), 3.29-3.35 (2H, m), 4.14-4.18 (2H, m), 7.01-7.06 (1H, m) 7.98-8.01 (1H, dd, J = 8.62 Hz, 5.29 Hz), 8.76 (1H, s).

Reference examples A7 to A14
The corresponding starting compounds were treated in the same manner as in Reference Example A6 to give the compounds listed in Table 104 below.

Reference Example A15
Preparation of 8-bromo-5-fluoro-4- (4-isobutylsulfanylpiperidin-1-yl) quinazoline

(1) After adding 8.4 mL of triethylamine at room temperature to a solution of 6.04 g of 1- (tert-butoxycarbonyl) -4-hydroxypiperidine in 100 mL of dichloromethane, 2.8 mL of methanesulfonyl chloride was added dropwise at room temperature. Stir for 7 hours. The reaction mixture was neutralized with 1M hydrochloric acid and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the precipitate was washed with ether / hexane, collected by filtration, and dried under reduced pressure to obtain 8.33 g of 1- (tert-butoxycarbonyl) -4-methanesulfonyloxypiperidine (yield). (Rate 99.4%).
¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.80-1.85 (2H, m), 1.93-1.97 (2H, m), 3.04 (3H , S), 3.25-3.35 (2H, m), 3.67-3.71 (2H, m), 4.87-4.90 (1H, m).

(2) To a solution of 2.26 g of the compound obtained in (1) above in 25 mL of dimethylformamide, 1.3 g of sodium methoxide and 2.6 mL of 2-methylpropane-1-thiol are added at room temperature, and the mixture is heated to 120 ° C. For 3 hours. The reaction mixture was poured into water and the mixture was extracted with ether. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel chromatography (solvent: hexane / ethyl acetate = 6/1) to give 4-isopropylsulfanylpiperidine-1-carboxylic acid tert-butyl ester. (1.74 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 0.97-1.00 (6H, d, J = 6.7 Hz), 1.45 (9H, s), 1.45-1.50 (2H, m) 1.71-1.84 (1H, m), 1.84-1.99 (2H, m), 2.41-2.44 (2H, d, J = 6.9 Hz), 2.61- 2.81 (1H, m), 2.81-2.98 (2H, m), 3.78-4.04 (2H, m).

(3) To 1.24 g of the compound obtained in (2) above, 12.4 mL of 4M hydrochloric acid / ethyl acetate was added, and the mixture was stirred at room temperature for 4 and a half hours. The reaction mixture was concentrated, and the resulting white precipitate was washed with ether, collected by filtration, and dried under reduced pressure to give 4-isopropylsulfanylpiperidine hydrochloride (858 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 0.93-0.95 (6H, d, J = 6.6 Hz), 1.53-1.81 (3H, m), 1.95-2. 11 (2H, m), 2.39-2.46 (2H, d, J = 6.9 Hz), 2.81-2.97 (3H, m), 3.16-3.27 (2H, m ), 8.93 (2H, brs).

  (4) A mixture of 1.7 g of 8-bromo-5-fluoro-3H-quinazolin-4-one, 0.6 mL of dimethylformamide and 20 mL of thionyl chloride was refluxed for 4 hours, and then the reaction mixture was concentrated under reduced pressure. A dichloromethane solution of the obtained residue was poured into an aqueous sodium hydrogen carbonate solution, and the mixture was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give 8-bromo-4-chloro-5-fluoroquinazoline (838 mg) as a brown solid.

(5) To a solution of 580 mg of the compound obtained in (4) above in 30 mL of dichloromethane, 512 mg of 4-isopropylsulfanylpiperidine hydrochloride and 0.92 mL of triethylamine were added, and the mixture was stirred at room temperature for 8 hours. Water was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in DMSO and purified by reverse phase HPLC [Column: Develosil ODS C18, 5 μm, 28 mm × 100 mm, Nomura Chemical; Mobile Phase A: 0.1% trifluoroacetic acid / water; Mobile Phase B: 0.06 % Trifluoroacetic acid / acetonitrile, flow rate 30 mL / min (mobile phase B 40% → 70% / 6 min.) Fractions containing the reaction product (RT = 3.66-4.90 min) are collected and concentrated to a residue The mixture was extracted with dichloromethane, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 438.6 mg of the title compound (yield 49.6%).
¹ H-NMR (CDCl ₃ ) δ: 0.99-1.02 (6H, d, J = 6.7 Hz), 1.71-1.85 (3H, m), 2.07-2.13 ( 2H, m), 2.45-2.48 (2H, d, J = 6.8 Hz), 2.80-3.02 (1H, m), 3.24-3.32 (2H, m), 4.07-4.13 (2H, m), 6.97-7.04 (1H, dd, J = 8.5 Hz, 10.7 Hz), 7.94-8.00 (1H, dd, J = 5.3 Hz, 8.4 Hz), 8.73 (1H, s).

Reference Example A16
Preparation of [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] (1-pyrrolidinyl) methanone

(1) 50 mL of dichloromethane was added to 3.0 g of 4-bromo-2-fluorobenzoic acid, then 1.22 mL of oxalyl chloride and 0.2 mL of DMF were added at room temperature, and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and a 30 mL solution of the resulting residue in dichloromethane was added dropwise to a suspension of 3.44 mL of pyrrolidine, 50 mL of dichloromethane, and 2 g of sodium bicarbonate under ice cooling. After the mixture was stirred at room temperature for 2 hours, 100 mL of water was added and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (solvent; hexane / ethyl acetate = 3/1) to obtain 4.02-g of (4-bromo-2-fluorophenyl) (1-pyrrolidinyl) methanone as an oily product (yield). Rate 108.8%).
¹ H-NMR (CDCl ₃ ) δ: 1.848-1.993 (4H, m), 3.288-3.321 (2H, t), 3.622-3.657 (2H, t), 7 .285-7.367 (3H, m).

(2) To 1.77 g of the compound obtained in (1) above, 1.82 g of bis (pinacolato) diboron, 1.92 g of potassium acetate, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II ) 160 mg of dichloride-dichloromethane complex and 15 mL of DMSO were added, and the mixture was deaerated and then stirred at 90 ° C. for 5 hours under a nitrogen atmosphere. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (solvent: hexane / ethyl acetate = 3/1) to give 1.78 g of the title compound as a light brown powder (yield). (Rate 93.0%).
¹ H-NMR (CDCl ₃ ) δ: 1.347 (12H, s), 1.862-1.981 (4H, m), 3.264-3.300 (2H, t), 3.631-3 .666 (2H, t), 7.384-7.419 (1H, t), 7.500-7.520 (1H, d, J = 9.84 Hz), 7.616-7.597 (1H, d, J = 7.36 Hz).

Reference Examples A17 to A23
The corresponding starting compounds were treated in the same manner as in Reference Example A16 to give the compounds listed in Table 105 below.

Reference Example A24
Preparation of 2-fluoro-N, N-dimethyl-4- (4-oxo-3,4-dihydroquinazolin-8-yl) benzamide

(1) 8-Iodo-3H-quinazolin-4-one in 3 g, 2.24 g of 4-carboxyl-3-fluorophenylboronic acid, 64 mL of 2M aqueous sodium carbonate, 1.0 g of tetrakis (triphenylphosphine) palladium (0) and After adding 160 mL of dioxane and degassing the mixture, the mixture was purged with nitrogen and stirred for 16 hours under reflux. The reaction mixture was poured into water, and diluted hydrochloric acid was added to the mixture to adjust the pH to 1. The precipitate was collected by filtration, washed with water, and dried under reduced pressure at 80 ° C. to obtain 3.21 g of 2-fluoro-4- (4-oxo-3,4-dihydroquinazolin-8-yl) benzoic acid.
MS (ESI) m / z: 287 [M + H] ^< +>.

(2) To 1.0 g of the compound obtained in (1) above, 20 mL of dichloromethane, 0.31 mL of oxalyl chloride and 0.1 mL of DMF were added, and the mixture was stirred at room temperature for 2 hours. Under ice-cooling, 1.6 mL of 50% aqueous dimethylamine solution and 1.0 g of sodium bicarbonate were added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. Dichloromethane and water were added to the reaction mixture, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with a small amount of dichloromethane to obtain 273.1 mg of the title compound (yield 24.9%).
MS (ESI) m / z: 312 [M + H] &lt; ⁺ &gt;.

Reference Example A25
Production of N, N-dimethyl-4- (4-oxo-3,4-dihydroquinazolin-8-yl) benzamide The corresponding starting material compound was treated in the same manner as in Reference Example A24 to obtain the following compound.

MS (ESI) m / z: 294 [M + H] ^< +>.

Reference Example A26
Preparation of 8- (4-mesylphenyl) -3H-quinazolin-4-one

To 5.4 g of 8-iodo-3H-quinazolin-4-one was added 4.38 g of 4-mesylphenylboronic acid, 71 mL of 2M aqueous sodium carbonate solution, 983 mg of tetrakis (triphenylphosphine) palladium (0) and 190 mL of dioxane, and the mixture After deaeration, the atmosphere was replaced with nitrogen, and the mixture was stirred for 40 hours under reflux. The reaction mixture was concentrated under reduced pressure, and the resulting residue was poured into water and acidified with concentrated hydrochloric acid. The precipitate was collected by filtration and purified by silica gel chromatography (solvent; chloroform) to give 3.30 g of the title compound. Got.
MS (ESI) m / z: 301 [M + H] ^< +>.

Reference Example A27
Preparation of 5-fluoro-8- (4-mesylphenyl) -3H-quinazolin-4-one

The corresponding starting material compound was treated in the same manner as in Reference Example A26 to give the title compound.
MS (ESI) m / z: 319 [M + H] ^< +>.

Reference Example A28
Preparation of 4-cyclohexylsulfanylpiperidine

(1) To a solution of 15.0 g of 4-hydroxypiperidine in 150 mL of methanol, 36 g of dicarboxylic acid ditert-butyl ester was added in several portions under ice cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with hexane, the precipitate was collected by filtration, washed with hexane, and dried under reduced pressure at 40 ° C. to obtain 22.48 g of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (yield) 75.3%).
¹ H-NMR (CDCl ₃ ) δ: 1.42-1.50 (12H, m), 1.84-1.88 (2H, m), 2.99-3.06 (2H, m), 3 .82-3.87 (3H, m)
(2) 22.4 g of the compound obtained in (1) above was added to a mixed solution of 220 mL of dichloromethane and 24 mL of triethylamine, and the mixture was stirred under ice cooling. To the reaction mixture, 13.3 mL of methanesulfonyl chloride was added dropwise over 15 minutes, followed by stirring at room temperature for 5 hours. The reaction mixture was extracted with dichloromethane, and the organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. Hexane was added to the residue, and the precipitate was collected by filtration, washed with hexane, and dried under reduced pressure to obtain 30.75 g of 4-methanesulfonyloxypiperidine-1-carboxylic acid tert-butyl ester (yield 98. 9%).
¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.79-1.86 (2H, m), 1.94-1.99 (2H, m), 3.04 (3H , S), 3.27-3.33 (2H, m), 3.68-3.73 (2H, m), 4.87-4.90 (1H, m).

(3) A mixture of 3.32 mL of cyclohexyl mercaptan and 100 mL of DMF was stirred under ice-cooling, and 1.2 g of 60% sodium hydride was added to the mixture in several portions, and the mixture was stirred at room temperature for 1 hour. Under ice-cooling, 7.35 g of the compound obtained in the above (1) was added in several portions to the reaction mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was extracted with dichloromethane. The organic layer is washed with water, dried over magnesium sulfate, concentrated under reduced pressure, and the resulting residue is purified by silica gel chromatography (solvent: hexane / ethyl acetate = 1/20) to give 4-cyclohexylsulfanylpiperidine-1- 5.80 g of carboxylic acid tert-butyl ester was obtained (yield 73.6%).
¹ H-NMR (CDCl ₃ ) δ: 1.31-1.35 (4H, m), 1.45-1.63 (13H, m), 1.76-1.77 (2H, m), 1 .88-1.96 (3H, m), 2.72-2.73 (1H, m), 2.84-2.94 (3H, m), 3.47-3.50 (1H, t) 3.88-3.94 (3H, m).

(4) To 4.22 g of 4-cyclohexylsulfanylpiperidine-1-carboxylic acid tert-butyl ester were added 80 mL of dichloromethane and 10 mL of trifluoroacetic acid, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, 50 mL of 30% aqueous potassium carbonate solution was added to the resulting residue, and the mixture was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 2.58 g of the title compound as an oil (yield 91.8%).
¹ H-NMR (CDCl ₃ ) δ: 1.28-1.35 (4H, m), 1.48-1.53 (3H, m), 1.76-1.77 (2H, m), 1 .92-1.98 (4H, m), 2.11 (2H, bs), 2.63-2.84 (4H, m), 3.09-3.14 (2H, m).

Reference Example A29
Preparation of 4- (4-methoxybenzylsulfanyl) piperidine

The title compound was obtained by treating the compound obtained in Reference Example A28 (2) and 4-methoxybenzylthioalcohol in the same manner as in Reference Example A28 (3)-(4).
¹ H-NMR (CDCl ₃ ) δ: 1.47-1.50 (2H, m), 1.88-1.97 (2H, m), 2.56-2.69 (2H, m), 3 .05-3.10 (3H, m), 3.72 (2H, s), 3.80 (2H, s), 6.83-6.85 (2H, d), 7.23-7.25 (2H, d)
MS (APCI) m / z: 238.1 [M + H] ^< +>.

Reference Example A30
Preparation of 1- [8- (4-dimethylcarbamoylphenyl) quinazolin-4-yl] piperidin-4-yl ester of methanesulfonic acid

(1) To 2.59 g of N, N-dimethyl-4- (4-oxo-3,4-dihydroquinazolin-8-yl) benzamide were added 18.2 mL of thionyl chloride and 0.96 mL of DMF, and the mixture was stirred for 4 hours under reflux. . The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane and washed with ice water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 2.96 g of 4- (4-chloroquinazolin-8-yl) -N, N-dimethylbenzamide. To the compound was added 100 mL of THF, 1.15 g of 4-hydroxypiperidine and 3.8 mL of diisopropylethylamine, and the mixture was stirred for 5 hours under reflux. The reaction mixture was concentrated under reduced pressure and the residue was extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (solvent; chloroform) to give 2.53 g of 4- [4- (4-hydroxypiperidin-1-yl) quinazolin-8-yl] -N, N-dimethylbenzamide as amorphous. Obtained as a powder (yield 70.8%).
¹ H-NMR (CDCl ₃ ) δ: 1.88-1.92 (2H, m), 2.07-2.12 (2H, m), 3.07-3.15 (6H, d), 4 .22-4.25 (3H, m), 4.33-4.39 (2H, m), 7.49-7.51 (2H, m), 7.56-7.58 (2H, m) 7.67-7.72 (1H, t, J = 6.0 Hz), 7.81-7.83 (1H, d, J = 5.4 Hz), 7.95-7.97 (1H, d , J = 6.3 Hz), 8.603 (1H, s).

(2) 0.78 mL of methanesulfonyl chloride was added to a mixture of 2.53 g of the compound obtained in (1) above, 25 mL of dichloromethane and 1.4 mL of triethylamine under ice cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was extracted with dichloromethane, and the organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (solvent; ethyl acetate → 10% methanol / ethyl acetate) to give 2.41 g of the title compound (yield 78.8%).
¹ H-NMR (CDCl ₃ ) δ: 2.11-2.15 (2H, m), 2.23-2.25 (2H, m), 3.10-3.15 (9H, m), 3 .66-3.71 (2H, m), 4.00-4.05 (2H, m), 5.06-5.08 (1H, m), 7.52-7.56 (3H, m) , 7.71-7.73 (2H, m), 7.78-7.79 (1H, d, J = 9.0 Hz), 7.90-7.89 (1H, d, J = 9.0 Hz) ), 8.795 (1H, s).

Reference Example A31
Preparation of 1- [8- (4-Methanesulfonylphenyl) quinazolin-4-yl] piperidin-4-ol

(1) 8-iodo-3H-quinazolin-4-one 544 mg, 2- (4-methanesulfonylphenyl) -4,4,5,5-tetramethyl- [1,3,2] dioxaborolane 440 mg and tetrakis (tri Phenylphosphine) palladium (0) 225 mg in dioxane 20 mL was added 2 M aqueous sodium carbonate solution 5 mL, and the mixture was stirred under reflux for 13 hours. The reaction mixture was concentrated, water and ethyl acetate were added to the residue, and the mixture was filtered through celite. The filtrate was extracted with ethyl acetate, the organic layer was concentrated, and the residue was purified by silica gel column chromatography to obtain 513.3 mg of 8- (4-methanesulfonylphenyl) -3H-quinazolin-4-one. (Yield: 85%).
MS (ESI) m / z: 301.1 [M + H] &lt; ⁺ &gt;.

(2) To 513.3 mg of the compound obtained in (1) above, DMF (180 μL) and thionyl chloride (3.5 mL) were added, and the mixture was stirred under reflux for 4.5 hours. The reaction mixture was concentrated and poured into saturated aqueous sodium bicarbonate and the mixture was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 20 mL of THF, 477 μL of triethylamine and 173 mg of 4-hydroxypiperidine were added to the solution, and the mixture was stirred at room temperature for 45 minutes. The reaction solution was concentrated, dissolved in dichloromethane, and filtered. The filtrate was concentrated and purified with a silica gel column (solvent; 5% methanol / chloroform) to give 297.6 mg of the title compound as a white powder (yield 45%).
MS (ESI) m / z: 384.1 [M + H] &lt; ⁺ &gt;.
¹ H-NMR (CDCl ₃ ) δ: 1.75-1.86 (2H, m), 2.09-2.15 (2H, m), 3.12 (3H, s), 3.46-3 .55 (2H, m), 4.07-4.19 (3H, m), 7.52-7.57 (1H, m), 7.75-7.78 (1H, dd, J = 1. 3 Hz, 7.2 Hz), 7.86-7.89 (2H, d, J = 8.4 Hz), 7.93-7.97 (1 H, dd, J = 1.3 Hz, 8.3 Hz), 8 .04-8.07 (2H, d, J = 8.4 Hz), 8.75 (1H, s).

Reference Example A32
Preparation of 2-fluoro-4- [5-fluoro-4- (4-hydroxypiperidin-1-yl) quinazolin-8-yl] -N, N-dimethylbenzamide

(1) To 1.5 g of 8-bromo-5-fluoro-3H-quinazolin-4-one, 0.5 mL of DMF and 25 mL of thionyl chloride were added, and the mixture was stirred for 5 hours under reflux. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in dichloromethane, the solution was poured into an aqueous sodium hydrogen carbonate solution, and the mixture was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 8-bromo-4-chloro-5-fluoroquinazoline as a crude product. The compound was dissolved in a mixture of 40 mL of tetrahydrofuran and 30 mL of dichloromethane, 2.6 mL of triethylamine and 874 mg of 4-hydroxypiperidine were added to the solution, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with dichloromethane. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; 10% methanol / dichloromethane) to give 1- (8-bromo-5-fluoroquinazolin-4-yl). 1.80 g of piperidin-4-ol was obtained (89% yield).
MS (ESI) m / z: 325.8 / 327.8 [M + H] &lt; ⁺ &gt;.
¹ H-NMR (CDCl ₃ ) δ: 1.67-1.78 (2H, m), 2.01-2.09 (2H, m), 3.38-3.47 (2H, m), 3 .96-4.03 (3H, m), 6.98-7.05 (1H, dd, J = 8.6 Hz, 10.7 Hz), 7.95-8.00 (1H, dd, J = 5) .3 Hz, 8.6 Hz), 8.73 (1H, s).

(2) 1.79 g of the compound obtained in the above (1), 2-fluoro-N, N-dimethyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane-2 -To a solution of 1.93 g of yl) benzamide and 632 mg of tetrakis (triphenylphosphine) palladium (0) in 39 mL of dioxane was added 13 mL of 2M aqueous sodium carbonate solution, and the mixture was stirred for 6 and a half hours under reflux. The reaction mixture was concentrated, 1M hydrochloric acid was added to the residue to adjust to pH 7, and the mixture was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent; dichloromethane-methanol) to give 1.44 g of the title compound (yield 64%).
MS (ESI) m / z: 412.8 [M + H] &lt; ⁺ &gt;.

Reference Example A33
Preparation of 2-fluoro-4- [4- (4-hydroxypiperidin-1-yl) quinazolin-8-yl] -N, N-dimethylbenzamide

(1) After dissolving 2.90 g of 4-chloro-8-iodoquinazoline in a mixed solution of 50 mL of THF and 30 mL of dichloromethane, 4.2 mL of triethylamine and 1.42 g of 4-hydroxypiperidine were added to the solution, and then 6.5 mL at room temperature. Stir for hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate and aqueous sodium hydrogen carbonate solution were added to the residue, and the mixture was filtered. The filtrate was extracted with ethyl acetate, the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent; 10% methanol / ethyl acetate) to give 1- (8-iodo). Quinazolin-4-yl) piperidin-4-ol 2.34 g was obtained (yield 66%).
MS (ESI) m / z: 355.8 [M + H] &lt; ⁺ &gt;.
¹ H-NMR (CDCl ₃ ) δ: 1.68-1.83 (2H, m), 2.05-2.13 (2H, m), 3.45-3.53 (2H, m), 4 .04-4.16 (3H, m), 7.16-7.21 (1H, dd, J = 7.7 Hz, 8.1 Hz), 7.84-7.87 (1H, d, J = 8) .3 Hz), 8.31-8.34 (1 H, dd, J = 7.4 Hz, 8.3 Hz), 8.82 (1 H, s).

(2) The compound (1.53 g) obtained in (1) above and 2-fluoro-N, N-dimethyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane By treating 2-yl) benzamide (1.52 g) in the same manner as in Reference Example A32 (2), the title compound (1.52 g) was obtained as an amorphous powder (yield 90%).
MS (ESI) m / z: 394.9 [M + H] &lt; ⁺ &gt;.

Reference Example A34
Preparation of 2-fluoro-4- [5-fluoro-4- (piperazin-1-yl) quinazolin-8-yl] -N, N-dimethylbenzamide dihydrochloride

(1) To 1.66 g of 8-bromo-5-fluoro-3H-quinazolin-4-one, 8 mL of thionyl chloride and 0.733 mL of dimethylformamide were added, and the mixture was stirred under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane. The solution was cooled under ice cooling with 1.91 g of piperazine-1-carboxylic acid tert-butyl ester, 2.83 g of potassium carbonate, 20 mL of water and 30 mL of dichloromethane. Dropped into the mixture. The mixture was stirred at room temperature overnight. The reaction mixture was extracted with dichloromethane, the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 5/1) to give 4- (8- Bromo-5-fluoroquinazolin-4-yl) piperidine-1-carboxylic acid tert-butyl ester 2.12 g was obtained (yield 75.5%).
MS (ESI) m / z: 464.3 [M + H] &lt; ⁺ &gt;.

(2) Compound (2.12 g) obtained in (1) above and 2-fluoro-N, N-dimethyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane 2- [yl] benzamide (1.81 g) was treated in the same manner as in Reference Example A32 (2) to give 4- [8- [3-fluoro-4- (dimethylcarbamoyl) phenyl] -5-fluoroquinazoline- 4-yl] piperazine-1-carboxylic acid tert-butyl ester (1.79 g) was obtained (yield 69.8%).
MS (ESI) m / z: 498 [M + H] &lt; ⁺ &gt;.

(3) The title compound (1.69 g) was obtained as a dihydrochloride salt by treating the compound (1.79 g) obtained in (3) in the same manner as in Reference Example A15 (3) (yield 99 .9%).
MS (ESI) m / z: 398 [M + H] ^< +>.

Reference Example A35
Preparation of 4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) -4-methylpiperidine hydrochloride

(1) To 50 mL of toluene, 2 g of 1-tert-butoxycarbonyl-4-methylpiperidine-4-carboxylic acid and 1.15 mL of triethylamine were added, and 1.07 mL of isobutyl chlorocarbonate was added dropwise to the mixture at 0 ° C., followed by 2 at room temperature. Stir for hours. To the reaction mixture, 837 mg of N′-hydroxy-2-methylpropanimidamide (compound obtained in Reference Example A1 (1)) and molecular sieves 4A (4 g) were added, and the mixture was stirred at 120 ° C. for 4 hours. The reaction product was cooled to room temperature, ethyl acetate was added, the organic layer was washed successively with water and saturated brine, and 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 (solvent; hexane / ethyl acetate = 91/9 → 80/20) to give 4- (3-isopropyl- [1,2, 4] 1.91 g of oxadiazol-5-yl) -4-methylpiperidine-1-carboxylic acid tert-butyl ester was obtained as a colorless liquid (yield 75%).
MS (APCI) m / z; 310 [M + H] +.

(2) To a solution of 1.91 g of the compound obtained in (1) above in 10 mL of 1,4-dioxane, 20 mL of 4N hydrochloric acid-dioxane was added, 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 1.44 g of the title compound as a colorless solid (yield 87%).
MS (APCI) m / z; 210 [M + H] +.

Reference Example A36
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 the above (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 Example A37
Preparation of 5-methyl-2- (piperidin-4-yl) pyrimidine

(1) To a suspension of 23.3 g of tert-butoxy potassium in 250 mL of tert-butanol, a solution of N-benzyl-4-piperidone in 5.0 g of dimethoxyethane in 50 mL was added dropwise, and the mixture was stirred at room temperature for 5 minutes. To the reaction mixture, a solution of 10.32 g of tosylmethyl isocyanide in 100 mL of dimethoxyethane was added dropwise, and the mixture was stirred at 60 ° C. for 2 hours. Water was added to the reaction mixture, followed by extraction with ether. 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 = 65/35 → 45/55) to obtain 4.20 g of 1-benzyl-4-cyanopiperidine. Obtained as a light brown liquid (79% yield).
MS (APCI) m / z; 201 [M + H] ^< +>.

(2) Under a nitrogen atmosphere, 21 mL of 2M trimethylaluminum-toluene solution was added dropwise to a solution of 2.47 g of ammonium chloride in 40 mL of toluene under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes, and further stirred at room temperature for 2 hours. To the reaction mixture, 4.19 g of the compound obtained in (1) above in 5 mL of toluene was added, and the mixture was stirred at 80 ° C. for 17 hours. The reaction mixture was cooled to room temperature, diluted with chloroform, added with 80 mL of silica gel, and filtered through celite. The filtrate was concentrated under reduced pressure, chloroform / methanol (4/1) was added to the resulting residue, and insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, ether was added to the resulting residue, and the precipitate was collected by filtration to obtain 3.20 g of 4-amidino-1-benzylpiperidine hydrochloride as a light brown powder (yield 60%). .
MS (APCI) m / z; 218 [M + H] ^< +>.

(3) To a solution of 500 mg of the compound obtained in (2) above and 446 mg of 3-dimethylamino-2-methyl-2-propenal in 5 mL of ethanol was added a 28% sodium methoxide-methanol solution, and Stir for hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (solvent; chloroform / methanol = 100/0 → 91/9) to give 2- (1-benzylpiperidin-4-yl)- 302 mg of 5-methylpyrimidine was obtained as a light brown solid (57% yield).
MS (APCI) m / z; 268 [M + H] ^< +>.

(4) 40 mg of 20% palladium hydroxide was added to an ethanol solution of 300 mg of the compound obtained in (3) above, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. The reaction mixture was further stirred at 50 ° C. for 6 hours and then at room temperature for 3 days. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 215 mg of the title compound as a yellow solid (yield 100%).
MS (APCI) m / z; 178 [M + H] ^< +>.

Reference Example A38
Preparation of 4- (5-isopropyl- [1,3,4] oxadiazol-2-yl) piperidine hydrochloride

(1) To 3.0 g of hydrazinecarboxylic acid tert-butyl ester and 6.3 mL of triethylamine in 50 mL of dichloromethane was added dropwise a solution of 2.6 mL of isobutyryl chloride in 10 mL of dichloromethane under ice-cooling, and the mixture was stirred at room temperature for 21 hours. Stir. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed successively with dilute hydrochloric acid 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) and then triturated with hexane to give N'-isobutyrylhydrazinecarboxylic acid tert-butyl ester 2 Obtained .63 g as a colorless solid (57% yield).
MS (APCI) m / z; 203 [M + H] ^< +>.

(2) To a solution of 2.63 g of the compound obtained in (1) above in 20 mL of 1,4-dioxane, 25 mL of 4N hydrochloric acid-dioxane was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was diluted with diethyl ether, and the precipitate was collected by filtration to give 1.59 g of isobutyryl hydrazine hydrochloride as a colorless powder (yield 88%).
MS (APCI) m / z; 103 [M + H] ^< +>.

(3) 2.19 g of N-tert-butoxycarbonylnipecotic acid, 1.59 g of 1-hydroxybenzotriazole monohydrate in a solution of 1.59 g of the compound obtained in the above (2) and 2.66 mL of triethylamine in 40 mL of dichloromethane. 19 g and 2.73 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride were added and the mixture was stirred at room temperature for 15 hours. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 50/50 → 0/100) to give 1-tert-butoxycarbonyl-4- (N ′ -2.28 g of isobutyrylhydrazinocarbonyl) piperidine was obtained as a colorless solid (yield 76%).
MS (APCI) m / z; 314 [M + H] ^< +>.

(4) 2.46 g of 2-chloro-1,3-dimethylimidazolinium chloride was added to a solution of 2.28 g of the compound obtained in the above (3) and 4.05 mL of triethylamine in 60 mL of dichloromethane, and the mixture was stirred at room temperature. Stir for hours. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with chloroform. 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 = 70/30 → 35/65) to give 1-tert-butoxycarbonyl-4- (5-isopropyl). -[1,3,4] oxadiazol-2-yl) piperidine (688 mg) was obtained as a colorless viscous oil (yield 32%).
MS (APCI) m / z; 296 [M + H] ^< +>.

(5) To a solution of 688 mg of the compound obtained in (4) above in 4 mL of 1,4-dioxane, 4 mL of 4N hydrochloric acid-dioxane was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with diethyl ether, and the precipitate was collected by filtration to give 550 mg of the title compound as a colorless powder (yield 100%).
MS (APCI) m / z; 196 [M + H] ^< +>.

Reference Example A39
Preparation of 2- (2-fluoro-4- (N, N-dimethylsulfamoyl) phenyl-4,4,5,5-tetramethyl- [1,3,2] dioxaborolane

(1) 3.25 mL of a 2M dimethylamine-tetrahydrofuran solution was diluted with 20 mL of THF, and 1.37 g of 4-bromo-3-fluorobenzenesulfonyl chloride was added thereto under ice cooling, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and ether was added to the resulting residue, followed by filtration. NH-silica gel (Chromatorex) was added to the filtrate, the mixture was filtered, and the filtrate was concentrated under reduced pressure. A mixed solvent of ether / hexane (1/1) was added to the obtained residue, and the precipitate was collected by filtration to obtain 624 mg of 4-bromo-3-fluoro-N, N-dimethylbenzenesulfonamide as a white solid. (Yield 44%).
MS (APCI) m / z; 282/284 [M + H] ^< +>.

(2) By treating 620 mg of the compound obtained in (1) above and 838 mg of bis (pinacolato) diboron in the same manner as in Reference Example A16 (2), 302 mg of the title compound was obtained as a white solid (yield 33 %).
MS (APCI) m / z; 330 [M + H] ^< +>.

Reference Example A40
Preparation of 2- (3-fluoro-4-methanesulfonylmethylphenyl) -4,4,5,5-tetramethyl- [1,3,2] dioxaborolane

  (1) To a solution of 2.68 g of 4-bromo-2-fluorobenzyl bromide in 10 mL of dimethylformamide was dropwise added 7.00 g of a 15% aqueous solution of methyl mercaptan at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract 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; ethyl acetate: hexane = 0: 100 → 10: 90), whereby 1.39 g of 4-bromo-2-fluoro-1-methylsulfanylmethylbenzene was colorless. Obtained as a liquid (yield 59%).

(2) To a solution of 1.39 mg of the compound obtained in (1) above in 10 mL of chloroform was added 2.24 g of metachloroperbenzoic acid at room temperature, and the mixture was stirred at the same temperature for 3 hours. The reaction solution was added to a saturated aqueous sodium hydrogen carbonate solution and extracted three times with ethyl acetate. The extract 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; ethyl acetate / hexane = 80/20 → 50/50) to give 702 mg of 4-bromo-2-fluoro-1-methanesulfonylmethylbenzene as a white solid. Obtained (yield 45%).
MS (APCI) m / z; 299/301 [M + H] ^< +>.

(3) The compound (534 mg) and bis (pinacolato) diboron (609 mg) obtained in (2) above were treated in the same manner as in Reference Example A16 (2) to obtain 585 mg of the title compound as a white solid (yield) 93%).
MS (APCI) m / z; 315 [M + H] ^< +>.

Reference Example A41
Preparation of 1- [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzyl] -1H-1,2,4-triazole

(1) To a solution of 2.68 g of 4-bromo-2-fluorobenzyl bromide and 1.38 g of triazole in 10 mL of DMF was added 0.80 g of 60% sodium hydride at room temperature, and the mixture was stirred at room temperature overnight. The reaction solution was added to an aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract 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 (solvent; ethyl acetate / hexane = 35/65 → 60/40) to give 1- (4-bromo-2-fluorobenzyl). 1.93 g of -1H-1,2,4-triazole was obtained as a white solid (yield 75%).
MS (APCI) m / z; 256/258 [M + H] ^< +>.

(2) The compound (512 mg) and bis (pinacolato) diboron (609 mg) obtained in (1) above were treated in the same manner as in Reference Example A16 (2) to give 303 mg of the title compound as a colorless liquid (yield) Rate 50%).
MS (APCI) m / z; 304 [M + H] ^< +>.

Reference Example A42
Preparation of 1- [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzyl] -1H-tetrazole

(1) To a solution of 2.68 g of 4-bromo-2-fluorobenzyl bromide and 1.48 g of triazole in 10 mL of DMF, 0.80 g of 60% sodium hydride was added at room temperature, and the mixture was stirred at room temperature overnight. The reaction solution was added to an aqueous ammonium chloride solution and extracted with ethyl acetate. The extract 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 (solvent; ethyl acetate / hexane = 20/80 → 60/40) to give 1- (4-bromo-2-fluorobenzyl). 0.95 g of -1H-tetrazole was obtained as a white solid (yield 37%).
MS (APCI) m / z; 257/259 [M + H] ^< +>.

(2) The compound (514 mg) and bis (pinacolato) diboron (609 mg) obtained in (3) above were treated in the same manner as in Reference Example A16 (2) to obtain 785 mg of the title compound as a colorless liquid (yield) Rate 75%).
MS (APCI) m / z; 305 [M + H] ^< +>.

Reference Example A43
Preparation of 1- [8- (4-dimethylcarbamoyl-2-fluorophenyl) -6-fluoroquinazolin-4-yl)] piperidine-4-carboxylic acid

(1) By treating 850 mg of 8-bromo-6-fluoro-3H-quinazolin-4-one and 605 mg of isonipecotic acid ethyl ester in the same manner as in Reference Example A6 (5), 1- (8-bromo-6-fluoro -Quinazolin-4-yl) piperidine-4-carboxylic acid ethyl ester 1.30 g was obtained as a colorless solid (yield 97%).
MS (APCI) m / z; 382, 384 [M + H] ^< +>.

(2) 1.29 g of the compound obtained in the above (1) and 2- [4- (N, N-dimethylcarbamoyl) -2-fluorophenyl] -4,4,5,5-tetramethyl- [1, 3,2] Dioxaborolane 1.48 g was treated as in Example A1 to give 1- [8- (4-dimethylcarbamoyl-2-fluorophenyl) -6-fluoroquinazolin-4-yl)] piperidine-4 -1.35 g of carboxylic acid ethyl ester was obtained as a colorless solid (yield 86%).
MS (APCI) m / z; 469 [M + H] ^< +>.

(3) 450 mg of the compound obtained in (2) above was dissolved in 9 mL (1: 1) of THF / methanol, and 576 μL of 2M aqueous sodium hydroxide solution was added dropwise to the solution, followed by stirring for 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, and filtered. The filtrate was concentrated under reduced pressure to give 408 mg of the title compound as a colorless solid (yield 96%). This compound was used in the next step reaction without further purification.
MS (APCI) m / z; 441 [M + H] ^< +>.

Reference Example A44
Preparation of 2- (3-fluoro-4-methylsulfanylphenyl) -4,4,5,5-tetramethyl- [1,3,2] dioxaborolane

  (1) To a solution of 1.00 g of 4-bromo-2-fluorothiophenol in 10 mL of N-methylpyrrolidone, 1.67 g of potassium carbonate and 0.60 mL of methyl iodide were added and stirred at 85 ° C. for 1 hour. 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 obtained residue was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 99/1 → 90/10) to give 1.02 g of 4-bromo-2-fluorothioanisole. Was obtained as a light brown liquid (96% yield).

  (2) In a nitrogen atmosphere, the compound (1.00 g) and bis (pinacolato) diboron (1.49 g) obtained in (1) above were treated in the same manner as in Reference Example A16 (2) to give 646 mg of the title compound. Was obtained as a pale green liquid (53% yield).

Reference Example A45
Preparation of N, N-dimethyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -2-trifluoromethylbenzoic acid amide

(1) To a suspension of 4-chloro-2-trifluoromethylbenzoic acid in 1.00 g of dichloromethane in 10 mL of dichloromethane was added 0.71 g of 1,1′-carbonyldiimidazole at room temperature, and the mixture was stirred for 1 hour. To the reaction mixture, 3.34 mL of 2M dimethylamine / THF solution was added at room temperature, and the mixture was stirred overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed 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 = 70/30 → 50/50) to give N, N-dimethyl-4-chloro-2- 1.07 g of trifluoromethylbenzoic acid amide was obtained as a colorless liquid (yield 96%).
MS (APCI) m / z; 252/254 [M + H] ^< +>.

(2) The compound (1.01 g) and bis (pinacolato) diboron (1.22 g) obtained in (1) above were treated in the same manner as in Reference Example A16 (2) under a nitrogen atmosphere. 711 mg of compound was obtained as a pale green liquid (yield 52%).
MS (APCI) m / z; 344 [M + H] ^< +>.

Reference example B1
Preparation of 7-bromo-5-fluoro-1H-indole-2,3-dione

A solution of 2-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. After adding 3 mL of bromine to the reaction mixture, the mixture was stirred for 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 B2
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 compound in the same manner as in Reference Example A6 (3) to (4).
MS (APCI) m / z: 243/245 [M + H] ^< +>.

Reference example B3
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 dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was triturated with hexane to give 10.1 g of the title compound. (Yield 93%)
MS (APCI) m / z: 261/263 [M + H] ^< +>.

Reference examples B4 to B5
By treating the corresponding starting material compound in the same manner as in Reference Example A1, the following compound was obtained.
Reference Example B4 4- (3-n-propyl- [1,2,4] oxadiazol-5-yl) piperidine hydrochloride

MS (APCI) m / z: 196 [M + H] ^< +>.
Reference Example B5 4- [3- (2,2,2-trifluoroethyl)-[1,2,4] oxadiazol-5-yl] piperidine hydrochloride

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

Reference examples B6 to B8
By treating the corresponding starting material compound in the same manner as in Reference Example A36, the following compound was obtained.
Reference Example B6 4- (5-n-propyl- [1,2,4] oxadiazol-3-yl) piperidine hydrochloride

MS (APCI) m / z: 196 [M + H] ^< +>.
Reference Example B7 4- (5-Cyclopropyl- [1,2,4] oxadiazol-3-yl) piperidine hydrochloride

MS (APCI) m / z: 194 [M + H] ^< +>.
Reference Example B8 4- (5-Trifluoromethyl- [1,2,4] oxadiazol-3-yl) piperidine hydrochloride

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

Reference Example B9
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 A36) 1.78 g of dichloromethane solution 30 mL of saturated aqueous sodium hydrogen carbonate solution 30 mL 1.80 g of 8-bromo-4-chloro-6-fluoro-quinazoline (compound obtained in Reference Example B3) was sequentially added, and the mixture was stirred at room temperature for 2 hours. The aqueous layer was separated from the reaction mixture and extracted with dichloromethane. The 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, 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 B10 to B14
The following compounds were obtained by treating the corresponding starting compounds in the same manner as in Reference Example B9.
Reference Example B10 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 B11 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 B12 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 B13 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 B14 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 B15
Preparation of 8-bromo-5-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl} quinazoline

8-Bromo-5-fluoro-3H-quinazolin-4-one (compound obtained in Reference Example A6 (1) to (4)) is added to a solution of 2.43 g of thionyl chloride in 1 mL of dimethylformamide, and the mixture is added. The mixture was stirred for 4 hours while refluxing. After cooling to room temperature, the solvent was distilled off under reduced pressure. A solution obtained by suspending the residue in 32 ml of dichloromethane was mixed with 2317 mg of 4- (5-isopropyl-1,2,4-oxadiazol-3-yl) piperidine hydrochloride (the compound obtained in Reference Example A36) and saturated carbonic acid. 25 ml of aqueous sodium hydride 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 B16
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, solvent; hexane / ethyl acetate = 99/1 to 95/5) to give 4-bromo-2-fluoro-1 1.13 g of-(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 degassed 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 B17 to B21
The following compounds were obtained by treating the corresponding starting compounds in the same manner as in Reference Example B16.
Reference Example B17 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 B18 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 B19 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 B20 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 B21 2- [2-Fluoro-4- (2-benzyloxyethyl) oxyphenyl] -4,4,5,5-tetramethyl- [1,3,2] dioxaborolane

Reference Example B22
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 B23
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 DMSO 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 B24
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. After deaeration, 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, solvent: hexane / ethyl acetate = 80 / 20-40 / 60) to give 262 mg of the title compound as a viscous oil. (Yield: 7%).
MS (APCI) m / z: 363
Reference Example B25
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 B16 (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 B26
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 B9) 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, solvent; hexane / ethyl acetate: 86/14 to 75/25, and solvent; hexane / ethyl acetate: 91/9 to 75/25. ) Twice to give 2-fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-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 previous item (1) was dissolved in a mixed solution of 13 mL of THF 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 B27 to B32
The following compounds were obtained by treating the corresponding starting compounds in the same manner as in Reference Example B26.
Reference Example B27 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 B28 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 B29 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 B30 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 B31 (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 B32 (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 B33
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-trifluoroethyl)-[1,2,4] oxadiazol-5-yl] piperidin-1-yl] quinazoline (Compound obtained in Reference Example B14) 1.00 mg and 4-carboxy-3-fluorophenylboronic acid 798 mg were treated in the same manner as in Example B1 to obtain 265 mg of the title compound as a colorless powder (yield: 24%).
MS (APCI) m / z: 520 [M + H] ^< +>.

Reference Example B34
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 B16 (yield: 32%).
MS (APCI) m / z: 358 [M + NH4] ^< +>.

Reference Example B35
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 (compound obtained in Reference Example B9) By treating 200 mg in the same manner as in Example B1, 109 mg of the title compound was obtained as a colorless powder (yield: 38%).
MS (APCI) m / z: 596 [M + H] ^< +>.

Reference examples B36 to B41
The following compounds were obtained by treating the corresponding starting compounds in the same manner as in Reference Example B35.
Reference Example B36 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 B37 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 B38 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 B39 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 B40 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 B41 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 B42
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 B9) Compound 780) was treated in the same manner as in Reference Example B26 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 the above (1) in the same manner as in Example B1, 96 mg of the title compound was obtained as a colorless powder (yield: 73%).
MS (APCI) m / z: 618 [M + H] ^< +>.

Reference Example B43
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 B9) Compound (420) and 4-cyano-3-fluorophenylboric acid (250 mg) were treated in the same manner as in Example B1 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 dichloromethane. 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 (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 B44
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 dichloromethane. 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] tetrahydropyran. 3.62 g was obtained as a colorless solid (yield: 50%).

(2) By treating 3.5 g of the compound obtained in the above (1) in the same manner as in Reference Example B16 (2), 2.6 g of the title compound was obtained as an oil (yield: 66%).
MS (APCI) m / z: 414 [M + NH4] ^< +>.

Reference Example B45
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 B44 to give the title compound.

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

Reference Example B46
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 B9) Compound 2) and 1.456 g of 4-tert-butoxycarbonylamino-3-fluorophenylboronic acid were treated in the same manner as in Example B1 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 B47
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 at 0 ° C. to a solution of 0.8 g of sodium hydride in 100 mL of dimethylformamide, a solution of 4.36 g of 4-bromo-1-bromomethyl-2-fluorobenzene in 100 mL of DMF 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 B16 (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 B48
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 B12) The obtained compound) 0.5 g and 3-fluoro-4-formylphenylboronic acid were treated in the same manner as in Example B1 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 THF, 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 B49
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 B15) and 700 μL of 2- (tert-butyldimethylsilyloxy) ethyl bromide in the same manner as in Example B16. 0.7 mg was obtained as a pale yellow powder (yield: 50%).
MS (APCI) m / z: 678 [M + H] ^< +>.

Reference Example B50
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 B297) 130 mg in 3 mL of dichloromethane were added 98 μL of thionyl chloride and 1 drop of DMF, 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 B51
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 B9) 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 B1. 426 mg was obtained as a colorless solid (yield: 82%).
MS (APCI) m / z: 437 [M + H] ^< +>.

Reference Example B52
[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 (the compound obtained in Reference Example B9) ) 420 mg and [2-Fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] acetic acid ethyl ester (compound obtained in Reference Example B53) By treating 610 mg in the same manner as in Example B1, 750 mg of the title compound was obtained as a colorless viscous oil (yield: 100%).
MS (APCI) m / z: 522 [M + H] ^< +>.

Reference Example B53
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 B22 (2)) 15.0 g of ethanol 150 mL / water 45 mL was added with 23.59 g of potassium hydroxide at room temperature, The mixture was stirred at 85 ° C. for 9.5 hours. 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 14.03 g of (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 B16 (2) (yield: 66%).
MS (APCI) m / z: 309 [M + H] ^< +>.

Reference Example B54
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 B35 to give the title compound (423.3 mg) as a colorless solid (yield: 64%).
MS (APCI) m / z: 634 [M + H] ^< +>.

Reference Example B55
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 B46 to give the titled compound (819.8 mg) as a colorless powder (yield: 85%).
MS (APCI) m / z: 447 [M + H] ^< +>.

Reference Example B56
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 B46, and then the reaction product was treated with 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 B57
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 ( The compound obtained in Reference Example B56) To a solution of 300 mg of tetrahydrofuran in 6 mL was added 172 μL of 2-chloroethyl isocyanate 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 B58
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 B57 to give the title compound (136.6 mg) as a colorless powder (yield: 69%).
MS (APCI) m / z; 516 [M + H] ^< +>.

Reference Example B59
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 B94) and 29 μL of acetoxyacetyl chloride in the same manner as in Example B9, 89.1 mg of the title compound was obtained as a colorless powder. (Yield: 100%).
MS (APCI) m / z; 634 [M + H] ^< +>.

Reference examples B60-61
The following compounds were obtained by treating the corresponding starting compounds in the same manner as in Reference Example B9.
Reference Example B63 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 B64 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 B62
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 B57, 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 B16, 5.80 g of the title compound is colorless and viscous. Obtained as an oil (yield: 51%).
MS (APCI) m / z: 417/419 [M + H] ^< +>.

Reference examples B63-B65
The following compounds were obtained by treating the corresponding starting compounds in the same manner as in Reference Example B62.
Reference Example B63 1- (4-Bromophenyl) -3- [2- (tert-butyldimethylsilyloxy) ethyl] imidazolidin-2-one

MS (APCI) m / z: 399/401 [M + H] ^< +>.
Reference Example B64 1- (4-Bromo-2-methylphenyl) -3- [2- (tert-butyldimethylsilyloxy) ethyl] imidazolidin-2-one

MS (APCI) m / z: 413/415 [M + H] ^< +>.
Reference Example B65 1- (4-Bromo-2-methylphenyl) -3- [3- (tetrahydropyran-2-yloxy) propyl] imidazolidin-2-one

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

Reference Example B66
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 at room temperature overnight. 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 B67-B68
The following compounds were obtained by treating the corresponding starting compounds in the same manner as in Reference Example B66.
(Reference Example B67) (R) -4- (tert-Butyldimethylsilyloxy) pyrrolidin-2-one

MS (APCI) m / z: 216 [M + H] ^< +>.
(Reference Example B68) (S) -5- (tert-Butyldimethylsilyloxymethyl) pyrrolidin-2-one

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

Reference Example B69
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 B66) 859 mg, 4-bromo-2-fluoro-1-iodobenzene 1 g, copper chloride 32 mg, N , N′-dimethylethylenediamine 36 μL and potassium phosphate 1.41 g in 15 mL of toluene were 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 B70 to B73
The following compounds were obtained by treating the corresponding starting compounds in the same manner as in Reference Example B6.
Reference Example B70 (R) -1- (4-Bromo-2-fluorophenyl) -4- (tert-butyldimethylsilyloxy) pyrrolidin-2-one

MS (APCI) m / z; 388/390 [M + H] ^< +>.
Reference Example B71 (R) -1- (4-Bromo-2-methylphenyl) -4- (tert-butyldimethylsilyloxy) pyrrolidin-2-one

MS (APCI) m / z; 384/386 [M + H] ^< +>.
(Reference Example B72) (R) -1- (4-Bromo-3-methylphenyl) -4- (tert-butyldimethylsilyloxy) pyrrolidin-2-one

MS (APCI) m / z; 384/386 [M + H] ^< +>.
Reference Example B73 4- (4-Bromo-2-fluorophenyl) -3-oxopiperazine-1-carboxylic acid tert-butyl ester

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

Reference Example B74
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 B68) 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 B75
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 B76
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 B75 to give the title compound.
MS (APCI) m / z; 286/288 [M + H] ^< +>.

Reference Example B77
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 B62 (1)) and 232 mg of ethyl bromoacetate in the same manner as in Example B16. 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) 7.6 mL of a solution of methylmagnesium bromide in THF (0.93 mol / L) was added dropwise over 5 minutes to a 20 mL THF solution of 810 mg of the compound obtained in (1) above at −40 ° C. in a nitrogen atmosphere. The mixture was stirred at room temperature for 100 minutes. To the reaction mixture, 7.6 mL of methylmagnesium bromide in THF (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, 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 B78
Production of (R) -3- (4-bromo-2-fluorophenyl) -5- (tert-butyldimethylsilyloxymethyl) oxazolidine-2-one

(1) To 100 ml of acetone solution of 5 g of 4-bromo-2-fluoroaniline, 20 mL of water and 4.66 g of sodium hydrogen carbonate were added at room temperature, and 16.5 g of 30% toluene solution of benzyl chloroformate was added dropwise thereto, 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 n-butyllithium hexane solution (1.54 mol / L) was added dropwise over 15 minutes in a nitrogen atmosphere at -78 ° C. 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 a 12 mL solution of 1.26 g of the compound obtained in (2) above in dimethylformamide, 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 B79
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 B14. (Yield 42%)
MS (APCI) m / z; 265/267 [M + H] ^< +>.

Reference Example B80
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 B62) 2 g of tetrahydrofuran / toluene ( 15 mL / 15 mL) solution was added dropwise with hexane solution (1.59 mol / L) of n-butyllithium 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 B81
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 B62) was referred to Reference Example B16 ( 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 B82 to B95
The following compounds were obtained by treating the corresponding starting compounds in the same manner as in Reference Example B81.
Reference Example B82 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 B83 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 B84 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 B85 (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 B86 (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 B87 (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 B88 (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 B89 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 B90 (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 B91 [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 B92) [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 B93 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 B94 (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 B95 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 B96
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 mixture, and the mixture was stirred at room temperature. The precipitated crystals were collected by filtration, washed with water, and dried at 50 ° C. to obtain 20.8 g of 2-amino-3-iodobenzoic acid 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 B97
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 A6 (4) to give 18.97 g of 8-bromo-3H-quinazolin-4-one (yield 90%).
MS (APCI) m / z: 225/227 [M + H] ^< +>.

Reference Example B98
Preparation of 4-chloro-8-iodo-quinazoline

One drop of DMF was added to 4.5 mL of a solution of 8-iodo-3H-quinazolin-4-one (compound obtained in Reference Example B96) 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 B99
Preparation of 8-bromo-4-chloro-quinazoline

The corresponding starting compound 5g was treated in the same manner as in Reference Example B3 to obtain 4.85 g of 8-bromo-4-chloro-quinazoline (yield 90%).
MS (APCI) m / z: 243/245 [M + H] ^< +>.

Reference Example B100
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 (the compound obtained in Reference Example A36 (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 B101
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 A36 (1)) 973 mg, triethylamine 669 μL in toluene 10 ml 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 B102
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 A36 (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 B103
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

4- (N-hydroxycarbamimidoyl) piperidine-1-carboxylic acid tert-butyl ester (compound obtained in Reference Example A36 (1)) in a solution of 920 mg in dichloromethane (23 mL) 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. Stir for 26.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. 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 B104 to B107
The corresponding compound was treated in the same manner as in Reference Example A368 (3) to give the following compound.
Reference Example B104 4- (5-Difluoromethyl- [1,2,4] oxadiazol-3-yl) piperidine hydrochloride

MS (APCI) m / z; 204 [M + H] ^< +>.
Reference Example B105 4- [5- (1-Acetyl-1-methylethyl)-[1,2,4] oxadiazol-3-yl] piperidine hydrochloride

MS (APCI) m / z; 254 [M + H] ^< +>.
Reference Example B106 4- [5- (1,1-difluoroethyl)-[1,2,4] oxadiazol-3-yl] piperidine hydrochloride

MS (APCI) m / z; 218 [M + H] ^< +>.
Reference Example B107 4- [5-Dimethylamino- [1,2,4] oxadiazol-3-yl] piperidine dihydrochloride

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

Reference examples B108 to B116
The following compounds were obtained by treating the corresponding starting compounds in the same manner as in Reference Example B9.
Reference Example B108 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 B109) 1- {3- [1- [8-Bromo-6-fluoroquinazolin-4-yl) piperidin-4-yl]-[1,2,4] oxadiazol-5-yl} acetate -1-methyl ethyl ester

MS (APCI) m / z; 478/480 [M + H] ^< +>.
Reference Example B110 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 B111 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 B112 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 B113 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 B114 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 B115)
{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 B116 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 B117
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 B15 to give the title compound (2662 mg) as a pale yellow solid (yield: 77%).

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

Reference examples B118-B121
The following compounds were obtained by treating the corresponding starting compounds in the same manner as in Reference Example B22.
Reference Example B118 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 B119 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 B120 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 B121 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 B122
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 B109) was treated in the same manner as in Example B11 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 B123
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 compound (201 mg obtained in Reference Example B122) was treated in the same manner as in Example B100 to give 125 mg of the title compound as a colorless solid (yield: 61.9%).
MS (APCI) m / z; 438/440 [M + H] ^< +>.

Reference example B124
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 dichloromethane, 8.75 mL of tert-butanol, 418 mg of 4-dimethylaminopyridine, and 1-ethyl-3- (3-dimethylamino) were cooled with ice. 5.25 g of propyl) 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 B16 (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 B125
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 B162) 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 B124) 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 B126 to B129
The following compounds were obtained by treating the corresponding starting compounds in the same manner as in Reference Example B125.
Reference Example B126 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 B127 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 B128 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 B129 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 B130 to B131
The following compounds were obtained by treating the compounds obtained by treating the corresponding starting compounds in the same manner as in Reference Example B46 with saturated aqueous sodium hydrogen carbonate solution.
Reference Example B130 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 B131 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 B132
3- (4-Bromo-2-fluorophenyl) -1- (2,4-dimethoxybenzyl) tetrahydropyrimidin-4-one

(1) After adding 1.7 mL of acrylic acid chloride to a 12 mL dichloromethane solution of 3.8 g of 4-bromo-2-fluorophenylamine at room temperature, 12 mL of dichloromethane was added and stirred at room temperature for 2 hours. Furthermore, after adding dichloromethane 12mL to the reaction liquid and stirring at room temperature for 16 hours, 325 microliters of acrylic acid chloride was added to this, and it 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, solvent; hexane / ethyl acetate: 70/30 to 50/50) to give N- (4-bromo-2- 413 mg of 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 37% formalin aqueous solution and 3 mL of THF 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, solvent; hexane / ethyl acetate: 75/25 to 43/57) to give 351.6 mg of the title compound as a colorless powder. Obtained (yield: 86.9%).
MS (APCI) m / z; 423/425 [M + H] ^< +>.

Reference Example B133
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 THF, 2.16 mL of bromoacetic acid chloride was added under ice cooling, and then stirred 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. Diisopropylethylamine 5.24 mL and 2,4-dimethoxybenzylamine 6.0 mL were sequentially added to a 200 mL dichloromethane solution of the obtained residue 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 1.53 g of the compound obtained in (1) above, 6.2 mL of 37% formalin aqueous solution, and 11.8 mL of THF 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 B134
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 THF, 2.16 mL of bromoacetic acid chloride was added 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 60 mL of THF, 6.9 mL of diisopropylethylamine, 3.62 mL of 2-aminoethanol, and 300 mg of sodium iodide were added at room temperature, and the mixture was stirred for 20 hours with heating under reflux. 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 B132 (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 B66, 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 B135 to B136
The following compounds were obtained by treating the corresponding starting compounds in the same manner as in Reference Example B66.
(Reference Example B135) (S) -3- (tert-Butyldimethylsilyloxy) pyrrolidin-2-one

MS (APCI) m / z; 216 [M + H] ^< +>.
(Reference Example B136) (R) -3- (tert-Butyldimethylsilyloxy) pyrrolidin-2-one

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

Reference examples B137 to B139
By treating the corresponding starting material compound in the same manner as in Reference Example B69, the following compound was obtained.
Reference Example B137 (S) -1- (4-Bromo-2-fluorophenyl) -3- (tert-butyldimethylsilyloxy) pyrrolidin-2-one

MS (APCI) m / z; 388/390 [M + H] ^< +>.
Reference Example B138 (R) -1- (4-Bromo-2-fluorophenyl) -3- (tert-butyldimethylsilyloxy) pyrrolidin-2-one

MS (APCI) m / z; 388/390 [M + H] ^< +>.
Reference Example B139 (S) -1- (4-Bromo-2-methylphenyl) -3- (tert-butyldimethylsilyloxy) pyrrolidin-2-one

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

Reference Example B140
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 B62 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 B141 to B142
The following compounds were obtained by treating the corresponding starting materials in the same manner as in Example B96.
Reference Example B141 1- (4-Bromo-2-fluorophenyl) pyrrolidin-2-one

MS (APCI) m / z; 258/260 [M + H] ^< +>.
Reference Example B142 1- (4-Bromo-3-methylphenyl) pyrrolidin-2-one

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

Reference Example B143
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 B124 (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 B144
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 B75 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 B145 to B155
The corresponding starting compound was treated in the same manner as in Reference Example B16 (2) to obtain the following compound.
Reference Example B145 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 B146 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 B147 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 B148 (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 B149 (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 B150 (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 B151 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 B152 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 B153 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 B154 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 B155) [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 B156
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 B157
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 B9 to give the title compound (2396 mg) as a colorless solid (yield: 89.4%).
MS (APCI) m / z; 335/337 [M + H] ^< +>.

Reference Example B158
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 B1 to give the title compound (301.7 mg) as a brown solid (yield: 95.1%).
MS (APCI) m / z; 684 [M + H] ^< +>.

Reference examples B159 to B160
By treating the corresponding starting material compound in the same manner as in Reference Example 35, the following compound was obtained.
Reference Example B159 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 B160 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 B161
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 B16 to give the title compound (1.02 g) as an oil (yield: 53%).
MS (APCI) m / z: 384 [M + H] ^< +>.

Reference Example B162
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 B9 to give the title compound (2.26 g) as a powder (yield: 95%).
MS (APCI) m / z: 446/448 [M + H] ^< +>.

Reference Example B163
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) 2.40 g of potassium carbonate and 1.27 mL of propyl iodide were added to a solution of the compound 2.20 g obtained in (1) above in 22 mL of DMF, 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 A1 (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 B164
Preparation of 1- [2-methyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl] -pyrrolidin-2-one

(1) 4-Bromo-2-methyl-phenylamine (3.00 g) and 4-chlorobutyryl chloride (2.71 mL) were treated in the same manner as in Example B99 to give 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 B16 (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 B165
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 mL 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 B16 (2) to obtain 222 mg of the title compound as a brown oil (yield 68%).
MS (APCI) m / z; 348 [M + H] ⁺
Reference Example B166
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 B16 (2), 285 mg of the title compound was obtained as a colorless solid (yield 25%).
MS (APCI) m / z; 349 [M + H] ⁺
Reference Example B167
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 B16 (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 B168
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 B167 (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 B16 (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 B169
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 B16 (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 B170
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) The compound 580 mg obtained in the above (1) was treated in the same manner as in Reference Example B16 (2) to obtain 358.7 mg of the title compound as a colorless solid (yield 53%).
MS (APCI) m / z; 354 [M + H] ⁺
Reference Example B171
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) 340 μL of N-methylmorpholine was added to 12 mL of 855 mg of tert-butyl alcohol, 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 the preceding item (1) in the same manner as in Reference Example B16 (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 B172
(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 B10) 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 B169) Compound) 396 mg was treated in the same manner as in Example B26 (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 B26 (2), 361 mg of the title compound was obtained as a colorless solid (yield 85%).
MS (APCI) m / z; 494 [M + H] ⁺
Reference Example B173
(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 B10) Compound) 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 B171) The obtained compound) was treated in the same manner as in Example B26 (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 B125 (2), 95 mg of the title compound was obtained as a colorless powder (yield 100%).
MS (APCI) m / z; 494 [M + H] ⁺
Reference Example B174
(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 B11) 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 B169) The obtained compound) (553 mg) was treated in the same manner as in Reference Example B26 (1) to give (4- [4- [4- (5-cyclopropyl- [1,2,4] oxadiazol-3-yl). )] Piperidin-1-yl] -6-fluoroquinazolin-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 B26 (2), 198 mg of the title compound was obtained as a colorless solid (yield 95%).
MS (APCI) m / z; 492 [M + H] ⁺
Reference Example B175
[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 (compound obtained in Reference Example B14) and [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] acetic acid [2-Fluoro-4- (6-fluoro-4- [4- [3- (3)] was obtained by treating 553 mg of the tert-butyl ester (the compound obtained in Reference Example B170) in the same manner as in Reference Example B125 (1). 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 B125 (2) to give 77 mg of the title compound as a colorless solid (yield 23%).
MS (APCI) m / z; 534 [M + H] ⁺
Reference Example B176
(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 (compound obtained in Reference Example B10) 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 B168) Compound (626 mg) was treated in the same manner as in Example B1 to give the title compound (682 mg) as a colorless solid (yield 83%).
MS (APCI) m / z; 579 [M + H] ⁺
Reference Example B177
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 (compound obtained in Example B133) in 12.2 mL of 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 (Chromatorex, solvent: 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 B178
(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 ) 650 mg of tert-butyl methylcarbamate (the compound obtained in Reference Example B176) was treated in the same manner as in Reference Example B177 to give 343 mg of the title compound as a colorless solid (yield 64%).
MS (APCI) m / z; 479 [M + H] ⁺
Reference Example B179
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 B177) 80 mg and acetic acid 1-chlorocarbamoyl-1-methylethyl ester (27.1 μL) were treated in the same manner as in Example B9 to obtain 78.1 mg of the title compound as a colorless solid ( Yield 80%).
MS (APCI) m / z; 593 [M + H] ⁺
Reference Example B180
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 ) By treating 80 mg of methylamine (compound obtained in Reference Example B178) and the corresponding starting material compound in the same manner as in Example B9, 83 mg of the title compound was obtained as a colorless solid (yield 86%).
MS (APCI) m / z; 579 [M + H] ⁺
Reference Example B181
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 B178) and the corresponding starting material compound were treated in the same manner as in Example B9 to give 80 mg of the title compound as a colorless solid (yield 79%).
MS (APCI) m / z; 607 [M + H] ⁺
Reference Example B182
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 (compound obtained in Reference Example B10) The corresponding starting material compound was treated in the same manner as in Example B1 to obtain 442 mg of the title compound as a colorless solid (yield 66%).
MS (APCI) m / z; 467, 469 [M + H] ⁺
Reference Example B183
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 B62 (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) By treating 460 mg of the compound obtained in (2) above in the same manner as in Reference Example B16 (2), 266 mg of the title compound was obtained as a colorless solid.
MS (APCI) m / z; 479 [M + H] ⁺
Reference Example B184
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 B13 and 95.6 mg of the compound obtained in Reference Example B183 in the same manner as in Reference Example B16 (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 B185
Preparation of acetic acid 2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzyl ester

A solution of 1.50 g of 4-bromo-2-fluorobenzyl bromide and 2.74 g of potassium acetate in 22.5 mL of DMSO 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 B186
(S) -4- (tert-Butyldimethylsilyloxy) -1- [2-fluoro-4- [6-fluoro-4- [4- (5-n-propyl- [1,2,4] oxadi) Azol-3-yl) piperidin-1-yl] quinazolin-8-yl] benzyl] pyrrolidin-2-one

(1) By treating 600 mg of the compound obtained in Reference Example B13 and 504 mg of the compound obtained in Reference Example B185 in the same manner as in Reference Example B16 (2), acetic acid 2-fluoro-4- [6-fluoro- 595 mg of 4- [4- (5-n-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] benzyl was obtained as a colorless solid (yield) 82%).
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 B11, (2-fluoro-4- [6-fluoro-4- [4- (5-n-propyl- [ 528 mg of 1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] phenyl) methanol 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- [ 427 mg of 4- (5-n-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline was obtained as a colorless solid (yield 72%).
MS (APCI) m / z; 528/530 [M + H] ⁺
(4) By treating 80 mg of the compound obtained in (3) in the same manner as in Example B19, 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 B187 to B189
The following compounds were obtained by treating the corresponding starting compounds in the same manner as in Reference Example B174.
Reference Example B187 (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 B188 (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 B189
Preparation of 4- (2-isopropyl-2H-tetrazol-5-yl) -piperidine hydrochloride

The title compound was obtained by treating the compound obtained in Reference Example B163 (1) and the corresponding starting material compound in the same manner as in Reference Example B163 (2) and (3).
MS (APCI) m / z: 196 [M + H] ^< +>.

Reference Example B190
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 (compound obtained in Reference Example B9) 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] Add 373 mg of dioxaborolane (the compound obtained in Reference Example B21), 35 mg of [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride-dichloromethane complex and 650 mg of cesium carbonate. The mixture 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] ^< +>.

Reference Example B191
Preparation of 3-fluoro-4- [6-fluoro-4- [1- (N-hydroxycarbamimidoyl) piperidin-4-yl] quinazolin-8-yl] -N, N-dimethylbenzamide

(1) 8-Bromo-4-chloro-6-fluoroquinazoline (compound obtained in Reference Example B3) in a solution of 1.00 g of 1,4-dioxane in 24 mL of 4- (4,4,5,5-tetramethyl) -[1,3,2] -Dioxaborolan-2-yl) -3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 1.18 g, tetrakis (triphenylphosphine) palladium 440 mg, cesium carbonate 2 .48 g and 6 mL of water were added and the mixture was stirred for 20 minutes at 140 ° C. in a microwave reactor (Initiator). 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 purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 93/7 to 72/28) to give 4- (8-bromo-6-fluoroquinazolin-4-yl) -3. , 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 671 mg was obtained as a pale yellow powder (yield: 43%).
MS (APCI) m / z; 408/410 [M + H] ^< +>.

(2) 200 mg of the compound obtained in the above (1) and 2- [4- (N, N-dimethylcarbamoyl) -2-fluorophenyl] -4,4,5,5-tetramethyl-1,3,2 -By treating 186 mg of dioxaborolane in the same manner as in Example B1, 4- [8- (4-dimethylcarbamoyl-2-fluorophenyl) -6-fluoroquinazolin-4-yl] -3,6-dihydro-2H- 199 mg of pyridine-1-carboxylic acid tert-butyl ester was obtained as a colorless powder (yield 82%).
MS (APCI) m / z; 495 [M + H] ^< +>.

(3) 30% of 10% palladium-carbon was added to a solution of 181 mg of the compound obtained in (2) above in 8 mL of ethanol / 4 mL of THF, and the mixture was stirred at 40 to 45 ° C. for 2 hours in a hydrogen atmosphere. The reaction mixture was cooled to room temperature and then filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (Chromatorex, solvent: hexane / ethyl acetate = 80 / 20-40 / 60) to give 4- [8- (4-dimethylcarbamoyl-2-fluorophenyl). ) -6-Fluoroquinazolin-4-yl] piperidine-1-carboxylic acid tert-butyl ester (143 mg) was obtained as a colorless powder (yield: 79%).
MS (APCI) m / z; 497 [M + H] ^< +>.

(4) 2N of 4N hydrochloric acid-dioxane solution and 1 mL of methanol were added to 1,4-dioxane solution of 122 mg of the compound obtained in (3) above, and the mixture was stirred at room temperature for 2.5 hours. The solvent was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure to obtain 99 mg of 3-fluoro-4- (6-fluoro-4-piperidin-4-yl-quinazolin-8-yl) -N, N-dimethylbenzamide as a pale yellow powder ( Yield: 100%).
MS (APCI) m / z; 397 [M + H] ^< +>.

(5) To a solution of 99 mg of the compound obtained in (4) above in 2 mL of ethanol and 1 mL of THF, 29 mg of cyanogen bromide and 64 mg of sodium bicarbonate were added, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with dichloromethane 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 95/5) to give 4- [4- (1-cyanopiperidin-4-yl) -6-fluoro. Quinazolin-8-yl] -3-fluoro-N, N-dimethylbenzamide (81 mg) was obtained as a colorless powder (yield: 77%).
MS (APCI) m / z; 422 [M + H] ^< +>.

(6) To a solution of 81 mg of the compound obtained in (5) above in 1 mL of isopropanol was added 25 mg of 50% aqueous hydroxylamine solution, and the mixture was stirred at 90 ° C. for 2.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give 87 mg of the title compound as a colorless powder (yield: 100%).
MS (APCI) m / z; 455 [M + H] ^< +>.

Reference Example B192
Preparation of 4- [4- (4-cyanopiperidin-1-yl) -6-fluoroquinazolin-8-yl] -2-fluoro-N, N-dimethylbenzamide

The corresponding starting material compound was treated in the same manner as in Example B1 to give 979 mg of the title compound as a colorless powder (yield: 78%).
MS (APCI) m / z; 422 [M + H] ^< +>.

Reference Example B193
Preparation of 8-bromo-6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) -piperazin-1-yl] -quinazoline

The corresponding starting material compound was treated in the same manner as in Reference Example B9 to give the title compound 769 mg as a pale yellow powder (yield: 96%).
MS (APCI) m / z; 421/423 [M + H] ^< +>.

Reference Example B194
Preparation of (S) -4- (8-bromo-6-fluoro-quinazolin-4-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester

The corresponding starting material compound was treated in the same manner as in Reference Example B9 to give 768 mg of the title compound as a pale yellow powder (yield: 95%).
MS (APCI) m / z; 425/427 [M + H] ^< +>.

Reference Example B195
8-Bromo-6-fluoro-4-[(S) -4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) -3-methylpiperazin-1-yl] -quinazoline Manufacturing

(1) 7 mL of 4N hydrochloric acid-dioxane solution was added to a solution of 768 mg of the compound obtained in Reference Example B194 in 1,4-dioxane, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was triturated with diethyl ether, whereby 774 mg of 8-bromo-6-fluoro-4-((S) -3-methylpiperazin-1-yl) quinazoline dihydrochloride was pale yellow. Obtained as a powder (yield: 100%).
MS (APCI) m / z; 325/327 [M + H] ^< +>.

(2) 191 mg of cyanogen bromide and 770 mg of sodium bicarbonate were added to a solution of the compound 774 mg obtained in (1) above in 15 mL of ethanol, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (Chromatorex, solvent: hexane / ethyl acetate = 83/17 to 63/37) to give (S) -4- (8-bromo-6-fluoroquinazoline). 539 mg of -1-yl) -2-methylpiperazine-1-carbonitrile was obtained as a colorless powder (yield: 85%).
MS (APCI) m / z; 350/352 [M + H] ^< +>.

(3) By treating 539 mg of the compound obtained in the above (2) in the same manner as in Reference Examples A36 (2) to (3), 275 mg of the title compound was obtained as a pale yellow powder (yield: 41%).
MS (APCI) m / z; 435/437 [M + H] ^< +>.

Reference Example B196
Of 8-bromo-6-fluoro-4-[(S) -4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) -2-methylpiperazin-1-yl] -quinazoline Manufacturing

The corresponding starting material compound was treated in the same manner as in Reference Example B9 to give the title compound as a colorless powder (423 mg, yield: 64%).
MS (APCI) m / z; 435/437 [M + H] ^< +>.

Reference Example B197
Production of (S) -1- (5-isopropyl- [1,2,4] oxadiazol-3-yl) -3-methylpiperazine dihydrochloride

(1) By treating 2.38 g of (S) -2-methylpiperazine-1-carboxylic acid-tert-butyl ester in the same manner as in Reference Example B195 (2), (S) -4-cyano-2-methyl Piperazine-1-carboxylic acid-tert-butyl ester (2.23 g) was obtained as a colorless powder (yield: 83%).
MS (APCI) m / z; 226 [M + H] ^< +>.

(2) By treating 2.23 g of the compound obtained in the above (1) in the same manner as in Reference Example A36, 1.42 g of the title compound was obtained as a colorless powder (yield: 53%).
MS (APCI) m / z; 211 [M + H] ^< +>.

Reference Example B198
6-Fluoro-8- [3-fluoro-4- [2- (tetrahydropyran-2-yloxy) ethylsulfanylmethyl] -4- [4- (5-isopropyl- [1,2,4] oxadiazole- 3-yl) piperazin-1-yl] quinazoline

The corresponding starting material compound was treated in the same manner as in Reference Example B35 to give 75 mg of the title compound as a colorless powder (yield: 26%).
MS (APCI) m / z; 611 [M + H] ^< +>.

Reference Example B199
(2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperazin-1-yl] quinazolin-8-yl] phenyl ) Production of acetic acid

The corresponding starting material compound was treated in the same manner as in Reference Example B174 to give 500 mg of the title compound as a colorless powder (yield: 72%).
MS (APCI) m / z; 495 [M + H] ^< +>.

Reference Example B200
Preparation of 8-bromo-6-fluoro-4-[(R) -4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) -3-methylpiperazin-1-yl] quinazoline

The corresponding starting material compound was treated in the same manner as in Reference Example B9 to give the title compound as a pale yellow powder (yield: 91%).
MS (APCI) m / z; 435/437 [M + H] ^< +>.

Reference example B201
Production of (R) -1- (5-isopropyl- [1,2,4] oxadiazol-3-yl) -2-methylpiperazine hydrochloride

The corresponding starting material compound was treated in the same manner as in Reference Example B197 to give 981 mg of the title compound as a colorless powder (yield: 31%).
MS (APCI) m / z; 211 [M + H] ^< +>.

Reference Example B202
Preparation of 8-bromo-6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl)-[1,4] diazepan-1-yl] quinazoline

The corresponding starting material compound was treated in the same manner as in Reference Example B9 to give the title compound as a pale yellow powder (yield: 91%).
MS (APCI) m / z; 435/437 [M + H] ^< +>.

Reference Example B203
Preparation of 1- (5-isopropyl- [1,2,4] oxadiazol-3-yl)-[1,4] diazepan hydrochloride

The corresponding starting material compound was treated in the same manner as in Reference Example B197 to give 980 mg of the title compound as a colorless powder (yield: 40%).
MS (APCI) m / z; 211 [M + H] ^< +>.

Reference Example B204
6-Fluoro-8- (3-fluoro-4-methylsulfanylmethylphenyl) -4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl)-[1,4] Production of [diazepan-1-yl] quinazoline

The corresponding starting material compound was treated in the same manner as in Reference Example B9 to give the title compound as a pale yellow powder (yield: 91%).
MS (APCI) m / z; 435/437 [M + H] ^< +>.

Reference Example B205
(2-Fluoro-4- [6-fluoro-4-[(S) -4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) -2-methyl-piperazine-1- Yl] -quinazolin-8-yl] -phenyl) acetic acid

The corresponding starting material compound was treated in the same manner as in Reference Example B174 to give the title compound as a colorless powder (yield: 72%).
MS (APCI) m / z; 509 [M + H] ^< +>.

Reference Example B206
Preparation of 2-fluoro-4- [6-fluoro-4- [4- (N-hydroxycarbamimidoyl) piperidin-1-yl] quinazolin-8-yl] -N, N-dimethylbenzamide

To a solution of 890 mg of the compound obtained in Reference Example B192 in 10 mL of isopropanol was added 279 μL of a 50% aqueous hydroxylamine solution, and the mixture was stirred at 90 ° C. for 5 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, and trituration with diethyl ether gave 837 mg of the title compound as a colorless powder (yield: 87%).
MS (APCI) m / z; 455 [M + H] ^< +>.

Reference Example B207
Preparation of 1- (5-isopropyl- [1,2,4] oxadiazol-3-yl) -piperazine hydrochloride

The corresponding starting material compound was treated in the same manner as in Reference Example B197 to give 1.21 g of the title compound as a colorless powder (yield: 62%).
MS (APCI) m / z; 197 [M + H] ^< +>.

Reference examples B208 to B211
The following compounds were obtained by treating the corresponding starting compounds in the same manner as in Reference Example B15.
Reference Example B208 8-bromo-5-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) -piperazin-1-yl] -quinazoline

MS (APCI) m / z; 421/423 [M + H] ^< +>.
Reference Example B209 8-Bromo-4- [4- (5-cyclobutyl- [1,2,4] oxadiazol-3-yl) -piperidin-1-yl] -5-fluoroquinazoline

MS (APCI) m / z; 432/434 [M + H] ^< +>.
Reference Example B210 8-bromo-5-fluoro-4- [4- [5- (1-methylisopropyl)-[1,2,4] oxadiazol-3-yl] -piperidin-1-yl] -Quinazoline

MS (APCI) m / z; 432/434 [M + H] ^< +>.
Reference Example B211 8-Bromo-5-fluoro-4- [4- [5- (1-fluoro-1-methylethyl)-[1,2,4] oxadiazol-3-yl] -piperidine-1 -Il] -Quinazoline

MS (APCI) m / z; 438/440 [M + H] ^< +>.

Reference examples B212 to B213
The following compounds were obtained by treating the corresponding starting compounds in the same manner as in Reference Example B5.
Reference Example B212 4- (5-Cyclobutyl- [1,2,4] oxadiazol-3-yl) piperidine hydrochloride

MS (APCI) m / z: 208 [M + H] ^< +>.
Reference Example B213 4- (5- (1-Methylcyclopropyl)-[1,2,4] oxadiazol-3-yl) piperidine hydrochloride

MS (APCI) m / z: 208 [M + H] ^< +>.

Reference Example B214
The corresponding starting material compound was treated in the same manner as in Reference Example B69 to give 5-bromo-2-[(R) -4- (tert-butyldimethylsilyloxy) -2-oxopyrrolidin-1-yl] benzonitrile. .

MS (APCI) m / z; 395/397 [M + H] ^< +>.

Reference Example B215
Production of (S) -1- (4-bromo-2-fluorophenyl) -5-oxopyrrolidine-2-carbonitrile

(1) By treating 2 g of 4-bromo-2-fluoro-1-iodobenzene and 1.25 g of (S) -5-oxopyrrolidine-2-carboxylic acid ethyl ester in the same manner as in Reference Example B74, (S)- 812 mg of 1- (4-bromo-2-fluorophenyl) -5-ethoxycarbonylpyrrolidin-2-one was obtained as a yellow oil (yield: 37%).
MS (APCI) m / z; 330/332 [M + H] ^< +>.

(2) To a solution of 800 mg of the compound obtained in (1) above in 4 mL of methanol was added 8 mL of 7N ammonia methanol solution at 0 ° C., and the mixture was stirred at 0 ° C. for 3 hours. 8 mL of 7N ammonia methanol solution was added to the reaction solution, followed by stirring at 0 ° C. for 1 hour and then at room temperature overnight. The reaction mixture was concentrated, a mixed solvent of hexane and ethyl acetate was added, and the precipitated solid was collected by filtration to give (S) -1- (4-bromo-2-fluorophenyl) -5-oxopyrrolidine-2-carboxamide. 749 mg was obtained as a pale yellow solid (yield: 98%).
MS (APCI) m / z; 301/303 [M + H] ^< +>.

(3) 1.05 mL of 1,8-diazabicyclo- [5,4,0] -undeca 7-ene (DBU) was added to a suspension of 745 mg of the compound obtained in (2) above in 20 mL of dichloromethane at 0 ° C. After dropwise addition of 558 μL of ethyldichlorophosphate, the mixture was allowed to stand at room temperature for 7 hours. Tetrahydrofuran 10mL and DBU0.35mL were added to the reaction liquid, and it stirred at room temperature all night. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 80/20 → 50/50) to give 597 mg of the title compound as a colorless solid (yield 90%). .
MS (APCI) m / z; 283/285 [M + H] ^< +>.

Reference examples B216 to B217
The following compounds were obtained by treating the corresponding starting compounds in the same manner as in Reference Example B81.
Reference Example B216 (R) -4- (tert-butyldimethylsilyloxy) -1- [2-cyano-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane- 2-yl) phenyl] pyrrolidin-2-one

MS (APCI) m / z; 443 [M + H] ^< +>.
Reference Example B217 (S) -5-cyano-1- [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] pyrrolidine -2-one

MS (APCI) m / z; 331 [M + H] ^< +>.

Reference Example B218
Preparation of 4- [5- (1-fluoro-1-methylethyl)-[1,2,4] oxadiazol-3-yl] piperidine hydrochloride

The corresponding starting material compound was treated in the same manner as in Reference Example B100, and then treated in the same manner as in Reference Example A36 (3) to give 606 mg of the title compound as a colorless powder (yield: 55%).
MS (APCI) m / z; 214 [M + H] ^< +>.

Reference Example B219
2-Fluoro-4- [5-fluoro-4- [4- [5- (1-fluoro-1-methylethyl)-[1,2,4] oxadiazol-3-yl] piperidin-1-yl ] Quinazolin-8-yl] Production of benzoic acid and hydrochloride

The corresponding starting material compound was treated in the same manner as in Reference Example B125 to give 166 mg of the title compound as a colorless powder (yield: 62%).
MS (APCI) m / z: 498 [M + H] ^< +>.

Reference Example B220
Preparation of (2S, 4R) -4-fluoropyrrolidine-2-carboxylic acid amide hydrochloride

(1) 7.5 mL of water and 7.5 mL of 1N aqueous sodium hydroxide solution were added to a solution of 993 mg of (2S, 4R) -4-fluoropyrrolidine-2-carboxylic acid in 15 mL of 1,4-dioxane, and ditert-dicarbonate- A solution of 1.63 g of butyl in 3 mL of 1,4-dioxane was added and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, aqueous citric acid solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 1930 mg of (2S, 4R) -4-fluoropyrrolidine-1,2-dicarboxylic acid-1-tert-butyl ester. Obtained as a colorless oil (yield: 100%).
MS (APCI) m / z; 234 [M + H] ^< +>.

(2) 1.93 g of the compound obtained in (1) above, 2.00 g of ammonium chloride, 1.71 g of N-hydroxybenzotriazole monohydrate (HOBt · H ₂ O), and 1-ethyl-3- To a solution of 2.13 g of (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC.HCl) in 40 mL of dimethylformamide was added 6.3 mL of triethylamine, and the mixture was stirred at room temperature for 17 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 obtained residue was purified by silica gel column chromatography (solvent; chloroform / methanol = 100/0 to 93/7) to give (2S, 4R) -2-carbamoyl-4-fluoro. 800 mg of pyrrolidine-1-carboxylic acid tert-butyl ester was obtained as a colorless powder (yield 46%).
MS (APCI) m / z; 233 [M + H] ^< +>.

(3) 3 mL of 4N hydrochloric acid-dioxane solution was added to 6 mL of 1,4-dioxane in 800 mg of the compound obtained in (2) above, and the mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated and triturated with diethyl ether to give 533 mg of the title compound as a colorless powder (yield 92%).
MS (APCI) m / z; 133 [M + H] ^< +>.

Reference example B221
Preparation of 8-bromo-4- [4- [5- (1-fluoro-1-methylethyl)-[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 B9 to give the title compound.
MS (APCI) m / z; 420/422 [M + H] ^< +>.

Reference Example B222
Production of (3R, 4R) -pyrrolidine-3,4-diol

200 mg of 10% palladium carbon and 10 mL of acetic acid were added to a solution of 966 mg of (3R, 4R) -1-benzylpyrrolidine-3,4-diol in 15 mL of ethanol, and the mixture was stirred at room temperature for 28 hours under hydrogen pressure (40 psi). The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. A 4N hydrochloric acid-dioxane solution was added to the obtained residue, followed by concentration under reduced pressure to obtain 373 mg of the title compound as a yellow solid (yield 99%).
MS (APCI) m / z; 104 [M + H] ^< +>.

Reference Example B223
Preparation of 1- (4-bromo-2-fluorophenyl) -1H-tetrazole

To a 50 mL acetic acid solution of 3.8 g of 4-bromo-2-fluoroaniline and 8.89 g of triethyl orthoformate, 1.56 g of sodium azide was added, and the mixture was stirred at 120 ° C. overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, 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 (ethyl acetate: hexane = 20: 80 → 40: 60) to give 4.0 g of the title compound as a white solid (yield 83%).
MS (APCI) m / z; 243/245 [M + H] ^< +>.

Reference Example B224
Preparation of 1- [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxoborolan-2-yl) -phenyl] -1H-tetrazole

Dichloro [1,1-bis (diphenylphosphino) was added to a solution of 972 mg of 1- (4-bromo-2-fluorophenyl) -1H-tetrazole, 1.22 g of bis (pinacolato) diborane and 765 mg of potassium acetate in 10 mL of dioxane / 1 mL of dimethyl sulfoxide. ) Ferrocene] palladium (II) dichloromethane (163 mg) was added, and the mixture was stirred at 80 ° C. overnight under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, poured into a saturated aqueous sodium hydrogen carbonate solution, 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 (ethyl acetate: hexane = 30: 70 → 50: 50) to give 1.16 g of the title compound as a yellow solid (yield 100%).
MS (APCI) m / z; 291 [M + H] ^< +>.

Reference Example B225
Preparation of 6- [6-Fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl] nicotinic acid ethyl ester

8-Bromo-6-fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazoline (compound obtained in Reference Example B13) To a solution of 500 mg and 6-chloronicotinic acid ethyl ester 221 mg in dioxane 10 mL, tetrakistriphenylphosphine palladium 138 mg and hexa n-butylditine 601 μL were added, and the mixture was stirred at 100 ° C. overnight. 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; hexane / ethyl acetate = 65 / 35-50 / 50) to give 45 mg of the title compound as a single yellow solid (yield). Rate: 8%).
MS (APCI) m / z; 491 [M + H] ^< +>.

Reference Example B226
(S) -3- (tert-Butyldimethylsilyloxy) -1- (2-fluoro-4- [6-fluoro-4- [4- (5-propyl- [1,2,4] oxadiazole)- 3-yl) -piperidin-1-yl] -quinazolin-8-yl] -benzyl) -pyrrolidin-2-one

The title compound (81 mg) was obtained as a colorless solid by treating the compound (80 mg) obtained in Reference Example B186 (3) and the compound (39 mg) obtained in Reference Example B135 in the same manner as in Reference Example B16. (Yield: 80%)
MS (APCI) m / z; 663 [M + H] ^< +>.

Reference Example B227
1- [3- [1- [8- (4-Dimethylcarbamoyl-3-fluorophenyl) -6-fluoroquinazolin-4-yl] piperidin-4-yl] [1,2,4] oxazole-acetic acid Preparation of 5-yl] -1-methylethyl ester

The corresponding starting material compound was treated in the same manner as in Example B1 to give the title compound.
MS (APCI) m / z; 304/306 [M + H] ^< +>.

Reference Example B228
Preparation of 6- [6-Fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] nicotinic acid

(1) 8-Bromo-6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazoline (obtained in Reference Example B9) 1) and 662 mg of 6-chloronicotinic acid ethyl ester were treated in the same manner as in Reference Example B225 to give 6- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxa Diazol-3-yl) piperidin-1-yl] quinazolin-8-yl] nicotinic acid ethyl ester 187 mg was obtained as a pale yellow solid (yield: 16%).
MS (APCI) m / z; 491 [M + H] ^< +>.

(2) The compound obtained in (1) above was treated in the same manner as in Example B12 to give 153 mg of the title compound as a yellow solid (yield: 89%).
MS (APCI) m / z; 463 [M + H] ^< +>.

Reference Example B229
Preparation of [2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] methylcarbamic acid tert-butyl ester

(1) To a solution of 2.03 g of (4-bromo-2-fluorophenyl) carbamic acid tert-butyl ester in 42 mL of tetrahydrofuran, 350 mg of sodium hydride was added little by little at 0 ° C., and the mixture was stirred for 1 hour. Was further stirred overnight at room temperature. 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, and concentrated. The residue was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 96/4 to 85/15) to obtain 2.08 g of (4-bromo-2-fluorophenyl) methylcarbamic acid tert-butyl ester as a pale yellow color. Obtained as a solid (yield: 98%).
MS (APCI) m / z; 304/306 [M + H] ^< +>.

(2) By treating 2.08 g of the compound obtained in (1) above in the same manner as in Reference Example B16 (2), 1.96 g of the title compound was obtained as a colorless powder (82%).
MS (APCI) m / z; 252 [M + H-Boc] ^<+> .

Reference Example B230
Preparation of [2- (pyrrolidin-1-yl) -5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] benzonitrile

(1) To a solution of 1 g of 5-bromo-2-fluorobenzonitrile in 5 mL of dimethyl sulfoxide, 500 μL of pyrrolidine and 1.25 g of potassium carbonate were added, and the mixture was heated at 100 ° C. for 3 hours in a microwave reactor (Initiator). 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; hexane / ethyl acetate = 95/5 to 85/15) to obtain 979 mg of 5-bromo-2- (pyrrolidin-1-yl) benzonitrile as a colorless powder. (Yield: 78%).
MS (APCI) m / z; 251/253 [M + H] +.

(2) The compound obtained in (1) (500 mg) was treated in the same manner as in Example B16 (2) to give the title compound (459 mg) as a colorless solid (77%).
MS (APCI) m / z; 299 [M + H] ^< +>.

Reference examples B231 to B233
The following compounds were obtained by treating the corresponding starting compounds in the same manner as in Reference Example A16.
(Reference Example B231)
2-Fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) N, N-dimethylbenzamide

MS (APCI) m / z; 294 [M + H] ^< +>.
(Reference Example B232)
3-Fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) N, N-dimethylbenzamide

MS (APCI) m / z; 294 [M + H] ^< +>.
(Reference Example B233)
5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) pyridine-2-carboxylic acid dimethylamide

MS (APCI) m / z; 277 [M + H] ^< +>.

Reference Example 234
Production of 2-methylamino-propane-1,3-diol

(1) To 50 mL of a tetrahydrofuran solution of 4 g of 2-amino-propane-1,3-diol was added 9.6 g of di-tert-butyl dicarbonate, 10 mL of a 1N aqueous sodium hydroxide solution and 10 mL of chloroform, and the mixture was stirred at room temperature overnight. The reaction mixture was made weakly acidic with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was washed with diethyl ether, collected by filtration, and dried to give 5.14 g of (2-hydroxy-1-hydroxymethyl-ethyl) -carbamic acid tert-butyl ester as a colorless solid. (Yield 61%).
MS (APCI) m / z; 192 [M + H] ^< +>.

(2) To 70 mL of a tetrahydrofuran solution of 1.59 g of aluminum hydride cooled to 0 ° C., 30 mL of a tetrahydrofuran solution of 2 g of the compound obtained in (1) above was added dropwise, and the mixture was heated to reflux for 2 hours. The reaction mixture was cooled to 0 ° C., water and 2N aqueous sodium hydroxide solution were added, and the mixture was filtered through celite. The filtrate was concentrated, and the residue was purified by NH silica gel column chromatography (solvent; chloroform / methanol = 100/0 to 90/10) to give 359 mg of the title compound as a colorless viscous oil (yield: 33 %)
MS (APCI) m / z; 106 [M + H] ^< +>.

Reference Example 235
3-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] benzoic acid Manufacturing of

The corresponding starting material compound was treated in the same manner as in Reference Example B26 to give the title compound.
MS (APCI) m / z; 480 [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 vectors pLG3-CRE6-CRE-VIP according to a known method 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)
Frozen L8-18 cells were thawed, suspended in 9 volumes of 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. A cell suspension was prepared. After the cell suspension was allowed to stand at room temperature for 15 minutes, 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% DMSO). 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 the 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 (the EC ₅₀ value of each analyte compound) are as shown in Tables 106 to 108 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 assignment 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), and AUC (0-120 min) in each administration group was calculated based on the measured value. SAS Institute Inc.) and tested by Student's t-Test.

result:
Tables 109 to 110 below show the blood glucose elevation-inhibiting action of each sample compound (value of the ratio of AUC (0 to 120 min) in the sample administration group when the AUC (0 to 120 min) in the control group is 100). It was.
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), and AUC (0-120 min) in each administration group was calculated based on the measured value. SAS Institute Inc.) and tested by Student's t-test.

result:
The blood glucose elevation inhibitory action of each sample compound (the value of the AUC (0-120 min) ratio of the sample administration group when the control group is 100 for AUC (0-120 min) based on the -60 min value) 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 (16)

Formula [I]:

[Where,
R ¹ is a hydrogen atom or a halogen atom,
Ring A is a 5- to 6-membered aryl group which may contain the same or different 1-4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom,
R ^A1 and R ^A2 are independently
1) a halogen atom;
2) a cyano group;
3) hydroxyl group;
4) an alkyl group (the alkyl group is a) a halogen atom, b) a hydroxyl group, c) a cyano group, d) a 5- to 6-membered nitrogen-containing heteroaryl group, e) a group represented by the formula: R ^a R ^b N— (R ^a and R ^b are the same or different and each represents a hydrogen atom or an alkyl group), f) a carboxyl group, g) a group represented by the formula: R ^c —S (═O) _m — (where R ^c is a hydroxyl group) And an alkyl group which may be substituted with a group selected from the group represented by the formula: R ^d R ^e NCO—, m is an integer of 0 to 2, and R ^d and R ^e are the same or different and are a hydrogen atom or an alkyl group. H) a group represented by the formula: HO-Alk-O- (where Alk represents an alkylene group), i) a group represented by the formula: R ^f R ^g NCO- (R ^f and R ^g are The same or different hydrogen atom, alkyl group, monohydroxyalkyl group or di- It is a droxyalkyl group, or both are bonded to each other and together with an adjacent nitrogen atom, a 5- to 6-membered aliphatic nitrogen-containing heteromonocyclic group (the cyclic group may be substituted with a hydroxyl group or a carbamoyl group) J) 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 Represents an alkanoyloxyalkanoyl group); and k) 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) It may be substituted with 1 to 3 groups selected from:
5) An alkoxy group (the alkoxy group is 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) May be);
6) a group ^{represented by the} formula: R ^k —S (═O) _n — (wherein R ^k is an alkyl group optionally substituted with a hydroxyl group or an alkoxy group, n represents an integer of 0 to 2);
7) an alkanoyl group;
8) a group represented by the formula: R ^m R ⁿ NC (═O) — (wherein R ^m and R ⁿ are the same or different, a) a hydrogen atom, an alkyl group, a mono- or dihydroxyalkyl group, mono- or di- A halogenoalkyl group, an alkoxycarbonylalkyl group, a cycloalkyl group (the group may be substituted with a hydroxyalkyl group), an alkoxycarbonylphenylalkyl group, a carboxyphenylalkyl group, or a 5- to 6-membered aliphatic sulfur-containing heterocyclic group A group (the hetero group may be substituted with 1 to 2 oxo groups), or b) both R ^m and R ⁿ are bonded together at the terminal, together with the adjacent nitrogen atom, a hydroxyl group, a cyano group , An oxo group, a hydroxyalkyl group and a carbamoyl group (the carbamoyl group may be substituted with 1 to 2 alkyl groups). It is expressed to form an even or 4-6 membered aliphatic nitrogen-containing heterocyclic group optionally);
9) an amino group (the amino group may be substituted with 1 to 2 groups selected from an alkyl group, an alkanoyl group, an alkoxycarbonyl group, an alkylsulfonyl group, an alkanoyloxyalkanoyl group and a hydroxyalkanoyl group);
10) A sulfamoyl group (the amino part of the group may be substituted with 1 to 2 alkyl groups);
11) The following formula:

(Here, ring A ⁰ represents a nitrogen-containing 5-membered aliphatic heterocyclic ring which may be substituted with an oxo group)
Or 12) a saturated or unsaturated 5- to 6-membered heterocyclic group (the heterocyclic group is the same or different 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom) And is substituted with one or two groups selected from the group consisting of a hydroxyl group, an oxo group, an alkyl group, a hydroxyalkyl group, an alkanoyl group, a hydroxyalkanoyl group, a carbamoyl group, a monoalkylcarbamoyl group, and a dialkylcarbamoyl group. You may)
Ring B is a 6 to 7-membered aliphatic nitrogen-containing heterocyclic group,
R ^B1 represents a hydrogen atom or an alkyl group,
R ^B2 is a hydrogen atom or a hydroxyl group,
R ^B3 is
1) hydroxyl group,
2) a cyano group;
3) an alkyl group;
4) a cycloalkylalkyl group;
5) an alkoxycarbonyl group;
6) a saturated or unsaturated 5- to 6-membered monocyclic heterocyclic group (the heterocyclic group contains 1 to 4 heteroatoms identical or different selected from an oxygen atom, a sulfur atom and a nitrogen atom, and An alkyl group which may be substituted with 1 to 3 halogen atoms; a hydroxyalkyl group; an alkoxyalkyl group (the alkoxyalkyl group may be substituted with 1 to 3 halogen atoms); a carboxyalkyl group; An amino group optionally substituted by 1 to 2 alkyl groups; an aminoalkyl group (the amino part of the aminoalkyl group may be substituted by 1 to 2 groups selected from an alkyl group and an alkoxycarbonyl group); good); and optionally substituted with one to two groups selected from cycloalkyl group); or 7): groups represented by -W-R ³ (where, W is oxygen Hara Represents a sulfur atom or a carbonyl group, R ³ is a) a phenyl group and alkoxyalkyl which may be an alkyl group substituted with a group selected from phenyl group, b) a cycloalkyl group, or c) an oxygen atom, a sulfur atom and a nitrogen atom The same or different 1 to 3 heteroatoms selected from: 1) a halogen atom, 2) an alkyl group, 3) an alkoxy group, 4) a cycloalkyl group, and 5) 1 to 2 (Represents a 5- to 6-membered monocyclic aryl group optionally substituted with 1 to 2 groups selected from an amino group optionally substituted with an alkyl group)
(Represents that)
Or a pharmaceutically acceptable salt thereof. Ring A is (A) the following formula:

(Where
R ^A1 is (1) a hydrogen atom,
(2) a halogen atom,
(3) an alkyl group optionally substituted by 1 to 3 halogen atoms,
(4) an alkoxy group,
(5) an alkanoyl group,
(6) an amino group optionally substituted with a group selected from an alkanoyl group and an alkylsulfonyl group,
(7) an alkoxycarbonyl group,
R ^A2 is (1) a hydrogen atom,
(2) a halogen atom,
(3) a cyano group,
(4) an alkyl group,
(5) an alkyl group substituted with a saturated or unsaturated 5- to 6-membered heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom and a nitrogen atom,
(6) an alkylthio group (the alkyl part may be substituted with a hydroxyl group),
(7) an alkylsulfonyl group (the alkyl moiety may be substituted with a hydroxyl group),
(8) an alkylthioalkyl group (the alkyl part may be substituted with a hydroxyl group),
(9) an alkylsulfonylalkyl group (the alkyl moiety may be substituted with a hydroxyl group),
(10) a) 1 to 2 groups selected from a) an alkyl group optionally substituted with 1 to 3 halogen atoms, b) a monohydroxyalkyl group and c) an alkyl group substituted with a hydroxyl group and an alkoxy group A carbamoyl group optionally substituted by
(11) a sulfamoyl group optionally substituted by 1 to 2 alkyl groups,
(12) an amino group optionally substituted by 1 to 2 groups selected from an alkyl group, an alkanoyl group, an alkoxycarbonyl group, an alkanoyloxyalkanoyl group, a hydroxyalkanoyl group and an alkylsulfonyl group;
(13) an alkanoyl group,
(14) an alkoxy group,
(15) a nitro group,
(16) an alkoxycarbonyl group,
(17) Formula: R ¹¹ R ¹² NC (=) O— group (where R ¹¹ and R ¹² are (a) independently a hydrogen atom, an alkyl group, or (b) both are bonded to each other at the end. And a nitrogen-containing 5- to 6-membered aliphatic heterocyclic group which may be substituted with one or two groups selected from a hydroxyl group, an oxo group and a hydroxyalkyl group together with the adjacent nitrogen atom (the heterocyclic group is hetero Represents an oxygen atom as an atom)),
(18) represents a saturated or unsaturated 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from an oxygen atom and a nitrogen atom and optionally substituted with an alkyl group)
Or (B) the following formula:

[Wherein, R ^A11 is (1) a hydrogen atom, (2) a cyano group, (3) an alkyl group, (4) an alkoxy group, (5) a morpholino group, (6) an alkyl group, or (7) 1-2. R ^A12 is a hydrogen atom or a halogen atom, R ^A13 is a hydrogen atom or an alkoxy group, and R ^A14 and R ^A15 independently represent a hydrogen atom or an alkyl group.
The compound according to claim 1, which is a substituted 5-membered or 6-membered heteroaryl group represented by the formula: Ring B is
(A) The following formula (i):

(Wherein R ² contains (a) a cyano group, or (b) the same or different 1-4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and 1-3 halogen atoms. Substituted with 1 to 2 groups selected from alkyl group, hydroxyalkyl group, alkoxyalkyl group, amino group optionally substituted with 1 to 2 alkyl groups and cycloalkyl group optionally substituted with Represents a saturated or unsaturated 5-6 membered monocyclic heterocyclic group which may be
R ²⁰ represents a hydrogen atom or an alkyl group)
Or (B) the following formula (ii):

(W ¹ represents an oxygen atom, a sulfur atom or a carbonyl group, R ³¹ is a) an alkyl group (the alkyl group may be substituted with a group selected from a phenyl group and an alkoxyphenyl group); b ) A cycloalkyl group; or c) a 5- to 6-membered monocyclic aryl group (the aryl group may contain 1 to 3 heteroatoms which are the same or different and are selected from an oxygen atom, a sulfur atom and a nitrogen atom) And 1) a halogen atom, 2) an alkyl group, 3) an alkoxy group, 4) a cycloalkyl group, and 5) 1-2 groups selected from amino groups optionally substituted by 1-2 alkyl groups. Which may be substituted with
Or (C) the following formula (iii):

(Wherein R ⁴ represents an alkyl group, a cycloalkylalkyl group, an alkoxycarbonyl group, or a nitrogen-containing or oxygen-containing 5- to 6-membered heteroaryl group (the heteroaryl group may be substituted with an alkyl group); R ⁴⁰ represents a hydrogen atom or an alkyl group)
Or (D) the following formula (iv):

(Where R ⁴ has the same meaning as above)
Or (E) the following formula (v):

(Here, R ^4A represents a nitrogen-containing or oxygen-containing 5- to 6-membered heteroaryl group (the heteroaryl group may be substituted with an alkyl group))
The compound of Claim 1 or 2 which is a substituted 6-membered or 7-membered aliphatic nitrogen-containing heterocyclic group shown by these. Ring A is represented by the following formula:

[Where,
Ring A ¹ is a benzene ring or a pyridine ring,
R ^A is 1) a cyano group;
2) a mono- or dihydroxyalkyl group;
3) (a) a hydroxyl group, (b) an alkyl group substituted with a group selected from the formula: R ^p R ^q NC (═O) — and (c) an alkylsulfonyl group (where R ^p and R ^q independently represents a hydrogen atom, an alkyl group or a hydroxyalkyl group which may be substituted with 1 to 3 halogen atoms, or both are bonded to each other at the terminal and together with the adjacent nitrogen atom, a halogen atom, Representing the formation of a 5-membered nitrogen-containing aliphatic heterocyclic group optionally substituted with 1 to 2 groups selected from a hydroxyl group, a cyano group and a carbamoyl group);
4) an alkoxy group;
5) a group represented by the formula: R ^r —S (═O) _n — (wherein R ^r is an alkyl group optionally substituted with a hydroxyl group or an alkoxy group, n represents an integer of 0 to 2);
6) an alkyl group substituted with a 5-membered heteroaryl group containing 1-3 nitrogen atoms as heteroatoms;
7) an alkoxycarbonylalkyl group;
8) a group represented by the formula: R ^s R ^t N (C═O) — (wherein R ^s and R ^t independently represent a hydrogen atom, an alkyl group, a hydroxyalkyl group or a dihalogenoalkyl group) Or a 4- to 6-membered nitrogen-containing aliphatic heterocyclic group which may be substituted with one or two groups selected from a halogen atom, a hydroxyl group, a cyano group, and a carbamoyl group together with the adjacent nitrogen atom. Represents the formation of
9) a sulfamoyl group optionally substituted by 1 to 2 alkyl groups;
10) an alkanoyl group;
11) an alkoxycarbonylamino group;
12) an alkanoylamino group;
13) an alkylsulfonylamino group;
14) The following formula:

(Here, ring A ⁰¹ represents a nitrogen-containing 5-membered aliphatic heterocyclic ring substituted with an oxo group)
Or 15) the same or different 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, and an oxo group, a hydroxyl group, an alkyl group, a hydroxyalkyl group, a carbamoylalkyl group, A saturated or unsaturated 5- to 6-membered heterocyclic group which may be substituted with 1 to 2 groups selected from a monoalkylcarbamoylalkyl group and a dialkylcarbamoylalkyl group;
R ^B represents a hydrogen atom, a halogen atom, a cyano group, an alkyl group or a trihalogenoalkyl group.
A group represented by
Ring B is represented by the following formula:

[Wherein R ^2A contains the same or different 1 to 3 heteroatoms selected from a nitrogen atom and an oxygen atom, and an alkyl group (the alkyl group may be substituted with 1 to 3 halogen atoms) A saturated or unsaturated 5-membered heterocyclic group substituted with a cycloalkyl group, an alkoxyalkyl group or an alkanoyloxyalkyl group, and R ²¹ represents a hydrogen atom or an alkyl group.
The compound of Claim 1 which is group shown by these. Ring A ¹ is a benzene ring,
R ^A is 1) a group represented by the formula: R ^u R ^v NCO—CH ₂ — (wherein R ^u and R ^v 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): R w -S (= O)}} 2 - group represented by ^{(R w} represents a substituted _{C 1-4} optionally alkyl with a group selected from hydroxyl and _{C 1-4} alkoxy) ;
3) A group represented by the formula: R ^x R ^y NC (═O) — (R ^x and R ^y are each independently an alkyl group or a monohydroxyalkyl group, or both are bonded at the end, together with the adjacent nitrogen atom, Representing the formation of a 5-membered aliphatic nitrogen-containing heterocyclic group substituted with 1 to 2 groups selected from a hydroxyl group, a cyano group and a carbamoyl group);
4) C _1-4 alkylsulfonylmethyl group; or 5) 1 to 2 containing 1 to 2 nitrogen atoms as heteroatoms and selected from an oxo group, a hydroxyl group and a hydroxy-C _1-4 alkyl group A saturated or unsaturated 5- or 6-membered nitrogen-containing heterocyclic group substituted with a group of the above (the cyclic group may further contain an oxygen atom as a hetero atom, and is a hydroxyl group, carbamoyl-C _1-4). An alkyl group or a di (C _1-4 alkyl) carbamoyl-C _1-4 alkyl group, which may be further substituted),
R ^B is a halogen atom, a cyano group or a C _1-4 alkyl group,
R ^2A contains the same or different 1 to 3 heteroatoms selected from an oxygen atom and a nitrogen atom, and a C _1-4 alkyl group (this group may be substituted with 1 to 3 halogen atoms) Or a saturated or unsaturated 5-membered heterocyclic group substituted with a C _3-6 cycloalkyl group, and R ²¹ is a hydrogen atom. Ring A ¹ is a benzene ring,
R ^A is 1) a group represented by the formula: R ^aa R ^bb NCO—CH ₂ — (where R ^aa represents a hydrogen atom, R ^bb represents a C _1-4 alkyl group, or both are bonded at the ends) A pyrrolidinyl group optionally substituted with a hydroxyl group together with the adjacent nitrogen atom));
2) a hydroxy- _C1-4 alkylsulfonyl group;
3) a carbamoyl group optionally substituted by 1 to 2 _C1-4 alkyl groups;
4) The following formula:

(Wherein R ^a3 and R ^a4 are the same or different and each represents a hydrogen atom, a hydroxyl group, a cyano group or a carbamoyl group)
Or a group represented by 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)
A cyclic group represented by
Contain identical or different 1 to 3 heteroatoms R ^2A is selected from oxygen atom and nitrogen atom, and optionally substituted with 1-3 fluorine atoms C _1-4 alkyl group or a C _3- The compound according to claim 5, which is a 5-membered heteroaryl group substituted with a _6- cycloalkyl group and R ²¹ is a hydrogen atom. Ring A is represented by the following formula:

(Wherein ring A ² is a benzene ring, ^RC is 1) an alkylsulfonyl group; 2) a carbamoyl group optionally substituted by 1 to 2 alkyl groups; or 3) a morpholinocarbonyl group, ^RD is hydrogen Represents an atom or a halogen atom)
A ring B is represented by the following formula:

(W ¹ is an oxygen atom or sulfur atom, R ³¹ is an alkyl group (the alkyl group may be substituted with an alkoxyphenyl group), a cycloalkyl group, a phenyl group (the phenyl group is a halogen atom, an alkyl group) A group, an alkoxy group and an amino group (the amino group may be substituted with 1 to 2 groups selected from 1 to 2 alkyl groups), or A 5- to 6-membered heteroaryl group (the heteroaryl group may be substituted with an alkyl group)
The compound of Claim 1 which is group shown by these. Ring A is represented by the following formula:

[Wherein ring A ³ is a benzene ring, R ^E is (a) an alkylsulfonyl group, (b) an alkylsulfonylalkyl group, (c) a carbamoylalkyl group (the amino moiety of the carbamoyl group is an alkyl group and a hydroxyalkyl group) (Which may be substituted with 1 to 2 groups selected) , (d) a nitrogen-containing 5-membered aliphatic heterocyclic group substituted with 1 to 2 groups selected from an oxo group and a hydroxyalkyl group, or (E) The following formula:

(Here, ring A ⁰² represents a nitrogen-containing 5-membered aliphatic heterocyclic ring substituted with a hydroxyl group)
And R ^F represents a hydrogen atom or a halogen atom.]
A ring B is represented by the following formula:

[Wherein, R ⁴¹ is (a) an alkoxycarbonyl group or (b) a 5-membered heteroaryl containing 1 to 3 heteroatoms which are the same or different and selected from an oxygen atom and a nitrogen atom, and substituted with an alkyl group Group, R ⁴² represents a hydrogen atom or an alkyl group]
The compound of Claim 1 which is group shown by these. R ^E is a C _1-4 alkylsulfonylmethyl group, a carbamoylalkyl group (the amino group portion of the carbamoyl group may be substituted with 1 to 2 alkyl groups) or the following formula:

(Herein, ring A ⁰² represents a nitrogen-containing 5-membered aliphatic heterocyclic ring substituted with a hydroxyl group.)
The compound according to claim 8, wherein R ⁴² is a hydrogen atom. A compound represented by the general formula [I] or a pharmacologically acceptable salt thereof,
4- [5-Fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl] -N, N-dimethyl Benzamide;
3-Fluoro-4- [4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl] -N, N-dimethyl Benzamide;
3-Fluoro-4- [5-fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl] -N , N-dimethylbenzamide;
5-fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] -8- (4-mesylphenyl) quinazoline;
4- [6-Fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl] -N, N-dimethyl Benzamide;
2-Fluoro-4- [5-fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl] -N , N-dimethylbenzamide;
3-Fluoro-4- [6-fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl] -N , N-dimethylbenzamide;
2-Fluoro-4- [5-fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl] -N -Methylbenzamide;
N-ethyl-2-fluoro-4- [5-fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazoline-8- Il] benzamide;
2-Fluoro-4- [6-fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl] -N , N-dimethylbenzamide;
2-Fluoro-4- [6-fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl] -N -Methylbenzamide;
6-Fluoro-4- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] -8- [3-fluoro-4-[(pyrrolidine-1 -Yl) carbonyl] phenyl] quinazoline;
2-fluoro-4- [6-fluoro-4- (3-n-propyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl] -N, N-dimethylbenzamide;
6-Fluoro-4- [4- (3-n-propyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] -8- [3-fluoro-4-[(pyrrolidine -1-yl) carbonyl] phenyl] quinazoline;
2-Fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] -N -Methylbenzamide;
4- [4- (3-Isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] -8- (4-mesylphenyl) quinazoline;
4- [4- [4- (3-Isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-1-yl] quinazolin-8-yl] -N, N-dimethylbenzamide;
3-Fluoro-4- [6-fluoro-4- [4- (5-n-propyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] -N, N-dimethylbenzamide;
2-Fluoro-4- [6-fluoro-4- [4- [3- (2,2,2-trifluoroethyl)-[1,2,4] oxadiazol-5-yl] piperidine-1- Yl] quinazolin-8-yl] -N, N-dimethylbenzamide;
2-Fluoro-4- [6-fluoro-4- [4- [5-cyclopropyl- [1,2,4] oxadiazol-3-yl] piperidin-1-yl] quinazolin-8-yl]- N- (2-hydroxyethyl) -N-methylbenzamide;
6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] -8- (3-fluoro-4-mesylphenyl) quinazoline; And 6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] -8- (3-fluoro-4-methylsulfonylmethylphenyl) 2. The compound according to claim 1, which is a compound selected from the group consisting of quinazoline or a pharmacologically acceptable salt thereof. The compound represented by the general formula [I] or a pharmacologically acceptable salt thereof is 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;
1- [2-Methyl-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;
6-Fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperazin-1-yl] -8- (3-fluoro-4-methylsulfonylmethylphenyl) Quinazoline,
[2-Fluoro-4- [5-fluoro-4- [4- [5- (1-fluoro-1-methylethyl)-[1,2,4] oxadiazol-3-yl] piperidine-1- Yl] quinazolin-8-yl] phenyl] (2-cyano-4-hydroxypyrrolidin-1-yl) methanone;
[2-Fluoro-4- [5-fluoro-4- [4- [5- (1-fluoro-1-methylethyl)-[1,2,4] oxadiazol-3-yl] piperidine-1- Yl] quinazolin-8-yl] phenyl] (3-hydroxypyrrolidin-1-yl) methanone;
[2-Fluoro-4- [5-fluoro-4- [4- [5- (1-fluoro-1-methylethyl)-[1,2,4] oxadiazol-3-yl] piperidine-1- Yl] quinazolin-8-yl] phenyl] (2-carbamoylpyrrolidin-1-yl) methanone;
1- [4- [5-Fluoro-4- [4- [5- (1,1-difluoroethyl)-[1,2,4] oxadiazol-3-yl] piperidin-1-yl] quinazoline- 8-yl] -2-methylphenyl] -4-hydroxypyrrolidin-2-one;
1- [4- [6-Fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-1-yl] quinazolin-8-yl] -2- Cyanophenyl] -4-hydroxypyrrolidin-2-one;
1- [2-Fluoro-4- [4- [4- [5- (1-fluoro-1-methylethyl)-[1,2,4] oxadiazol-3-yl] piperidin-1-yl] Quinazolin-8-yl] phenyl] -3- (2-hydroxyethyl) imidazolidin-2-one;
1- [2-Fluoro-4- [4- [4- [5-n-propyl- [1,2,4] oxadiazol-3-yl] piperidin-1-yl] quinazolin-8-yl] phenyl ] -3- (2-hydroxyethyl) imidazolidin-2-one; and [2-fluoro-4- [6-fluoro-4- [4- (5-isopropyl- [1,2,4] oxadiazole) A compound selected from the group consisting of -3-yl) piperazin-1-yl] quinazolin-8-yl] benzyl] (2-hydroxypyrrolidin-1-yl) methanone or a pharmaceutically acceptable salt thereof. 1. The compound according to 1.     A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 or a pharmacologically acceptable salt thereof as an active ingredient.     13. The pharmaceutical composition according to claim 12, 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 13.     The pharmaceutical composition according to claim 13, wherein the cardiovascular disease is arteriosclerosis, hypertension, coronary disease or myocardial infarction.     The regulator of GPR119 activity which uses the compound of any one of Claims 1-11, or its pharmacologically acceptable salt as an active ingredient.