TW201202230A - Novel quinazoline compound - Google Patents

Abstract

The present invention provides quinazoline compounds which have GPR119 receptor agonistic activity and are useful as medicine, which are compounds of the general formula [I]: wherein R1 is hydrogen or halogen, Ring A is 5- to 6-membered aryl in which the aryl may comprise the same or different 1 to 4 heteroatoms selected from O, S and N, RA1 and RA2 are independently halogen, cyano, etc., Ring B is 6- to 7-membered aliphatic nitrogen-containing heterocycle, RB1 is hydrogen or alkyl, RB2 is hydrogen or hydroxyl, RB3 is hydroxyl, cyano, etc., or pharmaceutically acceptable salts thereof.

Description

201202230 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to a novel quinazoline compound or pharmacologically useful as a novel GPR119 receptor agonist. Salt that can be tolerated. [Prior Art] GPR119, which belongs to the G protein-coupled receptor (G pr〇tein_c〇upled recept〇r, GPCR), is the father of the cell and intestinal cytoplasmic expression of the pancreas. The body has been reported to act as a ligand for the receptor by a compound such as sulfhydryl decylamine (0EA) belonging to the natural long-chain fatty acid decylamine and a low molecular weight synthesis ligand (PSN632408). And the activation of the receptor, and the effect of suppressing food intake and inhibiting weight gain was observed in a high-fat diet rat (Non-patent document). Furthermore, according to a recent study on the physiological role of GPR119 using a selective low molecular agonist (AR231453), it is known to increase cAMP (adenylate cyclase) by activation of φ the receptor. "Activation" enhances the glucose-dependent insulin in the pancreatic cells, and thus, glucose homeostasis (Non-Patent Document 2). Moreover, it can be considered that the system is enhanced by excretion of an incretin class (glucagon-like peptide-Kglucagon-like peptide)/GLiM, which is also called an endogenous anti-diabetic hormone. Insulin peptide/GIP)' regulates glucose constant (non-patent for low-molecular GPim9 agonists, which can be expected to indirectly protect the pancreas directly and/or by incretin 323135 4 201202230 pancreatic hormone (for islet cells) The anti-apoptotic effect and/or the promotion of proliferative effect. From the above findings, GpRn9 has attracted attention as a glaring therapeutic target for metabolic diseases including diabetes and obesity. Now as a GPR119 agonist, In addition to the above-mentioned oea, PSN632408, and AR231453, a bipiperidine compound (Patent Document 1) and a 1H-bisazolo[3,4-d]pyrimidin-4-yloxypiperidine compound are known (Patent Document 2) , 6,7-dioxa-5H-pyrrolo[2,3-d]pyrimidin-4-yloxy-1-bunking compound, 2,3-dihydro-1-indol-4-yloxy Base-1-piperidine compound (Patent Document 3), 4-(benzo[b][l,4]indole, etc. 4(3H)-yl) piperidine compound Patent Document 4) and the like, but there has not been reported so far that the compound of the present invention (a compound having a structure in which a piperidine or a piperidin is bonded at the 4-position of a quinazoline ring) has an agonistic effect on GPR119. [Prior Art Document] [Patent [Patent Document 1] W02008/076243 [Patent Document 2] W02005/007658 [Patent Document 3] W02008/008895 [Patent Document 4] W02008/137435 [Non-Patent Document] [Non-Patent Document 1] Cell Metabolism 3: 167 -175 (2006) [Non-Patent Document 2] Endocrinology 149(5): 2035-2037 (2008) [Non-Patent Document 3] Endocrinology 149(5): 2038-2047 5 323135 201202230 (2008) [Summary of Invention] (Invention The object of the present invention is to provide a sulphate compound which has excellent (IV) 19 receptor agonism and is useful as a medicine. It is excellent (a means for solving the problem). The present invention relates to the following a compound of the formula [I] or a salt thereof:

Wherein R1 represents a hydrogen atom or a tooth atom, and ring A represents a 5- to 6-membered aryl group which may contain the same or different 1 to 4 hetero atoms from an oxygen atom, a sulfur atom and a nitrogen atom, and RA1 and RA2 are independent The ground represents 1) a halogen atom; 2) a cyano group; 3) a hydroxyl group; 4) an alkyl group (which may also be substituted with 3 groups selected from a) to k): a) atom, b) Passage group, c) cyano group, ca to ^ heteroaryl 'e) formula: RaRbN- group (wherein and Rb are the same or different, representing a hydrogen atom or an alkyl group), f) carboxyl group, g) : r_s (= 〇乂 之 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Integer, Rd & Re is the same or different 'is a hydrogen atom or a burnt group' 'h) Formula: H〇-Alk-0~· (base, Aik stands for alkylene) 'i Formula: RfRgNC (=〇)--based group (Rf and Rg are the same or different, and represent a hydrogen atom, a pyridyl group, a mono-alkyl group or a dihydroxyalkyl group, or a combination of both The nitrogen atoms together form a 5 to 6 membered aliphatic nitrogen-containing heteromonocyclic group (this The cyclic group may also be substituted by a hydroxyl group or an amine thiol group)), j): a group represented by RhRiN- (Rh and f are the same or different, and represent a hydrogen atom, an alkyl group, an alkyl fluorenyl group, a hydroxyalkyl fluorenyl group) , alkoxycarbonyl or alkynyloxyalkyl fluorenyl); and k) 5 to 6 membered aliphatic nitrogen-containing heterocyclic group (the heterocyclic group may also be derived from a trans group, a pendant oxy group (0X0), Substituted in the thiol and amine oxime groups)); 5) alkoxy groups (the alkoxy groups may also be derived from hydroxyl groups, alkoxycarbonyl groups, amine sulfhydryl groups (the amine moiety of the group may also be 1 to 2 alkyl substitutions) and the selected group of the phenyl group); 6) a radical of the formula R-S(=0)n- (wherein 'Rk represents a group which may be substituted by a base or an alkoxy group The base of the alkyl group, η represents an integer of 0 to 2); 7) an alkane group; 8) a group of the formula: RmRnNC(=0)- (here, Rm and Rn are the same or different, and represent a) hydrogen Atom, alkyl, mono or dihydroxyalkyl, mono or dihalogen, alkoxycarbonylalkyl, cycloalkyl (the group may also be substituted by hydroxyalkyl), alkoxycarbonylphenylalkyl, Carboxyphenylalkyl, amine mercaptoalkyl or 5 to 6 member aliphatic thia a group (the heterocyclic group may also be substituted by 1 to 2 pendant oxy groups), or b) both of Rm and Rn are bonded at the end to form a nitrogen atom adjacent to the 7 323 135 201202230, which may be derived from a hydroxyl group, a cyano group, a side group selected from the group consisting of a pendant oxy group, a hydroxyalkyl group, an aminocarboxylic acid alkyl group, and an amine fluorenyl group (which may be substituted by 1 to 2 alkyl groups), and may also be condensed with a cycloalkyl ring. a 4- to 6-membered aliphatic nitrogen-containing heterocyclic group (the heterocyclic group may also contain an oxygen atom as a hetero atom other than a nitrogen atom)); 9) an amine group (the amine group may also be derived from an alkyl group or an alkyl group) , alkoxycarboyl, alkyl thiol, aryloxy thiol and 1 to 2 substituents selected from the group consisting of sulfhydryl groups; 10) amine sulfonyl group (amine of the group) The base moiety may also be substituted by 1 to 2 alkyl groups; 11) a group of the formula: (wherein the ring represents a nitrogen-containing 5-membered aliphatic heterocyclic ring which may be substituted by a pendant oxy group); or ~ 12) a saturated or unsaturated 5- to 6-membered heterocyclic group (the heterocyclic group having the same or different oxime selected from an oxygen atom, a sulfur atom, and a nitrogen atom to 4 hetero atoms, or may be bridged by a wire) 1 to 3 substituents which can be selected from the group consisting of: hydroxyl group, pendant oxy group, cyano group, silk which can be substituted by 1 to 3 self-materials, recorded silk, county yard, amine hydrazine Sulfhydryl group, mono or dialkyl amine sulfhydryl base, burn county, Jingji Xuanji, amine methyl sulfhydryl, monoalkylamine sulfhydryl, and dimorphic amine amide base; Β represents 6 to 7 members of the aliphatic nitrogen-containing heterocyclic group, R represents a milk atom or a burnt group, 323135 8 201202230 R represents a hydrogen atom, a halogen atom or a hydroxyl group, RB3 represents 1) a radical; 2) a cyano group; 3) an alkane 4) a cycloalkylalkyl group; 5) an alkoxycarbonyl group; 6) a saturated or unsaturated 5 to 6 membered monocyclic heterocyclic group (the heterocyclic group containing an oxygen atom, a sulfur atom and a nitrogen atom) I or 4 heteroatoms which are the same or different, and may also be substituted with 1 to 2 groups selected from the group consisting of: a group which may be substituted by 1 to 3 halogen atoms; a hydroxy group; an alkoxy group An alkyl group (the alkoxyalkyl group may be substituted by 1 to 3 halogen atoms); a carboxyalkyl group; an amine group which may be substituted by 1 to 2 alkyl groups; an aminoalkyl group (an amine of the aminoalkyl group) The base portion can also be 1 to 2 substituents selected from the oxycarbonyl group; and a cycloalkyl group which may be substituted by a south atom or an alkyl group; or 7) a group represented by the formula: -W-R3 (here, W represents an oxygen atom) , a sulfur atom or a carbonyl group 'R3 represents a) an alkyl group which may be substituted with a group selected from a phenyl group and an alkoxyphenyl group, b) a cycloalkyl group, c) a 5- to 6-membered monocyclic aryl group; The 5- to 6-membered monocyclic aryl group may have the same or different one to three hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and may be selected from the following cl) to c5) 1 to 2 base substitutions: cl) a halogen atom, c2) an alkyl group, c3) an alkoxy group, a c4) cycloalkyl group, and c5) an amine group which may be substituted by 1 to 2 alkyl groups)]. Further, the present invention relates to a pharmaceutical composition comprising the above compound [I] or a pharmacologically acceptable salt thereof as an active ingredient. Further, the present invention is a GPR119 activity modulator (particularly a GPR119 agonist) which is obtained by using the above compound [Π or a pharmacologically acceptable salt thereof as an active ingredient) in the above-mentioned compound. [Embodiment] In the compound [I] of the present invention, the ring A may contain 5 to 6 membered aryl groups of the same or different 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, Examples of the aryl group include a phenyl group, a thiol group, a fluorenyl group, an oxadiazolyl group, a oxazolyl group, a thiadiazolyl group, a pyridyl group, and a pyrimidinyl group. When the substituent (RA1 or RA2) on the ring A is an unsubstituted alkyl group, the alkyl group such as methyl, ethyl, n-propyl, isopropyl or n-butyl may not be mentioned. Substituting Cl-6 alkyl. When the substituent (RA1 or RA2) on the ring A is a group substituted by 1 to 3 halogen atoms, the substituted group thus substituted may, for example, be a trifluoromethyl group, a monofluoroethyl group or a difluoroethyl group. A mono-, di- or trihalo-Cl-6 alkyl group such as a trifluoroethyl group. When the substituent (RA1 or RA2) on the ring A is an alkyl group substituted with a hydroxy group, the alkyl group thus substituted may, for example, be a hydroxy-Ci group such as a hydroxy fluorenyl group, a hydroxyethyl group or a hydroxy φ propyl group. -6 alkyl. When the substituent (RA1 or RA2) on the ring A is an alkyl group substituted with a cyano group, the alkyl group to be substituted may, for example, be a cyano-Ch alkyl group such as a cyanoguanidino group. When the substituent (RA1 or RA2) on the ring A is a group substituted with a nitrogen-containing 5-membered heteroaryl group, the alkyl group thus substituted may, for example, be a triazolyl fluorenyl group or a tetradecyl fluorenyl group. A Cl-6 alkyl group substituted by a nitrogen-containing 5-membered heteroaryl group. When the substituent (RA1 or rA2) on the ring A is a group substituted by a group represented by the formula: RC: _s(=〇)n_, the alkyl group thus substituted may, for example, be exemplified by: (a) 10 323135 201202230 Sulfhydryl-Cl-6 alkyl group via a base thiol group or a propyl thiomethyl group; (b) dimethylamine carbaryl sulfhydryl hydrazine Di-(Cw alkyl)amine broth-Cl-6 sulphur-based _Cl-6 alkyl; (C) fluorenyl sulfhydryl-Chal (d) Cw alkylsulfonyl-G-6 alkyl such as fluorenylsulfonylmethyl; (e) hydroxy-Cw such as hydroxyethylsulfonyl fluorenyl or hydroxypropylsulfonyl fluorenyl Alkylsulfonyl-Cw alkyl; or bis(Cw alkyl)amine-mercapto-Cw alkylsulfonyl-Cl-6, such as (indenyl) fluorenyl sulfhydryl fluorenyl When the substituent (RA1 or RA2) on the ring A is an alkyl group substituted with a carboxyl group, the alkyl group to be substituted may, for example, be a carboxy-G-6 alkyl group such as a carboxyl group. When the substituent (RA1 or RA2) is a group-substituted alkyl group represented by the formula: RfRgNC(=0)-, the alkyl group thus substituted may, for example, be exemplified by: (a) N-methylamine N-Cm alkylamine-mercapto-Ch alkyl or N,N-di(G-6 alkyl)amine fluorenyl φ such as fluorenyl or n,N-dimercaptoalkyl fluorenyl ~Cl_6 alkyl; (b) N-hydroxyethylamine methyl hydrazinomethyl or N-hydroxypropylamine decyl fluorenyl N-(trans-g-6 alkyl)amine fluorenyl-Cm Alkyl; (c) N-transmethylmethyl-N-decylamine-methylhydrazine-methyl, etc. N-(hydroxy-Chalkyl)-N-Ci-6alkyl-aminecarboxamido-indole_ 6 alkyl; (d) N-dihydroxypropylamine fluorenyl fluorenyl and the like N-(dihydroxy-Cm alkyl)amine fluorenyl-Cm alkyl; (e) (amino) (dimethylamine a mercapto group such as a Ci-e alkyl group substituted by an amine group and a bis(Cl_6 alkyl)aminecarbamyl group; or (f) pyrrolidinylcarbonylmethyl group, hydroxypyrrolidinylmethyl group or amine a pyrrolidinylcarbonyl-Cl 6 alkyl group which is unsubstituted, substituted by a hydroxy group or substituted with an amine aryl group, etc. 11 323135 201202230 Substituent on ring A (1^ or RA2) When the group is substituted by a group represented by the formula: H0-Alk-0-, the alkyl group may, for example, be a hydroxy-G-6 alkoxy-G-6 alkane such as a methoxycarbonyl group. Base. Replacement on ring A When (RA1 or RA2) is a group-substituted alkyl group represented by the formula: RhRiN-, the alkyl group to be substituted may, for example, be NG-6 alkane such as (a) anthracenyloxycarbonylaminomethyl group. oxy-carbonylamino-Cm alkyl; (b) N-acetoxyethyl fluorenyl fluorenyl or N-(2-hydroxyisobutyl decyl) amino fluorenyl N-C2-7 aryloxy -C2-7, arylamino-Ci_6 alkyl; (c) N-(hydroxy-C2-7 alkyl fluorenyl)amino-indole-6 alkyl, etc. Or (d) N-(hydroxy-C2-7 alkylindenyl_N_Cl-6 alkylamino-Cl-6 alkyl group such as N-hydroxyethylindenyl-N-decylaminomethyl. When the substituent (RA1 or RA2) on the ring A is an alkyl group substituted with a 5- to 6-membered aliphatic nitrogen-containing heteromonocyclic group, the alkyl group thus substituted may, for example, be (a) pyrrolidine. The methyl group and the pendant oxy group are unsubstituted, substituted with a hydroxy group, substituted with a pendant oxy group, substituted with an amine thiol group, or substituted with a pyridylmethyl group or an amine fluorenyl group. Substituted by a base and a pendant oxy group is less than or slightly substituted by a G-7 alkane, or a (b) 0 to π well sulfhydryl group or an ethylenic ruthenium group. Mercapto substituted pyridyl-Cw alkyl and the like. When the substituent (ra1 or rA2) on the ring A is an alkoxy group which is unsubstituted or substituted, such an unsubstituted or substituted alkoxy group can be exemplified by a hydroxyl group, a Cm alkoxy group. a carbonyl group, an amine carbhydryl group (the amine moiety of the group may also be substituted with 1 to 2 (^6 alkyl) and a selected group of phenyl groups to alkoxy). More specifically, the The alkoxy group may, for example, be an methoxy group, an ethoxy group, a n-propyloxy group or an isopropyloxy group, a hydroxymethoxy group, a hydroxyethoxy group, a 323135 12 201202230 oxycarbonyl methoxy group, a decyloxy group. Carbonyl ethoxy, amine methyl decyl methoxy, N-methyl amine decyl methoxy, N, N-dimethylamine methoxymethyl, alum, phenethyloxy The substituent on the ring A (RA1 or RA2) is a formula: Rk-S (=〇) n_^ indicates the base such that the substituent is, for example, (a) methylthio, B a Cl-6 alkylthio group such as a thiol, n-propylthio or isopropylthio; (b) a thiol group via a base-Cl-6 group such as a thioethyl group; (c) a methoxy group Ci-e alkoxy-Ci-6 alkylthio group such as ethyl ethyl thio or methoxy propyl thio; d) mercapto subgroup sulfhydryl or ethyl sulphate S basket base Ci_6 succinyl sulphate base, (e) methyl continuation base, etc. Ci_6 burns its thiol group; (f) a thiol group such as a fluorenyloxy group such as a fluorenyloxy group or a fluorenyl propyl sulfonyl group; When the substituent (RA1 or RA2) is an alkano group, the substituent may, for example, be a C2-7 calcined group such as an ethyl fluorenyl group, a propyl fluorenyl group, a butyl group, an isobutyl group or a propyl group. When the substituent (RA1 or RA2) is a group represented by RnRnNC (=〇)-, the substituent may, for example, be exemplified by: (a) an amine carbaryl group, an N-decylamine fluorenyl group, and N- Unsubstituted, mono-Cl-6 alkane such as ethylamine sulfhydryl, N-propylamine fluorenyl, N,N-didecylaminocarboxamyl, N-ethyl-N-methylaminecarbamyl Aminomethyl group substituted with or substituted with diCl-6 alkyl; (b) N-(ylethyl)amine oxime, N-(propylidene)aminecarboxamide or N-(di N-(mono or di-based-Ci_6 alkyl) amidamyl group such as propyl propylamine; 323135 13 201202230 (c) N-hydroxyethyl-N-methylamine oxime , N-(hydroxypropyl)-N-methylamine fluorenyl, N-(dihydroxypropyl)-N-methylamine fluorenyl or N-(hydroxybutyl)-N-methylamine N-(mono or dihydroxyCl_6 alkyl)-N-Ci-6 alkylamine fluorenyl such as methyl sulfhydryl; (d) n-(single or bis) N-(difluoroethyl)amine _ Ci-6 base) Amine oxime; (e) N-(Ci 6 alkoxycarbonyl-Cl-6 alkyl)amine oxime group such as N-(ethoxycarbonylethyl)amine carbhydryl (f) N-(unsubstituted or 1-hydroxymethyl-substituted cyclopentyl)amine fluorenyl, etc. N-(C3 8 cycloalkyl unsubstituted or substituted by hydroxyCl-6 alkyl) Amine oxime N-(aminoindenyl-indol-6-alkyl)amine such as N-(aminocarbonyl) aminyl or N-(aminomethylmethyl)amine sulfhydryl (h) a tetrahydrothiopyranyl-amine fluorenyl group which is unsubstituted or substituted with a pendant oxy group (or a di-oxy group); (i) a 1-pyrrole carbonyl group, a hydroxy group An unsubstituted or substituted pyrrolidinylcarbonyl group, such as a substituted fluorenylcarbonyl group, a pyrrolidinylcarbonyl group substituted by a hydroxymethyl group, or a 1-° ratio of a thiol group substituted by an amine carbaryl group (j) a (7)-piperidinylcarbonyl group which is unsubstituted or substituted with a hydroxy group such as a piperidin〇carb〇nyl or a (N-pyristyl)carbonyl group substituted by (k) (N-morphinyl)carbonyl (m〇rph〇Un〇carb〇nyl); (l) N-methoxycarbonyl alumhylamine fluorenyl and the like N_(Ci 6 alkoxy-carbonyl- Alum amide base; or 14 323135 201202230 (m) N-sulfanyl methylamine thiol and the like. When the substituent (RA1 or RA2) on the ring A is a substituted amine group, the substituted amine group may be exemplified by a C alkyl group, a C2-7 alkyl group, a Cw alkoxy group and a Cw. One to two substituted amino groups selected from alkylsulfonyl groups. More specifically, (a) a single Cm such as N-decylamino group, N-ethylamino group, N,N-didecylamino group or N-ethyl-N-methylamino group An alkyl or di-Cm alkylamino group; (b) an N-acetylamino group such as N-ethenylamino; (c) N-decyloxycarbonylamino, N-isopropyloxycarbonyl N-Ch alkoxy-carbonylamino group such as amine or N-tertiary butoxycarbonyl-based amine group; (d) N-Cw alkylsulfonylamino group such as N-methylsulfonylamino group (e) N-Cl-6 alkyl-N-(Cl-6 alkyl) amine group such as N-fluorenyl-N-(fluorenylsulfonyl)amine; (f) N- N-(transalkyl-C2-7 decyl) amine group such as ethylamino group; (g) N-(C2-7 alkyl decyloxy group) such as N-ethoxymethoxyethyl hydrazino group (2) N-(C2-7 succinyl)-N-(Ci-6 alkyl)amino group; (h) N-ethinyl-N-methylamino group; i) N-(hydroxy C2-7 alkylmercaptoalkyl)amine such as N-hydroxyethyl-N-methylamine; (j) N-ethyloxyethyl-N-decylamine An N-(C2-7 decyloxy-C2-7 alkyl fluorenyl hN-CCw alkyl) amine group or the like. When the substituent (RA1 or RA2) on the ring A is an aminesulfonyl group substituted with 1 to 2 alkyl groups, the substituent may, for example, be N-methylaminesulfonyl or N,N-difluorene. A mono- or di-G-6 alkylamine sulfonyl group such as a sulfamidino group. When the substituent (RA1 or RA2) on the ring A is a group represented by the following formula: XQ) Such a substituent may, for example, be a pyrrolidinylethyl group or a pendant oxy group 15 323135 201202230 pyrrolidinyl fluorenyl group Wait. When the substituent (1^ or 1^2) on the ring is saturated or unsaturated, the heterocyclic group contains the same or different from the oxygen atom, the sulfur atom and the nitrogen atom. 1 to 4 heteroatoms, may also be extended by a Cm extension such as an anthracene group or an exoethyl group, and may also be derived from a hydroxyl group, a pendant oxy group, a cyano group, a Cl_6 alkyl group, a base group-Cm alkyl group, Halogen-Cl_6 alkyl, carboxy_Cl_6 alkyl, amine ruthenium-Ch-alkyl, mono or bis(Cl-6 alkyl)amine sulfhydryl-Cl_6 alkyl, c2_7# aryl, hydroxy-Cw alkyl fluorenyl One to three base substitutions selected from the group consisting of an amidino group and a mono- or di-Cw alkylamine broth. As such a substituent (RA1 or RA2), more specifically, for example, a) may be derived from a hydroxyl group, a pendant oxy group, a cyano group, a hydroxy Cw alkyl group (hydroxy fluorenyl group, etc.), a halogen-Ci 1-6 alkyl (monofluoroindolyl) and the like 1 to 2 substituted pyrrrolidyl 'b) may be substituted by a pendant oxy group, c) may be removed from the side oxygen a group, a Ci-6 alkyl group (fluorenyl group, etc.), a hydroxy Cw alkyl group (hydroxyl decyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxybutyl group, etc.), a halogen-Cm alkyl group (monofluoroethyl group, etc.), C2-7 alkane 醯 yl group (ethenyl group, etc.), unsubstituted aminyl-G-6 alkyl group (amine fluorenyl fluorenyl group, etc.) and amine fluorenyl group substituted by mono or diCh alkyl group 1 to 3 substituted imidazolidinyl groups selected from -G-6 alkyl (didecylaminomethyl) and the like, d) isotetrahydrothiazolyl substituted by 1 to 2 pendant oxy groups (isothiazolidinyl), e) 曙σ, which can be substituted with 1 to 2 groups of oxazolidinyl from the pendant oxy group and the C -6 alkyl group (hydroxymethyl group, etc.) , g) can be taken by Cw alkyl (indenyl, ethyl, n-propyl, isopropyl, etc.) Instead of oxadiazolyl, h) triazolyl, i) tetrazolyl which may be substituted by hydroxy Ci-6 alkyl (hydroxyethyl, etc.), j) may be derived from Cw alkyl (methyl, 16 323 135 201202230 Ethyl group, etc., side oxy group, hydroxyCl -6 alkyl group (hydroxyethyl group, etc.) and hydroxy C2-7 alkyl fluorenyl group (hydroxyethyl hydrazyl group, etc.) selected from i to 2 substituted pyridyl groups' k) m琳rph〇linyl which may be substituted by a pendant oxy group, 1) B is 0-based, m) pyrimidinyl, η) is derived from a pendant oxy group, a C1-6 alkyl group (methyl, ethyl, etc.) And a dihydro-1,3-indenyl group which may be substituted with a pendant oxy group by a 1 to 2 substituted tetrahydropyrimidinyl group selected from the group Ci_6 (based on a benzyl group, etc.), or P) Azabicycloheptyl substituted by 1 to 3 groups selected from a pendant oxy group and a hydroxyl group. Preferred examples of the ring A (containing the substituents R1 & RA2) include a substituted phenyl group as shown in the following formula: (a):

Ra2 (Al) [wherein, RA1 represents (1) a hydrogen atom, (2) a halogen atom, (3) an alkyl group which may be substituted by 1 to 3 tooth atoms, (4) a thiol group or (5) Cyano group, and RAZ represents (1) a hydrogen atom, (2) a halogen atom, (3) a cyano group, 323135 17 201202230 (4) an alkyl group, (5) a substituted alkyl group, and the alkyl group is contained a saturated or unsaturated 5- to 6-membered heterocyclic group of one to four heteroatoms selected from an oxygen atom and a nitrogen atom, (6) an alkylthio group (the alkyl moiety of which may also be substituted by a hydroxy group), (7) A thiol group (the base portion of the group may also be substituted by a thiol group), (8) an alkylsulfanyl group (the alkyl moiety of which may also be substituted by a hydroxy group), (9) an alkyl group Sulfoalkyl (the alkyl portion of the group may also be substituted by a hydroxyl group), (10) an amine which may be substituted with one to two groups selected from the following a), b) and c) a group, a) an alkyl group which may be substituted by 1 to 3 functional atoms, b) a monohydroxyalkyl group, and c) an alkyl group substituted by a hydroxyl group and an alkoxy group, (11) may be substituted by 1 to 2 alkyl groups Amidoxime, (12) can be derived from alkyl, alkanoyl, alkoxycarbonyl, alkynyloxy One to two substituted amino groups selected from alkyl hydrazino groups, hydroxyalkyl fluorenyl groups and alkyl sulfonyl groups, '(13) alkyl fluorenyl groups, (14) alkoxy groups, (15) nitro groups, (16) Alkoxycarbonyl, (17) Formula: R"R12NC(=)0- (wherein R11 and γ are (a) independently represent a ruthenium atom or a ruthenium group, or (b) The ends are bonded to each other to form a nitrogen-containing 5 to 6-membered aliphatic heterocyclic ring 323135 which can be substituted with 1 to 2 groups selected from a hydroxyl group, a pendant oxy group and a transalkyl group, and an adjacent nitrogen atom. The cyclic group may also contain an oxygen atom as a hetero atom), or (18) a saturated or unsaturated 5 to 6 membered heterocyclic group containing the same or different one selected from a nitrogen atom, a sulfur atom and an oxygen atom. 4 heteroatoms, and may also be from a pendant oxy group, a hydroxyl group, an alkyl group, a hydroxyalkyl group, an amidinoalkyl group, a monoalkylamine, a mercaptoalkyl group, and a dialkylamine, a mercaptoalkyl group. 1 to 2 base substitutions selected; or (B) substituted 5 or 6 member heteroaryl groups as shown in the following formula:

φ (wherein RAU represents (1) a hydrogen atom, (2) a cyano group, a (3) alkyl group, a (4) alkoxy group, a (5) N-morpholinyl group, a (6) alkyl group, or (7) The amine sulfhydryl group RA12 which may be substituted by 1 to 2 alkyl groups represents a hydrogen atom or a tooth atom, RA13 represents a hydrogen atom or an alkoxy group, and RA14 and independently represents a hydrogen atom or an alkyl group. The 6 to 7-membered aliphatic nitrogen-containing heterocyclic ring represented by the ring is, for example, a lycopene ring, a homopiperazine ring (that is, 1,4-diazepane). Ring) and so on. When the substituent (RB3) on the ring B is a saturated or unsaturated 5- to 6-membered monocyclic hetero-based group, such a heterocyclic group may, for example, be a dihydrocarbazolyl group or a thiophene 19 323135 201202230 % oxazolyl, triazolyl, tetrazolyl, etc., unsaturated, oxygen-containing, sulfur-containing or 3-nitrogen, 5-membered mono-heterocyclic heterocyclic group, or unsaturated azide-containing 6-membered heterocyclic group such as acridinyl or pyrimidinyl Ring base, etc. Further, the substituent on the saturated or unsaturated 5- to 6-membered monocyclic heterocyclic group may, for example, be the same or different one to two groups selected from the following: a) An alkyl group such as an ethyl group, an ethyl group, a n-propyl group, an isopropyl group or a tertiary butyl group, or a cycloalkyl group such as a cyclopropyl group, a cyclopentyl group or a cyclobutyl group (the cycloalkyl group may also be a chlorine atom or a fluorine atom). a halogen atom such as an atom or an alkyl group such as 曱φ group or ethyl group), c) difluoromethyl, difluoroethyl, trifluoromethyl, difluoroethyl or monofluoropropyl is 1 to 3 a halogen atom-substituted alkyl group, d) a hydroxyalkyl group such as a hydroxypropyl group, an alkoxyalkyl group such as e) a methoxyethyl group, and f) a difluoroethoxyethyl group substituted with 1 to 3 halogen atoms An alkoxyalkyl group, §) an alkoxy group such as an ethoxylated oxime group or an ethoxypropyl group; an amine substituted with a fluorenyl or a dialkyl group; An amino group such as an aminomethyl group or an amino group (the amine moiety of the group may also be an alkyl group (methyl group) or an alkoxy group (tertiary butoxy group) Etc.))). _ When the substituent (RB3) on ring B is a group represented by -W-R3, and R3 is a 5- to 6-membered monocyclic aryl group, the 5- to 6-membered monocyclic aryl group may also contain The same or different one to three hetero atoms selected from the oxygen atom, the sulfur atom and the nitrogen atom, and specific examples of such a 5- to 6-membered monocyclic aryl group may be exemplified by a base group, an sigh base group, and an 11-slice group. Dimercapto, fluorenyl, hydrazinyl, tridecyl, pyridyl, pyrimidinyl and the like. Further, the above 5- to 6-membered monocyclic aryl (or heteroaryl) group may also be derived from 1) a halogen atom (e.g., a chlorine atom, a fluorine atom, a bromine atom, a moth atom, etc.), 2) an alkyl group (e.g., a fluorenyl group). , ethyl, isopropyl, etc.), 3) alkoxy (methoxy, ethoxy, propoxy, butoxy, etc.), 4) cycloalkyl (eg ring 323135 20 201202230 propyl, cyclobutyl) a base, a cyclopentyl group, a cyclohexyl group, etc.) and 5) 1 to 2 groups selected from an amine group substituted with 1 to 2 leukosyl groups (for example, an amine group, a mercaptoamine group, a dimethylamino group, etc.) Replace. A preferred example of the ring B (including RB1, RB2, and RB3) is exemplified by (A) a group represented by the following formula (i): R20 r\~\ -N^)-r2 (i) φ [wherein R2 represents (a) cyano or (b) a saturated or unsaturated 5 to 6 membered monocyclic heterocyclic group; wherein 'the saturated or unsaturated 5 to 6 membered monocyclic heterocyclic group contains an oxygen atom, sulfur 1 to 4 hetero atoms selected from the same or different atoms and nitrogen atoms, and may also be substituted with 1 to 2 groups selected from the following (bl) to (b5): (bl) may be 1 to a 3-dentate-substituted alkyl group, (b2) hydroxyalkyl group, (b3) alkoxyalkyl group, (b4) an amine group which may be substituted by 1 to 2 alkyl groups, and (b5) cycloalkyl group; R2° Represents a hydrogen atom, a halogen atom or an alkyl group; • (B) a group represented by the following formula (ii): -N^-WlR31 (9) [wherein, W1 represents an oxygen atom, a sulfur atom or a carbonyl group, and R31 represents a) an alkane. a group (the alkyl group may also be substituted with a group selected from a phenyl group and an alkoxy group); b) a ring-based group; or c) a 5- to 6-membered monocyclic aryl group (the aryl group may also contain One or three or more heteroatoms selected from the group consisting of oxygen atoms, sulfur atoms and nitrogen atoms, and may also be selected from the following 1) to 5) 1 to 2 base substitutions: 1) a halogen atom, 2) an alkyl group, 3) an alkoxy group, 4) a cycloalkyl group, and 5) an amine group which may be substituted by 1 to 2 alkyl groups 21 323135 201202230]]; C) The base shown in the following formula (iii):

Wherein R4 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 also be subjected to 1 to 3 halogens) Substituted by an alkyl group or a cycloalkyl group, R4° represents a hydrogen atom or an alkyl group; (D) a group represented by the following formula (iv): wherein R4 has the same meaning as defined above; Is (E) a substituted 6-membered or 7-membered aliphatic nitrogen-containing heterocyclic group represented by the following formula (v): —<^N-R4A (V) [wherein R4A represents nitrogen or oxygen-containing 5 to 6 membered heteroaryl (the heteroaryl group may also be substituted by an alkyl group)]. In the compound [I] of the present invention, a preferred compound is, for example, a compound or a pharmacologically acceptable salt thereof, and a ring A is a group represented by the following formula:

22 323135 201202230 [wherein, ring A1 represents a benzene ring or a "biter ring, RA represents 1" a cyano group; 2) a mono or dihydroxyalkyl group; 3) is obtained from (a) a hydroxyl group, (b) a formula: rPRqnc ( a group represented by 〇)) and (c) an alkyl group selected by a group selected from alkylsulfonyl groups (wherein Rp and Rq independently represent a halogen atom, an alkyl group which may be substituted by 1 to 3 tooth atoms) Or a hydroxyalkyl group, or a combination of two, which together with a contiguous nitrogen atom, form a nitrogen-containing member which can be substituted with one to two groups selected from a halogen atom, a hydroxyl group, a cyano group and an aminomethyl group. Aliphatic heterocyclic group; 4) alkoxy group; 5) Formula: ΐη(=0)η-based group (in this case, a group which can be substituted by a hydroxyl group or a oxy group, η represents 〇 to 2 6) The substituted alkyl group is substituted by a 5-membered heteroaryl group containing 1 to 3 nitrogen atoms φ as a hetero atom; 7) alkoxycarbonylalkyl; 8) 0% (00) - the group shown (here, the ruler 3 and Rt independently represent a gas atom, a burnt group, a carbyl group or a dihalogen group) or a combination of both and a neighboring nitrogen atom From the atom a 4- to 6-membered nitrogen-containing aliphatic heterocyclic group substituted with 1 to 2 groups selected from a cyano group, a cyano group and an amine fluorenyl group; 9) an amine sulfonyl group which may be substituted with 1 to 2 alkyl groups; 10) alkyl sulfhydryl; 323135 23 201202230 11) alkoxyamino group; 12) alkyl hydrazino group; 13) alkyl group hydrazino group; 14) group of the formula: 3 (in Thus, ring A111 represents a nitrogen-containing 5-membered aliphatic heterocyclic ring substituted by a pendant oxy group; or 15) a saturated or unsaturated 5- to 6-membered heterocyclic group which is selected from a nitrogen atom, a sulfur atom and an oxygen atom. 1 or 4 heteroatoms which are the same or different, and may also be derived from pendant oxy, hydroxy, alkyl, hydroxyalkyl, amidinoalkyl, monoalkylamine, mercaptoalkyl and dialkyl One to two substituents selected from the amine mercaptoalkyl group; RB represents a hydrogen atom, a halogen atom, a cyano group, an alkyl group or a trihaloalkyl group; and, the ring B is a group represented by the following formula:

-N

R2A R21 [wherein R2A represents a saturated or unsaturated 5-membered heterocyclic group containing the same or different one to three hetero atoms selected from a nitrogen atom and an oxygen atom, and is alkyl (the alkyl group is also Any one may be substituted by 1 to 3 halogen atoms), a cycloalkyl group, an alkoxyalkyl group or an alkylalkyloxyalkyl group; and R21 represents a hydrogen atom or an alkyl group. Among the above compounds, a more preferable compound is, for example, a compound or a pharmacologically acceptable salt thereof, and a ring A1 represents a benzene ring, and 24 323 135 201202230 RA represents 1) Formula · RuRvNC(=0)-CH2- The base (here, RU& RV is the same or different, represents a hydrogen atom or a Ch alkyl group, or a combination of two and a neighboring nitrogen atom is formed from a minus, a cyano group and a pendant oxy group. 1 to 2 substituted 5-membered nitrogen-containing aliphatic heterocyclic groups; 2) Formula: rs(=0)2- (wherein "can be selected from light bases and Ci 4 alkoxy groups" Substituted C1_4 alkyl);

P:), (x〇)~ The neon x and Ry shown independently represent an alkyl group or both of them bonded at the end and adjacent to a nitrogen atom - a 5-membered di-, cyano and amin-yl group The selected 1 S 2 base substituted 5 members s 虱爿 肪 aliphatic heterocyclic group); 4) 〇 4 alkyl sulfonyl methyl; or 5) saturated or unsaturated ... 2 nitrogen atoms as a miscellaneous Atom, a base, having 1 to 2 mercapto groups selected from the group consisting of 1 to 2, a mercapto group and a trans group-Ch are heteroatoms, and may be further substituted by a di- or / (the ring group may also be an oxygen atom) Acryl group; alkalyl group; alkyl group; alkyl fluorenyl or bis (Cl-4:: represents a hospital base; R is the same or phase of the non-privile nitrogen atom selected from the same or phase , which contains from an oxygen atom and an alkyl group (the group may also be deuterated to 1 to 3 heteroatoms, and is substituted by deuterium-4 and R21 represents a hydrogen atom = atom) or a C3_6 cycloalkyl group; In the compound, the compound or the pharmacologically acceptable compound thereof may, for example, be 323135 25 201202230. Ring A1 represents a benzene ring, and RA represents 1) Formula: RaaRbbNC(=0)-CH2- Base (here, Raa represents a hydrogen atom, Rbb a Ci-4 alkyl group, or both of which are bonded at the end to form an 11-mercapto group which may be substituted by a radical with a nitrogen atom; 2) a base group of _Cl-4; An amidino group which may be substituted by 1 to 2 Ch alkyl groups; 4) a group represented by the following formula:

Wherein, Ra3 and Ra4 are the same or different and represent a hydrogen atom, a hydroxyl group, a cyano group or an amine sulfhydryl group; or 5) a cyclic group represented by the following formula:

[wherein, Ral represents a hydrogen atom, a trans group or a via-Ci-4 alkyl group, and Ra2 represents a mercapto-Cl-4 alkyl group, an amine-mercapto-Cl-4 group or a di(Cl-4) group. An amine aryl group _Cl-4 alkyl group; 1^ is a 5-membered heteroaryl group containing the same or different one to three hetero atoms selected from an oxygen atom and a nitrogen atom, and is capable of undergoing 1 Substituted to a G atom-substituted G-4 alkyl group or a C3-6 cycloalkyl group; and R21 is a hydrogen atom. In the compound [I] of the present invention, other preferred compounds are, for example, 26 323 135 201202230, such as the compound or a pharmacologically acceptable salt thereof, and the ring A is a group represented by the following formula.

Rd rC-^~ [wherein ring A2 represents a benzene ring RC represents a hydrazine) alkyl sulfonyl group; 2) an amine fluorenyl group which may be substituted with i to 2 alkyl groups; or 3) (N_morpholine) a carbonyl group, {^ represents a hydrogen atom or a halogen atom];

—N

Wlr 31 Also, ring B is a group represented by the formula: wherein W1 represents an oxygen atom or a sulfur atom, r31 represents an alkyl group (the substituent is also substituted by an alkoxyphenyl group), a cycloalkyl group, a benzene group. a group (the phenyl group may also be substituted with 1 to 2 groups selected from a tooth atom, an alkyl group, an alkoxy group, and an amine group (the amine group may also be substituted with 2 alkyl groups)) or Nitrogen or a sulfur-containing 5 to 6 membered heteroaryl group (the heteroaryl group may also be substituted by an alkyl group). In the compound [I] of the present invention, other preferred compounds other than the above may be, for example, the compound or a pharmacologically acceptable salt thereof, and the ring A is a group represented by the following formula: rf

[wherein, ring A3 represents a stupid ring, re represents (a) an alkylsulfonyl group, and (b) an alkylsulfonylalkyl group (a phthalocyanyl group (the amine moiety of the amine group may also be , selected from the base of the saponin and the sublimation base to 2 bases), (4) 1 to 2 filaments selected from the side oxy group and the fluorenyl group, the nitrogen-containing 5 member lipid 323135 27 201202230 a group, or (e) a group represented by the following formula: (here, a ring Γ represents a nitrogen-containing 5-membered aliphatic heterocyclic ring substituted with a hydroxy group), and 'R represents a hydrogen atom or a halogen atom]; and, ring B The base shown in the following formula:

Wherein R41 represents (a) an alkoxycarbonyl group or (b) a 5-membered heteroaryl group, wherein the (b) 5-membered heteroaryl group contains the same or different ones selected from the oxygen atom and the nitrogen atom. To 3 heteroatoms, substituted by an alkyl group; R42 represents a hydrogen atom or an alkyl group]. Among the compounds which are more preferred, such as the compound or a pharmacologically acceptable salt thereof, 'P system 烷基4 alkylsulfonylmethyl group, amine mercaptoalkyl group (the amine group of the amine group) The moiety may also be substituted by 1 to 2 alkyl groups, or the group shown by the lower formula.

(here, the symbol has the same meaning as the above) and 'R42 is a hydrogen atom. In the compound [I] of the present invention as described above, a particularly preferred compound is, for example, a compound selected from the group consisting of the following compounds or a pharmacologically acceptable salt thereof: 4 [5~Fluorine_ 4~[4~(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidine 323135 28 201202230 -1-yl],oxazoline-8-yl]-N,N- Dimercaptobenzamine; 3 gas 4-[4-[4-(3-isopropyl-[ι,2,4]卩, etc. 2° all-5_ base) 11 bottom 0 _1 Quinazoline-8-yl]-N,N-dimercapto amidoxime; 3-fluoro-4-[5-fluoro-4-[4-(3-isopropyl-[ι,2, 4]oxadiazole_5_yl)piperidin-1-yl]quinazoline-8-yl]_N,N-dimethylbenzamide; 5-fluoro-4-[4-(3-iso Propyl-[H4]oxadiazole_5_yl)piperidine-1_yl]-8-(4-oxasulfonylphenyl)quinazoline; 4-[6-fluoro-4-[4-( 3-isopropyl-[H4]oxadiazole_5-yl)piperidine-diyl]quinazoline-8-yl]-N,N-dimercaptobenzamide; 2-fluoro-4- [5-Fluoro-4-[4-(3-isopropyl-[I 2 , 4]oxadiazole-5-yl)piperidin-1-yl]quinazoline-8-yl]-n, n- Dimercaptobenzamide; 3-fluoro-4-[6-fluoro-4-[4-(3-isopropyl-[1,2,4]oxadiazole-5-yl) piperidine-12-quinazoline-8-yl]-N,N-dimercaptobenzamide; 2-fluoro-4-[5-fluoro-4-[4-(3-isopropyl-[1,2 , 4] oxadiazole _5"yl)piperidin-1-yl]quinazoline-8-yl]-N-methylbenzamide; N-ethyl-2-fluoro-4-[5-fluoro 4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidine-indolyl]quinazoline-8-yl]benzamide; 2- Fluoro-4-[6-fluoro-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidinyl-1]quinazoline-8-yl]-n , n-dimethylbenzamide; 2-fluoro-4-[6-fluoro-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin Pyridin-1-yl]quinazoline_8_kib N-methylbenzamide; 6-fluoro-4-[4-(3-isopropyl-[1,2,4]oxadiazole- 5-yl) piperidine-;[_yl]-8-[3-fluoro-4-[(pyrrolidinyl-p-yl)carbonyl]phenyl]quinazoline; 2-fluoro-4-[6-fluoro- 4-(3-n-propyl-indole, 2,4]oxadiazole_5-yl)piperidin 323135 29 201202230 pyridine-1-yl]quinazoline-8-yl]-N,N-dimercaptobenzene Methionine; 6-fluoro-4-[4-(3-n-propyl-[1,2,4]t3⁄4diazol-5-yl)piperidin-1-yl]-8-[3-fluoro-4 -[(pyrrolidin-1_yl)carbonyl]phenyl]quinazoline; 2-fluoro~4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4]噚Diazol-3-yl) n啶-1-yl] quinazolinyl]nonylbenzamide; 4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidine-1 — -8-(4-oxasulfonylphenyl)quinazoline; soil 4 [4 [4-(3-isopropyl-[1,2,4]indole-5-yl). Binaxy] quinazoline-8-yl]-indole, hydrazine-dimethylphenyl hydrazide; 3-fluoro-4-[6-fluoro-4-[4-(5-n-propyl-[1 , 2, 4] oxadiazole _3_yl) piperidin-1-yl] quinazoline _8-yl]_ν, ν-dimethylbenzamide; 2-fluoro-4-[6-fluoro -4-[4-[3-(2, 2, 2-trifluoroethyl)-[1,2,4] % diazol-5-yl]piperidin-1-yl]quinazoline_8_ Base]_ΝΝ_dimethylbenzamide; 2-fluoro-4-[6-fluoro-4-[4-[5-cyclopropyl-[1,2,4]oxadiazole-3- • piperidinyl] quinazoline _8-yl]-indole-(2-hydroxyethyl)-indole-methylbenzamide; 6-fluoro-4-[4-(5-isopropyl) -[1,2,4]oxadiazol-3-yl)piperidin-1-yl]-8-(3-fluoro-4-methylsulfonylphenyl)quinazoline; and 6-fluoro-4 -[4-(5-isopropyl-[1,2,4]oxadiazol-3-yl)piperidine-buyl]-8-(3-fluoro-4-methylsulfonylmethylbenzene Base) quinazoline. In the above compound [I] of the present invention, other particularly preferred compounds are, for example, those selected from the group consisting of the following compounds or pharmacologically acceptable salts thereof: 323135 30 201202230 2_[2_|l-4 -[6-IL-4K5-isopropyl-oxadiazol-3-yl]pyrazine+yl]phenyl]_N_methylethylamine; 6-gas-^[4-(5-isopropyl) -[1,2,4M2. sit a 3-unit) pyridine-b-yl]-8-[3-fluoro-4-(2-hydroxyethylsulfonyl)phenyl]quinazoline; [2 -Fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4]oxadiazole-3-yl)piperidin-1-yl]quinazoline_8_ Phenyl]phenyl](3-hydroxypyrrolidinyl)-methanone; Κ2-fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4]噚Diazol-3-yl)piperidin-1-yl]quinazoline-8-yl]phenyl]_3_(2-hydroxyethyl)imidazolidine-2-one; 6-fluoro-4_[4-(5~ N-propyl-[1,2,4]oxadiazol-3-yl)piperidinyl-byl]-8-[3-fluoro-4-[(3-hydroxy.pyrrolidinyl)-carbonyl) Phenyl]quinazoline; 1-[2-fluoro-4-[6-fluoro-4-[4-(5-cyclopropyl-[1,2,4]Pf oxazol-3-yl)piperidin Pyridin-1-yl]quinazoline-8-yl]phenyl]_3_(2-hydroxyethyl)imidazolidine-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; Bu [2_fluoro[6~ fluoro-4-[4-(3-isopropyl-[1,2,4]oxadiazole-5] -yl)piperidin-1-yl]quinazoline-8-yl]phenyl]_3_(2-hydroxyethyl)imidazolidine-2-one; 1-[2_fluoro-4-[5-fluoro-4 -[4-(5-isopropyl-[1,2,4]oxadiazol-3-yl)piperidin-1-yl]quinazolinyl]phenyl]_3_(2-hydroxyethyl) 323135 31 201202230 sinidin-2-one; 卜 [4-[6-fluoro-4-[4-(5-isopropyl-oxadiazol-3-yl) brigade-buki] quinalin I ]_2_fluorophenyl]_4_peptidylpyrazine bite_2~ ketone; fluorinated-4-[6-fluoro-4-[4-(5-trifluoromethyl-[!,2,4]卩琴二唑-3-基Μ bit-il sits 琳|基]phenyl](3, ββ比洛 bit__基基) ketone; [4 [6 fluoro 4 [4-(5-isopropyl) A [ι,2,4] oxadiphenyl-3-yl) ketone-1-yl] 啥嗤琳_8-基]_3_methylphenyl] 洛洛 bite a 2 嗣; 2 [2 fluoro 4-[6-fluoro-4-[4-(5-n-propyl-7,2,4)indole di-sial-3-yl) face+yl](tetra)lin|yl]phenyl hydrazine Ethyl ketone; 1 [2 fluoro 4 [4-[4-(5-isopropyl-[1,2,4] oxadiazole _3 yl) Diazin-buyl]indole porphyrin-8-yl]phenyl-31 hydroxyethyl)imidazolidine-one; methyl 4 [6-fluoro-4_[4-(5-isopropyl~[1, 2,4 bis-saltyl] oxime-end 8 _ yl] phenyl] '3 syl-ethyl) scent 3 Y y 2 - fluoro - 4 - [6_ fluoro - 4 * (5 isopropyl ~ [1 , 2,4 oxadiazolyl) ketone-1-yl] 噎嗤琳 I base] phenyl] Niang 哄 2 ketone; 3 US t fluorosis ~ 4 * (5_ n-propyl ~ [1 ,2,4]噚二唾细余-8-yl]phenyl]perylene)flavor 323135 32 201202230 +based Mm]噎 琳琳_8_基]Phenyl]_3_(2_ylidylethyl) Taste bite-2-_ ; 1 [2-fluoro-1 2 3 4-[5~ fluoro-4-[4-(5-isopropyl-[1,2,4] oxadiazole-3-yl ) bottom bite - 1_'yl] oxazolidine-8-yl] phenyl]-4-pyridyl pyridine 2-one; fluoro-4-[5-fluoro-4-[4-(5- N-propyl-[1,2,4]oxadiazol-3-yl](tetra)lin+yl]phenyl]_4_ylidene ketone; 1_[2~ fluoro-4-[5_ fluoro-4-[ 4-(5-cyclopropyl-[1,2,4]oxadiazol-3-yl)-biting_Buji]啥啥琳+基]Phenyl 4-hydroxylamine bite| 1-[2- Fluorine_4_[6_ fluoro_4_[4_(5_isopropyl-[^4] oxadiazole... soil) ° bottom ting 'buki> baolin-8-yl] phenyl]-3-(2 ,-2-yl-propylidene)imidazolium_2-_; soil 323135 33 1 ~[4-[6-fluoro-4-[4-(5-cyclopropyl-[1,2,4]oxadiazole-3~yl) _ 々1 yl] 啥 啥-8-8 ]-3-methylphenyl> called bite-2-_; a 4 [4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4]oxadiazole- 3-yl)-1-yl]quinazoline-8-yl]-3-methylphenyl]-morphine_3_one; 2 1 (2 fluoro-4-{6-fluoro-4-[4- (5-isopropyl-[1,2,4]oxadiazole-3-yl)piperidinyl]quinazolin-8-yl}phenyl)imidazolidine-5-one; 3 3~[2- Fluoro-4-[4-[4-(5-isopropyl-[1,2,4]diod-3-yl)piperidinyl]quinazolin-8-yl]phenyl]-3- Hydroxypyrrolidine-4-one; soil 4 1 [2-fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4]oxadiazole-3-yl) henidine _丨_yl]quinazoline_8_yl]phenyl]hydroxymethylpyrrolidine 201202230-2-one; 2-[l-[2-fluoro-4-[6-fluoro-4-[4-( 5-isopropyl-[1,2,4]oxadiazol-3-yl)piperidin-1-yl]quinazolinyl]phenyl]_2_trioxyimidazol-3-yl]-N , N-dimethylacetamide; [2-fluoro-4-[6-fluoro-4-[4-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)唆+基]啥峻琳+基]Phenyl](2_amine-branching base biting-1-yl)methanone;

卜L2-Fluoro-4-[4-[4-[5-(1,1-di-haloethyl Hl,2,4]oxadiazol-3-yl] Ninja bite-!-基]啥0坐琳_8-yl]phenyl]_3_(2_transethylidene imidazolidin-2-one; 1 [2- gas-4-[6-fluoro-4-[4-(5-tris-methyl-n-n) , 2, 4] oxadiazol-3-yl) 唆 唆 卜 卜 卜 卜 卜 _ _ _ _ _ _ _ _ _ _ _ _ _ _ 苯基 苯基 苯基 苯基 苯基 苯基 -1- -1- -1- -1- -1- -1- -1- Ketone; [2_ fluoro + [5_ fluoro-4-[4~(5-isopropyl_[1,2,4] oxadiazole | base) pie bite 1 base] 喧 w _8_ base] phenyl ](2-cyano-4-in--1-yl)methanone; [2-fluoro-4-[5-fluoro(5-isopropyl-pyridylpyrazole-10-ischen 1 bit) _8-yl]phenyl](3_经基比比洛唆-1~基) 二MW1,1-:气乙)_[1,2,4 川+ΑW+基]嗤°坐#-8 _基]phenyl](3々基° such as a 4'[6' gas-4~[4~(5~isopropyl_[1,2,4]Bf diazole-3' fluorenyl] quinazoline Phenyl]phenyl](2-amine f-ylpyrrolidine 323135 34 201202230 base) anthrone; 1 [2-methyl-4-[5-fluoro-4-[4-(5-isopropyl-oxime) , 2,4]曙二嗤-3-yl), 咬, 基, 基, 基, _, _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 4_[6一气_4_[4_(5_三气methyl一RU]曙二基)娘定1-基]啥唾琳_8_ ]Phenyl]-3-1 (2-cyanoethylidazolidin-2-one; _^1, [2'methyl~4_[6~gas+[4-(5~cyclopropyl-[1,2] , 4] 曙二0坐土定-1-基]喧唾琳_8_基]phenyl]1(2-monoethyloxazolidin-2-one; τ 6-fluoro-4-[4-( 5-isopropyl-[丨,2,例υ_基)派哄+土咄-(3-fluoro-4-methylsulfonylmethylnaphthyl)quinazoline; 3F4-4H4-[ 4_[5-(1-Gas-B-methylethyl Hl,2,4]:Sit + Μ Μ + 基 基 基 基 基 基 _ _ _ _ _ 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基Pyridin-1-yl)methanone; gasophilic + [4-[5-(Buqi-i-methylethyl)-[1,2,4]yl)methanone; Bu [2-Fluor m4_[4_[5_( 1_mk base printing, terminal group]- lysine|yl]phenyl](2-aminomethylpyridylpyrrolidin-1-yl)methanone; soil 1 um[4-[5_(1, difluoroethyl Base)_[12 shoulders two hearts 2:1_base] 喧 terminal 8-base] 2-methylphenyl]-4-yl radical 323135 35 201202230 卜 [4-[6-敦-4_[4_(5 1-isopropyl-π, 2,4 hongsii + piperidin-buki] 喧 琳 琳 I base]_2_cyanophenyl]_4_ carbazide; 疋乙二嗤Υ2美气二4— [4—[4-[5—0-qi-b-methylethyl][1,2, for example, W 4/定-1-基]啥啥琳一8一]Phenyl]—3 A (2~-ylethyl) β-salt bite-2-_ ; Bu [2-fluoro-4~[4-[4-[5-n-propyl-", to] Oxadiazole _3 ttr-based] Baolin-8'-yl]phenyl]-3-(2~-ylethyl)imidium (4) ~[1-Fluoro-4Pfluent-4-[4-(5~ Propyl~[1,2,4 bay disin + ketone 1 yl] fluorenyl (tetra) phenyl]] 2-trans-base---[2-fluoro-4-[6-fluoro- 4_[4_[5_(1,卜二氟乙Ηι,2,4^丫--基> 唆-卜基]啥啥琳_8-基]phenyl](3_ pyridine) 1-yl)methanone; order -i2 fluoro- 4_[4-[5~(b-fluoro+methylethyl)-[1,2,4] °-yl]piperidin-1-yl]quinazoline I group]phenyl](3-hydroxyindole 〇 〇 -1- 基 基 ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; - Methyl benzoic acid amine; 3 [1 [2-Fluoro-4-[5-fluoro-4-[4-(5-isopropyl-[i,2,4]曙t-t-yl) (IV)- 1-yl]Baolin+yl]phenyl]2-2-oxo-oxy-3-yl]-propanol; and 323135 36 201202230 l_[2-|L-4-[5-fluoro- 4- [4-(5-isopropyl-[1,2,4]卩, etc. 2-11--3-yl)11 bottom biting-1-yl]0i:11 坐琳-8-基]笨基]-4 - Each bite through the base layer - 2-嗣. When the compound [I] of the present invention has an asymmetric carbon atom in the molecule, a plurality of stereoisomers (that is, a non-image isomer, an optical isomer) may be present depending on the asymmetric carbon atom, and the present invention Each of these stereoisomers or mixtures thereof may be included. Since the compound [I] of the present invention has an excellent action to the GPR119 receptor, it is useful for preventing/treating various diseases or states which can be expected to be improved by regulating the activity of the receptor, for example, including obesity, Hyperglycemia, diabetes (including insulin-dependent diabetes mellitus, non-insulin-dependent type 2 diabetes, or intermediate diabetes) and/or its complications, metabolic syndrome, glucose loss, hypermembranceemia, high Metabolic diseases such as lipemia, hypercholesterolemia, hypertriglyceridemia, and abnormal lipid metabolism; or cardiovascular diseases such as arteriosclerosis, hypertension, coronary artery disease, and myocardial infarction. In other words, the present invention encompasses administration of a therapeutically effective amount of the compound [I] of the present invention or a pharmacologically acceptable salt thereof to a patient in need thereof, and a method of treatment or prevention of the above various diseases or conditions. The present invention also relates to the use of the compound [I] of the present invention or a pharmacologically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of the above various diseases or conditions. The present invention also relates to a pharmaceutical composition comprising the compound [I] of the present invention or a pharmacologically acceptable salt thereof as an active ingredient, and the pharmaceutical composition of the present invention 37 323135 201202230 may further contain a pharmaceutically acceptable carrier . Examples of such pharmaceutically acceptable carriers include diluents, binders (arabis gum, polyvinylpyrrolidone, etc.), excipients (lactose 'sucrose, etc.), and lubricants (magnesium stearate, etc.). , a disintegrating agent (potato starch, etc.), a wetting agent (sodium lauryl sulfate, etc.), and the like. The compound [I] of the present invention or a pharmacologically acceptable salt thereof is low in toxicity and has an advantage of being a medical safety. The compound [I] of the present invention can be used for medical use in a free form or in the form of such pharmacologically acceptable salts. The pharmacologically acceptable salt may, for example, be a hydrochloride, a sulfate, a phosphate or a hydrobromide J mineral acid; an acetate, a trifluoroacetate, a fumarate or an oxalic acid. An organic acid salt such as a salt, a citrate, a methanesulfonate, a besylate, a p-toluenesulfonate or a maleate. The compound [I] or its pharmacologically acceptable salt of the present invention includes any one of a knife 1 and an adduct, a solvate or a hydrate of 5 liters. The compound [I] of the present invention or a pharmacologically acceptable salt thereof can be administered orally or parenterally, and can also be used as a pharmaceutical preparation such as a tablet, a granule, a capsule, a powder, an injection or an inhalation. And use. The dose of the compound [I] of the present invention or a pharmacologically acceptable salt thereof or a therapeutically effective dose varies depending on the administration method, the age, body weight, and state of the patient, but it is preferably an injection.丨天为约〇. 〇〇1 to wo mg/kg 'Specially good for about 〇. 〇1 to 1〇mg/kg or so for oral administration, usually about 1〇 to 0001mg/kg per day. The best is about 〇. i to 1 〇〇 around. 323135 38 201202230 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 or the like of the subject to be treated. Examples of such a drug can be exemplified below. (a) Antihypertensive drugs: angi〇tensin transforming enzyme inhibitors (enalapril maleate, imidapril hydrochloride, etc.), type II gold tubes A gonadotropin receptor antagonist (losartan potassium, candesartan cilexetil, etc.), a stone blocker (Attino ^ (ateno101), fumarate bsupro ( Bisoprolol fumarate), α / /3 blocker (carvedil〇i, labetalol hydrochloride, etc.), calcium antagonist (amlodipine besilate ), diitiazem hydrochloride, etc., α 1 blocker (doxazosin mesilate, prazosin hydrochloride, etc.), mesocyclic α 2 agonist Or other centrally acting drugs ^ (clonidine hydrochloride, respine, etc.), vasodilators (hydralazine hydrochloride, minoxidil, etc.); Diuretic: tiofenide (t Hiazide) is a diuretic (chlorthiophene, hydrochlorospur, etc.), loop diuretic (bumetanide, furosemide, etc.), traitive diuretic (hydrochloric acid) Miloride hydrochloride, triamterene, etc.; (c) Heart failure treatment: nitrate (nitroglycerin, etc.), foxglove preparation 39 323135 201202230 (digoxin) , digitoxin, etc., catecholamines (dobutamine hydrochloride, denobamine, etc.), endothelin-resistant drugs (bosentan, etc.), Acid diesterase inhibitor (milrinone lactate, amrinone, etc.), neutral endopeptidase inhibitor (fasidotril, etc.), atrium Sexual diuretic peptide, etc.

(d) Antiarrhythmic drugs: Na channel blockers (procainamide hydrochloride, flecainide acetate, etc.); K channel blockers (amiodarone hydrochloride) 〇ne hydrochloride), etc., Ca channel blocker (verapamil hydrochloride, etc.), etc.; (e) tfj lipemia drug: HMG-CoA reductase inhibitor (pravastatin sodium ), atorvastatin potassium, fluvastatins dium, etc., fibrate derivatives (bezafibrate, clofibme), _ (squalene) synthetase inhibitors, etc.; (1) antithrombotic drugs: blood coagulation inhibitors (warfarin warfarin, heparin, etc.), thrombolytic drugs (urokinase (6) also recommended), t-PA, etc. Platelet drugs (aspirin, ticlopidine hydrochloride, etc.); === urinary complications _: 姨 素, __ = Vida tvlldagliptin), sitar (Xianxian (10) 'glucose Saki Pharmaceutical (v〇glib〇Se), A 323135 40 201202230 carbose (acarbose) , miglitol, emiglitate, etc., biguanide (metformin hydrochloride, buformin, phenformin, etc.) ), insulin resistance improving drugs (pioglitazone, troglitazone, rosiglitazone, etc.), insulin secretion promoting drugs (tolbutamide, tolbutamide, Greeben) (glibenclamide), gliclazide, glyclopyramide, chlorpropamide, glimepiride, gram, glipizide, gledidine Glybuzole, tolazamide, acetoxime hexamide, etc., guanyl urea compound, pramlintide, etc. Aldose reductase inhibitor (epalrestat, tolrestat, zenarestat, f idarestat, minarrestat) , teptostat (zopolrestat, etc.), neurotrophic factor (NGF, etc.) , AGE inhibitors (Pimagedine, pyratoxathine, etc.), neurotrophic factor production promoting drugs, etc.; (h) Anti-obesity drugs: central anti-obesity drugs (Malay 〇1), fenfluramine, sibutramine, etc., pancreatic lipase inhibitor (orlistat, etc.), agonist (SB-226552, BMS-196085, etc.), win Peptide appetite suppressant (leptin, etc.), cholecystokinin receptor agonist (lintitript, etc.); 323135 41 201202230 (i) non-steroidal anti-inflammatory drug: acetaminophen (acetaminophen), ibuprofen, etc.; (j) chemotherapeutic agents: metabolic antagonists (5-fluorouracil, methotrexate, etc.), anticancer agents (Changchunxin) Alkali (vincristine), taxol, cisplatin, etc.; (k) immunomodulators: immunosuppressants (cyclosporin, tacrolimus) Etc.), immunopotentiator (krestin®, knitz listen (lentina) n) etc.), cytokine (interleukin 1, interferon, etc.), cyclooxygenase inhibitor (indomethacin, celecoxib, etc.) ), anti-TNFa antibody (infliximab, etc.), etc. When the compound [I] of the present invention is used in combination with other agents, the form of administration thereof may be exemplified by (1) administration of a single preparation (mixture) containing the compound [I] and other agents, and (2) inclusion of a compound [ The preparation of I] is administered in combination with a preparation containing other pharmaceutical agents. Further, when (2) the combination is administered, the administration route and the administration time of the individual preparations may differ. For example, the compound [I] of the present invention can be produced in accordance with the following Synthesis Methods 1 to 31. Synthesis Method 1) (Reaction Process A):

)-rB2 rB3

Transition metal catalyst

rB1 卜rB2 rB3 42 323135 201202230 [In the above scheme, 'X1 represents a leaving group; r, and R' 'is a hydrogen atom or an alkyl group, or a combination of the two to represent a stretching group, and other symbols have the same meaning as the foregoing. ]. Synthesis 2) (Reaction B):

Φ [In the above scheme, X2 represents a halogen atom, and ring Ba represents a 6-membered nitrogen-containing aliphatic heterocyclic ring, and other symbols have the same meaning as described above]. The reaction of the compound [la] in the above Reaction Scheme A with the boric acid compound [28] can be carried out in a solvent in the presence of a transition metal catalyst and at room temperature to the reflux temperature of the solvent, preferably at 5 Torr. It is carried out from °C to the reflux temperature of the solvent. The leaving group represented by X1 is preferably a halogen atom such as a bromine atom, a gas atom or an iodine atom. The solvent may be any one as long as it does not inhibit the reaction. For example, an alcohol such as ethanol or an amide such as N,N-dimethylformamide or the like, diterpene, 1,2-dimethoxyl An ether such as an alkane or tetrahydrofuran, or an aromatic tobacco such as water. The transition metal catalyst may, for example, be tetrakis(triphenylphosphine) ruthenium (iridium), palladium acetate (II), bis(dibenzylidene fluorene) palladium (0) (; bis (dibenzylideneacetone) palladium ( O)), bis(triphenylphosphine) palladium (II) dichloride, bis(trio-p-phenylphosphine)palladium (11) di-vapor, bis(tricyclohexylphosphine)palladium(II) dichloride Or a palladium catalyst such as [丨,i,-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, L3-bis(diphenylphosphino)propane nickel (ruthenium) dichloride or Nickel catalyst such as bis(triphenylphosphine)nickel(II) dihydride, 323135 43 201202230, and the like. The alkali system may, for example, be potassium phosphate, sodium carbonate, carbonic acid planer, sodium hydrogencarbonate, potassium fluoride, triethylamine or lithium chloride. The boronic acid compound [2a] of the present invention can be used in an amount of 1 to 3 equivalents, preferably 1 to 1.5 equivalents, based on the compound [la]. The catalyst may be used in an amount of from 0.01 to 0.3 equivalents, preferably from 〇3 to 0.06 equivalents, based on the compound [ia]. The amount of the base relative to the compound [la]' may be from 1 to 1 equivalent, preferably from 2 to 7. The reaction of the compound [lb] in the above Reaction Scheme B with the cyclic amine compound [2" can be carried out in a solvent in the presence or absence of a base at a reflux temperature of _2 〇 < t to the solvent. Preferably, it is carried out in -10 to 4 (rc). As shown in 乂2, the i atom is preferably a bromine atom, a chlorine atom or an iodine atom. The solvent may be any one as long as it does not hinder the reaction, and for example, it may be exemplified by two gases. Halogenated aliphatic hydrocarbons such as methyl, chloroform or 1,2-dichloroethane; ugly amines such as dipyridyl ketone, dimercaptoamine or dimercaptoacetamide, 1,2-dimethoxy Examples of the ethyl ketone, the methyl sulfite, the tetrahydrogen or the bismuth, and the ketones such as acetone, such as acetophenone or stupid aromatic spring hydrocarbons, such as acetone, are exemplified by sodium hydride, carbonic acid unloading, and pyridine. , diethylamine, diisopropylethylamine, 4-mercaptomorpholine, 1,8-diazabicyclo[5,4'0]undecene (DBU), etc. In the above reaction, The compound [2b] may be used in an amount of from 丨 to 3 equivalents, preferably from 1 to 1.5 equivalents, based on the compound [lb]. The base used in the compound [113] or the compound [21)] may be 1 to 5 equivalents, preferably 1 to 2 equivalents. In the compound [I] of the present invention, a compound having an alkylsulfonyl group (or an alkylsulfonyl group-containing group) as a substituent on the ring A may also have an alkane The corresponding compound [I] having a thio group as a substituent is used in a solvent (dichloromethane 323135 44 201202230, a hydrocarbon, an alcohol such as ethanol, a ketone such as acetone, or the like), and an acid (methic acid, trifluoromethane). Acetic acid or the like is produced by treating τ with oxygen (tetra) (tetra), gas peroxybenzoic acid, etc. Synthesis method 3-1) The compound of the present invention (1) is a compound represented by the following formula [Buc],

Rv-. V/'^W-0113 [I·. ] φ [where the symbol has the same meaning as the above]

By the compound of the formula [lc], ϊ RA2 [wherein, the symbol has the same meaning as described above] and the compound of the formula [2c], r3-〇H [2c] [in the formula, It has the same meaning as the above] _ in the solvent 'in azodiacetate siu vinegar (azo diphilic diacetate, diazo carboxylic acid diisopropyl ester, etc.) and trisubstituted phosphines (three stupid base) Phosphine, tributylphosphine, etc.). In the presence of the reaction, it is produced by reacting at room temperature to the reflux temperature of the solvent, preferably at room temperature to 5 ° C. (4) As long as it is not hindered by the reaction, P may, for example, be a dentified aliphatic hydrocarbon such as a gas-fired, gas-steamed or 2-dichloroethane, 1-mercaptopurine or dimethylformamidine. Amines such as amines or dimethyl ethanoamines, 1,2, 2, bismuth, dimethyl sulphate, tetrazofuran or bismuth, etc., aromatic benzene such as benzene or benzene Wait. In the present reaction 323135 45 201202230, the compound [2C] may be used in an amount of from h 至 to 3.0 equivalents, preferably from ι·〇 to 1.5 equivalents, based on the compound [lc]. The diazo carboxylic acid dialkyl ester may be used in an amount of from 1. 〇 to 3. 〇 equivalent, preferably from 1.0 to 1.5 equivalents, based on the compound [1〇]. The trisubstituted phosphine may be used in an amount of from 1.0 to 3.0 equivalents, preferably from 1 to 15 equivalents, based on the compound [1〇]. Synthesis Method 3-2) ^ Further, in the compound [Ι-C] of the present invention, a compound represented by the following formula,

[wherein R32 represents a group which may be substituted with a group selected from a phenyl group and an alkoxyphenyl group], for example, the above compound [1C] and an alkyl halide represented by the following formula (alkyl) Halide) R32-Xu [a] [wherein, X11 represents a halogen atom, and other symbols have the same meanings as described above.] • In a solvent (such as an ether such as tetrahydrofuran or a guanamine such as dimethylamine), The base (hydrogenated alkali metal such as sodium hydride or alkyllithium such as n-butyllithium) is produced by reacting at a reflux temperature of 10 C to a solvent, preferably at room temperature to medium. The tooth atom shown by X" is preferably a gas atom or an atom. In the present reaction, the compound [a] may be used in an amount of from 1 to 10 equivalents, preferably from i to 3 equivalents, based on the compound [lc]. The base may be used in an amount of from 1 to 3 equivalents, preferably from 1 to 3 equivalents, per mole of the compound or the compound [a]. Synthesis method 4) 323135 46 201202230 In the compound [I] of the present invention, a compound represented by the following formula [Ι-D],

[wherein the symbol has the same meaning as described above] is a compound represented by the formula [Id]

[wherein, X3 represents a leaving group, and other symbols have the same meaning as described above] and a compound of the formula [2d] R3-SH [2d] [wherein the symbol has the same meaning as described above] in a solvent, It is produced by reacting in the presence of a base at a temperature ranging from room temperature to the reflux temperature of the solvent, preferably from 50 ° C to the reflux temperature of the solvent. The leaving group represented by X3 may, for example, be a decanesulfonyloxy group, a trifluoromethanesulfonyloxy group or the like. The solvent may be any one which does not inhibit the reaction, and examples thereof include alcohols such as decyl alcohol. Examples of the alkali system include a burnt metal test such as sodium methoxide, and an argon test metal. In the present reaction, the compound [2d] may be used in an amount of from 1 to 10 equivalents, preferably from 2 to 4 equivalents, based on the compound [Id]. The base may be used in an amount of from 1 to 10 equivalents, preferably from 1 to 2 equivalents, based on the compound [1 d ] or the compound [2d ]. Synthesis method 5) In the compound [I] of the present invention, a compound represented by the following formula [Ι-E], 47 323135 201202230

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

[In the formula, the symbol has the same meaning as described above] and the compound R41-X4 [2e] represented by the following formula [2e] wherein R41 represents an alkyl group, a cycloalkyl-alkyl group, or a nitrogen-containing compound. Or an oxygen-containing 5 to 6 membered heteroaryl group (the heteroaryl group may also be substituted by an alkyl group), X4 represents a halogen atom], or may be produced by reacting the aforementioned compound [le] with A reactive derivative of the compound represented by the formula [2e-2]: R42-C00H [2e-2] wherein R42 represents an alkoxy group is produced by a reaction. The reaction of the compound [1 e ] with the compound [2e] can be carried out in a solvent in the presence of an activator (catalytic amount of potassium, etc.) at room temperature to the reflux temperature of the solvent, preferably It is carried out at 50 to 100 °C. The solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include decylamines such as dimethyl decylamine and ethers such as dioxane. The alkali system may, for example, be an alkali metal carbonate such as potassium carbonate 48 323135 201202230. In the present reaction, the compound [2e] is used in an amount of from 1.0 to 3.0 equivalents, preferably from 1. 〇 to 2· 〇 equivalent, based on the compound [1 e ]. 0至3. 0当量。 The compound is used in an amount of from 1. 至 to 5 〇 eq. The reactive derivative of the compound [le] (for example, the corresponding acid vapor) and the reaction of the compound [2e-2] can be used in a solvent (dichloromethane or the like) in the presence of a triethylamine or the like. It is carried out at 40 ° C, preferably at 〇 to 3 ° °c. _Synthesis method 6) In the compound [I] of the present invention, a compound represented by the following formula Π-F],

Wherein A represents a benzene ring or a bite ring (the benzene ring or n may be substituted by a halogen atom or a burnt group), and other marks have the same meaning as described above]

The amine compound represented by the following formula "If 1" (wherein the symbol has the same meaning as described above) and the amine compound represented by the following formula [2f] or a salt thereof (such as hydrochloric acid) Salt and other mineral salts, etc.)

RaRbNH [2f] [wherein the symbol has the same meaning as described above] 323135 49 201202230 A cereal agent is produced by reacting in the presence or absence of an activator in the presence of a condensing agent. The solvent may be an inactive/mixing agent which does not inhibit the reaction, and examples of the solvent include, for example, a denatured aliphatic L-type such as dichloromethane or a chelating amine such as N,N-methylformamide or the like. Tetrahydro D-fusane, etc., water, etc. The condensing agent may, for example, be 丨_ethyl_3_(3-dimethylaminopropyl) carbodiimide hydrochloride (WSC · HC1), N, N, _ dicyclohexyl carbon ruthenium Imine, diethyl cyanophosphonate, 4-(4,6-didecyloxy-1,3,5-trin-2-yl)-4-indolylmorpholinium chloride hydrate DMT-MM) and so on. The activator may, for example, be hydrazine-hydroxybenzotriazole·1 hydrate or hydrazine-hydroxybutanediamine. The base may, for example, be triethylamine, diisopropylethylamine, pyridinium or methylmorpholine. In the present reaction, the amount of the compound [2f] may be from 丨.0 to 5. 〇 equivalent, preferably from 1 () to 1.5 equivalents, based on the compound.至至1. 5当量。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。. Synthesis method 7)

In the compound [I] of the present invention, a compound represented by the following formula [I-G],

[In the formula, the symbol has the same meaning as described above], for example, by converting a compound represented by the following formula [lg] into a corresponding one.

50 323135 201202230 [In the formula, the symbol has the same meaning as described above] The Si chloride is compounded with the compound of the following formula [2g]

H3C [2g] In a solvent (halogenated aliphatic hydrocarbon such as chloroform or an ether such as tetrahydrofuran or an aromatic hydrocarbon such as toluene), the temperature is from -10 ° C to the reflux temperature of the solvent, preferably 4 (TC to solvent). The reaction is carried out at a reflux temperature, and the reaction product is then dissolved in a solvent (a halogenated hydrocarbon such as dichloromethane or an ether such as tetrahydrofuran or an aromatic hydrocarbon such as toluene), or an azodicarboxylate (azo). It is produced by treating a trisubstituted phosphine (triphenylphosphine, tributylphosphine, etc.) with a trisubstituted phosphine (triphenylphosphine, tributylphosphine, etc.). Synthesis method 8) The compound of the present invention [ In the formula I], a compound represented by the following formula [IH],

• [wherein, R°° represents an alkyl group, an alkoxyalkyl group or a cycloalkyl group, and other symbols have the same meanings as described above], for example, by using the aforementioned compound [lg] in a solvent (aromatic such as anthracene) In the presence of a base (triethylamine, diisopropylethylamine, etc.) in the presence of a base (such as an ether such as a hydrocarbon or tetrahydrofuran or a halogenated aliphatic hydrocarbon such as a gasoline), a chlorodecanoate After converting to a corresponding mixed acid anhydride by treatment with butyl ester, isopropyl chloroformate or the like, the mixed acid anhydride and the compound represented by the following formula [1h]

51 323135 201202230 [where the symbol has the same meaning as the above] := etc.): =^ . (: Reverse to the reflux temperature of the solvent; degree, preferably 4; Synthetic method 9) $ 匕 = 匕 compound (1) in the 'ring'

==;: There are,) the compound can be borrowed from: the base of the hydroxyl group) or protected (or contains the protected amine group (or contains the protected amine compound [I]' due to the protective group (B Conventional deprotection of thiol, tetrahydropyranyl, benzodiazepine, 2/_f methoxybenzyl, tert-butyldimethylmethyl, tert-butoxy-4-yl, etc. It is produced by reaction. When the protection is acetaminophen, the protective base can be removed by the treatment of (4) silk chemical. Baoxian is tetrahydroindenyl, tertiary oxygen or 2, Ioxy. In the case of benzyl group, the protecting group can be removed by acid treatment of fluorene fluoride. When the protecting group is a benzene group, the sulfonate can be treated by using an acid such as nitrogen acid/acetic acid. When the lysyl group is a tertiary butyl dimethyl fluorene group, the protecting group can be removed by treatment with tetra-n-butylammonium fluoride (10)F) or hydrazine. Synthetic method 10) The compound [I] of the present invention a compound having a substituent comprising a sulfonium group or a sulfonyl sulfonyl group as a substituent on the ring oxime, which can be obtained by using a corresponding compound having a group containing an alkylthio group as a substituent [π, ^ (Toothed aliphatic hydrocarbons such as dichloromethane, alcohols such as ethanol, ketones such as acetone, 323135 52 201202230 water, etc.), in the presence of an acid (methanesulfonic acid, trifluoroacetic acid, etc.), an oxidizing agent (inter-chlorine) It is produced by treatment with peroxybenzoic acid or the like. Synthesis method 11) The compound [I] wherein the substituent on the ring A is an alkoxycarbonylalkoxy group, the corresponding compound [I] wherein the corresponding substituent is a hydroxyl group, and the compound X shown in the following formula -Aik 丨-C00Raa [laa] [wherein, X1 represents a halogen atom, Aik1 represents an alkylene group, and Raa represents an alkyl group]. It is a solvent (dimethyl sulfoxide, N,N-didecyl decylamine, etc.). In an ether such as an amine or tetrahydrofuran, it is produced by reacting in the presence of a base (such as an alkali metal carbonate such as potassium carbonate or a hydrogenation test such as sodium hydride). Synthetic method 12) The compound [I] ' wherein the substituent on the ring A is an amine group substituted with a fluorenyloxyalkyl fluorenyl group can be obtained by substituting the corresponding compound [I] with the corresponding substituent as an amine group a compound of the formula φ Rbb-X2 [lbb] [wherein, X2 represents a halogen atom, and Rbb represents an alkanoyloxyalkyl fluorenyl group or a hydroxyalkyl fluorenyl group] in a solvent (halogenated aliphatic hydrocarbon such as monofluoromethane or the like) In the case of an ether such as tetrahydrofuran or the like, it is produced by a reaction in the presence of a test (diethylamine, a carbonic acid such as a carbonated carbon dioxide or the like). Synthesis method 13) A compound in which a substituent on ring A is an amidinomethyloxy group [丨], which is a corresponding compound which can be a methoxyl group methyloxy group by a corresponding substituent 323135 53 201202230 The compound [i] is produced by reacting ammonia with a solvent (such as an alcohol such as methanol or an ether such as dioxane). Synthesis method 14) The compound [I] wherein the substituent on the ruthenium A comprises a carboxyl group and a hydroxyalkyl group can be obtained by using the corresponding compound [I] as a group containing an alkoxy group in a solvent ( In the case of an alcohol such as methanol or an ether such as tetrahydrofuran, water, or a mixture thereof, it is produced by treatment (such as an alkali metal hydroxide such as sodium hydroxide) or an acid (hydrochloric acid or the like). #合成法15) The compound [I] in which the substituent on the bad A is a hydroxyethyl group can be obtained by using the corresponding compound (1) in the solvent (an ether such as tetrahydrofuran). After reacting with 9, heterobicyclo[3.31]壬(10)_brain, the reaction product is produced by treating hydrogen peroxide in the presence of hydrogen peroxide or the like. Synthesis method 16)

The substituent on the ring A is a compound (1) having a group represented by the following formula,

Corresponding to the amine group by the corresponding substituent

...the corresponding compound [I] in the solvent, such as self-chemical fat (four), etc.

Il-l· ΛΑ· \ . 323135 54 201202230

Xa-(CH2)P-C0-Xb [lcc] or Xa-(CH2)q-0-C0-Xb [ldd] [wherein, Xa and Xb represent the same or different halogen atoms, p is 3 to 4 Integral, q is an integer of 2 to 3] The reaction product is produced by treating a reaction product in the above solvent with a base (hydrogenated alkali metal such as sodium hydride or alkali metal carbonate such as potassium carbonate). Synthetic method 17)

The compound [丨] in which the substituent on the ring A is a group represented by the following formula may be reacted with a compound represented by the following formula by reacting a corresponding compound [丨] having a corresponding substituent as an amine group, [lii ]

Xaa-CH2-C0-X

[wherein, Xaa and Xbb represent an atom], and the reaction product is represented by a compound HO-(CH2)2-Xcc [1 jj] [wherein xee represents a halogen atom] in the above solvent, It is produced by reacting in the presence of a base (a hydrogenated alkali metal such as sodium hydride or a carbonic acid such as potassium carbonate). Synthesis method 18) In the compound [I] of the present invention, a compound represented by the following formula [b...

55 323135 201202230 [The same formula means that A° means benzene ring or (four) ring' other mark system has the same phase as before

For example, a compound represented by the following formula [lc] /=N ^ R2 [lc] [wherein the symbol has the same meaning as described above] and a compound represented by the following formula [lee] can be used.

Xc-(CH2)2-N=C=0 [lee] [wherein Xc represents a south atom] In a solvent (an ether such as tetrahydrofuran or an aromatic hydrocarbon such as toluene), in a base (-ethylamine) After the reaction is carried out in the presence or absence of a secondary amine or the like, the ruthenium product is produced by treating the ruthenium product in the above solvent with a base (hydrogenated alkali metal such as sodium hydride or alkali metal carbonate or the like). Synthetic method 19)

[Ic [wherein, Rdd represents an alkyl group or a hydroxyalkyl group, and other symbols are the same as defined above]. For example, (a) the above compound [ι-b] is represented by the following formula [lff]m. Alkylating agent (alkyl dentate such as iodo nordane), etc. ' 323135 56 201202230 [Iff]

Rdl-Xd [wherein, Rd1 represents an alkyl group or a hydroxyalkyl group (the hydroxyl moiety of the group may also be protected), and Xd represents a halogen atom] in a solvent (an amine such as dimercaptoamine or an ether such as tetrahydrofuran) In the case of a base (such as an alkali metal such as sodium hydride or an alkali metal carbonate such as potassium carbonate); or (b) the above compound [Ib] and an aldehyde compound represented by the following formula [lff-2] Zb0-Alkb-CH0 [lff-2] ® [wherein, Zb0 represents a protected hydroxyl group, and Alkb represents a linear or branched alkyl group having a carbon number of 4 to 5] in a suitable solvent (halogenated hydrocarbon such as dichloroethane) In the above, it is produced by reacting in the presence of a reducing agent (such as an alkali metal borohydride such as sodium triethoxyhydride borohydride), and then removing a protective group of a hydroxyl group from the reaction product as needed. Further, the protective group of the above-mentioned hydroxyl group is not particularly limited as long as it does not inhibit the progress of the reaction, and is preferably an alkylsulfonyl group such as a tertiary butyldimethylhydrazine group or a tetrahydropyranyl group. Synthesis method 2 0) The compound of the following formula [I-d] in the compound [I] of the present invention,

[wherein, Ree represents a hydroxyalkyl group, and other symbols have the same meaning as described above] can be obtained by, for example, combining the above compound [I -b ] with the formula [1 gg ]: 57 323135 201202230, Z0-Alk2 -Xe [lgg] [wherein Z0 represents a protected hydroxyl group, Aik2 represents a chromanyl group, and 6 represents a halogen atom] in a solvent (ether such as tetrahydrofuran or decylamine such as dimercaptoamine). After the reaction is carried out in the presence of a base (such as an alkali metal such as sodium hydride such as sodium hydride or an alkali metal carbonate such as potassium carbonate), the protective group (Z) is removed from the reaction product. The protecting group of the hydroxyl group may, for example, be a group such as a tertiary butyl fluorenyl fluorenyl group, a tridecyl fluorenyl group or a 2-tetrahydropyranyl group. The removal of the protecting group can be carried out according to a conventional method in accordance with the type thereof. For example, if the protecting group is to be removed from a compound having a hydroxyl group protected by a tertiary dimethyl fluorenyl sulfhydryl group (TBDMS), the compound can be fluorinated by using the compound in a solvent (an ether such as tetrahydrofuran). It is carried out by treating a 4-grade ammonium salt such as butylammonium (TBAF). Synthetic method 21) The compound φ [I] wherein the substituent on the ring A is alkoxy group substituted by a hydroxy group, can be obtained by using a corresponding compound [I] wherein the corresponding substituent is a halogen atom (such as a fluorine atom) (in the case of a guanamine such as dimethylacetamide or a dimercaptopurine, etc.), in the presence of a base (such as an alkali metal such as sodium hydride or potassium carbonate or a tertiary amine such as triethylamine), [lhh] The alkanediol compound shown is reacted to produce H0-Alk3-0H [lhh] [wherein, Aik3 represents an alkylene group]. Synthesis method 22) Compound [I] wherein the substituent on ring A is a group represented by the following formula, 58 323135 201202230

[In the formula, the ring Ad represents a 5- to 6-membered aliphatic nitrogen-containing heterocyclic group which may be substituted with a group selected from the group, the side, and the calcined base], and the corresponding substituent may be a self-methyl group. The corresponding compound (1) (chloromethyl group, etc.) is tested in a solvent (such as dimethyl ketone or the like) in a solvent (hydrogenation of hydrogenation, metal hydride, carbonic acid, etc., triethylamine). In the presence of a primary amine or the like, in the presence of a cyclic amine compound represented by the following formula [Ex.], HN^a^) [Iff] [wherein, the 5-hexene system has the same meaning as described above. ]. Synthetic method 23) The compound (1) wherein the substituent on JA is a group represented by the following formula, φ [wherein the symbol has the same meaning as described above], the corresponding substituent is _ atom (a gas atom, etc.) The corresponding compound [1] and the cyclic amine compound [Iff] are in a solvent (such as guanamine such as dimethylacetamide) or in the absence of a solvent, in a base (triethylamine such as triethylamine, hydrogenation). It is produced by carrying out a reaction in the presence of a hydrogenation alkali metal such as sodium or an alkali metal carbonate equivalent. Synthetic method 24) The compound [I] wherein the substituent on the soil A is an amidinoyl group which may be substituted by an alkyl group, may be suitably determined by using a compound having a corresponding substituent as a hydroxyl group [J] at 59 323 135 201202230 In the solvent (reading, etc.), the amine phthalic acid compound or i in the following formula

RJJRkkN-C00H (wherein Rn& Rkk represents the same or different alkyl group) is produced by reacting a suitable derivative (corresponding acid dentate or the like). Synthetic method 25) ^ The compound having a substituent represented by the following formula Π], -N AeN-Rmm

[wherein, ring r represents a 5 U-rutate-producing county which can be substituted with a group selected from a base group and a pendant oxy group, and the "pure pure base" has the same meaning as the above] a compound in which the substituent is a K group of the following formula (1)

—N AeNH

[In the formula, the symbol has the same meaning as the above] = = =, etc.) is replaced by a reverse solvent in the presence of a suitable solvent (such as a tribasic amine such as a base amine). A compound [I] having a group represented by the formula: [wherein the 'marker has the same meaning as defined above>) is a group of a core which can be produced by removing a protecting group of an amine group from a corresponding substituent. 323135 60 201202230 -N AeN-Rnn in the compound [1] [wherein, Rnn represents the protection of the amine group. The other symbols have the same meaning as the foregoing]. The protecting group of the amine group may, for example, be a fluorenyl group, a secondary butoxycarbonyl group or the like, and the protecting group may be removed by a protecting group in a suitable solvent (~ & halogenated hydrocarbon such as cyanonane) The compound [I] is carried out by acid deficiency (treatment with trifluoroacetic acid or the like). Synthetic method 27) Ring Rff-

The compound (1) wherein the substituent on B is a group represented by the formula: [wherein, R" represents an alkane A which may be substituted by 1 to 3 south atoms] may be carried out by a turbidity on the corresponding ring β The substituent is a compound of the formula 下'ΗΟ η2ν^\ and a compound represented by the following formula [lgg]

Rff-cox6 [lgg] [In the formula, X is not a ruthenium atom, and other symbols are prepared by reacting with an aromatic hydrocarbon such as benzene (such as benzene). Or a third grade such as ethylamine or (B) reacting the corresponding net β-amine in a suitably dissolved substituent domain Μ compound (1) with an alcohol such as iso-alcohol, etc., and then reacting the reaction 323135 61 201202230 = Do not: the above compound [1 slave] is produced by reacting in an appropriate solvent (aromatic hydrocarbon such as toluene) in the presence of a test (such as a tertiary amine such as diethylamine). Synthetic method 28) Intermediary: I The substituent of the substituent or ring β is a group containing a functional group, and the (four) (four) condition is taken to contain a secret base soil, and a suitable solvent (a halogenated hydrocarbon such as dichlorosilane or the like) is used as a toothing agent. Ethylaminosulfur trifluoride (10), etc. are treated.

The compound (1) wherein the substituent is a group represented by the following formula: wherein the 'A table is not substituted by a pendant oxy group, the 4 to 6 member aliphatic nitrogen-containing heterocyclic ring is the corresponding substituent. The compound group of the group represented by the following formula is produced by treating other symbols with the above-mentioned (four) meaning = alcohol-transfer type, etc. The compound [1] which is a tetidine base, or a compound which is a thiol group, can also be used in a solvent (halogenated aliphatic tobacco such as dichloro-tau: etc.). Lack of, create. Gongchai Temple) is made by treating with sulphur (tetrafluoroacetic acid, etc.) 323135 62 201202230 Synthetic method 31)

The compound [I] wherein the substituent on the ring A is an amine fluorenyl group, an amine mercaptoalkyl group or a mono or dialkylamino decylalkyl group may also be a carboxyl group or a corresponding substituent. After converting a carboxyalkyl group into a reactive derivative such as a corresponding acid chloride, the reactive derivative is represented by an amine compound RxxRyyNH represented by the following formula.

In the formula, Rxx and Ryy each independently represent a hydrogen atom or an alkyl group, and are produced by reacting in a solvent (a halogenated aliphatic hydrocarbon such as dichlorosilane or the like). In the intermediate compound [la] of the present invention, a compound represented by the following formula [la-Ι], „ rb1

82 [la-1] [wherein the symbol has the same meaning as described above] can be produced, for example, according to the following reaction scheme.

63 323135 201202230 [The symbol in the above process has the same meaning as the above]. Conversion from the compound [lla] to the compound [12a] can be carried out, for example, by treating the compound [11a] with an alkali metal sulfate (sodium sulfate or the like), chloral hydrate and an acid (concentrated hydrochloric acid, etc.). The reaction is carried out by reacting with a hydroxylamine or a salt thereof (sulfate or the like). The solvent is not particularly limited as long as it does not inhibit the reaction. The solvent may, for example, be an alcohol such as ethanol or a mixture thereof with water. The reaction can be carried out at a temperature from 50 ° C to the reflux temperature of the solvent, preferably from 8 Torr to the reflux temperature of the solvent. Conversion from the compound [12a] to the compound [13a] can be carried out, for example, by treating the compound [12a] with concentrated sulfuric acid. The reaction may be carried out at 4 ° C to 100 ° C, preferably at 6 °. (: is carried out at 80 ° C. Conversion from the compound [13a] to the compound [i4a] can be carried out, for example, by using the compound [13a] in a solvent (water or the like) in the presence of a base (sodium hydroxide or the like). This reaction can be carried out by treatment with hydrogen peroxide. The reaction can be carried out in a hydrazine, preferably in the range of 50 ° C to 70 ° C. The conversion from the compound [14a] to the compound [15a] can be carried out. This is carried out, for example, by treating the compound [14a] with decylamine. The reaction system can be carried out at a temperature of 1 Torr. (: to the reflux temperature of the solvent (formamide), preferably to the temperature of 19 〇. It is carried out in ° C. The conversion from the compound [15a] to the compound [16a] can be carried out by using, for example, the compound [❿] in the presence or absence of dissolution, in the presence of I' of dimethylformamide. In the case of the solvent, the solvent may be, for example, a chiral amine such as dimethylformamide, an aromatic hydrocarbon such as toluene or benzene, or a tetrahydrocarbamate or the like. Burning, 323135 64 201202230 Toothified aliphatic hydrocarbons such as di-ethane or chloroform, etc. The reaction can be carried out at a temperature of from 40 ° C to the reflux temperature of the solvent, preferably The reaction is carried out at a temperature of from 60 ° C to the reflux temperature of the solvent. The reaction of the compound [16a] and the compound [2b] can be carried out in the same manner as in the reaction of the aforementioned compound [lb] and the compound [2b] (reaction scheme B). In the intermediate compound [la] of the invention, a compound represented by the following formula [la-2],

[wherein the symbol has the same meaning as described above] is, for example, a compound of the above formula [16a] and a dioxa oxaboro ane compound represented by the following formula:

Me M^0: B-CN-RB3 M7a'1]

In the formula, Me represents a thiol group, and other symbols have the same meaning as described above. In a suitable solvent (such as an ether such as 1,4-dioxane), the reaction is carried out in the presence of a base (such as an alkali metal carbonate such as cesium carbonate). Then, the reaction product is reduced in the presence of a catalyst (palladium-carbon or the like) to produce it. The intermediate compound [1 b ] of the present invention can be produced, for example, according to the following reaction scheme.

323135 201202230 [In the above scheme, χ2 represents a halogen atom, and other symbols have the same meaning as described above]. The reaction of the compound [lib] and the compound [2a] can be carried out in the same manner as the reaction of the above compound [1 a] and the compound [2a] (reaction scheme A).

The conversion from the compound [13b] to the compound [lb]' can be carried out by treating the compound [13b] with a halogenating agent (sulfuric chloride/dimethylamine or the like) in a solvent. The solvent is not particularly limited as long as it does not inhibit the reaction. Examples of such a solvent include decylamines such as dimethyl decylamine, aromatic hydrocarbons such as phenyl or benzene, and ethers such as tetrahydrofuran, and dichloro decane. Halogenated aliphatic hydrocarbons such as ethyl chloride or chloroform. The reaction can be carried out at a temperature of from 4 ° C to the reflux temperature of the solvent, preferably from 60 ° C to the reflux temperature of the solvent. The intermediate compound [1〇:] of the present invention can be obtained, for example, by dissolving the above compound [lb] and 4-hydroxypiperidine in a solvent (such as an ether such as tetrahydrofuran) in diisopropylethylamine or the like. Manufactured in the presence of a reaction. The intermediate compound [ld] of the present invention can be produced, for example, by converting the hydroxyl group of the above-mentioned compound [lc] into a desired decomposing group. For example, a compound [1 d ] in which χ3 is a σ group (tetra) fluorenyl group or a difluorofluorenyl fluorenyl group can be used in a solvent (a halogenated hydrocarbon such as dichloromethane or the like) in a solvent (such as a halogenated hydrocarbon such as dichloromethane). The base amine [b] -C1 (wherein X31 represents a methylsulfonyl group or a trifluoromethylsulfonyl group) which is produced by reacting with a compound represented by the following formula in the presence of the compound of the formula: Preferably, the reaction system is carried out at a temperature of from -10 ° C to the reflux temperature of the solvent at room temperature. 66 323135 201202230 The intermediate compound [le] of the present invention can be, for example, a compound represented by the following formula [I-E1]

[wherein, Boc represents a tertiary butoxycarbonyl group, and other symbols have the same meanings as described above] and are produced by treating with an acid in a solvent. The solvent may be any one which does not inhibit the reaction. Examples of the solvent include halogenated aliphatic hydrocarbons such as dichloromethane or chloroform, esters such as ethyl acetate, and ethers such as dioxane or mixtures thereof. Wait. The acid system may, for example, be hydrochloric acid or trifluoroacetic acid. The reaction can be carried out at -10 ° C to the reflux temperature of the solvent, preferably at room temperature to the reflux temperature of the solvent. In the intermediate compound of the present invention, a compound represented by the following formula [I-F1], RB1

[wherein, the ring Ab represents a 5- to 6-membered aryl group which may be substituted with a group selected from a halogen atom, a cyano group and an alkyl group (the aryl group may also contain the same one selected from an oxygen atom, a sulfur atom and a nitrogen atom) Or 1 or 2 hetero atoms which are different from each other, and other symbols have the same meaning as described above], for example, by reacting the aforementioned compound [la] with a boric acid compound represented by the following formula [2a-1] Manufactured 67 323135 201202230 p A1 ρκ B: , OR- [2a-l] [wherein, the symbol has the same meaning as described above]. This reaction can be carried out in the same manner as in the above Synthesis Method 1 (Reaction Scheme A). The starting compound [2a] or [2b] of the present invention is a known compound itself, or a commercially available known compound can be produced by a conventional organic chemical method such as the method described in the reference example of the present invention. In the present invention, "halogen atom" means a fluorine atom, a chlorine atom, an iodine atom or a bromine atom, and "alkyl" or "alkoxy" means a carbon number of 1 to 8, preferably a carbon number of 1 to 6. The linear or branched alkyl or alkoxy group, "cycloalkyl" means a cycloalkyl group having 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. Further, "alkylene group" means a linear or branched alkyl group having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, and "alkyl fluorenyl group" means a carbon number of 2 to 8, A linear or branched alkyl fluorenyl group having 2 to 6 carbon atoms is preferred. Incidentally, the abbreviations used in the present specification have the following meanings as long as there is no other special definition.

Boc: tertiary butoxycarbonyl Me: mercapto Et: ethyl i-Pr: isopropyl i-Bu: isobutyl Ph: phenyl Ac: ethyl sulfonyl 68 323135 201202230 TBDMS (or TBDS): tertiary Butyl dimethyl fluorenyl DMF : dimethylformamide DMS0 : dimethyl sulfoxide THF : tetrahydrofuran TFA : trifluoroacetic acid DAST : (diethylamino) sulfur trichloride CDI : 1, hydrazine - carbonyl Diimidazole HOBt: 1-hydroxybenzotriazole DIAD: Diisopropyl azodicarboxylate BOP: benzotriazol-1-yloxyscale hexafluorophosphate dppf: diphenylphosphinoferrocene PPh3: Triphenylphosphine HPLC: High Speed Liquid Chromatography (Example)

Example A1 2-Fluoro-4-[5-fluoro-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-1-yl]quinazoline Manufacture of porphyrin-8-yl]-N-methylbenzamide hydrochloride

N^N h3c 4N HCI/AcOEt r CH3 ch3 2-fluoro-N-mercapto-4-(4, 4, 5, 5-tetradecyl-[1,3, 2]dioxaborolan Alkyl-2-ylbenzophenone 150 mg, 2 M sodium carbonate aqueous solution 1. 66 mL, tetrakis(triphenylphosphine)palladium (0) 30 mg, and dioxane 30 mL were added to 8-69 323135 201202230 Mo-5-[4 -(3-Isopropyl-[1,2,4]indole di-sal-5-yl) bridging β--1-yl] 啥 吓 _ 200 200 mg in a microwave reactor (Emrys Optimizer, Biotage) , react at 110 ° C for 30 minutes. The reaction mixture was extracted with methylene chloride. The residue was dissolved in DMS0 and purified by reverse phase HPLC [column: Capce 1 pack C18 UG80, Shiseido, 5 // m, 20 mm x 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 B35% - 80%)]. The fraction containing the reaction product ® was collected, concentrated, and the residue was dissolved in methanol. This solution was treated with MT-Carbonate (Biotage) to remove trifluoroacetic acid, and then concentrated under reduced pressure. The residue was dissolved in a mixture of ethyl acetate and ethyl acetate. EtOAc (EtOAc) (EtOAc) Rate 22.6%) ° MS (ESI) m/z: 493.3 [M+H] + lH-NMR (CDC13) (5: 1. 24-1.26 (6H, d, J=6. 95Hz), 1. 89-φ 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-[ Manufacture of 1,2,4]nonyl)dibenzylidene-1-yl]quinazolin-8-yl]-N,N-dimercaptobenzamide hydrochloride 70 323135 201202230

(1) Add sulphur sulphonate 1. 8 mL, DMFO. lmL to 8-(3-fluoro-4-didecylamino decylphenyl)-3H-indolyl-4-one 273. lmg The mixture was stirred at 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 with sulfuric acid and concentrated under reduced pressure to give 4-(4-chlorothiazolin-8-yl)-2-fluoro-N,N-dimethyl Benzoguanamine 260 mg. 3 mL of THF was added to the compound (46. 2 mg), and after stirring the mixture at room temperature, 4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidine was added to the solution. 27. 4 mg and diisopropylethylamine 〇·〇 5 mL 'The mixture was stirred at room temperature overnight. The reaction mixture was extracted with dichloromethane. The residue was purified by silica gel chromatography (solvent: gas) to give 2-fluoro-4-[4-[4-(3-isopropyl-indole, 2,4]oxadiazole-5-yl) 5重量。 (yield 60. 7%). 1,3- yl quinazoline-8-yl] hydrazine, an oil of dimethyl dimethyl phthalamide. !H-NMR (CDCh) 5 : l. 35-1. 37 (6H, d, J=7Hz) > 2. 20-2. 34 (4H, m), 3.06-3.17 (7H, m), 331_3 .41(3H,m), 4 32_ 4. 35 (2H,m), 7. 46-7. 56 (4H,m,), 7. 76-7· 78 (1H,d, J=6.92Hz) , 7.93 - 7.95 (1H, t), 8.80 (1H, s). '323135 71 201202230 (2) 4 mL of hydrochloric acid/acetic acid ethyl acetate 〇 5 mL was added to a solution of the compound obtained in the above (1) (41. 5 mg) in diethyl ether (3 mL), and stirred overnight. The precipitate was taken up, washed with diethyl ether, and then evaporated to dryness crystals crystalssssssssssssssssssssss 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 = 8.99Hz), 7. 30-7. 31 ® (lH, d, J = 7.70Hz), 7.61 - 7.64 (lH, t, J = 7.22), 7.7l -7.64 (lH, t, J = 7.86), 7.85-7.86 (lH, 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

6-say-8-(2-fluoro-4-indolylphenyl)-4-[4-(3-isopropyl-[1, 2,4]oxadiazol-5-yl)piperidine Manufacture of -1-yl]quinazoline

Adding 29/L of methanesulfonic acid and 29 mg of m-chloroperoxybenzoic acid to 6-fluoro-8-(2-fluoro-4-methylthiophenyl)-4-[4-(3-isopropyl a solution of benzyl-[1,2,4]oxadiazol-5-yl)piperidin-1-yl]quinazoline (the compound obtained in Example A31) in a solution of 20.0 mg of di-methane in 1 mL of the mixture Stir at room temperature overnight. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with a saturated aqueous solution of argon carbonate, water and saturated brine. The filtrate was concentrated under reduced pressure, and the residue was dissolved in 1.5 mL of dioxane. To the solution, methanesulfonic acid and m-chloroperoxy succinic acid 58 mg were added and stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with saturated aqueous sodium hydrogen sulfate, water and brine, and then evaporated. 2% (Yield 18.1%). The powder of the title compound was obtained in a yield of 5. 2 mg (yield 18.1%). ). Call MS (APCI) m/z ; 514 [M+H]+ . Example A4 1^,1^-dimethyl-4-[4_[4-(3-mercaptobutylthio)-small _1_yl] quinazoline-8-yl]phenylamine Manufacturing

Add 3-methylbutane-1-thiol 42/zL and 5M sodium methoxide-methanol solution 7〇eL to methanesulfonate [8-(4-didecylaminomethylphenyl) hydrazine After 50 mg of oxazolin-4-yl]piperidin-4-yl ester, it was heated at 1 l ° C for 1 hour in a microwave reactor (Emrys Optimizer, Biotage). The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure, and the residue was purified by reverse phase HPLC [column: Capcelpack C18 UG80, 5 // m, 20 mm x 00 mm, Shiseido; mobile phase A : 0.05% trifluoroacetic acid / water; mobile phase Β: 〇·〇 5% trifluoroacetic acid / acetonitrile, flow rate 15 mL / min (mobile phase B35% - 80%)]. After the separation of the reaction product of 73 323 135 201202230 was carried out, the residue was added with a saturated aqueous solution of sodium bicarbonate and m. Yield 49.9%). MS (ESI) m/z; 463. 1 [M+H]+. Example A5 2-Fluoro-4-[5-fluoro-4-[4-(4fluorophenoxy) π chen-1-yl]啥嗤琳-8-yl]-oxime, Ν-dimethyl Manufacture of benzamide

Adding diisopropyl azodicarboxylate 62//L to 2-fluoro-4-[5-fluoro-4-(4-hydroxypiperidin-1-yl)quinazolin-8-yl]-oxime , Ν-dimethylbenzamide 100 mg, 4-fluorophenol 32. 6 mg and triphenylphosphine 76. 3 mg of THF 2. 5 mL of the solution, 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 purified by reverse phase HPLC [column. XBridge ODS C18, 5/zm, 19 mm x 100 mm, Waters Corporation; mobile phase a: l mM mM ammonium carbonate / Water; mobile phase B: B guess 'flow rate 15mL / min (mobile phase B60% - 90% / 6 minutes). The fractions containing the reaction product (RT = 3 92 to 4 23 min) were collected and concentrated to give the title compound 59. 〇mg (yield 48%). MS (ESI) m/z: 507. 2 [m+h]+. 'H-NMR (CDC13) (5: 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), Θ. 88-6. 94 (2H, 74 323135 201202230 m), 6. 96-7. 〇3 (2H, m), 7.14-7.20 (1H, dd, J=8.3Hz, 10. 9Hz) ' T. 41-7. 52 (3H, m) > 7 67-7. 72 (1H, dd, J=5. 8Hz, 8. 2Hz), 8.65 (1H, s). Example A6 2-Fluoro-N,N-dimercapto-4-[4 -[4-(4-Mercapentyl)-d--1-yl] quinazoline-8-yl]benzamide

CHa K2C03, κΓ

Potassium carbonate 122 mg, catalytic amount of potassium telluride and 1-bromo-4-methylpentane 38#L were added to 2-fluoro-N,N-dimercapto-4-[4-(α- morphine- To a solution of 1-methyl)hydrazin-8-yl]benzamideamine hydrochloride in 10 mL of DMF, the mixture was stirred at 50 ° C for 10 hours. The reaction mixture was heated to 9 ° C and then mixed for 6 hours. The reaction mixture was concentrated and water was added to the residue, which was adjusted to pH 7 with 1N hydrochloric acid, and then extracted with dichloromethane. The organic layer was dried with a celite column and dried over magnesium sulfate. The residue was dissolved in DMS0 and purified by reverse phase HPLC [column: XBridge ODS, C18, 5#m ' 19 mm x 100 mm,

Waters Corporation; mobile phase A: 10·ammonium carbonate/water; mobile phase B: acetonitrile, flow rate 15 mL/min (mobile phase B 60% - 90% / 6 minutes)]. 2 mg (yield 32%) was obtained as a white powder of the title compound (yield: 32%). MS (ESI) m/z: 464.3 [M+H] + ???H-NMR (CDCh) (5: 0. 89-0. 92 (6H, d, J = 6. 6 Hz) Ί. 18-1. 26 323135 75 201202230 (2H,ra), 1. 53-1· 64 (3H,m), 2. 48-2. 53 (2H,m), 2·78 (4H, brs), 3. 〇5 ( (3H, s) 94-7. 94 (1H, dd, J=l. 3Hz, 8. 3Hz) λ 8. 77 (1H, s). Example A7 4_[4-(4-Cyclohexylmethylpipedyl)-5 -Production of fluoroquinazolin-8-yl]-2-fluoro-N,N-dimercaptobenzamine

Add 117 mg of potassium carbonate, 3.5 mg of potassium iodide and 45 //L of decylcyclohexane bromide to 2-fluoro-4-[5-fluoro-4-0-indol-1-yl) quinazoline-8- In a 2 mL solution of -N,N-dimethylbenzamide 2 hydrochloride in 10% DMF, the mixture was stirred at 90 ° C for 6 hours. After adding potassium hydride and 135 a L of methylcyclohexane bromide to the reaction mixture, the mixture was stirred at 90 ° C for 14 hours. The reaction mixture was concentrated, and after adding water, the mixture was adjusted to pH 7 with 1N hydrochloric acid. The mixture was extracted with dichloromethane, and the organic layer was dried over celite column and magnesium sulfate. The residue was dissolved in dimethyl sulfoxide and purified by reverse phase HPLC [column: XBridge 0DS column, C18, 5 " m, 19 mm x 10 mm, Waters Corporation; mobile phase A: 10 mM ammonium carbonate / water; Mobile phase B. B guess 'flow rate 15mL / min (mobile phase B80% - 100% / 6 minutes)]. The fractions containing the reaction product were collected (RT = 3.60 to 4. 21 min), and then concentrated to give the title compound as pale yellow powder 15.3 mg (yield is 76 323135 201202230%). MS (ESI) m/z: 494. 3 [Μ+ΗΓ. j-NMR (CDC13) 5 : 0.87-0.95 (2Η, m), 1.19-1.27 (2Η, m), 1. 49-1· 56 (1H, m), 1. 64-1. 83 (6H, m ), 2· 18-2· 21 (2H, d, J=7. 1Hz), 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. 3Hz, 10. 8Hz), 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-曱-oxybenzyloxy)- s-i-yl] 啥 琳 三氟 三氟 三氟 三氟

-8-yl]-indole, indolinyl benzoylamine 60% sodium hydride 6. 4 mg was added to 4-[4-(4- via nucleoside-1-yl)

A solution of quinazoline-8-yl]-N,N-dimercaptobenzamine 30 mg in THF 5 mL was stirred at room temperature for 1 hour. 4-Methoxyphenylhydrazine gas 22/zL was added to the reaction mixture and stirred for additional 15 hours. The reaction mixture was extracted by gas imitation. The organic layer was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by reverse phase HPLC [column: CaPcelpack C18 UG80, 5,, 20 mm x 100 mm, Shiseido; mobile phase A: 0.05 % trifluoroacetic acid / water; mobile phase B: 0.05% trifluoroacetic acid / acetonitrile, flow rate 15 mL / min (mobile phase B35% - 80%)]. The title compound I8. 7 mg (yield 38.3 323135 77 201202230%) was obtained. MS (ESI) m/z: 495 [M+H]+. Examples A9 to A147 The compounds described in the following Tables 1 to 16 were obtained by treating the corresponding starting compounds in the same manner as in Example A1.

78 323135 201202230 Table 1

EXAMPLES Structural Properties Values, etc. A9 ch3 Powder MS (ESI) m/z: 478 〇ί+Η]+ A10 h3co2sh (Jm^ Powder MS (ESI) m/z: 512 [M+H]+ All (H3c> 2N〇c-^H^ Cl Powder MS (ESI) m/z: 505 [M+Hf A12 (H3C)2NOC~^Jh^-F Powder MS (ESI) m/z: 489 [M+H]+ A13 Ch3 MS (ESI) m/z: 443 [M+H] + A14 MS (ESI)::::::::::::::::: (ESI) m/z: 418 [M+H] + A17 H3co-l w ^ o MS (ESI) m/z: 473 [M+H]+ 79 323135 201202230 Example 2 Structural Properties of Structural Properties A18 MS (ESI) m/z: 515 [M+Hf.sup.ss.sssssssssssssssssssssssssssssssss 471 [M+H]+ A21 MS (ESI) m/z: 495 [M+H] + A22 h3c-nh ^=7 MS(ESl)m/z: 457 [M+H]+ A23 MS (ESI m/z: 485 [M+H]+ A24 „μ<γ·ν MS(ESI) m/z: 493 [M+H]+ A25 powder MS (ESI) m/z: 489 [M+H] + A26 Powder MS (ESI) m/z: 467 [M+H]+ 80 323135 201202230 Table 3

EXAMPLES Structural Properties, Value, etc. A27 Powder MS (APCI) m/z: 507 [M+H]+ A28 NC Touch~Λ Solid MS (APCI) m/z: 443 [M+H]+ A29 Solid MS (APCI) m/z: 503 [M+H]+ A30 F powder MS (APCI) m/z: 496 [M+H]+ A31 FF powder MS (APCI) m/z: 482 [M+H]+ A32 powder MS (APCI) m/z: 475 [M+H]+ A33 hydrochloride powder MS (APCI) m/z: 457 [M+H]+ A34 〇n^n (η3〇/^^Ο^η3 salt Acid powder MS (APCI) m/z: 475 [M+H]+ A35 h3c〇2s-^J-\J hydrochloride powder MS (APCI) m/z: 464 [M+H]+ A36 - secret Hydrochloride powder MS (APCI) m/z: 482 [M+H]+ 81 323135 201202230 Table 4

EXAMPLES Structural Properties Values A37 Hydrochloride MS (APCI) m/z: 468 ΓΜ+Η1+ A38 Powder MS (APCI) m/z: 489 [M+H]+ A39 ch3 CVO8 C»3 〇KVO-F Solid MS (APCI) m/z: 485 [M+H]+ A40 N^yN^_/ipcH3. (H3C)2N \=/ hydrochloride powder not MS (APCI) m/z: 475 fM+Hl+ A41 (h3c>2N WF hydrochloride powder MS (APCI) m/z: 493 ΓΜ+Η1+ A42 h3co2s-^ J-^-f hydrochloride MS (APCI) m/z: 482 [M+H1+ A43 n N; KHNrcH3 hw-QhQhp F hydrochloride powder MS (APCI) m/z: 500 [M+H1+ A44 Hydrochloric acid Salt powder not MS (APCI) m/z: 486 ΓΜ+Η1+ A45 H3C-NH hydrochloride powder MS (APCI) m/z: 461 FM+H1+ A46 or/〇^F〇frCH3 hydrochloride powder MS (APCI )m/z: 517ΓΜ+Η1+ 82 323135 201202230 Table 5

EXAMPLES Structural Properties Values, etc. A47 Wide N Powder MS (APCI) m/z: 461 [M+H]+ A48 n VNv_>-s ch3 HsCO.S-^Qh-QhF 1h3 F Powder MS (APCI) m/ z: 492[M+H]+ A49 H3co2s-H〇^JF F Powder MS (APCI) m/z: 514 [M+H]+ A50 powder MS (APCI) m/z: 509 [M+H]+ A51 F powder MS (APCI) m/z: 461 [M+H]+ A52 ^C)^PK>f F hydrochloride powder MS (APCI) m/z: 507 [M+H]+ A53 hydrochloride Powder MS (APCI) in/z: 505 fM+H]+ A54 (h3c)2nKIK? FF powder MS (APCI) m/z: 507 [M+H]+ A55 w-vib* (H3C)2N>-q -<>f F hydrochloride powder MS (APCI) m/z: 505 [M+H]+ 83 323135 201202230 Table 6 • Reference examples Structural properties Physical values A56 H3c F Hydrochloride powder not MS (APCI) m/z: 507 [M+H]+ A57. CKP CH3c) 2n M hydrochloride powder MS (APCI) m/z: 493 [M+H]+ A58 /-yN^_/r^cH3 h3c-nh hydrochloride powder MS (APCI) m/z: 479 [M+H]+ A59 (H3C)2N W Mf hydrochloride powder MS (APCI) m/z: 507 [M+H]+ A60 λν^-^Λ3 °K>Q h3c-nh )=^ M Hydrochloride powder MS (APCI) m/z: 493 [M+H] + A61 HjC FF hydrochloride powder MS (APCI) m/z: 507 [M+H] + A62 h; Hydrochloride powder MS (APCI) m/z: 521 [M+H]+ ch3 hydrochloride powder A63 MS (APCI) m/z: F 533 [M+H]+ 84 323135 201202230 Table 7

EXAMPLES Structural Properties Values, etc. A64 3 F Hydrochloride Powder No MS (APCI) m/z: 521 [M+H]+ A65 F Hydrochloride Powder MS (APCI) m/z: 549 [M+H] + A66 ch3 FF hydrochloride powder MS (APCI) m/z: 479 [M+H]+ A67 H>tNCK/ ai3c>2N WMFF hydrochloride powder MS (APCI) m/z: 505 [Μ+ΗΓ A68 FF hydrochloride powder MS APCI)m/z: 491 [M+H]+ A69 (C2H5)HN^ hydrochloride powder MS APCI)m/z: 505 [M+H]+ A70 HCl salt MS (APCI) m/z: 519 [M+H]+ A71 hydrochloride powder MS (APCI) m/z: 531 [M+H1+ 85 323135 201202230 Table 8

EXAMPLES Structural properties such as A72 〇n^NF hydrochloride powder MS (APCI) m/z: 519 ΓΜ+ΗΓ A73 hydrochloride powder MS (APCI) m/z: 547 [M+Hf A74 F Hydrochloride powder MS (APCI) m/z: 477 ΓΜ+Η1+ A75 〇n, n F hydrochloride powder MS (APCI) m/z: 493 [M+H]+ A76 〇n^NF Hydrochloric acid Salt powder MS (APCI) m/z: 507 {M+Hf A77 F hydrochloride powder not MS (APCI) m/z: 519 ΓΜ+ΗΓ A78 O n^n (4) X-guide^0^〇^ch3 F hydrochloric acid Salt powder MS (APCI) m/z: 507 fM+H1+ A79 0 broad N^S^JN^NF On ^^H3 hydrochloride powder MS (APCI) m/z: 535 [M+H]+ A80 H; ^ ^ FF Hydrochloride Powder MS (APCI) m/z: 465 ΓΜ+Η1+ 86 323135 201202230 Table 9

EXAMPLES Structural properties, etc. A81 (H3C) 2N μ FF hydrochloride powder MS (APCI) m/z: 507 [M+H]+ A82 ^CHr- (h3c)hn )=^ FF hydrochloride powder MS (APCI) m/z: 493 [M+H]+ A83 H>^NCH3r (〇2Η5)ΗΝ ^ ^ hydrochloride powder MS (APCI) m/z: 507 ΓΜ+ΗΓ A84 hydrochloride powder not MS (APCI) m/z: 521 ΓΜ+Hf A85 o F ό-ίί^Ηϊ Hydrochloride powder MS (APCI) m/z: 533 [Μ+ΗΓ A86 (CjHsXHjON W hydrochloride powder MS (APCI) m /z: 521 ΓΜ+ΗΓ A87 F hydrochloride powder not MS (APCI) m/z: 549 ΓΜ+Η1+ A88 FF hydrochloride powder not MS (APCI) m/z: 479 [M+H]+ A89 ο ν^·ν hydrochloride powder MS(APCI)m/z: 507 ΓΜ+Η1+ A90 〇n^-N hydrochloride powder not MS(APCI)m/z: 491 ΓΜ+Η1+ 87 323135 201202230 第ίο

EXAMPLES Structural properties and the like A91 {h3c>hn r=^ F Hydrochloride powder MS (APCI) m/z: 493 ΓΜ+Η1+ A92 0 vr^-N hydrochloride powder not MS (APCI) m/ z: 505 ΓΜ+Η1+ A93 r~\ CH3 (〇2Η5)ΗΝ^=λλ^- hydrochloride powder not MS(APCI)ra/z: 507 [M+H]+ A94 hydrochloride powder MS (APCI) m/z: 521 ΓΜ+Η1+ A95 hydrochloride powder not MS(APCI)m/z: 519 ΓΜ+Η1+ A96 , qing^0^:0^guang CH3 hydrochloride powder not MS(APCI)m/z: 521 ΓΜ+Η1+ A97 hydrochloride powder MS(APCI)m/z: 521 [Μ+Η]+ A98 hydrochloride powder not MS(APCI)m/z: 519 ΓΜ+Η1+ A99 hydrochloride powder MS (APCI )m/z: 478 ΓΜ+Η1+ 88 323135 201202230 Table 11

EXAMPLES Structural properties, etc. A100 F hydrochloride powder MS (APCI) m/z: 476 [M+H]+ A101 FF hydrochloride powder MS (APCI) m/z: 478 [M+H]+ A102 ch3f hydrochloride powder not MS (APCI) m/z: 521 [M+H]+ A103 hydrochloride powder MS (APCI) m/z: 479 fM+HH A104 hydrochloride powder MS (APCI) m/ z:477 ΓΜ+Η1+ A105 hydrochloride powder not MS(APCI) m/z:479 ΓΜ+Η1+ A106 hydrochloride powder MS(APCI) m/z:476 [M+H]+ A107 FF hydrochloride powder MS(APCI) m/z: 519 [M+H]+ 89 323135 201202230 Table 12

EXAMPLES Structural property values, etc. A108 (H3C)HN )===^ FF Hydrochloride powder MS (APCI) m/z: 505 [M+H]+ A109 FF hydrochloride powder MS (APCI) m/ z:491 [M+H]+ A110 hydrochloride powder MS (APCI) m/z: 490 [M+H]+ A111 hydrochloride powder not MS (APCI) m/z: 519 [M+H]+ A112 (H3〇2N μ MFF hydrochloride powder not MS (APCI) m/z: 493 [M+H]+ A113 FF hydrochloride powder not MS (APCI) m/z: 505 [M+H]+ A114 Province CHIT-Hydrate Powder No MS (APCI) m/z: 507 [M+H]+ A115 Powder MS (APCI)ra/z: 489 [M+H]+ 90 323135 201202230 Table 13 Example Structure Physical property values, etc. A116 read powder MS (APCI) m/z: 494 [M+H]+ A117 powder MS (APCI) m/z: 496 [M+H]+ A118 0 ν^Ν (H3C)2i^Q^ ^Nr^cH3 F Powder MS (APCI) m/z: 507 [M+H]+ A119 〇m^n FF Powder MS (APCI) m/z: 507 [M+H]+ A120 F Powder MS (APCI) m/z: 510 [M+H]+ A121 ch3, F powder MS (APCI) m/z: 496 [M+H]+ A122 solid MS (APCI) m/z: 523/525 [M+H]+ A123 F powder MS (APCI) m/z: 503 [M+H]+ A124 FF powder MS (APCI) m/z: 521 [M+H]+ 91 323135 201202230

Table 14 Example Structural property values, etc. A125 ch3 Powder MS (APCI) m/z: 489 [M+H]+ A126 Solid MS (APCI) m/z: 503 [M+H]+ A127 (h3C)2NK =^Qf Solid MS (APCI) m/z: 503 M+H]+ A128 (H3C)2N w M. Powder MS (APCI) m/z: 489 [M+H]+ A129 ch3 H>〇N' ( HaC)^ M, ^ Powder MS(APCI)m/z: 507 [M+H]+ A130 η ίΚΚ^Η3 H3C0.SOQ F Powder MS(APCI)m/z: 496 [M+H]+ A131 NC ;4Λ Solid MS (APCI) m/z: 444 [M+H]+ A132 (H3c)2N 1 Mf Powder MS (APCI) m/z: 507 [M+H]+ A133 O n^N ch3c)2n^ )L^〇V^ F Powder MS(APCl)m/z: 507 [M+H]+ 92 323135 201202230

Table 15 Example Structural property values, etc. A134 Solid MS (APCI) m/z: 509/511 [M+H]+ A135 η 〇jO~0~f Solid MS (APCI) m/z: 504 [M+ H]+ A136 Qing powder MS (APCI) m/z: 507 [M+H]+ A137 powder MS (APCI) m/z: 489 [M+H]+ A138 MS (APCI) m/z: 496 [M +H]+ A139 Η>〇-ρ Ν· (h3c)hn F powder MS(APCI)m/z: 493 [M+H]+ A140 ch3 FF powder MS(APCI)m/z: 493 [M+H ] + A141 Powder MS (APCI) m/z: 507 [M+H]+ A142 Powder MS (APCI) m/z: 543 [M+H]+ 93 323135 201202230 Table 16 will give examples of structural properties, etc. A143 solid MS (APCI) m/z: 507 [M+H]+ A144 powder MS (APCI) m/z: 528 [M+H]+ A145 viscous oil MS (APCI) m/z: 517 psl +Hf A146 solid MS (APCI) m/z: 518 [M+Hf A147 c2hs powder MS (APCI) m/z: 561 [M+H]+ Examples A148 to A166

The compound of the following Tables 17 to 19 was obtained by treating the corresponding starting compound in the same manner as in Example A2. 94 323135 201202230

Table 17 Example Structural property values, etc. A148 Trifluoroacetate powder MS (ESI) m/z: 472 fM + ΗΓ A149 H3C02SY^ N0N ^a0rrCF3 Trifluoroacetate viscous oil MS (ESI) m/z :52B [M+H]+ A150 〇·〇0 Trifluoroacetate MS (ESI) m/z: 520 [M+H]+ A151 ο Ν^Ν Trifluoroacetate viscous oil MS (ESI) m/z: 490 [M+H]+ A152 powder MS (ESI) m/z: 458 [M+H] + A153 .3: r 〇〇 trifluoroacetate viscous oil MS (ESI) m/ z:467 [M+H]+ A154 Trifluoroacetate viscous oil MS (ESI) m/z: 475 [M+H]+ A155 0 (Η3〇)2νΛ〇.Γ1 OCR Trifluoroacetate Sticky Oil MS (ESI) m/z: 499 [M+H]+ 95 323135 201202230 Table 18

EXAMPLES Structural properties, etc. A156 h3c〇2s-^-Q Trifluoroacetate viscous oil MS (ESI) m/z: 497 [M+H]屮A157 NryNf>〇^〇h3co2shQ-^ Acetate viscous oil MS (ESI) m / z: 474 [M + H] + A158 hydrochloride powder MSCESI) m / z: 475 [M + H] + A159 (Nh = mj hydrochloride powder MS (ESI)ra/z: 471 ΓΜ+ΗΙ+ A160 n fK>〇h3cozsh[JmQ MS(ESI)m/z:482 [M+H]+ A161 η ίΚΗΆ WshQ-Qhf Powder MS (APCI) m/ z:496 [M+H]+ A162 Order 3 From ~〇Ρόη 0 Powder MS(APCI)m/2:487 [M+H]+ r\_ /-\ N VnwN-^ U Solid A163 MS (APCI m/z: 469 Η3^-〇-〇[M+H]+ 96 323135 201202230 Table 19 Example Structural property values A164 (H3c) 2/vTM hydrochloride powder MS (APCI) m/ z: 475 [M+H]+ A165 威 NFF powder MS (APCI) m/z: 489 [M+H]+ A166 (H3C)2N Μ ^ F Powder MS (APCI) m/z: 507 [M+H ]+

Examples A167 to A174 The compounds of the following Table 20 were obtained by treating the corresponding starting compounds in the same manner as in Example A4.

97 323135 201202230

Example 20 Structural property value, etc. A167 ch3 Nf»HCH3 °K>Q (H3C)2N x=/ Powder MS (ESI) m/z: 449 [M+H]+ A168 H3C〇2Sy^ N^N MS (ESI) m / z: 476 [ Μ ΗΓ 169 169 169 169 169 169 169 169 169 169 169 169 506 506 506 506 506 506 506 506 506 506 506 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 公478 [M+H]+ A171 H3C02S%^\ n*^n MS(ESl)m/z:468 [M+H]+ A172 广 N Powder MS(APCI)m/z:456 [M+H]+ A173 Hydrochloride powder MS (APCI) m/z: 467 [M+H]+ A174 o (H3C>2N human 〆, N~ :) αόίαχτ3 Powder MS (APCI) m/z: 535 [M+Hf 98 323135 201202230 Examples A175 to A187 The compounds described in the following Tables 21 to 22 were obtained by treating the corresponding starting compounds in the same manner as in Example A5.

99 323135 201202230 Table 21

EXAMPLES Structural Properties and the like. A175 MS (ESI) m/z: 478 [M+H] + A176 MS (ESI) m/z: 478 [M+H] + A177 H3C〇2Sy^ N^N MS (ESI )m/z:478 [M+H]+ A178 H3C〇2S&gt;^\ n^n Sya0£iCH3 MS(ESI)m/z:475 [M+H]+ A179 Chat 4丫1 N 公N ^ya0xx0CH3 MS (ESI) m/z: 495 [M+H] + A </ s </ s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s : 503 [M+H]+ A182 F^Wa0xxF hydrochloride powder MS (APCI) m/z: 489 [M+H]+ 100 323135 201202230 Table 22 Example Structural properties 箄A183 (H3Q2NOC>^\ Powder MS (APCI) m/z: 471 [M+H]+ A184 (H3C)2N〇C 1SI Male NF^6ia0xxCH3 Powder MS (APCI) m/z:503 [Μ+ΗΓ A185 Hydrochloride Powder MS (APCI) m/z: 503 [M+H]+ A186 (HaQjNOCs^. Ν^Ν 2 hydrochloride powder MS(APCI) m/z:490 [M+H]+ A187 (HsC^OC^^rs^ Ν1ίΓ&gt ;^ Powder MS (APCI) ra/z: 504 [M+H]+ Example A188

The compound of the following Table 23 was obtained by treating the corresponding starting compound in the same manner as in Example A6. Example 23 Structural Formula Property Values, etc. A188 0 ^ Vi fXxC〇j〇 Powder MS (APCI) m/z: 494 [M+Hf 101 323135 201202230 Example A189 By using the corresponding starting compound in the same manner as in Example A7 The compound described in the following Table 24 was obtained by the same treatment. Table 24 Example Structural Properties and the like ~ A189 (H3C)2NOC-^Qh-^J Difluoroacetate viscous oil MS (ESI) m/z: 460 fM+Hf • Example A190 2-Fluoro -4-[6-fluoro-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-1-yl]quinazoline-8-yl] Manufacture of _N_(3-hydroxypropyl)_N_methylbenzamide

F Ν^Ν

H3c ^nyVyVfch3 O (1) by biting 8-bromo-6-fluoro-4-[4-(3-isopropyl-[1,2,4]噚wow-5~yl)啥嗤 ( (refer to the compound obtained in Reference Example 2) 5 〇〇 mg and 4- lin | fluorophenyl meal 328 mg in a practical manner, and get 2 # # "fi # , n ^ 2 乱-4_ [6-贶-4-[4-(3-isopropyl-H, 4 purchased disyl) (tetra) + yl] (d) Lin I base] benzoic acid..., color solid 280 mg (yield 49%). 102 201202230 MS (APCI) m/z ; 480 [M+H]+ (2) 3-(methylamino)-1-propanol 23.4//L was added dropwise to the compound obtained in the above (1) 50 mg 47.4 mg of 1-ethyl-3-(3-didecylaminopropyl)carbodiimide hydrochloride and 1-3.4 mg of benzotriazole in 33.4 mg of chloroform in 1.3 mL of the mixture The mixture was stirred overnight, and water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and brine, dried over magnesium sulfate and filtered. The residue obtained was purified by NH-矽 rubber column chromatography® (Chromatorex; Fuji SILYSIA chemistry, solvent: hexane/acetic acid ethyl acetate = 60/40-10/90). 6 mg (yield 44%) 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,N-dimercaptophenylhydrazine Amine

(1) Add sulfite chloride 29.8#L to Bu [8-(4-didecylamine decyl-2-fluorophenyl)-6-gas 0 sitin-4-yl]] brigade bite -4-acidification 90 mg of 103 323135 201202230 In a chloroform 900 yL solution, the mixture was stirred at 65 ° C for 1 hour. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure to give the corresponding acid chloride as a yellow solid. To the solution of L-valerol (L-Valinol) 52.7 mg of chloroform solution, 4 mL was added dropwise to the acid vaporized chloroform 900 / L solution for 20 minutes. After the mixture was disturbed for 2 hours, water was added and 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 residue obtained was purified by NH--------------- 1-Hydroxymercapto-2-methylpropyl-1-[8-(4-didecylaminoindolyl-2-phenyl)-6-indole. Sesin-4-yl] acridine-4-carboxamide is a colorless solid of 47. 8 mg (the rate is 45%). Omg and triphenylphosphine were added to the compound of the above (1). The compound obtained by the above (1) was added dropwise to the compound (1). 58. 6 mg of dichlorodecane 5. 6 mL of solution 'The mixture was stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with a dioxane. 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 residue was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted ). MS (APCI) m/z; 508 [M+H] + 〇 Example A192 3-fluoro-4-[6-fluoro-4-[4-[3-(2-methoxyethyl)-[1 Manufacture of 2,4]oxadiazol-5-yl]piperidin-1-yl]quinazoline-8-yl]_N,N-dimethylbenzamide 104 323135 201202230

(1) 23.6 eL of isobutyl methacrylate was added dropwise to l-[8-(4-dimethylaminomethylidene-2-fluorophenyl)-6-fluoroquinazolin-4-yl at 〇 °C 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 hour. N-hydroxy-3-methoxypropenoximeimine 21. 5 mg was added dropwise to the reaction mixture. The mixture was stirred at 120 ° C for 6 hours. Water was added to the reaction mixture to extract with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. EtOAc m. (Yield 71%). MS (APCI) m/z ; 523 [Μ+ΗΓ. The compounds of the following Table 25 were obtained by treating the corresponding starting compounds in the same manner as in Example A1. 105 323135 201202230 Table 25 Example Structural property values, etc. A193 H3CS-P^^V3 Powder MS (APCI) m/z: 482 [M+H]+ A194 Έ F Powder MS (APCI)ra/z:517 [ M+H]+ A195 Η3ς0 FF Powder MS (APCI) ni/z: 528 [M+H]+ A196 f3c Powder MS (APCI) m/z: 557 [M+H}+

Examples A197 to A198 The compounds of the following Table 26 were obtained by treating the corresponding starting compounds in the same manner as in Example A3. 106 323135 201202230 Table 26

Examples A199 to A202 The compounds described in the following Table 27 were obtained by treating the corresponding starting compounds in the same manner as in Example A190. 107 323135 201202230 Table 27 Example Structural properties Values, etc. A199 Powder MS (APCI) m/z: 537 [M+H]+ A200 FF Powder MS (APCI) m/z: 537 [M+H]+ A201 Έ F powder MS (APCI) m/z: 537 [M+H]+ A202 Έ F powder MS (APCI) m/z: 543 [M+H]+

Example B1 Fluoro-8-[3-fluoro-4-(2-decyloxyethylthio)phenyl]-4-[4-(5-isopropyl-[1,2,4]fluorene Manufacture of oxazol-3-yl)piperidin-1-yl]quinazoline

N^N

Pd(PPh3)4 GS2〇〇3 dioxane/h2o

1 mL of water, 2-[3-fluoro-4-(2-decyloxyethylthio)phenyl]-4, 4, 5, 5-tetramethyl-[1,3, 2]dioxa Boronocyclopentane (Compound obtained in Reference Example B16) 148. 6 mg, tetrakis(triphenylphosphine)le 27. 5 mg and cesium carbonate 108 323135 201202230 155 mg added to 8-bromo.fluorine_4_[4_(5-different Propyl seven 2 (tetra) disani-3-yl) fluorene + yl] sputum (the compound obtained in Reference Example B9) in a 1,4-dihydrogenated 4 mL solution, the mixture is under nitrogen atmosphere Stir at 9 °f for 16 hours. After adding water to the reaction mixture, it was extracted with ethyl acetate. The product was purified by concentrating under reduced pressure, and then purified by chromatography (Chromatorex, solvent: hexane / ethyl acetate = 95/5 to 75/25) to give the title compound as a colorless solid. (Yield: 5〇%). MS (APCI) m/z ; 526 [M+H]+.

Example B2 [2-i.-4-[6-a-4-[4-(5-#^^_[1&gt;2)4]nf^^_3. base) brigade bit + base) ketone Manufacturing

2-Fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[!,2,4]oxadiazole-3-yl)piperidin-1-yl]quinazoline-8 - benzoic acid (Compound Ref. B26) -3-(3-Dimercaptoaminopropyl) carbodiimide hydrochloride 27 mg and hydroxybenzotriazolium hydrate 19 mg of gas in 0. 9 mL of solution 'The mixture was stirred at room temperature All night. Water was added to the reaction mixture, and the mixture was extracted with a gas-like atmosphere. The organic layer was concentrated under reduced pressure, and the residue was obtained by chromatography on a NH-stone cartridge (Chromatorex, solvent: chloroform / decyl alcohol = 100/0 to 97 / 3) and gel permeation chromatography (JAIGEL- 323135 109 201202230 1H, 2H · Nippon Analytical Industry Co., Ltd., 2〇mmx600 赖, mobile phase: chloroform, flow rate 4mL/min), refined from ethyl acetate and two Crystallization was carried out on the isopropyl surface. Thus, 41 mg (yield: 80%) of the title compound was obtained as colorless solid. MS (APCI) m/z ; 549 [M+H]+. Example B3. 6-Fluoro-8-[3-fluoro-4-(2-hydroxyethylthio)phenyl]isopropyl-[1,2,4]nonane-3-yl)定~1-基]啥. Guilin's system;

Add 4N hydrochloric acid-dioxane solution 0.5 mL to 6-say-8-[3~ gas~4 [2-(tetrahydropyran-2-yloxy)ethylthio]phenyl]-4 -[4-(5~iso-diyl-[1,2,4]diosyl-3-yl)-trans- -1-yl] 啥 琳 ( (refer to the case of the lang $ compound) l 〇 9 mg of 1 In a 4 mL solution of 4-dithizone, the current character was stirred at room temperature for 1.5 hours. After adding a saturated aqueous solution of sodium hydrogencarbonate to the reaction mixture, it was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&&& The title compound was obtained as a colorless solid (yield: 86%). 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]曙二β坐-3-yl) π bottom bite-1-yl] 啥 琳 琳 323 135135 110 201202230

To the solution of the compound obtained in Example B3, 75 mg of dichlorohydrazine in a 2 mL solution was added to the mixture, and the mixture was stirred at room temperature for 40 minutes. An aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium hydrogencarbonate were added to the reaction mixture, which was extracted by gas. _ Concentrated organic layer 'The residue obtained was purified by NH-Shih Hose column chromatography (Chromatorex, solvent: hexane / ethyl acetate = 5 〇 5 〇 to o / ioo) to give the title compound as colorless powder 39 mg (yield: 49%). MS (APCI) m/z ; 544 [M+H]+. Example B5 6-Fluoro-4-[4-(5-isopropyl-[1,2,4]indole disani-3-yl)-biting-1-

The compound obtained by the reference example B9 (252 mg) and the compound obtained in Reference Example B23 (203 mg) were produced by the method of the compound of the formula (b). This was treated in the same manner as in Example B1 to give 179 mg (yield: 57%) of the title compound. MS (APCI) m/z ; 524 [M+H]+. Example B6 6-Den-4-[4-(5-isopropyl-[1,2,4]卩萼2α-s--3-yl)-α-bottom-1-yl]-8-(4 Manufacture of 曱 亚 确 确 甲基 methyl-3-methylthiophenyl) 啥 琳 111 111 323135 201202230

Add 88 mg of m-chloroperoxybenzoic acid (25% in water) to 6-fluoro-4-[4-(5-isopropyl-[1,2,4]oxadiazol-3-yl)piperidine- 1-yl]-8-(3-mercaptothio-4-mercaptothiononylphenyl) quinazoline (compound obtained in Example B5) 149 mg of a solution of trifluoroacetic acid in 6 mL Stir at room temperature for 3 hours. After a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, ethyl acetate was evaporated. The organic layer was concentrated under reduced pressure, and the residue was purified by EtOAc (EtOAc: EtOAc: EtOAc) %). 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]quinazoline Manufacture of porphyrin-8-yl]phenol hydrobromide

Add 2 mL of 25% bromic citric acid-acetic acid solution to 8-(4-benzyloxy-3-fluorophenyl)-6-fluoro-4-[4-(5-isopropyl-[1,2 , 4] oxadiazol-3-yl) ketone-1-yl] 坐 ° sitting on the compound (the compound obtained in Example B23) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. Toluene was added to the residue, and the residue was evaporated to ethyl ether. The residue was purified by ethyl acetate. MS (APCI) m/z ; 452 [M+H]+. Example B8 [2-Fluoro-4-[6-Gas-4_[4-(5-isopropyl-[1,2,4]-trans)ylpiperidin-1-yl]quinazoline-8 -Phenyl]phenoxy]acetate

Add ethyl bromoacetate 20.5 mg and potassium carbonate, 1382. lmg to 2 gas--4_[6- defeat_4-[4-(5-isopropyl-[1,2,yl) brigade bite-1- To a solution of 532 mg of dimethylformamide in 5 mL of quinazolin-8-yl]phenol (Compound obtained in Example B7), the mixture was stirred at room temperature for 16 hours. After adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified eluting eluted eluted eluted eluted eluted eluted eluted elution 380 mg (yield: 71%). MS (APCI) m/z ; 538 [M+H]+. Example B9 N-(2- -4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4]indole-2-yl-3-yl)-biting-1- Manufacture of thiophene-8-yl]phenyl)-2-ethyloxyacetamide

323135 113 201202230 ethoxylated oxime oxime 0. 68 mg and triethylamine 〇. 〇 7 mL added to 2-fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[1 , 2, 4] Π萼二吐-3-yl) Nichinin-1-yl] quinoxaline-8-yl] aniline (free compound of the compound obtained in Reference Example B46) in a solution of 110 mg of dichloromethane in 4 mL, The mixture was stirred at room temperature for 16 hours. After a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, ethyl acetate was evaporated. The organic layer was concentrated under reduced pressure, and the residue was purified eluted eluted eluted eluted eluted eluted eluted eluted Lu 83mg (edience rate: 60%). MS (APCI) m/z ; 551 [M+H]+.

Example BIO 2-[2-Fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4]indoledin-3-yl)-bran-1-yl Manufacture of quinazolin-8-yl]phenoxy]acetamide

A solution of 108 mg of the compound obtained in Example B8 in 4 mL of 2N ammonia-decanol was stirred at 50 ° C for 16 hours. The reaction mixture was concentrated, and the residue obtained was purified by silica gel column chromatography (solvent: chloroform / dec. . MS (APCI) m/z ; 509 [M+H]+. Example Bll N-[2-Fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4]oxadiazol-3-yl)piperidin-1-yl Manufacture of quinazolin-8-yl]phenyl]-2-hydroxyacetamide 114 323135 201202230

THF/MeOH

NaOH

OH

^(2-Fluoro~4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4]曙2.sodium-3-yl) °chen-1-yl]啥 — — 8- 8-yl]phenyl)-2-ethlyoxyacetamide (the compound obtained in Example B9) 75 mg of 2N sodium hydroxide 2 mL, THF 2 mL and decyl alcohol 2 mL solution were stirred at room temperature for 2 hr. To the reaction mixture, 1 OmL of an aqueous solution of 136 g of potassium dihydrogen phosphate 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 under reduced pressure, and the residue was evaporated to ethyl ether. MS (APCI) m/z ; 509 [M+H]+ ° Example B12

2~ gas-4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4]indole.sodium-3-yl)piperidin-1-yl]quinazoline- Manufacture of 8-yl]phenylacetic acid

2-degraded 4-[4-[4-(4-(4-(4-(4-(4-(4-yl)-[1,2,4]]indol-3-yl))- benzyl-1-quinazoline-8 Ethyl acetate (Compound of Reference Example b52) 750 mg of 2N sodium hydroxide 20 mL, THF 10 mL, and decyl alcohol 10 mL solution were stirred overnight at room temperature. A 2 N 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 with water and saturated brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was evaporated to dryness, mjjjjjjj MS (APCI) m/z ; 494 [M+H]+. Example B13 2-[2_Gas_4-[6_Gas_4_[4_(3_isopropyl-[1,2,4]卩琴二峻-5-yl) 辰辰 bit-1-yl]0i: 11 Scare scare *-8-yl] phenyl] ethanol manufacturing

Add 9-borabicyclo[3,3,1]decane (9-BBN) in THF 0. 5mol/L solution 0. 82mL to 6_gas_8_(3_气-4- Ethylphenyl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-1-yl] 喧 ° sitting (refer to the sample B48) 5小时。 The mixture was stirred at room temperature for 3.5 hours. After the reaction mixture was cooled to 0 ° C, a 2N aqueous solution of sodium hydroxide (0. 2 mL) and a 30% aqueous hydrogen peroxide solution was added, and the mixture was stirred at 50 ° C for 2 hours. A saturated aqueous solution of ammonium hydride was added to the reaction mixture, which was extracted with dioxane. The organic layer was concentrated, and the residue obtained was purified by silica gel column chromatography (solvent: hexane/ethyl acetate=65/35 to 20/80) to give the title compound as colorless powder 30mg (yield: 30%) . MS (APCI) m/z ; 480 [M+H]+ ° Example B14 3_[2-|L-4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4 Manufacture of 曙20 -3-yl)piperidin-1-yl]quinazolin-8-yl]phenyl]oxazolidin-2-one 116 323135 201202230

2-Chloroethyl chloroformate 32 μL and triethylamine 1〇7 as [added to 2-fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[1,2, 4] Oxazol-3-yl)

Pyridin-1-yl]quinolate-8-yl]aniline 2 hydrochloride (Compound obtained in Reference Example b46) was dissolved in 3 mL of tetrahydrofuran (3 mL), and the mixture was stirred at room temperature for 3 days. 2-Chloroacetate 32 β L was added to the reaction mixture, and the mixture was stirred at room temperature for 1 day, and then stirred at 5 ° for 5 hours. Add water to the reaction mixture towel to the second gas? Take it. 5小时时。 The organic layer was condensed, and the residue was dissolved in THF (3 mL). After adding water to the reaction mixture, it was taken freshly with dichloropurine. 6克(Yield: 86%) The colorless powder of the title compound was obtained by the mp EtOAc (EtOAc: EtOAc). MS (APCI) m/z ; 521 [M+H]+. Example B15 1 [2 Fluorine 4 [6-fluoro-4~[4~(5, isopropyl-[u'4] fluorene. Sodium-3-yl) Bite bite + base] 啥 琳 琳 | base] Phenyl] taste bite bite_2_ hole

Me O-N F

Adding 2-acetylacetic acid isocyanate 53/U and triethylamine to gas-4-[6-fluoro-4-[4-(5-iso-diyl)-based

Me nY^ A 2HCI N^N lv^Pvlu 323135 117 201202230 bitten-1-yl]hydrazin-8-yl]aniline 2 hydrochloride (Compound obtained in Reference Example B46) 160 mg in THF 3 mL suspension, The mixture was stirred at room temperature for 3 days. 2-Chloroethyl isocyanate 53 was added to the reaction mixture, and the mixture was stirred at room temperature for 1 day, and further stirred at 5 (TC for 5 hours). After adding water to the reaction mixture, it was extracted with di-methane. The organic layer was concentrated, and the obtained residue was dissolved in THF (3 mL), then 20% of sodium hydride was added to the solution, and the mixture was stirred at room temperature for 4 hours. After adding water to the reaction mixture, it was extracted with dichlorohydrazine. The organic layer was concentrated to obtain The residue was purified by a silica gel column chromatography (solvent: chloroform/methanol = 1 〇〇 / 〇 to 95/5) to give the title compound as a colorless powder 146. 5 mg (yield: 92%). MS (APCI) m/z; 520 [M+H]+. Example B16 l-[2-Fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4]噚2 Manufacture of oxazol-3-yl)piperidin-1-yl]quinazolin-8-yl]phenyl]-3-indolyl sulphonate_2_ ketone

Add 4 mg of sodium hydride to 1-[2-fluoro-4-[6-fluoro-4-[4~(5-isopropyl-[1,2,4]oxadiazol-3-yl)piperidine- 1-yl]quinazolinyl]benzene or] oxime 0 - 2-3 with (the compound obtained in Example B15) 45 mg of diammonium in 1 mL of a solution of meglumine, the mixture was stirred at room temperature 1 Minutes. Mothane 11 /zL was added to the reaction mixture, followed by stirring at room temperature for 1 hour. After adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer 323135 118 201202230 was purified by silica gel column chromatography (solvent: chloroform/methanol = 1 (10) / Q to 95/5) to give the title compound (yield: 54%). MS (APCI) m/z ; 534 [M+H]+. Example B17 l-[2-Fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[H4]oxadiazol-3-yl) brigade + base] 啥 啥 | | Manufacture of _3_(2--ylethyl) oxazolidin-2-one

Adding 35 mg of tetrabutylammonium fluoride to 1-[2-(tertiary butyl fluorenyl fluorenyloxy)ethyl]-3-(2-fluoro-4-[6-fluoro-4-[4 -(5-isopropyl-[1,2,4]卩foxazol-3-yl)piperidin-1-yl]quinazoline-8-yl]phenyl)imidazolidine-2-one (Reference) The compound obtained in Example B49 was dissolved in 3 mL of THF (3 mL). 7 mg (Yield: 85%), the title compound was obtained as a colorless powder (yield: 85%).舫 (APCI) m/z ; 564 [M+H]+ . Example B18 2-[5-[6-Fluoro-4-[4-(5-isopropyl-[1,2,4]oxadiazol-3-yl) 〇辰°定基] quinazoline-8 -Based on the manufacture of pyridin-2-yloxy]ethanol

6 mg of sodium hydride was added to 6-fluoro-8-(6-fluoropyridin-3-yl)-4-[4-119 323135 201202230

(5-isopropyl-[1,2,4]oxadiazol-3-yl)piperidine-i-yl]quinazoline (Compound obtained in Reference Example B51) 5 mg of dimethylacetamidine The mixture was stirred at room temperature for 5 minutes while the amine hydrazine was 5 mL and ethylene glycol 1 mL solution. The reaction mixture was heated at 100 ° C for 30 minutes in a microwave reactor (Initiator, manufactured by Biotage Co., Ltd.). 6 mg of sodium hydride was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes, and then further heated at 100 ° C for 1 hour in the same microwave reaction apparatus. After adding water to the reaction mixture, it was extracted with ethyl acetate. The title compound was obtained as a colorless powder (yield: 25%) (yield: 5%). MS (APCI) m/z ; 479 [M+H]+. Example B19 l-[2-Fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4]oxadiazol-3-yl) brigade-1-yl啥 啥 琳 _8 基 一 一 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^

Me 0-NF N&gt;^N HN^ Add 12 mg of sodium hydride to 8_(4-chloromethylfluorophenyl)_6-fluoro-4-[4-(5-isopropyl-[1,2,4] 5小时。 The oxazol-3-yl)piperidine _i-yl] quinazoline (reference compound B50) 95mg of pyrrolidine 2 ketone 1mL solution, the mixture was stirred at room temperature for 3.5 hours. After adding water to the reaction mixture, it was extracted with monogas methane. Lmg(Yield: The colorless powder of the compound of the title 323135 120 201202230 is obtained by the gelatinization column chromatography (solvent: gas / methanol = 1 / / to 95 / 5). 75%). MS (APCI) m/z ; 533 [M+H]+. Examples B20 to B27 By treating the corresponding starting compounds in the same manner as in Example B1, the compounds described in Table 28 below were obtained.

121 323135 201202230 Table 28

EXAMPLES Structural property values, etc. B20 Fv F a-〇CH3 H3,k&gt;8^s Powder MS (APCI) m/z: 540 [M+H]+ B21 CHj Powder MS (APCI) m/z: 475 [ M+Hf B22 powder MS (APCI) m/z: 475 [M+H]+ B23 powder MS (APCI) m/z: 542 [M+H]+ B24 powder MS (APCI) m/z: 448 [M +Hf B25 «3C NO h3c N^N ll^L^SCHs Viscous oil MS (APCI) m/z: 524 [M+H]+ B26 powder MS (APCI) m/z: 576 [M+H ]+ B27 powder MS (APCI) m/z: 555 [M+H]+ 122 323135 201202230 Examples B28 to B66 By treating the corresponding starting compound in the same manner as in Example B2, the following 29th was obtained. Table to the compound described in Table 34.

123 323135 201202230 29th table

EXAMPLES Structural Properties, Value, etc. B28 Powder MS (APCI) m/z: 577 [M+H]+ B29 Powder MS (APCI) m/z: 563 [M+H]+ B30 Powder MS (APCI) m/z : 611 [M+H]+ B31 _pH3 \ .OH ν^ν ο Powder MS(APCI)m/z: 563 [M+H]+ B32 κχρ&quot;Η Powder MS(APCI)m/z: 549 [M+ H]+ B33 powder MS (APCI) m/z: 563 [M+H]+ B34 FF rfH powder MS (APCI)ra/z: 535 [MH-H]+ B35 powder MS (APCI) m/z: 576 [M+HJ+ 124 323135 201202230 Table 30

EXAMPLES Structural properties Physical properties, etc. B36 Powder MS (APCI) m/z: 576 [M+H]+ B37 F F ΓΛ-ΟΗ h3c5?k&gt;8^. : powder MS (APCI) m/z: 563 [M+H]+ B38 FC^V〇H powder MS (APCI) m/z: 549 [M+H]+ B39 powder MS (APCI) m/z: 549 [M+Hf B40 powder MS (APCI) m/z: 563 [M+H]+ B41, powder MS (APCI) m/z: 563 [M+H]+ B42 powder MS (APCI) m/z: 577 [M+H]+ 125 323135 201202230 31st table

EXAMPLES Structural property values, etc. B43 1 F &gt; NCH3 Viscous oil MS (APCI) m/z: 567 [M+H]+ B44 No_ 〇H h3c//〇-Vn ch3 Powder MS (APCI) m /z: 549 [M+H]+ B45^ / 〇-OH h3C,K&gt;S^° ch3 Powder MS (APCI) m/z: 549 [M+H]+ B46 K-LCr0H H3CjK&gt;B^. Powder MS (APCI) m/z: 549 [M+H]+ B47 fv__^ cr0H Powder MS (APCI) m/z: 549 [M+H]+ B48 Fv F 0, /^/0H Powder MS (APCI) m/z: 563 [M+H]+ B49 powder MS (APCI) m/z: 563 [M+H]+ 126 323135 201202230 Table 32

EXAMPLES Structural Properties Value B50 Powder MS (APCI) m/z: 521 [M+H]+ B51 F FO /-^〇Η °'Ν ^ Ν-^ Powder MS (APCI) m/z: 551 [ M+H]+ B52 OH powder MS(APCI)m/z: 567 [M+H]+ B53 F FO PH3 as s^nh powder MS(APCI)m/z: 507 [M+H] 十B54 h3CPH3 o Powder MS (APCI) m/z: 627 [M+H]+ B55 y^OH powder MS (APCI) m/z: 589 [M+H]+ B56 t〇&gt;OH powder MS (APCI) m/z : 589 [M+H]+ 127 323135 201202230 Table 33

EXAMPLES Structural Properties Values, etc. B57 Powder MS (APCI) m/z: 616 [M+H]+ B58 OH Powder MS (APCI) m/z: 537 [M+H]+ B59 F FO .CH3 H3CrJtNM^_V ^N ch3 powder MS (APCI) m/z: 521 [M+H]+ B60 FF 0 CH, 〇/- i&gt;^NH h3cJ/〇vn ch3 powder MS (APCI) m/z: 507 [M+H ]+ B61 ^ / Cr0H Powder MS (APCI) m/z: 549 [M+H]+ B62 H3CJK&gt;i&gt; Powder MS (APCI) m/z: 549 [M+H]+ B63 H3C ~b N j powder MS(APCI)m/z: 576 [M+H]+ 128 323135 201202230

Examples B67 to B74 By treating the corresponding starting compounds in the same manner as in Example B3, the compound described in Table 35 below was obtained.

129 323135 201202230 Table 35

EXAMPLES Structural Properties Values, etc. B67 Powder MS (APCI) m/z: 494 [M+H]+ B68 Fy^ Fw Powder MS (APCI) m/z: 512 [M+H]+ B69 FF ΠΗ ♦w~ °NN j hydrochloride powder not MS (APCI) m/z: 548 [M+H]+ B70 FF /〇H 〇'N ^ viscous oil MS (APCI) m/z: 526 [M+H ]+ B71 Fv / S^0H Powder MS (APCI) m/z: 526 [M+H]+ B72 N·^ Powder MS (APCI) m/z: 540 [M+Hf B73 ΗΊ H viscous oil MS (APCI) m / z: 540 [Μ + ΗΓ B74 powder MS (APCI) m / z: 518 [M + H] + 130 323135 201202230 Examples B75 to B83 by the corresponding raw materials The compound was treated in the same manner as in Example B4 to give the compound described in the following Tables 36 to 37. Table 36

EXAMPLES Structural properties Physical properties, etc. B75 F F 〇CH3 powder MS (APCI) m/z: 558 [M+H]+ B76 Fv F r〇cn3 as in. Powder MS (APCI) m/z: 572 [M+H]+ B77 powder MS (APCI) m/z: 526 [M+H]+ B78 F, F, PH powder MS (APCI) m/z: 544 [ M+H]+ B79 powder MS (APCI) m/z: 599 [M+H]+ B80 Η々κ&gt;δ^ Powder MS (APCI) m/z: 558 [MfH]+ 131 323135 201202230 Table 37 implementation Example Structural Properties, etc. B81 Powder MS (APCI) m/z: 558 [M+H]+ B82 〆H Powder MS (APCI) m/z: 572 [M+H]+ B83 ff α _^οκ O 'N nj powder MS (APCI) m/z: 572 [M+Hf

Example B84 5-Fluoro-4-[4-(5-isopropyl-[1,2,4]oxadiazol-3-yl)-piperidin-1-yl]-8-(4-indenyl) Manufacture of sulfinylmethyl-3-mercaptothiophenyl)quinazoline

The title compound was obtained as a solid (yield: 39%). MS (APCI) m/z : 540 [Μ+ΗΓ . Example B85 A compound of the following Table 38 was obtained by treating the corresponding starting compound in the same manner as in Example B11. 132 323135 201202230 Table 38 Greedy Example 1 Structural Property Value Stupid 々Η85 々Η Powder MS (APCI) m/z: 496 (M+H)+ Example B86

4-[[2-Fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4]indoledin-3-yl)piperidin-1-yl] Manufacture of quinazoline-8-yl]phenylhydrazinyl]aminomethyl]benzoic acid

The title compound was obtained as a powder (yield: 65%).

MS (APCI) ηι/ζ : 613 [M+H]+ ° Example B87 l-[2-fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[1,2, 4]Manufacture of Pf oxadiazol-3-yl)piperidin-1-yl]quinazoline-8-yl]phenyl]pyrrolidine-2-one

Me Ρ·ν r:

NaH

2HQ by 'fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4]oxadiazol-3-yl)piperidine-hydrazinyl]-quinazoline 80 mg of the compound of the phenylamine 2 hydrochloride (refer to the compound obtained by 323135 133 201202230 B46) and 4-methylbutyric acid 42 were treated in the same manner as in Example B14 to give the title compound as colorless. Powder 40.4 mg (yield: 64%). MS (APCI) m/z: 519 [M+H] + &lt;&quot;&&&&&&&&&&&&&&&&&&&&&& Manufacture of oxazol-3-yl]piperidin-1-yl]-8-[3-fluoro-4-(2-o-oxetyrridin-1-yl)phenyl]

The powder of the title compound was obtained in the same manner as in Example B11 to give the title compound (yield: 90.8%). MS (APCI) m/z · 535 [M+H] + 〇 Example B89 (foot)-1-[5-[6-fluoro-4-[4-(5-isopropyl-[1,2, 4]Manufacture of oxadiazole-3-yl)piperidin-1-yl]quinazolin-8-yl]pyridin-2-yl]pyrrolidin-3-ol

Add 179 mg of carbonic acid planing to 6-fluoro-8-(6-fluoropyridin-3-yl)-4-[4-(5-isopropyl-[1,2,4]Pf-diazol-3-yl) Piperidin-1-yl]wowline (compound obtained in Reference Example B51) 8 〇mg and (r)-3-trans-base 32mg 323135 134 201202230 dimethylethanoamine 2mL solution, the mixture It was heated at 150 ° C for 1 hour in a microwave reactor (Initiator). After adding water to the reaction mixture, it was extracted with ethyl acetate. 6 mg (yield: 63%), a yellow powder of the title compound was obtained by the title compound (yield: 63%). MS (APCI) m/z ; 504 [M+H]+. Example B90 4-[4-[6-Fluoro-4-[4-(5-isopropyl-[1,2,4]sozo-β-yl-3-yl) _ 派-1-基]喧Manufacture of 嗤琳基]-3-methylphenyl]morphin-3-one

4-[6-Fluoro-4-[4-(5-isopropyl-[1,2,4]oxadiazol-3-yl)piperidin-1-yl]quinoxaline-8-yl] 2-Hydroxyaniline 2-hydrochloride (Compound obtained in Reference Example 55) i 〇 0 mg and bromoethoxime 32//l were treated in the same manner as in Example -9. 2-chloroethanol 39//L and sodium hydride 23 mg were added at -78 °C, and the mixture was stirred at room temperature for 2 hr. 23 mg of sodium hydride was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, which was extracted with acetic acid, and the organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (by solvent chromatography: solvent:methanol/methanol = 1 〇〇 / 〇至94/6) Refining 2 times' to give the title compound as a colorless powder 33. lmg (received 135 323135 201202230 rate: 35%). MS (APCI) m/z; 531 [Μ+Η]+ 〇Example Β91 4-ethyl-1-[2-fluoro-4-[6-fluoro-4-[4-(5-isopropyl)- [ι,2,4] oxadiazol-3-yl)piperidin-1-yl]quinazoline-8-yl; Iphenyl]piperidine-2-one

Add 峨乙烧43/zL and ethyldiisopropylamine ii5eL to 1-[2-fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[1,2, 4 Oxadiazol-3-yl)pyr-1-1-yl]quinazoline-8-yl]phenyl]pyridin-2-one (compound obtained in Example B94) 2 hydrochloride 6 mg acetonitrile 2 mL Suspension The mixture was heated in a microwave reaction apparatus (Initiator) at i2 ° C for 4 hours. The reaction mixture was sequentially subjected to silica gel column chromatography (solvent: chloroform / decyl alcohol = 100/0 to 93/7) and NH EtOAc (Chromatorex, solvent: hexane / ethyl acetate = 40 / 6 mg (yield: 10%). The colorless powder of the title compound was obtained. MS (APCI) m/z: 562 [M+H] + Example B92 [4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4]oxadiazole] Manufacture of 3_yl)piperidin-1-yl]quinazolin-8-yl]-2-methylindolyl]_3_(2-transethylethyl)imidazolidine-2-one 323135 136 201202230

By [4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4]oxadiazol-3-yl)piperidin-1-yl]quinazolinyl ]_2_Methylphenyl]imidazolidine-2-one (Compound obtained in Reference Example B57) 100 mg and 2-(tris-butyldi-nonyl-fluorenylfluorenyloxy)ethyl 125"L as in Example B16 The obtained crude product was treated in the same manner as in Example B17 to give the title compound (yield: 26%). MS (APCI) m/z: 560 [M+H]+ Example B93 l-[2-Fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4]oxadiazol-3-yl) Manufacture of piperidin-1-yl]quinazolin-8-yl]phenyl]-3-(3-hydroxypropyl)imidazolidine-2-one

Azoxazol-3-yl)piperidine-1-yl]quinazolin-8-yl]phenyl]imidazole (a compound obtained in Example B15) 10 mg and 2-(3-bromopropoxy) And the colorless powder of the title compound was obtained in the same manner as in Example B3, and the title compound was obtained as a colorless powder 46. 9 mg. (Yield: 42%). MS (APCI) m/z: 578 [M+H] + </RTI> Example B94 l-[2-fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[1,2, 4]曙二0坐-3-基)Bottom bite-1 _基]喧°坐琳-8-yl]phenyl]Pan 哄~2- ketone manufacture

Di-acetic acid 21111 (added to 4_[2- gas-4-[6-gas-4-[4-(5-isopropyl-[1,2,4]oxadiazol-3-yl)) Ding-1-yl] quinazoline-8-yl]phenyl]-3-oxooxypiperin-1-carboxylic acid tert-butyl ester (compound obtained in Reference Example B54) 420 mg of dioxin 2 mL solution The mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated, and the residue was dissolved in 3 mL of dichloromethane and 3 mL of ethanol, and then 4N hydrochloric acid-dibenzoate was added and stirred overnight. 5重量。 The title compound decanoate 350. 7mg. 2 mL of dichloromethane (0 mL) and triethylamine 0.5 ml were added to the compound (2 hydrochloride), and the mixture was stirred for 10 minutes. _ ^ The reaction mixture was sequentially subjected to silica gel column chromatography (solvent: chloroform) 6mg (methanol = 1 〇〇 / () to 91 / 9) and NH-gelatin chromatography (Chromatorex 'solvent: chloroform / methanol = 100 / 0 to 97 / 3) to give the title compound of the colorless 7. 6mg ( Yield: 73%). 323135 138 201202230 MS (APCI) m/z : 534 [M+H]+. Example B95 (R)-l-[4-[4-[4-(5-Cyclopropyl-[1,2,4]oxadiazol-3-yl)piperidin-1-yl]-5- Manufacture of fluoroquinazolin-8-yl]-2-fluorophenyl]-4-hydroxypyrrolidin-2-one 1) PdCI2(dppf)-CH2Cl2 CS2CO3

8-Desc-4-[4-(5-Cyclopropyl-[1,2,4]oxadiazol-3-yl)piperidinyl-pyridyl-5-fluoroindole (refer to Example B119) Compound) 96. 2 mg, (R)-4-(tertiary butyldidecylfluorenyloxy)-bu [2_fluoro_4_(4, 4, 5, 5_ tetramethyl-[1,3 , 2] dioxaborolan-2-yl)phenyl]pyrrolidin-2-one (compound obtained in Reference Example B86) 12〇.6 mg, [M,_bis(diphenylphosphino)di Ferrocene] palladium (II) dichloride-dichloromethane complex 9.4 mg and anaerobic I87 mg of 1,4-dioxin/water (3.6 mL / 0.4 mL) solution under nitrogen atmosphere at 9 After the reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. It will be refined by NH-Shixi gum column chromatography (chrome tor ex, solvent: hexane/ethyl acetate: 80/20 to 55/45). The title compound was obtained (yield: 67.7%) (yield: 67.7%). 323135 139 201202230 MS (APCI) m/z; 533 [M+H]+ = Example B96 [4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4]卩萼2 Manufacture of piperidin-1-yl]quinazolin-8-yl]-2-mercapto]hydroxypropyl)imidazolidine-2-one 1

Me Me 〇

Me

-3-yl)piperidin-1-yl]quinazoline (Compound Ref. 9) 15 和 and 1-[2-mercapto-4-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-phenyl]-3-[3-(tetrahydropyran-2-yloxy)propyl]imidazolidin-2- The ketone of 190 mg was treated in the same manner as in Example </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; MS (APCI) m/z: 574 [M+H] + 〇 Example B97 3-[2-fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[1,2, Manufacture of 4]oxadiazol-3-yl)piperidin-1-yl]quinazoline-8-yl]phenyl]imidazolidinyl-4-one ketone 140 323135 201202230

1) PdCI2 (dpp〇-CH2Cl2 CS2CO3 dioxane/h2o

8-Bromo-6-fluoro-4-[4-(5-isopropyl-[1,2,4]dioxins__3-)piperidin-1-yl]quinazoline (Reference example) Compound obtained by B9) 21〇,

1-(2,4-Dimethoxybenzyl)-3-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3, 2]dioxaboron Cyclopentan-2-yl) phenyl] imidazolium _4__ steel (compound obtained in Reference Example B146) 342 mg, [1, Γ-bis(diphenylphosphino)]

Iron]Palladium(II) dichloride-dichloromethane complex 20.40 mg and carbonic acid 407 mg of a 1,4-dioxane/water (9 mL/lmL) solution was stirred under nitrogen for 1 hour. After the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed, prepared, and dried in the order of water and saturated brine, and filtered after drying with acid i-magnesium. The filtrate is concentrated under reduced pressure and will be obtained? |丨 J &lt; The residue was purified by NH-矽 rubber column chromatography (Chromatorex, solvent: hexane/this/ethyl acetate 68/32 to 41/59). After adding a fluoroacetic acid hydrogen hydride solution to the reaction mixture, the obtained crude product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 &amp; US (APCI) m/z ; 520 [M+H]+ 0

3 mL, the mixture was stirred at room temperature for 22 hours. Addition of saturated example B98 323135 141 201202230 1-[2-Fluoro-4-[6-fluoro-4-[4-[5-(1-pyridyl-1-fluorenylethyl)-[1,2,4 Π%二α坐-3-基]旅咬-1-基]啥°坐淋-8*'基]Phenyl]_3_ (2-ylethyl) imipenone-2-_

1-[3-[1-(8-Deep-6-fluoroindol-4-yl) π-acetate-]-[1,2,4]曙disin-5-yl]-1 - mercaptoacetic acid (compound obtained by reference to Blog) 95. 7 mg, 1-[2-(tertiary butyl dimethyl fluorenyloxy)ethyl]-3-[2-fluoro-4-( 4, 4, 5, 5-tetramethyl-[1,3, 2]dioxaborolane-2-yl)phenyl] sigma-d-butan-2-one (refer to Example B81) Compound) 112 mg, [1,1'-bis(diphenylphosphino)ferrocene]palladium (11) dichloride-one gas sputum compound complex 8. 2 mg and cesium carbonate 163 mg of 1, 4- 1⁄4 烧/水(3. 6mL / 0. 4mL) solution was stirred at 9 (TC for 3.5 hours under nitrogen atmosphere. After the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The order of the saturated brine was washed, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was chromatographed on a NH-purine column chromatography (Chromatorex' solvent: hexane/ethyl acetate: 72/ 28 to 50/50) Refining: The obtained crude product was treated in the same manner as in Example B11 to give 1-[2-(tris-butyldidecylfluorenyloxy)ethyl; _3_ [2- -4-(6-fluoro-4-{4-[5-(1-hydroxy-didecylethyl 2, 4] 142 323135 201202230 oxadiazole-3-yl]piperidine-1-yl}quinazoline- 4- (1) phenyl]imidazolidin-2-one 81.4 mg (yield: 58.7 %) and the title compound as a colorless solid, 18.3 mg (yield: 15.8%) MS (APCI) m/ z ; 533 [M+H]+ ° Example B99 [4-[4-[4-(5-cyclopropyl-[1,2,4]oxadiazol-3-yl)piperidine-1] Manufacture of 啥 啥 啥 -8 -8-8-yl]-2-fluorophenyl] π

Adding 4-chlorobutyric acid 51//L and triethylamine 84eL to 4-[4-[4-(5-cyclopropyl-[1,2,4]oxadiazol-3-yl) Piperridin-1-yl]-6-fluoroindol-8-yl]-2-fluoroaniline (Compound obtained in Reference Example B130) 67 mg of tetrahydrofuran 1. 5 mL of suspension. The mixture was stirred at room temperature for 15 hours. 5小时。 The reaction mixture was added to a solution of 4 mg of tetrabutylammonium bromide, 6N sodium hydroxide, and stirred at room temperature for 22.5 hours. Water was added to the reaction mixture and extracted with a gas pattern. The organic layer was concentrated to give the residue as a colorless powder of the title compound (H.sub.2). 6l.7mg (yield: 79 9 %) 〇MS (APCI) m/z; 517 [M+H]+〇Example B100 l-[2-Fluoro-4-[6-fluoro-4-[4- [5-U-fluoro-1-indolylethyl)-[1,2,4]indole, etc. Diazol-3-yl]piperidine-yl-yl]quinazoline-8-yl]phenyl]pyrrole 143 323135 201202230 Manufacture of pyridine-2-one

Add DAST 18. 5/zL to 1-[2-fluoro-4-[6-fluoro-4-[4-[5-(i-hydroxy-l-methylethyl)-[1,2] under ice cooling , 4]oxadiazol-3-yl]piperidin-1-yl]indole-8-yl]phenyl]pyrazine-2-one (compound obtained in Example B88) 67 mg of dichloromethane In a 7 mL solution, stir at 0 to 5 ° C for 2 hours. A saturated aqueous solution of sodium cesium carbonate was added to the mixture and extracted with chloroform. The organic layer was concentrated, and the residue obtained was sequentially subjected to NH-purine column chromatography (Chromatorex 'solvent: hexane/ethyl acetate: 67/33 to 33/67) and reverse phase HPLC [column: CAPCELL PAK C18 MG, 5//m '20mmx50mm, Shiseido; mobile phase A: decyl alcohol; mobile phase B: 1 OmM aqueous ammonium carbonate solution, flow rate 40mL/min (mobile phase B60%-&gt; 75%/5 minutes)] refined The yield of the title compound was 15.1 mg (yield: 40. 1%). Called MS (APCI) m/z; 537 [Μ+ΗΓ. EXAMPLES ΒΙΟΙ 1-[2-Fluoro-4-[6-fluoro-4-[4-[5-(1-fluoro-1-methylethyl)_[1,2,4]oxadiazole-3 -yl]piperidin-1-yl]quinazolin-8-yl]phenyl]-3-(2-ylethylethyl)pyrene. Manufacturing

Add DAST 30.8/zL to Bu [2-(tert-butyl butyl 144 323135 201202230) under ice cooling

Indolyl methoxy)ethyl]-3-[2-fluoro-4-[6-fluoro-4-[4-[5-(l-hydroxy-1-methylethyl)-[1,2 4]oxadiazol-3-yl]piperidin-1 -yl]quinazolin-8-yl]phenyl]imidazin-2-one 81. 4 mg (compound obtained in example B98) 81 mg of dichloro In a solution of decane i. 2 mL, the mixture was stirred at 0 to 5 C for 40 minutes. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, which was extracted with chloroform. The organic layer was concentrated, and the residue obtained was purified by ethylamine chromatography (chrome, hexane/ethyl acetate: 76/24 to 55/45). The obtained crude product was treated in the same manner as in Example B17 by reverse phase HPLC [column: CAPCELL PAK C18 MG, 5 // m ' 20 mm x 50 mm, Shiseido; mobile phase A: decyl alcohol; mobile phase B : 10 mM ammonium carbonate aqueous solution 'flow rate 4 〇 mL / min (mobile phase B 60% - 75%)] purified to give the title compound as a colorless powder 34 mg (yield: 50.1%). MS (APCI) m/z; 582 [M+H] + &lt;&quot;&&&&&&&&&&&&&&&&& Manufacture of 2,4]oxadiazol-3-yl)piperidin-1-yl]quinazolin-8-yl]phenyl]isoxamid-4-one

Add acetaldehyde 7.9 / / L, acetic acid 6eL and triacetoxy boron IL 29.7mg to 3-[2- gas-4-[6-fluoro~4-[4-(5-) Isopropyl-[1,2,4]oxadiazol-3-yl)piperidin-1-yl]quinazolin-8-yl]phenyl]imidazin-4-one 81. 4 mg (Example B97 The obtained compound) 36. 4 mg of 145 323 135 201202230 chloroethene in 1 · 4 mg of solution 'The mixture was stirred at room temperature for $hour. Further, acetaldehyde 7.9/zL and sodium triethoxysulfonium hydride 29.7 mg' were added to the reaction mixture for 19 hours at room temperature. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and extracted with chloroform. The organic layer was concentrated, and the residue obtained was purified by silica gel column chromatography (solvent: chloroform / decyl alcohol: 1 〇〇 / 〇 to 97 / 3) to give the title compound as a colorless powder (21. .5%). MS (APCI) m/z ; 548 [M+H]+. Example B103 _ 3-[2-Fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[!,2,4]oxadiazol-3-yl]-biting-1- Manufacture of phenyl]-8-yl)phenyl]-bu (2-cyanoethyl) 0-oxazolidin-4-one

Add (tri-tert-butyl fluorenyl oxetyloxy) ethylbenzene 69# [, • 11 eL of acetic acid and 5 gmg of sodium ethoxide hydride to 3-[2-fluoro-4-[ 6-fluoro-4-[4-(5-isopropyl-[1,2,4]oxadiazol-3-yl)piperidin-1-yl] 啥 琳 -8-8-yl] benzyl] σ 81.4 mg of rice ketone (the compound obtained in Example B97) 47.5 mg of dioxane i. 8 mg solution, the mixture was stirred at room temperature for 18.5 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was evaporated. The organic layer was concentrated, and the residue obtained was purified by silica gel column chromatography (solvent: chloroform/methanol: 100/0 to 97/3). The resulting crude product was treated in the same manner as in Example B17: β 323 135 146 201202230 to a colorless powder of title compound 14.3 mg (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]nonane-3-yl--- 1-based] 喧Junlin-8-yl]phenyl]tetrahydrofuran. Manufacture of 1,4-ketone

Add 14 mL of trifluoroacetic acid to 1-(2,4-dimethoxyanthracene)-3-[2-fluoro-4-[6-gas-4-[4-(5-isopropyl-[ 1, 2, 4] 曙2°--3-yl)oxaridin-1-yl]quinazolin-8-yl]phenyl]tetrahydropyrimidin-4-one (Compound B158) 278 In 8 mg, the mixture was stirred at room temperature for 5 hours. After adding a saturated aqueous solution of sodium bismuth carbonate to the reaction mixture, it was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and evaporated. The residue obtained 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 the title compound (102) to give the title compound (yield: 5.6%). MS (APCI) m/z ; 562 [M+H]+. Examples B105 to 138 The compounds described in the following Tables 39 to 43 were obtained by treating the corresponding starting compounds in the same manner as in Example B1. 147 323135 201202230 Table 39

EXAMPLES Structural Properties Values, etc. B105 Powder MS (APCI) m/z: 497 [M+H]+ B106 Powder MS (APCI) m/z: 515 [M+H]+ B107 Powder MS (APCI) m/z : 513 [M+H]+ B108 ♦妒Nb Powder MS(APCI)m/z: 515 |M+H]+ B109 Powder MS(APCI)m/z: 515 [M+H]+ B110 Powder MS (APCI ) m/z: 513 [M+H]+ Bill Powder MS (APCI) m/z: 541 [M+H]+ B112 ^K&gt;^Nb Powder MS (APC〇m/z: 515 [M+H] + 148 323135 201202230 Table 40

EXAMPLES Structural Properties Values, etc. B113 Powder MS (APCI) m/z: 515 [M+H]+ B114 Powder MS (APCI) m/z: 515 [M+H]+ B115 Powder MS (APCI) m/z : 513 [M+H]+ B116 ch3 powder MS (APCI) m/z: 515 [M+H]+ B117 powder MS (APCI) m/z: 515 [M+H]+ B118 powder MS (APCI) m /z: 513 [M+H]+ B119 powder MS (APCI) m/z: 515 [M+H]+ B120 powder MS (APCI) m/z: 541 [M+H]+ 149 323135 201202230 Table 41

EXAMPLES Structural property values, etc. B121 H3C~hKK&gt; Powder MS (APCI) m/z: 515 [M+Hf B122 powder MS (APCI) m/z: 515 [M+H]+ B123 N. 〇 powder MS ( APCI)m/z: 515 [M+Hf B124 H3C^-Cn powder MS (APCI) m/z: 497 [M+H]4 B125 ΗϊΟγ^Ν N j ch3 powder MS (APCI) m/z: 497 [ M+H]+ B126 Powder MS (APCI) m/z: 527 [M+H]+ B127 °'N ^ N j Powder MS (APCI) m/z: 577 [M+H]+ B128 Powder MS (APCI )m/z: 562 [M+H]+ 150 323135 201202230 Table 42

EXAMPLES Structural Properties Values, etc. BI29 Powder MS (APCI) m/z: 501 [M+H]+ B130 Powder MS (APCI) m/z: 434 [M+H]+ B131 Powder MS (APCI) m/z : 523 [M+H]+ B132 CH3 0 Powder MS(APCI)m/z: 523 [M+H]+ B133 η3°^ν«Ν )==0-^3⁄4^0 CH3 Powder MS(APCI)m /z: 565 [M+Hf B134 powder MS (APCI) m/z: 526 [M+Hf B135 powder MS (APCI) m/z: 497 [M+H]+ B136 妒b powder MS (APCI) m /z: 502 [M+H]+ 151 323135 201202230 Table 43 Example B137 Structural physical property values, etc. Powder MS (APCI) m/z: 523 [M+H]+ B138 Powder MS (APCI) m/z: 561 [M+H]+

Examples B139 to B176 By treating the corresponding starting compounds in the same manner as in Example B2, the compounds described in Tables 44 to 48 below were obtained.

152 323135 201202230 Table 44

EXAMPLES Structural Properties Values, etc. B139 Powder MS (APCI) m/z: 535 [M+H]+ B140 FF Ο ^〇H Powder MS (APCI) m/z: 549 [M+H]+ B141 fl f 1 , 〇H powder MS (APCI) m/z: 549 [M+H]+ B142 Fv F ov ~OH powder MS (APCI) m/z: 561 [M+H]+ B143 F Cr0H powder MS (APCI) m /z: 575 [M+H]+ B144 ,F〇_^H Powder MS(APCI)m/z: 537 [M+H]+ B145 Powder MS(APCI)m/z: 551 [M+H]+ B146 F FO ^〇H Powder MS (APCI) m/z: 551 [M+H]+ 153 323135 201202230 Table 45

EXAMPLES Structural Properties, etc. B147 FF 粉末 Powder MS (APCI) m/z: 563 [M+H]+ B148 Powder MS (APCI) m/z: 590 [M+H]+ B149 F. F 〇, / ^〇H Powder MS (APCI) m/z: 603 [M+H]+ B150 Fv_ F\_ WH ^^Nar Powder MS (APCI) m/z: 563 [M+H]+ B151 H3Q PH powder MS ( APCI)m/z: 551 [M+H]+ B152 F. F 0 CH3 &quot;3 Powder MS (APCI) m/z: 521 [M+H]+ B153 Powder MS (APCI) m/z: 602 [ M+H]+ B154 Fv Fv 〇^〇H Η,:κ&gt;δ^&quot;tH3 Powder MS(APCI)m/z: 551 [M+H]+ 154 323135 201202230 Table 46

EXAMPLES Structural property values, etc. B155 F&gt;_ N.〇_ p&lt;y^ Powder MS (APCI) m/z: 591 [M+H]+ B156 Powder MS (APCI) m/z: 584 [M+H ]+ B157 Powder MS (APCI) m/z: 630 [M+H]+ B158 \ / 〇''OH Ρ3ΪΚ&gt;Β^. Powder MS (APCI) m/z: 575 [M+H]+ B159 F, F \ V〇H powder MS (APCI) m/z: 589 [M+H]+ B160 fc^h^&gt;^0H 3ίΚ&gt ;^ Powder MS (APCI) m/z: 589 [M+H]+ B161 / Q /^0H FC ^ F^d^NCr Powder MS (APCI) m/z: 589 [M+H]+ 155 323135 201202230 Table 47

EXAMPLES Structural Properties Values, etc. B162 Powder MS (APCI) m/z: 575 [M+H]+ B163 FC^ 3iK&gt;U Powder MS (APCI) m/z: 602 [M+H]+ B164 F OH ° ° Powder MS (APCI) m/z: 618 [M+H]+ B165 OH F\_ r~&lt; N-^N powder MS (APCI) m/z: 577 [M+Hf B166 F OH Nd1, ϋ Powder MS (APCI) m/z: 600 [M+H]+ BI67 OH ° Powder MS (APCI) m/z: 600 [M+H]+ B168 OH °W&gt;^o^NH2 N-^ ° 〇 powder MS (APCI) m/z: 618 [M+H]+ B169 F3CiK&gt;H^ Powder MS (APCI) m/z: 580 [M+HJ+ 156 323135 201202230 Table 48

EXAMPLES Structural Properties, etc. B170 cH3rr〇H Powder MS (APCI) m/z: 571 [M+H]+ B171 HO Powder MS (APCI) m/z: 574 [M+H]+ B172 Powder MS (APCI m/z: 549 [M+H]+ B173 powder MS (APCI) in/z: 576 [M+H]+ B174 ^:^0H powder MS (APCI) m/z: 571 [M+H] B175 powder MS (APCI) m/z: 598 [M+H]+ B176 HO powder MS (APCI) m/z: 596 [M+H]+ 157 323135 201202230 Examples B177 to B251 by the corresponding starting compounds The compound described in the following Tables 49 to 58 was obtained in the same manner as in Example B95.

158 323135 201202230第49表

EXAMPLES Structural properties Physical properties, etc. B177 HC _ ^ Powder MS (APCI) m/z: 564 [M+H]+ B178 H3CjK&gt;^ Powder MS (APCI) m/z: 564 [M+H]+ B179~. η powder MS(APCl)m/z: 564 [M+H]+ B180 :^0:^03⁄4 ~- Powder MS (APCI) m/z: 564 [M+H]+ B181 〜.粉末 Powder MS (APCI) m/z: 564 [M+H]+ B182 CH3 Powder MS (APCI) m/z: 535 [M+H]+ B183 F3jK&gt;B^&quot;nJ Powder MS (APCI) m/ z: 604 [M+H]+ B184 Ρ3?^Λ _p^·heart~ Powder MS(APCI)m/z: 590 [M+H]+ 159 323135 201202230

Table 50 Example Structure Structural property value, etc. B185 ~. Η Powder MS (APCI) m/z: 546 [M+H]+ B186 Post~.粉末 Powder MS (APCI) m/z: 564 [M+H]+ B187 〜. Η Powder MS (APCI) m/z: 562 [M+H]+ B188 ~. Η Ν '—^ N· Powder MS (APCI) m/z: 564 [M+H]+ B189 H^〇F^O^h Powder MS (APCI) m/z: 535 [M+H]+ B190 powder MS (APCI) m/z: 535 [M+H]+ B191 powder MS (APCI) m/z: 535 [M+H]+ B192 powder MS (APCI) m/z: 578 [M+H]+ B193 Powder MS (APCI) m/z: 517 [M+H] + 160 323135 201202230 Example 51 Structural Formula Structural Values, etc. B194 Powder MS (APCI) m/z: 561 [M+H]+ B195 Η3. ~ Powder MS (APCI) m/z: 535 [M+H]+ B196 H3C^k&gt;8^&quot;n, °h Powder MS (APCI) m/z: 535 [M+H]+ B197 H3C^^ N_^^Nbs〇H Powder MS (APCI) m/z: 535 [M+H]+ B198 powder MS (APCI) m/z: 533 [M+H]+ B199~. H powder MS (APCI) m/z: 546 [M+H]+ B200 powder MS (APCI) m/z: 551 [M+H]+ B201, 0H powder MS (APCI) m/z: 535 [M+ H]+ 161 323135 201202230 Table 52

EXAMPLES Structural Properties Values, etc. B202 Powder MS (APCI) m/z: 535 [M+H]+ B203 Powder MS (APCI) m/z: 533 [M+H]+ B204 Powder MS (APCI) m/z : 535 [M+Hf B205 Powder MS (APCI) m/z: 533 [M+H]+ B206 Powder MS (APCI) m/z: 572 [M+H]+ B207 射 A t)H Powder MS (APCI ) m/z: 517 [M+Hf B208 F3C^K&gt;i&gt; Powder MS (APCI) m/z: 561 [M+H]+ B209 H,~·^^- Powder MS (APCI) m/z : 535 [M+H]+ 162 323135 201202230 Table 53

EXAMPLES Structural Properties Values, etc. B210 Powder MS (APCI) m/z: 517 [M+H]+ B211 Powder MS (APCI) m/z: 533 [M+H]+ B212 ΗΟ-^ Powder MS (APCI) m/z: 549 [M+H]+ B213 bn powder MS (APCI) m/z: 515 [M+H]+ B214 MS (APCI) m/z: 543 [M+H]+ B215 bH powder MS ( APCI)m/z: 543 [M+H]+ B216 , 0H powder MS (APCI) m/z: 543 [M+H]+ B217 powder MS (APCI) m/z: 515 [M+H]+ 163 323135 201202230 Table 54

EXAMPLES Structural Properties Values, etc. B218 Powder MS (APCI) m/z: 575 [M+H]+ B219 OH Powder MS (APCI) m/z: 553 [M+H]+ B220 Powder MS (APCI) m/ z: 531 [M+H]+ B221 powder MS (APCI) m/z: 531 [M+H]+ B222 end MS (APCI) m/z: 572 [M+H]+ B223 η%·〇8 ^&quot;ν, Powder MS (APCI)ra/z: 539 [M+H]+ B224 Powder MS (APCI) m/z: 568 [M+H]+ B225 Η ΐ/Ό, Ν_/ 0 Powder MS ( APCI) ni/z: 578 [M+H]+ 164 323135 201202230 Table 55

EXAMPLES Structural Properties Values, etc. B226 Powder MS (APCI) m/z: 561 [M+H]+ B227 Powder MS (APCI) m/z: 549 [M+H]+ B228 H3C^〇f^O^) Powder MS (APCI) m/z: 549 [M+H]+ B229 powder MS (APCI) m/z: 547 [M+H]+ B230 PH3 9 ^, 粉末 Powder MS (APCI) m/z: 560 [ M+H]+ B231 Powder MS(APCI)m/z: 560 [M+H]+ B232 Powder MS(APCI)m/z: 558 [M+H]+ B233 F3c』_P^~心~ Χ/Λ ^ΝΛ^Ν Powder MS (APCI) m/z: 586 [M+H]+ 165 323135 201202230 Table 56

EXAMPLES Structural Properties, Value, etc. B234 Powder MS (APCI) m/z: 586 [M+H]+ B235 Discrimination N Powder MS (APCI) m/z: 568 [M+H] 十B236 ^ ΗΟ-^ Powder MS (APCI) m/z: 575 [M+H]+ B237 powder MS (APCI) m/z: 557 [M+H]+ B238 powder MS (APCI) m/z: 560 [M+H]+ B239 Powder MS (APCI) m/z: 558 [M+H]+ B240 03⁄4~. H powder MS (APCI) m/z: 560 [M+H]+ B241 jj^x^Sw^'N ^ N·^ Powder MS (APCI) m/z: 560 [M+H]+ 166 323135 201202230 57 table

EXAMPLES Structural Properties, etc. B242 Powder MS (APCI) m/z: 557 [M+H]+ B243 Kn1n Powder MS (APCI) m/z: 557 [M+H]+ B244 Powder MS (APCI) m/ z: 564 [M+H]+ B245 powder MS (APCI) m/z: 562 [M+H]+ B246 powder MS (APCI) m/z: 564 [M+H]+ B247 powder MS (APCI) m /z: 531 [M+H]+ B248 Powder MS (APCI) m/z: 531 [M+H]+ B249 F3Cs^-8^n^〇h Powder MS (APCI) m/z: 572 [M+ H]+ 167 323135 201202230

Example B252 The compound (15.4 mg) (yield: 65%) of the following Table 59 was obtained by treating the corresponding starting compound in the same manner as in Example B17. Table 59 Example Structure Structural property value, etc. B252 H3c. L OH powder MS (APCI) m/z: 549 [M+H]+

Examples B253 to B260 The compounds described in the following Table 60 were obtained by treating the corresponding starting compounds in the same manner as in Example B96. 168 323135 201202230 Table 60

EXAMPLES Structural Properties Values, etc. B253 Powder MS (APCI) m/z: 592 [M+H]+ B254 Powder MS (APCI) m/z: 556 [M+H]+ B255 as a 〇 'N V_y N j Powder MS (APCI) m/z: 574 [M+H]+ B256 ch3o^ powder MS (APCI) m/z: 574 [M+H]+ B257 powder MS (APCI) m/z: 572 [M+H ]+ B258 FC, powder MS (APCI) m/z: 600 [M+H]+ B259 powder MS (APCI) m/z: 600 [M+H}+ B260 powder MS (APCI) m/z: 582 [ M+H]+169 323135 201202230 Examples B261 to B262 By treating the corresponding starting compounds in the same manner as in Example B2, the compound described in the following Table 61 was obtained. Table 61 Example Structure Structural property value, etc. B261 F F OH such as Iraq. Powder MS (APCI) m/z: 496 [M+H]+ B262 FF OH ° 'NUN j powder MS (APCI) m/z: 494 [M+H]+ Examples B263 to B265 by corresponding raw materials The compound was treated in the same manner as in Example B9 to give the compound described in Table 62 below. Table 62 Example Structural Properties Values, etc. B263 Powder MS (APCI) m/z: 562 [M+H]+ B264 Powder MS (APCI) m/z: 565 [M+H]+ B265 Powder MS (APCI) m/z: 563 [M+H]+ 170 323135 201202230 Examples B266 to B272 The compounds of the following Table 63 were obtained by treating the corresponding starting compounds in the same manner as in Example B11.

171 323135 201202230 Table 63

EXAMPLES Structural Properties, Value, etc. B266 Powder MS (APCI) m/z: 592 [M+H]+ B267 Powder MS (APCI) m/z: 535 [M+H]+ B268 FF Plant OH KI { Powder MS (APCI)m/z: 523 [M+H]+ B269 ch3 F, F H3C'i-〇H H3(&quot;xk&gt;B^ 〇Powder MS(APCI)m/z: 551 [M+H]+ B270 powder MS (APCI) m/z: 537 [M+H]+ B271 HCv-y powder MS (APCI) m/z: 565 [M+H]+ B272 powder MS (APCI) m/z: 521 [M +H]+ 172 323135 201202230 Examples B273 to B276 By treating the corresponding starting compounds in the same manner as in Example B14, the compounds described in the following Table 64 were obtained. Value B273 Powder MS (APCI) m/z: 533 [M+H]+ B274 Powder MS (APCI) m/z: 529 [M+H]+ B275 Powder MS (APCI) m/z: 529 [M+ Hf B276 Powder MS (APCI) m/z: 531 [M+Hf </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 173 323135 201202230 Table 65 Example Structural Properties Values, etc. B277 FF 0 VoW Powder MS (APCI) m/z. 518 [M+Hf B278 如妒&amp; Powder M S (APCI) m/z: 520 [M+H] + Examples B279 to B280 The compound of the following Table 66 was obtained by treating the corresponding starting compound in the same manner as in Example B16. Example No. 66, Structural Property Value, etc. B279 ch3 Powder MS (APCI) m/z: 605 [M+H]+ B280 Powder MS (APCI) m/z: 577 [M+H]+ Example B281 by The corresponding raw material compound was treated in the same manner as in Example B89 to obtain the compound described in the following Table 67. 174 323135 201202230

The compound of the following Table 68 was obtained by treating the corresponding starting compound in the same manner as in Example B89.

Example B285 The product of the following Table 69 was obtained by subjecting the corresponding starting compound to a private treatment in the same manner as in Example B90. 323135 175 201202230 Example 69 Structural structural property values, etc. B285 ON b N j MS(APCI)m/z: 535 [M+Hf Example B286 is treated in the same manner as in Example B91 by the corresponding raw material compound The compound described in the following Table 70 was obtained.

Example 70 Structural Formulary Property Values, etc. B286 Powder MS (APCI) m/z: 578 [M+H]+ Examples B287 to B289 were treated in the same manner as in Example B92 by using the corresponding starting compound. The compound described in the following Table 71 was obtained. Table 71

EXAMPLES Structural Properties Values, etc. B287 Powder MS (APCI) m/z: 562 [M+H]+ B288 Powder MS (APCI) m/z: 564 [M+H]+ B289 Powder MS (APCI) m/z : 560 [M+H]+ 176 323135 201202230 Example B290 The compound of the following Table 72 was obtained by treating the corresponding starting compound in the same manner as in Example B98. Table 72 Example Structure Structural property value, etc. B290 ° 'N N j Powder MS (APCI) m/z: 551 [M+H]+

Examples B291 to B295 The compounds described in the following Table 73 were obtained by treating the corresponding starting compounds in the same manner as in Example B99.

177 323135 201202230 Table 73 Example Structural property values B291 such as powder MS (APCI) m/z: 515 [M+Hf B292 MS(APCI)m/z: 515 [M+H]+ B293 F H3C 〇° 'NN j powder MS (APCI) m/z: 517 [M+H]+ B294 as P powder MS (APCI) m/z: 517 [M+H]+ B295 °'NN j powder MS (APCI) m/ z: 551 [M+H wide

Example B296 The compound of the following Table 74 was obtained by treating the corresponding starting compound in the same manner as in Example B103. Table 74 Example Nod physical property values, etc. B296 Powder MS (APCI) tn/z: 578 [M+Hf Example B297 [2-Fluoro-4-[6-fluoro-4-[4-(5-iso) Manufacture of propyl-[1,2,4]oxadiazole-3- 178 323135 201202230 yl)piperidinyl]quinazoline-8-yl]phenyl]methanol W0-N F Ν^Ν

Me, Me

1) PdCI (dppf) CH2CI2 CS2CO3 dioxane / HaO

Water 2 · 5mL, acetic acid 2-fluoro-4-(4,4, 5, 5-tetramethyl-[H2]

Dioxol heterocyclopenten-2-yl)benzaldehyde vinegar (Compound B185 compound) 294mg, [1,1-bis(diphenylphosphino)ferrocene]palladium(1)) dichloride - 2 mg of methane methane complex and 650 mg of cesium carbonate were added to 8_bromo-6-fluoro-4-[4-(5-isopropyl-[丨'2,4]oxadiazole-3-yl)piperidin The pyridine-hydrazinyl group (the compound obtained in Reference Example B9) was dissolved in a solution of 21 mg of hydrazine in a solution of 4 噚m. After the reaction solution was returned to room temperature, a 2N aqueous sodium hydroxide solution was added and stirred for 1 hour. The reaction mixture was extracted with diethyl ether, and the organic layer was concentrated. The residue obtained was chromatographed with NH-hydrazine column chromatography (Chr〇mat〇rex) , Solvent: hexane/ethyl acetate: 90/10 to 50/50), to give the title compound (yield: 69%) MS (APCI) m/z; 466 [Μ+ΗΓ. B298 to B299 were treated in the same manner as in Example B297 to obtain the compound described in the following Table 75. 179 323135 201202230 Example of the 75th table is stable~1'~~· .-- -- Object 'Μ: Broadcasting cage B298 _ Value 1 * Wang lance powder MS (APCI) m / z: 510 [M + H] + B299 powder MS (APCI) m / z: 510 [M + H] + Example B300

2-fluoro-4-[5-fluoro-4-[4-(5-methylpyrimidin-2-yl)-piperidin-1-yl] 喧junlin-8-yl]-N,N-dimethyl Manufacture of benzoylamine

2-Fluoro-4-[5-fluoro-4-(piperidin-yl)quinazoline-8-yl]-N,N-dimercaptobenzamine 2 hydrochloride (Compound A34) 5 〇 mg and 2-gas-5-mercaptopyrimidine 20. 5 mg of DMS0 solution imL was stirred at 8 (TC overnight). After the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. After washing with saturated brine, the mixture was dried with sulfuric acid, and then filtered. The filtrate was concentrated, and the obtained crude product was obtained by using NH-D. 25 to 40/60) a colorless powder of the title compound, 15.3 mg (yield: 6 2 ). MS (APCI) m/z; 490 [M+H]+ 323135 180 201202230 Example B301 3- Fluoro-4-[6-fluoro-4-[1-(5-isopropyl-[1,2,4]oxadiazol-3-yl)piperidin-4-yl]quinazoline-8-yl Manufacture of -N,N-dimercaptobenzamide

Adding triethylamine 27//L and chloroisobutyric acid 20# L to 3-Dun-4-[6-fluoro-4-[1-(Ν-hydroxy曱 brand) σ bottom under ice cooling咬-4-基]喧峻琳-8-yl]-Ν,Ν-dimercaptobenzamide (3-『111〇1:〇-4-[6-于111〇1*〇-4- [l-(N-hydroxycarbamimidoyl)piperidin-4-y1Jquinazol 111-811]^-(1111161±^^61^311^(16) (Compound compound obtained in Reference Example 8191) 87 mg of toluene 1. 5 mL of solution, The mixture was stirred at 130 ° C for 2.5 hours. After 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 concentrated under reduced pressure. Column chromatography (solvent: gas imitation / sterol = 100/0 to φ 95/5), and then passed through a gel permeator (JAIGEL-1H, 2H; 曰 analysis industry, mobile phase: gas simulation) Refining to give 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-Trisylethyl)-[1,2,4]oxadiazol-3-yl)piperidin-1-yl]quinazolin-8-yl]- Manufacture of N,N-dimercaptobenzamine 181 32313 5 201202230

Adding a 50% aqueous solution of a solution of the base amine to 28-L to 4-[4-(4-carbyl ketone-1-yl)-6-fluoroquinazolin-8-yl]-2-fluoro-N,N - Dimercaptobenzamide (Compound obtained in Reference Example B192) 9 mg of isopropanol in 1 mL of a solution, the mixture was stirred at 90 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure, and then, to the residue obtained, toluene was added to the residue, and then triethylamine 36/L and 35 mg of 3,3,3-trifluoropropane gas were added under ice cooling, and the mixture was placed at 110. (: Stirring for 2 hours. Add a saturated aqueous solution of sodium hydrogencarbonate to the reaction mixture and extract with methylene chloride. The organic layer was concentrated under reduced pressure. Refining to give 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-di Manufacture of mercapto nicotinamide

M62NH

2N sodium hydroxide aqueous solution 〇. 5mL was added to 6_[6_Fluor_4_[4_(3-isopropyl-[1,2, 4]卩, etc. dipyridin-5-yl)) Wow _8_ yl] final base 酞 曰 曰 曰 参考 参考 参考 参考 参考 参考 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 After neutralizing the reaction mixture with 2N hydrochloric acid, the reaction solution was concentrated, and 323135 182 201202230 was added to the crude product of the household and the THF solution of dimethylamine (2mQi/L, 69 &quot;L)/tC*. After 2 mL of methyl decylamine and 73 mg of BOP, 48 liter of isopropylethylamine was added, and the mixture was stirred overnight at room temperature. Saturated aqueous sodium carbonate solution was added to the reaction mixture, and extracted with dichloromethane. The residue was purified by silica gel column chromatography (solvent: chloroform/methanol = 100/0 to 92/8) to give the title compound as a colorless solid 26 mg (yield: 58) %). MS (APCI) m/z ; 490 [Μ+ΗΓ. Example B304 (5)-1-[2-Fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4]oxadiazol-3-yl)piperidine Manufacture of -1-yl]quinazolin-8-yl]phenyl-3-didecylamine-mercaptooxypyrrolidin-2-one

Add dimethyl sulfhydryl sulfhydryl gas 90/zL to (S)-l-[2-fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4] ] oxadiazol-3-yl) fluoren-1-yl] quinazolin-8-yl]phenyl-3-hydroxypyrrolidin-2-one (compound obtained in Example B191) 50 mg in 2 mL solution 'The mixture was mixed at 80 C for 4 hours. After adding 90 eL of dimethylaminoformyl chloride to the reaction mixture, it was stirred at 80 ° C for 9 hours. After adding decylamine decyl chloride 90/zL to the reaction mixture, it was stirred at 8 (TC for 5 hours. After adding 1N hydrochloric acid to the reaction mixture, it was extracted with ethyl acetate, and the organic layer was saturated with carbon 323 135 183 201202230 2重量(Yield: 45) The colorless powder of the title compound was obtained in the title compound: 25 mg (yield: 45) %) MS (APCI) m/z; 606 [M+H]+. Examples B305 to B338 were treated in the same manner as in Example B1 to give the following Table 7 to The compound described in Table 79.

184 323135 201202230 Table 76

EXAMPLES Structural Properties Values, etc. B305 F, F H3C Powder MS (APCI) m/z: 505 [M+H]+ B306 F. F qHsC rH3 Powder MS (APCI) m/z: 563 [M+H]+ B307 Powder MS (APCI) m/z: 515 [M+H]+ B308 F CN Powder MS (APCI) m/z: 512 [M+H]+ B309 Powder MS (APCI) m/z: 515 [M+ H]+ B310 Powder MS (APCI) m/z: 515 [M+H]+ B311 Powder MS (APCI) m/z: 490 [M+H]+ B312 %〇神_ Powder MS(APCI)m/z : 511 [M+H]+ B313 F Me Powder MS (APCI) m/z: 467/469 [M+H]+ 185 323135 201202230 Table 77

EXAMPLES Structural Properties Values, etc. B314 Powder MS (APCI)ra/z: 510 [M+H]+ B315 Powder MS (APCI) m/z: 524 [M+H]+ B316 Powder MS (APCI) m/z : 551 [M+Hf B317 F, F. H3C Powder MS (APCI) m/z: 507 [M+H]+ B318 Powder MS (APCI) m/z: 507 [M+H]+ B319 bo-^ On ^C/'C^ Powder MS (APCI) m/z: 496 [M+H]+ B320 powder MS (APCI) m/z: 504 [M+H]+ B321 powder MS (APCI) m/z: 461 [M+H]+ B322 Vy^N(CH3)2 κ-yr^0 Powder MS(APCI)m/z: 547 [M+H]+ B323 ch3 Hh^-^(CH3)2 η4:κ:4 ^0 Powder MS (APCI) m/z: 507 [M+H]+ 186 323135 201202230 Table 78

EXAMPLES Structural Properties, Value, etc. B324 Powder MS (APCI) m/z: 490 [M+H]+ B325 H3Cr%o&amp;^H3 Powder MS (APCI) m/z: 490 [M+H]+ B326 MS ( APCI)m/z: 493 [M+H]+ B327 powder MS (APCI) m/z: 544 [M+H]+ B328 powder MS (APCI) m/z: 526 [M+H]+ B329 powder MS (APCI) m/z: 497 [M+H]+ B330 °'N N-^ Powder MS (APCI) m/z: 483 [M+H]+ B331 ^o^CH3 Powder MS (APCI) m/z : 497 [M+H]+ 187 323135 201202230 Table 79

EXAMPLES Structural Properties Values, etc. B332 MS(APCI) m/z: 522 [M+H]+ B333 Powder MS (APCI) m/z: 511 [M+H]+ B334 Powder MS (APCI) m/z: 522 [M+H]+ B335 powder MS (APCI) m/z: 511 [M+H]+ B336 FF ti yN(cH3)2 °&quot;N N-^ powder MS(APCI)m/z; 522 [M+H]+ B337 F, f Η3ς Powder MS (APCI) m/z: 50$ [M+H]+ B338 Powder MS (APCI) m/z: 508 [M+H]+ 188 323135 201202230 EXAMPLE B339 to B380 were treated in the same manner as in Example B2 to obtain the compound described in the following Tables 80 to 85.

189 323135 201202230 Table 80

EXAMPLES Structural properties Physical properties, etc. B339 Powder MS (APCI) m/z: 490 [M+H]+ B340 F FMe, ^-〇H F3CiK&gt;S^. Powder MS (APCI) m/z: 563 [M+H]+ B341 OH F FMe .· Powder MS (APCI) m/z: 577 [M+H]+ B342 N^n 〇 powder MS (APCI) m/ z: 591 [M+H]+ B343 〇 powder MS (APCI) m/z: 577 [M+H]+ B344 N·^ 〇 powder MS (APCI) m/z: 577 [M+H]+ B345 Me hCrV/^lR^: powder MS(APCI)m/z: 555 [M+H]+ B346 3 jN powder MS(APCI)m/z: 522 [M+H]+ 190 323135 201202230第81表

EXAMPLES Structural Property Values, etc. B347 F. F 0. Households&gt;Λ_/^ί Powder MS(APCI)m/z: 508 [M+H]+ B348 F, F Ο, U'N N~/ N-^ Powder MS (APCI) m/z: 564 [M+H]+ B349 OH 0, N plant v~~f N-^ Powder MS (APCI) m/z: 552 [M+H]+ B350 FF 0 /Me powder MS (APCI) m / z: 536 [M + H] + B351 FFO / ^ 〇 H powder MS (APCI) m / z: 578 [M + H] + B352 OH powder MS (APCI) m / z: 566 [M+H]+ B353 FF Factory OH. H powder MS (APCI) m/z: 553 [M+H]+ B354 F F Me plant OH powder MS (APCI) m/z: 567 [M+H]+ 191 323135 201202230 Table 82

EXAMPLES Structural Properties Values, etc. B355 CH3 F 〇 Powder MS (APCI) m/z: 537 [M+H]+ B356 FF Plant OH Powder MS (APCI) m/z: 537 [M+H] 十B357 H3C^ o ' 〇 powder MS (APCI) ni / z: 537 [M + H] + B358 FF plant OH powder MS (APCI) m / z: 523 [M + H] + B359 〇 powder MS (APCI) m / z : 537 [M+H]+ B360 CH )_V7=WJH(CH3) 〇,N &gt;~^ N j Powder MS(APCI)m/z: 493 [M+H]+ B361 OH Powder MS(APCI)m /z: 537 [M+H]+ B362 〇 powder MS (APCI) m/z: 537 [M+H]+ 192 323135 201202230第83表

EXAMPLES Structural Properties Values, etc. B363 Powder MS (APCI) m/z: 537 [M+Hf B364 FF Me / -OH Powder MS (APCI) m/z: 537 [Μ+ΗΓ B365 F FMe y-OH Powder MS (APCI) m/z: 537 [M+H]+ B366 F FMe, plant OH ρΊκ&gt;δ^. Powder MS (APCI) m/z: 577 [M+H]+ B367 F F Me j-QVi H3C^H&gt;§^. Powder MS (APCI) m/z: 537 [M+H]+ B368 F FMe Plant OH Powder MS (APCI) m/z: 535 [M+H]+ B369 H3cJ oh HjC^〇WA Powder MS (APCI)m /z: 592 [M+H]+ B370 Powder MS (APCI) m/z: 567 [M+H]+ 193 323135 201202230 Table 84

EXAMPLES Structural Properties, Value, etc. B371 Powder MS (APCI) m/z: 594 [M+H]+ B372 Powder MS (APCI) m/z: 594 [M+H]+ B373 N-^NO o' Powder MS (APCI) m/z: 594 [M+H]+ B374 CH3 OH Η3^^^Α°η N*^- 〇 Powder MS (APCI) m/z: 565 [M+H]+ B375 Powder MS (APCI m/z: 612 [M+H]+ B376 powder MS (APCI) m/z: 606 [M+H]+ B377 F ^κί8^Ν Powder MS (APCI) m/z: 594 [M+H] + 194 323135 201202230 Table 85 Example Structural Properties Values, etc. B378 FMe V-NH2 Powder MS (APCI) m/z: 568 [M+H]+ B379 Powder MS (APCI) m/z: 591 [M+H ]+ B380 °, Ν ^f N-^ Powder MS (APCI) m/z: 565 [M+H]+

Example B381 The compound of the following Table 86 was obtained by treating the corresponding starting compound in the same manner as in Example B3. Table 86 Example Structure Structural property value, etc. B381 f f _y~0H Powder MS (APCI) m/z: 527 [M+H]+

Examples B382 to B391 The compounds described in the following Tables 87 to 88 were obtained by treating the corresponding starting compounds in the same manner as in Example B4. 195 323135 201202230 Table 87

EXAMPLES Structural Properties, Values, etc. B382 • 妒- Powder MS (APCI)ra/z: 514 [M+H]+ B383 Powder MS (APCI) m/z: 514 [M+H] 十B384 FFW /=( S 〇2CH3 powder MS (APCI) m/z: 528 [M+H]+ B385 FF °'N vf N-^ Powder MS (APCI) m/z: 515 [M+H]+ B386 Shanghai A Powder MS&lt;APCI m/z: 529 [M+H]+ B387 Powder MS (APCI) m/z: 543 [M+H]+ B388 〇K^s^0H H3々K&gt;# Powder MS (APCI) m/z: 559 [M+HJ+ B389 Powder MS (APCI) m/z: 543 [M+H]+ 196 323135 201202230

Examples B392 to B395 were treated in the same manner as in Example B9 to give the compound described in Table 89 below. Table 89 Example Structural Properties Values, etc. B392 Powder MS (APCI) m/z: 563 [M+H]+ B393 Powder MS (APCI) m/z: 505 [M+H]+ B394 Powder MS (APCI) Rayz: 529 [M+H]+ B395 powder MS (APCI) m/z: 493 [M+H]+ 197 323135 201202230 Examples B396 to B397 were treated in the same manner as in Example B11 by the corresponding raw materials. The compound described in the following Table 90 was obtained.

Examples B398 to B402 were treated in the same manner as in Example B16 to give the compound described in Table 91 below.

198 323135 201202230 Table 91 Example Structural Properties Values, etc. B398 Powder MS (APCI) m/z: 543 [M+rff B399 Powder MS (APCI) m/z: 507 [M+H]+ B400 Powder MS (APCI m/z: 563 [M+H]+ B401 powder MS (APCI) m/z: 574 [M+H]+ B402 powder MS (APa) m/z: 620 [M+H]+ Example B403 The compound of the following Table 92 was obtained by treating the corresponding starting compound in the same manner as in Example B17. 199 323135 201202230 Table 92 Example Structural property value B403 H3C^^N /—\ &gt;==( 〇 'N^\-^N n-^NF 〇-〇H Powder MS (APCI) m/z 549 [M+H]+ Example B404 The compound of the following Table 93 was obtained by treating the corresponding starting compound in the same manner as in Example B94. B404 Powder MS (APCI) m/z: 463 [M+H] + EXAMPLES B405 to B436 By treating the corresponding starting compound in the same manner as in Example B95, the following Tables 94 to 97 were obtained. Compounds listed in the table. 200 323135 201202230 Table 94

EXAMPLES Structural Properties Values, etc. B405 Powder MS (APCI) m/z: 565 [M+H]+ B406 Powder MS (APCI) m/z: 536 [M+H]+ B407 Powder MS (APCI) m/z : 553 [M+H]+ B408 Me Ο 乂MS(APCI)m/z: 535 [M+H]Tea B409 Powder MS (APCI) m/z: 542 [MfH]+ B410 Powder MS (APCI) m/ z: 564 [M+H]+ B411 Powder MS (APCI) m/z: 582 [M+H]+ B412 Heart ~ °'n\-^ n-^ Powder MS (APCI) m/z: 546 [M +H]+ 201 323135 201202230 95th table

EXAMPLES Structural Properties Values, etc. B413 Powder MS (APCI) m/z: 517 [M+H]+ B414 MS (APCI) m/z: 517 [M+H]+ B415 powder MS (APCI) m/z: 517[M+H]+ B416 powder MS (APCI) m/z: 560 [M+Hf B417 powder MS (APCI) m/z: 578 [M+H]+ B418 powder MS (APCI) m/z: 542 [M+H]+ B419 powder MS (APCI) m/z; 542 [M+H]+ B420 powder MS (APCI) m/z: 571 [M+H]+ 202 323135 201202230 Table 96

EXAMPLES Structural Properties Values, etc. B421 F 0 Powder MS (APCI) m/z: 567 [M+H]+ B422 Powder MS &lt;APCI) m/z: 535 [M+H]+ B423 Powder MS (APCI) m /z: 536 [M+H]+ B424 Powder MS (APCI) m/z: 536 [M+H]+ B425^k&gt;:8^n^〇h MS(APCI)m/z: 547 [M+ H]+ B426 powder MS (APCI) m/z: 547 [M+H]+ B427 powder MS (APCI) m/z: 561 [M+H]+ B428 powder MS (APCI) m/2: 561 [M +H]+ 203 323135 201202230 Table 97

EXAMPLES Structural Properties Values, etc. B429 MS(APCI)m/z: 542 [Μ+ΗΓ B430 Me 0 Powder MS (APCI) m/z: 549 [M+H]+ B431 Powder MS (APCI) m/z: 550 [M+H]+ B432 Powder MS (APCI) m/z: 550 [M+H]+ B433 Powder MS (APCI) m/z: 553 [M+Hf B434 ^:^〇H Powder MS (APCI) m/z: 535 [M+H]+ B435 Me 〇 powder MS (APCI) m/z: 532 [M+H]+ B436 F Me 〇 powder MS (APCI) m/z: 532 [M+H]+ 204 323135 201202230 Example B437 The compound of the following Table 98 was obtained by treating the corresponding starting compound in the same manner as in Example B96. Table 98 Example Structure Structural property value, etc. B437 Powder MS (APCI) m/z: 592 [M+H]+

Examples B438 to B441 The compounds described in the following Table 99 were obtained by treating the corresponding starting compounds in the same manner as in Example B100. Table 99 Example Structural Properties Value Equivalent Β438 F FMe Powder MS (APCI) in/z: 525 [M+H]+ Β439 〇'N^\_yN Powder MS (APCI) m/z: 548 [M+H ]+ Β440 powder MS (APCI) m/z: 544 [M+H]+ Β441 powder MS (APCI) m/z: 551 [M+H]+ 205 323135 201202230 Examples B442 to B443 by corresponding raw materials The compound was treated in the same manner as in Example B301 to give the compound described in Table 100 below.

Examples B444 to B447 The compounds described in the following Table 101 were obtained by treating the corresponding starting compounds in the same manner as in Example B192.

206 323135 201202230 Table 101 Example Structural property values, etc. B444 FF Me /}~\ /=\Ν·Μβ Powder MS (APCI) m/z: 622 [M+H]+ B445 FF Me Powder MS (APCI) m/z: 521 [M+H]+ B446 FF Me /}—n /=\ N-Me Powder MS (APCI) m/z: 547 [M+H]+ B447 Powder MS (APCI) m/z: 591 [M+H]+ Examples B448 to B450 Compounds of the following Table 102 were obtained by treating the corresponding starting compound in the same manner as in Example B191.

207 323135 201202230 Table 102 Example Structural property values, etc. B448 F* F Me _ s. /=\ N*Me Powder MS (APCI) m/z: 508 [M+H]+ B449 FF Me H Powder MS ( APCI) m/z: 480 [M+H]+ B450 v FKMwe h3c 0 powder MS (APCI) m/z: 480 [M+H]+ Example B451 6-Fluoro- 8-(3-fluoro-4- Methylthiononylphenyl)-4-[(R)-4-(5-isopropyl-[1,2,4]oxadiazol-3-yl)-3-methylpiperidin-1 -based quinazoline production

The title compound was obtained by the same procedure as in Example B1. MS (APCI) m/z ; 511 [M+H]+. Example B452 5-Fluoro-8-(3-fluoro-4-methylthiophenyl)-4-[4-(5-isopropyl-[1,2,4]oxadiazol-3-yl Manufacture of piperidin-1-yl]quinazoline 208 323135 201202230

The title compound was obtained by treating the corresponding starting material compound in the same manner as in the procedure of Example Bi. MS (APCI) m/z ; 482 [Μ+ΗΓ. Example B453

6-Fluoro-8-(3-fluoro-4-methylthiophenyl)-4-[4-(5-isopropyl-[1,2,4]oxadiazol-3-yl)piperidine Manufacture of -1-yl]quinazoline

The title compound was obtained by treating the corresponding starting material compound in the same manner as in Example B1. MS (APCI) m/z ; 482 [Μ+ΗΓ. Example B454 (1R, 4S, 5R, 6S)-2-[2-Fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4]indole-disc-- Manufacture of 3-based) brittle base] 啥 琳 -8-8-yl]phenyl]-5,6-dihydroxy-2-azabicyclo[2. 2·1]heptan-3-one 209 323135 201202230

Under ice cooling, 3 mL of concentrated hydrochloric acid was added dropwise to (13, 21{, 65, 71 〇-8-[2-fluoro-4-(4, 4, 5, 5-tetradecyl-[1,3, 2 Dioxaborolan-2-yl) φ phenyl]-4, 4-dimercapto-3, 5-dioxa-8-azabicyclo[5. 2. 1. 02' 6] The terpene-9-one (the compound obtained in Reference Example B271) was dissolved in a solution of 48 mg of sterol in 5 mL of 'the mixture was stirred at room temperature for 10 minutes. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate to dichlorin. After the organic layer was dried with sulphuric acid, the filtrate was concentrated. The residue was purified by silica gel column chromatography (solvent: chloroform / decyl alcohol = 100/0 to 96/4) to give the title compound 38 mg ( 84%) MS (APCI) m/z: 577 [M+H]. % Example B455 2-[3-[2-Fluoro-4~[5-fluoro-4-[4-(5- Propyl-[1,2,4]oxadiazol-3-yl)piperidin-1-yl]quinazolinyl-8-yl]phenyl]_2_trioxyimidazolidine-1-yl]-2 -Production of mercaptopropionic acid 323135 210 201202230

Add 1 mL of trifluoroacetic acid to 2-[3-[2-fluoro-4-[5-fluoro-4-[4- φ(5-isopropyl-[1,2,4]oxadiazole-3- ))piperidin-1-yl]quinazolinyl] phenyl]2- oxo η 嗤 _ ι ι _ ι ] ( ( ( ( ( ( ( ( ( 255 255 255 255 255 255 255 255 255 255 255 255 255 The solution was stirred at room temperature for 2 hours in dichloromethane (5 mL). The reaction mixture was concentrated under reduced pressure, and then dichloromethane was evaporated. The reaction mixture was concentrated under reduced pressure. ethyl acetate was evaporated. The organic layer was concentrated under reduced pressure, and the residue was purified by ethyl acetate / EtOAc (EtOAc). %) 〇MS (APCI) m/z ; 606 [M+H]+ . Example B456 3-[3-[4-[4-[4-[5-(1,Bufluoroethyl)-[1,2,4]. Manufacture of -3-yl] ketone-1-yl] 啥 琳 -8-8-yl]-2-fluorophenyl]-2-yloxytrmoxazin-1-yl]propanamide 211 323135 201202230

8-Bromo-4-[4-[5-(l,1-difluoroethyl)-[H4]oxadiazole-3-yl]piperidin-1-yl]quinazoline (Reference Example B114) Compound) 42 mg, 3-[3-[2-fluoro-4-(4,4,5'5-tetradecyl 41,3,2]dioxaborolan-2-yl)phenyl] -2-Sideoxyimidazolium hydrazide-yl]tertyl butyl triacrylate (compound obtained in Reference Example B236) 52 mg, [1,1,_bis(diphenylphosphino)ferrocene]palladium (π A solution of 4 mg of dichloride-dichloromethane complex and 81 mg of cesium carbonate/water (4 mL/lmL) of cesium carbonate was stirred at 8 ° C for 6 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and then filtered with EtOAc (EtOAc). The residue obtained was purified by NH_矽 gum column chromatography (Chromatorex, solvent: hexane/ethyl acetate: 6 〇 / 4 Torr to 30/70), and dichloromethane 5 was added to the obtained crude product.汕, trifluoroacetic acid 1 mL' was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. &lt;RTI ID=0.0&gt;&gt; The reaction mixture was concentrated, and the residue was applied to ethylamine sulfate Organic 323135 212 201202230 The layer was concentrated under reduced pressure. The residue obtained was purified by Shih-Hui-gel column chromatography (solvent/chloroform/nonanol. 95/5 to 80/20), and added to the obtained crude organism. One simmered 3 mL 'In this solution, N-mercapto acetonyl chloropyristate 16 yL was added to the solution at 〇 ° C. (: stirring for 10 minutes. Add ammonia %) 1 mL to the reaction solution, and stir at room temperature overnight. The product is obtained as a colorless powder of the title compound (1,7 mg (yield 28). %). MS (APCI) m/z ; 595 [M+H]+. # Example B457 (Fantasy-: 1-[2-fluoro-4-[5-fluoro-4-[4-(5-isopropyl-[1,2,4]oxadiazol-3-yl)piperidin Manufacture of pyridin-1-yl]quinazolin-8-yl]phenyl]-5-oxoxypyrrolidin-3-carboxydecylamine

(1) by 8-bromo-5-fluoro-4-[4-(5-isopropyl-[1,2,4]oxadiazol-3-yl)piperidin-1-yl]quinazoline Porphyrin (Compound obtained in Reference Example B15) 84 mg and (R)-l-[2-|L-4-(4, 4, 5, 5-tetramethyl-[1,3, 2]dioxole Cyclopentyl-2-yl)phenyl]-5-side oxy-α is more than 嘻3_carboxylic acid methyl ester (compound obtained in Reference Example B266) 87. lmg in the same manner as in the example βΐ 323135 213 201202230 Treatment, and obtain (R) — l-[2-fluoro-4-[5-fluoro-4-[4-(5~isopropyl~[1 &gt; 2, 4] 1% a β-sitting) . 1-1 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ (2) 1. 4 mL of gas water was added to 2 mL of a decyl alcohol solution of the mixture obtained in the above (1), and stirred overnight. The reaction mixture was neutralized with 2N hydrochloric acid and 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 obtained residue was added to the solution of 2 mL of the gas, and the solution of the gas was added to the solution of the gas, for example, 18 4 Φ &quot;L, N-mercaptomorpho 15.6 &quot; L, ammonia lmL, The mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and methylene chloride and water were added to the residue, and extracted with difluoromethane. 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 obtained crude product was purified by silica gel column chromatography to yield 51 mg (yield: 78%) of the title compound. MS (APCI) m/z; 561 [M+H]+ &lt;&gt; Example B458 • I-[2-Cyano-4-[4-[4-(5-isopropyl-[1,2] , 4]Indolin-3-yl)piperidin-1-yl]quinazolin-8-yl]phenyl]pyrrolidin-2-one

The powder of the title compound was 13.9 mg (yield 14%) by the same. 214 323135 201202230 MS (APCI) m/z ; 508 [Μ+ΗΓ. Examples B459 to B46〇 The compounds described in the following Table 103 were obtained by treating the corresponding starting compounds in the same manner as in Example 455. Table 103 Example Structural property values, etc. B459 Powder MS (APCI) m/z: 578 [M+HJ+ B460 powder MS (APCI) m/z: 592 [M+H]+ Example Β461 4-hydroxy-1 -[2-Fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4]oxadiazol-3-yl)-3-methylpiped-1- Manufacture of quinazolin-8-yl]phenyl]pyrrolidin-2-one

By treating the corresponding starting compound in the same manner as in Example 95, 85 mg of the title compound (yield: 83%) was obtained. MS (APCI) m/z ; 550 [M+H]+. Examples B462 to B514 The compounds described in the following Tables 104 to 110 were obtained by treating the corresponding starting compounds in the same manner as in Example B2. 215 323135 201202230 Table 104

EXAMPLES Structural Properties, Value, etc. B462 Powder MS (APCI) m/z: 577 |M+H]+ B463 Viscous Oil MS (APCI) m/z: 585 [M+H]+ B464 Powder MS (APCI )m/z: 598 [M+H1+ B465 \ /Cr0H Η3%·ο·δ^° viscous oil MS(APCI)m/z: 571 [M+H]+ B466 Γ^ΝγΦνν -Hj Ν^ Ν lU\Nv^〇H 0 viscous oil MS (APCI) m/z: 559 [M+H]+ B467 powder MS (APCI) m/z: 567 [M+H]+ B468 powder MS (APCI ) m/z: 581 [M+H]+ B469 H3C f , νΛ〇y4^0^h3 N^N lkAlfN&gt;s^〇H 0 Powder MS(APCI)m/z: 555 (M+H]+ 216 323135 201202230 Table 105

EXAMPLES Structural Properties, Values, etc. B470 °*N ^ N-^ Powder MS (APCI) m/z: 594 [M+H]+ B471 ch3 'eg, grasping powder MS (APCI) m/z: 605 [M+ H]+ B472 乂 powder MS (APCI) m/z: 591 [M+H]+ B473 powder MS (APCI) m/z: 591 [M+H]+ B474 Η^^^Ν(εΗΛ Un \_/ ]sj*^ Powder MS (APCI) m/z: 605 [M+H]+ B475 Powder MS (APCI) m/z: 608 [M+H]+ B476 H3C^ Ν^Νγζ\γ?Η3〇Ns^ N 1^γΝ^ΑΝΗ2 0 Powder MS (APCI) m/z: 582 [M+H]+ B477 Powder MS (APCI) m/z: 549 [M+H]+ 217 323135 201202230 Table 106

EXAMPLES Structural properties, value, etc. B478 Powder MS (APCI) m/z: 563 [M+H]+ B479 Powder MS (APCI) m/z: 576 [M+Hf B480 H3C F pH ^ n-^n 04 powder MS (APCI) m/z: 574 [M+Hf B481 HV L Λ n^n 0 ^ powder MS (APCI) m/z: 592 [M+H]+ B482 powder MS (APCI) m/z: 596 [ M+H]+ B483 powder MS(APCl)m/z: 568 [M+H]+ B484 powder MS(APCI)m/z: 595 [M+Hf B485 F〇rOH Hi&gt;vj ^f^O~C ^〇h3c%&gt;-nwnvn Powder MS (APCI) m/z: 550 [M+H]+ 218 323135 201202230 Table 107

EXAMPLES Structural Properties Values, etc. B486 H? Powder MS (APCI)ra/z: 575 [M+H]+ B487 ch3 Mail Order V Factory ο °Ν ^ Ν-^ Powder MS (APCI) m/z: 578[ M+H]+ B488 ρ〇Γ〇Η F3cr. ^-ο-ύ-ζ 〇·^Νν-^Ν Ν-^Ν Powder MS(APCI)m/z: 576 [M+H]+ B489 Powder MS (APCI) m/z: 603 [M+H]+ B490 ΟΗ 0 lj, powder MS (APCI) m/z: 601 [M+H]+ B491 ρ〇^〇Η Ί Powder MS (APCI) m/z : 565 [M+H]+ B492 Powder MS (APCI) m/z: 592 [M+H]+ B493 powder MS (APCI) m/z: 605 [M+H]+ 219 323135 201202230 Table 108

EXAMPLES Structural Properties Values, etc. B494 ° n^nwn Powder MS (APCI) m/z: 576 [M+H]+ B495 Powder MS (APCI) m/z: 591 [M+H]+ B496 Powder MS (APCI )ra/z: 608 [M+H]+ B497 F OH 0 powder MS (APCI) m/z: 590 [M+H]+ B498 CH3 Ph ~ grab A powder MS (APCI) m/z: 592 [M +H]+ B499 viscous oil MS (APCI) m/z: 594 [M+H]+ B500 N«^no viscous oil MS (APCI) m/z: 567 [M+H]+ B501 Powder MS (APCI) m/z: 581 [M+H]+ 220 323135 201202230 Page 109

EXAMPLES Structural Properties Values, etc. B502 F3CyN VNwN-i&gt; Powder MS (APCI) m/z: 603 [M+H]+ B503 FCF 〇H Powder MS (APCI) m/z: 601 [M+H]+ B504 Powder MS (APCI) m/z: 564 [M+H]+ B505 ch3 oh powder MS (APCI) m/z: 589 [M+H]+ B506 powder MS (APCI) m/z: 590 [M+H ]+ B507 Powder MS (APCI) m/z: 563 [M+H]+ B508 /N^0H Powder MS (APCI) m/z: 572 [M+H]+ B509 °N ^ N-^ Powder MS ( APCI)m/z: 599 [M+H]+ 221 323135 201202230 Table 110 Example structure ^ ----- Physical property value, etc. B510 ---——__ Powder MS (APCI) m/z: 564 [M +H]+ B511 such as -I -----·, powder MS (APCI) m/z: 573 [Μ+ίί]+ B512 powder MS (APCI) m/z: 587 [M+H]+ B513 heart ^^nh2 Powder MS (APCI) in/z: 591 [M+Hf B514 H3C?Ki8^ 心八, _ __-- Powder MS (APCI) m/z: 605 [M+H]+

Examples B515 to B539 The compounds described in the following Table 1 (1) were obtained by the same method as in Example B95. 323135 222 201202230第111表

EXAMPLES Structural property values, etc. B515 Ph3 .oh h^Vn^n^S^N? °·Ν W Ν_^ ^ Powder MS(APCI)m/z: 554 [M+H]+ B516 Tn“〆(.粉末 Powder MS (APCI) m/z: 554 [M+H]+ B517 Powder MS (APCI) m/z: 548 [M+H]+ B518 / /)H ο Powder MS (APCI) m/z: 534 [M+H]+ B519 ' /OH -Vc^N? Powder MS(APCI)m/z: 568 [M+H]+ B520 F ,,〇H Powder MS(APCI)m/z: 516[M+ H]+ B521 pN ΌΗ Powder MS(APd)m/z: 554 [M+H]+ B522 PN pw 〇N V_/ Powder MS(APCI)m/z: 554 [M+H]+ B523 yCN ΌΗ ^K3 : Ji Powder MS (APCI) m/z: 560 [M+H]+ 223 323135 201202230 Table 112 Example Structural Properties Values, etc. B524 _ΡΝ .OH Powder MS (APCI) m/z: 542 [M+H] + B525 F 0 Powder MS (APCI) m/z: 576 [M+H]+ B526 / ^〇H MS powder (APCI) m/z: 551 [M+H]+ B527 ,F ^OH powder MS ( APCI)m/z: 567 [M+H]+ B528 妒?.Η Powder MS(APCI)m/z: 535 [M+H]+ B529 -^=&amp;^ΝΧ0Η Powder MS(APCI)m/z : 549 [M+H]+ B530 Powder MS (APCI) m/z: 553 [M+tq+ B531 H3CSk&gt;^&quot;n? Powder MS (APCI) m/z: 535 [M+H]+ 224 323135 201202230 Table 113

EXAMPLES Structural Properties, Value, etc. B532 0-N Ηυ Powder MS (APCI) m/z: 564 [M+H]+ B533 Powder MS (APCI) m/z: 550 [M+H]+ B534 Powder MS (APCI )m/z: 549 [M+H]+ B535 F\ rJ &gt;〇H I N? °NW N_^ ^ Powder MS(APCI)ni/z: 550 [M+H]+ B536 Η, κί8^Ν • Powder MS (APCI) m/z: 535 [M+H]+ B537 powder MS (APCI) m/z: 533 [M+H]+ B538 powder MS (APCI) m/z: 549 \M+H\ + B539 Powder MS (APCI) m/z: 547 [M+H]+ 225 323135 201202230 Reference Example A1 4-(3-Isopropyl-[1,2,4]%-嗤-5-yl) Manufacture of hydrochloride

H2noh B〇C’

Ch3 h3c^N0H nh2 f^s^C00H

4N HCI/EtOAc hchO1^3

(1) A 50% aqueous solution of a solution of the base amine was added to 440 mL of an ethanol solution of isobutyl citrate 61 I7g, and the mixture was poured under reflux for 7 hours. The reaction mixture was concentrated under reduced pressure, and toluene (3 mL) was added to the residue and azeotropically dehydrated and then 'concentrated under reduced pressure' to obtain an oil of Ν'-carbamoyl-mercaptopropanimide. 82. 98 g (yield 91.8%). !H-NMR (CDCh) δ · 1. 16-1. 20 (6Η'd' J=6. 9Hz) ' 2. 40-2. 50 (1H, q), 4. 52 (2H, brs). (2) A solution of 1,1'-carbonyldiimidazole 45 g of DMF 275 mL was added dropwise to N-tert-butoxycarbony lisonipecotic acid 56.9 g of DMF 500 mL for 30 minutes. In the solution, the mixture was stirred at room temperature for 30 minutes. A solution of 32.4 g of the compound obtained in the above (1) in DMF (500 mL) was added dropwise to the reaction mixture for 30 minutes, and the mixture was stirred at room temperature for 12 hours. After a dropwise addition of 1, Γ-carbonyldiimidazole 45 g of DMF 275 mL solution to the reaction mixture for 30 minutes, 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 eluted eluted eluted eluted eluted elut elut嗤-5-基)Brigade bite-1_ 226 323135 201202230 Oil of tertiary butyl carboxylic acid 21.75 g (yield 29.5%). W-NMR (CDC13) 6 : 1. 32-1· 34 (6H, d), 1. 47 (9H, s), 1. 79-1. 88 (2H, m), 2. 03-2. 08 (2H, m), 2.94 (2H, t), 3. 03-3. 10 (2H, m), 4·09-4.13 (2H, m). (3) 44 mL of 4N hydrochloric acid/ethyl acetate was added to a solution of 10.44 g of ethyl acetate (50 mL) obtained in the above (2), and the mixture was stirred at 60 to 70 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure. EtOAc was evaporated. !H-NMR (DMSO-de) δ : 1.25-1.26 (6Η &gt; d ' J=6. 74Hz) &gt; 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 compounds of the following Table 114 were obtained by treating the corresponding starting compounds in the same manner as in Reference Example A1. 227 323135 201202230 Table 114 Reference Example No. Chemical structure physical property value, etc. A2 rv^CH3 HNs^J Hydrochloride xH-NMR (DMSO-d6) δ : 1.21-1.24 (3Η, t), 1.92-1.97 (2H, m), 2.16-2.19 (2H, m), 2.69-2.73 (2H, q), 2.99-3.03 (2H, m), 3.31-3.48 (3H, m), 8.97 (1H, brs), 9.09 (1H, Brs) A3 〇-N HN J hydrochloride ^-NMRCDMSO-di) δ : 0.86-0.89 (2H, m), 1.06-1.08 (2H, m), 1.87-1.94 (2H, m), 2.11-2.16 ( 3H, m), 2.97-3.02 (2H, m), 3.25-3.29 (2H, m), 3.37-3.41 (1H, m), 8.97-9.09 (23⁄4 brs) A4 〇-N HI〇 salt ' salt 'H -NMRODMSO-^) 6 : 1.88-1.99 (3H, m), 2.01-2.10 (1H, m), 2.17-2.34 (6H, m), 3.00-3.05 (2H, m), 3.27-3.31 (2H, m ), 3.37-3.43 (1H, m), 3.61-3.68 (1H, m), 9.11 (23⁄4 brs)

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

HaC^O^N M3U CH3 0

K2C03

Add 10 mL of trifluoroacetic acid to 4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acid tert-butyl butyl ester 5. 94 g of dichloromethane In a 30 mL solution, the mixture was stirred at 40 ° C for 4 hours and then left at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane. After adding a 30% aqueous solution of potassium carbonate, the organic layer was dried (MgSO4) Ή-NMR (CDCh) δ : 1. 32-1. 35 (6H&gt; d' J=6. 9Hz) &gt; 1. 96-2. 01 (2H, m), 2. 16-2. 22 (2H , m), 2. 86-2. 95 (2H, m), 3. 05-3. 14 228 323135 201202230 (2H, m), 3.24-3.30 (2H, m). Reference Example A6 4] 2,5-bromo-4-[4-(2,yl)-5-fluoroquinazoline Manufacturing

(1) Hydrated gas aldehyde 26. lg, concentrated hydrochloric acid 5.6 mL and 2-bromo-5-fluoroaniline (25 g) were added to a solution of 18.7 g of sodium sulfate in 5 mL of water, and the mixture was stirred at room temperature. Hydroxylamine 2 sulfate 32. Red and ethanol 190 mL were added to the reaction mixture, and the mixture was stirred at 8 (TC 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. After that, it was washed with water to give N-(2-bromo-5-fluorophenyl)-2-hydroxyiminoacetamide 28. Og (yield: 81%). MS (APCI) m/z: 261 263 [M+H]+ (2) 163 mL of concentrated sulfuric acid was added to the compound obtained in the above (1), 28. Og, and stirred at 75 ° C for 1 hour. The reaction solution was poured into ice (about 〇. 5 L). The mixture was extracted twice with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and then evaporated to dryness to give bromo-4- 229 323135 201202230 -2,3-dione 24·9g (yield: 95%) MS (APCI) ra/z : 244/246 [M+H]+ 〇(3) 24.9 g of the compound obtained in the above (2) To a solution of 24. 5 g of water in 195 mL of hydrogenation solution, 24 mL of an aqueous hydrogen peroxide solution was added dropwise to the solution under ice cooling, and the mixture was mixed overnight at room temperature. After adding 300 mL of water to the reaction mixture, the solution was In the mixture O.sub.2 (yield: 96%) was obtained by adding 4 mL of 6N-hydrochloric acid, and the residue was collected by filtration. m/z : 234/236 [M+H]+ ° (4) Add 5 mL of the guanamine ii to the compound obtained in the above (3) 23. Og 'The mixture was stirred at i5 for 5 hours. However, 640 mL of water was added to room temperature, and the precipitate was collected by filtration and washed with water to obtain 8-bromo-5-fluoro-3H-quinazolin-4-one l3.〇g by drying at 50 ° C. Rate: 54.4%) 〇MS (APCI) m/z : 243/245 [M+H]+ ° φ (5) Add 8 mL of sulfoxide and 0.733 mL of dimethyl decylamine to the above (4) The compound was stirred for 2 hours under reflux. The reaction mixture was concentrated under reduced pressure and the residue of dioxane was dropwisely evaporated to 4-(3-cyclopropyl-[[1], 4] oxadiazol-5-yl)piperidine hydrochloride 2.84 g, potassium carbonate 12 g, water 3 〇 mL and dichloromethane (30 mL) mixture. The mixture was stirred at room temperature overnight, two Extraction of methyl chloride. After drying the organic layer with sulfuric acid, concentrate under reduced pressure and the residue was chromatographed (solvent: hexane*/ Ethyl acetate = 3/1) was purified to give the title compound: 2.49 g (yield: 72.3%). 230 323135 201202230 [H-NMR (CDC13) 6 : 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 (lH, m), 7. 98-8· 01 (1H, dd, J=8. 62Hz, 5.29Hz), 8.76 (1H, s). Reference Examples A7 to A14 The compounds described in the following Table 115 were obtained by treating the corresponding starting compounds in the same manner as in Reference Example A6.

231 323135 201202230 Table 115

Reference Example No. Chemical structure physical property value, etc. A7 ch3 Powder MS (ESI) m/z: 402 [M+H]+ A8 Total 1cHtch3 'H-NMRCCDCls) δ : 1.32-1.36 (3H, t, J = 7.56 Hz) , 2.15-2.19 (2H, m), 2.27-2.31 (2H, m), 2.75-2.80 (2H, q, J= 7.56 Hz), 3.26-3.32 (1H, m), 3.36-3.42 (2H, m) , 7.19-7.23 (1H, ζ J= 7.86 Hz), 7.88-7.86 (1H, m), 8.34-8.36 (1H, d, J= 7.25 Hz), 8.85 (1H, s) A9 Br'v^_F powder MS (ESI) m / z: 406 [M+H] + A10 F 'H-NMR^DCla) δ : 1.33-1.36 (3H, t), 2.13-2.22 (2H, m), 2.28-2.32 (2H, t), 2.75-2.81 (2H, q), 3.27-3.41-(3H, m), 4.24-4.28 (2H, d), 7.48-7.51 (1H, d), 7.88-7.91 (1H, d), 8.86 (1H, s) All Br-Q F 'H-NMRCCDCb) δ : 1.03-1.08 (4H, m), 2.06-2.17 (3H, m)5 2.24-2.28 (2H, m), 3.21-3.26 (1H, m), 3.33-3.40 (2H, m), 7.48-7.50 (1H, dd, J= 8.77 Hz, 2.72 Hz), 7.88-7.91 (1H, dd, J= 7.86 Hz, 2.72 Hz), 8.86 (13⁄4 s) A12 .ch3 Br〇F 'H-NMRCCDClg) δ : 0.98-1.02 (3H, t, J = 7.41 Hz), 1.74-1.81 (2H, sxt, J = 7.44 Hz), 2.07-2.16 (2H, m) , 2.23-2.28 (2H, m), 2.69-2.73 (2H, m), 3.23-3.36 (3H, m), 4.16^.20 (2H, m), 7.02-7.07 (1H, D4 J = 10.88 Hz, 8.46 Hz), 7.98-8.02 (1H, dd, J = 8.46 Hz, 5.44 Hz), 8.76 (lH, s) A13 ch3 Cl 'H-NMRCCDCla) δ : 1.34-1.37 (6H,d , J= 7.1 Hz), 2.11-2.23 (2H, m), 2.27-2.33 (2H, m), 3.05-3.15 (1H, m), 3.25-3.44 (3H, m), 4.25-4.32 (2H, m ), 7.83-7.84 (1H, d, J = 1.8 Hz), 8.29-8.30 (1H, d, J = 2.2 Hz), 8.83 (1H, s) A14 minutes o: /7 Br-Cf F 'H-NMRCCDCb δ : 1.99-2.23 (4H,m), 2.28-2.43 (6H, m), 3.26-3.41 (3H, m), 4.23-4.29 (2H, m), 7.49-7.52 (1H, dd, J- 8.77 Hz, 2.72 Hz), 7.88-7.91 (1H, dd, J= 7.86 Hz, 2.72 Hz), 8.86 (13⁄4 s) 232 323135 201202230 Reference Example A15 !- Desert-5-Fluoro-4-(4-Isobutyl Sulfur based. Chen bite base)

Create Boc. CH3SO2CI „ aNEt3 b°cn^s nu —^

ΌΗ 4N HGI/AcOEt -►WH hs^VCH3 ch3 -► SO3CH3 NaOCHa

Boc. a

HCI HI SOCI2 ,ch3 s,yCH3 CH3

Br F Cl 广 N^N hcihn[&gt;s ch3 βγ&gt;ύΛ^Λν^ ...··NitT*&quot; ULp O^s-yCHs Br CH3 F Cl (1) Triethylamine 8 at room temperature After adding 4 mL of a solution of 1-(tris-butoxycarbonyl)-4-hydroxypiperidine 6. 04 g in dichloromethane (100 mL), then added dropwise methanesulfonium chloride 2. 8 mL, and the mixture was stirred at room temperature 7 hour. After the reaction mixture was neutralized with 1 M hydrochloric acid, it was extracted with methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the precipitate was washed with ether / hexane, and then filtered, and then dried over vacuo to give 1-(tris-butoxycarbonyl)-4-methanesulfonyloxy Acridine 8·33 g (yield 99.4%). W-NMR (CDC13) (5: 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) at room temperature 1.3 g of sodium decoxide and 2-mercaptopropane-1-thiol 2. 6 mL of a solution of the compound obtained in the above (1) 2.26 g of dimethyl decylamine in 25 mL, the mixture was at 120 ° C is stirred for 3 hours. The reaction mixture is 233 323135 201202230. The mixture is poured into water, and the mixture is extracted with ether. The organic layer is dried over magnesium sulfate and then concentrated under reduced pressure. The residue is purified by chromatography. Ethyl acetate (6/1) refined t, and 4-isobutylthio-based bite-tert-butyl tertiary butyl ester (1.74 g) was obtained. H-NMR (CDC13) (5: 0.97-1. GG (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. 9Hz), 2·6 Bu 2. 81 (1H, m), 2. 8 Bu 2. 98 (2H, m), 3. 78-4. 04 (2H, m). (3) 4M hydrochloric acid / ethyl acetate 12.4mL was added to the compound obtained in the above (2) 1. 24g, the mixture was at room temperature After stirring for 4 and a half hours, the reaction mixture was concentrated, and the resulting white solid was washed with ether and then filtered, and then evaporated to dryness to afford 4-isobutylthiopiperidine hydrochloride (858 mg). ^-NMR (DMSO-de) δ : 0. 93-0. 95 (6Η &gt; d ' J=6. 6Hz) &gt; 1. 53-1. 81 (3H, m), 1. 95-2. 11 (2H, m), 2·39-2. 46 (2H, d, J=6. 9Hz), 2·8b 2. 97 (3H, m), 3. 16-3. 27 (2H, m , 8·93 (2H, brs). (4) 8-Bromo-5-fluoro-3H-quinazolin-4-one 1.7 g, dimethylformamide 0.6 g and sulfinium chloride After a mixture of 20 mL of the mixture was refluxed for 4 hours, the reaction mixture was concentrated under reduced pressure, and the residue was evaporated to m. Filtration was carried out by concentrating the filtrate under reduced pressure to give a brown solid ( 838 mg) of bromo-4-chloro-5-fluoroquinazoline. (5) 4- butyl thiol brittle hydrochloride 512 mg and triethylamine 234 323 135 201202230 0.92 mL were added to the compound (4) obtained in the above (4) in 380 mg of dioxazole in 30 mL of solution. Stir at room temperature for 8 hours. Water was added to the reaction mixture. The mixture was extracted with a methylene gas. The organic layer was dried with sulfuric acid and then concentrated under reduced pressure. The residue was dissolved in DMS0 and purified by reverse phase HpLC [column · Develosil ODS C18 ' 5 &quot; m, 28 mm x l00 mm, Nomura Chemical; mobile phase A : 0 · 1 % trifluoroacetic acid / water; mobile phase b : 〇. 〇 6 % trifluoroacetic acid / acetonitrile 'flow rate 30 mL / min (mobile phase &gt; 70% / 6 min). The fraction containing the reaction product (RT = 3.66 to 4.90 minutes) φ was collected, concentrated, and the residue was poured into an aqueous sodium hydrogencarbonate solution, and the mixture was extracted with dichloromethane. After the organic layer was dried over magnesium sulfate, the title compound was obtained (yield: 49.6%). ^-NMR (CDCh) 5 : 0. 99-1. 02 (6H&gt; J=6. 7HZ) &gt; 1. 71-1. 85 (3H, m), 2· 07-2. 13 (2H, m ), 2. 45-2. 48 (2H, d, J = 6. 8Hz), 2. 80-3. 02 (1H, m), 3. 24-3· 32 (2H, m), 4. 〇 7_4. 13 (2H, m), 6·97-7. 04 (lH, dd, J=8. 5Hz, l〇· 7hz), 7 94-8 〇〇 (ih, dd, J=5.3Hz, 8.4 Hz), 8.73 (1H, s). ® Reference Example A16 [2-Fluoro-4-(4, 4' 5, 5-tetradecyl-[1,3, 2]dioxaborolan-2-yl)phenyl](pyrrole) Manufacture of pyridine) ketone 323135 235 201202230

Br xsr χ&gt;&lt;ύ

(C0CI) 2/DMF βλγ

hnO

HaC H3C h3c as

AcOK.PdCI2(dppf)CH2CI2

DMSO (1) 50 mL of dioxane was added to 3 〇g of 4-bromo-2-fluorobenzoic acid, and then 122 mL of oxalate gas and MF 〇. 2 Torr were added at room temperature, and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (3 mL, EtOAc, m. After the mixture was stirred at room temperature for 2 hours, water i 〇〇 mL was added, and the mixture was extracted with di-methane. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and dried over EtOAc. The residue was purified by silica gel chromatography (solvent·hexane/ethyl acetate=3/1) to give (4-bromo-2-fluorophenyl)(1-pyrrolidinyl)fluorenone as an oil. 4. 02g (yield 108.8%). φ 'H-NMR (CDCh)^ : 1.884-1.993 (4H ' m) &gt; 3. 288-3. 321 (2H, t), 3.622-3.657 (2H, t), 7.285-7.367 (3H, m) . (2) 1.82g of bis(pinacolato) diboron, 1.92g of potassium acetate, [1,1,-bis(diphenylphosphino)ferrocene]palladium (Π) The gasification-digas hydrazine complex i6 〇 mg and DMS 015 mL were added to the compound 1.77 g obtained in the above (1), and the mixture was degassed and 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 MgSO4, EtOAc EtOAc (EtOAc (EtOAc) Yield 93.0%). 'H-NMR (CDCh) δ : 1. 347 (12Η, s) &gt; 1. 862-1. 981 (4H, in) &gt; 3· 264-3. 300 (2H, t), 3· 63 3. 666 (2H, t), 7. 384-7. 419 (1H, t), 7. 500-7. 520 (1H, d, J = 9.84Hz), 7·616-7. 597 (1H , d, J = 7.36Hz). Reference Examples A17 to A23: The compound of the following Table 116 was obtained by treating the corresponding starting compound in the same manner as in Reference Example A16.

237 323135 201202230 Table 116 Reference Example Να Chemical structure physical property value Α17 #&gt;year „2 'H-NMRiCDCb) δ: 1.36(12H,s), 5.88(lH,s), 6.72-6.73(lH,d) , 7.53-7.57(lH,d), 7.67-7.69(lH,d),8.01-8.13(lH,t) Α18 §0 engine 3 'H-NMRCCDCb) δ: 1,35(12H,s), 3.03- 3.04(3H,d), 6.80-6.82(lH,d), 7.51 -7.54(lH,d), 7.65-7.67(lH,d), 8.07-8. ll(lH,t) Α19 Μβ Λ ^ ^- NMROCDCb) 6: U9-1.26(3H,m), 1.35(12H,s), 3.49-3.55(2H,m), 6.77(lH,brs), 7.50-7.53(lH,d), 7.65-7.67(lH ,d), 8.06-8.10(13⁄4) Α20 'H-NMR(CDC13) 5:0.98-L01(3H,t), 1.35(12H,s), 1.61-L70(2H^n), 3.43-3.47(2HUn ), 6.77-6.80(lH,t), 7.50-7.53(lH,d), 7.65-7.67(lH,d), 8.06-8.10(lH,t) Α21 'H-NMR(CDC13) 5:1.22-1.26 (3H,m), 1.35(12H,s), 2.86-3.09(3H,d), 3.19-3.21(lH,m), 3.59-3.61(lH^n), 7.30-7.38(lH^n), 7.49 -7.52(lH^i), 7.60-7.62(lH,m) Α22^-NMRCCDCb) 5:1.35(12H,s), 3.31(2H,brs), 3.61-3.64(^^1), 3.76-3.81( 4H^n), 7.37-7.40(lH,t), 7.50-7.52(lH,d), 7.62-7.64(lH,d) Α23 锬年3 ^-NMR^DCb) δ:1.36(12Η^), 2.65 -2.66(3H,d), 7.53-7.56(111,(1), 7.61-7.63(lH, d), 7.82-7.85(1H,t) Reference Example A24 Manufacture of 8-(3-fluoro-4-didecylamine phenyl phenyl)_3H-wollen-4-one 238 323135 201202230

Nh(ch3)2 -_ NaHC03

(1) 4-bromo-3-fluorophenylboronic acid 2.24g, 2M sodium carbonate aqueous solution 64mL, tetrakis(triphenylphosphine) l£(0)1.0g and diterpene 16〇mL were added to 8峨After the mixture was degassed, the mixture was subjected to nitrogen removal, and stirred under reflux for 16 hours. The reaction mixture was poured into water, and dilute hydrochloric acid was added to the mixture to adjust to pH 1. After the precipitate was collected by filtration and washed with water, the mixture was dried under reduced pressure at 80 ° C to give 2-fluoro-4-(4-s-oxy-3,4-dihydroquinazolin-8-yl)benzoic acid. 3. 21g. MS (ESI) m/z: 287 [M+H]+ (2) hexanes 20 mL, oxalyl chloride 0. 31 mL, and DMF 0.1 mL were added to the compound (1) obtained in the above (1). The mixture was stirred at room temperature for 2 hours. To the reaction mixture were added dropwise a solution of 1% 6 mL of dimethylamine in hexanes and sodium hydrogen carbonate (1 g), 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. The residue was washed with a small amount of dichloromethane to give the title compound 273·lmg (yield 24.9%). MS (ESI) m/z: 312 [M+H]+ ° Reference Example A25 Manufacture of 8-(4-dimethylaminodecylphenyl) 3H__quinazoline _4 ketone by The starting compound was treated in the same manner as in Reference Example A 323135 239 201202230 to give the following compound.

MS (ESI) m/z: 294 [M+H]+. Reference Example A26 Manufacture of 8-(4-methylsulfonylphenyl)-3H-quinazolin-4-one 0 H3C'b: 乂"~Qing] 2 〇-2-► h3c-s Na2C03. Pd( PPh3)4 添加 4-38-sulfonylphenylboronic acid 4.38g, 2M sodium carbonate aqueous solution 71mL, tetrakis(triphenylphosphine)palladium (0) 983mg and dioxane 190mL were added to 8-moth sitting-4 After the mixture was degassed, the mixture was purged with nitrogen and stirred under reflux for 40 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was poured into water, and the residue was acidified, and the residue was purified by chromatography (yield: chloroform) to give the title compound 3.30 g. MS (ESI) ra/z : 301 [M+H]+ ° Reference Example A27 5-Gas-8 _(4-曱 酿 phenyl)-3 H-喧 喧 _ 嗣

0

F 240 323135 201202230 The title compound was obtained by treating the corresponding starting material compound in the same manner as in the title compound. MS (ESI) m/z: 319 [M+H]. Reference Example A28 Manufacture of 4-cyclohexylthiopiperidine

0〇H

OH

BocO^ SO3CH3 ΒοοΌ^ CH3SO2CI Et3N 】

(1) 36 g of di(tertiary butyl carbonate) dicarbonate was added in several portions to a solution of 15.0 g of 4-hydroxypiperidine in 150 mL of decyl alcohol 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 dioxane. The organic layer was washed with saturated aqueous The residue was washed with hexane, and the precipitate was filtered, washed with hexane, and then dried under reduced pressure at 40 ° C to give 4-hydroxypiperidine-1-carboxylic acid acid tert-butyl ester 22.48 g ( Yield: 75.3%). Ή-NMR (CDCh) (5: 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) The compound obtained in the above (1), 22·4 g, was added to a mixture of 220 mL of dichloromethane and 24 mL of triethylamine, and the mixture was stirred under ice cooling. After sulfonium gas 13·3 mL was added dropwise to the reaction mixture, the mixture was stirred at room temperature for 5 hours. The reaction mixture was extracted with dioxane. The organic layer was washed with water and dried over magnesium sulfate. 241 323135 201202230 The residue was taken from the slag and washed with hexane. After drying under reduced pressure, 30.75 g of 4-decyloxypiperidine-1-carboxylic acid tert-butyl ester was obtained. 98.9%). ^-NMR (CDCh) 5 : 1.46 (9H, s), 1.79-1.86 (2H, in), 1.94-1.99 (2H, m) &gt; 3. 04 (3H, s), 3.27-3.33 (2H, m), 3. 68-3.73 (2H, m), 4. 87-4. 90 (1H, m) (3) After stirring a mixture of cyclohexyl mercaptan 3.32 mL and DMF 10OmL under ice cooling Adding 60% sodium hydride 1.2g to the mixture in several times' The mixture was spoiled at room temperature for 1 hour. Under ice cooling, the compound obtained in the above (1) was obtained. 7. 35g was added to the reaction mixture in several portions, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and extracted with methylene chloride. The organic layer was washed with water and dried with sulfuric acid. After that, it was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (solvent: hexane / ethyl acetate = 1 / 20) to give 4-cyclohexylthiopiperidine-carboxylic acid tert-butyl butyl ester 5.80 g (yield 73.6%) φ !H-NMR (CDC13) 5 : 1.31-1.35 (4H, in), 1.45-1.63 (13H, m), 1. 7 6 _ 1 · 7 7 ( 2 Η ,in ),1 · 8 8 ~ 1. 9 6 ( 3 Η,m ),2 7 2—2 7 3 (1H, m), 2.84-2.94 (3H, m), 3.47-3.50 (ih, t) , 3 88-3·94 (3H, m) (4) Add 2 mL of di-methane methane and i〇mL of trifluoroacetic acid to 4.22 g of 4_cyclohexylthiopiperidine-1-carboxylic acid tert-butyl ester. The mixture was stirred at room temperature for one night. The reaction mixture was concentrated under reduced pressure, and then 50% of aqueous solution of potassium carbonate was added to the residue, and then extracted with dichloromethane. The organic layer was dried over magnesium sulfate. The title compound was obtained as an oil 323135 242 201202230 2. 58 g (yield: 91.8%). . ^-NMR (CDCh) δ : 1. 28-1. 35 (4H, m), 1. 48-1. 53 (3H, in), 1-76-1.77 (2H, in), 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 Production of 4-(4-methoxyphenylhydrazinothio)piperidine

HN^ys

The compound obtained in Reference Example A28 (2) and 4-methoxybenzyl mercaptan were treated in the same manners as in References A28 (3) to (4) to give the title compound. Ή-NMR (CDCh) 5 : 1. 47-1. 50 (2H, in), 1. 88-1. 97 (2H, ra) 2.56-2.69 (2H, m), 3.05-3.10 (3H, m) ,3· 72 (10)' 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 曱Mulphonic acid l-[8-(4-didecylaminoindolyl) quinazolinpiperidin-4-ester

323135 243 201202230 (1) The sulphur sulphide gas 18.2mL and DMF 0. 96mL was added to 8_(4-didecylaminodecylphenyl)-3H-quinazolin-4-one 2. 59g, Stir under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in dioxane and washed with ice water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 4-(4-chloroquinazoline <RTI ID=0.0>8 </RTI> </RTI> <RTIgt; To the compound were added THF 1 mL, 4····················· The reaction mixture was concentrated under reduced pressure and the residue was purified eluting The organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was purified by silica gel chromatography (solvent: gas) to give 4-[4-(4-hydroxypiperidin-indoleyl) quinazolin-8-yl]-Ν' N-dimercaptobenzene The amorphous powder of guanamine was 2.53 g (yield 70.8%). Old-臓 (CDC13) 5 : 1.88-1.92 (2H, m), 2.07-2. 12 (2H m), 3. 07-3. 15 (10), 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. 0Hz), 7. 81-7. 83 (1H, d, J = 5. 4Hz) 7.95-7.97 (1H, d, J = 6.3Hz), 8.603 (1H, s). (2) To a mixture of 2.53 g of the compound obtained in the above (1), 25 mL of di-methane methane, and i.4 mL of triethylamine, and the mixture was stirred at room temperature under ice-cooling. All night. The reaction mixture was extracted with EtOAc (EtOAc). The residue was purified by silica gel chromatography (yield: ethyl acetate - 10% EtOAc/EtOAc). j-NMR (CDC13) (5: 2.11-2. 15 (2H, m), 2. 23-2.25 (2H 323135 244 201202230 3., 10~3. 15 (9H, m) m.7l (2H, ffl ), 4·00_4.05 ^ 5.06-5.08 (1«,,)&gt; 7.52-7.56 (3Η, m) ^7. 71-2H,m),7·78—7. 79 (1H' d,J =9.〇Hz), 7. 90-7. 89 UH, d' J=9. 0Hz), 8. 795 (1H, s). #考例A31 [8~(4-oxasulfonylphenyl)quinazoline~yl]pyrylene_4_ol

(1) 5 mL of a 2 M sodium carbonate aqueous solution was added to 544 mg of 8__iodo_3H_quinazoline-4-one, 44 mg of 4-methanesulfonylphenylborate, and 225 mg of tetrakis(triphenylphosphine)palladium(0) In the mOmL solution, the Wei compound was searched for 13 hours under reflux. The reaction mixture was concentrated, and water and ethyl acetate were added to the silk, and the mixture was filtered. After the liquid red liquid is transferred to the thick layer, the residue is purified by a silica gel column chromatography to obtain 8_(4_methylsulfonyl phenyl)-3H-indole-4-copper 513. 3 mg (Yield: 85%). MS (ESI) m/z: 301. 1 [M+H]+. 5小时时。 The mixture was stirred under reflux for 4. 5 hours. The mixture was stirred under reflux for 4. 5 hours. The reaction mixture was concentrated, poured into a saturated aqueous solution of sodium bicarbonate, and the mixture was extracted with chlorobenzene, 323 135 245 201202230. The organic layer was dried over magnesium sulfate and then reduced in vacuo. The residue was dissolved in THF (2 mL). EtOAc (yield: The reaction solution was concentrated, dissolved in a gas, and then simmered. The filtrate was concentrated to give a white powder of the title compound (yield: 45%) (yield: 45%). MS (ESI) m/z: 384. 1 [M+H]+. j-NMR (CDCI3) 5 : 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) &gt; 7.75-7.78 (1H, dd, J=1.3HZ 7. 2Hz), 7.86-7. 89 (2H, d, J=8. 4Hz), 7. 93- 7. 97 (ijj dd J=1.3Hz, 8. 3Ηζ), 8·04-8. 07 (2H, d, J=8.4Hz), 8.75 (ih Reference Example A32

Manufacture of 2-gas-4-[5-fluoro-4-(4-transpyridin-1-yl)pyrene-N,N-dimercaptobenzamide φ^·ΝΗ SOClz/DMF Br (Heart cool p Me

Pd(PPh3)4

Na2C03 (1) Add DmL 0.5mL and sulfite gas 25mL to R, cold 0~ thirst ~ gas -3H-quinazolin-4-one 1 · 5g, the mixture is given under reflux

J 323135 246 201202230 The reaction mixture was concentrated under reduced pressure. After the residue was dissolved in di-methane, the mixture was poured into aqueous sodium hydrogencarbonate, and the mixture was extracted with methane. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give a crude product of 8-br. This compound was dissolved in a mixture of tetrahydrofuran 4 〇乩 and dichloromethane (30 mL). 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, and water was added to the residue, and then evaporated. The organic layer was dried with sulfuric acid, concentrated under reduced pressure, and refined in a gel column chromatography (solvent: 10% methanol / di-methane) to give 1-(8-bromo-5-fluoroquino. Polin-4-yl)piperidin-4-ol nog (yield 89%). MS (ESI) m/z : 325.8/327.8 [M+H]+〇

^-NMR (CDCh) (5: 1.67-1.78 (2H, m) &gt; 2. 01-2. 09 (2H m), 3. 38-3. 47 (2H, m), 3.96-4. 03 (3h, m), 6. 98-7 〇5

(1H, dd, J=8. 6Hz, 10·7Ηζ), 7.95~8. 〇〇 (iH, dd, j=5 3Hz 8. 6Hz), 8.73 (1H, s). (2) Adding 13 μL of 2M aqueous sodium carbonate solution to the compound obtained by the above (丨) 1. 79 g, 2-fluoro-N,N-dimercapto-4-(4, 4, 5, 5-tetradecyl-[ 1,3, 2] dioxaborolan-2-yl)benzamide 1.93 g and tetrakis(triphenyl) palladium (0) 632 mg of dioxane in 39 mL of the solution Stir under reflux for 6 and a half hours. The reaction mixture was concentrated, and 1M hydrochloric acid was added to the residue to adjust to ρΗ7, and then the mixture was extracted with methylene chloride. The organic layer was dried (MgSO4). MS (ESI) m/z: 412.8 [M+H]+. Reference Example A33 Manufacture of 2-fluoro-4-[4-(4-hydroxybine-1-yl)quinoxaline_8_yl]_叱^dimercaptobenzamide j!p°l 'xypL 1 10 MEt3

(H3C)2N ;^Β〇ΐ1 F CH3 0H Pd(PPh3)4.Na2C〇3

(1) 4-gas-8-iodoquinazoline 2. 90g was dissolved in a mixture of 50 mL of THF and 30 mL of dichlorohydrazine, and after adding 1. 2 mL of triethylamine and 1.42 g of 4-hydroxylidine in the solution, Stir at room temperature for 6.5 hours. The reaction mixture was concentrated under reduced pressure. ethyl acetate and aqueous The filtrate was extracted with ethyl acetate. The organic layer was dried (MgSO4), evaporated, evaporated, evaporated.啥I»坐琳-4-yl) α辰咬-4_ alcohol 2.34g (yield 66%). MS (ESI) m/z: 355.8 [M+H]+. • H-NMR (CDCh)d: 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. 7Hz, 8. 1Hz) &gt; 7. 84-7. 87 (1H, d, J=8. 3Hz) &gt ; 8.31-8.34 (1H, dd, J=7.4Hz, 8. 3Hz), 8.82 (1H, s). (2) The compound obtained by the above (1) (1.53 g) and 2-fluoro-N,N-dimethyl-4-(4,4,5,5-tetradecyl-[1,3 , 2]dioxaborolan-2-yl)phenyl hydrazide (1.52 g) was obtained in the same manner as in Reference Example A32 (2) at 248 323 135 201202230 to obtain an amorphous powder of the title compound. (1. 52g) (yield 90%). MS (ESI) m/z: 394.9 [M+H]+. Reference Example A34 2-Den-4-[5-fluoro-4-(pyrene-1-yl)indole. Manufacture of lysine-8-yl]-?'1,?'1-dimercaptobenzamide 2 hydrochloride

Ch3 (1) 8 mL of sulphur sulphide and 0.733 mL of dimethyl decylamine were added to 8-di-5-fluoro-3 Η-°|: β-isolin-4-one 1.66 g, and the mixture was refluxed. Stir under 4 hours. The reaction mixture is concentrated under reduced pressure, and the residue is dissolved in dichloromethane, and the solution is added dropwise to the piperidin-1-carboxylic acid tert-butyl ester 1.91 g, potassium carbonate 2.83 g, water 20 mL and Chlorosulfonium 30mL mixture • medium. The mixture was stirred overnight at room temperature. The reaction mixture was extracted with dichloromethane. EtOAc was evaporated. 8-odor-5-1 quinine σ 琳 -4- -4- ) σ - - - - - - - - - - - - - - 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨464.3 [M+H]+. (2) The compound obtained by the above (1) (2.22 g) and 2-fluoro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-[1,3 , 2] dioxaborolane 249 323135 201202230 -2-yl)benzamide (1.83 g) was treated in the same manner as in Reference Example A32 (2) to give 4-[8-(3) -Fluoro-4-dimethylamine-m-decylphenyl)-5-fluorooxazoline-4-yl]piperidine-1-carboxylic acid tert-butyl butyl ester (1.79 g) (yield 69.8%) . MS (ESI) m/z: 495 [M+H]+. (3) The title compound (1.69 g) of the 2 hydrochloride salt was obtained (yield: 99.9). %). MS (ESI) m/z: 398 [Μ+ΗΓ.

Reference Example A35 Manufacture of 4-(3-isopropyl-[1,2,4]indole dipyrid-5-yl)-4-methylpyramine hydrochloride

(1) Adding 1 - 2 -butoxyl-based _4_ fluorenyl β-biting _4_ retinoic acid 2 g and triethylamine 1.15 mL to toluene 5 〇 mL in the mixture at 〇 ° c After adding dropwise isobutyl chlorocarbonate 1·〇7 mL, it was stirred at room temperature for 2 hours. To the reaction mixture, 837 mg of yt-hydroxy-2-mercaptopropane iminoamine (the compound obtained in Reference Example Al (l)) and molecular sieve 4A (4 g) were added, and the mixture was stirred at 120 ° C for 4 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was added to wash the organic layer in the order of water and saturated brine, and the organic layer was dried over sulfuric acid. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 91 / 9 - 80 / 20) to give 4-(3-isopropyl) - [1,2,4]oxadiazole _5_yl)_4-tert-piperidin-1-carboxylic acid tert-butyl butyl colorless liquid l.91 g (yield 75%). MS (APCI) m/z; 310 [M+H]+. (2) 4N Hydrochloric acid-11⁄2 was added to the above-mentioned compound (1), 1. 9 g of 1,4-dioxane in 10 mL of a solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAc m. MS (APCI) m/z ; 210 [M+H]+. Reference Example A36 Preparation of 4-(5-isopropyl-[1,2,4]indole disani-3-yl)π-bite hydrochloride

iPrCOOH CICOO(i-Bu) NH2 Et3N

(1) 400 mg of 50% aqueous hydroxylamine solution was added dropwise to 4-cyanopiperidin-1 monocarboxylic acid tert-butyl ester 1.27 g of 2-propanol 6. OmL solution, the mixture was stirred at 80 ° C All night. After the reaction mixture was cooled to room temperature, ethyl acetate was added, and the organic layer was washed with water and saturated brine. The organic layer was dried over magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure to give 4-(N-hydroxymethylmethyl)piperidine-1-carboxylic acid tert-butyl ester as a colorless solid 1.34 g Rate 323135 251 201202230 91%). MS (APCI) m/z ; 244 [M+H]+. (2) I.41 mL of isobutyl carbonate was added dropwise to a mixture of 1 mL of Olanza, Triethylamine oxime, 52 mL and 66 mL of toluene at 〇 °c, and the mixture was stirred at room temperature. 1 hour. 2·65 g of the compound obtained above was added to the reaction mixture, and the mixture was stirred at 120 Torr for 4 hours. After the mixture was cooled to room temperature, it was filtered over Celite, and filtrate was concentrated under reduced pressure. The residue obtained is purified by a silica gel column chromatography (solvent: hexane: ® 酉 酉 = 91 : 9-80 : 20) to obtain 4-(5-isopropyl, [n 4] 噚- Base) bite-1-reacid three-stage Ding Zizhi colorless solid 2 l8g (yield MS (APCI) m/z; 296 [Μ+ΗΓ. (3) Add 4N hydrochloric acid-dioxane 25mL to the above (2) In the U-World War II 13mL solution of the obtained person 2.5Gg, the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue, which was washed with ether and dried under reduced pressure. The title compound 1 = ethyl Ulg (yield: 87%) was obtained.., color solid MS (APCI) m/z; 196 [M+H]+ ° Reference Example A37 5-mercapto-2-(piperidin-4- Manufacture of pyrimidine bite PH3 0

Ph^

重量。 [0] _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ The mixture was stirred at room temperature for 5 minutes in a suspension of 30 mL of butanol in 250 mL. A solution of 10.32 g of dimethoxyethane in 100 ml of tosylmethyl isocyanide was added dropwise to the reaction mixture, and the mixture was stirred at 60 ° C for 2 hours. After adding water to the reaction mixture, it was extracted with ether. 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 residue obtained was purified by silica gel column chromatography (solvent: hexane/ethyl acetate=65/35-45/55) to give 1-phenylmethyl-4- cyano Piper a pale brown liquid 4.20 g (yield 79%). MS (APCI) m/z ; 201 [M+H]+. (2) Under a nitrogen atmosphere, 21 mL of 2M trimethylaluminum-toluene solution was added dropwise to a 40 mL solution of ammonium chloride 2·47 g in toluene under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes and then at room temperature. Stir for 2 hours. To the reaction mixture, a solution of 4.19 g of the compound obtained in the above (1), 5 mL of toluene was added, and the mixture was stirred at 80 ° C for 17 hours. After the reaction mixture was cooled to room temperature, it was diluted with φ chloroform, and 80 mL of saponin was added thereto, followed by filtration over celite. The filtrate was concentrated under reduced pressure, and chloroform / decyl alcohol (4/1) was added to the residue, and the insoluble matter was filtered. The filtrate is concentrated under reduced pressure, and the residue is added to the residue, and the precipitate is obtained by filtration to give 4-bromo-1-phenylmethylpiperidine hydrochloride as a pale brown powder 3.20 g (yield 60) %). MS (APCI) m/z ; 218 [Μ+ΗΓ. (3) adding a 28% sodium decoxide-methanol solution to a solution of 500 mg of the compound obtained in the above (2) and 5 mL of 3-dimethylamine-2-methyl-2-propenal 446 mg of ethanol, the mixture is At 90X: disturbed for 7 hours. Reaction Mixing 253 323135 201202230 After cooling to room temperature, 'add water' was extracted with a gas pattern. The organic layer was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (solvent: chloroform/methanol = 100/0-91/9) to give 2-(1-phenylhydrazinopiperidin Base) _5_ methylpyrimidine pale brown solid 302 mg (yield 57%). MS (APCI) m/z ; 268 [M+H] + 〇 (4) 20% cerium oxide 4Omg was added to the 300 mg ethanol solution of the above-mentioned (3). The mixture was subjected to hydrogen atmosphere. Mix at room temperature overnight. The reaction mixture was further stirred at 50 ° C for 6 hours and then allowed to stand at room temperature for 3 days. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 215 mg (yield: 1%) of the title compound. MS (APCI) m/z; 178 [M+H]+. Reference Example A38 4-(5-Isopropyl-[1,3,4]fluoren-2-yl)Nylonbitate hydrochloride system \ 9h3 1Y^ch3 Ο 3οοΝ^ Η Ο BocN^ Let BocHN· Η 9Η3 h2n*ny^ch3 ο ^η3 ch3 ^CH3 CH,

HmL (1) Isobutyl chlorohydrin 2. 6mL of dioxane 10mL solution was added dropwise to the carboxylic acid tert-butyl butyl ester 3. Og and triethylamine 6. 3mL of dichloro decane 50mL solution The mixture was stirred at room temperature for 21 hours. After adding water to the reaction mixture, it was extracted with chloroform. The organic layer was washed with diluted hydrochloric acid and saturated brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (solvent: hexane: 254 323135 51 201202230 ethyl acetate), and then obtained by hexane to obtain N, 2. 63 g (yield 57%) of a colorless solid of dimethyl carboxylic acid. MS (APCI) m/z ; 203 [M+H]+. (2) To a solution of the above-mentioned (!), 2.63 g of 1,4-dioxane in 20 mL of a solution of 4N hydrochloric acid was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was obtained by diluting a residue of &lt;RTI ID=0.0&gt;&gt; • MS (APCI) m/z ; 103 [M+H]+. (3) N-tertiary butoxycarbonylpiperidinic acid 2.19 g, butyl benzotriazole 1 hydrate 2. 19 g and 1-ethyl-3-(3-dimethylaminopropyl) 2.73 g of carbodiimide hydrochloride was added to a solution of 159 g of the compound obtained in the above (2) and 2.66 mL of dichloromethane (40 mL), and the mixture was stirred at room temperature for 15 hr. After water and a saturated aqueous solution of sodium hydrogencarbonate were added to the reaction mixture, the mixture was extracted with a gas. The organic layer was concentrated under reduced pressure, and then the residue was purified by hexane column chromatography (solvent: hexane / ethyl acetate = 50 / 50 - o / loo) to give a tri-butyloxycarbonyl group. 4 (N, _ Isobutylhydrazinocarbonyl) piperidine as a colorless solid 2·28 g (yield: 76%). MS (APCI) m/z ; 314 [M+H] + ° (4) 2-46 g of 2-chloro-1,3-dimethylimidazole sulphide was added to the above-obtained compound 2.28 g and triethylamine 4. 〇 5 mL of a second gas, 6 liters of DlL / combined solution, and the mixture was stirred at room temperature for 21 hours. After adding water and a saturated aqueous solution of sodium bismuth carbonate to the reaction mixture, it was extracted by gas chromatography. The organic extract was washed with saturated brine, dried over magnesium sulfate, and filtered through 255 323 135 201202230. The filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (solvent: hexane/ethyl acetate=70/30-35/65) to give 1-tris-butoxycarbonyl-4- (5-isopropyl-[1,3,4]oxadiazol-2-yl)piperidine 688 mg (yield 32%) as a colorless viscous oil. MS (APCI) m/z ; 296 [M+H]+. (5) 4 mL of 4N hydrochloric acid-dibenzoic acid was added to 688 mg of the compound obtained in the above (4) in a 1,4-dihydrogen 4 mL solution, and (4) the mixture was stirred at room temperature for 2 hours. The reaction mixture was subjected to dichlorobenzene, and the precipitate was filtered to give the title compound (yield: 55) (yield: %). MS (APCI) m/z ; 196 [M+H]+ ° Reference Example A39 2-(2-Fluoro-4-(10)-dimethylaminesulfonyl)phenyl 4,5,5-tetramethyl -[1,3, 2]Production of monooxaborolane

, α

Br

N&quot; CH •CH, ^Π3

CHg • ch3 (1) Dilute 2Μ dimethylaminotetrahydrofuran solution 3 ' in 〇 mL and add 4 g -3- 醯 醯 L37g under ice cooling, and mix the mixture at room temperature _ overnight . The reaction solution was concentrated under reduced pressure, and then ether was added to the obtained mixture, and then NH-stone (Chray atorex) was added to the air, and the mixture was passed, and the filtrate was concentrated under reduced pressure. A white solid of 624 mg (yield 44%) of 4-molybdenylamine was obtained by extracting the precipitate from the obtained dough (4) / hexane (9). 323135 256 201202230 MS (APCI) m/z; 282/284 [M+H]+. (2) The compound 62 (〇) and the 380 mg of the boronic acid pinacol ester obtained in the above (1) were treated in the same manner as in the reference example A16 (2). ). Inch ^ MS (APCI) ra/z ; 330 [M+H]+ ° Reference Example A40 2-(3-Fluoro-4-methylsulfonylmethylphenyl)-4, 4, 5, Tetramethoate [1,3, 2]Production of dioxaborolane'

S-CHq wrcH3

Br

O-BMi5/xb Me Me

卜ch3 &quot;(;): 3: 15% methyl mercaptan sodium water is dripped ~ into 4-bromo-2-fluorobenzol bromide 2. 68g of dimethyl ketone λ, ^ ^ soil After the indoleamine 1 OmL solution, the mixture was taken at the same temperature overnight. The reaction solution was added to a saturated aqueous solution of sodium hydrogencarbonate to obtain a (tetra) compound from ethyl acetate: the extract was dried, and then the solution was cooled and reduced under reduced pressure. The obtained residue was purified by Shih-Hybrid column chromatography (solvent: Acetic acid s- 10-(10) to obtain 4-dichloromethane; - 7-colorless liquid 1.39 g (yield 59%). /2) The addition of m-chloroperoxybenzoic acid 2 to the above-mentioned (1) at room temperature. In a solution of 1.39 mg of chloroform in 1Q mL, the mixture was taken at = temperature for _3 hr. The reaction solution was added to a saturated aqueous solution of sodium hydrogencarbonate, which was extracted three times with ethyl acetate. The extract was dried over magnesium sulfate, filtered over 323 135 257 201202230, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by a silica gel column chromatography (solvent: ethyl acetate / hexane = 80 / 20 - 50 / 50) to give 4-di-2-fluoro-1-methylsulfonyl fluorenyl The white solid of benzene was 7 〇 2 mg (yield 45%). MS (APCI) m/z; 299/301 [M+H]+° (3) By the compound (534 mg) obtained in the above (2) and the benzoic acid pinacol ester (609 mg), and Reference Example A16 ( 2) The same procedure was used to give 585 mg (yield: 93%) of white solid. ® MS (APCI) m/z ; 315 [M+H]+ ° Reference Example A41 1 [2 Dun-4-(4,4,5,5-tetramethyl-[1,3,2]dioxa Manufacture of boron boroxime 2 -yl)phenylhydrazino]-1H-1,2, 4-trisole

(1) 0.80 g of 60% sodium hydride was added to a solution of 2.68 g of 4~ benzoyl bromide and 1.38 g of triazole in a DMF 10 mL solution at room temperature, and the mixture was stirred overnight at room temperature. The reaction solution was added to an aqueous solution of ammonium sulfate, 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 residue obtained was purified by silica gel column chromatography (solvent: ethyl acetate/hexane = 35/65-60/40) to give bromo-2-fluorophenylhydrazinyl-1. -1,2,4-triazole white solid i.93 g (yield 75%). MS (APCI) m/z; 256/258 [M+H]+ 〇323135 258 201202230 (2) By reference to the compound (512 mg) obtained above (1) and the benzoic acid pinacol ester (609 mg) Example A16 (2) was treated in the same manner to give the title compound as a colorless liquid (3,3 mg). MS (APCI) m/z ; 304 [Μ+ΗΓ. Reference Example A42 Manufacture of 1-[2-fluoro-4-(4,4,5,5-tetramethyl 2]dioxaborolanepentan-2-yl)phenylindole]-in-tetrazole

(1) 0.80 g of 60% sodium hydride was added to a solution of 2.68 g of tetrabromofluoromethane bromide and 1.48 g of tetrazole in DMF 10 mL at room temperature, and the mixture was stirred overnight at room temperature. 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. The residue obtained was purified by silica gel column chromatography (solvent: ethyl acetate /hexane = 20 / 80 - 60 / 40) The base is -1 Η - 4 0 sitting white solid 0. 95 g (yield 37%). MS (APCI) m/z; 257/259 [M+H] + 〇(2) by the compound (5i4mg) obtained in the above (3) and the acid pinacol ester (609 mg) and Reference Example A16 (2) The same procedure was used to obtain 785 mg (yield: 75%) of the title compound. MS (APCI) m/z ; 305 [M+H] + 〇 Reference Example A43 1-[8-(4-Dimercaptocarbamoyl-2-fluorophenyl)-6-fluoroquinazoline-4 - 259 323135 201202230 Manufacture of piperidine-4-carboxylic acid

(1) By treating 850 mg of 8-di-6-1-3H-oxime ketone-4-ketone and 605 mg of ethyl citrate, in the same manner as in Reference Example A6 (5), 1-(8-Bromo-6-fluoroquinazolin-4-yl)piperidine-4- decanoic acid ethyl ester as a colorless solid 1.30 g (yield: 97%). MS (APCI) m/z; 382,384 [M+H]+. (2) The compound i. 29g obtained by the above (1) and 2-[4-(N,N-dimercaptomethylmercapto)-2-fluorophenyl]-4, 4, 5, 5 - 1.80 g of tetramethyl-[1,3,2]dioxaborolane was treated in the same manner as in Example A1 to give 1-[8-(4-didecylamino) 1-35 g (yield 86%) of a colorless solid of ethyl 2-fluorophenyl)-6-fluoroquinazoline- 4- φ yl]piperidine- 4-carboxylate. MS (APCI) m/z ; 469 [M+H]+. (3) 450 mg of the compound obtained in the above (2) was dissolved in THF / decyl alcohol 9M1 (1:1). After the dropwise addition of 576 # L of 2M aqueous sodium hydroxide solution, the mixture was stirred for 5 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and filtered. By concentrating the filtrate under reduced pressure, 408 mg (yield: 96%) of the title compound. Further, the present compound was not further refined and was used in the next step of the reaction. 323135 260 201202230 MS (APCI) m/z ; 441 [M+H]+. Reference Example A44 Manufacture of 2-(3-fluoro-4-methylthiophenyl)-4,4,5,5-tetramethyl-[132] dioxaborolane

(1) Potassium carbonate 1.67 g and iodonane 0.60 mL were added to a solution of 1.0 g of fluorobenzene sulfonate in a 10 mL solution of N-mercaptopurine 17 each of the ketones, and the mixture was stirred for 1 hour. Water was added to the reaction mixture and extracted with a solution of EtOAc. The organic layer was washed in the order of water and saturated brine, dried with citric acid, and filtered. The filtrate was concentrated under reduced pressure, and the residue obtained was purified by chromatography (solvent: hexane/ethyl acetate=99/1 - 90/10) to give 4-bromo-2-fluorophenylhydrazine. Light brown liquid of thioether 1. 〇 2 g (yield 96%). (2) The compound (1〇〇g) obtained in the above (1) and the pinacol ester of borazonate (1·49 g) were treated in the same manner as in Reference Example A16(2) under a nitrogen atmosphere. 646 mg (yield 53%) of the pale green liquid of the title compound. Reference Example A45 N,N-Dimercapto-4-(4,4,5,5-tetradecyl-[1,3,2]dioxaborolan-2-yl)-2-tri Manufacture of fluorenyl benzoic acid decylamine

(1) 1 , Γ-carbonyl dim 嗤〇.79g was added to a suspension of 1.0 mL of 4-chloro-2-trifluoromethyl benzoic acid in 1 mL of methylene chloride in 1 mL of a suspension. 261 323135 201202230 The mixture was stirred for 1 hour. At room temperature

Dimethylamine/THF solution The mixture was stirred overnight. Add saturation and extract with chloroform. The organic layer was added to the reaction mixture with a solution of 3.34 mL of sodium bicarbonate, and the mixture was diluted with aqueous sodium chloride and brine. Columns> Washed with water and dried with magnesium sulfate. The liquid will be obtained by the rubber column chromatography (solvent: hexane

MS (APCI) m/z; 252/254 [M+H]+ 〇(2) The compound obtained by the above (1) (1 〇 ig) and the boronic acid pinacol ester (1.22 g) under a nitrogen atmosphere. It was treated in the same manner as in Reference Example A16 (2) to obtain 7 Umg (yield 52%) of the pale green liquid of the title compound. MS (APCI) m/z ; 344 [M+H]+ 〇 Reference Example B1 Manufacture of 7-bromo-5-fluoro-1H-indole-2, 3-dione

A solution of 5-fluoroporin (2-nuorosatin) 20.6 g of ethanol in 240 mL was added to 80 C. After 14 minutes of dropwise addition of 14 mL of bromine, the mixture was stirred for 1 hour. After adding 3 mL of bromine to the reaction mixture, it was stirred for 2 minutes. The reaction mixture was cooled to room temperature &lt;RTIgt;&lt;/RTI&gt; MS (APCI) m/z: 242/244 [M+H]+. Reference example B2 262 323135 201202230 8-Moist-6-gas-3H-啥'1 Manufacture of 琳琳-4-嗣

2克。 The title compound was obtained in the same manner as in Reference Example A6 (3) to (4) to give the title compound 49. 2g. MS (APCI) m/z : 243/245 [M+H]+.

Reference Example B3 Manufacture of 8-bromo-4-gas-6-fluorophthalocyanine

Add 1 drop of decylguanamine to a solution of 8-bromo-6-fluoro-3H-quinazolin-4-one 10. lg sulfoxide in 100 mL, and stir the mixture at 80 °C. hour. After cooling to room temperature, the solvent was distilled off under reduced pressure. A saturated aqueous solution of sodium hydrogencarbonate was added, and ethyl acetate and dichloromethane were evaporated. The obtained residue was subjected to hexane (yield: 93%). MS (APCI) m/z : 261/263 [Μ+ΗΓ . Reference Examples B4 to B5 By treating the corresponding starting compound in the same manner as in Reference Example A1, the following compound was obtained. (Reference Example B4) 4-(3-propyl-[1,2,4]曙2° sitting-5-yl) Pieces Hydrochloric Acid 263 323135 201202230

HCI MS (APCI) m/z : 196 [M+H]+. (Reference Example B5) 4-[3-(2, 2, 2-Trifluoroethyl)-[l, 2, 4]oxadiazol-5-yl]D bottom bite hydrochloride

HCI MS (APCI) m/z: 236 [M+H] + ° Reference Example B6 to B8 The corresponding compound was treated in the same manner as in Reference Example A36. (Reference Example B6) 4-(5-propyl-[1,2,4]oxadiazol-3-yl)piperidine hydrochloride

(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 264 323135 201202230 Hydrochloride

〇'N

HCI F3G, V^i

k^NH MS (APCI) m/z : 222 [M+H]+. Reference Example B9 8-Moist... 6-Fluoro-4-[4-(5-isopropyl-[1,2,4]indolediyl) brigade Bitten-1-yl]

Adding saturated sodium bicarbonate solution 30 inL and 8-di-4-fluoro-6-aeroquinazoline (Compound obtained in Reference Example B3) 1.80 g to 4-(5-isopropyl-[1,2 4, oxadiazol-3-yl)piperidine hydrochloride (Compound obtained in Reference Example A36) was stirred in a solution of 1.78 g of dioxane in 30 mL, and the mixture was stirred at room temperature for 2 hr. The aqueous layer was taken out from the reaction mixture and extracted with dichloromethane. The organic layer was combined, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc The crude crystals were washed with hexane, and then filtered, and then evaporated to dryness. MS (APCI) m/z ; 420/422 [M+H]+. Reference Examples B10 to B14 265 323135 201202230 The following compounds were obtained by treating the corresponding starting compounds in the same manner as in Reference Example B9. (Reference Example B10) 8_漠_6_败-4_[4_(5_propyl_[ 1,2,4]曙二. Sitting -3-基)派咬-1-基]喧11坐琳

MS (APCI) m/z : 420/422 [M+H]. (Reference Example B11) 8_臭-6-败-4_[4-(5-cyclopropyl-[1,2,4]曙二嗤-3-yl)-ββ--1-yl]啥嗤琳

MS (APCI) m/z : 418/420 [Μ+ΗΓ. (Reference Example B12) 8_漠_6-说-4_[4_(3-Isopropyl-[1,2,4] succinyl-5-yl) π α 定 -1-yl] 啥嗤Lin

MS (APCI) m / z : 420 / 422 [M + H] + ° (Reference Example B13) 8- Desert-6-iL-4-[4-(3-propyl-[1,2, 4]曙二唆-5-*)β辰咬-1-基]喧吐琳266 323135 201202230

MS (APCI) m/z : 420/422 [M+H]+. (Reference example 'B14) 8-Di--6-fluoro-4-[4-[3-(2,2,2-trifluoroethyl)-[1,2,4]nonane-5-yl] °Bottom bite-1-base]喧°坐琳

N^N MS (APCI) m/z : 460/462 [M+H]+. Reference Example B15 8-Moist-5-Fail-4-[4-(5-isopropyl-[1,2,4]曙disal-3-yl)α

Manufacture of pyridine-1-yl]quinazoline 0 F ΗΝ

Br Add 1 drop of decylguanamine to 8-bromo-5-fluoro-3H-quinazolin-4-one (compounds of Reference Examples A6(l) to (4)) 2.43 g of sulfurous acid In a 25 mL helium gas solution, the mixture was stirred for 4 hours while refluxing. After cooling to room temperature, the solvent was distilled off under reduced pressure. The residue was suspended in 32 ml of di-methane to prepare a solution, and the solution was slowly added to 4-(5-isopropyl-[1,2,4]oxadiazol-3-yl at room temperature. 2,517 mg of piperidine hydrochloride (the compound obtained in Reference Example A36) and 25 ml of a saturated aqueous sodium hydrogencarbonate solution were stirred in a reaction mixture of 267 323 135 201202230. After further stirring at room temperature for 50 minutes, water was added and evaporated. The resulting residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc: %). MS (APCI) m/z ; 420/422 [M+H]+. Reference Example B16 2-[3-Fluoro-4-(2-methoxyethylthio)phenyl]-4, 4, 5, 5-tetramethyl-[1,3, 2]dioxaboron Manufacture of heterocyclic pentane

(1) 2-Butyloxy bromide ruthenium bromide. 68 mL, potassium carbonate 1.34 g added to 4-wet-2-fluoro-benzenethione 1. 〇〇g N-mercapto π piroxime _ In a lmL solution, stir at 85 ° C for 1 hour. The reaction mixture was cooled to room temperature, water was added and ethyl acetate was evaporated. 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 obtained residue was purified eluting with EtOAc EtOAc EtOAc EtOAc A colorless liquid of fluoro-1-(2-decyloxyethylthio)benzene was 1·13 g (yield 88%). (2) 1.40 g of diboronic acid pinacol ester, potassium acetate i.37 g, [1,1,-bis(diphenylphosphino)ferrocene]palladium(II) di-vapor-diqimethane 173 mg of the substance and 15 mL of dimethyl subhard were added to the compound 1·13 g obtained in the above (1), and the mixture was degassed, and then stirred under a nitrogen atmosphere at 8 (TC, 6 268 323 135 201202230 hours. The reaction mixture was injected thereto. Water, 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 under reduced pressure and the residue was purified by chromatography. By hexane/ethyl acetate = 91/9 to 80/20), the title compound was obtained as a colorless liquid 1.14 g (yield: 86%). Reference Examples B17 to B21 By reference to the corresponding starting compounds Example B16 was treated in the same manner to give the compound below. (Reference Example B17) 2-[3-Fluoro-4-(3-methoxypropylthio)phenyl]- 4, 4, 5, 5 -tetramethyl-[1,3,2]dioxaborolan

MS (APCI) m/z : 327 [M+H]+. (Reference Example B18) 2-[3-Fluoro-4-[2-(tetrahydropyran-2-yloxy)ethyl

Ruthenyl]phenyl]-4,4,5,5-tetradecyl-[1,3,2]dioxonacyclopentan

S-^OTHP

[2-Gas_4_[2_(tetrahydroindan-2-yloxy)ethyl ' 5-tetradecyl-[1,3'2]dioxaborolane MS (APCI) m/ z : 400 [M+NH4]+. (Reference Example B19) 2-[2-Fluoro-4-[2-thio]phenyl]-4, 4, 5, 5-tetradecyl-[: 323135 269 201202230

S-^0THP MS (APCI) m/z : 400 [Μ+ΝΗ4]+. ^Γ40)4Γ[_4'[2'(α4^-2-4^^^^ ΜθμΓ,' '5 tetramethyl[1'3'2]dioxaborolane Me^VB Ο. S ^S^OTHP MS (APCI) m/z : 382 [Μ+ΝΗ4]+. (Reference Example B21) 2-[2-Fluoro-4-indole (present methyloxyethyloxy) stupyl] Mel, A Base—[1,3,2]dioxo_heterocyclic ship Me ° btS ls^〇*^N^〇Bn Reference Example B22 2-Fluoro-4-(4, 4, 5, 5-tetramethyl-[ i,3, 2] 2~yl) phenylacetonitrile production oxaborane Βγγβγ — Brxxcw ^ (1) 168 g sodium cyanide was added to bromide 8.04 g of dimethyl sulfoxide at room temperature 5〇mL solution

Β^Χ〇Ν 4 winter 2' fluoro-p-methyl on 9 "C search and mixing 323135 270 201202230 night. The reaction mixture was cooled to room temperature and aq. 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 residue obtained was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = 9 〇 /1 〇 to 80/20) to give bromo-2-fluorophenylacetonitrile. Yellow liquid 3 6ig (yield: 56%). (2) 2 62 g of bisphosphonate pinacol ester, 168 g of potassium acetate, [u, a bis(diphenylphosphino)ferrocene]palladium (π) divaporate-methylene chloride complex 351 mg and dimethyl 1 mL of sulfoxide and 1 mL of water were added to the above-obtained compound L84g, which was degassed at 80 under a nitrogen atmosphere. (: Stirring overnight. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate, 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 residue was purified by silica gel chromatography (solvent: hexane / ethyl acetate = 9 〇 /1 〇 to 70 / 30) to give the title compound as a colorless viscous oil. Rate: 99%). Reference Example B23 4'4, 5, 5-Tetramethyl-2-(3-methylsulfanyl-4-mercaptothiononyl)-[1,3, 2] Manufacture of dioxaborolane

(1) 14.21 g of sodium decyl thiolate was added to a solution of 13.40 g of dimethyl sulfoxide in 1 〇 0 mL of 4-bromo-2-fluorobenzino bromide at room temperature, and the mixture was stirred for 271 323 135 201202230 night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed in the order of water and saturated brine. After drying over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by chromatography (solvent: hexane/ethyl acetate = 100/0 to 90/10) to give 4-bromo-2-methylthio- 1-methylthiomethyl group 12.32 g of a color liquid (yield: 94%).

(2) boronic acid pinacol ester 3. 〇 5g, potassium acetate i.96g, [1, Γ-bis(diphenylphosphino)ferrocene] palladium (II) dichloride - dioxane 4 〇 8 mg, DMSO 5 mL, and water 0.5 mL were added to 2.35 g of the compound obtained in the above (1), and the mixture was degassed and then subjected to a nitrogen atmosphere at 8 Torr. (: stirring overnight. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate, 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 residue was purified by EtOAc (EtOAc:EtOAc:HHHHHHHHH Yield: 99%). Reference Example B24 ^[442-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl Manufacture of benzyl] piperazine-i-yl] ethyl ketone

(1) Add 1.5 mL of triethylamine to 4_bromo-2-fluorobenzyl bromide at room temperature 2. 63⁄4 and acetylsulfate L 28g of dimethyl hydrazine 4 〇 mL 272 323135 201202230 Stir in the liquid for 1 hour. To the reaction solution, 3.80 g of bisphosphoric acid pinacol ester, 2.00 g of potassium acetate, [1,1'-bis(diphenylphosphino)ferrocene] and (II) dichloride-dichloromethane were added. The compound was 410 mg, and after the mixture was degassed, it was stirred overnight at 70 ° C under a nitrogen atmosphere. The reaction mixture was poured into water. The mixture was extracted with ethyl acetate. The organic layer was washed in the order of water and saturated brine, and dried under magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue obtained was purified by chromatography (chromate, solvent: hexane/ethyl acetate = 80/20 to 40/60) to give the title compound. The oil was 262 mg (yield: 7%). MS (APCI) m/z : 363 Reference Example B25 2-[2-Fluoro-4-(4, 4, 5, 5-tetradecyl-[1,3, 2]dioxaborolane_ Manufacture of 2-yl)phenyl]isotetrahydrothiazole-1,1-dioxide

(1) Add 2 mL of pyridine 2 mL, 3~ chloropropane-1-sulfonium chloride, 1 g of methane methane in 10 mL to a solution of 4-bromo-2-fluorobenzamide 19 〇g in dioxane 2 〇mL. Stir at room temperature for 3 hours. 1N Hydrochloric acid was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with hydrochloric acid, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was pulverized with methylene chloride (dichloromethane) to give 2-(4-bromo-2-fluorophenyl)isotetrahydrothiazole-1,1-dioxide. The dark purple powder of the material was 27 g (yield: 43%). 323135 273 201202230 (2) The title compound was obtained as a colorless powder 1.40 g (yield: 1%) by the method of the compound (1). ). MS (APCI) m/z : 359 [M+NH4]+ 〇Reference Example B26 2-Fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4]噚Manufacture of oxazol-3-yl) ketone-1-yl]pyrene-8-yl]benzoic acid

(1) 8-Bromo-6-fluoro-4-[4-(5-isopropyl-[1,2,4]oxadiazol-3-yl)piperidin-1-yl]quinazoline ( Refer to the compound obtained in the example B9) i. 36 g, 3-fluoro-4-cyclopropoxycarbylphenylborate 〇. 961 g, tetrakis(triphenylphosphine), spring 0. 37 snake, carbonic acid planing 2. llg dissolved in In 54 mL of 1,4-dioxane and 13 mL of water, the mixture was heated and mixed at 90 ° C for 7 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. 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 residue obtained was purified by chromatography (Chromatorex 'solvent / hexane / acetic acid): 86/14 to 75/25, and solvent: hexane/ethyl acetate: 91/ 9 to 75/25) 2 times to obtain 2-fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4]oxadiazol-3-yl) 323135 274 201202230 唆-1-yl] quinazoline _8_yl] phthalic acid decyl methacrylate colorless crystallization. 767 g (yield: 48%). (2) 760 mg of the compound obtained in the above item (!) was dissolved in a mixed solution of 13 mL of THF and 13 mL of decyl alcohol. After neutralizing the reaction mixture with 2N aqueous hydrochloric acid solution, water was added and stirred for 30 minutes. The precipitated crystals were collected by filtration,yield to dryness to dryness to yield 695 mg (yield: 94%) of the title compound. MS (APCI) m/z : 480 [M+H]+ . Reference Examples B27 to B32 By treating the corresponding starting compound in the same manner as in Reference Example B26, the following compound was obtained. (Reference Example B27) 2-Fluoro-4-[6-fluoro-4-[4-(5-propyl-[;1,2,4]indole disani-3-yl)-spin-1-yl]啥β坐淋_8-base] stupid formic acid

MS (APCI) m/z : 480 [Μ+Η]+. (Reference Example B28) 4-[4-[4-(5-Cyclopropyl-[1,2,4]噚二嗤_3_yl) ° 啶 -1--1-yl]-6-fluoroquinazoline -8-yl]-2~fluorobenzoic acid

MS (APCI) m/z: 478 [M+H]+ 〇323135 275 201202230 (Reference Example B29) 2-Fluoro-4-[6-fluoro-4-[4-(3-isopropyl-[1, 2, 4]曙二°坐-5-基)旅°定-1-基]啥唾琳-8-yl]benzoic acid

MS (APCI) m/z : 480 [Μ+ΗΓ. (Reference Example B30) 2-Fluoro-4-[6-fluoro-4-[4-(3-propyl-[1,2, 4]噚2

Salami-5-yl)piperidin-1-yl]quinazolin-8-yl]benzoic acid

MS (APCI) ιη/ζ : 480 [M+H]+ 〇 (Reference Example B31) 2_Fluoro-4-[6-fluoro-4-[4-(3-isopropyl-[1,2, 4 Oxazol-5-yl)piperidin-1-yl]quinazolin-8-yl]phenylacetic acid

Nn^N MS (APCI) m/z : 494 [M+H]+ 〇 (Reference Example _ 2-Fluoro-4-[m-oxadiazol-3-yl)quinazolin-8-yl]phenylhydrazinesulfur Acetate

MS (APCI) ιη/ζ : 540 [M+H]+ ° 323135 276 201202230 Reference Example B33

By biting 8-bromo-6-fluoro-4-[4-[3_(2, 2, 2-trifluoroethyl)_[1' 2' 4] oxadi--5-yl] 1.00 g of the compound (Compound obtained in Reference Example Bu) and 798 mg of 4-carboxy-3-fluorophenylboronic acid were treated in the same manner as in Example B1 to give 265 mg (yield: 24). %). MS (APCI) m/z : 520 [M+H]+ 〇Reference Example B34 [2-Fluoro-4-(4, 4, 5, 5-tetramethyl-[1,3, 2] dioxa side Manufacture of heterocyclic pentan-2-yl)phenylhydrazinyl]acetic acid decyl acetate

• Br^F HS-C02Me Br^F

Llsi^Br -1isi^S^C〇2Me ^ Me^〇Bnj^F ^N^S^C02Me (1) Add 18.3g of potassium carbonate and 6 7g of 4-bromo-2-fluorophenylindenyl bromide to In a solution of 2.7 g of thioglycolate in DMF 50 mL, the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture to extract with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and filtered. 5克(Yield: &gt; 323135 277 201202230 99%). The colorless viscous oil of (4-bromo-2-fluoroindoleylthio)acetic acid methyl ester was obtained. (2) The title compound was obtained as a colorless viscous oil (yield: 32%) by the compound of the compound (3). MS (APCI) m/z: 358 [Μ+ΝΗ4]+. Reference Example 35 6-Fluoro-8-[3-fluoro-4-[2-(tetrahydropyran-2-yloxy)ethylthio]phenyl]-4-[4-(5-isopropyl Manufacture of quinolyl-[1,2,4]oxadiazole-3-yl)piperidine-fluorenyl] quinazoline

-3-yl) dentate-1-yl] oxime oxime (Reference Example Bg was treated in the same manner as in Example B1, while Jing powder 109 mg (yield: 38%). 1 β9 compound) 2 〇 〇mg to give the title compound as colorless MS (APCI) m/z: 596 [M+H] + 〇 Reference Examples B36 to B41 The following compounds were obtained by treating the corresponding starting compounds with the reference examples. In the same manner as in Reference Example B35 (Reference Example B36) 6-Fluoro-8-[4-[2~(四气

-1-yl]quinazoline-anthyl-2-yloxy)ethyl 嗤2嗤_3_ base) π bottom bite 323135 278 201202230

^ν^ΟΤΗΡ MS (APCI) m/z : 578 [Μ+Η]+. (Reference Example )37) 6 - Deficient _8-[2-Fluoro-4-[2-(tetrazirinium oxa-2-yloxy)ethylthio]phenyl]-4-[4-(5 -isopropyl-[1,2,4]oxadiazol-3-yl) travel bite-1-yl]啥ί sitting

s, s^0THP MS (APCI) m/z : 596 [M+H]+ ° (Reference Example B38) 6 -Gas_8-[3 -Fluoro-4-[[2-(tetrazo]51 喃 _ 2-yloxy)ethylthio]indolyl]phenyl]-4-[4-(5-isopropyl-[1,2,4]oxadiazol-3-yl) brigade 11-1-1 -基]嗤嗤琳

MS (APCI) m/z : 610 [M+H]+. (Reference Example B39) 6-Fluoro-8-[3-fluoro-4-[[3-(tetrahydropyran-2-yloxy)propylthio]indolyl]phenyl]-4-[4 -(5-isopropyl-[1,2,4]oxadiazol-3-yl) brigade bite-l-yl]

MS (APCI) m/z : 624 [Μ+ΗΓ. 279 323135 201202230 (Reference Example B40) 6-Fluoro-8-[3-fluorotetrahydropyran-2-yloxy)ethylthio]methyl]phenyl]-4-[4-(3) Propyl gas 1,2,4]oxadiazole-5-yl)

(Reference Example B41) 6-Fluoro-8-[3-fluorotetrahydropyrano-2-yloxy)propylthio]methyl]phenyl]-4-[4-(3-isopropyl) One, 2, 4] oxadiazole

S^^OTHP MS (APCI) m/z : 624 [Μ+ΗΓ. Reference Example 42 · 2-tertiary butoxycarbonylamino-2-[4-[6-fluoro-4-[4-(5-isopropyl-[1' 2, 4]oxadiazole-3- Manufacture of hydrazino-l-yl]quinazolinyl]phenyl]indole, fluorene-dimethylacetamide

(1) by using 8-bromo-6-fluoro-4-[4~(5-isopropyl-[1 oxazolyl)piperidin-1-yl]quinazoline (Reference Example 9 U) rlJ 丞·'Ll, 2,4] 噚2B9) 323135 280 201202230 780mg was treated in the same manner as in Reference Example B26 to give 2-3-tert-butoxy ylamino-2-[4 -[6-fluoro-4-[4-(5-isopropyl-[1,2 4]diazol-3-yl)piperidin-1-yl]quinazoline _8-yl] stupid] 450 mg of a colorless powder of acetic acid (yield: 35%). MS (APCI) m/z : 591 [M+H]+. (2) The compound i5 〇 mg obtained in the above (1) was treated in the same manner as in Example B2 to give the title compound as colorless powder (yield: 73%) 〇

MS (APCI) m/z: 618 [M+H]+. Reference Example B43 6-Fluoro-8-[3-fluoro-4-[2-[2-(tetrahydropiperidin-2-yloxy)ethyl]-2H-tetras-5-yl]phenyl] Manufacture of _4_[4_(5-isopropyl-[12,4]indole-di-sial-3-yl)piperidin-1-yl]quinazoline

OTHP (1) by using 8-bromo-6-fluoro-4_[4_(5-isopropyl-[12, oxadi-3-ylindole (reference compound B9) compound 42 〇mg and 4-cyano-fluorophenyl Wei 25Gmg was treated in the same manner as in Example B1 to obtain 2 ϋϋ[4_(5_isopropyl_[U'4Bay dis-salt] 底 基 啥 | | | Base] benzene ^^

S 323135 281 201202230 Colorless powder 334 mg (yield: 73%). MS (APCI) m/z : 461 [Μ+ΗΓ. (2) 200 mg of sodium azide and 400 mg of triethylamine hydrochloride were added to a solution of 138 mg of the compound obtained in the above (1) in 6 mL of toluene, and the mixture was stirred at 100 ° C for 20 hours. After cooling the reaction mixture to room temperature, water was added and the precipitate was collected by filtration. Water was added to the filtrate, and the mixture was extracted three times with dichloromethane. The filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (solvent: chloroform / decyl alcohol = 1 〇〇 / 〇 至 to 80 / 20) to give 6-fluoro-8-[3-fluoro 4-(2H-tetrazol-5-yl)phenyl]-4-[4-(5-isopropyl-[1,2,4]oxadiazol-3-yl)piperidine-bu] 113 mg (yield: 74%) of quinazoline as a colorless solid. (3) Add 8 mg of sodium hydride and 33 mg of 2-(2-chloroethoxy)tetrahydrobine to the solution of 9 mg of the compound obtained in the above (2) in dimethylformamide, and mix at room temperature 16 hours. 13 8 mg of potassium carbonate was added to the reaction mixture, and stirred at 10 ° C for 16 hours. After the reaction mixture was cooled to room temperature, Φ water was added and extracted with ethyl acetate. After the organic layer was dried over magnesium sulfate, it was filtered, and the mash was concentrated under reduced pressure. The residue obtained was obtained from NH-Shixi gum column chromatography (Chromatorex; Fuji SILYSIA chemistry, solvent: hexane/ethyl acetate = 90/ The residue was purified to give the title compound (yield: 49%). Reference Example B44 2-[2-[2-Fluoro-4-(4, 4, 5, 5-tetradecyl-[1,3, 2]dioxaborolan-2-yl)benzene Manufacture of thiol]ethoxy]tetrahydropyran 282 323135 201202230

S^OTHP

S-^ OTHP (1) 2.28 g of potassium thioacetate was added to a solution of 5.34 g of dimercaptoguanamine in 50 mL of 4-bromo-2-fluorophenylhydrazine bromide, and the mixture was stirred at room temperature for 1 hour. After adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. To a solution of 2.5 g of 2-(2-chloroethoxy)tetrahydropyran. Warmly mix the whole night. Water and saturated brine were added to the reaction mixture, and extracted three times with dichloromethane. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was evaporated. The residue obtained is purified by silica gel column chromatography (solvent: gas/merol = 100/0 to 90/10) to obtain 2_[2_(4-bromo-2-fluorophenylindenylthio) A colorless solid of oxy]tetrahydropyran 3 62 (yield: 50%). &lt;(2) By treating 3.5 g of the compound obtained in the above (1) in the same manner as in the referenced Example b16 (2), the title compound was obtained as an oil (26%: 66%). * MS (APCI) m/z : 414 [M+NH4]+° Reference Example B45,2-[3-[2-Fluoro_4_(4,4,5,5-tetradecyl-7,3,2] Manufacture of Dioxanthene pentan-2-yl)benzylthio]propoxy]tetrahydropyran 323135 283 201202230

XX

S^x^OTHP was treated in the same manner as in Reference Example 44 to give the title compound. MS (APCI) m/z : 428 [Μ+ΝΗ4]+ . Reference example 46

2-fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4]oxadiazole-3-yl)piperidin-1-yl]quinazoline-8 -Based on the manufacture of aniline 2 hydrochloride

(1) by 8-bromo-6-fluoro-4-[4-(5-isopropyl-[1,2,4]-oxadiazol-3-yl)piperidin-1-yl]quin 2 g of oxazoline (Compound obtained in Reference Example 9) and 1.456 g of 4-dimethoxybutoxylamino-3-trifluorophenyl rotten acid were treated in the same manner as in Example B1 to obtain 2_n [6_gas Colorless powder of _4_[4_(5-isopropyl-[1,2,4]Pf diazol-3-yl)piperidinyl]quinazoline-8-yl]phenylamine phthalic acid butyl butylate 9845 g (yield: π%). (2) 5 mL of a 4N hydrochloric acid-dioxane solution was added to 1.98 g of the compound obtained in the above (1) in 15 mL of dioxane and ethanol 15 pyridine solution, and the mixture was allowed to stand at room temperature for 3 hours and 3 minutes. The reaction mixture was concentrated, and the residue was crystallized from ethyl acetate and ethyl acetate to afford crystals of the title compound (yield: (y): 93%). MS (APCI) m/z : 451 [M+H]+. 323135 284 201202230 Reference Example B47 2-[2-Fluoro-4-(4,4,5,5-tetramethyl-[1,3, 2]dicyclopentan-2-yl)acetate Manufacture of oxy]ethyl ester

b M^o F 仏一Ιο, one (10). BtX-(1) Adds 2-hydroxyethyl acetate 2. is added to sodium hydride o. 8g of dimethylformamide in 100mL solution after o'c. A solution of 5.36 g of 2-fluorobenzene in DMF 100 mL was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 90/1 〇 to 4 〇 / 6 〇) to give 2-(4-bromo- Colorless liquid of 2-fluorobenzyloxy)ethyl ester 1.50 g (yield: 28%). (2) By treating the compound i.5〇g obtained in the above (1) in the same manner as the test φ Bl6 (2), the title compound is obtained as a colorless viscous oil 〇· 86 g (yield :51%).

Ms (APCI) m/z : 356 [M+NH4]+ ° Reference Example B48 6-Fluoro-8-(3-fluoro-4-vinylphenyl)-4-[4-(3-isopropyl) [1' 2, 4] 二二β坐-5-基)旅唆-1-基]喧峻琳的制造323135 285 201202230

0. 5g and bromophenyl were treated in the same manner as in Example Bi to give 2-1 + [6_fluoro_4-7-(3_isopropyl-[; 1,2, oxadiazole] -5-yl)piperidin-1-yl]quinazoline-8-yl]benzoquinone oxime 34 g (yield: 62%). (2) a solution of n-butyllithium in hexane h 54m〇1/L at -78 ° C. 32 mL was added dropwise to 174 mg of methyl bromide bromide in tetrahydroanthranone 5 mL·suspension. The mixture was stirred at -78 °C for 10 minutes. To the reaction mixture, a solution of the φ compound WOmg obtained in the above (1) was dissolved in THF, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated, water was poured into a residue, and the mixture was extracted with ethyl acetate. The organic layer was purified by chromatography (yield: hexanes / ethyl acetate = EtOAc / EtOAc / EtOAc) MS (APCI) m/z: 462 [M+H]+. Reference Example B49 1 -[2-(tertiary butyldidecylsulfanyloxy)ethyl]-3-[2-fluoro-4-[6-fluoro-4-[4-(5-isopropyl) _[1,2,4]曙Disani-3-yl) brigade-1-yl] 286 323135 201202230 啥 琳 -8 -8-8-yl] phenyl] scented »»

By 1-[2-fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4] ortho-oxazol-3-yl)piperidin-1 -喹 quinazoline -8-yl]phenyl]imidazolidine-2-one (compound obtained in Example )15) 848ing and 2-(tri-tert-butyldimethyl oxalyloxy)ethyl bromide Mg eL 550. 7 mg (yield: 50%) was obtained as a pale yellow powder of the title compound. MS (APCI) m/z : 678 [M+H]. Reference Example B50 8 (4-Gasmethyl-3-murinephenyl)-6-Ga-4-[4-(5-isopropyl-[1,2,4]nonane-3-yl) Manufacture of bitten-1-yl] quinazoline

Add sulfite chloride 98/z L, 1 drop of DMF to [2-fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4] oxadiazole- 3-yl) piperidinyl-fluorenyl-quinazoline-8-yl]phenyl]methanol (the compound obtained in Example B297) 丨3〇mg of dioxindole in 3mL solution 'dissolved at room temperature 2 Hours 2 minutes. The reaction mixture was concentrated, and a saturated aqueous solution of sodium bicarbonate 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 (yield: hexanes / EtOAc EtOAc) 323135 287 201202230 MS (APCI) m/z : 484/486 [M+H]+. Reference Example B51 6-Fluoro-8-(6-fluoroacridin-3-yl)-4-[4-(5-isopropyl-[1,2,4]oxadiazol-3-yl) 1-Base] oxazole

By 8-bromo-6-fluoro-4-[4-(5-isopropyl-[1,2,4]-oxadiazol-3-yl)bend-1-yl]quinazoline ( Reference compound of Example B9) 5 〇 0 mg and 2-fluoro-5-(4, 4, 5, 5-tetramethyl-[1,3, 2]dioxaborolan-2-yl) 343 mg of pyridine was treated in the same manner as in Example B1 to give 426 mg (yield: 82%) of the title compound. MS (APCI) m/z : 437 [M+H]+ 〇 Reference Example B52 2-fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[i,2,4]噚Diazol-3-yl)

323135 288 201202230 Sex oil 750 mg (yield: 100%). MS (APCI) m/z : 522 [Μ+ΗΓ. Reference Example B53 Preparation of ethyl 2-fluoro-4-(4,4,5,5-tetramethyl-[1,-2-yl)phenylacetate BrVCCcN — W dioxaborolane

BrXX C02Et Μβ&gt;-〇

^s^C02Et (1) Add 23.59 g of potassium hydroxide to 4_/odor-2-fluorophenylacetonitrile at room temperature (refer to the compound of Example 22(2) in ethanol 15 mL / water 45 mL solution, the mixture is 85.0 Still 9.5. When the reaction was cooled to room temperature, the pH was adjusted to pH with 6N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine. Filtration, by concentrating the hydrazine under reduced pressure, and a brown solid of 彳β 4 dimethylacetic acid, l5.4 lg (yield: 94%) ° (2) 2 mL of sulfuric acid was added to the compound 16 obtained in the above (1) The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and filtered. The resulting residue was pulverized by diisopropyl ether/hexane to give 14.03 g (yield: 58%) of 4-bromo-2-fluorophenylacetic acid as a colorless solid. MS (APCI) m /z : 261/263 [M+H]+〇289 323135 201202230 A colorless solid with reference to the title compound (received (3) by the former fan (2) Compound 2. 00g B16 (2) was treated in the same manner to obtain a standard rate: 66%). ' MS (APCI) m/z : 3〇9[M+H]+ Reference Example B54 4_[2~ Fluorine- H6j-4_[4_(5)Isopropyl--:fine base (4) sitin-8-yl]phenyl: 1 carboxylic acid tertiary butyl ester

〇

Me le is the same as the reference example by using the corresponding raw material compound. The title compound was obtained as a colorless solid (10).3mg) (yield: 6 formula 4 MS (APCI) m/z : 634 [M+H] + ° Reference Example B55

290 323135 201202230 %). MS (APCI) m/z : 447 [M+H] + ° Reference Example B56 4-[6-fluoro-4-[4-(5-isopropyl-[1' 2, 4]oxadiazole-3 —基)派咬-1-yl]quinazolin-8-yl]-2-methylaniline Me

The reaction product was treated with a saturated aqueous solution of sodium hydrogencarbonate to give the title compound as a pale yellow powder (458·7 mg). 10Q%). 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]quinazoline -8-yl]_2_mercaptoyl]imidazolidine-2-one

2-Chloroethyl isocyanate 172 &quot; L was added to 4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4]oxadiazol-3-yl) at room temperature A solution of 300 mg of tetrahydrofuran in 6 mL of a solution of butyl-1-yl]quinazolin-8-yl]-2-methylaniline (Compound B56) was mixed for 19 hours. To the reaction mixture was added 4 mg of molybdenum tetrabutylammonium 12.4 mg, 6N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by silica gel column chromatography (solvent: EtOAc/MeOH: EtOAc: EtOAc) MS (APCI) m/z ; 516 _]+. Reference Example B58 1-[4-[6-Fluoro-4-[4-(5-isopropyl-[1,2,4]protonodiazol-3-yl)-indolyl-1-yl]quinazoline Porphyrin_8_yl]-3-mercaptophenyl]imidazolium_2-_

The title compound was obtained as a colorless powder (136·6 mg) (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]-indolyl-3-yl)piperidin-1-yl] Manufacture of quinazoline _8-yl]phenyl]_4_(2-ethoxyethoxyethyl) phenamine 1-2-one

323135 292 201202230 by 卜[2_Fluor+[6-gas+[4_(5_内内基七,2,_二唾_3~基) Niangbit + base]啥吐琳_8_基] Phenyl]methane-2, ^, compound of Example B94) 2 hydrochloride (8 mg) and ethoxylated ethyl chloride 29eL were treated in the same manner as in Example B9 to give the title compound as colorless. Powder 89·lmg (yield: 1%). MS (APCI) m/z; 634 [M+H]+. Reference Examples B60 to 61 The following compounds were obtained by treating the corresponding starting compound in the same manner as in Reference Example B9. (Reference Example B60) 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 B61) 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 Odor _2_gas phenyl)-3-[2-(tertiary butyldimethylammonyloxy) 293 323135 201202230 Manufacture of ethyl]imidazolidine-2-one

XX (1) was obtained by treating 4-bromo-2-fluoroaniline l〇g in the same manner as in Reference Example B57 to obtain 1_(^_bromo-2-fluorophenyl)-scented bite-2_one. Colorless powder 13.57 g (yield 99%). MS (APCI) m/z; 259/261 [M+H]+° φ (2) 7 g of the compound obtained in the above (1) and 2-(tert-butyl dimethyl decyloxy) bromide 8 〇g (yield: 51%) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; MS (APCI) ra/z: 417 / 419 [M+H] + ° Reference Example B63 to B65 The following compound was obtained by treating the corresponding raw material compound in the same manner as in Reference Example B62. % (Reference Example B63) 1-(4-Bromophenyl)-3-[2-(tertiary butyldimethylmethyloxy)ethyl]0 m salivary bite - 2-brew)

MS (APCI) m/z : 399/401 [M+H]+. (Reference Example B64) 1-(4-Bromo-2-methylphenyl)-3-[2-(tertiary butyl fluorenylmethyl decyloxy)ethyl]imidazolidine-2-one 323135 294 201202230

Br

OTBDMS MS (APCI) m/z: 413/415 [M+H]+. (Reference Example B65) 1-(4-Bromo-2-indolylphenyl)-3-[3-(tetrahydropyran-2-yloxy)propyl]imidazolidine-2-one

Br

0ΤΗΡ φ MS (APCI) m/z : 397/399 [M+H]+. Reference Example B66 (S)-4-(tertiary butyldidecylfluorenyloxy)-pyrrolidin-2-one

Household TBDMS

TBDMSC1 咪唾 -»

DMF (S)-4-hydroxypyrrolidin-2-one 2. 02g, gasified tertiary butyl dimethyl decane 3.16g and imidazole 2 · 04g of dimethylformamide 20mL suspension in the room Stir at night. The water was added to the reaction mixture, and the solid was separated by filtration. To give the title compound as a colorless powder 3.90 g (yield: 90%) 〇MS (APCI) m/z: 216 [M+H] +. Reference Examples B67 to B68 The following compounds were obtained by treating the corresponding starting compound in the same manner as in the Reference Example. 295 323135 201202230 (Reference Example B67) (R)-4-(tertiary butyl dimethyl fluorenyloxypyrrolidin-2-one)

^^ OTBDMS MS (APCI) m/z : 216 [M+H]+. (Reference Example 68) (S)-5-(tris-butyl dimethyl fluorenyl fluorenyl) &gt;

MS (APCI) m/z : 230 [M+H]+ ° Reference Example B69 (S)-l-(4-Bromo-2-fluorophenyl)-4-(tri-butyl dimethyl decyloxy) Manufacture of pyrrolidin-2-one

Cul Κ3Ρ0,

1) TBDMS (S)-4-(tertiary butyl fluorenyl fluorenyloxy) π piroxicam-2-indole (Compound 166) 859 mg, 4-bromo-2-fluoro- 1-iodobenzene lg, vaporized copper 32mg, N,N'-dimethylethylidene diamine 36#L and sulphuric acid clock 1.41g of benzene 15mL suspension, under nitrogen atmosphere at 80 ° C Stir for 15 hours. The reaction mixture was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = 100/0 to 80/20). 296 323135 201202230 MS (APCI) m/z ; 388/390 [M+H]+ . Reference Examples B70 to B73 By treating the corresponding starting compound in the same manner as in Reference Example 69, the following compound was obtained. (Reference Example 70) (R)_l_(4-Di_2-fluorophenyl)-4-(tertiary butyldihydrazinyloxy)πpyrrolidin-2-one

MS (APCI) m/z ; 388/390 [Μ+ΗΓ . (Reference Example B71) (R)-l-(4-Bromo-2-methylphenyl)-4-(tertiary butyldidecylfluorenyloxy)pyrrolidin-2-one

Me 0

MS (APCI) m/z; 384/386 [M+H]+. • (Reference Example B72) (R)-l-(4-Bromo-3-indolylphenyl)-4-(tertiary butyldidecyloxy)pyrrolidin-2-one

MS (APCI) m/z ; 384/386 [M+H]+ ° (Reference Example B73) 4-(4-bromo-2-fluorophenyl)-3-oxoxypiperidine-1-carboxylic acid Butyl 297 323135 201202230

MS (APCI) m/z; 373/375 [M+H]+. Reference Example B74 (S)-l-(4-Molyphenyl)-5-(tri-butyl bis-indenyl fluorenylmethyl)pyrrolidin-2-one

Br iir1 + TBDMSOV^7 α:

Cul K3PO4 toluene

(S)-5-(tris-butyldimethylsilyloxymethyl)pyrrolidine-2-indole (Compound Example B68) 8 g, 4-'; - Mothbenzene 1 Og, copper chloride 316 mg, trans-cyclohexan-1,2-diamine 758 mg, and acid-filled clock 17.6 g of toluene 150 mL suspension, stirred at 110 ° C for 11 hours under a nitrogen atmosphere . Water was added to the reaction mixture, which was extracted with ethyl acetate. The yield of the residue was purified by a silica gel column chromatography (solvent: hexanes / EtOAc / EtOAc / EtOAc (EtOAc) 46%). MS (APCI) m/z ; 402/404 [M+H]+. Reference Example B75 Manufacture of 4-bromo-3-mercaptophenylamine decanoic acid tert-butyl butyl ester

Me Br nh2

Bo〇2〇, EtsN MeOH

298 323135 201202230 6 mL of triethylamine was added to a solution of 4-bromo-3-methylaniline 4 g, di(tertiary butyl dicarbonate) 4.7 g of sterol in 160 mL, and the mixture was stirred at room temperature for 1 day. . Further, to the reaction mixture were added 4.7 mg of di(tributyl hydride carbonate) and 6 mL of triethylamine, and the mixture was stirred at room temperature for 17 hr. Further, ruthenium di(tris(butylate)) 4.5 g and 6 mL of triethylamine were added to the reaction mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = 100/0 to 90/10). 74%). MS (APCI) m/z ; 286/288 [Μ+ΗΓ. Reference Example B76 Manufacture of 4-bromo-2-methylphenylamine decanoic acid tert-butyl butyl ester

The title compound was obtained by treating the corresponding material compound in the same manner as in the title compound. MS (APCI) m/z ; 286/288 [M+H]+ ° Reference Example B77 1-(4-Diethyl-2-fluorophenyl)-3-[2_indolyl-2-(tetrahydro-sulphur Manufacture of m--2-yloxy)propyl]imidazolidin-2-one 299 323135 201202230

(1) by using 1-(4-bromo-2-fluorophenyl)mi-pyrene-2-one (the compound obtained in Reference Example B62 (l)) lg and ethyl bromoacetate 232 mg in the same manner as in Example B16 In the same manner, a yield of 814. 3 mg (yield: 61%) of 1-(4-bromo-2-fluorophenyl)-3-ethoxycarbonylmercapazolidin-2-one. MS (APCI) m/z ; 345/347 [M+H]+ 〇(2) A solution of bismuth bromide in THF (0. 93 mol/L) at -40 ° C for 5 minutes under nitrogen atmosphere. 7. 6 mL of a solution of 810 mg of the compound obtained in the above (1) in THF 20 mL was added, and the mixture was stirred at room temperature for 1 hr. A THF solution of methylmagnesium bromide (〇.93 mol/L) 7.6 mL was added dropwise to the reaction mixture. The mixture was stirred at room temperature for 2 hours. A saturated ammonium chloride solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = 65/35 to 35/65). The obtained crude product was dissolved in 5 mL of dichloromethane, and 3,4-dioxa-2Η-π butyl 430 y L and pyromphenyl-4-sulfonic acid pyridinium salt 59 mg were added thereto. The mixture was mixed at room temperature. 5 hours. Further, 3,4-dihydro-2H-pyrano 430 // L and guanidin-4-3⁄4 acid 10 were added to the reaction mixture, and the mixture was taken up 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 the title compound as colorless powder 323135 300 201202230 206. lmg (yield: 21%) . MS (APCI) m/z ; 286/288 [M+H]+. Reference Example B78 Manufacture of (R)-3-(4-indol-2-epoxyphenyl)-5-(tertiary butyldidecylphosphoryloxy) oxazolidin-2-one 乂Xh2 — ~^ F 0 F 0 -^ Br ημ -► Br—

^V-〇H ^V^OTBDMS (1) 20 mL of water and 4.66 g of sodium cesium carbonate were added to a solution of 4-bromo-2-fluoroaniline 5 g of acetone in 100 mL at room temperature, and benzoic acid benzoate was added dropwise thereto. The ester was stirred at room temperature for 19 hours. After adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated, and cold hexane (0 ° C) was added to the residue obtained, and the solid was collected by filtration and dried to give 4-bromo-2-fluoroamine phenyl phthalate. The colorless powder was 8. 06 g (yield 94%). MS (APCI) m/z ; 341/343 [M+H]+ ° (2) hexane solution of n-butyllithium (1. 54mo 1 /L) at -78 ° C for 15 minutes under nitrogen atmosphere 6. 6 mL of a solution of 3 g of the compound obtained in the above (1) in tetrahydrofuran (70 mL) was added dropwise, and the mixture was stirred for 1 hour. 1.57 mL of (R)-l-epoxyethyl methyl butyrate was added dropwise to the reaction mixture at -78 ° C, and the mixture was stirred at room temperature for 22 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate 301 323135 201202230 = 55/45 to 25/75) to obtain (R) 1.27 g (yield: 47%) of -3-(4-bromo-2-fluorophenyl)-5-hydroxymethyloxazolin-2-one as a colorless solid. MS (APCI) m/z; 290/292 [M+H]+. (3) 443 mg of imidazole and 0. 72 g of tributyl decyl decane chloride were added to a solution of 1.26 g of the compound obtained in the above (2) in 12 mL of dimethyl decylamine, and the mixture was stirred at room temperature 2.5. hour. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 90/10 to 75 / 25) to give the title compound 1.42 g (yield: 81%). . MS (APCI) m/z ; 404/406 [M+H]+ ° Reference Example B79 Manufacture of 5-bromo-2-(2-oxo-pyrrolidin-1-yl)benzonitrile

2 g of 2-amino-5-bromobenzonitrile and 1.36 g of gasified 4-chlorobutyric acid were treated in the same manner as in Example B14 to give the title compound as a yellow solid. ). MS (APCI) m/z ; 265/267 [M+H]+. Reference Example B80 Manufacture of 4-[3-[2-(tris-butyldidecylsulfanyloxy)ethyl]-2-oxooxyimidazolidine-1-yl]-3-fluorophenylboronic acid 302 323135 201202230

Oc;i \^n~〇TMms

A solution of n-butyllithium in hexane (1.59 mol/L) 3.92 mL was added dropwise to 1-(4-bromo-2-fluorophenyl)-3-[2-(three) at -80 °C for 10 minutes. To a solution of 2 g of tetrahydrofuran/toluene (15 mL/i 5 mL) in butyl dimethyl fluorenyloxy)ethyl]imidazolidin-2-one (Compound obtained in Reference Example B62), the mixture was stirred for 90 minutes. The trimethoxyborane 752eL was added to the reaction φ mixture and the mixture was stirred for 2 hours. The reaction mixture is given in 〇. (: Add 10 mL of saturated ammonium chloride solution, water imL and 85% aqueous acid solution 〇·5 mL 'The mixture was stirred for 90 minutes. The reaction mixture was extracted with acetic acid. The organic layer was dried with sulfuric acid and concentrated. 2 mg(Yield: 11%). The obtained residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = 95/5 to 35/65). MS (APCI) m/z ; 383 [Μ+ΗΓ. Reference Example B81 1 [2 (2nd butyl-fluorenyl oximeoxy)ethyl]_3_[2-fluoro-4-(4, 4, 5 Manufacture of 5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]imidazolidine-2-one

By using 1-(4-bromo-2-fluorophenyl)-3-[2-(tertiary butyldidecylmercaptooxy)ethyl]imidazolidin-2-one (refer to Example B62) The compound was obtained in the same manner as the reference compound B16 (2), and the pale red solid was 1.10 g (yield: 49%). MS (APCI) m/z: 465 [M+H] + </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; (Reference Example B82) [2-(tertiary butyldimethylmethyl decyloxy)ethyl]_3_ [4-(4, 4, 5, 5-tetramethyl-[1,3, 2] Oxaborolan-2-yl)phenyl]imidazolidin-2-one

MS (APCI) m/z : 447 [M+H]+ ° (Reference Example B83) [2-(tertiary butyldifluorenyloxy)ethyl]_3_ [2-mercapto-4- (4, 4, 5, 5-tetramethyl-[1,3, 2]dioxaborolan-2-yl)phenyl]

MS (APCI) m/z : 461 [M+H]+. (Reference Example B84) 1-[2-Methyl-4-(4,4,5,5-tetradecyl-[1,3, 2]dioxazacyclopentan-2-yl)phenyl ]-3-[3-(tetrahydroindan-2-yloxy)propyl]°m° sitbit-2-one 323135 304 201202230

Me Me

Me u MS (APCI) m/z : 445 [M+H]+ ° (Reference Example B85) (S)-4-(tertiary butyl dimethyl fluorenyloxy) _ [2 fluoro-4 -(4, 4, 5, 5-tetradecyl-[1,3, 2]dioxaborolan-2-yl)phenyl]D is more than 17 ketone-2-one

MS (APCI) m/z : 436 [M+H]+. (Reference Example B86) (R)-4-(tertiary butyldiindenyloxy)-1-[2-fluoroi_4-(4, 4, 5, 5-tetradecyl-[1,3 , 2] dioxin, heterocyclic pentyl-2-yl) phenyl] ° than bite-2-ketone

MS (APCI) m/z : 436 [M+H] + ° (Reference Example B87) (R)-4-(tert-butyl dimethyl decyloxy)-b [2-methyl-4- (4, 4, 5, 5-tetradecyl-[1,3, 2]dioxaborolan-2-yl)phenyl]indole-2-one

MS (APCI) m/z : 432 [M+H]+ ° 305 323135 201202230 (Reference Example B88) (R)-4-(tertiary butyl dimethyl decyloxy) _ [3 methyl -4-(4, 4, 5, 5-tetradecyl-[1,3, 2]dioxaborolan-2-yl)phenyl]β ratio 11 each bit-2-one m~ 〇rw #°^N^〇tbdms MS (APCI) m/z : 432 [M+H]+ ° (Reference Example B89) 4-[2-Fluoro-4-(4, 4, 5, 5-A Base-[i,3,2]dioxo•heteroborolan-2-yl)phenyl]-3-oxooxypiped D-i-carboxylic acid tert-butyl acrylate

MS (APCI) m/z : 421 [M+H]+. (Reference Example B90) (S)-5-(tertiary butyl dimethyl fluorenyloxymethyl)-1-[2-fluoro-4-(4, 4, 5, 5-tetramethyl-[ 1,3, 2]dioxaborolan-2-yl)benzine]πpyrrolidine-2 -copper

MS (APCI) m/z : 450 [M+H]+ 〇 (Reference Example B91) [3-indolyl-4-(4, 4, 5, 5-tetradecyl-[1,3, 2] Oxaborolan-2-yl)phenyl]aminecarboxylic acid tert-butyl 306 323135 201202230

ο Bu NH MS (APCI) m/z : 351 [M+H]+ ° (Reference Example B92) [2-mercapto-4-(4, 4, 5, 5-tetradecyl-[1,3, 2] Dioxaborolan-2-yl)phenyl]amine decanoic acid tert-butyl butyl ester

Ip-ό-0^ MS (APCI) m/z : 351 [M+H]+ . (Reference Example B93) 1-[2-Fluoro-4-(4,4,5,5-tetradecyl-[1,3,2]dioxaborolan-2-yl)phenyl] -3-[2-mercapto-2-(tetrahydropyran-2-yloxy)propyl]mizone snail-2-one

(Reference Example 94) (R)-5-(tertiary butyl dimethyl fluorenyl fluorenyl) _3_ [2-fluoro-4-(4, 4, 5, 5_tetradecyl _[1, 3, 2] Dioxahyterocyclic pentene 2-1-yl)phenyl]oxazolidin-2-one

MS (APCI) m/z : 452 [Μ+Η]+ . (Reference Example B95) 2-(2-Sideoxypyrrolidin-1-yl)-5~(4, 4, 5, 5_四323135 307 201202230 Mercapto-[1,3, 2]dioxaboron Heterocyclic pentan-2-yl) carbonitrile nitrile MS (APCI) m/z : 313 [M+H]+ 〇Reference example B96 8- job-311-啥啥琳-4-_Manufacture

Aq.NaOH 30% H202

Na2S〇4, CI3CCH(OH)2 (nh2oh)2 h2so4 -► c.HCI, H20, EtOH

H21^) co2h C.H2SO4

The sulphate sulphate sulphate sulphate sulphate sulphate sulphate sulphate sulphate sulphate sulphate sulphate sulphate sulphate sulphate sulphate sulphate sulphate

The mixture was stirred at 8 Torr for 2 hours in 680 mL of water. After cooling the reaction mixture to room temperature, it was further stirred under ice cooling, and the precipitated crystals were collected by filtration. After washing, it was dried to give 2-(hydroxyimino)-indole-(2-iodophenyl)ethylamine yellow. The brown powder was 27. 7 g (53% yield). MS (APCI) m/z; 291 [M+H] + (2) The compound obtained in the above (1) 2?. 7 g of concentrated sulfuric acid 15 〇 this solution was hungry for four hours. The anti-composite is injected into the ice water diagram, and the precipitated crystals are taken for 1 hour, and after washing with water, the reddish brown powder of the crude product of two to two is dried by drying. 323135 308 201202230 MS (APCI) m / z ; 274 [M + H] + &gt; 306 [M + MeOH] + (3) The compound obtained in the above (2) 27. lg was added to sodium hydroxide

22. Into a solution of 9 g of water, 180 ml of a 30% aqueous hydrogen peroxide solution was slowly added dropwise to the mixture under ice cooling, and then stirred at room temperature for 1 hour. After 97 mL of 6N hydrochloric acid was slowly added dropwise to the reaction mixture under ice cooling, the mixture was stirred for 1 hour. And the light brown powder of 2-amino-3-iodobenzoic acid was obtained in an amount of 20. 8 g ( The yield was 83% (calculated from (2) in total of 2 stages). MS (APCI) m/z; 264 [M+H]+ (4) Add the meglumine l〇〇mL to the compound obtained in the above (3), 20. 7 g, the mixture was stirred at 丨5 (rc 6 The reaction mixture was cooled to room temperature. After adding 400 mL of water and stirring for 30 minutes, the precipitated crystals were collected by filtration and washed with water and diethyl ether to give 8-iodo-3H-quinazoline-4-one. Brown powder 18.2g (yield 85%) MS (APCI) m/z ; 273 [M+H]+ 〇Reference Example B97 Manufacture of 8-bromo-3H-quinazolin-4-one

The corresponding raw material compound 2Q. 13g was treated in the same manner as in Reference Example A6(4) to obtain 8-tone 311 dec*#_4, 18 90%). • Dry 323135 309 201202230 MS (APCI) m/z : 225/227 [M+H]+. Reference example B98

Manufacture of 4-chloro-8-iodine 啥 琳 琳 Ο ΗΝ

Add 1 drop of DMF to 8_break_3Η_喧. The mixture was refluxed overnight at 80 ° C in a solution of 450 mg of a sulfoxide solution of 450 mg of a sulfite solution. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate solution was added to the residue, and ethyl acetate was evaporated. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and filtered. The filtrate was concentrated, and the obtained crystals were evaporated, mjjjjjjjjjj MS (APCI) m/z; 291,293 [M+H]+. Reference example B99 8-Mix-4-chlorine 啥 坐 之 之 manufacture

The title compound 4.85 g (yield 90%) was obtained from the title compound. MS (APCI) m/z : 243/245 [M+H]. 310 323135 201202230 Reference Example B100 Manufacture of 4-(5-difluoromethyl-[1,2,4]nonane-3-yl)piperidine-4-tert-butylate

BocN

4-(N-hydroxyformamyl)piperidine-1 -carboxylic acid tert-butyl ester (compound obtained in Reference Example A36 (l)) 973 mg, ethyl difluoroacetate 4 ml in 1 〇 (: stirring 14 The reaction mixture is concentrated under reduced pressure. The residue obtained is purified by chromatography eluting elut elut elut elut elut elut 757 mg (yield: 62.4%) MS (APCI) m/z; 204 [M+H-Boc]+. Reference Example [ 4-[5-(1-Ethyloxy-1-indole Manufacture of tert-butyl butyl ethyl)-[1,2,4]oxadiyl]piperidine-1-carboxylic acid

Slowly, a 2-mL solution of 2-ethyloxy-2-mercaptopropionic acid 63〇VL was added dropwise to 4-(Ν-hydroxymethylindenyl)piperidine-hydrazine-carboxylic acid three under ice cooling. The butyl ester (the compound obtained in Reference Example A36 (l)) was 973 mg, and the triethylamine 669 # L was added to the benzene benzene solution. After the mixture was stirred at room temperature for a few minutes, the mixture was stirred at EtOAc (EtOAc). After drying over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure of 323 135 311 201202230. The residue obtained was purified by silica gel column chromatography (solvent: hexane/ethyl acetate: 80/20 to 65/35). The title compound was obtained as a pale yellow oil, 1183 mg (yield: 83.7%). MS (APCI) m/z; 354 [M+H]+. Reference Example B102 4-[5-(1,1- Manufacture of tert-butyl butyl difluoroethyl)-[1,2,4]oxadiazol-3-yl]piperidine-1-carboxylic acid

HATU

[Dimethylamino-([1,2,3]triazolo[4,5-b]acridin-3-yloxy)indenyl]didecyl ammonium hexafluorophosphate (HATU) 1711 mg, diisopropylethylamine 1.3111^ was added to a 15 mL solution of 2,2-difluoropropanoic acid 500 hydrazine dimercaptocarboxamide, and the mixture was stirred for 25 minutes. 730 mg of 4-(N-hydroxyindenyl)piperidine-1-carboxylic acid tert-butyl ester (the compound obtained in Reference Example A36 (l)) was added to the reaction mixture, and the mixture was stirred at room temperature for 21 hours. Water # was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The resulting residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate: EtOAc: EtOAc: EtOAc: %). * 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 butyl ester, and 4-[5 -Dimethylamino-[1,2,4]oxadiazole-3~yl] 323135 312 201202230 Manufacture of piperidine-1-carboxylic acid tert-butyl butyl ester

[Dimethylamino-([1,2,3]triazolo[4,5-b]indazin-3-yloxy)indenyl]didecylammonium hexafluorophosphate HATU) 1725 mg, 2,2-difluoro-propionic acid 500 mg, diisopropylethylamine 1.32 mL added to 4-(N-hydroxyindenyl)piperidine-1-carboxylic acid tert-butyl ester (Reference example) 5小时。 The mixture was stirred at room temperature for 26.5 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, which was extracted with di-methane. The organic layer was dried over magnesium sulfate, filtered, and evaporated. The residue obtained will be purified by Shixi rubber column chromatography (solvent: hexane/ethyl acetate: 95/5 to 40/60) to give 4-[5-(1,1-difluoroethyl). _[ι,2,4] oxadiazol-3-yl]piperidine-i-carboxylic acid tert-butyl butyl ester (Compound R1〇6A) as a colorless oil 193mg (yield: μ. i%), 4_[5-Dimethylamino 2,4] % diazol-3-yl]piperidine-indole-carboxylic acid tert-butyl butyl ester (Compound R1〇6B) pale yellow φ color solid 489 mg (yield: 43 · 6%).

(Compound R106A): MS (Compound R106B): MS (m/m): s. The following compounds were obtained in the same manner as in the following Reference Example A36 (3). (Reference Example B104) Pyridine hydrochloride (5-difluoromethyl-[1,2,4]oxadiazol-3-yl)piper 323135 313 201202230

F

MS (APCI) m/z ; 204 [M+H]+. (Reference Example B105) 4-[5-(l-Ethyl-1-methylethyl)-[1,2,4]Pf 二η坐_3 -yl]u- bottom α-hydrochloride

0 person Me _ MS (APCI) m/z ; 254 [M+H]. (Reference Example B106) 4-[5-(1,1-DiIethyl)-[1,2,4]曙二〇?-3-yl]π bottom bite hydrochloride

MS (APCI) m/z ; 218 [off +. (Reference Example B107) 4-[5-Dimercaptoamino-[1,2,4]oxadiazol-3-yl]

2HCI HN MS (APCI) m/z; 197 [M+H] + ° Reference Example B108 to B116 The corresponding compound was obtained in the same manner as in Reference Example B9. 314 323135 201202230 (Reference Example B108) 8_漠_4_[4_(5-Digasthiol-[1,2,4]卩二〇坐-3-yl)α bottom bite-1-yl]-6 - Fluorine

MS (APCI) m/z ; 428/430 [Μ+ΗΓ . (Reference Example B109) Acetic acid 1 -[3-[ 1 -(8- _ _6-fluoro 啥 ° 吓 & _ _ 4-yl) piperidin-4-yl]-[1,2, 4] oxadiazole -5-yl]-1-methylethyl ester

N^N MS (APCI) m/z; 478/480 [M+H]+. (Reference Example B110) 8-bromo-6-fluoro-4-[4-(2-propyl-2H-tetrazol-5-yl) π chen-1-yl] 噎 琳 琳

Ν^Ν

Μ~Ν,Ν1 F MS (APCI) m/z ; 420/422 [Μ+Η]+. (Reference Example Bill) 8-bromo-6-fluoro-4-[4-(2-isopropyl-2H-tetrazole-5-

Base) brigade bite-1-base] 喧 琳 琳 Me, NcN F

Me

Br 315 323135 201202230 MS (APCI) m/z ; 420/422 [M+H]+. (Reference Example B112) 8-iodo-4-[4-(5-isopropyl-[1,2,4]oxadiazol-3-yl) slightly bite-1 -yl]啥吐琳

MS (APCI) ra/z ; 450 [M+H]+ °

(Reference Example B113) 8_漠-4_[4-(5_propyl-[1,2,4]曙二°坐_3-基) 旅咬-1-基]°Ι:α坐琳

Br MS (APCI) m/z; 402/404 [M+H]+ ° (Reference Example B114) 8-bromo-4-[4-[5-(l,difluoroethyl)-[l,2 , 4] humiliation two sitting -3- base] π 辰 bit -1- base] 喧 β sit

Br

MS (APCI) m/z ; 424/426 [M+H]+. (Reference Example B115) [3_[ 1_(8_漠-啥α坐琳_4_基) Piebit-4-yl]-[1,2,4]oxadiazol-5-yl]didecylamine 316 323135 201202230

MS (APCI) m/z ; 403/405 [M+H]+〇 (Reference Example B116) 8-Moth-4-[4-(3-isopropyl-[i,2, 4]卩萼二啥基)娘°定-1 - 基]啥嗤琳

MS (APCI) m/z ; 450 [Μ+ΗΓ. Reference Example B117 Manufacture of 8-bromo-5-fluoro-4-[4-(3-isopropyl-[1,2,4]oxadiazole~5~yl)piperidine-1 -yl]

The title compound was obtained as a pale yellow solid (yield: j%). · MS (APCI) m/z: 420/422 [M+H]+. Reference Examples B118 to B121 The following compounds were obtained by treating the corresponding starting compound in the same manner as in Reference Example 22. 201202230 (Reference Example B118) 8-bromo-5-fluoro-4-[4-(5-propyl-[1,2,4]oxadiazol-3-yl) dent-1-yl]indole. Sitting

MS (APCI) ra/z ; 420/422 [M+H]+ ° (Reference Example B119) 8-bromo-4-[4-(5-cyclopropyl-[1,2,4]oxadiazole- 3-base) ° 辰β定-1 -基]-5-气: saliva

MS (APCI) m/z ; 418/420 [Μ+Η]+ . (Reference Example B120) 8-Moly-5-fluoro-4-[4-(5-trifluoromethyl-[1,2,4]indole yttrium-3-yl] decyl-1-yl] Sputum

MS (APCI) m/z ; 446/448 [Μ+Η]+ . (Reference Example B121) Desert-4-[4-[5-( 1,1-dihydroethyl)-[1,2, 4] 曙dis-3-yl]α辰 bit-1 -yl]- 5-fluoro salicin

N&lt;^N

Br 318 323135 201202230 MS (APCI) m/z ; 442/444 [M+H]+. Reference Example B122 2-[3-[ 1-(8-Moline-6- 啥 -4--4-yl) Paid e-4-yl]_ [1,2, 4]oxadi-5-yl] Manufacture of propan-2-ol

By 1-[3-[1-(8-bromo-6-fluoroquinazolin-4-yl)piperidin-4-yl]-[1,2,4]indole-5-yl acetate </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; MS (APCI) m/z ; 436/438 [M+H]+. Reference Example B123 Bromo-6-fluoro-4-[4-[5-(l-fluoro-1-indenylethyl)-[1,2,4]曙一0 sitting_3-基]Ningbite-1 -基]啥β坐琳的制造

By 2-[3-[1-(8-bromo-6-fluoro 0-salt-4-yl) is sent. ?-4-yl]~[l'2,4]Pf-diazol-5-yl]propan-2-ol (Compound obtained in Reference Example 122) 201 mg was treated in the same manner as Example B100 to give the title compound The colorless solid was 125 mg (yield: 61.9%). MS (APCI) m/z ; 438/440 [M+H]+. Reference Example B124 323135 319 201202230 2-Fluorine~4-(4,4,5,5, tetramethyl-d,3,-2-yl) acetocarboxylic acid tert-butyl butyl ester ‘ Oxazacyclopentane

&quot;C02H (1) Under ice cooling, add 3 75 mmol of 4-butanol and 4-H - 5.25 g to "odor, 2 to fluoro succinic acid, amine salt solution, and stir the mixture at room temperature for 19 hours." : A winding, :: solution to the reaction mixture, with: and the double acid gas, the residue will be obtained by the town chromatography (= organic layer = (10) refined 'to get ... J, and Ding Yuri Colorless liquid 2.GGg (yield 32% 卜I Jiajun three CO^Bu 0-

(2) The compound 2 〇〇g obtained in the above (1) was treated in the same manner as in Bl6 (2) to obtain the title compound of the title compound (7 g) (yield: 73%). , liquid Ms UPCI) m/z ·· 323 [Μ+ΗΓ. Reference Example B125 1-4-[6-Gas-4-[4-(5-TriI fluorenyl-[1,2,4]卩__ | base) n 唆 唆-1-yl] 啥 琳 琳 - Manufacture of g-yl]benzoic acid•hydrochloride 323135 320 201202230

(1) 8-Bromo-6-fluoro-4-[4-(5-trifluoromethyl-[l 2,4]oxadiazol-3-yl)piperidin-1-yl]quinazoline ( Reference compound β162 (a compound)) 68 GmgH4-(4'4,5,5-tetramethyl41,3,2]dioxolane-2-yl)benzoic acid tert-butyl ester (Reference Example M24) The obtained compound) 638 mg, [1,1'-bis(diphenylphosphino)ferrocene]palladium (π) dichlorodi-dichloromethane complex 125 mg and cesium carbonate 2993 mg of 1,4- The dioxane/water (24 mL / 6 mL) solution was stirred at room temperature for 2 hours under nitrogen. After the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The organic layer was taken in water and saturated brine. After washing, it was dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate: 90/10 to 75/25). And 2_fluoro_4_[6_fluoro-4-[4-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)piperidin-1-yl]porphyrin- 8.5 mg of 8-yl]benzoic acid tert-butyl ester (yield: 64%) MS (APCI) m/z: 562 [M+H]+ (2) 4N hydrochloric acid-dioxane solution HmL was added to Compound 5 obtained in the above (1) A solution of 45 mg of 1,4-dioxane in 5 mL of EtOAc (m.) 〇〇%). 323135 321 201202230 MS (APCI) m/z : 506 [M+H]+. Reference Examples B126 to B129 By treating the corresponding starting compounds in the same manner as in Reference Example 125, the following were obtained. (Reference Example 126) 2-Fluoro-4-[5-|t-4-[4-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)piperidine- 1-yl]quinazolin-8-yl]benzoquinone hydrochloride

MS (APCI) m/z ; 506 [Μ+ΗΓ. (Reference Example B127) 2-Fluoro-4-[5-fluoro-4-[4-(5-isopropyl-[1,2,4]oxadiazol-3-yl)piperidin-1-yl] Quinazoline-8-yl]benzoquinone 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-fluoroquinazolin-8-yl]-2-fluorophthalide hydrochloride

MS (APCI) m/z ; 502 [Μ+ΗΓ. 322 323135 201202230 (Reference Example B129) 4-[5-Fluoro-4-[4-(5-trifluoromethyl-[1,2,4]indoledin-3-yl)piperidine-i-yl] Quinazoline _8_yl]_2 monomethyl benzoate

Me COzH MS (APCI) m/z ; 502 [M+H]+. Reference example B130 to B131

The following compound (Reference Example B130) was obtained by treating the corresponding starting compound in the same manner as in Reference Example B46, and then the obtained compound was subjected to a saturated aqueous sodium hydrogencarbonate solution (Reference Example B130) 4-[4-[4 -(5-cyclopropyl-[1,2,4]oxadiazole 0 chen-1-yl]-6-fluoroindole-8-yl]-2-fluoroanilino)

Ms (APCI) m/z ; 449 [M+H]+. (Reference Example B131) 3-Fluoro-4-[6-fluoro-4-[4-(5-isopropyl-mono-l-disial-3-yl)-peptid-1-yl]啥 琳琳_8_基Aniline, 2, 4]

MS (APCI) m/z; 451 [M+H]+. Reference example B132

32313S 323 201202230 Manufacture of 3-(4-bromo-2-fluorophenyl)-1-(2,4-dimethoxyphenylhydrazino)tetrahydropyrimidine-4-one

(1) After adding 1.7 mL of acrylonitrile chloride to a solution of 4-bromo-2-fluoroaniline 3.8 g of dichloromethane at room temperature, 12 mL of dichloromethane was added, and the mixture was stirred at room temperature for 2 hours. The mixture was stirred at room temperature for 23.5 hours. After stirring at room temperature for 16 hours, propylene chloride 325 was added thereto and stirred at room temperature for 23.5 hours. Water was added to the reaction mixture under ice cooling, and after stirring for 5 kn. The obtained residue was washed with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium carbonate and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue obtained was purified by evaporation under reduced pressure to afford 3797 mg of N-(4-bromo-2-fluorophenyl)propenylamine as a colorless powder. : 77. 8%). MS (APCI) m/z ; 244/246 [Μ+ΗΓ. (2) A solution of the compound (24411) and 2,4-didecyloxyphenyl hydrazinoamine 451 / / L obtained in the above (1) was dissolved in 8 mL. (:3 hours of mixing. After cooling the reaction mixture to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was obtained on a NH-stone cartridge (Chromatorex ' solvent: hexane /Acyl acetate: 70/30 to 50/50) Refined to give N-(4-bromo-2-fluorophenyl)-3-(2,4-dimethoxybenzene 324 323135 201202230 amine 413 mg (yield: 100%) of a colorless powder of propylamine. MS (APCI) m/z; 411/413 [M+H]+ (3) 393 mg, 37% of the compound obtained in the above (2) A mixture of 2 mL of aqueous formaldehyde solution and 3 mL of THF was stirred at room temperature for 9 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by NH--------------- : hexanes/acetic acid ethyl acetate: 75/25 to 43/57), to give the title compound as a colorless powder 351·6 mg (yield: 86.9%) MS (APCI) m/z; 423/425 [ M+H]+° Reference Example B133 Manufacture of 3-(4-bromo-2-fluorophenyl)-1-(2,4-dioxalylphenyl)imidazolidin-4-one

(1) Ethyl bromide chloride 2.16 mL was added to a solution of 4-chloro-2-phenylamine, 3. 8 g, triethylamine, 4.18 mL, in THF 100 mL, and the mixture was stirred for 1 hour under ice cooling. The reaction mixture was further stirred at room temperature for 3 days and then concentrated. 100 mL of 〇·5N hydrochloric acid was added to the obtained residue, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and dried over EtOAc. Adding diisopropyl-l-ethylamine 5.24 虬 and 2,4-dimethoxybenzylamine 6.0 依 to a solution of 323 135 325 201202230 in dichloromethane 200 mL at room temperature, the mixture was Stir at room temperature for 18 hours. 5小时。 After adding the basic sodium, 300mg to the reaction mixture was stirred at room temperature for 21 hours, stirred under reflux for 5. 5 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous solution of sodium hydrogencarbonate was added and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and evaporated. The residue obtained was purified by a silica gel column chromatography (solvent: hexane/ethyl acetate: 75/25 to 25/75). _(4_Bromo-2-fluorophenyl)- 2-(2,4-dimethoxy- oxalylamino) acetamide as a brown oil 5.68 g (yield: 71.5 %).

Ms (APCI) m / z ; 397 / 399 [M + H] + 〇 (2) The mixture of the compound obtained in the above (1) 丨.53g, 37% aqueous formaldehyde solution 6. 2mL and THF 11.8mL was stirred at room temperature. 1 hour. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The obtained residue was washed with diisopropyl ether, and dried (MgSO4). Lu MS (APCI) m/z; 409/411 [M+H]+. Reference Example B134 3-(4-&gt;Smell-2-fluorophenyl)-1-[2-(tert-butyl dimethyl dimethyl fluorenyloxy) ethyl] sigma-methylene-4-one Manufacturing 323135 326 201202230

^1. OTBDMS ^ u) Add 2.26mL of bromoacetic acid chloride to a solution of 4.-bromo-2-fluoroaniline 3. 8g, triethylamine 4 · 18ml in THF1〇〇mL under ice cooling,

A

The mixture was stirred for 1 hour under ice cooling and then at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure. &lt;RTI ID=0.0&gt;&gt; The organic layer was washed with a saturated aqueous solution of sodium hydrogen sulfate and dried over magnesium sulfate. Diethylethylamine 6·99 mL, 2-aminoethanol 3.62 mL, and 3 〇〇mg of bismuth steel were added to the THF 6 OmL solution of the slag, and the mixture was shaken under heating and reflux. Hour. The reaction mixture was cooled to room temperature, then aq. The organic layer was dried over MgSO.sub.4, filtered and evaporated. The residue obtained is purified by a silica gel column chromatography (solvent: chloroform/methanol: 100/0 to 85/15) to obtain N~(4~~_2_ phenyl)-2-(2-hydroxyl) Ethylamino)acetamide as a brown solid 2. 〇 2 g (yield: 69.5%). MS (APCI) m/z; 291/293 [M+H]+. (2) 1.75 g of the compound obtained in the above (1) was treated in the same manner as in Reference Example B132 (3), and was added to 3_(4_&gt;smelly~2~fluoro stupid)_ι一[2-hydroxyethyl The yellow oil of the imidazolidin-4-one is 1.75 g (the ratio: 95. 9 323135 327 201202230%). MS (APCI) m / z ; 303 / 305 [M + H] + 〇 (3) The compound i, 82 g obtained in the above (2) was treated in the same manner as in the above-mentioned B66 to give the title compound. Yellow oil 2. 3 g (yield: 92.1%). MS (APCI) m/z ; 417/419 [Μ+ΗΓ. Reference Examples B135 to B136 The following compounds were obtained by treating the corresponding starting compound in the same manner as in Reference Example B66. Χ (Reference Example 135) (S)-3-(tertiary butyl dimethyl decyloxy each bite ~2-ketone

HN^^-OTBDMS MS (APCI) m/z; 216 [M+H]+. (Reference Example B136) 00-3-(tertiary butyl dimethyl decyloxypyrrolidine, 2-ketone

HN^**'〇TBDMS(APCI) m/z; 216 [M+H]+ ° Reference Examples B137 to B139 The following compounds were obtained by treating the corresponding starting compound in the same manner as in Reference Example B69. (Reference Example B137) (S)-l-(4-Bromo-2-fluorophenyl)_3_(tris-butyldimethylammonyloxy)pyrrolidin-2-one 323135 328 201202230

MS (APCI) m/z ; 388/390 [M+H]+. (Reference Example B138) (R)-l_(4-Dihydro-2-phenyl)-3-(tertiary butyl fluorenyl yloxy) η

φ MS (APCI) m/z ; 388/390 [Μ+ΗΓ. (Reference Example B139) (S)-l_(4_漠_2_nonylphenyl)-3_(tertiarybutyldidecylfluorenyloxy)pyridinium each. Ding-2-one

MS (APCI) m/z ; 384/386 [Μ+ΗΓ. Reference Example B140 Manufacture of 1-(4-di-2-fluorophenyl)-3-[2-(tertiary butyl fluorenyl fluorenyloxy)ethyl]tetrafluoropyrimidin-2-one

Otbdms Ό The title compound was obtained as a pale yellow solid (yield: 38.7%). MS (APCI) m/z; 431/433 [M+H] + ° Reference Example B141 to B142 329 323135 201202230 The following compound was obtained by treating the corresponding starting compound in the same manner as in Example B14. (Reference Example B141) 1-(4-Di-2-Phenylphenyl) π 比洛唆_2_

MS (APCI) m/z ; 258/260 [Μ+Η]+. (Reference Example B142) 1-(4-Bromo-3-indolylphenyl)pyrrolidin-2-one

MS (APCI) ra/z ; 254/256 [M+H]+ ° Reference Example B143 Manufacture of 4-bromo-2-methylbenzoic acid tert-butyl butyl ester

The title compound was obtained as a pale yellow viscous oil (5585 mg) (yield: 51.5%). MS (APCI) m/z ; 271/273 [M+H]+. Reference Example B144 Manufacture of 4-bromo-3-fluorophenylaminecarboxylic acid tert-butyl butyl ester

330 323135 201202230 The title compound was obtained as a colorless solid (12. 19 g) (yield: 73.8 %). MS (APCI) m/z ; 290/292 [M+H]+. Reference Examples B145 to B155 By treating the corresponding starting compound in the same manner as in Reference Example B16 (2), the following compound was obtained. (Reference Example B145) 1-(2,4-Dimethoxyphenylphenyl)-3-[2-fluoro-4-(4, 4, 5, 5-tetramethyl-[1,3, 2] Dioxaborolan-2-yl)phenyl]tetrahydrobutyrate-4-one

MS (APCI) m/z ; 471 [M+H]+. (Reference Example B146) 1-(2,4-Dimethoxyphenylphenyl)-3-[2-fluoro-4-# (4, 4, 5, 5-tetramethyl-[1,3, 2 Dioxaborolan-2-yl)phenyl] 17m stimuli-4-嗣

MS (APCI) m/z ; 457 [Μ+ΗΓ. (Reference Example B147) 1-[2-(Tertiary butyl fluorenyl fluorenyloxy)ethyl]-3-[2-fluoro-4-(4, 4, 5, 5-tetramethyl-[ 1,3, 2]dioxane heterocyclic pentan-2-yl)phenyl]imidazolidine-4-one 331 323135 201202230

Me Me Me

Me

OTBDMS MS (APCI) m/z; 465 [M+H]+. (Reference Example B148) (S)-3-(tertiary butyldimethylmethyl decyloxy)_i_[2-fluoro-4-(4, 4, 5, 5-tetradecyl-[1,3, 2]dioxaborolan-2-yl)phenyl]° ratio p each 2-ketone

:^&gt;&lt;yhc

OTBDMS

Me MS (APCI) m/z ; 436 [M+H]+. (Reference Example B149) 00-3-(tertiary butyl decyl fluorenyloxy) fluoro~4-(4, 4, 5, 5-tetradecyl-[1,3, 2]dioxaboron Heterocyclic pentane-2-yl)phenyl]pyrrolidin-2-one

MS

Me MS (APCI) m/z ; 436 [M+H]+. (Reference Example B150) (S)-3-(tertiary butyldimethylmethyloxy)-i-[2-methyl-4-(4, 4, 5, 5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)phenyl&gt;bibromidine-2-one

MS

s:b^OTBD

Me MS (APCI) m/z ; 432 [M+H]+. 332 323135 201202230 (Reference Example B151) 1-[2-(tertiary butyldimethylmethyl decyloxy)ethyl] _3-[2-fluoro-4-(4, 4, 5, tetradecyl-[ 1, 3, 2] dioxane, heterocyclic pentane, pyro-2,yl)phenyl]tetrahydro, ketone-2-one

OTBDMS Μ Me Me MS (APCI) m/z ; 479 [M+H]+ . (Reference Example B152) l-[2-Fluoro-4-(4,4,5,5-tetradecyl-[1,3,2]diφoxaborolan-2-yl)phenyl Pyrrolidin-2-one

Me〆b

Me ten O'

Me MS (APCI) ra/z ; 306 [M+H]+ ° (Reference Example B153) l-[3-indolyl-4-(4, 4,5,5-tetradecyl-[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]diox Tertiary butyl bromide-2-yl)benzoic acid

Me /==( OtBu Μμ:$.Β&lt;Η

Me MS (APCI) m/z ; 336 [Μ+ΝΜΓ. 333 323135 201202230 (Reference Example B155) 3-Fluoro-4-(4, 4, 5, 5-tetramethyl-[1,3, 2]dioxa

L-cyclopentan-2-yl)phenylaminecarboxylic acid tert-butyl acrylate MS (APCI) m/z; 338 [M+H]+. Reference Example B156 (2S, 4R)-4-Hydroxypiperidine-2-carbonitrile hydrochloride

(1) Under ice cooling, 'triethylamine 663// L, bismuth citrate from 455 to L (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate 丨__ three Grade butyl vinegar • 〇g of the four gas biting domain 17inL solution 'mix the mixture for go minutes. 28% aqueous ammonia was added to the reaction mixture at the same temperature, and 18 J was applied at room temperature. A saturated aqueous solution of emulsified money was added to the reaction mixture, and extracted with chloroform. The organic layer was concentrated, and the residue obtained was purified by a silica gel column chromatography (solvent: gas/methanol=95/5-80/20) to obtain (2s,4R)_2-amine thiol~4- Base ϋ bite _ι_wei acid tert-butyl butyl ester 2i6mg (yield 22%). (2) 1.77 mL of trifluoroacetic anhydride was added to a solution of 1.15 g of the pyridine i2 mL obtained in the above (1) at -20 ° C, and the mixture was stirred at room temperature for 21 hours. After adding water and ethyl acetate to the reaction mixture, the mixture was washed with 2N hydrochloric acid, 2N aqueous sodium hydroxide solution and saturated brine, and then, 323 135 334 201202230 was dried over magnesium sulfate and filtered. The crude product of (2S,4R)-2-cyano-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester was obtained by concentrating the filtrate under reduced pressure. 8 mL of a 4N hydrochloric acid-dioxane solution was added to a 9 mL solution of the compound in dioxane methane, and stirred at room temperature for 1 hour. Hexane was added to the reaction mixture, and the crystals were crystallized, and dried under reduced pressure to give the title compound 460 mg (yield: 62%). MS (APCI) m/z ; 113 _]+. Reference example B157

1 - (8-Moline-6-Fluoroprene-4-yl) α bottom bite -4- 曱 猜 制作

N~N

The title compound was obtained as a colorless solid (yield: 89.4%). MS (APCI) m/z ; 335/337 [M+H]+. Reference Example B158 1-(2,4-Dimethoxyphenylphenyl)-3-[2-fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[1,2, Manufacture of 4]oxadiazol-3-yl)piperidin-1-yl]quinazolin-8-yl]phenyl]tetrahydropyrimidin-4-one

335 323135 201202230 The title compound was obtained as a brown solid (yield: 95. 1%). MS (APCI) m/z; 684 [M+H] + ° References B159 to B160 The following compounds were obtained by the same procedure as in Reference Example B1. (Reference Example B159) 6-Fluoro-8-[3- gas-4-[2-(tetrazole α-pyran-2-yloxy)ethoxy]phenyl]-4-[4-(5- Isopropyl-[1,2,4]oxadiazol-3-yl)piper® bite &gt;i-based]01:0

MS (APCI) m/z : 580 [M+H]+ ° (Reference Example B160) 6-Fluor-8_[3_gas_4_[2_(tetraz-n-n-yl-2-yloxy)ethoxy Manufacture of phenyl]-4-[4-(5-cyclopropyl-[1,2,4]oxadiazol-3-yl]piperidin-1-yl)quinazoline

MS (APCI) m/z : 578 [M+H]+. Reference Example B161 2-[3-It-4-[2-(Tetrahydrobine~South-2_yloxy)ethoxy]phenyl]-4,4,5,5-tetradecyl-[1 , 3, 2] manufacture of dioxaborolane 336 323135 201202230

MeJ;! MeJ^ Me^〇*

0 B χχ 〇 〇 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 MS (APCI) m/z : 384 [M+H]+. Reference Example B162 8-Bromo-6-fluoro-4-[4-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl) Φ Ninjabit-1-yl]啥Salina Manufacturing

The title compound (2.26 g) (yield: 95%) was obtained from the title compound. MS (APCI) m/z : 446/448 [Μ+ΗΓ .

Reference Example B163 Manufacture of 4-(2-propyl-2H-tetrazol-5-yl)piperidine hydrochloride

(1) 3.86 g of sodium azide and 3.45 g of ammonium sulfate were added to a solution of 5.00 g of 4-cyanopiperidine-1-carboxylic acid in 3 mL of dimethylformamide, and the mixture was 100. C disturbed for 18 hours. An aqueous solution of citric acid was added to the reaction mixture 337 323135 201202230 and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The residue obtained is purified by silica gel chromatography (solvent: chloroform/methanol = 99/1 to 80/20) to obtain 4-(2H-tetradec-5-yl)-biting-1_slow-acid tertiary butyl The colorless powder of vinegar was 4.75 g (yield 79%). MS (APCI) m/z : 254 [M+H]. 5小时。 The mixture was stirred at room temperature for 1.5 hours. The mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed in the order of water and saturated brine, dried over magnesium sulfate and filtered. The residue obtained was purified by Shihic acid chromatography (solvent: hexane/ethyl acetate = 75/25 to 35/65) to give 4-(2-propyl-2H-tetrazol-5-yl). The colorless liquid of piperidine-1-carboxylic acid tert-butyl ester 2. 04 g (yield 8 %). MS (APCI) m/z: 296 [M+H]+. (3) The compound obtained in the above (2) (2 g) was obtained in the same manner as the the the the MS (APCI) m/z : 196 [Μ+ΗΓ. Reference Example B164 1-[2-Methyl·~4-(4,4,5,5-tetradecyl-[1,3,2]dioxaborolan-2-yl)phenyl] Manufacture of pyrrolidine-2 ketone 338 323135 201202230

(1) 1-(4-bromo-2-indole) was obtained by treating 4-bromo-2-methylaniline 3. 00 g and gasified 4-chlorobutyric acid 2.71 mL in the same manner as in Example B99. The colorless solid of phenyl phenyl pyrrolidine-2-one was 3.75 g (yield 92%). MS (APCI) m/z; 254, 256 [M+H] + (2) The title compound was obtained as colorless by the compound of the compound (1). 1.21 g of solid (38% yield). MS (APCI) m/z; 302 [M+H]+ Reference Example B165 l-[2-[2-fluoro-4-(4, 4, 5, 5-tetradecyl-[1,3, 2] Manufacture of dioxaborolan-2-yl)phenyl]-2-oxoethyl]pyrrolidin-2-one

(1) Adding 3.33g of tetra-n-butylammonium tribromide to 4-bromo-2-fluoroacetophenone 1. 50g of dichlorodecane / decyl alcohol (2 / l) 90mL solution, the mixture Stir at room temperature for 20 hours. The reaction mixture is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (hexane/acetic acid ethyl acetate = 95/5 to 85/15) to obtain 2-di-1 - (4- Crude product of dimethyl-2-fluorophenyl)ethanone 339 323135 201202230 1.88g. (2) 4 mL of a solution of 400 mg of the compound obtained in the above (1) and 147 mg of 2-methoxy-1-pyrroline was stirred at 60 ° C for 3 hours. The reaction mixture was cooled to room temperature, water was added, and ethyl acetate was evaporated. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography eluting with EtOAc (ethyl acetate / ethyl acetate = 50/50 to 0/100) to give 1-[2-(4-bromo-2-) Fluorylphenyl)-2-oxoethylethyl 281 mg of a colorless solid of pyridin-2-one (63% in total from the yield of the step (1)). MS (APCI) m/z; 300/302 [M+H]. (3) 280 mg of the compound obtained in the above (2). Brown oil 222 mg (yield 68%). MS (APCI) m/z ; 348 [M+H]+ Reference Example B166 (S)-l-[2-Fluoro-4-(4, 4, 5, 5-tetradecyl-[1,3, 2 Manufacture of dioxaboryl-heterocyclopentan-2-yl)phenylhydrazinyl]pyrrolidine-2-carboxylic acid decylamine

(1) 4-bromo-2-fluorophenylindenyl bromide 1. 07g and triethylamine 613 VL are added to a solution of (S)-n ratio p -2- acesulfame 502 mg of acetonitrile in 18 mL, The mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with EtOAc. The residue obtained in 340 323135 201202230 was purified by a rubber column chromatography (hexane/ethyl acetate = 60/40 to 20/80) to obtain (S)-l-(4-bromo-2-fluorophenylhydrazine). 995 mg (yield 83%) of a colorless solid of pyridin-2-carboxylic acid decylamine. MS (APCI) m/z; 348 [M+H] + (2) 990 mg of the compound of the above (1). (Yield 25%). MS (APCI) m/z ; 349 [M+H] + Reference Example B167 2-fluoro-4-(4, 4, 5, 5-tetradecyl-[1,3, 2]dioxaboroline Manufacture of pentane-2-yl)benzoylamine decanoic acid tert-butyl butyl ester

(1) 4-bromo-2-fluorobenzylamine 6g and diisopropylethylamine

• 10. 2 mL was added to a solution of 7.2 g of dicarboxylic acid di(tertiary butyl ester) in dichlorosilane (120 mL), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The resulting residue was purified by Shih-Hui-gel column chromatography (hexane/acetic acid from 95/5 to 85/15) to obtain (4-bromo-2-fluorophenylindenyl)amine decanoic acid The colorless solid of the butyl ester was 8.32 g (yield 93%). MS (APCI) m/z; 304, 306 [M+H] + (2) The title compound is obtained by the same procedure as the reference compound 341 323 135 201202230 B16 (2). Colorless viscous oil 852 mg (yield 74%). MS (APCI) m/z ; 252 [M+2H-Boc]+ Reference Example B168 [2-fluoro-4-(4, 4, 5, 5-tetramethyl-[1,3, 2]dioxa Manufacture of tributyl butyl bromide-2-yl)benzyl] decylamine decanoate # 8 double'. Seven-gong Yiyi. Seven-$ cut. (1) Cooling a solution of sodium hydride sulfhydryl sulfoxide in 15 mL to 〇 ° C ', wherein 4-bromo-2-fluorobenzoylamine decanoic acid tert-butyl ester (reference compound B167 (l)) i. 5g, the mixture was stirred for 15 minutes. Methyl iodide 0. 34 mL was added dropwise to the reaction mixture, 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 with water and brine, dried over magnesium sulfate and evaporated. (4-bromofluorobenzyl) decylamine is obtained by refining it to the residue or by chromatography on silica gel column chromatography (chloroform/ethyl acetate = 0/100 to 1/99). 146g of colorless viscous oil of butyl citrate (yield. MS (APCI) m/z; 318,320 [M+H]+ (2) by the compound of the above (1) The product was treated with 648 mg (yield: 59%) of the title compound as a colorless viscous oil. MS (APCI) m/z; 366 [M+H]+ Reference Example B169 323135 342 201202230 Manufacture of ethyl 2-fluoro-4-(4,4,5,5-tetramethyl-[1,3, 2]dioxaborolan-2-yl)phenylacetate

The title compound was obtained as a colorless solid i.56 g (yield: 66%) of ethyl 4-bromo-2-fluorophenylacetate. MS (APCI) ra/z ; 309 [M+H]+ Reference Example B170 2-fluoro-4-(4, 4, 5, 5-tetramethyl-[1,3, 2]dioxaborane Manufacture of pentane-2-yl)phenylacetic acid tert-butyl butyl ester

HCI tBuOH CH2CI2

(1) Concentrated sulfuric acid 3. 5 mL was added to magnesium sulfate 31. 5 g of dichlorohydrazine in 200 mL of solution. The mixture was stirred for 15 minutes. To the reaction mixture was added a solution of 4-bromo-2-fluorophenylacetic acid (15. The reaction mixture was filtered through Celite, and ice and saturated aqueous NaHCO? After separating the organic layer, the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with sodium sulfate and filtered. The residue obtained was purified by Shih-Hybrid column chromatography (hexane/acetic acid ethyl acetate = 95/5 to 90/9) to give 4-bromo-2-fluorophenylacetic acid tert-butyl ester as a colorless solid. g (yield 88 323135 343 201202230%). MS (APCI) m/z; 289, 291 [M+H] + (2) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 358. 7 mg (yield 53%). MS (APCI) m/z ; 354 [M+H] + Reference Example B171 3-fluoro-4-(4, 4, 5, 5-tetradecyl-[1,3, 2]dioxaborane Manufacture of tributyl butyl bromide-2-yl)phenylacetate

(1) Adding 340 μL of N-methylmorpholine to 6 〇〇mg of 4-bromo-3-fluorophenylacetic acid and vaporizing 4-(4,6-dimethoxyl-1,3, 5- Triton-2-yl)-4-mercapto-whallin η hydrate (DMT-MM) 855 mg of tertiary butanol in 12 mL of solution 'The mixture was stirred at 50 ° C for 2 hours. The reaction mixture was cooled to room temperature. EtOAc was evaporated, evaporated, evaporated, evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate = 97/3 to 85/15) to give pale yellow viscous of 4-bromo-3-fluorophenylacetic acid tert-butyl ester. The oil was 5 〇 9 mg (yield 68%). (2) By treating 500 mg of the compound obtained in the above (1) in the same manner as the the the MS (APCI) m/z ; 436 [M+H]+ 323135 344 201202230 Reference Example B172 2-Fluoro-4-[6-fluoro-4-[4-(5-propyl-[1,2,4] Manufacture of oxadiazole _3_yl)piperidin-1-yl]quinazolin-8-yl]phenylacetic acid

-3-yl)piperidin-1-yl]quinazoline (Compound obtained in Reference Example B1) 450 mg and 2-fluoro-4-(4, 4, 5, 5-tetramethyl-[U 3, 2 Ethyl dioxaborolan-2-yl)phenylacetate (Compound obtained in Reference Example M69) 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]oxadiazol-3-yl)piperidine-diyl] 啥0 sits scared 8 base] Solid 476 mg (yield 85%). MS (APCI) m/z; 522 [M+H] + (2) Compound (45%) of (b) Colorless solid 361 mg (yield 85%). MS CAPCI) m/z ; 494 [M+H]+ Reference Example B173 3-Fluoro-4-[6-fluoro-4-[4-(5-propyl-[1,2,4]曙二曙- Manufacture of 3-yl)piperidin-1-yl]quinazolin-8-yl]phenylacetic acid 323135 345 201202230

(1) by 8-bromo-6-fluoro-4-[4-(5-propyl-[1,2,4]oxadiazol-3-yl)piperidine-fluorenyl]quinazoline (Refer to the compound obtained in Example B1) 15 〇 mg and 3-fluoro_4_(4, 4, 5, 5_tetramethyl-7,3, 2]dioxa-substituted heterocyclic 'oxime-2-yl) 144 mg of the phenylacetic acid tert-butylate (the compound obtained in Reference Example Bm) was treated in the same manner as in Example B26 (1) to give difluoro-4-[6-fluoro-4-[4-(5- Propyl-[1,2,4]oxadiazol-3-yl)piperidinyl]quinazolin-8-yl]phenylacetic acid tert-butyl butyl U5 mg of a colorless solid (yield: 59%). MS (APCI) m/z; 550 [M+H] + (2) The title compound was obtained in the same manner as the reference compound % B 125 (2). 95 mg of a colorless powder (yield 1%). MS (APCI) m/z ; 494 [M+H] + Reference Example B174 4-[4[4-(5-cyclopropyl-[1,2,4]Nadazole-3-yl)]piperidine ——Buji] ~6-Fluorine-8-yl]-2-fluorophenylacetic acid 323135 346 201202230

(1) by using 8-bromo-4-[4-(5-cyclopropyl-[1,2,4]isosin-3-yl) as a -1-yl]-6-fluoroanthracene Scared (refer to the person obtained in Example B11) _呃 and [2_fluoro-4-(4, 4, 5, 5_tetradecyl-[i,3, 2]dioxaborolane pentane Ethyl -2-yl)phenyl]acetate (Compound obtained in Reference Example B169) 553 mg was obtained in the same manner as in the titled compound B26C1) to give (4_[4_[4-(5-cyclopropyl-[1, 2,4]oxadiazol-3-yl)]piperidinyl-diyl]_6_ 啥 ° sitin-8-yl)-2-fluorophenyl) ethyl acetate as a colorless solid 276mg (yield 44%) MS (APCI) m/z; 520 [M+H] + (2) The title compound was obtained by the same procedure as the reference φ B26 (2). The colorless solid was 198 mg (yield 95%). MS (APCI) m/z; 492 [M+H]+ Reference Example B175 2-fluoro-4-[6-fluoro-4-[4_[3-(2, 2, 2-triethylethyl)_[ Manufacture of 1,2,4] %-oxazol-5-yl]piperidin-1-yl]quinazoline-8-yl]phenylacetic acid 347 323135 201202230

(1) by 8-bromo-6-fluoro-4-[4-[3-(2, 2, 2-trifluoroethyl)__[l'2,4]Pf diazol-5-yl] Piperidin-1-yl] quinazoline (compound of φ obtained in Reference Example EM) 33 〇 mg and 2-fluoro-4-(4,4,5,5-tetramethyl 3 oxaborolane- 553 mg of 2-phenyl)phenylacetic acid tert-butyl ester (Compound obtained in Reference Example B17) was treated in the same manner as in Reference Example B125C1) to give 2-fluoro-4-[6-fluoro-4-[4- [3-(2, 2, 2-trifluoroethyl)-[1,2,4]indole di-sal-5-yl]η辰鸣_ι_基]啥唾琳_8_基]phenylacetic acid A colorless solid of 1,3-butyl ester was 336 mg (yield: 79%). MS (APCI) m/z; 590 [M+H]+ (2) Compound (m) Compound Compound Compound Compound Compound Compound (Yield 23%). MS (APCI) m/z ; 534 [M+H] + Reference Example B176 [2-fluoro-4-[6-fluoro-4-[4-(5-propyl-[1,2,4]噚Manufacture of azole-3-yl)piperidin-1-yl]quinazolin-8-yl]benzyl]decylamine decanoic acid tert-butyl 348 323135 201202230

Base) π bottom bit-1-yl] 啥 淋 (compound obtained in Reference Example B10) 600 mg and [2-fluoro-4-(4, 4, 5, 5-tetradecyl-[1,3, 2] Dioxoborolan-2-yl)benzyl]mercaptoamine decanoic acid tert-butyl ester (Chemical compound obtained in Reference Example B168) 626 mg was treated in the same manner as in Example B1 to give the title compound The colorless solid was 682 mg (yield 83%). MS (APCI) m/z ; 579 [M+H]+ Reference Example B177 2 -Fluoro-4-[6-It-4-[4-(5-propyl-[1,2,4]曙二曙-3-yl) 唆 唆-1-yl] quinine "Spiral-8-yl] phenylhydrazine amine manufacturing

6.1 mL of trifluoroacetic acid was added to 2-fluoro-4-[6-fluoro-4-[4-(5-propyl-[1,2,4]% disial-3-yl)indole </RTI> </RTI> </RTI> </RTI> </RTI> </RTI> </RTI> </RTI> </RTI> <RTIgt; The reaction mixture was concentrated under reduced pressure, and water, methylene chloride and 1N aqueous sodium hydroxide were added to the mixture and lion. The mixture was extracted with a gas chamber, and the organic layer was washed with water and saturated brine in the order of sulfur-dried, 323135 349 201202230. The filtrate was concentrated under reduced pressure, and the residue was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted elution Mg (yield 82%). MS (APCI) m/z; 465 [M+H] + Reference Example B178 [2-fluoro-4-[6-fluoro-4-[4-(5-propyl-[1,2,4]噚2 Manufacture of oxazol-3-yl)piperidinyl]quinazoline-8-yl] azainyl]methylamine

By [2-fluoro-4-[6-fluoro-4-[4-(5-propyl-[1,2,4]oxadiazole-3-yl)piperidin-1-yl]quinazoline_ 8_yl]phenylhydrazinyl]methylamine decanoic acid tri-tert-butyl Sa (Compound obtained in Reference Example B176) 65 〇 mg was treated in the same manner as in Reference Example B177 to give the title compound as a colorless solid (%) (yield) 64%). MS (APCI) m/z; 479 [M+H]+ Reference Example B179 acetic acid H2-fluoro-4-[6- </ RTI> </ RTI> 4-[4-(5-propyl-[i, 2, 4] 曙唾-3-yl) Ninjabita-Buji] 啥Salina _8_yl]benzylamine amide]+Methyl ethyl ester

323135 350 201202230 by 2_Fluoro-446-Fluoro-4-[4-(5-propyl-[1'2,4 bay disani-3-yl) brigade + base] 喧嗤-8- 80 mg of the methylamine (the compound obtained in Reference Example (IV)) and 80 mg of 1-chloroamine hydrazinyl-hydrazinylethyl π^ &quot; L were treated in the same manner as in Example B9 to obtain the target soil. Insulation: a colorless solid of 78. 1 mg (yield 80%). MS (APCI) m/z ; 593 [M+H]+ Reference Example B180 acetic acid [[2-fluoro-4-[6-say-4-[4-(5-propyl-[u'4 bay quinone] -3-Base) 咬 + + base 喧 喧 琳 -8-8-yl] benzyl] methyl amine methyl ketone] methyl ester manufacturing

By (2-fluoro-4-[6-fluoro-4-[4-(5-propyl-[1,2,4]oxadiazol-3-yl)piperidin-1-yl]quinazoline 8 mg of the oxo-8-yl]benzyl)methylamine (the compound obtained in Reference Example B178) and the corresponding starting compound were treated in the same manner as Example B9 to give the title compound as colorless solid (yield 86) %). MS (APCI) m/z ; 579 [M+H] + Reference Example B181 酉夂 1-[[2-fluoro-4-[6-|^_4-[4-(5-propyl-[1,2 Manufacture of 4,oxadiazol-3-yl)piperidin-1-yl]quinazoline-8-yl]benzyl]methylamine-methylamino]-1-indenylethyl ester 323135 351 201202230

By [2-Fluoro-4-[6-fluoro-4-[4-(5-propyl-7), decyl-3-yl)-glycol]-yl]-phenyl]methyl]methylamine Carrying (refer to the compound obtained in Example B178) and the corresponding starting compound in the same manner as in Example B9

In the same manner, the colorless yield of the title compound was 79%) 〇MS (APCI) m/z; 607 [M+H]+ Reference Example B182 8-(6-chloro-2-mercaptopyridine- Manufacture of 3-yl)_6_fluoro_4_[4_(5-propyl-[1,2,4]oxadiazol-3-yl)bistidin-1-yl]quinazoline

By using 8-bromo-6-fluoro-4-[4-(5-propyl-[1,2,4]oxadiazol-3-yl)bistidin-1-yl]quinazoline (reference example) 6 〇〇mg of the compound obtained by B10, and the corresponding starting material compound were treated in the same manner as Example B1 to give 442 mg (yield: 66%) of the title compound. MS (APCI) m/z; 467, 469 [M+H] + Reference Example B183 l-[2-(tert-butyl dimethyl decyloxy)ethyl] 3-[2-fluoro-4-(4) , 4, 5, 5-tetradecyl-[1,3,2]dioxaborolan-yl)phenyl]imidazole pyridine-2,4-dione 352 323135 201202230

(00) 4-bromo-2-fluorophenyl isocyanate 2. 00g and triethylamine at room temperature

1.29 mL was added to the amidoacetic acid ethyl acetate i.29 g of the dichlorohydrazine solution in 4 mL of mL. The mixture was spoiled overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in ethanol (20 mL), and sodium decoxide (28% methanol/yield) was added to the mixture. Further, 1.52 g of sodium methoxide (28% methanol solution) was added to the reaction mixture, and the mixture was stirred at 8 ° C for 1 day. After the reaction mixture was cooled to room temperature, it was concentrated under reduced vacuo. (The mixture was stirred for 3.5 hours. After the reaction mixture was cooled to room temperature, it was poured into a saturated aqueous solution of sodium carbonate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. The residue is dissolved in a small amount of a mixed solution of dichloromethane and methanol, and recrystallized from diethyl ether to obtain 3-(4-bromo-2-fluorophenyl)imidazolidinium- a colorless solid of 2,4-dione 1.19 g (yield 47%) MS (APCI) m/z; 273, 275 [M+H] + (2) Compound 5 obtained by the above (1) 〇〇mg was treated in the same manner as in Reference Example 2(2) to give 3-(4-bromo-2-fluorophenyl(tris-butyldidecylfluorenyloxy)ethyl]imidazolidinium- 466 mg (yield 59%) of 2,4-dione as a colorless solid. MS (APCI) m/z; 431, 433 [ Μ + ΗΓ (3) 460 mg of the compound obtained by the above (2) and reference example 353 323135 201202230 B16(2) was treated in the same manner to give the title compound as colorless solid 266mg 〇MS (APCI) m/z; 479 [M+H]+ Reference Example B184 1-[2-(tri-butyl dimethyl Mercaptooxy)ethyl]_3~[2~fluoro[6-fluoro-4-[4- Manufacture of (5-propyl-[1,2,4]oxadiazol-3-yl)piperidine hydrazide, hydrazino] phenyl] miso sitting bite-2, 4-di

9 mg (yield 62%) of the title compound as a colorless solid (yield: 62%) of the title compound of the title compound. MS (APCI) m/z ; 692 [M+H]+ Reference example B185

Manufacture of pentyl-2-yl) phenylmethyl ester

4-Bromo-2-fluorophenylhydrazine bromide 15 〇g and potassium acetate I?* Hall 0 22. 5 mL solution was stirred overnight at room temperature. The combination of the reaction mixture 1 _ Ulg, i, bis (diphenylphosphino) ferrocene (= dichloride-dichloro decane complex 229mg to, the mixture is stirred at 8 〇 354 323135 201202230 When the reaction mixture is cooled to room temperature, water is added and the mixture is extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and then concentrated under reduced pressure. Solvent: hexane/ethyl acetate = 95/5 to 83/17) EtOAc (m. Example B186

(S)-4-(tertiary butyl dimethyl fluorenyloxy [2 fluoro-4-[6-fluoro-4-[4-(5-propyl-[1,2,4] oxadiazole- Manufacture of 3-yl)piperidin-1-yl]quinazoline-8-yl]phenylhydrazinyl]pyrrolidine-2-one

(1) By treating the compound 6〇〇nig obtained in Reference Example B10 and 504 mg of the compound obtained in Reference Example B185 in the same manner as in Reference Example B1, 2-fluoro-4-[6-fluoro-4-acetic acid was obtained. [4-(5-propyl-[1,2,4]oxadiazole~3~.yl))-piperidin-1-yl]quinazoline-8-yl]phenylindole-based colorless solid 595mg (yield 82%). (APCI) m/z; 508 [M+H] + (2) By treating 59 〇mg of the compound obtained in the above (i) in the same manner as in Example 355 323135 201202230 B11, [2_Fluorine_ 4-gas 6_fluoro_4_[4 _ yl-[1,2'4]oxadiazol-3-yl)piperidin-buki]quinazoline _8-yl] phenyl sterol colorless solid 528mg ( Yield 98%). MS (APCI) m/z ; 466 [M+H]+

(3) The 525 mg of the compound obtained in the above (2) and the methylene chloride tribromide i53 were dissolved in a 10.5 mL solution at room temperature for 2.5 hours. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The residue obtained was purified by column chromatography (hexane/ethyl acetate = 75/25 to 40/60) to give 8-(4-bromo-decyl- 3-fluorophenyl)-6-fluoro 427 mg (yield 72%) of -4-[4-(5-propyl-[1,2,4]oxadiazol-3-yl)piperidinyl- quinazoline as a colorless solid. ^ (APCI) m/z; 528 / 530 [M+H] + (4) The title compound was obtained as a colorless viscous oil by 80 mg of the compound obtained in the above (3) in the same manner as in Example B19. 30.8 mg (yield 31%).

Ms (APCI) m/z; 663 [M+H] + Reference Examples B187 to B189 The following compounds were obtained by treating the corresponding starting compound in the same manner as in Reference Example B174. (Reference Example B187) 3-Fluoro-4-[5-fluoro-4-[4-(5-trifluoromethyl-[1,2, 4]

Π9 二哇-3-yl)piperidin-1-yl]quinazolin-8-yl]phenylacetic acid 356 323135 201202230 MS (APCI) m/z ; 520 [M+H]+ (Reference Example B188) 3 -Gas-4-[6-Gas-4_[4-(5-Trifluoromethyl-[1,2,4] 曙Disal_3_yl)b-Bottom--1-yl]喧喧淋-8 -phenyl]phenylacetic acid

MS (APCI) m/z ; 520 [M+H]+. Reference Example B189 Manufacture of 4-(2-isopropyl-2H-tetrazol-5-yl)piperidine hydrochloride

The title compound was obtained by treating the compound obtained in Reference Example B 163 (1) and the corresponding material compound in the same manner as in References B163 (2) and (3). MS (APCI) m/z : 196 [Μ+ΗΓ. Reference Example B190 8-[4-(2-Ethyloxyethoxy)-2-phenylphenyl]-6-^-4_[4-(5-isopropyl-[1,2,4]噚Manufacture of oxazol-3-yl)piperidin-1-yl]quinazoline hydrogen bromide 357 323135 201202230

® ~&quot;4, 4, 5, 5_tetradecyl-[1,3, 2]dioxaborolane (Compound obtained in Reference Example B21) 373 mg, [1, Γ-bis(diphenyl) Phosphinyl)ferrocene]palladium(II) dichloride-dichloromethane complex 35mg and cesium carbonate 65mg added to 8-di-6-fluoro-4-[4-(5-isopropyl Base ~[1,2,4]oxadiazol-3-yl)piperazin 1 base] 啥 ° sits lin (reference compound B9) 168 mg of 1,4-dioxane 8 mL solution in nitrogen atmosphere Next 'the mixture is at 9 〇. After the addition of acetic acid, ethyl acetate, water, and saturated brine, the mixture was filtered over Celite, and the filtrate was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue obtained was purified by a ΝΗ_矽 rubber column chromatography (Chromatorex; Fuji SILYSIA chemistry, solvent: hexane/ethyl acetate: 90/10 to 70/30). 2 mL of a 25% acetic acid solution of hydrogen bromide was added to the crude product and stirred at room temperature for 1 hour. The reaction liquid was concentrated, and the residue was azeotroped with benzene (yield: EtOAc) (yield: 17%). MS (APCI) m/z ; 538 [Μ+ΗΓ. Reference Example B191 323135 358 201202230 3- Said 4-[6-fluoro-4-[1-(Ν-hydroxyindolyl)piperidinyl]oxime-8-yl]-N,N-didecyl Manufacture of benzamide

c〇NMe, Pd&lt;pPh^

Cl^Br

Boc-N^-b^ Boc.n ~ρ«κρρζ&gt;

(1) 4-(4,4,5,5-tetradecyl-[1,3,2]-dioxaindole-2-yl)-3,6-dihydro-2H- Pyridin-1-carboxylic acid tert-butyl butyl l.i8g, tetrakis(triphenylphosphine)palladium 44〇mg, carbonic acid planing 2.48g and water 6mL added to the simium bromide-4-gas-6-fluoroindole (refer to The compound obtained in Example B3) was dissolved in a microwave reaction apparatus (Initiat) and the mixture was stirred at 140 C for 20 minutes in a solution of 丨.〇〇§^/dioxane 24 mL. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. The residue obtained was purified by silica gel chromatography (solvent: hexane/ethyl acetate = 93/7 to 72/28) to give 4-(8-bromo-6-fluoroquinazoline). - 3, 6-Dihydro-2H-acridine ~ carboxylic acid secondary vinegar pale yellow powder 671 mg (yield: 43%). 323135 359 201202230 MS (APCI) m/z; 408/410 [M+H]+. (2) 200 mg of the compound obtained in the above (1) and 2 to [4, (n-dimethylaminoindenyl)-2-fluorophenyl]-4, 4, 5, 5-tetradecyl- 1,3&gt; oxaborolane 186 mg was treated in the same manner as in Example B1 to give 4-[8-(4-dimercaptoamine-2-carbonylphenyl)-6-fluoroindole. Colorless powder 19 (yield 82%) of tris-butyl 6- 6-dihydro-2H-pyridine-1-carboxylic acid. % MS (APCI) m/z ; 495 [M+H]+ °

(3) 30 mg of 10% by weight of carbon was added to a solution of 181 mg of ethanol obtained in the above (2) in 8 mL of a solution of THF (4 mL), and the mixture was stirred at 40 to 45 ° C for 2 hours under a hydrogen atmosphere. After cooling the reaction mixture to room temperature &quot;, the filtrate was concentrated under reduced pressure. The residue obtained was purified by NH-Kunga's "Chromatorex" (solvent: hexane / ethyl acetate = 8 〇 / 40 / 60) to obtain 4-[8-(4-曱-Aminoguanidino-2 to air-form) -6-fluoroquinazolin-4-yl]piperidine-1-carboxylic acid tert-butyl butyl ester was colorless at 143 mg (yield: 79%). MS (APCI) m/z ; 497 [M+H]+. (4) 2 mL of a 4N hydrochloric acid-dioxane solution and 1 mL of methanol were added to a solution of the compound (2) obtained in the above (3) (yield: 22 mg) in 1,4-dioxane, and the mixture was stirred at room temperature for 2.5 hours. After the solvent was concentrated under reduced pressure, a saturated aqueous solution of &lt;RTI ID=0.0&gt; By decomposing the organic layer under reduced pressure, 3-fluoro-4-(6-fluoro-4-piperidin-4-ylquinazolin-8-yl)4, a pale yellowish Powder 99 mg (yield: 100%). MS (APCI) m/z ; 397 [M+H]+ 〇323135 360 201202230 (5) Add 29 mg of cyanogen bromide and 64 mg of sodium hydrogen bromide to the compound obtained in the above (4) 9 9 mg of ethanol 2 mL, THF 1 mL The mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with di-methane, filtered, and then filtered. The residue obtained was purified by silica gel column chromatography (solvent: chloroform/methanol = 100/0 to 95/5) to give 4-[4-(1-cyanopiperidin-4-yl)-6- 81 mg (yield: 77%) of a colorless powder of fluoroquinazoline-8-yl]-3-fluoro-N,N-dimercaptobenzamine. MS (APCI) m/z ; 422 [M+H]+. (5) The mixture was stirred at 90 ° C for 2.5 hours. The mixture was stirred at 90 ° C for 2.5 hours. After the reaction mixture was cooled to room temperature, the title compound was obtained (yield: 100%). MS (APCI) m/z ; 455 [M+H]+ ° Reference Example B192 4_[4-(4-Cyano*1Bottom)-6-Fluorine喧°坐琳-8-yl]-2- Manufacture of I-N, N-dimercaptobenzamide

The title compound was obtained as a colorless powder (yield: 78%). MS (APCI) m/z ; 422 [M+H]+. Reference Example B193 8-Bromo-6-fluoro-4-[4-(5-isopropyl-[1,2,4]oxadiazol-3-yl)- 361 323135 201202230 Piper-1-yl]- Manufacture of quinazoline

The title compound was obtained as a pale yellow powder (yield: 96%). MS (APCI) m/z ; 421/423 [M+H]+ ° Reference Example B194 (S)-4-(8-Bromo-6-fluoroquinazolin-4-yl)-2-mercaptopiped Manufacture of 1-carboxylic acid tert-butyl butyl ester

The title compound was obtained 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, Manufacture of 4]oxadiazol-3-yl)-3-indolylpiperidin-1-yl]quinazoline

362 323135 201202230 (1) 7 mL of a 4N hydrochloric acid-dioxane solution was added to 768 mg of the compound obtained in Reference Example 194, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was pulverized with diethylamine to give 8-bromo-6-fluoro-4-((S)-3~methylpiped-indole-yl) quinazoline 2 The pale yellow powder of the hydrochloride salt was 774 mg (yield: 1 〇 0%). MS (APCI) m/z; 325/327 [M+H]+. (2) 91 ml of desert cyanide I and 770 mg of sodium hydrogencarbonate were added to a solution of 774 mg of the obtained compound (1) in 15 mL of ethanol, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, which was then evaporated. The organic layer was dried over MgSO.sub.4, filtered and evaporated. The residue obtained was purified by a NH-hydrazine gel column chromatography (Chromatorex 'solvent: hexane/ethyl acetate = 83/17 to 63/37) to obtain (S)-4-(8-bromo-6-). 539 mg (yield: 85%) of a colorless powder of fluoroquinazolin-4-yl)-2-mercaptophenan-1-one. MS (APCI) m / z ; 350 / 352 [M + H] + 〇 (3) By treating 539 mg of the compound obtained in the above (2) in the same manner as in Reference Examples A36 (1) to (2), 275 mg (yield: 41%) of the pale yellow powder of the title compound. MS (APCI) m/z; 435/437 [M+H]. Reference Example B196 8-Bromo-6-fluoro-4-[(S)-4-(5-isopropyl-[1,2,4]oxadiazol-3-yl)-2-methyl -1-基]-啥嗤琳的制造363 323135 201202230

The title compound was obtained as a colorless powder (yield: 64%). MS (APCI) m/z; 435/437 [M+H]+ ° Reference Example B197 (3)-1-(5-isopropyl-[1,2,4]oxadiazol-3-yl)- Manufacture of 3-mercaptopiped φ 2 hydrochloride

(1) By (S)-2-methylpiperidine-1-carboxylic acid-tertiary butyl ester 2.38 g was treated in the same manner as in Reference Example B195 (2) to obtain (S)-4- The cyano-2-indenyl porphyrin-1-low-acid-tertiary butyl S was used as a colorless powder of 2.23 g (yield: 83%). MS (APCI) m/z; 226 [M+H] + (2) (2) Compound: 2.23 g of the compound obtained in the above (1). (Yield: 53%). MS (APCI) m/z ; 211 [M+H]+. Reference Example B198 6-Fluoro-8-[3-fluoro-4-[2-(tetrahydropyran-2-yloxy)ethylthiomethyl]-4-[4-(5-isopropyl) -[1,2,4]oxadiazol-3-yl)piped-1-yl] 喧嗤 之 364 364 323135 201202230

The title compound was obtained 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)piperidin-1-yl]quinazoline Manufacture of porphyrin-8-yl]phenylacetic acid

The title compound was obtained as a colorless powder (yield: 72%). MS (APCI) m/z ; 495 [M+H]+.

Reference Example B200 8-Di-6-fluoro-4-[(R)-4-(5-isopropyl-[1,2,4]卩萼2β-3-yl)-3-methylpiperidin Manufacture of cultivating 1-yl]quinazoline

The title compound was obtained as a pale yellow powder (yield: 91%). 365 323135 201202230 MS (APCI) m/z; 435/437 [M+H]+. Reference Example B201 (R)-l-(5-Isopropyl-[1,2,4]oxadiazol-3-yl)-2-indenyl wells Hydrochloride

The title compound was obtained as a colorless powder of 981 mg (yield: 31%). MS (APCI) m/z ; 211 [M+H]+ ° Reference Example B202 8-&gt;Smell-6-fluoro-4-[4-(5-isopropyl-[1,2,4] 1»Sitting_3__base) - Manufacture of [1,4]diazepan-i-yl]quinazoline

N^N 755 mg (yield: 91%) of the pale yellow powder of the title compound. MS (APCI) m/z; 435/437 [M+H]+ ° Reference Example B203 1-(5-isopropyl-[1,2,4]oxadiazol-3-yl)-[1,4 Manufacture of diazepane hydrochloride salt 323135 366 201202230

The title compound was obtained as a colorless powder (yield: 40%). MS (APCI) m/z ; 211 [Μ+ΗΓ. Reference Example B204 6-Fluoro-8-(3-fluoro-4-mercaptothiononylphenyl)-4-[4-(5-isopropyl-yl-[1,2,4]oxadiazole- Manufacture of 3-yl)-[1,4]diazepan-1-yl]quinazoline

The title compound was obtained as a pale yellow powder (yield: 91%). φ MS (APCI) m/z ; 435/437 [M+H]+ . Reference Example B205 [2-Fluoro-4-[6-IL-4-[(S)-4-(5-isopropyl-[1,2, 4]卩, etc.) Manufacture of -methyl 哄-1-yl]-啥 淋-8-yl]phenyl]acetic acid

The title compound was obtained as a colorless powder (yield: 72%). MS (APCI) m/z ; 509 [Μ+ΗΓ. Reference Example B206 2-Fluoro-4-[6-fluoro-4-[4-(N-carbamicinyl)pyrylene] Porphyrin-8-yl]-N,N-dimethylbenzene Manufacture of guanamine

A 5% by weight solution of 890 mg of a compound obtained by adding 279 / L of a solution of the base amine to VII / 92 of Reference Example ΐ 92 was stirred at 9 ° C for 5 hours. After cooling to room temperature, the solvent was evaporated to dryness. MS (APCI) m/z ; 455 [M+H]+. Reference Example B207 Preparation of 1-(5-isopropyl-[1,2,4]oxadiazol-3-yl)-piperazine hydrochloride

The title compound was obtained as a colorless powder (yield: 62%) from the title compound. MS (APCI) m/z ; 197 [M+H]+. Reference Examples B208 to B211 The following compounds were obtained by treating the corresponding starting compound in the same manner as in Reference Example M 323 135 368 201202230. (Reference Example B208) 8-Oxo-5-fluoro-4-[4-(5-isopropyl-[1,2,4]acrine disani-3-yl)-piperidin-i-yl]- Quinazoline

N^N MS (APCI) m/z ; 421/423 [M+H]+° (Reference Example B209) 8-bromo-4-[4-(5-cyclobutyl-[1,2,4]卩Oxadiazole-3-® base) nchen bite **1-yl]-5-gas 0i: 嗤琳

MS (APCI) m/z; 432/434 [M+H]+° (Reference Example B210) 8_bromo-5-fluoro-4-[4-[5-(1-decylcyclopropyl)_ [ 1,2,4]曙二唆-3-yl]-11 Chenbit-1-yl]啥啥琳

MS (APCI) m/z; 432/434 [Μ+Η]+. (Reference Example B211) 8_Bromo-5-fluoro-4-[4-[5-(l-fluoro-didecylethyl)-[1,2,4]fluorene-β-sodium-3-yl]α-bottom -1-基]啥唾琳

323135 369 201202230 MS (APCI) m/z ; 438/440 [M+H]+. Reference Examples B212 to B213 By treating the corresponding starting compound in the same manner as in Reference Example A36, the following compound was obtained. (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-U-decylcyclopropyl)-[1,2,4]oxadiazol-3-yl)唆辰唆HCl

MS (APCI) m/z : 208 [Μ+Η]+. Reference Example B214: 5-bromo-2-[(R)-4-(tertiary butyldifluorenyloxy)-2 was obtained by treating the corresponding starting compound in the same manner as in Reference Example B69. -Side oxetyrridin-1-yl]benzonitrile.

MS (APCI) m/z; 395/397 [M+H]+ ° Reference Example B215 (S)-l-(4-bromo-2-fluorophenyl)-5-side oxetyridine-2- Carbonitrile 370 323135 201202230 manufacturing

(1) 1.25 g of 4-moth-21-1-mothene 2g Ms) and 5-side oxypyrrolidine-2-carboxylic acid acetate were treated in the same manner as in Reference Example B74 to obtain (S)- 1-(4-Derivative-2-1 phenyl)-5-ethoxy ketone π is slightly biting _2, and the yellow oil is 812 mg (yield: 37%). MS (APCI) m/z; 330/332 [M+H]+° (2) 8 mL of 7N ammonia methanol solution was added to a solution of the above-obtained compound 800 mg of methanol in 4 mL at 0 C, and stirred for 3 hours. After the 7N ammonia methanol solution was applied to the reaction solution, it was dropped for 1 hour, and then the mixture was stirred at room temperature. The reaction solution was concentrated, and a mixed solvent of hydrazine and ethyl acetate was added thereto, and a solid was precipitated by filtration to obtain hydrazine 1 (4-bromo-2-fluorophenyl)-5-oxypyrrolidine-2-carboxyguanamine. Light yellow solid? 491^ (yield: 98%). MS (APCI) m/z ; 301/303 [Μ+Η]+. (3) Adding 1,8--aza-ring~[5,4,〇]_deca-7-ene (DBU) 1.00 mL to 0 c to the compound obtained in the above (2) In the suspension, after dropping 25 grams of diethylene vinegar, 323135 371 201202230 The mixture was stirred at room temperature for 7 hours. 10 mL of tetrahydrofuran and 35 mL of DBUO. were added to the reaction mixture, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj MS (APCI) m/z ; 283/285 [Μ+ΗΓ. Reference Examples 216 to 217 The following compounds were obtained by treating the corresponding starting compound in the same manner as in Reference Example 16(2). (Reference Example 216) (R)-4-(tertiary butyldimethylmethyloxy)-1-[2-cyano-4-(4, 4, 5, 5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)phenyl]pyrrolidin-2-one

_ MS (APCI) m/z ; 443 _]+. (Reference Example B217) (S)-5-Cyano-l-[2-fluoro-4-(4,4,5,5-tetradecyl-[1,3, 2]dioxaborolan Alkan-2-yl)phenyl]pyrrolidin-2-one

MS (APCI) m/z ; 331 [M+H]+ ° Reference Example B218 372 323135 201202230 4]Π弯二嗤_3~基] Pieces Ί Ί, methyl ethyl) _π, 2, hydrochloride Manufacturing

=: The starting material compound was treated in the same manner as in Reference Example Em in the same manner as in Reference Example 36 (3) to obtain 606 mg (yield: 55%) of a colorless powder of the oxime compound.

MS (APCI) m/z ; 214 [Μ+ΗΓ. Reference Example B219 2_Fluoro+[5-fluoro-4—[4m-methylethylhi,2,4]oxadiazole-3-yl]piperidine-indenyl]quinazoline-8-yl]phenylhydrazine Manufacture of acid and hydrochloride

The title compound was obtained as a colorless powder (yield: 62%). MS (APCI) m/ζ : 498 [M+H]+ . Reference Example B220 (2S, 4R)-4-Fluoro 11 piroxime-2-carboxylate-acid amide hydrochloride

Conh2 h0 HCI CONH, (1) Add 7. 5mL of water and 7. 5mL of IN sodium hydroxide solution to 323135 373 201202230 (2S,4R)-4-fluorotrolidine-2-carboxylic acid 993mg, 4_ To a solution of dioxane in 15 mL, a solution of 1.63 g of 1,4-dioxane in 3 mL of di-dicarbonate was added and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. EtOAc EtOAc. The organic layer was washed with water, dried over sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to give (2S,4R)-4-fluoropyrrolidine _i,2-dicarboxylic acid _ι_ ternary butyl ester 1930 mg of a colorless oil (yield: 1%). MS (APCI) m/z; 234 [M+H]. (2) 6.3 mL of triethylamine was added to the compound obtained in the above (1) 1. 93 g, ammonium chloride 2·〇〇g, N-hydroxybenzotriazole·1 hydrate (HOBt · H2〇) 71g and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (WSC · HC1) 2. 13g of dimercaptocaramine 4〇mL solution, 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 filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (solvent: chloroform/methanol = 100/0 to 93/7) to give (2S, 4R) Colorless powder of fluoropyrrolidine-1-carboxylic acid tert-butyl ester 8 〇〇 mg (yield 46%). MS (APCI) m/z ; 233 [M+H] + ° (3) 3 m hydrochloric acid-dioxane solution 3 m was added to the above-obtained compound 800 mg of 1,4-dioxane 6 mL solution at room temperature Stir for 7 hours. The reaction mixture was concentrated to give 533 mg (yield: 92%) of the title compound. MS (APCI) m/z ; 133 [M+H]+. Reference Example B221 323135 374 201202230 8- Desert-4-[4-[5-(l-fail-1-methylethyl)-[1,2,4]曙. Manufacture of -3-yl]-Brigade β-1,4-a-based]

The title compound was obtained by treating the corresponding starting material compound in the same manner as the the the MS (APCI) m/z ; 420/422 [M+H]+ ° Reference Example B222 (3R, 4R)-°Bilo bite-3, 4-diol production

H2, Pd-C ♦

OHm0w〇H

200 mg of 10% palladium on carbon and 10 mL of acetic acid were added to a solution of (3R, 4RM-phenylhydrazonolide), 4-diol 966 mg of ethanol in 15 mL, and stirred under a hydrogen atmosphere (40 psi) at room temperature for 28 hours. The reaction mixture was filtered over EtOAc (EtOAc)EtOAc. MS (APCI) m/z ; 104 [M+H]+ . Reference Example B223 1-(4-Moly-2-fluorophenyl)-1 Η-Sijun

NaN3, HC(〇Et)3

375 323135 2 201202230 1.56 g of sodium azide was added to a solution of 4-bromofluoroaniline 3.%, triethyl orthoformate 8.89 g of acetic acid in 5 mL, and stirred at 120 C overnight. The reaction mixture was cooled to room temperature and then concentrated. A saturated aqueous solution of sodium hydrogencarbonate was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: hexanes: EtOAc: EtOAc: EtOAc) MS (APCI) m/z ; 243/245 [M+H]+»

Reference Example B224 Ethylene difluoride: =; base [1'3, 2] two gas _ ring

Adding 163 mg of [1,Bus(diphenylphosphino)ferrocene]palladium(11) di-vapor-chloroindole complex to 1-(4-bromo«, gas-based)-1Η-four The azole is 972mg, the diboronic acid pinacol ester is 1.22g, the acetic acid is unloaded by 765. The 10mL/dimethyl-hardened lmL solution is in the nitrogen atmosphere at 8〇$. After the reaction mixture was cooled to room temperature, it was poured into saturated sodium hydrogencarbonate aqueous solution. The mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The residue was obtained by the method of the residue of the residue, which was obtained by the title of 323135 376 201202230. Yield 100%). MS (APCI) m/z; 291 [M+H]+. Reference example B225

6-[6-Fluoro-4-[4-(3-isopropyl-[1,2,4]protonadiazol-5-yl)piperidin-1-yl]quinazoline-8-yl] Manufacture of ethyl nicotinic acid

Add 138 mg of tetrakis(triphenylphosphine)palladium and hexa-n-butylditin 601 &quot;L to 8-bromo-6-fluoro-4-[4-(3-isopropyl-[1,2, 4] Pf diazol-5-yl)piperidine 1 -yl]quinazoline (Compound obtained in Reference Example B13) 5 〇〇 mg and 6-chloronicotinate ethyl ester 221 mg of dioxane 10 inL solution, the mixture was 10 〇 ° 〇 stir all night. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture. The organic layer is subjected to subtraction (four) shrinkage, and the residue is obtained by chromatography on silica gel column chromatography (solvent: calcined / ethyl acetate = 65/35 to 50/5 Torr) to give the title compound as a pale yellow (tetra) 45 mg. (Yield month MS (APCI) m/z; 491 [M+H]+. 〇). Reference Example B226 (S)-3-(tertiary butyldidecylfluorenyloxy)+(2 + [4-(5-propyl-[1,2, 4M disa_3_yl)) Manufacture of biting ~1 1 -8-yl]phenylhydrazinyl)pyrrolidine-2-one | quinazolyl 323135 377 201202230

(S) &gt; - OTBDMS 80 mg of the compound obtained in Reference Example B 186 (3), and 39 mg of the compound obtained in the title compound B135 were obtained in the same manner as in Example B19 to give the title compound (yield: 80%). ). MS (APCI) m/z ; 663 [M+H]+. Reference Example B227 1-[3-[l-[8-(4-Dimercaptoamineyl)-3-phenyl)-6-fluoroquinazolin-4-yl]piperidin-4-yl]- Manufacture of [1,2,4]oxazol-5-yl]-1-methylethyl ester

The title compound was obtained by the same procedure as in Example B1. MS (APCI) m/z ; 304/306 [M+H]+ ° Reference Example B228 6-[6-fluoro-4-[4-(5-isopropyl-[1,2,4]oxadiazole -3-yl) piperidine_1_yl]01^ sitting _8-based] in the manufacture of acid test 378 323135 201202230

(1) by using 8-bromo-6-fluoro-4-[4-(5-isopropyl-[nyoxadiazol-3-yl)piperidin-1-yl]quinazoline (Reference Example β9) The obtained compound and 662 mg of 6-gas nicotinic acid ethyl ester were treated in the same manner as in Reference Example 225 to give 6-[6-fluoro-4-[4-(5~isopropyl-[^,彳]噚. Diazole _3_ yl) yttrium-1-yl] oxazolidine-8-yl] 187 mg (yield: 16%) as a pale yellow solid of ethyl acetate. MS (APCI) m/z; M+H]+ 〇(2) 153 mg (yield: 89%) of the title compound as a yellow solid (yield: 89%) of the compound obtained in the above (1). ^/ζ; 463 [Μ+ΗΓ. Reference Example B229-[Fluoro-4-(4,4,5,5-tetradecyl-[1,3, 2]dioxaborolane-2] Manufacture of dimethyl carbamic acid tert-butyl 323135 379 201202230

(1) Adding 350 mg of sodium hydride in a small amount to o(c) in a small amount of (4-di-2-IL phenyl) phthalic acid tert-butyl butyl ester 2 〇 3 g of tetrahydrofuran in 42 mL of a solution of 'mixing the mixture 7 minute. Add iodomethane hydrazine. 7 mL to the reaction solution was stirred at 〇C for 1 hour, and then the reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture to extract with ethyl acetate. The organic layer was washed with 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 give (4-bromo-2-fluorophenyl)decylamine decanoic acid three-stage. The pale yellow solid of butyl ester was 2.08 g (yield: 98%). MS (APCI) m/z ; 304/306 [M+H]+. (2) The compound obtained in the above (1) was obtained in the same manner as in the title compound B16 (2) to give the title compound as a colorless powder, 1.96 g (82%). MS (APCI) m/z ; 252 _-Boc]+. Reference Example B230 2-(p-Butyl-1-yl)-5-(4,4,5,5-tetradecyl-[1,3,2]dioxaborolan-2-yl Manufacture of benzonitrile

Me (〇^B

K2C〇3 -J DMSO

(PinB) 2

PdCI2(dppf)CH2CI2

AcOK -►

DMSO 380 323135 201202230 (1) Pyrrolidine 500; (/1^ and potassium carbonate 1.25 were added to 5-bromo-2-fluorobenzonitrile lg dimethyl sulfoxide 5mL solution 'The mixture was subjected to microwave reaction In an Initiator, it was heated at 100 ° C for 3 hours. After adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was subjected to silica gel column chromatography (solvent: hexane / ethyl acetate = 95 / 5 to 85/15), 979 mg (&amp; rate: 78%) of 5-bromo-2-(indolyl-1-yl)benzoquinone as a colorless powder. MS (APCI) m/z; / 253 [M+H] + (2) The title compound was obtained as a colorless solid 459 mg (77%). (APCI) m/z; 299 [M+H]+. Reference Examples B231 to B233 The following compounds were obtained by treating the corresponding starting compound in the same manner as in Reference Example a16.

(Reference Example B231) 2-Fluoro-4-(4, 4' 5, 5-tetradecyl-7,3, 2]boron-2-yl)N,N-dimethylbenzamide

Mele

Me Me

Ms (APCI) m/z ; 294 [M+H]+. (Reference Example B232) 3-Fluoro-4-(4, 4, 5, 5-tetramethyl-[I 3, 2] _ &amp; rotten heterocyclopentan-2-yl) M-trimethyl silk? ‘ 一孔杂 323135 381 201202230

O F

Me ^\ν.Μ6 Ο MS (APCI) m/z ; 294 [M+H]+ . (Reference Example B233) 5-(4,4,5,5-tetradecyl-[1,3,2]dioxaborolan-2-yl)pyridine-2-carboxylic acid dimethylhydrazine amine

V^N Me Ο MS (APCI) m/z ; 277 [Μ+Η]+ . Reference Example B234 Manufacture of 2-methylaminopropanone-1,3-diol

(B〇C) 2〇

(1) Adding 9.6 g of di(dibutyl phthalate), 10 mL of 1 N aqueous sodium hydroxide solution, and 10 mL of chloroform to 50 mL of a solution of 4-aminopropanone-1,3-diol 4 g in tetrahydrofuran, in a chamber Stir at night. The reaction mixture was weakly acidic by 1N hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and evaporated. The resulting crude product was washed with diethyl ether, and then filtered to give (2-hydroxy-1-hydroxydecylethyl)amine carboxylic acid tert-butyl ester as a colorless solid 5.14 g (yield 61%). 382 323135 201202230 MS (APCI) m/z ; 192 [M+H]+ . (2) A solution of 2 g of the compound obtained in the above (1) in tetrahydrofuran (30 mL) was added dropwise to a solution of hydr. The reaction mixture was cooled to 0 ° C, and water and a 2N aqueous sodium hydroxide solution were added and then filtered over Celite. The filtrate was concentrated, and the residue was purified by ethylamine chromatography (solvent: chloroform/methanol = 100/0 to 90/10) to give 359 mg (yield: 33%) MS (APCI) m/z ; 106 [M+H]+. Reference Example B235 3-Fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4]oxadiazol-3-yl) TB-1-yl]quinazoline Manufacture of lyo-8-yl]benzoic acid

The title compound was obtained by treating the corresponding starting material compound in the same manner as in the title compound B26. MS (APCI) m/z ; 480 [M+H]+ = Reference Example B236 3-[3-[2-Fluoro-4-(4, 4, 5, 5-tetramethyl·3, 2] Diox Manufacture of tributyl butyl acrylate 323135 383 201202230

(1) The acrylic acid tri-butyl sulfonate was added dropwise to a 2-amine, ethanol, 3.07 mL, and stirred at room temperature overnight at 0 °C. After adding 5 〇 mL of tetrahydrofuran to the reaction mixture, a solution of 4-bromo-2-pyrene cyanide 10 g of tetrahydrofuran in 20 mL of is added dropwise at 0 ° C. The mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated, and the residue was recrystallized from hexane/di- methane. The precipitate was collected by filtration and dried to give 3-[3-(4-bromo-2~~~~~~ Colorless powder of ethyl)ureido]tertyl butyl acrylate 18.55g (yield 99%) MS (APCI) m/z ; 405/407 [M+H]+ • (2) 50 mL of carbon was added to a solution of 18.53 g of the compound obtained in the above (1), and 17.99 g of triphenylphosphine in a solution of dihydromethane in 250 mL, and the mixture was stirred overnight. The reaction mixture was concentrated, and the obtained residue was subjected to a solubilization column (solvent). : hexane / ethyl acetate = 90/10 to 75 / 25) refined to obtain θ3 々 _ (4-diethyl-2-phenyl) + (2-chloroethyl) glycosyl] propionic acid A crude product of vinegar, 300 mL of tetrahydrofuran, 85 g of tetrabutylammonium iodide, 100 mL of 6N aqueous sodium hydroxide solution were added to the crude product, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by chromatography (solvent: hexane/ethyl acetate = 80/20 to 55/45). With hexane After crystallization, the precipitate was collected by filtration, and dried to obtain 3__[3_(4_ odor _2-1 phenyl)-2 _ oxy oxime α sitt-1 -yl] propionic acid tert-butyl The colorless powder 13.48g (yield: 76%). MS (APCI) m / z; 387 / 389 [M + H] + (3) boronic acid pinacol ester 7. 87g, potassium acetate 3. 8g, di r τ-V-phenylene phenylacetone) dipalladium (0) 473mg, 2-dicyclohexylphosphino-2,4,e,~triisopropylbiphenyl 985mg and 1,4-two 100 mL of the compound obtained by the above (?) ® was added, and the mixture was degassed, and then stirred at 9 ° C for 3 hours under a nitrogen atmosphere. Magnesium sulfate was added to the reaction mixture, and the mixture was filtered over Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by Shih-Crystal chromatography (solvent: hexane/ethyl acetate = 80/20 to 60/40), recrystallized from hexane, and the precipitate was collected by filtration, and dried. 10.46 g (yield: 93%) of a colorless powder of the title compound. MS (APCI) m/z ; 435 [M+H]+ »

Reference Example B237 [3-[2-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxanthene^pentan-2-yl)phenyl] -2-Sideoxy σ 嗤 -1- 1-yl] acetic acid tertiary butyl |

(1) 285 mg of sodium hydride (60% oily suspension) was added to i 323135 385 201202230 (4-dichloro-2-fluorophenyl) ° m at 0 °C. A solution of 1.64 g of dimethylguanamine in 35 mL of β-butan-2-one (Compound obtained in Reference Example B62 (l)) was stirred and stirred for 1 minute. Add 3.74 mL of the third grade butyl ester of Molybdenum to the reaction mixture and stir for 1 hour at 〇 °c. 285 mg of sodium hydride (60% oily suspension) and 3.74 mL of butyl acetate triacetate were added to the reaction mixture at 0 ° C, and the mixture was stirred for 2 hours under the same overflow. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate. The residue obtained was purified by Shihic acid chromatography (solvent: hexane/ethyl acetate = 85/15 to 65/35) to give [3-[4-bromo-2-phenylphenyl]- 2-sided oxy-flavored β-sodium-1 -yl]-tert-butyl acetate, 1.21 g of a colorless solid (yield: 51%). MS (APCI) m/z; 373/375 [M+H]+. (2) The title compound (yield: 84%) was obtained from the title compound (2). g

MS (APCI) m/z ; 421 [M+H]+ ° Reference Example B238 2-[3-[2-Fluoro-4-(4' 4, 5, 5_Tetramethyl-3, 2] Diox Manufacture of tert-butyl butyl ketone

The title compound was obtained from the title compound (yield: 71%). MS (APCI) m/z; 449 [M+H] + ° References B239 to B241 The following compounds were obtained by treating the corresponding starting compound in the same manner as in Reference Example B1. (Reference Example B239) 2-[3-[2-Fluoro-4-[5-fluoro-4-[4-(5-isopropyl)-

[1' 2, 4]% diindol-3-yl)pyrazine-1-yl]啥 琳琳_8_yl]phenyl]-2- oxooxypyrazine α-1 -yl 1 - 2-methylpropionic acid

Ms (APCI) m/z ; 662 [Μ+Η]. (Reference Example B240) [3-[2-Fluoro-4-[5-fluoro-4-[4-(5-isopropyl-[1,2,4]卩f-dis-s--3-yl)) -1-yl] 啥 琳 -8-8-yl]phenyl]-2-oxo-imidazolidine-1-yl]acetic acid tert-butyl acrylate

MS (APCI) m/z; 634 [M+H] + 〇 (Reference Example B241) 3-[3-[2-fluoro-4-[5-fluoro-4_[4-(5-isopropyl-4] 1,2,4]曙二唾-3-yl) pie bite-1-yl]嗟哇琳_8-yl] stupid]_2_ sideoxyimidazolidin-1-yl]propionic acid tert-butyl 323135 387 201202230

MS (APCI) m/z ; 648 [M+H]+. Reference example B242 •3==(;22

Manufacture of propionic acid

F Ο

Under the nitrogen atmosphere, 8-E-4-[4-(5-iso^ 嗤-3-ylbuyl]0 reference example β112 was inhibited by 200mg, [3-[2-fluoro-4-( 4, 4, 5, 5-tetramethyl-[I 3 , 2]dioxane cyclopentan-2-yl)phenyl]-2-oxo-imidazolium-1 -yl]propionic acid Grade butyl vinegar (Compound obtained in Reference Example B236) 232 mg, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex 18 mg and acid-breaking A solution of 362 mg of 1,4-dioxane/water (5 mL/lmL) was stirred at 80 ° C for 3 hours. After the reaction mixture was cooled to room temperature, it was treated with NH-Chromatorex, and the filtrate was decompressed. The residue was purified by NH-ruthenium rubber column 388 323135 201202230 (Chromatorex, solvent: hexane/ethyl acetate: 70/30 to 40/60), and added 2 mL of trimethylacetate, trifluoroacetic acid. 5 mL to the obtained crude product, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and then 5 mL of dichloromethane and 4N hydrochloric acid-ethyl acetate solution was added to the residue, and then stirred at room temperature. 10 minutes. Concentrate the reaction mixture, add 1 OmL of acetic acid to the residue &gt; Neutralization of the aqueous solution of the gas-oxidized sodium. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: chloroform / decyl alcohol, 90/10 to 80/20) to give the title compound. Colorless powder #2 213. 2 mg (yield 84%) MS (APCI) m/z; 574 [M+H]+. Reference Example B243 3-[3-[2-fluoro-4-[5-fluoro- 4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-1-yl]quinazolin-8-yl]phenyl]-2-oxyloxy Manufacture of pyridazin-1-yl]propionic acid

The title compound was obtained by the title compound (yield: 44%). MS (APCI) m/z; 592 [M+H] + 〇 References B244 to B246 The following compounds were obtained by the same procedure as in Reference Example B197. 389 323135 201202230 (Reference Example B244) 1-(5-Cyclopropyl-[1,2,4]oxadiazole-3-yl)piperidine monohydrochloride

HCI

Oh MS (APCI) m/z ; 195 [Μ+ΗΓ. -Based) (Reference Example B245) 1-(5-Trifluoromethyl-[1,2,4]indole di-salt-3-one monohydrochloride

MS (APCI) m/z ; 223 [M+H]. (Reference example) (8)-H5-isopropyl-[12,dioxin+yl)-2-indenyl-piperidine monohydrochloride

Ms (APCI) m/z ; 211 [M+H]+ 〇 Reference Examples 247 to 248 are treated in the same manner as Reference Examples bi95(2), (3) by the following reference materials: B274, Reference Example A36 (3) was treated in the same manner to give the following compound. ^Reference Example B247) 1-[5-(1,1-Difluoroethyl)_&quot;,2,4]oxadiazole_3_yl]piperidin monohydrochloride 323135 390 201202230

HC

MS (APCI) m/z ; 219 [M+H]+. (Reference Example B248) 1-[5-(1_Fluoro-1-indolylethyl)-[1,2,4]oxadiazole-3-yl]piperidine monohydrochloride

MS (APCI) m/z ; 215 [_+. Reference Examples B249 to 253 By treating the corresponding starting compound in the same manner as in Reference Example B15, the following compound was obtained. (Reference Example B249) 8-Bromo-4-[4-[5-(1,1-difluoroethyl)-[1,2,4]oxadiazol-3-yl]piped-1-yl] -5-fluoroquinazoline•Schuanyi pills

N^N

Ms (APCI) m/z ; 443, 445 [M+H] + 〇仏 test case B250) 8-Mo-5 - gas _4 - [4 - [5_(bu fluoride + methyl ethyl) _ L1'2, 4]oxadiazol-3-yl]piperidin-indolyl]quinazoline

323135 391 201202230 MS (APCI) m/z ; 439, 441 [M+H]+. (Reference Example B251) 8-bromo-5-fluoro-4-[4-(5-trifluoromethyl-[1, 2,4]indan-3-yl)π-inden-1-yl]anthracene Saliva

MS (APCI) ra/z ; 447,449 [M+H]+ ° (Reference Example B252) 8-,; odor-5-fluoro-4-[(S)-4-(5-isopropyl-[1, 2, 4] oxadiazol-3-yl)-3-methylpiped-1-yl]quinazoline

MS (APCI) m/z; 435,437 [M+H]+ ° (Ref. B253) 8-bromo-4-[4-(5-cyclopropyl-[1,2,4]oxadiazole-3- ))α辰哄-1-yl]-5-fluoroquinone

N^N MS (APCI) ra/z; 419, 421 [M+H] + ° Reference Examples B254 to B257 The following compounds were obtained in the same manner as in Reference Example B9. (Reference Example B254) 8- Desert-4-[4-[5-(1,1-Difluoroethyl)-[1,2, 4] 392 323135 201202230

曙二唾-3-基]旅哄-1-基]啥.坐琳 N^N MS (APCI) m/z ; 425,427 [M+H]+ ° (Reference Example B255) 8-bromo-4-[4-[5-(l,1-difluoroethyl)-[ l,2,4] 曙二峻_3_*]nchen 卩井_1_基]- Dunhuang. Sitting

N^.N MS (APCI) m/z; 443,445 [M+H]+. (Reference Example B256) 8-bromo-6-fluoro-4-[4-(5-trifluoromethyl-[1,2,4]indole-β-s--3-yl)α- morphin-1-yl] Yu Lin

Ν^Ν MS (APCI) ra/z ; 447,449 [M+H]+ ° (Reference Example B257) 8-bromo-4-[4-(5-cyclopropyl-[1,2,4]oxadiazole -3- base) Niang D well-1 - base] 喧吐琳

N^N MS (APCI) ra/z; 401,403 [M+H]+ ° Reference Example B258 to B261 393 323135 201202230 The following compound was obtained by treating the corresponding starting compound. In the same way as Reference Example B26

Ms (APCI) m/z ; 499 [M+H]+. (Reference Example B259) 2-Fluoro-4-[5-fluoro-4-[4-(5-isopropyl-[1,2,4]oxazol-3-yl)piped-1-yl Quinazoline _8_yl]benzoic acid

〇

MS (APCI) m/z; 481 [M+H]+. (Reference Example B260) 2-Fluoro-4-[5-fluoro-4-[(S)-4-(5-isopropyl-[1,2,4]nonane-3-yl)-3- Methyl brigade a well-1-yl]啥 琳琳_8_基]benzoic acid

MS (APCI) m/z ; 495 [M+H]+ 〇 323135 394 201202230 (Reference Example B261) 4-[4-[4-[5-(1, Difluoroethyl)

Azazolium-3-yl]piperidin]-yl]_6-fluoroquinazoline I-based]_2_fluoropropionic acid

Ms (APCI) m/z ; 503 [Μ+ΗΓ. Reference example B262 to B263

The following compound was obtained by treating the corresponding starting compound in the same manner as in Reference Example B125. (Reference Example B262) 2 House 4-[5-1-4-[4-(5-Tri-Gas-methyl-[! 2 4]

• HCI 嗜 二 唾 -3 一 一 一 一 一 基 基 基 基 基 基 基 基 基 MS MS MS MS MS MS MS MS MS MS MS MS 507 507 507 507 507 507 507 507 507 507 507 507 507 507 507 (Reference Example B263) 2-Fluoro-4-[6-fluoro-4-[4-(5-trifluoromethyl-[1,2,4·

Ν^Ν MS (APCI) m/z ; 507 [M+H] oxadiazol-3-yl)piped-1-yl]quinazolin-8-yl]benzoic acid monohydrochloride _ Reference example B264 323135 395 201202230 [3-[2-|l-4-[5-Fluoro-4 - [4-(5-isopropyl-[i,2,4]indole dis--3-yl) piperidine- Manufacture of 1-yl]quinazoline-8-yl]phenyl]_2_sideoxyimidazolidin-1-yl]acetic acid

(1) by 8-bromo-5-fluoro-4-[4-(5-isopropyl-[1,2,4]oxadiazol-3-yl)piped-1-yl]quinazoline Porphyrin (Compound obtained in Reference Example B2〇8) 100 mg and [3-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3, 2]dioxaborole) Alkyl-2-yl)phenyl]-2-oxo-imidazolidinyl]acetic acid tert-butyl hydrazine (Compound Ref. B237) ii9. 7 mg was treated in the same manner as Reference Example B1 to give [3- [2-Fluoro-4-[5-fluoro-4-[4-[5-isopropyl-[1' 2, 4]indole-di-sial-3-yl]pyr-1-yl] 啥嗤琳基A colorless powder of phenyl]-2-oxo-imidazolidine-1-yl]acetic acid tert-butyl acrylate (yield 82%). MS (APCI) m/z ; 635 [M+H]+. (2) 1.2 ml of difluoroacetic acid was added to a solution of 124 mg of the compound obtained in the above (1) in dichloromethane (2 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and dioxane and water were added to the obtained crude product. The organic layer was washed with water and saturated 396 323 135 201202230 brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. EtOAc (EtOAc m. MS (APCI) ra/z ; 579 [M+H]+ ° Reference Example B265 (R)-l-(4-bromo-2-fluorophenyl)-5-oxoxypyrrolidine-3-carboxylic acid hydrazine Manufacture of esters (Compound A) and (R)-l-(4-bromo-2-fluorophenyl)-5-sideoxylpyrrolidine-3-carboxylate (Compound B)

(1) Into (TC) ruthenium chloride 3.66 mL was added dropwise to (R)-5-sideoxy-1- • ((R)-pophenylethyl)pyrrolidine-3-carboxylic acid 10 g The mixture was stirred at room temperature for 5 hours in methanol (100 mL), and the mixture was concentrated under reduced pressure to give (R)-5-s. 5 添加 曱 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 (1) The obtained compound was dissolved in a solution of 12.3 g of toluene in 200 mL, and the mixture was heated under reflux for 4 days. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure, and the residue obtained was chromatographed on 397 323 135 201202230. Purification by the method (chloroform/hexane = 100/0 to 100/10) to obtain a mixture of (R)-5-oxo-oxypyrrolidine-3-carboxylic acid decyl ester and the corresponding ethyl ester (oxime ester/ethyl ester) = a colorless powder of about 2/1) 3. 52 g. (3) The title compound A and the compound B were respectively obtained by the method of the above-mentioned (2), 2.5 g, to give the title compound A and the compound B, respectively. And 959 mg, and any one of them is a colorless viscous oil. Compound A; MS (A PCI) m/z; 316/318 [M+H]+. Compound B; MS (APCI) m/z; 330/332 [M+H]+.

Reference Example B266 (R)-l-[2-Fluoro-4-(4, 4, 5, 5-tetramethyl-[1,3, 2]dioxaborolan-2-yl)benzene Manufacture of 5-yloxypyrrolidine-3-carboxylic acid decyl ester

By (R)-Bu(4-bromo-2-fluorophenyl)_5_sideoxy 0-pyridyl_3_-acid-acid S1 (Compound A obtained in Reference Example B265) 7_g is the same as Reference Example B16(2) The title compound was obtained as a brown viscous oil 305 mg (yield 38%). MS (APCI) m/z ; 304 [M+H]+ 〇Reference Example (R) Tert-butyl dimethyl fluorenyl fluorenyl)-bu [2-fluoro-4- (4'4'5 ,5 tetramethyl-[I3,2]dioxaborolan-2-yl)phenyl] 398 323135 201202230 Manufacture of pyrrolidin-2-one

:XX

F

(1) 120 mg of sodium borohydride was added to (by -1_(4-bromo-2-fluorophenyl)-5-side oxocarboate-3-carboxylic acid ethyl ester at 0 C (reference example B265) Compound B) 950 mg of ethanol 9. 5 mL of the solution, the mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, and the residue was obtained by chromatography on silica gel column chromatography (solvent: hexane/ethyl acetate Ester = 89/11 to 1 〇 / 9 〇) refined, and (R)-l-(4-Ao-2-phenylphenyl)-4-pyrimidinyl-pyridyl-2-ketone is obtained. Viscous oil 678mg (yield 82%) MS (APCI) m/z ; 288/290 [M+H]+ ° (2) Imidazole 239mg, tert-butyl dimethyl fluorenyl chloride 371mg Adding to the 675 mg of the compound obtained in the above (1) in DMF, the mixture was stirred for 8 hours. Then, 2 mL of diisopropylethylamine, σ米0, 7 98 mg, and tertiary butyl were added to the reaction mixture. After the hydrazino chloride 17 66 mg, the mixture was stirred overnight. After adding water to the reaction mixture, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and filtered. Concentrated under reduced pressure, the residue will be obtained Purified by a rubber column chromatography (solvent: hexane/ethyl acetate = 97/3 to 70/30) to give 323135 399 201202230 (R)-l-(4-bromo-2-fluorophenyl)-4 - (tri-butyl dimethyl decyloxymethyl) pyrrolidine-2-one as a colorless viscous oil 853 mg (yield: 91%). MS (APCI) m/z; 402/404 [Μ (3) 845 mg (yield: 47%) of the title compound as a brown viscous oil of the title compound. (APCI) m/z ; 450 [M+H]+ ° Reference Example B268 Manufacture of 4-fluorophenyl 1-fluorophenylpropanecarboxylate 2 〇FX^rVc,- 18-crown at-6 _ tBuOK ^

Fj〇rV (1) 2 hours at room temperature, bromo 40.3 g of dioxane 4 〇 mL solution was added dropwise to 4-gas-4'-fluorobutyrene benzene 50.6 g of dichlorodecane 13 〇 mL Solution =, the mixture was stirred for 3 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified eluting EtOAc EtOAc EtOAc EtOAc Phenyl) butane-1 - _ 73 · 6 g (yield 1%). (2) 18-crown-6 (18-crown-6) (3.5 g), potassium fluoride 9.8 g was added to the solution of the compound obtained in the above (1), 23. 8 g of toluene in 120 mL, and mixed. The mixture was stirred at 85 C for 3 hours. After adding 0.9 g of potassium fluoride to the reaction mixture, the mixture was stirred for 19 hours, and then gasification was carried out to remove 323135 400 201202230 9. 8 g, and the mixture was stirred for 7 hours. A-crown-6 (0.5 g) and potassium fluoride (5 g) were added to the reaction mixture, and after stirring for 18 hours, 5 g of potassium fluoride was added and stirred for 4 hours. After the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The lyophilized 135iqL was dissolved in the third-grade butanol 135iqL. The resulting reaction product was purified by hydrazine column chromatography (hexane/ethyl acetate 400/0 to 19/1). To which was added potassium tributoxide potassium 〇.4g 'the mixture was at 45. (: stirring for 2 hours. After cooling the reaction mixture to room temperature, water was added and extracted with ethyl acetate. The organic layer was dried over barium sulfate and then dried. The residue was purified by chromatography (hexane/ethyl acetate = 19/1) to give (3-fluorocyclopropyl)(4-fluorophenyl)methanone 4.36 g (yield 28%). 3) 6 g of m-benzoic acid benzoic acid was added to the compound obtained in the above (2), 5.69 g of a gas-like 60 mL solution, and the mixture was stirred for 22 hours, and the reaction mixture was ice-cooled. After filtration, the filtrate was washed with sulfur sulphate aqueous sodium sulphate solution, N. 5N sodium hydroxide and saturated brine, dried over magnesium sulfate, and then dried over EtOAc.过g to the obtained residue, the mixture was stirred at 75 C for 16 hours. After the reaction mixture was ice-cooled, it was filtered, and the filtrate was filtered with sodium thiosulfate aqueous solution and 0.5 N hydrogen. The order of the sodium oxide and the saturated brine is washed. After drying with magnesium sulfate, the mixture is allowed to undergo a transition. The residue obtained was purified by hydrazine column chromatography (hexane / ethyl acetate ethyl acetate / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / Example B269 Manufacture of 4-[5~(l-fluorocyclopropyl)-[1' 2, 4] oxadiazole _3_yl]piperidine hydrochloride

NH-HCI by using 1-fluorocyclopropane sulphuric acid fluoroacetic acid (the compound obtained in Reference Example B268) 4.59 g and 4-(N-hydroxymethyl hydrazino)piperidine hydrazine __ tempered acid tertiary butyl vinegar (Reference Example A36C1) The compound obtained was obtained in the same manner as in Reference Example 74, and the resulting product was treated in the same manner as in the reference to the above-mentioned j A36 (3) to obtain the colorless powder 2 of the title compound ( Yield 42%).

Ms (APCI) m/z : 212 [Μ+ΗΓ. Reference Example B270 (18, 21?, 65, 7 ft)-8-[2-Fluoro-4-(4,4,5,5-tetramethyl-[13 2]-' oxazepine Manufacture of -2-yl)phenyl]-4,4-dimercapto-5-oxa~8-azabicyclo[5. 2. 02'6]decane-9-one

(1) by (IS, 2R, 6S, 7R)-4, 4-dimethyl~3 5_ _ , a hydrazine azatricyclo[5. 2. 1. 02'6] 癸-9 -_ 0. 99g is treated in the same way as the virtual moxibustion test, and (lS, 2R, 6S, 7R) ~ 8~(4_^__2_i| 323135 402 201202230 basis)-4, 4- 曱- 3, 5-Dioxa-8-azatricyclo[5. 2. 1. 02,6] oxime-9-one 1. 55 g (yield 80%). MS (APCI) m/z: 356 / 358 [M+H], (2) The title compound was obtained by treating the compound obtained in the above (1) 丨.53 g in the same manner as in Reference Example B19 (2). 591 mg (yield 34%). MS (APCI) m/z : 404 [M+H]+. Reference Example B271 (13, 2 feet, 68, 7 feet)-8-[2-Fluoro-4-[6-1-4-[4-(5-isopropyl-[1,2, 4]Pf II唾-3-yl) 唆-1-yl-quinazolin-8-yl]phenyl]_4,4-dimercapto-3, 5-dioxa-8-azabicyclo[5. 1. Manufacture of 〇2'6]decane-9-one

8-Bromo-6-fluoro-4-[4-(5-isopropyl-[1,2,4] % disazolyl-3-yl)-piperidin-1-yl]- under nitrogen atmosphere Quinazoline (Compound obtained in Reference Example) 841^, (13, 2165, 7[〇-8-[2-Fluoro-4-(4,4,5,5-tetradecyl-[1,3, 2 a gas spur heterocyclic pentyl-2-yl)phenyl]-4,4-dimercapto-3,5-dioxa-8-azabicyclo[5· 2. 1. 〇2,6 ] decane-9-one (compound obtained in Reference Example B27) 89 mg, [1,1,-bis(diphenylphosphino)ferrocene]palladium(11) dichloride-diqimethane complex 7mg and cesium carbonate i63mg of 1,4-di 323135 403 201202230 simmering / water (2mL / 0. 5mL) solution at 8 〇 槐 sample for 18 hours. After the reaction mixture was cooled to room temperature, 'add water, to acetic acid The organic layer is washed in the order of water and saturated brine, dried with sulfuric acid, and filtered. The filtrate is concentrated under reduced pressure, and the residue is obtained by chromatography on silica gel column (hexane/acetic acid). The ethyl ester: 50/50 to 20/80) was purified to give the title compound (yield: 39%). MS (APCI) m/z: 617 [M+H]+ 〇 Reference Example B272 ® 3-Gas-2 Synthesis of 2-dimercaptopropionic acid vinegar

COOMe H〇v\ 1) Tf2o Μ-COOMe -

' 2) TBAF In a nitrogen atmosphere, trifluoromethanesulfonic anhydride 5.12 mL· was added dropwise to 3-hydroxy-2,2-dimercaptopropionate 3·63 g, 2,6- at -78 °C. After 4.8 parts of dimethylpyridine in 50 mL of dichloromethane solution, the mixture was stirred for 3 minutes, and then the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into a 2N aqueous solution of hydrochloric acid, and the organic layer was separated, and then the aqueous layer was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and evaporated. The residue was dissolved in 15 mL of tetrahydrofuran, and 7.19 g of tetrabutylammonium fluoride was slowly added thereto under ice cooling, and the mixture was stirred overnight at room temperature. After the reaction mixture was concentrated under reduced pressure and dichloromethane and water was evaporated to the residue, the organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was evaporated. The residue obtained was distilled to give 268 mg (yield: 7%) of a yellow liquid of the title compound. No reference example Β 273 323135 404 201202230 4-Fluoro-4 - (N_ via base-lung-based) sent 0--1-retributed acid three

Synthesis of butyl esters POCI3

(1) Adding 15 mL of 6N ammonium-nonanol solution to ethyl ι_(=-butoxycarbonyl)-4-fluoropiperidine-4-carboxylate 1. 00 g at room temperature, and mixing the mixture overnight . The reaction mixture was concentrated under reduced pressure to give 933 mg (yield: 1%) of 4-amine s. MS (APCI) m/z ; 247 [Μ+ΗΓ.

(2) 612 mg of oxychlorinated chlorinated solution was added dropwise to (1) 894 mg of the obtained &amp; 894 mg of triethylamine 735 mg of dioxane methane, and the mixture was stirred at room temperature for 3 hours. . The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and the organic layer was separated. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was purified by chromatography (solvent: hexane/ethyl acetate = 70/30 to 40/60) to give 4-cyanide. A white solid (yield 74%) of butyl-4-fluoropyrylene-1-tert-butylate. MS (APCI) m/z; 229 [M+H]+. (3) 196 mg of a 50% aqueous solution of hydroxylamine was added dropwise to 5 mL of an isopropyl alcohol solution of (2) of the obtained compound at 60 ° C, and the mixture was heated to a flow of 135 405 201202230 for 1 hour. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = 50/50 to 30/70) to give 4-fluoro-4. - (N-Hydroxymethyl hydrazino) piperidine ~ decyl citrate as a white solid 709 mg (yield: 1%). MS (APCI) m/z ; 262 [M+H]+ 〇Reference Example B274 4_[5~(2-Fluoro-1,1-didecylethyl)-[ι,2, 4]曙二哇~ Synthesis of piperidine-1-carboxylic acid tert-butyl butyl nh2

COOMe 200 mg of sodium hydride (60% oily suspension) was added to 268 mg of the compound obtained in Reference Example B272 and 584 mg of a dioxane solution obtained in Reference Example A36 (l) at room temperature, The mixture was stirred overnight. The reaction mixture was poured into an aqueous solution of ammonium chloride, and ethyl acetate was added thereto, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with sulphuric acid and then filtered. The obtained residue was purified by silica gel column chromatography (yield: hexane/ethyl acetate=95/5 to 65/35) to afford 360 mg (yield: 55%) of the title compound. MS (APCI) m/z ; 328 [M+H]+ ° Reference Example B275 4-Fluoro-4-(5-isopropyl-[1,2,4] 嗤二嗤基)σ辰咬一1_ Synthesis of tert-butyl tertiary butyl ester 323135 406 201202230

After isobutylphosphoric chloride 0. 27 mL was added dropwise to 3 mL of a solution of the compound obtained in Reference Example B273 and 327 mg of triethylamine, the mixture was heated under reflux for 4 hours. After cooling the reaction mixture to room temperature, it was poured into a saturated aqueous sodium hydrogencarbonate solution and the organic layer was separated. The aqueous layer was extracted with EtOAc. EtOAc evaporated. The residue was purified by silica gel column chromatography (solvent: hexanes: ethyl acetate = 70/30 to 50/50) to yield 155 mg (yield: 18%) of the title compound. m/z ; 314 [M+H]+ . Reference example B276

By treating the corresponding starting compound in the same manner as in Reference Example B274, 4-(5-tri-butyl-[H4]oxadiazole-3-yl)piperidine-l-carboxylic acid tertiary was obtained. Butyl ester.

Ms (APCI) m/z; 310 [M+H]+ ° Reference Examples B277 to B279 The following compounds were obtained by treating the corresponding starting compound in the same manner as in Reference Example A 3 6 (3).

323135 407 201202230 二吐-3-基]派咬

MS (APCI) m/z ; 228 [Μ+ΗΓ. (Reference Example B278) 4-Fluoro-4-(5-isopropyl-[1,2,4]oxadiazol-3-yl)piperidine hydrochloride

MS (APCI) m/z ; 214 [M+H]+. (Reference Example B279) 4-(5-Tributyl-[1,2,4]oxadiazol-3-yl)piperidine hydrochloride

MS (APCI) m/z; 210 [M+H] + ° Reference Example B280 to B283 The corresponding compound was obtained in the same manner as in Reference Example B15. (Reference Example B280) 8-Moly-5-Ga-4-[4-[5-(2-Fluoro-1,1-dimercaptoethyl)-[1,2,.4]oxadiazole-3 -yl]piperidin-1-yl]quinazoline

N^N MS (APCI) m/z ; 452/454 [M+H]+ ° 408 323135 201202230 (Reference Example B281) 8-bromo-5-fluoro-4-[4-fluoro-4-(5-iso) Propyl-[1,2,4] 曙dis-3-yl) 底 bottom bite-1-yl]

MS (APCI) ra/z ; 438/440 [M+H]+ ° (Reference Example B282) 8-bromo-4-[4-(5-tri-butyl-[1,2,4]oxadiazole -3-基)旅唆-1-基]-5-Fluoro°|:11 sitting shower

N^N MS (APCI) m/z ; 434/436 [Μ+ΗΓ. (Reference Example B283) 8-May-5-Fail-4-[4-[5-(1_Dencyclopropyl)_[1,2,4]曙Disal-3-yl]°辰唆-1 -基]啥11 坐琳

MS (APCI) ra / z ; 436 / 438 [M + H] + ° Reference Examples B284 to B288 The following compounds were obtained by treating the corresponding starting compound in the same manner as in Reference Example B26. (Reference Example B284) 2-Fluoro-4-(5-(a)-[4-[5-(2-fluoro-1,1-didecylethyl)-[1,2,4]oxadiazole -3-yl)piperidin-1-yl]quinazolin-8-yl] 409 323135 201202230 Benzoic acid

COOH MS (APCI) m/z ; 512 [M+H]+ 〇 (Reference Example B285) 2—Fluoro-4-[5-fluoro-4~[4-fluoro-4-(5-isopropyl-[ 1,2, 4], eat -3-yl), bite-1-yl]quinazoline _8-yl]benzoic acid

F

COOH MS (APCI) ra/z ; 498 [M+H]+ ° (Reference Example B286) 4-[4_[4-(5-Tris-butyl-[丨,2,4]卩, etc. 2唆一3_ ))-1-yl]-5-fluoroquinazoline-8-yl;|~2-fluorobenzoic acid

COOH MS (APCI) ra/z ; 494 [M+H]+ 〇 (Reference Example B287) 2-Fluoro-4-[5-fluoro-4—[4-[5-(--fluorocyclopropyl)-[1 , 2, 4] 曙二吃-3-基]旅咬-1-基] quinazoline _8_ base] benzoic acid

&quot;COOH MS (APCI) ra/z ; 496 [M+H]+ 〇323135 410 201202230 (Reference Example B288) 2-Fluoro-4-[6-fluoro-4-[4-[5-(l-fluoro) —甲武ethyl)-[1,2,4]曙二°坐-3-基]α底咬-1_基]01:°坐琳基]benzoic acid

MS (APCI) m/z : 498 [Μ+ΗΓ. Reference Examples B289 to B291 The following compounds were obtained by treating the corresponding starting compound in the same manner as in Reference Example B9. (Reference Example B289) 8- Desert-4-[4-[5-(1,1-Difluoroethyl)-[ 1,2 4] 曙dis-3-yl]piperidin-1-yl]- 6-fluoroquinazoline Br

Light yellow powder. The yield was 85%. Ms (APCI) m/z ; 442/444 [Μ+Η]+. (Reference Example B29G) 8-Bromo-6-fluoro-4-[4-[5-(o-o-methylethyl). [1,2,4]oxadiazole-3-yl]piperidine_1_ Quinol Me Me

Colorless powder. Yield 80% 323135 411 201202230 MS (APCI) m/z ; 438/440 [M+H]+〇 (Reference Example B291) 8-bromo-4-[4-[5-(l-fluoro-i_曱Base ethyl)_[1,2,4]曙二嗤-3-yl]Break π定基]啥撒琳

Br Colorless powder. The yield was 69%. MS (APCI) m/z ; 420 / 422 [M+H] + 〇 Reference Example B292 2-fluoro-4-[4-[4-[5-U-fluoro-1-methylethyl 2, 4]噚二嗤-3-基]派咬-1-基]喧嗤琳-8-yl] benzoic acid manufacturing

8-Bromo-4-[4-[5-(l-fluoro-1-indenyl)-[l,2,4]Df-diazol-3-yl]piperidine-1 under nitrogen atmosphere -yl]quinazoline (Compound obtained in Reference Example B291) 1. 52 g, 2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborane Ethyl pentan-2-yl)benzoate 859mg, [1,1,-bis(diphenylphosphino)ferrocene]palladium(II) di-vapor-di-halogen methane complex 148mg and carbonic acid planer 2 94g of 1,4-di-Ilfane/water (36mL/9mL) solution was stirred at 9 (TC for 21 hours. After cooling the reaction mixture to room temperature, 2N hydrochloric acid was added to adjust to pH 4. The mixture was diatomaceous earth. Filtration and extraction of the filtrate by gas chromatography. The organic layer was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. 412 323 135 201202230 The residue obtained was obtained by column chromatography (solvent: chloroform/methanol: 100/0 to 90/10) Refining to obtain 1200 mg (yield: 69%) of pale brown powder of title compound. MS (APCI) m/z : 480 [M+H]+ ° Reference Example B293 4-[4-[4- [5-(1,1-Difluoroethyl)-[1,2,4]oxadiazol-3-yl]piperidin-1-yl]-6-fluoroquinazolin-8-yl]-2 -Production of fluorobenzoic acid hydrochloride

The title compound was obtained as a colorless powder (yield: 73%). MS (APCI) m/z ; 502 [Μ+ΗΓ. Reference Example B294 (R)-l-(5_Isopropyl-[1,2,4]曙2β--3-yl)-3_methyl π 哄 哄 HCl

The title compound was obtained as a colorless powder (yield: 388 mg). MS (APCI) m/z ; 211 [M+H]+ ° 413 323135 201202230 Reference Example B295 8-bromofluoro-4-[(R)-4-(5-isopropylisopropyl-[1,2, 4]Oxadiazole-3~yl)2曱基π辰明:_ι__基]啥嗤琳的制造

MS (APCI) m/z; 435 / 437 [M+H] + 〇 </ br> </ br> </ br> </ br> </ br> Rate: 98%). 2-Fluoro~4-[6-fluoro-4-[〇〇-4-[5-isopropyl-[I 2 , 4]oxadiazol-3-yl]-2-methylpyr-1-yl]奎佐琳_8_一一笑审酩夕

Oxazol-3-yl)-2-methylpiperidinyl-yl]-quinazoline (Compound of the compound of Example 295) 460 mg was treated in the same manner as in the the the Yield 81%). MS (APCI) m/z ; 455 [M+H] + 〇 Reference Example B297 8-bromo-6-fluoro-4-[(S)-4-(5-isopropyl-[1,2,4]噚二唾__3_ 基)-3-Methyl Niang η well-1 A base] 啥 琳 之 之 manufacture 323135 414 201202230

Br by (S)-l-(5-isopropyl-[^," oxadiazole^- keto-methyl-piperidine monohydrochloride (referred to as compound B248) i. 7 g and the corresponding starting materials were treated in the same manners as the crude crystals of the title compound, to give the title compound as a yellow powder 1.72 g (yield: 1%). MS (APCI) m/z; 435/437 [M+H] +»Experimental Example 1 (Object of the present experiment) The purpose of this experiment was to evaluate the GPR119 agonistic activity of these compounds by adding a sample compound to CH0 cells expressing human GPR119 and measuring the amount of CAMP production of the cells. (In vitro) (Production of CH0 cells expressing human GPR119) CH0 cells (L8-18) expressing human GPR119 are according to the well-known method described in The Journal of Biological Chemistry Vol. 274 (34), pp. 23940-23947. By introducing the vector pMSF 1-GPR119 (Genet iciη resistance) carrying the human GPR119 gene into the CH0 cell into which the luciferase-bearing vector pLG3-CRE6-CRE-VIP (Hygromycin B resistance) has been introduced ( Manufactured in LM-3; Mock cells. (Test method) After freezing the frozen L8-18 cells, suspend them in 9-fold portions. 415 323135 201202230 Analytical buffer 'centrifugation at room temperature (l rpm, 5 minutes). After removing the supernatant, 'will sink; the cells will be suspended in the assay buffer 4mL, added to it The cell suspension containing 0.74 x 105 cells/mL was prepared by using an assay buffer of IBMX (manufactured by Sigma, #n〇18-lG). After the cell suspension was allowed to stand at room temperature for 15 minutes, the cell suspension was allowed to stand at room temperature for 15 minutes. Cell suspension 20//L and sample compound solution or AR231453 solution 5/z 1 (final concentration: 1500 cells/well, 500 yM IBMX '1% DMS0) was added to 96 half well white plate (manufactured by Corning Incorporated, #3693 In each of the wells (weii), the mixed broth was incubated at 37 ° C for 30 minutes, and then a 20-fold dilution of cAMP-d2 and Anti cAMP-Cryptate of HTRF cAMP KIT (manufactured by Cisbio, #62AM4PEC) Each 12.5 aL/well) was added to each well. After stirring the mixture, 'Stabilize for 1 hour under light-shield', the fluorescence mode was analyzed by the time of a micr〇plate reader (ARV0 or SpectraMax M5e). Ex: 320 nm, Em: 665 nm, 620 nm) The fluorescence intensity was measured. In the case of ARVO, the Ratio value of cAMP-d2 relative to Anti cAMP- φ CryPtate is calculated from the obtained fluorescence intensity [Ratio = (665 nm / 620 nm) xl 〇 4]] ' Using the Ratio value and GraphPad Prism The cAMP standard curve 'further calculates the cAMP concentration in each well from the cAMP standard curve. In the case of SpectraMax M5e, cAMP sensitivity in each well was calculated from a standard curve prepared from the obtained fluorescence intensity and Sofmax pro. ECs of the sample compounds. The value was calculated by adding the value of the experimental group of the diterpene kiln to 0%, and calculating the maximum reaction value of AR231453 (cAMP concentration at the time of addition) as 1%. 416 323135 201202230 (Results) The results of this experiment (ec5 values of each sample compound) are shown in Tables 117 to 119 below. Furthermore, "++" and "+++" in this table have the following meanings. ++ · 3 /z Μ &gt; EC50 ^ 1 /ζ Μ +++ : 1 // Μ &gt; ECso

417 323135 201202230第117表

Sample Compound Ε〇50 Compound of Example A1 + + + Compound of Example A9 + + + Compound of Example A12 + + + Compound of Example A14 + + + Compound of Example A17 + + + Example A24 Compound + + + Compound of Example A29 + + + Compound of Example A31 + + + Compound of Example A44 + + + Compound of Example A47 + + + Compound of Example A73 + + + Compound of Example A122 + + + Compound of Example A135 + + + Compound of Example A146 + + + Compound of Example A162 + + + Compound of Example A169 + + + Compound of Example A181 + + + Compound of Example A196 + + + Compound of Example A200 + + + Compound of Example A202 + + + 418 323135 201202230 Table 118

Sample Compound Ε〇50 Compound of Example B2 + + + Compound of Example B4 + + + Compound of Example B13 + + + Compound of Example B14 + + + Compound of Example B16 + + + Example B17 Compound + + + Compound of Example B27 + + + Compound of Example B32 + + + Compound of Example B50 + + + Compound of Example B51 + + + Compound of Example B53 + + + Compound of Example B59 + + + compound of example B60 + + + compound of example B61 + + + compound of example B76 + + + compound of example B87 + + + compound of example B89 + + + compound of example B91 + + + Compound of Example B92 + + + Compound of Example B95 + + + Compound of Example Bill + + + Compound of Example B127 + + + Compound of Example B130 + + Compound of Example B134 + + + Example B138 Compound + + + Compound of Example B252 + + + Compound of Example B280 + + + Compound of Example B285 + + + 419 323135 201202230 Table 119

Sample Compound ECs 0 Compound of Example B301 + + + Compound of Example B303 + + + Compound of Example B313 + + + Compound of Example B320 + + + Compound of Example B327 + + + Compound of Example B349 + + + compound of example B376 + + + compound of example B386 + + + compound of example B388 + + + compound of example B391 + + + compound of example B396 + + + compound of example B402 + + + compound of example B403 + + + compound of example B426 + + + compound of example B429 + + + compound of example B439 + + + compound of example B444 + + + compound of example B447 + + + implementation Compound of Example B454 + + + Compound of Example B460 + + + Compound of Example B474 + + + Compound of Example B476 + + + Compound of Example B497 + + + Compound of Example B505 + + + Example B517 Compound + + + Compound of Example B525 + + + 420 323135 201202230 Experimental Example 2 (Inhibition of jk sugar uptake by the compound of the present invention) Experimental method: C57BL/6N male mouse After 21 hours of hunger strike (18 hours until grouping), stratified random assignment (n=8) was performed using SAS 9. 1. 3 (SAS Institute Inc.) according to body weight. The mouse is orally administered with a vehicle (solvent: 0.1% Tween 80/0.5% propyl decyl cellulose) (control group) or a solution of the sample compound suspended in the vehicle ( The injection (sample group) was subjected to a glucose load (3 g/kg, ρ·〇.) 1 hour after the administration of the sample. The blood collection of the test mice was before the administration of the drug (-60 min), immediately before the sugar load (Omin), after the sugar load for 30 minutes (30 min), after 60 minutes (60 min) and after 120 minutes (120 min). It is implemented at each time point. The blood glucose level at each time point was measured using glucose CII-Test Wako (manufactured by Wako Pure Chemical Industries, Ltd.) Auc (〇-120 min) in each administration group was calculated based on the measured value, and SAS 9.1·3 (SAS Institute Inc.) was used. Tested with Student's t-Test. Zero result: The effect of inhibition of blood glucose by each sample compound (when AUC (〇120ιηιη) of the control group is taken as 1〇0, the ratio of AUC (〇_12〇min) of the test group is indicated) Table 120 to Table 121. Furthermore, "*" and "* *" in this table have the following meanings. * : P &lt; 0. 05 * * : p &lt; 0. 01 421 323135 201202230 Table 120 Sample compound administration amount (mg/kg) Effect of lowering blood sugar Example Α195 Compound 10 76.9** Example Α197 compound 10 86.2** * * : p&lt;0.01 (vs to the media group) Table 121

Sample compound administration (mg/kg) Effect of lowering blood glucose Compound 3 of Example B4 87. 2" Compound 3 of Example B17 80.5** Compound 3 of Example B61 87. 1* Compound 1 of Example B90 84. 0* Compound 3 of Example B143 87. 0* Compound 1 of Example B147 82.0** Compound 1 of Example B153 74.〇** Compound 1 of Example B171 83.0** Compound 1 of Example B210 82.0 ** Compound 1 of Example B279 84. 0* Compound 3 of Example B287 78.0** Compound 1 of Example B369 88. 0* * : p &lt; 0.05 (vs administered vehicle liquid group) * * : ρ &lt;0 · 01 (vs administration of vehicle liquid group) Experimental example 3 (2 of the compound of the present invention for inhibiting blood sugar rise) Experimental method: 422 323135 201202230

Zucker Fatty male rats were subjected to stratified randomization (n=7) using SAS 9.1.3 (SAS Institute Inc.) after 21 hours of fasting (up to 18 hours). The rats were orally administered with a vehicle (solvent: 0.1% Tween 80/0.5% hydroxypropylmethylcellulose) (control group) or a solution of the suspended sample compound in the vehicle (injection) The sample group) was subjected to a glucose load (3.5 g/kg, p. 〇.) 1 hour after the administration of the sample. The blood collection of the tested rats is before the administration of the drug (-6〇min), immediately before the sugar loss (Omin), 30 minutes after the sugar load (30min), 60 minutes later (60min) Φ and 丨2 Execute at each time point after 〇 (l2〇min). The blood glucose level at each time point was measured using glucose CII_Test Wako (manufactured by Wako Pure Chemical Industries, Ltd.), and the AUC (0-120 min) in each of the administered groups was calculated based on the measured value, and SAS 9. 1. 3 (SAS Institute Inc.) was used. ) Tested by Student, s t-test. RESULTS: The blood glucose-suppressing effect of each sample compound (for AUC (0-120 min) based on the value of _6〇min, and the AUC of the test group when the control group was used as 1〇〇 (0-120 min) The ratio of ) is shown in the following table 122*. Furthermore, "*" and "**" in this table have the following meanings. * : p &lt; 0. 05 * * : p &lt; 0. 01 323135 423 201202230 M22 sample compound administration amount (mg / kg) effect of lowering blood glucose Compound 1 of Example B92 75. 0 * Compound of Example B95 1 51.0** Compound 1 of Example B371 43.0** * : p &lt; 0.05 (vs administration media group) * * : p &lt; 0. 01 (vs administration media group) (industrial availability) The compound [I] of the present invention or a pharmacologically acceptable salt thereof has an agonistic action on the GPR119 receptor, and therefore, is useful as a preventive/treating agent which can be expected to be improved by regulating the activity of the receptor. A disease or state of medicine, such as: obesity, hyperglycemia, diabetes and its complications, metabolic syndrome, glucose intolerance, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriuretic acid Metabolic diseases such as glycerolipidemia and abnormal lipid metabolism; or cardiovascular diseases such as arteriosclerosis, high blood pressure, coronary artery disease, and myocardial infarction. [Simple description of the diagram] None. [Main component symbol description] None. 424 323135

Claims (1)

201202230 VII. Patent application scope: 1. A compound represented by the following formula [I] or its pharmacologically permissible [in the formula, R represents a hydrogen atom or a tooth atom, and ring A represents a 5- to 6-membered aryl group which may contain the same or different one to four hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and RA1 &amp; RA2 independently represents 1) a halogen atom; 2) a cyano group; 3) a hydroxyl group; 4) a pyridyl group which may be substituted with 1 to 3 groups selected from the following a) to k): a) a halogen atom, b) Base, c) cyano group, d) 5 to 6 membered nitrogen-containing hetero group, e) formula: RaRbN- group (y and Rb are the same or different, representing a hydrogen atom or an alkyl group), f) carboxyl group , g): a group represented by Re_s(=〇)n_ (here, Re represents an alkyl group which may be substituted with a group selected from a hydroxyl group and a group represented by the formula: RdReNC (=〇), and m is 〇 An integer of 2; R and Re are the same or different, meaning a hydrogen atom or an alkyl group, and h) is a group represented by the formula: H0-Alk-0- (here, Aik represents an alkylene group),丨): R%NC (=0) _ shows the base (Rf &amp; ^ 323135 1 201202230 identical or different, indicating a ruthenium atom, an alkyl group, a monohydroxyalkyl group or a dihydroxyalkyl group' or both Combines with each other and forms a 5- to 6-member aliphatic group with adjacent nitrogen atoms. a heteromonocyclic group (the ring group may also be substituted by a hydroxyl group or an amine thiol group)) 'j) Formula: RhRW-based group (furnace and Ri are the same or different, representing a hydrogen atom, an alkyl group, an alkane group) a hydroxyalkylalkyl group, an alkoxy group or a decyloxy group; and k) a 5 to 6 membered aliphatic nitrogen-containing heterocyclic group (the heterocyclic group may also be derived from a hydroxyl group, a side oxygen group) a group selected from the group consisting of a group selected from the group consisting of an alkyl group and an amine group; (5) an alkoxy group (the alkoxy group may also be derived from a hydroxyl group, an alkoxycarbonyl group, an amine group) The amine moiety of the group may also be substituted by 1 to 2 alkyl groups) and the group selected from the phenyl group; 6) Formula: Rk-S(=0)n- (wherein Rk represents a base substituted by a radical or an alkoxy group, η represents an integer of 0 to 2); 7) an alkane group; 8) a formula: a group represented by RmRnNC(=0)- (here, Rn and R&quot; Identical or different, meaning a) a hydrogen atom, an alkyl group, a mono or dihydroxyalkyl group, an early or a decyl group, an azoxy group, a cycloalkyl group (the group may also be substituted by a hydroxyalkyl group) Alkoxycarbonylphenylalkyl, carboxyphenylalkyl, amidinoalkylene a 5- to 6-membered aliphatic sulfur-containing heterocyclic group (the heterocyclic group may also be substituted by 1 to 2 pendant oxy groups), or b) both Rm &amp; Rn are bonded at the end together with the adjacent nitrogen atom The formation may be substituted by a group selected from a hydroxyl group, a cyano group, a pendant oxy group, a hydroxyalkyl group, an aminomethylalkyl group, and an amine carbenyl group (the amine carbenyl group may also be substituted by 1 to 2 alkyl groups). And 4 to 6 member aliphatic nitrogen-containing heterocyclic group condensed with a cycloalkyl ring 2 323135 201202230 (the heterocyclic group may also contain an oxygen atom as a hetero atom other than a nitrogen atom)); 9) an amine group ( The amine group may also be substituted by 1 to 2 groups selected from an alkyl group, an alkyl fluorenyl group, an alkoxycarbonyl group, an alkyl sulfonyl group, an alkyl fluorenylalkyl fluorenyl group and a hydroxyalkyl fluorenyl group; Aminesulfonyl group (the amine moiety of the group may also be substituted by 1 to 2 alkyl groups); 11) the basic meaning of the formula 5) (here, the ring A° means that it can be substituted by a pendant oxy group) a nitrogen-containing 5-membered aliphatic heterocyclic ring; or 12) a saturated or unsaturated 5- to 6-membered heterocyclic group (the heterocyclic group containing the same or different ones to four selected from the oxygen atom, the sulfur atom, and the nitrogen atom) a hetero atom, which can be extended via a Cl 2 bridge, and can also be a base group, a pendant oxy group, a cyano group, a group which can be substituted with 1 to 3 halogen atoms, a base group, a reduced filament, an amine formazan. Base, mono- or di-sodium amide-alkyl, (tetra), benzyl, amine? The group, the monoalkylaminomethyl group and the dialkylamine carbenyl group are selected from H to 3 groups of substituted groups; the ring B represents 6 to 7 members of the aliphatic nitrogen-containing heterocyclic group, and RB1 represents a hydrogen atom. Or a ketone group, RB2 represents a hydrogen atom, a halogen atom or a hydroxyl group, RB3 represents 323135 3 201202230 1) a thiol group; 2) a cyano group; 3) an alkyl group; 4) a cycloalkylalkyl group; 5) an alkoxy group; 6) a saturated or unsaturated 5 to fluorene monocyclic heterocyclic group (the group containing the same or phase selected from the oxygen atom, the sulfur atom and the nitrogen atom = 1 to 4 hetero atoms, and may also be derived from the following groups 1 to 2 base substitutions selected in the group: alkyl groups which can be substituted to 3 functional atoms; hydroxyalkyl groups; alkoxyalkyl groups (the alkoxyalkyl groups can be cleaved to 3&amp; a halogen atom substituted; a carboxyalkyl group; an amine group which may be substituted by 1 to 2 alkyl groups; an aminoalkyl group (the amine moiety of the aminoalkyl group may also be derived from an alkyl group and an alkoxy group Ik group) One to two substituents are selected; and a cycloalkyl group which may be substituted by a halogen atom or a burnt group); or 7) a group represented by the formula: -W-R3 (here, w represents an oxygen atom, a sulfur atom or Carbonyl, R3 Represents a) an alkyl group which 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; wherein the 5 to 6 member singles The cyclic aryl group may have the same or different one to three hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and may be substituted with 1 to 2 groups selected from the following cl) to c5) : cl) a halogen atom, c2) alkyl group, c3) alkoxy group, c4) cycloalkyl group and c5) an amine group which may be substituted by 1 to 2 alkyl groups)]. 2. A compound as claimed in claim 1 or a pharmacologically acceptable salt thereof, wherein ring A is 4 323 135 201202230 (A) Substituted as shown in the following formula: RA1 Ra2 (Al) (wherein, RA1 represents (1) a hydrogen atom, (2) a halogen atom, (3) an alkyl group which may be substituted by 1 to 3 halogen atoms, (4) an alkylthio group, or (5) Cyano group, RA2 represents (1) a hydrogen atom, (2) a halogen atom, (3) a cyano group, (4) an alkyl group, (5) a substituted alkyl group, which is contained from an oxygen atom and a nitrogen atom. a saturated or unsaturated 5- to 6-membered heterocyclic group of one to four heteroatoms selected, (6) an alkylthio group (the alkyl moiety of which may also be substituted with a trans group), (7) an alkane a sulfonyl group (the alkyl moiety of the group may also be substituted by a trans group), (8) an alkylsulfanyl group (the alkyl moiety of which may also be substituted with a thiol group), 323135 5 201202230 (9) The aryl group (the base of the base can also be substituted by a thiol group), (10) the amine mercapto group which can be substituted with 1 to 2 groups selected from the following a) to c): a) An alkyl group which may be substituted by 1 to 3 atoms, b) a monoalkyl group, and c) a group substituted by a group and an alkoxy group, (11) an amine which may be substituted by 1 to 2 alkyl groups Sulfhydryl, (12) can be derived from alkyl, alkanoyl, alkoxycarbonyl, alkanoyl An oxyalkyl group, an amine group substituted with 1 to 2 groups selected from a thiol group and a decyl group, (13) an alkyl group, (14) an alkoxy group, (15) a nitro group, (16) alkoxycarbonyl group, (17) Formula: RuR12NC(=)0- (wherein r11 and r12 systems (a) independently represent a hydrogen atom or an alkyl group, or both Combining with a neighboring nitrogen atom to form a nitrogen-containing 5 to 6-membered aliphatic heterocyclic group which may be selected from a hydroxyl group, a pendant oxy group and a hydroxyalkyl group to 2 groups. The heterocyclic group may also contain oxygen. An atom as a hetero atom)), or (18) a saturated or unsaturated 5 to 6 membered heterocyclic group containing the same or different one to four hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, and It may also be selected from 1 to 2 of a pendant oxy group, a thiol group, a decyl group, a aryl group, an amine aryl group, a single-base amine amide, and a methanyl group. Base substitution); or 323135 6 201202230 (B) substituted 5 or 6 member heteroaryl as shown in the formula: (B-1) (B-2) or (B-3) Wherein RA11 represents (1) a hydrogen atom, (2) a cyano group, a (3) alkyl group, a (4) decyloxy group, a (5) N-morpholino group, a (6) alkyl group, or (7) An amidoxime group substituted with 1 to 2 alkyl groups, rA12 represents a hydrogen atom or a halogen atom 'RA13 represents a hydrogen atom or an alkoxy group, and rA14 and rA15 independently represent a hydrogen atom or a burnt group]. A compound according to the first or second aspect of the patent application, or a pharmacologically acceptable salt thereof, wherein the ring B system (A) The group of the following formula (i): R20 r\-\ -N^)--r2 (i) (where R 2 represents (a) cyano or (b) saturated or unsaturated 5 to 6 a monocyclic heterocyclic group; wherein the (b) saturated or unsaturated 5 to 6 membered monocyclic heterocyclic group contains the same or different one or four selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom. a hetero atom, and may also be substituted with 1 to 2 groups selected from the following (bl) to (b5): (bl) may be taken from 1 to 3 i atoms, 323135 201202230, and (b2) a base group, (b3) an alkoxyalkyl group, (μ) an amine group which may be substituted by 1 to 2 alkyl groups, and (b5) a cycloalkyl group; R2° represents a hydrogen atom, a halogen atom or an alkyl group; B) a group represented by the following formula (ii): -N^~WlR31 (9) (here, W1 represents an oxygen atom, a sulfur atom or a carbonyl group, and R31 represents a) an alkyl group (the alkyl group may also be derived from a phenyl group and an alkane group) a selected alkyl group in the oxyphenyl group; b) a cycloalkyl group; or c) a 5 to 6 membered monocyclic aryl group (the aryl group may also contain the same one selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom or 1 to 3 heteroatoms different, and may also be replaced by i to 2 bases selected from 1) to 5) below: 1) An atom, 2) an alkyl group, 3) an alkoxy group, 4) a ring group and 5) an amine group which may be substituted by 1 to 2 alkyl groups)); (C) a group represented by the following formula (iii): R40 -Ν''Ν-R4 (wherein R4 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) It may also be substituted by an alkyl group or a cycloalkyl group which may be substituted with three halogen atoms) 'R4° represents a gas atom or a burnt group); (D) A group represented by the following formula (iv): T[^N -R4 (iv) (herein, R4 has the same meaning as described above); or 8 323135 201202230 (E) substituted 6- or 7-membered aliphatic nitrogen-containing heterocyclic group represented by the following formula (v): —^ Vf-R4A (v) (herein, R4A represents a nitrogen or oxygen-containing 5 to 6 membered heteroaryl group (the heteroaryl group may also be substituted by an alkyl group)). 4. As claimed in the first item The compound or a pharmacologically acceptable salt thereof, wherein the ring A is a group represented by the following formula: [wherein, ring A1 represents a benzene ring or a β-β ring, RA represents 1) a cyano group; 2) a mono- or dihydroxyalkyl group; • 3) is obtained from (a) a hydroxyl group, (b) formula: RTNC (= a group represented by 0)- and a (c) alkyl group selected from the alkylsulfonyl group (here, RP&amp; Rq independently represents a money atom, a group which can be substituted by 1 to 3 _ sub- or The base group or the two are bonded to each other to transfer a nitrogen atom to form a 5-member nitrogen-containing fat which can be substituted with one to two groups selected from a halogen atom, a trans group, a cyano group and an amine f group. a group of a heterocyclic groups; 4) an alkoxy group; 5) a formula: Rr-S(=0)n-, wherein i (wherein R represents an alkyl group which may be substituted by a hydroxy group or an alkoxy group, η represents an integer from 〇 to 2); 323135 9 201202230 6) Substituted alkyl group which is substituted by a 5-membered heteroaryl group having 1 to 3 gas atoms as a hetero atom; 7) alkoxycarbonyl group Alkyl; 8) Formula: ΠΓΝ (ΠΓΝ)- (wherein Rt independently represents an argon atom, an alkyl group, a hydroxyalkyl group or a dialkylene group, or a combination of both and a contiguous nitrogen atom) Together can be formed from _ atoms, a 4- to 6-membered nitrogen-containing aliphatic heterocyclic group substituted with 1 to 2 groups selected from the group consisting of a cyano group and an amide group; 9) an amine fluorenyl group which may be substituted by 1 to 2 alkyl groups; Alkalyl group; 11) alkoxyalkylamino group; 12) alkylalkylamino group; 13) alkylsulfonylamino group; 14) group represented by the formula: IX (here, ring A111) a nitrogen-containing 5-membered aliphatic heterocyclic ring substituted by a pendant oxy group; or 15) a saturated or unsaturated 5- to 6-membered heterocyclic group containing the same or different from the nitrogen atom, the sulfur atom and the oxygen atom 1 to 4 heteroatoms, and may also be derived from a pendant oxy group, a hydroxy group, an alkyl group, a hydroxyalkyl group, an amine alkyl group, a monoalkylamine methyl decyl group, and a dialkylamine carbhydryl group. One to two substituents selected from the alkyl group, RB represents a hydrogen atom, a halogen atom, a cyano group, an alkyl group or a trihaloalkyl group; 10 323135 201202230 The ring B is a group represented by the following formula: Wherein R 2A represents a saturated or unsaturated 5-membered heterocyclic group containing the same or different one to three hetero atoms selected from a nitrogen atom and an oxygen atom, and is alkyl (the alkyl group may also be 1 to 3 functional atom substitutions), cycloalkyl, alkoxyalkyl or alkylalkyloxyalkyl groups; R21 represents a hydrogen atom or a pyridyl group]. 5. The compound of claim 4 or a pharmacologically acceptable salt thereof, wherein ring A1 represents a stupid ring and RA represents 1) a formula: RuRvNC(=0)-CH2- Here, Rv is the same or different and represents a hydrogen atom or a C1-4 alkyl group, or a combination of two and a neighboring nitrogen atom to form one to two selected from a hydroxyl group, a cyano group and a pendant oxy group. a 5-membered nitrogen-containing aliphatic heterocyclic group substituted by a group; 2) a group represented by the formula: RW_S(=0)2- (FT represents a group-substituted Ch-burn which can be selected from a hydroxyl group and a ruthenium _Cl_4 alkoxy group) (3) Formula: RxRyNC(=0)-based group ({^ and Ry independently represent an alkyl group or a monohydroxyalkyl group, or both are bonded at the end to form a hydroxyl group together with a contiguous nitrogen atom. a 5-membered nitrogen-containing aliphatic heterocyclic group selected from the group consisting of a cyano group and an amine carbaryl group; 4) a Ci]alkyl fluorenyl fluorenyl group; &lt; 5) saturated or unsaturated 5 a nitrogen-containing heterocyclic group having 1 to 2 nitrogen atoms as a hetero atom' and substituted by 1 to 2 groups selected from a pendant oxy group, a hydroxyl group, and a hydroxy group 323135 11 201202230 -G-4 alkyl group (this ring The base may further contain an oxygen atom as a hetero atom, and may be further substituted by a hydroxyl group, an amine fluorenyl-0-4 alkyl group or a bis(Cl-4alkyl)amine aryl-Cl-4 group; RB represents a halogen atom, a cyano group or a Cm alkyl group, and R2A represents a saturated or unsaturated 5-membered heterocyclic group which contains the same or different one to three hetero atoms selected from an oxygen atom and a nitrogen atom, and is Ch An alkyl group (this group may also be substituted by 1 to 3 halogen atoms) or a C3-6 cycloalkyl group; _ and R21 represents an argon atom. 6. The compound of claim 5 or a pharmacologically acceptable salt thereof, wherein ring A1 represents a benzene ring; RA represents 1) formula: RaaRbbNC(=0)-CH2·^ Thus, Raa represents a hydrogen atom, Rbb represents a Ch alkyl group, or both are bonded at the end to form a pyrrolidinyl group which may be substituted by a hydroxy group together with a contiguous nitrogen atom); 2) a base-Cl-4 base group; 3) an amine group which may be substituted by 1 to 2 Ch alkyl groups; 4) a group represented by the following formula: (wherein, Ra3 and Ra4 are the same or different and represent a hydrogen atom, a hydroxyl group, a cyano group or an amine sulfhydryl group); or 5) a cyclic group represented by the following formula: 12 323135 201202230 a gas atom, a radical or a radical _Ci genus, ... a base selected from the group and the nitrogen atom ::=:: bis, the original one: replaced by the 1 i3 substituting '3 = the compound of the first item or its pharmacologically acceptable salt R: where the 'soil A system is the formula : (Here, the bad guys table: ^11^, 0 (: 1%% R represents 1) alkylsulfonyl; 2) can be 1 to 2 alkyl groups are substituted for the amine sulfhydryl group of Xisongtian; or 3) N-morpholinylcarbonyl group, R is a hydrogen atom or a smear, and ring B is a group represented by the following formula: -N^ ^—WlR31 (herein, W1 represents an oxygen atom or a sulfur atom, 眇 represents an alkyl group (the alkyl group may also be substituted by an alkoxy group), a cycloalkyl group, a stupid group (the phenyl group may also be derived from a halogen atom) , alkyl, alkoxy and amine groups (the amine group may also be substituted by 1 to 2 alkyl groups), or nitrogen or sulfur containing 323135 13 201202230 5 to 6 a heteroaryl group (the heteroaryl group may also be substituted by an alkyl group. 8. The compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein the ring A is a group represented by the following formula; : Wherein ring A3 represents a stupid ring and RE represents (a) alkylsulfonyl, alkylsulfonylalkyl, (c) amine mercaptoalkyl (the amine moiety of the amine carbenyl group may also be a nitrogen-containing 5-membered aliphatic heterocyclic ring selected from the group consisting of an alkyl group and a hydroxyalkyl group to two substituents, (d) a fluorene selected from a pendant oxy group and a hydroxyalkyl group, and a two-substituted hydrazine. The base or the (e) of the following formula 0, soil (in this 'ring A ° 2 indicates that the nitrogen-containing 5 group is substituted by the secret and RF represents a hydrogen atom or a halogen atom], clothing, ring B system The base shown in the following formula: ~NwN~R41 [wherein R41 represents (a) an alkoxy group or a (6) 5-membered heteroaryl group, wherein the 5-membered heteroaryl group has the same or it 丄 to 3 selected from an oxygen atom and a nitrogen atom. a hetero atom and substituted by an alkyl group; R42 represents a hydrogen atom or a hospital group]. 9. The patent application _ 帛 8 of the compound or its pharmacologically acceptable fox ', medium, R system C1-4 alkyl thiol methyl, amine formazan complex (the amine 曱 之 县Some may also be replaced by 丨^ Μ base) 323135 14 201202230 or the base shown in the following formula, (Here, ring A°2 represents a nitrogen-containing 5-membered aliphatic heterocyclic ring substituted with a hydroxyl group) and an 'R42-based hydrogen atom. 10. The compound of claim 1 or a pharmacologically acceptable salt thereof, wherein the compound represented by the formula [I] is a compound selected from the group consisting of the following compounds: 4- [ 5- Qi-4-[4-(3-isopropyl-[1,2,4]fluorenyl-5-yl)piperidin-1-yl]quinazoline-8-yl]-N, N-dimercaptobenzamine; 3-fluoro-4-[4-[4-(3-isopropyl-[1,2,4]曙2°--5-yl) piperidine-1- a quinazoline -8 amino group;|_N,N-dimethylbenzamide; fluoro-4-[5-fluoro-4-[4-(3-isopropyl-[1,2, 4 ] oxadiazole-1~yl)piperidin-1-yl]quinazoline-8-yl]_N,N-dimethylbenzamide; 15 323135 1 fluoro-4-[4-(3-iso Propyl-[1,2,4]oxadiazol-5-yl)α-bottom-1-1-yl-8-(4-methylsulfonylphenyl)quinazoline; 4-[6-fluoro- 4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]quinazoline-8-yl]-indole, fluorene-dimethyl Benzalamine; 2~fluoro-4-[1-fluoro-4-[4-(3-isopropyl-[12,4]oxadiazol-5yl)piperidin-1-yl]quinazoline _ 8_基]_Ν, Ν-dimethylbenzyl amide; 3-fluoro-4-[6-fluoro-4-[4-(3-isopropyl-[U 2, 4] oxadiazole 5 yl Piperidine-1-yl] Quinazoline-8-yl]-indole, fluorene-dimethylbenzhydryl 201202230 amine; 2 monofluoro-4-[5, fluoro~4-[4-(3-isopropyl-[^4]噚Oxazol-5-yl)diyl]indole (tetra)_8_yl]_N_methylbenzoquinone; 』N-ethyl-2-fluoro]4-[5-fluoro-4-[4-(3-iso Propyl-[1,2,4] oxazolidine-5-yl)piperidine-1 monobenzyl]quinazoline-8-yl]phenylhydrazine; 2 gas _4_[6' fluoro~4- [4-(3-isopropyl-H4]oxadiazolyl) bottom bite 1 base] 啥 琳 琳 ] ] _ _ ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; [4-(3-isopropyl-[1,2,4]oxadiazolyl)-indenyl-1 quinazoline-8-yl]-N-mercapto-carboxamide; 6-fluoro- 4- [4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)piperidinyl-1]]-[3-fluoro-4-[pyridyl] Phenyl]oxazoline; 2-fluoro-4-[6-fluoro-4-(3-n-propyl-[丨,2, 噚 噚 噚 _ 5 _ ) ) -1- -1- -1- What.琳琳基基]-N,N-dimethylbenzamide; • 6_Fluoro-4 - [4~(3-n-propyl-[1,2,4-bayoxadiazol-5-yl)piperidin 2-pyridyl]-8-[3-fluoro-4-[(pyrrolidinyl)carbonyl]phenyl]quinazoline; 2-fluoro-4-[6-fluoro-4-[4-(5- Isopropyl-[丨,2,4]oxadiazole+yl)-bite-buki]啥Waolin I-based]I-methylbenzamide; 4-[4_(3-isopropyl 412,4 Oxazol-5-yl)piperidin-1-yl]-8-(4-methanesulfonylphenyl)quinazoline; 4 - [4-[4-(3-isopropyl)- Azole-5-yl) piperidine + hydrazino-8-yl]-N,N-dimethylphenyl hydrazine; 16 323135 201202230 3-fluoro-4-[6-fluoro-4-[4- (5-n-propyl-[1,2,4]Π§ oxazol-3-yl)piperidin-1-yl]quinazolin-8-yl;|_Ν,Ν-dimethylphenylguanamine ; 2-fluoro-4-[6-fluoro-4-[4-[3-(2, 2, 2-trifluoroethyl)-[1,2,4]oxadiazol-5-yl]piperidine -1-yl]quinazolin-8-yl]-oxime, fluorenyl-dimercaptocarboxamide; 2-fluoro-4-[6-fluoro-4-[4-[5-cyclopropyl-[1,2,4]nonane-3-yl]piperidin-1-yl]quinazoline-8 -yl]-indole-(2-hydroxyethyl)-indole-methyl carbamide; 6-fluoro-4-[4-(5-isopropyl-[1,2,4]fluorene-fluorene- 3-base) brigade bite base]-8-(3-gas-4-decene decylphenyl) 喧 琳 ;; and 6-fluoro-4-[4-(5-isopropyl-[1,2 , 4] 曙二嗤-3-yl) pie bite 1 base] 8-(3- gas-4-mercapto continued phenyl phenyl) 啥u sitting. The compound of the above formula, or a pharmacologically acceptable salt thereof, wherein the compound of the formula [I] is a compound selected from the group consisting of the following compounds: 2-[2 -Fluoro-4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4]oxadiazole-3-yl)piperidine-fluorenyl]quinazoline _8-yl Phenyl]-nonylmethylacetamide; 6-fluoro-4-[4-(5-isopropyl-[l 2,4]oxadiazole-3-yl)piperidine 1-yl]- 8-[3-Fluoro-4-(2-hydroxyethylsulfonyl)phenyl]quinazoline; [2-fluoro-4-[6-fluoro-4-[4-(5-isopropyl)- [1,2,4]oxadiazole 3~yl) °Chen Mouth-Buji]啥Salina-8-yl]Phenyl](3- via 吼基洛 bite a base) A; 323135 17 201202230 1-[2-1*-4-[6-fluoro-4-[4-(5-isopropyl-[1,2,4]indip-3-yl)-唆-1-yl]quina Oxazoline -8-yl]phenyl]_3_(2-hydroxyethyl)imidazolidine-2-one; 6-gas-4-[4-(5-n-propyl-[1,2,4]噚2 Zyrid-3-yl)piperidin-1-yl]-8-[3-1-4-[(3-hydroxypyrrolidin-1-yl)carbonyl]phenyl]quinazoline; 1-[2-fluoro -4-[6-fluoro-4-[4-(5-cyclopropyl-[1,2,4]噚二°坐_3_基) 派-1-yl]quinazoline-8-yl Phenyl]-3-(2-hydroxyethyl bromide Imidazolidin-2-one; 1-[2-fluoro-4-[6-fluoro-4-[4_(5-n-propyl-[1,2,4]indoledin-3-yl)) bite -1-yl]quinazoline _8-yl]phenyl]_3_(2-hydroxyethyl) imipenone-2-one; 1-[2-fluoro-4-[6-fluoro-4-[ 4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)piperidinyl]quinazoline-8-yl]phenyl]_3_(2-hydroxyethyl) °定-2-_ ; # 1-[2-Fluoro-4-[5-fluoro-4-[4-(5-isopropyl-[1,2, 4]噚二唾_3_))° Bottom bite-buki]啥哇琳-8-yl]phenyl]-3-(2-transethylethyl)imidazole bit-2-one; Bu [4-[6-fluoro-4-[4-( 5-isopropyl-[ι,2,4]oxadiazole-3-yl) ketone-1-yl]pyrene _8_yl]_2_qiphenyl]_4 〇 〇 〇 - - 2-tactile [2-fluoro-4-[6-fluoro-4-[4-(5-trifluorof-yl-[1,2,4]indole-3-yl) Ninjabita-Buji]喧Salicin _8_yl]phenyl](3-pyridylpyridin-1~yl)methanone; 18 323135 201202230 卜[4-[6-fluoro-4-[4-(5-isopropyl- [1,2,4]oxadiazol-3-yl)piperidin-1-yl]quinazoline __8-yl]_3-methylphenyl]pyrrolidine-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]-bu (3-hydroxypyrrolidin-1-yl)ethanone; [2-fluoro-4-[4-[4-(5-isopropyl-[丨,2,4]oxadiazole] -3- 基)基-1-基]喧唾琳_8_基]Phenyl]_3_(2_ylidylethyl)isoxyridin-2-one; Bu [2-methyl-4-[6_Fluorine_ 4_[4_(5_isopropyl-7,2,4]fluorenyl]hydrazine-8-yl]phenyl(tetra)-perylethyl)mi-bito-2-one; bu [2-fluoro-4- [6-fluoro-4-[4-(5-isopropyl-oxazol-3-yl)piperidine-fluorenyl]-quino[,A4]-sodium sulfoxide I-based] 2-one ketone; Bu-gas + fluoro- 4-[4-(5-n-propazol-3-yl)piperidin-bu]quina, A4"b-group&gt;^ phase; 14 base] Benkib 3'(2_ 乙卜[2-Fluoro-4-[5-fluoro-4-[4-(5-cyclopropyl alkidine-2-one; benzyl)] hydroxypyrrole A gas , 5-fluoro-4 remaining n-propyl-[1,2, even two 323135 19 201202230 -3--3-yl) brigade bite-丨_yl]oxazoline _8_yl]phenyl]_4_hydroxypyrrole bite -2-; 1-[2-Ga-4-[5-fluoro-4-[4-(5-cyclopropyl-[1,2,4]oxadiazol-3-yl)piperidine-oxime _ yl] quinazoline _8_ yl] phenyl]_4 hydroxypyrrole-2-one; 1 a [2_ fluoro_4-[6-fluoro~4-[4-(5-isopropyl-[ 1,2,4]oxadiazol-3-yl)piperidine-1-yl]quinazoline-8-yl]phenyl]_3 (2-hydroxy-2-mercaptopropyl)imidazolidinium_2_ ketone Lub [4-[6-1-4-[4-(5-cyclopropyl-[1,2,4]indole-3-yl)piperidin-1-yl]quinazolinyl]_3 _Mercaptophenyl]pyrrolidine-2-one; 4-[4-[6-fluoro-4-[4-(5-isopropyl-[I 2,4]oxadiazole-3-yl) +基基啥啥琳 I基]_3_methylphenylbumlin-3_ ketone; Bu (2-fluoro-4-{6-fluoro-4-[4_(5_isopropyl-[124]曙2参 坐 啥 啥 啥 啥 -8 -8 -8 -8 -8 -8 -8 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 4] 曙二唾一3_基)Brigade bite-1-yl]啥 琳琳 I base] phenyl]_34 base ton money a 4 ketone; Κ2_ fluoro-4~[6~ fluoro-4-[4-(5 -isopropyl-[1,2,4]oxadiazol-3-yl)piperidin-1-yl]quinazoline-8-yl]phenyl]-5-hydroxymethylpyrrolidin-2-one ; 1 2- [l-[2-Fluoro-4-[6~ fluoro-4_[4_(5_isopropyl 41,2,4]曙二°坐_3—基)))]喧(四)-8- Phenyl-2-yloxy 323135 20 201202230 imidazol-3-yl]-N,N-dimethylacetamide; fluorofluoro-4, fluoro as (5-trifluoromethyl-fi 嗤1 Base&gt; bottom bite-buki] 啥 琳 琳 I base] phenyl] (2, amine A = ° pirate-1-yl) ketone; brewing base 1-difluoroethyl)-[1,2 , 4] fluorenyl] phenyl]-3-(2 -Hydroxyl H2-fluoro-4-[4-[4-[5-(1, oxazol-3-yl) piperidinyl] quinazoline ethyl). Sit 2-ketone; [2-Fluoro-4,-Gas-4-[4_(5-Trifluoromethyl, 胛-嗤-3-yl) 唆-Buji]噎噎琳|基]Phenyl]&amp;Cyano~ = pyrrolidin-1-yl)methanone; 规 [2_说一4-m[4-(i-isopropyl-[1,2,4-thoracic-di-sial-3-yl)(tetra)-buyl]喧Junlin _8_yl]phenyl](2-cyanopyrrolidin-1-yl)methanone; raw coil [2- Dun-4-[5-fluoro-4-[4-(5-isopropyl) -[u'4] oxadiazol-3-yl)-l-yl] 啥m_8_yl] stupid base] (3_ via base n ratio slightly 1~ base) ketone; $ [2- Fluoro-4-[5-fluoro-4-[4-[5-(1,difluoroethylHl,2,4]3-oxazol-3-yl]piperidin-1-yl]quinazoline_ 8_yl]phenyl]hydroxy σ-haridin-1-yl)methanone; [2-fluoro-4-[6-fluoro-4—[4_(5-isopropyl-[^, oxadiazole] a 3'-base) Bite-1-yl] sputum _8_yl] phenyl] (2-aminomethyl hydrazide 〇 Ρ Ρ 1- 1- 1- 1- 1- 1- ; ; ; ; ; ; ; ; ; ; -4- -4- -4- -4- -4- -4- [5-Any-4-[4-(5-isopropyl-[1,2,4]carbazole~3-yl)piperidin-1-yl]quinazoline_8-yl]phenyl]_3_ (2_hydroxy 323135 21 201202230 ethyl) imidazolium ~2-ketone; 』一一一[2~f base-4-[6-fluoro-4-[4_(5-trifluoromethyl-fl, 2, 4] ^ monoazole-3~yl) piperidine-1-yl] quinazoline -8-yl]phenyl]-3-(2-hydroxyethyl)imidazolidine-2-one; 1-yl-4-[6-fluoro-4-[4-(5-cyclopropyl-[1 , 2, 4] squat 3 base) piperidin-1-yl] quinazoline -8 amino] phenyl] _ 3 - (2 hydroxyethyl) imidazolidin-2-one; 6Fluoro[4-(5-isopropyl-[1,2,4]Pfoxadiazol-3-yl)pyridin-1-yl]-8-(3-fluoro-4-methylsulfonyl) Methylphenyl)quinazoline; [2fluoro-4-[5-fluoro-4-[4-[5-(l-fluoro-b-methylethyl)-[1,2,4]曙二嗤-3 -基&gt; Chendi-1-yl]喧 淋-8-yl]phenyl](2-cyano-4-hydroxypyrrolidine-fluorenyl)methanone; fluorine +[5ϋ[4-[5 -(卜氟-卜methylethyl)-[1,2,4 湾二°坐-3-基]定定-I-基]^坐淋_8-基]phenyl] (3-hydroxypyrrolidine-1 ] μ base) ketone; L2-: + [5_ fluoride strip [5_(bu fluoride + methyl ethyl) - , , 4 3 a sit 3- base] mouth bottom 唆 a base] 啥 啥 一 a 8 1-yl]phenyl](2-aminoindolylpyrrolidinyl)-methanone; 1 [4 [5-fluoro-4-[4-[5-(l,i-difluoroethyl)][ Ι2 4]噚二吐-3-基如小基]啥姆|基]_2_基笨基]_4_ hydroxy° than singe-2-one; Dun Niang (5-isopropyl seven, 2, even Diazole _ ke) ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke -(l-fluoro+methylethyl)_[], 2, 4] %-sodium 3-yl]piperidinyl-p-yl]quinazoline-8-yl]phenyl]-3_(2 Hydroxyethyl) sodium sputum-2-ketone; 1 [2 fluoro-4-[4-[4-[5-n-propyl-[i,2,4] 〇f diazole-3-yl] brigade bite基 啥 琳 I I 基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- -isopropyl _fl, 2, 4] oxadiazole 基](四)琳+基]Benzyl](2_基基吼咬-1-基)methanone; r』Γ 4~[6-气-4~[4_[5-(1' Bu 二气Ethyl)-[1,2,4]3-sial-3-yl]Nylon bite_Buji]啥Salina _8-yl]phenyl](3-pyridylpyridin-1-yl)-methyl; [2,4~[6-fluoro-4~[4-[5-(i-fluoroethyl)_ 1' 2' 4]1⁄2 monoazole _3_yl]piperidinyl]quinazolinyl] Phenyl](3-hydroxypyrrolidin-1-yl)anthone; Γ1 4'[6~^'4~[4~[5-〇-^-1-f &amp; 6 *)- one,,% Diazole~3-yl]piperidin-1-yl]quinazolin-8-yl]-N-(2-fathylethyl)-glycolylbenzamide; _ 3 [1 [2-fluoro- 4-[5-fluoro_4-[4-(5-isopropyl-[i,2,4]Pf-s--3-yl)-materials+yl]---[8-yl]phenyl]_2_ Side oxy-sit-3-yl]~propanamine; and 〇丨[2' gas~4~[5-fluoro-4-[4-(5-isopropyl-[l,2,4]flf Diyl) piperidine~1-yl]quinazolin-8-yl] phenyl]-4-hydroxymethyl 0 is a bite--2-. 323135 201202230 12. 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 preventive/therapeutic agent for a metabolic disease or a cardiovascular disease treatable by activation of GPR119. 14. The pharmaceutical composition according to claim 13, wherein the metabolic diseases are obesity, hyperglycemia, diabetes and/or complications thereof, metabolic syndrome, glucose intolerance, hyperinsulinemia, and high fat. Hypertension, hypercholesterolemia, hypertriglyceridemia or abnormal lipid metabolism. 15. The pharmaceutical composition according to claim 13, wherein the cardiovascular disease is arteriosclerosis, hypertension, coronary artery disease or myocardial infarction. A compound for the GPR119 activity, which comprises the compound according to any one of claims 1 to 11 or a pharmacologically acceptable salt thereof as an active ingredient. 24 323135 201202230 IV. Designated representative map: (1) The representative representative of the case is: There is no schema in this case. (2) A brief description of the symbol of the representative figure: None. 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 3 323135