TW202110844A - Dispiro-diketopiperazine compounds - Google Patents

Abstract

The present invention provides anticancer agents that have a novel structure and demonstrate highly selective effects on cancer cells. Compounds that have a dispiro diketopiperazine structure that is represented by general formula (I), pharmaceutically acceptable salts of such compounds, or pharmaceutical compositions that contain such compounds. (The X, Y, Z, n1, n2, n3, and n4 in formula (I) are as defined in the description).

Description

Compounds with dispirodiketopiperidin structure

The present invention relates to a novel compound or a pharmaceutically acceptable salt thereof, which exhibits a highly selective effect on cancer cells and is useful as a medicine, especially as an anticancer agent.

構造的化合物的抗癌劑。 [先前技術文獻] [非專利文獻]Since the 1940s, many anticancer agents have been developed, including alkylating agents (Non-Patent Document 1). However, many anticancer agents currently in use are cytotoxic, and because they have an effect on all proliferating cells, they can affect both cancer cells and normal cells. This also applies to successful drugs such as irinotecan for colorectal cancer, taxane for breast cancer, carboplatin for ovarian cancer and small cell lung cancer. Cytotoxic substances such as anti-cancer agents have selective anti-cancer properties rather than selective anti-cell proliferation effects. Therefore, the selectivity of cancer cells to normal cells is moderate (Non-Patent Document 2). Due to this situation, the development of anticancer agents with high selectivity to cancer cells is required. Also, so far, it has not been known to use dispirodiketopa

Structured compounds as anticancer agents. [Prior technical literature] [Non-patent literature]

[Non-Patent Document 1] Nat. Rev. Cancer, 2005, 5, 65-72. [Non-Patent Document 2] Current Cancer Drug Targets, 2001, 1(1) 33-47.

[Summary of Invention] [The problem to be solved by the invention]

A compound with a novel structure is provided, which exhibits a highly selective effect on cancer cells. [Means to solve the problem]

構造的化合物係具有強力且癌細胞選擇性的細胞毒性，遂而完成本發明。In order to solve the above-mentioned problems, the present inventors synthesized compounds having various structures and searched for compounds that selectively exhibit cytocidal effects on cancer cells. As a result, it was found that dispirodiketon

The constructed compound has strong and selective cytotoxicity of cancer cells, thus completing the present invention.

The present invention relates to the following (1) to (13). (1) A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof,

[In formula (I), Z represents any one of the following (i) to (iii), (i) having 1 to 3 independently selected from the group containing oxygen atoms, nitrogen atoms, and sulfur atoms in the ring A 9- or 10-membered 2-ring aromatic heterocyclic group of heteroatoms (the 9- or 10-membered 2-ring aromatic heterocyclic group may have 1 or 2 substituents independently selected from the following A group) , (Ii) A 6-membered aromatic heterocyclic group having 1 to 3 nitrogen atoms in the ring, or a phenyl group (the 6-membered aromatic heterocyclic group and phenyl group may have 1 or 2 independently selected from Substituents of the following group B), (iii) -CO-R ¹ (R ¹ represents a 4- to 6-member aliphatic heterocyclic group having 1 or 2 nitrogen atoms in the ring, having 1 or A 6-membered aromatic heterocyclic group with 2 nitrogen atoms, a 9- or 10-membered 2-ring aromatic group having 1 to 3 heteroatoms independently selected from the group containing nitrogen atoms, oxygen atoms and sulfur atoms in the ring A heterocyclic group or a phenyl group, the aliphatic heterocyclic group, aromatic heterocyclic group, bicyclic aromatic heterocyclic group and phenyl group may have 1 to 3 substitutions each independently selected from the following C groups Radical), n ¹ and n ² each independently represent an integer of 1 to 3, n ³ and n ⁴ each independently represent an integer of 1 to 3, X represents CR ² R ³ , a sulfur atom, an oxygen atom, or NR ⁴ , R ² and R ³ each independently represent a hydrogen atom, a halogen atom, or an ethynyl group, or R ² and R ³ may be formed in a ring together with the bonded carbon atom. 3-6 members with 1 or 2 nitrogen atoms may have An aliphatic heterocyclic ring with an unsaturated bond, R ⁴ represents a hydrogen atom or a C ₁ -C ₆ alkyl group, Y represents a phenyl group, a 6-membered aromatic heterocyclic group having 1 or 2 nitrogen atoms in the ring, or A 9- or 10-membered 2-ring aromatic heterocyclic group having 1 to 3 heteroatoms independently selected from the group containing nitrogen atoms, oxygen atoms and sulfur atoms in the ring (the phenyl group, the aromatic heterocyclic group and the The bicyclic aromatic heterocyclic group may have 1 or 2 substituents each independently selected from the following D group)]; A group: halogen atom, hydroxyl group, nitro group, vinyl group, ethynyl group, cyano group, C ₁ -C ₆ alkyl group which may be substituted by 1 to 3 halogen atoms, C ₁ -C ₆ alkoxy group which may be substituted by 1 to 3 halogen atoms, C ₃ -which may be substituted by 1 to 3 halogen atoms C ₆ cycloalkyl, C ₃ -C ₆ cycloalkoxy, (C ₁ -C ₆ alkyl) amino, di (C ₁ -C ₆ alkyl) amino, (C ₁ -C ₆ alkyl) Carbonyl, (C ₁ -C ₆ alkoxy) carbonyl, azido and diazirine group; Group B: halogen atom, ethynyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ Alkoxy and C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl group; C group: halogen atom, cyano group, ethynyl group and C ₁ -C ₆ alkyl group; D group: halogen atom, can be C ₁ -C ₆ alkyl substituted by 1 to 3 halogen atoms, which may be substituted by 1 to 3 halogen atoms C ₁ -C ₆ alkoxy, ethynyl, azido and diazepine.

(2) The compound described in (1) or a pharmaceutically acceptable salt thereof, wherein Z is a 10-membered 2-ring aromatic heterocyclic group having 1 or 2 nitrogen atoms in the ring, and the 2 of 10 members The cyclic aromatic heterocyclic group may have 1 or 2 substituents each independently selected from the following E group, n ¹ and n ² are each independently 1 or 2; E group: halogen atom, ethynyl group, _{C 1} -C ₆ alkyl substituted with 1 to 3 halogen atoms, C ₁ -C ₆ alkoxy substituted with 1 to 3 halogen atoms, C ₃ -C _{6 substituted with 1 to 3 halogen atoms} Cycloalkyl and C ₃ -C ₆ cycloalkoxy.

啉基、呔

基、

啶基或吡啶并嘧啶基， 該噻吩并嘧啶基、喹啉基、異喹啉基、喹唑啉基、

啉基、呔

基、

啶基及吡啶并嘧啶基，可具有1或2個獨立選自包含鹵素原子、可被1～3個鹵素原子取代的C₁ -C₆ 烷基及可被1～3個鹵素原子取代的C₁ -C₆ 烷氧基的群組的取代基， n¹ 及n² 皆為1。(3) The compound described in (1) or a pharmaceutically acceptable salt thereof, wherein Z is thienopyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl,

Linyl, X

base,

Ridinyl or pyridopyrimidinyl, the thienopyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl,

Linyl, X

base,

_{The pyridino and pyridopyrimidinyl groups may have 1 or 2 independently selected from C 1} -C ₆ alkyl groups which contain halogen atoms, which may be substituted by 1 to 3 halogen atoms, and C which may be substituted by 1 to 3 halogen atoms. In the substituent of the _1- C ₆ ^{alkoxy group, n 1} and n ² are both 1.

(4) The compound described in (1) or a pharmaceutically acceptable salt thereof, wherein Z is -CO-R ⁵ , and R ⁵ represents a phenyl group, a pyridyl group, or an azo group, and the phenyl group, a pyridyl group, and a nitrogen group The group may have 1 to 3 substituents each independently selected from the following F group, n ¹ and n ² are each independently 1 or 2; F group: halogen atom and C ₁ -C ₆ alkyl group.

(5) The compound according to any one of (1) to (4) or a pharmaceutically acceptable salt thereof, wherein both n ³ and n ⁴ are 2, and X is CF ₂ .

(6) The compound described in any one of (1) to (4) or a pharmaceutically acceptable salt thereof, wherein

n ³ and n ⁴ are both 2, and X is the following formula (II),

。

.

(7) The compound according to any one of (1) to (6) or a pharmaceutically acceptable salt thereof, wherein Y is a phenyl group or a pyridyl group, and the phenyl group and the pyridyl group may each have 1 or 2 Substituents independently selected from the following G group; G group: halogen atom, C ₁ -C ₆ alkyl group which may be substituted by 1 to 3 halogen atoms, and C ₁ -which may be substituted by 1 to 3 halogen atoms C ₆ alkoxy.

(8) The compound described in (1) or a pharmaceutically acceptable salt thereof, wherein Z is a C ₁ -C ₆ alkane having 1 or 2 independently selected from containing halogen atoms, which may be substituted by 1 to 3 halogen atoms The quinazolinyl group and the _{substituent of the C 1} -C ₆ alkoxy group which may be substituted by 1 to 3 halogen atoms ^{, n 1} and n ² are both 1, n ³ and n ⁴ are both 2, X is CF ₂ , Y is having 1 or 2 independently selected from containing halogen atoms, C ₁ -C ₆ alkyl groups which may be substituted by 1 to 3 halogen atoms, and C ₁ -which may be substituted by 1 to 3 halogen atoms The phenyl group is a substituent of the C _{6 alkoxy group.}

(9) A compound selected from the following group or a pharmaceutically acceptable salt thereof: 2-[7-(1,1-difluoroethyl)quinazolin-4-yl]-5-{ [4-Difluoromethoxy-3-fluorophenyl]methyl}-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6 ,14-dione, 2-[2-chloro-7-(1,1-difluoroethyl)quinazolin-4-yl]-5-[(4-chloro-3-fluorophenyl)methyl ]-10,10-Difluoro-2,5,13-Triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione, 5-[(4-chloro-3-fluoro Phenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazolin-4-yl]-10,10-difluoro-2,5,13-triazabispiro[3.2 .5 ⁷ .2 ⁴ ]tetradecane-6,14-dione, 2-[7-(1,1-difluoroethyl)-2-methoxyquinazolin-4-yl]-5- {[4-Difluoromethoxy-3-fluorophenyl]methyl}-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane- 6,14-dione, (-)-2-(4-chloro-2,6-difluorobenzyl)-6-[(4-chloro-3-fluorophenyl)methyl]-11, 11-Difluoro-2,6,14-Triazadispiro[4.2.5 ⁸ .2 ⁵ ]pentadecane-7,15-dione, (+)-6-[(4-chloro-3-fluoro Phenyl)methyl]-2-[(5-chloro-3-fluoropyridin-2-yl)carbonyl]-11,11-difluoro-2,6,14-triazabispiro[4.2.5 ⁸ . 2 ⁵ ]pentadecane-7,15-dione, 7-[(4-chloro-3-fluorophenyl)methyl]-3-[(3-ethylazepine-1-yl)carbonyl]- 12,12-difluoro-3,7,15-triazabispiro[5.2.5 ⁹ .2 ⁶ ]hexadecane-8,16-dione, and 2-(6-butylpyrimidin-4-yl )-5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane- 6,14-dione.

(10) A compound selected from the following group or a pharmaceutically acceptable salt thereof: 2-[7-(1,1-difluoroethyl)quinazolin-4-yl]-5-{ [4-Difluoromethoxy-3-fluorophenyl]methyl}-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6 ,14-dione, 2-[2-chloro-7-(1,1-difluoroethyl)quinazolin-4-yl]-5-[(4-chloro-3-fluorophenyl)methyl ]-10,10-Difluoro-2,5,13-Triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione, 5-[(4-chloro-3-fluoro Phenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazolin-4-yl]-10,10-difluoro-2,5,13-triazabispiro[3.2 .5 ⁷ .2 ⁴ ]tetradecane-6,14-dione, and 2-[7-(1,1-difluoroethyl)-2-methoxyquinazolin-4-yl]-5 -{[4-Difluoromethoxy-3-fluorophenyl]methyl}-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane -6,14-dione.

(11) A pharmaceutical composition containing the compound described in any one of (1) to (10) or a pharmaceutically acceptable salt thereof as an active ingredient.

(12) An anticancer agent comprising the compound described in any one of (1) to (10) or a pharmaceutically acceptable salt thereof as an active ingredient.

(13) The anticancer agent as described in (12), wherein the cancer is leukemia, malignant lymphoma, multiple myeloma, brain tumor, head and neck cancer, esophageal cancer, stomach cancer, appendix cancer, colorectal cancer, anal cancer, gallbladder cancer , Cholangiocarcinoma, pancreatic cancer, gastrointestinal stromal tumor, lung cancer, liver cancer, mesothelioma, thyroid cancer, kidney cancer, prostate cancer, bladder cancer, neuroendocrine tumors, neuroblastoma, melanoma, breast cancer, uterus Body cancer, cervical cancer, ovarian cancer, testicular cancer, osteosarcoma, soft tissue sarcoma, Kaposi's sarcoma (Kaposi's sarcoma) or sarcoma.

In terms of another aspect of the present invention, it relates to the following (1A) to (38A).

(1A) A compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, [in formula (I), Z represents any one of the following (i) to (iii), (i) in A 9- or 10-membered 2-ring aromatic heterocyclic group having 1 to 3 heteroatoms independently selected from the group containing oxygen atoms, nitrogen atoms and sulfur atoms (the 9- or 10-member 2-ring aromatic heterocyclic group The heterocyclic group may have 1 or 2 substituents independently selected from the following group A), (ii) a 6-membered aromatic heterocyclic group having 1 to 3 nitrogen atoms in the ring, or a phenyl group (The 6-membered aromatic heterocyclic group and the phenyl group may have 1 or 2 substituents each independently selected from the following B group), (iii) -CO-R ¹ (R ¹ means having 1 in the ring Or a 4- to 6-membered aliphatic heterocyclic group with 2 nitrogen atoms, a 6-membered aromatic heterocyclic group with 1 or 2 nitrogen atoms in the ring, and 1 to 3 in the ring are independently selected from containing nitrogen A 9- or 10-membered bicyclic aromatic heterocyclic group or a phenyl group of heteroatoms of the group of atoms, oxygen atoms, and sulfur atoms, the aliphatic heterocyclic group, aromatic heterocyclic group, and bicyclic aromatic group The heterocyclic group and the phenyl group may have 1 to 3 substituents each independently selected from the following C group), n ¹ and n ² each independently represent an integer of 1 to 3, and n ³ and n ⁴ each independently represent An integer of 1 to 3, X represents CR ² R ³ , a sulfur atom, an oxygen atom or NR ⁴ , R ² and R ³ each independently represent a hydrogen atom, a halogen atom or an ethynyl group, or R ² and R ³ may be bonded to each other The carbon atoms in the ring together form an aliphatic heterocyclic ring with 1 or 2 nitrogen atoms of 3-6 members which may have unsaturated bonds, R ⁴ represents a hydrogen atom or a C ₁ -C ₆ alkyl group, and Y represents a phenyl group , A 6-membered aromatic heterocyclic group having 1 or 2 nitrogen atoms in the ring, or 9 having 1 to 3 heteroatoms independently selected from the group containing nitrogen atoms, oxygen atoms and sulfur atoms in the ring Or a 10-membered 2-ring aromatic heterocyclic group (the phenyl, aromatic heterocyclic group, and 2-ring aromatic heterocyclic group may have 1 or 2 substituents each independently selected from the following D group) ]; Group A: halogen atoms, hydroxyl groups, nitro groups, vinyl groups, ethynyl groups, cyano groups, C ₁ -C ₆ alkyl groups that can be substituted by 1 to 3 halogen atoms, and can be substituted by 1 to 3 halogen atoms the C ₁ -C ₆ alkoxy group which may be substituted with 1 to 3 halogen atoms, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkoxy, (C ₁ -C ₆ alkyl) amine , Two (C ₁ -C ₆ alkyl) amine group, (C ₁ -C ₆ alkyl) carbonyl group, (C ₁ -C ₆ alkoxy) carbonyl group, azido group and diazoxide group; Group B: Halogen atom, ethynyl group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group and C ₁ -C ₆ alkoxy group C ₁ -C ₆ alkyl group; C group: halogen atom, cyano group, acetylene Group and C ₁ -C ₆ alkyl group; D group: halogen atom, C ₁ -C ₆ alkane which can be substituted by 1 to 3 halogen atoms _{Group, C 1} -C ₆ alkoxy group, ethynyl group, azido group and diazepine group which may be substituted by 1 to 3 halogen atoms.

(2A) The compound described in (1A) or a pharmaceutically acceptable salt thereof, wherein Z is a 10-membered 2-ring aromatic heterocyclic group having 1 or 2 nitrogen atoms in the ring, and 2 of the 10 members The cyclic aromatic heterocyclic group may have 1 or 2 substituents each independently selected from the following E group, n ¹ and n ² are each independently 1 or 2; E group: halogen atom, ethynyl group, _{C 1} -C ₆ alkyl substituted with 1 to 3 halogen atoms, C ₁ -C ₆ alkoxy substituted with 1 to 3 halogen atoms, C ₃ -C _{6 substituted with 1 to 3 halogen atoms} Cycloalkyl and C ₃ -C ₆ cycloalkoxy.

啉基、呔

基、

啶基或吡啶并嘧啶基， 該噻吩并嘧啶基、喹啉基、異喹啉基、喹唑啉基、

啉基、呔

基、

啶基及吡啶并嘧啶基可具有1或2個獨立選自包含鹵素原子、可被1～3個鹵素原子取代的C₁ -C₆ 烷基及可被1～3個鹵素原子取代的C₁ -C₆ 烷氧基的群組的取代基， n¹ 及n² 皆為1。(3A) The compound described in (1A) or a pharmaceutically acceptable salt thereof, wherein Z is thienopyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl,

Linyl, X

base,

Ridinyl or pyridopyrimidinyl, the thienopyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl,

Linyl, X

base,

Piperidinyl and pyridinyl and pyrimidinyl group may have 1 or 2 substituents independently selected from C comprising a halogen atom, may be substituted with 1 to 3 halogen atoms and ₁ -C ₆ alkyl which may be substituted with 1 to 3 halogen atoms, _a C In the substituent of the _{-C 6} ^{alkoxy group, n 1} and n ² are both 1.

(4A) The compound according to (1A) or a pharmaceutically acceptable salt thereof, wherein Z is -CO-R ⁵ , and R ⁵ represents a phenyl group, a pyridyl group or an azo group, and the phenyl group, a pyridyl group and a nitrogen group The group may have 1 to 3 substituents each independently selected from the following F group, n ¹ and n ² are each independently 1 or 2; F group: halogen atom and C ₁ -C ₆ alkyl group.

(5A) The compound described in any one of (1A) to (4A) or a pharmaceutically acceptable salt thereof, wherein both n ³ and n ⁴ are 2, and X is CF ₂ .

(6A) The compound described in any one of (1A) to (4A) or a pharmaceutically acceptable salt thereof, wherein n ³ and n ⁴ are both 2, and X is the above formula (II).

(7A) The compound according to any one of (1A) to (6A) or a pharmaceutically acceptable salt thereof, wherein Y is a phenyl group or a pyridyl group, and the phenyl group and the pyridyl group may have 1 or 2 independently substituent group selected from the following group G; group G: halogen atoms, which may be substituted with 1 to 3 halogen atoms and C ₁ -C ₆ alkyl group which may be substituted with 1 to 3 halogen atoms, C ₁ -C ₆ alkoxy.

(8A) The compound as described in (1A) or a pharmaceutically acceptable salt thereof, wherein Z is a C ₁ -C ₆ alkane having 1 or 2 independently selected from containing halogen atoms, which may be substituted by 1 to 3 halogen atoms The quinazolinyl group and the _{substituent of the C 1} -C ₆ alkoxy group which may be substituted by 1 to 3 halogen atoms ^{, n 1} and n ² are both 1, n ³ and n ⁴ are both 2, X is CF ₂ , Y is having 1 or 2 independently selected from containing halogen atoms, C ₁ -C ₆ alkyl groups which may be substituted by 1 to 3 halogen atoms, and C ₁ -which may be substituted by 1 to 3 halogen atoms The phenyl group is a substituent of the C _{6 alkoxy group.}

(9A) The compound described in (1A) or a pharmaceutically acceptable salt thereof, which is any one selected from the following group: 2-[7-(1,1-difluoroethyl)quinazoline -4-yl]-5-{[4-difluoromethoxy-3-fluorophenyl]methyl}-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione, 2-[2-chloro-7-(1,1-difluoroethyl)quinazolin-4-yl]-5-[(4-chloro -3-fluorophenyl)methyl]-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione, 5- [(4-Chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazolin-4-yl]-10,10-difluoro-2,5 ,13-Triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione, 2-[7-(1,1-difluoroethyl)-2-methoxyquinazole Lin-4-yl]-5-{[4-difluoromethoxy-3-fluorophenyl]methyl}-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione, (-)-2-(4-chloro-2,6-difluorobenzyl)-6-[(4-chloro-3-fluoro (Phenyl)methyl]-11,11-difluoro-2,6,14-triazabispiro[4.2.5 ⁸ .2 ⁵ ]pentadecane-7,15-dione, (+)-6- [(4-Chloro-3-fluorophenyl)methyl]-2-[(5-chloro-3-fluoropyridin-2-yl)carbonyl]-11,11-difluoro-2,6,14-tri Azodispiro[4.2.5 ⁸ .2 ⁵ ]pentadecane-7,15-dione, 7-[(4-chloro-3-fluorophenyl)methyl]-3-[(3-ethylnitrogen Phen-1-yl)carbonyl]-12,12-difluoro-3,7,15-triazabispiro[5.2.5 ⁹ .2 ⁶ ]hexadecane-8,16-dione, 2-(6 -Butylpyrimidin-4-yl)-5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione, 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)quinazoline-4 -Yl]-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione, 5-[(4-chloro-3 -Fluorophenyl)methyl]-2-[7-(difluoromethoxy)-2-methoxyquinazolin-4-yl]-10,10-difluoro-2,5,13-tris Azodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione, and 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1, 1-Difluoroethyl)-2-methoxyquinazolin-4-yl)-10,10-bis Fluoro-2,5,13-triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione.

(10A) 5-[(4-chloro-3-fluorophenyl)methyl)-2-[7-(1,1-difluoroethyl)quinazolin-4-yl) as described in (1A) -10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ] tetradecane-6,14-dione or a pharmaceutically acceptable salt thereof.

(11A) 2-[7-(1,1-difluoroethyl)-2-methoxyquinazolin-4-yl]-5-{[4-difluoromethoxy as described in (1A) -3-fluorophenyl]methyl}-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione or its pharmaceutical products Tolerable salt on the table.

(12A) 5-[(4-chloro-3-fluorophenyl)methyl)-2-[7-(difluoromethoxy)quinazolin-4-yl]-10 as recorded in (1A), 10-Difluoro-2,5,13-triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione or a pharmaceutically acceptable salt thereof.

(13A) 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)-2-methoxyquinazoline-4 as described in (1A) -Yl]-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione or a pharmaceutically acceptable salt thereof.

(14A) 5-[(4-chloro-3-fluorophenyl)methyl)-2-[7-(1,1-difluoroethyl)-2-methoxyquinazole as described in (1A) 4-yl] 10,10-difluoro two -2,5,13- triaza-spiro ^{[7.2 4} 3.2.5] tetradecane-6,14-dione or a pharmaceutically tolerable salt.

(15A) 5-[(4-chloro-3-fluorophenyl)methyl)-2-[7-(difluoromethoxy)quinazolin-4-yl]-10 as described in (1A), 10-Difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione hydrochloride.

(16A) A crystal of 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)quinazoline-4- as described in (1A) Yl]-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione hydrochloride crystal, which uses CuKα radiation The powder X-ray diffraction is selected from 6.80±0.2, 13.85±0.2, 15.25±0.2, 17.20±0.2, 18.65±0.2, 19.65±0.2, 21.75±0.2, 23.20±0.2, 24.40±0.2 and 25.35±0.2 The diffraction angle (2θ) has at least 5 crests.

(17A) 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)-2-methoxyquinazoline-4 as described in (1A) -Yl]-10,10-difluoro-2,5,13-triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione hydrochloride.

(18A) A crystal, which is 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)-2-methoxy as described in (1A) Quinazolin-4-yl]-10,10-difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione hydrochloride crystal , Which is selected from 8.34±0.2, 10.40±0.2, 12.15±0.2, 16.20±0.2, 17.70±0.2, 19.15±0.2, 20.45±0.2, 22.75±0.2, 24.50 in powder X-ray diffraction using CuKα radiation The diffraction angle (2θ) of ±0.2 and 25.90±0.2 has at least 5 crests.

(19A) 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazolin-4-yl) as described in (1A) -10,10-difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ] tetradecane-6,14-dione oxalate.

(20A) A crystal of 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazoline as described in (1A) -4-yl]-10,10-difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione oxalate crystal, which is In powder X-ray diffraction using CuKα radiation, it is selected from 10.10±0.2, 12.35±0.2, 13.30±0.2, 17.05±0.2, 17.75±0.2, 18.70±0.2, 20.55±0.2, 23.25±0.2, 25.25±0.2 and The diffraction angle (2θ) of 29.30±0.2 has at least 5 crests.

(21A) 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazolin-4-yl) as described in (1A) -10,10-Difluoro-2,5,13-Triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione methanesulfonate.

(22A) A crystal of 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazoline as described in (1A) -4-yl]-10,10-difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione methanesulfonate crystal, which In powder X-ray diffraction using CuKα radiation, it is selected from 6.85±0.2, 10.82±0.2, 11.69±0.2, 13.77±0.2, 15.67±0.2, 16.30±0.2, 18.39±0.2, 20.49±0.2, 22.88±0.2 And the diffraction angle (2θ) of 26.17±0.2 has at least 5 crests.

(23A) 5-[(4-chloro-3-fluorophenyl)methyl)-2-[7-(difluoromethoxy)quinazolin-4-yl)-10 as recorded in (1A), 10-Difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione methanesulfonate.

(24A) A crystal of 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)quinazoline-4- as described in (1A) Yl]-10,10-difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione methanesulfonate crystal, which is used in CuKα The powder X-ray diffraction of radiation is selected from 8.15±0.2, 11.25±0.2, 12.40±0.2, 15.75±0.2, 17.20±0.2, 18.95±0.2, 20.45±0.2, 22.95±0.2, 23.60±0.2 and 24.60± The diffraction angle (2θ) of 0.2 has at least 5 crests.

(25A) 5-[(4-chloro-3-fluorophenyl)methyl)-2-[7-(1,1-difluoroethyl)quinazolin-4-yl) as described in (1A) -10,10-Difluoro-2,5,13-Triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ethanesulfonate.

(26A) A crystal of 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazoline as described in (1A) -4-yl]-10,10-difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ethanesulfonate crystal, which In powder X-ray diffraction using CuKα radiation, it is selected from 5.82±0.2, 7.71±0.2, 9.31±0.2, 11.72±0.2, 15.31±0.2, 16.55±0.2, 18.36±0.2, 18.62±0.2, 19.23±0.2 And the diffraction angle (2θ) of 23.38±0.2 has at least 5 crests.

(27A) A crystal of 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazoline as described in (1A) -4-yl]-10,10-difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ethanesulfonic acid salt hydrate crystal , Which is selected from 6.87±0.2, 9.40±0.2, 10.74±0.2, 13.83±0.2, 15.66±0.2, 16.28±0.2, 16.68±0.2, 18.15±0.2, 18.93 in powder X-ray diffraction using CuKα radiation The diffraction angle (2θ) of ±0.2 and 20.29±0.2 has at least 5 crests.

(28A) 5-[(4-chloro-3-fluorophenyl)methyl)-2-[7-(1,1-difluoroethyl)quinazolin-4-yl) as described in (1A) -10,10-Difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dionebenzenesulfonate.

(29A) A crystal of 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazoline as described in (1A) -4-yl]-10,10-difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dionebenzenesulfonate crystal, which In powder X-ray diffraction using CuKα radiation, it is selected from 6.20±0.2, 10.16±0.2, 12.45±0.2, 14.89±0.2, 17.22±0.2, 18.03±0.2, 18.65±0.2, 22.29±0.2, 22.53±0.2 And the diffraction angle (2θ) of 26.55±0.2 has at least 5 crests.

(30A) A pharmaceutical composition containing the compound described in any one of (1A) to (29A), its pharmaceutically acceptable salt or crystal as an active ingredient.

(31A) An anticancer agent, which contains the compound described in any one of (1A) to (29A), or a pharmaceutically acceptable salt or crystal thereof as an active ingredient.

(32A) The anticancer agent as described in (31A), wherein the cancer is leukemia, malignant lymphoma, multiple myeloma, brain tumor, head and neck cancer, esophageal cancer, gastric cancer, appendix cancer, colorectal cancer, anal cancer, gallbladder cancer , Cholangiocarcinoma, pancreatic cancer, gastrointestinal stromal tumor, lung cancer, liver cancer, mesothelioma, thyroid cancer, kidney cancer, prostate cancer, bladder cancer, neuroendocrine tumors, neuroblastoma, melanoma, breast cancer, uterus Body cancer, cervical cancer, ovarian cancer, testicular cancer, osteosarcoma, soft tissue sarcoma, Kaposi’s sarcoma, or sarcoma.

(33A) A method for the treatment of cancer characterized by administering the compound described in any one of (1A) to (29A), its pharmaceutically acceptable salt or crystal.

(34A) The treatment method as described in (33A), wherein the cancer is leukemia, malignant lymphoma, multiple myeloma, brain tumor, head and neck cancer, esophageal cancer, stomach cancer, appendix cancer, colorectal cancer, anal cancer, gallbladder cancer, Cholangiocarcinoma, pancreatic cancer, gastrointestinal stromal tumor, lung cancer, liver cancer, mesothelioma, thyroid cancer, kidney cancer, prostate cancer, bladder cancer, neuroendocrine tumors, neuroblastoma, melanoma, breast cancer, uterine body Cancer, cervical cancer, ovarian cancer, testicular cancer, osteosarcoma, soft tissue sarcoma, Kaposi’s sarcoma, or sarcoma.

(35A) A compound described in any one of (1A) to (29A), or a pharmaceutically acceptable salt or crystal thereof, used for the treatment of cancer.

(36A) The compound described in (35A), its pharmaceutically acceptable salt or crystal, wherein the cancer is leukemia, malignant lymphoma, multiple myeloma, brain tumor, head and neck cancer, esophageal cancer, gastric cancer, appendix cancer, Colorectal cancer, anal cancer, gallbladder cancer, cholangiocarcinoma, pancreatic cancer, gastrointestinal stromal tumor, lung cancer, liver cancer, mesothelioma, thyroid cancer, kidney cancer, prostate cancer, bladder cancer, neuroendocrine tumors, neuroblasts Tumor, melanoma, breast cancer, uterine body cancer, cervical cancer, ovarian cancer, testicular cancer, osteosarcoma, soft tissue sarcoma, Kaposi’s sarcoma, or sarcoma.

(37A) Use of a compound as described in any one of (1A) to (29A), a pharmaceutically acceptable salt or crystal thereof, in the manufacture of a pharmaceutical composition for the treatment of cancer.

(38A) The use as in (37A), wherein the cancer is leukemia, malignant lymphoma, multiple myeloma, brain tumor, head and neck cancer, esophageal cancer, gastric cancer, appendix cancer, colorectal cancer, anal cancer, gallbladder cancer, cholangiocarcinoma , Pancreatic cancer, gastrointestinal stromal tumor, lung cancer, liver cancer, mesothelioma, thyroid cancer, kidney cancer, prostate cancer, bladder cancer, neuroendocrine tumors, neuroblastoma, melanoma, breast cancer, uterine body cancer, Cervical cancer, ovarian cancer, testicular cancer, osteosarcoma, soft tissue sarcoma, Kaposi's sarcoma, or sarcoma.

As far as another aspect of the present invention is concerned, it relates to the following (39A) to (63A).

(39A) A crystal of 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazoline as described in (1A) -4-yl]-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione crystal, which uses CuKα radiation The powder X-ray diffraction is selected from 10.20±0.2, 11.20±0.2, 11.75±0.2, 14.30±0.2, 16.55±0.2, 20.10±0.2, 20.70±0.2, 23.45±0.2, 24.15±0.2 and 22.25±0.2 The diffraction angle (2θ) has at least 5 crests.

(40A) A crystal of 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)-2- as described in (1A) Methoxyquinazolin-4-yl]-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione or Pharmaceutically acceptable salt crystal, which is selected from 6.80±0.2, 7.65±0.2, 14.55±0.2, 15.45±0.2, 14.20±0.2, 18.05±0.2, 20.15 in powder X-ray diffraction using CuKα radiation The diffraction angles (2θ) of ±0.2, 24.00±0.2, 27.50±0.2, and 28.00±0.2 have at least 5 peaks.

(41A) 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazolin-4-yl) as described in (1A) -10,10-Difluoro-2,5,13-Triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione hydrochloride.

(42A) A crystal of 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazoline as described in (1A) -4-yl]-10,10-difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione hydrochloride crystal, which is In powder X-ray diffraction using CuKα radiation, selected from 8.45±0.2, 11.35±0.2, 12.30±0.2, 15.75±0.2, 16.65±0.2, 17.15±0.2, 17.80±0.2, 19.15±0.2, 19.85±0.2 and The diffraction angle (2θ) of 24.50±0.2 has at least 5 crests.

(43A) 5-[(4-chloro-3-fluorophenyl)methyl)-2-[7-(1,1-difluoroethyl)quinazolin-4-yl) as described in (1A) -10,10-Difluoro-2,5,13-Triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione sulfate.

(44A) A crystal of 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazoline as described in (1A) -4-yl]-10,10-difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione sulfate crystal, which is used in The powder X-ray diffraction of CuKα radiation is selected from 6.85±0.2, 8.30±0.2, 9.25±0.2, 11.05±0.2, 13.55±0.2, 17.35±0.2, 18.35±0.2, 19.00±0.2, 20.55±0.2 and 22.25 The diffraction angle (2θ) of ±0.2 has at least 5 crests.

(45A) 5-[(4-chloro-3-fluorophenyl)methyl)-2-[7-(difluoromethoxy)quinazolin-4-yl]-10 as recorded in (1A), 10-Difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione sulfate.

(46A) A crystal of 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)quinazoline-4- as described in (1A) Base]-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione sulfate crystal, which is used in the use of CuKα radiation In powder X-ray diffraction, it is selected from 10.00±0.2, 11.45±0.2, 12.35±0.2, 16.40±0.2, 17.60±0.2, 20.25±0.2, 24.00±0.2, 24.65±0.2, 25.40±0.2 and 29.25±0.2 The diffraction angle (2θ) has at least 5 crests.

(47A) 5-[(4-chloro-3-fluorophenyl)methyl)-2-[7-(difluoromethoxy)-2-methoxyquinazoline-4 as described in (1A) -Yl]-10,10-difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione sulfate.

(48A) A crystal, which is 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)-2-methoxy as described in (1A) Quinazolin-4-yl]-10,10-difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione sulfate crystal, It is selected from 8.50±0.2, 10.70±0.2, 11.20±0.2, 16.50±0.2, 18.85±0.2, 19.95±0.2, 23.00±0.2, 24.65±0.2, 27.45± in powder X-ray diffraction using CuKα radiation. The diffraction angle (2θ) of 0.2 and 27.80±0.2 has at least 5 crests.

(49A) 5-[(4-chloro-3-fluorophenyl)methyl)-2-[7-(1,1-difluoroethyl)quinazolin-4-yl) as described in (1A) -10,10-difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ] tetradecane-6,14-dione nitrate.

(50A)) A crystal of 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazole as described in (1A) Lin-4-yl]-10,10-difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione nitrate crystal, which is In powder X-ray diffraction using CuKα radiation, it is selected from 8.65±0.2, 15.25±0.2, 16.80±0.2, 17.55±0.2, 18.20±0.2, 19.90±0.2, 22.10±0.2, 23.25±0.2, 24.50±0.2 and The diffraction angle (2θ) of 29.85±0.2 has at least 5 crests.

(51A) 5-[(4-chloro-3-fluorophenyl)methyl)-2-[7-(difluoromethoxy)-2-methoxyquinazoline-4 as described in (1A) -Yl]-10,10-difluoro-2,5,13-triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione methanesulfonate.

(52A) A crystal, which is 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)-2-methoxy as described in (1A) Quinazolin-4-yl]-10,10-difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione methanesulfonate Crystal, which is selected from 6.75±0.2, 8.15±0.2, 12.20±0.2, 12.85±0.2, 15.00±0.2, 16.70±0.2, 18.10±0.2, 18.70±0.2, in powder X-ray diffraction using CuKα radiation, The diffraction angle (2θ) of 20.65±0.2 and 22.10±0.2 has at least 5 crests.

(53A) 5-[(4-chloro-3-fluorophenyl)methyl)-2-[7-(1,1-difluoroethyl)-2-methoxyquinazole as described in (1A) 4-yl] 10,10-difluoro two -2,5,13- triaza-spiro ^{[7.2 4} 3.2.5] tetradecane-6,14-dione methanesulfonate.

(54A) 2-[7-(1,1-difluoroethyl)-2-methoxyquinazolin-4-yl]-5-{[4-difluoromethoxy as described in (1A) -3-fluorophenyl]methyl}-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione methanesulfonic acid salt.

(55A) A crystal of 2-[7-(1,1-difluoroethyl)-2-methoxyquinazolin-4-yl]-5-{[4- Difluoromethoxy-3-fluorophenyl]methyl}-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14- The crystal of diketo methanesulfonate is selected from 6.60±0.2, 7.15±0.2, 9.30±0.2, 11.05±0.2, 13.30±0.2, 16.80±0.2, 18.80 in powder X-ray diffraction using CuKα radiation. The diffraction angles (2θ) of ±0.2, 20.45±0.2, 23.40±0.2, and 26.85±0.2 have at least 5 crests.

(56A) 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazolin-4-yl) as described in (1A) -10,10-difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione p-toluenesulfonate.

(57A) A crystal of 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazoline as described in (1A) -4-yl]-10,10-difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione p-toluenesulfonate crystal, In powder X-ray diffraction using CuKα radiation, it is selected from 7.75±0.2, 13.05±0.2, 15.70±0.2, 16.00±0.2, 17.05±0.2, 19.15±0.2, 19.60±0.2, 21.45±0.2, 23.80± The diffraction angle (2θ) of 0.2 and 25.30±0.2 has at least 5 crests.

(58A) 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)quinazolin-4-yl]-10 as recorded in (1A), 10-Difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione p-toluenesulfonate.

(59A) A crystal of 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)quinazoline-4- as described in (1A) Yl]-10,10-difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione p-toluenesulfonate crystal, which is used in The powder X-ray diffraction of CuKα radiation is selected from 6.90±0.2, 8.00±0.2, 9.05±0.2, 10.80±0.2, 17.90±0.2, 19.10±0.2, 20.15±0.2, 22.10±0.2, 24.55±0.2 and 26.40 The diffraction angle (2θ) of ±0.2 has at least 5 crests.

(60A) 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)-2-methoxyquinazoline-4 as described in (1A) -Yl]-10,10-difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione p-toluenesulfonate.

(61A) A crystal, which is 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)-2-methoxy as described in (1A) Quinazolin-4-yl]-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione p-toluenesulfonate The crystal of which is selected from 6.75±0.2, 8.15±0.2, 12.20±0.2, 12.85±0.2, 15.00±0.2, 16.70±0.2, 18.10±0.2, 18.70±0.2 in powder X-ray diffraction using CuKα radiation The diffraction angle (2θ) of 20.65±0.2 and 22.10±0.2 has at least 5 crests.

(62A) 5-[(4-chloro-3-fluorophenyl)methyl)-2-[7-(1,1-difluoroethyl)-2-methoxyquinazole as described in (1A) Lin-4-yl]-10,10-difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione p-toluenesulfonate.

(63A) A crystal of 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)-2- as described in (1A) Methoxyquinazolin-4-yl]-10,10-difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione p-toluene The crystal of sulfonate, which is selected from 6.65±0.2, 9.05±0.2, 11.20±0.2, 12.90±0.2, 14.25±0.2, 17.05±0.2, 18.10±0.2, in powder X-ray diffraction using CuKα radiation, The diffraction angles (2θ) of 19.60±0.2, 22.85±0.2, and 25.85±0.2 have at least 5 crests. [Effects of Invention]

構造的化合物。According to the present invention, it is possible to provide a novel dispirodiketopiper with a highly selective effect on cancer cells.

Structured compound.

[Form to implement the invention]

In the present invention, the "halogen atom" includes, for example, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

In the present invention, the "C ₁ -C ₃ alkyl group" is a straight or branched chain alkyl group having 1 to 3 carbon atoms, and examples thereof include methyl, ethyl, propyl or isopropyl.

In the present invention, the so-called "C ₁ -C ₆ alkyl group" is a straight or branched chain alkyl group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl or 4-methylpentyl Wait.

In the present invention, the so-called "C ₁ -C ₃ alkoxy group" is a group to which the above-mentioned C ₁ -C ₃ alkyl group is bonded to the oxy group. Examples include methoxy, ethoxy, propoxy or iso Propoxy and so on.

In the present invention, the so-called "C ₁ -C ₆ alkoxy group" is a group in which the above-mentioned C ₁ -C ₆ alkyl group is bonded to the hydroxyl group, and examples thereof include: methoxy, ethoxy, propoxy, iso Propoxy, butoxy, isobutoxy, secondary butoxy or tertiary butoxy, etc.

In the present invention, the "C ₃ -C ₆ cycloalkyl group" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In the present invention, the so-called "C ₃ -C ₆ cycloalkoxy group" is a group in which the above-mentioned C ₃ -C ₆ cycloalkyl group is bonded to a hydroxyl group. Examples thereof include cyclopropoxy, cyclobutoxy, and cyclopentyl. Oxy or cyclohexyloxy, etc.

In the present invention, the so-called "(C ₁ -C ₆ alkyl)amino group" is a group in which one of the above C ₁ -C ₆ alkyl groups is bonded to the amino group, and examples thereof include methylamino and ethyl Amino, propylamino, isopropylamino, butylamino, isobutylamino, secondary butylamino or tertiary butylamino, etc.

In the present invention, the so-called "bis(C ₁ -C ₆ alkyl)amino group" is a group in which two identical or different C ₁ -C ₆ alkyl groups are bonded to the amine group. Examples include dimethyl Amino group, diethylamino group, ethylmethylamino group, dipropylamino group or diisopropylamino group, etc.

In the present invention, the so-called "(C ₁ -C ₆ alkyl)carbonyl group" is a group in which the aforementioned C ₁ -C ₆ alkyl group is bonded to the carbonyl group, and examples thereof include methylcarbonyl, ethylcarbonyl, and propylcarbonyl , Isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, 2-butylcarbonyl or tertiarybutylcarbonyl, etc.

In the present invention, the so-called "(C ₁ -C ₆ alkoxy) carbonyl group" is a group in which the aforementioned C ₁ -C ₆ alkoxy group is bonded to the carbonyl group, and examples thereof include methoxycarbonyl and ethoxycarbonyl , Propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, secondary butoxycarbonyl or tertiary butoxycarbonyl, etc.

In the present invention, the so-called "C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl group" is a group in which the above C ₁ -C ₆ alkoxy group is bonded to the above C ₁ -C ₆ alkyl group, and examples thereof include For example, methoxymethyl, methoxyethyl, ethoxymethyl, or ethoxyethyl.

啉基、呔

基、

啶基或吡啶并嘧啶基等。In the present invention, the so-called "2-cyclic aromatic heterocyclic group with 9 or 10 members having 1 to 3 heteroatoms independently selected from the group containing oxygen atoms, nitrogen atoms and sulfur atoms in the ring" is defined by 9 Or a group derived from a 10-membered 2-ring aromatic heterocyclic ring, where as the constituent atoms of the ring, in addition to carbon atoms, it also contains 1 to 3 independently selected from the group consisting of oxygen atoms, nitrogen atoms and sulfur atoms Of heteroatoms. Examples include: thienopyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl,

Linyl, X

base,

Iridinyl or pyridopyrimidinyl and the like.

基、嘧啶基或吡

基等。In the present invention, the so-called "6-membered aromatic heterocyclic group having 1 or 2 nitrogen atoms in the ring" refers to a group derived from a 6-membered aromatic heterocyclic ring, in which, as the constituent atoms of the ring, in addition to containing carbon In addition to atoms, it also contains 1 or 2 nitrogen atoms. For example, pyridyl, da

Base, pyrimidinyl or pyridine

Base and so on.

基、嘧啶基、吡

基或三

基等。In the present invention, the so-called "6-membered aromatic heterocyclic group having 1 to 3 nitrogen atoms in the ring" refers to a group derived from a 6-membered aromatic heterocyclic ring, in which, as the constituent atoms of the ring, except for containing carbon In addition to atoms, it also contains 1 to 3 nitrogen atoms. For example, pyridyl, da

Pyrimidinyl, pyrimidinyl, pyridine

Base or three

Base and so on.

基等。In the present invention, the so-called "4--6 membered aliphatic heterocyclic group having 1 or 2 nitrogen atoms in the ring" refers to a group derived from a 4--6 membered aliphatic heterocyclic ring, which is the constituent atom of the ring In addition to carbon atoms, it also contains 1 or 2 nitrogen atoms. Examples include azepine, piperidinyl, pyrrolidinyl, imidazolidinyl or piperidine

Base and so on.

環、二氮吮環或氮呾環等。In the present invention, the so-called "3--6 aliphatic heterocyclic ring with 1 or 2 nitrogen atoms in the ring which may have unsaturated bonds" is used as the constituent atom of the ring, and in addition to carbon atoms, it also includes 1 or An aliphatic heterocyclic ring of 3 to 6 members with 2 nitrogen atoms, and is a ring that may have a double bond in the ring. Examples include nitrogen

Ring, diazonium ring or nitrogen ring, etc.

Next, suitable substituents in the general formula (I) will be explained.

啉基、呔

基、

啶基或吡啶并嘧啶基。For suitable Z, it is thienopyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, which may have 1 or 2 substituents each independently selected from the above-mentioned E group,

Linyl, X

base,

Ridinyl or pyridopyrimidinyl.

Another aspect of suitable Z is any one of ^{Z 1} to Z ^{10 described below.}

In the above-mentioned Z ¹ to Z ¹⁰ , W represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a C ₃ -C ₆ cycloalkyl group, (C _1- C ₆ alkyl) amine group or di(C ₁ -C ₆ alkyl) amine group, V represents halogen atom, nitro group, vinyl group, ethynyl group, cyano group, which may be substituted by 1 to 3 halogen atoms C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group which may be substituted by 1 to 3 halogen atoms, C ₃ -C ₆ cycloalkyl group which may be substituted by 1 to 3 halogen atoms, C ₃ -C _6- cycloalkoxy, di(C ₁ -C ₆ alkyl)amino, (C ₁ -C ₆ alkyl)carbonyl or (C ₁ -C ₆ alkoxy)carbonyl.

For suitable Y, it is 4-methoxyphenyl, 3-chlorophenyl, 3-fluoro-4-chlorophenyl, 3-fluoro-4-trifluoromethoxyphenyl, 3-fluoro- 4-Difluoromethoxyphenyl or 3-fluoro-4-methoxyphenyl.

For suitable n ¹ and n ² , both n ¹ and n ² are 1.

For suitable n ³ and n ⁴ , both n ³ and n ⁴ are 2.

For suitable X, it is CF ₂ .

For suitable combinations of Z, Y, n ¹ , n ² , n ³ , n ⁴ , and X, Z represents Z ¹ , Y represents 3-fluoro-4-chlorophenyl, n ¹ and n ^{2 both} represent 1 , N ³ and n ^{4 both} represent 2, and X is CF ₂ .

Another aspect suitable for the present invention is the following general formula (III).

Of formula (III), R ^{7 is} a hydrogen atom or a C ₁ -C ₃ alkoxy, R ⁸ represents an optionally substituted 1 or 2 halogen atoms, C ₁ -C ₃ alkyl group, R ⁹ represents a hydrogen atom or a halogen atom , R ¹⁰ _{represents a halogen atom, or a C 1} -C ₃ alkoxy group which may be substituted by 1 or 2 halogen atoms.

啉鹽、葡萄糖胺鹽、苯基甘胺酸烷基酯鹽、乙二胺鹽、N-甲基還原葡糖胺鹽、胍鹽、二乙基胺鹽、三乙基胺鹽、二環己基胺鹽、N,N’-二苄基乙二胺鹽、氯普魯卡因(chloroprocaine)鹽、普魯卡因鹽、二乙醇胺鹽、N-苄基苯乙基胺鹽、哌

鹽、四甲基銨鹽、參(羥甲基)胺基甲烷鹽的胺鹽；及如甘胺酸鹽、離胺酸鹽、精胺酸鹽、鳥胺酸鹽、麩胺酸鹽、天冬胺酸鹽的胺基酸鹽。In the present invention, "pharmaceutically acceptable salt" refers to a salt that has no significant toxicity and can be used as a pharmaceutical composition. The compound having an acidic substituent can be made into a salt by reacting with a base. Examples include: alkali metal salts such as sodium salt, potassium salt, and lithium salt; alkaline earth metal salts such as calcium salt and magnesium salt; metal salts such as aluminum salt and iron salt; inorganic salts such as ammonium salt; such as tertiary butyl Base amine salt, tertiary octyl amine salt, dibenzyl amine salt,

Phospholine salt, glucamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methyl reduced glucosamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexyl Amine salt, N,N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine

Salt, tetramethylammonium salt, amine salt of ginseng (hydroxymethyl) aminomethane salt; and such as glycinate, lysine, spermine, ornithine, glutamine, and The amino acid salt of winter amine.

A compound having a basic substituent can be reacted with an acid to form a salt. Examples include: hydrogen halides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate, and phosphate; _{C 1} -C ₆ alkyl sulfonates of sulfonate, trifluoromethanesulfonate, and ethanesulfonate; such as benzenesulfonate and arylsulfonate of p-toluenesulfonate; such as acetate, apple Organic acid salts of acid salts, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, adipate, and maleate; and such as glycinate , Lysine, arginine, ornithine, glutamate, aspartate amino acid salt.

The compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof may absorb water molecules and become a hydrate due to being placed in the air or undergoing recrystallization. Such hydrates are also included in the present invention. invention.

The compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof may absorb a certain solvent and become a solvate due to being placed in a solvent or undergoing recrystallization. Such solvate Also included in the present invention.

In addition, under physiological conditions in the living body, the compound is converted into a compound represented by the general formula (I) of the present invention due to a reaction caused by enzymes or gastric acid, that is, it causes enzymatic oxidation, reduction, hydrolysis, etc. to change into Compounds of compounds represented by general formula (I) or compounds that are transformed into compounds represented by general formula (I) by hydrolysis or the like caused by gastric acid, etc., are also included as "medically acceptable prodrug compounds" invention.

With regard to the above-mentioned prodrugs, when there is an amine group in the compound represented by the general formula (I), there can be exemplified compounds in which the amine group is acylated, alkylated, or phosphorylated (for example, the amine group is oxidized, alkylated, or phosphorylated). Decacylation, propylamine carbonylation, pentylamino carbonylation, (5-methyl-2-oxo-1,3-dioxopenten-4-yl) methoxycarbonylation, tetrahydrofuran Compounds such as methylation, pyrrolidinyl methylation, trimethylacetoxymethylation, tertiary butylation, etc.), etc.; when a hydroxyl group is present in the compound represented by the general formula (I), examples include Compounds in which the hydroxyl group is acylated, alkylated, phosphorylated, or borated (for example, the hydroxy group is acetylated, palmitoylated, propionated, trimethyl acetylated, succinylated Compounds such as carbonylation, fumaration, propylamination, dimethylaminomethyl carbonylation, etc.). In addition, in the case where a carboxyl group is present in the compound represented by the general formula (I), a compound in which the carboxyl group is esterified or aminated (for example, the carboxyl group is esterified with ethyl, phenyl esterified, carboxymethyl Esterification, dimethylaminomethyl esterification, trimethylacetoxymethyl esterification, ethoxycarbonyloxyethyl esterification or methyl amidation compounds, etc.).

The prodrug in the present invention can be produced from the compound represented by the general formula (I) by a known method. In addition, the prodrug in the present invention also includes compounds that change into compounds represented by general formula (I) under physiological conditions as described in "Development of Pharmaceuticals", Volume 7, Molecular Design, pp. 163 to 198, published by Guangchuan Bookstore, 1990.

The compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof includes all isomers (diasteres, optical isomers, geometric isomers, rotational isomers, etc.) ).

In the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof, these isomers and mixtures of these isomers are all represented by a single formula, that is, by the general formula (I) To represent. Therefore, the present invention also includes all of these isomers and mixtures of these isomers in any ratio.

The compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof may contain an unnatural ratio of atomic isotopes in one or more of the atoms constituting the compound. In terms of atomic isotopes, for example, deuterium ( ² H), tritium ( ³ H), iodine-125 ( ¹²⁵ I), or carbon-14 ( ¹⁴ C), etc. In addition, the aforementioned compounds can be radioactively labeled by radioisotopes ^{such as tritium (3} H), iodine-125 ( ¹²⁵ I), or carbon-14 ( ^{14 C).} Radiolabeled compounds are useful as therapeutic or preventive agents, research reagents, such as analytical reagents and diagnostic agents, for example, in vivo imaging diagnostic agents. All isotopic variants of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.

As another aspect of the present invention, it is a crystal of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof.

In the present invention, crystalline refers to a solid whose internal structure is three-dimensionally composed of regular repetitions of constituent atoms or molecules. It is different from an amorphous solid or amorphous body that does not have such a regular internal structure. the difference.

In the present invention, crystals include crystals of compounds represented by general formula (I), hydrate crystals of compounds represented by general formula (I), solvate crystals of compounds represented by general formula (I), and general formula ( I) The crystal of the pharmaceutically acceptable salt of the compound represented by the formula (I), the hydrate crystal of the pharmaceutically acceptable salt of the compound represented by the general formula (I), and the pharmaceutically acceptable salt of the compound represented by the general formula (I) The tolerable salt solvate crystallizes.

The hydrate crystals of the present invention can be, for example, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9 or 5.0 hydrate form, and the increase or decrease of hydration water may occur depending on humidity.

In the present invention, the crystalline form of the compound represented by the general formula (I) and its pharmaceutically acceptable salt can be confirmed by observation with a polarizing microscope, powder X-ray crystal analysis, or single crystal X-ray diffraction measurement . Furthermore, it is also possible to specify the type of crystal by comparing it with data based on each index based on the characteristics of the crystal that has been measured in advance. Therefore, according to the preferred aspect of the present invention, the crystals caused by the present invention can be determined to be crystals by this measuring method.

In the present invention, not only the crystals with the same diffraction angle in powder X-ray diffraction, but also the crystals with the same diffraction angle within the range of ±0.2 are also included in the present invention. Generally speaking, there are inherent fluctuations in the peak value due to differences in measuring instruments, samples, and sample preparations, so this is a general practice. This is because the diffraction angle (2θ) of powder X-ray diffraction may have an error within the range of ±0.2, so the value of the above-mentioned diffraction angle must be understood as including a value within the range of about ±0.2.

Crystals of the present invention (hereinafter, referred to as "crystals of present invention example 43", "crystals of present invention example 53", "crystals of present invention example 71", and "crystals of present invention example 72" "Crystal from Example 73 of the Invention", "Crystal from Example 74 of the Invention", "Crystal from Example 75 of the Invention", "Crystal from Example 76 of the Invention", "Crystal from Example 77 of the Invention" "Crystal from Example 78 of the Invention", "Crystal from Example 79 of the Invention", "Crystal from Example 80 of the Invention", "Crystal from Example 81 of the Invention", "Crystal from Example 83 of the Invention" , "Crystal from Example 84 of the Invention", "Crystal from Example 85 of the Invention", "Crystal from Example 86 of the Invention", "Crystal from Example 87 of the Invention", "Crystal from Example 88 of the Invention" , "Crystals of Example 89 of the present invention" and "Crystals of Example 90 of the present invention") The crystals can be stably supplied as raw materials used in pharmaceutical manufacturing, and are excellent in hygroscopicity or stability. In particular, these crystal forms can be distinguished by powder X-ray diffraction.

In the present invention, "cancer" means all malignant tumors.

Cancer can be classified into "solid cancer" and "blood cancer". Solid cancer can be classified into "epithelial cell carcinoma" and "non-epithelial cell carcinoma". Epithelial cell carcinoma is cancer that occurs from epithelial cells, and examples thereof include lung cancer, stomach cancer, liver cancer, kidney cancer, prostate cancer, pancreatic cancer, colorectal cancer, breast cancer, and ovarian cancer. Non-epithelial cell carcinoma is cancer that occurs from non-epithelial cells such as bone or muscle, and examples thereof include osteosarcoma, chondrosarcoma, and rhabdomyosarcoma. Hematological cancers are cancers that occur from hematopoietic organs, and can be classified, for example, into malignant lymphoma, leukemia, multiple myeloma, and the like.

Malignant lymphoma, for example, can be classified into Hodgkin's lymphoma and non-Hodgkin's lymphoma. Non-Hodgkin’s lymphoma includes, for example: Mantle cell lymphoma (Mantle cell lymphoma, also known as MCL), Diffuse large B-cell lymphoma (also known as DLBCL), adult T cell Leukemia/lymphoma (Adult T-cell leukemia/lymphoma, also known as ATLL), non-specific peripheral T-cell lymphoma (NOS, also known as PTCL), etc.

Leukemia can be classified into, for example: Acute myelogenous leukemia (also known as AML), chronic myelogenous leukemia (also known as CML), acute lymphoid leukemia (also known as ALL) ), chronic lymphoid leukemia (chronic lymphoid leukemia, also known as CLL).

In this specification, "treatment" and its derivatives mean the alleviation, alleviation and/or delay of deterioration of the clinical symptoms of cancer in patients with cancer.

The compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof can be used in combination with other antitumor agents. For example: alkylating agents, metabolic antagonists, anti-tumor antibiotics, anti-tumor plant ingredients, BRM (biological reactive control substances), hormones, vitamins, anti-tumor antibodies, molecular target drugs, other anti-tumor剂 etc.

系烷基化劑；二溴甘露醇(dibromomannitol)或二溴半乳糖醇(dibromodulcitol)等之環氧化物系烷基化劑；卡莫司汀(carmustine)、洛莫司丁(lomustine)、司莫司汀(semustine)、鹽酸尼莫司汀(nimustine hydrochloride)、鏈脲黴素(streptozocin)、氯脲黴素(chlorozotocin)或雷莫司汀(ranimustine)等之亞硝基脲系烷基化劑；白消安(busulfan)、甲苯磺酸英丙舒凡(improsulfan tosilate)或達卡巴仁(dacarbazine)等。More specifically, as the alkylating agent, for example, alkylating agents such as nitrogen mustard, nitrogen mustard N-oxide or chlorambucil; carboquone Or thiotepa and other nitrogen

Alkylating agent; epoxide-based alkylating agent such as dibromomannitol or dibromodulcitol; carmustine, lomustine, and Alkylation of nitrosourea such as semustine, nimustine hydrochloride, streptozocin, chlorozotocin or ranimustine Agents; busulfan (busulfan), improsulfan tosilate (improsulfan tosilate) or dacarbazine (dacarbazine) and so on.

As various metabolic antagonists, for example, purine metabolism antagonists such as 6-mercaptopurine, 6-thioguanine or thioinosine; fluorouracil, tegafur, tegafur-uracil ( Pyrimidine metabolism antagonists such as tegafur-uracil, carmofur, doxifluridine, broxuridine, cytarabine or enocitabin; Folate metabolism antagonists such as methotrexate or trimetrexate.

Examples of antitumor antibiotics include: mitomycin C, bleomycin, peplomycin, daunorubicin, aclarubicin ), doxorubicin, pirarubicin, THP-adriamycin, 4'-epidoxorubicin or epirubicin ) And other anthracyclines (anthracycline) are antibiotic antitumor agents; chromomycin A3 (chromomycin A3) or actinomycin D (actinomycin D) and so on.

Examples of anti-tumor plant ingredients include: vindesine (vindesine), vincristine (vincristine) or vinblastine (vinblastine) and other vinca alkaloids (vinca alkaloid); paclitaxel (paclitaxel), poly Taxanes such as docetaxel; or epipodophyllotoxin such as etoposide or teniposide.

Examples of BRM include tumor necrosis factor and indomethacin.

Examples of hormones include hydrocortisone, dexamethasone, methylprednisolone, prednisolone, prasterone, Betamethasone, triamcinolone, oxymetholone, nandrolone, metenolone, fosfestrol, ethinyl estradiol), chlormadinone or medroxyprogesterone, etc.

Examples of vitamins include vitamin C, vitamin A, and the like.

Examples of anti-tumor antibodies and molecular target drugs include: trastuzumab, rituximab, cetuximab, and nimotuzumab , Denosumab (denosumab), bevacizumab (bevacizumab), infliximab (infliximab), imatinib (imatinib), gefitinib (gefitinib), erlotinib (erlotinib), Shu Nitinib (sunitinib), lapatinib (lapatinib), sorafenib (sorafenib), dasatinib (dasatinib), nilotinib (nilotinib), vemurafenib (vemurafenib) or osimertin Ni (osimertinib) and so on.

As other anti-tumor agents, for example, cisplatin, carboplatin, oxaliplatin, tamoxifen, camptothecin, and ephramide can be cited. (ifosfamide), cyclophosphamide, melphalan, L-asparaginase, aceglatone, schizophyllan, Pipibanil, procarbazine, pipobroman, neocarzinostatin, hydroxyurea, ubenimex or krestin, etc.

The compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof can be administered in various forms. The administration form includes, for example, oral administration using tablets, capsules, granules, emulsions, pills, powders, syrups (liquids), etc.; or injections (intravenous, intramuscular) , Subcutaneous or intraperitoneal administration), intravenous drops, suppositories (rectal administration) and other parenteral administration. These various preparations can be generally used in the technical field of pharmaceutical preparations such as excipients, binders, disintegrating powders, lubricants, flavoring agents, dissolution aids, suspending agents, coating agents, etc., as the main drug. The auxiliary agent used is formulated.

In the case of tablet use, as the carrier, for example: lactose, sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and other excipients; water, Binders such as ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, etc.; dried starch , Sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, etc. Powders; disintegration inhibitors for sugar, stearin, cocoa butter, hydrogenated oil, etc.; absorption enhancers for quaternary ammonium salts, sodium lauryl sulfate, etc.; humectants for glycerin, starch, etc.; Adsorbents for starch, lactose, kaolin, bentonite, colloidal silicic acid, etc.; lubricants for purified talc, stearate, boric acid powder, polyethylene glycol, etc. Moreover, it can be made into tablets with usual skins as necessary, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double-layer tablets, multi-layer tablets, and the like.

When used as a pill, as a carrier, for example, excipients such as glucose, lactose, cocoa butter, starch, hardened vegetable oil, kaolin, talc, etc.; gum arabic powder, tragacanth powder, gelatin Binders such as, ethanol, etc.; disintegrating powders such as laminarum, agar, etc.

When used as a suppository, those well-known in this field can be widely used as a carrier, and examples thereof include polyethylene glycol, cocoa butter, higher alcohols, higher alcohol esters, gelatin, and semi-synthetic glycerides.

When used as an injection, a liquid, emulsion or suspension can be used. These liquids, emulsions or suspensions are preferably sterilized and isotonic with blood. The solvent used in the manufacture of these liquids, emulsions or suspensions is not particularly limited as long as it can be used as a medical diluent, and examples include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, Polyoxyisostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. In addition, in this case, the preparation may include salt, glucose, or glycerin in an amount sufficient to prepare an isotonic solution, and may also include usual dissolution aids, buffers, analgesics, and the like.

In addition, the above-mentioned preparations may contain colorants, preservatives, fragrances, flavors, sweeteners, etc., as necessary, and may also contain other medicines.

The amount of the compound contained in the above formulation is not particularly limited, and can be appropriately selected from a wide range, but usually, the total composition contains 0.5 to 70% by weight, preferably 1 to 30% by weight.

The dosage varies according to the symptoms and age of patients (warm-blooded animals, especially humans), but in the case of oral administration, the upper limit is 2000 mg (preferably 100 mg) per day for adults. The lower limit is 0.1 mg (preferably 1 mg, more preferably 10 mg), and it is hoped that it will be administered 1 to 6 times per day in response to symptoms.

Next, a representative production method of the compound represented by the general formula (I) will be described. The compound of the present invention can be produced by various production methods, and the production method shown below is an example, and the present invention should not be limited to these.

The compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof can be produced by utilizing the characteristics based on the type of its basic skeleton or substituents, and applying various well-known production methods. As for the well-known methods, for example, there are methods described in "ORGANIC FUNCTIONAL GROUP PREPARATIONS", 2nd edition, ACADEMIC PRESS, INC. 1989; "Comprehensive Organic Transformations", VCH Publishers Inc. 1989, etc.

At this time, depending on the type of functional group present in the compound, there are cases where the following is effective in the production technology: at the stage of the raw material or intermediate, the functional group is pre-protected with an appropriate protective group, or replaced with a protective group in advance. It is easily converted into the functional group.

For such functional groups, for example, there are amine groups, hydroxyl groups, and carboxyl groups. For their protecting groups, for example, they are described in TW Greene and PG Wuts, "Greene's Protective Groups in Organic Synthesis", 4th edition, Protective base of John Wiley & Sons, Inc. 2006.

The protecting group or a group that can be easily converted into the functional group may be used as long as it is appropriately selected in accordance with the respective reaction conditions of the production method for the compound production.

According to this method, after introducing the group and carrying out the reaction, the protecting group can be removed as necessary, or converted into the desired group, thereby obtaining the desired compound.

In addition, the compound prodrug system can be produced by introducing a specific group at the stage of the raw material or intermediate, or using the obtained compound, and reacting, similarly to the above-mentioned protective group. The reaction for producing the prodrug can be carried out by applying a method known to a person having ordinary knowledge in the art, such as ordinary esterification, amination, dehydration, and hydrogenation.

[Production Method 1] Among the compounds represented by the formula (I), the compound 1a shown below can be produced by, for example, the following method. X, Y, R ¹ , n ¹ , n ² , n ³ and n ⁴ are synonymous with the definitions in the specification.

啉、吡啶、2,6-二甲吡啶、二氮雜雙環[5.4.0]十一-7-烯等，就無機鹼而言，例如碳酸鉀、碳酸鈉、碳酸氫鈉等)之存在下，使用適當的縮合劑(例如N,N´-二環己基碳二亞胺、1-乙基-3-(3-二甲基胺基丙基)碳二亞胺、六氟磷酸N-[1-(氰基-2-乙氧基-2-側氧亞乙基胺基氧基)二甲基胺基(

啉基)]脲鎓(N-[1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino (morpholino)]uronium hexafluorophosphate)、六氟磷酸3-氧化1-[雙(二甲基胺基)亞甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo [4,5-b]pyridinium 3-oxide hexafluorophosphate)、1,1´-羰基二咪唑等)使化合物2a與化合物3a縮合。反應可於-78℃至反應所使用的溶劑之沸點為止的範圍下實施，但較佳為0℃至50℃。又，因應需要可添加1-羥基苯并三唑、N-羥基琥珀醯亞胺、1-羥基-7-氮雜苯并三唑等作為反應促進劑。The conversion from compound 2a to compound 1a can be carried out by using an appropriate solvent that does not affect the reaction (such as N,N-dimethylformamide, N,N-dimethylacetamide, etc.) , Tetrahydrofuran, dimethyl sulfide, dichloromethane, 1,2-dichloroethane, chloroform, 1,2-dimethoxyethane, acetonitrile, etc., or a mixed solvent of these), in a suitable Base (for organic bases, such as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, N-methyl

In the presence of morpholine, pyridine, 2,6-lutidine, diazabicyclo[5.4.0]undec-7-ene, etc., in terms of inorganic bases, such as potassium carbonate, sodium carbonate, sodium bicarbonate, etc.) , Use an appropriate condensing agent (such as N,N´-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, hexafluorophosphate N-[ 1-(cyano-2-ethoxy-2-oxoethyleneaminooxy) dimethylamino (

(N-[1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino (morpholino)]uronium hexafluorophosphate), hexafluorophosphate 3-oxide 1-[bis(dimethylamino) Methyl]-1H-1,2,3-triazolo[4,5-b]pyridinium (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo [4,5-b ]pyridinium 3-oxide hexafluorophosphate), 1,1´-carbonyldiimidazole, etc.) to condense compound 2a with compound 3a. The reaction can be carried out in the range of -78°C to the boiling point of the solvent used in the reaction, but it is preferably 0°C to 50°C. In addition, 1-hydroxybenzotriazole, N-hydroxysuccinimide, 1-hydroxy-7-azabenzotriazole, etc. can be added as a reaction accelerator as required.

啉、吡啶、2,6-二甲吡啶、二氮雜雙環[5.4.0]十一-7-烯等，就無機鹼而言，例如碳酸鉀、碳酸鈉、碳酸氫鈉等)之存在下反應而獲得化合物1a。反應可於-78℃至反應所使用的溶劑之沸點為止的範圍下實施，但較佳於-10℃至室溫附近下實施。 為製造原料的化合物2a，例如，可按照參考例記載之方法而合成。為製造原料的化合物3a，可使用市售者，或例如可按照參考例記載之方法而合成。Also, as another method, an appropriate solvent that does not affect the reaction (for example, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, dimethylsulfene, In dichloromethane, 1,2-dichloroethane, chloroform, 1,2-dimethoxyethane, acetonitrile, etc., or a mixed solvent of these), the carboxylic acid halide compound of compound 2a and compound 3a is mixed in Appropriate base (for organic bases, such as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, N-methyl

In the presence of morpholine, pyridine, 2,6-lutidine, diazabicyclo[5.4.0]undec-7-ene, etc., in terms of inorganic bases, such as potassium carbonate, sodium carbonate, sodium bicarbonate, etc.) The reaction yields compound 1a. The reaction can be carried out in the range of -78°C to the boiling point of the solvent used in the reaction, but it is preferably carried out at -10°C to around room temperature. To produce compound 2a as a raw material, for example, it can be synthesized according to the method described in the reference example. To produce compound 3a as a raw material, a commercially available product can be used, or it can be synthesized, for example, according to the method described in the reference example.

[Production Method 2] Among the compounds represented by the formula (I), the compound 1b shown below can be produced, for example, by the following method. X, Y, n ¹ , n ² , n ³ and n ⁴ are synonymous with the definitions in the specification. R ^a represents a 4 to 6 of the 1 or 2 nitrogen atoms in the aliphatic heterocyclic ring group, W represents a halogen atom, a cyano, ethynyl or a C ₁ -C ₆ alkyl.

啉、吡啶、2,6-二甲吡啶、二氮雜雙環[5.4.0]十一-7-烯等，就無機鹼而言，例如碳酸鉀、碳酸鈉、碳酸氫鈉等)之存在下，使化合物2a及化合物4a與1,1´-羰基二咪唑、碳酸雙(三氯甲基)酯等反應。反應可於-78℃至反應所使用的溶劑之沸點為止的範圍下實施，但較佳於0℃至100℃下實施。化合物4a，例如可使用由東京化成工業、Enamine Ltd.等販售的化合物。The conversion from compound 2a to compound 1b can be carried out by using an appropriate solvent that does not affect the reaction (such as N-methyl-2-pyrrolidone, N,N-dimethylformamide) , N,N-dimethylacetamide, tetrahydrofuran, dimethyl sulfide, dichloromethane, chloroform, etc., or a mixed solvent of these, in an appropriate base (for organic bases, such as triethyl Amine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, N-methyl

In the presence of morpholine, pyridine, 2,6-lutidine, diazabicyclo[5.4.0]undec-7-ene, etc., in terms of inorganic bases, such as potassium carbonate, sodium carbonate, sodium bicarbonate, etc.) , Make compound 2a and compound 4a react with 1,1´-carbonyldiimidazole, bis(trichloromethyl) carbonate, etc. The reaction can be carried out in the range of -78°C to the boiling point of the solvent used in the reaction, but it is preferably carried out at 0°C to 100°C. As the compound 4a, for example, a compound sold by Tokyo Chemical Industry, Enamine Ltd., etc. can be used.

[Production Method 3] Among the compounds represented by the formula (1), the compound 1c shown below can be produced, for example, by the following method. X, Y, Z, n ¹ , n ² , n ³ and n ⁴ are synonymous with the definitions in the specification. Hal represents a halogen atom such as a chlorine atom, a bromine atom, or an iodine atom.

啉、吡啶、2,6-二甲吡啶、二氮雜雙環[5.4.0]十一-7-烯之有機鹼、或碳酸鉀、碳酸鈉、碳酸氫鈉等之無機鹼)處理。反應可於-30℃至反應所使用的溶劑之沸點為止的範圍下實施，但較佳於室溫至反應所使用的溶劑之沸點下實施。The conversion from compound 2a to compound 1c can be carried out by adding the compound in an appropriate solvent that does not affect the reaction (for example, methanol, ethanol, 2-propanol, etc., or a mixed solvent of these) 2a and compound 5a are combined with an appropriate base (e.g., triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, N-methyl

Phytoline, pyridine, 2,6-lutidine, diazabicyclo[5.4.0]undec-7-ene organic base, or potassium carbonate, sodium carbonate, sodium bicarbonate and other inorganic bases). The reaction can be carried out at a temperature ranging from -30°C to the boiling point of the solvent used in the reaction, but is preferably carried out at room temperature to the boiling point of the solvent used in the reaction.

啉、吡啶、2,6-二甲吡啶、二氮雜雙環[5.4.0]十一-7-烯之有機鹼、或碳酸鉀、碳酸鈉、碳酸氫鈉等之無機鹼)存在下，於封管中或微波照射下處理化合物2a及化合物5a。於封管中或微波照射下的反應時間較佳為10分鐘至72小時，更佳為30分鐘至24小時。化合物5a，可使用例如由東京化成工業、Sigma Aldrich等販售的化合物，或例如可按照參考例記載之方法而合成。As another method, it can also be carried out by the following: in an appropriate solvent that does not affect the reaction (for example, methanol, ethanol, 2-propanol, etc., or a mixed solvent of these), in an appropriate base ( For example, such as triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, N-methyl

In the presence of phylloline, pyridine, 2,6-lutidine, diazabicyclo[5.4.0]undec-7-ene organic base, or potassium carbonate, sodium carbonate, sodium bicarbonate, etc., in the presence of Treat compound 2a and compound 5a in a sealed tube or under microwave irradiation. The reaction time in a sealed tube or under microwave irradiation is preferably 10 minutes to 72 hours, more preferably 30 minutes to 24 hours. For compound 5a, for example, a compound sold by Tokyo Chemical Industry, Sigma Aldrich, etc. can be used, or it can be synthesized, for example, according to the method described in the Reference Examples.

The compound produced by the above method can be isolated and purified by well-known methods, such as extraction, precipitation, distillation, chromatography, staged crystallization, recrystallization, and the like. In addition, in the case where the compound or the intermediate of the production has asymmetric carbon, there are enantiomers. These enantiomers can be isolated and purified by common methods such as segmented crystallization (salt separation) or column chromatography. The conditions for separating the mirror isomer from the racemate can be referred to, for example, "Enantiomers, Racemates and Resolution", J. Jacques, A. Collet and SH Wilen, John Wiley & Sons, Inc., New York, 1981 . [Example]

Hereinafter, reference examples, examples, and test examples are cited to further explain the present invention in detail, but the scope of the present invention is not limited to these, and these are not limitedly interpreted in any sense. In addition, in this specification, reagents, solvents, and starting materials that are not specifically described can be easily obtained from commercially available sources.

The extraction in the column chromatography of the reference example and the example was performed under observation using TLC (Thin Layer Chromatography). For TLC observation, use the silica gel 60F ₂₅₄ or silica gel 60NH ₂ F ₂₅₄ S manufactured by Merck as the TLC plate, use the solvent used as the extraction solvent in column chromatography as the developing solvent, and use the UV detector as the detection law. The silica gel for the column is the same as the silica gel SK-85 made by Merck (230-400 mesh) or Fuji Silysia Chemical's Chromatorex NH (200-350 mesh). In addition to the usual column chromatography, it is also appropriate to use the automatic purification device (Purif) of SHOKO SCIENCE company or the automatic purification device of Biotage company (HORIZON, SP1 or Isolera), and the Purif-Pack series made by SHOKO SCIENCE company are appropriately used. , Biotage's SNAP box series are used as its tube cartridges. The extraction solvent is used in each reference example and the solvent specified in the examples. In addition, the abbreviations used in the reference examples and examples have the following meanings. mg: milligrams, g: grams, μl: microliters, ml: milliliters, L: liters, MHz: megahertz.

In the following reference examples and examples, nuclear magnetic resonance (hereafter, ¹ H NMR: 400MHz) spectroscopy is based on tetramethylsilane as a standard substance, and the chemical shift value is recorded as a δ value (ppm). In the split pattern system, the singlet is represented by s, the doublet is represented by d, the triplet is represented by t, the quartet is represented by q, the multiplet is represented by m, and the broad peak is represented by br.

In the following examples, Bruker D8 Discover is used for powder X-ray diffraction, and the X-ray generation conditions are set to 40kV, 40mA, at a wavelength of 1.54Å (copper Kα line), a scanning speed of 10°/min, and a scanning range of 5-40 °, Measured under the condition of 0.05° sampling width. Use a glass sample holder as the sample holder. Regarding the powder X-ray diffraction of Example 79, Example 84, Example 85 and Example 90, using Rigaku SmartLab, the X-ray generation conditions were set to 45kV, 200mA, and the wavelength was 1.54Å (Kα rays of copper), scanning The speed is 20°/min, the scanning range is 3-40°, and the sampling width is 0.01°. Use a non-reflective sample holder as the sample holder.

The abbreviations used in the following reference examples and examples have the following meanings. CDCl ₃ : deuterated chloroform, CD ₃ OD: deuterated methanol, DMSO-d ₆ : deuterated dimethylsulfene. In the reference examples and examples, unless otherwise specified, hexane means n-hexane.

[Reference Example B-1] 4-(Difluoromethyl)-3-fluorobenzaldehyde

[Step 1] Dissolve 4-bromo-2-fluorobenzaldehyde (2.51g, 12.4mmol) in dichloromethane (80ml) under a nitrogen atmosphere with 4-bromo-1-difluoromethyl-2-fluorobenzene, and cool At -15°C, bis(2-methoxyethyl)aminosulfur trifluoride (5.31ml, 24.7mmol) was added. After stirring the reaction solution at room temperature for 15 hours, slowly add saturated sodium bicarbonate water under ice cooling, and extract with dichloromethane after the bubbles disappeared. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=5:95-70:30) to obtain the title compound (2.08 g, 9.24 mmol, 75%). ¹ H-NMR (CDCl ₃ ) δ: 7.51-7.44 (1H, m), 7.43-7.39 (1H, m), 7.36-7.31 (1H, m), 6.85 (1H, t, J = 55.0 Hz).

[Step 2] 4-Difluoromethyl-3-fluorobenzaldehyde The compound (6.07g, 27.0mmol) obtained in the above step 1 was dissolved in N,N-dimethylformamide (120ml), and sodium formate ( 2.94g, 43.2mmol), triphenylphosphine (708mg, 2.70mmol), after nitrogen replacement, degassed using ultrasound. After replacing with carbon monoxide, bis(triphenylphosphine) palladium(II) dichloride (1.89 g, 2.70 mmol) was added, replaced with carbon monoxide again, and stirred at 110°C for 4 hours. The reaction solution was returned to room temperature, and after diluting with ethyl acetate, water and saturated brine were added, followed by extraction with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=3:97-20:80) to obtain the title compound (610 mg, 3.50 mmol, 13%). ¹ H-NMR (CDCl ₃ ) δ: 10.04-10.03 (1H, m), 7.83-7.76 (2H, m), 7.67-7.63 (1H, m), 6.94 (1H, t, J = 54.6 Hz).

[Reference Example B-2] 1-(4-Difluoromethoxy-3-fluorophenyl)methylamine

[Step 1] 4-Difluoromethoxy-3-fluorobenzonitrile Dissolve 3-fluoro-4-hydroxybenzonitrile (6.20g, 45.2mmol) in N,N-dimethylformamide (62ml ), water (6.2ml), add cesium carbonate (20.6g, 63.2mmol) and sodium chlorodifluoroacetate (15.9g, 104mmol), and stir at 110°C for 4.5 hours. After cooling to room temperature, toluene and water were added to perform liquid separation operation. The organic layer was washed with water and saturated brine, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-40:60) to obtain the title compound (7.87 g, 42.1 mmol, 93%) . ¹ H-NMR (CDCl ₃ ) δ: 7.53-7.47 (2H, m), 7.41-7.35 (1H, m), 6.65 (1H, t, J = 72.1 Hz).

[Step 2] [(4-Difluoromethoxy-3-fluorophenyl)methyl] carbamic acid tertiary butyl ester The compound (7.87 g, 42.1 mmol) obtained in the above step 1 was dissolved in methanol (58 ml) Add a methanol (19 ml) solution of di-tertiary butyl dicarbonate (20.2 g, 92.6 mmol) and nickel chloride hexahydrate (1.00 g, 4.21 mmol) and stir. Under ice cooling, sodium borohydride (9.60 g, 250 mmol) was added to the reaction solution 4 times. Methanol (16 ml) was added, and the mixture was stirred at room temperature for 17 hours. Diethylenetriamine (10.0ml, 92.6mmol) and methanol (16ml) were added to the reaction solution and stirred for 1 hour. After the solvent was distilled off under reduced pressure, saturated sodium bicarbonate water and ethyl acetate were added and stirred for 1 hour. The liquid separation operation was performed, and the organic layer was washed with saturated sodium bicarbonate water and saturated brine, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-50:50) to obtain the title compound (9.74g, 33.4mmol, 80%) . ¹ H-NMR (CDCl ₃ ) δ: 7.22-7.16 (1H, m), 7.14-7.09 (1H, m), 7.06-7.02 (1H, m), 6.53 (1H, t, J = 73.6 Hz), 4.90 (1H, br s), 4.32-4.26 (2H, m), 1.46 (9H, s).

烷(11ml)，冰冷下，添加4N鹽酸/1,4-二

烷溶液(33ml)，於室溫攪拌1小時。於反應液中添加二異丙基醚(88ml)，攪拌30分鐘。濾取析出的固體，減壓下乾燥。將獲得的固體懸浮於乙酸乙酯，冰冷下，添加飽和碳酸氫鈉水而調整為鹼性。分液操作後，將有機層以飽和食鹽水洗淨。以無水硫酸鈉乾燥後，減壓下餾除溶劑，獲得標題化合物(5.95g，31.1mmol，93%)。¹ H-NMR (CDCl₃ ) δ : 7.23-7.15 (2H, m), 7.11-7.05 (1H, m), 6.53 (1H, t, J = 73.6 Hz), 3.87 (2H, s), 1.49 (2H, br s).[Step 3] 1-(4-Difluoromethoxy-3-fluorophenyl)methylamine The compound (9.74 g, 33.4 mmol) obtained in the above step 2 was dissolved in 1,4-Di

Alkane (11ml), under ice cooling, add 4N hydrochloric acid/1,4-bis

The alkane solution (33ml) was stirred at room temperature for 1 hour. Diisopropyl ether (88 ml) was added to the reaction liquid, and the mixture was stirred for 30 minutes. The precipitated solid was collected by filtration and dried under reduced pressure. The obtained solid was suspended in ethyl acetate, and under ice cooling, saturated sodium bicarbonate water was added to adjust the alkalinity. After the liquid separation operation, the organic layer was washed with saturated brine. After drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (5.95 g, 31.1 mmol, 93%). ¹ H-NMR (CDCl ₃ ) δ: 7.23-7.15 (2H, m), 7.11-7.05 (1H, m), 6.53 (1H, t, J = 73.6 Hz), 3.87 (2H, s), 1.49 (2H) , br s).

[Reference Example B-3] 3-Fluoro-4-[( ² H ₃ )methoxy]benzaldehyde

[Step 1] 3-Fluoro-4-[( ² H ₃ )methoxy]benzaldehyde Dissolve 3-fluoro-4-hydroxybenzaldehyde (5.00g, 35.7mmol) in N,N-dimethylformaldehyde Amine (100 ml), iodine ( ² H ₃ ) methane (6.00 g, 41.4 mmol) and potassium carbonate (7.40 g, 53.5 mmol) were added, and the mixture was stirred at room temperature for 4 days. The reaction solution was filtered to remove insoluble materials, water and saturated brine were added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=95:5-60:40) to obtain the title compound (5.33 g, 33.9 mmol, 95%). ¹ H-NMR (CDCl ₃ ) δ: 9.88-9.85 (1H, m), 7.69-7.59 (2H, m), 7.11-7.05 (1H, m).

[Reference Example C-1] 4,4-Difluoro-1-{[(2,2,2-trichloroethoxy)carbonyl]amino}cyclohexane-1-carboxylic acid

[Step 1] 8,8-Difluoro-1,3-diazaspiro[4,5]decane-2,4-dione Dissolve ammonium carbonate (85.3g, 888mmol) in water (1L) and add After sodium cyanide (9.13 g, 181 mmol), 4,4-difluorocyclohexanone (20.0 g, 145 mmol) was added, and the mixture was stirred at 70°C for 15 hours. The reaction solution was ice-cooled and stirred for a while, and the resulting solid was collected by filtration to obtain the title compound (28.6 g, 140 mmol, 97%). ¹ H-NMR (DMSO-d ₆ ) δ: 10.77 (1H, s), 8.53 (1H, s), 1.95-2.15 (4H, m), 1.80-1.90 (2H, m), 1.69-1.77 (2H, m).

烷(73ml)而攪拌。一邊冷卻至-5℃一邊同時滴下氯甲酸2,2,2-三氯乙酯(14.1ml，105mmol)之1,4-二

烷(105ml)溶液及1N氫氧化鈉水溶液(105ml)，並於室溫使其攪拌36小時。冰冷下，添加1N氫氧化鈉水溶液(30ml)而將液性調整至pH10附近，以二乙基醚洗淨。冰冷下，添加2N鹽酸水溶液而將液性調整至pH5附近，以乙酸乙酯萃取。以飽和食鹽水洗淨後，以無水硫酸鈉乾燥。減壓下餾除溶劑，獲得標題化合物(22.8g，64.3mmol，92%)。¹ H-NMR (CDCl₃ ) δ : 7.26 (1H, s), 5.31-5.26 (1H, br s), 4.75 (2H, s), 2.30-2.22 (4H, m), 2.20-2.06 (2H, m), 2.04-1.87 (2H, m).[Step 2] 4,4-Difluoro-1-{[(2,2,2-trichloroethoxy)carbonyl]amino}cyclohexane-1-carboxylic acid obtained in step 1 above (14.3 g, 69.9 mmol) was suspended in 8N sodium hydroxide aqueous solution (80ml), heated to 120°C and stirred for 18 hours. The reaction liquid was ice-cooled, and a 5N hydrochloric acid aqueous solution (128 ml) was added and neutralized to obtain a suspension. In the obtained suspension, under ice cooling, 4N sodium hydroxide aqueous solution (17.5ml, 69.9mmol) and 1,4-bis

Alkane (73ml) while stirring. While cooling to -5°C, drop 1,4-bis of 2,2,2-trichloroethyl chloroformate (14.1ml, 105mmol) at the same time

A solution of alkane (105ml) and a 1N aqueous sodium hydroxide solution (105ml) were stirred at room temperature for 36 hours. Under ice cooling, a 1N sodium hydroxide aqueous solution (30 ml) was added to adjust the liquidity to around 10 pH, and washed with diethyl ether. Under ice cooling, a 2N aqueous hydrochloric acid solution was added to adjust the liquidity to around pH 5, and the mixture was extracted with ethyl acetate. After washing with saturated brine, it was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (22.8 g, 64.3 mmol, 92%). ¹ H-NMR (CDCl ₃ ) δ: 7.26 (1H, s), 5.31-5.26 (1H, br s), 4.75 (2H, s), 2.30-2.22 (4H, m), 2.20-2.06 (2H, m ), 2.04-1.87 (2H, m).

[Reference Example C-2] (1S)-1-[(tertiary butoxycarbonyl)amino]-3,3-difluorocyclopentanecarboxylic acid

呃(264mg，0.221mmol)、經脫氣及氬氣置換的脫水甲苯(25ml)之混合物，於氬氣環境下，於室溫攪拌2小時。添加聚甲基氫矽氧烷(polymethylhydrosiloxane) (2.66ml)，並於室溫攪拌1小時。於室溫，將3-({[三級丁基(二甲基)矽基]氧基}甲基)環戊-2-烯-1-酮(依Tetrahedron: Asymmetry, 2013, 24, 449-456.記載之方法而合成)(5.01g，22.1mmol)之經脫氣及氬氣置換的脫水甲苯(30ml)溶液，使用套管而滴下，於相同溫度下攪拌3小時。於反應混合物中添加四氫呋喃(25ml)後，於水浴添加氫氧化鈉(3.01g，75.3mmol)之水(25ml)溶液，於室溫攪拌2小時。將反應混合物注入水中，以二乙基醚萃取。將有機層依序以水、飽和食鹽水洗淨，以無水硫酸鈉乾燥。減壓下餾除溶劑，將獲得的殘留物以矽膠管柱層析(乙酸乙酯-己烷)純化，獲得標題化合物(3.49g，15.3mmol，69%)。¹ H-NMR (CDCl₃ ) δ : 3.65-3.62 (2H, m), 2.47-2.25 (3H, m), 2.23-2.00 (3H, m), 1.82-1.71 (1H, m), 0.89 (9H, s), 0.06-0.03 (6H, m).[Step 1] 3-({[Tributyl(dimethyl)silyl]oxy}methyl)cyclopent-2-en-1-one copper(II) acetate monohydrate (45.4mg, 0.221mmol), (R)-(-)-5,5´-bis[bis(3,5-di-tertiarybutyl-4-methoxyphenyl)phosphino]-4,4´-bis -1,3-benzodi

A mixture of (264 mg, 0.221 mmol), degassed and argon-replaced dehydrated toluene (25 ml), stirred at room temperature for 2 hours under argon atmosphere. Add polymethylhydrosiloxane (2.66ml) and stir at room temperature for 1 hour. At room temperature, the 3-({[tertiary butyl(dimethyl)silyl]oxy}methyl)cyclopent-2-en-1-one (according to Tetrahedron: Asymmetry, 2013, 24, 449- 456. Degassed and argon-replaced dehydrated toluene (30 ml) solution synthesized by the method described in (5.01 g, 22.1 mmol) was dropped using a cannula, and stirred at the same temperature for 3 hours. After adding tetrahydrofuran (25 ml) to the reaction mixture, a water (25 ml) solution of sodium hydroxide (3.01 g, 75.3 mmol) was added to a water bath, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with diethyl ether. The organic layer was washed sequentially with water and saturated brine, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (3.49 g, 15.3 mmol, 69%). ¹ H-NMR (CDCl ₃ ) δ: 3.65-3.62 (2H, m), 2.47-2.25 (3H, m), 2.23-2.00 (3H, m), 1.82-1.71 (1H, m), 0.89 (9H, s), 0.06-0.03 (6H, m).

[Step 2] (3R)-3-(Hydroxymethyl)cyclopentanone was added to the tetrahydrofuran (50ml) solution of the compound (3.31g, 14.5mmol) obtained in step 1 above, and tetrabutyl fluoride was added at 0°C Ammonium (1.00mol/L tetrahydrofuran solution) (17.4ml, 17.4mmol), and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (1.63 g, 14.3 mmol, 99%). ¹ H-NMR (CDCl ₃ ) δ: 3.76-3.64 (2H, m), 2.52-2.28 (3H, m), 2.27-2.10 (2H, m), 2.08-1.97 (1H, m), 1.80-1.68 ( 1H, m), 1.57-1.46 (1H, m).

[Step 3] (3R)-3-{[(Benzyloxy)methoxy]methyl}cyclopentanone in the compound obtained in step 2 above (1.63g, 14.3mmol) in dehydrated dichloromethane (50ml ) To the solution, add benzyl chloromethyl ether (2.97ml, 21.4mmol) and N,N-diisopropylethylamine (6.11ml, 35.7mmol) at 0°C, and stir at room temperature for 16 hours. At 0°C, benzyl chloromethyl ether (990 μl, 7.14 mmol) and N,N-diisopropylethylamine (2.44 ml, 14.3 mmol) were further added, and the mixture was stirred at room temperature for 3 hours. After adding ice, the reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (3.25 g, 13.9 mmol, 97%). ¹ H-NMR (CDCl ₃ ) δ: 7.39-7.27 (5H, m), 4.77 (2H, s), 4.60 (2H, s), 3.63-3.59 (2H, m), 2.57-2.46 (1H, m) , 2.43-2.27 (2H, m), 2.25-2.10 (2H, m), 2.07-1.98 (1H, m), 1.79-1.68 (1H, m).

[Step 4] [({[(1R)-3,3-Difluorocyclopentyl]methoxy}methoxy)methyl]benzene in the compound (3.25g, 13.9mmol) obtained in the above step 3 To the dichloromethane (45ml) solution, slowly add (diethylamino)sulfur trifluoride (50.5ml, 347mmol) at 0°C, and stir at room temperature for 63 hours. The reaction solution was cooled to -78°C and saturated aqueous sodium bicarbonate solution was slowly dropped to quench the reaction. After the reaction mixture was extracted with diethyl ether, the organic layer was washed with saturated sodium bicarbonate aqueous solution, water, and saturated brine in this order, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (2.68 g, 10.5 mmol, 75%). ¹ H-NMR (CDCl ₃ ) δ: 7.39-7.27 (5H, m), 4.76 (2H, s), 4.60 (2H, s), 3.55-3.50 (2H, m), 2.49-2.37 (1H, m) , 2.32-1.78 (5H, m), 1.61-1.50 (1H, m).

[Step 5] [(1R)-3,3-Difluorocyclopentyl]methanol was added to the methanol (105ml) solution of the compound (2.68g, 10.5mmol) obtained in step 4 above, and hydrochloric acid (5.49) was added at 0°C ml, concentration 35%, 62.7mmol), stirred at 55°C for 4 hours. After the solvent was distilled off under reduced pressure, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water, saturated sodium bicarbonate aqueous solution, saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (1.29 g, 9.48 mmol, 91%). ¹ H-NMR (CDCl ₃ ) δ: 3.66-3.55 (2H, m), 2.43-1.79 (6H, m), 1.63-1.51 (1H, m), 1.45-1.40 (1H, m).

[Step 6] Carbamate [(1R)-3,3-difluorocyclopentyl] methyl ester in the dichloromethane (40ml) solution of the compound (1.29g, 9.48mmol) obtained in the above step 5, in 0 Add trichloroacetate isocyanate (1.35ml, 11.4mmol) at°C, and stir at the same temperature for 30 minutes. The residue obtained by distilling off the solvent under reduced pressure was dissolved in methanol (60 ml), tetrahydrofuran (20 ml), water (10 ml), potassium carbonate (6.55 g, 47.4 mmol) was added at 0°C, and the mixture was stirred at room temperature for 2 hours . The reaction mixture was filtered through Celite, concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (1.70 g, 9.48 mmol, 100%). ¹ H-NMR (CDCl ₃ ) δ: 4.65 (2H, br s), 4.09-3.96 (2H, m), 2.54-2.42 (1H, m), 2.33-1.78 (4H, m), 1.63-1.51 (2H) , m).

[Step 7] (5S)-7,7-Difluoro-3-oxo-1-azaspiro[4.4]nonane-2-one The compound (1.70g, 9.48mmol) obtained in step 6 above, bis[ Rhodium (α,α,α´,α´-tetramethyl-1,3-benzenedipropionic acid)] (0.383g, 0.482mmol), iodobenzene diacetate (4.07g, 12.4mmol), A mixture of magnesium oxide (891 mg, 22.1 mmol) and dehydrated benzene (100 ml) was stirred at 60°C for 1 hour and 10 minutes. After cooling to room temperature, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, and washed with water and saturated brine. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (940 mg, 5.31 mmol, 56%). ¹ H-NMR (CDCl ₃ ) δ: 6.36 (1H, br s), 4.36-4.26 (2H, m), 2.54-2.06 (6H, m).

[Step 8] (5S)-7,7-difluoro-2-oxo-3-oxo-1-azaspiro[4.4]nonane-1-carboxylic acid tertiary butyl ester in the compound obtained in the above step 7 ( 940mg, 5.31mmol) in dichloromethane (55ml) solution, add triethylamine (1.84ml, 13.3mmol), di-tertiary butyl dicarbonate (2.23g, 9.71mmol), 4-dicarbonate at room temperature Methylaminopyridine (66.9 mg, 0.531 mmol), and stirred at the same temperature for 1 hour. Let stand at 0°C for 88 hours. After adding ice, the reaction mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, and dried with anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (1.33 g, 4.80 mmol, 90%) as a solid. ¹ H-NMR (CDCl ₃ ) δ: 4.27-4.07 (2H, m), 3.06-2.92 (1H, m), 2.69-2.42 (2H, m), 2.34-2.25 (1H, m), 2.22-2.08 ( 1H, m), 1.99-1.90 (1H, m), 1.57 (9H, s).

[Step 9] [(1S)-3,3-Difluoro-1-(hydroxymethyl)cyclopentyl] carbamic acid tertiary butyl ester in the compound obtained in the above step 8 (1.33 g, 4.80 mmol), methanol To a mixture of (40ml), tetrahydrofuran (13ml), and water (6.67ml), potassium carbonate (3.41g, 24.7mmol) was added at room temperature, and the mixture was stirred at the same temperature for 2.5 hours. Let stand in the freezer for 16 hours. After the reaction mixture was filtered through Celite, the residue obtained by concentrating the filtrate was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (1.11 g, 4.42 mmol, 92%) as a solid. ¹ H-NMR (CDCl ₃ ) δ: 4.86 (1H, br s), 3.72-3.67 (2H, m), 3.31 (1H, br s), 2.49-2.23 (3H, m), 2.23-2.08 (1H, m), 2.08-1.91 (2H, m), 1.44 (9H, s).

[Step 10] (1S)-1-[(tertiary butoxycarbonyl)amino]-3,3-difluorocyclopentanecarboxylic acid in the compound obtained in the above step 9 (1.11g, 4.42mmol), 1 -Oxy-2,2,6,6-tetramethylpiperidine (2,2,6,6-tetramethylpiperidine 1-oxyl) radical (146mg, 0.916mmol), acetonitrile (27ml), phosphate buffer solution (19.0 ml, pH 6.7, 0.67 mol/l), drip sodium chlorite (3.01g, 26.6mmol) in water (29ml) and sodium hypochlorite solution (687μl, effective chlorine 5.0%) at 35℃ for 30 minutes. The above) water (14.5ml) solution was stirred at the same temperature for 16 hours. Water (60 ml) was added, and after adjusting the pH from 9 to 10 with a 4N sodium hydroxide aqueous solution (3.65 ml, 14.6 mmol) at 0°C, a water (39 ml) solution of sodium sulfite (5.01 g, 39.8 mmol) was added. After the organic solvent was distilled off under reduced pressure, it was washed twice with diethyl ether. The aqueous layer was adjusted from pH 2 to 3 with a 2N aqueous hydrochloric acid solution (6.69 ml), and the aqueous layer was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.14 g, 4.30 mmol, 97%). ¹ H-NMR (CDCl ₃ ) δ: 5.06 (1H, br s), 3.05-2.85 (1H, m), 2.60-2.22 (4H, m), 2.19-2.01 (1H, m), 1.45 (9H, s) ).

[Reference Example C-3] 6-[(tertiary butoxycarbonyl)amino]-1,4-diazaspiro[2.5]oct-1-ene-carboxylic acid

[Step 1] 1-[(tertiary butoxycarbonyl)amino]-4-oxocyclohexane-1-carboxylic acid benzyl ester in 1-[(tertiary butoxycarbonyl)amino]-4- To a solution of oxocyclohexane-1-carboxylic acid (10.0g, 38.9mmol) in dichloromethane (100ml), add benzyl alcohol (5.20ml, 50.6mmol) and 1-ethyl-3 under ice-cooling and nitrogen flow. -(3-Dimethylaminopropyl)carbodiimide hydrochloride (9.70g, 50.6mmol), 4-dimethylaminopyridine (475mg, 3.89mmol) and triethylamine (7.30ml, 50.6 mmol) and stirred at room temperature for 4 days. The reaction solution was diluted with dichloromethane and washed with water. It was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=30:70-50:50) to obtain the title compound (11.2 g, 32.3 mmol, 83%). ¹ H-NMR (CDCl ₃ ) δ: 7.41-7.32 (5H, m), 5.21 (2H, s), 4.95 (1H, br s), 2.55-2.32 (8H, m), 1.44 (9H, s).

[Step 2] 6-[(tertiary butoxycarbonyl)amino]-1,4-diazaspiro[2.5]oct-1-enecarboxylic acid benzyl ester in the compound (11.2g, 32.3 mmol) in methanol (225ml), under ice-cold, nitrogen flow, add 2mol/l ammonia-methanol solution (675ml) and stir for 2 hours, then add hydroxylamine-O-sulfonic acid (5.05g, 44.7mmol) in methanol (45ml) solution and stirred at room temperature for 16 hours. After the ammonia in the reaction solution was distilled off under reduced pressure, triethylamine (13.5ml, 93.6mmol) and iodine (11.2g, 43.8mmol) were added under ice cooling and nitrogen flow and stirred for 1 hour. The reaction solution was diluted with dichloromethane, and washed with saturated sodium thiosulfate aqueous solution and water. It was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=5:95-40:60) to obtain the title compound (7.66 g, 21.3 mmol, 66%). ¹ H-NMR (CDCl ₃ ) δ: 7.40-7.35(5H, m), 5.21 (2H, s), 4.79 (1H, bs), 2.32-2.12 (4H, m), 1.87-1.72 (2H, m) , 1.44(9H, s), 0.90-0.75 (2H, m).

[Step 3] 6-[(tertiary butoxycarbonyl)amino]-1,4-diazaspiro[2.5]oct-1-enecarboxylic acid in the compound obtained in step 2 above (7.66g, 21.3mmol) To a solution of tetrahydrofuran (80ml), methanol (50ml) and water (10ml), lithium hydroxide monohydrate (1.40g, 33.4mmol) was added and stirred for 3 days. The reaction liquid was washed with diethyl ether, the aqueous layer was made acidic with a 1N hydrochloric acid aqueous solution, diluted with dichloromethane, and the organic layer was washed with 10% citric acid aqueous solution and water. It was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=25:75-70:30) to obtain the title compound (4.16 g, 15.5 mmol, 73%). ¹ H-NMR (DMSO-d ₆ ) δ: 7.20 (1H, br s), 2.18-1.99 (2H, m), 1.93-1.74 (4H, m), 1.39 (9H, s), 0.65-0.52 (2H , m).

[Reference Example C-4] 1-[(tertiary butoxycarbonyl)amino]-4,4-difluorocyclohexane-1-carboxylic acid

烷(500ml)，冰冷下，添加4N氫氧化鈉水溶液(44.8ml，0.179mol)。接著，冰冷下，交互地添加二碳酸二-三級丁酯(58.6g，0.269mol)及1N氫氧化鈉水溶液(269ml，0.269mol)，並於室溫攪拌48小時。將反應液冰冷，添加2N鹽酸水溶液(300ml，0.600mol)調整為酸性。以乙酸乙酯萃取，以飽和食鹽水洗淨。以無水硫酸鈉乾燥後，減壓下餾除溶劑而獲得粗製物。於此粗製物中少量添加乙酸乙酯後，大量添加己烷並進行超音波處理。濾取生成的固體，獲得標題化合物(18.5g，66.2mmol，37%)。¹ H-NMR (CDCl₃ ) δ : 4.82 (1H, br s), 2.30-1.87 (8H, m), 1.45 (9H, s).The compound (36.5 g, 0.179 mol) obtained in Step 1 of Reference Example C-1 was suspended in an 8N aqueous sodium hydroxide solution (200 ml, 1.60 mol), heated to 120° C. and stirred for 25 hours. The reaction liquid was ice-cooled, and a 5N aqueous hydrochloric acid solution (320 ml, 1.60 mol) was added to neutralize to obtain a suspension. Add 1,4-Di to the obtained suspension

Alkane (500ml), under ice cooling, add 4N sodium hydroxide aqueous solution (44.8ml, 0.179mol). Then, under ice cooling, di-tertiary butyl dicarbonate (58.6 g, 0.269 mol) and 1N sodium hydroxide aqueous solution (269 ml, 0.269 mol) were added alternately, and the mixture was stirred at room temperature for 48 hours. The reaction liquid was ice-cooled, and a 2N aqueous hydrochloric acid solution (300 ml, 0.600 mol) was added to adjust it to acidity. It was extracted with ethyl acetate and washed with saturated brine. After drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain a crude product. After adding a small amount of ethyl acetate to this crude product, a large amount of hexane was added and ultrasonic treatment was performed. The resulting solid was collected by filtration to obtain the title compound (18.5 g, 66.2 mmol, 37%). ¹ H-NMR (CDCl ₃ ) δ: 4.82 (1H, br s), 2.30-1.87 (8H, m), 1.45 (9H, s).

[Reference Example C-5] 4,4-Difluoro-1-(2,2,2-trifluoroacetamide)cyclohexane-1-carboxylic acid

[Step 1] 1-Amino-4,4-difluorocyclohexane-1-carboxylic acid The compound (44.3 g, 0.217 mol) obtained in Step 1 of Reference Example C-1 was suspended in an 8N aqueous sodium hydroxide solution ( 271ml, 2.17mol), heated to 120°C and stirred for 28 hours. The reaction solution was ice-cooled, and a 5N aqueous hydrochloric acid solution (434 ml, 2.17 mol) was added to neutralize, and the mixture was stirred for a while. The resulting solid was collected by filtration to obtain the title compound (30.8 g, 0.172 mol, 79%). ¹ H-NMR (DMSO-d ₆ ) δ: 7.71-7.53 (2H, br m), 2.52-2.48 (4H, m), 2.28-2.13 (1H, m), 2.08-1.85 (2H, m), 1.71 -1.61 (1H, m).

[Step 2] 4,4-Difluoro-1-(2,2,2-trifluoroacetamide)cyclohexane-1-carboxylic acid The compound (15.0 g, 83.7 mmol) obtained in the above step 1 and methanol Potassium (6.46g, 92.1mmol) was suspended in methanol (20ml) and stirred at 50°C for 30 minutes. After allowing to cool to room temperature, ethyl trifluoroacetate (20.0 ml, 167 mmol) was added, and the mixture was stirred again at 50°C for 6 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. A 1N hydrochloric acid aqueous solution was added to the obtained residue to make it acidic, and ethyl acetate was added and stirred. The insoluble matter was filtered through Celite, and the filtrate was extracted with ethyl acetate. It was washed with 2N hydrochloric acid aqueous solution and saturated brine, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (19.0 g, 69.2 mmol, 83%). ¹ H-NMR (DMSO-d ₆ ) δ: 13.09 (1H, br s), 9.51 (1H, br s), 2.28-2.19 (2H, m), 2.07-1.85 (6H, m).

[Reference Example C-6] 1-(2,2,2-Trifluoroacetamide)cycloheptane-1-carboxylic acid

[Step 1] A mixture of 1-(2,2,2-trifluoroacetamide)cycloheptane-1-carboxylic acid and 1-aminocycloheptanecarboxylic acid (1.00g, 6.36mmol) in trifluoroacetic acid (6ml) Under ice cooling, trifluoroacetic anhydride (1.77 ml, 12.7 mmol) was dropped, the temperature was raised to room temperature, and the mixture was stirred for 18.5 hours. The solvent was distilled off under reduced pressure, water was added to the obtained residue, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, methanol was added to the obtained residue, and the solvent was distilled off under reduced pressure again to obtain the title compound (1.17 g, 4.60 mmol, 72%). ¹ H-NMR (DMSO-d ₆ ) δ: 12.56 (1H, br s), 9.34 (1H, s), 2.10-1.50 (12H, m).

[Reference Example D-1] 6-[(4-chloro-3-fluorophenyl)methyl]-11,11-difluoro-2,6,14-triazabispiro[4.2.5 ⁸ .2 ⁵ ]Pentadecane-7,15-dione hydrochloride

啉-4-基)乙基]胺甲醯基}吡咯啶-1-甲酸三級丁酯 將3-側氧吡咯啶酮-1-甲酸三級丁酯(539mg，2.82mmol)溶解於甲醇(20ml)，添加1-(4-氯-3-氟苯基)甲胺(360μl，2.82mmol)，加溫至55℃而攪拌1小時半。回到室溫後，添加參考例C-1所獲得的化合物(1.00g，2.82mmol)、2-

啉基乙基異腈(417μl，2.96mmol)，再次加溫至55℃，並攪拌8小時。減壓下餾除溶劑，將獲得的殘留物以矽膠管柱層析(甲醇-二氯甲烷=5:95)純化，而獲得標題化合物(1.07g，1.30mmol，46%)。[Step 1] 3-{[(4-chloro-3-fluorophenyl)methyl](4,4-difluoro-1-{[(2,2,2-trichloroethoxy)carbonyl]amine Yl}cyclohexane-1-carbonyl)amino}-3-{[2-(

Lin-4-yl)ethyl)aminomethanyl}pyrrolidine-1-carboxylic acid tertiary butyl ester 3-oxopyrrolidone-1-carboxylic acid tertiary butyl ester (539mg, 2.82mmol) was dissolved in methanol ( 20ml), add 1-(4-chloro-3-fluorophenyl)methylamine (360μl, 2.82mmol), heat to 55°C and stir for 1.5 hours. After returning to room temperature, the compound (1.00 g, 2.82 mmol) obtained in Reference Example C-1, 2-

Linyl ethyl isonitrile (417 μl, 2.96 mmol), heated again to 55° C., and stirred for 8 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol-dichloromethane=5:95) to obtain the title compound (1.07 g, 1.30 mmol, 46%).

[Step 2] 6-[(4-chloro-3-fluorophenyl)methyl]-11,11-difluoro-7,15-dioxo-2,6,14-triazabispiro[4.2. ⁵⁸ .2 ⁵ ] Pentadecane-2-carboxylic acid tertiary butyl ester Zinc (powdered, 388 mg, 5.35 mmol) was suspended in tetrahydrofuran (10 ml), and acetic acid (5 ml) was added. Under ice cooling, a tetrahydrofuran (10 ml) solution of the compound (1.07 g, 1.30 mmol) obtained in step 1 above was added, and the mixture was heated to room temperature and stirred for 24 hours. The reaction solution was diluted with dichloromethane and filtered through Celite to remove insoluble materials. The residue obtained by distilling off the solvent under reduced pressure was dissolved in toluene (10 ml), and acetic acid (0.5 ml) was added at room temperature. After heating to 80°C and stirring for 3 hours, toluene was distilled off under reduced pressure. The obtained residue was dissolved in dichloromethane, and saturated sodium bicarbonate water was added under ice cooling to adjust the alkalinity. Extract with dichloromethane and dry with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=5:95-100:0) to obtain the title compound (221 mg, 0.429 mmol, 33%). ¹ H-NMR (CDCl ₃ ) δ: 7.38-7.33 (1H, m), 7.26-7.21 (1H, m), 6.98-6.86 (2H, m), 4.89-4.33 (2H, m), 3.98-3.86 ( 1H, m), 3.79-3.49 (3H, m), 2.55-1.95 (8H, m), 1.93-1.78 (2H, m), 1.45 (9H, br s).

烷(10ml)，冰冷下，添加4N鹽酸/1,4-二

烷溶液(5ml)而攪拌14小時。減壓下餾除溶劑，添加二乙基醚而攪拌片刻。濾取生成的固體，獲得標題化合物(537mg，1.19mmol，59%)。¹ H-NMR (CD₃ OD) δ : 7.48-7.43 (1H, m), 7.14-7.10 (1H, m), 7.05-7.01 (1H, m), 4.96-4.91 (1H, m), 4.55-4.48 (1H, m), 3.78-3.73 (1H, m), 3.61-3.56 (2H, m), 3.52-3.45 (1H, m), 3.36-3.31 (1H, m), 2.63-2.55 (1H, m), 2.50-2.41 (1H, m), 2.41-1.92 (8H, m).[Step 3] 6-[(4-chloro-3-fluorophenyl)methyl]-11,11-difluoro-2,6,14-triazabispiro[4.2.5 ⁸ .2 ⁵ ] fifteen Alkane-7,15-dione hydrochloride The compound (1.04g, 2.01mmol) obtained in step 2 above was suspended in 1,4-dione

Alkane (10ml), under ice cooling, add 4N hydrochloric acid/1,4-bis

The alkane solution (5ml) was stirred for 14 hours. The solvent was distilled off under reduced pressure, and diethyl ether was added and stirred for a while. The resulting solid was collected by filtration to obtain the title compound (537 mg, 1.19 mmol, 59%). ¹ H-NMR (CD ₃ OD) δ: 7.48-7.43 (1H, m), 7.14-7.10 (1H, m), 7.05-7.01 (1H, m), 4.96-4.91 (1H, m), 4.55-4.48 (1H, m), 3.78-3.73 (1H, m), 3.61-3.56 (2H, m), 3.52-3.45 (1H, m), 3.36-3.31 (1H, m), 2.63-2.55 (1H, m) , 2.50-2.41 (1H, m), 2.41-1.92 (8H, m).

[Reference Example D-2-1] (+)-6-[(4-chloro-3-fluorophenyl)methyl]-11,11-difluoro-2,6,14-triazabispiro[4.2 .5 ⁸ .2 ⁵ ]pentadecane-7,15-dione hydrochloride

[Step 1] 6-[(4-chloro-3-fluorophenyl)methyl]-11,11-difluoro-7,15-dioxo-2,6,14-triazabispiro[4.2. ⁵⁸ .2 ⁵ ] Pentadecane-2-carboxylic acid (+)-tertiary butyl ester The compound (7.00 g, 13.6 mmol) obtained in Step 2 of Reference Example D-1 was optically divided under the following conditions. Column: CHIRALPAK IG 50mmIDx250mmL of Daicel. Extraction solvent: methanol. Flow rate: 35.4mL/min. Temperature: 40°C. The title compound (3.30g, 6.40mmol) was obtained as the first peak. Specific optical rotation [α] _D ²⁰ = +2.121 (c=1.0, chloroform) ¹ H-NMR (CDCl ₃ ) δ: 7.38-7.32 (1H, m), 7.27-7.20 (1H, br m), 6.99-6.83 (2H, m), 4.86-4.68 (1H, br m), 4.54-4.32 (1H, br m), 3.97-3.88 (1H, m), 3.77-3.68 (1H, m), 3.63-3.53 (2H, m), 2.58-2.23 (4H, m), 2.23-2.13 (1H, m), 2.12-1.93 (2H, m), 1.91-1.80 (2H, m), 1.53-1.52 (1H, m), 1.45 ( 9H, br s).

[Step 2] (+)-6-[(4-chloro-3-fluorophenyl)methyl]-11,11-difluoro-2,6,14-triazabispiro[4.2.5 ⁸ .2 ⁵ ] Pentadecane-7,15-dione hydrochloride Using the compound (3.30 g, 6.40 mmol) obtained in step 1 above, the title was obtained by performing the same operation as in step 3 of Reference Example D-1 Compound (2.76 g, 6.10 mmol, 95%). ¹ H-NMR (CD ₃ OD) δ: 7.48-7.43 (1H, m), 7.14-7.09 (1H, m), 7.04-7.01 (1H, m), 4.96-4.90 (1H, m), 4.55-4.48 (1H, m), 3.78-3.73 (1H, m), 3.66-3.55 (3H, m), 3.35-3.32 (1H, m), 2.64-1.92 (10H, m).

[Reference Example D-2-2] (-)-6-[(4-chloro-3-fluorophenyl)methyl]-11,11-difluoro-2,6,14-triazabispiro[4.2 .5 ⁸ .2 ⁵ ]pentadecane-7,15-dione hydrochloride

[Step 1] 6-[(4-chloro-3-fluorophenyl)methyl]-11,11-difluoro-7,15-dioxo-2,6,14-triazabispiro[4.2. 5 ⁸ .2 ⁵ ] Pentadecane-2-carboxylic acid (-)-tertiary butyl ester was subjected to the same operation as in Reference Example D-2-1 to obtain the title compound (3.30 g, 6.40 mmol) as the second peak . Specific optical rotation [α] _D ²⁰ = -2.432 (c=1.0, chloroform) ¹ H-NMR (CDCl ₃ ) δ: 7.84-7.68 (1H, br m), 7.38-7.32 (1H, m), 6.99-6.83 (2H, m), 4.89-4.28 (2H, m), 3.99-3.86 (1H, m), 3.80-3.43 (3H, m), 2.55-1.95 (8H, m), 1.91-1.78 (2H, m) , 1.44 (9H, br s).

[Step 2] (-)-6-[(4-chloro-3-fluorophenyl)methyl]-11,11-difluoro-2,6,14-triazabispiro[4.2.5 ⁸ .2 ⁵ ] Pentadecane-7,15-dione hydrochloride Using the compound (3.30 g, 6.40 mmol) obtained in step 1 above, the title was obtained by performing the same operation as in step 3 of Reference Example D-1 Compound (2.84 g, 6.28 mmol, 98%). ¹ H-NMR (CD ₃ OD) δ: 7.48-7.43 (1H, m), 7.13-7.09 (1H, m), 7.04-7.00 (1H, m), 4.95-4.92 (1H, m), 4.53-4.47 (1H, m), 3.77-3.73 (1H, m), 3.66 (1H, s), 3.59-3.54 (2H, m), 3.35-3.30 (1H, m), 2.63-1.91 (10H, m).

Using a commercially available amine and the compound obtained in Reference Example, the following compound was obtained by performing the same operation as in Reference Example D-1.

6-(1,3-苯并

唑-6-基甲基)-11,11-二氟-2,6,14-三氮二螺[4.2.5⁸ .2⁵ ]十五烷-7,15-二酮 鹽酸鹽 ¹ H-NMR (DMSO-d₆ ) δ : 9.47-9.35 (1H, m), 9.13-8.97 (2H, m), 8.72 (1H, s), 7.76 (1H, d, J = 8.5 Hz), 7.62 (1H, s), 7.28 (1H, d, J = 8.5 Hz), 4.96 (1H, d, J = 16.8 Hz), 4.72 (1H, d, J = 16.8 Hz), 3.78-3.55 (2H, m), 3.36-3.22 (3H, m), 2.37-1.87 (9H, m). 製造原料：參考例C-1、6-(胺基甲基)苯并

唑 鹽酸鹽 D-4

6-(1,3-苯并噻唑-6-基甲基)-11,11-二氟-2,6,14-三氮二螺[4.2.5⁸ .2⁵ ]十五烷-7,15-二酮 鹽酸鹽 ¹ H-NMR (DMSO-d₆ ) δ : 9.58-9.48 (1H, m), 9.35 (1H, s), 9.14-9.02 (2H, m), 8.07-7.99 (2H, m), 7.41 (1H, d, J = 8.5 Hz), 4.98 (1H, d, J = 16.8 Hz), 4.75 (1H, d, J = 16.8 Hz), 4.09-3.64 (3H, m), 3.53-3.22 (2H, m), 2.39-1.92 (9H, m). 製造原料：參考例C-1、6-(胺基甲基)苯并噻唑 D-7

11,11-二氟-6-[(3-氟-4-甲氧基苯基)甲基]-2,6,14-三氮二螺[4.2.5⁸ .2⁵ ]十五烷-7,15-二酮 鹽酸鹽 ¹ H-NMR (DMSO-d₆ ) δ : 9.39 (1H, br s), 9.01 (1H, br s), 7.13-7.04 (2H, m), 7.00-6.96 (1H, m), 4.74 (1H, d, J = 17.1 Hz), 4.50 (1H, d, J = 17.1 Hz), 3.81 (3H, s), 3.71-3.63 (1H, m), 3.53-3.42 (1H, m), 3.41-3.21 (4H, m), 2.36-2.02 (8H, m). 製造原料：參考例C-1、(3-氟-4-甲氧基苯基)甲胺 [Table 1] Reference example D-3

6-(1,3-Benzo

(Azol-6-ylmethyl)-11,11-difluoro-2,6,14-triazodispiro[4.2.5 ⁸ .2 ⁵ ]pentadecane-7,15-dione hydrochloride ¹ H-NMR (DMSO-d ₆ ) δ: 9.47-9.35 (1H, m), 9.13-8.97 (2H, m), 8.72 (1H, s), 7.76 (1H, d, J = 8.5 Hz), 7.62 (1H, s), 7.28 (1H, d, J = 8.5 Hz), 4.96 (1H, d, J = 16.8 Hz), 4.72 (1H, d, J = 16.8 Hz), 3.78-3.55 (2H, m) , 3.36-3.22 (3H, m), 2.37-1.87 (9H, m). Production material: Reference example C-1, 6-(aminomethyl)benzo

Azole hydrochloride D-4

6-(1,3-benzothiazol-6-ylmethyl)-11,11-difluoro-2,6,14-triazabispiro[4.2.5 ⁸ .2 ⁵ ]pentadecane-7, 15-diketone hydrochloride ¹ H-NMR (DMSO-d ₆ ) δ: 9.58-9.48 (1H, m), 9.35 (1H, s), 9.14-9.02 (2H, m), 8.07-7.99 (2H, m), 7.41 (1H, d, J = 8.5 Hz), 4.98 (1H, d, J = 16.8 Hz), 4.75 (1H, d, J = 16.8 Hz), 4.09-3.64 (3H, m), 3.53-3.22 (2H, m), 2.39-1.92 (9H, m). Manufacturing raw materials: Reference Example C-1, 6-(aminomethyl)benzothiazole D-7

11,11-difluoro-6-[(3-fluoro-4-methoxyphenyl)methyl]-2,6,14-triazabispiro[4.2.5 ⁸ .2 ⁵ ]pentadecane- 7,15-dione hydrochloride ¹ H-NMR (DMSO-d ₆ ) δ: 9.39 (1H, br s), 9.01 (1H, br s), 7.13-7.04 (2H, m), 7.00-6.96 (1H, m), 4.74 (1H, d, J = 17.1 Hz), 4.50 (1H, d, J = 17.1 Hz), 3.81 (3H, s), 3.71-3.63 (1H, m), 3.53-3.42 (1H, m), 3.41-3.21 (4H , m), 2.36-2.02 (8H, m). Manufacturing raw materials: Reference Example C-1, (3-Fluoro-4-methoxyphenyl)methylamine

[Reference Example D-5] (8S)-6-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-2,6,13-triazaspiro[4.2.4 ⁸ .2 ⁵ ]tetradecane-7,14-dione hydrochloride

啉-4-基)乙基]胺甲醯基}吡咯啶-1-甲酸三級丁酯 使用參考例C-2所獲得的化合物(1.14g，4.30mmol)，藉由進行與參考例D-1之步驟1同樣的操作，而獲得標題化合物(543mg)。[Step 1] 3-({(1S)-1-[(tertiary butoxycarbonyl)amino]-3,3-difluorocyclopentane-1-carbonyl}[(4-chloro-3-fluoro Phenyl)methyl]amino)-3-{[2-(

Lin-4-yl)ethyl]aminomethanyl}pyrrolidine-1-carboxylic acid tertiary butyl ester Using the compound (1.14 g, 4.30 mmol) obtained in Reference Example C-2, the compound (1.14 g, 4.30 mmol) was combined with Reference Example D- The same procedure as in step 1 of 1 was performed to obtain the title compound (543 mg).

[Step 2] (8S)-6-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-7,14-dioxo-2,6,13-triazadi Spiro[4.2.4 ⁸ .2 ⁵ ]tetradecane-2-carboxylic acid tertiary butyl ester was added to the methanol (6ml) solution of the compound (543mg) obtained in step 1 above, and chlorotrimethylsilane ( 1.55ml, 12.3mmol). After stirring at room temperature for 6 hours, the solvent was concentrated under reduced pressure. To the obtained residue in tetrahydrofuran (8ml), add triethylamine (3.20ml, 23.1mmol) at room temperature, stir at 50°C for 3 hours, stand at room temperature for 16 hours, and stir at 50°C for 4 hours . Di-tertiary butyl dicarbonate (532 mg, 2.32 mmol) was added at 0°C, and stirred at room temperature for 16 hours. The solvent was concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain a low-polarity compound (103 mg, 0.205 mmol, a total yield of 4.8% in 2 steps) and a high-polarity compound ( 104mg, 0.207mmol, 2 steps total yield 4.8%). Low polarity compound ¹ H-NMR (CDCl ₃ ) δ: 7.39-7.33 (1H, m), 7.01-6.85 (3H, m), 4.98-4.31 (2H, m), 4.00-3.93 (1H, m), 3.77 -3.47 (3H, m), 3.25-2.94 (1H, m), 2.68-2.55 (1H, m), 2.54-2.25 (4H, m), 2.23-2.00 (2H, m), 1.44 (9H, s) . Highly polar compounds ¹ H-NMR (CDCl ₃ ) δ: 7.39-7.33 (1H, m), 6.99-6.86 (2H, m), 6.73-6.48 (1H, m), 4.90-4.66 (1H, m), 4.62-4.37 (1H, m), 3.98-3.88 (1H, m), 3.74-3.48 (3H, m), 3.20-2.87 (1H, m), 2.77-2.25 (5H, m), 2.21-1.97 (2H , m), 1.44 (9H, s).

[Step 3] (8S)-6-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-2,6,13-triazaspiro[4.2.4 ⁸ .2 ⁵ ] Tetradecane-7,14-dione hydrochloride used the highly polar compound (104 mg, 0.207 mmol) obtained in step 2 above, and the source was obtained by performing the same operation as in step 3 of Reference Example D-1 From the highly polar title compound (D-5-1) (93.9 mg, 0.214 mmol, quantitative). ¹ H-NMR (CD ₃ OD) δ: 7.48-7.43 (1H, m), 7.17-7.13 (1H, m), 7.07-7.03 (1H, m), 5.02-4.96 (1H, m), 4.55-4.49 (1H, m), 3.73-3.68 (1H, m), 3.63-3.46 (2H, m), 3.36-3.33 (1H, m), 3.14-3.01 (1H, m), 2.61-2.27 (6H, m) , 2.21-2.12 (1H, m). Using the low-polarity compound (103mg, 0.205mmol) obtained in step 2 above, by performing the same operation, the title compound (D-5-2) derived from the low-polarity was obtained (94.0 mg, 0.214 mmol, quantitative). ¹ H-NMR (CD ₃ OD) δ: 7.51-7.42 (1H, m), 7.18-7.11 (1H, m), 7.08-7.00 (1H, m), 4.95 (1H, d, J = 17.2 Hz), 4.55 (1H, d, J = 17.2 Hz), 3.77-3.72 (1H, m), 3.63-3.50 (2H, m), 3.39-3.34 (1H, m), 2.94-2.80 (1H, m), 2.67- 2.29 (6H, m), 2.18-2.07 (1H, m).

[Reference Example D-6] 14-[(4-Methoxyphenyl)methyl]-1,2,7,11,14-Pentazatrispiro[2.2.2.4 ⁹ .2 ⁶ .2 ³ ] ten Hepta-1-ene-8,15-dione hydrochloride

啉(1.05g，7.49mmol)之甲醇(7.6ml)溶液、及參考例C-3所獲得的化合物(2.00g，7.44mmol)，於外溫50℃攪拌8小時。將反應液以甲醇(32ml)稀釋，冰冷下，添加氯三甲基矽烷(10.0ml，79.2mmol)並於室溫攪拌16小時。再於反應液中添加氯三甲基矽烷(5.00ml，39.6mmol)並攪拌2小時。減壓下餾除反應溶劑，減壓下乾燥。將殘留物以刮勺作成粉狀，添加四氫呋喃(50ml)，冰冷下，添加三乙基胺(10.0ml，69.3mmol)，於氮氣流下，於外溫50℃攪拌4小時。回到室溫後，添加二碳酸二-三級丁酯(4.00g，18.3mmol)，並於室溫攪拌16小時。將反應液以二氯甲烷稀釋，以10%檸檬酸水溶液及水洗淨。以無水硫酸鎂乾燥，減壓下餾除溶劑。將獲得的殘留物以矽膠管柱層析(乙酸乙酯-己烷=50:50-75:25)純化，而獲得標題化合物(672mg，1.39mmol，19%)。¹ H-NMR (DMSO-d₆ ) δ : 8.80 (1H, s), 7.13-6.85 (4H, m), 4.78-4.38 (4H, m), 3.72 (3H, s), 3.67-3.27 (2H, m), 2.35-2.15 (4H, m), 1.92-1.67 (4H, m), 1.49-1.24 (9H, m), 1.16-1.01 (2H, m).[Step 1] 14-[(4-Methoxyphenyl)methyl]-8,15-dioxo-1,2,7,11,14-Pentazatrispiro[2.2.2.4 ⁹ .2 ⁶ .2 ³ ]Heptadecene-1-ene-11-carboxylic acid tertiary butyl ester, 1-(4-methoxyphenyl)methylamine (1.03g, 7.51mmol), 3-oxopyrrolidine-1-carboxylic acid A solution of tertiary butyl ester (1.38 g, 7.45 mmol) in methanol (3.5 ml) was stirred at room temperature for 30 minutes under a stream of nitrogen. Add 4-(2-isocyanoethyl)

A methanol (7.6 ml) solution of morpholine (1.05 g, 7.49 mmol) and the compound (2.00 g, 7.44 mmol) obtained in Reference Example C-3 were stirred at an external temperature of 50°C for 8 hours. The reaction solution was diluted with methanol (32 ml), and under ice cooling, chlorotrimethylsilane (10.0 ml, 79.2 mmol) was added and stirred at room temperature for 16 hours. Chlorotrimethylsilane (5.00 ml, 39.6 mmol) was added to the reaction solution and stirred for 2 hours. The reaction solvent was distilled off under reduced pressure, and dried under reduced pressure. The residue was powdered with a spatula, tetrahydrofuran (50ml) was added, triethylamine (10.0ml, 69.3mmol) was added under ice cooling, and stirred at an external temperature of 50°C for 4 hours under nitrogen flow. After returning to room temperature, di-tertiary butyl dicarbonate (4.00 g, 18.3 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with dichloromethane, and washed with 10% citric acid aqueous solution and water. It was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=50:50-75:25) to obtain the title compound (672 mg, 1.39 mmol, 19%). ¹ H-NMR (DMSO-d ₆ ) δ: 8.80 (1H, s), 7.13-6.85 (4H, m), 4.78-4.38 (4H, m), 3.72 (3H, s), 3.67-3.27 (2H, m), 2.35-2.15 (4H, m), 1.92-1.67 (4H, m), 1.49-1.24 (9H, m), 1.16-1.01 (2H, m).

烷溶液(18ml)，於室溫攪拌5小時。於反應液中添加二乙基醚並攪拌。濾取生成的固體，而獲得標題化合物(580mg，1.38mmol，94%)。¹ H-NMR (DMSO-d₆ ) δ : 10.05 (1H, br s), 9.21 (1H, br s), 9.07 (1H,s), 7.17-6.88 (4H, m), 4.83-4.57 (2H, m), 3.73 (3H, s), 3.63-3.24 (4H, m), 2.48-2.08 (4H, m), 1.93-1.67 (4H, m), 1.14-1.01 (2H, m).[Step 2] 14-[(4-Methoxyphenyl)methyl]-1,2,7,11,14-Pentazatrispiro[2.2.2.4 ⁹ .2 ⁶ .2 ³ ]17-17 -En-8,15-dione hydrochloride in the tetrahydrofuran (18ml) solution of the compound (712mg, 1.47mmol) obtained in step 1 above, under ice-cooling, add 4N hydrochloric acid/1,4-dione

The alkane solution (18ml) was stirred at room temperature for 5 hours. Diethyl ether was added to the reaction liquid and stirred. The resulting solid was collected by filtration to obtain the title compound (580 mg, 1.38 mmol, 94%). ¹ H-NMR (DMSO-d ₆ ) δ: 10.05 (1H, br s), 9.21 (1H, br s), 9.07 (1H,s), 7.17-6.88 (4H, m), 4.83-4.57 (2H, m), 3.73 (3H, s), 3.63-3.24 (4H, m), 2.48-2.08 (4H, m), 1.93-1.67 (4H, m), 1.14-1.01 (2H, m).

[Reference Example D-8] 7-[(4-chloro-3-fluorophenyl)methyl]-12,12-difluoro-3,7,15-triazabispiro[5.2.5 ⁹ .2 ⁶ ]Hexadecane-8,16-dione hydrochloride

[Step 1] 7-[(4-chloro-3-fluorophenyl)methyl]-12,12-difluoro-8,16-dioxo-3,7,15-triazabispiro[5.2. 5 ⁹ .2 ⁶ ]hexadecane-3-carboxylic acid tertiary butyl ester Using the compound (2.63 g, 9.40 mmol) obtained in Reference Example C-4, by performing the same operation as in Step 1 of Reference Example D-6 , And the title compound (348 mg, 0.656 mmol, 7%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 7.69 (1H, br s), 7.39-7.30 (1H, m), 6.95-6.83 (2H, m), 4.88-4.35 (2H, br m), 4.20-3.81 ( 2H, br m), 3.65-3.21 (2H, br m), 2.53-2.35 (2H, m), 2.35-2.19 (2H, m), 2.19-1.71 (8H, m), 1.46 (9H, s).

[Step 2] 7-[(4-chloro-3-fluorophenyl)methyl]-12,12-difluoro-3,7,15-triazabispiro[5.2.5 ⁹ .2 ⁶ ] hexadecane Alkane-8,16-dione hydrochloride used the compound (348 mg, 0.656 mmol) obtained in the above step 1, and the title compound (286 mg, 0.614 mmol) was obtained by performing the same operation as in the step 3 of Reference Example D-1 mmol, 94%). ¹ H-NMR (DMSO-d ₆ ) δ: 9.18-8.97 (1H, m), 8.91-8.64 (2H, m), 7.55-7.46 (1H, m), 7.28-7.20 (1H, m), 7.12- 7.04 (1H, m), 4.76 (2H, s), 3.53-3.10 (4H, m), 2.36-1.72 (12H, m).

[Reference Example D-9] 5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]Tetradecane-6,14-dione hydrochloride

[Step 1] {[(4-Chloro-3-fluorophenyl)methyl]amino}-3-cyanoazepine-1-carboxylic acid tertiary butyl ester Grade butyl ester (20.0g, 0.113mol) was dissolved in methanol (400ml), added 4-chloro-3-fluorobenzylamine (19.0g, 0.113mol), acetic acid (32.4ml, 0.567mol) and stirred at room temperature for 10 minute. Potassium cyanide (7.53 g, 0.113 mol) was added to the reaction solution, and the mixture was stirred at 60°C for 16 hours. After allowing to cool to room temperature, the solvent was distilled off under reduced pressure, and water was added to the obtained residue and stirred. The resulting solid was collected by filtration to obtain the title compound (36.3 g, 0.107 mol, 94%). ¹ H-NMR (CDCl ₃ ) δ: 7.40-7.35 (1H, m), 7.23-7.19 (1H, m), 7.12-7.09 (1H, m), 4.26 (2H, d, J = 9.2 Hz), 3.88 (2H, d, J = 9.2 Hz), 3.83 (2H, d, J = 6.7 Hz), 1.93-1.90 (1H, m), 1.45 (9H, s).

[Step 2] 1-(Tertiary butoxycarbonyl)-3-{[(4-chloro-3-fluorophenyl)methyl]amino}azepine-3-carboxylic acid The compound obtained in step 1 above (36.3g, 0.107mol) was suspended in dimethyl sulfoxide (350ml), and hydrogen peroxide water (17.6ml, 0.213mol) was added. Under ice cooling, potassium carbonate (44.5 g, 0.320 mol) was added, and the mixture was stirred for 24 hours while raising the temperature to room temperature. Water was slowly added to the reaction solution, extracted with ethyl acetate, and washed with water and saturated brine. The solvent was distilled off under reduced pressure, the residue obtained by drying was suspended in ethanol (600 ml), and 8N potassium hydroxide aqueous solution (57.5 ml, 0.460 mol) was added, followed by stirring at 80°C for 16 hours. After the solvent was distilled off under reduced pressure, it was diluted with water, and under ice cooling, 2N aqueous hydrochloric acid (230 ml, 0.460 mol) was added to neutralize. The resulting solid was collected by filtration to obtain the title compound (34.6 g, 96.4 mmol, 90%). ¹ H-NMR (DMSO-d ₆ ) δ: 8.24 (1H, br s), 7.56-7.49 (1H, m), 7.44-7.37 (1H, m), 7.25-7.19 (1H, m), 4.09-3.94 (2H, br m), 3.81-3.70 (2H, br m), 3.68 (2H, s), 1.38 (9H, s).

[Step 3] 5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-6,14-dioxo-2,5,13-triazabispiro[3.2. ^{57 4} .2] tetradecane -2- three carboxylate the compound (19.7g, 71.5mmol) reference Example C-5 obtained was suspended in dichloromethane (350ml), at room temperature was added oxalyl acyl chloride (6.13ml, 71.5mmol), N,N-dimethylformamide (1ml) and stir for 3 hours. The solvent was distilled off under reduced pressure to obtain chlorine. The compound (17.1 g, 47.7 mmol) obtained in step 2 above was placed in another flask and suspended in N,N-dimethylformamide (500 ml). Under ice cooling, N,N-diisopropylethylamine (16.3ml, 95.3mmol) was added, and then the N,N-dimethylformamide (100ml) solution of chlorine prepared in advance was dropped. After stirring for 14 hours at room temperature, under ice cooling, 1,1´-carbonyldiimidazole (23.2g, 143mmol) was added, and the mixture was stirred at room temperature for 10 minutes and at 80°C for 8 hours. After returning to room temperature, 1N aqueous hydrochloric acid solution and water were added, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and ethanol was added to the obtained residue to perform ultrasonic treatment. The resulting solid was collected by filtration to obtain the title compound (12.0 g, 23.9 mmol, 50%). ¹ H-NMR (CDCl ₃ ) δ: 7.40-7.35 (1H, m), 7.07 (1H, br s), 6.99-6.93 (2H, m), 4.91 (2H, br s), 4.56-4.49 (2H, m), 4.00-3.93 (2H, m), 2.39-2.25 (4H, m), 2.12-1.95 (2H, m), 1.81-1.72 (2H, m), 1.45 (9H, s).

烷溶液(125ml)而攪拌14小時。減壓下餾除溶劑，添加二乙基醚而攪拌片刻。濾取生成的固體，獲得標題化合物(10.5g，23.9mmol，定量的)。¹ H-NMR (DMSO-d₆ ) δ : 9.26-9.11 (2H, m), 7.58-7.52 (1H, m), 7.40-7.36 (1H, m), 7.19-7.15 (1H, m), 4.96 (2H, s), 4.42-4.33 (2H, m), 4.24-4.14 (2H, m), 2.27-2.01 (6H, m), 1.93-1.84 (2H, m).[Step 4] 5-[(4-Chloro-3-fluorophenyl)methyl]-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ] fourteen Alkane-6,14-dione hydrochloride Suspend the compound (12.0g, 23.9mmol) obtained in step 3 above in dichloromethane (250ml), add 4N hydrochloric acid/1,4-dione under ice cooling

The alkane solution (125ml) was stirred for 14 hours. The solvent was distilled off under reduced pressure, and diethyl ether was added and stirred for a while. The resulting solid was collected by filtration to obtain the title compound (10.5 g, 23.9 mmol, quantitative). ¹ H-NMR (DMSO-d ₆ ) δ: 9.26-9.11 (2H, m), 7.58-7.52 (1H, m), 7.40-7.36 (1H, m), 7.19-7.15 (1H, m), 4.96 ( 2H, s), 4.42-4.33 (2H, m), 4.24-4.14 (2H, m), 2.27-2.01 (6H, m), 1.93-1.84 (2H, m).

[Reference Example D-10] 10,10-difluoro-5-[(5-fluoro-6-methoxypyridin-3-yl)methyl]-2,5,13-triazabispiro [3.2. 5 ⁷ .2 ⁴ ]tetradecane-6,14-dione hydrochloride

[Step 1] 3-{[(5-Fluoro-6-methoxypyridin-3-yl)methyl]amino}azepine-1,3-dicarboxylate 1-tertiary butyl 3-ethyl ester will 3-Amino azepine-1,3-dicarboxylate 1-tertiary butyl 3-ethyl ester (530 mg, 2.17 mmol) and 5-fluoro-6-methoxypyridine-3-carbaldehyde (404 mg, 2.60 mmol) Suspended in 1,2-dichloroethane (15ml), sequentially added acetic acid (0.75ml), sodium triacetoxyborohydride (920mg, 4.34mmol), and stirred at room temperature for 15 hours. The solvent was distilled off directly under reduced pressure, saturated sodium bicarbonate water was added, extracted with ethyl acetate, and washed with saturated brine. After drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=5:95-80:20) to obtain the title compound (790 mg, 2.06mmol, 95%). ¹ H-NMR (CDCl ₃ ) δ: 7.86 (1H, s), 7.45 (1H, d, J = 10.9 Hz), 4.40-4.19 (4H, m), 4.04 (3H, s), 3.87 (2H, d) , J = 8.5 Hz), 3.64 (2H, s), 2.14 (1H, brs), 1.48 (9H, s), 1.36 (3H, t, J = 7.3 Hz).

[Step 2] 1-(Tertiary butoxycarbonyl)-3-{[(5-fluoro-6-methoxypyridin-3-yl)methyl]amino}azepine-3-carboxylic acid 1 The obtained compound (790 mg, 2.06 mmol) was dissolved in ethanol (8 ml), a 2N aqueous sodium hydroxide solution (8 ml) was added, and the mixture was stirred at 50°C for 1 hour. After the reaction liquid was ice-cooled, 1N hydrochloric acid aqueous solution was added to neutralize, and a suspension was obtained. The suspension was directly allowed to stand for 60 hours, and the precipitated solid was filtered and washed with water. The obtained solid was dried under reduced pressure at 70° C. for 10 hours to obtain the title compound (674 mg, 1.90 mmol, 92%). ¹ H-NMR (DMSO-d ₆ ) δ: 7.92 (1H, s), 7.67 (1H, d, J = 11.5 Hz), 4.12-3.88 (5H, m), 3.85-3.76 (2H, m), 3.65 (2H, s), 1.39 (9H, s).

[Step 3] 10,10-Difluoro-5-[(5-fluoro-6-methoxypyridin-3-yl)methyl]-6,14-dioxo-2,5,13-triazide Dispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-2-carboxylic acid tertiary butyl ester used the compound obtained in step 2 above (674 mg, 1.90 mmol) and the compound obtained in Reference Example C-5 (522 mg, 1.90 mmol), by performing the same operation as in Step 3 of Reference Example D-9 to obtain the title compound (316 mg, 0.634 mmol, 33%). ¹ H-NMR (DMSO-d ₆ ) δ: 8.93 (1H, s), 7.87 (1H, s), 7.59 (1H, d, J = 11.5 Hz), 4.79 (2H, s), 4.36-4.24 (2H , m), 4.04-3.89 (5H, m), 2.32-1.95 (6H, m), 1.89-1.73 (2H, m), 1.38 (9H, s).

[Step 4] 10,10-difluoro-5-[(5-fluoro-6-methoxypyridin-3-yl)methyl]-2,5,13-triazabispiro[3.2.5 ⁷ . 2 ⁴ ] Tetradecane-6,14-dione hydrochloride Using the compound (313 mg, 0.628 mmol) obtained in the above step 3, the title compound was obtained by performing the same operation as in the step 4 of Reference Example D-9 (270 mg, 0.205 mmol, 33%). MS (m/z): 399 (M+H) ⁺ .

Using the compound obtained in Reference Example, by performing the same operation as in Reference Example D-10, the following compound was obtained.

5-{[4-(二氟甲基)-3-氟苯基]甲基}-10,10-二氟-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 鹽酸鹽 ¹ H-NMR (DMSO-d₆ ) δ : 9.58 (1H, br s), 9.29-9.14 (2H, m), 7.62-7.56 (1H, m), 7.40-7.02 (3H, m), 5.06 (2H, s), 4.44-4.31 (2H, m), 4.26-4.11 (2H, m), 2.30-2.00 (6H, m), 1.97-1.83 (2H, m). 製造原料：參考例B-1、參考例C-5 D-17

11,11-二氟-6-({3-氟-4-[(² H₃ )甲基氧基]苯基}甲基)-2,6,14-三氮二螺[4.2.5⁸ .2⁵ ]十五烷-7,15-二酮 鹽酸鹽 ¹ H-NMR (DMSO-D₆ ) δ : 9.78 (1H, br s), 9.20-9.02 (2H, m), 7.14-7.05 (2H, m), 7.04-6.97 (1H, m), 4.76 (1H, d,J = 16.4 Hz), 4.55 (1H, d,J = 16.4 Hz), 3.71-3.62 (1H, m), 3.51-3.43 (1H, m), 3.37-3.24 (2H, m), 2.55-2.41 (1H, m), 2.35-2.03 (7H, m), 1.99-1.88 (2H, m). 製造原料：參考例B-3、參考例C-1 [Table 2] Reference example D-11

5-{[4-(Difluoromethyl)-3-fluorophenyl]methyl}-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ] ten Tetraoxane-6,14-dione hydrochloride ¹ H-NMR (DMSO-d ₆ ) δ: 9.58 (1H, br s), 9.29-9.14 (2H, m), 7.62-7.56 (1H, m), 7.40-7.02 (3H, m), 5.06 (2H , s), 4.44-4.31 (2H, m), 4.26-4.11 (2H, m), 2.30-2.00 (6H, m), 1.97-1.83 (2H, m). Manufacturing raw materials: Reference Example B-1, Reference Example C-5 D-17

11,11-Difluoro-6-({3-Fluoro-4-[( ² H ₃ )methyloxy]phenyl}methyl)-2,6,14-Triazabispiro[4.2.5 ⁸ .2 ⁵ ]pentadecane-7,15-dione hydrochloride ¹ H-NMR (DMSO-D ₆ ) δ: 9.78 (1H, br s), 9.20-9.02 (2H, m), 7.14-7.05 (2H, m), 7.04-6.97 (1H, m), 4.76 (1H , d, J = 16.4 Hz), 4.55 (1H, d, J = 16.4 Hz), 3.71-3.62 (1H, m), 3.51-3.43 (1H, m), 3.37-3.24 (2H, m), 2.55- 2.41 (1H, m), 2.35-2.03 (7H, m), 1.99-1.88 (2H, m). Manufacturing raw materials: Reference Example B-3, Reference Example C-1

Using commercially available reagents and the compound obtained in Reference Example, the following compound was obtained by performing the same operation as in Reference Example D-9.

5-{[4-(二氟甲氧基)-3-氟苯基]甲基}-10,10-二氟-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 鹽酸鹽 ¹ H-NMR (DMSO-d₆ ) δ : 9.62 (1H, br s), 9.33-9.01 (2H, br m), 7.39-7.27 (2H, m), 7.22 (1H, t, J = 73.2 Hz), 7.19-7.11 (1H, m), 4.99 (2H, s), 4.36 (2H, d, J = 11.6 Hz), 4.19 (2H, d, J = 11.6 Hz), 2.28-1.97 (6H, m), 1.95-1.79 (2H, m). 製造原料：參考例B-2、參考例C-5 D-13

10,10-二氟-5-(喹啉-6-基甲基)-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 鹽酸鹽 ¹ H-NMR (DMSO-d₆ ) δ : 10.30-9.82 (1H, br m), 9.32-9.09 (3H, m), 8.96-8.76 (1H, m), 8.38-8.20 (1H, m), 8.15-7.83 (3H, m), 5.38-5.23 (2H, m), 4.48-4.31 (2H, m), 4.31-4.16 (2H, m), 2.32-1.79 (8H, m). 製造原料：參考例C-5、喹啉-6-基甲胺 [table 3] Reference example D-12

5-{[4-(Difluoromethoxy)-3-fluorophenyl]methyl}-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ] Tetradecane-6,14-dione hydrochloride ¹ H-NMR (DMSO-d ₆ ) δ: 9.62 (1H, br s), 9.33-9.01 (2H, br m), 7.39-7.27 (2H, m), 7.22 (1H, t, J = 73.2 Hz) , 7.19-7.11 (1H, m), 4.99 (2H, s), 4.36 (2H, d, J = 11.6 Hz), 4.19 (2H, d, J = 11.6 Hz), 2.28-1.97 (6H, m), 1.95-1.79 (2H, m). Manufacturing raw materials: Reference Example B-2, Reference Example C-5 D-13

10,10-Difluoro-5-(quinolin-6-ylmethyl)-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione salt Acid salt ¹ H-NMR (DMSO-d ₆ ) δ: 10.30-9.82 (1H, br m), 9.32-9.09 (3H, m), 8.96-8.76 (1H, m), 8.38-8.20 (1H, m), 8.15 -7.83 (3H, m), 5.38-5.23 (2H, m), 4.48-4.31 (2H, m), 4.31-4.16 (2H, m), 2.32-1.79 (8H, m). Manufacturing raw materials: Reference Example C-5, Quinolin-6-methylamine

[Reference Example D-14] 10,10-difluoro-5-[(3-fluoro-4-methoxyphenyl)methyl]-2,5,13-triazabispiro [3.2.5 ⁷ . 2 ⁴ ]tetradecane-6,14-dione hydrochloride

[Step 1] 3-{[(3-Fluoro-4-methoxyphenyl)methyl]amino}azepine-1,3-dicarboxylate 1-tertiary butyl 3-methyl ester using 3-fluoro Anisaldehyde (3-fluoro-p-anisaldehyde) (705 mg, 4.57 mmol) was followed by the same operation as in Step 1 of Reference Example D-10 to obtain the title compound (955 mg, 2.59 mmol, 60%). ¹ H-NMR (CDCl ₃ ) δ: 7.10 (1H, dd, J = 12.0, 2.4 Hz), 7.06-6.99 (1H, m), 6.94-6.87 (1H, m), 4.19 (2H, d, J = 8.4 Hz), 3.88 (3H, s), 3.86 (2H, d, J = 8.4 Hz), 3.81 (3H, s), 3.59 (2H, s), 2.11 (1H, br s), 1.45 (9H, s) ).

[Step 2] 1-(Tertiary butoxycarbonyl)-3-{[(3-fluoro-4-methoxyphenyl)methyl]amino}azepine-3-carboxylic acid is obtained using step 1 above The compound (955 mg, 2.59 mmol) of, by performing the same operation as in Step 2 of Reference Example D-10, to obtain the title compound (937 mg, 2.64 mmol, quantitative). ¹ H-NMR (DMSO-d ₆ ) δ: 7.27-7.21 (1H, m), 7.16-7.09 (2H, m), 4.09-3.92 (2H, m), 3.86-3.71 (5H, m), 3.68 ( 2H, s), 1.38 (9H, s).

[Step 3] 3-{[(4,4-Difluoro-1-{[(2,2,2-trichloroethoxy)carbonyl]amino}cyclohexyl)carbonyl](3-fluoro-4- Methoxybenzyl)amino}azepine-1,3-dicarboxylate 1-tertiary butyl 3-methyl ester obtained from the compound (937 mg, 2.64 mmol) obtained in step 2 above, and obtained from Reference Example C-1 To the mixture of the compound (984mg, 2.78mmol), 4-dimethylaminopyridine (64.6mg, 0.529mmol) in N,N-dimethylformamide (26mL), add diisopropylcarbodiimide (1.64ml, 10.6mmol) and stirred at room temperature for 1.5 hours. To this mixture, methanol (13 ml) was added, and the mixture was stirred at room temperature for 1 hour. The residue obtained by distilling out most of the methanol under reduced pressure was separated with water and ethyl acetate, and the combined organic layer was washed with water and saturated brine, and dried with anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-30:70) to obtain the title compound (755 mg, 1.07 mmol, 41%). ¹ H-NMR (CDCl ₃ ) δ: 7.10-7.01 (2H, m), 6.99-6.92 (1H, m), 5.16 (1H, s), 4.99-4.68 (2H, m), 4.63-4.04 (4H, m), 4.00 (2H, d, J = 10.0 Hz), 3.88 (3H, s), 3.82 (3H, s), 2.57-2.29 (2H, m), 2.28-2.01 (4H, m), 1.99-1.77 (2H, m), 1.42 (9H, s).

[Step 4] 10,10-Difluoro-5-[(3-fluoro-4-methoxyphenyl)methyl]-6,14-dioxo-2,5,13-triazabispiro[ 3.2.5 ⁷ .2 ⁴ ] Tetradecane-2-carboxylic acid tertiary butyl ester was added to the compound (755mg, 1.07mmol) obtained in step 3 above in acetic acid (5ml) and tetrahydrofuran (10ml) solution, and zinc powder ( 350mg, 5.35mmol) and stirred at room temperature for 5 hours. The reaction mixture was filtered through Celite, washed with tetrahydrofuran and incorporated, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-40:60) to obtain the title compound (414 mg, 0.833 mmol, 78%). ¹ H-NMR (CDCl ₃ ) δ: 7.84 (1H, br s), 6.98-6.88 (3H, m), 5.02-4.70 (2H, m), 4.49 (2H, d, J = 9.2 Hz), 4.02 ( 2H, d, J = 9.2 Hz), 3.88 (3H, s), 2.47-2.18 (4H, m), 2.18-1.97 (2H, m), 1.83-1.66 (2H, m), 1.44 (9H, s) .

[Step 5] 10,10-Difluoro-5-[(3-fluoro-4-methoxyphenyl)methyl]-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ] Tetradecane-6,14-dione hydrochloride used the compound (414 mg, 0.833 mmol) obtained in the above step 4, and by performing the same operation as in the step 4 of Reference Example D-9, the title compound (346 mg, 0.798mmol, 96%). ¹ H-NMR (DMSO-d ₆ ) δ: 9.68 (1H, br s), 9.25-9.09 (2H, br m), 7.23-6.93 (3H, m), 4.93 (2H, s), 4.41-4.28 ( 2H, m), 4.28-4.10 (2H, m), 3.80 (3H, s), 2.29-1.96 (6H, m), 1.94-1.77 (2H, m).

[Reference Example D-15] 5-[(4-chloro-3-fluorophenyl)methyl]-2,5,14-triazabispiro[3.2.6 ⁷ .2 ⁴ ]pentadecane-6, 15-diketone hydrochloride

[Step 1] 5-[(4-chloro-3-fluorophenyl)methyl]-6,15-dioxo-2,5,14-triazabispiro[3.2.6 ⁷ .2 ⁴ ] ten Using the compound (508 mg, 2.01 mmol) obtained in Reference Example C-6 with tertiary butyl pentane-2-carboxylate, the title compound (182 mg, 2.01 mmol) was obtained by performing the same operation as in Step 3 of Reference Example D-9. 0.379 mmol, 23%). ¹ H-NMR (CDCl ₃ ) δ: 7.39-7.32 (1H, m), 6.98 (1H, dd, J = 9.6, 2.0 Hz), 6.95-6.91 (1H, m), 6.81 (1H, s), 4.88 (2H, br s), 4.51 (2H, d, J = 10.0 Hz), 3.94 (2H, d, J = 10.0 Hz), 2.31-2.18 (2H, m), 1.83-1.71 (2H, m), 1.69 -1.47 (8H, m), 1.44 (9H, s).

[Step 2] 5-[(4-chloro-3-fluorophenyl)methyl]-2,5,14-triazabispiro[3.2.6 ⁷ .2 ⁴ ]pentadecane-6,15-di Ketone hydrochloride used the compound (182 mg, 0.379 mmol) obtained in the above step 1, and the title compound (138 mg, 0.332 mmol, 88%) was obtained by performing the same operation as in the step 4 of Reference Example D-9. ¹ H-NMR (DMSO-d ₆ ) δ: 9.63 (1H, br s), 9.18 (1H, br s), 9.05 (1H, s), 7.57-7.55 (1H, m), 7.37-7.29 (1H, m), 7.16-7.07 (1H, m), 4.97 (2H, s), 4.40-4.26 (2H, m), 4.25-4.08 (2H, m), 2.11-1.93 (2H, m), 1.75-1.33 ( 10H, m).

[Reference Example D-16] 5-[(4-Chloro-3-fluorophenyl)methyl]-10-thio-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]14 Alkane-6,14-dione hydrochloride

[Step 1] 5-[(4-chloro-3-fluorophenyl)methyl]-6,14-dioxo-10-thio-2,5,13-triazabispiro [3.2.5 ⁷ . 2 ⁴ ] Tetradecane-2-carboxylic acid tertiary butyl ester is the compound (984 mg, 2.74 mmol) obtained in Step 2 of Reference Example D-9, 4-N-Pentylmethyloxycarbonylamino-4- To the N,N-dimethylformamide (27ml) mixture of carboxytetrahydrothiopyran (1.10g, 2.88mmol) and 4-dimethylaminopyridine (67.0mg, 0.548mmol), add diisopropyl group Carbodiimide (1.70ml, 11.0mmol) and stirred at room temperature for 1.5 hours. To this mixture, methanol (13 ml) was added and stirred at room temperature for 1 hour, and most of the methanol was distilled off under reduced pressure. The obtained residue was separated with water and ethyl acetate, and the combined organic layer was washed with water and saturated brine, and dried with anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-30:70-50:50) to obtain a crude intermediate. This was dissolved in N,N-dimethylformamide (12 ml), piperidine (2 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was separated with 1N hydrochloric acid aqueous solution and ethyl acetate, and the combined organic layer was washed with 1N hydrochloric acid aqueous solution and saturated brine in this order, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-35:65-50:50-100:0, amino silica gel) to obtain the title Compound (493 mg, 1.02 mmol, 40%). ¹ H-NMR (CDCl ₃ ) δ: 7.39-7.33 (1H, m), 7.02 (1H, brs), 6.99-6.90 (2H, m), 4.89 (2H, brs), 4.53 (2H, d, J = 9.2 Hz), 3.95 (2H, d, J = 9.2 Hz), 2.88-2.63 (4H, m), 2.47-2.33 (2H, m), 1.90-1.79 (2H, m), 1.44 (9H, s).

[Step 2] 5-[(4-Chloro-3-fluorophenyl)methyl]-10-thio-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6 ,14-Diketone Hydrochloride Using the compound (193 mg, 0.399 mmol) obtained in the above step 1, and by performing the same operation as in the step 4 of Reference Example D-9, the title compound (149 mg, 0.353 mmol, 89% ). ¹ H-NMR (DMSO-d ₆ ) δ: 9.78 (1H, br s), 9.16 (1H, br s), 9.09 (1H, s), 7.55-7.48 (1H, m), 7.41-7.35 (1H, m), 7.17-7.11 (1H, m), 4.98 (2H, s), 4.40-4.25 (2H, m), 4.23-4.04 (2H, m), 2.97-2.76 (2H, m), 2.70-2.53 ( 2H, m), 2.16-2.00 (2H, m), 1.95-1.78 (2H, m).

[Reference Example X-1] 4-ethynyl-2,6-difluorobenzoic acid

[Step 1] Methyl 2,6-difluoro-4-[(trimethylsilyl)ethynyl]benzoate and methyl 4-bromo-2,6-difluorobenzoate (2.00g, 7.73mmol) , Copper iodide (14.7 mg, 0.0773 mmol), and bis(triphenylphosphine) palladium(II) dichloride (217 mg, 0.309 mmol) were placed in a glass tube and replaced with nitrogen. Add N,N-diisopropylethylamine (1.98ml, 11.6mmol), N,N-dimethylformamide (15ml), trimethylsilylacetylene (1.34ml, 9.66mmol), and replace with nitrogen The tube was sealed and treated with a microwave reaction device at 100°C for 2 hours. After cooling to room temperature, the insoluble matter was filtered with Celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-5:95) to obtain the title compound (1.26 g, 4.71 mmol, 61%). ¹ H-NMR (CDCl ₃ ) δ: 7.26 (1H, s), 7.05-7.00 (2H, m), 3.95 (3H, s), 0.25 (9H, s).

[Step 2] 4-ethynyl-2,6-difluorobenzoic acid The compound (1.26 g, 4.71 mmol) obtained in the above step 1 was dissolved in methanol (50 ml), and potassium carbonate (846 mg, 6.12 mmol) was added at room temperature ) Aqueous solution (8ml) and stirred for 2 hours. Water was added to the reaction mixture, and methanol was distilled off under reduced pressure. After washing the obtained water layer with dichloromethane, under ice cooling, a 1N aqueous hydrochloric acid solution was added to adjust the acidity. It was extracted with ethyl acetate and washed with saturated brine. After drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (678 mg, 3.72 mmol, 79%). ¹ H-NMR (CDCl ₃ ) δ: 7.13-7.08 (2H, m), 3.31 (1H, s).

[Reference Example Q-1] 4-chloro-7-(1,1-difluoroethyl)quinazoline

[Step 1] 1-Chloro-4-(1,1-difluoroethyl)-2-nitrobenzene in 1-(4-chloro-3-nitrophenyl)ethane-1-one (14.0g , 70.1mmol) in dichloromethane (200ml) solution, add bis(2-methoxyethyl)aminosulfur trifluoride (50.6g, 210mmol) under ice cooling, and stir at room temperature for 48 hours. Under ice cooling, slowly pour into saturated sodium bicarbonate water and extract with dichloromethane. Dry over anhydrous sodium sulfate, distill off the solvent under reduced pressure, and purify the obtained residue by silica gel column chromatography (ethyl acetate-hexane=0:100-10:90) to obtain the title compound (13.4g, 60.5) mmol, 86%). ¹ H-NMR (CDCl ₃ ) δ: 8.02 (1H, s), 7.68-7.62 (2H, m), 1.95 (3H, t, J = 18.1 Hz).

[Step 2] 4-(1,1-Difluoroethyl)-2-nitrobenzonitrile The compound (14.9 g, 67.4 mmol) obtained in the above step 1 was dissolved in N-methyl-2-pyrrolidine Ketone (55ml), copper cyanide (12.3g, 135mmol) was added, and the mixture was heated and stirred at 160°C for 18 hours. The reaction liquid was diluted with ethyl acetate, and a saturated aqueous ammonium chloride solution was added and stirred. The resulting insoluble matter was filtered through Celite, extracted with ethyl acetate, and washed with water and saturated brine. Dry over anhydrous sodium sulfate, distill off the solvent under reduced pressure, and purify the obtained residue by silica gel column chromatography (ethyl acetate-hexane=0:100-25:75) to obtain the title compound (10.6g, 49.9 mmol, 74%). ¹ H-NMR (CDCl ₃ ) δ: 8.47 (1H, s), 8.02 (1H, d, J = 8.0 Hz), 7.96 (1H, d, J = 8.0 Hz), 2.00 (3H, t, J = 18.1 Hz).

[Step 3] 4-(1,1-Difluoroethyl)-2-nitrobenzamide in dimethyl sulfoxide (115ml) solution of the compound (9.43g, 44.5mmol) obtained in step 2 above In, while cooling, hydrogen peroxide water (7.32 ml, 88.9 mmol) was added, and then potassium carbonate (18.4 g, 133 mmol) was added, and the mixture was stirred at room temperature for 18 hours. Water and saturated brine were added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. Dry over anhydrous sodium sulfate, and distill off the solvent under reduced pressure. The obtained residue was suspended in a small amount of dichloromethane, hexane was added for ultrasonic treatment, and the mixture was stirred at room temperature for a while. The resulting solid was collected by filtration to obtain the title compound (9.43 g, 41.0 mmol, 92%). ¹ H-NMR (CDCl ₃ ) δ: 8.22 (1H, s), 7.86-7.81 (1H, m), 7.67 (1H, d, J = 8.0 Hz), 5.88-5.76 (2H, br m), 1.97 ( 3H, t, J = 18.1 Hz).

[Step 4] 2-Amino-4-(1,1-difluoroethyl)benzamide The compound (9.43 g, 41.0 mmol) obtained in the above step 3 was dissolved in ethanol (380 ml), and 10% was added Palladium on carbon (M) (1.8g), heated to 60°C and stirred for 5 hours under a hydrogen atmosphere. The catalyst was filtered off with Celite, and the solvent was distilled off under reduced pressure to obtain the title compound (7.72 g, 38.6 mmol, 94%). ¹ H-NMR (CDCl ₃ ) δ: 7.40 (1H, d, J = 8.0 Hz), 6.81 (1H, s), 6.77-6.73 (1H, m), 6.14-5.43 (3H, br m), 1.88 ( 3H, t, J = 18.1 Hz).

[Step 5] 7-(1,1-difluoroethyl)quinazolin-4(3H)-one The compound (2.67 g, 13.3 mmol) obtained in the above step 4, formamidine acetate (formamidine acetate) ( 4.17g, 40.0mmol) was dissolved in ethanol (80ml) and heated to reflux for 5 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. Water was added to the obtained residue, and after ultrasonic treatment, the mixture was stirred at room temperature for a while. The solid was filtered to obtain the title compound (2.59 g, 12.3 mmol, 93%). ¹ H-NMR (DMSO-d ₆ ) δ: 12.42 (1H, br s), 8.22 (1H, d, J = 8.6 Hz), 8.18 (1H, s), 7.81 (1H, s), 7.71-7.67 ( 1H, m), 2.04 (3H, t, J = 19.0 Hz).

[Step 6] 4-Chloro-7-(1,1-difluoroethyl)quinazoline The compound (2.59 g, 12.3 mmol) obtained in the above step 5 was suspended in toluene (55 ml), and under ice cooling, N was added , N-Diisopropylethylamine (6.02ml, 34.6mmol), phosphorus oxychloride (5.69g, 37.0mmol), heated to 100°C and stirred for 4 hours. After returning to room temperature, dilute with ethyl acetate. Under ice cooling, slowly pour into saturated sodium bicarbonate water, extract with ethyl acetate, and wash with water and saturated brine. After drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-20:80) to obtain the title compound (2.64 g, 11.5 mmol, 93%). ¹ H-NMR (CDCl ₃ ) δ: 9.11 (1H, s), 8.36 (1H, d, J = 8.6 Hz), 8.23 (1H, s), 7.88-7.84 (1H, m), 2.04 (3H, t , J = 18.4 Hz).

[Reference Example Q-2] 4-chloro-7-(propan-2-yloxy)quinazoline

[Step 1] Methyl 2-bromo-4-(propan-2-yloxy)benzoate in methyl 2-bromo-4-hydroxybenzoate (400mg, 1.73mmol), potassium carbonate (479mg, 3.46mmol) To the N,N-dimethylformamide (8ml) suspension, add 2-iodopropane (260μl, 2.60mmol) and stir at room temperature for 64 hours. Water was added to the reaction mixture to extract with ethyl acetate, and the combined organic layer was washed with water and saturated brine, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (457 mg, 1.67 mmol, 97%). ¹ H-NMR (CDCl ₃ ) δ: 7.84 (1H, d, J = 9.2 Hz), 7.17 (1H, d, J = 2.4 Hz), 6.83 (1H, dd, J = 9.2, 2.4 Hz), 4.67- 4.51 (1H, m), 3.89 (3H, s), 1.35 (6H, d, J = 6.0 Hz).

(96.7mg，0.167mmol)、乙酸鈀(II)(37.5mg，0.167mmol)之1,4-二

烷(7ml)懸浮液進行脫氣，添加二苯甲酮亞胺(benzophenone imine)(421μl，2.51mmol)，氮氣環境下，於100℃加熱回流4小時。濾除不溶物後，將減壓下濃縮濾液而獲得的殘留物溶解於四氫呋喃(2.5ml)，添加2N鹽酸水溶液(2.5ml)而於室溫攪拌15分鐘。於反應混合物中添加水而以乙酸乙酯萃取，將合併的有機層以飽和碳酸氫鈉水、飽和食鹽水洗淨，以無水硫酸鈉乾燥。減壓下餾除溶劑，將獲得的殘留物以矽膠管柱層析(乙酸乙酯-己烷=0:100-15:85)純化，而獲得標題化合物(279mg，1.33mmol，80%)。¹ H-NMR (CDCl₃ ) δ : 7.77 (1H, d, J = 9.2 Hz), 6.20 (1H, dd, J = 9.2, 2.4 Hz), 6.09 (1H, d, J = 2.4 Hz), 5.73 (2H, br s), 4.60-4.50 (1H, m), 3.83 (3H, s), 1.33 (6H, d, J = 6.0 Hz).[Step 2] Methyl 2-amino-4-[(propan-2-yl)oxy]benzoate The compound obtained in step 1 above (457 mg, 1.67 mmol), cesium carbonate (1.09 g, 3.34 mmol) , 4,5-bis(diphenylphosphino)-9,9-dimethyl

(96.7mg, 0.167mmol), palladium(II) acetate (37.5mg, 0.167mmol) 1,4-bis

The alkane (7 ml) suspension was degassed, benzophenone imine (421 μl, 2.51 mmol) was added, and the mixture was heated to reflux at 100° C. for 4 hours under a nitrogen atmosphere. After filtering off the insoluble matter, the residue obtained by concentrating the filtrate under reduced pressure was dissolved in tetrahydrofuran (2.5 ml), 2N aqueous hydrochloric acid (2.5 ml) was added, and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-15:85) to obtain the title compound (279 mg, 1.33 mmol, 80%). ¹ H-NMR (CDCl ₃ ) δ: 7.77 (1H, d, J = 9.2 Hz), 6.20 (1H, dd, J = 9.2, 2.4 Hz), 6.09 (1H, d, J = 2.4 Hz), 5.73 ( 2H, br s), 4.60-4.50 (1H, m), 3.83 (3H, s), 1.33 (6H, d, J = 6.0 Hz).

[Step 3] 7-[(Propan-2-yl)oxy]quinazolin-4(3H)-one The compound obtained in step 2 above (279 mg, 1.33 mmol), formamidine acetate (417 mg, 4.00 mmol) ) And a mixture of 2-methoxyethanol (4ml), heated to reflux at 130°C for 2 hours. After cooling to room temperature, a large amount of water was added, and the precipitated solid was collected by filtration to obtain the title compound (220 mg, 1.08 mmol, 81%). ¹ H-NMR (DMSO-d ₆ ) δ: 12.06 (1H, br s), 8.02 (1H, s), 8.00-7.95 (1H, m), 7.07-7.02 (2H, m), 4.85-4.72 (1H , m), 1.30 (6H, d, J = 6.4 Hz).

[Step 4] 4-Chloro-7-(propan-2-yloxy)quinazoline used the compound (411 mg, 2.01 mmol) obtained in step 3 above, and proceeded in the same way as step 6 of Reference Example Q-1 The title compound (343 mg, 1.54 mmol, 77%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 8.91 (1H, s), 8.13 (1H, d, J = 8.8 Hz), 7.32-7.25 (2H, m), 4.83-4.72 (1H, m), 1.44 (6H , d, J = 6.4 Hz).

[Reference Example Q-3] 4-chloro-7-nitroquinazoline

Using 7-nitro-3H-4-quinazoline (1.80g, 9.44mmol), the title compound (1.35g, 6.42mmol, 68%) was obtained by performing the same operation as in Step 6 of Reference Example Q-1 ). ¹ H-NMR (CDCl ₃ ) δ: 9.22 (1H, s), 8.96 (1H, s), 8.53-8.46 (2H, m).

[Reference Example Q-4] 4,7-Dichloropyrido[4,3-d]pyrimidine

[Step 1] Mix 6-chloro-4-[(4-methoxybenzyl)amino]pyridine-3-carboxylic acid methyl ester in 4,6-dichloronicotinic acid methyl ester (4.00g, 19.4mmol) To the dimethyl sulfoxide (40ml) solution, 4-methoxybenzylamine (2.51ml, 19.4mmol) and triethylamine (5.38ml, 38.8mmol) were added sequentially, and the mixture was stirred at room temperature for 74 hours. The reaction mixture was diluted with ethyl acetate, water was added for liquid separation, and the combined organic layer was washed with water and saturated brine, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (5.67 g, 18.5 mmol, 95%). ¹ H-NMR (CDCl ₃ ) δ: 8.68 (1H, s), 8.43 (1H, t, J = 5.6 Hz), 7.26-7.19 (2H, m), 6.93-6.84 (2H, m), 6.56 (1H , s), 4.34 (2H, d, J = 5.6 Hz), 3.87 (3H, s), 3.80 (3H, s).

[Step 2] 4-Amino-6-chloropyridine-3-carboxylic acid methyl ester The compound (5.67 g, 18.5 mmol) obtained in the above step 1 was dissolved in trifluoroacetic acid (48 ml), and heated and stirred at 60°C for 12 hours , Cool to room temperature. Ethanol was added to the residue obtained by concentration under reduced pressure, and it was concentrated again under reduced pressure. Ethanol was added to the obtained residue, the slurry was washed to remove the precipitated solid, and the ethanol was washed, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-40:60-50:50, amino silica gel) to obtain the title compound (2.46g, 13.2mmol, 71% ). ¹ H-NMR (CDCl ₃ ) δ: 8.68 (1H, s), 6.57 (1H, s), 3.90 (3H, s).

[Step 3] 7-Chloropyrido[4,3-d]pyrimidin-4(3H)-one The compound obtained in the above step 2 (1.20g, 6.43mmol) and formamidine acetate (1.34g, 12.9mmol) Suspended in 2-methoxyethanol (12ml), heated to reflux at 130°C for 5 hours. After cooling to room temperature, formamidine acetate (5.36 g, 51.4 mmol) was added, and the mixture was heated to reflux at 140° C. for 22.5 hours. After cooling to room temperature, most of the solvent was distilled off under reduced pressure. Add a large amount of water to filter out the precipitated insoluble matter, and wash with water and ethanol. After standing the filtrate, the precipitated solid was collected by filtration. The filtrate was concentrated under reduced pressure, and most of the ethanol was removed by distillation, and the precipitated solid was filtered out and washed with water. It was dried together with the previously filtered solid to obtain the title compound (550 mg, 3.03 mmol, 47%). ¹ H-NMR (DMSO-d ₆ ) δ: 12.75 (1H, s), 9.09 (1H, s), 8.33 (1H, s), 7.73 (1H, s).

[Step 4] 4,7-Dichloropyrido[4,3-d]pyrimidine was added to a suspension of sulfite chloride (14ml) of the compound (250mg, 1.38mmol) obtained in step 3 above, N,N- Dimethylformamide (160μl, 2.07mmol) was heated to reflux at 90°C for 5.5 hours. After cooling to room temperature, it was concentrated under reduced pressure. Toluene was added to the obtained residue, the operation of concentration under reduced pressure was repeated twice, and the solution was further dissolved in dichloromethane, and concentrated under reduced pressure to obtain the title compound (258 mg, 1.29 mmol, 94%). ¹ H-NMR (CDCl ₃ ) δ: 9.51 (1H, s), 9.19 (1H, s), 7.97 (1H, s).

[Reference Example Q-5] 4-chloro-7-difluoromethoxyquinazoline

[Step 1] A suspension of potassium carbonate (1.53g, 11.0mmol) in N,N-dimethylformamide (16ml) heated and stirred at 100°C with methyl 2-bromo-4-difluoromethoxybenzoate In the dropping funnel, slowly drop N,N-dimethyl 2-bromo-4-hydroxybenzoate (1.70g, 7.36mmol) and sodium chlorodifluoroacetate (2.24g, 14.7mmol) over 1 hour. A solution of methylcarbamide (28ml). After completion of the dropping, it was heated and stirred at the same temperature for 2.5 hours, and then cooled to room temperature. Water was added to the reaction mixture, liquid separation was performed with ethyl acetate, and the combined organic layer was washed with water and saturated brine, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-10:90) to obtain the title compound (1.05 g, 3.72 mmol, 51%). ¹ H-NMR (CDCl ₃ ) δ: 7.87 (1H, d, J = 8.8 Hz), 7.44 (1H, d, J = 2.4 Hz), 7.12 (1H, dd, J = 8.8, 2.4 Hz), 6.57 ( 1H, t, J = 72.4 Hz), 3.93 (3H, s).

(215mg，0.372mmol)、乙酸鈀(83.5mg，0.372mmol)之1,4-二

烷(16ml)懸浮液進行脫氣，添加二苯甲酮亞胺(1.01g，5.58mmol)，於氮氣環境下於100℃加熱回流4小時，冷卻至室溫。將不溶物過濾而去除，以乙酸乙酯洗滌併入，減壓下濃縮濾液。將獲得的殘留物溶解於四氫呋喃(5.5ml)，添加2N鹽酸水溶液(5.50ml，11.0mmol)而於室溫攪拌15分鐘。添加水而以乙酸乙酯萃取，將合併的有機層以飽和碳酸氫鈉水、飽和食鹽水洗淨，以無水硫酸鈉乾燥。將減壓下餾除溶劑而獲得的殘留物以矽膠管柱層析(乙酸乙酯-己烷=0:100-15:85)純化，而獲得標題化合物(730mg，3.36mmol，90%)。¹ H-NMR (CDCl₃ ) δ : 7.86 (1H, d, J = 8.4 Hz), 6.53 (1H, t, J = 73.6 Hz), 6.39-6.30 (2H, m), 5.86 (2H, br s), 3.86 (3H, s).[Step 2] Methyl 2-amino-4-difluoromethoxybenzoate The compound obtained in step 1 above (1.05g, 3.72mmol), cesium carbonate (2.42g, 7.44mmol), 4,5- Bis(diphenylphosphino)-9,9-dimethyl

(215mg, 0.372mmol), palladium acetate (83.5mg, 0.372mmol) of 1,4-bis

The alkane (16 ml) suspension was degassed, benzophenone imine (1.01 g, 5.58 mmol) was added, and the mixture was heated to reflux at 100° C. for 4 hours under a nitrogen atmosphere and cooled to room temperature. The insoluble matter was removed by filtration, washed with ethyl acetate and incorporated, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (5.5 ml), a 2N aqueous hydrochloric acid solution (5.50 ml, 11.0 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. Water was added to extract with ethyl acetate, and the combined organic layer was washed with saturated sodium bicarbonate water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-15:85) to obtain the title compound (730 mg, 3.36 mmol, 90%). ¹ H-NMR (CDCl ₃ ) δ: 7.86 (1H, d, J = 8.4 Hz), 6.53 (1H, t, J = 73.6 Hz), 6.39-6.30 (2H, m), 5.86 (2H, br s) , 3.86 (3H, s).

[Step 3] Using the compound (730 mg, 3.36 mmol) obtained in step 2 above for 7-difluoromethoxyquinazolin-4(3H)-one, the same procedure as in step 3 of Reference Example Q-4 was carried out. Operation to obtain the title compound (543 mg, 2.56 mmol, 76%). ¹ H-NMR (DMSO-d ₆ ) δ: 12.33 (1H, br s), 8.15 (1H, d, J = 8.4 Hz), 8.13 (1H, s), 7.50 (1H, t, J = 73.2 Hz) , 7.37 (1H, d, J = 1.6 Hz), 7.30 (1H, dd, J = 8.4, 1.6 Hz).

[Step 4] The compound (609 mg, 2.87 mmol) obtained in the above step 3 was used for 4-chloro-7-difluoromethoxyquinazoline, and the same operation as that in the step 4 of Reference Example Q-4 was carried out. The title compound (618 mg, 2.68 mmol, 93%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 9.03 (1H, s), 8.30 (1H, d, J = 8.8 Hz), 7.70 (1H, d, J = 2.4 Hz), 7.50 (1H, dd, J = 8.8 , 2.4 Hz), 6.76 (1H, t, J = 72.0 Hz).

[Reference Example Q-6] 4-chloro-7-(2,2-difluoroethyl)quinazoline

[Step 1] Methyl 4-diazoacetin-2-nitrobenzoate was suspended in dichloromethane (110ml) of 1-methyl 2-nitroterephthalate (5.00g, 22.2mmol), Add glufosinate chloride (2.29ml, 26.6mmol) and N,N-dimethylformamide (0.4ml), stir at room temperature for 2.5 hours, further add glufosinate chloride (571μl, 6.66mmol), and stir at room temperature After 30 minutes, it was concentrated under reduced pressure to obtain acetonitrile. This was dissolved in acetonitrile (30 ml), a 2.0 M diethyl ether solution (22.0 ml, 44.4 mmol) of trimethylsilyldiazomethane was added under ice cooling, and the mixture was stirred at the same temperature for 3 hours. Add acetic acid, quench the excess amount of trimethylsilyldiazomethane, extract with water and ethyl acetate, wash the combined organic layer with saturated sodium bicarbonate water and saturated brine, and dry with anhydrous sodium sulfate . The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-40:60-50:50) to obtain the title compound (4.53g, 18.2mmol , 82%). ¹ H-NMR (CDCl ₃ ) δ: 8.28 (1H, d, J = 2.0 Hz), 8.06 (1H, dd, J = 8.0, 2.0 Hz), 7.82 (1H, d, J = 8.0 Hz), 5.99 ( 1H, s), 3.95 (3H, s).

[Step 2] 4-(2-tertiary butoxy-2-oxoethyl)-2-nitrobenzoic acid methyl ester was added to the compound (4.53g, 18.2mmol) obtained in step 1 above, tertiary The mixture of butyl alcohol (50ml) was heated and refluxed, and a solution of silver benzoate (1.25g, 5.46mmol) in triethylamine (8ml) was added dropwise over 1 hour. After further heating and refluxing for 1 hour, it was cooled to room temperature. . The reaction mixture was filtered through Celite, washed with ethyl acetate and incorporated, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-20:80). The fractions containing the target substance were collected, concentrated under reduced pressure, dissolved in diethyl ether, and separated with saturated sodium bicarbonate water. The combined organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (2.73 g, 9.25 mmol, 51%). ¹ H-NMR (CDCl ₃ ) δ: 7.83 (1H, d, J = 2.0 Hz), 7.71 (1H, d, J = 8.0 Hz), 7.58 (1H, dd, J = 8.0, 2.0 Hz), 3.91 ( 3H, s), 3.64 (2H, s), 1.45 (9H, s).

[Step 3] [4-Methoxycarbonyl-3-nitrophenyl] acetic acid was added to the dichloromethane (45ml) solution of the compound (2.73g, 9.25mmol) obtained in step 2 above, and trifluoroacetic acid ( 45ml), stirred at room temperature for 6 hours, and concentrated under reduced pressure. Dichloromethane was added, and the mixture was dried by concentration under reduced pressure to obtain the title compound (2.23 g, 9.34 mmol, quantitative). ¹ H-NMR (CDCl ₃ ) δ: 12.65 (1H, br s), 7.98 (1H, d, J = 1.6 Hz), 7.82 (1H, d, J = 8.0 Hz), 7.72 (1H, dd, J = 8.0, 1.6 Hz), 3.83 (3H, s), 3.82 (2H, s).

[Step 4] Methyl 4-(2-hydroxyethyl)-2-nitrobenzoate was added to the tetrahydrofuran (50ml) solution of the compound (2.23g, 9.34mmol) obtained in step 3 above, and borane dimethyl The thioether complex (1.33ml, 14.0mmol) was stirred at room temperature for 17.5 hours. Water and saturated sodium bicarbonate water were added to extract with ethyl acetate, and the combined organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-60:40) to obtain the title compound (2.03 g, 9.02 mmol, 97%) . ¹ H-NMR (CDCl ₃ ) δ: 7.77 (1H, d, J = 1.2 Hz), 7.70 (1H, d, J = 7.2 Hz), 7.55 (1H, dd, J = 7.2, 1.2 Hz), 3.98- 3.88 (2H, m), 3.91 (3H, s), 2.98 (2H, t, J = 6.0 Hz), 1.48 (1H, t, J = 5.2 Hz).

[Step 5] Methyl 2-nitro-4-(2-oxoethyl)benzoate in dichloromethane (25ml) solution of the compound (1.13g, 5.02mmol) obtained in step 4 above, under ice cooling Add 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodooxy-3-(1H)-one (2.34g, 5.52mmol), warm up to room temperature and Stir for 1 hour. Saturated sodium bicarbonate water was added, extracted with dichloromethane, the combined organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-30:70) to obtain the title compound (814 mg, 3.65 mmol, 73%). ¹ H-NMR (CDCl ₃ ) δ: 9.84 (1H, t, J = 1.2 Hz), 7.76 (1H, d, J = 7.2 Hz), 7.76 (1H, d, J = 1.6 Hz), 7.52 (1H, dd, J = 7.2, 1.6 Hz), 3.93 (3H, s), 3.90 (2H, d, J = 1.2 Hz).

[Step 6] 4-(2,2-Difluoroethyl)-2-nitrobenzoic acid methyl ester was added to the dichloromethane (18ml) solution of the compound (814mg, 3.65mmol) obtained in the above step 5 (2-Methoxyethyl)aminosulfur trifluoride (1.33ml, 6.20mmol), and stirred at room temperature for 4 days. Saturated sodium bicarbonate water was added to the reaction mixture, extracted with dichloromethane, and the combined organic layer was washed with saturated brine, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-20:80) to obtain the title compound (715 mg, 2.92 mmol, 80%). ¹ H-NMR (CDCl ₃ ) δ: 7.81 (1H, d, J = 1.2 Hz), 7.74 (1H, d, J = 8.0 Hz), 7.58 (1H, dd, J = 8.0, 1.2 Hz), 6.01 ( 1H, tt, J = 55.6, 4.0 Hz), 3.93 (3H, s), 3.28 (2H, dt, J = 17.2, 4.0 Hz).

[Step 7] Methyl 2-amino-4-(2,2-difluoroethyl)benzoate was added to the ethanol (29ml) solution of the compound (715mg, 2.92mmol) obtained in Step 6 above and 10% Palladium on carbon (71.5 mg) was heated and stirred at 60°C for 1.5 hours under a hydrogen atmosphere, and then cooled to room temperature. The reaction mixture was filtered through Celite, washed with ethyl acetate and incorporated, and the filtrate was concentrated under reduced pressure. Dissolve in ethanol (29ml) again, add 10% palladium on carbon (71.5mg), heat and stir at 60°C for 2 hours in a hydrogen environment, cool to room temperature, filter with celite, wash with ethyl acetate and incorporate. The filtrate was concentrated under reduced pressure to obtain the title compound (605 mg, 2.81 mmol, 96%). ¹ H-NMR (CDCl ₃ ) δ: 7.81 (1H, d, J = 7.6 Hz), 6.55 (1H, s), 6.53 (1H, d, J = 7.6 Hz), 5.92 (1H, tt, J = 56.4 , 4.8 Hz), 5.74 (2H, br s), 3.86 (3H, s), 3.05 (2H, dt, J = 17.2, 4.8 Hz).

[Step 8] 7-(2,2-Difluoroethyl)quinazolin-4(3H)-one The compound (605 mg, 2.81 mmol) obtained in the above step 7 was used by proceeding with Reference Example Q-4 The same operation as in step 3 was performed to obtain the title compound (489 mg, 2.33 mmol). ¹ H-NMR (DMSO-d ₆ ) δ: 12.24 (1H, br s), 8.09 (1H, s), 8.07 (1H, d, J = 8.4 Hz), 7.65-7.60 (1H, m), 7.45 ( 1H, dd, J = 8.4, 1.6 Hz), 6.35 (1H, tt, J = 56.4, 4.4 Hz), 3.36 (2H, dt, J = 18.4, 4.4 Hz).

[Step 9] 4-Chloro-7-(2,2-difluoroethyl)quinazoline used the compound (405 mg, 1.93 mmol) obtained in the above step 8 by proceeding to the step 4 of Reference Example Q-4 The same operation was performed to obtain the title compound (404 mg, 1.77 mmol). ¹ H-NMR (CDCl ₃ ) δ: 9.05 (1H, s), 8.26 (1H, d, J = 8.4 Hz), 8.00-7.94 (1H, m), 7.65 (1H, dd, J = 8.4, 1.2 Hz ), 6.07 (1H, tt, J = 56.4, 4.4 Hz), 3.42 (2H, dt, J = 17.2, 4.4 Hz).

[Reference Example Q-7] 2,4-Dichloro-7-(1,1-difluoroethyl)quinazoline

[Step 1] 7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione The compound obtained in step 4 of Reference Example Q-1 (7.72g, 38.6mmol ) Was dissolved in tetrahydrofuran (385ml), added with 1,1´-carbonyldiimidazole (20.8g, 116mmol), and heated to reflux at 70°C for 8 hours. The solvent was distilled off under reduced pressure, and dichloromethane and a 1N aqueous hydrochloric acid solution were added to the obtained residue to perform ultrasonic treatment. The resulting solid was collected by filtration, washed with 1N aqueous hydrochloric acid, water, and dichloromethane in this order, and dried under reduced pressure to obtain the title compound (6.51 g, 28.8 mmol). ¹ H-NMR (DMSO-d ₆ ) δ: 11.45 (1H, s), 11.30 (1H, s), 7.98 (1H, d, J = 8.0 Hz), 7.34 (1H, d, J = 8.0 Hz), 7.31 (1H, s), 1.97 (3H, t, J = 19.0 Hz).

[Step 2] 2,4-Dichloro-7-(1,1-difluoroethyl)quinazoline The compound (1.39g, 6.13mmol) obtained in the above step 1 was suspended in toluene (55ml), under ice cooling , Phosphorus oxychloride (3.80g, 24.5mmol) and N,N-diisopropylethylamine (3.15ml, 18.4mmol) were added, and it was heated to reflux for 12 hours. After returning the reaction mixture to room temperature, it was poured into ice-cold saturated sodium bicarbonate water. It was extracted with ethyl acetate and washed with saturated brine. It was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-10:90) to obtain the title compound (974 mg, 3.70 mmol, 60%). ¹ H-NMR (CDCl ₃ ) δ: 8.34 (1H, d, J = 8.0 Hz), 8.16 (1H, s), 7.87-7.84 (1H, m), 2.02 (3H, t, J = 18.1 Hz).

[Reference Example Q-8] 2,4-Dichloro-7-difluoromethoxyquinazoline

[Step 1] 7-Difluoromethoxyquinazoline-2,4(1H,3H)-dione The compound obtained in Step 2 of Reference Example Q-5 (1.81g, 8.32mmol), urea (2.50 g, 41.6 mmol), heated and stirred at 180°C for 6 hours, and then cooled to 100°C. After adding water and stirring at 100°C for 5 minutes, it was cooled to room temperature, ethyl acetate was added, and ultrasonic treatment was performed, and the precipitated solid was filtered out. After washing the solid with water and ethyl acetate, it was dried under reduced pressure to obtain the title compound (1.28 g, 5.62 mmol, 68%). ¹ H-NMR (DMSO-d ₆ ) δ: 11.26 (2H, br s), 7.92 (1H, d, J = 8.4 Hz), 7.37 (1H, t, J = 72.4 Hz), 6.96 (1H, dd, J = 8.4, 2.0 Hz), 6.85 (1H, d, J = 2.0 Hz).

[Step 2] Using the compound (1.28 g, 5.62 mmol) obtained in the above step 1, 2,4-dichloro-7-difluoromethoxyquinazoline was performed in the same manner as in the step 2 of Reference Example Q-7 Operation to obtain the title compound (1.08 g, 4.07 mmol, 72%). ¹ H-NMR (CDCl ₃ ) δ: 8.28 (1H, d, J = 8.8 Hz), 7.63 (1H, d, J = 2.0 Hz), 7.49 (1H, dd, J = 8.8, 2.0 Hz), 6.75 ( 1H, t, J = 71.6 Hz).

[Reference Example Q-9] 7-chloro-2-ethylquinazolin-4(3H)-one

A mixture of triethyl orthopropionate (1.65ml, 8.33mmol) and 2-amino-4-chlorobenzamide (284mg, 1.67mmol) was heated and refluxed at 160°C for 6 hours, then cooled to room temperature, and further Add triethyl orthopropionate (3.30ml, 16.7mmol), heat and stir at 150°C for 12 hours, and cool to room temperature. Saturated brine was added to the reaction mixture, extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-50:50-80:20) to obtain the title compound (86.9mg, 0.416mmol , 25%). ¹ H-NMR (DMSO-d ₆ ) δ: 12.32 (1H, br s), 8.05 (1H, d, J = 8.4 Hz), 7.64 (1H, d, J = 1.6 Hz), 7.48 (1H, dd, J = 8.4, 1.6 Hz), 2.61 (2H, q, J = 7.6 Hz), 1.22 (3H, t, J = 7.6 Hz).

[Reference Example Q-10] 7-chloro-2-cyclopropylquinazolin-4(3H)-one

[Step 1] 7-chloro-2-cyclopropylquinazolin-4(3H)-one in 2-bromo-4-chlorobenzoic acid (1.00g, 4.25mmol), cyclopropanecarboxamidine hydrochloride (768mg , 6.37mmol) of N,N-dimethylformamide (20ml), add cesium carbonate (2.77g, 8.49mmol), stir at room temperature for 5 minutes, add copper iodide (162mg, 0.849mmol) , Heat and stir at 100°C for 3.5 hours in a nitrogen environment, then cool to room temperature. Add 1N hydrochloric acid aqueous solution (pay attention to foaming) and a large amount of water, stir for a while at room temperature, and filter the precipitated solid. The solid was washed with a large amount of water and diethyl ether, and dried under reduced pressure to obtain the title compound (729 mg, 3.31 mmol, 78%). ¹ H-NMR (DMSO-d ₆ ) δ: 12.57 (1H, br s), 8.02 (1H, d, J = 8.8 Hz), 7.50 (1H, d, J = 1.6 Hz), 7.41 (1H, dd, J = 8.8, 1.6 Hz), 2.01-1.86 (1H, m), 1.16-0.94 (4H, m).

[Reference Example Q-11] 7-(2-fluoroethyl)quinazolin-4(3H)-one

[Step 1] Methyl 4-(2-fluoroethyl)-2-nitrobenzoate in a dichloromethane (20ml) solution of the compound (900mg, 4.00mmol) obtained in Step 4 of Reference Example Q-6 , Bis(2-methoxyethyl)amino sulfur trifluoride (1.03ml, 4.80mmol) was added, and the mixture was stirred at room temperature for 4 days. Saturated sodium bicarbonate water was added to the reaction mixture, extracted with dichloromethane, and the combined organic layer was washed with saturated brine, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-20:80) to obtain the title compound (654 mg, 2.88 mmol, 72%). ¹ H-NMR (CDCl ₃ ) δ: 7.77 (1H, d, J = 1.6 Hz), 7.72 (1H, d, J = 8.0 Hz), 7.55 (1H, dd, J = 8.0, 1.6 Hz), 4.69 ( 2H, dt, J = 46.4, 6.0 Hz), 3.91 (3H, s), 3.12 (2H, dt, J = 26.0, 6.0 Hz).

[Step 2] Methyl 2-amino-4-(2-fluoroethyl)benzoate used the compound (654 mg, 2.88 mmol) obtained in step 1 above, and proceeded in the same manner as step 7 of Reference Example Q-6 Operation to obtain the title compound (558mg, 2.83mmol, 98%). ¹ H-NMR (CDCl ₃ ) δ: 7.79 (1H, d, J = 8.0 Hz), 6.56-6.48 (2H, m), 5.70 (2H, br s), 4.62 (2H, dt, J = 47.2, 6.0 Hz), 3.86 (3H, s), 2.92 (1H, dt, J = 24.0, 6.0 Hz).

[Step 3] 7-(2-Fluoroethyl)quinazolin-4(3H)-one Using the compound (558 mg, 2.83 mmol) obtained in step 2 above, by proceeding to step 3 of Reference Example Q-2 The same operation was performed to obtain the title compound (383 mg, 1.99 mmol, 70%). ¹ H-NMR (DMSO-d ₆ ) δ: 12.19 (1H, br s), 8.07 (1H, s), 8.05 (1H, d, J = 8.4 Hz), 7.60-7.53 (1H, m), 7.43 ( 1H, dd, J = 8.4, 1.6 Hz), 4.72 (2H, dt, J = 46.8, 6.0 Hz), 3.13 (2H, dt, J = 25.6, 6.0 Hz).

[Reference Example Q-12] 7-vinylquinazolin-4(3H)-one

-2-基)氧基]喹唑啉 於7-碘喹唑啉-4(3H)-酮(3.71g，13.6mmol)之N,N-二甲基甲醯胺(65ml)懸浮液中，添加3,4-二氫-2H-哌喃(4.98ml，54.6mmol)、對甲苯磺酸一水合物(260mg，1.36mmol)，於室溫攪拌18小時。於反應液中添加水、飽和碳酸氫鈉水，並以乙酸乙酯萃取。將有機層以水、飽和食鹽水洗淨，以無水硫酸鈉乾燥。減壓下餾除溶劑，將獲得的殘留物以矽膠管柱層析(乙酸乙酯-己烷=0:100-20:80)純化，而獲得標題化合物(3.85g，10.8mmol，79%)。¹ H-NMR (CDCl₃ ) δ : 8.27 (1H, s), 8.12 (1H, d, J = 2.0 Hz), 7.97 (1H, d, J = 8.0 Hz), 7.79 (1H, dd, J = 8.0, 2.0 Hz), 5.90 (1H, dd, J = 11.2, 2.4 Hz), 4.24-4.17 (1H, m), 3.78-3.69 (1H, m), 2.07-1.98 (2H, m), 1.86-1.48 (4H, m).[Step 1] 7-iodine-4-[(oxygen

-2-yl)oxy]quinazoline in 7-iodoquinazolin-4(3H)-one (3.71g, 13.6mmol) in N,N-dimethylformamide (65ml) suspension, Add 3,4-dihydro-2H-piperan (4.98ml, 54.6mmol) and p-toluenesulfonic acid monohydrate (260mg, 1.36mmol), and stir at room temperature for 18 hours. Water and saturated sodium bicarbonate water were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-20:80) to obtain the title compound (3.85 g, 10.8 mmol, 79%) . ¹ H-NMR (CDCl ₃ ) δ: 8.27 (1H, s), 8.12 (1H, d, J = 2.0 Hz), 7.97 (1H, d, J = 8.0 Hz), 7.79 (1H, dd, J = 8.0 , 2.0 Hz), 5.90 (1H, dd, J = 11.2, 2.4 Hz), 4.24-4.17 (1H, m), 3.78-3.69 (1H, m), 2.07-1.98 (2H, m), 1.86-1.48 ( 4H, m).

(721μl，4.21mmol)、碳酸鉀(776mg，5.62mmol)之1,4-二

烷(27ml)、水(3ml)混合物中，添加[1,1´-雙(二苯基膦基)二茂鐵]二氯化鈀(II)二氯甲烷加成物(229mg，0.281mmol)，進行脫氣，氮氣環境下，於100℃加熱攪拌1小時。冷卻至室溫後，添加飽和食鹽水，以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨，以無水硫酸鈉乾燥。減壓下餾除溶劑，將獲得的殘留物以矽膠管柱層析(乙酸乙酯-己烷=0:100-25:75)純化，而獲得標題化合物(568mg，2.22mmol，79%)。¹ H-NMR (CDCl₃ ) δ : 8.28 (1H, s), 8.24 (1H, d, J = 8.4 Hz), 7.68 (1H, d, J = 1.2 Hz), 7.56 (1H, dd, J = 8.4, 1.2 Hz), 6.83 (1H, dd, J = 17.6, 11.2 Hz), 5.96 (1H, d, J = 17.6 Hz), 5.94 (1H, dd, J = 10.8, 2.4 Hz), 5.47 (1H, d, J = 11.2 Hz), 4.28-4.16 (1H, m), 3.82-3.67 (1H, m), 2.09-1.97 (2H, m), 1.85-1.53 (4H, m).[Step 2] 7-vinyl-4-(tetrahydro-2H-piperan-2-yloxy)quinazoline in the compound obtained in step 1 above (1.00 g, 2.81 mmol), 4,4,5 ,5-Tetramethyl-2-vinyl-1,3,2-dioxboron

(721μl, 4.21mmol), potassium carbonate (776mg, 5.62mmol) of 1,4-bis

To a mixture of alkane (27ml) and water (3ml), add [1,1´-bis(diphenylphosphino)ferrocene] dichloropalladium(II) dichloromethane adduct (229mg, 0.281mmol) , Degassing, heating and stirring at 100°C for 1 hour in a nitrogen environment. After cooling to room temperature, saturated brine was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-25:75) to obtain the title compound (568 mg, 2.22 mmol, 79%). ¹ H-NMR (CDCl ₃ ) δ: 8.28 (1H, s), 8.24 (1H, d, J = 8.4 Hz), 7.68 (1H, d, J = 1.2 Hz), 7.56 (1H, dd, J = 8.4 , 1.2 Hz), 6.83 (1H, dd, J = 17.6, 11.2 Hz), 5.96 (1H, d, J = 17.6 Hz), 5.94 (1H, dd, J = 10.8, 2.4 Hz), 5.47 (1H, d , J = 11.2 Hz), 4.28-4.16 (1H, m), 3.82-3.67 (1H, m), 2.09-1.97 (2H, m), 1.85-1.53 (4H, m).

[Step 3] 7-Vinylquinazolin-4(3H)-one The compound (200mg, 0.780mmol) obtained in the above step 2 was dissolved in methanol (5ml), and p-toluenesulfonic acid monohydrate (148mg, 0.780mmol), heated and stirred at 50°C for 6 hours. After cooling to room temperature, it was concentrated under reduced pressure, water, saturated sodium bicarbonate water, and ethyl acetate were added to the obtained residue, and liquid separation was performed. The organic layer was washed with saturated brine, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (118 mg, 0.685 mmol, 88%). ¹ H-NMR (DMSO-d ₆ ) δ: 12.22 (1H, br s), 8.10-8.04 (2H, m), 7.71-7.66 (2H, m), 6.89 (1H, dd, J = 18.4, 10.8 Hz ), 6.09 (1H, d, J = 18.4 Hz), 5.48 (1H, d, J = 10.8 Hz).

[Reference Example Q-13] 7-Cyclopropylquinazolin-4(3H)-one

烷(18ml)、水(2ml)混合物進行脫氣，添加[1,1´-雙(二苯基膦基)二茂鐵]二氯化鈀(II)二氯甲烷加成物(115mg，0.140mmol)，於氮氣環境下於100℃加熱攪拌6小時，冷卻至室溫。添加飽和食鹽水，以乙酸乙酯萃取，將合併的有機層以飽和食鹽水洗淨，以無水硫酸鈉乾燥。將減壓下餾除溶劑而獲得的殘留物以矽膠管柱層析(乙酸乙酯-己烷=0:100-25:75)純化，獲得偶合體。將其溶解於甲醇(2ml)，添加對甲苯磺酸一水合物(46.3mg，0.243mmol)，於室溫攪拌21.5小時。將減壓下濃縮而獲得的殘留物以水、飽和碳酸氫鈉水、乙酸乙酯進行分液，將合併的有機層以飽和食鹽水洗淨，以無水硫酸鈉乾燥。減壓下餾除溶劑，將獲得的殘留物以矽膠管柱層析(乙酸乙酯-己烷=0:100-20:80)純化，而獲得標題化合物(23.2mg，0.125mmol，9%)。¹ H-NMR (DMSO-d₆ ) δ : 12.11 (1H, br s), 8.03 (1H, s), 7.96 (1H, d, J = 8.8 Hz), 7.33 (1H, d, J = 1.2 Hz), 7.20 (1H, dd, J = 8.8, 1.2 Hz), 2.14-2.01 (1H, m), 1.11-1.00 (2H, m), 0.86-0.74 (2H, m).Combine 7-iodo-4-tetrahydropiperan-2-yloxy-quinazoline (500mg, 1.40mmol), cyclopropylboronic acid (241mg, 2.81mmol), potassium carbonate (485mg, 3.51mmol) 1, 4-two

The mixture of alkane (18ml) and water (2ml) was degassed, and [1,1´-bis(diphenylphosphino)ferrocene] dichloropalladium(II) dichloromethane adduct (115mg, 0.140) was added. mmol), heating and stirring at 100° C. for 6 hours under a nitrogen atmosphere, and cooling to room temperature. Saturated brine was added, extraction was performed with ethyl acetate, and the combined organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-25:75) to obtain a coupling body. This was dissolved in methanol (2 ml), p-toluenesulfonic acid monohydrate (46.3 mg, 0.243 mmol) was added, and the mixture was stirred at room temperature for 21.5 hours. The residue obtained by concentration under reduced pressure was separated with water, saturated sodium bicarbonate water, and ethyl acetate, and the combined organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-20:80) to obtain the title compound (23.2mg, 0.125mmol, 9%) . ¹ H-NMR (DMSO-d ₆ ) δ: 12.11 (1H, br s), 8.03 (1H, s), 7.96 (1H, d, J = 8.8 Hz), 7.33 (1H, d, J = 1.2 Hz) , 7.20 (1H, dd, J = 8.8, 1.2 Hz), 2.14-2.01 (1H, m), 1.11-1.00 (2H, m), 0.86-0.74 (2H, m).

[Reference Example Q-14] 7-Ethylquinazolin-4(3H)-one

To the ethanol (5 ml) mixture of the compound (92.0 g, 0.534 mmol) obtained in Step 3 of Reference Example Q-12, 10% palladium on carbon (10 mg) was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen environment. The reaction mixture was filtered through Celite, washed with ethanol and incorporated. The filtrate was concentrated under reduced pressure to obtain the title compound (92.4 mg, 0.530 mmol, 99%). ¹ H-NMR (DMSO-d ₆ ) δ: 12.16 (1H, br s), 8.05 (1H, s), 8.02 (1H, d, J = 8.4 Hz), 7.48 (1H, d, J = 1.2 Hz) , 7.38 (1H, dd, J = 8.4, 1.2 Hz), 2.75 (2H, q, J = 7.2 Hz), 1.23 (3H, t, J = 7.2 Hz).

[Reference Example Q-15] 7-ethoxyquinazolin-4(3H)-one

[Step 1] Ethyl 4-ethoxy-2-nitrobenzene in 4-hydroxy-2-nitrobenzoic acid (300mg, 1.64mmol), potassium carbonate (679mg, 4.91mmol) in N,N-dimethyl To the methylformamide (5 ml) suspension, ethyl iodide (394 μl, 4.91 mmol) was added, and the mixture was stirred at room temperature for 19 hours. Water was added to the reaction mixture, extracted with ethyl acetate, and washed with water and saturated brine. It was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (384 mg, 1.60 mmol, 98%). ¹ H-NMR (CDCl ₃ ) δ: 7.77 (1H, d, J = 8.4 Hz), 7.21 (1H, d, J = 2.4 Hz), 7.08 (1H, dd, J = 8.4, 2.4 Hz), 4.34 ( 2H, q, J = 7.2 Hz), 4.12 (2H, q, J = 7.2 Hz), 1.46 (3H, t, J = 7.2 Hz), 1.34 (3H, t, J = 7.2 Hz).

[Step 2] Ethyl 2-amino-4-ethoxybenzoate was added to the ethanol (16ml) solution of the compound (384mg, 1.60mmol) obtained in Step 1 above, 10% palladium on carbon (38mg), hydrogen Under ambient conditions, stir at room temperature for 4 hours. The reaction mixture was filtered through Celite, washed with ethyl acetate and incorporated. The filtrate was concentrated under reduced pressure to obtain the title compound (338 mg, 1.62 mmol, quantitative). ¹ H-NMR (CDCl ₃ ) δ: 7.80 (1H, d, J = 9.2 Hz), 6.22 (1H, dd, J = 9.2, 2.4 Hz), 6.09 (1H, d, J = 2.4 Hz), 5.76 ( 2H, br s), 4.29 (2H, q, J = 7.2 Hz), 4.01 (2H, q, J = 7.2 Hz), 1.40 (3H, t, J = 7.2 Hz), 1.36 (3H, t, J = 7.2 Hz).

[Step 3] Using the compound (338 mg, 1.62 mmol) obtained in step 2 above for 7-ethoxyquinazolin-4(3H)-one, by performing the same operation as step 3 of Reference Example Q-2, The title compound (175 mg, 0.920 mmol, 57%) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 12.08 (1H, br s), 8.03 (1H, d, J = 3.6 Hz), 7.99 (1H, d, J = 9.6 Hz), 7.10-7.01 (2H, m), 4.15 (2H, q, J = 7.2 Hz), 1.36 (3H, t, J = 7.2 Hz).

[Reference Example Q-16] 7-Propoxyquinazolin-4(3H)-one

[Step 1] Propyl 2-nitro-4-propoxybenzoate was used with 1-iodopropane (478 μl, 4.91 mmol), and the title compound was obtained by performing the same operation as in Step 1 of Reference Example Q-15 (421 mg, 1.58 mmol, 96%). ¹ H-NMR (CDCl ₃ ) δ: 7.79 (1H, d, J = 9.2 Hz), 7.20 (1H, d, J = 2.4 Hz), 7.09 (1H, dd, J = 9.2, 2.4 Hz), 4.24 ( 2H, t, J = 6.4 Hz), 4.00 (2H, t, J = 6.4 Hz), 1.91-1.79 (2H, m), 1.78-1.66 (2H, m), 1.05 (3H, t, J = 7.2 Hz) ), 0.98 (3H, t, J = 7.2 Hz).

[Step 2] Using the compound (421 mg, 1.58 mmol) obtained in the above step 1 and performing the same operation as in the step 2 of Reference Example Q-15, propyl 2-amino-4-propoxybenzoate was used, and The title compound (371 mg, 1.56 mmol, 99%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 7.80 (1H, d, J = 9.2 Hz), 6.23 (1H, dd, J = 9.2, 2.4 Hz), 6.10 (1H, d, J = 2.4 Hz), 5.76 ( 2H, br s), 4.19 (2H, t, J = 6.8 Hz), 3.90 (2H, t, J = 6.8 Hz), 1.86-1.68 (4H, m), 1.07-0.94 (6H, m).

[Step 3] Using the compound (371 mg, 1.56 mmol) obtained in step 2 above for 7-propoxyquinazolin-4(3H)-one, by performing the same operation as step 3 of Reference Example Q-2, The title compound (245 mg, 1.20 mmol, 77%) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 12.08 (1H, br s), 8.04 (1H, s), 7.99 (1H, dd, J = 8.0, 2.0 Hz), 7.12-7.01 (2H, m), 4.06 (2H, t, J = 6.4 Hz), 1.84-1.64 (2H, m), 0.99 (3H, t, J = 7.2 Hz).

[Reference Example Q-17] 7-fluoromethoxyquinazolin-4(3H)-one

[Step 1] 4-[(Methylhydrothio)methoxy]-2-nitrobenzoic acid methyl ester in 4-hydroxy-2-nitrobenzoic acid methyl ester (500mg, 2.54mmol) N, N -In a mixture of dimethylformamide (6ml), under ice cooling, sodium hydride (61% oily, 151mg, 3.80mmol) was added and the temperature was raised to room temperature. After stirring for 5 minutes, chloromethyl methyl sulfide (272μl , 3.30 mmol) and stirred at room temperature for 14 hours. Water was added to the reaction mixture, extracted with ethyl acetate, and the combined organic layer was washed with water and saturated brine, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-25:75, amino silica gel) to obtain the title compound (516 mg, 2.01 mmol, 79%). ¹ H-NMR (CDCl ₃ ) δ: 7.79 (1H, d, J = 8.8 Hz), 7.32 (1H, d, J = 2.4 Hz), 7.16 (1H, dd, J = 8.8, 2.4 Hz), 5.23 ( 2H, s), 3.89 (3H, s), 2.26 (3H, s).

[Step 2] Methyl 4-fluoromethoxy-2-nitrobenzoate The compound (516 mg, 2.01 mmol) obtained in the above step 1 was dissolved in dichloromethane (10 ml), and sulfuric acid chloride (244 μl, 3.01 mmol), after stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (10 ml), tetrabutylammonium fluoride 1 mol/L tetrahydrofuran solution (4.01 ml, 4.01 mmol) was added under ice cooling, and the mixture was heated to room temperature and stirred for 72 hours. Concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-20:80, amino silica gel) to obtain the title compound (322 mg, 1.41 mmol, 70%) ). ¹ H-NMR (CDCl ₃ ) δ: 7.81 (1H, d, J = 8.4 Hz), 7.49 (1H, d, J = 2.4 Hz), 7.32 (1H, dd, J = 8.4, 2.4 Hz), 5.79 ( 2H, d, J = 52.4 Hz), 3.90 (3H, s).

[Step 3] Using the compound (257 mg, 1.29 mmol) obtained in step 2 above for 7-fluoromethoxyquinazolin-4(3H)-one, the same operation as that in step 3 of Reference Example Q-2 was performed , And the title compound (185 mg, 0.954 mmol, 74%) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 12.23 (1H, s), 8.10 (1H, d, J = 9.2 Hz), 8.09 (1H, s), 7.29 (1H, d, J = 2.4 Hz), 7.25 (1H, dd, J = 9.2, 2.4 Hz), 6.01 (2H, d, J = 54.0 Hz).

[Reference Example Q-18] 7-(2,2,2-trifluoroethoxy)quinazolin-4(3H)-one

[Step 1] Methyl 2-nitro-4-(2,2,2-trifluoroethoxy)benzoate in methyl 4-hydroxy-2-nitrobenzoate (400mg, 2.03mmol), potassium carbonate (561mg, 4.06mmol) of N,N-dimethylformamide (10ml) suspension, add 2,2,2-trifluoroethyl trifluoromethanesulfonate (586μl, 4.06mmol) at room temperature Stir for 1.5 hours. Water was added, and extraction was performed with ethyl acetate. The combined organic layer was washed with water and saturated brine, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (561 mg, 2.01 mmol, 99%). ¹ H-NMR (CDCl ₃ ) δ: 7.82 (1H, d, J = 8.8 Hz), 7.35 (1H, d, J = 2.4 Hz), 7.19 (1H, dd, J = 8.8, 2.4 Hz), 4.46 ( 2H, q, J = 7.6 Hz), 3.90 (3H, s).

[Step 2] Methyl 2-amino-4-(2,2,2-trifluoroethoxy)benzoate The compound obtained in step 1 above (561 mg, 2.01 mmol), 10% palladium on carbon (56.1 mg ) In ethanol (20ml), heated and stirred at 60°C for 3 hours in a hydrogen atmosphere. After cooling to room temperature, it was filtered with Celite, washed with ethyl acetate and incorporated. The title compound (473 mg, 1.90 mmol, 95%) was obtained by concentrating the filtrate under reduced pressure. ¹ H-NMR (CDCl ₃ ) δ: 7.83 (1H, dd, J = 8.8 Hz), 6.25 (1H, dd, J = 8.8, 2.4 Hz), 6.14 (1H, d, J = 2.4 Hz), 5.83 ( 2H, br s), 4.33 (2H, q, J = 8.0 Hz), 3.85 (3H, s).

[Step 3] 7-(2,2,2-trifluoroethoxy)quinazolin-4(3H)-one The compound (473 mg, 1.90 mmol) obtained in the above step 2 was used by proceeding with reference example The same operation of step 3 of Q-2 was performed to obtain the title compound (330 mg, 1.35 mmol, 71%). ¹ H-NMR (DMSO-d ₆ ) δ: 12.19 (1H, br s), 8.08 (1H, s), 8.05 (1H, d, J = 8.4 Hz), 7.26 (1H, d, J = 2.4 Hz) , 7.19 (1H, dd, J = 8.4, 2.4 Hz), 4.95 (2H, q, J = 8.8 Hz).

[Reference Example Q-19] 7-Trifluoromethoxyquinazolin-4(3H)-one

[Step 1] 2-Nitro-4-trifluoromethoxybenzonitrile used 1-chloro-2-nitro-4-trifluoromethoxybenzene (3.00g, 12.4mmol), by proceeding and reference The same operation was performed in step 2 of Example Q-1 to obtain the title compound (1.16 g, 4.99 mmol, 40%). ¹ H-NMR (CDCl ₃ ) δ: 8.21-8.16 (1H, m), 8.00 (1H, d, J = 8.4 Hz), 7.70-7.64 (1H, m).

[Step 2] 2-Nitro-4-trifluoromethoxybenzamide Using the compound (1.19 g, 5.13 mmol) obtained in Step 1 above, the title compound (540 mg, 2.16 mmol, 42%) was obtained by performing the same operation as in Step 3 of Reference Example Q-1.

[Step 3] 2-Amino-4-trifluoromethoxybenzamide is added to a mixture of the compound (540mg, 2.16mmol) obtained in step 2 above in ethanol (11ml) and water (11ml), and sulfurous acid is added Sodium hydride (4.71g, 21.6mmol), heated to reflux at 120°C for 15 hours. After cooling to room temperature, most of the ethanol was distilled off under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (156 mg, 0.707 mmol, 33%). ¹ H-NMR (DMSO-d ₆ ) δ: 7.80 (1H, br s), 7.62 (1H, d, J = 8.8Hz), 7.20 (1H, br s), 6.91 (2H, s), 6.64-6.57 (1H, m), 6.42-6.33 (1H, m).

[Step 4] Using the compound (156 mg, 0.707 mmol) obtained in step 3 above for 7-trifluoromethoxyquinazolin-4(3H)-one, the same as in step 5 of Reference Example Q-1 Operation to obtain the title compound (88.6 mg, 0.385 mmol, 54%). ¹ H-NMR (CDCl ₃ ) δ: 11.41 (1H, br s), 8.35 (1H, d, J = 9.2 Hz), 8.14 (1H, s), 7.61 (1H, d, J = 1.2 Hz), 7.41 -7.33 (1H, m).

[Reference Example Q-20] 7-ethynylquinazolin-4(3H)-one

[Step 1] 7-Trimethylsilylethynylquinazolin-4(3H)-one in 7-iodo-1H-quinazolin-4-one (500mg, 1.84mmol), [1,1-bis (Diphenylphosphino)ferrocene] palladium(II) dichloride dichloromethane adduct (75.0mg, 0.0919mmol), copper(I) iodide (17.5mg, 0.0919mmol) N,N- In a mixture of dimethylformamide (9ml), add trimethylsilylacetylene (509μl, 3.68mmol) and N,N-diisopropylethylamine (1.60ml, 9.19mmol) under a nitrogen atmosphere. Stir at room temperature for 17 hours. Saturated brine was added to the reaction mixture, extracted with ethyl acetate, the combined organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-60:40) to obtain the title compound (155 mg, 0.640 mmol, 35%). ¹ H-NMR (CDCl ₃ ) δ: 11.63 (1H, br s), 8.22 (1H, d, J = 8.4 Hz), 8.12 (1H, s), 7.84 (1H, d, J = 1.2 Hz), 7.58 (1H, dd, J = 8.4, 1.2 Hz), 0.29 (9H, s).

[Step 2] 7-Ethynylquinazolin-4(3H)-one The compound (155mg, 0.640mmol) obtained in step 1 above, potassium carbonate (181mg, 1.31mmol) in methanol (6ml) was mixed at room temperature Stir for 3 hours. 1N aqueous hydrochloric acid solution and saturated brine were added to the reaction mixture, extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (91.6 mg, 0.538 mmol, 84%). ¹ H-NMR (CDCl ₃ ) δ: 10.11 (1H, br s), 8.24 (1H, d, J = 8.4 Hz), 8.06 (1H, s), 7.88 (1H, d, J = 1.2 Hz), 7.60 (1H, dd, J = 8.4, 1.2 Hz), 3.32 (1H, s).

[Reference Example Q-21] 7-Trifluoromethylquinazolin-4(3H)-one

[Step 1] 2-Amino-4-trifluoromethyl benzoic acid used 2-nitro-4-trifluoromethyl benzoic acid (2.00 g, 8.51 mmol), by carrying out the same procedure as in Reference Example Q-1 4 The same operation was performed to obtain the title compound (1.73 g, 8.42 mmol, 99%). ¹ H-NMR (DMSO-d ₆ ) δ: 7.85 (1H, d, J = 8.8 Hz), 7.13-7.04 (1H, m), 6.78-6.69 (1H, m).

[Step 2] 7-Trifluoromethylquinazolin-4(3H)-one The solution of the compound (1.73g, 8.42mmol) obtained in the above step 1 in formamide (16ml) was heated and stirred at 180°C for 4.5 hours After that, it was cooled to room temperature. After adding water and stirring for a while, it was extracted with ethyl acetate, and washed with water and saturated brine. After drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. Recrystallization was performed using diethyl ether/hexane, and the precipitated crystals were collected by filtration to obtain the title compound (891 mg, 4.16 mmol, 49%). ¹ H-NMR (CDCl ₃ ) δ: 11.11 (1H, br s), 8.43 (1H, d, J = 8.0 Hz), 8.17 (1H, s), 8.06 (1H, s), 7.76 (1H, d, J = 8.0 Hz).

[Reference Example Q-22] 7-Dimethylaminoquinazolin-4(3H)-one

Using methyl 2-amino-4-dimethylaminobenzoate (622 mg, 3.20 mmol), the title compound (477 mg, 2.52 mmol, 79%). ¹ H-NMR (DMSO-d ₆ ) δ: 11.00 (1H, br s), 8.11 (1H, d, J = 8.8 Hz), 8.02-7.95 (1H, m), 6.91 (1H, dd, J = 8.8 , 2.4 Hz), 6.82 (1H, d, J = 2.4 Hz), 3.12 (6H, s).

[Reference Example Q-23] 7-Cyclopropyloxyquinazolin-4(3H)-one

[Step 1] In a mixture of 2-bromo-4-hydroxybenzoic acid (6.45g, 29.7mmol) in methanol (60ml), methyl 2-bromo-4-hydroxybenzoate was added dropwise with sulfuric acid (3.19ml, 59.4 mmol), heating to reflux at 70°C for 11.5 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. The obtained residue was separated with saturated brine and ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (6.75 g, 29.1 mmol, 98%). ¹ H-NMR (CDCl ₃ ) δ: 7.83 (1H, d, J = 8.8 Hz), 7.18 (1H, d, J = 2.4 Hz), 6.82 (1H, dd, J = 8.8, 2.4 Hz), 3.90 ( 3H, s).

[Step 2] Methyl 2-bromo-4-vinyloxybenzoate A suspension of copper(II) acetate (3.14g, 17.3mmol) in dichloromethane (120ml) was stirred at room temperature for 10 minutes, and the above was added The compound obtained in step 1 (4.00 g, 17.3 mmol), vinyl boronic anhydride pyridine complex (2.79 g, 11.6 mmol), and pyridine (14.0 ml, 173 mmol) were stirred at room temperature for 66.5 hours. The reaction mixture was filtered through Celite, washed with dichloromethane and incorporated, and the filtrate was concentrated under reduced pressure. Toluene was added to the obtained residue, and it was concentrated again under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-10:90) to obtain the title compound (2.67 g, 10.4 mmol, 60%). ¹ H-NMR (CDCl ₃ ) δ: 7.81 (1H, d, J = 8.4 Hz), 7.30 (1H, d, J = 2.4 Hz), 6.97 (1H, dd, J = 8.4, 2.4 Hz), 6.63 ( 1H, dd, J = 14.0, 6.0 Hz), 4.93 (1H, dd, J = 14.0, 2.0 Hz), 4.62 (1H, dd, J = 6.0, 2.0 Hz), 3.91 (3H, s).

[Step 3] Methyl 2-bromo-4-cyclopropyloxybenzoate in diethyl zinc (1.09mol/L hexane solution) (19.1ml, 20.8mmol) in dichloromethane (18ml), Under ice cooling, a solution of trifluoroacetic acid (1.59ml, 20.8mmol) in dichloromethane (18ml) was dropped and stirred at the same temperature for 20 minutes. Then, while ice-cooling, a dichloromethane (12 ml) solution of diiodomethane (1.67 ml, 20.8 mmol) was dropped into the reaction solution and stirred at the same temperature for 20 minutes. A dichloromethane (12 ml) solution of the compound (2.67 g, 10.4 mmol) obtained in step 2 above was further added, the temperature was raised to room temperature, and the mixture was stirred for 21 hours. After adding 1N hydrochloric acid aqueous solution to the reaction mixture, it was stirred for a while, and extracted with dichloromethane. The organic layer was washed with saturated brine, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-5:95) to obtain the title compound (2.25 g, 8.29 mmol, 80%) . ¹ H-NMR (CDCl ₃ ) δ: 7.85 (1H, d, J = 8.6 Hz), 7.36 (1H, d, J = 2.5 Hz), 6.99 (1H, dd, J = 8.6, 2.5 Hz), 3.90 ( 3H, s), 3.80-3.74 (1H, m), 0.88-0.75 (4H, m).

[Step 4] Using the compound (2.25 g, 8.29 mmol) obtained in the above step 3 for methyl 2-amino-4-cyclopropyloxybenzoate, the same procedure as in step 2 of Reference Example Q-2 was carried out. Operation to obtain the title compound (1.51 g, 7.30 mmol, 88%). ¹ H-NMR (CDCl ₃ ) δ: 7.81-7.75 (1H, m), 6.35-6.28 (2H, m), 5.78 (2H, br s), 3.84 (3H, s), 3.75-3.69 (1H, m) ), 0.81-0.73 (4H, m).

[Step 5] 7-Cyclopropyloxyquinazolin-4(3H)-one The compound (503 mg, 2.43 mmol) obtained in the above step 4 was used by performing the same procedure as in the step 3 of Reference Example Q-2 Operation to obtain the title compound (415 mg, 2.05 mmol). ¹ H-NMR (DMSO-d ₆ ) δ: 12.10 (1H, br s), 8.05 (1H, s), 8.01 (1H, d, J = 8.8 Hz), 7.28 (1H, d, J = 2.4 Hz) , 7.12 (1H, dd, J = 8.8, 2.4 Hz), 4.06-3.95 (1H, m), 0.90-0.81 (2H, m), 0.75-0.66 (2H, m).

[Reference Example Q-24] 7-Difluoromethylquinazolin-4(3H)-one

-2-基)氧基]喹唑啉 使用7-溴喹唑啉-4(3H)-酮(780mg，3.47mmol)，藉由進行與參考例Q-12之步驟1同樣的操作，而獲得標題化合物(1.05g，3.40mmol，98%)。¹ H-NMR (CDCl₃ ) δ : 8.30 (1H, s), 8.15 (1H, d, J = 8.5 Hz), 7.90 (1H, d, J = 1.8 Hz), 7.60 (1H, dd, J = 8.5, 1.8 Hz), 5.94-5.88 (1H, m), 4.26-4.18 (1H, m), 3.79-3.70 (1H, m), 2.09-2.00 (2H, m), 1.88-1.52 (4H, m).[Step 1] 7-Bromo-4-[(oxygen

-2-yl)oxy]quinazoline was obtained by using 7-bromoquinazolin-4(3H)-one (780mg, 3.47mmol) by performing the same operation as in Step 1 of Reference Example Q-12 Title compound (1.05 g, 3.40 mmol, 98%). ¹ H-NMR (CDCl ₃ ) δ: 8.30 (1H, s), 8.15 (1H, d, J = 8.5 Hz), 7.90 (1H, d, J = 1.8 Hz), 7.60 (1H, dd, J = 8.5 , 1.8 Hz), 5.94-5.88 (1H, m), 4.26-4.18 (1H, m), 3.79-3.70 (1H, m), 2.09-2.00 (2H, m), 1.88-1.52 (4H, m).

-2-基)氧基]喹唑啉-7-甲醛 將上述步驟1所獲得的化合物(520mg，1.68mmol)溶解於N,N-二甲基甲醯胺(10ml)，添加甲酸鈉(183mg，2.69mmol)、三苯基膦(44.1mg，0.168mmol)，進行氮氣置換後，使用超音波而進行脫氣。置換為一氧化碳後，添加雙(三苯基膦)二氯化鈀(II)(118mg，0.168mmol)，再次置換為一氧化碳，於110℃攪拌4小時。將反應液冷卻至室溫後，以乙酸乙酯稀釋並以矽藻土過濾。於濾液中添加水、飽和食鹽水，並以乙酸乙酯萃取。將有機層依序以水、飽和食鹽水洗淨，以無水硫酸鈉乾燥後，減壓下餾除溶劑。將獲得的殘留物以矽膠管柱層析(乙酸乙酯-己烷=10:90-80:20)純化，而獲得標題化合物(182mg，0.705mmol，42%)。¹ H-NMR (CDCl₃ ) δ : 10.18 (1H, s), 8.43 (1H, d, J = 8.2 Hz), 8.37 (1H, s), 8.18 (1H, d, J = 1.6 Hz), 7.97 (1H, dd, J = 8.2, 1.6 Hz), 5.95-5.90 (1H, m), 4.26-4.20 (1H, m), 3.79-3.71 (1H, m), 2.11-2.01 (2H, m), 1.87-1.56 (4H, m).[Step 2] 4-[(oxygen

-2-yl)oxy]quinazoline-7-carbaldehyde The compound (520mg, 1.68mmol) obtained in step 1 above was dissolved in N,N-dimethylformamide (10ml), and sodium formate (183mg, 2.69mmol), triphenylphosphine (44.1mg, 0.168mmol), after nitrogen replacement, degassed using ultrasound. After replacing with carbon monoxide, bis(triphenylphosphine) palladium(II) dichloride (118 mg, 0.168 mmol) was added, replaced with carbon monoxide again, and stirred at 110°C for 4 hours. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate and filtered with Celite. Water and saturated brine were added to the filtrate, and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=10:90-80:20) to obtain the title compound (182 mg, 0.705 mmol, 42%). ¹ H-NMR (CDCl ₃ ) δ: 10.18 (1H, s), 8.43 (1H, d, J = 8.2 Hz), 8.37 (1H, s), 8.18 (1H, d, J = 1.6 Hz), 7.97 ( 1H, dd, J = 8.2, 1.6 Hz), 5.95-5.90 (1H, m), 4.26-4.20 (1H, m), 3.79-3.71 (1H, m), 2.11-2.01 (2H, m), 1.87- 1.56 (4H, m).

-2-基)氧基]喹唑啉 氮氣環境下，將上述步驟2所獲得的化合物(132mg，0.511mmol)溶解於二氯甲烷(5ml)，冷卻至-15℃下，添加雙(2-甲氧基乙基)胺基三氟化硫(300μl，1.54mmol)。將反應溶液於0℃攪拌7小時，於室溫攪拌60小時。冰冷下，慢慢添加飽和碳酸氫鈉水，氣泡消失後以二氯甲烷萃取。將有機層以水、飽和食鹽水洗淨，以無水硫酸鈉乾燥後，減壓下餾除溶劑。將獲得的殘留物以矽膠管柱層析(乙酸乙酯-己烷=5:95-70:30)純化，而獲得標題化合物(117mg，0.417mmol，82%)。¹ H-NMR (CDCl₃ ) δ : 8.39 (1H, d, J = 8.2 Hz), 8.34 (1H, s), 7.85 (1H, s), 7.62 (1H, d, J = 8.2 Hz), 6.76 (1H, t, J = 55.9 Hz), 5.95-5.91 (1H, m), 4.25-4.20 (1H, m), 3.78-3.71 (1H, m), 2.09-2.01 (2H, m), 1.85-1.52 (4H, m).[Step 3] 7-Difluoromethyl-4-[(oxy

-2-yl)oxy]quinazoline under nitrogen atmosphere, the compound (132mg, 0.511mmol) obtained in step 2 above was dissolved in dichloromethane (5ml), cooled to -15°C, added bis(2- Methoxyethyl)aminosulfur trifluoride (300 μl, 1.54 mmol). The reaction solution was stirred at 0°C for 7 hours and at room temperature for 60 hours. Under ice cooling, slowly add saturated sodium bicarbonate water, extract with dichloromethane after the bubbles disappear. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=5:95-70:30) to obtain the title compound (117 mg, 0.417 mmol, 82%). ¹ H-NMR (CDCl ₃ ) δ: 8.39 (1H, d, J = 8.2 Hz), 8.34 (1H, s), 7.85 (1H, s), 7.62 (1H, d, J = 8.2 Hz), 6.76 ( 1H, t, J = 55.9 Hz), 5.95-5.91 (1H, m), 4.25-4.20 (1H, m), 3.78-3.71 (1H, m), 2.09-2.01 (2H, m), 1.85-1.52 ( 4H, m).

[Step 4] 7-Difluoromethylquinazolin-4(3H)-one The compound (149 mg, 0.532 mmol) obtained in the above step 3 was dissolved in methanol (3 ml), and p-toluenesulfonic acid monohydrate ( 50.0mg, 0.263mmol), stirred at room temperature for 1 hour. Further, p-toluenesulfonic acid monohydrate (60.0 mg, 0.315 mmol) was added to the reaction solution, and stirred at room temperature for 2 hours. After diluting with ethyl acetate, saturated sodium bicarbonate water and water were added to stop the reaction, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-dichloromethane=2:98-8:92) to obtain the title compound (88.4 mg, 0.451 mmol, 85%). ¹ H-NMR (DMSO-d ₆ ) δ: 12.46 (1H, br s), 8.25 (1H, d, J = 8.2 Hz), 8.18 (1H, s), 7.85 (1H, s), 7.69 (1H, d, J = 8.2 Hz), 7.21 (1H, t, J = 55.3 Hz).

[Example 1-1] (-)-2-(4-chloro-2,6-difluorobenzyl)-6-[(4-chloro-3-fluorophenyl)methyl]-11, 11-Difluoro-2,6,14-Triazabisspiro[4.2.5 ⁸ .2 ⁵ ]pentadecane-7,15-dione

啉基)]脲鎓 (156mg，0.365mmol)，於室溫攪拌24小時。於反應液中添加水，以乙酸乙酯萃取，以飽和食鹽水洗淨。以無水硫酸鈉乾燥，減壓下餾除溶劑，將獲得的殘留物以矽膠管柱層析(乙酸乙酯-己烷=5:95-100:0)純化，而獲得標題化合物之外消旋體(137mg，0.232mmol，70%)。[Step 1] The compound (150 mg, 0.332 mmol) obtained in Reference Example D-1 was dissolved in dimethylformamide (5 ml), and triethylamine (92.4 μl, 0.663 mmol) was added and stirred. Under ice cooling, add 4-chloro-2,6-difluorobenzoic acid (83.0mg, 0.431mmol), N,N-diisopropylethylamine (116μl, 0.663mmol), hexafluorophosphate N-[1- (Cyano-2-ethoxy-2-oxoethyleneaminooxy) dimethylamino (

(Hydroxy)]uronium (156 mg, 0.365 mmol), stirred at room temperature for 24 hours. Water was added to the reaction solution, extracted with ethyl acetate, and washed with saturated brine. Dry over anhydrous sodium sulfate, distill off the solvent under reduced pressure, and purify the obtained residue by silica gel column chromatography (ethyl acetate-hexane=5:95-100:0) to obtain the title compound racemic Body (137mg, 0.232mmol, 70%).

[Step 2] Under the following conditions, the compound obtained in the above step 1 was optically divided. Column: Daicel’s CHIRALPAK IB 20mmIDx250mmL Extraction solvent: Hexane: 2-propanol=50:50(V/V) Flow rate: 15.0ml/min Temperature: 25℃ Take the first peak (retention time: 9.7 minutes) , And obtain the title compound. Specific optical rotation [α] _D ²⁰ = -4.798 (c=1.0, chloroform) ¹ H-NMR (CDCl ₃ ) δ: 8.28-8.02 (1H, m), 7.40-7.29 (1H, m), 7.07-6.78 ( 4H, m), 4.92-4.70 (1H, m), 4.48-4.34 (1H, m), 4.22-4.11 (1H, m), 4.09-3.97 (1H, m), 3.81-3.66 (1H, m), 3.57-3.46 (1H, m), 2.61-1.99 (8H, m), 1.95-1.83 (2H, m). MS (m/z): 590 (M+H) ⁺ .

[Example 1-2] (+)-2-(4-chloro-2,6-difluorobenzyl)-6-[(4-chloro-3-fluorophenyl)methyl]-11, 11-Difluoro-2,6,14-Triazabisspiro[4.2.5 ⁸ .2 ⁵ ]pentadecane-7,15-dione

[Step 1] The compound obtained in Step 1 of Example 1-1 was subjected to optical division in the same manner as Step 2 of Example 1-1, and the second peak (retention time: 12.9 minutes) was separated to obtain the title compound. Specific optical rotation [α] _D ²⁰ = +4.724 (c=1.0, chloroform) ¹ H-NMR (CDCl ₃ ) δ: 8.13-7.92 (1H, m), 7.40-7.29 (1H, m), 7.07-6.78 ( 4H, m), 4.94-4.70 (1H, m), 4.48-4.35 (1H, m), 4.22-4.12 (1H, m), 4.07-3.98 (1H, m), 3.82-3.66 (1H, m), 3.57-3.46 (1H, m), 2.61-1.98 (8H, m), 1.95-1.84 (2H, m). MS (m/z): 590 (M+H) ⁺ .

Using the compound obtained in Reference Example, the same operation as in Step 1 of Example 1-1 was performed to obtain the following compound. In addition, with regard to Examples 6-1, 6-2, 7-1, and 7-2, the optical division was performed by the same operation as Step 2 of Example 1-1 and Step 1 of Example 1-2.

(+)-6-[(4-氯-3-氟苯基)甲基]-2-[(5-氯-3-氟吡啶-2-基)羰基]-11,11-二氟-2,6,14-三氮二螺[4.2.5⁸ .2⁵ ]十五烷-7,15-二酮 比旋光度[α]_D ²⁰ = +8.095 (c=1.0，氯仿)¹ H-NMR (CDCl₃ ) δ : 8.43-8.17 (1H, m), 7.61-7.50 (1H, m), 7.38-7.29 (1H, m), 6.99-6.83 (3H, m), 4.94-4.40 (2H, m), 4.28-3.73 (4H, m), 2.63-2.17 (6H, m), 2.14-1.82 (4H, m). MS (m/z) : 573 (M+H)⁺ . 製造原料：參考例D-2-1、5-氯-3-氟吡啶-2-甲酸 3

6-(1,3-苯并

唑-6-基甲基)-2-(4-氯-2,6-二氟苯甲醯基)-11,11-二氟-2,6,14-三氮二螺[4.2.5⁸ .2⁵ ]十五烷-7,15-二酮 ¹ H-NMR (CDCl₃ ) δ : 8.27-7.93 (1H, m), 7.83-7.61 (1H, m), 7.53-6.68 (4H, m), 5.24-4.83 (1H, m), 4.70-4.50 (1H, m), 4.34-3.94 (2H, m), 3.86-3.46 (2H, m), 2.69-1.76 (10H, m). MS (m/z) : 577 (M-H)^- . 製造原料：參考例D-3、4-氯-2,6-二氟苯甲酸 4

6-(1,3-苯并噻唑-6-基甲基)-2-(4-氯-2,6-二氟苯甲醯基)-11,11-二氟-2,6,14-三氮二螺[4.2.5⁸ .2⁵ ]十五烷-7,15-二酮 ¹ H-NMR (CDCl₃ ) δ : 9.01-8.99 (1H, m), 8.13-8.04 (1H, m), 7.78-7.63 (2H, m), 7.37-7.21 (1H, m), 7.06-7.01 (2H, m), 5.16-4.93 (1H, m), 4.70-4.53 (1H, m), 4.26-3.98 (2H, m), 3.83-3.48 (2H, m), 2.64-1.87 (10H, m). MS (m/z) : 596 (M+H)⁺ . 製造原料：參考例D-4、4-氯-2,6-二氟苯甲酸 5-1

(-)-(8S)-2-(4-氯-2,6-二氟苯甲醯基)-6-[(4-氯-3-氟苯基)甲基-10,10-二氟-2,6,13-三氮二螺[4.2.4⁸ .2⁵ ]十四烷-7,14-二酮 非鏡像異構物-1 比旋光度[α]_D ²⁰ = -9.339 (c=0.947，氯仿) ¹ H-NMR (CDCl₃ ) δ : 7.40-7.29 (1H, m), 7.06-7.01 (1H, m), 6.99-6.89 (2H, m), 6.88-6.76 (1H, m), 6.65-6.59 (1H, m), 4.91-4.33 (2H, m), 4.24-4.03 (2H, m), 3.82-3.63 (1H, m), 3.57-3.46 (1H, m), 3.22-3.03 (1H, m), 2.70-2.06 (7H, m). MS (m/z) : 576 (M+H)⁺ . 製造原料：參考例D-5-1、4-氯-2,6-二氟苯甲酸 5-2

(-)-(8S)-2-(4-氯-2,6-二氟苯甲醯基)-6-[(4-氯-3-氟苯基)甲基]-10,10-二氟-2,6,13-三氮二螺[4.2.4⁸ .2⁵ ]十四烷-7,14-二酮 非鏡像異構物-2 比旋光度[α]_D ²⁰ = -4.083 (c=0.882，氯仿)¹ H-NMR (CDCl₃ ) δ : 7.40-7.29 (1H, m), 7.06-6.77 (4H, m), 6.69-6.58 (1H, m), 4.90-4.70 (1H, m), 4.53-4.40 (1H, m), 4.23-3.97 (2H, m), 3.87-3.44 (2H, m), 3.20-2.85 (1H, m), 2.71-1.88 (7H, m). MS (m/z) : 576 (M+H)⁺ . 製造原料：參考例D-5-2、4-氯-2,6-二氟苯甲酸 6-1

(-)-11-(4-乙炔基-2,6-二氟苯甲醯基)-14-[(4-甲氧基苯基)甲基]-1,2,7,11,14-五氮三螺[2.2.2.4⁹ .2⁶ .2³ .]十七-1-烯-8,15-二酮 使用Daicel之CHIRALPAK IA(己烷/2-丙醇)而分取第1波峰 比旋光度[α]_D ²⁰ = -5.808  (c=1.007，氯仿)¹ H-NMR (CDCl₃ ) δ: 8.17-8.00(1H, m), 7.21-6.78(6H, m), 4.98-3.22(9H, m), 2.68-2.36(4H, m), 1.99-0.87(7H, m). MS (m/z) : 548 (M+H)⁺ . 製造原料：參考例D-6、參考例X-1 6-2

(+)-11-(4-乙炔基-2,6-二氟苯甲醯基)-14-[(4-甲氧基苯基)甲基]-1,2,7,11,14-五氮三螺[2.2.2.4⁹ .2⁶ .2³ .]十七-1-烯-8,15-二酮 使用Daicel之CHIRALPAK IA(己烷/2-丙醇)而分取第2波峰 比旋光度[α]_D ²⁰ = +4.403  (c=1.006，氯仿)¹ H-NMR (CDCl₃ ) δ : 8.22-8.02(1H, m), 7.24-6.75(6H, m), 4.96-3.25(9H, m), 2.68-2.33(4H, m), 1.98-0.87(7H, m). MS (m/z) : 548 (M+H)⁺ . 製造原料：參考例D-6、參考例X-1 7-1

(+)-2-[(5-氯-3-氟吡啶-2-基)羰基]-11,11-二氟-6-[(3-氟-4-甲氧基苯基)甲基]-2,6,14-三氮二螺[4.2.5⁸ .2⁵ ]十五烷-7,15-二酮 使用Daicel之CHIRALPAK IA(己烷/乙醇)而分取第1波峰 比旋光度[α]_D ²⁰ = +8.295  (c=1.008，氯仿)¹ H-NMR (CDCl₃ ) δ : 8.44-8.20 (1H, m), 7.61-7.50 (1H, m), 7.25-6.79 (4H, m), 4.90-4.79 (1H, m), 4.46-4.38 (1H, m), 4.27-3.88 (2H, m), 3.87 (3H, s), 3.84-3.74 (2H, m), 2.58-2.24 (6H, m), 2.13-1.72 (4H, m). MS (m/z) : 569 (M+H)⁺ . 製造原料：參考例D-7、5-氯-3-氟吡啶-2-甲酸 7-2

(-)-2-[(5-氯-3-氟吡啶-2-基)羰基]-11,11-二氟-6-[(3-氟-4-甲氧基苯基)甲基]-2,6,14-三氮二螺[4.2.5⁸ .2⁵ ]十五烷-7,15-二酮 使用Daicel之CHIRALPAK IA(己烷/乙醇)而分取第2波峰 比旋光度[α]_D ²⁰ = -8.046  (c=1.006，氯仿)¹ H-NMR (CDCl₃ ) δ: 8.44-8.21 (1H, m), 7.61-7.50 (1H, m), 7.37-7.00 (1H, m), 6.95-6.79 (3H, m), 4.90-4.79 (1H, m), 4.47-4.37 (1H, m), 4.27-3.88 (2H, m), 3.87 (3H, s), 3.80-3.74 (2H, m), 2.58-2.20 (6H, m), 2.12-1.73 (4H, m).  MS (m/z) : 569 (M+H)⁺ . 製造原料：參考例D-7、5-氯-3-氟吡啶-2-甲酸 [Table 4] Example 2

(+)-6-[(4-chloro-3-fluorophenyl)methyl]-2-[(5-chloro-3-fluoropyridin-2-yl)carbonyl]-11,11-difluoro-2 ,6,14-Triazabispiro[4.2.5 ⁸ .2 ⁵ ]pentadecane-7,15-dione Specific optical rotation [α] _D ²⁰ = +8.095 (c=1.0, chloroform) ¹ H-NMR (CDCl ₃ ) δ: 8.43-8.17 (1H, m), 7.61-7.50 (1H, m), 7.38-7.29 ( 1H, m), 6.99-6.83 (3H, m), 4.94-4.40 (2H, m), 4.28-3.73 (4H, m), 2.63-2.17 (6H, m), 2.14-1.82 (4H, m). MS (m/z): 573 (M+H) ⁺ . Manufacturing raw materials: Reference Example D-2-1, 5-chloro-3-fluoropyridine-2-carboxylic acid 3

6-(1,3-Benzo

(Azol-6-ylmethyl)-2-(4-chloro-2,6-difluorobenzyl)-11,11-difluoro-2,6,14-triazabispiro[4.2.5 ⁸ .2 ⁵ ]pentadecane-7,15-dione ¹ H-NMR (CDCl ₃ ) δ: 8.27-7.93 (1H, m), 7.83-7.61 (1H, m), 7.53-6.68 (4H, m), 5.24-4.83 (1H, m), 4.70-4.50 ( 1H, m), 4.34-3.94 (2H, m), 3.86-3.46 (2H, m), 2.69-1.76 (10H, m). MS (m/z): 577 (MH) ^- . Manufacturing raw materials: Reference Example D-3, 4-chloro-2,6-difluorobenzoic acid 4

6-(1,3-Benzothiazol-6-ylmethyl)-2-(4-chloro-2,6-difluorobenzyl)-11,11-difluoro-2,6,14- Triazodispiro[4.2.5 ⁸ .2 ⁵ ]pentadecane-7,15-dione ¹ H-NMR (CDCl ₃ ) δ: 9.01-8.99 (1H, m), 8.13-8.04 (1H, m), 7.78-7.63 (2H, m), 7.37-7.21 (1H, m), 7.06-7.01 ( 2H, m), 5.16-4.93 (1H, m), 4.70-4.53 (1H, m), 4.26-3.98 (2H, m), 3.83-3.48 (2H, m), 2.64-1.87 (10H, m). MS (m/z): 596 (M+H) ⁺ . Manufacturing raw materials: Reference Example D-4, 4-chloro-2,6-difluorobenzoic acid 5-1

(-)-(8S)-2-(4-Chloro-2,6-difluorobenzyl)-6-[(4-chloro-3-fluorophenyl)methyl-10,10-difluoro -2,6,13-Triazabispiro[4.2.4 ⁸ .2 ⁵ ]tetradecane-7,14-dione diastereomer-1 Specific optical rotation [α] _D ²⁰ = -9.339 (c =0.947, chloroform) ¹ H-NMR (CDCl ₃ ) δ: 7.40-7.29 (1H, m), 7.06-7.01 (1H, m), 6.99-6.89 (2H, m), 6.88-6.76 (1H, m), 6.65-6.59 ( 1H, m), 4.91-4.33 (2H, m), 4.24-4.03 (2H, m), 3.82-3.63 (1H, m), 3.57-3.46 (1H, m), 3.22-3.03 (1H, m), 2.70-2.06 (7H, m). MS (m/z): 576 (M+H) ⁺ . Manufacturing raw materials: Reference example D-5-1, 4-chloro-2,6-difluorobenzoic acid 5-2

(-)-(8S)-2-(4-Chloro-2,6-difluorobenzyl)-6-[(4-chloro-3-fluorophenyl)methyl]-10,10-bis Fluoro-2,6,13-triazodispiro[4.2.4 ⁸ .2 ⁵ ]tetradecane-7,14-dione diastereomer-2 Specific optical rotation [α] _D ²⁰ = -4.083 (c=0.882, chloroform) ¹ H-NMR (CDCl ₃ ) δ: 7.40-7.29 (1H, m), 7.06-6.77 (4H, m), 6.69-6.58 ( 1H, m), 4.90-4.70 (1H, m), 4.53-4.40 (1H, m), 4.23-3.97 (2H, m), 3.87-3.44 (2H, m), 3.20-2.85 (1H, m), 2.71-1.88 (7H, m). MS (m/z): 576 (M+H) ⁺ . Manufacturing raw materials: Reference example D-5-2, 4-chloro-2,6-difluorobenzoic acid 6-1

(-)-11-(4-ethynyl-2,6-difluorobenzyl)-14-[(4-methoxyphenyl)methyl]-1,2,7,11,14- Pentaazatrispiro[2.2.2.4 ⁹ .2 ⁶ .2 ³ .]heptadec-1-ene-8,15-dione Use Daicel’s CHIRALPAK IA (hexane/2-propanol) to divide the first peak specific rotation [α] _D ²⁰ = -5.808 (c=1.007, chloroform) ¹ H-NMR (CDCl ₃ ) δ: 8.17- 8.00(1H, m), 7.21-6.78(6H, m), 4.98-3.22(9H, m), 2.68-2.36(4H, m), 1.99-0.87(7H, m). MS (m/z): 548 (M+H) ⁺ . Manufacturing raw materials: Reference Example D-6, Reference Example X-1 6-2

(+)-11-(4-ethynyl-2,6-difluorobenzyl)-14-[(4-methoxyphenyl)methyl]-1,2,7,11,14- Pentaazatrispiro[2.2.2.4 ⁹ .2 ⁶ .2 ³ .]heptadec-1-ene-8,15-dione Use Daicel's CHIRALPAK IA (hexane/2-propanol) to divide the second peak specific rotation [α] _D ²⁰ = +4.403 (c=1.006, chloroform) ¹ H-NMR (CDCl ₃ ) δ: 8.22- 8.02(1H, m), 7.24-6.75(6H, m), 4.96-3.25(9H, m), 2.68-2.33(4H, m), 1.98-0.87(7H, m). MS (m/z): 548 (M+H) ⁺ . Manufacturing raw materials: Reference Example D-6, Reference Example X-1 7-1

(+)-2-[(5-chloro-3-fluoropyridin-2-yl)carbonyl]-11,11-difluoro-6-[(3-fluoro-4-methoxyphenyl)methyl] -2,6,14-Triazabisspiro[4.2.5 ⁸ .2 ⁵ ]pentadecane-7,15-dione Use Daicel's CHIRALPAK IA (hexane/ethanol) to divide the first peak specific rotation [α] _D ²⁰ = +8.295 (c=1.008, chloroform) ¹ H-NMR (CDCl ₃ ) δ: 8.44-8.20 (1H , m), 7.61-7.50 (1H, m), 7.25-6.79 (4H, m), 4.90-4.79 (1H, m), 4.46-4.38 (1H, m), 4.27-3.88 (2H, m), 3.87 (3H, s), 3.84-3.74 (2H, m), 2.58-2.24 (6H, m), 2.13-1.72 (4H, m). MS (m/z): 569 (M+H) ⁺ . Manufacturing raw materials: Reference Example D-7, 5-chloro-3-fluoropyridine-2-carboxylic acid 7-2

(-)-2-[(5-chloro-3-fluoropyridin-2-yl)carbonyl]-11,11-difluoro-6-[(3-fluoro-4-methoxyphenyl)methyl] -2,6,14-Triazabisspiro[4.2.5 ⁸ .2 ⁵ ]pentadecane-7,15-dione Use Daicel's CHIRALPAK IA (hexane/ethanol) to separate the second peak specific rotation [α] _D ²⁰ = -8.046 (c=1.006, chloroform) ¹ H-NMR (CDCl ₃ ) δ: 8.44-8.21 (1H , m), 7.61-7.50 (1H, m), 7.37-7.00 (1H, m), 6.95-6.79 (3H, m), 4.90-4.79 (1H, m), 4.47-4.37 (1H, m), 4.27 -3.88 (2H, m), 3.87 (3H, s), 3.80-3.74 (2H, m), 2.58-2.20 (6H, m), 2.12-1.73 (4H, m). MS (m/z): 569 (M+H) ⁺ . Manufacturing raw materials: Reference Example D-7, 5-chloro-3-fluoropyridine-2-carboxylic acid

[Example 8] 7-[(4-chloro-3-fluorophenyl)methyl]-3-[(3-ethylazone-1-yl)carbonyl]-12,12-difluoro-3, 7,15-Triazabisspiro[5.2.5 ⁹ .2 ⁶ ]hexadecane-8,16-dione

To the N-methyl-2-pyrrolidone (2ml) mixture of the compound (50.0mg, 0.107mmol) obtained in Reference Example D-8, 1,1´-carbonyldiimidazole (19.1mg, 0.118mmol), N,N-Diisopropylethylamine (93.4μl, 0.536mmol), heated and stirred at 80°C for 1 hour, and cooled to room temperature. To this solution was added 3-ethyl azatrifluoroacetic acid (49.7 μl, 0.322 mmol), heated and stirred at 100° C. for 20.5 hours, and cooled to room temperature. Water, saturated brine, and ethyl acetate were added for liquid separation, and the combined organic layer was washed with water and saturated brine, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=50:50-100:0) to obtain the title compound (31.4 mg, 0.0580 mmol, 54%) . ¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (2H, m), 6.92-6.84 (2H, m), 4.57 (2H, s), 4.06-3.97 (2H, m), 3.81-3.72 (2H, m), 3.61-3.44 (4H, m), 2.50-2.21 (5H, m), 2.15-1.72 (8H, m), 1.63-1.50 (2H, m), 0.85 (3H, t, J = 7.2 Hz) . MS (m/z): 541 (M+H) ⁺ .

[Example 9] 2-(7-Bromoquinazolin-4-yl)-5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-2,5,13 -Triazadispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione

The compound (580 mg, 1.32 mmol) and 7-bromo-4-chloroquinazoline (357 mg, 1.46 mmol) obtained in Reference Example D-9 were suspended in 2-propanol (13 ml), and N,N-diisopropyl was added Benzylethylamine (923μl, 5.30mmol), heated to reflux at 80°C for 6.5 hours. After cooling to room temperature, water and saturated brine were added, followed by extraction with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-35:65) to obtain the title compound (754 mg, 1.24 mmol, 94%). ¹ H-NMR (CDCl ₃ ) δ: 8.65 (1H, s), 8.08 (1H, d, J = 1.6 Hz), 7.58 (1H, br s), 7.53-7.50 (1H, m), 7.44 (1H, d, J = 8.8 Hz), 7.37-7.31 (1H, m), 7.00-6.95 (1H, m), 6.94-6.89 (1H, m), 5.07 (2H, d, J = 9.6 Hz), 5.01 (2H , s), 4.57 (2H, d, J = 9.6 Hz), 2.44-2.13 (4H, m), 2.13-1.90 (2H, m), 1.87-1.73 (2H, m). MS (m/z): 608 (M+H) ⁺ .

Using the compound described in the Reference Example, the same operation as in Example 9 was performed to obtain the following compound.

5-[(4-氯-3-氟苯基)甲基]-2-(7-氯喹唑啉-4-基)-10,10-二氟-2,5,13-三氮螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (CD₃ OD) δ : 8.46 (1H, s), 7.86 (1H, d, J = 8.5 Hz), 7.76-7.75 (1H, m), 7.50-7.46 (1H, m), 7.42-7.37 (1H, m), 7.17-7.13 (1H, m), 7.08-7.03 (1H, m), 5.11-4.98 (5H, m), 4.83-4.69 (2H, m), 2.35-2.06 (6H, m), 2.00-1.90 (2H, m). MS (m/z) : 564 (M+H)⁺ . 製造原料：參考例D-9、4,7-二氯喹唑啉 11

5-[(4-氯-3-氟苯基)甲基]-10,10-二氟-2-(7-甲氧基喹唑啉-4-基)-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (CDCl₃ ) δ : 8.59 (1H, s), 7.49 (1H, d, J = 9.2 Hz), 7.37-7.30 (1H, m), 7.25-7.21 (1H, m), 7.05-6.96 (2H, m), 6.95-6.89 (1H, m), 6.61 (1H, br s), 5.08 (2H, d, J = 9.2 Hz), 5.02 (2H, br s), 4.56 (2H, d, J = 9.2 Hz), 3.94 (3H, s), 2.42-2.28 (4H, m), 2.10-1.91 (2H, m), 1.88-1.76 (2H, m). MS (m/z) : 560 (M+H)⁺ . 製造原料：參考例D-9、4-氯-7-甲氧基喹唑啉 12

5-[(4-氯-3-氟苯基)甲基]-2-(7-氯-2-甲基喹唑啉-4-基)-10,10-二氟-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (CDCl₃ ) δ : 7.82-7.81 (1H, m), 7.50-7.46 (1H, m), 7.37-7.24 (3H, m), 7.01-6.97 (1H, m), 6.94-6.91 (1H, m), 5.06 (2H, d, J = 9.8 Hz), 5.01 (2H, s), 4.55 (2H, d, J = 9.8 Hz), 2.62 (3H, s), 2.42-2.21 (4H, m), 2.11-1.93 (2H, m), 1.86-1.76 (2H, m). MS (m/z) : 578 (M+H)⁺ . 製造原料：參考例D-9、4,7-二氯-2-甲基喹唑啉 13

4-[5-[(4-氯-3-氟苯基)甲基]-10,10-二氟-6,14-二側氧-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-2-基]喹唑啉-7-甲腈 ¹ H-NMR (CDCl₃ ) δ : 8.73 (1H, s), 8.25-8.22 (1H, m), 7.67 (1H, d, J = 8.8 Hz), 7.60-7.56 (1H, m), 7.38-7.32 (1H, m), 7.01-6.95 (1H, m), 6.94-6.90 (1H, m), 6.82 (1H, br s), 5.11 (2H, d, J = 9.6 Hz), 5.01 (2H, br s), 4.62 (2H, d, J = 9.6 Hz), 2.43-2.24 (4H, m), 2.08-1.90 (2H, m), 1.88-1.77 (2H, m). MS (m/z) : 555 (M+H)⁺ . 製造原料：參考例D-9、4-氯喹唑啉-7-甲腈 14

5-[(4-氯-3-氟苯基)甲基]-10,10-二氟-2-[7-甲基喹唑啉-4-基]-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (CDCl₃ ) δ : 8.64 (1H, s), 7.71-7.65 (1H, m), 7.48 (1H, d, J = 8.0 Hz), 7.42 (1H, br s), 7.36-7.30 (1H, m), 7.26-7.22 (1H, m), 7.01-6.95 (1H, m), 6.94-6.89 (1H, m), 5.08 (2H, d, J = 9.6 Hz), 5.02 (2H, br s), 4.57 (2H, d, J = 9.6 Hz), 2.52 (3H, s), 2.41-2.18 (4H, m), 2.10-1.92 (2H, m), 1.86-1.74 (2H, m). MS (m/z) : 544 (M+H)⁺ . 製造原料：參考例D-9、4-氯-7-甲基喹唑啉 15

5-[(4-氯-3-氟苯基)甲基]-2-(7-氯吡啶并[3,2-d]嘧啶-4-基)-10,10-二氟-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (CDCl₃ ) δ : 8.60 (1H, s), 8.59-8.58 (1H, m), 8.10-8.09 (1H, m), 7.35-7.31 (1H, m), 7.12 (1H, s), 7.01-6.97 (1H, m), 6.95-6.91 (1H, m), 5.38-5.32 (1H, m), 5.02-4.93 (4H, m), 4.47-4.41 (1H, m), 2.43-2.21 (4H, m), 2.10-1.92 (2H, m), 1.86-1.77 (2H, m). MS (m/z) : 565 (M+H)⁺ . 製造原料：參考例D-9、4,7-二氯吡啶并[3,2-d]嘧啶 16

4-{5-[(4-氯-3-氟苯基)甲基]-10,10-二氟-6,14-二側氧-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-2-基}喹唑啉-7-甲酸甲酯 ¹ H-NMR (CDCl₃ ) δ: 8.73 (1H, s), 8.58-8.57 (1H, m), 8.04-8.00 (1H, m), 7.65 (1H, d, J = 9.1 Hz), 7.37-7.32 (1H, m), 7.22 (1H, br s), 7.01-6.97 (1H, m), 6.95-6.91 (1H, m), 5.11 (2H, d, J = 9.8 Hz), 5.03 (2H, br s), 4.61 (2H, d, J = 9.8 Hz), 4.00 (3H, s), 2.42-2.21 (4H, m), 2.09-1.92 (2H, m), 1.86-1.76 (2H, m). MS (m/z) : 588 (M+H)⁺ . 製造原料：參考例D-9、4-氯喹唑啉-7-甲酸甲酯 17

2-(6-溴噻吩并[3,2-d]嘧啶-4-基)-5-[(4-氯-3-氟苯基)甲基]-10,10-二氟-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (CDCl₃ ) δ : 8.55 (1H, s), 7.45 (1H, s), 7.39-7.33 (2H, m), 6.99 (1H, dd, J = 9.6, 1.6 Hz), 6.94 (1H, dd, J = 8.0, 1.6 Hz), 5.00 (2H, s), 4.95 (2H, d, J = 10.0 Hz), 4.41 (2H, d, J = 10.0 Hz), 2.42-2.14 (4H, m), 2.11-1.90 (2H, m), 1.86-1.72 (2H, m).  MS (m/z) : 614 (M+H)⁺ . 製造原料：參考例D-9、6-溴-4-氯噻吩并[3,2-d]嘧啶 18

5-[(4-氯-3-氟苯基)甲基]-2-[2,7-二氯喹唑啉-4-基]-10,10-二氟-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (DMSO-d₆ ) δ : 9.13 (1H, s), 7.89 (1H, d, J = 9.2 Hz), 7.76-7.74 (1H, m), 7.54-7.49 (2H, m), 7.34-7.30 (1H, m), 7.13-7.09 (1H, m), 5.21 (1H, d, J = 9.8 Hz), 5.07-4.86 (3H, m), 4.79-4.68 (1H, m), 4.44-4.30 (1H, m), 2.32-2.03 (6H, m), 1.95-1.84 (2H, m). MS (m/z) : 598 (M+H)⁺ . 製造原料：參考例D-9、2,4,7-三氯喹唑啉 19

5-[(4-氯-3-氟苯基)甲基]-2-(2-氯-7-甲氧基喹唑啉-4-基)-10,10-二氟-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮    ¹ H-NMR (CDCl₃ ) δ : 7.54 (1H, br s), 7.45 (1H, d, J = 9.2 Hz), 7.38-7.33 (1H, m), 7.17-7.16 (1H, m), 7.02-6.96 (2H, m), 6.93-6.90 (1H, m), 5.09 (2H, d, J = 10.0 Hz), 4.99 (2H, br s), 4.59 (2H, d, J = 10.0 Hz), 3.91 (3H, s), 2.42-2.17 (4H, m), 2.10-1.93 (2H, m), 1.85-1.76 (2H, m). MS (m/z) : 594 (M+H)⁺ . 製造原料：參考例D-9、2,4-二氯-7-甲氧基喹唑啉 20

2-(7-氯喹唑啉-4-基)-10,10-二氟-5-[(5-氟-6-甲氧基吡啶-3-基)甲基]-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (CDCl₃ ) δ : 8.63 (1H, s), 7.88 (1H, s), 7.76 (1H, s), 7.53 (1H, d, J = 9.0 Hz), 7.38-7.30 (2H, m), 7.30-7.25 (1H, m), 5.06 (2H, d, J = 9.8 Hz), 4.95 (2H, s), 4.60 (2H, d, J = 9.8 Hz), 3.97 (3H, s), 2.40-2.15 (4H, m), 2.08-1.87 (2H, m), 1.81-1.70 (2H, m). MS (m/z) : 561 (M+H)⁺ . 製造原料：參考例D-10、4,7-二氯喹唑啉 21

2-(7-氯喹唑啉-4-基)-5-{[4-(二氟甲基)-3-氟苯基]甲基}-10,10-二氟-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (DMSO-d₆ ) δ : 9.09 (1H, s), 8.48 (1H, s), 7.89 (1H, d, J = 8.5 Hz), 7.80 (1H, s), 7.63-7.43 (2H, m), 7.36-7.11 (3H, m), 5.35-4.18 (6H, m), 2.36-2.00 (6H, m), 1.99-1.72 (2H, m). MS (m/z) : 580 (M+H)⁺ . 製造原料：參考例D-11、4,7-二氯喹唑啉 22

2-(7-氯喹唑啉-4-基)-5-{[4-(二氟甲氧基)-3-氟苯基]甲基}-10,10-二氟-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (CDCl₃ ) δ : 8.66 (1H, s), 7.91-7.89 (1H, m), 7.78 (1H, br s), 7.53 (1H, d, J = 9.2 Hz), 7.39-7.35 (1H, m), 7.22-7.18 (1H, m), 7.04-7.00 (1H, m), 6.98-6.94 (1H, m), 6.54 (1H, t, J = 72.8 Hz), 5.08 (2H, d, J = 10.4 Hz), 5.03 (2H, br s), 4.59 (2H, d, J = 10.4 Hz), 2.42-2.32 (2H, m), 2.30-2.15 (2H, m), 2.11-1.93 (2H, m), 1.86-1.76 (2H, m). MS (m/z) : 596 (M+H)⁺ . 製造原料：參考例D-12、4,7-二氯喹唑啉 23

2-(7-氯喹唑啉-4-基)-10,10-二氟-5-(喹啉-6-基甲基)-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (DMSO-d₆ ) δ : 9.14 (1H, s), 8.87-8.79 (1H, m), 8.43 (1H, s), 8.25-8.18 (1H, m), 7.99-7.91 (1H, m), 7.84-7.77 (1H, m), 7.77-7.74 (1H, m), 7.74-7.69 (1H, m), 7.67-7.59 (1H, m), 7.50-7.44 (1H, m), 7.44-7.39 (1H, m), 5.38-4.18 (4H, m), 5.15 (2H, s), 2.36-2.01 (6H, m), 2.01-1.81 (2H, m). MS (m/z) : 563 (M+H)⁺ . 製造原料：參考例D-13、4,7-二氯喹唑啉 24

2-(7-氯喹唑啉-4-基)-10,10-二氟-5-[(3-氟-4-甲氧基苯基)甲基]-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (CDCl₃ ) δ : 8.64 (1H, s), 7.89 (1H, d, J = 2.4 Hz), 7.51 (1H, d, J = 8.4 Hz), 7.35 (1H, dd, J = 8.4, 2.4 Hz), 6.98-6.93 (1H, m), 6.89 (1H, br s), 6.87-6.76 (2H, m), 5.04 (2H, d, J = 10.0 Hz), 4.97 (2H, s), 4.62 (2H, d, J = 10.0 Hz), 3.84 (3H, s), 2.45-2.23 (4H, m), 2.10-1.89 (2H, m), 1.86-1.73 (2H, m). MS (m/z) : 560 (M+H)⁺ . 製造原料：參考例D-14、4,7-二氯喹唑啉 25

5-[(4-氯-3-氟苯基)甲基]-2-(7-氯喹唑啉-4-基)-2,5,14-三氮二螺[3.2.6⁷ .2⁴ ]十五烷-6,15-二酮    ¹ H-NMR (CDCl₃ ) δ : 8.64 (1H, s), 7.90-7.85(1H, m), 7.54 (1H, d, J = 9.2 Hz), 7.39-7.29 (2H, m), 7.02-6.96 (1H, m), 6.93-6.87 (1H, m), 6.55 (1H, br s), 5.08 (2H, d, J = 9.6 Hz), 4.98 (2H, s), 4.55 (2H, d, J = 9.6 Hz), 2.37-2.24 (2H, m), 1.88-1.45 (10H, m). MS (m/z) : 542 (M+H)⁺ . 製造原料：參考例D-15、4,7-二氯喹唑啉 26

5-[(4-氯-3-氟苯基)甲基]-2-(7-氯喹唑啉-4-基)-10-硫-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H NMR (CDCl₃ ) δ : 8.65 (1H, s), 7.88 (1H, d, J = 2.0 Hz), 7.52 (1H, d, J = 9.2 Hz), 7.39-7.30 (2H, m), 7.01-6.95 (1H, m), 6.94-6.85 (2H, m), 5.08 (2H, d, J = 9.6 Hz), 5.00 (2H, s), 4.56 (2H, d, J = 9.6 Hz), 2.86-2.65 (4H, m), 2.53-2.35 (2H, m), 1.96-1.84 (2H, m). MS (m/z) : 546 (M+H)⁺ . 製造原料：參考例D-16、4,7-二氯喹唑啉 27

(-)-6-[(4-氯-3-氟苯基)甲基]-2-(7-氯-5-氟喹唑啉-4-基)-11,11-二氟-2,6,14-三氮二螺[4.2.5⁸ .2⁵ ]十五烷-7,15-二酮 比旋光度[α]_D ²⁰ = -27.179 (c=1.0，二甲基亞碸)¹ H-NMR (CDCl₃ ) δ : 8.55 (1H, s), 7.67-7.65 (1H, m), 7.30-7.24 (1H, m), 7.10-7.05 (1H, m), 6.88-6.78 (2H, m), 6.74-6.70 (1H, m), 4.73-4.65 (1H, m), 4.53-4.43 (1H, m), 4.29-4.13 (2H, m), 4.01-3.92 (1H, m), 2.61-2.53 (1H, m), 2.49-2.22 (6H, m), 2.11-1.96 (2H, m), 1.95-1.83 (2H, m). MS (m/z) : 596 (M+H)⁺ . 製造原料：參考例D-2-1、4,7-二氯-5-氟喹唑啉 28-1

(-)-2-(7-氯喹唑啉-4-基)-11,11-二氟-6-({3-氟-4-[(² H₃ )甲基氧基]苯基}甲基)-2,6,14-三氮二螺[4.2.5⁸ .2⁵ ]十五烷-7,15-二酮 使用Daicel之CHIRALFLASH IC(己烷/乙醇)而分取第1波峰¹ H-NMR (CDCl₃ ) δ : 8.60 (1H, s), 8.52 (1H, br s), 7.97-7.79 (2H, m), 7.33 (1H, d, J = 7.8 Hz), 6.87-6.63 (3H, m), 4.75 (1H, d, J = 15.7 Hz), 4.52 (1H, d, J = 15.7 Hz), 4.45-4.18 (4H, m), 2.66-2.38 (4H, m), 2.37-2.01 (4H, m), 2.00-1.84 (2H, m). MS (m/z) : 577, 578, 579 (M+H)⁺ . 製造原料：參考例D-17、4,7-二氯喹唑啉 28-2

(+)-2-(7-氯喹唑啉-4-基)-11,11-二氟-6-({3-氟-4-[(² H₃ )甲基氧基]苯基}甲基)-2,6,14-三氮二螺[4.2.5⁸ .2⁵ ]十五烷-7,15-二酮 使用Daicel之CHIRALFLASH IC(己烷/乙醇)而分取第2波峰 比旋光度[α]_D ²⁰ = +23.387 (c=1.0，二甲基亞碸)¹ H-NMR (CDCl₃ ) δ: 8.60 (1H, s), 8.50 (1H, br s), 7.97-7.79 (2H, m), 7.33 (1H, d, J = 7.8 Hz), 6.87-6.63 (3H, m), 4.75 (1H, d, J = 15.7 Hz), 4.52 (1H, d, J = 15.7 Hz), 4.45-4.18 (4H, m), 2.66-2.38 (4H, m), 2.37-2.01 (4H, m), 2.00-1.84 (2H, m). MS (m/z) : 577, 578, 579 (M+H)⁺ . 製造原料：參考例D-17、4,7-二氯喹唑啉 [table 5] Example 10

5-[(4-chloro-3-fluorophenyl)methyl]-2-(7-chloroquinazolin-4-yl)-10,10-difluoro-2,5,13-triazaspiro[3.2 .5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CD ₃ OD) δ: 8.46 (1H, s), 7.86 (1H, d, J = 8.5 Hz), 7.76-7.75 (1H, m), 7.50-7.46 (1H, m), 7.42- 7.37 (1H, m), 7.17-7.13 (1H, m), 7.08-7.03 (1H, m), 5.11-4.98 (5H, m), 4.83-4.69 (2H, m), 2.35-2.06 (6H, m) ), 2.00-1.90 (2H, m). MS (m/z): 564 (M+H) ⁺ . Manufacturing raw materials: Reference example D-9, 4,7-dichloroquinazoline 11

5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-2-(7-methoxyquinazolin-4-yl)-2,5,13-triazide Dispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CDCl ₃ ) δ: 8.59 (1H, s), 7.49 (1H, d, J = 9.2 Hz), 7.37-7.30 (1H, m), 7.25-7.21 (1H, m), 7.05-6.96 (2H, m), 6.95-6.89 (1H, m), 6.61 (1H, br s), 5.08 (2H, d, J = 9.2 Hz), 5.02 (2H, br s), 4.56 (2H, d, J = 9.2 Hz), 3.94 (3H, s), 2.42-2.28 (4H, m), 2.10-1.91 (2H, m), 1.88-1.76 (2H, m). MS (m/z): 560 (M+ H) ⁺ . Manufacturing raw materials: Reference Example D-9, 4-chloro-7-methoxyquinazoline 12

5-[(4-chloro-3-fluorophenyl)methyl]-2-(7-chloro-2-methylquinazolin-4-yl)-10,10-difluoro-2,5,13 -Triazadispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CDCl ₃ ) δ: 7.82-7.81 (1H, m), 7.50-7.46 (1H, m), 7.37-7.24 (3H, m), 7.01-6.97 (1H, m), 6.94-6.91 ( 1H, m), 5.06 (2H, d, J = 9.8 Hz), 5.01 (2H, s), 4.55 (2H, d, J = 9.8 Hz), 2.62 (3H, s), 2.42-2.21 (4H, m ), 2.11-1.93 (2H, m), 1.86-1.76 (2H, m). MS (m/z): 578 (M+H) ⁺ . Manufacturing raw materials: Reference Example D-9, 4,7-dichloro-2-methylquinazoline 13

4-[5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-6,14-dioxo-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecyl-2-yl]quinazoline-7-carbonitrile ¹ H-NMR (CDCl ₃ ) δ: 8.73 (1H, s), 8.25-8.22 (1H, m), 7.67 (1H, d, J = 8.8 Hz), 7.60-7.56 (1H, m), 7.38-7.32 (1H, m), 7.01-6.95 (1H, m), 6.94-6.90 (1H, m), 6.82 (1H, br s), 5.11 (2H, d, J = 9.6 Hz), 5.01 (2H, br s) ), 4.62 (2H, d, J = 9.6 Hz), 2.43-2.24 (4H, m), 2.08-1.90 (2H, m), 1.88-1.77 (2H, m). MS (m/z): 555 ( M+H) ⁺ . Manufacturing raw materials: Reference Example D-9, 4-chloroquinazoline-7-carbonitrile 14

5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-2-[7-methylquinazolin-4-yl]-2,5,13-triazine Spiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CDCl ₃ ) δ: 8.64 (1H, s), 7.71-7.65 (1H, m), 7.48 (1H, d, J = 8.0 Hz), 7.42 (1H, br s), 7.36-7.30 ( 1H, m), 7.26-7.22 (1H, m), 7.01-6.95 (1H, m), 6.94-6.89 (1H, m), 5.08 (2H, d, J = 9.6 Hz), 5.02 (2H, br s) ), 4.57 (2H, d, J = 9.6 Hz), 2.52 (3H, s), 2.41-2.18 (4H, m), 2.10-1.92 (2H, m), 1.86-1.74 (2H, m). MS ( m/z): 544 (M+H) ⁺ . Manufacturing raw materials: Reference Example D-9, 4-chloro-7-methylquinazoline 15

5-[(4-chloro-3-fluorophenyl)methyl]-2-(7-chloropyrido[3,2-d]pyrimidin-4-yl)-10,10-difluoro-2,5 ,13-Triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CDCl ₃ ) δ: 8.60 (1H, s), 8.59-8.58 (1H, m), 8.10-8.09 (1H, m), 7.35-7.31 (1H, m), 7.12 (1H, s) , 7.01-6.97 (1H, m), 6.95-6.91 (1H, m), 5.38-5.32 (1H, m), 5.02-4.93 (4H, m), 4.47-4.41 (1H, m), 2.43-2.21 ( 4H, m), 2.10-1.92 (2H, m), 1.86-1.77 (2H, m). MS (m/z): 565 (M+H) ⁺ . Manufacturing raw materials: Reference Example D-9, 4,7-dichloropyrido[3,2-d]pyrimidine 16

4-{5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-6,14-dioxo-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecyl-2-yl}quinazoline-7-methyl carboxylate ¹ H-NMR (CDCl ₃ ) δ: 8.73 (1H, s), 8.58-8.57 (1H, m), 8.04-8.00 (1H, m), 7.65 (1H, d, J = 9.1 Hz), 7.37-7.32 (1H, m), 7.22 (1H, br s), 7.01-6.97 (1H, m), 6.95-6.91 (1H, m), 5.11 (2H, d, J = 9.8 Hz), 5.03 (2H, br s) ), 4.61 (2H, d, J = 9.8 Hz), 4.00 (3H, s), 2.42-2.21 (4H, m), 2.09-1.92 (2H, m), 1.86-1.76 (2H, m). MS ( m/z): 588 (M+H) ⁺ . Manufacturing raw materials: Reference Example D-9, 4-chloroquinazoline-7-methyl carboxylate 17

2-(6-Bromothieno[3,2-d]pyrimidin-4-yl)-5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-2,5 ,13-Triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CDCl ₃ ) δ: 8.55 (1H, s), 7.45 (1H, s), 7.39-7.33 (2H, m), 6.99 (1H, dd, J = 9.6, 1.6 Hz), 6.94 (1H , dd, J = 8.0, 1.6 Hz), 5.00 (2H, s), 4.95 (2H, d, J = 10.0 Hz), 4.41 (2H, d, J = 10.0 Hz), 2.42-2.14 (4H, m) , 2.11-1.90 (2H, m), 1.86-1.72 (2H, m). MS (m/z): 614 (M+H) ⁺ . Manufacturing raw materials: Reference Example D-9, 6-bromo-4-chlorothieno[3,2-d]pyrimidine 18

5-[(4-chloro-3-fluorophenyl)methyl]-2-[2,7-dichloroquinazolin-4-yl]-10,10-difluoro-2,5,13-triazide Dispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (DMSO-d ₆ ) δ: 9.13 (1H, s), 7.89 (1H, d, J = 9.2 Hz), 7.76-7.74 (1H, m), 7.54-7.49 (2H, m), 7.34 -7.30 (1H, m), 7.13-7.09 (1H, m), 5.21 (1H, d, J = 9.8 Hz), 5.07-4.86 (3H, m), 4.79-4.68 (1H, m), 4.44-4.30 (1H, m), 2.32-2.03 (6H, m), 1.95-1.84 (2H, m). MS (m/z): 598 (M+H) ⁺ . Manufacturing raw materials: Reference example D-9, 2,4,7-trichloroquinazoline 19

5-[(4-chloro-3-fluorophenyl)methyl]-2-(2-chloro-7-methoxyquinazolin-4-yl)-10,10-difluoro-2,5, 13-Triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CDCl ₃ ) δ: 7.54 (1H, br s), 7.45 (1H, d, J = 9.2 Hz), 7.38-7.33 (1H, m), 7.17-7.16 (1H, m), 7.02- 6.96 (2H, m), 6.93-6.90 (1H, m), 5.09 (2H, d, J = 10.0 Hz), 4.99 (2H, br s), 4.59 (2H, d, J = 10.0 Hz), 3.91 ( 3H, s), 2.42-2.17 (4H, m), 2.10-1.93 (2H, m), 1.85-1.76 (2H, m). MS (m/z): 594 (M+H) ⁺ . Manufacturing raw materials: Reference Example D-9, 2,4-Dichloro-7-methoxyquinazoline 20

2-(7-chloroquinazolin-4-yl)-10,10-difluoro-5-[(5-fluoro-6-methoxypyridin-3-yl)methyl]-2,5,13- Triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CDCl ₃ ) δ: 8.63 (1H, s), 7.88 (1H, s), 7.76 (1H, s), 7.53 (1H, d, J = 9.0 Hz), 7.38-7.30 (2H, m ), 7.30-7.25 (1H, m), 5.06 (2H, d, J = 9.8 Hz), 4.95 (2H, s), 4.60 (2H, d, J = 9.8 Hz), 3.97 (3H, s), 2.40 -2.15 (4H, m), 2.08-1.87 (2H, m), 1.81-1.70 (2H, m). MS (m/z): 561 (M+H) ⁺ . Manufacturing raw materials: Reference example D-10, 4,7-dichloroquinazoline twenty one

2-(7-chloroquinazolin-4-yl)-5-{[4-(difluoromethyl)-3-fluorophenyl]methyl}-10,10-difluoro-2,5,13- Triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (DMSO-d ₆ ) δ: 9.09 (1H, s), 8.48 (1H, s), 7.89 (1H, d, J = 8.5 Hz), 7.80 (1H, s), 7.63-7.43 (2H , m), 7.36-7.11 (3H, m), 5.35-4.18 (6H, m), 2.36-2.00 (6H, m), 1.99-1.72 (2H, m). MS (m/z): 580 (M +H) ⁺ . Manufacturing raw materials: Reference example D-11, 4,7-dichloroquinazoline twenty two

2-(7-chloroquinazolin-4-yl)-5-{[4-(difluoromethoxy)-3-fluorophenyl]methyl}-10,10-difluoro-2,5,13 -Triazadispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CDCl ₃ ) δ: 8.66 (1H, s), 7.91-7.89 (1H, m), 7.78 (1H, br s), 7.53 (1H, d, J = 9.2 Hz), 7.39-7.35 ( 1H, m), 7.22-7.18 (1H, m), 7.04-7.00 (1H, m), 6.98-6.94 (1H, m), 6.54 (1H, t, J = 72.8 Hz), 5.08 (2H, d, J = 10.4 Hz), 5.03 (2H, br s), 4.59 (2H, d, J = 10.4 Hz), 2.42-2.32 (2H, m), 2.30-2.15 (2H, m), 2.11-1.93 (2H, m), 1.86-1.76 (2H, m). MS (m/z): 596 (M+H) ⁺ . Manufacturing raw materials: Reference example D-12, 4,7-dichloroquinazoline twenty three

2-(7-chloroquinazolin-4-yl)-10,10-difluoro-5-(quinolin-6-ylmethyl)-2,5,13-triazabispiro[3.2.5 ⁷ . 2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (DMSO-d ₆ ) δ: 9.14 (1H, s), 8.87-8.79 (1H, m), 8.43 (1H, s), 8.25-8.18 (1H, m), 7.99-7.91 (1H, m), 7.84-7.77 (1H, m), 7.77-7.74 (1H, m), 7.74-7.69 (1H, m), 7.67-7.59 (1H, m), 7.50-7.44 (1H, m), 7.44- 7.39 (1H, m), 5.38-4.18 (4H, m), 5.15 (2H, s), 2.36-2.01 (6H, m), 2.01-1.81 (2H, m). MS (m/z): 563 ( M+H) ⁺ . Manufacturing raw materials: Reference example D-13, 4,7-dichloroquinazoline twenty four

2-(7-chloroquinazolin-4-yl)-10,10-difluoro-5-[(3-fluoro-4-methoxyphenyl)methyl]-2,5,13-triazine Spiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CDCl ₃ ) δ: 8.64 (1H, s), 7.89 (1H, d, J = 2.4 Hz), 7.51 (1H, d, J = 8.4 Hz), 7.35 (1H, dd, J = 8.4 , 2.4 Hz), 6.98-6.93 (1H, m), 6.89 (1H, br s), 6.87-6.76 (2H, m), 5.04 (2H, d, J = 10.0 Hz), 4.97 (2H, s), 4.62 (2H, d, J = 10.0 Hz), 3.84 (3H, s), 2.45-2.23 (4H, m), 2.10-1.89 (2H, m), 1.86-1.73 (2H, m). MS (m/ z): 560 (M+H) ⁺ . Manufacturing raw materials: Reference example D-14, 4,7-dichloroquinazoline 25

5-[(4-chloro-3-fluorophenyl)methyl]-2-(7-chloroquinazolin-4-yl)-2,5,14-triazabispiro[3.2.6 ⁷ .2 ⁴ ] Pentadecane-6,15-dione ¹ H-NMR (CDCl ₃ ) δ: 8.64 (1H, s), 7.90-7.85(1H, m), 7.54 (1H, d, J = 9.2 Hz), 7.39-7.29 (2H, m), 7.02-6.96 (1H, m), 6.93-6.87 (1H, m), 6.55 (1H, br s), 5.08 (2H, d, J = 9.6 Hz), 4.98 (2H, s), 4.55 (2H, d, J = 9.6 Hz), 2.37-2.24 (2H, m), 1.88-1.45 (10H, m). MS (m/z): 542 (M+H) ⁺ . Manufacturing raw materials: Reference example D-15, 4,7-dichloroquinazoline 26

5-[(4-chloro-3-fluorophenyl)methyl]-2-(7-chloroquinazolin-4-yl)-10-thio-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H NMR (CDCl ₃ ) δ: 8.65 (1H, s), 7.88 (1H, d, J = 2.0 Hz), 7.52 (1H, d, J = 9.2 Hz), 7.39-7.30 (2H, m), 7.01 -6.95 (1H, m), 6.94-6.85 (2H, m), 5.08 (2H, d, J = 9.6 Hz), 5.00 (2H, s), 4.56 (2H, d, J = 9.6 Hz), 2.86- 2.65 (4H, m), 2.53-2.35 (2H, m), 1.96-1.84 (2H, m). MS (m/z): 546 (M+H) ⁺ . Manufacturing raw materials: Reference example D-16, 4,7-dichloroquinazoline 27

(-)-6-[(4-chloro-3-fluorophenyl)methyl]-2-(7-chloro-5-fluoroquinazolin-4-yl)-11,11-difluoro-2, 6,14-Triazabisspiro[4.2.5 ⁸ .2 ⁵ ]pentadecane-7,15-dione Specific optical rotation [α] _D ²⁰ = -27.179 (c=1.0, dimethyl sulfide) ¹ H-NMR (CDCl ₃ ) δ: 8.55 (1H, s), 7.67-7.65 (1H, m), 7.30- 7.24 (1H, m), 7.10-7.05 (1H, m), 6.88-6.78 (2H, m), 6.74-6.70 (1H, m), 4.73-4.65 (1H, m), 4.53-4.43 (1H, m) ), 4.29-4.13 (2H, m), 4.01-3.92 (1H, m), 2.61-2.53 (1H, m), 2.49-2.22 (6H, m), 2.11-1.96 (2H, m), 1.95-1.83 (2H, m). MS (m/z): 596 (M+H) ⁺ . Manufacturing raw materials: Reference example D-2-1, 4,7-dichloro-5-fluoroquinazoline 28-1

(-)-2-(7-chloroquinazolin-4-yl)-11,11-difluoro-6-({3-fluoro-4-[( ² H ₃ )methyloxy]phenyl)methan Base)-2,6,14-Triazabisspiro[4.2.5 ⁸ .2 ⁵ ]pentadecane-7,15-dione Use Daicel's CHIRALFLASH IC (hexane/ethanol) to separate the first peak ¹ H-NMR (CDCl ₃ ) δ: 8.60 (1H, s), 8.52 (1H, br s), 7.97-7.79 (2H, m) , 7.33 (1H, d, J = 7.8 Hz), 6.87-6.63 (3H, m), 4.75 (1H, d, J = 15.7 Hz), 4.52 (1H, d, J = 15.7 Hz), 4.45-4.18 ( 4H, m), 2.66-2.38 (4H, m), 2.37-2.01 (4H, m), 2.00-1.84 (2H, m). MS (m/z): 577, 578, 579 (M+H) ⁺ . Manufacturing raw materials: Reference example D-17, 4,7-dichloroquinazoline 28-2

(+)-2-(7-chloroquinazolin-4-yl)-11,11-difluoro-6-({3-fluoro-4-[( ² H ₃ )methyloxy]phenyl)methan Base)-2,6,14-Triazabisspiro[4.2.5 ⁸ .2 ⁵ ]pentadecane-7,15-dione Use Daicel's CHIRALFLASH IC (hexane/ethanol) to divide the specific rotation of the second peak [α] _D ²⁰ = +23.387 (c=1.0, dimethylsulfene) ¹ H-NMR (CDCl ₃ ) δ: 8.60 (1H, s), 8.50 (1H, br s), 7.97-7.79 (2H, m), 7.33 (1H, d, J = 7.8 Hz), 6.87-6.63 (3H, m), 4.75 (1H, d, J = 15.7 Hz), 4.52 (1H, d, J = 15.7 Hz), 4.45-4.18 (4H, m), 2.66-2.38 (4H, m), 2.37-2.01 (4H, m), 2.00-1.84 (2H , m). MS (m/z): 577, 578, 579 (M+H) ⁺ . Manufacturing raw materials: Reference example D-17, 4,7-dichloroquinazoline

[Example 29] 5-[(4-chloro-3-fluorophenyl)methyl]-2-[2-ethoxy-7-methoxyquinazolin-4-yl]-10,10- Difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione

A mixture of the compound (100 mg, 0.168 mmol) obtained in Example 19 and a 20% ethanol solution (2 ml) of sodium ethoxide was heated to reflux at 80° C. for 6.5 hours, and then cooled to room temperature. A 1N aqueous hydrochloric acid solution was added to the reaction mixture to adjust the pH to a weakly acidic region, saturated sodium bicarbonate water was added to extract with ethyl acetate, and the combined organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-50:50). The fractions containing the desired product were concentrated under reduced pressure, the obtained residue was dissolved in ethyl acetate, hexane was added, and the precipitated solid was collected by filtration and dried to obtain the title compound (45.9 mg, 0.0760 mmol, 45%). ¹ H-NMR (CDCl ₃ ) δ: 7.39 (1H, d, J = 9.2 Hz), 7.36-7.30 (1H,m), 7.27 (1H, br s), 7.03 (1H, d, J = 2.4 Hz) , 7.00-6.94 (1H, m), 6.93-6.87 (1H, m), 6.82 (1H, dd, J = 9.2, 2.4 Hz), 5.06 (2H, d, J = 9.6 Hz), 4.99 (2H, s ), 4.53 (2H, d, J = 9.6 Hz), 4.45 (2H, q, J = 6.8 Hz), 3.91 (3H, s), 2.43-2.14 (4H, m), 2.11-1.89 (2H, m) , 1.85-1.69 (2H, m), 1.44 (3H, t, J = 6.8 Hz). MS (m/z): 604 (M+H) ⁺ .

[Example 30] 4-{5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-6,14-dioxo-2,5,13-triazadi Spiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-2-yl}-7-methoxyquinazoline-2-carbonitrile

The compound obtained in Example 19 (60.0mg, 0.101mmol), 1,4-diazabicyclo[2.2.2]octane (13.6g, 0.121mmol) in dimethylsulfene (1ml), water ( 0.2ml) Sodium cyanide (7.40mg, 0.121mmol) was added to the mixture, heated and stirred at 90°C for 5 hours, and cooled to room temperature. Water was added, and extraction was performed with ethyl acetate. The combined organic layer was washed with water and saturated brine, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-50:50) to obtain the title compound (40.4mg, 0.0691mmol, 68%) . ¹ H-NMR (DMSO-d ₆ ) δ: 9.10 (1H, s), 7.83 (1H, d, J = 9.2 Hz), 7.53-7.45 (1H, m), 7.34-7.28 (1H,m), 7.28 -7.26 (1H, m), 7.25-7.19 (1H, m), 7.12-7.06 (1H, m), 5.24-5.08 (1H, m), 5.04-4.83 (3H, m), 4.81-4.64 (1H, m), 4.44-4.28 (1H, m), 3.91 (3H, s), 2.32-1.99 (6H, m), 1.96-1.76 (2H, m). MS (m/z): 585 (M+H) ⁺ .

[Example 31] 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-chloro-2-(methylamino)quinazolin-4-yl]-10,10 -Difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione

To the tetrahydrofuran (1ml) suspension of the compound (80.0mg, 0.134mmol) obtained in Example 18, a 2.0mol/L tetrahydrofuran solution (270μl, 0.534mmol) of methylamine was added, and it was heated to reflux at 70°C for 5.5 hours. Cool to room temperature. Saturated brine was added, extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-80:20) to obtain the title compound (50.6 mg, 0.0853 mmol, 64%) ). ¹ H-NMR (CDCl ₃ ) δ: 7.51 (1H, br s), 7.37-7.31 (1H, m), 7.29 (1H, d, J = 8.8 Hz), 7.20 (1H, br s), 7.02-6.97 (1H, m), 6.97-6.89 (2H, m), 5.08-4.86 (5H, m), 4.46 (2H, d, J = 9.6 Hz), 3.02 (3H, d, J = 4.8 Hz), 2.46- 2.19 (4H, m), 2.12-1.89 (2H, m), 1.86-1.73 (2H, m). MS (m/z): 593 (M+H) ⁺ .

[Example 32] 2-[7-chloro-2-(dimethylamino)quinazolin-4-yl]-5-[(4-chloro-3-fluorophenyl)methyl]-10, 10-Difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione

To the tetrahydrofuran (1ml) suspension of the compound (80.0mg, 0.13mmol) obtained in Example 18, a 2.0mol/L tetrahydrofuran solution (270μl, 0.534mmol) of dimethylamine was added and heated to reflux at 70°C for 5.5 hours , Cool to room temperature. Saturated brine was added, extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-35:65) to obtain the title compound (65.1mg, 0.107mmol, 80%) ). ¹ H-NMR (CDCl ₃ ) δ: 7.51-7.47 (1H, m), 7.37-7.31 (1H, m), 7.29-7.24 (1H, m), 7.05-6.97 (2H, m), 6.95-6.87 ( 2H, m), 5.06-4.93 (4H, m), 4.46 (2H, d, J = 10.0 Hz), 3.19 (6H, s), 2.46-2.19 (4H, m), 2.13-1.90 (2H, m) , 1.87-1.70 (2H, m). MS (m/z): 607 (M+H) ⁺ .

[Example 33] 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-chloro-2-methoxyquinazolin-4-yl]-10,10-difluoro -2,5,13-Triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione

The compound (80.0 mg, 0.134 mmol) obtained in Example 18 was suspended in methanol (1 ml), potassium methoxide (37.5 mg, 0.534 mmol) was added, and the mixture was heated under reflux for 5 hours. After returning to room temperature, 1N hydrochloric acid aqueous solution was used to adjust to a weakly acidic area, and then a maximum amount of saturated sodium bicarbonate water was poured into it and extracted with ethyl acetate. After drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-50:50) to obtain the title compound (68.6 mg , 0.115mmol, 86%). ¹ H-NMR (CDCl ₃ ) δ: 7.71 (1H, d, J = 2.0 Hz), 7.43 (1H, d, J = 9.2 Hz), 7.36-7.30 (1H, m), 7.21-7.14 (2H, br m), 6.99-6.94 (1H, m), 6.92-6.87 (1H, m), 5.07 (2H, d, J = 9.6 Hz), 4.99 (2H, s), 4.56 (2H, d, J = 9.6 Hz ), 4.02 (3H, s), 2.42-2.18 (4H, m), 2.09-1.90 (2H, m), 1.85-1.72 (2H, m). MS (m/z): 594 (M+H) ⁺ .

[Example 34] 2-(7-Acetylquinazolin-4-yl)-5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-2,5 ,13-Triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione

[Step 1] 5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-2-[7-(1-hydroxyethyl)quinazolin-4-yl]- 2,5,13-Triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione The compound (200mg, 0.328mmol) obtained in Example 9 was dissolved in N,N-dione Methylformamide (4 ml), sodium formate (35.0 mg, 0.515 mmol) and triphenylphosphine (10.0 mg, 0.0381 mmol) were added, and after nitrogen substitution, ultrasonic wave was used to degas. After replacing with carbon monoxide, bis(triphenylphosphine) palladium(II) dichloride (24.0 mg, 0.0342 mmol) was added, replaced with carbon monoxide again, and stirred at 110°C for 3 hours. The reaction solution was returned to room temperature, water and saturated brine were added, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a crude purified product. The obtained crude product was dissolved in tetrahydrofuran (2ml), and while stirring at 0°C, a tetrahydrofuran solution of methylmagnesium bromide (0.97M, 0.400ml, 0.390mmol) was added, and the mixture was stirred at room temperature for 15 hours. Under ice cooling, after adding saturated ammonium chloride aqueous solution to stop the reaction, water and saturated brine were further added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-dichloromethane=1:99-10:90) to obtain the title compound (35.4 mg, 0.0617 mmol, 19%). ¹ H-NMR (CDCl ₃ ) δ: 8.63 (1H, s), 7.85-7.83 (1H, m), 7.58-7.50 (2H, m), 7.48-7.44 (1H, m), 7.35-7.30 (1H, m), 7.00-6.95 (1H, m), 6.93-6.89 (1H, m), 5.09-4.98 (5H, m), 4.57 (2H, d, J = 9.8 Hz), 2.57 (1H, br s), 2.40-2.29 (2H, m), 2.28-2.16 (2H, m), 2.09-1.92 (2H, m), 1.83-1.74 (2H, m), 1.55 (3H, d, J = 6.7 Hz).

[Step 2] 2-(7-Acetylquinazolin-4-yl)-5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-2,5, 13-Triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione under nitrogen atmosphere, the compound (35.4mg, 0.0617mmol) obtained in step 1 above was dissolved in dichloromethane ( 2ml), under ice-cooling, add Dess-Martin reagent (52.3mg, 0.123mmol), and stir at 0°C for 30 minutes and at room temperature for 15 hours. Under ice cooling, after adding sodium thiosulfate aqueous solution and saturated sodium bicarbonate water to stop the reaction, it was extracted with dichloromethane, and washed with water and saturated brine. After drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol-dichloromethane=1:99-10:90) to obtain the title compound (22.2mg, 0.0388mmol, 63%). ¹ H-NMR (CDCl ₃ ) δ: 8.73 (1H, s), 8.44 (1H, s), 8.00-7.96 (1H, m), 7.77 (1H, br s), 7.66 (1H, d, J = 9.1 Hz), 7.37-7.32 (1H, m), 7.01-6.96 (1H, m), 6.95-6.91 (1H, m), 5.10 (2H, d, J = 9.7 Hz), 5.03 (2H, s), 4.62 (2H, d, J = 9.7 Hz), 2.73 (3H, s), 2.43-2.31 (2H, m), 2.29-2.14 (2H, m), 2.11-1.92 (2H, m), 1.87-1.75 (2H , m). MS (m/z): 572 (M+H) ⁺ .

[Example 35] 5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-2-[7-(2-fluoropropane-2-yl)quinazoline-4 -Yl]-2,5,13-triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione

[Step 1] 4-[5-[(4-chloro-3-fluorophenyl)methyl-10,10-difluoro-6,14-dioxo-2,5,13-triazadispiro[ 3.2.5 ⁷ .2 ⁴ ]tetradecyl-2-yl]quinazoline-7-methyl carboxylate The compound (131 mg, 0.223 mmol) obtained in Example 16 was dissolved in tetrahydrofuran (6 ml), cooled with ice, and dropped 1mol/l methylmagnesium bromide-tetrahydrofuran solution (1.34ml, 1.34mmol). After stirring for 100 hours, a saturated aqueous ammonium chloride solution was added to the reaction solution and stirred for a while. Extract with ethyl acetate and wash with water and saturated brine. It was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol-dichloromethane=5:95-10:90) to obtain the title compound (85.8 mg, 0.146). mmol, 65%). ¹ H-NMR (CDCl ₃ ) δ: 8.67 (1H, s), 7.97-7.95 (1H, m), 7.65-7.56 (2H, m), 7.36-7.31 (1H, m), 7.01-6.97 (1H, m), 6.95-6.90 (1H, m), 6.56 (1H, br s), 5.10 (2H, d, J = 9.8 Hz), 5.02 (2H, s), 4.59 (2H, d, J = 9.8 Hz) , 2.42-2.28 (4H, m), 2.06-1.93 (2H, m), 1.87-1.78 (2H, m), 1.66 (6H, s).

[Step 2] 5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-2-[7-(2-fluoropropane-2-yl)quinazoline-4- yl] two -2,5,13- triaza-spiro ^{[7.2 4} 3.2.5] tetradecane-6,14-dione compound (40.0mg, 0.0680mmol) obtained in the above step 1 was dissolved in diethyl Chloromethyl (5ml), under ice cooling, add (diethylamino)sulfur trifluoride (11.6μl, 0.0884mmol), and stir at room temperature for 3 hours. Water was added to the reaction solution and extracted with dichloromethane. Dry over anhydrous sodium sulfate, distill off the solvent under reduced pressure, and purify the obtained residue by silica gel column chromatography (methanol-dichloromethane=5:95) to obtain the title compound (27.4mg, 0.0464mmol, 68%) ). ¹ H-NMR (CDCl ₃ ) δ: 8.68-8.65 (1H, m), 7.92-7.84 (1H, m), 7.62-7.57 (1H, m), 7.55-7.49 (1H, m), 7.36-7.31 ( 1H, m), 7.02-6.97 (1H, m), 6.95-6.90 (1H, m), 6.55 (1H, br s), 5.10 (2H, d, J = 9.8 Hz), 5.03 (2H, s), 4.59 (2H, d, J = 9.8 Hz), 2.42-2.29 (4H, m), 2.06-1.91 (2H, m), 1.87-1.71 (8H, m). MS (m/z): 590 (M+ H) ⁺ .

啶-4-基)-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮[Example 36] 5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-2-(7-methoxy-1,5-

(Pyridin-4-yl)-2,5,13-triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione

啶(48.8mg，0.251mmol)、N-甲基-2-吡咯啶(2ml)、N,N-二異丙基乙基胺(156μl，0.913mmol)置入玻璃管並封管，以微波反應裝置使其於120℃反應3小時。以乙酸乙酯稀釋後，以水、飽和食鹽水洗淨，以無水硫酸鈉乾燥。減壓下餾除溶劑，將獲得的殘留物以矽膠管柱層析(甲醇-二氯甲烷=5:95)純化，而獲得標題化合物(33.0mg，0.0589mmol，26%)。¹ H-NMR (CDCl₃ ) δ : 8.47-8.45 (1H, m), 8.41-8.40 (1H, m), 7.52-7.49 (1H, m), 7.37-7.32 (1H, m), 7.05-7.01 (1H, m), 6.99-6.95 (1H, m), 6.79-6.66 (1H, m), 6.21-6.19 (1H, m), 5.11-4.93 (4H, m), 4.70-4.50 (2H, m), 3.95 (3H, s), 2.42-2.26 (4H, m), 2.09-1.92 (2H, m), 1.85-1.77 (2H, m). MS (m/z) : 560 (M+H)⁺ .The compound (100 mg, 0.228 mmol) obtained in Reference Example D-9, 8-chloro-3-methoxy-1,5-

Pyridine (48.8mg, 0.251mmol), N-methyl-2-pyrrolidine (2ml), N,N-diisopropylethylamine (156μl, 0.913mmol) were placed in a glass tube and sealed, and reacted by microwave The device was allowed to react at 120°C for 3 hours. After diluting with ethyl acetate, it was washed with water and saturated brine, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol-dichloromethane=5:95) to obtain the title compound (33.0 mg, 0.0589 mmol, 26%). ¹ H-NMR (CDCl ₃ ) δ: 8.47-8.45 (1H, m), 8.41-8.40 (1H, m), 7.52-7.49 (1H, m), 7.37-7.32 (1H, m), 7.05-7.01 ( 1H, m), 6.99-6.95 (1H, m), 6.79-6.66 (1H, m), 6.21-6.19 (1H, m), 5.11-4.93 (4H, m), 4.70-4.50 (2H, m), 3.95 (3H, s), 2.42-2.26 (4H, m), 2.09-1.92 (2H, m), 1.85-1.77 (2H, m). MS (m/z): 560 (M+H) ⁺ .

啉-4-基)-5-[(4-氯-3-氟苯基)甲基]-10,10-二氟-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮[Example 37] 2-(7-Chlorine

Lin-4-yl)-5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]Tetradecane-6,14-dione

啉(35.0mg，0.176mmol)並封管，以微波反應裝置使其於120℃反應1小時。減壓下濃縮反應液，將獲得的殘留物以矽膠管柱層析(乙酸乙酯-己烷=30:70-100:0，胺基矽膠)純化，而獲得標題化合物(15.5mg，0.0275mmol，24%)。¹ H-NMR (DMSO-d₆ ) δ : 9.11 (1H, s), 8.41 (1H, s), 8.19 (1H, d, J = 2.4 Hz), 7.92 (1H, d, J = 9.2 Hz), 7.57 (1H, dd, J = 9.2, 2.4 Hz), 7.54-7.49 (1H, m), 7.35-7.30 (1H, m), 7.13-7.09 (1H, m), 5.01-4.89 (4H, m), 4.74-4.65 (2H, m), 2.29-2.04 (6H, m), 1.93-1.82 (2H, m). MS (m/z) : 564 (M+H)⁺ .The compound obtained in Reference Example D-9 (50.0mg, 0.114mmol), N,N-diisopropylethylamine (75.0μl, 0.440mmol), N,N-dimethylformamide (2ml) Put it in a glass tube and add 4,7-dichloride

The tube was sealed and the tube was sealed, and reacted at 120°C for 1 hour with a microwave reaction device. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=30:70-100:0, amino silica gel) to obtain the title compound (15.5 mg, 0.0275 mmol) ,twenty four%). ¹ H-NMR (DMSO-d ₆ ) δ: 9.11 (1H, s), 8.41 (1H, s), 8.19 (1H, d, J = 2.4 Hz), 7.92 (1H, d, J = 9.2 Hz), 7.57 (1H, dd, J = 9.2, 2.4 Hz), 7.54-7.49 (1H, m), 7.35-7.30 (1H, m), 7.13-7.09 (1H, m), 5.01-4.89 (4H, m), 4.74-4.65 (2H, m), 2.29-2.04 (6H, m), 1.93-1.82 (2H, m). MS (m/z): 564 (M+H) ⁺ .

-1-基)-10,10-二氟-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮[Example 38] 5-[(4-chloro-3-fluorophenyl)methyl]-2-(6-chlorophenyl

1-yl) 10,10-difluoro-two -2,5,13- triaza-spiro ^{[7.2 4} 3.2.5] tetradecane-6,14-dione

(35.0mg，0.176mmol)，藉由進行與實施例37同樣的操作，而獲得標題化合物(11.7mg，0.0207mmol，18%)。¹ H-NMR (CDCl₃ ) δ : 9.01 (1H, s), 7.87 (1H, d, J = 1.8 Hz), 7.69 (1H, dd, J = 8.5, 1.8 Hz), 7.56 (1H, d, J = 8.5 Hz), 7.38-7.29 (2H, m), 7.03-7.00 (1H, m), 6.99-6.95 (1H, m), 5.15-5.08 (4H, m), 4.55 (2H, d, J = 9.8 Hz), 2.41-2.31 (2H, m), 2.30-2.17 (2H, m), 2.08-1.91 (2H, m), 1.85-1.75 (2H, m). LCMS (m/z):564(M+H)⁺ .Using the compound (50.0 mg, 0.114 mmol) obtained in Reference Example D-9, 1,6-dichlorobenzene

(35.0 mg, 0.176 mmol), and by performing the same operation as in Example 37, the title compound (11.7 mg, 0.0207 mmol, 18%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 9.01 (1H, s), 7.87 (1H, d, J = 1.8 Hz), 7.69 (1H, dd, J = 8.5, 1.8 Hz), 7.56 (1H, d, J = 8.5 Hz), 7.38-7.29 (2H, m), 7.03-7.00 (1H, m), 6.99-6.95 (1H, m), 5.15-5.08 (4H, m), 4.55 (2H, d, J = 9.8 Hz), 2.41-2.31 (2H, m), 2.30-2.17 (2H, m), 2.08-1.91 (2H, m), 1.85-1.75 (2H, m). LCMS (m/z): 564(M+ H) ⁺ .

[Example 39] 5-[(4-chloro-3-fluorophenyl)methyl]-2-(7-chloroquinolin-4-yl)-10,10-difluoro-2,5,13-tris Azodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione

The compound (50.4mg, 0.114mmol) obtained in Reference Example D-9, 1,4-diazabicyclo[2.2.2]octane (38.1mg, 0.339mmol) and 2-propanol (3ml) were placed In a glass tube, 4,7-dichloroquinoline (35.0 mg, 0.177 mmol) was added to seal the tube, and the tube was reacted at 120° C. for 3.5 hours with a microwave reactor. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=30:70-100:0) to obtain the title compound (4.00 mg, 0.00710 mmol, 6%) . ¹ H-NMR (CDCl ₃ ) δ: 8.59 (1H, d, J = 5.5 Hz), 8.02 (1H, d, J = 2.4 Hz), 7.57 (1H, d, J = 9.2 Hz), 7.41-7.35 ( 1H, m), 7.35-7.31 (1H, m), 7.07-7.01 (1H, m), 7.01-6.96 (1H, m), 6.83 (1H, br s), 6.28 (1H, d, J = 5.5 Hz ), 5.13 (2H, br s), 4.88 (2H, d, J = 9.2 Hz), 4.45 (2H, d, J = 9.2 Hz), 2.45-2.25 (4H, m), 2.09-1.91 (2H, m ), 1.86-1.77 (2H, m). LCMS (m/z): 563(M+H) ⁺ .

[Example 40] 2-(6-Butylpyrimidin-4-yl)-5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-2,5,13- Triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione

The compound obtained in Reference Example D-9 (50.0 mg, 0.114 mmol), 4-butyl-6-chloropyrimidine (21.4 mg, 0.125 mmol), 2-propanol (2.5 ml), N,N-diiso Propylethylamine (78.1 μl, 0.456 mmol) was placed in a glass tube and sealed, and reacted at 120° C. for 1 hour with a microwave reaction device. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol-dichloromethane=5:95) to obtain the title compound (48.0 mg, 0.0896 mmol, 79%). ¹ H-NMR (CDCl ₃ ) δ: 8.58-8.57 (1H, m), 7.39-7.34 (1H, m), 6.99-6.95 (1H, m), 6.95-6.91 (1H, m), 6.67-6.60 ( 1H, m), 6.08-6.07 (1H, m), 4.98 (2H, br s), 4.65 (2H, d, J = 9.2 Hz), 4.18 (2H, d, J = 9.2 Hz), 2.63-2.57 ( 2H, m), 2.40-2.26 (4H, m), 2.05-1.88 (2H, m), 1.84-1.75 (2H, m), 1.71-1.61 (2H, m), 1.41-1.33 (2H, m), 0.93 (3H, t, J = 7.4 Hz). LCMS (m/z): 536 (M+H) ⁺ .

[Example 41] 5-[(4-Chloro-3-fluorophenyl)methyl]-2-(6-chloropyrimidin-4-yl)-10,10-difluoro-2,5,13-tri Azodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione

Using the compound (220 mg, 0.502 mmol) and 4,6-dichloropyrimidine (89.7 mg, 0.602 mmol) obtained in Reference Example D-9, the title compound (233 mg, 0.453mmol, 90%). ¹ H-NMR (CDCl ₃ ) δ: 8.44-8.42 (1H, m), 7.40-7.35 (1H, m), 6.99-6.95 (1H, m), 6.93-6.90 (1H, m), 6.59 (1H, br s), 6.26 (1H, s), 4.95 (2H, br s), 4.66 (2H, d, J = 9.8 Hz), 4.22 (2H, d, J = 9.8 Hz), 2.41-2.27 (4H, m ), 2.06-1.90 (2H, m), 1.85-1.76 (2H, m). MS (m/z): 514 (M+H) ⁺ .

[Example 42] 5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-2-(6-propoxypyrimidin-4-yl)-2,5,13 -Triazadispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione

To the mixture of the compound (16.0 mg, 0.0311 mmol) obtained in Example 41 and 1-propanol (1.2 ml), potassium tertiary butoxide (19.7 mg, 0.176 mmol) was added at room temperature, and the mixture was stirred at room temperature for 10 minutes . The reaction solution was heated to 80°C, and after stirring for 3.5 hours, it was allowed to stand overnight at room temperature. After the solvent was distilled off under reduced pressure, the obtained residue was diluted with ethyl acetate, and washed with water and saturated brine. After the aqueous layer was extracted with ethyl acetate, all the obtained organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=20:80-80:20, amino silica gel) to obtain the title compound (16.4 mg, 0.0305 mmol, 98%). ¹ H-NMR (DMSO-d ₆ ) δ: 9.01 (1H, s), 8.21 (1H, s), 7.55-7.50 (1H, m), 7.35-7.31 (1H, m), 7.12-7.07 (1H, m), 5.75 (1H, s), 4.87 (2H, s), 4.46-4.39 (2H, m), 4.19-4.09 (4H, m), 2.26-1.78 (8H, m), 1.71-1.64 (2H, m), 0.93 (3H, t, J = 7.3 Hz). MS (m/z): 538(M+H) ⁺ .

[Example 43] 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazolin-4-yl]-10,10 -Difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione

The compound (5.71 g, 13.0 mmol) obtained in Reference Example D-9 and the compound (3.13 g, 13.7 mmol) obtained in Reference Example Q-1 were suspended in 2-propanol (130 ml), and N,N-di Isopropylethylamine (9.08ml, 52.1mmol), heated to reflux at 80°C for 5 hours. After returning to room temperature, the solvent was distilled off under reduced pressure. The obtained residue was diluted with ethyl acetate and washed with water and saturated brine. It was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-35:65) to obtain the title compound (6.79 g, 11.4 mmol, 88%). ¹ H-NMR (CDCl ₃ ) δ: 8.71 (1H, s), 8.04 (1H, s), 7.66 (1H, d, J = 8.6 Hz), 7.56-7.53 (1H, m), 7.36-7.32 (1H , m), 7.01-6.97 (1H, m), 6.94-6.91 (1H, m), 6.69 (1H, br s), 5.11 (2H, d, J = 9.8 Hz), 5.02 (2H, s), 4.60 (2H, d, J = 9.8 Hz), 2.42-2.27 (4H, m), 2.06-1.92 (5H, m), 1.87-1.78 (2H, m). MS (m/z): 594 (M+H ) ⁺ .

Using the compound obtained in Reference Example, the same operation as in Example 43 was performed to obtain the following compound.

5-[(4-氯-3-氟苯基)甲基]-10,10-二氟-2-[7-(丙烷-2-基氧基)喹唑啉-4-基]-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (CDCl₃ ) δ : 8.58 (1H, s), 7.47 (1H, d, J = 9.2 Hz), 7.43 (1H, br s), 7.36-7.30 (1H,m), 7.20 (1H, d, J = 2.4 Hz), 7.01-6.95 (2H, m), 6.94-6.89 (1H, m), 5.05 (2H, d, J = 9.6 Hz), 5.01 (2H, s), 4.78-4.66 (1H, m), 4.54 (2H, d, J = 9.6 Hz), 2.46-2.14 (4H, m), 2.11-1.89 (2H, m), 1.88-1.72 (2H, m), 1.41 (6H, d, J = 6.4 Hz). MS (m/z) : 588 (M+H)⁺ . 製造原料：參考例D-9、參考例Q-2 45

5-[(4-氯-3-氟苯基)甲基]-10,10-二氟-2-(7-硝基喹唑啉-4-基)-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (CDCl₃ ) δ : 8.77 (1H, s), 8.74 (1H, d, J = 2.4 Hz), 8.17 (1H, dd, J = 9.2, 2.4 Hz), 7.74 (1H, d, J = 9.2 Hz), 7.53 (1H, br s), 7.39-7.31 (1H, m), 7.00-6.95 (1H, m), 6.95-6.90 (1H, m), 5.12 (2H, d, J = 10.4 Hz), 5.02 (2H, s), 4.64 (2H, d, J = 10.4 Hz), 2.44-2.13 (4H, m), 2.10-1.89 (2H, m), 1.87-1.73 (2H, m). MS (m/z) : 575 (M+H)⁺ . 製造原料：參考例D-9、參考例Q-3 46

5-[(4-氯-3-氟苯基)甲基]-2-(7-氯吡啶并[4,3-d]嘧啶-4-基)]-10,10-二氟-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (DMSO-d₆ ) δ : 9.11 (1H, s), 8.98 (1H, s), 8.57 (1H, s), 7.72 (1H, s), 7.52-7.45 (1H, m), 7.33-7.27 (1H, m), 7.12-7.06 (1H, m), 5.28-5.11 (1H, m), 5.10-4.82 (3H, m), 4.81-4.66 (1H, m), 4.45-4.23 (1H, m), 2.31-1.99 (6H, m), 1.96-1.78 (2H, m). MS (m/z) : 565 (M+H)⁺ . 製造原料：參考例D-9、參考例Q-4 47

5-[(4-氯-3-氟苯基)甲基]-2-[7-(二氟甲氧基)喹唑啉-4-基]-10,10-二氟-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (CDCl₃ ) δ : 8.65 (1H, s), 7.59 (1H, d, J = 8.4 Hz), 7.54 (1H, d, J = 2.4 Hz), 7.50 (1H, br s), 7.37-7.31 (1H, m), 7.21-7.15 (1H, m), 7.01-6.95 (1H, m), 6.94-6.89 (1H, m), 6.69 (1H, t, J = 72.8 Hz), 5.07 (2H, d, J = 9.6 Hz), 5.01 (2H, s), 4.58 (2H, d, J = 9.6 Hz), 2.47-2.13 (4H, m), 2.10-1.89 (2H, m), 1.86-1.71 (2H, m). MS (m/z) : 596 (M+H)⁺ . 製造原料：參考例D-9、參考例Q-5 48

5-[(4-氯-3-氟苯基)甲基]-2-[7-(2,2-二氟乙基)喹唑啉-4-基]-10,10-二氟-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (CDCl₃ ) δ : 8.67 (1H, s), 7.81-7.77 (1H, m), 7.57 (1H, d, J = 8.4 Hz), 7.39-7.11 (3H, m), 7.02-6.95 (1H, m), 6.94-6.88 (1H, m), 6.02 (1H, tt, J = 55.6, 4.4 Hz), 5.09 (2H, d, J = 9.6 Hz), 5.02 (2H, s), 4.58 (2H, d, J = 9.6 Hz), 3.31 (2H, td, J = 17.2, 4.4 Hz), 2.44-2.17 (4H, m), 2.09-1.88 (2H, m), 1.85-1.72 (2H, m). MS (m/z) : 594 (M+H)⁺ . 製造原料：參考例D-9、參考例Q-6 49

2-[2-氯-7-(1,1-二氟乙基)喹唑啉-4-基]-5-[(4-氯-3-氟苯基)甲基]-10,10-二氟-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (CDCl₃ ) δ : 7.96 (1H, s), 7.63 (1H, d, J = 8.6 Hz), 7.55-7.51 (1H, m), 7.38-7.33 (1H, m), 7.01-6.95 (2H, m), 6.94-6.90 (1H, m), 5.20-5.08 (2H, m), 5.07-4.93 (2H, m), 4.70-4.60 (2H, m), 2.42-2.23 (4H, m), 2.09-1.91 (5H, m), 1.87-1.77 (2H, m). MS (m/z) : 628 (M+H)⁺ . 製造原料：參考例D-9、參考例Q-7 50

2-[2-氯-7-(二氟甲氧基)喹唑啉-4-基]-5-[(4-氯-3-氟苯基)甲基]-10,10-二氟-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (CDCl₃ ) δ : 7.93 (1H, br s), 7.56 (1H, d, J = 9.2 Hz), 7.48-7.43 (1H, m), 7.39-7.31 (1H, m), 7.19-7.13 (1H, m), 6.98-6.94 (1H, m), 6.93-6.89 (1H, m), 6.67 (1H, t, J = 72.0 Hz), 5.09 (2H, d, J = 9.6 Hz), 4.99 (2H, s), 4.62 (2H, d, J = 9.6 Hz), 2.45-2.28 (2H, m), 2.27-2.11 (2H, m), 2.10-1.89 (2H, m), 1.88-1.71 (2H, m). MS (m/z) : 630 (M+H)⁺ . 製造原料：參考例D-9、參考例Q-8 51

2-[7-(1,1-二氟乙基)喹唑啉-4-基]-5-{[4-二氟甲氧基-3-氟苯基]甲基}-10,10-二氟-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (CDCl₃ ) δ : 8.71 (1H, s), 8.05-8.01 (1H, m), 7.68-7.63 (1H, m), 7.56-7.51 (1H, m), 7.34 (1H, br s), 7.22-7.16 (1H, m), 7.05-6.99 (1H, m), 6.98-6.92 (1H, m), 6.53 (1H, t, J = 72.8 Hz), 5.10 (2H, d, J = 9.6 Hz), 5.03 (2H, s), 4.61 (2H, d, J = 9.6 Hz), 2.44-2.16 (4H, m), 2.10-1.90 (2H, m), 1.99 (3H, t, J = 17.6 Hz), 1.86-1.74 (2H, m). MS (m/z) : 626 (M+H)⁺ . 製造原料：參考例D-12、參考例Q-1 [Table 6] Example 44

5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-2-[7-(propan-2-yloxy)quinazolin-4-yl]-2, 5,13-Triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CDCl ₃ ) δ: 8.58 (1H, s), 7.47 (1H, d, J = 9.2 Hz), 7.43 (1H, br s), 7.36-7.30 (1H,m), 7.20 (1H, d, J = 2.4 Hz), 7.01-6.95 (2H, m), 6.94-6.89 (1H, m), 5.05 (2H, d, J = 9.6 Hz), 5.01 (2H, s), 4.78-4.66 (1H , m), 4.54 (2H, d, J = 9.6 Hz), 2.46-2.14 (4H, m), 2.11-1.89 (2H, m), 1.88-1.72 (2H, m), 1.41 (6H, d, J = 6.4 Hz). MS (m/z): 588 (M+H) ⁺ . Manufacturing raw materials: Reference Example D-9, Reference Example Q-2 45

5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-2-(7-nitroquinazolin-4-yl)-2,5,13-triazine Spiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CDCl ₃ ) δ: 8.77 (1H, s), 8.74 (1H, d, J = 2.4 Hz), 8.17 (1H, dd, J = 9.2, 2.4 Hz), 7.74 (1H, d, J = 9.2 Hz), 7.53 (1H, br s), 7.39-7.31 (1H, m), 7.00-6.95 (1H, m), 6.95-6.90 (1H, m), 5.12 (2H, d, J = 10.4 Hz ), 5.02 (2H, s), 4.64 (2H, d, J = 10.4 Hz), 2.44-2.13 (4H, m), 2.10-1.89 (2H, m), 1.87-1.73 (2H, m). MS ( m/z): 575 (M+H) ⁺ . Manufacturing raw materials: Reference Example D-9, Reference Example Q-3 46

5-[(4-chloro-3-fluorophenyl)methyl]-2-(7-chloropyrido[4,3-d]pyrimidin-4-yl)]-10,10-difluoro-2, 5,13-Triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (DMSO-d ₆ ) δ: 9.11 (1H, s), 8.98 (1H, s), 8.57 (1H, s), 7.72 (1H, s), 7.52-7.45 (1H, m), 7.33 -7.27 (1H, m), 7.12-7.06 (1H, m), 5.28-5.11 (1H, m), 5.10-4.82 (3H, m), 4.81-4.66 (1H, m), 4.45-4.23 (1H, m), 2.31-1.99 (6H, m), 1.96-1.78 (2H, m). MS (m/z): 565 (M+H) ⁺ . Manufacturing raw materials: Reference Example D-9, Reference Example Q-4 47

5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)quinazolin-4-yl]-10,10-difluoro-2,5, 13-Triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CDCl ₃ ) δ: 8.65 (1H, s), 7.59 (1H, d, J = 8.4 Hz), 7.54 (1H, d, J = 2.4 Hz), 7.50 (1H, br s), 7.37 -7.31 (1H, m), 7.21-7.15 (1H, m), 7.01-6.95 (1H, m), 6.94-6.89 (1H, m), 6.69 (1H, t, J = 72.8 Hz), 5.07 (2H , d, J = 9.6 Hz), 5.01 (2H, s), 4.58 (2H, d, J = 9.6 Hz), 2.47-2.13 (4H, m), 2.10-1.89 (2H, m), 1.86-1.71 ( 2H, m). MS (m/z): 596 (M+H) ⁺ . Manufacturing raw materials: Reference Example D-9, Reference Example Q-5 48

5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(2,2-difluoroethyl)quinazolin-4-yl]-10,10-difluoro-2 ,5,13-Triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CDCl ₃ ) δ: 8.67 (1H, s), 7.81-7.77 (1H, m), 7.57 (1H, d, J = 8.4 Hz), 7.39-7.11 (3H, m), 7.02-6.95 (1H, m), 6.94-6.88 (1H, m), 6.02 (1H, tt, J = 55.6, 4.4 Hz), 5.09 (2H, d, J = 9.6 Hz), 5.02 (2H, s), 4.58 ( 2H, d, J = 9.6 Hz), 3.31 (2H, td, J = 17.2, 4.4 Hz), 2.44-2.17 (4H, m), 2.09-1.88 (2H, m), 1.85-1.72 (2H, m) . MS (m/z): 594 (M+H) ⁺ . Manufacturing raw materials: Reference Example D-9, Reference Example Q-6 49

2-[2-Chloro-7-(1,1-difluoroethyl)quinazolin-4-yl]-5-[(4-chloro-3-fluorophenyl)methyl]-10,10- Difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CDCl ₃ ) δ: 7.96 (1H, s), 7.63 (1H, d, J = 8.6 Hz), 7.55-7.51 (1H, m), 7.38-7.33 (1H, m), 7.01-6.95 (2H, m), 6.94-6.90 (1H, m), 5.20-5.08 (2H, m), 5.07-4.93 (2H, m), 4.70-4.60 (2H, m), 2.42-2.23 (4H, m) , 2.09-1.91 (5H, m), 1.87-1.77 (2H, m). MS (m/z): 628 (M+H) ⁺ . Manufacturing raw materials: Reference Example D-9, Reference Example Q-7 50

2-[2-Chloro-7-(difluoromethoxy)quinazolin-4-yl]-5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro- 2,5,13-Triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CDCl ₃ ) δ: 7.93 (1H, br s), 7.56 (1H, d, J = 9.2 Hz), 7.48-7.43 (1H, m), 7.39-7.31 (1H, m), 7.19- 7.13 (1H, m), 6.98-6.94 (1H, m), 6.93-6.89 (1H, m), 6.67 (1H, t, J = 72.0 Hz), 5.09 (2H, d, J = 9.6 Hz), 4.99 (2H, s), 4.62 (2H, d, J = 9.6 Hz), 2.45-2.28 (2H, m), 2.27-2.11 (2H, m), 2.10-1.89 (2H, m), 1.88-1.71 (2H , m). MS (m/z): 630 (M+H) ⁺ . Manufacturing raw materials: Reference Example D-9, Reference Example Q-8 51

2-[7-(1,1-difluoroethyl)quinazolin-4-yl]-5-{[4-difluoromethoxy-3-fluorophenyl]methyl}-10,10- Difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CDCl ₃ ) δ: 8.71 (1H, s), 8.05-8.01 (1H, m), 7.68-7.63 (1H, m), 7.56-7.51 (1H, m), 7.34 (1H, br s) ), 7.22-7.16 (1H, m), 7.05-6.99 (1H, m), 6.98-6.92 (1H, m), 6.53 (1H, t, J = 72.8 Hz), 5.10 (2H, d, J = 9.6 Hz), 5.03 (2H, s), 4.61 (2H, d, J = 9.6 Hz), 2.44-2.16 (4H, m), 2.10-1.90 (2H, m), 1.99 (3H, t, J = 17.6 Hz ), 1.86-1.74 (2H, m). MS (m/z): 626 (M+H) ⁺ . Manufacturing raw materials: Reference Example D-12, Reference Example Q-1

[Example 52] 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)-2-methoxyquinazolin-4-yl]- 10,10-Difluoro-2,5,13-Triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione

Using the compound obtained in Example 50, the title compound was obtained by performing the same operation as in Example 33. ¹ H-NMR (CDCl ₃ ) δ: 7.51 (1H, d, J = 9.2 Hz), 7.46 (1H, br s), 7.37-7.29 (2H, m), 7.02-6.94 (2H, m), 6.93- 6.88 (1H, m), 6.67 (1H, t, J = 72.4 Hz), 5.07 (2H, d, J = 9.6 Hz), 4.99 (2H, s), 4.56 (2H, d, J = 9.6 Hz), 4.03 (3H, s), 2.44-2.12 (4H, m), 2.10-1.89 (2H, m), 1.86-1.70 (2H, m). MS (m/z): 626 (M+H) ⁺ .

[Example 53] 5-[(4-Chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)-2-methoxyquinazoline-4- Base]-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione

Using the compound obtained in Example 49, the title compound was obtained by performing the same operation as in Example 33. ¹ H-NMR (CDCl ₃ ) δ: 7.85 (1H, s), 7.59-7.55 (1H, m), 7.37-7.31 (2H, m), 7.13-7.09 (1H, m), 6.99-6.95 (1H, m), 6.93-6.89 (1H, m), 5.14-5.06 (2H, br m), 5.00 (2H, br s), 4.63-4.55 (2H, br m), 4.05 (3H, s), 2.41-2.21 (4H, m), 2.08-1.91 (5H, m), 1.84-1.76 (2H, m). MS (m/z): 624 (M+H) ⁺ .

[Example 54] 2-[7-(1,1-difluoroethyl)-2-methoxyquinazolin-4-yl]-5-{[4-difluoromethoxy-3-fluoro Phenyl]methyl}-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione

[Step 1] 2-[2-Chloro-7-(1,1-difluoroethyl)quinazolin-4-yl]-5-{[4-difluoromethoxy-3-fluorophenyl] Methyl}-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione The compound obtained using Reference Example D-12 And the compound obtained in Reference Example Q-7, the title compound was obtained by performing the same operation as in Example 43. ¹ H-NMR (CDCl ₃ ) δ: 7.97-7.93 (1H, m), 7.63 (1H, d, J = 9.2 Hz), 7.53 (1H, dd, J = 9.2, 1.6 Hz), 7.44 (1H, br s), 7.24-7.15 (1H, m), 7.04-6.98 (1H, m), 6.97-6.92 (1H, m), 6.54 (1H, t, J = 72.4 Hz), 5.13 (2H, d, J = 9.2 Hz), 5.00 (2H, s), 4.65 (2H, d, J = 9.2 Hz), 2.44-2.17 (4H, m), 2.11-1.88 (2H, m), 1.96 (3H, t, J = 17.6 Hz), 1.87-1.72 (2H, m). MS (m/z): 660 (M+H) ⁺ .

[Step 2] 2-[7-(1,1-Difluoroethyl)-2-methoxyquinazolin-4-yl]-5-{[4-(difluoromethoxy)-3- Fluorophenyl]methyl}-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione is obtained using step 1 above By performing the same operation as in Example 33, the title compound was obtained. ¹ H-NMR (CDCl ₃ ) δ: 7.87-7.81 (1H, m), 7.57 (1H, d, J = 8.4 Hz), 7.50-7.42 (1H, m), 7.37-7.30 (1H, m), 7.21 -7.14 (1H, m), 7.04-6.97 (1H, m), 6.97-6.90 (1H, m), 6.52 (1H, t, J = 72.8 Hz), 5.10 (2H, d, J = 9.6 Hz), 5.00 (2H, s), 4.59 (2H, d, J = 9.6 Hz), 4.04 (3H, s), 2.42-2.15 (4H, m), 2.10-1.88 (2H, m), 1.97 (3H, t, J = 18.4 Hz), 1.85-1.73 (2H, m). MS (m/z): 656 (M+H) ⁺ .

[Example 55] 2-(7-chloro-2-ethylquinazolin-4-yl)-5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro- 2,5,13-Triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione

The compound obtained in Reference Example Q-9 (41.9 mg, 0.201 mmol), hexafluorophosphate 1H-benzotriazol-1-yloxyginseng (dimethylamino) phosphonium (88.8 mg, 0.201 mmol) To the N,N-dimethylformamide (2ml) mixture, add 1,8-diazabicyclo[5.4.0]-7-undecene (65.4μl, 0.438mmol), and stir at room temperature for 15 minutes . The compound (80.0 mg, 0.183 mmol) obtained in Reference Example D-9 was added to this mixture, and the mixture was stirred at room temperature for 64 hours. Water was added to the reaction mixture, extracted with ethyl acetate, the combined organic layer was washed with water, saturated sodium bicarbonate water, and saturated brine in this order, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane=0:100-50:50). The fractions containing the target substance were collected, concentrated under reduced pressure, and the obtained residue was purified again by silica gel column chromatography (ethyl acetate-hexane=0:100-50:50, amino silica gel) to obtain Title compound (52.8 mg, 0.0891 mmol, 49%). ¹ H-NMR (CDCl ₃ ) δ: 7.84 (1H, d, J = 2.0 Hz), 7.48 (1H, d, J = 9.2 Hz), 7.38-7.31 (1H, m), 7.31-7.27 (1H, m ), 7.03-6.88 (3H, m), 5.06 (2H, d, J = 9.6 Hz), 5.02 (2H, s), 4.54 (2H, d, J = 9.6 Hz), 2.86 (2H, q, J = 7.2 Hz), 2.49-2.20 (4H, m), 2.10-1.90 (2H, m), 1.90-1.72 (2H, m), 1.35 (3H, t, J = 7.2 Hz). MS (m/z): 592 (M+H) ⁺ .

Using the compound obtained in Reference Example, the same operation as in Example 55 was performed to obtain the following compound.

2-(7-氯-2-環丙基喹唑啉-4-基)-5-[(4-氯-3-氟苯基)甲基]-10,10-二氟-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (CDCl₃ ) δ : 7.80-7.74 (1H, m), 7.43 (1H, d, J = 9.2 Hz), 7.38-7.31 (1H, m), 7.25-7.20 (1H, m), 7.02-6.96 (1H, m), 6.95-6.89 (1H, m), 6.87 (1H, br s), 5.04-4.96 (4H, m), 4.49 (2H, d, J = 9.6 Hz), 2.47-2.23 (4H, m), 2.19-2.09 (1H, m), 2.09-1.90 (2H, m), 1.88-1.71 (2H, m), 1.16-1.08 (2H, m), 1.04-0.93 (2H, m).  MS (m/z) : 604 (M+H)⁺ . 製造原料：參考例Q-10、參考例D-9 57

5-[(4-氯-3-氟苯基)甲基]-10,10-二氟-2-[7-(2-氟乙基)喹唑啉-4-基]-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (CDCl₃ ) δ : 8.66 (1H, s), 7.80-7.74 (1H, m), 7.55 (1H, d, J = 8.4 Hz), 7.37-7.29 (2H, m), 7.14 (1H, br s), 7.02-6.95 (1H, m), 6.95-6.88 (1H, m), 5.09 (2H, d, J = 10.0 Hz), 5.02 (2H, s), 4.72 (2H, dt, J = 47.2, 6.0 Hz), 4.58 (2H, d, J = 10.0 Hz), 3.18 (2H, dt, J = 25.2, 6.0 Hz), 2.50-2.17 (4H, m), 2.10-1.89 (2H, m), 1.87-1.73 (2H, m). MS (m/z) : 576 (M+H)⁺ . 製造原料：參考例Q-11、參考例D-9 58

5-[(4-氯-3-氟苯基)甲基]-2-(7-乙烯基喹唑啉-4-基)-10,10-二氟-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (CDCl₃ ) δ : 8.66 (1H, s), 7.87-7.81 (1H, m), 7.59-7.48 (2H, m), 7.37-7.31 (1H, m), 7.03-6.90 (3H, m), 6.85 (1H, dd, J = 17.6, 10.4 Hz), 5.97 (1H, d, J = 17.6 Hz), 5.49 (1H, d, J = 10.4 Hz), 5.10 (2H, d, J = 9.6 Hz), 5.02 (2H, s), 4.59 (2H, d, J = 9.6 Hz), 2.51-2.19 (4H, m), 2.12-1.90 (2H, m), 1.88-1.75 (2H, m). MS (m/z) : 556 (M+H)⁺ . 製造原料：參考例Q-12、參考例D-9 59

5-[(4-氯-3-氟苯基)甲基]-2-(7-環丙基喹唑啉-4-基)-10,10-二氟-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (CDCl₃ ) δ : 8.62 (1H, s), 7.54-7.51 (1H, m), 7.47 (1H, d, J = 8.4 Hz), 7.36-7.29 (1H, m), 7.15-7.10 (1H, m), 7.03-6.85 (3H, m), 5.07 (2H, d, J = 10.0 Hz), 5.01 (2H, s), 4.56 (2H, d, J = 10.0 Hz), 2.43-2.21 (4H, m), 2.09-1.89 (3H, m), 1.87-1.73 (2H, m), 1.15-1.08 (2H, m), 0.91-0.82 (2H, m). MS (m/z) : 570 (M+H)⁺ . 製造原料：參考例Q-13、參考例D-9 60

5-[(4-氯-3-氟苯基)甲基]-2-(7-乙基喹唑啉-4-基)-10,10-二氟-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (CDCl₃ ) δ : 8.65 (1H, s), 7.74-7.68 (1H, m), 7.51 (1H, d, J = 8.4 Hz), 7.36-7.31 (1H, m), 7.30-7.27 (1H, m), 7.02-6.96 (2H, m), 6.95-6.88 (1H, m), 5.09 (2H, d, J = 9.6 Hz), 5.02 (2H, s), 4.57 (2H, d, J = 9.6 Hz), 2.82 (2H, q, J = 7.2 Hz), 2.46-2.19 (4H, m), 2.11-1.89 (2H, m), 1.88-1.75 (2H, m), 1.32 (3H, t, J = 7.2 Hz). MS (m/z) : 558 (M+H)⁺ . 製造原料：參考例Q-14、參考例D-9 61

5-[(4-氯-3-氟苯基)甲基]-2-(7-乙氧基喹唑啉-4-基)-10,10-二氟-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (CDCl₃ ) δ : 8.59 (1H, s), 7.48 (1H, d, J = 9.2 Hz), 7.37-7.31 (1H, m), 7.20 (1H, d, J = 2.4 Hz), 7.04-6.95 (3H, m), 6.95-6.89 (1H, m), 5.06 (2H, d, J = 9.6 Hz), 5.02 (2H, s), 4.55 (2H, d, J = 9.6 Hz), 4.17 (2H, q, J = 7.2 Hz), 2.48-2.19 (4H, m), 2.11-1.89 (2H, m), 1.87-1.73 (2H, m), 1.48 (3H, t, J = 7.2 Hz).  MS (m/z) : 574 (M+H)⁺ . 製造原料：參考例Q-15、參考例D-9 62

5-[(4-氯-3-氟苯基)甲基]-10,10-二氟-2-(7-丙氧基喹唑啉-4-基)-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (CDCl₃ ) δ : 8.59 (1H, s), 7.48 (1H, d, J = 9.2 Hz), 7.37-7.30 (1H, m), 7.20 (1H, d, J = 2.4 Hz), 7.05-6.89 (4H, m), 5.06 (2H, d, J = 9.6 Hz), 5.02 (2H, s), 4.55 (2H, d, J = 9.6 Hz), 4.06 (2H, t, J = 6.8 Hz), 2.47-2.21 (4H, m), 2.10-1.70 (6H, m), 1.07 (3H, t, J = 7.2 Hz). MS (m/z) : 588 (M+H)⁺ . 製造原料：參考例Q-16、參考例D-9 63

5-[(4-氯-3-氟苯基)甲基]-10,10-二氟-2-[7-(氟甲氧基)喹唑啉-4-基]-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (DMSO-d₆ ) δ : 9.17 (1H, s), 8.80 (1H, s), 8.02 (1H, d, J = 9.2 Hz), 7.54-7.48 (1H, m), 7.47-7.41 (1H, m), 7.41-7.37 (1H, m), 7.36-7.29 (1H, m), 7.14-7.08 (1H, m), 6.07 (2H, d, J = 53.6 Hz), 5.47-5.25 (1H, br m), 5.23-5.05 (1H, br m), 5.05-4.74 (3H, br m), 4.64-4.39 (1H, br m), 2.34-1.99 (6H, m), 1.98-1.80 (2H, m). MS (m/z) : 578 (M+H)⁺ . 製造原料：參考例Q-17、參考例D-9 64

5-[(4-氯-3-氟苯基)甲基]-10,10-二氟[7-(2,2,2-三氟乙氧基)喹唑啉-4-基]-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (CDCl₃ ) δ : 8.62 (1H, s), 7.54 (1H, d, J = 9.2 Hz), 7.37-7.31 (1H, m), 7.22-7.19 (1H, m), 7.14-7.08 (1H, m), 7.02-6.89(3H, m), 5.07 (2H, d, J = 9.6 Hz), 5.02 (2H, s), 4.56 (2H, d, J = 9.6 Hz), 4.48 (2H, q, J = 8.0 Hz), 2.47-2.20 (4H, m), 2.11-1.89 (2H, m), 1.88-1.74 (2H, m). MS (m/z) : 628 (M+H)⁺ . 製造原料：參考例Q-18、參考例D-9 65

5-[(4-氯-3-氟苯基)甲基]-10,10-二氟-2-[7-(三氟甲氧基)喹唑啉-4-基]-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (CDCl₃ ) δ : 8.67 (1H, s), 7.74-7.70 (1H, m), 7.63 (1H, d, J = 9.2 Hz), 7.37-7.32 (1H, m), 7.28-7.22 (1H, m), 7.00-6.96 (1H, m), 6.94-6.90 (1H, m), 6.86 (1H, br s), 5.09 (2H, d, J = 10.4 Hz), 5.02 (2H, s), 4.59 (2H, d, J = 10.4 Hz), 2.46-2.21 (4H, m), 2.11-1.88 (2H, m), 1.88-1.72 (2H, m). MS (m/z) : 614 (M+H)⁺ . 製造原料：參考例Q-19、參考例D-9 66

5-[(4-氯-3-氟苯基)甲基]-2-[7-乙炔基喹唑啉-4-基]-10,10-二氟-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (CDCl₃ ) δ : 8.67 (1H, s), 8.03-8.01 (1H, m), 7.53 (1H, d, J = 8.4 Hz), 7.48-7.42 (2H, m), 7.37-7.30 (1H, m), 7.01-6.95 (1H, m), 6.94-6.89 (1H, m), 5.08 (2H, d, J = 9.6 Hz), 5.01 (2H, s), 4.58 (2H, d, J = 9.6 Hz), 3.29 (1H, s), 2.45-2.14 (4H, m), 2.12-1.89 (2H, m), 1.87-1.70 (2H, m). MS (m/z) : 554 (M+H)⁺ . 製造原料：參考例Q-20、參考例D-9 67

5-[(4-氯-3-氟苯基)甲基]-10,10-二氟-2-[7-(三氟甲基)喹唑啉-4-基]-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (CDCl₃ ) δ : 8.74 (1H, s), 8.21-8.17 (1H, m), 7.71 (1H, d, J = 9.2 Hz), 7.62-7.57 (1H, m), 7.37-7.31 (1H, m), 7.02 (1H, brs), 7.00-6.96 (1H, m), 6.95-6.89 (1H, m), 5.13 (2H, d, J = 10.4 Hz), 5.04 (2H, s), 4.63 (2H, d, J = 10.4 Hz), 2.46-2.17 (4H, m), 2.12-1.90 (2H, m), 1.89-1.76 (2H, m). MS (m/z) : 598 (M+H)⁺ . 製造原料：參考例Q-21、參考例D-9 68

5-[(4-氯-3-氟苯基)甲基]-2-[7-(二甲基胺基)喹唑啉-4-基)]-10,10-二氟-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (CDCl₃ ) δ : 8.50 (1H, s), 7.41 (1H, d, J = 9.2 Hz), 7.36-7.30 (1H, m), 7.17 (1H, br s), 7.02-6.96 (1H, m), 6.95-6.85 (3H, m), 5.04 (2H, d, J = 10.0 Hz), 5.02 (2H, s), 4.51 (2H, d, J = 10.0 Hz), 3.10 (6H, s), 2.43-2.19 (4H, m), 2.11-1.90 (2H, m), 1.87-1.73 (2H, m).  MS (m/z) : 573 (M+H)⁺ . 製造原料：參考例Q-22、參考例D-9 69

5-[(4-氯-3-氟苯基)甲基]-2-[7-(環丙基氧基)喹唑啉-4-基]-10,10-二氟-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (CDCl₃ ) δ : 8.60 (1H, s), 7.57 (1H, d, J = 2.4 Hz), 7.48 (1H, d, J = 9.2 Hz), 7.37-7.30 (1H, m), 7.19 (1H, br s), 7.04-6.95 (2H, m), 6.95-6.88 (1H, m), 5.06 (2H, d, J = 9.6 Hz), 5.01 (2H, s), 4.55 (2H, d, J = 9.6 Hz), 3.92-3.81 (1H, m), 2.47-2.14 (4H, m), 2.10-1.89 (2H, m), 1.86-1.71 (2H, m), 0.96-0.73 (4H, m). MS (m/z) : 586 (M+H)⁺ . 製造原料：參考例Q-23、參考例D-9 70

5-[(4-氯-3-氟苯基)甲基]-2-[7-(二氟甲基)喹唑啉-4-基]-10,10-二氟-2,5,13-三氮二螺[3.2.5⁷ .2⁴ ]十四烷-6,14-二酮 ¹ H-NMR (CDCl₃ ) δ : 8.72 (1H, s), 8.01 (1H, s), 7.69 (1H, d, J = 8.6 Hz), 7.57-7.54 (1H, m), 7.36-7.31 (1H, m), 7.17 (1H, br s), 7.00-6.96 (1H, m), 6.94-6.63 (2H, m), 5.10 (2H, d, J = 9.8 Hz), 5.02 (2H, s), 4.60 (2H, d, J = 9.8 Hz), 2.43-2.19 (4H, m), 2.09-1.89 (2H, m), 1.86-1.74 (2H, m). MS (m/z) : 580 (M+H)⁺ . 製造原料：參考例Q-24、參考例D-9 [Table 7] Example 56

2-(7-chloro-2-cyclopropylquinazolin-4-yl)-5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-2,5, 13-Triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CDCl ₃ ) δ: 7.80-7.74 (1H, m), 7.43 (1H, d, J = 9.2 Hz), 7.38-7.31 (1H, m), 7.25-7.20 (1H, m), 7.02 -6.96 (1H, m), 6.95-6.89 (1H, m), 6.87 (1H, br s), 5.04-4.96 (4H, m), 4.49 (2H, d, J = 9.6 Hz), 2.47-2.23 ( 4H, m), 2.19-2.09 (1H, m), 2.09-1.90 (2H, m), 1.88-1.71 (2H, m), 1.16-1.08 (2H, m), 1.04-0.93 (2H, m). MS (m/z): 604 (M+H) ⁺ . Manufacturing materials: Reference Example Q-10, Reference Example D-9 57

5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-2-[7-(2-fluoroethyl)quinazolin-4-yl]-2,5, 13-Triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CDCl ₃ ) δ: 8.66 (1H, s), 7.80-7.74 (1H, m), 7.55 (1H, d, J = 8.4 Hz), 7.37-7.29 (2H, m), 7.14 (1H , br s), 7.02-6.95 (1H, m), 6.95-6.88 (1H, m), 5.09 (2H, d, J = 10.0 Hz), 5.02 (2H, s), 4.72 (2H, dt, J = 47.2, 6.0 Hz), 4.58 (2H, d, J = 10.0 Hz), 3.18 (2H, dt, J = 25.2, 6.0 Hz), 2.50-2.17 (4H, m), 2.10-1.89 (2H, m), 1.87-1.73 (2H, m). MS (m/z): 576 (M+H) ⁺ . Manufacturing raw materials: Reference Example Q-11, Reference Example D-9 58

5-[(4-chloro-3-fluorophenyl)methyl]-2-(7-vinylquinazolin-4-yl)-10,10-difluoro-2,5,13-triazine Spiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CDCl ₃ ) δ: 8.66 (1H, s), 7.87-7.81 (1H, m), 7.59-7.48 (2H, m), 7.37-7.31 (1H, m), 7.03-6.90 (3H, m), 6.85 (1H, dd, J = 17.6, 10.4 Hz), 5.97 (1H, d, J = 17.6 Hz), 5.49 (1H, d, J = 10.4 Hz), 5.10 (2H, d, J = 9.6 Hz), 5.02 (2H, s), 4.59 (2H, d, J = 9.6 Hz), 2.51-2.19 (4H, m), 2.12-1.90 (2H, m), 1.88-1.75 (2H, m). MS (m/z): 556 (M+H) ⁺ . Manufacturing raw materials: Reference Example Q-12, Reference Example D-9 59

5-[(4-chloro-3-fluorophenyl)methyl]-2-(7-cyclopropylquinazolin-4-yl)-10,10-difluoro-2,5,13-triazide Dispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CDCl ₃ ) δ: 8.62 (1H, s), 7.54-7.51 (1H, m), 7.47 (1H, d, J = 8.4 Hz), 7.36-7.29 (1H, m), 7.15-7.10 (1H, m), 7.03-6.85 (3H, m), 5.07 (2H, d, J = 10.0 Hz), 5.01 (2H, s), 4.56 (2H, d, J = 10.0 Hz), 2.43-2.21 ( 4H, m), 2.09-1.89 (3H, m), 1.87-1.73 (2H, m), 1.15-1.08 (2H, m), 0.91-0.82 (2H, m). MS (m/z): 570 ( M+H) ⁺ . Manufacturing raw materials: Reference Example Q-13, Reference Example D-9 60

5-[(4-chloro-3-fluorophenyl)methyl]-2-(7-ethylquinazolin-4-yl)-10,10-difluoro-2,5,13-triazine Spiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CDCl ₃ ) δ: 8.65 (1H, s), 7.74-7.68 (1H, m), 7.51 (1H, d, J = 8.4 Hz), 7.36-7.31 (1H, m), 7.30-7.27 (1H, m), 7.02-6.96 (2H, m), 6.95-6.88 (1H, m), 5.09 (2H, d, J = 9.6 Hz), 5.02 (2H, s), 4.57 (2H, d, J = 9.6 Hz), 2.82 (2H, q, J = 7.2 Hz), 2.46-2.19 (4H, m), 2.11-1.89 (2H, m), 1.88-1.75 (2H, m), 1.32 (3H, t, J = 7.2 Hz). MS (m/z): 558 (M+H) ⁺ . Manufacturing raw materials: Reference Example Q-14, Reference Example D-9 61

5-[(4-chloro-3-fluorophenyl)methyl]-2-(7-ethoxyquinazolin-4-yl)-10,10-difluoro-2,5,13-triazide Dispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CDCl ₃ ) δ: 8.59 (1H, s), 7.48 (1H, d, J = 9.2 Hz), 7.37-7.31 (1H, m), 7.20 (1H, d, J = 2.4 Hz), 7.04-6.95 (3H, m), 6.95-6.89 (1H, m), 5.06 (2H, d, J = 9.6 Hz), 5.02 (2H, s), 4.55 (2H, d, J = 9.6 Hz), 4.17 (2H, q, J = 7.2 Hz), 2.48-2.19 (4H, m), 2.11-1.89 (2H, m), 1.87-1.73 (2H, m), 1.48 (3H, t, J = 7.2 Hz). MS (m/z): 574 (M+H) ⁺ . Manufacturing materials: Reference Example Q-15, Reference Example D-9 62

5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-2-(7-propoxyquinazolin-4-yl)-2,5,13-triazide Dispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CDCl ₃ ) δ: 8.59 (1H, s), 7.48 (1H, d, J = 9.2 Hz), 7.37-7.30 (1H, m), 7.20 (1H, d, J = 2.4 Hz), 7.05-6.89 (4H, m), 5.06 (2H, d, J = 9.6 Hz), 5.02 (2H, s), 4.55 (2H, d, J = 9.6 Hz), 4.06 (2H, t, J = 6.8 Hz) ), 2.47-2.21 (4H, m), 2.10-1.70 (6H, m), 1.07 (3H, t, J = 7.2 Hz). MS (m/z): 588 (M+H) ⁺ . Manufacturing materials: Reference Example Q-16, Reference Example D-9 63

5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-2-[7-(fluoromethoxy)quinazolin-4-yl]-2,5,13 -Triazadispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (DMSO-d ₆ ) δ: 9.17 (1H, s), 8.80 (1H, s), 8.02 (1H, d, J = 9.2 Hz), 7.54-7.48 (1H, m), 7.47-7.41 (1H, m), 7.41-7.37 (1H, m), 7.36-7.29 (1H, m), 7.14-7.08 (1H, m), 6.07 (2H, d, J = 53.6 Hz), 5.47-5.25 (1H , br m), 5.23-5.05 (1H, br m), 5.05-4.74 (3H, br m), 4.64-4.39 (1H, br m), 2.34-1.99 (6H, m), 1.98-1.80 (2H, m). MS (m/z): 578 (M+H) ⁺ . Manufacturing materials: Reference Example Q-17, Reference Example D-9 64

5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro[7-(2,2,2-trifluoroethoxy)quinazolin-4-yl]-2 ,5,13-Triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CDCl ₃ ) δ: 8.62 (1H, s), 7.54 (1H, d, J = 9.2 Hz), 7.37-7.31 (1H, m), 7.22-7.19 (1H, m), 7.14-7.08 (1H, m), 7.02-6.89(3H, m), 5.07 (2H, d, J = 9.6 Hz), 5.02 (2H, s), 4.56 (2H, d, J = 9.6 Hz), 4.48 (2H, q, J = 8.0 Hz), 2.47-2.20 (4H, m), 2.11-1.89 (2H, m), 1.88-1.74 (2H, m). MS (m/z): 628 (M+H) ⁺ . Manufacturing materials: Reference Example Q-18, Reference Example D-9 65

5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-2-[7-(trifluoromethoxy)quinazolin-4-yl]-2,5, 13-Triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CDCl ₃ ) δ: 8.67 (1H, s), 7.74-7.70 (1H, m), 7.63 (1H, d, J = 9.2 Hz), 7.37-7.32 (1H, m), 7.28-7.22 (1H, m), 7.00-6.96 (1H, m), 6.94-6.90 (1H, m), 6.86 (1H, br s), 5.09 (2H, d, J = 10.4 Hz), 5.02 (2H, s) , 4.59 (2H, d, J = 10.4 Hz), 2.46-2.21 (4H, m), 2.11-1.88 (2H, m), 1.88-1.72 (2H, m). MS (m/z): 614 (M +H) ⁺ . Manufacturing raw materials: Reference Example Q-19, Reference Example D-9 66

5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-ethynylquinazolin-4-yl]-10,10-difluoro-2,5,13-triazide Spiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CDCl ₃ ) δ: 8.67 (1H, s), 8.03-8.01 (1H, m), 7.53 (1H, d, J = 8.4 Hz), 7.48-7.42 (2H, m), 7.37-7.30 (1H, m), 7.01-6.95 (1H, m), 6.94-6.89 (1H, m), 5.08 (2H, d, J = 9.6 Hz), 5.01 (2H, s), 4.58 (2H, d, J = 9.6 Hz), 3.29 (1H, s), 2.45-2.14 (4H, m), 2.12-1.89 (2H, m), 1.87-1.70 (2H, m). MS (m/z): 554 (M+ H) ⁺ . Manufacturing raw materials: Reference Example Q-20, Reference Example D-9 67

5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-2-[7-(trifluoromethyl)quinazolin-4-yl]-2,5,13 -Triazadispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CDCl ₃ ) δ: 8.74 (1H, s), 8.21-8.17 (1H, m), 7.71 (1H, d, J = 9.2 Hz), 7.62-7.57 (1H, m), 7.37-7.31 (1H, m), 7.02 (1H, brs), 7.00-6.96 (1H, m), 6.95-6.89 (1H, m), 5.13 (2H, d, J = 10.4 Hz), 5.04 (2H, s), 4.63 (2H, d, J = 10.4 Hz), 2.46-2.17 (4H, m), 2.12-1.90 (2H, m), 1.89-1.76 (2H, m). MS (m/z): 598 (M+ H) ⁺ . Manufacturing raw materials: Reference Example Q-21, Reference Example D-9 68

5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(dimethylamino)quinazolin-4-yl)]-10,10-difluoro-2,5 ,13-Triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CDCl ₃ ) δ: 8.50 (1H, s), 7.41 (1H, d, J = 9.2 Hz), 7.36-7.30 (1H, m), 7.17 (1H, br s), 7.02-6.96 ( 1H, m), 6.95-6.85 (3H, m), 5.04 (2H, d, J = 10.0 Hz), 5.02 (2H, s), 4.51 (2H, d, J = 10.0 Hz), 3.10 (6H, s) ), 2.43-2.19 (4H, m), 2.11-1.90 (2H, m), 1.87-1.73 (2H, m). MS (m/z): 573 (M+H) ⁺ . Manufacturing materials: Reference Example Q-22, Reference Example D-9 69

5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(cyclopropyloxy)quinazolin-4-yl]-10,10-difluoro-2,5, 13-Triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CDCl ₃ ) δ: 8.60 (1H, s), 7.57 (1H, d, J = 2.4 Hz), 7.48 (1H, d, J = 9.2 Hz), 7.37-7.30 (1H, m), 7.19 (1H, br s), 7.04-6.95 (2H, m), 6.95-6.88 (1H, m), 5.06 (2H, d, J = 9.6 Hz), 5.01 (2H, s), 4.55 (2H, d) , J = 9.6 Hz), 3.92-3.81 (1H, m), 2.47-2.14 (4H, m), 2.10-1.89 (2H, m), 1.86-1.71 (2H, m), 0.96-0.73 (4H, m) ). MS (m/z): 586 (M+H) ⁺ . Manufacturing raw materials: Reference Example Q-23, Reference Example D-9 70

5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethyl)quinazolin-4-yl]-10,10-difluoro-2,5,13 -Triazadispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ¹ H-NMR (CDCl ₃ ) δ: 8.72 (1H, s), 8.01 (1H, s), 7.69 (1H, d, J = 8.6 Hz), 7.57-7.54 (1H, m), 7.36-7.31 (1H , m), 7.17 (1H, br s), 7.00-6.96 (1H, m), 6.94-6.63 (2H, m), 5.10 (2H, d, J = 9.8 Hz), 5.02 (2H, s), 4.60 (2H, d, J = 9.8 Hz), 2.43-2.19 (4H, m), 2.09-1.89 (2H, m), 1.86-1.74 (2H, m). MS (m/z): 580 (M+H ) ⁺ . Manufacturing materials: Reference Example Q-24, Reference Example D-9

[Analysis of the crystals obtained] For the crystals of the compounds obtained in Example 43 and Example 53, elemental analysis and powder X-ray diffraction measurement were performed, respectively.

(Analysis results of the crystals of the compound obtained in Example 43) Regarding the crystals of the compound obtained in Example 43, the powder X-ray diffraction pattern is shown in FIG. 1, and the diffraction pattern in the powder X-ray diffraction spectrum is shown in Table 8. Fire angle (2θ), lattice spacing (d value) and relative strength. Analysis calculated value for C ₂₈ H ₂₅ ClF ₅ N ₅ O ₂ : C, 56.62; H, 4.24; Cl, 5.97; F, 15.99; N, 11.79. Measured value: C, 56.48; H, 4.45; Cl, 6.15; F, 15.88; N, 11.55.

[Table 8] Crest number 2θ d value Relative Strength Crest number 2θ d value Relative Strength 1 10.20 8.67 20 6 20.10 4.42 62 2 11.20 7.90 39 7 20.70 4.29 41 3 11.75 7.53 31 8 23.45 3.79 34 4 14.30 6.19 42 9 24.15 3.69 26 5 16.55 5.36 100 10 22.25 4.00 9

(Analysis result of the crystal of the compound obtained in Example 53) Regarding the crystals of the compound obtained in Example 53, the powder X-ray diffraction pattern is shown in Fig. 2, and the diffraction angle (2θ), lattice spacing (d value) and the powder X-ray diffraction spectrum in the powder X-ray diffraction spectrum are described in Table 9. Relative Strength. Found: C, 55.31; H, 4.88; Cl, 5.39; F, 14.50; N, 10.56.

[Table 9] Crest number 2θ d value Relative Strength Crest number 2θ d value Relative Strength 1 6.80 13.00 18 6 18.05 4.91 41 2 7.65 11.56 100 7 20.15 4.41 52 3 14.55 6.09 62 8 24.00 3.71 45 4 15.45 5.74 35 9 27.50 3.24 43 5 14.20 5.16 44 10 28.00 3.19 71

[Example 71] 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazolin-4-yl]-10,10 -Difluoro-2,5,13-triazabispiro [3.2.5 ⁷ .2 ⁴ ] tetradecane-6,14-dione hydrochloride The compound obtained in Example 43 (40.0 mg, 0.0673 mmol ) Was dissolved in tetrahydrofuran (2ml), hydrochloric acid (11.6μl, concentration 35%, 0.135mmol) was added, and the mixture was stirred at room temperature for 20 minutes. Concentrate under reduced pressure, add ethanol to the obtained residue, perform ultrasonic treatment, and concentrate under reduced pressure. This operation was repeated 3 times, and the obtained solid was dried under reduced pressure to obtain crystals of the title compound (33.5 mg). For the crystals of the obtained compound, elemental analysis and powder X-ray diffraction measurement were performed. The powder X-ray diffraction diagram is shown in FIG. 3, and the diffraction angle (2θ), lattice spacing (d value), and relative intensity in the powder X-ray diffraction spectrum are described in Table 10. ¹ H-NMR (DMSO-d ₆ ) δ: 9.18 (1H, s), 8.86 (1H, s), 8.12 (1H, d, J = 8.8 Hz), 8.01-7.96 (1H, m), 7.86-7.79 (1H, m), 7.55-7.48 (1H, m), 7.37-7.31 (1H, m), 7.15-7.08 (1H, m), 5.53- 5.33 (1H, m), 5.25-5.08 (1H, m) , 5.03-4.83 (3H, m), 4.63-4.44 (1H, m), 2.35-1.99 (6H, m), 2.06 (3H, t, J = 19.2 Hz), 1.98-1.84 (2H, m). Actual measurement Value: C, 53.03; H, 4.10; Cl, 11.06; F, 14.83; N, 10.78.

[Table 10] Crest number 2θ d value Relative Strength Crest number 2θ d value Relative Strength 1 8.45 10.46 twenty three 6 17.15 5.17 29 2 11.35 7.80 27 7 17.80 4.98 58 3 12.30 7.20 38 8 19.15 4.63 44 4 15.75 5.63 99 9 19.85 4.47 54 5 16.65 5.32 35 10 24.50 3.63 100

烷溶液(45.0μl，0.180mmol)而於室溫攪拌2小時。減壓下濃縮，於獲得的殘留物中添加乙醇，進行超音波處理，並於減壓下濃縮。重複3次此操作，藉由於減壓下乾燥獲得的固體，而獲得標題化合物之結晶(51.9mg)。 對於獲得的化合物之結晶，進行元素分析及粉末X射線繞射測定。將粉末X射線繞射圖記載於圖4，於表11中記載粉末X射線繞射光譜中的繞射角(2θ)、晶格間隔(d值)及相對強度。¹ H-NMR (DMSO-d₆ ) δ : 9.19 (1H, s), 8.84 (1H, s), 8.09 (1H, d, J = 9.1 Hz), 7.79-7.41 (4H, m), 7.37-7.32 (1H, m), 7.14-7.10 (1H, m), 5.47-5.31 (1H, m), 5.23-5.08 (1H, m), 5.04-4.85 (3H, m), 4.62-4.46 (1H, m), 2.31-2.03 (7H, m), 1.97-1.85 (2H, m). 實測值：C, 50.38; H, 4.04; Cl, 11.05; F, 15.09; N, 10.73.[Example 72] 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)quinazolin-4-yl]-10,10-difluoro -2,5,13-Triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione hydrochloride The compound (50.0 mg, 0.0839 mmol) obtained in Example 47 was dissolved in Tetrahydrofuran (2ml), add 4N hydrochloric acid/two

The alkane solution (45.0 μl, 0.180 mmol) was stirred at room temperature for 2 hours. Concentrate under reduced pressure, add ethanol to the obtained residue, perform ultrasonic treatment, and concentrate under reduced pressure. This operation was repeated 3 times, and the crystal of the title compound (51.9 mg) was obtained by drying the obtained solid under reduced pressure. For the crystals of the obtained compound, elemental analysis and powder X-ray diffraction measurement were performed. The powder X-ray diffraction diagram is shown in FIG. 4, and the diffraction angle (2θ), lattice spacing (d value), and relative intensity in the powder X-ray diffraction spectrum are described in Table 11. ¹ H-NMR (DMSO-d ₆ ) δ: 9.19 (1H, s), 8.84 (1H, s), 8.09 (1H, d, J = 9.1 Hz), 7.79-7.41 (4H, m), 7.37-7.32 (1H, m), 7.14-7.10 (1H, m), 5.47-5.31 (1H, m), 5.23-5.08 (1H, m), 5.04-4.85 (3H, m), 4.62-4.46 (1H, m) , 2.31-2.03 (7H, m), 1.97-1.85 (2H, m). Measured value: C, 50.38; H, 4.04; Cl, 11.05; F, 15.09; N, 10.73.

[Table 11] Crest number 2θ d value Relative Strength Crest number 2θ d value Relative Strength 1 6.80 13.00 57 6 19.65 4.52 50 2 13.85 6.39 37 7 21.75 4.09 51 3 15.25 5.81 35 8 23.20 3.83 57 4 17.20 5.16 100 9 24.40 3.65 59 5 18.65 4.76 50 10 25.35 3.51 57

[Example 73] 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)-2-methoxyquinazolin-4-yl]- 10,10-difluoro-two -2,5,13- triaza-spiro ^{[7.2 4} 3.2.5] tetradecane-6,14-dione hydrochloride the compound of Example 52 obtained in Example (40.0 mg , 0.0639mmol) was dissolved in tetrahydrofuran (2ml), hydrochloric acid (11.0μl, concentration 35%, 0.128mmol) was added, and the mixture was stirred at room temperature for 1 hour. Concentrate under reduced pressure, add ethanol to the obtained residue, perform ultrasonic treatment, and concentrate under reduced pressure. 2-propanol was added to the obtained residue, ultrasonic treatment was performed, and the mixture was concentrated under reduced pressure. This operation was repeated 3 times, and by drying the obtained solid under reduced pressure, crystals of the title compound (41.6 mg) were obtained. For the crystals of the obtained compound, elemental analysis and powder X-ray diffraction measurement were performed. The powder X-ray diffraction diagram is shown in FIG. 5, and the diffraction angle (2θ), lattice spacing (d value), and relative intensity in the powder X-ray diffraction spectrum are described in Table 12. ¹ H-NMR (DMSO-d ₆ ) δ: 9.14 (1H, s), 7.93 (1H, d, J = 9.2 Hz), 7.53 (1H, t, J = 72.8 Hz), 7.51 (1H, dd, J = 8.0, 8.0 Hz), 7.33 (1H, dd, J = 10.4, 2.0 Hz), 7.27-7.19 (2H, m), 7.13-7.08 (1H, m), 5.37-5.19 (1H, m), 5.14- 4.69 (4H, m), 4.59-4.34 (1H, m), 3.99 (3H, s), 2.30-1.99 (6H, m), 1.95-1.83 (2H, m). Measured value: C, 49.94; H, 3.80; Cl, 10.30; F, 14.16; N, 10.35.

[Table 12] Crest number 2θ d value Relative Strength Crest number 2θ d value Relative Strength 1 8.34 10.60 twenty four 6 19.15 4.63 51 2 10.40 8.51 32 7 20.45 4.34 59 3 12.15 7.28 34 8 22.75 3.91 69 4 16.20 5.47 57 9 24.50 3.63 100 5 17.70 5.01 44 10 25.90 3.44 63

[Example 74] 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazolin-4-yl]-10,10 -Difluoro-2,5,13-triazabisspiro[3.2.5 ⁷ .2 ⁴ ] tetradecane-6,14-dione sulfate The compound obtained in Example 43 (40.0 mg, 0.0673 mmol) Dissolve in tetrahydrofuran (2ml), add sulfuric acid (3.60μl, concentration 64%, 0.0673mmol), and stir at room temperature for 20 minutes. It was concentrated under reduced pressure, 2-propanol was added to the obtained residue to perform ultrasonic treatment, and it was concentrated under reduced pressure. After repeating this operation three times, 2-propanol was further added to collect the precipitated solid, and the solid obtained was dried under reduced pressure to obtain crystals of the title compound (37.7 mg). For the crystals of the obtained compound, elemental analysis and powder X-ray diffraction measurement were performed. The powder X-ray diffraction diagram is shown in FIG. 6, and the diffraction angle (2θ), lattice spacing (d value), and relative intensity in the powder X-ray diffraction spectrum are described in Table 13. ¹ H-NMR (DMSO-d ₆ ) δ: 9.19 (1H, s), 8.90 (1H, s), 8.13 (1H, d, J = 9.2 Hz), 7.94-7.91 (1H, m), 7.87-7.82 (1H, m), 7.55-7.48 (1H, m), 7.37-7.30 (1H, m), 7.15-7.09 (1H, m), 5.56-5.36 (1H, m), 5.29-5.11 (1H, m) , 5.06-4.82 (3H, m), 4.66-4.44 (1H, m), 2.34-2.00 (6H, m), 2.05 (3H, t, J = 19.2 Hz), 1.99-1.83 (2H, m). Actual measurement Value: C, 48.08; H, 3.74; Cl, 5.22; F, 13.69; N, 9.81; S, 4.58.

[Table 13] Crest number 2θ d value Relative Strength Crest number 2θ d value Relative Strength 1 6.85 12.90 90 6 17.35 5.11 99 2 8.30 10.65 36 7 18.35 4.83 100 3 9.25 9.56 33 8 19.00 4.67 96 4 11.05 8.01 60 9 20.55 4.32 43 5 13.55 6.53 38 10 22.25 4.00 51

[Example 75] 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)quinazolin-4-yl]-10,10-difluoro -2,5,13-Triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione sulfate The compound obtained in Example 47 (50.0 mg, 0.0839 mmol) was dissolved in tetrahydrofuran (2ml), sulfuric acid (15.0μl, concentration 64%, 0.139mmol) was added and stirred at room temperature for 2 hours. It was concentrated under reduced pressure, and a mixed solvent of hexane-ethyl acetate was added to the obtained residue to perform ultrasonic treatment, and the generated solid was filtered out. By drying the obtained solid under reduced pressure, crystals of the title compound (43.1 mg) were obtained. For the crystals of the obtained compound, elemental analysis and powder X-ray diffraction measurement were performed. The powder X-ray diffraction diagram is shown in FIG. 7, and the diffraction angle (2θ), lattice spacing (d value), and relative intensity in the powder X-ray diffraction spectrum are described in Table 14. ¹ H-NMR (DMSO-d ₆ ) δ: 9.20 (1H, s), 8.87 (1H, s), 8.10 (1H, d, J = 9.1 Hz), 7.82-7.39 (4H, m), 7.38-7.30 (1H, m), 7.16-7.09 (1H, m), 5.48-5.37 (1H, m), 5.24-5.12 (1H, m), 5.04-4.85 (3H, m), 4.61-4.51 (1H, m) , 2.35-2.02 (7H, m), 1.98-1.86 (2H, m). Measured value: C, 39.55; H, 4.17; Cl, 4.26; F, 11.16; N, 8.51; S. 6.50.

[Table 14] Crest number 2θ d value Relative Strength Crest number 2θ d value Relative Strength 1 10.00 8.85 19 6 20.25 4.39 100 2 11.45 7.73 39 7 24.00 3.71 75 3 12.35 7.17 50 8 24.65 3.61 70 4 16.40 5.41 65 9 25.40 3.51 63 5 17.60 5.04 97 10 29.25 3.05 73

[Example 76] 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)-2-methoxyquinazolin-4-yl]- 10,10-Difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione sulfate The compound obtained in Example 52 (40.0 mg, 0.0639 mmol) was dissolved in tetrahydrofuran (2 ml), sulfuric acid (3.42 μl, concentration 64%, 0.0639 mmol) was added, and the mixture was stirred at room temperature for 3.5 hours. Concentrate under reduced pressure, add ethanol to the obtained residue, and concentrate under reduced pressure. After repeating this operation 3 times, 2-propanol was added to perform ultrasonic treatment, and it was concentrated under reduced pressure. After repeating this operation twice, a small amount of 2-propanol was added to the residue, and ultrasonic treatment was performed to filter the precipitated solid. The solid obtained was dried under reduced pressure to obtain crystals of the title compound (38.7 mg) . For the crystals of the obtained compound, elemental analysis and powder X-ray diffraction measurement were performed. The powder X-ray diffraction diagram is shown in FIG. 8, and the diffraction angle (2θ), lattice spacing (d value), and relative intensity in the powder X-ray diffraction spectrum are described in Table 15. ¹ H-NMR (DMSO-d ₆ ) δ: 9.14 (1H, s), 7.94 (1H, d, J = 9.2 Hz), 7.53 (1H, t, J = 72.8 Hz), 7.51 (1H, dd, J = 8.0, 8.0 Hz), 7.33 (1H, dd, J = 10.4, 2.0 Hz), 7.27-7.19 (2H, m), 7.14- 7.08 (1H, m), 5.39-5.23 (1H, m), 5.14- 5.01 (1H, m), 5.00-4.77 (3H, m), 4.56-4.41 (1H, m), 4.00 (3H, s), 2.30-2.02 (6H, m), 1.96-1.82 (2H, m). Measured value: C, 46.09; H, 4.06; Cl, 4.65; F, 12.74; N, 9.00; S, 4.27.

[Table 15] Crest number 2θ d value Relative Strength Crest number 2θ d value Relative Strength 1 8.50 10.40 100 6 19.95 4.45 78 2 10.70 8.27 38 7 23.00 3.87 55 3 11.20 7.90 38 8 24.65 3.61 30 4 16.50 5.37 51 9 27.45 3.25 40 5 18.85 4.71 71 10 27.80 3.21 50

[Example 77] 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazolin-4-yl]-10,10 -Difluoro-2,5,13-triazabisspiro[3.2.5 ⁷ .2 ⁴ ] tetradecane-6,14-dione nitrate The compound obtained in Example 43 (40.0 mg, 0.0673 mmol) It was dissolved in tetrahydrofuran (1.5 ml), nitric acid (1.42) (43.4 μl, 0.0673 mmol) was added, and the mixture was stirred at room temperature for 3 hours. It was concentrated under reduced pressure, ethanol was added to the obtained residue for ultrasonic treatment, and concentrated under reduced pressure. This operation was repeated 3 times, and the crystal of the title compound (26.1 mg) was obtained by drying the obtained solid under reduced pressure. For the crystals of the obtained compound, elemental analysis and powder X-ray diffraction measurement were performed. The powder X-ray diffraction diagram is shown in FIG. 9, and the diffraction angle (2θ), lattice spacing (d value), and relative intensity in the powder X-ray diffraction spectrum are described in Table 16. ¹ H-NMR (DMSO-d ₆ ) δ: 9.19 (1H, s), 8.89 (1H, s), 8.12 (1H, d, J = 8.4 Hz), 7.93-7.89 (1H, m), 7.87-7.81 (1H, m), 7.55-7.49 (1H, m), 7.38-7.31 (1H, m), 7.15-7.09 (1H, m), 5.55-5.35 (1H, m), 5.28-5.10 (1H, m) , 5.05-4.80 (3H, m), 4.65-4.46 (1H, m), 2.30-2.00 (6H, m), 2.07 (3H, t, J = 18.8 Hz), 1.99-1.84 (2H, m). C ₂₈ H ₂₅ ClF ₅ N ₅ O ₂ ×HNO ₃ Analysis calculated value: C, 51.19; H, 3.99; Cl, 5.40; F, 14.46; N, 12.79. Measured value: C, 51.26; H, 3.99; Cl, 5.44; F, 14.27; N, 12.88.

[Table 16] Crest number 2θ d value Relative Strength Crest number 2θ d value Relative Strength 1 8.65 10.22 36 6 19.90 4.46 42 2 15.25 5.81 100 7 22.10 4.02 20 3 16.80 5.28 18 8 23.25 3.83 46 4 17.55 5.05 74 9 24.50 3.63 38 5 18.20 4.87 46 10 29.85 2.99 37

[Example 78] 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazolin-4-yl]-10,10 -Difluoro-2,5,13-triazabispiro [3.2.5 ⁷ .2 ⁴ ] tetradecane-6,14-dione oxalate The compound obtained in Example 43 (40.0 mg, 0.0673 mmol ) Was dissolved in tetrahydrofuran (1.5 ml), oxalic acid (6.10 mg, 0.0673 mmol) was added, and the mixture was stirred at room temperature for 20 hours. It was concentrated under reduced pressure, ethanol was added to the obtained residue for ultrasonic treatment, and concentrated under reduced pressure. This operation was repeated 3 times, and the crystal of the title compound (28.8 mg) was obtained by drying the obtained solid under reduced pressure. For the crystals of the obtained compound, elemental analysis and powder X-ray diffraction measurement were performed. The powder X-ray diffraction diagram is shown in FIG. 10, and the diffraction angle (2θ), lattice spacing (d value), and relative intensity in the powder X-ray diffraction spectrum are described in Table 17. ¹ H-NMR (DMSO-d ₆ ) δ: 9.08 (1H, s), 8.56 (1H, s), 7.97 (1H, d, J = 8.8 Hz), 7.90-7.87 (1H, m), 7.65-7.60 (1H, m), 7.54-7.48 (1H, m), 7.35-7.29 (1H, m), 7.13-7.08 (1H, m), 5.39-4.11 (6H, m), 2.32-1.97 (6H, m) , 2.04 (3H, t, J = 18.8 Hz), 1.96-1.82 (2H, m). C ₂₈ H ₂₅ ClF ₅ N ₅ O ₂ ×C ₇ H ₈ O ₃ S Analysis calculated value: C, 54.87; H , 4.34; Cl, 4.63; F, 12.40; N, 9.14; S, 4.18. Measured value: C, 54.70; H, 4.32; Cl, 4.60; F, 12.50; N, 9.25; S, 4.12.

[Table 17] Crest number 2θ d value Relative Strength Crest number 2θ d value Relative Strength 1 10.10 8.76 35 6 18.70 4.75 54 2 12.35 7.17 39 7 20.55 4.32 56 3 13.30 6.66 58 8 23.25 3.83 100 4 17.05 5.20 89 9 25.25 3.53 36 5 17.75 5.00 85 10 29.30 3.05 48

[Example 79] 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazolin-4-yl]-10,10 -Difluoro-2,5,13-triazabispiro [3.2.5 ⁷ .2 ⁴ ] tetradecane-6,14-dione methanesulfonate compound obtained in Example 43 (100mg, 0.169mmol ) And methanesulfonic acid (17.0 mg, 0.177 mmol), add 80% water-containing 2-propanol (824 μL), and stir at room temperature for about 24 hours. The precipitated solid was collected by filtration and dried overnight at room temperature to obtain crystals (105 mg) of the title compound. For the crystals of the obtained compound, elemental analysis and powder X-ray diffraction measurement were performed. The powder X-ray diffraction diagram is shown in FIG. 11, and the diffraction angle (2θ), lattice spacing (d value), and relative intensity in the powder X-ray diffraction spectrum are described in Table 18. ¹ H-NMR (DMSO-d ₆ ) δ: 9.20 (1H, s), 8.91 (1H, s), 8.17-8.11 (1H, m), 7.95 (1H, s), 7.88-7.83 (1H, m) , 7.55-7.49 (1H, m), 7.37-7.31 (1H, m), 7.15-7.09 (1H, m), 6.09-6.07 (2H, m), 5.55-5.40 (1H, m), 5.28-5.13 ( 1H, m), 5.05-4.84 (3H, m), 4.64-4.49 (1H, m), 2.32 (3H, s), 2.25-2.00 (9H, m). Measured value: C, 49.22; H, 4.41; Cl: 4.93; F: 13.65; N: 9.73; S: 4.37.

[Table 18] Crest number 2θ d value Relative Strength Crest number 2θ d value Relative Strength 1 6.85 12.90 35 6 16.30 5.44 71 2 10.82 8.18 27 7 18.39 4.82 58 3 11.69 7.57 47 8 20.49 4.33 45 4 13.77 6.43 73 9 22.88 3.89 100 5 15.67 5.66 87 10 26.17 3.41 twenty two

[Example 80] 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)quinazolin-4-yl]-10,10-difluoro -2,5,13-Triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione methanesulfonate The compound (50.0 mg, 0.0839 mmol) obtained in Example 47 was dissolved To tetrahydrofuran (2ml), a 2mol/l methanesulfonic acid solution (45.0μl, 0.0900mmol) was added and stirred at room temperature for 2 hours. The resulting solid was collected by filtration and washed with tetrahydrofuran. The operation of adding ethanol to the obtained solid and concentrating under reduced pressure was repeated three times. By drying the obtained solid under reduced pressure, crystals of the title compound (45.1 mg) were obtained. For the crystals of the obtained compound, elemental analysis and powder X-ray diffraction measurement were performed. The powder X-ray diffraction diagram is shown in FIG. 12, and the diffraction angle (2θ), lattice spacing (d value), and relative intensity in the powder X-ray diffraction spectrum are described in Table 19. ¹ H-NMR (DMSO-d ₆ ) δ: 9.19 (1H, s), 8.84 (1H, s), 8.09 (1H, d, J = 9.1 Hz), 7.80-7.41 (4H, m), 7.37-7.31 (1H, m), 7.15-7.09 (1H, m), 5.49-5.32 (1H, m), 5.25-5.09 (1H, m), 5.06-4.84 (3H, m), 4.63-4.47 (1H, m) , 2.35-2.03 (10H, m), 1.98-1.86 (2H, m). Measured value: C, 47.55; H, 4.14; Cl, 5.01; F, 13.64; N, 9.87; S. 4.52.

[Table 19] Crest number 2θ d value Relative Strength Crest number 2θ d value Relative Strength 1 8.15 10.85 33 6 18.95 4.68 80 2 11.25 7.87 44 7 20.45 4.34 68 3 12.40 7.14 52 8 22.95 3.88 88 4 15.75 5.63 45 9 23.60 3.77 98 5 17.20 5.16 100 10 24.60 3.62 86

[Example 81] 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)-2-methoxyquinazolin-4-yl]- 10,10-difluoro-2,5,13-triazabispiro [3.2.5 ⁷ .2 ⁴ ] tetradecane-6,14-dione methanesulfonate The compound obtained in Example 52 (40.0 mg, 0.0639mmol) was dissolved in tetrahydrofuran (1.5ml), 2mol/l methanesulfonic acid solution (32.0μl, 0.0639mmol) was added and stirred at room temperature for 20 minutes. The precipitated solid was collected by filtration, washed with tetrahydrofuran, and dried under reduced pressure. The operation of adding ethanol to the obtained solid and concentrating under reduced pressure was performed three times. To the obtained residue, 2-propanol was added for ultrasonic treatment, and it was concentrated under reduced pressure. This operation was repeated 3 times, and by drying the obtained solid under reduced pressure, crystals of the title compound (39.7 mg) were obtained. For the crystals of the obtained compound, elemental analysis and powder X-ray diffraction measurement were performed. The powder X-ray diffraction diagram is shown in FIG. 13, and the diffraction angle (2θ), lattice spacing (d value), and relative intensity in the powder X-ray diffraction spectrum are described in Table 20. 1H-NMR (DMSO-d ₆ ) δ: 9.15 (1H, s), 7.94 (1H, d, J = 8.4 Hz), 7.53 (1H, t, J = 72.4 Hz), 7.51 (1H, dd, J = 8.0, 8.0 Hz), 7.33 (1H, dd, J = 10.4, 2.0 Hz), 7.28-7.19 (2H, m), 7.11 (1H, dd, J = 8.0, 2.0 Hz), 5.40-5.22 (1H, m ), 5.14-5.02 (1H, m), 5.01-4.78 (3H, m), 4.56-4.40 (1H, m), 4.00 (3H, s), 2.29 (3H, s), 2.26-2.00 (6H, m) ), 1.94-1.83 (2H, m). Measured value: C, 47.78; H, 3.94; Cl, 4.84; F, 12.77; N, 9.55; S, 4.36.

[Table 20] Crest number 2θ d value Relative Strength Crest number 2θ d value Relative Strength 1 6.75 13.10 100 6 16.70 5.31 34 2 8.15 10.85 28 7 18.10 4.90 34 3 12.20 7.25 twenty one 8 18.70 4.75 76 4 12.85 6.89 32 9 20.65 4.30 25 5 15.00 5.91 29 10 22.10 4.02 41

[Example 82] 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)-2-methoxyquinazoline-4- yl] 10,10-difluoro two -2,5,13- triaza-spiro ^{[7.2 4} 3.2.5] tetradecane-6,14-dione methanesulfonate obtained in Example 53 The compound (911 mg, 1.46 mmol) was dissolved in tetrahydrofuran (30 ml), a 2 mol/l methanesulfonic acid solution (730 μl, 1.46 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration, washed with tetrahydrofuran, and dried under reduced pressure. Ethanol was added to the obtained solid for ultrasonic treatment, and it was concentrated under reduced pressure. This operation was repeated twice, 2-propanol was added to the obtained residue, and ultrasonic treatment was performed to concentrate under reduced pressure. This operation was performed twice, 2-propanol was added to the obtained residue, and ultrasonic treatment was performed. The precipitated solid was filtered out and dried under reduced pressure to obtain an amorphous solid of the title compound (735 mg). For the obtained compound, elemental analysis was performed. 1H-NMR (DMSO-d ₆ ) δ: 9.17 (1H, s), 8.02 (1H, d, J = 8.4 Hz), 7.70 (1H, s), 7.62 (1H, d, J = 8.4 Hz), 7.52 (1H, dd, J = 8.4, 8,4 Hz), 7.34 (1H, dd, J = 10.4, 2.0 Hz), 7.13 (1H, dd, J = 8.4, 2.0 Hz), 5.48-5.34 (1H, m ), 5.22-5.06 (1H, m), 5.03-4.83 (3H, m), 4.63-4.47 (1H, m), 4.05 (3H, s), 2.31 (3H, s), 2.28-1.97 (6H, m) ), 2.04 (3H, t, J = 19.2 Hz), 1.96-1.84 (2H, m). Measured value: C, 50.59; H, 5.36; Cl, 4.41; F, 12.24; N, 8.51; S, 12.24.

[Example 83] 2-[7-(1,1-difluoroethyl)-2-methoxyquinazolin-4-yl]-5-[4-(difluoromethoxy)-3- fluorobenzyl] 10,10-difluoro two -2,5,13- triaza-spiro ^{[7.2 4} 3.2.5] tetradecane-6,14-dione methanesulfonate Example 54 The obtained compound (1.03 g, 1.58 mmol) was dissolved in tetrahydrofuran (40 ml), a 2 mol/l methanesulfonic acid solution (788 μl, 1.58 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The precipitated solid was collected by filtration, washed with tetrahydrofuran, and dried under reduced pressure. Ethanol was added to the obtained solid for ultrasonic treatment, and it was concentrated under reduced pressure. This operation was repeated 3 times, 2-propanol was added to the obtained residue, and ultrasonic treatment was performed to concentrate under reduced pressure. This operation was performed twice to add 2-propanol to the obtained residue, and ultrasonic treatment was performed. The precipitated solid was filtered out, washed with 2-propanol and dried under reduced pressure to obtain crystals of the title compound ( 0.865g). For the crystals of the obtained compound, elemental analysis and powder X-ray diffraction measurement were performed. The powder X-ray diffraction diagram is shown in FIG. 14, and the diffraction angle (2θ), lattice spacing (d value), and relative intensity in the powder X-ray diffraction spectrum are described in Table 21. 1H-NMR (DMSO-d ₆ ) δ: 9.16 (1H, s), 8.02 (1H, d, J = 8.4 Hz), 7.68 (1H, s), 7.61 (1H, d, J = 8.4 Hz), 7.34 -7.26 (2H, m), 7.20 (1H, t, J = 72.8 Hz), 7.14-7.08 (1H, m), 5.51-5.32 (1H, m), 5.22-5.07 (1H, m), 5.03-4.79 (3H, m), 4.61-4.47 (1H, m), 4.04 (3H, s), 2.30 (3H, s), 2.27-1.99 (6H, m), 2.02 (3H, t, J = 18.8 Hz), 1.95-1.81 (2H, m). Measured value: C, 48.58; H, 4.44; F, 17.17; N, 9.08; S, 17.17.

[Table 21] Crest number 2θ d value Relative Strength Crest number 2θ d value Relative Strength 1 6.60 13.39 100 6 16.80 5.28 84 2 7.15 12.36 61 7 18.80 4.72 84 3 9.30 9.51 31 8 20.45 4.34 67 4 11.05 8.01 38 9 23.40 3.80 77 5 13.30 6.66 41 10 26.85 3.32 62

[Example 84] 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazolin-4-yl]-10,10 -Difluoro-2,5,13-triazabispiro [3.2.5 ⁷ .2 ⁴ ] tetradecane-6,14-dione ethanesulfonate compound obtained in Example 43 (500mg, 0.842mmol ) And ethanesulfonic acid (97.4 mg, 0.884 mmol), add 2-propanol (10 ml) containing 2% water, and stir at 40°C for about 15 hours. The precipitated solid was collected by filtration, and dried overnight at room temperature to obtain crystals of the title compound (575 mg). For the crystals of the obtained compound, elemental analysis and powder X-ray diffraction measurement were performed. The powder X-ray diffraction diagram is shown in FIG. 15, and the diffraction angle (2θ), lattice spacing (d value), and relative intensity in the powder X-ray diffraction spectrum are described in Table 22. ¹ H-NMR (DMSO-d ₆ ) δ: 9.20 (1H, s), 8.91 (1H, s), 8.17-8.11 (1H, m), 7.96 (1H, s), 7.89-7.83 (1H, m) , 7.55-7.49 (1H, m), 7.37-7.31 (1H, m), 7.15-7.10 (1H, m), 5.55-5.40 (1H, m), 5.28-5.12 (1H, m), 5.05-4.85 ( 3H, m), 4.66-4.49 (1H, m), 2.39 (2H, q, J = 7.4 Hz), 2.29-2.00 (9H, m), 1.98-1.87 (2H, m), 1.06 (3H, t, J = 7.4 Hz). C ₂₈ H ₂₅ ClF ₅ N ₅ O ₂ ×C ₂ H ₆ O ₃ S Analytical calculation value: C, 51.17; H, 4.44; Cl, 5.04; F, 13.49; N, 9.95; S , 4.55. Measured value: C, 50.30; H, 4.56; Cl, 4.87; F, 13.48; N, 9.74; S, 4.76.

[Table 22] Crest number 2θ d value Relative Strength Crest number 2θ d value Relative Strength 1 5.82 15.19 35 6 16.55 5.36 29 2 7.71 11.47 36 7 18.36 4.83 100 3 9.31 9.50 18 8 18.62 4.77 13 4 11.72 7.55 69 9 19.23 4.62 75 5 15.31 5.79 35 10 23.38 3.80 19

[Example 85] 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazolin-4-yl]-10,10 -Difluoro-2,5,13-triazabispiro [3.2.5 ⁷ .2 ⁴ ] tetradecane-6,14-dione ethanesulfonate monohydrate The compound obtained in Example 43 (100 mg , 0.169mmol) and ethanesulfonic acid (19.5mg, 0.177mmol), add 80% water-containing acetone (826μl), and stir at room temperature for about 24 hours. The precipitated solid was collected by filtration and dried overnight at room temperature to obtain crystals of the title compound (114 mg). For the crystals of the obtained compound, elemental analysis and powder X-ray diffraction measurement were performed. The powder X-ray diffraction diagram is shown in FIG. 16, and the diffraction angle (2θ), lattice spacing (d value), and relative intensity in the powder X-ray diffraction spectrum are described in Table 23. ¹ H-NMR (DMSO-d ₆ ) δ: 9.19 (1H, br s), 8.89 (1H, br s), 8.16-8.11 (1H, m), 7.93 (1H, br s), 7.87-7.82 (1H , m), 7.55-7.49 (1H, m), 7.37-7.31 (1H, m), 7.14-7.10 (1H, m), 5.53-5.36 (1H, m), 5.26-5.10 (1H, m), 5.04 -4.84 (3H, m), 4.64-4.48 (1H, m), 2.37 (2H, q, J = 7.4 Hz), 2.30-1.99 (9H, m), 1.97-1.86 (2H, m), 1.05 (3H , t, J = 7.4 Hz). C ₂₈ H ₂₅ ClF ₅ N ₅ O ₂ ×C ₂ H ₆ O ₃ S×H ₂ O Analysis and calculation value: C, 49.90; H, 4.61; Cl, 4.91; F, 13.15; N, 9.70; S, 4.44. Measured value: C, 49.76; H, 4.58; Cl, 4.84; F, 13.16; N, 9.61; S, 4.43.

[Table 23] Crest number 2θ d value Relative Strength Crest number 2θ d value Relative Strength 1 6.87 12.87 43 6 16.28 5.44 69 2 9.40 9.41 29 7 16.68 5.32 39 3 10.74 8.24 twenty four 8 18.15 4.89 40 4 13.83 6.40 100 9 18.93 4.69 38 5 15.66 5.66 80 10 20.29 4.38 twenty four

[Example 86] 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazolin-4-yl]-10,10 -Difluoro-2,5,13-triazabispiro [3.2.5 ⁷ .2 ⁴ ] tetradecane-6,14-dione p-toluenesulfonate The compound obtained in Example 43 (40.0 mg, 0.0673 mmol) was dissolved in tetrahydrofuran (1.5 ml), p-toluenesulfonic acid monohydrate (12.8 mg, 0.0673 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. It was concentrated under reduced pressure, ethanol was added to the obtained residue for ultrasonic treatment, and concentrated under reduced pressure. This operation was repeated 3 times, and the crystal of the title compound (28.8 mg) was obtained by drying the obtained solid under reduced pressure. For the obtained crystals of the compound, powder X-ray diffraction measurement was performed. The powder X-ray diffraction diagram is shown in FIG. 17, and the diffraction angle (2θ), lattice spacing (d value), and relative intensity in the powder X-ray diffraction spectrum are described in Table 24. ¹ H-NMR (DMSO-d ₆ ) δ: 9.18 (1H, s), 8.88 (1H, s), 8.12 (1H, d, J = 9.2 Hz), 7.93-7.89 (1H, m), 7.86-7.81 (1H, m), 7.55-7.49 (1H, m), 7.49-7.44 (2H, m), 7.37-7.31 (1H, m), 7.15-7.07 (3H, m), 5.54-5.34 (1H, m) , 5.28-5.09 (1H, m), 5.06-4.81 (3H, m), 4.65-4.42 (1H, m), 2.29 (3H, s), 2.27-1.99 (6H, m), 2.05 (3H, t, J = 18.8 Hz), 1.98-1.84 (2H, m).

[Table 24] Crest number 2θ d value Relative Strength Crest number 2θ d value Relative Strength 1 7.75 11.41 100 6 19.15 4.63 90 2 13.05 6.78 33 7 19.60 4.53 67 3 15.70 5.64 30 8 21.45 4.14 36 4 16.00 5.54 15 9 23.80 3.74 41 5 17.05 5.20 15 10 25.30 3.52 42

[Example 87] 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)quinazolin-4-yl]-10,10-difluoro -2,5,13-Triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione p-toluenesulfonate The compound obtained in Example 47 (50.0 mg, 0.0839 mmol) Dissolved in tetrahydrofuran (2ml), added p-toluenesulfonic acid monohydrate (16.0mg, 0.0839mmol) and stirred at room temperature for 1 hour, then added tetrahydrofuran (0.5ml) and stirred for further 1 hour. The resulting solid was collected by filtration and washed with tetrahydrofuran. By drying the obtained solid under reduced pressure, crystals of the title compound (40.5 mg) were obtained. For the crystals of the obtained compound, elemental analysis and powder X-ray diffraction measurement were performed. The powder X-ray diffraction diagram is shown in FIG. 18, and the diffraction angle (2θ), lattice spacing (d value), and relative intensity in the powder X-ray diffraction spectrum are described in Table 25. ¹ H-NMR (DMSO-d ₆ ) δ: 9.19 (1H, s), 8.84 (1H, s), 8.09 (1H, d, J = 9.1 Hz), 7.80-7.41 (7H, m), 7.38-7.31 (1H, m), 7.15-7.08 (2H, m), 5.48-5.34 (1H, m), 5.24-5.11 (1H, m), 5.03-4.86 (3H, m), 4.63-4.50 (1H, m) , 2.34-2.03 (10H, m), 2.00-1.86 (2H, m). Measured value: C, 51.56; H, 4.38; Cl, 4.41; F, 12.08; N, 8.76; S. 3.97.

[Table 25] Crest number 2θ d value Relative Strength Crest number 2θ d value Relative Strength 1 6.90 12.81 41 6 19.10 4.65 67 2 8.00 11.05 39 7 20.15 4.41 100 3 9.05 9.77 40 8 22.10 4.02 83 4 10.80 8.19 38 9 24.55 3.63 64 5 17.90 4.96 67 10 26.40 3.38 76

[Example 88] 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)-2-methoxyquinazolin-4-yl]- 10,10-difluoro-two -2,5,13- triaza-spiro ^{[7.2 4} 3.2.5] tetradecane-6,14-dione the compound obtained in Example 52 of the embodiment toluenesulfonate ( 40.0 mg, 0.0639 mmol) was dissolved in tetrahydrofuran (1.5 ml), p-toluenesulfonic acid monohydrate (12.2 mg, 0.0639 mmol) was added, and the mixture was stirred at room temperature for 20 hours. It was concentrated under reduced pressure, ethanol was added to the obtained residue for ultrasonic treatment, and concentrated under reduced pressure. This operation was repeated twice, and 2-propanol was added to the obtained residue for ultrasonic treatment, and it was concentrated under reduced pressure. This operation was repeated 3 times to add a small amount of 2-propanol to the obtained residue, which was subjected to ultrasonic treatment, and the precipitated solid was filtered out and dried under reduced pressure to obtain crystals of the title compound (41.5 mg). For the crystals of the obtained compound, elemental analysis and powder X-ray diffraction measurement were performed. The powder X-ray diffraction diagram is shown in FIG. 19, and the diffraction angle (2θ), lattice spacing (d value), and relative intensity in the powder X-ray diffraction spectrum are described in Table 26. 1H-NMR (DMSO-d ₆ ) δ: 9.15 (1H, s), 7.94 (1H, d, J = 9.2 Hz), 7.54 (1H, t, J = 72.0 Hz), 7.51 (1H, dd, J = 8.0, 8.0 Hz), 7.47-7.43 (2H, m), 7.33 (1H, dd, J = 10.4, 2.0 Hz), 7.27-7.19 (2H, m), 7.13-7.07 (3H, m), 5.39-5.20 (1H, m), 5.15-4.75 (4H, m), 4.56-4.38 (1H, m), 3.99 (3H, s), 2.27 (3H, s), 2.26-2.00 (6H, m), 1.95-1.80 (2H, m). Measured value: C, 52.29; H, 4.19; Cl, 4.17; F, 12.05; N, 8.65; S, 3.84.

[Table 26] Crest number 2θ d value Relative Strength Crest number 2θ d value Relative Strength 1 6.75 13.10 100 6 16.70 5.31 34 2 8.15 10.85 28 7 18.10 4.90 34 3 12.20 7.25 twenty one 8 18.70 4.75 76 4 12.85 6.89 32 9 20.65 4.30 25 5 15.00 5.91 29 10 22.10 4.02 41

[Example 89] 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)-2-methoxyquinazoline-4- yl] 10,10-difluoro two -2,5,13- triaza-spiro ^{[7.2 4} 3.2.5] tetradecane-6,14-dione the p-toluenesulfonate obtained in Example 53 embodiment The compound (40.0 mg, 0.0641 mmol) was dissolved in tetrahydrofuran (1.5 ml), p-toluenesulfonic acid monohydrate (12.2 mg, 0.0639 mmol) was added, and the mixture was stirred at room temperature for 18.5 hours. It was concentrated under reduced pressure, ethanol was added to the obtained residue, and concentrated under reduced pressure again. This operation was repeated 3 times to add 2-propanol to the obtained residue, perform ultrasonic treatment, and concentrate under reduced pressure. This operation was repeated 3 times, diethyl ether was added to the obtained residue, ultrasonic treatment was performed, and the mixture was concentrated under reduced pressure. Diethyl ether was added to the obtained residue again, and ultrasonic treatment was performed. The precipitated solid was filtered out, washed with diethyl ether, and dried under reduced pressure to obtain crystals of the title compound (19.8 mg). For the crystals of the obtained compound, elemental analysis and powder X-ray diffraction measurement were performed. The powder X-ray diffraction diagram is shown in FIG. 20, and the diffraction angle (2θ), lattice spacing (d value), and relative intensity in the powder X-ray diffraction spectrum are described in Table 27. 1H-NMR (DMSO-d ₆ ) δ: 9.15 (1H, s), 8.00 (1H, d, J = 8.4 Hz), 7.67 (1H, s), 7.59 (1H, d, J = 8.4 Hz), 7.50 (1H, dd, J = 8.0, 8.0 Hz), 7.48-7.43 (2H, m), 7.33 (1H, dd, J = 10.4, 2.0 Hz), 7.14-7.06 (3H, m), 5.47-5.28 (1H , m), 5.19-5.03 (1H, m), 5.02-4.78 (3H, m), 4.61-4.43 (1H, m), 4.02 (3H, s), 2.30-1.95 (6H, m), 2.28 (3H) , s), 2.02 (3H, t, J = 18.8 Hz), 1.94-1.83 (2H, m). Measured value: C, 52.31; H, 4.65; Cl, 4.21; F, 11.52; N, 8.12; S, 4.05.

[Table 27] Crest number 2θ d value Relative Strength Crest number 2θ d value Relative Strength 1 6.65 13.29 100 6 17.05 5.20 72 2 9.05 9.77 twenty four 7 18.10 4.90 40 3 11.20 7.90 twenty three 8 19.60 4.53 44 4 12.90 6.86 twenty one 9 22.85 3.89 32 5 14.25 6.22 29 10 25.85 3.45 38

[Example 90] 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazolin-4-yl]-10,10 -Difluoro-2,5,13-triazabispiro [3.2.5 ⁷ .2 ⁴ ] tetradecane-6,14-dione benzenesulfonate compound obtained in Example 43 (100mg, 0.169mmol ) And benzenesulfonic acid (28.1 mg, 0.178 mmol) were added with 80% water-containing 2-propanol (825 μL), and stirred at 40°C for about 14 hours. The precipitated solid was collected by filtration, and dried overnight at room temperature to obtain crystals (117 mg) of the title compound. For the crystals of the obtained compound, elemental analysis and powder X-ray diffraction measurement were performed. The powder X-ray diffraction diagram is shown in FIG. 21, and the diffraction angle (2θ), lattice spacing (d value), and relative intensity in the powder X-ray diffraction spectrum are described in Table 28. ¹ H-NMR (DMSO-d ₆ ) δ: 9.20 (1H, s), 8.91 (1H, s), 8.17-8.11 (1H, m), 7.93 (1H, s), 7.88-7.83 (1H, m) , 7.61-7.56 (2H, m), 7.55-7.49 (1H, m), 7.37-7.28 (4H, m), 7.15-7.10 (1H, m), 5.54-5.40 (1H, m), 5.27-5.14 ( 1H, m), 5.05-4.84 (3H, m), 4.63-4.50 (1H, m), 2.31-2.00 (9H, m), 1.99-1.86 (2H, m). Measured value: C, 52.92; H, 4.31; Cl, 4.46; F, 12.60; N, 8.96; S, 4.09.

[Table 28] Crest number 2θ d value Relative Strength Crest number 2θ d value Relative Strength 1 6.20 14.26 100 6 18.03 4.92 30 2 10.16 8.71 17 7 18.65 4.76 55 3 12.45 7.11 93 8 22.29 3.99 25 4 14.89 5.95 80 9 22.53 3.95 32 5 17.22 5.15 twenty four 10 26.55 3.36 39

The test examples are presented below.

[Test Example 1] Evaluation of the colony formation inhibitory activity of SK-N-SH cells will be suspended in EMEM medium (Thermo Fisher Scientific #11095-080) containing a final concentration of 10% fetal bovine serum (GE Healthcare #SH30910.03) The human neuroblastoma cell line SK-N-SH (European Collection of Authenticated Cell Cultures) was centrifuged at 1000 rpm at room temperature for 3 minutes, and the supernatant was removed. Using DMEM/F12 (Thermo Fisher Scientific #11330-032) medium (hereinafter referred to as ``DMEM/F12 (Thermo Fisher Scientific #11330-032)) containing bFGF (Peprotech #100-18B), EGF (Peprotech #AF-100-15), B27 (Thermo Fisher Scientific #12587-010) NS medium) 10 mL of the cells were suspended, centrifuged at 1000 rpm at room temperature for 3 minutes, and the supernatant was removed. The cells were suspended in 10 mL of NS medium to prepare a ^{cell concentration of 1.78 x 10 5} cells/1 mL (hereinafter referred to as solution A). Mix 40 mL of MethoCult H4100 (STEMCELL Technologies, #04100) with 60 mL of NS medium (hereinafter referred to as liquid B). Mix solution A and solution B at a ratio of 3:5, and dispens 30 μL into each well of a 384-well flat plate (Corning #3827), and incubate at 37°C and 5% CO ₂ for 24 hours. Next, a D300e digital dispenser (Tecan) was used to add the compound solution of the example diluted with DMSO to the specified concentration _{, and cultured at 37°C and 5% CO 2} for 1 week. After incubation, the CellTiter-Glo 3D Cell Viability Assay (Promega #G9682) was used to perform the reaction according to the attached manual, and then the luminescence of each well was measured with a plate reader. From the amount of luminescence of the compound addition group (T), the compound non-addition group (C), and the cell non-addition group (B), the cell survival rate was calculated based on the following formula.

Cell survival rate (%)=[(T-B)/(C-B)]×100

The concentration (IC50 value) of the compound that inhibits the colonization of SK-N-SH cells by 50% was calculated by plotting the cell survival rate at each concentration and the compound concentration in a semi-logarithmic plot. The results are shown in Table 29.

[Test Example 2] Evaluation of the proliferation inhibitory activity against SH-SY5Y cells, NCI-H446 cells, and ARPE-19 cells. Freedom EVO 150 (Tecan Trading AG) was used to dilute the compounds of the examples (from 10 mM to 19.5 μM). Or from 1 mM to 1.95 μM at a common ratio of 2, 10 concentrations), using Echo555 (Labcyte Inc.), add 100 nL/well of the compound to a 384-well tissue culture dish (Thermo Fisher Scientific # 142761) ( The final concentration is from 25000 nM to 48.8 nM or from 2500 nM to 4.88 nM). The flat plate to which the prepared compound was added was stored at -30°C until use, and was thawed before use. Human neuroblastoma cell line SH-SY5Y (European Certified Cell Culture Collection) is based on a MEM/F12 medium (Thermo Fisher Scientific) containing a final concentration of 15% fetal bovine serum (Hyclone #SH30084.03 or #SH30910.03) #11095 and #11765) are subcultured and maintained. The human small cell lung cancer strain NCI-H446 (American Type Culture Collection) is based on RMPI1640 medium (Thermo Fisher Scientific # 11875) The human retinal pigment epithelial cell line ARPE-19 (American Type Culture Collection) was maintained in DMEM/F12 medium (Thermo Fisher Scientific #11330) containing a final concentration of 10% fetal bovine serum. After the cell lines were stripped and recovered by TrypLE Express (Thermo Fisher Scientific #12605), they were centrifuged at 1000 rpm at room temperature for 5 minutes to remove the supernatant. Suspend the cells in the same medium, prepare SH-SY5Y cells to 20,000 cells/1 mL, NCI-H446 cells to 50,000 cells/1 mL, and ARPE-19 cells to 10,000 cells/1 mL. 40 μL of the compound was dispensed into each well of the flat plate (day 0). Cultivate for 3 days at 37°C and 5% CO _2. On the day of compound addition (day 0) and 3 days after the compound addition (day 3), 10 μL/well of each well was added with CellTiter-Glo 2.0 Assay (Promega #G9242), a reagent for ATP measurement, and each well was measured by EnVision. The amount of light from the hole. From the luminescence amount on the day of compound addition (C0), the luminescence amount of the compound non-addition group (C3) and the compound addition group (T3) after 3 days of culture, the cell growth rate was calculated based on the following formula.

Cell proliferation rate (%)=[(T3-C0)/(C3-C0)]×100

The concentration of the compound that inhibits the growth of each cell by 50% (GI50 value) is calculated by plotting the cell proliferation rate in each concentration and the compound concentration in a semi-logarithmic plot. The results are shown in Table 29.

[Table 29] Test example 1 Test example 2 SK-N-SH SH-SY5Y NCI-H446 ARPE-19 Example No. IC50 (nM) GI50 (nM) GI50 (nM) GI50 (nM) 1-1 12.1 289 142 664 1-2 595 5020 4590 12200 2 25.0 213 178 601 3 68.1 184 123 466 4 85.7 540 393 1210 5-1 96.7 1020 855 2660 6-1 6.38 64.1 55.0 173 6-2 1260 7260 6300 15400 7-1 11.0 80.6 48.3 276 7-2 775 4510 3950 24200 8 4.70 60.5 44.5 361 9 4.92 118 92.9 357 10 13.7 369 125 1720 11 1.39 25.4 13.4 42.8 12 18.7 217 177 828 13 40.5 366 248 1590 14 10.4 128 96.4 460 15 162 2390 1920 6130 16 35.5 1040 477 1650 17 94.7 1990 1250 5850 18 23.7 570 492 1716 19 1.70 40.2 18.5 90.2 20 25.6 141 181 1730 twenty one 53.9 1110 549 4160 twenty two 17.3 170 108 519 twenty three 78.8 569 266 1490 twenty four 3.93 57.0 48.8 5250 25 27.3 695 625 2240 26 29.3 677 394 1710 27 7.08 118 114 368 28-2 9.92 168 160 852 29 2.48 49.0 23.0 94.3 30 2.95 43.0 22.8 96.3 31 43.0 680 613 2910 32 69.7 1370 1350 4240 33 19.9 229 204 1060 34 3.44 21.7 12.6 53.9 35 1.79 53.7 32.5 138 36 37.5 398 333 815 37 15.3 224 63.0 577 38 53.5 1260 658 6430 39 30.7 982 511 3020 40 13.6 197 108 680 41 2370 15,800 12200 23800 42 43.0 945 467 3710 43 1.95 83.1 40.7 141 44 2.93 79.5 44.3 233 45 11.8 115 89.9 412 46 110 1610 599 3670 47 2.12 55.6 27.4 122 48 3.75 82.5 53.1 151 49 4.00 152 96.7 265 50 2.66 110 79.1 644 51 2.60 52.4 27.0 111 52 2.25 58.8 43.8 178 53 3.38 68.7 35.2 238 54 3.44 49.7 53.9 216 55 27.4 547 458 3680 56 43.9 987 823 3420 57 4.01 54.7 39.0 173 58 2.70 48.9 34.1 186 59 0.520 23.6 13.6 68.2 60 1.21 30.7 22.7 103 61 3.38 114 51.4 242 62 29.6 822 580 2230 63 2.51 59.1 30.2 124 64 56.0 986 590 2240 65 4.21 146 94.5 278 66 4.34 95.7 51.5 234 67 5.97 164 130 504 68 21.2 362 113 438 69 2.79 80.3 46.5 167 70 8.26 108 82.3 627

[Test Example 3] Evaluation of the proliferation inhibitory activity against various types of cells. The human prostate cancer cell line LNCaP clone FGC (American Type Culture Collection) is a RPMI1640 medium containing a final concentration of 10% fetal bovine serum (Hyclone #SH30910.03) (FUJIFILM Wako Pure Chemical #187-02705), the human esophageal cancer cell line TE10 (Riken BioResource Center) is maintained by the RPMI1640 medium (Thermo Fisher Scientific #11875) containing the final concentration of 10% fetal bovine serum, human The esophageal cancer cell line TE14 (Riken BioResource Center) is subcultured with RPMI1640 medium (Thermo Fisher Scientific #11875) containing a final concentration of 10% fetal bovine serum. The human head and neck cancer cell line Detroit 562 (American Type Culture Collection) The line was maintained with EMEM medium (FUJIFILM Wako Pure Chemical #051-07615) containing a final concentration of 10% fetal bovine serum, and the human head and neck cancer cell line HSC3 (Riken BioResource Center) was lined with a final concentration of 10% fetal bovine serum. EMEM medium (FUJIFILM Wako Pure Chemical #051-07615) was subcultured and maintained, and the human leukemia cell line AML193 (American Type Culture Collection) was lined with a final concentration of 5% fetal bovine serum and ITS Liquid Media Supplement (SIGMA I3146) and the final The IMDM medium (Thermo Fisher Scientific #12440) with a concentration of 5 ng/mL human GM-CSF (Miltenyi Biotec #130-095-372) was maintained for subculture, and the human lung cancer cell line NCI-H1395 (American Type Culture Collection) RPMI1640 medium (FUJIFILM Wako Pure Chemical #187-02705) containing a final concentration of 10% fetal bovine serum was maintained, and the human lung cancer cell line NCI-H23 (American Type Culture Collection) was lined with a final concentration of 10% fetal bovine serum The RPMI1640 medium (FUJIFILM Wako Pure Chemical #187-02705) was subcultured and maintained, and the human melanoma cell line A375 (American Type Culture Collection) was lined with DMEM medium (F UJIFILM Wako Pure Chemical #043-30085) was subcultured and maintained. The human pancreatic cancer cell line BxPC-3 (American Type Culture Collection) was lined with RPMI1640 medium (FUJIFILM Wako Pure Chemical #187) containing a final concentration of 10% fetal bovine serum. -02705). The human lung cancer cell line LK-2 (Health Science Research Resources Bank) was subcultured and maintained with RPMI1640 medium (Thermo Fisher Scientific #11875) containing a final concentration of 10% fetal bovine serum. After the cell lines were stripped and recovered by TrypLE Express (Thermo Fisher Scientific #12605), they were centrifuged at 1000 rpm at room temperature for 5 minutes to remove the supernatant. Suspend the cells in the same medium, adjust each cell to a cell concentration of 20,000 cells/1mL, dispense 100 μL into each well of a 96-well flat plate (Corning #3904), and culture it _{at 37°C and 5% CO 2 for 24} hour. Next, 50 μL of the compound solution of the example diluted to the specified concentration in each medium was added to each well (day 1), _{and cultured at 37°C and 5% CO 2} for 3 days. On the day of compound addition (day 1) and 3 days after compound addition (day 4), 30 μL/well of CellTiter-Glo 2.0 Assay (Promega #G9242), a reagent for ATP measurement, was added to each well, and the volume of each well was measured by EnVision. The amount of light. From the luminescence amount on the day of compound addition (C1), the luminescence amount of the compound non-addition group (C4) and the compound addition group (T4) after 3 days of culture, the cell growth rate was calculated based on the following formula.

Cell proliferation rate (%)=[(T4-C1)/(C4-C1)]×100

The concentration of the compound that inhibits the growth of each cell by 50% (GI50 value) is calculated by plotting the cell proliferation rate in each concentration and the compound concentration in a semi-logarithmic plot. The results are shown in Table 30.

[Table 30] Example 1-1 2 10 43 51 53 54 Cell line GI50(nM) LNCaP - - - 5.86 4.04 9.99 7.61 TE10 13.8 - - 10.6 - - - TE14 41.5 - - 18.0 - - - Detroit562 71.0 - - 9.64 - - - HSC3 93.3 - - 66.0 - - - AML193 30.1 90.4 105 - - - - NCI-H1395 73.9 - - - - - - NCI-H23 64.6 - - - - - - A375 26.7 - 95.1 - - - - BxPC3 48.7 - 160 - - - - LK2 21.3 - 75.9 - - - -

no.

Figure 1 shows the powder X-ray diffraction pattern of the crystal of Example 43. The vertical axis of the graph represents the diffraction intensity with the relative line intensity, and the horizontal axis represents the value of the diffraction angle 2θ. Figure 2 shows the powder X-ray diffraction pattern of the crystal of Example 53. The vertical axis of the graph represents the diffraction intensity with the relative line intensity, and the horizontal axis represents the value of the diffraction angle 2θ. Fig. 3 shows the powder X-ray diffraction pattern of the crystal of Example 71. The vertical axis of the graph represents the diffraction intensity with the relative line intensity, and the horizontal axis represents the value of the diffraction angle 2θ. Fig. 4 shows the powder X-ray diffraction pattern of the crystal of Example 72. The vertical axis of the graph represents the diffraction intensity with the relative line intensity, and the horizontal axis represents the value of the diffraction angle 2θ. Fig. 5 shows the powder X-ray diffraction pattern of the crystal of Example 73. The vertical axis of the graph represents the diffraction intensity with the relative line intensity, and the horizontal axis represents the value of the diffraction angle 2θ. Fig. 6 shows the powder X-ray diffraction pattern of the crystal of Example 74. The vertical axis of the graph represents the diffraction intensity with the relative line intensity, and the horizontal axis represents the value of the diffraction angle 2θ. Fig. 7 shows the powder X-ray diffraction pattern of the crystal of Example 75. The vertical axis of the graph represents the diffraction intensity with the relative line intensity, and the horizontal axis represents the value of the diffraction angle 2θ. Fig. 8 shows the powder X-ray diffraction pattern of the crystal of Example 76. The vertical axis of the graph represents the diffraction intensity with the relative line intensity, and the horizontal axis represents the value of the diffraction angle 2θ. Fig. 9 shows the powder X-ray diffraction pattern of the crystal of Example 77. The vertical axis of the graph represents the diffraction intensity with the relative line intensity, and the horizontal axis represents the value of the diffraction angle 2θ. Fig. 10 shows the powder X-ray diffraction pattern of the crystal of Example 78. The vertical axis of the graph represents the diffraction intensity with the relative line intensity, and the horizontal axis represents the value of the diffraction angle 2θ. Figure 11 shows the powder X-ray diffraction pattern of the crystal of Example 79. The vertical axis of the graph represents the diffraction intensity with the relative line intensity, and the horizontal axis represents the value of the diffraction angle 2θ. Fig. 12 shows the powder X-ray diffraction pattern of the crystal of Example 80. The vertical axis of the graph represents the diffraction intensity with the relative line intensity, and the horizontal axis represents the value of the diffraction angle 2θ. Fig. 13 shows the powder X-ray diffraction pattern of the crystal of Example 81. The vertical axis of the graph represents the diffraction intensity with the relative line intensity, and the horizontal axis represents the value of the diffraction angle 2θ. Fig. 14 shows the powder X-ray diffraction pattern of the crystal of Example 83. The vertical axis of the graph represents the diffraction intensity with the relative line intensity, and the horizontal axis represents the value of the diffraction angle 2θ. Fig. 15 shows the powder X-ray diffraction pattern of the crystal of Example 84. The vertical axis of the graph represents the diffraction intensity with the relative line intensity, and the horizontal axis represents the value of the diffraction angle 2θ. Fig. 16 shows the powder X-ray diffraction pattern of the crystal of Example 85. The vertical axis of the graph represents the diffraction intensity with the relative line intensity, and the horizontal axis represents the value of the diffraction angle 2θ. Fig. 17 shows the powder X-ray diffraction pattern of the crystal of Example 86. The vertical axis of the graph represents the diffraction intensity with the relative line intensity, and the horizontal axis represents the value of the diffraction angle 2θ. Figure 18 shows the powder X-ray diffraction pattern of the crystal of Example 87. The vertical axis of the graph represents the diffraction intensity with the relative line intensity, and the horizontal axis represents the value of the diffraction angle 2θ. Fig. 19 shows the powder X-ray diffraction pattern of the crystal of Example 88. The vertical axis of the graph represents the diffraction intensity with the relative line intensity, and the horizontal axis represents the value of the diffraction angle 2θ. Fig. 20 shows the powder X-ray diffraction pattern of the crystal of Example 89. The vertical axis of the graph represents the diffraction intensity with the relative line intensity, and the horizontal axis represents the value of the diffraction angle 2θ. Fig. 21 shows the powder X-ray diffraction pattern of the crystal of Example 90. The vertical axis of the graph represents the diffraction intensity with the relative line intensity, and the horizontal axis represents the value of the diffraction angle 2θ.

no.

Claims (38)

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

[In formula (I), Z represents any one of the following (i) to (iii), (i) having 1 to 3 independently selected from the group containing oxygen atoms, nitrogen atoms, and sulfur atoms in the ring A 9- or 10-membered 2-ring aromatic heterocyclic group of heteroatoms (the 9- or 10-membered 2-ring aromatic heterocyclic group may have 1 or 2 substituents independently selected from the following A group) , (Ii) A 6-membered aromatic heterocyclic group having 1 to 3 nitrogen atoms in the ring, or a phenyl group (the 6-membered aromatic heterocyclic group and phenyl group may have 1 or 2 independently selected from Substituents of the following group B), (iii) -CO-R ¹ (R ¹ represents a 4- to 6-member aliphatic heterocyclic group having 1 or 2 nitrogen atoms in the ring, having 1 or A 6-membered aromatic heterocyclic group with 2 nitrogen atoms, a 9- or 10-membered 2-ring aromatic group having 1 to 3 heteroatoms independently selected from the group containing nitrogen atoms, oxygen atoms and sulfur atoms in the ring A heterocyclic group or a phenyl group, the aliphatic heterocyclic group, aromatic heterocyclic group, bicyclic aromatic heterocyclic group and phenyl group may have 1 to 3 substitutions each independently selected from the following C groups Radical), n ¹ and n ² each independently represent an integer of 1 to 3, n ³ and n ⁴ each independently represent an integer of 1 to 3, X represents CR ² R ³ , a sulfur atom, an oxygen atom, or NR ⁴ , R ² and R ³ each independently represent a hydrogen atom, a halogen atom, or an ethynyl group, or R ² and R ³ may be formed in a ring together with the bonded carbon atom. 3-6 members with 1 or 2 nitrogen atoms may have An aliphatic heterocyclic ring with an unsaturated bond, R ⁴ represents a hydrogen atom or a C ₁ -C ₆ alkyl group, Y represents a phenyl group, a 6-membered aromatic heterocyclic group having 1 or 2 nitrogen atoms in the ring, or A 9- or 10-membered 2-ring aromatic heterocyclic group having 1 to 3 heteroatoms independently selected from the group containing nitrogen atoms, oxygen atoms and sulfur atoms in the ring (the phenyl group, the aromatic heterocyclic group and the The bicyclic aromatic heterocyclic group may have 1 or 2 substituents each independently selected from the following D group)]; A group: halogen atom, hydroxyl group, nitro group, vinyl group, ethynyl group, cyano group, C ₁ -C ₆ alkyl group which may be substituted by 1 to 3 halogen atoms, C ₁ -C ₆ alkoxy group which may be substituted by 1 to 3 halogen atoms, C ₃ -which may be substituted by 1 to 3 halogen atoms C ₆ cycloalkyl, C ₃ -C ₆ cycloalkoxy, (C ₁ -C ₆ alkyl) amino, di (C ₁ -C ₆ alkyl) amino, (C ₁ -C ₆ alkyl) Carbonyl, (C ₁ -C ₆ alkoxy) carbonyl, azido and diazirine group; Group B: halogen atom, ethynyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ Alkoxy and C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl group; C group: halogen atom, cyano group, ethynyl group and C ₁ -C ₆ alkyl group; D group: halogen atom, can be C ₁ -C ₆ alkyl substituted by 1 to 3 halogen atoms, which may be substituted by 1 to 3 halogen atoms C ₁ -C ₆ alkoxy, ethynyl, azido and diazepine. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is a 10-membered 2-ring aromatic heterocyclic group having 1 or 2 nitrogen atoms in the ring, and the 10-membered 2-ring aromatic heterocyclic group The heterocyclic group may have 1 or 2 substituents each independently selected from the following E group, n ¹ and n ² are each independently 1 or 2; E group: halogen atom, ethynyl group, 1 to 3 halogens Atom-substituted C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group which may be substituted by 1 to 3 halogen atoms, C ₃ -C ₆ cycloalkyl group which may be substituted by 1 to 3 halogen atoms, and C _3- C ₆ cycloalkoxy. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is thienopyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl,

Linyl, X

base,

Ridinyl or pyridopyrimidinyl, the thienopyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl,

Linyl, X

base,

Piperidinyl and pyridinyl and pyrimidinyl group may have 1 or 2 substituents independently selected from C comprising a halogen atom, may be substituted with 1 to 3 halogen atoms and ₁ -C ₆ alkyl which may be substituted with 1 to 3 halogen atoms, _a C In the substituent of the _{-C 6} ^{alkoxy group, n 1} and n ² are both 1. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is -CO-R ⁵ , and R ⁵ represents a phenyl group, a pyridyl group or an azo group, and the phenyl group, a pyridyl group and an aza group may have 1 ~3 substituents each independently selected from the following F group, n ¹ and n ² are each independently 1 or 2; F group: halogen atom and C ₁ -C ₆ alkyl group. Such as the compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein n ³ and n ⁴ are both 2, and X is CF ₂ . For example, the compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein n ³ and n ⁴ are both 2, and X is the following formula (II),

. The compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein Y is a phenyl group or a pyridyl group, the phenyl group and the pyridyl group may have 1 or 2 independently selected from the following G group Substituents of the group; Group G: a halogen atom, a C ₁ -C ₆ alkyl group which may be substituted by 1 to 3 halogen atoms, and a C ₁ -C ₆ alkoxy group which may be substituted by 1 to 3 halogen atoms. _{The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is a C 1} -C ₆ alkyl group having 1 or 2 independently selected from containing halogen atoms, which may be substituted by 1 to 3 halogen atoms, and may be For the quinazolinyl group of the _{substituent of the C 1} -C ₆ alkoxy group substituted with 1 to 3 halogen atoms ^{, n 1} and n ² are both 1, n ³ and n ⁴ are both 2, and X is CF ₂ , Y contains a halogen atom having 1 or 2 substituents independently selected from the group, which may be substituted with 1 to 3 halogen atoms and C ₁ -C ₆ alkyl group which may be substituted with 1 to 3 halogen atoms, C ₁ -C ₆ alkoxy The phenyl group is the substituent of the group. The compound of claim 1 or a pharmaceutically acceptable salt thereof, which is any one selected from the following group: 2-[7-(1,1-difluoroethyl)quinazolin-4-yl ]-5-{[4-Difluoromethoxy-3-fluorophenyl]methyl}-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ] Tetradecane-6,14-dione, 2-[2-chloro-7-(1,1-difluoroethyl)quinazolin-4-yl]-5-[(4-chloro-3-fluoro phenyl) methyl] 10,10-difluoro-two -2,5,13- triaza-spiro ^{[7.2 4} 3.2.5] tetradecane-6,14-dione, 5 - [(4- Chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazolin-4-yl]-10,10-difluoro-2,5,13-tris Azodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione, 2-[7-(1,1-difluoroethyl)-2-methoxyquinazoline-4- Base]-5-{[4-Difluoromethoxy-3-fluorophenyl]methyl}-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]Tetradecane-6,14-dione, (-)-2-(4-chloro-2,6-difluorobenzyl)-6-[(4-chloro-3-fluorophenyl)methan Base]-11,11-difluoro-2,6,14-triazabispiro[4.2.5 ⁸ .2 ⁵ ]pentadecane-7,15-dione, (+)-6-[(4- Chloro-3-fluorophenyl)methyl]-2-[(5-chloro-3-fluoropyridin-2-yl)carbonyl]-11,11-difluoro-2,6,14-triazodispiro[ 4.2.5 ⁸ .2 ⁵ ]pentadecane-7,15-dione, 7-[(4-chloro-3-fluorophenyl)methyl]-3-[(3-ethylazepine-1- Yl)carbonyl]-12,12-difluoro-3,7,15-triazabispiro[5.2.5 ⁹ .2 ⁶ ]hexadecane-8,16-dione, 2-(6-butylpyrimidine -4-yl)-5-[(4-chloro-3-fluorophenyl)methyl]-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ] Tetradecane-6,14-dione, 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)quinazolin-4-yl]- 10,10-Difluoro-2,5,13-Triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione, 5-[(4-chloro-3-fluorophenyl )Methyl]-2-[7-(Difluoromethoxy)-2-methoxyquinazolin-4-yl]-10,10-difluoro-2,5,13-triazabisspiro[ 3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione, and 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoro (Ethyl)-2-methoxyquinazolin-4-yl)-10,10-difluoro-2,5, 13-Triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione. As in claim 1 of 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazolin-4-yl]-10,10 -Difluoro-2,5,13-triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione or a pharmaceutically acceptable salt thereof. As in claim 1 of 2-[7-(1,1-difluoroethyl)-2-methoxyquinazolin-4-yl]-5-{[4-difluoromethoxy-3-fluoro on phenyl] methyl} 10,10-difluoro-two -2,5,13- triaza-spiro ^{[7.2 4} 3.2.5] tetradecane-6,14-dione or a pharmaceutically tolerable salt. As in claim 1 of 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)quinazolin-4-yl]-10,10-difluoro -2,5,13-Triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione or a pharmaceutically acceptable salt thereof. As in claim 1 of 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)-2-methoxyquinazolin-4-yl]- 10,10-difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione or a pharmaceutically acceptable salt thereof. As in claim 1 of 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)-2-methoxyquinazoline-4- Yl]-10,10-difluoro-2,5,13-triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione or a pharmaceutically acceptable salt thereof. As in claim 1 of 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)quinazolin-4-yl]-10,10-difluoro -2,5,13-Triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione hydrochloride. A 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)quinazolin-4-yl]-10,10-bis as claimed in claim 1 The crystal of fluorine-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione hydrochloride, which is used in powder X-ray diffraction using CuKα radiation, It has a diffraction angle (2θ) selected from 6.80±0.2, 13.85±0.2, 15.25±0.2, 17.20±0.2, 18.65±0.2, 19.65±0.2, 21.75±0.2, 23.20±0.2, 24.40±0.2 and 25.35±0.2 At least 5 crests. As in claim 1 of 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)-2-methoxyquinazolin-4-yl]- 10,10-Difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione hydrochloride. A 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)-2-methoxyquinazolin-4-yl] as claimed in claim 1 -10,10-Difluoro-2,5,13-Triazabispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione hydrochloride crystal, which is used in the powder of CuKα radiation In X-ray diffraction, it is selected from 8.34±0.2, 10.40±0.2, 12.15±0.2, 16.20±0.2, 17.70±0.2, 19.15±0.2, 20.45±0.2, 22.75±0.2, 24.50±0.2 and 25.90±0.2 The firing angle (2θ) has at least 5 crests. As in claim 1 of 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazolin-4-yl]-10,10 -Difluoro-2,5,13-triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione oxalate. A 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazolin-4-yl]-10 as claimed in claim 1, The crystal of 10-difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ] tetradecane-6,14-dione oxalate, which is used in powder X-ray winding using CuKα radiation In the shot, at a diffraction angle selected from 10.10±0.2, 12.35±0.2, 13.30±0.2, 17.05±0.2, 17.75±0.2, 18.70±0.2, 20.55±0.2, 23.25±0.2, 25.25±0.2 and 29.30±0.2. 2θ) has at least 5 crests. As in claim 1 of 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazolin-4-yl]-10,10 -Difluoro-2,5,13-triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione methanesulfonate. A 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazolin-4-yl]-10 as claimed in claim 1, The crystal of 10-difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione methanesulfonate, which is used in powder X-rays using CuKα radiation In diffraction, the diffraction angle selected from 6.85±0.2, 10.82±0.2, 11.69±0.2, 13.77±0.2, 15.67±0.2, 16.30±0.2, 18.39±0.2, 20.49±0.2, 22.88±0.2 and 26.17±0.2 (2θ) has at least 5 crests. As in claim 1 of 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)quinazolin-4-yl]-10,10-difluoro -2,5,13-Triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione methanesulfonate. A 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(difluoromethoxy)quinazolin-4-yl]-10,10-bis as claimed in claim 1 Fluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione methanesulfonate crystal, which is used in powder X-ray diffraction using CuKα radiation , At diffraction angles (2θ) selected from 8.15±0.2, 11.25±0.2, 12.40±0.2, 15.75±0.2, 17.20±0.2, 18.95±0.2, 20.45±0.2, 22.95±0.2, 23.60±0.2 and 24.60±0.2 Has at least 5 wave crests. As in claim 1 of 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazolin-4-yl]-10,10 -Difluoro-2,5,13-triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ethanesulfonate. A 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazolin-4-yl]-10 as claimed in claim 1, The crystal of 10-difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dione ethanesulfonate, which is used in powder X-rays using CuKα radiation In diffraction, the diffraction angle selected from 5.82±0.2, 7.71±0.2, 9.31±0.2, 11.72±0.2, 15.31±0.2, 16.55±0.2, 18.36±0.2, 18.62±0.2, 19.23±0.2 and 23.38±0.2 (2θ) has at least 5 crests. A 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazolin-4-yl]-10 as claimed in claim 1, 10-Difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ] tetradecane-6,14-dione ethanesulfonic acid salt hydrate crystal, which is used in the powder of CuKα radiation In X-ray diffraction, it is selected from 6.87±0.2, 9.40±0.2, 10.74±0.2, 13.83±0.2, 15.66±0.2, 16.28±0.2, 16.68±0.2, 18.15±0.2, 18.93±0.2 and 20.29±0.2 The firing angle (2θ) has at least 5 crests. As in claim 1 of 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazolin-4-yl]-10,10 -Difluoro-2,5,13-triazabisspiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dionebenzenesulfonate. A 5-[(4-chloro-3-fluorophenyl)methyl]-2-[7-(1,1-difluoroethyl)quinazolin-4-yl]-10 as claimed in claim 1, The crystal of 10-difluoro-2,5,13-triazodispiro[3.2.5 ⁷ .2 ⁴ ]tetradecane-6,14-dionebenzenesulfonate, which is used in powder X-rays using CuKα radiation In diffraction, the diffraction angle selected from 6.20±0.2, 10.16±0.2, 12.45±0.2, 14.89±0.2, 17.22±0.2, 18.03±0.2, 18.65±0.2, 22.29±0.2, 22.53±0.2 and 26.55±0.2 (2θ) has at least 5 crests. A pharmaceutical composition containing the compound of any one of claims 1 to 29, its pharmaceutically acceptable salt or crystal as an active ingredient. An anticancer agent, which contains the compound of any one of claims 1 to 29, its pharmaceutically acceptable salt or crystal as an active ingredient. The anticancer agent of claim 31, wherein the cancer is leukemia, malignant lymphoma, multiple myeloma, brain tumor, head and neck cancer, esophageal cancer, gastric cancer, appendix cancer, colorectal cancer, anal cancer, gallbladder cancer, cholangiocarcinoma, Pancreatic cancer, gastrointestinal stromal tumor, lung cancer, liver cancer, mesothelioma, thyroid cancer, kidney cancer, prostate cancer, bladder cancer, neuroendocrine tumors, neuroblastoma, melanoma, breast cancer, uterine body cancer, children Cervical cancer, ovarian cancer, testicular cancer, osteosarcoma, soft tissue sarcoma, Kaposi's sarcoma (Kaposi's sarcoma) or sarcoma. A method for treating cancer, which is characterized by administering a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt or crystal thereof. The treatment method of claim 33, wherein the cancer is leukemia, malignant lymphoma, multiple myeloma, brain tumor, head and neck cancer, esophageal cancer, gastric cancer, appendix cancer, colorectal cancer, anal cancer, gallbladder cancer, cholangiocarcinoma, pancreas Visceral cancer, gastrointestinal stromal tumor, lung cancer, liver cancer, mesothelioma, thyroid cancer, kidney cancer, prostate cancer, bladder cancer, neuroendocrine tumor, neuroblastoma, melanoma, breast cancer, uterine body cancer, cervix Carcinoma, ovarian cancer, testicular cancer, osteosarcoma, soft tissue sarcoma, Kaposi’s sarcoma, or sarcoma. A compound according to any one of claims 1 to 29, and a pharmaceutically acceptable salt or crystal thereof for the treatment of cancer. Such as the compound of claim 35, its pharmaceutically acceptable salt or crystal, wherein the cancer is leukemia, malignant lymphoma, multiple myeloma, brain tumor, head and neck cancer, esophageal cancer, gastric cancer, appendix cancer, colorectal cancer, anal cancer Cancer, gallbladder cancer, cholangiocarcinoma, pancreatic cancer, gastrointestinal stromal tumor, lung cancer, liver cancer, mesothelioma, thyroid cancer, kidney cancer, prostate cancer, bladder cancer, neuroendocrine tumor, neuroblastoma, melanoma , Breast cancer, uterine body cancer, cervical cancer, ovarian cancer, testicular cancer, osteosarcoma, soft tissue sarcoma, Kaposi’s sarcoma or sarcoma. A use of a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt or crystal thereof in the manufacture of a pharmaceutical composition for the treatment of cancer. Such as the use of claim 37, wherein the cancer is leukemia, malignant lymphoma, multiple myeloma, brain tumor, head and neck cancer, esophageal cancer, gastric cancer, appendix cancer, colorectal cancer, anal cancer, gallbladder cancer, cholangiocarcinoma, pancreas Cancer, gastrointestinal stromal tumor, lung cancer, liver cancer, mesothelioma, thyroid cancer, kidney cancer, prostate cancer, bladder cancer, neuroendocrine tumor, neuroblastoma, melanoma, breast cancer, uterine body cancer, cervical cancer , Ovarian cancer, testicular cancer, osteosarcoma, soft tissue sarcoma, Kaposi’s sarcoma or sarcoma.

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