Optically active azabicyclic derivative

Abstract

To provide an antitumor agent having a high therapeutic effect.SOLUTION: The present invention provides a compound represented by formula (1a) [where p represents 1 or 2, R1 to R4 represent hydrogen atoms or the like, and a to d represent 1 or 2], or a pharmaceutically acceptable salt thereof, which exhibits antitumor activity by inhibiting the binding between a MLL fusion protein fused with AF4, AF9, or the like, which are representative fusion partner genes causing MLL leukemia, and menin.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to optically active azabicyclo derivatives and pharma- ceutical acceptable salts thereof that are useful as pharmaceuticals, as well as pharmaceutical compositions containing them, or therapeutic or prophylactic agents for pathologies involving the binding between menin and MLL that contain these compositions. [Background technology]

[0002] MLL leukemia accounts for approximately 6-7% of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), and approximately 1,100 people are newly diagnosed with MLL leukemia annually in the United States. It has been reported that the main fusion partner genes that cause MLL leukemia are AF9, ELL, ENL, AF10, and AF6 in AML, and AF4, ENL, and AF9 in ALL (Non-Patent Document 1).

[0003] It is speculated that MLL fusion proteins fused to fusion partner genes in this way induce unlimited proliferation of undifferentiated hematopoietic cells, resulting in leukemia (Non-Patent Document 2). It has been reported that MLL fusion proteins first bind to menin to form a complex. Therefore, it is expected that carcinogenesis caused by MLL fusion proteins can be prevented by inhibiting the first step, the binding between MLL fusion proteins and menin (Non-Patent Document 3).

[0004] It has been reported that MLL acts as a coactivator of androgen signaling in prostate cancer. Therefore, small molecule inhibitors that target the binding between menin and MLL fusion protein are expected to be useful as therapeutic agents for this cancer (Non-Patent Document 4). It has been reported that menin acts as a coactivator of estrogen signaling in breast cancer, and therefore small molecule inhibitors targeting the binding between menin and MLL fusion protein are expected to be useful as therapeutic agents for this cancer (Non-Patent Document 5). It has been reported that menin or MLL is important for tumor growth in Ewing's sarcoma, liver cancer, and p53 gain-of-function mutant cancers, and small molecule inhibitors that target the binding between menin and MLL fusion protein are expected to be useful as therapeutic agents for these cancers (Non-Patent Document 6).

[0005] To date, patent documents 1 to 3 have disclosed small molecule inhibitors targeting inhibition of the binding between menin and MLL fusion protein, but none of them disclose or suggest the compound of the present invention represented by the below-mentioned formula (1), which is an optically active azabicyclo derivative. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2017 / 112768 [Patent Document 2] International Publication No. 2017 / 214367 [Patent Document 3] International Publication No. 2018 / 050686 [Non-patent literature]

[0007] [Non-Patent Document 1] Look A. T, Science, 278 (5340): 1059-1064 (1997) [Non-Patent Document 2] Yokoyama A, et al., Cell 123 (2): 207-18 (2005) [Non-Patent Document 3] Yokoyama A, et al., Cancer Cell. 14(1): 34-46 (2008) [Non-Patent Document 4] Malik, R. et al., Nature Medicine. 21(4):344-352 (2015) [Non-Patent Document 5] Imacho, H et al., Breast Cancer Res Treat. 122(2):395-407 (2010) [Non-Patent Document 6] Svoboda, LK et al., Oncotargrt. 8(1):458-471 (2017) Summary of the Invention [Problem to be solved by the invention]

[0008] The problem to be solved by the present invention is to provide a compound that exerts an anticancer effect by inhibiting the binding of menin to MLL (mixed lineage leukemia) fusion proteins in which AF4, AF9, etc., which are representative fusion partner genes that cause MLL leukemia, are fused. More preferably, the problem to be solved by the present invention is to provide a compound that exerts an anticancer effect by inhibiting the binding of menin to MLL fusion proteins, and that is expected to be highly safe by having a gap between the compound concentration that inhibits cell proliferation and the compound concentration that inhibits hERG current. In other words, the problem to be solved by the present invention is to provide an antitumor agent with a high therapeutic effect. [Means for solving the problem]

[0009] As a result of intensive investigations, the present inventors have found that a compound represented by the following formula (1) or a pharma- ceutical acceptable salt thereof (hereinafter, sometimes referred to as "the compound of the present invention") has a strong inhibitory effect on the binding between menin and MLL fusion protein and thereby exhibits an excellent antitumor effect, thereby completing the present invention.

[0010] That is, the present invention is as follows.

[0011] [Section 1] Formula (1): [ka] [In the formula, p represents 1 or 2; R1 , R 2 , R 3 and R 4 each independently represents a hydrogen atom, a halogen atom, a cyano, a nitro, a carboxyl, a sulfonic acid, or -OR 7 , -SR 7 , -COR 8 , -CO2R 8 , -CONR 9 R 10 , -SO2R 8 , -SO2NR 9 R 10 , -OCOR 8 , -OCO2R 8 , -OCONR 9 R 10 , -NR 9 R 10 , -NR 11 COR 8 , -NR 11 CO2R 8 , -NR 11 CONR 9 R 10 , -NR 11 SO2R 8 , -NR 11 SO2NR 9 R 10 , or -MQ, or R 1 and R 2 and / or R 3 and R 4 But together, and independently, =O, =CR 12A R 13A , =N-NR 12B R 13B OR =N-OR 12B may form When there are more than one M, each M is independently an optionally substituted C 1-6 Alkylene, optionally substituted C 2-6 Alkenylene, optionally substituted C 2-6 Alkynylene, optionally substituted C 3-10 Cycloalkylene, optionally substituted 3- to 10-membered saturated heterocyclic group, optionally substituted C 6-10 represents an arylene or an optionally substituted 5- to 12-membered heteroarylene; Q, when present in plural, each independently represents a hydrogen atom or an optionally substituted C 3-10 Cycloalkyl, optionally substituted 3- to 10-membered saturated heterocyclic group, optionally substituted C 6-10 represents an aryl or an optionally substituted 5-12 membered heteroaryl, R 7 When there are more than one, each independently represents a hydrogen atom or an optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 3- to 10-membered saturated heterocyclic group, optionally substituted C 6-10 represents an aryl or an optionally substituted 5-12 membered heteroaryl, R 8 If there are multiple, each is independently 1-6 represents an alkyl group, R 9 , R 10 and R 11 are each independently a hydrogen atom or C 1-6 represents alkyl, R 9 , R 10 or R 11 If there are multiple, R 9 , R 10 or R 11 may be the same or different, wherein each of R 9 and R 10 Both are C 1-6 When they are alkyl, they may form a 3- to 8-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which they are bonded, R 12A and R 13A each independently represents a hydrogen atom, a halogen atom, a cyano, a nitro, a carboxyl, a sulfonic acid, -COR 14 , -CO2R 14 , -CONR 15 R 16 , -SO2R 14 , -SO2NR 15 R16 , optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 3- to 10-membered saturated heterocyclic group, optionally substituted C 6-10 R represents an aryl or an optionally substituted 5-12 membered heteroaryl. 12A or R 13A If there are multiple, R 12A or R 13A may be the same or different, where R 12A and R 13A and C, both of which are optionally substituted. 1-6 When they are alkyl, they may be joined together with the carbon atom to which they are attached to form a 3- to 8-membered saturated carbocyclic ring; R 12B and R 13B each independently represents a hydrogen atom or an optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 3- to 10-membered saturated heterocyclic group, optionally substituted C 6-10 R represents an aryl or an optionally substituted 5-12 membered heteroaryl. 12B or R 13B If there are multiple, R 12B or R 13B may be the same or different, where R 12B and R 13B and C, both of which are optionally substituted. 1-6 When they are alkyl, they may form a 3- to 8-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which they are bonded, R 14 If there are multiple, each is independently 1-6 represents an alkyl group, R 15 and R 16are each independently a hydrogen atom or C 1-6 represents alkyl, R 15 or R 16 If there are multiple, R 15 or R 16 may be the same or different, wherein each of R 15 and R 16 Both are C 1-6 When they are alkyl, they may form a 3- to 8-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which they are bonded, X is -C(O)- or C 1-6 represents alkylene, a, b, c, and d each independently represent 1 or 2; R 5A , R 5B , R 6A , R 6B , R 6C and R 6D each independently represents a hydrogen atom, a halogen atom, a cyano, a nitro, a carboxyl, a sulfonic acid, or -OR 17 , -SR 17 , -COR 18 , -CO2R 18 , -CONR 19 R 20 , -SO2R 18 , -SO2NR 19 R 20 , -OCOR 18 , -OCO2R 18 , -OCONR 19 R 20 , -NR 19 R 20 , -NR 21 COR 18 , -NR 21 CO2R 18 , -NR 21 CONR 19 R 20 , -NR 21 SO2R 18 , -NR 21 SO2NR 19 R 20 , optionally substituted C 1-6 Alkyl, optionally substituted C 2-6Alkenyl or optionally substituted C 2-6 represents alkynyl, R 17 , R 19 , R 20 and R 21 are each independently a hydrogen atom or C 1-6 represents alkyl, R 17 , R 19 , R 20 or R 21 If there are multiple 17 , R 19 , R 20 or R 21 may be the same or different, wherein each of R 19 and R 20 Both are C 1-6 When they are alkyl, they may form a 3- to 8-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which they are bonded, R 18 If there are multiple, each is independently 1-6 represents an alkyl group, U is for CR 22 or a nitrogen atom, R 22 is a hydrogen atom, a halogen atom, C 1-3 Alkyl (the alkyl is a fluorine atom, -OR 23 and -NR 23 R 24 may be substituted with 1 to 5 identical or different substituents selected from 25 , -CONR 26 R 27 or cyano, R 23 and R 24 are each independently a hydrogen atom or C 1-6 represents alkyl, R 23 or R 24 If there are multiple, R 23 or R 24 may be the same or different, wherein each of R 23 and R 24 Both are C 1-6When they are alkyl, they may form a 3- to 8-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which they are bonded, R 25 is C 1-6 represents an alkyl group, R 26 and R 27 are each independently a hydrogen atom or C 1-6 alkyl, where R 26 and R 27 Both are C 1-6 When they are alkyl, they may form a 3- to 8-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which they are bonded, Y is -O-, -S-, -CR 28 R 29 -, -NR 28 - represents R 28 and R 29 are each independently a hydrogen atom or C 1-6 represents an alkyl group, Z is a hydrogen atom, a halogen atom, cyano, nitro, carboxyl, sulfonic acid, -OR 30 , -SR 30 , -COR 31 , -CO2R 31 , -CONR 32 R 33 , -SO2R 31 , -SO2NR 32 R 33 , -OCOR 31 , -OCO2R 31 , -OCONR 32 R 33 , -NR 32 R 33 , -NR 34 COR 31 , -NR 34 CO2R 31 , -NR 34 CONR 32 R 33 , -NR 34 SO2R 31 , -NR 34 SO2NR 32 R 33 , optionally substituted C1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 3- to 10-membered saturated heterocyclic group, optionally substituted C 6-10 represents an aryl or an optionally substituted 5-12 membered heteroaryl, R 30 , R 32 , R 33 and R 34 are each independently a hydrogen atom, C 1-6 Alkyl (the alkyl may be substituted with 1 to 5 identical or different substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom and a hydroxyl group) or C 3-10 represents a cycloalkyl, wherein R 32 and R 33 Both are C 1-6 When they are alkyl, they may form a 3- to 8-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which they are bonded, R 31 C may be substituted with 1 to 5 identical or different substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom and a hydroxyl group. 1-6 represents alkyl] or a pharma- ceutically acceptable salt thereof.

[0012] [Section 2] R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, a halogen atom, or -OR 7 or -MQ, or R 1 and R 2 and / or R 3 and R 4 Together, they are independently =O or =CR. 12A R 13A may form R 12A and R 13Aeach independently represents a hydrogen atom, a halogen atom, a cyano, or an optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 3- to 10-membered saturated heterocyclic group, optionally substituted C 6-10 aryl or an optionally substituted 5-12 membered heteroaryl; R 12A or R 13A If there are multiple, R 12A or R 13A may be the same or different, where R 12A and R 13A and C, both of which are optionally substituted. 1-6 When they are alkyl, they may be joined together with the carbon atom to which they are attached to form a 3- to 8-membered saturated carbocyclic ring. Item 1. The compound according to item 1 or a pharma- ceutically acceptable salt thereof.

[0013] [Section 3] M, Q, Z, R 5A , R 5B , R 6A , R 6B , R 6C , R 6D , R 7 , R 12A , R 12B , R 13A and R 13B Optionally substituted C in 1-6 Alkylene, optionally substituted C 2-6 Alkenylene, optionally substituted C 2-6 Alkynylene, optionally substituted C 3-10 Cycloalkylene, optionally substituted 3- to 10-membered saturated heterocyclic group, optionally substituted C 6-10 Arylene, optionally substituted 5- to 12-membered heteroarylene, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6Alkynyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted C 6-10 Aryl and optionally substituted 5- to 12-membered heteroaryl are (1) a halogen atom, (2) hydroxyl group, (3) C 6-10 Aryl, (4) 5- to 12-membered heteroaryl, (5) C 1-6 Alkyl, (6) C 2-6 Alkenyl, (7) C 2-6 Alkynyl, (8) C 1-6 Alkoxy, (9) C 3-10 Cycloalkyl, (10) a 3- to 10-membered saturated heterocyclic group, (11) carboxyl, (12)-COR 35A , (13)-CO2R 35A , (14)-CONR 36A R 37A , (15)-NR 36A R 37A , (16)-NR 36A COR 35A , (17)-NR 36A SO2R 35A , (18)-SO2R 35A , (19)-SO2NR 36A R 37A , (20) sulfonic acids, (21) Phosphoric acid, (22) Cyano, and (23) Nitro may be substituted with 1 to 5 identical or different substituents selected from the group consisting of Here, the above (3)C 6-10 Aryl, (4) 5-12 membered heteroaryl, (5) C1-6 Alkyl, (6)C 2-6 Alkenyl, (7)C 2-6 Alkynyl, (8)C 1-6 Alkoxy, (9)C 3-10 Cycloalkyl and (10) 3-10 membered saturated heterocyclic group are (a) a halogen atom, (b) a hydroxyl group, (c)C 6-10 Aryl, (d) 5-10 membered heteroaryl, (e)C 1-6 Alkyl, (f)C 2-6 Alkenyl, (g) C 2-6 Alkynyl, (h)C 1-6 Alkoxy, (I C 3-10 Cycloalkyl, (j) a 3- to 10-membered saturated heterocyclic group, (k) carboxyl, (l)-COR 35B , (m)-CO2R 35B , (n)-CONR 36B R 37B , (o)-NR 36B R 37B , (p)-NR 36B COR 35B , (q)-NR 36B SO2R 35B , (r)-SO2R 35B , (s)-SO2NR 36B R 37B , (t) sulfonic acids, (u) phosphoric acid, (v) cyano, and (w) Nitro may be substituted with 1 to 5 identical or different substituents selected from the group consisting of R 35AIf there are multiple, each is independently 1-6 represents an alkyl group, R 36A and R 37A are each independently a hydrogen atom or C 1-6 represents alkyl, R 36A or R 37A If there are multiple, R 36A or R 37A may be the same or different, wherein each of R 36A and R 37A Both are C 1-6 When they are alkyl, they may form a 3- to 8-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which they are bonded, R 35B If there are multiple, each is independently 1-6 represents an alkyl group, R 36B and R 37B are each independently a hydrogen atom or C 1-6 represents alkyl, R 36B or R 37B If there are multiple, R 36B or R 37B may be the same or different, wherein each of R 36B and R 37B Both are C 1-6 When they are alkyl, they may form a 3- to 8-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which they are bonded. Item 3. The compound according to item 1 or 2, or a pharma- ceutically acceptable salt thereof.

[0014] [Section 4] M, Q, Z, R 5A , R 5B , R 6A , R 6B , R 6C , R 6D , R 7 , R 12A , R 12B , R 13A and R 13B Optionally substituted C in 1-6Alkylene, optionally substituted C 2-6 Alkenylene, optionally substituted C 2-6 Alkynylene, optionally substituted C 3-10 Cycloalkylene, optionally substituted 3- to 10-membered saturated heterocyclic group, optionally substituted C 6-10 Arylene, optionally substituted 5- to 12-membered heteroarylene, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted C 6-10 Aryl and optionally substituted 5- to 12-membered heteroaryl are (1) a halogen atom, (2) hydroxyl group, (3) phenyl, (4) 5-6 membered heteroaryl, (5) C optionally substituted with 1 to 3 hydroxyl groups 1-6 Alkyl, (6) C 2-6 Alkynyl, (7) C 1-6 Alkoxy, (8) C 3-7 Cycloalkyl, (9) a 3- to 7-membered saturated heterocyclic group, (10)-COR 35A , (11)-CO2R 35A , (12)-CONR 36A R 37A , (13)-NR 36A R 37A , (14)-NR 36A COR 35A , (15)-NR 36A SO2R 35A , (16)-SO2R 35A , (17)-SO2NR 36A R 37A , (18) Cyano, and (19) Nitro may be substituted with 1 to 5 identical or different substituents selected from the group consisting of R 35A However, if there are multiple, each is independently C 1-6 is alkyl, R 36A and R 37A are each independently a hydrogen atom or C 1-6 is alkyl, R 36A or R 37A If there are multiple, R 36A or R 37A may be the same or different, wherein each of R 36A and R 37A Both are C 1-6 When they are alkyl, they may form a 3- to 6-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which they are bonded. Item 4. The compound according to any one of Items 1 to 3, or a pharma- ceutically acceptable salt thereof.

[0015] [Section 5] X is -C(O)-; Y is -O-; Item 5. The compound according to any one of Items 1 to 4, or a pharma- ceutically acceptable salt thereof.

[0016] [Section 6] R 5A , R 5B , R 6A , R 6B and R 6D is a hydrogen atom, R 6C is a fluorine atom; Item 6. The compound according to any one of Items 1 to 5, or a pharma- ceutically acceptable salt thereof.

[0017] [Section 7] U is CR 22 or a nitrogen atom, R 22 is -CF3 or cyano; Item 7. The compound according to any one of Items 1 to 6, or a pharma- ceutically acceptable salt thereof.

[0018] [Section 8] U is a nitrogen atom; Item 8. The compound according to any one of Items 1 to 7, or a pharma- ceutically acceptable salt thereof.

[0019] [Section 9] Z is -conr 32 R 33 , a 3- to 6-membered saturated heterocyclic group (the saturated heterocyclic group is 1-3 Alkyl or C 3-6 cycloalkyl), phenyl (the phenyl is optionally substituted by cyano, 1 to 3 hydroxyl groups, 1-3 Alkyl and C 3-6 cycloalkyl), or 1 to 3 C 1-3 is a 5- to 6-membered heteroaryl optionally substituted with alkyl; R 32 and R 33 are each independently a hydrogen atom or C 1-3 alkyl, where R 32 and R 33 Both are C 1-6 When they are alkyl, they may form a 3- to 6-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which they are bonded. Item 9. The compound according to any one of items 1 to 8, or a pharma- ceutically acceptable salt thereof.

[0020] [Section 10] Z is the following formula (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8) or (Z-9): [ka] [wherein * represents the bonding position to the aromatic ring] That is, Item 10. The compound according to any one of items 1 to 9, or a pharma- ceutically acceptable salt thereof.

[0021] [Section 11] Z is (Z-3); Item 11. The compound according to item 10 or a pharma- ceutically acceptable salt thereof.

[0022] [Section 12] When there are multiple M's, each M is independently C 1-6 Alkylene (the alkylene is a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, C 2-4 Alkynyl, C 1-3 Alkoxy, -CONR 36A R 37A , -NR 36A R 37A , -NR 36A COR 35A , -NR 36A SO2R 35A , -SO2R 35A , -SO2NR 36A R 37A and cyano), C 2-6 Alkenylene, C 2-6 Alkynylene, C 3-10 Cycloalkylene, 3-10 membered saturated heterocyclic group, C 6-10 Arylene or 5-12-membered heteroarylene (the alkenylene, the alkynylene, the cycloalkylene, the saturated heterocyclic group, the arylene and the heteroarylene each independently represent a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, C 1-3 Alkyl, C 2-4 Alkynyl, C 1-3 Alkoxy, -CONR 36A R 37A , -NR 36A R 37A , -NR 36A COR 35A , -NR 36A SO2R 35A , -SO2R 35A , -SO2NR 36A R 37Aand cyano), When Q is more than one, each independently represents a hydrogen atom or C 3-10 Cycloalkyl, 3-10 membered saturated heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl (the cycloalkyl, the saturated heterocyclic group, the aryl and the heteroaryl each independently represent a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, C 1-3 Alkyl, C 2-4 Alkynyl, C 1-3 Alkoxy, -CONR 36A R 37A , -NR 36A R 37A , -NR 36A COR 35A , -NR 36A SO2R 35A , -SO2R 35A , -SO2NR 36A R 37A and cyano), R 7 If there are multiple, each independently represents a hydrogen atom, C 1-6 Alkyl (the alkyl is a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a phenyl, a 5- to 6-membered heteroaryl, C 2-4 Alkynyl, C 3-7 Cycloalkyl, 3- to 7-membered saturated heterocyclic group, C 1-3 Alkoxy, -CONR 36A R 37A , -NR 36A R 37A , -NR 36A COR 35A , -NR 36A SO2R 35A , -SO2R 35A , -SO2NR 36A R 37A and cyano), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered saturated heterocyclic group, C6-10 Aryl or 5-12 membered heteroaryl (the alkenyl, the alkynyl, the cycloalkyl, the saturated heterocyclic group, the aryl and the heteroaryl each independently represent a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, C 1-3 Alkyl, C 2-4 Alkynyl, C 1-3 Alkoxy, -CONR 36A R 37A , -NR 36A R 37A , -NR 36A COR 35A , -NR 36A SO2R 35A , -SO2R 35A , -SO2NR 36A R 37A and cyano), R 12A and R 13A are each independently a hydrogen atom, a halogen atom, a cyano, or C 1-6 Alkyl (the alkyl is a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, C 2-4 Alkynyl, C 1-3 Alkoxy, -CONR 36A R 37A , -NR 36A R 37A , -NR 36A COR 35A , -NR 36A SO2R 35A , -SO2R 35A , -SO2NR 36A R 37A and cyano), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered saturated heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl (the alkenyl, the alkynyl, the cycloalkyl, the saturated heterocyclic group, the aryl and the heteroaryl each independently represent a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, C 1-3 Alkyl, C 2-4Alkynyl, C 1-3 Alkoxy, -CONR 36A R 37A , -NR 36A R 37A , -NR 36A COR 35A , -NR 36A SO2R 35A , -SO2R 35A , -SO2NR 36A R 37A and cyano, 12A or R 13A If there are multiple, R 12A or R 13A may be the same or different, where R 12A and R 13A Both are C 1-6 When they are alkyl, they may be joined together with the carbon atom to which they are attached to form a 3- to 8-membered saturated carbocyclic ring; R 35A However, if there are multiple, each is independently C 1-6 represents an alkyl group, R 36A and R 37A are each independently a hydrogen atom or C 1-6 represents alkyl, R 36A or R 37A If there are multiple, R 36A or R 37A may be the same or different, wherein each of R 36A and R 37A Both are C 1-6 When they are alkyl, they may form a 3- to 8-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which they are bonded. Item 12. The compound according to any one of items 1 to 11, or a pharma- ceutically acceptable salt thereof.

[0023] [Section 13] Formula (1a): [ka] [In the formula, p represents 1 or 2; R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, a halogen atom, or -OR 7 , or -MQ, or R 1 and R 2 and / or R 3 and R 4 Together, they are independently =O or =CR. 12A R 13A may form When there are multiple M's, each M is independently C 1-6 Alkylene (the alkylene is a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, C 2-4 Alkynyl, C 1-3 Alkoxy, -CONR 36A R 37A , -NR 36A R 37A , -NR 36A COR 35A , -NR 36A SO2R 35A , -SO2R 35A , -SO2NR 36A R 37A and cyano), C 2-6 Alkenylene, C 2-6 Alkynylene, C 3-10 Cycloalkylene, 3-10 membered saturated heterocyclic group, C 6-10 Arylene or 5-12-membered heteroarylene (the alkenylene, the alkynylene, the cycloalkylene, the saturated heterocyclic group, the arylene and the heteroarylene each independently represent a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, C 1-3 Alkyl, C 2-4 Alkynyl, C 1-3 Alkoxy, -CONR 36A R 37A , -NR 36A R 37A , -NR 36A COR 35A , -NR 36A SO2R35A , -SO2R 35A , -SO2NR 36A R 37A and cyano), Q, when present in plural, is independently a hydrogen atom, C 3-10 Cycloalkyl, 3-10 membered saturated heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl (the cycloalkyl, the saturated heterocyclic group, the aryl and the heteroaryl each independently represent a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, C 1-3 Alkyl, C 2-4 Alkynyl, C 1-3 Alkoxy, -CONR 36A R 37A , -NR 36A R 37A , -NR 36A COR 35A , -NR 36A SO2R 35A , -SO2R 35A , -SO2NR 36A R 37A and cyano), R 7 When there are multiple, each independently represents a hydrogen atom, C 1-6 Alkyl (the alkyl is a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a phenyl, a 5- to 6-membered heteroaryl, C 2-4 Alkynyl, C 3-7 Cycloalkyl, 3- to 7-membered saturated heterocyclic group, C 1-3 Alkoxy, -CONR 36A R 37A , -NR 36A R 37A , -NR 36A COR 35A , -NR 36A SO2R 35A , -SO2R 35A , -SO2NR 36A R 37A and cyano), C 2-6Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered saturated heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl (the alkenyl, the alkynyl, the cycloalkyl, the saturated heterocyclic group, the aryl and the heteroaryl each independently represent a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, C 1-3 Alkyl, C 2-4 Alkynyl, C 1-3 Alkoxy, -CONR 36A R 37A , -NR 36A R 37A , -NR 36A COR 35A , -NR 36A SO2R 35A , -SO2R 35A , -SO2NR 36A R 37A and cyano), R 12A and R 13A are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl (the alkyl is a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, C 2-4 Alkynyl, C 1-3 Alkoxy, -CONR 36A R 37A , -NR 36A R 37A , -NR 36A COR 35A , -NR 36A SO2R 35A , -SO2R 35A , -SO2NR 36A R 37A and cyano), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered saturated heterocyclic group, C 6-10Aryl or 5-12 membered heteroaryl (the alkenyl, the alkynyl, the cycloalkyl, the saturated heterocyclic group, the aryl and the heteroaryl each independently represent a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, C 1-3 Alkyl, C 2-4 Alkynyl, C 1-3 Alkoxy, -CONR 36A R 37A , -NR 36A R 37A , -NR 36A COR 35A , -NR 36A SO2R 35A , -SO2R 35A , -SO2NR 36A R 37A and cyano, each of which may be the same or different, and 1 to 5 substituents selected from the group consisting of 12A or R 13A If there are multiple, R 12A or R 13A may be the same or different, where R 12A and R 13A Both are C 1-6 When they are alkyl, they may be joined together with the carbon atom to which they are attached to form a 3- to 8-membered saturated carbocyclic ring; R 35A If there are multiple, each is independently 1-6 represents an alkyl group, R 36A and R 37A are each independently a hydrogen atom or C 1-6 represents alkyl, R 36A or R 37A If there are multiple, R 36A or R 37A may be the same or different, wherein each of R 36A and R 37A Both are C 1-6 When they are alkyl, they may form a 3- to 6-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which they are bonded, a, b, c and d each independently represent 1 or 2. Item 2. The compound according to item 1, which is represented by the following formula: or a pharma- ceutically acceptable salt thereof.

[0024] [Section 14] When there are multiple M's, each M is independently C 1-6 Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C 2-4 Alkynyl, C 1-3 Alkoxy, -CONR 36A R 37A , -NR 36A R 37A , -NR 36A COR 35A , -NR 36A SO2R 35A , -SO2R 35A , -SO2NR 36A R 37A and cyano), R 35A However, if there are multiple, each is independently C 1-6 represents an alkyl group, R 36A and R 37A are each independently a hydrogen atom or C 1-6 represents alkyl, R 36A or R 37A If there are multiple, R 36A or R 37A may be the same or different, wherein each of R 36A and R 37A Both are C 1-6 When they are alkyl, they may form a 3- to 6-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which they are bonded. Item 14. The compound according to any one of Items 1 to 13, or a pharma- ceutically acceptable salt thereof.

[0025] [Section 15] When there are multiple Qs, each Q is independently C 3-10 Cycloalkyl, 3-10 membered saturated heterocyclic group, C 6-10Aryl or 5-12 membered heteroaryl (the cycloalkyl, the saturated heterocyclic group, the aryl and the heteroaryl each independently represent a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, C 1-3 Alkyl, C 2-4 Alkynyl, C 1-3 Alkoxy, -CONR 36A R 37A , -NR 36A R 37A , -NR 36A COR 35A , -NR 36A SO2R 35A , -SO2R 35A , -SO2NR 36A R 37A and cyano), R 35A However, if there are multiple, each is independently C 1-6 represents an alkyl group, R 36A and R 37A are each independently a hydrogen atom or C 1-6 represents alkyl, R 36A or R 37A If there are multiple, R 36A or R 37A may be the same or different, wherein each of R 36A and R 37A Both are C 1-6 When they are alkyl, they may form a 3- to 6-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which they are bonded. Item 15. The compound according to any one of items 1 to 14, or a pharma- ceutically acceptable salt thereof.

[0026] [Section 16] R 7 If there are multiple, each independently represents a hydrogen atom, C 1-6 Alkyl (the alkyl is a fluorine atom, a phenyl, C 3-7 may be substituted with 1 to 5 identical or different substituents selected from the group consisting of cycloalkyl and 3- to 7-membered saturated heterocyclic groups, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered saturated heterocyclic group (the cycloalkyl and the saturated heterocyclic group each independently represent a fluorine atom and C 1-3 alkyl), C 6-10 Aryl or 5-12 membered heteroaryl (the aryl and the heteroaryl each independently represent a fluorine atom, a chlorine atom, a bromine atom, or C 1-3 alkyl, each of which may be substituted with 1 to 5 identical or different substituents selected from the group consisting of Item 16. The compound according to any one of items 1 to 15, or a pharma- ceutically acceptable salt thereof.

[0027] [Section 17] R 7 When there are a plurality of C groups, each C group may be independently substituted by a hydrogen atom or one phenyl group. 1-6 Alkyl or C 2-6 alkenyl, Item 17. The compound according to any one of items 1 to 16, or a pharma- ceutically acceptable salt thereof.

[0028] [Section 18] R 12A and R 13A are each independently a hydrogen atom, C 1-6 Alkyl (the alkyl is a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, C 2-4 Alkynyl, C 1-3 Alkoxy, -CONR 36A R 37A , -NR 36A R 37A , -NR 36A COR 35A , -NR 36A SO2R 35A , -SO2R 35A , -SO2NR 36A R 37A and cyano), C 3-10 Cycloalkyl, 3-10 membered saturated heterocyclic group, C6-10 Aryl or 5-12 membered heteroaryl (the cycloalkyl, the saturated heterocyclic group, the aryl and the heteroaryl each independently represent a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, C 1-3 Alkyl, C 2-4 Alkynyl, C 1-3 Alkoxy, -CONR 36A R 37A , -NR 36A R 37A , -NR 36A COR 35A , -NR 36A SO2R 35A , -SO2R 35A , -SO2NR 36A R 37A and cyano, 12A or R 13A If there are multiple, R 12A or R 13A may be the same or different, where R 12A and R 13A Both are C 1-6 When they are alkyl, they may be joined together with the carbon atom to which they are attached to form a 3- to 8-membered saturated carbocyclic ring; R 35A However, if there are multiple, each is independently C 1-6 represents an alkyl group, R 36A and R 37A are each independently a hydrogen atom or C 1-6 represents alkyl, R 36A or R 37A If there are multiple, R 36A or R 37A may be the same or different, wherein each of R 36A and R 37A Both are C 1-6 When they are alkyl, they may form a 3- to 6-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which they are bonded. Item 18. The compound according to any one of items 1 to 17, or a pharma- ceutically acceptable salt thereof.

[0029] [Section 19] p is 1 or 2; R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, a halogen atom, or -OR 7 , or -MQ, or R 1 and R 2 and / or R 3 and R 4 Together, they are independently =O or =CR. 12A R 13A may form When there are multiple M's, each M is independently C 1-6 Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C 2-4 Alkynyl, C 1-3 Alkoxy, -CONR 36A R 37A , -NR 36A R 37A , -NR 36A COR 35A , -NR 36A SO2R 35A , -SO2R 35A , -SO2NR 36A R 37A and cyano), When there are multiple Qs, each Q is independently C 3-10 Cycloalkyl, 3-10 membered saturated heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl (the cycloalkyl, the saturated heterocyclic group, the aryl and the heteroaryl each independently represent a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, C 1-3 Alkyl, C 2-4 Alkynyl, C 1-3 Alkoxy, -CONR 36A R 37A , -NR 36A R 37A , -NR 36A COR 35A , -NR 36A SO2R 35A, -SO2R 35A , -SO2NR 36A R 37A and cyano), R 7 When there are a plurality of C groups, each C group may be independently substituted by a hydrogen atom or one phenyl group. 1-6 Alkyl or C 2-6 alkenyl, R 12A and R 13A are each independently a hydrogen atom, C 1-6 Alkyl (the alkyl is a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, C 2-4 Alkynyl, C 1-3 Alkoxy, -CONR 36A R 37A , -NR 36A R 37A , -NR 36A COR 35A , -NR 36A SO2R 35A , -SO2R 35A , -SO2NR 36A R 37A and cyano), C 3-10 Cycloalkyl, 3-10 membered saturated heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl (the cycloalkyl, the saturated heterocyclic group, the aryl and the heteroaryl each independently represent a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, C 1-3 Alkyl, C 2-4 Alkynyl, C 1-3 Alkoxy, -CONR 36A R 37A , -NR 36A R 37A , -NR 36A COR 37A , -NR 36A SO2R 35A , -SO2R 35A , -SO2NR 37A R 37Aand cyano, 12A or R 13A If there are multiple, R 12A or R 13A may be the same or different, where R 12A and R 13A Both are C 1-6 When they are alkyl, they may be joined together with the carbon atom to which they are attached to form a 3- to 8-membered saturated carbocyclic ring; R 35A However, if there are multiple, each is independently C 1-6 is alkyl, R 36A and R 37A are each independently a hydrogen atom or C 1-6 is alkyl, R 36A or R 37A If there are multiple, R 36A or R 37A may be the same or different, wherein each of R 36A and R 37A Both are C 1-6 When it is an alkyl group, it may form a 3- to 6-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which it is bonded. a, b, c and d are each independently 1 or 2; Item 19. The compound according to any one of items 1 to 18, or a pharma- ceutically acceptable salt thereof.

[0030] [Section 20] R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, a fluorine atom, or -MQ; or R 1 and R 2 and / or R 3 and R 4 Together, they are independently =O or =CR. 12A R 13A and 20. The compound according to any one of items 1 to 19, or a pharma- ceutically acceptable salt thereof.

[0031] [Section 21] When there are multiple M's, each M is independently C 1-3 Alkylene (the alkylene is a fluorine atom, C 2-4 Alkynyl, C 1-3 Alkoxy, -NR 36A R 37A and cyano), R 36A and R 37A are each independently a hydrogen atom or C 1-6 is alkyl, R 36A or R 37A If there are multiple, R 36A or R 37A may be the same or different, wherein each of R 36A and R 37A Both are C 1-6 When it is an alkyl group, it may form a 3- to 6-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which it is bonded. 21. The compound according to any one of items 1 to 20, or a pharma- ceutically acceptable salt thereof.

[0032] [Section 22] When there are multiple M's, each M is independently C 1-3 is alkylene, 22. The compound according to any one of items 1 to 21, or a pharma- ceutically acceptable salt thereof.

[0033] [Section 23] When there are multiple Qs, each Q is independently C 3-6 Cycloalkyl, a 3- to 6-membered saturated heterocyclic group, a phenyl, or a 5- to 6-membered heteroaryl (the cycloalkyl, the saturated heterocyclic group, the phenyl, and the heteroaryl each independently represent a fluorine atom, a chlorine atom, a bromine atom, C 1-3 Alkyl, C 2-4 Alkynyl, C 1-3 Alkoxy, -CONR36A R 37A , -NR 36A R 37A , -NR 36A COR 35A , -NR 36A SO2R 35A , -SO2R 35A , -SO2NR 36A R 37A and cyano), R 35A However, if there are multiple, each is independently C 1-6 is alkyl, R 36A and R 37A are each independently a hydrogen atom or C 1-6 is alkyl, R 36A or R 37A If there are multiple, R 36A or R 37A may be the same or different, wherein each of R 36A and R 37A Both are C 1-6 When it is an alkyl group, it may form a 3- to 6-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which it is bonded. 23. The compound according to any one of items 1 to 22, or a pharma- ceutically acceptable salt thereof.

[0034] [Section 24] When there are multiple Qs, each Q is independently C 3-6 Cycloalkyl, a 3- to 6-membered saturated heterocyclic group, a phenyl or a 5- to 6-membered heteroaryl (the cycloalkyl, the saturated heterocyclic group, the phenyl and the heteroaryl each independently represent a fluorine atom, C 1-3 Alkyl, -NR 36A SO2R 35A , -SO2NR 36A R 37A and cyano), R 35A However, if there are multiple, each is independently C 1-6is alkyl, R 36A and R 37A are each independently a hydrogen atom or C 1-6 is alkyl, R 36A or R 37A If there are multiple, R 36A or R 37A may be the same or different, wherein each of R 36A and R 37A Both are C 1-6 When it is an alkyl group, it may form a 3- to 6-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which it is bonded. 24. The compound according to any one of items 1 to 23, or a pharma- ceutically acceptable salt thereof.

[0035] [Section 25] When there are multiple Qs, each Q is independently C 3-6 Cycloalkyl (the cycloalkyl is a fluorine atom, C 1-3 Alkyl, -NR 36A SO2R 35A , -SO2NR 36A R 37A and cyano, 25. The compound according to any one of items 1 to 24, or a pharma- ceutically acceptable salt thereof.

[0036] [Section 26] R 12A and R 13A are each independently a hydrogen atom, C 1-6 Alkyl (the alkyl is a fluorine atom, -NR 36A SO2R 35A , -SO2NR 36A R 37A and cyano), C 3-10 Cycloalkyl (the cycloalkyl is a fluorine atom, C 1-3 Alkyl, -NR 36A SO2R 35A , -SO2NR 36A R37A and cyano, each of which may be the same or different, and 1 to 3 substituents selected from the group consisting of 12A or R 13A If there are multiple, R 12A or R 13A may be the same or different, where R 12A and R 13A Both are C 1-3 When they are alkyl, they may be joined together with the carbon atom to which they are attached to form a 3- to 6-membered saturated carbocyclic ring; R 35A However, if there are multiple, each is independently C 1-6 is alkyl, R 36A and R 37A are each independently a hydrogen atom or C 1-6 is alkyl, R 36A or R 37A If there are multiple, R 36A or R 37A may be the same or different, wherein each of R 36A and R 37A Both are C 1-6 When it is an alkyl group, it may form a 3- to 6-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which it is bonded. 26. The compound according to any one of items 1 to 25, or a pharma- ceutically acceptable salt thereof.

[0037] [Section 27] R 12A and R 13A are each independently a hydrogen atom, C 3-6 Cycloalkyl (the cycloalkyl is a fluorine atom, C 1-3 Alkyl, -NR 36A SO2R 35A , -SO2NR 36A R 37A and cyano, 12A and R 13A If there are multiple, R 12A and R 13Amay be the same or different, R 35A However, if there are multiple, each is independently C 1-6 is alkyl, R 36A and R 37A are each independently a hydrogen atom or C 1-6 is alkyl, R 36A or R 37A If there are multiple, R 36A or R 37A may be the same or different, wherein each of R 36A and R 37A Both are C 1-6 When it is an alkyl group, it may form a 3- to 6-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which it is bonded. 27. The compound according to any one of items 1 to 26, or a pharma- ceutically acceptable salt thereof.

[0038] [Section 28] a and c are 1, b and d are both 1 or 2; 28. The compound according to any one of items 1 to 27, or a pharma- ceutically acceptable salt thereof.

[0039] [Section 29] p is 1 or 2; R 1 , R 2 , R 3 and R 4 each independently represents a hydrogen atom, a fluorine atom, or -MQ, or R 1 and R 2 and / or R 3 and R 4 Together, they are independently =O or =CR. 12A R 13A may form When there are multiple M's, each M is independently C 1-3 represents alkylene, When there are multiple Qs, each Q is independently C 3-6 Cycloalkyl (the cycloalkyl is a fluorine atom, C1-3 Alkyl, -NR 36A SO2R 35A , -SO2NR 36A R 37A and cyano), R 12A and R 13A are each independently a hydrogen atom, C 3-6 Cycloalkyl (the cycloalkyl is a fluorine atom, C 1-3 Alkyl, -NR 36A SO2R 35A , -SO2NR 36A R 37A and cyano, 12A or R 13A If there are multiple, R 12A or R 13A may be the same or different, R 35A However, if there are multiple, each is independently C 1-6 is alkyl, R 36A and R 37A are each independently a hydrogen atom or C 1-6 is alkyl, R 36A or R 37A If there are multiple, R 36A or R 37A may be the same or different, wherein each of R 36A and R 37A Both are C 1-6 When they are alkyl, they may form a 3- to 6-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which they are bonded, a and c are 1, b and d are both 1 or 2; 29. The compound according to any one of items 1 to 28, or a pharma- ceutically acceptable salt thereof.

[0040] [Section 30] R 1 , R 2 , R3 and R 4 are each independently a hydrogen atom, a fluorine atom, or -MQ; or R 1 and R 2 and / or R 3 and R 4 But together and independently =CR 12A R 13A and 30. The compound according to any one of items 1 to 29, or a pharma- ceutically acceptable salt thereof.

[0041] [Section 31] M is methylene; 31. The compound according to any one of items 1 to 30, or a pharma- ceutically acceptable salt thereof.

[0042] [Section 32] When there are multiple Qs, each Q is independently C 3-6 Cycloalkyl (the cycloalkyl is a fluorine atom and C 1-3 alkyl, each of which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of 32. The compound according to any one of items 1 to 31, or a pharma- ceutically acceptable salt thereof.

[0043] [Section 33] When there are multiple Qs, each Q is independently C 3-6 is cycloalkyl, 33. The compound according to any one of items 1 to 32, or a pharma- ceutically acceptable salt thereof.

[0044] [Section 34] R 12A and R 13A are each independently a hydrogen atom or C 3-6 is cycloalkyl, 34. The compound according to any one of items 1 to 33, or a pharma- ceutically acceptable salt thereof.

[0045] [Section 35] R 12A and R 13A is a hydrogen atom, 35. The compound according to any one of items 1 to 34, or a pharma- ceutically acceptable salt thereof.

[0046] [Section 36] p is 1 or 2; R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, a fluorine atom, or -MQ; 1 and R 2 and / or R 3 and R 4 may be taken together to form =CH2, When there are two or more M's, each M is independently methylene; When there are multiple Qs, each Q is independently C 3-6 is cycloalkyl, a and c are 1, b and d are both 1 or 2; 36. The compound according to any one of items 1 to 35, or a pharma- ceutically acceptable salt thereof.

[0047] [Section 37] R 1 and R 2 is a hydrogen atom, R 3 and R 4 are each independently a hydrogen atom or a fluorine atom, However, R 3 and R 4 is not a hydrogen atom at the same time, 37. The compound according to any one of items 1 to 36, or a pharma- ceutically acceptable salt thereof.

[0048] [Section 38] R 1 and R 2 are each independently a hydrogen atom or -MQ; R 3 and R 4 are each independently a hydrogen atom or a fluorine atom, However, R 1 and R2 is not a hydrogen atom at the same time, 37. The compound according to any one of items 1 to 36, or a pharma- ceutically acceptable salt thereof.

[0049] [Section 39] R 1 is a hydrogen atom, R 2 But -MQ, R 3 is a hydrogen atom, R 4 is a hydrogen atom or a fluorine atom; 37. The compound according to any one of items 1 to 36, or a pharma- ceutically acceptable salt thereof.

[0050] [Section 40] R 1 But -MQ, R 2 is a hydrogen atom, R 3 is a hydrogen atom or a fluorine atom, R 4 is a hydrogen atom, 37. The compound according to any one of items 1 to 36, or a pharma- ceutically acceptable salt thereof.

[0051] [Section 41] R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, or R 1 and R 2 and / or R 3 and R 4 may be taken together to form =CH2, However, R 1 , R 2 , R 3 and R 4 are not all hydrogen atoms at the same time, 37. The compound according to any one of items 1 to 36, or a pharma- ceutically acceptable salt thereof.

[0052] [Section 42] R1 and R 2 Together, they are =CH2, R 3 and R 4 is a hydrogen atom, 37. The compound according to any one of items 1 to 36, or a pharma- ceutically acceptable salt thereof.

[0053] [Section 43] R 1 and R 2 is a hydrogen atom, R 3 and R 4 together, =CH2. 37. The compound according to any one of items 1 to 36, or a pharma- ceutically acceptable salt thereof.

[0054] [Section 44] a, b, c and d are 1; 44. The compound according to any one of items 1 to 43, or a pharma- ceutically acceptable salt thereof.

[0055] [Section 45] a and c are 1, b and d are 2; 44. The compound according to any one of items 1 to 43, or a pharma- ceutically acceptable salt thereof.

[0056] [Section 46] p is 1, Item 46. The compound according to any one of Items 1 to 45, or a pharma- ceutically acceptable salt thereof.

[0057] [Section 47] p is 2, Item 46. The compound according to any one of Items 1 to 45, or a pharma- ceutically acceptable salt thereof.

[0058] [Section 48] The compound according to item 1, selected from the following compounds, or a pharma- ceutically acceptable salt thereof: 2-[(4-{7-[(1S,3S,4R,6S)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide (Example 1), 2-[(4-{6-[(1S,3S,4R,6S)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide (Example 3), 2-[(4-{7-[(1S,3S,4R,6R)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide (Example 4), 2-[(4-{6-[(1S,3S,4R,6R)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide (Example 5), 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (Example 6), 5-fluoro-2-[(4-{6-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (Example 7), 5-fluoro-2-[(4-{7-[(1S,3S,4R)-6-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (Example 8), 5-fluoro-2-[(4-{6-[(1S,3S,4R)-6-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (Example 9), 5-fluoro-2-[(4-{6-[(1S,3S,4S,5S)-5-fluoro-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (Example 10), 2-[(4-{6-[(1R,3S,4R)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide (Example 11), 5-Fluoro-2-[(4-{7-[(1S,3S,4S)-5-oxo-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (Example 12), 2-[(4-{7-[(1S,3S,4S,5S,6S)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide (Example 14), 2-[(4-{6-[(1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide (Example 15), 2-[(4-{7-[(1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide (Example 16), 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.1]heptane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (Example 18), 2-[(4-{7-[(1S,3S,4S,5R,6R)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide (Example 19) and 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-( 2 H2) Methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (Example 20).

[0059] [Section 49] The compound according to item 1, selected from the following compounds, or a pharma- ceutically acceptable salt thereof: 2-[(4-{7-[(1S,3S,4R,6S)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide (Example 1), 2-[(4-{6-[(1S,3S,4R,6S)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide (Example 3), 2-[(4-{7-[(1S,3S,4R,6R)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide (Example 4) and 2-[(4-{6-[(1S,3S,4R,6R)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide (Example 5).

[0060] [Section 50] The compound according to item 1, or a hydrochloride, L(+)-tartrate or succinate thereof, selected from the following compounds: 2-[(4-{7-[(1S,3S,4R,6S)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide (Example 1), 2-[(4-{6-[(1S,3S,4R,6S)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide (Example 3), 2-[(4-{7-[(1S,3S,4R,6R)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide (Example 4) and 2-[(4-{6-[(1S,3S,4R,6R)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide (Example 5).

[0061] [Section 51] The compound according to item 1, selected from the following compounds, or a pharma- ceutically acceptable salt thereof: 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (Example 6), 5-fluoro-2-[(4-{6-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (Example 7), 2-[(4-{6-[(1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide (Example 15), 2-[(4-{7-[(1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide (Example 16), 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.1]heptane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (Example 18) and 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-( 2 H2) Methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (Example 20).

[0062] [Section 52] The compound according to item 1, or a hydrochloride, L(+)-tartrate or succinate thereof, selected from the following compounds: 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (Example 6), 5-fluoro-2-[(4-{6-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (Example 7), 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.1]heptane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (Example 18) and 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-( 2 H2) Methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (Example 20).

[0063] [Section 53] 2-[(4-{7-[(1S,3S,4R,6S)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide (Example 1) or its hydrochloride, L(+)-tartrate or succinate.

[0064] [Section 54] 2-[(4-{6-[(1S,3S,4R,6S)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide (Example 3) or its hydrochloride, L(+)-tartrate or succinate.

[0065] [Section 55] 2-[(4-{7-[(1S,3S,4R,6R)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide (Example 4) or its hydrochloride, L(+)-tartrate or succinate.

[0066] [Section 56] 2-[(4-{6-[(1S,3S,4R,6R)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide (Example 5) or its hydrochloride, L(+)-tartrate or succinate.

[0067] [Section 57] 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (Example 6) or its hydrochloride, L(+)-tartrate or succinate.

[0068] [Section 58] 5-Fluoro-2-[(4-{6-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (Example 7) or its hydrochloride, L(+)-tartrate or succinate.

[0069] [Section 59] 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.1]heptane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (Example 18) or its hydrochloride, L(+)-tartrate or succinate.

[0070] [Section 60] 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-( 2H2) Methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]non-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (Example 20) or its hydrochloride, L(+)-tartrate or succinate.

[0071] [Section 61] 61. A medicine comprising the compound according to any one of items 1 to 60 or a pharma- ceutically acceptable salt thereof as an active ingredient.

[0072] [Section 62] 61. An antitumor agent comprising the compound according to any one of items 1 to 60 or a pharma- ceutically acceptable salt thereof as an active ingredient.

[0073] [Section 63] Tumors include acute leukemia (including MLL acute leukemia, MLL partial tandem duplication acute leukemia, NPM mutant acute leukemia, MOZ acute leukemia, NUP98 acute leukemia, and CALM acute leukemia), chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma (including B-cell lymphoma), myeloma (including multiple myeloma), brain tumors, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, Item 63. The antitumor agent according to Item 62, which is breast cancer, gastric cancer, gallbladder / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, anal cancer, chorioepithelial cancer, uterine cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial cancer, kidney cancer, renal cell carcinoma, prostate cancer, testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, or skin cancer.

[0074] [Section 64] Item 64. The antitumor agent according to Item 62 or 63, wherein the tumor is acute leukemia (including MLL acute leukemia, MLL partial tandem duplication acute leukemia, NPM mutated acute leukemia, MOZ acute leukemia, NUP98 acute leukemia, and CALM acute leukemia), chronic myeloid leukemia, malignant lymphoma (including B-cell lymphoma), myeloma (including multiple myeloma), brain tumor, prostate cancer, breast cancer, neuroblastoma, Ewing's sarcoma, or liver cancer.

[0075] [Section 65] Item 65. The antitumor agent according to any one of Items 62 to 64, wherein the tumor is MLL acute leukemia, MLL partial tandem duplication acute leukemia, NPM mutated acute leukemia, MOZ acute leukemia, NUP98 acute leukemia, CALM acute leukemia, chronic myeloid leukemia, B-cell lymphoma, multiple myeloma, neuroblastoma, or prostate cancer.

[0076] [Section 66] Item 66. The antitumor agent according to any one of Items 62 to 65, wherein the tumor is MLL acute leukemia, MLL partial tandem duplication acute leukemia, NPM mutant acute leukemia, MOZ acute leukemia, NUP98 acute leukemia, CALM acute leukemia, chronic myeloid leukemia, B cell lymphoma, or multiple myeloma.

[0077] [Section 67] Item 67. The antitumor agent according to any one of Items 62 to 66, wherein the tumor is MLL acute leukemia or NPM-mutated acute leukemia.

[0078] [Section 68] Item 68. The antitumor agent according to any one of Items 62 to 67, wherein the tumor is a tumor accompanied by high expression of the HOXa gene group or the MEIS gene group.

[0079] [Section 69] Item 69. The antitumor agent according to any one of Items 62 to 68, wherein the tumor is a tumor associated with a p53 gain-of-function mutation.

[0080] [Section 70] A method for treating a tumor, comprising administering the compound according to any one of items 1 to 60 or a pharma- ceutically acceptable salt thereof to a patient in need of such treatment.

[0081] [Section 71] The method of claim 70, wherein the tumor is a Menin-MLL-associated tumor.

[0082] [Section 72] Item 61. Use of the compound or a pharma- ceutically acceptable salt thereof according to any one of Items 1 to 60 for the manufacture of an antitumor agent.

[0083] [Section 73] Item 61. The compound or a pharma- ceutically acceptable salt thereof according to any one of items 1 to 60 for use in treating a tumor.

[0084] [Section 74] A pharmaceutical composition comprising the compound according to any one of items 1 to 60 or a pharma- ceutical acceptable salt thereof in combination with another drug or a pharma- ceutical acceptable salt thereof, wherein the other drug is at least one selected from the group consisting of antitumor alkylating agents, antitumor antimetabolites, antitumor antibiotics, plant-derived antitumor agents, antitumor platinum coordination compounds, antitumor camptothecin derivatives, antitumor tyrosine kinase inhibitors, antitumor serine-threonine kinase inhibitors, antitumor phospholipid kinase inhibitors, antitumor monoclonal antibodies, interferons, biological response modifiers, hormone preparations, angiogenesis inhibitors, immune checkpoint inhibitors, epigenetics-related molecule inhibitors, protein post-translational modification inhibitors, proteasome inhibitors, and other antitumor agents.

[0085] [Section 75] Item 60. The compound or pharma- ceutical acceptable salt thereof according to any one of Items 1 to 60, for use in combination with another drug or a pharma- ceutical acceptable salt thereof to treat a tumor, wherein the other drug is at least one selected from the group consisting of an antitumor alkylating agent, an antitumor antimetabolite, an antitumor antibiotic, a plant-derived antitumor drug, an antitumor platinum coordination compound, an antitumor camptothecin derivative, an antitumor tyrosine kinase inhibitor, an antitumor serine threonine kinase inhibitor, an antitumor phospholipid kinase inhibitor, an antitumor monoclonal antibody, an interferon, a biological response modifier, a hormone preparation, an angiogenesis inhibitor, an immune checkpoint inhibitor, an epigenetics-related molecule inhibitor, a protein post-translational modification inhibitor, a proteasome inhibitor, and other antitumor agents, or a pharma-ceutical acceptable salt thereof. Effect of the Invention

[0086] The present invention provides a binding inhibitor between menin and MLL fusion protein, which comprises an optically active azabicyclo derivative or a pharma- ceutical acceptable salt thereof. The compound of the present invention is useful as a therapeutic agent for diseases involving the binding between menin and MLL, and is specifically applicable to patients with MLL acute leukemia, NPM mutant acute leukemia, prostate cancer, breast cancer, Ewing's sarcoma, liver cancer, p53 gain-of-function mutant cancer, etc. [Brief description of the drawings]

[0087] [Figure 1] 2 shows the powder X-ray diffraction pattern of Form I crystal of the compound of Example 21. The horizontal axis shows the diffraction angle 2θ (°), and the vertical axis shows the count number (the same applies to Figs. 2 to 5 below). [Diagram 2] 1 shows the powder X-ray diffraction pattern of Form II crystal of the compound of Example 22. [Diagram 3] 1 shows the powder X-ray diffraction pattern of the crystal form III of the compound of Example 23. [Figure 4] 4 shows the powder X-ray diffraction pattern of Form IV crystal of the compound of Example 24. [Diagram 5] 1 shows the powder X-ray diffraction pattern of Form V crystal of the compound of Example 25. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0088] The terms used in this specification are explained below.

[0089] The term "halogen atom" includes, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc. A fluorine atom is preferable.

[0090] "C 1-6 "Alkyl" means an alkyl having 1 to 6 carbon atoms, and "C6 alkyl" means an alkyl having 6 carbon atoms, and similarly for other numbers.

[0091] "C 1-6 "Alkyl" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. 1-6 As the alkyl, preferably "C 1-4 alkyl" and more preferably "C 1-3 "C alkyl" is one example. 1-3 Specific examples of "alkyl" include methyl, ethyl, propyl, 1-methylethyl, etc. 1-4 Specific examples of "alkyl" include the above-mentioned "C 1-3 In addition to the specific examples of "alkyl", butyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl, etc. are also included. 1-6 Specific examples of "alkyl" include the above-mentioned "C 1-4 In addition to the specific examples of "alkyl", pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, hexyl, and the like are included.

[0092] "C 2-6 "Alkenyl" means a straight or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing 1 to 3 double bonds. 2-6Alkenyl is preferably "C 2-4 Alkenyl" is one example. 2-4 Specific examples of "alkenyl" include vinyl, propenyl, methylpropenyl, butenyl, etc. 2-6 Specific examples of alkenyl include the above-mentioned "C 2-4 In addition to the specific examples of "alkenyl", pentenyl, hexenyl, etc. are included.

[0093] "C 2-6 The term "alkynyl" refers to a straight or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing one triple bond. 2-6 Alkynyl" is preferably "C 2-4 "Alkynyl" is one example. 2-4 Specific examples of "alkynyl" include propynyl, methylpropynyl, butynyl, etc. 2-6 Specific examples of alkynyl include the above-mentioned "C 2-4 In addition to the specific examples of "alkynyl", methylbutynyl, pentynyl, hexynyl, etc. are included.

[0094] "C 1-6 Alkoxy means "C 1-6 "C alkyloxy" 1-6 The "C alkyl" portion is 1-6 "C" is synonymous with "alkyl". 1-6 The "alkoxy" is preferably "C 1-4 Alkoxy" is preferred, and "C 1-3 "Alkoxy" is one example. 1-3 Specific examples of "alkoxy" include methoxy, ethoxy, propoxy, 1-methylethoxy, etc. 1-4 Specific examples of "alkoxy" include the above-mentioned "C 1-3 In addition to the specific examples of "alkyl", butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, 2-methylpropoxy, etc. are also included. 1-6 Specific examples of "alkoxy" include the above-mentioned "C 1-4In addition to the specific examples of "alkyl", pentyloxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, hexyloxy, and the like.

[0095] "C 1-6 "Alkylene" means a linear or branched divalent saturated hydrocarbon group having 1 to 6 carbon atoms. 1-6 As the alkylene, preferably "C 1-4 alkylene", more preferably "C 1-3 "C alkylene" is one example. 1-3 Specific examples of "alkylene" include methylene, ethylene, propylene, trimethylene, etc. 1-4 Specific examples of alkylene include the above-mentioned "C 1-3 In addition to the specific examples of "alkylene", butylene, 1,1-dimethylethylene, 1,2-dimethylethylene, 1-methyltrimethylene, 2-methyltrimethylene, etc. are also included. 1-6 Specific examples of alkylene include the above-mentioned "C 1-4 In addition to the specific examples of "alkylene", pentylene, 1,1-dimethyltrimethylene, 1,2-dimethyltrimethylene, 1-methylbutylene, 2-methylbutylene, 1-methylpentylene, 2-methylpentylene, 3-methylpentylene, hexylene, and the like can be mentioned.

[0096] "C 2-6 The term "alkenylene" refers to a straight-chain or branched-chain divalent unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing 1 to 3 double bonds. 2-6 As the alkenylene, preferably, 2-4 Alkenylene" is one example. 2-4 Specific examples of "alkenylene" include vinylene, propenylene, methylpropenylene, butenylene, etc. 2-6 Specific examples of alkenylene include the above-mentioned "C 2-4In addition to the specific examples of "alkenyl", pentenylene, hexenylene, etc. are included.

[0097] "C 2-6 The term "alkynylene" refers to a straight-chain or branched-chain divalent unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing 1 to 3 triple bonds. 2-6 As the alkynylene, preferably, 2-4 Alkynylene" is one example. 2-4 Specific examples of "alkynylene" include, for example, ethynylene, propynylene, butynylene, etc. 2-6 Specific examples of alkynylene include the above-mentioned "C 2-4 In addition to the specific examples of "alkynylene", methylbutynylene, pentynylene, hexynylene, etc. are included.

[0098] "C 3-10 "Cycloalkyl" means a cyclic saturated hydrocarbon group having 3 to 10 carbon atoms, including those having a partially unsaturated bond and those having a bridged structure. 3-10 Cycloalkyl" is preferably "C 3-7 "Cycloalkyl" is one example. 3-7 Specific examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. 3-10 Specific examples of "cycloalkyl" include the above-mentioned "C 3-7 In addition to the specific examples of "cycloalkyl", cyclooctyl, cyclononyl, cyclodecyl, adamantyl, etc. are included. Also, "C 3-10 "Cycloalkyl" includes the above C 3-10 Bicyclic compounds in which a cycloalkyl group and an aromatic hydrocarbon ring are condensed are also included. Specific examples of such condensed compounds include the structures shown below. [ka]

[0099] "C 3-10 "Cycloalkylene" means a cyclic divalent saturated hydrocarbon group having 3 to 10 carbon atoms, and includes those having a partially unsaturated bond and those having a crosslinked structure. 3-10 Cycloalkylene is preferably "C 3-7 "Cycloalkylene" is one example. 3-7 Specific examples of "cycloalkylene" include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, and the like. 3-10 Specific examples of "cycloalkyl" include the above-mentioned "C 3-7 In addition to the specific examples of "cycloalkyl", cyclooctylene, cyclononylene, cyclodecylene, adamantylene, etc. are included.

[0100] The term "3- to 8-membered saturated carbocyclic ring" refers to a cyclic saturated hydrocarbon having 3 to 8 carbon atoms. A preferred example of the "3- to 8-membered saturated carbocyclic ring" is a "4- to 6-membered saturated carbocyclic ring". Specific examples of the "4- to 6-membered saturated carbocyclic ring" include a cyclobutane ring, a cyclopentane ring, and a cyclohexane ring. Specific examples of the "3- to 8-membered saturated carbocyclic ring" include the above-mentioned specific examples of the "4- to 6-membered saturated carbocyclic ring", as well as a cyclopropane ring, a cycloheptane ring, and a cyclooctane ring.

[0101] The term "3- to 10-membered saturated heterocyclic group" refers to a monovalent or divalent saturated heterocyclic group composed of 1 to 2 atoms independently selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms, and 2 to 9 carbon atoms, and includes those having a partially unsaturated bond and those having a bridged structure. The atoms constituting the ring may include those oxidized, such as -C(O)-, -S(O)-, and -SO2-. The "3- to 10-membered saturated heterocyclic group" is preferably a "4- to 7-membered monocyclic saturated heterocyclic group", and more preferably a "5- or 6-membered monocyclic saturated heterocyclic group". Specific examples of the "5- or 6-membered monocyclic saturated heterocyclic group" include, for example, tetrahydrofuryl, pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxooxazolidinyl, dioxooxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyl, tetrahydropi Examples of the "4- to 7-membered monocyclic saturated heterocyclic group" include, in addition to the specific examples of the "5- or 6-membered monocyclic saturated heterocyclic group", oxetanyl, azetidinyl, oxetanylene, azetidinylene, etc. Examples of the "4- to 7-membered monocyclic saturated heterocyclic group" include oxetanyl, azetidinyl, azetidinylene, etc. Examples of the "3- to 10-membered saturated heterocyclic group" include, in addition to the specific examples of the "4- to 7-membered monocyclic saturated heterocyclic group", oxiranyl, aziridinyl, oxiranylene, aziridinylene, etc. The "3- to 10-membered saturated heterocyclic group" also includes a bicyclic group in which the 3- to 10-membered saturated heterocyclic group and a 6-membered aromatic hydrocarbon ring or a 6-membered aromatic heterocyclic ring form a condensed ring. Examples of the 6-membered aromatic hydrocarbon ring forming the condensed ring include a benzene ring. Examples of the 6-membered aromatic heterocyclic ring forming the condensed ring include pyridine, pyrimidine, and pyridazine. Specific examples of the bicyclic "3- to 10-membered saturated heterocyclic group" forming a fused ring include dihydroindolyl, dihydroisoindolyl, dihydropurinyl, dihydrothiazolopyrimidinyl, dihydrobenzodioxanyl, isoindolyl, indazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydronaphthyridinyl, dihydroindolylene, dihydroisoindolylene, dihydropurinylene, dihydrothiazolopyrimidinylene, dihydrobenzodioxanylene, isoindolylene, indazolylene, tetrahydroquinolinylene, tetrahydroisoquinolinylene, tetrahydronaphthyridinylene, and the like.

[0102] The term "3- to 8-membered nitrogen-containing saturated heterocycle" refers to a saturated heterocycle composed of one nitrogen atom and 2 to 7 carbon atoms. The "3- to 8-membered nitrogen-containing saturated heterocycle" is preferably a "4- to 6-membered nitrogen-containing saturated heterocycle". Specific examples of the "4- to 6-membered nitrogen-containing saturated heterocycle" include an azetidine ring, a pyrrolidine ring, and a piperidine ring. Specific examples of the "3- to 8-membered nitrogen-containing saturated heterocycle" include, in addition to the specific examples of the "4- to 6-membered nitrogen-containing saturated heterocycle", an aziridine ring, an azepane ring, and an azocane ring.

[0103] "C 6-10 "Aryl" means an aromatic hydrocarbon ring group having 6 to 10 carbon atoms. 6-10 Specific examples of "aryl" include phenyl, 1-naphthyl, 2-naphthyl, etc. Preferably, phenyl is used. Also, "C 6-10 "Aryl" includes the above C 6-10 Aryl and C 4-6Also included are bicyclic rings formed by condensing with a cycloalkyl or a 5-6 membered saturated heterocycle. 6-10 Specific examples of "aryl" include the groups shown below. [ka]

[0104] "C 6-10 "Arylene" means a divalent aromatic hydrocarbon ring group having 6 to 10 carbon atoms. 6-10 Specific examples of "arylene" include phenylene, 1-naphthylene, 2-naphthylene, etc. Phenylene is preferable.

[0105] The "aromatic hydrocarbon ring" refers to the above "C 6-10 Aryl" and the above "C 6-10 It means the ring portion of "arylene."

[0106] The term "5-12-membered heteroaryl" refers to a monocyclic 5- to 7-membered aromatic heterocyclic ring group or a bicyclic 8- to 12-membered aromatic heterocyclic ring group containing 1 to 4 atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. A "5- to 7-membered monocyclic heteroaryl" is preferred. A pyridyl, pyrimidinyl, quinolyl, or isoquinolyl is more preferred. A pyridyl is even more preferred. Specific examples of the "5- to 7-membered monocyclic heteroaryl" include pyridyl, pyridazinyl, isothiazolyl, pyrrolyl, furyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, triazinyl, triazolyl, oxadiazolyl, triazolyl, and tetrazolyl. Specific examples of the "5- to 12-membered heteroaryl" include, in addition to the specific examples of the "5- to 7-membered monocyclic heteroaryl", indolyl, indazolyl, chromenyl, quinolyl, isoquinolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzimidazolyl, etc.

[0107] The term "5- to 12-membered heteroarylene" refers to a divalent monocyclic 5- to 7-membered aromatic heterocycle or a divalent bicyclic 8- to 12-membered aromatic heterocycle containing 1 to 4 atoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms. A "5- to 7-membered monocyclic heteroarylene" is preferred. A pyridylene, pyrimidylene, quinolylene, or isoquinolylene is more preferred. A pyridylene is even more preferred. Specific examples of the "5- to 7-membered monocyclic heteroarylene" include pyridylene, pyridazinylene, isothiazolylene, pyrrolylene, furylene, thienylene, thiazolylene, imidazolylene, pyrimidinylene, thiadiazolylene, pyrazolylene, oxazolylene, isoxazolylene, pyrazinylene, triazinylene, triazolylene, oxadiazolylene, triazolylene, and tetrazolylene. Specific examples of the "5- to 12-membered heteroarylene" include, in addition to the specific examples of the "5- to 7-membered monocyclic heteroarylene", indolylene, indazolylene, chromenylene, quinolylene, isoquinolylene, benzofuranylene, benzothienylene, benzoxazolylene, benzothiazolylene, benzoisoxazolylene, benzoisothiazolylene, benzotriazolylene, benzimidazolylene, and the like.

[0108] The term "aromatic heterocycle" means the ring portion of the above "5- to 12-membered heteroaryl" and the above "5- to 12-membered heteroarylene".

[0109] In this specification, a bond traversing a ring as represented by the following formula (W) means that a "group" is bonded at a substitutable position on the group. For example, the following formula (W): [ka] When represented by the following formula (W-1), (W-2) or (W-3): [ka] This means that.

[0110] In the present specification, the stereochemistry of the substituents in the compound represented by formula (1) and the compounds described in the Examples is, for example, as illustrated below. [ka] Here, a wedge-shaped bond represents a substituent on the front side of the page, a dashed bond represents a substituent on the back side of the page, a wavy bond represents that the substituents on the front side and the back side of the page are present in any ratio, and a straight bond extending outward from a ring represents that the substituent is either on the front side or the back side of the page.

[0111] In the present invention, "cancer" and "tumor" are synonymous and both refer to malignant tumors, including carcinomas, sarcomas, and hematological malignancies. Specific examples of "cancer" or "tumor" include acute leukemia (including MLL acute leukemia, MLL partial tandem duplication acute leukemia, NPM mutant acute leukemia, MOZ acute leukemia, NUP98 acute leukemia, and CALM acute leukemia), chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma (including B-cell lymphoma), myeloma (including multiple myeloma), brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, Small cell lung cancer, non-small cell lung cancer, breast cancer, gastric cancer, gallbladder / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, anal cancer, chorioepithelial cancer, uterine cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial cancer, kidney cancer, renal cell carcinoma, prostate cancer, testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, skin cancer, etc. may be included. In addition, the above tumors may be accompanied by an increase in expression or mutation of a specific gene. Examples of tumors accompanied by an increase in gene expression include tumors accompanied by high expression of the HOXa gene group, tumors accompanied by high expression of the MEIS gene group, etc. In addition, examples of tumors accompanied by gene mutations include tumors accompanied by p53 gain-of-function mutations, etc.

[0112] In the compound of the present invention represented by formula (1), p, X, Y, Z, M, Q, a, b, c, d, U, R 1 , R2 , R 3 , R 4 , R 5A , R 5B , R 6A , R 6B , R 6C , R 6D , R 7 , R 8 , R 9 , R 10 , R 11 , R 12A , R 12B , R 13A , R 13B , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35A , R 35B , R 36A , R 36B , R 37A and R 37B The preferred ones are as follows, but the technical scope of the present invention is not limited to the range of the compounds listed below.

[0113] One embodiment of p is 1. Furthermore, one embodiment of p is 2.

[0114] X is preferably -C(O)-.

[0115] Y is preferably --O--.

[0116] Z is preferably (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8) or (Z-9). More preferably, it is (Z-3).

[0117] M is preferably a fluorine atom, C 2-4 Alkynyl, C 1-3 Alkoxy, -NR 36A R 37A and cyano, 1-3 More preferably, C 1-3 Alkylene is preferable. More preferable is methylene.

[0118] Q is preferably a fluorine atom, C 1-3 Alkyl, -NR 36A SO2R 35A , -SO2NR 36A R 37A and cyano, 3-6 Cycloalkyl; Fluorine atom, C 1-3 Alkyl, -NR 36A SO2R 35A , -SO2NR 36A R 37A a 3- to 6-membered saturated heterocyclic group which may be substituted by 1 to 3 identical or different substituents selected from the group consisting of cyano, and a fluorine atom; 1-3 Alkyl, -NR 36A SO2R 35A , -SO2NR 36A R 37A and cyano; 1-3 Alkyl, -NR 36A SO2R 35A , -SO2NR 36A R 37A and cyano. More preferred are fluorine atoms, C1-3 Alkyl, -NR 36A SO2R 35A , -SO2NR 36A R 37A and cyano, 3-6 Cycloalkyl is more preferred. 1-3 C, which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl 3-6 Cycloalkyl is particularly preferred. 3-6 It is cycloalkyl.

[0119] As a and c, 1 is preferable.

[0120] One embodiment of b and d both includes 1. Furthermore, one embodiment of b and d both includes 2.

[0121] U is preferably a nitrogen atom.

[0122] R 1 is preferably a hydrogen atom or -MQ.

[0123] R 2 is preferably a hydrogen atom or -MQ.

[0124] R 3 is preferably a hydrogen atom or a fluorine atom.

[0125] R 4 is preferably a hydrogen atom or a fluorine atom.

[0126] R 1 and R 2 As another embodiment of the present invention, R 1 and R 2 Together, =CR 12A R 13A More preferably, =CH2 is formed.

[0127] R 3 and R 4 As another embodiment of the present invention, R 3 and R 4 Together, =CR 12A R 13A More preferably, =CH2 is formed.

[0128] R 1 , R 2 , R 3 and R 4 As another embodiment of the present invention, R 1 is a hydrogen atom, R 2 -MQ,R 3 is a hydrogen atom, R 4 is a hydrogen atom or a fluorine atom.

[0129] R 1 , R 2 , R 3 and R 4 As another embodiment of the present invention, R 1 -MQ,R 2 is a hydrogen atom, R 3 is a hydrogen atom or a fluorine atom, R 4 is a hydrogen atom.

[0130] R 1 , R 2 , R 3 and R 4 As another embodiment of the present invention, R 1 and R 2 are both hydrogen atoms, and R 3 and R 4 together to form =CH2.

[0131] R 1 , R 2 , R 3 and R 4 As another embodiment of the present invention, R 3 and R 4 are both hydrogen atoms, and R 1 and R 2 together to form =CH2.

[0132] R 1 , R 2 , R 3 and R 4 As another embodiment of the present invention, R 1 and R 2 are both hydrogen atoms, and R 3 is a hydrogen atom, R 4 is a fluorine atom.

[0133] R 1 , R 2 , R 3 and R 4 As another embodiment of the present invention, R 1 and R 2 are both hydrogen atoms, and R 3 is a fluorine atom, R 4 is a hydrogen atom.

[0134] R 5A and R 5B is preferably a hydrogen atom.

[0135] R 6A , R 6B and R 6D is preferably a hydrogen atom.

[0136] R 6C is preferably a fluorine atom.

[0137] R 7 is preferably a hydrogen atom, or C optionally substituted with one phenyl 1-6 Alkyl or C 2-6 Alkenyl is an example.

[0138] R 8 , R 14 , R 18 , R 25 , R 31 , R 35A and R 35B As the above, preferably C 1-3 It is an alkyl.

[0139] R9 , R 10 , R 11 , R 15 , R 16 , R 17 , R 19 , R 20 , R 21 , R 23 , R 24 , R 26 , R 27 , R 28 , R 29 , R 30 , R 32 , R 33 , R 34 , R 36A , R 36B , R 37A and R 37B is preferably a hydrogen atom or C 1-3 Examples of such alkyl groups include alkyl.

[0140] R 12A and R 13A is preferably a hydrogen atom or a fluorine atom, C 1-3 Alkyl, -NR 36A SO2R 35A , -SO2NR 36A R 37A and cyano, 3-6 Cycloalkyl is preferred. A hydrogen atom is more preferred.

[0141] R 12B and R 13B As the above, preferably C 1-3 It is an alkyl.

[0142] R 22 is preferably -CF3 or cyano.

[0143] One embodiment of the compound of the present invention represented by formula (1) includes the following (A). (A) Formula (1) is formula (1a), p is 1 or 2; R1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, a fluorine atom, or -MQ; or R 1 and R 2 and / or R 3 and R 4 Together, they are independently =O or =CR. 12A R 13A and When there are multiple M's, each M is independently C 1-3 is alkylene, When there are multiple Qs, each Q is independently C 3-6 Cycloalkyl (the cycloalkyl is a fluorine atom, C 1-3 Alkyl, -NR 36A SO2R 35A , -SO2NR 36A R 37A and cyano), R 12A and R 13A are each independently a hydrogen atom, C 3-6 Cycloalkyl (the cycloalkyl is a fluorine atom, C 1-3 Alkyl, -NR 36A SO2R 35A , -SO2NR 36A R 37A and cyano), R 35A However, if there are multiple, each is independently C 1-6 is alkyl, R 36A and R 37A are each independently a hydrogen atom or C 1-6 is alkyl, R 36A or R 37A If there are multiple, R 36A or R 37A may be the same or different, wherein each of R 36A and R 37A Both are C1-6 When they are alkyl, they may form a 3- to 6-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which they are bonded, a and c are 1, b and d are both 1 or 2; A compound or a pharma- ceutically acceptable salt thereof.

[0144] One embodiment of the compound of the present invention represented by formula (1) includes the following (B). (B) p is 1 or 2; R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, a fluorine atom, or -MQ; or R 1 and R 2 and / or R 3 and R 4 Together, they are independently =O or =CR. 12A R 13A may form When there are multiple M's, each M is independently C 1-3 is alkylene, When there are multiple Qs, each Q is independently C 3-6 Cycloalkyl (the cycloalkyl is a fluorine atom, C 1-3 Alkyl, -NR 36A SO2R 35A , -SO2NR 36A R 37A and cyano), R 12A and R 13A are each independently a hydrogen atom, C 3-6 Cycloalkyl (the cycloalkyl is a fluorine atom, C 1-3 Alkyl, -NR 36A SO2R 35A , -SO2NR 36A R 37Aand cyano), R 35A However, if there are multiple, each is independently C 1-6 is alkyl, R 36A and R 37A are each independently a hydrogen atom or C 1-6 is alkyl, R 36A or R 37A If there are multiple, R 36A or R 37A may be the same or different, wherein each of R 36A and R 37A Both are C 1-6 When they are alkyl, they may form a 3- to 6-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which they are bonded, X is -C(O)-; a and c are 1, b and d are both 1 or 2; R 5A , R 5B , R 6A , R 6B and R 6D is a hydrogen atom, R 6C is a fluorine atom, U is a nitrogen atom, Y is -O-; Z is (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8) or (Z-9), A compound or a pharma- ceutically acceptable salt thereof.

[0145] One embodiment of the compound of the present invention represented by formula (1) includes the following (C). (C) p is 1 or 2; R 1 , R 2 , R 3 and R 4are each independently a hydrogen atom, a fluorine atom, or -MQ; or R 1 and R 2 and / or R 3 and R 4 Together, they are independently =O or =CR. 12A R 13A may form When there are multiple M's, each M is independently C 1-3 is alkylene, When there are multiple Qs, each Q is independently C 3-6 Cycloalkyl (the cycloalkyl is a fluorine atom, C 1-3 Alkyl, -NR 36A SO2R 35A , -SO2NR 36A R 37A and cyano), R 12A and R 13A are each independently a hydrogen atom, C 3-6 Cycloalkyl (the cycloalkyl is a fluorine atom, C 1-3 Alkyl, -NR 36A SO2R 35A , -SO2NR 36A R 37A and cyano), R 35A However, if there are multiple, each is independently C 1-6 is alkyl, R 36A and R 37A are each independently a hydrogen atom or C 1-6 is alkyl, R 36A or R 37A If there are multiple, R 36A or R 37A may be the same or different, wherein each of R 36A and R 37A Both are C 1-6When they are alkyl, they may form a 3- to 6-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which they are bonded, X is -C(O)-; a and c are 1, b and d are both 1 or 2; R 5A , R 5B , R 6A , R 6B and R 6D is a hydrogen atom, R 6C is a fluorine atom, U is CR 22 and R 22 is -CF3 or cyano, Y is -O-; Z is (Z-3); A compound or a pharma- ceutically acceptable salt thereof.

[0146] One embodiment of the compound of the present invention represented by formula (1) includes the following (D). (D) Formula (1) is formula (1a), p is 1 or 2; R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, a fluorine atom, or -MQ; 1 and R 2 and / or R 3 and R 4 may be taken together to form =CH2, When there are two or more M's, each M is independently methylene; When there are multiple Qs, each Q is independently C 3-6 is cycloalkyl, a and c are 1, b and d are both 1 or 2; A compound or a pharma- ceutically acceptable salt thereof.

[0147] One embodiment of the compound of the present invention represented by formula (1) includes the following (E). (E) p is 1 or 2; R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, a fluorine atom, or -MQ; 1 and R 2 and / or R 3 and R 4 may be taken together to form =CH2, When there are two or more M's, each M is independently methylene; When there are multiple Qs, each Q is independently C 3-6 is cycloalkyl, X is -C(O)-; a and c are 1, b and d are both 1 or 2; R 5A , R 5B , R 6A , R 6B and R 6D is a hydrogen atom, R 6C is a fluorine atom, U is a nitrogen atom, Y is -O-; Z is (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8) or (Z-9), A compound or a pharma- ceutically acceptable salt thereof.

[0148] One embodiment of the compound of the present invention represented by formula (1) includes the following (F). (F) p is 1 or 2; R 1 , R 2 , R 3 and R 4are each independently a hydrogen atom, a fluorine atom, or -MQ; 1 and R 2 and / or R 3 and R 4 may be taken together to form =CH2, When there are two or more M's, each M is independently methylene; When there are multiple Qs, each Q is independently C 3-6 is cycloalkyl, X is -C(O)-; a and c are 1, b and d are both 1 or 2; R 5A , R 5B , R 6A , R 6B and R 6D is a hydrogen atom, R 6C is a fluorine atom, U is CR 22 and R 22 is -CF3 or cyano, Y is -O-; Z is (Z-3); A compound or a pharma- ceutically acceptable salt thereof.

[0149] One embodiment of the compound of the present invention represented by formula (1) includes the following (G). (G) Formula (1) is formula (1a), p is 1 or 2; R 1 and R 2 is a hydrogen atom, R 3 and R 4 are each independently a hydrogen atom or a fluorine atom, a and c are 1, b and d are both 1 or 2; However, R 3 and R 4 is not a hydrogen atom at the same time, A compound or a pharma- ceutically acceptable salt thereof.

[0150] One embodiment of the compound of the present invention represented by formula (1) includes the following (H). (H) p is 1 or 2; R 1 and R 2 is a hydrogen atom, R 3 and R 4 are each independently a hydrogen atom or a fluorine atom, X is -C(O)-; a and c are 1, b and d are both 1 or 2; R 5A , R 5B , R 6A , R 6B and R 6D is a hydrogen atom, R 6C is a fluorine atom, U is a nitrogen atom, Y is -O-; Z is (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8) or (Z-9), However, R 3 and R 4 is not a hydrogen atom at the same time, A compound or a pharma- ceutically acceptable salt thereof.

[0151] One embodiment of the compound of the present invention represented by formula (1) includes the following (I). (I) p is 1 or 2; R 1 and R 2 is a hydrogen atom, R 3 and R 4 are each independently a hydrogen atom or a fluorine atom, X is -C(O)-; a and c are 1, b and d are both 1 or 2; R 5A , R 5B , R 6A , R 6B and R 6D is a hydrogen atom, R 6C is a fluorine atom, U is CR 22 and R 22 is -CF3 or cyano, Y is -O-; Z is (Z-3), However, R 3 and R 4 is not a hydrogen atom at the same time, A compound or a pharma- ceutically acceptable salt thereof.

[0152] One embodiment of the compound of the present invention represented by formula (1) includes the following (J). (J) Formula (1) is formula (1a), p is 1 or 2; R 1 and R 2 are each independently a hydrogen atom or -MQ; R 3 and R 4 are each independently a hydrogen atom or a fluorine atom, When there are two or more M's, each M is independently methylene; When there are multiple Qs, each Q is independently C 3-6 is cycloalkyl, a and c are 1, b and d are both 1 or 2; However, R 1 and R 2 is not a hydrogen atom at the same time, A compound or a pharma- ceutically acceptable salt thereof.

[0153] One embodiment of the compound of the present invention represented by formula (1) includes the following (K). (K) p is 1 or 2; R 1 and R 2 are each independently a hydrogen atom or -MQ; R 3 and R 4 are each independently a hydrogen atom or a fluorine atom, When there are two or more M's, each M is independently methylene; When there are multiple Qs, each Q is independently C 3-6 is cycloalkyl, X is -C(O)-; a and c are 1, b and d are both 1 or 2; R 5A , R 5B , R 6A , R 6B and R 6D is a hydrogen atom, R 6C is a fluorine atom, U is a nitrogen atom, Y is -O-; Z is (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8) or (Z-9), However, R 1 and R 2 is not a hydrogen atom at the same time, A compound or a pharma- ceutically acceptable salt thereof.

[0154] One embodiment of the compound of the present invention represented by formula (1) includes the following (L). (L) p is 1 or 2; R 1 and R 2 are each independently a hydrogen atom or -MQ; R 3 and R 4 are each independently a hydrogen atom or a fluorine atom, When there are two or more M's, each M is independently methylene; When there are multiple Qs, each Q is independently C 3-6 is cycloalkyl, X is -C(O)-; a and c are 1, b and d are both 1 or 2; R 5A , R 5B , R 6A , R 6B and R 6D is a hydrogen atom, R 6C is a fluorine atom, U is CR 22 and R 22 is -CF3 or cyano, Y is -O-; Z is (Z-3), However, R 1 and R 2 is not a hydrogen atom at the same time, A compound or a pharma- ceutically acceptable salt thereof.

[0155] One embodiment of the compound of the present invention represented by formula (1) includes the following (M). (M) Formula (1) is formula (1a), p is 1 or 2; R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, or R 1 and R 2 and / or R 3 and R 4 may be taken together to form =CH2, a and c are 1, b and d are both 1 or 2; However, R 1 , R 2 , R 3 and R 4 is not a hydrogen atom at the same time, A compound or a pharma- ceutically acceptable salt thereof.

[0156] One embodiment of the compound of the present invention represented by formula (1) includes the following (N). (N) p is 1 or 2; R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, or R 1 and R 2 and / or R 3 and R 4 may be taken together to form =CH2, X is -C(O)-; a and c are 1, b and d are both 1 or 2; R 5A , R 5B , R 6A , R 6B and R 6D is a hydrogen atom, R 6C is a fluorine atom, U is a nitrogen atom, Y is -O-; Z is (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8) or (Z-9), However, R 1 , R 2 , R 3 and R 4 is not a hydrogen atom at the same time, A compound or a pharma- ceutically acceptable salt thereof.

[0157] One embodiment of the compound of the present invention represented by formula (1) includes the following (O). (O) p is 1 or 2; R 1 , R 2 , R 3 and R 4are each independently a hydrogen atom, or R 1 and R 2 and / or R 3 and R 4 may be taken together to form =CH2, X is -C(O)-; a and c are 1, b and d are both 1 or 2; R 5A , R 5B , R 6A , R 6B and R 6D is a hydrogen atom, R 6C is a fluorine atom, U is CR 22 and R 22 is -CF3 or cyano, Y is -O-; Z is (Z-3), However, R 1 , R 2 , R 3 and R 4 is not a hydrogen atom at the same time, A compound or a pharma- ceutically acceptable salt thereof.

[0158] The following describes the process for producing the compound of the present invention represented by formula (1) with reference to examples, but the process for producing the compound of the present invention is not limited to these. The compounds used in the following processes may form salts as long as they do not interfere with the reaction.

[0159] The compound of the present invention can be produced using a known compound as a starting material by, for example, the following production methods A, B, C, D, E, F, G, H, I, J, K, L, M, N and O or methods similar thereto or a synthesis method known to a person skilled in the art in an appropriate combination.

[0160] Manufacturing method A The compound of the present invention represented by formula (1) can be produced, for example, by the following method. [ka] [In the formula, a, b, c, d, p, R 1 , R 2 , R 3 , R 4 , R 5A , R 5B , R 6A , R 6B , R 6C , R 6D , U, X, Y and Z are as defined in item 1; LG 1 means a leaving group, P 1 means an amino protecting group. LG 1 Examples of the aryl group include halogen atoms, methanesulfonyloxy, p-toluenesulfonate oxy, trifluoromethanesulfonate oxy, phenoxy, trifluorophenoxy, tetrafluorophenoxy, pentafluorophenoxy, and nitrophenoxy. 1 Examples of the protecting groups include the amino protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999). * indicates that the stereochemistry of the carbon is not inverted by the reaction.]

[0161] [Process 1] Compound (a3) ​​can be produced by reacting compound (a1) obtained by the production method described below with compound (a2) obtained by the production method described below in a suitable solvent in the presence or absence of a suitable base. Compound (a1) that can be used includes compound (a1) obtained by the following production method B, compound (D1) obtained by the following production method D, or compound (E1) obtained by the following production method E. Compound (a2) that can be used includes compound (F1) obtained by the following production method F, or compound (G1) obtained by the following production method G. Examples of the base include organic bases such as triethylamine, diisopropylethylamine, tributylamine, 1.5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, 4-dimethylaminopyridine, picoline, and N-methylmorpholine (NMM), and inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide. Examples of the base that are preferred include triethylamine, diisopropylethylamine, potassium carbonate, and sodium hydroxide. The solvent is not particularly limited as long as it is a solvent that does not react under the reaction conditions of this step, and examples thereof include alcohol solvents such as methanol, ethanol, 2-propanol (isopropyl alcohol), and tert-butanol; ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, anisole, and xylene; ester solvents such as ethyl acetate and methyl acetate; aprotic solvents such as acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, and dimethylsulfoxide; or mixtures thereof. Preferred examples of the solvent include 2-propanol, tetrahydrofuran, toluene, acetonitrile, and N,N-dimethylformamide. The reaction temperature is usually from -80°C to reflux, preferably from 25°C to 90°C. The reaction time is usually 30 minutes to 48 hours, and preferably 6 to 12 hours.

[0162] As another method, a coupling reaction of compound (a1) and compound (a2) may be carried out in a suitable solvent in the presence of a suitable metal catalyst. Examples of the reaction conditions include Ulmann-type conditions (e.g., a method in which a metal catalyst such as copper(II) acetate is used in an aprotic solvent such as DMF and the like, and the reaction is refluxed under heating), Buchwald-type conditions (e.g., a method in which an alkali metal carbonate such as cesium carbonate, BINAP, a palladium catalyst such as Pd2(dba)3 or Pd(OAc)2, and a ligand such as dppf or Xantphos are used in a solvent inert to the reaction conditions such as toluene and the like, and the like). The solvent is not particularly limited as long as it is a solvent that does not react under the reaction conditions of this step, and examples thereof include alcohol solvents such as methanol, ethanol, 2-propanol (isopropyl alcohol), and tert-butanol; ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, anisole, and xylene; ester solvents such as ethyl acetate and methyl acetate; aprotic solvents such as acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, and dimethylsulfoxide; water; or a mixture thereof. Preferred examples of the solvent include tetrahydrofuran, toluene, acetonitrile, and N,N-dimethylformamide. The reaction temperature is usually from -80°C to reflux, preferably from 25°C to 90°C. The reaction time is usually 30 minutes to 48 hours, and preferably 6 to 12 hours.

[0163] [Process 2] Compound (1) is a protecting group P of compound (a3). 1This step can be carried out, for example, in accordance with the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999).

[0164] Manufacturing method B The compound represented by formula (a1) can be produced, for example, by the following method. [ka] [In the formula, R 5A , R 5B , R 6A , R 6B , R 6C , R 6D , U, Y and Z are as defined in item 1; LG 1 is the same as that described in Production Method A, and LG 2 means a leaving group, P 2 means a protecting group for a hydroxyl group. LG 2 Examples of the aryl group include halogen atoms, methanesulfonyloxy, p-toluenesulfonate oxy, trifluoromethanesulfonate oxy, phenoxy, trifluorophenoxy, tetrafluorophenoxy, pentafluorophenoxy, and nitrophenoxy. 2 Examples of the protecting groups include the hydroxyl protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).

[0165] Compound (b1) and compound (b2) are commercially available.

[0166] [Process 1] Compound (b3) can be produced from compound (b1) and compound (b2) by the method described in step 1 of production method A or a method analogous thereto.

[0167] [Process 2] Compound (b4) is a compound (b3) having a protecting group P 2 This step can be carried out, for example, in accordance with the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999).

[0168] [Process 3] Compound (a1) can be produced from compound (b4) by a method described in J. Med. Chem., 53(16): 6129-6152 (2010), J. Med. Chem., 59(17): 7936-7949 (2016), J. Org. Chem., 76(10): 4149-4153 (2011), European Journal of Medicinal Chemistry, 44(10): 4179-4191 (2009), or the like, or a method similar thereto.

[0169] Manufacturing method C The compound represented by formula (b3) can also be produced, for example, by the following method. [ka] [In the formula, R 5A , R 5B , R 6A , R 6B , R 6C , R 6D , U, Y and Z are as defined in item 1; LG 2 and P 2 are the same as those in Production Method B.]

[0170] Compound (c1) is commercially available, and compound (c2) can be produced by a method described in International Publication No. 2017 / 214367 or a method analogous thereto, or is commercially available.

[0171] [Process 1] Compound (b3) can be produced from compound (c1) and compound (c2) by the method described in step 1 of production method A or a method analogous thereto.

[0172] Manufacturing method D In formula (a1), the compound represented by formula (D1) can be produced, for example, by the following method. [ka] [In the formula, R 6A , R 6B , R 6C , R 6D , U and Z are as defined in item 1, and LG 1 are the same as those in Production Method A.]

[0173] Compound (d1) can be produced by the method described in International Publication No. 2017 / 214367 or a method similar thereto, or is commercially available.

[0174] [Process 1] Compound (d2) can be produced from compound (d1) by the method described in Bioorganic & Medicinal Chemistry Letters, 22(24): 7456-7460 (2012), Bioorganic & Medicinal Chemistry Letters, 12(8): 1185-1187 (2002), Bioorganic & Medicinal Chemistry, 23(1): 132-140 (2015), Bioorganic & Medicinal Chemistry, 19(1): 211-220 (2011), or the like, or a method similar thereto.

[0175] [Process 2] Compound (d3) can be produced from compound (d2) by the methods described in European Journal of Medicinal Chemistry, 23(1): 53-62 (1988), Tetrahedron, 62(23): 5469-5473 (2006), WO 2008 / 092049, WO 2015 / 175707, etc., or methods similar thereto. [Process 3] Compound (d4) can be produced from compound (d3) by the methods described in J. Med. Chem., 23(9): 1026-1031 (1980), WO 2003 / 087067, WO 2000 / 061562, etc., or methods analogous thereto.

[0176] [Step 4] Compound (D1) can be produced from compound (d4) by a method described in European Journal of Medicinal Chemistry, 44(10): 4179-4191 (2009), J. Org. Chem., 76(10): 4149-4153 (2011), J. Med. Chem., 53(16): 6129-6152 (2010), J. Med. Chem., 59(17): 7936-7949 (2016), etc., or a method similar thereto.

[0177] Manufacturing method E In formula (a1), the compound represented by formula (E1) can be produced, for example, by the following method. [ka] [In the formula, R 6A , R 6B , R 6C , R 6D and Z are as defined in item 1, and LG 1 are the same as those in Production Method A.]

[0178] Compound (d1) can be produced by the method described in International Publication No. 2017 / 214367 or a method similar thereto, or is commercially available.

[0179] [Process 1] Compound (e1) can be produced from compound (d1) by the method described in step 1 of production method C or a method analogous thereto.

[0180] [Process 2] Compound (e2) can be produced from compound (e1) by a method described in J. Org. Chem., 82(17): 8933-8942 (2017), Tetrahedron, 68(29): 5845-5851 (2012), J. Am. Chem. Soc., 139(16): 5998-6007 (2017), Angewandte Chemie, International Edition, 45(46): 7781-7786 (2006), etc., or a method similar thereto.

[0181] [Process 3] Compound (E1) can be produced from compound (e2) by the methods described in WO 2017 / 214367, WO 2009 / 137733, etc., or methods analogous thereto.

[0182] Manufacturing method F In formula (a2), the compound represented by formula (F1) can be produced, for example, by the following method. [ka] [In the formula, a, b, c, d, p, R 1 , R 2 , R 3 and R 4 is synonymous with term 1, and P 1 is synonymous with Manufacturing Method A, and LG 3 means a leaving group, P 3 means an amino protecting group. LG 3Examples of the P include a halogen atom and a hydroxyl group. 3 Examples of the protecting groups include the amino protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999). * indicates that the stereochemistry of the carbon is not inverted by the reaction.]

[0183] Compound (f1) is commercially available.

[0184] Compound (f2) is described in JP-T 2007-510619, J. Chem. Soc., Chem. Commun., 1599-1601 (1988), Tetrahedron Letters, 43: 5957-5960 (2002), Tetrahedron Asymmetry, 2: 1263-1282 (1991), Tetrahedron Asymmetry, 27: 1062-1068 (2016), Comprehensive Organic Transformation 2 nd Edition (Larock RC, John Wiley & Sons, Inc., 1989) or a method similar thereto, or they are commercially available.

[0185] [Process 1] Compound (f3) can be produced by reacting compound (f1) with compound (f2), which is a carboxylic acid, an acid chloride, or the like, in a suitable solvent in the presence of a suitable condensing agent and / or a suitable base. Examples of the base include amines such as triethylamine, diisopropylethylamine, pyridine, etc., and alkali metal carbonates such as potassium carbonate, sodium carbonate, sodium hydrogencarbonate, etc. The base is preferably triethylamine, diisopropylethylamine, or pyridine. The condensing agent is appropriately selected from those commonly used in organic synthetic chemistry, and preferred examples include 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-hydroxybenzotriazole, and the like. The solvent is not particularly limited as long as it is a solvent that does not react under the reaction conditions of this step, and examples thereof include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, 1,4-dioxane, etc.; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, anisole, xylene, etc.; ester solvents such as ethyl acetate, methyl acetate, etc.; aprotic solvents such as acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, dimethylsulfoxide, etc.; halogenated hydrocarbon solvents such as dichloromethane (methylene chloride), chloroform, 1,2-dichloroethane, etc.; or mixtures thereof. Preferred examples of the solvent include tetrahydrofuran, toluene, acetonitrile, N,N-dimethylformamide, dichloromethane, etc. The reaction time is usually 5 minutes to 72 hours, and preferably 30 minutes to 24 hours. The reaction temperature is usually from -78°C to 200°C, and preferably from -78°C to 80°C.

[0186] [Process 2] Compound (F1) is a protecting group P of compound (f3). 3 This step can be carried out, for example, in accordance with the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999).

[0187] Manufacturing method G In formula (a2), the compound represented by formula (G1) can be produced, for example, by the following method. [ka] [In the formula, a, b, c, d, p, R 1 , R 2 , R 3 and R 4 is synonymous with term 1, and P 1 is the same as Production Method A, and P 3 is synonymous with Process F. Also, * means that the stereochemistry of the carbon is not inverted by the reaction.

[0188] Compound (f1) is commercially available.

[0189] Compound (g1) was synthesized by the method described in JP-A-2007-510619, J. Chem. Soc., Chem. Commun., 1599-1601 (1988), Tetrahedron Letters, 43: 5957-5960 (2002), Tetrahedron Asymmetry, 2: 1263-1282 (1991), Tetrahedron Asymmetry, 27: 1062-1068 (2016), Comprehensive Organic Transformation 2 nd Edition (Larock RC, John Wiley & Sons, Inc., 1989) or a method similar thereto, or they are commercially available.

[0190] [Process 1] Compound (g2) can be produced from compound (f1) and compound (g1) by the method described in J. Am. Chem. Soc., 93(12): 2897-2904 (1971), J. Org. Chem., 37(10): 1673-1674 (1972), J. Org. Chem., 61(11): 3849-3862 (1996), Tetrahedron, 60: 7899-7906 (2004), or the like, or a method analogous thereto.

[0191] [Process 2] Compound (G1) is a compound (g2) having a protecting group P 3 This step can be carried out, for example, in accordance with the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999).

[0192] Manufacturing method H The compound of the present invention represented by formula (H1) can be produced, for example, by the following method. [ka] [In the formula, a, b, c, d, p, R 1 , R 2 , R 3 , R 4 , R 5A , R 5B , R 6A , R 6B , R 6C , R 6D , U, Y and Z are as defined in item 1; LG 1 is the same as that described in Production Method A, and LG 3 is the same as that described in Production Method F, and P 1 is the same as Production Method A, and P 4 means an amino protecting group. 4 Examples of the protecting groups include the amino protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999). * indicates that the stereochemistry of the carbon is not inverted by the reaction.]

[0193] Compound (h1) is commercially available.

[0194] [Process 1] Compound (h2) can be produced from compound (a1) and compound (h1) by the method described in step 1 of production method A or a method analogous thereto.

[0195] [Process 2] Compound (h3) is a compound (h2) having a protecting group P 4 This step can be carried out, for example, in accordance with the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999).

[0196] [Process 3] Compound (h4) can be produced from compound (h3) and compound (f2) by the method described in step 1 of production method F or a method analogous thereto.

[0197] [Step 4] Compound (H1) is a protecting group P of compound (h4). 1 This step can be carried out, for example, in accordance with the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999).

[0198] Manufacturing method I The compound of the present invention represented by formula (I1) can be produced, for example, by the following method. [ka] [In the formula, a, b, c, d, p, R 1 , R 2 , R 3 , R 4 , R 5A , R 5B , R 6A , R6B , R 6C , R 6D , U, Y and Z are as defined in item 1; P 1 is synonymous with Process A. Also, * means that the stereochemistry of the carbon is not inverted by the reaction.

[0199] [Process 1] Compound (i1) can be produced from compound (h3) and compound (g1) by the method described in step 1 of production method G or a method analogous thereto.

[0200] [Process 2] Compound (I1) is a compound (i1) having a protecting group P 1 This step can be carried out, for example, in accordance with the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999).

[0201] Manufacturing method J In formula (f2), the compound represented by formula (J1) can be produced, for example, by the following method. [ka] [In the formula, p and Q are defined as in item 1, and P 1 is the same as that described in Production Method A, and P 5 means a protecting group for a carboxylic acid. 5 Examples of the protecting group include the carboxylic acid protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999). In addition, * means that the stereochemistry of the carbon is not inverted by the reaction.]

[0202] Compound (j1) was synthesized by the method described in JP-A-2007-510619, J. Chem. Soc., Chem. Commun., 1599-1601 (1988), Tetrahedron Letters, 43: 5957-5960 (2002), Tetrahedron Asymmetry, 2: 1263-1282 (1991), Tetrahedron Asymmetry, 27: 1062-1068 (2016), Comprehensive Organic Transformation 2 nd Edition (Larock RC, John Wiley & Sons, Inc., 1989) or a method similar thereto, or they are commercially available.

[0203] [Process 1] Compound (j2) can be produced from compound (j1) by the method described in Tetrahedron Letters, 27: 2567-2570 (1986), Synthesis, 12: 1930-1935 (2011), Bioorganic & Medicinal Chemistry Letters, 23: 4493-4500 (2013), European Journal of Organic Chemistry, 10: 2485-2490 (1999), or the like, or a method analogous thereto.

[0204] [Process 2] Compound (j3) can be produced from compound (j2) by the method described in Synthetic Communications, 28: 1743-1753 (1998), Chemistry Letters, 6: 875-878 (1983), Journal of Organic Chemistry, 28: 6-16 (1963), or the like, or a method analogous thereto.

[0205] [Process 3] Compound (j4) can be produced from compound (j3) by the methods described in Tetrahedron Letters, 23: 477-480 (1982), Synlett, 443-444 (1995), Synlett, 96-98 (1999), Tetrahedron, 56: 2779-2788 (2000), etc., or methods analogous thereto.

[0206] [Step 4] Compound (J1) is a protecting group P of compound (j4). 5 This step can be carried out, for example, in accordance with the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999).

[0207] Manufacturing method K In formula (f2), the compound represented by formula (K1) can be produced, for example, by the following method. [ka] [In the formula, p and Q are defined as in item 1, and P 1 is the same as that described in Production Method A, and P 5 is the same as that described in Production Method J. Also, * means that the stereochemistry of the carbon is not inverted by the reaction.]

[0208] The compound (k1) is commercially available.

[0209] [Process 1] Compound (j3) can be produced from compound (j1) and compound (k1) by the methods described in Journal of the American Chemical Society, 126: 14206-14216 (2004), Synthetic Communications, 20: 839-847 (1990), Synthesis, 23: 3821-3826 (2011), Advanced Synthesis & Catalysis, 352: 153-162 (2010), or the like, or methods analogous thereto.

[0210] [Process 2] Compound (K1) is a protecting group P of compound (j3). 5 This step can be carried out, for example, in accordance with the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999).

[0211] Manufacturing method L In formula (f2), the compound represented by formula (L1) can be produced, for example, by the following method. [ka] [In the formula, p, M and Q are defined as in item 1, and LG 4 means a leaving group, P 1 is the same as that described in Production Method A, and P 5 is the same as that described in Production Method J. LG 4 Examples of the group include halogen atoms, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, phenoxy, trifluorophenoxy, tetrafluorophenoxy, pentafluorophenoxy, and nitrophenoxy. * indicates that the stereochemistry of the carbon is not inverted by the reaction.

[0212] Compound (l1) is commercially available.

[0213] [Process 1] Compound (l2) can be produced from compound (j1) and compound (l1) by the methods described in Journal of the American Chemical Society, 132: 1236-1237 (2010), Journal of Medicinal Chemistry, 49: 4409-4424 (2006), Advanced Synthesis & Catalysis, 357: 2803-2808 (2015), Tetrahedron Letters, 47(19): 3233-3237 (2006), Angewandte Chemie, International Edition, 44(34): 5516-5519 (2005), etc., or methods similar thereto.

[0214] [Process 2] Compound (L1) is a protecting group P of compound (l2). 5 This step can be carried out, for example, in accordance with the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999).

[0215] Manufacturing method M The compound of the present invention represented by formula (1) can be produced, for example, by the following method. [ka] [In the formula, a, b, c, d, p, R 1 , R 2 , R 3 , R 4 , R 5A , R 5B , R 6A , R 6B , R 6C , R6D , U, X, Y and Z are as defined in item 1; LG 1 is synonymous with Process A. Also, * means that the stereochemistry of the carbon is not inverted by the reaction.

[0216] Compound (1) can be produced from compound (a1) and compound (m1) obtained by the production method described below, by the method described in step 1 of production method A or a method analogous thereto. As the compound (m1), a compound (N1) obtained by the following production process N or a compound (O1) obtained by the following production process O can be used.

[0217] Manufacturing method N In formula (m1), the compound represented by formula (N1) can be produced, for example, by the following method. [ka] [In the formula, a, b, c, d, p, R 1 , R 2 , R 3 , and R 4 is the same as in item 1, and LG 3 is the same as that described in Production Method F, and P 1 is synonymous with Process A. Also, * means that the stereochemistry of the carbon is not inverted by the reaction.

[0218] Compound (n1) is commercially available.

[0219] [Process 1] Compound (n2) can be produced from compound (n1) and compound (f2) by the method described in step 1 of production method F or a method analogous thereto.

[0220] [Process 2] Compound (N1) is a protecting group P of compound (n2). 1This step can be carried out, for example, in accordance with the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999).

[0221] Manufacturing method O In formula (m1), the compound represented by formula (O1) can be produced, for example, by the following method. [ka] [In the formula, a, b, c, d, p, R 1 , R 2 , R 3 , and R 4 is the same as in item 1, and P 1 is synonymous with Process A. Also, * means that the stereochemistry of the carbon is not inverted by the reaction.

[0222] [Process 1] Compound (o1) can be produced from compound (n1) and compound (g1) by the method described in step 1 of production method G or a method analogous thereto.

[0223] [Process 2] Compound (O1) is a compound (o1) having a protecting group P 1 This step can be carried out, for example, in accordance with the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999).

[0224] In the above-described production methods, starting materials or intermediates for which the production method is not described are either commercially available or can be synthesized from commercially available compounds by methods known to those skilled in the art or methods similar thereto.

[0225] In each reaction of the above-described production method, even if the use of a protecting group is not specifically specified, a protecting group can be used as necessary. For example, when any functional group other than the reaction site changes under the reaction conditions described, or when the method described is inappropriate to carry out without a protecting group, the target compound can be obtained by protecting the functional group other than the reaction site as necessary and deprotecting the functional group after the reaction or after a series of reactions. Examples of the protecting group include those described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999). Specific examples of the protecting group for amino include benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl, etc. Specific examples of the protecting group for hydroxyl include trialkylsilyl such as trimethylsilyl and tert-butyldimethylsilyl, acetyl, benzyl, etc. Introduction and removal of the protecting group can be carried out by a method commonly used in organic synthesis (for example, see the above-mentioned Protective Groups in Organic Synthesis) or a method analogous thereto.

[0226] In this specification, protecting groups, condensing agents, etc. may be represented by abbreviations according to IUPAC-IUB (Intergovernmental Board of Biochemical Nomenclature) commonly used in this technical field. Note that the names of compounds used in this specification do not necessarily follow the IUPAC nomenclature.

[0227] The intermediates or target compounds in the above-described production methods can be converted into other compounds included in the present invention by appropriately converting their functional groups (for example, by protecting or deprotecting the functional groups as necessary, and by carrying out various conversions using amino, hydroxyl, carbonyl, halogen atoms, etc. as a stepping stone). The conversion of the functional groups can be carried out by a commonly used general method (for example, see Comprehensive Organic Transformations, RC Larock, John Wiley & Sons Inc. (1999), etc.).

[0228] The intermediates and target compounds in the above-described production methods can be isolated and purified by purification methods commonly used in organic synthesis chemistry (e.g., neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography, etc.). In addition, the intermediates can be used in the next reaction without any particular purification.

[0229] The "pharmaceutical acceptable salt" includes acid addition salts and base addition salts. For example, the acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, and phosphate, and organic acid salts such as citrate, oxalate, phthalate, fumarate, maleate, succinate, malate, acetate, formate, propionate, benzoate, trifluoroacetate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, and camphorsulfonate. In addition, the base addition salts include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, barium salt, and aluminum salt, and organic base salts such as trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, dicyclohexylamine, and N,N-dibenzylethylamine. Furthermore, the "pharmaceutically acceptable salts" also include amino acid salts with basic or acidic amino acids such as arginine, lysine, ornithine, aspartic acid, or glutamic acid.

[0230] Suitable salts of starting materials and intermediates, as well as salts acceptable as pharmaceutical raw materials, are conventional non-toxic salts, which may be appropriately selected by those skilled in the art, including, for example, acid addition salts such as organic acid salts (e.g., acetate, trifluoroacetate, maleate, fumarate, citrate, tartrate, methanesulfonate, benzenesulfonate, formate, p-toluenesulfonate, etc.) and inorganic acid salts (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.), salts with amino acids (e.g., arginine, aspartic acid, glutamic acid, etc.), metal salts such as alkali metal salts (e.g., sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g., calcium salt, magnesium salt, etc.), ammonium salts, organic base salts (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), etc.

[0231] In the present invention, the term "hydrogen atom" includes 1 H and 2 H(D) and any one or more of the compounds represented by formula (1) 1 H 2 Deuterium converted to H(D) is also included in the compound represented by formula (1).

[0232] The present invention includes a compound represented by formula (1) or a pharma- ceutically acceptable salt thereof. In addition, the compound of the present invention may exist in the form of a hydrate and / or a solvate with various solvents (such as an ethanolate), and these hydrates and / or solvates are also included in the compound of the present invention.

[0233] Furthermore, the compounds of the present invention include all possible isomers such as optical isomers based on optically active centers, atropisomers based on axial or planar chirality caused by restricted intramolecular rotation, other stereoisomers, tautomers, geometric isomers, and all types of crystal forms, as well as mixtures thereof.

[0234] In particular, optical isomers and atropisomers can be obtained as racemates, or as optically active isomers when optically active starting materials or intermediates are used. If necessary, at an appropriate stage of the above-mentioned production method, the corresponding racemates of the starting materials, intermediates or final products can be physically or chemically resolved into their optical antipodes by known separation methods such as a method using an optically active column or a fractional crystallization method. Examples of such resolution methods include a diastereomeric method in which a racemate is reacted with an optically active resolving agent to synthesize two diastereomers, and the two diastereomers are resolved by a method such as fractional crystallization, taking advantage of the difference in physical properties.

[0235] When it is desired to obtain a pharma- ceutically acceptable salt of the compound of the present invention, if the compound represented by formula (1) is obtained in the form of a pharma- ceutically acceptable salt, it may be purified as it is, or, if it is obtained in the free form, it may be dissolved or suspended in a suitable organic solvent, and an acid or a base may be added to form a salt by a conventional method.

[0236] In the present invention, the term "concomitant drug" refers to an antitumor drug that can be used in combination with or in combination with the compound of the present invention. Examples of the "concomitant drug" include antitumor alkylating agents, antitumor antimetabolites, antitumor antibiotics, plant-derived antitumor agents, antitumor platinum coordination compounds, antitumor camptothecin derivatives, antitumor tyrosine kinase inhibitors, antitumor serine threonine kinase inhibitors, antitumor phospholipid kinase inhibitors, antitumor monoclonal antibodies, interferons, biological response modifiers, hormone preparations, immune checkpoint inhibitors, epigenetics-related molecule inhibitors, protein post-translational modification inhibitors, and other antitumor agents. Specific examples of "concomitant drugs" include, for example, azacitidine, vorinostat, decitabine, romidepsin, idarubicin, daunorubicin, doxorubicin, enocitabine, cytarabine, mitoxantrone, thioguanine, etoposide, ifosfamide, cyclophosphamide, dacarbazine, temozolomide, nimustine, busulfan, procarbazine, melphalan, ranimustine, all-trans retinoic acid, tamibarotene, cisplatin, carboplatin, oxaliplatin, irinotecan, bleomycin, mitomycin C, methotrexate, paclitaxel, docetaxel, gemcitabine, tamoxifen, thiotepa, tegafur, fluorouracil, and everolim. sirolimus, gefitinib, erlotinib, imatinib, crizotinib, osimertinib, afatinib, dasatinib, bosutinib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, lapatinib, nilotinib, ibrutinib, ceritinib, alectinib, tofacitinib, baricitinib, ruxolitinib, orola These include parib, sorafenib, vemurafenib, dabrafenib, trametinib, palbociclib, bortezomib, carfilzomib, rituximab, cetuximab, trastuzumab, bevacizumab, panitumumab, nivolumab, atezolizumab, mogamulizumab, alemtuzumab, ofatumumab, ipilimumab, ramucirumab, brentuximab vedotin, gemtuzumab ozogamicin, and inotuzumab ozogamicin.

[0237] The route of administration of the compound of the present invention may be oral administration, parenteral administration, rectal administration or ophthalmic administration, and the daily dosage varies depending on the type of compound, the administration method, the symptoms and age of the patient, etc. For example, in the case of oral administration, about 0.01 to 1000 mg, more preferably about 0.1 to 500 mg per kg body weight of a human or mammal can be administered once or in several divided doses. In the case of parenteral administration such as intravenous injection, about 0.01 mg to 300 mg, more preferably about 1 mg to 100 mg per kg body weight of a human or mammal can be administered.

[0238] The compound of the present invention can be administered orally or parenterally, directly or after preparation using a suitable dosage form. The dosage form includes, but is not limited to, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, poultices, etc. The preparation is produced by a known method using pharma- ceutically acceptable additives.

[0239] As additives, excipients, disintegrants, binders, fluidizing agents, lubricants, coating agents, solubilizers, solubilizing aids, thickeners, dispersants, stabilizers, sweeteners, flavors, etc. can be used depending on the purpose. Specific examples of additives include lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc, etc. EXAMPLES

[0240] The present invention will be explained in more detail below with reference to Reference Examples, Examples and Test Examples, but the present invention is not limited thereto.

[0241] The following abbreviations may be used in this specification: THF: tetrahydrofuran TFA: Trifluoroacetic acid DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide MeCN: Acetonitrile Me: Methyl Et: Ethyl Ph: Phenyl Bn: Benzyl Boc: tert-butoxycarbonyl n-: Normal tert-: tertiary- p-:para- BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) Ac: Acetyl dppf: 1,1'-bis(diphenylphosphino)ferrocene Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene Dess-Martin Reagent: Dess-Martin Periodinane (1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3-(1H)-one) Petasis Reagent: Bis(cyclopentadienyl)dimethyltitanium Bredereck's reagent: tert-butoxy-bis(dimethylamino)methane HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate WSCI·HCl: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HOBt: 1-hydroxybenzotriazole

[0242] The NMR (Nuclear Magnetic Resonance) data used for compound identification was obtained using a JNM-ECS400 nuclear magnetic resonance spectrometer (400 MHz) manufactured by JEOL Ltd. The symbols used in NMR are s for singlet, d for doublet, dd for doublet of doublets, t for triplet, td for doublet of triplets, q for quartet, m for multiplet, br for broad, brs for broad singlet, brm for broad multiplet and J for coupling constant.

[0243] The LC / MS (Liquid Chromatography-Mass Spectrometry) analysis conditions used for compound identification are as follows. Among the observed mass spectrometry values ​​[MS (m / z)], the value corresponding to the monoisotopic mass (accurate mass consisting of only the main isotope) is [M+H] + , [MH] - Or [M+2H] 2+ etc., and retention time is indicated as Rt (min).

[0244] LC / MS method: Analysis conditions A Detection equipment: ACQUITY (registered trademark) SQ detector (Waters) HPLC: ACQUITY UPLC (registered trademark) system Column: Waters ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm, 2.1 mm × 30 mm) Solvent: Solution A: 0.06% formic acid / H2O, Solution B: 0.06% formic acid / MeCN Gradient condition:0.0-1.3min Linear gradient from B 2% to 96% Flow rate: 0.8mL / min UV: 220nm and 254nm Column temperature: 40℃ Analysis conditions B Detection equipment: LCMS-2020 (Shimadzu Corporation) HPLC: Nexera X2 Column: Phenomenex Kinetex(registered trademark) 1.7μm C18(50mm×2.1mm) Solvent: A liquid: 0.05%TFA / H2O, B liquid: MeCN Gradient condition:0.0-1.7min Linear gradient from B 10% to 99% Flow rate: 0.5mL / min UV: 220nm and 254nm Column temperature: 40℃

[0245] The powder X-ray diffraction measurements in the examples were performed under the following conditions. The obtained diffraction patterns (XRD spectra) are shown in Figs. The crystal form may be identified based on the characteristic diffraction peaks of each crystal shown in the diffraction diagrams of FIGS. The main diffraction peaks and characteristic diffraction peaks identified from the diffraction patterns of Figures 1 to 5 are listed below. Note that the diffraction peak values ​​at the diffraction angle 2θ (°) described in the following examples may have some measurement error depending on the measuring device or the measuring conditions. Specifically, the measurement error may be within the range of ±0.2, preferably ±0.1.

[0246] Powder X-ray diffraction measurement: Detection equipment: Spectris Power X-ray diffraction system Empyrian X-ray tube: CuKα (wavelength: 1.54 angstroms) Tube voltage: 45kV Tube current: 40mA Measurement range: 4 to 40 degrees (2θ) Step width: 0.013 degrees Accumulation time: 100 seconds / step

[0247] Reference example 1: 2-[(4-chloropyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide [ka]

[0248] a) Preparation of 5-fluoro-2-methoxy-N,N-di(propan-2-yl)benzamide 5-Fluoro-2-methoxybenzoic acid (100 g) was dissolved in dichloromethane (1.0 L), and diisopropylamine (251 mL) and HATU (235 g) were added at 0° C. and stirred at room temperature for 1 day. The reaction solution was quenched with a 5 mol / L aqueous hydrochloric acid solution. The resulting aqueous solution was extracted twice with ethyl acetate. The resulting organic layer was washed with saturated saline and dried over magnesium sulfate, then filtered off and the solvent was distilled off under reduced pressure to obtain the crude product (200 g) of the title compound. LC-MS; [M+H] + 254.0 / Rt (min) 0.96 (Analysis conditions A)

[0249] b) Preparation of 5-fluoro-2-hydroxy-N,N-di(propan-2-yl)benzamide 5-Fluoro-2-methoxy-N,N-di(propan-2-yl)benzamide (70.0 g) was dissolved in dichloromethane (400 mL), and boron tribromide (39.2 mL) was added at 0° C., followed by stirring at 0° C. for 1 day. The reaction solution was quenched with 8 mol / L aqueous ammonia solution. The resulting aqueous solution was extracted twice with chloroform. The resulting organic layer was washed with saturated saline and dried over magnesium sulfate, then filtered off, and the solvent was distilled off under reduced pressure to obtain the title compound (56.0 g). LC-MS; [M+H] + 240.0 / Rt (min) 0.85 (Analysis conditions A)

[0250] c) Preparation of 5-fluoro-N,N-di(propan-2-yl)-2-[(pyrimidin-5-yl)oxy]benzamide 5-Fluoro-2-hydroxy-N,N-di(propan-2-yl)benzamide (118.0 g) was suspended in DMF (250 mL), 5-bromopyrimidine (35.9 g) and cesium carbonate (73.5 g) were added at room temperature, and the mixture was stirred under heating and reflux for 1 day. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was added to a saturated aqueous solution of sodium bicarbonate for quenching. The resulting aqueous solution was extracted twice with ethyl acetate. The resulting organic layer was washed with saturated saline and dried over magnesium sulfate, and then filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (20.0 g). LC-MS; [M+H] + 317.7 / Rt (min) 0.86 (Analysis conditions A)

[0251] d) 5-fluoro-2-[(1-oxo-1λ 5 -pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide 5-Fluoro-N,N-di(propan-2-yl)-2-[(pyrimidin-5-yl)oxy]benzamide (72.1 g) was dissolved in dichloromethane (900 mL), metachloroperbenzoic acid (112 g) was added at 0° C., and the mixture was stirred at 0° C. for 2 days. The reaction solution was quenched with tributylphosphine (56.7 mL) and a saturated aqueous solution of sodium hydrogen carbonate. After cooling, dichloromethane was concentrated under reduced pressure, and the resulting aqueous solution was extracted twice with ethyl acetate. The resulting organic layer was washed with saturated saline and dried over magnesium sulfate, and then filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (42.3 g). LC-MS; [M+H] + 334.0 / Rt (min) 0.76 (Analysis conditions A)

[0252] e) Preparation of 2-[(4-chloropyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide (Reference Example 1) 5-Fluoro-2-[(1-oxo-1λ 5-pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (36.0 g) was dissolved in chloroform (300 mL), N,N-diisopropylethylamine (37.6 mL) and phosphoryl chloride (40 mL) were added at 0°C, and the mixture was stirred at 0°C for 6 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was added to a saturated aqueous solution of sodium bicarbonate for quenching. The resulting aqueous solution was extracted twice with ethyl acetate. The resulting organic layer was washed with saturated saline and dried over magnesium sulfate, and then filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (27.8 g). 1 H-NMR (DMSO-D6)δ: 8.77 (1H, s), 8.24 (1H, s), 7.53-7.30 (3H, m), 3.68-3.61 (1H, m), 3.54-3.48 (1H, m), 1.37 (3H, d, J = 6.7 Hz), 1.19 (3H, d, J = 7.3 Hz), 1.08 (6H, d, J = 6.7 Hz). LC-MS; [M+H] + 351.9 / Rt (min) 1.00 (Analysis conditions A)

[0253] Reference example 2: 2-{[4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl]oxy}-5-fluoro-N,N-di(propan-2-yl)benzamide [ka]

[0254] a) Preparation of tert-butyl 2-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate 2-[(4-chloropyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide (27.0 g) was dissolved in 2-propanol (500 mL), and N,N-diisopropylethylamine (40.1 mL) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride (30.3 g) were added at 0° C. and stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (33.0 g). LC-MS; [M+H] + 542.1 / Rt (min) 1.23 (Analysis conditions A)

[0255] b) Preparation of 2-{[4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl]oxy}-5-fluoro-N,N-di(propan-2-yl)benzamide (Reference Example 2) tert-Butyl 2-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (44.0 g) was dissolved in dichloromethane (500 mL), TFA (65 mL) was added at 0° C., and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by amine silica gel column chromatography (chloroform / methanol) to obtain the title compound (35.0 g). 1 H-NMR (DMSO-D6)δ: 8.26 (1H, s), 7.73 (1H, s), 7.24-7.19 (2H, m), 7.03-7.00 (1H, m), 3.87-3.78 (4H, m), 3.71-3.67 (1H, m), 3.54-3.51 (1H, m), 2.58-2.55 (4H, m), 1.59-1.56 (4H, m), 1.44 (3H, d, J = 6.7 Hz), 1.35 (3H, d, J = 6.7 Hz), 1.09 (3H, d, J = 6.7 Hz), 1.00 (3H, d, J = 6.7 Hz). LC-MS; [M+H] +442.3 / Rt (min) 1.33 (Analysis condition B)

[0256] Reference example 3: 2-{[4-(2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl]oxy}-5-fluoro-N,N-di(propan-2-yl)benzamide [ka]

[0257] a) Preparation of tert-butyl 6-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate Using 2-[(4-chloropyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide (1.0 g) and 2,6-diazaspiro[3,3]heptane-2-carboxylic acid tert-butyl ester hemioxalate (1.0 g), the title compound (1.4 g) was obtained in the same manner as described in Reference Example 2, step a). LC-MS; [M+H] + 514.1 / Rt (min) 0.96 (Analysis conditions A)

[0258] b) Preparation of 2-{[4-(2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl]oxy}-5-fluoro-N,N-di(propan-2-yl)benzamide (Reference Example 3) Using tert-butyl 6-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (1.4 g), the title compound (1.0 g) was obtained in the same manner as described in Reference Example 2, step b). 1H-NMR (DMSO-D6)δ: 8.26 (1H, s), 7.74 (1H, s), 7.23-7.17 (2H, m), 6.99-6.96 (1H, m), 4.25-4.23 (2H, m), 4.15-4.12 (2H, m), 3.69-3.66 (1H, m), 3.52-3.50 (5H, m), 1.43 (3H, d, J = 6.7 Hz), 1.33 (3H, d, J = 6.7 Hz), 1.07 (3H, d, J = 6.7 Hz), 0.99 (3H, d, J = 6.7 Hz). LC-MS; [M+2H] 2+ 207.5 / Rt (min) 0.64 (Analysis conditions A)

[0259] Reference example 4: 2-{[4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl]oxy}-5-fluoro-N,N-di(propan-2-yl)benzamide [ka]

[0260] a) Preparation of tert-butyl 7-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate 2-[(4-chloropyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide (150 mg) was dissolved in 2-propanol (10 mL), triethylamine (0.2 mL) and 2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester (193 mg) were added at 0° C., and the mixture was stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (169 mg). LC-MS; [M+H] + 542.1 / Rt (min) 1.22 (Analysis conditions A)

[0261] b) Preparation of 2-{[4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl]oxy}-5-fluoro-N,N-di(propan-2-yl)benzamide (Reference Example 4) tert-Butyl 7-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (169 mg) was dissolved in dichloromethane (10 mL), TFA (2.0 mL) was added at 0° C., and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by amine silica gel column chromatography (chloroform / methanol) to obtain the title compound (122 mg). LC-MS; [M+H] + 442.3 / Rt (min) 1.12 (Analysis conditions A)

[0262] Reference example 5: (1S,3S,4S,5R)-2-(tert-butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylic acid Reference example 6: (1S,3S,4R,6S)-2-(tert-butoxycarbonyl)-6-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylic acid [ka]

[0263] a) Preparation of ethyl (2E)-{[(1R)-1-phenylethyl]imino}acetate Ethyl oxoacetate (100 mL) was added to (R)-1-phenylethylamine (63 mL), stirred at room temperature for 1 hour, and then concentrated under reduced pressure to obtain the crude product of the title compound. The product obtained was used in the next reaction without purification.

[0264] b) Preparation of ethyl (1S,3S,4R)-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.2]oct-5-ene-3-carboxylate Molecular sieves 4A (powder, 10 g) was added to a dichloromethane (475 mL) solution of ethyl (2E)-{[(1R)-1-phenylethyl]imino}acetate obtained as a crude product in the above step a), and the reaction solution was cooled to -70°C. Trifluoroacetic acid (32 mL) and boron trifluoride diethyl ether complex (53 mL) were added dropwise and stirred for 15 minutes, and then 1,3-cyclohexadiene (42 mL) was added dropwise. The reaction solution was warmed to room temperature and stirred overnight. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate. Sodium sulfate was added to the organic layer to dry it, and after filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (59.4 g). LC-MS; [M+H] + 286.2 / Rt (min) 0.53 (Analysis conditions A)

[0265] c) Preparation of a mixture of ethyl (1S,3S,4S,5R)-5-hydroxy-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.2]octane-3-carboxylate and ethyl (1S,3S,4R,6S)-6-hydroxy-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.2]octane-3-carboxylate 1.0 mol / L borane-THF complex (300 mL) was added dropwise to a solution of ethyl (1S,3S,4R)-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.2]oct-5-ene-3-carboxylate (85.5 g) in THF (500 mL) at 0-5°C, and the mixture was stirred overnight at room temperature. 3 mol / L aqueous sodium hydroxide solution (62 mL) and 30% aqueous hydrogen peroxide solution (62 mL) were added to the reaction solution under ice cooling, and the mixture was stirred for 30 minutes, after which an aqueous sodium thiosulfate solution was added and the mixture was stirred for 1 hour. The reaction solution was extracted with ethyl acetate / chloroform, and the organic layer was washed with saturated saline. The organic layer was dried by adding sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the crude product (51.7 g) of the title compound as a mixture of positional isomers. LC-MS; [M+H] + 304.2 / Rt (min) 0.53 (Analysis conditions A)

[0266] d) Preparation of ethyl (1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylate and ethyl (1S,3S,4R,6S)-6-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylate 10% palladium hydroxide (10.2 g) was added to a solution of the mixed product (51.7 g) obtained in the above step c) in ethanol (500 mL), and the mixture was stirred at room temperature for 6 hours under a pressurized hydrogen gas atmosphere (0.3-0.4 MPa). The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compounds ethyl (1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylate (19.0 g) and ethyl (1S,3S,4R,6S)-6-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylate (5.05 g), respectively. Ethyl (1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylate LC-MS; [M+H] +200.2 / Rt (min) 0.27 (Analysis conditions A) Ethyl (1S,3S,4R,6S)-6-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylate LC-MS; [M+H] + 200.1 / Rt (min) 0.36 (Analysis conditions A)

[0267] e) Preparation of (1S,3S,4S,5R)-2-(tert-butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylic acid (Reference Example 5) A 1 mol / L aqueous sodium hydroxide solution (238 mL) was added to a solution of ethyl (1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylate (10.48 g) in 1,4-dioxane (153 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was then cooled to 0° C., and di-tert-butyl dicarbonate (11.48 g) was added. After stirring for 1 hour, 1 mol / L hydrochloric acid was added to make the reaction solution acidic, and saturated saline was added, followed by extraction with a 10% ethanol / chloroform mixed solvent. The organic layer was dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was washed with diisopropyl ether, collected by filtration, and dried to obtain the title compound (8.40 g). 1 H-NMR (DMSO-D6) δ: 12.55 (1H, br s), 4.86 (1H, br s), 3.96-3.81 (3H, m), 2.09-1.69 (4H, m), 1.59-1.49 (1H, m), 1.36 (3H, s), 1.31 (6H, s), 1.29-1.17 (2H, m).

[0268] f) Preparation of (1S,3S,4R,6S)-2-(tert-butoxycarbonyl)-6-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylic acid (Reference Example 6) Using ethyl (1S,3S,4R,6S)-6-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylate (5.05 g), the title compound (1.60 g) was obtained in the same manner as in step e). 1 H-NMR (DMSO-D6) δ: 4.09-4.05 (3H, m), 2.28-2.20 (1H, m), 2.18-2.05 (2H, m), 1.91-1.80 (1H, m), 1.63-1.50 (3H, m), 1.45 (3H, s), 1.40 (6H, s).

[0269] Reference example 7: (1S,3S,4S,5R)-2-(tert-butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylic acid [ka]

[0270] a) Preparation of ethyl (1S,3S,4R)-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate Using ethyl (2E)-{[(1R)-1-phenylethyl]imino}acetate (12.0 g) and cyclopentadiene (4.92 mL), the title compound (10.8 g) was obtained in the same manner as described in Reference Example 5, step b). LC-MS; [M+H] + 272.2 / Rt (min) 0.54 (Analysis conditions A)

[0271] b) Preparation of ethyl (1S,3S,4S,5R)-5-hydroxy-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate Using ethyl (1S,3S,4R)-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate (10.8 g), the title compound (7.49 g) was obtained in the same manner as described in Reference Example 5, step c). LC-MS; [M+H] + 290.2 / Rt (min) 0.46 (Analysis conditions A)

[0272] c) Preparation of ethyl (1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylate Using ethyl (1S,3S,4S,5R)-5-hydroxy-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate (7.49 g), the title compound (2.89 g) was obtained in the same manner as described in Reference Example 5, step d). LC-MS; [M+H] + 186.1 / Rt (min) 0.27 (Analysis conditions A)

[0273] d) Preparation of (1S,3S,4S,5R)-2-(tert-butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (Reference Example 7) Using ethyl (1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylate (2.88 g), the title compound (980 mg) was obtained in the same manner as described in Reference Example 5, step e). 1 H-NMR (DMSO-D6) δ: 4.99 (1H, br s), 4.11-3.95 (1H, m), 3.95-3.82 (1H, m), 3.48-3.40 (1H, m), 2.41-2.31 (1H, m), 1.90-1.75 (1H, m), 1.69-1.49 (2H, m), 1.45-1.19 (10H, m).

[0274] Reference example 8: 3-Benzyl 2-tert-butyl (1S,3S,4S)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate [ka]

[0275] a) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate Benzyl bromide (12.3mL) was added to a solution of (1S,3S,4S,5R)-2-(tert-butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylic acid (28.0g) and potassium carbonate (28.5g) in acetonitrile (300mL) at room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. Sodium sulfate was added to the organic layer to dry it, and after filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (33.1g). LC-MS; [M+H] + 362.3 / Rt (min) 0.95 (Analysis conditions A)

[0276] b) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4S)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (Reference Example 8) Dess-Martin reagent (46.5 g) was added to a solution of 3-benzyl 2-tert-butyl (1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (33.0 g) in dichloromethane (400 mL) at room temperature, and the mixture was stirred at room temperature overnight. Aqueous sodium thiosulfate and aqueous sodium hydrogen carbonate were added to the reaction solution, and the mixture was extracted with chloroform. Sodium sulfate was added to the organic layer to dry it, and the organic layer was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the crude product (33.8 g) of the title compound. LC-MS; [M+H] + 360.2 / Rt (min) 1.02 (Analysis conditions A) 1H-NMR (CDCl3) δ: 7.38-7.28 (5H, m), 5.33-5.05 (2H, m), 4.66-4.42 (2H, m), 2.80-2.69 (1H, m), 2.59-2.45 (1H, m), 2.36-2.16 (2H, m), 1.82-1.62 (3H, m), 1.45 (2.5H, s), 1.31 (6.5H, s).

[0277] Reference example 9: (1S,3S,4S)-2-(tert-butoxycarbonyl)-5-oxo-2-azabicyclo[2.2.2]octane-3-carboxylic acid [ka] 3-benzyl 2-tert-butyl (1S,3S,4S)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (1.0 g) in methanol (30 mL) was added with 5 mol / L aqueous sodium hydroxide solution (2.7 mL) and heated and stirred at 50° C. for 5 hours. After cooling the reaction solution to room temperature, 1 mol / L hydrochloric acid was added for neutralization and extracted with chloroform. Sodium sulfate was added to the organic layer to dry it, and after filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.42 g). LC-MS; [M+H] + 270.0 / Rt (min) 0.59 (Analysis conditions A)

[0278] Reference example 10: (1S,3S,4R)-2-(tert-butoxycarbonyl)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carboxylic acid [ka]

[0279] a) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate To a solution of 3-benzyl 2-tert-butyl (1S,3S,4S)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (3.0 g) in THF (30 mL), Petasis reagent (5% THF / toluene solution, 35 g) was added at room temperature and stirred at 95 ° C for 5 hours. The mixture was returned to room temperature, Petasis reagent (5% THF / toluene solution, 10 g) was added, and the mixture was heated to reflux at 130 ° C. After cooling, diethyl ether was added, the precipitated orange solid was removed by filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.9 g). LC-MS; [M+H] + 358.0 / Rt (min) 1.21 (Analysis conditions A)

[0280] b) Preparation of (1S,3S,4R)-2-(tert-butoxycarbonyl)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carboxylic acid (Reference Example 10) Using 3-benzyl 2-tert-butyl (1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (1.9 g), the title compound (0.99 g) was obtained in the same manner as in Reference Example 9. LC-MS; [M+H] + 268.0 / Rt (min) 0.83 (Analysis conditions A)

[0281] Reference example 11: (1S,3S,4R)-2-(tert-butoxycarbonyl)-6-methylidene-2-azabicyclo[2.2.2]octane-3-carboxylic acid [ka]

[0282] a) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4R,6S)-6-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate Using (1S,3S,4R,6S)-2-(tert-butoxycarbonyl)-6-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylic acid (80.0 g), the title compound (65.5 g) was obtained in the same manner as in Reference Example 8, step a). LC-MS; [M+H] + 362.1 / Rt (min) 0.95 (Analysis conditions A)

[0283] b) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4R)-6-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate Using 3-benzyl 2-tert-butyl (1S,3S,4R,6S)-6-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (10.0 g), the title compound (6.0 g) was obtained in the same manner as in Reference Example 8, step b). LC-MS; [M+H] + 360.1 / Rt (min) 1.02 (Analysis conditions A)

[0284] c) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4R)-6-methylidene-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate Using 3-benzyl 2-tert-butyl (1S,3S,4R)-6-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (4.0 g), the title compound (2.12 g) was obtained in the same manner as in Reference Example 10, step a). LC-MS; [M+H] + 358.0 / Rt (min) 1.29 (Analysis conditions A)

[0285] d) Preparation of (1S,3S,4R)-2-(tert-butoxycarbonyl)-6-methylidene-2-azabicyclo[2.2.2]octane-3-carboxylic acid (Reference Example 11) Using 3-benzyl 2-tert-butyl (1S,3S,4R)-6-methylidene-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (2.1 g), the title compound (1.4 g) was obtained in the same manner as in Reference Example 9. LC-MS; [M+H] + 268.0 / Rt (min) 0.82 (Analysis conditions A)

[0286] Reference example 12: 3-Benzyl 2-tert-butyl (1S,3S,4S)-5-oxo-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate [ka]

[0287] a) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate Using (1S,3S,4S,5R)-2-(tert-butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.5 g), the title compound (1.73 g) was obtained in the same manner as in step a) of Reference Example 8. LC-MS; [M+H] + 348.2 / Rt (min) 0.92 (Analysis conditions A)

[0288] b) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4S)-5-oxo-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (Reference Example 12) Using 3-benzyl 2-tert-butyl (1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (1.73 g), the title compound (1.40 g) was obtained in the same manner as in Reference Example 8, step b). LC-MS; [M+H] + 346.2 / Rt (min) 1.01 (Analysis conditions A)

[0289] Reference example 13: (1S,3S,4R)-2-(tert-butoxycarbonyl)-5-methylidene-2-azabicyclo[2.2.1]heptane-3-carboxylic acid [ka]

[0290] a) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate Using 3-benzyl 2-tert-butyl (1S,3S,4S)-5-oxo-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (1.40 g), the title compound (1.10 g) was obtained in the same manner as in Reference Example 10, step a). LC-MS; [M+H] + 344.2 / Rt (min) 1.18 (Analysis conditions A)

[0291] b) Preparation of (1S,3S,4R)-2-(tert-butoxycarbonyl)-5-methylidene-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (Reference Example 13) Using 3-benzyl 2-tert-butyl (1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (1.10 g), the title compound (0.69 g) was obtained in the same manner as in Reference Example 9. LC-MS; [M+H] + 254.3 / Rt (min) 0.82 (Analysis conditions A)

[0292] Reference example 14: 3-Benzyl 2-tert-butyl (1S,3S,4S,6E)-6-(cyclopropylmethylidene)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate [ka]

[0293] a) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4S,6E)-6-[(dimethylamino)methylidene]-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate Bredereck reagent (32.8 g) was added to a solution of 3-benzyl 2-tert-butyl (1S,3S,4S)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (33.8 g) in N,N-dimethylformamide (180 mL), and the mixture was heated and stirred at 100° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the crude product of the title compound (39.0 g). LC-MS; [M+H] + 415.4 / Rt (min) 0.95 (Analysis conditions A)

[0294] b) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4S,6E)-6-(cyclopropylmethylidene)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (Reference Example 14) A solution of 3-benzyl 2-tert-butyl (1S,3S,4S,6E)-6-[(dimethylamino)methylidene]-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (39.0 g) in tetrahydrofuran (300 mL) was cooled to 0° C., and cyclopropylmagnesium bromide (0.5 mol / L tetrahydrofuran solution, 245 mL) was added dropwise and stirred at room temperature for 6 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried by adding sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (32.3 g). LC-MS; [M+H] + 412.4 / Rt (min) 1.16 (Analysis conditions A) 1H-NMR (CDCl3) δ: 7.39-7.27 (5H, m), 5.91 (1H, t, J = 11.0 Hz), 5.38-5.04 (3H, m), 4.50-4.36 (1H, m), 2.90-2.76 (1H, m), 2.37-2.22 (1H, m), 1.82-1.59 (4H, m), 1.44 (3H, s), 1.31 (6H, s), 1.09-0.95 (2H, m), 0.73-0.58 (2H, m).

[0295] Reference example 15: 3-Benzyl 2-tert-butyl (1S,3S,4S)-6-(cyclopropylmethyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate [ka]

[0296] a) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4S)-6-(cyclopropylmethyl)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate To a solution of 3-benzyl 2-tert-butyl (1S,3S,4S,6E)-6-(cyclopropylmethylidene)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (32.3 g) in tetrahydrofuran (300 mL), copper(I) hydride(triphenylphosphine) hexamer (38.5 g) was added and stirred at room temperature for 12 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (23.2 g) as a stereoisomeric mixture. LC-MS; [M+H] + 414.1 / Rt (min) 1.22 (Analysis conditions A)

[0297] b) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4S)-6-(cyclopropylmethyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (Reference Example 15) A solution of 3-benzyl 2-tert-butyl (1S,3S,4S)-6-(cyclopropylmethyl)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (23.2 g) in methanol (200 mL) was cooled to 0°C, sodium borohydride (2.12 g) was added, and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain a mixture of stereoisomers of the less polar side of the title compound (9.3 g) and a mixture of stereoisomers of the more polar side (10.2 g). Mixture of less polar stereoisomers: 3-benzyl 2-tert-butyl (1S,3S,4S,5S)-6-(cyclopropylmethyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate LC-MS; [M+H] + 416.1 / Rt (min) 1.13 (Analysis conditions A) Mixture of highly polar stereoisomers: 3-benzyl 2-tert-butyl (1S,3S,4S,5R)-6-(cyclopropylmethyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate LC-MS; [M+H] + 416.1 / Rt (min) 1.01 (Analysis conditions A)

[0298] Reference example 16: (1S,3S,4S,5R,6R)-2-(tert-butoxycarbonyl)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-3-carboxylic acid Reference example 17: (1S,3S,4S,5R,6S)-2-(tert-butoxycarbonyl)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-3-carboxylic acid Reference example 18: (1S,3S,4S,5S,6R)-2-(tert-butoxycarbonyl)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-3-carboxylic acid Reference example 19: (1S,3S,4S,5S,6S)-2-(tert-butoxycarbonyl)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-3-carboxylic acid [ka]

[0299] a) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4S,5R,6R)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate and 3-benzyl 2-tert-butyl (1S,3S,4S,5R,6S)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate A solution of 3-benzyl 2-tert-butyl (1S,3S,4S,5S)-6-(cyclopropylmethyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (9.3 g), which is a mixture of stereoisomers on the low polarity side of the product of Reference Example 15, in dichloromethane (80 mL) was cooled to 0° C., (diethylamino)sulfur trifluoride (5.91 mL) was added, and the mixture was stirred overnight at room temperature. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the mixture was extracted with chloroform. Sodium sulfate was added to the organic layer to dry it, and after filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 3-benzyl 2-tert-butyl (1S, 3S, 4S, 5R, 6R)-6- (cyclopropylmethyl) -5-fluoro-2-azabicyclo [2.2.2] octane-2,3-dicarboxylate (3.6 g) and 3-benzyl 2-tert-butyl (1S, 3S, 4S, 5R, 6S)-6- (cyclopropylmethyl) -5-fluoro-2-azabicyclo [2.2.2] octane-2,3-dicarboxylate (3.7 g). 3-Benzyl 2-tert-butyl (1S,3S,4S,5R,6R)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate LC-MS; [M+H] + 418.4 / Rt (min) 1.29 (Analysis conditions A) 3-Benzyl 2-tert-butyl (1S,3S,4S,5R,6S)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate LC-MS; [M+H] + 418.4 / Rt (min) 1.35 (Analysis conditions A)

[0300] b) Preparation of (1S,3S,4S,5R,6R)-2-(tert-butoxycarbonyl)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-3-carboxylic acid (Reference Example 16) Palladium hydroxide / carbon (1.2 g) was added to a solution of 3-benzyl 2-tert-butyl (1S,3S,4S,5R,6R)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (3.6 g) and ammonium formate (5.4 g) in tetrahydrofuran (50 mL), and the mixture was heated under reflux for 3 hours. After cooling to room temperature, the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (2.8 g). LC-MS; [MH] - 326.4 / Rt (min) 0.95 (Analysis conditions A)

[0301] c) Preparation of (1S,3S,4S,5R,6S)-2-(tert-butoxycarbonyl)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-3-carboxylic acid (Reference Example 17) Using 3-benzyl 2-tert-butyl (1S,3S,4S,5R,6S)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (108 mg), the crude product of the title compound (108 mg) was obtained in the same manner as in Reference Example 16, step b). LC-MS; [MH] - 326.4 / Rt (min) 0.95 (Analysis conditions A)

[0302] d) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4S,5S,6R)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate and 3-benzyl 2-tert-butyl (1S,3S,4S,5S,6S)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate Using 3-benzyl 2-tert-butyl (1S, 3S, 4S, 5R)-6-(cyclopropylmethyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (363 mg), which is a mixture of stereoisomers on the high polarity side of the product of Reference Example 15, in the same manner as in step a) of Reference Example 16, 3-benzyl 2-tert-butyl (1S, 3S, 4S, 5S, 6R)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (86 mg) and 3-benzyl 2-tert-butyl (1S, 3S, 4S, 5S, 6S)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (152 mg) were obtained. 3-Benzyl 2-tert-butyl (1S,3S,4S,5S,6R)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate LC-MS; [M+H] + 418.4 / Rt (min) 1.27 (Analysis conditions A) 3-Benzyl 2-tert-butyl (1S,3S,4S,5S,6S)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate LC-MS; [M+H] + 418.4 / Rt (min) 1.29 (Analysis conditions A)

[0303] e) Preparation of (1S,3S,4S,5S,6R)-2-(tert-butoxycarbonyl)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-3-carboxylic acid (Reference Example 18) Using 3-benzyl 2-tert-butyl (1S,3S,4S,5S,6R)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (82 mg), the crude product of the title compound (73 mg) was obtained in the same manner as in Reference Example 16, step b). LC-MS; [MH] -326.4 / Rt (min) 0.94 (Analysis conditions A)

[0304] f) Preparation of (1S,3S,4S,5S,6S)-2-(tert-butoxycarbonyl)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-3-carboxylic acid (Reference Example 19) Using 3-benzyl 2-tert-butyl (1S,3S,4S,5S,6S)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (147 mg), the crude product of the title compound (140 mg) was obtained in the same manner as in Reference Example 16, step b). LC-MS; [MH] - 326.3 / Rt (min) 0.95 (Analysis conditions A)

[0305] Reference example 20: (1S,3S,4R,6S)-2-(tert-butoxycarbonyl)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carboxylic acid Reference example 21: (1S,3S,4R,6R)-2-(tert-butoxycarbonyl)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carboxylic acid [ka]

[0306] a) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4S,5R,6R)-6-(cyclopropylmethyl)-5-[(phenoxycarbonothioyl)oxy]-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate and 3-benzyl 2-tert-butyl (1S,3S,4S,5R,6S)-6-(cyclopropylmethyl)-5-[(phenoxycarbonothioyl)oxy]-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate A solution of 3-benzyl 2-tert-butyl (1S,3S,4S,5R)-6-(cyclopropylmethyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (7.3 g), which is a mixture of stereoisomers on the high polarity side of the product of Reference Example 15, in acetonitrile (50 mL) was cooled to 0° C., 4-(dimethylamino)pyridine (8.6 g) and phenyl chlorothionoformate (4.74 mL) were added, and the mixture was heated and stirred at 50° C. for 12 hours. After cooling the reaction solution to room temperature, saturated saline was added, and the mixture was extracted with ethyl acetate. Magnesium sulfate was added to the organic layer to dry it, and after filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give a crude product (1.80 g) of 3-benzyl 2-tert-butyl (1S, 3S, 4S, 5R, 6R)-6- (cyclopropylmethyl) -5- [(phenoxycarbonothioyl) oxy] -2-azabicyclo [2.2.2] octane-2, 3-dicarboxylate and a crude product (7.90 g) of 3-benzyl 2-tert-butyl (1S, 3S, 4S, 5R, 6S)-6- (cyclopropylmethyl) -5- [(phenoxycarbonothioyl) oxy] -2-azabicyclo [2.2.2] octane-2, 3-dicarboxylate. 3-Benzyl 2-tert-butyl (1S,3S,4S,5R,6R)-6-(cyclopropylmethyl)-5-[(phenoxycarbonothioyl)oxy]-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate LC-MS; [M+H] + 552.2 / Rt (min) 1.42 (Analysis conditions A) 3-Benzyl 2-tert-butyl (1S,3S,4S,5R,6S)-6-(cyclopropylmethyl)-5-[(phenoxycarbonothioyl)oxy]-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate LC-MS; [M+H] + 552.2 / Rt (min) 1.45 (Analysis conditions A)

[0307] b) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4R,6S)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate A solution of 3-benzyl 2-tert-butyl (1S,3S,4S,5R,6R)-6-(cyclopropylmethyl)-5-[(phenoxycarbonothioyl)oxy]-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (1.80 g) in toluene (50 mL) was cooled to 0° C., tris(trimethylsilyl)silane (5.03 mL) and 2,2'-azobis(2-methylpropionitrile) (0.11 g) were added, and the mixture was heated and stirred at 50° C. for 5 hours. After cooling the reaction solution to room temperature, saturated saline was added and the mixture was extracted with ethyl acetate. Magnesium sulfate was added to the organic layer to dry it, and after filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.80 g). LC-MS; [M+H] + 400.2 / Rt (min) 1.38 (Analysis conditions A)

[0308] c) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4R,6R)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate Using 3-benzyl 2-tert-butyl (1S,3S,4S,5R,6S)-6-(cyclopropylmethyl)-5-[(phenoxycarbonothioyl)oxy]-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (7.90 g), the title compound (5.50 g) was obtained in the same manner as in Reference Example 20, step b). LC-MS; [M+H] + 400.2 / Rt (min) 1.40 (Analysis conditions A)

[0309] d) Preparation of (1S,3S,4R,6S)-2-(tert-butoxycarbonyl)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carboxylic acid (Reference Example 20) Using 3-benzyl 2-tert-butyl (1S,3S,4R,6S)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (5.50 g), the title compound (3.90 g) was obtained in the same manner as in Reference Example 16, step b). LC-MS; [M+H] + 310.2 / Rt (min) 1.02 (Analysis conditions A)

[0310] e) Preparation of (1S,3S,4R,6R)-2-(tert-butoxycarbonyl)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carboxylic acid (Reference Example 21) Using 3-benzyl 2-tert-butyl (1S,3S,4R,6R)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (1.20 g), the title compound (980 mg) was obtained in the same manner as in Reference Example 16, step b). LC-MS; [M+H] + 310.2 / Rt (min) 1.04 (Analysis conditions A)

[0311] Reference example 22: tert-Butyl (1S,3S,4S)-3-[2-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]-5-oxo-2-azabicyclo[2.2.2]octane-2-carboxylate [ka] To a chloroform (2 mL) solution of 2-{[4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl]oxy}-5-fluoro-N,N-di(propan-2-yl)benzamide (164 mg) obtained in Reference Example 2, (1S,3S,4S)-2-(tert-butoxycarbonyl)-5-oxo-2-azabicyclo[2.2.2]octane-3-carboxylic acid (100 mg) obtained in Reference Example 9, WSCI·HCl (85 mg), HOBt (68 mg) and N,N-diisopropylethylamine (0.13 mL) were added and stirred at room temperature for 2 hours. Water was added to the reaction solution, and it was extracted with chloroform. The obtained organic layer was dried over sodium sulfate, filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (245 mg). LC-MS; [M+H] + 693.2 / Rt (min) 0.97 (Analysis conditions A)

[0312] Reference example 23: tert-Butyl (1S,3S,4S)-3-[2-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]-5-(methoxyimino)-2-azabicyclo[2.2.2]octane-2-carboxylate [ka] To a solution of tert-butyl (1S,3S,4S)-3-[2-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]-5-oxo-2-azabicyclo[2.2.2]octane-2-carboxylate (100 mg) obtained in Reference Example 22 in ethanol (1 mL) and water (2 mL), O-methylhydroxylamine hydrochloride (24 mg) and sodium acetate (35 mg) were added and stirred at 75 ° C. for 3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over sodium sulfate, filtered off, and the solvent was distilled off under reduced pressure to obtain the title compound (89 mg). LC-MS; [M+H] + 722.6 / Rt (min) 0.98 (Analysis conditions A)

[0313] Reference example 24: tert-Butyl (1R,3S,4R)-3-[7-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carbonyl]-2-azabicyclo[2.2.2]octane-2-carboxylate [ka] Using 2-{[4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl]oxy}-5-fluoro-N,N-di(propan-2-yl)benzamide (122 mg) obtained in Reference Example 4 and commercially available (1S,3S,4R)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.2]octane-3-carboxylic acid (85 mg), the title compound (100 mg) was obtained in the same manner as in Reference Example 22. LC-MS; [M+H] + 679.0 / Rt (min) 1.89 (Analysis conditions B)

[0314] Reference examples 25~40: Using the corresponding starting compounds, the compounds of Reference Examples 25 to 40 shown in the following table were obtained in the same manner as in Reference Example 22. [ka] [Table 1] TIFF2025060871000045.tif224170

[0315] Reference example 41: tert-Butyl (1S,3S,4R)-3-[2-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]-5-( 2 H2) Methylidene-2-azabicyclo[2.2.2]octane-2-carboxylate [ka]

[0316] a) 3-benzyl 2-tert-butyl (1S,3S,4R)-5-( 2 H2) Preparation of methylidene-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate ( 2H3) Methyl(triphenyl)phosphanium iodide (2.83 g) in THF (14 mL) was added dropwise with n-butyllithium (1.57 mol / L hexane solution, 3.54 mL) at -78°C, and stirred at 0°C for 1.5 hours. The mixture was cooled again to -78°C, and 3-benzyl 2-tert-butyl (1S,3S,4S)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (1.0 g) was added little by little, and stirred for 5 hours. The reaction solution was returned to room temperature, and then quenched by adding saturated aqueous ammonium chloride. Extraction was performed with ethyl acetate. The obtained organic layer was washed with water and saturated saline, and dried by adding anhydrous sodium sulfate, and then filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.46 g). LC-MS; [M+H] + 360.4 / Rt (min) 1.22 (Analysis conditions A)

[0317] b) (1S,3S,4R)-2-(tert-butoxycarbonyl)-5-( 2 H2) Preparation of methylidene-2-azabicyclo[2.2.2]octane-3-carboxylic acid 3-Benzyl 2-tert-butyl (1S,3S,4R)-5-( 2 H2) Aqueous sodium hydroxide solution (5 mol / L, 1.8 mL) and 2 mL of water were added to a solution of methylidene-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate in methanol (10 mL), and the mixture was heated and stirred at 50°C for 4 hours. After the reaction solution was cooled to room temperature, methanol was distilled off under reduced pressure, and the resulting aqueous solution was extracted with chloroform. The aqueous layer was acidified by adding 1 mol / L hydrochloric acid, and extracted with chloroform. The organic layer was washed with saturated saline, dried by adding anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain the title compound (0.31 g). The compound obtained was used in the next reaction without purification. LC-MS; [M+H] + 270.2 / Rt (min) 0.89 (Analysis conditions A) 1H-NMR (DMSO-D6) δ: 12.60 (1H, br s), 4.17-3.95. (total 2H, m), 2.74-2.60 (total 1H, m), 2.60-2.43 (total 1H, m), 2.34-2.23 (total 1H, m), 1.94-1.54 (total 3H, m), 1.54-1.41 (total 1H, m), 1.41-1.19 (total 9H, m).

[0318] c) tert-Butyl (1S,3S,4R)-3-[2-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]-5-( 2 H2) Preparation of methylidene-2-azabicyclo[2.2.2]octane-2-carboxylate (Reference Example 41) (1S,3S,4R)-2-(tert-butoxycarbonyl)-5-( 2 H2) Using methylidene-2-azabicyclo[2.2.2]octane-3-carboxylic acid (36 mg), the title compound (80 mg) was obtained in the same manner as in Reference Example 22. LC-MS; [M+H] + 693.6 / Rt (min) 0.99 (Analysis conditions A)

[0319] Reference example 42: tert-Butyl 7-[(1S,3S,4R)-2-(tert-butoxycarbonyl)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-carboxylate [ka]

[0320] a) Preparation of tert-butyl 7-[(1S,3S,4S,5R)-2-(tert-butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-carboxylate To a solution of the compound (20.0 g) obtained in Reference Example 5 in dichloromethane (200 mL), tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (18.4 g), WSCI·HCl (18.4 g), HOBt (13.0 g) and N,N-diisopropylethylamine (16.7 mL) were added at room temperature, and the mixture was stirred overnight at room temperature. Chloroform was added to the reaction solution, which was washed with a saturated aqueous ammonium chloride solution, water, and saturated saline in that order, and anhydrous sodium sulfate was added for drying, which was then filtered off. The solvent was distilled off under reduced pressure, and the resulting residue was crystallized from diisopropyl ether / hexane (1 / 1) to obtain the title compound (33.9 g). LC-MS; [M+H] + 480.1 / Rt (min) 0.83 (Analysis conditions A) 1 H-NMR (DMSO-D6) δ: 4.48 and 4.39 (total 1H, each m), 4.27-4.302 (total 2H, m), 3.73-3.25 (total 9H, m), 2.41 and 2.32 (total 1H, each m), 2.15 (1H, br m), 1.98-1.51 (total 10H, m), 1.46-1.42 (total 13H, m), 1.39-1.36 (5H, m).

[0321] b) Preparation of tert-butyl 7-[(1S,3S,4S)-2-(tert-butoxycarbonyl)-5-oxo-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-carboxylate Dimethylsulfoxide (11.1mL) was added dropwise to a solution of oxalyl chloride (8.94mL) in dichloromethane (300mL) at -78°C under a nitrogen atmosphere, and the mixture was stirred at -78°C for 30 minutes. A solution of tert-butyl 7-[(1S,3S,4S,5R)-2-(tert-butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-carboxylate (25.0g) in dichloromethane (100mL) was added dropwise at -65°C or lower, and the mixture was further stirred at -78°C for 1 hour. Triethylamine (36.3mL) was added dropwise at -78°C, the mixture was returned to room temperature, and the mixture was further stirred for 30 minutes. The reaction mixture was diluted with chloroform, washed with saturated aqueous ammonium chloride, water, and saturated saline, and the organic layer was dried over anhydrous sodium sulfate and filtered off. The solvent was removed under reduced pressure, and the residue was crystallized from hexane to give the title compound (22.5 g). LC-MS; [M+H] + 478.1 / Rt (min) 0.90 (Analysis conditions A) 1 H-NMR (CDCl3) δ: 4.79 and 4.73 (total 1H, each m), 4.70 and 4.55 (total 1H, each m), 3.74-3.25 (total 8H, m), 2.67-2.29 (total 4H, m), 2.01-1.50 (total 7H, m), 1.50-1.41 (total 12H, m), 1.39 (6H, s).

[0322] c) Preparation of tert-butyl 7-[(1S,3S,4R)-2-(tert-butoxycarbonyl)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-carboxylate (Reference Example 42) To a suspension of methyl(triphenyl)phosphanium bromide (25.2 g) in THF (300 mL), potassium tert-butoxide (7.9 g) was added under ice cooling and stirred for 1 hour. To the reaction solution, tert-butyl 7-[(1S,3S,4S)-2-(tert-butoxycarbonyl)-5-oxo-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-carboxylate (22.5 g) was added and stirred at room temperature for 2 hours. Methyl(triphenyl)phosphanium bromide (8.4 g) and potassium tert-butoxide (2.6 g) were added and stirred at room temperature for another 1 hour. The reaction solution was diluted with ethyl acetate and washed with water and saturated saline. The obtained organic layer was dried by adding anhydrous sodium sulfate, and then filtered off. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (24.2 g). LC-MS; [M+H] + 476.1 / Rt (min) 1.09 (Analysis conditions A) 1 H-NMR (CDCl3) δ: 4.94 (1H, br s), 4.78 (1H, m), 4.57 and 4.50 (total 1H, each m), 4.38 and 4.23 (total 1H, each br s), 3.77-3.26 (total 8H, m), 2.67-2.49 (total 1H, m), 2.47 and 2.41 (total 1H, each m), 2.38-2.27 (total 1H, m), 2.26-2.13 (total 1H, m), 1.98-1.47 (total 7H, m), 1.47-1.39 (total 12H, m), 1.37 (6H, s).

[0323] Example 1: 2-[(4-{7-[(1S,3S,4R,6S)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide [ka] To the dichloromethane (1mL) solution of tert-butyl (1S,3S,4R,6S)-6-(cyclopropylmethyl)-3-[2-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]-2-azabicyclo[2.2.2]octane-2-carboxylate (62mg) obtained in Reference Example 25, TFA (1mL) was added at room temperature and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified by amine silica gel column chromatography (ethyl acetate / methanol) to obtain the title compound (28mg). LC-MS; [M+H] + 633.4 / Rt (min) 1.64 (Analysis conditions B) 1 H-NMR (CDCl3)δ: 8.39 (1H, s), 7.80 (1H, d, J = 3.1 Hz), 7.02-6.95 (2H, m), 6.74 (1H, m), 4.03 (2H, m), 3.96-3.86 (3H, m), 3.79 (1H, m), 3.67-3.46 (3H, m), 3.30 (2H, brs), 2.85 (1H, brs), 2.16 (1H, m), 2.03 (1H, m), 1.80-1.59 (6H, m), 1.53 (3H, d, J = 6.7 Hz), 1.48 (3H, d, J = 6.7 Hz), 1.39-1.23 (4H, m), 1.16-1.08 (7H, m), 0.88 (1H, m), 0.68 (1H, m), 0.45-0.37 (2H, m), 0.08-0.03 (2H, m).

[0324] Example 2: 2-[(4-{7-[(1R,3S,4R)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[4.4]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide [ka] Using tert-butyl (1R,3S,4R)-3-[7-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carbonyl]-2-azabicyclo[2.2.2]octane-2-carboxylate (100 mg) obtained in Reference Example 24, the title compound (89 mg) was obtained in the same manner as in Example 1. LC-MS; [M+H] + 579.0 / Rt (min) 1.50 (Analysis conditions B) 1 H-NMR (CDCl3)δ: 8.34-8.30 (1H, m), 7.85-7.79 (1H, m), 7.22-7.18 (2H, m), 6.89-6.80 (2H, m), 3.72-3.23 (11H, m), 2.87-2.69 (1H, m), 1.87-1.54 (8H, m), 1.44-1.43 (4H, m), 1.35-1.24 (6H, m), 1.08-1.02 (8H, m), 0.88-0.85 (1H, m).

[0325] Examples 3 to 19: Using the corresponding starting compounds, the compounds of Examples 3 to 19 shown in the following table were obtained in the same manner as in Example 1. [ka] [Table 2] TIFF2025060871000052.tif181170 TIFF2025060871000053.tif249170 TIFF2025060871000054.tif194170 TIFF2025060871000055.tif194170 TIFF2025060871000056.tif240170

[0326] Example 20: 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-( 2 H2) Methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide [ka] The tert-butyl (1S,3S,4R)-3-[2-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]-5-( 2 H2) Using methylidene-2-azabicyclo[2.2.2]octane-2-carboxylate (80 mg), the title compound (23 mg) was obtained in the same manner as in Example 1. LC-MS; [M+H] + 593.6 / Rt (min) 0.70 (Analysis conditions A) 1H-NMR (DMSO-D6) δ: 8.27 (1H, s), 7.73 (1H, d, J = 4.1 Hz), 7.26-7.16 (2H, m), 7.03 (1H, m), 4.05-3.90 (total 3H, brs), 3.87 (2H, m), 3.67 (1H, m), 3.57-3.45 (2H, m), 3.45-3.19 (total 3H, m), 3.07 (1H, s), 2.52 (1H, brs), 2.33 (1H, brs), 2.27 (1H, dd, J = 2.5, 17.1 Hz), 1.79-1.60 (total 5H, brm), 1.55 (1H, m), 1.48-1.37 (5H, m), 1.33 (3H, d, J = 6.9 Hz), 1.07 (3H, d, J = 6.4 Hz), 0.98 (3H, d, J = 6.4 Hz).

[0327] Example 21: 2-[(4-{7-[(1S,3S,4R,6R)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide 1L(+)-tartrate [ka] L(+)-tartaric acid (0.11 g) was added to a solution of the compound of Example 4 (0.50 g) in ethyl acetate / ethanol (10 / 1, 11 mL) and the mixture was stirred at room temperature for 3 days. The precipitated solid was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to obtain the title compound (0.54 g) as crystals (I-form crystals). 1H-NMR (400 MHz, DMSO-d6) δ: 8.27 (1H, s), 7.74 (1H, s), 7.26-7.18 (2H, m), 7.04 (1H, m), 4.27 (1H, br s), 3.96 (2H, br s), 3.91-3.80 (total 4H, m), 3.67 (1H, m), 3.57-3.43 (3H, m), 3.38 (2H, br s), 3.29 (1H, br s), 1.94 (1H, br s), 1.91-1.78 (3H, m), 1.70 (4H, br m), 1.62-1.20 (total 12H, m), 1.07 (3H, d, J = 6.1 Hz), 0.97 (3H, d, J = 6.1 Hz), 0.68 (1H, m), 0.40 (2H, m), 0.07 (2H, m). [Form I] The powder X-ray diffraction pattern is shown in FIG. Major diffraction peaks: 2θ(°)=5.3, 8.0, 11.2, 13.0, 13.5, 15.9, 16.4, 17.5, 17.9, 18.2, 20.0 Characteristic diffraction peaks: 2θ(°)=5.3, 11.2, 13.0, 15.9, 17.9, 18.2

[0328] Example 22: 2-[(4-{7-[(1S,3S,4R,6R)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide monohydrochloride [ka] To a solution of the compound of Example 4 (50 mg) in ethyl acetate (1 mL), 4 mol / L hydrochloric acid-ethyl acetate (19 μL) was added and stirred at room temperature for 4 hours. The precipitated solid was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to obtain the title compound (30 mg) as crystals (Form II crystals). 1H-NMR (400 MHz, DMSO-d6) δ: 8.27 (1H, s), 7.75 (1H, d, J = 1.8 Hz), 7.26-7.19 (2H, m), 7.04 (1H, m), 4.36 (1H, br s), 4.07-3.92 (2H, br s), 3.92-3.81 (2H, m), 3.67 (1H, m), 3.61-3.46 (3H, m), 3.45-3.36 (3H, m), 2.00 (1H, br s), 1.96-1.80 (3H, m), 1.79 -1.21 (total 16H, m), 1.08 (3H, d, J = 6.9 Hz), 0.97 (3H, d, J = 6.4 Hz), 0.68 (1H, m), 0.41 (2H, m), 0.09 (2H, m). [Form II] The powder X-ray diffraction pattern is shown in FIG. Major diffraction peaks: 2θ(°)=5.3, 9.9, 10.6, 11.9, 13.1, 13.6, 15.9, 16.3, 17.9, 18.9, 21.2 Characteristic diffraction peaks: 2θ(°)=5.3, 9.9, 10.6, 15.9, 16.3, 17.9

[0329] Example 23: 2-[(4-{7-[(1S,3S,4R,6R)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide dihydrochloride [ka] To a solution of the compound of Example 4 (0.50 g) in ethyl acetate / ethanol (10 / 1, 11 mL), 4 mol / L hydrochloric acid-ethyl acetate (0.38 mL) was added and stirred at room temperature for 3 days. The precipitated solid was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to obtain the dihydrochloride salt of the compound of Example 4 (0.49 g) as crystals (crystal form III). 1H-NMR (400 MHz, DMSO-d6) δ: 9.22 (1H, br s), 8.53 (1H, s), 8.03 (1H, br d, J = 12.8 Hz), 7.85 (1H, br s), 7.36-7.25 (3H, m), 4.40 (1H, br s), 4.34-3.97 (total 4H, br m), 3.67 (1H, m), 3.59-3.47 (3H, m), 3.46-3.37 (3H, m), 2.01 (1H, br s), 1.96-1.82 (3H, m), 1.75 (4H, br s), 1.66-1.27 (total 12H, m), 1.09 (3H, d, J = 6.7 Hz), 0.93 (3H, d, J = 6.7 Hz), 0.67 (1H, m), 0.40 (2H, m), 0.10 (2H, m). [Crystal Form III] The powder X-ray diffraction pattern is shown in FIG. Main diffraction peaks: 2θ(°)=4.3, 7.0, 9.9, 10.6, 11.8, 15.2, 15.5, 15.9, 16.5, 16.8, 17.9 Characteristic diffraction peaks: 2θ(°)=4.3, 7.0, 10.6, 15.9, 16.5, 16.8

[0330] Example 6: 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide [ka] Example 6 can also be prepared by the following method. TFA (11 mL) was added dropwise at room temperature to a solution of tert-butyl 7-[(1S,3S,4R)-2-(tert-butoxycarbonyl)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-carboxylate (7.0 g) obtained in Reference Example 42 in chloroform (11 mL), and the mixture was stirred overnight at room temperature. The reaction solution was distilled under reduced pressure, and acetonitrile (70 mL) was added for dilution, and then 5 mol / L aqueous sodium hydroxide solution (28 mL) was added dropwise under ice cooling. 2-[(4-chloropyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide (4.9 g) obtained in Reference Example 1 was added, and the mixture was stirred at room temperature for 5 hours. Water (200 mL) was added to the reaction solution, and the precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure to obtain the title compound (7.3 g).

[0331] Example 24: 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide 1L(+)-tartrate [ka] L(+)-tartaric acid (0.48 g) was added to a solution of the compound of Example 6 (2.0 g) in THF (5 mL), and the mixture was stirred for 1 hour at 60° C. After cooling, the precipitated solid was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give the title compound (2.0 g) as crystals (Form IV crystals). 1H-NMR (400 MHz, DMSO-d6) δ: 8.28 (1H, s), 7.73 (1H, d, J = 5.5 Hz), 7.26-7.17 (2H, m), 7.02 (1H, m), 5.08 (1H, s), 4.85 (1H, s), 4.32 (1H, s), 4.06-3.83 (total 6H, m), 3.68 (1H, m), 3.63-3.39 (total 4H, m), 3.32 (2H, br s), 2.66 (1H, m), 2.54 (1H, br s), 2.39 (1H, m), 1.91-1.64 (total 5H, m), 1.60-1.47 (3H, m), 1.42 (3H, d, J = 6.9 Hz), 1.33 (3H, d, J = 6.4 Hz), 1.08 (3H, d, J = 6.9 Hz), 0.98 (3H, d, J = 6.4 Hz). [Form IV] The powder X-ray diffraction pattern is shown in FIG. Major diffraction peaks: 2θ(°)=5.1, 6.3, 9.0, 10.5, 12.3, 12.6, 13.3, 15.3, 17.1, 17.2, 18.0 Characteristic diffraction peaks: 2θ(°)=5.1, 6.3, 9.0, 15.3, 17.2, 18.0

[0332] Example 25 : 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide di-succinate [ka] To a solution of the compound of Example 6 (2.0 g) in ethyl acetate (8 mL), succinic acid (0.78 g) was added and the mixture was stirred for 1 hour at 60° C. After cooling, the precipitated solid was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to obtain the title compound (1.9 g) as crystals (V-form crystals). 1H-NMR (400 MHz, DMSO-d6) δ: 8.27 (1H, s), 7.75 (1H, d, J = 4.6 Hz), 7.25-7.18 (2H, m), 7.06 (1H, m), 5.03 (1H, s), 4.81 (1H, s), 4.81 (1H, s), 3.96 (2H, br s), 3.87 (2H, br d, J = 9.1 Hz), 3.68 (1H, m), 3.60-3.37 (total 3H, m), 3.31 (3H, br s), 2.59 (1H, br d, J = 17.4 Hz), 2.47 (1H, br s), 2.40-2.27 (total 9H, m), 1.85-1.62 (total 5H, m), 1.57-1.45 (total 3H, m), 1.42 (3H, d, J = 6.9 Hz), 1.33 (3H, d, J = 6.4 Hz), 1.08 (3H, d, J = 6.4 Hz), 0.98 (3H, d, J = 6.9 Hz). [Form V] The powder X-ray diffraction pattern is shown in FIG. Major diffraction peaks: 2θ(°)=4.9, 8.1, 8.6, 9.8, 13.9, 14.5, 17.2, 17.8, 18.4, 19.0, 20.5 Characteristic diffraction peaks: 2θ(°)=8.1, 8.6, 9.8, 14.5, 17.2, 17.8, 18.4

[0333] Test Example Test Example 1: Menin-MLL binding inhibition experiment Menin, which has an N-terminal 6xHis tag and an HA tag, and a C-terminal myc tag 1-615 (Hereafter His-Menin 1-615) was diluted with assay buffer (25 mmol / L HEPES, 150 mmol / L NaCl, 1 mmol / L dithiothreitol, 0.5% (w / v) Tween 80, 0.3% (w / v) BSA, 0.3% (w / v) skim milk) to a final concentration of 30 nmol / L. The evaluation compound was diluted with assay buffer to a compound concentration of 0.005 to 5 μmol / L. 1-615 The mixture was added to a light-shielding 384-well low-volume plate (Corning, #4514) at 2 μL / well, and the compound to be evaluated was added at 6 μL / well, and incubated at room temperature for 3 hours with a light-shielding lid (Corning, #3935). After incubation, MLL with a FLAG tag inserted at the C-terminus was 1-172 (M.L.L. 1-172 -FLAG) was diluted with the assay buffer to a final concentration of 50 nmol / L. 1-172 -FLAG was added to the plate at 2 μL / well, the plate was covered with a light-proof lid, and incubated at room temperature for 1 hour. Next, anti-6HIS-d2 antibody (cisbio, 61HISDLA) and anti-FLAGM2-K antibody (cisbio, 61FG2KLA) were diluted with antibody dilution buffer (50 mmol / L Tris, 150 mmol / L NaCl, 800 mmol / L KF, pH 7.4) to a final concentration of 1.4 μg / mL to prepare an antibody mixture. The prepared antibody mixture was added to the previous plate at 10 μL / well, covered, and incubated at 4°C for 17 to 24 hours. After incubation, signals were detected using a RUBYstar (BMG LABTECH). The binding inhibition rate (%) at each concentration of the evaluation compound was calculated using the formula shown below, and the IC corresponding to the concentration of the evaluation compound at which the binding inhibition rate was 50% was calculated. 50 The value was calculated.

[0334] Binding inhibition rate (%)={1-(AC) / (BC)}×100 A: Signal in the presence of the test compound B: Signal in negative control (absence of test compound) C: Signal in positive control (in the presence of a known compound at a concentration of 100% inhibition)

[0335] The evaluation results of Test Example 1 are shown in the table below. [Table 3]

[0336] As shown in the above table, the compounds of Examples 1, 3, 4, 5, 6, 7, 8, 9, 10 and 11 exhibited strong Menin-MLL binding inhibitory activity. Among them, the compounds of Examples 3, 6, 7 and 10 exhibited particularly strong Menin-MLL binding inhibitory activity in cells.

[0337] Test Example 2: Cell proliferation inhibition experiment RS4;11 cells were obtained from the American Type Culture Collection (ATCC). The cells were cultured in RPMI1640 medium containing 10% fetal bovine serum and 1% penicillin / streptomycin at 37°C in the presence of 5% CO2. Separately, MOLM-13 cells were obtained from DSMZ (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH). The cells were cultured in RPMI1640 medium containing 20% ​​fetal bovine serum and 1% penicillin / streptomycin at 37°C in the presence of 5% CO2. 2000 cells were seeded per well in a 96-well plate, and the evaluation compound was added so that the final concentration of DMSO was 0.1%, and the cells were cultured for 7 days. After the culture was completed, the cell viability was calculated using PrestoBlue (registered trademark) Cell Viability Reagent (Invitrogen, A13261). From the survival curve, the IC value, which corresponds to the concentration of the evaluation compound that shows a 50% inhibition rate of cell proliferation, was calculated. 50 The value was calculated.

[0338] The evaluation results of Test Example 2 are shown in the table below. [Table 4]

[0339] As shown in the above table, the compounds of Examples 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 14, 15, 16, 18, 19 and 20 exhibited strong cell proliferation inhibitory effects.

[0340] Test Example 3: mRNA transcription regulation experiment by test substance MV4;11 cells were obtained from the American Type Culture Collection (ATCC). The cells were cultured in RPMI1640 medium containing 10% fetal bovine serum and 1% penicillin / streptomycin at 37°C and 5% CO2. The MV4;11 cells were added with a final concentration of 1 μmol / L of the evaluation compound, and then cultured at 37°C and 5% CO2 for 20 to 24 hours. After the culture was completed, total RNA was extracted from the cells using RNeasy (registered trademark) Mini Kit (QIAGEN, 74106), and cDNA was synthesized using Superscript (registered trademark) VILO (registered trademark) cDNA Synthesis Kit (Invitrogen, #11754250). The mRNA expression level was quantified from the obtained cDNA using TaqMan® Gene Expression Master Mix (Applied Biosystems, 4369016) and TaqMan® probe (Applied Biosystems) on a 7900HT (Applied Biosystems). The mRNA expression level of each gene (MEIS1 and HOXA9) obtained was corrected by the mRNA expression level of GAPDH.

[0341] The evaluation results of Test Example 3 are shown in the table below. [Table 5]

[0342] As shown in the above table, the compounds of Examples 1, 3, 4, 5, 6, 7, 8, 9, 10 and 11 showed mRNA transcriptional regulation resulting from inhibition of binding between Menin and MLL fusion protein. In particular, the compound of Example 5 exhibited a good cell proliferation inhibitory effect.

[0343] Test Example 4: hERG Inhibition Test Test substances were added to cultured CHO cell line cells stably expressing the hERG (human Ether-a-go-go Related Gene) gene so that the final DMSO concentration was 0.0135-0.5%. The hERG current was measured using a QPatch HT (Sophion), and the concentration at which each test substance inhibited the hERG current by 50% (IC 50 Values ​​(μM) were calculated.

[0344] The compounds obtained in the Examples were subjected to the test shown in Test Example 4. For each compound in the Examples, the compound concentration at which the hERG current obtained in Test Example 4 was inhibited by 50% was divided by the compound concentration at which the proliferation inhibition rate of RS4;11 cells obtained in Test Example 2 was inhibited by 50% to calculate hERG / RS4;11. The results are shown in the table below. [Table 6]

[0345] As shown in the above table, the compounds of Examples 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 18 and 19 were shown to have a 100-fold or greater difference between the compound concentration at which the proliferation inhibition rate of RS4;11 cells was 50% and the compound concentration at which the hERG current was 50% inhibited. In particular, the compounds of Examples 6, 7, 15, 16 and 18 were shown to have a favorable 1000-fold or greater difference between the compound concentration at which the proliferation inhibition rate of RS4;11 cells was 50% and the compound concentration at which the hERG current was 50% inhibited. [Industrial Applicability]

[0346] The compounds of the present invention can exert anticancer effects by inhibiting the binding of MLL fusion protein to menin.

Claims

[Claim 1] The invention described in the specification.

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