JP7454520B2 - Pharmaceuticals consisting of optically active azabicyclo ring derivatives - Google Patents

Description

The present invention relates to optically active azabicyclo ring derivatives useful as pharmaceuticals, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing these, or to pathological conditions involving the binding of menin and MLL containing these compositions. The present invention relates to a therapeutic or preventive agent for.

MLL leukemia is a disease that accounts for about 6-7% of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), and about 1100 people are newly diagnosed with MLL leukemia every year 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).

It is speculated that the MLL fusion protein fused with the fusion partner gene in this manner causes unrestricted proliferation of undifferentiated hematopoietic cells and causes leukemia (Non-Patent Document 2). It has been reported that MLL fusion protein first binds to menin to form a complex. Therefore, by inhibiting the binding between the MLL fusion protein and menin, which is the first step, it is expected to prevent canceration caused by the MLL fusion protein (Non-Patent Document 3).

It has been reported that MLL acts as a coactivator of androgen signals in prostate cancer. Therefore, small molecule inhibitors targeting the inhibition of the binding between menin and MLL fusion protein are expected to be useful as therapeutic agents for the cancer (Non-Patent Document 4).
In breast cancer, menin has been reported to act as a coactivator of estrogen signals. Therefore, small molecule inhibitors targeting the inhibition of the binding between menin and MLL fusion protein are expected to be useful as therapeutic agents for the 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 cancer. It is expected to be useful as a therapeutic agent for cancer (Non-Patent Document 6).

So far, Patent Documents 1 to 3 have been disclosed as small molecule inhibitors targeting inhibition of binding between menin and MLL fusion protein. However, the compound of the present invention represented by the below-mentioned formula (1), which is an optically active azabicyclo ring derivative, is not disclosed or suggested in these documents.

International Publication No. 2017/112768 International Publication No. 2017/214367 International Publication No. 2018/050686

Look A. T, Science, 278 (5340): 1059-1064 (1997) Yokoyama A, et al., Cell 123 (2): 207-18 (2005) Yokoyama A, et al., Cancer Cell. 14(1): 34-46 (2008) Malik, R. et al., Nature Medicine. 21(4):344-352 (2015) Imacho, H et al., Breast Cancer Res Treat. 122(2):395-407 (2010) Svoboda, L. K. et al., Oncotargrt. 8(1):458-471 (2017)

The problem to be solved by the present invention is to prevent cancer by inhibiting the binding of MLL (mixed lineage leukemia) fusion protein with AF4, AF9, etc., which are typical fusion partner genes that cause MLL leukemia, and menin. The objective is to provide compounds that exhibit this effect. More preferably, in addition to exhibiting an anticancer effect by inhibiting the binding between menin and the MLL fusion protein, the compound has a wide disparity between the concentration of the compound that suppresses cell proliferation and the concentration of the compound that suppresses hERG current. The objective is to provide compounds that can be expected to be highly safe. That is, the objective is to provide an antitumor agent with high therapeutic efficacy.

As a result of extensive studies, the present inventors have found that the compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as the "compound of the present invention") The present inventors have discovered that they exhibit excellent antitumor effects by having a strong inhibitory effect on the binding between MLL fusion protein and MLL fusion protein, and have completed the present invention.

That is, the present invention is as follows.

[Section 1]
Formula (1):
[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, cyano, nitro, carboxyl, sulfonic acid, -OR ⁷ , -SR ⁷ , -COR ⁸ , -CO ₂ R ⁸ , -CONR ⁹ R ¹⁰ , -SO ₂ R ⁸ , -SO ₂ NR ⁹ R ¹⁰ , -OCOR ⁸ , -OCO ₂ R ⁸ , -OCONR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ , -NR ¹¹ COR ⁸ , - NR ¹¹ CO ₂ R ⁸ , -NR ¹¹ CONR ⁹ R ¹⁰ , -NR ¹¹ SO ₂ R ⁸ , -NR ¹¹ SO ₂ NR ⁹ R ¹⁰ , or -MQ, or R ¹ and R ² and /or R ³ and R ⁴ may each independently form =O, =CR ^12A R ^13A , =N-NR ^12B R ^13B or =N-OR ^12B together,
When there is a plurality of M, each independently represents an optionally substituted C _1-6 alkylene, an optionally substituted C _2-6 alkenylene, an optionally substituted C 2-6 alkynylene, or an 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, or optionally substituted 5- to 12-membered represents heteroarylene,
If there are multiple Qs, each independently represents a hydrogen atom, an optionally substituted C _3-10 cycloalkyl, an optionally substituted 3- to 10-membered saturated heterocyclic group, an optionally substituted C _6-10 aryl or optionally substituted 5- to 12-membered heteroaryl,
If there is more than one R ⁷ , each independently represents a hydrogen atom, an optionally substituted C _1-6 alkyl, an optionally substituted C _2-6 alkenyl, an 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 optionally substituted 5 ～represents a 12-membered heteroaryl,
If there are multiple R ^8s , each independently represents C _1-6 alkyl;
R ⁹ , R ¹⁰ and R ¹¹ each independently represent a hydrogen atom or C _1-6 alkyl, and when there is a plurality of R ⁹ , R ¹⁰ or R ¹¹ , each of R ⁹ , R ¹⁰ or R ¹¹ may be the same or different, and here, when R ⁹ and R ¹⁰ that are bonded to the same nitrogen atom are both C _1-6 alkyl, these together with the nitrogen atom that they are bonded to are 3 to 8 may form a nitrogen-containing saturated heterocycle,
R ^12A and R ^13A are each independently a hydrogen atom, a halogen atom, cyano, nitro, carboxyl, sulfonic acid, -COR ¹⁴ , -CO ₂ R ¹⁴ , -CONR ¹⁵ R ¹⁶ , -SO ₂ R ¹⁴ , - SO ₂ NR ¹⁵ R ¹⁶ , optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _3-10 cycloalkyl, an optionally substituted 3- to 10-membered saturated heterocyclic group, an optionally substituted C _6-10 aryl, or an optionally substituted 5- to 12-membered heteroaryl, When there is a plurality of R ^12A or R ^13A , each of R ^12A or R ^13A may be the same or different; here, when R ^12A and R ^13A are both optionally substituted C _1-6 alkyl, These may form a 3- to 8-membered saturated carbon ring together with the carbon atoms to which they are bonded,
R ^12B and R ^13B are each independently a hydrogen atom, an optionally substituted C _1-6 alkyl, an optionally substituted C _2-6 alkenyl, an 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 optionally substituted 5- to Represents a 12-membered heteroaryl, and when there is a plurality of R ^12B or R ^13B , each of R ^12B or R ^13B may be the same or different, and here, R ^12B and R ^13B may both be substituted. When C _1-6 alkyl, these may form a 3- to 8-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which they are bonded,
When there are multiple R ¹⁴ , each independently represents C _1-6 alkyl,
R ¹⁵ and R ¹⁶ each independently represent a hydrogen atom or C _1-6 alkyl, and when there is a plurality of R ¹⁵ or R ¹⁶ , each of R ¹⁵ or R ¹⁶ may be the same or different; In, when R ¹⁵ and R ¹⁶ bonded to the same nitrogen atom are both C _1-6 alkyl, they form a 3- to 8-membered nitrogen-containing saturated heterocycle together with the nitrogen atom bonded to each. It is okay to do
X represents -C(O)- or C _1-6 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 are each independently a hydrogen atom, a halogen atom, cyano, nitro, carboxyl, sulfonic acid, -OR ¹⁷ , -SR ¹⁷ , -COR ¹⁸ , -CO ₂ R ¹⁸ , -CONR ¹⁹ R ²⁰ , -SO ₂ R ¹⁸ , -SO ₂ ^{NR 19} R ²⁰ , -OCOR ¹⁸ , -OCO ₂ R ¹⁸ , -OCONR ¹⁹ R ²⁰ , -NR ¹⁹ R ²⁰ , - NR ²¹ COR ¹⁸ , -NR ²¹ CO ₂ R ¹⁸ , -NR ²¹ CONR ¹⁹ R ²⁰ , -NR ²¹ SO ₂ R ¹⁸ , -NR ²¹ SO ₂ NR ¹⁹ R ²⁰ , optionally substituted C _1-6 alkyl , represents an optionally substituted C _2-6 alkenyl or an optionally substituted C _2-6 alkynyl,
R ¹⁷ , R ¹⁹ , R ²⁰ and R ²¹ each independently represent a hydrogen atom or C _1-6 alkyl, and when there is a plurality of R ¹⁷ , R ¹⁹ , R ²⁰ or R ²¹ , R ¹⁷ , R ¹⁹ , R ²⁰ or R ²¹ may be the same or different, and here, when R ¹⁹ and R ²⁰ bonded to the same nitrogen atom are both C _1-6 alkyl, these are the same or different from the nitrogen atom bonded to each. Together, they may form a 3- to 8-membered nitrogen-containing saturated heterocycle,
When there are multiple R ^18s , each independently represents C _1-6 alkyl;
U represents CR ²² or a nitrogen atom,
R ²² is a hydrogen atom, a halogen atom, a C _1-3 alkyl (the alkyl is substituted with the same or different 1 to 5 substituents selected from a fluorine atom, -OR ²³ and -NR ²³ R ²⁴ ); ), -CO ₂ R ²⁵ , -CONR ²⁶ R ²⁷ or cyano;
R ²³ and R ²⁴ each independently represent a hydrogen atom or C _1-6 alkyl, and when there is a plurality of R ²³ or R ²⁴ , each of R ²³ or R ²⁴ may be the same or different; In, when R ²³ and R ²⁴ bonded to the same nitrogen atom are both C _1-6 alkyl, these together with the nitrogen atom bonded to each form a 3- to 8-membered nitrogen-containing saturated heterocycle. It is okay to do
R ²⁵ represents C _1-6 alkyl,
R ²⁶ and R ²⁷ each independently represent a hydrogen atom or C _1-6 alkyl, and when R ²⁶ and R ²⁷ bonded to the same nitrogen atom are both C _1-6 alkyl, they are Each may form a 3- to 8-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which it is bonded,
Y represents -O-, -S-, -CR ²⁸ R ²⁹ -, -NR ²⁸ -,
R ²⁸ and R ²⁹ each independently represent a hydrogen atom or C _1-6 alkyl,
Z is a hydrogen atom, a halogen atom, cyano, nitro, carboxyl, sulfonic acid, -OR ³⁰ , -SR ³⁰ , -COR ³¹ , -CO ₂ R ³¹ , -CONR ³² R ³³ , -SO ₂ R ³¹ , -SO ₂ NR ³² R ³³ , -OCOR ³¹ , -OCO ₂ R ³¹ , -OCONR ³² R ³³ , -NR ³² R ³³ , -NR ³⁴ COR ³¹ , -NR ³⁴ CO ₂ R ³¹ , -NR ³⁴ CONR ³² R ³³ , -NR ³⁴ SO ₂ R ³¹ , -NR ³⁴ SO ₂ NR ³² R ³³ , 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 optionally substituted C 6-10 aryl represents a good 5- to 12-membered heteroaryl,
R ³⁰ , R ³² , R ³³ and R ³⁴ are each independently a hydrogen atom, C _1-6 alkyl (the alkyl is the same or (optionally substituted with 1 to 5 different substituents) or C _3-10 cycloalkyl, where R ³² and R ³³ bonded to the same nitrogen atom are both C _1-6 alkyl , these may form a 3- to 8-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which they are bonded,
R ³¹ represents C _1-6 alkyl which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom and hydroxyl group]
A medicament containing the compound represented by or a pharmaceutically acceptable salt thereof.

[Section 2]
R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, a halogen atom, -OR ⁷ or -MQ, or R ¹ and R ² and/or R ³ and R ⁴ may be taken together and each independently form =O or =CR ^12A R ^13A ,
R ^12A and R ^13A are each independently a hydrogen atom, a halogen atom, a cyano, an optionally substituted C _1-6 alkyl, an optionally substituted C _2-6 alkenyl, an 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 substituted is a 5- to 12-membered heteroaryl which may be a 5- to 12-membered heteroaryl, and when there is a plurality of R ^12A or R ^13A , each of R ^12A or R ^13A may be the same or different, and here, R ^12A and R ^13A are both substituted. When C _1-6 alkyl, which may be
The medicament according to item 1.

[Section 3]
C _1-6 alkylene which may be substituted in 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 _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 5-12 membered The heteroaryl of
(1) Halogen atom,
(2) hydroxyl group,
(3) C _6-10 aryl,
(4) 5-12 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) 3- to 10-membered saturated heterocyclic group,
(11) carboxyl,
(12)-COR ^35A ,
(13)-CO ₂ R ^35A ,
(14)-CONR ^36A R ^37A ,
(15)-NR ^36A R ^37A ,
(16)-NR ^36A COR ^35A ,
(17)-NR ^36A SO ₂ R ^35A ,
(18)-SO ₂ R ^35A ,
(19)-SO ₂ NR ^36A R ^37A ,
(20) sulfonic acid,
(21) phosphoric acid,
(22) cyano, and (23) may be substituted with 1 to 5 different substituents selected from the group consisting of nitro;
Here, the above (3) C _6-10 aryl, (4) 5-12 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, and (10) 3- to 10-membered saturated heterocyclic group,
(a) halogen atom,
(b) 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) 3- to 10-membered saturated heterocyclic group,
(k) carboxyl,
(l)-COR ^35B ,
(m)-CO ₂ R ^35B ,
(n)-CONR ^36B R ^37B ,
(o)-NR ^36B R ^37B ,
(p)-NR ^36B COR ^35B ,
(q)-NR ^36B SO ₂ R ^35B ,
(r)-SO ₂ R ^35B ,
(s)-SO ₂ NR ^36B R ^37B ,
(t) sulfonic acid,
(u) phosphoric acid,
(v) cyano, and (w) nitro, which may be substituted with 1 to 5 same or different substituents;
If there are multiple R ^35A , each independently represents C _1-6 alkyl;
R ^36A and R ^37A each independently represent a hydrogen atom or C _1-6 alkyl, and when there is a plurality of R ^36A or R ^37A , each of R ^36A or R ^37A may be the same or different; In, when R ^36A and R ^37A bonded to the same nitrogen atom are both C _1-6 alkyl, these together with the nitrogen atom bonded to each form a 3- to 8-membered nitrogen-containing saturated heterocycle. It is okay to do
When there are multiple R ^35B , each independently represents C _1-6 alkyl,
R ^36B and R ^37B each independently represent a hydrogen atom or C _1-6 alkyl, and when there is a plurality of R ^36B or R ^37B , each of R ^36B or R ^37B may be the same or different; In, when R ^36B and R ^37B bonded to the same nitrogen atom are both C _1-6 alkyl, these together with the nitrogen atom bonded to each form a 3- to 8-membered nitrogen-containing saturated heterocycle. You may do so.
The medicament according to item 1 or 2.

[Section 4]
Optionally substituted C _1-6 alkylene in 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 _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 5-12 membered The heteroaryl of
(1) Halogen atom,
(2) hydroxyl group,
(3) phenyl,
(4) 5- to 6-membered heteroaryl,
(5) C _1-6 alkyl optionally substituted with 1 to 3 hydroxyl groups,
(6) C _2-6 alkynyl,
(7) C _1-6 alkoxy,
(8) C _3-7 cycloalkyl,
(9) 3- to 7-membered saturated heterocyclic group,
(10)-COR ^35A ,
(11)-CO ₂ R ^35A ,
(12)-CONR ^36A R ^37A ,
(13)-NR ^36A R ^37A ,
(14)-NR ^36A COR ^35A ,
(15)-NR ^36A SO ₂ R ^35A ,
(16)-SO ₂ R ^35A ,
(17)-SO ₂ NR ^36A R ^37A ,
(18) cyano, and (19) may be substituted with 1 to 5 different substituents selected from the group consisting of nitro;
When there are multiple R ^35A , each independently is C _1-6 alkyl,
R ^36A and R ^37A are each independently a hydrogen atom or C _1-6 alkyl, and when there is a plurality of R ^36A or R ^37A , each of R ^36A or R ^37A may be the same or different; In, when R ^36A and R ^37A bonded to the same nitrogen atom are both C _1-6 alkyl, these together with the nitrogen atom bonded to each form a 3- to 6-membered nitrogen-containing saturated heterocycle. You may do so.
The medicament according to any one of Items 1 to 3.

[Section 5]
X is -C(O)-,
Y is -O-,
The medicament according to any one of Items 1 to 4.

[Section 6]
R ^5A , R ^5B , R ^6A , R ^6B and R ^6D are hydrogen atoms,
R ^6C is a fluorine atom,
The medicament according to any one of Items 1 to 5.

[Section 7]
U is CR ²² or a nitrogen atom,
R ²² is -CF ₃ or cyano,
The medicament according to any one of Items 1 to 6.

[Section 8]
U is a nitrogen atom,
The medicament according to any one of items 1 to 7.

[Section 9]
Z is -CONR ³² R ³³ , a 3- to 6-membered saturated heterocyclic group (the saturated heterocyclic group is the same or different 1 to 3 members selected from C _1-3 alkyl or C _3-6 cycloalkyl); (optionally substituted with a substituent), phenyl ( _the phenyl _is the same or a 5- to 6-membered heteroaryl which may be substituted with 1 to 3 different substituents), or a 5- to 6-membered heteroaryl which may be substituted with 1 to 3 C _1-3 alkyl,
R ³² and R ³³ are each independently a hydrogen atom or C _1-3 alkyl, and when R ³² and R ³³ bonded to the same nitrogen atom are both C _1-6 alkyl, these are Each may form a 3- to 6-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which it is bonded,
The medicament according to any one of items 1 to 8.

[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):
[In the formula, * represents the bonding position with the aromatic ring]
is,
Item 10. The medicament according to any one of Items 1 to 9.

[Section 11]
Z is (Z-3),
The medicament according to item 10.

[Section 12]
When there is more than one M, each independently represents C _1-6 alkylene (the alkylene is a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a C _2-4 alkynyl, a C _1-3 alkoxy, -CONR ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A , and 1 to 5 different ones selected from the group consisting of 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, a C _1-3 alkyl, a C _2-4 alkynyl, C _1-3 alkoxy, -CONR ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano), which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of
When there is a plurality of Q, each independently represents a hydrogen atom, a C _3-10 cycloalkyl, a 3- to 10-membered saturated heterocyclic group, a C _6-10 aryl, or a 5- to 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, a C _1-3 alkyl, a C _2-4 alkynyl, a C _1-3 alkoxy, -CONR The same or different 1 selected from the group consisting of ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano (optionally substituted with ~5 substituents),
When there is more than one R ⁷ , each independently represents a hydrogen atom, a C _1-6 alkyl (the alkyl is a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, phenyl, a 5- to 6-membered heteroaryl, a 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 SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano), C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3- to 10-membered saturated heterocyclic group, C _6-10 aryl or 5- to 12-membered heteroaryl (said alkenyl, said alkynyl, said cycloalkyl, said saturated heterocyclic group) The group, the aryl, and the heteroaryl each independently represent a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a C _1-3 alkyl, a C _2-4 alkynyl, a C _1-3 alkoxy, -CONR ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and 1 to 5 same or different selected from the group consisting of cyano (optionally substituted with a substituent),
R ^12A and R ^13A are each independently a hydrogen atom, a halogen atom, a cyano, a C _1-6 alkyl (the alkyl is a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a C _2-4 alkynyl, a C _{1- 3} alkoxy, -CONR ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3- to 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) , 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 SO ₂ R ^35A , -SO ₂ (optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of R ^35A , -SO ₂ NR ^{36A ,} R ^37A and cyano), and when there is a plurality of R ^12A or R ^13A , , R ^12A or R ^13A may be the same or different, and here, when R ^12A and R ^13A are both C _1-6 alkyl, these together with the carbon atoms to which they are bonded represent 3 to It may form an 8-membered saturated carbon ring,
When there are multiple R ^35A , each independently represents C _1-6 alkyl,
R ^36A and R ^37A each independently represent a hydrogen atom or C _1-6 alkyl, and when there is a plurality of R ^36A or R ^37A , each of R ^36A or R ^37A may be the same or different; In, when R ^36A and R ^37A bonded to the same nitrogen atom are both C _1-6 alkyl, these together with the nitrogen atom bonded to each form a 3- to 8-membered nitrogen-containing saturated heterocycle. You may do so.
The medicament according to any one of Items 1 to 11.

[Section 13]
Formula (1a):
[In the formula,
p represents 1 or 2,
R ¹ , R ² , R ³ and R ⁴ each independently represent a hydrogen atom, a halogen atom, -OR ⁷ , or -MQ, or R ¹ and R ² and/or R ³ and R ⁴ may be taken together and each independently form =O or =CR ^12A R ^13A ,
When there is more than one M, each independently represents C _1-6 alkylene (the alkylene is a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a C _2-4 alkynyl, a C _1-3 alkoxy, -CONR ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A , and 1 to 5 different ones selected from the group consisting of 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, a C _1-3 alkyl, a C _2-4 alkynyl, C _1-3 alkoxy, -CONR ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano), which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of
If there is more than one Q, each Q independently represents a hydrogen atom, a C _3-10 cycloalkyl, a 3- to 10-membered saturated heterocyclic group, a C _6-10 aryl, or a 5- to 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, a C _1-3 alkyl, a C _2-4 alkynyl, a C _1-3 alkoxy, -CONR The same or different 1 selected from the group consisting of ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano - optionally substituted with 5 substituents),
When there is more than one R ⁷ , each independently represents a hydrogen atom, a C _1-6 alkyl (the alkyl is a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, phenyl, a 5- to 6-membered heteroaryl, a 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 SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano), C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3- to 10-membered saturated heterocyclic group, C _6-10 aryl or 5- to 12-membered heteroaryl (said alkenyl, said alkynyl, said cycloalkyl, said saturated heterocyclic group) The group, the aryl, and the heteroaryl each independently represent a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a C _1-3 alkyl, a C _2-4 alkynyl, a C _1-3 alkoxy, -CONR ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and 1 to 5 same or different selected from the group consisting of cyano (optionally substituted with a substituent),
R ^12A and R ^13A each independently represent a hydrogen atom, a halogen atom, a C _1-6 alkyl (the alkyl is a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a C _2-4 alkynyl, a C _1-3 alkoxy , -CONR ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano or may be substituted with 1 to 5 different substituents), C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3- to 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 SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano), and when there are multiple R ^12A or R ^13A , R Each of ^12A or R ^13A may be the same or different, and when R ^12A and R ^13A are both C _1-6 alkyl, these together with the carbon atom to which they are bonded are 3- to 8-membered. may form a saturated carbon ring,
When there are multiple R ^35A , each independently represents C _1-6 alkyl;
R ^36A and R ^37A each independently represent a hydrogen atom or C _1-6 alkyl, and when there is a plurality of R ^36A or R ^37A , each of R ^36A or R ^37A may be the same or different; In, when R ^36A and R ^37A bonded to the same nitrogen atom are both C _1-6 alkyl, these together with the nitrogen atom bonded to each form a 3- to 6-membered nitrogen-containing saturated heterocycle. It is okay to do
a, b, c and d each independently represent 1 or 2]
The medicament according to item 1, which is represented by:

[Section 14]
When there is more than one M, each independently represents C _1-6 alkylene (the alkylene is a fluorine atom, a hydroxyl group, a C _2-4 alkynyl, a C _1-3 alkoxy, -CONR ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano, substituted with the same or different 1 to 5 substituents ), and
When there are multiple R ^35A , each independently represents C _1-6 alkyl,
R ^36A and R ^37A each independently represent a hydrogen atom or C _1-6 alkyl, and when there is a plurality of R ^36A or R ^37A , each of R ^36A or R ^37A may be the same or different; In, when R ^36A and R ^37A bonded to the same nitrogen atom are both C _1-6 alkyl, these together with the nitrogen atom bonded to each form a 3- to 6-membered nitrogen-containing saturated heterocycle. You may do so.
The medicament according to any one of Items 1 to 13.

[Section 15]
When there is a plurality of Q, each independently represents a C _3-10 cycloalkyl, a 3- to 10-membered saturated heterocyclic group, a C _6-10 aryl, or a 5- to 12-membered heteroaryl (the cycloalkyl, the saturated heterocyclic group) The ring group, the aryl, and the heteroaryl each independently represent a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a C _1-3 alkyl, a C _2-4 alkynyl, a C _1-3 alkoxy, -CONR ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A , and 1 to 5 different ones selected from the group consisting of cyano (optionally substituted with a substituent),
When there are multiple R ^35A , each independently represents C _1-6 alkyl,
R ^36A and R ^37A each independently represent a hydrogen atom or C _1-6 alkyl, and when there is a plurality of R ^36A or R ^37A , each of R ^36A or R ^37A may be the same or different; In, when R ^36A and R ^37A bonded to the same nitrogen atom are both C _1-6 alkyl, these together with the nitrogen atom bonded to each form a 3- to 6-membered nitrogen-containing saturated heterocycle. You may do so.
The medicament according to any one of Items 1 to 14.

[Section 16]
When there is a plurality of R ⁷ s, each independently represents a hydrogen atom, a C _1-6 alkyl (the alkyl is a group consisting of a fluorine atom, phenyl, a C _3-7 cycloalkyl, and a 3- to 7-membered saturated heterocyclic group). ), C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3- to 10-membered saturated heterocycle group (the cycloalkyl and the saturated heterocyclic group may each be independently substituted with the same or different 1 to 5 substituents selected from the group consisting of a fluorine atom and C _1-3 alkyl) ), C _6-10 aryl or 5-12 membered heteroaryl (said aryl and said heteroaryl are each independently selected from the group consisting of fluorine atom, chlorine atom, bromine atom and C _1-3 alkyl) optionally substituted with the same or different 1 to 5 substituents),
The medicament according to any one of Items 1 to 15.

[Section 17]
When there are multiple R ⁷ s, each independently represents a hydrogen atom, C _1-6 alkyl optionally substituted with one phenyl, or C _2-6 alkenyl;
Item 17. The medicament according to any one of Items 1 to 16.

[Section 18]
R ^12A and R ^13A are each independently a hydrogen atom, a C _1-6 alkyl (the alkyl is a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a C _2-4 alkynyl, a C _1-3 alkoxy, -CONR The same or different 1 selected from the group consisting of ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano (optionally substituted with ~5 substituents), 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, a C _1-3 alkyl, a C _2-4 alkynyl, a C _1-3 alkoxy, -CONR The same or different 1 selected from the group consisting of ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano (optionally substituted with ~5 substituents), and when there is a plurality of R ^12A or R ^13A , each of R ^12A or R ^13A may be the same or different; here, R ^12A and R 13A are When both ^13A are C _1-6 alkyl, these may form a 3- to 8-membered saturated carbon ring together with the carbon atoms to which they are bonded,
When there are multiple R ^35A , each independently represents C _1-6 alkyl,
R ^36A and R ^37A each independently represent a hydrogen atom or C _1-6 alkyl, and when there is a plurality of R ^36A or R ^37A , each of R ^36A or R ^37A may be the same or different; In, when R ^36A and R ^37A bonded to the same nitrogen atom are both C _1-6 alkyl, these together with the nitrogen atom bonded to each form a 3- to 6-membered nitrogen-containing saturated heterocycle. You may do so.
Item 18. The medicament according to any one of Items 1 to 17.

[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 ⁷ , or -MQ, or R ¹ and R ² and/or R ³ R ⁴ may be taken together and each independently form =O or =CR ^12A R ^13A ,
When there is more than one M, each independently represents C _1-6 alkylene (the alkylene is a fluorine atom, a hydroxyl group, a C _2-4 alkynyl, a C _1-3 alkoxy, -CONR ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano, substituted with the same or different 1 to 3 substituents ), and
When there is a plurality of Q, each independently represents a C _3-10 cycloalkyl, a 3- to 10-membered saturated heterocyclic group, a C _6-10 aryl, or a 5- to 12-membered heteroaryl (the cycloalkyl, the saturated heterocyclic group) The ring group, the aryl, and the heteroaryl each independently represent a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a C _1-3 alkyl, a C _2-4 alkynyl, a C _1-3 alkoxy, -CONR ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A , and 1 to 3 different ones selected from the group consisting of cyano (optionally substituted with a substituent),
When there are multiple R ⁷ s, each independently represents a hydrogen atom, C _1-6 alkyl optionally substituted with one phenyl, or C _2-6 alkenyl;
R ^12A and R ^13A are each independently a hydrogen atom, a C _1-6 alkyl (the alkyl is a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a C _2-4 alkynyl, a C _1-3 alkoxy, -CONR The same or different 1 selected from the group consisting of ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano ), C _3-10 cycloalkyl, 3- to 10-membered saturated heterocyclic group, C _6-10 aryl or 5- to 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, a C _1-3 alkyl, a C _2-4 alkynyl, a C _1-3 alkoxy, -CONR The same or different 1 selected from the group consisting of ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^37A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^37A R ^37A and cyano -3 substituents), and when there is a plurality of R ^12A or R ^13A , each of R ^12A or R 13A may be the same or different; here, R 12A and R ^13A may be the same or ^different ; When both ^13A are C _1-6 alkyl, these may form a 3- to 8-membered saturated carbon ring together with the carbon atoms to which they are bonded,
When there are multiple R ^35A , each independently is C _1-6 alkyl,
R ^36A and R ^37A are each independently a hydrogen atom or C _1-6 alkyl, and when there is a plurality of R ^36A or R ^37A , each of R ^36A or R ^37A may be the same or different; In, when R ^36A and R ^37A bonded to the same nitrogen atom are both C _1-6 alkyl, these together with the bonded nitrogen atom form a 3- to 6-membered nitrogen-containing saturated heterocycle. It's okay,
a, b, c and d are each independently 1 or 2,
Item 19. The medicament according to any one of Items 1 to 18.

[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 are may be taken together and each independently form =O or =CR ^12A R ^13A ,
20. The medicament according to any one of items 1 to 19.

[Section 21]
When there is a plurality of M, each independently represents C _1-3 alkylene (the alkylene is selected from the group consisting of a fluorine atom, C _2-4 alkynyl, C _1-3 alkoxy, -NR ^36A R ^37A and cyano); may be substituted with the same or different 1 to 3 substituents),
R ^36A and R ^37A are each independently a hydrogen atom or C _1-6 alkyl, and when there is a plurality of R ^36A or R ^37A , each of R ^36A or R ^37A may be the same or different; In, when R ^36A and R ^37A bonded to the same nitrogen atom are both C _1-6 alkyl, these together with the bonded nitrogen atom form a 3- to 6-membered nitrogen-containing saturated heterocycle. may be,
Item 20. The medicament according to any one of Items 1 to 20.

[Section 22]
When there are multiple M, each independently is C _1-3 alkylene,
Item 22. The medicament according to any one of Items 1 to 21.

[Section 23]
When there is a plurality of Q, each independently represents a C _3-6 cycloalkyl, a 3- to 6-membered saturated heterocyclic group, 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, a C _1-3 alkyl, a C _2-4 alkynyl, a C _1-3 alkoxy, -CONR ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano, substituted with the same or different 1 to 3 substituents ), and
When there are multiple R ^35A , each independently is C _1-6 alkyl,
R ^36A and R ^37A are each independently a hydrogen atom or C _1-6 alkyl, and when there is a plurality of R ^36A or R ^37A , each of R ^36A or R ^37A may be the same or different; In, when R ^36A and R ^37A bonded to the same nitrogen atom are both C _1-6 alkyl, these together with the bonded nitrogen atom form a 3- to 6-membered nitrogen-containing saturated heterocycle. may be,
Item 23. The medicament according to any one of items 1 to 22.

[Section 24]
When there is a plurality of Q, each independently represents a C _3-6 cycloalkyl, a 3- to 6-membered saturated heterocyclic group, phenyl, or a 5- to 6-membered heteroaryl (the cycloalkyl, the saturated heterocyclic group, the Phenyl and the heteroaryl are each independently the same or different 1- to 1-3 selected from the group consisting of a fluorine atom, C _1-3 alkyl, -NR ^36A SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A , and cyano. optionally substituted with 3 substituents),
When there are multiple R ^35A , each independently is C _1-6 alkyl,
R ^36A and R ^37A are each independently a hydrogen atom or C _1-6 alkyl, and when there is a plurality of R ^36A or R ^37A , each of R ^36A or R ^37A may be the same or different; In, when R ^36A and R ^37A bonded to the same nitrogen atom are both C _1-6 alkyl, these together with the bonded nitrogen atom form a 3- to 6-membered nitrogen-containing saturated heterocycle. may be,
The medicament according to any one of Items 1 to 23.

[Section 25]
When there is a plurality of Q, each independently represents C _3-6 cycloalkyl (the cycloalkyl is a fluorine atom, C _1-3 alkyl, -NR ^36A SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano (optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of),
25. The medicament according to any one of items 1 to 24.

[Section 26]
R ^12A and R ^13A are each independently a hydrogen atom, C _1-6 alkyl (the alkyl is selected from the group consisting of a fluorine atom, -NR ^36A SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano); may be substituted with the same or different 1 to 3 substituents), C _3-10 cycloalkyl (the cycloalkyl is a fluorine atom, C _1-3 alkyl, -NR ^36A SO ₂ R ^35A , -SO ₂ NR ^36A (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of R ^37A and cyano), and when there are multiple R ^12A or R ^13A , R ^12A Alternatively, each of R ^13A may be the same or different, and here, when R ^12A and R ^13A are both C _1-3 alkyl, these together with the carbon atom to which they are bonded represent a 3- to 6-membered May form a saturated carbon ring,
When there are multiple R ^35A , each independently is C _1-6 alkyl,
R ^36A and R ^37A are each independently a hydrogen atom or C _1-6 alkyl, and when there is a plurality of R ^36A or R ^37A , each of R ^36A or R ^37A may be the same or different; In, when R ^36A and R ^37A bonded to the same nitrogen atom are both C _1-6 alkyl, these together with the bonded nitrogen atom form a 3- to 6-membered nitrogen-containing saturated heterocycle. may be,
Item 26. The medicament according to any one of Items 1 to 25.

[Section 27]
R ^12A and R ^13A each independently represent a hydrogen atom, C _3-6 cycloalkyl (the cycloalkyl is a fluorine atom, C _1-3 alkyl, -NR ^36A SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano), and when there are multiple R ^12A and R ^13A , each of R ^12A and R ^13A is May be the same or different;
When there are multiple R ^35A , each independently is C _1-6 alkyl,
R ^36A and R ^37A are each independently a hydrogen atom or C _1-6 alkyl, and when there is a plurality of R ^36A or R ^37A , each of R ^36A or R ^37A may be the same or different; In, when R ^36A and R ^37A bonded to the same nitrogen atom are both C _1-6 alkyl, these together with the bonded nitrogen atom form a 3- to 6-membered nitrogen-containing saturated heterocycle. may be,
Item 27. The medicament according to any one of Items 1 to 26.

[Section 28]
a and c are 1,
b and d are both 1 or 2,
Item 28. The medicament according to any one of Items 1 to 27.

[Section 29]
p is 1 or 2,
R ¹ , R ² , R ³ and R ⁴ each independently represent a hydrogen atom, a fluorine atom, or -MQ, or R ¹ and R ² and/or R ³ and R ⁴ are Together, each independently may form =O or =CR ^12A R ^13A ,
When there are multiple M, each independently represents C _1-3 alkylene,
When there is a plurality of Q, each independently represents C _3-6 cycloalkyl (the cycloalkyl is a fluorine atom, C _1-3 alkyl, -NR ^36A SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano (optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of),
R ^12A and R ^13A each independently represent a hydrogen atom, C _3-6 cycloalkyl (the cycloalkyl is a fluorine atom, C _1-3 alkyl, -NR ^36A SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano), and when there is a plurality of R ^12A or R ^13A , each of R ^12A or R ^13A is May be the same or different;
When there are multiple R ^35A , each independently is C _1-6 alkyl,
R ^36A and R ^37A are each independently a hydrogen atom or C _1-6 alkyl, and when there is a plurality of R ^36A or R ^37A , each of R ^36A or R ^37A may be the same or different; In, when R ^36A and R ^37A bonded to the same nitrogen atom are both C _1-6 alkyl, these together with the nitrogen atom bonded to each form a 3- to 6-membered nitrogen-containing saturated heterocycle. It is okay to do
a and c are 1,
b and d are both 1 or 2,
Item 29. The medicament according to any one of Items 1 to 28.

[Section 30]
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 are Together, each independently may form =CR ^12A R ^13A ,
Item 30. The medicament according to any one of Items 1 to 29.

[Section 31]
M is methylene,
Item 31. The medicament according to any one of Items 1 to 30.

[Section 32]
When there is a plurality of Q, each independently represents C _3-6 cycloalkyl (the cycloalkyl is the same or different 1 to 3 substituents selected from the group consisting of a fluorine atom and C _1-3 alkyl) may be substituted),
Item 32. The medicament according to any one of Items 1 to 31.

[Section 33]
When there is more than one Q, each independently is C _3-6 cycloalkyl,
Item 33. The medicament according to any one of Items 1 to 32.

[Section 34]
R ^12A and R ^13A are each independently a hydrogen atom or C _3-6 cycloalkyl,
The medicament according to any one of Items 1 to 33.

[Section 35]
R ^12A and R ^13A are hydrogen atoms,
Item 35. The medicament according to any one of Items 1 to 34.

[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, or R ¹ and R ² and/or R ³ and R ⁴ are together and may form = _CH2 ,
When there are multiple M, each independently is methylene,
When there is more than one Q, each independently represents C _3-6 cycloalkyl;
a and c are 1,
b and d are both 1 or 2,
Item 36. The medicament according to any one of Items 1 to 35.

[Section 37]
R ¹ and R ² are hydrogen atoms,
R ³ and R ⁴ are each independently a hydrogen atom or a fluorine atom,
However, R ³ and R ⁴ are not hydrogen atoms at the same time,
Item 37. The medicament according to any one of Items 1 to 36.

[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 R ² are not hydrogen atoms at the same time,
Item 37. The medicament according to any one of Items 1 to 36.

[Section 39]
R ¹ is a hydrogen atom,
R ² is -MQ,
R ³ is a hydrogen atom,
R ⁴ is a hydrogen atom or a fluorine atom,
Item 37. The medicament according to any one of Items 1 to 36.

[Section 40]
R ¹ is -MQ,
R ² is a hydrogen atom,
R ³ is a hydrogen atom or a fluorine atom,
R ⁴ is a hydrogen atom,
Item 37. The medicament according to any one of Items 1 to 36.

[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 together form =CH ₂ It is okay to do
However, R ¹ , R ² , R ³ and R ⁴ are not all hydrogen atoms at the same time,
Item 37. The medicament according to any one of Items 1 to 36.

[Section 42]
R ¹ and R ² are together =CH ₂ ;
R ³ and R ⁴ are hydrogen atoms,
Item 37. The medicament according to any one of Items 1 to 36.

[Section 43]
R ¹ and R ² are hydrogen atoms,
R ³ and R ⁴ together are =CH ₂ ;
Item 37. The medicament according to any one of Items 1 to 36.

[Section 44]
a, b, c and d are 1,
Item 44. The medicament according to any one of Items 1 to 43.

[Section 45]
a and c are 1,
b and d are 2,
Item 44. The medicament according to any one of Items 1 to 43.

[Section 46]
p is 1,
Item 46. The medicament according to any one of Items 1 to 45.

[Section 47]
p is 2,
Item 46. The medicament according to any one of Items 1 to 45.

[Section 48]
The medicament according to item 1, wherein the compound represented by formula (1) is 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),
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] heptane-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] heptane-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 H ₂ )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).

[Section 49]
The medicament according to item 1, wherein the compound represented by formula (1) is 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]heptane- 2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide (Example 5).

[Section 50]
A medicament containing a compound selected from the following compounds or its hydrochloride, L(+)-tartrate or succinate:
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]heptane- 2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide (Example 5).

[Section 51]
The medicament according to item 1, wherein the compound represented by formula (1) is 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] heptane-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 H ₂ )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).

[Section 52]
A medicament containing a compound selected from the following compounds or its hydrochloride, L(+)-tartrate or succinate:
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] heptane-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 H ₂ )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).

[Item 53]
A medicine containing 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.

[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(+ ) - medicines containing tartrates or succinates.

[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(+ ) - medicines containing tartrates or succinates.

[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(+ ) - medicines containing tartrates or succinates.

[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 Medicines containing acid salts.

[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] heptane-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (Example 7) or its hydrochloride, L(+)-tartrate or succinate Medicines containing acid salts.

[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 Medicines containing acid salts.

[Section 60]
5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-( ² H ₂ )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) or its hydrochloride, L(+) -Medicinal products containing tartrates or succinates.

[Section 61]
Item 61. A medicament containing the compound according to any one of Items 1 to 60 or a pharmaceutically acceptable salt thereof as an active ingredient.

[Section 62]
Item 61. An antitumor agent containing the compound according to any one of Items 1 to 60 or a pharmaceutically acceptable salt thereof as an active ingredient.

[Section 63]
The tumor is acute leukemia (including MLL acute leukemia, MLL partial tandem duplication acute leukemia, NPM mutation acute leukemia, MOZ acute leukemia, NUP98 acute leukemia, and CALM acute leukemia), chronic lymphocytic leukemia, chronic myeloid leukemia, and myelodysplasia. 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 Cellular lung cancer, breast cancer, stomach cancer, gallbladder/bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, anal cancer, chorioepithelial cancer, endometrial cancer, cervix Cancer, ovarian cancer, bladder cancer, urothelial cancer, renal cancer, renal cell cancer, prostate cancer, testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, malignant melanoma, 63. The antitumor agent according to item 62, which is neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, or skin cancer.

[Section 64]
If the tumor is acute leukemia (including 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, malignant lymphoma (B-cell lymphoma) Item 62 or 63. The antitumor agent according to item 62 or 63, wherein the antitumor agent is for cancer (including multiple myeloma), myeloma (including multiple myeloma), brain tumor, prostate cancer, breast cancer, neuroblastoma, Ewing's sarcoma, or liver cancer.

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

[Section 66]
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. The antitumor agent according to any one of 62 to 65.

[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 mutant acute leukemia.

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

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

[Section 70]
61. A method for treating a tumor, the method comprising administering the compound according to any one of Items 1 to 60 or a pharmaceutically acceptable salt thereof to a patient in need of treatment.

[Section 71]
71. The method according to item 70, wherein the tumor is a tumor associated with Menin-MLL.

[Section 72]
Use of the compound according to any one of Items 1 to 60 or a pharmaceutically acceptable salt thereof for producing an antitumor agent.

[Section 73]
61. A compound according to any one of Items 1 to 60 or a pharmaceutically acceptable salt thereof for use in the treatment of tumors.

[Section 74]
61. A pharmaceutical composition comprising the compound according to any one of Items 1 to 60 or a pharmaceutically acceptable salt thereof in combination with another drug or a pharmaceutically acceptable salt thereof, The other drugs include antitumor alkylating agents, antitumor antimetabolites, antitumor antibiotics, plant-derived antitumor agents, antitumor platinum coordination compounds, antitumor camptothecin derivatives, and antitumor tyrosine. Kinase inhibitors, anti-tumor serine-threonine kinase inhibitors, anti-tumor phospholipid kinase inhibitors, anti-tumor monoclonal antibodies, interferons, biological response modifiers, hormonal preparations, angiogenesis inhibitors, immune checkpoint inhibitors , epigenetics-related molecule inhibitors, protein post-translational modification inhibitors, proteasome inhibitors, and other antitumor agents.

[Section 75]
61. The medicament according to any one of Items 1 to 60, for treating a tumor in combination with another drug or a pharmaceutically acceptable salt thereof, wherein the other drug is an antitumor drug. anti-tumor alkylating agents, anti-tumor antimetabolites, anti-tumor antibiotics, plant-derived anti-tumor agents, anti-tumor platinum coordination compounds, anti-tumor camptothecin derivatives, anti-tumor tyrosine kinase inhibitors, anti-tumor serine Threonine kinase inhibitors, anti-tumor phospholipid kinase inhibitors, anti-tumor 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.

The present invention provides an inhibitor of binding between menin and MLL fusion protein, which comprises an optically active azabicyclo ring derivative or a pharmaceutically acceptable salt thereof. The compounds of the present invention are useful as therapeutic agents for diseases involving the binding of menin and MLL, specifically, MLL acute leukemia, NPM mutant acute leukemia, prostate cancer, breast cancer, Ewing's sarcoma, and liver cancer. , can be applied to patients with p53 gain-of-function mutant cancer, etc.

2 shows a 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 (hereinafter, the same applies to FIGS. 2 to 5). 2 shows a powder X-ray diffraction pattern of Form II crystals of the compound of Example 22. 2 shows a powder X-ray diffraction pattern of Form III crystals of the compound of Example 23. 2 shows a powder X-ray diffraction pattern of Form IV crystals of the compound of Example 24. 2 shows a powder X-ray diffraction pattern of a V-form crystal of the compound of Example 25.

Terms used in this specification will be explained below.

Examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Preferably it is a fluorine atom.

"C _1-6 alkyl" means an alkyl having 1 to 6 carbon atoms, and "C ₆ alkyl" means an alkyl having 6 carbon atoms. The same applies to other numbers.

"C _1-6 alkyl" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Preferred examples of C _1-6 alkyl include "C _1-4 alkyl", more preferably "C _1-3 alkyl". Specific examples of "C _1-3 alkyl" include methyl, ethyl, propyl, 1-methylethyl, and the like. Specific examples of "C _1-4 alkyl" include, in addition to those listed above as specific examples of "C _1-3 alkyl", butyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methyl Examples include propyl. Specific examples of "C _1-6 alkyl" include pentyl, 1,1 _- dimethylpropyl, 1,2-dimethylpropyl, 1 -Methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, hexyl and the like.

"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. Preferred examples of "C _2-6 alkenyl" include "C _2-4 alkenyl." Specific examples of "C _2-4 alkenyl" include vinyl, propenyl, methylpropenyl, butenyl, and the like. Specific examples of "C _2-6 alkenyl" include pentenyl, hexenyl, and the like, in addition to those listed above as specific examples of "C _2-4 alkenyl."

"C _2-6 alkynyl" means a straight or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing one triple bond. “C _2-6 alkynyl” preferably includes “C _2-4 alkynyl”. Specific examples of "C _2-4 alkynyl" include propynyl, methylpropynyl, butynyl, and the like. Specific examples of "C _2-6 alkynyl" include methylbutynyl, pentynyl, hexynyl, and the like, in addition to those listed above as specific examples of "C _2-4 alkynyl."

"C _1-6 alkoxy" means "C _1-6 alkyloxy", and the "C _1-6 alkyl" moiety has the same meaning as the above-mentioned "C _1-6 alkyl". "C _1-6 alkoxy" preferably includes "C _1-4 alkoxy", and more preferably "C _1-3 alkoxy". Specific examples of "C _1-3 alkoxy" include methoxy, ethoxy, propoxy, 1-methylethoxy, and the like. Specific examples of "C _1-4 alkoxy" include, in addition to those listed above as specific examples of "C _1-3 alkyl", butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, 2-methyl Examples include propoxy. Specific examples of “C _1-6 alkoxy” include pentyloxy, 1,1 _- dimethylpropoxy, 1,2-dimethylpropoxy, 1 -methylbutoxy, 2-methylbutoxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, hexyloxy and the like.

"C _1-6 alkylene" means a straight or branched divalent saturated hydrocarbon group having 1 to 6 carbon atoms. As "C _1-6 alkylene", preferably "C _1-4 alkylene" is mentioned, and more preferably "C _1-3 alkylene" is mentioned. Specific examples of "C _1-3 alkylene" include methylene, ethylene, propylene, trimethylene, and the like. Specific examples of “C _1-4 alkylene” include butylene, 1,1 _- dimethylethylene, 1,2-dimethylethylene, 1 -methyltrimethylene, 2-methyltrimethylene and the like. Specific examples of "C _1-6 alkylene" include pentylene, 1,1-dimethyltrimethylene, 1,2-dimethyltrimethylene, in addition to those listed as specific examples of "C _1-4 alkylene" above. , 1-methylbutylene, 2-methylbutylene, 1-methylpentylene, 2-methylpentylene, 3-methylpentylene, hexylene, and the like.

“C _2-6 alkenylene” means a linear or branched divalent unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing 1 to 3 double bonds. do. Preferred examples of "C _2-6 alkenylene" include "C _2-4 alkenylene." Specific examples of "C _2-4 alkenylene" include vinylene, propenylene, methylpropenylene, butenylene, and the like. Specific examples of "C _2-6 alkenylene" include pentenylene, hexenylene, and the like, in addition to those listed above as specific examples of "C _2-4 alkenyl."

"C _2-6 alkynylene" means a straight or branched divalent unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing 1 to 3 triple bonds. . Preferred examples of "C _2-6 alkynylene" include "C _2-4 alkynylene". Specific examples of "C _2-4 alkynylene" include ethynylene, propynylene, butynylene, and the like. Specific examples of "C _2-6 alkynylene" include, for example, methylbutynylene, pentynylene, hexynylene, etc. in addition to those listed above as specific examples of "C _2-4 alkynylene".

"C _3-10 cycloalkyl" means a cyclic saturated hydrocarbon group having 3 to 10 carbon atoms, and includes those having a partially unsaturated bond and those having a crosslinked structure. Preferred examples of "C _3-10 cycloalkyl" include "C _3-7 cycloalkyl." Specific examples of "C _3-7 cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Specific examples of "C _3-10 cycloalkyl" include, for example, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, and the like, in addition to those listed above as specific examples of "C _3-7 cycloalkyl."
Furthermore, "C _3-10 cycloalkyl" includes a bicyclic ring in which the C _3-10 cycloalkyl and an aromatic hydrocarbon ring are condensed. Specific examples of the ring-fused compound include the structures shown below.

"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. Preferred examples of "C _3-10 cycloalkylene" include "C _3-7 cycloalkylene". Specific examples of "C _3-7 cycloalkylene" include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, and the like. Specific examples of "C _3-10 cycloalkyl" include, in addition to those listed above as specific examples of "C _3-7 cycloalkyl", cyclooctylene, cyclononylene, cyclodecylene, adamantylene, and the like.

"3- to 8-membered saturated carbocycle" means a cyclic saturated hydrocarbon having 3 to 8 carbon atoms. The "3- to 8-membered saturated carbocycle" preferably includes "4- to 6-membered saturated carbocycle." Specific examples of the "4- to 6-membered saturated carbocycle" include, for example, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, and the like. Specific examples of the "3- to 8-membered saturated carbocycle" include, for example, in addition to those listed as specific examples of the "4- to 6-membered saturated carbocycle", a cyclopropane ring, a cycloheptane ring, a cyclooctane ring, etc.

A "3- to 10-membered saturated heterocyclic group" is 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. It means a monovalent or divalent saturated heterocyclic group, and also includes those having a partially unsaturated bond and those having a crosslinked structure. The atoms constituting the ring may include oxidized atoms such as -C(O)-, -S(O)-, and -SO ₂ -. The "3- to 10-membered saturated heterocyclic group" is preferably a "4- to 7-membered monocyclic saturated heterocyclic group", and more preferably "5- or 6-membered monocyclic saturated heterocyclic group". ``heterocyclic group''. Specific examples of "5- or 6-membered monocyclic saturated heterocyclic group" include tetrahydrofuryl, pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneiminyl, oxazolidinyl , thiazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxooxazolidinyl, dioxooxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrofuryrene, pyrrolidinylene, imidazolidinylene , piperidinylene, morpholinylene, thiomorpholinylene, dioxothiomorpholinylene, hexamethylene iminylene, oxazolidinylene, thiazolidinylene, oxoimidazolidinylene, dioxoimidazolidinylene, oxooxazolidinylene, dioxoxa Examples include zolidinylene, dioxothiazolidinylene, tetrahydrofuranylene, and tetrahydropyranylene. Examples of the "4- to 7-membered monocyclic saturated heterocyclic group" include those listed as specific examples of the "5- or 6-membered monocyclic saturated heterocyclic group", as well as oxetanyl, azetidinyl, , oxetanylene, azetidinylene, and the like. Examples of the "3- to 10-membered saturated heterocyclic group" include oxiranyl, aziridinyl, oxiranylene, aziridinylene, etc., in addition to those listed as specific examples of the "4- to 7-membered monocyclic saturated heterocyclic group" above. can be mentioned.
In addition, the "3- to 10-membered saturated heterocyclic group" includes a fused ring formed by the 3- to 10-membered saturated heterocyclic group and a 6-membered aromatic hydrocarbon ring or a 6-membered aromatic heterocyclic ring. Bicyclic types are also included. Examples of the 6-membered aromatic hydrocarbon ring forming the condensed ring include a benzene ring. Examples of the 6-membered aromatic heterocycle forming the condensed ring include pyridine, pyrimidine, and pyridazine. Specific examples of the bicyclic "3- to 10-membered saturated heterocyclic group" forming a condensed ring include dihydroindolyl, dihydroisoindolyl, dihydropurinyl, dihydrothiazolopyrimidinyl, dihydrobenzodioxa Nil, isoindolyl, indazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydronaphthyridinyl, dihydroindolylene, dihydroisoindolylene, dihydropurinylene, dihydrothiazolopyrimidinylene, dihydrobenzodioxanylene, isoindo Examples include rylene, indazolylene, tetrahydroquinolinylene, tetrahydroisoquinolinylene, and tetrahydronaphthyridinylene.

The term "3- to 8-membered nitrogen-containing saturated heterocycle" means a saturated heterocycle composed of one nitrogen atom and 2 to 7 carbon atoms. The "3- to 8-membered nitrogen-containing saturated heterocycle" preferably includes "4- to 6-membered nitrogen-containing saturated heterocycle." Specific examples of the "4- to 6-membered nitrogen-containing saturated heterocycle" include, for example, an azetidine ring, a pyrrolidine ring, a piperidine ring, and the like. 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, an azocane ring, etc. Examples include rings.

"C _6-10 aryl" means an aromatic hydrocarbon ring group having 6 to 10 carbon atoms. Specific examples of "C _6-10 aryl" include phenyl, 1-naphthyl, 2-naphthyl, and the like. Preferred is phenyl.
Further, "C _6-10 aryl" includes a bicyclic ring in which the C _6-10 aryl and a C _4-6 cycloalkyl or a 5- to 6-membered saturated heterocycle form a condensed ring. Specific examples of the bicyclic "C _6-10 aryl" forming a condensed ring include the groups shown below.

"C _6-10 arylene" means a divalent aromatic hydrocarbon ring group having 6 to 10 carbon atoms. Specific examples of "C _6-10 arylene" include phenylene, 1-naphthylene, 2-naphthylene, and the like. Preferred is phenylene.

"Aromatic hydrocarbon ring" means the ring moiety of the above "C _6-10 aryl" and the above "C _6-10 arylene".

"5- to 12-membered heteroaryl" means 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 nitrogen atoms, oxygen atoms, and sulfur atoms. A "5- to 7-membered monocyclic heteroaryl" is preferable. More preferably, it is pyridyl, pyrimidinyl, quinolyl, or isoquinolyl. Even more preferably, it is pyridyl. Specific examples of "5- to 7-membered monocyclic heteroaryl" include, for example, pyridyl, pyridazinyl, isothiazolyl, pyrrolyl, furyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, triazinyl, triazolyl, oxadiazolyl, triazolyl, tetrazolyl, and the like. Specific examples of "5- to 12-membered heteroaryl" include those listed above as specific examples of "5- to 7-membered monocyclic heteroaryl", as well as indolyl, indazolyl, chromenyl, quinolyl, isoquinolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, and benzimidazolyl.

"5- to 12-membered heteroarylene" refers to a divalent monocyclic 5- to 7-membered heteroarylene containing 1 to 4 atoms independently selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms. It means an aromatic heterocycle or a divalent bicyclic 8- to 12-membered aromatic heterocycle. Preferably, it is a "5- to 7-membered monocyclic heteroarylene." More preferred are pyridylene, pyrimidylene, quinolylene, or isoquinolylene. More preferred is pyridylene. Specific examples of "5- to 7-membered monocyclic heteroarylene" include pyridylene, pyridazinylene, isothiazolylene, pyrrolilene, furylene, thienylene, thiazolilene, imidazolylene, pyrimidinylene, thiadiazolilene, pyrazolylene, oxazorylene, isoxazorylene, pyrazinylene , triazinylene, triazolelene, oxadiazolelene, triazolelene, tetrazolylene, and the like. Specific examples of "5- to 12-membered heteroarylene" include indolylene, indazolylene, chromenylene, quinorylene, isoquinorylene, benzofuranylene, benzothienylene, in addition to those listed as the above-mentioned specific examples of "5- to 7-membered monocyclic heteroarylene". , benzoxazorylene, benzothiazolylene, benzisoxazorylene, benzisothiazolylene, benzotriazolylene, benzimidazolylene, and the like.

"Aromatic heterocycle" means the ring moiety of the above "5- to 12-membered heteroaryl" and the above-mentioned "5- to 12-membered heteroarylene".

In this specification, a bond crossing a ring as represented by the following formula (W) means that a "group" is bonded at a substitutable position in the group.
For example, the following formula (W):
When represented by the following formula (W-1), (W-2) or (W-3):
It means that.

In the present specification, the stereochemistry of the substituents in the compound represented by formula (1) and the compounds described in the Examples is illustrated as follows, for example.
Here, bonds drawn in a wedge shape represent substituents on the front side of the paper, and bonds drawn with broken lines represent substituents on the back side of the paper. Bonds drawn with wavy lines indicate that substituents on the front side of the page and on the back side of the page are present in arbitrary proportions, and when bonds extending outward from the ring are drawn with straight lines, they are on the front side of the page or the back side of the page. Indicates that it is a substituent on either side.

"Cancer" and "tumor" have the same meaning in the present invention, and both mean a malignant tumor, including cancer, sarcoma, and hematological malignant tumor. Specific examples of "cancer" or "tumor" include, for example, acute leukemia (including MLL acute leukemia, MLL partial tandem duplication acute leukemia, NPM mutation 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, esophagus Cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, stomach cancer, gallbladder/bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, anal cancer , chorioepithelial carcinoma, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial cancer, renal 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, and skin cancer. Furthermore, the above-mentioned tumors may be accompanied by increased expression or mutations of specific genes. Examples of tumors with increased gene expression include tumors with high expression of the HOXa gene group, tumors with high expression of the MEIS gene group, and the like. Furthermore, examples of tumors with genetic mutations include tumors with p53 gain-of-function mutations.

In the compound of the present invention represented by formula (1), p, X, Y, Z, M, Q, a, b, c, d, U, R 1 , R ² , 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 , ^R17 , ^R18 , ^R19 , ^R20 , R21, ^{R22 , R23} , ^R24 , ^R25 , R26, ^R27 , ^R28 , ^R29 , ^R30 , ^R31 , ^{R32 ,} Preferred examples of R ³³ , R ³⁴ , R ^35A , R ^35B , R ^36A , R ^36B , R ^37A and R ^37B are as follows; however, the technical scope of the present invention is limited to the range of the compounds listed below. It's not something you can do.

One example of p is 1. Moreover, 2 is mentioned as one aspect of p.

X is preferably -C(O)-.

Y is preferably -O-.

Z is preferably (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z- 8) and (Z-9). More preferred is (Z-3).

M is preferably substituted with the same or different 1 to 3 substituents selected from the group consisting of fluorine atom, C _2-4 alkynyl, C _1-3 alkoxy, -NR ^36A R ^37A and cyano. Examples include C _1-3 alkylene. More preferred is C _1-3 alkylene. More preferred is methylene.

Q is preferably the same or different 1 to 3 substituents selected from the group consisting of fluorine atom, C _1-3 alkyl, -NR ^36A SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano. C _3-6 cycloalkyl which may be substituted; the same or different 1 selected from the group consisting of fluorine atom, C _1-3 alkyl, -NR ^36A SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano; 3- to 6-membered saturated heterocyclic group optionally substituted with ~3 substituents; from fluorine atom, C _1-3 alkyl, -NR ^36A SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano phenyl which may be substituted with the same or different 1 to 3 substituents selected from the group; and fluorine atom, C _1-3 alkyl, -NR ^36A SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A 5- to 6-membered heteroaryl optionally substituted with 1 to 3 same or different substituents selected from the group consisting of and cyano. More preferably, it is substituted with the same or different 1 to 3 substituents selected from the group consisting of fluorine atom, C _1-3 alkyl, -NR ^36A SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano. C _3-6 cycloalkyl which may be substituted. More preferred is C _{3-6 cycloalkyl which may be substituted with 1 to 3 same or different substituents selected from the group consisting of a fluorine atom and C 1-3 alkyl} . Particularly preferred is C _3-6 cycloalkyl.

Preferably, a and c are 1.

One embodiment of b and d is 1 for both. Moreover, as one aspect of b and d, 2 can be mentioned for both.

U is preferably a nitrogen atom.

Preferably, R ¹ is a hydrogen atom or -MQ.

R ² is preferably a hydrogen atom or -MQ.

Preferably, R ³ is a hydrogen atom or a fluorine atom.

Preferably, R ⁴ is a hydrogen atom or a fluorine atom.

Another embodiment of R ¹ and R ² is when R ¹ and R ² are taken together to form =CR ^12A R ^13A . More preferably, = _CH2 .

Another embodiment of R ³ and R ⁴ is when R ³ and R ⁴ are taken together to form =CR ^12A R ^13A . More preferably, = _CH2 .

Another embodiment of R ¹ , R ² , R ³ and R ⁴ is a case where R ¹ is a hydrogen atom, R ² is -MQ, R ³ is a hydrogen atom, and R ⁴ is a hydrogen atom or a fluorine atom. It will be done.

Another embodiment of R ¹ , R ² , R ³ and R ⁴ is a case where R ¹ is -MQ, R ² is a hydrogen atom, R ³ is a hydrogen atom or a fluorine atom, and R ⁴ is a hydrogen atom. It will be done.

Another embodiment of R ¹ , R ² , R ³ and R ⁴ is a case where R ¹ and R ² are both hydrogen atoms, and R ³ and R ⁴ are taken together to form =CH ₂ .

Another embodiment of R ¹ , R ² , R ³ and R ⁴ is a case where R ³ and R ⁴ are both hydrogen atoms and R ¹ and R ² are taken together to form =CH ₂ .

Another embodiment of R ¹ , R ² , R ³ and R ⁴ is a case where R ¹ and R ² are both hydrogen atoms, R ³ is a hydrogen atom, and R ⁴ is a fluorine atom.

Another embodiment of R ¹ , R ² , R ³ and R ⁴ is a case where R ¹ and R ² are both hydrogen atoms, R ³ is a fluorine atom, and R ⁴ is a hydrogen atom.

R ^5A and R ^5B are preferably hydrogen atoms.

R ^6A , R ^6B and R ^6D are preferably hydrogen atoms.

R ^6C is preferably a fluorine atom.

R ⁷ is preferably a hydrogen atom, C _1-6 alkyl or C _2-6 alkenyl which may be substituted with one phenyl.

R ⁸ , R ¹⁴ , R ¹⁸ , R ²⁵ , R ³¹ , R ^35A and R ^35B are preferably C _1-3 alkyl.

^R9 , ^R10 , ^R11 , ^R15 , ^R16 , ^R17 , ^R19 , ^R20 , ^R21 , ^R23 , ^R24 , R26, ^R27 , ^{R28 , R29 , R30} , ^R32 , R ³³ , R ³⁴ , R ^36A , R ^36B , R ^37A and R ^37B are preferably a hydrogen atom or C _1-3 alkyl.

R ^12A and R ^13A are preferably the same or different 1 selected from the group consisting of a hydrogen atom or a fluorine atom, C _1-3 alkyl, -NR ^36A SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano. Examples include C _3-6 cycloalkyl optionally substituted with ~3 substituents. More preferred is a hydrogen atom.

R ^12B and R ^13B are preferably C _1-3 alkyl.

R ²² is preferably -CF ₃ or cyano.

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,
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 are Together, each independently may form =O or =CR ^12A R ^13A ,
When there are multiple M, each independently represents C _1-3 alkylene,
When there is a plurality of Q, each independently represents C _3-6 cycloalkyl (the cycloalkyl is a fluorine atom, C _1-3 alkyl, -NR ^36A SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano (optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of),
R ^12A and R ^13A each independently represent a hydrogen atom, C _3-6 cycloalkyl (the cycloalkyl is a fluorine atom, C _1-3 alkyl, -NR ^36A SO ₂ R ^35A , -SO ₂ NR ^36A R (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of ^37A and cyano),
When there are multiple R ^35A , each independently is C _1-6 alkyl,
R ^36A and R ^37A are each independently a hydrogen atom or C _1-6 alkyl, and when there is a plurality of R ^36A or R ^37A , each of R ^36A or R ^37A may be the same or different; In, when R ^36A and R ^37A bonded to the same nitrogen atom are both C _1-6 alkyl, these together with the nitrogen atom bonded to each form a 3- to 6-membered nitrogen-containing saturated heterocycle. It is okay to do
a and c are 1,
b and d are both 1 or 2,
A compound or a pharmaceutically acceptable salt thereof.

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 are Together, each independently may form =O or =CR ^12A R ^13A ,
When there are multiple M, each independently represents C _1-3 alkylene,
When there is a plurality of Q, each independently represents C _3-6 cycloalkyl (the cycloalkyl is a fluorine atom, C _1-3 alkyl, -NR ^36A SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano (optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of),
R ^12A and R ^13A each independently represent a hydrogen atom, C _3-6 cycloalkyl (the cycloalkyl is a fluorine atom, C _1-3 alkyl, -NR ^36A SO ₂ R ^35A , -SO ₂ NR ^36A R (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of ^37A and cyano),
When there are multiple R ^35A , each independently is C _1-6 alkyl,
R ^36A and R ^37A are each independently a hydrogen atom or C _1-6 alkyl, and when there is a plurality of R ^36A or R ^37A , each of R ^36A or R ^37A may be the same or different; In, when R ^36A and R ^37A bonded to the same nitrogen atom are both C _1-6 alkyl, these together with the nitrogen atom bonded to each form a 3- to 6-membered nitrogen-containing saturated heterocycle. It is okay to do
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 are hydrogen atoms,
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 pharmaceutically acceptable salt thereof.

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 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 are Together, each independently may form =O or =CR ^12A R ^13A ,
When there are multiple M, each independently represents C _1-3 alkylene,
When there is a plurality of Q, each independently represents C _3-6 cycloalkyl (the cycloalkyl is a fluorine atom, C _1-3 alkyl, -NR ^36A SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano (optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of),
R ^12A and R ^13A each independently represent a hydrogen atom, C _3-6 cycloalkyl (the cycloalkyl is a fluorine atom, C _1-3 alkyl, -NR ^36A SO ₂ R ^35A , -SO ₂ NR ^36A R (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of ^37A and cyano),
When there are multiple R ^35A , each independently is C _1-6 alkyl,
R ^36A and R ^37A are each independently a hydrogen atom or C _1-6 alkyl, and when there is a plurality of R ^36A or R ^37A , each of R ^36A or R ^37A may be the same or different; In, when R ^36A and R ^37A bonded to the same nitrogen atom are both C _1-6 alkyl, these together with the nitrogen atom bonded to each form a 3- to 6-membered nitrogen-containing saturated heterocycle. It is okay to do
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 are hydrogen atoms,
R ^6C is a fluorine atom,
U is CR ²² ,
R ²² is -CF ₃ or cyano,
Y is -O-,
Z is (Z-3),
A compound or a pharmaceutically acceptable salt thereof.

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, or R ¹ and R ² and/or R ³ and R ⁴ are together and may form = _CH2 ,
When there are multiple M, each independently is methylene,
When there is more than one Q, each independently represents C _3-6 cycloalkyl;
a and c are 1,
b and d are both 1 or 2,
A compound or a pharmaceutically acceptable salt thereof.

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, or R ¹ and R ² and/or R ³ and R ⁴ are together and may form = _CH2 ,
When there are multiple M, each independently is methylene,
When there is more than one Q, each independently represents C _3-6 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 are hydrogen atoms,
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 pharmaceutically acceptable salt thereof.

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 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 are together and may form = _CH2 ,
When there are multiple M, each independently is methylene,
When there is more than one Q, each independently represents C _3-6 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 are hydrogen atoms,
R ^6C is a fluorine atom,
U is CR ²² ;
R ²² is -CF ₃ or cyano,
Y is -O-,
Z is (Z-3),
A compound or a pharmaceutically acceptable salt thereof.

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 are hydrogen atoms,
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 are not hydrogen atoms at the same time,
A compound or a pharmaceutically acceptable salt thereof.

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 are hydrogen atoms,
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 are hydrogen atoms,
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 are not hydrogen atoms at the same time,
A compound or a pharmaceutically acceptable salt thereof.

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 are hydrogen atoms,
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 are hydrogen atoms,
R ^6C is a fluorine atom,
U is CR ²² ;
R ²² is -CF ₃ or cyano,
Y is -O-,
Z is (Z-3),
However, R ³ and R ⁴ are not hydrogen atoms at the same time,
A compound or a pharmaceutically acceptable salt thereof.

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 multiple M, each independently is methylene,
When there is more than one Q, each independently represents C _3-6 cycloalkyl;
a and c are 1,
b and d are both 1 or 2,
However, R ¹ and R ² are not hydrogen atoms at the same time,
A compound or a pharmaceutically acceptable salt thereof.

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 multiple M, each independently is methylene,
When there is more than one Q, each independently represents C _3-6 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 are hydrogen atoms,
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 are not hydrogen atoms at the same time,
A compound or a pharmaceutically acceptable salt thereof.

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 multiple M, each independently is methylene,
When there is more than one Q, each independently represents C _3-6 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 are hydrogen atoms,
R ^6C is a fluorine atom,
U is CR ²² ;
R ²² is -CF ₃ or cyano,
Y is -O-,
Z is (Z-3),
However, R ¹ and R ² are not hydrogen atoms at the same time,
A compound or a pharmaceutically acceptable salt thereof.

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 together form =CH ₂ It is okay to do
a and c are 1,
b and d are both 1 or 2,
However, R ¹ , R ² , R ³ and R ⁴ are not hydrogen atoms at the same time,
A compound or a pharmaceutically acceptable salt thereof.

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 together form =CH ₂ It is okay to do
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 are hydrogen atoms,
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 are not hydrogen atoms at the same time,
A compound or a pharmaceutically acceptable salt thereof.

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 ⁴ are each independently a hydrogen atom, or R ¹ and R ² and/or R ³ and R ⁴ together form =CH ₂ It is okay to do
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 are hydrogen atoms,
R ^6C is a fluorine atom,
U is CR ²² ;
R ²² is -CF ₃ or cyano,
Y is -O-,
Z is (Z-3),
However, R ¹ , R ² , R ³ and R ⁴ are not hydrogen atoms at the same time,
A compound or a pharmaceutically acceptable salt thereof.

The method for producing the compound of the present invention represented by formula (1) will be explained below by giving examples, but the method for producing the compound of the present invention is not limited to these. The compounds used in the following production methods may form salts as long as they do not interfere with the reaction.

The compounds of the present invention can be produced using known compounds as starting materials, for example, by the following production methods A, B, C, D, E, F, G, H, I, J, K, L, M, N, and O. It can be produced by appropriately combining methods similar to those methods or synthetic methods well known to those skilled in the art.

Manufacturing method A
The compound of the present invention represented by formula (1) can be produced, for example, by the following method.
[wherein 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 has the same meaning as described in Item 1, LG ¹ means a leaving group, and P ¹ means an amino protecting group. Examples of LG ¹ include a halogen atom, methanesulfonyloxy, p-toluenesulfonic acidoxy, trifluoromethanesulfonic acidoxy, phenoxy, trifluorophenoxy, tetrafluorophenoxy, pentafluorophenoxy, nitrophenoxy, and the like. Examples of P ¹ include the amino protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999). Also, * means that the stereochemistry of the carbon is not inverted by the reaction. ]

[Step 1]
Compound (a3) can be obtained by reacting compound (a1) obtained by the following production method with compound (a2) obtained by the following production method in an appropriate solvent in the presence or absence of an appropriate base. It can be manufactured by
As the compound (a1), a compound (a1) obtained by the following production method B, a compound (D1) obtained by the following production method D, a compound (E1) obtained by the following production method E, etc. can be used. can. As the compound (a2), a compound (F1) obtained by the following production method F, a compound (G1) obtained by the following production method G, etc. can be used.
Examples of the base include 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, organic bases such as N-methylmorpholine (NMM), or sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, hydroxide Examples include inorganic bases such as potassium. Preferable examples of the base include triethylamine, diisopropylethylamine, potassium carbonate, and sodium hydroxide.
The solvent is not particularly limited as long as it does not react under the reaction conditions of this step, but examples include alcoholic solvents such as methanol, ethanol, 2-propanol (isopropyl alcohol), and tert-butanol; diethyl ether, diisopropyl Ether solvents such as 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; acetonitrile, Aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, dimethylsulfoxide; or mixtures thereof. . Preferred solvents include 2-propanol, tetrahydrofuran, toluene, acetonitrile, N,N-dimethylformamide, and the like.
The reaction temperature is usually -80°C to heating under reflux, preferably 25°C to 90°C.
The reaction time is usually 30 minutes to 48 hours, preferably 6 to 12 hours.

As another method, the coupling reaction of compound (a1) and compound (a2) may be carried out in a suitable solvent in the presence of a suitable metal catalyst. These reaction conditions include, for example, Ulmann type conditions (for example, a method of heating to reflux using a metal catalyst such as copper (II) acetate in an aprotic solvent such as DMF), Buchwald type conditions (for example, Alkali metal carbonates such as cesium carbonate; BINAP; palladium catalysts such as Pd ₂ (dba) ₃ and Pd(OAc) ₂ ; and ligands such as dppf and Xantphos are used to inert to the reaction conditions such as toluene. method of heating under reflux in a suitable solvent, etc.).
The solvent is not particularly limited as long as it does not react under the reaction conditions of this step, but examples include alcoholic solvents such as methanol, ethanol, 2-propanol (isopropyl alcohol), and tert-butanol; diethyl ether, diisopropyl Ether solvents such as 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; acetonitrile, Aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, dimethylsulfoxide; water; or a mixture thereof. Can be mentioned. Preferred solvents include tetrahydrofuran, toluene, acetonitrile, N,N-dimethylformamide and the like.
The reaction temperature is usually -80°C to heating under reflux, preferably 25°C to 90°C.
The reaction time is usually 30 minutes to 48 hours, preferably 6 to 12 hours.

[Step 2]
Compound (1) can be produced by removing the protecting group P ¹ of compound (a3). This step can be performed, for example, according to the method described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).

Manufacturing method B
The compound represented by formula (a1) can be produced, for example, by the following method.
[wherein 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 as defined in Production Method A, LG ² means a leaving group, and P ² means a hydroxyl group protecting group. Examples of LG ² include a halogen atom, methanesulfonyloxy, p-toluenesulfonic acidoxy, trifluoromethanesulfonic acidoxy, phenoxy, trifluorophenoxy, tetrafluorophenoxy, pentafluorophenoxy, nitrophenoxy, and the like. Examples of P ² 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). ]

Compound (b1) and compound (b2) are available as commercial products.

[Step 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.

[Step 2]
Compound (b4) can be produced by removing the protecting group P ² of compound (b3). This step can be performed, for example, according to the method described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).

[Step 3]
Compound (a1) is 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), etc., or a method similar thereto, produced from compound (b4). be able to.

Manufacturing method C
The compound represented by formula (b3) can also be produced, for example, by the following method.
[In the formula, R ^5A , R ^5B , R ^6A , R ^6B , R ^6C , R ^6D , U, Y, and Z have the same meanings as described in Item 1, and LG ² and P ² have the same meanings as described in Production method B. It is. ]

Compound (c1) is available as a commercial product, and compound (c2) can be produced by the method described in International Publication No. 2017/214367 etc. or a method analogous thereto, or can be obtained as a commercial product. available.

[Step 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.

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

Compound (d1) can be produced by the method described in International Publication No. 2017/214367 etc. or a method analogous thereto, or is available as a commercially available product.

[Step 1]
Compound (d2) is 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), etc., or a method analogous thereto, it can be produced from compound (d1).

[Step 2]
Compound (d3) is described in European Journal of Medicinal Chemistry, 23(1): 53-62 (1988), Tetrahedron, 62(23): 5469-5473 (2006), International Publication No. 2008/092049, International Publication No. 2015 It can be produced from compound (d2) by the method described in No./175707 or similar methods.
[Step 3]
Compound (d4) can be prepared by the method described in J. Med. Chem., 23(9): 1026-1031 (1980), WO 2003/087067, WO 2000/061562, etc., or a method similar thereto. It can be produced from compound (d3) depending on the method.

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

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

Compound (d1) can be produced by the method described in International Publication No. 2017/214367 etc. or a method analogous thereto, or is available as a commercially available product.

[Step 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.

[Step 2]
Compound (e2) is 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), or a method analogous thereto.

[Step 3]
Compound (E1) can be produced from compound (e2) by the method described in International Publication No. 2017/214367, International Publication No. 2009/137733, etc., or a method analogous thereto.

Manufacturing method F
In formula (a2), the compound represented by formula (F1) can be produced, for example, by the following method.
[In the formula, a, b, c, d, p, R ¹ , R ² , R ³ and R ⁴ have the same meaning as in term 1, P ¹ has the same meaning as in production method A, and LG ³ is the elimination group, and P ³ means an amino protecting group. Examples of LG ³ include a halogen atom and a hydroxyl group. Examples of ^P3 include the amino protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999). Also, * means that the stereochemistry of the carbon is not inverted by the reaction. ]

Compound (f1) is available as a commercial product.

Compound (f2) is listed in Japanese Patent Publication No. 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 ^2nd Edition (written by Larock RC, published by John Wiley & Sons, Inc., 1989), etc., or the method described therein. It can be synthesized by a conventional method or is available as a commercial product.

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

[Step 2]
Compound (F1) can be produced by removing the protecting group ^P3 of compound (f3). This step can be carried out, for example, according to the method described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).

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

Compound (f1) is available as a commercial product.

Compound (g1) is listed in Japanese Patent Publication No. 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 ^2nd Edition (written by Larock RC, published by John Wiley & Sons, Inc., 1989), etc., or the method described therein. It can be synthesized by a conventional method or is available as a commercial product.

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

[Step 2]
Compound (G1) can be produced by removing the protecting group ^P3 of compound (g2). This step can be performed, for example, according to the method described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).

Manufacturing method H
The compound of the present invention represented by formula (H1) can be produced, for example, by the following method.
[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 LG 1 has the same meaning as the description in Production Method A, LG ³ has the same meaning as the description in Production Method ^F , P ¹ has the same meaning as Production Method A, and P ⁴ has the same meaning as the description in Production Method A. means a protecting group. Examples of ^P4 include the amino protecting groups described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999). Also, * means that the stereochemistry of the carbon is not inverted by the reaction. ]

Compound (h1) is available as a commercial product.

[Step 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 similar thereto.

[Step 2]
Compound (h3) can be produced by removing the protecting group ^P4 of compound (h2). This step can be carried out, for example, according to the method described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).

[Step 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 similar thereto. .

[Step 4]
Compound (H1) can be produced by removing the protecting group ^P1 of compound (h4). This step can be performed, for example, according to the method described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).

Manufacturing method I
The compound of the present invention represented by formula (I1) can be produced, for example, by the following method.
[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 It has the same meaning as described in Item 1, and P ¹ has the same meaning as Production Method A. Also, * means that the stereochemistry of the carbon is not inverted by the reaction. ]

[Step 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 similar thereto.

[Step 2]
Compound (I1) can be produced by removing the protecting group P ¹ of compound (i1). This step can be performed, for example, according to the method described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).

Manufacturing method J
In formula (f2), the compound represented by formula (J1) can be produced, for example, by the following method.
[In the formula, p and Q have the same meanings as in term 1, ^P1 has the same meaning as described in Production Method A, and ^P5 means a carboxylic acid protecting group. Examples of P ⁵ 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). Also, * means that the stereochemistry of the carbon is not inverted by the reaction. ]

Compound (j1) is listed in Japanese Patent Publication No. 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 ^2nd Edition (written by Larock RC, published by John Wiley & Sons, Inc., 1989), etc., or the method described therein. It can be synthesized by a conventional method or is available as a commercial product.

[Step 1]
Compound (j2) is 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 a similar method thereto.

[Step 2]
Compound (j3) can be prepared by the methods 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. It can be produced from compound (j2) by a method similar to .

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

[Step 4]
Compound (J1) can be produced by removing the protecting group ^P5 of compound (j4). This step can be carried out, for example, according to the method described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).

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

Compound (k1) is available as a commercial product.

[Step 1]
Compound (j3) has been published 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 a similar method thereto, it can be produced from compound (j1) and compound (k1).

[Step 2]
Compound (K1) can be produced by removing the protecting group ^P5 of compound (j3). This step can be performed, for example, according to the method described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).

Manufacturing method L
In formula (f2), the compound represented by formula (L1) can be produced, for example, by the following method.
[In the formula, p, M and Q have the same meanings as in term 1, LG ⁴ means a leaving group, P ¹ has the same meaning as described in Production Method A, and P ⁵ has the same meaning as in Production Method J. It is. Examples of LG ⁴ include a halogen atom, methanesulfonyloxy, p-toluenesulfonic acidoxy, trifluoromethanesulfonic acidoxy, phenoxy, trifluorophenoxy, tetrafluorophenoxy, pentafluorophenoxy, nitrophenoxy, and the like. Also, * means that the stereochemistry of the carbon is not inverted by the reaction. ]

Compound (l1) is available as a commercial product.

[Step 1]
Compound (l2) has been 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), Compound (j1) and the method described in Tetrahedron Letters, 47(19): 3233-3237 (2006), Angewandte Chemie, International Edition, 44(34): 5516-5519 (2005), etc. or a method similar thereto. It can be produced from compound (l1).

[Step 2]
Compound (L1) can be produced by removing the protecting group ^P5 of compound (12). This step can be carried out, for example, according to the method described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).

［式中、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及びＺは項１の記載と同義であり、ＬＧ^１は製造法Ａと同義である。また、＊の炭素の立体化学は反応によって反転していないことを意味する。］ Manufacturing method M
The compound of the present invention represented by formula (1) can be produced, for example, by the following method.

[wherein 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 has the same meaning as described in Item 1, and LG ¹ has the same meaning as in Production Method A. Also, * means that the stereochemistry of the carbon is not inverted by the reaction. ]

Compound (1) can be produced from compound (a1) and compound (m1) obtained by the following production method by the method described in Step 1 of Production Method A or a method similar thereto.
As the compound (m1), a compound (N1) obtained by the following production method N, a compound (O1) obtained by the following production method O, etc. can be used.

［式中、ａ、ｂ、ｃ、ｄ、ｐ、Ｒ^１、Ｒ^２、Ｒ^３、及びＲ^４は項１の記載と同義であり、ＬＧ^３は製造法Ｆの記載と同義であり、Ｐ^１は製造法Ａと同義である。また、＊の炭素の立体化学は反応によって反転していないことを意味する。］ Manufacturing method N
In formula (m1), the compound represented by formula (N1) can be produced, for example, by the following method.

[In the formula, a, b, c, d, p, R ¹ , R ² , R ³ , and R ⁴ have the same meaning as described in Item 1, LG ³ has the same meaning as described in Production method F, and P ¹ is synonymous with manufacturing method A. Also, * means that the stereochemistry of the carbon is not inverted by the reaction. ]

Compound (n1) is available as a commercial product.

[Step 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.

[Step 2]
Compound (N1) can be produced by removing the protecting group ^P1 of compound (n2). This step can be performed, for example, according to the method described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).

［式中、ａ、ｂ、ｃ、ｄ、ｐ、Ｒ^１、Ｒ^２、Ｒ^３、及びＲ^４は項１の記載と同義であり、Ｐ^１は製造法Ａと同義である。また、＊の炭素の立体化学は反応によって反転していないことを意味する。］ Manufacturing method O
In formula (m1), the compound represented by formula (O1) can be produced, for example, by the following method.

[In the formula, a, b, c, d, p, R ¹ , R ² , R ³ , and R ⁴ have the same meanings as described in Item 1, and P ¹ has the same meaning as in Production Method A. Also, * means that the stereochemistry of the carbon is not inverted by the reaction. ]

[Step 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 similar thereto.

[Step 2]
Compound (O1) can be produced by removing the protecting group P ¹ of compound (o1). This step can be carried out, for example, according to the method described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).

In the production methods explained above, those that do not describe the production method of starting materials or intermediates are available as commercial products, or can be obtained from commercially available compounds by methods known to those skilled in the art or methods similar thereto. Can be synthesized.

In each reaction of the production method explained above, a protecting group can be used as necessary, even when the use of a protecting group is not specifically specified. For example, if any functional group other than the reactive site changes under the described reaction conditions or is inappropriate in the absence of a protecting group to carry out the described method, other functional groups other than the reactive site may be protected as necessary. Then, the target compound can be obtained by deprotecting the compound after the completion of the reaction or after performing a series of reactions.
As the protecting group, for example, the protecting groups described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999) can be used. Specific examples of amino protecting groups include benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl and the like. Specific examples of the hydroxyl protecting group include trialkylsilyl such as trimethylsilyl and tert-butyldimethylsilyl, acetyl, and benzyl.
The introduction and removal of a protecting group can be carried out by a method commonly used in organic synthetic chemistry (for example, see the above-mentioned Protective Groups in Organic Synthesis) or a method analogous thereto.

In this specification, protecting groups, condensing agents, etc. are sometimes represented by abbreviations according to IUPAC-IUB (Biochemical Nomenclature Committee) commonly used in this technical field. Note that the compound names used herein do not necessarily follow IUPAC nomenclature.

The intermediates or target compounds in the production method explained above should be modified as appropriate by converting their functional groups (e.g., protecting and deprotecting functional groups as necessary, and using amino, hydroxyl, carbonyl, halogen atoms, etc.) as a foothold. (by various transformations), it is also possible to lead to other compounds included in the present invention. Transformation of the functional group can be performed by a commonly used method (see, for example, Comprehensive Organic Transformations, RC Larock, John Wiley & Sons Inc. (1999), etc.).

The intermediates and target compounds in the production method explained above are isolated by purification methods commonly used in organic synthetic chemistry (e.g., neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, etc.). Can be purified. Furthermore, the intermediate can be used in the next reaction without being particularly purified.

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

Suitable salts and pharmaceutically acceptable salts of the starting materials and intermediates are the customary non-toxic salts. These include, for example, organic acid salts such as acetates, trifluoroacetates, maleates, fumarates, citrates, tartrates, methanesulfonates, benzenesulfonates, formates, p-toluene acid addition salts such as sulfonates, etc.) and inorganic acid salts (e.g. hydrochlorides, hydrobromides, hydroiodides, sulfates, nitrates, phosphates, etc.), amino acids (e.g. arginine, aspartic acid, glutamic acid, etc.), metal salts such as alkali metal salts (e.g. sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g. calcium salts, magnesium salts, etc.), ammonium salts, organic base salts (e.g. trimethylamine salts, Triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.) and the like can be appropriately selected by those skilled in the art.

In the present invention, the "hydrogen atom" includes ¹ H and ² H(D), and any one or more ¹ H of the compound represented by formula (1) is replaced by ² H(D) A deuterium converter converted into is also included in the compound represented by formula (1).

The present invention includes a compound represented by formula (1) or a pharmaceutically acceptable salt thereof. Furthermore, since the compounds of the present invention may exist in the form of hydrates and/or solvates with various solvents (ethanolates, etc.), these hydrates and/or solvates are also included in the present invention. Included in the compounds of the invention.

Furthermore, the compounds of the present invention include optical isomers based on optically active centers, atropisomers based on axial or planar chirality caused by intramolecular rotation constraints, other stereoisomers, tautomers, It includes all possible isomers such as geometric isomers and all forms of crystalline forms, as well as mixtures thereof.

In particular, optical isomers and atropisomers can be obtained as racemates or as optically active forms when optically active starting materials or intermediates are used. In addition, if necessary, at an appropriate stage of the production method, the corresponding raw material, intermediate, or racemic form of the final product may be separated by a known separation method such as a method using an optically active column or a fractional crystallization method. They can be physically or chemically separated into their optical antipodes. These resolution methods include, for example, reacting a racemate with an optically active resolving agent to synthesize two diastereomers, and then taking advantage of their different physical properties to resolve the diastereomers by methods such as fractional crystallization. Examples include the stereomer method.

When you want to obtain a pharmaceutically acceptable salt of the compound of the present invention, if the compound represented by formula (1) is obtained in the form of a pharmaceutically acceptable salt, you can simply purify it as it is. If it is obtained in free form, it may be dissolved or suspended in a suitable organic solvent, and an acid or base may be added to form a salt by a conventional method.

In the present invention, "another drug" means an antitumor agent that can be used in combination with or in combination with the compound of the present invention. Examples of "other drugs" include antitumor alkylating agents, antitumor antimetabolites, antitumor antibiotics, plant-derived antitumor agents, antitumor platinum coordination compounds, antitumor camptothecin derivatives, Anti-tumor tyrosine kinase inhibitors, anti-tumor serine-threonine kinase inhibitors, anti-tumor phospholipid kinase inhibitors, anti-tumor monoclonal antibodies, interferons, biological response modifiers, hormonal preparations, immune checkpoint inhibitors, Examples include epigenetics-related molecule inhibitors, protein post-translational modification inhibitors, and other antitumor agents. Specific examples of "other drugs" include 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, everolimus , temsirolimus, gefitinib, erlotinib, imatinib, crizotinib, osimertinib, afatinib, dasatinib, bosutinib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, lapatinib, nilotinib, ibrutinib, ceritinib, alectinib, tofacitinib, vali Citinib, ruxolitinib, olaparib, sorafenib, vemurafenib , dabrafenib, trametinib, palbociclib, bortezomib, carfilzomib, rituximab, cetuximab, trastuzumab, bevacizumab, panitumumab, nivolumab, atezolizumab, mogamulizumab, alemtuzumab, ofatumumab, ipilimumab, ramucirumab, brentuximab vedotin, gemtuzumab ozogamicin, inotuzumab ozogamicin etc.

The administration route of the compound of the present invention may be oral administration, parenteral administration, intrarectal administration, or ophthalmic administration, and the daily dosage varies depending on the type of compound, administration method, patient's symptoms, age, etc. . For example, in the case of oral administration, it is usually about 0.01 to 1000 mg, more preferably about 0.1 to 500 mg per kg of human or mammalian body weight, and can be administered in one to several divided doses. In the case of parenteral administration such as intravenous injection, it is usually possible to administer, for example, about 0.01 mg to 300 mg, more preferably about 1 mg to 100 mg, per 1 kg body weight of a human or mammal.

The compounds of the present invention can be administered orally or parenterally, either directly or formulated using suitable dosage forms. Examples of dosage forms include, but are not limited to, tablets, capsules, powders, granules, solutions, suspensions, injections, patches, and poultices. The formulation is manufactured by a known method using pharmaceutically acceptable additives.

Additives include excipients, disintegrants, binders, flow agents, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers, and sweeteners, depending on the purpose. Agents, fragrances, etc. can be used. Specific examples of additives include lactose, mannitol, crystalline cellulose, low-substituted hydroxypropylcellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl Examples include alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, and talc.

The present invention will be explained in more detail below using reference examples, working examples, and test examples, but the present invention is not limited thereto.

In this specification, the following abbreviations may be used.
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 Pd ₂ (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-benziodoxol-3-(1H)-one)
Petasis reagent: bis(cyclopentadienyl)dimethyltitanium Bredereck 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

NMR (Nuclear Magnetic Resonance) data used for compound identification was obtained using a JNM-ECS400 nuclear magnetic resonance apparatus (400 MHz) manufactured by JEOL Ltd.
Symbols used in NMR include s for singlet, d for doublet, dd for doublet, t for triplet, td for triplet doublet, q for quartet, m stands for multiplet, br for broad, brs for broad singlet, brm for broad multiplet and J for coupling constant.

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 only of the main isotope) is expressed as [M+H] ⁺ , [MH] ^- or [M+2H] ²⁺ etc., and the retention time is indicated as Rt (minutes).

LC/MS measurement method:
Analysis conditions A
Detection device: 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 x 30 mm)
Solvent: A solution: 0.06% formic acid/H ₂ O, B solution: 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 x 2.1mm)
Solvent: A liquid: 0.05% TFA/H ₂ O, 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℃

Powder X-ray diffraction measurements in Examples were performed under the conditions shown below. The obtained diffraction patterns (XRD spectra) are shown in FIGS. 1 to 5.
The crystal form may be determined based on the characteristic diffraction peaks of each crystal shown in the diffraction diagrams of FIGS. 1 to 5.
The main diffraction peaks and characteristic diffraction peaks identified from the diffraction patterns in FIGS. 1 to 5 are listed below. It should be noted that the diffraction peak values at the diffraction angle 2θ (°) described in the following examples may have some measurement error depending on the measuring equipment, measurement conditions, etc. Specifically, the measurement error may be within the range of ±0.2, preferably ±0.1.

Powder X-ray diffraction measurement method:
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 Accumulated time: 100 seconds/step

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

a) Production 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 obtained organic layer was washed with saturated brine, dried over magnesium sulfate, filtered off, and the solvent was distilled off under reduced pressure to obtain a crude product (200 g) of the title compound.
LC-MS; [M+H] ⁺ 254.0/Rt (min) 0.96 (Analysis conditions A)

b) Production 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), boron tribromide (39.2 mL) was added at 0°C, and the mixture was stirred 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 obtained organic layer was washed with saturated brine, dried over magnesium sulfate, 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)

c) Production of 5-fluoro-N,N-di(propan-2-yl)-2-[(pyrimidin-5-yl)oxy]benzamide 5-fluoro-2-hydroxy-N,N-di(propane- 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 under reflux for 1 day. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was added to a saturated aqueous sodium hydrogen carbonate solution for quenching. The resulting aqueous solution was extracted twice with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over magnesium 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 (20.0 g).
LC-MS; [M+H] ⁺ 317.7/Rt (min) 0.86 (Analysis conditions A)

d) Production of 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), and metachloroperbenzoic acid (112 g) was added at 0°C. The mixture was stirred for 2 days. The reaction was quenched with tributylphosphine (56.7 mL) and saturated aqueous sodium bicarbonate solution. After cooling, dichloromethane was concentrated under reduced pressure, and the resulting aqueous solution was extracted twice with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over magnesium sulfate, 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)

e) Production 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), and 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 sodium hydrogen carbonate solution for quenching. The resulting aqueous solution was extracted twice with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over magnesium 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 (27.8 g).
¹ H-NMR (DMSO-D ₆ )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)

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

a) tert-butyl 2-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7 -Production of 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). 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 the mixture was stirred at room temperature. Stirred 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)

b) 2-{[4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl]oxy}-5-fluoro-N,N-di(propan-2-yl) Production of 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-D ₆ )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 conditions B)

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

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

b) 2-{[4-(2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl]oxy}-5-fluoro-N,N-di(propan-2-yl) Production of benzamide (Reference Example 3) tert-butyl 6-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,6-diazaspiro[3 .3] Using heptane-2-carboxylate (1.4 g), the title compound (1.0 g) was obtained in the same manner as described in Step b) of Reference Example 2.
¹ H-NMR (DMSO-D ₆ )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)

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

a) tert-butyl 7-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2 -Production of 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). Then, 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)

b) 2-{[4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl]oxy}-5-fluoro-N,N-di(propan-2-yl) Production of 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)

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

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

b) Production of ethyl (1S,3S,4R)-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.2]oct-5-ene-3-carboxylate Above step a) Molecular sieve 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 -70 Cooled to ℃. Trifluoroacetic acid (32 mL) and boron trifluoride diethyl ether complex (53 mL) were added dropwise and stirred for 15 minutes, followed by dropwise addition of 1,3-cyclohexadiene (42 mL). The reaction solution was heated to room temperature and stirred overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried by adding 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 (59.4 g).
LC-MS; [M+H] ⁺ 286.2/Rt (min) 0.53 (Analysis conditions A)

c) 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] Preparation of mixture with octane-3-carboxylate 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). A 1.0 mol/L borane-THF complex (300 mL) was added dropwise at 0 to 5°C, and the mixture was stirred at room temperature overnight. A 3 mol/L aqueous sodium hydroxide solution (62 mL) and a 30% hydrogen peroxide solution (62 mL) were added to the reaction mixture under ice cooling, and the mixture was stirred for 30 minutes, and then an aqueous sodium thiosulfate solution was added and stirred for 1 hour. Ethyl acetate/chloroform was added to the reaction solution for extraction, and the organic layer was washed with saturated brine. The organic layer was dried by adding 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 a 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)

d) Ethyl (1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylate and ethyl (1S,3S,4R,6S)-6-hydroxy-2 - Production of 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 step c) above in ethanol (500 mL). was added and 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 compound, 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) were obtained.
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)

e) Production of (1S,3S,4S,5R)-2-(tert-butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylic acid (Reference Example 5) Ethyl ( 1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylate (10.48g) in 1,4-dioxane (153mL) solution with 1 mol/L hydroxide. After adding an aqueous sodium solution (238 mL) and stirring at room temperature for 1 hour, the reaction solution was cooled to 0° C. and di-tert-butyl dicarbonate (11.48 g) was added. After stirring for 1 hour, the reaction solution was made acidic by adding 1 mol/L hydrochloric acid, saturated brine was added, and the mixture was extracted with a 10% ethanol/chloroform mixed solvent. The organic layer was dried with sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was washed with diisopropyl ether, filtered, and dried to obtain the title compound (8.40 g).
¹ H-NMR (DMSO-D ₆ ) 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).

f) Production of (1S,3S,4R,6S)-2-(tert-butoxycarbonyl)-6-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylic acid (Reference Example 6) Ethyl ( The title compound ( 1.60 g) was obtained.
¹ H-NMR (DMSO-D ₆ ) 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).

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

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

b) Production of ethyl (1S,3S,4S,5R)-5-hydroxy-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate Ethyl ( Reference example using 1S,3S,4R)-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate (10.8 g) The title compound (7.49g) was obtained by a method similar to that described in step c) of 5.
LC-MS; [M+H] ⁺ 290.2/Rt (min) 0.46 (Analysis conditions A)

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

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 in the method described in Reference Example 5, step e).
^1H -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).

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

a) Production of 3-benzyl 2-tert-butyl (1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (1S,3S, 4S,5R)-2-(tert-butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylic acid (28.0 g) and potassium carbonate (28.5 g) in acetonitrile ( Benzyl bromide (12.3 mL) was added to the solution (300 mL) at room temperature, and the mixture was stirred overnight. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried by adding 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 (33.1 g).
LC-MS; [M+H] ⁺ 362.3/Rt (min) 0.95 (Analysis conditions A)

b) Production of 3-benzyl 2-tert-butyl (1S,3S,4S)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (Reference Example 8) 3- Solution of 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) Dess-Martin reagent (46.5 g) was added to the mixture at room temperature, and the mixture was stirred at room temperature overnight. A sodium thiosulfate aqueous solution and a sodium bicarbonate aqueous solution were added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried by adding 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 as a crude product (33.8 g).
LC-MS; [M+H] ⁺ 360.2/Rt (min) 1.02 (Analysis conditions A)
¹ H-NMR (CDCl ₃ ) 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).

Reference example 9:
(1S,3S,4S)-2-(tert-butoxycarbonyl)-5-oxo-2-azabicyclo[2.2.2]octane-3-carboxylic acid
Solution of 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) A 5 mol/L aqueous sodium hydroxide solution (2.7 mL) was added thereto, and the mixture was heated and stirred at 50°C for 5 hours. After the reaction solution was cooled to room temperature, it was neutralized by adding 1 mol/L hydrochloric acid and extracted with chloroform. The organic layer was dried by adding sodium sulfate, 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 (0.42 g).
LC-MS; [M+H] ⁺ 270.0/Rt (min) 0.59 (Analysis conditions A)

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

a) Production of 3-benzyl 2-tert-butyl (1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate 3-benzyl 2-tert- Petasis reagent was added to a solution of butyl (1S,3S,4S)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (3.0 g) in THF (30 mL) at room temperature. (5% THF/toluene solution, 35 g) was added and stirred at 95° C. for 5 hours. The temperature 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 filtered off, 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)

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

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

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

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

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

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

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

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

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

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

a) Production of 3-benzyl 2-tert-butyl (1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate 3-benzyl 2-tert- The same procedure as in step a) of Reference Example 10 was carried out using 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.
LC-MS; [M+H] ⁺ 344.2/Rt (min) 1.18 (Analysis conditions A)

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 condition A)

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

a) 3-Benzyl 2-tert-butyl (1S,3S,4S,6E)-6-[(dimethylamino)methylidene]-5-oxo-2-azabicyclo[2.2.2]octane-2,3- Production of dicarboxylate 3-benzyl 2-tert-butyl (1S,3S,4S)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (33.8 g) Bredereck reagent (32.8 g) was added to a solution of 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 a crude product (39.0 g) of the title compound.
LC-MS; [M+H] ⁺ 415.4/Rt (min) 0.95 (Analysis conditions A)

b) 3-benzyl 2-tert-butyl (1S,3S,4S,6E)-6-(cyclopropylmethylidene)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-di Production of carboxylate (Reference Example 14) 3-benzyl 2-tert-butyl (1S,3S,4S,6E)-6-[(dimethylamino)methylidene]-5-oxo-2-azabicyclo[2.2.2 ] A solution of octane-2,3-dicarboxylate (39.0 g) in tetrahydrofuran (300 mL) was cooled to 0°C, cyclopropylmagnesium bromide (0.5 moL/L tetrahydrofuran solution, 245 mL) was added dropwise, and the mixture was heated at room temperature for 6 hours. Stir for hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried by adding 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 (32.3 g).
LC-MS; [M+H] ⁺ 412.4/Rt (min) 1.16 (Analysis conditions A)
¹ H-NMR (CDCl ₃ ) 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).

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

a) 3-benzyl 2-tert-butyl (1S,3S,4S)-6-(cyclopropylmethyl)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate Production 3-benzyl 2-tert-butyl (1S,3S,4S,6E)-6-(cyclopropylmethylidene)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxy Copper (I) hydride (triphenylphosphine) hexamer (38.5 g) was added to a solution of Rate (32.3 g) in tetrahydrofuran (300 mL), and the mixture was 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 stereoisomer mixture.
LC-MS; [M+H] ⁺ 414.1/Rt (min) 1.22 (Analysis conditions A)

b) 3-benzyl 2-tert-butyl (1S,3S,4S)-6-(cyclopropylmethyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate ( Production of Reference Example 15) 3-benzyl 2-tert-butyl (1S,3S,4S)-6-(cyclopropylmethyl)-5-oxo-2-azabicyclo[2.2.2]octane-2,3- A solution of 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 less polar stereoisomers (9.3 g) and a mixture of more polar stereoisomers (9.3 g) of the title compound. 10.2g) was obtained.
Less polar stereoisomer mixture: 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)
More polar stereoisomer mixture: 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)

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

a) 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, Production of 3-dicarboxylate 3-benzyl 2-tert-butyl (1S,3S,4S,5S)-6-(cyclopropylmethyl)- which is a mixture of stereoisomers on the less polar side of the product of Reference Example 15 A solution of 5-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (9.3 g) in dichloromethane (80 mL) was cooled to 0°C, and (diethylamino)sulfur trifluoride (5. 91 mL) was added thereto, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried by adding 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 give 3-benzyl 2-tert-butyl (1S,3S,4S,5R,6R)-6-(cyclopropylmethyl)-5-fluoro-2- Azabicyclo[2.2.2]octane-2,3-dicarboxylate (3.6g) 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) was obtained.
3-benzyl 2-tert-butyl (1S,3S,4S,5R,6R)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxy rate
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-dicarboxy rate
LC-MS; [M+H] ⁺ 418.4/Rt (min) 1.35 (Analysis conditions A)

b) (1S,3S,4S,5R,6R)-2-(tert-butoxycarbonyl)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-3-carbonyl Production of acid (Reference Example 16) 3-benzyl 2-tert-butyl (1S,3S,4S,5R,6R)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2] Palladium hydroxide/carbon (1.2 g) was added to a solution of 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 the reaction solution was cooled to room temperature, it 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)

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

d) 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, Production of 3-dicarboxylate 3-benzyl 2-tert-butyl (1S,3S,4S,5R)-6-(cyclopropylmethyl)- which is a mixture of more polar stereoisomers of the product of Reference Example 15 Using 5-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (363 mg), 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) was obtained.
3-benzyl 2-tert-butyl (1S,3S,4S,5S,6R)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxy rate
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-dicarboxy rate
LC-MS; [M+H] ⁺ 418.4/Rt (min) 1.29 (Analysis conditions A)

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

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

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

a) 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 Production 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) in acetonitrile (50 mL) The mixture 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 the reaction solution was cooled to room temperature, saturated brine was added and extracted with ethyl acetate. The organic layer was dried by adding magnesium 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 give 3-benzyl 2-tert-butyl (1S,3S,4S,5R,6R)-6-(cyclopropylmethyl)-5-[(phenoxycarboxylate). [notioyl)oxy]-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate crude product (1.80 g) 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 crude product (7 .90g) was obtained.
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)

b) Production of 3-benzyl 2-tert-butyl (1S,3S,4R,6S)-6-(cyclopropylmethyl)-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 A solution of -2,3-dicarboxylate (1.80 g) in toluene (50 mL) was cooled to 0°C and mixed with tris(trimethylsilyl)silane (5.03 mL) and 2,2'-azobis(2-methylpropionitrile). ) (0.11 g) was added, and the mixture was heated and stirred at 50° C. for 5 hours. After the reaction solution was cooled to room temperature, saturated brine was added and extracted with ethyl acetate. The organic layer was dried by adding magnesium 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 (0.80 g).
LC-MS; [M+H] ⁺ 400.2/Rt (min) 1.38 (Analysis conditions A)

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

d) (1S,3S,4R,6S)-2-(tert-butoxycarbonyl)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carboxylic acid (Reference Example 20) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4R,6S)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (5. The title compound (3.90 g) was obtained in the same manner as in step b) of Reference Example 16 using 50 g).
LC-MS; [M+H] ⁺ 310.2/Rt (min) 1.02 (Analysis conditions A)

e) (1S,3S,4R,6R)-2-(tert-butoxycarbonyl)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carboxylic acid (Reference Example 21) Production of 3-benzyl 2-tert-butyl (1S,3S,4R,6R)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (1. The title compound (980 mg) was obtained in the same manner as in step b) of Reference Example 16 using 20 g).
LC-MS; [M+H] ⁺ 310.2/Rt (min) 1.04 (Analysis conditions A)

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
2-{[4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl]oxy}-5-fluoro-N,N-di(propane) obtained in Reference Example 2 -2-yl)benzamide (164 mg) in chloroform (2 mL) was added (1S,3S,4S)-2-(tert-butoxycarbonyl)-5-oxo-2-azabicyclo[2] obtained in Reference Example 9. .2.2] Octane-3-carboxylic acid (100 mg), WSCI.HCl (85 mg), HOBt (68 mg) and N,N-diisopropylethylamine (0.13 mL) were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. After drying the obtained organic layer with sodium sulfate, it 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 title compound (245 mg).
LC-MS; [M+H] ⁺ 693.2/Rt (min) 0.97 (Analysis conditions A)

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
tert-Butyl (1S,3S,4S)-3-[2-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidine-4- obtained in Reference Example 22) yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]-5-oxo-2-azabicyclo[2.2.2]octane-2-carboxylate (100 mg) in ethanol (1 mL) and water. (2 mL) solution, O-methylhydroxylamine hydrochloride (24 mg) and sodium acetate (35 mg) were added, and the mixture was stirred at 75° C. for 3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying the obtained organic layer with sodium sulfate, it was 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)

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

Reference examples 25 to 40:
Compounds of Reference Examples 25 to 40 shown in the table below were obtained by a method similar to that described in Reference Example 22 using the corresponding raw material compounds.

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 H ₂ )methylidene-2-azabicyclo[2.2.2]octane-2-carboxylate

a) Production of 3-benzyl 2-tert-butyl (1S,3S, _4R )-5-( ^2H2 )methylidene-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate ( ² H ₃ ) To a suspension of methyl(triphenyl)phosphanium iodide (2.83 g) in THF (14 mL) was added n-butyllithium (1.57 mol/L hexane solution, 3.54 mL) at -78°C. was added dropwise, and the mixture was stirred at 0°C for 1.5 hours. It 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. 0g) was added little by little and stirred for 5 hours. After the reaction solution was returned to room temperature, it was quenched by adding saturated ammonium chloride water. Extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, dried over anhydrous 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 (0.46 g).
LC-MS; [M+H] ⁺ 360.4/Rt (min) 1.22 (Analysis conditions A)

b) Production of (1S,3S,4R)-2-(tert-butoxycarbonyl)-5-( ² H ₂ )methylidene-2-azabicyclo[2.2.2]octane-3-carboxylic acid 3-benzyl 2 -tert-Butyl (1S,3S,4R)-5-( ² H ₂ ) methylidene-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate in methanol (10 mL) was added with hydroxide. Aqueous sodium solution (5 mol/L, 1.8 mL) and 2 mL of water were added, 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 brine, dried over anhydrous sodium sulfate, filtered off, and the solvent was distilled off under reduced pressure to obtain the title compound (0.31 g). The obtained compound was used in the next reaction without being purified.
LC-MS; [M+H] ⁺ 270.2/Rt (min) 0.89 (Analysis conditions A) ¹ H-NMR (DMSO-D ₆ ) 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).

c) tert-butyl (1S,3S,4R)-3-[2-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2, Production of 7-diazaspiro[3.5]nonane-7-carbonyl]-5-( ² H ₂ )methylidene-2-azabicyclo[2.2.2]octane-2-carboxylate (Reference Example 41) (1S, 3S,4R)-2-(tert-butoxycarbonyl)-5-( ^2H2 )methylidene-2-azabicyclo[ _2.2.2 ]octane-3-carboxylic acid (36 mg) was used in Reference Example 22. The title compound (80 mg) was obtained by a method similar to that described.
LC-MS; [M+H] ⁺ 693.6/Rt (min) 0.99 (Analysis conditions A)

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

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 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, dried by adding anhydrous sodium sulfate, and then filtered off. The solvent was evaporated 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 condition A)
^1H -NMR (DMSO- _D6 ) δ: 4.48 and 4.39 (total 1H, each m), 4.27-4.02 (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).

b) tert-butyl 7-[(1S,3S,4S)-2-(tert-butoxycarbonyl)-5-oxo-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7- Production of diazaspiro[3.5]nonane-2-carboxylate Dimethyl sulfoxide (11.1 mL) was added dropwise to a solution of oxalyl chloride (8.94 mL) in dichloromethane (300 mL) at -78°C under a nitrogen atmosphere. , and stirred at -78°C for 30 minutes. tert-Butyl 7-[(1S,3S,4S,5R)-2-(tert-butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7- A solution of diazaspiro[3.5]nonane-2-carboxylate (25.0 g) in dichloromethane (100 mL) was added dropwise at -65°C or below, and the mixture was further stirred at -78°C for 1 hour. Triethylamine (36.3 mL) was added dropwise at -78°C, the mixture was warmed to room temperature, and stirred for an additional 30 minutes. The reaction solution was diluted with chloroform, washed successively with saturated ammonium chloride aqueous solution, water, and saturated brine, and the resulting organic layer was dried by adding anhydrous sodium sulfate, and then filtered off. The solvent was distilled off under reduced pressure, and the residue was crystallized from hexane to obtain the title compound (22.5.g).
LC-MS; [M+H] ⁺ 478.1/Rt (min) 0.90 (Analysis conditions A)
¹ H-NMR (CDCl ₃ ) 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).

c) tert-butyl 7-[(1S,3S,4R)-2-(tert-butoxycarbonyl)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7- Production of diazaspiro[3.5]nonane-2-carboxylate (Reference Example 42) Potassium tert- Butoxide (7.9 g) was added 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 the mixture was further stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate and washed with water and saturated brine. The obtained organic layer was dried by adding anhydrous sodium sulfate, and then filtered off. The solvent was distilled off 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 (CDCl ₃ ) 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).

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
tert-Butyl (1S,3S,4R,6S)-6-(cyclopropylmethyl)-3-[2-(5-{2-[di(propan-2-yl)carbamoyl]) obtained in Reference Example 25 -4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]-2-azabicyclo[2.2.2]octane-2-carboxylate (62 mg) TFA (1 mL) was added to a dichloromethane (1 mL) solution at room temperature, and the mixture was 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 (28 mg).
LC-MS; [M+H] ⁺ 633.4/Rt (min) 1.64 (Analysis conditions B)
¹ H-NMR (CDCl ₃ )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).

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
tert-Butyl (1R,3S,4R)-3-[7-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidine-4- obtained in Reference Example 24) yl)-2,7-diazaspiro[4.4]nonane-2-carbonyl]-2-azabicyclo[2.2.2]octane-2-carboxylate (100 mg) in the same manner as in Example 1. The title compound (89 mg) was obtained.
LC-MS; [M+H] ⁺ 579.0/Rt (min) 1.50 (Analysis conditions B)
¹ H-NMR (CDCl ₃ )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).

Examples 3-19:
Compounds of Examples 3 to 19 shown in the table below were obtained in the same manner as in Example 1 using the corresponding raw material compounds.

参考例４１で得られたｔｅｒｔ－ブチル （１Ｓ，３Ｓ，４Ｒ）－３－［２－（５－｛２－［ジ（プロパン－２－イル）カルバモイル］－４－フルオロフェノキシ｝ピリミジン－４－イル）－２，７－ジアザスピロ［３．５］ノナン－７－カルボニル］－５－（^２Ｈ_２）メチリデン－２－アザビシクロ［２．２．２］オクタン－２－カルボキシレート（８０ｍｇ）を用い、実施例１と同様の方法にて、表題化合物（２３ｍｇ）を得た。
LC-MS; [M+H]^＋ 593.6／Rt（分） 0.70（分析条件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). Example 20:
5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-( ² H ₂ )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

tert-Butyl (1S,3S,4R)-3-[2-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidine-4- obtained in Reference Example 41) using ₍ 80 ^mg ) In the same manner as in Example 1, the title compound (23 mg) was obtained.
LC-MS; [M+H] ⁺ 593.6/Rt (min) 0.70 (Analysis conditions A)
¹ H-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, m), 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).

実施例４の化合物（０．５０ｇ）の酢酸エチル／エタノール（１０／１、１１ｍＬ）溶液にＬ（＋）－酒石酸（０．１１ｇ）を加え室温で３日間撹拌した。析出した固体をろ取し、酢酸エチルで洗浄、減圧乾燥することにより表題化合物（０．５４ｇ）を結晶（Ｉ形晶）として得た。
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).
［Ｉ形晶］粉末Ｘ線回折パターンは図１に示す。
主要回折ピーク：２θ（°）＝５．３、８．０、１１．２、１３．０、１３．５、１５．９、１６．４、１７．５、１７．９、１８．２、２０．０
特徴的回折ピーク：２θ（°）＝５．３、１１．２、１３．０、１５．９、１７．９、１８．２ 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

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 (form I crystal).
¹ H-NMR (400 MHz, DMSO-d ₆ ) 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 crystal] The powder X-ray diffraction pattern is shown in FIG.
Main 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

実施例４の化合物（５０ｍｇ）の酢酸エチル（１ｍＬ）溶液に４ｍｏｌ／Ｌ塩酸－酢酸エチル（１９μＬ）を加え室温で４時間撹拌した。析出した固体をろ取し、酢酸エチルで洗浄、減圧乾燥することにより表題化合物（３０ｍｇ）を結晶（ＩＩ形晶）として得た。
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).
［ＩＩ形晶］粉末Ｘ線回折パターンは図２に示す。
主要回折ピーク：２θ（°）＝５．３、９．９、１０．６、１１．９、１３．１、１３．６、１５．９、１６．３、１７．９、１８．９、２１．２
特徴的回折ピーク：２θ（°）＝５．３、９．９、１０．６、１５．９、１６．３、１７．９ 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

4 mol/L hydrochloric acid-ethyl acetate (19 μL) was added to a solution of the compound of Example 4 (50 mg) in ethyl acetate (1 mL), and the mixture was 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).
¹ H-NMR (400 MHz, DMSO-d ₆ ) 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 crystal] The powder X-ray diffraction pattern is shown in FIG.
Main 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

実施例４の化合物（０．５０ｇ）の酢酸エチル／エタノール（１０／１、１１ｍＬ）溶液に４ｍｏｌ／Ｌ塩酸－酢酸エチル（０．３８ｍＬ）を加え室温で３日間撹拌した。析出した固体をろ取し、酢酸エチルで洗浄、減圧乾燥することにより実施例４の化合物の２塩酸塩（０．４９ｇ）を結晶（ＩＩＩ形晶）として得た。
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).
［ＩＩＩ形晶］粉末Ｘ線回折パターンを図３に示す。
主要回折ピーク：２θ（°）＝４．３、７．０、９．９、１０．６、１１．８、１５．２、１５．５、１５．９、１６．５、１６．８、１７．９
特徴的回折ピーク：２θ（°）＝４．３、７．０、１０．６、１５．９、１６．５、１６．８ 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

4 mol/L hydrochloric acid-ethyl acetate (0.38 mL) 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 dihydrochloride salt (0.49 g) of the compound of Example 4 as crystals (form III crystals).
¹ H-NMR (400 MHz, DMSO-d ₆ ) 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).
[Form III crystal] 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

実施例６は下記の方法によっても製造することができる。参考例４２で得られたｔｅｒｔ－ブチル ７－［（１Ｓ，３Ｓ，４Ｒ）－２－（ｔｅｒｔ－ブトキシカルボニル）－５－メチリデン－２－アザビシクロ［２．２．２］オクタン－３－カルボニル］－２，７－ジアザスピロ［３．５］ノナン－２－カルボキシレート（７．０ｇ）のクロロホルム（１１ｍL）溶液に、ＴＦＡ（１１ｍＬ）を室温で滴下して加え、室温で一終夜撹拌した。反応液を減圧留去し、アセトニトリル（７０ｍＬ）を加えて希釈した後、５ｍｏｌ／Ｌ水酸化ナトリウム水溶液（２８ｍＬ）を、氷冷下、滴下して加えた。参考例１で得られた２－［（４－クロロピリミジン－５－イル）オキシ］－５－フルオロ－Ｎ，Ｎ－ジ（プロパン－２－イル）ベンズアミド（４．９ｇ）を加えて室温で５時間撹拌した。反応液に水（２００ｍＬ）を加え、析出した固体をろ取し、水で洗浄した後、減圧下乾燥させることで表題化合物（７．３ｇ）を得た。 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

Example 6 can also be produced by the following method. tert-butyl 7-[(1S,3S,4R)-2-(tert-butoxycarbonyl)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl] obtained in Reference Example 42 TFA (11 mL) was added dropwise to a solution of -2,7-diazaspiro[3.5]nonane-2-carboxylate (7.0 g) in chloroform (11 mL) at room temperature, and the mixture was stirred at room temperature overnight. The reaction solution was distilled off under reduced pressure, diluted with acetonitrile (70 mL), and then a 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 heated at room temperature. Stirred 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).

実施例６の化合物（２．０ｇ）のＴＨＦ（５ｍＬ）溶液にＬ（＋）－酒石酸（０．４８ｇ）を加え６０℃で１時間撹拌した。放冷後、析出した固体をろ取し、酢酸エチルで洗浄、減圧乾燥することにより表題化合物（２．０ｇ）を結晶（ＩＶ形晶）として得た。
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).
［ＩＶ形晶］粉末Ｘ線回折パターンを図４に示す。
主要回折ピーク：２θ（°）＝５．１、６．３、９．０、１０．５、１２．３、１２．６、１３．３、１５．３、１７．１、１７．２、１８．０
特徴的回折ピーク：２θ（°）＝５．１、６．３、９．０、１５．３、１７．２、１８．０ 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

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 at 60° C. for 1 hour. After cooling, the precipitated solid was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to obtain the title compound (2.0 g) as crystals (form IV crystals).
¹ H-NMR (400 MHz, DMSO-d ₆ ) 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 crystal] The powder X-ray diffraction pattern is shown in FIG.
Main 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

実施例６の化合物（２．０ｇ）の酢酸エチル（８ｍＬ）溶液にコハク酸（０．７８ｇ）を加え６０℃で１時間撹拌した。放冷後、析出した固体をろ取し、酢酸エチルで洗浄、減圧乾燥することにより表題化合物（１．９ｇ）を結晶（Ｖ形晶）として得た。
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).
［Ｖ形晶］粉末Ｘ線回折パターンを図５に示す。
主要回折ピーク：２θ（°）＝４．９、８．１、８．６、９．８、１３．９、１４．５、１７．２、１７．８、１８．４、１９．０、２０．５
特徴的回折ピーク：２θ（°）＝８．１、８．６、９．８、１４．５、１７．２、１７．８、１８．４ 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 disuccinate

Succinic acid (0.78 g) was added to a solution of the compound of Example 6 (2.0 g) in ethyl acetate (8 mL), and the mixture was stirred at 60° C. for 1 hour. 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 (form V crystals).
¹ H-NMR (400 MHz, DMSO-d ₆ ) 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).
[V-form crystal] The powder X-ray diffraction pattern is shown in FIG.
Main 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

Test example
Test Example 1: Menin-MLL binding inhibition experiment Menin _1-615 (hereinafter referred to as His-Menin _1-615 ) in which a 6xHis tag and a HA tag were inserted at the N-terminus and a myc tag at the C-terminus was used at a final concentration of 30 nmol/L. 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). Furthermore, the evaluation compound was diluted with assay buffer so that the evaluation compound concentration was 0.005 to 5 μmol/L. The prepared His-Menin _1-615 was added at 2 μL/well and the evaluation compound at 6 μL/well into a light-shielding 384-well low volume plate (Corning, #4514), and a light-shielding lid (Corning, #3935) was added. and incubated for 3 hours at room temperature. After incubation, separately, MLL _1-172 (MLL _1-172 -FLAG) in which a FLAG tag was inserted at the C-terminus was diluted with assay buffer to a final concentration of 50 nmol/L. The prepared MLL _1-172 -FLAG was added to the above plate at 2 μL/well, covered with a light-blocking lid, and incubated at room temperature for 1 hour.
Next, anti-6HIS-d2 antibody (cisbio, 61HISDLA) and anti-FLAGM2-K antibody (cisbio, 61FG2KLA) were added to antibody dilution buffer (50 mmol/L Tris, 150 mmol/L NaCl) to a final concentration of 1.4 μg/mL. , 800 mmol/L KF, pH 7.4) to prepare an antibody mixture. The prepared antibody mixture was added to the above plate at 10 μL/well, covered, and incubated at 4° C. for 17 to 24 hours. After incubation, signals were detected using RUBYstar (BMG LABTECH). The binding inhibition rate (%) at each concentration of the evaluation compound was determined using the formula shown below, and the IC ₅₀ value corresponding to the concentration of the evaluation compound at which the binding inhibition rate was 50% was calculated.

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

The evaluation results of Test Example 1 are shown in the table below.

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

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, the evaluation compound was added so that the final concentration of DMSO was 0.1%, and the cells were cultured for 7 days. After completion of the culture, cell viability was calculated using PrestoBlue (registered trademark) Cell Viability Reagent (Invitrogen, A13261). From the survival rate curve, an IC ₅₀ value corresponding to the concentration of the evaluation compound at which the inhibition rate of cell proliferation was 50% was calculated.

The evaluation results of Test Example 2 are shown in the table below.

As shown in the table above, the compounds of Examples 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 14, 15, 16, 18, 19 and 20 have a strong cell proliferation inhibitory effect. showed that.

Test Example 3: mRNA transcription control experiment using 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 in the presence of 5% _CO2 . After adding the evaluation compound to MV4;11 cells at a final concentration of 1 μmol/L, the cells were cultured at 37° C. in the presence of 5% CO ₂ for 20 to 24 hours. After culturing, total RNA was extracted from the cells using RNeasy (registered trademark) Mini Kit (QIAGEN, 74106) and extracted using Superscript (registered trademark) VILO (registered trademark) cDNA Synthesis Kit (Invitrogen, #11754250). cDNA was synthesized. Using TaqMan(R) Gene Expression Master Mix (Applied Biosystems, 4369016) and TaqMan(R) Probe (Applied Biosystems), The amount of mRNA expression was quantified from the obtained cDNA using the following method. The obtained mRNA expression level of each gene (MEIS1 and HOXA9) was corrected by the mRNA expression level of GAPDH.

The evaluation results of Test Example 3 are shown in the table below.

As shown in the table above, the compounds of Examples 1, 3, 4, 5, 6, 7, 8, 9, 10, and 11 exhibited mRNA transcription regulation resulting from inhibition of the binding between Menin and MLL fusion protein. .

Test Example 4: hERG Inhibition Test A test substance was added to cultured CHO cell line cells stably expressing the hERG (human Ether-a-go-go Related Gene) gene at a final DMSO concentration of 0.0135 to 0.5%. Added. The hERG current was measured using QPatch HT (Sophion), and the concentration (IC ₅₀ value; μM) at which each test substance suppressed the hERG current by 50% was calculated.

The test shown in Test Example 4 was conducted on the compounds obtained in Examples. In addition, for the compounds of each example, the concentration of the compound that suppresses the hERG current obtained in Test Example 4 by 50% is the concentration of the compound that suppresses the proliferation of RS4;11 cells obtained in Test Example 2 by 50%. The divided value was calculated as hERG/RS4;11. The results are shown in the table below.

As shown in the table above, the compounds of Examples 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 18 and 19 inhibited the proliferation of RS4; It was shown that there is a difference of 100 times or more between the compound concentration showing an inhibition rate of 50% and the compound concentration suppressing hERG current by 50%. In particular, the compounds of Examples 6, 7, 15, 16, and 18 showed a good deviation of more than 1000 times between the compound concentration showing a 50% growth inhibition rate of RS4;11 cells and the compound concentration suppressing hERG current by 50%. It was shown that it has a wide range.

The compounds of the present invention can exert anticancer effects by inhibiting the binding between MLL fusion protein and menin.

Claims (58)

Formula (1a):

[In the formula,
p represents 1 or 2,
R ¹ , R ² , R ³ and R ⁴ each independently represent a hydrogen atom, a halogen atom, -OR ⁷ , or -MQ, or R ¹ and R ² and/or R ³ and R ⁴ may be taken together and each independently form =O or =CR ^12A R ^13A ,
When there is more than one M, each independently represents C _1-6 alkylene (the alkylene is a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a C _2-4 alkynyl, a C _1-3 alkoxy, -CONR ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A , and 1 to 5 different ones selected from the group consisting of 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, a C _1-3 alkyl, a C _2-4 alkynyl, C _1-3 alkoxy, -CONR ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano), which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of
If there is more than one Q, each Q independently represents a hydrogen atom, a C _3-10 cycloalkyl, a 3- to 10-membered saturated heterocyclic group, a C _6-10 aryl, or a 5- to 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, a C _1-3 alkyl, a C _2-4 alkynyl, a C _1-3 alkoxy, -CONR The same or different 1 selected from the group consisting of ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano - optionally substituted with 5 substituents),
When there is more than one R ⁷ , each independently represents a hydrogen atom, a C _1-6 alkyl (the alkyl is a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, phenyl, a 5- to 6-membered heteroaryl, a 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 SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano), C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3- to 10-membered saturated heterocyclic group, C _6-10 aryl or 5- to 12-membered heteroaryl (said alkenyl, said alkynyl, said cycloalkyl, said saturated heterocyclic group) The group, the aryl, and the heteroaryl each independently represent a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a C _1-3 alkyl, a C _2-4 alkynyl, a C _1-3 alkoxy, -CONR ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and 1 to 5 same or different selected from the group consisting of cyano (optionally substituted with a substituent),
R ^12A and R ^13A each independently represent a hydrogen atom, a halogen atom, a C _1-6 alkyl (the alkyl is a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a C _2-4 alkynyl, a C _1-3 alkoxy , -CONR ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano or may be substituted with 1 to 5 different substituents), C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3- to 10-membered saturated heterocyclic group, C _{6- 10} aryl or 5- to 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 SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano), and when there are multiple R ^12A or R ^13A , R Each of ^12A or R ^13A may be the same or different, and here, when R ^12A and R ^13A are both C _1-6 alkyl, these together with the carbon atom to which they are bonded are 3- to 8-membered. may form a saturated carbon ring,
If there are multiple R ^35A , each independently represents C _1-6 alkyl;
R ^36A and R ^37A each independently represent a hydrogen atom or C _1-6 alkyl, and when there is a plurality of R ^36A or R ^37A , each of R ^36A or R ^37A may be the same or different; In, when R ^36A and R ^37A bonded to the same nitrogen atom are both C _1-6 alkyl, these together with the nitrogen atom bonded to each form a 3- to 6-membered nitrogen-containing saturated heterocycle. It is okay to do
a, b, c and d each independently represent 1 or 2]
A medicament containing the compound represented by or a pharmaceutically acceptable salt thereof. When there is more than one M, each independently represents C _1-6 alkylene (the alkylene is a fluorine atom, a hydroxyl group, a C _2-4 alkynyl, a C _1-3 alkoxy, -CONR ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano, substituted with the same or different 1 to 5 substituents ),
The medicament according to claim 1. When there is a plurality of Q, each independently represents a C _3-10 cycloalkyl, a 3- to 10-membered saturated heterocyclic group, a C _6-10 aryl, or a 5- to 12-membered heteroaryl (the cycloalkyl, the saturated heterocyclic group) The ring group, the aryl, and the heteroaryl each independently represent a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a C _1-3 alkyl, a C _2-4 alkynyl, a C _1-3 alkoxy, -CONR ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A , and 1 to 5 different ones selected from the group consisting of cyano optionally substituted with a substituent),
The medicament according to claim 1 or 2. When there is a plurality of R ⁷ s, each independently represents a hydrogen atom, a C _1-6 alkyl (the alkyl is a group consisting of a fluorine atom, phenyl, a C _3-7 cycloalkyl, and a 3- to 7-membered saturated heterocyclic group). ), C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3- to 10-membered saturated heterocycle group (the cycloalkyl and the saturated heterocyclic group may each be independently substituted with the same or different 1 to 5 substituents selected from the group consisting of a fluorine atom and C _1-3 alkyl) ), C _6-10 aryl or 5-12 membered heteroaryl (said aryl and said heteroaryl are each independently selected from the group consisting of fluorine atom, chlorine atom, bromine atom and C _1-3 alkyl) optionally substituted with the same or different 1 to 5 substituents),
The medicament according to any one of claims 1 to 3. When there are multiple R ⁷ s, each independently represents a hydrogen atom, C _1-6 alkyl optionally substituted with one phenyl, or C _2-6 alkenyl;
The medicament according to any one of claims 1 to 4. R ^12A and R ^13A are each independently a hydrogen atom, a C _1-6 alkyl (the alkyl is a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a C _2-4 alkynyl, a C _1-3 alkoxy, -CONR The same or different 1 selected from the group consisting of ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano (optionally substituted with ~5 substituents), 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, a C _1-3 alkyl, a C _2-4 alkynyl, a C _1-3 alkoxy, -CONR The same or different 1 selected from the group consisting of ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano (optionally substituted with ~5 substituents), and when there is a plurality of R ^12A or R ^13A , each of R ^12A or R ^13A may be the same or different; here, R ^12A and R 13A are When both ^13A are C _1-6 alkyl, these may form a 3- to 8-membered saturated carbon ring together with the carbon atoms to which they are bonded,
The medicament according to any one of claims 1 to 5. p is 1 or 2,
R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, a halogen atom, -OR ⁷ , or -MQ, or R ¹ and R ² and/or R ³ R ⁴ may be taken together and each independently form =O or =CR ^12A R ^13A ,
When there is more than one M, each independently represents C _1-6 alkylene (the alkylene is a fluorine atom, a hydroxyl group, a C _2-4 alkynyl, a C _1-3 alkoxy, -CONR ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano, substituted with the same or different 1 to 3 substituents ), and
When there is a plurality of Q, each independently represents a C _3-10 cycloalkyl, a 3- to 10-membered saturated heterocyclic group, a C _6-10 aryl, or a 5- to 12-membered heteroaryl (the cycloalkyl, the saturated heterocyclic group) The ring group, the aryl, and the heteroaryl each independently represent a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a C _1-3 alkyl, a C _2-4 alkynyl, a C _1-3 alkoxy, -CONR ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A , and 1 to 3 different ones selected from the group consisting of cyano (optionally substituted with a substituent),
When there are multiple R ⁷ s, each independently represents a hydrogen atom, C _1-6 alkyl optionally substituted with one phenyl, or C _2-6 alkenyl;
R ^12A and R ^13A are each independently a hydrogen atom, a C _1-6 alkyl (the alkyl is a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a C _2-4 alkynyl, a C _1-3 alkoxy, -CONR The same or different 1 selected from the group consisting of ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano ), C _3-10 cycloalkyl, 3- to 10-membered saturated heterocyclic group, C _6-10 aryl or 5- to 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, a C _1-3 alkyl, a C _2-4 alkynyl, a C _1-3 alkoxy, -CONR The same or different 1 selected from the group consisting of ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^37A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^37A R ^37A and cyano -3 substituents), and when there is a plurality of R ^12A or R ^13A , each of R ^12A or R 13A may be the same or different; here, R 12A and R ^13A may be the same or ^different ; When both ^13A are C _1-6 alkyl, these may form a 3- to 8-membered saturated carbon ring together with the carbon atoms to which they are bonded,
When there are multiple R ^35A , each independently is C _1-6 alkyl,
R ^36A and R ^37A are each independently a hydrogen atom or C _1-6 alkyl, and when there is a plurality of R ^36A or R ^37A , each of R ^36A or R ^37A may be the same or different; In, when R ^36A and R ^37A bonded to the same nitrogen atom are both C _1-6 alkyl, these together with the bonded nitrogen atom form a 3- to 6-membered nitrogen-containing saturated heterocycle. It's okay,
a, b, c and d are each independently 1 or 2,
The medicament according to any one of claims 1 to 6. 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 are may be taken together and each independently form =O or =CR ^12A R ^13A ,
The medicament according to any one of claims 1 to 7. When there is a plurality of M, each independently represents C _1-3 alkylene (the alkylene is selected from the group consisting of a fluorine atom, C _2-4 alkynyl, C _1-3 alkoxy, -NR ^36A R ^37A and cyano); may be substituted with the same or different 1 to 3 substituents),
The medicament according to any one of claims 1 to 8. When there are multiple M, each independently is C _1-3 alkylene,
The medicament according to any one of claims 1 to 9. When there is a plurality of Q, each independently represents a C _3-6 cycloalkyl, a 3- to 6-membered saturated heterocyclic group, 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, a C _1-3 alkyl, a C _2-4 alkynyl, a C _1-3 alkoxy, -CONR ^36A R ^37A , -NR ^36A R ^37A , -NR ^36A COR ^35A , -NR ^36A SO ₂ R ^35A , -SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano, substituted with the same or different 1 to 3 substituents ),
The medicament according to any one of claims 1 to 10. When there is a plurality of Q, each independently represents a C _3-6 cycloalkyl, a 3- to 6-membered saturated heterocyclic group, phenyl, or a 5- to 6-membered heteroaryl (the cycloalkyl, the saturated heterocyclic group, the Phenyl and the heteroaryl are each independently the same or different 1- to 1-3 selected from the group consisting of a fluorine atom, C _1-3 alkyl, -NR ^36A SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A , and cyano. optionally substituted with 3 substituents),
The medicament according to any one of claims 1 to 11. When there is a plurality of Q, each independently represents C _3-6 cycloalkyl (the cycloalkyl is a fluorine atom, C _1-3 alkyl, -NR ^36A SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano (optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of),
The medicament according to any one of claims 1 to 12. R ^12A and R ^13A are each independently a hydrogen atom, C _1-6 alkyl (the alkyl is selected from the group consisting of a fluorine atom, -NR ^36A SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano); may be substituted with the same or different 1 to 3 substituents), C _3-10 cycloalkyl (the cycloalkyl is a fluorine atom, C _1-3 alkyl, -NR ^36A SO ₂ R ^35A , -SO ₂ NR ^36A (optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of R ^37A and cyano), and when there are multiple R ^12A or R ^13A , R ^12A Alternatively, each of R ^13A may be the same or different, and here, when R ^12A and R ^13A are both C _1-3 alkyl, these together with the carbon atom to which they are bonded represent a 3- to 6-membered May form a saturated carbon ring,
The medicament according to any one of claims 1 to 13. R ^12A and R ^13A each independently represent a hydrogen atom, C _3-6 cycloalkyl (the cycloalkyl is a fluorine atom, C _1-3 alkyl, -NR ^36A SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano), and when there are multiple R ^12A and R ^13A , each of R ^12A and R ^13A is Can be the same or different
The medicament according to any one of claims 1 to 14. a and c are 1,
b and d are both 1 or 2,
The medicament according to any one of claims 1 to 15. p is 1 or 2,
R ¹ , R ² , R ³ and R ⁴ each independently represent a hydrogen atom, a fluorine atom, or -MQ, or R ¹ and R ² and/or R ³ and R ⁴ are Together, each independently may form =O or =CR ^12A R ^13A ,
When there are multiple M, each independently represents C _1-3 alkylene,
When there is a plurality of Q, each independently represents C _3-6 cycloalkyl (the cycloalkyl is a fluorine atom, C _1-3 alkyl, -NR ^36A SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano (optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of),
R ^12A and R ^13A each independently represent a hydrogen atom, C _3-6 cycloalkyl (the cycloalkyl is a fluorine atom, C _1-3 alkyl, -NR ^36A SO ₂ R ^35A , -SO ₂ NR ^36A R ^37A and cyano), and when there is a plurality of R ^12A or R ^13A , each of R ^12A or R ^13A is May be the same or different;
When there are multiple R ^35A , each independently is C _1-6 alkyl,
R ^36A and R ^37A are each independently a hydrogen atom or C _1-6 alkyl, and when there is a plurality of R ^36A or R ^37A , each of R ^36A or R ^37A may be the same or different; In, when R ^36A and R ^37A bonded to the same nitrogen atom are both C _1-6 alkyl, these together with the nitrogen atom bonded to each form a 3- to 6-membered nitrogen-containing saturated heterocycle. It is okay to do
a and c are 1,
b and d are both 1 or 2,
The medicament according to any one of claims 1 to 16. 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 are Together, each independently may form =CR ^12A R ^13A ,
The medicament according to any one of claims 1 to 17. M is methylene,
The medicament according to any one of claims 1 to 18. When there is a plurality of Q, each independently represents C _3-6 cycloalkyl (the cycloalkyl is the same or different 1 to 3 substituents selected from the group consisting of a fluorine atom and C _1-3 alkyl) may be substituted),
The medicament according to any one of claims 1 to 19. When there is more than one Q, each independently is C _3-6 cycloalkyl,
The medicament according to any one of claims 1 to 20. R ^12A and R ^13A are each independently a hydrogen atom or C _3-6 cycloalkyl,
The medicament according to any one of claims 1 to 21. R ^12A and R ^13A are hydrogen atoms,
The medicament according to any one of claims 1 to 22. 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 are together and may form = _CH2 ,
When there are multiple M, each independently is methylene,
When there is more than one Q, each independently represents C _3-6 cycloalkyl;
a and c are 1,
b and d are both 1 or 2,
The medicament according to any one of claims 1 to 23. R ¹ and R ² are hydrogen atoms,
R ³ and R ⁴ are each independently a hydrogen atom or a fluorine atom,
However, R ³ and R ⁴ are not hydrogen atoms at the same time,
The medicament according to any one of claims 1 to 24. 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 R ² are not hydrogen atoms at the same time,
The medicament according to any one of claims 1 to 24. R ¹ is a hydrogen atom,
R ² is -MQ,
R ³ is a hydrogen atom,
R ⁴ is a hydrogen atom or a fluorine atom,
The medicament according to any one of claims 1 to 24. R ¹ is -MQ,
R ² is a hydrogen atom,
R ³ is a hydrogen atom or a fluorine atom,
R ⁴ is a hydrogen atom,
The medicament according to any one of claims 1 to 24. 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 together form =CH ₂ It is okay to do
However, R ¹ , R ² , R ³ and R ⁴ are not all hydrogen atoms at the same time,
The medicament according to any one of claims 1 to 24. R ¹ and R ² are together =CH ₂ ;
R ³ and R ⁴ are hydrogen atoms,
The medicament according to any one of claims 1 to 24. R ¹ and R ² are hydrogen atoms,
R ³ and R ⁴ together are =CH ₂ ;
The medicament according to any one of claims 1 to 24. a, b, c and d are 1,
The medicament according to any one of claims 1 to 31. a and c are 1,
b and d are 2,
The medicament according to any one of claims 1 to 31. p is 1,
The medicament according to any one of claims 1 to 33. p is 2,
The medicament according to any one of claims 1 to 33. The medicament according to claim 1, wherein the compound represented by formula (1a) is 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,
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,
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,
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,
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,
5-Fluoro-2-[(4-{6-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3 .3] heptane-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide,
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,
5-Fluoro-2-[(4-{6-[(1S,3S,4R)-6-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3 .3] heptane-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide,
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,
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,
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,
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,
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,
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,
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,
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 and 5-fluoro-2- [(4-{7-[(1S,3S,4R)-5-( ² H ₂ )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. The medicament according to claim 1, wherein the compound represented by formula (1a) is 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,
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,
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 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}pyrimidine -5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide. A medicament containing a compound selected from the following compounds or its hydrochloride, L(+)-tartrate or succinate:
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,
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,
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 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}pyrimidine -5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide. The medicament according to claim 1, wherein the compound represented by formula (1a) is 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,
5-Fluoro-2-[(4-{6-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3 .3] heptane-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide,
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,
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,
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 and 5-fluoro-2-[(4-{7-[(1S,3S ,4R)-5-( ² H ₂ )methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5- yl)oxy]-N,N-di(propan-2-yl)benzamide. A medicament containing a compound selected from the following compounds or its hydrochloride, L(+)-tartrate or succinate:
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,
5-Fluoro-2-[(4-{6-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3 .3] heptane-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide,
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 and 5-fluoro-2-[(4-{7-[(1S,3S ,4R)-5-( ² H ₂ )methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5- yl)oxy]-N,N-di(propan-2-yl)benzamide. 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 or its hydrochloride, L(+)-tartrate or Medicines containing succinate. 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 or its hydrochloride, L(+)-tartrate or Medicines containing succinate. 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 or its hydrochloride, L(+)-tartrate or Medicines containing succinate. 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 or its hydrochloride, L(+)-tartrate or Medicines containing succinate. 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3 .5] Contains nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or its hydrochloride, L(+)-tartrate or succinate Medicine. 5-Fluoro-2-[(4-{6-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3 .3] containing heptane-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or its hydrochloride, L(+)-tartrate or succinate Medicine. 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.1]heptane-3-carbonyl]-2,7-diazaspiro[3 .5] Contains nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or its hydrochloride, L(+)-tartrate or succinate Medicine. 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-( ² H ₂ )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 or its hydrochloride, L(+)-tartrate or succinate Medicines containing acid salts. An antitumor agent containing the compound according to any one of claims 1 to 48 or a pharmaceutically acceptable salt thereof as an active ingredient. The tumor is acute leukemia (including MLL acute leukemia, MLL partial tandem duplication acute leukemia, NPM mutation acute leukemia, MOZ acute leukemia, NUP98 acute leukemia, and CALM acute leukemia), chronic lymphocytic leukemia, chronic myeloid leukemia, and myelodysplasia. 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 Cellular lung cancer, breast cancer, stomach cancer, gallbladder/bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, anal cancer, chorioepithelial cancer, endometrial cancer, cervix Cancer, ovarian cancer, bladder cancer, urothelial cancer, kidney cancer, renal cell cancer, prostate cancer, testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, malignant melanoma, The antitumor agent according to claim 49, which is neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, or skin cancer. If the tumor is acute leukemia (including 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, malignant lymphoma (B-cell lymphoma) 51. The antitumor agent according to claim 49 or 50, wherein the antitumor agent is cancerous for cancer (including multiple myeloma), myeloma (including multiple myeloma), brain tumor, prostate cancer, breast cancer, neuroblastoma, Ewing's sarcoma, or liver cancer. The tumor is MLL acute leukemia, MLL partial tandem duplication acute leukemia, NPM mutation acute leukemia, MOZ acute leukemia, NUP98 acute leukemia, CALM acute leukemia, chronic myeloid leukemia, B-cell lymphoma, multiple myeloma, neuroblastoma. , or prostate cancer, the antitumor agent according to any one of claims 49 to 51. A claim where the tumor is MLL acute leukemia, MLL segmental 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. The antitumor agent according to any one of Items 49 to 52. The antitumor agent according to any one of claims 49 to 53, wherein the tumor is MLL acute leukemia or NPM mutant acute leukemia. The antitumor agent according to any one of claims 49 to 54, wherein the tumor is a tumor with high expression of the HOXa gene group or the MEIS gene group. The antitumor agent according to any one of claims 49 to 55, wherein the tumor is a tumor with a p53 gain-of-function mutation. A pharmaceutical composition comprising the compound according to any one of claims 1 to 48 or a pharmaceutically acceptable salt thereof, in combination with another drug or a pharmaceutically acceptable salt thereof. , the other drug is an antitumor alkylating agent, an antitumor antimetabolite, an antitumor antibiotic, a plant-derived antitumor agent, an antitumor platinum coordination compound, an antitumor camptothecin derivative, an antitumor Tyrosine kinase inhibitors, anti-tumor serine-threonine kinase inhibitors, anti-tumor phospholipid kinase inhibitors, anti-tumor monoclonal antibodies, interferons, biological response modifiers, hormonal preparations, angiogenesis inhibitors, immune checkpoint inhibition A pharmaceutical composition comprising at least one selected from the group consisting of antitumor agents, epigenetics-related molecule inhibitors, protein post-translational modification inhibitors, proteasome inhibitors, and other antitumor agents. 49. The medicament according to any one of claims 1 to 48, for treating a tumor in combination with another drug or a pharmaceutically acceptable salt thereof, wherein the other drug is an anti-inflammatory drug. Tumor alkylating agents, anti-tumor antimetabolites, anti-tumor antibiotics, plant-derived anti-tumor agents, anti-tumor platinum coordination compounds, anti-tumor camptothecin derivatives, anti-tumor tyrosine kinase inhibitors, anti-tumor properties serine-threonine kinase inhibitors, anti-tumor phospholipid kinase inhibitors, anti-tumor monoclonal antibodies, interferons, biological response modifiers, hormonal preparations, angiogenesis inhibitors, immune checkpoint inhibitors, epigenetics-related molecule inhibition at least one selected from the group consisting of antitumor agents, protein post-translational modification inhibitors, proteasome inhibitors, and other antitumor agents.

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