1h-pyrazole-3-amine derivative having bicyclic backbone

Abstract

The present invention provides a compound that exhibits an anticancer effect based on Checkpoint Kinase 1 (CHK1) inhibition. It is discovered that a compound represented by formula (1) or a pharmaceutically acceptable salt thereof has a strong inhibitory effect on CHK1, and exhibits an excellent antitumour effect. As a result, the present disclosure was achieved. [In the formula, R1, L, V, W, Q, ring A, Y1a, Y1b, Z1a, and Z1b are each as defined in the description].

Description

1H-Pyrazol-3-amine derivatives having bicyclic skeletons

[0001] The present disclosure relates to 1H-pyrazol-3-amine derivatives and pharmaceutically acceptable salts thereof having a bicyclic skeleton, which inhibit Checkpoint Kinase 1 (CHK1) and are useful as pharmaceuticals for treating or preventing cancers characterized by defects in deoxyribonucleic acid (DNA) replication, chromosome segregation, or cell division; pharmaceutical compositions containing these; liposomes containing these; and therapeutic or preventive agents for pathologies involving CHK1, which contain these compositions or liposomes.

[0002] CHK1 is a serine / threonine protein kinase downstream of ATR in the DNA damage checkpoint signaling pathway during the cell cycle. In mammalian cells, CHK1 is phosphorylated in an ATR-dependent manner in response to DNA damage caused by ionizing radiation or DNA replication stress resulting from excessive cell proliferation or genomic instability in cancer cells (Non-Patent Documents 1-5). This phosphorylation activates CHK1, causing CHK1 to phosphorylate CDC25A, inhibiting CDC25A-mediated dephosphorylation of cyclin E / CDK2 and halting progression from the S phase. CHK1 also phosphorylates CDC25C, inhibiting CDC25C-mediated dephosphorylation of cyclin B / CDK1, halting progression from the G2M phase. In both cases, regulation of CDK activity induces cell cycle arrest, preventing cell division in the presence of DNA damage and promoting DNA damage repair. CHK1 inhibition suppresses the checkpoint function of DNA damage in the cell cycle in cancer cells, causing DNA repair failure and uncontrollable DNA synthesis in the presence of DNA damage, resulting in DNA fragmentation, replication catastrophe, and cell death (Patent Documents 1 and 2).

[0003] Various inhibitors of CHK1 have been reported (Patent Documents 1 to 4).

[0004] International Publication No. 2010 / 077758 International Publication No. 2012 / 064548 International Publication No. 2017 / 132928 International Publication No. 2021 / 043208

[0005] Dai Y and Grant S, Clin Cancer Res, 16(2):376-383 (2010)Benada J and Macurek L, Biomolecules, 5:1912-1937 (2015)King C, Mol Cancer Ther, 14(9):2004-2013 (2015)Dent P, Expert Opinion on Investigational drugs, 28(12):1095-1100 (2019)Evangelisti G. et al, Expert Opinion on Investigational Drugs, 29(8):779-792 (2020)David H. et al, J Clin Oncol, 34:1764-1771 (2016)

[0006] The present disclosure provides compounds that exert anticancer effects based on CHK1 inhibition. Preferably, the compounds are compounds having a gap between the compound concentration that inhibits the proliferation of CHK1-expressing cancer cells and the compound concentration that inhibits hERG current, compounds having a gap between the compound concentration that inhibits CHK1 inhibitory activity and the compound concentration that causes toxicity to hematopoietic cells, and / or compounds that are encapsulated in liposomes and released from the liposomes in a sustained manner. In other words, the present disclosure provides antitumor agents that have a high therapeutic effect while reducing side effects.

[0007] As a result of intensive research, the present inventors have found that a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof (hereinafter, also referred to as "the compound of the present disclosure") has a strong inhibitory effect on CHK1 and thereby exhibits an excellent antitumor effect, thereby completing the present disclosure.

[0008] That is, the present disclosure is as follows.

[0009] [Section 1] [In the formula, R １ represents a hydrogen atom, a halogen atom, a cyano, a nitro, a carboxyl, a sulfonic acid, a phosphoric acid, or -OR ２ , -SR ２ , -COR ３ , -CO２ R ３ , -CONR ４ R ５ , -SO ２ R ３ , -SO ２ NR ４ R ５ , -OCOR ３ , -OCO ２ R ３ , -OCONR ４ R ５ , -NR ４ R ５ , -NR ６ COR ３ , -NR ６ CO ２ R ３ , -NR ６ CONR ４ R ５ , -NR ６ SO ２ R ３ , -NR ６ SO ２ NR ４ R ５ , optionally substituted C １－６ Alkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, optionally substituted C ３－１０ Cycloalkyl, optionally substituted 3- to 10-membered saturated heterocyclic group, optionally substituted C ６－１０ R represents an aryl or an optionally substituted 5- to 12-membered heteroaryl; ２ is a hydrogen atom or C １－６ represents alkyl, R ３ is C １－６ represents alkyl, R ４ , R ５ and R ６ are each independently a hydrogen atom or C １－６ alkyl, wherein R ４ and R ５ Both are C １－６ When they are alkyl, they may be joined together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle; １ａand Y １ｂ each independently represents a carbon atom or a nitrogen atom; Z １ａ is a nitrogen atom or CR ７a represents Z １ｂ is a nitrogen atom or CR ７ｂ represents R ７a and R ７ｂ are each independently a hydrogen atom, a halogen atom, cyano, nitro, carboxyl, sulfonic acid, phosphoric acid, -OR ８ , -SR ８ , -COR ９ , -CO ２ R ９ , -CONR １０ R １１ , -SO ２ R ９ , -SO ２ NR １０ R １１ , -OCOR ９ , -OCO ２ R ９ , -OCONR １０ R １１ , -NR １０ R １１ , -NR １２ COR ９ , -NR １２ CO ２ R ９ , -NR １２ CONR １０ R １１ , -NR １２ SO ２ R ９ , -NR １２ SO ２ NR １０ R １１ , optionally substituted C １－６ Alkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, optionally substituted C ３－１０ Cycloalkyl, optionally substituted 3- to 10-membered saturated heterocyclic group, optionally substituted C ６－１０ R represents an aryl or an optionally substituted 5- to 12-membered heteroaryl; ８ is a hydrogen atom or C １－６represents alkyl, R ９ is C １－６ represents alkyl, R １０ , R １１ and R １２ are each independently a hydrogen atom or C １－６ alkyl, wherein R １１ and R １２ Both are C １－６ When they are alkyl, they may form a 3- to 8-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which they are bonded, ring A represents an optionally substituted 3- to 10-membered cycloalkane, an optionally substituted 6- to 10-membered arene, an optionally substituted 4- to 10-membered aromatic heterocycle, or an optionally substituted 4- to 10-membered non-aromatic heterocycle, L represents a single bond or an optionally substituted C １－６ alkylene; V is a single bond, carbonyl, thiocarbonyl, or optionally substituted C ２－６ Alkenylene, optionally substituted C ３－１０ Cycloalkylene, optionally substituted C ３－１０ Cycloalkenylene, an optionally substituted 3- to 10-membered divalent saturated heterocyclic group, or —C(═NR １３ )-, R １３ is a hydrogen atom or C １－６ alkyl; W is a single bond or an optionally substituted C １－６ represents an alkylene; Q represents a hydrogen atom or NHR １４ represents R １４ represents a hydrogen atom, an optionally substituted C １－６ Alkyl, optionally substituted C ３－１０ [Item 2] R represents a cycloalkyl, or an optionally substituted 3- to 10-membered saturated heterocyclic group, or a pharmaceutically acceptable salt thereof. １ , R ７a , R ７ｂ , R １４ , optionally substituted C in rings A, L, V, and W １－６ Alkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C２－６ Alkynyl, optionally substituted C ２－６ Alkenylene, optionally substituted C ３－１０ Cycloalkyl, optionally substituted 3- to 10-membered saturated heterocyclic group, optionally substituted 6- to 10-membered arene, optionally substituted 4- to 10-membered aromatic heterocycle, optionally substituted 3- to 10-membered cycloalkane, optionally substituted 4- to 10-membered non-aromatic heterocycle, optionally substituted C ６－１０ Aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted C １－６ Alkylene, optionally substituted C ３－１０ Cycloalkylene, optionally substituted C ３－１０ The cycloalkenylene or optionally substituted 3- to 10-membered divalent saturated heterocyclic group is each independently (1) a halogen atom, (2) a hydroxyl group, or (3) C ６－１０ (4) 5- to 12-membered heteroaryl; (5) C １－６ alkyl, (6) C ２－６ alkenyl, (7) C ２－６ alkynyl, (8) C １－６ Alkoxy, (9) C １－６ Alkylthio (10) C ３－１０ (11) a 3- to 10-membered saturated heterocyclic group, (12) a carboxyl, (13) -COR １５ , (14)-CO ２ R １５ , (15)-CONR １６ R １７ , (16)-NR １６ R １７ , (17)-NR １８ COR １５ , (18)-NR １８ CO ２ R １５ , (19)-NR １８ SO ２ R １５ , (20)-NR １８ CONR １６ R １７ , (21)-NR １８ SO ２NR １６ R １７ , (22)-SO ２ R １５ , (23)-SO ２ NR １６ R １７ , (24)-OCOR １５ , (25)-OCO ２ R １５ , (26)-OCONR １６ R １７ (27) sulfonic acid, (28) phosphoric acid, (29) cyano, and (30) nitro, wherein the (3) C ６－１０ (4) 5- to 12-membered heteroaryl; (5) C １－６ alkyl, (6) C ２－６ alkenyl, (7) C ２－６ alkynyl, (8) C １－６ Alkoxy, (9) C １－６ Alkylthio, (10)C ３－１０ The group shown in cycloalkyl and (11) 3- to 10-membered saturated heterocyclic group is (a) a halogen atom, (b) a hydroxyl group, or (c) C ６－１０ (d) 5- to 12-membered heteroaryl; (e) C １－６ (f) alkyl, ２－６ alkenyl, (g) C ２－６ alkynyl, (h) C １－６ Alkoxy, (i) C ３－１０ (j) a 3- to 10-membered saturated heterocyclic group; (k) a carboxyl; (l) —COR １５ , (m)-CO ２ R １５ , (n)-CONR １６ R １７ , (o)-NR １６ R １７ , (p)-NR １８ COR １５ , (q)-NR １８ SO ２ R １５ , (r)-SO ２ R １５, (s)-SO ２ NR １６ R １７ (t) sulfonic acid, (u) phosphate, (v) cyano, and (w) nitro; R １５ However, if there are multiple, each independently, C １－６ alkyl, R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When R is alkyl, they may be combined with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle, １８ is a hydrogen atom or C １－６ Item 3: The compound according to Item 1, or a pharmaceutically acceptable salt thereof, wherein R is alkyl. １ , R ７a , R ７ｂ , R １４ , optionally substituted C in rings A, L, V, and W １－６ Alkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, optionally substituted C ２－６ Alkenylene, optionally substituted C ３－１０ Cycloalkyl, optionally substituted 3- to 10-membered saturated heterocyclic group, optionally substituted 6- to 10-membered arene, optionally substituted 4- to 10-membered aromatic heterocycle, optionally substituted 3- to 10-membered cycloalkane, optionally substituted 4- to 10-membered non-aromatic heterocycle, optionally substituted C ６－１０ Aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted C １－６ Alkylene, optionally substituted C ３－１０Cycloalkylene, optionally substituted C ３－１０ The cycloalkenylene or optionally substituted 3- to 10-membered divalent saturated heterocyclic group is each independently (1) a halogen atom, (2) a hydroxyl group, or (3) C ６－１０ (4) 5- to 12-membered heteroaryl; (5) C optionally substituted with 1 to 3 halogen atoms; １－６ alkyl, (6) C ２－６ alkenyl, (7) C ２－６ alkynyl, (8) C １－６ Alkoxy, (9) C ３－１０ (10) a 3- to 10-membered saturated heterocyclic group, (11) a carboxyl, (12) —COR １５ , (13)-CO ２ R １５ , (14)-CONR １６ R １７ , (15)-NR １６ R １７ , (16)-SO ２ R １５ , (17)-SO ２ NR １６ R １７ (18) sulfonic acid, (19) phosphoric acid, (20) cyano, and (21) nitro; R １５ However, if there are multiple, each independently, C １－６ alkyl, R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６When R is alkyl, they may be joined together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle, or a pharmaceutically acceptable salt thereof. １ , R ７a , R ７ｂ , R １４ , optionally substituted C in rings A, L, V, and W １－６ Alkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, optionally substituted C ２－６ Alkenylene, optionally substituted C ３－１０ Cycloalkyl, optionally substituted 3- to 10-membered saturated heterocyclic group, optionally substituted 6- to 10-membered arene, optionally substituted 4- to 10-membered aromatic heterocycle, optionally substituted 3- to 10-membered cycloalkane, optionally substituted 4- to 10-membered non-aromatic heterocycle, optionally substituted C ６－１０ Aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted C １－６ Alkylene, optionally substituted C ３－１０ Cycloalkylene, optionally substituted C ３－１０ Cycloalkenylene or an optionally substituted 3- to 10-membered divalent saturated heterocyclic group, each independently, is (1) a halogen atom, (2) a hydroxyl group, (3) a phenyl, (4) a 5- or 6-membered heteroaryl, or (5) a C optionally substituted with 1 to 3 halogen atoms. １－６ alkyl, (6) C １－６ Alkoxy, (7) C ３－７ (8) a 3- to 7-membered saturated heterocyclic group, (9) —COR １５ , (10)-CO ２ R １５ , (11)-CONR １６ R １７ , (12)-NR １６ R １７ , (13)-SO ２ R １５ , (14)-SO ２ NR １６R １７ (15) optionally substituted with 1 to 5 identical or different substituents selected from the group consisting of cyano, １５ However, if there are multiple, each independently, C １－６ alkyl, R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When R is alkyl, they may be joined together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle, or a pharmaceutically acceptable salt thereof. １ is a hydrogen atom, a halogen atom, cyano, -OR ２ , -CO ２ R ３ , C １－６ Alkyl, C ３－１０ Item 6. The compound according to any one of Items 1 to 4, wherein R is a cycloalkyl or a 3- to 10-membered saturated heterocyclic group, or a pharmaceutically acceptable salt thereof. １ is a hydrogen atom, a halogen atom, cyano, -CO ２ R ３ or C １－６ The compound according to any one of Items 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R is alkyl. [Item 6A] １ is a hydrogen atom, a halogen atom, cyano, -CO ２ R ３ [Item 7] The compound according to any one of Items 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R １ [Item 8] The compound according to any one of Items 1 to 4, wherein R is cyano, or a pharmaceutically acceptable salt thereof. ７a and R ７ｂ are each independently a hydrogen atom, a halogen atom, cyano, or —OR８ , -CO ２ R ９ , -CONR １０ R １１ , -NR １０ R １１ , -NR １２ COR ９ , C １－６ Alkyl (the alkyl is a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a phenyl, a 5- to 6-membered heteroaryl, C １－６ Alkoxy, C ３－７ cycloalkyl, 3- to 7-membered saturated heterocyclic group, —CONR １６ R １７ , -NR １６ R １７ and cyano), C ３－１０ Cycloalkyl (the cycloalkyl is a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a phenyl, a 5- to 6-membered heteroaryl, C １－６ Alkyl, C １－６ Alkoxy, C ３－７ cycloalkyl, 3- to 7-membered saturated heterocyclic group, —CONR １６ R １７ , -NR １６ R １７ and cyano), a 3- to 10-membered saturated heterocyclic group (the saturated heterocyclic group is optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, phenyl, a 5- or 6-membered heteroaryl, C １－６ Alkyl, C １－６ Alkoxy, C ３－７ cycloalkyl, 3- to 7-membered saturated heterocyclic group, —CONR １６ R １７ , -NR １６ R １７ and cyano), phenyl (the phenyl is optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, phenyl, 5- to 6-membered heteroaryl, C １－６ Alkyl, C １－６ Alkoxy, C ３－７ cycloalkyl, 3- to 7-membered saturated heterocyclic group, —CONR １６R １７ , -NR １６ R １７ and cyano), or 5- to 6-membered heteroaryl (the heteroaryl is a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, phenyl, a 5- to 6-membered heteroaryl, C １－６ Alkyl, C １－６ Alkoxy, C ３－７ cycloalkyl, 3- to 7-membered saturated heterocyclic group, —CONR １６ R １７ , -NR １６ R １７ and cyano), and R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When R is alkyl, they may be joined together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle, or a pharmaceutically acceptable salt thereof. ７a and R ７ｂ are each independently a hydrogen atom, a halogen atom, or -OR ９ , C １－６ Alkyl (the alkyl is a fluorine atom, a hydroxyl group, C １－３ Alkoxy, —NR １６ R １７ and cyano), C ３－７ Cycloalkyl (the cycloalkyl is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７and cyano), a 3- to 7-membered saturated heterocyclic group (the saturated heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), phenyl (the phenyl may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), or a 5- or 6-membered heteroaryl (the heteroaryl is optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When R is alkyl, they may be joined together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle, or a pharmaceutically acceptable salt thereof. ７a and R ７ｂ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or C １－６ Alkyl (the alkyl is a fluorine atom, a hydroxyl group, C １－３ Alkoxy, —NR １６ R １７and cyano), or a 5- or 6-membered heteroaryl (the heteroaryl may be substituted with 1 or 2 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When ring A is an alkyl, it may be taken together with the nitrogen atom to which it is bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle, or a pharmaceutically acceptable salt thereof. [Item 11] The compound according to any one of Items 1 to 7, wherein ring A is a 3- to 10-membered cycloalkane (the cycloalkane is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, phenyl, a 5- or 6-membered heteroaryl, C １－６ Alkyl, C １－６ Alkoxy, C ３－７ cycloalkyl, 3- to 7-membered saturated heterocyclic group, —CONR １６ R １７ , -NR １６ R １７ and cyano), a 6- to 10-membered arene (the arene may be substituted with a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a phenyl, a 5- to 6-membered heteroaryl, C １－６ Alkyl, C １－６ Alkoxy, C ３－７ cycloalkyl, 3- to 7-membered saturated heterocyclic group, —CONR １６ R １７ , -NR １６ R １７and cyano), a 4- to 10-membered aromatic heterocycle (the aromatic heterocycle is optionally substituted with a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, phenyl, a 5- or 6-membered heteroaryl, C １－６ Alkyl, C １－６ Alkoxy, C ３－７ cycloalkyl, 3- to 7-membered saturated heterocyclic group, —CONR １６ R １７ , -NR １６ R １７ and cyano), or a 4- to 10-membered non-aromatic heterocycle (the non-aromatic heterocycle is optionally substituted with a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, phenyl, a 5- or 6-membered heteroaryl, C １－６ Alkyl, C １－６ Alkoxy, C ３－７ cycloalkyl, 3- to 7-membered saturated heterocyclic group, —CONR １６ R １７ , -NR １６ R １７ and cyano), and R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ [Item 12] The compound according to any one of Items 1 to 10, wherein when Ring A is an alkyl, it may be taken together with the nitrogen atom to which it is bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle, or a pharmaceutically acceptable salt thereof. [Item 13] The compound according to any one of Items 1 to 10, wherein Ring A is a 3- to 10-membered cycloalkane (the cycloalkane does not contain a fluorine atom, a hydroxyl group, a C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７and cyano), a 6- to 10-membered arene (the arene may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, a C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), a 4- to 10-membered aromatic heterocycle (the aromatic heterocycle may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), or a 4- to 10-membered non-aromatic heterocycle (the non-aromatic heterocycle may be substituted with 1 to 3 identical or different substituents selected from the group consisting of fluorine atom, hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When the ring A is an alkyl, it may be taken together with the nitrogen atom to which it is bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle, or a pharmaceutically acceptable salt thereof. [Item 13] The compound according to any one of Items 1 to 10, wherein ring A is a 4- to 10-membered aromatic heterocycle (the aromatic heterocycle does not contain a fluorine atom, a hydroxyl group, a C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７and cyano), or a 4- to 10-membered non-aromatic heterocycle (the non-aromatic heterocycle may be substituted with 1 to 2 identical or different substituents selected from the group consisting of fluorine atom, hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ [Item 14] The compound according to any one of Items 1 to 10, wherein when L is alkyl, they may be taken together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle, or a pharmaceutically acceptable salt thereof. １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６[Item 15] The compound according to any one of Items 1 to 13, wherein when V is alkyl, they may be taken together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle, or a pharmaceutically acceptable salt thereof. ２－６ Alkenylene (the alkenylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), C ３－１０ Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), C ３－１０ Cycloalkenylene (the cycloalkenylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a fluorine atom, a hydroxyl group, a C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), or —C(═NR １３ )- and R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R１６ and R １７ Both are C １－６ [Item 16] The compound according to any one of Items 1 to 14, wherein when W is alkyl, they may be taken together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle, or a pharmaceutically acceptable salt thereof. １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkoxy, —NR １６ R １７ and cyano), and R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When R is alkyl, they may be joined together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle, or a pharmaceutically acceptable salt thereof. [Item 17] R １４ is a hydrogen atom, C １－６ Alkyl (the alkyl is a fluorine atom, a hydroxyl group, C １－３ Alkoxy, —NR １６ R １７ and cyano), C ３－１０ Cycloalkyl (the cycloalkyl is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), or a 3- to 10-membered saturated heterocyclic group (the saturated heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, a C １－３ Alkyl, C１－３ Alkoxy, —NR １６ R １７ and cyano), and R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When the alkyl is alkyl, they may be taken together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle, or a pharmaceutically acceptable salt thereof. [Item 18] The compound according to any one of Items 1 to 16, wherein the formula (1) is the following formula (2): [In the formula, R １ represents a hydrogen atom, a halogen atom, cyano, -CO ２ R ３ represents R ３ is C １－６ represents alkyl, Y １ａ and Y １ｂ each independently represents a carbon atom or a nitrogen atom; Z １ａ is a nitrogen atom or CR ７a represents Z １ｂ is a nitrogen atom or CR ７ｂ represents R ７a and R ７ｂ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or C １－６ Alkyl (the alkyl is a fluorine atom, a hydroxyl group, C １－３ Alkoxy, —NR １６ R １７ and cyano), or a 5- or 6-membered heteroaryl (the heteroaryl may be substituted with 1 or 2 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R１７ and cyano), ring A represents a 5- or 6-membered aromatic heterocycle (the aromatic heterocycle may contain a fluorine atom, a hydroxyl group, a C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), or a 5- to 8-membered non-aromatic heterocycle (the non-aromatic heterocycle is optionally substituted with 1 to 2 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), wherein L represents a single bond, or １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), V represents a single bond, C ２－６ Alkenylene (the alkenylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), C ３－１０ Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), C ３－１０ Cycloalkenylene (the cycloalkenylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７and cyano), or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a fluorine atom, a hydroxyl group, a C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), W represents a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkoxy, —NR １６ R １７ and cyano), Q represents a hydrogen atom, or NHR １４ represents R １４ is a hydrogen atom, C １－６ Alkyl (the alkyl is a fluorine atom, a hydroxyl group, C １－３ Alkoxy, —NR １６ R １７ and cyano), C ３－１０ Cycloalkyl (the cycloalkyl is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), or a 3- to 10-membered saturated heterocyclic group (the saturated heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, a C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple１６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ and when R is alkyl, they may be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered nitrogen-containing saturated heterocycle, or a pharmaceutically acceptable salt thereof. [Item 18A] R １ [Item 19] The compound according to any one of Items 1 to 18, or a pharmaceutically acceptable salt thereof, wherein Z is cyano. １ａ But, CR ７ａ [Item 20] The compound according to any one of Items 1 to 18 and 18A, or a pharmaceutically acceptable salt thereof, wherein Z １ｂ But, CR ７ｂ [Item 21] The compound according to any one of Items 1 to 19, or a pharmaceutically acceptable salt thereof, wherein Z １ｂ [Item 22] The compound according to any one of Items 1 to 19, wherein R is a nitrogen atom, or a pharmaceutically acceptable salt thereof. ７a and R ７ｂ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or C １－６ Alkyl (the alkyl is a fluorine atom, a hydroxyl group, and １－３ [Item 23] The compound according to any one of Items 1 to 21, wherein R is a substituted or unsubstituted alkyl group, and R is an alkyl group, and R is an alkoxy group, and R is an alkyl group, and R is an alkoxy group, and R is an alkyl group, and R is an alkoxy group. ７a and R ７ｂ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or C １－３ [Item 24] The compound according to any one of Items 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R is alkyl. ７a and R ７ｂ [Item 25] The compound according to any one of items 1 to 21, wherein L is a single bond, or C is a hydrogen atom, or a pharmaceutically acceptable salt thereof. １－６Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ [Item 26] The compound according to any one of items 1 to 24, wherein V is a single bond, C ２－６ Alkenylene (the alkenylene is a fluorine atom, a hydroxyl group, C １－３ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, cyclohexyl ... ３－１０ Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, C １－３ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, cyclohexyl ... ３－１０ Cycloalkenylene (the cycloalkenylene is a fluorine atom, a hydroxyl group, C １－３ a 3- to 10-membered divalent saturated heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, and cyano), or a 3- to 10-membered divalent saturated heterocyclic group (which may be substituted with a fluorine atom, a hydroxyl group, a C １－３ [Item 27] ​​The compound according to any one of items 1 to 25, wherein W is a single bond, or C １－６ [Item 28] The compound according to any one of Items 1 to 26, wherein R is alkylene (the alkylene may be substituted with 1 to 2 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano), or a pharmaceutically acceptable salt thereof. １４ is a hydrogen atom, or C １－６ The compound according to any one of Items 1 to 27, wherein Q is alkyl (the alkyl may be substituted with 1 to 2 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano), or a pharmaceutically acceptable salt thereof. [Item 29] Q is a hydrogen atom, NH ２[Item 30] The compound according to any one of Items 1 to 28, or a pharmaceutically acceptable salt thereof, wherein Ring A is a 5- or 6-membered aromatic heterocycle (the aromatic heterocycle does not contain a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ [Item 31] The compound according to any one of items 1 to 29, wherein ring A is a 5- to 8-membered non-aromatic heterocycle (which may be substituted with the same or different 1 to 2 substituents selected from the group consisting of alkoxy and cyano), or a pharmaceutically acceptable salt thereof. [Item 32] The compound according to any one of items 1 to 29, wherein ring A is a 5- to 8-membered non-aromatic heterocycle (which may be substituted with a fluorine atom, a hydroxyl group, a C １－３ Alkyl, C １－３ [Item 32] The compound according to any one of Items 1 to 29, wherein -L-V-W- is C, or a pharmaceutically acceptable salt thereof. １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and Q is NHR １４ and R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ [Item 33] The compound according to any one of Items 1 to 31, or a pharmaceutically acceptable salt thereof, wherein when L is C, it may be taken together with the nitrogen atom to which it is bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle. １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR１６ R １７ and cyano), and V is a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is optionally substituted with a fluorine atom, a C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), W is a single bond, Q is a hydrogen atom, R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ [Item 34] The compound according to any one of Items 1 to 31, wherein when L is alkyl, they may be taken together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle, or a pharmaceutically acceptable salt thereof. １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and V is C ３－１０ Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and W is a single bond or C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkoxy, —NR１６ R １７ and cyano), and Q is NHR １４ and R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When Y is alkyl, they may be joined together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle. [Item 34A] The compound according to any one of Items 1 to 31, or a pharmaceutically acceptable salt thereof. １ｂ [Item 35] The compound according to any one of items 1 to 34, or a pharmaceutically acceptable salt thereof, wherein the formula (1) is the following formula (3): [In the formula, Y １ｂ represents a carbon atom or a nitrogen atom, and ring B is a 5- or 6-membered aromatic heterocycle (the aromatic heterocycle is not particularly limited to a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ and C is a single bond, or １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ and C represents a single bond, ２－６ Alkenylene (the alkenylene is a fluorine atom, a hydroxyl group, C １－３ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, cyclohexyl ... ３－１０ Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, C １－３optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, cyclohexyl ... ３－１０ Cycloalkenylene (the cycloalkenylene is a fluorine atom, a hydroxyl group, C １－３ a 3- to 10-membered divalent saturated heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, cyclohexyl ... １－３ and C represents a single bond, or C １－３ represents an alkylene group (which may be substituted with 1 to 2 substituents selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano group); Q represents a hydrogen atom, or NHR １４ represents R １４ is a hydrogen atom, or C １－３ Item 36. The compound according to Item 35, wherein ring B is an unsubstituted 5- or 6-membered aromatic heterocycle, or a pharmaceutically acceptable salt thereof. Item 37. The compound according to Item 1, wherein ring B is an unsubstituted 5- or 6-membered aromatic heterocycle, or a pharmaceutically acceptable salt thereof. Item 38. The compound according to Item 1, wherein ring B is an unsubstituted 5- or 6-membered aromatic heterocycle, or a pharmaceutically acceptable salt thereof. Item 39. The compound according to Item 2, wherein ring B is an unsubstituted 5- or 6-membered aromatic heterocycle, or a pharmaceutically acceptable salt thereof. Item 40. The compound according to Item 2, wherein ring B is an unsubstituted 5- or 6-membered aromatic heterocycle, or a pharmaceutically acceptable salt thereof. Item 41. The compound according to Item 2, wherein ring B is an unsubstituted 5- or 6-membered aromatic heterocycle, or a pharmaceutically acceptable salt thereof. Item 42. The compound according to Item 2, wherein ring B is an unsubstituted 5- or 6-membered aromatic heterocycle, or a pharmaceutically acceptable salt thereof. Item 43. The compound according to Item 2, wherein ring B is an unsubstituted 5- or 6-membered aromatic heterocycle, or a pharmaceutically acceptable salt thereof. Item 44. The compound according to Item 2 １ｂ [Item 38] The compound according to item 35 or 36, wherein L is a single bond, or C is a carbon atom, or a pharmaceutically acceptable salt thereof. １－６ Alkylene (the alkylene is a fluorine atom or C １－３ [Item 39] The compound according to any one of Items 1 to 31 and 35 to 37, or a pharmaceutically acceptable salt thereof, wherein V is a single bond, C ２－６ Alkenylene (the alkenylene is a hydroxyl group and C １－３ alkyl), C ３－１０ Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, and a C１－３ alkyl), C ３－１０ Cycloalkenylene (the cycloalkenylene is a hydroxyl group and C １－３ alkyl), or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C １－３ [Item 40] The compound according to any one of items 1 to 31 and 35 to 38, wherein W is a single bond, or C optionally substituted with 1 to 2 fluorine atoms, or a pharmaceutically acceptable salt thereof. １－３ [Item 41] The compound according to any one of Items 1 to 31 and Items 35 to 39, or a pharmaceutically acceptable salt thereof, wherein R is alkylene. １４ is a hydrogen atom, or C １－６ [Item 42] The compound according to any one of Items 1 to 31 and 35 to 40, or a pharmaceutically acceptable salt thereof, wherein Q is a hydrogen atom, or NH ２ [Item 42A] The compound according to any one of Items 1 to 31 and 35 to 41, or a pharmaceutically acceptable salt thereof, wherein -L-V-W- is C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and Q is NHR １４ and R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C１－６ When L is alkyl, they may be taken together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle, or a pharmaceutically acceptable salt thereof. [Item 42B] The compound according to any one of Items 35 to 42, wherein L is C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and V is a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is optionally substituted with a fluorine atom, a C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), W is a single bond, Q is a hydrogen atom, R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When L is alkyl, they may be taken together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle, or a pharmaceutically acceptable salt thereof. [Item 42C] The compound according to any one of Items 35 to 42, wherein L is a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and V is C ３－１０Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and W is a single bond or C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkoxy, —NR １６ R １７ and cyano), and Q is NHR １４ and R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When the alkyl is alkyl, they may be taken together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle, The compound according to any one of Items 35 to 42, or a pharmaceutically acceptable salt thereof. [Item 43] The compound according to any one of Items 35 to 42, wherein the formula (1) is the following formula (4): [Wherein, L is a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom or C １－３ alkyl), V represents a single bond, C ２－６ Alkenylene (the alkenylene is a hydroxyl group and C １－３ alkyl), C ３－１０ Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, and a C １－３ alkyl), C ３－１０Cycloalkenylene (the cycloalkenylene is a hydroxyl group and C １－３ alkyl), or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C １－３ alkyl, optionally substituted with one substituent selected from the group consisting of alkyl; W represents a single bond, or C optionally substituted with 1 to 2 fluorine atoms; １－３ represents alkylene, and Q is a hydrogen atom or NH ２ [Item 44] The compound according to Item 1, or a pharmaceutically acceptable salt thereof, wherein V represents a single bond, C ２－６ Alkenylene, C ３－１０ cycloalkylene (the cycloalkylene may be substituted with 1 to 3 fluorine atoms); C ３－１０ Cycloalkenylene, or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C group optionally substituted with a fluorine atom and 1 to 2 fluorine atoms). １－３ [Item 45] The compound according to any one of items 1 to 31, 43 to 44, or a pharmaceutically acceptable salt thereof, wherein Q is a hydrogen atom. [Item 46] The compound according to any one of items 1 to 31, 43 to 44, or a pharmaceutically acceptable salt thereof, wherein Q is NH ２ [Item 46A] The compound according to any one of Items 1 to 31 and 43 to 44, or a pharmaceutically acceptable salt thereof, wherein -L-V-W- is C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and Q is NHR １４ and R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R１６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When L is alkyl, they may be taken together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle, or a pharmaceutically acceptable salt thereof. [Item 46B] The compound according to any one of Items 43 to 46, wherein L is C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and V is a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is optionally substituted with a fluorine atom, a C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), W is a single bond, Q is a hydrogen atom, R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When L is alkyl, they may be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered nitrogen-containing saturated heterocycle, or a pharmaceutically acceptable salt thereof. [Item 46C] The compound according to any one of Items 43 to 46, wherein L is a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and V is C ３－１０ Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and W is a single bond or C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkoxy, —NR １６ R １７ and cyano), and Q is NHR １４ and R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When the alkyl is alkyl, they may be taken together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle, The compound according to any one of Items 43 to 46, or a pharmaceutically acceptable salt thereof. [Item 47] The compound according to any one of Items 43 to 46, wherein the formula (1) is the following formula (5): [In the formula, R １ represents a hydrogen atom, a halogen atom, cyano, -CO ２ R ３ represents R ３ is C １－６ Ring C represents an alkyl group, and ring C is a 5- to 8-membered non-aromatic heterocycle (the non-aromatic heterocycle may contain a fluorine atom, a hydroxyl group, or C １－３ Alkyl, C １－３and C is a single bond, or １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ and C represents a single bond, ２－６ Alkenylene (the alkenylene is a fluorine atom, a hydroxyl group, C １－３ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, cyclohexyl ... ３－１０ Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, C １－３ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, cyclohexyl ... ３－１０ Cycloalkenylene (the cycloalkenylene is a fluorine atom, a hydroxyl group, C １－３ a 3- to 10-membered divalent saturated heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, cyclohexyl ... １－３ and C represents a single bond, or C １－３ represents an alkylene group (which may be substituted with 1 to 2 substituents selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano group); Q represents a hydrogen atom, or NHR １４ represents R １４ is a hydrogen atom, or C １－３ Item 48. The compound according to Item 1, or a pharmaceutically acceptable salt thereof, wherein R is an alkyl group optionally substituted with one substituent selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano group. １[Item 48] The compound according to Item 47, wherein ring C is an unsubstituted 5- to 8-membered non-aromatic heterocycle, or a pharmaceutically acceptable salt thereof. [Item 49] L is a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom or C １－３ [Item 50] The compound according to any one of Items 1 to 31 and 48, or a pharmaceutically acceptable salt thereof, wherein V is a single bond, C ２－６ Alkenylene (the alkenylene is a hydroxyl group and C １－３ alkyl), C ３－１０ Cycloalkylene (the cycloalkylene is a hydroxyl group and a C １－３ alkyl), C ３－１０ Cycloalkenylene (the cycloalkenylene is a hydroxyl group and C １－３ alkyl), or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C group optionally substituted with a fluorine atom, a hydroxyl group, and 1 to 2 hydroxyl groups or fluorine atoms). １－３ [Item 51] The compound according to any one of Items 1 to 31 and Items 48 to 49, wherein W is a single bond, or C １－３ [Item 52] The compound according to any one of Items 1 to 31 and Items 48 to 50, or a pharmaceutically acceptable salt thereof, wherein R is alkylene. １４ is a hydrogen atom, or C １－６ [Item 53] The compound according to any one of Items 46 to 51, or a pharmaceutically acceptable salt thereof, wherein Q is a hydrogen atom NH ２ or NMeH. [Item 53A] The compound according to any one of Items 1 to 31 and 48 to 52, or a pharmaceutically acceptable salt thereof, wherein -L-V-W- is C１－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and Q is NHR １４ and R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When L is alkyl, they may be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered nitrogen-containing saturated heterocycle, The compound according to any one of Items 47 to 53, or a pharmaceutically acceptable salt thereof. [Item 53B] L is C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and V is a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is optionally substituted with a fluorine atom, a C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), W is a single bond, Q is a hydrogen atom, R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７may be the same or different, and R １６ and R １７ Both are C １－６ When L is alkyl, they may be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered nitrogen-containing saturated heterocycle, or a pharmaceutically acceptable salt thereof. [Item 53C] The compound according to any one of Items 47 to 53, wherein L is a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and V is C ３－１０ Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and W is a single bond or C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkoxy, —NR １６ R １７ and cyano), and Q is NHR １４ and R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６When the alkyl is alkyl, they may be taken together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle, The compound according to any one of Items 47 to 53, or a pharmaceutically acceptable salt thereof. [Item 54] The compound according to any one of Items 47 to 53, wherein the formula (1) is the following formula (6): [Wherein, L is a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom or C １－３ alkyl), V represents a single bond, C ２－６ Alkenylene (the alkenylene is a hydroxyl group and C １－３ alkyl), C ３－１０ Cycloalkylene (the cycloalkylene is a hydroxyl group and a C １－３ alkyl), C ３－１０ Cycloalkenylene (the cycloalkenylene is a hydroxyl group and C １－３ alkyl), or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C １－３ alkyl, optionally substituted with one substituent selected from the group consisting of alkyl; W represents a single bond, or C optionally substituted with 1 to 2 fluorine atoms; １－３ represents alkylene, Q is a hydrogen atom NH ２ [Item 55] The compound according to Item 1, or a pharmaceutically acceptable salt thereof, wherein V is a single bond, C ２－６ Alkenylene, C ３－１０ Cycloalkylene, C ３－１０ Cycloalkenylene, or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C group optionally substituted with a fluorine atom and 1 to 2 fluorine atoms). １－３Item 56: The compound according to Item 54, or a pharmaceutically acceptable salt thereof, wherein W is a single bond, or C １－３ [Item 57] The compound according to any one of items 1 to 31 and 55 to 56, wherein Q is alkylene, or a pharmaceutically acceptable salt thereof. [Item 58] The compound according to any one of items 1 to 31 and 55 to 56, wherein Q is a hydrogen atom, or a pharmaceutically acceptable salt thereof. [Item 59] The compound according to any one of items 1 to 31 and 56 to 56, wherein Q is NH ２ [Item 59] The compound according to any one of Items 1 to 31 and 55 to 56, or a pharmaceutically acceptable salt thereof, wherein Q is NHMe. [Item 59A] The compound according to any one of Items 1 to 31 and 55 to 56, or a pharmaceutically acceptable salt thereof, wherein -L-V-W- is C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and Q is NHR １４ and R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When L is alkyl, they may be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered nitrogen-containing saturated heterocycle, The compound according to any one of Items 54 to 59, or a pharmaceutically acceptable salt thereof. [Item 59B] L is C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７and cyano), and V is a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is optionally substituted with a fluorine atom, a C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), W is a single bond, Q is a hydrogen atom, R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When L is alkyl, they may be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered nitrogen-containing saturated heterocycle, or a pharmaceutically acceptable salt thereof. [Item 59C] The compound according to any one of Items 54 to 59, wherein L is a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and V is C ３－１０ Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and W is a single bond or C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkoxy, —NR １６ R１７ and cyano), and Q is NHR １４ and R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When the alkyl is alkyl, they may be taken together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle, The compound according to any one of Items 54 to 59, or a pharmaceutically acceptable salt thereof. [Item 60] The compound according to any one of Items 54 to 59, wherein the formula (1) is the following formula (7): [In the formula, Y １ｂ represents a carbon atom or a nitrogen atom, and ring D represents a 5- to 8-membered non-aromatic heterocycle or a 5- to 6-membered aromatic heterocycle (the non-aromatic heterocycle and aromatic heterocycle may contain a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ and C is a single bond, or １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ and C represents a single bond, ２－６ Alkenylene (the alkenylene is a fluorine atom, a hydroxyl group, C １－３ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, cyclohexyl ... ３－１０ Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, C １－３ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, cyclohexyl ... ３－１０Cycloalkenylene (the cycloalkenylene is a fluorine atom, a hydroxyl group, C １－３ a 3- to 10-membered divalent saturated heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, cyclohexyl ... １－３ and C represents a single bond, or C １－３ represents an alkylene group (which may be substituted with one substituent selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano group); Q represents a hydrogen atom, or NHR １４ represents R １４ is a hydrogen atom, or C １－３ Item 61. The compound according to Item 1, or a pharmaceutically acceptable salt thereof, wherein Y is an alkyl group (which may be substituted with one substituent selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano). １ｂ [Item 62] The compound according to Item 60, or a pharmaceutically acceptable salt thereof, wherein Y is a carbon atom. １ｂ [Item 63] The compound according to any one of items 60 to 62, wherein ring D is a 5- to 8-membered non-aromatic heterocycle, or a pharmaceutically acceptable salt thereof. [Item 64] The compound according to any one of items 60 to 63, wherein ring D is a 5- to 6-membered aromatic heterocycle, or a pharmaceutically acceptable salt thereof. [Item 65] L is a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom or C １－３ [Item 66] The compound according to any one of Items 1 to 31 and 60 to 64, or a pharmaceutically acceptable salt thereof, wherein V is a single bond, C ２－６ Alkenylene, C ３－１０cycloalkylene (the cycloalkylene may be substituted with 1 to 3 fluorine atoms); C ３－１０ Cycloalkenylene, or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C group optionally substituted with a fluorine atom and 1 to 2 hydroxyl groups or fluorine atoms). １－３ [Item 67] The compound according to any one of Items 1 to 31 and 60 to 65, wherein W is a single bond, or C １－３ [Item 68] The compound according to any one of Items 1 to 31 and Items 60 to 66, or a pharmaceutically acceptable salt thereof, wherein R is alkylene. １４ is a hydrogen atom, or C １－６ The compound according to any one of Items 1 to 31 and 60 to 67, or a pharmaceutically acceptable salt thereof. [Item 69] Q is a hydrogen atom, or NH ２ [Item 69A] The compound according to any one of Items 1 to 31 and 60 to 68, or a pharmaceutically acceptable salt thereof, wherein -L-V-W- is C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and Q is NHR １４ and R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６When L is alkyl, they may be joined together with the nitrogen atom to which they are attached to form a 3- to 8-membered nitrogen-containing saturated heterocycle, The compound according to any one of Items 60 to 69, or a pharmaceutically acceptable salt thereof. [Item 69B] L is C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and V is a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is optionally substituted with a fluorine atom, a C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), W is a single bond, Q is a hydrogen atom, R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When L is alkyl, they may be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered nitrogen-containing saturated heterocycle, The compound according to any one of Items 60 to 69, or a pharmaceutically acceptable salt thereof. [Item 69C] L is C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and V is C ３－１０ Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, C１－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and W is C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkoxy, —NR １６ R １７ and cyano), and Q is NHR １４ and R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When the alkyl is alkyl, they may be taken together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle, The compound according to any one of Items 60 to 69, or a pharmaceutically acceptable salt thereof. [Item 70] The compound according to any one of Items 60 to 69, wherein the formula (1) is the following formula (8): [Wherein, L is a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom and C １－３ alkyl), V represents a single bond, C ２－６ Alkenylene (the alkenylene is a hydroxyl group and C １－３ alkyl), C ３－１０ Cycloalkylene (the cycloalkylene is a hydroxyl group and a C １－３ alkyl), C ３－１０ Cycloalkenylene (the cycloalkenylene is a hydroxyl group and C １－３alkyl), or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C １－３ and W represents a single bond or a C group optionally substituted with 1 to 2 fluorine atoms; １－３ represents alkylene, Q is a hydrogen atom NH ２ Item 71. The compound according to Item 1, wherein L is C, or a pharmaceutically acceptable salt thereof. １－６ [Item 72] The compound according to any one of items 1 to 31 and 70, wherein V is alkylene, or a pharmaceutically acceptable salt thereof. [Item 73] The compound according to any one of items 1 to 31 and 70 to 71, wherein V is a single bond, or a pharmaceutically acceptable salt thereof. [Item 74] W is a single bond, or C １－３ [Item 74] The compound according to any one of Items 1 to 31 and 70 to 72, or a pharmaceutically acceptable salt thereof, wherein Q is NH ２ [Item 74A] The compound according to any one of Items 1 to 31 and 70 to 73, or a pharmaceutically acceptable salt thereof, wherein -L-V-W- is C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and Q is NHR １４ and R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６When L is alkyl, they may be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered nitrogen-containing saturated heterocycle, The compound according to any one of Items 70 to 74, or a pharmaceutically acceptable salt thereof. [Item 74B] L is C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and V is a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is optionally substituted with a fluorine atom, a C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), W is a single bond, Q is a hydrogen atom, R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When L is alkyl, they may be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered nitrogen-containing saturated heterocycle, The compound according to any one of Items 70 to 74, or a pharmaceutically acceptable salt thereof. [Item 74C] L is C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and V is C ３－１０ Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, C１－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and W is C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkoxy, —NR １６ R １７ and cyano), and Q is NHR １４ and R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６Item 75. The compound according to any one of Items 70 to 74, or a pharmaceutically acceptable salt thereof, wherein when each is alkyl, they may be taken together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle. [Item 76] A compound according to Item 1, or a pharmaceutically acceptable salt thereof, selected from the following compounds: 5-({5-[7-(3-aminopropoxy)quinolin-8-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Example 1), 5-({5-[6-(3-aminopropoxy)-1-benzofuran-7-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Example 2), 5-({5-[6-(3-aminopropoxy)-2,3-dihydro-1-benzofuran-7-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Example 3), 5-{[5-(6-{[1-(aminomethyl)cyclopropyl]methoxy}-2,3-dihydro-1-benzofuran-7-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile (Example 4), 5-[(5-{6-[(3-methylazetidin-3-yl)methoxy]-2,3-dihydro-1-benzofuran-7-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 5), 5-({5-[6-(3-aminopropoxy)pyrazolo[1,5-a]pyridin-7-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Example 6), 5-({5-[6-(3-aminopropoxy)pyrazolo[1,5-a]pyrimidin-7-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Example 7), 5-({5-[3-(3-aminopropoxy)-1,5-naphthyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Example 8), 5-({5-[3-(3-amino-2,2-difluoropropoxy)-1,5-naphthyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Example 9), 5-{[5-(3-{[1-(aminomethyl)cyclopropyl]methoxy}-1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile (Example 10),5-[(5-{3-[(3-methylazetidin-3-yl)methoxy]-1,5-naphthyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 11), 5-{[5-(3-{[(2S)-morpholin-2-yl]methoxy}-1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile (Example 12), 5-({5-[6-(3-aminopropoxy)-2,3-dihydrofuro[3,2-b]pyridin-7-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Example 13), 5-{[5-(6-{[1-(aminomethyl)cyclopropyl]methoxy}-2,3-dihydrofuro[3,2-b]pyridin-7-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile (Example 14), 5-[(5-{6-[(3-methylazetidin-3-yl)methoxy]-2,3-dihydrofuro[3,2-b]pyridin-7-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 15), 5-({5-[6-(3-aminopropoxy)-2-methyl-1,3-benzoxazol-7-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Example 16), 5-{[5-(6-{[1-(aminomethyl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyridin-7-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile (Example 17), 5-[(5-{6-[(3-methylazetidin-3-yl)methoxy]pyrazolo[1,5-a]pyridin-7-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 18), 5-{[5-(6-{[1-(aminomethyl)cyclopropyl]methoxy}-1-benzofuran-7-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile (Example 19), 5-{[5-(6-{[1-(aminomethyl)-2,2-difluorocyclopropyl]methoxy}-1-benzofuran-7-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile (Example 20),5-{[5-(6-{[(1R,3R)-3-aminocyclopentyl]oxy}-2,3-dihydrofuro[3,2-b]pyridin-7-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile (Example 21), 5-{[5-(6-{[3-(difluoromethyl)azetidin-3-yl]methoxy}-2,3-dihydrofuro[3,2-b]pyridin-7-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile (Example 22), 5-[(5-{6-[(3-fluoroazetidin-3-yl)methoxy]-2,3-dihydrofuro[3,2-b]pyridin-7-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 23), 5-{[5-(6-{[(1R,3S)-3-aminocyclohexyl]oxy}-2,3-dihydrofuro[3,2-b]pyridin-7-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile (Example 24), 5-[(5-{6-[(1R)-1-(azetidin-3-yl)ethoxy]-2,3-dihydrofuro[3,2-b]pyridin-7-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 25), 5-{[5-(6-{[(3S)-pyrrolidin-3-yl]methoxy}-2,3-dihydrofuro[3,2-b]pyridin-7-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile (Example 26), 5-[(5-{6-[3-(methylamino)propoxy]-2,3-dihydrofuro[3,2-b]pyridin-7-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 27), 5-[(5-{6-[(2R)-3-amino-2-methylpropoxy]-2,3-dihydrofuro[3,2-b]pyridin-7-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 28), 5-{[5-(6-{[(1R,2S,4S,5S)-4-aminobicyclo[3.1.0]hexan-2-yl]oxy}-2,3-dihydrofuro[3,2-b]pyridin-7-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile (Example 29),5-[(5-{6-[(2S)-3-amino-2-methylpropoxy]-2,3-dihydrofuro[3,2-b]pyridin-7-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 30), 5-{[5-(6-{[2-(aminomethyl)propyl-2-en-1-yl]oxy}-2,3-dihydrofuro[3,2-b]pyridin-7-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile (Example 31), N-{5-[6-(3-aminopropoxy)-2,3-dihydrofuro[3,2-b]pyridin-7-yl]-1H-pyrazol-3-yl}-5-chloropyrazin-2-amine (Example 32), methyl 5-({5-[6-(3-aminopropoxy)-2,3-dihydrofuro[3,2-b]pyridin-7-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carboxylate (Example 33), 5-{[5-(3-{[(1R,2S)-2-(aminomethyl)cyclopentyl]oxy}-1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile (Example 34), 5-[(5-{3-[(3-fluoroazetidin-3-yl)methoxy]-1,5-naphthyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 35), 5-{[5-(3-{[(1R,3S)-3-aminocyclohexyl]oxy}-1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile (Example 36), 5-{[5-(3-{[(1R,3R)-3-aminocyclopentyl]oxy}-1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile (Example 37), 5-{[5-(3-{[1-(aminomethyl)-3,3-difluorocyclobutyl]methoxy}-1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile (Example 38). [Item 76] The compound according to Item 1 below or a pharmaceutically acceptable salt thereof: 5-({5-[7-(3-aminopropoxy)quinolin-8-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Example 1),5-({5-[3-(3-aminopropoxy)-1,5-naphthyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Example 8), 5-({5-[3-(3-amino-2,2-difluoropropoxy)-1,5-naphthyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Example 9), 5-{[5-(3-{[1-(aminomethyl)cyclopropyl]methoxy}-1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile (Example 10), 5-[(5-{3-[(3-methylazetidin-3-yl)methoxy]-1,5-naphthyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 11), 5-({5-[6-(3-aminopropoxy)-2,3-dihydrofuro[3,2-b]pyridin-7-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Example 13), 5-{[5-(6-{[1-(aminomethyl)cyclopropyl]methoxy}-2,3-dihydrofuro[3,2-b]pyridin-7-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile (Example 14), 5-[(5-{6-[(1R)-1-(azetidin-3-yl)ethoxy]-2,3-dihydrofuro[3,2-b]pyridin-7-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 25), 5-{[5-(6-{[(3S)-pyrrolidin-3-yl]methoxy}-2,3-dihydrofuro[3,2-b]pyridin-7-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile (Example 26), 5-[(5-{6-[3-(methylamino)propoxy]-2,3-dihydrofuro[3,2-b]pyridin-7-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 27), 5-[(5-{6-[(2R)-3-amino-2-methylpropoxy]-2,3-dihydrofuro[3,2-b]pyridin-7-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 28),5-[(5-{3-[(3-fluoroazetidin-3-yl)methoxy]-1,5-naphthyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 35), 5-{[5-(3-{[1-(aminomethyl)-3,3-difluorocyclobutyl]methoxy}-1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile (Example 38). [Item 77] The compound according to item 1 below or a pharmaceutically acceptable salt thereof: 5-({5-[7-(3-aminopropoxy)quinolin-8-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Example 1), 5-({5-[3-(3-aminopropoxy)-1,5-naphthyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Example 8), 5-{[5-(3-{[1-(aminomethyl)cyclopropyl]methoxy}-1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile (Example 10), 5-({5-[6-(3-aminopropoxy)-2,3-dihydrofuro[3,2-b]pyridin-7-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Example 13), 5-{[5-(6-{[1-(aminomethyl)cyclopropyl]methoxy}-2,3-dihydrofuro[3,2-b]pyridin-7-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile (Example 14), 5-[(5-{6-[(1R)-1-(azetidin-3-yl)ethoxy]-2,3-dihydrofuro[3,2-b]pyridin-7-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 25), 5-[(5-{6-[(2R)-3-amino-2-methylpropoxy]-2,3-dihydrofuro[3,2-b]pyridin-7-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 28). [Item 78] A liposome comprising the compound according to any one of Items 1 to 77, or a pharmaceutically acceptable salt thereof. [Item 79] A pharmaceutical composition comprising, as an active ingredient, the compound according to any one of Items 1 to 77, or a pharmaceutically acceptable salt thereof. [Item 80]A pharmaceutical composition comprising a liposome encapsulating the compound according to any one of Items 1 to 77, or a pharmaceutically acceptable salt thereof. [Item 81] The pharmaceutical composition according to Item 80, wherein the liposome further comprises a phospholipid. [Item 82] The pharmaceutical composition according to Item 80 or 81, wherein the liposome comprises: (1) the compound according to any one of Items 1 to 77, or a pharmaceutically acceptable salt thereof, and (2) a phospholipid. [Item 83] The pharmaceutical composition according to Item 81 or 82, wherein the phospholipid is one or a combination of two or more selected from the group consisting of phosphatidylcholine, phosphatidylglycerol, phosphatidic acid, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, soybean lecithin, egg yolk lecithin, hydrogenated egg yolk lecithin, and hydrogenated soybean lecithin. [Item 84] The pharmaceutical composition of any one of Items 80 to 83, wherein the liposome further comprises a sterol. [Item 85] The pharmaceutical composition of Item 84, wherein the sterol is cholesterol. [Item 86] The pharmaceutical composition of any one of Items 80 to 85, wherein the liposome further comprises a polymer-modified lipid. [Item 87] The pharmaceutical composition of Item 86, wherein the polymer moiety of the polymer-modified lipid is polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, methoxypolyethylene glycol, methoxypolypropylene glycol, methoxypolyvinyl alcohol, methoxypolyvinylpyrrolidone, ethoxypolyethylene glycol, ethoxypolypropylene glycol, ethoxypolyvinyl alcohol, ethoxypolyvinylpyrrolidone, propoxypolyethylene glycol, propoxypolypropylene glycol, propoxypolyvinyl alcohol, or propoxypolyvinylpyrrolidone. [Item 88] The pharmaceutical composition of Item 86 or 87, wherein the lipid moiety of the polymer-modified lipid is phosphatidylethanolamine or diacylglycerol. [Item 89]The pharmaceutical composition of any one of Items 86 to 88, wherein the polymer-modified lipid comprises polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, methoxypolyethylene glycol, methoxypolypropylene glycol, methoxypolyvinyl alcohol, methoxypolyvinylpyrrolidone, ethoxypolyethylene glycol, ethoxypolypropylene glycol, ethoxypolyvinyl alcohol, ethoxypolyvinylpyrrolidone, propoxypolyethylene glycol, propoxypolypropylene glycol, propoxypolyvinyl alcohol, or propoxypolyvinylpyrrolidone as a polymer moiety, and phosphatidylethanolamine or diacylglycerol as a lipid moiety. [Item 90] The pharmaceutical composition of any one of Items 80 to 89, wherein the liposome comprises: (1) the compound of any one of Items 1 to 77, or a pharmaceutically acceptable salt thereof, (2) 40 to 70 mol % of a phospholipid, (3) 30 to 50 mol % of cholesterol, and (4) 1 to 10 mol % of a polymer-modified lipid. [Item 91] The pharmaceutical composition according to any one of Items 80 to 90, wherein the liposome further comprises an additive selected from the group consisting of inorganic acids, inorganic acid salts, organic acids, organic acid salts, sugars, buffers, antioxidants, and polymers. [Item 92] An agent for treating and / or preventing cancer, comprising as an active ingredient the compound according to any one of Items 1 to 77, or a pharmaceutically acceptable salt thereof. [Item 93] The therapeutic and / or prophylactic agent according to Item 92, wherein the cancer is at least one type of cancer selected from the group consisting of acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma, plasma cell neoplasm, multiple myeloma, brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thymoma / thymic cancer, breast cancer, gastric cancer, gallbladder / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, anal cancer, gastrointestinal stromal tumor, chorioepithelial carcinoma, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial cancer, kidney cancer, renal cell carcinoma, prostate cancer, testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms' tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, and skin cancer. [Section 94]A method for treating and / or preventing cancer, comprising administering to a patient in need of such treatment and / or prevention a therapeutically and / or prophylactically effective amount of the compound according to any one of Items 1 to 77, or a pharmaceutically acceptable salt thereof, or the liposome according to Item 78, or the pharmaceutical composition according to Items 79 to 91, or the therapeutic and / or prophylactic agent according to Item 92 or 93. [Item 95] The method for treatment and / or prevention according to Item 94, wherein the cancer is at least one type of cancer selected from the group consisting of acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma, plasma cell neoplasm, multiple myeloma, brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thymoma / thymic cancer, breast cancer, gastric cancer, gallbladder / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, anal cancer, gastrointestinal stromal tumor, chorioepithelial carcinoma, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial cancer, kidney cancer, renal cell carcinoma, prostate cancer, testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms' tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, and skin cancer. [Item 96] Use of the compound according to any one of Items 1 to 77, or a pharmaceutically acceptable salt thereof, or the liposome according to Item 78, or the pharmaceutical composition according to Items 79 to 91, or the therapeutic and / or prophylactic agent according to Item 92 or 93, for the manufacture of a therapeutic and / or prophylactic agent for cancer. [Item 97]The cancer is acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma, plasma cell neoplasm, multiple myeloma, brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thymoma / thymic cancer, breast cancer, stomach cancer, gallbladder / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, anal cancer, gastrointestinal stromal tumor, chorioepithelial carcinoma, uterine cancer, cervical cancer, or ovarian cancer. Use of the compound according to Item 96, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, or a liposome, or a therapeutic and / or preventive agent for at least one type of cancer selected from the group consisting of bladder cancer, urothelial cancer, kidney cancer, renal cell carcinoma, prostate cancer, testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms' tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, and skin cancer. [Item 98] Use of the compound according to any one of Items 1 to 77, or a pharmaceutically acceptable salt thereof, or the liposome according to Item 78, or the pharmaceutical composition according to Items 79 to 91, or the therapeutic and / or preventive agent according to Item 92 or 93, for use in the treatment and / or prevention of cancer. [Item 99] The cancer is acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma, plasma cell neoplasm, multiple myeloma, brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thymoma / thymic cancer, breast cancer, stomach cancer, gallbladder / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, anal cancer, gastrointestinal stromal tumor, chorioepithelial carcinoma, uterine cancer, cervical cancer, ovarian cancer, Item 100: The compound according to Item 98, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, or a liposome, or a therapeutic and / or preventive agent for at least one type of cancer selected from the group consisting of bladder cancer, urothelial cancer, kidney cancer, renal cell carcinoma, prostate cancer, testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms' tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, and skin cancer.Item 101. The compound according to any one of Items 1 to 77, or a pharmaceutically acceptable salt thereof, or the liposome according to Item 78, for use in combination with a concomitant drug or a pharmaceutically acceptable salt thereof to treat cancer, wherein the concomitant drug is at least one or more selected from the group consisting of hormone therapeutic agents, chemotherapeutic agents, immunotherapeutic agents, and agents that inhibit the action of cell growth factors and their receptors. [Item 102] Item 78. The compound according to any one of Items 1 to 77, or a pharmaceutically acceptable salt thereof, or the liposome according to Item 78, for use in combination with a concomitant drug or a pharmaceutically acceptable salt thereof to treat cancer, wherein the concomitant drug is a 5-FU drug, cytarabine, doxorubicin hydrochloride, gemcitabine, methotrexate, pemetrexed, etoposide, irinotecan, topotecan, cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, ionizing radiation, bevacizumab, liposome. at least one compound selected from the group consisting of liposomal doxorubicin, rucaparib, olaparib, niraparib, trabectedin, pazopanib, pembrolizumab, nivolumab, ipilimumab, durvalumab, avelumab, atezolizumab, larotrectinib, entrectinib, nab-paclitaxel, erlotinib, liposomal irinotecan, leucovorin, cetuximab, eribulin, ifosfamide, and dacarbazine, or a pharmaceutically acceptable salt thereof, or a liposome. [Item 102] The compound according to any one of Items 1 to 77, or a pharmaceutically acceptable salt thereof, or the liposome according to Item 78, for use in combination with a concomitant drug or a pharmaceutically acceptable salt thereof to treat cancer, wherein the concomitant drug is at least one or more selected from the group consisting of 5-FU drugs, irinotecan, gemcitabine, cisplatin, carboplatin, oxaliplatin, paclitaxel, ionizing radiation, rucaparib, olaparib, niraparib, pembrolizumab, and nivolumab. [Item 103]A pharmaceutical composition comprising the compound according to any one of Items 1 to 77, or a pharmaceutically acceptable salt thereof, in combination with a concomitant drug, or the pharmaceutical composition according to any one of Items 79 to 91, wherein the concomitant drug is at least one or more selected from the group consisting of hormone therapeutic agents, chemotherapeutic agents, immunotherapeutic agents, and agents that inhibit the action of cell growth factors and their receptors. [Item 104] A pharmaceutical composition comprising the compound according to any one of Items 1 to 77, or a pharmaceutically acceptable salt thereof, in combination with a concomitant drug, or the pharmaceutical composition according to any one of Items 79 to 91, wherein the concomitant drug is at least one or more selected from the group consisting of 5-FU drugs, cytarabine, doxorubicin hydrochloride, gemcitabine, methotrexate, pemetrexed, etoposide, irinotecan, topotecan, cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, ionizing radiation, benzamidine, ribonucleotides, methylprednisolone ... A pharmaceutical composition comprising at least one selected from the group consisting of bacilizumab, liposomal doxorubicin, rucaparib, olaparib, niraparib, trabectedin, pazopanib, pembrolizumab, nivolumab, ipilimumab, durvalumab, avelumab, atezolizumab, larotrectinib, entrectinib, nab-paclitaxel, erlotinib, liposomal irinotecan, leucovorin, cetuximab, eribulin, ifosfamide, and dacarbazine. [Item 105] A pharmaceutical composition comprising the compound according to any one of Items 1 to 77, or a pharmaceutically acceptable salt thereof, in combination with a concomitant drug; or the pharmaceutical composition according to any one of Items 79 to 91, wherein the concomitant drug is at least one or more selected from the group consisting of 5-FU drugs, irinotecan, gemcitabine, cisplatin, carboplatin, oxaliplatin, paclitaxel, ionizing radiation, rucaparib, olaparib, niraparib, pembrolizumab, and nivolumab.

[0010] The present disclosure provides a CHK1 inhibitor comprising a 1H-pyrazol-3-amine derivative having a bicyclic skeleton or a pharmaceutically acceptable salt thereof. The compound of the present disclosure combines excellent CHK1 inhibitory activity with high safety, and is encapsulated in liposomes and released sustainedly from the liposomes. The compound of the present disclosure is useful as a therapeutic agent for diseases in which CHK1 is involved, and specifically, is applicable to patients with pancreatic cancer, ovarian cancer, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, and the like.

[0011] The present disclosure will be described in more detail below. Throughout this specification, unless otherwise specified, singular expressions should be understood to include the plural concept. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, it should be understood that terms used in this specification are used in the sense commonly used in the relevant field unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the case of conflict, the present specification (including definitions) will prevail.

[0012] The terms used in this specification are explained below.

[0013] In this specification, the number of substituents in a group defined as "optionally substituted" is not particularly limited as long as substitution is possible. Furthermore, unless otherwise specified, the description of each group also applies to the case where the group is a part or substituent of another group.

[0014] Examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. A fluorine atom or a chlorine atom is preferred.

[0015] "C １－６ "Alkyl" means a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. ６ "Alkyl" means alkyl having 6 carbon atoms, and the same applies to other numbers. １－６As the alkyl, preferably "C １－４ alkyl", and more preferably "C １－３ "C alkyl" is an example. １－３ Specific examples of "alkyl" include methyl, ethyl, propyl, 1-methylethyl, etc. １－４ Specific examples of "alkyl" include the above-mentioned "C １－３ In addition to the specific examples of "alkyl", butyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl, etc. are also included. １－６ Specific examples of "alkyl" include the above-mentioned "C １－４ In addition to the specific examples of "alkyl", pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, hexyl, and the like can be mentioned.

[0016] "C ２－６ "Alkenyl" means a straight or branched chain unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing 1 to 3 double bonds. ２－６ Alkenyl is preferably "C ２－４ "C alkenyl" is an example. ２－４ Specific examples of "alkenyl" include vinyl, propenyl, methylpropenyl, butenyl, etc. ２－６ Specific examples of "alkenyl" include the above-mentioned "C ２－４ In addition to the specific examples of "alkenyl", pentenyl, hexenyl, etc. are also included.

[0017] "C ２－６ "Alkynyl" means a straight or branched chain unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing one triple bond. ２－６ As the "alkynyl", preferably "C ２－４ "C alkynyl" is an example. ２－４ Specific examples of "alkynyl" include propynyl, methylpropynyl, butynyl, etc. ２－６ Specific examples of "alkynyl" include the above-mentioned "C ２－４In addition to the specific examples of "alkynyl", methylbutynyl, pentynyl, hexynyl, etc. are included.

[0018] "C １－６ "Alkoxy" means "C １－６ "C alkyloxy" １－６ The "C alkyl" moiety is １－６ "C" is synonymous with "alkyl." １－６ The "alkoxy" is preferably "C １－４ Alkoxy" is preferred, and "C １－３ "Alkoxy" is an example. １－３ Specific examples of "alkoxy" include methoxy, ethoxy, propoxy, 1-methylethoxy, etc. １－４ Specific examples of "alkoxy" include the above-mentioned "C １－３ In addition to the specific examples of "alkoxy", butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, 2-methylpropoxy, etc. are also included. １－６ Specific examples of "alkoxy" include the above-mentioned "C １－４ In addition to the specific examples of "alkoxy", pentyloxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, hexyloxy, and the like can be mentioned.

[0019] "C １－６ "C" in "Alkylthio" １－６ The "C alkyl" moiety is １－６ "C" is synonymous with "alkyl." １－６ As the alkylthio, preferably "C １－４ alkylthio", and more preferably "C １－３ "C alkylthio" is an example. １－３ Specific examples of "alkylthio" include methylthio, ethylthio, propylthio, 1-methylethylthio, etc. １－４ Specific examples of "alkylthio" include the above-mentioned "C １－３In addition to the specific examples of "alkylthio", butylthio, 1,1-dimethylethylthio, 1-methylpropylthio, 2-methylpropylthio, etc. are also included. １－６ Specific examples of "alkylthio" include the above-mentioned "C １－４ In addition to the specific examples of "alkylthio", pentylthio, 1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 1-methylbutylthio, 2-methylbutylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 1-methylpentylthio, hexylthio, and the like can be mentioned.

[0020] "C １－６ "Alkylene" means a divalent saturated hydrocarbon group having 1 to 6 carbon atoms, which may be straight or branched. １－６ As the "alkylene", preferably "C １－４ alkylene", and more preferably "C １－３ "C alkylene" is an example. １－３ Specific examples of "alkylene" include a methylene group, an ethylene group, and a propylene group. １－４ Specific examples of "alkylene" include the above-mentioned "C １－３ In addition to the specific examples of "alkylene," examples include a butylene group, a 1,1-dimethylethylene group, a 1,2-dimethylethylene group, a 1-methyltrimethylene group, and a 2-methyltrimethylene group. １－６ Specific examples of "alkylene" include the above-mentioned "C １－４ In addition to the specific examples of "alkylene," examples include a pentylene group, a 1,1-dimethyltrimethylene group, a 1,2-dimethyltrimethylene group, a 1-methylbutylene group, a 2-methylbutylene group, a 1-methylpentylene group, a 2-methylpentylene group, a 3-methylpentylene group, a hexylene group, and the like.

[0021] "C ２－６ "Alkenylene" means a straight or branched chain divalent unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing 1 to 3 double bonds. ２－６ As the alkenylene, preferably "C ２－４"C alkenylene" is an example. ２－４ Specific examples of "alkenylene" include a vinylene group, a vinylidene group, a propenylene group, a methylpropenylene group, and a butenylene group. ２－６ Specific examples of "alkenyl" include the above-mentioned "C ２－４ In addition to the specific examples of "alkenyl", pentenylene group, hexenylene group, etc. are also included.

[0022] "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 bridged structure. ３－１０ As the "cycloalkyl", preferably "C ３－７ "Cycloalkyl" is an example. ３－７ Specific examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. ３－１０ Specific examples of "cycloalkyl" include the above-mentioned "C ３－７ In addition to the specific examples of "cycloalkyl", cyclooctyl, cyclononyl, cyclodecyl, adamantyl, etc. are included.

[0023] Also, "C ３－１０ "Cycloalkyl" includes the above C ３－１０ Bicyclic compounds in which a cycloalkyl and an aromatic hydrocarbon ring are fused together are also included. Specific examples of such fused ring compounds include the structures shown below.

[0024] Specific examples of the crosslinked structure include the structures shown below.

[0025] "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 bridged structure. ３－１０ As the "cycloalkylene", preferably "C ３－７ "Cycloalkylene" is an example. ３－７Specific examples of "cycloalkylene" include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, etc. ３－１０ Specific examples of "cycloalkyl" include the above-mentioned "C ３－７ In addition to the specific examples of "cycloalkyl", cyclooctylene, cyclononylene, cyclodecylene, adamantylene, etc. are included.

[0026] Specific examples of the crosslinked structure include the structures shown below.

[0027] "C ３－１０ "Cycloalkenylene" means a cyclic divalent unsaturated hydrocarbon group having 3 to 10 carbon atoms, and includes those having a bridged structure. ３－１０ Specific examples of "cycloalkenylene" include cyclobutenylene, cyclopentenylene, cyclohexenylene, and the like.

[0028] The term "3- to 10-membered saturated carbocyclic ring" refers to a cyclic saturated hydrocarbon having 3 to 10 carbon atoms. A preferred example of the "3- to 10-membered saturated carbocyclic ring" is a "4- to 6-membered saturated carbocyclic ring." Specific examples of the "4- to 6-membered saturated carbocyclic ring" include a cyclobutane ring, a cyclopentane ring, and a cyclohexane ring. Specific examples of the "3- to 10-membered saturated carbocyclic ring" include, in addition to the specific examples of the "4- to 6-membered saturated carbocyclic ring" mentioned above, a cyclopropane ring, a cycloheptane ring, cyclooctane, cyclononane, and cyclodecane.

[0029] The term "3- to 10-membered saturated heterocyclic group" refers to a monovalent saturated heterocyclic group consisting of 1 to 2 atoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, and 2 to 9 carbon atoms, and includes groups having a partially unsaturated bond and a bridged structure. The atoms constituting the ring are -C(O)-, -S(O)-, -SO ２-, and may include those oxidized to -. As the "3- to 10-membered saturated heterocyclic group", preferably, a "4- to 7-membered monocyclic saturated heterocyclic group" is mentioned. Specific examples of the "4- to 7-membered monocyclic saturated heterocyclic group" include, for example, oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxooxazolidinyl, dioxooxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and the like. Examples of the "3- to 10-membered saturated heterocyclic group" include oxiranyl, aziridinyl, etc., in addition to the specific examples of the "4- to 7-membered monocyclic saturated heterocyclic group". The "3- to 10-membered saturated heterocyclic group" also includes bicyclic groups in which the 3- to 10-membered saturated heterocyclic group and a 6-membered aromatic hydrocarbon ring or a 6-membered aromatic heterocyclic ring form a fused ring. Examples of the 6-membered aromatic hydrocarbon ring forming a fused ring include a benzene ring. Examples of the 6-membered aromatic heterocyclic ring forming a fused ring include pyridine, pyrimidine, pyridazine, etc. Specific examples of the bicyclic "3- to 10-membered saturated heterocyclic group" forming a fused ring include dihydroindolyl, dihydroisoindolyl, dihydropurinyl, dihydrothiazolopyrimidinyl, dihydrobenzodioxanyl, isoindolyl, indazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydronaphthyridinyl, and the like.

[0030] The term "3- to 8-membered nitrogen-containing saturated heterocycle" refers to a saturated heterocycle consisting of one nitrogen atom and 2 to 7 carbon atoms. A preferred example of the "3- to 8-membered nitrogen-containing saturated heterocycle" is a "4- to 6-membered nitrogen-containing saturated heterocycle". Specific examples of the "4- to 6-membered nitrogen-containing saturated heterocycle" include an azetidine ring, a pyrrolidine ring, and a piperidine ring. Specific examples of the "3- to 8-membered nitrogen-containing saturated heterocycle" include, in addition to the specific examples of the "4- to 6-membered nitrogen-containing saturated heterocycle", an aziridine ring, an azepane ring, and an azocane ring.

[0031] The term "3- to 10-membered divalent saturated heterocyclic group" refers to a divalent saturated heterocyclic group consisting of 1 to 2 atoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, and 2 to 9 carbon atoms, and includes those having a partially unsaturated bond and those having a bridged structure. The atoms constituting the ring are -C(O)-, -S(O)-, -SO ２ -, and may include those oxidized such as -. As the "3- to 10-membered saturated heterocyclic group", preferably, a "4- to 7-membered monocyclic saturated heterocyclic group" is mentioned. Specific examples of the "4- to 7-membered monocyclic saturated heterocyclic group" include, for example, oxetanylene, azetidinylene, tetrahydrofurylene, pyrrolidinylene, imidazolidinylene, piperidinylene, morpholinylene, thiomorpholinylene, dioxothiomorpholinylene, hexamethyleneiminylene, oxazolidinylene, thiazolidinylene, oxoimidazolidinylene, dioxoimidazolidinylene, oxooxazolidinylene, dioxooxazolidinylene, dioxothiazolidinylene, tetrahydrofuranylene, tetrahydropyranylene, and the like. Examples of the "3- to 10-membered saturated heterocyclic group" include the specific examples of the "4- to 7-membered monocyclic saturated heterocyclic group" as well as oxiranylene, aziridinylene, etc.

[0032] Furthermore, the "3- to 10-membered saturated heterocyclic group" also includes a bicyclic group in which the above-mentioned 3- to 10-membered saturated heterocyclic group and a 6-membered aromatic hydrocarbon ring or a 6-membered aromatic heterocyclic ring form a fused ring. Examples of the 6-membered aromatic hydrocarbon ring forming a fused ring include a benzene ring. Examples of the 6-membered aromatic heterocyclic ring forming a fused ring include pyridine, pyrimidine, and pyridazine. Specific examples of the bicyclic "3- to 10-membered saturated heterocyclic group" forming a fused ring include dihydroindolylene, dihydroisoindolylene, dihydropurinylene, dihydrothiazolopyrimidinylene, dihydrobenzodioxanylene, isoindolylene, indazolylene, tetrahydroquinolinylene, tetrahydroisoquinolinylene, and tetrahydronaphthyridinylene.

[0033] "C ６－１０ "Aryl" means an aromatic hydrocarbon ring group having 6 to 10 carbon atoms.６－１０ Specific examples of "aryl" include phenyl, 1-naphthyl, 2-naphthyl, etc. Preferably, phenyl is used.

[0034] Also, "C ６－１０ "Aryl" includes the above C ６－１０ Aryl and C ４－６ Also included are bicyclic rings formed by condensing with a cycloalkyl or a 5- to 6-membered saturated heterocycle. ６－１０ Specific examples of "aryl" include groups shown below.

[0035] The "aromatic hydrocarbon ring" is defined as the ring ６－１０ The term "aryl" refers to the ring portion of an "aryl."

[0036] "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, oxygen, and sulfur atoms. A "5- to 7-membered monocyclic heteroaryl" is preferred. More preferred is pyridyl, pyrimidinyl, quinolyl, or isoquinolyl. Even more preferred is pyridyl. Specific examples of a "5- to 7-membered monocyclic heteroaryl" include pyridyl, pyridazinyl, isothiazolyl, pyrrolyl, furyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, triazinyl, triazolyl, oxadiazolyl, triazolyl, and tetrazolyl. Specific examples of the "5- to 12-membered heteroaryl" include, in addition to the specific examples of the "5- to 7-membered monocyclic heteroaryl", indolyl, indazolyl, chromenyl, quinolyl, isoquinolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzotriazolyl, benzimidazolyl, etc.

[0037] The term "aromatic heterocycle" refers to the ring moiety of the above "5- to 12-membered heteroaryl".

[0038] "3- to 10-membered cycloalkane" means a cyclic saturated hydrocarbon having 3 to 10 carbon atoms, and includes those having a partially unsaturated bond and those having a bridged structure, and a part of the ring may be fused with another ring. Specific examples of "3- to 10-membered cycloalkane" include cyclobutane, cyclopentane, cyclohexane, cycloheptane, etc.

[0039] The term "6- to 10-membered arene" refers to a cyclic aromatic hydrocarbon having 6 to 10 carbon atoms, and a part of the ring may be fused with another ring. Specific examples of the "6- to 10-membered arene" include benzene and naphthalene.

[0040] The term "4- to 10-membered aromatic heterocycle" refers to a monocyclic 4- to 7-membered aromatic heterocycle or a bicyclic 8- to 12-membered aromatic heterocycle containing 1 to 4 atoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, and a portion of the ring may be fused with another ring. Preferred examples include "5- to 6-membered aromatic heterocycles," "5-membered aromatic heterocycles," and "6-membered aromatic heterocycles." Specific examples of "5- to 6-membered aromatic heterocycles" include furan, thiophene, oxazole, pyridine, pyrazine, pyrimidine, pyridazine, etc. Specific examples of "5-membered aromatic heterocycles" include furan, thiophene, oxazole, etc. Specific examples of "6-membered aromatic heterocycles" include pyridine, pyrazine, pyrimidine, pyridazine, etc.

[0041] The term "4- to 10-membered non-aromatic heterocycle" refers to a non-aromatic heterocycle composed of 2 to 9 carbon atoms and 1 to 2 atoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, and includes those having a partially unsaturated bond and a bridged structure, and a portion of the ring may be fused with another ring. Preferred examples include "5- to 8-membered non-aromatic heterocycles," and more preferred examples include "5- to 6-membered non-aromatic heterocycles," "5-membered non-aromatic heterocycles," and "6-membered non-aromatic heterocycles." Specific examples of "5- to 8-membered non-aromatic heterocycles" include tetrahydrofuran, dihydrofuran, tetrahydropyran, tetrahydrothiophene, dihydrothiophene, pyrrolidine, piperidine, oxepane, and azepane. Specific examples of "5- to 6-membered non-aromatic heterocycles" include tetrahydrofuran, dihydrofuran, tetrahydropyran, tetrahydrothiophene, dihydrothiophene, pyrrolidine, and piperidine. Specific examples of the "5-membered non-aromatic heterocycle" include tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, etc. Specific examples of the "6-membered non-aromatic heterocycle" include tetrahydropyran.

[0042] "Cancer" and "tumor" are used interchangeably in this disclosure and both refer to malignant tumors, including carcinomas, sarcomas, and hematological malignancies. Specific examples of "cancer" or "tumor" include, for example, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma, plasma cell neoplasm, multiple myeloma, brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thymoma / thymic carcinoma, breast cancer, gastric cancer, gallbladder / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, anal cancer, gastrointestinal stromal tumor, chorioepithelial carcinoma, uterine cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial cancer, kidney cancer, renal cell carcinoma, prostate cancer, testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms' tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, and skin cancer.

[0043] Prexasertib is a compound having the following structure:

[0044] In the compounds of the present disclosure represented by formula (1), (2), (3), (4), (5), (6), (7), or (8), R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ａ , R ７ｂ , R ８ , R ９ , R １０ , R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , ring A, ring B, ring C, ring D, Y １ａ , Y １ｂ , Z １ａ , Z １ｂ Preferred values ​​for L, V, W and Q are as follows, but the technical scope of the present disclosure is not limited to the range of compounds listed below.

[0045] R １ Preferred embodiments of the group include a hydrogen atom, a halogen atom, cyano, -OR ２ , -CO ２ R ３ , C １－６ Alkyl, C ３－１０ cycloalkyl, or a 3- to 10-membered saturated heterocyclic group. １ More preferred embodiments of the group include a hydrogen atom, a halogen atom, cyano, —CO ２ R ３ , etc. １ More preferred embodiments of R include a hydrogen atom and cyano. １ An even more preferred embodiment of is cyano.

[0046] R ２ A preferred embodiment of is a hydrogen atom or C １－６ alkyl. ２ A more preferred embodiment of the above is C １－６Examples of alkyl include:

[0047] R ３ A preferred embodiment of the formula is C １－６ alkyl. ３ A more preferred embodiment of is a methyl group.

[0048] R ４ , R ５ and R ６ A preferred embodiment of is a hydrogen atom or C １－６ alkyl, wherein R ４ and R ５ Both are C １－６ When they are alkyl, they may be joined together with the nitrogen atom to which they are attached to form a 3- to 8-membered nitrogen-containing saturated heterocycle.

[0049] R ７ａ and R ７ｂ Preferred embodiments of the group include a hydrogen atom, a halogen atom, or —OR ９ , C １－６ Alkyl (the alkyl is a fluorine atom, a hydroxyl group, C １－３ Alkoxy, —NR １６ R １７ and cyano), C ３－７ Cycloalkyl (the cycloalkyl is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), a 3- to 7-membered saturated heterocyclic group (the saturated heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, a C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), phenyl (the phenyl may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７and cyano), or 5- or 6-membered heteroaryl (the heteroaryl is optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano). ７ａ and R ７ｂ More preferred embodiments of the group include a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, and C １－６ Alkyl (the alkyl is a fluorine atom, a hydroxyl group, C １－３ Alkoxy, —NR １６ R １７ and cyano), or 5- or 6-membered heteroaryl (the heteroaryl is optionally substituted with 1 to 2 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano). ７ａ and R ７ｂ In a more preferred embodiment, the group is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or C １－３ alkyl. ７ａ and R ７ｂ An even more preferred embodiment of is a hydrogen atom.

[0050] R ８ A preferred embodiment of is a hydrogen atom or C １－６ Examples of alkyl include:

[0051] R ９ A preferred embodiment of the formula is C １－６ Examples of alkyl include:

[0052] R １０ , R １１ and R １２ A preferred embodiment of is a hydrogen atom or C １－６alkyl, wherein R １１ and R １２ Both are C １－６ When they are alkyl, they may be joined together with the nitrogen atom to which they are attached to form a 3- to 8-membered nitrogen-containing saturated heterocycle.

[0053] R １３ A preferred embodiment of is a hydrogen atom or C １－６ Examples of alkyl include:

[0054] R １４ A preferred embodiment of is a hydrogen atom or C １－６ alkyl. ９ A more preferred embodiment of the above is C １－３ alkyl. ９ A more preferred embodiment of is a methyl group.

[0055] R １０ A preferred embodiment of the formula is C １－３ alkyl. １０ A more preferred embodiment of is a methyl group.

[0056] R １１ , R １２ and R １３ A preferred embodiment of is a hydrogen atom or C １－６ alkyl. １１ , R １２ and R １３ A more preferred embodiment of the above is C １－３ alkyl. １１ , R １２ and R １３ A more preferred embodiment of is a methyl group.

[0057] R １４ Preferred embodiments of the group include a hydrogen atom, C １－６ Alkyl (the alkyl is a fluorine atom, a hydroxyl group, C １－３ Alkoxy, —NR １６ R １７ and cyano), C ３－１０Cycloalkyl (the cycloalkyl is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), or a 3- to 10-membered saturated heterocyclic group (the saturated heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, a C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano). １４ In a more preferred embodiment, it is a hydrogen atom or C １－６ alkyl (the alkyl may be substituted with 1 to 2 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano). １４ More preferred embodiments of R include a hydrogen atom or a methyl group (the alkyl may be substituted with 1 to 2 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano). １４ An even more preferred embodiment of is a hydrogen atom.

[0058] R １５ A preferred embodiment of the formula is C １－６ alkyl. １５ A more preferred embodiment of the above is C １－３ Examples of alkyl include:

[0059] R １６ and R １７ A preferred embodiment of is a hydrogen atom or C １－６ alkyl, and R １６ and R １７ Both are C １－６ When R is alkyl, they may be combined with the nitrogen atom to which they are attached to form a 3- to 8-membered nitrogen-containing saturated heterocycle. １６ and R １７ A more preferred embodiment of the above is C １－６ alkyl.１６ and R １７ A more preferred embodiment of the formula is C １－３ Examples of alkyl include:

[0060] R １８ A preferred embodiment of is a hydrogen atom or C １－６ alkyl. １８ A more preferred embodiment of the above is C １－６ alkyl. １８ A more preferred embodiment of the formula is C １－３ Examples of alkyl include:

[0061] A preferred embodiment of ring A is a 3- to 10-membered cycloalkane (the cycloalkane may contain a fluorine atom, a hydroxyl group, a C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), a 6- to 10-membered arene (the arene may be substituted with fluorine atoms, hydroxyl groups, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), a 4- to 10-membered aromatic heterocycle or a 4- to 10-membered non-aromatic heterocycle (the aromatic heterocycle or the non-aromatic heterocycle may contain a fluorine atom, a hydroxyl group, a C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano). A more preferred embodiment of ring A is a 4- to 10-membered aromatic heterocycle or a 4- to 10-membered non-aromatic heterocycle (the aromatic heterocycle or non-aromatic heterocycle is optionally substituted with a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７and cyano). More preferred embodiments of ring A include a 5- to 6-membered aromatic heterocycle or a 5- to 8-membered non-aromatic heterocycle.

[0062] A preferred embodiment of ring B is a 5- or 6-membered aromatic heterocycle (the aromatic heterocycle may contain a fluorine atom, a hydroxyl group, a C １－３ Alkyl, C １－３ (Optionally substituted with 1 to 2 identical or different substituents selected from the group consisting of alkoxy and cyano.) A more preferred embodiment of ring B is a 5- or 6-membered aromatic heterocycle.

[0063] A preferred embodiment of ring C is a 5- to 8-membered non-aromatic heterocycle, or a 5- to 6-membered aromatic heterocycle (the non-aromatic heterocycle and aromatic heterocycle may contain no fluorine atom, hydroxyl group, C １－３ Alkyl, C １－３ (Optionally substituted with 1 to 2 identical or different substituents selected from the group consisting of alkoxy and cyano.) A more preferred embodiment of Ring C is a 5- to 8-membered non-aromatic heterocycle.

[0064] Preferred embodiments of ring D include a 5- to 8-membered non-aromatic heterocycle, or a 5- to 6-membered aromatic heterocycle (the non-aromatic heterocycle and aromatic heterocycle may contain no fluorine atom, hydroxyl group, C １－３ Alkyl, C １－３ (Optionally substituted with 1 to 2 identical or different substituents selected from the group consisting of alkoxy and cyano.) More preferred embodiments of Ring D include a 5- to 8-membered non-aromatic heterocycle or a 5- or 6-membered aromatic heterocycle.

[0065] Preferred embodiments of L include a single bond or C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７and cyano). A more preferred embodiment of L is a single bond or C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ A more preferred embodiment of L is a single bond or C １－６ Alkylene (the alkylene is a fluorine atom or C １－３ alkyl).

[0066] Preferred embodiments of V include a single bond, carbonyl, thiocarbonyl, optionally substituted C ２－６ Alkenylene, C ３－１０ Cycloalkylene, C ３－１０ Cycloalkenylene (the alkenylene, cycloalkylene, or cycloalkenylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a fluorine atom, a hydroxyl group, a C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), or —C(═NR １３ More preferred embodiments of V include a single bond, C ２－６ Alkenylene, C ３－１０ Cycloalkylene, C ３－１０ Cycloalkenylene (the alkenylene, cycloalkylene, or cycloalkenylene is a fluorine atom, a hydroxyl group, C １－３a 3- to 10-membered divalent saturated heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, and cyano), or a 3- to 10-membered divalent saturated heterocyclic group (which may be substituted with a fluorine atom, a hydroxyl group, 1 to 2 C １－３ and optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl and cyano. ２－６ Alkenylene, C ３－１０ Cycloalkylene, C ３－１０ Cycloalkenylene (the alkenylene, cycloalkylene, and cycloalkenylene are substituted with a fluorine atom, a hydroxyl group, and C １－３ alkyl), or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C １－３ Further preferred embodiments of V include a single bond, C ２－６ Alkenylene, C ３－１０ cycloalkylene (the cycloalkylene may be substituted with 1 to 3 fluorine atoms), C ３－１０ Cycloalkenylene, or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C group optionally substituted with a fluorine atom and 1 to 2 fluorine atoms). １－３ and alkyl.

[0067] Preferred embodiments of W include a single bond or C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkoxy, —NR １６ R １７ and cyano). １－６An alkylene group (the alkylene group may be substituted with 1 to 2 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano group) is preferred. A more preferred embodiment of W is a single bond or a C group optionally substituted with 1 to 2 fluorine atoms. １－３ In another more preferred embodiment of W, it is a single bond or C １－３ Examples include alkylene.

[0068] Preferred embodiments of Q include a hydrogen atom or NHR １４ More preferred embodiments of Q include a hydrogen atom, NH ２ In a more preferred embodiment, Q is a hydrogen atom or NH ２ An even more preferred embodiment of Q is a hydrogen atom. Another even more preferred embodiment of Q is NH ２ Examples include:

[0069] One embodiment of the compound represented by formula (1) is the following (A): (A) R １ is a hydrogen atom, a halogen atom, cyano, -CO ２ R ３ or C １－６ alkyl, R ３ But C １－６ is alkyl, and Y １ａ and Y １ｂ are each independently a carbon atom or a nitrogen atom; Z １ａ is a nitrogen atom or CR ７a and Z １ｂ is a nitrogen atom or CR ７ｂ and R ７a and R ７ｂ are each independently a hydrogen atom, a halogen atom, or -OR ９ , C １－６ Alkyl (the alkyl is a fluorine atom, a hydroxyl group, C １－３ Alkoxy, —NR １６ R １７ and cyano), C３－７ Cycloalkyl (the cycloalkyl is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), a 3- to 7-membered saturated heterocyclic group (the saturated heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), phenyl (the phenyl may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), or a 5- or 6-membered heteroaryl (the heteroaryl is optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and R ９ But C １－６ alkyl, R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When the ring A is an alkyl, it may be combined with the nitrogen atom to which it is bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle, and when the ring A is a 3- to 10-membered cycloalkane (the cycloalkane may contain no fluorine atom, hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR１６ R １７ and cyano), a 6- to 10-membered arene (the arene may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, a C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), a 4- to 10-membered aromatic heterocycle (the aromatic heterocycle may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), or a 4- to 10-membered non-aromatic heterocycle (the non-aromatic heterocycle may be substituted with 1 to 3 identical or different substituents selected from the group consisting of fluorine atom, hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and L is a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), and V is a single bond, carbonyl, thiocarbonyl, C ２－６ Alkenylene (the alkenylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), C ３－１０ Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７and cyano), C ３－１０ Cycloalkenylene (the cycloalkenylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a fluorine atom, a hydroxyl group, a C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), or —C(═NR １３ )-, W is a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkoxy, —NR １６ R １７ and cyano), and Q is a hydrogen atom, or NHR １４ and R １４ is a hydrogen atom, C １－６ Alkyl (the alkyl is a fluorine atom, a hydroxyl group, C １－３ Alkoxy, —NR １６ R １７ and cyano), C ３－１０ Cycloalkyl (the cycloalkyl is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), or a 3- to 10-membered saturated heterocyclic group (the saturated heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, a C １－３ Alkyl, C １－３ Alkoxy, —NR１６ R １７ and cyano, or a pharmaceutically acceptable salt thereof.

[0070] One embodiment of the compound represented by formula (2) is the following (B): １ is a hydrogen atom, a halogen atom, cyano, -CO ２ R ３ and R ３ But C １－６ is alkyl, and Z １ａ But, CR ７ａ and Z １ｂ is a nitrogen atom or CR ７ｂ and R ７a and R ７ｂ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or C １－３ alkyl, and ring A is a 5- or 6-membered aromatic heterocycle (the aromatic heterocycle does not contain a fluorine atom, a hydroxyl group, or a C １－３ Alkyl, C １－３ and L is a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ and C is a single bond, ２－６ Alkenylene (the alkenylene is a fluorine atom, a hydroxyl group, C １－３ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, cyclohexyl ... ３－１０ Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, C １－３ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, cyclohexyl ... ３－１０ Cycloalkenylene (the cycloalkenylene is a fluorine atom, a hydroxyl group, C １－３a 3- to 10-membered divalent saturated heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, and cyano), or a 3- to 10-membered divalent saturated heterocyclic group (which may be substituted with a fluorine atom, a hydroxyl group, a C １－３ and C is a single bond, or C １－６ alkylene (the alkylene may be substituted with the same or different 1 to 2 substituents selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano), and Q is a hydrogen atom, or NHR １４ and R １４ is a hydrogen atom, or C １－６ A compound or a pharmaceutically acceptable salt thereof, wherein the alkyl is optionally substituted with 1 to 2 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano.

[0071] One embodiment of the compound represented by formula (2) is the following (C): １ is a hydrogen atom, a halogen atom, cyano, -CO ２ R ３ and R ３ But C １－６ is alkyl, and Z １ａ But, CR ７ａ and Z １ｂ is a nitrogen atom or CR ７ｂ and R ７a and R ７ｂ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or C １－３ alkyl, and ring A is a 5- to 8-membered non-aromatic heterocycle (the non-aromatic heterocycle is not particularly limited to a fluorine atom, a hydroxyl group, a C １－３ Alkyl, C １－３ and L is a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３and C is a single bond, ２－６ Alkenylene (the alkenylene is a fluorine atom, a hydroxyl group, C １－３ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, cyclohexyl ... ３－１０ Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, C １－３ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, cyclohexyl ... ３－１０ Cycloalkenylene (the cycloalkenylene is a fluorine atom, a hydroxyl group, C １－３ a 3- to 10-membered divalent saturated heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, and cyano), or a 3- to 10-membered divalent saturated heterocyclic group (which may be substituted with a fluorine atom, a hydroxyl group, a C １－３ and C is a single bond, or C １－６ alkylene (the alkylene may be substituted with the same or different 1 to 2 substituents selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano), and Q is a hydrogen atom, or NHR １４ and R １４ is a hydrogen atom, or C １－６ A compound or a pharmaceutically acceptable salt thereof, wherein the alkyl is optionally substituted with 1 to 2 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano.

[0072] One embodiment of the compound represented by formula (2) is the following (D): １ is a hydrogen atom, a halogen atom, cyano, -CO ２ R ３ and R ３ But C １－６ is alkyl, and Z １ａ But, CR ７ａ and Z １ｂis a nitrogen atom, CR ７ｂ and R ７a and R ７ｂ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or C １－３ alkyl, and ring A is a 5- to 6-membered aromatic heterocycle (the aromatic heterocycle does not contain a fluorine atom, a hydroxyl group, a C １－３ Alkyl, C １－３ alkoxy, and cyano), or a 5- to 8-membered non-aromatic heterocycle (the non-aromatic heterocycle may be substituted with 1 to 2 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, a C １－３ Alkyl, C １－３ and L is a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ and C is a single bond, ２－６ Alkenylene (the alkenylene is a fluorine atom, a hydroxyl group, C １－３ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, cyclohexyl ... ３－１０ Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, C １－３ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, cyclohexyl ... ３－１０ Cycloalkenylene (the cycloalkenylene is a fluorine atom, a hydroxyl group, C １－３ a 3- to 10-membered divalent saturated heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, and cyano), or a 3- to 10-membered divalent saturated heterocyclic group (which may be substituted with a fluorine atom, a hydroxyl group, a C １－３ and C is a single bond, or C １－６alkylene (the alkylene may be substituted with the same or different 1 to 2 substituents selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano), and Q is a hydrogen atom, or NHR １４ and R １４ is a hydrogen atom, or C １－６ A compound or a pharmaceutically acceptable salt thereof, wherein the alkyl is optionally substituted with 1 to 2 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano.

[0073] One embodiment of the compound represented by formula (3) is the following (E): １ｂ is a carbon atom, ring B is a 5- to 6-membered aromatic heterocycle, L is a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom or C １－３ alkyl), and V is a single bond, C ２－６ Alkenylene (the alkenylene is a hydroxyl group and C １－３ alkyl), C ３－１０ Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, and a C １－３ alkyl), C ３－１０ Cycloalkenylene (the cycloalkenylene is a hydroxyl group and C １－３ alkyl), or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C １－３ alkyl), and W is a single bond or C optionally substituted with 1 to 2 fluorine atoms. １－３ alkylene, and Q is a hydrogen atom or NH ２ or a pharmaceutically acceptable salt thereof.

[0074] One embodiment of the compound represented by formula (4) is the following (F): １－６ Alkylene (the alkylene is a fluorine atom or C １－３ alkyl), and V is a single bond, C ２－６ Alkenylene, C ３－１０ cycloalkylene (the cycloalkylene may be substituted with 1 to 3 fluorine atoms); C ３－１０ Cycloalkenylene, or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C group optionally substituted with a fluorine atom and 1 to 2 fluorine atoms). １－３ alkyl), and W is a single bond or C optionally substituted with 1 to 2 fluorine atoms. １－３ A compound or a pharmaceutically acceptable salt thereof, wherein: Q is a hydrogen atom;

[0075] One embodiment of the compound represented by formula (4) is the following (G): １－６ Alkylene (the alkylene is a fluorine atom or C １－３ alkyl), and V is a single bond, C ２－６ Alkenylene, C ３－１０ cycloalkylene (the cycloalkylene may be substituted with 1 to 3 fluorine atoms); C ３－１０ Cycloalkenylene, or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C group optionally substituted with a fluorine atom and 1 to 2 fluorine atoms). １－３ alkyl), and W is a single bond or C optionally substituted with 1 to 2 fluorine atoms. １－３ Alkylene Q is NH ２ or a pharmaceutically acceptable salt thereof.

[0076] One embodiment of the compound represented by formula (5) is the following (H): １ represents a hydrogen atom, a halogen atom, cyano, -CO ２ R ３ and R ３ is C １－６ alkyl, ring C is a 5- to 8-membered non-aromatic heterocycle, L is a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom or C １－３ alkyl), and V is a single bond, C ２－６ Alkenylene (the alkenylene is a hydroxyl group and C １－３ alkyl), C ３－１０ Cycloalkylene (the cycloalkylene is a hydroxyl group and a C １－３ alkyl), C ３－１０ Cycloalkenylene (the cycloalkenylene is a hydroxyl group and C １－３ alkyl), or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C group optionally substituted with a fluorine atom, a hydroxyl group, and 1 to 2 hydroxyl groups or fluorine atoms). １－３ alkyl), and W is a single bond, or C １－３ alkylene, and Q is a hydrogen atom NH ２ or NMeH, or a pharmaceutically acceptable salt thereof.

[0077] One embodiment of the compound represented by formula (6) is the following (I): １－６ Alkylene (the alkylene is a fluorine atom or C １－３ alkyl), and V is a single bond, C ２－６ Alkenylene, C ３－１０ Cycloalkylene, C３－１０ Cycloalkenylene, or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C group optionally substituted with a fluorine atom and 1 to 2 fluorine atoms). １－３ alkyl), and W is a single bond, or C １－３ alkylene, and Q is a hydrogen atom NH ２ or NMeH, or a pharmaceutically acceptable salt thereof.

[0078] One embodiment of the compound represented by formula (7) is the following (J): １ｂ is a carbon atom, ring D is a 5- to 8-membered non-aromatic heterocycle, L is a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom or C １－３ alkyl), and V is a single bond, C ２－６ Alkenylene, C ３－１０ Cycloalkylene, C ３－１０ Cycloalkenylene, or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C group optionally substituted with a fluorine atom and 1 to 2 hydroxyl groups or fluorine atoms). １－３ alkyl), and W is a single bond, or C １－３ alkylene, and Q is a hydrogen atom or NH ２ or a pharmaceutically acceptable salt thereof.

[0079] One embodiment of the compound represented by formula (7) is the following (K): １ｂ is a carbon atom or a nitrogen atom, ring D is a 5- to 6-membered aromatic heterocycle, L is a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom or C １－３ alkyl), and V is a single bond, C ２－６ Alkenylene, C３－１０ cycloalkylene (the cycloalkylene may be substituted with 1 to 3 fluorine atoms); C ３－１０ Cycloalkenylene, or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C group optionally substituted with a fluorine atom and 1 to 2 hydroxyl groups or fluorine atoms). １－３ alkyl), and W is a single bond, or C １－３ alkylene, and Q is a hydrogen atom or NH ２ or a pharmaceutically acceptable salt thereof.

[0080] One embodiment of the compound represented by formula (7) is the following (K): １ｂ is a carbon atom, ring D is a 5- to 6-membered aromatic heterocycle, L is a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom or C １－３ alkyl), and V is a single bond, C ２－６ Alkenylene, C ３－１０ cycloalkylene (the cycloalkylene may be substituted with 1 to 3 fluorine atoms); C ３－１０ Cycloalkenylene, or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C group optionally substituted with a fluorine atom and 1 to 2 hydroxyl groups or fluorine atoms). １－３ alkyl), and W is a single bond, or C １－３ alkylene, and Q is a hydrogen atom or NH ２ or a pharmaceutically acceptable salt thereof.

[0081] One embodiment of the compound represented by formula (8) is (L) below. １－６ alkylene, V is a single bond, W is a single bond, or C １－３ alkylene, and Q is NH ２or a pharmaceutically acceptable salt thereof.

[0082] When administering the compound of the present disclosure, the dosage will vary depending on the symptoms, age, administration method, etc., but for example, in the case of intravenous injection, an effect can be expected by administering a daily dose of 0.01 mg (preferably 0.1 mg) as a lower limit to 1000 mg (preferably 100 mg) as an upper limit to an adult in a single dose or in divided doses depending on the symptoms. Examples of administration schedules include a single dose, once daily administration for three consecutive days, or twice daily administration for one week. Furthermore, each of the administration methods described above can be repeated at intervals of about 1 day to about 60 days.

[0083] The compounds of the present disclosure may be administered parenterally or orally, but are preferably administered parenterally, more preferably by intravenous injection. The compounds of the present disclosure are also preferably formulated and administered in a pharmaceutically acceptable carrier, such as liposomes.

[0084] Liposomes encapsulating compounds of the present disclosure contain at least one or more phospholipids, such as phosphatidylcholine, phosphatidylglycerol, phosphatidic acid, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, and sphingomyelin.

[0085] The fatty acid residue in the phospholipid is not particularly limited, and examples thereof include saturated or unsaturated fatty acid residues having 14 to 18 carbon atoms, and specific examples include acyl groups derived from fatty acids such as myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, etc. Furthermore, phospholipids derived from natural products such as egg yolk lecithin and soybean lecithin, as well as hydrogenated egg yolk lecithin and hydrogenated soybean lecithin (also called hydrogenated soybean phospholipid or hydrogenated soybean phosphatidylcholine) in which the unsaturated fatty acid residues of these phospholipids have been hydrogenated, can also be used.

[0086] The amount (molar fraction) of phospholipids to be mixed with respect to the total liposome membrane components is not particularly limited, but is preferably 30 to 80%, more preferably 40 to 70%.

[0087] Liposomes encapsulating the compounds of the present disclosure may contain sterols. Examples of sterols include cholesterol, β-sitosterol, stigmasterol, campesterol, brassica sterol, ergosterol, and fucosterol. Cholesterol is a preferred example of the sterol. The amount (molar fraction) of sterols relative to the total liposome membrane components is not particularly limited, but is preferably 0 to 60%, more preferably 10 to 50%, and even more preferably 30 to 50%.

[0088] Liposomes encapsulating the compounds of the present disclosure may contain polymer-modified lipids to improve in vivo retention. The amount (molar fraction) of the polymer-modified lipid relative to the total liposome membrane components is not particularly limited, but is preferably 0-20%, more preferably 1-10%. The polymer moiety of the polymer-modified lipid is preferably a hydrophilic polymer, more preferably a hydrophilic polymer in which the end of the polymer not bound to the lipid is alkoxylated. Specific examples of the polymer moiety of the polymer-modified lipid include, but are not limited to, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, methoxypolyethylene glycol, methoxypolypropylene glycol, methoxypolyvinyl alcohol, methoxypolyvinylpyrrolidone, ethoxypolyethylene glycol, ethoxypolypropylene glycol, ethoxypolyvinyl alcohol, ethoxypolyvinylpyrrolidone, propoxypolyethylene glycol, propoxypolypropylene glycol, propoxypolyvinyl alcohol, and propoxypolyvinylpyrrolidone. The polymer portion of the polymer-modified lipid preferably includes polyethylene glycol, methoxypolyethylene glycol, methoxypolypropylene glycol, ethoxypolyethylene glycol, ethoxypolypropylene glycol, propoxypolyethylene glycol, and propoxypolypropylene glycol.The polymer portion of the polymer-modified lipid more preferably includes polyethylene glycol, methoxypolyethylene glycol, ethoxypolyethylene glycol, ethoxypolypropylene glycol, and propoxypolyethylene glycol.The polymer portion of the polymer-modified lipid is even more preferably includes polyethylene glycol and methoxypolyethylene glycol.The polymer portion of the polymer-modified lipid is most preferably includes methoxypolyethylene glycol.The molecular weight of the polymer portion of the polymer-modified lipid is not particularly limited, but may be, for example, 100 to 10,000 daltons, preferably 1,000 to 7,000 daltons, more preferably 1,500 to 5,000 daltons, and most preferably 1,500 to 3,000 daltons.

[0089] The lipid moiety of the polymer-modified lipid is not particularly limited, and examples thereof include phosphatidylethanolamine and diacylglycerol. Preferred examples of the lipid moiety of the polymer-modified lipid include phosphatidylethanolamine having a saturated or unsaturated fatty acid residue having 14 to 18 carbon atoms, and diacylglycerol having a saturated or unsaturated fatty acid residue having 14 to 18 carbon atoms, more preferred examples include phosphatidylethanolamine having a saturated fatty acid residue having 14 to 18 carbon atoms, and diacylglycerol having a saturated fatty acid residue having 14 to 18 carbon atoms, and even more preferred examples include phosphatidylethanolamine having a palmitoyl group or a stearoyl group, and diacylglycerol having a palmitoyl group or a stearoyl group. The most preferred example of the lipid moiety of the polymer-modified lipid is distearoylphosphatidylethanolamine.

[0090] Liposomes encapsulating the compounds of the present disclosure can contain pharmaceutically acceptable additives, such as inorganic acids, inorganic acid salts, organic acids, organic acid salts, sugars, buffers, antioxidants, and polymers.

[0091] Inorganic acids include, for example, phosphoric acid, hydrochloric acid, and sulfuric acid.

[0092] Inorganic acid salts include, for example, sodium hydrogen phosphate, sodium chloride, ammonium sulfate, and magnesium sulfate.

[0093] Organic acids include, for example, citric acid, acetic acid, succinic acid, and tartaric acid.

[0094] Organic acid salts include, for example, sodium citrate, sodium acetate, disodium succinate, and sodium tartrate.

[0095] Sugars include, for example, glucose, sucrose, mannitol, sorbitol, and trehalose.

[0096] Examples of buffering agents include L-arginine, L-histidine, trometamol (trishydroxymethylaminomethane, Tris) and salts thereof.

[0097] Antioxidants include, for example, sodium sulfite, L-cysteine, sodium thioglycolate, sodium thiosulfate, ascorbic acid, and tocopherol.

[0098] Polymers include, for example, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, and sodium carboxymethylcellulose.

[0099]

[0039] Below, examples of methods for producing the compounds of the present disclosure represented by formula (1) will be described, but the methods for producing the compounds of the present disclosure are 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.

[0100] The compounds of the present disclosure 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, O, P, Q, R, and S, or methods similar thereto, or by appropriately combining synthesis methods known to those skilled in the art. Compounds of the present disclosure other than formula (a2) can also be produced by appropriately combining methods similar thereto or synthesis methods known to those skilled in the art.

[0101] Production Method A The compound of the present disclosure represented by formula (a2) can be produced, for example, by the following method. [In the formula, R １ , R １４ , Y １ａ , Y １ｂ , Z １ａ , Z １ｂ , rings A, L, V and W are as defined in item 1; P １ means an amino protecting group. １Examples of the protecting groups include the amino protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).

[0102] [Step 1] Compound (a2) can be prepared by removing the protecting group P of compound (a1) obtained by the following production method. １ This step can be carried out, for example, in accordance with the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).

[0103] Production Method B The compound of the present disclosure represented by formula (a1) can be produced, for example, by the following method. [In the formula, R １ , R １４ , Y １ａ , Y １ｂ , Z １ａ , Z １ｂ , rings A, L, V and W are as defined in item 1; P １ means an amino protecting group, and P ２ means a protecting group for phenol. １ Examples of the protecting groups include the amino protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999). ２ Examples of the protecting groups include the phenol protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).

[0104] Compound (b3) is commercially available.

[0105] [Step 1] Compound (b2) can be prepared by removing the protecting group P of compound (b1) obtained by the following production method. ２ This step can be carried out, for example, in accordance with the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).

[0106] [Step 2] Compound (a1) can be produced by subjecting compound (b2) and compound (b3) to Mitsunobu reaction in an appropriate solvent in the presence of a Mitsunobu reagent.

[0107] Examples of Mitsunobu reagents include diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), N,N,N',N'-tetraisopropylazodicarboxamide (TIPA), 1,1'-(azodicarbonyl)dipiperidine (ADDP), N,N,N',N'-tetramethylazodicarboxamide (TMAD), triphenylphosphine, tributylphosphine, and the like. Cyanomethylenetrimethylphosphorane (CMMP) and cyanomethylenetributylphosphorane (CMBP) can also be used.

[0108] The solvent is not particularly limited as long as it is inert under the reaction conditions of this step, and examples thereof include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, 1,4-dioxane, etc.; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, xylene, etc.; ester solvents such as ethyl acetate, methyl acetate, etc.; aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, etc.; or mixed solvents thereof, etc. Preferred examples of the solvent include toluene, benzene, THF, 1,4-dioxane, and mixed solvents thereof.

[0109] The reaction time is usually 5 minutes to 72 hours, preferably 12 to 24 hours.

[0110] The reaction temperature is usually 0°C to 100°C, preferably 0°C to 50°C.

[0111] Production Method C The compound of the present disclosure represented by formula (b1) can be produced, for example, by the following method. [In the formula, R １ , Y １ａ , Y １ｂ , Z １ａ , Z １ｂ and ring A is as defined in item 1, and P ２ means a protecting group for phenol. ２ Examples of the protecting groups include the phenol protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).

[0112] [Step 1] Compound (c2) can be produced by reacting compound (c1) with hydrazine monohydrate in a suitable solvent in the presence or absence of a suitable acid.

[0113] Examples of the acid include acetic acid, propionic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, hydrochloric acid, sulfuric acid, camphorsulfonic acid, etc. Preferred examples of the acid include acetic acid and p-toluenesulfonic acid.

[0114] The solvent is not particularly limited as long as it is inert under the reaction conditions of this step, and examples thereof include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, 1,4-dioxane, etc.; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, xylene, etc.; ester solvents such as ethyl acetate, methyl acetate, etc.; aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, etc.; alcohol solvents such as methanol, ethanol, isopropyl alcohol, butanol, etc.; or mixtures thereof. Preferred examples of the solvent include 1,4-dioxane, toluene, ethanol, etc.

[0115] The reaction time is usually 5 minutes to 72 hours, preferably 12 to 24 hours.

[0116] The reaction temperature is usually 0°C to 200°C, preferably 50°C to 100°C.

[0117] [Step 2] Compound (b1) can be produced by reacting compound (c2) with a 5-chloropyrazine derivative in the presence of a suitable base in a suitable solvent.

[0118] Examples of the base include organic bases such as triethylamine, diisopropylethylamine, tributylamine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, dimethylaminopyridine, picoline, N-methylmorpholine (NMM), and N-ethylmorpholine, and inorganic bases such as sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide. Preferred examples of the base include triethylamine, diisopropylethylamine, and N-ethylmorpholine.

[0119] The solvent is not particularly limited as long as it is inert under the reaction conditions of this step, and examples thereof include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, 1,4-dioxane, etc.; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, xylene, etc.; ester solvents such as ethyl acetate, methyl acetate, etc.; aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, etc.; or mixtures thereof. Preferred examples of the solvent include tetrahydrofuran, toluene, dimethyl sulfoxide, etc.

[0120] The reaction time is usually 5 minutes to 48 hours, preferably 1 hour to 6 hours.

[0121] The reaction temperature is usually 0°C to 200°C, preferably 50°C to 100°C.

[0122] Production Method D The compound of the present disclosure represented by formula (c1) can be produced, for example, by the following method.

[0123] [In the formula, Y １ａ , Y １ｂ , Z １ａ , Z １ｂ and ring A is as defined in item 1, and P ２ means a protecting group for phenol, and P ３ means a protecting group for a carboxylic acid. ２ Examples of the protecting groups include the phenol protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999). ３Examples of the protecting group include the carboxylic acid protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).

[0124] [Step 1] Compound (c1) can be produced by reacting compound (d1) with acetonitrile in the presence of a suitable base in a suitable solvent.

[0125] Examples of the base include alkali metal hydrides such as sodium hydride, alkali metal halides such as potassium fluoride, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogencarbonate, alkali metal alkoxides such as sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, and alkali metal alkoxides such as lithium diisopropylamide, n-butyllithium, methyllithium and isopropylmagnesium bromide. Preferred examples of the base include sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and n-butyllithium.

[0126] The solvent is not particularly limited as long as it is inert under the reaction conditions of this step, and examples thereof include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, 1,4-dioxane, etc.; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, xylene, etc.; ester solvents such as ethyl acetate, methyl acetate, etc.; aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, etc.; alcohol solvents such as methanol, ethanol, isopropyl alcohol, butanol, etc.; and mixtures thereof. Preferred solvents include tetrahydrofuran, toluene, etc.

[0127] The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 6 hours, and the reaction temperature is usually −100° C. to 100° C., preferably −100° C. to 30° C.

[0128] Production Method E The compound of the present disclosure represented by formula (b1) can be produced, for example, by the following method. [In the formula, R １ , Y １ａ , Y １ｂ , Z １ａ , Z １ｂ and ring A is as defined in item 1, and P ２ means a protecting group for phenol. ２ Examples of the protecting groups include the phenol protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).

[0129] [Step 1] Compound (e2) can be produced by reacting compound (e1) with carbon disulfide and iodomethane in the presence of a suitable base in a suitable solvent.

[0130] Examples of the base include alkali metal hydrides such as sodium hydride, alkali metal halides such as potassium fluoride, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogencarbonate, alkali metal alkoxides such as sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, and alkali metal alkoxides such as lithium diisopropylamide, n-butyllithium, methyllithium and isopropylmagnesium bromide. Preferred examples of the base include sodium hydride and potassium tert-butoxide.

[0131] The solvent is not particularly limited as long as it is inert under the reaction conditions of this step, and examples thereof include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, 1,4-dioxane, etc.; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, xylene, etc.; ester solvents such as ethyl acetate, methyl acetate, etc.; aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, etc.; alcohol solvents such as methanol, ethanol, isopropyl alcohol, butanol, etc.; and mixtures thereof. Preferred examples of the solvent include tetrahydrofuran, toluene, N,N-dimethylformamide, etc.

[0132] The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 2 hours.

[0133] The reaction temperature is usually from -78°C to 200°C, preferably from 0°C to 25°C.

[0134] [Step 2] Compound (e3) can be produced by reacting compound (e2) with a 5-aminopyrazine derivative in the presence of a suitable base in a suitable solvent.

[0135] Examples of the base include organic bases such as triethylamine, diisopropylethylamine, tributylamine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, dimethylaminopyridine, picoline, N-methylmorpholine (NMM), and N-ethylmorpholine, and inorganic bases such as sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide. Preferred examples of the base include triethylamine and diisopropylethylamine.

[0136] The solvent is not particularly limited as long as it is inert under the reaction conditions of this step, and examples thereof include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, 1,4-dioxane, etc.; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, xylene, etc.; ester solvents such as ethyl acetate, methyl acetate, etc.; aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, etc.; or mixtures thereof. Preferred examples of the solvent include tetrahydrofuran, toluene, dimethyl sulfoxide, etc.

[0137] The reaction time is usually 5 minutes to 48 hours, preferably 2 to 8 hours.

[0138] The reaction temperature is usually 0°C to 200°C, preferably 50°C to 100°C.

[0139] [Step 3] Compound (b1) can be produced by reacting compound (e3) with hydrazine monohydrate in a suitable solvent in the presence or absence of a suitable acid.

[0140] Examples of the acid include acetic acid, propionic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, hydrochloric acid, sulfuric acid, camphorsulfonic acid, etc. Preferred examples of the acid include acetic acid.

[0141] The solvent is not particularly limited as long as it is inert under the reaction conditions of this step, and examples thereof include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, and xylene; ester solvents such as ethyl acetate and methyl acetate; aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, and dimethyl sulfoxide; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and butanol; or mixtures thereof. Preferred solvents include 1,4-dioxane and ethanol.

[0142] The reaction time is usually 5 minutes to 72 hours, preferably 12 to 24 hours.

[0143] The reaction temperature is usually 0°C to 200°C, preferably 50°C to 100°C.

[0144] Production Method F The compound of the present disclosure represented by formula (c1) can be produced, for example, by the following method. [In the formula, Y １ａ , Y １ｂ , Z １ａ , Z １ｂ and ring A is as defined in item 1, and P ２ means a protecting group for phenol. ２ Examples of the protecting groups include the phenol protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).

[0145] [Step 1] Compound (f1) can be produced by reacting compound (e1) with dimethylformamide dimethyl acetal in an appropriate solvent.

[0146] The solvent is not particularly limited as long as it is inert under the reaction conditions of this step, and examples thereof include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, 1,4-dioxane, etc.; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, xylene, etc.; ester solvents such as ethyl acetate, methyl acetate, etc.; aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, etc.; or mixtures thereof. Preferred examples of the solvent include N,N-dimethylformamide, etc.

[0147] The reaction time is usually 5 minutes to 48 hours, preferably 24 to 48 hours.

[0148] The reaction temperature is usually 0°C to 200°C, preferably 60°C to 120°C.

[0149] [Step 2] Compound (f2) can be produced by reacting compound (f1) with hydroxylamine hydrochloride in an appropriate solvent.

[0150] The solvent is not particularly limited as long as it is inert under the reaction conditions of this step, and examples thereof include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, 1,4-dioxane, etc.; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, xylene, etc.; ester solvents such as ethyl acetate, methyl acetate, etc.; aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, etc.; alcohol solvents such as methanol, ethanol, isopropyl alcohol, butanol, etc.; or mixtures thereof. Preferred examples of the solvent include ethanol and isopropyl alcohol.

[0151] The reaction time is usually 5 minutes to 48 hours, preferably 6 to 12 hours.

[0152] The reaction temperature is usually 0°C to 200°C, preferably 40°C to 80°C.

[0153] [Step 3] Compound (c1) can be produced by reacting compound (f2) with a base in an appropriate solvent.

[0154] Examples of the base include inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, etc. Preferred examples of the base include sodium hydroxide and potassium hydroxide.

[0155] The solvent is not particularly limited as long as it is inert under the reaction conditions of this step, and examples thereof include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, 1,4-dioxane, etc.; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, xylene, etc.; ester solvents such as ethyl acetate, methyl acetate, etc.; aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, etc.; protic solvents such as water, methanol, ethanol, isopropyl alcohol, butanol, etc.; or mixtures thereof. Preferred examples of the solvent include a mixed solvent of water and ethanol.

[0156] The reaction time is usually 5 minutes to 48 hours, preferably 1 hour to 6 hours.

[0157] The reaction temperature is usually 0°C to 200°C, preferably 20°C to 50°C.

[0158] Production Method G The compound of the present disclosure represented by formula (a1) can be produced, for example, by the following method. [In the formula, R １ , R １４ , Y １ａ , Y １ｂ , Z １ａ , Z １ｂ , rings A, L, V and W are as defined in item 1; P １ means an amino protecting group.１ Examples of the protecting groups include the amino protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).

[0159] [Step 1] Compound (g2) can be produced from compound (g1) obtained by the following production method by the method described in Step 1 of Production Method C or a method analogous thereto.

[0160] [Step 2] Compound (a1) can be produced from compound (g2) by the method described in Step 2 of Production Method C or a method analogous thereto.

[0161] Production Method H The compound represented by formula (a1) can be produced, for example, by the following method. [In the formula, R １ , R １４ , Y １ａ , Y １ｂ , Z １ａ , Z １ｂ , rings A, L, V and W are as defined in item 1; P １ means an amino protecting group. １ Examples of the protecting groups include the amino protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).

[0162] [Step 1] Compound (h2) can be produced from compound (h1) obtained by the following production method by the method described in Step 1 of Production Method E or a method analogous thereto.

[0163] [Step 2] Compound (h3) can be produced from compound (h2) by the method described in step 2 of production method E or a method analogous thereto. [Step 3] Compound (a1) can be produced from compound (h3) by the method described in step 3 of production method E or a method analogous thereto.

[0164] Production Method I The compound represented by formula (g1) can be produced, for example, by the following method. [In the formula, R １４ , Y １ａ , Y １ｂ , Z １ａ , Z １ｂ , rings A, L, V and W are as defined in item 1; P １ means an amino protecting group. １ Examples of the protecting groups include the amino protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).

[0165] [Step 1] Compound (i1) can be produced from compound (h1) obtained by the following production method by the method described in Step 1 of Production Method F or a method analogous thereto.

[0166] [Step 2] Compound (i2) can be produced from compound (i1) by the method described in step 2 of production method F or a method similar thereto. [Step 3] Compound (g1) can be produced from compound (i2) by the method described in step 3 of production method F or a method similar thereto.

[0167] Production Method J The compound represented by formula (g1) can also be produced, for example, by the following method. [In the formula, R １４ , Y １ａ , Y １ｂ , Z １ａ , Z １ｂ , rings A, L, V and W are as defined in item 1; P １ means an amino protecting group, and P ３ means a protecting group for a carboxylic acid. １Examples of the protecting groups include the amino protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999). ３ Examples of the protecting groups include the amino protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).

[0168] [Step 1] Compound (g1) can be produced from compound (j1) obtained by the following production method by the method described in Step 1 of Production Method D or a method analogous thereto.

[0169] Production Method K The compound of the present disclosure represented by formula (d1) can be produced, for example, by the following method. [In the formula, Y １ａ , Y １ｂ , Z １ａ , Z １ｂ and ring A is as defined in item 1, and P ２ means a protecting group for phenol, and P ３ means a protecting group for a carboxylic acid. ２ Examples of the protecting groups include the phenol protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999). ３ Examples of the protecting group include the carboxylic acid protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).

[0170] The compound (k1) is commercially available.

[0171] [Step 1] Compound (d1) can be produced from compound (k1) by, for example, the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).

[0172] Production Method L The compound of the present disclosure represented by formula (e1) can be produced, for example, by the following method. [In the formula, Y １ａ , Y １ｂ , Z １ａ , Z １ｂ and ring A is as defined in item 1, and P ２ means a protecting group for phenol. ２ Examples of the protecting groups include the phenol protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).

[0173] Compound (l1) is commercially available.

[0174] [Step 1] Compound (e1) can be produced from compound (l1), for example, by the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).

[0175] Production Method M The compound of the present disclosure represented by formula (j1) can be produced, for example, by the following method. [In the formula, R １４ , Y １ａ , Y １ｂ , Z １ａ , Z １ｂ , rings A, L, V and W are as defined in item 1; P １ means an amino protecting group, and P ３means a protecting group for a carboxylic acid. １ Examples of the protecting groups include the amino protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999). ３ Examples of the protecting groups include the amino protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).

[0176] The compound (k1) and the compound (b3) are commercially available.

[0177] [Step 1] Compound (j1) can be produced from compound (k1) and compound (b3) by the method described in step 2 of production method B or a method analogous thereto.

[0178] Production Method N The compound of the present disclosure represented by formula (j1) can be produced, for example, by the following method. [In the formula, R １４ , Y １ａ , Y １ｂ , Z １ａ , Z １ｂ , rings A, L, V and W are as defined in item 1; P １ means an amino protecting group, and P ３ means a protecting group for a carboxylic acid, and LG means a leaving group. １ Examples of the protecting groups include the amino protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999). ３Examples of LG include the amino-protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999), and examples of LG include halogen, methanesulfonyloxy, p-toluenesulfonyloxy, and trifluoromethanesulfonyloxy.]

[0179] The compound (k1) and the compound (n1) are commercially available.

[0180] [Step 1] Compound (j1) can be produced by reacting compound (k1) with compound (n1) in a suitable solvent in the presence or absence of a suitable base. Examples of the base include organic bases such as triethylamine, diisopropylethylamine, tributylamine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, 4-dimethylaminopyridine, picoline, and N-methylmorpholine (NMM), and inorganic bases such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide. Preferred examples of the base include triethylamine, diisopropylethylamine, potassium carbonate, and sodium hydroxide.

[0181] The solvent is not particularly limited as long as it is inert under the reaction conditions of this step, and examples thereof include alcoholic solvents such as methanol, ethanol, 2-propanol (isopropyl alcohol), tert-butanol, etc.; etheric solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, 1,4-dioxane, etc.; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, anisole, xylene, etc.; ester solvents such as ethyl acetate, methyl acetate, etc.; aprotic solvents such as acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, etc.; or mixtures thereof. Preferred examples of the solvent include 2-propanol, tetrahydrofuran, toluene, acetonitrile, N,N-dimethylformamide, etc.

[0182] The reaction temperature is usually from -80°C to reflux, preferably from 25°C to 90°C.

[0183] The reaction time is usually 30 minutes to 48 hours, preferably 6 to 12 hours.

[0184] Production Method O The compound of the present disclosure represented by formula (h1) can be produced, for example, by the following method. [In the formula, R １４ , Y １ａ , Y １ｂ , Z １ａ , Z １ｂ , rings A, L, V and W are as defined in item 1; P １ means an amino protecting group. １ Examples of the protecting groups include the amino protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).

[0185] The compound (l1) and the compound (b3) are commercially available.

[0186] [Step 1] Compound (h1) can be produced from compound (l1) and compound (b3) by the method described in step 2 of production method B or a method analogous thereto.

[0187] Production Method P The compound of the present disclosure represented by formula (h1) can be produced, for example, by the following method. [In the formula, R １４ , Y １ａ , Y １ｂ , Z １ａ , Z １ｂ , rings A, L, V and W are as defined in item 1; P １ means an amino protecting group, and LG means a leaving group. １ Examples of LG include the amino-protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999). Examples of LG include halogen, methanesulfonyloxy, p-toluenesulfonyloxy, and trifluoromethanesulfonyloxy.]

[0188] Compound (l1) and compound (n1) are commercially available.

[0189] [Step 1] Compound (h1) can be produced from compound (l1) and compound (n1) by the method described in step 2 of production method N or a method analogous thereto.

[0190] Production Method Q The compound of the present disclosure represented by formula (d1) can be produced, for example, by the following method. [In the formula, Y １ａ , Y １ｂ , Z １ａ , Z １ｂ and ring A is as defined in item 1; Ａ means a halogen atom, and P ２ means a protecting group for phenol, and P ３ means a protecting group for a carboxylic acid. ２Examples of the protecting groups include the phenol protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999). ３ Examples of the protecting group include the carboxylic acid protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).

[0191] Compound (q1) is commercially available.

[0192] [Step 1] Compound (q2) can be produced by reacting compound (q1) with N-halosuccinimide in the presence of a suitable acid in a suitable solvent.

[0193] Examples of the acid include acetic acid, propionic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, hydrochloric acid, sulfuric acid, camphorsulfonic acid, etc. Preferably, the acid is p-toluenesulfonic acid.

[0194] The solvent is not particularly limited as long as it is inert under the reaction conditions of this step, and examples thereof include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, 1,4-dioxane, etc.; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, xylene, etc.; ester solvents such as ethyl acetate, methyl acetate, etc.; aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, etc.; or mixtures thereof. A preferred solvent is acetonitrile.

[0195] The reaction time is usually 5 minutes to 48 hours, preferably 1 hour to 6 hours.

[0196] The reaction temperature is usually 0°C to 200°C, preferably 50°C to 100°C.

[0197] [Step 2] Compound (q3) can be produced from compound (q2), for example, by the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).

[0198] [Step 3] Compound (d1) can be produced by reacting compound (q3) with ethyl chloroformate in the presence of a suitable base in a suitable solvent.

[0199] Examples of the base include alkali metal hydrides such as sodium hydride, alkali metal halides such as potassium fluoride, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogencarbonate, alkali metal alkoxides such as sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, and alkali metal alkoxides such as lithium diisopropylamide, n-butyllithium, methyllithium and isopropylmagnesium bromide. A preferred base is n-butyllithium.

[0200] The solvent is not particularly limited as long as it is inert under the reaction conditions of this step, and examples thereof include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, 1,4-dioxane, etc.; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, xylene, etc.; ester solvents such as ethyl acetate, methyl acetate, etc.; aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, etc.; alcohol solvents such as methanol, ethanol, isopropyl alcohol, butanol, etc.; and mixtures thereof. Preferred solvents include tetrahydrofuran, toluene, etc.

[0201] The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 6 hours, and the reaction temperature is usually −100° C. to 100° C., preferably −100° C. to −50° C.

[0202] Production Method R The compound of the present disclosure represented by formula (d1) can be produced, for example, by the following method. [In the formula, Y １ａ , Y １ｂ , Z １ａ , Z １ｂ and ring A is as defined in item 1, and P ２ means a protecting group for phenol, and P ３ means a protecting group for a carboxylic acid. ２ Examples of the protecting groups include the phenol protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999). ３ Examples of the protecting group include the carboxylic acid protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).

[0203] Compound (q1) is commercially available.

[0204] [Step 1] Compound (r1) can be produced from compound (q1) by, for example, the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).

[0205] [Step 2] Compound (d1) can be produced by reacting compound (r1) with alkyl chloroformate in the presence of a suitable base in a suitable solvent.

[0206] Examples of the base include alkali metal hydrides such as sodium hydride, alkali metal halides such as potassium fluoride, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogencarbonate, alkali metal alkoxides such as sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, and alkali metal alkoxides such as lithium diisopropylamide, n-butyllithium, methyllithium, isopropylmagnesium bromide, etc. A preferred base is lithium diisopropylamide.

[0207] The solvent is not particularly limited as long as it is inert under the reaction conditions of this step, and examples thereof include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, 1,4-dioxane, etc.; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, xylene, etc.; ester solvents such as ethyl acetate, methyl acetate, etc.; aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, etc.; alcohol solvents such as methanol, ethanol, isopropyl alcohol, butanol, etc.; and mixtures thereof. Preferred solvents include tetrahydrofuran, toluene, etc.

[0208] The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 6 hours.

[0209] The reaction temperature is usually -100°C to 100°C, preferably -100°C to -50°C.

[0210] Production Method S The compound of the present disclosure represented by formula (e1) can be produced, for example, by the following method. [In the formula, Y １ａ , Y １ｂ , Z １ａ , Z １ｂ and ring A is as defined in item 1, and P ２ means a protecting group for phenol.２ Examples of the protecting groups include the phenol protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).

[0211] [Step 1] Compound (q3) can be produced by reacting compound (r1) with a halogenating agent in the presence of a suitable base in a suitable solvent.

[0212] Examples of halogenating agents include N-chlorosuccinimide, Br ２ , N-bromosuccinimide, I ２ , N-iodosuccinimide, etc. As the halogenating agent, Br ２ , I ２ Examples include:

[0213] Examples of the base include alkali metal hydrides such as sodium hydride, alkali metal halides such as potassium fluoride, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogencarbonate, alkali metal alkoxides such as sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, and alkali metal alkoxides such as lithium diisopropylamide, n-butyllithium, methyllithium and isopropylmagnesium bromide. A preferred base is n-butyllithium.

[0214] The solvent is not particularly limited as long as it is inert under the reaction conditions of this step, and examples thereof include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, 1,4-dioxane, etc.; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, xylene, etc.; ester solvents such as ethyl acetate, methyl acetate, etc.; aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, etc.; alcohol solvents such as methanol, ethanol, isopropyl alcohol, butanol, etc.; and mixtures thereof. Preferred solvents include tetrahydrofuran, toluene, etc.

[0215] The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 6 hours.

[0216] The reaction temperature is usually -100°C to 100°C, preferably -100°C to -50°C.

[0217] [Step 2] Compound (s1) can be produced by reacting compound (q3) with tributyl(1-ethoxyvinyl)stannane in the presence of a suitable palladium catalyst in a suitable solvent.

[0218] As the palladium catalyst, a palladium-phosphine complex can be used. Examples of the palladium-phosphine complex include tetrakis(triphenylphosphine)palladium(0), bis(tri-tert-butylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride, bis(tri-o-tolylphosphine)palladium(II), [1,2-bis(diphenylphosphino)ethane]palladium(II), bis(diphenylphosphino)ferrocene]dichloropalladium(II), and [1,3-bis(diphenylphosphino)propane]palladium(II). As the palladium catalyst, preferably, bis(diphenylphosphino)ferrocene]dichloropalladium(II) is used.

[0219] The solvent is not particularly limited as long as it is inert under the reaction conditions of this step, and examples thereof include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, 1,4-dioxane, etc.; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, xylene, etc.; ester solvents such as ethyl acetate, methyl acetate, etc.; aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, etc.; alcohol solvents such as methanol, ethanol, isopropyl alcohol, butanol, etc.; and mixtures thereof. Preferred examples of the solvent include 1,4-dioxane, tetrahydrofuran, toluene, etc.

[0220] The reaction time is usually 5 minutes to 72 hours, preferably 6 to 30 hours.

[0221] The reaction temperature is usually 0°C to 200°C, preferably 100°C to 150°C.

[0222] In the above-described production methods, starting materials or intermediates for which production methods are not described are either commercially available or can be synthesized from commercially available compounds by methods known to those skilled in the art or methods similar thereto.

[0223] In each reaction of the production method described above, even when the use of a protecting group is not specifically specified, a protecting group can be used as needed. For example, when any functional group other than the reactive site changes under the reaction conditions described, or when the method described is inappropriate to carry out without a protecting group, the target compound can be obtained by protecting the functional group other than the reactive site as needed and deprotecting it after the reaction or after a series of reactions.

[0224] Examples of the protecting group that can be used include those described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999). Specific examples of the amino protecting group include benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl, etc. Specific examples of the hydroxyl protecting group include trialkylsilyl such as trimethylsilyl and tert-butyldimethylsilyl, acetyl, benzyl, etc.

[0225] Introduction and removal of the protecting group can be carried out by a method commonly used in organic synthetic chemistry (for example, see the aforementioned Protective Groups in Organic Synthesis) or a method analogous thereto.

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

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

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

[0229] Examples of the protecting group that can be used include those described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999). Specific examples of the amino protecting group include benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl, etc. Specific examples of the hydroxyl protecting group include trialkylsilyl such as trimethylsilyl and tert-butyldimethylsilyl, acetyl, benzyl, etc.

[0230] Introduction and removal of the protecting group can be carried out by a method commonly used in organic synthetic chemistry (for example, see the aforementioned Protective Groups in Organic Synthesis) or a method analogous thereto.

[0231] In this specification, protecting groups, condensing agents, etc. may be represented by abbreviations according to IUPAC-IUB (International Board of Biochemical Nomenclature) commonly used in this technical field. Note that the names of compounds used in this specification do not necessarily conform to the IUPAC nomenclature.

[0232] The intermediates or target compounds in the above-described production methods can be converted into other compounds included in the present disclosure by appropriately converting their functional groups (for example, by protecting or deprotecting the functional groups as necessary, and then performing various conversions using amino, hydroxyl, carbonyl, halogen, etc. as a stepping stone). The conversion of functional groups can be performed by a commonly used method (see, for example, Comprehensive Organic Transformations, R. C. Larock, John Wiley & Sons Inc. (1999)).

[0233] The intermediates and target compounds in the above-described production methods can be isolated and purified by purification methods commonly used in organic synthetic chemistry (e.g., neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography, etc.). In addition, the intermediates can also be used in the next reaction without any particular purification.

[0234] "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, and phosphate, and organic acid salts such as citrate, oxalate, phthalate, fumarate, maleate, succinate, malate, acetate, formate, propionate, benzoate, trifluoroacetate, methanesulfonate, benzenesulfonate, para-toluenesulfonate, and camphorsulfonate. Furthermore, base addition salts include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, barium salt, and aluminum salt, and organic base salts such as trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, dicyclohexylamine, and N,N-dibenzylethylamine. Furthermore, "pharmaceutically acceptable salts" also include amino acid salts with basic or acidic amino acids such as arginine, lysine, ornithine, aspartic acid, or glutamic acid.

[0235] Suitable salts of starting materials and intermediates, as well as salts acceptable as pharmaceutical raw materials, are conventional non-toxic salts, including, for example, acid addition salts such as organic acid salts (e.g., acetate, trifluoroacetate, maleate, fumarate, citrate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.) and inorganic acid salts (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.), salts with amino acids (e.g., arginine, aspartic acid, glutamic acid, etc.), metal salts such as alkali metal salts (e.g., sodium salt, potassium salt), alkaline earth metal salts (e.g., calcium salt, magnesium salt), ammonium salts, organic base salts (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), and others that can be appropriately selected by those skilled in the art.

[0236] In the present disclosure, any one or more of the compounds represented by formulas (1) to (8) １ H ２ Deuterium-converted products converted to H(D) are also included in the compounds represented by formulas (1) to (8).

[0237] The present disclosure includes compounds represented by formulas (1) to (8) or pharmaceutically acceptable salts thereof. In addition, the compounds of the present disclosure may exist in the form of hydrates and / or solvates with various solvents (such as ethanol solvates), and these hydrates and / or solvates are also included in the compounds of the present disclosure.

[0238] Furthermore, the compounds of the present disclosure include all possible isomers such as optical isomers based on optically active centers, atropisomers based on axial or planar chirality resulting from restricted intramolecular rotation, other stereoisomers, tautomers, geometric isomers, and the like, as well as all types of crystalline forms, and mixtures thereof.

[0239] In particular, optical isomers and atropisomers can be obtained as racemates, or as optically active isomers when optically active starting materials or intermediates are used. Furthermore, if necessary, at an appropriate stage of the production method, the racemate of the corresponding starting material, intermediate, or final product can be physically or chemically resolved into its optical antipodes by known separation methods such as a method using an optically active column or fractional crystallization. Examples of such resolution methods include a diastereomeric method in which a racemate is reacted with an optically active resolving agent to synthesize two diastereomers, which are then separated by a method such as fractional crystallization, taking advantage of their different physical properties.

[0240] When it is desired to obtain a pharmaceutically acceptable salt of a compound of the present disclosure, if the compound represented by formulas (1) to (8) is obtained in the form of a pharmaceutically acceptable salt, it may be purified as is, or if it is obtained in the free form, it may be dissolved or suspended in an appropriate organic solvent, and an acid or a base may be added to form a salt by a conventional method.

[0241] Liposomes encapsulating the compounds of the present disclosure can be produced, for example, by the following method.

[0242] [Step 1] Membrane components such as phospholipids and cholesterol are dissolved in an organic solvent such as chloroform, and the organic solvent is evaporated in a flask to form a thin film of the lipid mixture on the inner wall of the flask. Alternatively, the lipid mixture may be obtained as a lyophilized product by dissolving the components in t-butyl alcohol or the like and then lyophilizing the solution. Alternatively, membrane components such as phospholipids and cholesterol may be dissolved in an organic solvent and then powdered using a CRUX instant vacuum dryer (manufactured by Hosokawa Micron Corporation) to obtain a lipid mixture, which is available from Nippon Fine Chemical Co., Ltd. under the name Presome (registered trademark).

[0243] [Step 2] An internal aqueous phase solution such as an aqueous ammonium sulfate solution is added to the lipid mixture obtained in step 1 and dispersed to obtain a crude liposome dispersion.

[0244] [Step 3] The crude liposome dispersion obtained in step 2 is passed through a filter using an extruder to obtain a desired particle size. Alternatively, the crude liposome dispersion obtained in step 2 is extruded from a nozzle at high pressure using a high-pressure homogenizer to obtain a desired particle size. The liposome particle size is not particularly limited, but is, for example, 10 nm to 200 nm, preferably 30 nm to 150 nm, more preferably 40 nm to 140 nm, even more preferably 50 to 120 nm, and most preferably 60 to 100 nm. The liposome particle size is an average value measured by dynamic light scattering, and can be measured, for example, using a Zetasizer Nano ZS (Malvern Instruments).

[0245] [Step 4] The external aqueous phase of the liposome solution obtained in step 3 is replaced by gel filtration, dialysis, tangential flow filtration, ultracentrifugation, or the like.

[0246] [Step 5] The liposome solution obtained in step 4, in which the external aqueous phase has been replaced, is incubated with the compound to be encapsulated, thereby encapsulating the compound in the liposomes.

[0247] [Step 6] The resulting liposomes encapsulating the compound are subjected to gel filtration, dialysis, tangential flow filtration, ultracentrifugation, etc. to remove any unencapsulated compound. Note that if a desired encapsulation rate is obtained in step 5, step 6 can be omitted.

[0248] The compounds of the present disclosure can be used in combination with other drugs to enhance their effects. Specifically, the compounds of the present disclosure can be used in combination with drugs such as hormone therapy agents, chemotherapy agents, immunotherapy agents, or drugs that inhibit cell growth factors and their receptor activity. Hereinafter, drugs that can be used in combination with the compounds of the present disclosure will be abbreviated as "concomitant drugs."

[0249] The compounds of the present disclosure exhibit excellent anticancer effects even when used as a single agent, but by further using them in combination with one or more of the above-mentioned concomitant drugs (multidrug combination), the effects can be further enhanced or the patient's QOL can be improved.

[0250] Examples of "hormonal therapeutic agents" include fosfestrol, diethylstilbestrol, chlorotrianisene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, dienogest, asoprisnil, allylestrenol, gestrinone, nomegestol, tadenane, mepartricin, raloxifene, ormeloxifene, levormeloxifene, antiestrogens (e.g., tamoxifen citrate, toremifene citrate, etc.), birth control pills, mepitiostane, testololactone, aminoglutethimide, LH-RH derivatives (LH-RH agonists (e.g., goserelin acetate, buserelin, levothyroxine), levothyroxine, ... prorelin, etc.), LH-RH antagonists), droloxifene, epitiostanol, ethinyl estradiol sulfonate, aromatase inhibitors (e.g., fadrozole hydrochloride, anastrozole, letrozole, exemestane, vorozole, formestane, etc.), antiandrogens (e.g., flutamide, enzalutamide, apalutamide, bicalutamide, nilutamide, etc.), adrenocortical hormone drugs (e.g., dexamethasone, prednisolone, betamethasone, triamcinolone, etc.), androgen synthesis inhibitors (e.g., abiraterone, etc.), retinoids, and agents that slow the metabolism of retinoids (e.g., liarozole, etc.).

[0251] Examples of "chemotherapeutic agents" that can be used include alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents, molecular targeted therapeutic agents, immunomodulators, and other chemotherapeutic agents. Representative examples are listed below.

[0252] Examples of the "alkylating agent" include nitrogen mustard, nitrogen mustard-N-oxide hydrochloride, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, carboquone, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, melphalan, dacarbazine, ranimustine, estramustine sodium phosphate, triethylenemelamine, carmustine, lomustine, streptozotocin, Examples of drugs include benzodiazepine, pipobroman, etoglucide, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine, pumitepa, ribomustine, temozolomide, treosulfan, trofosfamide, zinostatin stimalamer, adozelesin, systostin, bizelesin, trabectedin, and DDS formulations thereof.

[0253] Examples of "antimetabolites" include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed, eocitabine, cytarabine, cytarabine ocfosfate, ancitabine hydrochloride, 5-FU drugs (e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur, galocitabine, emitefur, capecitabine, etc.), aminopterin, nelzarabine, leucoporin calcium, tabloid, butosin, folinate calcium, levofolinate calcium, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, piritrexim, idoxuridine, mitoguazone, tiazofurin, ambamustine, bendamustine, and DDS preparations thereof.

[0254] Examples of "anticancer antibiotics" include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, neocarzinostatin, mithramycin, sarkomycin, carzinophilin, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, eribulin, and DDS preparations thereof.

[0255] Examples of "plant-derived anticancer agents" include etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, DJ-927, vinorelbine, irinotecan, topotecan, and DDS formulations thereof.

[0256] Examples of "molecular targeted therapeutic agents" include imatinib, gefitinib, erlotinib, sorafenib, dasatinib, sunitinib, nilotinib, lapatinib, pazopanib, ruxolitinib, crizotinib, vemurafenib, vandetanib, ponatinib, cabozantinib, tofacitinib, regorafenib, bosutinib, axitinib, dabrafenib, trametinib, nintedanib, idelalisib, ceritinib, lenvatinib, palbociclib, alectinib, afatinib, osimertinib, ribociclib, and abemaciclib. , brigatinib, neratinib, copanlisib, cobimetinib, ibrutinib, acalabrutinib, encorafenib, binimetinib, baricitinib, fostamatinib, lorlatinib, erdafitinib, entrectinib, dacomitinib, sirolimus, everolimus, temsirolimus, olaparib, rucaparib, niraparib, venetoclax, azacitidine, decitabine, vorinostat, panobinostat, romidepsin, bortezomib, carfilzomib, larotrectinib, and ixazomib.

[0257] "Immunomodulators" include, for example, lenalidomide and pomalidomide.

[0258] Examples of "other chemotherapeutic agents" include sobuzoxane.

[0259] Examples of "immunotherapeutic agents (BRM)" include picibanil, krestin, sizofiran, lentinan, ubenimex, interferon, interleukin, macrophage colony-stimulating factor, granulocyte colony-stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, Corynebacterium parvum, levamisole, polysaccharide K, procodazole, anti-CTLA4 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, and Toll-like receptor agonists (e.g., TLR7 agonist, TLR8 agonist, TLR9 agonist, etc.).

[0260] The cell growth factor in the drug that inhibits the action of cell growth factors and their receptors may be any substance that promotes cell growth, and typically includes a peptide with a molecular weight of 20,000 or less that exerts its effect at low concentrations by binding to a receptor. Specifically, EGF (epidermal growth factor) or a substance having substantially the same activity as EGF (e.g., TGFalpha, etc.), insulin or a substance having substantially the same activity as insulin (e.g., insulin, IGF (insulin-like growth factor)-1, IGF-2, etc.), FGF (fibroblast growth factor) or a substance having substantially the same assay as FGF (e.g., acidic FGF, basic FGF, KGK (keratinocyte growth factor), FGF-10, etc.), and other cell growth factors (e.g., CSF (colony stimulating factor), EPO (erythropoietin), IL-2 (interleukin-2), NGF (nerve growth factor), etc.). growth factor), PDGF (platelet-derived growth factor), TGF-beta (transforming growth factor beta), HGF (hepatocyte growth factor), VEGF (vascular endothelial growth factor), heregulin, angiopoietin, etc.

[0261] The administration period of the compound of the present disclosure and the concomitant drug is not limited, and they may be administered to the subject simultaneously or at staggered times. The compound of the present disclosure and the concomitant drug may also be used as a combination drug. The dose of the concomitant drug can be appropriately selected based on clinically used doses. The compounding ratio of the compound of the present disclosure to the concomitant drug can be appropriately selected depending on the subject, administration route, target disease, symptoms, combination, etc. For example, when the subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present disclosure. Furthermore, for the purpose of suppressing side effects, the compound of the present disclosure may be used in combination with drugs (concomitant drugs) such as antiemetics, hypnotics, and anticonvulsants.

[0262] In this specification, "or" is used when "at least one or more" of the items listed in the sentence can be employed. The same applies to "alternative." When specified in this specification as "within a range of two values," the range includes the two values ​​themselves.

[0263] All references cited herein, including scientific literature, patents, patent applications, and the like, are incorporated by reference in their entirety to the same extent as if each were specifically set forth.

[0264] The present disclosure has been described above by showing preferred embodiments for ease of understanding. The present disclosure will be described below based on examples. However, the above description and the following examples are provided for illustrative purposes only and are not intended to limit the present disclosure. Therefore, the scope of the present invention is not limited to the embodiments or examples specifically described herein, but is limited only by the claims.

[0265] The present disclosure will be explained in more detail below with reference to Reference Examples, Examples and Test Examples, but the present invention is not limited thereto.

[0266] The following abbreviations may be used herein: Ts: p-toluenesulfonyl THF: tetrahydrofuran TFA: trifluoroacetic acid DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide MeCN: acetonitrile Me: methyl Boc: tert-butoxycarbonyl Dess-Martin reagent: Dess-Martin periodinane (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one) SEMCl: 2-(trimethylsilyl)ethoxymethyl chloride DIEA: N,N-diisopropylethylamine PTSA: p-toluenesulfonic acid NIS: N-iodosuccinimide DMAP: 4-dimethylaminopyridine MOMCl: chloromethyl methyl ether p-TsCl: p-toluenesulfonyl chloride TBAI: tetrabutylammonium iodide

[0267] The NMR (Nuclear Magnetic Resonance) data used for compound identification was obtained using a JNM-ECS400 nuclear magnetic resonance spectrometer (400 MHz) manufactured by JEOL Ltd.

[0268] Symbols used in NMR include s for singlet, d for doublet, dd for doublet of doublets, t for triplet, td for doublet of triplets, q for quartet, m for multiplet, br for broad, brs for broad singlet, brm for broad multiplet, and J for coupling constant.

[0269] The LC / MS (Liquid Chromatography-Mass Spectrometry) analysis conditions used for compound identification are as follows: Among the observed mass spectrometry values ​​[MS (m / z)], the value corresponding to the monoisotopic mass (accurate mass consisting of only the main isotope) was defined as [M+H]. ＋ , [M-H] － or [M+2H] ２＋ etc., and retention time is indicated as Rt (min).

[0270] LC / MS measurement method: Analysis condition A Detector: ACQUITY (registered trademark) SQ detector (Waters) HPLC: ACQUITY UPLC (registered trademark) system Column: Waters ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm, 2.1 mm × 30 mm) Solvent: Solution A: 0.06% formic acid / 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℃

[0271] Measurement condition B Detection equipment: Shimadzu LCMS-2020 system Column: L-column-2 ODS (4.6 mm x 35 mm) Gradient condition: MeCN / H ２ O / HCO ２ H=10 / 90 / 0.1 → 100 / 0 / 0.1 (0-2min), 100 / 0 / 0.1 (2-4min) Flow rate: 2mL / min Column temperature: 40℃

[0272] Reference Example 1: tert-butyl (3-{[8-(3-amino-1H-pyrazol-5-yl)quinolin-7-yl]oxy)propyl)carbamate

[0273] a) Preparation of 8-bromo-7-{[2-(trimethylsilyl)ethoxy]methoxy}quinoline SEMCl (1.25 mL) and DIEA (1.66 mL) were added to a solution of 8-bromo-7-quinolinol (1.06 g) in DMF (23.7 mL) under ice-cooling, and the mixture was stirred at 0°C for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.66 g). LC-MS: 354.1, 356.1 / Rt (min) 1.170 (measurement condition A).

[0274] b) Preparation of ethyl 7-{[2-(trimethylsilyl)ethoxy]methoxy}quinoline-8-carboxylate. To a solution of 8-bromo-7-{[2-(trimethylsilyl)ethoxy]methoxy}quinoline (1.65 g) in THF (23.3 mL), n-butyllithium (2.69 M, 2.60 mL) was added dropwise at −78° C., and the mixture was stirred for 30 minutes. Ethyl chloroformate (2.22 mL) was added at −78° C., and the mixture was further stirred at −78° C. for 15 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, then filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.25 g). LC-MS; [M+H] ＋ 348.0 / Rt (min) 1.146 (measurement condition A)

[0275] c) Preparation of ethyl 7-hydroxyquinoline-8-carboxylate PTSA monohydrate (137 mg) was added to a solution of ethyl 7-{[2-(trimethylsilyl)ethoxy]methoxy}quinoline-8-carboxylate (1.25 g) in ethanol (18.0 mL) at room temperature, and the mixture was stirred at 50° C. for 5 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (781 mg) as a crude product. LC-MS; [M+H] ＋ 218.1 / Rt (min) 0.441 (measurement condition A)

[0276] d) Preparation of ethyl 7-[3-{(tert-butoxycarbonyl)amino}propoxy]quinoline-8-carboxylate Potassium carbonate (994 mg) and t-butyl N-(3-bromopropyl)carbamate (1.28 g) were added to a solution of ethyl 7-hydroxyquinoline-8-carboxylate (781 mg) in DMF (18.0 mL) at room temperature, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by aminosilica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.29 g). LC-MS: [M+H] ＋ 375.0 / Rt (min) 0.882 (measurement condition A)

[0277] e) Preparation of tert-butyl (3-{[8-(2-cyanoacetyl)quinolin-7-yl]oxy}propyl)carbamate To a solution of MeCN (0.283 mL) in THF (13.6 mL) was added dropwise n-butyllithium (1.58 M, 2.58 mL) at −78° C., and the mixture was stirred at −78° C. for 1 hour. Ethyl 7-[3-{(tert-butoxycarbonyl)amino}propoxy]quinoline-8-carboxylate (1.02 g) in THF (13.6 mL) was added at −78° C., and the mixture was stirred at −78° C. for an additional 2.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, then filtered off, and the solvent was evaporated under reduced pressure to give the title compound (1.00 g) as a crude product. LC-MS; [M+H] ＋ 370.3 / Rt (min) 0.808 (measurement condition A)

[0278] f) Preparation of tert-butyl (3-{[8-(3-amino-1H-pyrazol-5-yl)quinolin-7-yl]oxy}propyl)carbamate (Reference Example 1) To a solution of tert-butyl (3-{[8-(2-cyanoacetyl)quinolin-7-yl]oxy}propyl)carbamate (1.00 g) in ethanol (13.6 mL) were added acetic acid (1.32 mL) and hydrazine monohydrate (1.55 mL) at room temperature, and the mixture was stirred under reflux for 2.5 hours. After cooling, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, then filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by aminosilica gel column chromatography (chloroform / methanol) to obtain Reference Example 1 (224 mg). LC-MS; [M+H] ＋ 384.3 / Rt (min) 0.685 (measurement condition A)

[0279] Reference Example 2: tert-butyl {[1-({[4-(3-amino-1H-pyrazol-5-yl)-1,5-naphthyridin-3-yl]oxy}methyl)cyclopropyl]methyl}carbamate

[0280] a) Preparation of 4-iodo-3-{[2-(trimethylsilyl)ethoxy]methoxy}-1,5-naphthyridine PTSA monohydrate (6.51 g) and NIS (11.6 g) were added to a solution of 1,5-naphthyridin-3-ol (5.00 g) in MeCN (86.0 mL) at room temperature, and the mixture was stirred at 60°C for 2 hours. The reaction mixture was concentrated and dissolved in DMF (50.0 mL). SEMCl (6.00 mL) and DIEA (29.8 mL) were added under ice-cooling, and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (10.7 g). LC-MS; [M+H] ＋ 403.2 / Rt (min) 1.168 (measurement condition A)

[0281] b) Preparation of ethyl 3-{[2-(trimethylsilyl)ethoxy]methoxy}-1,5-naphthyridine-4-carboxylate. To a solution of 4-iodo-3-{[2-(trimethylsilyl)ethoxy]methoxy}-1,5-naphthyridine (805 mg) in THF (10.0 mL) was added dropwise n-butyllithium (2.69 M, 1.12 mL) at −78° C., and the mixture was stirred for 30 minutes. Ethyl chloroformate (0.950 mL) was added at −78° C., and the mixture was further stirred at −78° C. for 15 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, then filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (492 mg). LC-MS; [M+H] ＋ 350.2 / Rt (min) 1.109 (measurement condition A)

[0282] c) Preparation of ethyl 3-hydroxy-1,5-naphthyridine-4-carboxylate PTSA monohydrate (461 mg) was added to a solution of ethyl 3-{[2-(trimethylsilyl)ethoxy]methoxy}-1,5-naphthyridine-4-carboxylate (845 mg) in ethanol (12.1 mL) at room temperature, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (324 mg). LC-MS: [M+H] ＋ 219.1 / Rt (min) 0.453 (measurement condition A)

[0283] d) Preparation of ethyl 3-[(1-{[(tert-butoxycarbonyl)amino]methyl}cyclopropyl)methoxy]-1,5-naphthyridine-4-carboxylate To a solution of ethyl 3-hydroxy-1,5-naphthyridine-4-carboxylate (162 mg) and 1,1'-dimethylethyl N-[[1-(hydroxymethyl)cyclopropyl]methyl]carbamate (299 mg) in THF (3.71 mL) was added 1,1'-(azodicarbonyl)dipiperidine (375 mg) at room temperature, and then tributylphosphine (0.366 mL) was added dropwise under ice-cooling, followed by stirring at room temperature for 3 hours. The reaction solution was filtered through Celite, and water was added to the filtrate, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, then filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by aminosilica gel column chromatography (hexane / ethyl acetate) to give the title compound (298 mg). LC-MS: [M+H] ＋ 403.3 / Rt (min) 0.930 (measurement condition A)

[0284] e) Preparation of tert-butyl {[1-({[4-(2-cyanoacetyl)-1,5-naphthyridin-3-yl]oxy}methyl)cyclopropyl]methyl}carbamate To a solution of MeCN (0.116 mL) in THF (3.71 mL) was added dropwise at −78° C., followed by stirring for 1 hour. Ethyl 3-[(1-{[(tert-butoxycarbonyl)amino]methyl}cyclopropyl)methoxy]-1,5-naphthyridine-4-carboxylate (298 mg) in THF (3.71 mL) was added at −78° C., followed by stirring at −78° C. for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title compound (294 mg) as a crude product. LC-MS: [M+H] ＋ 397.3 / Rt (min) 0.890 (measurement condition A)

[0285] f) Preparation of tert-butyl {[1-({[4-(3-amino-1H-pyrazol-5-yl)-1,5-naphthyridin-3-yl]oxy}methyl)cyclopropyl]methyl}carbamate (Reference Example 2) Acetic acid (0.425 mL) and hydrazine monohydrate (0.360 mL) were added to a solution of tert-butyl {[1-({[4-(2-cyanoacetyl)-1,5-naphthyridin-3-yl]oxy}methyl)cyclopropyl]methyl}carbamate (294 mg) in ethanol (3.71 mL) at room temperature, and the mixture was stirred under reflux for 5 hours. After cooling, water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, then filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by amino silica gel column chromatography (hexane / ethyl acetate) to obtain Reference Example 2 (87.2 mg). LC-MS; [M+H] ＋ 411.4 / Rt (min) 0.712

[0286] Reference Example 3: tert-Butyl 3-methyl-3-[(tosyloxy)methyl]azetidine-1-carboxylate

[0287] Preparation of tert-butyl 3-methyl-3-[(tosyloxy)methyl]azetidine-1-carboxylate (Reference Example 3) DMAP (0.182 g), triethylamine (1.39 mL), and p-TsCl (1.42 g) were added to a solution of t-butyl 3-(hydroxymethyl)-3-methylazetidine-1-carboxylate (1.00 g) in dichloromethane (16.6 mL) at room temperature, 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. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, then filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain Reference Example 3 (1.04 g). LC-MS; [M+H] ＋ 356.2 / Rt (min) 1.066 (measurement condition A)

[0288] Reference Example 4: tert-Butyl 3-({[7-(3-amino-1H-pyrazol-5-yl)-2,3-dihydrofuro[3,2-b]pyridin-6-yl]oxy}methyl)-3-methylazetidine-1-carboxylate

[0289] a) Preparation of 6-(methoxymethoxy)furo[3,2-b]pyridine To a solution of 1-(7-hydroxyquinolin-8-yl)ethan-1-one (3.00 g) in DMF (40.0 mL), potassium carbonate (6.14 g) and MOMCl (1.84 mL) were added dropwise under ice-cooling, and the mixture was stirred at room temperature for 4 hours. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by aminosilica gel column chromatography (chloroform / methanol) to give the title compound (2.00 g). LC-MS; [M+H] ＋ 181.1 / Rt (min) 0.602 (measurement condition A)

[0290] b) Preparation of 6-(methoxymethoxy)-2,3-dihydrofuro[3,2-b]pyridine To a solution of 6-(methoxymethoxy)furo[3,2-b]pyridine (5.00 g) in ethanol (20.0 mL), 10% palladium-carbon (2.97 g) was added at room temperature, and the mixture was stirred under a hydrogen atmosphere at room temperature for 8 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by aminosilica gel column chromatography (chloroform / methanol) to give the title compound (4.00 g). LC-MS; [M+H] ＋ 183.1 / Rt (min) 0.525 (measurement condition A)

[0291] c) Preparation of 7-bromo-6-(methoxymethoxy)-2,3-dihydrofuro[3,2-b]pyridine To a solution of 6-(methoxymethoxy)-2,3-dihydrofuro[3,2-b]pyridine (1.37 g) in THF (20.0 mL), n-butyllithium (2.60 M, 3.49 mL) was added dropwise at −78° C., and the mixture was stirred for 1 hour. Br2 (0.584 mL) was added at −78° C., and the mixture was further stirred at −78° C. for 2 hours. A 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, then filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.00 g). LC-MS: 260.1, 262.1 / Rt (min) 0.720 (measurement condition A).

[0292] d) Preparation of 7-(1-ethoxyvinyl)-6-(methoxymethoxy)-2,3-dihydrofuro[3,2-b]pyridine. To a solution of 7-bromo-6-(methoxymethoxy)-2,3-dihydrofuro[3,2-b]pyridine (1.44 g) in 1,4-dioxane (20.0 mL), tributyl(1-ethoxyvinyl)stannane (2.75 mL) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.904 g) were added under ice-cooling, and the mixture was stirred at 120°C for 15 hours. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.14 g). LC-MS [M+H] ＋ 252.2 / Rt (min) 0.741 (measurement condition A)

[0293] e) Preparation of 1-(6-hydroxy-2,3-dihydrofuro[3,2-b]pyridin-7-yl)ethan-1-one To a solution of 7-(1-ethoxyvinyl)-6-(methoxymethoxy)-2,3-dihydrofuro[3,2-b]pyridine (1.50 g) in methanol (20.0 mL) was added 5M aqueous HCl solution (2.00 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (567 mg). LC-MS; [M+H] ＋ 180.0 / Rt (min) 0.618 (measurement condition A)

[0294] f) Preparation of tert-butyl 3-{[(7-acetyl-2,3-dihydrofuro[3,2-b]pyridin-6-yl)oxy]methyl}-3-methylazetidine-1-carboxylate. To a solution of 1-(6-hydroxy-2,3-dihydrofuro[3,2-b]pyridin-7-yl)ethan-1-one (420 mg) in DMF (20.0 mL) were added Reference Example 3 (1.25 g), TBAI (43.3 mg), and cesium carbonate (1.53 g) under ice-cooling, and the mixture was stirred at room temperature for 12 hours. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (400 mg). LC-MS; [M+H] ＋ 363.3 / Rt (min) 0.886 (measurement condition A)

[0295] g) Preparation of tert-butyl (E)-3-[({7-[3-(dimethylamino)acroyl]-2,3-dihydrofuro[3,2-b]pyridin-6-yl}oxy)methyl]-3-methylazetidine-1-carboxylate To a solution of tert-butyl 3-{[(7-acetyl-2,3-dihydrofuro[3,2-b]pyridin-6-yl)oxy]methyl}-3-methylazetidine-1-carboxylate (400 mg) in DMF (10.0 mL) was added N,N-dimethylformamide dimethyl acetal (1.32 g) under ice-cooling, and the mixture was stirred at 115°C for 3 hours. The reaction mixture was concentrated to obtain the title compound (440 mg) as a crude product. LC-MS; [M+H] ＋ 419.4 / Rt (min) 0.726 (measurement condition A)

[0296] h) Preparation of tert-butyl 3-({[7-(isoxazol-5-yl)-2,3-dihydrofuro[3,2-b]pyridin-6-yl)oxy]methyl}-3-methylazetidine-1-carboxylate To a solution of tert-butyl (E)-3-[({7-[3-(dimethylamino)acroyl]-2,3-dihydrofuro[3,2-b]pyridin-6-yl}oxy)methyl]-3-methylazetidine-1-carboxylate (440 mg) in ethanol (30.0 mL) was added hydroxylamine hydrochloride (880 mg) under ice-cooling, and the mixture was stirred at 65°C for 2 hours. Saturated brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (200 mg). LC-MS; [M+H] ＋ 388.3 / Rt (min) 0.918 (measurement condition A)

[0297] i) Preparation of tert-butyl 3-({[7-(2-cyanoacetyl)-2,3-dihydrofuro[3,2-b]pyridin-6-yl)oxy]methyl}-3-methylazetidine-1-carboxylate To a solution of tert-butyl 3-({[7-(isoxazol-5-yl)-2,3-dihydrofuro[3,2-b]pyridin-6-yl)oxy]methyl}-3-methylazetidine-1-carboxylate (260 mg) in ethanol / HO (4:1, 25 mL) was added potassium hydroxide (75.0 mg) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered off to obtain the title compound (250 mg) as a crude product. LC-MS; [M+H] ＋ 388.3 / Rt (min) 0.921 (measurement condition A)

[0298] j) Preparation of tert-butyl 3-({[7-(3-amino-1H-pyrazol-5-yl)-2,3-dihydrofuro[3,2-b]pyridin-6-yl]oxy}methyl)-3-methylazetidine-1-carboxylate (Reference Example 4) To a solution of tert-butyl 3-({[7-(2-cyanoacetyl)-2,3-dihydrofuro[3,2-b]pyridin-6-yl)oxy]methyl}-3-methylazetidine-1-carboxylate (250 mg) in ethanol (10.0 mL) were added acetic acid (0.369 mL) and hydrazine monohydrate (0.314 mL) at 0° C., and the mixture was stirred under reflux for 2 hours. After cooling, a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then filtered off to obtain Reference Example 4 (100 mg) as a crude product. LC-MS; [M+H] ＋ 402.4 / Rt (min) 0.720 (measurement condition A)

[0299] Reference Example 5: 1-(6-hydroxy-2-methylbenzo[d]oxazol-7-yl)ethan-1-one

[0300] Preparation of 1-(6-hydroxy-2-methylbenzo[d]oxazol-7-yl)ethan-1-one (Reference Example 5) 4.5% palladium (1.44 g) was added to a solution of 1-(2,6-dihydroxy-3-nitrophenyl)ethan-1-one (2.40 g) in ethanol (30.0 mL) at room temperature, and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated. The residue was dissolved in methanol (30.0 mL), and trimethyl orthoacetate (3.05 mL) and hydrochloric acid (0.051 mL) were added, followed by stirring under reflux for 5 hours. The reaction solution was concentrated, and water was added to the residue, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and then filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain Reference Example 5 (0.550 g). LC-MS; [M+H] ＋ 192.1 / Rt (min) 0.728 (measurement condition A)

[0301] Reference Example 6: Ethyl 6-(methoxymethoxy)pyrazolo[1,5-a]pyrimidine-7-carboxylate

[0302] a) Preparation of 6-(methoxymethoxy)pyrazolo[1,5-a]pyrimidine MOMCl (1.25 mL) was added to a solution of pyrazolo[1,5-a]pyrimidin-6-ol (1.50 g) and DIEA (3.83 mL) in THF (50.0 mL) under ice-cooling, and the mixture was stirred at room temperature for 12 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.10 g). LC-MS; [M+H] ＋ 180.1 / Rt (min) 0.539 (measurement condition A)

[0303] b) Preparation of ethyl 6-(methoxymethoxy)pyrazolo[1,5-a]pyrimidine-7-carboxylate (Reference Example 6) n-BuLi (1.58 M, 0.389 mL) was added dropwise to a solution of diisopropylamine (87.0 μL) in THF (5.00 mL) at −78° C., and the mixture was stirred at 0° C. for 15 minutes. A THF solution of 6-(methoxymethoxy)pyrazolo[1,5-a]pyrimidine (100 mg) was added dropwise to the reaction mixture, and the mixture was stirred at −78° C. for 30 minutes. Ethyl chloroformate (70.0 μL) was then added, and the mixture was allowed to react for an additional 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then filtered to give Reference Example 6 (52.0 mg). LC-MS; [M+H] ＋ 252.2 / Rt (min) 0.741 (measurement condition A)

[0304] Reference Examples 7 to 32: Using the corresponding starting compounds, the compounds of Reference Examples 7 to 32 shown in the table below were obtained in the same manner as in Reference Examples 1 to 5.

[0305] Reference Example 20: tert-Butyl {3-[(8-{3-[(5-cyanopyrazin-2-yl)amino]-1H-pyrazol-5-yl}quinolin-7-yl)oxy]propyl}carbamate

[0306] Preparation of tert-butyl {3-[(8-{3-[(5-cyanopyrazin-2-yl)amino]-1H-pyrazol-5-yl}quinolin-7-yl)oxy]propyl}carbamate (Reference Example 20) To a solution of Reference Example 1 (219 mg) in DMSO (2.50 mL) were added 4-ethylmorpholine (0.108 mL) and 5-chloropyrazine-2-carbonitrile (96.0 mg) at room temperature, followed by stirring at 80°C for 2 hours. The reaction solution was ice-cooled, and ice-cooled methanol (7.50 mL) was added, followed by stirring at 0°C for an additional 1 hour. The resulting precipitate was collected by filtration, washed with ice-cooled methanol, and the resulting solid was dried to give Reference Example 20 (81.6 mg). LC-MS; [M+H] ＋ 487.4 / Rt (min) 0.891

[0307] Reference example 21:

[0308] Preparation of Reference Example 21 To a solution of Reference Example 17 (600 mg) in 1,4-dioxane (10.0 mL), 2,5-dichloropyrazine (319 μL), tris(dibenzylideneacetone)dipalladium(0) (146 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (185 mg), and cesium carbonate (1041 mg) were added at room temperature, and the mixture was stirred at 150°C for 2 hours under microwave irradiation. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, then filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by amino silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound as a crude product. LC-MS; [M+H] ＋ 488.2 / Rt (min) 1.022 (measurement condition A)

[0309] Reference Examples 22 to 57: Using the corresponding starting compounds, the compounds of Reference Examples 22 to 57 shown in the table below were obtained in the same manner as in Reference Example 20.

[0310] Example 1: 5-({5-[7-(3-aminopropoxy)quinolin-8-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile

[0311] Tert-butyl {3-[(8-{3-[(5-cyanopyrazin-2-yl)amino]-1H-pyrazol-5-yl}quinolin-7-yl)oxy]propyl}carbamate (79.4 mg) obtained in Reference Example 20 was dissolved in formic acid (3.00 mL) and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, the residue was suspended in ethyl acetate, and the resulting precipitate was collected by filtration. The collected solid was suspended in ethanol / water (2:1, 6 mL) and heated to 90°C, followed by the addition of 2M aqueous potassium phosphate trihydrate (0.10 mL), ice-cooling, and stirring at 0°C for 30 minutes. The resulting solid was collected by filtration, washed with water, ice-cooled ethanol, and diethyl ether, and the resulting solid was dried to obtain Example 1 (51.8 mg). LC-MS; [M+H] ＋ 387.2 / Rt (min) 0.552 1 H-NMR (DMSO-D6) δ: 8.96 (1H, dd, J = 4.3, 1.8 Hz), 8.68 (1H, d, J=1.2 Hz), 8.51 (1H, br s), 8.40 (1H, dd, J = 8.5, 1.8 Hz), 8.02 (1H, d, J =9.1Hz), 7.69 (1H, d, J = 9.1 Hz), 7.48 (1H, dd, J = 8.5, 4.3 Hz), 7.41 (1H, brs),4.36 (2H, t,J = 6.1 Hz), 2.83 (2H, t, J = 6.4 Hz), 1.97-1.91 (2H, m).

[0312] Examples 2 to 38: Using the corresponding starting compounds, the compounds of Examples 2 to 38 shown in the table below were obtained in the same manner as in Example 1. Test Example

[0313] Test Example 1: CHK1 inhibitory activity test IMAP TR-FRET Screening Express Kit (R8160) was obtained from Molecular Device, Inc. CHK1 kinase (02-117, Carna Bio), FAM-labeled CHK1tide (R7185, Molecular Device, Inc.), and ATP were diluted with assay buffer to final concentrations of 4 μg / mL, 2 μM, and 20 μM, respectively. FAM-PKAtide (R7255, Molecular Device) and FAM-Phospho-PKAtide (R7304, Molecular Device) were diluted and mixed to create a calibration standard series with phosphorylation levels ranging from 0 to 100%. 5 μL of compound dissolved in 0.4% DMSO was added to a 384-well plate. A compound test group was added with 5 μL each of CHK1, CHK1tide, and ATP, and a standard group was added with 20 μL each of the standard. The kinase reaction was carried out at 30°C for 3 hours. Then, 60 μL of Binding Reagent (80% Buffer A, 20% Buffer B, 1:600 ​​Binding Reagent, 1:400 Tb-Donor) was added, and the binding reaction was carried out at room temperature for 2 hours. Fluorescence intensities at 520 nm and 490 nm upon excitation at 340 nm were measured using a SpectraMax Paradigm (Molecular Devices). The phosphorylation level of CHK1tide was calculated using the standard. The DMSO-treated group was set to a phosphorylation level of 100%, and kinase activity was calculated using the formula below. The IC40 corresponding to the concentration of the compound at which kinase activity was 50% was calculated. ５０ The value was calculated.

[0314] Kinase inhibition (%) = 100 - A / B x 100 A: Signal in the presence of the compound to be evaluated B: Signal in the negative control (DMSO-treated group)

[0315] The compounds obtained in the Examples and Plexasertib purchased from MedChemExpress (the same supplier was used in the following Test Examples) were subjected to the test shown in Test Example 1. ５０ The values ​​(nM) are shown in the table below.

[0316] As shown in the above table, the compounds of Examples 1 to 6, 8, 10 to 32, 36 and 37 exhibited stronger inhibitory effects on CHK1 activity than prexasertib.

[0317] Test Example 2: Cell proliferation inhibition experiment ES-2 cells were obtained from the American Type Culture Collection (ATCC). The cells were cultured in McCoy's 5a medium containing 10% fetal bovine serum and 1% penicillin / streptomycin at 37°C and 5% CO ２ 500 cells were seeded per well in a 384-well plate, and the test compound was added so that the final DMSO concentration was 0.1%, followed by culturing for 2 days. After the culture was completed, the cell viability was calculated using CellTiter-Glo® 3D Reagent (Promega, G968B). From the viability curve, the IC value, which corresponds to the concentration of the test compound that shows 50% inhibition of cell proliferation, was determined. ５０ The value was calculated.

[0318] The compounds obtained in the Examples and Prexasertib were subjected to the test shown in Test Example 2. The concentration of each test substance that inhibits 50% of cell growth (IC ５０ The values ​​(nM) are shown in the table below.

[0319] As shown in the above table, the compounds of Examples 1 to 6, 8 to 15, 17 to 32, 34 to 37 and 38 exhibited good cell growth inhibitory effects equivalent to those of prexasertib.

[0320] Test Example 3: hERG current inhibition test Test substances were added to cultured CHO cell lines stably expressing the hERG (human Ether-a-go-go Related Gene) gene at concentrations of 0.27 to 100 μM. hERG current under voltage stimulation was measured using Qube384 (Sophion Bioscience), and the concentration (IC) of each test substance at which the hERG current was inhibited by 50% was determined. ５０ The values ​​(μM) were calculated.

[0321] The compounds obtained in the Examples and Prexasertib were subjected to the test shown in Test Example 3. In addition, for the compounds of each Example, the IC value of hERG obtained in Test Example 3 was ５０ The IC value of ES-2 cell proliferation inhibition obtained in Test Example 2 was used. ５０ The value obtained by dividing by was calculated as hERG / ES-2. The results are shown in the table below.

[0322] As shown in the table above, the compounds of Examples 1, 8, 9, 10, 11, 13, 14, 21, 25, 26, 27, 28, 31, 35 and 38 had IC values ​​of 0.01 to 0.01 for inhibiting ES-2 cell proliferation. ５０ and hERG IC ５０ It was shown that there was a discrepancy of more than 800 times between the two.

[0323] The compounds of Examples 8, 9, 10, 13, 14, 25 and 28 had an IC ５０ and hERG IC ５０ These five compounds showed a difference of more than 3 times compared to prexasertib, and have heterogeneous effects with high safety.

[0324] Among them, the compounds of Examples 8 and 13 had IC values ​​of 0.01 and 0.02 for ES-2 cell proliferation inhibition. ５０ and hERG IC ５０ These two compounds showed a difference of more than 12 times compared to prexasertib, and have heterogeneous effects with high safety.

[0325] Test Example 4. Liposome Encapsulation Test A liposome encapsulation test was carried out for representative example compounds and prexasertib.

[0326] 6.48 g of hydrogenated soybean phosphatidylcholine (COATSOME NC-21E, NOF Corporation), 2.32 g of cholesterol (Sigma), and 2.06 g of distearoylphosphatidylethanolamine-methoxypolyethylene glycol 2000 (SUNBRIGHT DSPE-020CN, NOF Corporation) were dissolved in 560 mL of t-butyl alcohol heated to 65°C. This solution was frozen in a dry ice-acetone bath, and then the t-butyl alcohol was removed by distillation under reduced pressure to obtain a lipid mixture.

[0327] To the lipid mixture, 200 mL of 250 mM ammonium sulfate solution was added, heated to 65°C, and dispersed using a homogenizer (ULTRA-TURRAX, manufactured by IKA Corporation) to obtain a crude liposome dispersion. The crude liposome dispersion was then dispersed using a high-pressure homogenizer (Nano-Mizer NM2, manufactured by Yoshida Kikai Kogyo Co., Ltd.) at 100 MPa to obtain liposomes with an average particle size (Z-average) of approximately 80 nm. Using a dialysis cassette (Slide-A-Lyzer G2 Dialysis Cassettes 20K MWCO, manufactured by Thermo Scientific), the outer aqueous phase of the liposomes was replaced with 10 mM L-histidine buffer / 10% sucrose solution (pH 6.5) to obtain a blank liposome solution. The mixture was filtered through a 0.22 μm membrane filter, and a 10 mM L-histidine buffer / 10% sucrose solution (pH 6.5) was added to adjust the total lipid concentration to 75 mM (75 μmol / mL) or 50 mM (50 μmol / mL). The amount of the mixture was adjusted as needed.

[0328] 2-3 mg of the test compound was weighed out, 1 mL of empty liposome solution with a total lipid concentration of 50 mM was added, and the pH was adjusted to 5.5-7 with 1 mol / L hydrochloric acid or 1 mol / L sodium hydroxide aqueous solution, and the mixture was heated in a water bath at 65°C for 10-30 minutes and then cooled on ice. Any insoluble matter was removed by centrifugation at 15,000 x g for 5 minutes.

[0329] The liposome encapsulation rate was calculated as follows. 100 μL of the liposome solution was placed in an ultrafiltration filter (Amicon Ultra, 100K, 0.5 mL, manufactured by Merck) and centrifuged at 4°C and 15,000 × g for 10 minutes. The compound concentration in the filtrate after ultrafiltration was measured by HPLC and used as the unencapsulated compound concentration. The liposome solution was diluted with a trifluoroacetic acid / water / methanol mixture (0.1 / 25 / 75) and allowed to stand at 5°C for 10 minutes or more. Insoluble matter was removed by centrifugation at 15,000 × g for 5 minutes, and the compound concentration in the supernatant was measured by HPLC and used as the compound concentration in the liposome solution. The encapsulation rate and encapsulation efficiency were calculated using the following formulas. Encapsulation rate (%) = (compound concentration in liposome solution - concentration of unencapsulated compound) x 100 / compound concentration in liposome solution Encapsulation efficiency (%) = (compound concentration in liposome solution - concentration of unencapsulated compound) x 100 / compound concentration at time of introduction

[0330] The HPLC measurement conditions are as follows: HPLC conditions Column: Acquity UPLC BEH C18, 1.7 μm, 50 × 2.1 mm Column temperature: 40°C Mobile phase: A: Water containing 0.1% trifluoroacetic acid B: Acetonitrile A / B (min): 95 / 5 (0) → 0 / 100 (3.5) → 0 / 100 (4) → 95 / 5 (4.01) → 95 / 5 (5) Flow rate: 0.8 mL / min Detection: UV-visible detector Measurement wavelength: 254 nm Injection volume: 2 to 5 μL

[0331]

[0332] It was confirmed that Prexasertib, Examples 1, 2, 6, 8, 10, 13, 14, 25, 27, 28, 36 and 38 were able to achieve a high encapsulation efficiency of 80% or more.

[0333] Test Example 5. Pharmacokinetics test The solution formulation of prexasertib, Examples 1, 2, 6, 8, 10, 13, 14, 25, 27, 28, 36, and 38, and the liposome formulation of prexasertib were intravenously administered to mice, and the concentrations of the test substances in the blood were measured.

[0334] For the solution formulation, the compound was dissolved in 10 mM glycine / 5% mannitol solution (pH 2) and then filtered through a 0.22 μm membrane filter.

[0335] The liposome preparations used were prepared by preparing liposomes encapsulating a test compound in the same manner as in Test Example 4, replacing the outer aqueous phase of the liposomes with 10 mM L-histidine buffer / 10% sucrose solution (pH 6.5) using a gel filtration column PD-10 (GE Healthcare), filtering the liposomes with a 0.22 μm membrane filter, and adjusting the concentration by adding 10 mM L-histidine buffer / 10% sucrose solution (pH 6.5).

[0336] <Administration test> The solution formulation or liposome formulation was intravenously administered to 7-week-old female BALB / c mice, and blood was collected from the jugular vein without anesthesia over time up to 72 hours after administration. Immediately after collection, four volumes of methanol were added to the blood, which was then centrifuged, and the concentration of the test compound in the resulting supernatant was quantified by LC-MS / MS.

[0337] The LC-MS / MS measurement conditions were as follows: HPLC: Prominence system (Shimadzu Corporation) MS / MS: 4000 QTRAP (SCIEX) Column: Cadenza CD-C18, 3 μm, 50 × 2 mm (Intact Corporation) Column temperature: 40°C Mobile phase: A: water containing 0.1% formic acid B: acetonitrile containing 0.1% formic acid A / B (min): 90 / 10 (0) → 10 / 90 (2.5) → 10 / 90 (3.5) → 90 / 10 (3.6) → 90 / 10 (5.0) Flow rate: 0.4 mL / min Detection: ESI (positive mode) Injection volume: 0.1 to 5 μL

[0338] The test results are shown in the tables below. In the tables, "mean" means the average and "S.D." means the standard deviation. The plasma concentrations of the test compound from 0 hours after administration to 72 hours after administration are shown in Tables 8 to 21.

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348] The AUC for the liposome formulations of Examples 1, 2, 6, 8, 10, 13, 14, 25, 27, 28, 36, 38 and prexasertib was calculated by the trapezoidal method from 0 hour after administration to the time point (t) at which the plasma test compound concentration could be quantified, and is shown in Table 22.

[0349] The above results confirmed that the liposome-encapsulated liposomes of Examples 1, 6, 8, 10, 13, 14, 27, 28, 36, and 38, when administered intravenously, each exhibited high blood retention. These results demonstrated the achievement of 72 hours of sustained exposure, which is important for maximizing the efficacy of prexasertib, as reported in non-clinical studies. Therefore, Examples 1, 6, 8, 10, 13, 14, 27, 28, 36, and 38 have excellent pharmacokinetic profiles and are highly useful as anticancer agents.

[0350] Test Example 6. Drug efficacy evaluation test using tumor-bearing mice transplanted with ES-2 cells. The antitumor activity was evaluated using a solution formulation of prexasertib and liposome formulations encapsulating Examples 8, 13 and 28.

[0351] The solution formulation of prexasertib was prepared by dissolving prexasertib in a 10 mM glycine / 5% mannitol solution (pH 2) containing 20% ​​sulfobutylether-β-cyclodextrin, and then filtering the solution through a 0.22 μm membrane filter.

[0352] A liposome formulation was prepared by the following method. A blank liposome solution with a total lipid concentration of 75 mM and an external aqueous phase of 10 mM L-histidine buffer / 9.4% sucrose solution (pH 6.5) was obtained in the same manner as in Test Example 4. A test compound was dispersed in 10 mM L-histidine buffer / 9.4% sucrose solution (pH 6.5), and the blank liposome solution was added to the solution so that the compound concentration was 2 mg / mL and the total lipid concentration was 50 mM, and the pH was adjusted to 6-7. This solution was heated in a 65°C water bath for 10 minutes, then cooled on ice and filtered through a 0.22 μm membrane filter.

[0353] 4-7 week-old BALB / c-nu / nu mice (CANN.Cg-Foxn1nu / CrlCrlj, female, Charles River Japan) were inoculated with 1 × 10 ES-2 cells (ATCC). ６ The tumors were intradermally transplanted around the ventral region to achieve a ratio of 1000 cells / mouse. After confirming the engraftment of ES-2 cells 5 to 14 days after transplantation, the solution formulation was administered intravenously once a week at a dose of 30 mg / kg or the liposome formulation at 4.5 mg / kg or 10 mg / kg. The tumor volume was measured over time from the start of administration, and the effect of compound administration on tumor volume reduction was evaluated. The tumor volume was calculated using the following formula, using the minor and major diameters of the tumor measured with an electronic caliper (Mitutoyo).

[0354] Tumor volume [mm ３ ] = 0.5×(breadth diameter [mm]) ２ × major axis [mm]

[0355] A control group administered with only the solvent was compared with a group administered with a compound of the present disclosure, and the T / C was calculated using the following formula to evaluate the antitumor effect. The percentage of individuals with complete tumor regression (CR) at the end of administration of the solution formulation or liposome formulation was also recorded. A blank liposome solution with a total lipid concentration of 50 mM was used as the control group.

[0356] T / C (%) = (tumor volume at the end of administration in the group administered with the compound of the present disclosure - tumor volume at the start of administration in the group administered with the compound of the present disclosure) / (tumor volume at the end of administration in the control administration group - tumor volume at the start of administration in the control administration group) × 100

[0357] Table 18 shows the T / C (%) and CR rate for tumor-bearing mice transplanted with ES-2 cells at each dose and administration period of the test compound.

[0358] In a drug efficacy evaluation test using tumor-bearing mice, liposome-formulated Examples 8, 13, and 28 achieved tumor regression at a dose of 10 mg / kg, which could not be achieved with the maximum tolerated dose of solution-formulated prexasertib. The results of this test demonstrate that Examples 8, 13, and 28 are promising compounds that exhibit excellent antitumor effects and have exceptional efficacy.

[0359] Test Example 7. Minimum effective dose evaluation test using tumor-bearing mice transplanted with ES-2 cells A minimum effective dose evaluation test was conducted in tumor-bearing mice transplanted with ES-2 cells in the same manner as in Test Example 6, using a solution formulation of prexasertib and liposome formulations encapsulating Examples 8 and 28.

[0360] The solution formulation of prexasertib was prepared by dissolving prexasertib in a 10 mM glycine / 5% mannitol solution (pH 2) containing 20% ​​sulfobutylether-β-cyclodextrin, and then filtering the solution through a 0.22 μm membrane filter.

[0361] The liposome formulations of Examples 8 and 28 were prepared by the following method. A blank liposome solution with a total lipid concentration of 75 mM and an external aqueous phase of 10 mM L-histidine buffer / 9.4% sucrose solution (pH 6.5) was prepared in the same manner as in Test Example 4. A test compound was dispersed in 10 mM L-histidine buffer / 9.4% sucrose solution (pH 6.5), and the blank liposome solution was added to the solution so that the compound concentration was 2 mg / mL and the total lipid concentration was 50 mM, and the pH was adjusted to 6-7. This solution was heated in a 65°C water bath for 10 minutes, then cooled on ice, and filtered through a 0.22 μm membrane filter.

[0362] The table below shows the T / C (%) and CR rate for tumor-bearing mice transplanted with ES-2 cells at each dose and administration period of the test compound.

[0363] In a drug efficacy evaluation test using tumor-bearing mice, liposomal formulations of Examples 8 and 28 achieved tumor regression effects at a dose of 1 mg / kg equal to or greater than the maximum tolerated dose of solution-formulated prexasertib. The results of this test showed that Examples 8 and 28 are promising compounds that exhibit antitumor effects at low doses and have particularly significant tumor regression effects.

[0364] Test Example 8. Measurement of neutrophil count using tumor-bearing mice transplanted with ES-2 cells 1×10 ES-2 cells (ATCC) were transplanted into 4- to 7-week-old BALB / c-nu / nu mice (CANN.Cg-Foxn1nu / CrlCrlj, female, Jackson Laboratory Japan). ６ The cells were intradermally transplanted around the abdominal region to form a 100% ES-2 cell / mouse ratio. After confirming the engraftment of ES-2 cells 5 to 18 days after transplantation, a liposome formulation encapsulating prexasertib and the liposome formulations encapsulating Examples 8 and 28 were administered intravenously in a single dose. After administration, blood was collected and the neutrophil count was measured. For comparison in this test, an empty liposome solution prepared in the same manner as in Test Example 4 was used.

[0365] A liposome formulation of plexasertib was prepared by the following method. A blank liposome solution with a total lipid concentration of 75 mM and an external aqueous phase of 10 mM L-histidine buffer / 10% sucrose solution (pH 6.5) was prepared in the same manner as in Test Example 4. plexasertib was added to the solution to a compound concentration of 3 mg / mL, and the pH was adjusted to 6-7. This solution was heated in a 65°C water bath for 15 minutes, then cooled on ice and filtered through a 0.22 μm membrane filter.

[0366] The liposome formulations of Examples 8 and 28 were prepared by the following method. A blank liposome solution with a total lipid concentration of 75 mM and an external aqueous phase of 10 mM L-histidine buffer / 9.4% sucrose solution (pH 6.5) was prepared in the same manner as in Test Example 4. A test compound was dispersed in 10 mM L-histidine buffer / 9.4% sucrose solution (pH 6.5), and the blank liposome solution was added to the solution so that the compound concentration was 2 mg / mL and the total lipid concentration was 50 mM, and the pH was adjusted to 6-7. This solution was heated in a 65°C water bath for 10 minutes, then cooled on ice, and filtered through a 0.22 μm membrane filter.

[0367] A control group administered with blank liposome solution was compared with treatment groups administered with liposome-formulated Examples 8 and 28 and liposome-formulated plexasertib, and the neutrophil survival rate was calculated using the following formula to evaluate the safety of each formulation.

[0368] Neutrophil survival rate (%) = (neutrophil count in the treatment group) / (neutrophil count in the control treatment group) × 100

[0369] The table below shows the neutrophil survival rate in tumor-bearing mice transplanted with ES-2 cells and the antitumor effect of each dose evaluated in the same manner as in Test Example 6. The antitumor effect was evaluated using TGI as an index, calculated using the following formula.

[0370] TGI (%) = {1 - (mean tumor volume of treatment group) / (mean tumor volume of control treatment group)} x 100

[0371] At a dose of 7.5 mg / kg, liposomal formulation of plexasertib showed a neutrophil survival rate of 4%, demonstrating both antitumor efficacy and hematotoxicity. On the other hand, liposomal formulations of Examples 8 and 28 showed stronger antitumor efficacy than liposomal formulation of plexasertib, a higher neutrophil survival rate, and reduced hematotoxic side effects at a dose of 4.5 mg / kg. These test results demonstrate that liposomal formulations of Examples 8 and 28 are superior compounds possessing both higher safety and efficacy than liposomal formulation of plexasertib, and exhibit exceptionally significant and unique effects.

[0372] Test Example 9. Cell proliferation inhibition test for various cancer cell lines HT1080 cells (derived from soft tissue sarcoma) were cultured in EMEM medium containing 10% fetal bovine serum and 1% penicillin / streptomycin at 37°C and 5% CO ２ SJCRH30 cells (derived from soft tissue sarcoma) and BxPC3 cells (derived from pancreatic cancer) were cultured in McCoy's 5a medium containing 10% fetal bovine serum and 1% penicillin / streptomycin at 37°C in 5% CO ２SW948 cells (derived from colon cancer) were cultured in L-15 medium containing 10% fetal bovine serum and 1% penicillin / streptomycin at 37°C under atmospheric conditions. Cells were seeded into a 96-well plate so that they were 70-90% confluent 96 hours after seeding, and the test compound was added to a final DMSO concentration of 0.1%, followed by culture for 3 days. After culture was completed, cell viability was calculated using CellTiter-Glo® 3D Reagent (Promega, G968B). From the viability curve, the IC value, which corresponds to the concentration of the test compound at which 50% cell growth inhibition was observed, was determined. ５０ The value was calculated.

[0373] The compounds obtained in the Examples and Prexasertib were subjected to the test shown in Test Example 2. The concentration of each test substance that inhibits 50% of cell growth (IC ５０ The values ​​(nM) are shown in the table below.

[0374] As shown in the table above, the compounds of Examples 8 and 28 exhibited stronger cell proliferation inhibitory effects than prexasertib against cancer cell lines derived from soft tissue sarcoma, pancreatic cancer, and colon cancer. The test results show that the compounds of Examples 8 and 28 have particularly significant cancer cell proliferation inhibitory effects against at least soft tissue sarcoma and pancreatic cancer.

[0375] Test Example 10. Human bone marrow cell colony formation test (blood toxicity evaluation test) For example, evaluation can be performed by the following method: Frozen human bone marrow CD34-positive hematopoietic stem cells were thawed in a 9:1 mixture of Methocult Express medium and RPMI 1640 medium containing 10% fetal bovine serum and 1% penicillin / streptomycin, and 5,000 cells were seeded per well in a 6-well plate. The cells were incubated at 37°C and 5% CO ２ The cells are cultured overnight in the presence of DMSO. The compound to be evaluated is added to a final concentration of 0.1% and 100 nM DMSO, and the cells are cultured for 48 hours. The cells are harvested and washed with PBS. One-sixth of the amount of cells is seeded into a 12-well plate and incubated at 37°C, 5% CO ２After completion of the culture, the number of colonies formed is counted using thiazolyl blue tetrazolium bromide (MTT).

[0376] Test Example 11. Kinase Selectivity Test For example, selectivity for various wild-type kinases can be evaluated using HotSpot Full Panel Kinase Profiling (Reaction Biology) under the following conditions: Buffer solution: 20 mM HEPES, pH 7.5, 10 mM MgCl, 2 mM MnCl (if necessary), 1 mM EGTA, 0.02% Brij35, 0.02 mg / mL BSA, 0.1 mM NaVO, 2 mM DTT, 1% DMSO ATP concentration: 10 μM Reaction time: 2 hours ATP conversion rate in 2 hours: 5 to 20% Compound concentration: 100 nM

[0377] Test Example 12: Cytotoxicity Test For example, cytotoxicity tests of various cells can be evaluated under the following conditions using OncoPanel Cell-Based Profiling Service (Eurofins).

[0378] Cells are seeded in a 384-well plate. Compounds are diluted 3.16-fold starting from 10 mM to create a 10-point dilution series. 24 hours after cell seeding, the diluted compounds and DMSO are added. Three days after compound addition, the cells are fixed, and the nuclei are stained and detected. Data from the compound-treated group for each cell group is normalized to vehicle data treated with 0.1% DMSO.

[0379] The compound represented by formula (6) has CHK1 inhibitory activity equal to or greater than that of prexasertib (Test Example 1) and exhibits a cell proliferation inhibitory effect of the same or greater degree (Test Example 2), while exhibiting lower cardiotoxicity than prexasertib (Test Example 3), thus exhibiting exceptionally significant and distinct effects. Furthermore, the compound represented by formula (6) can be efficiently encapsulated in liposomes by a simple encapsulation procedure (Test Example 4). The liposomally formulated compound represented by formula (6) exhibits favorable pharmacokinetics (Test Example 5) and exhibits exceptionally significant antitumor effects in tumor-bearing mice transplanted with ES-2 cells (Test Examples 6 and 7). While the liposomally formulated compound represented by formula (6) has such an excellent antitumor effect, it also exhibits a distinct effect in which the risk of hematotoxicity is significantly reduced compared to that of prexasertib (Test Example 8). In addition, the compound represented by formula (6) exhibits a stronger cell proliferation inhibitory effect than prexasertib against cancer cell lines derived from soft tissue sarcoma and pancreatic cancer, and has an exceptional cancer cell proliferation inhibitory effect (Test Example 9). As described above, the compound represented by formula (6) is particularly excellent in efficacy and safety among the compounds represented by formula (1), and has an exceptionally remarkable and unique effect that can exhibit an excellent antitumor effect with high safety when formulated in liposomes.

[0380] The compound of Example 8, a representative compound within formula (4), exhibits CHK1 inhibitory activity and cell proliferation inhibitory effect equivalent to or greater than that of prexasertib (Test Examples 1 and 2). Additionally, the compound of Example 8 exhibits a cell proliferation inhibitory activity and hERG inhibitory activity that differ by more than 5,000-fold, and exhibits exceptionally significant and heterogeneous effects with extremely low cardiotoxicity compared to prexasertib (Test Example 3). Furthermore, the compound of Example 8 was efficiently encapsulated in liposomes using a simple encapsulation procedure (Test Example 4), and the liposomal formulation exhibited favorable pharmacokinetics (Test Example 5). Furthermore, the liposomal formulation of the compound of Example 8 exhibited exceptional antitumor activity in tumor-bearing mice implanted with ES-2 cells (Test Examples 6 and 7), demonstrating a heterogeneous effect in which the risk of hematotoxicity is significantly reduced compared to that of liposomal formulation of prexasertib (Test Example 8). Furthermore, the compound of Example 8 exhibited a stronger cell proliferation inhibitory effect than prexasertib against cancer cell lines derived from soft tissue sarcoma and pancreatic cancer, and had an especially significant cancer cell proliferation inhibitory effect (Test Example 9). As described above, the compound of Example 8 is particularly excellent in efficacy and safety among the compounds represented by formula (4), and has an especially significant and unique effect that can exert an excellent antitumor effect with high safety by being formulated in a liposome.

[0381] The compounds of Examples 13 and 28, which are representative compounds of formula (6), have CHK1 inhibitory activity equivalent to or greater than that of prexasertib (Test Example 1). The compound of Example 13 exhibits a similar level of cell proliferation inhibitory effect, and the compound of Example 28 exhibits a cell proliferation inhibitory effect equivalent to or greater than that of prexasertib (Test Example 2). In addition, the compounds of Examples 13 and 28 have a cell proliferation inhibitory activity and a hERG inhibitory activity that differ by more than 1,500 times, and have exceptionally significant and distinct effects with extremely low cardiotoxicity compared to prexasertib (Test Example 3). Furthermore, the compounds of Examples 13 and 28 can be efficiently encapsulated in liposomes using a simple encapsulation procedure (Test Example 4), and these liposome formulations exhibit good pharmacokinetics (Test Example 5). Furthermore, the liposomally formulated compounds of Examples 13 and 28 exhibited exceptionally remarkable antitumor effects in tumor-bearing mice transplanted with ES-2 cells (Test Examples 6 and 7), and the liposomally formulated compound of Example 28 exhibited a heterogeneous effect in which the risk of hematotoxicity was significantly reduced compared to liposomally formulated prexasertib (Test Example 8). Furthermore, the compound of Example 28 exhibited a more potent cell proliferation inhibitory effect than prexasertib against cancer cell lines derived from soft tissue sarcoma and pancreatic cancer, demonstrating exceptional cancer cell proliferation inhibitory effects (Test Example 9). From the above, the compounds of Examples 13 and 28 are particularly excellent in efficacy and safety among the compounds represented by formula (6), and when formulated in liposomes, they exhibit exceptionally remarkable and heterogeneous effects that enable them to exert excellent antitumor effects with a high level of safety.

[0382] As described above, the present disclosure has been illustrated using preferred embodiments thereof, but it is understood that the scope of the present disclosure should be interpreted solely by the claims. This application claims priority to Japanese Patent Application Nos. 2021-210843 (filed December 24, 2021) and 2022-87175 (filed May 27, 2022), the contents of which are incorporated herein by reference in their entirety. It is understood that the patents, patent applications, and literature cited herein should be incorporated herein by reference in their entirety as if the contents themselves were specifically set forth herein.

[0383] The compounds of the present disclosure potently inhibit Checkpoint Kinase 1 (CHK1). These liposome preparations achieve sustained drug exposure due to their sustained release effect, thereby exhibiting potent antitumor effects based on the inhibitory action of CHK1. Therefore, the compounds of the present disclosure and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, and liposome preparations containing them are useful as therapeutic or preventive agents for pathologies involving CHK1.

Claims

【Request Item 1】 【Chemistry 1】 [In the formula, R １ represents a hydrogen atom, a halogen atom, a cyano, a nitro, a carboxyl, a sulfonic acid, a phosphoric acid, or -OR ２ , -SR ２ , -COR ３ , -CO ２ R ３ , -CONR ４ R ５ , -SO ２ R ３ , -SO ２ NR ４ R ５ , -OCOR ３ , -OCO ２ R ３ , -OCONR ４ R ５ , -NR ４ R ５ , -NR ６ COR ３ , -NR ６ CO ２ R ３ , -NR ６ CONR ４ R ５ , -NR ６ SO ２ R ３ , -NR ６ SO ２ NR ４ R ５ , 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 5- to 12-membered heteroaryl; R ２ is a hydrogen atom or C １－６ represents alkyl, R ３ is C １－６ represents alkyl, R ４ , R ５ and R ６ are each independently a hydrogen atom or C １－６ alkyl, wherein R ４ and R ５ Both are C １－６ When they are alkyl, they may be joined together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle, Y １ａ and Y １ｂ each independently represents a carbon atom or a nitrogen atom, Z １ａ is a nitrogen atom or CR ７a represents Z １ｂ is a nitrogen atom or CR ７ｂ represents R ７a and R ７ｂ are each independently a hydrogen atom, a halogen atom, cyano, nitro, carboxyl, sulfonic acid, phosphoric acid, -OR ８ , -SR ８ , -COR ９ , -CO ２ R ９ , -CONR １０ R １１ , -SO ２ R ９ , -SO ２ NR １０ R １１ , -OCOR ９ , -OCO ２ R ９ , -OCONR １０ R １１ , -NR １０ R １１ , -NR １２ COR ９ , -NR １２ CO ２ R ９ , -NR １２ CONR １０ R １１ , -NR １２ SO ２ R ９ , -NR １２ SO ２ NR １０ R １１ , 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 5- to 12-membered heteroaryl; R ８ is a hydrogen atom or C １－６ represents alkyl, R ９ is C １－６ represents alkyl, R １０ , R １１ and R １２ are each independently a hydrogen atom or C １－６ alkyl, wherein R １１ and R １２ Both are C １－６ When they are alkyl, they may be joined together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle, Ring A represents an optionally substituted 3- to 10-membered cycloalkane, an optionally substituted 6- to 10-membered arene, an optionally substituted 4- to 10-membered aromatic heterocycle, or an optionally substituted 4- to 10-membered non-aromatic heterocycle; L is a single bond or an optionally substituted C １－６ represents alkylene, V is a single bond, carbonyl, thiocarbonyl, optionally substituted C ２－６ Alkenylene, optionally substituted C ３－１０ Cycloalkylene, optionally substituted C ３－１０ Cycloalkenylene, an optionally substituted 3- to 10-membered divalent saturated heterocyclic group, or —C(═NR １３ )-, R １３ is a hydrogen atom or C １－６ represents alkyl, W is a single bond or an optionally substituted C １－６ represents alkylene, Q is a hydrogen atom or NHR １４ represents R １４ represents a hydrogen atom, an optionally substituted C １－６ Alkyl, optionally substituted C ３－１０ cycloalkyl, or an optionally substituted 3- to 10-membered saturated heterocyclic group]. The compound or a pharmaceutically acceptable salt thereof.

2. R １ , R ７a , R ７ｂ , R １４ , optionally substituted C in rings A, L, V, and W １－６ Alkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, optionally substituted C ２－６ Alkenylene, optionally substituted C ３－１０ Cycloalkyl, optionally substituted 3- to 10-membered saturated heterocyclic group, optionally substituted 6- to 10-membered arene, optionally substituted 4- to 10-membered aromatic heterocycle, optionally substituted 3- to 10-membered cycloalkane, optionally substituted 4- to 10-membered non-aromatic heterocycle, optionally substituted C ６－１０ Aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted C １－６ Alkylene, optionally substituted C ３－１０ Cycloalkylene, optionally substituted C ３－１０ cycloalkenylene or optionally substituted 3- to 10-membered divalent saturated heterocyclic group, each independently (1) a halogen atom, (2) a hydroxyl group, (3) C ６－１０ aryl, (4) 5- to 12-membered heteroaryl, (5) C １－６ Alkyl, (6) C ２－６ alkenyl, (7) C ２－６ Alkynyl, (8) C １－６ Alkoxy, (9) C １－６ Alkylthio (10) C ３－１０ cycloalkyl, (11) a 3- to 10-membered saturated heterocyclic group, (12) carboxyl, (13)-COR １５ 、 (14)-CO ２ R １５ 、 (15) - COCOA １６ R １７ 、 (16)-NR １６ R １７ 、 (17)-NR １８ COR １５ 、 (18)-NR １８ CO ２ R １５ 、 (19)-NR １８ SO ２ R １５ 、 (20)-NR １８ CONR １６ R １７ 、 (21))-NR １８ 45 ２ NR １６ - １７ 、 (22)-SO ２ R １５ 、 (23)-SO ２ NR １６ R １７ 、 (24) - OCCURRENCE １５ 、 (25)-OCO ２ R １５ 、 (26)-OCONR １６ R １７ 、 (27) sulfonic acid, (28) phosphoric acid, (29) cyano, and (30) Nitro and optionally substituted with 1 to 5 identical or different substituents selected from the group consisting of: Here, the (3) C ６－１０ (4) 5- to 12-membered heteroaryl; (5) C １－６ alkyl, (6) C ２－６ alkenyl, (7) C ２－６ alkynyl, (8) C １－６ Alkoxy, (9) C １－６ Alkylthio, (10)C ３－１０ The groups shown in (11) cycloalkyl and (11) 3- to 10-membered saturated heterocyclic group are (a) a halogen atom, (b) a hydroxyl group, (c) C ６－１０ aryl, (d) 5- to 12-membered heteroaryl; (e) C １－６ Alkyl, (f) C ２－６ alkenyl, (g) C ２－６ Alkynyl, (h) C １－６ Alkoxy, (i) C ３－１０ cycloalkyl, (j) a 3- to 10-membered saturated heterocyclic group, (k) carboxyl, (l)-COR １５ 、 (m)-CO ２ R １５ 、 (n)-CONR １６ R １７ 、 (o)-NR １６ R １７ 、 (p)-NR １８ COR １５ 、 (q)-NR １８ SO ２ R １５ 、 (r)-SO ２ R １５ 、 (s)-SO ２ NR １６ R １７ 、 (t) sulfonic acid, (u) phosphoric acid, (v) cyano, and (w) Nitro and optionally substituted with 1 to 5 identical or different substituents selected from the group consisting of: R １５ However, if there are multiple, each independently, C １－６ is alkyl, R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When they are alkyl, they may be joined together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle, R １８ is a hydrogen atom or C １－６ is alkyl, 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

3. R １ is a hydrogen atom, a halogen atom, cyano, -OR ２ , -CO ２ R ３ , C １－６ Alkyl, C ３－１０ cycloalkyl, or a 3- to 10-membered saturated heterocyclic group; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

4. R １ is a hydrogen atom, a halogen atom, cyano, -CO ２ R ３ That is, 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

5. R １ But it is cyano.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

6. R ７a and R ７ｂ are each independently a hydrogen atom, a halogen atom, cyano, or —OR ８ , -CO ２ R ９ , -CONR １０ R １１ , -NR １０ R １１ , -NR １２ COR ９ , C １－６ Alkyl (the alkyl is a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a phenyl, a 5- to 6-membered heteroaryl, C １－６ Alkoxy, C ３－７ cycloalkyl, 3- to 7-membered saturated heterocyclic group, —CONR １６ R １７ , -NR １６ R １７ and cyano), C ３－１０ Cycloalkyl (the cycloalkyl is a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a phenyl, a 5- to 6-membered heteroaryl, C １－６ Alkyl, C １－６ Alkoxy, C ３－７ cycloalkyl, 3- to 7-membered saturated heterocyclic group, —CONR １６ R １７ , -NR １６ R １７ and cyano), a 3- to 10-membered saturated heterocyclic group (the saturated heterocyclic group is optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, phenyl, a 5- or 6-membered heteroaryl, C １－６ Alkyl, C １－６ Alkoxy, C ３－７ cycloalkyl, 3- to 7-membered saturated heterocyclic group, —CONR １６ R １７ , -NR １６ R １７ and cyano), phenyl (the phenyl is optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, phenyl, 5- to 6-membered heteroaryl, C １－６ Alkyl, C １－６ Alkoxy, C ３－７ cycloalkyl, 3- to 7-membered saturated heterocyclic group, —CONR １６ R １７ , -NR １６ R １７ and cyano), or 5- to 6-membered heteroaryl (the heteroaryl is a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, phenyl, a 5- to 6-membered heteroaryl, C １－６ Alkyl, C １－６ Alkoxy, C ３－７ cycloalkyl, 3- to 7-membered saturated heterocyclic group, —CONR １６ R １７ , -NR １６ R １７ and cyano), R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When they are alkyl, they may be joined together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

7. R ７a and R ７ｂ However, each independently, hydrogen atoms, fluorine atoms, chlorine atoms, bromine atom, C １－６ Alkyl (the alkyl is a fluorine atom, a hydroxyl group, C １－３ Alkoxy, —NR １６ R １７ and cyano), or 5-6 membered heteroaryl (the heteroaryl is not limited to a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano, R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When they are alkyl, they may be joined together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

8. Ring A is 3- to 10-membered cycloalkane (the cycloalkane may contain a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a phenyl, a 5- to 6-membered heteroaryl, C １－６ Alkyl, C １－６ Alkoxy, C ３－７ cycloalkyl, 3- to 7-membered saturated heterocyclic group, —CONR １６ R １７ , -NR １６ R １７ and cyano), 6- to 10-membered arenes (the arenes may be substituted with fluorine atoms, chlorine atoms, bromine atoms, hydroxyl groups, phenyl, 5- to 6-membered heteroaryl, C １－６ Alkyl, C １－６ Alkoxy, C ３－７ cycloalkyl, 3- to 7-membered saturated heterocyclic group, —CONR １６ R １７ , -NR １６ R １７ and cyano), 4- to 10-membered aromatic heterocycle (the aromatic heterocycle is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, phenyl, a 5- to 6-membered heteroaryl, C １－６ Alkyl, C １－６ Alkoxy, C ３－７ cycloalkyl, 3- to 7-membered saturated heterocyclic group, —CONR １６ R １７ , -NR １６ R １７ and cyano), or 4- to 10-membered non-aromatic heterocycle (the non-aromatic heterocycle is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, phenyl, a 5- to 6-membered heteroaryl, C １－６ Alkyl, C １－６ Alkoxy, C ３－７ cycloalkyl, 3- to 7-membered saturated heterocyclic group, —CONR １６ R １７ , -NR １６ R １７ and cyano), R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When they are alkyl, they may be joined together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

9. Ring A is 4- to 10-membered aromatic heterocycle (the aromatic heterocycle is not particularly limited to a fluorine atom, a hydroxyl group, a C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), or 4- to 10-membered non-aromatic heterocycle (the non-aromatic heterocycle is not particularly limited to a fluorine atom, a hydroxyl group, a C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano, R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When they are alkyl, they may be joined together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

10. L, a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When they are alkyl, they may be joined together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

11. V, single bond, carbonyl, thiocarbonyl, C ２－６ Alkenylene (the alkenylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), C ３－１０ Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), C ３－１０ Cycloalkenylene (the cycloalkenylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C group optionally substituted with a fluorine atom, a hydroxyl group, or 1 to 2 hydroxyl groups or fluorine atoms); １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), or -C(=NR １３ ) - and R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When they are alkyl, they may be joined together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

12. W is, a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkoxy, —NR １６ R １７ and cyano), R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When they are alkyl, they may be joined together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

13. R １４ but, hydrogen atoms, C １－６ Alkyl (the alkyl is a fluorine atom, a hydroxyl group, C １－３ Alkoxy, —NR １６ R １７ and cyano), C ３－１０ Cycloalkyl (the cycloalkyl is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), or 3- to 10-membered saturated heterocyclic group (the saturated heterocyclic group is not limited to a fluorine atom, a hydroxyl group, a C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When they are alkyl, they may be joined together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

14. Formula (1) is changed to the following formula (2): 【Chemistry 2】 [In the formula, R １ represents a hydrogen atom, a halogen atom, cyano, -CO ２ R ３ represents R ３ is C １－６ represents alkyl, Y １ａ and Y １ｂ each independently represents a carbon atom or a nitrogen atom, Z １ａ is a nitrogen atom or CR ７a represents Z １ｂ is a nitrogen atom or CR ７ｂ represents R ７a and R ７ｂ are each independently hydrogen atoms, fluorine atoms, chlorine atoms, bromine atom, C １－６ Alkyl (the alkyl is a fluorine atom, a hydroxyl group, C １－３ Alkoxy, —NR １６ R １７ and cyano), or 5-6 membered heteroaryl (the heteroaryl is not limited to a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), Ring A is 5- to 6-membered aromatic heterocycle (the aromatic heterocycle is not particularly limited to a fluorine atom, a hydroxyl group, a C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), or 5- to 8-membered non-aromatic heterocycle (the non-aromatic heterocycle is not particularly limited to a fluorine atom, a hydroxyl group, a C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), L is, a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), V is, single bond, C ２－６ Alkenylene (the alkenylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), C ３－１０ Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), C ３－１０ Cycloalkenylene (the cycloalkenylene is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C group optionally substituted with a fluorine atom, a hydroxyl group, or 1 to 2 fluorine atoms); １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), W is a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ Alkoxy, —NR １６ R １７ and cyano), Q is, a hydrogen atom, or NHR １４ represents R １４ teeth, hydrogen atoms, C １－６ Alkyl (the alkyl is a fluorine atom, a hydroxyl group, C １－３ Alkoxy, —NR １６ R １７ and cyano), C ３－１０ Cycloalkyl (the cycloalkyl is a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), or 3- to 10-membered saturated heterocyclic group (the saturated heterocyclic group is not limited to a fluorine atom, a hydroxyl group, a C １－３ Alkyl, C １－３ Alkoxy, —NR １６ R １７ and cyano), R １６ and R １７ are each independently a hydrogen atom or C １－６ represents alkyl, and R １６ or R １７ If there are multiple １６ or R １７ may be the same or different, and R １６ and R １７ Both are C １－６ When each is an alkyl, they may be taken together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

15. R １ But it is cyano.

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof.

16. Z １ａ But, CR ７ａ That is, 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof.

17. Z １ｂ But, CR ７ｂ That is, 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof.

18. Z １ｂ is a nitrogen atom, 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof.

19. R ７a and R ７ｂ are each independently hydrogen atoms, fluorine atoms, chlorine atoms, a bromine atom, or C １－６ Alkyl (the alkyl is a fluorine atom, a hydroxyl group, and １－３ alkoxy), 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof.

20. R ７a and R ７ｂ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or C １－３ is alkyl, 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof.

21. R ７a and R ７ｂ is a hydrogen atom, 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof.

22. L, a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ optionally substituted with 1 to 2 identical or different substituents selected from the group consisting of alkyl, cyclohexyl ...

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof.

23. V, single bond, C ２－６ Alkenylene (the alkenylene is a fluorine atom, a hydroxyl group, C １－３ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, and cyano); C ３－１０ Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, C １－３ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, and cyano); C ３－１０ Cycloalkenylene (the cycloalkenylene is a fluorine atom, a hydroxyl group, C １－３ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, and cyano; or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C group optionally substituted with a fluorine atom, a hydroxyl group, or 1 to 2 fluorine atoms); １－３ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl and cyano; 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof.

24. W is, a single bond, or C １－６ alkylene (the alkylene may be substituted with 1 to 2 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, and cyano); 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof.

25. R １４ but, a hydrogen atom, or C １－６ alkyl (the alkyl may be substituted with 1 to 2 identical or different substituents selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano); 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof.

26. Q is, hydrogen atoms, NH ２ , or NMeH, 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof.

27. Ring A is a 5- to 6-membered aromatic heterocycle (the aromatic heterocycle does not contain a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ optionally substituted with 1 to 2 identical or different substituents selected from the group consisting of alkoxy and cyano; 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof.

28. Ring A is a 5- to 8-membered non-aromatic heterocycle (the non-aromatic heterocycle is not particularly limited to a fluorine atom, a hydroxyl group, a C １－３ Alkyl, C １－３ optionally substituted with 1 to 2 identical or different substituents selected from the group consisting of alkoxy and cyano; 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof.

29. Formula (1) is changed to the following formula (3): 【Transformation 3】 [In the formula, Y １ｂ teeth, a carbon atom, or represents a nitrogen atom, Ring B is a 5- or 6-membered aromatic heterocycle (the aromatic heterocycle may contain a fluorine atom, a hydroxyl group, a C １－３ Alkyl, C １－３ optionally substituted with 1 to 2 identical or different substituents selected from the group consisting of alkoxy and cyano; L is, a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ optionally substituted with 1 to 2 substituents selected from the group consisting of alkyl, and cyano; V is, single bond, C ２－６ Alkenylene (the alkenylene is a fluorine atom, a hydroxyl group, C １－３ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, and cyano); C ３－１０ Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, C １－３ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, and cyano); C ３－１０ Cycloalkenylene (the cycloalkenylene is a fluorine atom, a hydroxyl group, C １－３ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, and cyano; or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C group optionally substituted with a fluorine atom, a hydroxyl group, or 1 to 2 hydroxyl groups or fluorine atoms); １－３ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl and cyano; W is a single bond, or C １－３ alkylene (the alkylene may be substituted with 1 to 2 substituents selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano); Q is, a hydrogen atom, or NHR １４ represents R １４ teeth, a hydrogen atom, or C １－３ alkyl (the alkyl may be substituted with one substituent selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano) 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

30. Ring B is an unsubstituted 5- or 6-membered aromatic heterocycle.

30. The compound of claim 29, or a pharmaceutically acceptable salt thereof.

31. Y １ｂ is a carbon atom, 30. The compound of claim 29, or a pharmaceutically acceptable salt thereof.

32. L, a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom or C １－３ alkyl, each of which may be substituted with 1 to 2 identical or different substituents selected from the group consisting of 30. The compound of claim 29, or a pharmaceutically acceptable salt thereof.

33. V, single bond, C ２－６ Alkenylene (the alkenylene is a hydroxyl group and C １－３ optionally substituted with one substituent selected from the group consisting of alkyl, C ３－１０ Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, and a C １－３ optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, C ３－１０ Cycloalkenylene (the cycloalkenylene is a hydroxyl group and C １－３ alkyl), or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C group optionally substituted with a fluorine atom, a hydroxyl group, and 1 to 2 fluorine atoms); １－３ and optionally substituted with one substituent selected from the group consisting of alkyl, 30. The compound of claim 29, or a pharmaceutically acceptable salt thereof.

34. W is, a single bond, or C optionally substituted with 1 to 2 fluorine atoms １－３ is alkylene, 30. The compound of claim 29, or a pharmaceutically acceptable salt thereof.

35. R １４ but, a hydrogen atom, or C １－６ is alkyl, 30. The compound of claim 29, or a pharmaceutically acceptable salt thereof.

36. Q is, a hydrogen atom, or NH ２ That is, 30. The compound of claim 29, or a pharmaceutically acceptable salt thereof.

37. Formula (1) is converted to the following formula (4): 【Chemistry 4】 [In the formula, L is, a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom or C １－３ alkyl), which may be substituted with 1 to 2 identical or different substituents selected from the group consisting of V is, single bond, C ２－６ Alkenylene (the alkenylene is a hydroxyl group and C １－３ optionally substituted with one substituent selected from the group consisting of alkyl, C ３－１０ Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, and a C １－３ optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, C ３－１０ Cycloalkenylene (the cycloalkenylene is a hydroxyl group and C １－３ alkyl), or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C group optionally substituted with a fluorine atom, a hydroxyl group, and 1 to 2 fluorine atoms); １－３ alkyl, W is a single bond, or C optionally substituted with 1 to 2 fluorine atoms １－３ represents alkylene, Q is, a hydrogen atom, or NH ２ Represents the 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

38. V, single bond, C ２－６ Alkenylene, C ３－１０ cycloalkylene (the cycloalkylene may be substituted with 1 to 3 fluorine atoms); C ３－１０ cycloalkenylene, or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C group optionally substituted with a fluorine atom and 1 to 2 fluorine atoms); １－３ and optionally substituted with one substituent selected from the group consisting of alkyl, 38. The compound of claim 37, or a pharmaceutically acceptable salt thereof.

39. Q is a hydrogen atom; 38. The compound of claim 37, or a pharmaceutically acceptable salt thereof.

40. Q is NH ２ That is, 38. The compound of claim 37, or a pharmaceutically acceptable salt thereof.

41. Formula (1) is changed to the following formula (5): 【Transformation 5】 [In the formula, R １ represents a hydrogen atom, a halogen atom, cyano, -CO ２ R ３ represents R ３ is C １－６ represents alkyl, Ring C is a 5- to 8-membered non-aromatic heterocycle (the non-aromatic heterocycle may contain a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ optionally substituted with 1 to 2 identical or different substituents selected from the group consisting of alkoxy and cyano; L is, a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ optionally substituted with 1 to 2 substituents selected from the group consisting of alkyl, and cyano; V is, single bond, C ２－６ Alkenylene (the alkenylene is a fluorine atom, a hydroxyl group, C １－３ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, and cyano); C ３－１０ Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, C １－３ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, and cyano); C ３－１０ Cycloalkenylene (the cycloalkenylene is a fluorine atom, a hydroxyl group, C １－３ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, and cyano; or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C group optionally substituted with a fluorine atom, a hydroxyl group, or 1 to 2 hydroxyl groups or fluorine atoms); １－３ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl and cyano; W is a single bond, or C １－３ alkylene (the alkylene may be substituted with 1 to 2 substituents selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano); Q is, a hydrogen atom, or NHR １４ represents R １４ teeth, a hydrogen atom, or C １－３ alkyl (the alkyl may be substituted with one substituent selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano) 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

42. R １ But it is cyano.

42. The compound of claim 41, or a pharmaceutically acceptable salt thereof.

43. Ring C is an unsubstituted 5- to 8-membered non-aromatic heterocycle.

42. The compound of claim 41, or a pharmaceutically acceptable salt thereof.

44. L, a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom or C １－３ alkyl, each of which may be substituted with 1 to 2 identical or different substituents selected from the group consisting of 42. The compound of claim 41, or a pharmaceutically acceptable salt thereof.

45. V, single bond, C ２－６ Alkenylene (the alkenylene is a hydroxyl group and C １－３ optionally substituted with one substituent selected from the group consisting of alkyl, C ３－１０ Cycloalkylene (the cycloalkylene is a hydroxyl group and a C １－３ optionally substituted with one substituent selected from the group consisting of alkyl, C ３－１０ Cycloalkenylene (the cycloalkenylene is a hydroxyl group and C １－３ alkyl), or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C group optionally substituted with a fluorine atom, a hydroxyl group, or 1 to 2 hydroxyl groups or fluorine atoms); １－３ and optionally substituted with one substituent selected from the group consisting of alkyl, 42. The compound of claim 41, or a pharmaceutically acceptable salt thereof.

46. W is, a single bond, or C １－３ is alkylene, 42. The compound of claim 41, or a pharmaceutically acceptable salt thereof.

47. R １４ but, a hydrogen atom, or C １－６ is alkyl, 42. The compound of claim 41, or a pharmaceutically acceptable salt thereof.

48. Q is, hydrogen atom NH ２ , or NMeH, 42. The compound of claim 41, or a pharmaceutically acceptable salt thereof.

49. Formula (1) is converted to the following formula (6): 【Transformation 6】 [In the formula, L is, a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom or C １－３ alkyl), which may be substituted with 1 to 2 identical or different substituents selected from the group consisting of V is, single bond, C ２－６ Alkenylene (the alkenylene is a hydroxyl group and C １－３ optionally substituted with one substituent selected from the group consisting of alkyl, C ３－１０ Cycloalkylene (the cycloalkylene is a hydroxyl group and a C １－３ optionally substituted with one substituent selected from the group consisting of alkyl, C ３－１０ Cycloalkenylene (the cycloalkenylene is a hydroxyl group and C １－３ alkyl), or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C group optionally substituted with a fluorine atom, a hydroxyl group, and 1 to 2 fluorine atoms); １－３ alkyl, W is a single bond, or C optionally substituted with 1 to 2 fluorine atoms １－３ represents alkylene, Q is, hydrogen atom NH ２ , or NMeH] 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

50. V, single bond, C ２－６ Alkenylene, C ３－１０ cycloalkylene, C ３－１０ cycloalkenylene, or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C group optionally substituted with a fluorine atom and 1 to 2 fluorine atoms); １－３ and optionally substituted with one substituent selected from the group consisting of alkyl, 50. The compound of claim 49, or a pharmaceutically acceptable salt thereof.

51. W is, a single bond, or C １－３ is alkylene, 50. The compound of claim 49, or a pharmaceutically acceptable salt thereof.

52. Q is a hydrogen atom; 50. The compound of claim 49, or a pharmaceutically acceptable salt thereof.

53. Q is NH ２ That is, 50. The compound of claim 49, or a pharmaceutically acceptable salt thereof.

54. Q is NHMe; 50. The compound of claim 49, or a pharmaceutically acceptable salt thereof.

55. Formula (1) is changed to the following formula (7): 【Transformation 7】 [In the formula, Y １ｂ teeth, a carbon atom, or represents a nitrogen atom, Ring D is a 5- to 8-membered non-aromatic heterocycle, or 5- to 6-membered aromatic heterocycle (the non-aromatic heterocycle and aromatic heterocycle may contain a fluorine atom, a hydroxyl group, C １－３ Alkyl, C １－３ optionally substituted with 1 to 2 identical or different substituents selected from the group consisting of alkoxy and cyano; L is, a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom, a hydroxyl group, C １－３ optionally substituted with 1 to 2 substituents selected from the group consisting of alkyl, and cyano; V is, single bond, C ２－６ Alkenylene (the alkenylene is a fluorine atom, a hydroxyl group, C １－３ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, and cyano); C ３－１０ Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, C １－３ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, and cyano); C ３－１０ Cycloalkenylene (the cycloalkenylene is a fluorine atom, a hydroxyl group, C １－３ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, and cyano; or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C group optionally substituted with a fluorine atom, a hydroxyl group, or 1 to 2 hydroxyl groups or fluorine atoms); １－３ optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl and cyano; W is a single bond, or C １－３ alkylene (the alkylene may be substituted with one substituent selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano); Q is, a hydrogen atom, or NHR １４ represents R １４ teeth, a hydrogen atom, or C １－３ alkyl (the alkyl may be substituted with one substituent selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano) 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

56. Y １ｂ is a carbon atom, 56. The compound of claim 55, or a pharmaceutically acceptable salt thereof.

57. Y １ｂ is a nitrogen atom, 56. The compound of claim 55, or a pharmaceutically acceptable salt thereof.

58. Ring D is a 5- to 8-membered non-aromatic heterocycle.

56. The compound of claim 55, or a pharmaceutically acceptable salt thereof.

59. Ring D is a 5- to 6-membered aromatic heterocycle.

56. The compound of claim 55, or a pharmaceutically acceptable salt thereof.

60. L, a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom or C １－３ alkyl, each of which may be substituted with 1 to 2 identical or different substituents selected from the group consisting of 56. The compound of claim 55, or a pharmaceutically acceptable salt thereof.

61. V, single bond, C ２－６ Alkenylene, C ３－１０ cycloalkylene (the cycloalkylene may be substituted with 1 to 3 fluorine atoms); C ３－１０ cycloalkenylene, or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C group optionally substituted with a fluorine atom and 1 to 2 hydroxyl groups or fluorine atoms); １－３ and optionally substituted with one substituent selected from the group consisting of alkyl, 56. The compound of claim 55, or a pharmaceutically acceptable salt thereof.

62. W is, a single bond, or C １－３ is alkylene, 56. The compound of claim 55, or a pharmaceutically acceptable salt thereof.

63. R １４ but, a hydrogen atom, or C １－６ is alkyl, 56. The compound of claim 55, or a pharmaceutically acceptable salt thereof.

64. Q is, a hydrogen atom, or NH ２ That is, 56. The compound of claim 55, or a pharmaceutically acceptable salt thereof.

65. Formula (1) is converted to the following formula (8): 【Transformation 8】 [In the formula, L is, a single bond, or C １－６ Alkylene (the alkylene is a fluorine atom and C １－３ alkyl), V is, single bond, C ２－６ Alkenylene (the alkenylene is a hydroxyl group and C １－３ optionally substituted with one substituent selected from the group consisting of alkyl, C ３－１０ Cycloalkylene (the cycloalkylene is a hydroxyl group and a C １－３ optionally substituted with one substituent selected from the group consisting of alkyl, C ３－１０ Cycloalkenylene (the cycloalkenylene is a hydroxyl group and C １－３ alkyl), or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a C group optionally substituted with a fluorine atom, a hydroxyl group, and 1 to 2 fluorine atoms); １－３ one selected from the group consisting of alkyl which may be substituted with a substituent of the formula W is a single bond, or C optionally substituted with 1 to 2 fluorine atoms １－３ represents alkylene, Q is, hydrogen atom NH ２ , or NHMe] 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

66. L is C １－６ is alkylene, 66. The compound of claim 65, or a pharmaceutically acceptable salt thereof.

67. V is a single bond; 66. The compound of claim 65, or a pharmaceutically acceptable salt thereof.

68. W is, a single bond, or C １－３ is alkylene, 66. The compound of claim 65, or a pharmaceutically acceptable salt thereof.

69. Q is NH ２ That is, 66. The compound of claim 65, or a pharmaceutically acceptable salt thereof.

70. 2. The compound of claim 1, selected from the following compounds, or a pharmaceutically acceptable salt thereof: 5-({5-[7-(3-aminopropoxy)quinolin-8-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, 5-({5-[6-(3-aminopropoxy)-1-benzofuran-7-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, 5-({5-[6-(3-aminopropoxy)-2,3-dihydro-1-benzofuran-7-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, 5-{[5-(6-{[1-(aminomethyl)cyclopropyl]methoxy}-2,3-dihydro-1-benzofuran-7-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile, 5-[(5-{6-[(3-methylazetidin-3-yl)methoxy]-2,3-dihydro-1-benzofuran-7-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-({5-[6-(3-aminopropoxy)pyrazolo[1,5-a]pyridin-7-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, 5-({5-[6-(3-aminopropoxy)pyrazolo[1,5-a]pyrimidin-7-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, 5-({5-[3-(3-aminopropoxy)-1,5-naphthyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, 5-({5-[3-(3-amino-2,2-difluoropropoxy)-1,5-naphthyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, 5-{[5-(3-{[1-(aminomethyl)cyclopropyl]methoxy}-1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile, 5-[(5-{3-[(3-methylazetidin-3-yl)methoxy]-1,5-naphthyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-{[5-(3-{[(2S)-morpholin-2-yl]methoxy}-1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile, 5-({5-[6-(3-aminopropoxy)-2,3-dihydrofuro[3,2-b]pyridin-7-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, 5-{[5-(6-{[1-(aminomethyl)cyclopropyl]methoxy}-2,3-dihydrofuro[3,2-b]pyridin-7-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile, 5-[(5-{6-[(3-methylazetidin-3-yl)methoxy]-2,3-dihydrofuro[3,2-b]pyridin-7-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-({5-[6-(3-aminopropoxy)-2-methyl-1,3-benzoxazol-7-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, 5-{[5-(6-{[1-(aminomethyl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyridin-7-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile, 5-[(5-{6-[(3-methylazetidin-3-yl)methoxy]pyrazolo[1,5-a]pyridin-7-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-{[5-(6-{[1-(aminomethyl)cyclopropyl]methoxy}-1-benzofuran-7-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile, 5-{[5-(6-{[1-(aminomethyl)-2,2-difluorocyclopropyl]methoxy}-1-benzofuran-7-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile, 5-{[5-(6-{[(1R,3R)-3-aminocyclopentyl]oxy}-2,3-dihydrofuro[3,2-b]pyridin-7-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile, 5-{[5-(6-{[3-(difluoromethyl)azetidin-3-yl]methoxy}-2,3-dihydrofuro[3,2-b]pyridin-7-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile, 5-[(5-{6-[(3-fluoroazetidin-3-yl)methoxy]-2,3-dihydrofuro[3,2-b]pyridin-7-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-{[5-(6-{[(1R,3S)-3-aminocyclohexyl]oxy}-2,3-dihydrofuro[3,2-b]pyridin-7-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile, 5-[(5-{6-[(1R)-1-(azetidin-3-yl)ethoxy]-2,3-dihydrofuro[3,2-b]pyridin-7-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-{[5-(6-{[(3S)-pyrrolidin-3-yl]methoxy}-2,3-dihydrofuro[3,2-b]pyridin-7-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile, 5-[(5-{6-[3-(methylamino)propoxy]-2,3-dihydrofuro[3,2-b]pyridin-7-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-[(5-{6-[(2R)-3-amino-2-methylpropoxy]-2,3-dihydrofuro[3,2-b]pyridin-7-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-{[5-(6-{[(1R,2S,4S,5S)-4-aminobicyclo[3.1.0]hexan-2-yl]oxy}-2,3-dihydrofuro[3,2-b]pyridin-7-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile, 5-[(5-{6-[(2S)-3-amino-2-methylpropoxy]-2,3-dihydrofuro[3,2-b]pyridin-7-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-{[5-(6-{[2-(aminomethyl)propyl-2-en-1-yl]oxy}-2,3-dihydrofuro[3,2-b]pyridin-7-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile, N-{5-[6-(3-aminopropoxy)-2,3-dihydrofuro[3,2-b]pyridin-7-yl]-1H-pyrazol-3-yl}-5-chloropyrazin-2-amine, methyl 5-({5-[6-(3-aminopropoxy)-2,3-dihydrofuro[3,2-b]pyridin-7-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carboxylate, 5-{[5-(3-{[(1R,2S)-2-(aminomethyl)cyclopentyl]oxy}-1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile, 5-[(5-{3-[(3-fluoroazetidin-3-yl)methoxy]-1,5-naphthyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-{[5-(3-{[(1R,3S)-3-aminocyclohexyl]oxy}-1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile, 5-{[5-(3-{[(1R,3R)-3-aminocyclopentyl]oxy}-1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile, 5-{[5-(3-{[1-(aminomethyl)-3,3-difluorocyclobutyl]methoxy}-1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile.

71. The compound of claim 1 or a pharmaceutically acceptable salt thereof: 5-({5-[7-(3-aminopropoxy)quinolin-8-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, 5-({5-[3-(3-aminopropoxy)-1,5-naphthyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, 5-({5-[3-(3-amino-2,2-difluoropropoxy)-1,5-naphthyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, 5-{[5-(3-{[1-(aminomethyl)cyclopropyl]methoxy}-1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile, 5-[(5-{3-[(3-methylazetidin-3-yl)methoxy]-1,5-naphthyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-({5-[6-(3-aminopropoxy)-2,3-dihydrofuro[3,2-b]pyridin-7-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, 5-{[5-(6-{[1-(aminomethyl)cyclopropyl]methoxy}-2,3-dihydrofuro[3,2-b]pyridin-7-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile, 5-[(5-{6-[(1R)-1-(azetidin-3-yl)ethoxy]-2,3-dihydrofuro[3,2-b]pyridin-7-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-{[5-(6-{[(3S)-pyrrolidin-3-yl]methoxy}-2,3-dihydrofuro[3,2-b]pyridin-7-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile, 5-[(5-{6-[3-(methylamino)propoxy]-2,3-dihydrofuro[3,2-b]pyridin-7-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-[(5-{6-[(2R)-3-amino-2-methylpropoxy]-2,3-dihydrofuro[3,2-b]pyridin-7-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-[(5-{3-[(3-fluoroazetidin-3-yl)methoxy]-1,5-naphthyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-{[5-(3-{[1-(aminomethyl)-3,3-difluorocyclobutyl]methoxy}-1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile.

72. The compound of claim 1 or a pharmaceutically acceptable salt thereof: 5-({5-[7-(3-aminopropoxy)quinolin-8-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, 5-({5-[3-(3-aminopropoxy)-1,5-naphthyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, 5-{[5-(3-{[1-(aminomethyl)cyclopropyl]methoxy}-1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile, 5-({5-[6-(3-aminopropoxy)-2,3-dihydrofuro[3,2-b]pyridin-7-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, 5-{[5-(6-{[1-(aminomethyl)cyclopropyl]methoxy}-2,3-dihydrofuro[3,2-b]pyridin-7-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile, 5-[(5-{6-[(1R)-1-(azetidin-3-yl)ethoxy]-2,3-dihydrofuro[3,2-b]pyridin-7-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-[(5-{6-[(2R)-3-amino-2-methylpropoxy]-2,3-dihydrofuro[3,2-b]pyridin-7-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile.

73. 5-({5-[3-(3-aminopropoxy)-1,5-naphthyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, or a pharmaceutically acceptable salt thereof.

74. 5-({5-[6-(3-aminopropoxy)-2,3-dihydrofuro[3,2-b]pyridin-7-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, or a pharmaceutically acceptable salt thereof.

75. 5-[(5-{6-[(2R)-3-amino-2-methylpropoxy]-2,3-dihydrofuro[3,2-b]pyridin-7-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, or a pharmaceutically acceptable salt thereof.

76. A liposome comprising the compound according to any one of claims 1 to 75, or a pharmaceutically acceptable salt thereof.

77. A pharmaceutical composition comprising the compound according to any one of claims 1 to 75, or a pharmaceutically acceptable salt thereof, as an active ingredient.

78. A pharmaceutical composition comprising a liposome encapsulating the compound according to any one of claims 1 to 75, or a pharmaceutically acceptable salt thereof.

79. 79. The pharmaceutical composition of claim 78, wherein the liposome further comprises a phospholipid.

80. The liposome is (1) A compound according to any one of claims 1 to 75, or a pharmaceutically acceptable salt thereof; and (2) phospholipids, 79. The pharmaceutical composition of claim 78, comprising:

81. 80. The pharmaceutical composition of claim 79, wherein the phospholipid is one or a combination of two or more selected from the group consisting of phosphatidylcholine, phosphatidylglycerol, phosphatidic acid, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, soybean lecithin, egg yolk lecithin, hydrogenated egg yolk lecithin, and hydrogenated soybean lecithin.

82. 79. The pharmaceutical composition of claim 78, wherein the liposome further comprises sterols.

83. 83. The pharmaceutical composition of claim 82, wherein the sterol is cholesterol.

84. 79. The pharmaceutical composition of claim 78, wherein the liposome further comprises a polymer-modified lipid.

85. 85. The pharmaceutical composition of claim 84, wherein the polymer portion of the polymer-modified lipid is polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, methoxypolyethylene glycol, methoxypolypropylene glycol, methoxypolyvinyl alcohol, methoxypolyvinylpyrrolidone, ethoxypolyethylene glycol, ethoxypolypropylene glycol, ethoxypolyvinyl alcohol, ethoxypolyvinylpyrrolidone, propoxypolyethylene glycol, propoxypolypropylene glycol, propoxypolyvinyl alcohol, or propoxypolyvinylpyrrolidone.

86. 85. The pharmaceutical composition of claim 84, wherein the lipid moiety of the polymer-modified lipid is phosphatidylethanolamine or diacylglycerol.

87. 85. The pharmaceutical composition of claim 84, wherein the polymer-modified lipid comprises polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, methoxypolyethylene glycol, methoxypolypropylene glycol, methoxypolyvinyl alcohol, methoxypolyvinylpyrrolidone, ethoxypolyethylene glycol, ethoxypolypropylene glycol, ethoxypolyvinyl alcohol, ethoxypolyvinylpyrrolidone, propoxypolyethylene glycol, propoxypolypropylene glycol, propoxypolyvinyl alcohol, or propoxypolyvinylpyrrolidone as the polymer moiety and phosphatidylethanolamine or diacylglycerol as the lipid moiety.

88. The liposome is (1) A compound according to any one of claims 1 to 75, or a pharmaceutically acceptable salt thereof. (2) 40 to 70 mol% of phospholipids; (3) 30 to 50 mol % cholesterol, and (4) 1 to 10 mol% of a polymer-modified lipid; 79. The pharmaceutical composition of claim 78, comprising:

89. 79. The pharmaceutical composition of claim 78, wherein the liposome further comprises an additive selected from the group consisting of inorganic acids, inorganic acid salts, organic acids, organic acid salts, sugars, buffers, antioxidants, and polymers.

90. 76. A cancer treatment and / or prevention agent comprising the compound according to any one of claims 1 to 75, or a pharmaceutically acceptable salt thereof, as an active ingredient.

91. 91. The therapeutic and / or prophylactic agent according to claim 90, wherein the cancer is at least one type of cancer selected from the group consisting of acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma, plasma cell neoplasm, multiple myeloma, brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thymoma / thymic cancer, breast cancer, gastric cancer, gallbladder / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, anal cancer, gastrointestinal stromal tumor, chorioepithelial carcinoma, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial cancer, kidney cancer, renal cell carcinoma, prostate cancer, testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms' tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, and skin cancer.

92. 76. A compound according to any one of claims 1 to 75, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of cancer.

93. 93. The compound of claim 92, or a pharmaceutically acceptable salt thereof, wherein the cancer is at least one cancer selected from the group consisting of acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma, plasma cell neoplasm, multiple myeloma, brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thymoma / thymic cancer, breast cancer, gastric cancer, gallbladder / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, anal cancer, gastrointestinal stromal tumor, chorioepithelial carcinoma, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial cancer, kidney cancer, renal cell carcinoma, prostate cancer, testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms' tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, and skin cancer.

94. The compound according to any one of claims 1 to 75, or a pharmaceutically acceptable salt thereof, for treating cancer in combination with a concomitant drug or a pharmaceutically acceptable salt thereof, wherein the concomitant drug is at least one or more selected from the group consisting of hormone therapeutic agents, chemotherapeutic agents, immunotherapeutic agents, and agents that inhibit the action of a cell growth factor and its receptor.

95. The compound according to any one of claims 1 to 75, or a pharmaceutically acceptable salt thereof, for treating cancer in combination with a concomitant drug or a pharmaceutically acceptable salt thereof, wherein the concomitant drug is a 5-FU drug, cytarabine, doxorubicin hydrochloride, gemcitabine, methotrexate, pemetrexed, etoposide, irinotecan, topotecan, cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, ionizing radiation, bevacizumab, liposomal At least one compound selected from the group consisting of doxorubicin, rucaparib, olaparib, niraparib, trabectedin, pazopanib, pembrolizumab, nivolumab, ipilimumab, durvalumab, avelumab, atezolizumab, larotrectinib, entrectinib, nab-paclitaxel, erlotinib, liposomal irinotecan, leucovorin, cetuximab, eribulin, ifosfamide, and dacarbazine, or a pharmaceutically acceptable salt thereof.

96. The compound according to any one of claims 1 to 75, or a pharmaceutically acceptable salt thereof, for use in combination with a concomitant drug or a pharmaceutically acceptable salt thereof to treat cancer, wherein the concomitant drug is at least one or more selected from the group consisting of 5-FU drugs, irinotecan, gemcitabine, cisplatin, carboplatin, oxaliplatin, paclitaxel, ionizing radiation, rucaparib, olaparib, niraparib, pembrolizumab, and nivolumab, or a pharmaceutically acceptable salt thereof.

97. A pharmaceutical composition comprising the compound according to any one of claims 1 to 75, or a pharmaceutically acceptable salt thereof, in combination with a concomitant drug, wherein the concomitant drug is at least one or more selected from the group consisting of hormone therapeutic agents, chemotherapeutic agents, immunotherapeutic agents, and agents that inhibit the action of a cell growth factor and its receptor.

98. A pharmaceutical composition comprising the compound according to any one of claims 1 to 75, or a pharmaceutically acceptable salt thereof, in combination with a concomitant drug, wherein the concomitant drug is a 5-FU drug, cytarabine, doxorubicin hydrochloride, gemcitabine, methotrexate, pemetrexed, etoposide, irinotecan, topotecan, cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, ionizing radiation, bevacizumab, liposomal A pharmaceutical composition comprising at least one or more drugs selected from the group consisting of doxorubicin, rucaparib, olaparib, niraparib, trabectedin, pazopanib, pembrolizumab, nivolumab, ipilimumab, durvalumab, avelumab, atezolizumab, larotrectinib, entrectinib, nab-paclitaxel, erlotinib, liposomal irinotecan, leucovorin, cetuximab, eribulin, ifosfamide, and dacarbazine.

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