Dihydrooxadiazinone compound and pharmaceutical use thereof

Abstract

To provide a compound that exhibits a PLD-inhibitory activity.SOLUTION: The present invention provides a compound represented by the following structural formula or the like, or a pharmaceutically acceptable salt thereof. (Each symbol in the formula is as defined in the specifications).SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to dihydrooxadiazinon compounds having phospholipase D (hereinafter referred to as "PLD") inhibitory activity or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the same, and pharmaceutical uses thereof. [Background technology]

[0002] Three key factors in thrombus formation are considered to be changes in blood components, changes in the properties of the blood vessel wall, and changes in blood flow. Arterial blood flow is laminar, faster in the center and slower near the vessel wall. The shear stress caused by this velocity difference strongly affects platelets flowing near the vessel wall, enhancing platelet aggregation. In arteries, thrombus formation is largely triggered by the rupture of atherosclerotic plaque. The reaction between collagen in the subendothelial tissue exposed by the rupture of atherosclerotic plaque, or von Willebrand factor (vWF) adhered to that collagen, and platelet membrane receptors triggers platelet activation signaling, leading to platelet aggregation and the initiation of thrombus formation. Therefore, platelet aggregation initiated at the site of plaque rupture in coronary arteries and cerebral arteries can cause rapid thrombotic occlusion, resulting in the onset of myocardial infarction or cerebral infarction. It is assumed that extremely high shear stress is generated in areas such as atherosclerotic stenosis where these pathological conditions are thought to occur. Recent studies using in vitro flow chambers incorporating a blood flow environment have revealed that platelet adhesion and aggregation mechanisms differ depending on the shear stress. Under high shear stress, platelet adhesion and aggregation reactions proceed by a mechanism completely different from the classical concepts established in conventional static or closed-loop agitation experimental systems (Non-patent documents 1, 2, 3, 4).

[0003] The primary role of thrombus formation in the body is a hemostatic mechanism to prevent blood leakage. The first step in this hemostatic mechanism is the adhesion of platelets to the site of damage to the blood vessel wall (primary hemostasis). The next step following platelet adhesion is platelet aggregation. Platelets firmly adhering to the damaged blood vessel wall capture and bind to platelets supplied via the bloodstream, causing platelet thrombi to grow spatially. Numerous factors activate platelets and induce platelet aggregation. Regardless of the type of inducing factor, the final reaction involves the cross-linking of platelets by fibrinogen or vWF to activated integrin αIIbβ3 (glycoprotein GPIIb / IIIa, GPIIb / IIIa) on the platelet membrane. Existing antiplatelet drugs, such as aspirin and clopidogrel, inhibit signals leading to platelet activation and impair primary hemostatic function; therefore, the risk of bleeding is an extension of their antithrombotic effect (Non-Patent Literature 5). As mentioned above, thrombus formation at atherosclerotic stenosis sites may be primarily due to platelet adhesion and aggregation under high shear stress. Therefore, drugs that can suppress only platelet aggregation reactions under high shear stress are expected to have a lower bleeding risk than existing drugs.

[0004] PLD1 and PLD2 are known as the main isoforms of PLD. PLD1 is encoded by the gene of the same name, and its expression has been confirmed throughout the body in humans. PLD1 is a phospholipid metabolic enzyme that hydrolyzes phosphatidylcholine (PC), a phospholipid that makes up biological membranes, to produce phosphatidic acid (PA). Since the PA produced by PLD1 acts as a signaling molecule, PLD1 is thought to regulate various cellular functions via PA. In addition, there is an enzyme called PLD2 that hydrolyzes PC into PA and choline in cells, similar to PLD1. PLD2 is also encoded by the gene of the same name, and its expression has been confirmed throughout the body in humans. The PLD activity observed in mammalian cells and tissues is thought to be due to these PLD1 and PLD2 enzymes (Non-Patent Literature 6).

[0005] Phenotypic analysis using PLD1 knockout mice revealed that these mice exhibited antithrombotic effects without showing a risk of bleeding. Furthermore, phenotypic analysis using PLD1 / 2 dual knockout mice showed that, in addition to the phenotype of PLD1 knockout mice, they also inhibited α-granule secretion from platelets. Analysis using platelets derived from these mice showed that inhibition of PLD1 and PLD2 inhibited platelet aggregation under high shear stress, and that it did not affect platelet aggregation induced by soluble agonists, which are inhibited by existing antiplatelet drugs (Non-patent documents 7, 8).

[0006] Furthermore, it has been reported that both PLD1 and PLD2 contribute to various phenomena such as cell proliferation, survival, metabolism, migration, and membrane fusion (Non-Patent Documents 9, 10, 11). Activation of PLD1 and PLD2 is thought to contribute to multiple pathological conditions, including cancer (Non-Patent Documents 12, 13), and elevated expression and activity have been detected in various human cancers, including those of the colon, breast, stomach, thyroid, brain, kidney, and uterine smooth muscle (Non-Patent Documents 11, 12, 13). In addition, numerous reports indicate that the PLD1 and PLD2 enzymes are directly involved in transformation and tumorigenesis in various cancer types, including breast cancer, ovarian cancer, lung cancer, colorectal cancer, kidney cancer, pancreatic cancer, prostate cancer, and brain tumors (Non-Patent Documents 11, 12, 13). Studies using PLD1 and PLD2 knockout mice, as well as their respective inhibitors, have confirmed that tumor tissue proliferation is suppressed (Non-Patent Documents 13, 14).

[0007] Based on the above, PLD inhibitors are considered to be therapeutic agents (e.g., secondary prophylactic agents, recurrence prevention agents, relapse prevention agents, etc.) or prophylactic agents for thrombosis (e.g., arterial thrombosis, acute coronary syndrome, stable angina pectoris, unstable angina pectoris, non-ST-elevation myocardial infarction, ST-elevation myocardial infarction, ischemic stroke, non-cardioembolic stroke, atherothrombotic stroke, cryptogenic stroke, embolic stroke of undetermined source (ESUS), lacunar infarction, transient ischemic attack, peripheral artery disease, etc.), and for perioperative and postoperative thrombosis associated with revascularization procedures (e.g., coronary artery bypass surgery, percutaneous coronary intervention, carotid endarterectomy, carotid artery stenting, thrombolytic therapy, lower limb revascularization, etc.) or aortic valve replacement (e.g., surgical aortic valve replacement, transcatheter aortic valve replacement, etc.). Furthermore, PLD inhibitors are also considered to be useful as therapeutic agents for cancer (e.g., breast cancer, ovarian cancer, lung cancer, colorectal cancer, kidney cancer, pancreatic cancer, prostate cancer, brain tumors, etc.). [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Cell. 1996 Jan 26; 84(2): 289-297 [Non-Patent Document 2] J Thromb Haemost. 2014; 12(3): 418-420 [Non-Patent Document 3] Nat Med. 2009 Jun; 15(6): 665-673 [Non-Patent Document 4] The Journal of Japanese College of Angiology. 2011; 51(3): 275-281 [Non-Patent Document 5] Thromb Haemost. 2010 Jun; 103(6):1128-1135 [Non-Patent Document 6] Chem Rev. 2011 Oct 12;111(10):6064-119. [Non-Patent Document 7] Sci Signal. 2010 Jan 5; 3(103): ra1 [Non-Patent Document 8] J Thromb Haemost. 2012 Nov;10(11):2361-72 [Non-Patent Document 9] J Biol Chem. 2014 Aug 15; 289(33): 22567-22574 [Non-Patent Document 10] J Biol Chem. 2014 Aug 15;289(33):22557-22566. [Non-Patent Document 11] J Biol Chem. 2014; 289(33): 22575-22582 [Non-Patent Document 12] Pharmacol Rev. 2014 Oct; 66(4): 1033-1079 [Non-Patent Document 13] Nat Rev Drug Discov. 2017 May; 16(5):351-367 [Non-Patent Document 14] Adv Biol Regul. 2018 Jan;67:134-140. [Overview of the project]

[0009] The present invention provides dihydrooxadiazinon compounds having PLD inhibitory activity or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the same, and pharmaceutical uses thereof. That is, the present invention includes embodiments as illustrated below.

[0010] [Section 1] The compound represented by formula [I] or a pharmaceutically acceptable salt thereof.

[0011] [ka]

[0012] [In the formula, A is CR10 or N; Cy is (1) C 6-10 aryl, (2) a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen atoms in addition to carbon atoms as ring-constituting atoms, or (3) a 9- or 10-membered partially unsaturated condensed ring group containing 1 or 2 oxygen atoms in addition to carbon atoms as ring-constituting atoms ; R 1 is (1) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b) cyano, (c) SO2R 11 (wherein R 11 is C 1-4 alkyl), or (d) NHCOR 12 (wherein R 12 is C 1-4 alkyl) may be substituted}, (2) C 2-4 alkenyl {wherein the alkenyl is NR 13 R 14 (wherein R 13 and R 14 are each independently hydrogen or C 1-4 alkyl) may be substituted}, (3) C 1-4 haloalkyl, (4) C 1-6 alkoxy (wherein the alkoxy may be substituted with phenyl), (5) NR 15 R 16 (wherein R 15 and R 16 are each independently (a) hydrogen, (b) C 1-4 alkyl {wherein the alkyl is (i) phenyl (wherein the phenyl may be substituted with halogen), or (ii) pyridyl) may be substituted}, (c)C 1-4 Alkoxy, or (d)C 3-4 (It is a cycloalkyl) (6) COR 17 (Here, R 17 C 1-4 (It is alkyl.) (7) CONR 18 R 19 (Here, R 18 and R 19 Each of them operates independently. (a) Hydrogen, (b)C 1-4 Alkyl, (c)C 3-4 Cycloalkyl, or (d)C 5-8 (It is a cross-linked cycloalkyl group.) (8)C 3-4 Cycloalkyl (where the cycloalkyl is, (a) Hydroxy, (b) halogens, or (c) May be substituted with phenyl), (9) A 4- to 7-membered heterocycloalkyl group containing, in addition to carbon atoms, one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms as ring constituent atoms {where the heterocycloalkyl group is (a) Hydroxy, (b) Oxo, (c)NR 20 R 21 (Here, R 20 and R 21 Each of them independently consists of hydrogen or C 1-4 (It is alkyl), or (d) may be substituted with phenyl, (10) A 6- to 11-membered spiroheterocycloalkyl group containing, in addition to carbon atoms, one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms as ring constituent atoms, (11) Phenyl (wherein the phenyl may be substituted with one or two halogens), (12) A 5- to 10-membered heteroaryl (where the heteroaryl contains 1 or 2 R atoms selected from the group consisting of nitrogen and oxygen atoms, in addition to carbon atoms as ring constituent atoms) 22 (may be replaced by), or (13) A saturated or partially unsaturated fused ring group having 8 to 10 members, containing 1 to 4 heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms (where the fused ring group is C 1-4 (May be substituted with a haloalkyl group) and; m R 2 Each of them operates independently. (1) Hydroxy, (2) Cyano, (3) Halogen, (4)C 1-6 Alkyl (where the alkyl is, (a) Hydroxy, or (b)C 3-4 (May be substituted with a cycloalkyl group), (5)C 2-4 Alkenyl (where the alkenyl is C 1-4 (May be substituted with alkoxy), (6)C 1-4 Haloalkyl, (7)C 1-4 Alkoxy (where the alkoxy is, (a) hydroxy, and (b) Halogen (May be substituted with 1 to 3 substituents selected from the group consisting of the following), (8) SR 23 (Here, R 23 C 1-4 (It is alkyl.) (9) COR 24 (Here, R 24 is hydroxy or C 1-4 (It is alkyl.) (10) CONR 25 R 26 (Here, R 25 and R 26 Each of them operates independently. (a) Hydrogen, (b)C 1-6 Alkyl, or (c)C 3-4 (It is a cycloalkyl) (11) SO2R 27 (Here, R 27 C 1-6 (It is alkyl.) (12)C 3-4 Cycloalkyl, (13) A 4- to 7-membered heterocycloalkyl (where the heterocycloalkyl is, (a) halogen, (b)C 1-4 Alkyl, and (c)C 1-4 (May be substituted with one or two substituents selected from the group consisting of haloalkyls), (14) A 5- to 9-membered crosslinked heterocycloalkyl group containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms, (15) A 6 to 11-membered spiroheterocycloalkyl, which contains one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms, or (16) Phenyl and; R 3 , R 4 , R 5 and R 6 Each of them independently consists of hydrogen or C 1-4 It is alkyl; R 7 and R 8 Both are hydrogen, or R 7 and R 8 They bond to each other, and together with the carbon atoms to which they bond, form a cyclopentane ring; R 9 is hydrogen or CONHR 28 (Here, R 28 C 3-4 (It is a cycloalkyl group) R 10 is (1) hydrogen, (2) hydroxy, or (3) halogen ; and one or two Rs 22 are each independently (1) halogen, (2) C 1-4 alkyl, (3) C 1-4 haloalkyl, (4) C 1-4 alkoxy, (5) NHCOR 29 (where R 29 is C 1-4 alkyl), or (6) SO2R 30 (where R 30 is C 1-4 alkyl) ; and m is 0, 1, 2 or 3

[0013] [Item 2] R 9 is hydrogen, the compound according to Item 1 or a pharmaceutically acceptable salt thereof.

[0014] [Item 3] A is N, the compound according to Item 1 or 2 or a pharmaceutically acceptable salt thereof.

[0015] [Item 4] A is CR 10 (where R 10 is as defined in Item 1), the compound according to Item 1 or 2 or a pharmaceutically acceptable salt thereof.

[0016] <x [Item 5] Formula [II]:

[0017] [Chemical formula]

[0018] [In the formula, Cy, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and m have the same meanings as defined in item 1.] The compound according to item 4 or a pharmaceutically acceptable salt thereof, represented by

[0019] [Item 6] R 3 is C 1-4 alkyl, the compound according to any one of items 1 to 5 or a pharmaceutically acceptable salt thereof.

[0020] [Item 7] A pharmaceutical composition comprising the compound according to any one of items 1 to 6 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0021] <​​​​​​​​​​​​​​​​​​​​​​

[0025] [Section 12] Use of any compound described in any one of sections 1 to 6 or a pharmaceutically acceptable salt thereof for the manufacture of a PLD1 inhibitor.

[0026] [Section 13] Use of any one of the compounds described in paragraphs 1 to 6 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic or prophylactic agent for a disease selected from the group consisting of thrombosis and cancer.

[0027] [Section 14] A compound described in any one of items 1 to 6, or a pharmaceutically acceptable salt thereof, for use in inhibiting PLD1.

[0028] [Section 15] A compound or a pharmaceutically acceptable salt thereof, as described in any one of items 1 to 6, for use in the treatment or prevention of a disease selected from the group consisting of thrombosis and cancer.

[0029] [Section 1a] The compound represented by formula [Ia] or a pharmaceutically acceptable salt thereof.

[0030] [ka]

[0031] [In the formula, A a CR 10a or N; A 2a CR 5a or O; Cy a teeth, (1)C 6-10 Ariel, (2) A 5- to 10-membered heteroaryl having one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms, (3) A 9- or 10-membered partially unsaturated condensed ring group containing one or two oxygen atoms in addition to carbon atoms as ring constituent atoms. and; R 1a teeth, (1)C 1-6 Alkyl {Here, the alkyl is, (a) Hydroxy, (b) Cyano, (c)SO2R 11 (Here, R 11 C 1-4 (It is alkyl), or (d) NHCOR 12 (Here, R 12 C 1-4 (which is alkyl) may be substituted, (2)C 2-4 alkenyl {where the alkenyl is 1 to 3 (a)NR 13 R 14 (Here, R 13 and R 14 Each of them independently consists of hydrogen or C 1-4 (It is alkyl.) (b) Halogen, (c)COR 35a (R here) 35a is hydroxy or C 1-4 (It is an alkoxy), (d)CONR 36a R 37a (Here, R 36a and R 37a Each of them independently consists of hydrogen or C 1-4 (It is alkyl), or (e) Partial structural formula:

[0032] [ka]

[0033] It may be replaced with}, (3)C 1-4 Haloalkyl (where the haloalkyl may be substituted with hydroxyl), (4)C 1-6 Alkoxy (where the alkoxy may be substituted with phenyl), (5)NR15 R 16 (Here, R 15 and R 16 Each of them operates independently. (a) Hydrogen, (b)C 1-4 Alkyl {Here, the alkyl is, (i) Phenyl (wherein phenyl may be substituted with a halogen), or (ii) May be substituted with pyridyl, (c)C 1-4 Alkoxy, or (d)C 3-4 (It is a cycloalkyl) (6) COR 17a (Here, R 17a C 1-4 (Alkyl or hydroxyl) (7) CONR 18a R 19a (Here, R 18a and R 19a Each of them operates independently. (a) Hydrogen, (b)C 1-4 Alkyl (where the alkyl may be substituted with hydroxyl), (c)C 3-4 Cycloalkyl, (d)C 5-8 Cross-linked cycloalkyl, (e)C 1-4 Haloalkyl, or (f)C 1-4 (It is an alkoxy), (8)C 3-4 Cycloalkyl (where the cycloalkyl is, (a) Hydroxy, (b) halogens, or (c) May be substituted with phenyl), (9) A 4- to 7-membered heterocycloalkyl group containing, in addition to carbon atoms, one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms as ring constituent atoms {where the heterocycloalkyl group is (a) Hydroxy, (b) Oxo, (c)NR20 R 21 (Here, R 20 and R 21 Each of them independently consists of hydrogen or C 1-4 (It is alkyl), or (d) may be substituted with phenyl, (10) A 6- to 11-membered spiroheterocycloalkyl group containing, in addition to carbon atoms, one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms as ring constituent atoms, (11) Phenyl (wherein phenyl is 1 or 2 (a) halogen, or (b)C 1-4 (May be substituted with a haloalkyl group), (12) A 5- to 10-membered heteroaryl (where the heteroaryl contains 1 or 2 R atoms selected from the group consisting of nitrogen and oxygen atoms, in addition to carbon atoms as ring constituent atoms) 22a (May be replaced by), (13) A saturated or partially unsaturated fused ring group having 8 to 10 members, containing 1 to 4 heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms (where the fused ring group is C 1-4 (may be substituted with a haloalkyl group), or (14) A 5- to 7-membered partially unsaturated ring group containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms (where the partially unsaturated ring group is an oxo group and C 1-4 (May be substituted with alkyl) and; m R 2a Each of them operates independently. (1) Hydroxy, (2) Cyano, (3) Halogen, (4)C 1-6 Alkyl (where the alkyl is, (a) Hydroxy, or (b)C 3-4 (May be substituted with a cycloalkyl group), (5)C 2-4 Alkenyl (where the alkenyl is C1-4 (May be substituted with alkoxy), (6)C 1-4 Haloalkyl, (7)C 1-4 Alkoxy (where the alkoxy is, (a) hydroxy, and (b) Halogen (May be substituted with 1 to 3 substituents selected from the group consisting of the following), (8) SR 23a (Here, R 23a C 1-4 Alkyl or C 1-4 (It is a haloalkyl) (9) COR 24a (Here, R 24a teeth, (a) Hydroxy, (b)C 1-4 Alkyl, or (c)C 1-4 (It is an alkoxy), (10) CONR 25a R 26a (Here, R 25a and R 26a Each of them operates independently. (a) Hydrogen, (b)C 1-6 Alkyl, or (c)C 3-4 It is cycloalkyl, or R 25a and R 26a These atoms bond to each other, and together with the nitrogen atoms to which they bond, form a 4- to 7-membered heterocycloalkyl group (where the heterocycloalkyl group contains, in addition to carbon atoms, one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms as ring constituent atoms, and the heterocycloalkyl group may be substituted with one or two halogens). (11) SO2R 27 (Here, R 27 C 1-6 (It is alkyl.) (12)C 3-4 Cycloalkyl, (13) A 4- to 7-membered heterocycloalkyl (where the heterocycloalkyl is, (a) halogen, (b)C 1-4 Alkyl, and (c)C 1-4 (May be substituted with one or two substituents selected from the group consisting of haloalkyl groups), (14) A 5- to 9-membered crosslinked heterocycloalkyl group containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms, (15) A 6 to 11-membered spiroheterocycloalkyl, which contains one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms, or (16) Phenyl and; R 3a teeth, (1) Hydrogen, (2)C 1-4 Alkyl, or (3)C 1-4 Haloalkyl and; R 4a teeth, (1) Hydrogen, (2)C 1-4 Alkyl, or (3) Cyano and; R 5a is hydrogen or C 1-4 It is alkyl; R 6a , R 7a and R 8a As for combinations, (1)R 6a is hydrogen or C 1-4 It is alkyl, R 7a and R 8a This is a combination where both are hydrogen. (2)R 6a is hydrogen or C 1-4 It is alkyl, R 7a and R8a These are combinations that bond to each other, and together with the carbon and spirocarbon atoms to which they bond, form a cyclopentane ring, or (3)R 6a and R 7a They bond to each other, and together with the carbon and spirocarbon atoms to which they are bonded, form a cyclopentane ring, R 8a The combination is hydrogen and; R 9a teeth, (1) Hydrogen, (2) CONHR 28 (Here, R 28 C 3-4 (It is cycloalkyl), or (3)C 1-4 Alkyl and; R 10a teeth, (1) Hydrogen, (2) Hydroxy, (3) Halogen, (4)C 1-4 Alkyl, (5) Cyano, or (6)C 1-4 Alkoxy and; 1 or 2 R 22a Each of them operates independently. (1) Halogen, (2)C 1-4 Alkyl, (3)C 1-4 Haloalkyl, (4)C 1-4 Alkoxy, (5) NHCOR 29 (Here, R 29 C 1-4 (It is alkyl.) (6) SO2R 30 (Here, R 30 C 1-4 (It is alkyl.) (7) Cyano, or (8)C 3-4 Cycloalkyl and; as well as m is 0, 1, 2, or 3.

[0034] [Section 2a] Formula [IIa]:

[0035] [ka]

[0036] [In the formula, A a Cy a , R 1a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a And m is synonymous with the definition in item 1a. The compounds described in item 1a, or pharmaceutically acceptable salts thereof, as indicated by [the relevant term].

[0037] [Section 3a] Formula [IIIa]:

[0038] [ka]

[0039] [In the formula, Cy a , R 1a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a And m is synonymous with the definition in item 1a. The compounds described in item 1a, or pharmaceutically acceptable salts thereof, as indicated by [the relevant term].

[0040] [Section 4a] Formula [IVa]:

[0041] [ka]

[0042] [In the formula, R 1b teeth, (1)C 1-6 Alkyl {Here, the alkyl is, (a) Hydroxy, (b) Cyano, (c)SO2R 11 (Here, R 11 C 1-4 (It is alkyl), or (d) NHCOR 12 (Here, R 12 C 1-4 (which is alkyl) may be substituted, (2)C 2-4 alkenyl {where the alkenyl is 1 to 3 (a)NR 13 R 14 (Here, R 13 and R 14 Each of them independently consists of hydrogen or C 1-4 (It is alkyl.) (b) Halogen, (c)COR 35a (R here) 35a is hydroxy or C 1-4 (It is an alkoxy), (d)CONR 36a R 37a (Here, R 36a and R 37a Each of them independently consists of hydrogen or C 1-4 (It is alkyl), or (e) Partial structural formula:

[0043] [ka]

[0044] It may be replaced with}, (3)C 1-6 Alkoxy (where the alkoxy may be substituted with phenyl), (4)NR15 R 16 (Here, R 15 and R 16 Each of them operates independently. (a) Hydrogen, (b)C 1-4 Alkyl {Here, the alkyl is, (i) Phenyl (wherein phenyl may be substituted with a halogen), or (ii) May be substituted with pyridyl, (c)C 1-4 Alkoxy, or (d)C 3-4 (It is a cycloalkyl) (5) CONR 18a R 19a (Here, R 18a and R 19a Each of them operates independently. (a) Hydrogen, (b)C 1-4 Alkyl (where the alkyl may be substituted with hydroxyl), (c)C 3-4 Cycloalkyl, (d)C 5-8 Cross-linked cycloalkyl, (e)C 1-4 Haloalkyl, or (f)C 1-4 (It is an alkoxy), (6) A 6- to 11-membered spiroheterocycloalkyl group containing, in addition to carbon atoms, one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms as ring constituent atoms, (7) A 5- to 10-membered heteroaryl having, in addition to carbon atoms, 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen atoms as ring constituent atoms (where the heteroaryl has 1 or 2 R 22a (May be replaced by), (8) A saturated or partially unsaturated fused ring group having 8 to 10 members, containing 1 to 4 heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms (where the fused ring group is C 1-4 (May be substituted with a haloalkyl group), or (9) A 5- to 7-membered partially unsaturated ring group containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms (where the partially unsaturated ring group is an oxo group and C 1-4 (May be substituted with alkyl) and; as well as Cy a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 22a And m is synonymous with the definition in item 1a. The compounds described in item 1a, or pharmaceutically acceptable salts thereof, as indicated by [the relevant symbol].

[0045] [Section 5a] Formula [Va]:

[0046] [ka]

[0047] [In the formula, Cy a , R 2a , R 3a , R 4a and m are synonymous with the definition in item 1a; and R 1b This is synonymous with the definition in item 4a. The compounds described in item 4a, or pharmaceutically acceptable salts thereof, as indicated by [reference].

[0048] [Section 6a] Formula [VIa]:

[0049] [ka]

[0050] [In the formula, Cy b teeth, (1)C 6-10 Aryl, or (2) A 5- or 6-membered heteroaryl compound containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms. and; R 1b This is synonymous with the definition in item 4a; and R 2a , R 3a , R 4a And m is synonymous with the definition in item 1a. The compounds described in item 4a, or pharmaceutically acceptable salts thereof, as indicated by [reference].

[0051] [Section 7a] Formula [VIIa]:

[0052] [ka]

[0053] [In the formula, Cy a , R 2a , R 3a , R 5a , R 6a , R 7a , R 8a and m are synonymous with the definition in item 1a; and R 1b This is synonymous with the definition in item 4a. The compounds described in item 4a, or pharmaceutically acceptable salts thereof, as indicated by [reference].

[0054] [Section 8a] Formula [VIIIa]:

[0055] [ka]

[0056] [In the formula, Cy a , R 2a , R 3a and m are synonymous with the definition in item 1a; and R 1b This is synonymous with the definition in item 4a. The compounds described in item 4a, or pharmaceutically acceptable salts thereof, as indicated by [reference].

[0057] [Section 9a] Formula [IXa]:

[0058] [ka]

[0059] [In the formula, Cy b This is synonymous with the definition in item 6a; R 1b This is synonymous with the definition in item 4a; and R 2a , R 3a And m is synonymous with the definition in item 1a. The compounds described in item 6a, or pharmaceutically acceptable salts thereof, as indicated by [reference].

[0060] [Section 10a] Equation [Xa]:

[0061] [ka]

[0062] [In the formula, Cy a , R 1a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 10a And m is synonymous with the definition in item 1a. The compounds described in item 1a, or pharmaceutically acceptable salts thereof, as indicated by [the relevant term].

[0063] [Section 11a] Formula [XIa]:

[0064] [ka]

[0065] [In the formula, Cy a , R 1a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 10a And m is synonymous with the definition in item 1a. The compounds described in item 1a, or pharmaceutically acceptable salts thereof, as indicated by [the relevant symbol].

[0066] [Section 12a] Formula [XIIa]:

[0067] [ka]

[0068] [In the formula, R 1b teeth, (1)C 1-6 Alkyl {Here, the alkyl is, (a) Hydroxy, (b) Cyano, (c)SO2R 11 (Here, R 11 C 1-4 (It is alkyl), or (d) NHCOR 12 (Here, R 12 C 1-4 (which is alkyl) may be substituted, (2)C 2-4 alkenyl {where the alkenyl is 1 to 3 (a)NR 13 R 14 (Here, R 13 and R 14 Each of them independently consists of hydrogen or C 1-4 (It is alkyl.) (b) Halogen, (c)COR 35a (R here)35a is hydroxy or C 1-4 (It is an alkoxy), (d)CONR 36a R 37a (Here, R 36a and R 37a Each of them independently consists of hydrogen or C 1-4 (It is alkyl), or (e) Partial structural formula:

[0069] [ka]

[0070] It may be replaced with}, (3)C 1-6 Alkoxy (where the alkoxy may be substituted with phenyl), (4)NR 15 R 16 (Here, R 15 and R 16 Each of them operates independently. (a) Hydrogen, (b)C 1-4 Alkyl {Here, the alkyl is, (i) Phenyl (wherein phenyl may be substituted with a halogen), or (ii) May be substituted with pyridyl, (c)C 1-4 Alkoxy, or (d)C 3-4 (It is a cycloalkyl) (5) CONR 18a R 19a (Here, R 18a and R 19a Each of them operates independently. (a) Hydrogen, (b)C 1-4 Alkyl (where the alkyl may be substituted with hydroxyl), (c)C 3-4 Cycloalkyl, (d)C 5-8 Cross-linked cycloalkyl, (e)C 1-4Haloalkyl, or (f)C 1-4 (It is an alkoxy), (6) A 6- to 11-membered spiroheterocycloalkyl group containing, in addition to carbon atoms, one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms as ring constituent atoms, (7) A 5- to 10-membered heteroaryl having, in addition to carbon atoms, 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen atoms as ring constituent atoms (where the heteroaryl has 1 or 2 R 22a (May be replaced by), (8) A saturated or partially unsaturated fused ring group having 8 to 10 members, containing 1 to 4 heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms (where the fused ring group is C 1-4 (may be substituted with a haloalkyl group), or (9) A 5- to 7-membered partially unsaturated ring group containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms (where the partially unsaturated ring group is an oxo group and C 1-4 (May be substituted with alkyl) and; as well as Cy a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 10a , R 22a And m is synonymous with the definition in item 1a. The compounds described in item 1a, or pharmaceutically acceptable salts thereof, as indicated by [the relevant term].

[0071] [Section 13a] Formula [XIIIa]:

[0072] [ka]

[0073] [In the formula, Cy a , R 2a, R 3a , R 4a , R 10a and m are synonymous with the definition in item 1a; and R 1b This is synonymous with the definition in item 12a. The compounds described in item 12a, or pharmaceutically acceptable salts thereof, as indicated by [reference].

[0074] [Section 14a] Formula [XIVa]:

[0075] [ka]

[0076] [In the formula, Cy b teeth, (1)C 6-10 Aryl, or (2) A 5- or 6-membered heteroaryl compound containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms. and; R 1b This is synonymous with the definition in item 12a; and R 2a , R 3a , R 4a , R 10a And m is synonymous with the definition in item 1a. The compounds described in item 12a, or pharmaceutically acceptable salts thereof, as indicated by [reference].

[0077] [Section 15a] Formula [XVa]:

[0078] [ka]

[0079] [In the formula, Cy a , R 2a , R 3a , R 5a , R 6a , R 7a , R 8a, R 10a and m are synonymous with the definition in item 1a; and R 1b This is synonymous with the definition in item 12a. The compounds described in item 12a, or pharmaceutically acceptable salts thereof, as indicated by [reference].

[0080] [Section 16a] Formula [XVIa]:

[0081] [ka]

[0082] [In the formula, Cy a , R 2a , R 3a , R 10a and m are synonymous with the definition in item 1a; and R 1b This is synonymous with the definition in item 12a. The compounds described in item 12a, or pharmaceutically acceptable salts thereof, as indicated by [reference].

[0083] [Section 17a] Formula [XVIIa]:

[0084] [ka]

[0085] [In the formula, Cy b This is synonymous with the definition in item 14a; R 1b This is synonymous with the definition in item 12a; and R 2a , R 3a , R 10a And m is synonymous with the definition in item 1a. The compounds described in item 14a, or pharmaceutically acceptable salts thereof, as indicated by [reference].

[0086] [Section 18a] The following formula:

[0087] [ka]

[0088] A compound selected from the group consisting of compounds represented by [the formula shown], or a pharmaceutically acceptable salt thereof.

[0089] [Section 19a] A pharmaceutical composition comprising a compound described in any one of items 1a to 18a or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0090] [Section 20a] A pharmaceutical composition comprising a compound described in any one of items 1a to 18a or a pharmaceutically acceptable salt thereof, in combination with one or more other agents, and a pharmaceutically acceptable carrier.

[0091] [Section 21a] A PLD inhibitor comprising a compound described in any one of items 1a to 18a or a pharmaceutically acceptable salt thereof.

[0092] [Section 22a] A PLD1 inhibitor comprising a compound described in any one of items 1a to 18a or a pharmaceutically acceptable salt thereof.

[0093] [Section 23a] A PLD1 / 2 inhibitor comprising a compound described in any one of items 1a to 18a or a pharmaceutically acceptable salt thereof.

[0094] [Section 24a] A therapeutic or prophylactic agent for diseases selected from the group consisting of thrombosis and cancer, comprising a compound described in any one of items 1a to 18a or a pharmaceutically acceptable salt thereof.

[0095] [Section 25a] A therapeutic or prophylactic agent for diseases selected from the group consisting of thrombosis and cancer, comprising one or more other drugs, comprising a compound described in any one of items 1a to 18a or a pharmaceutically acceptable salt thereof.

[0096] [Section 26a] A method for inhibiting PLD in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of items 1a to 18a.

[0097] [Section 27a] A method for inhibiting PLD1 in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of items 1a to 18a.

[0098] [Section 28a] A method for inhibiting PLD1 / 2 in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of items 1a to 18a.

[0099] [Section 29a] A method for treating or preventing a disease selected from the group consisting of thrombosis and cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of items 1a to 18a.

[0100] [Section 30a] A method for treating or preventing a disease selected from the group consisting of thrombosis and cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of items 1a to 18a, in combination with one or more other agents.

[0101] [Section 31a] Use of any compound described in any one of items 1a to 18a or a pharmaceutically acceptable salt thereof for the manufacture of a PLD inhibitor.

[0102] [Section 32a] Use of any compound described in any one of items 1a to 18a or a pharmaceutically acceptable salt thereof for the manufacture of a PLD1 inhibitor.

[0103] [Section 33a] Use of any compound described in any one of items 1a to 18a or a pharmaceutically acceptable salt thereof for the manufacture of a PLD1 / 2 inhibitor.

[0104] [Section 34a] Use of any compound described in any one of items 1a to 18a or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic or prophylactic agent for a disease selected from the group consisting of thrombosis and cancer.

[0105] [Section 35a] Use of any compound described in any one of items 1a to 18a or a pharmaceutically acceptable salt thereof, in combination with one or more other agents, for the manufacture of a therapeutic or prophylactic agent for a disease selected from the group consisting of thrombosis and cancer.

[0106] [Section 36a] A compound described in any one of items 1a to 18a, or a pharmaceutically acceptable salt thereof, for use in inhibiting PLDs.

[0107] [Section 37a] A compound described in any one of items 1a to 18a, or a pharmaceutically acceptable salt thereof, for use in inhibiting PLD1.

[0108] [Section 38a] A compound described in any one of items 1a to 18a, or a pharmaceutically acceptable salt thereof, for use in inhibiting PLD1 / 2.

[0109] [Section 39a] A compound or a pharmaceutically acceptable salt thereof, as described in any one of items 1a to 18a, for use in the treatment or prevention of a disease selected from the group consisting of thrombosis and cancer.

[0110] [Section 40a] A compound described in any one of subheadings 1a to 18a, or a pharmaceutically acceptable salt thereof, used in combination with one or more other agents, for the treatment or prevention of a disease selected from the group consisting of thrombosis and cancer. [Effects of the Invention]

[0111] The compounds represented by formula [I] or formula [Ia] of the present invention, or pharmaceutically acceptable salts thereof, possess PLD inhibitory activity and may be useful in the treatment or prevention of thrombosis and cancer. [Modes for carrying out the invention]

[0112] The definitions of terms used herein are as follows:

[0113] "Halogens" include, for example, fluorine, chlorine, bromine, and iodine.

[0114] "C 1-4 "Alkyl" refers to a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms. 1-4 "Alkyl" includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. Preferred "C 1-4 Examples of alkyl groups include methyl, ethyl, n-propyl, n-butyl, isobutyl, and tert-butyl.

[0115] "C 1-6 "Alkyl" refers to a linear or branched saturated hydrocarbon group with 1 to 6 carbon atoms. 1-6 "Alkyl" includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-ethyl-2-methylpropyl, and 3,3-dimethylbutyl. Preferred "C 1-6 Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

[0116] "C 2-4"Alkenyl" refers to a linear or branched hydrocarbon group having 2 to 4 carbon atoms and containing a carbon-carbon double bond. 2-4 "Alkenyl" includes, for example, vinyl, allyl, propa-1-en-1-yl, propa-1-en-2-yl, 2-methylpropa-1-en-yl, buta-3-en-1-yl, buta-2-en-1-yl, and buta-2-en-2-yl. Preferred "C 2-4 Examples of "alkenyls" include vinyl, propa-1-en-1-yl, and 2-methylpropa-1-en-yl.

[0117] "C 1-4 "Haloalkyl" refers to the above "C" which is substituted with 1 to 5 halogens independently selected from the above "halogen" group. 1-4 It means "alkyl". 1-4 "Haloalkyl" includes, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 1,1-difluoroethyl, 1-fluoro-1-methylethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, and 4,4,4-trifluorobutyl. Preferred "C 1-4 Examples of "haloalkyl" include difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, and 3,3,3-trifluoropropyl.

[0118] "C 1-4 "Alkoxy" refers to the above "C 1-4 "Alkyl" refers to a group bonded to an oxygen atom. 1-4 "Alkoxy" includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, and tert-butoxy. Preferred "C 1-4 Examples of "alkoxys" include methoxy, ethoxy, n-propoxy, isobutoxy, and tert-butoxy.

[0119] "C 1-6"Alkoxy" refers to the above "C 1-6 "Alkyl" refers to a group bonded to an oxygen atom. 1-6 "Alkoxy" includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, n-pentyloxy, (3-methylbutan-2-yl)oxy, and n-hexyloxy. Preferred "C 1-6 Examples of "alkoxys" include methoxy, ethoxy, n-propoxy, isobutoxy, and tert-butoxy.

[0120] "C 3-4 "Cycloalkyl" refers to a monocyclic saturated hydrocarbon group with 3 or 4 carbon atoms. 3-4 "Cycloalkyl" includes cyclopropyl and cyclobutyl. Preferred "C 3-4 An example of a "cycloalkyl" is cyclopropyl.

[0121] "C 5-8 "Cross-linked cycloalkyl" refers to a 5- to 8-membered, cross-linked cyclic saturated hydrocarbon group. 5-8 "Cross-linked cycloalkyls" include, for example, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl. Preferred "C 5-8 Examples of "crosslinked cycloalkyls" include bicyclo[1.1.1]pentyl.

[0122] "C 6-10 "Aryl" refers to an aromatic hydrocarbon group with 6 to 10 carbon atoms. 6-10 The "aryl" includes phenyl and naphthyl. Preferred "C 6-10 Phenyle is an example of an "aryl" compound.

[0123] "A 4- to 7-membered heterocycloalkyl group containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms" means a 4- to 7-membered saturated heterocyclic group containing one or two nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms. Examples of "4- to 7-membered heterocycloalkyl groups containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms" include azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidyl, tetrahydropyranil, dioxanil, piperazinyl, morpholinil, and azepanil. Preferred "4- to 7-membered heterocycloalkyl groups containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms" include azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidyl, dioxanil, and morpholinil.

[0124] "A 5- to 9-membered cross-linked heterocycloalkyl group containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms" means a 5- to 9-membered cross-linked heterocyclic group containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms. Examples of "a 5- to 9-membered cross-linked heterocycloalkyl group containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms" include 6-azabicyclo[3.1.1]heptyl, 7-azabicyclo[2.2.1]heptyl, 3-oxa-6-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, and 8-oxa-3-azabicyclo[3.2.1]octyl. Preferred "5- to 9-membered cross-linked heterocycloalkyls containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms" include 2-oxa-5-azabicyclo[2.2.1]heptyl and 8-oxa-3-azabicyclo[3.2.1]octyl.

[0125] "A 6- to 11-membered spiroheterocycloalkyl group containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms" means a 6- to 11-membered spiro-type heterocyclic group containing one or two nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms. Examples of "a 6- to 11-membered spiroheterocycloalkyl group containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms" include 2-azaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 5-azaspiro[2.4]heptyl, 4-oxa-7-azaspiro[2.5]octyl, 2,8-diazaspiro[4.5]decyl, and 3-oxa-9-azaspiro[5.5]undecyl. Preferred "6 to 11-membered spiroheterocycloalkyls containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms" include 2-oxa-6-azaspiro[3.3]heptyl, 5-azaspiro[2.4]heptyl, and 4-oxa-7-azaspiro[2.5]octyl.

[0126] "A 5- or 6-membered heteroaryl group containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms" means a 5- or 6-membered aromatic heterocyclic group containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms. Examples of "5- or 6-membered heteroaryl groups containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms" include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl. Preferred examples of "5- or 6-membered heteroaryl groups containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms" include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl.

[0127] "A 5- to 10-membered heteroaryl group containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms" means a 5- to 10-membered aromatic heterocyclic group containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms. Examples of "5- to 10-membered heteroaryl groups containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms" include pyrrolyl, imidazolyl, pyrazolyl, pyradyl, pyrazinyl, pyrimidinyl, pyridadinyl, indolyl, benzimidazolyl, indazolyl, indolidinyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, quinolyl, isoquinolyl, and quinoxalyl. Preferred "5- to 10-membered heteroaryl compounds containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms" include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, and pyrazolo[1,5-a]pyridyl.

[0128] "A 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen atoms, in addition to carbon atoms, as ring constituent atoms" means a 5- to 10-membered aromatic heterocyclic group containing 1 to 3 nitrogen and oxygen atoms, in addition to carbon atoms, as ring constituent atoms. "A 5- to 10-membered heteroaryl compound containing 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms" includes, for example, pyrrolyl, furyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, triazinyl, indolyl, benzofuranil, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl, indolidinyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, quinolyl, isoquinolyl, and quinoxalyl. Preferred "5- to 10-membered heteroaryl compounds containing 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms" include pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isoxazolyl, 1,2,4-oxadiazolyl, pyridyl, pyrimidinyl, pyridadinyl, pyrazinyl, indolyl, benzofuranyl, benzimidazolyl, indolidinyl, imidazo[1,2-a]pyridyl, and pyrazolo[1,5-a]pyridyl.

[0129] A "5- to 7-membered partially unsaturated ring group containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms" means a 5- to 7-membered partially unsaturated ring group containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms. Examples of "5- to 7-membered partially unsaturated ring groups containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms" include dihydropyrrolyl, dihydropyridyl, and dihydropyrimidinyl. Dihydropyridyl is a preferred example of a "5- to 7-membered partially unsaturated ring group containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms."

[0130] "An 8- to 10-membered saturated or partially unsaturated condensed ring group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms" means an 8- to 10-membered condensed heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms, and the condensed ring having at least one saturated ring in the ring forming the condensed ring. "8 to 10 membered saturated or partially unsaturated condensed ring groups containing 1 to 4 heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms" include, for example, octahydro-2H-isoindolyl, dihydrobenzofuranyl, benzo[d][1,3]dioxolyl, isoindolyl, dihydroisoquinolyl, dihydro-1,6-naphthilidinyl, dihydro-1,7-naphthilidinyl, dihydroisoxazolo[4,3-c]pyridyl, dihydropyrazolo[1,5-a]pyradinyl, and dihydrotriazolo[1,5-a]pyradinyl.

[0131] A "9- or 10-membered partially unsaturated condensed ring group containing one or two oxygen atoms in addition to carbon atoms as ring constituent atoms" means a 9- or 10-membered condensed heterocyclic group containing one or two oxygen atoms in addition to carbon atoms as ring constituent atoms, and the condensed ring having one saturated ring in the ring forming the condensed ring. Examples of "9- or 10-membered partially unsaturated condensed ring groups containing one or two oxygen atoms in addition to carbon atoms as ring constituent atoms" include 2,3-dihydrobenzo[b][1,4]dioxyranyl, dihydrobenzofuranyl, and benzo[d][1,3]dioxolyl. Preferred examples of "9- or 10-membered partially unsaturated condensed ring groups containing one or two oxygen atoms in addition to carbon atoms as ring constituent atoms" include dihydrobenzofuranyl and benzo[d][1,3]dioxolyl.

[0132] "Substituent α may be substituted with substituent β" means that substituent α is either unsubstituted or substituted with substituent β at any substitutable position of substituent α (any hydrogen is replaced by substituent β). For example, "C may be substituted with hydroxyl." 1-6"Alkyl" refers to C 1-6 The alkyl group is either unsubstituted or C 1-6 This means that any hydrogen atom in an alkyl group is substituted with a hydroxyl group.

[0133] Specific embodiments of the substituents of the compound represented by formula [I] (hereinafter also referred to as "compound [I]" in this specification) and the compound represented by formula [Ia] (hereinafter also referred to as "compound [Ia]" in this specification) are exemplified below, but each substituent of compound [I] and compound [Ia] is not limited to its specific embodiment, and compound [I] and compound [Ia] also include embodiments that combine any two or more of the specific embodiments of each substituent. First, specific examples of each substituent in compound [I] are given below.

[0134] A is preferably CR 10 (Here, R 10 (These are hydrogen, hydroxyl, or halogen.)

[0135] Cy is preferably, (1)C 6-10 Aryl, or (2) A 5- or 6-membered heteroaryl having one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms.

[0136] R 3 Preferably, C 1-4 It is alkyl.

[0137] R 4 Preferably, it is hydrogen.

[0138] R 5 Preferably, it is hydrogen.

[0139] R 6 Preferably, it is hydrogen.

[0140] R 7 and R 8 Preferably, both are hydrogen.

[0141] R 9 Preferably, it is hydrogen.

[0142] m is preferably 1 or 2.

[0143] One preferred embodiment of compound [I] is formula [II]:

[0144] [ka]

[0145] [In the formula, Cy, (1)C 6-10 Aryl, or (2) A 5- or 6-membered heteroaryl compound containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms. and; R 1 but, (1)C 1-6 Alkyl {Here, the alkyl is, (a) Hydroxy, (b) Cyano, (c)SO2R 11 (Here, R 11 C 1-4 (It is alkyl), or (d) NHCOR 12 (Here, R 12 C 1-4 (which is alkyl) may be substituted, (2)C 2-4 alkenyl {where the alkenyl is NR 13 R 14 (Here, R 13 and R 14 Each of them independently consists of hydrogen or C 1-4 (which is alkyl) may be substituted, (3)C 1-4 Haloalkyl, (4)C 1-6 Alkoxy (where the alkoxy may be substituted with phenyl), (5)NR15 R 16 (Here, R 15 and R 16 Each of them operates independently. (a) Hydrogen, (b)C 1-4 Alkyl {Here, the alkyl is, (i) Phenyl (wherein phenyl may be substituted with a halogen), or (ii) Pyridyl may be substituted, (c)C 1-4 Alkoxy, or (d)C 3-4 (It is a cycloalkyl) (6) COR 17 (Here, R 17 C 1-4 (It is alkyl.) (7) CONR 18 R 19 (Here, R 18 and R 19 Each of them operates independently. (a) Hydrogen, (b)C 1-4 Alkyl, (c)C 3-4 Cycloalkyl, or (d)C 5-8 (It is a cross-linked cycloalkyl group.) (8)C 3-4 Cycloalkyl (where the cycloalkyl is, (a) Hydroxy, (b) halogens, or (c) May be substituted with phenyl), (9) A 4- to 7-membered heterocycloalkyl group containing, in addition to carbon atoms, one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms as ring constituent atoms {where the heterocycloalkyl group is (a) Hydroxy, (b) Oxo, (c)NR 20 R 21 (Here, R 20 and R 21 Each of them independently consists of hydrogen or C 1-4 (It is alkyl), or (d) may be substituted with phenyl, (10) A 6- to 11-membered spiroheterocycloalkyl group containing, in addition to carbon atoms, one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms as ring constituent atoms, (11) Phenyl (wherein the phenyl may be substituted with one or two halogens), (12) A 5- to 10-membered heteroaryl (where the heteroaryl contains 1 or 2 R atoms selected from the group consisting of nitrogen and oxygen atoms, in addition to carbon atoms as ring constituent atoms) 22 (may be replaced by), or (13) A saturated or partially unsaturated fused ring group having 8 to 10 members, containing 1 to 4 heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms (where the fused ring group is C 1-4 (May be substituted with a haloalkyl group) and; m R 2 However, each is independent of the others. (1) Hydroxy, (2) Cyano, (3) Halogen, (4)C 1-6 Alkyl (where the alkyl is, (a) Hydroxy, or (b)C 3-4 (May be substituted with a cycloalkyl group), (5)C 2-4 Alkenyl (where the alkenyl is C 1-4 (May be substituted with alkoxy), (6)C 1-4 Haloalkyl, (7)C 1-4 Alkoxy (where the alkoxy is, (a) hydroxy, and (b) Halogen (May be substituted with 1 to 3 substituents selected from the group consisting of the following), (8) SR 23 (Here, R 23 C 1-4 (It is alkyl.) (9) COR 24 (Here, R 24 is hydroxy or C 1-4 (It is alkyl.) (10) CONR 25 R 26 (Here, R 25 and R 26 Each of them operates independently. (a) Hydrogen, (b)C 1-6 Alkyl, or (c)C 3-4 (It is a cycloalkyl) (11) SO2R 27 (Here, R 27 C 1-6 (It is alkyl.) (12)C 3-4 Cycloalkyl, (13) A 4- to 7-membered heterocycloalkyl (where the heterocycloalkyl is, (a) halogen, (b)C 1-4 Alkyl, and (c)C 1-4 (May be substituted with one or two substituents selected from the group consisting of haloalkyls), (14) A 5- to 9-membered crosslinked heterocycloalkyl group containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms, (15) A 6 to 11-membered spiroheterocycloalkyl, which contains one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms, or (16) Phenyl and; R 3 However, C 1-4 It is alkyl; R 4 , R 5 , R 6 , R 7 , R 8 and R 9However, they are all hydrogen; R 10 but, (1) Hydrogen, (2) Hydroxy, or (3) Halogen and; 1 or 2 R 22 However, each is independent of the others. (1) Halogen, (2)C 1-4 Alkyl, (3)C 1-4 Haloalkyl, (4)C 1-4 Alkoxy, (5) NHCOR 29 (Here, R 29 C 1-4 (It is alkyl), or (6) SO2R 30 (Here, R 30 C 1-4 (It is alkyl.) and m is 1 or 2. It is a compound represented by [the formula shown].

[0146] Preferred specific embodiments of compound [I] include the compounds of Examples 1 to 339, as described in Tables 1-1 to 1-43 below.

[0147] Next, specific embodiments of each substituent in compound [Ia] are illustrated below. Note that compound [Ia] includes compound [I].

[0148] A a Preferably, CR 10a That is the case. In another aspect, A a Preferably, it is N. A 2a Preferably, CR 5a That is the case.

[0149] Cy a Preferably, (1)C 6-10 Aryl, or (2) A 5- or 6-membered heteroaryl compound containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms. That is the case.

[0150] R 1a Preferably, (1)C 1-6 Alkyl {Here, the alkyl is, (a) Hydroxy, (b) Cyano, (c)SO2R 11 (Here, R 11 C 1-4 (It is alkyl), or (d) NHCOR 12 (Here, R 12 C 1-4 (which is alkyl) may be substituted, (2)C 2-4 alkenyl {where the alkenyl is 1 to 3 (a)NR 13 R 14 (Here, R 13 and R 14 Each of them independently consists of hydrogen or C 1-4 (It is alkyl.) (b) Halogen, (c)COR 35a (R here) 35a is hydroxy or C 1-4 (It is an alkoxy), (d)CONR 36a R 37a (Here, R 36a and R 37a Each of them independently consists of hydrogen or C 1-4 (It is alkyl), or (e) Partial structural formula:

[0151] [ka]

[0152] It may be replaced with}, (3)C 1-6Alkoxy (where the alkoxy may be substituted with phenyl), (4)NR 15 R 16 (Here, R 15 and R 16 Each of them operates independently. (a) Hydrogen, (b)C 1-4 Alkyl {Here, the alkyl is, (i) Phenyl (wherein phenyl may be substituted with a halogen), or (ii) Pyridyl may be substituted, (c)C 1-4 Alkoxy, or (d)C 3-4 (It is a cycloalkyl) (5) CONR 18a R 19a (Here, R 18a and R 19a Each of them operates independently. (a) Hydrogen, (b)C 1-4 Alkyl (where the alkyl may be substituted with hydroxyl), (c)C 3-4 Cycloalkyl, (d)C 5-8 Cross-linked cycloalkyl, (e)C 1-4 Haloalkyl, or (f)C 1-4 (It is an alkoxy), (6) A 6- to 11-membered spiroheterocycloalkyl group containing, in addition to carbon atoms, one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms as ring constituent atoms, (7) A 5- to 10-membered heteroaryl having, in addition to carbon atoms, 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen atoms as ring constituent atoms (where the heteroaryl has 1 or 2 R 22a It may be replaced with (where each R 22a This is synonymous with the above.)) (8) A saturated or partially unsaturated fused ring group having 8 to 10 members, containing 1 to 4 heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms (where the fused ring group is C 1-4 (may be substituted with a haloalkyl group), or (9) A 5- to 7-membered partially unsaturated ring group containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms (where the partially unsaturated ring group is an oxo group and C 1-4 (May be substituted with alkyl) That is the case.

[0153] In another aspect, R 1a Preferably, (1)NR 15 R 16 (Here, R 15 and R 16 Each of them operates independently. (a) Hydrogen, (b)C 1-4 Alkyl {Here, the alkyl is, (i) Phenyl (wherein phenyl may be substituted with a halogen), or (ii) Pyridyl may be substituted, (c)C 1-4 Alkoxy, or (d)C 3-4 (It is a cycloalkyl) (2) CONR 18a R 19a (Here, R 18a and R 19a Each of them operates independently. (a) Hydrogen, (b)C 1-4 Alkyl (where the alkyl may be substituted with hydroxyl), (c)C 3-4 Cycloalkyl, (d)C 5-8 Cross-linked cycloalkyl, (e)C 1-4 Haloalkyl, or (f)C 1-4 (It is an alkoxy), or (3) A 5- to 10-membered heteroaryl containing, in addition to carbon atoms, 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen atoms as ring constituent atoms (where the heteroaryl contains 1 or 2 R 22a It may be replaced with (where each R 22a This is synonymous with the above.) That is the case.

[0154] m R 2a Each of them is independent, preferably, (1) Cyano, (2) Halogen, or (3)C 1-6 Alkyl (where the alkyl is, (a) Hydroxy, or (b)C 3-4 (May be substituted with cycloalkyl) That is the case.

[0155] R 3a Preferably, C 1-4 It is alkyl. In another aspect, R 3a Preferably, it is methyl.

[0156] R 4a Preferably, it is hydrogen.

[0157] R 5a Preferably, it is hydrogen.

[0158] R 6a , R 7a and R 8a Preferably, the combination is (1)R 6a is hydrogen, and R 7a and R 8a This is a combination where both are hydrogen. (2)R 6a is hydrogen, and R 7a and R 8a These are combinations that bond to each other, and together with the carbon and spirocarbon atoms to which they bond, form a cyclopentane ring, or (3)R 6a and R 7a They bond to each other, and together with the carbon and spirocarbon atoms to which they are bonded, form a cyclopentane ring, R 8a The combination is hydrogen That is the case. In another aspect, R 6a , R 7a and R 8a Preferably, all of them are hydrogen.

[0159] R 9a Preferably, it is hydrogen.

[0160] R 10a Preferably, (1) Hydrogen, (2) Hydroxy, or (3) Cyano That is the case.

[0161] 1 or 2 R 22a Each of them is independent, preferably, (1) Halogen, (2)C 1-4 Alkyl, (3)C 1-4 Haloalkyl, (4)C 1-4 Alkoxy, (5) NHCOR 29 (Here, R 29 C 1-4 (It is alkyl.) (6) Cyano, or (7)C 3-4 Cycloalkyl That is the case.

[0162] m is preferably 1 or 2.

[0163] One preferred embodiment of compound [Ia] is formula [IIa]:

[0164] [ka]

[0165] [In the formula, A a Cy a , R 1a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0166] Another preferred embodiment of compound [Ia] is formula [IIIa]:

[0167] [ka]

[0168] [In the formula, Cy a , R 1a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0169] Another preferred embodiment of compound [Ia] is formula [IVa]:

[0170] [ka]

[0171] [In the formula, Cy a , R 1b , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8aAnd m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0172] Another preferred embodiment of compound [Ia] is formula [Va]:

[0173] [ka]

[0174] [In the formula, Cy a , R 1b , R 2a , R 3a , R 4a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0175] Another preferred embodiment of compound [Ia] is formula [VIa]:

[0176] [ka]

[0177] [In the formula, Cy b , R 1b , R 2a , R 3a , R 4a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0178] Another preferred embodiment of compound [Ia] is formula [VIIa]:

[0179] [ka]

[0180] [In the formula, Cy a , R 1b , R 2a , R 3a , R 5a, R 6a , R 7a , R 8a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0181] Another preferred embodiment of compound [Ia] is formula [VIIIa]:

[0182] [ka]

[0183] [In the formula, Cy a , R 1b , R 2a , R 3a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0184] Another preferred embodiment of compound [Ia] is formula [IXa]:

[0185] [ka]

[0186] [In the formula, Cy b , R 1b , R 2a , R 3a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0187] Another preferred embodiment of compound [Ia] is formula [Xa]:

[0188] [ka]

[0189] [In the formula, Cy a , R 1a , R 2a , R 3a, R 4a , R 5a , R 6a , R 7a , R 8a , R 10a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0190] Another preferred embodiment of compound [Ia] is formula [XIa]:

[0191] [ka]

[0192] [In the formula, Cy a , R 1a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 10a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0193] Another preferred embodiment of compound [Ia] is formula [XIIa]:

[0194] [ka]

[0195] [In the formula, Cy a , R 1b , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 10a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0196] Another preferred embodiment of compound [Ia] is formula [XIIIa]:

[0197] [ka]

[0198] [In the formula, Cy a , R 1b , R 2a , R 3a , R 4a , R 10a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0199] Another preferred embodiment of compound [Ia] is formula [XIVa]:

[0200] [ka]

[0201] [In the formula, Cy b , R 1b , R 2a , R 3a , R 4a , R 10a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0202] Another preferred embodiment of compound [Ia] is formula [XVa]:

[0203] [ka]

[0204] [In the formula, Cy a , R 1b , R 2a , R 3a , R 5a , R 6a , R 7a , R 8a , R10a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0205] Another preferred embodiment of compound [Ia] is formula [XVIa]:

[0206] [ka]

[0207] [In the formula, Cy a , R 1b , R 2a , R 3a , R 10a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0208] Another preferred embodiment of compound [Ia] is formula [XVIIa]:

[0209] [ka]

[0210] [In the formula, Cy b , R 1b , R 2a , R 3a , R 10a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0211] Another preferred embodiment of compound [Ia] is formula [XVIIIa]:

[0212] [ka]

[0213] [In the formula, Cy b , R 1b , R 2aAnd m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0214] Another preferred embodiment of compound [Ia] is formula [XIXa]:

[0215] [ka]

[0216] [In the formula, R 1c teeth, (1)C 1-4 Haloalkyl (where the haloalkyl may be substituted with hydroxyl), (2) COR 17a (Here, R 17a C 1-4 (Alkyl or hydroxyl) (3)C 3-4 Cycloalkyl (where the cycloalkyl is, (a) Hydroxy, (b) halogens, or (c) May be substituted with phenyl), (4) A 4- to 7-membered heterocycloalkyl group containing, in addition to carbon atoms, one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms as ring constituent atoms {where the heterocycloalkyl group is (a) Hydroxy, (b) Oxo, (c)NR 20 R 21 (Here, R 20 and R 21 Each of them independently consists of hydrogen or C 1-4 (It is alkyl), or (d) may be substituted with phenyl, or (5) Phenyl (wherein the phenyl is 1 or 2 (a) halogen, or (b)C 1-4 (May be substituted with a haloalkyl group) and Cya , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0217] Another preferred embodiment of compound [Ia] is formula [XXa]:

[0218] [ka]

[0219] [In the formula, Cy a , R 1c , R 2a , R 3a , R 4a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0220] Another preferred embodiment of compound [Ia] is formula [XXIa]:

[0221] [ka]

[0222] [In the formula, Cy b , R 1c , R 2a , R 3a , R 4a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0223] Another preferred embodiment of compound [Ia] is formula [XXIIa]:

[0224] [ka]

[0225] [In the formula, Cy a , R 1c , R 2a , R 3a , R 5a , R 6a , R 7a , R 8a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0226] Another preferred embodiment of compound [Ia] is formula [XXIIIa]:

[0227] [ka]

[0228] [In the formula, Cy a , R 1c , R 2a , R 3a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0229] Another preferred embodiment of compound [Ia] is formula [XXIVa]:

[0230] [ka]

[0231] [In the formula, Cy b , R 1c , R 2a , R 3a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0232] Another preferred embodiment of compound [Ia] is formula [XXVa]:

[0233] [ka]

[0234] [In the formula, Cy b , R 1c , R 2a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0235] Another preferred embodiment of compound [Ia] is formula [XXVIa-1], formula [XXVIa-2], formula [XXVIa-3], formula [XXVIa-4], formula [XXVIa-5], formula [XXVIa-6], formula [XXVIa-7], formula [XXVIa-8], or formula [XXVIa-9]:

[0236] [ka]

[0237] [In the formula, R 1b , R 2a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0238] Another preferred embodiment of compound [Ia] is formula [XXVIIa-1], formula [XXVIIa-2], formula [XXVIIa-3], formula [XXVIIa-4], formula [XXVIIa-5], formula [XXVIIa-6], formula [XXVIIa-7], formula [XXVIIa-8], formula [XXVIIa-9], formula [XXVIIa-10], or formula [XXVIIa-11]:

[0239] [ka]

[0240] [In the formula, ma is 0, 1, or 2. R 1b and R 2a This is synonymous with the definition above. It is a compound represented by [the formula shown].

[0241] Another preferred embodiment of compound [Ia] is formula [XXVIIIa]:

[0242] [ka]

[0243] [In the formula, Cy b , R 1b , R 2a , R 10a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0244] Another preferred embodiment of compound [Ia] is formula [XXIXa]:

[0245] [ka]

[0246] [In the formula, Cy a , R 1c , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 10a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0247] Another preferred embodiment of compound [Ia] is formula [XXXa]:

[0248] [ka]

[0249] [In the formula, Cy a , R 1c , R 2a , R 3a , R4a , R 10a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0250] Another preferred embodiment of compound [Ia] is formula [XXXIa]:

[0251] [ka]

[0252] [In the formula, Cy b , R 1c , R 2a , R 3a , R 4a , R 10a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0253] Another preferred embodiment of compound [Ia] is formula [XXXIIa]:

[0254] [ka]

[0255] [In the formula, Cy a , R 1c , R 2a , R 3a , R 5a , R 6a , R 7a , R 8a , R 10a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0256] Another preferred embodiment of compound [Ia] is formula [XXXIIIa]:

[0257] [ka]

[0258] [In the formula, Cy a , R 1c , R 2a , R 3a , R 10a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0259] Another preferred embodiment of compound [Ia] is formula [XXXIVa]:

[0260] [ka]

[0261] [In the formula, Cy b , R 1c , R 2a , R 3a , R 10a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0262] Another preferred embodiment of compound [Ia] is formula [XXXVa]:

[0263] [ka]

[0264] [In the formula, Cy b , R 1c , R 2a , R 10a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0265] Another preferred embodiment of compound [Ia] is formula [XXXVIa-1], formula [XXXVIa-2], formula [XXXVIa-3], formula [XXXVIa-4], formula [XXXVIa-5], formula [XXXVIa-6], formula [XXXVIa-7], formula [XXXVIa-8], or formula [XXXVIa-9]:

[0266] [ka]

[0267] [In the formula, R 1b , R 2a , R 10a And m is synonymous with the definition above. It is a compound represented by [the formula shown].

[0268] Another preferred embodiment of compound [Ia] is formula [XXXVIIa-1], formula [XXXVIIa-2], formula [XXXVIIa-3], formula [XXXVIIa-4], formula [XXXVIIa-5], formula [XXXVIIa-6], formula [XXXVIIa-7], formula [XXXVIIa-8], formula [XXXVIIa-9], formula [XXXVIIa-10], or formula [XXXVIIa-11]:

[0269] [ka]

[0270] [In the formula, R 1b , R 2a , R 10a And ma are synonymous with the definitions above. It is a compound represented by [the formula shown].

[0271] Preferred specific embodiments of compound [Ia] include the compounds of Examples 1 to 339 and Examples 2-001 to 2-172, as described in Tables 1-1 to 1-61 below.

[0272] A "pharmaceutically acceptable salt" is any salt known in the art that does not exhibit excessive toxicity. Specifically, this includes salts with inorganic acids, organic acids, inorganic bases, and organic bases. Various forms of pharmaceutically acceptable salts are well known in the art and are described, for example, in the following references: (a)Berge et al., J.Pharm.Sci., 66, p1-19 (1977); (b)Stahl et al., "Handbook of Pharmaceutical Salt: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany,2002); (c) Paulekuhn et al., J. Med. Chem., 50, p6665-6672 (2007). A pharmaceutically acceptable salt thereof can be obtained by reacting compound [I] or compound [Ia] with an inorganic acid, organic acid, inorganic base, or organic base according to a method known to the present day.

[0273] Examples of salts with inorganic acids include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, or sulfuric acid. Preferably, salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, or hydrobromic acid are used.

[0274] Examples of salts with organic acids include acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylenecitric acid, benzoic acid, benzenesulfonic acid, calcium edetate, camphoric acid, camphor-10-sulfonic acid, carbonic acid, citric acid, edetate, ethane-1,2-disulfonic acid, dodecyl sulfate, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glucoheptonic acid, glycolylarsanilic acid, hexylresorcinic acid, hydroxynaphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, lactobionic acid, Examples include salts with malic acid, maleic acid, mandelic acid, methanesulfonic acid, methylsulfuric acid, methylnitrate, methylenebis(salicylic acid), galactaric acid, naphthalene-2-sulfonic acid, 2-naphthoic acid, 1,5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic acid, pantothenic acid, pectinic acid, picric acid, propionic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, theoclic acid, thiocyanic acid, trifluoroacetic acid, p-toluenesulfonic acid, undecanoic acid, aspartic acid, or glutamic acid. Preferably, salts with oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoic acid, glucuronic acid, oleic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or 2-hydroxy-1-ethanesulfonic acid are used.

[0275] Examples of salts with inorganic bases include salts with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth, or ammonium. Preferably, salts with sodium, potassium, calcium, magnesium, or zinc are used.

[0276] Examples of salts with organic bases include salts with arecoline, betaine, choline, cremisole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine, or lysine. Preferably, salts with tris(hydroxymethyl)methylamine, N-methylglucamine, or lysine are used.

[0277] Compound [I] or compound [Ia] or a pharmaceutically acceptable salt thereof may exist as a solvate. A "solvate" is, for example, a solvent molecule coordinated to compound [I] or compound [Ia] or a pharmaceutically acceptable salt thereof. The solvate may be any pharmaceutically acceptable solvate, such as a hydrate, acetate, ethanol, or dimethyl sulfoxide of compound [I] or compound [Ia] or a pharmaceutically acceptable salt thereof. Specifically, examples include the hemihydrate, monohydrate, dihydrate, monoacetate, or monoethanolate of compound [I] or compound [Ia], or the monohydrate or 2 / 3 ethanolate of the sodium salt of compound [I] or compound [Ia]. These solvates can be obtained by known methods.

[0278] Compound [I] or compound [Ia] may exist as a tautomer. In that case, compound [I] or compound [Ia] may exist as individual tautomers or as a mixture of tautomers. Compound [I] or compound [Ia] may contain a carbon-carbon double bond. In that case, compound [I] or compound [Ia] may exist as the E-isomer, the Z-isomer, or a mixture of the E-isomer and the Z-isomer. Compound [I] or compound [Ia] may have stereoisomers that should be recognized as cis / trans isomers. In such cases, compound [I] or compound [Ia] may exist as the cis isomer, the trans isomer, or a mixture of the cis and trans isomers.

[0279] Compound [I] or compound [Ia] may have one or more chiral carbon atoms. In that case, compound [I] or compound [Ia] may exist as a single enantiomer, a single diastereomer, a mixture of enantiomers, or a mixture of diastereomers. Compound [I] or compound [Ia] may exist as atropisomers. In that case, compound [I] or compound [Ia] may exist as individual atropisomers or as a mixture of atropisomers. Compound [I] or compound [Ia] may simultaneously contain multiple structural features that give rise to the above-mentioned isomers. Furthermore, compound [I] or compound [Ia] may contain the above-mentioned isomers in any proportion.

[0280] Formulas, chemical structures, or compound names expressed herein without specifying stereochemistry include all possible isomers unless otherwise noted. For example, the following formula:

[0281] [ka]

[0282] The structure described above is, unless otherwise noted, (1) The following formula:

[0283] [ka]

[0284] A mixture of two diastereomers (where the stereochemistry of the chiral carbon indicated by * is S and R), (2)* The stereochemistry of the chiral carbon shown is S diastereomer, and (3)* The stereochemistry of the chiral carbon shown is R diastereomer It means including all of them.

[0285] Diastereomer mixtures can be separated into their individual diastereomers by conventional methods such as chromatography and crystallization. Alternatively, each diastereomer can be synthesized using stereochemically monolithic starting materials or through stereoselective reactions.

[0286] Separation of each single enantiomer from a mixture of enantiomers can be carried out by methods well known in the art. For example, from a mixture of enantiomers and a mixture of diastereomers formed by reacting with a compound that is a substantially pure enantiomer and known as a chiral auxiliary, a standard method such as fractional crystallization or chromatography can be used to separate an isomer ratio-enhanced or substantially pure single diastereomer. The separated diastereomer can be converted to the target enantiomer by cleaving and removing the added chiral auxiliary. Also, a mixture of enantiomers can be directly separated by a chromatography method using a chiral stationary phase, which is well known in the art. Alternatively, either enantiomer can also be obtained by using a substantially pure optically active starting material or by performing stereoselective synthesis (asymmetric induction) using a chiral auxiliary or an asymmetric catalyst on a prochiral intermediate.

[0287] The absolute configuration can be determined by X-ray crystallographic analysis of the crystalline product or intermediate. In that case, a crystalline product or intermediate derivatized with a reagent having an asymmetric center with a known configuration may be used if necessary.

[0288] Compound [I] or compound [Ia] is an isotope 2 H(D), 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 18 O, 18 F, 35 S, 123Compounds [I] or [Ia] may be labeled with isotope-labeled compounds. For example, if compound [I] or compound [Ia] has methyl groups, these methyl groups may be replaced with -CD3. Such labeled compounds [I] or compound [Ia] are also included in the present invention. Compounds [I] or [Ia] labeled with isotopes may be useful in pharmaceuticals, pharmacokinetic studies, in vitro and / or in vivo assays, and / or diagnostics (positron emission tomography (PET), single-photon emission computed tomography (SPECT), etc.). Compounds [I] or [Ia] labeled with isotopes may be prepared by known methods or by the methods described herein, using isotope-labeled reagents instead of non-isotope-labeled reagents.

[0289] Compound [I] or Compound [Ia] or a pharmaceutically acceptable salt thereof is preferably substantially purified. More preferably, Compound [I] or Compound [Ia] or a pharmaceutically acceptable salt thereof is purified to a purity of 80% or higher.

[0290] The pharmaceutical compositions described herein may be prepared by mixing a therapeutically effective amount of an active ingredient (e.g., compound [I] or compound [Ia] or a pharmaceutically acceptable salt thereof) with at least one pharmaceutically acceptable carrier, etc., as appropriate, according to methods known in the pharmaceutical technology. The content of the active ingredient in the pharmaceutical composition varies depending on the dosage form, dose, etc., but is, for example, 0.1 to 100% by weight of the total composition.

[0291] Dosage forms of pharmaceutical compositions containing compound [I] or compound [Ia] or a pharmaceutically acceptable salt thereof include oral preparations such as tablets, capsules, granules, powders, lozenges, syrups, emulsions, and suspensions, and parenteral preparations such as topical preparations, suppositories, injections, eye drops, nasal preparations, and pulmonary preparations.

[0292] Examples of "pharmaceutically acceptable carriers" include various organic or inorganic carrier substances commonly used as pharmaceutical materials, such as excipients, disintegrants, binders, fluidizers, lubricants, etc. in solid formulations; solvents, solubilizers, suspending agents, isotonic agents, buffers, analgesics, etc. in liquid formulations; and bases, emulsifiers, wetting agents, stabilizers, dispersants, plasticizers, pH adjusters, absorption enhancers, gelling agents, preservatives, fillers, solvents, solubilizers, suspending agents, etc. in semi-solid formulations. Furthermore, additives such as preservatives, antioxidants, colorants, and sweeteners may be added as needed.

[0293] Examples of "excipients" include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, and gum arabic. Examples of "disintegrants" include carmellose, carmellose calcium, carmellose sodium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, and crystalline cellulose. Examples of "binding agents" include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, and gum arabic. Examples of "fluidizing agents" include light anhydrous silicic acid and magnesium stearate. Examples of "lubricants" include magnesium stearate, calcium stearate, and talc. Examples of "solvents" include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, and olive oil. Examples of "solubilizing agents" include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, and sodium citrate. Examples of "suspending agents" include benzalkonium chloride, carmellose, hydroxypropylcellulose, propylene glycol, povidone, methylcellulose, and glyceryl monostearate. Examples of "isotonic agents" include glucose, D-sorbitol, sodium chloride, and D-mannitol. Examples of "buffering agents" include sodium hydrogen phosphate, sodium acetate, sodium carbonate, and sodium citrate. Examples of "pain-relieving agents" include benzyl alcohol. Examples of "bases" include water, animal and vegetable oils (olive oil, corn oil, peanut oil, sesame oil, castor oil, etc.), lower alcohols (ethanol, propanol, propylene glycol, 1,3-butylene glycol, phenol, etc.), higher fatty acids and their esters, waxes, higher alcohols, polyhydric alcohols, hydrocarbons (white petrolatum, liquid paraffin, paraffin, etc.), hydrophilic petrolatum, refined lanolin, absorbent ointment, hydrated lanolin, hydrophilic ointment, starch, pullulan, gum arabic, tragacanth gum, gelatin, dextran, cellulose derivatives (methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.), synthetic polymers (carboxyvinyl polymer, sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, etc.), propylene glycol, macrogol (macrogol 200-600, etc.), and combinations of two or more of these. Examples of "preservatives" include ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, and sorbic acid. Examples of "antioxidants" include sodium sulfite and ascorbic acid. Examples of "coloring agents" include food colorings (such as Food Red No. 2 or 3, Food Yellow No. 4 or 5, etc.) and beta-carotene. Examples of sweeteners include sodium saccharin, dipotassium glycyrrhizinate, and aspartame.

[0294] The above-mentioned pharmaceutical composition can be administered orally or parenterally (topically, rectally, intravenously, intramuscularly, subcutaneously, etc.) to humans and other mammals (mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cattle, horses, sheep, monkeys, etc.). The dosage (hereinafter also referred to as the "therapeutically effective dose" in this specification) varies depending on the target of administration, route of administration, target disease, symptoms, severity of the disease, dosage form, etc. For example, when administered orally to a human (adult patient) (body weight 60 kg), the lower limit of the therapeutically effective dose may be approximately 0.01 mg, approximately 0.1 mg, approximately 0.5 mg, approximately 1 mg, approximately 10 mg, approximately 20 mg, or approximately 50 mg per day, and the upper limit of the therapeutically effective dose may be approximately 1 mg, approximately 5 mg, approximately 10 mg, approximately 20 mg, approximately 50 mg, approximately 100 mg, approximately 200 mg, approximately 500 mg, or approximately 1000 mg per day. These amounts can be administered in divided doses once, twice, three times, or more times per day.

[0295] "Inhibiting PLD" means inhibiting the function of PLD, thereby eliminating or reducing its activity. For example, it means inhibiting the function of PLD based on the conditions of Test Example 1 and / or Test Example 2 described later. Inhibition of PLD function or elimination or reduction of its activity is preferably performed in a clinical indication in humans. "Inhibiting PLD" can also mean "inhibiting PLD1." "Inhibiting PLD1" means inhibiting the function of PLD1, thereby eliminating or reducing its activity. For example, it means inhibiting the function of PLD1 based on the conditions of Test Example 1 described later. Inhibition of PLD1 function or elimination or reduction of its activity is preferably performed in human clinical indications. "Inhibiting PLD" can also mean "inhibiting PLD1 / 2." "Inhibiting PLD1 / 2" means inhibiting the function of PLD1 and PLD2, thereby eliminating or reducing their activity. For example, it means inhibiting the function of PLD1 and PLD2 based on the conditions of Test Example 1 and Test Example 2 described later. The inhibition of the function of PLD1 and PLD2, or the elimination or reduction of their activity, is preferably performed in a clinical indication in humans.

[0296] Preferably, "inhibits PLD" means "inhibits human PLD."

[0297] A "PLD inhibitor" refers to a substance that binds to PLD and inhibits its function. Preferably, the "PLD inhibitor" is a "human PLD inhibitor." One embodiment of a "PLD inhibitor" is a "PLD1 inhibitor." A "PLD1 inhibitor" refers to a substance that binds to PLD1 and inhibits its function. Preferably, the "PLD1 inhibitor" is a "human PLD1 inhibitor." One embodiment of a "PLD inhibitor" is a "PLD1 / 2 inhibitor." A "PLD1 / 2 inhibitor" refers to a substance that binds to PLD1 and PLD2 and inhibits the function of PLD1 and PLD2. Preferably, the "PLD1 / 2 inhibitor" is a "human PLD1 / 2 inhibitor."

[0298] Compound [I] or compound [Ia] or its pharmaceutically acceptable salts possess PLD inhibitory activity and may be useful in the treatment and / or prevention of various diseases or conditions that can be expected to improve by regulating PLD activity. Examples of diseases or conditions that can be expected to improve by regulating PLD activity include thrombosis (e.g., arterial thrombosis, acute coronary syndrome, stable angina, unstable angina, non-ST-elevation myocardial infarction, ST-elevation myocardial infarction, ischemic stroke, non-cardioembolic stroke, atherothrombotic stroke, cryptogenic stroke, and embolic stroke of undetermined origin). Examples include thrombosis during and after the perioperative period associated with revascularization procedures (coronary artery bypass surgery, percutaneous coronary intervention, carotid endarterectomy, carotid artery stenting, thrombolytic therapy, lower extremity revascularization, etc.) or aortic valve replacement (surgical aortic valve replacement, transcatheter aortic valve replacement, etc.), and cancer (e.g., breast cancer, ovarian cancer, lung cancer, colorectal cancer, kidney cancer, pancreatic cancer, prostate cancer, brain tumors, etc.).

[0299] In this specification, “treatment” includes improvement of symptoms, prevention of worsening, maintenance of remission, prevention of relapse, secondary prevention, and prevention of recurrence.

[0300] In this specification, "prevention" includes suppressing the onset of symptoms.

[0301] In some embodiment, a PLD inhibitor or pharmaceutical composition may be provided in the form of a kit (such as an administration, treatment, and / or prevention kit), package (such as a packaging), or drug set (and / or container), along with a statement indicating that it may or should be used for treatment and / or prevention. Such a kit, package, or drug set may comprise one or more containers filled with the PLD inhibitor and / or other drugs or substances (or components). Examples of such kits, packages, and drug sets include commercial kits, packages, and drug sets appropriately directed for the treatment and / or prevention of the target disease. The statements included in such kits, packages, and drug sets may include warnings or package inserts in the form directed by a government agency that regulates the manufacture, use, or sale of pharmaceutical or biological products, indicating the approval of such government agency for the manufacture, use, or sale of the product in relation to human administration. The above-mentioned kits, packages, and drug sets may also include packaged products, structures configured for appropriate administration steps, and structures configured to achieve more favorable medical treatment and / or prevention, including treatment and / or prevention of the target disease.

[0302] Compound [I] or compound [Ia] of the present invention, or a pharmaceutically acceptable salt thereof, may be used in combination with one or more other drugs (hereinafter also referred to as "combination drugs" in the present invention) as long as their efficacy is not impaired. In this case, the timing of administration is not limited; they may be administered to the target patient simultaneously or with a time difference. Furthermore, a single formulation containing a combination of Compound [I] or compound [Ia] of the present invention, or a pharmaceutically acceptable salt thereof, and the combination drug may also be administered. The form of administration of the combination drug is not particularly limited; it is sufficient that Compound [I] or compound [Ia] of the present invention, or a pharmaceutically acceptable salt thereof, is combined with the combination drug. The dosage of the concomitant drug can be appropriately selected based on clinically used doses. Furthermore, the mixing ratio of compound [I] or compound [Ia] of the present invention or its pharmaceutically acceptable salt with the concomitant drug can be appropriately selected depending on the target patient, route of administration, target disease, symptoms, combination, etc. The combination of PLD inhibitors and existing thrombosis treatments is expected to suppress arterial thrombus formation without increasing the risk of bleeding.

[0303] Examples of concomitant medications include antiplatelet agents, anticoagulants, and thrombolytic agents. Examples of antiplatelet agents include aspirin, ticlopidine, cilostazol, clopidogrel, prasugrel, ticagrelor, ceratogrel, glenzosimab, zarunfiban, rebacept, amfibatide, PZ-128, bicagrel, tirofiban, and absicimab. Examples of anticoagulants include warfarin, rivaroxaban, apixaban, edoxaban, dabigatran, heparin, heparinoids, fondaparinux, argatroban, tecalfarin, avelacimab, milbexian, asundexan, BAY-2306001, TRx1, osocimab, AB-023, and dimoregine. Examples of thrombolytic agents include recombinant tissue-type plasminogen activator and urokinase.

[0304] In this specification, the presentation of preferred embodiments and options of the compounds, methods, uses and compositions of the present invention also includes the presentation of combinations of such preferred embodiments and options, provided that they are combinatorial and inconsistent.

[0305] [General manufacturing method] Examples of general methods for producing compound [I] or compound [Ia] or its pharmaceutically acceptable salts are given below. However, the methods for producing compound [I] or compound [Ia] or its pharmaceutically acceptable salts are not limited to these methods. Furthermore, unless otherwise specified, the salts of each compound in the general methods may be appropriately selected from the "pharmaceutically acceptable salts" listed above. The compounds obtained in each step can be isolated and / or purified by known methods such as distillation, recrystallization, and column chromatography, as needed. However, in some cases, the process can proceed to the next step without isolation and / or purification. In this specification, room temperature refers to the temperature in an uncontrolled state, and one embodiment is a range of 1°C to 40°C.

[0306] The abbreviations used are as follows: THF: Tetrahydrofuran DMF: N,N-dimethylformamide CDCl3: Deuterated chloroform Pt-C: Platinum-activated carbon Pd-C: Palladium-Activated Carbon DMSO: Dimethyl sulfoxide LiHMDS: Lithium bis(trimethylsilyl)amide NaHMDS: Sodium bis(trimethylsilyl)amide TBAF: Tetra-n-butylammonium fluoride DBU: Diazabicycloundesen CDI: 1,1'-Carbonyldiimidazole WSC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazole[4,5-b]pyridinium 3-oxide hexafluorophosphate DMT-MM:4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride HOAt: 1-Hydroxy-7-Azabenzotriazole DMAP: 4-Dimethylaminopyridine CPME: Cyclopentyl methyl ether DMA: Dimethylacetamide Boc2O: Di-tert-butyl dicarbonate LDA: Lithium diisopropylamide

[0307] Manufacturing method A1: Method for producing compound [I] or its salt Compound [I] or a salt thereof can be produced, for example, by production method A1 shown below.

[0308]

Chemical formula

[0309] [wherein, A, Cy, R 1 ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​Examples of solvents include DMF, acetonitrile, and THF. The preferred solvent is DMF. The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C. Also, for example, L 11 If is hydroxyl, compound [I] or a salt thereof can also be prepared by reacting compound [A1-1] or a salt thereof with compound [A1-2] or a salt thereof in a solvent in the presence of a condensing agent and a base. Examples of suitable bases include triethylamine and N,N-diisopropylethylamine. The preferred base is N,N-diisopropylethylamine. Examples of condensing agents include WSC, HATU, and DMT-MM. The preferred condensing agent is WSC or HATU. Examples of solvents include DMF, acetonitrile, methanol, and THF. The preferred solvent is DMF. The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C. Compound [A1-1] or a salt thereof may be commercially available or produced from a commercially available product by known methods, for example, by the production methods B1 and B2 described below. Compound [A1-2] or its salt may be commercially available or may be prepared from a commercially available product by known methods. Substitute compound [A1-1] or its salt with R in a known reaction. 2 Using a compound or salt thereof having a functional group on Cy that can be converted to or a protected functional group, the present manufacturing method is carried out to obtain a compound or salt thereof corresponding to compound [I], and then the functional group is R 2 Compound [I] or a salt thereof may be produced by converting to .

[0311] Manufacturing method A2: Method for producing compound [I-2] or its salt In compound [I] or its salt, R 1 NR 31 R 32Compound [I-2] or a salt thereof can be produced, for example, by the following production method A2.

[0312] [ka]

[0313] [In the formula, A, Cy, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 And m are synonymous with the definitions above, R 31 and R 32 Each of them operates independently. (1) Hydrogen, (2)C 1-4 Alkyl {Here, the alkyl is, (a) Phenyl (wherein phenyl may be substituted with a halogen), or (b) May be substituted with pyridyl, (3)C 1-4 Alkoxy, or (4)C 3-4 Is it cycloalkyl? Alternatively, R 31 and R 32 However, they bond with each other, and together with the nitrogen atom they bond to, (5) A 4- to 7-membered heterocycloalkyl group containing, in addition to carbon atoms, one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms as ring constituent atoms {where the heterocycloalkyl group is (a) Hydroxy, (b) Oxo, (c)NR 20 R 21 (Here, R 20 and R 21 Each of them independently consists of hydrogen or C 1-4 (It is alkyl), or (d) may be substituted with phenyl, (6) A 6- to 11-membered spiroheterocycloalkyl, which contains one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms, or (7) A saturated or partially unsaturated fused ring group of 8 to 10 members containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from the group consisting of nitrogen and oxygen atoms (where the fused ring group is C 1-4 [May be substituted with a haloalkyl group]

[0314] (Process A2-1) Compound [I-2] or a salt thereof can be produced by reacting compound [A1-1] or a salt thereof with compound [A2-1] or a salt thereof in a solvent in the presence of a urea-forming agent and a base. Examples of ureating agents include CDI and triphosgene. The preferred ureating agent is CDI. Examples of suitable bases include N-methylmorpholine, triethylamine, and N,N-diisopropylethylamine. The preferred base is N-methylmorpholine. Examples of solvents include THF, acetonitrile, DMF, water, and mixtures thereof. Preferred solvents are THF or a mixture of THF and water. The reaction temperature is, for example, 0°C to 80°C, preferably 30°C to 60°C. Compound [A2-1] or its salt may be commercially available or may be prepared from a commercially available product by known methods. Substitute compound [A1-1] or its salt with R in a known reaction. 2 Using a compound or salt thereof having a functional group on Cy that can be converted to or a protected functional group, the present manufacturing method is carried out to obtain a compound or salt thereof corresponding to compound [I-2], and then the functional group is R 2 Compound [I-2] or a salt thereof may be produced by converting to [I-2].

[0315] Manufacturing method A3: Method for producing compound [Ia] or its salt Compound [Ia] or its salt can be produced, for example, by the following production method A3.

[0316] [ka]

[0317] [In the formula, A a , A 2a Cy a , R 1a , R 2a , R 3a , R 4a , R 6a , R 7a , R 8a , R 9a And m are synonymous with the definitions above, L 11a [The group is a hydroxyl group or a leaving group (e.g., a halogen).]

[0318] (Process A3-1) Compound [I] or a salt thereof can be produced by reacting compound [A3-1] or a salt thereof with compound [A3-2] or a salt thereof. For example, L 11a If is a halogen, compound [Ia] or a salt thereof can be produced by reacting compound [A3-1] or a salt thereof with compound [A3-2] or a salt thereof in a solvent in the presence of a base. Examples of suitable bases include triethylamine and N,N-diisopropylethylamine. The preferred base is N,N-diisopropylethylamine. Examples of solvents include DMF, acetonitrile, and THF. The preferred solvent is DMF. The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C. Also, for example, L 11aIf is hydroxyl, compound [Ia] or a salt thereof can also be prepared by reacting compound [A3-1] or a salt thereof with compound [A3-2] or a salt thereof in a solvent in the presence of a condensing agent and a base. Examples of suitable bases include triethylamine and N,N-diisopropylethylamine. The preferred base is N,N-diisopropylethylamine. Examples of condensing agents include WSC, HATU, and DMT-MM. The preferred condensing agent is WSC or HATU. Examples of solvents include DMF, acetonitrile, methanol, and THF. The preferred solvent is DMF. The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C. Compound [A3-1] or its salt may be commercially available or produced from a commercially available product by known methods, for example, by production methods B3 and B4 described below. Compound [A3-2] or its salt may be commercially available or may be prepared from a commercially available product by known methods. Substitute compound [A3-1] or its salt with R in a known reaction. 2a Functional groups that can be converted to Cy or protected functional groups a Using the above compound or a salt thereof, the present manufacturing method is carried out to obtain a compound corresponding to compound [Ia] or a salt thereof, and then its functional group is R 2a Compound [Ia] or a salt thereof may be produced by converting to .

[0319] Manufacturing method A4: Method for producing compound [Ia-2] or its salt In compound [Ia] or its salt, R 1a NR 31 R 32 Compound [Ia-2] or its salt can be produced, for example, by the following production method A4.

[0320] [ka]

[0321] [wherein, A a , Cy a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a , R 31 , R 32 and m are synonymous with the definitions given above.] (Step A4-1) Compound [Ia-2] or a salt thereof can be produced by reacting compound [A3-1] or a salt thereof with compound [A2-1] or a salt thereof in a solvent in the presence of a ureating agent and a base. Examples of the ureating agent include CDI, triphosgene, etc. A preferred ureating agent is CDI. Examples of the base include N-methylmorpholine, triethylamine, N,N-diisopropylethylamine, etc. A preferred base is N-methylmorpholine. Examples of the solvent include THF, acetonitrile, DMF, water, mixed solvents thereof, etc. A preferred solvent is THF or a mixed solvent of THF and water. The reaction temperature is, for example, from 0°C to 80°C, preferably from 30°C to 60°C. Instead of compound [A3-1] or a salt thereof, a compound or a salt thereof having a functional group or a protected functional group that can be converted to R 2a on Cy a is used to carry out this production method. After obtaining a compound or a salt thereof corresponding to compound [Ia-2], compound [Ia-2] or a salt thereof may be produced by converting the functional group to R 2a .

[0322] Manufacturing method B1: Method for producing compound [B1-7] or its salt In compound [A1-1] or a salt thereof used in production methods A1 and A2, A is CR 10 , and R 9Compounds [B1-7] or salts thereof, in which hydrogen is present, can be produced, for example, by the following production method B1.

[0323] [ka]

[0324] [In the formula, Cy, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 And m are synonymous with the definitions above, P 11 [These are protecting groups for amines (e.g., tert-butoxycarbonyl, benzyloxycarbonyl, etc.)]

[0325] (Process B1-1) Compound [B1-2] or its salt can be produced by reacting compound [B1-1] or its salt with trimethylsilyl cyanide in a solvent in the presence of a catalyst. Examples of catalysts include lithium chloride and DMAP. Lithium chloride or DMAP are preferred catalysts. Examples of solvents include THF and acetonitrile. THF is the preferred solvent. The reaction temperature is, for example, 0°C to 60°C, preferably 15°C to 30°C. Compound [B1-1] or a salt thereof may be commercially available or may be prepared from a commercially available product by known methods.

[0326] (Process B1-2) Compound [B1-4] or its salt can be produced by reacting compound [B1-2] or its salt with compound [B1-3] or its salt in a solvent in the presence of a catalyst and a base. Alternatively, steps B1-1 and B1-2 can be carried out in a one-pot process. Examples of catalysts include lithium chloride and DMAP. Lithium chloride or DMAP are preferred catalysts. Examples of bases include LiHMDS, NaHMDS, LDA, and n-butyllithium. The preferred bases are LiHMDS or NaHMDS. Examples of solvents include THF, n-hexane, and toluene. Preferred solvents are THF or toluene. The reaction temperature is, for example, -100°C to 0°C, preferably -78°C to -50°C. Compound [B1-3] or its salt may be commercially available or produced from a commercially available product by a known method, for example, by the production method C1 described below.

[0327] (Process B1-3) Compound [B1-5] or its salt can be produced by reacting compound [B1-4] or its salt in a solvent in the presence of a desilylating agent and an acid. Examples of desilylation agents include TBAF and pyridine hydrogen fluoride. The preferred desilylation agent is TBAF. Examples of acids include acetic acid. The preferred acid is acetic acid. Examples of solvents include THF and acetonitrile. The preferred solvent is THF. The reaction temperature is, for example, 0°C to 60°C, preferably 15°C to 30°C.

[0328] (Process B1-4) Compound [B1-6] or its salt can be produced by reacting compound [B1-5] or its salt in a solvent in the presence of a base, CDI, and hydrazine monohydrate. Examples of bases include DBU and N-methylimidazole. The preferred base is DBU. Examples of solvents include THF, DMF, and acetonitrile. THF or DMF are preferred solvents. The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C.

[0329] (Process B1-5) Compound [B1-7] or its salt can be produced by reacting compound [B1-6] or its salt in a solvent in the presence of an acid. Examples of acids include hydrochloric acid and acetic acid. Hydrochloric acid is the preferred acid. Examples of solvents include THF, water, and toluene. The preferred solvent is THF. The reaction temperature is, for example, 15°C to 120°C, preferably 20°C to 60°C. Substitute compound [B1-1] or its salt with R in a known reaction. 2 Using a compound or salt thereof having a functional group that can be converted to or a protected functional group on Cy, the present manufacturing method is carried out to obtain a compound or salt thereof corresponding to compound [B1-7], and then the functional group is R 2 Compounds [B1-7] or their salts may be produced by converting them to [the appropriate compound].

[0330] Manufacturing method B2: Method for producing compound [B2-8] or its salt In the compound [A1-1] or its salt used in manufacturing methods A1 and A2, A is N, and R 9 Compound [B2-8] or a salt thereof, in which hydrogen is present, can be produced, for example, by the production method B2 shown below.

[0331] [ka]

[0332] [In the formula, Cy, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 And m are synonymous with the definitions above, P 12 and P 13These are, independently, amine protecting groups (e.g., tert-butoxycarbonyl).

[0333] (Process B2-1) Compound [B2-2] or a salt thereof can be produced by reacting compound [B1-2] or a salt thereof with compound [B2-1] or a salt thereof according to step B1-2. Compound [B2-1] or its salt may be commercially available or may be prepared from a commercially available product by known methods.

[0334] (Process B2-2) Compound [B2-3] or a salt thereof can be produced by reacting compound [B2-2] or a salt thereof according to step B1-3.

[0335] (Process B2-3) Compound [B2-4] or a salt thereof can be produced by reacting compound [B2-3] or a salt thereof according to step B1-4.

[0336] (Process B2-4) Compound [B2-5] or a salt thereof can be produced by reacting compound [B2-4] or a salt thereof according to steps B1-5.

[0337] (Process B2-5) Compound [B2-7] or its salt can be produced by reacting compound [B2-5] or its salt with compound [B2-6] or its salt in a solvent in the presence of a base. Examples of suitable bases include triethylamine and N,N-diisopropylethylamine. The preferred base is triethylamine. Examples of solvents include methanol, acetonitrile, and THF. Methanol is a preferred solvent. The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C. Compound [B2-6] or its salt may be commercially available or may be prepared from a commercially available product by known methods.

[0338] (Process B2-6) Compound [B2-8] or its salt contains the protecting group P of compound [B2-7] or its salt. 13 It can be produced by removing P through a deprotection reaction. The deprotection reaction involves P 13 It should be carried out under conditions appropriate to the type of product. For example, P 13 If the compound is tert-butoxycarbonyl, compound [B2-8] or its salt can be produced by reacting compound [B2-7] or its salt with an acid in a solvent. Examples of acids include hydrochloric acid and trifluoroacetic acid. Hydrochloric acid is the preferred acid. Examples of solvents include CPME and ethyl acetate. Preferred solvents are CPME or ethyl acetate. The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C. Substitute compound [B1-2] or its salt with R in a known reaction. 2 Using a compound or salt thereof having a functional group that can be converted to or a protected functional group on Cy, the present manufacturing method is carried out to obtain a compound or salt thereof corresponding to compound [B2-8], and then the functional group is R 2 Compound [B2-8] or a salt thereof may be produced by converting to [the specified compound].

[0339] Manufacturing method B3: Method for producing compound [B3-7] or its salt In the compound [A3-1] or its salt used in manufacturing methods A3 and A4, a CR 10a And R 9a Compounds [B3-7] or salts thereof, in which hydrogen is present, can be produced, for example, by the production method B3 shown below.

[0340] [ka]

[0341] [In the formula, A 2aCy a , R 2a , R 3a , R 4a , R 6a , R 7a , R 8a , R 10a And m are synonymous with the definitions above, P 11a [These are protecting groups for amines (e.g., tert-butoxycarbonyl, benzyloxycarbonyl, etc.)]

[0342] (Process B3-1) Compound [B3-2] or its salt can be produced by reacting compound [B3-1] or its salt with trimethylsilyl cyanide in a solvent in the presence of a catalyst. Examples of catalysts include lithium chloride and DMAP. Lithium chloride or DMAP are preferred catalysts. Examples of solvents include THF and acetonitrile. THF is the preferred solvent. The reaction temperature is, for example, 0°C to 60°C, preferably 15°C to 30°C. Compound [B3-1] or a salt thereof may be commercially available or may be prepared from a commercially available product by known methods.

[0343] (Process B3-2) Compound [B3-4] or its salt can be produced by reacting compound [B3-2] or its salt with compound [B3-3] or its salt in a solvent in the presence of a catalyst and a base. Alternatively, steps B3-1 and B3-2 can be carried out in a one-pot process. Examples of catalysts include lithium chloride and DMAP. Lithium chloride or DMAP are preferred catalysts. Examples of bases include LiHMDS, NaHMDS, LDA, and n-butyllithium. The preferred bases are LiHMDS or NaHMDS. Examples of solvents include THF, n-hexane, and toluene. Preferred solvents are THF or toluene. The reaction temperature is, for example, -100°C to 0°C, preferably -78°C to -50°C. Compound [B3-3] or a salt thereof may be commercially available or produced from a commercially available product by known methods, for example, by the production method C2 described below.

[0344] (Process B3-3) Compound [B3-5] or its salt can be produced by reacting compound [B3-4] or its salt in a solvent in the presence of a desilylating agent and an acid. Examples of desilylation agents include TBAF and pyridine hydrogen fluoride. The preferred desilylation agent is TBAF. Examples of acids include acetic acid. The preferred acid is acetic acid. Examples of solvents include THF and acetonitrile. The preferred solvent is THF. The reaction temperature is, for example, 0°C to 60°C, preferably 15°C to 30°C.

[0345] (Process B3-4) Compound [B3-6] or its salt can be produced by reacting compound [B3-5] or its salt in a solvent in the presence of a base, CDI, and hydrazine monohydrate. Examples of bases include DBU and N-methylimidazole. The preferred base is DBU. Examples of solvents include THF, DMF, and acetonitrile. THF or DMF are preferred solvents. The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C.

[0346] (Process B3-5) Compound [B3-7] or its salt can be produced by reacting compound [B3-6] or its salt in a solvent in the presence of an acid. Examples of acids include hydrochloric acid and acetic acid. Hydrochloric acid is the preferred acid. Examples of solvents include THF, water, and toluene. The preferred solvent is THF. The reaction temperature is, for example, 15°C to 120°C, preferably 20°C to 60°C. Substitute compound [B3-1] or its salt with R in a known reaction. 2a Functional groups that can be converted to Cy or protected functional groups a Using the above compound or a salt thereof, the present manufacturing method is carried out to obtain a compound or a salt thereof corresponding to compound [B3-7], and then its functional group is R 2a Compound [B3-7] or a salt thereof may be produced by converting to [the specified compound].

[0347] Manufacturing method B4: Method for producing compound [B4-8] or its salt In the compound [A3-1] or its salt used in manufacturing methods A3 and A4, a N is R 9a Compounds [B4-8] or salts thereof, in which hydrogen is present, can be produced, for example, by the following production method B4.

[0348] [ka]

[0349] [In the formula, A 2a Cy a , R 2a , R 3a , R 4a , R 6a , R 7a , R 8a And m are synonymous with the definitions above, P 12a and P 13a These are, independently, amine protecting groups (e.g., tert-butoxycarbonyl, benzyloxycarbonyl, etc.).

[0350] (Process B4-1) Compound [B4-2] or a salt thereof can be produced by reacting compound [B3-2] or a salt thereof with compound [B4-1] or a salt thereof according to step B3-2. Compound [B4-1] or its salt may be commercially available or may be prepared from a commercially available product by known methods.

[0351] (Process B4-2) Compound [B4-3] or a salt thereof can be produced by reacting compound [B4-2] or a salt thereof according to step B3-3.

[0352] (Process B4-3) Compound [B4-4] or a salt thereof can be produced by reacting compound [B4-3] or a salt thereof according to step B3-4.

[0353] (Process B4-4) Compound [B4-5] or a salt thereof can be produced by reacting compound [B4-4] or a salt thereof according to step B3-5.

[0354] (Process B4-5) Compound [B4-7] or its salt can be produced by reacting compound [B4-5] or its salt with compound [B4-6] or its salt in a solvent in the presence of a base. Examples of suitable bases include triethylamine and N,N-diisopropylethylamine. The preferred base is triethylamine. Examples of solvents include methanol, acetonitrile, and THF. Methanol is a preferred solvent. The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C. Compound [B4-6] or its salt may be commercially available or may be prepared from a commercially available product by known methods.

[0355] (Process B4-6) Compound [B4-8] or its salt contains the protecting group P of compound [B4-7] or its salt. 13aIt can be produced by removing P through a deprotection reaction. The deprotection reaction involves P 13a It should be carried out under conditions appropriate to the type of product. For example, P 13a If the compound is tert-butoxycarbonyl, compound [B4-8] or its salt can be produced by reacting compound [B4-7] or its salt with an acid in a solvent. Examples of acids include hydrochloric acid and trifluoroacetic acid. Hydrochloric acid is the preferred acid. Examples of solvents include CPME and ethyl acetate. Preferred solvents are CPME or ethyl acetate. The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C. Substitute compound [B3-2] or its salt with R in a known reaction. 2a Functional groups that can be converted to Cy or protected functional groups a Using the above compound or a salt thereof, carry out this manufacturing method to obtain a compound or a salt thereof corresponding to compound [B4-8], and then the functional group thereof is R 2a Compound [B4-8] or a salt thereof may be produced by converting to [the specified compound].

[0356] Manufacturing method C1: Method for producing compound [C1-9] or its salt In the compound [B1-3] or its salt used in manufacturing method B1, R 10 Compounds [C1-9] or salts thereof, in which hydrogen is present, can be produced, for example, by the following production method C1.

[0357] [ka]

[0358] [In the formula, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and P 11 This is synonymous with the definition above, R33 and R 34 Each of them is independent of C 1-4 It is alkyl, P 14 [These are protecting groups for amines (e.g., benzyl, (S)-1-phenylethyl, etc.)]

[0359] (Process C1-1) Compound [C1-3] or its salt can be produced by reacting compound [C1-1] or its salt with compound [C1-2] or its salt in a solvent in the presence of a base. Examples of bases include sodium ethoxide, sodium hydride, and DBU. The preferred base is sodium ethoxide. Examples of solvents include ethanol, THF, and DMF. Ethanol is a preferred solvent. The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C. Compound [C1-1] or a salt thereof may be commercially available or may be prepared from a commercially available product by known methods. Compound [C1-2] or its salt may be commercially available or may be prepared from a commercially available product by known methods.

[0360] (Process C1-2) Compound [C1-4] or its salt can be produced by catalytic hydrogenation of compound [C1-3] or its salt in a solvent in the presence of a metal catalyst. Examples of metal catalysts include Pd-C, Pt-C, and palladium hydroxide. Preferred metal catalysts are Pd-C or palladium hydroxide. Examples of solvents include methanol, ethanol, and THF. The preferred solvent is THF. The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C.

[0361] (Process C1-3) Compound [C1-6] or its salt can be produced by reductive amination of compound [C1-4] or its salt and compound [C1-5] or its salt in a solvent. Examples of reductive amination reactions include those using an acid and a reducing agent. Examples of reducing agents include sodium triacetoxyborohydride, sodium cyanoborohydride, and sodium borohydride. The preferred reducing agent is sodium triacetoxyborohydride. Examples of acids include acetic acid, trifluoroacetic acid, and hydrochloric acid. The preferred acid is acetic acid. Examples of solvents include THF, chloroform, toluene, and N-methylpyrrolidone. The preferred solvent is THF. The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C. Compound [C1-5] or its salt may be commercially available or may be prepared from a commercially available product by known methods. In compounds [C1-6] or their salts, R 3 is methyl, R 4 , R 5 , R 6 , R 7 and R 8 The following compounds [C1-10] are composed of hydrogen.

[0362] [ka]

[0363] [In the formula, P 14 This is synonymous with the definition above. Alternatively, the salt thereof can be produced by, for example, carrying out step C1-3 using (S)-1-phenethylamine as compound [C1-5] or its salt, stirring the resulting diastereomer mixture or salt thereof in a solvent, and filtering off the precipitated solid. Examples of solvents include toluene, THF, and ethyl acetate. The preferred solvent is ethyl acetate.

[0364] (Process C1-4) Compound [C1-7] or its salts have the protecting group P of compound [C1-6] or its salts. 14 It can be produced by removing P through a deprotection reaction. The deprotection reaction involves P 14 It should be carried out under conditions appropriate to the type of product. For example, P 14 If (S)-1-phenylethyl is present, compound [C1-7] or a salt thereof can be produced by reacting compound [C1-6] or a salt thereof according to step C1-2.

[0365] (Process C1-5) Compound [C1-8] or its salt contains a protecting group P on compound [C1-7] or its salt. 11 It can be manufactured by introducing a protective group. 11 It should be carried out under conditions appropriate to the type of product. For example, P 11 If the compound is tert-butoxycarbonyl, compound [C1-8] or its salt can be prepared by reacting compound [C1-7] or its salt with the corresponding carbamate agent in a solvent. A base may be added depending on the conditions. Examples of corresponding carbamate agents include Boc2O. The preferred corresponding carbamate agent is Boc2O. Examples of bases include sodium hydroxide and sodium bicarbonate. Examples of solvents include THF, water, and mixtures thereof. A preferred solvent is a mixture of THF and water. The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C.

[0366] (Process C1-6) Compound [C1-9] or its salt can be produced by reacting compound [C1-8] or its salt in a solvent in the presence of a catalyst. Examples of catalysts include trifluoroacetic acid, p-toluenesulfonic acid, and p-toluenesulfonic acid pyridine salt. The preferred catalyst is p-toluenesulfonic acid pyridine salt. Examples of solvents include THF, acetone, water, and mixtures thereof. A preferred solvent is a mixture of acetone and water. The reaction temperature is, for example, 20°C to 100°C, preferably 40°C to 80°C.

[0367] Method C2: Method for producing compound [C2-9] or its salt In the compound [B3-3] or its salt used in manufacturing method B3, R 10a is hydrogen, A 2a CR 5a Compound [C2-9] or a salt thereof can be produced, for example, by the following production method C2.

[0368] [ka]

[0369] [In the formula, R 3a , R 4a , R 5a , R 6a , R 7a , R 8a and P 11a This is synonymous with the definition above, R 33a and R 34a Each of them is independent of C 1-4 It is alkyl, P 14a [These are protecting groups for amines (e.g., benzyl, (S)-1-phenylethyl, etc.)]

[0370] (Process C2-1) Compound [C2-3] or its salt can be produced by reacting compound [C2-1] or its salt with compound [C2-2] or its salt in a solvent in the presence of a base. Examples of bases include sodium ethoxide, sodium hydride, and DBU. The preferred base is sodium ethoxide. Examples of solvents include ethanol, THF, and DMF. Ethanol is a preferred solvent. The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C. Compound [C2-1] or its salt may be commercially available or may be prepared from a commercially available product by known methods. Compound [C2-2] or its salt may be commercially available or may be prepared from a commercially available product by known methods.

[0371] (Process C2-2) Compound [C2-4] or its salt can be produced by catalytic hydrogenation of compound [C2-3] or its salt in a solvent in the presence of a metal catalyst. Examples of metal catalysts include Pd-C, Pt-C, and palladium hydroxide. Preferred metal catalysts are Pd-C or palladium hydroxide. Examples of solvents include methanol, ethanol, and THF. The preferred solvent is THF. The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C.

[0372] (Process C2-3) Compound [C2-6] or its salt can be produced by reductive amination of compound [C2-4] or its salt and compound [C2-5] or its salt in a solvent. Examples of reductive amination reactions include those using an acid and a reducing agent. Examples of reducing agents include sodium triacetoxyborohydride, sodium cyanoborohydride, and sodium borohydride. The preferred reducing agent is sodium triacetoxyborohydride. Examples of acids include acetic acid, trifluoroacetic acid, and hydrochloric acid. The preferred acid is acetic acid. Examples of solvents include THF, chloroform, toluene, and N-methylpyrrolidone. The preferred solvent is THF. The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C. Compound [C2-5] or its salt may be commercially available or may be prepared from a commercially available product by known methods. In compound [C2-6] or its salt, R 3a is methyl, R 4a , R 5a , R 6a , R 7a and R 8a The following compounds [C2-10] are composed of hydrogen.

[0373] [ka]

[0374] [In the formula, P 14a This is synonymous with the definition above. Alternatively, the salt can be produced by, for example, carrying out step C2-3 using (S)-1-phenethylamine as compound [C2-5] or its salt, stirring the resulting diastereomer mixture or salt in a solvent, and filtering off the precipitated solid. Examples of solvents include toluene, THF, and ethyl acetate. The preferred solvent is ethyl acetate.

[0375] (Process C2-4) Compound [C2-7] or its salt contains the protecting group P of compound [C2-6] or its salt. 14a It can be produced by removing P through a deprotection reaction. The deprotection reaction involves P 14a It should be carried out under conditions appropriate to the type of product. For example, P 14a If (S)-1-phenylethyl is present, compound [C2-7] or a salt thereof can be produced by reacting compound [C2-6] or a salt thereof according to step C2-2.

[0376] (Process C2-5) Compound [C2-8] or its salt contains a protecting group P on compound [C2-7] or its salt. 11a It can be manufactured by introducing a protective group. 11a It should be carried out under conditions appropriate to the type of product. For example, P 11a If the compound is tert-butoxycarbonyl, compound [C2-8] or its salt can be prepared by reacting compound [C2-7] or its salt with the corresponding carbamate agent in a solvent. A base may be added depending on the conditions. Examples of corresponding carbamate agents include Boc2O. The preferred corresponding carbamate agent is Boc2O. Examples of bases include sodium hydroxide and sodium bicarbonate. Examples of solvents include THF, water, and mixtures thereof. A preferred solvent is a mixture of THF and water. The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C.

[0377] (Process C2-6) Compound [C2-9] or its salt can be produced by reacting compound [C2-8] or its salt in a solvent in the presence of a catalyst. Examples of catalysts include trifluoroacetic acid, p-toluenesulfonic acid, and p-toluenesulfonic acid pyridine salt. The preferred catalyst is p-toluenesulfonic acid pyridine salt. Examples of solvents include THF, acetone, water, and mixtures thereof. A preferred solvent is a mixture of acetone and water. The reaction temperature is, for example, 20°C to 100°C, preferably 40°C to 80°C. [Examples]

[0378] Next, a method for producing compound [I] or compound [Ia] of the present invention or a pharmaceutically acceptable salt thereof will be specifically described with reference to production examples. However, the method for producing compound [I] or compound [Ia] of the present invention or a pharmaceutically acceptable salt thereof is not limited to these. The compounds obtained in each step can be isolated and / or purified by known methods such as distillation, recrystallization, and column chromatography, as needed. However, in some cases, the process can proceed to the next step without isolation and / or purification. In this specification, room temperature refers to the temperature in an uncontrolled state, and one embodiment is a range of 1°C to 40°C.

[0379] [Production Example 1]: Synthesis of tert-butyl (S)-(1-(4-oxocyclohexyl)propan-2-yl)carbamate

[0380] [ka]

[0381] (1) Ethyl 4-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)-3-oxobutanoate

[0382] [ka]

[0383] Under an argon atmosphere, a solution of 2-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)acetic acid (1.4 kg) in THF (6.2 kg) was added dropwise to a solution of carbonyldiimidazole (1 kg) in DMF (4.7 kg) at room temperature and stirred. The washing solution with DMF (0.7 kg) was added and stirred for 3 hours. Monoethyl potassium malonate (1.3 kg) was added, and magnesium chloride (0.6 kg) was added in installments. The mixture was stirred all day, and at an internal temperature of 5°C, water (4.2 kg) and 6 M hydrochloric acid (3.1 kg) were added and stirred at room temperature for 1 hour. Toluene (6.1 kg) was added and extracted, and toluene (2.4 kg) was added to the aqueous layer and re-extracted. The combined organic layer was washed twice with 20% saline solution (7 kg). The organic layer was concentrated under reduced pressure, and methanol (2.2 kg) was added and azeotropic. Methanol (3.3 kg) was added to the resulting residue to obtain a methanol solution. The methanol solution described above was combined with a methanol solution obtained by the same procedure from 2-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)acetic acid (8 kg) to obtain a methanol solution (34 kg) of the title compound. A portion of this solution was concentrated to obtain an NMR sample. 1H-NMR (CDCl3) δ: 4.44-4.31 (1H, m), 4.19 (2H, q, J = 7.1 Hz), 3.46-3.27 (1H, m), 3.40 (2H, s), 2.43 (2H, d, J = 6.3 Hz), 2.04-1.93 (2H, m), 1.88-1.69 (3H, m), 1.44 (9H, s), 1.28 (3H, t, J = 7.1 Hz), 1.19-0.97 (4H, m).

[0384] (2) tert-butyl (trans-4-(2-oxopropyl)cyclohexyl)carbamate

[0385] [ka]

[0386] A methanol solution (34 kg) of ethyl 4-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)-3-oxobutanoate obtained in (1) was heated to 35°C, and a 4M aqueous sodium hydroxide solution (20 kg) was added and stirred. The mixture was stirred at 40°C for 2 hours, and a solution of citric acid (8.4 kg) in water (19 kg) was added dropwise at 45°C. Ethyl acetate (25 kg) was added and stirred for 20 minutes, and then a solution of citric acid (8.4 kg) in water (19 kg) was added dropwise. After stirring for 3 hours, the mixture was returned to room temperature, ethyl acetate (25 kg) was added, and the mixture was separated. The organic layer was washed with 10% saline solution (47 kg) and concentrated under reduced pressure. Ethyl acetate (17 kg) was added and concentrated under reduced pressure to obtain the title compound (8.1 kg) in 87% yield. 1H-NMR (CDCl3) δ: 4.36 (1H, br s), 3.35 (1H, br s), 2.31 (2H, d, J = 6.4 Hz), 2.12 (3H, s), 2.02-1.95 (2H, m), 1.83-1.71 (3H, m), 1.44 (9H, s), 1.18-0.95 (4H, m).

[0387] (3) tert-butyl (trans-4-((S)-2-(((S)-1-phenylethyl)amino)propyl)cyclohexyl)carbamate acetate

[0388] [ka]

[0389] A methanol (67 kg) solution of tert-butyl (trans-4-(2-oxopropyl)cyclohexyl)carbamate (8.1 kg) obtained in (2) was prepared, and under an Ar atmosphere, a water (1.7 kg) suspension of (S)-1-phenethylamine (4.4 kg), acetic acid (1.2 kg), and 2% Pt-C (0.42 kg) was added at room temperature and stirred. This was stirred under a hydrogen atmosphere (4 atm) at 40°C for 20 hours. After cooling to room temperature, 2% Pt-C was filtered off using KC floc® as a filter aid, and the mixture was washed twice with methanol (15 kg). The obtained solution was concentrated under reduced pressure, isopropyl alcohol (20 kg) was added, and the solution was concentrated under reduced pressure again. The same procedure was repeated, and isopropyl alcohol (43 kg) was added to the obtained solid to prepare a suspension. This suspension was heated to 70°C, and acetic acid (1 kg) was added dropwise. After stirring for 2 hours, the mixture was slowly cooled to room temperature and stirred for 17 hours. After stirring for another 2 hours at an internal temperature of 5°C, the resulting solid was filtered and washed with ice-cold isopropyl alcohol (20 kg). It was dried at 30°C for 19 hours to obtain the title compound (9 kg) in 65% yield. 1H-NMR (DMSO-D6) δ: 7.35-7.25 (4H, m), 7.21-7.15 (1H, m), 6.62 (1H, d, J = 7.5 Hz), 3.80 (1H, q, J = 6.5 Hz), 3.17-3.01 (1H, m), 2.48-2.38 (1H, m), 1.90 (3H, s), 1.77-1.59 (3H, m), 1.54-1.28 (11H, m), 1.23-0.66 (12H, m).

[0390] (4) tert-butyl (S)-(trans-4-(2-aminopropyl)cyclohexyl)carbamate acetate

[0391] [ka]

[0392] To a methanol (85 kg) solution of tert-butyl (trans-4-((S)-2-(((S)-1-phenylethyl)amino)propyl)cyclohexyl)carbamate acetate (8.9 kg) obtained in (3), a suspension of 5% Pd-C (PE type) (0.89 kg) in water (1.8 kg) was added at room temperature under an Ar atmosphere and stirred. This was stirred at 35°C for 2 hours under a hydrogen atmosphere (4 atm). After slow cooling to room temperature, 5% Pd-C was filtered off using KC floc® as a filter aid, and the mixture was washed with methanol (21 kg). The solution was concentrated under reduced pressure, and acetonitrile (21 kg) was added and azeotropic reaction was performed. Methanol (42 kg) was added to the resulting solid to obtain a methanol solution of the title compound. An NMR sample was obtained by concentrating a portion of this solution. 1H-NMR (DMSO-D6) δ: 6.71-6.64 (1H, m), 6.14 (3H, br s), 3.21-3.02 (1H, m), 2.99-2.86 (1H, m), 1.84-1.58 (7H, m), 1.37 (9H, s), 1.32-1.04 (5H, m), 1.03-0.96 (3H, m), 0.94-0.75 (2H, m).

[0393] (5) Benzyl (S)-(1-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)propan-2-yl)carbamate

[0394] [ka]

[0395] (4) The same method was used to obtain tert-butyl (S)-(trans-4-(2-aminopropyl)cyclohexyl)carbamate acetate (218 g) in a solution of DMF (1080 ml), to which triethylamine (100 ml) was added at room temperature and the mixture was stirred. Under water cooling, N-carbobenzooxyoxysuccinimide (179 g) was added and the mixture was stirred at room temperature for 6 hours. Under water cooling, water (2160 ml) was added and the mixture was stirred for 1 hour. The resulting solid was filtered, washed with water (1200 ml), and dried at room temperature for 48 hours to obtain seed crystals (257 g) of the title compound in 97% yield. To a methanol solution of tert-butyl (S)-(trans-4-(2-aminopropyl)cyclohexyl)carbamate acetate obtained in (4), triethylamine (5.1 kg) and acetonitrile (14 kg) solution of N-carbobenzooxyoxysuccinimide (5.8 kg) were added at 10°C and stirred. A washing solution with acetonitrile (3.5 kg) was added and stirred for 3 hours. Water (8.9 kg) was added, seed crystals obtained by the same method as above were inoculated and stirred for 2 hours. The resulting solid was filtered, washed with 50% methanol aqueous solution (24 kg), and dried for 69 hours to obtain the title compound (8 kg) in 97% yield. 1H-NMR (DMSO-D6) δ: 7.41-7.27 (5H, m), 7.06 (1H, d, J = 8.2 Hz), 6.66 (1H, d, J = 8.2 Hz), 5.03 (1H, d, J = 12.0 Hz), 4.98 (1H, d, J = 12.0 Hz), 3.66-3.52 (1H, m), 3.19-3.03 (1H, m), 1.80-1.51 (4H, m), 1.43-1.26 (1H, m), 1.37 (9H, s), 1.23-0.75 (6H, m), 1.01 (3H, d, J = 6.7 Hz).

[0396] (6) Benzyl (S)-(1-(trans-4-aminocyclohexyl)propan-2-yl)carbamate p-toluenesulfonate

[0397] [ka]

[0398] A suspension of benzyl (S)-(1-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)propan-2-yl)carbamate (257 g), obtained by the same method as in (5), was heated to 80°C, p-toluenesulfonic acid monohydrate (188 g) was added, and the mixture was stirred for 3 hours. After cooling to room temperature, it was left to stand for the entire day. The resulting solid was filtered and washed with ethyl acetate (236 ml). After drying under reduced pressure at 50°C for 8 hours, it was dried under reduced pressure at room temperature for the entire day to obtain seed crystals of the title compound (281 g) in 92% yield. A suspension of benzyl (S)-(1-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)propan-2-yl)carbamate (8 kg) obtained in (5) was prepared in ethyl acetate (58 kg), and p-toluenesulfonic acid monohydrate (5.1 kg) was added at room temperature and stirred. A washing solution with ethyl acetate (1.4 kg) was added and stirred for 1 hour. Seed crystals obtained by the same method as above were inoculated and stirred for 1 hour, then heated to 55°C and stirred for 4 hours. After slow cooling to room temperature, it was stirred for 14 hours. The obtained solid was filtered and washed with ethyl acetate (22 kg). It was dried at 50°C for 23 hours to obtain the title compound (9 kg) in 96% yield. 1H-NMR (DMSO-D6) δ: 7.67 (3H, br s), 7.47 (2H, d, J = 8.2 Hz), 7.41-7.28 (5H, m), 7.14-7.06 (3H, m), 5.02 (1H, d, J = 12.7 Hz), 4.98 (1H, d, J = 12.7 Hz), 3.66-3.53 (1H, m), 2.98-2.83 (1H, m), 2.29 (3H, s), 1.95-1.60 (4H, m), 1.39-0.81 (7H, m), 1.02 (3H, d, J = 6.7 Hz).

[0399] (7) Benzyl (S)-(1-trans-(4-aminocyclohexyl)propan-2-yl)carbamate

[0400] [ka]

[0401] To a solution of benzyl (S)-(1-(trans-4-aminocyclohexyl)propan-2-yl)carbamate p-toluenesulfonate (30 g) obtained in (6) in 2-methyltetrahydrofuran (120 ml), 17 ml of 4 M sodium hydroxide aqueous solution was added at room temperature and the mixture was stirred for 1.5 hours. Water (120 ml) was added and the mixture was extracted. The organic layer was washed twice with water (120 ml) and saturated brine (120 ml), and sodium sulfate was added and the mixture was dried. Sodium sulfate was filtered off and the mixture was concentrated under reduced pressure. Methanol (90 ml) was added and the mixture was concentrated under reduced pressure to obtain the title compound (18 g) in 96% yield. 1H-NMR (DMSO-D6) δ: 7.41-7.25 (5H, m), 7.05 (1H, d, J = 8.5 Hz), 5.03 (1H, d, J = 12.5 Hz), 4.97 (1H, d, J = 12.5 Hz), 3.68-3.50 (1H, m), 2.46-2.33 (1H, m), 1.81-0.71 (13H, m), 1.01 (3H, d, J = 6.5 Hz).

[0402] (8) Benzyl (S)-(1-(4-oxocyclohexyl)propan-2-yl)carbamate

[0403] [ka]

[0404] 3,5-di-tert-butyl-1,2-benzoquinone (14 g) was added to a methanol (90 ml) solution of benzyl (S)-(1-trans-(4-aminocyclohexyl)propan-2-yl)carbamate (18 g) obtained in (7) at room temperature and stirred for 1.5 hours. Water (18 ml), acetone (72 ml), and DOWEX (45 g) were added and stirred for 1.5 hours. DOWEX (9 g) was added and stirred for 30 minutes. The mixture was filtered with ethyl acetate and the filtrate was concentrated under reduced pressure. Ethyl acetate (72 ml) and water (36 ml) were added and extracted, and sodium sulfate was added to the organic layer and dried. Sodium sulfate was filtered off and the mixture was concentrated under reduced pressure. Ethyl acetate (36 ml) and silica gel (18 g) were added and stirred for 30 minutes. The mixture was filtered with ethyl acetate and the filtrate was concentrated under reduced pressure. Diisopropyl ether (18 ml) was added to the obtained residue and heated to an internal temperature of 48°C. Heptane (72 ml) was added dropwise, and the mixture was stirred for 1.5 hours. The resulting solid was filtered and washed with heptane. The title compound (15 g) was obtained in 83% yield by drying under reduced pressure at 60°C for 3 hours and at room temperature for the entire day. 1H-NMR (DMSO-D6) δ: 7.41-7.25 (5H, m), 7.15 (1H, d, J = 8.6 Hz), 5.03 (1H, d, J = 12.4 Hz), 4.99 (1H, d, J = 12.4 Hz), 3.70-3.55 (1H, m), 2.40-2.10 (4H, m), 2.08-1.66 (3H, m), 1.49-1.18 (4H, m), 1.06 (3H, d, J = 6.5 Hz).

[0405] (9) tert-butyl (S)-(1-(4-oxocyclohexyl)propan-2-yl)carbamate

[0406] [ka]

[0407] To a methanol (145 ml) solution of benzyl (S)-(1-(4-oxocyclohexyl)propan-2-yl)carbamate (15 g) obtained in (8), 10% Pd-C (1.5 g) and Boc2O (12 g) were added under an argon atmosphere at room temperature. The mixture was stirred under a hydrogen atmosphere (1 atm) for 4 hours. After purging with nitrogen, 10% Pd-C was filtered off by Celite filtration and washed with methanol. The mixture was concentrated under reduced pressure, and acetone (27 ml) was added to the resulting residue and stirred at room temperature. Water (82 ml) was added and stirred all day. The resulting solid was filtered and washed with water. The mixture was dried under reduced pressure at 60°C for 3 hours and all day at room temperature to obtain the title compound (12 g) in 88% yield. Using benzyl(S)-(1-(trans-4-aminocyclohexyl)propan-2-yl)carbamate p-toluenesulfonate (211 g), the same procedure as in (7)-(9) above was performed to obtain the title compound (60 g). 1H-NMR (DMSO-D6) δ: 6.65 (1H, d, J = 8.6 Hz), 3.63-3.46 (1H, m), 2.42-2.10 (4H, m), 2.08-1.97 (1H, m), 1.94-1.83 (1H, m), 1.80-1.66 (1H, m), 1.46-1.16 (4H, m), 1.38 (9H, s), 1.02 (3H, d, J = 6.5 Hz).

[0408] [Manufacturing example 2]:N 1 -((S)-1-(cis-5-(2-bromo-4-cyanophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4-en-9-yl)propane-2-yl)-N 2 - Synthesis of methyloxalamide (Example 57)

[0409] [ka]

[0410] (1) tert-butyl ((S)-1-(cis-4-(2-bromo-4-cyanobenzoyl)-4-((trimethylsilyl)oxy)cyclohexyl)propan-2-yl)carbamate

[0411] [ka]

[0412] To a solution of 3-bromo-4-formylbenznitrile (2.1 g) in THF (4 ml), lithium chloride (0.043 g) and trimethylsilyl cyanide (1.5 ml) were added at room temperature and the mixture was stirred for 1 hour. THF (26 ml) was added and the mixture was cooled to -78 °C. 10.2 ml of 1 M NaHMDS-THF solution was added and the mixture was stirred for 3 minutes. A solution of tert-butyl (S)-(1-(4-oxocyclohexyl)propan-2-yl)carbamate (2 g), obtained by the same method as in (9) of [Preparation Example 1], in THF (10 ml) was added and the mixture was stirred for 30 minutes. The mixture was then heated to -10 °C over 1 hour, and water and ethyl acetate were added for extraction. Ethyl acetate was added to the aqueous layer for re-extraction twice, and the combined organic layers were washed with saturated brine and dried over sodium sulfate. Sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (1.2 g) in 28% yield. 1H-NMR (CDCl3) δ: 7.89 (1H, s), 7.62 (1H, d, J = 8.1 Hz), 7.39 (1H, d, J = 8.1 Hz), 4.30-4.15 (1H, m), 3.84-3.56 (1H, m), 2.01-1.92 (2H, m), 1.86-1.70 (3H, m), 1.64-1.52 (1H, m), 1.43 (9H, s), 1.40-1.18 (5H, m), 1.11 (3H, d, J = 6.5 Hz), 0.04 (9H, s).

[0413] (2) tert-butyl ((S)-1-(cis-4-(2-bromo-4-cyanobenzoyl)-4-hydroxycyclohexyl)propan-2-yl)carbamate

[0414] [ka]

[0415] To a solution of tert-butyl ((S)-1-(cis-4-(2-bromo-4-cyanobenzoyl)-4-((trimethylsilyl)oxy)cyclohexyl)propan-2-yl)carbamate obtained in (1) and the same compound obtained by the same method as above (total 1.4 g) in THF (2.7 ml), acetic acid (0.42 ml) and 1 M TBAF-THF solution (3.7 ml) were added and the mixture was stirred at room temperature for 15 minutes. Saturated ammonium chloride aqueous solution, water, and ethyl acetate were added and the mixture was extracted. Ethyl acetate was added to the aqueous layer and re-extracted twice. The combined organic layers were washed with saturated sodium bicarbonate solution and saturated brine, and sodium sulfate was added and the mixture was dried. Sodium sulfate was filtered off and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane) to obtain the title compound (1.1 g) in 93% yield. 1H-NMR (CDCl3) δ: 7.89 (1H, s), 7.65 (1H, d, J = 8.1 Hz), 7.32 (1H, d, J = 7.5 Hz), 4.30-4.17 (1H, m), 3.84-3.67 (1H, m), 2.66 (1H, s), 1.93-1.74 (5H, m), 1.69-1.60 (1H, m), 1.50-1.22 (5H, m), 1.43 (9H, s), 1.10 (3H, d, J = 5.9 Hz).

[0416] (3) 4-(cis-9-((S)-2-aminopropyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4-en-5-yl)-3-bromobenzonitrile hydrochloride

[0417] [ka]

[0418] To a solution of tert-butyl ((S)-1-(cis-4-(2-bromo-4-cyanobenzoyl)-4-hydroxycyclohexyl)propan-2-yl)carbamate (1.1 g) obtained in (2) in THF (11 ml), DBU (0.052 ml) and CDI (0.55 g) were added at room temperature and the mixture was stirred for 1 hour. Hydrazine monohydrate was added and the mixture was stirred for 30 minutes, then 10% citric acid aqueous solution and ethyl acetate were added and the mixture was extracted. Ethyl acetate was added to the aqueous layer and re-extracted twice, and the combined organic layers were washed with saturated brine, sodium sulfate was added and the mixture was dried. Sodium sulfate was filtered off and the mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane, ethyl acetate / methanol). THF (6.5 ml) and 6 M hydrochloric acid (3.2 ml) were added to the obtained solid at room temperature and the mixture was stirred all day, then stirred at 50°C for 5 hours. The reaction mixture was concentrated under reduced pressure, and the title compound (0.61 g) was obtained by azeotropic distillation twice with THF (2 ml). 1H-NMR (DMSO-D6) δ: 11.37 (1H, s), 8.39 (1H, s), 7.99 (1H, d, J = 8.1 Hz), 7.90-7.72 (3H, m), 7.70 (1H, d, J = 8.1 Hz), 3.27-3.13 (1H, m), 2.23-2.10 (2H, m), 1.62-1.17 (9H, m), 1.13 (3H, d, J = 5.4 Hz).

[0419] (4)N 1 -((S)-1-(cis-5-(2-bromo-4-cyanophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4-en-9-yl)propane-2-yl)-N 2 - Methyloxalamide

[0420] [ka]

[0421] To a solution of 4-(cis-9-((S)-2-aminopropyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4-en-5-yl)-3-bromobenzonitrile hydrochloride (0.57 g) obtained in (3) in DMF (8.4 ml), 2-methylamino-2-oxoacetic acid (0.24 g), HOAt (0.33 g), and N,N-diisopropylethylamine (1.0 ml) were added at room temperature. WSC (0.47 g) was added and the mixture was stirred at room temperature for the entire day. Water, saturated sodium bicarbonate solution, and ethyl acetate were added and the mixture was extracted. Ethyl acetate was added to the aqueous layer and re-extracted twice. The combined organic layers were washed with saturated brine, and sodium sulfate was added and dried. Sodium sulfate was filtered off and the mixture was concentrated under reduced pressure. The mixture was azeotropically removed twice with toluene (10 ml), and the resulting residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane), followed by reverse-phase silica gel chromatography (developing solvent: acetonitrile / water). The obtained solid was recrystallized in ethyl acetate (8.4 ml) / isopropyl ether (8.4 ml) at 50°C and stirred at room temperature for the entire day. The resulting suspension was filtered, and the obtained solid was washed three times with an ice-cold ethyl acetate / isopropyl ether = 1:1 mixed solvent (1 ml), and dried under reduced pressure at 50°C for 4 hours to obtain the title compound (0.30 g) in 57% yield. 1H-NMR (CDCl3) δ: 8.24 (1H, s), 7.97 (1H, d, J = 1.6 Hz), 7.68 (1H, dd, J = 7.9, 1.6 Hz), 7.44-7.39 (1H, m), 7.33 (1H, d, J = 7.9 Hz), 7.18-7.14 (1H, m), 4.08-4.00 (1H, m), 2.89 (3H, d, J = 5.3 Hz), 2.34-2.28 (2H, m), 1.79-1.72 (1H, m), 1.60-1.51 (2H, m), 1.50-1.31 (5H, m), 1.30-1.21 (1H, m), 1.16 (3H, d, J = 6.5 Hz).

[0422] [Manufacturing example 3]:(S)-N 1-(1-(5-(2-bromo-4-fluorophenyl)-2-oxo-1-oxa-3,4,9-triazaspiro[5.5]undeca-4-en-9-yl)propan-2-yl)-N 2 - Synthesis of methyloxalamide (Example 179)

[0423] [ka]

[0424] (1) tert-butyl 4-(2-bromo-4-fluorobenzoyl)-4-((trimethylsilyl)oxy)piperidine-1-carboxylate

[0425] [ka]

[0426] 1.2 ml of 2-bromo-4-fluorobenzaldehyde and 0.015 g of DMAP were mixed in 20 ml of acetonitrile. 1.5 ml of trimethylsilyl cyanide was added at room temperature and the mixture was stirred for 3 hours. After concentrating the reaction mixture, 18 ml of THF was added and the mixture was cooled to -78°C. 10 ml of 1.1 M LiHMDS-n-hexane solution was added and the mixture was stirred for 30 minutes. 2 g of tert-butyl 4-oxopiperidine-1-carboxylate was added in 9 ml of THF and the mixture was stirred for 1 hour. 12 ml of 2 M hydrochloric acid was added and the mixture was stirred at room temperature all day. The reaction mixture was cooled on ice, 12.5 ml of 2 M sodium hydroxide solution was added and the mixture was stirred at room temperature for 30 minutes. Water and ethyl acetate were added and the mixture was extracted. Ethyl acetate was added to the aqueous layer for re-extraction, and magnesium sulfate was added to the combined organic layer and dried. The magnesium sulfate was filtered off and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: ethyl acetate / n-hexane = 15 / 85~35 / 65) to obtain the title compound (1.8 g) in 34% yield. 1H-NMR (DMSO-D6) δ: 7.74 (1H, dd, J = 8.7, 2.4 Hz), 7.62 (1H, dd, J = 8.6, 6.0 Hz), 7.38 (1H, td, J = 8.6, 2.5 Hz), 3.66 (2H, dt, J = 13.9, 4.0 Hz), 3.24-3.14 (2H, m), 1.92-1.83 (2H, m), 1.82-1.75 (2H, m), 1.38 (9H, s), 0.06 (9H, s).

[0427] (2) tert-butyl 4-(2-bromo-4-fluorobenzoyl)-4-hydroxypiperidine-1-carboxylate

[0428] [ka]

[0429] To a solution of tert-butyl 4-(2-bromo-4-fluorobenzoyl)-4-((trimethylsilyl)oxy)piperidine-1-carboxylate (1.0 g) obtained in (1) in THF (8.8 ml), 1.9 ml of 1 M TBAF-THF solution was added at room temperature and the mixture was stirred for 1 hour. Saturated aqueous ammonium chloride solution and ethyl acetate were added and the mixture was extracted. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (eluent: ethyl acetate / n-hexane = 20 / 80~40 / 60) to obtain the title compound (0.74 g) in 92% yield. 1H-NMR (DMSO-D6) δ: 7.67 (1H, dd, J = 8.8, 2.5 Hz), 7.58 (1H, dd, J = 8.6, 6.0 Hz), 7.34 (1H, td, J = 8.6, 2.4 Hz), 5.70 (1H, s), 3.84-3.73 (2H, m), 3.15-2.92 (2H, m), 1.81-1.66 (4H, m), 1.40 (9H, s).

[0430] (3) tert-butyl 5-(2-bromo-4-fluorophenyl)-2-oxo-1-oxa-3,4,9-triazaspiro[5.5]undeca-4-ene-9-carboxylate

[0431] [ka]

[0432] (2) A solution of tert-butyl 4-(2-bromo-4-fluorobenzoyl)-4-hydroxypiperidine-1-carboxylate (0.74 g) obtained in (2) was mixed with THF (6.9 ml) at room temperature, and DBU (0.026 ml) and CDI (0.42 g) were added and stirred for 1 hour. Hydrazine monohydrate (0.25 ml) was added and stirred for 1 hour, then 1 M hydrochloric acid and ethyl acetate were added and extracted. Ethyl acetate was added to the aqueous layer and extracted again, and the combined organic layers were washed with saturated sodium bicarbonate solution and saturated saline solution, and magnesium sulfate was added and dried. Sodium sulfate was filtered off and the mixture was concentrated under reduced pressure. THF (7.3 ml) and 6 M hydrochloric acid (3.7 ml) were added to the obtained residue at room temperature and stirred for 20 hours. After neutralization with 4 M sodium hydroxide aqueous solution (6.0 ml), Boc2O (0.44 ml) was added and stirred for 1 hour. After extraction with ethyl acetate, the organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (eluent: ethyl acetate / n-hexane = 30 / 70~50 / 50) to obtain the title compound (0.60 g) in 79% yield. 1H-NMR (DMSO-D6) δ: 11.35 (1H, s), 7.76 (1H, dd, J = 8.6, 2.5 Hz), 7.57 (1H, dd, J = 8.7, 5.9 Hz), 7.36 (1H, td, J = 8.5, 2.6 Hz), 3.90-3.78 (2H, m), 3.10-2.91 (2H, m), 2.16-2.06 (2H, m), 1.59-1.46 (2H, m), 1.35 (9H, s).

[0433] (4) 5-(2-bromo-4-fluorophenyl)-1-oxa-3,4,9-triazaspiro[5.5]undeca-4-en-2-one hydrochloride

[0434] [ka]

[0435] To the tert-butyl 5-(2-bromo-4-fluorophenyl)-2-oxo-1-oxa-3,4,9-triazaspiro[5,5]undec-4-ene-9-carboxylate (0.60 g) obtained in (3), 4 M hydrogen chloride-CPME solution (5.6 ml) was added at room temperature and the mixture was stirred for 3 hours. The resulting reaction mixture was concentrated under reduced pressure to obtain the title compound (0.53 g) in 100% yield. 1H-NMR (DMSO-D6) δ: 11.48 (1H, s), 8.87-8.70 (1H, m), 8.56-8.40 (1H, m), 7.81 (1H, dd, J = 8.6, 2.5 Hz), 7.61 (1H, dd, J = 8.7, 5.9 Hz), 7.44 (1H, td, J = 8.5, 2.6 Hz), 3.28-3.20 (2H, m), 3.11-2.99 (2H, m), 2.36-2.26 (2H, m), 1.99-1.85 (2H, m).

[0436] (5) tert-butyl (S)-(1-(5-(2-bromo-4-fluorophenyl)-2-oxo-1-oxa-3,4,9-triazaspiro[5.5]undeca-4-en-9-yl)propan-2-yl)carbamate

[0437] [ka]

[0438] To a methanol (5.3 ml) solution of 5-(2-bromo-4-fluorophenyl)-1-oxa-3,4,9-triazaspiro[5.5]undeca-4-en-2-one hydrochloride (0.53 g) obtained in (4), triethylamine (0.89 ml) and tert-butyl (S)-4-methyl-1,2,3-oxathiazolidined-3-carboxylate 2,2-dioxide (0.36 g) were added under ice cooling and the mixture was stirred for 5 hours. Methanol was removed by distillation, and THF (5.3 ml), water (5.3 ml), and potassium bisulfate (0.52 g) were added and the mixture was stirred at room temperature for 2 days. Saturated sodium bicarbonate solution and ethyl acetate were added and the mixture was extracted. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by thin-layer chromatography (eluent: ethyl acetate / n-hexane = 67 / 33) to obtain the title compound (0.57 g) in 84% yield. 1H-NMR (DMSO-D6) δ: 11.24 (1H, s), 7.75 (1H, dd, J = 8.7, 2.7 Hz), 7.53 (1H, dd, J = 8.6, 6.0 Hz), 7.36 (1H, td, J = 8.5, 2.6 Hz), 6.45-6.38 (1H, m), 3.64-3.51 (1H, m), 2.81-2.71 (1H, m), 2.63-2.57 (1H, m), 2.35-2.24 (1H, m), 2.24-2.01 (5H, m), 1.68-1.44 (2H, m), 1.28 (9H, s), 0.94 (3H, d, J = 6.5 Hz).

[0439] (6)(S)-9-(2-aminopropyl)-5-(2-bromo-4-fluorophenyl)-1-oxa-3,4,9-triazaspiro[5.5]undec-4-en-2-one 2-hydrochloride

[0440] [ka]

[0441] To the tert-butyl (S)-(1-(5-(2-bromo-4-fluorophenyl)-2-oxo-1-oxa-3,4,9-triazaspiro[5.5]undeca-4-en-9-yl)propan-2-yl)carbamate (0.12 g) obtained in (5), 1.1 ml of 4 M hydrogen chloride-CPME solution was added at room temperature and the mixture was stirred for 3 hours. The resulting reaction mixture was concentrated under reduced pressure to obtain the title compound (0.13 g). 1H-NMR (DMSO-D6) δ: 11.59-11.30 (1H, m), 10.86-10.59 (1H, m), 8.46-8.13 (2H, m), 7.79 (1H, dd, J = 8.6, 2.5 Hz), 7.58 (1H, dd, J = 8.6, 6.0 Hz), 7.41 (1H, td, J = 8.5, 2.5 Hz), 3.90-3.53 (5H, m), 3.49-3.30 (1H, m), 2.44-2.10 (4H, m), 1.68-1.42 (2H, m), 1.31-1.13 (3H, m).

[0442] (7)(S)-N 1 -(1-(5-(2-bromo-4-fluorophenyl)-2-oxo-1-oxa-3,4,9-triazaspiro[5.5]undeca-4-en-9-yl)propan-2-yl)-N 2 - Methyloxalamide

[0443] [ka]

[0444] (6) (S)-9-(2-aminopropyl)-5-(2-bromo-4-fluorophenyl)-1-oxa-3,4,9-triazaspiro[5.5]undec-4-en-2-one 2-hydrochloride salt (0.04 g) obtained in (6) was dissolved in acetonitrile (0.34 ml) and 2-methylamino-2-oxoacetic acid (0.014 g), HOAt (0.018 g), and N,N-diisopropylethylamine (0.059 ml) were added at room temperature. WSC (0.026 g) was added and the mixture was stirred at room temperature for 3 hours. Saturated sodium bicarbonate solution and ethyl acetate were added and the mixture was extracted. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by thin-layer chromatography (eluent: ethyl acetate) to obtain the title compound (0.029 g) in 87% yield. 1H-NMR (DMSO-D6) δ: 11.25 (1H, s), 8.63 (1H, q, J = 4.7 Hz), 8.35 (1H, d, J = 8.8 Hz), 7.75 (1H, dd, J = 8.6, 2.5 Hz), 7.54 (1H, dd, J = 8.6, 5.8 Hz), 7.36 (1H, td, J = 8.6, 2.5 Hz), 3.96-3.89 (1H, m), 2.72-2.60 (2H, m), 2.64 (3H, d, J = 4.7 Hz), 2.42 (1H, dd, J = 12.5, 8.3 Hz), 2.33-2.19 (3H, m), 2.10-2.02 (2H, m), 1.64-1.48 (2H, m), 1.04 (3H, d, J = 6.5 Hz).

[0445] [Manufacturing example 4]:N 1 -((S)-1-(cis-5-(2-bromo-5-cyanophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4-en-9-yl)propane-2-yl)-N 2 - Synthesis of methyloxalamide (Example 198)

[0446] [ka]

[0447] (1) tert-butyl ((S)-1-(cis-4-(2-bromo-5-cyanobenzoyl)-4-((trimethylsilyl)oxy)cyclohexyl)propan-2-yl)carbamate

[0448] [ka]

[0449] 54 g of 4-bromo-3-formylbenznitrile and 1.1 g of lithium chloride were added to a 350 ml THF solution, and trimethylsilyl cyanide was added under water cooling and stirred for 1 hour. The mixture was cooled to -78°C, and 225 ml of 1.1 M LiHMDS-n-hexane solution was added and stirred for 2 hours. The temperature was raised to -60°C, and a 100 ml THF solution of 50 g of tert-butyl (S)-(1-(4-oxocyclohexyl)propan-2-yl)carbamate obtained in (9) of [Preparation Example 1] was added and stirred for 1.5 hours. 15 ml of acetic acid was added and the temperature was raised to -20°C, and water (250 ml) was added. After stirring at room temperature for 10 minutes, water (250 ml) and toluene (500 ml) were added and the mixture was extracted. The organic layer was washed three times with water (500 ml) and then with 20% saline solution (500 ml), sodium sulfate was added, and the layer was dried. After filtering off the sodium sulfate, the title compound (150 g), containing a small amount of toluene, was obtained by concentration under reduced pressure at room temperature. 1H-NMR (DMSO-D6) δ: 8.01-7.98 (1H, m), 7.96 (1H, d, J = 8.3 Hz), 7.89-7.85 (1H, m), 6.59 (1H, d, J = 8.6 Hz), 3.62-3.48 (1H, m), 2.01-1.91 (2H, m), 1.77-1.50 (4H, m), 1.40-1.07 (5H, m), 1.36 (9H, s), 0.99 (3H, d, J = 6.5 Hz), 0.00 (9H, s).

[0450] (2) tert-butyl ((S)-1-(cis-4-(2-bromo-5-cyanobenzoyl)-4-hydroxycyclohexyl)propan-2-yl)carbamate

[0451] [ka]

[0452] To the tert-butyl ((S)-1-(cis-4-(2-bromo-5-cyanobenzoyl)-4-((trimethylsilyl)oxy)cyclohexyl)propan-2-yl)carbamate (150 g) obtained in (1), 310 ml of THF, 14 ml of acetic acid, and 230 ml of 1 M TBAF-THF solution were added at room temperature and stirred for 1.5 hours. Water (500 ml) and toluene (500 ml) were added and extracted. The resulting organic layer was washed with 5% sodium bicarbonate solution (500 ml), water (500 ml), and saturated brine (500 ml), and sodium sulfate was added and dried. Sodium sulfate was filtered off and the mixture was concentrated under reduced pressure. Methanol (150 ml) was added and the mixture was concentrated again under reduced pressure. Methanol (270 ml) and water (90 ml) were added to the resulting residue and stirred for two days. The mixture was stirred for a full day under ice cooling and the resulting solid was filtered. The solid was washed with a mixed solvent of ice-cold methanol (68 ml) and water (22 ml). The compound was dried under reduced pressure at 60°C for 3 hours and at room temperature for the entire day to obtain the title compound (52 g) in 58% yield. 1H-NMR (DMSO-D6) δ: 7.92-7.88 (2H, m), 7.83-7.79 (1H, m), 6.59 (1H, d, J = 8.1 Hz), 5.28 (1H, s), 3.64-3.48 (1H, m), 1.88-1.78 (2H, m), 1.71-1.09 (9H, m), 1.38 (9H, s), 0.99 (3H, d, J = 6.5 Hz).

[0453] (3)3-(cis-9-((S)-2-aminopropyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4-en-5-yl)-4-bromobenzonitrile

[0454] [ka]

[0455] To a solution of tert-butyl ((S)-1-(cis-4-(2-bromo-5-cyanobenzoyl)-4-hydroxycyclohexyl)propan-2-yl) carbamate (48 g) obtained in (2) in THF (240 ml), DBU (2.4 ml) and CDI (25 g) were added at room temperature and the mixture was stirred for 1 hour. Hydrazine monohydrate (10 ml) was added and the mixture was stirred for 30 minutes. Water (240 ml) and ethyl acetate (240 ml) were added and the mixture was extracted. The resulting organic layer was washed with 10% citric acid aqueous solution (240 ml), water (240 ml), and 20% saline solution (240 ml), and sodium sulfate was added and the mixture was dried. Sodium sulfate was filtered off and the mixture was concentrated under reduced pressure. Ethyl acetate (530 ml) was added to the resulting residue and the mixture was stirred at room temperature for 1 hour. The solid was filtered off and the mixture was concentrated under reduced pressure. To the concentrate, 240 ml of THF and 120 ml of 6M hydrochloric acid were added at room temperature and the mixture was stirred at 50°C for 5 hours. After slow cooling to room temperature, 242 ml of water and 91 ml of 8M sodium hydroxide solution were added and the mixture was stirred for 5 minutes. 120 ml of THF and 240 ml of toluene were added and extracted. 96 ml of THF and 120 ml of toluene were added to the aqueous layer and re-extracted. The combined organic layers were washed with 240 ml of 20% saline solution, sodium sulfate was added and the mixture was dried. Sodium sulfate was filtered off and the mixture was concentrated under reduced pressure. 144 ml of ethyl acetate was added and the mixture was concentrated again under reduced pressure. 54 ml of ethyl acetate was added to the resulting residue at room temperature and the mixture was stirred all day. The resulting solid was filtered and washed with 36 ml of ice-cold ethyl acetate. The title compound (32 g) was obtained in 89% yield by drying under reduced pressure at 60°C for 3 hours and at room temperature all day. 1H-NMR (DMSO-D6) δ: 11.29 (1H, br s), 8.04-7.96 (2H, m), 7.91-7.84 (1H, m), 2.87-2.75 (1H, m), 2.19-2.05 (2H, m), 1.80-1.03 (11H, m), 0.92 (3H, d, J = 5.9 Hz).

[0456] (4)N 1 -((S)-1-(cis-5-(2-bromo-5-cyanophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4-en-9-yl)propane-2-yl)-N2 - Methyloxalamide

[0457] [ka]

[0458] To a solution of 3-(cis-9-((S)-2-aminopropyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4-en-5-yl)-4-bromobenzonitrile (0.02 g) obtained by the same method as in (3) in DMF (0.5 ml), 2-methylamino-2-oxoacetic acid (0.008 g), HOAt (0.007 g), WSC (0.014 g), and N,N-diisopropylethylamine (0.026 ml) were added at room temperature and the mixture was stirred all day. Water and ethyl acetate were added and the mixture was extracted. Ethyl acetate was added to the aqueous layer and the mixture was re-extracted. The combined organic layers were washed with water and saturated brine, and sodium sulfate was added and the mixture was dried. Sodium sulfate was filtered off and the mixture was concentrated under reduced pressure. The title compound (0.021 g) was obtained in 87% yield by purification by thin-layer chromatography (eluent: ethyl acetate). 1H-NMR (DMSO-D6) δ: 11.29 (1H, s), 8.65-8.59 (1H, m), 8.41 (1H, d, J = 9.0 Hz), 8.00 (1H, d, J = 1.8 Hz), 7.98 (1H, d, J = 8.3 Hz), 7.86 (1H, dd, J = 8.3, 1.8 Hz), 3.98-3.85 (1H, m), 2.64 (3H, d, J = 4.9 Hz), 2.16-2.04 (2H, m), 1.69-1.59 (1H, m), 1.59-1.13 (8H, m), 1.06 (3H, d, J = 6.5 Hz).

[0459] (5)N 1 -((S)-1-(cis-5-(2-bromo-5-cyanophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4-en-9-yl)propane-2-yl)-N 2 - Methyloxalamide crystals

[0460] [ka]

[0461] Under a nitrogen atmosphere, 3-(cis-9-((S)-2-aminopropyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4-en-5-yl)-4-bromobenzonitrile (42 g), 2-methylamino-2-oxoacetic acid (13 g), and WSC (24 g) were prepared in a DMF (210 ml) solution. HOAt (7.1 g) was added at room temperature and the mixture was stirred for 1 hour. 5% sodium bicarbonate solution (420 ml) and ethyl acetate (420 ml) were added and the mixture was extracted. Ethyl acetate (210 ml) was added to the aqueous layer and the mixture was re-extracted. The combined organic layers were washed with 5% sodium bicarbonate solution (210 ml), water (210 ml x 2), and saturated saline solution (210 ml). Sodium sulfate and activated carbon (1.3 g) were added and the mixture was stirred for 1.5 hours, after which the solid was filtered off. The obtained solution was concentrated under reduced pressure, and 115 ml of DMF was added to the resulting amorphous solid. The obtained solution was concentrated under reduced pressure, and after removing ethyl acetate, the solution was filtered to remove dust. Washed with 139 ml of DMF, 150 ml of water was added to the obtained DMF solution at room temperature. After confirming the precipitation of the solid, 612 ml of water was added dropwise, and the resulting suspension was stirred at room temperature for 5 days. The suspension was heated to 50°C and stirred overnight, then cooled to room temperature. The suspension was filtered and washed with water. The obtained wet crystals were air-dried overnight, and the title compound (45 g) was obtained by drying under reduced pressure at 60°C for 3 hours.

[0462] [Production Example 5]: Synthesis of 1-((S)-1-(cis-5-(2-bromo-5-cyanophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4-en-9-yl)propan-2-yl)-3-cyclopropylurea (Example 222)

[0463] [ka]

[0464] (1)1-((S)-1-(cis-5-(2-bromo-5-cyanophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4-en-9-yl)propan-2-yl)-3-cyclopropylurea

[0465] [ka]

[0466] To a solution of 3-(cis-9-((S)-2-aminopropyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4-en-5-yl)-4-bromobenzonitrile (0.020 g), obtained by the same method as in (3) of [Preparation Example 4], in THF (0.4 ml), cyclopropyl isocyanate (0.005 ml) was added at room temperature and the mixture was stirred for 3 hours. Water and ethyl acetate were added and the mixture was extracted. Ethyl acetate was added to the aqueous layer and extracted again. The combined organic layers were washed with water and saturated brine and dried over sodium sulfate. The sodium sulfate was filtered off and the mixture was concentrated under reduced pressure. The resulting residue was purified by thin-layer chromatography (eluent: ethyl acetate) to obtain the title compound (0.019 g) in 79% yield. 1H-NMR (DMSO-D6) δ: 11.30 (1H, s), 8.03 (1H, d, J = 1.8 Hz), 7.99 (1H, d, J = 8.3 Hz), 7.87 (1H, dd, J = 8.4, 2.0 Hz), 5.89 (1H, d, J = 2.8 Hz), 5.46 (1H, d, J = 8.6 Hz), 3.72-3.61 (1H, m), 2.40-2.31 (1H, m), 2.19-2.07 (2H, m), 1.70-1.57 (1H, m), 1.56-1.06 (8H, m), 0.97 (3H, d, J = 6.5 Hz), 0.56-0.46 (2H, m), 0.31-0.22 (2H, m).

[0467] [Manufacturing example 6]:N 1-((S)-1-(cis-5-(4-chloro-6-methylpyridine-3-yl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4-en-9-yl)propan-2-yl)-N 2 - Synthesis of methyloxalamide (Example 230)

[0468] [ka]

[0469] (1) tert-butyl ((S)-1-(cis-4-(4-chloro-6-methylnicotinoyl)-4-((trimethylsilyl)oxy)cyclohexyl)propan-2-yl)carbamate

[0470] [ka]

[0471] A mixture of 4-chloro-6-methylnicotinaldehyde (0.55 g) and lithium chloride (0.015 g) was mixed with trimethylsilyl cyanide (0.55 ml) and stirred at room temperature for 10 minutes. THF (7 ml) was added and the mixture was cooled to -78 °C. 1 M NaHMDS-THF solution (1.9 ml) was added and stirred for 5 minutes. Tert-butyl (S)-(1-(4-oxocyclohexyl)propan-2-yl)carbamate (0.7 g), obtained by the same method as in (9) of [Preparation Example 1], was added and stirred for 30 minutes. The mixture was then heated to 0 °C over 1 hour, and water and ethyl acetate were added for extraction. Ethyl acetate was added to the aqueous layer for re-extraction twice, and the combined organic layers were washed with saturated brine, and sodium sulfate was added and dried. Sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (1.1 g) in 83% yield. 1H-NMR (CDCl3) δ: 8.58 (1H, s), 7.25 (1H, s), 4.32-4.15 (1H, m), 3.84-3.65 (1H, m), 2.57 (3H, s), 1.99-1.88 (2H, m), 1.83-1.68 (3H, m), 1.66-1.55 (1H, m), 1.43 (9H, s), 1.41-1.21 (5H, m), 1.11 (3H, d, J = 6.5 Hz), 0.06 (9H, s).

[0472] (2) tert-butyl ((S)-1-(cis-4-(4-chloro-6-methylnicotinoyl)-4-hydroxycyclohexyl)propan-2-yl)carbamate

[0473] [ka]

[0474] To a solution of tert-butyl ((S)-1-(cis-4-(4-chloro-6-methylnicotinoyl)-4-((trimethylsilyl)oxy)cyclohexyl)propan-2-yl)carbamate (1.1 g) obtained in (1) in THF (2.2 ml), acetic acid (0.39 ml) and 1 M TBAF-THF solution (3.4 ml) were added and stirred at room temperature for 15 minutes, then allowed to stand for the entire day. Saturated ammonium chloride aqueous solution, water, and ethyl acetate were added and extracted. Ethyl acetate was added to the aqueous layer and re-extracted twice, and the combined organic layers were washed with saturated brine, sodium sulfate was added and dried. Sodium sulfate was filtered off and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane) to obtain the title compound (0.80 g) in 86% yield. 1H-NMR (CDCl3) δ: 8.39 (1H, s), 7.26 (1H, s), 4.29-4.16 (1H, m), 3.83-3.65 (1H, m), 2.93 (1H, s), 2.58 (3H, s), 1.87-1.73 (5H, m), 1.67-1.59 (1H, m), 1.43 (9H, s), 1.41-1.22 (5H, m), 1.10 (3H, d, J = 6.5 Hz).

[0475] (3) cis-9-((S)-2-aminopropyl)-5-(4-chloro-6-methylpyridine-3-yl)-1-oxa-3,4-diazaspiro[5.5]undec-4-en-2-one 2 hydrochloride

[0476] [ka]

[0477] To a solution of tert-butyl ((S)-1-(cis-4-(4-chloro-6-methylnicotinoyl)-4-hydroxycyclohexyl)propan-2-yl)carbamate (0.8 g) obtained in (2) in THF (8 ml), DBU (0.044 ml) and CDI (0.47 g) were added at room temperature and the mixture was stirred for 1 hour. Hydrazine monohydrate (0.19 ml) was added and the mixture was stirred for 1 hour, then 10% citric acid aqueous solution and ethyl acetate were added and the mixture was extracted. Ethyl acetate was added to the aqueous layer and re-extracted twice, and the combined organic layers were washed with saturated brine, sodium sulfate was added and the mixture was dried. Sodium sulfate was filtered off and the mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane). THF (9.0 ml) and 6 M hydrochloric acid (4.5 ml) were added to the obtained solid at room temperature and the mixture was stirred all day, then stirred at 50°C for 6 hours. The reaction mixture was concentrated under reduced pressure, and the title compound (0.98 g) was obtained by azeotropic distillation twice with THF (10 ml). 1H-NMR (DMSO-D6) δ: 11.40 (1H, s), 8.64 (1H, s), 8.08-7.97 (3H, m), 7.81 (1H, s), 3.25-3.14 (1H, m), 2.59 (3H, s), 2.18-2.08 (2H, m), 1.62-1.19 (9H, m), 1.15 (3H, d, J = 6.5 Hz).

[0478] (4)N 1 -((S)-1-(cis-5-(4-chloro-6-methylpyridine-3-yl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4-en-9-yl)propan-2-yl)-N 2 - Methyloxalamide

[0479] [ka]

[0480] To a solution of cis-9-((S)-2-aminopropyl)-5-(4-chloro-6-methylpyridine-3-yl)-1-oxa-3,4-diazaspiro[5.5]undec-4-en-2-one dihydrochloride (0.1 g) obtained in (3) in DMF (1.5 ml), 2-methylamino-2-oxoacetic acid (0.045 g), HOAt (0.062 g), and N,N-diisopropylethylamine (0.23 ml) were added at room temperature. WSC (0.087 g) was added, and the mixture was stirred at room temperature for 15 minutes and left to stand for the entire day. Water, saturated sodium bicarbonate solution, and ethyl acetate were added and extracted. Ethyl acetate was added to the aqueous layer and re-extracted twice, and the combined organic layers were washed with saturated saline solution, sodium sulfate was added and dried. Sodium sulfate was filtered off and the mixture was concentrated under reduced pressure. The compound was azeotropically dissolved in toluene (5 ml), and the resulting residue was purified by silica gel chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (0.067 g) in 71% yield. 1H-NMR (DMSO-D6) δ: 11.28 (1H, s), 8.62 (1H, q, J = 4.8 Hz), 8.48 (1H, s), 8.41 (1H, d, J = 9.2 Hz), 7.58 (1H, s), 3.98-3.83 (1H, m), 2.64 (3H, d, J = 4.8 Hz), 2.51 (3H, s), 2.15-2.02 (2H, m), 1.71-1.59 (1H, m), 1.57-1.15 (8H, m), 1.05 (3H, d, J = 6.5 Hz).

[0481] [Production Example 7]: Synthesis of N-((S)-1-(cis-5-(2-bromo-4-fluorophenyl)-9-hydroxy-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4-en-9-yl)propan-2-yl)-3-methyl-1H-pyrazole-5-carboxamide (Example 320)

[0482] [ka]

[0483] (1) 1,4-Dioxaspiro[4.5]deca-7-en-8-yl trifluoromethanesulfonate

[0484] [ka]

[0485] A 50 ml solution of 1,4-dioxaspiro[4.5]decane-8-one was cooled to -78°C, and 31 ml of 1.1 M LiHMDS-n-hexane solution was added and the mixture was stirred for 10 minutes. The mixture was raised to 0°C and stirred for 20 minutes, then cooled to -78°C, and 14 g of Comins' reagent was added. After stirring for 30 minutes, the mixture was raised to 0°C and stirred for a further 1.5 hours. Saturated sodium bicarbonate solution, water, and ethyl acetate were added and the mixture was extracted. Ethyl acetate was added to the aqueous layer and re-extracted. The combined organic layers were washed with saturated brine, and sodium sulfate was added and dried. The sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (7.5 g) in 81% yield. 1H-NMR (CDCl3) δ: 5.69-5.65 (1H, m), 4.00 (4H, t, J = 2.4 Hz), 2.54 (2H, t, J = 6.5 Hz), 2.41 (2H, d, J = 2.7 Hz), 1.91 (2H, t, J = 6.7 Hz).

[0486] (2)(S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate

[0487] [ka]

[0488] 10 g of tert-butyl (S)-(1-hydroxypropan-2-yl)carbamate was dissolved in 100 ml of THF, to which 16 ml of triethylamine was added at room temperature. The mixture was cooled to 0°C, 11 g of methanesulfonic anhydride was added, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (13.7 g) in 95% yield. 1H-NMR (CDCl3) δ: 4.68-4.49 (1H, m), 4.28-4.19 (1H, m), 4.15 (1H, dd, J = 9.7, 4.3 Hz), 4.04-3.88 (1H, m), 3.04 (3H, s), 1.45 (9H, s), 1.24 (3H, d, J = 7.0 Hz).

[0489] (3) tert-butyl (S)-(1-(1,4-dioxaspiro[4.5]deca-7-en-8-yl)propan-2-yl)carbamate

[0490] [ka]

[0491] To a DMA (100 ml) solution of 1,4-dioxaspiro[4.5]deca-7-en-8-yl trifluoromethanesulfonate (5 g) obtained in (1), (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate (7.9 g), nickel(II) iodide (0.093 ml), 2,2':6',2''-terpyridine (0.61 g), manganese (2.9 g), and sodium iodide (1.3 g) obtained in (2) were added at room temperature and stirred at 80°C for 1.5 hours. Water and ethyl acetate were added at room temperature and extracted. Ethyl acetate was added to the aqueous layer and re-extracted twice, and the combined organic layer was washed with saturated brine, sodium sulfate was added and dried. Sodium sulfate was filtered off and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane) to obtain the title compound (1.9 g) in 37% yield. 1H-NMR (CDCl3) δ: 5.34 (1H, s), 4.40-4.21 (1H, m), 3.97 (4H, s), 3.88-3.71 (1H, m), 2.30-1.98 (6H, m), 1.75 (2H, t, J = 6.5 Hz), 1.43 (9H, s), 1.10 (3H, d, J = 6.5 Hz).

[0492] (4) tert-butyl (S)-(1-(4-oxocyclohexa-1-en-1-yl)propan-2-yl)carbamate

[0493] [ka]

[0494] To a solution of tert-butyl (S)-(1-(1,4-dioxaspiro[4,5]deca-7-en-8-yl)propan-2-yl)carbamate (0.5 g) obtained in (3) in 2 ml of water, 8 ml of acetic acid was added at room temperature and the mixture was stirred for 15 minutes, then allowed to stand for the entire day. The reaction mixture was concentrated under reduced pressure and azeotropically removed three times with toluene (2 ml). The resulting residue was purified by silica gel chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (0.37 g) in 87% yield. 1H-NMR (CDCl3) δ: 5.49 (1H, s), 4.37-4.22 (1H, m), 3.91-3.76 (1H, m), 2.85 (2H, s), 2.60-2.30 (4H, m), 2.22-2.09 (2H, m), 1.42 (9H, s), 1.14 (3H, d, J = 6.5 Hz).

[0495] (5) tert-butyl ((2S)-1-(4-(2-bromo-4-fluorobenzoyl)-4-((trimethylsilyl)oxy)cyclohexa-1-en-1-yl)propan-2-yl)carbamate

[0496] [ka]

[0497] 2-bromo-4-fluorobenzaldehyde (0.16 g) and lithium chloride (0.003 g) were mixed with trimethyl cyanide (0.12 ml) at room temperature and stirred for 10 minutes. THF (1.5 ml) was added, the mixture was cooled to -78°C, and 1 M NaHMDS-THF solution (0.77 ml) was added and stirred for 5 minutes. The tert-butyl (S)-(1-(4-oxocyclohexa-1-en-1-yl)propan-2-yl)carbamate (0.15 g) obtained in (4) was added to the reaction mixture and stirred for 30 minutes. The mixture was heated to 0°C over 1 hour, and water and ethyl acetate were added for extraction. Ethyl acetate was added to the aqueous layer for re-extraction twice, and the combined organic layers were washed with saturated brine, sodium sulfate was added, and the mixture was dried. The sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (0.22 g) in 66% yield. 1H-NMR (CDCl3) δ: 7.65 (0.3H, dd, J = 8.6, 6.5 Hz), 7.56 (0.7H, dd, J = 8.1, 6.5 Hz), 7.36 (1H, d, J = 8.1 Hz), 7.04 (1H, t, J = 8.4 Hz), 5.36 (1H, s), 4.37-4.21 (1H, m), 3.88-3.74 (1H, m), 2.81-2.67 (1H, m), 2.34-1.92 (7H, m), 1.45 (3H, s), 1.43 (6H, s), 1.14 (2.1H, d, J = 6.5 Hz), 1.12 (0.9H, d, J = 6.5 Hz), 0.01 (6.3H, s), 0.00 (2.7H, s).

[0498] (6) tert-butyl ((2S)-1-(4-(2-bromo-4-fluorobenzoyl)-4-hydroxycyclohexa-1-en-1-yl)propan-2-yl)carbamate

[0499] [ka]

[0500] To a solution of tert-butyl ((2S)-1-(4-(2-bromo-4-fluorobenzoyl)-4-((trimethylsilyl)oxy)cyclohexa-1-en-1-yl)propan-2-yl)carbamate (0.22 g) obtained in (5) in THF (0.41 ml), acetic acid (0.067 ml) and 1 M TBAF-THF solution (0.59 ml) were added at room temperature, and the mixture was stirred for 15 minutes and left to stand at room temperature for the entire day. Saturated ammonium chloride aqueous solution, water, and ethyl acetate were added and the mixture was extracted. Ethyl acetate was added to the aqueous layer and re-extracted twice, and the combined organic layers were washed with saturated sodium bicarbonate solution and saturated brine, and sodium sulfate was added and the mixture was dried. Sodium sulfate was filtered off and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (0.17 g) in 66% yield. 1H-NMR (CDCl3) δ: 7.50-7.41 (0.3H, m), 7.40-7.29 (1.7H, m), 7.12-6.96 (1H, m), 5.43-5.35 (1H, m), 4.37-4.18 (1H, m), 4.01 (0.3H, s), 3.90-3.73 (1H, m), 3.10 (0.7H, s), 2.82-2.50 (1H, m), 2.30-1.88 (7H, m), 1.39-1.38 (2.7H, s), 1.37-1.35 (6.3H, s), 1.14 (0.9H, d, J = 7.5 Hz), 1.12 (2.1H, d, J = 6.5 Hz).

[0501] (7) tert-butyl ((2S)-1-(5-(2-bromo-4-fluorophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4,8-dien-9-yl)propan-2-yl)carbamate

[0502] [ka]

[0503] To a solution of tert-butyl ((2S)-1-(4-(2-bromo-4-fluorobenzoyl)-4-hydroxycyclohexa-1-en-1-yl)propan-2-yl)carbamate (0.17 g) obtained in (6) in THF (1.7 ml), DBU (0.009 ml) and CDI (0.093 g) were added at room temperature and the mixture was stirred for 30 minutes. Hydrazine monohydrate (0.037 ml) was added and the mixture was stirred at room temperature for 30 minutes. 10% citric acid aqueous solution and ethyl acetate were added and the mixture was extracted. Ethyl acetate was added to the aqueous layer and re-extracted twice. The combined organic layers were washed with saturated brine, sodium sulfate was added and the mixture was dried. Sodium sulfate was filtered off and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane). THF (1.5 ml) and 6 M hydrochloric acid (0.73 ml) were added to the resulting solid at room temperature and the mixture was stirred for 15 minutes and left to stand for the entire day. The reaction mixture was stirred at 50°C for 1.5 hours and then concentrated under reduced pressure. Azeotropic mixing was performed twice with THF (2 ml), and saturated sodium bicarbonate solution (0.65 ml), THF (1.3 ml), water (0.65 ml), and Boc2O (0.19 ml) were added to the resulting solid at room temperature and stirred for 24 hours. Water and ethyl acetate were added and the mixture was extracted. Ethyl acetate was added to the aqueous layer and re-extracted twice. The combined organic layers were washed with saturated brine, sodium sulfate was added, and the mixture was dried. Sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (0.12 g) in 88% yield. 1H-NMR (CDCl3) δ: 8.13 (1H, s), 7.44-7.39 (1H, m), 7.24-7.16 (1H, m), 7.13-7.02 (1H, m), 5.31-5.18 (1H, m), 4.40-4.14 (1H, m), 3.86-3.67 (1H, m), 2.71-2.60 (1H, m), 2.44-2.08 (4H, m), 2.07-1.91 (2H, m), 1.78-1.66 (1H, m), 1.43 (2.7H, s), 1.32 (6.3H, s), 1.12 (0.9H, d, J = 7.0 Hz), 1.07 (2.1H, d, J = 7.0 Hz).

[0504] (8) tert-butyl ((S)-1-(cis-5-(2-bromo-4-fluorophenyl)-9-hydroxy-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4-en-9-yl)propan-2-yl)carbamate (cis isomer), and tert-butyl ((S)-1-(trans-5-(2-bromo-4-fluorophenyl)-9-hydroxy-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4-en-9-yl)propan-2-yl)carbamate (trans isomer)

[0505] [ka]

[0506] To a solution of tert-butyl ((2S)-1-(5-(2-bromo-4-fluorophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4,8-dien-9-yl)propan-2-yl)carbamate (0.12 g) obtained in (7) in THF (1.8 ml), cobalt(II)acetylacetone (0.063 g) and phenylsilane (0.30 ml) were added and stirred under an oxygen atmosphere for the entire day. Saturated sodium thiosulfate aqueous solution, water, and ethyl acetate were added and extracted. Ethyl acetate was added to the aqueous layer and re-extracted twice, and the combined organic layers were washed with saturated brine, sodium sulfate was added and dried. Sodium sulfate was filtered off and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: ethyl acetate / n-hexane) to obtain the cis isomer of the title compound (0.047 g) in 27% yield and the trans isomer of the title compound (0.060 g) in 30% yield. (Cis isomer) 1H-NMR (CDCl3) δ: 8.22-8.08 (1H, m), 7.43 (1H, dd, J = 8.1, 2.2 Hz), 7.27-7.22 (1H, m), 7.11 (1H, td, J = 8.1, 2.5 Hz), 4.63 (1H, d, J = 6.5 Hz), 3.81-3.67 (1H, m), 2.32-2.22 (2H, m), 2.19 (1H, s), 2.00-1.84 (3H, m), 1.84-1.48 (5H, m), 1.42 (9H, s), 1.15 (3H, d, J = 6.5 Hz). (Trans isomer) 1H-NMR (CDCl3) δ: 8.10 (1H, s), 7.40 (1H, dd, J = 8.1, 2.2 Hz), 7.28-7.22 (1H, m), 7.10 (1H, t, J = 8.6 Hz), 4.59-4.44 (1H, m), 3.99-3.81 (1H, m), 3.81-3.66 (1H, m), 2.19 (1H, s), 2.15-2.03 (1H, m), 2.03-1.89 (2H, m), 1.85-1.73 (2H, m), 1.73-1.50 (4H, m), 1.41 (9H, s), 1.17 (3H, d, J = 7.0 Hz).

[0507] (9) cis-9-((S)-2-aminopropyl)-5-(2-bromo-4-fluorophenyl)-9-hydroxy-1-oxa-3,4-diazaspiro[5.5]undeca-4-en-2-one

[0508] [ka]

[0509] (8) The tert-butyl ((S)-1-(cis-5-(2-bromo-4-fluorophenyl)-9-hydroxy-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4-en-9-yl)propan-2-yl) carbamate (0.039 g) obtained in (8) was dissolved in chloroform (0.39 ml) and trifluoroacetic acid (0.39 ml) was added at room temperature and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (InertSep® SCX, developing solvent: methanol / 2M ammonia-methanol solution) to obtain the title compound (0.030 g) in 85% yield. 1H-NMR (DMSO-D6) δ: 11.30-11.21 (1H, m), 7.75 (1H, dd, J = 8.6, 2.7 Hz), 7.56 (1H, dd, J = 8.9, 5.7 Hz), 7.40-7.32 (1H, m), 2.97-2.85 (1H, m), 2.10-1.97 (2H, m), 1.81-1.27 (9H, m), 1.09-0.99 (2H, m), 0.96 (3H, d, J = 6.5 Hz).

[0510] (10)N-((S)-1-(cis-5-(2-bromo-4-fluorophenyl)-9-hydroxy-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4-en-9-yl)propan-2-yl)-3-methyl-1H-pyrazole-5-carboxamide

[0511] [ka]

[0512] To a solution of cis-9-((S)-2-aminopropyl)-5-(2-bromo-4-fluorophenyl)-9-hydroxy-1-oxa-3,4-diazaspiro[5.5]undec-4-en-2-one (0.013 g) obtained in (9) in DMF (0.2 ml), 3-methyl-1H-pyrazole-5-carboxylic acid (0.005 g), HOAt (0.006 g), and N,N-diisopropylethylamine (0.017 ml) were added at room temperature. WSC (0.008 g) was added, and the mixture was stirred at room temperature for 15 minutes and left to stand for the entire day. Water, saturated sodium bicarbonate solution, and ethyl acetate were added and the mixture was extracted. The aqueous layer was re-extracted twice with ethyl acetate, and the combined organic layers were washed with saturated brine and dried over sodium sulfate. The sodium sulfate was filtered off and the mixture was concentrated under reduced pressure. The compound was azeotropically removed twice with toluene (2 ml), and the resulting residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane), followed by reverse-phase silica gel chromatography (developing solvent: acetonitrile / water) to obtain the title compound (0.004 g) in 26% yield. 1H-NMR (DMSO-D6) δ: 12.81 (1H, s), 11.24 (1H, s), 7.90-7.79 (1H, m), 7.74 (1H, d, J = 8.1 Hz), 7.59-7.48 (1H, m), 7.39-7.26 (1H, m), 6.29 (1H, s), 4.59 (1H, s), 4.07-3.93 (1H, m), 2.25 (3H, s), 2.11-1.94 (2H, m), 1.78-1.28 (8H, m), 1.12 (3H, d, J = 5.9 Hz).

[0513] [Production Example 8]: Synthesis of N-((S)-1-(trans-5-(2-bromo-4-fluorophenyl)-9-hydroxy-2-oxo-1-oxa-3,4-diazaspiro[5,5]undeca-4-en-9-yl)propan-2-yl)-3-methyl-1H-pyrazole-5-carboxamide (Example 322)

[0514] [ka]

[0515] (1) trans-9-((S)-2-aminopropyl)-5-(2-bromo-4-fluorophenyl)-9-hydroxy-1-oxa-3,4-diazaspiro[5.5]undeca-4-en-2-one

[0516] [ka]

[0517] To a solution of tert-butyl ((S)-1-(trans-5-(2-bromo-4-fluorophenyl)-9-hydroxy-2-oxo-1-oxa-3,4-diazaspiro[5,5]undeca-4-en-9-yl)propan-2-yl)carbamate (0.056 g) obtained in (8) of [Preparation Example 7], trifluoroacetic acid (0.44 ml) was added at room temperature and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (InertSep® SCX, developing solvent: methanol / 2M ammonia-methanol solution) to obtain the title compound (0.036 g) in 100% yield. LC-MS(M+1): 414

[0518] (2)N-((S)-1-(trans-5-(2-bromo-4-fluorophenyl)-9-hydroxy-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4-en-9-yl)propan-2-yl)-3-methyl-1H-pyrazole-5-carboxamide

[0519] [ka]

[0520] To a solution of trans-9-((S)-2-aminopropyl)-5-(2-bromo-4-fluorophenyl)-9-hydroxy-1-oxa-3,4-diazaspiro[5,5]undeca-4-en-2-one (0.016 g) obtained in (1) in DMF (0.24 ml), 3-methyl-1H-pyrazole-5-carboxylic acid (0.006 g), HOAt (0.007 g), and N,N-diisopropylethylamine (0.020 ml) were added at room temperature. WSC (0.010 g) was added, and the mixture was stirred at room temperature for 15 minutes and left to stand for the entire day. Water, saturated sodium bicarbonate solution, and ethyl acetate were added and the mixture was extracted. The aqueous layer was re-extracted twice with ethyl acetate, and the combined organic layers were washed with saturated brine and dried over sodium sulfate. The sodium sulfate was filtered off and the mixture was concentrated under reduced pressure. The compound was azeotropically removed twice with toluene (2 ml), and the resulting residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane), followed by reverse-phase silica gel chromatography (developing solvent: acetonitrile / water) to obtain the title compound (0.007 g) in 34% yield. 1H-NMR (DMSO-D6) δ: 12.80 (1H, s), 11.18 (1H, s), 7.85 (1H, d, J = 7.5 Hz), 7.74 (1H, dd, J = 8.6, 2.7 Hz), 7.51 (1H, dd, J = 8.6, 5.9 Hz), 7.37 (1H, ddd, J = 8.6, 8.1, 2.7 Hz), 6.31 (1H, s), 4.25-4.08 (1H, m), 4.21 (1H, s), 2.24 (3H, s), 1.97-1.82 (2H, m), 1.82-1.66 (3H, m), 1.66-1.34 (5H, m), 1.12 (3H, d, J = 6.5 Hz).

[0521] [Manufacturing example 9]:N 1 -((S)-1-(trans-5-(2-bromo-3-fluorophenyl)-9-cyano-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4-en-9-yl)propane-2-yl)-N 2 - Synthesis of methyloxalamide (Example 2-153)

[0522] [ka]

[0523] (1) tert-butyl (S)-(1-(8-cyano-1,4-dioxaspiro[4.5]decane-8-yl)propan-2-yl)carbamate

[0524] [ka]

[0525] A solution of 1,4-dioxaspiro[4.5]decane-8-carbonitrile (7.5 g) in THF (75 ml) was cooled to -78°C, and a 1.11 M LDA-THF / n-hexane solution (48.5 ml) was added and the mixture was stirred for 1 hour. 12.8 g of tert-butyl (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide was added, the temperature was raised to 0°C, and the mixture was stirred for 1 hour. 135 ml of 1 M hydrochloric acid was added and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate and water were added for extraction, and the organic layer was washed with saturated brine. Sodium sulfate was added and the mixture was dried. The sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: ethyl acetate / n-hexane = 25 / 75~55 / 45) and concentrated under reduced pressure to obtain the title compound (14.3 g) in 98% yield. 1H-NMR (DMSO-D6) δ: 6.78 (1H, d, J = 8.6 Hz), 3.87 (4H, s), 3.78-3.63 (1H, m), 2.06-1.44 (10H, m), 1.37 (9H, s), 1.06 (3H, d, J = 6.5 Hz).

[0526] (2) tert-butyl (S)-(1-(1-cyano-4-oxocyclohexyl)propan-2-yl)carbamate

[0527] [ka]

[0528] To a solution of tert-butyl (S)-(1-(8-cyano-1,4-dioxaspiro[4.5]decane-8-yl)propan-2-yl)carbamate (10.9 g) obtained in (1) in THF (54.5 ml), 6 M hydrochloric acid (28 ml) was added at room temperature and the mixture was stirred at 60 °C for 6 hours. After standing at room temperature for 3 days, 10 M aqueous sodium hydroxide solution (16.8 ml) and Boc₂O (23.4 ml) were added and the mixture was stirred for 2 hours. Ethyl acetate and water were added for extraction, the organic layer was washed with saturated brine, and sodium sulfate was added and dried. Sodium sulfate was filtered off and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane = 30 / 70~65 / 35) and concentrated under reduced pressure to obtain the title compound (5.59 g) in 59% yield. 1H-NMR (DMSO-D6) δ: 6.84 (1H, d, J = 9.2 Hz), 3.83-3.67 (1H, m), 2.55-2.39 (2H, m), 2.36-2.10 (4H, m), 1.92-1.75 (3H, m), 1.65 (1H, dd, J = 14.3, 3.5 Hz), 1.38 (9H, s), 1.09 (3H, d, J = 6.5 Hz).

[0529] (3) tert-butyl ((S)-1-(trans-4-(2-bromo-3-fluorobenzoyl)-1-cyano-4-((trimethylsilyl)oxy)cyclohexyl)propan-2-yl)carbamate

[0530] [ka]

[0531] Under an argon atmosphere, 0.38 g of 2-bromo-3-fluorobenzaldehyde and 0.008 g of lithium chloride were added to 0.8 ml of THF solution, to which 0.27 ml of trimethylsilyl cyanide was added at room temperature and the mixture was stirred for 30 minutes. 5.2 ml of THF was added, the mixture was cooled to -78°C and stirred for 5 minutes, then 1.6 ml of 1.13 M LiHMDS-n-hexane solution was added and the mixture was stirred for 10 minutes. 0.40 g of tert-butyl (S)-(1-(1-cyano-4-oxocyclohexyl)propan-2-yl)carbamate obtained in (2) was added and the mixture was stirred for 30 minutes. The mixture was then heated to 0°C over 1 hour, and water and ethyl acetate were added for extraction. The organic layer was washed with saturated brine, and sodium sulfate was added and the mixture was dried. Sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: ethyl acetate / n-hexane = 3 / 97~30 / 70) and concentrated under reduced pressure to obtain the title compound (0.62 g) in 78% yield. 1H-NMR (DMSO-D6) δ: 7.59-7.41 (2H, m), 7.39-7.33 (1H, m), 6.84 (1H, d, J = 8.6 Hz), 3.82-3.67 (1H, m), 2.07-1.49 (10H, m), 1.37 (9H, s), 1.08 (3H, d, J = 6.5 Hz), 0.04 (9H, s).

[0532] (4) tert-butyl ((S)-1-(trans-4-(2-bromo-3-fluorobenzoyl)-1-cyano-4-hydroxycyclohexyl)propan-2-yl)carbamate

[0533] [ka]

[0534] To a solution of tert-butyl ((S)-1-(trans-4-(2-bromo-3-fluorobenzoyl)-1-cyano-4-((trimethylsilyl)oxy)cyclohexyl)propan-2-yl)carbamate (0.62 g) obtained in (3) in THF (3.1 ml), acetic acid (0.19 ml) and 1 M TBAF-THF solution (1.7 ml) were added at room temperature and the mixture was stirred for 2 hours. After extraction with saturated sodium bicarbonate solution and ethyl acetate, the organic layer was dried with sodium sulfate. The sodium sulfate was filtered off and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: ethyl acetate / n-hexane = 30 / 70~60 / 40) and concentrated under reduced pressure to obtain the title compound (0.25 g) in 46% yield. 1H-NMR (DMSO-D6) δ: 7.55-7.39 (2H, m), 7.32-7.27 (1H, m), 6.81 (1H, d, J = 8.6 Hz), 5.53 (1H, s), 3.83-3.69 (1H, m), 2.02-1.49 (10H, m), 1.37 (9H, s), 1.07 (3H, d, J = 6.5 Hz).

[0535] (5) Trans-9-((S)-2-aminopropyl)-5-(2-bromo-3-fluorophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4-en-9-carbonitride hydrochloride

[0536] [ka]

[0537] To a solution of tert-butyl ((S)-1-(trans-4-(2-bromo-3-fluorobenzoyl)-1-cyano-4-hydroxycyclohexyl)propan-2-yl)carbamate (0.25 g) obtained in (4) in THF (2.5 ml), CDI (0.13 g) and DBU (0.012 ml) were added at room temperature and the mixture was stirred for 30 minutes. Hydrazine monohydrate (0.069 ml) was added and the mixture was stirred for 30 minutes, then 10% citric acid aqueous solution and ethyl acetate were added and the mixture was extracted. Sodium sulfate was added to the organic layer and dried, then the sodium sulfate was filtered off and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane = 50 / 50~90 / 10) and concentrated under reduced pressure. THF (2.3 ml) and 6 M hydrochloric acid (1.1 ml) were added to the resulting solid and the mixture was stirred at 50°C for 2 hours. The reaction mixture was concentrated under reduced pressure and azeotropically analyzed with THF to obtain the title compound (0.17 g) in 72% yield. 1H-NMR (DMSO-D6) δ: 11.45 (1H, s), 7.93 (3H, br s), 7.62-7.50 (2H, m), 7.42-7.36 (1H, m), 3.44-3.34 (1H, m), 2.31-2.19 (2H, m), 2.03-1.81 (4H, m), 1.78-1.58 (4H, m), 1.31 (3H, d, J = 6.5 Hz).

[0538] (6)N 1 -((S)-1-(trans-5-(2-bromo-3-fluorophenyl)-9-cyano-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4-en-9-yl)propane-2-yl)-N 2 - Methyloxalamide

[0539] [ka]

[0540] To a solution of trans-9-((S)-2-aminopropyl)-5-(2-bromo-3-fluorophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4-ene-9-carbonitrile hydrochloride (0.025 g) obtained in (5) in DMF (0.4 ml), 2-methylamino-2-oxoacetic acid (0.007 g), N,N-diisopropylethylamine (0.048 ml), and HATU (0.025 g) were added at room temperature and the mixture was stirred for 1 hour. The reaction mixture was purified by reverse-phase silica gel chromatography (eluent: acetonitrile / water = 5 / 95~70 / 30), further purified by thin-layer chromatography (eluent: ethyl acetate), and concentrated under reduced pressure to obtain the title compound (0.018 g) in 65% yield. 1H-NMR (DMSO-D6) δ: 11.39 (1H, s), 8.72 (1H, d, J = 9.2 Hz), 8.63-8.57 (1H, m), 7.58-7.47 (2H, m), 7.38-7.34 (1H, m), 4.17-4.04 (1H, m), 2.64 (3H, d, J = 4.8 Hz), 2.27-1.95 (4H, m), 1.81-1.53 ​​(6H, m), 1.12 (3H, d, J = 6.5 Hz).

[0541] [Manufacturing example 10]:N 1 -((S)-1-(trans-5-(2-bromo-5-cyanophenyl)-9-methoxy-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4-en-9-yl)propan-2-yl)-N 2 - Synthesis of methyloxalamide (Examples 2-123)

[0542] [ka]

[0543] (1) 1-(8-methoxy-1,4-dioxaspiro[4.5]decane-8-yl)propan-2-one

[0544] [ka]

[0545] To a methanol (50 ml) solution of 1,4-dioxaspiro[4.5]decan-8-one (5.0 g), dimethyl (2-oxopropyl)phosphonate (5.9 g) and 28% sodium methoxide-methanol solution (23.5 ml) were added at room temperature and the mixture was stirred for 24 hours. Water (20 ml) was added, and methanol was removed by distillation under reduced pressure. After dilution with ethyl acetate, the mixture was washed with saturated brine. Sodium sulfate was added to the resulting organic layer, dried, and the sodium sulfate was filtered off. The mixture was then concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: ethyl acetate / n-hexane = 20 / 80~50 / 50), and the title compound (2.1 g) was obtained in 28% yield by concentration under reduced pressure. 1H-NMR (DMSO-D6) δ: 3.83 (4H, s), 3.15 (3H, s), 2.57 (2H, s), 2.11 (3H, s), 1.78-1.68 (2H, m), 1.66-1.41 (6H, m).

[0546] (2)(S)-1-(8-methoxy-1,4-dioxaspiro[4.5]decane-8-yl)-N-((S)-1-phenylethyl)propan-2-amine

[0547] [ka]

[0548] To a solution of 1-(8-methoxy-1,4-dioxaspiro[4.5]decan-8-yl)propan-2-one (2.1 g) obtained in (1) in THF (31 ml), (S)-1-phenethylamine (1.3 ml), acetic acid (0.52 ml), and sodium triacetoxyborohydride (3.6 g) were added at room temperature and the mixture was stirred for 3 hours. Under ice cooling, 4 M sodium hydroxide aqueous solution (11.3 ml) and water were added, followed by dilution with ethyl acetate. The resulting organic layer was washed with saturated saline solution. Sodium sulfate was added to the organic layer and dried, then the sodium sulfate was filtered off and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (developing solvent: methanol / ethyl acetate / n-hexane = 0 / 25 / 75~0 / 100 / 0~5 / 95 / 0) and concentrated under reduced pressure to obtain the title compound (1.4 g) in 46% yield. 1H-NMR (DMSO-D6) δ: 7.36-7.23 (4H, m), 7.20-7.15 (1H, m), 3.82 (4H, s), 3.78 (1H, q, J = 6.7 Hz), 3.04 (3H, s), 2.66-2.56 (1H, m), 1.89-1.29 (11H, m), 1.24-1.10 (3H, m), 0.90 (3H, d, J = 6.6 Hz).

[0549] (3) tert-butyl (S)-(1-(8-methoxy-1,4-dioxaspiro[4.5]decane-8-yl)propan-2-yl)carbamate

[0550] [ka]

[0551] (2) The (S)-1-(8-methoxy-1,4-dioxaspiro[4.5]decane-8-yl)-N-((S)-1-phenylethyl)propan-2-amine (1.4 g) obtained in (2) was dissolved in THF (14 ml), to which acetic acid (0.48 ml) and 20% palladium hydroxide-activated carbon were added at room temperature, and the mixture was stirred all day under a hydrogen atmosphere (1 atm). The reaction mixture was filtered through Celite and washed with THF (14 ml). To the obtained THF solution, water (4.8 ml), sodium bicarbonate (1.1 g), and Boc2O (1.1 ml) were added at room temperature, and the mixture was stirred for 2 hours. After dilution with ethyl acetate, saturated saline solution was added and washed. Sodium sulfate was added to the obtained organic layer, dried, and the sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (eluent: ethyl acetate / n-hexane = 15 / 85~50 / 50) and concentrated under reduced pressure to obtain the title compound (1.0 g) in 76% yield. 1H-NMR (DMSO-D6) δ: 6.62 (1H, d, J = 8.1 Hz), 3.83 (4H, s), 3.65-3.48 (1H, m), 3.02 (3H, s), 1.79-1.27 (10H, m), 1.36 (9H, s), 1.03 (3H, d, J = 6.5 Hz).

[0552] (4) tert-butyl (S)-(1-(1-methoxy-4-oxocyclohexyl)propan-2-yl)carbamate

[0553] [ka]

[0554] To a solution of tert-butyl (S)-(1-(8-methoxy-1,4-dioxaspiro[4,5]decane-8-yl)propan-2-yl)carbamate (1.0 g) obtained in (3) in a mixed solvent of acetone (10 ml) and water (4.2 ml), pyridinium p-toluenesulfonate (0.16 g) was added at room temperature and the mixture was stirred at 60°C for 6 hours. Saturated sodium bicarbonate solution (5 ml) was added at room temperature and the acetone was removed by distillation. After extraction with ethyl acetate, the resulting organic layer was washed with saturated brine, dried with sodium sulfate, the sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: ethyl acetate / n-hexane = 20 / 80~55 / 45) and concentrated under reduced pressure to obtain the title compound (0.77 g) in 85% yield. 1H-NMR (DMSO-D6) δ: 6.68 (1H, d, J = 8.6 Hz), 3.70-3.54 (1H, m), 3.14 (3H, s), 2.48-2.31 (2H, m), 2.11-1.92 (4H, m), 1.78-1.54 (4H, m), 1.36 (9H, s), 1.06 (3H, d, J = 6.5 Hz).

[0555] (5) tert-butyl ((S)-1-(trans-4-(2-bromo-5-cyanobenzoyl)-1-methoxy-4-((trimethylsilyl)oxy)cyclohexyl)propan-2-yl)carbamate

[0556] [ka]

[0557] Under an argon atmosphere, 0.24 g of 4-bromo-3-formylbenzonitrile and 0.005 g of lithium chloride were mixed in 0.5 ml of THF, to which 0.16 ml of trimethylsilyl cyanide was added and the mixture was stirred at room temperature for 30 minutes. 3.3 ml of THF was added, the mixture was cooled to -78°C and stirred for 5 minutes, then 1.0 ml of 1.13 M LiHMDS-n-hexane solution was added and the mixture was stirred for 10 minutes. 0.25 g of tert-butyl (S)-(1-(1-methoxy-4-oxocyclohexyl)propan-2-yl)carbamate obtained in (4) was added and the mixture was stirred for 30 minutes. The mixture was then heated to 0°C over 1 hour, and water and ethyl acetate were added for extraction. The organic layer was washed with saturated brine, and sodium sulfate was added and the mixture was dried. Sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: ethyl acetate / n-hexane = 5 / 95~33 / 67) and concentrated under reduced pressure to obtain the title compound (0.23 g) in 45% yield. 1H-NMR (DMSO-D6) δ: 8.05-7.82 (3H, m), 6.69 (1H, d, J = 8.1 Hz), 3.67-3.51 (1H, m), 3.00 (3H, s), 2.01-1.31 (10H, m), 1.36 (9H, s), 1.04 (3H, d, J = 6.5 Hz), 0.00-0.03 (9H, m).

[0558] (6) tert-butyl ((S)-1-(trans-4-(2-bromo-5-cyanobenzoyl)-4-hydroxy-1-methoxycyclohexyl)propan-2-yl)carbamate

[0559] [ka]

[0560] To a solution of tert-butyl ((S)-1-(trans-4-(2-bromo-5-cyanobenzoyl)-1-methoxy-4-((trimethylsilyl)oxy)cyclohexyl)propan-2-yl)carbamate (0.22 g) obtained in (5) in THF (2.2 ml), acetic acid (0.067 ml) and 1 M TBAF-THF solution (0.58 ml) were added at room temperature and the mixture was stirred for 2 hours. Saturated sodium bicarbonate solution and ethyl acetate were added and the mixture was extracted. The organic layer was washed with saturated brine, sodium sulfate was added and the mixture was dried. Sodium sulfate was filtered off and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: ethyl acetate / n-hexane = 30 / 70~60 / 40) and concentrated under reduced pressure to obtain the title compound (0.15 g) in 78% yield. 1H-NMR (DMSO-D6) δ: 7.93-7.88 (2H, m), 7.84-7.79 (1H, m), 6.64 (1H, d, J = 8.1 Hz), 5.31 (1H, s), 3.69-3.56 (1H, m), 3.04 (3H, s), 1.97-1.31 (10H, m), 1.36 (9H, s), 1.04 (3H, d, J = 6.5 Hz).

[0561] (7)3-(trans-9-((S)-2-aminopropyl)-9-methoxy-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4-en-5-yl)-4-bromobenzonitrile hydrochloride

[0562] [ka]

[0563] To a solution of tert-butyl ((S)-1-(trans-4-(2-bromo-5-cyanobenzoyl)-4-hydroxy-1-methoxycyclohexyl)propan-2-yl) carbamate (0.15 g) obtained in (6) in THF (1.5 ml), CDI (0.073 g) and DBU (0.007 ml) were added and the mixture was stirred at room temperature for 30 minutes. Hydrazine monohydrate (0.045 ml) was added and the mixture was stirred for 30 minutes. After extraction with 10% citric acid aqueous solution and ethyl acetate, sodium sulfate was added to the organic layer and dried. Sodium sulfate was filtered off and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane = 50 / 50~90 / 10). The mixture was concentrated under reduced pressure, and THF (1.6 ml) and 6 M hydrochloric acid (0.8 ml) were added to the resulting solid and the mixture was stirred at 50°C for 2 hours. After cooling to room temperature, the reaction mixture was concentrated and azeotropically distilled with THF to obtain the title compound (0.14 g) in 96% yield. 1H-NMR (DMSO-D6) δ: 11.38 (1H, s), 8.12-8.08 (1H, m), 8.05-8.00 (1H, m), 7.93-7.86 (1H, m), 7.71 (3H, br s), 3.68-3.49 (1H, m), 2.98 (3H, s), 2.07-1.93 (2H, m), 1.84-1.45 (8H, m), 1.22 (3H, d, J = 6.5 Hz).

[0564] (8)N 1 -((S)-1-(trans-5-(2-bromo-5-cyanophenyl)-9-methoxy-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4-en-9-yl)propan-2-yl)-N 2 - Methyloxalamide

[0565] [ka]

[0566] To a solution of 3-(trans-9-((S)-2-aminopropyl)-9-methoxy-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4-en-5-yl)-4-bromobenzonitrile hydrochloride (0.050 g) obtained in (7) in DMF (0.75 ml), 2-methylamino-2-oxoacetic acid (0.016 g), N,N-diisopropylethylamine (0.074 ml), and HATU (0.060 g) were added at room temperature and the mixture was stirred for 1 hour. The reaction mixture was purified by reverse-phase silica gel chromatography (eluent: acetonitrile / water = 5 / 95~65 / 35), further purified by thin-layer chromatography (eluent: ethyl acetate / n-hexane = 67 / 33), and concentrated under reduced pressure to obtain the title compound (0.049 g) in 89% yield. 1H-NMR (DMSO-D6) δ: 11.32 (1H, s), 8.65-8.54 (2H, m), 8.09-8.05 (1H, m), 8.03-7.98 (1H, m), 7.91-7.86 (1H, m), 4.01-3.92 (1H, m), 2.92 (3H, s), 2.67-2.63 (3H, m), 1.99-1.42 (10H, m), 1.08 (3H, d, J = 6.5 Hz).

[0567] Compounds of other examples were obtained by the same manufacturing method or method as described above, or by known methods as necessary. The structural formulas and physical properties of compounds from Examples 1 to 339, and from 2-001 to 2-172 are shown in Tables 1-1 to 1-61.

[0568] [Table 1-1]

[0569] [Table 1-2]

[0570] [Table 1-3]

[0571] Table 1-4

[0572] Table 1-5

[0573] Table 1-6

[0574] Table 1-7

[0575] Table 1-8

[0576] Table 1-9

[0577] Table 1-10

[0578] Table 1-11

[0579] Table 1-12

[0580] Table 1-13

[0581] Table 1-14

[0582] Table 1-15

[0583] Table 1-16

[0584] Table 1-17

[0585] Table 1-18

[0586] Table 1-19

[0587] Table 1-20

[0588] Table 1-21

[0589] Table 1-22

[0590] Table 1-23

[0591] Table 1-24

[0592] Table 1-25

[0593] Table 1-26

[0594] Table 1-27

[0595] Table 1-28

[0596] Table 1-29

[0597] Table 1-30

[0598] Table 1-31

[0599] Table 1-32

[0600] Table 1-33

[0601] Table 1-34

[0602] Table 1-35

[0603] Table 1-36

[0604] Table 1-37

[0605] Table 1-38

[0606] Table 1-39

[0607] Table 1-40

[0608] Table 1-41

[0609] Table 1-42

[0610] Table 1-43

[0611] Table 1-44

[0612] Table 1-45

[0613] Table 1-46

[0614] Table 1-47

[0615] Table 1-48

[0616] Table 1-49

[0617] Table 1-50

[0618] Table 1-51

[0619] Table 1-52

[0620] Table 1-53

[0621] Table 1-54

[0622] [Table 1-55]

[0623] [Table 1-56]

[0624] [Table 1-57]

[0625] [Table 1-58]

[0626] [Table 1-59]

[0627] [Table 1-60]

[0628] [Table 1-61]

[0629] Test Example 1: Evaluation of Human PLD1 Enzyme Inhibitory Activity The following describes a method for measuring the inhibitory activity of human PLD1 enzyme using an enzyme to which a FLAG-tag has been added to the N-terminus of the full-length human PLD1 (1-1036 amino acids). 1. Creation of a human PLD1 full-length expression plasmid Using the PCR method, a commercially available human PLD1 gene (Promega KK) was used as a template to amplify a DNA fragment in which a FLAG-tag sequence was added to the 5' end of the full-length human PLD1 gene. The amplified DNA fragment and the baculovirus vector pVL1393 (Pharmingen), digested with BamHI and EcoRI, were ligated using the In-Fusion HD Cloning Kit (Takara Bio). From E. coli DH5α (TOYOBO) transformed with the obtained In-Fusion reaction product, the full-length human PLD1 expression plasmid DNA for baculovirus was isolated. Next, using the full-length human PLD1 expression plasmid DNA for baculovirus as a template, a DNA fragment in which a FLAG-tag sequence was added to the 5' end of the full-length human PLD1 gene was amplified by PCR. The amplified DNA fragment and a DNA fragment in which a linker sequence was introduced into pcDNA3.4-TOPO (Life Technologies) were ligated using the In-Fusion HD Cloning Kit. From E. coli DH5α transformed with the obtained in-fusion reaction product, full-length human PLD1 expression plasmid DNA for animal cells was isolated. The nucleotide sequence of the full-length human PLD1 cloned into a vector was determined by the Dye Terminator method using the BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems). The determined sequence was the full-length human PLD1 (GenBank Accession Number: NM_001130081) with a FLAG-tag sequence inserted at the 5' end.

[0630] 2. Production of full-length human PLD1 protein using the Expi293F cell expression system Expi293F cells (Life Technologies) were cultured with shaking at 37°C in the presence of 8% CO2 using Expi293 Expression Medium (Life Technologies). The gene transfection reagent PEI used was Polyethylenimine Max (nominally MW 40,000) (Polysciences) dissolved in Milli-Q water, pH adjusted to 7.0 with NaOH to a concentration of 1 mg / mL, and filtered through a 0.22 μm filter. Human PLD1 full-length expression plasmid DNA for animal cells was transfected into Expi293F cells using PEI, and the cells were harvested after 48 hours of shaking culture and stored at -80°C.

[0631] 3. Purification of human PLD1 full-length protein Human PLD1 full-length expressing cells were treated with Homogenate buffer (20 mmol / L Na-phosphate pH 7.5, 250 mmol / L NaCl, 1 mmol / L MgCl2, 1% β-OG, 0.05 mmol / L DTT + complete EDTA-free (Roche Diagnostics KK)) and the cells were disrupted using a Microfluidizer Processor M-110EH (Mizuho Industries). The lysates were centrifuged at 4°C at 10,100 × g for 15 minutes, and the supernatant was collected and filtered through a 0.45 μm filter. Anti-flag M2 Affinity Gel (SIGMA-Aldrich) resin, equilibrated with Homogenate buffer, was added to the centrifugation supernatant and stirred at 4°C for at least 1 hour. This mixture was packed into a polyprep column, and the resin was washed with Wash Buffer (20 mmol / L Na-phosphate pH 7.5, 150 mmol / L NaCl, 1 mmol / L MgCl2, 0.02% Triton, 0.05 mmol / L DTT). Wash Buffer containing 400 μg / mL DYKDDDDK Peptide (Scrum Co., Ltd.) was added to elute the proteins bound to the resin. The eluted fraction was identified by SDS-PAGE followed by CBB staining to identify the fraction containing full-length human PLD1. The full-length human PLD1 eluted fractions were collected and concentrated using Amicon Ultra-15 100k (Merck Millipore). The concentrated fractions were rapidly frozen in liquid nitrogen and stored at -80°C.

[0632] 4. Evaluation of human PLD1 inhibitory activity 5 μL / well of DMSO diluted with Assay Buffer (50 mmol / L HEPES pH 7.5, 80 mmol / L KCl, 3 mmol / L EGTA, 3.6 mmol / L MgCl2, 0.01% NP-40, 0.1% BSA) or a test substance solution (DMSO final concentration 5%) was added to a 384-well Assay Plate (Black, Polystyrene, Non-Treated, Cat No. 3573, Corning). 5 μL / well of human PLD1 full-length enzyme solution diluted to 6 nmol / L with Assay Buffer was added (Assay Buffer was added to the blank wells). 5 μL / well of 1,2-diheptanoyl-sn-glycero-3-phosphocholine (Avanti Polar Lipids) substrate solution diluted to 6 mmol / L with Assay Buffer was added, and the enzymatic reaction was carried out at room temperature for 60 minutes. Immediately before stopping the reaction, a detection solution containing the reaction stopper 4 μmol / L 5-fluoro-2-indolideschlorohalopemide (R&D Systems) was prepared in Assay buffer (200 μmol / L AmplexRed (Thermofisher), 0.1 U / mL Choline Oxidase (Sigma-Aldrich), 4 U / mL Horseradish peroxidase (Thermofisher)), and 5 μL was added per well to stop the enzymatic reaction. Immediately after stopping the reaction and after incubation at room temperature for 30 minutes, the fluorescence values ​​at Ex: 531 nm / Em: 590 nm were measured using ARVO X5 (PerkinElmer). The inhibition rate was calculated using the change in fluorescence values ​​immediately after stopping the reaction and after 30 minutes. The data was obtained by subtracting the average fluorescence value of the blank well from the average fluorescence value of the wells treated for each treatment. The inhibition rate for each concentration of the test substance was calculated using the following formula:

[0633]

number

[0634] IC of the test substance 50The values ​​(50% inhibitory concentration) were calculated by fitting the inhibition rates of each concentration of the test substance to a logistic curve. The results for each example compound are shown in Tables 2-1 to 2-14 below. For Examples 34, 186, 2-047, 2-099, 2-101, 2-150, and 2-171, the inhibition rate of PLD1 at 10 μM of compound is shown, with Example 34 showing 36% inhibition, Example 186 showing 33% inhibition, Example 2-047 showing 32% inhibition, Example 2-099 showing 21% inhibition, Example 2-101 showing 13% inhibition, Example 2-150 showing 25% inhibition, and Example 2-171 showing 12% inhibition.

[0635] Test Example 2: Evaluation of Human PLD2 Enzyme Inhibitory Activity The following describes a method for measuring the inhibitory activity of human PLD2 enzyme using an enzyme to which a FLAG-tag has been added to the N-terminus of the full-length human PLD2 (1-933 amino acids). 1. Creation of a human PLD2 full-length expression plasmid Using the PCR method, a commercially available human PLD2 gene (Promega KK) was used as a template to amplify a DNA fragment in which a FLAG-tag sequence was added to the 5' end of the full-length human PLD2 gene. The amplified DNA fragment and the baculovirus vector pVL1393 (Pharmingen), digested with BamHI and EcoRI, were ligated using the In-Fusion HD Cloning Kit (Takara Bio). From E. coli DH5α (TOYOBO) transformed with the obtained In-Fusion reaction product, the full-length human PLD2 expression plasmid DNA for baculovirus was isolated. Next, using the full-length human PLD2 expression plasmid DNA for baculovirus as a template, a DNA fragment in which a FLAG-tag sequence was added to the 5' end of the full-length human PLD2 gene was amplified by PCR. The amplified DNA fragment and a DNA fragment in which a linker sequence was introduced into pcDNA3.4-TOPO (Life Technologies) were ligated using the In-Fusion HD Cloning Kit. From E. coli DH5α transformed with the obtained in-fusion reaction product, full-length human PLD2 expression plasmid DNA for animal cells was isolated. The nucleotide sequence of the full-length human PLD2 cloned into a vector was determined by the Dye Terminator method using the BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems). The determined sequence was the full-length human PLD2 (GenBank Accession Number: NM_002663) with a FLAG-tag sequence inserted at the 5' end.

[0636] 2. Production of full-length human PLD2 protein using the Expi293F cell expression system Expi293F cells (Life Technologies) were cultured with shaking at 37°C in the presence of 8% CO2 using Expi293 Expression Medium (Life Technologies). The gene transduction reagent PEI used was Polyethylenimine Max (nominally MW 40,000) (Polysciences) dissolved in Milli-Q water, pH adjusted to 7.0 with NaOH to a concentration of 1 mg / mL, and filtered through a 0.22 μm filter. Human PLD2 full-length expression plasmid DNA for animal cells was transfected into Expi293F cells using PEI, and the cells were harvested after 48 hours of shaking culture and stored at -80°C.

[0637] 3. Purification of human PLD2 full-length protein Human PLD2 full-length expressing cells were treated with Homogenate buffer (20 mmol / L Na-phosphate pH 7.5, 250 mmol / L NaCl, 1 mmol / L MgCl2, 1% β-OG, 0.05 mmol / L DTT + complete EDTA-free (Roche Diagnostics KK)) and the cells were disrupted using a Microfluidizer Processor M-110EH (Mizuho Industries). The lysates were centrifuged at 4°C at 10,100 × g for 15 minutes, and the supernatant was collected and filtered through a 0.45 μm filter. Anti-flag M2 Affinity Gel (SIGMA-Aldrich) resin, equilibrated with Homogenate buffer, was added to the centrifugation supernatant and stirred at 4°C for at least 1 hour. This mixture was packed into a polyprep column, and the resin was washed with Wash Buffer (20 mmol / L Na-phosphate pH 7.5, 150 mmol / L NaCl, 1 mmol / L MgCl2, 0.02% Triton, 0.05 mmol / L DTT). Wash Buffer containing 400 μg / mL DYKDDDDK Peptide (Scrum Co., Ltd.) was added to elute the proteins bound to the resin. The eluted fraction was identified by SDS-PAGE followed by CBB staining to identify the fraction containing full-length human PLD2. The full-length human PLD2 eluted fractions were combined and concentrated using Amicon Ultra-15 100k (Merck Millipore). The concentrated fractions were rapidly frozen in liquid nitrogen and stored at -80°C.

[0638] 4. Evaluation of human PLD2 inhibitory activity 5 μL / well of DMSO diluted with Assay Buffer (50 mmol / L HEPES pH 7.5, 80 mmol / L KCl, 3 mmol / L EGTA, 3.6 mmol / L MgCl2, 0.01% NP-40, 0.1% BSA) or a test substance solution (DMSO final concentration 5%) was added to a 384-well Assay Plate (Black, Polystyrene, Non-Treated, Cat No. 3573, Corning). 5 μL / well of human PLD2 full-length enzyme solution diluted to 6 nmol / L with Assay Buffer was added (Assay Buffer was added to the blank wells). 5 μL / well of 1,2-diheptanoyl-sn-glycero-3-phosphocholine (Avanti Polar Lipids) substrate solution diluted to 6 mmol / L with Assay Buffer was added, and the enzymatic reaction was carried out at room temperature for 60 minutes. Immediately before stopping the reaction, a detection solution containing the reaction stopper 4 μmol / L 5-fluoro-2-indolideschlorohalopemide (R&D Systems) was prepared in Assay buffer (200 μmol / L AmplexRed (Thermofisher), 0.1 U / mL Choline Oxidase (Sigma-Aldrich), 4 U / mL Horseradish peroxidase (Thermofisher)), and 5 μL was added per well to stop the enzymatic reaction. Immediately after stopping the reaction and after incubation at room temperature for 30 minutes, the fluorescence values ​​at Ex: 531 nm / Em: 590 nm were measured using ARVO X5 (PerkinElmer). The inhibition rate was calculated using the change in fluorescence values ​​immediately after stopping the reaction and after 30 minutes. The data was obtained by subtracting the average fluorescence value of the blank well from the average fluorescence value of the wells treated for each treatment. The inhibition rate for each concentration of the test substance was calculated using the following formula:

[0639]

number

[0640] IC of the test substance 50The values ​​(50% inhibitory concentration) were calculated by fitting the inhibition rates of each concentration of the test substance to a logistic curve. The results for each example compound are shown in Tables 2-1 to 2-14 below. For Examples 34, 186, 2-047, 2-101, 2-112, 2-150, and 2-171, the inhibition rate of PLD2 at 10 μM of compound is shown, with Example 34 showing 17% inhibition, Example 186 showing 18% inhibition, Example 2-047 showing 34% inhibition, Example 2-101 showing 28% inhibition, Example 2-112 showing 39% inhibition, Example 2-150 showing 30% inhibition, and Example 2-171 showing 23% inhibition.

[0641] [Table 2-1]

[0642] [Table 2-2]

[0643] [Table 2-3]

[0644] [Table 2-4]

[0645] [Table 2-5]

[0646] [Table 2-6]

[0647] [Table 2-7]

[0648] [Table 2-8]

[0649] [Table 2-9]

[0650] [Table 2-10]

[0651] [Table 2-11]

[0652] [Table 2-12]

[0653] [Table 2-13]

[0654] [Table 2-14]

[0655] Examples of formulations of the present invention include the following formulations. However, the present invention is not limited to these examples of formulations.

[0656] Formulation Example 1: Capsule Manufacturing (1) Compound from Example 1: 30 mg (2) Microcrystalline cellulose 10 mg (3) Lactose 19mg (4) Magnesium stearate 1 mg Mix ingredients (1), (2), (3), and (4) and fill them into gelatin capsules.

[0657] Formulation example 2: Tablet manufacturing (1) Compound from Example 1: 10 g (2) Lactose 50g (3) Corn starch 15g (4) Carmellose calcium 44g (5) Magnesium stearate 1g The entire amounts of components (1), (2), and (3) and 30 g of component (4) are kneaded with water, vacuum-dried, and then granulated. 14 g of component (4) and 1 g of component (5) are mixed into this granulated powder and compressed into tablets using a tablet press. In this way, 1000 tablets are obtained, each containing 10 mg of the compound of Example 1. [Industrial applicability]

[0658] Compound [I] or compound [Ia] of the present invention, or a pharmaceutically acceptable salt thereof, may be useful in the treatment or prevention of thrombosis and cancer because it has PLD inhibitory activity.

Claims

1. The compound represented by formula [Ia] or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 [In the formula, A a CR 10a or N; A 2a CR 5a or O; Cy a teeth, (1) C 6-10 Ariel, (2) A 5- to 10-membered heteroaryl having one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms, (3) A 9- or 10-membered partially unsaturated condensed ring group containing one or two oxygen atoms in addition to carbon atoms as ring constituent atoms. And; R 1a teeth, (1) C 1-6 Alkyl {Here, the alkyl is, (a) Hydroxy, (b) Cyano, (c) SO 2 R 11 (where R 11 is C 1-4 alkyl), or (d) NHCOR 12 (Here, R 12 C 1-4 (It may be substituted with alkyl) (2) C 2-4 alkenyl {where the alkenyl is 1 to 3 (a) NR 13 R 14 (Here, R 13 and R 14 Each of them independently consists of hydrogen or C 1-4 (It is alkyl.) (b) Halogen, (c) COR 35a (R here) 35a is hydroxy or C 1-4 (It is an alkoxy.) (d) CONR 36a R 37a (Here, R 36a and R 37a Each of them independently consists of hydrogen or C 1-4 (It is alkyl), or (e) Partial structural formula: 【Chemistry 2】 It may be replaced with}, (3) C 1-4 Haloalkyl (where the haloalkyl may be substituted with hydroxyl), (4) C 1-6 Alkoxy (where the alkoxy may be substituted with phenyl), (5) NR 15 R 16 (Here, R 15 and R 16 Each of them operates independently. (a) Hydrogen, (b) C 1-4 Alkyl {Here, the alkyl is, (i) Phenyl (wherein phenyl may be substituted with a halogen), or (ii) May be substituted with pyridyl}, (c) C 1-4 Alkoxy, or (d) C 3-4 (It is cycloalkyl.) (6) COR 17a (Here, R 17a C 1-4 (It is alkyl or hydroxyl.) (7) CONR 18a R 19a (Here, R 18a and R 19a Each of them operates independently. (a) Hydrogen, (b) C 1-4 Alkyl (where the alkyl may be substituted with hydroxyl), (c) C 3-4 Cycloalkyl, (d) C 5-8 Cross-linked cycloalkyl, (e) C 1-4 Haloalkyl, or (f) C 1-4 (It is an alkoxy.) (8) C 3-4 Cycloalkyl (where the cycloalkyl is, (a) Hydroxy, (b) Halogen, or (c) May be substituted with phenyl) (9) A 4- to 7-membered heterocycloalkyl compound containing, in addition to carbon atoms, one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms as ring constituent atoms {where the heterocycloalkyl compound is, (a) Hydroxy, (b) Oxo, (c) NR 20 R 21 (Here, R 20 and R 21 Each of them independently consists of hydrogen or C 1-4 (It is alkyl), or (d) May be substituted with phenyl, (10) A 6- to 11-membered spiroheterocycloalkyl group containing, in addition to carbon atoms, one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms as ring constituent atoms, (11) Phenyl (wherein phenyl is 1 or 2 (a) Halogen, or (b) C 1-4 (May be substituted with a haloalkyl group.) (12) A 5- to 10-membered heteroaryl compound containing, in addition to carbon atoms, 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen atoms as ring constituent atoms (where the heteroaryl compound contains 1 or 2 R 22a (May be replaced by) (13) A saturated or partially unsaturated fused ring group having 8 to 10 members, containing 1 to 4 heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms (where the fused ring group is C 1-4 (May be substituted with a haloalkyl group), or (14) A 5- to 7-membered partially unsaturated ring group containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms (where the partially unsaturated ring group is an oxo group and C 1-4 (May be substituted with alkyl) And; m individual R 2a Each of them operates independently. (1) Hydroxy, (2) Cyano, (3) Halogen, (4) C 1-6 Alkyl (where the alkyl is, (a) Hydroxy, or (b) C 3-4 (May be substituted with cycloalkyl groups.) (5) C 2-4 alkenyl (where the alkenyl is C 1-4 (May be substituted with alkoxy) (6) C 1-4 Haloalkyl, (7) C 1-4 Alkoxy (where the alkoxy is, (a) hydroxy, and (b) Halogen (May be substituted with 1 to 3 substituents selected from the group consisting of) (8) SR 23a (Here, R 23a C 1-4 Alkyl or C 1-4 (It is a haloalkyl) (9) COR 24a (Here, R 24a teeth, (a) Hydroxy, (b) C 1-4 Alkyl, or (c) C 1-4 (It is an alkoxy.) (10) CONR 25a R 26a (Here, R 25a and R 26a Each of them operates independently. (a) Hydrogen, (b) C 1-6 Alkyl, or (c) C 3-4 It is cycloalkyl, or R 25a and R 26a These atoms bond to each other, and together with the nitrogen atom to which they bond, form a 4- to 7-membered heterocycloalkyl group (where the heterocycloalkyl group contains, in addition to carbon atoms, one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms as ring constituent atoms, and the heterocycloalkyl group may be substituted with one or two halogens). (11) SO 2 R 27 (Here, R 27 C 1-6 (It is alkyl.) (12) C 3-4 Cycloalkyl, (13) A 4- to 7-membered heterocycloalkyl (where the heterocycloalkyl is, (a) Halogen, (b) C 1-4 Alkyl, and (c) C 1-4 which may be substituted with one or two substituents selected from the group consisting of haloalkyl), (14) A 5- to 9-membered crosslinked heterocycloalkyl group containing, in addition to carbon atoms, one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms as ring constituent atoms, (15) A 6- to 11-membered spiroheterocycloalkyl, which contains one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms, or (16) Phenyl And; R 3a teeth, (1) Hydrogen, (2) C 1-4 Alkyl, or (3) C 1-4 Haloalkyl And; R 4a teeth, (1) Hydrogen, (2) C 1-4 Alkyl, or (3) Cyano And; R 5a is hydrogen or C 1-4 alkyl; R 6a , R 7a and R 8a As for combinations, (1) R 6a is hydrogen or C 1-4 It is alkyl, R 7a and R 8a This is a combination where both are hydrogen. (2) R 6a is hydrogen or C 1-4 It is alkyl, R 7a and R 8a These are combinations that bond to each other, and together with the carbon and spirocarbon atoms to which they bond, form a cyclopentane ring, or (3) R 6a and R 7a They bond to each other, and together with the carbon and spirocarbon atoms to which they are bonded, form a cyclopentane ring, R 8a The combination is hydrogen And; R 9a teeth, (1) Hydrogen, (2) CONHR 28 (Here, R 28 C 3-4 (It is cycloalkyl), or (3) C 1-4 Alkyl And; R 10a teeth, (1) Hydrogen, (2) Hydroxy, (3) Halogen, (4) C 1-4 Alkyl, (5) Cyano, or (6) C 1-4 Alkoxy And; 1 or 2 R 22a Each of them operates independently. (1) Halogen, (2) C 1-4 Alkyl, (3) C 1-4 Haloalkyl, (4) C 1-4 Alkoxy, (5) NHCOR 29 (Here, R 29 C 1-4 (It is alkyl.) (6) SO 2 R 30 (Here, R 30 C 1-4 (It is alkyl.) (7) Cyano, or (8) C 3-4 Cycloalkyl and; as well as m is 0, 1, 2, or 3.

2. Formula [IIa]: 【Transformation 3】 [In the formula, A a Cy a , R 1a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a And m is the same as the definition in claim 1. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, as shown in [the formula].

3. Formula [IIIa]: 【Chemistry 4】 [In the formula, Cy a , R 1a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a And m is the same as the definition in claim 1. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, as shown in [the formula].

4. Formula [IVa]: 【Transformation 5】 [In the formula, R 1b teeth, (1) C 1-6 Alkyl {Here, the alkyl is, (a) Hydroxy, (b) Cyano, (c) SO 2 R 11 (Here, R 11 C 1-4 (It is alkyl), or (d) NHCOR 12 (Here, R 12 C 1-4 (It may be substituted with alkyl) (2) C 2-4 alkenyl {where the alkenyl is 1 to 3 (a) NR 13 R 14 (Here, R 13 and R 14 Each of them independently consists of hydrogen or C 1-4 (It is alkyl.) (b) Halogen, (c) COR 35a (R here) 35a is hydroxy or C 1-4 (It is an alkoxy.) (d) CONR 36a R 37a (Here, R 36a and R 37a Each of them independently consists of hydrogen or C 1-4 (It is alkyl), or (e) Partial structural formula: 【Transformation 6】 It may be replaced with}, (3) C 1-6 Alkoxy (where the alkoxy may be substituted with phenyl), (4) NR 15 R 16 (Here, R 15 and R 16 Each of them operates independently. (a) Hydrogen, (b) C 1-4 Alkyl {Here, the alkyl is, (i) Phenyl (wherein phenyl may be substituted with a halogen), or (ii) May be substituted with pyridyl}, (c) C 1-4 Alkoxy, or (d) C 3-4 (It is cycloalkyl.) (5) CONR 18a R 19a (Here, R 18a and R 19a Each of them operates independently. (a) Hydrogen, (b) C 1-4 Alkyl (where the alkyl may be substituted with hydroxyl), (c) C 3-4 Cycloalkyl, (d) C 5-8 Cross-linked cycloalkyl, (e) C 1-4 Haloalkyl, or (f) C 1-4 (It is an alkoxy.) (6) A 6- to 11-membered spiroheterocycloalkyl, which contains one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms. (7) A 5- to 10-membered heteroaryl compound containing, in addition to carbon atoms, 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen atoms as ring constituent atoms (where the heteroaryl compound contains 1 or 2 R 22a (May be replaced by) (8) A saturated or partially unsaturated fused ring group having 8 to 10 members, containing 1 to 4 heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms (where the fused ring group is C 1-4 (May be substituted with a haloalkyl group), or (9) A 5- to 7-membered partially unsaturated ring group containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms (where the partially unsaturated ring group is an oxo group and C 1-4 (May be substituted with alkyl) and; as well as Cy a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 22a And m is the same as the definition in claim 1. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, as shown in [the formula].

5. Formula [Va]: 【Transformation 7】 [In the formula, Cy a , R 2a , R 3a , R 4a and m are the same as the definitions in claim 1; and R 1b This is synonymous with the definition in claim 4. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, as shown in [the formula].

6. Formula [VIa]: 【Transformation 8】 [In the formula, Cy b teeth, (1) C 6-10 Aryl, or (2) A 5- or 6-membered heteroaryl compound containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms. And; R 1b This is synonymous with the definition in claim 4; and R 2a , R 3a , R 4a And m is the same as the definition in claim 1. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, as shown in [the formula].

7. Formula [VIIa]: 【Chemistry 9】 [In the formula, Cy a , R 2a , R 3a , R 5a , R 6a , R 7a , R 8a and m are the same as the definitions in claim 1; and R 1b This is synonymous with the definition in claim 4. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, as shown in [the formula].

8. Formula [VIIIa]: 【Chemistry 10】 [In the formula, Cy a , R 2a , R 3a and m are the same as the definitions in claim 1; and R 1b This is synonymous with the definition in claim 4. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, as shown in [the formula].

9. Formula [IXa]: 【Chemistry 11】 [In the formula, Cy b This is synonymous with the definition in claim 6; R 1b This is synonymous with the definition in claim 4; and R 2a , R 3a And m is the same as the definition in claim 1. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, as shown in [the formula].

10. Formula [Xa]: 【Chemistry 12】 [In the formula, Cy a , R 1a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 10a And m is the same as the definition in claim 1. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, as shown in [the formula].

11. Formula [XIa]: 【Chemistry 13】 [In the formula, Cy a , R 1a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 10a And m is the same as the definition in claim 1. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, as shown in [the formula].

12. Formula [XIIa]: 【Chemistry 14】 [In the formula, R 1b teeth, (1) C 1-6 Alkyl {Here, the alkyl is, (a) Hydroxy, (b) Cyano, (c) SO 2 R 11 (Here, R 11 C 1-4 (It is alkyl), or (d) NHCOR 12 (Here, R 12 C 1-4 (It may be substituted with alkyl) (2) C 2-4 alkenyl {where the alkenyl is 1 to 3 (a) NR 13 R 14 (Here, R 13 and R 14 Each of them independently consists of hydrogen or C 1-4 (It is alkyl.) (b) Halogen, (c) COR 35a (R here) 35a is hydroxy or C 1-4 (It is an alkoxy.) (d) CONR 36a R 37a (Here, R 36a and R 37a Each of them independently consists of hydrogen or C 1-4 (It is alkyl), or (e) Partial structural formula: 【Chemistry 15】 It may be replaced with}, (3) C 1-6 Alkoxy (where the alkoxy may be substituted with phenyl), (4) NR 15 R 16 (Here, R 15 and R 16 Each of them operates independently. (a) Hydrogen, (b) C 1-4 Alkyl {Here, the alkyl is, (i) Phenyl (wherein phenyl may be substituted with a halogen), or (ii) May be substituted with pyridyl}, (c) C 1-4 Alkoxy, or (d) C 3-4 (It is cycloalkyl.) (5) CONR 18a R 19a (Here, R 18a and R 19a Each of them operates independently. (a) Hydrogen, (b) C 1-4 Alkyl (where the alkyl may be substituted with hydroxyl), (c) C 3-4 Cycloalkyl, (d) C 5-8 Cross-linked cycloalkyl, (e) C 1-4 Haloalkyl, or (f) C 1-4 (It is an alkoxy.) (6) A 6- to 11-membered spiroheterocycloalkyl, which contains one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms. (7) A 5- to 10-membered heteroaryl compound containing, in addition to carbon atoms, 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen atoms as ring constituent atoms (where the heteroaryl compound contains 1 or 2 R 22a (May be replaced by) (8) A saturated or partially unsaturated fused ring group having 8 to 10 members, containing 1 to 4 heteroatoms selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring constituent atoms (where the fused ring group is C 1-4 (May be substituted with a haloalkyl group), or (9) A 5- to 7-membered partially unsaturated ring group containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms (where the partially unsaturated ring group is an oxo group and C 1-4 (May be substituted with alkyl) and; as well as Cy a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 10a , R 22a And m is the same as the definition in claim 1. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, as shown in [the formula].

13. Formula [XIIIa]: 【Chemistry 16】 [In the formula, Cy a , R 2a , R 3a , R 4a , R 10a and m are the same as the definitions in claim 1; and R 1b This is synonymous with the definition in claim 12. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, as shown in [the formula].

14. Formula [XIVa]: 【Chemistry 17】 [In the formula, Cy b teeth, (1) C 6-10 Aryl, or (2) A 5- or 6-membered heteroaryl compound containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms. And; R 1b This is synonymous with the definition of claim 12; and R 2a , R 3a , R 4a , R 10a And m is the same as the definition in claim 1. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, as shown in [the formula].

15. Formula [XVa]: [Chemistry 18] [In the formula, Cy a , R 2a , R 3a , R 5a , R 6a , R 7a , R 8a , R 10a and m are the same as the definitions in claim 1; and R 1b This is synonymous with the definition in claim 12. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, as shown in [the formula].

16. Formula [XVIa]: 【Chemistry 19】 [In the formula, Cy a , R 2a , R 3a , R 10a and m are the same as the definitions in claim 1; and R 1b This is synonymous with the definition in claim 12. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, as shown in [the formula].

17. Formula [XVIIa]: 【Chemistry 20】 [In the formula, Cy b This is synonymous with the definition in claim 14; R 1b This is synonymous with the definition of claim 12; and R 2a , R 3a , R 10a And m is the same as the definition in claim 1. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, as shown in [the relevant figure].

18. The following formula: 【Chemistry 21】 A compound selected from the group consisting of compounds represented by [the formula], or a pharmaceutically acceptable salt thereof.

19. The following formula: 【Chemistry 22】 The compound indicated by or a pharmaceutically acceptable salt thereof.

20. The following formula: 【Chemistry 23】 The compound indicated by or a pharmaceutically acceptable salt thereof.

21. The following formula: 【Chemistry 24】 The compound indicated by or a pharmaceutically acceptable salt thereof.

22. The following formula: 【Chemistry 25】 The compound indicated by or a pharmaceutically acceptable salt thereof.

23. The following formula: 【Chemistry 26】 The compound indicated by or a pharmaceutically acceptable salt thereof.

24. The following formula: 【Chemistry 27】 The compound indicated by or a pharmaceutically acceptable salt thereof.

25. The following formula: 【Chemistry 28】 The compound indicated by or a pharmaceutically acceptable salt thereof.

26. The following formula: 【Chemistry 29】 The compound indicated by or a pharmaceutically acceptable salt thereof.

27. ​​The following formula: 【Transformation 30】 The compound indicated by or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

29. A PLD inhibitor comprising a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof.

30. A PLD1 inhibitor comprising a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof.

31. A PLD1 / 2 inhibitor comprising a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof.

32. A therapeutic or prophylactic agent for a disease selected from the group consisting of thrombosis and cancer, comprising a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof.

33. A method for treating or preventing a disease selected from the group consisting of thrombosis and cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 27.

Images