Dihydro-oxadiazinone compound and pharmaceutical application thereof

Abstract

The present invention provides a compound having PLD inhibitory activity. The present invention provides a compound of the following structural formula, and the like, or a pharmaceutically acceptable salt thereof. And each symbol in the # imgabs0 # is as defined in the specification.

Description

Technical Field

[0001] The present invention relates to a dihydrooxadiazinone compound having phospholipase D (hereinafter referred to as "PLD") inhibitory activity or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same, and pharmaceutical use thereof, etc. Background Art

[0002] Three important factors of thrombosis are said to be changes in blood composition, 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 blood vessel wall. The shear stress generated by this speed difference exerts a strong influence on the platelets flowing near the blood vessel wall and enhances the platelet aggregation ability. Thrombosis in arteries is largely triggered by the rupture of atherosclerotic plaques. Platelet membrane receptors react with collagen in the subendothelial tissue exposed when atherosclerotic plaques rupture or von Willebrand factor (vWF) adhered to collagen, triggering platelet activation signals, which in turn lead to platelet aggregation, thereby initiating thrombosis. Therefore, platelet aggregation initiated at the site of plaque rupture in coronary arteries and cerebral arteries may cause rapid thrombotic occlusion, leading to the development of myocardial infarction and stroke. It is presumed that extremely high shear stress is generated at sites where these conditions are believed to occur, such as atherosclerotic stenosis. Recent studies using in vitro flow chambers incorporating a blood flow environment have shown that platelet adhesion and aggregation mechanisms differ depending on shear stress. Under high shear stress, platelet adhesion and aggregation reactions proceed through mechanisms that are completely different from the classical concepts established in conventional static systems and closed stirring experimental systems (Non-Patent Documents 1, 2, 3, and 4).

[0003] The main role of thrombosis in vivo is the hemostatic mechanism to prevent blood leakage. As the first step in the hemostatic mechanism, platelets adhere to the site of the damaged vascular wall (initial hemostasis). The next step after platelet adhesion is platelet aggregation reaction. Platelets firmly adhered to the damaged vascular wall capture and successively combine with platelets supplied by blood flow, resulting in the spatial growth of platelet thrombi. There are many factors that activate platelets and induce platelet aggregation. Regardless of the type of triggering factor, the final reaction is to cross-link platelets to each other through the combination of fibrinogen or vWF and integrin αIIbβ3 (glycoprotein GPIIb / IIIa, GPIIb / IIIa) activated on the platelet membrane. Since all existing antiplatelet drugs represented by aspirin and clopidogrel have the effect of inhibiting the signal that causes platelet activation and damaging the initial hemostatic function, these drugs have a bleeding risk as an extension of their antithrombotic effect (non-patent literature 5). As described above, thrombosis at the site of atherosclerotic stenosis may be mainly caused by platelet adhesion and aggregation caused by high shear stress. Therefore, drugs that can inhibit only the platelet aggregation reaction under high shear stress are expected to have a lower bleeding risk than existing drugs.

[0004] PLD1 and PLD2 are known as the main subtypes of PLD. PLD1 is encoded by the gene of the same name, and its expression has been confirmed throughout the human body. PLD1 is a phospholipid metabolism enzyme that hydrolyzes the phospholipids, phosphatidylcholine (PC) that constitute biological membranes to produce phosphatidic acid (PA). Since the PA produced by PLD1 acts as a signaling molecule, PLD1 is believed to regulate various cell functions via PA. In addition, PLD2 exists as an enzyme that hydrolyzes PC into PA and choline in cells such as PLD1. PLD2 is also encoded by the gene of the same name, and its expression has also been confirmed throughout the human body. The PLD activity confirmed in mammalian cells and tissues is believed to be due to these PLD1 and PLD2 (Non-Patent Literature 6).

[0005] As a result of phenotypic analysis using PLD1 knockout mice, it was clarified that the mice showed antithrombotic effects without showing bleeding risk. In addition, as a result of phenotypic analysis using PLD1 / 2 double knockout mice, it was shown that in addition to the phenotype of PLD1 knockout mice, they also had an inhibitory effect on α-granule secretion from platelets. As a result of analysis using platelets derived from these mice, it was shown that inhibition of PLD1 and PLD2 inhibited platelet aggregation under high shear stress, but did not affect soluble agonist-induced platelet aggregation that was shown to be inhibited by existing antiplatelet drugs (Non-Patent Documents 7 and 8).

[0006] Both PLD1 and PLD2 are reported to contribute to various phenomena, such as cell proliferation, survival, metabolism, migration and membrane fusion (non-patent literature 9, 10 and 11). The activation of PLD1 and PLD2 is considered to contribute to the various pathologies including cancer (non-patent literature 12 and 13), and their expression and activity increase have been detected in various human cancers in colon, breast, stomach, thyroid, brain, kidney, uterine smooth muscle, etc. (non-patent literature 11, 12 and 13). In addition, there are many reports that PLD1 and PLD2 enzymes are directly involved in the transformation and tumorigenesis of various cancer types, such as breast cancer, ovarian cancer, lung cancer, colorectal cancer, kidney cancer, pancreatic cancer, prostate cancer and brain tumors (non-patent literature 11, 12 and 13). In the study using PLD1 and PLD2 knockout mice and their respective inhibitors, it has been confirmed that the growth of tumor tissue is inhibited (non-patent literature 13 and 14).

[0007] In view of the above, PLD inhibitors are considered to be therapeutic agents (e.g., secondary prevention drugs, recurrence prevention drugs, disease progression prevention drugs, etc.) or preventive agents for thrombosis (e.g., arterial thrombosis, acute coronary syndrome, stable angina, unstable angina, non-ST-segment elevation myocardial infarction, ST-segment elevation myocardial infarction, ischemic stroke, non-cardioembolic stroke, atherosclerotic stroke, cryptogenic stroke, embolic stroke of unknown origin (ESUS), lacunar stroke, transient ischemic attack, peripheral arterial disease, etc.) and perioperative and postoperative thrombosis associated with revascularization (coronary artery bypass grafting, percutaneous coronary intervention, carotid endarterectomy, carotid artery stenting, thrombolysis, lower limb revascularization, etc.) or aortic valve replacement (surgical aortic valve replacement, transcatheter aortic valve replacement, etc.). Furthermore, PLD inhibitors are also considered to be useful as therapeutic agents for cancers (eg, breast cancer, ovarian cancer, lung cancer, colorectal cancer, kidney cancer, pancreatic cancer, prostate cancer, brain tumors, etc.).

[0008] Reference list

[0009] Non-patent literature

[0010] [Non-patent document 1] Cell. 1996 Jan 26; 84(2): 289-297

[0011] [Non-patent document 2] J Thromb Haemost. 2014; 12(3): 418-420

[0012] [Non-patent document 3] Nat Med. 2009 June; 15(6): 665-673

[0013] [Non-patent document 4] The Journal of Japanese College of Angiology. 2011; 51(3): 275-281

[0014] [Non-patent document 5] Thromb Haemost. 2010 June; 103(6): 1128-1135

[0015] [Non-patent document 6] Chem Rev. 2011 Oct 12;111(10):6064-119.

[0016] [Non-patent document 7] Sci Signal. 2010 January 5; 3(103): ra1

[0017] [Non-patent document 8] J Thromb Haemost. 2012 November; 10(11): 2361-72

[0018] [Non-patent document 9] J Biol Chem. 2014. August 15; 289(33): 22567-22574

[0019] [Non-patent document 10] J Biol Chem. 2014 Aug 15;289(33):22557-22566.

[0020] [Non-patent document 11] J Biol Chem. 2014; 289(33): 22575-22582

[0021] [Non-patent document 12] Pharmacol Rev. 2014 Oct; 66(4): 1033-1079

[0022] [Non-patent document 13] Nat Rev Drug Discov. 2017 May; 16(5): 351-367

[0023] [Non-patent document 14] Adv Biol Regul. 2018 Jan;67:134-140. SUMMARY OF THE INVENTION

[0025] The present invention provides a dihydrooxadiazinone compound having PLD inhibitory activity or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the same, and pharmaceutical use thereof. Therefore, the present invention includes the following exemplary embodiments.

[0026] [Project 1]

[0027] A compound represented by formula [I] or a pharmaceutically acceptable salt thereof:

[0028]

[0029] in

[0030] A is CR 10 or N;

[0031] Cy is

[0032] (1)C 6-10 Aryl,

[0033] (2) a 5- or 6-membered heteroaryl group which contains, in addition to carbon atoms, 1 or 2 nitrogen atoms as ring-constituting atoms, or

[0034] (3) a 9- or 10-membered partially unsaturated fused ring group which contains, in addition to carbon atoms, 1 or 2 oxygen atoms as ring-constituting atoms;

[0035] R 1 yes

[0036] (1)C 1-6 Alkyl, wherein the alkyl is optionally substituted by

[0037] (a) hydroxyl group,

[0038] (b) cyano,

[0039] (c)SO2R 11 , where R 11 C 1-4 Alkyl, or

[0040] (d) NHCOR 12 , where R 12 C 1-4 alkyl,

[0041] (2)C 2-4 Alkenyl, wherein the alkenyl is optionally NR 13 R 14 Substitution, where R 13 and R 14 are independently hydrogen or C 1-4 alkyl,

[0042] (3)C 1-4 Haloalkyl,

[0043] (4)C 1-6 an alkoxy group, wherein the alkoxy group is optionally substituted with a phenyl group,

[0044] (5)NR 15 R 16 , where R 15 and R 16 Each independently

[0045] (a) hydrogen,

[0046] (b)C 1-4 Alkyl, wherein the alkyl is optionally substituted by

[0047] (i) phenyl, wherein the phenyl is optionally substituted by halogen, or

[0048] (ii) pyridyl,

[0049] (c)C 1-4 Alkoxy, or

[0050] (d)C 3-4 Cycloalkyl,

[0051] (6)COR 17 , where R 17 C 1-4 alkyl,

[0052] (7)CONR 18 R 19 , where R 18 and R 19 Each independently

[0053] (a) hydrogen,

[0054] (b)C 1-4 alkyl,

[0055] (c)C 3-4 Cycloalkyl, or

[0056] (d)C 5-8 A bridged cycloalkyl group,

[0057] (8)C 3-4 Cycloalkyl, wherein the cycloalkyl is optionally substituted with

[0058] (a) hydroxyl group,

[0059] (b) halogen, or

[0060] (c) phenyl,

[0061] (9) a 4- to 7-membered heterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring, wherein the heterocycloalkyl group is optionally substituted by the following substituents

[0062] (a) hydroxyl group,

[0063] (b) oxo,

[0064] (c)NR 20 R 21 , where R20 and R 21 are independently hydrogen or C 1-4 Alkyl, or

[0065] (d) phenyl,

[0066] (10) a 6- to 11-membered spiroheterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring,

[0067] (11) phenyl, wherein the phenyl is optionally substituted by 1 or 2 halogens,

[0068] (12) a 5- to 10-membered heteroaryl group containing, in addition to carbon atoms, 1 to 3 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring, wherein the heteroaryl group is optionally substituted by 1 or 2 R 22 Replace, or

[0069] (13) an 8- to 10-membered saturated or partially unsaturated fused ring group containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen and oxygen atoms as ring-constituting atoms, wherein the fused ring group is optionally C 1-4 haloalkyl substitution;

[0070] R 2 The number of is m, each of which is independently

[0071] (1) Hydroxyl group,

[0072] (2) cyano group,

[0073] (3) Halogen,

[0074] (4)C 1-6 Alkyl, wherein the alkyl is optionally substituted by

[0075] (a) hydroxyl group, or

[0076] (b)C 3-4 Cycloalkyl,

[0077] (5)C 2-4 Alkenyl, wherein the alkenyl is optionally substituted with C 1-4 Alkoxy substitution,

[0078] (6)C 1-4 Haloalkyl,

[0079] (7)C 1-4 Alkoxy, wherein the alkoxy is optionally substituted with 1 to 3 substituents selected from the following:

[0080] (a) hydroxyl groups, and

[0081] (b) halogen,

[0082] (8)SR 23 , where R 23 C 1-4 alkyl,

[0083] (9)COR 24 , where R 24 Hydroxyl or C 1-4 alkyl,

[0084] (10)CONR 25 R 26 , where R 25 and R 26 Each independently

[0085] (a) hydrogen,

[0086] (b)C 1-6 Alkyl, or

[0087] (c)C 3-4 Cycloalkyl,

[0088] (11) SO2R 27 , where R 27 C 1-6 alkyl,

[0089] (12)C 3-4 Cycloalkyl,

[0090] (13) a 4- to 7-membered heterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring, wherein the heterocycloalkyl group is optionally substituted by 1 or 2 substituents selected from the following

[0091] (a) halogen,

[0092] (b)C 1-4 Alkyl, and

[0093] (c)C 1-4 Haloalkyl,

[0094] (14) a 5- to 9-membered bridged heterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring,

[0095] (15) a 6- to 11-membered spiroheterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring, or

[0096] (16) phenyl;

[0097] R 3 , R 4 , R 5 and R 6are independently hydrogen or C 1-4 alkyl;

[0098] R 7 and R 8 Both are hydrogen, or R 7 and R 8 bonded to one another so as to form, together with the carbon atoms to which they are bonded, a cyclopentane ring;

[0099] R 9 For hydrogen or CONHR 28 , where R 28 C 3-4 Cycloalkyl;

[0100] R 10 yes

[0101] (1) Hydrogen,

[0102] (2) hydroxyl group, or

[0103] (3) Halogen;

[0104] 1 or 2 R 22 Each independently

[0105] (1) Halogen,

[0106] (2)C 1-4 alkyl,

[0107] (3)C 1-4 Haloalkyl,

[0108] (4)C 1-4 Alkoxy,

[0109] (5) NHCOR 29 , where R 29 C 1-4 Alkyl, or

[0110] (6) SO2R 30 , where R 30 C 1-4 alkyl; and

[0111] m is 0, 1, 2 or 3.

[0112] [Project 2]

[0113] The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein R 9 For hydrogen.

[0114] [Item 3]

[0115] The compound according to item 1 or 2, or a pharmaceutically acceptable salt thereof, wherein A is N.

[0116] [Item 4]

[0117] The compound according to item 1 or 2 or a pharmaceutically acceptable salt thereof, wherein A is CR 10 , where R 10 As defined in item 1.

[0118] [Item 5]

[0119] The compound according to item 4 or a pharmaceutically acceptable salt thereof, which is represented by formula [II]:

[0120]

[0121] in

[0122] Cy, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and m is as defined in item 1.

[0123] [Item 6]

[0124] The compound according to any one of items 1 to 5 or a pharmaceutically acceptable salt thereof, wherein R 3 C 1-4 alkyl.

[0125] [Item 7]

[0126] A pharmaceutical composition comprising a compound as defined in any one of items 1 to 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0127] [Item 8]

[0128] A PLD1 inhibitor comprising a compound as defined in any one of items 1 to 6 or a pharmaceutically acceptable salt thereof.

[0129] [Item 9]

[0130] A medicament for treating or preventing a disease selected from thrombosis and cancer, comprising a compound as defined in any one of Items 1 to 6 or a pharmaceutically acceptable salt thereof.

[0131] [Item 10]

[0132] A method for inhibiting PLD1 in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound as defined in any one of items 1 to 6 or a pharmaceutically acceptable salt thereof.

[0133] [Item 11]

[0134] A method for treating or preventing a disease selected from thrombosis and cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound as defined in any one of items 1 to 6 or a pharmaceutically acceptable salt thereof.

[0135] [Item 12]

[0136] Use of a compound as defined in any one of items 1 to 6 or a pharmaceutically acceptable salt thereof in the manufacture of a PLD1 inhibitor.

[0137] [Item 13]

[0138] Use of a compound as defined in any one of items 1 to 6 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease selected from thrombosis and cancer.

[0139] [Item 14]

[0140] A compound as defined in any one of items 1 to 6 or a pharmaceutically acceptable salt thereof for use in inhibiting PLD1.

[0141] [Item 15]

[0142] A compound as defined in any one of items 1 to 6 or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease selected from thrombosis and cancer.

[0143] [Item 1a]

[0144] A compound represented by formula [Ia] or a pharmaceutically acceptable salt thereof:

[0145]

[0146] in

[0147] A a CR 10a or N;

[0148] A 2a CR 5a or O;

[0149] Cy a for

[0150] (1)C 6-10 Aryl,

[0151] (2) a 5- to 10-membered heteroaryl group which contains 1 or 2 nitrogen atoms as ring-constituting atoms in addition to carbon atoms, or

[0152] (3) a 9- or 10-membered partially unsaturated fused ring group which contains, in addition to carbon atoms, 1 or 2 oxygen atoms as ring-constituting atoms;

[0153] R 1a for

[0154] (1)C 1-6 Alkyl, wherein the alkyl is optionally substituted by

[0155] (a) hydroxyl group,

[0156] (b) cyano,

[0157] (c)SO2R 11 , where R 11 C 1-4 Alkyl, or

[0158] (d) NHCOR 12 , where R 12 C 1-4 alkyl,

[0159] (2)C 2-4 Alkenyl, wherein the alkenyl is optionally substituted by 1 to 3 of the following substituents

[0160] (a)NR 13 R 14 , where R 13 and R 14 are independently hydrogen or C 1-4 alkyl,

[0161] (b) halogen,

[0162] (c)COR 35a , where R 35a Hydroxyl or C 1-4 Alkoxy,

[0163] (d)CONR 36a R 37a , where R 36a and R 37a are independently hydrogen or C 1-4 Alkyl, or

[0164] (e) Partial structural formula:

[0165]

[0166] (3)C 1-4 haloalkyl, wherein the haloalkyl is optionally substituted with hydroxy,

[0167] (4)C 1-6 an alkoxy group, wherein the alkoxy group is optionally substituted with a phenyl group,

[0168] (5)NR 15 R 16 , where R 15 and R 16 Each independently

[0169] (a) hydrogen,

[0170] (b)C 1-4 Alkyl, wherein the alkyl is optionally substituted by

[0171] (i) phenyl, wherein the phenyl is optionally substituted by halogen, or

[0172] (ii) pyridyl,

[0173] (c)C 1-4 Alkoxy, or

[0174] (d)C 3-4 Cycloalkyl,

[0175] (6)COR 17a , where R 17a C 1-4 Alkyl or hydroxyl,

[0176] (7)CONR 18a R 19a , where R 18a and R 19a Each independently

[0177] (a) hydrogen,

[0178] (b)C 1-4 an alkyl group, wherein the alkyl group is optionally substituted with a hydroxy group,

[0179] (c)C 3-4 Cycloalkyl,

[0180] (d)C 5-8 A bridged cycloalkyl group,

[0181] (e)C 1-4 haloalkyl, or

[0182] (f)C 1-4 Alkoxy,

[0183] (8)C 3-4 Cycloalkyl, wherein the cycloalkyl is optionally substituted with

[0184] (a) hydroxyl group,

[0185] (b) halogen, or

[0186] (c) phenyl,

[0187] (9) a 4- to 7-membered heterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring, wherein the heterocycloalkyl group is optionally substituted by the following groups

[0188] (a) hydroxyl group,

[0189] (b) oxo,

[0190] (c)NR 20 R 21 , where R 20 and R 21 are independently hydrogen or C 1-4 Alkyl, or

[0191] (d) phenyl,

[0192] (10) a 6- to 11-membered spiroheterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring,

[0193] (11) phenyl, wherein the phenyl is optionally substituted by one or two of the following substituents

[0194] (a) halogen, or

[0195] (b)C 1-4 Haloalkyl,

[0196] (12) a 5- to 10-membered heteroaryl group containing, in addition to carbon atoms, 1 to 3 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring, wherein the heteroaryl group is optionally substituted by 1 or 2 R 22a replace,

[0197] (13) an 8- to 10-membered saturated or partially unsaturated fused ring group containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen and oxygen atoms as ring-constituting atoms, wherein the fused ring group is optionally C 1-4 haloalkyl substituted, or

[0198] (14) a 5- to 7-membered partially unsaturated cyclic group containing, in addition to carbon atoms, 1 or 2 nitrogen atoms as ring-constituting atoms, wherein the partially unsaturated cyclic group is optionally substituted by an oxo group and a C 1-4 Alkyl substitution;

[0199] R 2a The number of is m, each of which is independently

[0200] (1) Hydroxyl group,

[0201] (2) cyano group,

[0202] (3) Halogen,

[0203] (4)C 1-6 Alkyl, wherein the alkyl is optionally substituted by

[0204] (a) hydroxyl group, or

[0205] (b)C 3-4 Cycloalkyl,

[0206] (5)C 2-4 Alkenyl, wherein the alkenyl is optionally substituted with C 1-4 Alkoxy substitution,

[0207] (6)C 1-4 Haloalkyl,

[0208] (7)C 1-4 Alkoxy, wherein the alkoxy is optionally substituted with 1 to 3 substituents selected from the following:

[0209] (a) hydroxyl groups, and

[0210] (b) halogen,

[0211] (8)SR 23a , where R 23a C 1-4 Alkyl or C 1-4 Haloalkyl,

[0212] (9)COR 24a , where R 24a for

[0213] (a) hydroxyl group,

[0214] (b)C 1-4 Alkyl, or

[0215] (c)C 1-4 Alkoxy,

[0216] (10)CONR 25a R 26a , where R 25a and R 26a Each independently

[0217] (a) hydrogen,

[0218] (b)C 1-6 Alkyl, or

[0219] (c)C 3-4 Cycloalkyl, or

[0220] R 25aand R 26a are bonded to each other to form, together with the nitrogen atom to which they are bonded, a 4- to 7-membered heterocycloalkyl group, wherein the heterocycloalkyl group contains, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring, and is optionally substituted by 1 or 2 halogens,

[0221] (11) SO2R 27 , where R 27 C 1-6 alkyl,

[0222] (12)C 3-4 Cycloalkyl,

[0223] (13) a 4- to 7-membered heterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring, wherein the heterocycloalkyl group is optionally substituted by 1 or 2 substituents selected from the following

[0224] (a) halogen,

[0225] (b)C 1-4 Alkyl, and

[0226] (c)C 1-4 Haloalkyl,

[0227] (14) a 5- to 9-membered bridged heterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring,

[0228] (15) a 6- to 11-membered spiroheterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring, or

[0229] (16) phenyl;

[0230] R 3a for

[0231] (1) Hydrogen,

[0232] (2)C 1-4 Alkyl, or

[0233] (3)C 1-4 Haloalkyl;

[0234] R 4a for

[0235] (1) Hydrogen,

[0236] (2)C 1-4 Alkyl, or

[0237] (3) cyano;

[0238] R5a is hydrogen or C 1-4 alkyl;

[0239] R 6a , R 7a and R 8a The combination of

[0240] (1) R 6a is hydrogen or C 1-4 Alkyl, and R 7a and R 8a The two are a combination of hydrogen.

[0241] (2) R 6a is hydrogen or C 1-4 Alkyl, and R 7a and R 8a are bonded to each other to form a cyclopentane ring together with the spiro carbon atoms and the carbon atoms to which they are bonded, or

[0242] (3) R 6a and R 7a are bonded to each other to form a cyclopentane ring together with the spiro carbon atom and the carbon atom to which they are bonded, and R 8a is a combination of hydrogen;

[0243] R 9a for

[0244] (1) Hydrogen,

[0245] (2)CONHR 28 , where R 28 C 3-4 Cycloalkyl, or

[0246] (3)C 1-4 alkyl;

[0247] R 10a for

[0248] (1) Hydrogen,

[0249] (2) Hydroxyl groups,

[0250] (3) Halogen,

[0251] (4)C 1-4 alkyl,

[0252] (5) cyano, or

[0253] (6)C 1-4 Alkoxy;

[0254] 1 or 2 R 22a Each independently

[0255] (1) Halogen,

[0256] (2)C 1-4 alkyl,

[0257] (3)C 1-4 Haloalkyl,

[0258] (4)C 1-4 Alkoxy,

[0259] (5) NHCOR 29 , where R 29 C 1-4 alkyl,

[0260] (6) SO2R 30 , where R 30 C 1-4 alkyl,

[0261] (7) cyano, or

[0262] (8)C 3-4 cycloalkyl; and

[0263] m is 0, 1, 2 or 3.

[0264] [Item 2a]

[0265] The compound according to item 1a or a pharmaceutically acceptable salt thereof, which is represented by formula [IIa]:

[0266]

[0267] in

[0268] A a , Cy a , R 1a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a and m is as defined in item 1a.

[0269] [Item 3a]

[0270] The compound according to item 1a or a pharmaceutically acceptable salt thereof, which is represented by formula [IIIa]:

[0271]

[0272] in

[0273] Cy a , R 1a , R 2a , R3a , R 4a , R 5a , R 6a , R 7a , R 8a and m is as defined in item 1a.

[0274] [Item 4a]

[0275] The compound according to item 1a or a pharmaceutically acceptable salt thereof, which is represented by formula [IVa]:

[0276]

[0277] in

[0278] R 1b for

[0279] (1)C 1-6 Alkyl, wherein the alkyl is optionally substituted by

[0280] (a) hydroxyl group,

[0281] (b) cyano,

[0282] (c)SO2R 11 , where R 11 C 1-4 Alkyl, or

[0283] (d) NHCOR 12 , where R 12 C 1-4 alkyl,

[0284] (2)C 2-4 Alkenyl, wherein the alkenyl is optionally substituted by 1 to 3 of the following substituents

[0285] (a)NR 13 R 14 , where R 13 and R 14 are independently hydrogen or C 1-4 alkyl,

[0286] (b) halogen,

[0287] (c)COR 35a , where R 35a Hydroxyl or C 1-4 Alkoxy,

[0288] (d)CONR 36a R 37a , where R 36a and R 37a are independently hydrogen or C 1-4Alkyl, or

[0289] (e) Partial structural formula:

[0290]

[0291] (3)C 1-6 an alkoxy group, wherein the alkoxy group is optionally substituted with a phenyl group,

[0292] (4)NR 15 R 16 , where R 15 and R 16 Each independently

[0293] (a) hydrogen,

[0294] (b)C 1-4 Alkyl, wherein the alkyl is optionally substituted by

[0295] (i) phenyl, wherein the phenyl is optionally substituted by halogen, or

[0296] (ii) pyridyl,

[0297] (c)C 1-4 Alkoxy, or

[0298] (d)C 3-4 Cycloalkyl,

[0299] (5)CONR 18a R 19a , where R 18a and R 19a Each independently

[0300] (a) hydrogen,

[0301] (b)C 1-4 an alkyl group, wherein the alkyl group is optionally substituted with a hydroxy group,

[0302] (c)C 3-4 Cycloalkyl,

[0303] (d)C 5-8 A bridged cycloalkyl group,

[0304] (e)C 1-4 haloalkyl, or

[0305] (f)C 1-4 Alkoxy,

[0306] (6) a 6- to 11-membered spiroheterocycloalkyl group which contains, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring,

[0307] (7) a 5- to 10-membered heteroaryl group containing, in addition to carbon atoms, 1 to 3 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring, wherein the heteroaryl group is optionally substituted by 1 or 2 R 22a replace,

[0308] (8) an 8- to 10-membered saturated or partially unsaturated fused ring group containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen and oxygen atoms as ring-constituting atoms, wherein the fused ring group is optionally C 1-4 haloalkyl substituted, or

[0309] (9) a 5- to 7-membered partially unsaturated cyclic group which contains, in addition to carbon atoms, 1 or 2 nitrogen atoms as ring-constituting atoms, wherein the partially unsaturated cyclic group is optionally substituted by an oxo group and a C 1-4 Alkyl substitution; and

[0310] Cy a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 22a and m is as defined in item 1a.

[0311] [Item 5a]

[0312] The compound according to item 4a or a pharmaceutically acceptable salt thereof, which is represented by formula [Va]:

[0313]

[0314] in

[0315] Cy a , R 2a , R 3a , R 4a and m is as defined in item 1a; and

[0316] R 1b As defined in item 4a.

[0317] [Item 6a]

[0318] The compound according to item 4a or a pharmaceutically acceptable salt thereof, which is represented by formula [VIa]:

[0319]

[0320] in

[0321] Cy b for

[0322] (1)C 6-10 Aryl, or

[0323] (2) a 5- or 6-membered heteroaryl group which contains, in addition to carbon atoms, 1 or 2 nitrogen atoms as ring-constituting atoms;

[0324] R 1b as defined in item 4a; and

[0325] R 2a , R 3a , R 4a and m is as defined in item 1a.

[0326] [Item 7a]

[0327] The compound according to item 4a or a pharmaceutically acceptable salt thereof, which is represented by formula [VIIa]:

[0328]

[0329] in

[0330] Cy a , R 2a , R 3a , R 5a , R 6a , R 7a , R 8a and m is as defined in item 1a; and

[0331] R 1b As defined in item 4a.

[0332] [Item 8a]

[0333] The compound according to item 4a or a pharmaceutically acceptable salt thereof, which is represented by formula [VIIIa]:

[0334]

[0335] in

[0336] Cy a , R 2a , R 3a and m is as defined in item 1a; and

[0337] R 1b As defined in item 4a.

[0338] [Item 9a]

[0339] The compound according to item 6a or a pharmaceutically acceptable salt thereof, which is represented by formula [IXa]:

[0340]

[0341] in

[0342] Cy b As defined in item 6a;

[0343] R 1b as defined in item 4a; and

[0344] R 2a , R 3a and m is as defined in item 1a.

[0345] [Item 10a]

[0346] The compound according to item 1a or a pharmaceutically acceptable salt thereof, which is represented by formula [Xa]:

[0347]

[0348] in

[0349] Cy a , R 1a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 10a and m is as defined in item 1a.

[0350] [Item 11a]

[0351] The compound according to item 1a or a pharmaceutically acceptable salt thereof, which is represented by formula [XIa]:

[0352]

[0353] in

[0354] Cy a , R 1a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 10a and m is as defined in item 1a.

[0355] [Item 12a]

[0356] The compound according to item 1a or a pharmaceutically acceptable salt thereof, which is represented by formula [XIIa]:

[0357]

[0358] in

[0359] R 1b for

[0360] (1)C 1-6 Alkyl, wherein the alkyl is optionally substituted by

[0361] (a) hydroxyl group,

[0362] (b) cyano,

[0363] (c)SO2R 11 , where R 11 C 1-4 Alkyl, or

[0364] (d) NHCOR 12 , where R 12 C 1-4 alkyl,

[0365] (2)C 2-4 Alkenyl, wherein the alkenyl is optionally substituted by 1 to 3 of the following substituents

[0366] (a)NR 13 R 14 , where R 13 and R 14 are independently hydrogen or C 1-4 alkyl,

[0367] (b) halogen,

[0368] (c)COR 35a , where R 35a Hydroxyl or C 1-4 Alkoxy,

[0369] (d)CONR 36a R 37a , where R 36a and R 37a are independently hydrogen or C 1-4 Alkyl, or

[0370] (e) Partial structural formula:

[0371]

[0372] (3)C 1-6 an alkoxy group, wherein the alkoxy group is optionally substituted with a phenyl group,

[0373] (4)NR 15 R16 , where R 15 and R 16 Each independently

[0374] (a) hydrogen,

[0375] (b)C 1-4 Alkyl, wherein the alkyl is optionally substituted by

[0376] (i) phenyl, wherein the phenyl is optionally substituted by halogen, or

[0377] (ii) pyridyl,

[0378] (c)C 1-4 Alkoxy, or

[0379] (d)C 3-4 Cycloalkyl,

[0380] (5)CONR 18a R 19a , where R 18a and R 19a Each independently

[0381] (a) hydrogen,

[0382] (b)C 1-4 an alkyl group, wherein the alkyl group is optionally substituted with a hydroxy group,

[0383] (c)C 3-4 Cycloalkyl,

[0384] (d)C 5-8 A bridged cycloalkyl group,

[0385] (e)C 1-4 haloalkyl, or

[0386] (f)C 1-4 Alkoxy,

[0387] (6) a 6- to 11-membered spiroheterocycloalkyl group which contains, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring,

[0388] (7) a 5- to 10-membered heteroaryl group containing, in addition to carbon atoms, 1 to 3 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring, wherein the heteroaryl group is optionally substituted by 1 or 2 R 22a replace,

[0389] (8) an 8- to 10-membered saturated or partially unsaturated fused ring group containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen and oxygen atoms as ring-constituting atoms, wherein the fused ring group is optionally C 1-4 haloalkyl substituted, or

[0390] (9) a 5- to 7-membered partially unsaturated cyclic group which contains, in addition to carbon atoms, 1 or 2 nitrogen atoms as ring-constituting atoms, wherein the partially unsaturated cyclic group is optionally substituted by an oxo group and a C 1-4 Alkyl substitution; and

[0391] Cy a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 10a , R 22a and m is as defined in item 1a.

[0392] [Item 13a]

[0393] The compound according to Item 12a or a pharmaceutically acceptable salt thereof, which is represented by formula [XIIIa]:

[0394]

[0395] in

[0396] Cy a , R 2a , R 3a , R 4a , R 10a and m is as defined in item 1a; and

[0397] R 1b As defined in item 12a.

[0398] [Item 14a]

[0399] The compound according to Item 12a or a pharmaceutically acceptable salt thereof, which is represented by formula [XIVa]:

[0400]

[0401] in

[0402] Cy b for

[0403] (1)C 6-10 Aryl, or

[0404] (2) a 5- or 6-membered heteroaryl group which contains, in addition to carbon atoms, 1 or 2 nitrogen atoms as ring-constituting atoms;

[0405] R 1b as defined in item 12a; and

[0406] R 2a , R 3a , R 4a , R 10a and m is as defined in item 1a.

[0407] [Item 15a]

[0408] The compound according to Item 12a or a pharmaceutically acceptable salt thereof, which is represented by formula [XVa]:

[0409]

[0410] in

[0411] Cy a , R 2a , R 3a , R 5a , R 6a , R 7a , R 8a , R 10a and m is as defined in item 1a; and

[0412] R 1b As defined in item 12a.

[0413] [Item 16a]

[0414] The compound according to Item 12a or a pharmaceutically acceptable salt thereof, which is represented by formula [XVIa]:

[0415]

[0416] in

[0417] Cy a , R 2a , R 3a , R 10a and m is as defined in item 1a; and

[0418] R 1b As defined in item 12a.

[0419] [Item 17a]

[0420] The compound according to Item 14a or a pharmaceutically acceptable salt thereof, which is represented by formula [XVIIa]:

[0421]

[0422] in

[0423] Cy b As defined in item 14a;

[0424] R 1b as defined in item 12a; and

[0425] R 2a , R 3a , R 10a and m is as defined in item 1a.

[0426] [Item 18a]

[0427] A compound selected from the group consisting of compounds represented by the following formula:

[0428]

[0429] or a pharmaceutically acceptable salt thereof.

[0430] [Item 19a]

[0431] A pharmaceutical composition comprising a compound as defined in any one of items 1a to 18a or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0432] [Item 20a]

[0433] A pharmaceutical composition comprising a compound as defined in any one of items 1a to 18a or a pharmaceutically acceptable salt thereof in combination with one or more other drugs, and a pharmaceutically acceptable carrier.

[0434] [Item 21a]

[0435] A PLD inhibitor comprising a compound as defined in any one of items 1a to 18a or a pharmaceutically acceptable salt thereof.

[0436] [Item 22a]

[0437] A PLD1 inhibitor comprising a compound as defined in any one of items 1a to 18a or a pharmaceutically acceptable salt thereof.

[0438] [Item 23a]

[0439] A PLD1 / 2 inhibitor comprising a compound as defined in any one of items 1a to 18a or a pharmaceutically acceptable salt thereof.

[0440] [Item 24a]

[0441] An agent for treating or preventing a disease selected from thrombosis and cancer, comprising a compound as defined in any one of items 1a to 18a or a pharmaceutically acceptable salt thereof.

[0442] [Item 25a]

[0443] A medicament for treating or preventing a disease selected from thrombosis and cancer, comprising a compound as defined in any one of items 1a to 18a or a pharmaceutically acceptable salt thereof in combination with one or more other drugs.

[0444] [Item 26a]

[0445] A method for inhibiting PLD in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound as defined in any one of items 1a to 18a or a pharmaceutically acceptable salt thereof.

[0446] [Item 27a]

[0447] A method for inhibiting PLD1 in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound as defined in any one of items 1a to 18a or a pharmaceutically acceptable salt thereof.

[0448] [Item 28a]

[0449] A method for inhibiting PLD1 / 2 in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound as defined in any one of items 1a to 18a or a pharmaceutically acceptable salt thereof.

[0450] [Item 29a]

[0451] A method for treating or preventing a disease selected from thrombosis and cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound as defined in any one of items 1a to 18a or a pharmaceutically acceptable salt thereof.

[0452] [Item 30a]

[0453] A method for treating or preventing a disease selected from thrombosis and cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound as defined in any one of items 1a to 18a or a pharmaceutically acceptable salt thereof in combination with one or more other drugs.

[0454] [Item 31a]

[0455] Use of a compound as defined in any one of items 1a to 18a or a pharmaceutically acceptable salt thereof in the manufacture of a PLD inhibitor.

[0456] [Item 32a]

[0457] Use of a compound as defined in any one of items 1a to 18a or a pharmaceutically acceptable salt thereof in the manufacture of a PLD1 inhibitor.

[0458] [Item 33a]

[0459] Use of a compound as defined in any one of items 1a to 18a or a pharmaceutically acceptable salt thereof in the manufacture of a PLD1 / 2 inhibitor.

[0460] [Item 34a]

[0461] Use of a compound as defined in any one of items 1a to 18a, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease selected from thrombosis and cancer.

[0462] [Item 35a]

[0463] Use of a compound as defined in any one of items 1a to 18a or a pharmaceutically acceptable salt thereof in combination with one or more other drugs in the manufacture of a medicament for treating or preventing a disease selected from thrombosis and cancer.

[0464] [Item 36a]

[0465] A compound as defined in any one of items 1a to 18a, or a pharmaceutically acceptable salt thereof, for use in inhibiting PLD.

[0466] [Item 37a]

[0467] A compound as defined in any one of items 1a to 18a, or a pharmaceutically acceptable salt thereof, for use in inhibiting PLD1.

[0468] [Item 38a]

[0469] A compound as defined in any one of items 1a to 18a, or a pharmaceutically acceptable salt thereof, for use in inhibiting PLD1 / 2.

[0470] [Item 39a]

[0471] A compound as defined in any one of items 1a to 18a, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease selected from thrombosis and cancer.

[0472] [Item 40a]

[0473] A compound as defined in any one of items 1a to 18a, or a pharmaceutically acceptable salt thereof, in combination with one or more other drugs for use in treating or preventing a disease selected from thrombosis and cancer.

[0474] Effects of the Invention

[0475] Since the compound represented by formula [I] or formula [Ia] of the present invention or a pharmaceutically acceptable salt thereof has PLD inhibitory activity, it can be used for treating or preventing thrombosis and cancer.

[0476] Embodiments of the present invention

[0477] Definitions of terms used herein are as follows.

[0478] Examples of "halogen" include fluorine, chlorine, bromine and iodine.

[0479] “C 1-4 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 4 carbon atoms. 1-4 Examples of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. Preferred "C 1-4 "Alkyl" means methyl, ethyl, n-propyl, n-butyl, isobutyl and tert-butyl.

[0480] “C 1-6 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. 1-6 Examples of "alkyl" include 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 "Alkyl" is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

[0481] “C 2-4 "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 4 carbon atoms and a carbon-carbon double bond. 2-4 Examples of "alkenyl" include vinyl, allyl, prop-1-en-1-yl, prop-1-en-2-yl, 2-methylprop-1-en-yl, but-3-en-1-yl, but-2-en-1-yl and but-2-en-2-yl. Preferred "C 2-4 "Alkenyl" is vinyl, prop-1-en-1-yl and 2-methylprop-1-en-yl.

[0482] “C 1-4 "Haloalkyl" refers to the above-mentioned "C 1-4 The "alkyl" is substituted by 1 to 5 halogens independently selected from the above-mentioned "halogen". 1-4 Examples of "haloalkyl" include 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 "Haloalkyl" is difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl and 3,3,3-trifluoropropyl.

[0483] “C 1-4 "Alkoxy" refers to a 1-4 A group formed by an alkyl group and an oxygen atom. 1-4 Examples of "alkoxy" include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy and tert-butoxy. Preferred "C 1-4 "Alkoxy" means methoxy, ethoxy, n-propoxy, isobutoxy and tert-butoxy.

[0484] “C 1-6 "Alkoxy" refers to a 1-6 A group formed by an alkyl group and an oxygen atom. 1-6 Examples of "alkoxy" include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, n-pentoxy, (3-methylbutan-2-yl)oxy and n-hexyloxy. Preferred "C 1-6 "Alkoxy" means methoxy, ethoxy, n-propoxy, isobutoxy and tert-butoxy.

[0485] “C 3-4 "Cycloalkyl" refers to a monocyclic saturated hydrocarbon group having 3 or 4 carbon atoms. 3-4 Examples of "cycloalkyl" include cyclopropyl and cyclobutyl. Preferred "C 3-4 "Cycloalkyl" is cyclopropyl.

[0486] “C 5-8 "Bridged cycloalkyl" refers to a 5- to 8-membered bridged cyclic saturated hydrocarbon group. 5-8 Examples of "bridged cycloalkyl" include bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl and bicyclo[2.2.2]octyl. Preferred "C 5-8 The "bridged cycloalkyl" is bicyclo[1.1.1]pentyl.

[0487] “C 6-10 "Aryl" refers to an aromatic hydrocarbon group having 6 to 10 carbon atoms. 6-10 Examples of "aryl" include phenyl and naphthyl. Preferred "C 6-10 "Aryl" is phenyl.

[0488] “A 4- to 7-membered heterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring” refers to a 4- to 7-membered saturated heterocyclic group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring. Examples of “a 4- to 7-membered heterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring” include azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, dioxane, piperazinyl, morpholinyl and azepanyl. Preferred “a 4- to 7-membered heterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring” are azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, dioxane and morpholinyl.

[0489] The “5- to 9-membered bridged heterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring” refers to a 5- to 9-membered bridged heterocyclic group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring. Examples of the “5- to 9-membered bridged heterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring” 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 bridged heterocycloalkyl groups containing 1 or 2 hetero atoms selected from nitrogen and oxygen atoms as atoms constituting the ring in addition to carbon atoms” are 2-oxa-5-azabicyclo[2.2.1]heptyl and 8-oxa-3-azabicyclo[3.2.1]octyl.

[0490] The “6- to 11-membered spiroheterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring” refers to a 6- to 11-membered spiroheterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring. Examples of the “6- to 11-membered spiroheterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring” 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 spiroheterocycloalkyl groups containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring” are 2-oxa-6-azaspiro[3.3]heptyl, 5-azaspiro[2.4]heptyl and 4-oxa-7-azaspiro[2.5]octyl.

[0491] “5- or 6-membered heteroaryl group containing 1 or 2 nitrogen atoms as ring-constituting atoms in addition to carbon atoms” refers to a 5- or 6-membered aromatic heterocyclic group containing 1 or 2 nitrogen atoms as ring-constituting atoms in addition to carbon atoms. Examples of the “5- or 6-membered heteroaryl group containing 1 or 2 nitrogen atoms as ring-constituting atoms in addition to carbon atoms” include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl. Preferred “5- or 6-membered heteroaryl group containing 1 or 2 nitrogen atoms as ring-constituting atoms in addition to carbon atoms” are pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl.

[0492] The “5- to 10-membered heteroaryl group containing 1 or 2 nitrogen atoms as atoms constituting the ring in addition to carbon atoms” refers to a 5- to 10-membered aromatic heterocyclic group containing 1 or 2 nitrogen atoms as atoms constituting the ring in addition to carbon atoms. Examples of the “5- to 10-membered heteroaryl group containing 1 or 2 nitrogen atoms as atoms constituting the ring in addition to carbon atoms” include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzimidazolyl, indazolyl, indolizinyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, quinolyl, isoquinolyl and quinoxalinyl. Preferred "5- to 10-membered heteroaryl groups containing 1 or 2 nitrogen atoms as ring-constituting atoms in addition to carbon atoms" are pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl and pyrazolo[1,5-a]pyridinyl.

[0493] The “5- to 10-membered heteroaryl group containing 1 to 3 hetero atoms selected from nitrogen and oxygen atoms as atoms constituting a ring in addition to carbon atoms” refers to a 5- to 10-membered aromatic heterocyclic group containing 1 to 3 nitrogen and oxygen atoms as atoms constituting a ring in addition to carbon atoms. Examples of the “5- to 10-membered heteroaryl group containing 1 to 3 hetero atoms selected from nitrogen and oxygen atoms in addition to carbon atoms as atoms constituting a ring” include pyrrolyl, furanyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, indolyl, benzofuranyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl, indolizinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, quinolyl, isoquinolyl and quinoxalinyl. Preferred “5- to 10-membered heteroaryl groups containing, in addition to carbon atoms, 1 to 3 hetero atoms selected from nitrogen and oxygen atoms as atoms constituting a ring” are pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isoxazolyl, 1,2,4-oxadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, benzofuranyl, benzimidazolyl, indolizinyl, imidazo[1,2-a]pyridyl and pyrazolo[1,5-a]pyridyl.

[0494] The “5- to 7-membered partially unsaturated cyclic group containing 1 or 2 nitrogen atoms as atoms constituting the ring in addition to carbon atoms” refers to a 5- to 7-membered partially unsaturated cyclic group containing 1 or 2 nitrogen atoms as atoms constituting the ring in addition to carbon atoms. Examples of the “5- to 7-membered partially unsaturated cyclic group containing 1 or 2 nitrogen atoms as atoms constituting the ring in addition to carbon atoms” include dihydropyrrolyl, dihydropyridyl and dihydropyrimidyl. A preferred “5- to 7-membered partially unsaturated cyclic group containing 1 or 2 nitrogen atoms as atoms constituting the ring in addition to carbon atoms” is dihydropyridyl.

[0495] The “8- to 10-membered saturated or partially unsaturated fused ring group containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring” refers to an 8- to 10-membered fused heterocyclic group containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring and containing at least one saturated ring in the fused ring. Examples of the “8- to 10-membered saturated or partially unsaturated fused ring group containing 1 to 4 hetero atoms selected from nitrogen and oxygen atoms in addition to carbon atoms as atoms constituting the ring” include octahydro-2H-isoindolyl, dihydrobenzofuranyl, benzo[d][1,3]dioxolyl, isoindolyl, dihydroisoquinolinyl, dihydro-1,6-naphthyridinyl, dihydro-1,7-naphthyridinyl, dihydroisoxazolo[4,3-c]pyridinyl, dihydropyrazolo[1,5-a]pyrazinyl and dihydrotriazolo[1,5-a]pyrazinyl.

[0496] "A 9- or 10-membered partially unsaturated fused ring group containing 1 or 2 oxygen atoms as atoms constituting the ring in addition to carbon atoms" refers to a 9- or 10-membered fused heterocyclic group containing 1 or 2 oxygen atoms as atoms constituting the ring in addition to carbon atoms and containing at least one saturated ring as a ring constituting the ring in the fused ring. Examples of the "9- or 10-membered partially unsaturated fused ring group containing 1 or 2 oxygen atoms as atoms constituting the ring in addition to carbon atoms" include 2,3-dihydrobenzo[b][1,4]dioxanyl, dihydrobenzofuranyl and benzo[d][1,3]dioxolyl. Preferred "9- or 10-membered partially unsaturated fused ring group containing 1 or 2 oxygen atoms as atoms constituting the ring in addition to carbon atoms" are dihydrobenzofuranyl and benzo[d][1,3]dioxolyl.

[0497] The expression that a substituent α is "optionally substituted" by a substituent β means that the substituent α is unsubstituted or is substituted by a substituent β at any substitutable position thereof (any hydrogen is replaced by a substituent γ). For example, "C 1-6 "Alkyl" refers to C 1-6 The alkyl group is unsubstituted or substituted with a hydroxy group at any substitutable position thereof.

[0498] The following illustrates specific embodiments of each substituent of the compound of formula [I] (hereinafter, also referred to as "compound [I]") and the compound of formula [Ia] (hereinafter, also referred to as "compound [Ia]"). Each group of compound [I] and compound [Ia] is not limited to its specific embodiment, and compound [I] and compound [Ia] also include a combination of two or more embodiments appropriately selected from the specific embodiments of each substituent.

[0499] First, specific embodiments of each substituent of compound [I] are illustrated below.

[0500] A is preferably CR 10 , where R 10 is hydrogen, hydroxy or halogen.

[0501] Cy is preferably

[0502] (1)C 6-10 Aryl, or

[0503] (2) A 5- or 6-membered heteroaryl group containing 1 or 2 nitrogen atoms as ring-constituting atoms in addition to carbon atoms.

[0504] R 3 Preferably C 1-4 alkyl.

[0505] R 4 Preferred is hydrogen.

[0506] R 5 Preferred is hydrogen.

[0507] R 6 Preferred is hydrogen.

[0508] R 7 and R 8 Both are preferably hydrogen.

[0509] R 9 Preferred is hydrogen.

[0510] m is preferably 1 or 2.

[0511] One of the preferred embodiments of compound [I] is a compound represented by formula [II]:

[0512]

[0513] in

[0514] Cy

[0515] (1)C 6-10 Aryl, or

[0516] (2) a 5- or 6-membered heteroaryl group which contains, in addition to carbon atoms, 1 or 2 nitrogen atoms as ring-constituting atoms;

[0517] R 1 for

[0518] (1)C 1-6 Alkyl, wherein the alkyl is optionally substituted by

[0519] (a) hydroxyl group,

[0520] (b) cyano,

[0521] (c)SO2R 11 , where R 11 C 1-4 Alkyl, or

[0522] (d) NHCOR 12 , where R 12 C 1-4 alkyl,

[0523] (2)C 2-4 Alkenyl, wherein the alkenyl is optionally NR 13 R 14 Substitution, where R 13 and R 14 are independently hydrogen or C 1-4 alkyl,

[0524] (3)C 1-4 Haloalkyl,

[0525] (4)C 1-6 an alkoxy group, wherein the alkoxy group is optionally substituted with a phenyl group,

[0526] (5)NR 15 R 16 , where R 15 and R 16 Each independently

[0527] (a) hydrogen,

[0528] (b)C 1-4 Alkyl, wherein the alkyl is optionally substituted by

[0529] (i) phenyl, wherein the phenyl is optionally substituted by halogen, or

[0530] (ii) pyridyl,

[0531] (c)C 1-4 Alkoxy, or

[0532] (d)C 3-4 Cycloalkyl,

[0533] (6)COR 17 , where R 17 C 1-4 alkyl,

[0534] (7)CONR 18 R 19 , where R 18 and R 19 Each independently

[0535] (a) hydrogen,

[0536] (b)C 1-4 alkyl,

[0537] (c)C 3-4 Cycloalkyl, or

[0538] (d)C 5-8 A bridged cycloalkyl group,

[0539] (8)C 3-4 Cycloalkyl, wherein the cycloalkyl is optionally substituted with

[0540] (a) hydroxyl group,

[0541] (b) halogen, or

[0542] (c) phenyl,

[0543] (9) a 4- to 7-membered heterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring, wherein the heterocycloalkyl group is optionally substituted by the following substituents

[0544] (a) hydroxyl group,

[0545] (b) oxo,

[0546] (c)NR 20 R 21 , where R 20 and R 21 are independently hydrogen or C 1-4 Alkyl, or

[0547] (d) phenyl,

[0548] (10) a 6- to 11-membered spiroheterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen atoms and oxygen atoms as atoms constituting the ring,

[0549] (11) phenyl, wherein the phenyl is optionally substituted by 1 or 2 halogens,

[0550] (12) a 5- to 10-membered heteroaryl group containing, in addition to carbon atoms, 1 to 3 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring, wherein the heteroaryl group is optionally substituted by 1 or 2 R 22 Replace, or

[0551] (13) an 8- to 10-membered saturated or partially unsaturated fused ring group containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen and oxygen atoms as ring-constituting atoms, wherein the fused ring group is optionally C 1-4 haloalkyl substitution;

[0552] R 2 The number of is m, each of which is independently

[0553] (1) Hydroxyl group,

[0554] (2) cyano group,

[0555] (3) Halogen,

[0556] (4)C 1-6 Alkyl, wherein the alkyl is optionally substituted by

[0557] (a) hydroxyl group, or

[0558] (b)C 3-4 Cycloalkyl,

[0559] (5)C 2-4 Alkenyl, wherein the alkenyl is optionally substituted with C 1-4 Alkoxy substitution,

[0560] (6)C 1-4 Haloalkyl,

[0561] (7)C 1-4 Alkoxy, wherein the alkoxy is optionally substituted with 1 to 3 substituents selected from the following:

[0562] (a) hydroxyl groups, and

[0563] (b) halogen,

[0564] (8)SR 23 , where R 23 C 1-4 alkyl,

[0565] (9)COR 24 , where R 24 Hydroxyl or C 1-4 alkyl,

[0566] (10)CONR 25 R 26 , where R 25 and R 26 Each independently

[0567] (a) hydrogen,

[0568] (b)C 1-6 Alkyl, or

[0569] (c)C 3-4 Cycloalkyl,

[0570] (11) SO2R 27 , where R 27 C 1-6 alkyl,

[0571] (12)C 3-4 Cycloalkyl,

[0572] (13) a 4- to 7-membered heterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring, wherein the heterocycloalkyl group is optionally substituted by 1 or 2 substituents selected from the following

[0573] (a) halogen,

[0574] (b)C 1-4 Alkyl, and

[0575] (c)C 1-4 Haloalkyl,

[0576] (14) a 5- to 9-membered bridged heterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring,

[0577] (15) a 6- to 11-membered spiroheterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring, or

[0578] (16) phenyl;

[0579] R 3 C 1-4 alkyl;

[0580] R 4 , R 5 , R 6 , R 7 , R 8 and R 9 All hydrogen;

[0581] R 10 for

[0582] (1) Hydrogen,

[0583] (2) hydroxyl group, or

[0584] (3) Halogen;

[0585] 1 or 2 R 22 Each independently

[0586] (1) Halogen,

[0587] (2)C 1-4 alkyl,

[0588] (3)C 1-4 Haloalkyl,

[0589] (4)C 1-4 Alkoxy,

[0590] (5) NHCOR 29 , where R 29 C 1-4 Alkyl, or

[0591] (6) SO2R 30 , where R 30 C 1-4 Alkyl; and

[0592] m is 1 or 2.

[0593] Preferred specific embodiments of compound [I] include the compounds of Examples 1 to 339 listed in Table 1-1 to Table 1-43 described later.

[0594] Next, specific embodiments of each substituent of compound [Ia] are exemplified below. Compound [Ia] includes compound [I].

[0595] A a Preferably CR 10a .

[0596] In another embodiment, A a Preferred is N.

[0597] A 2a Preferably CR 5a .

[0598] Cy a Preferably

[0599] (1)C 6-10 Aryl, or

[0600] (2) A 5- or 6-membered heteroaryl group containing 1 or 2 nitrogen atoms as ring-constituting atoms in addition to carbon atoms.

[0601] R 1a Preferably

[0602] (1)C 1-6 Alkyl, wherein the alkyl is optionally substituted by

[0603] (a) hydroxyl group,

[0604] (b) cyano,

[0605] (c)SO2R 11 , where R 11 C 1-4 Alkyl, or

[0606] (d) NHCOR 12 , where R 12 C 1-4 alkyl,

[0607] (2)C 2-4 Alkenyl, wherein the alkenyl is optionally substituted by 1 to 3 of the following substituents

[0608] (a)NR 13 R 14 , where R 13 and R 14 are independently hydrogen or C 1-4 alkyl,

[0609] (b) halogen,

[0610] (c)COR 35a , where R 35a Hydroxyl or C 1-4Alkoxy,

[0611] (d)CONR 36a R 37a , where R 36a and R 37a are independently hydrogen or C 1-4 Alkyl, or

[0612] (e) Partial structural formula:

[0613]

[0614] (3)C 1-6 an alkoxy group, wherein the alkoxy group is optionally substituted with a phenyl group,

[0615] (4)NR 15 R 16 , where R 15 and R 16 Each independently

[0616] (a) hydrogen,

[0617] (b)C 1-4 Alkyl, wherein the alkyl is optionally substituted by

[0618] (i) phenyl, wherein the phenyl is optionally substituted by halogen, or

[0619] (ii) pyridyl,

[0620] (c)C 1-4 Alkoxy, or

[0621] (d)C 3-4 Cycloalkyl,

[0622] (5)CONR 18a R 19a , where R 18a and R 19a Each independently

[0623] (a) hydrogen,

[0624] (b)C 1-4 an alkyl group, wherein the alkyl group is optionally substituted with a hydroxy group,

[0625] (c)C 3-4 Cycloalkyl,

[0626] (d)C 5-8 A bridged cycloalkyl group,

[0627] (e)C 1-4 haloalkyl, or

[0628] (f)C 1-4 Alkoxy,

[0629] (6) a 6- to 11-membered spiroheterocycloalkyl group which contains, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring,

[0630] (7) a 5- to 10-membered heteroaryl group containing, in addition to carbon atoms, 1 to 3 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring, wherein the heteroaryl group is optionally substituted by 1 or 2 R 22a Substitute, where each R 22a As defined above,

[0631] (8) an 8- to 10-membered saturated or partially unsaturated fused ring group containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen and oxygen atoms as ring-constituting atoms, wherein the fused ring group is optionally C 1-4 haloalkyl substituted, or

[0632] (9) a 5- to 7-membered partially unsaturated cyclic group which contains, in addition to carbon atoms, 1 or 2 nitrogen atoms as ring-constituting atoms, wherein the partially unsaturated cyclic group is optionally substituted by an oxo group and a C 1-4 Alkyl substitution.

[0633] In another embodiment, R 1a Preferably

[0634] (1)NR 15 R 16 , where R 15 and R 16 Each independently

[0635] (a) hydrogen,

[0636] (b)C 1-4 Alkyl, wherein the alkyl is optionally substituted by

[0637] (i) phenyl, wherein the phenyl is optionally substituted by halogen, or

[0638] (ii) pyridyl,

[0639] (c)C 1-4 Alkoxy, or

[0640] (d)C 3-4 Cycloalkyl,

[0641] (2)CONR 18a R 19a , where R 18a and R 19a Each independently

[0642] (a) hydrogen,

[0643] (b)C1-4 an alkyl group, wherein the alkyl group is optionally substituted with a hydroxy group,

[0644] (c)C 3-4 Cycloalkyl,

[0645] (d)C 5-8 A bridged cycloalkyl group,

[0646] (e)C 1-4 haloalkyl, or

[0647] (f)C 1-4 Alkoxy, or

[0648] (3) a 5- to 10-membered heteroaryl group containing, in addition to carbon atoms, 1 to 3 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring, wherein the heteroaryl group is optionally substituted by 1 or 2 R 22a Substitute, where each R 22a As defined above.

[0649] R 2a The number is m, each of which is independently preferably

[0650] (1) cyano group,

[0651] (2) Halogen, or

[0652] (3)C 1-6 Alkyl, wherein the alkyl is optionally substituted by

[0653] (a) hydroxyl group, or

[0654] (b)C 3-4 Cycloalkyl.

[0655] R 3a Preferably C 1-4 alkyl.

[0656] In another embodiment, R 3a Preferred is methyl.

[0657] R 4a Preferred is hydrogen.

[0658] R 5a Preferred is hydrogen.

[0659] R 6a , R 7a and R 8a The combination is preferably

[0660] (1) R 6a is hydrogen and R 7a and R 8a The two are a combination of hydrogen.

[0661] (2) R 6a is hydrogen, and R 7a and R 8a are bonded to each other to form a cyclopentane ring together with the spiro carbon atoms and the carbon atoms to which they are bonded, or

[0662] (3) R 6a and R 7a are bonded to each other to form a cyclopentane ring together with the spiro carbon atoms and the carbon atoms to which they are bonded and R 8a It is a combination of hydrogen.

[0663] In another embodiment, R 6a , R 7a and R 8a Preferably all of them are hydrogen.

[0664] R 9a Preferred is hydrogen.

[0665] R 10a Preferably

[0666] (1) Hydrogen,

[0667] (2) hydroxyl group, or

[0668] (3) Cyano group.

[0669] 1 or 2 R 22a Each independently preferably

[0670] (1) Halogen,

[0671] (2)C 1-4 alkyl,

[0672] (3)C 1-4 Haloalkyl,

[0673] (4)C 1-4 Alkoxy,

[0674] (5) NHCOR 29 , where R 29 C 1-4 alkyl,

[0675] (6) cyano, or

[0676] (7)C 3-4 Cycloalkyl.

[0677] m is preferably 1 or 2.

[0678] One of the preferred embodiments of compound [Ia] is a compound represented by formula [IIa]:

[0679]

[0680] in

[0681] A a , Cy a , R 1a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a and m are as defined above.

[0682] Another preferred embodiment of compound [Ia] is a compound represented by formula [IIIa]:

[0683]

[0684] in

[0685] Cy a , R 1a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a and m are as defined above.

[0686] Another preferred embodiment of compound [Ia] is a compound represented by formula [IVa]:

[0687]

[0688] in

[0689] Cy a , R 1b , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a and m are as defined above.

[0690] Another preferred embodiment of compound [Ia] is a compound represented by formula [Va]:

[0691]

[0692] in

[0693] Cy a , R 1b , R 2a , R 3a , R4a and m are as defined above.

[0694] Another preferred embodiment of compound [Ia] is a compound represented by formula [VIa]:

[0695]

[0696] in

[0697] Cy b , R 1b , R 2a , R 3a , R 4a and m are as defined above.

[0698] Another preferred embodiment of compound [Ia] is a compound represented by formula [VIIa]:

[0699]

[0700] in

[0701] Cy a , R 1b , R 2a , R 3a , R 5a , R 6a , R 7a , R 8a and m are as defined above.

[0702] Another preferred embodiment of compound [Ia] is a compound represented by formula [VIIIa]:

[0703]

[0704] in

[0705] Cy a , R 1b , R 2a , R 3a and m are as defined above.

[0706] Another preferred embodiment of compound [Ia] is a compound represented by formula [IXa]:

[0707]

[0708] in

[0709] Cy b , R 1b , R 2a , R 3a and m are as defined above.

[0710] Another preferred embodiment of compound [Ia] is a compound represented by formula [Xa]:

[0711]

[0712] in

[0713] Cy a , R 1a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 10a and m are as defined above.

[0714] Another preferred embodiment of compound [Ia] is a compound represented by formula [XIa]:

[0715]

[0716] in

[0717] Cy a , R 1a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 10a and m are as defined above.

[0718] Another preferred embodiment of compound [Ia] is a compound represented by formula [XIIa]:

[0719]

[0720] in

[0721] Cy a , R 1b , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 10a and m are as defined above.

[0722] Another preferred embodiment of compound [Ia] is a compound represented by formula [XIIIa]:

[0723]

[0724] in

[0725] Cy a , R 1b , R 2a , R 3a , R 4a , R 10a and m are as defined above.

[0726] Another preferred embodiment of compound [Ia] is a compound represented by formula [XIVa]:

[0727]

[0728] in

[0729] Cy b , R 1b , R 2a , R 3a , R 4a , R 10a and m are as defined above.

[0730] Another preferred embodiment of compound [Ia] is a compound represented by formula [XVa]:

[0731]

[0732] in

[0733] Cy a , R 1b , R 2a , R 3a , R 5a , R 6a , R 7a , R 8a , R 10a and m are as defined above.

[0734] Another preferred embodiment of compound [Ia] is a compound represented by formula [XVIa]:

[0735]

[0736] in

[0737] Cy a , R 1b , R 2a , R 3a , R 10a and m are as defined above.

[0738] Another preferred embodiment of compound [Ia] is a compound represented by formula [XVIIa]:

[0739]

[0740] in

[0741] Cy b , R 1b , R 2a , R 3a , R 10a and m are as defined above.

[0742] Another preferred embodiment of compound [Ia] is a compound represented by formula [XVIIIa]:

[0743]

[0744] in

[0745] Cy b , R 1b , R 2a and m are as defined above.

[0746] Another preferred embodiment of compound [Ia] is a compound represented by formula [XIXa]:

[0747]

[0748] in

[0749] R 1c for

[0750] (1)C 1-4 haloalkyl, wherein the haloalkyl is optionally substituted with hydroxy,

[0751] (2) COR 17a , where R 17a C 1-4 Alkyl or hydroxyl,

[0752] (3)C 3-4 Cycloalkyl, wherein the cycloalkyl is optionally substituted with

[0753] (a) hydroxyl group,

[0754] (b) halogen, or

[0755] (c) phenyl,

[0756] (4) a 4- to 7-membered heterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring, wherein the heterocycloalkyl group is optionally substituted by the following substituents

[0757] (a) hydroxyl group,

[0758] (b) oxo,

[0759] (c)NR 20 R 21 , where R 20 and R 21 are independently hydrogen or C 1-4 Alkyl, or

[0760] (d) phenyl, or

[0761] (5) Phenyl, wherein the phenyl group is optionally substituted by one or two of the following substituents

[0762] (a) halogen, or

[0763] (b)C 1-4 haloalkyl, and

[0764] Cy a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a and m are as defined above.

[0765] Another preferred embodiment of compound [Ia] is a compound represented by formula [XXa]:

[0766]

[0767] in

[0768] Cy a , R 1c , R 2a , R 3a , R 4a and m are as defined above.

[0769] Another preferred embodiment of compound [Ia] is a compound represented by formula [XXIa]:

[0770]

[0771] in

[0772] Cy b , R 1c , R 2a , R 3a , R 4a and m are as defined above.

[0773] Another preferred embodiment of compound [Ia] is a compound represented by formula [XXIIa]:

[0774]

[0775] in

[0776] Cy a , R 1c , R 2a , R 3a , R 5a , R 6a , R 7a , R 8a and m are as defined above.

[0777] Another preferred embodiment of compound [Ia] is a compound represented by formula [XXIIIa]:

[0778]

[0779] in

[0780] Cy a , R 1c , R 2a , R 3a and m are as defined above.

[0781] Another preferred embodiment of compound [Ia] is a compound represented by formula [XXIVa]:

[0782]

[0783] in

[0784] Cy b , R 1c , R 2a , R 3a and m are as defined above.

[0785] Another preferred embodiment of compound [Ia] is a compound represented by formula [XXVa]:

[0786]

[0787] in

[0788] Cy b , R 1c , R 2a and m are as defined above.

[0789] Another preferred embodiment of compound [Ia] is a compound represented by 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]:

[0790]

[0791] in

[0792] R 1b , R 2a and m are as defined above.

[0793] Another preferred embodiment of compound [Ia] is a compound represented by 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]:

[0794]

[0795] in

[0796] ma is 0, 1, or 2, and

[0797] R 1b and R 2a As defined above.

[0798] Another preferred embodiment of compound [Ia] is a compound represented by formula [XXVIIIa]:

[0799] in

[0800] Cy b , R 1b , R 2a , R 10a and m are as defined above.

[0801] Another preferred embodiment of compound [Ia] is a compound represented by formula [XXIXa]:

[0802]

[0803] in

[0804] Cy a , R 1c , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 10a and m are as defined above.

[0805] Another preferred embodiment of compound [Ia] is a compound represented by formula [XXXa]:

[0806]

[0807] in

[0808] Cy a , R 1c , R 2a , R 3a , R 4a , R 10a and m are as defined above.

[0809] Another preferred embodiment of compound [Ia] is a compound represented by formula [XXXIa]:

[0810]

[0811] in

[0812] Cy b , R 1c , R 2a , R 3a , R 4a , R 10a and m are as defined above.

[0813] Another preferred embodiment of compound [Ia] is a compound represented by formula [XXXIIa]:

[0814]

[0815] in

[0816] Cy a , R 1c , R 2a , R 3a , R 5a , R 6a , R 7a , R 8a , R 10a and m are as defined above.

[0817] Another preferred embodiment of compound [Ia] is a compound represented by formula [XXXIIIa]:

[0818]

[0819] in

[0820] Cy a , R 1c , R 2a , R3a , R 10a and m are as defined above.

[0821] Another preferred embodiment of compound [Ia] is a compound represented by formula [XXXIVa]:

[0822]

[0823] in

[0824] Cy b , R 1c , R 2a , R 3a , R 10a and m are as defined above.

[0825] Another preferred embodiment of compound [Ia] is a compound represented by formula [XXXVa]:

[0826]

[0827] in

[0828] Cy b , R 1c , R 2a , R 10a and m are as defined above.

[0829] Another preferred embodiment of compound [Ia] is a compound represented by 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]:

[0830]

[0831] in

[0832] R 1b , R 2a , R 10a and m are as defined above.

[0833] Another preferred embodiment of compound [Ia] is a compound represented by 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]:

[0834]

[0835] in

[0836] R 1b , R 2a , R 10a and ma are as defined above.

[0837] Preferred specific embodiments of compound [Ia] include the compounds of Examples 1 to 339 and Examples 2-001 to 2-172 listed in Table 1-1 to Table 1-61 described later.

[0838] "Pharmaceutically acceptable salt" may be any salt known in the art, as long as it is not associated with excessive toxicity. Specific examples thereof include salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases. Various forms of pharmaceutically acceptable salts are well known in the art, and they are described in the following documents.

[0839] (a) Berge et al., J. Pharm. Sci., 66, pp. 1-19 (1977),

[0840] (b) Stahl et al., "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002),

[0841] (c) Paulekuhn et al., J. Med. Chem, 50, pp. 6665–6672 (2007)

[0842] A pharmaceutically acceptable salt can be obtained by reacting compound [I] or compound [Ia] with an inorganic acid, an organic acid, an inorganic base or an organic base according to a known method.

[0843] Examples of the salt with an inorganic acid include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid and sulfuric acid, preferably salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid and hydrobromic acid.

[0844] Examples of salts with organic acids include salts with acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, dehydrated methylene citric acid, benzoic acid, benzenesulfonic acid, calcium edetate, camphoric acid, camphor-10-sulfonic acid, carbonic acid, citric acid, ethylenediaminetetraacetic acid, ethane-1,2-disulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glucoheptonic acid, glycollylarsanilic acid, hexylresorcinoic acid, acid), hydroxynaphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, lactobionic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, methylsulfuric acid, methylnitric acid, methylenebis(salicylic acid), galactonic acid, naphthalene-2-sulfonic acid, 2-naphthoic acid, 1,5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic acid, pantothenic acid, pectic acid, picric acid, propionic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, teoclic acid, thiocyanic acid, trifluoroacetic acid, p-toluenesulfonic acid, undecanoic acid, aspartic acid, and glutamic acid. Preferred are 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 and 2-hydroxy-1-ethanesulfonic acid.

[0845] Examples of the salt with an inorganic base include salts with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth and ammonium, preferably salts with sodium, potassium, calcium, magnesium and zinc.

[0846] Examples of the salt with an organic base include salts with arecoline, betaine, choline, clemizole, ethylenediamine, N-methylglucamine, N-benzylphenylethylamine, tris(hydroxymethyl)methylamine, arginine and lysine, preferably salts with tris(hydroxymethyl)methylamine, N-methylglucamine and lysine.

[0847] Compound [I] or Compound [Ia] or a pharmaceutically acceptable salt thereof may exist as a solvate. The term "solvate" refers to Compound [I] or Compound [Ia] or a pharmaceutically acceptable salt thereof coordinated with a solvent molecule. The solvate may be any pharmaceutically acceptable solvate, and includes hydrates, ethanolates, acetic acid solvates, dimethylsulfoxidates, etc. of Compound [I] or Compound [Ia] or a pharmaceutically acceptable salt thereof.

[0848] Specific examples include hemihydrate, monohydrate, dihydrate, monoacetic acid solvate and monoethanolate of compound [I] or compound [Ia], monohydrate of sodium salt of compound [I] or compound [Ia], and 2 / 3 ethanolate of monohydrochloride of compound [I] or compound [Ia]. These solvates can be obtained according to known methods.

[0849] Compound [I] or compound [Ia] may exist as tautomers. In this case, compound [I] or compound [Ia] may be a single tautomer or a mixture thereof.

[0850] Compound [I] or compound [Ia] may have a carbon-carbon double bond. In this case, compound [I] or compound [Ia] may be in the E form, the Z form or a mixture thereof.

[0851] Compound [I] or compound [Ia] may exist as stereoisomers, which should be regarded as cis / trans isomers. In this case, compound [I] or compound [Ia] may exist as cis, trans or a mixture thereof.

[0852] Compound [I] or Compound [Ia] may contain one or more asymmetric carbons. In this case, Compound [I] or Compound [Ia] may exist as a single enantiomer, a single diastereomer, a mixture of enantiomers, or a mixture of diastereomers.

[0853] Compound [I] or Compound [Ia] may exist as an atropisomer. In this case, Compound [I] or Compound [Ia] may exist as a single atropisomer or a mixture thereof.

[0854] Compound [I] or compound [Ia] may contain a plurality of structural features that give rise to the above isomers. In addition, compound [I] or compound [Ia] may contain the above isomers in any ratio.

[0855] The formulas, chemical structures and compound names indicated herein include all the above isomers that may exist, without specifying their stereochemistry, unless otherwise specified. For example, the structure represented by the following formula:

[0856]

[0857] Includes all of the following

[0858] (1) A mixture of two diastereomers (the stereochemistry of the asymmetric carbon marked with * is S or R), represented by the following formula:

[0859]

[0860] (2) a diastereomer wherein the stereochemistry of the asymmetric carbon marked with an * is S, and

[0861] (3) wherein the stereochemistry of the asymmetric carbon marked with * is a diastereomer of R,

[0862] Unless otherwise stated.

[0863] Diastereomeric mixtures may be separated into their individual diastereomers by conventional methods such as chromatography and crystallization or the individual diastereomers may be prepared by employing stereochemically unique starting materials or by synthetic methods utilizing stereoselective reactions.

[0864] Enantiomeric mixtures can be separated into each single enantiomer by methods well known in the art. For example, first, diastereomeric mixtures can be prepared by reacting enantiomeric mixtures with substantially pure enantiomeric compounds called chiral auxiliary agents. Next, the obtained diastereomeric mixtures can be separated into single diastereomers or substantially pure single diastereomers with high isomer ratios by conventional methods (such as fractional crystallization and chromatography). Finally, the isolated diastereomers can be converted into the desired enantiomers by removing the added chiral auxiliary by cracking. In addition, enantiomeric mixtures can also be directly separated by chromatography using chiral solid phases well known in the art. Alternatively, one of the enantiomers can also be obtained by using substantially pure optically active starting materials or by using chiral auxiliary agents and asymmetric catalysts to stereoselectively synthesize (asymmetric induction) prochiral intermediates.

[0865] The absolute stereoconfiguration may be determined by X-ray crystallography of crystalline products or intermediates. In such cases, the crystalline products or intermediates may be derivatized, if desired, with a reagent having an asymmetric center of known stereoconfiguration.

[0866] Compound [I] or compound [Ia] may be treated with isotopes [ 2 H(D), 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 18 O. 18 F. 35 S. 123I, etc.] labeling. For example, when compound [I] or compound [Ia] has a methyl group, the methyl group may be substituted by -CD3. Such labeled compound [I] or compound [Ia] is also included in the present invention. Compound [I] or compound [Ia] labeled with an isotope can be used for drugs, pharmacokinetic studies, in vitro and / or in vivo tests and / or diagnosis (e.g., positron emission tomography (PET), single photon emission computed tomography (SPECT)). An isotope-labeled reagent can be used instead of a non-isotope-labeled reagent to prepare an isotope-labeled compound [I] or compound [Ia] according to known methods or the methods described herein.

[0867] Compound [I] or compound [Ia] or a pharmaceutically acceptable salt thereof is preferably substantially purified compound [I] or compound [Ia] or a pharmaceutically acceptable salt thereof. More preferably, it is compound [I] or compound [Ia] or a pharmaceutically acceptable salt thereof purified to a purity of 80% or more.

[0868] The pharmaceutical composition of the present invention can be prepared by appropriately blending 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., according to methods known in the field of pharmaceutical preparations. The content of the active ingredient in the pharmaceutical composition varies depending on the dosage form, dosage, etc. For example, it is 0.1 to 100% by weight of the entire composition.

[0869] Examples of dosage forms of the pharmaceutical composition 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 external preparations, suppositories, injections, eye drops, nasal preparations and pulmonary preparations.

[0870] Examples of "pharmaceutically acceptable carriers" include various organic or inorganic carrier substances conventionally used as formulation materials, and specifically include excipients, disintegrants, binders, glidants, lubricants, etc. for solid preparations; solvents, solubilizers, suspending agents, isotonic agents, buffers, soothing agents, etc. for liquid preparations; and bases, emulsifiers, wetting agents, stabilizers, tranquilizers, dispersants, plasticizers, pH regulators, absorption promoters, gelling agents, preservatives, fillers, solvents, solubilizers, suspending agents, etc. for semi-solid preparations. If necessary, additives such as preservatives, antioxidants, colorants, sweeteners, etc. may be used.

[0871] Examples of the "excipient" include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, gum arabic and the like.

[0872] Examples of the "disintegrant" include carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, sodium carboxymethyl starch, cross-linked carboxymethylcellulose sodium, cross-linked polyvidone, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose and the like.

[0873] Examples of the "binder" include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, sodium carboxymethyl cellulose, gum arabic and the like.

[0874] Examples of the "glidant" include light anhydrous silicic acid, magnesium stearate and the like.

[0875] Examples of the "lubricant" include magnesium stearate, calcium stearate, talc and the like.

[0876] Examples of the "solvent" include purified water, ethanol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil and the like.

[0877] Examples of the "solubilizing agent" include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate and the like.

[0878] Examples of the "suspending agent" include benzalkonium chloride, carboxymethylcellulose, hydroxypropylcellulose, propylene glycol, povidone, methylcellulose, glyceryl monostearate and the like.

[0879] Examples of the "isotonic agent" include glucose, D-sorbitol, sodium chloride, D-mannitol and the like.

[0880] Examples of the "buffer" include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate and the like.

[0881] Examples of the "soothing agent" include benzyl alcohol and the like.

[0882] Examples of the “base” include water, animal and plant 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, polyols, hydrocarbons (white petrolatum, liquid paraffin, paraffin, etc.), hydrophilic petrolatum, purified lanolin, absorbent ointment, aqueous lanolin, hydrophilic ointment, starch, pullulan, gum arabic, tragacanth, gelatin, dextran, cellulose derivatives (methyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc.), synthetic polymers (carboxyvinyl polymers, sodium polyacrylate, polyvinyl alcohol, polyvinyl pyrrolidone, etc.), propylene glycol, polyethylene glycol (polyethylene glycol 200 to 600), and combinations of two or more types thereof.

[0883] Examples of the "preservative" include ethyl paraben, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid and the like.

[0884] Examples of the "antioxidant" include sodium sulfite, ascorbic acid and the like.

[0885] Examples of the "colorant" include food coloring (food coloring red No. 2 or No. 3, and food coloring yellow No. 4 or No. 5, etc.), β-carotene, and the like.

[0886] Examples of the "sweetener" include saccharin sodium, dipotassium glycyrrhizinate, aspartame and the like.

[0887] The pharmaceutical composition can be administered orally or parenterally (topical administration, rectal administration, intravenous administration, intramuscular administration and subcutaneous administration, etc.) to humans and mammals other than humans (mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cattle, horses, sheep, monkeys, etc.). The dosage (hereinafter also referred to as "therapeutically effective amount") varies according to the subject of administration, route of administration, target disease, symptoms, severity of disease, dosage form, etc. For example, when orally administered to humans (adult patients) (weight 60 kg), the lower limit of the therapeutically effective amount is, for example, about 0.01 mg, about 0.1 mg, about 0.5 mg, about 1 mg, about 10 mg, about 20 mg or about 50 mg per day, and the upper limit of the therapeutically effective amount is, for example, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 500 mg or about 1000 mg per day. The amount can be administered once, twice, three times or more per day.

[0888] The expression "inhibiting PLD" means eliminating or weakening the activity of PLD by inhibiting its function. For example, it means inhibiting the function of PLD based on the conditions in Experimental Example 1 and / or Experimental Example 2 described below. Inhibiting the function of PLD or eliminating or weakening the activity of PLD is preferably performed in human clinical indications.

[0889] One embodiment of "inhibiting PLD" is "inhibiting PLD1"

[0890] The expression "inhibiting PLD1" means eliminating or weakening the activity of PLD1 by inhibiting its function. For example, it means inhibiting the function of PLD1 based on the conditions in Experimental Example 1 and / or Experimental Example 2 described below. Inhibiting the function of PLD1 or eliminating or weakening the activity of PLD1 is preferably performed in human clinical indications.

[0891] One embodiment of "inhibiting PLD" is "inhibiting PLD1 / 2"

[0892] The expression "inhibit PLD1 / 2" means eliminating or weakening the activity of PLD1 and PLD2 by inhibiting their functions. For example, it means inhibiting the functions of PLD1 and PLD2 based on the conditions in Experimental Example 1 and / or Experimental Example 2 described below. Inhibiting the functions of PLD1 and PLD2 or eliminating or weakening the activities of PLD1 and PLD2 is preferably performed in human clinical indications.

[0893] "Inhibiting PLD" is preferably "inhibiting human PLD".

[0894] "PLD inhibitor" refers to a substance that binds to PLD and inhibits the function of PLD. "PLD inhibitor" is preferably a "human PLD inhibitor".

[0895] One embodiment of a "PLD inhibitor" is a "PLD1 inhibitor".

[0896] A "PLD1 inhibitor" refers to a substance that binds to PLD1 and inhibits the function of PLD1. A "PLD1 inhibitor" is preferably a "human PLD1 inhibitor".

[0897] One embodiment of a "PLD inhibitor" is a "PLD1 / 2 inhibitor".

[0898] "PLD1 / 2 inhibitor" refers to a substance that binds to PLD1 and PLD2 and inhibits the functions of PLD1 and PLD2. "PLD1 / 2 inhibitor" is preferably a "human PLD1 / 2 inhibitor".

[0899] Compound [I] or compound [Ia] or a pharmaceutically acceptable salt thereof has PLD inhibitory activity and can be used for treating and / or preventing various diseases or conditions that are expected to be improved by controlling PLD activity. Examples of various diseases or conditions that are expected to be improved by controlling PLD activity include thrombosis (e.g., arterial thrombosis, acute coronary syndrome, stable angina, unstable angina, non-ST-segment elevation myocardial infarction, ST-segment elevation myocardial infarction, ischemic stroke, non-cardioembolic stroke, atherosclerotic stroke, cryptogenic stroke, embolic stroke of unknown origin (ESUS), lacunar stroke, transient ischemic attack, peripheral arterial disease, etc.), perioperative and postoperative thrombosis associated with revascularization (coronary artery bypass grafting, percutaneous coronary intervention, carotid endarterectomy, carotid artery stenting, thrombolysis, lower limb 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.).

[0900] The term "treating" as used herein includes ameliorating symptoms, preventing severity, maintaining remission, preventing exacerbations, secondary prevention, and preventing relapses.

[0901] As used herein, the term "preventing" includes inhibiting the onset of symptoms.

[0902] In some embodiments, the PLD inhibitor or pharmaceutical composition may be provided in the form of a kit (administration, treatment and / or prevention kit, etc.), package (packaged product, etc.) and pharmaceutical set (and / or container), and the associated written material indicates that it can or should be used to prevent or treat the above-mentioned diseases. Such kits, packages and pharmaceutical sets may contain one or more containers containing PLD inhibitors and / or other drugs or drugs (or components). Examples of such kits, packages and pharmaceutical sets include commercial kits, commercial packages and commercial drugs, which are appropriately directed to the treatment and / or prevention of the target disease. Examples of written materials contained therein include precautions or package inserts in the form of guidance by a governmental organization that regulates the manufacture, use or sale of drugs or biological products, which show the approval of the governmental organization for the manufacture, use or sale of products related to human administration. In the above-mentioned kits, packages and pharmaceutical sets, packaging products may also be included, and structures constructed for suitable administration steps may also be included, and structures constructed to achieve more preferred medical treatment and / or prevention (including the treatment and / or prevention of the target disease) may also be included.

[0903] The 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 "concomitant drug") (hereinafter referred to as concomitant use) as long as the drug efficacy is not impaired. The administration time is not limited, and they can be administered to the subject at the same time or at a given interval. In addition, the combination of compound [I] or compound [Ia] or a pharmaceutically acceptable salt thereof and a concomitant drug may also be administered as a single preparation. The administration form of the concomitant drug is not particularly limited, and it only requires that the compound [I] or compound [Ia] of the present invention or a pharmaceutically acceptable salt thereof be combined with the concomitant drug.

[0904] The dosage of the combined drug can be appropriately selected based on the dosage used in clinical practice. The ratio of the compound [I] or compound [Ia] of the present invention or a pharmaceutically acceptable salt thereof to the combined drug can be appropriately selected according to the subject of administration, route of administration, target disease, symptoms and combination.

[0905] The combination of PLD inhibitors with existing antithrombotic agents is expected to inhibit arterial thrombosis without increasing the risk of bleeding.

[0906] Examples of combined medications include antiplatelet agents, anticoagulants, thrombolytic agents, and the like.

[0907] Examples of antiplatelet agents include aspirin, ticlopidine, cilostazol, clopidogrel, prasugrel, ticagrelor, selatogrel, glenzoshimab, sarunfiban, revacept, anfibotide, PZ-128, vicargrel, tirofiban, abciximab and the like.

[0908] Examples of anticoagulants include warfarin, rivaroxaban, apixaban, edoxaban, dabigatran, heparin, heparinoids, fondaparinux, argatroban, ticafarine, abelacimab, milvexian, asundexian, BAY-2306001, TRx1, osocimab, AB-023, dimolegin, and the like.

[0909] Examples of thrombolytic agents include recombinant tissue plasminogen activator, urokinase, and the like.

[0910] The description herein of preferred embodiments and options of the compounds, methods, uses and compositions of the invention also includes the description of combinations of such preferred embodiments and options, as long as they are combinable and consistent.

[0911] [General preparation method]

[0912] The general preparation method of compound [I] or compound [Ia] or a pharmaceutically acceptable salt thereof is explained below. However, the general preparation method of compound [I] or compound [Ia] or a pharmaceutically acceptable salt thereof is not limited to these preparation methods. Unless otherwise specified, the salt of each compound in the general preparation method can be appropriately selected from the above-mentioned "pharmaceutically acceptable salts".

[0913] The compound obtained in each step may be isolated or purified according to a method known per se (such as distillation, recrystallization and column chromatography) if necessary, or may be directly used in the next step without isolation or purification.

[0914] Room temperature as used herein refers to a temperature in an uncontrolled state, and one embodiment includes 1°C to 40°C.

[0915] The abbreviations used are as follows.

[0916] THF: Tetrahydrofuran

[0917] DMF: N,N-dimethylformamide

[0918] CDCl3: deuterated chloroform

[0919] Pt-C: Platinum activated carbon

[0920] Pd-C: Palladium activated carbon

[0921] DMSO: dimethyl sulfoxide

[0922] LiHMDS: Lithium bis(trimethylsilyl)amide

[0923] NaHMDS: Sodium bis(trimethylsilyl)amide

[0924] TBAF: Tetra-n-butylammonium fluoride

[0925] DBU: Diazabicycloundecene

[0926] CDI: 1,1'-Carbonyldiimidazole

[0927] WSC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0928] HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine-3-oxide hexafluorophosphate

[0929] DMT-MM: 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine chloride

[0930] HOAt: 1-Hydroxy-7-azobenzotriazole

[0931] DMAP: 4-dimethylaminopyridine

[0932] CPME: Cyclopentyl Methyl Ether

[0933] DMA: dimethylacetamide

[0934] Boc2O: di-tert-butyl dicarbonate

[0935] LDA: lithium diisopropylamide

[0936] Preparation method A1: Preparation method of compound [I] or its salt

[0937] Compound [I] or a salt thereof can be produced, for example, according to the following production method A1.

[0938]

[0939] in

[0940] A, Cy, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7, R 8 , R 9 and m are as defined above, and

[0941] L 11 is a hydroxyl group or a leaving group (such as halogen, etc.).

[0942] (Step A1-1)

[0943] Compound [I] or a salt thereof can be produced by reacting compound [A1-1] or a salt thereof with compound [A1-2] or a salt thereof.

[0944] For example, when L 11 In the case of a halogen atom, the compound [I] or a salt thereof can be prepared by reacting the compound [A1-1] or a salt thereof with the compound [A1-2] or a salt thereof in a solvent in the presence of a base.

[0945] Examples of the base include triethylamine, N,N-diisopropylethylamine, etc. A preferred base is N,N-diisopropylethylamine.

[0946] Examples of the solvent include DMF, acetonitrile, THF, etc. A preferred solvent is DMF.

[0947] The reaction temperature is, for example, 0°C to 60°C, and preferably 20°C to 40°C.

[0948] Or, for example, when L 11 In the case of a hydroxyl group, 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.

[0949] Examples of the base include triethylamine, N,N-diisopropylethylamine, etc. A preferred base is N,N-diisopropylethylamine.

[0950] Examples of the condensing agent include WSC, HATU, DMT-MM, etc. A preferred condensing agent is WSC or HATU.

[0951] Examples of the solvent include DMF, acetonitrile, methanol, THF, etc. A preferred solvent is DMF.

[0952] The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C.

[0953] The compound [A1-1] or a salt thereof may be a commercially available product, or may be produced from a commercially available product by a known method, for example, it may also be produced according to the production methods B1 and B2 described below.

[0954] The compound [A1-2] or a salt thereof may be a commercially available product, or may be prepared from a commercially available product by a known method.

[0955] Alternatively, compound [I] or a salt thereof can also be prepared by using a compound having a molecule which can be converted to R by a known reaction. 2 The preparation method is carried out by replacing compound [A1-1] or a salt thereof with a compound having a functional group on R or a protected functional group on Cy, to obtain a compound or a salt thereof corresponding to compound [I], and then converting the functional group of the compound or the salt thereof to R 2 .

[0956] Preparation method A2: Preparation method of compound [I-2] or its salt

[0957] Compound [I] or a salt thereof (wherein R 1 NR 31 R 32 ), that is, compound [I-2] or a salt thereof, can be produced, for example, according to the following production method A2.

[0958]

[0959] in

[0960] A, Cy, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and m are as defined above, and

[0961] R 31 and R 32 Each independently

[0962] (1) Hydrogen,

[0963] (2)C 1-4 Alkyl, wherein the alkyl is optionally substituted by

[0964] (a) phenyl, wherein the phenyl is optionally substituted by halogen, or

[0965] (b) pyridyl,

[0966] (3)C 1-4 Alkoxy, or

[0967] (4)C 3-4 Cycloalkyl, or

[0968] R 31 and R 32 bonded to each other to form, together with the nitrogen atoms to which they are bonded,

[0969] (5) a 4- to 7-membered heterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring, wherein the heterocycloalkyl group is optionally substituted by the following substituents

[0970] (a) hydroxyl group,

[0971] (b) oxo,

[0972] (c)NR 20 R 21 , where R 20 and R 21 are independently hydrogen or C 1-4 Alkyl, or

[0973] (d) phenyl,

[0974] (6) a 6- to 11-membered spiroheterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring, or

[0975] (7) an 8- to 10-membered saturated or partially unsaturated fused ring group which, in addition to carbon atoms, contains 1 to 4 heteroatoms selected from nitrogen and oxygen atoms as ring-constituting atoms, wherein the fused ring group is optionally C 1-4 Haloalkyl substitution.

[0976] (Step A2-1)

[0977] The compound [I-2] or a salt thereof can be produced by reacting the compound [A1-1] or a salt thereof with the compound [A2-1] or a salt thereof in a solvent in the presence of a ureating agent and a base.

[0978] Examples of the ureating agent include CDI, triphosgene, etc. A preferred ureating agent is CDI.

[0979] Examples of the base include N-methylmorpholine, triethylamine, N,N-diisopropylethylamine, etc. A preferred base is N-methylmorpholine.

[0980] Examples of the solvent include THF, acetonitrile, DMF, water, a mixed solvent thereof, etc. A preferred solvent is THF or a mixed solvent of THF and water.

[0981] The reaction temperature is, for example, 0°C to 80°C, preferably 30°C to 60°C.

[0982] The compound [A2-1] or a salt thereof may be a commercially available product, or may be prepared from a commercially available product by a known method.

[0983] Alternatively, compound [I-2] or a salt thereof can also be prepared by using a compound having a molecule which can be converted into R by a known reaction. 2The preparation method is carried out by replacing compound [A1-1] or a salt thereof with a compound having a functional group on R or a protected functional group on Cy, to obtain a compound corresponding to compound [I-2] or a salt thereof, and then converting the functional group of the compound or the salt thereof to R 2 .

[0984] Preparation method A3: Preparation method of compound [Ia] or its salt

[0985] Compound [Ia] or a salt thereof can be produced, for example, according to the following production method A3.

[0986]

[0987] in

[0988] 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 as defined above, and

[0989] L 11a is a hydroxyl group or a leaving group (such as halogen, etc.).

[0990] (Step A3-1)

[0991] 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.

[0992] For example, when L 11a In the case of a halogen atom, the compound [Ia] or a salt thereof can be produced by reacting the compound [A3-1] or a salt thereof with the compound [A3-2] or a salt thereof in a solvent in the presence of a base.

[0993] Examples of the base include triethylamine, N,N-diisopropylethylamine, etc. A preferred base is N,N-diisopropylethylamine.

[0994] Examples of the solvent include DMF, acetonitrile, THF, etc. A preferred solvent is DMF.

[0995] The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C.

[0996] Or, for example, when L 11aIn the case of a hydroxy group, 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.

[0997] Examples of the base include triethylamine, N,N-diisopropylethylamine, etc. A preferred base is N,N-diisopropylethylamine.

[0998] Examples of the condensing agent include WSC, HATU, DMT-MM, etc. A preferred condensing agent is WSC or HATU.

[0999] Examples of the solvent include DMF, acetonitrile, methanol, THF, etc. A preferred solvent is DMF.

[1000] The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C.

[1001] The compound [A3-1] or a salt thereof may be a commercially available product, or may be produced from a commercially available product by a known method, for example, it may also be produced according to Production Methods B3 and B4 described below.

[1002] The compound [A3-2] or a salt thereof may be a commercially available product, or may be prepared from a commercially available product by a known method.

[1003] Alternatively, compound [Ia] or a salt thereof can also be prepared by using a compound having a molecule which can be converted to R by a known reaction. 2a Functional groups or Cy a The preparation method is carried out by replacing compound [A3-1] or a salt thereof with a compound having a protected functional group on the compound [A3-1] or a salt thereof to obtain a compound corresponding to compound [Ia] or a salt thereof, and then converting the functional group of the compound or the salt thereof to R 2a .

[1004] Preparation method A4: Preparation method of compound [Ia-2] or its salt

[1005] Compound [Ia] or a salt thereof (wherein R 1a NR 31 R 32 ), that is, compound [Ia-2] or a salt thereof, can be prepared, for example, according to the following preparation method A4.

[1006]

[1007] in

[1008] A a , Cy a , R 2a , R 3a , R 4a , R 5a , R6a , R 7a , R 8a , R 9a , R 31 , R 32 and m are as defined above.

[1009] (Step A4-1)

[1010] The compound [Ia-2] or a salt thereof can be produced by reacting the compound [A3-1] or a salt thereof with the compound [A2-1] or a salt thereof in a solvent in the presence of a ureidating agent and a base.

[1011] Examples of the ureating agent include CDI, triphosgene, etc. A preferred ureating agent is CDI.

[1012] Examples of the base include N-methylmorpholine, triethylamine, N,N-diisopropylethylamine, etc. A preferred base is N-methylmorpholine.

[1013] Examples of the solvent include THF, acetonitrile, DMF, water, a mixed solvent thereof, etc. A preferred solvent is THF or a mixed solvent of THF and water.

[1014] The reaction temperature is, for example, 0°C to 80°C, preferably 30°C to 60°C.

[1015] Alternatively, compound [Ia-2] or a salt thereof can also be prepared by using a compound having a molecule which can be converted to R by a known reaction. 2a Functional groups or Cy a The preparation method is carried out by replacing compound [A3-1] or a salt thereof with a compound having a protected functional group on the compound [A3-1] or a salt thereof to obtain a compound corresponding to compound [Ia-2] or a salt thereof, and then converting the functional group of the compound or the salt thereof to R 2a .

[1016] Preparation method B1: Preparation method of compound [B1-7] or its salt

[1017] Compound [A1-1] or a salt thereof (for use in the preparation methods A1 and A2), wherein A is CR 10 And R 9 is hydrogen, that is, compound [B1-7] or a salt thereof can be produced, for example, according to the following production method B1.

[1018]

[1019] in

[1020] Cy, R 2 , R 3 , R 4 , R 5 , R 6 , R7 , R 8 , R 10 and m are as defined above, and

[1021] P 11 is a protecting group for amine (for example, tert-butyloxycarbonyl, benzyloxycarbonyl, etc.).

[1022] (Step B1-1)

[1023] The compound [B1-2] or a salt thereof can be prepared by reacting the compound [B1-1] or a salt thereof with trimethylsilyl cyanide in a solvent in the presence of a catalyst.

[1024] Examples of the catalyst include lithium chloride, DMAP, etc. A preferred catalyst is lithium chloride or DMAP.

[1025] Examples of the solvent include THF, acetonitrile, etc. A preferred solvent is THF.

[1026] The reaction temperature is, for example, 0°C to 60°C, preferably 15°C to 30°C.

[1027] The compound [B1-1] or a salt thereof may be a commercially available product, or may be prepared from a commercially available product by a known method.

[1028] (Step B1-2)

[1029] Compound [B1-4] or a salt thereof can be prepared by reacting compound [B1-2] or a salt thereof with compound [B1-3] or a salt thereof in a solvent in the presence of a catalyst and a base. Step B1-1 and Step B1-2 can also be carried out in one pot.

[1030] Examples of the catalyst include lithium chloride, DMAP, etc. A preferred catalyst is lithium chloride or DMAP.

[1031] Examples of the base include LiHMDS, NaHMDS, LDA, n-butyllithium, etc. A preferred base is LiHMDS or NaHMDS.

[1032] Examples of the solvent include THF, n-hexane, toluene, etc. A preferred solvent is THF or toluene.

[1033] The reaction temperature is, for example, -100°C to 0°C, preferably -78°C to -50°C.

[1034] The compound [B1-3] or a salt thereof may be a commercially available product, or may be produced from a commercially available product by a known method, for example, it may also be produced according to Production Method C1 described below.

[1035] (Step B1-3)

[1036] The compound [B1-5] or a salt thereof can be prepared by reacting the compound [B1-4] or a salt thereof in a solvent in the presence of a desilylation agent and an acid.

[1037] Examples of the desilylation agent include TBAF, hydrogen fluoride-pyridine, etc. A preferred desilylation agent is TBAF.

[1038] Examples of the acid include acetic acid, etc. A preferred acid is acetic acid.

[1039] Examples of the solvent include THF, acetonitrile, etc. A preferred solvent is THF.

[1040] The reaction temperature is, for example, 0°C to 60°C, preferably 15°C to 30°C.

[1041] (Step B1-4)

[1042] The compound [B1-6] or a salt thereof can be prepared by reacting the compound [B1-5] or a salt thereof in a solvent in the presence of a base, CDI and hydrazine monohydrate.

[1043] Examples of the base include DBU, N-methylimidazole, etc. A preferred base is DBU.

[1044] Examples of the solvent include THF, DMF, acetonitrile, etc. A preferred solvent is THF or DMF.

[1045] The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C.

[1046] (Step B1-5)

[1047] The compound [B1-7] or a salt thereof can be produced by reacting the compound [B1-6] or a salt thereof in a solvent in the presence of an acid.

[1048] Examples of the acid include hydrochloric acid, acetic acid, etc. A preferred acid is hydrochloric acid.

[1049] Examples of the solvent include THF, water, toluene and the like, and a preferred solvent is THF.

[1050] The reaction temperature is, for example, 15 to 120°C, preferably 20 to 60°C.

[1051] Alternatively, compound [B1-7] or a salt thereof can also be prepared by using a compound having a molecule which can be converted into R by a known reaction. 2 The preparation method is carried out by replacing compound [B1-1] or a salt thereof with a compound having a functional group on R or a protected functional group on Cy, to obtain a compound corresponding to compound [B1-7] or a salt thereof, and then converting the functional group of the compound or the salt thereof to R 2 .

[1052] Preparation method B2: Preparation method of compound [B2-8] or its salt

[1053] Compound [A1-1] or a salt thereof (for use in the preparation methods A1 and A2), wherein A is N and R 9 is hydrogen, that is, compound [B2-8] or a salt thereof can be produced, for example, according to the following production method B2.

[1054]

[1055] in

[1056] Cy, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and m are as defined above, and

[1057] P 12 and P 13 Each is independently a protecting group for an amine (eg, tert-butyloxycarbonyl, etc.).

[1058] (Step B2-1)

[1059] The compound [B2-2] or a salt thereof can be produced by reacting the compound [B1-2] or a salt thereof with the compound [B2-1] or a salt thereof according to step B1-2.

[1060] The compound [B2-1] or a salt thereof may be a commercially available product, or may be prepared from a commercially available product by a known method.

[1061] (Step B2-2)

[1062] The compound [B2-3] or a salt thereof can be produced by reacting the compound [B2-2] or a salt thereof according to step B1-3.

[1063] (Step B2-3)

[1064] The compound [B2-4] or a salt thereof can be produced by reacting the compound [B2-3] or a salt thereof according to step B1-4.

[1065] (Step B2-4)

[1066] The compound [B2-5] or a salt thereof can be produced by reacting the compound [B2-4] or a salt thereof according to step B1-5.

[1067] (Step B2-5)

[1068] The compound [B2-7] or a salt thereof can be produced by reacting the compound [B2-5] or a salt thereof with the compound [B2-6] or a salt thereof in a solvent in the presence of a base.

[1069] Examples of the base include triethylamine, N,N-diisopropylethylamine, etc. A preferred base is triethylamine.

[1070] Examples of the solvent include methanol, acetonitrile, THF, etc. A preferred solvent is methanol.

[1071] The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C.

[1072] The compound [B2-6] or a salt thereof may be a commercially available product, or can be prepared from a commercially available product by a known method.

[1073] (Step B2-6)

[1074] Compound [B2-8] or a salt thereof can be prepared by removing the protective group P of compound [B2-7] or a salt thereof by a deprotection reaction. 13 The deprotection reaction can be carried out in a suitable 13 type of conditions.

[1075] For example, when P 13 In the case of a tert-butoxycarbonyl group, the compound [B2-8] or a salt thereof can be prepared by reacting the compound [B2-7] or a salt thereof with an acid in a solvent.

[1076] Examples of the acid include hydrochloric acid, trifluoroacetic acid, etc. A preferred acid is hydrochloric acid.

[1077] Examples of the solvent include CPME, ethyl acetate, etc. The preferred solvent is CPME or ethyl acetate.

[1078] The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C.

[1079] Alternatively, compound [B2-8] or a salt thereof can also be prepared by using a compound having a molecule which can be converted into R by a known reaction. 2 The preparation method is carried out by replacing compound [B1-2] or a salt thereof with a compound having a functional group on R or a protected functional group on Cy, to obtain a compound corresponding to compound [B2-8] or a salt thereof, and then converting the functional group of the compound or the salt thereof to R 2 .

[1080] Preparation method B3: Preparation method of compound [B3-7] or its salt

[1081] Compound [A3-1] or a salt thereof (for use in the preparation methods A3 and A4), wherein A a CR 10a And R9a is hydrogen, that is, compound [B3-7] or a salt thereof can be produced, for example, according to the following production method B3.

[1082]

[1083] in

[1084] A 2a , Cy a , R2 a 、R3 a 、R4 a 、R6 a 、R7 a 、R8 a , R 10a and m are as defined above, and

[1085] P 11a It is a protecting group for amine (eg, tert-butyloxycarbonyl, benzyloxycarbonyl, etc.).

[1086] (Step B3-1)

[1087] The compound [B3-2] or a salt thereof can be prepared by reacting the compound [B3-1] or a salt thereof with trimethylsilyl cyanide in a solvent in the presence of a catalyst.

[1088] Examples of the catalyst include lithium chloride, DMAP, etc. A preferred catalyst is lithium chloride or DMAP.

[1089] Examples of the solvent include THF, acetonitrile, etc. A preferred solvent is THF.

[1090] The reaction temperature is, for example, 0°C to 60°C, preferably 15°C to 30°C.

[1091] The compound [B3-1] or a salt thereof may be a commercially available product, or may be prepared from a commercially available product by a known method.

[1092] (Step B3-2)

[1093] Compound [B3-4] or a salt thereof can be prepared by reacting compound [B3-2] or a salt thereof with compound [B3-3] or a salt thereof in a solvent in the presence of a catalyst and a base. Step B3-1 and Step B3-2 can also be carried out in one pot.

[1094] Examples of the catalyst include lithium chloride, DMAP, etc. A preferred catalyst is lithium chloride or DMAP.

[1095] Examples of the base include LiHMDS, NaHMDS, LDA, n-butyllithium, etc. A preferred base is LiHMDS or NaHMDS.

[1096] Examples of the solvent include THF, n-hexane, toluene, etc. A preferred solvent is THF or toluene.

[1097] The reaction temperature is, for example, -100°C to 0°C, and preferably -78°C to -50°C.

[1098] The compound [B3-3] or a salt thereof may be a commercially available product, or may be produced from a commercially available product by a known method, for example, it may also be produced according to Production Method C2 described below.

[1099] (Step B3-3)

[1100] The compound [B3-5] or a salt thereof can be prepared by reacting the compound [B3-4] or a salt thereof in a solvent in the presence of a desilylation agent and an acid.

[1101] Examples of the desilylation agent include TBAF, hydrogen fluoride-pyridine, etc. A preferred desilylation agent is TBAF.

[1102] Examples of the acid include acetic acid, etc. A preferred acid is acetic acid.

[1103] Examples of the solvent include THF, acetonitrile, etc. A preferred solvent is THF.

[1104] The reaction temperature is, for example, 0°C to 60°C, preferably 15°C to 30°C.

[1105] (Step B3-4)

[1106] The compound [B3-6] or a salt thereof can be prepared by reacting the compound [B3-5] or a salt thereof in a solvent in the presence of a base, CDI and hydrazine monohydrate.

[1107] Examples of the base include DBU, N-methylimidazole, etc. A preferred base is DBU.

[1108] Examples of the solvent include THF, DMF, acetonitrile, etc. A preferred solvent is THF or DMF.

[1109] The reaction temperature is, for example, 0°C to 60°C, and preferably 20°C to 40°C.

[1110] (Step B3-5)

[1111] The compound [B3-7] or a salt thereof can be produced by reacting the compound [B3-6] or a salt thereof in a solvent in the presence of an acid.

[1112] Examples of the acid include hydrochloric acid, acetic acid, etc. A preferred acid is hydrochloric acid.

[1113] Examples of the solvent include THF, water, toluene, etc. A preferred solvent is THF.

[1114] The reaction temperature is, for example, 15 to 120°C, preferably 20 to 60°C.

[1115] Alternatively, compound [B3-7] or a salt thereof can also be prepared by using a compound having a molecule which can be converted to R by a known reaction. 2a Functional groups or Cy a The preparation method is carried out by replacing compound [B3-1] or a salt thereof with a compound having a protected functional group on R or a salt thereof to obtain a compound corresponding to compound [B3-7] or a salt thereof, and then converting the functional group of the compound or the salt thereof to R 2a .

[1116] Preparation method B4: Preparation method of compound [B4-8] or its salt

[1117] Compound [A3-1] or a salt thereof (for use in the preparation methods A3 and A4), wherein A a N and R 9a is hydrogen, that is, compound [B4-8] or a salt thereof can be produced, for example, according to the following production method B4.

[1118]

[1119] in

[1120] A 2a , Cy a , R 2a , R 3a , R 4a , R 6a , R 7a , R 8a and m are as defined above, and

[1121] P 12a and P 13a Each is independently a protecting group for an amine (eg, tert-butyloxycarbonyl, benzyloxycarbonyl, etc.).

[1122] (Step B4-1)

[1123] The compound [B4-2] or a salt thereof can be produced by reacting the compound [B3-2] or a salt thereof with the compound [B4-1] or a salt thereof according to step B3-2.

[1124] The compound [B4-1] or a salt thereof may be a commercially available product, or may be prepared from a commercially available product by a known method.

[1125] (Step B4-2)

[1126] The compound [B4-3] or a salt thereof can be produced by reacting the compound [B4-2] or a salt thereof according to step B3-3.

[1127] (Step B4-3)

[1128] The compound [B4-4] or a salt thereof can be produced by reacting the compound [B4-3] or a salt thereof according to step B3-4.

[1129] (Step B4-4)

[1130] The compound [B4-5] or a salt thereof can be produced by reacting the compound [B4-4] or a salt thereof according to step B3-5.

[1131] (Step B4-5)

[1132] The compound [B4-7] or a salt thereof can be produced by reacting the compound [B4-5] or a salt thereof with the compound [B4-6] or a salt thereof in a solvent in the presence of a base.

[1133] Examples of the base include triethylamine, N,N-diisopropylethylamine, etc. A preferred base is triethylamine.

[1134] Examples of the solvent include methanol, acetonitrile, THF, etc. A preferred solvent is methanol.

[1135] The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C.

[1136] The compound [B4-6] or a salt thereof may be a commercially available product, or can be prepared from a commercially available product by a known method.

[1137] (Step B4-6)

[1138] Compound [B4-8] or a salt thereof can be prepared by removing the protective group P of compound [B4-7] or a salt thereof by a deprotection reaction. 13a The deprotection reaction can be carried out in a suitable 13a type of conditions.

[1139] For example, when P 13a In the case of a tert-butoxycarbonyl group, the compound [B4-8] or a salt thereof can be prepared by reacting the compound [B4-7] or a salt thereof with an acid in a solvent.

[1140] Examples of the acid include hydrochloric acid, trifluoroacetic acid, etc. A preferred acid is hydrochloric acid.

[1141] Examples of the solvent include CPME, ethyl acetate, etc. The preferred solvent is CPME or ethyl acetate.

[1142] The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C.

[1143] Alternatively, compound [B4-8] or a salt thereof can also be prepared by using a compound having a molecule which can be converted into R by a known reaction. 2a Functional groups or Cy a The preparation method is carried out by replacing compound [B3-2] or a salt thereof with a compound having a protected functional group on R or a salt thereof to obtain a compound corresponding to compound [B4-8] or a salt thereof, and then converting the functional group of the compound or the salt thereof to R 2a .

[1144] Preparation method C1: Preparation method of compound [C1-9] or its salt

[1145] Compound [B1-3] or a salt thereof (for use in the preparation method B1), wherein R 10 is hydrogen, that is, compound [C1-9] or a salt thereof can be produced, for example, according to the following production method C1.

[1146]

[1147] in

[1148] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and P 11 As defined above,

[1149] R 33 and R 34 Each independently is C 1-4 Alkyl, and

[1150] P 14 is a protecting group for an amine (eg, benzyl, (S)-1-phenylethyl, etc.).

[1151] (Step C1-1)

[1152] The compound [C1-3] or a salt thereof can be produced by reacting the compound [C1-1] or a salt thereof with the compound [C1-2] or a salt thereof in a solvent in the presence of a base.

[1153] Examples of the base include sodium ethoxide, sodium hydride, DBU, etc. A preferred base is sodium ethoxide.

[1154] Examples of the solvent include ethanol, THF, DMF, etc. A preferred solvent is ethanol.

[1155] The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C.

[1156] The compound [C1-1] or a salt thereof may be a commercially available product, or may be prepared from a commercially available product by a known method.

[1157] The compound [C1-2] or a salt thereof may be a commercially available product, or may be prepared from a commercially available product by a known method.

[1158] (Step C1-2)

[1159] The compound [C1-4] or a salt thereof can be produced by subjecting the compound [C1-3] or a salt thereof to catalytic hydrogenation in a solvent in the presence of a metal catalyst.

[1160] Examples of the metal catalyst include Pd-C, Pt-C, palladium hydroxide, etc. A preferred metal catalyst is Pd-C or palladium hydroxide.

[1161] Examples of the solvent include methanol, ethanol, THF, etc. A preferred solvent is THF.

[1162] The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C.

[1163] (Step C1-3)

[1164] Compound [C1-6] or a salt thereof can be prepared by subjecting compound [C1-4] or a salt thereof to a reductive amination reaction with compound [C1-5] or a salt thereof in a solvent. The reductive amination reaction includes, for example, a reaction using an acid and a reducing agent.

[1165] Examples of the reducing agent include sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, etc. A preferred reducing agent is sodium triacetoxyborohydride.

[1166] Examples of the acid include acetic acid, trifluoroacetic acid, hydrochloric acid, etc. A preferred acid is acetic acid.

[1167] Examples of the solvent include THF, chloroform, toluene, N-methylpyrrolidone, etc. A preferred solvent is THF.

[1168] The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C.

[1169] The compound [C1-5] or a salt thereof may be a commercially available product, or may be prepared from a commercially available product by a known method.

[1170] Compound [C1-6] or a salt thereof, wherein R 3 is methyl, and R 4 , R 5 , R 6 , R 7 and R 8 All are hydrogen, that is, the following compound [C1-10]

[1171]

[1172] in

[1173] P 14 As defined above,

[1174] or a salt thereof can be prepared by, for example, carrying out step C1-3 using (S)-1-phenylethylamine as compound [C1-5] or a salt thereof, stirring the obtained diastereoisomer mixture or a salt thereof in a solvent, and then collecting the precipitated solid by filtration.

[1175] Examples of the solvent include toluene, THF, ethyl acetate, etc. A preferred solvent is ethyl acetate.

[1176] (Step C1-4)

[1177] Compound [C1-7] or a salt thereof can be prepared by removing the protecting group P of compound [C1-6] or a salt thereof by a deprotection reaction. 14 The deprotection reaction can be carried out in a suitable 14 type of conditions.

[1178] For example, when P 14 In the case of (S)-1-phenylethyl, the compound [C1-7] or a salt thereof can be produced by reacting the compound [C1-6] or a salt thereof according to step C1-2.

[1179] (Step C1-5)

[1180] Compound [C1-8] or a salt thereof can be prepared by removing the protective group P 11 The protective group can be introduced into compound [C1-7] or a salt thereof. 11 type of conditions.

[1181] For example, when P 11 In the case of a tert-butyloxycarbonyl group, the compound [C1-8] or a salt thereof can be prepared by reacting the compound [C1-7] or a salt thereof with a corresponding carbamate-forming agent in a solvent. A base can be added according to the conditions.

[1182] Examples of the corresponding carbamate-forming agent include Boc2O, etc. A preferred corresponding carbamate-forming agent is Boc2O.

[1183] Examples of the base include sodium hydroxide, sodium bicarbonate and the like.

[1184] Examples of the solvent include THF, water, a mixed solvent thereof, etc. A preferred solvent is a mixed solvent of THF and water.

[1185] The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C.

[1186] (Step C1-6)

[1187] The compound [C1-9] or a salt thereof can be produced by reacting the compound [C1-8] or a salt thereof in a solvent in the presence of a catalyst.

[1188] Examples of the catalyst include trifluoroacetic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, etc. A preferred catalyst is pyridinium p-toluenesulfonate.

[1189] Examples of the solvent include THF, acetone, water, a mixed solvent thereof, etc. A preferred solvent is a mixed solvent of acetone and water.

[1190] The reaction temperature is, for example, 20°C to 100°C, preferably 40°C to 80°C.

[1191] Preparation method C2: Preparation method of compound [C2-9] or its salt

[1192] Compound [B3-3] or a salt thereof (for use in the preparation method B3), wherein R 10a is hydrogen and A 2a CR 5a , that is, compound [C2-9] or a salt thereof, can be prepared, for example, according to the following preparation method C2.

[1193]

[1194] in

[1195] R 3a , R 4a , R 5a , R 6a , R 7a , R 8a and P 11a As defined above,

[1196] R 33a and R 34a Each independently is C 1-4 Alkyl, and

[1197] P 14a It is a protecting group for an amine (eg, benzyl, (S)-1-phenylethyl, etc.).

[1198] (Step C2-1)

[1199] The compound [C2-3] or a salt thereof can be produced by reacting the compound [C2-1] or a salt thereof with the compound [C2-2] or a salt thereof in a solvent in the presence of a base.

[1200] Examples of the base include sodium ethoxide, sodium hydride, DBU, etc. A preferred base is sodium ethoxide.

[1201] Examples of the solvent include ethanol, THF, DMF, etc. A preferred solvent is ethanol.

[1202] The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C.

[1203] The compound [C2-1] or a salt thereof may be a commercially available product, or can be prepared from a commercially available product by a known method.

[1204] The compound [C2-2] or a salt thereof may be a commercially available product, or can be prepared from a commercially available product by a known method.

[1205] (Step C2-2)

[1206] The compound [C2-4] or a salt thereof can be produced by subjecting the compound [C2-3] or a salt thereof to catalytic hydrogenation in a solvent in the presence of a metal catalyst.

[1207] Examples of the metal catalyst include Pd-C, Pt-C, palladium hydroxide, etc. A preferred metal catalyst is Pd-C or palladium hydroxide.

[1208] Examples of the solvent include methanol, ethanol, THF, etc. A preferred solvent is THF.

[1209] The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C.

[1210] (Step C2-3)

[1211] The compound [C2-6] or a salt thereof can be prepared by subjecting the compound [C2-4] or a salt thereof and the compound [C2-5] or a salt thereof to a reductive amination reaction in a solvent. The reductive amination reaction includes, for example, a reaction using an acid and a reducing agent.

[1212] Examples of the reducing agent include sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, etc. A preferred reducing agent is sodium triacetoxyborohydride.

[1213] Examples of the acid include acetic acid, trifluoroacetic acid, hydrochloric acid, etc. A preferred acid is acetic acid.

[1214] Examples of the solvent include THF, chloroform, toluene, N-methylpyrrolidone, etc. A preferred solvent is THF.

[1215] The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C.

[1216] The compound [C2-5] or a salt thereof may be a commercially available product, or can be prepared from a commercially available product by a known method.

[1217] Compound [C2-6] or a salt thereof, wherein R 3a is methyl, and R4a , R 5a , R 6a , R 7a and R 8a All of them are hydrogen, that is, the following compound [C2-10]

[1218]

[1219] in

[1220] P 14a As defined above

[1221] or a salt thereof can be prepared by, for example, carrying out step C2-3 using (S)-1-phenylethylamine as compound [C2-5] or a salt thereof, stirring the obtained diastereoisomer mixture or a salt thereof in a solvent, and then collecting the precipitated solid by filtration.

[1222] Examples of the solvent include toluene, THF, ethyl acetate, etc. A preferred solvent is ethyl acetate.

[1223] (Step C2-4)

[1224] Compound [C2-7] or a salt thereof can be prepared by removing the protective group P of compound [C2-6] or a salt thereof by a deprotection reaction. 14a The deprotection reaction can be carried out in a suitable 14a type of conditions.

[1225] For example, when P 14a In the case of (S)-1-phenylethyl, the compound [C2-7] or a salt thereof can be produced by reacting the compound [C2-6] or a salt thereof according to step C2-2.

[1226] (Step C2-5)

[1227] Compound [C2-8] or a salt thereof can be prepared by removing the protective group P 11a The introduction of the protecting group can be carried out in a suitable 11a type of conditions.

[1228] For example, when P 11a In the case of a tert-butoxycarbonyl group, the compound [C2-8] or a salt thereof can be prepared by reacting the compound [C2-7] or a salt thereof with a corresponding carbamate-forming agent in a solvent. A base can be added according to the conditions.

[1229] Examples of the corresponding carbamate-forming agent include Boc2O, etc. A preferred corresponding carbamate-forming agent is Boc2O.

[1230] Examples of the base include sodium hydroxide, sodium bicarbonate and the like.

[1231] Examples of the solvent include THF, water, a mixed solvent thereof, etc. A preferred solvent is a mixed solvent of THF and water.

[1232] The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C.

[1233] (Step C2-6)

[1234] The compound [C2-9] or a salt thereof can be produced by reacting the compound [C2-8] or a salt thereof in a solvent in the presence of a catalyst.

[1235] Examples of the catalyst include trifluoroacetic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, etc. A preferred catalyst is pyridinium p-toluenesulfonate.

[1236] Examples of the solvent include THF, acetone, water, a mixed solvent thereof, etc. A preferred solvent is a mixed solvent of acetone and water.

[1237] The reaction temperature is, for example, 20°C to 100°C, preferably 40°C to 80°C. Example

[1238] Next, the preparation method of the compound [I] or compound [Ia] of the present invention or its pharmaceutically acceptable salt will be specifically explained with reference to the following preparation examples. However, the preparation method of the compound [I] or compound [Ia] of the present invention or its pharmaceutically acceptable salt should not be limited to these preparation examples.

[1239] The compound obtained in each step may be isolated or purified according to a method known per se (e.g., distillation, recrystallization, column chromatography) if necessary, or directly used in the next step without isolation or purification.

[1240] Room temperature as used herein refers to a temperature in an uncontrolled state, and one embodiment includes 1°C to 40°C.

[1241] [Preparation Example 1]: Synthesis of tert-butyl (S)-(1-(4-oxocyclohexyl)propan-2-yl)carbamate

[1242]

[1243] (1) Ethyl 4-(trans-4-((tert-butyloxycarbonyl)amino)cyclohexyl)-3-oxobutanoate

[1244]

[1245] Under argon atmosphere, to a solution of 2-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)acetic acid (1.4 kg) in THF (6.2 kg) was added dropwise a solution of carbonyldiimidazole (1 kg) in DMF (4.7 kg) at room temperature, and the mixture was stirred. The mixture washed with DMF (0.7 kg) was then combined, and the mixture was stirred for 3 hours. Malonic acid monoethyl ester potassium salt (1.3 kg) was added thereto, and then magnesium chloride (0.6 kg) was added thereto in batches. After stirring for a whole day, water (4.2 kg) and 6M hydrochloric acid (3.1 kg) were added thereto at an internal temperature of 5° C., and the mixture was stirred for 1 hour at room temperature. Toluene (6.1 kg) was added thereto, the mixture was subjected to extraction, and the aqueous layer was re-extracted with toluene (2.4 kg). The combined organic layer was washed twice with 20% brine (7 kg). The organic layer is concentrated under reduced pressure, and then azeotroped with methanol (2.2kg). In the obtained residue, methanol (3.3kg) is added to obtain a methanol solution. The above-mentioned methanol solution is merged with the methanol solution obtained with the same procedure by 2-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)acetic acid (8kg), to obtain a methanol solution (34kg) of the title compound. A portion of it is concentrated to obtain an NMR sample.

[1246] 1H-NMR(CDCl3)δ:4.44-4.31(1H,m),4.19(2H,q,J=7.1Hz),3.46-3.27(1H,m),3.40(2H,s),2.43(2H,d, J=6.3Hz),2.04-1.93(2H,m),1.88-1.69(3H,m),1.44(9H,s),1.28(3H,t,J=7.1Hz),1.19-0.97(4H,m).

[1247] (2) tert-Butyl (trans-4-(2-oxopropyl)cyclohexyl)carbamate

[1248]

[1249] A methanol solution (34 kg) of ethyl 4-(trans-4-((tert-butyloxycarbonyl)amino)cyclohexyl)-3-oxobutanoate obtained in (1) was heated to 35° C., a 4M aqueous sodium hydroxide solution (20 kg) was added thereto, and the mixture was stirred. After stirring at 40° C. for 2 hours, a solution of citric acid (8.4 kg) in water (19 kg) was added dropwise thereto at 45° C. Ethyl acetate (25 kg) was added thereto, the mixture was stirred for 20 minutes, and a solution of citric acid (8.4 kg) in water (19 kg) was added dropwise thereto. After stirring for 3 hours, the mixture was cooled to room temperature, ethyl acetate (25 kg) was added thereto, and the mixture was subjected to liquid separation. The organic layer was washed with 10% brine (47 kg) and concentrated under reduced pressure. Ethyl acetate (17 kg) was added thereto, and the mixture was concentrated under reduced pressure to obtain the title compound (8.1 kg) with a yield of 87%.

[1250] 1H-NMR(CDCl3)δ:4.36(1H,br s),3.35(1H,br s),2.31(2H,d,J=6.4Hz),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).

[1251] (3) tert-butyl (trans-4-((S)-2-(((S)-1-phenylethyl)amino)propyl)cyclohexyl)carbamate acetate

[1252]

[1253] A solution of tert-butyl (trans-4-(2-oxopropyl)cyclohexyl)carbamate (8.1 kg) obtained in (2) in methanol (67 kg) was prepared, and (S)-1-phenylethylamine (4.4 kg), acetic acid (1.2 kg) and a suspension of 2% Pt-C (0.42 kg) in water (1.7 kg) were added thereto under an Ar atmosphere at room temperature, and the mixture was stirred. The mixture was stirred for 20 hours under a hydrogen atmosphere (4 atm) at 40° C. After cooling to room temperature, 2% Pt-C was removed by filtration using KC flock (registered trademark) as a filter aid, and washed twice with methanol (15 kg). The obtained solution was concentrated under reduced pressure, isopropanol (20 kg) was added thereto, and the mixture was concentrated under reduced pressure. The same operation was performed again, and isopropanol (43 kg) was added to the obtained solid to prepare a suspension. The suspension was heated to 70° C., and acetic acid (1 kg) was added dropwise thereto. After stirring for 2 hours, the mixture was cooled to room temperature and stirred for 17 hours. The mixture was stirred for an additional 2 hours at an internal temperature of 5° C., and the obtained solid was collected by filtration, washed with ice-cold isopropanol (20 kg), and dried at 30° C. for 19 hours to obtain the title compound (9 kg) in a yield of 65%.

[1254] 1H-NMR(DMSO-D6)δ:7.35-7.25(4H,m),7.21-7.15(1H,m),6.62(1H,d,J=7.5Hz),3.80(1H,q,J=6.5Hz),3.1 7-3.01(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).

[1255] (4) (S)-(trans-4-(2-aminopropyl)cyclohexyl)carbamic acid tert-butyl acetate

[1256]

[1257] To a solution of tert-butyl (trans-4-((S)-2-(((S)-1-phenylethyl)amino)propyl)cyclohexyl)carbamate acetate (8.9 kg) obtained in (3) in methanol (85 kg) was added a suspension of 5% Pd—C (PE type) (0.89 kg) in water (1.8 kg) at room temperature under Ar atmosphere, and the mixture was stirred. The mixture was stirred for 2 hours under a hydrogen atmosphere (4 atm) at 35° C. After gradually cooling to room temperature, 5% Pd—C was removed by filtration using KC flock (registered trademark) as a filter aid, and washed with methanol (21 kg). The filtrate was concentrated under reduced pressure and then azeotroped with acetonitrile (21 kg). Methanol (42 kg) was added to the obtained solid to obtain a methanol solution of the title compound. A portion thereof was concentrated to obtain an NMR sample.

[1258] 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).

[1259] (5) (S)-(1-(trans-4-((tert-butyloxycarbonyl)amino)cyclohexyl)propan-2-yl)benzyl carbamate

[1260]

[1261] At room temperature in DMF (1080ml) in (S) - (trans-4- (2-aminopropyl) cyclohexyl) carbamic acid tert-butyl ester acetate (218g) (obtained in the same manner as (4)) solution, add triethylamine (100ml), and stir the mixture. Under water-cooling, add N-benzyloxycarbonyl oxysuccinimide (179g), and the mixture was stirred at room temperature for 6 hours. Under water-cooling, add water (2160ml), and the mixture was stirred for 1 hour. Collect the obtained solid by filtration, wash with water (1200ml), and dry at room temperature for 48 hours, to obtain the seed crystal (257g) of the title compound with a yield of 97%.

[1262] To a methanol solution of (S)-(trans-4-(2-aminopropyl)cyclohexyl)carbamic acid tert-butyl ester acetate obtained in (4) was added a solution of triethylamine (5.1 kg) and N-benzyloxycarbonyloxysuccinimide (5.8 kg) in acetonitrile (14 kg) at 10°C, and the mixture was stirred. The mixture washed with acetonitrile (3.5 kg) was then combined, and the mixture was stirred for 3 hours. Water (8.9 kg) was added thereto, and seed crystals obtained in the same manner as above were added thereto, and the mixture was stirred for 2 hours. The obtained solid was collected by filtration, washed with 50% methanol aqueous solution (24 kg), and dried for 69 hours to obtain the title compound (8 kg) with a yield of 97%.

[1263] 1H-NMR(DMSO-D6)δ:7.41-7.27(5H,m),7.06(1H,d,J=8.2Hz), 6.66(1H,d,J=8.2Hz), 5.03(1H,d,J=12.0Hz), 4.98(1H,d,J=12.0Hz) ,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=6.7Hz).

[1264] (6) (S)-(1-(trans-4-aminocyclohexyl)propan-2-yl)carbamic acid benzyl p-toluenesulfonate

[1265]

[1266] A suspension of (S)-(1-(trans-4-((tert-butyloxycarbonyl)amino)cyclohexyl)propan-2-yl)benzylcarbamate (257 g) (obtained in the same manner as in (5)) in ethyl acetate (2570 ml) was heated to 80° C., p-toluenesulfonic acid monohydrate (188 g) was added thereto, and the mixture was stirred for 3 hours. After gradually cooling to room temperature, the mixture was allowed to stand for a whole day. The obtained solid was collected by filtration and washed with ethyl acetate (236 ml). The solid was dried under reduced pressure, dried at 50° C. for 8 hours, and then dried under reduced pressure at room temperature for a whole day to obtain seed crystals (281 g) of the title compound in a yield of 92%.

[1267] A suspension of (S)-(1-(trans-4-((tert-butyloxycarbonyl)amino)cyclohexyl)propan-2-yl)benzylcarbamate (8 kg) obtained in (5) was prepared in ethyl acetate (58 kg), to which p-toluenesulfonic acid monohydrate (5.1 kg) was added at room temperature, and the mixture was stirred. The mixture washed with ethyl acetate (1.4 kg) was then combined, and the mixture was stirred for 1 hour. Seed crystals obtained in the same manner as above were added thereto, and the mixture was stirred for 1 hour, heated to 55° C., and stirred for 4 hours. After gradually cooling to room temperature, the mixture was stirred for 14 hours. The obtained solid was collected by filtration, washed with ethyl acetate (22 kg), and dried at 50° C. for 23 hours to obtain the title compound (9 kg) in a yield of 96%.

[1268] 1H-NMR(DMSO-D6)δ:7.67(3H,br s),7.47(2H,d,J=8.2Hz),7.41-7.28(5H,m),7.14-7.06(3H,m),5.02(1H,d,J=12.7Hz), 4.98(1H,d,J=12.7Hz), 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=6.7Hz).

[1269] (7) (S)-(1-trans-(4-aminocyclohexyl)propan-2-yl)carbamic acid benzyl ester

[1270]

[1271] At room temperature, 4M aqueous sodium hydroxide solution (17ml) was added to a solution of (S)-(1-(trans-4-aminocyclohexyl) propan-2-yl) benzyl carbamate p-toluenesulfonate (30g) obtained in 2-methyltetrahydrofuran (120ml), and the mixture was stirred for 1.5 hours. Water (120ml) was added thereto, the mixture was subjected to extraction, and the organic layer was washed with water (120ml, twice) and saturated brine (120ml), and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. Methanol (90ml) was added thereto, and the mixture was concentrated under reduced pressure to obtain the title compound (18g) with a yield of 96%.

[1272] 1H-NMR(DMSO-D6)δ:7.41-7.25(5H,m),7.05(1H,d,J=8.5Hz),5.03(1H,d,J=12.5Hz),4.97(1H, d,J=12.5Hz),3.68-3.50(1H,m),2.46-2.33(1H,m),1.81-0.71(13H,m),1.01(3H,d,J=6.5Hz).

[1273] (8) (S)-(1-(4-oxocyclohexyl)propan-2-yl)carbamic acid benzyl ester

[1274]

[1275] At room temperature, 3,5-di-tert-butyl-1,2-benzoquinone (14 g) was added to a solution of (S)-(1-trans-(4-aminocyclohexyl)propan-2-yl)benzylcarbamate (18 g) obtained in (7) in methanol (90 ml), and the mixture was stirred for 1.5 hours. Water (18 ml), acetone (72 ml) and DOWEX (45 g) were added thereto, and the mixture was stirred for 1.5 hours. Additional DOWEX was added thereto, and the mixture was stirred for 30 minutes. The mixture was filtered through ethyl acetate, and the filtrate was concentrated under reduced pressure. Ethyl acetate (72 ml) and water (36 ml) were added thereto, the mixture was subjected to extraction, and the organic layer was dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate (36 ml) and silica gel (18 g) were added thereto, and the mixture was stirred for 30 minutes. The mixture was filtered through ethyl acetate, and the filtrate was concentrated under reduced pressure. Diisopropyl ether (18 ml) was added to the obtained residue, and the mixture was heated to an internal temperature of 48° C. Heptane (72 ml) was added dropwise thereto, and the mixture was stirred for 1.5 hours. The obtained solid was collected by filtration, washed with heptane, and dried under reduced pressure at 60° C. for 3 hours, then dried at room temperature for a whole day, to obtain the title compound (15 g) in a yield of 83%.

[1276] 1H-NMR(DMSO-D6)δ:7.41-7.25(5H,m),7.15(1H,d,J=8.6Hz), 5.03(1H,d,J=12.4Hz), 4.99(1H,d,J=12. 4Hz),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=6.5Hz).

[1277] (9) tert-Butyl (S)-(1-(4-oxocyclohexyl)propan-2-yl)carbamate

[1278]

[1279] At room temperature, under argon atmosphere, 10% Pd-C (1.5 g) and Boc2O (12 g) were added to a solution of (S)-(1-(4-oxocyclohexyl)propan-2-yl)benzylcarbamate (15 g) obtained in (8) in methanol (145 ml). The mixture was stirred for 4 hours under a hydrogen atmosphere (1 atm). After purging with nitrogen, 10% Pd-C was removed by diatomite filtration and washed with methanol. The filtrate was concentrated under reduced pressure, acetone (27 ml) was added to the obtained residue, and the mixture was stirred at room temperature. Water (82 ml) was added thereto, and the mixture was stirred all day. The obtained solid was collected by filtration, washed with water, and dried under reduced pressure for 3 hours at 60 ° C, then dried all day at room temperature, to obtain the title compound (12 g) with a yield of 88%. The same procedures as in the above (7) to (9) were carried out using benzyl (S)-(1-(trans-4-aminocyclohexyl)propan-2-yl)carbamate p-toluenesulfonate (211 g) to give the title compound (60 g).

[1280] 1H-NMR(DMSO-D6)δ:6.65(1H,d,J=8.6Hz),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=6.5Hz).

[1281] [Preparation Example 2]: N 1 -((S)-1-(cis-5-(2-bromo-4-cyanophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-N 2 -Synthesis of Methyloxamide (Example 57)

[1282]

[1283] (1) Tert-butyl ((S)-1-(cis-4-(2-bromo-4-cyanobenzoyl)-4-((trimethylsilyl)oxy)cyclohexyl)propan-2-yl)carbamate

[1284]

[1285] To a solution of 3-bromo-4-cyanobenzaldehyde (2.1 g) in THF (4 ml) was added lithium chloride (0.043 g) and trimethylsilylcyanide (1.5 ml) at room temperature, and the mixture was stirred at room temperature for 1 hour. THF (26 ml) was added thereto, and the mixture was cooled to -78°C. 1M NaHMDS-THF solution (10.2 ml) was added thereto, and the mixture was stirred for 3 minutes. A solution of (S)-(1-(4-oxocyclohexyl)propan-2-yl)carbamic acid tert-butyl ester (2 g) (obtained in the same manner as in (9) of [Preparation Example 1]) in THF (10 ml) was added thereto, and the mixture was stirred for 30 minutes, and heated to -10°C within 1 hour. Water and ethyl acetate were added thereto, and the mixture was subjected to extraction. The water layer was subjected to re-extraction twice with ethyl acetate, and the combined organic layer was washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane) to obtain the title compound (1.2 g) in a yield of 28%.

[1286] 1H-NMR(CDCl3)δ:7.89(1H,s),7.62(1H,d,J=8.1Hz),7.39(1H,d,J=8.1Hz),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=6.5Hz),0.04(9H,s).

[1287] (2) tert-Butyl ((S)-1-(cis-4-(2-bromo-4-cyanobenzoyl)-4-hydroxycyclohexyl)propan-2-yl)carbamate

[1288]

[1289] 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 in the same manner as above (1.4 g in total) in THF (2.7 ml) were added acetic acid (0.42 ml) and 1M TBAF-THF solution (3.7 ml) at room temperature, and the mixture was stirred for 15 minutes. Saturated aqueous ammonium chloride solution, water and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction twice with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane) to obtain the title compound (1.1 g) with a yield of 93%.

[1290] 1H-NMR(CDCl3)δ:7.89(1H,s),7.65(1H,d,J=8.1Hz),7.32(1H,d,J=7.5Hz),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=5.9Hz).

[1291] (3) 4-(cis-9-((S)-2-aminopropyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-5-yl)-3-bromobenzonitrile hydrochloride

[1292]

[1293] 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) at room temperature, DBU (0.052 ml) and CDI (0.55 g) were added, and the mixture was stirred for 1 hour. Hydrazine monohydrate was added thereto, and the mixture was stirred for 30 minutes. A 10% aqueous solution of citric acid and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction twice with ethyl acetate, and the combined organic layers were washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate 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 6M hydrochloric acid (3.2 ml) were added to the obtained solid at room temperature, and the mixture was stirred for a whole day, and then stirred at 50° C. for 5 hours. The reaction solution was concentrated under reduced pressure, followed by azeotroping with THF (2 ml) twice to give the title compound (0.61 g).

[1294] 1H-NMR(DMSO-D6)δ:11.37(1H,s),8.39(1H,s),7.99(1H,d,J=8.1Hz),7.90-7.72(3H,m),7.70( 1H,d,J=8.1Hz),3.27-3.13(1H,m),2.23-2.10(2H,m),1.62-1.17(9H,m),1.13(3H,d,J=5.4Hz).

[1295] (4)N 1 -((S)-1-(cis-5-(2-bromo-4-cyanophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-N 2 -Methyloxalamide

[1296]

[1297] To a solution of 4-(cis-9-((S)-2-aminopropyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-ene-5-yl)-3-bromobenzonitrile hydrochloride (0.57 g) obtained in (3) in DMF (8.4 ml) at room temperature were added 2-methylamino-2-oxoacetic acid (0.24 g), HOAt (0.33 g) and N,N-diisopropylethylamine (1.0 ml). WSC (0.47 g) was added thereto, and the mixture was stirred at room temperature for a whole day. Water, saturated aqueous sodium bicarbonate solution and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to reextraction twice with ethyl acetate, and the combined organic layers were washed with saturated brine and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was subjected to azeotropy twice with toluene (10 ml), and the obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane), and then purified by reversed-phase silica gel chromatography (developing solvent: acetonitrile / water). At 50° C., the obtained solid was subjected to recrystallization in ethyl acetate (8.4 ml) / isopropyl ether (8.4 ml), and the mixture was stirred at room temperature for a whole day. The obtained suspension was filtered, and the obtained solid was washed three times with an ice-cold mixed solvent of ethyl acetate:isopropyl ether=1:1 (1 ml), and dried under reduced pressure at 50° C. for 4 hours to obtain the title compound (0.30 g) with a yield of 57%.

[1298] 1H-NMR(CDCl3)δ:8.24(1H,s),7.97(1H,d,J=1.6Hz),7.68(1H,dd,J=7.9,1 .6Hz),7.44-7.39(1H,m),7.33(1H,d,J=7.9Hz),7.18-7.14(1H,m),4.08-4. 00(1H,m),2.89(3H,d,J=5.3Hz),2.34-2.28(2H,m),1.79-1.72(1H,m),1.6 0-1.51(2H,m),1.50-1.31(5H,m),1.30-1.21(1H,m),1.16(3H,d,J=6.5Hz).

[1299] [Preparation Example 3]: (S)-N 1 -(1-(5-(2-bromo-4-fluorophenyl)-2-oxo-1-oxa-3,4,9-triazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-N 2 -Synthesis of Methyloxamide (Example 179)

[1300]

[1301] (1) tert-Butyl 4-(2-bromo-4-fluorobenzoyl)-4-((trimethylsilyl)oxy)piperidine-1-carboxylate

[1302]

[1303] At room temperature, trimethylsilyl cyanide (1.5ml) was added to the solution of 2-bromo-4-fluorobenzaldehyde (1.2ml) and DMAP (0.015g) in acetonitrile (20ml), and the mixture was stirred for 3 hours. The reaction solution was concentrated, THF (18ml) was added thereto, and the mixture was cooled to -78 ° C. 1.1M LiHMDS-n-hexane solution (10ml) was added thereto, and the mixture was stirred for 30 minutes. A solution of 4-oxopiperidin-1-carboxylic acid tert-butyl ester (2g) in THF (9ml) was added thereto, and the mixture was stirred for 1 hour. 2M hydrochloric acid (12ml) was added thereto, and the mixture was stirred at room temperature for a whole day. The reaction solution was ice-cooled, 2M sodium hydroxide aqueous solution (12.5ml) was added thereto, and the mixture was stirred at room temperature for 30 minutes. Water and ethyl acetate were added thereto, and the mixture was subjected to extraction. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane = 15 / 85 to 35 / 65) to give the title compound (1.8 g) in a yield of 34%.

[1304] 1H-NMR(DMSO-D6)δ:7.74(1H,dd,J=8.7,2.4Hz),7.62(1H,dd,J=8.6,6.0Hz),7.38(1H,td,J=8.6,2.5Hz),3.6 6(2H,dt,J=13.9,4.0Hz),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).

[1305] (2) tert-Butyl 4-(2-bromo-4-fluorobenzoyl)-4-hydroxypiperidine-1-carboxylate

[1306]

[1307] 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) was added 1M TBAF-THF solution (1.9 ml) at room temperature, and the mixture was stirred for 1 hour. Saturated aqueous ammonium chloride solution and ethyl acetate were added thereto, and the mixture was subjected to extraction. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane=20 / 80 to 40 / 60) to obtain the title compound (0.74 g) with a yield of 92%.

[1308] 1H-NMR(DMSO-D6)δ:7.67(1H,dd,J=8.8,2.5Hz),7.58(1H,dd,J=8.6,6.0Hz),7.34(1H,td,J=8 .6,2.4Hz),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).

[1309] (3) tert-Butyl 5-(2-bromo-4-fluorophenyl)-2-oxo-1-oxa-3,4,9-triazaspiro[5.5]undec-4-ene-9-carboxylate

[1310]

[1311] At room temperature, DBU (0.026 ml) and CDI (0.42 g) were added to a solution of 4-(2-bromo-4-fluorobenzoyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (0.74 g) obtained in (2) in THF (6.9 ml), and the mixture was stirred for 1 hour. Hydrazine monohydrate (0.25 ml) was added thereto, and the mixture was stirred for 1 hour. 1 M hydrochloric acid and ethyl acetate were added thereto, and the mixture was subjected to extraction. The water layer was subjected to re-extraction with ethyl acetate, and the combined organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine, and dried over magnesium sulfate. Sodium sulfate was removed by filtration, and the filtrate 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 the mixture was stirred for 20 hours. The mixture was neutralized with 4 M sodium hydroxide aqueous solution (6.0 ml), Boc O (0.44 ml) was added thereto, and the mixture was stirred for 1 hour. Ethyl acetate was added thereto, and the mixture was subjected to extraction. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane=30 / 70 to 50 / 50) to give the title compound (0.60 g) in a yield of 79%.

[1312] 1H-NMR(DMSO-D6)δ:11.35(1H,s),7.76(1H,dd,J=8.6,2.5Hz),7.57(1H,dd,J=8.7,5.9Hz),7.36(1H,td, J=8.5,2.6Hz),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).

[1313] (4) 5-(2-Bromo-4-fluorophenyl)-1-oxa-3,4,9-triazaspiro[5.5]undec-4-en-2-one hydrochloride

[1314]

[1315] At room temperature, 4M hydrogen chloride-CPME solution (5.6 ml) was added to 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), and the mixture was stirred for 3 hours. The obtained reaction solution was concentrated under reduced pressure to obtain the title compound (0.53 g) with a yield of 100%.

[1316] 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=8.6,2.5Hz),7.61(1H,dd,J= 8.7,5.9Hz),7.44(1H,td,J=8.5,2.6Hz),3.28-3.20(2H,m),3.11-2.99(2H,m),2.36-2.26(2H,m),1.99-1.85(2H,m).

[1317] (5) (S)-tert-butyl (1-(5-(2-bromo-4-fluorophenyl)-2-oxo-1-oxa-3,4,9-triazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)carbamate

[1318]

[1319] Under ice cooling, triethylamine (0.89 ml) and (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2,2-dioxide (0.36 g) were added to a solution of 5-(2-bromo-4-fluorophenyl)-1-oxa-3,4,9-triazaspiro[5.5]undec-4-ene-2-one hydrochloride (0.53 g) obtained in (4) in methanol (5.3 ml) and the mixture was stirred for 5 hours. Methanol was evaporated, THF (5.3 ml), water (5.3 ml) and potassium hydrogen sulfate (0.52 g) were added thereto, and the mixture was stirred at room temperature for 2 days. Saturated sodium bicarbonate aqueous solution and ethyl acetate were added thereto, and the mixture was subjected to extraction. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (developing solvent: ethyl acetate / n-hexane=67 / 33) to obtain the title compound (0.57 g) with a yield of 84%.

[1320] 1H-NMR(DMSO-D6)δ:11.24(1H,s),7.75(1H,dd,J=8.7,2.7Hz),7.53(1H,dd,J=8.6,6.0Hz),7.36(1H,td,J=8.5,2.6Hz),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=6.5Hz).

[1321] (6) (S)-9-(2-aminopropyl)-5-(2-bromo-4-fluorophenyl)-1-oxa-3,4,9-triazaspiro[5.5]undec-4-en-2-one dihydrochloride

[1322]

[1323] To tert-butyl (S)-(1-(5-(2-bromo-4-fluorophenyl)-2-oxo-1-oxa-3,4,9-triazaspiro[5.5]undec-4-ene-9-yl)propan-2-yl)carbamate (0.12 g) obtained in (5) was added 4 M hydrogen chloride-CPME solution (1.1 ml) at room temperature, and the mixture was stirred for 3 hours. The obtained reaction solution was concentrated under reduced pressure to obtain the title compound (0.13 g).

[1324] 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=8.6,2.5Hz),7.58(1H,dd,J=8.6, 6.0Hz),7.41(1H,td,J=8.5,2.5Hz),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).

[1325] (7)(S)-N 1 -(1-(5-(2-bromo-4-fluorophenyl)-2-oxo-1-oxa-3,4,9-triazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-N 2 -Methyloxalamide

[1326]

[1327] To a solution of (S)-9-(2-aminopropyl)-5-(2-bromo-4-fluorophenyl)-1-oxa-3,4,9-triazaspiro[5.5]undec-4-ene-2-one dihydrochloride (0.04 g) obtained in (6) in acetonitrile (0.34 ml) at room temperature were added 2-methylamino-2-oxoacetic acid (0.014 g), HOAt (0.018 g) and N,N-diisopropylethylamine (0.059 ml). WSC (0.026 g) was added thereto, and the mixture was stirred at room temperature for 3 hours. Saturated sodium bicarbonate aqueous solution and ethyl acetate were added thereto, and the mixture was subjected to extraction. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (developing solvent: ethyl acetate) to obtain the title compound (0.029 g) with a yield of 87%.

[1328] 1H-NMR(DMSO-D6)δ:11.25(1H,s),8.63(1H,q,J=4.7Hz),8.35(1H,d,J=8.8Hz),7.7 5(1H,dd,J=8.6,2.5Hz),7.54(1H,dd,J=8.6,5.8Hz),7.36(1H,td,J=8.6,2.5Hz),3. 96-3.89(1H,m),2.72-2.60(2H,m),2.64(3H,d,J=4.7Hz),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=6.5Hz).

[1329] [Preparation Example 4]: N 1 -((S)-1-(cis-5-(2-bromo-5-cyanophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-N 2 -Synthesis of Methyloxamide (Example 198)

[1330]

[1331] (1) Tert-butyl ((S)-1-(cis-4-(2-bromo-5-cyanobenzoyl)-4-((trimethylsilyl)oxy)cyclohexyl)propan-2-yl]carbamate

[1332]

[1333] Under water cooling, trimethylsilyl cyanide (34 ml) was added to a solution of 4-bromo-3-cyanobenzaldehyde (54 g) and lithium chloride (1.1 g) in THF (350 ml), and the mixture was stirred for 1 hour. The mixture was cooled to -78°C, 1.1 M LiHMDS-n-hexane solution (225 ml) was added thereto, and the mixture was stirred for 2 hours. The mixture was heated to -60°C, a solution of (S)-(1-(4-oxocyclohexyl)propan-2-yl)carbamic acid tert-butyl ester (50 g) (obtained in (9) of [Preparation Example 1]) in THF (100 ml) was added thereto, and the mixture was stirred for 1.5 hours. Acetic acid (15 ml) was added thereto, the mixture was heated to -20°C, and water (250 ml) was added thereto. After stirring at room temperature for 10 minutes, water (250 ml) and toluene (500 ml) were added thereto, and the mixture was subjected to extraction. The organic layer was washed with water (500 ml, three times) and 20% brine (500 ml), and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure at room temperature to give the title compound (150 g) containing a small amount of toluene.

[1334] 1H-NMR(DMSO-D6)δ:8.01-7.98(1H,m),7.96(1H,d,J=8.3Hz),7.89-7.85(1H,m),6.59(1H,d,J=8.6Hz),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=6.5Hz),0.00(9H,s).

[1335] (2) Tert-butyl ((S)-1-(cis-4-(2-bromo-5-cyanobenzoyl)-4-hydroxycyclohexyl)propan-2-yl]carbamate

[1336]

[1337] THF (310 ml), acetic acid (14 ml) and 1M TBAF-THF solution (230 ml) were added to tert-butyl ((S)-1-(cis-4-(2-bromo-5-cyanobenzoyl)-4-((trimethylsilyl)oxy)cyclohexyl)propan-2-yl)carbamate (150 g) obtained in (1) at room temperature, and the mixture was stirred at room temperature for 1.5 hours. Water (500 ml) and toluene (500 ml) and toluene were added thereto, and the mixture was subjected to extraction. The obtained organic layer was washed with 5% sodium bicarbonate aqueous solution (500 ml), water (500 ml) and saturated brine (500 ml), and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. Methanol (150 ml) was added thereto, and the mixture was concentrated again under reduced pressure. Methanol (270 ml) and water (90 ml) were added to the obtained residue, and the mixture was stirred for two days. Under ice cooling, the mixture was stirred again for a whole day, and the obtained solid was collected by filtration. The solid was washed with a mixed solvent of ice-cooled methanol (68 ml) and water (22 ml), and dried under reduced pressure at 60° C. for 3 hours, and then dried at room temperature for a whole day to obtain the title compound (52 g) with a yield of 58%.

[1338] 1H-NMR(DMSO-D6)δ:7.92-7.88(2H,m),7.83-7.79(1H,m),6.59(1H,d,J=8.1Hz),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=6.5Hz).

[1339] (3) 3-(cis-9-((S)-2-aminopropyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-5-yl)-4-bromobenzonitrile

[1340]

[1341] At room temperature, DBU (2.4 ml) and CDI (25 g) were added to a solution of (S)-1-(cis-4-(2-bromo-5-cyanobenzoyl)-4-hydroxycyclohexyl)propan-2-yl)t-butyl carbamate (48 g) obtained in (2) in THF (240 ml), and the mixture was stirred for 1 hour. Hydrazine monohydrate (10 ml) was added thereto, and the mixture was stirred for 30 minutes. Water (240 ml) and ethyl acetate (240 ml) were added thereto, and the mixture was subjected to extraction. The obtained organic layer was washed with 10% citric acid aqueous solution (240 ml), water (240 ml) and 20% brine (240 ml), and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate (530 ml) was added to the obtained residue, and the mixture was stirred at room temperature for 1 hour. Solids were removed by filtration, and the filtrate was concentrated under reduced pressure. At room temperature, THF (240ml) and 6M hydrochloric acid (120ml) were added to the concentrate, and the mixture was stirred at 50°C for 5 hours. The mixture was gradually cooled to room temperature, water (242ml) and 8M sodium hydroxide aqueous solution (91ml) were added thereto, and the mixture was stirred for 5 minutes. THF (120ml) and toluene (240ml) were added thereto, and the mixture was subjected to extraction. The water layer was subjected to re-extraction with THF (96ml) and toluene (120ml). The combined organic layer was washed with 20% brine (240ml) and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate (144ml) was added thereto, and the mixture was concentrated again under reduced pressure. Ethyl acetate (54ml) was added to the obtained residue at room temperature, and the mixture was stirred for a whole day. The obtained solid was collected by filtration, washed with ice-cooled ethyl acetate (36 ml), and dried under reduced pressure at 60°C for 3 hours and then at room temperature for a whole day to give the title compound (32 g) in 89% yield.

[1342] 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=5.9Hz).

[1343] (4)N 1 -((S)-1-(cis-5-(2-bromo-5-cyanophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-N 2 -Methyloxalamide

[1344]

[1345] To a solution of 3-(cis-9-((S)-2-aminopropyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-ene-5-yl)-4-bromobenzonitrile (0.02 g) (obtained in the same manner as in (3)) in DMF (0.5 ml) was added 2-methylamino-2-oxoacetic acid (0.008 g), HOAt (0.007 g), WSC (0.014 g) and N,N-diisopropylethylamine (0.026 ml) at room temperature, and the mixture was stirred for a whole day. Water and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction with ethyl acetate. The combined organic layers were washed with water and saturated brine, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography (developing solvent: ethyl acetate) to give the title compound (0.021 g) in a yield of 87%.

[1346] 1H-NMR(DMSO-D6)δ:11.29(1H,s),8.65-8.59(1H,m),8.41(1H,d,J=9.0Hz),8.00(1H,d,J=1.8Hz),7.98(1H,d,J=8.3Hz),7.86(1H,dd,J =8.3,1.8Hz),3.98-3.85(1H,m),2.64(3H,d,J=4.9Hz),2.16-2.04(2H,m),1.69-1.59(1H,m),1.59-1.13(8H,m),1.06(3H,d,J=6.5Hz).

[1347] (5)N 1 -((S)-1-(cis-5-(2-bromo-5-cyanophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-N 2 -Methyloxamide crystals

[1348]

[1349] To a solution of 3-(cis-9-((S)-2-aminopropyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-5-yl)-4-bromobenzonitrile (42 g) (obtained in the same manner as in (3)), 2-methylamino-2-oxoacetic acid (13 g) and WSC (24 g) in DMF (210 ml) was added HOAt (7.1 g) at room temperature under a nitrogen atmosphere, and the mixture was stirred for 1 hour. A 5% aqueous sodium bicarbonate solution (420 ml) and ethyl acetate (420 ml) were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction with ethyl acetate (210 ml), and the combined organic layer was washed with a 5% aqueous sodium bicarbonate solution (210 ml), water (210 ml×2) and saturated brine (210 ml). Sodium sulfate and activated carbon (1.3g) are added thereto, the mixture is stirred for 1.5 hours, and solids are removed by filtration. The obtained solution is concentrated under reduced pressure, and DMF (115ml) is added to the amorphous solid obtained. The obtained solution is concentrated under reduced pressure, ethyl acetate is evaporated, and the obtained solution is subjected to dust removal filtration, and then washed with DMF (139ml). Water (150ml) is added to the obtained DMF solution at room temperature. After confirming the solid precipitation, water (612ml) is added dropwise thereto, and the obtained suspension is stirred at room temperature for 5 days. The suspension is heated to 50 ℃, stirred overnight, and allowed to cool to room temperature. The suspension is filtered, and the solid is washed with water. The obtained wet crystals are air-dried overnight, then dried under reduced pressure at 60 ℃ for 3 hours, to obtain the title compound (45g).

[1350] [Preparation Example 5]: Synthesis of 1-((S)-1-(cis-5-(2-bromo-5-cyanophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-3-cyclopropylurea (Example 222)

[1351]

[1352] (1) 1-((S)-1-(cis-5-(2-bromo-5-cyanophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-3-cyclopropylurea

[1353]

[1354] At room temperature, cyclopropyl isocyanate (0.005 ml) was added to a solution of 3-(cis-9-((S)-2-aminopropyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-ene-5-yl)-4-bromobenzonitrile (0.020 g) (obtained in the same manner as in (3) of [Preparation Example 4]) in THF (0.4 ml), and the mixture was stirred for 3 hours. Water and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction with ethyl acetate, and the combined organic layers were washed with water and saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography (developing solvent: ethyl acetate) to obtain the title compound (0.019 g) with a yield of 79%.

[1355] 1H-NMR(DMSO-D6)δ:11.30(1H,s),8.03(1H,d,J=1.8Hz),7.99(1H,d,J=8.3Hz ),7.87(1H,dd,J=8.4,2.0Hz),5.89(1H,d,J=2.8Hz),5.46(1H,d,J=8.6Hz),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=6.5Hz),0.56-0.46(2H,m),0.31-0.22(2H,m).

[1356] [Preparation Example 6]: N 1 -((S)-1-(cis-5-(4-chloro-6-methylpyridin-3-yl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-N 2 -Synthesis of Methyloxamide (Example 230)

[1357]

[1358] (1) Tert-butyl ((S)-1-(cis-4-(4-chloro-6-methylnicotinoyl)-4-((trimethylsilyl)oxy)cyclohexyl)propan-2-yl)carbamate

[1359]

[1360] Trimethylsilyl cyanide (0.55 ml) was added to a mixture of 4-chloro-6-methylnicotinaldehyde (0.55 g) and lithium chloride (0.015 g), and the mixture was stirred at room temperature for 10 minutes. THF (7 ml) was added thereto, and the mixture was cooled to -78 ° C. 1M NaHMDS-THF solution (1.9 ml) was added thereto, and the mixture was stirred for 5 minutes. (S)-(1-(4-oxocyclohexyl)propan-2-yl)carbamic acid tert-butyl ester (0.7 g) (obtained in the same manner as in (9) of [Preparation Example 1]) was added thereto, and the mixture was stirred for 30 minutes, and heated to 0 ° C within 1 hour. Water and ethyl acetate were added thereto, and the mixture was subjected to extraction. The water layer was subjected to re-extraction twice with ethyl acetate, and the combined organic layer was washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane) to give the title compound (1.1 g) in a yield of 83%.

[1361] 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=6.5Hz),0.06(9H,s).

[1362] (2) Tert-butyl ((S)-1-(cis-4-(4-chloro-6-methylnicotinoyl)-4-hydroxycyclohexyl)propan-2-yl)carbamate

[1363]

[1364] 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) were added acetic acid (0.39 ml) and 1M TBAF-THF solution (3.4 ml) at room temperature, and the mixture was stirred for 15 minutes and allowed to stand for a whole day. Saturated aqueous ammonium chloride solution, water and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction twice with ethyl acetate, and the combined organic layers were washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane) to obtain the title compound (0.80 g) in a yield of 86%.

[1365] 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=6.5Hz).

[1366] (3) cis-9-((S)-2-aminopropyl)-5-(4-chloro-6-methylpyridin-3-yl)-1-oxa-3,4-diazaspiro[5.5]undec-4-en-2-one dihydrochloride

[1367]

[1368] 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) were added DBU (0.044 ml) and CDI (0.47 g) at room temperature, and the mixture was stirred for 1 hour. Hydrazine monohydrate (0.19 ml) was added thereto, and the mixture was stirred for 1 hour. A 10% citric acid aqueous solution and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction twice with ethyl acetate, and the combined organic layers were washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate 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 6M hydrochloric acid (4.5 ml) were added to the obtained solid at room temperature, and the mixture was stirred all day and then stirred at 50° C. for 6 hours. The reaction solution was concentrated under reduced pressure, followed by azeotroping with THF (10 ml) twice to give the title compound (0.98 g).

[1369] 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=6.5Hz).

[1370] (4)N 1 -((S)-1-(cis-5-(4-chloro-6-methylpyridin-3-yl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-N 2 -Methyloxalamide

[1371]

[1372] To a solution of cis-9-((S)-2-aminopropyl)-5-(4-chloro-6-methylpyridin-3-yl)-1-oxa-3,4-diazaspiro[5.5]undec-4-ene-2-one dihydrochloride (0.1 g) obtained in (3) in DMF (1.5 ml) at room temperature were added 2-methylamino-2-oxoacetic acid (0.045 g), HOAt (0.062 g) and N,N-diisopropylethylamine (0.23 ml). WSC (0.087 g) was added thereto, and the mixture was stirred at room temperature for 15 minutes and allowed to stand for a whole day. Water, saturated aqueous sodium bicarbonate solution and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to reextraction twice with ethyl acetate, and the combined organic layers were washed with saturated brine and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure and then azeotroped with toluene (5 ml). The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane) to give the title compound (0.067 g) in a yield of 71%.

[1373] 1H-NMR(DMSO-D6)δ:11.28(1H,s),8.62(1H,q,J=4.8Hz),8.48(1H,s),8.41(1H,d,J=9.2Hz),7.58(1H,s),3.98-3.83(1H ,m),2.64(3H,d,J=4.8Hz),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=6.5Hz).

[1374] [Preparation Example 7]: Synthesis of N-((S)-1-(cis-5-(2-bromo-4-fluorophenyl)-9-hydroxy-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-3-methyl-1H-pyrazole-5-carboxamide (Example 320)

[1375]

[1376] (1) 1,4-Dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate

[1377]

[1378] A solution of 1,4-dioxaspiro[4.5]decane-8-one (5g) in THF (50ml) was cooled to -78°C, 1.1M LiHMDS-n-hexane solution (31ml) was added thereto, and the mixture was stirred for 10 minutes. The mixture was heated to 0°C, stirred for 20 minutes, and cooled to -78°C, and Comins reagent (14g) was added thereto. The mixture was stirred for 30 minutes, heated to 0°C, and stirred for an additional 1.5 hours. Saturated aqueous sodium bicarbonate solution, water and ethyl acetate were added thereto, and the mixture was subjected to extraction. The water layer was subjected to re-extraction with ethyl acetate, and the combined organic layers were washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane) to obtain the title compound (7.5g) with a yield of 81%.

[1379] 1H-NMR (CDCl3) δ: 5.69-5.65 (1H, m), 4.00 (4H, t, J = 2.4Hz), 2.54 (2H, t, J = 6.5Hz), 2.41 (2H, d, J = 2.7Hz), 1.91 (2H, t, J = 6.7Hz).

[1380] (2) (S)-2-((tert-Butyloxycarbonyl)amino)methanesulfonic acid propyl ester

[1381]

[1382] At room temperature, triethylamine (16 ml) was added to a solution of (S)-(1-hydroxypropyl-2-yl)carbamic acid tert-butyl ester (10 g) in THF (100 ml). The mixture was cooled to 0° C., methanesulfonic anhydride (11 g) was added thereto, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane) to obtain the title compound (13.7 g) with a yield of 95%.

[1383] 1H-NMR(CDCl3)δ:4.68-4.49(1H,m),4.28-4.19(1H,m),4.15(1H,dd,J=9.7, 4.3Hz),4.04-3.88(1H,m),3.04(3H,s),1.45(9H,s),1.24(3H,d,J=7.0Hz).

[1384] (3) Tert-butyl (S)-(1-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)propan-2-yl)carbamate

[1385]

[1386] To a solution of 1,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (5 g) obtained in (1) in DMA (100 ml) were added (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate (7.9 g) obtained in (2), nickel (II) iodide (0.093 ml), 2,2':6',2"-tripyridine (0.61 g), manganese (2.9 g) and sodium iodide (1.3 g) at room temperature, and the mixture was stirred at 80°C for 1.5 hours. Water and ethyl acetate were added thereto at room temperature, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction twice with ethyl acetate, and the combined organic layers were washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane) to obtain the title compound (1.9 g) with a yield of 37%.

[1387] 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=6.5Hz),1.43(9H,s),1.10(3H,d,J=6.5Hz).

[1388] (4) Tert-butyl (S)-(1-(4-oxocyclohex-1-en-1-yl)propan-2-yl)carbamate

[1389]

[1390] At room temperature, acetic acid (8 ml) was added to a solution of tert-butyl (S)-(1-(1,4-dioxaspiro[4,5]dec-7-ene-8-yl)propan-2-yl)carbamate (0.5 g) obtained in (3) in water (2 ml), and the mixture was stirred for 15 minutes and allowed to stand for a whole day. The reaction solution was concentrated under reduced pressure, then azeotroped with toluene (2 ml) three times, and the obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane) to obtain the title compound (0.37 g) with a yield of 87%.

[1391] 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=6.5Hz).

[1392] (5) tert-Butyl ((2S)-1-(4-(2-bromo-4-fluorobenzoyl)-4-((trimethylsilyl)oxy)cyclohex-1-en-1-yl)propan-2-yl)carbamate

[1393]

[1394] At room temperature, trimethyl cyanide (0.12ml) was added to 2-bromo-4-fluorobenzaldehyde (0.16g) and lithium chloride (0.003g), and the mixture was stirred for 10 minutes. THF (1.5ml) was added thereto, and the mixture was cooled to -78°C. 1M NaHMDS-THF solution (0.77ml) was added thereto, and the mixture was stirred for 5 minutes. (S)-(1-(4-oxocyclohex-1-ene-1-yl) propan-2-yl) tert-butyl carbamate (0.15g) obtained in (4) was added to the reaction solution, and the mixture was stirred for 30 minutes. The mixture was heated to 0°C in 1 hour, water and ethyl acetate were added thereto, and the mixture was subjected to extraction. The water layer was subjected to re-extraction twice with ethyl acetate, and the combined organic layer was washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane) to give the title compound (0.22 g) in a yield of 66%.

[1395] 1H-NMR(CDCl3)δ:7.65(0.3H,dd,J=8.6,6.5Hz), 7.56(0.7H,dd,J=8.1,6.5Hz), 7.36(1H,d,J=8.1Hz),7.04(1H,t,J=8.4Hz),5.36(1H,s),4.37-4.21(1H,m),3.8 8-3.74(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=6.5Hz), 1.12(0.9H,d,J=6.5Hz), 0.01(6.3H,s), 0.00(2.7H,s).

[1396] (6) tert-Butyl ((2S)-1-(4-(2-bromo-4-fluorobenzoyl)-4-hydroxycyclohex-1-en-1-yl)propan-2-yl)carbamate

[1397]

[1398] To a solution of tert-butyl ((2S)-1-(4-(2-bromo-4-fluorobenzoyl)-4-((trimethylsilyl)oxy)cyclohex-1-ene-1-yl)propan-2-yl)carbamate (0.22 g) obtained in (5) in THF (0.41 ml) was added acetic acid (0.067 ml) and 1M TBAF-THF solution (0.59 ml) at room temperature, and the mixture was stirred for 15 minutes and allowed to stand at room temperature for a whole day. Saturated aqueous ammonium chloride solution, water and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction twice with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane) to obtain the title compound (0.17 g) in a yield of 66%.

[1399] 1H-NMR(CDCl3)δ:7.50-7.41(0.3H,m),7.40-7.29(1.7H,m),7.12-6.96(1 H,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 = 7.5Hz), 1.12 (2.1H, d, J = 6.5Hz).

[1400] (7) tert-Butyl ((2S)-1-(5-(2-bromo-4-fluorophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4,8-dien-9-yl)propan-2-yl)carbamate

[1401]

[1402] To a solution of tert-butyl ((2S)-1-(4-(4-(2-bromo-4-fluorobenzoyl)-4-hydroxycyclohex-1-en-1-yl)propan-2-yl)carbamate (0.17 g) obtained in (6) in THF (1.7 ml) were added DBU (0.009 ml) and CDI (0.093 g) at room temperature, and the mixture was stirred for 30 minutes. Hydrazine monohydrate (0.037 ml) was added thereto, and the mixture was stirred at room temperature for 30 minutes. A 10% citric acid aqueous solution and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction twice with ethyl acetate, and the combined organic layers were washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane). THF was added to the obtained solid at room temperature. HF (1.5ml) and 6M hydrochloric acid (0.73ml), and the mixture was stirred for 15 minutes, and it was allowed to stand all day. The mixture was stirred at 50 ℃ for 1.5 hours, and the reaction solution was concentrated under reduced pressure, followed by azeotropy twice with THF (2ml). At room temperature, saturated sodium bicarbonate aqueous solution (0.65mL), THF (1.3ml), water (0.65ml) and Boc2O (0.19ml) were added to the obtained solid, and the mixture was stirred all day. Water and ethyl acetate were added thereto, and the mixture was subjected to extraction. The water layer was subjected to re-extraction twice with ethyl acetate, and the combined organic layer was washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane) to obtain the title compound (0.12g) with a yield of 88%.

[1403] 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 = 7.0Hz), 1.07 (2.1H, d, J = 7.0Hz).

[1404] (8) tert-butyl ((S)-1-(cis-5-(2-bromo-4-fluorophenyl)-9-hydroxy-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-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]undec-4-en-9-yl)propan-2-yl)carbamate (trans isomer)

[1405]

[1406] At room temperature, to a solution of tert-butyl ((2S)-1-(5-(2-bromo-4-fluorophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]11 carbon-4,8-diene-9-yl)propan-2-yl)carbamate (0.12 g) obtained in (7) in THF (1.8 ml) was added cobalt (II) acetylacetonate (0.063 g) and phenylsilane (0.30 ml), and the mixture was stirred under an oxygen atmosphere for a whole day. Saturated aqueous sodium thiosulfate solution, water and ethyl acetate were added thereto, and the mixture was subjected to extraction. The water layer was subjected to re-extraction twice with ethyl acetate, and the combined organic layer was washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane) to give a cis isomer (0.047 g) of the title compound in 27% yield and a trans isomer (0.060 g) of the title compound in 30% yield.

[1407] (cis isomer)

[1408] 1H-NMR(CDCl3)δ:8.22-8.08(1H,m),7.43(1H,dd,J=8.1,2.2Hz),7.27-7.22(1H,m),7.11(1H,td,J=8.1,2.5Hz), 4.63(1H,d,J=6. 5Hz),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=6.5Hz).

[1409] (Trans isomer)

[1410] 1H-NMR(CDCl3)δ:8.10(1H,s),7.40(1H,dd,J=8.1,2.2Hz),7.28-7.22(1H,m),7.10(1H,t,J=8.6Hz),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=7.0Hz).

[1411] (9) cis-9-((S)-2-aminopropyl)-5-(2-bromo-4-fluorophenyl)-9-hydroxy-1-oxa-3,4-diazaspiro[5.5]undec-4-en-2-one

[1412]

[1413] To a solution of tert-butyl ((S)-1-(cis-5-(2-bromo-4-fluorophenyl)-9-hydroxy-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)carbamate (0.039 g) obtained in (8) in chloroform (0.39 ml) was added trifluoroacetic acid (0.39 ml) at room temperature, and the mixture was stirred for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (InertSep (registered trademark) SCX, developing solvent: methanol / 2 M ammonia-methanol solution) to give the title compound (0.030 g) with a yield of 85%.

[1414] 1H-NMR(DMSO-D6)δ:11.30-11.21(1H,m),7.75(1H,dd,J=8.6,2.7Hz),7.56(1H,dd,J=8.9,5.7Hz),7.40-7.3 2(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=6.5Hz).

[1415] (10) N-((S)-1-(cis-5-(2-bromo-4-fluorophenyl)-9-hydroxy-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-3-methyl-1H-pyrazole-5-carboxamide

[1416]

[1417] 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) at room temperature were added 3-methyl-1H-pyrazole-5-carboxylic acid (0.005 g), HOAt (0.006 g) and N,N-diisopropylethylamine (0.017 ml). WSC (0.008 g) was added thereto, and the mixture was stirred at room temperature for 15 minutes and allowed to stand for a whole day. Water, saturated aqueous sodium bicarbonate solution and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction twice with ethyl acetate, and the combined organic layers were washed with saturated brine and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure and then azeotroped twice with toluene (2 ml). The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane) and then by reverse phase silica gel chromatography (developing solvent: acetonitrile / water) to obtain the title compound (0.004 g) in a yield of 26%.

[1418] 1H-NMR(DMSO-D6)δ:12.81(1H,s),11.24(1H,s),7.90-7.79(1H,m),7.74(1H,d,J=8.1Hz),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=5.9Hz).

[1419] [Preparation Example 8]: Synthesis of N-((S)-1-(trans-5-(2-bromo-4-fluorophenyl)-9-hydroxy-2-oxo-1-oxa-3,4-diazaspiro[5,5]undec-4-en-9-yl)propan-2-yl)-3-methyl-1H-pyrazole-5-carboxamide (Example 322)

[1420]

[1421] (1) trans-9-((S)-2-aminopropyl)-5-(2-bromo-4-fluorophenyl)-9-hydroxy-1-oxa-3,4-diazaspiro[5.5]undec-4-en-2-one

[1422]

[1423] 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]undec-4-en-9-yl)propan-2-yl)carbamate (0.056 g) (obtained in (8) of [Preparation Example 7]) in chloroform (0.44 ml) was added trifluoroacetic acid (0.44 ml) at room temperature, and the mixture was stirred for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (InertSep (registered trademark) SCX, developing solvent: methanol / 2M ammonia-methanol solution) to obtain the title compound (0.036 g) with a yield of 100%.

[1424] LC-MS(M+1):414

[1425] (2) N-((S)-1-(trans-5-(2-bromo-4-fluorophenyl)-9-hydroxy-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-3-methyl-1H-pyrazole-5-carboxamide

[1426]

[1427] To a solution of trans-9-((S)-2-aminopropyl)-5-(2-bromo-4-fluorophenyl)-9-hydroxy-1-oxa-3,4-diazaspiro[5,5]undec-4-ene-2-one (0.016 g) obtained in (1) in DMF (0.24 ml) at room temperature were added 3-methyl-1H-pyrazole-5-carboxylic acid (0.006 g), HOAt (0.007 g) and N,N-diisopropylethylamine (0.020 ml). WSC (0.010 g) was added thereto, and the mixture was stirred at room temperature for 15 minutes and allowed to stand for a whole day. Water, saturated aqueous sodium bicarbonate solution and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction twice with ethyl acetate, and the combined organic layers were washed with saturated brine and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure and then azeotroped twice with toluene (2 ml). The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane) and then by reverse phase silica gel chromatography (developing solvent: acetonitrile / water) to give the title compound (0.007 g) in a yield of 34%.

[1428] 1H-NMR(DMSO-D6)δ:12.80(1H,s),11.18(1H,s),7.85(1H,d,J=7.5Hz),7.7 4(1H,dd,J=8.6,2.7Hz),7.51(1H,dd,J=8.6,5.9Hz),7.37(1H,ddd,J=8.6, 8.1,2.7Hz),6.31(1H,s),4.25-4.08(1H,m),4.21(1H,s),2.24(3H,s),1.9 7-1.82(2H,m),1.82-1.66(3H,m),1.66-1.34(5H,m),1.12(3H,d,J=6.5Hz).

[1429] [Preparation Example 9]: N 1 -((S)-1-(trans-5-(2-bromo-3-fluorophenyl)-9-cyano-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-N 2 -Synthesis of Methyloxamide (Example 2-153)

[1430]

[1431] (1) Tert-butyl (S)-(1-(8-cyano-1,4-dioxaspiro[4.5]decane-8-yl)propan-2-yl)carbamate

[1432]

[1433] A solution of 1,4-dioxaspiro [4.5] decane-8-carbonitrile (7.5 g) in THF (75 ml) was cooled to -78 ° C, 1.11 MLDA-THF / n-hexane solution (48.5 ml) was added thereto, and the mixture was stirred for 1 hour. (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2,2-dioxide (12.8 g) was added thereto, and the mixture was heated to 0 ° C and stirred for 1 hour. 1 M hydrochloric acid (135 ml) was added thereto, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate and water were added thereto, and the mixture was subjected to extraction. The organic layer was washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane = 25 / 75 to 55 / 45), and the fractions were concentrated under reduced pressure to give the title compound (14.3 g) in a yield of 98%.

[1434] 1H-NMR (DMSO-D6) δ: 6.78 (1H, d, J = 8.6Hz), 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 = 6.5Hz).

[1435] (2) Tert-butyl (S)-(1-(1-cyano-4-oxocyclohexyl)propan-2-yl)carbamate

[1436]

[1437] At room temperature, to a solution of (S)-(1-(8-cyano-1,4-dioxaspiro[4.5]decane-8-yl)propan-2-yl)carbamic acid tert-butyl ester (10.9 g) obtained in (1) in THF (54.5 ml) was added 6 M hydrochloric acid (28 ml), and the mixture was stirred at 60 ° C for 6 hours. After standing at room temperature for 3 days, 10 M sodium hydroxide aqueous solution (16.8 ml) and Boc2O (23.4 ml) were added thereto, and the mixture was stirred for 2 hours. Ethyl acetate and water were added thereto, and the mixture was subjected to extraction. The organic layer was washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane=30 / 70 to 65 / 35), and the fractions were concentrated under reduced pressure to obtain the title compound (5.59 g) with a yield of 59%.

[1438] 1H-NMR(DMSO-D6)δ:6.84(1H,d,J=9.2Hz),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=14.3,3.5Hz),1.38(9H,s),1.09(3H,d,J=6.5Hz).

[1439] (3) Tert-butyl ((S)-1-(trans-4-(2-bromo-3-fluorobenzoyl)-1-cyano-4-((trimethylsilyl)oxy)cyclohexyl)propan-2-yl)carbamate

[1440]

[1441] Under argon atmosphere, at room temperature, trimethylsilyl cyanide (0.27ml) was added to a solution of 2-bromo-3-fluorobenzaldehyde (0.38g) and lithium chloride (0.008g) in THF (0.8ml), and the mixture was stirred for 30 minutes. THF (5.2ml) was added thereto, and the mixture was cooled to -78°C and stirred for 5 minutes. 1.13M LiHMDS-n-hexane solution (1.6ml) was added thereto, and the mixture was stirred for 10 minutes. (S)-(1-(1-cyano-4-oxocyclohexyl)propan-2-yl) tert-butyl carbamate (0.40g) obtained in (2) was added thereto, and the mixture was stirred for 30 minutes. Then, the mixture was heated to 0°C in 1 hour, water and ethyl acetate were added thereto, and the mixture was subjected to extraction. The organic layer was washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane = 3 / 97 to 30 / 70), and the fractions were concentrated under reduced pressure to give the title compound (0.62 g) in a yield of 78%.

[1442] 1H-NMR(DMSO-D6)δ:7.59-7.41(2H,m),7.39-7.33(1H,m),6.84(1H,d,J=8.6Hz),3.8 2-3.67(1H,m),2.07-1.49(10H,m),1.37(9H,s),1.08(3H,d,J=6.5Hz),0.04(9H,s).

[1443] (4) tert-Butyl ((S)-1-(trans-4-(2-bromo-3-fluorobenzoyl)-1-cyano-4-hydroxycyclohexyl)propan-2-yl)carbamate

[1444]

[1445] To a solution of tert-butyl ((S)-1-(trans-4-(2-bromo-3-fluorobenzoyl)-1-cyano-4-((trimethylsilyl)oxy)cyclohexyl)propan-2-yl)carbamate obtained in (3) in THF (3.1 ml) at room temperature, acetic acid (0.19 ml) and 1M TBAF-THF solution (1.7 ml) were added, and the mixture was stirred for 2 hours. Saturated aqueous sodium bicarbonate solution and ethyl acetate were added thereto, and the mixture was subjected to extraction, and the organic layer was dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane=30 / 70 to 60 / 40), and the fractions were concentrated under reduced pressure to obtain the title compound (0.25 g) with a yield of 46%.

[1446] 1H-NMR(DMSO-D6)δ:7.55-7.39(2H,m),7.32-7.27(1H,m),6.81(1H,d,J=8.6Hz),5.5 3(1H,s),3.83-3.69(1H,m),2.02-1.49(10H,m),1.37(9H,s),1.07(3H,d,J=6.5Hz).

[1447] (5) trans-9-((S)-2-aminopropyl)-5-(2-bromo-3-fluorophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-ene-9-carbonitrile hydrochloride

[1448]

[1449] 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) at room temperature, CDI (0.13 g) and DBU (0.012 ml) were added, and the mixture was stirred for 30 minutes. Hydrazine monohydrate (0.069 ml) was added, and the mixture was stirred for 30 minutes. A 10% aqueous citric acid solution and ethyl acetate were added thereto, and the mixture was subjected to extraction. The organic layer was dried over sodium sulfate, the sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane=50 / 50 to 90 / 10), and the fractions were concentrated under reduced pressure. To the obtained solid were added THF (2.3 ml) and 6M hydrochloric acid (1.1 ml), and the mixture was stirred at 50° C. for 2 hours. The reaction solution was concentrated under reduced pressure, followed by azeotropy with THF to give the title compound (0.17 g) in a yield of 72%.

[1450] 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=6.5Hz).

[1451] (6)N 1 -((S)-1-(trans-5-(2-bromo-3-fluorophenyl)-9-cyano-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-N 2-Methyloxalamide

[1452]

[1453] To a solution of trans-9-((S)-2-aminopropyl)-5-(2-bromo-3-fluorophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-ene-9-carbonitrile hydrochloride (0.025 g) obtained in (5) in DMF (0.4 ml) were added 2-methylamino-2-oxoacetic acid (0.007 g), N,N-diisopropylethylamine (0.048 ml) and HATU at room temperature, and the mixture was stirred for 1 hour. The reaction solution was purified by reverse phase silica gel chromatography (developing solvent: acetonitrile / water = 5 / 95 to 70 / 30) and then by thin layer chromatography (developing solvent: ethyl acetate), and the fractions were concentrated under reduced pressure to obtain the title compound (0.018 g) with a yield of 65%.

[1454] 1H-NMR(DMSO-D6)δ:11.39(1H,s),8.72(1H,d,J=9.2Hz),8.63-8.57(1H,m),7.58-7.47(2H,m),7.38-7.34(1 H,m),4.17-4.04(1H,m),2.64(3H,d,J=4.8Hz),2.27-1.95(4H,m),1.81-1.53(6H,m),1.12(3H,d,J=6.5Hz).

[1455] [Preparation Example 10]: N 1 -((S)-1-(trans-5-(2-bromo-5-cyanophenyl)-9-methoxy-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-N 2 -Synthesis of Methyloxamide (Example 2-123)

[1456]

[1457] (1) 1-(8-methoxy-1,4-dioxaspiro[4.5]decane-8-yl)propan-2-one

[1458]

[1459] At room temperature, dimethyl (2-oxopropyl) phosphonate (5.9 g) and 28% sodium methoxide-methanol solution (23.5 ml) were added to a solution of 1,4-dioxaspiro[4.5]decane-8-one (5.0 g) in methanol (50 ml), and the mixture was stirred for a whole day. Water (20 ml) was added thereto, and the mixture was concentrated under reduced pressure to evaporate methanol. The mixture was diluted with ethyl acetate and washed with saturated brine. The obtained organic layer was dried over sodium sulfate, sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane=20 / 80 to 50 / 50), and the fractions were concentrated under reduced pressure to obtain the title compound (2.1 g) with a yield of 28%.

[1460] 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).

[1461] (2) (S)-1-(8-methoxy-1,4-dioxaspiro[4.5]decane-8-yl)-N-((S)-1-phenylethyl)propan-2-amine

[1462]

[1463] At room temperature, to a solution of 1-(8-methoxy-1,4-dioxaspiro[4.5]decane-8-yl)propan-2-one (2.1 g) obtained in (1) in THF (31 ml), (S)-1-phenylethylamine (1.3 ml), acetic acid (0.52 ml) and sodium triacetoxyborohydride (3.6 g) were added, and the mixture was stirred for 3 hours. Under ice cooling, 4M aqueous sodium hydroxide solution (11.3 ml) and water were added thereto, and the mixture was diluted with ethyl acetate. The obtained organic layer was washed with saturated brine. The organic layer was dried over sodium sulfate, sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: methanol / ethyl acetate / n-hexane=0 / 25 / 75 to 0 / 100 / 0 to 5 / 95 / 0), and the fractions were concentrated under reduced pressure to obtain the title compound (1.4 g) with a yield of 46%.

[1464] 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=6.7Hz), 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=6.6Hz).

[1465] (3) Tert-butyl (S)-(1-(8-methoxy-1.4-dioxaspiro[4.5]decane-8-yl)propan-2-yl)carbamate

[1466]

[1467] At room temperature, acetic acid (0.48 ml) and 20% palladium hydroxide-activated carbon were added to a solution of (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) in THF (14 ml), and the mixture was stirred for a whole day under a hydrogen atmosphere (1 atm). The reaction solution was filtered through diatomaceous earth and subsequently washed with THF (14 ml). Water (4.8 ml), sodium bicarbonate (1.1 g) and Boc2O (1.1 ml) were added to the obtained THF solution at room temperature, and the mixture was stirred for 2 hours. The mixture was diluted with ethyl acetate and washed with saturated brine. The obtained organic layer was dried over sodium sulfate, the sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane = 15 / 85 to 50 / 50), and the fractions were concentrated under reduced pressure to give the title compound (1.0 g) in a yield of 76%.

[1468] 1H-NMR(DMSO-D6)δ:6.62(1H,d,J=8.1Hz),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=6.5Hz).

[1469] (4) (S)-tert-Butyl (1-(1-methoxy-4-oxocyclohexyl)propan-2-yl)carbamate

[1470]

[1471] At room temperature, 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, and the mixture was stirred at 60 ° C for 6 hours. Saturated sodium bicarbonate aqueous solution (5 ml) was added thereto at room temperature, and acetone was evaporated. Ethyl acetate was added thereto, and the mixture was subjected to extraction. The obtained organic layer was washed with saturated brine and dried over sodium sulfate, sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane=20 / 80 to 55 / 45), and the fractions were concentrated under reduced pressure to obtain the title compound (0.77 g) with a yield of 85%.

[1472] 1H-NMR(DMSO-D6)δ:6.68(1H,d,J=8.6Hz),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=6.5Hz).

[1473] (5) tert-Butyl ((S)-1-(trans-4-(2-bromo-5-cyanobenzoyl)-1-methoxy-4-((trimethylsilyl)oxy)cyclohexyl)propan-2-yl)carbamate

[1474]

[1475] Under argon atmosphere, trimethylsilyl cyanide (0.16ml) was added to a solution of 4-bromo-3-cyanobenzaldehyde (0.24g) and lithium chloride (0.005g) in THF (0.5ml), and the mixture was stirred at room temperature for 30 minutes. THF (3.3ml) was added thereto, and the mixture was cooled to -78°C and stirred for 5 minutes. 1.13M LiHMDS-n-hexane solution (1.0ml) was added thereto, and the mixture was stirred for 10 minutes. (S)-(1-(1-methoxy-4-oxocyclohexyl)propan-2-yl) tert-butyl carbamate (0.25g) obtained in (4) was added thereto, and the mixture was stirred for 30 minutes. The mixture was then heated to 0°C in 1 hour, water and ethyl acetate were added thereto, and the mixture was subjected to extraction. The organic layer was washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane = 5 / 95 to 33 / 67), and the fractions were concentrated under reduced pressure to give the title compound (0.23 g) in a yield of 45%.

[1476] 1H-NMR(DMSO-D6)δ:8.05-7.82(3H,m),6.69(1H,d,J=8.1Hz),3.67-3.51(1H,m),3.0 0(3H,s),2.01-1.31(10H,m),1.36(9H,s),1.04(3H,d,J=6.5Hz),0.00-0.03(9H,m).

[1477] (6) Tert-butyl ((S)-1-(trans-4-(2-bromo-5-cyanobenzoyl)-4-hydroxy-1-methoxycyclohexyl)propan-2-yl)carbamate

[1478]

[1479] To a solution of tert-butyl ((S)-1-(trans-4-(2-bromo-5-cyanobenzoyl)-1-methoxy-4-((trimethylsilyl)oxy)cyclohexyl)propan-2-yl)carbamate obtained in (5) in THF (2.2 ml) at room temperature, acetic acid (0.067 ml) and 1M TBAF-THF solution (0.58 ml) were added, and the mixture was stirred for 2 hours. Saturated aqueous sodium bicarbonate solution and ethyl acetate were added thereto, and the mixture was subjected to extraction. The organic layer was washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane=30 / 70 to 60 / 40), and the fractions were concentrated under reduced pressure to obtain the title compound (0.15 g) with a yield of 78%.

[1480] 1H-NMR(DMSO-D6)δ:7.93-7.88(2H,m),7.84-7.79(1H,m),6.64(1H,d,J=8.1Hz),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=6.5Hz).

[1481] (7) 3-(trans-9-((S)-2-aminopropyl)-9-methoxy-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-5-yl)-4-bromobenzonitrile hydrochloride

[1482]

[1483] To a solution of tert-butyl ((S)-1-(trans-4-(2-bromo-5-cyanobenzoyl)-4-hydroxy-1-methoxycyclohexyl)propan-2-yl)carbamate obtained in (6) in THF (1.5 ml) were added CDI (0.073 g) and DBU (0.007 ml), and the mixture was stirred at room temperature for 30 minutes. Hydrazine monohydrate (0.045 ml) was added thereto, and the mixture was stirred for 30 minutes. A 10% aqueous citric acid solution and ethyl acetate were added thereto, and the mixture was subjected to extraction, and the organic layer was dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane=50 / 50 to 90 / 10), and the fractions were concentrated under reduced pressure. To the obtained solid were added THF (1.6 ml) and 6M hydrochloric acid (0.8 ml), and the mixture was stirred at 50° C. for 2 hr. The mixture was cooled to room temperature, and the reaction solution was concentrated and then azeotroped with THF to give the title compound (0.14 g) in 96% yield.

[1484] 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=6.5Hz).

[1485] (8)N 1-((S)-1-(trans-5-(2-bromo-5-cyanophenyl)-9-methoxy-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-N 2 -Methyloxalamide

[1486]

[1487] To a solution of 3-(trans-9-((S)-2-aminopropyl)-9-methoxy-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-5-yl)-4-bromobenzonitrile hydrochloride (0.050 g) obtained in (7) in DMF (0.75 ml) were added 2-methylamino-2-oxoacetic acid (0.016 g), N,N-diisopropylethylamine (0.074 ml) and HATU (0.060 g) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified by reverse phase silica gel chromatography (developing solvent: acetonitrile / water = 5 / 95 to 65 / 35) and then by thin layer chromatography (developing solvent: ethyl acetate / n-hexane = 67 / 33), and the fractions were concentrated under reduced pressure to obtain the title compound (0.049 g) with a yield of 89%.

[1488] 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=6.5Hz).

[1489] The compounds of other examples are obtained by using the same method as the above preparation method or the preparation example, and when necessary, by using a known method. The structural formulas and physical property data of the compounds of Examples 1 to 339 and 2-001 to 2-172 are shown in Tables 1-1 to 1-61.

[1490] Table 1-1

[1491]

[1492] Table 1-2

[1493]

[1494] Table 1-3

[1495]

[1496] Table 1-4

[1497]

[1498] Table 1-5

[1499]

[1500] Table 1-6

[1501]

[1502] Table 1-7

[1503]

[1504] Table 1-8

[1505]

[1506] Table 1-9

[1507]

[1508] Table 1-10

[1509]

[1510] Table 1-11

[1511]

[1512] Table 1-12

[1513]

[1514] Table 1-13

[1515]

[1516] Table 1-14

[1517]

[1518] Table 1-15

[1519]

[1520] Table 1-16

[1521]

[1522] Table 1-17

[1523]

[1524] Table 1-18

[1525]

[1526] Table 1-19

[1527]

[1528] Table 1-20

[1529]

[1530] Table 1-21

[1531]

[1532] Table 1-22

[1533]

[1534] Table 1-23

[1535]

[1536] Table 1-24

[1537]

[1538] Table 1-25

[1539]

[1540] Table 1-26

[1541]

[1542] Table 1-27

[1543]

[1544] Table 1-28

[1545]

[1546] Table 1-29

[1547]

[1548] Table 1-30

[1549]

[1550] Table 1-31

[1551]

[1552] Table 1-32

[1553]

[1554] Table 1-33

[1555]

[1556] Table 1-34

[1557]

[1558] Table 1-35

[1559]

[1560] Table 1-36

[1561]

[1562] Table 1-37

[1563]

[1564] Table 1-38

[1565]

[1566] Table 1-39

[1567]

[1568] Table 1-40

[1569]

[1570] Table 1-41

[1571]

[1572] Table 1-42

[1573]

[1574] Table 1-43

[1575]

[1576] Table 1-44

[1577]

[1578] Table 1-45

[1579]

[1580] Table 1-46

[1581]

[1582] Table 1-47

[1583]

[1584] Table 1-48

[1585]

[1586] Table 1-49

[1587]

[1588] Table 1-50

[1589]

[1590] Table 1-51

[1591]

[1592] Table 1-52

[1593]

[1594] Table 1-53

[1595]

[1596] Table 1-54

[1597]

[1598] Table 1-55

[1599]

[1600] Table 1-56

[1601]

[1602] Table 1-57

[1603]

[1604] Table 1-58

[1605]

[1606] Table 1-59

[1607]

[1608] Table 1-60

[1609]

[1610] Table 1-61

[1611]

[1612] Experimental Example 1: Evaluation of human PLD1 enzyme inhibitory activity

[1613] Shown below is a method for measuring human PLD1 enzyme inhibitory activity using an enzyme in which a FLAG tag is added to the N-terminus of full-length human PLD1 (1-1036 amino acids).

[1614] 1. Preparation of Full-length Human PLD1 Expression Plasmid

[1615] Using the commercially available human PLD1 gene (Promega KK) as a template, a DNA fragment in which the FLAG tag sequence is added to the 5' end of the full-length human PLD1 is amplified by the PCR method. The amplified DNA fragment is fused with the vector pVL1393 (Pharmingen) for baculovirus production digested with BamHI and EcoRI using the In-Fusion HD cloning kit (TakaraBio). The baculovirus full-length human PLD1 expression plasmid DNA is isolated from the Escherichia coli DH5α (TOYOBO) transformed with the obtained In-Fusion reaction product. Next, using the full-length human PLD1 expression plasmid DNA for baculovirus as a template, a DNA fragment in which the FLAG tag sequence is added to the 5' end of the full-length human PLD1 is amplified by the PCR method. The amplified DNA fragment is fused with the DNA fragment in which the linker sequence is introduced into pcDNA3.4-TOPO (Life Technologies) using the In-Fusion HD cloning kit (Takara Bio). The full-length human PLD1 expression plasmid DNA for animal cells was isolated from E. coli DH5α transformed with the obtained In-Fusion reaction product. The base sequence of the full-length human PLD1 cloned into the vector was determined by the dye terminator method using the BigDyeTerminator v3.1 cycle sequencing kit (Applied Biosystems). The determined sequence is a sequence in which the FLAG tag sequence is inserted into the 5' end of the full-length human PLD1 (GenBank accession number: NM_001130081).

[1616] 2. Preparation of full-length human PLD1 protein in the Expi293F cell expression system

[1617] Expi293 expression medium (Life Technologies) was used as a culture medium, and Expi293F cells (Life Technologies) were cultured with shaking at 37°C and in the presence of 8% CO2. The gene introduction reagent PEI was prepared by dissolving Polyethyleenimine Max (nominal MW 40,000) (Polysciences) in MilliQ water, adjusting the pH of the solution to 7.0 with NaOH to obtain a 1 mg / mL solution, and then filtering the solution through a 0.22 μm filter. Full-length human PLD1 expression plasmid DNA for animal cells was transfected into Expi293F cells using PEI, and after 48 hours of shaking culture, the cells were collected and stored at -80°C.

[1618] 3. Purification of Full-length Human PLD1 Protein

[1619] Homogenization buffer (20 mmol / L pH 7.5 sodium phosphate, 250 mmol / L NaCl, 1 mmol / L MgCl2, 1% β-OG, 0.05 mmol / L DTT + completely EDTA-free (Roche Diagnostics KK)) was added to cells expressing full-length human PLD1, and the cells were lysed by a microfluidizer M-110EH (Mizuho Kogyo Co., Ltd.). The lysate was centrifuged at 10,100 × g for 15 minutes at 4°C, and the supernatant was collected and filtered through a 0.45 μm filter. ANTI-FLAG M2 affinity gel (SIGMA Aldrich) resin equilibrated with homogenization buffer was added to the centrifuged supernatant, and the mixed solution was stirred at 4°C for 1 hour or more. The mixed solution was loaded onto a Poly-Prep column and the resin was washed with a wash buffer (20 mmol / L pH 7.5 sodium phosphate, 150 mmol / L NaCl, 1 mmol / L MgCl2, 0.02% Triton, 0.05 mmol / L DTT). A wash buffer containing 400 μg / mL DYKDDDDK peptide (Scrum Inc.) was added to the column to elute the protein bound to the resin. The eluted fractions were subjected to SDS-PAGE and subsequently stained with CBB to identify the fractions containing the full-length human PLD1. The eluted fractions of the full-length human PLD1 were collected and concentrated using Amicon Ultra-15100k (Merck Millipore). The concentrated fractions were collected, quickly frozen in liquid nitrogen and stored at -80°C.

[1620] 4. Evaluation of Human PLD1 Inhibitory Activity

[1621] A DMSO or test substance solution (DMSO final concentration: 5%) prepared by diluting DMSO or a test substance with an 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) was added to a 384-well assay plate (black, polystyrene, untreated, catalog number 3573, Corning) at 5 μL / well. A full-length human PLD1 enzyme solution (6 nmol / L) diluted with an assay buffer was added thereto at 5 μL / well (the assay buffer was added to the blank well). A 1,2-diheptanoyl-sn-glycero-3-phosphocholine (Avanti Polar Lipids) substrate solution (6 mmol / L) diluted with an assay buffer was added thereto at 5 μL / well, and the enzyme reaction was carried out at room temperature for 60 minutes. Immediately before stopping the reaction, a detection solution (200 μmol / L AmplexRed (Thermofisher), 0.1 U / mL choline oxidase (Sigma-Aldrich), 4 U / mL horseradish peroxidase (Thermofiser)) containing 4 μmol / L 5-fluoro-2-indolyl dechlorohaloperamide (R&D Systems) as a reaction terminator was prepared with an assay buffer, and the detection solution was added thereto at 5 μL / well to terminate the enzyme reaction. Immediately after stopping the reaction and incubating at room temperature for 30 minutes, the fluorescence value at Ex: 531nm / Em: 590nm was measured by ARVOX5 (PerkinElmer). The inhibition rate was calculated based on the change in fluorescence value immediately after the reaction was stopped and 30 minutes later. Data was obtained by subtracting the average fluorescence value of the blank wells from the average fluorescence value of the treated wells. The inhibition rate of each concentration of the test substance was calculated according to the following formula:

[1622] 100-(B / A)×100

[1623] A: Data of solvent control

[1624] B: Test Substance-Processing Data

[1625] The IC of the test compound was calculated by fitting the inhibition rate of each concentration of the test compound to a logistic curve. 50Value (50% inhibition concentration). The results of 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 compound is shown, and Example 34 gives 36% inhibition, Example 186 gives 33% inhibition, Example 2-047 gives 32% inhibition, Example 2-099 gives 21% inhibition, Example 2-101 gives 13% inhibition, Example 2-150 gives 25% inhibition, and Example 2-171 gives 12% inhibition.

[1626] Experimental Example 2: Evaluation of human PLD2 enzyme inhibitory activity

[1627] Shown below is a method for measuring human PLD2 enzyme inhibitory activity using an enzyme in which a FLAG tag is added to the N-terminus of full-length human PLD2 (1-933 amino acids).

[1628] 1. Preparation of Full-length Human PLD2 Expression Plasmid

[1629] Using the commercially available human PLD2 gene (Promega KK) as a template, a DNA fragment in which the FLAG tag sequence is added to the 5' end of the full-length human PLD2 is amplified by the PCR method. The amplified DNA fragment is fused with the vector pVL1393 (Pharmingen) for baculovirus production digested with BamHI and EcoRI using the In-Fusion HD cloning kit (TakaraBio). The baculovirus full-length human PLD2 expression plasmid DNA is isolated from the Escherichia coli DH5α (TOYOBO) transformed with the obtained In-Fusion reaction product. Next, using the full-length human PLD2 expression plasmid DNA for baculovirus as a template, a DNA fragment in which the FLAG tag sequence is added to the 5' end of the full-length human PLD2 is amplified by the PCR method. The amplified DNA fragment is fused with the DNA fragment in which the linker sequence is introduced into pcDNA3.4-TOPO (Life Technologies) using the In-Fusion HD cloning kit (Takara Bio). The full-length human PLD2 expression plasmid DNA for animal cells was isolated from E. coli DH5α transformed with the obtained In-Fusion reaction product. The base sequence of the full-length human PLD2 cloned into the vector was determined by the dye terminator method using the BigDyeTerminator v3.1 cycle sequencing kit (Applied Biosystems). The determined sequence is a sequence in which the FLAG tag sequence is inserted into the 5' end of the full-length human PLD2 (GenBank accession number: NM_002663).

[1630] 2. Preparation of full-length human PLD2 protein in the Expi293F cell expression system

[1631] Expi293 expression medium (Life Technologies) was used as a culture medium, and Expi293F cells (Life Technologies) were cultured with shaking at 37°C and in the presence of 8% CO2. The gene introduction reagent PEI was prepared by dissolving Polyethyleenimine Max (nominal MW 40,000) (Polysciences) in MilliQ water, adjusting the pH of the solution to 7.0 with NaOH to obtain a 1 mg / mL solution, and then filtering the solution through a 0.22 μm filter. Full-length human PLD2 expression plasmid DNA for animal cells was transfected into Expi293F cells using PEI, and after 48 hours of shaking culture, the cells were collected and stored at -80°C.

[1632] 3. Purification of Full-length Human PLD2 Protein

[1633] Homogenization buffer (20 mmol / L pH 7.5 sodium phosphate, 250 mmol / L NaCl, 1 mmol / L MgCl2, 1% β-OG, 0.05 mmol / L DTT + completely EDTA-free (Roche Diagnostics KK)) was added to cells expressing full-length human PLD2, and the cells were lysed by a microfluidizer M-110EH (Mizuho Kogyo Co., Ltd.). The lysate was centrifuged at 10,100 × g for 15 minutes at 4°C, and the supernatant was collected and filtered through a 0.45 μm filter. ANTI-FLAG M2 affinity gel (SIGMA Aldrich) resin equilibrated with homogenization buffer was added to the centrifuged supernatant, and the mixed solution was stirred at 4°C for 1 hour or more. The mixed solution was loaded onto a Poly-Prep column and the resin was washed with a wash buffer (20 mmol / L pH 7.5 sodium phosphate, 150 mmol / L NaCl, 1 mmol / L MgCl2, 0.02% Triton, 0.05 mmol / L DTT). A wash buffer containing 400 μg / mL DYKDDDDK peptide (Scrum Inc.) was added to the column to elute the protein bound to the resin. The eluted fractions were subjected to SDS-PAGE and subsequently stained with CBB to identify the portion containing the full-length human PLD2. The eluted fractions of the full-length human PLD2 were collected and concentrated using Amicon Ultra-15100k (Merck Millipore). The concentrated fractions were collected, quickly frozen in liquid nitrogen and stored at -80°C.

[1634] 4. Evaluation of Human PLD2 Inhibitory Activity

[1635] A DMSO or test substance solution (DMSO final concentration: 5%) prepared by diluting DMSO or a test substance with an 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) was added to a 384-well assay plate (black, polystyrene, untreated, catalog number 3573, Corning) at 5 μL / well. A full-length human PLD2 enzyme solution (6 nmol / L) diluted with an assay buffer was added thereto at 5 μL / well (the assay buffer was added to the blank well). A 1,2-diheptanoyl-sn-glycero-3-phosphocholine (Avanti Polar Lipids) substrate solution (6 mmol / L) diluted with an assay buffer was added thereto at 5 μL / well, and the enzyme reaction was carried out at room temperature for 60 minutes. Immediately before stopping the reaction, a detection solution (200 μmol / L AmplexRed (Thermofisher), 0.1 U / mL choline oxidase (Sigma-Aldrich), 4 U / mL horseradish peroxidase (Thermofiser)) containing 4 μmol / L 5-fluoro-2-indolyl dechlorohaloperamide (R&D Systems) as a reaction terminator was prepared with an assay buffer, and the detection solution was added thereto at 5 μL / well to terminate the enzyme reaction. Immediately after stopping the reaction and incubating at room temperature for 30 minutes, the fluorescence value at Ex: 531nm / Em: 590nm was measured by ARVOX5 (PerkinElmer). The inhibition rate was calculated based on the change in fluorescence value immediately after the reaction was stopped and 30 minutes later. Data was obtained by subtracting the average fluorescence value of the blank wells from the average fluorescence value of the treated wells. The inhibition rate of each concentration of the test substance was calculated according to the following formula:

[1636] 100-(B / A)×100

[1637] A: Data of solvent control

[1638] B: Test Substance-Processing Data

[1639] The IC of the test compound was calculated by fitting the inhibition rate of each concentration of the test compound to a logistic curve. 50Value (50% inhibition concentration). The results of 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 compound is shown, and Example 34 gives 17% inhibition, Example 186 gives 18% inhibition, Example 2-047 gives 34% inhibition, Example 2-101 gives 28% inhibition, Example 2-112 gives 39% inhibition, Example 2-150 gives 30% inhibition, and Example 2-171 gives 23% inhibition.

[1640] Table 2-1

[1641] Example No. <![CDATA[DLD1 IC 50 (μM)]]> <![CDATA[DLD2 IC 50 (μM)]]> 1 0.033 ＜0.010 2 0.020 ＜0.010 3 0.027 ＜0.010 4 0.036 0.011 5 0.164 0.171 6 0.069 0.120 7 0.030 0.044 8 0.030 0.010 9 0.083 0.056 10 0.092 0.106 11 0.228 0.394 12 ＜0.010 ＜0.010 13 0.036 ＜0.010 14 0.010 ＜0.010 15 0.025 ＜0.010 16 0.926 0.968 17 0.816 1.044 18 0.852 0.157 19 0.017 0.010 20 1.646 3.769 21 0.307 0.346 22 0.066 0.049 23 0.039 0.051 24 0.041 0.031 25 0.108 0.101 26 ＜0.010 ＜0.010 27 0.014 0.013 28 0.341 0.303 29 0.999 1.715 30 0.123 0.153 31 0.024 ＜0.010 32 0.032 ＜0.010 33 0.025 ＜0.010 34 36% inhibition at 10 μM 17% inhibition at 10 μM 35 0.257 0.367 36 0.221 0.137 37 ＜0.010 ＜0.010 38 0.035 0.088 39 0.093 0.024 40 0.013 ＜0.010

[1642] Table 2-2

[1643] 41 0.229 0.500 42 0.247 0.261 43 0.221 0.184 44 0.018 <0.010 45 0.027 0.023 46 0.012 <0.010 47 0.119 <0.010 48 0.014 <0.010 49 0.031 0.011 50 0.033 0.051 51 0.033 0.016 52 0.021 <0.010 53 0.019 <0.010 54 0.020 <0.010 55 0.015 <0.010 56 0.026 0.017 57 0.016 <0.010 58 0.014 <0.010 59 <0.010 <0.010 60 <0.010 <0.010 61 0.014 0.011 62 0.140 0.223 63 <0.010 <0.010 64 0.018 <0.010 65 <0.010 <0.010 66 0.016 <0.010 67 <0.010 <0.010 68 2.028 4.659 69 <0.010 <0.010 70 0.028 0.020 71 <0.010 <0.010 72 0.034 0.024 73 0.023 0.015 74 <0.010 <0.010 75 1.628 1.992 76 0.017 0.017 77 0.026 <0.010 78 0.350 0.252 79 <0.010 <0.010 80 <0.010 <0.010

[1644] Table 2-3

[1645] 81 0.012 <0.010 82 0.421 0.358 83 0.259 0.221 84 0.070 0.053 85 0.012 <0.010 86 0.013 <0.010 87 0.039 <0.010 88 0.056 0.065 89 0.038 0.037 90 0.045 0.018 91 0.023 0.015 92 0.026 0.013 93 0.032 <0.010 94 0.068 0.060 95 8.056 6.165 96 0.018 <0.010 97 <0.010 <0.010 98 0.057 0.078 99 0.241 0.373 100 0.041 0.033 101 <0.010 <0.010 102 0.288 0.666 103 0.170 0.379 104 0.075 0.217 105 0.027 0.041 106 0.026 0.048 107 0.085 0.139 108 0.025 0.038 109 0.012 <0.010 110 0.083 0.099 111 0.017 0.021 112 0.031 0.020 113 0.017 0.013 114 0.013 <0.010 115 0.015 <0.010 116 0.043 0.037 117 0.021 0.018 118 0.050 0.073 119 0.011 <0.010 120 0.012 0.011

[1646] Table 2-4

[1647] 121 <0.010 <0.010 122 <0.010 <0.010 123 0.202 0.502 124 0.638 2.736 125 0.040 0.057 126 0.013 <0.010 127 0.025 <0.010 128 0.186 0.060 129 0.018 <0.010 130 0.018 <0.010 131 0.010 <0.010 132 0.014 <0.010 133 0.029 0.031 134 0.021 0.030 135 0.086 0.033 136 0.155 0.170 137 0.505 1.586 138 0.774 1.396 139 <0.010 <0.010 140 <0.010 <0.010 141 0.141 0.164 142 0.022 <0.010 143 0.027 0.025 144 0.011 <0.010 145 0.017 <0.010 146 0.020 <0.010 147 0.032 0.032 148 0.020 0.018 149 0.012 <0.010 150 0.880 0.640 151 0.018 <0.010 152 0.023 0.013 153 0.027 0.028 154 0.027 0.014 155 0.014 <0.010 156 0.236 0.412 157 <0.010 <0.010 158 0.027 0.015 159 0.028 <0.010 160 0.026 0.017

[1648] Table 2-5

[1649] 161 0.020 0.013 162 0.322 0.536 163 ＜0.010 ＜0.010 164 0.038 ＜0.010 165 0.019 ＜0.010 166 0.019 ＜0.010 167 0.020 ＜0.010 168 0.056 0.035 169 0.034 0.020 170 0.019 ＜0.010 171 0.013 ＜0.010 172 0.023 0.012 173 0.029 0.010 174 0.042 0.017 175 0.021 0.015 176 0.029 0.029 177 0.010 ＜0.010 178 0.014 0.017 179 0.025 ＜0.010 180 0，028 0.012 181 0.013 ＜0.010 182 0.019 ＜0.010 183 0.042 0.107 184 ＜0.010 ＜0.010 185 0.068 0.064 186 33% inhibition at 10 μM 18% inhibition at 10 μM 187 0.222 0.455 188 0.044 0.033 189 0.130 0.140 190 0.642 0.776 191 0.038 ＜0.010 192 0.021 ＜0.010 193 0.055 0.046 194 ＜0.010 ＜0.010 195 0.039 0.067 196 0.027 ＜0.010 197 0.026 ＜0.010 198 0.011 ＜0.010 199 0.010 ＜0.010 200 0.103 0.082

[1650] Table 2-6

[1651] 201 0.328 0.371 202 0.832 1.247 203 0.012 <0.010 204 0.123 0.146 205 0.035 0.102 206 0.036 0.013 207 0.025 <0.010 208 0.045 0.224 209 0.018 0.018 210 0.296 1.087 211 0.102 0.429 212 <0.010 <0.010 213 0.086 0.115 214 <0.010 <0.010 215 <0.010 <0.010 216 0.029 0.019 217 0.017 <0.010 218 0.023 0.013 219 <0.010 <0.010 220 0.042 0.033 221 0.016 <0.010 222 0.059 0.171 223 0.396 0.246 224 0.013 <0.010 225 0.513 0.203 226 0.018 <0.010 227 0.019 <0.010 228 0.028 <0.010 229 0.197 0.310 230 0.021 <0.010 231 0.024 0.012 232 2.580 2.132 233 1.861 1.796 234 0.247 0.474 235 0.035 0.013 236 0.015 <0.010 237 0.034 <0.010 238 0.012 <0.010 239 0.018 <0.010 240 0.013 <0.010

[1652] Table 2-7

[1653] 241 0.017 <0.010 242 0.016 <0.010 243 0.024 <0.010 244 0.019 <0.010 245 0.040 0.107 246 0.015 <0.010 247 0.014 <0.010 248 0.017 <0.010 249 0.025 <0.010 250 0.022 <0.010 251 0.017 <0.010 252 0.174 0.335 253 0.252 0.324 254 0.029 <0.010 255 0.032 0.014 256 0.027 <0.010 257 0.262 0.215 258 0.186 0.249 259 1.450 2.499 260 0.031 <0.010 261 0.168 0.313 262 0.015 <0.010 263 2.777 4.499 264 0.036 <0.010 265 0.013 <0.010 266 0.015 <0.010 267 0.026 <0.010 268 0.030 <0.010 269 0.018 <0.010 270 0.017 <0.010 271 0.018 <0.010 272 0.015 <0.010 273 0.019 <0.010 274 0.017 <0.010 275 0.025 <0.010 276 0.021 <0.010 277 0.017 <0.010 278 0.246 1.176 279 0.086 0.044 280 0.147 0.316

[1654] Table 2-8

[1655] 281 0.169 0.232 282 0.097 0.146 283 0.043 0.048 284 0.061 0.040 285 <0.010 <0.010 286 0.014 <0.010 287 0.013 <0.010 288 0.026 <0.010 289 0.018 <0.010 290 0.122 0.046 291 0.150 0.234 292 0.023 <0.010 293 0.127 0.325 294 0.011 <0.010 295 <0.010 <0.010 296 0.013 <0.010 297 0.013 <0.010 298 0.015 <0.010 299 0.025 <0.010 300 0.038 <0.010 301 0.030 <0.010 302 0.017 <0.010 303 0.011 <0.010 304 <0.010 <0.010 305 0.015 <0.010 306 <0.010 <0.010 307 0.013 <0.010 308 0.015 <0.010 309 0.015 <0.010 310 0.014 <0.010 311 0.015 <0.010 312 0.029 <0.010 313 0.023 0.025 314 <0.010 <0.010 315 0.025 0.024 316 0.046 0.061 317 0.071 0.065 318 0.037 0.041 319 2.092 0.744 320 3.881 1.577

[1656] Table 2-9

[1657] 321 0.042 <0.010 322 0.030 <0.010 323 0.010 <0.010 324 0.020 0.022 325 0.015 <0.010 326 0.054 0.038 327 0.110 0.051 328 0.048 0.034 329 0.051 <0.010 330 3.151 0.026 331 0.032 0.022 332 2.595 0.015 333 0.025 <0.010 334 0.026 <0.010 335 0.126 <0.010 336 0.033 <0.010 337 0.074 0.028 338 0.024 <0.010 339 0.039 0.010

[1658] Table 2-10

[1659] 2-001 0.041 <0.010 2-002 1.254 1.865 2-003 0.038 0.012 2-004 0.068 <0.010 2-005 0.433 0.035 2-006 0.056 0.011 2-007 0.028 <0.010 2-008 0.062 0.011 2-009 2.154 1.037 2-010 1.015 1.258 2-011 2.110 2.943 2-012 2.044 0.245 2-013 0.012 <0.010 2-014 0.022 <0.010 2-015 0.026 0.012 2-016 0.019 <0.010 2-017 0.099 0.045 2-018 0.022 <0.010 2-019 0.012 <0.010 2-020 0.021 0.016 2-021 0.027 0.015 2-022 0.738 0.388 2-023 0.102 0.064 2-024 0.046 0.028 2-025 0.219 0.205 2-026 0.012 <0.010 2-027 0.013 <0.010 2-028 0.045 0.032 2-029 1.507 8.407 2-030 0.031 0.018 2-031 0.019 <0.010 2-032 0.011 <0.010 2-033 0.035 <0.010 2-034 0.031 0.010 2-035 0.021 <0.010 2-036 0.017 <0.010 2-037 0.043 0.013 2-038 0.060 0.011 2-039 0.153 0.264 2-040 0.021 <0.010

[1660] Table 2-11

[1661] 2-041 0.148 0.103 2-042 3.018 0.383 2-043 0.033 0.152 2-044 ＜0.010 ＜0.010 2-045 0.018 ＜0.010 2-046 0.024 0.118 2-047 32% inhibition at 10 μM 34% inhibition at 10 μM 2-048 0.644 1.014 2-049 1.743 1.443 2-050 0.012 ＜0.010 2-051 0.025 ＜0.010 2-052 0.021 ＜0.010 2-053 0.676 0.245 2-054 0.037 ＜0.010 2-055 0.011 ＜0.010 2-056 0.017 ＜0.010 2-057 0.018 ＜0.010 2-058 0.026 0.066 2-059 0.731 0.505 2-060 0.027 0.011 2-061 0.014 ＜0.010 2-062 0.025 0.025 2-063 0.173 0.106 2-064 0.027 0.011 2-065 0.021 ＜0.010 2-066 0.015 ＜0.010 2-067 0.015 ＜0.010 2-068 ＜0.010 ＜0.010 2-069 ＜0.010 ＜0.010 2-070 0.068 0.038 2-071 0.013 ＜0.010 2-072 0.014 0.024 2-073 0.014 0.002 2-074 0.011 ＜0.010 2-075 0.016 ＜0.010 2-076 0.011 ＜0.010 2-077 0.015 ＜0.010 2-078 ＜0.010 ＜0.010 2-079 0.011 0.010 2-080 ＜0.010 ＜0.010

[1662] Table 2-12

[1663] 2-081 ＜0.010 ＜0.010 2-082 ＜0.010 ＜0.010 2-083 ＜0.010 ＜0.010 2-084 0.013 ＜0.010 2-085 0.022 ＜0.010 2-086 0.015 ＜0.010 2-087 0.012 ＜0.010 2-088 0.019 ＜0.010 2-089 0.018 ＜0.010 2-090 0.013 ＜0.010 2-091 ＜0.010 ＜0.010 2-092 0.026 ＜0.010 2-093 0.038 0.013 2-094 0.026 ＜0.010 2-095 0.035 0.012 2-096 0.055 0.031 2-097 0.020 ＜0.010 2-098 0.013 ＜0.010 2-099 21% inhibition at 10 μM 6.889 2-100 0.015 ＜0.010 2-101 13% inhibition at 10 μM 28% inhibition at 10 μM 2-102 0.014 ＜0.010 2-103 0.023 ＜0.010 2-104 0.021 0.011 2-105 0.017 ＜0.010 2-106 0.073 0.127 2-107 0.011 ＜0.010 2-108 <0.010 ＜0.010 2-109 0.011 <0.010 2-110 0.021 <0.010 2-111 0.025 0.029 2-112 3.590 39% inhibition at 10 μM 2-113 0.014 ＜0.010 2-114 0.052 ＜0.010 2-115 0.038 ＜0.010 2-116 0.081 0.017 2-117 0.030 ＜0.010 2-118 0.019 ＜0.010 2-119 0.034 ＜0.010 2-120 0.021 ＜0.010

[1664] Table 2-13

[1665] 2-121 0.026 0.021 2-122 0.014 ＜0.010 2-123 0.026 ＜0.010 2-124 0.022 ＜0.010 2-125 0.043 0.016 2-126 0.035 0.014 2-127 ＜0.010 ＜0.010 2-128 ＜0.010 ＜0.010 2-129 0.025 ＜0.010 2-130 0.032 ＜0.010 2-131 0.015 ＜0.010 2-132 0.011 ＜0.010 2-133 0.014 ＜0.010 2-134 0.018 ＜0.010 2-135 0.020 ＜0.010 2-136 0.017 0.015 2-137 0.029 0.033 2-138 0.014 ＜0.010 2-139 0.014 ＜0.010 2-140 0.017 ＜0.010 2-141 ＜0.010 ＜0.010 2-142 0.012 ＜0.010 2-143 0.262 0.738 2-144 0.012 ＜0.010 2-145 0.014 ＜0.010 2-146 0.019 0.016 2-147 0.136 0.152 2-148 0.140 0.046 2-149 0.045 0.023 2-150 25% inhibition at 10 μM 30% inhibition at 10 μM 2-151 0.024 ＜0.010 2-152 0.016 ＜0.010 2-153 0.016 ＜0.010 2-154 0.021 0.017 2-155 ＜0.010 ＜0.010 2-156 0.013 ＜0.010 2-157 0.017 ＜0.010 2-158 0.016 ＜0.010 2-159 0.015 ＜0.010 2-160 0.011 ＜0.010

[1666] Table 2-14

[1667] 2-161 0.014 ＜0.010 2-162 0.021 ＜0.010 2-163 ＜0.010 ＜0.010 2-164 ＜0.010 ＜0.010 2-165 ＜0.010 ＜0.010 2-166 0.011 ＜0.010 2-167 0.011 ＜0.010 2-168 ＜0.010 ＜0.010 2-169 0.045 0.100 2-170 0.009 0.002 2-171 12% inhibition at 10 μM 23% inhibition at 10 μM 2-172 0.020 0.003

[1668] The formulation examples of the present invention include the following formulations. However, the present invention is not limited to such formulation examples.

[1669] Preparation Example 1 (Preparation of Capsules)

[1670]

[1671] 1), 2), 3) and 4) are mixed and filled into gelatin capsules.

[1672] Preparation Example 2 (Preparation of Tablets)

[1673]

[1674] The total amount of 1), 2), 3) and 30 g of 4) were mixed with water, vacuum dried, and then granulated. The granulated powder was mixed with 14 g of 4) and 1 g of 5), and the mixture was compressed with a tablet press. In this way, 1000 tablets containing 10 mg of the compound of Example 1 were obtained.

[1675] Industrial Applicability

[1676] Since the compound [I] or compound [Ia] of the present invention or a pharmaceutically acceptable salt thereof has PLD inhibitory activity, it can be used for treating or preventing thrombosis and cancer.

Claims

1. A compound represented by formula [Ia] or a pharmaceutically acceptable salt thereof: in A a CR 10a or N; A 2a CR 5a or O; Cy a for (1)C 6-10 Aryl, (2) a 5- to 10-membered heteroaryl group which contains 1 or 2 nitrogen atoms as ring-constituting atoms in addition to carbon atoms, or (3) a 9- or 10-membered partially unsaturated fused ring group which contains, in addition to carbon atoms, 1 or 2 oxygen atoms as ring-constituting atoms; R 1a for (1)C 1-6 Alkyl, wherein the alkyl is optionally substituted by (a) hydroxyl group, (b) cyano, (c)SO2R 11 , where R 11 C 1-4 Alkyl, or (d) NHCOR 12 , where R 12 C 1-4 alkyl, (2)C 2-4 Alkenyl, wherein the alkenyl is optionally substituted with 1 to 3 of the following substituents (a)NR 13 R 14 , where R 13 and R 14 are independently hydrogen or C 1-4 alkyl, (b) halogen, (c)COR 35a , where R 35a Hydroxyl or C 1-4 Alkoxy, (d)CONR 36a R 37a , where R 36a and R 37a are independently hydrogen or C 1-4 Alkyl, or (e) Partial structural formula: (3)C 1-4 haloalkyl, wherein the haloalkyl is optionally substituted with hydroxy, (4)C 1-6 Alkoxy, wherein the alkoxy is optionally substituted with phenyl, (5)NR 15 R 16 , where R 15 and R 16 Each independently (a) hydrogen, (b)C 1-4 Alkyl, wherein the alkyl is optionally substituted by (i) phenyl, wherein the phenyl is optionally substituted by halogen, or (ii) pyridyl, (c)C 1-4 Alkoxy, or (d)C 3-4 Cycloalkyl, (6)COR 17a , where R 17a C 1-4 alkyl, (7)CONR 18a R 19a , where R 18a and R 19a Each independently (a) hydrogen, (b)C 1-4 alkyl, wherein the alkyl is optionally substituted with hydroxy, (c)C 3-4 Cycloalkyl, (d)C 5-8 A bridged cycloalkyl group, (e)C 1-4 haloalkyl, or (f)C 1-4 Alkoxy, (8)C 3-4 Cycloalkyl, wherein the cycloalkyl is optionally substituted with (a) hydroxyl group, (b) halogen, or (c) phenyl, (9) a 4- to 7-membered heterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring, wherein the heterocycloalkyl group is optionally substituted by the following substituents (a) hydroxyl group, (b) oxo, (c)NR 20 R 21 , where R 20 and R 21 are independently hydrogen or C 1-4 Alkyl, or (d) phenyl, (10) a 6- to 11-membered spiroheterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring, (11) Phenyl, wherein the phenyl group is optionally substituted by one or two of the following substituents: (a) halogen, or (b)C 1-4 Haloalkyl, (12) a 5- to 10-membered heteroaryl group containing, in addition to carbon atoms, 1 to 3 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting a ring, wherein the heteroaryl group is optionally substituted by 1 or 2 R 22 replace, (13) an 8- to 10-membered saturated or partially unsaturated condensed ring group containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen and oxygen atoms as ring-constituting atoms, wherein the condensed ring group is optionally substituted by C 1-4 haloalkyl substituted, or (14) a 5- to 7-membered partially unsaturated cyclic group containing, in addition to carbon atoms, 1 or 2 nitrogen atoms as ring-constituting atoms, wherein the partially unsaturated cyclic group is optionally substituted by an oxo group and a C 1-4 Alkyl substitution; R 2a The number of is m, each of which is independently (1) Hydroxyl group, (2) cyano group, (3) Halogen, (4)C 1-6 Alkyl, wherein the alkyl is optionally substituted by (a) hydroxyl group, or (b)C 3-4 Cycloalkyl, (5)C 2-4 Alkenyl, wherein the alkenyl is optionally substituted with C 1-4 Alkoxy substitution, (6)C 1-4 Haloalkyl, (7)C 1-4 Alkoxy, wherein the alkoxy is optionally substituted with 1 to 3 substituents selected from the group consisting of: (a) hydroxyl groups, and (b) halogen, (8)SR 23a , where R 23a C 1-4 Alkyl or C 1-4 Haloalkyl, (9)COR 24a , where R 24a for (a) hydroxyl group, (b)C 1-4 Alkyl, or (c)C 1-4 Alkoxy, (10)CONR 25a R 26a , where R 25a and R 26a Each independently (a) hydrogen, (b)C 1-6 Alkyl, or (c)C 3-4 Cycloalkyl, or R 25a and R 26a are bonded to each other to form, together with the nitrogen atom to which they are bonded, a 4- to 7-membered heterocycloalkyl group, wherein The heterocycloalkyl group contains 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring in addition to carbon atoms, and is optionally substituted by 1 or 2 halogens, (11) SO2R 27 , where R 27 C 1-6 alkyl, (12)C 3-4 Cycloalkyl, (13) a 4- to 7-membered heterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring, wherein the heterocycloalkyl group is optionally substituted by 1 or 2 substituents selected from the following (a) halogen, (b)C 1-4 Alkyl, and (c)C 1-4 Haloalkyl, (14) a 5- to 9-membered bridged heterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring, (15) a 6- to 11-membered spiroheterocycloalkyl group containing, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring, or (16) phenyl; R 3a for (1) Hydrogen, (2)C 1-4 Alkyl, or (3)C 1-4 Haloalkyl; R 4a for (1) Hydrogen, (2)C 1-4 Alkyl, or (3) cyano; R 5a is hydrogen or C 1-4 alkyl; R 6a , R 7a and R 8a The combination of (1) R 6a is hydrogen or C 1-4 Alkyl, and R 7a and R 8a The two are a combination of hydrogen. (2) R 6a is hydrogen or C 1-4 Alkyl, and R 7a and R 8a bonded to each other so as to form a combination of a cyclopentane ring together with the spiro carbon atoms and the carbon atoms to which they are bonded, or (3) R 6a and R 7a are bonded to each other to form a cyclopentane ring together with the spiro carbon atom and the carbon atom to which they are bonded, and R 8a is a combination of hydrogen; R 9a for (1) Hydrogen, (2)CONHR 28 , where R 28 C 3-4 Cycloalkyl, or (3)C 1-4 alkyl; R 10a for (1) Hydrogen, (2) Hydroxyl groups, (3) Halogen, (4)C 1-4 alkyl, (5) cyano, or (6)C 1-4 Alkoxy; 1 or 2 R 22a 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 C 1-4 alkyl, (6) SO2R 30 , where R 30 C 1-4 alkyl, (7) cyano, or (8)C 3-4 cycloalkyl; and m is 0, 1, 2 or 3.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is represented by formula [IIa]: in A a , Cy a , R 1a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a and m as defined in claim 1.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is represented by formula [IIIa]: in Cy a , R 1a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a and m as defined in claim 1.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is represented by formula [IVa]: in R 1b for (1)C 1-6 Alkyl, wherein the alkyl is optionally substituted by (a) hydroxyl group, (b) cyano, (c)SO2R 11 , where R 11 C 1-4 Alkyl, or (d) NHCOR 12 , where R 12 C 1-4 alkyl, (2)C 2-4 Alkenyl, wherein the alkenyl is optionally substituted with 1 to 3 of the following substituents (a)NR 13 R 14 , where R 13 and R 14 are independently hydrogen or C 1-4 alkyl, (b) halogen, (c)COR 35a , where R 35a Hydroxyl or C 1-4 Alkoxy, (d)CONR 36a R 37a , where R 36a and R 37a are independently hydrogen or C 1-4 Alkyl, or (e) Partial structural formula: (3)C 1-6 Alkoxy, wherein the alkoxy is optionally substituted with phenyl, (4)NR 15 R 16 , where R 15 and R 16 Each independently (a) hydrogen, (b)C 1-4 Alkyl, wherein the alkyl is optionally substituted by (i) phenyl, wherein the phenyl is optionally substituted by halogen, or (ii) pyridyl, (c)C 1-4 Alkoxy, or (d)C 3-4 Cycloalkyl, (5)CONR 18a R 19a , where R 18a and R 19a Each independently (a) hydrogen, (b)C 1-4 alkyl, wherein the alkyl is optionally substituted with hydroxy, (c)C 3-4 Cycloalkyl, (d)C 5-8 A bridged cycloalkyl group, (e)C 1-4 haloalkyl, or (f)C 1-4 Alkoxy, (6) a 6- to 11-membered spiroheterocycloalkyl group which contains, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring, (7) a 5- to 10-membered heteroaryl group containing, in addition to carbon atoms, 1 to 3 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring, wherein the heteroaryl group is optionally substituted by 1 or 2 R 22a replace, (8) an 8- to 10-membered saturated or partially unsaturated condensed ring group containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen and oxygen atoms as ring-constituting atoms, wherein the condensed ring group is optionally substituted by C 1-4 haloalkyl substituted, or (9) a 5- to 7-membered partially unsaturated cyclic group containing, in addition to carbon atoms, 1 or 2 nitrogen atoms as ring-constituting atoms, wherein the partially unsaturated cyclic group is optionally substituted by an oxo group and a C 1-4 Alkyl substitution; and Cy a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 22a and m as defined in claim 1.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, which is represented by formula [Va]: in Cy a , R 2a , R 3a , R 4a and m as defined in claim 1; and R 1b As defined in claim 4.

6. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, which is represented by formula [VIa]: in Cy b for (1)C 6-10 Aryl, or (2) a 5- or 6-membered heteroaryl group which contains, in addition to carbon atoms, 1 or 2 nitrogen atoms as ring-constituting atoms; R 1b As defined in claim 4; and R 2a , R 3a , R 4a and m as defined in claim 1.

7. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, which is represented by formula [VIIa]: in Cy a , R 2a , R 3a , R 5a , R 6a , R 7a , R 8a and m as defined in claim 1; and R 1b As defined in claim 4.

8. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, which is represented by formula [VIIIa]: in Cy a , R 2a , R 3a and m as defined in claim 1; and R 1b As defined in claim 4.

9. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, which is represented by formula [IXa]: in Cy b As defined in claim 6; R 1b As defined in claim 4; and R 2a , R 3a and m as defined in claim 1.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is represented by formula [Xa]: in Cy a , R 1a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 10a and m as defined in claim 1.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is represented by formula [XIa]: in Cy a , R 1a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 10a and m as defined in claim 1.

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is represented by formula [XIIa]: in R 1b for (1)C 1-6 Alkyl, wherein the alkyl is optionally substituted by (a) hydroxyl group, (b) cyano, (c)SO2R 11 , where R 11 C 1-4 Alkyl, or (d) NHCOR 12 , where R 12 C 1-4 alkyl, (2)C 2-4 Alkenyl, wherein the alkenyl is optionally substituted with 1 to 3 of the following substituents (a)NR 13 R 14 , where R 13 and R 14 are independently hydrogen or C 1-4 alkyl, (b) halogen, (c)COR 35a , where R 35a Hydroxyl or C 1-4 Alkoxy, (d)CONR 36a R 37a , where R 36a and R 37a are independently hydrogen or C 1-4 Alkyl, or (e) Partial structural formula: (3)C 1-6 Alkoxy, wherein the alkoxy is optionally substituted with phenyl, (4)NR 15 R 16 , where R 15 and R 16 Each independently (a) hydrogen, (b)C 1-4 Alkyl, wherein the alkyl is optionally substituted by (i) phenyl, wherein the phenyl is optionally substituted by halogen, or (ii) pyridyl, (c)C 1-4 Alkoxy, or (d)C 3-4 Cycloalkyl, (5)CONR 18a R 19a , where R 18a and R 19a Each independently (a) hydrogen, (b)C 1-4 alkyl, wherein the alkyl is optionally substituted with hydroxy, (c)C 3-4 Cycloalkyl, (d)C 5-8 A bridged cycloalkyl group, (e)C 1-4 haloalkyl, or (f)C 1-4 Alkoxy, (6) a 6- to 11-membered spiroheterocycloalkyl group which contains, in addition to carbon atoms, 1 or 2 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring, (7) a 5- to 10-membered heteroaryl group containing, in addition to carbon atoms, 1 to 3 heteroatoms selected from nitrogen and oxygen atoms as atoms constituting the ring, wherein the heteroaryl group is optionally substituted by 1 or 2 R 22a replace, (8) an 8- to 10-membered saturated or partially unsaturated condensed ring group containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen and oxygen atoms as ring-constituting atoms, wherein the condensed ring group is optionally substituted by C 1-4 haloalkyl substituted, or (9) a 5- to 7-membered partially unsaturated cyclic group containing, in addition to carbon atoms, 1 or 2 nitrogen atoms as ring-constituting atoms, wherein the partially unsaturated cyclic group is optionally substituted by an oxo group and a C 1-4 Alkyl substitution; and Cy a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 10a , R 22a and m as defined in claim 1.

13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, which is represented by formula [XIIIa]: in Cy a , R 2a , R 3a , R 4a , R 10a and m as defined in claim 1; and R 1b As defined in claim 12.

14. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, which is represented by formula [XIVa]: in Cy b for (1)C 6-10 Aryl, or (2) a 5- or 6-membered heteroaryl group which contains, in addition to carbon atoms, 1 or 2 nitrogen atoms as ring-constituting atoms; R 1b As defined in claim 12; and R 2a , R 3a , R 4a , R 10a and m as defined in claim 1.

15. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, which is represented by formula [XVa]: in Cy a , R 2a , R 3a , R 5a , R 6a , R 7a , R 8a , R 10a and m as defined in claim 1; and R 1b As defined in claim 12.

16. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, which is represented by formula [XVIa]: in Cy a , R 2a , R 3a , R 10a and m as defined in claim 1; and R 1b As defined in claim 12.

17. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, which is represented by formula [XVIIa]: in Cy b As defined in claim 14; R 1b As defined in claim 12; and R 2a , R 3a , R 10a and m as defined in claim 1.

18. A compound selected from the group consisting of compounds represented by the following formula: or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

20. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof in combination with one or more other drugs, and a pharmaceutically acceptable carrier.

21. A PLD inhibitor comprising a compound as defined in any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof.

22. A PLD1 inhibitor comprising a compound as defined in any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof.

23. A PLD1 / 2 inhibitor comprising a compound as defined in any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof.

24. An agent for treating or preventing a disease selected from thrombosis and cancer, comprising a compound as defined in any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof.

25. A medicament for treating or preventing a disease selected from thrombosis and cancer, comprising a combination of a compound as defined in any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof and one or more other drugs.

26. A method for inhibiting PLD in a mammal, which comprises administering to the mammal a therapeutically effective amount of a compound as defined in any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof.

27. A method for inhibiting PLD1 in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound as defined in any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof.

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

29. A method for treating or preventing a disease selected from thrombosis and cancer in a mammal, which comprises administering to the mammal a therapeutically effective amount of a compound as defined in any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof.

30. A method for treating or preventing a disease selected from thrombosis and cancer in a mammal, which comprises administering to the mammal a therapeutically effective amount of a compound as defined in any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof in combination with one or more other drugs.

31. Use of a compound as defined in any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, in the manufacture of a PLD inhibitor.

32. Use of a compound as defined in any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, in the manufacture of a PLD1 inhibitor.

33. Use of a compound as defined in any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof in the manufacture of a PLD1 / 2 inhibitor.

34. Use of a compound as defined in any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a disease selected from thrombosis and cancer.

35. Use of a compound as defined in any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, in combination with one or more other drugs in the manufacture of a medicament for the treatment or prevention of a disease selected from thrombosis and cancer.

36. A compound as defined in any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for use in inhibiting PLD.

37. A compound as defined in any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for use in inhibiting PLD1.

38. A compound as defined in any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for use in inhibiting PLD1 / 2.

39. A compound as defined in any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease selected from thrombosis and cancer.

40. A compound as defined in any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for use in combination with one or more other drugs in the treatment or prevention of a disease selected from thrombosis and cancer.

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