Indazole compound and pharmaceutical use thereof

Abstract

The purpose of the present invention is to provide a compound that exhibits an H-PGDS inhibitory activity. The present invention relates to a compound expressed by formula [I] or a pharmaceutically acceptable salt thereof (in the formula, each reference sign is as defined in the specification).

Description

Indazole compounds and their medical uses

[0001] The present invention relates to an indazole compound or a pharmaceutically acceptable salt thereof having inhibitory activity against hematopoietic prostaglandin D synthase (hereinafter abbreviated as "H-PGDS"), a pharmaceutical composition containing the same, and medical uses thereof.

[0002] Prostaglandin D synthase (PGDS) synthesizes prostaglandin H ２ (P.G.H. ２ ) as a substrate, and prostaglandin D ２ (PGD ２ PGDS is an enzyme that synthesizes hematopoietic PGDS (H-PGDS) and lipocalin PGDS (L-PGDS). There are two types of PGDS: hematopoietic PGDS (H-PGDS) and lipocalin PGDS (L-PGDS). These two types of enzymes have no homology in amino acid sequence and also differ in tissue distribution and cellular localization. H-PGDS is expressed in large amounts in blood cells such as mast cells, neutrophils, and macrophages, and is involved in allergies and inflammation. On the other hand, L-PGDS is mainly expressed in the central nervous system and plays a role in regulating sleep and pain sensation.

[0003] The uses of H-PGDS inhibitors are described below. (1) Peripheral arterial disease (PAD) and cardiovascular disease (CAD) In ​​a femoral artery ligation model, a PAD model, H-PGDS knockout mice exhibited increased lower limb blood flow compared to wild-type mice, suggesting that collateral circulation is involved in this increased lower limb blood flow (Patent Document 1). It has also been reported that PAD patients with more developed collateral circulation have better walking function (Non-Patent Document 1). Furthermore, collateral circulation is also present in the heart, and it has been reported that CAD patients with more developed collateral circulation have a better prognosis (Non-Patent Document 2). Based on these findings, H-PGDS inhibitors are expected to be effective in treating PAD and CAD by increasing blood flow to the lower limbs and heart via collateral circulation. PAD is classified into mild intermittent claudication (IC) and severe chronic comprehensive limb threatening ischemia (CLTI), and H-PGDS inhibitors are thought to be therapeutic agents for these disease symptoms (Non-Patent Documents 8 and 9). Peripheral arterial disease is also called chronic arterial occlusion or arteriosclerosis obliterans.

[0004] (2) Allergic asthma and chronic obstructive pulmonary disease PGD ２ It has been reported that D-prostanoid (DP) receptors, which are receptors for PGD, and chemical receptor-like molecules (CRTH2) receptors expressed in Th2 cells, are involved in allergic asthma and chronic obstructive pulmonary disease (COPD). In an asthma model, DP receptor knockout mice were found to show reduced infiltration of eosinophils and lymphocytes into the lungs and reduced airway hyperresponsiveness, compared to wild-type mice (Non-Patent Document 3). In addition, PGD ２ It has been reported that H-PGDS inhibitors recruit eosinophils into the airways via the CRTH2 receptor, exacerbating inflammation (Non-Patent Document 4), and that CRTH2 receptor inhibitors improve bronchial inflammation in COPD model mice (Non-Patent Document 5). Based on these findings, it is believed that H-PGDS inhibitors have the potential to inhibit PGD ２By inhibiting production and suppressing inflammation in the airways, it is expected to have a therapeutic effect on allergic asthma and COPD.

[0005] (3) Duchenne Muscular Dystrophy: It has been reported that H-PGDS expression is increased in the muscle tissue of Duchenne Muscular Dystrophy (DMD) patients and mdx mice, a DMD model mouse (Non-Patent Document 6). Furthermore, it has been reported that the H-PGDS inhibitor HQL-79 suppresses muscle necrosis and increases muscle strength in mdx mice (Non-Patent Document 7). Based on these findings, H-PGDS inhibitors may also be effective in treating DMD. (4) Allergic Rhinitis: In an animal model of allergic rhinitis, it has been reported that PGD2 concentrations increase in nasal lavage fluid, and that administration of an H-PGDS inhibitor improves nasal obstruction (Non-Patent Document 10). Based on these results, it is believed that H-PGDS inhibitors could be used to treat allergic rhinitis. (5) Sarcopenia: In an animal model of sarcopenia, administration of an H-PGDS inhibitor has been reported to inhibit muscle atrophy (Patent Document 2). Based on the above results, H-PGDS inhibitors are considered to be a therapeutic agent for sarcopenia.

[0006] International Publication No. 2011 / 052628 International Publication No. 2019 / 203296

[0007] McDermott MM, et al., JACC Cardiovasc Imaging. 2013 Jun;6(6):687-94.Steg PG, et al., Circulation. 2010 Jun 29;121(25):2724-30.Matsuoka T, et al., Science. 2000 Mar 17;287(5460):2013-7.George L, et al., Ther Adv Chronic Dis. 2016 Jan;7(1):34-51.Sargent C, et al., Br J Pharmacol 7 (2009): 003P.Okinaga T, et al., Acta Neuropathol. 2002 Oct;104(4):377-84.Mohri I, et al., Am J Pathol. 2009 May;174(5):1735-44.Hamburg NM, et al., Circulation J 2017;81:281-289Tran B, Heart 2021; 107: 1835-1843Kajiwara D, et al., European Journal of Pharmacology 667 (2011) 389-395.

[0008] The present invention provides an indazole compound having H-PGDS inhibitory activity or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same, and medical uses thereof, etc. That is, the present invention is as follows.

[0009] [Item 1] The following structural formula:

[0010]

[0011]

[0012]

[0013]

[0014]

[0015]

[0016]

[0017]

[0018]

[0019]

[0020] A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0021] [Item 2] A pharmaceutical composition comprising the compound of Item 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0022] [Item 3] An H-PGDS inhibitor comprising the compound according to Item 1 or a pharmaceutically acceptable salt thereof.

[0023] [Item 4] A therapeutic or preventive agent for a disease selected from the group consisting of peripheral arterial disease, cardiovascular disease, allergic asthma, chronic obstructive pulmonary disease, and Duchenne muscular dystrophy, comprising the compound according to Item 1 or a pharmaceutically acceptable salt thereof.

[0024] [Item 5] A method for inhibiting H-PGDS in a mammal, which comprises administering to the mammal a pharmaceutically effective amount of the compound according to Item 1 or a pharmaceutically acceptable salt thereof.

[0025] [Item 6] A method for treating or preventing a disease selected from the group consisting of peripheral arterial disease, cardiovascular disease, allergic asthma, chronic obstructive pulmonary disease, and Duchenne muscular dystrophy in a mammal, comprising administering to the mammal a pharmaceutically effective amount of the compound according to Item 1 or a pharmaceutically acceptable salt thereof.

[0026] [Item 7] Use of the compound according to Item 1 or a pharmaceutically acceptable salt thereof for the production of an H-PGDS inhibitor.

[0027] [Item 8] Use of the compound according to Item 1 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic or preventive agent for a disease selected from the group consisting of peripheral arterial disease, cardiovascular disease, allergic asthma, chronic obstructive pulmonary disease, and Duchenne muscular dystrophy.

[0028] [Item 9] The compound according to Item 1 or a pharmaceutically acceptable salt thereof for use in inhibiting H-PGDS.

[0029] [Item 10] The compound according to Item 1 or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease selected from the group consisting of peripheral arterial disease, cardiovascular disease, allergic asthma, chronic obstructive pulmonary disease, and Duchenne muscular dystrophy.

[0030] [Item 11] A commercial package comprising the pharmaceutical composition according to Item 2 and a description of the pharmaceutical composition, which describes that the pharmaceutical composition can be used to treat or prevent a disease selected from the group consisting of peripheral arterial disease, cardiovascular disease, allergic asthma, chronic obstructive pulmonary disease, and Duchenne muscular dystrophy.

[0031] [Item 12] A kit comprising the pharmaceutical composition according to Item 2 and a description of the pharmaceutical composition, which describes that the pharmaceutical composition can be used for the treatment or prevention of a disease selected from the group consisting of peripheral arterial disease, cardiovascular disease, allergic asthma, chronic obstructive pulmonary disease, and Duchenne muscular dystrophy.

[0032] [Item 1A] A compound of formula [II] or a pharmaceutically acceptable salt thereof.

[0033]

[0034] [In the formula, X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 and Y 4 are each independently a carbon or nitrogen atom (wherein X 1 , X 2 , X 3 and X 4 The total number of nitrogen atoms in Y is 0 or 1, 1 , Y 2 , Y 3 and Y 4 the total number of nitrogen atoms is 0, 1 or 2), m is 0, 1 or 2, n is 0, 1 or 2, and R 1are (1) hydroxy, (2) cyano, and (3) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 (4) C 1-4 Alkoxy, (5) Halogen, (6) C 1-4 haloalkyl, or (7) C 3-6 cycloalkyl, and m R 2 are each independently: (1) cyano, (2) C 1-4 Alkyl, (3) C 1-4 Alkoxy, (4) halogen, or (5) C 1-4 haloalkyl, n R 3 are each independently: (1) C 1-4 Alkyl, (2) C 1-4 (3) halogen, and R 4 (1) a ring Cy (wherein the ring Cy is: (a) C 4-6 Cycloalkyl, wherein the cycloalkyl is: (I) hydroxy, (II) cyano, (III) oxo, (IV) C 1-6 Alkyl, wherein the alkyl is: (i) hydroxy, (ii) carboxy, (iii) -CONH2, (iv) -CO-C 1-4 Alkoxy, (v) -SO2-C 1-4 alkyl, or (vi) a group of the formula:

[0035]

[0036] (V) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (VI) carboxy, (VII) -CO-NR 5 R 6 [where R 5 and R 6 are each independently C 1-4 Alkyl (wherein the alkyl is C 1-4alkoxy), or R 5 and R 6 together with the nitrogen atom to which they are attached contain 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein said heterocycloalkyl is selected from the group consisting of: (i) hydroxy, and (ii) C 1-6 alkyl (wherein the alkyl is optionally substituted with hydroxy), (VIII) -NR 7 R 8 {where R 7 and R 8 are each independently C 1-4 Alkyl, or -CO-C 1-6 alkyl (wherein the alkyl is optionally substituted with cyano)}, (IX) -OC 1-6 Haloalkyl, (X) a group of the formula:

[0037]

[0038] (XI) a group represented by the formula:

[0039]

[0040] {In the formula, R 9 is C 1-4 Alkyl (wherein the alkyl is C 1-4 (XII) a group represented by the formula:

[0041]

[0042] (In the formula, R 10 is C 1-4 (b) a group represented by the formula: 5-8 bridged cycloalkyl {wherein the bridged cycloalkyl is: (I) hydroxy, (II) C 1-6Alkyl, wherein the alkyl is: (i) hydroxy, (ii) carboxy, (iii) -CONH2, (iv) -CO-C 1-4 Alkoxy, (v) -SO2-C 1-4 alkyl, or (vi) a group of the formula:

[0043]

[0044] (III) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (IV) carboxy, (V) -CO-C 1-4 Alkoxy, (VI)-OC 1-6 haloalkyl, or (VII) a group of formula:

[0045]

[0046] (c) a 5- or 6-membered heterocycloalkyl containing one nitrogen atom, wherein the heterocycloalkyl is (I) oxo, (II) C 1-6 Alkyl, (III) -CO-R 11 {where R 11 (i) C 1-6 alkyl, wherein the alkyl is: (A) hydroxy, (B) cyano, or (C) C 1-4 (ii) C 1-6 Alkoxy, (iii) C 1-6 haloalkyl, (iv) C 3-6 (v) a 4- to 6-membered heterocycloalkyl containing one oxygen atom, wherein the heterocycloalkyl is optionally substituted with halogen; and (IV) a group of the formula:

[0047]

[0048] (d) an 8-membered bridged heterocycloalkyl containing one nitrogen atom {wherein the bridged heterocycloalkyl is -CO-R 11 (e) a 7- to 11-membered spiroheterocycloalkyl containing one nitrogen atom {wherein the spiroheterocycloalkyl is -CO-R 11 (f) a 6- to 9-membered saturated or partially unsaturated fused ring group containing 1 or 2 nitrogen atoms (wherein the fused ring group is -CO-R 11 (g) a compound of the formula:

[0049]

[0050] (h) a group represented by the formula:

[0051]

[0052] or (i) a group of the formula:

[0053]

[0054] (2) C 1-4 alkyl {wherein the alkyl is: (a) C 3-6 Cycloalkyl (wherein the cycloalkyl is hydroxy and optionally hydroxy-substituted C 1-4 (b) optionally substituted with phenyl; or (3) C 1-4 Haloalkyl (wherein the haloalkyl is optionally substituted with hydroxy). 3-6 (which may be substituted with cycloalkyl)

[0055] [Item 2A] The compound of Item 1A represented by formula [I] or a pharmaceutically acceptable salt thereof.

[0056]

[0057] (Each symbol in the formula has the same meaning as in Item 1A)

[0058] [Section 3A] Y 1 , Y 2 , Y 3 and Y 4 The compound or pharmaceutically acceptable salt thereof according to Item 1A or 2A, wherein the total number of nitrogen atoms is 1 or 2.

[0059] [Item 4A] The compound according to Item 1A, which is represented by formula [IA], or a pharmaceutically acceptable salt thereof.

[0060]

[0061] (Each symbol in the formula has the same meaning as in Item 1A)

[0062] [Section 5A] R 3 The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1A to 4A, wherein is halogen.

[0063] [Section 6A] R 4 is ring Cy, or a pharmaceutically acceptable salt thereof according to any one of Items 1A to 5A.

[0064] [Item 7A] The compound according to Item 1A, which is represented by formula [IB], or a pharmaceutically acceptable salt thereof.

[0065]

[0066] (Each symbol in the formula has the same meaning as in Item 1A)

[0067] [Section 8A] R 1 However, (1) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 (2) C 1-4 Alkoxy, (3) halogen, or (4) C 1-4 The compound according to any one of Items 1A to 7A, or a pharmaceutically acceptable salt thereof, wherein:

[0068] [Section 9A] R 2 The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1A to 8A, wherein is halogen.

[0069] [Item 10A] Ring Cy is (1) C 4-6cycloalkyl, wherein the cycloalkyl is: (a) hydroxy, (b) cyano, (c) oxo, (d) C 1-6 Alkyl (wherein the alkyl is: (I) hydroxy, (II) carboxy, (III) -CONH2, (IV) -CO-C 1-4 Alkoxy, (V) -SO2-C 1-4 alkyl, or (VI) a group of the formula:

[0070]

[0071] (e) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (f) carboxy, (g) -CO-NR 5 R 6 [where R 5 and R 6 are each independently C 1-4 Alkyl (wherein the alkyl is C 1-4 alkoxy), or R 5 and R 6 together with the nitrogen atom to which they are attached, contain one or two heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein said heterocycloalkyl is selected from the group consisting of: (I) hydroxy, and (II) C 1-6 alkyl (wherein the alkyl is optionally substituted with hydroxy); (h) —NR 7 R 8 {where R 7 and R 8 are each independently C 1-4 Alkyl, or -CO-C 1-6 alkyl (wherein the alkyl is optionally substituted with cyano); (i) —OC 1-6 haloalkyl, (j) a group of the formula:

[0072]

[0073] (k) a group represented by the formula:

[0074]

[0075] {In the formula, R 9 is C 1-4 Alkyl (wherein the alkyl is C 1-4 (m) a group represented by the formula:

[0076]

[0077] (In the formula, R 10 is C 1-4 (2) C 5-8 a bridged cycloalkyl {wherein the bridged cycloalkyl is: (a) hydroxy, (b) C 1-6 Alkyl (wherein the alkyl is: (I) hydroxy, (II) carboxy, (III) -CONH2, (IV) -CO-C 1-4 Alkoxy, (V) -SO2-C 1-4 alkyl, or (VI) a group of the formula:

[0078]

[0079] (c) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (e) -CO-C 1-4 Alkoxy, (f) -OC 1-6 haloalkyl, or (g) a group of the formula:

[0080]

[0081] (3) a 5- or 6-membered heterocycloalkyl containing one nitrogen atom, wherein the heterocycloalkyl is (a) oxo, (b) C 1-6alkyl, (c) -CO-R 11 {where R 11 (I) C 1-6 alkyl, wherein the alkyl is: (i) hydroxy, (ii) cyano, or (iii) C 1-4 (II) C 1-6 Alkoxy, (III) C 1-6 haloalkyl, (IV) C 3-6 (V) a 4- to 6-membered heterocycloalkyl containing one oxygen atom, wherein the heterocycloalkyl is optionally substituted with halogen; and (d) a group of the formula:

[0082]

[0083] (4) an 8-membered bridged heterocycloalkyl containing one nitrogen atom {wherein the bridged heterocycloalkyl is -CO-R 11 (5) a 7- to 11-membered spiroheterocycloalkyl containing one nitrogen atom {wherein the spiroheterocycloalkyl is -CO-R 11 (6) a 6- to 9-membered saturated or partially unsaturated fused ring group containing one or two nitrogen atoms, wherein the fused ring group is -CO-R 11 The compound according to any one of Items 1A to 9A, or a pharmaceutically acceptable salt thereof, wherein:

[0084] [Item 11A] Ring Cy is (1) C 4-6 cycloalkyl, wherein the cycloalkyl is: (a) hydroxy, (b) cyano, (c) oxo, (d) C 1-6 Alkyl (wherein the alkyl is: (I) hydroxy, (II) carboxy, (III) -CONH2, (IV) -CO-C 1-4Alkoxy, (V) -SO2-C 1-4 alkyl, or (VI) a group of the formula:

[0085]

[0086] (e) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (f) carboxy, (g) -CO-NR 5 R 6 [where R 5 and R 6 are each independently C 1-4 Alkyl (wherein the alkyl is C 1-4 alkoxy), or R 5 and R 6 together with the nitrogen atom to which they are attached, contain one or two heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein said heterocycloalkyl is selected from the group consisting of: (I) hydroxy, and (II) C 1-6 alkyl (wherein the alkyl is optionally substituted with hydroxy); (h) —NR 7 R 8 {where R 7 and R 8 are each independently C 1-4 Alkyl, or -CO-C 1-6 alkyl (wherein the alkyl is optionally substituted with cyano); (i) —OC 1-6 haloalkyl, (j) a group of the formula:

[0087]

[0088] (k) a group represented by the formula:

[0089]

[0090] {In the formula, R 9 is C 1-4Alkyl (wherein the alkyl is C 1-4 (m) a group represented by the formula:

[0091]

[0092] (In the formula, R 10 is C 1-4 (2) C 5-8 a bridged cycloalkyl {wherein the bridged cycloalkyl is: (a) hydroxy, (b) C 1-6 Alkyl (wherein the alkyl is: (I) hydroxy, (II) carboxy, (III) -CONH2, (IV) -CO-C 1-4 Alkoxy, (V) -SO2-C 1-4 alkyl, or (VI) a group of the formula:

[0093]

[0094] (c) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (e) -CO-C 1-4 Alkoxy, (f) -OC 1-6 haloalkyl, or (g) a group of the formula:

[0095]

[0096] (3) a 5- or 6-membered heterocycloalkyl containing one nitrogen atom, wherein the heterocycloalkyl is (a) oxo, (b) C 1-6 alkyl, (c) -CO-R 11 {where R 11 (I) C 1-6 alkyl, wherein the alkyl is: (i) hydroxy, (ii) cyano, or (iii) C 1-4(II) C 1-6 Alkoxy, (III) C 1-6 haloalkyl, (IV) C 3-6 (V) a 4- to 6-membered heterocycloalkyl containing one oxygen atom, wherein the heterocycloalkyl is optionally substituted with halogen; and (d) a group of the formula:

[0097]

[0098] (4) an 8-membered bridged heterocycloalkyl containing one nitrogen atom {wherein the bridged heterocycloalkyl is -CO-R 11 The compound according to any one of Items 1A to 9A, or a pharmaceutically acceptable salt thereof, wherein:

[0099] [Item 12A] Ring Cy is (1) C 4-6 cycloalkyl, wherein the cycloalkyl is: (a) hydroxy, (b) cyano, (c) oxo, (d) C 1-6 Alkyl (wherein the alkyl is: (I) hydroxy, (II) carboxy, (III) -CONH2, (IV) -CO-C 1-4 Alkoxy, (V) -SO2-C 1-4 alkyl, or (VI) a group of the formula:

[0100]

[0101] (e) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (f) carboxy, (g) -CO-NR 5 R 6 [where R 5 and R 6 are each independently C 1-4Alkyl (wherein the alkyl is C 1-4 alkoxy), or R 5 and R 6 together with the nitrogen atom to which they are attached, contain one or two heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein said heterocycloalkyl is selected from the group consisting of: (I) hydroxy, and (II) C 1-6 alkyl (wherein the alkyl is optionally substituted with hydroxy); (h) —NR 7 R 8 {where R 7 and R 8 are each independently C 1-4 Alkyl, or -CO-C 1-6 alkyl (wherein the alkyl is optionally substituted with cyano); (i) —OC 1-6 haloalkyl, (j) a group of the formula:

[0102]

[0103] (k) a group represented by the formula:

[0104]

[0105] {In the formula, R 9 is C 1-4 Alkyl (wherein the alkyl is C 1-4 (m) a group represented by the formula:

[0106]

[0107] (In the formula, R 10 is C 1-4 (1) a group represented by the formula: 5-8 a bridged cycloalkyl {wherein the bridged cycloalkyl is: (a) hydroxy, (b) C 1-6Alkyl (wherein the alkyl is: (I) hydroxy, (II) carboxy, (III) -CONH2, (IV) -CO-C 1-4 Alkoxy, (V) -SO2-C 1-4 alkyl, or (VI) a group of the formula:

[0108]

[0109] (c) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (e) -CO-C 1-4 Alkoxy, (f) -OC 1-6 haloalkyl, or (g) a group of the formula:

[0110]

[0111] The compound according to any one of Items 1A to 9A, or a pharmaceutically acceptable salt thereof, wherein the compound is:

[0112] [Item 13A] The ring Cy is (1) cyclohexyl (wherein the cyclohexyl is (a) hydroxy, (b) cyano, (c) oxo, (d) C 1-6 Alkyl (wherein the alkyl is: (I) hydroxy, (II) carboxy, (III) -CONH2, (IV) -CO-C 1-4 Alkoxy, (V) -SO2-C 1-4 alkyl, or (VI) a group of the formula:

[0113]

[0114] (e) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (f) carboxy, (g) -CO-NR 5 R 6 [where R 5 and R6 are each independently C 1-4 Alkyl (wherein the alkyl is C 1-4 alkoxy), or R 5 and R 6 together with the nitrogen atom to which they are attached, contain one or two heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein said heterocycloalkyl is selected from the group consisting of: (I) hydroxy, and (II) C 1-6 alkyl (wherein the alkyl is optionally substituted with hydroxy); (h) —NR 7 R 8 {where R 7 and R 8 are each independently C 1-4 Alkyl, or -CO-C 1-6 alkyl (wherein the alkyl is optionally substituted with cyano); (i) —OC 1-6 haloalkyl, (j) a group of the formula:

[0115]

[0116] (k) a group represented by the formula:

[0117]

[0118] {In the formula, R 9 is C 1-4 Alkyl (wherein the alkyl is C 1-4 (m) a group represented by the formula:

[0119]

[0120] (In the formula, R 10 is C 1-4 (1) a group of the formula:

[0121]

[0122] wherein the group represented by the formula is: (a) hydroxy, (b) C 1-6 Alkyl (wherein the alkyl is: (I) hydroxy, (II) carboxy, (III) -CONH2, (IV) -CO-C 1-4 Alkoxy, (V) -SO2-C 1-4 alkyl, or (VI) a group of the formula:

[0123]

[0124] (c) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (e) -CO-C 1-4 Alkoxy, (f) -OC 1-6 haloalkyl, or (g) a group of the formula:

[0125]

[0126] The compound according to any one of Items 1A to 9A, wherein the compound is a group represented by the formula: which may be substituted with a group represented by the formula: or a pharmaceutically acceptable salt thereof.

[0127] [Item 14A] Ring Cy is (1) Formula:

[0128]

[0129] (In the formula, R 12 and R 13 are each independently: (a) hydrogen, (b) hydroxy, (c) cyano, or (d) C 1-6 Alkyl (wherein the alkyl is: (I) hydroxy, (II) carboxy, (III) -CONH2, (IV) -CO-C 1-4 Alkoxy, (V) -SO2-C 1-4 alkyl, or (VI) a group of the formula:

[0130]

[0131] (e) C1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (f) carboxy, (g) -CO-NR 5 R 6 [where R 5 and R 6 are each independently C 1-4 Alkyl (wherein the alkyl is C 1-4 alkoxy), or R 5 and R 6 together with the nitrogen atom to which they are attached, contain one or two heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein said heterocycloalkyl is selected from the group consisting of: (I) hydroxy, and (II) C 1-6 alkyl (wherein the alkyl is optionally substituted with hydroxy); (h) —NR 7 R 8 {where R 7 and R 8 are each independently C 1-4 Alkyl, or -CO-C 1-6 alkyl (wherein the alkyl is optionally substituted with cyano); (i) —OC 1-6 haloalkyl, (j) a group of the formula:

[0132]

[0133] (k) a group represented by the formula:

[0134]

[0135] {In the formula, R 9 is C 1-4 Alkyl (wherein the alkyl is C 1-4 (m) a group represented by the formula:

[0136]

[0137] (In the formula, R 10is C 1-4 alkyl), or R 12 and R 13 may be taken together to form oxo), or (2) a group represented by the formula:

[0138]

[0139] (In the formula, R 14 is (a) hydrogen, (b) hydroxy, (c) C 1-6 Alkyl (wherein the alkyl is: (I) hydroxy, (II) carboxy, (III) -CONH2, (IV) -CO-C 1-4 Alkoxy, (V) -SO2-C 1-4 alkyl, or (VI) a group of the formula:

[0140]

[0141] (d) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (e) carboxy, (f) -CO-C 1-4 Alkoxy, (g) -OC 1-6 haloalkyl, or (h) a group of the formula:

[0142]

[0143] The compound according to any one of Items 1A to 9A, wherein R is a group represented by the formula: or a pharmaceutically acceptable salt thereof.

[0144] [Item 15A] A compound of formula [IC] according to item 1A or 14A, or a pharmaceutically acceptable salt thereof.

[0145]

[0146] (In the formula, X 1 , R 1 , R 2 and m are the same as those in Item 1A, and R 12 has the same meaning as in paragraph 14A)

[0147] [Section 16A] R 12 (1) Hydroxy, (2) Cyano, (3) C 1-6 Alkyl, wherein the alkyl is: (a) hydroxy; (b) carboxy; (c) -CONH2; (d) -CO-C 1-4 Alkoxy, (e) -SO2-C 1-4 alkyl, or (f) a group of the formula:

[0148]

[0149] (4) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (5) —CO—NR 5 R 6 [where R 5 and R 6 together with the nitrogen atom to which they are attached, form a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the heterocycloalkyl is C 1-6 (6) -NR 7 R 8 {where R 7 and R 8 are each independently C 1-4 Alkyl, or -CO-C 1-6 alkyl, wherein the alkyl is optionally substituted with cyano; (7) a compound of the formula:

[0150]

[0151] (8) a group represented by the formula:

[0152]

[0153] {In the formula, R 9 is C 1-4 Alkyl (wherein the alkyl is C 1-4 (9) a group represented by the formula:

[0154]

[0155] (In the formula, R 10 is C 1-4 The compound according to Item 15A, wherein R is a group represented by the formula: R is alkyl; or a pharmaceutically acceptable salt thereof.

[0156] [Item 17A] A compound of formula [ID] according to item 1A or 14A, or a pharmaceutically acceptable salt thereof.

[0157]

[0158] (In the formula, X 1 , R 1 , R 2 and m are the same as those in Item 1A, and R 14 has the same meaning as in paragraph 14A)

[0159] [Section 18A] R 14 But C 1-6 The compound according to item 17A, wherein the alkyl is alkyl (wherein the alkyl is optionally substituted with hydroxy), or a pharmaceutically acceptable salt thereof.

[0160] [Item 19A] The following structural formula:

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174] The compound according to Item 1A, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

[0175] [Item 20A] A compound of formula [III] or a pharmaceutically acceptable salt thereof.

[0176]

[0177] {In the formula, X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 and Y 4 are each independently a carbon or nitrogen atom (wherein X 1 , X 2 , X 3 and X 4 The total number of nitrogen atoms in Y is 0 or 1, 1 , Y 2 , Y 3 and Y 4 The total number of nitrogen atoms is 0, 1 or 2), and other symbols have the same meanings as in item 1A.

[0178] [Item 21A] A compound of formula [IV] or a pharmaceutically acceptable salt thereof.

[0179]

[0180] {In the formula, X 1 , X 5 , X 6 , Y 1 , Y 2 , Y 3 and Y 4 are each independently a carbon or nitrogen atom (wherein X 5 and X 6 The total number of nitrogen atoms in Y is 1. 1 , Y 2 , Y 3 and Y 4 The total number of nitrogen atoms is 0, 1 or 2), and other symbols have the same meanings as in item 1A.

[0181] [Item 22A] A pharmaceutical composition comprising the compound according to any one of Items 1A to 21A or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0182] [Item 23A] An H-PGDS inhibitor comprising the compound according to any one of Items 1A to 21A or a pharmaceutically acceptable salt thereof.

[0183] [Item 24A] A therapeutic or preventive agent for a disease selected from the group consisting of peripheral arterial disease, cardiovascular disease, allergic asthma, chronic obstructive pulmonary disease, and Duchenne muscular dystrophy, comprising the compound according to any one of Items 1A to 21A or a pharmaceutically acceptable salt thereof.

[0184] [Item 25A] A method for inhibiting H-PGDS in a mammal, which comprises administering to the mammal a pharmaceutically effective amount of the compound according to any one of Items 1A to 21A or a pharmaceutically acceptable salt thereof.

[0185] [Item 26A] A method for treating or preventing a disease selected from the group consisting of peripheral arterial disease, cardiovascular disease, allergic asthma, chronic obstructive pulmonary disease, and Duchenne muscular dystrophy in a mammal, comprising administering to the mammal a pharmaceutically effective amount of the compound according to any one of Items 1A to 21A or a pharmaceutically acceptable salt thereof.

[0186] [Item 27A] Use of the compound according to any one of Items 1A to 21A or a pharmaceutically acceptable salt thereof for the production of an H-PGDS inhibitor.

[0187] [Item 28A] Use of the compound according to any one of Items 1A to 21A or a pharmaceutically acceptable salt thereof for the manufacture of an agent for the treatment or prevention of a disease selected from the group consisting of peripheral arterial disease, cardiovascular disease, allergic asthma, chronic obstructive pulmonary disease, and Duchenne muscular dystrophy.

[0188] [Item 29A] The compound according to any one of Items 1A to 21A or a pharmaceutically acceptable salt thereof for use in inhibiting H-PGDS.

[0189] [Item 30A] The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1A to 21A for use in the treatment or prevention of a disease selected from the group consisting of peripheral arterial disease, cardiovascular disease, allergic asthma, chronic obstructive pulmonary disease, and Duchenne muscular dystrophy.

[0190] [Item 31A] A commercial package comprising the pharmaceutical composition according to Item 22A and a description of the pharmaceutical composition, which describes that the pharmaceutical composition can be used to treat or prevent a disease selected from the group consisting of peripheral arterial disease, cardiovascular disease, allergic asthma, chronic obstructive pulmonary disease, and Duchenne muscular dystrophy.

[0191] [Item 32A] A commercial kit comprising the pharmaceutical composition according to Item 22A and a description of the pharmaceutical composition, which describes that the pharmaceutical composition can be used to treat or prevent a disease selected from the group consisting of peripheral arterial disease, cardiovascular disease, allergic asthma, chronic obstructive pulmonary disease, and Duchenne muscular dystrophy.

[0192] [Item 33A] The following structural formula:

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207] A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0208] [Item 34A] A pharmaceutical composition comprising the compound according to any one of Items 1A to 21A and 33A or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0209] [Item 35A] An H-PGDS inhibitor comprising the compound according to any one of Items 1A to 21A and 33A or a pharmaceutically acceptable salt thereof.

[0210] [Item 36A] A therapeutic or preventive agent for a disease selected from the group consisting of peripheral arterial disease, cardiovascular disease, allergic asthma, chronic obstructive pulmonary disease, allergic rhinitis, sarcopenia, and Duchenne muscular dystrophy, comprising the compound according to any one of Items 1A to 21A and 33A or a pharmaceutically acceptable salt thereof.

[0211] [Item 37A] The therapeutic or preventive agent according to Item 36A, wherein the peripheral arterial disease is intermittent claudication or global severe chronic lower limb ischemia due to PAD.

[0212] [Item 38A] A method for inhibiting H-PGDS in a mammal, which comprises administering to the mammal a pharmaceutically effective amount of the compound according to any one of Items 1A to 21A and 33A or a pharmaceutically acceptable salt thereof.

[0213] [Item 39A] A method for treating or preventing a disease selected from the group consisting of peripheral arterial disease, cardiovascular disease, allergic asthma, chronic obstructive pulmonary disease, allergic rhinitis, sarcopenia, and Duchenne muscular dystrophy in a mammal, comprising administering to the mammal a pharmaceutically effective amount of the compound according to any one of Items 1A to 21A and 33A or a pharmaceutically acceptable salt thereof.

[0214] [Item 40A] The method according to Item 39A, wherein the peripheral arterial disease is intermittent claudication due to PAD or global severe chronic lower limb ischemia.

[0215] [Item 41A] Use of the compound or a pharmaceutically acceptable salt thereof according to any one of Items 1A to 21A and 33A for the production of an H-PGDS inhibitor.

[0216] [Item 42A] Use of the compound according to any one of Items 1A to 21A and 33A or a pharmaceutically acceptable salt thereof for the manufacture of an agent for the treatment or prevention of a disease selected from the group consisting of peripheral arterial disease, cardiovascular disease, allergic asthma, chronic obstructive pulmonary disease, allergic rhinitis, sarcopenia, and Duchenne muscular dystrophy.

[0217] [Item 43A] The use according to Item 42A, wherein the peripheral arterial disease is intermittent claudication or global severe chronic lower limb ischemia due to PAD.

[0218] [Item 44A] A compound or a pharmaceutically acceptable salt thereof according to any one of Items 1A to 21A and 33A for use in inhibiting H-PGDS.

[0219] [Item 45A] The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1A to 21A and 33A for use in the treatment or prevention of a disease selected from the group consisting of peripheral arterial disease, cardiovascular disease, allergic asthma, chronic obstructive pulmonary disease, allergic rhinitis, sarcopenia, and Duchenne muscular dystrophy.

[0220] [Item 46A] The compound according to Item 45A or a pharmaceutically acceptable salt thereof, wherein the peripheral arterial disease is intermittent claudication or global severe chronic lower limb ischemia due to PAD.

[0221] [Item 47A] A commercial package comprising the pharmaceutical composition according to Item 34A and a description of the pharmaceutical composition, which describes that the pharmaceutical composition can be used to treat or prevent a disease selected from the group consisting of peripheral arterial disease, cardiovascular disease, allergic asthma, chronic obstructive pulmonary disease, allergic rhinitis, sarcopenia, and Duchenne muscular dystrophy.

[0222] [Item 48A] A commercial kit comprising the pharmaceutical composition according to Item 34A and a description of the pharmaceutical composition, which describes that the pharmaceutical composition can be used to treat or prevent a disease selected from the group consisting of peripheral arterial disease, cardiovascular disease, allergic asthma, chronic obstructive pulmonary disease, allergic rhinitis, sarcopenia, and Duchenne muscular dystrophy.

[0223] The definitions of terms used in this specification are as follows.

[0224] In the chemical formula:

[0225]

[0226] The wavy line indicated by indicates the bonding site of the structure or group represented by the chemical formula.

[0227] In the chemical formula:

[0228]

[0229] The bond represented by represents a single bond or a double bond.

[0230] "C 1-4 "Alkyl" means a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms. 1-4 "Alkyl" includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. 1-4 "Alkyl" is methyl, ethyl, or isopropyl. 1-4 "Alkyl" is methyl or ethyl.

[0231] "C 1-6 "Alkyl" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. 1-6Examples of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 2-methylbutyl, 1,1-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. 1-6 "Alkyl" is methyl, ethyl, isopropyl, isobutyl, tert-butyl, or isopentyl. 1-6 "Alkyl" is methyl, ethyl, isopropyl, isobutyl, or tert-butyl.

[0232] "C 1-4 "Alkoxy" refers to the above "C 1-4 "C" means a group in which "alkyl" is bonded to an oxygen atom. 1-4 "Alkoxy" includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, and tert-butoxy. 1-4 "Alkoxy" is methoxy or ethoxy.

[0233] "C 1-6 "Alkoxy" refers to the above "C 1-6 "C" means a group in which "alkyl" is bonded to an oxygen atom. 1-6 Examples of "alkoxy" include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, 2-methylbutoxy, 1,1-dimethylpropoxy, 1-ethylpropoxy, hexyloxy, isohexyloxy, 1,1-dimethylbutoxy, 2,2-dimethylbutoxy, 3,3-dimethylbutoxy, and 2-ethylbutoxy. Preferred "C 1-6 "Alkoxy" is methoxy, ethoxy, n-propoxy, isopropoxy, isobutoxy, tert-butoxy, or isopentyloxy.

[0234] "Halogen" includes, for example, fluorine, chlorine, bromine, and iodine. Preferred "halogen" is fluorine or chlorine.

[0235] "C 1-4 "Haloalkyl" refers to the above "C" substituted with 1 to 7 halogens independently selected from the above "halogen" group. 1-4 "C" means "alkyl". 1-4 "Haloalkyl" includes, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 1-fluoro-1-methylethyl, 2,2,2-trifluoro-1-methylethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 1,1-difluoropropyl, 3,3,3-trifluoropropyl, and 4,4,4-trifluorobutyl. Preferred "C 1-4 "Haloalkyl" is difluoromethyl, trifluoromethyl, or 2,2-difluoroethyl.

[0236] "C 1-6 "Haloalkyl" refers to the above "C" substituted with 1 to 9 halogens independently selected from the above "halogen" group. 1-6 "C" means "alkyl". 1-6 Examples of "haloalkyl" include monofluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 1-fluoro-1-methylethyl, 2,2,2-trifluoro-1-methylethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 1,1-difluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, and 6,6,6-trifluorohexyl. Preferred "C 1-6"Haloalkyl" is difluoromethyl, trifluoromethyl, 1-fluoro-1-methylethyl, or 2,2,2-trifluoroethyl.

[0237] "C 4-6 "Cycloalkyl" means a monocyclic saturated hydrocarbon ring group having 4 to 6 carbon atoms. 4-6 "Cycloalkyl" includes, for example, cyclobutyl, cyclopentyl, and cyclohexyl. Preferred "C 4-6 "Cycloalkyl" is cyclobutyl or cyclohexyl. 4-6 "Cycloalkyl" is cyclohexyl.

[0238] "C 3-6 "Cycloalkyl" means a monocyclic saturated hydrocarbon ring group having 3 to 6 carbon atoms. 3-6 "Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Preferred "C 3-6 "Cycloalkyl" is cyclopropyl, cyclobutyl, or cyclohexyl.

[0239] "4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms" refers to a 4- to 6-membered monocyclic saturated heterocyclic group containing, in addition to carbon atoms, 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms as ring-constituting atoms. Examples of "4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms" include azetidinyl, oxetanyl, diazetidinyl, dioxetanyl, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, piperidinyl, tetrahydropyranyl, 1,3-diazacyclohexanyl, piperazinyl, morpholinyl, tetrahydro-1,2-oxazinyl, and dioxanyl. A preferred "4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms" is azetidinyl, pyrrolidinyl, or morpholinyl.

[0240] "5- or 6-membered heterocycloalkyl containing one nitrogen atom" refers to a 5- to 6-membered monocyclic saturated heterocyclic group containing one nitrogen atom in addition to carbon atoms as a ring-constituting atom. Examples of "5- or 6-membered heterocycloalkyl containing one nitrogen atom" include pyrrolidinyl and piperidinyl. A preferred "5- or 6-membered heterocycloalkyl containing one nitrogen atom" is piperidinyl.

[0241] "4- to 6-membered heterocycloalkyl containing one oxygen atom" refers to a 4- to 6-membered monocyclic saturated heterocyclic group containing one oxygen atom in addition to carbon atoms as a ring-constituting atom. Examples of "4- to 6-membered heterocycloalkyl containing one oxygen atom" include oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl. Preferred "4- to 6-membered heterocycloalkyl containing one oxygen atom" are oxetanyl and tetrahydropyranyl.

[0242] "C 5-8 "Bridged cycloalkyl" means a 5- to 8-membered bridged cyclic saturated hydrocarbon group. 5-8 "Bridged cycloalkyl" includes, for example, 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 or bicyclo[2.2.2]octyl. 5-8 A "bridged cycloalkyl" is bicyclo[1.1.1]pentyl.

[0243] The term "8-membered bridged heterocycloalkyl containing one nitrogen atom" refers to an 8-membered bridged saturated heterocyclic group containing one nitrogen atom as a ring-constituting atom in addition to carbon atoms. The term "8-membered bridged heterocycloalkyl containing one nitrogen atom" includes, for example, the following groups:

[0244]

[0245] Includes:

[0246] "7- to 11-membered spiroheterocycloalkyl containing one nitrogen atom" means a 7- to 11-membered spiro-type saturated heterocyclic group containing one nitrogen atom in addition to carbon atoms as a ring-constituting atom. "7- to 11-membered spiroheterocycloalkyl containing one nitrogen atom" includes, for example, the following groups:

[0247]

[0248] Includes:

[0249] The term "6- to 9-membered saturated or partially unsaturated fused ring group containing one or two nitrogen atoms" refers to a 6- to 9-membered fused heterocyclic group containing one or two nitrogen atoms as ring-constituting atoms other than carbon atoms, and a fused ring group containing at least one saturated ring among the rings constituting the fused ring. Examples of the "6- to 9-membered saturated or partially unsaturated fused ring group containing one or two nitrogen atoms" include the following groups:

[0250]

[0251] Includes:

[0252] The expression "α may be substituted" with β means that α is unsubstituted or any substitutable hydrogen of α is substituted with β. For example, "C optionally substituted with hydroxy" 1-6 "Alkyl" means C 1-6 The alkyl is unsubstituted or C 1-6 This means that any hydrogen in the alkyl is replaced with hydroxy.

[0253] Specific embodiments of each substituent of the compound of formula [II] are exemplified below, but the substituents of the compound of formula [II] are not limited to these specific embodiments, and the compound of formula [II] also includes embodiments in which any two or more of the specific embodiments of each substituent are combined.

[0254] Y 1 is preferably a nitrogen atom.

[0255] Y 2 is preferably a nitrogen atom.

[0256] Y 3 is preferably a carbon atom.

[0257] Y 4 is preferably a carbon atom.

[0258] R 1 Preferred embodiments of the formula (1) are hydroxy, (2) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 (3) C 1-4 Alkoxy, (4) halogen, or (5) C 1-4 It is haloalkyl.

[0259] R 1 A more preferred embodiment of the present invention is (1) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 (2) halogen, or (3) C 1-4 It is haloalkyl.

[0260] R 1 Preferred examples of are methyl, fluorine, chlorine, difluoromethyl, or trifluoromethyl.

[0261] m R 2 A preferred embodiment of is each independently halogen.

[0262] m R 2 Preferred examples of are fluorine and chlorine.

[0263] m is preferably 0 or 1.

[0264] n R 3 A preferred embodiment of is each independently halogen.

[0265] n R 3 Preferred examples of are fluorine and chlorine.

[0266] n is preferably 0 or 1.

[0267] R ４ is preferably: (a) C 4-6Cycloalkyl, wherein the cycloalkyl is: (I) hydroxy, (II) cyano, (III) oxo, (IV) C 1-6 Alkyl, wherein the alkyl is: (i) hydroxy, (ii) carboxy, (iii) -CONH2, (iv) -CO-C 1-4 Alkoxy, (v) -SO2-C 1-4 alkyl, or (vi) a group of the formula:

[0268]

[0269] (V) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (VI) carboxy, (VII) -CO-NR 5 R 6 [where R 5 and R 6 are each independently C 1-4 Alkyl (wherein the alkyl is C 1-4 alkoxy), or R 5 and R 6 together with the nitrogen atom to which they are attached contain 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein said heterocycloalkyl is selected from the group consisting of: (i) hydroxy, and (ii) C 1-6 alkyl (wherein the alkyl is optionally substituted with hydroxy), (VIII) -NR 7 R 8 {where R 7 and R 8 are each independently C 1-4 Alkyl, or -CO-C 1-6 alkyl (wherein the alkyl is optionally substituted with cyano)}, (IX) -OC 1-6 Haloalkyl, (X) a group of the formula:

[0270]

[0271] (XI) a group represented by the formula:

[0272]

[0273] {In the formula, R 9 is C 1-4 Alkyl (wherein the alkyl is C 1-4 (XII) a group represented by the formula:

[0274]

[0275] (In the formula, R 10 is C 1-4 (b) a group represented by the formula: 5-8 bridged cycloalkyl {wherein the bridged cycloalkyl is: (I) hydroxy, (II) C 1-6 Alkyl, wherein the alkyl is: (i) hydroxy, (ii) carboxy, (iii) -CONH2, (iv) -CO-C 1-4 Alkoxy, (v) -SO2-C 1-4 alkyl, or (vi) a group of the formula:

[0276]

[0277] (III) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (IV) carboxy, (V) -CO-C 1-4 Alkoxy, (VI)-OC 1-6 haloalkyl, or (VII) a group of formula:

[0278]

[0279] (c) a 5- or 6-membered heterocycloalkyl containing one nitrogen atom, wherein the heterocycloalkyl is (I) oxo, (II) C 1-6 Alkyl, (III) -CO-R 11 {where R 11 (i) C 1-6 alkyl, wherein the alkyl is: (A) hydroxy, (B) cyano, or (C) C 1-4 (ii) C 1-6 Alkoxy, (iii) C 1-6 haloalkyl, (iv) C 3-6 (v) a 4- to 6-membered heterocycloalkyl containing one oxygen atom, wherein the heterocycloalkyl is optionally substituted with halogen; and (IV) a group of the formula:

[0280]

[0281] (d) an 8-membered bridged heterocycloalkyl containing one nitrogen atom {wherein the bridged heterocycloalkyl is -CO-R 11 (e) a 7- to 11-membered spiroheterocycloalkyl containing one nitrogen atom {wherein the spiroheterocycloalkyl is -CO-R 11 or (f) a 6- to 9-membered saturated or partially unsaturated fused ring group containing one or two nitrogen atoms, wherein the fused ring group is -CO-R 11 (which may be substituted with).

[0282] R ４ is more preferably: (a) C 4-6 Cycloalkyl, wherein the cycloalkyl is: (I) hydroxy, (II) cyano, (III) oxo, (IV) C 1-6Alkyl, wherein the alkyl is: (i) hydroxy, (ii) carboxy, (iii) -CONH2, (iv) -CO-C 1-4 Alkoxy, (v) -SO2-C 1-4 alkyl, or (vi) a group of the formula:

[0283]

[0284] (V) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (VI) carboxy, (VII) -CO-NR 5 R 6 [where R 5 and R 6 are each independently C 1-4 Alkyl (wherein the alkyl is C 1-4 alkoxy), or R 5 and R 6 together with the nitrogen atom to which they are attached contain 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein said heterocycloalkyl is selected from the group consisting of: (i) hydroxy, and (ii) C 1-6 alkyl (wherein the alkyl is optionally substituted with hydroxy), (VIII) -NR 7 R 8 {where R 7 and R 8 are each independently C 1-4 Alkyl, or -CO-C 1-6 alkyl (wherein the alkyl is optionally substituted with cyano)}, (IX) -OC 1-6 Haloalkyl, (X) a group of the formula:

[0285]

[0286] (XI) a group represented by the formula:

[0287]

[0288] {In the formula, R 9 is C 1-4 Alkyl (wherein the alkyl is C 1-4 (XII) a group represented by the formula:

[0289]

[0290] (In the formula, R 10 is C 1-4 (b) a group represented by the formula: 5-8 bridged cycloalkyl {wherein the bridged cycloalkyl is: (I) hydroxy, (II) C 1-6 alkyl, wherein the alkyl is: (i) hydroxy; or (ii) —SO—C 1-4 (III) carboxy, or (IV) -CO-C 1-4 (c) a 5- or 6-membered heterocycloalkyl containing one nitrogen atom, wherein the heterocycloalkyl is (I) oxo, (II) C 1-6 alkyl, and (III) -CO-R 11 {where R 11 (i) C 1-6 alkyl, wherein the alkyl is: (A) hydroxy, (B) cyano, or (C) C 1-4 (ii) C 1-6 Alkoxy, (iii) C 1-6 haloalkyl, (iv) C 3-6(v) a 4- to 6-membered heterocycloalkyl containing one oxygen atom, wherein the heterocycloalkyl is optionally substituted with a halogen atom; (d) an 8-membered bridged heterocycloalkyl containing one nitrogen atom {wherein the bridged heterocycloalkyl is selected from the group consisting of -CO-R 11a {where R 11a (i) C 1-6 (ii) alkyl (wherein the alkyl is optionally substituted with: (A) hydroxy; or (B) cyano; or 1-6 (e) a 7- to 11-membered spiroheterocycloalkyl containing one nitrogen atom {wherein the spiroheterocycloalkyl is -CO-R 11a or (f) a 6- to 9-membered saturated or partially unsaturated fused ring group containing one or two nitrogen atoms, wherein the fused ring group is -CO-C 1-6 alkyl (wherein the alkyl is optionally substituted with hydroxy).

[0291] R ４ is more preferably: (a) C 4-6 Cycloalkyl, wherein the cycloalkyl is: (I) hydroxy, (II) cyano, (III) C 1-6 Alkyl, wherein the alkyl is: (i) hydroxy, (ii) carboxy, (iii) -CONH2, (iv) -CO-C 1-4 Alkoxy, (v) -SO2-C 1-4 alkyl, or (vi) a group of the formula:

[0292]

[0293] (IV) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C1-4 (V) —CO—NR 5 R 6 [where R 5 and R 6 together with the nitrogen atom to which they are attached, form a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the heterocycloalkyl is C 1-6 (VI) -NR 7 R 8 {where R 7 and R 8 are each independently C 1-4 Alkyl, or -CO-C 1-6 alkyl, wherein the alkyl is optionally substituted with cyano; (VII) a compound of the formula:

[0294]

[0295] (VIII) a group represented by the formula:

[0296]

[0297] {In the formula, R 9 is C 1-4 Alkyl (wherein the alkyl is C 1-4 (IX) a group represented by the formula:

[0298]

[0299] (In the formula, R 10 is C 1-4 (b) C 5-8 Bridged cycloalkyl {wherein the bridged cycloalkyl is C 1-6 (c) a 5- or 6-membered heterocycloalkyl containing one nitrogen atom, wherein the heterocycloalkyl is -CO-R 11 {where R 11(i) C 1-6 alkyl, wherein the alkyl is: (A) hydroxy, (B) cyano, or (C) C 1-4 (ii) C 1-6 Alkoxy, (iii) C 1-6 haloalkyl, (iv) C 3-6 (v) a 4- to 6-membered heterocycloalkyl containing one oxygen atom, wherein the heterocycloalkyl is optionally substituted with halogen; or (d) an 8-membered bridged heterocycloalkyl containing one nitrogen atom, wherein the bridged heterocycloalkyl is -CO-C 1-6 alkyl (wherein the alkyl is optionally substituted with (A) hydroxy, or (B) cyano);

[0300] Specific embodiments of each substituent of the compound of formula [I] are exemplified below, but each substituent of the compound of formula [I] is not limited to the specific embodiments, and the compound of formula [I] also includes embodiments in which any two or more of the specific embodiments of each substituent are combined.

[0301] Y 1 is preferably a nitrogen atom.

[0302] Y 2 is preferably a nitrogen atom.

[0303] Y 3 is preferably a carbon atom.

[0304] Y 4 is preferably a carbon atom.

[0305] R 1 Preferred embodiments of the formula (1) are hydroxy, (2) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 (3) C 1-4Alkoxy, (4) halogen, or (5) C 1-4 It is a haloalkyl.

[0306] R 1 A more preferred embodiment of the present invention is (1) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 (2) halogen, or (3) C 1-4 It is a haloalkyl.

[0307] R 1 Preferred examples of are methyl, fluorine, chlorine, difluoromethyl, or trifluoromethyl.

[0308] m R 2 A preferred embodiment of is each independently halogen.

[0309] m R 2 Preferred examples of are fluorine and chlorine.

[0310] m is preferably 0 or 1.

[0311] n R 3 A preferred embodiment of is each independently halogen.

[0312] n R 3 Preferred examples of are fluorine and chlorine.

[0313] n is preferably 0 or 1.

[0314] R ４ is preferably: (a) C 4-6 Cycloalkyl, wherein the cycloalkyl is: (I) hydroxy, (II) cyano, (III) oxo, (IV) C 1-6 Alkyl, wherein the alkyl is: (i) hydroxy, (ii) carboxy, (iii) -CONH2, (iv) -CO-C 1-4 Alkoxy, (v) -SO2-C 1-4 alkyl, or (vi) a group of the formula:

[0315]

[0316] (V) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (VI) carboxy, (VII) -CO-NR 5 R 6 [where R 5 and R 6 are each independently C 1-4 Alkyl (wherein the alkyl is C 1-4 alkoxy), or R 5 and R 6 together with the nitrogen atom to which they are attached contain 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein said heterocycloalkyl is selected from the group consisting of: (i) hydroxy, and (ii) C 1-6 alkyl (wherein the alkyl is optionally substituted with hydroxy), (VIII) -NR 7 R 8 {where R 7 and R 8 are each independently C 1-4 Alkyl, or -CO-C 1-6 alkyl (wherein the alkyl is optionally substituted with cyano)}, (IX) -OC 1-6 Haloalkyl, (X) a group of the formula:

[0317]

[0318] (XI) a group represented by the formula:

[0319]

[0320] {In the formula, R 9 is C 1-4 Alkyl (wherein the alkyl is C 1-4 (XII) a group represented by the formula:

[0321]

[0322] (In the formula, R 10 is C 1-4 (b) a group represented by the formula: 5-8 bridged cycloalkyl {wherein the bridged cycloalkyl is: (I) hydroxy, (II) C 1-6 Alkyl, wherein the alkyl is: (i) hydroxy, (ii) carboxy, (iii) -CONH2, (iv) -CO-C 1-4 Alkoxy, (v) -SO2-C 1-4 alkyl, or (vi) a group of the formula:

[0323]

[0324] (III) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (IV) carboxy, (V) -CO-C 1-4 Alkoxy, (VI)-OC 1-6 haloalkyl, or (VII) a group of formula:

[0325]

[0326] (c) a 5- or 6-membered heterocycloalkyl containing one nitrogen atom, wherein the heterocycloalkyl is (I) oxo, (II) C 1-6 Alkyl, (III) -CO-R 11 {where R 11 (i) C 1-6 alkyl, wherein the alkyl is: (A) hydroxy, (B) cyano, or (C) C 1-4 (ii) C 1-6 Alkoxy, (iii) C1-6 haloalkyl, (iv) C 3-6 (v) a 4- to 6-membered heterocycloalkyl containing one oxygen atom, wherein the heterocycloalkyl is optionally substituted with halogen; and (IV) a group of the formula:

[0327]

[0328] (d) an 8-membered bridged heterocycloalkyl containing one nitrogen atom {wherein the bridged heterocycloalkyl is -CO-R 11 (e) a 7- to 11-membered spiroheterocycloalkyl containing one nitrogen atom {wherein the spiroheterocycloalkyl is -CO-R 11 or (f) a 6- to 9-membered saturated or partially unsaturated fused ring group containing one or two nitrogen atoms, wherein the fused ring group is -CO-R 11 (which may be substituted with).

[0329] R ４ is more preferably: (a) C 4-6 Cycloalkyl, wherein the cycloalkyl is: (I) hydroxy, (II) cyano, (III) oxo, (IV) C 1-6 Alkyl, wherein the alkyl is: (i) hydroxy, (ii) carboxy, (iii) -CONH2, (iv) -CO-C 1-4 Alkoxy, (v) -SO2-C 1-4 alkyl, or (vi) a group of the formula:

[0330]

[0331] (V) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4(VI) carboxy, (VII) -CO-NR 5 R 6 [where R 5 and R 6 are each independently C 1-4 Alkyl (wherein the alkyl is C 1-4 alkoxy), or R 5 and R 6 together with the nitrogen atom to which they are attached contain 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein said heterocycloalkyl is selected from the group consisting of: (i) hydroxy, and (ii) C 1-6 alkyl (wherein the alkyl is optionally substituted with hydroxy), (VIII) -NR 7 R 8 {where R 7 and R 8 are each independently C 1-4 Alkyl, or -CO-C 1-6 alkyl (wherein the alkyl is optionally substituted with cyano)}, (IX) -OC 1-6 Haloalkyl, (X) a group of the formula:

[0332]

[0333] (XI) a group represented by the formula:

[0334]

[0335] {In the formula, R 9 is C 1-4 Alkyl (wherein the alkyl is C 1-4 (XII) a group represented by the formula:

[0336]

[0337] (In the formula, R 10 is C 1-4(b) a group represented by the formula: 5-8 bridged cycloalkyl {wherein the bridged cycloalkyl is: (I) hydroxy, (II) C 1-6 alkyl, wherein the alkyl is: (i) hydroxy; or (ii) —SO—C 1-4 (III) carboxy, or (IV) -CO-C 1-4 (c) a 5- or 6-membered heterocycloalkyl containing one nitrogen atom, wherein the heterocycloalkyl is (I) oxo, (II) C 1-6 alkyl, and (III) -CO-R 11 {where R 11 (i) C 1-6 alkyl, wherein the alkyl is: (A) hydroxy, (B) cyano, or (C) C 1-4 (ii) C 1-6 Alkoxy, (iii) C 1-6 haloalkyl, (iv) C 3-6 (v) a 4- to 6-membered heterocycloalkyl containing one oxygen atom, wherein the heterocycloalkyl is optionally substituted with a halogen atom; (d) an 8-membered bridged heterocycloalkyl containing one nitrogen atom {wherein the bridged heterocycloalkyl is selected from the group consisting of -CO-R 11a {where R 11a (i) C 1-6 (ii) alkyl (wherein the alkyl is optionally substituted with: (A) hydroxy; or (B) cyano; or 1-6(e) a 7- to 11-membered spiroheterocycloalkyl containing one nitrogen atom {wherein the spiroheterocycloalkyl is -CO-R 11a or (f) a 6- to 9-membered saturated or partially unsaturated fused ring group containing one or two nitrogen atoms, wherein the fused ring group is -CO-C 1-6 alkyl (wherein the alkyl is optionally substituted with hydroxy).

[0338] R ４ is more preferably: (a) C 4-6 Cycloalkyl, wherein the cycloalkyl is: (I) hydroxy, (II) cyano, (III) C 1-6 Alkyl, wherein the alkyl is: (i) hydroxy, (ii) carboxy, (iii) -CONH2, (iv) -CO-C 1-4 Alkoxy, (v) -SO2-C 1-4 alkyl, or (vi) a group of the formula:

[0339]

[0340] (IV) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (V) —CO—NR 5 R 6 [where R 5 and R 6 together with the nitrogen atom to which they are attached, form a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the heterocycloalkyl is C 1-6 (VI) -NR 7 R 8 {where R 7 and R 8 are each independently C1-4 Alkyl, or -CO-C 1-6 alkyl, wherein the alkyl is optionally substituted with cyano; (VII) a compound of the formula:

[0341]

[0342] (VIII) a group represented by the formula:

[0343]

[0344] {In the formula, R 9 is C 1-4 Alkyl (wherein the alkyl is C 1-4 (IX) a group represented by the formula:

[0345]

[0346] (In the formula, R 10 is C 1-4 (b) C 5-8 Bridged cycloalkyl {wherein the bridged cycloalkyl is C 1-6 (c) a 5- or 6-membered heterocycloalkyl containing one nitrogen atom, wherein the heterocycloalkyl is -CO-R 11 {where R 11 (i) C 1-6 alkyl, wherein the alkyl is: (A) hydroxy, (B) cyano, or (C) C 1-4 (ii) C 1-6 Alkoxy, (iii) C 1-6 haloalkyl, (iv) C 3-6(v) a 4- to 6-membered heterocycloalkyl containing one oxygen atom, wherein the heterocycloalkyl is optionally substituted with halogen; or (d) an 8-membered bridged heterocycloalkyl containing one nitrogen atom, wherein the bridged heterocycloalkyl is -CO-C 1-6 alkyl (wherein the alkyl is optionally substituted with (A) hydroxy, or (B) cyano)}.

[0347] The formula in formula [I]:

[0348]

[0349] The partial structure represented by X is preferably 1 is a carbon or nitrogen atom; m is 0 or 1; R 1 are (1) hydroxy, (2) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 (3) C 1-4 Alkoxy, (4) halogen, or (5) C 1-4 haloalkyl; and m R 2 are each independently a halogen.

[0350] More preferably, X 1 is a carbon or nitrogen atom; m is 0 or 1; R 1 (1) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 (2) halogen, or (3) C 1-4 haloalkyl; and m R 2 are each independently a halogen.

[0351] Specific embodiments of each substituent of the compound of formula [III] are exemplified below, but the substituents of the compound of formula [III] are not limited to these specific embodiments, and the compound of formula [III] also includes embodiments in which any two or more of the specific embodiments of each substituent are combined.

[0352] R 1 A preferred embodiment of the present invention is (1) C 1-4 Alkyl, (2) C 1-4 haloalkyl, or (3) C 3-6 It is a cycloalkyl.

[0353] R 1 A more preferred embodiment of the present invention is 1-4 Alkyl.

[0354] R 1 A preferred example of is methyl.

[0355] m R 2 Preferred embodiments of the above are, each independently, (1) cyano, (2) C 1-4 Alkyl, (3) C 1-4 (4) halogen;

[0356] m R 2 A more preferred embodiment of is that each independently represents halogen.

[0357] m R 2 Preferred examples of are fluorine and chlorine.

[0358] m is preferably 0 or 1.

[0359] n R 3 A preferred embodiment of is each independently halogen.

[0360] n R 3 Preferred examples of are fluorine and chlorine.

[0361] R ４ is preferably: (a) C 4-6 Cycloalkyl, wherein the cycloalkyl is: (I) hydroxy, (II) cyano, (III) oxo, (IV) C 1-6Alkyl, wherein the alkyl is: (i) hydroxy, (ii) carboxy, (iii) -CONH2, (iv) -CO-C 1-4 Alkoxy, (v) -SO2-C 1-4 alkyl, or (vi) a group of the formula:

[0362]

[0363] (V) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (VI) carboxy, (VII) -CO-NR 5 R 6 [where R 5 and R 6 are each independently C 1-4 Alkyl (wherein the alkyl is C 1-4 alkoxy), or R 5 and R 6 together with the nitrogen atom to which they are attached contain 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein said heterocycloalkyl is selected from the group consisting of: (i) hydroxy, and (ii) C 1-6 alkyl (wherein the alkyl is optionally substituted with hydroxy), (VIII) -NR 7 R 8 {where R 7 and R 8 are each independently C 1-4 Alkyl, or -CO-C 1-6 alkyl (wherein the alkyl is optionally substituted with cyano)}, (IX) -OC 1-6 Haloalkyl, (X) a group of the formula:

[0364]

[0365] (XI) a group represented by the formula:

[0366]

[0367] {In the formula, R 9 is C 1-4 Alkyl (wherein the alkyl is C 1-4 (XII) a group represented by the formula:

[0368]

[0369] (In the formula, R 10 is C 1-4 (b) a group represented by the formula: 5-8 bridged cycloalkyl {wherein the bridged cycloalkyl is: (I) hydroxy, (II) C 1-6 Alkyl, wherein the alkyl is: (i) hydroxy, (ii) carboxy, (iii) -CONH2, (iv) -CO-C 1-4 Alkoxy, (v) -SO2-C 1-4 alkyl, or (vi) a group of the formula:

[0370]

[0371] (III) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (IV) carboxy, (V) -CO-C 1-4 Alkoxy, (VI)-OC 1-6 haloalkyl, or (VII) a group of formula:

[0372]

[0373] (c) a 5- or 6-membered heterocycloalkyl containing one nitrogen atom, wherein the heterocycloalkyl is (I) oxo, (II) C 1-6Alkyl, (III) -CO-R 11 {where R 11 (i) C 1-6 alkyl, wherein the alkyl is: (A) hydroxy, (B) cyano, or (C) C 1-4 (ii) C 1-6 Alkoxy, (iii) C 1-6 haloalkyl, (iv) C 3-6 (v) a 4- to 6-membered heterocycloalkyl containing one oxygen atom, wherein the heterocycloalkyl is optionally substituted with halogen; and (IV) a group of the formula:

[0374]

[0375] (d) a 6- to 9-membered saturated or partially unsaturated fused ring group containing 1 or 2 nitrogen atoms (wherein the fused ring group is -CO-R 11 (e) a group of the formula:

[0376]

[0377] It is a group represented by the formula:

[0378] R ４ is more preferably: (a) C 4-6 Cycloalkyl, wherein the cycloalkyl is: (I) hydroxy, (II) cyano, (III) C 1-6 alkyl, wherein the alkyl is: (i) hydroxy, (ii) carboxy, or (iii) —SO—C 1-4 alkyl, optionally substituted with (IV) -OC 1-6 Haloalkyl, (V) a group of the formula:

[0379]

[0380] and (VI) a group represented by the formula:

[0381]

[0382] {In the formula, R 9 is C 1-4 (b) a group represented by the formula: 5-8 bridged cycloalkyl {wherein the bridged cycloalkyl is: (I) hydroxy, (II) C 1-6 alkyl, wherein the alkyl is: (i) hydroxy, (ii) carboxy, or (iii) -CO-C 1-4 (III) alkoxy, optionally substituted with (III) carboxy, optionally substituted with (III) carboxy; (c) a 5- or 6-membered heterocycloalkyl containing one nitrogen atom, wherein the heterocycloalkyl is of the formula:

[0383]

[0384] (d) a 6- to 9-membered saturated or partially unsaturated fused ring group containing 1 or 2 nitrogen atoms; or (e) a group of the formula:

[0385]

[0386] It is a group represented by the formula:

[0387] Specific embodiments of each substituent of the compound of formula [IV] are exemplified below, but each substituent of the compound of formula [IV] is not limited to the specific embodiments, and the compound of formula [IV] also includes embodiments in which any two or more of the specific embodiments of each substituent are combined.

[0388] Y 1 is preferably a nitrogen atom.

[0389] Y 2 is preferably a nitrogen atom.

[0390] Y 3 is preferably a carbon atom.

[0391] Y 4is preferably a carbon atom.

[0392] R 1 A preferred embodiment of 1-4 It is alkyl.

[0393] R 1 A preferred example of is methyl.

[0394] m is preferably 0.

[0395] n R 3 A preferred embodiment of is each independently halogen.

[0396] n R 3 A preferred example of is fluorine.

[0397] n is preferably 0 or 1.

[0398] R ４ is preferably C 4-6 Cycloalkyl, wherein the cycloalkyl is: (I) hydroxy, (II) cyano, (III) oxo, (IV) C 1-6 Alkyl, wherein the alkyl is: (i) hydroxy, (ii) carboxy, (iii) -CONH2, (iv) -CO-C 1-4 Alkoxy, (v) -SO2-C 1-4 alkyl, or (vi) a group of the formula:

[0399]

[0400] (V) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (VI) carboxy, (VII) -CO-NR 5 R 6 [where R 5 and R 6 are each independently C 1-4 Alkyl (wherein the alkyl is C 1-4 alkoxy), or R 5 and R6 together with the nitrogen atom to which they are attached contain 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein said heterocycloalkyl is selected from the group consisting of: (i) hydroxy, and (ii) C 1-6 alkyl (wherein the alkyl is optionally substituted with hydroxy), (VIII) -NR 7 R 8 {where R 7 and R 8 are each independently C 1-4 Alkyl, or -CO-C 1-6 alkyl (wherein the alkyl is optionally substituted with cyano)}, (IX) -OC 1-6 Haloalkyl, (X) a group of the formula:

[0401]

[0402] (XI) a group represented by the formula:

[0403]

[0404] {In the formula, R 9 is C 1-4 Alkyl (wherein the alkyl is C 1-4 (XII) a group represented by the formula:

[0405]

[0406] (In the formula, R 10 is C 1-4 and (a) a group represented by the formula: wherein R is an alkyl group; and ...

[0407] R ４ is more preferably C 4-6 cycloalkyl, wherein the cycloalkyl is: (I) hydroxy; or (II) C 1-6alkyl, wherein the alkyl is optionally substituted with: (i) hydroxy; or (ii) carboxy.

[0408] One preferred embodiment of the compound of formula [II] is X 1 , X 2 , X 3 and X 4 are each independently a carbon or nitrogen atom (wherein X 1 , X 2 , X 3 and X 4 the total number of nitrogen atoms is 0 or 1; Y 1 and Y 2 is a nitrogen atom; Y 3 and Y 4 is a carbon atom; m is 0 or 1; n is 0 or 1; R 1 are (1) hydroxy, (2) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 (3) C 1-4 Alkoxy, (4) halogen, or (5) C 1-4 haloalkyl; m R 2 are each independently a halogen; n R 3 are each independently a halogen; ４ (a) C 4-6 Cycloalkyl, wherein the cycloalkyl is: (I) hydroxy, (II) cyano, (III) oxo, (IV) C 1-6 Alkyl, wherein the alkyl is: (i) hydroxy, (ii) carboxy, (iii) -CONH2, (iv) -CO-C 1-4 Alkoxy, (v) -SO2-C 1-4 alkyl, or (vi) a group of the formula:

[0409]

[0410] (V) C 1-6Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (VI) carboxy, (VII) -CO-NR 5 R 6 [where R 5 and R 6 are each independently C 1-4 Alkyl (wherein the alkyl is C 1-4 alkoxy), or R 5 and R 6 together with the nitrogen atom to which they are attached contain 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein said heterocycloalkyl is selected from the group consisting of: (i) hydroxy, and (ii) C 1-6 alkyl (wherein the alkyl is optionally substituted with hydroxy), (VIII) -NR 7 R 8 {where R 7 and R 8 are each independently C 1-4 Alkyl, or -CO-C 1-6 alkyl (wherein the alkyl is optionally substituted with cyano)}, (IX) -OC 1-6 Haloalkyl, (X) a group of the formula:

[0411]

[0412] (XI) a group represented by the formula:

[0413]

[0414] {In the formula, R 9 is C 1-4 Alkyl (wherein the alkyl is C 1-4 (XII) a group represented by the formula:

[0415]

[0416] (In the formula, R10 is C 1-4 (b) a group represented by the formula: 5-8 bridged cycloalkyl {wherein the bridged cycloalkyl is: (I) hydroxy, (II) C 1-6 Alkyl, wherein the alkyl is: (i) hydroxy, (ii) carboxy, (iii) -CONH2, (iv) -CO-C 1-4 Alkoxy, (v) -SO2-C 1-4 alkyl, or (vi) a group of the formula:

[0417]

[0418] (III) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (IV) carboxy, (V) -CO-C 1-4 Alkoxy, (VI)-OC 1-6 haloalkyl, or (VII) a group of formula:

[0419]

[0420] (c) a 5- or 6-membered heterocycloalkyl containing one nitrogen atom, wherein the heterocycloalkyl is (I) oxo, (II) C 1-6 Alkyl, (III) -CO-R 11 {where R 11 (i) C 1-6 alkyl, wherein the alkyl is: (A) hydroxy, (B) cyano, or (C) C 1-4 (ii) C 1-6 Alkoxy, (iii) C 1-6 haloalkyl, (iv) C 3-6(v) a 4- to 6-membered heterocycloalkyl containing one oxygen atom, wherein the heterocycloalkyl is optionally substituted with halogen; and (IV) a group of the formula:

[0421]

[0422] (d) an 8-membered bridged heterocycloalkyl containing one nitrogen atom {wherein the bridged heterocycloalkyl is -CO-R 11 (e) a 7- to 11-membered spiroheterocycloalkyl containing one nitrogen atom {wherein the spiroheterocycloalkyl is -CO-R 11 or (f) a 6- to 9-membered saturated or partially unsaturated fused ring group containing one or two nitrogen atoms, wherein the fused ring group is -CO-R 11 and (optionally substituted with)

[0423] A more preferred embodiment of the compound of formula [II] is X 1 , X 2 , X 3 and X 4 are each independently a carbon or nitrogen atom (wherein X 1 , X 2 , X 3 and X 4 the total number of nitrogen atoms is 0 or 1; Y 1 and Y 2 is a nitrogen atom; Y 3 and Y 4 is a carbon atom; m is 0 or 1; n is 0 or 1; R 1 (1) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 (2) halogen, or (3) C 1-4 haloalkyl; m R 2are each independently a halogen; n R 3 are each independently a halogen; ４ (a) C 4-6 Cycloalkyl, wherein the cycloalkyl is: (I) hydroxy, (II) cyano, (III) oxo, (IV) C 1-6 Alkyl, wherein the alkyl is: (i) hydroxy, (ii) carboxy, (iii) -CONH2, (iv) -CO-C 1-4 Alkoxy, (v) -SO2-C 1-4 alkyl, or (vi) a group of the formula:

[0424]

[0425] (V) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (VI) carboxy, (VII) -CO-NR 5 R 6 [where R 5 and R 6 are each independently C 1-4 Alkyl (wherein the alkyl is C 1-4 alkoxy), or R 5 and R 6 together with the nitrogen atom to which they are attached contain 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein said heterocycloalkyl is selected from the group consisting of: (i) hydroxy, and (ii) C 1-6 alkyl (wherein the alkyl is optionally substituted with hydroxy), (VIII) -NR 7 R 8 {where R 7 and R 8 are each independently C 1-4 Alkyl, or -CO-C1-6 alkyl (wherein the alkyl is optionally substituted with cyano)}, (IX) -OC 1-6 Haloalkyl, (X) a group of the formula:

[0426]

[0427] (XI) a group represented by the formula:

[0428]

[0429] {In the formula, R 9 is C 1-4 Alkyl (wherein the alkyl is C 1-4 (XII) a group represented by the formula:

[0430]

[0431] (In the formula, R 10 is C 1-4 (b) a group represented by the formula: 5-8 bridged cycloalkyl {wherein the bridged cycloalkyl is: (I) hydroxy, (II) C 1-6 alkyl, wherein the alkyl is: (i) hydroxy; or (ii) —SO—C 1-4 (III) carboxy, or (IV) -CO-C 1-4 (c) a 5- or 6-membered heterocycloalkyl containing one nitrogen atom, wherein the heterocycloalkyl is (I) oxo, (II) C 1-6 alkyl, and (III) -CO-R 11 {where R 11 (i) C 1-6 alkyl, wherein the alkyl is: (A) hydroxy, (B) cyano, or (C) C 1-4 (ii) C 1-6Alkoxy, (iii) C 1-6 haloalkyl, (iv) C 3-6 (v) a 4- to 6-membered heterocycloalkyl containing one oxygen atom, wherein the heterocycloalkyl is optionally substituted with a halogen atom; (d) an 8-membered bridged heterocycloalkyl containing one nitrogen atom {wherein the bridged heterocycloalkyl is selected from the group consisting of -CO-R 11a {where R 11a (i) C 1-6 (ii) alkyl (wherein the alkyl is optionally substituted with: (A) hydroxy; or (B) cyano; or 1-6 (e) a 7- to 11-membered spiroheterocycloalkyl containing one nitrogen atom {wherein the spiroheterocycloalkyl is -CO-R 11a or (f) a 6- to 9-membered saturated or partially unsaturated fused ring group containing one or two nitrogen atoms, wherein the fused ring group is -CO-C 1-6 The compound of formula [II] is: wherein the alkyl is optionally substituted with alkyl (wherein the alkyl is optionally substituted with hydroxy).

[0432] A further preferred embodiment of the compound of formula [II] is X 1 , X 2 , X 3 and X 4 are each independently a carbon or nitrogen atom (wherein X 1 , X 2 , X 3 and X 4 the total number of nitrogen atoms is 0 or 1; Y 1 and Y 2 is a nitrogen atom; Y 3 and Y 4 is a carbon atom; m is 0 or 1; n is 0 or 1; R 1(1) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 (2) halogen, or (3) C 1-4 haloalkyl; m R 2 are each independently a halogen; n R 3 are each independently a halogen; ４ (a) C 4-6 Cycloalkyl, wherein the cycloalkyl is: (I) hydroxy, (II) cyano, (III) C 1-6 Alkyl, wherein the alkyl is: (i) hydroxy, (ii) carboxy, (iii) -CONH2, (iv) -CO-C 1-4 Alkoxy, (v) -SO2-C 1-4 alkyl, or (vi) a group of the formula:

[0433]

[0434] (IV) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (V) —CO—NR 5 R 6 [where R 5 and R 6 together with the nitrogen atom to which they are attached, form a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the heterocycloalkyl is C 1-6 (VI) -NR 7 R 8 {where R 7 and R 8 are each independently C 1-4 Alkyl, or -CO-C 1-6 alkyl, wherein the alkyl is optionally substituted with cyano; (VII) a compound of the formula:

[0435]

[0436] (VIII) a group represented by the formula:

[0437]

[0438] {In the formula, R 9 is C 1-4 Alkyl (wherein the alkyl is C 1-4 (IX) a group represented by the formula:

[0439]

[0440] (In the formula, R 10 is C 1-4 (b) C 5-8 Bridged cycloalkyl {wherein the bridged cycloalkyl is C 1-6 (c) a 5- or 6-membered heterocycloalkyl containing one nitrogen atom, wherein the heterocycloalkyl is -CO-R 11 {where R 11 (i) C 1-6 alkyl, wherein the alkyl is: (A) hydroxy, (B) cyano, or (C) C 1-4 (ii) C 1-6 Alkoxy, (iii) C 1-6 haloalkyl, (iv) C 3-6 (v) a 4- to 6-membered heterocycloalkyl containing one oxygen atom, wherein the heterocycloalkyl is optionally substituted with halogen; or (d) an 8-membered bridged heterocycloalkyl containing one nitrogen atom, wherein the bridged heterocycloalkyl is -CO-C 1-6and (B) cyano, or (C) hydroxy.

[0441] One preferred embodiment of the compound of formula [I] is X 1 is a carbon or nitrogen atom; Y 1 and Y 2 is a nitrogen atom; Y 3 and Y 4 is a carbon atom; m is 0 or 1; n is 0 or 1; R 1 are (1) hydroxy, (2) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 (3) C 1-4 Alkoxy, (4) halogen, or (5) C 1-4 haloalkyl; m R 2 are each independently a halogen; n R 3 are each independently a halogen; ４ (a) C 4-6 Cycloalkyl, wherein the cycloalkyl is: (I) hydroxy, (II) cyano, (III) oxo, (IV) C 1-6 Alkyl, wherein the alkyl is: (i) hydroxy, (ii) carboxy, (iii) -CONH2, (iv) -CO-C 1-4 Alkoxy, (v) -SO2-C 1-4 alkyl, or (vi) a group of the formula:

[0442]

[0443] (V) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (VI) carboxy, (VII) -CO-NR 5 R 6 [where R5 and R 6 are each independently C 1-4 Alkyl (wherein the alkyl is C 1-4 alkoxy), or R 5 and R 6 together with the nitrogen atom to which they are attached contain 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein said heterocycloalkyl is selected from the group consisting of: (i) hydroxy, and (ii) C 1-6 alkyl (wherein the alkyl is optionally substituted with hydroxy), (VIII) -NR 7 R 8 {where R 7 and R 8 are each independently C 1-4 Alkyl, or -CO-C 1-6 alkyl (wherein the alkyl is optionally substituted with cyano)}, (IX) -OC 1-6 Haloalkyl, (X) a group of the formula:

[0444]

[0445] (XI) a group represented by the formula:

[0446]

[0447] {In the formula, R 9 is C 1-4 Alkyl (wherein the alkyl is C 1-4 (XII) a group represented by the formula:

[0448]

[0449] (In the formula, R 10 is C 1-4 (b) a group represented by the formula: 5-8bridged cycloalkyl {wherein the bridged cycloalkyl is: (I) hydroxy, (II) C 1-6 Alkyl, wherein the alkyl is: (i) hydroxy, (ii) carboxy, (iii) -CONH2, (iv) -CO-C 1-4 Alkoxy, (v) -SO2-C 1-4 alkyl, or (vi) a group of the formula:

[0450]

[0451] (III) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (IV) carboxy, (V) -CO-C 1-4 Alkoxy, (VI)-OC 1-6 haloalkyl, or (VII) a group of formula:

[0452]

[0453] (c) a 5- or 6-membered heterocycloalkyl containing one nitrogen atom, wherein the heterocycloalkyl is (I) oxo, (II) C 1-6 Alkyl, (III) -CO-R 11 {where R 11 (i) C 1-6 alkyl, wherein the alkyl is: (A) hydroxy, (B) cyano, or (C) C 1-4 (ii) C 1-6 Alkoxy, (iii) C 1-6 haloalkyl, (iv) C 3-6(v) a 4- to 6-membered heterocycloalkyl containing one oxygen atom, wherein the heterocycloalkyl is optionally substituted with halogen; and (IV) a group of the formula:

[0454]

[0455] (d) an 8-membered bridged heterocycloalkyl containing one nitrogen atom {wherein the bridged heterocycloalkyl is -CO-R 11 (e) a 7- to 11-membered spiroheterocycloalkyl containing one nitrogen atom {wherein the spiroheterocycloalkyl is -CO-R 11 or (f) a 6- to 9-membered saturated or partially unsaturated fused ring group containing one or two nitrogen atoms, wherein the fused ring group is -CO-R 11 and (optionally substituted with)

[0456] A more preferred embodiment of the compound of formula [I] is 1 is a carbon or nitrogen atom; Y 1 and Y 2 is a nitrogen atom; Y 3 and Y 4 is a carbon atom; m is 0 or 1; n is 0 or 1; R 1 (1) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 (2) halogen, or (3) C 1-4 haloalkyl; m R 2 are each independently a halogen; n R 3 are each independently a halogen; ４ (a) C 4-6 Cycloalkyl, wherein the cycloalkyl is: (I) hydroxy, (II) cyano, (III) oxo, (IV) C1-6 Alkyl, wherein the alkyl is: (i) hydroxy, (ii) carboxy, (iii) -CONH2, (iv) -CO-C 1-4 Alkoxy, (v) -SO2-C 1-4 alkyl, or (vi) a group of the formula:

[0457]

[0458] (V) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (VI) carboxy, (VII) -CO-NR 5 R 6 [where R 5 and R 6 are each independently C 1-4 Alkyl (wherein the alkyl is C 1-4 alkoxy), or R 5 and R 6 together with the nitrogen atom to which they are attached contain 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein said heterocycloalkyl is selected from the group consisting of: (i) hydroxy, and (ii) C 1-6 alkyl (wherein the alkyl is optionally substituted with hydroxy), (VIII) -NR 7 R 8 {where R 7 and R 8 are each independently C 1-4 Alkyl, or -CO-C 1-6 alkyl (wherein the alkyl is optionally substituted with cyano)}, (IX) -OC 1-6 Haloalkyl, (X) a group of the formula:

[0459]

[0460] (XI) a group represented by the formula:

[0461]

[0462] {In the formula, R 9 is C 1-4 Alkyl (wherein the alkyl is C 1-4 (XII) a group represented by the formula:

[0463]

[0464] (In the formula, R 10 is C 1-4 (b) a group represented by the formula: 5-8 bridged cycloalkyl {wherein the bridged cycloalkyl is: (I) hydroxy, (II) C 1-6 alkyl, wherein the alkyl is: (i) hydroxy; or (ii) —SO—C 1-4 (III) carboxy, or (IV) -CO-C 1-4 (c) a 5- or 6-membered heterocycloalkyl containing one nitrogen atom, wherein the heterocycloalkyl is (I) oxo, (II) C 1-6 alkyl, and (III) -CO-R 11 {where R 11 (i) C 1-6 alkyl, wherein the alkyl is: (A) hydroxy, (B) cyano, or (C) C 1-4 (ii) C 1-6 Alkoxy, (iii) C 1-6 haloalkyl, (iv) C 3-6(v) a 4- to 6-membered heterocycloalkyl containing one oxygen atom, wherein the heterocycloalkyl is optionally substituted with a halogen atom; (d) an 8-membered bridged heterocycloalkyl containing one nitrogen atom {wherein the bridged heterocycloalkyl is selected from the group consisting of -CO-R 11a {where R 11a (i) C 1-6 (ii) alkyl (wherein the alkyl is optionally substituted with: (A) hydroxy; or (B) cyano; or 1-6 (e) a 7- to 11-membered spiroheterocycloalkyl containing one nitrogen atom {wherein the spiroheterocycloalkyl is -CO-R 11a or (f) a 6- to 9-membered saturated or partially unsaturated fused ring group containing one or two nitrogen atoms, wherein the fused ring group is -CO-C 1-6 The compound of formula [I] is: wherein the alkyl is optionally substituted with alkyl (wherein the alkyl is optionally substituted with hydroxy).

[0465] A further preferred embodiment of the compound of formula [I] is 1 is a carbon or nitrogen atom; Y 1 and Y 2 is a nitrogen atom; Y 3 and Y 4 is a carbon atom; m is 0 or 1; n is 0 or 1; R 1 (1) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 (2) halogen, or (3) C 1-4 haloalkyl; m R 2 are each independently a halogen; n R 3 are each independently a halogen; ４(a) C 4-6 Cycloalkyl, wherein the cycloalkyl is: (I) hydroxy, (II) cyano, (III) C 1-6 Alkyl, wherein the alkyl is: (i) hydroxy, (ii) carboxy, (iii) -CONH2, (iv) -CO-C 1-4 Alkoxy, (v) -SO2-C 1-4 alkyl, or (vi) a group of the formula:

[0466]

[0467] (IV) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (V) —CO—NR 5 R 6 [where R 5 and R 6 together with the nitrogen atom to which they are attached, form a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the heterocycloalkyl is C 1-6 (VI) -NR 7 R 8 {where R 7 and R 8 are each independently C 1-4 Alkyl, or -CO-C 1-6 alkyl, wherein the alkyl is optionally substituted with cyano; (VII) a compound of the formula:

[0468]

[0469] (VIII) a group represented by the formula:

[0470]

[0471] {In the formula, R 9 is C 1-4Alkyl (wherein the alkyl is C 1-4 (IX) a group represented by the formula:

[0472]

[0473] (In the formula, R 10 is C 1-4 (b) C 5-8 Bridged cycloalkyl {wherein the bridged cycloalkyl is C 1-6 (c) a 5- or 6-membered heterocycloalkyl containing one nitrogen atom, wherein the heterocycloalkyl is -CO-R 11 {where R 11 (i) C 1-6 alkyl, wherein the alkyl is: (A) hydroxy, (B) cyano, or (C) C 1-4 (ii) C 1-6 Alkoxy, (iii) C 1-6 haloalkyl, (iv) C 3-6 (v) a 4- to 6-membered heterocycloalkyl containing one oxygen atom, wherein the heterocycloalkyl is optionally substituted with halogen; or (d) an 8-membered bridged heterocycloalkyl containing one nitrogen atom, wherein the bridged heterocycloalkyl is -CO-C 1-6 and (B) cyano, or (C) hydroxy.

[0474] One preferred embodiment of the compound of formula [IC] is the compound of formula [ICa]:

[0475]

[0476] (In the formula, X1 , R 1 , R 2 , R 12 and m is as defined above).

[0477] One of the more preferred embodiments of the compound of formula [IC] is the compound of formula [ICa], wherein X 1 , R 1 , R 2 and m are as defined above: R 12 are (1) hydroxy, (2) cyano, and (3) C 1-6 Alkyl, wherein the alkyl is: (a) hydroxy; (b) carboxy; (c) -CONH2; (d) -CO-C 1-4 Alkoxy, (e) -SO2-C 1-4 alkyl, or (f) a group of the formula:

[0478]

[0479] (4) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (5) —CO—NR 5 R 6 [where R 5 and R 6 together with the nitrogen atom to which they are attached, form a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the heterocycloalkyl is C 1-6 (6) -NR 7 R 8 {where R 7 and R 8 are each independently C 1-4 Alkyl, or -CO-C 1-6 alkyl, wherein the alkyl is optionally substituted with cyano; (7) a compound of the formula:

[0480]

[0481] (8) a group represented by the formula:

[0482]

[0483] {In the formula, R 9 is C 1-4 Alkyl (wherein the alkyl is C 1-4 (9) a group represented by the formula:

[0484]

[0485] (In the formula, R 10 is C 1-4 The compound is a group represented by the formula:

[0486] One preferred embodiment of the compound of formula [III] is 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 and Y 4 are each independently a carbon or nitrogen atom (wherein X 1 , X 2 , X 3 and X 4 The total number of nitrogen atoms in Y is 0 or 1, 1 , Y 2 , Y 3 and Y 4 the total number of nitrogen atoms is 0, 1 or 2; m is 0 or 1; n is 0, 1 or 2; R 1 (1) C 1-4 Alkyl, (2) C 1-4 haloalkyl, or (3) C 3-6 cycloalkyl; m R 2 are each independently: (1) cyano, (2) C 1-4 Alkyl, (3) C 1-4 (4) halogen; n R 3 are each independently a halogen; ４ (a) C 4-6Cycloalkyl, wherein the cycloalkyl is: (I) hydroxy, (II) cyano, (III) oxo, (IV) C 1-6 Alkyl, wherein the alkyl is: (i) hydroxy, (ii) carboxy, (iii) -CONH2, (iv) -CO-C 1-4 Alkoxy, (v) -SO2-C 1-4 alkyl, or (vi) a group of the formula:

[0487]

[0488] (V) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (VI) carboxy, (VII) -CO-NR 5 R 6 [where R 5 and R 6 are each independently C 1-4 Alkyl (wherein the alkyl is C 1-4 alkoxy), or R 5 and R 6 together with the nitrogen atom to which they are attached contain 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein said heterocycloalkyl is selected from the group consisting of: (i) hydroxy, and (ii) C 1-6 alkyl (wherein the alkyl is optionally substituted with hydroxy), (VIII) -NR 7 R 8 {where R 7 and R 8 are each independently C 1-4 Alkyl, or -CO-C 1-6 alkyl (wherein the alkyl is optionally substituted with cyano)}, (IX) -OC 1-6 Haloalkyl, (X) a group of the formula:

[0489]

[0490] (XI) a group represented by the formula:

[0491]

[0492] {In the formula, R 9 is C 1-4 Alkyl (wherein the alkyl is C 1-4 (XII) a group represented by the formula:

[0493]

[0494] (In the formula, R 10 is C 1-4 (b) a group represented by the formula: 5-8 bridged cycloalkyl {wherein the bridged cycloalkyl is: (I) hydroxy, (II) C 1-6 Alkyl, wherein the alkyl is: (i) hydroxy, (ii) carboxy, (iii) -CONH2, (iv) -CO-C 1-4 Alkoxy, (v) -SO2-C 1-4 alkyl, or (vi) a group of the formula:

[0495]

[0496] (III) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (IV) carboxy, (V) -CO-C 1-4 Alkoxy, (VI)-OC 1-6 haloalkyl, or (VII) a group of formula:

[0497]

[0498] (c) a 5- or 6-membered heterocycloalkyl containing one nitrogen atom, wherein the heterocycloalkyl is (I) oxo, (II) C 1-6 Alkyl, (III) -CO-R 11 {where R 11 (i) C 1-6 alkyl, wherein the alkyl is: (A) hydroxy, (B) cyano, or (C) C 1-4 (ii) C 1-6 Alkoxy, (iii) C 1-6 haloalkyl, (iv) C 3-6 (v) a 4- to 6-membered heterocycloalkyl containing one oxygen atom, wherein the heterocycloalkyl is optionally substituted with halogen; and (IV) a group of the formula:

[0499]

[0500] (d) a 6- to 9-membered saturated or partially unsaturated fused ring group containing 1 or 2 nitrogen atoms (wherein the fused ring group is -CO-R 11 (e) a group of the formula:

[0501]

[0502] The compound is a compound of formula [III], which is a group represented by the formula:

[0503] A more preferred embodiment of the compound of formula [III] is 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 and Y 4 are each independently a carbon or nitrogen atom (wherein X 1 , X 2 , X3 and X 4 The total number of nitrogen atoms in Y is 0 or 1, 1 , Y 2 , Y 3 and Y 4 the total number of nitrogen atoms is 0, 1 or 2; m is 0 or 1; n is 0, 1 or 2; R 1 is C 1-4 alkyl; m R 2 are each independently a halogen; n R 3 are each independently a halogen; ４ (a) C 4-6 Cycloalkyl, wherein the cycloalkyl is: (I) hydroxy, (II) cyano, (III) C 1-6 alkyl, wherein the alkyl is: (i) hydroxy, (ii) carboxy, or (iii) —SO—C 1-4 alkyl, optionally substituted with (IV) -OC 1-6 Haloalkyl, (V) a group of the formula:

[0504]

[0505] and (VI) a group represented by the formula:

[0506]

[0507] {In the formula, R 9 is C 1-4 (b) a group represented by the formula: 5-8 bridged cycloalkyl {wherein the bridged cycloalkyl is: (I) hydroxy, (II) C 1-6 alkyl, wherein the alkyl is: (i) hydroxy, (ii) carboxy, or (iii) -CO-C 1-4(III) alkoxy, optionally substituted with (III) carboxy, optionally substituted with (III) carboxy; (c) a 5- or 6-membered heterocycloalkyl containing one nitrogen atom, wherein the heterocycloalkyl is of the formula:

[0508]

[0509] (d) a 6- to 9-membered saturated or partially unsaturated fused ring group containing 1 or 2 nitrogen atoms; or (e) a group of the formula:

[0510]

[0511] The compound is a compound of formula [III], which is a group represented by the formula:

[0512] One preferred embodiment of the compound of formula [IV] is X 1 , X 5 and X 6 are each independently a carbon or nitrogen atom (wherein X 5 and X 6 The total number of nitrogen atoms in 1 and Y 2 is a nitrogen atom; Y 3 and Y 4 is a carbon atom; m is 0; n is 0 or 1; R 1 is C 1-4 alkyl; n R 3 are each independently a halogen; ４ is C 4-6 Cycloalkyl, wherein the cycloalkyl is: (I) hydroxy, (II) cyano, (III) oxo, (IV) C 1-6 Alkyl, wherein the alkyl is: (i) hydroxy, (ii) carboxy, (iii) -CONH2, (iv) -CO-C 1-4 Alkoxy, (v) -SO2-C 1-4 alkyl, or (vi) a group of the formula:

[0513]

[0514] (V) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO2-C 1-4 (VI) carboxy, (VII) -CO-NR 5 R 6 [where R 5 and R 6 are each independently C 1-4 Alkyl (wherein the alkyl is C 1-4 alkoxy), or R 5 and R 6 together with the nitrogen atom to which they are attached contain 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein said heterocycloalkyl is selected from the group consisting of: (i) hydroxy, and (ii) C 1-6 alkyl (wherein the alkyl is optionally substituted with hydroxy), (VIII) -NR 7 R 8 {where R 7 and R 8 are each independently C 1-4 Alkyl, or -CO-C 1-6 alkyl (wherein the alkyl is optionally substituted with cyano)}, (IX) -OC 1-6 Haloalkyl, (X) a group of the formula:

[0515]

[0516] (XI) a group represented by the formula:

[0517]

[0518] {In the formula, R 9 is C 1-4 Alkyl (wherein the alkyl is C 1-4 (XII) a group represented by the formula:

[0519]

[0520] (In the formula, R 10 is C 1-4 and (III) is an alkyl group, and (IV) is a group represented by the formula (IV)

[0521] A more preferred embodiment of the compound of formula [IV] is X 1 , X 5 and X 6 are each independently a carbon or nitrogen atom (wherein X 5 and X 6 The total number of nitrogen atoms in 1 and Y 2 is a nitrogen atom; Y 3 and Y 4 is a carbon atom; m is 0; n is 0 or 1; R 1 is C 1-4 alkyl; n R 3 are each independently a halogen; ４ is C 4-6 cycloalkyl, wherein the cycloalkyl is: (I) hydroxy; or (II) C 1-6 and (ii) a carboxy group, optionally substituted with (i) hydroxy, or (ii) carboxy.

[0522] A "pharmaceutically acceptable salt" may be any salt known in the art that is not excessively toxic. Specific examples include salts with inorganic acids, organic acids, inorganic bases, and organic bases. Various forms of pharmaceutically acceptable salts are well known in the art and are described, for example, in the following references: (a) Berge et al., J. Pharm. Sci., 66, pp. 1-19 (1977); (b) Stahl et al., "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002); (c) Paulekuhn et al., J. Med. Chem., 50, pp. 6665-6672 (2007). Pharmaceutically acceptable salts can be obtained by reacting the compound of the present invention with an inorganic acid, organic acid, inorganic base, or organic base according to known methods.

[0523] Examples of salts with inorganic acids include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, and sulfuric acid. Examples of salts with organic acids include salts with acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylenecitric acid, benzoic acid, benzenesulfonic acid, calcium edetate, camphoric acid, camphor-10-sulfonic acid, carbonic acid, citric acid, edetic acid, ethane-1,2-disulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glycolylarsanilic acid, hexylresorcylic acid, hydroxynaphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, lactobionic acid, malic acid, Examples include salts with maleic acid, mandelic acid, methanesulfonic acid, methylsulfuric acid, methyl nitrate, methylenebis(salicylic acid), galactaric acid, naphthalene-2-sulfonic acid, 2-naphthoic acid, 1,5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic acid, pantothenic acid, pectinic acid, picric acid, propionic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, teoclic acid, thiocyanic acid, trifluoroacetic acid, p-toluenesulfonic acid, undecanoic acid, aspartic acid, or glutamic acid.

[0524] Examples of salts with inorganic bases include salts with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth, or ammonium.

[0525] Examples of salts with organic bases include salts with arecoline, betaine, choline, clemizole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine, or lysine.

[0526] Preferred embodiments of "pharmaceutically acceptable salts" are as follows. Examples of salts with inorganic acids include salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, or hydrobromic acid. Examples of salts with organic acids include salts with oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoic acid, glucuronic acid, oleic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or 2-hydroxy-1-ethanesulfonic acid. Examples of salts with inorganic bases include salts with sodium, potassium, calcium, magnesium, or zinc. Examples of salts with organic bases include salts with tris(hydroxymethyl)methylamine, N-methylglucamine, or lysine.

[0527] The compound of the present invention or a pharmaceutically acceptable salt thereof may exist as a solvate. A "solvate" is a compound in which solvent molecules are coordinated to the compound of the present invention or a pharmaceutically acceptable salt thereof, and includes hydrates. The solvate is preferably a pharmaceutically acceptable solvate, and examples thereof include a hydrate, ethanol solvate, and dimethyl sulfoxide solvate of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0528] Specific examples include the hemihydrate, monohydrate, dihydrate, or monoethanolate of the compound of the present invention, or the monohydrate or 2 / 3 ethanolate of the sodium salt or dihydrochloride of the compound of the present invention. These solvates can be obtained according to known methods.

[0529] The compounds of the present invention may exist as tautomers. In that case, the compounds of the present invention may exist as individual tautomers or mixtures of tautomers. For example, the compounds of the following formula:

[0530]

[0531] Unless otherwise noted, the structure shown in (1)

[0532]

[0533] (2)

[0534]

[0535] or (3) a mixture thereof.

[0536] The compound of the present invention may contain a carbon-carbon double bond, and in that case, the compound may exist as an E-isomer, a Z-isomer, or a mixture of E- and Z-isomers.

[0537] The compounds of the present invention may have stereoisomers known as cis / trans isomers, in which case the compounds may exist as cis, trans or mixtures of cis and trans isomers.

[0538] The compounds of the present invention may contain one or more asymmetric carbon atoms, in which case they may exist as a single enantiomer, a single diastereomer, a mixture of enantiomers, or a mixture of diastereomers.

[0539] The compounds of the present invention may exist as atropisomers, and in that case, the compounds of the present invention may exist as individual atropisomers or mixtures of atropisomers.

[0540] The compounds of the present invention may simultaneously contain structural features that give rise to the above isomers, and may contain the above isomers in any ratio.

[0541] In this specification, formulae, chemical structures or compound names expressed without specifying stereochemistry include all of the above-mentioned possible isomers unless otherwise noted.

[0542] Diastereomeric mixtures can be separated into individual diastereomers by conventional methods such as chromatography or crystallization, or individual diastereomers can be prepared by synthetic methods using stereochemically pure starting materials or stereoselective reactions.

[0543] Separation of individual enantiomers from a mixture of enantiomers can be accomplished by methods well known in the art. For example, enriched or substantially pure single diastereomers can be separated from a diastereomeric mixture formed by reacting a mixture of enantiomers with a substantially pure enantiomer, known as a chiral auxiliary, by standard methods such as fractional crystallization or chromatography. The separated diastereomer can be converted to the desired enantiomer by removing the added chiral auxiliary via a cleavage reaction. Alternatively, a mixture of enantiomers can be directly separated by chromatographic methods using chiral stationary phases, which are well known in the art. Alternatively, one enantiomer can be obtained by using substantially pure optically active starting materials or by stereoselective synthesis (asymmetric induction) of prochiral intermediates using a chiral auxiliary or asymmetric catalyst.

[0544] Absolute configuration may be determined by X-ray crystallography of crystalline products or intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known configuration.

[0545] The compound of the present invention isotopic ２ H(D), ３ H. １４ C. １８ F. ３５ For example, when the compound of formula [I] has a methyl group, the methyl group may be labeled with -CD ３ The compounds thus obtained are also included in the present invention.

[0546] The compound of the present invention or a pharmaceutically acceptable salt thereof is preferably a substantially purified compound of the present invention or a pharmaceutically acceptable salt thereof, more preferably a compound of the present invention or a pharmaceutically acceptable salt thereof purified to a chemical purity of 80% or more.

[0547] The pharmaceutical composition of the present invention may be produced by appropriately mixing the compound of the present invention or a pharmaceutically acceptable salt thereof with at least one or more pharmaceutically acceptable carriers, etc. in appropriate amounts, according to a method known in the technical field of pharmaceutical formulation. The content of the compound of the present invention or a pharmaceutically acceptable salt thereof in the pharmaceutical composition varies depending on the dosage form, dosage, etc., but is, for example, 0.1 to 100% by weight of the total composition.

[0548] Dosage forms of the pharmaceutical composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof (hereinafter also referred to as "pharmaceutical composition of the present invention" in this specification) include oral preparations such as tablets, capsules, granules, powders, troches, syrups, emulsions, and suspensions, and parenteral preparations such as topical preparations, suppositories, injections, eye drops, nasal preparations, and pulmonary preparations.

[0549] Examples of "pharmaceutically acceptable carriers" include various organic or inorganic carrier substances commonly used as formulation materials, such as excipients, disintegrants, binders, fluidizing agents, lubricants, etc. in solid preparations, solvents, solubilizing agents, suspending agents, isotonicity agents, buffers, soothing agents, etc. in liquid preparations, and bases, emulsifiers, wetting agents, stabilizers, dispersants, plasticizers, pH adjusters, absorption enhancers, gelling agents, preservatives, fillers, solubilizers, solubilizing agents, suspending agents, etc. in semi-solid preparations. Furthermore, additives such as preservatives, antioxidants, colorants, sweeteners, etc. may be used, if necessary.

[0550] Examples of "excipients" include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, and gum arabic. Examples of "disintegrants" include carmellose, carmellose calcium, carmellose sodium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, and crystalline cellulose. Examples of "binders" include hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, and gum arabic. Examples of "flow agents" include light anhydrous silicic acid and magnesium stearate. Examples of "lubricants" include magnesium stearate, calcium stearate, and talc. Examples of "solvents" include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, etc. Examples of "solubilizing agents" include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, etc. Examples of "suspending agents" include benzalkonium chloride, carmellose, hydroxypropyl cellulose, propylene glycol, povidone, methylcellulose, glycerin monostearate, etc. Examples of "isotonic agents" include glucose, D-sorbitol, sodium chloride, D-mannitol, etc. Examples of "buffering agents" include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate, etc. Examples of "soothing agents" include benzyl alcohol, etc.Examples of the "base" include water, animal and vegetable oils (olive oil, corn oil, peanut oil, sesame oil, castor oil, etc.), lower alcohols (ethanol, propanol, propylene glycol, 1,3-butylene glycol, phenol, etc.), higher fatty acids and their esters, waxes, higher alcohols, polyhydric alcohols, hydrocarbons (white petrolatum, liquid paraffin, paraffin, etc.), hydrophilic petrolatum, purified lanolin, absorbent ointment, hydrated lanolin, hydrophilic ointment, starch, pullulan, gum arabic, tragacanth gum, gelatin, dextran, cellulose derivatives (methyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc.), synthetic polymers (carboxyvinyl polymer, sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, etc.), propylene glycol, macrogol (macrogol 200-600, etc.), and combinations of two or more thereof. Examples of "preservatives" include ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid, etc. Examples of "antioxidants" include sodium sulfite, ascorbic acid, etc. Examples of "coloring agents" include food dyes (Food Red No. 2 or No. 3, Food Yellow No. 4 or No. 5, etc.), β-carotene, etc. Examples of "sweeteners" include saccharin sodium, dipotassium glycyrrhizinate, aspartame, etc.

[0551] The pharmaceutical compositions of the present invention can be administered orally or parenterally (topical, rectal, intravenous, intramuscular, subcutaneous, etc.) to humans and non-human mammals (e.g., mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cows, horses, sheep, monkeys, etc.). The dosage of the compound of the present invention or a pharmaceutically acceptable salt thereof (hereinafter also referred to as the "pharmaceutically effective amount" in this specification) can be varied appropriately depending on the subject, route of administration, target disease, symptoms, severity of disease, and combinations thereof. For example, the dosage for oral administration to an adult patient is typically in the range of about 0.01 mg to 1 g per day of the compound of the present invention as the active ingredient. These amounts can be administered in one or several divided doses.

[0552] The compound of the present invention or a pharmaceutically acceptable salt thereof has an H-PGDS inhibitory effect and is therefore useful for the treatment and / or prevention of various diseases or conditions that can be expected to be improved by regulating H-PGDS activity, such as peripheral arterial disease (e.g., intermittent claudication and global severe chronic lower limb ischemia), cardiovascular disease, allergic asthma, chronic obstructive pulmonary disease, allergic rhinitis, sarcopenia, and Duchenne muscular dystrophy.

[0553] "Inhibiting H-PGDS" means inhibiting the function of H-PGDS and eliminating or attenuating its activity, and for example, means inhibiting the function of H-PGDS based on Test Example 1 described below. "Inhibiting H-PGDS" preferably means "inhibiting human H-PGDS."

[0554] The term "H-PGDS inhibitor" refers to a substance that inhibits the function of H-PGDS. For example, H-PGDS inhibitors are expected to be useful in the treatment and / or prevention of diseases selected from the group consisting of peripheral arterial disease (e.g., intermittent claudication and global severe chronic lower limb ischemia), cardiovascular disease, allergic asthma, chronic obstructive pulmonary disease, allergic rhinitis, sarcopenia, and Duchenne muscular dystrophy.

[0555] As used herein, "treatment" includes alleviating symptoms, preventing aggravation, maintaining remission, preventing relapse, and even preventing recurrence. As used herein, "prevention" means suppressing the onset of symptoms.

[0556] Unless one embodiment disclosed in one place in this specification contradicts an embodiment disclosed in another place, any combination of two or more of these is also intended to be encompassed by the present invention.

[0557] A preferred specific embodiment of the active ingredient in the H-PGDS inhibitor or pharmaceutical composition of the present invention is the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0558] [General Process for Producing the Compound of the Present Invention or a Pharmaceutically Acceptable Salt Thereof] General processes for producing a compound of formula [I] or a pharmaceutically acceptable salt thereof, a compound of formula [II] or a pharmaceutically acceptable salt thereof, a compound of formula [III] or a pharmaceutically acceptable salt thereof, or a compound of formula [IV] or a pharmaceutically acceptable salt thereof are exemplified below. However, the processes for producing a compound of formula [I] or a pharmaceutically acceptable salt thereof, a compound of formula [II] or a pharmaceutically acceptable salt thereof, a compound of formula [III] or a pharmaceutically acceptable salt thereof, or a compound of formula [IV] or a pharmaceutically acceptable salt thereof are not limited to these processes.

[0559] The compounds obtained in each step can be isolated and / or purified by known methods such as distillation, recrystallization, column chromatography, etc., as necessary, but in some cases, they can be used to proceed to the next step without isolation and / or purification.

[0560] In this specification, room temperature refers to a temperature in an uncontrolled state, and one embodiment is a temperature of 1°C to 40°C.

[0561] Production Method A1: Production Method of Compound [II] or a Salt Thereof Compound [II] or a salt thereof can be produced, for example, by the following Production Method A1.

[0562]

[0563] [In the formula, X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 and Y 4 are each independently a carbon or nitrogen atom (wherein X 1 , X 2 , X 3 and X 4 The total number of nitrogen atoms in Y is 0 or 1, 1 , Y 2 , Y 3 and Y 4 the total number of nitrogen atoms in R is 0, 1 or 2; A11is a protecting group for carboxy (e.g., methyl, ethyl, and tert-butyl), and L A11 is a leaving group {e.g., halogens, boronic acids, and boronic esters (e.g., pinacol boronic acid esters)}; R 1 , R 2 , R 3 , R 4 , m and n are as defined above.

[0564] (Step A1-1) Compound [A1-3] or a salt thereof can be obtained 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 base, optionally with the addition of a metal catalyst.

[0565] Examples of the solvent include tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, and mixtures thereof. A preferred solvent is N,N-dimethylformamide.

[0566] Examples of the base include potassium tert-butoxide, potassium carbonate, cesium carbonate, and pyridine. A preferred base is potassium carbonate.

[0567] Metal catalysts include, for example, copper(I) iodide and copper(II) acetate.

[0568] The reaction temperature is, for example, 20°C to 120°C, preferably 20°C to 90°C.

[0569] Compound [A1-1] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method.

[0570] The compound [A1-2] or a salt thereof is commercially available, or may be prepared from a commercially available product by a known method.

[0571] (Step A1-2) Compound [A1-4] or a salt thereof can be prepared by reacting R A11 The deprotection reaction can be carried out by removing R A11 The conditions should be appropriate depending on the type of R.A11 When is ethyl, the compound [A1-4] or a salt thereof can be produced by hydrolyzing the compound [A1-3] or a salt thereof in a solvent in the presence of a base.

[0572] Examples of bases include lithium hydroxide monohydrate, sodium hydroxide, and potassium hydroxide.

[0573] Examples of the solvent include methanol, tetrahydrofuran, water, and a mixture thereof. A preferred solvent is a mixture of tetrahydrofuran and water.

[0574] The reaction temperature is, for example, 20°C to 80°C, preferably 20°C to 30°C.

[0575] (Step A1-3) Compound [II] or a salt thereof can be produced by reacting compound [A1-4] or a salt thereof with compound [A1-5] or a salt thereof in a solvent in the presence of a condensing agent and a base.

[0576] Condensation agents include, for example, dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC·HCl), diisopropylcarbodiimide, 1,1'-carbonyldiimidazole (CDI), 1-hydroxy-7-azabenzotriazole, O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), (benzotriazole-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylaminomorpholinocarbenium hexafluorophosphate (COMU), and diphenylphosphoryl azide. A preferred condensation agent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC·HCl).

[0577] Examples of the base include triethylamine and N,N-diisopropylethylamine. A preferred base is triethylamine.

[0578] Examples of the solvent include tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, and mixtures thereof. A preferred solvent is N,N-dimethylformamide.

[0579] The reaction temperature is, for example, 20°C to 30°C.

[0580] Compound [A1-5] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method, for example, by the preparation methods B1 to B4 described below.

[0581] Instead of compound [A1-5] or a salt thereof, this production method may be carried out using a compound having a functional group or a protected functional group that can be converted into compound [A1-5] or a salt thereof by a known reaction, or a salt thereof, to obtain a compound corresponding to compound [II] or a salt thereof, and then converting the functional group to produce compound [II] or a salt thereof.

[0582] Production method A1a: Production method for compound [I] or a salt thereof

[0583]

[0584] (wherein each symbol has the same meaning as defined above)

[0585] Compound [I] or a salt thereof can be prepared by carrying out Preparation Method A1 using compound [A1a-1] or a salt thereof instead of compound [A1-1] or a salt thereof.

[0586]

[0587] (wherein each symbol has the same meaning as defined above)

[0588] The compound [A1a-1] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method.

[0589] Preparation Method A2: Alternative method for preparing compound [II] or a salt thereof Compound [II] or a salt thereof can also be prepared, for example, by the following preparation method A2.

[0590]

[0591] [In the formula, X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 and Y 4 are each independently a carbon or nitrogen atom (wherein X 1 , X 2 , X 3 and X 4 The total number of nitrogen atoms in Y is 0 or 1, 1 , Y 2 , Y 3 and Y 4 the total number of nitrogen atoms in L is 0, 1 or 2; A11 , R 1 , R 2 , R 3 , R 4 , m and n are as defined above.

[0592] (Step A2-1) The compound [A2-2] or a salt thereof can be prepared by reacting the compound [A2-1] or a salt thereof with the compound [A1-5] or a salt thereof according to Step A1-3.

[0593] The compound [A2-1] or a salt thereof is commercially available, or may be prepared from a commercially available product by a known method.

[0594] (Step A2-2) Compound [II] or a salt thereof can be prepared by reacting compound [A2-2] or a salt thereof with compound [A1-1] or a salt thereof according to step A1-1.

[0595] The compound [A2-1] or a salt thereof is commercially available, or may be prepared from a commercially available product by a known method.

[0596] Instead of compound [A1-5] or a salt thereof, this production method may be carried out using a compound having a functional group or a protected functional group that can be converted into compound [A1-5] or a salt thereof by a known reaction, or a salt thereof, to obtain a compound corresponding to compound [II] or a salt thereof, and then converting the functional group to produce compound [II] or a salt thereof.

[0597] Preparation method A2a: Alternative method for preparing compound [I] or a salt thereof Compound [I] or a salt thereof can be prepared by carrying out preparation method A2 using compound [A1a-1] or a salt thereof instead of compound [A1-1] or a salt thereof.

[0598] Production Method A3: Production Method of Compound [III] or a Salt Thereof Compound [III] or a salt thereof can be produced, for example, by the following Production Method A3.

[0599]

[0600] [In the formula, X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 and Y 4 are each independently a carbon or nitrogen atom (wherein X 1 , X 2 , X 3 and X 4 The total number of nitrogen atoms in Y is 0 or 1, 1 , Y 2 , Y 3 and Y 4 the total number of nitrogen atoms in L is 0, 1 or 2; A31 is a leaving group {e.g., halogens, boronic acids, and boronic esters (e.g., pinacol boronic acid esters)}; R A31 is a halogen, a boronic acid, or a boronic acid ester (e.g., a boronic acid pinacol ester)}, where L A31 In the case of halogen, R A31 is a boronic acid or boronic ester, and L A31 is a boronic acid or boronic ester, R A31 is a halogen), R 1 , R 2 , R 3 , R 4 , R A11 , m and n are as defined above.

[0601] (Step A3-1) The compound [A3-2] or a salt thereof can be obtained by reacting the compound [A3-1] or a salt thereof with the compound [A1-2] or a salt thereof in a solvent in the presence of a base and a catalyst.

[0602] Examples of the solvent include toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, cyclopentyl methyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, and mixtures of these with water. A preferred solvent is a mixture of 1,2-dimethoxyethane and water.

[0603] Examples of the base include potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate, and tetrabutylammonium acetate. A preferred base is potassium phosphate.

[0604] Examples of the catalyst include palladium acetate, tetrakistriphenylphosphinepalladium, bis(triphenylphosphine)palladium dichloride, (bis(diphenylphosphino)ferrocene)palladium dichloride-methylene chloride complex, and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate. A preferred catalyst is (bis(diphenylphosphino)ferrocene)palladium dichloride-methylene chloride complex.

[0605] The reaction temperature is, for example, 70 to 100°C.

[0606] The compound [A3-1] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method.

[0607] (Step A3-2) The compound [A3-3] or a salt thereof can be produced by reacting the compound [A3-2] or a salt thereof according to Step A1-2.

[0608] (Step A3-3) Compound [III] or a salt thereof can be prepared by reacting compound [A3-3] or a salt thereof with compound [A1-5] or a salt thereof according to step A1-3.

[0609] Alternatively, instead of compound [A1-5] or a salt thereof, a compound having a functional group or a protected functional group that can be converted into compound [A1-5] or a salt thereof by a known reaction, or a salt thereof, may be used in this production method to obtain a compound corresponding to compound [III] or a salt thereof, and then the functional group may be converted to produce compound [III] or a salt thereof.

[0610] Production Method A4: Production Method of Compound [IV] or a Salt Thereof Compound [IV] or a salt thereof can be produced, for example, by the following Production Method A4.

[0611]

[0612] [In the formula, X 1 , X 5 , X 6 , Y 1 , Y 2 , Y 3 and Y 4 are each independently a carbon or nitrogen atom (wherein X 5 and X 6 The total number of nitrogen atoms in Y is 1. 1 , Y 2 , Y 3 and Y 4 the total number of nitrogen atoms in L is 0, 1 or 2; A41 is a leaving group {e.g., halogens, boronic acids, and boronic esters (e.g., pinacol boronic acid esters)}; R A41 is hydrogen, halogen, boronic acid, or boronic acid ester (e.g., boronic acid pinacol ester)}, where L A41 In the case of halogen, R A41 is hydrogen, a boronic acid or a boronic ester, and L A41 is a boronic acid or boronic ester, R A41 is hydrogen or halogen), R 1 , R 2 , R 3 , R4 , R A11 , m and n are as defined above.

[0613] (Step A4-1) The compound [A4-2] or a salt thereof can be prepared by reacting the compound [A4-1] or a salt thereof with the compound [A1-2] or a salt thereof according to Step A3-1.

[0614] The compound [A4-1] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method.

[0615] (Step A4-2) The compound [A4-3] or a salt thereof can be prepared by reacting the compound [A4-2] or a salt thereof according to Step A1-2.

[0616] (Step A4-3) Compound [IV] or a salt thereof can be prepared by reacting compound [A4-3] or a salt thereof with compound [A1-5] or a salt thereof according to step A1-3.

[0617] Alternatively, instead of compound [A1-5] or a salt thereof, a compound having a functional group or a protected functional group that can be converted into compound [A1-5] or a salt thereof by a known reaction, or a salt thereof, may be used in this production method to obtain a compound corresponding to compound [IV] or a salt thereof, and then the functional group may be converted to produce compound [IV] or a salt thereof.

[0618] Production method B: Production method of compound [A1-5] or a salt thereof

[0619]

[0620] (In the formula, R 4 are as defined above)

[0621] For example, [A1-5] or a salt thereof can be obtained by the following production methods B1 to B4. In each production method, the starting materials are commercially available products or may be produced from commercially available products by known methods.

[0622] Production method B1: Production method for compound [A1-5-B1] or a salt thereof

[0623]

[0624] [In the formula, R B11 is an amino protecting group (e.g., benzyloxycarbonyl), and R B12 is a protecting group for hydroxy (e.g., trimethylsilyl), and R B13 and R B14 are each independently hydrogen or C 1-4 alkyl, and R B15 is a protecting group for hydroxy (e.g., benzyl), Cy=O is a group in which two hydrogen atoms on the same carbon atom constituting the ring Cy are substituted with oxo, and the ring Cy has the same definition as above.

[0625] (Step B1-1) The compound [B1-3] or a salt thereof can be produced by reacting the compound [B1-1] or a salt thereof and the compound [B1-2] or a salt thereof with an acid and a reducing agent in a solvent.

[0626] The acid includes, for example, trimethylsilyl trifluoromethanesulfonate.

[0627] Examples of reducing agents include triethylsilane and trimethylsilane. A preferred reducing agent is triethylsilane.

[0628] Examples of solvents include acetonitrile and dichloromethane. A preferred solvent is acetonitrile.

[0629] The reaction temperature is, for example, 0°C to 10°C.

[0630] Compound [B1-1] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method.

[0631] Compound [B1-2] or a salt thereof is commercially available, or may be prepared from a commercially available product by a known method.

[0632] (Step B1-2) Compound [A1-5-B1] or a salt thereof is prepared by reacting R B11 and R B15 The deprotection reaction can be carried out by removing R B11 and R B15For example, R B11 is benzyloxycarbonyl, and R B15 However, in the case of benzyl, compound [A1-5-B1] or a salt thereof can be obtained by subjecting compound [B1-3] or a salt thereof to catalytic hydrogenation. For example, compound [A1-5-B1] or a salt thereof can be obtained by reacting compound [B1-2] or a salt thereof in a solvent under a hydrogen atmosphere in the presence of a catalyst.

[0633] Examples of the solvent include methanol, ethanol, tetrahydrofuran, ethyl acetate, acetic acid, and mixtures thereof. A preferred solvent is methanol.

[0634] The pressure of the hydrogen gas is, for example, 1 to 10 atmospheres, and preferably 1 to 4 atmospheres.

[0635] Examples of the catalyst include palladium on carbon and palladium hydroxide on carbon, with palladium hydroxide on carbon being preferred.

[0636] The reaction temperature is, for example, 20°C to 30°C.

[0637] Production method B2: Production method for compound [A1-5-B2] or a salt thereof

[0638]

[0639] [In the formula, R B21 and R B22 are each independently an amino protecting group (e.g., benzyl), and R B23 , R B24 and R B26 are each independently C 1-4 alkyl, and R B25 are each independently a halogen, and the ring Cy has the same definition as defined above.

[0640] (Step B2-1) The compound [B2-3] or a salt thereof can be obtained by reacting the compound [B2-1] or a salt thereof with the compound [B2-2] in a solvent in the presence of a metal catalyst.

[0641] The solvent may be, for example, dichloromethane.

[0642] Examples of metal catalysts include rhodium(II) acetate and rhodium(II) octoate. A preferred metal catalyst is rhodium(II) acetate.

[0643] The reaction temperature is, for example, 20°C to 40°C.

[0644] The compound [B2-1] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method.

[0645] Compound [B2-2] is a commercially available product, or may be prepared from a commercially available product by a known method.

[0646] (Step B2-2) The compound [B2-5] or a salt thereof can be obtained by reacting the compound [B2-3] or a salt thereof with the compound [B2-4] in a solvent in the presence of a base.

[0647] Examples of the solvent include diethyl ether, tetrahydrofuran, dimethoxyethane, benzene, toluene, hexamethylphosphoric triamide, and mixtures thereof. The preferred solvent is tetrahydrofuran.

[0648] Examples of bases include potassium hexamethyldisilazide, sodium hexamethyldisilazide, lithium hexamethyldisilazide, and lithium diisopropylamide.

[0649] The reaction temperature is, for example, from -78°C to 30°C.

[0650] Compound [B2-4] is a commercially available product, or may be prepared from a commercially available product by a known method.

[0651] (Step B2-3) The compound [B2-7] or a salt thereof can be obtained by reacting the compound [B2-5] or a salt thereof with the compound [B2-6] according to Step B2-2.

[0652] Compound [B2-6] is a commercially available product, or may be prepared from a commercially available product by a known method.

[0653] (Step B2-4) The compound [B2-8] or a salt thereof can be prepared by reducing the compound [B2-7] or a salt thereof in a solvent.

[0654] Examples of reducing agents include lithium aluminum hydride and sodium borohydride. A preferred reducing agent is lithium aluminum hydride.

[0655] The solvent may be, for example, tetrahydrofuran.

[0656] The reaction temperature is, for example, 0°C to 20°C, preferably 0°C to 10°C.

[0657] (Step B2-5) Compound [A1-5-B2] or a salt thereof is reacted with R B21 and R B22 can be obtained by removing R B21 and R B22 The process may be carried out under suitable conditions depending on the type of each. For example, B21 and R B22 However, in the case of benzyl, the compound [A1-5-B2] or a salt thereof can be obtained by reacting the compound [B2-8] or a salt thereof in a solvent under a hydrogen atmosphere in the presence of a catalyst.

[0658] Examples of the solvent include methanol, ethanol, tetrahydrofuran, ethyl acetate, acetic acid, and mixtures thereof. A preferred solvent is a mixture of methanol and tetrahydrofuran.

[0659] The pressure of the hydrogen gas is, for example, 1 to 10 atmospheres, and preferably 1 to 4 atmospheres.

[0660] Examples of the catalyst include palladium on carbon and palladium hydroxide on carbon, with palladium hydroxide on carbon being preferred.

[0661] The reaction temperature is, for example, 20°C to 30°C.

[0662] Production method B3: Production method for compound [A1-5-B3] or a salt thereof

[0663]

[0664] [In the formula, R B31 is an amino-protecting group (e.g., tert-butoxycarbonyl and benzyloxycarbonyl, preferably tert-butoxycarbonyl), R B32 and R B38 are each independently C 1-4 alkyl, and R B33 is a halogen, and R B34 , R B35 , R B36 and R B37 are each independently hydrogen or C 1-4 alkyl, and the ring Cy has the same meaning as defined above.

[0665] (Step B3-1) The compound [B3-3] or a salt thereof can be obtained by reacting the compound [B3-1] or a salt thereof with the compound [B3-2] or a salt thereof in a solvent in the presence of a condensing agent and a base.

[0666] Examples of the solvent include 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether, toluene, hexane, xylene, dichloromethane, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, pyridine, and mixtures thereof. A preferred solvent is N,N-dimethylformamide.

[0667] Condensation agents include, for example, dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC·HCl), diisopropylcarbodiimide, 1,1'-carbonyldiimidazole (CDI), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylaminomorpholinocarbenium hexafluorophosphate (COMU), and diphenylphosphoryl azide. A preferred condensation agent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC·HCl).

[0668] Examples of bases include pyridine, triethylamine, and N,N-diisopropylethylamine. A preferred base is N,N-diisopropylethylamine.

[0669] The reaction temperature is, for example, 0°C to 60°C, preferably 0°C to 40°C.

[0670] The compound [B3-1] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method.

[0671] The compound [B3-2] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method.

[0672] (Process B3-2-1) R B34 When is hydrogen, the compound [B3-5] or a salt thereof can be obtained by subjecting the compound [B3-3] or a salt thereof to a reduction reaction in a solvent.

[0673] Examples of the solvent include 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether, and mixtures thereof. The preferred solvent is tetrahydrofuran.

[0674] Examples of reducing agents include diisobutylaluminum hydride and lithium aluminum hydride. A preferred reducing agent is lithium aluminum hydride.

[0675] The reaction temperature is, for example, from -78°C to 40°C, preferably from -78°C to 0°C.

[0676] (Process B3-2-2) R B34 But C 1-4 When it is alkyl, the compound [B3-5] or a salt thereof can be obtained by reacting the compound [B3-3] or a salt thereof with the compound [B3-4] in a solvent.

[0677] Examples of the solvent include 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether, and mixtures thereof. The preferred solvent is tetrahydrofuran.

[0678] The reaction temperature is, for example, from -78°C to 40°C, preferably from 0°C to 20°C.

[0679] Compound [B3-4] is a commercially available product, or may be prepared from a commercially available product by a known method.

[0680] (Step B3-3) The compound [B3-7] or a salt thereof can be obtained by reacting the compound [B3-5] or a salt thereof with the compound [B3-6] or a salt thereof in a solvent in the presence of a base.

[0681] Examples of the solvent include tetrahydrofuran, dimethoxyethane, benzene, toluene, methanol, ethanol, and mixtures thereof. The preferred solvent is tetrahydrofuran.

[0682] Examples of the base include sodium hydride, sodium methoxide, sodium ethoxide, and n-butyllithium. A preferred base is sodium hydride.

[0683] The reaction temperature is, for example, from -78°C to 100°C, preferably from 0°C to 70°C.

[0684] Compound [B3-6] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method.

[0685] (Step B3-4) Compound [B3-8] or a salt thereof can be obtained by subjecting compound [B3-7] or a salt thereof to catalytic hydrogenation. For example, compound [B3-8] or a salt thereof can be obtained by reacting compound [B3-7] or a salt thereof in a solvent under a hydrogen atmosphere in the presence of a catalyst.

[0686] Examples of the solvent include methanol, ethanol, tetrahydrofuran, ethyl acetate, acetic acid, and mixtures thereof. A preferred solvent is a mixture of methanol and tetrahydrofuran.

[0687] The pressure of the hydrogen gas is, for example, 1 to 10 atmospheres, and preferably 1 to 4 atmospheres.

[0688] Examples of catalysts include palladium on carbon and palladium hydroxide on carbon. A preferred palladium catalyst is palladium on carbon.

[0689] The reaction temperature is, for example, 0°C to 70°C, preferably 0°C to 40°C.

[0690] (Step B3-5) The compound [A1-5-B3] or a salt thereof is reacted with the compound [B3-8] or a salt thereof to form a compound [A1-5-B3] or a salt thereof. B31 The deprotection reaction can be carried out by removing R B31 For example, R B31 However, when it is tert-butoxycarbonyl, the compound [A1-5-B3] or a salt thereof can be obtained by reacting the compound [B3-8] or a salt thereof with an acid in a solvent.

[0691] Examples of the solvent include ethyl acetate, 1,4-dioxane, methanol, cyclopentyl methyl ether, and a mixture thereof. Preferred solvents are ethyl acetate, methanol, or a mixture thereof.

[0692] Acids include, for example, hydrogen chloride, sulfuric acid, and trifluoroacetic acid. A preferred acid is hydrogen chloride.

[0693] The reaction temperature is, for example, 0°C to 50°C, preferably 0°C to 30°C.

[0694] Production method B4: Production method for compound [A1-5-B4] or a salt thereof

[0695]

[0696] [In the formula, R B41 and R B43 are each independently C 1-4 alkyl, and R B42 is a halogen, and R B31 , R B34 and the ring Cy has the same meaning as defined above.

[0697] (Step B4-1) The compound [B4-1] or a salt thereof can be obtained by reacting the compound [B3-5] or a salt thereof with Meldrum's acid in a solvent in the presence of a Lewis acid and a base.

[0698] Examples of the solvent include benzene, toluene, dichloromethane, chloroform, tetrahydrofuran, and mixtures thereof. The preferred solvent is tetrahydrofuran.

[0699] An example of the Lewis acid is titanium tetrachloride.

[0700] Examples of bases include piperidine, morpholine, and pyridine. A preferred base is pyridine.

[0701] The reaction temperature is, for example, 0°C to 50°C, preferably 0°C to 30°C.

[0702] The compound [B3-5] or a salt thereof can be obtained according to Step B3-1 and Step B3-2-1 or B3-2-2 of Production Method B3.

[0703] (Step B4-2) Compound [B4-3] or a salt thereof can be obtained by reacting compound [B4-1] or a salt thereof with compound [B4-2] in a solvent.B34 But C 1-4 In the case of alkyl, it is preferable to add copper(I) bromide to the reaction system.

[0704] Examples of the solvent include diethyl ether, tetrahydrofuran, dimethoxyethane, and mixtures thereof. The preferred solvent is tetrahydrofuran.

[0705] The reaction temperature is, for example, 0°C to 40°C.

[0706] Compound [B4-2] is a commercially available product, or may be prepared from a commercially available product by a known method.

[0707] (Step B4-3) The compound [B4-5] or a salt thereof can be obtained by reacting the compound [B4-3] or a salt thereof in a solvent [B4-4].

[0708] Examples of the solvent [B4-4] include methanol, ethanol, and tert-butyl alcohol. A preferred solvent [B4-4] is methanol.

[0709] The reaction temperature is, for example, 20°C to 110°C, preferably 60°C to 100°C.

[0710] (Step B4-4) The compound [B4-6] or a salt thereof can be obtained by reacting the compound [B4-5] or a salt thereof in a solvent in the presence of sodium chloride.

[0711] Examples of the solvent include dimethyl sulfoxide, water, and a mixture thereof. A preferred solvent is a mixture of dimethyl sulfoxide and water.

[0712] The reaction temperature is, for example, 100 to 160°C, preferably 120 to 150°C.

[0713] (Step B4-5) Compound [A1-5-B4] or a salt thereof is reacted with R B31 can be prepared by removing the compound by deprotection reaction according to step B3-5.

[0714] Next, a method for producing the compound of the present invention or a pharmaceutically acceptable salt thereof will be specifically described, but the method for producing the compound of the present invention or a pharmaceutically acceptable salt thereof is not limited to the following.

[0715] The compounds obtained in each step can be isolated and / or purified by known methods such as distillation, recrystallization, column chromatography, etc., as necessary, but in some cases, they can be used to proceed to the next step without isolation and / or purification.

[0716] In this specification, room temperature refers to a temperature in an uncontrolled state, and one embodiment is 1° C. to 40° C. NMR was measured at 400 MHz.

[0717] [Production Example 1] Example 1: Production of 2-(6-fluoro-3-methyl-1H-indazol-1-yl)-N-(trans-4-(2-hydroxypropan-2-yl)cyclohexyl)pyrimidine-5-carboxylic acid amide

[0718]

[0719] Step 1-1: ethyl 2-(6-fluoro-3-methyl-1H-indazol-1-yl)pyrimidine-5-carboxylate

[0720]

[0721] A suspension of 6-fluoro-3-methyl-1H-indazole (200 mg), ethyl 2-chloropyrimidinecarboxylate (161 mg), and cesium carbonate (698 mg) in N,N-dimethylformamide (2.0 mL) was stirred for 4 hours at 90° C. Water was added to this reaction mixture at room temperature, and the precipitated solid was collected by filtration and dried under reduced pressure at 70° C. to obtain the title compound (158 mg). 1H-NMR (DMSO-D6) δ: 9.28 (2H, s), 8.42 (1H, dd, J = 10.5, 2.2 Hz), 7.94 (1H, dd, J = 8.2, 5.2 Hz), 7.30 (1H, ddd, J = 10.5, 8.2, 2.2 Hz), 4.40 (2H, q, J = 7.2 Hz), 2.61 (3H, s), 1.37 (3H, t, J = 7.2 Hz).

[0722] Step 1-2: 2-(6-fluoro-3-methyl-1H-indazol-1-yl)pyrimidine-5-carboxylic acid

[0723]

[0724] To a suspension of ethyl 2-(6-fluoro-3-methyl-1H-indazol-1-yl)pyrimidine-5-carboxylate (158 mg) in methanol / tetrahydrofuran (2.37 mL, methanol / tetrahydrofuran = 1 / 2) was added 4M aqueous sodium hydroxide (0.263 mL) at room temperature and stirred for 2 hours. To this reaction mixture, 2M hydrochloric acid (0.526 mL) and water were added at room temperature, and the precipitated solid was collected by filtration and dried under reduced pressure at 70 ° C to give a crude product (65.6 mg) containing the title compound.

[0725] Step 1-3: 2-(6-fluoro-3-methyl-1H-indazol-1-yl)-N-(trans-4-(2-hydroxypropan-2-yl)cyclohexyl)pyrimidine-5-carboxylic acid amide

[0726]

[0727] To a suspension of the crude product (30 mg) containing 2-(6-fluoro-3-methyl-1H-indazol-1-yl)pyrimidine-5-carboxylic acid, 2-(trans-4-aminocyclohexyl)propan-2-ol (22.53 mg), and triethylamine (0.023 mL) in N,N-dimethylformamide (0.6 mL) was added 1-hydroxy-7-azabenzotriazole (4.5 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (31.7 mg) at room temperature. The mixture was stirred for 30 minutes, allowed to stand overnight, and then stirred for an additional 6 hours. Water and ethyl acetate were added to the reaction mixture at room temperature. After separation, the aqueous layer was extracted once with ethyl acetate. The combined organic layers were washed twice with water and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was subjected to slurry purification. The solid was collected by filtration and dried at 70 °C under reduced pressure to yield the title compound (8.5 mg). 1 H-NMR (DMSO-D6)δ: 9.23 (2H, s), 8.54 (1H, d, J = 8.2 Hz), 8.40 (1H, dd, J = 10.2, 2.0 Hz), 7.94 (1H, dd, J = 8.6, 5.6 Hz), 7.29 (1H, ddd, J = 10.2, 8.6, 2.0 Hz), 4.05 (1H, br s), 3.81-3.68 (1H, m), 2.61 (3H, s), 1.96 (2H, d, J = 10.5 Hz), 1.86 (2H, d, J = 10.5 Hz), 1.40-1.26 (2H, m), 1.25-1.00 (3H, m), 1.06 (6H, s).MS(M+H):412 MS(MH):410

[0728] Step 1-4: 2-(6-fluoro-3-methyl-1H-indazol-1-yl)pyrimidine-5-carboxylic acid

[0729]

[0730] To a suspension of ethyl 2-(6-fluoro-3-methyl-1H-indazol-1-yl)pyrimidine-5-carboxylate (177.68 g) synthesized in a similar manner to step 1-1 in tetrahydrofuran / water (2.132 L, tetrahydrofuran / water = 2 / 1), 4M aqueous lithium hydroxide solution (192 mL) was added dropwise at room temperature and stirred under a nitrogen atmosphere for 2 hours. 2M hydrochloric acid (385 mL) and water (1060 mL) were added dropwise to this reaction mixture at room temperature, followed by stirring for 6 hours and then standing overnight. The precipitated solid was collected by filtration, washed with water (1440 mL), air-dried for 3 days, and then dried under reduced pressure at 60 °C to give the title compound (166.22 g).

[0731] Step 1-5: 2-(6-fluoro-3-methyl-1H-indazol-1-yl)-N-(trans-4-(2-hydroxypropan-2-yl)cyclohexyl)pyrimidine-5-carboxylic acid amide monohydrate

[0732]

[0733] To a suspension of 2-(6-fluoro-3-methyl-1H-indazol-1-yl)pyrimidine-5-carboxylic acid (150 g), 2-(trans-4-aminocyclohexyl)propan-2-ol (104 g), and 1-hydroxy-7-azabenzotriazole (75 g) in N,N-dimethylformamide (1.95 L) was added triethylamine (115 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (158 g), and N,N-dimethylformamide (75 mL) at room temperature and stirred for 5 hours under a nitrogen atmosphere. To this reaction mixture, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (52.8 g) and N,N-dimethylformamide (75 mL) were added at room temperature and stirred overnight under a nitrogen atmosphere. To this reaction mixture, a 5.0 wt% aqueous solution of sodium bicarbonate (4.2 L) was added dropwise at room temperature, followed by stirring for 2 hours. The solid was collected by filtration, washed with water (1.5 L), air-dried for 2 days, and then dried under reduced pressure at 60°C to give the title compound as a crystal (α crystal, 219.92 g).

[0734] Step 1-6: 2-(6-fluoro-3-methyl-1H-indazol-1-yl)-N-(trans-4-(2-hydroxypropan-2-yl)cyclohexyl)pyrimidine-5-carboxylic acid amide

[0735]

[0736] A suspension of 2-(6-fluoro-3-methyl-1H-indazol-1-yl)-N-(trans-4-(2-hydroxypropan-2-yl)cyclohexyl)pyrimidine-5-carboxylic acid amide monohydrate crystals (α crystals, 37.4 g) in acetonitrile (748 mL) was stirred under an argon atmosphere at room temperature for 2 days. The precipitated solid was filtered by nitrogen pressure filtration and dried under reduced pressure at 60 °C to give the title compound crystals (β crystals, 34.42 g).

[0737] Step 1-7: 2-(6-fluoro-3-methyl-1H-indazol-1-yl)-N-(trans-4-(2-hydroxypropan-2-yl)cyclohexyl)pyrimidine-5-carboxylic acid amide monohydrate

[0738] A suspension of 2-(6-fluoro-3-methyl-1H-indazol-1-yl)-N-(trans-4-(2-hydroxypropan-2-yl)cyclohexyl)pyrimidine-5-carboxylic acid amide monohydrate crystals (α crystals, 500 mg) in tetrahydrofuran / water (6.0 mL, tetrahydrofuran / water = 5 / 1) was stirred at 75 °C until a solution was formed. Water (4.0 mL) was added dropwise to this reaction mixture at the same temperature and stirred for 30 minutes, then returned to room temperature and stirred for 1 hour. Water (5.0 mL) was added dropwise to this reaction mixture at room temperature and stirred for 3 hours. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound crystals (γ crystals, 466.6 mg).

[0739] [Production Example 2] Example 2: Production of N-(trans-4-(2-hydroxy-2-methylpropyl)cyclohexyl)-2-(3-methyl-1H-pyrazolo[3,4-c]pyridin-1-yl)pyrimidine-5-carboxylic acid amide

[0740]

[0741] Step 2-1: tert-butyl 2-chloropyrimidine-5-carboxylate

[0742]

[0743] To a solution of 2-chloropyrimidine-5-carboxylic acid (2.0 g) and N,N-dimethyl-4-aminopyridine (0.462 g) in tert-butyl alcohol / chloroform (30 mL, tert-butyl alcohol / chloroform = 2 / 1), di-tert-butyl dicarbonate (5.51 g) was added at room temperature, and the mixture was stirred at 60 °C for 90 minutes and allowed to stand overnight. Ethyl acetate was added to the reaction mixture at room temperature, and the organic layer was washed sequentially with saturated aqueous sodium bicarbonate, aqueous citric acid, and saturated brine. The organic layer was dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate) to give the title compound (990 mg). 1 H-NMR (DMSO-D6) δ: 9.13 (2H, s), 1.57 (9H, s).

[0744] Step 2-2: tert-butyl 2-(3-methyl-1H-pyrazolo[3,4-c]pyridin-1-yl)pyrimidine-5-carboxylate

[0745]

[0746] A suspension of tert-butyl 2-chloropyrimidine-5-carboxylate (100 mg), 3-methyl-1H-pyrazolo[3,4-c]pyridine (62 mg), and cesium carbonate (182 mg) in N,N-dimethylformamide (1.0 mL) was stirred at room temperature for 30 minutes and then allowed to stand overnight. Water was added to the reaction mixture at room temperature, and the precipitated solid was collected by filtration and dried at 70°C under reduced pressure to give the title compound (130 mg). 1 H-NMR (DMSO-D6) δ: 10.01 (1H, s), 9.29 (2H, s), 8.55 (1H, d, J = 5.2 Hz), 7.95 (1H, d, J = 5.2 Hz), 2.67 (3H, s), 1.61 (9H, s).

[0747] Step 2-3: 2-(3-methyl-1H-pyrazolo[3,4-c]pyridin-1-yl)pyrimidine-5-carboxylic acid monohydrochloride

[0748]

[0749] To a suspension of tert-butyl 2-(3-methyl-1H-pyrazolo[3,4-c]pyridin-1-yl)pyrimidine-5-carboxylate (130 mg) in ethyl acetate (0.26 mL) was added 4 M hydrogen chloride / ethyl acetate solution (1.3 mL) at room temperature, stirred for 6 hours, and allowed to stand overnight. The reaction mixture was concentrated under reduced pressure. Trifluoroacetic acid (0.65 mL) was added to the residue at room temperature, stirred for 5 hours, and allowed to stand overnight. To this reaction mixture was added 4 M hydrogen chloride / ethyl acetate solution at room temperature, and the precipitated solid was collected by filtration and dried at 70°C under reduced pressure to give the title compound (97.8 mg). 1 H-NMR (DMSO-D6) δ: 13.73 (1H, br s), 10.06 (1H, s), 9.34 (2H, s), 8.62 (1H, d, J = 5.5 Hz), 8.15-8.08 (1H, m), 2.70 (3H, s).

[0750] Step 2-4: N-(trans-4-(2-hydroxy-2-methylpropyl)cyclohexyl)-2-(3-methyl-1H-pyrazolo[3,4-c]pyridin-1-yl)pyrimidine-5-carboxylic acid amide

[0751]

[0752] To a suspension of 2-(3-methyl-1H-pyrazolo[3,4-c]pyridin-1-yl)pyrimidine-5-carboxylic acid monohydrochloride (30 mg), 2-(trans-4-aminocyclohexyl)propan-2-ol (19.41 mg), 1-hydroxy-7-azabenzotriazole (4.2 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (29.6 mg) in N,N-dimethylformamide (0.6 mL) was added triethylamine (0.0215 mL) at room temperature, stirred for 45 minutes, and then allowed to stand overnight. The reaction mixture was purified by reverse-phase silica gel column chromatography (eluent: water / acetonitrile = 95 / 5 to 0 / 100) to give the title compound (35.1 mg). 1 H-NMR (DMSO-D6) δ: 9.99 (1H, s), 9.28 (2H, s), 8.58 (1H, d, J = 7.6 Hz), 8.53 (1H, d, J = 5.3 Hz), 7.94 (1H, d, J = 5.3 Hz), 4.05 (1H, br s), 3.81-3.68 (1H, m), 2.66 (3H, s), 1.97 (2H, d, J = 10.2 Hz), 1.86 (2H, d, J = 10.2 Hz), 1.40-1.26 (2H, m), 1.25-1.03 (3H, m), 1.06 (6H, s).MS(M+H):395 MS(MH):393

[0753] [Production Example 3] Example 3: Production of N-(trans-4-(2-hydroxy-2-methylpropyl)cyclohexyl)-2-(3-methyl-1H-pyrazolo[3,4-c]pyridin-1-yl)pyrimidine-5-carboxylic acid amide

[0754]

[0755] Step 3-1: tert-butyl 2-chloropyrimidine-5-carboxylate

[0756]

[0757] To a solution of 2-chloropyrimidine-5-carboxylic acid (2.0 g) and N,N-dimethyl-4-aminopyridine (0.462 g) in tert-butyl alcohol / chloroform (30 mL, tert-butyl alcohol / chloroform = 2 / 1), di-tert-butyl dicarbonate (5.51 g) was added at room temperature, and the mixture was stirred at 60 °C for 90 minutes and allowed to stand overnight. Ethyl acetate was added to the reaction mixture at room temperature, and the organic layer was washed sequentially with saturated aqueous sodium bicarbonate, aqueous citric acid, and saturated brine. The organic layer was dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate) to give the title compound (990 mg). 1 H-NMR (DMSO-D6) δ: 9.13 (2H, s), 1.57 (9H, s).

[0758] Step 3-2: tert-butyl 2-(3-methyl-1H-pyrazolo[3,4-c]pyridin-1-yl)pyrimidine-5-carboxylate

[0759]

[0760] A suspension of tert-butyl 2-chloropyrimidine-5-carboxylate (100 mg), 3-methyl-1H-pyrazolo[3,4-c]pyridine (62 mg), and cesium carbonate (182 mg) in N,N-dimethylformamide (1.0 mL) was stirred at room temperature for 30 minutes and then allowed to stand overnight. Water was added to the reaction mixture at room temperature, and the precipitated solid was collected by filtration and dried at 70°C under reduced pressure to give the title compound (130 mg). 1 H-NMR (DMSO-D6) δ: 10.01 (1H, s), 9.29 (2H, s), 8.55 (1H, d, J = 5.2 Hz), 7.95 (1H, d, J = 5.2 Hz), 2.67 (3H, s), 1.61 (9H, s).

[0761] Step 3-3: 2-(3-methyl-1H-pyrazolo[3,4-c]pyridin-1-yl)pyrimidine-5-carboxylic acid monohydrochloride

[0762]

[0763] To a suspension of tert-butyl 2-(3-methyl-1H-pyrazolo[3,4-c]pyridin-1-yl)pyrimidine-5-carboxylate (130 mg) in ethyl acetate (0.26 mL) was added 4 M hydrogen chloride / ethyl acetate solution (1.3 mL) at room temperature, stirred for 6 hours, and allowed to stand overnight. The reaction mixture was concentrated under reduced pressure. Trifluoroacetic acid (0.65 mL) was added to the residue at room temperature, stirred for 5 hours, and allowed to stand overnight. To this reaction mixture was added 4 M hydrogen chloride / ethyl acetate solution at room temperature, and the precipitated solid was collected by filtration and dried at 70°C under reduced pressure to give the title compound (97.8 mg). 1 H-NMR (DMSO-D6) δ: 13.73 (1H, br s), 10.06 (1H, s), 9.34 (2H, s), 8.62 (1H, d, J = 5.5 Hz), 8.15-8.08 (1H, m), 2.70 (3H, s).

[0764] Step 3-4: ethyl 2-(trans-4-(dibenzylamino)cyclohexyl)acetate

[0765]

[0766] To a suspension of ethyl 2-(trans-4-aminocyclohexyl)acetate monohydrochloride (3.0 g) and potassium carbonate (5.99 g) in acetonitrile (30 mL) was added benzyl bromide (3.4 mL) at room temperature and stirred overnight. Water (30 mL) and ethyl acetate (30 mL) were added to the reaction mixture at room temperature, and the layers were separated. The aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layers were washed with saturated brine and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 96 / 4 to 74 / 26) to give a crude product (5.068 g) containing the title compound.

[0767] Step 3-5: 1-(trans-4-(dibenzylamino)cyclohexyl)-2-methylpropan-2-ol

[0768]

[0769] To a solution of the crude product (3.847 g) containing ethyl 2-(trans-4-(dibenzylamino)cyclohexyl)acetate in tetrahydrofuran (20 mL) was added a 3.0 M tetrahydrofuran solution of methylmagnesium bromide (11 mL) under ice cooling, and the mixture was gradually warmed to room temperature and stirred overnight. To this reaction mixture was added saturated aqueous ammonium chloride (15 mL) and ethyl acetate (20 mL) under ice cooling. After separation, the organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 94 / 6 to 53 / 47) to give the title compound (1.45 g). 1 H-NMR (DMSO-D6) δ: 7.35-7.26 (8H, m), 7.21-7.17 (2H, m), 3.96 (1H, s), 3.57 (4H, s), 2.38-2.31 (1H, m), 1.85-1.76 (4H, m), 1.42-1.31 (3H, m), 1.21-1.15 (2H, m), 1.06 (6H, s), 0.82-0.73 (2H, m).

[0770] Step 3-6: 1-(trans-4-aminocyclohexyl)-2-methylpropan-2-ol

[0771]

[0772] To a solution of 1-(trans-4-(dibenzylamino)cyclohexyl)-2-methylpropan-2-ol (1.45 g) in methanol (20 mL) was added 20% palladium hydroxide on carbon (368 mg) at room temperature. The mixture was stirred overnight at room temperature under a hydrogen atmosphere at 1 atmosphere pressure. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (692 mg). 1 H-NMR (DMSO-D6) δ: 3.98 (1H, br s), 2.44-2.37 (1H, m), 1.76-1.67 (4H, m), 1.47 (2H, br s), 1.34-1.22 (4H, m), 1.07 (6H, s), 0.99-0.84 (3H, m).

[0773] Step 3-7: N-(trans-4-(2-hydroxy-2-methylpropyl)cyclohexyl)-2-(3-methyl-1H-pyrazolo[3,4-c]pyridin-1-yl)pyrimidine-5-carboxylic acid amide

[0774]

[0775] To a suspension of 2-(3-methyl-1H-pyrazolo[3,4-c]pyridin-1-yl)pyrimidine-5-carboxylic acid monohydrochloride (30 mg), 1-(trans-4-aminocyclohexyl)-2-methylpropan-2-ol (21.14 mg), 1-hydroxy-7-azabenzotriazole (4.5 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (31.7 mg) in N,N-dimethylformamide (0.6 mL) was added triethylamine (0.0215 mL) at room temperature, stirred for 45 minutes, and then allowed to stand overnight. The reaction mixture was purified by reverse-phase silica gel column chromatography (eluent: water / acetonitrile = 95 / 5 to 0 / 100) to give the title compound (22.4 mg). 1 H-NMR (DMSO-D6) δ: 9.99 (1H, s), 9.27 (2H, s), 8.56 (1H, d, J = 7.6 Hz), 8.53 (1H, d, J = 5.3 Hz), 7.94 (1H, d, J = 5.3 Hz), 4.04 (1H, br MS(M+H):409 MS(MH):407

[0776] [Production Example 4] Example 4: Production of N-(trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl)-2-(3-methyl-1H-indazol-1-yl)pyrimidine-5-carboxylic acid amide

[0777]

[0778] Step 4-1: ethyl 2-(3-methyl-1H-indazol-1-yl)pyrimidine-5-carboxylate

[0779]

[0780] A suspension of 3-methyl-1H-indazole (5.0 g), ethyl 2-chloropyrimidinecarboxylate (8.47 g), and cesium carbonate (24.65 g) in N,N-dimethylformamide (25 mL) was stirred at 90 °C for 3 hours. Water, ethyl acetate, and chloroform were added to the reaction mixture at room temperature. After separation, the aqueous layer was extracted once with ethyl acetate. The combined organic layers were washed with saturated brine, dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 85 / 15 to 0 / 100) to give a crude product containing the title compound (9.5 g). To this crude product containing the title compound (9.5 g), n-hexane / ethyl acetate (30 mL, n-hexane / ethyl acetate = 1 / 2) was added, and the mixture was purified by slurry. The solid was collected by filtration and dried under reduced pressure to give a crude product containing the title compound (7.8 g). A chloroform solution of this crude product (7.8 g) containing the title compound was purified by silica gel column chromatography (developing solvent: chloroform) to obtain the title compound (6.4 g). 1 H-NMR (DMSO-D6) δ: 9.26 (2H, s), 8.69-8.67 (1H, m), 7.90-7.88 (1H, m), 7.66-7.62 (1H, m), 7.43-7.39 (1H, m), 4.39 (2H, q, J = 7.1 Hz), 2.62 (3H, s), 1.37 (3H, t, J = 7.2 Hz).

[0781] Step 4-2: 2-(3-methyl-1H-indazol-1-yl)pyrimidine-5-carboxylic acid

[0782]

[0783] To a solution of ethyl 2-(3-methyl-1H-indazol-1-yl)pyrimidine-5-carboxylate (3.0 g) in tetrahydrofuran (60 mL) was added 2M aqueous sodium hydroxide (15.94 mL) at room temperature and stirred for 3 hours. To this reaction mixture was added 2M aqueous sodium hydroxide (5.31 mL) at room temperature, stirred for 1 hour, and allowed to stand overnight. To this reaction mixture was added 2M hydrochloric acid (21.25 mL) at room temperature and stirred for 30 minutes. To this reaction mixture was added water at room temperature, stirred for 30 minutes, and the precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (2.47 g). 1 H-NMR (DMSO-D6) δ: 13.64 (1H, br s), 9.26 (2H, s), 8.70 (1H, d, J = 8.2 Hz), 7.89 (1H, d, J = 7.5 Hz), 7.66-7.62 (1H, m), 7.41 (1H, t, J = 7.5 Hz), 2.62 (3H, s).

[0784] Step 4-3: trans-4-(dibenzylamino)cyclohexan-1-ol

[0785]

[0786] To a suspension of trans-4-aminocyclohexan-1-ol (5.0 g) and potassium carbonate (13.2 g) in acetonitrile (80 mL) was added benzyl bromide (10.9 mL) at room temperature and stirred overnight. Water (100 mL) was added to this reaction mixture at room temperature, and the precipitated solid was collected by filtration, washed three times with water (40 mL), and dried under reduced pressure at 80 °C to give the title compound (12.88 g). The title compound (10.38 g) was obtained from the starting material trans-4-aminocyclohexan-1-ol (5.0 g) using a similar procedure. 1H-NMR (DMSO-D6) δ: 7.35-7.27 (8H, m), 7.21-7.17 (2H, m), 4.43 (1H, br s), 3.55 (4H, s), 3.36-3.29 (1H, m), 2.39-2.31 (1H, m), 1.83-1.76 (4H, m), 1.43-1.37 (2H, m), 1.03-0.93 (2H, m).

[0787] Step 4-4: ethyl 2-{[trans-4-(dibenzylamino)cyclohexyl]oxy}acetate

[0788]

[0789] To a solution of trans-4-(dibenzylamino)cyclohexan-1-ol (5.0 g) in dichloromethane (50 mL) was added rhodium(II) acetate dimer (22.4 mg) at room temperature, followed by dropwise addition of 15 wt% ethyl diazoacetate / toluene solution (57.5 mL) over 2 hours and stirring for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 93 / 7 to 40 / 60) to give the title compound (5.779 g). 1 H-NMR (CDCl3) δ: 7.38-7.32 (4H, m), 7.31-7.24 (4H, m), 7.23-7.17 (2H, m), 4.20 (2H, q, J = 7.4 Hz), 4.07 (2H, s), 3.60 (4H, s), 3.32-3.20 (1H, m), 2.58-2.47 (1H, m), 2.13-2.05 (2H, m), 1.96-1.87 (2H, m), 1.43-1.16 (7H, m).

[0790] Step 4-5: 1-{[trans-4-(dibenzylamino)cyclohexyl]oxy}-2-methylpropan-2-ol

[0791]

[0792] To a solution of ethyl 2-{[trans-4-(dibenzylamino)cyclohexyl]oxy}acetate (5.779 g) in tetrahydrofuran (57.8 mL), a 1.02 M solution of methylmagnesium bromide in tetrahydrofuran (44.6 mL) was added under ice cooling, and the mixture was stirred at the same temperature for 2 hours. To this reaction mixture, saturated aqueous ammonium chloride was added under ice cooling. Ethyl acetate was added to the reaction mixture at room temperature, and the layers were separated. The aqueous layer was extracted once with ethyl acetate. The combined organic layers were washed successively with water and saturated brine, dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 93 / 7 to 40 / 60) to give the title compound (4.04 g). 1 H-NMR (CDCl3) δ: 7.38-7.33 (4H, m), 7.32-7.25 (4H, m), 7.23-7.17 (2H, m), 3.60 (4H, s), 3.24 (2H, s), 3.22-3.12 (1H, m), 2.57-2.47 (1H, m), 2.33 (1H, s), 2.10-2.01 (2H, m), 1.96-1.86 (2H, m), 1.43-1.33 (2H, m), 1.20-1.10 (8H, m).

[0793] Step 4-6: 1-((trans-4-aminocyclohexyl)oxy)-2-methylpropan-2-ol

[0794]

[0795] To a solution of 1-{[trans-4-(dibenzylamino)cyclohexyl]oxy}-2-methylpropan-2-ol (3.715 g) in methanol / tetrahydrofuran (40 mL, methanol / tetrahydrofuran = 1 / 1) was added 20% palladium hydroxide on carbon (310 mg) at room temperature. The mixture was stirred overnight at room temperature under a hydrogen atmosphere at 1 atmosphere pressure. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (1.926 g). 1H-NMR (DMSO-D6) δ: 4.17 (1H, br s), 3.18-3.11 (2H, m), 2.55-2.48 (2H, m), 1.92-1.86 (2H, m), 1.75-1.68 (2H, m), 1.47 (2H, br s), 1.20-1.09 (2H, m), 1.06-0.96 (2H, m), 1.04 (6H, s).

[0796] Step 4-7: N-(trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl)-2-(3-methyl-1H-indazol-1-yl)pyrimidine-5-carboxylic acid amide

[0797]

[0798] A suspension of 2-(3-methyl-1H-indazol-1-yl)pyrimidine-5-carboxylic acid (30 mg), 1-((trans-4-aminocyclohexyl)oxy)-2-methylpropan-2-ol (27 mg), 1-hydroxy-7-azabenzotriazole (16 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (35 mg) in N,N-dimethylformamide (1.0 mL) was stirred overnight. To this reaction mixture, saturated aqueous sodium bicarbonate (2.0 mL) and water (3.0 mL) were added at room temperature. The precipitate was collected by filtration and dried under reduced pressure to give the title compound (44.8 mg). 1 H-NMR (DMSO-D6) δ: 9.22 (2H, s), 8.67 (1H, d, J = 8.6 Hz), 8.53 (1H, d, J = 7.6 Hz), 7.89 (1H, d, J = 7.9 Hz), 7.65-7.61 (1H, m), 7.42-7.38 (1H, m), 4.22 (1H, s), 3.85-3.76 (1H, m), 3.29-3.22 (1H, m), 3.19 (2H, s), 2.62 (3H, s), 2.06-2.01 (2H, m), 1.95-1.91 (2H, m), 1.45-1.23 (4H, m), 1.08 (6H, s). MS(M+H): 424 MS(MH): 422

[0799] [Production Example 5] Example 5: Production of N-(trans-4-(2-hydroxy-2-methylpropyl)cyclohexyl)-2-(3-methyl-1H-pyrazolo[3,4-c]pyridin-1-yl)pyrimidine-5-carboxylic acid amide

[0800]

[0801] Step 5-1: tert-butyl 2-chloropyrimidine-5-carboxylate

[0802]

[0803] To a solution of 2-chloropyrimidine-5-carboxylic acid (2.0 g) and N,N-dimethyl-4-aminopyridine (0.462 g) in tert-butyl alcohol / chloroform (30 mL, tert-butyl alcohol / chloroform = 2 / 1), di-tert-butyl dicarbonate (5.51 g) was added at room temperature, and the mixture was stirred at 60 °C for 90 minutes and allowed to stand overnight. Ethyl acetate was added to the reaction mixture at room temperature, and the organic layer was washed sequentially with saturated aqueous sodium bicarbonate, aqueous citric acid, and saturated brine. The organic layer was dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate) to give the title compound (990 mg). 1 H-NMR (DMSO-D6) δ: 9.13 (2H, s), 1.57 (9H, s).

[0804] Step 5-2: tert-butyl 2-(3-methyl-1H-pyrazolo[3,4-c]pyridin-1-yl)pyrimidine-5-carboxylate

[0805]

[0806] A suspension of tert-butyl 2-chloropyrimidine-5-carboxylate (500 mg), 3-methyl-1H-pyrazolo[3,4-c]pyridine (310 mg), and cesium carbonate (911 mg) in N,N-dimethylformamide (5.0 mL) was stirred at room temperature for 1 hour and then allowed to stand overnight. Water was added to the reaction mixture at room temperature, and the precipitated solid was collected by filtration and dried at 70°C under reduced pressure to give the title compound (618 mg). 1 H-NMR (DMSO-D6) δ: 10.01 (1H, s), 9.29 (2H, s), 8.55 (1H, d, J = 5.3 Hz), 7.95 (1H, dd, J = 5.3, 0.9 Hz), 2.67 (3H, s), 1.60 (9H, s).

[0807] Step 5-3: 2-(3-methyl-1H-pyrazolo[3,4-c]pyridin-1-yl)pyrimidine-5-carboxylic acid monohydrochloride

[0808]

[0809] A solution of tert-butyl 2-(3-methyl-1H-pyrazolo[3,4-c]pyridin-1-yl)pyrimidine-5-carboxylate (618 mg) in trifluoroacetic acid (3.09 mL) was stirred for 2 hours and allowed to stand overnight. A 4 M hydrogen chloride / ethyl acetate solution was added to the reaction mixture at room temperature and stirred for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure at 70 °C to give the title compound (563 mg). 1 H-NMR (DMSO-D6) δ: 13.77 (1H, br s), 10.08 (1H, s), 9.35 (2H, s), 8.66 (1H, d, J = 5.2 Hz), 8.23 ​​(1H, d, J = 5.2 Hz), 2.72 (3H, s).

[0810] Step 5-4: trans-4-(dibenzylamino)cyclohexan-1-ol

[0811]

[0812] To a suspension of trans-4-aminocyclohexan-1-ol (5.0 g) and potassium carbonate (13.2 g) in acetonitrile (80 mL) was added benzyl bromide (10.9 mL) at room temperature and stirred overnight. Water (100 mL) was added to the reaction mixture at room temperature, and the precipitated solid was collected by filtration, washed three times with water (40 mL), and dried under reduced pressure at 80°C to give the title compound (12.88 g). 1 H-NMR (DMSO-D6) δ: 7.35-7.27 (8H, m), 7.21-7.17 (2H, m), 4.43 (1H, br s), 3.55 (4H, s), 3.36-3.29 (1H, m), 2.39-2.31 (1H, m), 1.83-1.76 (4H, m), 1.43-1.37 (2H, m), 1.03-0.93 (2H, m).

[0813] Step 5-5: ethyl 2-{[trans-4-(dibenzylamino)cyclohexyl]oxy}acetate

[0814]

[0815] To a solution of trans-4-(dibenzylamino)cyclohexan-1-ol (5.0 g) in dichloromethane (50 mL) was added rhodium(II) acetate dimer (22.4 mg) at room temperature, followed by dropwise addition of 15 wt% ethyl diazoacetate / toluene solution (57.5 mL) over 2 hours and stirring for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 93 / 7 to 40 / 60) to give the title compound (5.779 g). 1 H-NMR (CDCl3) δ: 7.38-7.32 (4H, m), 7.31-7.24 (4H, m), 7.23-7.17 (2H, m), 4.20 (2H, q, J = 7.4 Hz), 4.07 (2H, s), 3.60 (4H, s), 3.32-3.20 (1H, m), 2.58-2.47 (1H, m), 2.13-2.05 (2H, m), 1.96-1.87 (2H, m), 1.43-1.16 (7H, m).

[0816] Step 5-6: 1-{[trans-4-(dibenzylamino)cyclohexyl]oxy}-2-methylpropan-2-ol

[0817]

[0818] To a solution of ethyl 2-{[trans-4-(dibenzylamino)cyclohexyl]oxy}acetate (5.779 g) in tetrahydrofuran (57.8 mL), a 1.02 M tetrahydrofuran solution of methylmagnesium bromide (44.6 mL) was added under ice cooling, and the mixture was stirred at the same temperature for 2 hours. To this reaction mixture, saturated aqueous ammonium chloride was added under ice cooling. Ethyl acetate was added to the reaction mixture at room temperature, and the layers were separated. The aqueous layer was extracted once with ethyl acetate. The combined organic layer was washed successively with water and saturated brine, dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 93 / 7 to 40 / 60) to give the title compound (4.04 g). 1 H-NMR (CDCl3) δ: 7.38-7.33 (4H, m), 7.32-7.25 (4H, m), 7.23-7.17 (2H, m), 3.60 (4H, s), 3.24 (2H, s), 3.22-3.12 (1H, m), 2.57-2.47 (1H, m), 2.33 (1H, s), 2.10-2.01 (2H, m), 1.96-1.86 (2H, m), 1.43-1.33 (2H, m), 1.20-1.10 (8H, m).

[0819] Step 5-7: 1-((trans-4-aminocyclohexyl)oxy)-2-methylpropan-2-ol

[0820]

[0821] To a solution of 1-{[trans-4-(dibenzylamino)cyclohexyl]oxy}-2-methylpropan-2-ol (3.715 g) in methanol (20 mL) was added 20% palladium hydroxide on carbon (310 mg) at room temperature. The mixture was stirred overnight at room temperature under a hydrogen atmosphere at 1 atm. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (1.926 g). 1 H-NMR (DMSO-D6) δ: 4.17 (1H, br s), 3.18-3.11 (2H, m), 2.55-2.48 (2H, m), 1.92-1.86 (2H, m), 1.75-1.68 (2H, m), 1.47 (2H, br s), 1.20-1.09 (2H, m), 1.06-0.96 (2H, m), 1.04 (6H, s).

[0822] Step 5-8: N-(trans-4-(2-hydroxy-2-methylpropyl)cyclohexyl)-2-(3-methyl-1H-pyrazolo[3,4-c]pyridin-1-yl)pyrimidine-5-carboxylic acid amide

[0823]

[0824] To a suspension of 2-(3-methyl-1H-pyrazolo[3,4-c]pyridin-1-yl)pyrimidine-5-carboxylic acid monohydrochloride (30 mg), 1-((trans-4-aminocyclohexyl)oxy)-2-methylpropan-2-ol (23.11 mg), 1-hydroxy-7-azabenzotriazole (4.2 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (29.6 mg) in N,N-dimethylformamide (0.6 mL) was added triethylamine (0.0215 mL) at room temperature, stirred for 2 hours, and allowed to stand overnight. Water was added to this reaction mixture at room temperature, and the precipitated solid was collected by filtration and dried under reduced pressure at 70 °C to give the title compound (41.4 mg). 1H-NMR (DMSO-D6) δ: 9.99 (1H, s), 9.27 (2H, s), 8.58 (1H, d, J = 7.5 Hz), 8.54 (1H, d, J = 5.2 Hz), 7.94 (1H, d, J = 5.2 Hz), 4.20 (1H, br s), 3.87-3.74 (1H, m), 3.51-3.22 (1H, m), 3.19 (2H, s), 2.67 (3H, s), 2.04 (2H, d, J = 10.5 Hz), 1.93 (2H, d, J = 10.5 Hz), 1.48-1.20 (4H, m), 1.07 (6H, s). MS(M+H):425 MS(MH):423

[0825] [Production Example 6] Example 6: Production of 2-(3-(difluoromethyl)-1H-indazol-1-yl)-N-(trans-4-(3-(methylsulfonyl)propoxy)cyclohexyl)pyrimidine-5-carboxylic acid amide

[0826]

[0827] Step 6-1: 3-(difluoromethyl)-1H-indazole

[0828]

[0829] To a solution of 1H-indazole-3-carbaldehyde (1.5 g) in dichloromethane (10 mL), N,N-diethylaminosulfur trifluoride (2.71 mL) was added under ice cooling. The mixture was gradually warmed to room temperature and stirred for 5 hours. Saturated aqueous sodium bicarbonate was added dropwise to the reaction mixture under ice cooling, followed by the addition of ethyl acetate. The layers were separated, and the aqueous layer was extracted once with ethyl acetate. The combined organic layers were washed with saturated brine, dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 95 / 5 to 80 / 20) and silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 85 / 15) to give the title compound (343 mg). The title compound (673 mg) was obtained from the starting material, 1H-indazole-3-carboxaldehyde, using a similar procedure. 1 H-NMR (DMSO-D6) δ: 13.59 (1H, s), 7.84 (1H, d, J = 8.2 Hz), 7.64 (1H, d, J = 9.0 Hz), 7.46 (1H, t, J = 7.5 Hz), 7.34 (1H, t, J = 53.9 Hz), 7.25 (1H, t, J = 7.5 Hz).

[0830] Step 6-2: ethyl 2-(3-(difluoromethyl)-1H-indazol-1-yl)pyrimidine-5-carboxylate

[0831]

[0832] A suspension of 3-(difluoromethyl)-1H-indazole (0.95 g), ethyl 2-chloropyrimidinecarboxylate (1.1 g), and cesium carbonate (2.2 g) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hours. Water was added to the reaction mixture under ice cooling, and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (1.73 g). 1H-NMR (DMSO-D6) δ: 9.38 (2H, s), 8.81 (1H, d, J = 8.6 Hz), 8.01 (1H, d, J = 8.1 Hz), 7.77 (1H, t, J = 8.4 Hz), 7.57 (1H, t, J = 54.0 Hz), 7.54 (1H, t, J = 7.6 Hz), 4.42 (2H, q, J = 7.1 Hz), 1.38 (3H, t, J = 7.1 Hz).

[0833] Step 6-3: 2-(3-(difluoromethyl)-1H-indazol-1-yl)pyrimidine-5-carboxylic acid

[0834]

[0835] To a solution of ethyl 2-(3-(difluoromethyl)-1H-indazol-1-yl)pyrimidine-5-carboxylate (1.73 g) in tetrahydrofuran (10 mL), 2M aqueous sodium hydroxide (5.03 mL) was added under ice cooling, and the mixture was gradually warmed to room temperature and stirred for 6 hours. To this reaction mixture, 2M hydrochloric acid (5.0 mL) was added under ice cooling, and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (1.45 g). 1 H-NMR (DMSO-D6) δ: 13.80 (1H, br s), 9.35 (2H, s), 8.82 (1H, d, J = 8.5 Hz), 8.01 (1H, d, J = 7.9 Hz), 7.78-7.74 (1H, m), 7.56 (1H, t, J = 54.0 Hz), 7.56-7.51 (1H, m).

[0836] Step 6-4: (E)-3-((trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)acrylate methyl

[0837]

[0838] To a suspension of tert-butyl (trans-4-hydroxycyclohexyl)carbamate (5.0 g) and 1,4-diazabicyclo[2.2.2]octane (0.261 g) in tetrahydrofuran (50 mL) was added dropwise methyl propargylate (1.935 mL) at room temperature, stirred for 1 hour, and then allowed to stand overnight. Ethyl acetate was added to the reaction mixture at room temperature, and the organic layer was washed sequentially twice with saturated aqueous ammonium chloride and once with saturated brine. The organic layer was dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure to give a crude product (7.42 g) containing the title compound.

[0839] Step 6-5: methyl 3-((trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)propionate

[0840]

[0841] To a solution of the crude product (2.0 g) containing methyl (E)-3-((trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)acrylate in methanol (9.37 mL) was added 10% palladium-carbon (187 mg) at room temperature. The mixture was stirred at room temperature under a hydrogen atmosphere at 1 atmosphere pressure for 3 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give a crude product (1.71 g) containing the title compound.

[0842] Step 6-6: 3-((trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)propionic acid

[0843]

[0844] To a solution of the crude product (0.974 mg) containing methyl 3-((trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)propionate in methanol (9.14 mL) was added 4 M aqueous sodium hydroxide solution (1.13 mL) at room temperature, stirred for 45 minutes, and allowed to stand overnight. The reaction mixture was concentrated under reduced pressure. Water and ethyl acetate were added to the residue, and the layers were separated. To the aqueous layer, 2 M hydrochloric acid (2.4 mL) was added, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine, dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure to give the title compound (0.94 g). 1 H-NMR (DMSO-D6) δ: 12.04 (1H, br s), 6.69 (1H, d, J = 7.4 Hz), 3.58 (2H, t, J = 6.4 Hz), 3.22-3.10 (2H, m), 2.39 (2H, t, J = 6.4 Hz), 1.94-1.85 (2H, m), 1.79-1.70 (2H, m), 1.37 (9H, s), 1.24-1.07 (4H, m).

[0845] Step 6-7: tert-butyl (trans-4-(3-hydroxypropoxy)cyclohexyl)carbamate

[0846]

[0847] To a solution of 3-((trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)propionic acid (0.94 g) and triethylamine (0.384 mL) in tetrahydrofuran (7.548 mL) was added isobutyl chloroformate (0.362 mL) under ice cooling, and the mixture was stirred for 30 minutes. The reaction mixture was filtered to remove insoluble matter. To the filtrate was added dropwise sodium borohydride (0.298 g) / 0.05 M aqueous sodium hydroxide solution (0.3774 mL) under ice cooling, and the mixture was stirred for 2 hours. The temperature was gradually returned to room temperature, and the mixture was stirred for 90 minutes. Saturated aqueous sodium bicarbonate, water, and ethyl acetate were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed successively with water and saturated brine, dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure to give the title compound (0.774 g). 1 H-NMR (DMSO-D6) δ: 6.68 (1H, d, J = 7.9 Hz), 4.32 (1H, t, J = 5.1 Hz), 3.46-3.38 (4H, m), 3.23-3.05 (2H, m), 1.95-1.86 (2H, m), 1.80-1.70 (2H, m), 1.65-1.55 (2H, m), 1.37 (9H, s), 1.22-1.04 (4H, m).

[0848] Step 6-8: 3-((trans-4-((tert-butyl-butoxycarbonyl)amino)cyclohexyl)oxy)propyl methanesulfonate

[0849]

[0850] To a solution of tert-butyl (trans-4-(3-hydroxypropoxy)cyclohexyl)carbamate (370 mg) and triethylamine (0.238 mL) in tetrahydrofuran (1.55 mL), methanesulfonic anhydride (297 mg) was added under ice cooling, and the mixture was allowed to warm to room temperature and stirred for 90 minutes. Water and ethyl acetate were added to the reaction mixture at room temperature, and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure to give the title compound (420 mg). 1 H-NMR (DMSO-D6) δ: 6.70 (1H, d, J = 7.2 Hz), 4.23 (2H, t, J = 6.4 Hz), 3.46 (2H, t, J = 6.2 Hz), 3.23-3.06 (2H, m), 3.15 (3H, s), 1.97-1.81 (4H, m), 1.80-1.69 (2H, m), 1.37 (9H, s), 1.23-1.05 (4H, m).

[0851] Step 6-9: tert-butyl (trans-4-(3-(methylsulfonyl)propoxy)cyclohexyl)carbamate

[0852]

[0853] A suspension of 3-((trans-4-((tert-butyl-butoxycarbonyl)amino)cyclohexyl)oxy)propyl methanesulfonate (420 mg), sodium methanesulfinate (242 mg), and sodium iodide (186 mg) in N,N-dimethylformamide (1.987 mL) was stirred at 70°C for 1 hour and then at 100°C for 3 hours. Water was added to this reaction mixture at room temperature, and the precipitated solid was collected by filtration and dried under reduced pressure at 60°C to obtain the title compound (220 mg). Steps 6-8 and 6-9 were performed separately to obtain the title compound (47.2 mg). 1H-NMR (DMSO-D6) δ: 6.70 (1H, d, J = 7.5 Hz), 3.47 (2H, t, J = 6.4 Hz), 3.24-3.06 (4H, m), 2.97 (3H, s), 1.98-1.81 (4H, m), 1.81-1.67 (2H, m), 1.37 (9H, s), 1.23-1.07 (4H, m).

[0854] Step 6-10: trans-4-(3-(methylsulfonyl)propoxy)cyclohexan-1-amine monohydrochloride

[0855]

[0856] To a suspension of tert-butyl (trans-4-(3-(methylsulfonyl)propoxy)cyclohexyl)carbamate (253 mg) in ethyl acetate (1.265 mL) was added 4 M hydrogen chloride / ethyl acetate solution (1.265 mL) at room temperature, the mixture was stirred for 2 hours, and then allowed to stand overnight. The precipitated solid was collected by filtration, washed with ethyl acetate, and dried under reduced pressure at 60° C. for 1 hour to give the title compound (202 mg). 1 H-NMR (DMSO-D6) δ: 7.87 (3H, br s), 3.50 (2H, t, J = 6.2 Hz), 3.24-3.15 (1H, m), 3.14-3.07 (2H, m), 3.03-2.91 (1H, m), 2.97 (3H, s), 2.04-1.82 (6H, m), 1.40-1.27 (2H, m), 1.26-1.13 (2H, m).

[0857] Step 6-11: 2-(3-(difluoromethyl)-1H-indazol-1-yl)-N-(trans-4-(3-(methylsulfonyl)propoxy)cyclohexyl)pyrimidine-5-carboxylic acid amide

[0858]

[0859] To a suspension of 2-(3-(difluoromethyl)-1H-indazol-1-yl)pyrimidine-5-carboxylic acid (30 mg), trans-4-(3-(methylsulfonyl)propoxy)cyclohexane-1-amine monohydrochloride (33.7 mg), and triethylamine (0.0261 mL) in N,N-dimethylformamide (0.5 mL) was added 1-hydroxy-7-azabenzotriazole (4.22 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (29.7 mg) at room temperature and stirred overnight. Water was added to this reaction mixture at room temperature, and the precipitated solid was collected by filtration and dried under reduced pressure. This solid was dissolved in dimethyl sulfoxide and purified by reverse-phase silica gel column chromatography (eluent: water / acetonitrile = 95 / 5 to 0 / 100) to give the title compound (38.5 mg). 1 H-NMR (DMSO-D6) δ: 9.30 (2H, s), 8.78 (1H, d, J = 8.6 Hz), 8.63 (1H, d, J = 7.5 Hz), 8.00 (1H, d, J = 8.1 Hz), 7.75 (1H, t, J = 8.1 Hz), 7.56 (1H, t, J = 53.9 Hz), 7.52 (1H, t, J = 7.5 Hz), 3.86-3.76 (1H, m), 3.53 (2H, t, J = 6.2 Hz), 3.30-3.25 (1H, m), 3.16-3.11 (2H, m), 2.99 (3H, s), 2.07-2.02 (2H, m), 1.97-1.87 (4H, m), 1.46-1.36 (2H, m), 1.33-1.23 (2H, m). MS(M+H):508 MS(MH):506

[0860] [Production Example 7] Example 7: Production of 2-(6-fluoro-3-methyl-1H-indazol-1-yl)-N-(3-(2-hydroxypropan-2-yl)bicyclo[1.1.1]pentan-1-yl)pyrimidine-5-carboxylic acid amide

[0861]

[0862] Step 7-1: ethyl 2-(6-fluoro-3-methyl-1H-indazol-1-yl)pyrimidine-5-carboxylate

[0863]

[0864] A suspension of 6-fluoro-3-methyl-1H-indazole (1.5 g), ethyl 2-chloropyrimidinecarboxylate (2.05 g), and cesium carbonate (6.51 g) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 hours and then allowed to stand overnight. Water was added to the reaction mixture at room temperature, and the precipitated solid was collected by filtration and dried under reduced pressure. The solid was dissolved in chloroform and purified by silica gel column chromatography (eluent: chloroform) to give the title compound (2.65 g). 1 H-NMR (DMSO-D6) δ: 9.30 (2H, s), 8.44 (1H, dd, J = 10.4, 2.1 Hz), 7.95 (1H, dd, J = 8.8, 5.3 Hz), 7.31 (1H, td, J = 8.9, 2.2 Hz), 4.40 (2H, q, J = 7.1 Hz), 2.61 (3H, s), 1.37 (3H, t, J = 7.1 Hz).

[0865] Step 7-2: 2-(6-fluoro-3-methyl-1H-indazol-1-yl)pyrimidine-5-carboxylic acid

[0866]

[0867] To a solution of ethyl 2-(6-fluoro-3-methyl-1H-indazol-1-yl)pyrimidine-5-carboxylate (2.65 g) in tetrahydrofuran (53 mL), 2M aqueous sodium hydroxide (13.24 mL) was added at room temperature, stirred for 3 hours, and allowed to stand overnight. To this reaction mixture, 2M aqueous sodium hydroxide (4.41 mL) was added at room temperature and stirred for 1 hour. To this reaction mixture, 2M hydrochloric acid (17.65 mL) was added at room temperature, stirred for 30 minutes, then allowed to stand overnight, and concentrated under reduced pressure. Water was added to the residue, stirred for 30 minutes, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (2.38 g). 1H-NMR (DMSO-D6) δ: 13.68 (1H, br s), 9.27 (2H, s), 8.44 (1H, dd, J = 10.5, 2.2 Hz), 7.95 (1H, dd, J = 9.0, 5.2 Hz), 7.31 (1H, td, J = 8.6, 2.0 Hz), 2.61 (3H, s).

[0868] Step 7-3: tert-butyl (3-(2-hydroxypropan-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

[0869]

[0870] To a solution of methyl 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylate (2.0 g) in tetrahydrofuran (10 mL), a 1.02 M solution of methylmagnesium bromide in tetrahydrofuran (33 mL) was added under ice cooling. The mixture was stirred at the same temperature for 1 hour, then returned to room temperature and stirred for 2 hours. To this reaction mixture, a saturated aqueous ammonium chloride solution (40 mL) was added under ice cooling. Ethyl acetate (40 mL) was added to the reaction mixture at room temperature. The layers were separated, and the aqueous layer was extracted once with ethyl acetate (10 mL). The combined organic layers were washed with saturated brine, dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure to give the title compound (2.0 g). 1 H-NMR (DMSO-D6) δ: 7.34 (1H, br s), 4.07 (1H, br s), 1.70 (6H, s), 1.37 (9H, s), 1.02 (6H, s).

[0871] Step 7-4: 2-(3-aminobicyclo[1.1.1]pentan-1-yl)propan-2-ol monohydrochloride

[0872]

[0873] To a solution of tert-butyl (3-(2-hydroxypropan-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (414 mg) in ethyl acetate (4.0 mL) was added 4 M hydrogen chloride / ethyl acetate solution (4.0 mL) at room temperature, and the mixture was stirred overnight. Ethyl acetate (10 mL) was added to the reaction mixture at room temperature, and the precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (271 mg). 1 H-NMR (DMSO-D6) δ: 8.79 (3H, br s), 4.21 (1H, br s), 1.80 (6H, s), 1.05 (6H, s).

[0874] Step 7-5: 2-(6-fluoro-3-methyl-1H-indazol-1-yl)-N-(3-(2-hydroxypropan-2-yl)bicyclo[1.1.1]pentan-1-yl)pyrimidine-5-carboxylic acid amide

[0875]

[0876] To a suspension of 2-(6-fluoro-3-methyl-1H-indazol-1-yl)pyrimidine-5-carboxylic acid (30 mg), 2-(3-aminobicyclo[1.1.1]pentan-1-yl)propan-2-ol monohydrochloride (28 mg), 1-hydroxy-7-azabenzotriazole (16 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (36 mg) in N,N-dimethylformamide (1.0 mL), triethylamine (0.030 mL) was added and stirred overnight. To this reaction mixture, saturated aqueous sodium bicarbonate (2.0 mL) and water (3.0 mL) were added at room temperature. The precipitate was collected by filtration and dried under reduced pressure to give the title compound (42.7 mg). 1H-NMR (DMSO-D6) δ: 9.24 (1H, br s), 9.22 (2H, s), 8.39 (1H, dd, J = 10.3, 2.2 Hz), 7.94 (1H, dd, J = 8.8, 5.3 Hz), 7.32-7.26 (1H, m), 4.20 (1H, s), 2.61 (3H, s), 1.96 (6H, s), 1.09 (6H, s). MS(M+H):396 MS(MH):394

[0877] [Preparation Example 8] Example 8: Preparation of 2-(3-(difluoromethyl)-1H-indazol-1-yl)-N-(trans-4-(5-(methoxymethyl)-1,3,4-oxadiazol-2-yl)cyclohexyl)pyrimidine-5-carboxylic acid amide

[0878]

[0879] Step 8-1: 3-(difluoromethyl)-1H-indazole

[0880]

[0881] To a solution of 1H-indazole-3-carbaldehyde (1.5 g) in dichloromethane (10 mL), N,N-diethylaminosulfur trifluoride (2.71 mL) was added under ice cooling. The mixture was gradually warmed to room temperature and stirred for 5 hours. Saturated aqueous sodium bicarbonate was added dropwise to the reaction mixture under ice cooling, followed by the addition of ethyl acetate. The layers were separated, and the aqueous layer was extracted once with ethyl acetate. The combined organic layers were washed with saturated brine, dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 95 / 5 to 80 / 20) and silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 85 / 15) to give the title compound (343 mg). The title compound (673 mg) was obtained from the starting material, 1H-indazole-3-carboxaldehyde, using a similar procedure. 1H-NMR (DMSO-D6) δ: 13.59 (1H, s), 7.84 (1H, d, J = 8.2 Hz), 7.64 (1H, d, J = 9.0 Hz), 7.46 (1H, t, J = 7.5 Hz), 7.34 (1H, t, J = 53.9 Hz), 7.25 (1H, t, J = 7.5 Hz).

[0882] Step 8-2: ethyl 2-(3-(difluoromethyl)-1H-indazol-1-yl)pyrimidine-5-carboxylate

[0883]

[0884] A suspension of 3-(difluoromethyl)-1H-indazole (0.95 g), ethyl 2-chloropyrimidinecarboxylate (1.1 g), and cesium carbonate (2.2 g) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hours. Water was added to the reaction mixture at room temperature, and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (1.73 g). 1 H-NMR (DMSO-D6) δ: 9.38 (2H, s), 8.81 (1H, d, J = 8.6 Hz), 8.01 (1H, d, J = 8.1 Hz), 7.77 (1H, t, J = 8.4 Hz), 7.57 (1H, t, J = 54.0 Hz), 7.54 (1H, t, J = 7.6 Hz), 4.42 (2H, q, J = 7.1 Hz), 1.38 (3H, t, J = 7.1 Hz).

[0885] Step 8-3: 2-(3-(difluoromethyl)-1H-indazol-1-yl)pyrimidine-5-carboxylic acid

[0886]

[0887] To a solution of ethyl 2-(3-(difluoromethyl)-1H-indazol-1-yl)pyrimidine-5-carboxylate (1.73 g) in tetrahydrofuran (10 mL), 2M aqueous sodium hydroxide (5.03 mL) was added under ice cooling, and the mixture was gradually warmed to room temperature and stirred for 6 hours. 2M hydrochloric acid (5.0 mL) was added to the reaction mixture at room temperature, and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (1.45 g). 1 H-NMR (DMSO-D6) δ: 13.80 (1H, br s), 9.35 (2H, s), 8.82 (1H, d, J = 8.5 Hz), 8.01 (1H, d, J = 7.9 Hz), 7.78-7.74 (1H, m), 7.56 (1H, t, J = 54.0 Hz), 7.56-7.51 (1H, m).

[0888] Step 8-4: tert-butyl (trans-4-(2-(2-methoxyacetyl)hydrazine-1-carbonyl)cyclohexyl)carbamate

[0889]

[0890] To trans-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (800 mg), methoxyacetic hydrazide (411 mg), 1-hydroxy-7-azabenzotriazole (134 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (819 mg) were added N,N-dimethylformamide (10 mL) and triethylamine (732 mg) in a water bath, and the mixture was stirred for 10 minutes and then at room temperature overnight. Water (20 mL) was added to this reaction mixture at room temperature, and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (650 mg). 1H-NMR (DMSO-D6) δ: 9.64 (2H, d, J = 7.5 Hz), 6.71 (1H, d, J = 7.5 Hz), 3.87 (2H, s), 3.31 (3H, s), 3.22-3.09 (1H, m), 2.14-2.01 (1H, m), 1.85-1.68 (4H, br m), 1.46-1.30 (11H, m), 1.21-1.09 (2H, m).

[0891] Step 8-5: tert-butyl (trans-4-(5-(methoxymethyl)-1,3,4-oxadiazol-2-yl)cyclohexyl)carbamate

[0892]

[0893] To a solution of tert-butyl (trans-4-(2-(2-methoxyacetyl)hydrazine-1-carbonyl)cyclohexyl)carbamate (650 mg), hexachloroethane (701 mg), and diisopropylethylamine (1.054 mL) in acetonitrile (12 mL), triphenylphosphine (725 mg) was added in two portions under ice cooling. The mixture was stirred for 15 minutes, then at room temperature for 30 minutes, and then at 70°C for 3 hours. To this reaction mixture, hexachloroethane (350 mg), diisopropylethylamine (0.5 mL), and triphenylphosphine (370 mg) were added in a water bath, and the mixture was stirred at 80°C for 2 hours. Toluene and water were added to the reaction mixture in a water bath, and the layers were separated. The organic layer was washed successively with 5 wt% aqueous potassium hydrogen sulfate solution and saturated brine, and then concentrated under reduced pressure. Ethyl acetate was added to the residue at room temperature, and the insoluble matter was removed by filtration. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate=34 / 66) to give a crude product (480 mg) containing the title compound.

[0894] Step 8-6: trans-4-(5-(methoxymethyl)-1,3,4-oxadiazol-2-yl)cyclohexan-1-amine

[0895]

[0896] To a solution of the crude product (480 mg) containing tert-butyl (trans-4-(5-(methoxymethyl)-1,3,4-oxadiazol-2-yl)cyclohexyl)carbamate in ethyl acetate (1.0 mL) was added trifluoroacetic acid (1.5 mL) at room temperature and stirred for 3 hours. Trifluoroacetic acid (5.0 mL) was added to this reaction mixture at room temperature and stirred at 40°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and Wakogel® 50NH2 (1.5 g) were added to the residue. The mixture was stirred for 30 minutes, filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified using Bond Elut SCX (Agilent technologies) (developing solvent: methanol to 1M ammonia / methanol solution) to give a crude product (190 mg) containing the title compound.

[0897] Step 8-7: 2-(3-(difluoromethyl)-1H-indazol-1-yl)-N-(trans-4-(5-(methoxymethyl)-1,3,4-oxadiazol-2-yl)cyclohexyl)pyrimidine-5-carboxylic acid amide

[0898]

[0899] A suspension of the crude product (51 mg) containing trans-4-(5-(methoxymethyl)-1,3,4-oxadiazol-2-yl)cyclohexan-1-amine, 2-(3-(difluoromethyl)-1H-indazol-1-yl)pyrimidine-5-carboxylic acid (50 mg), triethylamine (52.3 mg), 1-hydroxy-7-azabenzotriazole (25.8 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (49.5 mg) in N,N-dimethylformamide (1.2 mL) was stirred overnight at room temperature. Water was added to this reaction mixture at room temperature, and the precipitated solid was collected by filtration and dried under reduced pressure. A solution of n-hexane / ethyl acetate (n-hexane / ethyl acetate = 1 / 1) was added to this solid, and the mixture was purified as a slurry. The solid was collected by filtration and dried under reduced pressure. This solid was dissolved in methanol and purified by amino silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 97 / 3) to give a crude product containing the title compound. Ethyl acetate was added to the crude product containing the title compound, followed by slurry purification. The solid was filtered and dried under reduced pressure to give the title compound (22 mg). 1 H-NMR (DMSO-D6) δ: 9.33 (2H, s), 8.79 (1H, d, J = 5.1 Hz), 8.74 (1H, d, J = 7.6 Hz), 8.01 (1H, d, J = 8.1 Hz), 7.78-7.74 (1H, m), 7.57 (1H, t, J = 53.0 Hz), 7.56-7.49 (1H, m), 4.63 (2H, s), 3.95-3.85 (1H, m), 3.35 (3H, s), 3.06-2.96 (1H, m), 2.24-2.22 (2H, br m), 2.18-2.16 (2H, br m), 1.75-1.46 (4H, m). MS(M+H):484 MS(MH):482

[0900] [Production Example 9] Example 9: 2-(3-(difluoromethyl)-1H-pyrazolo[3,4-c]pyridin-1-yl)-N-(trans-4-(2-hydroxypropan-2-yl)cyclohexyl)pyrimidine-5-carboxylic acid amide

[0901]

[0902] Step 9-1: 3-iodo-1H-pyrazolo[3,4-c]pyridine

[0903]

[0904] To a suspension of 1H-pyrazolo[3,4-c]pyridine (4.95 g) and potassium carbonate (17.23 g) in N,N-dimethylformamide (49.5 mL), iodine (10.55 g) was added under ice cooling and stirred at room temperature for 3 hours. The reaction mixture was added to 10% by weight aqueous sodium thiosulfate solution (300 mL) at room temperature and stirred for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (8.66 g). 1 H-NMR (DMSO-D6) δ: 14.06 (1H, s), 9.05 (1H, s), 8.30 (1H, d, J = 6.0 Hz), 7.45 (1H, d, J = 6.0 Hz).

[0905] Step 9-2: 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine

[0906]

[0907] To a suspension of sodium hydride (0.612 g, 60 wt% oil dispersion) in N,N-dimethylformamide (10 mL), a solution of 3-iodo-1H-pyrazolo[3,4-c]pyridine (3.0 g) in N,N-dimethylformamide (30 mL) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1 hour. To this reaction mixture, 2-(chloromethoxy)ethyltrimethylsilane (2.7 mL) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture and ethyl acetate were added to water (60 mL) at room temperature, and the layers were separated. The aqueous layer was extracted once with ethyl acetate. The combined organic layer was washed successively with water and saturated brine, dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 50 / 50) to give the title compound (2.55 g).1 H-NMR (DMSO-D6) δ: 9.26 (1H, s), 8.38 (1H, d, J = 6.0 Hz), 7.49 (1H, d, J = 6.0 Hz), 5.88 (2H, s), 3.54 (2H, t, J = 7.9 Hz), 0.80 (2H, t, J = 7.9 Hz), -0.12 (9H, s).

[0908] Step 9-3: 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine-3-carbaldehyde

[0909]

[0910] To a solution of 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (1.1 g) in tetrahydrofuran (20 mL), a 2.0 M solution of isopropylmagnesium chloride (2.198 mL) was added dropwise under ice-salt bath cooling, and the mixture was stirred for 1 hour. N,N-Dimethylformamide (0.908 mL) was added at the same temperature, and the mixture was stirred for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture at the same temperature. Ethyl acetate was added at room temperature, and the layers were separated. The organic layer was washed successively with water and saturated brine, dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 0 / 100) to give the title compound (0.26 g). 1 H-NMR (DMSO-D6) δ: 10.42 (1H, s), 9.44 (1H, s), 8.42 (1H, d, J = 6.0 Hz), 8.05 (1H, d, J = 6.0 Hz), 6.22 (2H, s), 3.64 (2H, t, J = 7.9 Hz), 0.85 (2H, t, J = 7.9 Hz), -0.10 (9H, s).

[0911] Step 9-4: 3-(difluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine

[0912]

[0913] To a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine-3-carbaldehyde (260 mg) in dichloromethane (5.0 mL), Deoxo-Fluor® (0.518 mL) was added dropwise under ice-cooling, and the mixture was stirred at the same temperature for 1 hour and then at room temperature for 4 hours. Saturated aqueous sodium bicarbonate was slowly added to the reaction mixture under ice-cooling. Ethyl acetate was added to the reaction mixture at room temperature, and the organic layer was washed successively with water and saturated brine. The organic layer was dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 90 / 10 to 0 / 100) to obtain the title compound (260 mg). 1 H-NMR (DMSO-D6) δ: 9.34 (1H, s), 8.25 (1H, d, J = 5.4 Hz), 7.75 (1H, d, J = 5.4 Hz), 7.75 (1H, t, J = 52.5 Hz), 5.99 (2H, s), 3.59 (2H, t, J = 7.9 Hz), 0.86 (2H, t, J = 7.9 Hz), -0.08 (9H, s).

[0914] Step 9-5: 3-(difluoromethyl)-1H-pyrazolo[3,4-c]pyridine

[0915]

[0916] To a solution of 3-(difluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (260 mg) in dichloromethane (1.5 mL) was added trifluoroacetic acid (1.5 mL) at room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was added chloroform and triethylamine (0.182 mL). The mixture was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate (containing 5% 2M ammonia / methanol solution) = 90 / 10 to 0 / 100) to give a crude product (83 mg) containing the title compound.

[0917] Step 9-6: ethyl 2-(3-(difluoromethyl)-1H-pyrazolo[3,4-c]pyridin-1-yl)pyrimidine-5-carboxylate

[0918]

[0919] A suspension of the crude product (54 mg) containing 3-(difluoromethyl)-1H-pyrazolo[3,4-c]pyridine, ethyl 2-chloropyrimidinecarboxylate (59.6 mg), and cesium carbonate (156 mg) in N,N-dimethylformamide (0.6 mL) was stirred at room temperature for 1 hour. Water was added to the reaction mixture at room temperature, and the precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure. The solid was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20 to 0 / 100) to give the title compound (70 mg). 1 H-NMR (DMSO-D6) δ: 10.13 (1H, d, J = 1.2 Hz), 9.42 (2H, s), 8.63 (1H, d, J = 5.4 Hz), 8.00 (1H, d, J = 5.4 Hz), 7.63 (1H, t, J = 53.1 Hz), 4.42 (2H, q, J = 7.1 Hz), 1.37 (3H, t, J = 7.1 Hz).

[0920] Step 9-7: 2-(3-(difluoromethyl)-1H-pyrazolo[3,4-c]pyridin-1-yl)pyrimidine-5-carboxylic acid

[0921]

[0922] To a solution of ethyl 2-(3-(difluoromethyl)-1H-pyrazolo[3,4-c]pyridin-1-yl)pyrimidine-5-carboxylate (70 mg) in tetrahydrofuran (1.0 mL) was added 2 M aqueous sodium hydroxide (0.329 mL) at room temperature and stirred overnight. 1 M hydrochloric acid (0.658 mL) was added to this reaction mixture at room temperature and stirred for 1 hour. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (33 mg). 1H-NMR (DMSO-D6) δ: 13.88 (1H, br s), 10.15 (1H, s), 9.41 (2H, s), 8.64 (1H, d, J = 5.4 Hz), 8.01 (1H, d, J = 5.4 Hz), 7.64 (1H, t, J = 53.1 Hz).

[0923] Step 9-8: 2-(3-(difluoromethyl)-1H-pyrazolo[3,4-c]pyridin-1-yl)-N-(trans-4-(2-hydroxypropan-2-yl)cyclohexyl)pyrimidine-5-carboxylic acid amide

[0924]

[0925] To a suspension of 2-(3-(difluoromethyl)-1H-pyrazolo[3,4-c]pyridin-1-yl)pyrimidine-5-carboxylic acid (33 mg) and 2-(trans-4-aminocyclohexyl)propan-2-ol (26.7 mg) in N,N-dimethylformamide (0.33 mL) was added triethylamine (0.0237 mL), 1-hydroxy-7-azabenzotriazole (15.42 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (26.1 mg) at room temperature. Water (2.0 mL) and saturated aqueous sodium bicarbonate (1.0 mL) were added to the reaction mixture at room temperature. After stirring for 1 hour, the precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (42 mg). 1 H-NMR (DMSO-D6) δ: 10.12 (1H, s), 9.35 (2H, s), 8.67 (1H, d, J = 7.5 Hz), 8.62 (1H, d, J = 5.4 Hz), 8.00 (1H, d, J = 5.4 Hz), 7.64 (1H, MS(M+H):431 MS(MH):429

[0926] [Production Example 10] Example 10: 2-(3-(difluoromethyl)-6-fluoro-1H-indazol-1-yl)-N-(3-(2-hydroxypropan-2-yl)bicyclo[1.1.1]pentan-1-yl)pyrimidine-5-carboxylic acid amide

[0927]

[0928] Step 10-1: 3-(difluoromethyl)-6-fluoro-1H-indazole

[0929]

[0930] To a suspension of 6-fluoro-1H-indazole-3-carbaldehyde (500 mg) in dichloromethane (15 mL), N,N-diethylaminosulfur trifluoride (0.805 mL) was added under ice cooling, and the mixture was allowed to warm to room temperature and stirred for 4 hours. To this reaction mixture, saturated aqueous sodium bicarbonate (10 mL) and water (5 mL) were added under ice cooling. Chloroform was added to this reaction mixture at room temperature, and the layers were separated. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 92 / 8 to 34 / 66) to give a crude product (205 mg) containing the title compound.

[0931] Step 10-2: ethyl 2-(3-(difluoromethyl)-6-fluoro-1H-indazol-1-yl)pyrimidine-5-carboxylate

[0932]

[0933] A suspension of the crude product (205 mg) containing 3-(difluoromethyl)-6-fluoro-1H-indazole, ethyl 2-chloropyrimidinecarboxylate (206 mg), and cesium carbonate (456 mg) in N,N-dimethylformamide (4.0 mL) was stirred at 60°C for 5 hours. Water (25 mL) was added to the reaction mixture at room temperature, and the precipitated solid was collected by filtration and dried under reduced pressure. This solid was dissolved in chloroform and purified twice by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 92 / 8 to 34 / 66) to give the title compound (275 mg). 1H-NMR (DMSO-D6) δ: 9.39 (2H, s), 8.57 (1H, dd, J = 10.4, 2.3 Hz), 8.05 (1H, dd, J = 8.8, 5.3 Hz), 7.57 (1H, t, J = 53.4 Hz), 7.48-7.42 (1H, m), 4.42 (2H, q, J = 7.2 Hz), 1.38 (3H, t, J = 7.2 Hz).

[0934] Step 10-3: 2-(3-(difluoromethyl)-6-fluoro-1H-indazol-1-yl)pyrimidine-5-carboxylic acid

[0935]

[0936] To a suspension of ethyl 2-(3-(difluoromethyl)-6-fluoro-1H-indazol-1-yl)pyrimidine-5-carboxylate (275 mg) in tetrahydrofuran (10 mL) was added 2M aqueous sodium hydroxide (0.85 mL) at room temperature and stirred for 8 hours. To this reaction mixture, 1M hydrochloric acid (1.7 mL) and water (15 mL) were added at room temperature and allowed to stand overnight. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (210 mg). 1 H-NMR (DMSO-D6) δ: 13.84 (1H, br s), 9.36 (2H, s), 8.56 (1H, dd, J = 10.2, 2.3 Hz), 8.04 (1H, dd, J = 8.8, 5.3 Hz), 7.56 (1H, t, J = 53.2 Hz), 7.47-7.42 (1H, m).

[0937] Step 10-4: tert-butyl (3-(2-hydroxypropan-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

[0938]

[0939] To a solution of methyl 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylate (2.0 g) in tetrahydrofuran (10 mL), a 1.02 M solution of methylmagnesium bromide in tetrahydrofuran (33 mL) was added under ice cooling. The mixture was stirred at the same temperature for 1 hour, then returned to room temperature and stirred for 2 hours. To this reaction mixture, a saturated aqueous ammonium chloride solution (40 mL) was added under ice cooling. Ethyl acetate (40 mL) was added to the reaction mixture at room temperature. The layers were separated, and the aqueous layer was extracted once with ethyl acetate (10 mL). The combined organic layers were washed with saturated brine, dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure to give the title compound (2.0 g). 1 H-NMR (DMSO-D6) δ: 7.34 (1H, br s), 4.07 (1H, br s), 1.70 (6H, s), 1.37 (9H, s), 1.02 (6H, s).

[0940] Step 10-5: 2-(3-aminobicyclo[1.1.1]pentan-1-yl)propan-2-ol monohydrochloride

[0941]

[0942] To a solution of tert-butyl (3-(2-hydroxypropan-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (414 mg) in ethyl acetate (4.0 mL) was added 4 M hydrogen chloride / ethyl acetate solution (4.0 mL) at room temperature, and the mixture was stirred overnight. Ethyl acetate (10 mL) was added to the reaction mixture at room temperature, and the precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (271 mg). 1 H-NMR (DMSO-D6) δ: 8.79 (3H, br s), 4.21 (1H, br s), 1.80 (6H, s), 1.05 (6H, s).

[0943] Step 10-6: 2-(3-(difluoromethyl)-6-fluoro-1H-indazol-1-yl)-N-(3-(2-hydroxypropan-2-yl)bicyclo[1.1.1]pentan-1-yl)pyrimidine-5-carboxylic acid amide

[0944]

[0945] To a suspension of 2-(3-(difluoromethyl)-6-fluoro-1H-indazol-1-yl)pyrimidine-5-carboxylic acid (62 mg), 2-(3-aminobicyclo[1.1.1]pentan-1-yl)propan-2-ol monohydrochloride (48 mg), 1-hydroxy-7-azabenzotriazole (31 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (49 mg) in N,N-dimethylformamide (1.0 mL) was added triethylamine (0.050 mL) and stirred overnight. To this reaction mixture, saturated aqueous sodium bicarbonate (1.0 mL) and water (12 mL) were added at room temperature. The precipitate was collected by filtration and dried under reduced pressure to give the title compound (74.5 mg). 1 H-NMR (DMSO-D6) δ: 9.33 (1H, br s), 9.30 (2H, s), 8.52 (1H, dd, J = 10.3, 2.2 Hz), 8.04 (1H, dd, J = 8.8, 5.3 Hz), 7.56 (1H, t, J = 53.2 Hz), 7.46-7.41 (1H, m), 4.21 (1H, s), 1.96 (6H, s), 1.09 (6H, s). MS(M+H):432 MS(MH):430

[0946] [Production Example 11] Example 229: Production of N-(trans-4-(1-hydroxy-2-methylpropoxy)cyclohexyl)-2-(3-methyl-1H-indazol-1-yl)pyrimidine-5-carboxylic acid amide

[0947]

[0948] Step 11-1: ethyl 2-{[trans-4-(dibenzylamino)cyclohexyl]oxy}-propionate

[0949]

[0950] A solution of ethyl 2-{[trans-4-(dibenzylamino)cyclohexyl]oxy}acetate (1.53 g), synthesized in the same manner as in Step 4-4 of Preparation 4, in tetrahydrofuran (15.3 mL) was added dropwise to a 1.13 M solution of lithium bis(trimethylsilyl)amide in n-hexane (7.81 mL) at −78°C and stirred at the same temperature for 20 minutes. Methyl iodide (1.003 mL) was added dropwise to the reaction mixture at the same temperature, and the mixture was stirred for 1 hour. The mixture was then allowed to stand overnight at room temperature. Water and ethyl acetate were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted once with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: n-hexane / ethyl acetate = 98 / 2 to 80 / 20) to give the title compound (422 mg). 1 H-NMR (DMSO-D6) δ: 7.33-7.26 (8H, m), 7.23-7.16 (2H, m), 4.13-4.00 (3H, m), 3.55 (4H, s), 3.25-3.15 (1H, m), 2.44-2.31 (1H, m), 2.07-1.88 (2H, m), 1.85-1.73 (2H, m), 1.46-1.30 (2H, m), 1.25-1.13 (6H, m), 1.10-0.88 (2H, m).

[0951] Step 11-2: ethyl 2-{[trans-4-(dibenzylamino)cyclohexyl]oxy}-2-methylpropionate

[0952]

[0953] A solution of ethyl 2-{[trans-4-(dibenzylamino)cyclohexyl]oxy}propionate (422 mg) in tetrahydrofuran (4.22 mL) was added dropwise to a 2.0 M solution of lithium diisopropylamide in tetrahydrofuran / n-heptane / ethylbenzene (1.174 mL) at −78°C and stirred at the same temperature for 30 minutes. Methyl iodide (0.267 mL) was added dropwise to the reaction mixture at the same temperature, followed by hexamethylphosphoric triamide (0.204 mL) and stirring for 40 minutes. The reaction mixture was allowed to warm to room temperature, stirred for 1 hour, and then allowed to stand overnight. Water and ethyl acetate were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted once with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: n-hexane / ethyl acetate = 98 / 2 to 78 / 22) to give the title compound (388 mg). 1 H-NMR (DMSO-D6) δ: 7.36-7.24 (8H, m), 7.23-7.16 (2H, m), 4.09 (2H, q, J = 7.2 Hz), 3.55 (4H, s), 3.27-3.20 (1H, m), 2.37-2.30 (1H, m), 1.95-1.84 (2H, m), 1.81-1.71 (2H, m), 1.50-1.35 (2H, m), 1.29 (6H, s), 1.19 (3H, t, J = 7.0 Hz), 1.11-0.97 (2H, m).

[0954] Step 11-3: 2-{[trans-4-(dibenzylamino)cyclohexyl]oxy}-2-methylpropan-1-ol

[0955]

[0956] To a suspension of lithium aluminum hydride (76 mg) in tetrahydrofuran (3.88 mL), a solution of ethyl 2-{[trans-4-(dibenzylamino)cyclohexyl]oxy}-2-methylpropionate (388 mg) in tetrahydrofuran (1.94 mL) was added dropwise under ice cooling, and the mixture was allowed to warm to room temperature, stirred for 1 hour, and then allowed to stand overnight. To this reaction mixture, water (0.076 mL), 4 M aqueous sodium hydroxide (0.076 mL), and water (0.228 mL) were added sequentially under ice cooling. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (329 mg). 1 H-NMR (DMSO-D6) δ: 7.36-7.25 (8H, m), 7.22-7.16 (2H, m), 4.45 (1H, t, J = 5.5 Hz), 3.55 (4H, s), 3.49-3.34 (1H, m), 3.16 (2H, d, J = 5.5 Hz), 2.39-2.30 (1H, m), 1.86-1.71 (4H, m), 1.51-1.39 (2H, m), 1.12-0.93 (8H, m).

[0957] Step 11-4: 2-((trans-4-aminocyclohexyl)oxy)-2-methylpropan-1-ol

[0958]

[0959] To a solution of 2-{[trans-4-(dibenzylamino)cyclohexyl]oxy}-2-methylpropan-1-ol (150 mg) in tetrahydrofuran / methanol (1.5 mL, tetrahydrofuran / methanol = 1 / 1) was added 20% palladium hydroxide on carbon (15 mg) at room temperature. The mixture was stirred overnight at room temperature under 1 atmosphere of hydrogen. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (68.8 mg). 1H-NMR (DMSO-D6) δ: 4.46 (1H, t, J = 5.1 Hz), 3.48-3.35 (2H, m), 3.17 (2H, d, J = 5.1 Hz), 2.25-1.91 (2H, m), 1.77-1.63 (4H, m), 1.25-0.96 (10H, m).

[0960] Step 11-5: N-(trans-4-(1-hydroxy-2-methylpropoxy)cyclohexyl)-2-(3-methyl-1H-indazol-1-yl)pyrimidine-5-carboxylic acid amide

[0961]

[0962] A suspension of 2-(3-methyl-1H-indazol-1-yl)pyrimidine-5-carboxylic acid (30 mg), 2-((trans-4-aminocyclohexyl)oxy)-2-methylpropan-1-ol (24.31 mg), 1-hydroxy-7-azabenzotriazole (4.82 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (33.9 mg) in N,N-dimethylformamide (0.6 mL) was stirred for 3 hours. Water (3.0 mL) was added to the reaction mixture at room temperature, and the precipitated solid was collected by filtration, washed with water, and dried at 70°C under reduced pressure to give a crude product (41.6 mg) containing the title compound. The crude product was purified by reverse-phase silica gel chromatography (developing solvent: water / acetonitrile = 95 / 5 to 0 / 100) to give the title compound (23.9 mg). 1H-NMR (DMSO-D6) δ: 9.21 (2H, s), 8.67 (1H, d, J = 8.3 Hz), 8.51 (1H, d, J = 7.4 Hz), 7.89 (1H, d, J = 7.6 Hz), 7.63 (1H, dd, J = 8.3, 7.5 Hz), 7.40 (1H, dd, J = 7.6, 7.5 Hz), 4.53 (1H, br s), 3.82-3.67 (1H, m), 3.58-3.45 (1H, m), 3.22 (2H, s), 2.62 (3H, s), 1.97-1.76 (4H, m), 1.51-1.22 (4H, m), 1.09 (6H, s). MS(M+H):424 MS(MH):422

[0963] [Preparation Example 12] Example 241: Preparation of 3-(trans-4-(2-(6-fluoro-3-methyl-1H-indazol-1-yl)pyrimidine-5-carboxamido)cyclohexyl)-3-methylbutyric acid

[0964]

[0965] Step 12-1: tert-butyl {trans-4-[methoxy(methyl)carbamoyl]cyclohexyl}carbamate

[0966]

[0967] Under a nitrogen atmosphere, a solution of trans-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid (25.0 g), N,O-dimethylhydroxylamine hydrochloride (13.1 g), and N,N-diisopropylethylamine (23.3 mL) in N,N-dimethylformamide (250 mL) was cooled with water and sequentially added in portions with 1-hydroxy-1H-benzotriazole monohydrate (20.5 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (25.7 g) and stirred for 7 days. Saturated aqueous sodium bicarbonate / water (250 mL, saturated aqueous sodium bicarbonate / water = 1 / 2) was added dropwise to the reaction mixture at room temperature and stirred. The precipitated solid was collected by filtration, washed with water (300 mL), and dried under reduced pressure to give the title compound (24.45 g). 1H-NMR (CDCl3) δ: 4.40-4.33 (1H, m), 3.69 (3H, s), 3.48-3.39 (1H, m), 3.17 (3H, s), 2.64-2.57 (1H, m), 2.11-2.07 (2H, m), 1.86-1.81 (2H, m), 1.67-1.57 (2H, m), 1.44 (9H, s), 1.14 (2H, ddd, J = 24.9, 12.7, 3.4 Hz).

[0968] Step 12-2: tert-butyl (trans-4-acetylcyclohexyl)carbamate

[0969]

[0970] Under an argon atmosphere, a 1.02 M tetrahydrofuran solution of methylmagnesium bromide (22.6 mL) was added to a solution of tert-butyl {trans-4-[methoxy(methyl)carbamoyl]cyclohexyl}carbamate (3.0 g) in tetrahydrofuran (20 mL) under ice-cooling, and the mixture was stirred for 3 hours. To this reaction mixture, saturated aqueous ammonium chloride (20 mL), water (10 mL), and ethyl acetate (30 mL) were added under ice-cooling, and the layers were separated. The aqueous layer was extracted once with ethyl acetate (20 mL). The combined organic layers were washed successively with water and saturated brine, dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure to give the title compound (2.464 g). 1 H-NMR (DMSO-D6) δ: 6.72 (1H, d, J = 7.9 Hz), 3.17-3.07 (1H, m), 2.27-2.20 (1H, m), 2.08 (3H, s), 1.87-1.76 (4H, m), 1.37 (9H, s), 1.26-1.09 (4H, m).

[0971] Step 12-3: tert-butyl (trans-4-(1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)ethyl)cyclohexyl)carbamate

[0972]

[0973] A 1.0 M solution of titanium(IV) tetrachloride in dichloromethane (31 mL) was added to tetrahydrofuran (20 mL) under ice cooling. A solution of tert-butyl (trans-4-acetylcyclohexyl)carbamate (2.464 g) and 2,2-dimethyl-1,3-dioxane-4,6-dione (1.619 g) in tetrahydrofuran (28 mL) and pyridine (4.54 mL) were added to the reaction mixture under ice cooling, and the mixture was then warmed to room temperature and stirred overnight. Saturated aqueous ammonium chloride (30 mL), water (15 mL), and ethyl acetate (60 mL) were added to the reaction mixture at room temperature. After separation, the organic layer was washed sequentially with water and saturated brine and concentrated under reduced pressure. Ethyl acetate (3.0 mL), n-hexane (30 mL), and water (10 mL) were added to the residue, and the mixture was stirred for 1 hour. The solid was collected by filtration and dried under reduced pressure to give the title compound (2.254 g). 1 H-NMR (DMSO-D6) δ: 6.75 (1H, d, J = 8.1 Hz), 3.42-3.35 (1H, m), 3.32-3.22 (1H, m), 2.29 (3H, s), 1.85-1.81 (2H, m), 1.67 (6H, s), 1.60-1.49 (4H, m), 1.38 (9H, s), 1.24-1.14 (2H, m).

[0974] Step 12-4: tert-butyl (trans-4-(2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)propan-2-yl)cyclohexyl)carbamate

[0975]

[0976] To a solution of copper(I) bromide (2.64 g) in tetrahydrofuran (20 mL), a 1.0 M solution of methylmagnesium bromide in tetrahydrofuran (37 mL) was added under ice cooling. To this reaction mixture, a solution of tert-butyl (trans-4-(1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)ethyl)cyclohexyl)carbamate (2.254 g) in tetrahydrofuran (40 mL) was added under ice cooling and stirred for 90 minutes. The mixture was then warmed to room temperature and stirred for another 90 minutes. Saturated aqueous ammonium chloride (60 mL) and ethyl acetate (80 mL) were added to the reaction mixture at room temperature. After separation, the organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 92 / 8 to 34 / 66) to give the title compound (217 mg). 1 H-NMR (DMSO-D6) δ: 6.66 (1H, d, J = 7.9 Hz), 3.81 (1H, s), 3.12 (1H, m), 1.82-1.77 (2H, m), 1.73 (3H, s), 1.69-1.60 (3H, m), 1.65 (3H, s), 1.37 (9H, s), 1.13-1.02 (4H, m), 1.02 (6H, s).

[0977] Step 12-5: methyl 3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)-3-methylbutyrate

[0978]

[0979] A solution of tert-butyl (trans-4-(2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)propan-2-yl)cyclohexyl)carbamate (205 mg) in methanol (6.0 mL) was stirred at 80°C for 8 hours and allowed to stand overnight. The reaction mixture was concentrated under reduced pressure. Dimethyl sulfoxide (2.0 mL), water (0.2 mL), and sodium chloride (70 mg) were added to the residue, and the mixture was stirred at 140°C for 7 hours. Water (15 mL) and ethyl acetate (15 mL) were added to the reaction mixture at room temperature, and the layers were separated. The aqueous layer was extracted once with ethyl acetate (5.0 mL). The combined organic layers were washed successively with water and saturated brine and concentrated under reduced pressure to give a crude product (179 mg) containing the title compound.

[0980] Step 12-6: Methyl 3-(trans-4-aminocyclohexyl)-3-methylbutyrate monohydrochloride

[0981]

[0982] To a solution of the crude product (179 mg) containing methyl 3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)-3-methylbutyrate in ethyl acetate (2.0 mL) was added 4 M hydrogen chloride / ethyl acetate (2.0 mL) at room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure to give the title compound (131 mg). 1 H-NMR (DMSO-D6) δ: 7.95 (3H, br s), 3.57 (3H, s), 2.92-2.85 (1H, m), 2.21 (2H, s), 1.99-1.96 (2H, m), 1.77-1.74 (2H, m), 1.33-0.96 (5H, m), 0.90 (6H, s).

[0983] Step 12-7: methyl 3-(trans-4-(2-(6-fluoro-3-methyl-1H-indazol-1-yl)pyrimidine-5-carboxamido)cyclohexyl)-3-methylbutyrate

[0984]

[0985] 2-(6-fluoro-3-methyl-1H-indazol-1-yl)pyrimidine-5-carboxylic acid (50 mg), 3-(trans-4-aminocyclohexyl)-3-methylbutyrate methyl monohydrochloride (55 mg), 1-hydroxy-7-azabenzotriazole (25 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (55 mg) were synthesized in the same manner as in step 1-2 of Preparation Example 1. To a suspension of N,N-dimethylformamide (1.5 mL), triethylamine (0.040 mL) was added at room temperature and stirred overnight. Saturated aqueous sodium bicarbonate (2.0 mL) and water (3.0 mL) were added sequentially to this reaction mixture at room temperature, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain a crude product (77 mg) containing the title compound.

[0986] Step 12-8: 3-(trans-4-(2-(6-fluoro-3-methyl-1H-indazol-1-yl)pyrimidine-5-carboxamido)cyclohexyl)-3-methylbutyric acid

[0987]

[0988] A suspension of the crude product (30 mg) containing methyl 3-(trans-4-(2-(6-fluoro-3-methyl-1H-indazol-1-yl)pyrimidine-5-carboxamido)cyclohexyl)-3-methylbutyrate, sodium iodide (67 mg), and chlorotrimethylsilane (0.05 mL) in acetonitrile (2.0 mL) was stirred at 85°C for 7 hours. Sodium iodide (63 mg) and chlorotrimethylsilane (0.05 mL) were added to the reaction mixture at room temperature, and the mixture was stirred at 85°C for 9 hours. Water (4.0 mL) and 1 M hydrochloric acid (0.5 mL) were added sequentially to the reaction mixture at room temperature, and the solid was collected by filtration. The solid was dissolved in dimethyl sulfoxide and purified by reverse-phase silica gel chromatography (developing solvent: water / acetonitrile = 90 / 10 to 0 / 100) to give the title compound (7.3 mg). 1H-NMR (DMSO-D6) δ: 9.27-9.26 (2H, m), 8.83-8.73 (1H, br m), 8.40 (1H, dd, J = 10.4, 2.3 Hz), 7.94 (1H, dd, J = 8.7, 5.4 Hz), 7.31-7.26 (1H, m), 3.75-3.65 (1H, m), 2.61 (3H, s), 1.94-1.90 (2H, m), 1.86-1.83 (2H, m), 1.85 (2H, s), 1.48-1.41 (1H, m), 1.36-1.27 (2H, m), 1.11-1.02 (2H, m), 0.91 (6H, s). MS(M+H): 454 MS(MH): 452

[0989] [Preparation Example 13] Example 306: Preparation of N-(trans-4-(((S)-1-hydroxypropan-2-yl)oxy)cyclohexyl)-2-(3-methyl-1H-indazol-1-yl)pyrimidine-5-carboxylic acid amide

[0990]

[0991] Step 13-1: (S)-((1-(benzyloxy)propan-2-yl)oxy)trimethylsilane

[0992]

[0993] To a solution of (S)-1-benzyloxy-2-propanol (500 mg) and triethylamine (0.922 mL) in tetrahydrofuran (5.0 mL), trimethylsilyl chloride (0.408 mL) was added in a water bath, stirred, and allowed to stand overnight. To this reaction mixture, n-hexane / ethyl acetate (n-hexane / ethyl acetate = 10 / 1) was added at room temperature. After stirring, insoluble matter was removed by filtration, and the filtrate was concentrated to give a crude product containing the title compound (767.8 mg).

[0994] Step 13-2: benzyl (trans-4-(((S)-1-(benzyloxy)propan-2-yl)oxy)cyclohexyl)carbamate

[0995]

[0996] To a solution of the crude product (767.8 mg) containing (S)-((1-(benzyloxy)propan-2-yl)oxy)trimethylsilane, benzyl (4-oxocyclohexyl)carbamate (1481 mg), and triethylsilane (1045 mg) in acetonitrile (20 mL), a solution of trimethylsilyl trifluoromethanesulfonate (1.094 mL) in acetonitrile (2.0 mL) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 3 hours. 1M hydrochloric acid and ethyl acetate were added to the reaction mixture, and the layers were separated. The organic layer was washed with saturated brine. The organic layer was dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: n-hexane / ethyl acetate = 80 / 20 to 76 / 24) to obtain the title compound (504.5 mg). 1 H-NMR (DMSO-D6) δ: 7.39-7.26 (10H, m), 7.17 (1H, d, J = 7.6 Hz), 4.99 (2H, s), 4.48 (2H, s), 3.74-3.65 (1H, m), 3.40-3.23 (4H, m), 1.91-1.85 (2H, m), 1.82-1.75 (2H, m), 1.21-1.14 (4H, m), 1.04 (3H, d, J = 6.3 Hz).

[0997] Step 13-3: (S)-2-((trans-4-aminocyclohexyl)oxy)propan-1-ol

[0998]

[0999] To a solution of benzyl (trans-4-(((S)-1-(benzyloxy)propan-2-yl)oxy)cyclohexyl)carbamate (504 mg) in methanol (10 mL) was added 20% palladium hydroxide on carbon (178 mg) at room temperature. The mixture was stirred under 4 atmospheres of hydrogen at room temperature overnight. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. To a solution of the residue in methanol (10 mL) was added 20% palladium hydroxide on carbon (178 mg) at room temperature. The mixture was stirred under 4 atmospheres of hydrogen at room temperature for 2 days. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified using Bond Elut SCX (Agilent technologies) (developing solvent: methanol, 1 M ammonia / methanol solution) to obtain the title compound (176 mg). 1 H-NMR (DMSO-D6) δ: 4.45 (1H, br s), 3.49-3.42 (1H, m), 3.34-3.14 (4H, m), 1.85-1.70 (4H, m), 1.61 (2H, br s), 1.18-0.95 (4H, m), 0.99 (3H, d, J = 5.0 Hz).

[1000] Step 13-4: N-(trans-4-(((S)-1-hydroxypropan-2-yl)oxy)cyclohexyl)-2-(3-methyl-1H-indazol-1-yl)pyrimidine-5-carboxylic acid amide

[1001]

[1002] To a suspension of 2-(3-methyl-1H-indazol-1-yl)pyrimidine-5-carboxylic acid (40 mg), synthesized in the same manner as in Step 4-2 of Preparation Example 4, and (S)-2-((trans-4-aminocyclohexyl)oxy)propan-1-ol (32.7 mg) in N,N-dimethylformamide (0.6 mL), triethylamine (0.0329 mL), 1-hydroxy-7-azabenzotriazole (21.41 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (36.2 mg) were added sequentially at room temperature, and the mixture was stirred at the same temperature for 20 hours. Water (0.6 mL) was added to the reaction mixture at room temperature, and the mixture was purified by reverse-phase silica gel chromatography (eluent: water (containing 0.1% formic acid) / acetonitrile = 100 / 0 to 60 / 40) and concentrated. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure to obtain the title compound (46.2 mg). 1 H-NMR (DMSO-D6) δ: 9.20 (2H, s), 8.66 (1H, d, J = 8.3 Hz), 8.51 (1H, d, J = 7.4 Hz), 7.87 (1H, d, J = 7.9 Hz), 7.63-7.60 (1H, m), 7.39-7.37 (1H, m), 4.48 (1H, t, J = 5.8 Hz), 3.80-3.73 (1H, m), 3.52-3.48 (1H, m), 3.39-3.31 (2H, m), 3.23-3.17 (1H, m), 2.61 (3H, s), 1.97-1.89 (4H, m), 1.43-1.20 (4H, m), 1.02 (3H, d, J = 6.2 Hz). MS(M+H):410 MS(MH):408

[1003] [Preparation Example 14] Example 335: Preparation of (S)-3-(trans-4-(4-(4-fluoro-1-methyl-1H-indazol-3-yl)benzoic acid amide)cyclohexyl)butanoic acid

[1004]

[1005] Step 14-1: methyl 4-(4-fluoro-1-methyl-1H-indazol-3-yl)benzoate

[1006]

[1007] Under a nitrogen atmosphere, a suspension of 4-bromo-1H-pyrrolo[3,2-c]pyridine (202 mg), (4-(methoxycarbonyl)phenyl)boronic acid (359 mg), potassium phosphate (769 mg), and [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride-dichloromethane adduct (74 mg) in 1,2-dimethoxyethane / water (5.0 mL, 1,2-dimethoxyethane / water = 4 / 1) was stirred at 100 °C for 45 minutes under microwave irradiation. The reaction solution was purified by silica gel chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30) to give the crude product (352 mg) containing the title compound.

[1008] Step 14-2: 4-(4-fluoro-1-methyl-1H-indazol-3-yl)benzoic acid

[1009]

[1010] A solution of the crude product (352 mg) containing methyl 4-(4-fluoro-1-methyl-1H-indazol-3-yl)benzoate in methanol (3.0 mL) was stirred under microwave irradiation at 100° C. for 20 minutes. 1 M hydrochloric acid was added to the reaction mixture at room temperature until a solid precipitated. The precipitated solid was collected by filtration and dried under reduced pressure at 60° C. to give a crude product (315 mg) containing the title compound.

[1011] Step 14-3: Ethyl 3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)-3-oxopropionate (estimated to be an enol-keto 1 / 9 mixture)

[1012]

[1013] Under a nitrogen atmosphere, 1,1'-carbonyldiimidazole (140 g) was added in portions over 7 minutes to a solution of trans-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid (200 g) in tetrahydrofuran (900 mL) at room temperature. Tetrahydrofuran (100 mL) was used for the wash-in. After stirring for 1.5 hours, potassium ethyl malonate (196 g) was added in portions over 2 minutes at room temperature, followed by magnesium chloride (110 g) in portions over 2 minutes. Tetrahydrofuran (200 mL) was used for the wash-in. The reaction mixture was stirred at room temperature for 26 hours. To this reaction mixture, 20 wt% aqueous citric acid (1000 mL) was added at room temperature, stirred for 20 minutes, ethyl acetate (1000 mL) was added, and the layers were separated. The organic layer was washed sequentially with 10 wt% aqueous citric acid (1000 mL), water (1000 mL), 7.5 wt% aqueous sodium bicarbonate (1000 mL), and saturated brine (1000 mL). This organic layer was dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in n-hexane / ethyl acetate (800 mL, n-hexane / ethyl acetate = 1 / 3). Insoluble material was removed by filtration, and the filtrate was concentrated and dried under reduced pressure to give the title compound (247 g). 1 H-NMR (CDCl3) δ: 12.14 (0.1H, s), 4.95 (0.1H, s), 4.36 (1H, br s), 4.19 (2H, q, J = 7.1 Hz), 3.47 (1.8H, s), 3.40 (1H, br s), 2.49-2.33 (0.9H, m), 2.16-2.05 (2H, m), 2.01-1.93 (2H, m), 1.93-1.89 (0.1H, m), 1.53-1.36 (11H, m), 1.27 (3H, t, J = 7.2 Hz), 1.17-1.07 (2H, m).

[1014] Step 14-4: (Z)-3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)-3-(tosyloxy)acrylate ethyl ester

[1015]

[1016] Under a nitrogen atmosphere, tetramethylethylenediamine (169 mL) and lithium chloride (47.5 g) were added to a solution of ethyl 3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)-3-oxopropionate (234.4 g) in acetonitrile / toluene (937 mL, acetonitrile / toluene = 1 / 3) at room temperature, and the mixture was stirred for 30 minutes. To this reaction mixture, a solution of p-toluenesulfonyl chloride (214 g) in acetonitrile / toluene (468 mL, acetonitrile / toluene = 1 / 3) was added dropwise over 20 minutes under ice-cooling. The mixture was washed down with acetonitrile / toluene (4118 mL, acetonitrile / toluene = 1 / 3). After stirring for 2 hours, a 5.0 wt % aqueous sodium bicarbonate solution (1172 mL) was added dropwise over 1 minute under ice-cooling. Toluene (937 mL) was added to this reaction mixture, and the layers were separated. The organic layer was washed sequentially with water (234 mL) and saturated brine (1172 mL). This organic layer was dried over sodium sulfate (234 g), and carboraffin-20 (23 g) was added. After filtration, the sodium sulfate and carboraffin-20 were removed, and the mixture was concentrated under reduced pressure. Ethyl acetate (200 mL) was added to the residue, and the mixture was dissolved at 85°C. Further ethyl acetate (150 mL) was added. n-Hexane (1050 mL) was added dropwise at 50°C, and seed crystals were added at 40°C. n-Hexane (2100 mL) was added dropwise to this suspension at 40°C, and the mixture was stirred at the same temperature for 2 hours. The mixture was then returned to room temperature and stirred for 15 hours. The precipitated solid was collected by filtration, washed with n-hexane / ethyl acetate (500 mL, n-hexane / ethyl acetate = 19 / 1), and dried under reduced pressure to obtain the title compound (302 g).

[1017] Synthesis of seed crystals of the title compound (ethyl (Z)-3-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-3-(p-toluenesulfonyloxy)acrylate)

[1018] Step 14-4-1: ethyl 3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)-3-oxopropionate

[1019]

[1020] To a solution of trans-4-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (1.0 g) in tetrahydrofuran (5 mL) was added 1,1'-carbonyldiimidazole (700 mg) at room temperature and stirred for 1 hour. After stirring, potassium ethyl malonate (839 mg) and magnesium chloride (470 mg) were added at room temperature and stirred for 1 hour at room temperature and then at 70°C for 3 hours. To this reaction mixture was added 10 wt% aqueous citric acid solution (5.0 mL) at room temperature and stirred for 15 minutes. Ethyl acetate (5.0 mL) was added and the layers were separated. The organic layer was washed once with 10 wt% aqueous citric acid solution (5.0 mL), once with water (5.0 mL), three times with saturated aqueous sodium bicarbonate solution (3.0 mL), and once with saturated brine. The organic layer was dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in n-hexane / ethyl acetate (n-hexane / ethyl acetate = 1 / 2), and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure and dried under reduced pressure to give a crude product (1.16 g) containing the title compound.

[1021] Step 14-4-2: (Z)-3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)-3-(tosyloxy)acrylate ethyl ester

[1022]

[1023] To a solution of ethyl 3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)-3-oxopropionate (1.15 g) in acetonitrile (9.26 mL) were added lithium chloride (235 mg) and tetramethylethylenediamine (0.829 mL) at room temperature, and the mixture was stirred for 15 minutes. To this reaction mixture, a solution of p-toluenesulfonyl chloride (1.056 g) in acetonitrile (2.3 mL) was added dropwise under ice-cooling, and the mixture was stirred for 1 hour. To this reaction mixture were added water (16 mL) and toluene (16 mL), and the layers were separated. The organic layer was washed successively with water, saturated aqueous sodium bicarbonate, and saturated brine. The organic layer was dried over sodium sulfate (234 g), filtered to remove the sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: n-hexane / ethyl acetate = 85 / 15 to 65 / 35) to obtain the title compound (1.40 g). 1 H-NMR (CDCl3) δ: 7.93-7.86 (2H, m), 7.38-7.31 (2H, m), 5.52-5.49 (1H, m), 4.34 (1H, br s), 4.05 (2H, q, J = 7.1 Hz), 3.36 (1H, br s), 2.46 (3H, s), 2.39-2.28 (1H, m), 2.10-1.98 (4H, m), 1.43 (9H, s), 1.29-1.15 (5H, m), 1.13-1.00 (2H, m).

[1024] Step 14-5: (E)-3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)-2-butenoic acid ethyl ester

[1025]

[1026] To a solution of ethyl (Z)-3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)-3-(tosyloxy)acrylate (210 g) in tetrahydrofuran (1050 mL), iron(III) chloride (3.64 g) was added under ice-cooling with sodium chloride, and a 1.0 M tetrahydrofuran solution of methylmagnesium bromide (1229 mL) was added dropwise. To this reaction mixture, under ice-cooling with sodium chloride, 10 wt% aqueous citric acid solution (1000 mL) was added and stirred at room temperature for 1 hour. Ethyl acetate (840 mL) was added, and the layers were separated. The organic layer was washed sequentially with 5.0 wt% aqueous sodium bicarbonate solution (1050 mL), water (1050 mL), and saturated brine (1050 mL). The organic layer was dried over sodium sulfate (210 g), and carboraffin-20 (21 g) was added. After filtration, the sodium sulfate and carboraffin-20 were removed, followed by concentration under reduced pressure. The residue was dissolved in n-hexane / ethyl acetate (1600 mL, n-hexane / ethyl acetate = 9 / 1) at 85 °C, and the mixture was allowed to cool to room temperature and stirred for 15 hours. The precipitated solid was collected by filtration, washed with n-hexane / ethyl acetate (400 mL, n-hexane / ethyl acetate = 19 / 1), and dried under reduced pressure to obtain a crude product (100 g) containing the title compound. The crude products (40 g and 60 g) containing the title compound were purified by silica gel chromatography (eluent: n-hexane / ethyl acetate = 95 / 5 to 50 / 50) to obtain the title compound (44.09 g). 1 H-NMR (CDCl3) δ: 5.65 (1H, s), 4.37 (1H, br s), 4.14 (2H, q, J = 7.1 Hz), 3.39 (1H, br s), 2.13 (3H, d, J = 1.2 Hz), 2.12-2.03 (2H, m), 1.99-1.88 (1H, m), 1.84-1.74 (2H, m), 1.44 (9H, s), 1.42-1.30 (2H, m), 1.27 (3H, t, J = 7.2 Hz), 1.20-1.06 (2H, m).

[1027] Step 14-6: (S)-3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)butanoate ethyl

[1028]

[1029] A solution of bis[η-(2,5-norbornadiene)]rhodium(I) tetrafluoroborate (0.36 g) and (R)-1-[(Sp)-2-(di-tert-butylphosphino)ferrocenyl]ethylbis(2-methylphenyl)phosphine (CAS number: 849924-76-1) (0.583 g) in methanol (120 mL) was stirred at room temperature for 1 hour under a nitrogen atmosphere. To this reaction mixture was added a solution of ethyl (E)-3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)-2-butenoate (30 g) in methanol (210 mL) at room temperature, and the mixture was stirred under 3.9 atmospheres of hydrogen for 2 days. The reaction mixture was concentrated under reduced pressure. Using a similar method, a crude product (46 g) containing the title compound was obtained, together with the concentrate obtained from ethyl (E)-3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)-2-butenoate (14 g).

[1030] Step 14-7: (S)-3-(trans-4-aminocyclohexyl)butanoic acid ethyl ester hydrochloride

[1031]

[1032] To a solution of the crude product (100 g) containing ethyl (S)-3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)butanoate (100 mL) in ethyl acetate (100 mL) was added dropwise over 10 minutes under ice-cooling, and the mixture was allowed to warm to room temperature and stirred for 90 minutes. To this reaction mixture was added n-hexane (300 mL), and the mixture was stirred for 30 minutes. The precipitated solid was collected by filtration, washed with n-hexane / ethyl acetate (100 mL, n-hexane / ethyl acetate = 9 / 1), and dried under reduced pressure to give the title compound (56.8 g). 1H-NMR (DMSO-D6) δ: 7.87 (3H, br s), 4.05 (2H, q, J = 7.1 Hz), 2.89 (1H, tt, J = 11.7, 3.8 Hz), 2.35 (1H, dd, J = 14.9, 5.2 Hz), 2.05 (1H, dd, J = 15.0, 9.0 Hz), 2.00-1.87 (2H, m), 1.83-1.71 (1H, m), 1.71-1.59 (2H, m), 1.33-1.20 (2H, m), 1.17 (3H, t, J = 7.2 Hz), 1.14-0.96 (3H, m), 0.83 (3H, d, J = 6.7 Hz).

[1033] Step 14-8: (S)-3-(trans-4-(4-(4-fluoro-1-methyl-1H-indazol-3-yl)benzoic acid amide)cyclohexyl)butanoic acid ethyl ester

[1034]

[1035] The crude product (50 mg) containing 4-(4-fluoro-1-methyl-1H-indazol-3-yl)benzoic acid, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (42.6 mg), 1-hydroxy-1H-benzotriazole monohydrate (31.2 mg), and (S)-3-(trans-4-aminocyclohexyl)butanoic acid ethyl hydrochloride (50.8 mg) in N,N-dimethylformamide (1.5 mL) was added at room temperature, triethylamine (0.064 mL) was added, and the mixture was stirred for 3 hours. Water was added to the reaction mixture at room temperature until a solid precipitated, and the precipitated solid was filtered and dried under reduced pressure to give the crude product (110 mg) containing the title compound.

[1036] Step 14-9: (S)-3-(trans-4-(4-(4-fluoro-1-methyl-1H-indazol-3-yl)benzoic acid amide)cyclohexyl)butanoic acid

[1037]

[1038] To a solution of the crude product (86.6 mg) containing ethyl (S)-3-(trans-4-(4-(4-fluoro-1-methyl-1H-indazol-3-yl)benzoic acid amide)cyclohexyl)butanoate in tetrahydrofuran / methanol (3 mL, tetrahydrofuran / methanol = 1 / 2) at room temperature, 2M aqueous sodium hydroxide solution (0.463 mL) was added and stirred at 100 ° C. under microwave irradiation for 20 minutes. To this reaction mixture, 2M hydrochloric acid (0.463 mL) was added at room temperature, and the precipitated solid was collected by filtration and dried under reduced pressure at 60 ° C. to obtain the title compound (68.7 mg). 1 H-NMR (DMSO-D6) δ: 11.98 (1H, br s), 8.30-8.24 (1H, m), 8.06-8.01 (2H, m), 8.00-7.95 (2H, m), 7.93-7.88 (1H, m), 7.81-7.76 (1H, m), 7.43-7.36 (1H, m), 4.14 (3H, s), 3.80-3.68 (1H, m), 2.35-2.27 (1H, m), 2.04-1.95 (1H, m), 1.94-1.86 (2H, m), 1.84-1.74 (1H, m), 1.73-1.65 (2H, m), 1.42-1.27 (2H, m), 1.25-1.06 (3H, m), 0.89-0.85 (3H, m). MS(M+H):438 MS(MH):436

[1039] [Preparation Example 15] Example 426: Preparation of N-(trans-4-(2-hydroxypropan-2-yl)cyclohexyl)-2-(3-methylimidazo[1,5-a]pyridin-1-yl)pyrimidine-5-carboxylic acid amide

[1040]

[1041] Step 15-1: 2,2,2-trifluoro-1-(3-methylimidazo[1,5-a]pyridin-1-yl)ethan-1-one

[1042]

[1043] To a solution of 2-picolylamine (2.098 g) and pyridine (6.2 mL) in chloroform (15 mL), acetyl chloride (1.4 mL) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 20 minutes. Trifluoroacetic anhydride (5.5 mL) was added dropwise to the reaction mixture under ice cooling, and the mixture was stirred overnight at room temperature. Saturated aqueous sodium bicarbonate (60 mL) was added to the reaction mixture at room temperature, and the layers were separated. The aqueous layer was extracted once with chloroform (15 mL). The combined organic layers were concentrated under reduced pressure, and toluene (30 mL) was added to the residue, which was then concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: n-hexane / ethyl acetate = 84 / 16 to 0 / 100) to give a crude product (1.98 g) containing the title compound.

[1044] Step 15-2: 3-methylimidazo[1,5-a]pyridine-1-carboxylic acid

[1045]

[1046] To a solution of the crude product (1.98 g) containing 2,2,2-trifluoro-1-(3-methylimidazo[1,5-a]pyridin-1-yl)ethan-1-one in methanol (20 mL) was added 2M aqueous sodium hydroxide (20 mL) at room temperature and stirred at 80 °C for 7 hours. 6M hydrochloric acid (6.6 mL) was added to the reaction mixture at room temperature, and the methanol contained in the reaction mixture was concentrated under reduced pressure. 1M hydrochloric acid (7.0 mL) was added to the residue at room temperature, and the precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (811 mg). 1 H-NMR (DMSO-D6) δ: 8.43-8.39 (1H, m), 8.04-8.01 (1H, m), 7.35-7.28 (1H, m), 7.09-7.03 (1H, m), 2.70 (3H, s).

[1047] Step 15-3: 3-methylimidazo[1,5-a]pyridine-1-carboxylic acid amide

[1048]

[1049] A mixture of 3-methylimidazo[1,5-a]pyridine-1-carboxylic acid (510 mg) and thionyl chloride (3.0 mL) was stirred at 70°C for 7 hours and then allowed to stand at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and 28% aqueous ammonia (5.0 mL) was added to the resulting residue under ice cooling. The mixture was then warmed to room temperature and stirred overnight. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give a crude product (352 mg) containing the title compound.

[1050] Step 15-4: 3-methylimidazo[1,5-a]pyridine-1-carbonitrile

[1051]

[1052] To a solution of the crude product (352 mg) containing 3-methylimidazo[1,5-a]pyridine-1-carboxylic acid amide and triethylamine (0.65 mL) in chloroform (5.0 mL), trifluoroacetic anhydride (0.37 mL) was added under ice cooling, and the mixture was allowed to warm to room temperature and stirred overnight. Triethylamine (0.33 mL) and trifluoroacetic acid (0.20 mL) were added to the reaction mixture under ice cooling, and the mixture was allowed to warm to room temperature and stirred overnight. Saturated aqueous sodium bicarbonate (5.0 mL) was added to the reaction mixture, and the layers were separated. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: n-hexane / ethyl acetate = 88 / 12 to 0 / 100) to give the title compound (254 mg). 1 H-NMR (DMSO-D6) δ: 8.41-8.39 (1H, m), 7.76-7.73 (1H, m), 7.29-7.25 (1H, m), 7.02-6.98 (1H, m), 2.64 (3H, s).

[1053] Step 15-5: ethyl 2-(3-methylimidazo[1,5-a]pyridin-1-yl)pyrimidine-5-carboxylate

[1054]

[1055] To a solution of 3-methylimidazo[1,5-a]pyridine-1-carbonitrile (254 mg) in methanol (7 mL) was added 5.0 M sodium methoxide in methanol (0.032 mL) at room temperature and stirred at the same temperature for 5 hours. To this reaction mixture was added 5.0 M sodium methoxide in methanol (0.32 mL) at room temperature and stirred overnight. To this reaction mixture was added 5.0 M sodium methoxide in methanol (0.32 mL) at room temperature and stirred overnight at room temperature. This process was repeated twice. To this reaction mixture was added ammonium chloride (463 mg) at room temperature and stirred for 72 hours, then filtered through Celite and concentrated under reduced pressure. N,N-dimethylformamide (4.0 mL), potassium carbonate (675 mg), and ethyl 2-formyl-3-oxopropionate (0.611 mL) were added sequentially at room temperature and stirred at 100°C for 7 hours. Ethyl acetate (20 mL) and water (15 mL) were added to this reaction mixture at room temperature. After separation, the aqueous layer was extracted once with ethyl acetate (10 mL). The combined organic layers were washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified twice by silica gel chromatography (eluent: n-hexane / acetone = 66 / 34 to 34 / 66, then chloroform / methanol = 90 / 10) to give the title compound (230 mg). 1 H-NMR (DMSO-D6) δ: 9.16 (2H, s), 8.55-8.53 (1H, m), 8.35 (1H, d, J = 6.5 Hz), 7.28-7.24 (1H, m), 7.00-6.96 (1H, m), 4.40-4.34 (2H, m), 2.70 (3H, s), 1.38-1.34 (3H, m).

[1056] Step 15-6: 2-(3-methylimidazo[1,5-a]pyridin-1-yl)pyrimidine-5-carboxylic acid

[1057]

[1058] To a suspension of ethyl 2-(3-methylimidazo[1,5-a]pyridin-1-yl)pyrimidine-5-carboxylate (180 mg) in methanol (3.0 mL) was added 2 M aqueous sodium hydroxide (0.7 mL) at room temperature, and the mixture was stirred overnight. 1 M hydrochloric acid (1.4 mL) and water (15.0 mL) were added sequentially at room temperature, and the precipitate was collected by filtration and dried under reduced pressure to give the title compound (82 mg). 1 H-NMR (DMSO-D6) δ: 13.54 (1H, br s), 9.21 (2H, s), 8.55 (1H, d, J = 9.2 Hz), 8.46-8.44 (1H, m), 7.39-7.35 (1H, m), 7.12-7.08 (1H, m), 2.78 (3H, s).

[1059] Step 15-7: N-(trans-4-(2-hydroxypropan-2-yl)cyclohexyl)-2-(3-methylimidazo[1,5-a]pyridin-1-yl)pyrimidine-5-carboxylic acid amide

[1060]

[1061] A suspension of 2-(3-methylimidazo[1,5-a]pyridin-1-yl)pyrimidine-5-carboxylic acid (30 mg), 2-(trans-4-aminocyclohexyl)propan-2-ol (25 mg), 1-hydroxy-7-azabenzotriazole (16 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (36 mg) in N,N-dimethylformamide (1.0 mL) was stirred overnight at room temperature. To this reaction mixture, saturated aqueous sodium bicarbonate (2.0 mL) and water (3.0 mL) were added at room temperature. The precipitate was collected by filtration and dried under reduced pressure to give the title compound (31.4 mg). 1H-NMR (DMSO-D6) δ: 9.13 (2H, s), 8.51 (1H, d, J = 8.8 Hz), 8.44 (1H, d, J = 7.9 Hz), 8.32 (1H, d, J = 6.7 Hz), 7.23-7.19 (1H, m), 6.97-6.93 (1H, m), 4.04 (1H, br s), 3.78-3.68 (1H, m), 2.70 (3H, s), 1.97-1.91 (2H, m), 1.88-1.82 (2H, m), 1.36-1.09 (5H, m), 1.05 (6H, s). MS(M+H):394 MS(MH):438

[1062] The compounds of the other examples were obtained by the same methods as those in the above-mentioned production methods and production examples, or by using known methods as necessary. The structural formula and physical property data of each example compound are shown in Table 1 below.

[1063]

[1064]

[1065]

[1066]

[1067]

[1068]

[1069]

[1070]

[1071]

[1072]

[1073]

[1074]

[1075]

[1076]

[1077]

[1078]

[1079]

[1080]

[1081]

[1082]

[1083]

[1084]

[1085]

[1086]

[1087]

[1088]

[1089]

[1090]

[1091]

[1092]

[1093]

[1094]

[1095]

[1096]

[1097]

[1098]

[1099]

[1100]

[1101]

[1102]

[1103]

[1104]

[1105]

[1106]

[1107]

[1108]

[1109]

[1110]

[1111]

[1112]

[1113]

[1114]

[1115]

[1116]

[1117] Test Example 1: Measurement of human H-PGDS binding inhibitory activity The H-PGDS binding inhibitory activity of test compounds was measured by AlphaLISA competitive assay. The specific protocol is as follows. First, 240 nL / well of compound solution or DMSO solution (solvent control) was added to an AlphaPlate-384 shallow well plate (Cat. 6008350, PerkinElmer), 3 μL / well of biotinylated H-PGDS inhibitor (see below) diluted in 2% (v / v) DMSO-containing Assay Buffer (50 mM HEPES-NaOH (pH 7.5), 2 mM GSH, 150 mM NaCl, 2 mM MgCl2, 0.005% Surfactant P20) (final concentration: 45 nmol / L), and 2 μL / well of His-tagged human H-PGDS (Cat. ATGP1557, ATgen) diluted in Assay Buffer (final concentration: 0.3 nmol / L) were added and mixed. 2 μL / well of Assay Buffer was added instead of His-tagged human H-PGDS as a blank. After the plate was left to stand at room temperature for 60 minutes, 5 μL / well of Nickel Chelate AlphaLISA Acceptor Beads (Cat. AL108C, Perkin Elmer) were added (final concentration: 20 μg / mL) and mixed. After 30 minutes of standing at room temperature in the dark, 5 μL / well of AlphaScreen Streptavidin donor beads (Cat. 6760002S, Perkin Elmer) were added (final concentration: 30 μg / mL) and mixed. After 60 minutes of standing at room temperature in the dark, the AlphaLISA signal (excitation wavelength: 680 nm, measurement wavelength: 615 nm) was measured using Enspire (Perkin Elmer). The H-PGDS binding inhibitory activity (inhibition rate) of each test compound was calculated as follows: IC 50 The value was calculated from the inhibition rate at two concentrations that sandwiched 50%.

[1118]

[1119] The results of human H-PGDS binding inhibitory activity are shown in Table 2 below.

[1120]

[1121]

[1122]

[1123]

[1124] The biotinylated H-PGDS inhibitor used in Test Example 1 was produced by biotinylating the H-PGDS inhibitor produced by the following steps. Either enantiomer A or B, described below, may be used as the H-PGDS inhibitor to be biotinylated, but enantiomer B was used in this test example.

[1125] Preparation of H-PGDS inhibitor (3-{4-[4-(3,7-difluoro-1H-pyrrolo[3,2-c]pyridin-4-yl)piperidine-1-carboxamido]bicyclo[2.2.2]octan-1-yl}butyric acid)

[1126] The following formula:

[1127]

[1128] The title compound represented by the formula (I) has an asymmetric carbon atom at the β-position of the carboxy group. In this production example, asymmetric reduction is carried out using a chiral phosphine ligand in Step 10A or Step 10B below. The compound obtained using the R-Sp form as the chiral phosphine ligand is referred to as Enantiomer A, and the compound obtained using the S-Rp form as the chiral phosphine ligand is referred to as Enantiomer B.

[1129] Step 1: tert-butyl 4-(7-fluoro-1H-pyrrolo[3,2-c]pyridin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[1130]

[1131] Under an argon atmosphere, a solution of 4-bromo-7-fluoro-1H-pyrrolo[3,2-c]pyridine (4.5 g) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (9.6 g) in toluene / ethanol (42 mL, toluene / ethanol = 2.5 / 1) was added with 2M aqueous sodium carbonate (21 mL) and [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride-dichloromethane adduct (1.7 g) at room temperature, and the mixture was stirred overnight at 100 °C. The reaction mixture was filtered through Celite, water and ethyl acetate were added, and the layers were separated. The organic layer was washed with saturated brine. The organic layer was dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 70 / 30 to 35 / 65) to obtain the title compound (6.3 g). 1 H-NMR (DMSO-D6) δ: 1.44 (9H, s), 2.68-2.71 (2H, m), 3.54-3.58 (2H, m), 4.08-4.11 (2H, m), 6.49-6.51 (1H, m), 6.86-6.88 (1H, m), 7.55-7.57 (1H, m), 8.10 (1H, d, J = 2.1 Hz), 12.20 (1H, br s).

[1132] Step 2: tert-butyl 4-(7-fluoro-1H-pyrrolo[3,2-c]pyridin-4-yl)piperidine-1-carboxylate

[1133]

[1134] To a solution of tert-butyl 4-(7-fluoro-1H-pyrrolo[3,2-c]pyridin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (6.3 g) in tetrahydrofuran / methanol (63 mL, tetrahydrofuran / methanol = 1 / 1) was added 10% palladium-carbon (1.3 g) at room temperature, and the mixture was stirred overnight under a hydrogen atmosphere at 1 atm. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (6.3 g). 1 H-NMR (DMSO-D6) δ: 1.42 (9H, s), 1.70-1.80 (4H, m), 2.83-2.99 (2H, m), 3.26-3.36 (1H, m), 4.04-4.10 (2H, m), 6.75-6.77 (1H, m), 7.49-7.51 (1H, m), 8.03 (1H, d, J = 2.7 Hz), 12.09 (1H, br s).

[1135] Step 3: tert-butyl 4-(3,7-difluoro-1H-pyrrolo[3,2-c]pyridin-4-yl)piperidine-1-carboxylate

[1136]

[1137] Under an argon atmosphere, acetic acid (6.6 mL) was added to a suspension of tert-butyl 4-(7-fluoro-1H-pyrrolo[3,2-c]pyridin-4-yl)piperidine-1-carboxylate (3.3 g) in acetonitrile (33 mL) at room temperature. N-Fluoro-N'-(chloromethyl)triethylenediaminebis(tetrafluoroborate) (5.5 g) was added in several portions to the reaction mixture at room temperature and stirred for 2 hours. The reaction mixture was added dropwise to saturated aqueous sodium bicarbonate (120 mL) over 10 minutes at room temperature. Sodium dithionite (2.5 g) was added to the reaction mixture at room temperature and stirred for 30 minutes. Ethyl acetate was added to the reaction mixture, and the layers were separated. The organic layer was washed with saturated brine. The organic layer was dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure. The residue was purified twice by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 80 / 20 to 50 / 50) to obtain the title compound (0.99 g). 1 H-NMR (CDCl3) δ: 1.48 (9H, s), 1.87-1.97 (4H, m), 2.84-2.94 (2H, m), 3.35-3.43 (1H, m), 4.22-4.34 (2H, m), 7.06 (1H, t, J = 2.8 Hz), 8.11 (1H, d, J = 2.7 Hz), 8.22 (1H, br s).

[1138] Step 4: 3,7-difluoro-4-(piperidin-4-yl)-1H-pyrrolo[3,2-c]pyridine dihydrochloride

[1139]

[1140] To a solution of tert-butyl 4-(3,7-difluoro-1H-pyrrolo[3,2-c]pyridin-4-yl)piperidine-1-carboxylate (0.99 g) in ethyl acetate (5.0 mL) was added 4M hydrogen chloride / ethyl acetate (9.9 mL) at room temperature and stirred for 3 hours. To this reaction mixture, ethyl acetate (5.0 mL) was added at room temperature and stirred for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (0.78 g).1 H-NMR (DMSO-D6) δ: 1.99-2.20 (4H, m), 3.04-3.13 (2H, m), 3.37-3.43 (2H, m), 3.53-3.60 (1H, m), 7.76 (1H, s), 8.27 (1H, s), 8.80 (1H, br s), 9.05 (1H, br s), 12.56 (1H, br s).

[1141] Step 5: methyl 4-[(tert-butoxycarbonyl)amino]bicyclo[2.2.2]octane-1-carboxylate

[1142]

[1143] To a suspension of methyl 4-aminobicyclo[2.2.2]octane-1-carboxylate (25 g) and triethylamine (23 mL) in tetrahydrofuran (250 mL) was added di-tert-butyl dicarbonate (38 mL) at room temperature and stirred for 15 hours. The reaction mixture was concentrated under reduced pressure, and n-hexane / ethyl acetate (100 mL, n-hexane / ethyl acetate = 90 / 10) was added to the residue. The precipitated solid was collected by filtration, washed with n-hexane / ethyl acetate (60 mL, n-hexane / ethyl acetate = 90 / 10), and dried under reduced pressure to give the title compound (37 g). 1 H-NMR (DMSO-D6) δ: 1.35 (9H, s), 1.73 (12H, s), 3.55 (3H, s), 6.44 (1H, br s).

[1144] Step 6: 4-[(tert-butoxycarbonyl)amino]bicyclo[2.2.2]octane-1-carboxylic acid

[1145]

[1146] To a suspension of methyl 4-[(tert-butoxycarbonyl)amino]bicyclo[2.2.2]octane-1-carboxylate (37 g) in tetrahydrofuran / methanol (370 mL, tetrahydrofuran / methanol = 1 / 1) was added 2 M aqueous sodium hydroxide (130 mL) at room temperature and stirred at 60 °C for 4 hours. To this reaction mixture was added 2 M hydrochloric acid (130 mL) under ice cooling and stirred for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (27 g). 1 H-NMR (DMSO-D6) δ: 1.35 (9H, s), 1.72 (12H, s), 6.41 (1H, br s), 11.98 (1H, s).

[1147] Step 7: tert-butyl {4-[methoxy(methyl)carbamoyl]bicyclo[2.2.2]octan-1-yl}carbamate

[1148]

[1149] To a solution of 4-[(tert-butoxycarbonyl)amino]bicyclo[2.2.2]octane-1-carboxylic acid (10 g) in N,N-dimethylformamide (100 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (17 g), N,O-dimethylhydroxylamine hydrochloride (4.4 g), and N,N-diisopropylethylamine (16 mL) at room temperature under an argon atmosphere, and the mixture was stirred for 4 hours. To this reaction mixture, N,N-diisopropylethylamine (2.6 mL) and N,O-dimethylhydroxylamine hydrochloride (1.5 g) were added at room temperature, and the mixture was stirred for 18 hours. Water (100 mL) and ethyl acetate (200 mL) were added to the reaction mixture at room temperature, and the layers were separated. The organic layer was washed successively with water (200 mL), saturated aqueous sodium bicarbonate (100 mL), and saturated brine (50 mL). The organic layer was dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure to give the title compound (12 g). 1H-NMR (CDCl3) δ: 1.42 (9H, s), 1.82-1.87 (6H, m), 1.95-1.99 (6H, m), 3.14 (3H, s), 3.64 (3H, s), 4.35 (1H, br s).

[1150] Step 8: tert-butyl (4-acetylbicyclo[2.2.2]octan-1-yl)carbamate

[1151]

[1152] Under an argon atmosphere, a 1.1 M solution of methylmagnesium bromide in tetrahydrofuran (57 mL) was added dropwise over 15 minutes to a solution of tert-butyl {4-[methoxy(methyl)carbamoyl]bicyclo[2.2.2]octan-1-yl}carbamate (8.0 g) in tetrahydrofuran (80 mL) under ice cooling, followed by stirring for 40 minutes. A 0.95 M solution of methylmagnesium bromide in tetrahydrofuran (22 mL) was added to the reaction mixture under ice cooling, and the mixture was stirred at the same temperature for 30 minutes and then at room temperature for 2.5 hours. A 10% (wt%) aqueous citric acid solution and ethyl acetate (100 mL) were added to the reaction mixture at room temperature, and the mixture was separated and washed with saturated brine. The organic layer was dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure. To the residue, n-hexane / ethyl acetate (13 mL, n-hexane / ethyl acetate = 2 / 1) was added and stirred. The precipitated solid was collected by filtration, washed with n-hexane / ethyl acetate (n-hexane / ethyl acetate = 10 / 1), and dried under reduced pressure to give the title compound (2.5 g). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 95 / 5 to 60 / 40) to give the title compound (3.6 g). 1 H-NMR (CDCl3) δ: 1.42 (9H, s), 1.78-1.83 (6H, m), 1.84-1.89 (6H, m), 2.08 (3H, s), 4.35 (1H, br s).

[1153] Step 9: Ethyl 3-{4-[(tert-butoxycarbonyl)amino]bicyclo[2.2.2]octan-1-yl}-2-butenoate

[1154]

[1155] Under an argon atmosphere, a solution of triethyl phosphonoacetate (10 g) in tetrahydrofuran (6.0 mL) was added dropwise over 20 minutes to a suspension of sodium hydride (1.8 g, 60 wt% oil dispersion) in tetrahydrofuran (60 mL) under ice cooling, followed by stirring for 1 hour. To this reaction mixture, a solution of tert-butyl (4-acetylbicyclo[2.2.2]octan-1-yl)carbamate (6.0 g) in tetrahydrofuran (30 mL) was added dropwise over 10 minutes under ice cooling. The reaction mixture was stirred at room temperature for 3 hours and then at 50°C for 15 hours. Saturated aqueous ammonium chloride (100 mL) and ethyl acetate (200 mL) were added to the reaction mixture at room temperature. The mixture was separated and washed with saturated brine (50 mL). The organic layer was dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 95 / 5 to 60 / 40) to obtain the title compound (4.1 g). 1 H-NMR (CDCl3) δ: 1.27 (3H, t, J = 7.2 Hz), 1.42 (9H, s), 1.68-1.72 (6H, m), 1.85-1.88 (6H, m), 2.10 (3H, s), 4.13 (2H, q, J = 7.2 Hz), 4.34 (1H, br s), 5.63 (1H, s).

[1156] Step 10A: (S)-3-{4-[(tert-butoxycarbonyl)amino]bicyclo[2.2.2]octan-1-yl}butyrate ethyl (Enantiomer A)

[1157]

[1158] A solution of bis[η-(2,5-norbornadiene)]rhodium(I) tetrafluoroborate (28 mg) and (R)-1-[(Sp)-2-(di-tert-butylphosphino)ferrocenyl]ethylbis(2-methylphenyl)phosphine (R-Sp form) (CAS number: 849924-76-1) (42 mg) in methanol (1.5 mL) was stirred at room temperature for 1 hour under an argon atmosphere. To this reaction mixture was added a solution of ethyl 3-{4-[(tert-butoxycarbonyl)amino]bicyclo[2.2.2]octan-1-yl}-2-butenoate (0.50 g) in methanol (4.0 mL) at room temperature, and the mixture was stirred under a hydrogen atmosphere at 4 atmospheres for 60 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 98 / 2 to 80 / 20) to obtain the title compound (0.46 g). 1 H-NMR (CDCl3) δ: 0.81 (3H, d, J = 6.7 Hz), 1.25 (3H, t, J = 7.2 Hz), 1.41-1.48 (6H, m), 1.42 (9H, s), 1.68-1.74 (1H, m), 1.76-1.81 (6H, m), 1.87 (1H, dd, J = 14.6, 10.9 Hz), 2.41 (1H, dd, J = 14.6, 3.2 Hz), 4.12 (2H, q, J = 7.2 Hz), 4.30 (1H, s).

[1159] Step 11A: (S)-3-(4-aminobicyclo[2.2.2]octan-1-yl)butyrate ethyl monohydrochloride (Enantiomer A)

[1160]

[1161] Ethyl (S)-3-{4-[(tert-butoxycarbonyl)amino]bicyclo[2.2.2]octan-1-yl}butyrate (Enantiomer A) (0.46 g) was added to 4 M hydrogen chloride / ethyl acetate (4.6 mL) at room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure and azeotroped with toluene to give the title compound (0.36 g). 1H-NMR (DMSO-D6) δ: 0.75 (3H, d, J = 6.7 Hz), 1.17 (3H, t, J = 7.1 Hz), 1.38-1.50 (6H, m), 1.59-1.68 (7H, m), 1.83 (1H, dd, J = 14.9, 10.6 Hz), 2.42 (1H, dd, J = 14.9, 3.1 Hz), 4.05 (2H, q, J = 7.1 Hz), 7.86-8.04 (3H, m).

[1162] Step 12A: (S)-3-{4-[4-(3,7-difluoro-1H-pyrrolo[3,2-c]pyridin-4-yl)piperidine-1-carboxamido]bicyclo[2.2.2]octan-1-yl}butyrate ethyl (Enantiomer A)

[1163]

[1164] Under an argon atmosphere, a suspension of (S)-3-(4-aminobicyclo[2.2.2]octan-1-yl)butyrate ethyl monohydrochloride (enantiomer A) (0.10 g) and N,N-diisopropylethylamine (0.14 mL) in tetrahydrofuran (3.0 mL) was added dropwise to a solution of triphosgene (36 mg) in tetrahydrofuran (1.5 mL) under ice-cooling, and the mixture was stirred for 1 hour. To this reaction mixture, N,N-diisopropylethylamine (0.16 mL), water (0.45 mL), and 3,7-difluoro-4-(piperidin-4-yl)-1H-pyrrolo[3,2-c]pyridine dihydrochloride (80 mg) were added under ice-cooling, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 85 / 15 to 30 / 70) to obtain the title compound (0.12 g). 1H-NMR (CDCl3) δ: 0.83 (3H, d, J = 6.7 Hz), 1.25 (3H, t, J = 7.1 Hz), 1.46-1.51 (6H, m), 1.71-1.73 (1H, m), 1.85-1.97 (11H, m), 2.44 (1H, dd. = 2.9 Hz), 8.10 (1H, d, J = 2.8 Hz), 8.31 (1H, br s).

[1165] Step 13A: (S)-3-{4-[4-(3,7-difluoro-1H-pyrrolo[3,2-c]pyridin-4-yl)piperidine-1-carboxamido]bicyclo[2.2.2]octan-1-yl}butyric acid (Enantiomer A)

[1166]

[1167] To a solution of (S)-ethyl 3-{4-[4-(3,7-difluoro-1H-pyrrolo[3,2-c]pyridin-4-yl)piperidine-1-carboxamido]bicyclo[2.2.2]octan-1-yl}butyrate (enantiomer A) (0.12 g) in tetrahydrofuran / methanol (2.4 mL, tetrahydrofuran / methanol = 1 / 1) was added 2M aqueous sodium hydroxide (0.59 mL) at room temperature and stirred at 65 °C for 2 hours. To this reaction mixture, 2M hydrochloric acid (0.59 mL), water, and ethyl acetate were added under ice cooling. After separation, the organic layer was washed with saturated brine. The organic layer was dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure to give the title compound (0.094 g). 1H-NMR (DMSO-D6) δ: 0.76 (3H, d, J = 6.7 Hz), 1.31-1.46 (6H, m), 1.50-1.61 (1H, m), 1.67-1.82 (11H, m), 2.33-2.39 (1H, m), 2.68-2.77 (2H, m), 3.21-3.29 (1H, m), 4.03-4.09 (2H, m), 5.60 (1H, s), 7.54 (1H, d, J = 2.5 Hz), 8.08 (1H, d, J = 3.0 Hz), 11.95 (2H, br s). MS(M+H):475 MS(MH):473

[1168] Step 10B: (R)-3-{4-[(tert-butoxycarbonyl)amino]bicyclo[2.2.2]octan-1-yl}butyrate ethyl (Enantiomer B)

[1169]

[1170] A solution of bis[η-(2,5-norbornadiene)]rhodium(I) tetrafluoroborate (28 mg) and (S)-1-[(Rp)-2-(di-tert-butylphosphino)ferrocenyl]ethylbis(2-methylphenyl)phosphine (S-Rp form) (CAS number: 849924-77-2) (45 mg) in methanol (1.5 mL) was stirred at room temperature for 1 hour under an argon atmosphere. To this reaction mixture was added a solution of ethyl 3-{4-[(tert-butoxycarbonyl)amino]bicyclo[2.2.2]octan-1-yl}-2-butenoate (0.50 g) in methanol (4.0 mL) at room temperature, and the mixture was stirred under a hydrogen atmosphere at 4 atmospheres for 65 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 98 / 2 to 80 / 20) to obtain the title compound (0.54 g). 1H-NMR (CDCl3) δ: 0.81 (3H, d, J = 6.7 Hz), 1.25 (3H, t, J = 7.2 Hz), 1.41-1.48 (6H, m), 1.42 (9H, s), 1.68-1.74 (1H, m), 1.76-1.81 (6H, m), 1.87 (1H, dd, J = 14.6, 10.9 Hz), 2.41 (1H, dd, J = 14.6, 3.2 Hz), 4.12 (2H, q, J = 7.2 Hz), 4.30 (1H, s).

[1171] Step 11B: (R)-3-(4-aminobicyclo[2.2.2]octan-1-yl)butyrate ethyl monohydrochloride (Enantiomer B)

[1172]

[1173] Ethyl (R)-3-{4-[(tert-butoxycarbonyl)amino]bicyclo[2.2.2]octan-1-yl}butyrate (Enantiomer B) (0.54 g) was added to 4 M hydrogen chloride / ethyl acetate (4.8 mL) at room temperature and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure and azeotroped with toluene to give the title compound (0.36 g). 1 H-NMR (CDCl3) δ: 0.82 (3H, d, J = 5.3 Hz), 1.23-1.27 (3H, m), 1.48-1.55 (6H, m), 1.73-1.79 (1H, m), 1.85-1.93 (7H, m), 2.38 (1H, d, J = 14.8 Hz), 4.09-4.15 (2H, m), 8.23 ​​(3H, br s).

[1174] Step 12B: (R)-3-{4-[4-(3,7-difluoro-1H-pyrrolo[3,2-c]pyridin-4-yl)piperidine-1-carboxamido]bicyclo[2.2.2]octan-1-yl}butyrate ethyl (Enantiomer B)

[1175]

[1176] Under an argon atmosphere, a suspension of (R)-3-(4-aminobicyclo[2.2.2]octan-1-yl)butyrate ethyl monohydrochloride (enantiomer B) (100 mg) and N,N-diisopropylethylamine (0.14 mL) in tetrahydrofuran (1.6 mL) was added dropwise to a solution of triphosgene (36 mg) in tetrahydrofuran (0.8 mL) under ice-cooling, and the mixture was stirred for 1 hour. To this reaction mixture, N,N-diisopropylethylamine (0.16 mL), 3,7-difluoro-4-(piperidin-4-yl)-1H-pyrrolo[3,2-c]pyridine dihydrochloride (80 mg), and water (0.24 mL) were added under ice-cooling, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 80 / 20 to 0 / 100) to obtain the title compound (62 mg). 1 H-NMR (CDCl3) δ: 0.83 (3H, d, J = 6.7 Hz), 1.25 (3H, t, J = 7.1 Hz), 1.46-1.51 (6H, m), 1.71-1.73 (1H, m), 1.85-1.97 (11H, m), 2.44 (1H, dd. = 2.9 Hz), 8.10 (1H, d, J = 2.8 Hz), 8.19 (1H, br s).

[1177] Step 13B: (R)-3-{4-[4-(3,7-difluoro-1H-pyrrolo[3,2-c]pyridin-4-yl)piperidine-1-carboxamido]bicyclo[2.2.2]octan-1-yl}butyric acid (Enantiomer B)

[1178]

[1179] To a solution of (R)-3-{4-[4-(3,7-difluoro-1H-pyrrolo[3,2-c]pyridin-4-yl)piperidine-1-carboxamido]bicyclo[2.2.2]octan-1-yl}butyrate (enantiomer B) (62 mg) in tetrahydrofuran / methanol (1.2 mL, tetrahydrofuran / methanol = 1 / 1) was added 2M aqueous sodium hydroxide (0.31 mL) at room temperature and stirred at 65 °C for 2 hours. To this reaction mixture, 2M hydrochloric acid (0.31 mL) and ethyl acetate were added at room temperature. After separation, the organic layer was washed with saturated brine. The organic layer was dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure to give the title compound (48 mg). 1 H-NMR (DMSO-D6) δ: 0.74 (3H, d, J = 6.7 Hz), 1.30-1.40 (6H, m), 1.51-1.58 (1H, m), 1.66-1.79 (11H, m), 2.31-2.37 (1H, m), 2.65-2.74 (2H, m), 3.21-3.27 (1H, m), 4.01-4.06 (2H, m), 5.59 (1H, s), 7.52-7.53 (1H, m), 8.06 (1H, d, J = 3.0 Hz), 11.90-11.97 (2H, m). MS(M+H):475 MS(MH):473

[1180] Biotinylation of the H-PGDS inhibitor ((R)-3-{4-[4-(3,7-difluoro-1H-pyrrolo[3,2-c]pyridin-4-yl)piperidine-1-carboxamido]bicyclo[2.2.2]octan-1-yl}butyric acid) (enantiomer B)

[1181] To a solution of (R)-3-{4-[4-(3,7-difluoro-1H-pyrrolo[3,2-c]pyridin-4-yl)piperidine-1-carboxamido]bicyclo[2.2.2]octan-1-yl}butyric acid (enantiomer B) (10 mg) and N-(35-amino-3,6,9,12,15,18,21,24,27,30,33-undecaoxapentatriacontyl)-5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide (16.25 mg) in N,N-dimethylformamide (0.5 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.85 mL) at room temperature. mg) and 1H-benzo[d][1,2,3]triazol-1-ol hydrate were added and allowed to stand overnight. The reaction mixture was purified by silica gel reverse-phase column chromatography (developing solvent: water / trifluoroacetic acid / acetonitrile) and then lyophilized. The residue was loaded onto a VariPure IPE column (Agilent) and eluted with methanol. The eluate was concentrated under reduced pressure and then dried under reduced pressure to obtain the title compound (14 mg).

[1182] Measurement of human H-PGDS inhibitory activity of the compound ((R)-3-{4-[4-(3,7-difluoro-1H-pyrrolo[3,2-c]pyridin-4-yl)piperidine-1-carboxamido]bicyclo[2.2.2]octan-1-yl}butyric acid) (enantiomer B)

[1183] (1) Preparation of purified human H-PGDS fraction. A DNA fragment containing human H-PGDS was amplified by polymerase chain reaction (PCR) using human H-PGDS expression plasmid DNA (pET28b / hH-PGDS) as a template. The fragment contained a NotI recognition sequence immediately before the translation initiation codon and a BamHI recognition sequence immediately downstream of the translation termination codon. The purified DNA fragment was fused with pET15b (Merck KGaA, Cat. No. 69661) digested with NotI and BamHI using the In-Fusion HD Cloning Kit (Takara Bio Inc., Cat. No. 639649). Human H-PGDS expression plasmid DNA was isolated from Escherichia coli DH5α (Toyobo, Cat. No. DNA-903) transformed with the resulting In-Fusion reaction product. The nucleotide sequence of human H-PGDS cloned into the vector was determined by the dye terminator method using the BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems, product number 4337456). The determined sequence was identical to the protein translation region sequence of human H-PGDS registered in the NCBI Reference Database (Accession number NM_014485.2).

[1184] E. coli BL21 (DE3) (Merck KGaA, product number 69450-4) transformed with human H-PGDS expression plasmid DNA was cultured in 2xYT medium (Becton Dextromethorphan). イThe cells were cultured at 37°C using a PBS (Duckson, model number 244020) until the optical density at 620 nm reached 0.6 or greater, and then cultured for 6 hours at 30°C in the presence of 1 mmol / L isopropyl β-D-1-thiogalactopyranoside. After incubation, the cells were harvested and suspended in Homogenate Buffer (PBS(-), cOmplete®, EDTA-free (Roche, model number 1873580)). The suspended cells were disrupted using an Ultrasonic Disruptor UD-201 (Tomy Seiko Co., Ltd.) for 15 seconds at output 4 and duty cycle 50. This process was repeated three times. After removing the precipitate by centrifugation (13,100 × g, 15 minutes, 4°C), ammonium sulfate was added to the supernatant to 40% saturation and the mixture was stirred at 4°C for at least 1 hour. The precipitate was then removed by centrifugation (13,100 × g, 10 min, 4°C). Ammonium sulfate was added to the supernatant to 60% saturation and stirred at 4°C for at least 1 hour. The precipitate was then suspended in PBS(-) and dialyzed twice for at least 2 hours against a dialysate containing 50 mmol / L potassium phosphate (pH 6.0), 150 mmol / L NaCl, and 1 mmol / L MgCl2. The dialyzed sample was centrifuged (21,100 × g, 10 min, 4°C) and the supernatant was loaded onto a Glutathione Sepharose 4B column (GE Healthcare, model number 17075604). After washing the column with dialysate, human H-PGDS was eluted with an eluent containing 5 mmol / L Tris-HCl (pH 8.0), 150 mmol / L NaCl, 1 mmol / L MgCl2, and 15 mmol / L glutathione. The eluate from the Glutathione Sepharose 4B column was loaded onto a gel filtration column (Superdex-200 30 / 100 GL (GE Healthcare, model number 17-5175-01)) and eluted with gel filtration buffer (5 mmol / L Tris-HCl (pH 8.0), 150 mmol / L NaCl, 1 mmol / L MgCl). The eluted fraction was collected and used as the purified human H-PGDS fraction.

[1185] The protein concentration of the purified human H-PGDS fraction was measured using Pierce 660nm Protein Assay Reagent (Thermo Fisher Scientific, model number 22660). The purified fraction was flash-frozen using liquid nitrogen and then stored at -80°C. Human H-PGDS was detected by Western blotting using rabbit anti-H-PGDS polyclonal antibody (LifeSpan BioSciences, Inc., model number LS-B6886).

[1186] (2) Evaluation of human H-PGDS inhibitory activity The H-PGDS inhibitory activity of compounds was calculated according to the following protocols attached to the Prostaglandin D Synthase Inhibitor Screening Assay Kit (Cat. No. 10006595, Cayman Chemical Company) and the Prostaglandin D2 Express ELISA Kit (Cat. No. 512041, Cayman Chemical Company). Human recombinant H-PGDS prepared as described above was used.

[1187] First, 10 μL / well of compound solution diluted in Assay buffer (0.1 mol / L Tris-HCl, pH 8.0) or DMSO solution (10% v / v) diluted in Assay buffer as a solvent control was added to a 96-well V-bottom plate (Cat. No. 3363, Costar), 10 μL / well of MgCl2 solution (final concentration 2 mmol / L), 10 μL / well of GSH solution (final concentration 0.8 mmol / L), and 10 μL / well of human recombinant H-PGDS (final concentration 1.6 μg / mL) or Assay buffer (blank) were added and mixed gently. The plate was then incubated at room temperature for 10 minutes, after which 10 μL / well of PGH2 (final concentration 50 μmol / L) was added to initiate the enzymatic reaction. The reaction was then allowed to proceed for 1 minute while mixing with a plate mixer. After the enzymatic reaction, 10 μL / well of 0.5 mol / L HCl was added to terminate the reaction. Furthermore, 10 μL / well of FeCl2 solution dissolved in 0.1 mol / L hydrochloric acid to a concentration of 0.4 mg / mL was added to reduce PGH2. This enzyme reaction mixture was diluted 4000-fold with EIA buffer, and the diluted enzyme reaction mixture was added to an ELISA plate at 50 μL / well. Prostaglandin D2 Express AChE Tracer and Prostaglandin D2 Express EIA Monoclonal Antibody were each added at 50 μL / well. In addition, 100 μL / well of EIA buffer and 50 μL / well of Prostaglandin D2 Express AChE Tracer were added to separate wells as the non-specific binding sample (NSB). The B0 sample consisted of 50 μL / well of EIA buffer, 50 μL / well of Prostaglandin D2 Express AChE Tracer, and 50 μL / well of Prostaglandin D2 Express EIA Monoclonal Antibody. The plate was incubated for 2 hours while mixing with a plate mixer. After the reaction was completed, the reaction solution was removed and 200 μL / well of wash buffer was added.This procedure was repeated five times to wash the plate. After washing the plate, 200 μL / well of Ellman's Reagent was added to all wells, and the mixture was mixed using a plate mixer while the reaction was carried out in the dark for 30 minutes. After the reaction was completed, the absorbance at 420 nm was measured using a microplate reader. The H-PGDS inhibitory activity (inhibition rate) of the compound was calculated as follows: IC for H-PGDS activity. 50 The value was calculated from the inhibition rate at two concentrations that sandwiched 50%.

[1188]

[1189] Furthermore, the compound (enantiomer A) was also tested for human H-PGDS inhibitory activity (IC 50 The values ​​were calculated.

[1190] The evaluation results for each compound are shown in Table 3 below.

[1191]

[1192] Examples of the formulation of the present invention include the following formulations: However, the present invention is not limited to these formulation examples.

[1193] Formulation Example 1: Preparation of capsules 1) Compound of Example 1 30 mg 2) Microcrystalline cellulose 10 mg 3) Lactose 19 mg 4) Magnesium stearate 1 mg 1), 2), 3) and 4) are mixed and filled into a gelatin capsule.

[1194] Formulation Example 2: Tablet Production 1) Compound of Example 1 10 g 2) Lactose 50 g 3) Cornstarch 15 g 4) Carmellose calcium 44 g 5) Magnesium stearate 1 g The total amount of 1), 2), and 3) and 30 g of 4) are kneaded with water, vacuum dried, and then sized. 14 g of 4) and 1 g of 5) are mixed with this sized powder and compressed into tablets using a tablet press. In this way, 1,000 tablets containing 10 mg of the compound of Example 1 per tablet are obtained.

[1195] The compound of the present invention or a pharmaceutically acceptable salt thereof has H-PGDS inhibitory activity and is therefore useful for the treatment and / or prevention of a disease selected from the group consisting of peripheral arterial disease (e.g., intermittent claudication and global severe chronic lower limb ischemia), cardiovascular disease, allergic asthma, chronic obstructive pulmonary disease, allergic rhinitis, sarcopenia, and Duchenne muscular dystrophy.

Claims

1. A compound of formula [I] or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 [During the ceremony, X 1 , Y 1 , Y 2 , Y 3 and Y 4 are each independently a carbon or nitrogen atom (wherein Y 1 , Y 2 , Y 3 and Y 4 the total number of nitrogen atoms is 0, 1 or 2), m is 0, 1 or 2; n is 0, 1 or 2; R 1 teeth, (1) Hydroxy, (2) Cyano, (3) C 1-4 alkyl (wherein the alkyl is hydroxy or C 1-4 optionally substituted with alkoxy); (4) C 1-4 Alkoxy, (5) halogens, (6) C 1-4 haloalkyl, or (7) C 3-6 cycloalkyl and m R 2 are each independently (1) Cyano, (2) C 1-4 Alkyl, (3) C 1-4 Alkoxy, (4) Halogen, or (5) C 1-4 Haloalkyl and n R 3 are each independently (1) C 1-4 Alkyl, (2) C 1-4 alkoxy, or (3) Halogen and R 4 teeth, (1) A ring Cy (wherein the ring Cy is (a) C 4-6 cycloalkyl, wherein the cycloalkyl is (I) hydroxy, (II) cyano, (III) oxo, (IV) C 1-6 alkyl, wherein the alkyl is (i) hydroxy, (ii) carboxy, (iii) -CONH 2 、 (iv) -CO-C 1-4 Alkoxy, (v) -SO 2 -C 1-4 alkyl, or (vi) Formula: 【Chemistry 2】 A group represented by may be replaced by (V) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO 2 -C 1-4 optionally substituted with alkyl); (VI) carboxy, (VII)-CO-NR 5 R 6 [where R 5 and R 6 are each independently C 1-4 Alkyl (wherein the alkyl is C 1-4 alkoxy), or R 5 and R 6 together with the nitrogen atom to which they are attached contain 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, a 4- to 6-membered heterocycloalkyl, wherein said heterocycloalkyl is (i) hydroxy, and (ii) C 1-6 alkyl (wherein the alkyl is optionally substituted with hydroxy); and optionally substituted with one or two substituents independently selected from the group consisting of: (VIII)-NR 7 R 8 {where R 7 and R 8 are each independently C 1-4 Alkyl, or -CO-C 1-6 alkyl (wherein the alkyl is optionally substituted with cyano)}, (IX) -OC 1-6 haloalkyl, (X) Formula: 【Transformation 3】 a group represented by (XI) Formula: 【Chemistry 4】 {In the formula, R 9 is C 1-4 Alkyl (wherein the alkyl is C 1-4 (optionally substituted with alkoxy) and (XII) Formula: 【Transformation 5】 (In the formula, R 10 is C 1-4 alkyl) A group represented by and optionally substituted with one or two substituents independently selected from the group consisting of: (b) C 5-8 a bridged cycloalkyl {wherein the bridged cycloalkyl is (I) hydroxy, (II) C 1-6 alkyl, wherein the alkyl is (i) hydroxy, (ii) carboxy, (iii) -CONH 2 、 (iv) -CO-C 1-4 Alkoxy, (v) -SO 2 -C 1-4 alkyl, or (vi) Formula: 【Transformation 6】 A group represented by may be replaced by (III) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO 2 -C 1-4 optionally substituted with alkyl); (IV) carboxy, (V) -CO-C 1-4 Alkoxy, (VI)-OC 1-6 haloalkyl, or (VII) Formula: 【Transformation 7】 A group represented by may be replaced by}, (c) a 5- or 6-membered heterocycloalkyl containing one nitrogen atom, wherein the heterocycloalkyl is (I) oxo, (II) C 1-6 Alkyl, (III) -CO-R 11 {where R 11 teeth, (I C 1-6 alkyl, wherein the alkyl is (A) Hydroxy, (B) cyano, or (C) C 1-4 Alkoxy may be replaced by (ii) C 1-6 Alkoxy, (iii) C 1-6 haloalkyl, (iv) C 3-6 cycloalkyl, wherein the cycloalkyl is optionally substituted with halogen; or (v) a 4- to 6-membered heterocycloalkyl containing one oxygen atom, wherein the heterocycloalkyl is optionally substituted with halogen; and (IV) Formula: 【Transformation 8】 A group represented by and optionally substituted with 1 to 3 substituents independently selected from the group consisting of: (d) an 8-membered bridged heterocycloalkyl containing one nitrogen atom, wherein the bridged heterocycloalkyl is —CO—R 11 may be replaced by}, (e) 7- to 11-membered spiroheterocycloalkyl containing one nitrogen atom {wherein the spiroheterocycloalkyl is —CO—R 11 may be replaced by}, (f) a 6- to 9-membered saturated or partially unsaturated fused ring group containing one or two nitrogen atoms (wherein the fused ring group is -CO-R 11 may be replaced by (g) Formula: 【Chemistry 9】 a group represented by (h) Formula: 【Chemistry 10】 or a group represented by (i) Formula: 【Chemistry 11】 A group represented by is], (2) C 1-4 alkyl {wherein the alkyl is (a) C 3-6 Cycloalkyl (wherein the cycloalkyl is hydroxy and optionally hydroxy-substituted C 1-4 alkyl), or (b) Phenyl may be replaced by}, or (3) C 1-4 Haloalkyl (wherein the haloalkyl is optionally substituted with hydroxy). 3-6 optionally substituted with cycloalkyl) is]

2. Y 1 , Y 2 , Y 3 and Y 4 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the total number of nitrogen atoms is 1 or 2.

3. 2. The compound according to claim 1, represented by formula [IA] or a pharmaceutically acceptable salt thereof. 【Chemistry 12】 (The symbols in the formula have the same meanings as in claim 1.)

4. R 3 The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein is halogen.

5. R 4 The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein is ring Cy.

6. The compound according to claim 1, represented by formula [IB] or a pharmaceutically acceptable salt thereof. 【Chemistry 13】 (The symbols in the formula have the same meanings as in claim 1.)

7. R 1 but, (1) C 1-4 alkyl (wherein the alkyl is hydroxy or C 1-4 optionally substituted with alkoxy); (2) C 1-4 Alkoxy, (3) Halogen, or (4) C 1-4 Haloalkyl 7. The compound according to any one of claims 1 to 6, wherein:

8. R 2 The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein is halogen.

9. The ring Cy is (1) C 4-6 cycloalkyl, wherein the cycloalkyl is (a) hydroxy, (b) cyano; (c) oxo, (d) C 1-6 alkyl, wherein the alkyl is (I) hydroxy, (II) carboxy, (III) -CONH 2 、 (IV) -CO-C 1-4 Alkoxy, (V) -SO 2 -C 1-4 alkyl, or (VI) Formula: 【Chemistry 14】 A group represented by may be replaced by (e) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO 2 -C 1-4 optionally substituted with alkyl); (f) carboxy, (g) -CO-NR 5 R 6 [where R 5 and R 6 are each independently C 1-4 Alkyl (wherein the alkyl is C 1-4 alkoxy), or R 5 and R 6 together with the nitrogen atom to which they are attached contain 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, a 4- to 6-membered heterocycloalkyl, wherein said heterocycloalkyl is (I) hydroxy, and (II) C 1-6 alkyl (wherein the alkyl is optionally substituted with hydroxy); and optionally substituted with one or two substituents independently selected from the group consisting of: (h) -NR 7 R 8 {where R 7 and R 8 are each independently C 1-4 Alkyl, or -CO-C 1-6 alkyl (wherein the alkyl is optionally substituted with cyano)}, (i) -OC 1-6 haloalkyl, (j) Formula: 【Chemistry 15】 a group represented by (k) Formula: 【Chemistry 16】 {In the formula, R 9 is C 1-4 Alkyl (wherein the alkyl is C 1-4 (optionally substituted with alkoxy) and (m) Formula: 【Chemistry 17】 (In the formula, R 10 is C 1-4 alkyl) A group represented by and optionally substituted with one or two substituents independently selected from the group consisting of: (2) C 5-8 a bridged cycloalkyl {wherein the bridged cycloalkyl is (a) hydroxy, (b) C 1-6 alkyl, wherein the alkyl is (I) hydroxy, (II) carboxy, (III) -CONH 2 、 (IV) -CO-C 1-4 Alkoxy, (V) -SO 2 -C 1-4 alkyl, or (VI) Formula: [Chemistry 18] A group represented by may be replaced by (c) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO 2 -C 1-4 optionally substituted with alkyl); (d) carboxy, (e) -CO-C 1-4 Alkoxy, (f) -OC 1-6 haloalkyl, or (g) Formula: 【Chemistry 19】 A group represented by may be replaced by}, (3) 5- or 6-membered heterocycloalkyl containing one nitrogen atom, wherein the heterocycloalkyl is (a) oxo, (b) C 1-6 Alkyl, (c) -CO-R 11 {where R 11 teeth, (I C 1-6 alkyl, wherein the alkyl is (i) hydroxy, (ii) cyano, or (iii) C 1-4 Alkoxy may be replaced by (II) C 1-6 Alkoxy, (III) C 1-6 haloalkyl, (IV) C 3-6 Cycloalkyl (wherein the cycloalkyl may be substituted with halogen) good), or (V) a 4- to 6-membered heterocycloalkyl containing one oxygen atom, wherein the heterocycloalkyl is optionally substituted with halogen; and (d) Formula: 【Chemistry 20】 A group represented by and optionally substituted with 1 to 3 substituents independently selected from the group consisting of: (4) an 8-membered bridged heterocycloalkyl containing one nitrogen atom {wherein the bridged heterocycloalkyl is —CO—R 11 may be replaced by}, (5) 7- to 11-membered spiroheterocycloalkyl containing one nitrogen atom {wherein the spiroheterocycloalkyl is —CO—R 11 may be replaced by}, or (6) A 6- to 9-membered saturated or partially unsaturated fused ring group containing one or two nitrogen atoms (wherein the fused ring group is -CO-R 11 may be replaced by 9. The compound according to any one of claims 1 to 8, wherein:

10. The ring Cy is (1) C 4-6 cycloalkyl, wherein the cycloalkyl is (a) hydroxy, (b) cyano; (c) oxo, (d) C 1-6 alkyl, wherein the alkyl is (I) hydroxy, (II) carboxy, (III) -CONH 2 、 (IV) -CO-C 1-4 Alkoxy, (V) -SO 2 -C 1-4 alkyl, or (VI) Formula: 【Chemistry 21】 A group represented by may be replaced by (e) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO 2 -C 1-4 optionally substituted with alkyl); (f) carboxy, (g) -CO-NR 5 R 6 [where R 5 and R 6 are each independently C 1-4 Alkyl (wherein the alkyl is C 1-4 alkoxy), or R 5 and R 6 together with the nitrogen atom to which they are attached contain 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, a 4- to 6-membered heterocycloalkyl, wherein said heterocycloalkyl is (I) hydroxy, and (II) C 1-6 alkyl (wherein the alkyl is optionally substituted with hydroxy); and optionally substituted with one or two substituents independently selected from the group consisting of: (h) -NR 7 R 8 {where R 7 and R 8 are each independently C 1-4 Alkyl, or -CO-C 1-6 alkyl (wherein the alkyl is optionally substituted with cyano)}, (i) -OC 1-6 haloalkyl, (j) Formula: 【Chemistry 22】 a group represented by (k) Formula: 【Chemistry 23】 {In the formula, R 9 is C 1-4 Alkyl (wherein the alkyl is C 1-4 (optionally substituted with alkoxy) and (m) Formula: 【Chemistry 24】 (In the formula, R 10 is C 1-4 alkyl) A group represented by and optionally substituted with one or two substituents independently selected from the group consisting of: (2) C 5-8 a bridged cycloalkyl {wherein the bridged cycloalkyl is (a) hydroxy, (b) C 1-6 alkyl, wherein the alkyl is (I) hydroxy, (II) carboxy, (III) -CONH 2 、 (IV) -CO-C 1-4 Alkoxy, (V) -SO 2 -C 1-4 alkyl, or (VI) Formula: 【Chemistry 25】 A group represented by may be replaced by (c) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO 2 -C 1-4 optionally substituted with alkyl); (d) carboxy, (e) -CO-C 1-4 Alkoxy, (f) -OC 1-6 haloalkyl, or (g) Formula: 【Chemistry 26】 A group represented by may be replaced by}, (3) 5- or 6-membered heterocycloalkyl containing one nitrogen atom, wherein the heterocycloalkyl is (a) oxo, (b) C 1-6 Alkyl, (c) -CO-R 11 {where R 11 teeth, (I C 1-6 alkyl, wherein the alkyl is (i) hydroxy, (ii) cyano, or (iii) C 1-4 Alkoxy may be replaced by (II) C 1-6 Alkoxy, (III) C 1-6 haloalkyl, (IV) C 3-6 cycloalkyl, wherein the cycloalkyl is optionally substituted with halogen; or (V) a 4- to 6-membered heterocycloalkyl containing one oxygen atom, wherein the heterocycloalkyl is optionally substituted with halogen; and (d) Formula: 【Chemistry 27】 A group represented by and optionally substituted with 1 to 3 substituents independently selected from the group consisting of: (4) an 8-membered bridged heterocycloalkyl containing one nitrogen atom {wherein the bridged heterocycloalkyl is —CO—R 11 may be replaced with 9. The compound according to any one of claims 1 to 8, wherein:

11. The ring Cy is (1) C 4-6 cycloalkyl, wherein the cycloalkyl is (a) hydroxy, (b) cyano; (c) oxo, (d) C 1-6 alkyl, wherein the alkyl is (I) hydroxy, (II) carboxy, (III) -CONH 2 、 (IV) -CO-C 1-4 Alkoxy, (V) -SO 2 -C 1-4 alkyl, or (VI) Formula: 【Chemistry 28】 A group represented by may be replaced by (e) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO 2 -C 1-4 optionally substituted with alkyl); (f) carboxy, (g) -CO-NR 5 R 6 [where R 5 and R 6 are each independently C 1-4 Alkyl (wherein the alkyl is C 1-4 alkoxy), or R 5 and R 6 together with the nitrogen atom to which they are attached contain 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, a 4- to 6-membered heterocycloalkyl, wherein said heterocycloalkyl is (I) hydroxy, and (II) C 1-6 alkyl (wherein the alkyl is optionally substituted with hydroxy); and optionally substituted with one or two substituents independently selected from the group consisting of: (h) -NR 7 R 8 {where R 7 and R 8 are each independently C 1-4 Alkyl, or -CO-C 1-6 alkyl (wherein the alkyl is optionally substituted with cyano)}, (i) -OC 1-6 haloalkyl, (j) Formula: 【Chemistry 29】 a group represented by (k) Formula: 【Transformation 30】 {In the formula, R 9 is C 1-4 Alkyl (wherein the alkyl is C 1-4 (optionally substituted with alkoxy) and (m) Formula: 【Chemistry 31】 (In the formula, R 10 is C 1-4 alkyl) A group represented by and optionally substituted with one or two substituents independently selected from the group consisting of: (2) C 5-8 a bridged cycloalkyl {wherein the bridged cycloalkyl is (a) hydroxy, (b) C 1-6 alkyl, wherein the alkyl is (I) hydroxy, (II) carboxy, (III) -CONH 2 、 (IV) -CO-C 1-4 Alkoxy, (V) -SO 2 -C 1-4 alkyl, or (VI) Formula: 【Chemistry 32】 A group represented by may be replaced by (c) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO 2 -C 1-4 optionally substituted with alkyl); (d) carboxy, (e) -CO-C 1-4 Alkoxy, (f) -OC 1-6 haloalkyl, or (g) Formula: 【Transformation 33】 A group represented by may be replaced with 9. The compound according to any one of claims 1 to 8, wherein:

12. The ring Cy is (1) cyclohexyl (wherein the cyclohexyl is (a) hydroxy, (b) cyano; (c) oxo, (d) C 1-6 alkyl, wherein the alkyl is (I) hydroxy, (II) carboxy, (III) -CONH 2 、 (IV) -CO-C 1-4 Alkoxy, (V) -SO 2 -C 1-4 alkyl, or (VI) Formula: 【Transformation 34】 A group represented by may be replaced by (e) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO 2 -C 1-4 optionally substituted with alkyl); (f) carboxy, (g) -CO-NR 5 R 6 [where R 5 and R 6 are each independently C 1-4 Alkyl (wherein the alkyl is C 1-4 alkoxy), or R 5 and R 6 together with the nitrogen atom to which they are attached contain 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, a 4- to 6-membered heterocycloalkyl, wherein said heterocycloalkyl is (I) hydroxy, and (II) C 1-6 alkyl (wherein the alkyl is optionally substituted with hydroxy); and optionally substituted with one or two substituents independently selected from the group consisting of: (h) -NR 7 R 8 {where R 7 and R 8 are each independently C 1-4 Alkyl, or -CO-C 1-6 alkyl (wherein the alkyl is optionally substituted with cyano)}, (i) -OC 1-6 haloalkyl, (j) Formula: 【Chemistry 35】 a group represented by (k) Formula: 【Transformation 36】 {In the formula, R 9 is C 1-4 Alkyl (wherein the alkyl is C 1-4 (optionally substituted with alkoxy) and (m) Formula: 【Chemistry 37】 (In the formula, R 10 is C 1-4 alkyl) A group represented by and optionally substituted with one or two substituents independently selected from the group consisting of: (2) Formula: 【Transformation 38】 {wherein the group represented by the formula is (a) hydroxy, (b) C 1-6 alkyl, wherein the alkyl is (I) hydroxy, (II) carboxy, (III) -CONH 2 、 (IV) -CO-C 1-4 Alkoxy, (V) -SO 2 -C 1-4 alkyl, or (VI) Formula: 【Chemistry 39】 A group represented by may be replaced by (c) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO 2 -C 1-4 optionally substituted with alkyl); (d) carboxy, (e) -CO-C 1-4 Alkoxy, (f) -OC 1-6 haloalkyl, or (g) Formula: 【Chemistry 40】 A group represented by may be replaced with 9. The compound according to claim 1 , wherein R is a group represented by the formula: or a pharmaceutically acceptable salt thereof.

13. The ring Cy is (1) Formula: 【Chemistry 41】 (In the formula, R 12 and R 13 are each independently (a) hydrogen, (b) hydroxy, (c) Cyano; (d) C 1-6 alkyl, wherein the alkyl is (I) hydroxy, (II) carboxy, (III) -CONH 2 、 (IV) -CO-C 1-4 Alkoxy, (V) -SO 2 -C 1-4 alkyl, or (VI) Formula: 【Chemistry 42】 A group represented by may be replaced by (e) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO 2 -C 1-4 optionally substituted with alkyl); (f) carboxy, (g) -CO-NR 5 R 6 [where R 5 and R 6 are each independently C 1-4 Alkyl (wherein the alkyl is C 1-4 alkoxy), or R 5 and R 6 together with the nitrogen atom to which they are attached contain 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, a 4- to 6-membered heterocycloalkyl, wherein said heterocycloalkyl is (I) hydroxy, and (II) C 1-6 alkyl (wherein the alkyl is optionally substituted with hydroxy); and optionally substituted with one or two substituents independently selected from the group consisting of: (h) -NR 7 R 8 {where R 7 and R 8 are each independently C 1-4 Alkyl, or -CO-C 1-6 alkyl (wherein the alkyl is optionally substituted with cyano)}, (i) -OC 1-6 haloalkyl, (j) Formula: 【Chemistry 43】 a group represented by (k) Formula: 【Chemistry 44】 {In the formula, R 9 is C 1-4 Alkyl (wherein the alkyl is C 1-4 (optionally substituted with alkoxy) or a group represented by (m) Formula: 【Chemistry 45】 (In the formula, R 10 is C 1-4 alkyl) or R 12 and R 13 may be taken together to form oxo), or (2) Formula: 【Chemistry 46】 (In the formula, R 14 teeth, (a) hydrogen, (b) hydroxy, (c) C 1-6 alkyl, wherein the alkyl is (I) hydroxy, (II) carboxy, (III) -CONH 2 、 (IV) -CO-C 1-4 Alkoxy, (V) -SO 2 -C 1-4 alkyl, or (VI) Formula: 【Chemistry 47】 A group represented by may be replaced by (d) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO 2 -C 1-4 optionally substituted with alkyl); (e) carboxy, (f) -CO-C 1-4 Alkoxy, (g) -OC 1-6 haloalkyl, or (h) Formula: 【Chemistry 48】 A group represented by is) 9. The compound according to claim 1 , wherein R is a group represented by the formula: or a pharmaceutically acceptable salt thereof.

14. 14. The compound of claim 1 or 13, represented by the formula [IC], or a pharmaceutically acceptable salt thereof. 【Chemistry 49】 (In the formula, X 1 , R 1 , R 2 and m have the same meaning as in claim 1; R 12 has the same meaning as in claim 13)

15. R 12 but (1) Hydroxy, (2) Cyano, (3) C 1-6 alkyl, wherein the alkyl is (a) hydroxy, (b) carboxy, (c) -CONH 2 、 (d) -CO-C 1-4 Alkoxy, (e) -SO 2 -C 1-4 alkyl, or (f) Formula: [Transformation 50] A group represented by may be replaced by (4) C 1-6 Alkoxy (wherein the alkoxy is hydroxy or -SO 2 -C 1-4 optionally substituted with alkyl); (5) -CO-NR 5 R 6 [where R 5 and R 6 together with the nitrogen atom to which they are attached, form a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the heterocycloalkyl is C 1-6 alkyl (wherein the alkyl is optionally substituted with hydroxy)}, (6) -NR 7 R 8 {where R 7 and R 8 are each independently C 1-4 Alkyl, or -CO-C 1-6 alkyl (wherein the alkyl is optionally substituted with cyano)}, (7) Formula: 【Chemistry 51】 a group represented by (8) Formula: 【Chemistry 52】 {In the formula, R 9 is C 1-4 Alkyl (wherein the alkyl is C 1-4 (optionally substituted with alkoxy) or a group represented by (9) Formula: 【Chemistry 53】 (In the formula, R 10 is C 1-4 alkyl) 15. The compound according to claim 14, wherein the compound is a group represented by the formula: or a pharmaceutically acceptable salt thereof.

16. 14. The compound of claim 1 or 13, represented by the formula [ID], or a pharmaceutically acceptable salt thereof. 【Chemistry 54】 (In the formula, X 1 , R 1 , R 2 and m have the same meaning as in claim 1; R 14 has the same meaning as in claim 13)

17. R 14 But C 1-6 17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, which is alkyl, wherein the alkyl is optionally substituted with hydroxy.

18. The following structural formula: 【Transformation 55】 【Transformation 56】 、 【Chemistry 57】 【Chemistry 58】 【Chemistry 59】 【Transformation 60】 【Chemistry 61】 【Transformation 62】 【Transformation 63】 【Chemistry 64】 【Transformation 65】 【Chemical Formula 66】 【Transformation 67】 【Transformation 68】 or a pharmaceutically acceptable salt thereof.

19. A compound having the following structural formula: 【Transformation 69】 or a pharmaceutically acceptable salt thereof.

20. A compound having the following structural formula: 【Transformation 70】 or a pharmaceutically acceptable salt thereof.

21. A compound of the following structural formula: 【Chemistry 71】 or a pharmaceutically acceptable salt thereof.

22. A compound having the following structural formula: 【Chemistry 72】 or a pharmaceutically acceptable salt thereof.

23. A compound having the following structural formula: 【Transformation 73】 or a pharmaceutically acceptable salt thereof.

24. A compound of the following structural formula: 【Chemistry 74】 or a pharmaceutically acceptable salt thereof.

25. A compound of the following structural formula: 【Chemistry 75】 or a pharmaceutically acceptable salt thereof.

26. A compound of the following structural formula: 【Transformation 76】 or a pharmaceutically acceptable salt thereof.

27. A compound of the following structural formula: 【Chemical 77】 or a pharmaceutically acceptable salt thereof.

28. A compound of the following structural formula: 【Transformation 78】 or a pharmaceutically acceptable salt thereof.

29. A compound having the following structural formula: 【Transformation 79】 or a pharmaceutically acceptable salt thereof.

30. A compound of the following structural formula: 【Chemistry 80】 or a pharmaceutically acceptable salt thereof.

31. A compound having the following structural formula: 【Chemistry 81】 or a pharmaceutically acceptable salt thereof.

32. A compound having the following structural formula: 【Chemistry 82】 or a pharmaceutically acceptable salt thereof.

33. 33. A pharmaceutical composition comprising a compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

34. 33. An H-PGDS inhibitor comprising the compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof.

35. A therapeutic or preventive agent for a disease selected from the group consisting of peripheral arterial disease, cardiovascular disease, allergic asthma, chronic obstructive pulmonary disease, allergic rhinitis, sarcopenia, and Duchenne muscular dystrophy, comprising the compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof.

36. The therapeutic or preventive agent according to claim 35, wherein the peripheral arterial disease is intermittent claudication or global severe chronic lower limb ischemia due to PAD.

37. 33. A method for inhibiting H-PGDS in a mammal, comprising administering to the mammal a pharmaceutically effective amount of a compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof.

38. A method for treating or preventing a disease selected from the group consisting of peripheral arterial disease, cardiovascular disease, allergic asthma, chronic obstructive pulmonary disease, allergic rhinitis, sarcopenia, and Duchenne muscular dystrophy in a mammal, comprising administering to the mammal a pharmaceutically effective amount of a compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof.

39. 39. The method of claim 38, wherein the peripheral arterial disease is intermittent claudication due to PAD or global severe chronic lower limb ischemia.

40. Use of the compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof for the manufacture of an H-PGDS inhibitor.

41. Use of the compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof for the manufacture of an agent for the treatment or prevention of a disease selected from the group consisting of peripheral arterial disease, cardiovascular disease, allergic asthma, chronic obstructive pulmonary disease, allergic rhinitis, sarcopenia, and Duchenne muscular dystrophy.

42. 42. The use according to claim 41, wherein the peripheral arterial disease is intermittent claudication due to PAD or global severe chronic lower limb ischemia.

43. 33. A compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, for use in inhibiting H-PGDS.

44. 33. The compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease selected from the group consisting of peripheral arterial disease, cardiovascular disease, allergic asthma, chronic obstructive pulmonary disease, allergic rhinitis, sarcopenia, and Duchenne muscular dystrophy.

45. 45. The compound according to claim 44, or a pharmaceutically acceptable salt thereof, wherein the peripheral arterial disease is intermittent claudication due to PAD or global severe chronic lower limb ischemia.

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