Nitrogen-containing bicyclic compounds containing pyrimidine

Abstract

The present invention provides a compound of the following general formula (1) or a salt thereof, which has excellent IRAK‑4 inhibitory activity and is useful as an active ingredient of a drug for preventing and / or treating diseases associated with IRAK‑4 inhibition.

Description

Technical Field

[0001] The present invention relates to novel nitrogen-containing bicyclic compounds or drugs using the compounds as effective ingredients. Background Art

[0002] Interleukin 1 receptor-associated kinase 4 (IRAK-4) is a protein phosphatase that plays an important role in downstream signal transduction of Toll-like receptors (TLRs), interleukin 1 receptor (IL-1R), IL-18R and IL-33R (Non-patent Document 1). The TLRs / IL-1 receptor family plays an important role in inflammation or body defense, so it is believed that this downstream signal plays a major role in a variety of diseases including inflammatory diseases and autoimmune diseases.

[0003] TLRs use pathogen-associated molecular patterns (PAMPs) derived from infectious microorganisms such as bacteria, fungi, parasites, and viruses as ligands. In addition, they can also recognize damage-associated molecular patterns (DAMPs) released by damaged cells or apoptotic cells and activate them. When the ligand binds to the TLRs and IL-1 receptor family, MyD88, which acts as a linker molecule, is recruited to a common intracellular region called the TIR (Toll / IL-1 receptor) region. It is believed that IRAK-4 is recruited to the receptor by interacting with MyD88 and initiates downstream signal transduction (Non-patent Document 2). IRAK-4 activates IRAK-1 and IRAK-2, and further controls the production of inflammatory mediators such as cytokines and chemokines through the activation of downstream signaling molecules such as NF-kB and MAPK.

[0004] It is reported that cells of human origin with IRAK-4 gene defect do not react with TLRs agonists other than TLR3 and IL-1β, IL-18 (non-patent literature 3). In addition, IRAK-4 gene defect mice also do not react with TLRs agonists other than TLR3 and IL-1β, IL-18 (non-patent literature 4). On the other hand, in IRAK-1 gene defect mice and IRAK-2 gene defect mice, it is only confirmed that these signals are partially suppressed (non-patent literature 5). Therefore, in the IRAK family, IRAK-4 is also considered to play a core role in these signal transductions. It is reported that in kinase activity-deficient IRAK-4 knock-in mice, the severity of arthritis or experimental autoimmune encephalomyelitis and atherosclerosis models is suppressed compared to wild-type mice (non-patent literature 6). Therefore, the kinase activity of IRAK-4 is essential for the signal transduction involved in pathogenesis, and IRAK-4 inhibitors may show high effectiveness in the treatment of acute and chronic inflammation, autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus, metabolic diseases such as gout or diabetes, tumors and other diseases.

[0005] As compounds having IRAK-4 inhibitory activity, for example, compounds described in Patent Documents 1 to 6 are known.

[0006] Prior art literature

[0007] Patent Literature

[0008] Patent Document 1: International Publication No. WO2016 / 144846 Pamphlet

[0009] Patent Document 2: International Publication No. WO2016 / 053771 Pamphlet

[0010] Patent Document 3: International Publication No. WO2015 / 048281 Pamphlet

[0011] Patent Document 4: International Publication No. WO2013 / 042137 Pamphlet

[0012] Patent Document 5: International Publication No. WO2012 / 068546 Pamphlet

[0013] Patent Document 6: International Publication No. WO2015 / 150995 Pamphlet

[0014] Non-patent literature

[0015] Non-patent document 1: Flannery S. & Bowie AG, Biochemical Pharmacology 80 (2010) 1981-1991

[0016] Non-patent document 2: Jain A. et al., Fronters in Immunology 5 (2014) Article 553

[0017] Non-patent document 3: Picad C. et al., Science 299 (2003) 2076-2079

[0018] Non-patent document 4: Suzuki N. et al., Nature 416 (2002) 750-754

[0019] Non-patent document 5: Wan Y. et al., J Biol Chem 284 (2009) 10367-10375

[0020] Non-patent document 6: Koziczak-Holbro M. et al., Arthritis & Rheumatism 60 (2009) 1661-1671 Summary of the invention

[0021] Problems to be solved by the invention

[0022] The problem to be solved by the present invention is to provide a new compound having IRAK-4 inhibitory activity. In addition, another problem is to provide a new compound useful as an active ingredient of a drug for preventing and / or treating a disease associated with IRAK-4 inhibition. Furthermore, another problem is to provide a drug containing the compound.

[0023] Means for solving problems

[0024] The present inventors have conducted intensive studies to solve the above problems and have found that the compounds of the present invention represented by the following formula (1) have excellent IRAK-4 inhibitory activity and are useful for the prevention and / or treatment of diseases associated with IRAK-4 inhibition, thereby completing the present invention.

[0025] That is, the present invention includes the following aspects.

[0026] [1] A compound represented by the following general formula (1) or a salt thereof:

[0027] [Chemistry 1]

[0028]

[0029] [In formula (1),

[0030] Rg is the following general formula (1-1) or the following general formula (1-2):

[0031] [Chemistry 2]

[0032]

[0033] [Chemistry 3]

[0034]

[0035] (a and b represent bonding directions),

[0036] R 1 is -H, -F, -Cl, methyl or C 1-3 Alkoxy, the above C 1-3 The alkoxy group may be substituted with a 1 1 to 3 identical or different substituents in the group;

[0037] The above G 1 The group is composed of -F, hydroxyl, cyano, halogenated C 1-6 Alkyl, C 1-4 The group consisting of an alkoxy group, a phenyl group, a 5- to 6-membered heteroaryl group, and a 3- to 7-membered saturated ring group, G1 The phenyl or 5- to 6-membered heteroaryl group in the group may be substituted with a Ar 1 to 3 identical or different substituents in the group;

[0038] The above G Ar The group is composed of -F, -Cl, hydroxyl, cyano, C 1-6 Alkyl, halogenated C 1-6 The group consisting of alkyl and -NH2;

[0039] R 2 C 1-6 Alkyl, halogenated C 1-6 Alkyl or 3-7 membered saturated ring group, the above R 2 Can be substituted with a selected from G 2 1 to 3 identical or different substituents in the group;

[0040] The above G 2 The group is composed of -F, hydroxyl, halogenated C 1-3 Alkyl and C 1-4 A group consisting of alkoxy groups;

[0041] Cy is the following general formula (2-1):

[0042] [Chemistry 4]

[0043]

[0044] In formula (2-1),

[0045] k is an integer of 0 or 1;

[0046] R Cy1 and R Cy2 are independently -H, -F, hydroxyl, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -NR 11 R 12 , phenyl, 5- to 6-membered heteroaryl or 3- to 7-membered saturated ring group, R Cy1 and R Cy2 The phenyl or 5- to 6-membered heteroaryl group in the Ar 1 to 3 identical or different substituents in the group, the above R Cy1 , R Cy2 G may be substituted with 1 1 to 3 identical or different substituents in the group;

[0047] R 11 and R 12 Each independently is -H, C 1-6 Alkyl, halogenated C 1-6Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, 3-7 membered saturated ring group, phenyl or 5-6 membered heteroaryl, R 11 and R 12 Can be substituted with a selected from G 1 1 to 3 identical or different substituents in the group;

[0048] or R 11 With R 12 Together, they form a 4- to 10-membered saturated ring or a 7- to 11-membered spiro ring, wherein the 4- to 10-membered saturated ring and the 7- to 11-membered spiro ring may have, in addition to N, 1 to 2 identical or different heteroatoms selected from the group consisting of O and N, or -S(O2)-, and the 4- to 10-membered saturated ring and the 7- to 11-membered spiro ring may be substituted with a 3 1 to 3 identical or different substituents in the group;

[0049] The above G 3 The group is composed of -F, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -C(O)R 14 、-NR 13 C(O)R 14 、-C(O)NR 13 R 14 、-C(O)NH2、-NR 13 S(O2)R 14 、-S(O2)NR 13 R 14 、-S(O2)NH2、-S(O2)R 14 , phenyl, a 5- to 6-membered heteroaryl and a 3- to 7-membered saturated ring group, wherein the above G 3 The phenyl or 5- to 6-membered heteroaryl group in the Ar 1 to 3 identical or different substituents in the group;

[0050] R 13 -H, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, halogenated C 1-3 Alkoxy C 1-3 Alkyl, phenyl, 5-6 membered heteroaryl or 3-7 membered saturated ring group, the above R 13The phenyl or 5- to 6-membered heteroaryl group in the Ar 1 to 3 identical or different substituents in the group;

[0051] R 14 C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, halogenated C 1-6 Alkoxy C 1-6 Alkyl, phenyl, 5-6 membered heteroaryl or 3-7 membered saturated ring group, the above R 14 The phenyl or 5- to 6-membered heteroaryl group in the Ar 1 to 3 identical or different substituents in the group;

[0052] or R 13 With R 14 Together they form a 4- to 7-membered saturated ring or a 7- to 11-membered spiro ring, wherein the 4- to 7-membered saturated ring and the 7- to 11-membered spiro ring may have, in addition to N, 1 to 2 identical or different heteroatoms selected from the group consisting of O and N, or -S(O2)-;

[0053] or R Cy1 With R Cy2 Together, they form a 4- to 7-membered saturated ring, wherein the 4- to 7-membered saturated ring may have 1 to 2 identical or different heteroatoms selected from the group consisting of O and N, or -S(O2)-, and the 4- to 7-membered saturated ring may be substituted with a group selected from the above G 1 1 to 3 identical or different substituents in the group].

[0054] [2] The compound or a salt thereof as described in [1], wherein Rg is the general formula (1-1).

[0055] [3] The compound or salt thereof as described in [2] above, wherein R 1 is -F, -Cl, methyl or C 1-3 Alkoxy.

[0056] [4] The compound or a salt thereof as described in [2] above, wherein R 1 C 1-3 Alkoxy.

[0057] [4-2] The compound or salt thereof as described in [2] above, wherein R 1 It is ethoxy, methoxy or methoxyethoxy.

[0058] [4-3] The compound or salt thereof as described in [2] above, wherein R 1 It is ethoxy or methoxy.

[0059] [5] The compound or a salt thereof as described in [2] above, wherein R 1 It is a methoxy group.

[0060] [6] The compound or salt thereof according to any one of [2] to [5] above, wherein

[0061] R 1 is -H;

[0062] Cy is the following general formula (2-1-1):

[0063] [Chemistry 5]

[0064]

[0065] (R 11 and R 12 Same meaning as above).

[0066] [6-2] The compound or salt thereof according to any one of [2] to [5] above, wherein R 11 and R 22 Each independently is -H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, 3-7 membered saturated ring group, phenyl or 5-6 membered heteroaryl, R 11 and R 12 G may be substituted with 1 1 to 3 identical or different substituents in the group.

[0067] [6-3] The compound or salt thereof according to any one of [2] to [5] above, wherein R 11 and R 22 Each independently is -H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, 3-7 membered saturated cyclic group or 5-6 membered heteroaryl group, R 11 and R 12 G may be substituted with 1 1 to 3 identical or different substituents in the group.

[0068] [6-4] The compound or salt thereof according to any one of [2] to [5] above, wherein R 11 and R 22 Each independently is -H, C 1-6 Alkyl, halogenated C 1-6 Alkyl or 3-5 membered saturated ring group, R 11 and R 12 G may be substituted with1 1 to 3 identical or different substituents in the group.

[0069] [6-5] The compound or salt thereof according to any one of [2] to [5] above, wherein R 11 With R 12 Together, they form a 4- to 10-membered saturated ring or a 7- to 11-membered spiro ring. In the above-mentioned 4- to 7-membered saturated ring and 7- to 11-membered spiro ring, in addition to N, they may also have 1 to 2 identical or different heteroatoms selected from the group consisting of O and N, or -S(O2)-. The above-mentioned 4- to 7-membered saturated ring and 7- to 11-membered spiro ring may be substituted with a substituted ... 3 1 to 3 identical or different substituents in the group.

[0070] [6-6] The compound or salt thereof according to any one of [2] to [5] above, wherein R 11 With R 12 Together, they form a 4- to 10-membered saturated ring or a 7- to 11-membered spiro ring. In the above-mentioned 4- to 7-membered saturated ring and 7- to 11-membered spiro ring, in addition to N, they may also have 1 to 2 identical or different heteroatoms selected from the group consisting of O and N, or -S(O2)-. The above-mentioned 4- to 7-membered saturated ring and 7- to 11-membered spiro ring may be substituted with a substituted ... 3 1 to 3 identical or different substituents in the group.

[0071] [6-7] The compound or salt thereof according to any one of [2] to [5] above, wherein R 11 With R 12 Together they form the following general formulas (2-1-1-a-1) to (2-1-1-a-7):

[0072] [Chemistry 6]

[0073]

[0074] Any saturated ring in, the saturated ring may be substituted with a ring selected from G 3 1 to 3 identical or different substituents in the group;

[0075] R 15 -H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, -C(O)R 16 、-S(O2)R 16 、-C(O)NR 16 R 17 、-C(O)OR 16 or a 3- to 7-membered saturated ring group, the above R15 Can be substituted with a selected from G 1 1 to 3 identical or different substituents in the group;

[0076] R 16 C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, halogenated C 1-6 Alkoxy C 1-6 Alkyl, phenyl, 5-6 membered heteroaryl or 3-7 membered saturated ring group, the above R 16 The phenyl or 5- to 6-membered heteroaryl group in the Ar 1 to 3 identical or different substituents in the group;

[0077] R 17 -H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, halogenated C 1-6 Alkoxy C 1-6 Alkyl, phenyl, 5-6 membered heteroaryl or 3-7 membered saturated ring group, the above R 17 The phenyl or 5- to 6-membered heteroaryl group in the Ar 1 to 3 identical or different substituents in the group;

[0078] or R 16 With R 17 Together they form a 4- to 7-membered saturated ring or a 7- to 11-membered spiro ring, wherein the 4- to 7-membered saturated ring and the 7- to 11-membered spiro ring may have, in addition to N, 1 to 2 identical or different heteroatoms selected from the group consisting of O and N, or -S(O2)-.

[0079] [6-8] The compound or salt thereof according to any one of [2] to [5] above, wherein R 11 With R 12 Together they form the following general formula (2-1-1-b-1):

[0080] [Chemistry 7]

[0081]

[0082] The saturated ring may be substituted with a saturated ring selected from G 3 1 to 3 identical or different substituents in the group;

[0083] X is O or NR 15 (R 15 Same meaning as above).

[0084] [6-9] The compound or salt thereof according to any one of [2] to [5] above, wherein R 11 With R 12 Together they form the following general formulas (2-1-1-c-1) to (2-1-1-c-3):

[0085] [Chemistry 8]

[0086]

[0087] The saturated ring may be substituted with a saturated ring selected from G 3 1 to 3 identical or different substituents in the group;

[0088] X is O or NR 15 (R 15 Same meaning as above).

[0089] [6-10] The compound or salt thereof according to any one of [2] to [5] above, wherein R 11 With R 12 Together they form the following general formulas (2-1-1-d-1) to (2-1-1-d-8):

[0090] [Chemistry 9]

[0091]

[0092] The saturated ring with a bridge bond may be substituted with a saturated ring selected from G 3 1 to 3 identical or different substituents in the group;

[0093] X is O or NR 15 (R 15 Same meaning as above).

[0094] [6-11] The compound or salt thereof according to any one of [2] to [5] above, wherein R 11 With R 12 Together they form the following general formula (2-1-1-e-1):

[0095] [Chemistry 10]

[0096] The saturated ring with a condensed ring may be substituted with a condensed ring selected from G 3 1 to 3 identical or different substituents in the group;

[0097] X is O or NR 15 (R 15 Same meaning as above).

[0098] [7] The compound or salt thereof according to any one of [2] to [6-11], wherein

[0099] Cy is represented by the following general formula (2-1-2):

[0100] [Chemistry 11]

[0101]

[0102] [In formula (2-1-2), R Cy3 C 1-4 Alkyl, halogenated C 1-4 alkyl;

[0103] X is O or NR 15 ;

[0104] R 15 -H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, -C(O)R 16 、-S(O2)R 16 、-C(O)NR 16 R 17 、-C(O)OR 16 or a 3- to 7-membered saturated ring group, the above R 15 Can be substituted with a selected from G 1 1 to 3 identical or different substituents in the group;

[0105] R 16 C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, halogenated C 1-6 Alkoxy C 1-6 Alkyl, phenyl, 5-6 membered heteroaryl or 3-7 membered saturated ring group, the above R 16 The phenyl or 5- to 6-membered heteroaryl group in the Ar 1 to 3 identical or different substituents in the group;

[0106] R 17 -H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-3 Alkoxy C 1-6 Alkyl, halogenated C 1-6 Alkoxy C 1-6 Alkyl, phenyl, 5-6 membered heteroaryl or 3-7 membered saturated ring group, the above R 17The phenyl or 5- to 6-membered heteroaryl group in the Ar 1 to 3 identical or different substituents in the group;

[0107] or R 16 With R 17 Together they form a 4- to 7-membered saturated ring or a 7- to 11-membered spiro ring, wherein the 4- to 7-membered saturated ring and the 7- to 11-membered spiro ring may have, in addition to N, 1 to 2 identical or different heteroatoms selected from the group consisting of O and N, or -S(O2)-].

[0108] It should be noted that the item numbers cited as in [2] to [6-11] are shown as a range, and if an item with a branch number such as [6-6] is configured within the range, it means that the item with a branch number such as [6-6] is also cited. The same applies to the following.

[0109] [8] The compound or salt thereof according to any one of [2] to [7] above, wherein X is NR 15 (R 15 Same meaning as above).

[0110] [9] The compound or salt thereof according to any one of [2] to [8] above, wherein Cy is the following general formula (2-1-3):

[0111] [Chemistry 12]

[0112]

[0113] (R Cy3 , X has the same meaning as above).

[0114]

[10] The compound or salt thereof according to any one of [2] to [9] above, wherein R 2 It is the following formula (3-1):

[0115] [Chemistry 13]

[0116]

[0117] Or n-propyl.

[0118]

[11] The compound or salt thereof according to any one of [2] to [9] above, wherein R 2 It is the following formula (3-1):

[0119] [Chemistry 14]

[0120]

[0121]

[12] The following formula:

[0122] [Chemistry 15]

[0123]

[0124] The compound represented by or a salt thereof.

[0125]

[13] The following formula:

[0126] [Chemistry 16]

[0127]

[0128] The compound represented by or a salt thereof.

[0129]

[14] The following formula:

[0130] [Chemistry 17]

[0131]

[0132] The compound represented by or a salt thereof.

[0133]

[15] The following formula:

[0134] [Chemistry 18]

[0135]

[0136] The compound represented by or a salt thereof.

[0137]

[16] The following formula:

[0138] [Chemistry 19]

[0139]

[0140] The compound represented by or a salt thereof.

[0141]

[17] The following formula:

[0142] [Chemistry 20]

[0143]

[0144] The compound represented by or a salt thereof.

[0145]

[18] The following formula:

[0146] [Chemistry 21]

[0147]

[0148] The compound represented by or a salt thereof.

[0149]

[19] The following formula:

[0150] [Chemistry 22]

[0151]

[0152] The compound represented by or a salt thereof.

[0153]

[20] The following formula:

[0154] [Chemistry 23]

[0155]

[0156] The compound represented by or a salt thereof.

[0157]

[21] The following formula:

[0158] [Chemistry 24]

[0159]

[0160] The compound represented by or a salt thereof.

[0161]

[22] The compound or a salt thereof as described in [1] above, wherein Rg is the general formula (1-2).

[0162]

[23] The compound or salt thereof as described in

[22] above, wherein R 1 It is -H or methoxy.

[0163]

[24] The compound or salt thereof as described in

[22] above, wherein R 1 is -H.

[0164]

[25] The compound or salt thereof according to any one of

[22] to

[24] , wherein

[0165] Cy is represented by the general formula (2-1);

[0166] [In formula (2-1),

[0167] k is an integer of 1;

[0168] R Cy1 and R Cy2 are independently -H, -F, hydroxyl, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -NR 11 R 12 , phenyl, 5- to 6-membered heteroaryl or 3- to 7-membered saturated ring group, R Cy1 and R Cy2 The phenyl or 5- to 6-membered heteroaryl group in the Ar 1 to 3 identical or different substituents in the group, the above R Cy1 , R Cy2It may be substituted with a compound selected from the above G 1 1 to 3 identical or different substituents (R 11 and R 12 Same meaning as above)].

[0169]

[26] The compound or salt thereof according to any one of

[22] to

[25] above, wherein Cy is the following general formula (2-1-1):

[0170] [Chemistry 25]

[0171]

[0172] (R 11 and R 12 Same meaning as above).

[0173] [26-2] The compound or salt thereof according to any one of

[22] to

[25] above, wherein R 11 and R 22 Each independently is -H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, 3-7 membered saturated ring group, phenyl or 5-6 membered heteroaryl, R 11 and R 12 It may be substituted with a compound selected from the above G 1 1 to 3 identical or different substituents in the group.

[0174] [26-3] The compound or salt thereof according to any one of

[22] to

[25] above, wherein R 11 and R 22 Each independently is -H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, 3-7 membered saturated cyclic group or 5-6 membered heteroaryl group, R 11 and R 12 It may be substituted with a compound selected from the above G 1 1 to 3 identical or different substituents in the group.

[0175] [26-4] The compound or salt thereof according to any one of

[22] to

[25] above, wherein R 11 and R 22 Each independently is -H, C 1-6 Alkyl, halogenated C 1-6 Alkyl or 3-5 membered saturated ring group, R 11 and R 12 It may be substituted with a compound selected from the above G 1 1 to 3 identical or different substituents in the group.

[0176] [26-5] The compound or salt thereof according to any one of

[22] to

[25] above, wherein R 11 With R 12 Together, they form a 4- to 10-membered saturated ring or a 7- to 11-membered spiro ring. In the above-mentioned 4- to 7-membered saturated ring and 7- to 11-membered spiro ring, in addition to N, they may also have 1 to 2 identical or different heteroatoms selected from the group consisting of O and N, or -S(O2)-. The above-mentioned 4- to 7-membered saturated ring and 7- to 11-membered spiro ring may be substituted with a substituted ... 3 1 to 3 identical or different substituents in the group.

[0177] [26-6] The compound or salt thereof according to any one of

[22] to

[25] above, wherein R 11 With R 12 Together, they form a 4- to 10-membered saturated ring or a 7- to 11-membered spiro ring. In the above-mentioned 4- to 7-membered saturated ring and 7- to 11-membered spiro ring, in addition to N, they may also have 1 to 2 identical or different heteroatoms selected from the group consisting of O and N, or -S(O2)-. The above-mentioned 4- to 7-membered saturated ring and 7- to 11-membered spiro ring may be substituted with a substituted ... 3 1 to 3 identical or different substituents in the group.

[0178] [26-7] The compound or salt thereof according to any one of

[22] to

[25] above, wherein R 11 With R 12 Together they form the following general formulas (2-1-1-a-1) to (2-1-1-a-7):

[0179] [Chemistry 26]

[0180]

[0181] (R 15 The saturated ring may be substituted with a saturated ring selected from G 3 1 to 3 identical or different substituents in the group.

[0182] [26-8] The compound or salt thereof according to any one of

[22] to

[25] above, wherein R 11 With R 12 Together they form the following general formula (2-1-1-b-1):

[0183] [Chemistry 27]

[0184] The saturated ring may be substituted with a saturated ring selected from G 3 1 to 3 identical or different substituents in the group;

[0185] X is O or NR 15 (R 15 Same meaning as above).

[0186] [26-9] The compound or salt thereof according to any one of

[22] to

[25] above, wherein R 11 With R 12 Together they form the following general formulas (2-1-1-c-1) to (2-1-1-c-3):

[0187] [Chemistry 28]

[0188]

[0189] The saturated ring may be substituted with a saturated ring selected from G 3 1 to 3 identical or different substituents in the group;

[0190] X is O or NR 15 (R 15 Same meaning as above).

[0191] [26-10] The compound or salt thereof according to any one of

[22] to

[25] above, wherein R 11 With R 12 Together they form the following general formulas (2-1-1-d-1) to (2-1-1-d-8):

[0192] [Chemistry 29]

[0193] The spiro ring may be substituted with a spiro ring selected from G 3 1 to 3 identical or different substituents in the group;

[0194] X is O or NR 15 (R 15 Same meaning as above).

[0195] [26-11] The compound or salt thereof according to any one of

[22] to

[25] above, wherein R 11 With R 12 Together they form the following general formula (2-1-1-e-1):

[0196] [Chemistry 30]

[0197]

[0198] The saturated ring with a condensed ring may be substituted with a condensed ring selected from G 3 1 to 3 identical or different substituents in the group;

[0199] X is O or NR15 (R 15 Same meaning as above).

[0200]

[27] The compound or salt thereof according to any one of

[22] to [26-11] above, wherein Cy is the following general formula (2-1-2):

[0201] [Chemistry 31]

[0202]

[0203] (R Cy3 Same meaning as above);

[0204] X is O or NR 15 (R 15 Same meaning as above).

[0205]

[28] The compound or salt thereof according to any one of

[22] to

[27] above, wherein X is NR 15 (R 15 Same meaning as above).

[0206]

[29] The compound or salt thereof according to any one of

[22] to

[28] above, wherein Cy is the following general formula (2-1-3):

[0207] [Chemistry 32]

[0208]

[0209] (R Cy3 , X has the same meaning as above).

[0210]

[30] The compound or salt thereof according to any one of

[22] to

[29] above, wherein R 2 It is the following formula (3-1):

[0211] [Chemistry 33]

[0212]

[0213] Or n-propyl.

[0214]

[31] The compound or salt thereof according to any one of

[22] to

[29] above, wherein R 2 It is the following formula (3-1):

[0215] [Chemistry 34]

[0216]

[0217]

[32] The following formula:

[0218] [Chemistry 35]

[0219]

[0220] The compound represented by or a salt thereof.

[0221]

[33] The following formula:

[0222] [Chemistry 36]

[0223]

[0224] The compound represented by or a salt thereof.

[0225]

[34] The following formula:

[0226] [Chemistry 37]

[0227]

[0228] The compound represented by or a salt thereof.

[0229]

[35] The following formula:

[0230] [Chemistry 38]

[0231]

[0232] The compound represented by or a salt thereof.

[0233]

[36] A medicament comprising the compound described in any one of [1] to

[35] above or a pharmaceutically acceptable salt thereof as an active ingredient.

[0234]

[35] The medicament as described in

[36] above, which is used for preventing and / or treating a disease associated with IRAK4 inhibition.

[0235]

[38] The drug as described in

[36] above, which is used for the prevention and / or treatment of rheumatic diseases.

[0236]

[39] An IRAK4 inhibitor comprising the compound described in any one of [1] to

[35] above or a pharmaceutically acceptable salt thereof as an active ingredient.

[0237]

[40] A pharmaceutical composition for preventing and / or treating rheumatic diseases, comprising the compound described in any one of [1] to

[35] above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0238]

[41] The compound according to any one of [1] to

[35] above, or a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of rheumatic diseases.

[0239]

[42] A method for preventing and / or treating rheumatic disease in a mammal, comprising the step of administering an effective amount of the compound described in any one of [1] to

[35] above or a pharmaceutically acceptable salt thereof to the mammal.

[0240] Effects of the Invention

[0241] "The compound represented by formula (1) or a salt thereof" (hereinafter sometimes simply described as "the compound of the present invention") has excellent IRAK-4 inhibitory activity. In addition, a certain embodiment of the compound of the present invention shows high selectivity for other kinases, particularly FLT3. In addition, a certain embodiment of the compound of the present invention shows low genotoxicity. In addition, a certain embodiment of the compound of the present invention can be used as an active ingredient of a drug for the prevention and / or treatment of diseases related to IRAK-4 inhibition, such as for the prevention and / or treatment of autoimmune diseases. In addition, a certain embodiment of the compound of the present invention can be used as a reagent having IRAK-4 inhibitory activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0242] Figure 1 This is a graph showing the swelling inhibitory effect of one embodiment of the compound of the present invention (Example c-01-01) in rat arthritis. DETAILED DESCRIPTION

[0243] The present invention is described in detail below.

[0244] Unless otherwise stated, in the present specification, a carbon atom may be represented simply as "C", a hydrogen atom may be represented as "H", an oxygen atom may be represented as "O", a sulfur atom may be represented as "S", and a nitrogen atom may be represented as "N". In addition, a carbonyl group may be represented simply as "-C(O)-", a carboxyl group may be represented as "-COO-", a sulfinyl group may be represented as "-S(O)-", a sulfonyl group may be represented as "-S(O)2-", an ether bond may be represented as "-O-", and a thioether bond may be represented as "-S-" (in this case, "-" indicates a bond).

[0245] Unless otherwise stated, in this specification, an alkyl group is a saturated hydrocarbon group that is a straight chain, branched chain, cyclic or a combination thereof. For example, methyl, ethyl, propyl, butyl, their isomers [normal (n), iso (iso), secondary (sec), tertiary (t), etc.], or cycloalkyl groups such as cyclopropyl or cyclobutyl can be exemplified. As an alkyl group, an alkyl group having 1 to 6 carbon atoms can be exemplified. As another embodiment, an alkyl group having 1 to 3 carbon atoms can be exemplified. An alkyl group having 1 to 6 carbon atoms is sometimes recorded as C 1-6 alkyl.

[0246] "Alkoxy" may be a linear, branched, cyclic or a combination thereof. For example, methoxy, ethoxy, propoxy, butoxy, their isomers [normal (n), iso (iso), secondary (sec), tertiary (t), etc.] or cycloalkoxy such as cyclopropyloxy or cyclobutyloxy. As an alkoxy group, an alkoxy group having 1 to 6 carbon atoms may be exemplified. As another embodiment, an alkoxy group having 1 to 3 carbon atoms may be exemplified. Alkoxy groups having 1 to 6 carbon atoms are sometimes recorded as C 1-6 Alkoxy.

[0247] "Alkylene" also includes straight-chain or branched alkylene groups. For example, methylene, ethylene, propylene, butylene, methylmethylene, ethylmethylene, methylethylene, 1,2-dimethylethylene, 1,1,2,2-tetramethylethylene, or 1-methylbutylene can be exemplified. As an alkylene group, an alkylene group having 1 to 6 carbon atoms can be exemplified. As another embodiment, an alkylene group having 1 to 3 carbon atoms can be exemplified. An alkylene group having 1 to 6 carbon atoms is sometimes recorded as C 1-6 Alkylene.

[0248] "Halogen" is fluorine (-F), chlorine (-Cl), bromine (-Br) or iodine (-I). As another embodiment, -F or -Cl can be exemplified. Furthermore, as another embodiment, -F can be exemplified. "Halo" means substituted with 1 to 7 halogens which may be the same or different. As another embodiment, it means substituted with 1 to 5 halogens which may be the same or different. Furthermore, as another embodiment, it means substituted with 1 to 3 halogens. Furthermore, as another embodiment, it means substituted with 1 halogen. -F can be exemplified.

[0249] As the "aromatic ring", there is no particular limitation as long as it is a ring with aromaticity, and examples include monocyclic to tricyclic aromatic rings. As the aromatic ring, examples include aromatic hydrocarbon rings or aromatic heterocyclic rings. Specifically, examples include benzene, naphthalene, phenanthrene, thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, pyrrole, pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrimidone, indole, isoindole, indazole, quinoline, isoquinoline, benzimidazole, benzotriazole, benzothiophene, benzofuran, benzothiazole, phthalazine, quinoxaline, pyrrolopyridine or carbazole.

[0250] Examples of the "aromatic ring group" include monovalent groups obtained by removing any one hydrogen atom from an aromatic ring. Any aromatic ring group may be a monocyclic to tricyclic aromatic ring group. For example, an aryl group or a heteroaryl group may be mentioned.

[0251] The "aryl group" may be a monocyclic to tricyclic aromatic hydrocarbon ring group. Aromatic hydrocarbon ring groups formed by condensation with a saturated hydrocarbon ring described later are also included in the aryl group. Examples include 6- to 14-membered aryl groups. As another embodiment, 6- to 10-membered aryl groups may be illustrated. Furthermore, as another embodiment, 6-membered aryl groups may be illustrated. Specifically, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indanyl or 1,2,3,4-tetrahydronaphthyl may be illustrated. As another embodiment, it is phenyl, and as another embodiment, it is naphthyl. Indanyl and 1,2,3,4-tetrahydronaphthyl are included in the 6- to 10-membered aryl groups.

[0252] The "heteroaryl group" may be a monocyclic to tricyclic aromatic heterocyclic group containing 1 to 4 heteroatoms as ring atoms. As heteroatoms, O, S or N can be exemplified. 5 to 14-membered heteroaryl groups can be exemplified. As another embodiment, 5 to 10-membered heteroaryl groups can be exemplified. Furthermore, as another embodiment, 5 to 6-membered heteroaryl groups can be exemplified. Specifically, thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyridonyl, pyrimidonyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, benzimidazolyl, benzotriazolyl, benzothienyl, benzofuranyl, benzothiazolyl, phthalazinyl, quinoxalinyl, pyrrolopyridinyl or carbazolyl can be exemplified.

[0253] Examples of the "saturated ring" include a saturated hydrocarbon ring and a saturated heterocyclic ring. The saturated ring may have a bridge bond, or may be condensed with the above-mentioned aromatic ring.

[0254] The "saturated hydrocarbon ring" may be a monocyclic to tricyclic saturated hydrocarbon ring. Examples include 3- to 10-membered saturated hydrocarbon rings. As another embodiment, 3- to 7-membered saturated hydrocarbon rings may be exemplified. Furthermore, as another embodiment, 5- or 6-membered saturated hydrocarbon rings may be exemplified. The saturated hydrocarbon ring may have a bridge bond, and may also be condensed with the above-mentioned aromatic ring. Specifically, examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, or adamantane.

[0255] As a "saturated heterocycle", it is sufficient that it is a monocyclic to tricyclic saturated heterocycle containing 1 to 4 heteroatoms as ring atoms. As heteroatoms, O, S or N can be exemplified. 3 to 10-membered saturated heterocycles can be exemplified. As another embodiment, 3 to 7-membered saturated heterocycles can be exemplified. Furthermore, as another embodiment, 5 or 6-membered saturated heterocycles can be exemplified. The saturated heterocycle may have a bridge bond and may also be condensed with the above-mentioned aromatic ring. Specifically, tetrahydropyran, tetrahydrofuran, piperidine, pyrrolidine, azetidine, oxetane, aziridine, ethylene oxide, tetrahydrothiopyran, tetrahydrothiophene, morpholine, oxazepane or piperazine can be exemplified.

[0256] As a "fused ring", there can be exemplified a cyclic compound in which two or more rings share two or more atoms and are bonded, and the two or more rings are each independently a 3-7 membered saturated ring. The fused ring may have 1 to 3 heteroatoms selected from O, S and N. As a fused ring, there can be exemplified a cyclic compound in which two rings share two adjacent atoms.

[0257] As a "spiro ring", a cyclic compound in which two rings contain a common carbon atom and the two rings are each independently a 3- to 7-membered saturated ring can be exemplified. The spiro ring may have 1 to 3 heteroatoms selected from O, S and N. When the number of atoms constituting the spiro ring is 7 to 11, the spiro ring is sometimes referred to as a 7- to 11-membered spiro ring. As a spiro ring, a 7- to 13-membered spiro ring can be exemplified. As another embodiment, a 7- to 11-membered spiro ring can be exemplified. Furthermore, as another embodiment, a 7- to 9-membered spiro ring can be exemplified.

[0258] As a "saturated cyclic group", a monovalent group obtained by removing any one hydrogen atom from a saturated ring, or a divalent group obtained by removing one hydrogen atom from two different ring-forming atoms in a saturated ring, can be cited. Saturated hydrocarbon ring groups or saturated heterocyclic groups can be exemplified. 3-10-membered saturated cyclic groups can be exemplified. As another embodiment, 3-7-membered saturated cyclic groups can be exemplified. Furthermore, as another embodiment, 5-membered or 6-membered saturated cyclic groups can be exemplified.

[0259] As a "saturated hydrocarbon ring group", a monovalent group obtained by removing any one hydrogen atom from a saturated hydrocarbon ring, or a divalent group obtained by removing one hydrogen atom from two different ring-forming atoms in a saturated hydrocarbon ring can be cited. It is sufficient as a monocyclic to tricyclic saturated hydrocarbon ring group. The saturated hydrocarbon ring group may have a bridge bond and may also be condensed with the above-mentioned aromatic ring. A 3- to 10-membered saturated hydrocarbon ring group can be exemplified. As another embodiment, a 3- to 7-membered saturated hydrocarbon ring group can be exemplified. Furthermore, as another embodiment, a 5- or 6-membered saturated hydrocarbon ring group can be exemplified. As a monovalent group, specifically, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or an adamantyl group can be exemplified. As a divalent group, specifically, a divalent group obtained by further removing a hydrogen atom from a ring-forming atom other than the ring-forming atom from which a hydrogen atom is removed in the specific examples of the above-mentioned monovalent groups can be cited.

[0260] As a "saturated heterocyclic group", a monovalent group obtained by removing any one hydrogen atom from a saturated heterocyclic ring, or a divalent group obtained by removing one hydrogen atom from two different ring-forming atoms in a saturated heterocyclic ring can be cited. It is sufficient as a monocyclic to tricyclic saturated heterocyclic group containing 1 to 4 heteroatoms as ring-forming atoms. The saturated heterocyclic group may have a bridge bond and may also be condensed with the above-mentioned aromatic ring. As heteroatoms, O, S or N can be exemplified. A 3- to 10-membered heterocyclic group can be exemplified. As another embodiment, a 3- to 7-membered saturated heterocyclic group can be exemplified. Furthermore, as another embodiment, a 5- or 6-membered saturated heterocyclic group can be exemplified. As a monovalent group, specifically, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, pyrrolidinyl, azetidinyl, oxetanyl, tetrahydrothiopyranyl, tetrahydrothienyl, morpholinyl or piperazinyl can be exemplified.

[0261] The "partially unsaturated cyclic group" may be a ring in which a part of a saturated cyclic group is unsaturated, and examples thereof include partially unsaturated hydrocarbon cyclic groups (partially unsaturated hydrocarbon cyclic groups) or partially unsaturated heterocyclic groups (partially unsaturated heterocyclic groups). Examples thereof include 3-10 membered partially unsaturated cyclic groups. As another embodiment, 3-7 membered partially unsaturated cyclic groups may be exemplified. Furthermore, as another embodiment, 5-membered or 6-membered partially unsaturated cyclic groups may be exemplified.

[0262] The "partially unsaturated hydrocarbon ring group" may be a group in which a part of a saturated hydrocarbon ring group is unsaturated. Specific examples thereof include a cyclopentenyl group, a cyclopentadienyl group, a cyclohexenyl group, a cyclohexadienyl group, and a bicyclooctatrienyl group.

[0263] The "partially unsaturated heterocyclic group" may be a group in which a part of a saturated heterocyclic group is unsaturated. Specific examples thereof include dihydropyranyl, dihydrofuranyl, dihydrothiopyranyl, dihydrothiophenyl, 1,2-dihydroquinolinyl, and 1,2,3,4-tetrahydroquinolinyl.

[0264] In the present invention, as long as there is no special explanation, isomers are all included in the present invention. For example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylene, alkenylene and alkynylene include straight-chain groups and branched groups. In addition, isomers based on double bonds, rings or condensed rings (E or Z isomers, or cis or trans isomers), isomers based on the presence of asymmetric carbon atoms, etc. (R- or S-isomers, isomers based on α- or β-configuration, mirror image isomers or diastereomers, etc.), optically active bodies with optical activity (D- or L-body, or d- or l-body), isomers based on polarity differences due to chromatographic separation (high polar body or low polar body), equilibrium compounds, rotational isomers, or mixtures or racemic mixtures of any proportion thereof are all included in the present invention.

[0265] In this specification, unless otherwise stated, the symbols are as clear to those skilled in the art:

[0266] [Chemistry 39]

[0267]

[0268] Indicates bonding to the back side of the paper plane (i.e., α-configuration), symbol:

[0269] [Chemistry 40]

[0270]

[0271] Indicates bonding to the front side of the paper plane (i.e. β-configuration), symbol:

[0272] [Chemistry 41]

[0273]

[0274] It represents either α-configuration or β-configuration or a mixture thereof.

[0275] The compound represented by formula (1) or a salt thereof will be described in detail below.

[0276] [Chemistry 42]

[0277]

[0278] In this specification, unless otherwise stated, "having or not having a substituent" means having no substitution or having 1 to 5 substituents which may be the same or different. In another embodiment, it means having no substitution or having 1 to 3 substituents which may be the same or different. In another embodiment, it means having no substitution or having 1 substituent. In another embodiment, it means having no substitution.

[0279] As Rg, the following general formula (1-1) can be exemplified:

[0280] [Chemistry 43]

[0281]

[0282] Or the following general formula (1-2):

[0283] [Chemistry 44]

[0284]

[0285] (a, b represent bonding directions).

[0286] As R 1 , -H, -F, -Cl, methyl or C 1-3As another embodiment, -H or C 1-3 Furthermore, as another embodiment, -H or a methoxy group can be exemplified.

[0287] The above R 1 Can be substituted with a selected from G 1 1 to 3 identical or different substituents in the group.

[0288] As the above G 1 The group can be exemplified by -F, hydroxyl, cyano, halogenated C 1-6 Alkyl, C 1-4 The group consisting of an alkoxy group, a phenyl group, a 5- to 6-membered heteroaryl group, and a 3- to 7-membered saturated ring group. 1-6 Alkyl, C 1-4 G is composed of an alkoxy group, a 5- to 6-membered heteroaryl group, and a 3- to 7-membered saturated ring group 11 Furthermore, as another embodiment, -F, hydroxyl, C 1-4 G composed of alkoxy, 5-membered heteroaryl and 4-5-membered saturated ring 12 Group.

[0289] The above G 1 The phenyl or 5- to 6-membered heteroaryl group in the group may be substituted with a Ar 1 to 3 identical or different substituents in the group.

[0290] As the above G Ar The group can be exemplified by -F, -Cl, hydroxyl, cyano, C 1-6 Alkyl, halogenated C 1-6 As another embodiment, there can be exemplified a group consisting of -F, -Cl, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl composition G Ar1 Group.

[0291] As R 2 , which can be exemplified by C 1-6 Alkyl, halogenated C 1-6 An alkyl group or a 3- to 7-membered saturated ring group. As another embodiment, a 3- to 7-membered saturated ring group can be exemplified.

[0292] The above R 2 Can be substituted with a selected from G 2 1 to 3 identical or different substituents in the group.

[0293] As the above G 2 The group can be exemplified by -F, hydroxyl, halogenated C 1-3 Alkyl and C 1-4As another embodiment, G composed of -F and hydroxyl groups can be exemplified. 21 Group.

[0294] As the above R 2 , specifically, the following groups can be exemplified.

[0295] [Chemistry 45]

[0296]

[0297] In addition, as the above R 2 In another embodiment of , specifically, the following groups can be exemplified.

[0298] [Chemistry 46]

[0299]

[0300] In addition, as the above R 2 Specifically, the following groups can be exemplified as other embodiments of .

[0301] [Chemistry 47]

[0302]

[0303] In addition, as the above R 2 Specifically, the following groups can be exemplified as other embodiments of .

[0304] [Chemistry 48]

[0305]

[0306] Examples of Cy include the following general formula (2-1).

[0307] [Chemistry 49]

[0308]

[0309] As k, an integer of 0 or 1 can be exemplified. As another aspect, an integer of 1 can be exemplified.

[0310] As R Cy1 and R Cy2 , each independently can be exemplified by -H, -F, hydroxyl, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -NR 11 R 12 , phenyl, 5- to 6-membered heteroaryl or 3- to 7-membered saturated ring group. As another embodiment, -H, -F, C 1-6 Alkyl, C 1-6 Alkoxy, -NR11 R 12 Furthermore, as another embodiment, -NR 11 R 12 .

[0311] The above R Cy1 and R Cy2 The phenyl or 5- to 6-membered heteroaryl group in the Ar 1 to 3 identical or different substituents in the group.

[0312] As the above G Ar The above G Ar Group, and the above G Ar1 Group method.

[0313] The above R Cy1 and R Cy2 It may be substituted with a compound selected from the above G 1 1 to 3 identical or different substituents in the group.

[0314] As the above G 1 The above G 1 Group, and the above G 11 ~G 12 Group method.

[0315] As the above R 11 and R 12 , each independently exemplifies -H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 An alkyl group, a 3- to 7-membered saturated ring group, a phenyl group, or a 5- to 6-membered heteroaryl group. 1-6 Alkyl, halogenated C 1-6 Alkyl group, 3- to 7-membered saturated ring group. Examples of the 3- to 7-membered saturated ring group include cyclopropane, cyclobutane, cyclopentane, oxetane, and bicyclo[1.1.1]pentane.

[0316] The above R 11 and R 12 It may be substituted with a compound selected from the above G 1 1 to 3 identical or different substituents in the group.

[0317] As the above G 1 The above G 1 Group, and the above G 11 ~G 12 Group method.

[0318] The above R11 With R 12 They may also form a 4- to 10-membered saturated ring or a 7- to 11-membered spiro ring. In the above 4- to 10-membered saturated ring and 7- to 11-membered spiro ring, in addition to N, they may have 1 to 2 identical or different heteroatoms selected from the group consisting of O and N, or -S(O2)-.

[0319] Examples of the 4- to 10-membered saturated ring include azetidine, pyrrolidine, piperidine, morpholine, oxazepane, piperazine, and homopiperazine. In another embodiment, examples include piperidine, morpholine, and piperazine. Furthermore, in another embodiment, examples include morpholine and piperazine.

[0320] As the above R 11 With R 12 When forming a 4- to 10-membered saturated ring including a bridge bond together, the following groups can be exemplified.

[0321] [Chemistry 50]

[0322]

[0323] (X has the same meaning as above)

[0324] As the above R 11 With R 12 When forming a 7- to 11-membered spiro ring together, the following groups can be exemplified.

[0325] [Chemistry 51]

[0326]

[0327] (X has the same meaning as above)

[0328] As the above R 11 With R 12 When forming a 4- to 10-membered saturated ring including a bridge bond together, the following groups can be exemplified.

[0329] [Chemistry 52]

[0330]

[0331] (X has the same meaning as above)

[0332] The above R 11 With R 12 The 4- to 10-membered saturated ring or 7- to 11-membered spiro ring formed together may be substituted with a 3 1 to 3 identical or different substituents in the group.

[0333] As the above G 3 The group includes -F, hydroxyl, C 1-6 Alkyl, halogenated C1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -C(O)R 14 、-NR 13 C(O)R 14 、-C(O)NR 13 R 14 、-C(O)NH2、-NR 13 S(O2)R 14 、-S(O2)NR 13 R 14 、-S(O2)NH2、-S(O2)R 14 , phenyl, 5- to 6-membered heteroaryl and 3- to 7-membered saturated ring group. 1-6 Alkyl, halogenated C 1-6 Alkyl, -C(O)R 14 、-C(O)NR 13 R 14 .

[0334] The above G 3 The phenyl or 5- to 6-membered heteroaryl group in the group may be substituted with a group selected from the above G Ar 1 to 3 identical or different substituents in the group.

[0335] As the above G Ar The above G Ar Group, and the above G Ar1 Group method.

[0336] As the above R 13 , which can be exemplified by -H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, halogenated C 1-6 Alkoxy C 1-6 An alkyl group, a phenyl group, a 5- to 6-membered heteroaryl group, or a 3- to 7-membered saturated ring group. 1-6 Alkyl, halogenated C 1-6 Furthermore, as another embodiment, -H can be exemplified.

[0337] As the above R 14 , which can be exemplified by C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, halogenated C 1-6Alkoxy C 1-6 An alkyl group, a phenyl group, a 5- to 6-membered heteroaryl group, or a 3- to 7-membered saturated ring group. 1-6 Alkoxy C 1-6 An alkyl group, a 5- to 6-membered heteroaryl group, or a 3- to 7-membered saturated ring group. Furthermore, as another embodiment, a 5- to 6-membered heteroaryl group can be exemplified.

[0338] Examples of the 5- to 6-membered heteroaryl group include pyridine, oxazole, isoxazole, and thiazole. In another embodiment, pyridine can be exemplified.

[0339] The above R 13 and R 14 The phenyl or 5- to 6-membered heteroaryl group in the Ar 1 to 3 identical or different substituents in the group.

[0340] As the above G Ar The above G Ar Group, and the above G Ar1 Group method.

[0341] The above R 13 With R 14 They may also form a 4- to 7-membered saturated ring or a 7- to 11-membered spiro ring. In the above 4- to 7-membered saturated ring and 7- to 11-membered spiro ring, in addition to N, they may have 1 to 2 identical or different heteroatoms selected from the group consisting of O and N, or -S(O2)-.

[0342] Examples of the 4- to 7-membered saturated ring include azetidine, pyrrolidine, piperidine, morpholine, oxazepane, or piperazine. In another embodiment, azetidine and pyrrolidine can be exemplified. Furthermore, in another embodiment, azetidine can be exemplified.

[0343] As the above R 11 With R 12 In another embodiment when a 4- to 10-membered saturated ring is formed together and the 4- to 10-membered saturated ring is morpholine or piperazine, the following groups can be exemplified.

[0344] [Chemistry 53]

[0345]

[0346] As X, O or NR 15 As another example, NR 15 .

[0347] As R Cy3 , which can be exemplified by C 1-4 Alkyl, halogenated C 1-4Alkyl. As another embodiment, methyl, ethyl, and isopropyl can be exemplified. Furthermore, as another embodiment, methyl can be exemplified.

[0348] As the above R 15 , which can be exemplified by -H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, -C(O)R 16 、-S(O2)R 16 、-C(O)NR 16 R 17 、-C(O)OR 16 or a 3- to 7-membered saturated ring group. 1-6 Alkyl, -C(O)R 16 、-S(O2)R 16 or -C(O)NR 16 R 17 Furthermore, as another embodiment, -C(O)R 16 .

[0349] As the above R 16 , which can be exemplified by C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, halogenated C 1-6 Alkoxy C 1-6 An alkyl group, a phenyl group, a 5- to 6-membered heteroaryl group, or a 3- to 7-membered saturated ring group. 1-6 Alkoxy C 1-6 An alkyl group, a 5- to 6-membered heteroaryl group, or a 3- to 7-membered saturated ring group. Furthermore, as another embodiment, a 5- to 6-membered heteroaryl group can be exemplified.

[0350] Examples of the 5- to 6-membered heteroaryl group include pyridine, oxazole, isoxazole, and thiazole. In another embodiment, pyridine can be exemplified.

[0351] As the above R 17 , which can be exemplified by -H, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, halogenated C 1-6 Alkoxy C 1-3 An alkyl group, a phenyl group, a 5- to 6-membered heteroaryl group, or a 3- to 7-membered saturated ring group. 1-6 Alkyl, halogenated C 1-6 Furthermore, as another embodiment, -H can be exemplified.

[0352] The above R 16 and R 17 The phenyl or 5- to 6-membered heteroaryl group in the Ar 1 to 3 identical or different substituents in the group.

[0353] As the above G Ar The above G Ar Group, and the above G Ar1 Group method.

[0354] The above R 16 With R 17 They may also form a 4- to 7-membered saturated ring or a 7- to 11-membered spiro ring. In the above 4- to 7-membered saturated ring and 7- to 11-membered spiro ring, in addition to N, they may have 1 to 2 identical or different heteroatoms selected from the group consisting of O and N, or -S(O2)-.

[0355] Examples of the 4- to 7-membered saturated ring include azetidine, pyrrolidine, piperidine, morpholine, oxazepane, or piperazine. In another embodiment, azetidine and pyrrolidine can be exemplified. Furthermore, in another embodiment, azetidine can be exemplified.

[0356] The above R 15 It may be substituted with a compound selected from the above G 1 1 to 3 identical or different substituents in the group.

[0357] As the above G 1 The above G 1 Group, and the above G 11 ~G 12 Group method.

[0358] As the above R 15 , specifically, the following groups can be exemplified.

[0359] [Chemistry 54]

[0360]

[0361] In addition, as the above R 15 In another embodiment of , specifically, the following groups can be exemplified.

[0362] [Chemistry 55]

[0363]

[0364] As the above R 11 With R 12In another embodiment when the 4- to 10-membered saturated ring is formed together and the 4- to 10-membered saturated ring is morpholine or piperazine, the following groups can be exemplified.

[0365] [Chemistry 56]

[0366]

[0367] (R Cy3 、X has the same meaning as above)

[0368] The above R Cy1 With R Cy2 They may also form a 4- to 7-membered saturated ring or a 7- to 11-membered spiro ring. In the above 4- to 7-membered saturated ring and 7- to 11-membered spiro ring, in addition to N, they may have 1 to 2 identical or different heteroatoms selected from the group consisting of O and N, or -S(O2)-.

[0369] As the above R Cy1 With R Cy2 Examples of the 4- to 7-membered saturated ring formed together include azetidine, pyrrolidine, and piperidine. In another embodiment, piperidine can be exemplified.

[0370] The above R Cy1 With R Cy2 The 4- to 7-membered saturated ring or 7- to 11-membered spiro ring formed together may be substituted with a 1 1 to 3 identical or different substituents in the group.

[0371] As the above G 1 The above G 1 Group, and the above G 11 ~G 12 Group method.

[0372] The following compounds can be exemplified as specific compounds included in the present invention, but the present invention is not limited to these compounds.

[0373] [Table 1]

[0374]

[0375] In the present specification, the "compound represented by formula (1)" is generally understood to be a free compound represented by formula (1). In addition, examples of salts of the compound include the following salts.

[0376] That is, as the salt of the compound represented by formula (1), its type is not particularly limited, and it can be any one of acid addition salt or base addition salt, or it can take the form of intramolecular counterion. In particular, when it is used as the active ingredient of a drug, as the salt, a pharmaceutically acceptable salt is preferred. In this specification, when it is disclosed in connection with the use as a drug, as the salt of the compound represented by formula (1), it is generally understood to be a pharmaceutically acceptable salt. As an acid addition salt, for example, it includes an acid addition salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid, or an acid addition salt with an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, citric acid, malic acid, tartaric acid, dibenzoyltartaric acid, mandelic acid, maleic acid, fumaric acid, aspartic acid or glutamic acid. Examples of base addition salts include base addition salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum, and base addition salts with organic bases such as methylamine, 2-aminoethanol, arginine, lysine, or ornithine. In particular, the types of salts are not limited to these, and those skilled in the art can of course select them appropriately.

[0377] The compound of the present invention includes a hydrate form. In addition, the compound of the present invention also includes an anhydrate form.

[0378] The compounds of the present invention include solvate forms. In addition, the compounds of the present invention also include ansolvate form.

[0379] The compound of the present invention includes a crystalline form. In addition, the compound of the present invention also includes an amorphous form.

[0380] The compounds of the present invention also include those labeled with various radioactive or non-radioactive isotopes.

[0381] More specifically, the compound of the present invention includes an anhydrate and ansolvate of the "compound represented by formula (1)", or a hydrate and / or solvate thereof, or further includes crystals thereof.

[0382] The compound of the present invention includes an anhydrate and ansolvate of the "salt of the compound represented by formula (1)", or a hydrate and / or solvate of the salt, or further includes crystals thereof.

[0383] The compounds of the present invention may also include pharmaceutically acceptable prodrugs of the "compound represented by formula (1)". Pharmaceutically acceptable prodrugs refer to compounds having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, etc. by solvent decomposition or under physiological conditions. For example, as a group that forms a prodrug for a hydroxyl group and an amino group, acyl groups and alkoxycarbonyl groups can be exemplified. In addition, as a group that forms a prodrug for a carboxyl group, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, amino, methylamino, ethylamino, dimethylamino or diethylamino can be exemplified.

[0384] For example, a prodrug-forming reagent such as a corresponding halide can be used to introduce a group that can suitably form a prodrug into any one or more groups selected from hydroxyl and amino groups in the compound of the present invention according to a conventional method, and then appropriately separated and purified according to a conventional method as needed to produce a prodrug. In addition, a prodrug-forming reagent such as a corresponding alcohol or amine can also be used to introduce a group that can suitably form a prodrug into a carboxyl group in the compound of the present invention according to a conventional method.

[0385] Conventional manufacturing method

[0386] The compound represented by formula (1) can be manufactured according to a known method, for example, the method shown below, according to the method shown in these methods or the embodiment. It should be noted that the compound as a raw material in each of the following manufacturing methods can be commercially available, or can be manufactured using a known method described in, for example, "Compendium of Organic Synthesis Methods, Vol. I-XII (Wiley-Interscience)".

[0387] Some intermediates can be used by introducing a protecting group or removing the protecting group by a known method, for example, the method described in “Peter GM Wuts, Greene's Protective Groups in Organic Chemistry, John Wiley & Sons, 2014”.

[0388] A mixture of stereoisomers can be separated by a known method, for example, the method described in "EL Eloel, SH Wilen, Stereochemistry of Organic compounds, John Wiley & Sons, 1994", a method in accordance therewith, or a method described in the Examples. Aggregates can also be separated by the above method.

[0389] The reaction for synthesizing the compound of the present invention is carried out in a selected appropriate solvent according to a known method. The appropriate solvent does not react substantially with the starting material, intermediate or product at the temperature (e.g., at a temperature ranging from the melting point to the boiling point of the solvent) at which the reaction is carried out. The reaction can be carried out in a single solvent or a mixed solvent. A solvent suitable for each reaction can be used.

[0390] The reaction can be followed by appropriate methods according to known methods. For example, the product can be detected by spectroscopic methods, such as 1 H or 13 The samples were tracked by nuclear magnetic resonance (NMR), infrared spectrophotometer (IR), mass spectrometer (MS), high performance liquid chromatography (HPLC), thin layer chromatography (TLC), etc.

[0391] The compounds represented by formula (1) and their intermediates can be prepared by the synthesis method described below. Unless otherwise stated, R in the following reaction formula and description is 1 , R 2 , R 11 , R 12 , R 15 , R cy3 , Cy have the same meaning as above. The method described in this specification and the technical common sense in the technical field are appropriately applied, and the compound of the present invention can also be manufactured by a method other than the method described in this specification. The purpose of reaction formula, embodiment, etc. is to illustrate, and does not limit the scope of the present invention.

[0392] The abbreviations used in the following routes are generally based on the abbreviations used in the technical field. The chemical abbreviations used in this specification and examples are defined as follows: DMF = N, N-dimethylformamide, DMSO = dimethyl sulfoxide, THF = tetrahydrofuran, DME = 1,2-dimethoxyethane, TFA = trifluoroacetic acid, h = time, rt = room temperature, RT = holding time, LG = leaving group.

[0393] The compound of the present invention represented by formula (1) can be produced, for example, according to the following reaction scheme. In the following scheme, "STEP" means a step, and for example, "STEP1" means step 1.

[0394] [Chemistry 57]

[0395]

[0396] The compound represented by formula (1) can be prepared by the method described in, for example, reaction scheme 1 (in the formula of each compound, L represents a leaving group such as -Cl, -Br, pentafluorophenyl, or a substituent such as a hydroxyl group that can form an amide bond. In addition, halo represents -Cl, -Br or -I. In addition, M represents a substituent such as ZnI, MgBr, boric acid, boric ester, etc. that can react by various couplings). The compounds represented by formulas (4) to (9) can be obtained commercially or can be prepared by known methods, such as the methods shown below, according to their methods.

[0397] Step 1

[0398] The compound represented by formula (1) can be produced by an amidation reaction, an acylation reaction, etc. of a compound represented by formula (4) and a compound represented by formula (5). As an amidation condensation agent, 1-propanephosphonic anhydride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, HATU, etc. can be used. As an amidation nucleophilic agent, HOBt, HOAt, etc. can be used. As a base, diisopropylethylamine, etc. can be used. As a reaction solvent, for example, DMF, dichloromethane, THF, etc. can be used. Regarding the reaction temperature, it can usually be carried out at 0°C to 150°C. The substituents Cy, R 1 , R 2 The substituents can be converted into the compound represented by formula (1) by further conversion, for example, by deprotection, reduction, reductive amination, alkylation, fluorination, or the like.

[0399] Step 2

[0400] Regarding the compound represented by formula (5), it can be manufactured by a coupling reaction using a metal catalyst in which the compound represented by formula (7) participates. More specifically, it can be manufactured by Suzuki-Miyaura coupling of the compound represented by formula (7) and the reagent represented by formula (6). As a reaction catalyst, for example, Pd(dppf)Cl2, PdAmphos, Pd(PPh3)4, etc. can be used. As a base, cesium carbonate, cesium fluoride, sodium carbonate, etc. can be used. As a reaction solvent, THF, 1,4-dioxane, DMF, acetonitrile, etc. can be used. Regarding the reaction temperature, it can usually be carried out at room temperature to 180°C.

[0401] Step 3

[0402] Regarding the compound represented by formula (5), it can be manufactured by a coupling reaction using a metal catalyst involving a compound represented by formula (9). More specifically, it can be manufactured by Suzuki-Miyaura coupling of a compound represented by formula (9) and a reagent represented by formula (8). As a reaction catalyst, for example, Pd(dppf)Cl2, PdAmphos, Pd(PPh3)4, etc. can be used. As a base, cesium carbonate, cesium fluoride, sodium carbonate, etc. can be used. As a reaction solvent, THF, 1,4-dioxane, DMF, acetonitrile, etc. can be used. Regarding the reaction temperature, it can usually be carried out at room temperature to 180°C.

[0403] Regarding the compound represented by formula (9), for example, it can be manufactured by a coupling reaction using a metal catalyst and a halogen-metal exchange reaction involving a compound represented by formula (7). More specifically, it can be manufactured by Suzuki-Miyaura coupling of a compound represented by formula (5) and bis(pinacolato)diboron, etc. As a reaction catalyst, for example, Pd(dppf)Cl2 can be used. As a base, potassium acetate, etc. can be used. As a reaction solvent, 1,4-dioxane, etc. can be used. Regarding the reaction temperature, it can usually be carried out at 40°C to 150°C.

[0404] [Chemistry 58]

[0405]

[0406] The compound represented by formula (1) can be prepared, for example, by the method described in reaction scheme 2 (in the formula of each compound, L represents a leaving group such as -Cl, -Br, pentafluorophenyl, or a substituent such as a hydroxyl group that can form an amide bond. In addition, halo represents -Cl, -Br or -I. In addition, M represents a substituent such as ZnI, MgBr, boric acid, boric ester, etc. that can react by various coupling reactions). The compounds represented by formulas (4), (6) to (8), (10), and (11) can be obtained commercially, or can be prepared by known methods, such as the method shown below, or by methods according to them.

[0407] Step 5

[0408] The compound represented by formula (1) can be produced by a coupling reaction using a metal catalyst involving a compound represented by formula (10). More specifically, it can be produced by Suzuki-Miyaura coupling of a compound represented by formula (10) with a reagent represented by formula (6). As a reaction catalyst, for example, Pd(dppf)Cl2, PdAmphos, Pd(PPh3)4, etc. can be used. As a base, cesium carbonate, cesium fluoride, sodium carbonate, etc. can be used. As a reaction solvent, THF, 1,4-dioxane, DMF, acetonitrile, etc. can be used. Regarding the reaction temperature, it can usually be carried out at room temperature to 180°C. The substituents Cy, R 1 , R 2 The substituents can be converted into the compound represented by formula (1) by further conversion, for example, by deprotection, reduction, reductive amination, alkylation, fluorination, or the like.

[0409] Step 6

[0410] The compound represented by formula (10) can be produced by an amidation reaction, an acylation reaction, etc. of a compound represented by formula (4) and a compound represented by formula (7). As an amidation condensation agent, 1-propanephosphonic anhydride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, HATU, etc. can be used. As an amidation nucleophilic agent, HOBt, HOAt, etc. can be used. As a base, diisopropylethylamine, etc. can be used. As a reaction solvent, for example, DMF, dichloromethane, THF, etc. can be used. Regarding the reaction temperature, it can usually be carried out at 0°C to 150°C.

[0411] Step 7

[0412] Regarding the compound represented by formula (1), it can be manufactured by a coupling reaction using a metal catalyst in which a compound represented by formula (11) participates. More specifically, it can be manufactured by Suzuki-Miyaura coupling of a compound represented by formula (11) and a reagent represented by formula (8). As a reaction catalyst, for example, Pd(dppf)Cl2, PdAmphos, Pd(PPh3)4, etc. can be used. As a base, cesium carbonate, cesium fluoride, sodium carbonate, etc. can be used. As a reaction solvent, THF, 1,4-dioxane, DMF, acetonitrile, etc. can be used. Regarding the reaction temperature, it can usually be carried out at room temperature to 180°C.

[0413] Step 8

[0414] Regarding the compound represented by formula (9), for example, it can be manufactured by a coupling reaction using a metal catalyst and a halogen-metal exchange reaction in which a compound represented by formula (10) participates. More specifically, it can be manufactured by Suzuki-Miyaura coupling of a compound represented by formula (10) and bis(pinacolato)diboron, etc. As a reaction catalyst, for example, Pd(dppf)Cl2, etc. can be used. As a base, potassium acetate, etc. can be used. As a reaction solvent, 1,4-dioxane, etc. can be used. Regarding the reaction temperature, it can usually be carried out at 40°C to 150°C.

[0415] [Chemistry 59]

[0416]

[0417] Among the compounds represented by formula (1), the compound (12) represented by formula (2-1-1) can be prepared by the method described in, for example, reaction scheme 3 (in the formula of each compound, L represents a leaving group such as -Cl, -Br, pentafluorophenyl, or a substituent capable of forming an amide bond such as a hydroxyl group). The compounds represented by formulas (5), (13), and (14) can be obtained commercially, or can be prepared by known methods, such as the methods described below, or by methods according to these methods.

[0418] Step 9

[0419] The compound represented by formula (10) can be prepared by a reductive amination reaction of a compound represented by formula (14). 11 R 12 It is produced by forming an imine in the presence of NH, followed by reduction of the imine using sodium triacetoxyborohydride. As a reaction solvent, THF or dichloromethane can be used. The reaction temperature is usually 0°C to 80°C. Substituent R 11 R 12 , R 1 , R 2 The substituents can be converted into the compound represented by formula (12) by further transformation, for example, deprotection, reduction, alkylation, fluorination, or the like.

[0420] Step 10

[0421] The compound represented by formula (14) can be prepared by an amidation reaction, an acylation reaction, etc. of a compound represented by formula (5) and a compound represented by formula (15). As an amidation condensation agent, 1-propanephosphonic anhydride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, HATU, etc. can be used. As an amidation nucleophilic agent, HOBt, HOAt, etc. can be used. As a base, diisopropylethylamine, etc. can be used. As a reaction solvent, for example, DMF, dichloromethane, THF, etc. can be used. Regarding the reaction temperature, it can usually be carried out at 0°C to 150°C.

[0422] [Chemistry 60]

[0423]

[0424] In the compound represented by formula (1), Cy is of formula (1-1-2), wherein X is NR 15 The compound (16) represented by the reaction scheme 4 can be prepared, for example, by CN The compounds represented by formula (14), (17) to (20) can be obtained commercially or can be produced by known methods, such as the methods shown below, or according to the methods described above.

[0425] Step 11

[0426] Regarding the compound represented by formula (16), it can be produced by a CN bond forming reaction such as amidation, acylation, alkylation, ureidation, etc. involving a compound represented by formula (18). More specifically, it can be produced by an amidation reaction of a compound represented by formula (18) with a reagent represented by formula (17). As an amidation condensation agent, 1-propanephosphonic anhydride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, HATU, etc. can be used. As an amidation nucleophilic agent, HOBt, HOAt, etc. can be used. As a base, diisopropylethylamine, etc. can be used. As a reaction solvent, for example, DMF, dichloromethane, THF, etc. can be used. Regarding the reaction temperature, it can usually be carried out at 0°C to 150°C. The substituent R 15 , R 1 , R 2 The substituents can be converted into the compound represented by formula (16) by further transformation, for example, deprotection, reduction, reductive amination, alkylation, fluorination, or the like.

[0427] Step 12

[0428] The compound represented by formula (18) can be produced by deprotecting the compound represented by formula (19). The deprotection reaction can be carried out according to a known method, for example, the method described in Greene's Protective Groups in Organic Synthesis, published by John Wiley and Sons (2014 edition).

[0429] Step 13

[0430] The compound represented by formula (19) can be prepared by a reduction amination reaction of the compound represented by formula (14). For example, it can be prepared by forming an imine in the presence of a compound represented by formula (20), followed by a reduction reaction of the imine using sodium triacetoxyborohydride. As a reaction solvent, THF or dichloromethane can be used. Regarding the reaction temperature, it can usually be carried out at 0°C to 80°C.

[0431] [Chemistry 61]

[0432]

[0433] In the compound represented by formula (7), Rg is the general formula (1-1), halo is bromine, R 1 By-OR al (R al is substituted or unsubstituted C 1-3 The compound (21) represented by an alkyl group can be prepared by, for example, reaction scheme 5 (wherein Y CO is a leaving group such as -Cl, -Br, -I, OTf, OMs or OTs, or a substituent such as a hydroxyl group that can form a CO bond. ac Represents acyl groups such as acetyl and cyclopropyl. In addition, L represents a leaving group such as -Cl, -Br, pentafluorophenyl, or a substituent such as a hydroxyl group that can form an amide bond. In addition, PG represents a protecting group published in Greene's Protective Groups in Organic Synthesis, John Wiley and Sons (2014 edition)) and is manufactured by the method described in the above. The compounds represented by formulas (22) to (30) can be commercially available or can be manufactured by known methods, such as the methods shown below, according to their methods.

[0434] Step 14

[0435] The compound represented by formula (21) can be prepared by deprotecting the compound represented by formula (19). The deprotection reaction is carried out according to a known method, for example, the method described in Greene's Protective Groups in Organic Synthesis, John Wiley and Sons (2014 edition). al The substituent can be converted into a compound represented by formula (21) by further conversion, for example, by deprotection, reduction, reductive amination, alkylation, fluorination, or the like.

[0436] Step 15

[0437] The compound represented by formula (22) can be produced by a CO bond forming reaction such as alkylation of a compound represented by formula (24) and a compound represented by formula (23), Mitsunobu reaction, etc. More specifically, it can be produced by an alkylation reaction of a compound represented by formula (24) and a reagent represented by formula (23). As an alkylating agent, iodomethane or the like can be used. As a base, diisopropylethylamine, potassium carbonate, etc. can be used. As a reaction solvent, for example, DMF, dichloromethane, THF, etc. can be used. Regarding the reaction temperature, it can usually be carried out at -78°C to 150°C.

[0438] Step 16

[0439] The compound represented by formula (24) can be produced by protecting the compound represented by formula (25). The protection reaction can be carried out according to a known method, for example, the method described in Greene's Protective Groups in Organic Synthesis, published by John Wiley and Sons (2014 edition).

[0440] Step 17

[0441] The compound represented by formula (25) can be produced by deacylation of the compound represented by formula (26). More specifically, it can be produced by hydrolyzing the compound represented by formula (26) in the presence of an acid. As the acid, hydrochloric acid or the like can be used. As the reaction solvent, methanol, water, THF or the like can be used. Regarding the reaction temperature, it can generally be carried out at room temperature to 100°C.

[0442] Step 18

[0443] The compound represented by formula (26) can be produced by aromatizing the compound represented by formula (27) in the presence of a base. As the base, DBU or the like can be used. As the reaction solvent, THF or the like can be used. The reaction temperature can generally be -20°C to 80°C.

[0444] Step 19

[0445] The compound represented by formula (27) can be prepared by brominating the compound represented by formula (28) in the presence of a base. Bromination agents such as bromine and NBS can be used. Acids such as hydrobromic acid can be used. Acetic acid can be used as reaction solvents. The reaction temperature can generally be carried out at room temperature to 60°C.

[0446] Step 20

[0447] The compound represented by formula (28) can be prepared by an amidation reaction, an acylation reaction, etc. of a compound represented by formula (30) and a compound represented by formula (29). As an acylating agent, an acid anhydride such as acetic anhydride can be used. As an amidation condensation agent, 1-propanephosphonic anhydride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, HATU, etc. can be used. As an amidation nucleophilic agent, HOBt, HOAt, etc. can be used. As a base, diisopropylethylamine, etc. can be used. As a reaction solvent, for example, DMF, dichloromethane, THF, etc. can be used. Regarding the reaction temperature, it can usually be carried out at 0°C to 150°C.

[0448] [Chemistry 62]

[0449]

[0450] In the compound represented by formula (10), Rg is the general formula (1-1), R 1 By-OR al (R al is substituted or unsubstituted C 1-3 The compound (31) represented by an alkyl group can be prepared by, for example, reaction scheme 6 (wherein Y CO The compound represented by formula (32) can be obtained commercially or can be manufactured by a known method, such as the method shown below, according to the method described in the invention.

[0451] Step 21

[0452] The compound represented by formula (31) can be prepared by a CO bond forming reaction such as alkylation or Mitsunobu reaction of a compound represented by formula (32) with a compound represented by formula (23). More specifically, the compound represented by formula (32) can be prepared by reacting Y in formula (23) with a compound represented by formula (32). COIt is produced by the Mitsunobu reaction of a reagent represented by a hydroxyl group. As the reagent of the Mitsunobu reaction, diethyl azocarboxylate, triphenylphosphine, etc. can be used. As the reaction solvent, THF, toluene, etc. can be used. Regarding the reaction temperature, it can be usually carried out at 0°C to 110°C.

[0453] [Chemistry 63]

[0454]

[0455] In the compound represented by formula (1), Rg is the general formula (1-1), R 1 By-OR al (R al is substituted or unsubstituted C 1-3 The compound (33) represented by an alkyl group can be prepared by, for example, reaction scheme 7 (wherein Y CO Represents a leaving group such as -Cl, -Br, -I, OTf, OMs or OTs, or a substituent such as a hydroxyl group that can form a CO bond. In addition, PG represents a protecting group published in Greene's Protective Groups in Organic Synthesis, John Wiley and Sons (2014 edition)) and is manufactured by the method described in the publication. The compounds represented by formula (23), formula (34) and formula (35) can be commercially available or can be manufactured by a known method, such as the method shown below, according to their methods.

[0456] Step 22

[0457] The compound represented by formula (33) can be prepared by deprotecting the compound represented by formula (34). The deprotection reaction can be carried out according to a known method, for example, the method described in Greene's Protective Groups in Organic Synthesis, John Wiley and Sons (2014 edition). al The substituent can be converted into a compound represented by formula (33) by further transformation, for example, deprotection, reduction, reductive amination, alkylation, fluorination, or the like.

[0458] Step 23

[0459] The compound represented by formula (34) can be produced by a CO bond forming reaction such as alkylation or Mitsunobu reaction between the compound represented by formula (35) and the compound represented by formula (23). More specifically, the compound represented by formula (35) can be produced by reacting Y in formula (23) with the compound represented by formula (34). COIt is produced by alkylation reaction of a reagent represented by a halogen group such as -Br or -I. As a base, diisopropylethylamine, cesium carbonate, etc. can be used. As a reaction solvent, for example, DMF, dichloromethane, THF, etc. can be used. Regarding the reaction temperature, it can usually be carried out at 0°C to 150°C.

[0460] [Chemistry 64]

[0461]

[0462] Among the compounds represented by formula (7), compound (36) in which Rg is represented by general formula (1-2) can be prepared, for example, by the method described in reaction scheme 8. Compounds represented by formulas (37) to (40) are commercially available or can be prepared by known methods, for example, the methods described below, or in accordance with these methods.

[0463] Step 24

[0464] The compound represented by formula (36) can be prepared by cyclization reaction of the compound represented by formula (37). As the base, potassium carbonate, DBU, etc. can be used. As the reaction solvent, DMF, etc. can be used. The reaction temperature can usually be 0°C to 180°C. The substituent R 1 The substituent can be converted into a compound represented by formula (36) by further transformation, for example, deprotection, reduction, reductive amination, alkylation, fluorination, or the like.

[0465] Step 25

[0466] The compound represented by formula (37) can be produced by reacting the compound represented by formula (38) with O-(trisyl)hydroxylamine. Chloroform or dichloromethane can be used as the reaction solvent. The reaction temperature is usually 0°C to 50°C.

[0467] Step 26

[0468] The compound represented by formula (38) can be prepared by cyaniding the compound represented by formula (39). As the cyaniding agent, sodium cyanide, potassium cyanide, etc. can be used. As the reaction solvent, ethanol, water, DMF, etc. can be used. Regarding the reaction temperature, it can be generally carried out at 0°C to 120°C.

[0469] Step 27

[0470] The compound represented by formula (39) can be prepared by brominating the compound represented by formula (40). As the brominating agent, N-bromosuccinimide, bromine, etc. can be used. As the reaction solvent, ethanol, water, DMF, etc. can be used. Regarding the reaction temperature, it can usually be carried out at 0°C to 120°C.

[0471] [Chemistry 65]

[0472]

[0473] Among the compounds represented by formula (6), the compound (41) represented by Z (Z represents a boron derivative such as boronic acid B(OH)2 or a boric acid ester) can be prepared by, for example, reaction scheme 8 (wherein LG 1 The compounds represented by formula (42) to (46) are commercially available or can be produced by known methods, such as the methods described below, or by methods according to these methods.

[0474] Step 28

[0475] The compound represented by formula (41) can be prepared by CH borylation of the compound represented by formula (42) using an iridium catalyst. As a boron source, for example, bis(pinacolato)diboron can be used. As a reaction solvent, THF can be used. Regarding the reaction temperature, it can usually be carried out at 20°C to 80°C.

[0476] Step 29

[0477] The compound represented by formula (42) can be prepared by etherifying the compound represented by formula (44) and the compound represented by formula (43) under alkaline conditions. As a base, for example, sodium hydride or sodium hydroxide can be used. As a catalyst, for example, tetrabutylammonium chloride can be used. As a reaction solvent, THF, DMF, dichloromethane can be used. Regarding the reaction temperature, it can usually be carried out at 0°C to 150°C.

[0478] Step 30

[0479] The compound represented by formula (42) can be prepared by etherifying the compound represented by formula (46) and the compound represented by formula (45) under alkaline conditions. As a base, for example, sodium hydride or sodium hydroxide can be used. As a catalyst, for example, tetrabutylammonium chloride can be used. As a reaction solvent, THF, DMF, dichloromethane can be used. Regarding the reaction temperature, it can usually be carried out at 0°C to 150°C.

[0480] Step 31

[0481] The compound represented by formula (46) can be produced by subjecting the compound represented by formula (44) to halogenation including chlorination. As the chlorinating agent, for example, thionyl chloride can be used. As the reaction solvent, dichloromethane can be used. The reaction temperature can generally be 0°C to 40°C.

[0482] [Chemistry 66]

[0483]

[0484] The compound represented by formula (6) can be prepared by, for example, reaction scheme 10 (wherein, LG 1 In the formula (8), (44), (45), (47), (48), the compounds represented by formula (8), (44), (45), (47), (48) can be obtained commercially or can be manufactured by known methods, such as the methods shown below, according to the methods thereof.

[0485] Step 32

[0486] Regarding the compound represented by formula (6), for example, it can be manufactured by a coupling reaction using a metal catalyst, a halogen-metal exchange reaction involving a compound represented by formula (8). More specifically, it can be manufactured by Suzuki-Miyaura coupling of a compound represented by formula (6) with bis(pinacolato)diboron, etc. As a reaction catalyst, for example, Pd(dppf)Cl2, etc. can be used. As a base, potassium acetate, etc. can be used. As a reaction solvent, 1,4-dioxane, etc. can be used. Regarding the reaction temperature, it can usually be carried out at 40°C to 150°C.

[0487] Step 33

[0488] The compound represented by formula (8) can be prepared by etherifying the compound represented by formula (47) and the compound represented by formula (44) under alkaline conditions. As a base, for example, sodium hydride or sodium hydroxide can be used. As a catalyst, for example, tetrabutylammonium chloride can be used. As a reaction solvent, THF, DMF, dichloromethane can be used. Regarding the reaction temperature, it can usually be carried out at 0°C to 150°C.

[0489] Step 34

[0490] The compound represented by formula (8) can be prepared by etherifying the compound represented by formula (48) and the compound represented by formula (45) under alkaline conditions. As a base, for example, sodium hydride or sodium hydroxide can be used. As a catalyst, for example, tetrabutylammonium chloride can be used. As a reaction solvent, THF, DMF, dichloromethane can be used. Regarding the reaction temperature, it can usually be carried out at 0°C to 150°C.

[0491] Step 35

[0492] The compound represented by formula (48) can be produced by subjecting the compound represented by formula (47) to halogenation including chlorination. As the chlorinating agent, for example, thionyl chloride can be used. As the reaction solvent, dichloromethane can be used. The reaction temperature can generally be 0°C to 40°C.

[0493] The method for producing the compound of the present invention is not limited to the method described herein. For example, the compound of the present invention can be produced by modifying / converting the substituent of the compound serving as a precursor thereof by combining one or more reactions described in common chemical literature.

[0494] Among the compounds of the present invention, as examples of methods for producing compounds containing asymmetric carbon atoms, there can be cited methods based on asymmetric reduction, methods using commercially available raw material compounds (or prepared by known methods or capable of being prepared according to known methods) whose parts corresponding to asymmetric carbon atoms have optical activity in advance, optical resolution using enzymes, or methods for producing optically active compounds, etc. In addition, there are methods for separating the compounds of the present invention or their precursors by conventional methods into optically active isomers. As such methods, there are, for example, the following methods: methods using high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC) using optically active columns; classical optical fractional crystallization methods in which an optically active reagent and a salt are formed, separated by fractional crystallization, etc., and then the salt is formed; or methods in which the generated diastereomers are separated and purified by condensation with an optically active reagent and then decomposed again, etc. When the precursor is separated to form an optically active form, the production method shown above is then implemented to produce an optically active compound of the present invention.

[0495] In the compound of the present invention, when the compound contains an acidic functional group such as a carboxyl group, a phenolic hydroxyl group or a tetrazole ring, it can also be made into a pharmaceutically acceptable salt (for example, an inorganic salt with sodium or an organic salt with triethylamine) by known means. For example, in the case of obtaining an inorganic salt, the compound of the present invention is preferably dissolved in water containing a hydroxide, carbonate, bicarbonate, etc. corresponding to the desired inorganic salt. In the reaction, an inert organic solvent miscible with water such as methanol, ethanol, acetone or dioxane can be mixed. For example, a solution of a sodium salt can be obtained by using sodium hydroxide, sodium carbonate or sodium bicarbonate.

[0496] In addition, in the compound of the present invention, when containing an amino group contained in the compound, or when containing a basic functional group in addition thereto, or when containing an aromatic ring (such as a pyridine ring, etc.) having a basic property itself, they can be made into pharmaceutically acceptable salts (such as salts with inorganic acids such as hydrochloric acid or salts with organic acids such as acetic acid) by known means. For example, in the case of obtaining a salt with an inorganic acid, the compound of the present invention is preferably dissolved in an aqueous solution containing the desired inorganic acid. In the reaction, an inert organic solvent miscible with water such as methanol, ethanol, acetone or dioxane can be mixed. For example, a solution of a hydrochloride can be obtained by using hydrochloric acid.

[0497] When a solid salt is desired, the solution may be evaporated or a water-miscible organic solvent having a certain degree of polarity such as n-butanol or ethyl methyl ketone may be further added to obtain the solid salt.

[0498] The various compounds described in the present invention can be purified by known methods, for example, various chromatography methods (column chromatography, flash column chromatography, thin layer chromatography, high performance liquid chromatography, supercritical fluid chromatography).

[0499] A certain embodiment of the compound of the present invention has IRAK-4 inhibitory activity and can be used as an IRAK-4 inhibitor. That is, a certain embodiment of the compound of the present invention can be used as a drug for preventing and / or treating diseases associated with IRAK-4 inhibition. Regarding diseases associated with IRAK-4 inhibition, if described in detail, diseases associated with IRAK-4 inhibition are diseases that exert effects through IRAK-4 inhibition, and more specifically, there is no particular limitation as long as the disease can be prevented and / or treated by inhibiting the production of inflammatory mediators such as TNFα and IL-6 due to the inhibition of TLRs or IL-1 family signal transduction system.

[0500] The IRAK-4 inhibitory activity can be measured, for example, by the method described in Test Example 1 or 2 below.

[0501] Diseases associated with IRAK-4 inhibition are not particularly limited as long as they are diseases that exert their effects through IRAK-4 inhibition. Specifically, examples include acute or chronic inflammation, autoimmune diseases (rheumatic arthritis, systemic lupus erythematosus, lupus nephritis, etc.), autoinflammatory diseases (TNF receptor-associated periodic syndrome (TRAPS), familial Mediterranean fever, cryopyrin-associated periodic fever syndrome, high IgD syndrome, etc.), metabolic diseases (gout, etc.), etc.

[0502] As shown in the test examples described below, one embodiment of the compound of the present invention has a TLR / IL-1β signaling inhibitory effect and is useful as an active ingredient of a drug. In particular, one embodiment of the compound of the present invention is preferably used for the prevention and / or treatment of diseases associated with IRAK-4 signaling.

[0503] One embodiment of the compound of the present invention shows high selectivity for other kinases. Examples of other kinases include FLT3, ITK, CK2, IKKb, JAK1, Syk, PKCθ, or p38. In another embodiment, FLT3 is particularly exemplified.

[0504] One embodiment of the drug of the present invention is useful for the prevention and / or treatment of diseases related to IRAK-4 signaling, which can be confirmed by, for example, a cytokine production inhibition test using immune cells or a collagen-induced arthritis model. Specifically, the method described in Test Example 3 described below can be exemplified.

[0505] A certain aspect of the drug of the present invention can be prepared in the form of a drug containing the compound represented by formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. For example, the case where a compound or a pharmaceutically acceptable salt thereof administered as a prodrug is metabolized in vivo to generate a compound represented by formula (1) or a pharmaceutically acceptable salt thereof is also included in the scope of the drug of the present invention.

[0506] The administration route of a certain aspect of the drug of the present invention is not particularly limited, and can be appropriately selected from, for example, oral administration, subcutaneous administration, intradermal administration, intramuscular injection, intravenous administration, transnasal administration, transvaginal administration, intrarectal administration, or topical administration to an affected area.

[0507] As the drug of the present invention, the compound represented by formula (1) or its pharmaceutically acceptable salt can be used directly, but it is preferred to add one or two or more pharmaceutically acceptable carriers to the compound represented by formula (1) or its pharmaceutically acceptable salt to prepare a pharmaceutical composition for administration. In addition, as the active ingredient of the drug of the present invention, a hydrate or solvate of the compound represented by formula (1) or its pharmaceutically acceptable salt can be used.

[0508] As the dosage form used for the preparation of the above-mentioned pharmaceutical composition, tablets, powders, granules, syrups, suspensions, capsules, inhalants or injections can be cited. In order to manufacture these dosage forms, various carriers corresponding to these preparations are used. For example, as a carrier for oral agents, excipients, adhesives, lubricants, fluidity promoters or colorants can be cited. As inhalants, powders of the pharmaceutical composition can be directly inhaled or reagents formed by dissolving or suspending the pharmaceutical composition in a solvent can be cited, or methods for inhaling the powders can be made into mist using a sprayer called an atomizer or a spray inhaler. In addition, in the case of injections, distilled water for injection, saline, glucose aqueous solution, vegetable oil for injection, propylene glycol or polyethylene glycol can usually be used as diluents. Further, bactericides, preservatives, stabilizers, isotonic agents or painless agents can be added as needed. The compound of the present invention can also be enclosed in cyclodextrin to form an inclusion compound and used as the drug of the present invention.

[0509] When a certain mode of administering the medicine of the present invention is used, it is appropriate to select a suitable dosage form and administer it by a suitable route. For example, it can be orally administered in the form of tablets, powders, granules, syrups, suspensions or capsules. In addition, it can be administered through the trachea in the form of an inhalant. In addition, it can be administered subcutaneously, intradermally, intravascularly, intramuscularly or intraperitoneally in the form of an injection including drip. In addition, it can be administered through the mucosa in the form of a sublingual agent or a suppository, and can be administered transdermally in the form of a gel, a lotion, an ointment, a cream or a spray. In addition, it can also be made into a continuous preparation, such as a sustained-release injection or an implant preparation (such as a film preparation) for administration.

[0510] The administration period of a certain mode of the medicine of the present invention is not particularly limited, and the principle is to administer the medicine during the period when it is judged that the disease shows clinical symptoms, usually for several weeks to one year. However, the administration period can be further extended according to the condition of the disease, or the administration can be further continued after the clinical symptoms recover. In addition, even in the state where clinical symptoms are not shown, preventive administration can be carried out according to the judgment of the clinician. The dosage of a certain mode of the medicine of the present invention is not particularly limited, for example, when the medicine of the present invention is orally administered, an adult can usually be given 0.01 to 1000 mg of the active ingredient once. The frequency of administration in this case can be once every 6 months to continuous administration, preferably once / day.

[0511] The daily and / or single dosage, dosage period, and dosage frequency can be appropriately increased or decreased depending on the patient's age, weight, physical health, and the type and severity of the disease to be treated, the route of administration, the dosage form (the sustained release of the active ingredient possessed by the carrier, etc.), and other conditions.

[0512] When a certain mode of medicine of the present invention is used for the prevention and / or treatment of the above-mentioned disease, a certain mode of medicine of the present invention can be used simultaneously with 1 or 2 or more medicaments selected from the medicament shown below or used together at different times. In addition, a certain mode of medicine of the present invention can also be prepared into so-called compound preparation together with the medicament illustrated above and be administered. As this compound preparation, not only can the form of administration with the form of complete mixture of active ingredients as typical compositions, but also comprise the administration form, test kit, packaging based on non-mixed type combination that is administered respectively from a plurality of containers equipped with each active ingredient.

[0513] Examples of drugs that can be used in combination with a certain embodiment of the drug of the present invention include immunosuppressants (tacrolimus, cyclosporin, rapamycin, mycophenolic acid mofetil, interferon preparations, cyclophosphamide, azathioprine, methotrexate, etc.), anti-inflammatory drugs (steroids (prednisolone, dexamethasone, betamethasone, cortisone), non-steroidal anti-inflammatory drugs (NSAIDs) (ibuprofen, celecoxib), disease-modifying antirheumatic drugs (gold preparations, methotrexate, leflunomide, sulfasalazine, penicillamine, iguratimod, chloroquine, tofacitinib, etc.), antimalarials (hydroxychloroquine, etc.), Multiple sclerosis therapeutic drugs (interferon, anti-α4 integrin preparations, fingolimod, mitoxantrone, etc.), anti-cytokine preparations (anti-TNFα preparations, anti-IL-6 preparations, anti-IL-12 / 23 preparations, etc.). In addition, biological drugs used as therapeutic drugs for autoimmune diseases (anti-CD20 preparations, CTLA-4-Ig, etc.), drugs for abnormal uric acid metabolism (colchicine, probenecid, bucolome, benzbromarone, allopurinol, etc.), hypoglycemic drugs (alogliptin, nateglinide, acarbose, methotrexate, etc.), guanidine, pioglitazone, insulin preparations, etc.), antihypertensive drugs (imidapril, valsartan, candesartan, etc.), bile secretion promoting drugs (ursodeoxycholic acid), bronchodilators (salmeterol and salbutamol as adrenergic β2 agonists, ipratropium and tiotropium bromide as anticholinergics, etc.), allergic disease therapeutic drugs (theophylline, etc.), antiallergic drugs (fexofenadine, epinastine, olopatadine, loratadine, cetirizine, bepotastine, ketotifen, sodium cromoglycate, pemirolast, chlorpheniramine, etc.), leukotriene antagonists (zafirlukast, montelukast, pranlukast, etc.), anti Hyperlipidemia drugs (atorvastatin, simvastatin, clinofibrate, bezafibrate, probucol, elastase, icosapentaenoic acid ethyl ester, etc.), neurotransmitter regulators (donepezil, galantamine, memantine, etc.), antioxidants (vitamin E, acetylcysteine, carnitine, betaine, pentoxifylline, etc.), antibiotics (various preparations such as β-lactam, macrolide, tetracycline, aminoglycoside, quinolone, chloramphenicol, etc.). In addition, it can be used in combination with various drugs to be created in the future. There is no limitation on these combined drugs as long as they are clinically significant combinations.

[0514] One embodiment of the compound of the present invention includes a compound having excellent safety (various toxicities, safety pharmacology) and pharmacokinetic properties, and its usefulness as an active ingredient of a drug can be confirmed by, for example, the method described below.

[0515] As safety-related tests, for example, the following tests are included, but not limited to the examples, including: cytotoxicity tests (tests using HL60 cells, hepatocytes, etc.), genotoxicity tests (Ames test, mouse lymphoma TK test, chromosome aberration test, micronucleus test, etc.), skin sensitization tests (Bueler method, GPMT method, APT method, LLNA test, etc.), skin photosensitivity tests (adjuvant and strip method, etc.), eye irritation tests (single eye drop, short-term continuous eye drop, repeated eye drop, etc.), safety pharmacology tests for the cardiovascular system (telemetry method, APD method, hERG inhibition evaluation method, etc.), safety pharmacology tests for the central nervous system (FOB method, Irwin's modified method, etc.), safety pharmacology tests for the respiratory system (measurement method using a respiratory function measurement device, measurement method using a blood gas analyzer, etc.), general toxicity tests, reproductive developmental toxicity tests, etc.

[0516] In addition, as tests related to pharmacokinetic performance, for example, the tests listed below are included, but not limited to the examples, including cytochrome P450 enzyme blocking or induction tests, cell permeability tests (tests using CaCO-2 cells, MDCK cells, etc.), drug transporter ATPase assay, oral absorption test, blood drug concentration transition measurement test, metabolic test (stability test, metabolic molecule species test, reactivity test, etc.), solubility test (solubility test based on turbidity method, etc.), etc.

[0517] The usefulness of a certain aspect of the compound of the present invention as an active ingredient of a drug can be confirmed by, for example, performing a cytotoxicity test. As a cytotoxicity test, methods using various cultured cells (e.g., human preleukemia cells HL-60 cells, primary isolated cultured cells of liver cells, neutrophil fractions prepared from human peripheral blood, etc.) can be cited. This test can be implemented by the method described below, but is not limited to this description. Prepare the cells into 10 5 / ml to 10 7 / ml of cell suspension, 0.01mL to 1mL of the suspension is dispensed into a microtube or microplate. A solution in which the compound is dissolved is added in an amount of 1 / 100 to 1 times the amount of the cell suspension, and cultured in a cell culture medium at a final concentration of the compound, such as 0.001μM to 1000μM, at 37°C and 5% CO2 for 30 minutes to several days. After the culture is completed, the cell survival rate is evaluated using the MTT method or the WST-I method (Ishiyama, M., et al., In Vitro Toxicology, 8, p.187, 1995). By measuring the cytotoxicity of the compound to cells, the usefulness of the active ingredient as a drug can be confirmed.

[0518] A certain aspect of the compound of the present invention is useful as an active ingredient of a drug, which can be confirmed by, for example, performing a genotoxicity test. As genotoxicity tests, Ames test, mouse lymphoma TK test, chromosome aberration test, micronucleus test, etc. can be cited. Ames test refers to the following method: using a specified strain of Salmonella, Escherichia coli, etc., to culture the bacteria on a petri dish mixed with a compound, thereby determining the reverse mutation (refer to II-1. Genotoxicity test in "Genetic Toxicity Test Guidelines" No. 1604 of the Japanese Pharmaceutical Review in 1999, etc.). In addition, the mouse lymphoma TK test refers to a test for detecting gene mutations using the thymidine kinase gene of mouse lymphoma L5178Y cells as a target (refer to II-3. Mouse lymphoma TK test in the 1999 Japanese Pharmaceutical Review No. 1604 "Guidelines for Genotoxicity Tests"; Clive, D. et al., Mutat. Res., 31, pp. 17-29, 1975; Cole, J., et al., Mutat. Res., 111, pp. 371-386, 1983, etc.). In addition, the chromosome aberration test refers to a method in which mammalian cultured cells are co-cultured with a compound, the cells are fixed, and the activity of causing chromosome aberrations is determined by staining and observing chromosomes (refer to II-2. Chromosome aberration test using mammalian cultured cells in the 1999 Japanese Pharmaceutical Review No. 1604 "Guidelines for Genotoxicity Tests", etc.). Furthermore, the micronucleus test is a test for evaluating the micronucleus formation ability caused by chromosomal aberrations, including methods using rodents (in vivo tests) (refer to II-4. Micronucleus test using rodents in the "Guidelines for Genotoxicity Tests" of Japan Pharmaceutical Review No. 1604 in 1999; Hayashi, M. et al., Mutat. Res., 312, pp. 293-304, 1994; Hayashi, M. et al., Environ. Mol. Mutagen., 35, pp. 234-252, 2000), methods using cultured cells (in vitro tests) (Fenech, M. et al., Mutat. Res., 147, pp. 29-36, 1985; Miller, B., et al., Mutat. Res., 392, pp. 45-59, 1997), etc. By clarifying the genotoxicity of a compound using any one or two or more of these methods, its usefulness as an active ingredient of a drug can be confirmed.

[0519] The usefulness of a certain embodiment of the compound of the present invention as an active ingredient of a drug can be confirmed by, for example, performing a skin sensitization test. Among the skin sensitization tests, as skin sensitization tests using guinea pigs, there are Buehler's method (Buehler, EV Arch. Dermatol., 91, pp. 171-177, 1965), GPMT method (maximum method (Magnusson, B. et al., J. Invest. Dermatol., 52, pp. 268-276, 1969)) or APT method (adjuvant and patch method (Sato, Y. et al., Contact Dermatitis, 7, pp. 225-237, 1981)). Furthermore, as a skin sensitization test using mice, there is the LLNA (Local Lymph node assay) method (OECD Guideline for the testing of chemicals 429, skin sensitization 2002; Takeyoshi, M. et al., Toxicol. Lett., 119 (3), pp. 203-8, 2001; Takeyoshi, M. et al., J. Appl. Toxicol., 25 (2), pp. 129-34, 2005), etc. By clarifying the skin sensitization of a compound using any one or two or more of these methods, the usefulness of the compound as an active ingredient of a drug can be confirmed.

[0520] The fact that a certain embodiment of the compound of the present invention is useful as an active ingredient of a medicine can be confirmed by conducting, for example, a skin photosensitivity test. Examples of the skin photosensitivity test include a skin photosensitivity test using a guinea pig (see "Explanation of the Guidelines for Non-clinical Trials of Pharmaceuticals 2002" Japan Yakuji Shimbun, 2002, 1-9: Skin photosensitivity test, etc.), and examples of the method include an adjuvant and keratostripping method (Ichikawa, H. et al., J. Invest. Dermatol., 76, pp. 498-501, 1981), a Harber method (Harber, LC, Arch. Dermatol., 96, pp. 646-653, 1967), a Horio method (Horio, T., J. Invest. Dermatol., 67, pp. 591-593, 1976), a Jordan method (Jordan, WP, Contact Dermatitis, 8, pp. 109-116, 1982), a Kochever method (Kochever, IE et al., J. Invest. Dermatol., 96, pp. 646-653, 1967), a al., J. Invest. Dermatol., 73, pp. 144-146, 1979), Maurer method (Maurer, T. et al., Br. J. Dermatol., 63, pp. 593-605, 1980), Morikawa method (Morikawa, F. et al., "Sunlight and man", Tokyo Univ. Press, Tokyo, pp. 529-557, 1974), Vinson method (Vinson, LJ, J. Soc. Cosm. Chem., 17, pp. 123-130, 1966), etc. By clarifying the skin photosensitivity of a compound using any one or two or more of these methods, its usefulness as an active ingredient of a drug can be confirmed.

[0521] A certain aspect of the compound of the present invention is useful as an active ingredient of a drug, which can be confirmed by, for example, performing an eye irritation test. As an eye irritation test, a single eye drop test method (only one eye drop) using rabbit eyes, monkey eyes, etc., a short-term continuous eye drop test method (eye drops multiple times at fixed intervals in a short period of time), a repeated eye drop test method (intermittent repeated eye drops between several days and dozens of days), etc., can be cited. There is a method for evaluating eye irritation symptoms for a certain period of time after eye drops based on the modified Draize score (Fukui, N. et al., Gendai no Rinsho, 4 (7), pp. 277-289, 1970). By using any one or more of these methods to clarify the eye irritation of the compound, the usefulness of the compound as an active ingredient of the drug can be confirmed.

[0522] The usefulness of a certain embodiment of the compound of the present invention as an active ingredient of a medicine can be confirmed by conducting, for example, a safety pharmacology test on the cardiovascular system. Examples of safety pharmacological tests for the cardiovascular system include telemetry (a method in which a compound is administered without anesthesia and the effects thereof on electrocardiogram, heart rate, blood pressure, blood flow, etc. are measured (Electrocardiogram, Echocardiography, Blood Pressure, and Pathological Examination of Animals for Basic and Clinical Use, edited by Shigeru Kanno, Hirokazu Tsubone, and Yoshitaka Nakata, published in 2003 by Maruzen Co., Ltd.), APD method (a method for measuring the duration of action potential of cardiomyocytes (Muraki, K. et al., AM. J. Physiol., 269, H524-532, 1995; Ducic, I. et al., J. Cardiovasc. Pharmacol., 30 (1), pp. 42-54, 1997)), hERG blockade evaluation method (patch clamp method (Chachin, M. et al., Nippon Yakurigaku Zasshi, 119, pp. 345-351, 2002), binding assay (Binding assay), and cytotoxicity assay. assay) method (Gilbert, JDet al., J.Pharm.Tox.Methods, 50, pp.187-199, 2004), Rb +Efflux assay (Cheng, CS et al., Drug Develop. Indust. Pharm., 28, pp. 177-191, 2002), membrane potential assay (Dorn, A. et al., J. Biomol. Screen., 10, pp. 339-347, 2005), etc. By using any one or two or more of these methods to clarify the effect of the compound on the cardiovascular system, the usefulness of the compound as an active ingredient of the drug can be confirmed.

[0523] A certain aspect of the compound of the present invention is useful as an active ingredient of a drug, which can be confirmed by, for example, conducting a safety pharmacology test for the central nervous system. As a safety pharmacology test for the central nervous system, the FOB method (Functional Observation Comprehensive Evaluation Method (Mattson, J. Let al., J. American College of Technology, 15 (3), pp. 239-254, 1996)), Irwin's modified method (a method for evaluating general symptoms and behavioral observations (Irwin, S. Comprehensive Observational Assessment (Berl.) 13, pp. 222-257, 1968), etc. can be cited. By using any one or more of these methods to clarify the effect of the compound on the central nervous system, the usefulness of the active ingredient as a drug can be confirmed.

[0524] A certain embodiment of the compound of the present invention is useful as an active ingredient of a drug, which can be confirmed by conducting, for example, a safety pharmacology test for the respiratory system. As a safety pharmacology test for the respiratory system, there can be cited a measurement method using a respiratory function measurement device (measuring the respiratory rate, ventilation volume per time, ventilation volume per time, etc.) (Drorbaugh, JE et al., Pediatrics, 16, pp. 81-87, 1955; Epstein, MA et al., Respir. Physiol., 32, pp. 105-120, 1978), a measurement method using a blood gas analyzer (measuring blood gas, hemoglobin oxygen saturation, etc.) (Matsuo, S. Medicina, 40, pp. 188-, 2003), etc. By using any one or two or more of these methods to clarify the effect of the compound on the respiratory system, the usefulness of the compound as an active ingredient of the drug can be confirmed.

[0525] A certain aspect of the compound of the present invention is useful as an active ingredient of a drug, which can be confirmed by, for example, performing a general toxicity test. A general toxicity test refers to the following method: using rodents such as rats and mice or non-rodents such as monkeys and dogs, a compound dissolved or suspended in an appropriate solvent is administered orally or intravenously once or repeatedly (over multiple days), and the observation of the general state of the administered animal, clinical chemical changes, pathological tissue changes, etc. are evaluated. By using these methods to clarify the general toxicity of the compound, the usefulness as an active ingredient of a drug can be confirmed.

[0526] The usefulness of a certain embodiment of the compound of the present invention as an active ingredient of a drug can be confirmed by, for example, conducting a reproductive developmental toxicity test. The reproductive developmental toxicity test is a test that uses rodents such as rats and mice or non-rodents such as monkeys and dogs to study the adverse effects of a compound on inducing reproductive development (see "Explanation of the Guidelines for Non-clinical Trials of Pharmaceuticals 2002" Japan Yakuji Shimbun 2002 Annual Issue 1-6: Reproductive Developmental Toxicity Test, etc.). Examples of reproductive developmental toxicity tests include tests related to fertilization ability and early embryonic development before implantation, tests related to prenatal and postnatal development and maternal function, and tests related to embryonic / fetal development (see "Reproductive Developmental Toxicity Test" in the Annex to the 2000 Japanese Pharmaceutical Review No. 1834 "Guidelines for Toxicity Testing of Pharmaceuticals" [3]). By clarifying the reproductive developmental toxicity of a compound using these test methods, its usefulness as an active ingredient of a drug can be confirmed.

[0527] That a certain embodiment of the compound of the present invention is useful as an active ingredient of a drug can be confirmed by, for example, performing a cytochrome P450 enzyme blocking or induction test (Gomez-Lechon, MJ et al., Curr. Drug Metab. 5(5), pp. 443-462, 2004). As a test for blocking or inducing cytochrome P450 enzymes, for example, there are methods of measuring in vitro whether a compound blocks the enzyme activity of cytochrome P450 enzymes of various molecular species purified from cells or prepared using genetic recombinants or human P450 expression microsomes (Miller, VP et al., Ann. NY Acad. Sci., 919, pp. 26-32, 2000); methods of measuring the expression of cytochrome P450 enzymes of various molecular species and changes in enzyme activity using human liver microsomes or cell disrupted fluid (Hengstler, JG et al., Drug Metab. Rev., 32, pp. 81-118, 2000); or methods of extracting RNA from human hepatocytes exposed to a compound and comparing the mRNA expression level with that of a control to investigate the enzyme inducing ability of the compound (Kato, M. et al., Drug Metab. Pharmacokinet., 20 (4), pp. 236-243, 2005). By using any one or two or more of these methods to clarify the enzyme-blocking or enzyme-inducing effect of the compound on cytochrome P450, the usefulness of the compound as an active ingredient of a drug can be confirmed.

[0528] The usefulness of a certain embodiment of the compound of the present invention as an active ingredient of a drug can be confirmed by, for example, performing a reactive metabolite generation confirmation test. Examples of reactive metabolite generation confirmation tests include a method in which a human liver microsome and a compound are cultured in the presence of NADPH and dansyl fluorescently labeled glutathione (dGSH), reactive metabolites are captured as dGSH adducts, and the peak caused by the reactive metabolites is detected as a whole according to the amount of dGSH adducts generated using fluorescence intensity as an index (Junping Gan et al., Chem. Res. Toxicol. 2005, 18, 896-903); a method in which a 14C-labeled form of a compound is cultured together with human liver microsomes in the presence of NADPH and the radioactivity covalently bound to the protein is measured (Baillie TA, Drug Metabolizing Enzymes. Cytochrome P450 and Other Enzymes in Drug Discovery and Development, pp. 147-154, 2003). By using any one or two or more of these methods, the risk of a compound causing idiosyncratic drug toxicity due to the generation of reactive metabolites can be clarified, thereby confirming its usefulness as an active ingredient of a drug.

[0529] The usefulness of a certain embodiment of the compound of the present invention as an active ingredient of a drug can be confirmed by, for example, performing a cell permeability test. Examples of cell permeability tests include a method for measuring the cell membrane permeability of a compound in an in vitro cell culture system using Caco-2 cells (Delie, F. et al., Crit. Rev. Ther. Drug Carrier Syst., 14, pp. 221-286, 1997; Yamashita, S. et al., Eur. J. Pham. Sci., 10, pp. 195-204, 2000; Ingels, FM et al., J. Pham. Sci., 92, pp. 1545-1558, 2003), or a method for measuring the cell membrane permeability of a compound in an in vitro cell culture system using MDCK cells (Irvine, J. Det al., J. Pham. Sci., 88, pp. 28-33, 1999). By clarifying the cell permeability of a compound using any one or two or more of these methods, its usefulness as an active ingredient of a drug can be confirmed.

[0530] A certain aspect of the compound of the present invention is useful as an active ingredient of a drug, which can be confirmed by, for example, performing a drug transporter ATPase assay as an ATP-binding cassette (ABC) transporter. As a drug transporter ATPase assay, there can be mentioned a method of investigating whether a compound is a substrate of P-gp using a baculovirus expression system of P-glycoprotein (P-gp) (Germann, UA, Methods Enzymol., 292, pp. 427-41, 1998). In addition, it can be confirmed by, for example, performing a transport assay using oocytes collected from Xenopus laevis as a solute carrier transporter (SLC) transporter. As a transport assay, there can be mentioned a method of investigating whether a compound is a substrate of OATP2 using an OATP2-expressing oocyte (Tamai I. et.al., Pharm Res. 2001 Sep; 18 (9): 1262-1269). By using these methods to clarify the action of a compound on an ABC transporter or an SLC transporter, it is possible to confirm its usefulness as an active ingredient of a drug.

[0531] A certain aspect of the compound of the present invention is useful as an active ingredient of a drug, which can be confirmed by, for example, performing an oral absorption test. As an oral absorption test, the following methods can be cited: using rodents, monkeys, dogs, etc., a certain amount of the compound is dissolved or suspended in an appropriate solvent, and the blood drug concentration after oral administration is measured over time, and the blood transportability of the compound after oral administration is evaluated by LC-MS / MS method (Kenichi Harada et al., "The Latest Mass Spectrometry for Life Sciences" Kodansha Science 2002, etc.). By clarifying the oral absorption of the compound using these methods, the usefulness as an active ingredient of a drug can be confirmed.

[0532] A certain aspect of the compound of the present invention is useful as an active ingredient of a drug, which can be confirmed by, for example, performing a blood drug concentration transition test. As a blood drug concentration transition test, the following methods can be cited: after the compound is administered orally or parenterally (for example, intravenously, intramuscularly, intraperitoneally, subcutaneously, transdermally, by eye drops or nasally, etc.) to rodents, monkeys or dogs, the concentration transition of the compound in the blood is measured by LC-MS / MS method (Kenichi Harada et al., "The Latest Mass Spectrometry for Life Sciences" Kodansha Science 2002, etc.). By clarifying the blood drug concentration transition of the compound using these methods, the usefulness as an active ingredient of a drug can be confirmed.

[0533] The usefulness of a certain embodiment of the compound of the present invention as an active ingredient of a drug can be confirmed by, for example, performing a metabolism test. Examples of metabolism tests include a blood stability test (a method for predicting the metabolic clearance rate in vivo from the metabolic rate of a compound in liver microsomes of humans or other animal species (see Shou, WZ et al., J. Mass Spectrom., 40 (10), pp. 1347-1356, 2005; Li, C. et al., Drug Metab. Dispos., 34 (6), 901-905, 2006), a metabolic molecular species test, and a reactive metabolite test. By using any one or two or more of these methods to clarify the metabolic profile of a compound, its usefulness as an active ingredient of a drug can be confirmed.

[0534] A certain aspect of the compound of the present invention is useful as an active ingredient of a drug, which can be confirmed by, for example, a solubility test. The evaluation of solubility in water can be exemplified by a method for confirming under acidic conditions, neutral conditions, or alkaline conditions, and further includes confirming the change in solubility caused by bile acid. As a solubility test, a solubility test method based on turbidity method (Lipinski, CA et al., Adv. Drug Deliv. Rev., 23, pp. 3-26, 1997; Bevan, CD et al., Anal. Chem., 72, pp. 1781-1787, 2000) and the like can be cited. By using these methods to clarify the solubility of the compound, it is possible to confirm its usefulness as an active ingredient of a drug.

[0535] A certain mode of the compound of the present invention is useful as an active ingredient of a drug, which can be confirmed by, for example, adjusting upper gastrointestinal disorders, renal dysfunction, etc. As a pharmacological test for the upper gastrointestinal tract, a fasting rat gastric mucosal injury model can be used to investigate the effect on the gastric mucosa. As a pharmacological test for renal function, renal blood flow glomerular filtration volume determination method [Physiology 18th Edition (Benkogdo), 1986, Chapter 17], etc. can be cited. By using any one or two or more of these methods to clarify the effect of the compound on the upper gastrointestinal tract and renal function, the usefulness of the active ingredient as a drug can be confirmed.

[0536] Example

[0537] The present invention will be described in more detail below by way of Examples and Test Examples (hereinafter sometimes referred to as “Examples, etc.”), but the scope of the present invention is not limited to the following Examples, etc.

[0538] All the purchased reagents are used without further refining. The purchased anhydrous solvent is used without further drying. In column chromatography, the BIOTAGE Dalton as an MS detector is connected to the medium-pressure preparative refining system SmartFlash manufactured by Shanshan or the medium-pressure preparative refining system Isolera ONE manufactured by BIOTAGE for use. The column uses either SNAP Ultra manufactured by Biotage or DispoPack AT manufactured by YMC. In some cases, BondElute SCX manufactured by Agilent is used as an ion exchange resin for refining. It should be noted that BondElute SCX is sometimes referred to as SCX below. As an example of the use of SCX, the following method can be cited: after the extraction column is washed with methanol and dichloromethane, the crude product is dissolved in a minimum volume of solvent (such as a mixed solvent of dichloromethane-methanol, etc.) to adsorb it. Thereafter, the impurities are rinsed with methanol while applying pressure, and the product is eluted with 2.0M ammonia-methanol. Thin layer chromatography (TLC) uses Precoated silica gel 60F254 (Merck, product number 5715-1M). After developing with chloroform:methanol (1:0 to 1:1) or ethyl acetate:hexane (1:0 to 0:1), UV (254nm or 365nm) is irradiated and confirmed by color development using iodine solution, potassium permanganate aqueous solution, phosphomolybdic acid (ethanol solution), etc. In preparative thin layer chromatography (hereinafter sometimes referred to as PTLC), one or more PLC plates of silica gel60F254, 20×20cm, layer thickness 2mm, with a concentration zone (4cm) (Merck, product number 13793-1M) are used for chromatography according to the amount of the sample. Anhydrous magnesium sulfate or anhydrous sodium sulfate is used for drying the organic solvent.

[0539] NMR

[0540] For the 1H (400 MHx) nuclear magnetic resonance analysis (hereinafter sometimes referred to as NMR), AVANCE III HD-400 MHz or AVANCE III HD-600 MHz manufactured by Bruker was used.

[0541] The internal standard uses the known value of the solvent or additive used. 1H NMR data record chemical shift, parts per million (hereinafter referred to as ppm), integral value (for example, recorded as 1H), multiple peaks (s, singlet; d, doublet; t, triplet; q, quartet; qui, quintet; m, multiplet; br, broad peak; dd, doublet of doublets; etc.).

[0542] Regarding LCMS, mass spectra were determined using liquid chromatography-mass spectrometry (LC-MS). Unless otherwise stated, a single quadrupole mass spectrometer SQD system (manufactured by Waters) was used as a mass spectrometer, and the mass spectrometer was measured by electrospray (ESI). The liquid chromatograph was manufactured using AcquityΜLtra Performance LC system manufactured by Waters. The separation column used ACQUITYUPLCBEH C18 2.1×50mm 1.7μm (manufactured by Waters).

[0543] Regarding LC conditions, for the examples or reference examples that are specifically described, the measurements were performed under the following solvent conditions. + or MH - ).

[0544] (LC-1) was measured under the following conditions: flow rate 0.6 mL / min, solution A = 10 mM ammonium acetate aqueous solution, solution B = acetonitrile, solution B was eluted with a linear gradient of 5-90% (v / v) from 0 min to 2.0 min, and solution B was eluted with a linear gradient of 90-98% (v / v) from 2.0 min to 2.5 min.

[0545] (LC-6) was measured under the following conditions: flow rate 0.6 mL / min, solution A = 10 mM ammonium acetate aqueous solution, solution B = acetonitrile, solution B was eluted with a linear gradient of 70-90% (v / v) from 0 min to 2.0 min, and solution B was eluted with a linear gradient of 90-98% (v / v) from 2.0 min to 2.5 min.

[0546] For HPLC purification, a preparative purification apparatus manufactured by Waters Japan was used, a Triart C18ExRS (manufactured by YMC) or the like was used as a column, and a 10 mM ammonium acetate aqueous solution-acetonitrile solution was used as an eluent.

[0547] The term "quant." in the following examples and descriptions of the synthesis methods of intermediates means that the target product was obtained in a quantitative manner.

[0548] Intermediate A-1-1: 2-(Chloromethyl)pyrimidine

[0549] [Chemistry 67]

[0550]

[0551] A solution of pyrimidine-2-ylmethanol (150 g, 1.36 mol) in dichloromethane (1350 mL) was cooled to 0°C, and thionyl chloride (148.4 mL, 2.04 mol) was added dropwise over 20 minutes. Stir at room temperature for 17 hours. The reaction solution was cooled to 0°C, and water (150 mL) was added dropwise. Then, 5N sodium hydroxide aqueous solution (780 mL) was added dropwise, and 1N hydrochloric acid (30 mL) and 5N sodium hydroxide aqueous solution (280 mL) were added while stirring at 0°C to maintain the pH at 7.2-7.5, and stirred at 0°C for 2 hours. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 1:0-1:2), thereby obtaining 2-(chloromethyl)pyrimidine (118.0 g, yield 67%).

[0552] 1H-NMR (CDCl3): δ (ppm) 8.78 (2H, d, J = 4.9Hz), 7.26 (1H, t, J = 4.9Hz), 4.76 (2H, s).

[0553] Intermediate A-1-2-a: 2-(((1S,2S)-2-(((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidine

[0554] [Chemistry 68]

[0555]

[0556] Intermediate A-1-2-b: 2-(((1R,2R)-2-(((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidine

[0557] [Chemistry 69]

[0558]

[0559] 2-(Chloromethyl)pyrimidine (Intermediate A-1-1; 117.9 g, 917 mmol) and trans-cyclopentane-1,2-diol (93.7 g, 917 mmol) were dissolved in DMF (920 mL). The solution was cooled to 0°C, and sodium hydride (60% by weight, dispersed in liquid paraffin, TCI) (44.0 g, 917 mmol) was added in 6 portions at 5-minute intervals. After stirring at 0°C for 20 minutes, the mixture was stirred at room temperature for 1 hour. The reaction solution was then cooled to 0°C, and imidazole (156 g, 2.29 mol) and TBSCl (207 g, 1.38 mol) were added in sequence, and stirred at room temperature for 1.5 hours. The obtained crude reaction mixture was cooled to 0°C, water (530 mL) was added, and diatomaceous earth was filtered. After extraction with ethyl acetate, the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:0-1:1) to obtain 2-((trans-2-(((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidine (97.9 g, yield 35%).

[0560] LCMS(LC-1);RT=2.10,m / z309[M+H] +

[0561] 1H-NMR (CDCl3): δ (ppm) 8.75 (2H, d, J = 4.9Hz), 7.20 (1H, t, J = 4.9Hz), 4.78 (2H, d, 7.3Hz), 4.26-4.23 (1H, m),3.86-3.83(1H,m)2.03-1.87(2H,m),1.75-1.67(3H,m),1.56-1.49(1H,m),0.86(9H,s),0.05(6H,s).

[0562] Optical isomers were separated and analyzed under the conditions of chiral HPLC shown below, thereby obtaining each optically active form with an optical purity of 99.7%ee or more.

[0563] Preparation conditions; column: CHIRALART CelluLose-SC (10 μm) 245×150 mm ID, eluent: heptane / 2-propanol (80 / 20) (v / v), flow rate: 518 mL / min, temperature: 24°C, detection: UV (245 nm), sample filling: 180 mL (9 g)

[0564] Analytical conditions; column: CHIRALART CelluLose-SC (5 μm) 250×4.6 mm ID, eluent: heptane / 2-propanol (80 / 20) (v / v), flow rate: 0.5 mL / min, temperature: 25°C, detection: UV (245 nm), injection: 10 μL (0.5 mg / mL) RT=11.6 (1S, 2S isomer; intermediate A-6-2-a), RT=16.5 (1R, 2R isomer; intermediate A-6-2-b)

[0565] Intermediate A-1-3: 2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrimidine

[0566] [Chemistry 70]

[0567]

[0568] 2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidine (intermediate A-1-2-a; 76.7 g, 249 mmol) was dissolved in THF (500 mL), and bis(pinacol)diboron (63.1 g, 249 mmol), (1,5-cyclooctadiene)(methoxy)iridium(I) (dimer) (1.64 g, 2.49 mmol) were added. ), 3,4,7,8-tetramethyl-1,10-phenanthroline (1.17 g, 4.97 mmol), stirred at 80 ° C for 15 hours, and the crude reaction mixture was concentrated to obtain 2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrimidine as a crude product.

[0569] LCMS(LC-1);RT=1.80,m / z353[M+H] + (as boric acid test)

[0570] 1H-NMR(CDCl3): δ(ppm)9.00(2H,s),4.78(2H,d,6.2Hz),4.25-4.22(1H,m),3.84-3.81(1H,m)1 .97-1.87(2H,m),1.72-1.65(3H,m),1.55-1.48(1H,m),1.35(12H,s),0.85(9H,s),0.05(6H,s).

[0571] Intermediate A-1-4: 6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-amine

[0572] [Chemistry 71]

[0573]

[0574] 6-Bromo-1,3-benzothiazol-2-amine (1.50 g, 6.5 mmol) was dissolved in THF (15 mL), and the crude product 2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrimidine (Intermediate A-1-3; 4.4 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.32 g, 0.44 mmol), cesium carbonate (4.3 g, 13.1 mmol), and water (2.9 mL) were added, and the mixture was irradiated with microwaves at 100° C. for 1.5 hours. The crude reaction mixture was diluted with ethyl acetate (29 mL) and washed with 10% brine (15 mL). The aqueous layer was extracted again with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate, filtered through celite, and concentrated under reduced pressure. The crude product was purified by automated silica gel column chromatography (eluent; hexane:ethyl acetate = 98:12-12:100) to obtain 6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazole-2-amine (1.13 g, yield 57%).

[0575] LCMS(LC-1);RT=2.07,m / z457[M+H] +

[0576] 1H-NMR (CDCl3): δ (ppm) 8.95 (2H, s), 7.79 (1H, J = 2.0), 7.76 (1H, J = 8.4), 7.51 (1H, J = 8.4, 2.0), 7.26 (2H, s), 5.33 (2H, s), 4.83-4.7 9(2H,m),4.29-4.26(1H,m),3.90-3.87(1H,m),2.05-1.89(2H,m),1.78-1.68(3H,m),1.58-1.50(1H,m).0.88(9H,s),0.07(6H,s).

[0577] Intermediate A-1-5: N-(6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanamide

[0578] [Chemistry 72]

[0579]

[0580] 6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazole-2-amine (Intermediate A-1-4; 30 mg, 66 μmol) was dissolved in dichloromethane (660 μL), and cyclopropanecarboxylic acid (19 mg, 0.22 mmol), N,N-diisopropylethylamine (100 μL, 0.59 mmol), 1-propanephosphonic anhydride (50 wt% ethyl acetate solution, 0.13 mL, 0.22 mmol) were added, and stirred at room temperature for 16 hours. To the obtained crude reaction mixture was added saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane to obtain a crude reaction mixture containing N-(6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanamide.

[0581] LCMS(LC-1);RT=2.27,m / z525[M+H] +

[0582] Example a-01-01: N-(6-(2-((((1S,2S)-2-hydrocyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanamide

[0583] [Chemistry 73]

[0584]

[0585] Under ice cooling, hydrochloric acid-methanol solution (2 mol / L, 2 mL) was added dropwise to the crude reaction mixture containing N-(6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanamide (Intermediate A-1-5, 2 mL), and stirred at room temperature for 30 minutes. The obtained crude reaction mixture was concentrated under reduced pressure and purified by SCX and HPLC to obtain N-(6-(2-((((1S,2S)-2-hydrocyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanamide (12 mg, yield 44%).

[0586] LCMS(LC-1);RT=1.13,m / z411[M+H] +

[0587] 1H-NMR(DMSOd6): δ(ppm)9.17(2H,s),8.45(1H,m),7.86(2H,m),4.71-4.69(3H, m),4.04-4.00(1H,m),3.83-3.80(1H,m),2.03-1.40(7H,m),0.98-0.96(4H,m).

[0588] The following compounds in the following table were synthesized by the same method. In the following table, "Reference Methods" indicates that the examples of the production method should be referred to.

[0589] [Table 2-1]

[0590]

[0591] [Table 2-2]

[0592]

[0593] Intermediate A-2-1: 2-(Propoxymethyl)pyrimidine

[0594] [Chemistry 74]

[0595]

[0596] Pyrimidin-2-ylmethanol (10 g, 91 mmol) was dissolved in DMF (300 mL), sodium hydride (4.8 g, 55 wt%, 109 mmol) was added under ice cooling, and the mixture was stirred for 10 minutes. 1-Iodopropane (13.2 mL, 136 mmol) was added dropwise to the reaction solution, and after stirring at room temperature for 2 hours, sodium hydride (4 g, 55 wt%, 91 mmol) and 1-iodopropane (10 mL, 103 mmol) were added, and the mixture was further stirred at room temperature for 1 hour. Water (300 mL) was added to the obtained crude reaction mixture to stop the reaction, and the mixture was extracted 3 times with ethyl acetate (300 mL). The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by autoclave silica gel column chromatography (eluent; hexane: ethyl acetate = 88:12 to 0:100), thereby obtaining 2-(propyloxymethyl)pyrimidine (10.1 g, yield 73%).

[0597] 1H-NMR (CDCl3): δ (ppm) 8.76 (2H, d, J = 4.9Hz), 7.21 (1H, dd, J = 4.9Hz), 4.75 (2H ,s), 3.60(2H,t,J=6.9Hz), 1.73(2H,tt,J=6.9,7.4Hz), 0.96(3H,t,J=7.4Hz).

[0598] Intermediate A-2-2: 2-(Propoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrimidine

[0599] [Chemistry 75]

[0600]

[0601] According to the synthesis method of intermediate A-1-3, 2-(propoxymethyl)pyrimidine (intermediate A-2-1; 10.1 g) was used instead of 2-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidine (intermediate A-1-2-a) to synthesize 2-propoxymethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)pyrimidine as a crude product.

[0602] LCMS(LC-1);RT=0.62,m / z197[M+H] + (as boric acid test)

[0603] Intermediate A-2-3: N-(6-bromo-1,3-benzothiazol-2-yl)cyclopropanecarboxamide

[0604] [Chemistry 76]

[0605]

[0606] 2-Amino-6-bromobenzothiazole (1 g, 4.36 mmol) was dissolved in DCM (44 mL), cyclopropanecarbonyl chloride (0.91 g, 8.73 mmol) and triethylamine (0.88 g, 8.37 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the resulting reaction mixture, and the mixture was extracted with chloroform. The organic layer was separated and concentrated under reduced pressure to obtain a crude reaction mixture containing N-(6-bromo-1,3-benzothiazol-2-yl)cyclopropanecarboxamide (739 mg, yield 57%).

[0607] LCMS(LC-1);RT=1.58,m / z297[M+H]

[0608] 1H-NMR (CDCl3): δ (ppm) 7.95 (1H, m), 7.68 (1H, m), 7.62 (2H, d, J = 8.5 Hz), 7.53 (2H, dd, J = 8.5, 2.0 Hz), 1.98-1.91 (1H, m), 1.27-1.23 (4H, m).

[0609] Example a-02-01: N-(6-(2-(propyloxymethyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanamide

[0610] [Chemistry 77]

[0611]

[0612] According to the synthesis method of intermediate A-1-4, N-(6-bromo-1,3-benzothiazol-2-yl)cyclopropanecarboxamide (intermediate A-2-3; 20 mg) was used instead of 6-bromo-1,3-benzothiazol-2-amine, 2-(propyloxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrimidine (intermediate A-2-2) was used instead of 2- ((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrimidine (intermediate A-1-3) was used to synthesize N-(6-(2-(propyloxymethyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanamide (10 mg, yield 20%).

[0613] LCMS(LC-1);RT=1.37,m / z369[M+H] +

[0614] 1H-NMR(DMSOd6): δ(ppm)9.17(2H,s),8.38(1H,m),7.83-7.77(2H,m),4.65(2H, s),3.52(2H,J=6.7Hz),1.97-1.91(1H,m),1.62-1.53(2H,m),0.93-0.88(7H,m).

[0615] Intermediate A-3-1: 5-bromo-2-(((trans-2-((tert-butyldimethylsilyl)oxy)-4,4-difluorocyclopentyl)oxy)methyl)pyrimidine

[0616] [Chemistry 78]

[0617]

[0618] 5-Bromo-2-(chloromethyl)pyrimidine (500 mg, 2.41 mmol) and trans-4,4-difluorocyclopentane-1,2-diol (500 mg, 3.62 mmol) were dissolved in dichloromethane (4 mL), tetrabutylammonium chloride (70 mg, 241 μmol) and 25 wt% sodium hydroxide aqueous solution (4 mL) were added, and the mixture was stirred under heating and reflux for 14 hours. The organic layer of the obtained reaction mixture was separated, dried over anhydrous magnesium sulfate, and then filtered. Imidazole (330 mg, 4.82 mmol) and TBSCl (545 mg, 3.62 mmol) were added thereto, and the mixture was stirred at room temperature for 6 hours. Then, imidazole (330 mg, 4.82 mmol) and TBSCl (545 mg, 3.62 mmol) were added, and the mixture was stirred at room temperature for 52 hours. Imidazole (330 mg, 4.82 mmol) and TBSCl (545 mg, 3.62 mmol) were further added, and the mixture was stirred at room temperature for 24 hours. Water was added to the obtained reaction mixture, and the mixture was extracted with chloroform. The organic layer was separated and concentrated under reduced pressure, and purified by autoclave silica gel column chromatography (eluent; hexane-ethyl acetate) to obtain 5-bromo-2-(((trans-2-((tert-butyldimethylsilyl)oxy)-4,4-difluorocyclopentyl)oxy)methyl)pyrimidine (131 mg, yield 13%).

[0619] LCMS(LC-1);RT=2.25,m / z424[M+H] +

[0620] 1H-NMR (CDCl3): δ (ppm) 8.79 (2H, s), 4.77 (2H, d, J = 2.1Hz) 4.36-4.31 (1H, m), 4.00-3.96 ( 1H,m),2.62-2.44(2H,m),2.32-2.19(1H,m),2.13-2.00(1H,m),0.87(9H,s),0.07(6H,s).

[0621] Intermediate A-3-2: N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)cyclopropanamide

[0622] [Chemistry 79]

[0623]

[0624] N-(6-bromo-1,3-benzothiazol-2-yl)cyclopropanecarboxamide (intermediate A-2-3; 400 mg, 1.35 mmol) was dissolved in 1,4-dioxane (13 mL), and bis(pinacol)diboron (513 mg, 2.03 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (98 mg, 0.13 mmol), and potassium acetate (400 mg, 2.69 mmol) were added. The mixture was stirred at 80 ° C for 3 hours. After cooling to room temperature, the solvent was concentrated under reduced pressure to obtain a crude reaction mixture containing N-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3-benzothiazol-2-yl]cyclopropaneamide.

[0625] LCMS(LC-1);RT=1.73,m / z346[M+2H] +

[0626] 1H-NMR (CDCl3): δ (ppm) 8.28 (2H, s), 7.86 (1H, d, J = 8.0 Hz), 7.71 (1H, d, J = 8.0 Hz), 1.80-1.74 (1H, m), 1.37 (12H, s), 1.26 (4H, s).

[0627] Intermediate A-3-3: N-(6-(2-(((trans-2-((tert-butyldimethylsilyl)oxy)-4,4-difluorocyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanamide

[0628] [Chemistry 80]

[0629]

[0630] 5-Bromo-2-(((trans-2-((tert-butyldimethylsilyl)oxy)-4,4-difluorocyclopentyl)oxy)methyl)pyrimidine (Intermediate A-3-1; 30 mg, 71 μmol) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)cyclopropanamide (Intermediate A-3-2; 36 mg, 0.11 mmol) were dissolved in 1,4-dioxane (1 mL), and water (200 μL), cesium carbonate (69 mg, 0.22 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5.8 mg, 7 μmol) were added, and stirred at 80°C overnight. The obtained crude reaction mixture was filtered through celite and concentrated under reduced pressure. The crude product was purified by automated silica gel column chromatography (eluent; chloroform:methanol) and HPLC to obtain N-(6-(2-(((trans-2-((tert-butyldimethylsilyl)oxy)-4,4-difluorocyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanamide (13.7 mg, yield 34%).

[0631] LCMS(LC-1);RT=2.14,m / z561[M+H] +

[0632] 1H-NMR (CDCl3): δ (ppm) 9.95 (1H, brs), 9.00 (2H, s), 8.02 (1H, d, J = 2.0Hz), 7.89 (1H ,d,J=8.4Hz),7.63(1H,dd,J=8.4,2.0Hz),4.92-4.84(2H,m),4.40-4.36(1H,m),4. 06-4.02(1H,m),2.65-2.47(2H,m),2.37-2.25(1H,m),2.15-2.03(1H,m),1.73-1.6 6(1H,m),1.30-1.26(2H,m),1.08-1.04(2H,m),0.88(9H,s),0.09(6H,d,J=1.6Hz).

[0633] Example a-03-01: N-(6-(2-((((1S,2S)-4,4-difluoro-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanamide

[0634] [Chemistry 81]

[0635]

[0636] According to the synthesis method of Example a-01-01, N-(6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)-4,4-difluorocyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanamide (Intermediate A-3~5; 13.7 mg) was used instead of N-(6-(2-(((trans-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanamide (Intermediate A-1-5) for synthesis, and the obtained stereoisomer mixture was purified by HPLC and chiral HPLC (column: CHIRALPAK IB (manufactured by DAICEL), mobile phase: n-hexane:ethanol = 30:70) was used for separation to obtain the desired N-(6-(2-((((1S,2S)-4,4-difluoro-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanamide (2.3 mg, yield 21%).

[0637] LCMS(LC-1);RT=1.23,m / z447[M+H] +

[0638] 1H-NMR(DMSOd6): δ(ppm)12.76(1H,brs),9.19(2H,s),8.46(1H,m),7.89-7.85(2H,m),5.36-5.35(1H,m),4.76 (2H,s),4.19(1H,m),4.03(1H,m),2.62-2.40(2H,m),2.26-2.14(1H,m),2.08-1.97(2H,m),0.99-0.97(4H,m).

[0639] Intermediate A-4-1: 5-bromo-2-(cyclopentyloxymethyl)pyrimidine

[0640] [Chemistry 82]

[0641]

[0642] 5-Bromo-2-(chloromethyl)pyrimidine (100 mg, 0.4 mmol) and cyclopentanol (41 mg, 0.48 mmol) were dissolved in dichloromethane (4 mL), and tetrabutylammonium chloride (11 mg, 40 μmol) and 25 wt% sodium hydroxide aqueous solution (2 mL) were added, and stirred at 60°C for 14 hours. Water was added to the obtained reaction mixture, extracted with chloroform, and the organic layer was separated and concentrated under reduced pressure, and purified by autoclaved silica gel column chromatography (eluent; chloroform-methanol), thereby obtaining 5-bromo-2-(cyclopentyloxymethyl)pyrimidine (87 mg, yield 85%).

[0643] LCMS(LC-1);RT=1.41,m / z258[M+H] +

[0644] 1H-NMR(CDCl3): δ(ppm)8.79(2H,s),4.67(2H,s),4.15-4.09(1H,m),1.88-1.68(6H,m),1.58-1.50(2H,m).

[0645] The following compounds in the following table were synthesized by the same method. In the following table, "Reference Methods" indicates that the examples of the production method should be referred to.

[0646] [Table 3]

[0647]

[0648] Example a-04-01: N-(6-(2-(cyclopentyloxymethyl)pyrimidin-5-yl)-1,3-benzo[d]thiazol-2-yl)cyclopropanamide

[0649] [Chemistry 83]

[0650]

[0651] 5-Bromo-2-(cyclopentyloxymethyl)pyrimidine (A-4-1; 40 mg, 0.16 mmol) was dissolved in 1,4-dioxane (778 μL), and N-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazol-2-yl]cyclopropanamide (intermediate A-3-2; 53.6 mg, 0.16 mmol), cesium carbonate (101 mg, 0.31 mm ol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11 mg, 0.02 mmol), heated to reflux for 15 hours, cooled to room temperature, concentrated the solvent under reduced pressure, and purified by automatic oxidation silica gel column chromatography (eluent; chloroform-methanol) to obtain N-[6-[2-(cyclopentyloxymethyl)pyrimidin-5-yl]-1,3-benzothiazol-2-yl]cyclopropanamide (4.8 mg, yield 8%).

[0652] LCMS(LC-1);RT=1.52,m / z395[M+H] +

[0653] 1H-NMR (CDCl3): δ (ppm) 9.00 (2H, s), 8.00 (2H, s), 7.89 (2H, d, J = 8.0 Hz), 7.63 (2H, d, J = 8.0 Hz), 4.79 (2H, s), 4. 25-4.22(1H,m),4.21-4.13(1H,m),1.84-1.74(4H,m),1.72-1.70(1H,m),1.29-1.25(2H,m),1.09-1.05(2H,m).

[0654] The following compounds in the following table were synthesized by the same method. In the following table, "Reference Methods" indicates that the examples of the production method should be referred to.

[0655] [Table 4]

[0656]

[0657] Intermediate A-5-1: (S)-5-bromo-2-(((tetrahydrofuran-2-yl)methoxy)methyl)pyrimidine

[0658] [Chemistry 84]

[0659]

[0660] 5-Bromo-2-(bromomethyl)pyrimidine (6.7 g, 27 mmol) and (S)-(tetrahydrofuran-2-yl)methanol (2.5 g, 24 mmol) were dissolved in tetrahydrofuran (80 mL), and 33% aqueous sodium hydroxide solution (30 mL) and tetrabutylammonium chloride (667 mg, 2.4 mmol) were added, and stirred at 40°C overnight. Water (100 mL) was added to the obtained crude reaction mixture, and the mixture was extracted three times with dichloromethane (150 mL). The obtained organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (eluent; petroleum ether: ethyl acetate = 5:1) to obtain (S)-5-bromo-2-(((tetrahydrofuran-2-yl)methoxy)methyl)pyrimidine (2.55 g, yield 39%).

[0661] LCMS(LC-1);RT=1.03,m / z273[M+H] +

[0662] 1H-NMR(CDCl3): δ(ppm)8.79(2H,s),4.84-4.75(2H,m),4.19-4.13(1H,m),3.92-3.86(1H,m), 3.80-3.75(1H,m),3.70-3.61(2H,m),2.03-1.95(1H,m),1.93-1.84(2H,m),1.70-1.61(1H,m).

[0663] Example a-05-01: (S)-N-(6-(2-((tetrahydrofuran-2-yl)methoxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanamide

[0664] [Chemistry 85]

[0665]

[0666] (S)-5-bromo-2-(((tetrahydrofuran-2-yl)methoxy)methyl)pyrimidine (Intermediate A-5-1; 150 mg, 0.55 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)cyclopropanamide (Intermediate A-3-2; 246 mg, 0.71 mmol) were dissolved in N,N-dimethylformamide (9 mL), and water (1 mL), potassium carbonate (152 mg, 1.1 mmol), and tetrakis(triphenylphosphine)palladium(0) (64 mg, 55 μmol) were added, and the mixture was stirred at 130 °C overnight. The obtained crude reaction mixture was concentrated under reduced pressure and purified by automated silica gel column chromatography (eluent; petroleum ether:ethyl acetate = 1:2) and HPLC to obtain (S)-N-(6-(2-((tetrahydrofuran-2-yl)methoxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanamide (45 mg, yield 20%).

[0667] LCMS(LC-1);RT=1.20,m / z411[M+H] +

[0668] 1H-NMR(DMSOd6): δ(ppm)12.76(1H,s),9.18(2H,s),8.47(1H,s),7.90-7.85(2H,m),4.71(2H,s),4.03-3.97(1H,m),3.77-3.7 1(1H,m),3.65-3.60(1H,m),3.56(2H,d,J=5.3Hz),2.06-1.99(1H,m),1.95-1.74(3H,m),1.65-1.55(1H,m),0.99-0.97(4H,m).

[0669] Intermediate B-1-1: N-(6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-oxocyclobutane-1-carboxamide

[0670] [Chemistry 86]

[0671]

[0672] 6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-amine (Intermediate A-1-4; 400 mg, 0.88 mmol) was suspended in dichloromethane (8.6 mL), and N-ethyldiisopropylamine (1.37 mL, 7.88 mmol), 3-oxocyclobutanecarboxylic acid (0.23 mL, 2.89 mmol), 1-propylphosphonic anhydride (0.78 mL, 2.63 mmol) were added and stirred at room temperature for 1.5 hours. Saturated aqueous sodium bicarbonate solution was added to the obtained reaction mixture, extracted with chloroform, and the organic layer was dried over sodium sulfate, filtered and concentrated. The mixture was purified by automatic oxidation silica gel column chromatography (eluent: chloroform-methanol 2%) to obtain N-(6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-oxocyclobutane-1-carboxamide (296.9 mg, yield: 61%).

[0673] LCMS(LC-1);RT=2.18,m / z553[M+H] +

[0674] 1H-NMR (CDCl3): δ (ppm) 10.4 (1H, brs) 9.02 (2H, s), 8.06 (1H, d, J = 1.5Hz), 7.88 (1H, d, J=8.0Hz),7.69-7.65(1H,m),7.59-7.55(1H,m),7.64-7.55(1H,m),4.98-4.74(2H,m), 4.35-4.18(1H,m),3.98-3.80(1H,m),3.71-3.59(2H,m),3.42-3.28(3H,m),2.11-1.8 4(2H,m),1.80-1.71(3H,m),1.61-1.37(1H,m),0.88(9H,s),0.08(3H,s),0.07(3H,s).

[0675] Intermediate B-1-2: N-(6-2-((((11S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-morpholinylcyclobutane-1-carboxamide

[0676] [Chemistry 87]

[0677]

[0678] N-(6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-oxocyclobutane-1-carboxamide (Intermediate B-1-1; 100 mg, 0.18 mmol) was dissolved in tetrahydrofuran (0.9 mL), and acetic acid (0.1 mL), sodium triacetoxyborohydride (77 mg, 0.36 mmol) and morpholine (23.74 μL, 0.27 mmol) were added, and the mixture was stirred at room temperature for 1.5 hours. Water and saturated aqueous sodium bicarbonate solution were added to the obtained reaction mixture, extracted with chloroform, and the organic layer was dried over sodium sulfate, filtered and concentrated. The target product was obtained by automatic oxidation silica gel column chromatography (eluent: chloroform-methanol 2%) and HPLC purification: N-(6-2-((((11S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-morpholinylcyclobutane-1-carboxamide (73.9 mg, yield 65.8%).

[0679] LCMS(LC-1);RT=2.15,m / z624[M+H] +

[0680] Example b-01-01: N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-morpholinylcyclobutane-1-carboxamide

[0681] [Chemistry 88]

[0682]

[0683] 2N hydrochloric acid / methanol solution (500 μL) was added to N-(6-2-((((11S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-morpholinylcyclobutane-1-carboxamide (Intermediate B-1-2; 45.5 mg, 0.07 mmol), and the mixture was stirred at room temperature. The reaction was terminated after 10 minutes, and the solvent was blown off with a nitrogen stream. A portion was purified by SCX, autoclaved silica gel column chromatography (eluent: chloroform-methanol 2%) to obtain N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-morpholinylcyclobutane-1-carboxamide: 2 mg. The remaining reaction mixture was purified by HPLC to give N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-morpholinylcyclobutane-1-carboxamide (13.6 mg, yield: 37%).

[0684] LCMS(LC-1);RT=1.01,m / z510[M+H] +

[0685] 1H-NMR (CDCl3): δ (ppm) 9.00 (2H, s), 8.00 (1H, d, J = 1.5Hz), 7.93-7.87 (1H, m), 7. 65-7.58(1H,m),5.09-4.77(3H,m),4.30-4.19(1H,m),4.07-3.98(3H,m),3.97-3. 91(1H,m),3.91-3.84(1H,m),3.30-3.15(2H,m),3.00-2.89(1H,m),2.76-2.63(2 H,m),2.35-2.22(2H,m),2.14-1.99(2H,m),1.77-1.69(2H,m),1.29-1.23(2H,m).

[0686] The following compounds in the following table were synthesized by the same method. In the following table, "Reference Methods" indicates that the examples of the production method should be referred to.

[0687] [Table 5]

[0688]

[0689] Intermediate B-2-1: (1S,2S)-2-((5-(2-aminobenzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentane-1-ol

[0690] [Chemistry 89]

[0691]

[0692] 2N-hydrochloric acid / methanol solution (6 mL) was added to 6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-amine (Intermediate A-1-4; 1.5 g, 3.28 mmol), and the mixture was stirred at room temperature for 15 minutes. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by autoclaved silica gel column chromatography (eluent: ethyl acetate-methanol) to obtain (1S,2S)-2-((5-2(aminobenzo[d]-6-yl)pyrimidin-2-yl)methoxy)cyclopentane-1-ol (1.41 g) as a crude product.

[0693] LCMS(LC-1);RT=0.89,m / z343[M+H] +

[0694] 1H-NMR (CDCl3): δ (ppm) 9.91-9.65 (2H, brs), 9.12 (2H, s), 8.34 (1H, d, J = 2. 0Hz), 8.12 (1H, d, J = 2.0Hz), 7.86 (1H, dd, J = 8.5, 2.0Hz), 7.65 (1H, d, J = 8.5 Hz),7.60-7.50(1H,m),7.50-7.32(1H,m),4.70-4.69(2H,m),4.02(2H,m), 3.99-3.72(3H,m),1.97-1.71(3H,m),1.68-1.52(5H,m),1.52-1.34(2H,m).

[0695] Intermediate B-2-2: N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)3-oxocyclobutane-1-carboxamide

[0696] [Chemistry 90]

[0697]

[0698] (1S,2S)-2-((5-(2-aminobenzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentane-1-ol (Intermediate B-2-1; 1.41 g, 4.11 mmol) was dissolved in dimethylformamide (20.5 mL), 3-oxocyclobutanecarboxylic acid (703 mg, 6.16 mmol), 1-hydroxybenzotriazole-1 hydrochloride (1.26 g, 8.21 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.57 g, 8, 21 mmol) were added, and heated and stirred at 60°C overnight. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and extracted with chloroform. The organic layer was dried over sodium sulfate, filtered and concentrated, and purified by autoclaved silica gel column chromatography (eluent: chloroform-methanol) to obtain N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)3-oxocyclobutane-1-carboxamide (264 mg, yield 15%).

[0699] LCMS(LC-1);RT=1.03,m / z439[M+H] +

[0700] 1H-NMR (CDCl3): δ (ppm) 9.00 (2H, s), 8.06-8.00 (1H, m), 7.89-7.77 (1H, m), 7.66-7.56 (1H, m), 4.97 (1H, d, J = 14.4Hz), 4.80 (1H, d,J=14.4Hz),4.31-4.11(1H,m),3.92-3.83(1H,m),3.70-3.56(2H,m),3.52-3.30(3H,m),2.17-1.99(2H,m),1.81-1.50(4H,m).

[0701] Example b-02-01: 3-((R)-3-fluoropyrrolidin-1-yl)-N-6-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide

[0702] [Chemistry 91]

[0703]

[0704] N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)3-oxocyclobutane-1-carboxamide (Intermediate B-2-2; 53.6 mg, 0.12 mmol) was dissolved in THF (2 mL), (R)-(-)3-fluoropyrrolidine hydrochloride (23 mg, 0.18 mmol) and sodium triacetoxyborohydride (51.81 mg, 0.24 mmol) were added, and stirred at room temperature. After 1 hour, acetic acid (50 μL) was added and stirring was continued for 1 hour. After the reaction, water, chloroform and saturated aqueous sodium bicarbonate solution were added to the reaction mixture, the mixture was stirred, and the organic layer was separated and concentrated with a nitrogen stream. The mixture was purified by HPLC to obtain 3-[(3R)-3-fluoropyrrolidin-1-yl]-N-[6-[2-[[(1S,2S)-2-hydroxycyclopentyloxy]methyl]pyrimidin-5-yl]-1,3-benzothiazol-2-yl]cyclobutanecarboxamide (10.3 mg, yield 16%).

[0705] LCMS(LC-1);RT=1.06,m / z512[M+H] +

[0706] 1H-NMR (CDCl3): δ (ppm) 9.00 (2H, s), 8.04-7.92 (1H, m), 7.83 (1H, brd, J = 7.1Hz), 7.63-7.53 (1H, m), 5.53-5.18 (2H, m), 5.10-4.79 (2H ,m),4.30-4.20(1H,m),3.93-3.82(1H,m),3.28-3.14(3H,m),2.78(5H,brs),2.35-2.23(3H,m),2.16-1.99(3H,m),1.62-1.48(2H,m).

[0707] The following compounds in the following table were synthesized by the same method. In the following table, "Reference Methods" indicates that the examples of the production method should be referred to.

[0708] [Table 6-1]

[0709]

[0710] [Table 6-2]

[0711]

[0712] [Table 6-3]

[0713]

[0714] [Table 6-4]

[0715]

[0716] [Table 6-5]

[0717]

[0718] [Table 6-6]

[0719]

[0720] [Table 6-7]

[0721]

[0722] [Table 6-8]

[0723]

[0724] [Table 6-9]

[0725]

[0726] [Table 6-10]

[0727]

[0728] Example b-03-01: 3-(Bicyclo[1,1,1]pentan-1-yl(methyl)amino)-N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide

[0729] [Chemistry 92]

[0730]

[0731] 3-(3-Bicyclo[1,1,1]pentenylamino)-N-[6-[2-[[(1S,2S)]2-hydroxycyclopentyloxy]methyl]pyrimidin-5-yl]-1,3-benzothiazol-2-yl]cyclobutanecarboxamide (Example b-02-29; 29 mg, 0.06 mmol) was dissolved in dichloromethane (1.3 mL) and THF (1 mL), and formaldehyde (10 μL) and sodium triacetoxyborohydride (18.25 mg, 0.09 mmol) were added, and the mixture was stirred at room temperature overnight. After the reaction, water, chloroform and saturated aqueous sodium bicarbonate solution were added to the reaction mixture for extraction, and the organic layer was concentrated with a nitrogen stream and purified by HPLC to give 3-(bicyclo[1,1,1]pentan-1-yl(methyl)amino)-N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide (12.9 mg, yield 43%).

[0732] LCMS(LC-1);RT=1.31,m / z520[M+H] +

[0733] 1H-NMR(CDCl3): δ(ppm)9.00(2H,s),8.06-7.99(1H,m),7.91-7.84(1H,m),7.67-7.58(1H,m),5.01-4.90(1H,m),4.84-4.75(1H,m),4.26-4 .15(1H,m),3.90-3.79(1H,m),3.18-3.08(1H,m),3.08-2.97(1H,m), 2.52-2.34(5H,m),2.17(3H,s),2.14-2.00(4H,m),1.78-1.50(5H,m).

[0734] The following compounds in the following table were synthesized by the same method. In the following table, "Reference Methods" indicates that the examples of the production method should be referred to.

[0735] [Table 7]

[0736]

[0737] Intermediate B-4-1: (1S,2S)-2-(pyrimidin-2-ylmethoxy)cyclopentyl acetate

[0738] [Chemistry 93]

[0739]

[0740] Dissolve (1S,2S)-2-(pyrimidin-2-ylmethoxy)cyclopentanol (39.03 g, 200.95 mmol) in dichloromethane (402 mL) and stir under cooling at 0°C. Add triethylamine (56.02 mL, 402 mmol), 4-dimethylaminopyridine (1.96 g, 16.08 mmol), and acetic anhydride (36.09 mL, 381.8 mmol) and stir. After 10 minutes, stir at room temperature for 1 hour. Cool the reaction mixture to 0°C, add water and saturated sodium bicarbonate aqueous solution and stir, and add dichloromethane for extraction. The aqueous layer was extracted again with dichloromethane, and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The product was purified by automatic silica gel column chromatography (eluent: chloroform-methanol 2%) to obtain the target product [(1S,2S)-2-(pyrimidin-2-ylmethoxy)cyclopentyl] acetate (22.73 g, yield 48%).

[0741] LCMS(LC-1);RT=0.92,m / z238[M+H] +

[0742] 1H-NMR (CDCl3): δ (ppm) 8.73 (2H, d, J = 5.0Hz), 7.19 (1H, dd, J = 5.0, 5.0Hz), 4.85-4.82 (2H, m), 4.36-4.24 ( 1H, m), 4.24-4.16 (1H, m), 4.19 (1H, dd, J = 4.0, 4.0Hz,), 2.12-1.95 (2H, m), 1.85-1.69 (4H, m), 1.75 (3H, s).

[0743] Intermediate B-4-2: (1S,2S)-2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate

[0744] [Chemistry 94]

[0745]

[0746] THF (339.5 mL) was added to (1S, 2S)-2-(pyrimidin-2-ylmethoxy)cyclopentyl acetate (intermediate B-4-1; 40.1 g, 169.7 mmol), bis(pinacolato)diboron (47.41 g, 186.7 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (0.8 g, 3.39 mmol), argon was replaced, and (1,5-cyclooctadiene)methoxy)iridium(I) dimer (1.13 g, 1.7 mmol) was further added, and the mixture was heated and stirred at 80°C overnight. (1,5-cyclooctadiene)methoxy)iridium(I) dimer (1.13 g, 1.7 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (0.8 g, 3.39 mmol), and bis(pinacolato)diboron (2.1 g, 8.5 mmol) were added, and the mixture was heated and stirred at 80°C for 6.5 hours. After the reaction was completed, the reaction mixture was concentrated and vacuum dried to obtain (1S,2S)-2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate (99.24 g) as a crude product.

[0747] LCMS(LC-1);RT=0.78,m / z281[M+H] + (as boric acid test)

[0748] 1H-NMR(CDCl3): δ(ppm)9.01(2H,s),4.89-4.77(2H,m),4.06-4.02(1H,m),2.02-2.01(3H,s),1.88-1.83(6H,m),1.36-1.35(12H,s).

[0749] Intermediate B-4-3: (1S,2S)-2-((5-(2-aminobenzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate

[0750] [Chemistry 95]

[0751]

[0752] 1,4-Dioxane (243.6 mL) was added to 2-amino-6-bromobenzothiazole (20.3 mg, 88.61 mmol) to dissolve it, and cesium carbonate (88.61 g, 265.82 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6.48 g, 8.86 mmol), [(1S,2S)-2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]methoxy]cyclopentyl]acetate (88.15 g, 15,63 mmol) and water (60.9 mL) were added, and the mixture was stirred with heating at 80°C overnight. Add [(1S,2S)-2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]methoxy]cyclopentyl]acetate (21 g, 58 mmol), cesium carbonate (28.4 g, 88.61 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.1 g, 26.6 mmol), and heat and stir at 90°C overnight. After the reaction is completed, the reaction mixture is filtered through celite and extracted with ethyl acetate. The aqueous layer is extracted again with ethyl acetate, the organic layers are combined, dried over sodium sulfate, filtered, and concentrated. The obtained crude product was purified by autoclaved silica gel column chromatography (eluent: chloroform-methanol 1-2%) to obtain (1S,2S)-2-((5-(2-aminobenzo[d]thiazol-6-yl)methoxy)cyclopentyl acetate (30.06 g, yield 88%).

[0753] LCMS(LC-1);RT=1.16,m / z385[M+H] +

[0754] 1H-NMR(CDCl3): δ(ppm)8.96(2H,s),7.84-7.75(1H,m),7.70-7.62(1H,m),7.57-7.45(1H,m),5.34-5.24(2H,m),5.24-5 .12(1H,m),4.94-4.80(2H,m),4.13-4.06(1H,m),2.23-2.11(1H,m),2.09-2.00(1H,m),2.04(3H,s),1.89-1.63(4H,m).

[0755] Intermediate B-4-4: (1S,2S)-2-((5-(2-(3-oxocyclobutane-1-carboxamide)benzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate

[0756] [Chemistry 96]

[0757]

[0758] Dissolve (1S,2S)-2-(((5-(2-aminobenzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate (intermediate B-4-3; 17 g, 44.22 mmol) in dichloromethane (250 mL) and THF (130 mL), add N-diisopropylamine (23.11 mL, 132.66 mmol), 3-oxocyclobutane-1-carboxylic acid (6.05 g, 53.06 mmol), and 1-propanephosphonic anhydride (19.74 mL, 66.33 mmol) , stirred at room temperature overnight. After the reaction was completed, sodium bicarbonate aqueous solution was added to the reaction mixture and extracted with chloroform. The aqueous layer was extracted with chloroform again, the organic layers were combined, dried over sodium sulfate, filtered and concentrated, and the resulting crude product was purified by silica gel column chromatography (eluent: chloroform-methanol 2-5%) to obtain (1S,2S)-2-((5-(2-(3-oxocyclobutane-1-carboxamide)benzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate (13.13 g, yield 62%).

[0759] LCMS(LC-1);RT=1.36,m / z481[M+H] +

[0760] 1H-NMR(CDCl3): δ(ppm)9.01(2H,s),8.04(1H,m),7.86(1H,m),7.68-7.61(1H,m),5.23-5.15(1H,m),4.89(2H,m),4.13-4.0 6(1H,m),3.69-3.58(1H,m),3.54-3.43(1H,m),3.43-3.31(2H,m),2.24-2.13(1H,m),2.06-2.02(3H,m),1.90-1.60(5H,m).

[0761] Intermediate B-4-5: tert-Butyl (S)-4-((1s,3R)-3-((6-2-((((1S,2S)-2-acetoxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)carbamoyl)cyclobutyl)-3-methylpiperazine-1-carboxylate

[0762] [Chemistry 97]

[0763]

[0764] (1S,2S)-2-((5-(2-(3-oxocyclobutane-1-carboxamido)benzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate (Intermediate B-4-4; 13.14 g, 27.34 mmol) was dissolved in dichloromethane (250 mL) and THF (100 mL), and (3S)-1-Boc-3-methylpiperazine (10.95 g, 54.68 mmol) was added, and the mixture was stirred at room temperature. After 15 minutes, sodium triacetoxyborohydride (8.69 g, 41.01 mmol) was added, and the mixture was stirred at room temperature for 2 hours. (3S)-1-Boc-3-methylpiperazine (2.73 g, 13.7 mmol) and sodium triacetoxyborohydride (1.7 g, 8.2 mmol) were added, and the mixture was further stirred for 2 hours. After the reaction was completed, aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The aqueous layer was extracted with chloroform again, filtered and concentrated, and the crude product was purified by silica gel column chromatography to obtain tert-butyl (S)-4-((1S,3R)-3-((6-2-((((1S,2S)-2-acetoxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)carbamoyl)cyclobutyl)-3-methylpiperazine-1-carboxylate (9.2548 g, yield 51%).

[0765] LCMS(LC-1);RT=1.69,m / z666[M+H] +

[0766] Example b-04-01: tert-Butyl (S)-4-((1S,3R)-3-((6-2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)carbamoyl)cyclobutyl)-3-methylpiperazine-1-carboxylate

[0767] [Chemistry 98]

[0768]

[0769] Methanol (30 mL) and THF (70 mL) were added to tert-butyl (S)-4-((1s,3R)-3-((6-2-((((1S,2S)-2-acetoxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)carbamoyl)cyclobutyl)-3-methylpiperazine-1-carboxylate (Intermediate B-4-5; 6.01 g, 9.04 mmol) to dissolve it, potassium carbonate (3.75 g, 27.12 mmol) was added, and stirred at room temperature for 1.5 hours. After the reaction was completed, water was added to the reaction mixture, and it was extracted with chloroform. The aqueous layer was extracted with chloroform again, dried over sodium sulfate, filtered, and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent; chloroform:methanol = 98:2) to obtain tert-butyl (S)-4-((1S,3R)-3-((6-2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)carbamoyl)cyclobutyl)-3-methylpiperazine-1-carboxylate (4.88 g, yield 87%).

[0770] LCMS(LC-1);RT=1.44,m / z623[M+H] +

[0771] Intermediate B-4-6: (1R,3s)-N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-((S)-2-methylpiperazin-1-yl)cyclobutane-1-carboxamide

[0772] [Chemistry 99]

[0773]

[0774] To tert-butyl (S)-4-((1S,3R)-3-((6-2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)carbamoyl)cyclobutyl)-3-methylpiperazine-1-carboxylate (Example b-04-01; 4.88 g, 7.84 mmol) was added dichloromethane (280 mL) and THF (120 mL) for dissolution, and hydrochloric acid (13 mL, 428.67 mmol) was added and stirred at room temperature for 15 minutes. The reaction mixture was purified by SCX to give (1R,3s)-N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-((S)-2-methylpiperazin-1-yl)cyclobutane-1-carboxamide (3.05 g, yield 74%).

[0775] LCMS(LC-1);RT=0.88,m / z524[M+H] +

[0776] 1H-NMR(CDCl3): δ(ppm)9.18(2H,s),8.52-8.45(1H,m),7.68-7.63(1H,m),7.48-7.34 (1H,m),4.72-4.67(2H,m),4.06-3.98(1H,m),3.89-3.77(1H,m),3.13-3.01(4H,m),2. 97-2.87(1H,m),2.87-2.78(1H,m),2.72-2.61(1H,m),2.43-2.22(3H,m),2.23-2.05( 2H,m),1.94-1.75(2H,m),1.68-1.53(3H,m),1.52-1.38(1H,m),1.07(3H,d,J=5.5Hz).

[0777] Example b-04-02: (1R, 3s)-N-(6-(2-((((1S, 2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)3-((S)-2-methyl-4-(2-methylisonicotinyl)piperazin-1-yl)cyclobutane-1-carboxamide

[0778] [Chemical 100]

[0779]

[0780] To (1R,3s)-N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-((S)-2-methylpiperazin-1-yl)cyclobutane-1-carboxamide (3.05 g, 5.84 mmol) was added dichloromethane (320 mL) and THF (160 mL) to dissolve it, and N-ethyldiisopropylamine (3.05 mL, 17.51 ​​mmol), 2-methoxyisonicotinic acid (960.3 mg, 7 mmol), and 1-propanephosphonic anhydride (5.14 mL) were added, and stirred at room temperature for 2 hours. After the reaction was completed, sodium bicarbonate aqueous solution was added to the reaction mixture, and the mixture was extracted with chloroform. The aqueous layer was extracted again with chloroform, and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent; ethyl acetate:methanol = 80:20) to give (1R,3s)-N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)3-((S)-2-methyl-4-(2-methylisonicotinoyl)piperazin-1-yl)cyclobutane-1-carboxamide (272.9 mg, 7% yield).

[0781] LCMS(LC-1);RT=1.08,m / z642[M+H] +

[0782] 1H-NMR(CD3OD): δ(ppm)9.01(s,2H),8.62-8.46(1H,m),8.10-8.00(1H,m),7.95-7.81(1H,m),7.71-7.57(1H,m),7.22 -7.14(1H,m),7.14-7.05(1H,m),5.02-4.90(1H,m),4.90-4.71(1H,m),4.28-4.07(1H,m),3.99-3.81(2H,m),3.81-3.6 7(1H,m),3.57-3.30(2H,m),3.29-3.09(2H,m),3.09-2.94(1H,m),2.84-2.73(1H,m),2.73-2.63(2H,m),2.63-2.58(3H ,m),2.49-2.32(3H,m),2.33-2.21(1H,m),2.18-1.96(2H,m),1.81-1.51(4H,m),1.18-1.09(1H,m),0.99-0.91(1H,m).

[0783] The following compounds in the following table were synthesized by the same method. In the following table, "Reference Methods" indicates that the examples of the production method should be referred to.

[0784] [Table 8-1]

[0785]

[0786] [Table 8-2]

[0787]

[0788] [Table 8-3]

[0789]

[0790] [Table 8-4]

[0791]

[0792] [Table 8-5]

[0793]

[0794] [Table 8-6]

[0795]

[0796] Example b-05-01: (1R, 3s)-3-((S)-4-acetyl-2-methylpiperazin-1-yl)N-(6-(2-((((1S, 2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide

[0797] [Chemistry 101]

[0798]

[0799] (1R,3s)-N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-((S)-2-methylpiperazin-1-yl)cyclobutane-1-carboxamide (Intermediate B-4-6; 27.7 mg, 0.05 mmol) was dissolved in dichloromethane (1.3 mL), acetyl chloride (4.52 μL, 0.06 mmol) and triethylamine (14.77 μL, 0.11 mmol) were added, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added an aqueous sodium bicarbonate solution, extracted with chloroform, and concentrated with a nitrogen stream. The crude product was purified by HPLC to give (1R, 3s)-3-((S)-4-acetyl-2-methylpiperazin-1-yl)N-(6-(2-((((1S, 2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide (14.2 mg, yield 47%).

[0800] LCMS(LC-1);RT=0.99,m / z565[M+H] +

[0801] 1H-NMR(CDCl3): δ(ppm)9.00-8.95(2H,m),8.02-7.98(1H,m),7.86-7.80(1H,m),7.63-7.57(1H,m) ,4.95-4.88(1H,m),4.81-4.71(1H,m),4.21-4.11(1H,m),3.85-3.78(1H,m),3.77-3.70(1H,m),3.5 9-3.52(1H,m),3.40-3.36(1H,m),3.35-3.25(1H,m),3.24-3.07(2H,m),3.06-2.96(1H,m),2.82-2. 71(1H,m),2.69-2.57(2H,m),2.08(4H,m),2.03-1.96(1H,m),1.77-1.49(5H,m),1.06-0.99(3H,m).

[0802] The following compounds in the following table were synthesized by the same method. In the following table, "Reference Methods" indicates that the examples of the production method should be referred to.

[0803] [Table 9]

[0804]

[0805] Intermediate B-6-1: tert-butyl (S)-4-((3R)-3-((6-(2-((((1S,2S)-2-acetoxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)carbamoyl)cyclobutyl)-3-methylpiperazine-1-carboxylate

[0806] [Chemistry 102]

[0807]

[0808] (1S,2S)-2-((5-(2-(3-oxocyclobutane-1-carboxamide)benzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate (Intermediate B-4-4; 15 g, 31.2 mmol) was dissolved in dichloromethane (156 mL), (3S)-1-BOC-3-methylpiperazine hydrochloride (1.5 g, 46.8 mmol) and sodium triacetoxyborohydride (13.2 g, 62.4 mmol) were added, and stirred at room temperature for 3 hours. 25% aqueous ammonia was added to the obtained crude reaction mixture, and extracted with chloroform. The obtained organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain tert-butyl (S)-4-((3R)-3-((6-(2-((((1S,2S)-2-acetoxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)carbamoyl)cyclobutyl)-3-methylpiperazine-1-carboxylate (10 g, yield 48%).

[0809] LCMS(LC-1);RT=1.68,m / z665[M+H] +

[0810] 1H-NMR (CDCl3): δ (ppm) 9.00 (s, 2H), 7.99 (brs, 1H), 7.87 (m, 1H), 7.61 (brd, J = 7. 5Hz,2H),7.55-7.27(m,2H),7.00(s,2H),5.36-5.16(m,2H),4.98-4.77(m,2H),4. 10(m,2H),3.82-3.31(m,7H),3.30-2.93(m,4H),2.67-2.48(m,3H),2.39-2.25(m, 2H),2.13(s,2H),2.04(s,3H),1.82(m,3H),1.54-1.45(m,9H),1.00-0.90(m,3H).

[0811] Intermediate B-6-2: (1S,2S)-2-((5-(2-((1R,3s)-3-((S)-2-methylpiperazin-1-yl)cyclobutane-1-carboxamide)benzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate

[0812] [Chemistry 103]

[0813]

[0814] To tert-butyl (S)-4-((3R)-3-((6-(2-((((1S,2S)-2-acetoxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)carbamoyl)cyclobutyl)-3-methylpiperazine-1-carboxylate (Intermediate B-6-1; 5.3 g, 7.97 mol) was added dichloromethane (80 mL) to dissolve it, trifluoroacetic acid (6.1 mL, 79.7 mmol) was added, and the mixture was stirred at room temperature. The obtained crude reaction mixture was neutralized with a saturated sodium bicarbonate aqueous solution and extracted with chloroform. The obtained organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain (1S,2S)-2-((5-(2-((1R,3s)-3-((S)-2-methylpiperazine-1-yl)cyclobutane-1-carboxamide)benzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate (3.7 g, yield 82%).

[0815] LCMS(LC-1);RT=1.12,m / z565[M+H] +

[0816] 1H-NMR (CDCl3): δ (ppm) 9.00 (s, 2H), 8.01 (d, J = 2.0Hz, 1H), 7.89 (d, J = 8.5Hz, 1H), 7.62 (dd ,J=8.5,2.0Hz,1H),5.20(d,J=6.5Hz,1H),4.98-4.77(m,2H),4.10(d,J=6.5Hz,1H),3.43-3 .16(m,3H),3.15-3.00(m,2H),2.97(brs,1H),2.92-2.70(m,2H),2.68-2.44(m,3H),2.44-2 .30(m,2H),2.22-1.98(m,5H),1.88-1.60(m,4H),1.43-1.19(m,1H),1.12(d,J=6.5Hz,3H).

[0817] Example b-06-01: (S)-N-ethyl-4-((1s, 3R)-3-((6-(2-((((1S, 2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)carbamoyl)-3-methylpiperazine-1-carboxamide

[0818] [Chemistry 104]

[0819]

[0820] To (1S,2S)-2-((5-(2-((1R,3s)-3-((S)-2-methylpiperazin-1-yl)cyclobutane-1-carboxamide)benzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate (Intermediate B-6-2; 31.9 mg, 0.06 mol) was added dichloromethane (1 mL) and THF (0.75 mL) to dissolve, and ethyl isocyanate (5.37 μL, 0.07 mmol) and triethylamine (15.75 μL, 0.11 mmol) were added, and the mixture was stirred at room temperature. Methanol (1 mL) and triethylamine (12 μL) were added to the obtained reaction mixture, and the mixture was stirred. Potassium carbonate (20 mg) and 2N-sodium hydroxide solution (50 μL) were further added, and the mixture was stirred at room temperature overnight. After the reaction, the solvent was concentrated with a nitrogen flow and purified by HPLC to obtain (S)-N-ethyl-4-((1s, 3R)-3-((6-(2-((((1S, 2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)carbamoyl)-3-methylpiperazine-1-carboxamide (8.4 mg, yield 25.0%).

[0821] LCMS(LC-1);RT=1.02,m / z594[M+H] +

[0822] 1H-NMR(CDCl3): δ(ppm)8.98-8.95(2H,m),8.02-7.94(1H,m),7.86-7.78(1H,m),7.62-7.56(1H,m),4 .94-4.86(1H,m),4.78-4.69(1H,m),4.20-4.09(1H,m),3.86-3.76(1H,m),3.50-3.40(2H,m),3.39-3. 32(2H,m),3.25-3.17(2H,m),3.17-3.08(1H,m),3.07-2.95(2H,m),2.74-2.65(1H,m),2.53-2.45(1H, m),2.45-2.29(3H,m),2.29-2.19(1H,m),2.11-1.95(2H,m),1.75-1.49(4H,m),1.01(3H,d,J=6.6Hz).

[0823] The following compounds in the following table were synthesized by the same method. In the following table, "Reference Methods" indicates that the examples of the production method should be referred to.

[0824] [Table 10]

[0825]

[0826] Example b-07-01: N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-((S)-2-methyl-4-2,2,2-trifluoroethyl)piperazin-1-yl)cyclobutane-1-carboxamide

[0827] [Chemistry 105]

[0828]

[0829] (1R,3s)-N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-((S)-2-methylpiperazin-1-yl)cyclobutane-1-carboxamide (Example B-4-6; 0.10 g, 0.19 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (42 μL, 0.29 mmol) were suspended in THF (634 μL), N-ethyldiisopropylamine (83 μL, 0.48 mmol) was added, and the mixture was stirred at 50° C. for 15 hours. Methanol (4 mL) and 1M aqueous sodium hydroxide solution (2 mL) were added to the obtained crude reaction mixture, and the mixture was extracted with chloroform. The crude product was purified by SCX and HPLC to obtain N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-((S)-2-methyl-4-2,2,2-trifluoroethyl)piperazin-1-yl)cyclobutane-1-carboxamide (22 mg, yield 19%).

[0830] LCMS(LC-1);RT=1.33,m / z605[M+H] +

[0831] 1H-NMR(DMSOd6): δ(ppm)9.14(2H,s),8.29(1H,m),7.75-7.65(2H,m),4.71-4. 67(3H,m),4.02(1H,brm),3.83-3.80(1H,m),3.17-3.07(2H,m),2.95-2.82(2H, m),2.67-2.62(3H,m),2.30-2.23(2H,m),2.54-2.43(2H,m),2.19-2.02(4H,m), 1.92-1.76(2H,m),1.65-1.55(3H,m),1.47-1.40(1H,m),0.95(3H,d,J=6.4Hz).

[0832] Intermediate B-8-1: tert-Butyl (S)-4-cyclopropyl-2-methylpiperazine-1-carboxylate

[0833] [Chemistry 106]

[0834]

[0835] Tert-butyl l(2S)-2-methylpiperazine-1-carboxylate (1g, 5.0mmol) and (1-ethoxycyclopropyloxy)trimethylsilane (1mL, 5.0mmol) were dissolved in methanol (10mL) and tetrahydrofuran (10mL), and acetic acid (0.57mL, 10mmol) and sodium cyanoborohydride (627mg, 10mmol) were added, and stirred at 60°C for 6 hours. The obtained crude reaction mixture was cooled to room temperature, and water (1mL) and 1M sodium hydroxide aqueous solution (6mL) were added, and the organic solvent was removed under reduced pressure. The obtained aqueous layer was extracted with chloroform (20mL), and the organic layer was washed with 1M sodium hydroxide aqueous solution. The combined aqueous layer was extracted with chloroform (6mL). The combined organic layer was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain tert-butyl (S)-4-cyclopropyl-2-methylpiperazine-1-carboxylate (1.21g) as a crude product.

[0836] 1H-NMR(CDCl3): δ(ppm)4.18-4.16(1H,m),3.79-3.76(1H,m),2.99-2.92(1H,m),2.86-2.83(1H,m),2.71-2.68(1H, m),2.36-2.33(1H,m),2.19-2.12(1H,m),1.57-1.52(1H,m),1.46(9H,s),1.13(3H,d,J=6.7Hz),0.44-0.28(4H,m).

[0837] Intermediate B-8-2: (S)-1-Cyclopropyl-3-methylpiperazine hydrochloride

[0838] [Chemistry 107]

[0839]

[0840] The crude product of tert-butyl (S)-4-cyclopropyl-2-methylpiperazine-1-carboxylate (intermediate B-8-1; 1.2 g) was dissolved in a 4M hydrochloric acid solution in 1,4-dioxane and stirred at room temperature for 30 minutes. The resulting crude reaction mixture was azeotroped with ethyl acetate three times to obtain a crude product of (S)-1-cyclopropyl-3-methylpiperazine hydrochloride (1.2 g).

[0841] 1H-NMR(CD3OD): δ(ppm)3.90-3.77(3H,m),3.74-3.70(1H,m),3.61-3.47(2H,m),3.36-3. 30(1H,m),2.98-2.92(1H,m),1.44(3H,d,J=6.5Hz),1.23-1.19(2H,m),1.02-0.96(2H,m).

[0842] Example b-08-01: 3-((S)-4-cyclopropyl-2-methylpiperazin-1-yl)N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide

[0843] [Chemistry 108]

[0844]

[0845] To N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)3-oxocyclobutane-1-carboxamide (Intermediate B-2-2; 40.2 mg, 0.09 mmol) was added dichloromethane (1.5 mL) and THF (1.3 mL) to dissolve it, (S)-1-cyclopropyl-3-methylpiperazine hydrochloride (Intermediate B-8-2; 25.7 mg, 0.18 mml) was added and stirred, and sodium triacetoxyborohydride (29.14 mg, 0.14 mmol) was further added, and stirred at room temperature overnight. (S)-1-cyclopropyl-3-methylpiperazine hydrochloride (25.7 mg, 0.18 mmol), acetic acid (200 μL), and sodium triacetoxyborohydride (29.14 mg, 0.14 mmol) were added, and the mixture was further stirred for 5 hours. After the reaction was completed, an aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated with a nitrogen stream and purified by HPLC to obtain 3-((S)-4-cyclopentyl-2-methylpiperazin-1-yl)N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide (4.3 mg, yield 8%).

[0846] LCMS(LC-1);RT=1.13,m / z563[M+H] +

[0847] 1H-NMR(CDCl3): δ(ppm)8.92(2H,s),7.93-7.88(1H,m),7.78-7.70(1H,m),7.55-7.48(1H,m),4.92 -4.81(1H,m),4.80-4.67(1H,m),4.18-4.09(1H,m),3.84-3.76(1H,m),3.36-3.30(1H,m),2.97-2.8 8(1H,m),2.78-2.70(2H,m),2.59(4H,s),2.49-2.37(4H,m),2.35-2.25(2H,m),2.23-2.11(2H,m),2 .08-1.92(3H,m),1.74-1.62(3H,m),1.61-1.48(3H,m),1.01(3H,brd,J=6.1Hz),0.45-0.33(4H,m).

[0848] Intermediate C-1-1: N-(7-oxo-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)acetamide

[0849] [Chemistry 109]

[0850]

[0851] 2-Amino-5,6-dihydro-4H-benzothiazol-7-one (60 g, 357 mmol) was suspended in acetic anhydride (300 mL) and stirred under heating reflux for 4 hours. The obtained crude reaction mixture was cooled to room temperature, and the precipitate was filtered, washed with water, and vacuum dried to obtain N-(7-oxo-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)acetamide (69.6 g, yield 93%).

[0852] LCMS(LC-1);RT=0.75,m / z211[M+H] +

[0853] 1H-NMR (DMSOd6): δ (ppm) 12.52 (1H, s), 2.85 (2H, t, J = 6.2Hz), 2.51-2.47 (2H, m), 2.18 (3H, s), 2.11-2.05 (2H, m).

[0854] Intermediate C-1-2: N-(6,6-dibromo-7-oxo-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)acetamide

[0855] [Chemistry 110]

[0856]

[0857] N-(7-Oxo-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)acetamide (Intermediate C-1-1; 30 g, 143 mmol) was suspended in acetic acid (300 mL), and 48% hydrobromic acid (3.2 mL, 29 mmol) and bromine (29 mL, 571 mmol) were added, and stirred at 60°C for 24 hours. Water (300 mL) was added to the obtained crude reaction mixture. The same operation was performed in two batches, and the obtained precipitates were combined and filtered, washed with water, and vacuum dried to obtain N-(6,6-dibromo-7-oxo-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)acetamide (75.3 g, 72%).

[0858] LCMS(LC-1);RT=1.21,m / z366[M+H] +

[0859] 1H-NMR (DMSOd6): δ (ppm) 12.88 (1H, s), 3.15 (2H, t, J = 5.8Hz), 2.97 (2H, t, J = 5.8Hz), 2.22 (3H, s).

[0860] Intermediate C-1-3: N-(6-bromo-7-hydroxybenzo[d]thiazol-2-yl)acetamide

[0861] [Chemistry 111]

[0862]

[0863] N-(6,6-dibromo-7-oxo-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)acetamide (Intermediate C-1-2; 37.6 g, 102 mmol) was suspended in tetrahydrofuran (300 mL), diazabicycloundecene (46 mL, 307 mmol) was added dropwise, and stirred at room temperature for 1 hour. Water (300 mL) was added to the obtained crude reaction mixture, and stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution (300 mL) was added, and stirring was stopped, and the mixture was allowed to stand for 30 minutes. The same operation was performed for 2 batches, and the obtained precipitate was filtered, washed with water, and vacuum dried to obtain N-(6-bromo-7-hydroxybenzo[d]thiazol-2-yl)acetamide (68.4 g) as a crude product.

[0864] LCMS(LC-1);RT=0.90,m / z286[M+H] +

[0865] 1H-NMR (DMSOd6): δ (ppm) 7.37 (1H, d, J = 8.4Hz), 6.86 (1H, d, J = 8.4Hz), 2.17 (3H, s).

[0866] The following compounds in the following table were synthesized by the same method. In the following table, "Reference Methods" indicates that the examples of the production method should be referred to.

[0867] [Table 11]

[0868]

[0869] Intermediate C-1-4: 2-amino-6-bromobenzo[d]thiazol-7-ol

[0870] [Chemistry 112]

[0871]

[0872] The crude product N-(6-bromo-7-hydroxybenzo[d]thiazol-2-yl)acetamide (intermediate C-1-3; 68.4 g) was suspended in methanol (240 mL) and 5M hydrochloric acid solution (360 mL) and stirred at 75°C for 14 hours. Methanol was removed from the obtained crude reaction mixture under reduced pressure, and 5M sodium hydroxide aqueous solution was added dropwise under ice cooling to neutralize. The obtained solid was filtered and vacuum dried to obtain 2-amino-6-bromobenzo[d]thiazol-7-ol as a crude product.

[0873] LCMS(LC-1);RT=0.84,m / z244[M+H] + (as boric acid test)

[0874] 1H-NMR (DMSOd6): δ (ppm) 9.92 (1H, s, br), 7.52 (2H, s), 7.28 (1H, d, J = 8.4Hz), 6.81 (1H, d, J = 8.4Hz).

[0875] Intermediate C-1-5: 2-(6-bromo-7-hydroxybenzo[d]thiazol-2-yl)isoindoline-1,3-dione

[0876] [Chemistry 113]

[0877]

[0878] The crude product 2-amino-6-bromobenzo[d]thiazol-7-ol (intermediate C-1-4; 163 mmol) was suspended in N,N-dimethylformamide (137 mL) and acetic acid (137 mL), and phthalic anhydride (48 g, 326 mmol) was added and stirred at 120°C for 5 hours. The obtained crude reaction mixture was cooled to room temperature, and the precipitate was filtered out, washed with water, and vacuum dried to obtain 2-(6-bromo-7-hydroxybenzo[d]thiazol-2-yl)isoindoline-1,3-dione (54.7 g, 3-step yield 89%).

[0879] LCMS(LC-1);RT=1.23,m / z374[M+H] +

[0880] 1H-NMR (DMSOd6): δ (ppm) 10.76 (1H, s), 8.08-8.04 (2H, m), 7.99-7.96 (2H, m), 7.65 (1H, d, J = 8.6), 7.49 (1H, d, J = 8.6).

[0881] Intermediate C-1-6: 2-(6-bromo-7-methoxybenzo[d]thiazol-2-yl)isoindoline-1,3-dione

[0882] [Chemistry 114]

[0883]

[0884] 2-(6-bromo-7-hydroxybenzo[d]thiazol-2-yl)isoindoline-1,3-dione (Intermediate C-1-5; 54.7 g, 146 mmol) was dissolved in N,N-dimethylformamide (547 mL), and iodomethane (27 mL, 437 mmol) and N-ethyldiisopropylamine (102 mL, 583 mmol) were added, and stirred at room temperature for 9 hours. Water (110 mL) was added to the obtained crude reaction mixture, and the mixture was filtered and dried in vacuo to obtain 2-(6-bromo-7-methoxybenzo[d]thiazol-2-yl)isoindoline-1,3-dione (52.0 g, 92%).

[0885] LCMS(LC-1);RT=1.74,m / z388[M+H] +

[0886] 1H-NMR(DMSOd6): δ(ppm)8.09-8.06(2H,m),8.01-7.96(2H,m),7.76(2H,m),4.03(3H,s.)

[0887] Intermediate C-1-7: 6-bromo-7-methoxybenzo[d]thiazol-2-amine

[0888] [Chemistry 115]

[0889]

[0890] 2-(6-bromo-7-methoxybenzo[d]thiazol-2-yl)isoindoline-1,3-dione (Intermediate C-1-6; 52.0 g, 134 mmol) was suspended in ethanol, hydrazine monohydrate (7.1 mL, 147 mmol) was added, and the mixture was stirred for 1 hour under heating and reflux. The obtained crude reaction mixture was cooled to 50°C, and the precipitate was filtered out and washed with tetrahydrofuran. The obtained filtrate was concentrated under reduced pressure to obtain 6-bromo-7-methoxybenzo[d]thiazol-2-amine (41.6 g) as a crude product.

[0891] LCMS(LC-1);RT=1.23,m / z258[M+H] +

[0892] 1H-NMR (DMSOd6): δ (ppm) 7.69 (2H, s), 7.40 (1H, d, J = 8.4Hz), 7.05 (1H, d, J = 8.4Hz), 3.85 (3H, s).

[0893] Intermediate C-1-8: (1S,2S)-2-((5-(2-amino-7-methoxybenzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate

[0894] [Chemistry 116]

[0895]

[0896] The crude product 6-bromo-7-methoxybenzo[d]thiazol-2-amine (Intermediate C-1-7; 12.35 g, 38.6 mmol) was suspended in 1,4-dioxane, and the crude product (1S,2S)-2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate (Intermediate B-4-2; 46.6 g, 77.2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5.7 g, 7.7 mmol), cesium carbonate (37.7 g, 116 mmol), and water (25 mL) were added, and stirred at 130° C. for 1 hour. The crude reaction mixture was diluted with ethyl acetate (200 mL) and washed with water (200 mL). The aqueous layer was extracted again with ethyl acetate (200 mL), and the combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by automated silica gel column chromatography (eluent; chloroform:methanol=100:0-95:5) to obtain (1S,2S)-2-((5-(2-amino-7-methoxybenzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate (19.3 g) as a crude product.

[0897] LCMS(LC-1);RT=1.22,m / z415[M+H] +

[0898] Intermediate C-1-9: (1S,2S)-2-((5-(2-amino-7-methoxybenzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentane-1-ol

[0899] [Chemistry 117]

[0900]

[0901] The crude product (1S,2S)-2-((5-(2-amino-7-methoxybenzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate (Intermediate C-1-8; 20 g) was dissolved in methanol (100 mL), and a 5M aqueous sodium hydroxide solution (100 mL) was added, followed by stirring at room temperature for 5 minutes. Water (100 mL), a saturated aqueous ammonium chloride solution (100 mL), and chloroform (400 mL) were added to the obtained crude reaction mixture, and the organic layer was separated. The aqueous layer was extracted twice with chloroform, and the combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by automated silica gel column chromatography (eluent; chloroform:methanol = 99:1-92:8) to obtain (1S,2S)-2-((5-(2-amino-7-methoxybenzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentane-1-ol (8.1 g, 2-step yield 54%).

[0902] LCMS(LC-1);RT=0.93,m / z373[M+H] +

[0903] 1H-NMR (DMSOd6): δ (ppm) 8.93 (2H, s), 7.73 (2H, s), 7.36 (1H, d, J = 8.3Hz), 7.24 (1H, d, J = 8.3Hz), 4.72 (1H, d, J = 4.0Hz), 4 .68(1H,m),4.05-4.01(1H,m),3.84-3.81(1H,m),3.70(3H,s),1.92-1.77(2H,m),1.69-1.53(3H,m),1.48-1.41(1H,m).

[0904] Example c-01-01: N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)-7-methoxybenzo[d]thiazol-2-yl)cyclopropanamide

[0905] [Chemistry 118]

[0906]

[0907] (1S,2S)-2-((5-(2-amino-7-methoxybenzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentan-1-ol (Intermediate C-1-9; 5.7 g, 15.3 mmol) was dissolved in tetrahydrofuran (31 mL), and N-ethyldiisopropylamine (8 mL, 46 mmol) and cyclopropanecarbonyl chloride (2.1 mL, 23 mmol) were added, and the mixture was stirred at room temperature for 5 minutes. Cyclopropanecarbonyl chloride (700 μL, 7.7 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 minute. N-ethyldiisopropylamine (1.66 mL, 7.7 mmol) and cyclopropanecarbonyl chloride (700 μL, 7.7 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. Methanol (122 mL) was added to the obtained crude reaction mixture, and the mixture was stirred at room temperature for 3 hours. Water (30 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Water (30 mL) was added to the obtained reaction mixture, and the mixture was extracted three times with chloroform-methanol (9:1, v / v). The combined organic layer was concentrated, and the obtained crude product was purified by automated silica gel column chromatography (eluent; hexane:ethyl acetate = 75:25-0:100, ethyl acetate:methanol = 100:0-90:10) to obtain N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)-7-methoxybenzo[d]thiazol-2-yl)cyclopropanamide (6.6 g, yield 98%).

[0908] LCMS(LC-1);RT=1.19,m / z441[M+H] +

[0909] 1H-NMR (CD3OD): δ (ppm) 9.01 (2H, s), 7.64 (1H, d, J = 8.3Hz), 7.53 (1H, d, J = 8.3Hz), 4.81 (2H, m), 4.20-4.17 (1H, m), 3.91- 3.88(1H,m),3.83(3H,s),2.06-1.93(3H,m),1.78-1.67(3H,m),1.60-1.52(1H,m),1.12-1.08(2H,m),1.07-1.01(2H,m).

[0910] Example c-02-01: (1R, 2R)-N-(6-(2-((((1S, 2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)-7-methoxybenzo[d]thiazol-2-yl)-2-methoxycyclopropane-1-carboxamide

[0911] [Chemistry 119]

[0912]

[0913] (1S,2S)-2-((5-(2-amino-7-methoxybenzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentane-1-ol (intermediate C-9-9; 540 mg, 110 μmol) and (1R,2R)-2-methylcyclopropane-1-carboxylic acid (16 mg, 160 μmol) were dissolved in N,N-dimethylformamide (537 μL), 1-hydroxybenzotriazole monohydrate (33 mg, 210 μmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (41 mg, 210 μmol) were added, and the mixture was stirred at 70°C for 5 hours. The obtained crude reaction mixture was purified by HPLC to obtain (1R,2R)-N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)-7-methoxybenzo[d]thiazol-2-yl)-2-methoxycyclopropane-1-carboxamide (33 mg, yield 67%).

[0914] LCMS(LC-1);RT=1.31,m / z455[M+H] +

[0915] 1H-NMR (CD3OD): δ (ppm) 9.01 (2H, s), 7.63 (1H, d, J = 8, 4Hz), 7.53 (1H, d, J = 8.4Hz), 4.81 (2H, m), 4.20-4.17 (1H, m), 3.91-3.88 (1H, m) ,3.83(3H,s),2.06-1.94(2H,m),1.78-1.67(4H,m),1.60-1.48(2H,m),1.33-1.29(1H,m),1.20(3H,d,J=6.0Hz),0.90-0.85(1H,m).

[0916] The following compounds in the following table were synthesized by the same method. In the following table, "Reference Methods" indicates that the examples of the production method should be referred to.

[0917] [Table 12]

[0918]

[0919] Intermediate C-3-1: N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)-7-methoxybenzo[d]thiazol-2-yl)-3-oxocyclobutane-1-carboxamide

[0920] [Chemistry 120]

[0921]

[0922] (1S,2S)-2-((5-(2-amino-7-methoxybenzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentane-1-ol (Intermediate C-9-9; 805 mg, 2.2 mmol) and (3-oxocyclobutyl)carboxylic acid (370 mg, 3.2 mmol) were dissolved in N,N-dimethylformamide (7.7 mL), 1-hydroxybenzotriazole monohydrate (662 mg, 4.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (829 mg, 4.3 mmol) were added, and the mixture was stirred at 60°C for 20 minutes. Chloroform and saturated sodium bicarbonate aqueous solution were added to the obtained crude reaction mixture, and the organic layer was separated. The aqueous layer was extracted again with chloroform, the combined organic layers were concentrated under reduced pressure, and the crude product was purified by automated oxidation silica gel column chromatography (eluent; chloroform:methanol = 98:2-80:20) to obtain N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)-7-methoxybenzo[d]thiazol-2-yl)-3-oxocyclobutane-1-carboxamide (990 mg, yield 98%).

[0923] LCMS(LC-1);RT=1.11,m / z469[M+H] +

[0924] 1H-NMR(CD3OD): δ(ppm)0.92(2H,m),7.66-7.61(1H,m),7.54-7.51(1H,m),4.81(2H,s),4.21-4.17(1H,m),3.91-3.8 8(1H,m),3.85(3H,s),3.58-3.35(5H,m),2.62-2.41(1H,m),2.06-1.94(2H,m),1.78-1.67(3H,m),1.60-1.52(1H,m).

[0925] Example c-03-01: tert-Butyl (S)-4-((1s,3R)-3-((6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)-7-methoxybenzo[d]thiazol-2-yl)carbamoyl)cyclobutyl)-3-methylpiperazine-1-carboxylate

[0926] [Chemistry 121]

[0927]

[0928] N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)-7-methoxybenzo[d]thiazol-2-yl)-3-oxocyclobutane-1-carboxamide (Intermediate C-3-1; 967 mg, 2.1 mmol) was dissolved in dichloromethane (19 mL) and tetrahydrofuran (3.8 mL), (3S)-1-BOC-3-methylpiperazine (827 mg, 4.1 mmol) and sodium triacetoxyborohydride (656 mg, 3.1 mmol) were added, and stirred at room temperature for 14 hours. Saturated aqueous sodium bicarbonate solution was added to the obtained crude reaction mixture, and the mixture was extracted with chloroform. The obtained organic layer was concentrated under reduced pressure, and the obtained crude product was purified by automatic oxidation silica gel column chromatography (eluent; chloroform:methanol=98:2-80:20) to obtain tert-butyl (S)-4-((1s,3R)-3-((6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)-7-methoxybenzo[d]thiazol-2-yl)carbamoyl)cyclobutyl)-3-methylpiperazine-1-carboxylate (1.18 g, yield 88%).

[0929] LCMS(LC-1);RT=1.48,m / z653[M+H] +

[0930] 1H-NMR (CD3OD): δ (ppm) 9.01 (2H, s), 7.63 (1H, d, J = 8.3Hz), 7.52 (1H, d, J = 8.3 Hz),4.81(2H,s),4.20-4.17(1H,m),3.91-3.88(1H,m),3.85(3H,s),3.51-3. 35(4H,m),2.73-2.68(1H,m),2.60(1H,m),2.52-2.17(5H,m),2.06-1.94(2H, m),1.78-1.67(3H,m),1.61-1.52(1H,m),1.46(9H,s),1.03(3H,d,J=6.5Hz).

[0931] Intermediate C-3-2: (1R,3s)-N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyridin-5-yl)-7-methoxybenzo[d]thiazol-2-yl)-3-((S)-2-methylpiperazin-1-yl)cyclobutane-1-carboxamide

[0932] [Chemistry 122]

[0933]

[0934] Tert-butyl (S)-4-((1s,3R)-3-((6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)-7-methoxybenzo[d]thiazol-2-yl)carbamoyl)cyclobutyl)-3-methylpiperazine-1-carboxylate (Example c-03-01; 1.16 g, 1.8 mmol) was dissolved in dichloromethane (10 mL), concentrated hydrochloric acid (2.5 mL) was added, and the mixture was stirred at room temperature for 15 minutes. Water (2 mL) and 28% aqueous ammonia (8 mL) were added to the obtained crude reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (1R,3s)-N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyridin-5-yl)-7-methoxybenzo[d]thiazol-2-yl)-3-((S)-2-methylpiperazin-1-yl)cyclobutane-1-carboxamide (1.0 g, quant.).

[0935] LCMS(LC-1);RT=0.92,m / z553[M+H] +

[0936] 1H-NMR (CD3OD): δ (ppm) 9.01 (2H, s), 7.62 (1H, d, J = 8.3Hz), 7.52 (1H, d, J = 8.3Hz) ),4.81(2H,s),4.20-4.17(1H,m),3.91-3.88(1H,m),3.84(3H,s),3.19-3.02(2H ,m),2.95-2.91(1H,m),2.85-2.73(3H,m),2.55-2.27(6H,m),2.18-2.11(1H,m) ,2.06-1.94(2H,m),1.78-1.67(3H,m),1.60-1.52(1H,m),1.06(3H,d,J=6.4Hz).

[0937] Example c-03-02: (1R, 3s)-N-(6-(2-((((1S, 2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)-7-methoxybenzo[d]thiazol-2-yl)-3-((S)-2-methyl-4-(2-methylisonicotinyl)piperazin-1-yl)cyclobutane-1-carboxamide

[0938] [Chemistry 123]

[0939]

[0940] (1R,3s)-N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyridin-5-yl)-7-methoxybenzo[d]thiazol-2-yl)-3-((S)-2-methylpiperazin-1-yl)cyclobutane-1-carboxamide (Intermediate C-3-2; 50 mg, 90 μmol) was dissolved in dichloromethane, 2-methylisonicotinic acid (15 mg, 110 μmol), N-ethyldiisopropylamine (47 μL, 270 mmol), propylphosphonic anhydride (1.7 M ethyl acetate solution; 80 μL, 140 mmol) were added, and stirred at room temperature for 10 minutes. Saturated sodium bicarbonate aqueous solution (1 mL) was added to the obtained crude reaction mixture, and chloroform was added for extraction. The organic layer was concentrated by blowing N2 and purified by HPLC to obtain (1R, 3s)-N-(6-(2-((((1S, 2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)-7-methoxybenzo[d]thiazol-2-yl)-3-((S)-2-methyl-4-(2-methylisonicotinoyl)piperazin-1-yl)cyclobutane-1-carboxamide (38 mg, yield 62%).

[0941] LCMS(LC-1);RT=1.11,m / z672[M+H] +

[0942] 1H-NMR (DMSOd6): δ (ppm) 12.52 (1H, brs), 8.99 (2H, s), 8.52 (1H, d, J = 5.0Hz), 7.63 (1H, d, J = 8.4Hz), 7.57 (1H, d, J = 8 .4),7.24-7.21(1H,m),7.17-7.13(1H,m),4.73-4.72(1H,m),4.70(2H,m),3.85-3.83(1H,m),3.81(3H,s),3.70-3.5 2(2H,m),3.25(2H,m),3.10-2.94(3H,m),2.68-2.63(1H,m),2.38-2.32(1H,m),2.28-2.21(2H,m),2.18-2.06(3H,m ),1.92-1.77(2H,m),1.66-1.55(3H,m),1.48-1.41(1H,m),1.25-1.24(1H,m),1.01-0.99(2H,m),0.88-0.82(2H,m).

[0943] The following compounds in the following table were synthesized by the same method. In the following table, "Reference Methods" indicates that the examples of the production method should be referred to.

[0944] [Table 13]

[0945]

[0946] Intermediate C-4-1: N-(6-bromo-7-methoxybenzo[d]thiazol-2-yl)cyclopropanamide

[0947] [Chemistry 124]

[0948]

[0949] N-(6-bromo-7-hydroxybenzo[d]thiazol-2-yl)cyclopropanamide (intermediate C-9-10; 1.5 g, 4.8 mmol) was dissolved in N,N-dimethylformamide (10 mL), and iodomethane (813 mg, 5.7 mmol), potassium iodide (79 mg, 478 μmol), and potassium carbonate (1.32 g, 9.6 mmol) were added, and stirred at room temperature overnight. The obtained crude reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent; petroleum ether: ethyl acetate = 3:1) to obtain N-(6-bromo-7-methoxybenzo[d]thiazol-2-yl)cyclopropanamide (400 mg, yield 26%).

[0950] LCMS(LC-1);RT=1.56,m / z326[M+H] +

[0951] 1H-NMR (DMSOd6): δ (ppm) 12.79 (1H, brs), 7.64 (1H, d, J = 8.4Hz), 7.46 (1H, d, J = 8.4Hz), 3.95 (3H, s), 2.01-1.99 (1H, m), 0.99-0.96 (4H, m).

[0952] Example c-04-01: N-(6-(2-((((1S,2S)-4,4-difluoro-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)-7-methoxybenzo[d]thiazol-2-yl)cyclopropanamide

[0953] [Chemistry 125]

[0954]

[0955] Trans-2-((5-bromopyrimidin-2-yl)methoxy)-4,4-difluorocyclopropane-1-ol (intermediate A-4-2; 1 g, 3.2 mmol) was dissolved in 1,4-dioxane (15 mL), and bis(pinacol)diboron (1.1 g, 4.8 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.24 g, 0.32 mmol), and potassium acetate (0.95 g, 9.7 mmol) were added, and stirred at 80°C overnight. The obtained crude reaction mixture was concentrated under reduced pressure to obtain 1.50 g of a crude reaction intermediate. The obtained crude reaction intermediate was dissolved in acetonitrile (8 mL) and water (1 mL), and N-(6-bromo-7-methoxybenzo[d]thiazol-2-yl)cyclopropanamide (Intermediate C-4-1; 400 mg, 1.22 mmol), cesium fluoride (0.37 g, 2.4 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (43 mg, 61 μmol) were added, and stirred at 130° C. for 2 hours under microwave irradiation. The obtained crude reaction mixture was concentrated and purified by silica gel column chromatography (eluent; chloroform:methanol=30:1) and HPLC to obtain N-(6-(2-(((trans-4,4-difluoro-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)-7-methoxybenzo[d]thiazol-2-yl)cyclopropanamide (160 mg, yield 28%). The obtained stereoisomer mixture was separated by chiral HPLC purification (CHIRALPAK IC (manufactured by DAICEL), mobile phase: n-hexane:ethanol = 50:50) to obtain the desired N-(6-(2-((((1S,2S)-4,4-difluoro-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)-7-methoxybenzo[d]thiazol-2-yl)cyclopropanamide (42.5 mg).

[0956] LCMS(LC-1);RT=1.30,m / z477[M+H] +

[0957] 1H-NMR (DMSOd6): δ (ppm) 9.00 (2H, s), 7.62 (1H, d, J = 8.4Hz), 7.56 (1H, d, J = 8.4Hz), 5.37-5.36 (1H, m), 4.77 (2H, s), 4.20(1H,m),4.05(1H,m),3.80(3H,s),2.58-2.44(2H,m),2.26-2.15(1H,m),2.09-1.97(2H,m),0.98-0.96(4H,m).

[0958] The following compounds in the following table were synthesized by the same method. In the following table, "Reference Methods" indicates that the examples of the production method should be referred to.

[0959] [Table 14]

[0960]

[0961] Intermediate C-5-1: tert-butyl 3-(((6-bromo-2-(cyclopropanamide)benzo[d]thiazol-7-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylate

[0962] [Chemistry 126]

[0963]

[0964] N-(6-bromo-7-methoxybenzo[d]thiazol-2-yl)cyclopropanamide (intermediate C-4-1; 0.2 g, 0.64 mmol), 1-BOC-3-fluoroazetidine-3-methanol (0.26 mg, 1.3 mmol), and triphenylphosphine (0.50 g, 1.9 mmol) were suspended in tetrahydrofuran (3.2 mL), and a tetrahydrofuran-toluene solution (6.4 mL, 1:1, v / v) of diethylazoformate (0.35 mL, 1.9 mmol) was added dropwise, and the mixture was stirred at room temperature for 15 minutes. The obtained crude reaction mixture was purified by automated silica gel column chromatography (eluent; hexane:ethyl acetate = 88:12 to 0:100) to obtain tert-butyl 3-(((6-bromo-2-(cyclopropanamide)benzo[d]thiazol-7-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylate (629 mg) as a crude product.

[0965] LCMS(LC-1);RT=1.86,m / z500[M+H] +

[0966] Intermediate C-5-2: tert-butyl 3-(((6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)-2-(cyclopropanamide)benzo[d]thiazol-7-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylate

[0967] [Chemistry 127]

[0968]

[0969] The crude product of tert-butyl 3-(((6-bromo-2-(cyclopropanamide)benzo[d]thiazol-7-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylate (Intermediate C-5-1; 344 mg) was suspended in acetonitrile (3.5 mL) and water (0.35 mL), and 2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrimidine (Intermediate A-1-3; 0.38 g, 0.70 mmol), cesium fluoride (106 mg, 0.70 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II)dichloride (50 mg, 70 μmol) were added, and the mixture was stirred at 130°C for 4 hours under microwave irradiation. Ethyl acetate (12 mL) and water (3 mL) were added to the obtained crude reaction mixture, and the organic layer was extracted and concentrated under reduced pressure. The obtained crude product was purified by automatic silica gel column chromatography (eluent; hexane:ethyl acetate = 88:12 to 0:100) to obtain tert-butyl 3-(((6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)-2-(cyclopropanamide)benzo[d]thiazol-7-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylate (116 mg, 2-step yield 46%).

[0970] LCMS(LC-6);RT=1.57,m / z728[M+H] +

[0971] Intermediate C-5-3: N-(7-((3-fluoroazetidin-3-yl)methoxy)-6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanamide

[0972] [Chemistry 128]

[0973]

[0974] Tert-butyl 3-(((6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)-2-(cyclopropanamide)benzo[d]thiazol-7-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylate (Intermediate C-5-2; 112 mg, 0.15 mmol) was dissolved in dichloromethane (1.6 mL), trifluoroacetic acid (0.40 mL) was added, and the mixture was stirred at room temperature for 3 hours. The obtained crude reaction mixture was purified by scx to obtain N-(7-((3-fluoroazetidine-3-yl)methoxy)-6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanamide as a crude product.

[0975] LCMS(LC-1);RT=0.98,m / z514[M+H] +

[0976] Example c-05-01: N-(7-((3-fluoro-1-methylazetidin-3-yl)methoxy)-6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanamide

[0977] [Chemistry 129]

[0978]

[0979] 1 / 3 of the crude product of N-(7-((3-fluoroazetidine-3-yl)methoxy)-6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanamide (intermediate C-5-3) was dissolved in methanol-dichloromethane (2 mL, 1:1, v / v), and formaldehyde (37% aqueous solution, 12 μL, 0.16 mmol) and sodium triacetoxyborohydride (34 mg, 0.16 mol) were added, and stirred at room temperature for 15 minutes. The obtained crude reaction mixture was purified by SCX and HPLC to obtain N-(7-((3-fluoro-1-methylazetidin-3-yl)methoxy)-6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanamide (13.9 mg, 2-step yield 50%).

[0980] LCMS(LC-1);RT=1.16,m / z528[M+H] +

[0981] 1H-NMR (CD3OD): δ (ppm) 9.02 (2H, s), 7.67 (1H, d, J = 8.3Hz), 7.55 (1H, d, J = 8.3Hz), 4.81 (2H, s), 4.23 (1H, s), 4.20-4.16 (2H, m), 3.90-3.8 7(1H,m),3.50-3.44(2H,m),3.21-3.13(2H,m),2.37(3H,s),2.05-1.93(3H,m),1.78-1.67(3H,m),1.60-1.52(1H,m),1.12-1.01(4H,m).

[0982] Intermediate C-6-1: N-(6-bromo-7-(methoxymethoxy)benzo[d]thiazol-2-yl)-N-(methoxymethoxy)cyclopropaneamide

[0983] [Chemistry 130]

[0984]

[0985] Add dichloromethane (173 mL) to N-(6-bromo-7-hydroxy-1,3-benzothiazol-2-yl)cyclopropanamide (Intermediate C-1-10; 5.41 g, 17.27 mmol), and cool and stir at 0°C. Slowly add N,N-diisopropylamine (15.04 mL, 86.37 mmol) and chloromethyl methyl ether (3.94 mL, 51.82 mmol) in 1 mL increments. After cooling and stirring at 0°C for a while, stir at room temperature for 1 hour. Add additional reagents. Add N,N-diisopropylamine (3.01 mL, 17.27 mmol) and chloromethyl methyl ether (0.66 mL, 8.63 mmol), and stir for 30 minutes. Add saturated sodium bicarbonate aqueous solution and saline, and add dichloromethane for extraction. Extract the aqueous layer again with dichloromethane. The organic layers were combined, washed again with brine, dried over sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (eluent; hexane:ethyl acetate = 80:20-70:30) to give N-(6-bromo-7-(methoxymethoxy)benzo[d]thiazol-2-yl)-N-(methoxymethoxy)cyclopropanamide (4.3 g, white solid, yield 63%).

[0986] LCMS(LC-1);RT=1.91,m / z401[M+H] +

[0987] 1H-NMR(CDCl3): δ(ppm)7.59-7.56(1H,m),7.49-7.43(1H,m),5.94-5.91(2H,s),5.32-5.30(2H,s ),3.72-3.69(3H,s),3.57-3.52(3H,s),1.30-1.25(2H,m),1.17-1.14(1H,m),1.11-1.05(2H,m).

[0988] Intermediate C-6-2: N-(6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)-7-(methoxymethoxy)benzo[d]thiazol-2-yl)-N-(methoxymethyl)cyclopropanamide

[0989] [Chemistry 131]

[0990]

[0991] 1,4-Dioxane (43 mL) was added to N-(6-bromo-7-(methoxymethoxy)benzo[d]thiazol-2-yl)-N-(methoxymethoxy)cyclopropanamide (Intermediate C-6-1; 4.2 g, 10.47 mmol), 2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrimidine (Intermediate A-1-3; 6.82 g, 15.71 mmol), cesium carbonate (10.24 g, 31.42 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (766.3 mg, 1.05 mmol), and water (10.64 mL), and the mixture was stirred under heating at 80°C for 30 minutes. The obtained reaction mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated, and the obtained crude product was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=60:40) to obtain the target product (5.13 g, yield 78%).

[0992] LCMS(LC-1);RT=2.16,2.27,m / z629[M+H] +

[0993] 1H-NMR (CDCl3): δ (ppm) 8.97 (2H, s), 7.71 (1H, d, J = 8.0Hz), 7.38 (1H, d, J = 8.0Hz), 5.97 (2 H,s),5.04(2H,s),4.96(1H,s),4.36-4.24(1H,m),3.95-3.85(2H,m),3.57(3H,s),3.29( 3H,s),2.31(1H,s),2.04-1.95(2H,m),1.76-1.73(2H,m),1.59-1.51(2H,m),1.32-1.28( 2H,m),1.19-1.16(1H,m),1.13-1.06(2H,m),0.99-0.94(1H,m),0.88(9H,s),0.08(6H,s).

[0994] Intermediate C-6-3: N-(7-hydroxy-6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanamide

[0995] [Chemistry 132]

[0996]

[0997] N-(6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)-7-(methoxymethoxy)benzo[d]thiazol-2-yl)-N-(methoxymethyl)cyclopropanamide (Intermediate C-6-2; 5 g, 7.95 mmol) was dissolved in THF (8 mL), 5N aqueous hydrochloric acid solution (80 mL) was added, and the mixture was stirred at 40°C overnight. 5N aqueous hydrochloric acid solution (8 mL) was added, and the mixture was further stirred for 5 hours before post-treatment. The reaction mixture was cooled to 0°C, neutralized with 5N aqueous sodium hydroxide solution (88 mL), and filtered to obtain N-(7-hydroxy-6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanamide (3.48 g, quant.).

[0998] LCMS(LC-1);RT=0.98,m / z427[M+H] +

[0999] 1H-NMR(DMSO): δ(ppm)12.7(1H,s),10.35-10.1(1H,m),8.96(2H,s),7.50-7.35(2H,m),4.78-4.70(1H,m),4.70-4.63(2H,m),4.0 8-3.96(1H,m),3.92-3.76(1H,m),2.10-1.98(1H,m),1.97-1.76(2H,m),1.70-1.52(3H,m),1.52-1.38(1H,m),1.00-0.96(2H,m).

[1000] Intermediate C-6-4: N-(7-((tert-butyldimethylsilyl)oxy)-6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanamide

[1001] [Chemistry 133]

[1002]

[1003] N-(7-hydroxy-6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanamide (Intermediate C-6-3; 3 g, 7.0 mmol) was dissolved in dichloromethane (30 mL), 2,6-lutidine (6.0 g, 56 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (11 g, 42 mmol) were added, and stirred at room temperature for 1 hour. The obtained crude reaction mixture was washed twice with water (50 mL), and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent; petroleum ether:ethyl acetate = 5:1) to obtain N-(7-((tert-butyldimethylsilyl)oxy)-6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanamide (3.0 g, yield 65%).

[1004] LCMS(LC-6);RT=2.46,m / z655[M+H] +

[1005] 1H-NMR (CDCl3): δ (ppm) 10.19 (1H, m), 8.93 (2H, m), 7.55 (1H, d, J = 8.2Hz), 7.34 (1H, d, J=8.2Hz),4.88-4.80(2H,m),4.29-4.26(1H,m),3.89-3.85(1H,m),3.77-3.73(1H,m), 2.05-1.89(2H,m),1.87-1.84(1H,m),1.76-1.68(2H,m),1.56-1.50(1H,m),1.30-1.2 6(2H,m),1.07-1.02(2H,m),0.96(9H,s),0.88(9H,s),0.07(6H,s),0.19(d,J=6.1Hz).

[1006] Intermediate C-6-5: N-(7-((tert-butyldimethylsilyl)oxy)-6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-N-(methoxymethyl)cyclopropanamide

[1007] [Chemistry 134]

[1008]

[1009] N-(7-((tert-butyldimethylsilyl)oxy)-6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanamide (Intermediate C-6-4; 4.5 g, 6.87 mmol) was dissolved in dichloromethane (50 mL), and N-ethyldiisopropylamine (3.6 mL, 21 mmol) and chloromethyl methyl ether (1.0 mL, 14 mmol) were added, and the mixture was stirred at room temperature overnight. The obtained crude reaction mixture was washed twice with water (50 mL), and the organic layer was concentrated under reduced pressure to obtain N-(7-((tert-butyldimethylsilyl)oxy)-6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-N-(methoxymethyl)cyclopropanamide (4.0 g, yield 83%).

[1010] LCMS(LC-6);RT=2.72,m / z699[M+H] +

[1011] Intermediate C-6-6: N-(6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-N-(methoxymethyl)cyclopropanamide

[1012] [Chemistry 135]

[1013]

[1014] N-(7-((tert-butyldimethylsilyl)oxy)-6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-N-(methoxymethyl)cyclopropanamide (Intermediate C-6-5; 4.0 g, 5.7 mmol) was dissolved in N,N-dimethylformamide (40 mL), and water (4 mL) and cesium carbonate (0.93 g, 2.9 mmol) were added, and stirred at room temperature for 1 hour. Water (300 mL) and dichloromethane (200 mL) were added to the obtained crude reaction mixture, and the vent layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent; petroleum ether:ethyl acetate = 2:1) to obtain N-(6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-N-(methoxymethyl)cyclopropanamide (2.0 g, yield 60%).

[1015] LCMS (LC-1); RT = 2.26 & 2.35 (bimodal, positional isomer mixture based on methoxymethyl protection), m / z 585 [M+H] +

[1016] Example c-06-01: N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)-7-(2-hydroxyethoxy)benzo[d]thiazol-2-yl)cyclopropanamide

[1017] [Chemistry 136]

[1018]

[1019] N-(6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-N-(methoxymethyl)cyclopropanamide (Intermediate C-6-6; 60 mg, 0.10 mmol) and 2-bromomethane-1-ol (25 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (2 mL), cesium carbonate (99 mg, 0.31 mmol) was added, and the mixture was stirred at 80°C for 3 hours. Dichloromethane and water were added to the obtained crude reaction mixture, and the organic layer was concentrated under reduced pressure. The obtained crude reaction mixture was purified by silica gel chromatography to obtain a crude reaction intermediate (3 mg). The obtained crude reaction intermediate (30 mg) was dissolved in 3M hydrochloric acid-methanol (3 mL) and stirred at room temperature for 3 hours. The obtained crude reaction mixture was concentrated under reduced pressure, and dichloromethane and sodium bicarbonate aqueous solution were added, and the organic layer was concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (eluent; dichloromethane:methanol=10:1) to obtain N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)-7-(2-hydroxyethoxy)benzo[d]thiazol-2-yl)cyclopropanamide (11.5 mg, yield 24%).

[1020] LCMS(LC-1);RT=1.00,m / z471[M+H] +

[1021] 1H-NMR (CDCl3): δ (ppm) 9.04 (2H, s), 7.62 (1H, d, J = 8.4Hz), 7.56 (1H, d, J = 8. 4Hz),4.86-4.84(1H,m),4.73-4.72(1H,m),4.69(2H,m),4.05-4.01(1H,m), 3.98-3.96(2H,m),3.85-3.82(1H,m),3.58-3.55(2H,m),2.04-1.98(1H,m), 1.92-1.77(2H,m),1.66-1.56(3H,m),1.48-1.41(1H,m),0.99-0.96(4H,m).

[1022] The following compounds in the following table were synthesized by the same method. In the following table, "Reference Methods" indicates that the examples of the production method should be referred to.

[1023] [Table 15]

[1024]

[1025] Intermediate C-7-1: 2-(Cyclopropanamide)-6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-7-yl trifluoromethanesulfonate

[1026] [Chemistry 137]

[1027]

[1028] THF (6 mL) and DMF (6 mL) were added to N-(7-hydroxy-6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanamide (Intermediate C-6-3; 500 mg, 1.17 mmol) to dissolve it, and N-ethyldiisopropylamine (613 μL, 3.52 mmol) and 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methylsulfonamide (629 mg, 1.76 mmol) were added, and stirred at room temperature for 5.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate, and the organic layers were combined, washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; chloroform:methanol=98:2) to obtain 2-(cyclopropanamide)-6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-7-yl trifluoromethanesulfonate (531.2 mg, yield 81%).

[1029] LCMS(LC-1);RT=1.46,m / z559[M+H] +

[1030] Example c-07-01: N-[6-[2-[[(1S,2S)-2-hydroxycyclopentyloxy]pyrimidin-5-yl]-7-methyl-1,3-benzothiazol-2-yl]cyclopropanamide

[1031] [Chemistry 138]

[1032]

[1033] [2-(Cyclopropanecarbonylamino)-6-[2-[[(1S, 2S)-2-hydroxycyclopentyloxy]methyl]pyrimidin-5-yl]-1,3-benzothiazol-7-yl]trifluoromethanesulfonate (Intermediate C-7-1; 30 mg, 50 μmol) was dissolved in dimethylacetamide (0.5 mL), tetramethyltin (48 mg, 270 μmol) and tetrakis(triphenylphosphine)palladium(0) (12 mg, 10 μmol) were added, and microwave irradiation was performed at 120°C for 1 hour. The obtained reaction mixture was diluted with saturated saline, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by HPLC to obtain N-[6-[2-[[(1S, 2S)-2-hydroxycyclopentyloxy]pyrimidin-5-yl]-7-methyl-1,3-benzothiazol-2-yl]cyclopropanamide (14.8 mg, yield 65%).

[1034] LCMS(LC-1);RT=1.20,m / z425[M+H] +

[1035] 1H-NMR (CDCl3): δ (ppm) 8.78 (2H, s), 7.72 (1H, d, J = 8.3Hz), 7.31 (1H, d, J = 8.3Hz), 5.02 (1H, d, J = 15.0Hz), 4.85 (1H, d, J = 15.0Hz) ,4.29-4.23(1H,m),3.93-3.88(1H,m),2.53(3H,s),2.13-2.03(1H,m),1.64-1.53(1H,m),1.30-1.26(2H,m),1.09-1.05(2H,m).

[1036] Example d-01-01: (1R, 2R)-N-(6-(2-((((1S, 2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-2-methylcyclopropane-1-carboxamide

[1037] [Chemistry 139]

[1038]

[1039] (1S,2S)-2-((5-(2-aminobenzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentane-1-ol (Intermediate B-2-1; 40 mg, 120 μmol) and (1R,2R)-2-methylcyclopropane-1-carboxylic acid (18 mg, 180 μmol) were dissolved in N,N-dimethylformamide (0.58 mL), 1-hydroxybenzotriazole monohydrate (36 mg, 0.23 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (45 mg, 0.23 mmol) were added, and the mixture was stirred at 70 °C for 5 hours. The obtained crude reaction mixture was purified by HPLC to obtain (1R,2R)-N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-2-methylcyclopropane-1-carboxamide (24 mg, yield 48%).

[1040] LCMS(LC-1);RT=1.24,m / z425[M+H] +

[1041] 1H-NMR(DMSOd6): δ(ppm)12.68(1H,s),9.17(2H,s),8.45(1H,s),7.86(2H,s),4.71-4.70(1H,m),4.69(2H,s),4.04-4.00(1 H,m),3.83-3.81(1H,m),1.91-1.75(3H,m),1.65-1.56(3H,m),1.47-1.37(2H,m),1.22-1.16(1H,m),1.13(3H,d,J=6.0Hz).

[1042] The following compounds in the following table were synthesized by the same method. In the following table, "Reference Methods" indicates that the examples of the production method should be referred to.

[1043] [Table 16]

[1044]

[1045] Intermediate D-2-1: (1S,2S)-2-((5-(2-((1s,3s)-3-hydroxycyclobutane-1-carboxamide)benzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate

[1046] [Chemistry 140]

[1047]

[1048] (1S,2S)-2-((5-(2-aminobenzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate (Intermediate B-4-3; 0.24 g, 0.61 mmol) and cis-3-hydroxycyclobutanecarboxylic acid (72 mg, 0.62 mmol) were dissolved in N,N-dimethylformamide (3.1 mL), 1-hydroxybenzotriazole monohydrate (0.15 g, 0.99 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.18 g, 0.95 mmol) were added, and stirred at 60°C for 15 minutes. The obtained crude reaction mixture was purified by HPLC. Ethyl acetate and saturated aqueous sodium bicarbonate solution were added to the obtained crude product, the organic layer was concentrated under reduced pressure, and purified by automatic oxidation silica gel column chromatography (eluent; chloroform:methanol) to obtain (1S,2S)-2-((5-(2-((1s,3s)-3-hydroxycyclobutane-1-carboxamide)benzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate (124 mg) as a crude product.

[1049] LCMS(LC-1);RT=1.19,m / z483[M+H] +

[1050] Intermediate D-2-2: (1S,2S)-2-((5-(2-((1s,3s)-3-(tert-butyloxy)cyclobutane-1-carboxamide)benzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate

[1051] [Chemistry 141]

[1052]

[1053] (1S,2S)-2-((5-(2-((1s,3s)-3-hydroxycyclobutane-1-carboxamide)benzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate (Intermediate D-2-1; 78 mg, 0.16 mmol) was dissolved in dichloromethane (1.6 mL), tert-butyl acetate (1.5 mL, 11 mmol) and 70% perchloric acid (42 μL, 0.49 mmol) were added, and stirred at room temperature for 30 minutes. Saturated sodium bicarbonate aqueous solution was added under ice cooling until the reaction solution became alkaline, thereby stopping the reaction. Another batch of the same operation was carried out using (1S,2S)-2-((5-(2-((1s,3s)-3-hydroxycyclobutane-1-carboxamide)benzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate (Intermediate D-2-1; 19 mg, 39 μmol). The combined crude reaction mixture was washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by autoclaved silica gel column chromatography (eluent; chloroform:methanol) to obtain (1S,2S)-2-((5-(2-((1s,3s)-3-hydroxycyclobutane-1-carboxamide)benzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate (152 mg) as a crude product.

[1054] LCMS(LC-1);RT=1.64,m / z539[M+H] +

[1055] Example d-02-01: (1s, 3s)-3-(tert-butoxy)-N-(6-(2-((((1S, 2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide

[1056] [Chemistry 142]

[1057]

[1058] The crude product (1S,2S)-2-((5-(2-((1s,3s)-3-(tert-butyloxy)cyclobutane-1-carboxamide)benzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate (Intermediate D-2-2; 152 mg) was dissolved in methanol (1.6 mL) and tetrahydrofuran (0.8 mL), potassium carbonate (22 mg, 0.16 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate and water were added to the obtained crude reaction mixture, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by HPLC to obtain (1s,3s)-3-(tert-butoxy)-N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide (31.5 mg).

[1059] LCMS(LC-1);RT=1.36,m / z497[M+H] +

[1060] 1H-NMR(DMSOd6): δ(ppm)12.42(1H,m),9.17(2H,s),8.45(1H,s),7.87-7.8 1(2H,m),4.72-4.70(1H,m),4.69(2H,s),4.14-4.07(1H,m),4.04-4.00(1H ,m),3.83-3.81(1H,m),2.94-2.84(1H,m),2.46-2.40(2H,m),2.13-2.06(2 H,m),1.91-1.77(2H,m),1.66-1.56(3H,m),1.48-1.40(1H,m),1.13(9H,s).

[1061] Intermediate D-3-1: tert-butyl 2-((6-2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)carbamoyl)7-azaspiro[3,5]nonane-7-carboxylate

[1062] [Chemistry 143]

[1063]

[1064] To (1S,2S)-2-((5-(2-aminobenzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentane-1-ol (Intermediate B-2-1; 604 mg, 1.76 mmol) was added dichloromethane (35 mL) and THF (25 mL) to dissolve it, and 7-[(tert-butoxy)carbonyl]7-azaspiro[3,5]nonane-2-carboxylic acid (950 mg, 3.53 mmol), N-ethyldiisopropylamine (921.1 μL, 5.29 mmol) and 1-propanephosphonic anhydride (1.24 mL, 4.17 mmol) were added, and the mixture was stirred at room temperature for 14 hours. 7-[(tert-Butoxy)carbonyl]7-azaspiro[3,5]nonane-2-carboxylic acid (950 mg, 3.53 mmol), N-ethyldiisopropylamine (921.1 μL, 5.29 mmol), and 1-propanephosphonic anhydride (1.24 mL, 4.17 mmol) were added, and the mixture was stirred for 2 hours. Aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The aqueous layer was further extracted with chloroform twice, and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent; chloroform:methanol=98:2) to obtain tert-butyl 2-((6-2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)carbamoyl)7-azaspiro[3,5]nonane-7-carboxylate (712 mg, yield 68%).

[1065] LCMS(LC-1);RT=1.58,m / z594[M+H] +

[1066] Intermediate D-3-2: N-(6-2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)carbamoyl)7-azaspiro[3,5]nonane-2-carboxylate

[1067] [Chemistry 144]

[1068]

[1069] Dichloromethane (27 mL) and THF (10 mL) were added to tert-butyl 2-((6-2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)carbamoyl)7-azaspiro[3,5]nonane-7-carboxylate (Intermediate D-3-1; 709.1 mg, 1.19 mmol) to dissolve the mixture, and trifluoroacetic acid (500 μL) was added, followed by stirring at room temperature. Trifluoroacetic acid (12.5 ml) was further added in 5 portions, followed by stirring at room temperature for 13 hours. The mixture was made alkaline using a 2N sodium hydroxide aqueous solution and extracted with chloroform. The aqueous layer was further extracted twice with chloroform, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain N-(6-2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)carbamoyl)7-azaspiro[3,5]nonane-2-carboxylate (142.2 mg, yield 24%).

[1070] LCMS(LC-1);RT=0.89,m / z494[M+H] +

[1071] 1H-NMR(CDCl3): δ(ppm)8.93(2H,s),8.00-7.95(1H,m),7.81-7.74(1H,m),7.59-7.52(1H,m),4.87-4.66(2H,m),4.16-4.04(1H,m),3.80-3.7 4(1H,m),3.25-3.16(1H,m),3.25-3.16(1H,m),2.76-2.66(2H,m),2.16 -2.06(4H,m),2.06-1.94(4H,m),1.72-1.52(4H,m),1.52-1.43(2H,m).

[1072] Example d-03-01: 7-acetyl-N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-7-azaspiro[3,5]nonane-2-carboxamide

[1073] [Chemistry 145]

[1074]

[1075] Dichloromethane (1.8 mL) and THF (0.8 mL) were added to N-(6-2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)carbamoyl)7-azaspiro[3,5]nonane-2-carboxylate (Intermediate D-3-2; 30 mg, 0.06 mmol) to dissolve it, and acetyl chloride (5.19 μL, 0.07 mmol) and triethylamine (16.9 μL, 0.12 mmol) were added, and stirred at room temperature for 20 minutes. Sodium bicarbonate aqueous solution was added to the reaction mixture, and extracted with chloroform. The organic layer was concentrated with a nitrogen stream and purified by HPLC to give 7-acetyl-N-(6-2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)carbamoyl)7-azaspiro[3,5]nonane-2-carboxamide (8.5 mg, yield 26%).

[1076] LCMS(LC-1);RT=1.08,m / z536[M+H] +

[1077] 1H-NMR(CDCl3): δ(ppm)8.98(2H,s),8.01(1H,s),7.90-7.73(1H,m),7.65-7.58(1H,m),4.97-4.87(1H,m),4.80-4.72(1H,m), 4.21-4.13(1H,m),3.86-3.78(1H,m),3.58-3.43(2H,m),3.43-3.26(3H,m),2.27-1.96(7H,m),2.06(3H,s),1.77-1.51(7H,m).

[1078] The following compounds in the following table were synthesized by the same method. In the following table, "Reference Methods" indicates that the examples of the production method should be referred to.

[1079] [Table 17]

[1080]

[1081] Intermediate D-4-1: tert-Butyl (1s, 3s)-3-ethoxycyclobutane-1-carboxylate

[1082] [Chemistry 146]

[1083]

[1084] Tert-butyl 3-hydroxycyclobutanecarboxylate (0.30 g, 1.7 mmol) was dissolved in N,N-dimethylformamide (3.5 mL), sodium hydride (55% oily, 5 mg, 2.1 mmol) was added under ice cooling, and stirred for 10 minutes. Ethyl iodide (0.28 mL, 3.5 mmol) was added to the reaction solution, and stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added to the reaction solution to stop the reaction, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the obtained crude product was purified by automatic oxidation silica gel column chromatography (eluent; hexane: ethyl acetate = 98:2-50:50), thereby obtaining tert-butyl (1s, 3s)-3-ethoxycyclobutane-1-carboxylate (203 mg, yield 58%).

[1085] 1H-NMR (CDCl3): δ (ppm) 3.87-3.80 (1H, m), 3.40 (2H, q, J = 7.0Hz), 2.57-2.42 (3H, m), 2.22-2.10 (2H, m), 1.44 (9H, s), 1.19 (3H, t, J = 7.0Hz).

[1086] Intermediate D-4-2: (1s,3s)-3-ethoxycyclobutane-1-carboxylic acid

[1087] [Chemistry 147]

[1088]

[1089] Tert-butyl (1s, 3s)-3-ethoxycyclobutane-1-carboxylate (Intermediate D-4-1; 40 mg, 0.20 mmol) was dissolved in formic acid (0.40 mL) and stirred at room temperature for 2 hours. The resulting crude reaction mixture was concentrated under reduced pressure and azeotroped with toluene three times to obtain (1s, 3s)-3-ethoxycyclobutane-1-carboxylic acid as a crude product.

[1090] 1H-NMR (CDCl3): δ (ppm) 3.93-3.86 (1H, m), 3.41 (2H, q, J = 7.0Hz), 2.73-2.74 (1H, m), 2.58-2.50 (2H, m), 2.28-2.20 (2H, m), 1.19 (3H, t, J = 7.0Hz).

[1091] Example d-04-01: (1s, 3s)-3-ethoxy-N-(6-(2-((((1S, 2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide

[1092] [Chemistry 148]

[1093]

[1094] The above-mentioned crude products (1s,3s)-3-ethoxycyclobutane-1-carboxylic acid (intermediate D-4-2) and (1S,2S)-2-((5-(2-aminobenzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentane-1-ol (intermediate B-2-1; 30 mg, 90 μmol) were dissolved in N,N-dimethylformamide (0.44 mL), and 1-hydroxybenzotriazole monohydrate (27 mg, 0.18 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (34 mg, 0.18 mmol) were added, and stirred at 60°C for 15 minutes. The obtained crude reaction mixture was purified by HPLC to obtain (1s,3s)-3-ethoxy-N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide (21 mg, yield 51%).

[1095] LCMS(LC-1);RT=1.19,m / z469[M+H] +

[1096] 1H-NMR(DMSOd6): δ(ppm)12.45(1H,s),9.18(2H,s),8.48(1H,m),7.89-7.84(2H,m) ,4.72-4.71(1H,m),4.69(2H,s),4.04-4.00(1H,m),3.95-3.88(1H,m),3.84-3.81( 1H,m),3.36(2H,q,J=7.0Hz),2.99-2.90(1H,m),2.48-2.44(2H,m),2.13-2.05(2H, m),1.91-1.77(2H,m),1.67-1.54(3H,m),1.48-1.40(1H,m),1.10(3H,t,J=7.0Hz).

[1097] The following compounds in the following table were synthesized by the same method. In the following table, "Reference Methods" indicates that the examples of the production method should be referred to.

[1098] [Table 18]

[1099]

[1100] Intermediate D-5-1: N-(6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-(methoxymethylene)cyclobutane-1-carboxamide

[1101] [Chemistry 149]

[1102]

[1103] THF (1.5 mL) was added to methoxymethyl (triphenyl) phosphonium chloride (254.2 mg, 0.74 mmol), and the mixture was cooled to 0°C. Potassium tert-butoxide (83.2 mg, 0.74 mmol) was added, and the mixture was stirred for 30 minutes. N-(6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-oxocyclobutane-1-carboxamide (Intermediate B-1-1; 292.8 mg, 0.53 mmol) was dissolved in THF (1.5 mL), and the mixture was added dropwise using a syringe. After stirring at 0°C for 10 minutes, the mixture was stirred at room temperature for 3.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; chloroform:methanol = 98:2) to obtain N-(6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-(methoxymethylene)cyclobutane-1-carboxamide (130.7 mg, yield 43%).

[1104] LCMS(LC-1);RT=2.31,m / z581[M+H] +

[1105] Intermediate D-5-2: 3-Formyl-N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide

[1106] [Chemistry 150]

[1107]

[1108] To N-(6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-(methoxymethylene)cyclobutane-1-carboxamide (Intermediate D-5-1; 111.3 mg, 0.19 mmol) was added THF (1 mL) to dissolve it, and 2N-hydrochloric acid aqueous solution (2 mL) was added and stirred for 40 minutes. To the reaction mixture was added sodium bicarbonate aqueous solution and extracted with chloroform. The aqueous layer was extracted with chloroform again, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 3-formyl-N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide (95 mg) as a crude product.

[1109] LCMS(LC-1);RT=1.09,m / z453[M+H] +

[1110] Example d-05-01: 3-((dimethylamino)methyl)-N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide

[1111] [Chemistry 151]

[1112]

[1113] 3-Formyl-N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide (Intermediate D-5-2; 32 mg, 0.07 mmol) was dissolved in dichloromethane (1 mL), and dimethylamine (71 μL, 1.4 mmol) and sodium triacetoxyborohydride (22.5 mg, 0.11 mmol) were added, and stirred at room temperature for 5 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, extracted with chloroform, and the organic layer was concentrated with a nitrogen stream and purified by HPLC to give 3-((dimethylamino)methyl)-N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide (4.8 mg, 14%).

[1114] LCMS(LC-1);RT=0.88,m / z482[M+H] +

[1115] 1H-NMR (CDCl3): δ (ppm) 8.98 (2H, d, J = 1.2Hz), 8.00 (1H, t, J = 1.8Hz), 7.86-7.78 (1H ,m),7.62-7.53(1H,m),4.96-4.88(1H,m),4.79-4.71(1H,m),4.21-4.12(1H,m),3.8 6-3.77(1H,m),3.40-3.35(1H,m),3.33-3.24(1H,m),3.25-3.14(1H,m),2.23-2.21 (3H,s),2.21-2.20(3H,s),2.13-1.97(4H,m),1.77-1.62(3H,m),1.60-1.50(1H,m).

[1116] The following compounds in the following table were synthesized by the same method. In the following table, "Reference Methods" indicates that the examples of the production method should be referred to.

[1117] [Table 19]

[1118]

[1119] Intermediate E-1-1: 5-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)pyrazolo[1,5-a]pyridin-2-amine

[1120] [Chemistry 152]

[1121]

[1122] 5-Chloropyrazolo[1,5-a]pyridin-2-amine (1.0 g, 5.97 mmol) was dissolved in 1,4-dioxane (12 mL), and the crude product 2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrimidine (Intermediate A-1-3; 8.96 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.44 g, 0.60 mmol), cesium carbonate (5.8 g, 27.9 mmol), and water (1.2 mL) were added, and the mixture was irradiated with microwaves at 100° C. for 5 hours. The crude reaction mixture was filtered through celite and concentrated under reduced pressure. The crude product was purified by automated silica gel column chromatography (eluent; ethyl acetate:methanol) to give 5-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)pyrazolo[1,5-a]pyridine-2-amine (1.3 g, yield 50%).

[1123] LCMS(LC-1);RT=2.00,m / z439[M+H] +

[1124] Example e-01-01: N-(5-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropanamide

[1125] [Chemistry 153]

[1126]

[1127] 5-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)pyrazolo[1,5-a]pyridin-2-amine (Intermediate E-1-1; 20 mg, 46 μmol) was dissolved in dichloromethane (455 μL), cyclopropanecarboxylic acid (12 μL, 0.15 mmol), N,N-diisopropylethylamine (70 μL, 0.41 mmol), 1-propanephosphonic anhydride (50 wt% ethyl acetate solution, 88 μL, 0.15 mmol) were added, and stirred at room temperature for 4 hours. Water was added to the obtained crude reaction mixture, and extracted with dichloromethane. Hydrochloric acid-methanol solution (2 mol / L) was added to the obtained crude reaction intermediate, and stirred at room temperature for 5 minutes. The obtained crude reaction mixture was purified by SCX and HPLC to obtain N-(5-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropanamide (4.2 mg, yield 24%).

[1128] LCMS(LC-1);RT=0.99,m / z394[M+H] +

[1129] 1H-NMR(CD3OD): δ(ppm)9.15(2H,s),8.51(1H,d,J=7.3Hz),7.95(1H,d,J=1.2Hz),7.18(1H,dd,J=7.2Hz,2.1Hz),6.96(1H,s),4.81(2H,s),4.19- 4.15(1H,m),3.90-3.86(1H,m),2.05-1.94(2H,m),1.90-1.84(1H,m),1. 77-1.66(3H,m),1.59-1.51(1H,m),1.02-0.98(2H,m),0.93-0.88(2H,m).

[1130] The following compounds in the following table were synthesized by the same method. In the following table, "Reference Methods" indicates that the examples of the production method should be referred to.

[1131] [Table 20]

[1132]

[1133] Intermediate E-2-1: (1S,2S)-2-((5-(2-aminopyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate

[1134] [Chemistry 154]

[1135]

[1136] 5-Chloropyrazolo[1,5-a]pyridin-2-amine (6.00 g, 35.8 mmol) was dissolved in 1,4-dioxane (358 mL), and [(1S,2S)-2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]methoxy]cyclopentyl]acetate (43.2 g, 71.6 mmol), cesium carbonate (34.9 g, 107 mmol), dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium (2.62 g, 3.58 mmol) and water (36 mL) were added, and the mixture was stirred at 100°C for 15 hours. After the reaction, methanol (30 mL) was added and the product was purified by silica gel column chromatography (eluent; chloroform:methanol=90:10) to obtain (1S,2S)-2-((5-(2-aminopyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate (9.82 g, 74%).

[1137] LCMS(LC-1);RT=1.09,m / z368[M+H] +

[1138] 1H-NMR(CDCl3): δ(ppm)9.03-8.91(2H,m),8.48-8.09(1H,m),7.52-7.28(2H,m ),6.97-6.47(1H,m),5.05-4.78(3H,m),4.21-4.01(3H,m),2.19-1.95(9H,m).

[1139] Intermediate E-2-2: (1S,2S)-2-((5-(2-aminopyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl)methoxy)cyclopentane-1-ol

[1140] [Chemistry 155]

[1141]

[1142] (1S,2S)-2-((5-(2-aminopyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate (17.9 g, 48.7 mmol) was dissolved in methanol (487 mL), potassium carbonate (33.7 g, 243 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, water was added, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent; chloroform:methanol=90:10-80:20) to obtain (1S,2S)-2-((5-(2-aminopyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl)methoxy)cyclopentane-1-ol (12.2 g, 77%).

[1143] LCMS(LC-1);RT=0.81,m / z326[M+H] +

[1144] 1H-NMR(CD3OD): δ(ppm)9.23-9.05(3H,m),8.27(1H,d,J=7.1Hz),7.67-7.63(1H,m),6.91(1H,dd,J=7.2,2.0Hz ),5.88(1H,s),4.83-4.66(2H,m),4.22-4.12(2H,m),4.11-3.83(2H,m),2.10-1.82(2H,m),1.77-1.48(4H,m).

[1145] Intermediate E-2-3: N-(5-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)pyrazolo[1,5-a]pyridin-2-yl)-3-oxocyclobutane-1-carboxamide

[1146] [Chemistry 156]

[1147]

[1148] (1S,2S)-2-((5-(2-aminopyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl)methoxy)cyclopentane-1-ol (Intermediate E-2-2; 3.22 g, 9.9 mmol) was dissolved in dichloromethane (50 mL) and stirred at 0°C with cooling. After adding N-ethyldiisopropylamine (5.17 mL, 29.7 mmol), 3-oxocyclobutane-1-carboxylic acid (1.36 g, 11.88 mmol), and 1-propanephosphonic anhydride (8.74 mL, 14.85 mmol), the mixture was stirred at room temperature for 5 hours. Saturated aqueous sodium bicarbonate solution and chloroform were added to the reaction mixture for extraction. The aqueous layer was extracted again with chloroform, and the organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol = 98:2-95:5) to obtain N-(5-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)pyrazolo[1,5-a]pyridin-2-yl)-3-oxocyclobutane-1-carboxamide (2.26 g, yield: 54.3%).

[1149] LCMS(LC-1);RT=0.92,m / z422[M+H] +

[1150] 1H-NMR (CDCl3): δ (ppm) 9.00 (2H, s), 8.36 (1H, d, J = 7Hz), 8.30 (1H, s), 7.66 (1H, d, J = 1.3Hz), 7.13 (1H, s), 6.91 (1H, dd, J = 7, 1.8Hz), 5.02-4.82(2H,m),4.27-4.22(1H,m),3.90-3.85(2H,m),3.66-3.60(2H,m),3.37-3.25(3H,m),2.13-2.02(2H,m),1.79-1.53(4H,m).

[1151] Intermediate E-2-4: tert-Butyl (S)-2-methyl-4-(2-methylisonicotinyl)piperazine-1-carboxylate

[1152] [Chemistry 157]

[1153]

[1154] Tert-butyl (S)-2-methylpiperazine-1-carboxylate (600 mg, 3.00 mmol) was dissolved in dichloromethane (30.0 mL), and 2-methylisonicotinic acid (821 mg, 6.00 mmol), N-ethyldiisopropylamine (3.2 mL, 18.0 mmol), and propanephosphonic anhydride (6.0 mL, 1.7 M ethyl acetate solution) were added, and stirred at room temperature for 1 hour. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, extracted with chloroform, and the organic layer was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 100:0 to 0:100) to obtain tert-butyl (S)-2-methyl-4-(2-methylisonicotinoyl)piperazine-1-carboxylate (1.025 g, quant.).

[1155] LCMS(LC-1);RT=1.21,m / z320[M+H] +

[1156] 1H-NMR (CDCl3): δ (ppm) 8.58 (1H, d, J = 4.9Hz), 7.14 (1H, brs), 7.07 (1H, brd, J=4.2Hz),4.58(0.5H,brd,J=13.1Hz),4.46(1H,brd,J=13.1Hz),4.22(0.5H, brs),3.96(0.5H,brd,J=13.7Hz),3.62-3.41(0.5H,m),3.34(1H,brs),3.21- 2.96(2H,m),2.96-2.83(1H,m),2.60(3H,s),1.47(9H,s),1.33-1.03(3H,m).

[1157] Intermediate E-2-5: (S)-(3-methylpiperazin-1-yl)(2-methylpyridin-4-yl)methanone

[1158] [Chemistry 158]

[1159]

[1160] Tert-butyl (S)-2-methyl-4-(2-methylisonicotinoyl)piperazine-1-carboxylate (1.56 g, 4.88 mmol) was dissolved in dichloromethane (25 mL), trifluoroacetic acid (7.5 mL, 97.6 mmol) was added, and stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was purified by SCX to obtain (S)-(3-methylpiperazin-1-yl)(2-methylpyridin-4-yl)methanone (896 mg, 83%).

[1161] LCMS(LC-1);RT=0.29,m / z220[M+H] +

[1162] 1H-NMR (CD3OD): δ (ppm) 8.51 (1H, d, J = 5.1Hz), 7.31 (1H, s), 7.23 (1H, d, J = 5.1Hz), 4.49 (1H, brd, J = 12.8Hz), 3.56- 3.39(1H,m),3.28-3.05(1H,m),2.95(1H,brd,J=12.8Hz),2.90-2.73(3H,m),2.65-2.56(4H,m),1.22-0.95(3H,m).

[1163] Example e-02-01: (1R, 3s)-N-(5-(2-((((1S, 2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)pyrazolo[1,5-a]pyridin-2-yl)-3-((S)-2-methyl-4-(2-methylisonicotinyl)piperazin-1-yl)cyclobutane-1-carboxamide

[1164] [Chemistry 159]

[1165]

[1166] N-(5-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)pyrazolo[1,5-a]pyridin-2-yl)-3-oxocyclobutane-1-carboxamide (Intermediate E-2-3; 60 mg, 0.14 mmol) was dissolved in dichloromethane (2.8 mL), and [(3S)-3-methylpiperazin-1-yl]-(2-methyl-4-pyridyl)methanone (62 mg, 0.28 mmol) and sodium triacetoxyborohydride (90 mg, 0.43 mmol) were added, and stirred at room temperature for 1 hour. Saturated sodium bicarbonate aqueous solution was then added to the reaction mixture, extracted with chloroform, and the organic layer was concentrated under reduced pressure. The crude product was purified by HPLC to give (1R,3s)-N-(5-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)pyrazolo[1,5-a]pyridin-2-yl)-3-((S)-2-methyl-4-(2-methylisonicotinyl)piperazin-1-yl)cyclobutane-1-carboxamide (13.7 mg, 15%).

[1167] LCMS(LC-1);RT=0.96,m / z625[M+H] +

[1168] 1H-NMR (DMSO-d6): δ (ppm) 10.78 (1H, s), 9.23 (2H, s), 8.66 (1H, d, J = 7.2Hz), 8.52 (1H, d, J = 5.0Hz), 8.12 (1H, s),7.30-7.12(3H,m),6.97(1H,s),5.76(1H,s),4.74-4.67(3H,m),4.02(1H,brd,J=3.1Hz),3.84-3.79(1H,m ),3.62(1H,m),3.28-3.21(1H,m),3.10-2.89(3H,m),2.77-2.59(2H,m),2.27(1H,brs),2.24-2.00(5H,m),1. 96-1.73(3H,m),1.68-1.51(4H,m),1.49-1.35(1H,m),0.99(1.5H,brd,J=6.2Hz),0.82(1.5H,brd,J=6.2Hz).

[1169] The following compounds in the following table were synthesized by the same method. In the following table, "Reference Methods" indicates that the examples of the production method should be referred to.

[1170] [Table 21-1]

[1171]

[1172] [Table 21-2]

[1173]

[1174] [Table 21-3]

[1175]

[1176] Intermediate E-3-1: 3-(tert-Butoxy)cyclobutane-1-carboxylic anhydride

[1177] [Chemistry 160]

[1178]

[1179] 3-tert-Butoxycyclobutanecarboxylic acid (60 mg, 0.35 mmol) was dissolved in dichloromethane (3.5 mL), trimethylamine (145 μL, 1.0 mmol) and 2-chloro-1-methylpyridinium iodide (134 mg, 0.52 mmol) were added, and the mixture was heated under reflux and stirred for 3 hours. The solvent of the reaction mixture was distilled off to obtain 3-(tert-butoxy)cyclobutane-1-carboxylic anhydride (55 mg, 96%).

[1180] LCMS(LC-1);RT=2.09,m / z327[M+H] +

[1181] 1H-NMR (CDCl3): δ (ppm) 4.09-3.94 (m, 2H), 2.70-2.61 (m, 2H), 2.55-2.46 (m, 4H), 2.30-2.21 (m, 4H), 2.05 (s, 2H), 1.19 (s, 18H).

[1182] Example e-03-01: 3-(tert-Butyloxy)-N-(5-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)pyrazolo[1,5-a]pyridin-2-yl)cyclobutane-1-carboxamide

[1183] [Chemistry 161]

[1184]

[1185] [(1S,2S)-2-[[5-(2-aminopyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl]methoxy]cyclopentyl]acetate (Intermediate E-2-2; 60 mg, 0.16 mmol) was dissolved in pyridine (0.8 mL), 3-(tert-butyloxy)cyclobutane-1-carboxylic anhydride (53 mg, 0.16 mmol) and dimethylaminopyridine (10 mg, 82 μmol) were added, and stirred at 120 degrees for 14 hours. After the reaction mixture was cooled to room temperature, methanol (0.8 mL) and 2M sodium hydroxide aqueous solution (400 μL, 0.82 mmol) were added, and stirred at room temperature for 1 hour. The reaction mixture was diluted with water, extracted with chloroform, the solvent was distilled off, and purification by HPLC was performed to obtain 3-(tert-butoxy)-N-(5-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)pyrazolo[1,5-a]pyridin-2-yl)cyclobutane-1-carboxamide (5.1 mg, 78%).

[1186] LCMS(LC-1);RT=1.51,m / z522[M+H] +

[1187] 1H-NMR (CD3OD): δ (ppm) 9.15 (s, 2H), 8.49 (d, J = 7.5Hz, 1H), 7.99-7.93 (m, 1H ),7.17(dd,J=7.5,2.0Hz,1H),7.01(s,1H),4.83-4.76(m,2H),4.28-4.01(m ,2H),3.90-3.87(m,1H),2.94-2.72(m,1H),2.57-2.38(m,2H),2.35-2.13(m ,2H),2.07-1.91(m,3H),1.81-1.63(m,4H),1.60-1.51(m,2H),1.20(s,9H).

[1188] Intermediate E-4-1: 2-(Bromomethyl)-4-chloro-3-methoxypyridine

[1189] [Chemistry 162]

[1190]

[1191] 4-Chloro-3-methoxy-2-methyl-pyridine (3.15 g, 20 mmol) was dissolved in carbon tetrachloride (40 mL), and N-bromosuccinimide (3.56 g, 20 mmol) and benzoyl peroxide (0.42 mL, 2 mmol) were added, and the mixture was stirred under heating reflux for 7 hours. The obtained reaction mixture was cooled to room temperature, the solid was filtered out, and the obtained filtrate was concentrated under reduced pressure. The obtained crude product was purified by autoclaved silica gel column chromatography (eluent; hexane: ethyl acetate = 96:4-66:34), thereby obtaining 2-(bromomethyl)-4-chloro-3-methoxypyridine (1.5 g, yield 32%).

[1192] LCMS(LC-1);RT=1.35,m / z235[M+H] +

[1193] 1H-NMR (CDCl3): δ (ppm) 8.25 (1H, d, J = 5.1Hz), 7.30 (1H, d, J = 5.1Hz), 4.63 (2H, s), 4.04 (3H, s).

[1194] Intermediate E-4-2: 2-(4-chloro-3-methoxypyridin-2-yl)acetonitrile

[1195] [Chemistry 163]

[1196]

[1197] 2-(Bromomethyl)-4-chloro-3-methoxy-pyridine (1.5 g, 6.34 mmol) and sodium cyanide (1.55 g, 32 mmol) were added to a mixed solvent of water (3.2 mL) and ethanol (3.1714 mL) and stirred at 60°C for 1 hour. Saturated sodium bicarbonate aqueous solution and chloroform were added to the obtained reaction crude mixture for extraction. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by automatic oxidation silica gel column chromatography (eluent; hexane: ethyl acetate = 94:6-50:50) to obtain 2-(4-chloro-3-methoxypyridin-2-yl)acetonitrile (691 mg, yield 60%).

[1198] LCMS(LC-1);RT=1.05,m / z183[M+H] +

[1199] 1H-NMR (CDCl3): δ (ppm) 8.25 (1H, d, J = 5.2Hz), 7.35 (1H, d, J = 5.2Hz), 4.01 (3H, s), 3.96 (2H, s).

[1200] Intermediate E-4-3: 5-chloro-4-methoxypyrazolo[1,5-a]pyridin-2-amine

[1201] [Chemistry 164]

[1202]

[1203] To a solution of ethyl O-mesitylenesulfonylacetyl hydroxamic acid (467 mg, 1.64 mmol, 1.1 eq.) in 1,4-dioxane (1 mL), add 70% aqueous perchloric acid (140 μL, 1.64 mmol, 1.1 eq.) and stir at 0 degrees for 30 minutes. The reaction mixture was diluted with cold water and hexane, and the precipitate was filtered to obtain a solid. The solid was added to a solution of 2-(4-chloro-3-methoxy-2-pyridyl)acetonitrile (intermediate E-4-2; 272 mg, 1.49 mmol) in dichloromethane (1 mL) and stirred at 0°C for 1 hour. The reaction mixture was concentrated, and a solution of potassium carbonate (103 mg, 74 mmol) in dimethylformamide (1 mL) was added, and heated and stirred at 120 degrees. After the reaction mixture was cooled to room temperature, saturated brine was added, extracted with ethyl acetate, dried over magnesium sulfate, and the solvent was distilled off. The crude product was purified by automatic oxidation silica gel column chromatography (eluent; hexane:ethyl acetate = 1:1) to obtain 5-chloro-4-methoxypyrazolo[1,5-a]pyridine-2-amine (112 mg, 38%).

[1204] LCMS(LC-1);RT=1.03,m / z198[M+H] +

[1205] 1H-NMR (CDCl3): δ (ppm) 8.02 (s, 2H), 7.91 (d, J = 7.3Hz, 2H), 6.50 (d, J = 7.3Hz, 2H), 5.86 (s, 2H), 3.98 (s, 3H).

[1206] Intermediate E-4-4: (1S,2S)-2-((5-(2-amino-4-methoxypyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate

[1207] [Chemistry 165]

[1208]

[1209] 5-Chloro-4-methoxypyrazolo[1,5-a]pyridin-2-amine (Intermediate E-4-3; 40 mg, 0.2 mmol) was dissolved in dimethylacetamide (1 mL), and the above crude product (1S,2S)-2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate (Intermediate B-4-2; 4.4 mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), sodium carbonate (42 mg, 0.4 mmol), and water (0.1 mL) were added, and the mixture was irradiated with microwaves at 185°C for 1 hour. The crude reaction mixture was concentrated under reduced pressure, and the crude product was purified by automated silica gel column chromatography (eluent; chloroform:methanol=95:5) to obtain (1S,2S)-2-((5-(2-amino-4-methoxypyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate (46.9 g, yield 58%).

[1210] LCMS(LC-1);RT=1.11,m / z398[M+H] +

[1211] 1H-NMR (CDCl3): δ (ppm) 9.01-8.96 (m, 2H), 8.12-8.05 (m, 1H), 6.56-6.48 (m, 1H), 6.01-5.93 (m, 1H), 5.21-5.19 (m, 2H), 4. 95-4.82(m,4H),4.12-4.09(m,3H),3.86-3.77(m,3H)2.28-2.14(m,2H),2.04(s,3H),1.89-1.79(m,4H)1.32-1.22(m,2H).

[1212] Intermediate E-4-5: (1S,2S)-2-((5-(2-(cyclopropanamide)-4-methoxypyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate

[1213] [Chemistry 166]

[1214]

[1215] (1S,2S)-2-((5-(2-amino-4-methoxypyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate (Intermediate E-4-4; 32 mg, 0.07 mmol) was dissolved in dichloromethane (1 mL), and cyclopropanecarbonyl chloride (16 μL, 0.18 mmol) and N-ethylisopropylamine (41 μL, 0.24 mmol) were added to a solution of dimethylamine (71 μL, 1.4 mmol) in dichloromethane (1.2 mL), and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off from the reaction mixture to obtain (1S,2S)-2-((5-(2-(cyclopropaneamide)-4-methoxypyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate (54.9 mg, 99%) as a crude product.

[1216] LCMS(LC-1);RT=1.32,m / z466[M+H] +

[1217] Example e-04-01: N-(5-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)-4-methoxypyrazolo[1,5-a]pyridin-2-yl)cyclopropanamide

[1218] [Chemistry 167]

[1219]

[1220] (1S,2S)-2-((5-(2-(cyclopropanamide)-4-methoxypyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate (Intermediate E-4-5; 54.9 mg, 0.12 mmol) was dissolved in methanol (1.2 mL), and a 2M sodium hydroxide aqueous solution (500 μL) was added, followed by stirring at room temperature for 30 minutes. Saturated brine was added to the reaction mixture, extracted with chloroform, dried over magnesium sulfate, and the solvent was distilled off and purified by HPLC to give N-(5-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)-4-methoxypyrazolo[1,5-a]pyridin-2-yl)cyclopropanamide (5.6 mg, 11%).

[1221] LCMS(LC-1);RT=1.06,m / z424[M+H] +

[1222] 1H-NMR (CDCl3): δ (ppm) 8.99 (s 2H),8.19(brs,1H),8.18-8.13(m,1H),7.25-7.19(m,1H),6.69(d,J=7.1Hz,1H),5.00(d,J=15Hz,1H),4.83(d,J=15Hz,1H),4 .28-4.20(m,1H),3.93(s,3H),3.91-3.84(m,1H),2.17-2.00(m,3H),1.77-1.71(m,4H),1.19-1.12(m,2H),0.98-0.90(m,2H).

[1223] <Test Example 1: Measurement of human IRAK-4 inhibitory activity>

[1224] (1) Measurement method

[1225] The activity of human IRAK-4 (Invitrogen, Cat. PV3362) was determined by the TR-FRET method for phosphorylation of an IRAK-4 peptide substrate (biotin-KKKKRFSFKKSFKC) in the presence of 10 μM ATP (Sigma Aldrich, Cat. A7699). The enzyme reaction was carried out in a reaction buffer consisting of 50 mM HEPES (pH 7.2), 1 mM DTT, 0.1 mM Na3VO4, 5 mM MgCl2, 1 mM MnCl2, and 0.1% bovine serum albumin. In order to determine the IRAK-4 inhibitory activity, the compound to be tested was added to a reaction buffer containing 1 nM IRAK-4, 0.5 μM peptide substrate, and 10 μM ATP, and incubated at 23°C for 30 minutes. Then, a detection solution consisting of europium cryptate-labeled antibody (0.3 μg / mL, the antibody was prepared using IRAK-4 peptide substrate as antigen), streptavidin-XL665 (2 μg / mL, CisBio, Cat. 610SAXLB), 50 mM HEPES (pH 7.2), 0.1% BSA, 120 mM KF, and 66.7 mM EDTA was added (each reagent is at the final concentration), and after the reaction was stopped, it was further incubated at 23°C for 60 minutes. The fluorescence intensity at wavelengths of 665 nm and 620 nm was measured using an ELISA reader, and the enzyme activity was calculated as the ratio of the fluorescence intensity at 665 nm / 620 nm. The IRAK-4 inhibition rate when 12.5 μM staurosporine (LC Laboratories, Cat. S-9300) was added was set as 100%, and the IRAK-4 inhibition rate when no test compound was added was set as 0%. The IC of the test compound was calculated using the 4-parameter logistic model of the data analysis software XLfit (ID Business Solutions Ltd.). 50 .

[1226] It should be noted that each operation and condition in the measurement can be appropriately changed within the range that can be understood by those skilled in the art and does not significantly affect the measurement.

[1227] (2) Measurement results

[1228] As shown below, one embodiment of the compound of the present invention exhibits excellent IRAK-4 inhibitory activity.

[1229] In addition, when multiple measurements are made, the average value is shown.

[1230] [Table 22]

[1231] Example <![CDATA[IC 50 (nM)]]> Example <![CDATA[IC 50 (nM)]]> a-01-01 1.89 b-02-10 3.94 a-01-02 1.98 b-02-11 2.87 a-01-03 2.69 b-02-12 3.37 a-01-04 1.73 b-02-13 3.77 a-01-05 2.08 b-02-14 2.41 a-01-06 3.29 b-02-15 2.25 a-01-07 1.73 b-02-16 2.01 a-01-08 2.66 b-02-17 1.59 a-01-09 1.81 b-02-18 2.92 a-01-10 12.11 b-02-19 2.54 a-01-11 7.89 b-02-20 4.28 a-01-12 7.75 b-02-21 2.12 a-02-01 16.05 b-02-22 1.89 a-03-01 1.41 b-02-23 2.52 a-04-01 1.38 b-02-24 1.91 a-04-02 1.26 b-02-25 1.98 a-04-03 2.32 b-02-26 1.75 a-04-04 2.32 b-02-27 1.48 a-05-01 7.81 b-02-28 2.17 b-01-01 3.39 b-02-29 2.43 b-01-02 3.33 b-02-30 4.12 b-02-01 3.16 b-02-31 2.36 b-02-02 2.79 b-02-32 2.37 b-02-03 2.53 b-02-33 1.63 b-02-04 3.64 b-02-34 2.52 b-02-05 2.12 b-02-35 2.52 b-02-06 1.34 b-02-36 1.82 b-02-07 2.28 b-02-37 2.22 b-02-08 2.76 b-02-38 2.98 b-02-09 2.42 b-02-39 1.90

[1232] [Table 23]

[1233] Example <![CDATA[IC 50 (nM)]]> Example <![CDATA[IC 50 (nM)]]> b-02-40 1.62 b-02-72 1.47 b-02-41 2.86 b-02-74 1.57 b-02-42 1.93 b-02-76 1.55 b-02-43 3.10 b-02-77 2.60 b-02-44 3.93 b-02-78 2.29 b-02-46 3.55 b-02-79 3.39 b-02-47 1.75 b-02-80 6.86 b-02-48 2.03 b-02-81 3.64 b-02-49 2.52 b-02-82 4.02 b-02-50 1.93 b-02-83 1.93 b-02-51 2.17 b-02-84 1.04 b-02-52 2.60 b-02-85 1.88 b-02-53 2.59 b-02-86 0.803 b-02-54 3.46 b-02-87 0.95 b-02-55 2.97 b-03-01 1.30 b-02-56 1.76 b-03-02 10.98 b-02-57 2.62 b-03-03 1.43 b-02-58 2.70 b-03-04 1.67 b-02-59 1.51 b-03-05 2.93 b-02-60 4.27 b-03-06 2.80 b-02-61 3.87 b-03-07 5.26 b-02-62 1.38 b-03-08 2.68 b-02-63 2.39 b-03-09 2.21 b-02-65 2.38 b-04-01 5.49 b-02-66 5.00 b-04-02 1.40 b-02-67 2.36 b-04-03 3.21 b-02-68 2.18 b-04-04 2.69 b-02-69 1.81 b-04-05 2.85 b-02-70 2.94 b-04-06 2.37 b-02-71 2.36 b-04-07 2.60

[1234] [Table 24]

[1235] Example <![CDATA[IC 50 (nM)]]> Example <![CDATA[IC 50 (nM)]]> b-04-08 2.48 b-04-38 0.85 b-04-09 2.58 b-04-39 0.66 b-04-10 3.94 b-04-40 0.89 b-04-11 1.89 b-04-41 0.69 b-04-12 1.93 b-04-42 0.49 b-04-13 1.70 b-04-43 0.65 b-04-14 1.50 b-04-44 0.46 b-04-15 1.61 b-04-45 0.66 b-04-16 1.51 b-04-46 0.58 b-04-17 1.58 b-04-47 0.54 b-04-18 1.11 b-04-48 0.52 b-04-19 1.38 b-05-01 1.90 b-04-20 1.12 b-05-02 2.47 b-04-21 1.15 b-05-03 1.81 b-04-22 1.30 b-05-04 4.38 b-04-23 1.41 b-05-05 1.95 b-04-24 0.76 b-05-06 2.25 b-04-25 0.88 b-05-07 2.51 b-04-26 1.22 b-05-09 2.13 b-04-27 1.60 b-06-02 4.19 b-04-28 1.58 b-07-01 2.34 b-04-29 1.60 b-08-01 1.97 b-04-30 1.49 c-01-01 3.92 b-04-31 1.73 c-02-01 3.70 b-04-32 1.57 c-02-04 3.35 b-04-33 1.99 c-02-05 4.64 b-04-34 1.65 c-02-06 2.13 b-04-35 2.08 c-02-07 1.56 b-04-36 0.90 c-02-08 2.44 b-04-37 0.81 c-03-01 16.59

[1236] [Table 25]

[1237] Example <![CDATA[IC 50 (nM)]]> Example <![CDATA[IC 50 (nM)]]> c-03-02 2.36 d-03-09 1.47 c-03-03 2.54 d-04-01 2.10 c-03-04 2.69 d-04-02 2.48 c-03-05 4.16 d-04-03 2.22 c-03-06 4.97 d-04-05 2.05 c-03-07 5.35 d-05-01 1.51 c-03-08 4.62 d-05-02 2.10 c-03-09 5.43 e-01-01 2.89 c-04-01 4.04 e-01-02 2.48 c-04-02 6.33 e-01-03 1.03 c-04-03 12.44 e-02-01 1.43 c-05-01 5.48 e-02-02 1.38 c-06-01 5.45 e-02-03 2.23 c-06-02 10.74 e-02-04 1.05 c-06-03 17.15 e-02-05 1.14 c-07-01 6.48 e-02-06 1.30 d-01-01 1.31 e-02-07 1.33 d-01-02 2.75 e-02-08 1.32 d-01-03 2.16 e-02-09 1.09 d-01-04 6.39 e-02-10 1.09 d-01-05 2.07 e-02-11 1.04 d-01-06 3.62 e-02-12 1.90 d-01-07 1.75 e-02-13 1.43 d-01-08 2.89 e-02-14 1.64 d-02-01 1.83 e-02-15 1.81 d-03-01 1.38 e-02-16 1.85 d-03-05 2.52 e-02-17 1.36 d-03-06 0.849 e-02-18 1.84 d-03-07 0.852 e-02-19 1.19 d-03-08 1.28 e-02-20 2.22

[1238] [Table 26]

[1239] Example <![CDATA[IC 50 (nM)]]> Example <![CDATA[IC 50 (nM)]]> e-02-21 1.73 e-02-26 1.86 e-02-22 1.29 e-02-27 1.38 e-02-23 0.88 e-03-01 1.75 e-02-24 1.27 e-04-01 3.74 e-02-25 1.58 e-04-02 1.07

[1240] <Test Example 2: LPS-stimulated TNFα production inhibition test using human acute monocytic leukemia cell line THP-1>

[1241] (1) Measurement method

[1242] The THP-1 assay can be used to evaluate the effect of the test compound on TNFα production induced by LPS stimulation. THP-1 cells (ATCC, Cat. TIB-202) were cultured at 1×10 5 cells / 160μL / well were inoculated in a 96-well plate, 20μL of the compound to be tested was added, and cultured in a 5% CO2 incubator at 37°C for 1 hour. Then 20μL of LPS (final concentration 2.5ng / mL, Sigma, Cat.L2630) was added and cultured for a further 4 hours. After culture, the plate was centrifuged and 100μL of supernatant was collected from each well for evaluation of TNFα amount based on HTRF (Cisbio, Cat.62TNFPEB). In the determination of TNFα amount, the supernatant was diluted 2-fold with culture medium, 10μL was added to a 384-well plate, and then anti-TNFα-cryptate (5μL) and anti-TNFα-XL665 (5μL) were added and left to stand overnight. The fluorescence intensity ratio at a wavelength of 620 / 665nm was measured using an ELISA reader, and the amount of TNFα in the supernatant was calculated using a calibration curve. The inhibition rate of TNFα production when LPS was not added was set as 100%, and the inhibition rate of TNFα production when the test compound was not added was set as 0%. The IC value of the test compound was calculated using the 4-parameter logistic model of the data analysis software XLfit (ID Business Solutions Ltd.). 50 .

[1243] After removing 100 μL of supernatant, the cell viability was measured in a 96-well plate to evaluate the effect of the test compound on off-target effects. 5 μL of CCK-8 (Dojindo, Cat. CK04-10) was added and cultured at 37°C for 1 hour. The absorbance at 450 nm was measured using an ELISA reader. The cell viability without LPS was taken as 100%, and the IC of the test compound was calculated using XLfit. 50 .

[1244] It should be noted that each operation and condition in the measurement can be appropriately changed within the range that can be understood by those skilled in the art and does not significantly affect the measurement.

[1245] (2) Measurement results

[1246] As shown below, one embodiment of the compound of the present invention exhibits excellent TNFα production inhibitory activity.

[1247] In addition, when multiple measurements are made, the average value is displayed, and the fourth decimal place is rounded off.

[1248] [Table 27]

[1249] Example <![CDATA[IC 50 (μM)]]> Example <![CDATA[IC 50 (μM)]]> a-01-01 0.121 b-02-10 0.141 a-01-02 0.180 b-02-11 0.152 a-01-03 0.141 b-02-12 0.17 a-01-04 0.151 b-02-13 0.175 a-01-05 0.121 b-02-14 0.164 a-01-06 0.17 b-02-15 0.157 a-01-07 0.148 b-02-16 0.107 a-01-08 0.161 b-02-17 0.12 a-01-09 0.14 b-02-18 0.164 a-01-10 0.678 b-02-19 0.144 a-01-11 0.437 b-02-20 0.078 a-01-12 0.361 b-02-21 0.066 a-02-01 0.33 b-02-22 0.208 a-03-01 0.057 b-02-23 0.166 a-04-01 0.261 b-02-24 0.18 a-04-02 0.241 b-02-25 0.199 a-04-03 0.355 b-02-26 0.126 a-04-04 0.444 b-02-27 0.159 a-05-01 0.304 b-02-28 0.103 b-01-01 0.154 b-02-29 0.124 b-01-02 0.177 b-02-30 0.137 b-02-01 0.195 b-02-31 0.194 b-02-02 0.195 b-02-32 0.041 b-02-03 0.166 b-02-33 0.051 b-02-04 0.146 b-02-34 0.116 b-02-05 0.131 b-02-35 0.14 b-02-06 0.066 b-02-36 0.145 b-02-07 0.164 b-02-37 0.094 b-02-08 0.113 b-02-38 0.15 b-02-09 0.142 b-02-39 0.182

[1250] [Table 28]

[1251] Example <![CDATA[IC 50 (μM)]]> Example <![CDATA[IC 50 (uM)]]> b-02-40 0.139 b-02-70 0.09 b-02-41 0.16 b-02-71 0.105 b-02-42 0.123 b-02-72 0.162 b-02-43 0.123 b-02-73 0.113 b-02-44 0.143 b-02-74 0.189 b-02-45 0.2 b-02-75 0.186 b-02-46 0.171 b-02-76 0.099 b-02-47 0.11 b-02-77 0.187 b-02-48 0.143 b-02-78 0.111 b-02-49 0.119 b-02-79 0.138 b-02-50 0.144 b-02-80 0.176 b-02-51 0.146 b-02-81 0.202 b-02-52 0.176 b-02-82 0.131 b-02-53 0.172 b-02-83 0.149 b-02-54 0.135 b-02-84 0.101 b-02-55 0.15 b-02-85 0.127 b-02-56 0.109 b-02-86 0.132 b-02-57 0.119 b-02-87 0.182 b-02-58 0.133 b-03-01 0.071 b-02-59 0.105 b-03-02 0.145 b-02-60 0.158 b-03-03 0.126 b-02-61 0.109 b-03-04 0.117 b-02-62 0.141 b-03-05 0.108 b-02-63 0.159 b-03-06 0.116 b-02-64 0.164 b-03-07 0.183 b-02-65 0.163 b-03-08 0.127 b-02-66 0.227 b-03-09 0.143 b-02-67 0.091 b-04-01 0.051 b-02-68 0.16 b-04-02 0.021 b-02-69 0.08 b-04-03 0.046

[1252] [Table 29]

[1253] Example <![CDATA[IC 50 (μM)]]> Example <![CDATA[IC 50 (μM)]]> b-04-04 0.049 b-04-34 0.066 b-04-05 0.054 b-04-35 0.037 b-04-06 0.064 b-04-36 0.048 b-04-07 0.06 b-04-37 0.035 b-04-08 0.053 b-04-38 0.087 b-04-09 0.055 b-04-39 0.044 b-04-10 0.03 b-04-40 0.025 b-04-11 0.038 b-04-41 0.076 b-04-12 0.039 b-04-42 0.064 b-04-13 0.027 b-04-43 0.096 b-04-14 0.025 b-04-44 0.023 b-04-15 0.028 b-04-45 0.015 b-04-16 0.023 b-04-46 0.022 b-04-17 0.022 b-04-47 0.026 b-04-18 0.03 b-04-48 0.035 b-04-19 0.039 b-05-01 0.048 b-04-20 0.039 b-05-02 0.056 b-04-21 0.033 b-05-03 0.05 b-04-22 0.05 b-05-04 0.024 b-04-23 0.054 b-05-05 0.05 b-04-24 0.095 b-05-06 0.046 b-04-25 0.071 b-05-07 0.044 b-04-26 0.086 b-05-08 0.081 b-04-27 0.108 b-05-09 0.044 b-04-28 0.072 b-06-01 0.093 b-04-29 0.055 b-06-02 0.046 b-04-30 0.062 b-07-01 0.058 b-04-31 0.055 b-08-01 0.056 b-04-32 0.05 c-01-01 0.143 b-04-33 0.055 c-02-01 0.11

[1254] [Table 30]

[1255] Example <![CDATA[IC 50 (μM)]]> Example <![CDATA[IC 50 (μM)]]> c-02-02 0.186 d-01-07 0.184 c-02-03 0.229 d-01-08 0.202 c-02-04 0.261 d-02-01 0.077 c-02-05 0.175 d-03-01 0.067 c-02-06 0.194 d-03-02 0.111 c-02-07 0.076 d-03-03 0.087 c-02-08 0.196 d-03-04 0.194 c-03-01 0.049 d-03-05 0.093 c-03-02 0.013 d-03-06 0.125 c-03-03 0.230 d-03-07 0.139 c-03-04 0.320 d-03-08 0.137 c-03-05 0.038 d-03-09 0.158 c-03-06 0.046 d-04-01 0.182 c-03-07 0.184 d-04-02 0.207 c-03-08 0.037 d-04-03 0.162 c-03-09 0.054 d-04-04 0.169 c-04-01 0.115 d-04-05 0.145 c-04-02 0.207 d-05-01 0.182 c-04-03 0.184 d-05-02 0.223 c-05-01 0.233 e-01-01 0.279 c-06-01 0.358 e-01-02 0.225 c-06-02 0.317 e-01-03 0.171 c-06-03 0.277 e-02-01 0.077 c-07-01 0.347 e-02-02 0.123 d-01-01 0.085 e-02-03 0.067 d-01-02 0.165 e-02-04 0.116 d-01-03 0.175 e-02-05 0.123 d-01-04 0.178 e-02-06 0.113 d-01-05 0.101 e-02-07 0.152 d-01-06 0.174 e-02-08 0.165

[1256] [Table 31]

[1257] Example <![CDATA[IC 30 (μM)]]> Example <![CDATA[IC 50 (μM)]]> e-02-09 0.065 e-02-20 0.244 e-02-10 0.131 e-02-21 0.188 e-02-11 0.095 e-02-22 0.106 e-02-12 0.129 e-02-23 0.111 e-02-13 0.077 e-02-24 0.117 e-02-14 0.139 e-02-25 0.053 e-02-15 0.167 e-02-26 0.08 e-02-16 0.175 e-02-27 0.054 e-02-17 0.2 e-03-01 0.168 e-02-18 0.2 e-04-01 0.431 e-02-19 0.191 e-04-02 0.314

[1258] <Test Example 3: Rat collagen-induced arthritis model>

[1259] (1) Measurement method

[1260] Female Lewis rats (SLC Inc.) aged 8 weeks were immunized with bovine type II collagen (CII, Collagen Technology Training Association, product number K41) to induce arthritis. A 1:1 mixed emulsion of incomplete Freund's adjuvant (Difco, Cat.263910) and CII 3mg / mL solution was prepared, and 0.7mL was injected into each rat, and 0.1mL was injected into 7 places in the skin of the base of the tail and the base of the two front and rear limbs. After 7 days, 0.2mL of an emulsion mixed with incomplete Freund's adjuvant and CII in a 1:1 ratio was added as on the first day, and 0.1mL was injected into 2 places in the base of the tail. After 12 days, the plantar volume of the two hind limbs of the animal was measured using a limb swelling meter (UGOBASILE, Cat.37140), and the plantar volume ratio and body weight relative to the normal group were grouped. After grouping, the test compound or solvent (solvent control: 0.5% methylcellulose) was administered orally twice a day for 7 days (on the grouping day, only once after grouping). After the start of administration, the plantar volume of both hind limbs of the animals was measured every 1 or 2 days using a limb swelling meter to evaluate the effects of the test compound.

[1261] On each measurement day, the average plantar volume of both hind limbs was calculated for each individual using Excel 2010 (Microsoft), and graphed using GraphPad Prism 7.03 (GraphPad Software, Inc.). The normal group was defined as 100%, and the solvent-administered group was defined as 0% inhibition control. The inhibition rate at each concentration of the test compound relative to these controls was calculated using Excel 2010 (Microsoft).

[1262] It should be noted that each operation and condition in the measurement can be appropriately changed within the range that can be understood by those skilled in the art and does not significantly affect the measurement.

[1263] (2) Measurement results

[1264] The results of the changes in plantar volume of each group are shown in Figure 1 The vertical axis represents the plantar volume, and the horizontal axis represents the number of days after the first immunization with bovine type II collagen. In addition, "n" represents the number of rats used.

[1265] When the dose of Example c-01-01 was 20, 60, and 120 mg / kg, the inhibition rates of the group given twice a day 19 days after the initial immunization were 45%, 65%, and 77%, respectively.

[1266] Thus, a certain embodiment of the compound of the present invention (Example c-01-01) showed an excellent swelling inhibitory effect in rat arthritis.

[1267] Industrial Applicability

[1268] The compound of the general formula (1) or a salt thereof has excellent IRAK-4 inhibitory activity and is useful as an active ingredient of a drug for preventing and / or treating a disease associated with IRAK-4 inhibition.

Claims

1. A compound represented by the following general formula (1) or a salt thereof: [Chemistry 1] In the general formula (1), Rg is the following general formula (1-1): [Chemistry 2] In the general formula (1-1), a and b represent the bonding directions; R 1 is -H, -F, -Cl, methyl or C 1-3 Alkoxy, the C 1-3 The alkoxy group may be substituted with a 1 1 to 3 identical or different substituents in the group; The G 1 The group is composed of -F, hydroxyl, cyano, halogenated C 1-6 Alkyl, C 1-4 The group consisting of an alkoxy group, a phenyl group, a 5- to 6-membered heteroaryl group, and a 3- to 7-membered saturated ring group, G 1 The phenyl or 5- to 6-membered heteroaryl group in the group may be substituted with a Ar 1 to 3 identical or different substituents in the group; The G Ar The group is composed of -F, -Cl, hydroxyl, cyano, C 1-6 Alkyl, halogenated C 1-6 The group consisting of alkyl and -NH2; R 2 C 1-6 Alkyl, halogenated C 1-6 Alkyl or 3-7 membered saturated ring group, said R 2 Can be substituted with a selected from G 2 1 to 3 identical or different substituents in the group; The G 2 The group is composed of -F, hydroxyl, halogenated C 1-3 Alkyl and C 1-4 A group consisting of alkoxy groups; Cy is the following general formula (2-1): [Chemistry 4] In the general formula (2-1), k is an integer of 0 or 1; R Cy1 and R Cy2 are independently -H, -F, hydroxyl, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -NR 11 R 12 , phenyl, 5- to 6-membered heteroaryl or 3- to 7-membered saturated ring group, R Cy1 and R Cy2 When it is phenyl or 5-6 membered heteroaryl, it may be substituted with a Ar 1 to 3 identical or different substituents in the group, the R Cy1 , R Cy2 When it is a group other than a phenyl group or a 5- to 6-membered heteroaryl group, it may be substituted with a group selected from the above 1 1 to 3 identical or different substituents in the group; R 11 and R 12 Each independently is -H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, 3-7 membered saturated ring group, phenyl or 5-6 membered heteroaryl, R 11 and R 12 Can be substituted with a selected from G 1 1 to 3 identical or different substituents in the group; or R 11 With R 12 Together, they form a 4- to 10-membered saturated ring or a 7- to 11-membered spiro ring, wherein the 4- to 10-membered saturated ring and the 7- to 11-membered spiro ring may have, in addition to N, 1 to 2 identical or different heteroatoms selected from the group consisting of O and N, and the 4- to 10-membered saturated ring and the 7- to 11-membered spiro ring may be substituted with a heteroatom selected from G 3 1 to 3 identical or different substituents in the group; The G 3 The group is composed of -F, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -C(O)R 14 、-C(O)NR 13 R 14 , -C(O)NH2, phenyl, 5-6 membered heteroaryl and 3-7 membered saturated ring group, wherein G 3 The phenyl or 5- to 6-membered heteroaryl group in the Ar 1 to 3 identical or different substituents in the group; R 13 -H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, halogenated C 1-6 Alkoxy C 1-6 Alkyl, phenyl, 5-6 membered heteroaryl or 3-7 membered saturated ring group, said R 13 The phenyl or 5- to 6-membered heteroaryl group in the Ar 1 to 3 identical or different substituents in the group; R 14 C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, halogenated C 1-6 Alkoxy C 1-6 Alkyl, phenyl, 5-6 membered heteroaryl or 3-7 membered saturated ring group, said R 14 The phenyl or 5- to 6-membered heteroaryl group in the Ar 1 to 3 identical or different substituents in the group; or R 13 With R 14 Together they form a 4- to 7-membered saturated ring or a 7- to 11-membered spiro ring, wherein the 4- to 7-membered saturated ring and the 7- to 11-membered spiro ring may have, in addition to N, 1 to 2 identical or different heteroatoms selected from the group consisting of O and N, or -S(O2)-; or R Cy1 With R Cy2 Together, they form a 4- to 7-membered saturated ring, wherein the 4- to 7-membered saturated ring may have 1 to 2 identical or different heteroatoms selected from the group consisting of O and N, and the 4- to 7-membered saturated ring may be substituted with a group selected from the G 1 1 to 3 identical or different substituents in the group.

2. The compound or salt thereof according to claim 1, wherein R 1 is -F, -Cl, methyl or C 1-3 Alkoxy.

3. The compound or salt thereof according to claim 1, wherein R 1 C 1-3 Alkoxy.

4. The compound or salt thereof according to claim 1, wherein R 1 It is a methoxy group.

5. The compound or salt thereof according to any one of claims 1 to 4, wherein R 1 is -H; Cy is the following general formula (2-1-1): [Chemistry 5] R 11 and R 12 Same meaning as above.

6. The compound or salt thereof according to any one of claims 1 to 4, wherein Cy is represented by the following general formula (2-1-2): [Chemistry 6] In the general formula (2-1-2), R Cy3 C 1-4 Alkyl, halogenated C 1-4 alkyl; X is O or NR 15 ; R 15 -H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, -C(O)R 16 、-C(O)NR 16 R 17 or a 3- to 7-membered saturated ring group, wherein R 15 Can be substituted with a selected from G 1 1 to 3 identical or different substituents in the group; R 16 C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, halogenated C 1-6 Alkoxy C 1-6 Alkyl, phenyl, 5-6 membered heteroaryl or 3-7 membered saturated ring group, said R 16 The phenyl or 5- to 6-membered heteroaryl group in the Ar 1 to 3 identical or different substituents in the group; R 17 -H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-3 Alkoxy C 1-6 Alkyl, halogenated C 1-6 Alkoxy C 1-6 Alkyl, phenyl, 5-6 membered heteroaryl or 3-7 membered saturated ring group, said R 17 The phenyl or 5- to 6-membered heteroaryl group in the Ar 1 to 3 identical or different substituents in the group; or R 16 With R 17 Together they form a 4- to 7-membered saturated ring or a 7- to 11-membered spiro ring, wherein the 4- to 7-membered saturated ring and the 7- to 11-membered spiro ring may have, in addition to N, 1 to 2 identical or different heteroatoms selected from the group consisting of O and N, or -S(O2)-.

7. The compound or salt thereof according to claim 6, wherein X is NR 15 , R 15 Same meaning as above.

8. The compound or salt thereof according to any one of claims 1 to 4, wherein Cy is the following general formula (2-1-3): [Chemistry 7] In the general formula (2-1-3), R Cy3 C 1-4 Alkyl, halogenated C 1-4 alkyl; X is O or NR 15 ; R 15 -H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, -C(O)R 16 、-C(O)NR 16 R 17 or a 3- to 7-membered saturated ring group, wherein R 15 Can be substituted with a selected from G 1 1 to 3 identical or different substituents in the group; R 16 C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, halogenated C 1-6 Alkoxy C 1-6 Alkyl, phenyl, 5-6 membered heteroaryl or 3-7 membered saturated ring group, said R 16 The phenyl or 5- to 6-membered heteroaryl group in the Ar 1 to 3 identical or different substituents in the group; R 17 -H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-3 Alkoxy C 1-6 Alkyl, halogenated C 1-6 Alkoxy C 1-6 Alkyl, phenyl, 5-6 membered heteroaryl or 3-7 membered saturated ring group, said R 17 The phenyl or 5- to 6-membered heteroaryl group in the Ar 1 to 3 identical or different substituents in the group; or R 16 With R 17 Together they form a 4- to 7-membered saturated ring or a 7- to 11-membered spiro ring, wherein the 4- to 7-membered saturated ring and the 7- to 11-membered spiro ring may have, in addition to N, 1 to 2 identical or different heteroatoms selected from the group consisting of O and N, or -S(O2)-.

9. The compound or salt thereof according to any one of claims 1 to 4, wherein R 2 It is the following formula (3-1): [Chemistry 8] Or n-propyl.

10. The compound or salt thereof according to any one of claims 1 to 4, wherein R 2 It is the following formula (3-1): [Chemistry 9] 11. A compound represented by the following formula or a salt thereof: [Chemistry 10] 12. A compound represented by the following formula or a salt thereof: [Chemistry 11] 13. A compound represented by the following formula or a salt thereof: [Chemistry 12] 14. A compound represented by the following formula or a salt thereof: [Chemistry 13] 15. A compound represented by the following formula or a salt thereof: [Chemistry 14] 16. A compound represented by the following formula or a salt thereof: [Chemistry 15] 17. A compound represented by the following formula or a salt thereof: [Chemistry 16] 18. A compound represented by the following formula or a salt thereof: [Chemistry 17] 19. A compound represented by the following formula or a salt thereof: [Chemistry 18] 20. A compound represented by the following formula or a salt thereof: [Chemistry 19]

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