TW202328123A - Nitrogen-containing bicyclic compounds containing pyrimidine - Google Patents

Abstract

The present invention is a compound of the following general formula (1) or a salt thereof, which has excellent IRAK-4 inhibitory activity and can be used as an active ingredient of a medicine for preventing and/or treating diseases related to IRAK-4 inhibition.

Description

Nitrogen-containing bicyclic compounds containing pyrimidine

The present invention relates to a novel nitrogen-containing bicyclic compound, or a medicine using the same as an active ingredient.

Interleukin-1 receptor-associated kinase 4 (IRAK-4) plays an important role in downstream signaling of Toll-like receptors (TLRs), interleukin-1 receptor (IL-1R), IL-18R and IL-33R Acting protein phosphatase (Non-Patent Document 1). Since the TLRs/IL-1 receptor family plays an important role in inflammation and biological defense, this downstream signal is considered to play a major role in many diseases including inflammatory diseases and autoimmune diseases.

TLRs use pathogen-associated molecular patterns (PAMPs) derived from infectious microorganisms such as bacteria, fungi, parasites, and viruses as ligands. Furthermore, TLRs can also recognize and activate damage-associated molecular patterns (DAMPs) released from damaged or apoptotic cells. If the ligand binds to TLRs or IL-1 receptor family, MyD88 as a transfer molecule will be recruited to a common intracellular region called TIR (Toll/IL-1 receptor) region. It is considered that IRAK-4 is recruited to the receptor by interacting with MyD88 and initiates downstream message transmission (Non-Patent Document 2). IRAK-4 activates IRAK-1 or IRAK-2, and then controls the production of inflammatory mediators such as cytokines and chemokines through the activation of downstream NF-kB or MAPK and other signaling molecules.

It has been reported that human cells deficient in the IRAK-4 gene do not respond to TLRs agonists other than TLR3, IL-1β, and IL-18 (Non-Patent Document 3). Also, IRAK-4 gene-deficient mice do not respond to TLRs agonists other than TLR3, IL-1β, and IL-18 (Non-Patent Document 4). On the other hand, these signals are only partially suppressed in IRAK-1 gene-deficient mice or IRAK-2 gene-deficient mice (Non-Patent Document 5). Therefore, IRAK-4 in the IRAK family is considered to play a central role in the transmission of these messages. It has been reported that compared with wild-type mice, IRAK-4 knock-in mice lacking kinase activity can inhibit the severity of arthritis, experimental autoimmune encephalomyelitis, and arteriosclerosis models (Non-Patent Document 6 ). Therefore, the kinase activity of IRAK-4 is necessary for disease-related information transmission, and IRAK-4 inhibitors may be effective in autoimmune diseases such as acute and chronic inflammation, rheumatoid arthritis, and systemic lupus erythematosus , Gout, diabetes and other metabolic diseases, tumors and other diseases have shown high effectiveness.

As a compound having an IRAK-4 inhibitory activity, for example, compounds described in Patent Documents 1 to 6 are known. [Prior Art Literature] [Patent Document]

[Patent Document 1] Specification of International Publication No. WO2016/144846 [Patent Document 2] Specification of International Publication No. WO2016/053771 [Patent Document 3] Specification of International Publication No. WO2015/048281 [Patent Document 4] Specification of International Publication No. WO2013/042137 [Patent Document 5] Specification of International Publication No. WO2012/068546 [Patent Document 6] Specification of International Publication No. WO2015/150995 [Non-patent literature]

[Non-Patent Document 1] Flannery S. & Bowie A.G., Biochemical Pharmacology 80 (2010) 1981–1991 [Non-Patent Document 2] Jain A. et al., Frontiers in Immunology 5 (2014) Article 553 [Non-Patent Document 3] Picad C. et al., Science 299 (2003) 2076-2079 [Non-Patent Document 4] Suzuki N. et al., Nature 416 (2002) 750-754 [Non-Patent Document 5] Wan Y. et al., J Biol Chem 284 (2009) 10367-10375 [Non-Patent Document 6] Koziczak-Holbro M. et al., Arthritis & Rheumatism 60 (2009) 1661-1671

[Problem to be solved by the invention]

The problem to be solved by the present invention is to provide a novel compound with IRAK-4 inhibitory activity. Furthermore, another problem to be solved by the present invention is to provide a novel compound that can be used as an active ingredient of a medicine for preventing and/or treating diseases related to IRAK-4 inhibition. Another problem to be solved by the present invention is to provide a medicine containing the compound. [Technical means to solve the problem]

In order to solve the above problems, the present inventors conducted intensive research and found that the compounds of the present invention represented by the following formula (1) have excellent IRAK-4 inhibitory activity, and these compounds can be used for the prevention and/or treatment of IRAK-4 inhibits related diseases, thereby completing the present invention.

That is, as this invention, the following are mentioned. [1] A compound or a salt thereof represented by the following general formula (1): [Chem. 1] [In the formula (1), Rg is the following general formula (1-1): [Chem. 2] Or the following general formula (1-2): [Chemical 3] (a, b represent the bonding orientation), R ¹ is -H, -F, -Cl, methyl, or C _1-3 alkoxy, and the above C _1-3 alkoxy can be selected from G ¹ group 1 to 3 of the same or different substituents are substituted; the above G ¹ group is composed of -F, hydroxyl, cyano, halogenated C _1-6 alkyl, C _1-4 alkoxy, phenyl, 5-6 The group consisting of 3-7 membered heteroaryl and 3-7 membered saturated ring group, the phenyl group or 5-6 membered heteroaryl group in ^G1 can be selected from 1 to 3 identical or different ones in G ^Ar group Substituent substitution; The above-mentioned G ^Ar group is a group consisting of -F, -Cl, hydroxyl, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl, and -NH ₂ ; R ² is C _1-6 alkyl, halogenated C _1-6 alkyl, or 3-7 membered saturated ring group, the above R ² may be substituted by 1 to 3 identical or different substituents selected from G ² group; the above G ² The group is composed of -F, hydroxyl, halogenated C _1-3 alkyl, and C _1-4 alkoxy; Cy is the following general formula (2-1): [Chemical 4] ; In 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, 5-6 membered heteroaryl, or 3-7 membered saturated ring, phenyl or 5-6 in R ^Cy1 and R ^Cy2 The membered heteroaryl group may be substituted by 1 to 3 identical or different substituents selected from the above G ^Ar group, and the above R ^Cy1 and R ^Cy2 may be substituted by 1 to 3 identical or different substituents selected from the above G ¹ group. Substituent substitution; R ¹¹ and R ¹² are independently -H, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy 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 may be substituted by 1 to 3 identical or different substituents selected from G ¹ group; Or R ¹¹ and R ¹² together form a 4-10-membered saturated ring or a 7-11-membered spiro ring, the above-mentioned 4-10-membered saturated ring and 7-11-membered spiro ring can be selected from O and N in addition to N 1 to 2 same or different heteroatoms or -S(O ₂ )- in the group, the above-mentioned 4-10 membered saturated ring and 7-11 membered spiro ring can be selected from 1 to 3 members in the ^G3 group The same or different substituents are substituted; the above-mentioned G ³ group is composed of -F, hydroxyl, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy 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)NH ₂ , -NR ¹³ S(O ₂ )R ¹⁴ , -S(O ₂ )NR ¹³ R ¹⁴ , -S(O ₂ )NH ₂ , -S(O ₂ )R ^14. A group consisting of phenyl, 5-6 membered heteroaryl, and 3-7 membered saturated ring group, the phenyl or 5-6 membered heteroaryl in the above ^G3 can be selected from the above G ^Ar group 1 to 3 of the same or different substituents; R ¹³ is -H, C _1-3 alkyl, halogenated C _1-3 alkyl, C _1-3 alkoxy C _1-3 alkyl, halogen Substituted C _1-3 alkoxy C _1-3 alkyl, phenyl, 5-6 membered heteroaryl, or 3-7 membered saturated ring group, the phenyl or 5-6 membered heteroaryl in the above R ¹³ Can be substituted by 1 to 3 identical or different substituents selected from the above G ^Ar group; R ¹⁴ is 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, phenyl or 5 in the above R ¹⁴ The -6-membered heteroaryl group may be substituted by 1 to 3 identical or different substituents selected from the above G ^Ar group; or R ¹³ and R ¹⁴ together form a 4-7-membered saturated ring or a 7-11-membered spiro ring, The above-mentioned 4-7 membered saturated ring and 7-11 membered spiro ring may have, in addition to N, 1 to 2 same or different heteroatoms or -S(O ₂ )- selected from the group consisting of O and N ; or R ^Cy1 and R ^Cy2 together form a 4-7 member saturated ring, the above-mentioned 4-7 member saturated ring may have 1-2 identical or different heteroatoms or -S( O ₂ )-, the aforementioned 4-7 membered saturated ring may be substituted by 1 to 3 identical or different substituents selected from the aforementioned G ¹ group].

[2] The compound or salt thereof according to [1], wherein Rg is the general formula (1-1). [3] The compound or a salt thereof according to the above [2], wherein R ¹ is -F, -Cl, methyl, or C _1-3 alkoxy. [4] The compound or a salt thereof according to the above [2], wherein R ¹ is C _1-3 alkoxy. [4-2] The compound or a salt thereof according to the above [2], wherein R ¹ is ethoxy, methoxy, or methoxyethoxy. [4-3] The compound or salt thereof according to [2] above, wherein R ¹ is ethoxy or methoxy. [5] The compound or a salt thereof according to the above [2], wherein R ¹ is methoxy.

[6] The compound or salt thereof as described in any one of the above-mentioned [2] to [5], wherein R ¹ is -H; Cy is the following general formula (2-1-1): [Chem. 5] (R ¹¹ and R ¹² have the same meaning as above). [6-2] The compound or salt thereof as described in any one of the above-mentioned [2] to [5], wherein R ¹¹ and R ²² are each independently -H, C _1-6 alkyl, halogenated C _{1 -6} alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, 3-7 membered saturated ring, phenyl, or 5-6 membered heteroaryl, R ¹¹ and R ¹² may be substituted with 1 to 3 identical or different substituents selected from the above group G ¹ . [6-3] The compound or salt thereof as described in any one of the above-mentioned [2] to [5], wherein R ¹¹ and R ²² are each independently -H, C _1-6 alkyl, halogenated C _{1 -6} alkyl group, 3-7 membered saturated ring group, or 5-6 membered heteroaryl group, R ¹¹ and R ¹² may be substituted by 1 to 3 identical or different substituents selected from the above G ¹ group.

[6-4] The compound or salt thereof as described in any one of the above [2] to [5], wherein R ¹¹ and R ²² are each independently -H, C _1-6 alkyl, halogenated C _{1 -6} alkyl group, or 3-5 membered saturated ring group, R ¹¹ and R ¹² may be substituted by 1 to 3 identical or different substituents selected from the above G ¹ group. [6-5] The compound or salt thereof as described in any one of the above-mentioned [2] to [5], wherein R ¹¹ and R ¹² together form a 4-10-membered saturated ring or a 7-11-membered spiro ring, and the above-mentioned 4 The -7-membered saturated ring and the 7-11-membered spirocycle may have, in addition to N, 1 to 2 identical or different heteroatoms or -S(O ₂ )- selected from the group consisting of O and N, the above The 4-7 membered saturated ring and the 7-11 membered spiro ring may be substituted with 1 to 3 identical or different substituents selected from the above ^G3 group. [6-6] The compound or salt thereof as described in any one of the above-mentioned [2] to [5], wherein R ¹¹ and R ¹² together form a 4-10-membered saturated ring or a 7-11-membered spiro ring, and the above-mentioned 4 The -7-membered saturated ring and the 7-11-membered spirocycle may have, in addition to N, 1 to 2 identical or different heteroatoms or -S(O ₂ )- selected from the group consisting of O and N, the above The 4-7 membered saturated ring and the 7-11 membered spiro ring may be substituted with 1 to 3 identical or different substituents selected from the above ^G3 group.

[6-7] The compound or salt thereof as described in any one of the above-mentioned [2] to [5], wherein R ¹¹ and R ¹² together form the following general formula (2-1-1-a-1)～ (2-1-1-a-7): [Chem. 6] Any of the saturated rings, the above-mentioned saturated rings may be substituted by 1 to 3 identical or different substituents selected from group ^G3 ; ^R15 is -H, _C1-6 alkyl, halogenated _C1-6 alkane group, hydroxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, -C(O)R ¹⁶ , -S(O ₂ )R ¹⁶ , -C(O)NR ¹⁶ R ¹⁷ , -C(O)OR ¹⁶ , or a 3-7 membered saturated ring group, the above R ¹⁵ may be substituted by 1 to 3 identical or different substituents selected from G ¹ group; R ¹⁶ is C _1-6 alkane Base, 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 phenyl or 5-6 membered heteroaryl group in the above R ¹⁶ may be substituted by 1 to 3 identical or different substituents selected from the above G ^Ar group; R ¹⁷ is -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 phenyl or 5-6 membered heteroaryl in the above R ¹⁷ can be selected from the same 1 to 3 members of the above G ^Ar group or different substituents; or R ¹⁶ and R ¹⁷ together form a 4-7-membered saturated ring or a 7-11-membered spiro ring, and the above-mentioned 4-7-membered saturated ring and 7-11-membered spiro ring may have 1 to 2 same or different heteroatoms or -S(O ₂ )- selected from the group consisting of O and N.

[6-8] The compound or salt thereof as described in any one of the above-mentioned [2] to [5], wherein R ¹¹ and R ¹² together form the following general formula (2-1-1-b-1): [chemical 7] The above saturated ring may be substituted by 1 to 3 identical or different substituents selected from group ^G3 ; X is O or NR ¹⁵ (R ¹⁵ has the same meaning as above). [6-9] The compound or salt thereof as described in any one of the above-mentioned [2] to [5], wherein R ¹¹ and R ¹² together form the following general formula (2-1-1-c-1)～ (2-1-1-c-3): [Chem. 8] The above-mentioned saturated ring can be substituted by 1 to 3 identical or different substituents selected from group ^G3 ; X is O or NR ¹⁵ (R ¹⁵ has the same meaning as above).

[6-10] The compound or salt thereof as described in any one of the above-mentioned [2] to [5], wherein R ¹¹ and R ¹² together form the following general formula (2-1-1-d-1) ~(2-1-1-d-8): [chemical 9] The bridging saturated ring with the above bridging saturated ring can be substituted by 1 to 3 identical or different substituents selected from group ^G3 ; X is O or NR ¹⁵ (R ¹⁵ has the same meaning as above).

[6-11] The compound or salt thereof as described in any one of the above-mentioned [2] to [5], wherein R ¹¹ and R ¹² together form the following general formula (2-1-1-e-1) : [Chem.10] The saturated ring of the condensed ring, the saturated ring with the above-mentioned condensed ring can be substituted by 1 to 3 identical or different substituents selected from the ^G3 group; X is O or NR ¹⁵ (R ¹⁵ has the same meaning as above).

[7] The compound or salt thereof as described in any one of [2] to [6-11], wherein Cy is the following general formula (2-1-2): [Chem. 11] [In formula (2-1-2), R ^Cy3 is C _1-4 alkyl, halogenated C _1-4 alkyl; X is O or NR ¹⁵ ; R ¹⁵ is -H, C _1-6 alkyl , halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, -C(O)R ¹⁶ , -S(O ₂ )R ¹⁶ , - C(O)NR ¹⁶ R ¹⁷ , -C(O)OR ¹⁶ , or a 3-7 membered saturated ring group, the above R ¹⁵ may be substituted by 1 to 3 identical or different substituents selected from G ¹ group; R ¹⁶ is 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, benzene group, 5-6 membered heteroaryl group, or 3-7 membered saturated ring group, the phenyl or 5-6 membered ^heteroaryl group in the above R ¹⁶ can be selected from 1 to 3 identical or Different substituents are substituted; R ¹⁷ is -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 phenyl or 5-6 membered heteroaryl in the above R ¹⁷ can be selected from the above G ^Ar 1-3 identical or different substituents in the group are substituted; or R ¹⁶ and R ¹⁷ together form a 4-7-membered saturated ring or a 7-11-membered spiro ring, the above-mentioned 4-7-membered saturated ring and 7-11-membered spiro ring The ring may have, in addition to N, 1 to 2 identical or different heteroatoms or -S(O ₂ )-] selected from the group consisting of O and N.

Furthermore, when the item numbers cited are expressed in ranges as in the above [2] to [6-11], and items with branch numbers such as [6-6] are arranged within the range, it means that items with [6] are also cited. -6] Items such as branch numbers. The same applies below.

[8] The compound or a salt thereof according to any one of the above-mentioned [2] to [7], wherein X is NR ¹⁵ (R ¹⁵ has the same meaning as above). [9] The compound or salt thereof as described in any one of the above-mentioned [2] to [8], wherein Cy is the following general formula (2-1-3): [Chem. 12] (R ^Cy3 and X have the same meaning as above).

[10] The compound or salt thereof according to any one of the above-mentioned [2] to [9], wherein R ² is the following formula (3-1): [Chem. 13] or n-propyl.

[11] The compound or salt thereof according to any one of the above-mentioned [2] to [9], wherein R ² is the following formula (3-1): [Chem. 14] .

[12] A compound or a salt thereof represented by the following formula: [Chem. 15] .

[13] A compound or a salt thereof represented by the following formula: [Chem. 16] .

[14] A compound or a salt thereof, which is represented by the following formula: [Chem. 17] .

[15] A compound or a salt thereof represented by the following formula: [Chem. 18] .

[16] A compound or a salt thereof represented by the following formula: [Chem. 19] .

[17] A compound or a salt thereof represented by the following formula: [Chem. 20] .

[18] A compound or a salt thereof represented by the following formula: [Chem. 21] .

[19] A compound or a salt thereof represented by the following formula: [Chem. 22] .

[20] A compound or a salt thereof, which is represented by the following formula: [Chem. 23] .

[21] A compound or a salt thereof represented by the following formula: [Chem. 24] .

[22] The compound or a salt thereof according to the above [1], wherein Rg is the general formula (1-2). [23] The compound or salt thereof according to [22] above, wherein R ¹ is -H or methoxy. [24] The compound or a salt thereof according to the above [22], wherein R ¹ is -H. [25] The compound or salt thereof as described in any one of [22] to [24], wherein Cy is the general formula (2-1); [in the formula (2-1), k is an integer 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 , 5-6-membered heteroaryl, or 3-7-membered saturated ring group, the phenyl or 5-6-membered heteroaryl in R ^Cy1 and R ^Cy2 can be selected from 1 to 3 of the above G ^Ar groups to be the same or different substituents, the above R ^Cy1 and R ^Cy2 may be substituted by 1 to 3 identical or different substituents selected from the above G ¹ group (R ¹¹ and R ¹² have the same meaning as above)].

[26] The compound or salt thereof as described in any one of the above-mentioned [22] to [25], wherein Cy is the following general formula (2-1-1): [Chem. 25] (R ¹¹ and R ¹² have the same meaning as above). [26-2] The compound or salt thereof according to any one of the above-mentioned [22] to [25], wherein R ¹¹ and R ²² are each independently -H, C _1-6 alkyl, halogenated C _{1 -6} alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, 3-7 membered saturated ring, phenyl, or 5-6 membered heteroaryl, R ¹¹ and R ¹² may be substituted with 1 to 3 identical or different substituents selected from the above group G ¹ . [26-3] The compound or salt thereof according to any one of the above-mentioned [22] to [25], wherein R ¹¹ and R ²² are each independently -H, C _1-6 alkyl, halogenated C _{1 -6} alkyl group, 3-7 membered saturated ring group, or 5-6 membered heteroaryl group, R ¹¹ and R ¹² may be substituted by 1 to 3 identical or different substituents selected from the above G ¹ group.

[26-4] The compound or salt thereof according to any one of the above-mentioned [22] to [25], wherein R ¹¹ and R ²² are each independently -H, C _1-6 alkyl, halogenated C _{1 -6} alkyl group, or 3-5 membered saturated ring group, R ¹¹ and R ¹² may be substituted by 1 to 3 identical or different substituents selected from the above G ¹ group. [26-5] The compound or salt thereof as described in any one of the above-mentioned [22] to [25], wherein R ¹¹ and R ¹² together form a 4-10-membered saturated ring or a 7-11-membered spiro ring, and the above-mentioned 4 The -7-membered saturated ring and the 7-11-membered spirocycle may have, in addition to N, 1 to 2 identical or different heteroatoms or -S(O ₂ )- selected from the group consisting of O and N, the above The 4-7 membered saturated ring and the 7-11 membered spiro ring may be substituted with 1 to 3 identical or different substituents selected from the above ^G3 group. [26-6] The compound or salt thereof as described in any one of the above-mentioned [22] to [25], wherein R ¹¹ and R ¹² together form a 4-10-membered saturated ring or a 7-11-membered spiro ring, and the above-mentioned 4 The -7-membered saturated ring and the 7-11-membered spirocycle may have, in addition to N, 1 to 2 identical or different heteroatoms or -S(O ₂ )- selected from the group consisting of O and N, the above The 4-7 membered saturated ring and the 7-11 membered spiro ring may be substituted with 1 to 3 identical or different substituents selected from the above ^G3 group.

[26-7] The compound or salt thereof as described in any one of the above-mentioned [22] to [25], wherein R ¹¹ and R ¹² together form the following general formula (2-1-1-a-1)～ (2-1-1-a-7): [Chem. 26] (R ¹⁵ has the same meaning as above), which may be substituted by 1 to 3 identical or different substituents selected from group G ³ .

[26-8] The compound or salt thereof as described in any one of the above-mentioned [22] to [25], wherein R ¹¹ and R ¹² together form the following general formula (2-1-1-b-1): [chem 27] The above saturated ring may be substituted by 1 to 3 identical or different substituents selected from group ^G3 ; X is O or NR ¹⁵ (R ¹⁵ has the same meaning as above).

[26-9] The compound or salt thereof as described in any one of the above-mentioned [22] to [25], wherein R ¹¹ and R ¹² together form the following general formula (2-1-1-c-1)～ (2-1-1-c-3): [Chem. 28] The above saturated ring may be substituted by 1 to 3 identical or different substituents selected from group ^G3 ; X is O or NR ¹⁵ (R ¹⁵ has the same meaning as above).

[26-10] The compound or salt thereof as described in any one of the above-mentioned [22] to [25], wherein R ¹¹ and R ¹² together form the following general formula (2-1-1-d-1)～ (2-1-1-d-8): [Chem. 29] The above-mentioned spiro ring may be substituted by 1 to 3 identical or different substituents selected from ^G3 group; X is O or NR ¹⁵ (R ¹⁵ has the same meaning as above).

[26-11] The compound or salt thereof as described in any one of the above-mentioned [22] to [25], wherein R ¹¹ and R ¹² together form the following general formula (2-1-1-e-1) : [Chem30] The saturated ring of the condensed ring, the saturated ring with the above-mentioned condensed ring can be substituted by 1 to 3 identical or different substituents selected from the ^G3 group; X is O or NR ¹⁵ (R ¹⁵ has the same meaning as above).

[27] The compound or a salt thereof as described in any one of the above-mentioned [22] to [26-11], wherein Cy is the following general formula (2-1-2): [Chemical 31] (R ^Cy3 has the same meaning as above); X is O or NR ¹⁵ (R ¹⁵ has the same meaning as above). [28] The compound or a salt thereof according to any one of the above-mentioned [22] to [27], wherein X is NR ¹⁵ (R ¹⁵ has the same meaning as above).

[29] The compound or a salt thereof as described in any one of the above-mentioned [22] to [28], wherein Cy is the following general formula (2-1-3): [Chemical 32] (R ^Cy3 and X have the same meaning as above).

[30] The compound or salt thereof as described in any one of the above-mentioned [22] to [29], wherein R ² is the following formula (3-1): [Chem. 33] or n-propyl.

[31] The compound or salt thereof as described in any one of the above-mentioned [22] to [29], wherein R ² is the following formula (3-1): [Chem. 34] .

[32] A compound or a salt thereof, which is represented by the following formula: [Chem. 35] .

[33] A compound or a salt thereof, which is represented by the following formula: [Chem. 36] .

[34] A compound or a salt thereof, which is represented by the following formula: [Chem. 37] .

[35] A compound or a salt thereof, which is represented by the following formula: [Chem. 38] .

[36] A medicine comprising the compound according to any one of the above [1] to [35] or a pharmaceutically acceptable salt thereof as an active ingredient. [35] The medicine according to the above [36], which is used for preventing and/or treating a disease associated with IRAK4 inhibition. [38] The medicine according to the above [36], which is used for preventing and/or treating rheumatism. [39] An IRAK4 inhibitor comprising, as an active ingredient, the compound described in any one of the above [1] to [35] or a pharmaceutically acceptable salt thereof.

[40] A pharmaceutical composition for the prevention and/or treatment of rheumatism, comprising the compound described in any one of the above-mentioned [1] to [35] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [41] The compound described in any one of the above-mentioned [1] to [35] or a pharmaceutically acceptable salt thereof, for preventing and/or treating rheumatism. [42] A method for preventing and/or treating rheumatism in mammals, comprising the steps of: administering an effective amount of the compound described in any one of the above-mentioned [1] to [35] or a pharmaceutically acceptable salt thereof to the mammal. [Effect of Invention]

The "compound represented by formula (1) or a salt thereof" (hereinafter, sometimes simply referred to as "the compound of the present invention") has excellent IRAK-4 inhibitory activity. Also, a certain aspect of the compound of the present invention exhibits higher selectivity for other kinases, especially FLT3. Furthermore, a certain aspect of the compound of the present invention exhibits lower genotoxicity. Furthermore, a certain aspect of the compound of the present invention can be used as an active ingredient of a medicine for preventing and/or treating diseases related to IRAK-4 inhibition, for example, for preventing and/or treating autoimmune diseases. Furthermore, a certain aspect of the compound of the present invention can be used as a reagent having IRAK-4 inhibitory activity.

The present invention will be specifically described below. Unless otherwise specified, in this specification, sometimes only "C" represents a carbon atom, "H" represents a hydrogen atom, "O" represents an oxygen atom, "S" represents a sulfur atom, and "N ” means a nitrogen atom. In addition, sometimes only "-C(O)-" represents a carbonyl group, "-COO-" represents a carboxyl group, "-S(O)-" represents a sulfinyl group, and "-S(O) ₂ - Represents a sulfonyl group, "-O-" represents an ether bond, and "-S-" represents a thioether bond (in this case, "-" represents a bond).

Unless otherwise specified, in this specification, an alkyl group should just be a linear, branched, cyclic, or a combination of these saturated hydrocarbon groups. Examples include: methyl, ethyl, propyl, butyl, and their isomers [normal (n), iso (iso), second (sec), third (t), etc.], or cyclopropyl Or a cycloalkyl group such as cyclobutyl. As the alkyl group, an alkyl group having 1 to 6 carbon atoms is exemplified. As another aspect, an alkyl group having 1 to 3 carbon atoms is exemplified. An alkyl group having 1 to 6 carbon atoms is sometimes described as a C _1-6 alkyl group.

The "alkoxy" may be straight-chain, branched, cyclic, or a combination thereof. For example: methoxy, ethoxy, propoxy, butoxy, isomers [normal (n), iso (iso), second (sec), third (t), etc.], Or a cycloalkoxy group such as cyclopropoxy or cyclobutoxy. As the alkoxy group, an alkoxy group having 1 to 6 carbon atoms is exemplified. As another aspect, an alkoxy group having 1 to 3 carbon atoms is exemplified. An alkoxy group having 1 to 6 carbon atoms is sometimes described as a C _1-6 alkoxy group.

"Alkylene" also includes linear or branched alkylene. Examples include: methylene, ethylidene, propylidene, butylene, methylmethylene, ethylmethylene, methylethylidene, 1,2-dimethylethylidene, 1, 1,2,2-Tetramethylethylene, or 1-methylbutylene. As the alkylene group, an alkylene group having 1 to 6 carbon atoms is exemplified. As another aspect, an alkylene group having 1 to 3 carbon atoms is exemplified. An alkylene group having 1 to 6 carbon atoms is sometimes described as a C _1-6 alkylene group. "Halogen" is fluorine (-F), chlorine (-Cl), bromine (-Br), or iodine (-I). As another aspect, -F or -Cl is exemplified. As yet another aspect, -F is exemplified. "Halo" means substituted by the same or different 1 to 7 halogens. As another aspect, it refers to substitution with the same or different 1 to 5 halogens. As yet another aspect, it refers to being substituted with 1 to 3 halogens. As yet another aspect, it means substituted with 1 halogen. Examples of substitution with -F are shown.

The "aromatic ring" is not particularly limited as long as it is an aromatic ring, and examples include monocyclic to tricyclic aromatic rings. As the aromatic ring, an aromatic hydrocarbon ring or an aromatic heterocyclic ring is exemplified. Specifically, benzene, naphthalene, phenanthrene, thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, pyrrole, pyrazole, imidazole, pyridine, pyrimidine, pyridine, pyrimidine, pyridone , pyrimidone, indole, isoindole, indazole, quinoline, isoquinoline, benzimidazole, benzotriazole, benzothiophene, benzofuran, benzothiazole, 呔𠯤, quinoline, pyrrole pyridine, or carbazole. The "aromatic ring group" may, for example, be a monovalent group formed by removing any one hydrogen atom from an aromatic ring. What is necessary is just a monocyclic to tricyclic aromatic ring group. For example, aryl or heteroaryl is exemplified.

The "aryl" may be a monocyclic to tricyclic aromatic hydrocarbon ring group. The aryl group also includes an aromatic hydrocarbon ring group condensed with a saturated hydrocarbon ring described below. Exemplary are 6-14 membered aryl groups. As another aspect, a 6-10 membered aryl group is exemplified. As yet another aspect, a 6-membered aryl group is exemplified. Specifically, phenyl, naphthyl, anthracenyl, phenanthrenyl, fenyl, indenyl, or 1,2,3,4-tetrahydronaphthyl are exemplified. In another aspect, it is phenyl, and in yet another aspect, it is naphthyl. The 6-10 membered aryl includes dihydroindenyl and 1,2,3,4-tetrahydronaphthyl.

The "heteroaryl" may be a monocyclic to tricyclic aromatic heterocyclic group containing 1 to 4 heteroatoms as ring-constituting atoms. As the hetero atom, O, S or N is exemplified. Exemplary are 5-14 membered heteroaryl groups. As another aspect, a 5-10 membered heteroaryl group is exemplified. As yet another aspect, a 5-6 membered heteroaryl group is exemplified. Specifically, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyrimidyl, ? Thienyl, benzofuryl, benzothiazolyl, thiazolyl, quinazolyl, pyrrolopyridyl, or carbazolyl.

As the "saturated ring", a saturated hydrocarbon ring or a saturated heterocyclic ring is exemplified. The saturated ring may have a bridge, and may be condensed with the above-mentioned aromatic ring. The "saturated hydrocarbon ring" may be any monocyclic to tricyclic saturated hydrocarbon ring. A 3-10 membered saturated hydrocarbon ring is exemplified. As another aspect, a 3-7 membered saturated hydrocarbon ring is exemplified. As yet another aspect, a 5- or 6-membered saturated hydrocarbon ring is exemplified. The saturated hydrocarbon ring may have a bridge, and may be condensed with the above-mentioned aromatic ring. Specifically, cyclopropane, cyclobutane, cyclopentane, cyclohexane, or adamantane are exemplified.

The "saturated heterocyclic ring" may be a monocyclic to tricyclic saturated heterocyclic ring containing 1 to 4 heteroatoms as ring-constituting atoms. As the hetero atom, O, S or N is exemplified. A 3-10 membered saturated heterocycle is exemplified. As another aspect, a 3-7 membered saturated heterocycle is exemplified. As yet another aspect, a 5- or 6-membered saturated heterocycle is exemplified. The saturated heterocyclic ring may have a bridge, and may be condensed with the above-mentioned aromatic ring. Specifically, tetrahydropyran, tetrahydrofuran, piperidine, pyrrolidine, azetidine, oxetane, aziridine, oxirane, tetrahydrothiopyran, tetrahydrothiophene, thioline, oxygen oxazepane, or piperazine.

As the "condensed ring", there are exemplified cyclic compounds in which two or more rings share two or more atoms and these atoms are bonded to each other, and in the cyclic compound, the above two or more rings are each independently 3 -7-membered saturated ring. The condensed ring may have 1-3 heteroatoms selected from O, S and N. As the condensed ring, a cyclic compound in which two rings share adjacent two atoms is exemplified.

The "spiro ring" is exemplified by a cyclic compound in which two rings contain one carbon atom in common, and in the cyclic compound, the above two rings are independently 3-7 membered saturated rings. The spirocycle may have 1-3 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 7-11 membered spiro ring. As the spiro ring, a 7- to 13-membered spiro ring is exemplified. As another aspect, a 7-11 membered spirocycle is exemplified. As yet another aspect, a 7-9 membered spirocycle is exemplified.

The "saturated ring group" may, for example, be a monovalent group formed by removing any one hydrogen atom from a saturated ring, or a group formed by removing one hydrogen atom from two different ring-forming atoms in a saturated ring. 2 valence base. A saturated hydrocarbon ring group or a saturated heterocyclic group is exemplified. Examples are 3-10 membered saturated ring groups. As another aspect, a 3-7 membered saturated ring group is exemplified. As yet another aspect, a 5- or 6-membered saturated ring group is exemplified.

The "saturated hydrocarbon ring group" may, for example, be a monovalent group formed by removing any one hydrogen atom from the saturated hydrocarbon ring, or remove one hydrogen atom from each of two different ring-forming atoms in the saturated hydrocarbon ring After the formation of the 2-valent base. Any monocyclic to tricyclic saturated hydrocarbon ring group may be used. The saturated hydrocarbon ring group may have a bridge, and may be condensed with the above-mentioned aromatic ring. A 3- to 10-membered saturated hydrocarbon ring group is exemplified. As another aspect, a 3-7 membered saturated hydrocarbon ring group is exemplified. As yet another aspect, a 5- or 6-membered saturated hydrocarbon ring group is exemplified. Specifically, as a monovalent group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or an adamantyl group is illustrated. Specifically, the divalent group may, for example, be a divalent group formed by further removing a hydrogen atom from a ring-forming atom different from the ring-forming atom in which a hydrogen atom was removed in the specific example of the above-mentioned monovalent group.

The "saturated heterocyclic group" includes, for example, a monovalent group formed by removing any one hydrogen atom from a saturated heterocyclic ring, or a hydrogen atom removed from each of two different ring-forming atoms in a saturated heterocyclic ring. After the formation of the 2-valent base. It may be a monocyclic to tricyclic saturated heterocyclic group containing 1 to 4 heteroatoms as ring constituting atoms. This saturated heterocyclic group may have a bridge, and may be condensed with the above-mentioned aromatic ring. As the hetero atom, O, S or N is exemplified. A 3-10 membered heterocyclic group is exemplified. As another aspect, a 3-7 membered saturated heterocyclic group is exemplified. As yet another aspect, a 5- or 6-membered saturated heterocyclic group is exemplified. As the monovalent group, specifically, tetrahydropyranyl, tetrahydrofuranyl, piperidyl, pyrrolidinyl, azetidinyl, oxetanyl, tetrahydrothiopyranyl, tetrahydrothiophenyl, 𠰌-line group, or piper-𠯤 group.

A "partially unsaturated ring group" is sufficient as long as a part of the saturated ring group is an unsaturated ring, and examples include a partially unsaturated hydrocarbon ring group (partially unsaturated hydrocarbon ring group) or a partially unsaturated heterocyclic group (partially unsaturated heterocyclic group). Cyclo). A 3- to 10-membered partially unsaturated ring group is exemplified. As another aspect, 3-7 membered partially unsaturated ring groups are exemplified. As yet another aspect, a 5- or 6-membered partially unsaturated ring group is exemplified.

The "partially unsaturated hydrocarbon ring group" only needs to have a part of the saturated hydrocarbon ring group be an unsaturated group. Specifically, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, or bicyclooctatriene are exemplified. The "partially unsaturated heterocyclic group" only needs to have a part of the saturated heterocyclic group be an unsaturated group. Specifically, dihydropyranyl, dihydrofuryl, dihydrothiopyranyl, dihydrothienyl, 1,2-dihydroquinolyl, or 1,2,3,4-tetrahydro Quinolinyl.

In the present invention, isomers include all of them unless otherwise specified. For example, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an alkylene group, an alkenylene group, and an alkynylene group include linear ones and branched ones. Furthermore, 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 carbons, etc. (R- or S-isomers) substances, isomers based on α- or β-configuration, enantiomers, or diastereomers, etc.), optically active substances with optical activity (D- or L-body, or d- or l- isomers), isomers (high polarity or low polarity), equilibrium compounds, rotamers, or mixtures of any proportion thereof based on chromatographic separation of polarity differences, or racemic mixtures are included in In the present invention.

In this specification, unless otherwise stated, the following symbols are obvious to practitioners, such as the following symbols: [化39] Indicates the bond with the other side of the paper (that is, the α-configuration), the following symbol: [Chemical 40] Indicates the bond with the near front side of the paper (ie β-configuration), the following symbol: [化41] Expressed as either α-configuration or β-configuration, or a mixture thereof.

Hereinafter, the compound represented by formula (1) or a salt thereof will be described in detail. [chem 42]

In this specification, "may be substituted" refers to being unsubstituted or having 1 to 5 substituents that are the same or different, unless otherwise specified. As another aspect, it means being unsubstituted or having the same or different 1 to 3 substituents. As yet another aspect, it means being unsubstituted or having one substituent. As a further aspect, it means unsubstituted.

As Rg, exemplify: following general formula (1-1): [Chemical 43] Or the following general formula (1-2): [Chemical 44] (a, b represent the bonding orientation).

R ¹ is, for example, -H, -F, -Cl, methyl, or C _1-3 alkoxy. As another aspect, exemplified: -H, or C _1-3 alkoxy. As yet another aspect, -H or methoxy is exemplified. The aforementioned R ¹ may be substituted with 1 to 3 identical or different substituents selected from group G ¹ . As the above-mentioned G ¹ group, exemplified by -F, hydroxyl, cyano, halogenated C _1-6 alkyl, C _1-4 alkoxy, phenyl, 5-6 membered heteroaryl, and 3-7 membered saturated A group of ring groups. As another aspect, G consisting of -F, hydroxyl, halogenated C _1-6 alkyl, C _1-4 alkoxy, 5-6 membered heteroaryl, and 3-7 membered saturated ring group is exemplified. ¹¹ groups. As yet another aspect, a ^G12 group consisting of -F, hydroxyl, _C1-4 alkoxy, 5-membered heteroaryl, and 4-5-membered saturated ring is exemplified. The phenyl group or 5-6 membered heteroaryl group in the above G ¹ group may be substituted by 1 to 3 same or different substituents selected from G ^Ar group. As the G ^Ar group, a group consisting of -F, -Cl, hydroxyl, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl, and -NH ₂ is exemplified. As another aspect, the G ^Ar1 group consisting of -F, -Cl, cyano, C _1-6 alkyl, and halogenated C _1-6 alkyl is exemplified.

R ² is, for example, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, or a 3-7 membered saturated ring group. As another aspect, a 3-7 membered saturated ring group is exemplified. The aforementioned R ² may be substituted with 1 to 3 identical or different substituents selected from group G ² . As the aforementioned ^G2 group, a group consisting of -F, hydroxyl, halogenated _C1-3 alkyl, and _C1-4 alkoxy is exemplified. As another aspect, the ^G21 group consisting of -F and hydroxyl is exemplified.

The following are specifically exemplified as the above-mentioned R ² . [chem 45] Moreover, as another aspect of the above-mentioned R ² , the following are specifically exemplified. [chem 46]

Moreover, as still another aspect of the above-mentioned R ² , the following are specifically exemplified. [chem 47] Moreover, as still another aspect of the above-mentioned R ² , the following are specifically exemplified. [chem 48]

As Cy, the following general formula (2-1) is illustrated. [chem 49]

An integer of 0 or 1 is exemplified as k. As another aspect, the integer 1 is exemplified. R ^Cy1 and R ^Cy2 are independently exemplified: -H, -F, hydroxyl, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, -NR ¹¹ R ¹² , phenyl, 5-6 membered heteroaryl, or 3-7 membered saturated ring group. As another aspect, -H, -F, C _1-6 alkyl, C _1-6 alkoxy, -NR ¹¹ R ¹² are exemplified. As yet another aspect, -NR ¹¹ R ¹² is exemplified. The phenyl or 5-6 membered heteroaryl in the above R ^Cy1 and R ^Cy2 may be substituted by 1 to 3 identical or different substituents selected from the above G ^Ar group. As the above-mentioned G ^Ar group, other than the above-mentioned G ^Ar group, aspects of the above-mentioned G ^Ar1 group are exemplified. The aforementioned R ^Cy1 and R ^Cy2 may be substituted with 1 to 3 identical or different substituents selected from the aforementioned G ¹ group. As the above-mentioned G ¹ group, in addition to the above-mentioned G ¹ group, aspects of the above-mentioned G ¹¹ to G ¹² groups are exemplified.

As the above R ¹¹ and R ¹² , each independently exemplifies: -H, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy C _{1- 6} alkyl, 3-7 membered saturated ring, phenyl, or 5-6 membered heteroaryl. As another aspect, exemplified: -H, C _1-6 alkyl, halogenated C _1-6 alkyl, 3-7 membered saturated ring group. Examples of the aforementioned 3-7 membered saturated ring group include cyclopropane, cyclobutane, cyclopentane, oxetane, or bicyclo[1.1.1]pentane. The aforementioned R ¹¹ and R ¹² may be substituted with 1 to 3 identical or different substituents selected from the aforementioned G ¹ group. As the above-mentioned G ¹ group, in addition to the above-mentioned G ¹ group, aspects of the above-mentioned G ¹¹ to G ¹² groups are exemplified.

The above R ¹¹ and R ¹² may also together form a 4-10 membered saturated ring or a 7-11 membered spiro ring. The above-mentioned 4-10 membered saturated ring and 7-11 membered spiro ring may have, in addition to N, 1 to 2 identical or different heteroatoms or -S(O ₂ )- selected from the group consisting of O and N . Examples of the aforementioned 4- to 10-membered saturated ring include azetidine, pyrrolidine, piperidine, phenoline, oxazepane, piperazine, or homopiperidine. As another aspect, piperidine, phenoline, or piperidine are exemplified. As yet another aspect, for example: phylloline or piperhexine.

Examples of the case where R ¹¹ and R ¹² together form a 4- to 10-membered saturated ring including a bridge are exemplified below. [chemical 50] (X has the same meaning as above)

Examples of the case where R ¹¹ and R ¹² together form a 7- to 11-membered spiro ring are exemplified below. [Chemical 51] (X has the same meaning as above)

Examples of the case where R ¹¹ and R ¹² together form a 4- to 10-membered saturated ring including a bridge are exemplified below. [Chemical 52] (X has the same meaning as above)

The above-mentioned 4-10 membered saturated ring or 7-11 membered spiro ring formed together by R ¹¹ and R ¹² may be substituted by 1 to 3 identical or different substituents selected from group G ³ . Examples of the above ^G3 group include: -F, hydroxyl, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkane Oxy-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)NH ₂ , -NR ¹³ S(O ₂ )R ¹⁴ , -S(O ₂ )NR ¹³ R ¹⁴ , -S(O ₂ )NH ₂ , -S(O ₂ )R ¹⁴ , phenyl, 5 -6-membered heteroaryl, and 3-7-membered saturated ring group. As another aspect, -F, C _1-6 alkyl, halogenated C _1-6 alkyl, -C(O)R ¹⁴ , -C(O)NR ¹³ R ¹⁴ are exemplified.

The phenyl group or 5-6 membered heteroaryl group in the above G ³ group may be substituted by 1 to 3 identical or different substituents selected from the above G ^Ar group. As the above-mentioned G ^Ar group, other than the above-mentioned G ^Ar group, aspects of the above-mentioned G ^Ar1 group are exemplified. Examples of R ¹³ above include: -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. As another aspect, exemplified: -H, C _1-6 alkyl, halogenated C _1-6 alkyl. As yet another aspect, -H is exemplified.

Examples of R ¹⁴ above include: 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. As another aspect, exemplified: C _1-6 alkoxy C _1-6 alkyl, 5-6 membered heteroaryl, or 3-7 membered saturated ring group. As yet another aspect, a 5-6 membered heteroaryl group is exemplified. Examples of the aforementioned 5-6 membered heteroaryl group include pyridine, oxazole, isoxazole and thiazole. As another aspect, pyridine is exemplified. The phenyl or 5-6 membered heteroaryl in the aforementioned R ¹³ and R ¹⁴ may be substituted by 1 to 3 identical or different substituents selected from the aforementioned G ^Ar group.

As the above-mentioned G ^Ar group, other than the above-mentioned G ^Ar group, aspects of the above-mentioned G ^Ar1 group are exemplified. The aforementioned R ¹³ and R ¹⁴ may also together form a 4-7 membered saturated ring or a 7-11 membered spiro ring. The above-mentioned 4-7 membered saturated ring and 7-11 membered spiro ring may have, in addition to N, 1 to 2 same or different heteroatoms or -S(O ₂ )- selected from the group consisting of O and N . Examples of the 4- to 7-membered saturated ring include azetidine, pyrrolidine, piperidine, phenoline, oxazepane, or piperidine. As another aspect, azetidine and pyrrolidine are illustrated. As yet another aspect, azetidine is exemplified.

As another aspect of the case where R ¹¹ and R ¹² together form a 4-10 membered saturated ring, and the above 4-10 membered saturated ring is phenoline or piperazine, the following are exemplified. [Chemical 53] As X, O or NR ¹⁵ is exemplified. As another aspect, NR ¹⁵ is exemplified. Examples of R ^Cy3 include C _1-4 alkyl and halogenated C _1-4 alkyl. As another aspect, a methyl group, an ethyl group, and an isopropyl group are illustrated. As yet another aspect, a methyl group is exemplified. Examples of R ¹⁵ above include: -H, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, -C (O)R ¹⁶ , -S(O ₂ )R ¹⁶ , -C(O)NR ¹⁶ R ¹⁷ , -C(O)OR ¹⁶ , or a 3-7 membered saturated ring group. As another aspect, a halogenated C _1-6 alkyl group, -C(O)R ¹⁶ , -S(O ₂ )R ¹⁶ , or -C(O)NR ¹⁶ R ¹⁷ is exemplified. As yet another aspect, -C(O)R ¹⁶ is exemplified.

Examples of R ¹⁶ above include: 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. As another aspect, exemplified: C _1-6 alkoxy C _1-6 alkyl, 5-6 membered heteroaryl, or 3-7 membered saturated ring group. As yet another aspect, a 5-6 membered heteroaryl group is exemplified. Examples of the aforementioned 5-6 membered heteroaryl group include pyridine, oxazole, isoxazole and thiazole. As another aspect, pyridine is exemplified. Examples of R ¹⁷ above include: -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 alkyl, phenyl, 5-6 membered heteroaryl, or 3-7 membered saturated ring. As another aspect, exemplified: -H, C _1-6 alkyl, halogenated C _1-6 alkyl. As yet another aspect, -H is exemplified. The phenyl or 5-6 membered heteroaryl in the above-mentioned R ¹⁶ and R ¹⁷ may be substituted by 1 to 3 same or different substituents selected from the above-mentioned G ^Ar group.

As the above-mentioned G ^Ar group, other than the above-mentioned G ^Ar group, aspects of the above-mentioned G ^Ar1 group are exemplified. The above-mentioned R ¹⁶ and R ¹⁷ may also together form a 4-7 membered saturated ring or a 7-11 membered spiro ring. The above-mentioned 4-7 membered saturated ring and 7-11 membered spiro ring may have, in addition to N, 1 to 2 same or different heteroatoms or -S(O ₂ )- selected from the group consisting of O and N . Examples of the 4- to 7-membered saturated ring include azetidine, pyrrolidine, piperidine, phenoline, oxazepane, or piperidine. As another aspect, azetidine and pyrrolidine are illustrated. As yet another aspect, azetidine is exemplified. The aforementioned R ¹⁵ may be substituted with 1 to 3 identical or different substituents selected from the aforementioned G ¹ group. As the above-mentioned G ¹ group, in addition to the above-mentioned G ¹ group, aspects of the above-mentioned G ¹¹ to G ¹² groups are exemplified.

As said R ¹⁵ , specifically, the following are exemplified. [Chemical 54]

Moreover, as another aspect of the above-mentioned R ¹⁵ , the following are specifically exemplified. [Chemical 55]

As yet another aspect of the case where R ¹¹ and R ¹² together form a 4-10 membered saturated ring, and the above 4-10 membered saturated ring is phenoline or piperazine, the following are exemplified. [Chemical 56] (R ^Cy3 , X have the same meaning as above)

The above R ^Cy1 and R ^Cy2 can also form a 4-7 membered saturated ring or a 7-11 membered spirocycle together. The aforementioned 4-7 membered saturated ring and 7-11 membered spiro ring have, in addition to N, 1 to 2 same or different heteroatoms or -S(O ₂ )- selected from the group consisting of O and N. Examples of the 4-7 membered saturated ring formed together by R ^Cy1 and R ^Cy2 include azetidine, pyrrolidine, and piperidine. As another aspect, piperidine is exemplified. The 4-7-membered saturated ring or the 7-11-membered spiro ring formed together by R ^Cy1 and R ^Cy2 may be substituted by 1 to 3 identical or different substituents selected from the above-mentioned G ¹ group. As the above-mentioned G ¹ group, in addition to the above-mentioned G ¹ group, aspects of the above-mentioned G ¹¹ to G ¹² groups are exemplified.

As specific compounds included in the present invention, the following compounds are exemplified, but not limited thereto. [Table 1]

In this specification, the "compound represented by formula (1)" can generally be understood as a free compound represented by formula (1). Moreover, the following salts are mentioned as its salt. That is, the type of the salt of the compound represented by formula (1) is not particularly limited, and may be either an acid addition salt or a base addition salt, and may also be in the form of an intramolecular counter ion. Especially when used as an active ingredient of a medicine, the salt of the compound represented by formula (1) is preferably a pharmaceutically acceptable salt. When disclosing its use as medicine in this specification, the salt of the compound represented by formula (1) can be generally understood as a pharmaceutically acceptable salt. The acid addition salts include, for example, acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, or phosphoric acid; or with formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid 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, etc. Acid addition salts of organic acids. Examples of base addition salts include base addition salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; and methylamine, 2-aminoethanol, arginine, lysine, or ornithine. Base addition salts of organic bases such as acids, etc. However, it goes without saying that the kind of salt is not limited thereto, and can be appropriately selected by a worker.

The compounds of the present invention include hydrate forms. In addition, the compounds of the present invention also include anhydrous forms. The compounds of the present invention include the form of solvates. In addition, the compounds of the present invention also include the form of ansolvates. The compounds of the present invention include crystalline forms. In addition, the compounds of the present invention also include amorphous forms. The compounds of the present invention also include forms labeled with various radioactive or non-radioactive isotopes. More specifically, the compound of the present invention includes the anhydrate and ansolvate of the "compound represented by formula (1)", or its hydrate and/or solvate, or further includes crystals thereof. In addition, the compound of the present invention includes anhydrous and ansolvate of the "salt of the compound represented by formula (1)", or hydrate and/or solvate of the salt thereof, or further includes crystals thereof.

The compound of the present invention may also include a pharmaceutically acceptable prodrug of the "compound represented by formula (1)". A pharmaceutically acceptable prodrug refers to a compound having a group that can be converted into an amine group, hydroxyl group, carboxyl group, etc. by solvolysis or under physiological conditions. For example, as the group that forms the prodrug of the relevant hydroxyl group and amino group, for example, an acyl group and an alkoxycarbonyl group are exemplified. In addition, as the group forming the prodrug of the carboxyl group, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second-butyl, third-butyl, amino, methyl Amino, ethylamino, dimethylamino, or diethylamino.

For example, it can be produced in the following manner: using a prodrug reagent such as a corresponding halide, according to a conventional method, introducing an appropriate prodrug-forming group into a compound selected from hydroxyl and amine groups of the present invention. After more than one arbitrary group, if necessary, perform isolation and purification according to conventional methods. In addition, a suitable prodrug-forming group can also be introduced into the carboxyl group of the compound of the present invention by using a prodrug-forming reagent such as a corresponding alcohol or amine according to a conventional method.

general manufacturing method The compound represented by formula (1) can be produced according to a known method, for example, the method shown below, the method based on them, or the method shown in the Examples. In addition, the raw material compounds in each of the following production methods can be obtained commercially, or can be produced using known methods described in "Compendium of Organic Synthesis Methods, Vol. I-XII (Wiley-Interscience)", for example.

Some intermediates can be used by introducing a protecting group or deprotecting them by known methods, such as the method described in "Peter G. M. Wuts, Greene's Protective Groups in Organic Chemistry, John Wiley & Sons, 2014".

The mixture of stereoisomers can be prepared by a known method, such as the method described in "E. L. Eloel, S. H. Wilen, Stereochemistry of Organic compounds, John Wiley & Sons, 1994", the method based on them, or the method shown in the Examples to separate. In addition, conglomerate can also be separated by the above method.

The reactions used in the synthesis of the compounds of the present invention are carried out in a selected appropriate solvent according to known methods. Suitable solvents are substantially nonreactive with the starting materials, intermediates, or products at the temperature at which the reaction is carried out (eg, a temperature ranging from the melting point to the boiling point of the solvent). The reaction can be carried out in a single solvent or a mixture of solvents. A solvent suitable for each reaction is utilized.

The reaction can be followed by an appropriate method according to known methods. For example, the product can be obtained using spectroscopic methods, nuclear magnetic resonance (NMR) such as ¹ H or ¹³ C, infrared spectrophotometer (IR), mass spectrometer (MS), high performance liquid chromatography (HPLC), thin layer Chromatography (TLC) etc. to track.

The compound represented by formula (1) and intermediates thereof can be produced by the synthesis method described below. Unless otherwise specified, R ¹ , R ² , R ¹¹ , R ¹² , R ¹⁵ , R ^cy3 , and Cy in the following reaction formulas or descriptions have the same meanings as above. In some cases, the compound of the present invention may be produced by a method other than the method described in the present specification by making appropriate use of the method described in the present specification and common technical knowledge in the technical field. Reaction formulas, examples, etc. are for the purpose of illustration and do not limit the scope of the present invention.

The abbreviations used in the following processes generally follow the abbreviations used in the technical field. The chemical abbreviations used in this specification and Examples are defined as follows, for example. DMF=N,N-dimethylformamide, DMSO=dimethylsulfene, THF=tetrahydrofuran, DME=1,2-dimethoxyethane, TFA=trifluoroacetic acid, h=hour, rt= Room temperature, RT=residence time, LG=leaving group.

The compound of the present invention represented by formula (1) can be produced, for example, according to the following reaction scheme. In the following flow, "STEP" refers to a step, for example, "STEP1" refers to step 1. [Chemical 57]

The compound represented by the formula (1) can be obtained, for example, by reaction scheme 1 (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. In addition, halo represents -Cl, -Br, or -I. Moreover, M represents various substituents that can react by coupling, such as ZnI or MgBr, boronic acid, boric acid ester, etc.) Manufactured by the method described in . The compounds represented by the formulas (4) to (9) can be obtained commercially, or can be produced according to known methods, such as the methods shown below, or standard methods.

STEP1 The compound represented by the formula (1) can be produced by the amidation reaction, or the amidation reaction, of the compound represented by the formula (4) and the compound represented by the formula (5). As the condensing agent for amidation, 1-propylphosphonic anhydride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, HATU, etc. can be used. As the nucleophile for amidation, HOBt, HOAt, etc. can be used. As the base, diisopropylethylamine or the like can be used. As a reaction solvent, DMF, dichloromethane, THF, etc. can be used, for example. The reaction temperature can generally be performed at 0°C to 150°C. The substituents of Cy, R ¹ , R ² can be converted into the compound represented by formula (1) by performing further transformations, such as deprotection, reduction, reductive amination, alkylation, fluorination, etc.

STEP2 The compound represented by the formula (5) can be produced by performing a coupling reaction with the compound represented by the formula (7) using a metal catalyst. More specifically, it can be produced by Suzuki-Miyaura coupling of a compound represented by formula (7) and a reagent represented by formula (6), or the like. As a reaction catalyst, for example, Pd(dppf)Cl ₂ , PdAmphos, Pd(PPh ₃ ) ₄ or the like can be used. As the base, cesium carbonate, cesium fluoride, sodium carbonate or the like can be used. As a reaction solvent, THF, 1,4-dioxane, DMF, acetonitrile, etc. can be used. The reaction temperature can generally be carried out at room temperature to 180°C.

STEP3 The compound represented by the formula (5) can be produced by performing a coupling reaction with the compound represented by the formula (9) using a metal catalyst. More specifically, it can be produced by Suzuki-Miyaura coupling or the like of a compound represented by formula (9) and a reagent represented by formula (8). As a reaction catalyst, for example, Pd(dppf)Cl ₂ , PdAmphos, Pd(PPh ₃ ) ₄ or the like can be used. As the base, cesium carbonate, cesium fluoride, sodium carbonate or the like can be used. As a reaction solvent, THF, 1,4-dioxane, DMF, acetonitrile, etc. can be used. The reaction temperature can generally be carried out at room temperature to 180°C.

The compound represented by formula (9) can be produced, for example, by performing a coupling reaction or a halogen-metal exchange reaction with a compound represented by formula (7) using a metal catalyst. More specifically, it can be produced by Suzuki-Miyaura coupling of a compound represented by formula (5) and bis(pinacolate) diboron or the like. As a reaction catalyst, for example, Pd(dppf)Cl ₂ or the like can be used. As the base, potassium acetate or the like can be used. As the reaction solvent, 1,4-dioxane or the like can be used. The reaction temperature can generally be performed at 40°C to 150°C.

[Chemical 58]

The compound represented by the formula (1) can be obtained, for example, by reaction scheme 2 (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. In addition, halo represents -Cl, -Br, or -I. Moreover, M represents various substituents that can react by coupling, such as ZnI or MgBr, boronic acid, boric acid ester, etc.) Manufactured by the method described in . Compounds represented by formulas (4), (6)-(8), (10), and (11) can be obtained commercially, or can be produced according to known methods, such as the methods shown below, or the standard methods .

STEP5 The compound represented by the formula (1) can be produced by performing a coupling reaction with the compound represented by the formula (10) using a metal catalyst. More specifically, it can be produced by Suzuki-Miyaura coupling of a compound represented by formula (10) and a reagent represented by formula (6), or the like. As a reaction catalyst, for example, Pd(dppf)Cl ₂ , PdAmphos, Pd(PPh ₃ ) ₄ or the like can be used. As the base, cesium carbonate, cesium fluoride, sodium carbonate or the like can be used. As a reaction solvent, THF, 1,4-dioxane, DMF, acetonitrile, etc. can be used. The reaction temperature can generally be carried out at room temperature to 180°C. The substituents of Cy, R ¹ , R ² can be converted into the compound represented by formula (1) by performing further transformations, such as deprotection, reduction, reductive amination, alkylation, fluorination, etc.

STEP6 The compound represented by formula (10) can be produced by amidation reaction or amidation reaction of the compound represented by formula (4) and the compound represented by formula (7). As the condensing agent for amidation, 1-propylphosphonic anhydride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, HATU, etc. can be used. As the nucleophile for amidation, HOBt, HOAt, etc. can be used. As the base, diisopropylethylamine or the like can be used. As a reaction solvent, DMF, dichloromethane, THF, etc. can be used, for example. The reaction temperature can generally be performed at 0°C to 150°C.

STEP7 The compound represented by formula (1) can be produced by coupling reaction with the compound represented by formula (11) using a metal catalyst. More specifically, it can be produced by Suzuki-Miyaura coupling of a compound represented by formula (11) and a reagent represented by formula (8), or the like. As a reaction catalyst, for example, Pd(dppf)Cl ₂ , PdAmphos, Pd(PPh ₃ ) ₄ or the like can be used. As the base, cesium carbonate, cesium fluoride, sodium carbonate or the like can be used. As a reaction solvent, THF, 1,4-dioxane, DMF, acetonitrile, etc. can be used. The reaction temperature can generally be carried out at room temperature to 180°C.

STEP8 The compound represented by the formula (9) can be produced, for example, by performing a coupling reaction or a halogen-metal exchange reaction with a compound represented by the formula (10) using a metal catalyst. More specifically, it can be produced by Suzuki-Miyaura coupling of a compound represented by formula (10) and bis(pinacolate) diboron or the like. As a reaction catalyst, for example, Pd(dppf)Cl ₂ or the like can be used. As the base, potassium acetate or the like can be used. As the reaction solvent, 1,4-dioxane or the like can be used. The reaction temperature can generally be performed at 40°C to 150°C.

[Chemical 59]

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

STEP9 The compound represented by the formula (10) can be produced by the reductive amination reaction of the compound represented by the formula (14). For example, an imine can be formed in the presence of R ¹¹ R ¹² NH followed by reduction of the imine using sodium triacetyloxyborohydride. As a reaction solvent, THF and dichloromethane can be used. The reaction temperature can generally be performed at 0°C to 80°C. The substituents of R ¹¹ R ¹² , R ¹ , R ² can be converted into the compound represented by formula (12) by performing further transformations, such as deprotection, reduction, alkylation, fluorination, etc.

STEP10 The compound represented by formula (14) can be produced by amidation reaction or amidation reaction of the compound represented by formula (5) and the compound represented by formula (15). As the condensing agent for amidation, 1-propylphosphonic anhydride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, HATU, etc. can be used. As the nucleophile for amidation, HOBt, HOAt, etc. can be used. As the base, diisopropylethylamine or the like can be used. As a reaction solvent, DMF, dichloromethane, THF, etc. can be used, for example. The reaction temperature can generally be performed at 0°C to 150°C.

[Chemical 60]

Among the compounds represented by the formula (1), Cy is represented by the formula (1-1-2), and the compound (16) wherein X represents NR ¹⁵ can be obtained by reaction scheme 4 (in the formula of each compound, Y ^CN represents a substituent capable of forming a CN bond such as a carboxyl group, an acyl chloride group, a haloalkyl group, an isocyanate group, etc.) and was produced by the method described in. The compounds represented by formulas (14), (17)-(20) can be obtained commercially, or can be produced according to known methods, such as the methods shown below, or standard methods.

STEP11 The compound represented by the formula (16) can be produced by a CN bond forming reaction such as amidation, acylation, alkylation, ureidation, etc. with the compound represented by the formula (18). More specifically, it can be produced by the amidation reaction of the compound represented by formula (18) and the reagent represented by formula (17), etc. As the condensing agent for amidation, 1-propylphosphonic anhydride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, HATU, etc. can be used. As the nucleophile for amidation, HOBt, HOAt, etc. can be used. As the base, diisopropylethylamine or the like can be used. As a reaction solvent, DMF, dichloromethane, THF, etc. can be used, for example. The reaction temperature can generally be performed at 0°C to 150°C. The substituents of substituents R ¹⁵ , R ¹ , R ² can be converted into compounds represented by formula (16) by performing further transformations, such as deprotection, reduction, reductive amination, alkylation, fluorination, and the like.

STEP12 The compound represented by formula (18) can be produced by deprotecting the compound represented by formula (19). The deprotection reaction may be performed 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).

STEP13 The compound represented by formula (19) can be produced by the reductive amination reaction of the compound represented by formula (14). For example, it can be produced by forming an imine in the presence of a compound represented by formula (20), and then reducing the imine using sodium triacetyloxyborohydride. As a reaction solvent, THF and dichloromethane can be used. The reaction temperature can generally be performed at 0°C to 80°C.

[Chemical 61]

Among the compounds represented by formula (7), Rg is represented by general formula (1-1), halo represents bromine, and ^R represents -OR ^al (R ^al is a substituted or unsubstituted C _1-3 alkyl group) The compound (21) can be obtained, for example, by reaction scheme 5 (in the formula of each compound, ^YCO represents -Cl, -Br, -I, OTf, OMs, or OTs and other leaving groups, or hydroxyl groups and other substitutions that can form CO bonds Also, R ^ac represents an acyl group such as an acetyl group or a cyclopropyl group. Also, L represents a leaving group such as -Cl, -Br, or pentafluorophenyl, or a substituent that can form an amide bond such as a hydroxyl group. PG represents a protecting group disclosed in Greene's Protective Groups in Organic Synthesis, published by John Wiley and Sons (2014 edition). It was produced by the method described in. The compounds represented by the formulas (22)-(30) can be obtained commercially, or can be produced according to known methods, such as the methods shown below, or standard methods.

STEP14 The compound represented by formula (21) can be produced by deprotecting the compound represented by formula (19). The deprotection reaction may be performed 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). The substituent of substituent R ^a1 can transform the compound represented by formula (21) by performing further transformations, such as deprotection, reduction, reductive amination, alkylation, fluorination, and the like.

STEP15 The compound represented by formula (22) can be produced by a C-O bond forming reaction such as alkylation of a compound represented by formula (24) and a compound represented by formula (23), Mitsunobu reaction, or the like. More specifically, it can be produced by, for example, an alkylation reaction of a compound represented by formula (24) and a reagent represented by formula (23). As the alkylating agent, methyl iodide or the like can be used. As the base, diisopropylethylamine, potassium carbonate and the like can be used. As a reaction solvent, DMF, dichloromethane, THF, etc. can be used, for example. The reaction temperature can usually be carried out at -78°C to 150°C.

STEP16 The compound represented by formula (24) can be produced by protecting the compound represented by formula (25). The protection reaction may 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).

STEP17 The compound represented by formula (25) can be produced by deacylating the compound represented by formula (26). More specifically, it can be produced by hydrolyzing the compound represented by the 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. The reaction temperature can usually be carried out at room temperature to 100°C.

STEP18 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 a reaction solvent, THF or the like can be used. The reaction temperature can usually be performed at -20°C to 80°C.

STEP19 The compound represented by formula (27) can be produced by brominating the compound represented by formula (28) in the presence of a base. As the brominating agent, bromine, NBS or the like can be used. As the acid, hydrobromic acid or the like can be used. As the reaction solvent, acetic acid or the like can be used. The reaction temperature can usually be carried out at room temperature to 60°C.

STEP20 The compound represented by formula (28) can be produced by amidation reaction, or acylation reaction, etc. of the compound represented by formula (30) and the compound represented by formula (29). As the acylation agent, an acid anhydride such as acetic anhydride or the like can be used. As the condensing agent for amidation, 1-propylphosphonic anhydride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, HATU, etc. can be used. As the nucleophile for amidation, HOBt, HOAt, etc. can be used. As the base, diisopropylethylamine or the like can be used. As a reaction solvent, DMF, dichloromethane, THF, etc. can be used, for example. The reaction temperature can generally be performed at 0°C to 150°C.

[chem 62]

Among the compounds represented by the formula (10), Rg is represented by the general formula (1-1), R ¹ represents the compound represented by -OR ^al (R ^al is a substituted or unsubstituted C _1-3 alkyl group) (31) For example, by reaction scheme 6 (in the formula of each compound, Y ^CO represents a leaving group such as -Cl, -Br, -I, OTf, OMs, or OTs, or a substituent capable of forming a CO bond such as a hydroxyl group. ) by the method described in ). The compound represented by the formula (32) can be obtained commercially, or can be produced according to a known method, for example, the method shown below, or a standard method thereof.

STEP21 The compound represented by the formula (31) can be produced by CO bond forming reactions such as alkylation of the compound represented by the formula (32) and the compound represented by the formula (23), Mitsunobu reaction. More specifically, it can be produced by the Mitsunobu reaction of a compound represented by formula (32) and a reagent in which Y ^CO represents a hydroxyl group in formula (23), or the like. As a reagent for the Mitsunobu reaction, diethyl azocarboxylate, triphenylphosphine, and the like can be used. As a reaction solvent, THF, toluene, or the like can be used. The reaction temperature can usually be performed at 0°C to 110°C.

[chem 63]

Among the compounds represented by the formula ( ^{1 )} , the _compound ( ³³ ) For example, by reaction scheme 7 (in the formula of each compound, Y ^CO represents -Cl, -Br, -I, OTf, OMs, or OTs and other leaving groups, or hydroxyl groups, etc. can form CO bond substituents. Also, PG represents a protecting group disclosed in Greene's Protective Groups in Organic Synthesis, published by John Wiley and Sons (2014 edition). It was produced by the method described in. The compounds represented by formula (23), formula (34), and formula (35) can be obtained commercially, or can be produced according to known methods, such as the methods shown below, or standard methods.

STEP22 The compound represented by formula (33) can be produced by deprotecting the compound represented by formula (34). The deprotection reaction may be performed 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). The substituent of substituent R ^a1 can transform the compound represented by formula (33) by performing further transformations, such as deprotection, reduction, reductive amination, alkylation, fluorination, etc.

STEP23 The compound represented by the formula (34) can be produced by CO bond forming reactions such as alkylation of the compound represented by the formula (35) and the compound represented by the formula (23), Mitsunobu reaction. More specifically, it can be produced by an alkylation reaction of a compound represented by formula (35) with a reagent in which Y ^CO represents a halogen group such as -Br or -I in formula (23). As the base, diisopropylethylamine, cesium carbonate and the like can be used. As a reaction solvent, DMF, dichloromethane, THF, etc. can be used, for example. The reaction temperature can generally be performed at 0°C to 150°C.

[chem 64]

Among the compounds represented by formula (7), Rg is compound (36) represented by general formula (1-2), which can be produced by the method described in Reaction Scheme 8, for example. The compounds represented by formulas (37) to (40) can be obtained commercially, or can be produced according to known methods, such as the methods shown below, or standard methods.

STEP24 The compound represented by formula (36) can be produced by the cyclization reaction of the compound represented by formula (37). As the base, potassium carbonate, DBU, and the like can be used. As the reaction solvent, DMF or the like can be used. The reaction temperature can generally be carried out at 0°C to 180°C. The substituent of the substituent R ¹ can be converted into a compound represented by formula (36) by performing further transformations such as deprotection, reduction, reductive amination, alkylation, fluorination, and the like.

STEP25 The compound represented by formula (37) can be produced by reacting the compound represented by formula (38) with O-(mesitylenesulfonyl)hydroxylamine. As a reaction solvent, chloroform and dichloromethane can be used. The reaction temperature can be usually carried out at 0°C to 50°C.

STEP26 The compound represented by formula (38) can be produced by cyanating the compound represented by formula (39). As a cyanation agent, sodium cyanide, potassium cyanide, etc. can be used. As a reaction solvent, ethanol, water, DMF, etc. can be used. The reaction temperature can generally be performed at 0°C to 120°C.

STEP27 The compound represented by formula (39) can be produced by brominating the compound represented by formula (40). As the brominating agent, N-bromosuccinimide, bromine, or the like can be used. As a reaction solvent, ethanol, water, DMF, etc. can be used. The reaction temperature can generally be performed at 0°C to 120°C.

[chem 65]

Among the compounds represented by formula (6), M represents Z (Z represents borane derivatives such as boric acid B(OH) ₂ or boric acid esters.) Compound (41) can be obtained, for example, by reaction scheme 8 (each compound In the formula, LG ¹ represents, for example, a leaving group such as -Cl, -Br, -I, OTf, OMs, or OTs.) and produced by the method described. The compounds represented by formulas (42) to (46) can be obtained commercially, or can be produced according to known methods, such as the methods shown below, and standard methods.

STEP28 The compound represented by formula (41) can be produced by subjecting the compound represented by formula (42) to C-H borylation using an iridium catalyst. As the borane source, for example, bis(pinacolate)diboron can be used. As a reaction solvent, THF can be used. The reaction temperature can generally be performed at 20°C to 80°C.

STEP29 The compound represented by formula (42) can be produced by etherifying the compound represented by formula (44) and the compound represented by formula (43) under basic conditions. As the base, for example, sodium hydride or sodium hydroxide can be used. As the catalyst, for example, tetrabutylammonium chloride can be used. As a reaction solvent, THF, DMF, and dichloromethane can be used. The reaction temperature can generally be performed at 0°C to 150°C.

STEP30 The compound represented by formula (42) can be produced by etherifying the compound represented by formula (46) and the compound represented by formula (45) under basic conditions. As the base, for example, sodium hydride or sodium hydroxide can be used. As the catalyst, for example, tetrabutylammonium chloride can be used. As a reaction solvent, THF, DMF, and dichloromethane can be used. The reaction temperature can generally be performed at 0°C to 150°C.

STEP31 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 performed at 0°C to 40°C.

[chem 66]

The compound represented by formula (6), for example, can be detached from groups such as -Cl, -Br, -I, OTf, OMs, or OTs by reaction scheme 10 (in the formula of each compound, LG ¹ for example. Also, halo represents- Cl, -Br, or -I. In addition, M represents various substituents capable of reacting by coupling, such as ZnI or MgBr, boronic acid, boric acid ester, etc.) and produced by the method described. Compounds represented by formulas (8), (44), (45), (47), and (48) can be obtained commercially, or can be produced according to known methods, such as the methods shown below, or the standard methods .

STEP32 The compound represented by the formula (6) can be produced, for example, by performing a coupling reaction or a halogen-metal exchange reaction with a compound represented by the formula (8) using a metal catalyst. More specifically, it can be produced by Suzuki-Miyaura coupling of a compound represented by formula (6) and bis(pinacolate) diboron or the like. As a reaction catalyst, for example, Pd(dppf)Cl ₂ or the like can be used. As the base, potassium acetate or the like can be used. As the reaction solvent, 1,4-dioxane or the like can be used. The reaction temperature can generally be performed at 40°C to 150°C.

STEP33 The compound represented by formula (8) can be produced by etherifying the compound represented by formula (47) and the compound represented by formula (44) under basic conditions. As the base, for example, sodium hydride or sodium hydroxide can be used. As the catalyst, for example, tetrabutylammonium chloride can be used. As a reaction solvent, THF, DMF, and dichloromethane can be used. The reaction temperature can generally be performed at 0°C to 150°C.

STEP34 The compound represented by formula (8) can be produced by etherifying the compound represented by formula (48) and the compound represented by formula (45) under basic conditions. As the base, for example, sodium hydride or sodium hydroxide can be used. As the catalyst, for example, tetrabutylammonium chloride can be used. As a reaction solvent, THF, DMF, and dichloromethane can be used. The reaction temperature can generally be performed at 0°C to 150°C.

STEP35 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 performed at 0°C to 40°C.

The production method of the compound of the present invention is not limited to the method described here. For example, the compound of the present invention can be produced by modifying and transforming the substituent of the precursor compound by combining one or more reactions described in general chemical literature and the like.

As an example of the production method of the compound containing an asymmetric carbon in the compound of the present invention, the following methods can be mentioned: a production method using asymmetric reduction; using a commercially available product that is optically active in advance using a part corresponding to the asymmetric carbon; (Can be prepared by a known method or based on a known method) the method of the raw material compound; the method of optically resolving or producing an optically active compound by an enzyme, etc. In addition, there is also a method of separating the compound of the present invention or its precursor into optically active isomers by conventional methods. As this method, for example, there are methods such as: performing high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC) using an optically active column; forming a salt with an optically active reagent and performing fractional crystallization; After separation, release the classical optical fractional crystallization method of the formation of the salt; or the method of separating and purifying the diastereomeric isomer formed by condensation with an optically active reagent, and then decomposing it again. When the precursor is isolated and used as an optically active substance, the compound of the present invention having optical activity can be produced by subsequently performing the production method shown previously.

In the compound of the present invention, when the compound contains acidic functional groups such as carboxyl group, phenolic hydroxyl group, or tetrazole ring, it can also be prepared into pharmaceutically acceptable salts (such as inorganic salts with sodium, etc., or with Organic salts such as triethylamine). For example, when an inorganic salt is to be obtained, it is preferable to dissolve the compound of the present invention in water containing hydroxide, carbonate, bicarbonate, etc. corresponding to the desired inorganic salt. In this reaction, a water-miscible inert organic solvent such as methanol, ethanol, acetone, or dioxane may also be mixed. Sodium salt solutions can be obtained, for example, by using sodium hydroxide, sodium carbonate or sodium bicarbonate.

In addition, in the compound of the present invention, when the compound contains the amino group contained therein, or other basic functional groups, or contains an aromatic ring (such as a pyridine ring, etc.) These are prepared into pharmaceutically acceptable salts (for example, salts with inorganic acids such as hydrochloric acid or salts with organic acids such as acetic acid) by known methods. For example, when a salt with a mineral acid is to be obtained, it is preferred to dissolve the compound of the present invention in an aqueous solution containing the desired mineral acid. In this reaction, a water-miscible inert organic solvent such as methanol, ethanol, acetone, or dioxane may also be mixed. A hydrochloride solution can be obtained, for example, by using hydrochloric acid.

When a solid salt is required, the solid salt can be obtained by evaporating the solution or adding a certain degree of polar water-miscible organic solvent such as n-butanol and methyl ethyl ketone. Various compounds described in the present invention can be purified by known methods, such as various chromatography methods (column, flash column, thin layer, high performance liquid phase, supercritical fluid).

A certain aspect 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 aspect of the compound of the present invention can be used to prevent and/or treat diseases related to IRAK-4 inhibition. The diseases related to IRAK-4 inhibition are described in detail. The diseases related to IRAK-4 inhibition are diseases that will be effective through IRAK-4 inhibition. More specifically, as long as it is by blocking TLRs or IL-1 family signals The diseases that can be prevented and/or treated by inhibiting the production of inflammatory mediators such as TNFα or IL-6 by delivery system are not particularly limited.

The IRAK-4 inhibitory activity can be measured, for example, by the method shown in Test Example 1 or 2 below. Diseases related to IRAK-4 inhibition are not particularly limited as long as they are diseases that can be effective by IRAK-4 inhibition. Specifically, for example, acute or chronic inflammation, autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, etc.), autoinflammatory diseases (TNF receptor-associated periodic syndrome (TRAPS), familial Mediterranean fever, cryopyrin-associated periodic syndromes (Cryopyrin-associated periodic syndromes), high IgD syndrome, etc.), metabolic diseases (gout, etc.), etc.

A certain aspect of the compound of the present invention has a TLR/IL-1β signal inhibitory effect as shown in the following test examples, and can be used as an active ingredient of medicine. In particular, a certain aspect of the compound of the present invention is preferably used for the prevention and/or treatment of diseases related to IRAK-4 signals.

A certain aspect of the compound of the present invention shows higher selectivity for other kinases. Examples of other kinases include FLT3, ITK, CK2, IKKb, JAK1, Syk, PKCθ, or p38. As another aspect, in particular, FLT3 is exemplified. A certain aspect of the medicine of the present invention can be used to prevent and/or treat diseases related to IRAK-4 signal, 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 the following Test Example 3 is illustrated.

A certain aspect of the medicine of the present invention can be prepared as a medicine containing the compound represented by formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient, but the scope of the medicine of the present invention also includes the following situations: administration in the form of a prodrug The given compound or its pharmaceutically acceptable salt is metabolized in the living body to produce the compound represented by formula (1) or its pharmaceutically acceptable salt.

The route of administration of the medicine of a certain aspect of the present invention is not particularly limited, for example, oral administration, subcutaneous administration, intradermal administration, intramuscular injection, intravenous administration, nasal administration, intravaginal administration, etc. An appropriate choice is made from intrarectal administration, local administration to the affected area, and the like.

As the medicine of the present invention, the compound represented by the formula (1) or its pharmaceutically acceptable salt can be used directly, preferably adding one kind of or two or more pharmaceutically acceptable carriers to prepare a pharmaceutical composition and administer it. Also, as the pharmaceutically active ingredient of the present invention, a hydrate or solvate of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof can also be used.

As the dosage form for formulating the above-mentioned pharmaceutical composition, there may be mentioned: tablets, powders, granules, syrups, suspensions, capsules, inhalants, or injections, etc. In order to manufacture these preparations, use these Various carriers corresponding to the preparation. For example, as a carrier of oral preparations, excipients, binders, lubricants, fluidity enhancers, or coloring agents may be mentioned. As for the inhalant, it can be exemplified: directly inhaling the powder of the pharmaceutical composition or the liquid medicine obtained by dissolving or suspending the pharmaceutical composition in a solvent, or inhaling after making a mist with a nebulizer or a nebulizer called NEBULIZER method etc. Also, when preparing injections and the like, distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, propylene glycol, polyethylene glycol, etc. are generally used as diluents. Bactericides, preservatives, stabilizers, isotonic agents, or analgesics can also be further added as needed. The inclusion compound can also be prepared by including the compound of the present invention with cyclodextrin, and then used as the medicine of the present invention.

When administering a medicine of a certain aspect of the present invention, it is only necessary to select an appropriate dosage form and administer through an appropriate route. For example, it can be administered orally in dosage forms such as tablets, powders, granules, syrups, suspensions, or capsules. Also, it can be administered through the respiratory tract in the form of an inhalant. In addition, it can be administered subcutaneously, intradermally, intravascularly, intramuscularly, or intraperitoneally in a dosage form including injection by dripping. Furthermore, it can be administered transmucosally in dosage forms such as sublingual preparations or suppositories, and can be administered transdermally in dosage forms such as gels, lotions, ointments, creams, or sprays. In addition, it can be administered in the form of sustained preparations, such as sustained-release injections, embedded preparations (such as film preparations, etc.).

The administration time of a certain aspect of the medicine of the present invention is not particularly limited. In principle, the administration is performed at the time when the clinical symptoms of the disease are judged to be manifested, and generally lasts for several weeks to one year. However, the administration time may be further extended according to the disease condition, or the administration may be continued after recurrence of clinical symptoms. Furthermore, even in a state where clinical symptoms do not appear, prophylactic administration can be performed according to the judgment of a clinician. The dose of the medicine of a certain aspect of the present invention is not particularly limited. For example, when the medicine of the present invention is orally administered, generally, an adult can administer 0.01 to 1000 mg of the active ingredient per dose. Regarding the frequency of administration in this case, it can be administered once to daily within 6 months, preferably once/day.

The dose, time and frequency of administration per day and/or once can be determined according to the patient's age, weight, physical health, type and severity of the disease to be treated, route of administration, and dosage form (carrier has Sustained release of active ingredients, etc.) and other conditions are appropriately increased or decreased.

When a certain aspect of the medicine of the present invention is used to prevent and/or treat the above-mentioned diseases, a certain aspect of the medicine of the present invention can be used simultaneously with one or more medicines selected from the medicines shown below , or at different times together. Furthermore, a certain aspect of the medicine of the present invention can also be administered together with the medicines exemplified above as a so-called mixture. Regarding the mixture, not only the administration form in which the active ingredient is administered in the form of a complete mixture like a typical composition, but also the administration form of a non-mixed combination in which each active ingredient is prepared and administered separately from a plurality of containers Form, set, packaging.

As a drug that can be used in combination with a certain aspect of the present invention, for example, immunosuppressants (tacrolimus, cyclosporine, rapamycin, mycophenolate mofetil, interferon preparations, cyclophosphine, etc.) amide, azathioprine, methotrexate, etc.), anti-inflammatory drugs (steroids (prednisolone, dexamethasone, betamethasone, cortisone), non-steroidal anti-inflammatory drugs (NSAIDs) (buproxen fen, celecoxib), disease-modifying antirheumatic drugs (gold preparations, methotrexate, leflunomide, sulfasalazine, penicillamine, iguratimod, chloroquine, tofacitinib, etc.), Anti-malarial drugs (hydroxychloroquine, etc.), multiple sclerosis drugs (interferon, anti-α4 integrin preparations, fingolimod, mitoxantrone, etc.), anti-cytohormone preparations (anti-TNFα preparations, anti-IL-6 preparations, anti-IL-12/23 preparations, etc.). In addition, biological agents (anti-CD20 preparations, CTLA-4-Ig, etc.) used for the treatment of autoimmune diseases, etc., for abnormal uric acid metabolism Drugs (colchicine, probenecid, bucolon, benzbromocoumarone, allopurinol, etc.), hypoglycemic drugs (alogliptin, nateglinide, acarbose, metformin, pyrrolidin ketones, insulin preparations, etc.), antihypertensive drugs (imidapril, valsartan, candesartan, etc.), bile secretion promoting drugs (ursodeoxycholic acid), bronchodilators (as adrenaline β2 agonists salmeterol and albuterol, anticholinergics such as ipratropium and tiotropium), drugs for the treatment of allergic diseases (theophylline, etc.), antiallergic drugs (fexofenadine, epinastine, Olopatadine, loratadine, cetirizine, bepotastine, codotifen, cromolyn sodium, pyramolast, chlorpheniramine, etc.), leukotriene antagonists (Zarul Dilast, Montelukast, Prenukast, etc.), antihyperlipidemic drugs (atorvastatin, simvastatin, Clibite, bezafibrate, probucol, elastase, eicosapentaene ethyl ester, etc.), neurotransmitter modifiers (donepezil, galantamine, memantine, etc.), antioxidants (vitamin E, acetylcysteine, carnitine, betaine, pentoxifylline, etc. ), antibiotics (β-lactamide-based, macrolide-based, tetracycline-based, aminoglycoside-based, quinolinone-based, and various preparations, chloramphenicol, etc.). Furthermore, it can also be used in combination with various agents created in the future. Such concomitant drugs are not limited in any way as long as they are clinically meaningful combinations.

A compound of an aspect of the present invention includes a compound having excellent safety (various toxicity or safety pharmacology) or pharmacokinetic properties, and its usefulness as a pharmaceutical active ingredient can be confirmed, for example, by the method shown below.

Examples of tests related to safety include, but are not limited to, the tests listed below. Including: cytotoxicity test (test using HL60 cells or liver cells, etc.), genotoxicity test (Ames test, mouse lymphoma TK test, chromosomal abnormality test, micronucleus test, etc.), skin sensitivity test (Buehler's test ( Buehler test) method, GPMT (Guinea pig maximization test, guinea pig maximization test) method, APT (Atopic patch test, ectopic patch test) method, LLNA test, etc.), skin photosensitivity test (adjuvant and cuticle peeling method) etc.), eye irritation test (single eye drop, short-term continuous eye drop, repeated eye drop, etc.), safety pharmacological test for cardiovascular system (telemetry, APD (Action potential duration, action potential time) method, hERG Obstruction evaluation method, etc.), safety pharmacological tests for the central nervous system (FOB (Functional Observation Battery, function observation combination test) method, Irwin's improved method, etc.), safety pharmacological tests for the respiratory system (using a respiratory function measurement device measurement method, measurement method using blood gas analysis equipment, etc.), general toxicity test, reproductive and developmental toxicity test, etc.

In addition, tests related to pharmacokinetic performance include, for example, the tests listed below, but are not limited to those listed here. Including: Cytochrome P450 enzyme inhibition or induction test, cell permeability test (test using CaCO-2 cells, MDCK cells, etc.), drug transporter ATPase test, oral absorption test, blood drug concentration transition test, Metabolism test (stability test, metabolic molecule type test, reactivity test, etc.), solubility test (solubility test by turbidity method, etc.), etc.

The usefulness of a certain aspect of the compound of the present invention as an active ingredient of medicine can be confirmed, for example, by conducting a cytotoxicity test. As the cytotoxicity test, methods using various cultured cells, such as HL-60 cells as human preleukemic cells, primary isolated cultured cells of liver cells, neutrophil fractions prepared from human peripheral blood, etc., can be exemplified . This test can be implemented by the method described below, but it is not limited to this description. Prepare cells into a cell suspension of 10 ⁵ to 10 ⁷ cells/ml, and dispense 0.01 mL to 1 mL of the suspension into microtubes or microplates, etc. Add 1/100 times to 1 times the amount of the cell suspension to the solution in which the compound is dissolved, and culture the cells at a final concentration of the compound such as 0.001 μM to 1000 μM at 37°C and 5% CO ₂ Incubate for 30 minutes to several days. After the culture, the cell viability was evaluated by the MTT method or the WST-1 method (Ishiyama, M., et al., In Vitro Toxicology, 8, p.187, 1995) or the like. The usefulness as a pharmaceutical active ingredient can be confirmed by measuring the cytotoxicity of the compound to cells.

The usefulness of a certain aspect of the compound of the present invention as an active ingredient of medicine can be confirmed, for example, by conducting a genotoxicity test. Examples of genotoxicity tests include Ames test, mouse lymphoma TK test, chromosomal abnormality test, and micronucleus test. Ames test refers to the method of using specified strains of Salmonella, Escherichia coli, etc. to culture the bacteria on a petri dish mixed with compounds to determine the reverse mutation (refer to the 1999 Japanese Medical Review No. 1604 "Genetoxicity Test II-1. Genotoxicity test, etc. in the "Guidelines"). In addition, the mouse lymphoma TK test refers to the gene mutation ability detection test using the thymidine kinase gene of mouse lymphoma L5178Y cells as a target (refer to II -3. Mouse lymphoma TK test; 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 chromosomal abnormality test refers to the method of co-cultivating mammalian cultured cells and compounds, fixing the cells, staining and observing the chromosomes, and thereby determining the activity that causes chromosomal abnormalities (refer to the 1999 Japanese Medical Trial No. 1604 "Genetics Toxicity test guidelines "II-2. Chromosomal abnormality test using mammalian cultured cells, etc.). Furthermore, the micronucleus test is a test for evaluating the ability to form micronuclei caused by chromosomal abnormalities, and there is a method using rodents (in vivo test) (refer to II- 4. Micronucleus test using rodents; Hayashi, M. et al., Mutat. Res., 312, pp. 293-304, 1994; Hayashi, M. et al., Environ. Mol. Mutagen., 35, pp. 234-252, 2000), and methods using cultured cells (in vitro assay) (Fenech, M. et al., Mutat. Res., 147, pp. 29-36, 1985; Miller, B., et al ., Mutat. Res., 392, pp. 45-59, 1997) etc. By using any one or two or more of these methods to clarify the genotoxicity of the compound, the usefulness as a pharmaceutical active ingredient can be confirmed.

The fact that a certain aspect of the compound of the present invention can be used as an active ingredient of a medicine can be confirmed, for example, by performing a skin sensitivity test. In the skin sensitivity test, as a skin sensitivity test using guinea pigs, there are Buehler's test method (Buehler, E. V. Arch. Dermatol., 91, pp. 171-177, 1965), GPMT method (Magnusson, B. et al., J. Invest. Dermatol., 52, pp. 268-276, 1969)) or APT method (adjuvant & patch method (Sato, Y. et al., Contact Dermatitis, 7, pp. 225-237, 1981)) etc. Furthermore, as a skin sensitivity 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 using any one or two or more of these methods to clarify the skin sensitivity of the compound, the usefulness as a pharmaceutical active ingredient can be confirmed.

The fact that a certain aspect of the compound of the present invention can be used as an active ingredient of medicine can be confirmed, for example, by performing a skin photosensitivity test. As a skin photosensitivity test, a skin photosensitivity test using guinea pigs can be exemplified (see "Explanation of Non-clinical Test Guidelines for Pharmaceutical Products 2002", 1-9 published by Nippon Yakuji Daily, 2002: Skin photosensitivity test, etc.) Etc., as the method, adjuvant and keratin stripping (Adjuvant and Strip) method (Ichikawa, H. et al., J. Invest. Dermatol., 76, pp.498-501, 1981), Harber method (Harber, L.C., Arch. Dermatol.,96, pp.646-653, 1967), horio method (Horio, T., J. Invest. Dermatol., 67, pp.591-593, 1976), Jordan method ( Jordan, W.P., Contact Dermatitis, 8, pp.109-116, 1982), Kochever method (Kochever, I.E. et 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, L.J., J. Soc. Cosm. Chem., 17, pp.123-130, 1966), etc. By using any one or two or more of these methods to clarify the skin photosensitivity of the compound, the usefulness as a pharmaceutical active ingredient can be confirmed.

The fact that a certain aspect of the compound of the present invention can be used as an active ingredient of a medicine can be confirmed, for example, by performing an eye irritation test. Examples of eye irritation tests include a single eye drop test using rabbit eyes, monkey eyes, etc. (only one eye drop), and a short-term continuous eye drop test (multiple eye drops at regular intervals in a short period of time). , and repeated eye drops test method (continuous several days to dozens of days, intermittently repeated eye drops), etc., there is a basis to improve the Draize score (Fukui, N. et al., Gendai no Rinsho, 4 (7), pp. 277-289, 1970) etc. to evaluate eye irritation symptoms for a certain period of time after eye drops. By using any one or two or more of these methods to clarify the eye irritation of the compound, the usefulness as a pharmaceutical active ingredient can be confirmed.

A certain aspect of the compound of the present invention can be used as an active ingredient of a medicine, which can be confirmed, for example, by conducting a safety pharmacological test on the cardiovascular system. As a safety pharmacological test for the cardiovascular system, for example: telemetry (a method for measuring the effects of administering a compound without anesthesia on electrocardiogram, heart rate, blood pressure, blood flow, etc. (Shigeru Kanno, Hiroichi Ju, Yoshiro Nakada The electrocardiogram, echocardiography, blood pressure, and pathological examination of animals used in basic and clinical studies were published in 2003 by Maruzen Co., Ltd.), APD method (a method for measuring the duration of myocardial cell action potential (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 inhibition evaluation method (Patch clamp method (Chachin, M. et al., Nippon Yakurigaku Zasshi, 119, pp. 345-351, 2002), binding assay (Gilbert, JD et 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.) etc. by using any one or two or more of these methods to clarify the effect of the compound on the cardiovascular system , can confirm the usefulness as an active ingredient of medicine.

A certain aspect of the compound of the present invention can be used as an active ingredient of medicine, which can be confirmed, for example, by conducting a safety pharmacological test on the central nervous system. As a safety pharmacological test for the central nervous system, for example: FOB method (functional observation comprehensive evaluation method (Mattson, J. L. et al., J. American College of Technology, 15 (3), pp. 239- 254, 1996)), Irwin's improved method (the method of evaluating general symptoms and behavior observation (Irwin, S. Comprehensive Observational Assessment (Berl.) 13, pp. 222-257, 1968), etc. By using these methods Any one or two or more methods to clarify the effect of the compound on the central nervous system can confirm the usefulness as a pharmaceutical active ingredient.

A certain aspect of the compound of the present invention can be used as an active ingredient of medicine, which can be confirmed, for example, by conducting safety pharmacological tests on the respiratory system. As a safety pharmacological test for the respiratory system, for example, a measurement method using a respiratory function measurement device (measurement of respiratory rate, 1st ventilation volume, minute ventilation volume, etc.) (Drorbaugh, J.E. et al., Pediatrics, 16, pp. 81-87, 1955; Epstein, M.A. et al., Respir.Physiol., 32, pp. 105-120, 1978), measurement method using blood gas analysis device (measurement of blood gas, blood 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 as a pharmaceutical active ingredient can be confirmed.

The usefulness of a certain aspect of the compound of the present invention as an active ingredient of medicine can be confirmed, for example, by conducting a general toxicity test. General toxicity test refers to the following method: using rodents such as rats and mice or non-rodents such as monkeys and dogs, and administering the compound dissolved or suspended in an appropriate solvent once or repeatedly (in multiple days) orally Or intravenous administration, etc., so as to evaluate the observation of the general state, clinical chemical changes and pathological tissue changes of the administered animals. By using these methods to clarify the general toxicity of a compound, the usefulness as a pharmaceutical active ingredient can be confirmed.

A certain aspect of the compound of the present invention can be used as an active ingredient of a medicine, which can be confirmed, for example, by performing a reproductive and developmental toxicity test. Reproductive and 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 compounds on reproductive development (refer to "Explanation of Non-clinical Test Guidelines for Pharmaceutical Products 2002" Japan Pharmaceutical Affairs Published by Daily News in 2002 1-6: Reproductive and Developmental Toxicity Test, etc.). Examples of reproductive and developmental toxicity tests include: tests related to conception ability and early embryonic development before implantation, tests related to prenatal and postnatal development and maternal function, and tests related to embryo and fetal development (refer to Japan 2000 [3] Reproductive and Developmental Toxicity Tests in the "Guidelines for the Toxicity Test of Drugs" in the Annex of Medical Approval No. 1834), etc.), etc. By using these test methods to clarify the reproductive and developmental toxicity of a compound, the usefulness as an active ingredient of a medicine can be confirmed.

A certain aspect of the compound of the present invention can be used as an active ingredient of a medicine, for example, by performing a cytochrome P450 enzyme inhibition or induction test (Gomez-Lechon, M. J. et al., Curr. Drug Metab. 5 (5 ), pp. 443-462, 2004) to confirm. As the inhibition or induction test of cytochrome P450 enzymes, for example, the following methods can be mentioned: using cytochrome P450 enzymes of various molecular species purified from cells or prepared by genetic recombinants or human P450 expressing microsomes, and measuring in test tubes Whether the compound inhibits the enzyme activity of cytochrome P450 enzymes of the above molecular types or human P450 expressing system microsomes (Miller, V.P. et al., Ann. N. Y. Acad.Sci., 919, pp. 26-32, 2000); use Human liver microsomes or cell lysate were used to determine the expression and activity of cytochrome P450 enzymes of various molecular species (Hengstler, J.G. et al., Drug Metab. Rev., 32, pp. 81-118, 2000); Alternatively, RNA was extracted from human hepatocytes exposed to the compound, and mRNA expression was compared with the control group 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 action of the compound on cytochrome P450 enzyme inhibition or enzyme induction, the usefulness as a pharmaceutical active ingredient can be confirmed. The fact that a certain aspect of the compound of the present invention can be used as an active ingredient of medicine can be confirmed, for example, by conducting a test for confirming the production of reactive metabolites. As a test for confirming the production of reactive metabolites, for example, the following method can be mentioned: adding human liver microsomes and compounds to NADPH (Nicotinamide adenine dinucleotide phosphate, nicotinamide adenine dinucleotide phosphate) and via dansyl Incubate in the presence of fluorescently labeled glutathione (dGSH) to capture reactive metabolites as dGSH conjugates, and use the fluorescence intensity as an indicator to comprehensively detect the resulting reaction based on the amount of dGSH conjugates produced The peak of metabolites (Junping Gan. et al., Chem. Res. Toxicol. 2005, 18, 896-903); the 14C marker of the compound was incubated with human liver microsomes in the presence of NADPH, and the protein Covalently bound radioactivity (Baillie T. A., 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 to clarify the risk of the specific drug toxicity of the compound due to the generation of reactive metabolites, the usefulness as a pharmaceutical active ingredient can be confirmed.

The fact that a certain aspect of the compound of the present invention can be used as an active ingredient of a medicine can be confirmed, for example, by performing a cell permeability test. As the cell permeability test, for example, the following method can be exemplified: Using Caco-2 cells, the cell membrane penetration ability of the compound is measured in the in vitro cell culture system (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, F. M. et al., J. Pham . Sci., 92, pp. 1545-1558, 2003); or use MDCK cells to measure the cell membrane permeability of compounds in an in vitro cell culture system (Irvine, J.D. et al., J. Pham. Sci., 88, pp. 28-33, 1999). By using any one or two or more of these methods to clarify the cell permeability of the compound, the usefulness as a pharmaceutical active ingredient can be confirmed.

A compound of an aspect of the present invention can be used as an active ingredient of a medicine, which can be confirmed, for example, by assaying drug transporter ATPase as an ATP-binding cassette (ABC) transporter. As a drug transporter ATPase assay, a method of investigating whether a compound is a substrate of P-gp using a P-glycoprotein (P-gp) baculovirus expression system can be exemplified (German, U. A., Methods Enzymol., 292, pp. . 427-41, 1998) etc. Furthermore, it can be confirmed, for example, by carrying out a transport test using oocytes (Oocytes) collected from Xenopus laevis as a solute carrier (SLC) transporter. Examples of transport tests include a method of investigating whether a compound is a substrate for OATP2 using OATP2-expressing oocytes (Tamai I. et. al., Pharm Res. 2001 Sep; 18 (9): 1262-1269 ). By using these methods to clarify the action of the compound on ABC transporter or SLC transporter, the usefulness as a pharmaceutical active ingredient can be confirmed.

The usefulness of a certain aspect of the compound of the present invention as an active ingredient of medicine can be confirmed, for example, by performing an oral absorption test. The oral absorbability test may, for example, be a method in which a certain amount of compound is dissolved or suspended in an appropriate solvent using rodents, monkeys, or dogs, and the blood drug concentration after oral administration is measured over time. , and use LC-MS/MS (Liquid Chromatography-tandem mass spectrometry, liquid chromatography-mass spectrometry) to evaluate Migration in Blood after Oral Administration of Compounds. By clarifying the oral absorbability of a compound using these methods, the usefulness as a pharmaceutical active ingredient can be confirmed.

The fact that a certain aspect of the compound of the present invention can be used as an active ingredient of a medicine can be confirmed, for example, by performing a blood drug concentration transition measurement test. The blood concentration transition measurement test may, for example, be a method in which a compound is administered to rodents orally or parenterally (for example, intravenously, intramuscularly, intraperitoneally, subcutaneously, transdermally, eyedrops, or nasally, etc.). After species, monkey, or dog, etc., the plasma concentration transition of the compound was measured using LC-MS/MS method (edited by Kenichi Harada et al., "The Latest Mass Spectrometry for Life Sciences", published by Kodansha Science, 2002, etc.). By using these methods to clarify the blood concentration transition of the compound, the usefulness as an active ingredient of medicine can be confirmed.

The usefulness of a certain aspect of the compound of the present invention as an active ingredient of medicine can be confirmed, for example, by performing a metabolism test. As a metabolic test, for example: blood drug stability test method (a method for predicting the metabolic clearance rate in the body based on the metabolic rate of the compound in the liver microsomes of human or other animal species (refer to Shou, W. Z. et al., J . Mass Spectrom., 40 (10), pp. 1347-1356, 2005; Li, C. et al., Drug Metab. Dispos., 34(6), 901-905, 2006) etc.), metabolic molecular species test method, reactive metabolite test method, etc. By using any one or two or more of these methods to clarify the metabolic profile of the compound, the usefulness as a pharmaceutical active ingredient can be confirmed.

The usefulness of a certain aspect of the compound of the present invention as an active ingredient of medicine can be confirmed, for example, by performing a solubility test. Regarding the evaluation of solubility in water, a method of confirming under acidic conditions, neutral conditions, or alkaline conditions is exemplified, and the confirmation of solubility changes depending on the presence or absence of bile acids is also included. As the solubility test, for example: a solubility test method based on the turbidity method (Lipinski, C.A. et al., Adv. Drug Deliv. Rev., 23, pp. 3-26, 1997; Bevan, C.D. et al., Anal. Chem., 72, pp. 1781-1787, 2000) etc. By using these methods to clarify the solubility of a compound, the usefulness as a pharmaceutical active ingredient can be confirmed.

The usefulness of a certain aspect of the compound of the present invention as an active ingredient of medicine can be confirmed, for example, by investigating upper gastrointestinal disorders, renal dysfunction, and the like. As a pharmacological test targeting the upper gastrointestinal tract, the gastric mucosal injury model of fasted rats can be used to investigate the effect on the gastric mucosa. As a pharmacological test for renal function, for example, renal blood flow and spheroid filtration measurement method [Physiology, 18th edition (Sunkodo), 1986, Chapter 17] and the like. By using any one or two or more of these methods to clarify the effect of the compound on the upper gastrointestinal tract and kidney function, the usefulness as an active ingredient of medicine can be confirmed. [Example]

Hereinafter, the present invention will be described more specifically with reference to examples and test examples (hereinafter, sometimes referred to as "example, etc."), but the scope of the present invention is not limited to the following examples. All reagents purchased were used without further purification. The purchased anhydrous solvents were used without further drying. In column chromatography, BIOTAGE Dalton, which is a mass spectrometer, is connected to SmartFlash, a medium-pressure fractionation and purification system manufactured by Yamazen, or Isolera ONE, a medium-pressure fractionation and purification system manufactured by BIOTAGE. As a column, either SNAP Ultra manufactured by Biotage Corporation or DispoPack AT manufactured by YMC Corporation was used. In many cases, BondElute SCX (Strong Cation-Exchanger) manufactured by Agilent was used as an ion exchange resin for purification. Note that BondElute SCX may be abbreviated as SCX below. As an example of use of SCX, a method of washing the cartridge with methanol and dichloromethane, and then dissolving the crude product in a solvent with a minimum volume (for example, a mixed solvent of dichloromethane-methanol, etc.) is used to perform adsorption. Thereafter, impurities were washed with methanol while applying pressure, and the product was eluted in 2.0 M ammonia-methanol. Preformed silica gel 60 F254 (product number 5715-1M manufactured by Merck) was used in thin layer chromatography (TLC). After developing with chloroform:methanol (1:0~1:1), or ethyl acetate:hexane (1:0~0:1), irradiate UV (254 nm or 365 nm), iodine solution, over Potassium manganate aqueous solution, phosphomolybdic acid (ethanol solution), etc. develop color to confirm. In preparative thin-layer chromatography (hereinafter, sometimes referred to as PTLC), one or several PLC plates are used according to the amount of the sample. Silica gel 60 F254, 20×20 cm, layer thickness 2 mm, with a concentration area ( 4 cm) (manufactured by Merck, product number 13793-1M). When drying the organic solvent, use anhydrous magnesium sulfate or anhydrous sodium sulfate.

NMR 1 H (400 MHx) nuclear magnetic resonance apparatus (hereinafter sometimes abbreviated as NMR) analysis used AVANCE III HD-400 MHz manufactured by Bruker, or AVANCE III HD-600 MHz manufactured by Bruker. Internal standards use known values of solvents or additives used. 1H NMR data records chemical shift, parts per million (hereinafter referred to as ppm), integral value (for example, recorded as 1H), multinomial (s is a singlet; d is a doublet; t is a triplet; q is a quadruplet). Doublet; qui is quintet; m is multiplet; br is broad; dd is double doublet, etc.).

Regarding LCMS, mass spectra were determined by liquid chromatography-mass spectrometry (LC-MS). Unless otherwise specified, a single quadrupole mass spectrometer SQD system (manufactured by Waters Corporation) was used as a mass spectrometer, and measurement was performed by an electrospray (ESI) method. As a liquid chromatography device, an Acquity MLtra Performance LC system manufactured by Waters Corporation was used. The separation column used was ACQUITY UPLC BEH C18 2.1×50 mm 1.7 μm (manufactured by Waters).

The Examples or Reference Examples specifically described about the LC conditions show that they were measured under the following solvent conditions. In addition, m/z represents mass spectrum data (MH ⁺ or MH ⁻ is described simultaneously).

(LC-1) Flow rate 0.6 mL/min, liquid A = 10 mM ammonium acetate aqueous solution, liquid B = acetonitrile, from 0 minute to 2.0 minutes, make liquid B elute with a linear gradient of 5-90% (v/v), and automatically From 2.0 minutes to 2.5 minutes, liquid B was dissolved with a linear gradient of 90-98% (v/v), and the measurement was carried out under this condition.

(LC-6) Flow rate 0.6 mL/min, solution A = 10 mM ammonium acetate aqueous solution, solution B = acetonitrile, from 0 minute to 2.0 minutes, make solution B elute with a linear gradient of 70-90% (v/v), and automatically From 2.0 minutes to 2.5 minutes, liquid B was dissolved with a linear gradient of 90-98% (v/v), and the measurement was carried out under this condition.

For HPLC purification, a fractionation and purification apparatus manufactured by Waters Corporation of Japan was used, Triart C18 ExRS (manufactured by YMC Corporation) was used as a column, and a 10 mM ammonium acetate aqueous solution-acetonitrile solution was used as an eluent.

In the following examples and descriptions of synthesis methods of intermediates, the notation quant. means that the target substance was obtained quantitatively.

Intermediate A-1-1: 2-(Chloromethyl)pyrimidine [Chem. 67]

A solution of pyrimidin-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. Next, 5 N aqueous sodium hydroxide solution (780 mL) was added dropwise, and while stirring at 0°C, 1 N aqueous hydrochloric acid (30 mL) and 5 N aqueous sodium hydroxide solution (280 mL ), 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 obtained crude product was purified by silica gel column chromatography (eluate; hexane:ethyl acetate=1:0-1:2), thereby obtaining 2-(chloromethyl)pyrimidine (118.0 g, Yield 67%). 1H-NMR (CDCl ₃ ): δ (ppm) 8.78 (2H, d, J = 4.9 Hz), 7.26 (1H, t, J = 4.9 Hz), 4.76 (2H, s).

Intermediate A-1-2-a: 2-(((1S,2S)-2-(((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidine[ [68] Intermediate A-1-2-b: 2-(((1R,2R)-2-(((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidine[ [69]

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 intervals of 5 minutes. After stirring at 0°C for 20 minutes, it was stirred at room temperature for 1 hour. Next, the reaction solution was cooled to 0°C, imidazole (156 g, 2.29 mol) and TBS chloride (207 g, 1.38 mol) were added sequentially, and stirred at room temperature for 1.5 hours. The obtained crude reaction mixture was cooled to 0° C., water (530 mL) was added, Celite filtration was performed, and ethyl acetate was used for extraction. 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 using silica gel column chromatography (eluate; hexane:ethyl acetate=1:0-1:1), thereby obtaining 2-((trans-2-((( tert-Butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidine (97.9 g, 35% yield). LCMS (LC-1); RT=2.10, m/z 309 [M+H] ⁺ 1H-NMR (CDCl ₃ ): δ (ppm) 8.75 (2H, d, J = 4.9 Hz), 7.20 (1H, t , J = 4.9 Hz), 4.78 (2H, d, 7.3 Hz), 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). Each optically active body was obtained with a purity of 99.7%ee or higher. Fractionation conditions: column: CHIRALART CelluLose-SC (10 um) 245×150 mm ID, eluent: heptane/2-propanol (80/20) (v/v), flow rate: 518 mL/min, temperature : 24°C, detection: UV (245 nm), load: 180 mL (9 g) analysis conditions: column: CHIRALART CelluLose-SC (5 um) 250×4.6mm 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 body; intermediate Material A-6-2-a), RT=16.5 (1R, 2R body; Intermediate A-6-2-b)

Intermediate A-1-3: 2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)-5-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine [Chem. 70]

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(pinacolate)diboron (63.1 g, 249 mmol), (1,5-cyclooctadiene)(methoxy)iridium was added (I) (dimer) (1.64 g, 2.49 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (1.17 g, 4.97 mmol), stirred at 80°C for 15 hours, The obtained crude reaction mixture was concentrated, thereby obtaining the crude product 2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy) methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine. LCMS (LC-1); RT=1.80, m/z 353 [M+H] ⁺ (detected as boronic acid) 1H-NMR (CDCl ₃ ): δ (ppm) 9.00 (2H, s), 4.78 (2H, d , 6.2 Hz), 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).

Intermediate A-1-4: 6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidine -5-yl)benzo[d]thiazol-2-amine [Chemical 71]

6-Bromo-1,3-benzothiazol-2-amine (1.50 g, 6.5 mmol) was dissolved in THF (15 mL), and the above crude product 2-((((1S,2S)-2-( (tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborin Alk-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), water (2.9 mL), and the mixture was irradiated with microwave 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 layers were dried over anhydrous sodium sulfate, filtered through celite, and concentrated under reduced pressure. The obtained crude product was purified by automatic silica gel column chromatography (eluent; hexane:ethyl acetate=98:12-12:100), thereby obtaining 6-(2-((((1S, 2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-amine (1.13 g, Yield 57%). LCMS (LC-1); RT=2.07, m/z 457 [M+H] ⁺ 1H-NMR (CDCl ₃ ): 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), 4.83-4.79 (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) .

Intermediate A-1-5: N-(6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl base) pyrimidin-5-yl) benzo [d] thiazol-2-yl) cyclopropaneformamide [Chem. 72]

6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo [d] Thiazol-2-amine (Intermediate A-1-4; 30 mg, 66 μmol) was dissolved in dichloromethane (660 μL), cyclopropanecarboxylic acid (19 mg, 0.22 mmol), N,N - Diisopropylethylamine (100 μL, 0.59 mmol), 1-propylphosphonic anhydride (50% by weight in ethyl acetate, 0.13 mL, 0.22 mmol), stirred at room temperature for 16 hours. Saturated sodium bicarbonate water was added to the obtained crude reaction mixture, and extracted with dichloromethane to obtain Crude reaction mixture of methylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide. LCMS (LC-1); RT=2.27, m/z 525 [M+H] ⁺

Example a-01-01: N-(6-(2-((((1S,2S)-2-hydrocyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazole -2-yl) cyclopropaneformamide [Chemical 73]

Containing N-(6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidine-5- To the crude reaction mixture of benzo[d]thiazol-2-yl)cyclopropanecarboxamide (intermediate A-1-5, 2 mL), hydrochloric acid-methanol solution (2 mol/ L, 2 mL), stirred at room temperature for 30 minutes. The obtained crude reaction mixture was concentrated under reduced pressure and purified using SCX and HPLC to obtain N-(6-(2-((((1S,2S)-2-hydrocyclopentyl)oxy)methanol yl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide (12 mg, 44% yield). LCMS (LC-1); RT=1.13, m/z 411 [M+H] ⁺ 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).

Using the same method, the following compounds in the following table were synthesized. In the following tables, "reference method" indicates that the examples of the production method should be referred to. [Table 2] example structure Reference method LCMS data a-01-02 Example a-01-01 Intermediate A-1-5 (LC-1); RT=0.97, m/z 429 [M+H] ⁺ a-01-03 Example a-01-01 Intermediate A-1-5 (LC-1); RT=01.16, m/z 429 [M+H] ⁺ a-01-04 Example a-01-01 Intermediate A-1-5 (LC-1); RT=1.09, m/z 429 [M+H] ⁺ a-01-05 Example a-01-01 Intermediate A-1-5 (LC-1); RT=1.15, m/z 488 [M+H] ⁺ a-01-06 Example a-01-01 Intermediate A-1-5 (LC-1); RT=1.17, m/z 454 [M+H] ⁺ a-01-07 Example a-01-01 Intermediate A-1-5 (LC-1); RT=1.13, m/z 491 [M+H] ⁺ a-01-08 Example a-01-01 Intermediate A-1-5 (LC-1); RT=1.14, m/z 488 [M+H] ⁺ a-01-09 Example a-01-01 Intermediate A-1-5 (LC-1); RT=1.22, m/z 495 [M+H] ⁺ a-01-10 Example a-01-01 Intermediate A-1-5 (LC-1); RT=1.48, m/z 517 [M+H] ⁺ a-01-11 Example a-01-01 Intermediates A-1-4, 5 (LC-1); RT=1.30, m/z 445 [M+H] ⁺ a-01-12 Example a-01-01 Intermediates A-1-4, 5 (LC-1); RT=1.24, m/z 429 [M+H] ⁺

Intermediate A-2-1: 2-(propoxymethyl)pyrimidine [Chem. 74]

Pyrimidin-2-ylmethanol (10 g, 91 mmol) was dissolved in DMF (300 mL), and sodium hydride (4.8 g, 55% by weight, 109 mmol) was added under cooling in an ice bath, and 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% by weight, 91 mmol), 1-iodopropane (10 mL, 103 mmol), and further stirred at room temperature for 1 hour. Water (300 mL) was added to the obtained crude reaction mixture to stop the reaction, and extracted three times with ethyl acetate (300 mL). The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained crude product was purified using automatic silica gel column chromatography (eluate; hexane:ethyl acetate=88:12-0:100), thereby obtaining 2-(propoxymethyl)pyrimidine ( 10.1 g, yield 73%). 1H-NMR (CDCl ₃ ): δ (ppm) 8.76 (2H, d, J = 4.9 Hz), 7.21 (1H, dd, J = 4.9 Hz), 4.75 (2H, s), 3.60 (2H, t, J = 6.9 Hz), 1.73 (2H, tt, J = 6.9, 7.4 Hz), 0.96 (3H, t, J = 7.4 Hz).

Intermediate A-2-2: 2-(propoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine [chem 75]

By following the synthesis method of Intermediate A-1-3, using 2-(propoxymethyl)pyrimidine (Intermediate A-2-1; 10.1 g) instead of 2-(((tert-butyldimethyl Silyl)oxy)methyl)pyrimidine (intermediate A-1-2-a) was synthesized to obtain the crude product 2-propoxymethyl-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyrimidine. LCMS (LC-1); RT=0.62, m/z 197 [M+H] ⁺ (detected as boronic acid)

Intermediate A-2-3: N-(6-bromo-1,3-benzothiazol-2-yl)cyclopropaneformamide [Chem. 76]

2-Amino-6-bromobenzothiazole (1 g, 4.36 mmol) was dissolved in DCM (44 mL), cyclopropylformyl chloride (0.91 g, 8.73 mmol) and triethylamine (0.88 g, 8.37 mmol), stirred at room temperature for 2 hours, added water to the obtained reaction mixture, extracted with chloroform, separated the organic layer, and concentrated under reduced pressure to obtain N-(6-bromo-1,3- Crude reaction mixture of benzothiazol-2-yl)cyclopropanecarboxamide (739 mg, 57% yield). LCMS (LC-1); RT=1.58, m/z 297 [M+H] 1H-NMR (CDCl ₃ ): 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).

Example a-02-01: N-(6-(2-(propoxymethyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide [Chem. 77]

By the synthesis method according to Intermediate A-1-4, using N-(6-bromo-1,3-benzothiazol-2-yl)cyclopropaneformamide (Intermediate A-2-3; 20 mg ) instead of 6-bromo-1,3-benzothiazol-2-amine, using 2-(propoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolin-2-yl)pyrimidine (intermediate A-2-2) instead of 2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy) ring Pentyl)oxy)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (intermediate A-1-3 ) to obtain N-(6-(2-(propoxymethyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide (10 mg, yield 20 %). LCMS (LC-1); RT=1.37, m/z 369 [M+H] ⁺ 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 = 6.7 Hz), 1.97-1.91 (1H, m),1.62-1.53 (2H, m),0.93-0.88(7H, m).

Intermediate A-3-1: 5-bromo-2-(((trans-2-((tert-butyldimethylsilyl)oxy)-4,4-difluorocyclopentyl)oxy ) methyl) pyrimidine [chemical 78]

Dissolve 5-bromo-2-(chloromethyl)pyrimidine (500 mg, 2.41 mmol), trans-4,4-difluorocyclopentane-1,2-diol (500 mg, 3.62 mmol) in di To methyl chloride (4 mL), tetrabutylammonium chloride (70 mg, 241 μmol) and 25% by weight aqueous sodium hydroxide solution (4 mL) were added, and stirred under 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 TBS chloride (545 mg, 3.62 mmol) were added thereto, followed by stirring at room temperature for 6 hours. Next, imidazole (330 mg, 4.82 mmol) and TBS chloride (545 mg, 3.62 mmol) were added and stirred at room temperature for 52 hours. Furthermore, imidazole (330 mg, 4.82 mmol) and TBS chloride (545 mg, 3.62 mmol) were added, and stirred at room temperature for 24 hours. Water was added to the obtained reaction mixture, extracted with chloroform, the organic layer was separated, concentrated under reduced pressure, and purified by automatic silica gel column chromatography (eluent: hexane-ethyl acetate), thereby obtaining 5-Bromo-2-(((trans-2-((tert-butyldimethylsilyl)oxy)-4,4-difluorocyclopentyl)oxy)methyl)pyrimidine (131 mg , Yield 13%). LCMS (LC-1); RT=2.25, m/z 424 [M+H] ⁺ 1H-NMR (CDCl ₃ ): δ (ppm) 8.79 (2H, s), 4.77 (2H, d, J = 2.1 Hz ) 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).

Intermediate A-3-2: N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d] Thiazol-2-yl)cyclopropanecarboxamide [Chem. 79]

N-(6-bromo-1,3-benzothiazol-2-yl)cyclopropaneformamide (Intermediate A-2-3; 400 mg, 1.35 mmol) was dissolved in 1,4-dioxane ( 13 mL), add bis(pinacolate) diboron (513 mg, 2.03 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (98 mg, 0.13 mmol), potassium acetate (400 mg, 2.69 mmol), stirred at 80°C for 3 hours, after cooling to room temperature, the solvent was concentrated under reduced pressure to obtain N-[6-(4,4,5 , Crude reaction mixture of 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide. LCMS (LC-1); RT=1.73, m/z 346 [M+2H] ⁺ 1H-NMR (CDCl ₃ ): 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).

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)cyclopropanecarboxamide [Chem. 80]

5-bromo-2-(((trans-2-((tert-butyldimethylsilyl)oxy)-4,4-difluorocyclopentyl)oxy)methyl)pyrimidine (intermediate Substance A-3-1; 30 mg, 71 μmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) benzo[d]thiazol-2-yl)cyclopropanecarboxamide (Intermediate A-3-2; 36 mg, 0.11 mmol) was dissolved in 1,4-dioxane (1 mL), added water (200 μL), cesium carbonate (69 mg, 0.22 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5.8 mg, 7 μmol), overnight at 80°C Stir. The obtained crude reaction mixture was filtered through celite and concentrated under reduced pressure. Use automatic silica gel column chromatography (eluent; chloroform:methanol), HPLC to purify the obtained crude product, thereby obtain N-(6-(2-(((trans-2-((third Butyldimethylsilyl)oxy)-4,4-difluorocyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide (13.7 mg, 34% yield). LCMS (LC-1); RT=2.14, m/z 561 [M+H] ⁺ 1H-NMR (CDCl ₃ ): δ (ppm) 9.95 (1H, brs), 9.00 (2H, s), 8.02 (1H , d, J = 2.0 Hz), 7.89 (1H, d, J = 8.4 Hz), 7.63 (1H, dd, J = 8.4, 2.0 Hz), 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), 1.73-1.66 (1H, m), 1.30- 1.26 (2H, m), 1.08-1.04 (2H, m), 0.88 (9H, s), 0.09 (6H, d, J = 1.6 Hz).

Example a-03-01: N-(6-(2-((((1S,2S)-4,4-difluoro-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl ) benzo [d] thiazol-2-yl) cyclopropane formamide [Chem. 81]

By the synthesis method according to Example a-01-01, using N-(6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)- 4,4-Difluorocyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide (Intermediate A-3-5; 13.7 mg) Instead of N-(6-(2-(((trans-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo [d] Thiazol-2-yl) cyclopropanecarboxamide (intermediate A-1-5), and purified by HPLC, chiral HPLC (column: CHIRALPAK IB (manufactured by DAICEL), mobile phase ; n-Hexane:ethanol=30:70) split the obtained mixture of stereoisomers, thereby obtaining the desired N-(6-(2-((((1S,2S)-4,4-di Fluoro-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide (2.3 mg, 21% yield). LCMS (LC-1); RT=1.23, m/z 447 [M+H] ⁺ 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).

Intermediate A-4-1: 5-bromo-2-(cyclopentyloxymethyl)pyrimidine [Chem. 82]

Dissolve 5-bromo-2-(chloromethyl)pyrimidine (100 mg, 0.4 mmol), cyclopentanol (41 mg, 0.48 mmol) in dichloromethane (4 mL), add tetrabutylammonium chloride (11 mg, 40 μmol), 25% by weight aqueous sodium hydroxide solution (2 mL), stirred at 60°C for 14 hours. Water was added to the obtained reaction mixture, extracted with chloroform, the organic layer was separated, concentrated under reduced pressure, and purified using automatic silica gel column chromatography (eluent; chloroform-methanol), thereby obtaining 5 -Bromo-2-(cyclopentyloxymethyl)pyrimidine (87 mg, 85% yield). LCMS (LC-1); RT=1.41, m/z 258 [M+H] ⁺ 1H-NMR (CDCl ₃ ): 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).

Using the same method, the following compounds in the following table were synthesized. In the following tables, "reference method" indicates that the examples of the production method should be referred to. [table 3] intermediate structure Reference method LCMS data A-4-2 Intermediate A-4-1 (LC-1); RT=1.05, m/z 308 [M+H] ⁺

Example a-04-01: N-(6-(2-(cyclopentyloxymethyl)pyrimidin-5-yl)-1,3-benzo[d]thiazol-2-yl)cyclopropaneformyl Amine [Chem. 83]

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]cyclopropanecarboxamide ( Intermediate A-3-2; 53.6 mg, 0.16 mmol), cesium carbonate (101 mg, 0.31 mmol), [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 using automatic silica gel column chromatography (eluate; chloroform-methanol), thereby obtaining N -[6-[2-(Cyclopentyloxymethyl)pyrimidin-5-yl]-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (4.8 mg, 8% yield). LCMS (LC-1); RT=1.52, m/z 395 [M+H] ⁺ 1H-NMR (CDCl ₃ ): 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).

Using the same method, the following compounds in the following table were synthesized. In the following tables, "reference method" indicates that the examples of the production method should be referred to. [Table 4] example structure Reference method LCMS data a-04-02 Example a-02-01 Intermediate A-2-1 (LC-1); RT=1.32, m/z 425 [M+H] ⁺ a-04-03 Example a-02-01 Intermediate A-2-1 (LC-1); RT=1.41, m/z 381 [M+H] ⁺ a-04-04 Example a-02-01 Intermediate A-2-1 (LC-1); RT=1.41, m/z 417 [M+H] ⁺

Intermediate A-5-1: (S)-5-bromo-2-(((tetrahydrofuran-2-yl)methoxy)methyl)pyrimidine [Chem. 84]

5-Bromo-2-(bromomethyl)pyrimidine (6.7 g, 27 mmol), (S)-(tetrahydrofuran-2-yl)methanol (2.5 g, 24 mmol) were dissolved in tetrahydrofuran (80 mL), and 33 % sodium hydroxide aqueous solution (30 mL), tetrabutylammonium chloride (667 mg, 2.4 mmol), stirred overnight at 40°C. Water (100 mL) was added to the obtained crude reaction mixture, and 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), thereby obtaining (S)-5-bromo-2-(((tetrahydrofuran-2 -yl)methoxy)methyl)pyrimidine (2.55 g, 39% yield). LCMS (LC-1); RT=1.03, m/z 273 [M+H] ⁺ 1H-NMR (CDCl ₃ ): 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).

Example a-05-01: (S)-N-(6-(2-((tetrahydrofuran-2-yl)methoxy)methyl)pyrimidin-5-yl)benzo[d]thiazole-2- base) cyclopropaneformamide [Chem. 85]

(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)cyclopropanecarboxamide (intermediate A-3-2; 246 mg, 0.71 mmol) was dissolved in N,N-dimethylformamide (9 mL), water (1 mL), potassium carbonate (152 mg, 1.1 mmol), tetrakis(triphenyl Phosphine) palladium (0) (64 mg, 55 μmol), stirred overnight at 130°C. The obtained crude reaction mixture was concentrated under reduced pressure, and purified using automatic silica gel column chromatography (eluate; 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)cyclopropanecarboxamide (45 mg, yield 20%). LCMS (LC-1); RT=1.20, m/z 411 [M+H] ⁺ 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), 3.77-3.71 (1H, m), 3.65-3.60 (1H, m), 3.56 (2H, d, J = 5.3 Hz), 2.06-1.99 (1H, m), 1.95-1.74 (3H, m), 1.65-1.55 (1H, m), 0.99-0.97 (4H, m).

Intermediate B-1-1: N-(6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl Base) pyrimidin-5-yl) benzo[d]thiazol-2-yl)-3-oxocyclobutane-1-carboxamide [Chem. 86]

Dichloromethane (8.6 mL) was suspended in 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), add 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), stirred at room temperature for 1.5 hours. Saturated sodium bicarbonate water was added to the obtained reaction mixture, extracted with chloroform, the organic layer was dried with sodium sulfate, filtered, concentrated, and purified by automatic silica gel column chromatography (eluent: Chloroform-methanol 2%), thereby obtaining 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%). LCMS (LC-1); RT=2.18, m/z 553 [M+H] ⁺ 1H-NMR (CDCl ₃ ): δ (ppm) 10.4 (1H, brs) 9.02 (2H, s), 8.06 (1H, d, J = 1.5 Hz), 7.88 (1H, d, J = 8.0 Hz), 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), 2.11-1.84 (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).

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-𠰌linylcyclobutane-1-carboxamide [Chemical 87]

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 THF (0.9 mL), Add acetic acid (0.1 mL), sodium triacetyloxyborohydride (77 mg, 0.36 mmol), and phospholine (23.74 μL, 0.27 mmol), and stir at room temperature for 1.5 hours. Water and saturated sodium bicarbonate water were added to the obtained reaction mixture, extracted with chloroform, and the organic layer was dried with sodium sulfate, filtered, concentrated, and automatically silica gel column chromatography (eluent; chloroform- Methanol 2%), HPLC purification to obtain the target object: N-(6-2-((((11S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy yl)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-?olinylcyclobutane-1-carboxamide (73.9 mg, 65.8% yield). LCMS (LC-1); RT=2.15, m/z 624 [M+H] ⁺

Example b-01-01: N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazole -2-yl)-3-𠰌linylcyclobutane-1-formamide [Chemical 88]

In N-(6-2-((((11S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl) Add 2 N hydrochloric acid/methanol solution ( 500 μL), stirred at room temperature. The reaction was terminated after 10 minutes, and the solvent was removed by blowing nitrogen gas. A part was purified by SCX and automatic 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-alphalinylcyclobutane-1-carboxamide: 2 mg. The remaining reaction mixture was purified by HPLC to obtain N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d ]thiazol-2-yl)-3-?olinylcyclobutane-1-carboxamide (13.6 mg, yield: 37%). LCMS (LC-1); RT=1.01, m/z 510 [M+H] ⁺ 1H-NMR (CDCl ₃ ): δ (ppm) 9.00 (2H, s), 8.00 (1H, d, J = 1.5 Hz ), 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 (2H, 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).

Using the same method, the following compounds in the following table were synthesized. In the following tables, "reference method" indicates that the examples of the production method should be referred to. [table 5] example structure Reference method LCMS data b-01-02 Example b-01-01 Intermediate B-1-2 (LC-1); RT=1.06, m/z 498 [M+H]+

Intermediate B-2-1: (1S,2S)-2-((5-(2-Aminobenzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentane- 1-alcohol [Chem. 89]

In 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) was added with 2 N-hydrochloric acid/methanol solution (6 mL), and stirred at room temperature for 15 minutes. Add saturated sodium bicarbonate water to the reaction mixture, extract with chloroform, dry the organic layer with sodium sulfate, filter and concentrate, and perform automatic silica gel column chromatography purification (eluent: ethyl acetate-methanol) , (1S,2S)-2-((5-2(aminobenzo[d]-6-yl)pyrimidin-2-yl)methoxy)cyclopentan-1-ol (1.41 g). LCMS (LC-1); RT=0.89, m/z 343 [M+H] ⁺ 1H-NMR (CDCl ₃ ): δ (ppm) 9.91-9.65 (2H, brs), 9.12 (2H, s), 8.34 (1H, d, J = 2.0 Hz), 8.12 (1H, d, J = 2.0 Hz), 7.86 (1H, dd, J = 8.5, 2.0 Hz), 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).

Intermediate B-2-2: N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazole -2-yl) 3-side oxycyclobutane-1-carboxamide [Chemical 90]

(1S,2S)-2-((5-(2-Aminobenzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentan-1-ol (intermediate B -2-1; 1.41 g, 4.11 mmol) was dissolved in dimethylformamide (20.5 mL), and 3-oxocyclobutanecarboxylic acid (703 mg, 6.16 mmol), 1-hydroxybenzotriazole -1 hydrochloride (1.26 g, 8.21 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.57 g, 8.21 mmol), overnight at 60°C Heat and stir. Saturated aqueous sodium bicarbonate was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried with sodium sulfate and filtered, concentrated, and purified by automatic 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 rate 15%). LCMS (LC-1); RT=1.03, m/z 439 [M+H] ⁺ 1H-NMR (CDCl ₃ ): 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 = 14.4 Hz), 4.80 (1H, d, J = 14.4 Hz), 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).

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 [Chemical 91]

N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)3- Oxycyclobutane-1-carboxamide (Intermediate B-2-2; 53.6 mg, 0.12 mmol) was dissolved in THF (2 mL), and (R)-(-)3-fluoropyrrolidinium salt was added Salt (23 mg, 0.18 mmol), sodium triacetyloxyborohydride (51.81 mg, 0.24 mmol), stirred at room temperature. After 1 hour, acetic acid (50 μL) was added and stirring was continued for 1 hour. After the reaction, add water, chloroform, and saturated sodium bicarbonate water to the reaction mixture for stirring, separate the organic layer, condense it with nitrogen gas, and perform HPLC purification to obtain 3-[(3R)-3-fluoropyridine -1-yl]-N-[6-[2-[[(1S,2S)-2-hydroxycyclopentyloxy]methyl]pyrimidin-5-yl]-1,3-benzothiazole-2- base] cyclobutanecarboxamide (10.3 mg, 16% yield). LCMS (LC-1); RT=1.06, m/z 512 [M+H] ⁺ 1H-NMR (CDCl ₃ ): δ (ppm) 9.00 (2H, s), 8.04-7.92 (1H, m), 7.83 (1H, brd, J = 7.1 Hz), 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).

Using the same method, the following compounds in the following table were synthesized. In the following tables, "reference method" indicates that the examples of the production method should be referred to. [Table 6] example structure Reference method LCMS data b-02-02 Example b-02-01 (LC-1); RT=1.06, m/z 512 [M+H] ⁺ b-02-03 Example b-02-01 (LC-1); RT=0.98, m/z 524 [M+H] ⁺ b-02-04 Example b-02-01 (LC-1); RT=1.29, m/z 544 [M+H] ⁺ b-02-05 Example b-02-01 (LC-1); RT=1.05, m/z 524 [M+H] ⁺ b-02-06 Example b-02-01 (LC-1); RT=1.05, m/z 524 [M+H] ⁺ b-02-07 Example b-02-01 (LC-1); RT=1.08, m/z 524 [M+H] ⁺ b-02-08 Example b-02-01 (LC-1); RT=1.08, m/z 524 [M+H] ⁺ b-02-09 Example b-02-01 (LC-1); RT=1.02, m/z 522 [M+H] ⁺ b-02-10 Example b-02-01 (LC-1); RT=1.29, m/z 544 [M+H] ⁺ b-02-11 Example b-02-01 (LC-1); RT=1.11, m/z 526 [M+H] ⁺ b-02-12 Example b-02-01 (LC-1); RT=1.17, m/z 516 [M+H] ⁺ b-02-13 Example b-02-01 (LC-1); RT=1.24, m/z 530 [M+H] ⁺ b-02-14 Example b-02-01 (LC-1); RT=0.97, m/z 524 [M+H] ⁺ b-02-15 Example b-02-01 (LC-1); RT=0.97, m/z 524 [M+H] ⁺ b-02-16 Example b-02-01 (LC-1); RT=1.18, m/z 526 [M+H] ⁺ b-02-17 Example b-02-01 (LC-1); RT=1.17, m/z 526 [M+H] ⁺ b-02-18 Example b-02-01 (LC-1); RT=1.23, m/z 538 [M+H] ⁺ b-02-19 Example b-02-01 (LC-1); RT=1.15, m/z 538 [M+H] ⁺ b-02-20 Example b-02-01 (LC-1); RT=1.15, m/z 538 [M+H] ⁺ b-02-21 Example b-02-01 (LC-1); RT=1.15, m/z 538 [M+H] ⁺ b-02-22 Example b-02-01 (LC-1); RT=0.90, m/z 523 [M+H] ⁺ b-02-23 Example b-02-01 (LC-1); RT=1.31, m/z 591 [M+H] ⁺ b-02-24 Example b-02-01 (LC-1); RT=1.09 m/z 550 [M+H] ⁺ b-02-25 Example b-02-01 (LC-1); RT=0.96, m/z 567 [M+H] ⁺ b-02-26 Example b-02-01 (LC-1); RT=0.93, m/z 508 [M+H] ⁺ b-02-27 Example b-02-01 (LC-1); RT=0.93, m/z 508 [M+H] ⁺ b-02-28 Example b-02-01 (LC-1); RT=1.09, m/z 549 [M+H] ⁺ b-02-29 Example b-02-01 (LC-1); RT=1.21, m/z 506 [M+H] ⁺ b-02-30 Example b-02-01 (LC-1); RT=1.18, m/z 550 [M+H] ⁺ b-02-31 Example b-02-01 (LC-1); RT=0.95, m/z 522 [M+H] ⁺ b-02-32- Example b-02-01 (LC-1); RT=1.26, m/z 552 [M+H] ⁺ b-02-33 Example b-02-01 (LC-1); RT=1.15, m/z 550 [M+H] ⁺ b-02-34 Example b-02-01 (LC-1); RT=1.26, m/z 552 [M+H] ⁺ b-02-35 Example b-02-01 (LC-1); RT=1.31, m/z 560 [M+H] ⁺ b-02-36 Example b-02-01 (LC-1); RT=0.98, m/z 538 [M+H] ⁺ b-02-37 Example b-02-01 (LC-1); RT=1.08, m/z 536 [M+H] ⁺ b-02-38 Example b-02-01 (LC-1); RT=0.96, m/z 551 [M+H] ⁺ b-02-39 Example b-02-01 (LC-1); RT=0.97, m/z 538 [M+H] ⁺ b-02-40 Example b-02-01 (LC-1); RT=0.87, m/z 510 [M+H] ⁺ b-02-41- Example b-02-01 (LC-1); RT=1.27, m/z 573 [M+H] ⁺ b-02-42 Example b-02-01 (LC-1); RT=1.13, m/z 531 [M+H] ⁺ b-02-43 Example b-02-01 (LC-1); RT=1.46, m/z 562 [M+H] ⁺ b-02-44 Example b-02-01 (LC-1); RT=1.46, m/z 562 [M+H] ⁺ b-02-45 Example b-02-01 (LC-1); RT=1.16, m/z 512 [M+H] ⁺ b-02-46 Example b-02-01 (LC-1); RT=1.32, m/z 544 [M+H] ⁺ b-02-47 Example b-02-01 (LC-1); RT=1.03, m/z 480 [M+H] ⁺ b-02-48 Example b-02-01 (LC-1); RT=0.96, m/z 494 [M+H] ⁺ b-02-49 Example b-02-01 (LC-1); RT=1.31, m/z 520 [M+H] ⁺ b-02-50 Example b-02-01 (LC-1); RT=0.97, m/z 508 [M+H] ⁺ b-02-51 Example b-02-01 (LC-1); RT=1.21, m/z 560 [M+H] ⁺ b-02-52 Example b-02-01 (LC-1); RT=1.10, m/z 504 [M+H] ⁺ b-02-53 Example b-02-01 (LC-1); RT=1.23, m/z 518 [M+H] ⁺ b-02-54 Example b-02-01 (LC-1); RT=1.35, m/z 578 [M+H] ⁺ b-02-55 Example b-02-01 (LC-1); RT=1.36, m/z 578 [M+H] ⁺ b-02-56 Example b-02-01 (LC-1); RT=1.26, m/z 530 [M+H] ⁺ b-02-57 Example b-02-01 (LC-1); RT=1.43, m/z 548 [M+H] ⁺ b-02-58 Example b-02-01 (LC-1); RT=1.31, m/z 548 [M+H] ⁺ b-02-59 Example b-02-01 (LC-1); RT=1.12, m/z 505 [M+H] ⁺ b-02-60 Example b-02-01 (LC-1); RT=1.40, m/z 574 [M+H] ⁺ b-02-61 Example b-02-01 (LC-1); RT=1.35, m/z 578 [M+H] ⁺ b-02-62 Example b-02-01 (LC-1); RT=1.20, m/z 560 [M+H] ⁺ b-02-63 Example b-02-01 (LC-1); RT=1.25, m/z 550 [M+H] ⁺ b-02-64 Example b-02-01 (LC-1); RT=1.18, m/z 530 [M+H] ⁺ b-02-65 Example b-02-01 (LC-1); RT=0.99, m/z 520 [M+H] ⁺ b-02-66 Example b-02-01 (LC-1); RT=1.56, m/z 542 [M+H] ⁺ b-02-67 Example b-02-01 (LC-1); RT=1.36, m/z 566 [M+H] ⁺ b-02-68 Example b-02-01 (LC-1); RT=1.16, m/z 550 [M+H] ⁺ b-02-69 Example b-02-01 (LC-1); RT=1.17, m/z 550 [M+H] ⁺ b-02-70 Example b-02-01 (LC-1); RT=1.37, m/z 578 [M+H] ⁺ b-02-71 Example b-02-01 (LC-1); RT=1.29, m/z 564 [M+H] ⁺ b-02-72 Example b-02-01 (LC-1); RT=0.87, m/z 498 [M+H] ⁺ b-02-73 Example b-02-01 (LC-1); RT=1.26, m/z 519 [M+H] ⁺ b-02-74 Example b-02-01 (LC-1); RT=0.97, m/z 550 [M+H] ⁺ b-02-75 Example b-02-01 (LC-1); RT=1.09, m/z 550 [M+H] ⁺ b-02-76 Example b-02-01 (LC-1); RT=1.23, m/z 506 [M+H] ⁺ b-02-77 Example b-02-01 (LC-1); RT=1.36, m/z 510 [M+H] ⁺ b-02-78 Example b-02-01 (LC-1); RT=1.21, m/z 564 [M+H] ⁺ b-02-79 Example b-02-01 (LC-1); RT=1.47, m/z 562 [M+H] ⁺ b-02-80 Example b-02-01 (LC-1); RT=1.59, m/z 576 [M+H] ⁺ b-02-81 Example b-02-01 (LC-1); RT=1.35, m/z 564 [M+H] ⁺ b-02-82 Example b-02-01 (LC-1); RT=1.41, m/z 578 [M+H] ⁺ b-02-83 Example b-02-01 (LC-1); RT=0.96, m/z 508 [M+H] ⁺ b-02-84 Example b-02-01 (LC-1); RT=0.97, m/z 522 [M+H] ⁺ b-02-85 Example b-02-01 (LC-1); RT=1.01, m/z 566 [M+H] ⁺ b-02-86 Example b-02-01 (LC-1); RT=1.06, m/z 537 [M+H] ⁺ b-02-87 Example b-02-01 (LC-1); RT=1.05, m/z 537 [M+H] ⁺

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 [Chemical 92]

3-(3-bicyclo[1,1,1]pentylamino)-N-[6-[2-[[(1S,2S)]2-hydroxycyclopentyloxy]methyl]pyrimidine-5 -yl]-1,3-benzothiazol-2-yl]cyclobutanecarboxamide (Example b-02-29; 29 mg, 0.06 mmol) was dissolved in dichloromethane (1.3 mL), THF (1 mL), add formaldehyde (10 μL), sodium triacetyloxyborohydride (18.25 mg, 0.09 mmol), and stir overnight at room temperature. After the reaction was completed, water, chloroform, and saturated sodium bicarbonate were added to the reaction mixture for extraction, nitrogen gas was passed through to concentrate the organic layer, and HPLC purification was performed to obtain 3-(bicyclo[1,1,1]pentane-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, 43% yield). LCMS (LC-1); RT=1.31, m/z 520 [M+H] ⁺ 1H-NMR (CDCl ₃ ): 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).

Using the same method, the following compounds in the following table were synthesized. In the following tables, "reference method" indicates that the examples of the production method should be referred to. [Table 7] example structure Reference method LCMS data b-03-02 Example b-03-01, Example b-02-29 (LC-1); RT=1.68, m/z 602 [M+H] ⁺ b-03-03 Example b-03-01, Example b-02-47 (LC-1); RT=1.16, m/z 494 [M+H] ⁺ b-03-04 Example b-03-01, Example b-02-49 (LC-1); RT=1.42, m/z 534 [M+H] ⁺ b-03-05 Example b-03-01, Example b-02-56 (LC-1); RT=1.42, m/z 544 [M+H] ⁺ b-03-06 Example b-03-01, Example b-02-42 (LC-1); RT=1.21, m/z 545 [M+H] ⁺ b-03-07 Example b-03-01, Example b-02-58 (LC-1); RT=1.43, m/z 562 [M+H] ⁺ b-03-08 Example b-03-01, Example b-02-64 (LC-1); RT=1.27, m/z 544 [M+H] ⁺ b-03-09 Example b-03-01, Example b-02-65 (LC-1); RT=1.07, m/z 534 [M+H] ⁺

Intermediate B-4-1: (1S,2S)-2-(pyrimidin-2-ylmethoxy)cyclopentyl acetate [Chem. 93]

(1S,2S)-2-(Pyrimidin-2-ylmethoxy)cyclopentanol (39.03 g, 200.95 mmol) was dissolved in dichloromethane (402 mL), and cooled and stirred at 0°C. Triethylamine (56.02 mL, 402 mmol), 4-dimethylaminopyridine (1.96 g, 16.08 mmol), and acetic anhydride (36.09 mL, 381.8 mmol) were added and stirred. After 10 minutes, stir at room temperature for 1 hour. The reaction mixture was cooled at 0°C, water and saturated sodium bicarbonate water were added, stirred, and dichloromethane was added for extraction. The aqueous layer was once again extracted with dichloromethane, the organic layers were combined, dried over sodium sulfate, filtered, concentrated, and purified by automatic silica gel column chromatography (eluent: chloroform-methanol 2%) to obtain The target [(1S,2S)-2-(pyrimidin-2-ylmethoxy)cyclopentyl] acetate (22.73 g, yield 48%). LCMS (LC-1); RT=0.92, m/z 238 [M+H] ⁺ 1H-NMR (CDCl ₃ ): δ (ppm) 8.73 (2H, d, J = 5.0 Hz), 7.19 (1H, dd , J = 5.0, 5.0 Hz), 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, 4.0 Hz), 2.12-1.95 (2H, m), 1.85-1.69 (4H, m), 1.75 (3H, s).

Intermediate B-4-2: (1S,2S)-2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) acetate Pyrimidin-2-yl)methoxy)cyclopentyl ester [Chemical 94]

To (1S,2S)-2-(pyrimidin-2-ylmethoxy)cyclopentyl acetate (intermediate B-4-1; 40.1 g, 169.7 mmol) was added THF (339.5 mL), bis(frequency Nacolate) diboron (47.41 g, 186.7 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (0.8 g, 3.39 mmol), argon replacement, and then add ( 1,5-Cyclooctadiene)methoxy)iridium(I) dimer (1.13 g, 1.7 mmol) was heated and stirred overnight at 80°C. Add (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), bis(pinacolate) diboron (2.1 g, 8.5 mmol), heated and stirred at 80° C. for 6.5 hours. After the reaction, the reaction mixture solution was concentrated and vacuum-dried to obtain the crude product acetic acid (1S,2S)-2-((5-(4,4,5,5-tetramethyl-1,3,2-di oxaborolan-2-yl)pyrimidin-2-yl)methoxy)cyclopentyl ester (99.24 g). LCMS (LC-1); RT=0.78, m/z 281 [M+H] ⁺ (detected as boronic acid) 1H-NMR (CDCl ₃ ): 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).

Intermediate B-4-3: (1S,2S)-2-((5-(2-aminobenzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentyl acetate [chem 95]

Add 1,4-dioxane (243.6 mL) to 2-amino-6-bromobenzothiazole (20.3 mg, 88.61 mmol) for dissolution, add 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), water (60.9 mL), heated and stirred overnight at 80°C. Add [(1S,2S)-2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2- methoxy]cyclopentyl]acetate (21 g, 58 mmol), cesium carbonate (28.4 g, 88.61 mmol), [1,1'-bis(diphenylphosphino)ferrocene]di Chloropalladium (II) (2.1 g, 26.6 mmol), heated and stirred overnight at 90°C. After the reaction, the reaction mixture was filtered through celite, and extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The obtained crude product was purified by automatic silica gel column chromatography (eluent; chloroform-methanol 1-2%) to obtain acetic acid (1S,2S)-2-((5-(2-amino Benzo[d]thiazol-6-yl)methoxy)cyclopentyl ester (30.06 g, 88% yield).LCMS (LC-1); RT=1.16, m/z 385 [M+H] ⁺ 1H -NMR (CDCl ₃ ): 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).

Intermediate B-4-4: (1S,2S)-2-((5-(2-(3-oxocyclobutane-1-carboxamide)benzo[d]thiazol-6-yl acetate ) pyrimidin-2-yl) methoxy) cyclopentyl ester [chemical 96]

Use dichloromethane (250 mL), THF (130 mL) to dissolve (1S,2S)-2-(((5-(2-aminobenzo[d]thiazol-6-yl)pyrimidin-2-yl )methoxy)cyclopentyl ester (intermediate B-4-3; 17 g, 44.22 mmol), add N-diisopropylamine (23.11 mL, 132.66 mmol), 3-oxocyclobutane-1 -Carboxylic acid (6.05 g, 53.06 mmol), 1-propylphosphonic acid anhydride (19.74 mL, 66.33 mmol), stirred overnight at room temperature. After the reaction, add sodium bicarbonate water to the reaction mixture, and use chloroform to carry out Extraction. The aqueous layer was extracted again with chloroform, the organic layers were combined, dried over sodium sulfate, filtered and concentrated, and the obtained product was purified by silica gel column chromatography (eluent: chloroform-methanol 2-5%) The crude product was purified to obtain (1S,2S)-2-((5-(2-(3-oxocyclobutane-1-carboxamide)benzo[d]thiazol-6-yl)pyrimidine acetate -2-yl)methoxy)cyclopentyl ester (13.13 g, 62% yield). LCMS (LC-1); RT=1.36, m/z 481 [M+H] ⁺ 1H-NMR (CDCl ₃ ) : 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) , 4.13-4.06 (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).

Intermediate B-4-5: (S)-4-((1s,3R)-3-((6-2-((((1S,2S)-2-Acetyloxycyclopentyl)oxy )methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)aminoformyl)cyclobutyl)-3-methylpiper-1-carboxylic acid tert-butyl ester [Chemical 97]

Dissolve acetic acid (1S,2S)-2-((5-(2-(3-oxocyclobutane-1-carboxamide)benzo[ d] Thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentyl ester (intermediate B-4-4; 13.14 g, 27.34 mmol), addition of (3S)-1-Boc-3-methyl Piperone (10.95 g, 54.68 mmol), stirred at room temperature. After 15 minutes, sodium triacetyloxyborohydride (8.69 g, 41.01 mmol) was added and stirred directly at room temperature for 2 hours. (3S)-1-Boc-3-methylpiperone (2.73 g, 13.7 mmol) and sodium triacetyloxyborohydride (1.7 g, 8.2 mmol) were added, followed by further stirring for 2 hours. After completion of the reaction, aqueous sodium bicarbonate was added to the reaction mixture, followed by extraction with chloroform. The aqueous layer was extracted with chloroform again, filtered and concentrated, and the obtained crude product was purified by silica gel column chromatography to obtain (S)-4-((1S,3R)-3-((6-2- ((((1S,2S)-2-Acetyloxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)carbamoyl)cyclobutyl )-tert-butyl 3-methylpiperone-1-carboxylate (9.2548 g, yield 51%). LCMS (LC-1); RT=1.69, m/z 666 [M+H] ⁺

Example b-04-01: (S)-4-((1S,3R)-3-((6-2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl )pyrimidin-5-yl)benzo[d]thiazol-2-yl)carbamoyl)cyclobutyl)-3-methylpiperone-1-carboxylic acid tertiary butyl ester [Chemical 98]

In (S)-4-((1s,3R)-3-((6-2-((((1S,2S)-2-acetyloxycyclopentyl)oxy)methyl)pyrimidine-5 -yl)benzo[d]thiazol-2-yl)carbamoyl)cyclobutyl)-3-methylpiperone-1-carboxylic acid tert-butyl ester (intermediate B-4-5; 6.01 g , 9.04 mmol), methanol (30 mL) and THF (70 mL) were added for dissolution, potassium carbonate (3.75 g, 27.12 mmol) was added, and stirred at room temperature for 1.5 hours. After completion of the reaction, water was added to the reaction mixture, followed by extraction with chloroform. The aqueous layer was extracted again with chloroform, dried over sodium sulfate, filtered and concentrated. The obtained crude product was purified by silica gel column chromatography (eluate; chloroform:methanol=98:2) to obtain (S)-4-((1S,3R)-3-((6-2- ((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)carbamoyl)cyclobutyl)-3 - tert-butyl methylpiperone-1-carboxylate (4.88 g, 87% yield). LCMS (LC-1); RT=1.44, m/z 623 [M+H] ⁺

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-methylpiper-1-yl)cyclobutane-1-carboxamide [Chemical 99]

In (S)-4-((1S,3R)-3-((6-2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl) Benzo[d]thiazol-2-yl)aminoformyl)cyclobutyl)-3-methylpiperone-1-carboxylic acid tert-butyl ester (Example b-04-01; 4.88 g, 7.84 mmol ) was added dichloromethane (280 mL), THF (120 mL) to dissolve, 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 obtain (1R,3s)-N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidine-5- yl)benzo[d]thiazol-2-yl)-3-((S)-2-methylpiper-1-yl)cyclobutane-1-carboxamide (3.05 g, yield 74%) . LCMS (LC-1); RT=0.88, m/z 524 [M+H] ⁺ 1H-NMR (CDCl ₃ ): 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 = 5.5 Hz).

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)piper-1-yl)cyclobutane-1-methanol Amide [Chem. 100]

In (1R,3s)-N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazole- Dichloromethane (320 mL), THF (160 mL) to dissolve, add N-ethyldiisopropylamine (3.05 mL, 17.51 mmol), 2-methoxyisonicotinic acid (960.3 mg, 7 mmol), 1-propylphosphonic anhydride (5.14 mL), stirred at room temperature for 2 hours. After completion of the reaction, aqueous sodium bicarbonate was added to the reaction mixture solution, followed by extraction with chloroform. The aqueous layer was extracted again with chloroform, and the organic layers were combined, dried over sodium sulfate, and concentrated by filtration. The obtained crude product was purified by silica gel column chromatography (eluate; ethyl acetate:methanol=80:20) to obtain (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)piperone-1-yl)cyclobutane-1-carboxamide (272.9 mg, 7% yield). LCMS (LC-1); RT=1.08, m/z 642 [M+H] ⁺ 1H-NMR (CD ₃ OD): 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), 3.81-3.67 (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).

Using the same method, the following compounds in the following table were synthesized. In the following tables, "reference method" indicates that the examples of the production method should be referred to. [Table 8] example structure Reference method LCMS data b-04-03 Example b-04-02 (LC-1); RT=1.14, m/z 642 [M+H] ⁺ b-04-04 Example b-04-02 (LC-1); RT=1.07, m/z 649 [M+H] ⁺ b-04-05 Example b-04-02 (LC-1); RT=1.05, m/z 621 [M+H] ⁺ b-04-06 Example b-04-02 (LC-1); RT=1.03, m/z 639 [M+H] ⁺ b-04-07 Example b-04-02 (LC-1); RT=1.03, m/z 621 [M+H] ⁺ b-04-08 Example b-04-02 (LC-1); RT=1.07, m/z 609 [M+H] ⁺ b-04-09 Example b-04-02 (LC-1); RT=1.04, m/z 635 [M+H] ⁺ b-04-10 Example b-04-02 (LC-1); RT=1.21, m/z 617 [M+H] ⁺ b-04-11 Example b-04-02 (LC-1); RT=1.06, m/z 628 [M+H] ⁺ b-04-12 Example b-04-02 (LC-1); RT=1.03, m/z 628 [M+H] ⁺ b-04-13 Example b-04-02 (LC-1); RT=1.02, m/z 628 [M+H] ⁺ b-04-14 Example b-04-02 (LC-1); RT=1.29, m/z 696 [M+H] ⁺ b-04-15 Example b-04-01, 02 intermediates B-4-5, 6 (LC-1); RT=1.23, m/z 656 [M+H] ⁺ b-04-16 Example b-04-01, 02 intermediates B-4-5, 6 (LC-1); RT=1.13, m/z 642 [M+H] ⁺ b-04-17 Example b-04-01, 02 intermediates B-4-5, 6 (LC-1); RT=1.20, m/z 649 [M+H] ⁺ b-04-18 Example b-04-01, 02 intermediates B-4-5, 6 (LC-1); RT=1.10, m/z 635 [M+H] ⁺ b-04-19 Example b-04-02 (LC-1); RT=1.30, m/z 696 [M+H] ⁺ b-04-20 Example b-04-02 (LC-1); RT=1.21, m/z 658 [M+H] ⁺ b-04-21 Example b-04-02 (LC-1); RT=1.11, m/z 642 [M+H] ⁺ b-04-22 Example b-04-02 (LC-1); RT=1.03, m/z 621 [M+H] ⁺ b-04-23 Example b-04-02 (LC-1); RT=1.03, m/z 621 [M+H] ⁺ b-04-24 Example b-04-01, 02 Intermediates A-2-2, B-4-3, 4, 5, 6 (LC-1); RT=1.24, m/z 586 [M+H] ⁺ b-04-25 Example b-04-01, 02 Intermediates A-2-2, B-4-3, 4, 5, 6 (LC-1); RT=1.21, m/z 579 [M+H] ⁺ b-04-26 Example b-04-01, 02 Intermediates A-2-2, B-4-3, 4, 5, 6 (LC-1); RT=1.50, m/z 654 [M+H] ⁺ b-04-27 Example b-04-02 (LC-1); RT=1.12, m/z 646 [M+H] ⁺ b-04-28 Example b-04-02 (LC-1); RT=0.98, m/z 629 [M+H] ⁺ b-04-29 Example b-04-02 (LC-1); RT=1.11, m/z 632 [M+H] ⁺ b-04-30 Example b-04-02 (LC-1); RT=1.21, m/z 696 [M+H] ⁺ b-04-31 Example b-04-02 (LC-1); RT=1.19, m/z 634 [M+H] ⁺ b-04-32 Example b-04-02 (LC-1); RT=1.11, m/z 662 [M+H] ⁺ b-04-33 Example b-04-02 (LC-1); RT=1.11, m/z 618 [M+H] ⁺ b-04-34 Example b-04-02 (LC-1); RT=1.03, m/z 629 [M+H] ⁺ b-04-35 Example b-04-02 (LC-1); RT=1.27, m/z 696 [M+H] ⁺ b-04-36 Example b-04-02 (LC-1); RT=1.08, m/z 632 [M+H] ⁺ b-04-37 Example b-04-02 (LC-1); RT=1.21, m/z 662 [M+H] ⁺ b-04-38 Example b-04-02 (LC-1); RT=1.00, m/z 629 [M+H] ⁺ b-04-39 Example b-04-02 (LC-1); RT=1.12, m/z 618 [M+H] ⁺ b-04-40 Example b-04-02 (LC-1); RT=1.09, m/z 656 [M+H] ⁺ b-04-41 Example b-04-01, 02 Intermediates A-2-2, B-4-3, 4, 5, 6 (LC-1); RT=1.33, m/z 604 [M+H] ⁺ b-04-42 Example b-04-01, 02 Intermediates A-2-2, B-4-3, 4, 5, 6 (LC-1); RT=1.32, m/z 600 [M+H] ⁺ b-04-43 Example b-04-01, 02 Intermediates A-2-2, B-4-3, 4, 5, 6 (LC-1); RT=1.34, m/z 620 [M+H] ⁺ b-04-44 Example b-04-02 (LC-1); RT=1.09, m/z 642 [M+H] ⁺ b-04-45 Example b-04-02 (LC-1); RT=1.17, m/z 658 [M+H] ⁺ b-04-46 Example b-04-02 (LC-1); RT=1.14, m/z 646 [M+H] ⁺ b-04-47 Example b-04-02 (LC-1); RT=1.14, m/z 642 [M+H] ⁺ b-04-48 Example b-04-02 (LC-1); RT=1.14, m/z 662 [M+H] ⁺

Example b-05-01: (1R,3s)-3-((S)-4-acetyl-2-methylpiper-1-yl)N-(6-(2-(((( 1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide [Chemical 101]

(1R,3s)-N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazole- 2-yl)-3-((S)-2-methylpiper-1-yl)cyclobutane-1-carboxamide (intermediate B-4-6; 27.7 mg, 0.05 mmol) was dissolved in di Chloromethane (1.3 mL), acetyl chloride (4.52 μL, 0.06 mmol) and triethylamine (14.77 μL, 0.11 mmol) were added, and stirred at room temperature for 1 hour. Sodium bicarbonate water was added to the reaction mixture, extracted with chloroform, concentrated by blowing nitrogen gas, and the obtained crude product was purified by HPLC to obtain (1R,3s)-3-((S)-4- Acetyl-2-methylpiper-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, 47% yield). LCMS (LC-1); RT=0.99, m/z 565 [M+H] ⁺ 1H-NMR (CDCl ₃ ): 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), 3.59-3.52 (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).

Using the same method, the following compounds in the following table were synthesized. In the following tables, "reference method" indicates that the examples of the production method should be referred to. [Table 9] example structure Reference method LCMS data b-05-02 Example b-05-01 (LC-1); RT=1.09, m/z 591 [M+H] ⁺ b-05-03 Example b-05-01 (LC-1); RT=1.00, m/z 595 [M+H] ⁺ b-05-04 Example b-05-01 (LC-1); RT=1.21, m/z 627 [M+H] ⁺ b-05-05 Example b-05-01 (LC-1); RT=1.06, m/z 579 [M+H] ⁺ b-05-06 Example b-05-01 (LC-1); RT=1.13, m/z 593 [M+H] ⁺ b-05-07 Example b-05-01 (LC-1); RT=1.18, m/z 605 [M+H] ⁺ b-05-08 Example b-05-01 (LC-1); RT=1.11, m/z 601 [M+H] ⁺ b-05-09 Example b-05-01 (LC-1); RT=1.07, m/z 606 [M+H] ⁺

Intermediate B-6-1: (S)-4-((3R)-3-((6-(2-((((1S,2S)-2-acetyloxycyclopentyl)oxy) Methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)aminoformyl)cyclobutyl)-3-methylpiperone-1-carboxylic acid tertiary butyl ester [Chem. 102]

Acetic acid (1S,2S)-2-((5-(2-(3-oxocyclobutane-1-carboxamide)benzo[d]thiazol-6-yl)pyrimidin-2-yl) Methoxy)cyclopentyl ester (Intermediate B-4-4; 15 g, 31.2 mmol) was dissolved in dichloromethane (156 mL), and (3S)-1-BOC-3-methylpiperone hydrochloride was added (1.5 g, 46.8 mmol), sodium triacetyloxyborohydride (13.2 g, 62.4 mmol), and stirred at room temperature for 3 hours. 25% aqueous ammonia was added to the obtained crude reaction mixture, followed by extraction with chloroform. The obtained organic layer was dried with magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain (S)-4-((3R)-3-((6-(2-((((1S,2S) -2-Acetyloxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)aminoformyl)cyclobutyl)-3-methylpiperone - tert-butyl 1-carboxylate (10 g, yield 48%). LCMS (LC-1); RT=1.68, m/z 665 [M+H] ⁺ 1H-NMR (CDCl ₃ ): δ (ppm) 9.00 (s, 2H), 7.99 (brs, 1H), 7.87 (m , 1H), 7.61 (brd, J = 7.5 Hz, 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).

Intermediate B-6-2: (1S,2S)-2-((5-(2-((1R,3s)-3-((S)-2-methylpiper-1-yl) ring Butane-1-carboxamide)benzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentyl ester [Chem. 103]

In (S)-4-((3R)-3-((6-(2-((((1S,2S)-2-acetyloxycyclopentyl)oxy)methyl)pyrimidine-5- Base) benzo[d]thiazol-2-yl)carbamoyl)cyclobutyl)-3-methylpiper-1-carboxylate tertiary butyl ester (intermediate B-6-1; 5.3 g, 7.97 mol) was added for dissolution by adding dichloromethane (80 mL), trifluoroacetic acid (6.1 mL, 79.7 mmol) was added, and stirred at room temperature. The obtained crude reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution, and extracted with chloroform. The obtained organic layer was dried with magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain acetic acid (1S, 2S)-2-((5-(2-((1R, 3s)-3-((S (3.7 g , yield 82%). LCMS (LC-1); RT=1.12, m/z 565 [M+H] ⁺ 1H-NMR (CDCl ₃ ): δ (ppm) 9.00 (s, 2H), 8.01 (d, J = 2.0 Hz, 1H ), 7.89 (d, J = 8.5 Hz, 1H), 7.62(dd, J = 8.5, 2.0 Hz, 1H), 5.20 (d, J = 6.5 Hz, 1H), 4.98-4.77 (m, 2H), 4.10 (d, J = 6.5 Hz, 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 = 6.5 Hz, 3H ).

Example b-06-01: (S)-N-ethyl-4-((1s,3R)-3-((6-(2-((((1S,2S)-2-hydroxycyclopentyl ) Oxygen) methyl) pyrimidin-5-yl) benzo [d] thiazol-2-yl) aminoformyl) -3-methylpiperone-1-formamide [Chemical 104]

(1S,2S)-2-((5-(2-((1R,3s)-3-((S)-2-methylpiper-1-yl)cyclobutane-1-formyl)acetic acid To amine)benzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentyl ester (Intermediate B-6-2; 31.9 mg, 0.06 mol) was added dichloromethane (1 mL) , THF (0.75 mL) were dissolved, ethyl isocyanate (5.37 uL, 0.07 mmol) and triethylamine (15.75 uL, 0.11 mmol) were added, and stirred at room temperature. Methanol (1 mL) and triethylamine (12 uL) were added to the obtained reaction mixture for stirring, and then potassium carbonate (20 mg) and 2 N sodium hydroxide solution (50 uL) were added, and left overnight at room temperature Stir. After the reaction was finished, feed nitrogen, concentrate the solvent, and perform HPLC purification, thereby obtaining (S)-N-ethyl-4-((1s,3R)-3-((6-(2-((((1S ,2S)-2-Hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)aminoformyl)-3-methylpiperone-1-methyl Amide (8.4 mg, yield 25.0%). LCMS (LC-1); RT=1.02, m/z 594 [M+H] ⁺ 1H-NMR (CDCl ₃ ): 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 = 6.6 Hz).

Using the same method, the following compounds in the following table were synthesized. In the following tables, "reference method" indicates that the examples of the production method should be referred to. [Table 10] example structure Reference method LCMS data b-06-02 Example b-06-01 (LC-1); RT=1.22, m/z 642 [M+H] ⁺

Example b-07-01: N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazole -2-yl)-3-((S)-2-methyl-4-(2,2,2-trifluoroethyl)piper-1-yl)cyclobutane-1-formamide [Chem 105]

(1R,3s)-N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo [d] Thiazol-2-yl)-3-((S)-2-methylpiper-1-yl)cyclobutane-1-carboxamide (Example B-4-6; 0.10 g, 0.19 mmol), 2,2,2-trifluoroethyl ester (42 μL, 0.29 mmol) were suspended in THF (634 μL), added N-ethyldiisopropylamine (83 μL, 0.48 mmol), at 50°C Stir for 15 hours. Methanol (4 mL) and 1 M aqueous sodium hydroxide solution (2 mL) were added to the obtained crude reaction mixture, followed by extraction with chloroform. The obtained crude product was purified by SCX and HPLC, thereby obtaining N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidine-5- Base) benzo[d]thiazol-2-yl)-3-((S)-2-methyl-4-(2,2,2-trifluoroethyl)piper-1-yl)cyclobutane -1-Formamide (22 mg, yield 19%). LCMS (LC-1); RT=1.33, m/z 605 [M+H] ⁺ 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 = 6.4 Hz).

Intermediate B-8-1: (S)-tert-butyl 4-cyclopropyl-2-methylpiperone-1-carboxylate [Chem. 106]

(2S)-2-methylpiperone-1-carboxylate tert-butyl ester (1 g, 5.0 mmol), (1-ethoxycyclopropoxy) trimethylsilane (1 mL, 5.0 mmol) Dissolve in methanol (10 mL), tetrahydrofuran (10 mL), add acetic acid (0.57 mL, 10 mmol), sodium cyanoborohydride (627 mg, 10 mmol), and stir at 60°C for 6 hours. The obtained crude reaction mixture was cooled to room temperature, water (1 mL), 1 M aqueous sodium hydroxide solution (6 mL) were added, and the organic solvent was removed under reduced pressure. The obtained aqueous layer was extracted with chloroform (20 mL), and the organic layer was washed with 1 M aqueous sodium hydroxide solution. The combined aqueous layers were extracted with chloroform (6 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product (S)-4-cyclopropyl-2-methyl tert-butyl piper-1-carboxylate (1.21 g). 1H-NMR (CDCl ₃ ): 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 = 6.7 Hz), 0.44-0.28 (4H, m).

Intermediate B-8-2: (S)-1-cyclopropyl-3-methylpiperone hydrochloride [Chem. 107]

The above crude product (S)-4-cyclopropyl-2-methylpiperone-1-carboxylate tert-butyl ester (intermediate B-8-1; 1.2 g) was dissolved in 4 M hydrochloric acid in 1,4 - Dioxane solution, stirred at room temperature for 30 minutes. The obtained crude reaction mixture was azeotroped 3 times with ethyl acetate to obtain crude product (S)-1-cyclopropyl-3-methylpiperone hydrochloride (1.2 g). 1H-NMR (CD ₃ OD): 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 = 6.5 Hz), 1.23-1.19 (2H, m), 1.02-0.96 (2H, m).

Example b-08-01: 3-((S)-4-cyclopropyl-2-methylpiper-1-yl)N-(6-(2-((((1S,2S)-2 -Hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide [Chem. 108]

In N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)3- Add dichloromethane (1.5 mL) and THF (1.3 mL) to the side oxycyclobutane-1-carboxamide (intermediate B-2-2; 40.2 mg, 0.09 mmol) to dissolve, add (S)- 1-Cyclopropyl-3-methylpiperone hydrochloride (intermediate B-8-2; 25.7 mg, 0.18 mml) was stirred, and then sodium triacetyloxyborohydride (29.14 mg, 0.14 mmol) was added , stirred overnight at room temperature. Add (S)-1-cyclopropyl-3-methylpiperone hydrochloride (25.7 mg, 0.18 mml), acetic acid (200 uL), sodium triacetyloxyborohydride (29.14 mg, 0.14 mmol), Furthermore, it stirred for 5 hours. After the reaction was completed, sodium bicarbonate water was added to the reaction mixture solution, extracted with chloroform, the organic layer was concentrated by nitrogen gas, and purified by HPLC to obtain 3-((S)-4-cyclopentyl-2-methyl Piper-1-yl)N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazole- 2-yl)cyclobutane-1-carboxamide (4.3 mg, 8% yield). LCMS (LC-1); RT=1.13, m/z 563 [M+H] ⁺ 1H-NMR (CDCl ₃ ): 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), 2.97-2.88 (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 = 6.1 Hz), 0.45-0.33 (4H, m).

Intermediate C-1-1: N-(7-oxo-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)acetamide [Chem. 109]

2-Amino-5,6-dihydro-4H-benzothiazol-7-one (60 g, 357 mmol) was suspended in acetic anhydride (300 mL), and stirred under reflux for 4 hours. The obtained crude reaction mixture was cooled to room temperature, the precipitate was filtered, washed with water, and vacuum-dried to obtain N-(7-oxo-4,5,6,7-tetrahydro Benzo[d]thiazol-2-yl)acetamide (69.6 g, 93% yield). LCMS (LC-1); RT=0.75, m/z 211 [M+H] ⁺ 1H-NMR (DMSOd6): δ (ppm) 12.52 (1H, s), 2.85 (2H, t, J = 6.2 Hz) , 2.51-2.47 (2H, m), 2.18 (3H, s), 2.11-2.05 (2H, m).

Intermediate C-1-2: N-(6,6-dibromo-7-oxo-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)acetamide [Chem 110]

Suspend N-(7-oxo-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)acetamide (Intermediate C-1-1; 30 g, 143 mmol) To acetic acid (300 mL), add 48% hydrobromic acid (3.2 mL, 29 mmol), bromine (29 mL, 571 mmol), and stir at 60°C for 24 hours. Water (300 mL) was added to the obtained crude reaction mixture. Two batches of the same operation were performed, the obtained precipitates were combined, 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%). LCMS (LC-1); RT=1.21, m/z 366 [M+H] ⁺ 1H-NMR (DMSOd6): δ (ppm) 12.88 (1H, s), 3.15 (2H, t, J = 5.8 Hz) , 2.97 (2H, t, J = 5.8 Hz), 2.22 (3H, s).

Intermediate C-1-3: N-(6-bromo-7-hydroxybenzo[d]thiazol-2-yl)acetamide [Chem. 111]

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, stirred at room temperature for 30 minutes, saturated aqueous ammonium chloride solution (300 mL) was added, stirring was stopped, and the mixture was allowed to stand for 30 minutes. Carry out 2 batches of the same operation, filter the obtained precipitate, wash with water, and carry out vacuum drying to obtain the crude product N-(6-bromo-7-hydroxybenzo[d]thiazole-2- base) acetamide (68.4 g). LCMS (LC-1); RT=0.90, m/z 286 [M+H] ⁺ 1H-NMR (DMSOd6): δ (ppm) 7.37 (1H, d, J = 8.4 Hz), 6.86 (1H, d, J = 8.4 Hz), 2.17 (3H, s).

Using the same method, the following compounds in the following table were synthesized. In the following tables, "reference method" indicates that the examples of the production method should be referred to. [Table 11] intermediate structure Reference method LCMS data C-1-10 Intermediate C-1-1, 2, 3 (LC-1); RT=1.14, m/z 312 [M+H] ⁺

Intermediate C-1-4: 2-Amino-6-bromobenzo[d]thiazol-7-ol [Chem. 112]

The above crude N-(6-bromo-7-hydroxybenzo[d]thiazol-2-yl)acetamide (intermediate C-1-3; 68.4 g) was suspended in methanol (240 mL), 5 M Hydrochloric acid water (360 mL), stirred at 75°C for 14 hours. Methanol was removed from the obtained crude reaction mixture under reduced pressure, neutralized by dropwise addition of 5 M aqueous sodium hydroxide solution under ice-bath cooling. The obtained solid was filtered and dried in vacuo, whereby crude product 2-amino-6-bromobenzo[d]thiazol-7-ol was obtained. LCMS (LC-1); RT=0.84, m/z 244 [M+H] ⁺ (detected as boronic acid) 1H-NMR (DMSOd6): δ (ppm) 9.92 (1H, s, br), 7.52 (2H, s), 7.28 (1H, d, J = 8.4 Hz), 6.81 (1H, d, J = 8.4 Hz).

Intermediate C-1-5: 2-(6-bromo-7-hydroxybenzo[d]thiazol-2-yl)isoindoline-1,3-dione [Chem. 113]

The above crude product 2-amino-6-bromobenzo[d]thiazol-7-ol (intermediate C-1-4; 163 mmol) was suspended in N,N-dimethylformamide (137 mL) , acetic acid (137 mL), added maleic anhydride (48 g, 326 mmol), and stirred at 120° C. for 5 hours. The obtained crude reaction mixture was cooled to room temperature, the precipitate was filtered, washed with water, and dried in vacuo to obtain 2-(6-bromo-7-hydroxybenzo[d]thiazole-2- base) isoindoline-1,3-dione (54.7 g, 89% yield over 3 steps). LCMS (LC-1); RT=1.23, m/z 374 [M+H] ⁺ 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).

Intermediate C-1-6: 2-(6-bromo-7-methoxybenzo[d]thiazol-2-yl)isoindoline-1,3-dione [Chem. 114]

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), added iodomethane (27 mL, 437 mmol), N-ethyldiisopropylamine (102 mL, 583 mmol), stirred at room temperature for 9 Hour. Water (110 mL) was added to the obtained crude reaction mixture, filtered, and vacuum-dried to obtain 2-(6-bromo-7-methoxybenzo[d]thiazol-2-yl)iso Indoline-1,3-dione (52.0 g, 92%). LCMS (LC-1); RT=1.74, m/z 388 [M+H] ⁺ 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.)

Intermediate C-1-7: 6-bromo-7-methoxybenzo[d]thiazol-2-amine [Chem. 115]

2-(6-Bromo-7-methoxybenzo[d]thiazol-2-yl)isoindoline-1,3-dione (Intermediate C-1-6; 52.0 g, 134 mmol) Suspend in ethanol, add hydrazine monohydrate (7.1 mL, 147 mmol), and stir under reflux for 1 hour. The obtained crude reaction mixture was cooled to 50° C., and the precipitate was filtered and washed with tetrahydrofuran. The obtained filtrate was concentrated under reduced pressure, whereby 6-bromo-7-methoxybenzo[d]thiazol-2-amine (41.6 g) was obtained as a crude product. LCMS (LC-1); RT=1.23, m/z 258 [M+H] ⁺ 1H-NMR (DMSOd6): δ (ppm) 7.69 (2H, s), 7.40 (1H, d, J = 8.4 Hz) , 7.05 (1H, d, J = 8.4 Hz), 3.85 (3H, s).

Intermediate C-1-8: (1S,2S)-2-((5-(2-amino-7-methoxybenzo[d]thiazol-6-yl)pyrimidin-2-yl)methyl acetate Oxy) cyclopentyl ester [Chem. 116]

Suspend the above crude product 6-bromo-7-methoxybenzo[d]thiazol-2-amine (intermediate C-1-7; 12.35 g, 38.6 mmol) in 1,4-dioxane, add the above Crude product (1S,2S)-2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl) acetate Methoxy)cyclopentyl ester (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), water (25 mL), stirred at 130°C for 1 hour. This 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 layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Use automatic silica gel column chromatography (eluent; chloroform:methanol=100:0-95:5) to purify the obtained crude product to obtain the crude product acetic acid (1S,2S)-2-((5-( 2-Amino-7-methoxybenzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentyl ester (19.3 g). LCMS (LC-1); RT=1.22, m/z 415 [M+H] ⁺

Intermediate C-1-9: (1S,2S)-2-((5-(2-amino-7-methoxybenzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy base) cyclopentan-1-ol [chemical 117]

The above crude product acetic acid (1S, 2S)-2-((5-(2-amino-7-methoxybenzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclo Amyl ester (intermediate C-1-8; 20 g) was dissolved in methanol (100 mL), 5 M aqueous sodium hydroxide solution (100 mL) was added, and stirred at room temperature for 5 minutes. Water (100 mL), saturated ammonium chloride aqueous 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 layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by automatic silica gel column chromatography (eluate; chloroform:methanol=99:1-92:8) to obtain (1S,2S)-2-((5-(2 -Amino-7-methoxybenzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentan-1-ol (8.1 g, 54% yield over 2 steps). LCMS (LC-1); RT=0.93, m/z 373 [M+H] ⁺ 1H-NMR (DMSOd6): δ (ppm) 8.93 (2H, s), 7.73 (2H, s), 7.36 (1H, d, J = 8.3 Hz), 7.24 (1H, d, J = 8.3 Hz), 4.72 (1H, d, J = 4.0 Hz), 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).

Example c-01-01: N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)-7-methoxy Benzo[d]thiazol-2-yl)cyclopropaneformamide [Chem. 118]

(1S,2S)-2-((5-(2-Amino-7-methoxybenzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentane-1 -alcohol (intermediate C-1-9; 5.7 g, 15.3 mmol) was dissolved in tetrahydrofuran (31 mL), N-ethyldiisopropylamine (8 mL, 46 mmol), cyclopropylformyl chloride (2.1 mL, 23 mmol), stirred at room temperature for 5 minutes. Cyclopropylformyl chloride (700 μL, 7.7 mmol) was added to the reaction mixture, followed by stirring at room temperature for 1 minute. N-Ethyldiisopropylamine (1.66 mL, 7.7 mmol) and cyclopropylformyl chloride (700 μL, 7.7 mmol) were added to the reaction mixture, followed by stirring at room temperature for 15 minutes. Methanol (122 mL) was added to the obtained crude reaction mixture, followed by stirring at room temperature for 3 hours. Water (30 mL) was added to the reaction mixture, followed by concentration under reduced pressure. Water (30 mL) was added to the obtained reaction mixture, and extracted three times with chloroform-methanol (9:1, v/v). Concentrate the combined organic layer, and use automatic silica gel column chromatography (eluate; hexane:ethyl acetate=75:25-0:100, ethyl acetate:methanol=100:0-90:10) The obtained crude product was purified, thereby obtaining N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)-7-methanol oxybenzo[d]thiazol-2-yl)cyclopropanecarboxamide (6.6 g, 98% yield). LCMS (LC-1); RT=1.19, m/z 441 [M+H] ⁺ 1H-NMR (CD ₃ OD): δ (ppm) 9.01 (2H, s), 7.64 (1H, d, J = 8.3 Hz), 7.53 (1H, d, J = 8.3 Hz), 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).

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 [Chem. 119]

(1S,2S)-2-((5-(2-Amino-7-methoxybenzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentane-1 -alcohol (intermediate C-9-9; 540 mg, 110 μmol), (1R,2R)-2-methylcyclopropane-1-carboxylic acid (16 mg, 160 μmol) dissolved in N,N-dimethyl To methylformamide (537 μL), add 1-hydroxybenzotriazole monohydrate (33 mg, 210 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide Amine hydrochloride (41 mg, 210 μmol), stirred at 70°C for 5 hours. The obtained crude reaction mixture was subjected to HPLC purification, thereby obtaining (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, 67% yield). LCMS (LC-1); RT=1.31, m/z 455 [M+H] ⁺ 1H-NMR (CD ₃ OD): δ (ppm) 9.01 (2H, s), 7.63 (1H, d, J = 8 , 4 Hz), 7.53 (1H, d, J = 8.4 Hz), 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 = 6.0 Hz), 0.90-0.85 (1H, m).

Using the same method, the following compounds in the following table were synthesized. In the following tables, "reference method" indicates that the examples of the production method should be referred to. [Table 12] example structure Reference method LCMS data c-02-02 Example c-02-01 (LC-1); RT=1.31, m/z 455 [M+H] ⁺ c-02-03 Example c-02-01 (LC-1); RT=1.31, m/z 455 [M+H] ⁺ c-02-04 Example c-02-01 (LC-1); RT=1.14, m/z 459 [M+H] ⁺ c-02-05 Example c-02-01 (LC-1); RT=1.02, m/z 485 [M+H] ⁺ c-02-06 Example c-02-01 (LC-1); RT=1.31, m/z 467 [M+H] ⁺ c-02-07 Example c-02-01 (LC-1); RT=1.46, m/z 527 [M+H] ⁺ c-02-08 Example c-02-01 (LC-1); RT=1.14, m/z 459 [M+H] ⁺

Intermediate C-3-1: N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)-7-methoxy Benzo[d]thiazol-2-yl)-3-oxocyclobutane-1-carboxamide [Chem. 120]

(1S,2S)-2-((5-(2-Amino-7-methoxybenzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentane-1 -alcohol (intermediate C-9-9; 805 mg, 2.2 mmol), (3-oxocyclobutyl)carboxylic acid (370 mg, 3.2 mmol) were dissolved in N,N-dimethylformamide ( 7.7 mL), add 1-hydroxybenzotriazole monohydrate (662 mg, 4.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ( 829 mg, 4.3 mmol), stirred at 60°C for 20 minutes. Chloroform and saturated sodium bicarbonate water 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 obtained crude The product was purified whereby N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)-7-methoxybenzene [d]thiazol-2-yl)-3-oxocyclobutane-1-carboxamide (990 mg, 98% yield). LCMS (LC-1); RT=1.11, m/z 469 [M+H] ⁺ 1H-NMR (CD ₃ OD): 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), 3.91-3.88 (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).

Example c-03-01: (S)-4-((1s,3R)-3-((6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl Base) pyrimidin-5-yl)-7-methoxybenzo[d]thiazol-2-yl)carbamoyl)cyclobutyl)-3-methylpiperone-1-carboxylic acid tert-butyl ester [chem 121]

N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)-7-methoxybenzo[d]thiazole- 2-yl)-3-oxocyclobutane-1-carboxamide (Intermediate C-3-1; 967 mg, 2.1 mmol) was dissolved in dichloromethane (19 mL), tetrahydrofuran (3.8 mL) , add (3S)-1-BOC-3-methylpiperone (827 mg, 4.1 mmol), sodium triacetyloxyborohydride (656 mg, 3.1 mmol), and stir at room temperature for 14 hours. Saturated aqueous sodium bicarbonate was added to the obtained crude reaction mixture, followed by extraction with chloroform. The obtained organic layer was concentrated under reduced pressure, and the obtained crude product was purified using automatic silica gel column chromatography (eluent; chloroform:methanol=98:2-80:20) to obtain ( 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-methylpiperone-1-carboxylate (1.18 g, yield 88%) . LCMS (LC-1); RT=1.48, m/z 653 [M+H] ⁺ 1H-NMR (CD ₃ OD): δ (ppm) 9.01 (2H, s), 7.63 (1H, d, J = 8.3 Hz), 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 = 6.5 Hz).

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-methylpiper-1-yl)cyclobutane-1-carboxamide [Chemical 122]

(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-methylpiperone-1-carboxylic acid tert-butyl ester (Example c-03- 01; 1.16 g, 1.8 mmol) was dissolved in dichloromethane (10 mL), added concentrated hydrochloric acid (2.5 mL), and stirred at room temperature for 15 minutes. Water (2 mL) and 28% aqueous ammonia (8 mL) were added to the obtained crude reaction mixture, followed by extraction 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-methylpiper-1-yl)ring Butane-1-carboxamide (1.0 g, quant.). LCMS (LC-1); RT=0.92, m/z 553 [M+H] ⁺ 1H-NMR (CD ₃ OD): δ (ppm) 9.01 (2H, s), 7.62 (1H, d, J = 8.3 Hz), 7.52 (1H, d, J = 8.3 Hz), 4.81 (2H, s), 4.20-4.17 (1H, m), 3.91-3.88 (1H, m), 3.84 (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 = 6.4 Hz).

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)piper-1-yl) Cyclobutane-1-carboxamide [Chem. 123]

(1R,3s)-N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyridin-5-yl)-7-methoxybenzene And[d]thiazol-2-yl)-3-((S)-2-methylpiper-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), stirred at room temperature for 10 minutes. Saturated aqueous sodium bicarbonate (1 mL) and chloroform were added to the obtained crude reaction mixture for extraction. The organic layer was concentrated by blowing N ₂ and purified by HPLC, whereby (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-methylisonicotine Acyl)piperyl-1-yl)cyclobutane-1-carboxamide (38 mg, 62% yield). LCMS (LC-1); RT=1.11, m/z 672 [M+H] ⁺ 1H-NMR (DMSOd6): δ (ppm) 12.52 (1H, brs), 8.99 (2H, s), 8.52 (1H, d, J = 5.0 Hz), 7.63 (1H, d, J = 8.4 Hz), 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), 3.70-3.52 (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).

Using the same method, the following compounds in the following table were synthesized. In the following tables, "reference method" indicates that the examples of the production method should be referred to. [Table 13] example structure Reference method LCMS data b-03-03 Example c-03-02 (LC-1); RT=1.06, m/z 625 [M+H] ⁺ b-03-04 Example c-03-02 (LC-1); RT=1.08, m/z 669 [M+H] ⁺ b-03-05 Example c-03-01 (LC-1); RT=1.42, m/z 544 [M+H] ⁺ b-03-06 Example c-03-01 (LC-1); RT=1.21, m/z 545 [M+H] ⁺ b-03-07 Example c-03-01 (LC-1); RT=1.43, m/z 562 [M+H] ⁺ b-03-08 Example c-03-02, Intermediate B-8-2 (LC-1); RT=1.27, m/z 544 [M+H] ⁺ b-03-09 Example c-03-02, b-07-01 (LC-1); RT=1.07, m/z 534 [M+H] ⁺

Intermediate C-4-1: N-(6-bromo-7-methoxybenzo[d]thiazol-2-yl)cyclopropaneformamide [Chem. 124]

N-(6-bromo-7-hydroxybenzo[d]thiazol-2-yl)cyclopropaneformamide (intermediate C-9-10; 1.5 g, 4.8 mmol) was dissolved in N,N-dimethyl To methylformamide (10 mL), 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 overnight at room temperature. The obtained crude reaction mixture was concentrated under reduced pressure, and purified using silica gel column chromatography (eluent; petroleum ether: ethyl acetate = 3:1), thereby obtaining N-(6-bromo-7 -Methoxybenzo[d]thiazol-2-yl)cyclopropanecarboxamide (400 mg, 26% yield). LCMS (LC-1); RT=1.56, m/z 326 [M+H] ⁺ 1H-NMR (DMSOd6): δ (ppm) 12.79 (1H, brs), 7.64 (1H, d, J = 8.4 Hz) , 7.46 (1H, d, J = 8.4 Hz), 3.95 (3H, s), 2.01-1.99 (1H, m), 0.99-0.96 (4H, m).

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)cyclopropaneformamide [Chemical 125]

Trans-2-((5-bromopyrimidin-2-yl)methoxy)-4,4-difluorocyclopropan-1-ol (intermediate A-4-2; 1 g, 3.2 mmol) was dissolved In 1,4-dioxane (15 mL), add bis(pinacolate) diboron (1.1 g, 4.8 mmol), [1,1'-bis(diphenylphosphino)ferrocene] di Chloropalladium (II) (0.24 g, 0.32 mmol) potassium acetate (0.95 g, 9.7 mmol), stirred overnight at 80°C. 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), water (1 mL), and N-(6-bromo-7-methoxybenzo[d]thiazol-2-yl)cyclopropanemethanol was added Amide (Intermediate C-4-1; 400 mg, 1.22 mmol), cesium fluoride (0.37 g, 2.4 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) dichloro Palladium(II) (43 mg, 61 μmol) was stirred at 130° C. for 2 hours under microwave irradiation. The obtained crude reaction mixture was concentrated, purified using silica gel column chromatography (eluate; 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)cyclopropanecarboxamide (160 mg, yield 28%). The obtained stereoisomer mixture was purified by chiral HPLC (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]thiazole -2-yl) cyclopropaneformamide (42.5 mg). LCMS (LC-1); RT=1.30, m/z 477 [M+H] ⁺ 1H-NMR (DMSOd6): δ (ppm) 9.00 (2H, s), 7.62 (1H, d, J = 8.4 Hz) , 7.56 (1H, d, J = 8.4 Hz), 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).

Using the same method, the following compounds in the following table were synthesized. In the following table, "reference method" indicates that the examples of the production method should be referred to. [Table 14] example structure Reference method LCMS data c-04-02 Example c-04-01, a-01-01 Intermediates C-4-1, A-1-3 (LC-1); RT=1.25, m/z 455 [M+H] ⁺ c-04-03 Example c-04-01, a-01-01 Intermediates C-4-1, A-1-3 (LC-1); RT=1.17, m/z 485 [M+H] ⁺

Intermediate C-5-1: 3-(((6-bromo-2-(cyclopropaneformamide)benzo[d]thiazol-7-yl)oxy)methyl)-3-fluoroazetidine -3-Butyl 1-carboxylate[Chem. 126]

N-(6-bromo-7-methoxybenzo[d]thiazol-2-yl)cyclopropaneformamide (intermediate C-4-1; 0.2 g, 0.64 mmol), 1-BOC-3 -Fluorozetidine-3-methanol (0.26 mg, 1.3 mmol), triphenylphosphine (0.50 g, 1.9 mmol) were suspended in tetrahydrofuran (3.2 mL), diethyl azocarboxylate (0.35 mL, 1.9 mmol) in THF-toluene (6.4 mL, 1:1, v/v), stirred at room temperature for 15 minutes. The obtained crude reaction mixture was purified by automatic silica gel column chromatography (eluate; hexane:ethyl acetate=88:12-0:100), thereby obtaining the crude product 3-(((6-bromo -tert-butyl 2-(cyclopropaneformylamide)benzo[d]thiazol-7-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylate (629 mg). LCMS (LC-1); RT=1.86, m/z 500 [M+H] ⁺

Intermediate C-5-2: 3-(((6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy )methyl)pyrimidin-5-yl)-2-(cyclopropanecarboxamide)benzo[d]thiazol-7-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylic acid Tributyl ester [Chem. 127]

The above crude product 3-(((6-bromo-2-(cyclopropanecarboxamide)benzo[d]thiazol-7-yl)oxy)methyl)-3-fluoroazetidine-1-carboxy Acetyl tert-butyl ester (intermediate C-5-1; 344 mg) was dissolved in acetonitrile (3.5 mL), water (0.35 mL), and 2-((((1S,2S)-2-(((third Butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)pyrimidine (Intermediate A-1-3; 0.38 g, 0.70 mmol), cesium fluoride (106 mg, 0.70 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) Dichloropalladium(II) (50 mg, 70 μmol) 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 (eluate; hexane:ethyl acetate=88:12-0:100), thereby obtaining 3-(((6-(2-( (((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)-2-(cyclopropanecarboxamide ) tert-butyl benzo[d]thiazol-7-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylate (116 mg, 46% yield over 2 steps). LCMS (LC-6); RT=1.57, m/z 728 [M+H] ⁺

Intermediate C-5-3: N-(7-((3-fluoroazetidin-3-yl)methoxy)-6-(2-((((1S,2S)-2-hydroxycyclopentene base) oxy) methyl) pyrimidin-5-yl) benzo [d] thiazol-2-yl) cyclopropanecarboxamide [Chemical 128]

3-(((6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidine-5 -yl)-2-(cyclopropaneformylamide)benzo[d]thiazol-7-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylic acid tert-butyl ester (intermediate C -5-2; 112 mg, 0.15 mmol) was dissolved in dichloromethane (1.6 mL), added trifluoroacetic acid (0.40 mL), and stirred at room temperature for 3 hours. The obtained crude reaction mixture was purified by scx to obtain the crude product N-(7-((3-fluoroazetidin-3-yl)methoxy)-6-(2-((((1S ,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide. LCMS (LC-1); RT=0.98, m/z 514 [M+H] ⁺

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)cyclopropaneformamide [Chem. 129]

The above crude product N-(7-((3-fluoroazetidin-3-yl)methoxy)-6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy )methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropaneformamide (intermediate C-5-3) 1/3 amount dissolved in methanol-dichloromethane (2 mL , 1:1, v/v), added formaldehyde (37% aqueous solution, 12 μL, 0.16 mmol), sodium triacetyloxyborohydride (34 mg, 0.16 mol), 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)cyclopropanecarboxamide (13.9 mg, 2 steps Yield 50%). LCMS (LC-1); RT=1.16, m/z 528 [M+H] ⁺ 1H-NMR (CD ₃ OD): δ (ppm) 9.02 (2H, s), 7.67 (1H, d, J = 8.3 Hz), 7.55 (1H, d, J = 8.3 Hz), 4.81 (2H, s), 4.23 (1H, s), 4.20-4.16 (2H, m), 3.90-3.87 (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).

Intermediate C-6-1: N-(6-bromo-7-(methoxymethoxy)benzo[d]thiazol-2-yl)-N-(methoxymethoxy)cyclopropanemethanol Amide [Chem. 130]

Dichloromethane ( 173 mL), cooled and stirred at 0°C. N,N-Diisopropylamine (15.04 mL, 86.37 mmol), chloromethyl methyl ether (3.94 mL, 51.82 mmol) were added slowly in 1 mL portions. After temporarily cooling and stirring at 0° C., the mixture was stirred at room temperature for 1 hour. Additional reagents. Additional N,N-diisopropylamine (3.01 mL, 17.27 mmol) and chloromethyl methyl ether (0.66 mL, 8.63 mmol) were added and stirred for 30 minutes. Saturated sodium bicarbonate water and brine were added, and dichloromethane was added for extraction. The aqueous layer was extracted again with dichloromethane. The organic layers were combined, washed with brine again, dried with sodium sulfate, filtered and concentrated, and silica gel column chromatography (eluent; hexane:ethyl acetate=80:20-70:30) Purification afforded N-(6-bromo-7-(methoxymethoxy)benzo[d]thiazol-2-yl)-N-(methoxymethoxy)cyclopropanecarboxamide (4.3 g, white solid, yield 63%). LCMS (LC-1); RT=1.91, m/z 401 [M+H] ⁺ 1H-NMR (CDCl ₃ ): 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).

Intermediate C-6-2: N-(6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl Base) pyrimidin-5-yl)-7-(methoxymethoxy)benzo[d]thiazol-2-yl)-N-(methoxymethyl)cyclopropanecarboxamide [Chem. 131]

In N-(6-bromo-7-(methoxymethoxy)benzo[d]thiazol-2-yl)-N-(methoxymethoxy)cyclopropaneformamide (intermediate C- 6-1; 4.2 g, 10.47 mmol), 2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)- Add 1 , 4-dioxane (43 mL), add cesium carbonate (10.24 g, 31.42 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (766.3 mg, 1.05 mmol), water (10.64 mL), heated and stirred 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 (eluate; hexane:ethyl acetate=60:40) to obtain (5.13 g, Yield 78%). LCMS (LC-1); RT=2.16, 2.27, m/z 629 [M+H] ⁺ 1H-NMR (CDCl ₃ ): δ (ppm) 8.97 (2H, s), 7.71 (1H, d, J = 8.0 Hz), 7.38 (1H, d, J = 8.0 Hz), 5.97 (2H, 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).

Intermediate C-6-3: N-(7-hydroxy-6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo [d]thiazol-2-yl)cyclopropaneformamide [Chem. 132]

N-(6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl )-7-(methoxymethoxy)benzo[d]thiazol-2-yl)-N-(methoxymethyl)cyclopropanecarboxamide (intermediate C-6-2; 5 g, 7.95 mmol) was dissolved in THF (8 mL), 5 N aqueous hydrochloric acid (80 mL) was added, and stirred overnight at 40°C. A 5 N aqueous hydrochloric acid solution (8 mL) was added thereto, followed by further stirring for 5 hours, followed by post-treatment. The reaction mixture solution was cooled to 0°C, neutralized by adding 5 N 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)cyclopropanecarboxamide (3.48 g, quant.). LCMS (LC-1); RT=0.98, m/z 427 [M+H] ⁺ 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), 4.08-3.96 (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).

Intermediate C-6-4: N-(7-((tertiary butyldimethylsilyl)oxy)-6-(2-((((1S,2S)-2-((tertiary butyl dimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide [Chem. 133]

N-(7-hydroxy-6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazole-2- base) cyclopropaneformamide (intermediate C-6-3; 3 g, 7.0 mmol) was dissolved in dichloromethane (30 mL), and 2,6-lutidine (6.0 g, 56 mmol), 3-Butyldimethylsilyl trifluoromethanesulfonate (11 g, 42 mmol) was 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. Use silica gel column chromatography (eluent; petroleum ether: ethyl acetate = 5: 1) to purify the obtained crude product, thereby obtaining N-(7-((tertiary butyldimethylsilyl )Oxy)-6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidine-5- yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide (3.0 g, 65% yield). LCMS (LC-6); RT=2.46, m/z 655 [M+H] ⁺ 1H-NMR (CDCl ₃ ): δ (ppm) 10.19 (1H, m), 8.93 (2H, m), 7.55 (1H , d, J = 8.2 Hz), 7.34 (1H, d, J = 8.2 Hz), 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), 1.30-1.26 (2H, m ), 1.07-1.02 (2H, m), 0.96 (9H, s), 0.88 (9H, s), 0.07 (6H, s), 0.19 (d, J = 6.1 Hz).

Intermediate C-6-5: N-(7-((tertiary butyldimethylsilyl)oxy)-6-(2-((((1S,2S)-2-((tertiary butyl Dimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-N-(methoxymethyl)cyclopropanemethyl Amide [Chem. 134]

N-(7-((tertiary butyldimethylsilyl)oxy)-6-(2-((((1S,2S)-2-((tertiary butyldimethylsilyl) Oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide (intermediate C-6-4; 4.5 g, 6.87 mmol) Dissolve in dichloromethane (50 mL), add N-ethyldiisopropylamine (3.6 mL, 21 mmol), chloromethyl methyl ether (1.0 mL, 14 mmol), and stir overnight at room temperature . 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 Base)-6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl) Benzo[d]thiazol-2-yl)-N-(methoxymethyl)cyclopropanecarboxamide (4.0 g, 83% yield). LCMS (LC-6); RT=2.72, m/z 699 [M+H] ⁺

Intermediate C-6-6: N-(6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl Base) pyrimidin-5-yl) benzo [d] thiazol-2-yl) -N- (methoxymethyl) cyclopropane carboxamide [chemical 135]

N-(7-((tertiary butyldimethylsilyl)oxy)-6-(2-((((1S,2S)-2-((tertiary butyldimethylsilyl) Oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-N-(methoxymethyl)cyclopropaneformamide (intermediate C- 6-5; 4.0 g, 5.7 mmol) was dissolved in N,N-dimethylformamide (40 mL), added water (4 mL), cesium carbonate (0.93 g, 2.9 mmol), stirred at room temperature 1 hour. Water (300 mL) and dichloromethane (200 mL) were added to the obtained crude reaction mixture, and the vented layer was concentrated under reduced pressure. Use silica gel column chromatography (eluent; petroleum ether: ethyl acetate = 2:1) to purify the obtained crude product, thereby obtaining N-(6-(2-((((1S,2S) -2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-N-(methyl oxymethyl)cyclopropanecarboxamide (2.0 g, 60% yield). LCMS (LC-1); RT=2.26 & 2.35 (2 peaks, mixture of positional isomers based on methoxymethyl protection), m/z 585 [M+H] ⁺

Example c-06-01: N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)-7-(2- Hydroxyethoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide [Chem. 136]

N-(6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl ) benzo[d]thiazol-2-yl)-N-(methoxymethyl)cyclopropanecarboxamide (intermediate C-6-6; 60 mg, 0.10 mmol), 2-bromomethane-1-ol (25 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (2 mL), and cesium carbonate (99 mg, 0.31 mmol) was added. Stir 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 column chromatography to obtain a crude reaction intermediate (30 mg). The obtained crude reaction intermediate (30 mg) was dissolved in 3 M hydrochloric acid-methanol (3 mL), and stirred at room temperature for 3 hours. The obtained crude reaction mixture was concentrated under reduced pressure, dichloromethane and sodium bicarbonate water were added, and the organic layer was concentrated under reduced pressure. The obtained crude product was purified by preparative thin-layer chromatography (eluate; dichloromethane:methanol=10:1), thereby obtaining N-(6-(2-((((1S,2S)- 2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)-7-(2-hydroxyethoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide (11.5 mg, Yield 24%). LCMS (LC-1); RT=1.00, m/z 471 [M+H] ⁺ 1H-NMR (CDCl ₃ ): δ (ppm) 9.04 (2H, s), 7.62 (1H, d, J = 8.4 Hz ), 7.56 (1H, d, J = 8.4 Hz), 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).

Using the same method, the following compounds in the following table were synthesized. In the following tables, "reference method" indicates that the examples of the production method should be referred to. [Table 15] example structure Reference method LCMS data c-06-02 Example c-06-01 (LC-1); RT=1.18, m/z 524 [M+H] ⁺ c-06-03 Example c-06-01 Intermediate C-5-1 (LC-1); RT=1.20, m/z 511 [M+H] ⁺

Intermediate C-7-1: 2-(cyclopropanecarboxamide)-6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl trifluoromethanesulfonate Pyrimidin-5-yl)benzo[d]thiazol-7-yl ester [Chem. 137]

In N-(7-hydroxy-6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazole-2- base) cyclopropaneformamide (intermediate C-6-3; 500 mg, 1.17 mmol) was dissolved by adding THF (6 mL), DMF (6 mL), and N-ethyldiisopropylamine (613 μL, 3.52 mmol), 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (629 mg, 1.76 mmol), stirred at room temperature for 5.5 hours . Water was added to the reaction mixture solution, extracted with ethyl acetate, the aqueous layer was extracted with ethyl acetate again, the organic layers were combined, washed with saturated brine, dried with sodium sulfate, filtered, and then Concentrate under pressure. The obtained crude product was purified by silica gel column chromatography (eluate; chloroform:methanol=98:2) to obtain trifluoromethanesulfonic acid 2-(cyclopropaneformamide)-6-(2-( (((1S,2S)-2-Hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-7-yl ester (531.2 mg, 81% yield). LCMS (LC-1); RT=1.46, m/z 559 [M+H] ⁺

Example c-07-01: N-[6-[2-[[(1S,2S)-2-hydroxycyclopentyloxy]pyrimidin-5-yl]-7-methyl-1,3-benzo Thiazol-2-yl]cyclopropanecarboxamide [Chem. 138]

Trifluoromethanesulfonate [2-(cyclopropanecarbonylamino)-6-[2-[[(1S,2S)-2-hydroxycyclopentyloxy]methyl]pyrimidin-5-yl]-1, 3-Benzothiazol-7-yl] ester (Intermediate C-7-1; 30 mg, 50 μmol) was dissolved in dimethylacetamide (0.5 mL), tetramethyltin (48 mg, 270 μmol), tetrakis(triphenylphosphine)palladium(0) (12 mg, 10 μmol), and microwave irradiation was carried out at 120° C. for 1 hour. The obtained reaction mixture was diluted with saturated brine, extracted with ethyl acetate, dried with 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]cyclopropaneformamide (14.8 mg, rate of 65%). LCMS (LC-1); RT=1.20, m/z 425 [M+H] ⁺ 1H-NMR (CDCl ₃ ): δ (ppm) 8.78 (2H, s), 7.72 (1H, d, J = 8.3 Hz ), 7.31 (1H, d, J = 8.3 Hz), 5.02 (1H, d, J = 15.0 Hz), 4.85 (1H, d, J = 15.0 Hz), 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).

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 [Chem. 139]

(1S,2S)-2-((5-(2-Aminobenzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentan-1-ol (intermediate B -2-1; 40 mg, 120 μmol), (1R,2R)-2-methylcyclopropane-1-carboxylic acid (18 mg, 180 μmol) dissolved in N,N-dimethylformamide (0.58 mL), add 1-hydroxybenzotriazole monohydrate (36 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (45 mg, 0.23 mmol), stirred at 70°C for 5 hours. The obtained crude reaction mixture was subjected to HPLC purification, thereby obtaining (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, 48% yield). LCMS (LC-1); RT=1.24, m/z 425 [M+H] ⁺ 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 (1H, 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 = 6.0 Hz).

Using the same method, the following compounds in the following table were synthesized. In the following table, "reference method" indicates that the examples of the production method should be referred to. [Table 16] example structure Reference method LCMS data d-01-02 Example d-01-01 (LC-1); RT=0.98, m/z 455 [M+H] ⁺ d-01-03 Example d-01-01 (LC-1); RT=1.16, m/z 469 [M+H] ⁺ d-01-04 Example d-01-01 (LC-1); RT=1.43, m/z 566 [M+H] ⁺ d-01-05 Example d-01-01 (LC-1); RT=1.18, m/z 495 [M+H] ⁺ d-01-06 Example d-01-01 (LC-1); RT=1.40, m/z 501 [M+H] ⁺ d-01-07 Example d-01-01 (LC-1); RT=1.04, m/z 467 [M+H] ⁺ d-01-08 Example d-01-01 (LC-1); RT=1.25, m/z 457 [M+H] ⁺

Intermediate D-2-1: (1S,2S)-2-((5-(2-((1s,3s)-3-hydroxycyclobutane-1-carboxamide)benzo[d]thiazole acetic acid -6-yl)pyrimidin-2-yl)methoxy)cyclopentyl ester [chemical 140]

(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), cis-3-hydroxycyclobutanecarboxylic acid (72 mg, 0.62 mmol) were dissolved in N,N-dimethylformamide (3.1 mL), and 1-hydroxybenzene Triazole monohydrate (0.15 g, 0.99 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.18 g, 0.95 mmol), at 60°C Stir for 15 minutes. The obtained crude reaction mixture was purified by HPLC. Ethyl acetate and saturated sodium bicarbonate water were added to the obtained crude product, the organic layer was concentrated under reduced pressure, and purified by automatic silica gel column chromatography (eluent; chloroform:methanol) to obtain Crude product (1S,2S)-2-((5-(2-((1s,3s)-3-hydroxycyclobutane-1-carboxamide)benzo[d]thiazol-6-yl)pyrimidine acetate -2-yl)methoxy)cyclopentyl ester (124 mg). LCMS (LC-1); RT=1.19, m/z 483 [M+H] ⁺

Intermediate D-2-2: (1S,2S)-2-((5-(2-((1s,3s)-3-(tert-butoxy)cyclobutane-1-carboxamide) acetic acid Benzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentyl ester [Chem. 141]

Acetic acid (1S,2S)-2-((5-(2-((1s,3s)-3-hydroxycyclobutane-1-carboxamide)benzo[d]thiazol-6-yl)pyrimidine- 2-yl)methoxy)cyclopentyl ester (Intermediate D-2-1; 78 mg, 0.16 mmol) was dissolved in dichloromethane (1.6 mL), and tert-butyl acetate (1.5 mL, 11 mmol) was added , 70% perchloric acid (42 uL, 0.49 mmol), stirred at room temperature for 30 minutes. Under cooling in an ice bath, saturated aqueous sodium bicarbonate was added until the reaction solution became alkaline, thereby stopping the reaction. Using (1S,2S)-2-((5-(2-((1s,3s)-3-hydroxycyclobutane-1-carboxamide)benzo[d]thiazol-6-yl)pyrimidine- 2-yl)methoxy)cyclopentyl ester (intermediate D-2-1; 19 mg, 39 μmol) was subjected to another batch of the same operation. The combined crude reaction mixture was washed with saturated sodium bicarbonate water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by automatic silica gel column chromatography (eluent; chloroform:methanol), thereby obtaining the crude product acetic acid (1S, 2S)-2-((5-(2-((1s, 3s)-3-Hydroxycyclobutane-1-carboxamide)benzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentyl ester (152 mg). LCMS (LC-1); RT=1.64, m/z 539 [M+H] ⁺

Example d-02-01: (1s,3s)-3-(tertiary butoxy)-N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy ) methyl) pyrimidin-5-yl) benzo [d] thiazol-2-yl) cyclobutane-1-carboxamide [Chemical 142]

The above-mentioned crude product acetic acid (1S, 2S)-2-((5-(2-((1s, 3s)-3-(tertiary butoxy)cyclobutane-1-formamide)benzo[d ]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentyl ester (intermediate D-2-2; 152 mg) was dissolved in methanol (1.6 mL), tetrahydrofuran (0.8 mL), and potassium carbonate ( 22 mg, 0.16 mmol), 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 subjected to HPLC purification, thereby obtaining (1s,3s)-3-(tert-butoxy)-N-(6-(2-((((1S,2S)-2-hydroxy cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide (31.5 mg). LCMS (LC-1); RT=1.36, m/z 497 [M+H] ⁺ 1H-NMR (DMSOd6): δ (ppm) 12.42 (1H, m), 9.17 (2H, s), 8.45 (1H, s), 7.87-7.81 (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 (2H, m), 1.91-1.77 (2H, m), 1.66-1.56 (3H, m), 1.48-1.40 (1H, m), 1.13 (9H, s).

Intermediate D-3-1: 2-((6-2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazole -2-yl)carbamoyl)tert-butyl 7-azaspiro[3,5]nonane-7-carboxylate [Chem. 143]

In (1S,2S)-2-((5-(2-aminobenzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentan-1-ol (intermediate B -2-1; 604 mg, 1.76 mmol), dichloromethane (35 mL), THF (25 mL) were added to dissolve, and 7-[(tertiary butoxy)carbonyl] 7-azaspiro[3 ,5] Nonane-2-carboxylic acid (950 mg, 3.53 mmol), N-ethyldiisopropylamine (921.1 μL, 5.29 mmol), 1-propylphosphonic anhydride (1.24 mL, 4.17 mmol), in Stir at room temperature for 14 hours. Add 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), 1-propylphosphonic anhydride (1.24 mL, 4.17 mmol), and stirred for 2 hours. Aqueous sodium bicarbonate was added to the reaction mixture solution, followed by extraction with chloroform. The aqueous layer was further extracted twice with chloroform, 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 2-((6-2-((((1S,2S)-2-hydroxyl ring Amyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)carbamoyl)7-azaspiro[3,5]nonane-7-carboxylic acid third Butyl ester (712 mg, 68% yield). LCMS (LC-1); RT=1.58, m/z 594 [M+H] ⁺

Intermediate D-3-2: N-(6-2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazole- 2-yl)carbamoyl)7-azaspiro[3,5]nonane-2-carboxylate [Chem. 144]

In 2-((6-2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)amine Acyl) tert-butyl 7-azaspiro[3,5]nonane-7-carboxylate (Intermediate D-3-1; 709.1 mg, 1.19 mmol) was added dichloromethane (27 mL), THF (10 mL) was dissolved, trifluoroacetic acid (500 μL) was added, and stirred at room temperature. Furthermore, trifluoroacetic acid (12.5 ml) was added five times, and the mixture was stirred at room temperature for 13 hours. It was made alkaline with 2 N aqueous sodium hydroxide 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 yl)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)carbamoyl)7-azaspiro[3,5]nonane-2-carboxylate (142.2 mg, yield rate 24%). LCMS (LC-1); RT=0.89, m/z 494 [M+H] ⁺ 1H-NMR (CDCl ₃ ): 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), 3.80-3.74 (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).

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 [Chem. 145]

N-(6-2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)carbamoyl dichloromethane (1.8 mL), THF (0.8 mL) After dissolution, 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. Aqueous sodium bicarbonate was added to the reaction mixture, followed by extraction with chloroform. The organic layer was concentrated by nitrogen gas, and purified by HPLC to obtain 7-acetyl-N-(6-2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidine -5-yl)benzo[d]thiazol-2-yl)carbamoyl)7-azaspiro[3,5]nonane-2-carboxamide (8.5 mg, 26% yield). LCMS (LC-1); RT=1.08, m/z 536 [M+H] ⁺ 1H-NMR (CDCl ₃ ): 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).

Using the same method, the following compounds in the following table were synthesized. In the following tables, "reference method" indicates that the examples of the production method should be referred to. [Table 17] example structure Reference method LCMS data d-03-02 Example d-03-01 (LC-1); RT=1.09, m/z 566 [M+H] ⁺ d-03-03 Example d-03-01 (LC-1); RT=1.22, m/z 562 [M+H] ⁺ d-03-04 Example d-03-01 (LC-1); RT=1.32, m/z 598 [M+H] ⁺ d-03-05 Example d-03-01 (LC-1); RT=1.26, m/z 564 [M+H] ⁺ d-03-06 Example d-03-01, b-04-02 (LC-1); RT=1.13, m/z 599 [M+H] ⁺ d-03-07 Example d-03-01, b-04-02 (LC-1); RT=1.10, m/z 599 [M+H] ⁺ d-03-08 Example d-03-01, b-07-01 (LC-1); RT=1.51, m/z 576 [M+H] ⁺ d-03-09 Example d-03-01, b-04-02 (LC-1); RT=1.07, m/z 578 [M+H] ⁺

Intermediate D-4-1: (1s,3s)-tert-butyl 3-ethoxycyclobutane-1-carboxylate [Chem. 146]

Dissolve tert-butyl 3-hydroxycyclobutanecarboxylate (0.30 g, 1.7 mmol) in N,N-dimethylformamide (3.5 mL), add sodium hydride (55% oily , 50 mg, 2.1 mmol), stirred for 10 minutes. Ethyl iodide (0.28 mL, 3.5 mmol) was added to the reaction solution, and stirred overnight at room temperature. A saturated ammonium chloride aqueous solution was added to the reaction liquid to stop the reaction, and extraction was performed with ethyl acetate. The organic layer was concentrated under reduced pressure, and the obtained crude product was purified by automatic silica gel column chromatography (eluate; hexane:ethyl acetate=98:2-50:50), thereby obtaining ( 1s,3s)-tert-butyl 3-ethoxycyclobutane-1-carboxylate (203 mg, 58% yield). 1H-NMR (CDCl ₃ ): δ (ppm) 3.87-3.80 (1H, m), 3.40 (2H, q, J = 7.0 Hz), 2.57-2.42 (3H, m), 2.22-2.10 (2H, m) , 1.44 (9H, s), 1.19 (3H, t, J = 7.0 Hz).

Intermediate D-4-2: (1s,3s)-3-ethoxycyclobutane-1-carboxylic acid [Chem. 147]

Dissolve (1s,3s)-tert-butyl 3-ethoxycyclobutane-1-carboxylate (Intermediate D-4-1; 40 mg, 0.20 mmol) in formic acid (0.40 mL) and in room temperature Stir at room temperature for 2 hours. The obtained crude reaction mixture was concentrated under reduced pressure and azeotroped three times with toluene to obtain crude product (1s,3s)-3-ethoxycyclobutane-1-carboxylic acid. 1H-NMR (CDCl ₃ ): δ (ppm) 3.93-3.86 (1H, m), 3.41 (2H, q, J = 7.0 Hz), 2.73-2.74 (1H, m), 2.58-2.50 (2H, m) , 2.28-2.20 (2H, m), 1.19 (3H, t, J = 7.0 Hz).

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 [Chem. 148]

The above crude product (1s,3s)-3-ethoxycyclobutane-1-carboxylic acid (intermediate D-4-2), (1S,2S)-2-((5-(2-amino Benzo[d]thiazol-6-yl)pyrimidin-2-yl)methoxy)cyclopentan-1-ol (intermediate B-2-1; 30 mg, 90 μmol) was dissolved in N,N-di To methylformamide (0.44 mL), add 1-hydroxybenzotriazole monohydrate (27 mg, 0.18 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiamide Imine hydrochloride (34 mg, 0.18 mmol), stirred at 60°C for 15 minutes. The obtained crude reaction mixture was subjected to HPLC purification, whereby (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, 51% yield). LCMS (LC-1); RT=1.19, m/z 469 [M+H] ⁺ 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 = 7.0 Hz), 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 = 7.0 Hz).

Using the same method, the following compounds in the following table were synthesized. In the following tables, "reference method" indicates that the examples of the production method should be referred to. [Table 18] example structure Reference method LCMS data d-04-02 Example d-04-01 intermediate D-4-1, 2 (LC-1); RT=1.10, m/z 499 [M+H] ⁺ d-04-03 Example d-04-01 intermediate D-4-1, 2 (LC-1); RT=1.33, m/z 483 [M+H] ⁺ d-04-04 Example d-04-01 intermediate D-4-1, 2 (LC-1); RT=1.31, m/z 495 [M+H] ⁺ d-04-05 Example d-04-01 intermediate D-4-1, 2 (LC-1); RT=1.13, m/z 532 [M+H] ⁺

Intermediate D-5-1: N-(6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl Base) pyrimidin-5-yl) benzo[d]thiazol-2-yl)-3-(methoxymethylene)cyclobutane-1-carboxamide [Chemical 149]

THF (1.5 mL) was added to methoxymethyl(triphenyl)phosphonium chloride (254.2 mg, 0.74 mmol), and cooled to 0°C. Potassium tert-butoxide (83.2 mg, 0.74 mmol) was added and stirred for 30 minutes. Thereafter, N-(6-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidine- 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) was added dropwise using a syringe. After stirring at 0°C for 10 minutes, it was stirred at room temperature for 3.5 hours. Water was added to the reaction mixture, followed by extraction 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 (eluate; chloroform:methanol=98:2) to obtain N-(6-(2-((((1S,2S)-2-(( tertiary butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-(methoxymethylene ) cyclobutane-1-carboxamide (130.7 mg, 43% yield). LCMS (LC-1); RT=2.31, m/z 581 [M+H] ⁺

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 [Chem. 150]

In 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) was dissolved, 2 N aqueous hydrochloric acid (2 mL) was added, and stirred for 40 minutes. Aqueous sodium bicarbonate was added to the reaction mixture, followed by extraction with chloroform. The aqueous layer was extracted with chloroform again, dried with sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product 3-formyl-N-(6-(2-((((1S,2S) -2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide (95 mg). LCMS (LC-1); RT=1.09, m/z 453 [M+H] ⁺

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 [Chemical 151]

3-Formyl-N-(6-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazole- 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) was added , Sodium triacetyloxyborohydride (22.5 mg, 0.11 mmol), stirred at room temperature for 5 hours. Saturated sodium bicarbonate water was added to the reaction mixture, extracted with chloroform, the organic layer was concentrated by passing nitrogen gas, and purified by HPLC to obtain 3-((dimethylamino)methyl)-N-(6- (2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclobutane-1-formyl Amine (4.8 mg, 14%). LCMS (LC-1); RT=0.88, m/z 482 [M+H] ⁺ 1H-NMR (CDCl ₃ ): δ (ppm) 8.98 (2H, d, J = 1.2 Hz), 8.00 (1H, t , J = 1.8 Hz), 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 ), 3.86-3.77 (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).

Using the same method, the following compounds in the following table were synthesized. In the following tables, "reference method" indicates that the examples of the production method should be referred to. [Table 19] example structure Reference method LCMS data d-05-02 Example d-05-01 (LC-1); RT=1.06, m/z 512 [M+H] ⁺

Intermediate E-1-1: 5-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidine -5-yl)pyrazolo[1,5-a]pyridin-2-amine[Chem. 152]

5-Chloropyrazolo[1,5-a]pyridin-2-amine (1.0 g, 5.97 mmol) was dissolved in 1,4-dioxane (12 mL), and the above crude product 2-((( (1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-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), water (1.2 mL), and the mixture thereof was irradiated with microwaves at 100° C. for 5 hours. The crude reaction mixture was filtered through celite and concentrated under reduced pressure. The obtained crude product was purified by automatic silica gel column chromatography (eluent; ethyl acetate:methanol), thereby obtaining 5-(2-((((1S,2S)-2-(((third Butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)pyrazolo[1,5-a]pyridin-2-amine (1.3 g, 50% yield ). LCMS (LC-1); RT=2.00, m/z 439 [M+H] ⁺

Example e-01-01: N-(5-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)pyrazolo[1, 5-a]pyridin-2-yl)cyclopropaneformamide [Chem. 153]

5-(2-((((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)methyl)pyrimidin-5-yl)pyrazole Do[1,5-a]pyridin-2-amine (intermediate E-1-1; 20 mg, 46 μmol) was dissolved in dichloromethane (455 μL), and cyclopropanecarboxylic acid (12 μL, 0.15 mmol ), N,N-diisopropylethylamine (70 μL, 0.41 mmol), 1-propylphosphonic anhydride (50% by weight in ethyl acetate, 88 μL, 0.15 mmol), stirred at room temperature for 4 hours . Water was added to the obtained crude reaction mixture, followed by extraction 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 using SCX and HPLC to obtain N-(5-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl ) pyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (4.2 mg, 24% yield). LCMS (LC-1); RT=0.99, m/z 394 [M+H] ⁺ 1H-NMR (CD ₃ OD): δ (ppm) 9.15 (2H, s), 8.51 (1H, d, J = 7.3 Hz), 7.95 (1H, d, J = 1.2 Hz), 7.18 (1H, dd, J = 7.2 Hz, 2.1 Hz), 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).

Using the same method, the following compounds in the following table were synthesized. In the following tables, "reference method" indicates that the examples of the production method should be referred to. [Table 20] example structure Reference method LCMS data e-01-02 Example e-01-01 (LC-1); RT=1.03, m/z 412 [M+H] ⁺ e-01-03 Example e-01-01 (LC-1); RT=1.10, m/z 408 [M+H] ⁺

Intermediate E-2-1: (1S,2S)-2-((5-(2-aminopyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl)methoxy acetic acid base) cyclopentyl ester [Chem. 154]

Dissolve 5-chloropyrazolo[1,5-a]pyridin-2-amine (6.00 g, 35.8 mmol) in 1,4-dioxane (358 mL), add acetic acid [(1S,2S)- 2-[[5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]methoxy]cyclopenta base] ester (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), water (36 mL), stirred at 100°C for 15 hours. After the reaction, methanol (30 mL) was added and purified by silica gel column chromatography (eluate; chloroform:methanol=90:10) to obtain acetic acid (1S,2S)-2-((5-(2- Aminopyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl)methoxy)cyclopentyl ester (9.82 g, 74%). LCMS (LC-1); RT=1.09, m/z 368 [M+H] ⁺ 1H-NMR (CDCl ₃ ): 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).

Intermediate E-2-2: (1S,2S)-2-((5-(2-aminopyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl)methoxy ) cyclopentan-1-ol [chemical 155]

(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 stirred at room temperature for 3 hours. After the reaction was completed, water was added, extracted with chloroform, the organic layer was concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (lyotrope; chloroform:methanol=90:10-80:20). Purification afforded (1S,2S)-2-((5-(2-aminopyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl)methoxy)cyclopentane- 1-alcohol (12.2 g, 77%). LCMS (LC-1); RT=0.81, m/z 326 [M+H] ⁺ 1H-NMR (CD ₃ OD): δ (ppm) 9.23-9.05 (3H, m), 8.27 (1H, d, J = 7.1 Hz), 7.67-7.63 (1H, m), 6.91 (1H, dd, J = 7.2, 2.0 Hz), 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).

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 [Chem. 156]

(1S,2S)-2-((5-(2-aminopyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl)methoxy)cyclopentane-1- Alcohol (Intermediate E-2-2; 3.22 g, 9.9 mmol) was dissolved in dichloromethane (50 mL), and cooled and stirred at 0°C. Add N-ethyldiisopropylamine (5.17 mL, 29.7 mmol), 3-oxocyclobutane-1-carboxylic acid (1.36 g, 11.88 mmol), 1-propylphosphonic anhydride (8.74 mL, 14.85 mmol), stirred at room temperature for 5 hours. Saturated sodium bicarbonate water 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 (eluate; chloroform:methanol=98:2-95:5), thereby obtaining N-(5-(2-((((1S,2S) -2-Hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)pyrazolo[1,5-a]pyridin-2-yl)-3-oxocyclobutane-1-formyl Amine (2.26 g, yield: 54.3%). LCMS (LC-1); RT=0.92, m/z 422 [M+H] ⁺ 1H-NMR (CDCl ₃ ): δ (ppm) 9.00 (2H, s), 8.36 (1H, d, J = 7 Hz ), 8.30 (1H, s), 7.66 (1H, d, J = 1.3 Hz), 7.13 (1H, s), 6.91 (1H, dd, J = 7, 1.8 Hz), 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).

Intermediate E-2-4: (S)-tert-butyl 2-methyl-4-(2-methylisonicotinyl)piperone-1-carboxylate [Chem. 157]

Dissolve (S)-tert-butyl 2-methylpiperone-1-carboxylate (600 mg, 3.00 mmol) in dichloromethane (30.0 mL), add 2-methylisonicotinic acid (821 mg , 6.00 mmol), N-ethyldiisopropylamine (3.2 mL, 18.0 mmol), propylphosphonic anhydride (6.0 mL, 1.7 M ethyl acetate solution), stirred at room temperature for 1 hour. Saturated sodium bicarbonate water was added to the reaction mixture, extraction was performed with chloroform, and the organic layer was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluate; hexane:ethyl acetate=100:0-0:100) to obtain (S)-2-methyl-4-(2- Methylisonicotinyl) piper-1-carboxylate tert-butyl ester (1.025 g, quant.). LCMS (LC-1); RT=1.21, m/z 320 [M+H] ⁺ 1H-NMR (CDCl ₃ ): δ (ppm) 8.58 (1H, d, J = 4.9 Hz), 7.14 (1H, brs ), 7.07 (1H, brd, J = 4.2 Hz), 4.58(0.5H, brd, J = 13.1 Hz), 4.46 (1H, brd, J = 13.1 Hz), 4.22(0.5H, brs), 3.96(0.5 H, brd, J = 13.7 Hz), 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).

Intermediate E-2-5: (S)-(3-Methylpiper-1-yl)(2-methylpyridin-4-yl)methanone [Chem. 158]

Dissolve (S)-tert-butyl 2-methyl-4-(2-methylisonicotinyl)piperone-1-carboxylate (1.56 g, 4.88 mmol) in dichloromethane (25 mL) , added trifluoroacetic acid (7.5 mL, 97.6 mmol), and stirred at room temperature for 1 hour. After the reaction, the reaction mixture was purified by SCX to obtain (S)-(3-methylpiper-1-yl)(2-methylpyridin-4-yl)methanone (896 mg, 83%). LCMS (LC-1); RT=0.29, m/z 220 [M+H] ⁺ 1H-NMR (CD ₃ OD): δ (ppm) 8.51 (1H, d, J = 5.1 Hz), 7.31 (1H, s), 7.23 (1H, d, J = 5.1 Hz), 4.49 (1H, brd, J = 12.8 Hz), 3.56-3.39 (1H, m), 3.28-3.05 (1H, m), 2.95 (1H, brd , J = 12.8 Hz), 2.90-2.73 (3H, m), 2.65-2.56 (4H, m), 1.22-0.95 (3H, m).

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)piperone-1-yl)ring Butane-1-formamide [Chem. 159]

N-(5-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)pyrazolo[1,5-a]pyridine-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-methylpiper-1-yl]-(2-methyl-4-pyridyl)methanone (62 mg, 0.28 mmol), sodium triacetyloxyborohydride (90 mg, 0.43 mmol), in Stir at room temperature for 1 hour. Thereafter, saturated sodium bicarbonate water was added to the reaction mixture, extraction was performed with chloroform, and the organic layer was concentrated under reduced pressure. HPLC purification of the crude product afforded (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)piperone-1-yl)ring Butane-1-carboxamide (13.7 mg, 15%). LCMS (LC-1); RT=0.96, m/z 625 [M+H] ⁺ 1H-NMR (DMSO-d ₆ ): δ (ppm) 10.78 (1H, s), 9.23 (2H, s), 8.66 (1H, d, J = 7.2 Hz), 8.52 (1H, d, J = 5.0 Hz), 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 = 3.1 Hz), 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 = 6.2 Hz), 0.82(1.5H, brd, J = 6.2 Hz).

Using the same method, the following compounds in the following table were synthesized. In the following tables, "reference method" indicates that the examples of the production method should be referred to. [Table 21] example structure Reference method LCMS data e-02-02 Example e-02-01 (LC-1); RT=0.96, m/z 611 [M+H] ⁺ e-02-03 Example e-02-01 (LC-1); RT=1.20, m/z 679 [M+H] ⁺ e-02-04 Example e-02-01 (LC-1); RT=1.18, m/z 588 [M+H] ⁺ e-02-05 Example e-02-01 (LC-1); RT=0.97, m/z 562 [M+H] ⁺ e-02-06 Example e-02-01 (LC-1); RT=1.08, m/z 588 [M+H] ⁺ e-02-07 Example e-02-01 (LC-1); RT=1.04, m/z 576 [M+H] ⁺ e-02-08 Example e-02-01 (LC-1); RT=0.90, m/z 548 [M+H] ⁺ e-02-09 Example e-02-01 (LC-1); RT=1.11, m/z 610 [M+H] ⁺ e-02-10 Example e-02-01 (LC-1); RT=1.00, m/z 574 [M+H] ⁺ e-02-11 Example e-02-01 (LC-1); RT=1.12, m/z 535 [M+H] ⁺ e-02-12 Example e-02-01 (LC-1); RT=0.94, m/z 611 [M+H] ⁺ e-02-13 Example e-02-01 (LC-1); RT=0.96, m/z 625 [M+H] ⁺ e-02-14 Example e-02-01 (LC-1); RT=1.12, m/z 583 [M+H] ⁺ e-02-15 Example e-02-01 (LC-1); RT=1.16, m/z 576 [M+H] ⁺ e-02-16 Example e-02-01 (LC-1); RT=1.37, m/z 637 [M+H] ⁺ e-02-17 Example e-02-01 (LC-1); RT=1.34, m/z 637 [M+H] ⁺ e-02-18 Example e-02-01 (LC-1); RT=1.17, m/z 583 [M+H] ⁺ e-02-19 Example e-02-01 (LC-1); RT=1.17, m/z 590 [M+H] ⁺ e-02-20 Example e-02-01 (LC-1); RT=1.11, m/z 535 [M+H] ⁺ e-02-21 Example e-02-01 (LC-1); RT=1.14, m/z 573 [M+H] ⁺ e-02-22 Example e-02-01 (LC-1); RT=1.27, m/z 603 [M+H] ⁺ e-02-23 Example e-02-01 (LC-1); RT=1.15, m/z 597 [M+H] ⁺ e-02-24 Example e-02-01 (LC-1); RT=0.98, m/z 615 [M+H] ⁺ e-02-25 Example e-02-01 (LC-1); RT=1.11, m/z 645 [M+H] ⁺ e-02-26 Example e-02-01 (LC-1); RT=1.01, m/z 601 [M+H] ⁺ e-02-27 Example e-02-01 (LC-1); RT=1.00, m/z 639 [M+H] ⁺

Intermediate E-3-1: 3-(tert-butoxy)cyclobutane-1-carboxylic anhydride [Chem. 160]

Dissolve 3-tert-butoxycyclobutanecarboxylic acid (60 mg, 0.35 mmol) in dichloromethane (3.5 mL), add trimethylamine (145 μL, 1.0 mmol), iodine 2-chloro-1-methyl Pyridinium (134 mg, 0.52 mmol), stirred under reflux for 3 hours. The solvent in the reaction mixture was distilled off to obtain 3-(tert-butoxy)cyclobutane-1-carboxylic anhydride (55 mg, 96%). LCMS (LC-1); RT=2.09, m/z 327 [M+H] ⁺ 1H-NMR (CDCl ₃ ): 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).

Example e-03-01: 3-(tert-butoxy)-N-(5-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidine- 5-yl)pyrazolo[1,5-a]pyridin-2-yl)cyclobutane-1-carboxamide [Chem. 161]

Acetic acid [(1S,2S)-2-[[5-(2-aminopyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl]methoxy]cyclopentyl] The ester (Intermediate E-2-2; 60 mg, 0.16 mmol) was dissolved in pyridine (0.8 mL), and 3-(tert-butoxy)cyclobutane-1-carboxylic anhydride (53 mg, 0.16 mmol) was added , Dimethylaminopyridine (10 mg, 82 μmol), stirred at 120°C for 14 hours. After cooling the reaction mixture to room temperature, methanol (0.8 mL) and 2 M aqueous sodium hydroxide 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 purified by HPLC 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 %). LCMS (LC-1); RT=1.51, m/z 522 [M+H] ⁺ 1H-NMR (CD ₃ OD): δ (ppm) 9.15 (s, 2H), 8.49 (d, J = 7.5 Hz, 1H), 7.99-7.93 (m, 1H), 7.17(dd, J = 7.5, 2.0 Hz, 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).

Intermediate E-4-1: 2-(bromomethyl)-4-chloro-3-methoxypyridine [Chem. 162]

4-Chloro-3-methoxy-2-methyl-pyridine (3.15 g, 20 mmol) was dissolved in carbon tetrachloride (40 mL), N-bromosuccinimide (3.56 g, 20 mmol), benzoyl peroxide (0.42 mL, 2 mmol), and stirred under reflux for 7 hours. The obtained reaction mixture was cooled to room temperature, the solid was separated by filtration, and the obtained filtrate was concentrated under reduced pressure. The obtained crude product was purified by automatic silica gel column chromatography (eluate; hexane:ethyl acetate=96:4-66:34), thereby obtaining 2-(bromomethyl)-4-chloro - 3-methoxypyridine (1.5 g, 32% yield). LCMS (LC-1); RT=1.35, m/z 235 [M+H] ⁺ 1H-NMR (CDCl ₃ ): δ (ppm) 8.25 (1H, d, J = 5.1 Hz), 7.30 (1H, d , J = 5.1 Hz), 4.63 (2H, s), 4.04 (3H, s).

Intermediate E-4-2: 2-(4-Chloro-3-methoxypyridin-2-yl)acetonitrile [Chem. 163]

2-(Bromomethyl)-4-chloro-3-methoxy-pyridine (1.5 g, 6.34 mmol), sodium cyanide (1.55 g, 32 mmol) were added to water (3.2 mL), ethanol (3.1714 mL ) in a mixed solvent at 60°C for one hour. Saturated sodium bicarbonate water and chloroform were added to the obtained crude reaction 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 silica gel column chromatography (eluate; hexane:ethyl acetate=94:6-50:50), thereby obtaining 2-(4-chloro-3-methoxy ylpyridin-2-yl)acetonitrile (691 mg, 60% yield). LCMS (LC-1); RT=1.05, m/z 183 [M+H] ⁺ 1H-NMR (CDCl ₃ ): δ (ppm) 8.25 (1H, d, J = 5.2 Hz), 7.35 (1H, d , J = 5.2 Hz), 4.01 (3H, s), 3.96 (2H, s).

Intermediate E-4-3: 5-Chloro-4-methoxypyrazolo[1,5-a]pyridin-2-amine [Chem. 164]

at O- Add 70% perchloric acid aqueous solution (140 μL, 1.64 mmol, 1.1 eq.), stirred at 0 degrees for 30 minutes. The reaction mixture was diluted with cold water and hexane, and the precipitate was collected by filtration 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) at Stir at 0°C for 1 hour. The reaction mixture was concentrated, a solution of potassium carbonate (103 mg, 74 mmol) in dimethylformamide (1 mL) was added, and heated and stirred at 120°C. After the reaction mixture was cooled to room temperature, saturated brine was added, extracted with ethyl acetate, dried with magnesium sulfate, and the solvent was distilled off, and the solvent was removed by automatic silica gel column chromatography (eluent; hexane: ethyl acetate ester=1:1) The obtained crude product was purified, thereby obtaining 5-chloro-4-methoxypyrazolo[1,5-a]pyridin-2-amine (112 mg, 38%). LCMS (LC-1); RT=1.03, m/z 198 [M+H] ⁺ 1H-NMR (CDCl ₃ ): δ (ppm) 8.02 (s, 2H), 7.91 (d, J = 7.3Hz, 2H ), 6.50 (d, J = 7.3 Hz, 2H), 5.86 (s, 2H), 3.98 (s, 3H).

Intermediate E-4-4: (1S,2S)-2-((5-(2-amino-4-methoxypyrazolo[1,5-a]pyridin-5-yl)pyrimidine- 2-yl)methoxy)cyclopentyl ester [Chem. 165]

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), add the above crude product acetic acid (1S,2S)-2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolin-2-yl) Pyrimidin-2-yl)methoxy)cyclopentyl ester (Intermediate B-4-2; 4.4 mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), sodium carbonate (42 mg , 0.4 mmol), water (0.1 mL), and the mixture was irradiated with microwave at 185° C. for 1 hour. The crude reaction mixture was concentrated under reduced pressure, and the obtained crude product was purified using automatic silica gel column chromatography (eluate; chloroform:methanol=95:5), thereby obtaining acetic acid (1S, 2S) -2-((5-(2-amino-4-methoxypyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl)methoxy)cyclopentyl ester (46.9 g , yield 58%). LCMS (LC-1); RT=1.11, m/z 398 [M+H] ⁺ 1H-NMR (CDCl ₃ ): 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).

Intermediate E-4-5: (1S,2S)-2-((5-(2-(cyclopropanecarboxamide)-4-methoxypyrazolo[1,5-a]pyridine-5 -yl)pyrimidin-2-yl)methoxy)cyclopentyl ester [Chem. 166]

(1S,2S)-2-((5-(2-amino-4-methoxypyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl)methoxy ) cyclopentyl ester (intermediate E-4-4; 32 mg, 0.07 mmol) was dissolved in dichloromethane (1 mL), in dichloromethane (1.2 mL) solution of dimethylamine (71 μL, 1.4 mmol) To this was added cyclopropylformyl chloride (16 μL, 0.18 mmol) and N-ethylisopropylamine (41 μL, 0.24 mmol), and stirred at room temperature for 30 minutes. The solvent in the reaction mixture was distilled off to obtain (1S,2S)-2-((5-(2-(cyclopropaneformamide)-4-methoxypyrazolo[1,5- a] pyridin-5-yl)pyrimidin-2-yl)methoxy)cyclopentyl ester (54.9 mg, 99%). LCMS (LC-1); RT=1.32, m/z 466 [M+H] ⁺

Example e-04-01: N-(5-(2-((((1S,2S)-2-hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)-4-methoxy Pyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide [Chem. 167]

(1S,2S)-2-((5-(2-(cyclopropanecarboxamide)-4-methoxypyrazolo[1,5-a]pyridin-5-yl)pyrimidine-2- methoxy)cyclopentyl ester (intermediate E-4-5; 54.9 mg, 0.12 mmol) was dissolved in methanol (1.2 mL), added 2 M aqueous sodium hydroxide solution (500 μL), and stirred at room temperature 30 minutes. Saturated brine was added to the reaction mixture, extracted with chloroform, dried with magnesium sulfate, and purified by HPLC to obtain N-(5-(2-((((1S,2S)-2- Hydroxycyclopentyl)oxy)methyl)pyrimidin-5-yl)-4-methoxypyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (5.6 mg, 11% ). LCMS (LC-1); RT=1.06, m/z 424 [M+H] ⁺ 1H-NMR (CDCl ₃ ): 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 = 15 Hz, 1H), 4.83 (d, J = 15 Hz, 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).

<Test Example 1: Determination of Human IRAK-4 Inhibitory Activity> (1) Measurement method Regarding the activity of human IRAK-4 (Invitrogen, Cat. PV3362), by TR-FRET (Time-Resolved Fluorescence Resonance Energy Transfer, time difference formula Fluorescence resonance energy transfer) method, in the presence of 10 μM ATP (Adenosine triphosphate, adenosine triphosphate) (Sigma Aldrich, Cat. A7699), the phosphorylation of IRAK-4 peptide substrate (biotin-KKKKRFSFKKSFKC) was determined. The enzymatic reaction was carried out with 50 mM HEPES (4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid, 4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid) (pH7.2), 1 mM DTT, 0.1 mM Na ₃ VO ₄ , 5 mM MgCl ₂ , 1 mM MnCl ₂ , 0.1% bovine serum albumin in reaction buffer. To measure IRAK-4 inhibitory activity, test compounds were added to reaction buffer containing 1 nM IRAK-4, 0.5 μM peptide matrix, and 10 μM ATP, and incubated at 23°C for 30 minutes. Then, antibodies containing europium cryptate-labeled (0.3 μg/mL, the antibody system was produced using IRAK-4 peptide matrix as antigen), streptavidin-XL665 (2 μg/mL, CisBio, Cat. 610SAXLB), 50 mM HEPES (pH7.2), 0.1% BSA, 120 mM KF, 66.7 mM EDTA (Ethylenediaminetetraacetic acid, ethylenediaminetetraacetic acid) detection solution (each reagent is the final concentration), after the reaction is terminated, Furthermore, it cultured at 23 degreeC for 60 minutes. Fluorescence intensities at wavelengths of 665 nm and 620 nm were measured using a microdisk reader, and enzyme activity was calculated as the ratio of the fluorescence intensities at 665 nm/620 nm. The IRAK-4 inhibition rate when 12.5 μM staurosporine (LC Laboratories, Cat. S-9300) was added was taken as 100%, and the IRAK-4 inhibition rate when no test compound was added was taken as 0%. Data analysis was used The IC ₅₀ of the tested compound was obtained by using the 4 Parameter Logistic Model of the software XLfit (ID Business Solutions Ltd.). In addition, each operation and conditions in the measurement can be appropriately changed within the range that can be understood by the practitioner and does not greatly affect the measurement.

(2) Measurement results As shown below, one aspect of the compound of the present invention exhibited excellent IRAK-4 inhibitory activity. In addition, when measuring multiple times, the average value is shown. [Table 22] example IC ₅₀ (nM) example 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

[Table 23] example IC ₅₀ (nM) example 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

[Table 24] example IC ₅₀ (nM) example 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

[Table 25] example IC ₅₀ (nM) example 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

[Table 26] example IC ₅₀ (nM) example 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

<Test Example 2: LPS-stimulated TNFα production inhibition test using the human acute monocytic leukemia cell line THP-1> (1) Measurement method In the THP-1 assay, the effect of the test compound on stimulation by LPS can be evaluated. Effect of Induced TNFα Production. Inoculate THP-1 cells (ATCC, Cat. TIB-202) into a 96-well plate at 1×10 ⁵ cells/160 μL/well, add 20 μL of the test compound, and use a 5% CO ₂ incubator at 37°C Incubate for 1 hour. Then, 20 μL of LPS (final concentration 2.5 ng/mL, Sigma, Cat. L2630) was added, and cultured for 4 hours. After incubation, the culture plate was centrifuged, and 100 μL of supernatant was taken out from each well, and the amount of TNFα was evaluated by HTRF (homogeneous time resolved fluorescence, homogeneous time resolved fluorescence) (Cisbio, Cat. 62TNFPEB). In the determination of the amount of TNFα, after diluting the supernatant to 2 times with the medium, add 10 μL to the 384-well plate, then add anti-TNFα cryptate (5 μL) and anti-TNFα-XL665 (5 μL), and statically Leave overnight. The ratio of fluorescence intensity at wavelength 620/665 nm was measured using a microdisk reader, and the amount of TNFα in the supernatant was calculated from the calibration curve. The TNFα production inhibition rate when no LPS was added was taken as 100%, and the TNFα production inhibition rate when no test compound was added was taken as 0%, using the four-parameter logarithmic model (4 Parameter Logistic Model) to calculate the IC ₅₀ of the tested compound.

Use the 96-well plate after removing 100 μL of the supernatant to measure the cell viability and evaluate the impact of the tested compound on off-target effects. After adding 5 μL of CCK-8 (Dojindo, Cat. CK04-10) and incubating at 37° C. for 1 hour, the absorbance at 450 nm was measured using a microplate reader. Taking the cell survival rate without adding LPS as 100%, the IC ₅₀ of the test compound was calculated using XLfit. In addition, each operation and conditions in the measurement can be appropriately changed within the range that can be understood by the practitioner and does not greatly affect the measurement.

(2) Measurement results As shown below, one aspect of the compound of the present invention exhibited excellent TNFα production inhibiting activity. In addition, when it measured plural times, the average value is shown. Round off to the 4th decimal place. [Table 27] example _IC50 (μM) example _IC50 (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

[Table 28] example _IC50 (μM) example _IC50 (μM) 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

[Table 29] example _IC50 (μM) example _IC50 (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

[Table 30] example _IC50 (μM) example _IC50 (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

[Table 31] example _IC50 (μM) example _IC50 (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

＜Test Example 3: Rat Collagen-Induced Arthritis Model＞ (1) Measurement method Eight-week-old female Lewis rats (SLC Inc.) were immunized with bovine type II collagen (CII, Collagen Technology Research Institute, product number K41) to induce arthritis. Make a 1:1 mixed emulsion of incomplete Freund's adjuvant (Difco, Cat. 263910) and CII 3 mg/mL solution, inject 0.1 mL, 0.7 mL in total. Seven days later, 0.1 mL of an emulsion mixed with incomplete Freund's adjuvant and CII at a ratio of 1:1 was added to the base of the tail in the same manner as on the first day, totaling 0.2 mL. After 12 days, use a Plethysmometer (UGO BASILE, Cat. 37140) to measure the volume of the paw and plantar of the two hind limbs of the animals, and group them according to the volume ratio of the paw and plantar relative to the normal group and body weight. After grouping, administration of the test compound or solvent (vehicle: 0.5% methylcellulose) was started, and oral administration was performed twice a day for 7 days (administration was only once after grouping on the grouping day). From the start of administration, the paw volume of the two hind limbs of the animal was measured every 1 or 2 days using a limb swelling measuring instrument, and the influence of the test compound was evaluated. For each individual on each measurement day, the average value of the paw and plantar volumes of both hind limbs was calculated using Excel 2010 (Microsoft), and graphed using GraphPad Prism 7.03 (GraphPad Software, Inc.). The normal group was defined as a 100% inhibition control, and the solvent-administered group was defined as a 0% inhibition control. Relative to these controls, the inhibition rate at each test compound concentration was calculated using Excel2010 (Microsoft). In addition, each operation and conditions in the measurement can be appropriately changed within the range that can be understood by the practitioner and does not greatly affect the measurement.

(2) Measurement results The change results of the plantar volume of each group are shown in Fig. 1 . The vertical axis represents the plantar volume, and the horizontal axis represents the days after the initial bovine type II collagen immunization. Also, "n" represents the number of rats used. In Example c-01-01, 20, 60, 120 mg/kg, twice a day, the inhibition rates were 45%, 65%, and 77% after 19 days from the first immunization of the groups administered twice a day, respectively. As described above, a certain aspect of the compound of the present invention (Example c-01-01) exhibited an excellent swelling-inhibiting effect on rat arthritis. [Industrial availability]

The compound of the general formula (1) or a salt thereof has excellent IRAK-4 inhibitory activity and can be used as an active ingredient of a medicine for preventing and/or treating diseases related to IRAK-4 inhibition.

Fig. 1 is a graph showing the swelling inhibitory effect of an aspect of the compound of the present invention (Example c-01-01) on arthritis in rats.

Claims (35)

A compound or a salt thereof, the compound is represented by the following general formula (1): [Chem. 1] [In the formula (1), Rg is the following general formula (1-1): [Chem. 2] Or the following general formula (1-2): [Chemical 3] (a, b represent the bonding orientation), R ¹ is -H, -F, -Cl, methyl, or C _1-3 alkoxy, and the above C _1-3 alkoxy can be selected from G ¹ group 1 to 3 of the same or different substituents are substituted; the above G ¹ group is composed of -F, hydroxyl, cyano, halogenated C _1-6 alkyl, C _1-4 alkoxy, phenyl, 5-6 The group consisting of 3-7 membered heteroaryl and 3-7 membered saturated ring group, the phenyl group or 5-6 membered heteroaryl group in ^G1 can be selected from 1 to 3 identical or different ones in G ^Ar group Substituent substitution; The above-mentioned G ^Ar group is a group consisting of -F, -Cl, hydroxyl, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl, and -NH ₂ ; R ² is C _1-6 alkyl, halogenated C _1-6 alkyl, or 3-7 membered saturated ring group, the above R ² may be substituted by 1 to 3 identical or different substituents selected from G ² group; the above G ² The group is composed of -F, hydroxyl, halogenated C _1-3 alkyl, and C _1-4 alkoxy; Cy is the following general formula (2-1): [Chemical 4] ; In 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, 5-6 membered heteroaryl, or 3-7 membered saturated ring, phenyl or 5-6 in R ^Cy1 and R ^Cy2 The membered heteroaryl group may be substituted by 1 to 3 identical or different substituents selected from the above G ^Ar group, and the above R ^Cy1 and R ^Cy2 may be substituted by 1 to 3 identical or different substituents selected from the above G ¹ group. Substituent substitution; R ¹¹ and R ¹² are independently -H, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy 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 may be substituted by 1 to 3 identical or different substituents selected from G ¹ group; Or R ¹¹ and R ¹² together form a 4-10-membered saturated ring or a 7-11-membered spiro ring, and the above-mentioned 4-10-membered saturated ring and 7-11-membered spiro ring can be selected from O and N in addition to N. 1 to 2 same or different heteroatoms or -S(O ₂ )- in the group, the above-mentioned 4-10 membered saturated ring and 7-11 membered spiro ring can be selected from 1 to 3 members in the ^G3 group The same or different substituents are substituted; the above-mentioned G ³ group is composed of -F, hydroxyl, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy 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)NH ₂ , -NR ¹³ S(O ₂ )R ¹⁴ , -S(O ₂ )NR ¹³ R ¹⁴ , -S(O ₂ )NH ₂ , -S(O ₂ )R ^14. A group consisting of phenyl, 5-6 membered heteroaryl, and 3-7 membered saturated ring group, the phenyl or 5-6 membered heteroaryl in the above ^G3 can be selected from the above G ^Ar group 1 to 3 of the same or different substituents; R ¹³ is -H, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, halogen Substituted C _1-6 alkoxy C _1-6 alkyl, phenyl, 5-6 membered heteroaryl, or 3-7 membered saturated ring group, the phenyl or 5-6 membered heteroaryl in the above R ¹³ Can be substituted by 1 to 3 identical or different substituents selected from the above G ^Ar group; R ¹⁴ is 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, phenyl or 5 in the above R ¹⁴ The -6-membered heteroaryl group may be substituted by 1 to 3 identical or different substituents selected from the above G ^Ar group; or R ¹³ and R ¹⁴ together form a 4-7-membered saturated ring or a 7-11-membered spiro ring, The above-mentioned 4-7 membered saturated ring and 7-11 membered spiro ring may have, in addition to N, 1 to 2 same or different heteroatoms or -S(O ₂ )- selected from the group consisting of O and N ; Or R ^Cy1 and R ^Cy2 together form a 4-7 member saturated ring, the above-mentioned 4-7 member saturated ring may have 1-2 identical or different heteroatoms or -S( O ₂ )-, the aforementioned 4-7 membered saturated ring may be substituted by 1 to 3 identical or different substituents selected from the aforementioned G ¹ group]. The compound or salt thereof as claimed in item 1, wherein Rg is the general formula (1-1). The compound or salt thereof as claimed in claim 2, wherein R ¹ is -F, -Cl, methyl, or C _1-3 alkoxy. The compound or salt thereof as claimed in claim 2, wherein R ¹ is C _1-3 alkoxy. The compound or salt thereof as claimed in claim 2, wherein R ¹ is methoxy. The compound or salt thereof as any one of claims 2 to 5, wherein R ¹ is -H; Cy is the following general formula (2-1-1): [Chemical 5] (R ¹¹ and R ¹² have the same meaning as above). The compound or salt thereof as any one of claims 2 to 6, wherein Cy is the following general formula (2-1-2): [Chemical 6] [In formula (2-1-2), R ^Cy3 is C _1-4 alkyl, halogenated C _1-4 alkyl; X is O or NR ¹⁵ ; R ¹⁵ is -H, C _1-6 alkyl , halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, -C(O)R ¹⁶ , -S(O ₂ )R ¹⁶ , - C(O)NR ¹⁶ R ¹⁷ , -C(O)OR ¹⁶ , or a 3-7 membered saturated ring group, the above R ¹⁵ may be substituted by 1 to 3 identical or different substituents selected from G ¹ group; R ¹⁶ is 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, benzene group, 5-6 membered heteroaryl group, or 3-7 membered saturated ring group, the phenyl or 5-6 membered ^heteroaryl group in the above R ¹⁶ can be selected from 1 to 3 identical or Different substituents are substituted; R ¹⁷ is -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 phenyl or 5-6 membered heteroaryl in the above R ¹⁷ can be selected from the above G ^Ar 1-3 identical or different substituents in the group are substituted; or R ¹⁶ and R ¹⁷ together form a 4-7-membered saturated ring or a 7-11-membered spiro ring, the above-mentioned 4-7-membered saturated ring and 7-11-membered spiro ring The ring may have, in addition to N, 1 to 2 identical or different heteroatoms or -S(O ₂ )-] selected from the group consisting of O and N. The compound or salt thereof according to any one of claims 2 to 7, wherein X is NR ¹⁵ (R ¹⁵ has the same meaning as above). The compound or salt thereof as any one of claims 2 to 8, wherein Cy is the following general formula (2-1-3): [Chemical 7] (R ^Cy3 and X have the same meaning as above). The compound or salt thereof as any one of claims 2 to 9, wherein ^R is the following formula (3-1): [Chem. 8] or n-propyl. The compound or salt thereof as any one of claims 2 to 9, wherein ^R is the following formula (3-1): [Chemical 9] . A compound or a salt thereof, the compound is represented by the following formula: [Chem. 10] . A compound or a salt thereof, the compound is represented by the following formula: [Chem. 11] . A compound or a salt thereof, the compound is represented by the following formula: [Chem. 12] . A compound or a salt thereof, the compound is represented by the following formula: [Chem. 13] . A compound or a salt thereof, the compound is represented by the following formula: [Chem. 14] . A compound or a salt thereof, the compound is represented by the following formula: [Chem. 15] . A compound or a salt thereof, the compound is represented by the following formula: [Chem. 16] . A compound or a salt thereof, the compound is represented by the following formula: [Chem. 17] . A compound or a salt thereof, the compound is represented by the following formula: [Chem. 18] . A compound or a salt thereof, the compound is represented by the following formula: [Chem. 19] . The compound or its salt according to claim 1, wherein Rg is the general formula (1-2). The compound or salt thereof as claimed in claim 22, wherein R ¹ is -H, or methoxy. The compound or salt thereof as claimed in item 22, wherein R ¹ is -H. Such as the compound or salt thereof of claims 22 to 24, wherein Cy is general formula (2-1); [in formula (2-1), k is an integer 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, 5-6 membered heteroaryl, or 3 -7-membered saturated ring group, the phenyl group or 5-6 membered heteroaryl group in R ^Cy1 and R ^Cy2 may be substituted by 1 to 3 identical or different substituents selected from the above-mentioned G ^Ar group, the above-mentioned R ^Cy1 , R ^Cy2 may be substituted by 1 to 3 identical or different substituents selected from the above group G ¹ (R ¹¹ and R ¹² have the same meaning as above)]. The compound or salt thereof as any one of claims 22 to 25, wherein Cy is the following general formula (2-1-1): [Chemical 20] (R ¹¹ and R ¹² have the same meaning as above). The compound or salt thereof as any one of claims 22 to 26, wherein Cy is the following general formula (2-1-2): [Chemical 21] (R ^Cy3 has the same meaning as above); X is O or NR ¹⁵ (R ¹⁵ has the same meaning as above). The compound or salt thereof according to any one of claims 22 to 27, wherein X is NR ¹⁵ (R ¹⁵ has the same meaning as above). The compound or salt thereof as any one of claims 22 to 28, wherein Cy is the following general formula (2-1-3): [Chemical 22] (R ^Cy3 and X have the same meaning as above). The compound or salt thereof as any one of claims 22 to 29, wherein R ² is the following formula (3-1): [Chemical 23] or n-propyl. The compound or salt thereof as any one of claims 22 to 29, wherein R ² is the following formula (3-1): [Chemical 24] . A compound or a salt thereof, the compound is represented by the following formula: [Chem. 25] . A compound or a salt thereof, the compound is represented by the following formula: [Chem. 26] . A compound or a salt thereof, the compound is represented by the following formula: [Chemical 27] . A compound or a salt thereof, the compound is represented by the following formula: [Chem. 28] .