TW202328149A - Macrocyclic compound having an excellent IRAK-4 inhibitory activity - Google Patents

Abstract

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

Description

Macrocycles

The present invention relates to a novel macrocyclic 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 formula (1), R ¹ 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 ¹² , -S(O ₂ )R ¹² , -C(O)NR ¹¹ R ¹² , -C(O)OR ¹² , or a 3-7 membered saturated ring group, the above R ¹ can be Substituted by 1 to 3 identical or different substituents selected from group ^G1 ; the group ^G1 above is composed of -F, hydroxyl, cyano, halogenated _C1-6 alkyl, _C1-4 alkoxy, A group consisting of phenyl, 5-6 membered heteroaryl, and 3-7 membered saturated ring group, the phenyl ^group or 5-6 membered heteroaryl group in ^G1 group can be selected from 1～ Substituted by 3 identical or different substituents; the above G ^Ar group is composed of -F, -Cl, hydroxyl, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl, and -NH ₂ Group; R ¹¹ 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, or 3-7 membered saturated ring; R ¹² 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, 3-7 membered saturated ring group, phenyl, or 5-6 membered heteroaryl, the phenyl or 5-6 membered heteroaryl in ^R can be selected from 1 to 3 substituents in the above G ^Ar group are substituted by the same or different substituents; R ² is -H, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, C _{1 -6} alkoxy C _1-6 alkyl, or 3-7 membered saturated ring; R ³ is -H, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl , C _1-6 alkoxy C _1-6 alkyl, or 3-7 membered saturated ring; Ar is 6-10 membered aryl or 5-10 membered heteroaryl, the above Ar can be selected from ^G2 group 1 to 3 of them are substituted by the same or different substituents; the above-mentioned ^G2 group consists of -F, -Cl, hydroxyl, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxyl C _{1 -6} alkyl, R ^Ar1 -OC _1-3 alkyl, R ^Ar1 -NR ¹³ -C _1-3 alkyl, -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 , -NH ₂ , -S(O ₂ )NH ₂ , -NR ¹³ R ¹⁴ , and -NHC (O) A group consisting of NHR ¹⁵ ; R ^Ar1 is -H, C _1-6 alkyl, halogenated C _1-6 alkyl, or a 3-7 membered saturated ring group, and the above R ^Ar1 can be selected from G ³ 1 to 3 substituents in the group are substituted by the same or different substituents; the above-mentioned G ³ group consists of -F, hydroxyl, C _1-3 alkyl, halogenated C _1-3 alkyl, pendant oxy, C _1-3 A group consisting of alkoxy, halogenated C _1-3 alkoxy, and 3-7 membered saturated ring; R ¹³ is -H, C _1-3 alkyl, halogenated C _1-3 alkyl, C _1-3 alkoxy C _1-3 alkyl, halogenated C _1-3 alkoxy C _1-3 alkyl, or 3-7 membered saturated ring; R ¹⁴ is C _1-3 alkyl, halogenated C _1-3 alkyl, C _1-3 alkoxy C _1-3 alkyl, halogenated C _1-3 alkoxy C _1-3 alkyl, or 3-7 membered saturated ring group; R ¹⁵ is - H, phenyl, or 5-6 membered heteroaryl, the above R ¹⁵ can be substituted by 1 to 3 identical or different substituents selected from the G ⁴ group; the above G ⁴ group is composed of halogen, cyano, C A group consisting of _1-3 alkyl and halogenated C _1-3 alkyl; X ¹ is N or CH; X ² is NH or O; X ³ is the following general formula (1-1): ] Or the following general formula (1-2): [Chemical 3] Or the following general formula (1-3): [Chemical 4] (a, b represent the bonding orientation), R ²¹ and R ²² are independently -H, C _1-3 alkyl, halogenated C _1-3 alkyl; X ⁴ is the following general formula (2-1) : [Chemical 5] (b, c represent the bonding orientation); in formula (2-1), n is an integer of 1 to 3; Y is NR ⁵¹ , or O; R ³¹ and R ³² are independently -H, C _1-3 Alkyl, halogenated C _1-3 alkyl; or R ³¹ and R ³² can together form a 3-6 membered saturated ring; R ⁴¹ and R ⁴² are independently -H, -F, hydroxyl, C _1-3 alkane Base, halogenated C _1-3 alkyl, C _1-3 alkoxy, halogenated C _1-3 alkoxy; or R ⁴¹ and R ⁴² can together form a 3-6 membered saturated ring; R ⁵¹ is -H , C _1-3 alkyl, halogenated C _1-3 alkyl; or R ⁵¹ and the above R ³¹ can form a 4-6 membered saturated ring together; the above X ⁴ can be selected from 1 to 3 of the G ⁵ group Substituting with the same or different substituents; the above group ^G5 is selected from -F, hydroxyl, C _1-3 alkyl, halogenated C _1-3 alkyl, C _1-3 alkoxy, halogenated C _1-3 Groups consisting of alkoxy groups].

[2] The compound or a salt thereof according to [1], wherein Ar is a 5-6 membered heteroaryl group. [2-2] The compound or a salt thereof as described in [1] above, wherein Ar is thienyl, thiazolyl, isothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, or pyridyl . [2-3] The compound or a salt thereof according to the above [1], wherein Ar is thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, or pyridolyl. [2-4] The compound or a salt thereof according to the above [1], wherein Ar is thiazolyl, isothiazolyl, pyridyl, or pyrimidinyl. [2-5] The compound or a salt thereof according to the above [1], wherein Ar is thiazolyl or pyrimidinyl.

[3] The compound or salt thereof according to any one of the above-mentioned [1] to [2], wherein R ¹ is -H, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy C _{1- 6} alkyl, C _1-6 alkoxy C _1-6 alkyl, or 3-7 membered saturated ring group, and the above R ¹ can be selected from 1 of G ¹ group (G ¹ group has the same meaning as above) Substituted by ~3 identical or different substituents. [3-2] The compound or salt thereof according to any one of the above-mentioned [1] to [2], wherein R ¹ is -H, C _1-6 alkyl, halogenated C _1-6 alkyl, C _{1 -6} alkoxy C _1-6 alkyl group, or 3-7 membered saturated ring group, and the above R ¹ may be selected from 1 to 3 of the G ¹ group (G ¹ group has the same meaning as above), which may be the same or different The substituents are substituted. [3-3] The compound or salt thereof as described in any one of the above-mentioned [1] to [2], wherein R ¹ is -H, C _1-6 alkyl, or a 3-7 membered saturated ring group, and the above-mentioned R ¹ may be substituted with 1 to 3 identical or different substituents selected from group G ¹ (group G ¹ has the same meaning as above).

[4] The compound or a salt thereof according to any one of the above-mentioned [1] to [3-3], wherein X ² is NH. Furthermore, when the cited item number is expressed in a range as in the above [1] to [3-3], and an item with a branch number such as [3-2] is arranged within the range, it means that the item number with [3] is also cited -2] and other branch numbers. The same applies to the following.

[5] The compound or salt thereof as described in any one of the above-mentioned [1] to [4], wherein X ³ is the following general formula (1-1): [Chemical 6] (R ²¹ and R ²² have the same meaning as above).

[6] The compound or salt thereof as described in any one of the above-mentioned [1] to [5], wherein X ³ is the following general formula (1-1-1): [Chem. 7] . [7] The compound or a salt thereof according to any one of the above-mentioned [1] to [6], wherein in the general formula (2-1) of X ⁴ , n is 1.

[8] The compound or salt thereof according to any one of the above-mentioned [1] to [8], wherein Ar is the following general formula (3-1): [Chem. 8] ; In formula (3-1), R ^Ar2 is -H, -F, -Cl, hydroxyl, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxyl C _1-6 alkyl, R ^Ar1 -OC _1-3 alkyl, or -NR ¹³ R ¹⁴ (R ^Ar1 , R ¹³ , and R ¹⁴ have the same meanings as above). [8-2] The compound or salt thereof as described in any one of the above-mentioned [1] to [7], wherein Ar is the general formula (3-1), and in the formula (3-1), R ^Ar2 is -H, C _1-6 alkyl, hydroxy C _1-6 alkyl, or R ^Ar1 -OC _1-3 alkyl (R ^Ar1 has the same meaning as above). [8-3] The compound or salt thereof as described in any one of the above-mentioned [1] to [8], wherein Ar is the general formula (3-1), and in the formula (3-1), R ^Ar2 is R ^Ar1 - OC _1-3 alkyl (R ^Ar1 has the same meaning as above).

[8-4] The compound or salt thereof as described in any one of the above-mentioned [1] to [8], wherein Ar is the general formula (3-1), and in the formula (3-1), R ^Ar2 is R ^Ar1 - OC _1-3 alkyl (R ^Ar1 has the same meaning as above), R ^Ar1 is C _1-6 alkyl or 3-7 membered saturated ring group, and the above R ^Ar1 can be selected from G ³ group (G ³ group has the same meaning as above 1 to 3 of the same or different substituents are substituted. [8-5] The compound or salt thereof as described in any one of the above-mentioned [1] to [8], wherein Ar is the general formula (3-1), and in the formula (3-1), R ^Ar2 is R ^Ar1 - OC _1-3 alkyl group (R ^Ar1 has the same meaning as above), R ^Ar1 is a C _1-6 alkyl group, and the above R ^Ar1 can be selected from 1 to 3 members of G ³ group (G ³ group has the same meaning as above) Substitution by the same or different substituents. [8-6] The compound or salt thereof as described in any one of the above-mentioned [1] to [8], wherein Ar is the general formula (3-1), and in the formula (3-1), R ^Ar2 is R ^Ar1 - OC _1-3 alkyl (R ^Ar1 has the same meaning as above), R ^Ar1 is a 3-7 membered saturated ring group, and the above R ^Ar1 can be selected from 1 to 3 groups in G ³ group (G ³ group has the same meaning as above). Substituted by the same or different substituents. [8-7] The compound or salt thereof as described in any one of the above-mentioned [1] to [7], wherein Ar is the general formula (3-1), and in the formula (3-1), R ^Ar2 is R ^Ar1 - OC _1-3 alkyl (R ^Ar1 has the same meaning as above), R ^Ar1 is a C _3-7 cycloalkyl group, and the above R ^Ar1 can be selected from 1 to 3 of G ³ groups (G ³ groups have the same meaning as above) Substituted by the same or different substituents.

[9] The compound or salt thereof as described in any one of the above-mentioned [1] to [8-7], wherein Ar is the general formula (3-1); in the formula (3-1), R ^Ar2 is -H, methyl, hydroxymethyl, -CH ₂ -OR ^Ar1 (R ^Ar1 has the same meaning as above). [9-2] The compound or salt thereof as described in any one of the above-mentioned [1] to [8-7], wherein Ar is the general formula (3-1), and in the formula (3-1), R ^Ar2 is R ^Ar1 -O-CH ₂ - (R ^Ar1 has the same meaning as above), R ^Ar1 is a C _1-6 alkyl group or a 3-7 membered saturated ring group, and the above R ^Ar1 can be selected from G ³ groups (G ³ groups are the same as the above-mentioned 1 to 3 of the same or different substituents are substituted. [9-3] The compound or salt thereof as described in any one of the above-mentioned [1] to [8-7], wherein Ar is the general formula (3-1), and in the formula (3-1), R ^Ar2 is R ^Ar1 -O-CH ₂ - (R ^Ar1 has the same meaning as above), R ^Ar1 is a C _1-6 alkyl group, and the above R ^Ar1 can be selected from 1 to 3 of G ³ groups (G ³ groups have the same meaning as above) Substituted by the same or different substituents.

[9-4] The compound or salt thereof as described in any one of the above-mentioned [1] to [8-7], wherein Ar is the general formula (3-1), and in the formula (3-1), R ^Ar2 is R ^Ar1 -O-CH ₂ - (R ^Ar1 has the same meaning as above), R ^Ar1 is a 3-7 membered saturated ring group, and the above R ^Ar1 can be selected from 1 to 1 in G ³ group (G ³ group has the same meaning as above). Substituted by 3 identical or different substituents. [9-5] The compound or salt thereof as described in any one of the above-mentioned [1] to [8-7], wherein Ar is the general formula (3-1), and in the formula (3-1), R ^Ar2 is R ^Ar1 -O-CH ₂ - (R ^Ar1 has the same meaning as above), R ^Ar1 is a C _3-7 cycloalkyl group, and the above R ^Ar1 can be selected from 1 to 1 in G ³ group (G ³ group has the same meaning as above). Substituted by 3 identical or different substituents. [9-6] The compound or salt thereof as described in any one of the above-mentioned [1] to [8-7], wherein Ar is the general formula (3-1), and in the formula (3-1), R ^Ar2 is formazan group, or hydroxymethyl group. [9-7] The compound or salt thereof as described in any one of the above-mentioned [1] to [8-7], wherein Ar is the general formula (3-1), and in the formula (3-1), R ^Ar2 is formazan base. [9-8] The compound or salt thereof as described in any one of the above-mentioned [1] to [8-7], wherein Ar is the general formula (3-1), and in the formula (3-1), R ^Ar2 is hydroxyl methyl.

[10] The compound or a salt thereof according to any one of the above-mentioned [1] to [9-8], wherein R ³ is -H. [11] The compound or salt thereof according to any one of the above-mentioned [1] to [10], wherein R ² is -H or methyl. [12] The compound or salt thereof according to any one of the above-mentioned [1] to [11], wherein R ¹ is -H, or C _1-3 alkyl. [12-2] The compound or a salt thereof according to any one of the above-mentioned [1] to [11], wherein R ¹ is -H. [12-3] The compound or a salt thereof according to any one of the above-mentioned [1] to [11], wherein R ¹ is a C _1-3 alkyl group. [12-4] The compound or salt thereof according to any one of the above-mentioned [1] to [11], wherein R ¹ is methyl or ethyl. [12-5] The compound or a salt thereof according to any one of the above-mentioned [1] to [11], wherein R ¹ is methyl. [12-6] The compound or a salt thereof according to any one of the above-mentioned [1] to [11], wherein R ¹ is ethyl.

[13] A compound or a salt thereof, which is represented by the following formula: [Chem. 9] .

[14] A compound or a salt thereof represented by the following formula: [Chem. 10] .

[15] A compound or a salt thereof represented by the following formula: [Chem. 11] .

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

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

[18] A compound or a salt thereof represented by the following formula: [Chem. 14] .

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

[20] A medicine comprising the compound according to any one of the above-mentioned [1] to [19] or a pharmaceutically acceptable salt thereof as an active ingredient. [21] The medicine according to the above [20], which is used for preventing and/or treating a disease associated with IRAK4 inhibition. [22] The medicine as described in [20] above, which is used for preventing and/or treating rheumatism. [23] An IRAK4 inhibitor comprising, as an active ingredient, the compound according to any one of the above-mentioned [1] to [19] or a pharmaceutically acceptable salt thereof.

[24] A pharmaceutical composition for the prevention and/or treatment of rheumatism, comprising the compound as described in any one of the above [1] to [19] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [25] The compound according to any one of the above-mentioned [1] to [19] or a pharmaceutically acceptable salt thereof, which is used for preventing and/or treating rheumatism. [26] 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 [1] to [19] 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, as follows: [Chem. 16] Indicates the bond with the other side of the paper (that is, the α-configuration), the following symbol: [Chem. 17] Indicates that it is bonded to the front side of the paper (that is, the β-configuration), as shown in the following symbol: [Chemical 18] 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. [chemical 19]

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.

Examples of R ¹ 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 ¹² , -S(O ₂ )R ¹² , -C(O)NR ¹¹ R ¹² , -C(O)OR ¹² , or a 3-7 membered saturated ring group. As another aspect, exemplified: -H, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, or 3-7 membered saturated ring group. As yet another aspect, exemplified: -H, C _1-6 alkyl, or 3-7 membered saturated ring group. As still another aspect, -H, methyl group, ethyl group are illustrated. As yet another aspect, a methyl group 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, there are exemplified those selected from -F, hydroxyl, cyano, halogenated C _1-6 alkyl, C _1-4 alkoxy, phenyl, 5-6 membered heteroaryl, and 3-7 membered A group composed of saturated ring groups. As another aspect, the group ^G11 selected from -F, hydroxyl, halogenated C _1-6 alkyl, C _1-4 alkoxy, and 3-7 membered saturated ring is exemplified. As yet another aspect, the group ^G12 selected from -F, hydroxyl, _C1-4 alkoxy, and 3-7 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 selected from -F, -Cl, hydroxyl, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl, and -NH ₂ is exemplified. As another aspect, the group G ^Ar1 selected from -F, -Cl, cyano, C _1-6 alkyl, and halogenated C _1-6 alkyl is exemplified. Examples of R ¹¹ 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 group, or 3-7 membered saturated ring group. As another aspect, a C _1-6 alkyl group, a C _1-6 alkoxy C _1-6 alkyl group, or a 3-7 membered saturated ring group is exemplified. Examples of R ¹² 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 alkane group, 3-7 membered saturated ring group, phenyl group, or 5-6 membered heteroaryl group. As another aspect, a C _1-6 alkyl group, a 3-7 membered saturated ring group, a phenyl group, or a 5-6 membered heteroaryl group is exemplified. As yet another aspect, C _1-6 alkyl, 3-7 membered saturated ring groups are exemplified. The phenyl group or 5-6 membered heteroaryl group in the above R ¹² may be substituted by 1 to 3 identical or different substituents selected from 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 also exemplified.

As R ² , -H, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, or 3-7 Member saturated ring group. As another aspect, -H, C _1-6 alkyl, or 3-7 membered saturated ring group are exemplified. As another aspect, -H, C _1-3 alkyl, or cyclopropyl is exemplified. As yet another aspect, -H or methyl is exemplified. As yet another aspect, -H is exemplified.

As R ³ , -H, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, or 3-7 Member saturated ring group. As another aspect, -H, C _1-6 alkyl, or 3-7 membered saturated ring group are exemplified. As yet another aspect, -H, C _1-3 alkyl, or cyclopropyl is exemplified. As yet another aspect, -H or methyl is exemplified. As yet another aspect, -H is exemplified.

Ar is exemplified by a 6-10 membered aryl group or a 5-10 membered heteroaryl group. As another aspect, phenyl or 5-6 membered heteroaryl is exemplified. As yet another aspect, a 5-6 membered heteroaryl group is exemplified. As the above-mentioned 6-10 membered aryl group in Ar, phenyl, naphthyl, or indenyl is exemplified. As another aspect, phenyl is exemplified.

In addition, examples of the above-mentioned 5-10 membered heteroaryl group in Ar include thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, Imidazolyl, pyridyl, pyrimidinyl, pyridyl, pyridyl, pyridinyl, pyrimidinyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolyl, benzimidazole group, benzotriazolyl, benzothienyl, benzofuryl, benzothiazolyl, thiol, quinazolyl, or pyrrolopyridyl. As another aspect, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl are exemplified , pyryl, pyridyl, pyridinonyl, or pyrimidinonyl. As yet another aspect, thienyl, thiazolyl, isothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, or pyridyl are exemplified. As yet another aspect, thienyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyridyl, or pyrimidinyl are exemplified. As still another aspect, thiazolyl, isothiazolyl, pyridyl, or pyrimidyl are exemplified. As yet another aspect, thiazolyl or pyrimidinyl is exemplified. As yet another aspect, pyrimidinyl is exemplified.

The aforementioned Ar may be substituted with 1 to 3 identical or different substituents selected from Group ^G2 . As the above ^G2 group, there are exemplified those selected from -F, -Cl, hydroxyl, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, R ^Ar1 -OC _{1- 3} alkyl, R ^Ar1 -NR ¹³ -C _1-3 alkyl, -NR ¹³ C(O)R ¹⁴ , -C(O)NR ¹³ R ¹⁴ , -C(O)NH ₂ , -NR ¹³ S( A group consisting of O ₂ )R ¹⁴ , -S(O ₂ )NR ¹³ R ¹⁴ , -NH ₂ , -S(O ₂ )NH ₂ , -NR ¹³ R ¹⁴ , and -NHC(O)NHR ¹⁵ . As another aspect, the group ^G21 selected from C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, or R ^Ar1 -OC _1-3 alkyl is exemplified. As yet another aspect, the group ^G22 selected from C _1-6 alkyl, hydroxy C _1-6 alkyl, or R ^Ar1 -OC _1-3 alkyl is exemplified. As yet another aspect, the group ^G22 selected from C _1-6 alkyl, hydroxy C _1-6 alkyl, or R ^Ar1 -OC _1-3 alkyl is exemplified. As yet another aspect, R ^Ar1 -OC _1-3 alkyl is exemplified. As yet another aspect, R ^Ar1 -O-methyl is exemplified. As yet another aspect, a methyl group is exemplified.

As above-mentioned R ^Ar1 , -H, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, or a 3-7 membered saturated ring group is exemplified. As another aspect, a C _1-6 alkyl group or a 3-7 membered saturated ring group is exemplified. As yet another aspect, a C _1-6 alkyl group is exemplified. As still another aspect, a n-propyl group is exemplified. As yet another aspect, cyclobutyl or cyclopentyl is exemplified. As yet another aspect, a cyclopentyl group is exemplified. As yet another aspect, a 3-7 membered saturated ring group is exemplified. As the aforementioned 3-7 membered saturated ring group, a C _3-7 membered saturated ring group or a 3-7 membered saturated heterocyclic group is exemplified. Examples of the aforementioned 3-7 membered saturated heterocyclic group include: oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl Pyranyl, thiolyl, or piperyl. As another aspect, a tetrahydrofuryl group is exemplified.

The above-mentioned R ^Ar1 may be substituted with 1 to 3 identical or different substituents selected from group ^G3 . As the above-mentioned ^G3 group, there are exemplified those selected from -F, hydroxyl, _C1-3 alkyl, halogenated _C1-3 alkyl, pendant oxy, _C1-3 alkoxy, halogenated _C1-3 alkoxy A group consisting of a group, and a 3-7 membered saturated ring group. As another aspect, a group ^G31 selected from -F, a hydroxyl group, and a 3-7 membered saturated ring group is exemplified. As yet another aspect, examples are selected from -F, hydroxyl, C _1-3 alkyl, halogenated C _1-3 alkyl, pendant oxy, C _1-3 alkoxy, and 3-7 membered saturated ring Formed G ³² group. As yet another aspect, the group ^G33 selected from -F, hydroxyl, or _C3-7 cycloalkyl is exemplified. As yet another aspect, the group ^G34 selected from -F, hydroxyl, or cyclopropyl is exemplified.

Examples of R ¹³ above include: -H, C _1-3 alkyl, halogenated C _1-3 alkyl, C _1-3 alkoxy C _1-3 alkyl, halogenated C _1-3 alkoxy C _1-3 alkyl, or 3-7 membered saturated ring. As another aspect, exemplified: -H, C _1-3 alkyl, halogenated C _1-3 alkyl, C _1-3 alkoxy C _1-3 alkyl, or halogenated C _1-3 alkyl . As yet another aspect, a 3-7 membered saturated ring group is exemplified.

Examples of R ¹⁴ above include: C _1-3 alkyl, halogenated C _1-3 alkyl, C _1-3 alkoxy C _1-3 alkyl, halogenated C _1-3 alkoxy C _1-3 Alkyl group, or 3-7 membered saturated ring group. As another aspect, C _1-3 alkyl, halogenated C _1-3 alkyl, C _1-3 alkoxy C _1-3 alkyl, or halogenated C _1-3 alkyl are exemplified. As yet another aspect, a 3-7 membered saturated ring group is exemplified. As the 3-7 membered saturated ring group in the above ^R13 and ^R14 , _C3-7 cycloalkyl or 3-7 membered saturated heterocyclic group is exemplified. As another aspect, a cyclopropyl group, a cyclobutyl group, or an oxetanyl group is exemplified.

Examples of R ¹⁵ above include: -H, phenyl, or 5-6 membered heteroaryl. Examples of the aforementioned 5-6 membered heteroaryl groups include thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridine Base, pyrimidinyl, pyridyl, or pyridyl. As another aspect of the above-mentioned R ¹³ , phenyl or trifluoromethylphenyl is exemplified.

The aforementioned R ¹⁵ may be substituted with 1 to 3 identical or different substituents selected from group G ⁴ . As the above-mentioned ^G4 group, a group selected from halogen, cyano, _C1-3 alkyl, and halogenated _C1-3 alkyl is exemplified. As another aspect, group ^G41 selected from -F, cyano, methyl, and trifluoromethyl is exemplified.

As another aspect of Ar above, formula (3-1) is illustrated. [chemical 20]

Examples of R ^Ar2 include -H, -F, -Cl, hydroxyl, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, R ^Ar1 -OC _{1- 3} alkyl, or -NR ¹³ R ¹⁴ (R ^Ar1 , R ¹³ , and R ¹⁴ have the same meanings as above). As another aspect, R ^Ar1 -OC _1-3 alkyl is exemplified. As yet another aspect, -CH ₂ -OR ^Ar1 ( ^RAr1 has the same meaning as above) is exemplified. As still another aspect, a methyl group or a hydroxymethyl group is exemplified. As yet another aspect, a methyl group is exemplified. As yet another aspect, a hydroxymethyl group is exemplified. As the above-mentioned R ^Ar1 -OC _1-3 alkyl group, specifically, for example, the following are exemplified. [chem 21]

Moreover, as another aspect of the above-mentioned R ^Ar1 -OC _1-3 alkyl group, specifically, for example, the following are exemplified. [chem 22]

N or CH is exemplified as X ¹ . As another aspect, N is exemplified. As yet another aspect, CH is exemplified. As X ² , NH or O is exemplified. As another aspect, NH is exemplified. X ³ is exemplified by the following general formulas (1-1) to (1-3) (a and b represent the bonding orientation). [chem 23]

As another aspect, the above general formula (1-1) is illustrated. As still another aspect, the following general formula (1-1-1) is illustrated. [chem 24]

Examples of R ²¹ and R ²² each independently include -H, C _1-3 alkyl, and halogenated C _1-3 alkyl. As another aspect, -H and methyl are exemplified. As yet another aspect, -H is exemplified.

X ⁴ is exemplified by the following general formula (2-1) (b, c represent the bonding orientation). [chem 25]

As n, the integer of 1-3 is illustrated. As another aspect, an integer of 1 is exemplified. As Y, NR ⁵¹ , or O is exemplified. As another aspect, NR ⁵¹ is exemplified. As yet another aspect, O is exemplified.

R ³¹ and R ³² are independently exemplified by -H, C _1-3 alkyl, and halogenated C _1-3 alkyl. As another aspect, -H and methyl are exemplified. As yet another aspect, -H is exemplified.

The above-mentioned R ³¹ and R ³² may also together form a 3-6 membered saturated ring. Examples of the 3-6 membered saturated ring include cyclopropyl, cyclobutyl, oxetanyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl and tetrahydropyranyl. As another aspect, a cyclopropyl group, a cyclobutyl group, and an oxetanyl group are illustrated. As yet another aspect, cyclopropyl and cyclobutyl are exemplified.

R ⁴¹ and R ⁴² are independently exemplified by -H, -F, hydroxyl, C _1-3 alkyl, halogenated C _1-3 alkyl, C _1-3 alkoxy, halogenated C _1-3 alkane Oxygen. As another aspect, -H, -F, C _1-3 alkyl, halogenated C _1-3 alkyl, C _1-3 alkoxy, halogenated C _1-3 alkoxy are exemplified. As yet another aspect, -H, -F, C _1-3 alkyl is exemplified. As yet another aspect, -H, -F, and methyl are exemplified. As still another aspect, -H, -F are illustrated.

The above R ⁴¹ and R ⁴² may together form a 3-6 membered saturated ring. Examples of the 3-6 membered saturated ring include cyclopropyl, cyclobutyl, oxetanyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl and tetrahydropyranyl. As another aspect, a cyclopropyl group, a cyclobutyl group, and an oxetanyl group are exemplified. As yet another aspect, cyclopropyl and cyclobutyl are exemplified. As yet another aspect, a cyclopropyl group is exemplified.

Examples of R ⁵¹ above include -H, C _1-3 alkyl, and halogenated C _1-3 alkyl. As another aspect, -H and methyl are exemplified. As yet another aspect, -H is exemplified.

The aforementioned R ⁵¹ and the aforementioned R ³¹ may together form a 4-6 membered saturated ring. Examples of the aforementioned 4-6 membered saturated ring include azetidinyl, pyrrolidinyl, and piperidinyl. As yet another aspect, pyrrolidinyl is exemplified.

The aforementioned X ⁴ may be substituted with 1 to 3 identical or different substituents selected from the group G ⁵ . As the above-mentioned ^G5 group, there are exemplified those selected from -F, hydroxyl, C _1-3 alkyl, halogenated C _1-3 alkyl, C _1-3 alkoxy, halogenated C _1-3 alkoxy group. As another aspect, the group ^G51 selected from -F, hydroxyl, and C _1-3 alkyl is exemplified. As still another aspect, it is exemplified to be selected from the ^G52 group consisting of -F and hydroxyl.

As said ^X4 , specifically, the following are illustrated, for example. [chem 26]

Moreover, as another aspect of the above-mentioned X ⁴ , specifically, for example, the following are exemplified. [chem 27]

As specific compounds included in the present invention, the following compounds are exemplified, but the scope of the present invention is 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 of the present invention can also be produced by methods other than the methods described in the present specification by appropriately utilizing the methods 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.

The macrocyclic compound represented by formula (1) contains 4 parts. That is, the nitrogen-containing bicyclic heterocyclic core, the substituted piperidine, the linker connecting the a-c part, and the aromatic ring directly bonded to the nitrogen-containing bicyclic heterocyclic core.

Scheme 1 is the first synthesis of macrocyclic compounds. That is, the following method: the substituted piperidine is bonded to the linking group connecting the ac site in advance, and reacts with the nitrogen-containing bicyclic heterocyclic core to form an X ² bond. Thereafter, a large membered ring is formed by forming an X ³ bond, and finally an aromatic ring directly bonded to the nitrogen-containing bicyclic heterocyclic core is introduced. [chem 28]

The compound represented by formula (1) can be reacted by reaction scheme 1 (in the formula of each compound, M, for example, represents ZnI, MgBr, boric acid, boric acid ester and other substituents that can react by coupling. Also, LG ¹ , LG ^2, for example, represent a leaving group such as -Cl, -Br, -I, -OTf, -OMs, or -OTs. Also, Q ¹ , Q ^2, for example, represent a hydroxyl group; or -Cl, -Br, -I, -OTf , -OMs, or -OTs and other detachment groups; or alkenyl ^, borane derivatives, etc. can form CO bonds, CC bond substituents. Also, Q ³ For example, it means that hydroxyl, amino, etc. Substituents that react to form CO bonds and CN bonds) were produced by the method described. The compounds represented by formulas (2) to (6) 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 formula (1) can be produced by coupling reaction with the compound represented by formula (2) using a metal catalyst. More specifically, it can be produced by Suzuki-Miyaura coupling of a compound represented by formula (2) and a reagent represented by formula (6), or the like. As the reaction catalyst, for example, Pd(dppf)Cl ₂ , PdAmphos, Pd(PPh ₃ ) ₄ and 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 usually be carried out under the conditions of room temperature to 180°C.

As the reagent represented by formula (6), commercially available boronic acid, pinacol ester, and catechol ester can be used. Also, it can be produced from commercially available aryl bromide, aryl chloride, and aryl iodide by a coupling reaction using a metal catalyst or a halogen-metal exchange reaction. More specifically, it can be produced by Suzuki-Miyaura coupling with 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 usually be carried out under the condition of 40°C to 150°C. In addition, in addition to the above two methods, it is also possible to use a boron source such as an iridium catalyst, an electron-donating bidentate ligand, and bis(pinacolate) diboron to utilize a CH-activated form that does not pass through an aryl halide. Borylation reaction to prepare the reagent shown in formula (6).

STEP2 The compound represented by formula (2) can be produced from the compound represented by formula (3) by using CO bond forming reactions such as alkylation and Mitsunobu reaction, and CC bond forming reactions such as metal coupling. In the Mitsunobu reaction, OH groups are prepared on the Q ¹ and Q ² positions in formula (3), and diethyl azodicarboxylate, diisopropyl azodicarboxylate, diisopropyl azodicarboxylate, diethyl azodicarboxylate, Any one of di-tert-butyl nitrogen dicarboxylate to react. As a reaction solvent, THF, toluene, or the like can be used. In order to make the intramolecular cyclization reaction proceed before the intermolecular reaction, it is carried out under the high dilution condition of 0.1 mol/L～0.001 mol/L. The reaction temperature can usually be carried out under the conditions of room temperature to 80°C. Regarding the alkylation reaction, a hydroxyl group is prepared at the Q ¹ site, and a leaving group such as -Cl, -Br, -I, -OTf, -OMs, or -OTs is prepared at the Q ² site, and sodium hydride, potassium carbonate, cesium carbonate, In the presence of a base such as diisopropylethylamine, the alkylation reaction is carried out under high dilution conditions. As the reaction solvent, THF, DMF, acetonitrile or the like can be used. The reaction temperature is usually from room temperature to 100°C.

STEP3 The compound represented by the formula (3) is synthesized by the alkylation reaction or metal coupling reaction of the substituted piperidine represented by the formula (4) and the compound represented by the formula (5). As an alkylation reaction, specifically, in the presence of a base such as sodium hydride, potassium carbonate, cesium carbonate, diisopropylethylamine, etc., using THF, DMF, acetonitrile, etc. as a reaction solvent, at room temperature to 100 ° C Down to react, can form CO or CN bond. As a metal coupling reaction, specifically, methanesulfonic acid [(2-di-tert-butylphosphine-3,6-dimethoxy-2',4',6'-triisopropyl Base-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) or tris(dibenzylideneacetone)dipalladium(0) with coordination The mixture of dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl, etc., the base system uses phosphazene base P ₂ -Et or sodium phenate. As a reaction solvent, THF, 1,4-dioxane, DMF, acetonitrile, etc. can be used. The reaction temperature can be usually at room temperature to 180°C. In addition, the compound represented by formula (3) can be synthesized even with a combination of reagents generally used in the Buchwald-Hartwig cross-coupling reaction in this field, and a CO or CN bond can be formed.

[chem 29]

The compound represented by formula (4) can be obtained, for example, by reaction scheme 2 (in the formula of each compound, ^Q2, for example, represents a hydroxyl group, or -Cl, -Br, -I, -OTf, -OMs, or -OTs, etc. , or alkenyl, borane derivatives, etc. can form a substituent of a CO bond or a CC bond. Also, Q3 ^, for example, represents a substituent that can form a CO bond or a CN bond by reacting with a ^LG2 group such as a hydroxyl group or an amino group ) to manufacture by the method described in. The compounds represented by formulas (6) and (7) can be obtained commercially, or can be produced according to known methods, such as the methods shown below, or standard methods.

STEP4 The compound represented by formula (4) is synthesized by reducing the ketone site of the compound represented by formula (6). As the reducing agent, sodium borohydride, lithium tri-butyl borohydride (L-selectride), etc., which can reduce only the ketone site in the presence of ester and amide, can be used. The solvent is methanol, THF or the like, and the reaction is usually carried out at -78°C to room temperature. Also, when the ^Q3 group is an amino group, after the hydroxyl group generated by reduction is converted into a leaving group such as -Cl, -Br, -I, -OTf, -OMs, or -OTs, it is converted into an azide base, and finally converted to NH ₂ . For example, in the presence of a base such as triethylamine in dichloromethane solvent, the secondary hydroxyl group of methanesulfonyl chloride, p-toluenesulfonyl chloride, etc. is converted into a leaving group. The reaction is usually carried out at 0°C to 40°C. By reacting it with sodium azide in DMF, the Q ³ site azide can be obtained. The azido group can be reduced to a primary amine by a hydrogenation reaction using palladium-carbon or palladium hydroxide, or a Staudinger reaction using triphenylphosphine.

STEP5 The compound represented by formula (6) is synthesized by amidation reaction, esterification reaction, or acylation reaction of the compound represented by formula (7). Specifically, the amide or ester of an amino alcohol hydroxyl protection body with a carbon number of 2-5 or a monohydroxyl protection body of a diol with a carbon number of 2-5 is bonded to the 4-oxopiperidine represented by formula (7) -2-Carboxylic acid derivatives. As a condensing agent for amidation and esterification, 1-propanephosphonic 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 usually be carried out at 0°C to 150°C. In the acylation reaction, use oxalyl chloride, isobutyl chloroformate, etc. to activate the carboxylic acid part of the 4-oxopiperidine-2-carboxylic acid derivative, and protect it with the amino alcohol hydroxyl group with 2-5 carbons. The body or the monohydroxy protection body of diols with 2-5 carbons can react to form amide bonds or ester bonds.

Scheme 3 is the second synthesis of macrocyclic compounds. That is, the following method: firstly, the nitrogen-containing bicyclic heterocyclic nucleus is reacted with a substituted piperidine to form an X ² bond, which is bonded to the linker connecting the ac site. Thereafter, in the same manner as in Scheme 1, the final product is obtained by forming a macromembered ring and introducing an aromatic ring into a nitrogen-containing bicyclic heterocyclic core.

In scheme 1, 3, the coupling reaction (STEP1) using the metal catalyst of the compound represented by formula (2) and the reagent represented by formula (6) and the compound represented by formula (3) as starting material The ring formation reaction (STEP2) is common to all systems. [chem 30]

The compound represented by formula (1) can be reacted by reaction scheme 3 (in the formula of each compound, M, for example, represents ZnI, MgBr, boronic acid, and boric acid ester and other substituents that can react by coupling. Also, LG ^1. LG ^2, for example, represents a leaving group such as -Cl, -Br, -I, -OTf, -OMs, or -OTs. Also, Q ¹ , Q ^2, for example, represent a hydroxyl group; or -Cl, -Br, -I, - OTf, -OMs, or -OTs and other detachment groups; or ^alkenyl , borane derivatives, etc. can form CO bonds, CC bond substituents. Also, ^Q3, for example, represents hydroxyl, amino, etc. The reaction to form a substituent of a CO bond and a CN bond) is produced by the method described in. The compounds represented by the formulas (2), (3), (5), (6), (8), and (9) can be obtained commercially, or according to known methods, such as the methods shown below, using them as standard method to manufacture.

STEP6 The compound represented by formula (3) can make the amino alcohol hydroxyl protection body of carbon number 2-5 or the single hydroxyl protection body amide or ester of carbon number 2-5 diol be bonded to the carboxyl group represented by formula (8) acid to synthesize. The reaction used is amidation reaction, esterification reaction, amidation reaction and the like. As a condensing agent for amidation and esterification, 1-propanephosphonic 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 usually be carried out at 0°C to 150°C. In the acylation reaction, use oxalyl chloride, isobutyl chloroformate, etc. to activate the carboxylic acid site, and make it react with the amino alcohol hydroxyl protection body with 2-5 carbons or the single hydroxyl protection body of diol with 2-5 carbons A reaction is performed whereby an amide bond or an ester bond can be formed.

STEP7 The compound represented by formula (8) is obtained by the alkylation reaction or metal coupling reaction of the substituted piperidine represented by formula (9) and the compound represented by formula (5), and the subsequent solvolysis of the ester to synthesize. The reaction conditions used in the alkylation reaction or metal coupling reaction are based on STEP 3 of Scheme 1. In the hydrolysis of the ester, the reaction is carried out at 40°C to 80°C using alkalis such as sodium hydroxide, potassium hydroxide, and lithium hydroxide, and using methanol, ethanol, etc. as solvents. In order to prevent the asymmetric isomerization of the 2-position of piperidine, it is recommended to carry out the reaction at 40°C. The compound represented by formula (9) can be synthesized according to STEP 5 of scheme 1-2. That is, using the 4-oxopiperidine-2-carboxylic acid derivative represented by the formula (7) as a raw material, methylation using trimethylsilyldiazomethane, or using 1-propanephosphonic anhydride , 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide, and HATU, etc. are used as condensing agents for esterification.

Scheme 4 is the third synthesis of macrocyclic compounds. That is, the following method: first, the substituted piperidine is bonded to the linking group connecting the ac part, and reacts with the nitrogen-containing bicyclic heterocyclic core to form an X ³ bond. Thereafter, a large membered ring is formed by forming an X ² bond, and finally an aromatic ring directly bonded to the nitrogen-containing bicyclic heterocyclic core is introduced. [chem 31]

The compound represented by formula (1), for example, can be reacted by reaction scheme 4 (in the formula of each compound, M, for example, represents various substituents that can react by coupling such as ZnI, MgBr, boric acid, and borate ester. Also, LG ^1. LG ^2, for example, represents a leaving group such as -Cl, -Br, -I, -OTf, -OMs, or -OTs. Also, Q ¹ , Q ^2, for example, represent a hydroxyl group; or -Cl, -Br, -I, - OTf, -OMs, or -OTs and other detachment groups; or alkenyl ^, borane derivatives, etc. can form CO bonds, CC bond substituents. Also, ^Q3, for example, represents hydroxyl, amino, etc. The reaction to form a substituent of a CO bond and a CN bond) is produced by the method described in. The compounds represented by formulas (2), (4)-(6), and (10) can be obtained commercially, or can be produced according to known methods, such as the methods shown below, or standard methods.

STEP8 The compound represented by formula (11) can be synthesized, for example, by using the intramolecular alkylation reaction or metal coupling reaction of the compound represented by formula (10) by using STEP 10 of Scheme 3 as a standard method. In this case, the compound represented by the formula (11) can be synthesized by carrying out the intramolecular reaction prior to the intermolecular reaction, for example, under high dilution conditions of 0.1 mol/L to 0.001 mol/L in terms of substrate concentration.

STEP9 The compound represented by formula (14) is synthesized by intermolecular Mitsunobu reaction or intermolecular alkylation reaction between the compound represented by formula (4) and the compound represented by formula (5). The reaction conditions are based on STEP 2 of Scheme 1, but in terms of substrate concentration, for example, the reaction can be carried out under the conditions of 1.0 mol/L-0.1 mol/L.

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. [Chemical 32] Method A-1

Intermediate A-1-2: 6-bromo-3-fluoro-2-nitrophenol [Chem. 33]

3-Fluoro-2-nitrophenol (Intermediate A-1-1; 30.9 g, 196 mmol) was dissolved in acetonitrile (20 mL), concentrated sulfuric acid (44 mL) was added and the reaction temperature was kept below 30 °C . Then, N-bromosuccinimide (35.4 g, 198 mmol) in acetonitrile solution (281 mL) was added dropwise over 1.5 hours under cooling in an ice bath. Thereafter, the reaction system was naturally warmed from 0° C. to room temperature, and stirred for 12 hours. After completion of the reaction, ice water (300 mL) was added and extracted with ethyl acetate, and 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 (62.1 g) was a mixture of target compound and bromine positional isomer, but was used in the next stage without separation and purification at this stage. LCMS (LC-1); RT=1.03, m/z 234 [MH] ^＋

Intermediate A-1-3: 2-(Benzyloxy)-1-bromo-4-fluoro-3-nitrobenzene [Chem. 34]

6-Bromo-3-fluoro-2-nitrophenol (intermediate A-1-2; 62.1 g, mixture of bromine positional isomers above) was dissolved in acetonitrile (1000 mL), and benzyl bromide (24.6 mL , 206 mmol), potassium carbonate (95.0 g, 689 mmol), and stirred at 90° C. for 1 hour. Thereafter, water (300 mL) was added to the reaction mixture at room temperature, extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluate; hexane:ethyl acetate=100:0-40:60), thereby obtaining 2-(benzyloxy)-1-bromo- 4-Fluoro-3-nitrobenzene (17.5 g, 27% yield over two stages). LCMS (LC-1); RT=1.95 (only UV detected) 1H-NMR (CDCl ₃ ): δ (ppm) 7.71 (1H, dd, J = 9.2, 5.6 Hz), 7.51 - 7.44 (2H, m) , 7.43 - 7.34 (3H, m), 6.99 (1H, t, 8.7 Hz), 5.19 (2H, s).

Intermediate A-1-4: (3-(Benzyloxy)-4-bromo-2-nitrophenyl)glycine methyl ester [Chem. 35]

2-(Benzyloxy)-1-bromo-4-fluoro-3-nitrobenzene (intermediate A-1-3; 30.5 g, 93.5 mmol), methylglycine hydrochloride (41.1 g, 327 mmol) was dissolved in acetonitrile (467 mL), N,N-diisopropylethylamine (95.0 mL, 542 mmol) and molecular sieve 4A (30.5 g) were added, and stirred at 50°C for 72 hours. Thereafter, the reaction solution was filtered through celite, and the filtrate was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluate; hexane:ethyl acetate=100:0-50:50) to obtain a crude purified product (43.1 g). It was used in the next reaction without further purification. LCMS (LC-1); RT=1.88, m/z 395 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 7.56 - 7.49 (3H, m), 7.43 - 7.32 (3H, m) , 6.39 - 6.30 (2H, m), 5.18 (2H, s), 3.98 (2H, d, J = 5.3 Hz), 3.81 (3H, s).

Intermediate A-1-5: 8-(Benzyloxy)-7-bromo-3,4-dihydroquinolin-2(1H)-one [Chem. 36]

In (3-(benzyloxy)-4-bromo-2-nitrophenyl)glycine methyl ester (intermediate A-1-4; 43.1 g, the above crude purified product), iron (97.5 g, 1744 mmol), ammonium chloride (58.3 g, 1090 mmol) were added ethanol (550 mL), water (550 mL) to suspend, and stirred at 80°C for 4 hours. After the reaction was completed, ethanol (100 mL) and chloroform (100 mL) were added at room temperature, followed by Celite filtration. The filtrate was concentrated under reduced pressure to obtain a crude product (29.6 g). It was used in the next reaction without purification. LCMS (LC-1); RT=1.51, m/z 331 [MH] ⁺ 1H-NMR (DMSO-d ₆ ): δ (ppm) 9.84 (1H, s), 7.58 (2H, d, J = 6.9 Hz ), 7.43 - 7.30 (3H, m), 6.99 (1H, d, J = 8.6 Hz), 6.45 (1H, d, J = 8.6 Hz), 6.22 (1H, s), 4.93 (2H, s), 3.68 (2H, s).

Intermediate A-1-6: 8-(Benzyloxy)-7-bromoquinolin-2(1H)-one [Chem. 37]

8-(Benzyloxy)-7-bromo-3,4-dihydroquinolin-2(1H)-one (intermediate A-1-5; 29.6 g, crude product above) was dissolved in tetrahydrofuran (592 mL), manganese dioxide (27.0 g, 311 mmol) was added, and stirred at 70°C for 12 hours. After the reaction was completed, tetrahydrofuran (300 mL) was added at room temperature, and filtered through celite. After the filtrate was concentrated under reduced pressure, tetrahydrofuran (40 mL), ethyl acetate (250 mL), and hexane (250 mL) were added to the obtained solid, and the mixture was stirred at room temperature for 30 minutes. Thereafter, the suspension was filtered, and the filtered solid was dried under reduced pressure to obtain 8-(benzyloxy)-7-bromoquinolin-2(1H)-one (19.9 g, tri Stage yield 64%). LCMS (LC-1); RT=1.49, m/z 331 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 9.05 (1H, brs), 8.18 (1H, s), 7.55 -7.48 (2H, m), 7.47 - 7.36 (5H, m), 5.18 (2H, s).

Intermediate A-1-7: 8-(Benzyloxy)-7-bromo-2-chloroquinoline [Chem. 38]

Dissolve 8-(benzyloxy)-7-bromoquinolin-2(1H)-one (Intermediate A-1-6; 1.0 g, 3.02 mmol) in thionyl chloride (10 mL), add N,N-Dimethylformamide (0.234 mL, 3.02 mmol), stirred at 80°C for 1 hour. After the reaction, water (30 mL) was added at room temperature, extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluate; hexane:ethyl acetate=100:0-60:40), thereby obtaining 8-(benzyloxy)-7-bromo- 2-Chloroquinoline (644 mg, 61% yield). LCMS (LC-1); RT=2.06, m/z 349 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 8.77 (1H, s), 7.91 (1H, d, J = 9.1 Hz ), 7.75 (1H, d, J = 9.1 Hz), 7.63 (2H, d, J = 7.4 Hz), 7.42 - 7.31 (3H, m), 5.48 (2H, s).

[Chemical 39] Method A-2

Intermediate A-2-3: (S)-2-((3-((tert-butyldiphenylsilyl)oxy)propyl)aminoformyl)-4-oxopiperidine-1 - Tertiary butyl carboxylate [Chem. 40]

(S)-1-(tert-butoxycarbonyl)-4-oxopiperidine-2-carboxylic acid (Intermediate A-2-1; 1.57 g, 6.46 mmol) was dissolved in tetrahydrofuran (33 mL) , added triethylamine (1.32 mL, 9.69 mmol) and isobutyl chloroformate (1.02 mL, 7.75 mmol) under ice cooling, and stirred for 30 minutes. Then, 3-((tert-butyldiphenylsilyl)oxy)propan-1-amine (intermediate A-2-2; 2.43 g, 7.76 mmol) was added and stirred at room temperature for 1 hour. After completion of the reaction, water (50 mL) was added, extracted with ethyl acetate, and 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. Using silica gel column chromatography (eluate; hexane:ethyl acetate=100:0-70:30), the obtained crude product was purified to obtain (S)-2-((3-( (tert-butyldiphenylsilyl)oxy)propyl)aminoformyl)-4-oxopiperidine-1-carboxylic acid tert-butyl ester (2.15 g, 62% yield). LCMS (LC-1); RT=2.26, m/z 539 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 7.64 (4H, dd, J = 7.8, 1.6 Hz), 7.46 - 7.35 (6H, m), 6.58 (1H, brs), 4.82 (1H, m), 3.96 - 3.80 (1H, m), 3.69 (2H, t, J = 5.4 Hz), 3.55 (1H, ddd, J = 13.3 , 8.3, 5.0 Hz), 3.39 (2H, m), 2.82 (1H, dd, J = 16.5, 2.8 Hz), 2.64 - 2.46 (2H, m), 2.45 - 2.35 (1H, m), 1.72 (1H, q, J = 6.3 Hz), 1.59 - 1.52 (1H, m), 1.47 (9H, s), 1.05 (9H, s).

Intermediate A-2-4: (2S,4R)-2-((3-((tert-butyldiphenylsilyl)oxy)propyl)carbamoyl)-4-hydroxypiperidine- 1-tert-Butyl Carboxylate [Chem. 41]

Make (S)-2-((3-((tert-butyldiphenylsilyl)oxy)propyl)aminoformyl)-4-oxopiperidine-1-carboxylic acid tert-butyl ester (Intermediate A-2-3; 2.15 g, 4.00 mmol) was dissolved in tetrahydrofuran (8 mL), and at -78°C, 1 M-tetrahydrofuran solution (6.0 mL, 6.00 mmol), stirred for 1 hour. After the reaction, saturated aqueous ammonium chloride solution (20 mL) was added, extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=100:0-0:100) to obtain (2S,4R)-2-((3- ((tert-butyldiphenylsilyl)oxy)propyl)carbamoyl)-tert-butyl 4-hydroxypiperidine-1-carboxylate (1.72 g, 80% yield). LCMS (LC-1); RT=2.25, m/z 541 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 7.65 (4H, dd, J = 7.8, 1.4 Hz), 7.46 - 7.35 (6H, m), 6.82 (1H, brs), 5.75 (1H, brs), 4.81 - 4.70 (1H, m), 4.08 - 4.00 (1H, br), 3.87 - 3.74 (1H, m), 3.73 - 3.53 (2H, m), 3.50 - 3.39 (1H, m), 3.38 - 3.28 (1H, m), 3.14 (1H, td, J = 13.3, 2.6 Hz), 2.30 - 2.16 (1H, m), 1.89 - 1.80 (1H, m), 1.79 - 1.67 (3H, m), 1.64 - 1.53 (1H, m), 1.46 (9H, m), 1.05 (9H, s).

Intermediate A-2-5: (2S,4R)-2-((3-((tert-butyldiphenylsilyl)oxy)propyl)carbamoyl)-4-((methylsulfonyl Acyl)oxy)piperidine-1-carboxylic acid tert-butyl ester [Chemical 42]

Make (2S,4R)-2-((3-((tert-butyldiphenylsilyl)oxy)propyl)aminoformyl)-4-hydroxypiperidine-1-carboxylic acid tertiary butyl The ester (Intermediate A-2-4; 1.72 g, 3.19 mmol) was dissolved in dichloromethane (6.4 mL), and triethylamine (0.80 mL, 5.74 mmol), methanesulfonyl chloride (0.345 mL, 4.47 mmol), stirred at 0°C for 2 hours. Thereafter, water (20 mL) was added at room temperature, followed by extraction with ethyl acetate, and 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 (2.46 g) was used in the next reaction without purification. LCMS (LC-1); RT=2.25, m/z 619 [M+H] ^＋

Intermediate A-2-6: (2S,4S)-4-azido-2-((3-((tert-butyldiphenylsilyl)oxy)propyl)aminoformyl)piper Pyridine-1-carboxylic acid tert-butyl ester [Chem. 43]

Make (2S,4R)-2-((3-((tert-butyldiphenylsilyl)oxy)propyl)aminoformyl)-4-((methylsulfonyl)oxy)piper Pyridine-1-carboxylic acid tert-butyl ester (intermediate A-2-5; 2.46 g, the above crude product) was dissolved in N,N-dimethylformamide (40 mL), and sodium azide ( 388 mg, 5.79 mmol) and stirred at 90°C for 6 hours. After the reaction, water (80 mL) was added at room temperature, extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluate; hexane:ethyl acetate=100:0-80:20) to obtain (2S,4S)-4-azido- tertiary butyl 2-((3-((tert-butyldiphenylsilyl)oxy)propyl)aminoformyl)piperidine-1-carboxylate (362 mg, 20% yield in two stages ). LCMS (LC-1); RT=2.47, m/z566 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 7.64 (4H, dd, J = 6.5, 4.0 Hz), 7.46 - 7.35 ( 6H, m), 6.46 - 5.85(1H, m), 4.92 - 4.62 (1H, m), 4.07 - 3.93 (0.5H, m), 3.91 - 3.75 (0.5H, m), 2.89 - 2.68 (1H, m ), 2.58 - 2.35 (1H, m), 3.69 (2H, t, J = 6.0 Hz), 3.49 - 3.29 (2H, m), 1.91 - 1.83 (1H, m), 1.73 (1H, quint, J = 6.4 Hz), 1.49 - 1.23 (12H, m), 1.05 (9H, s), 0.91 - 0.84(1H, m).

Intermediate A-2-7: (2S,4S)-4-amino-2-((3-((tert-butyldiphenylsilyl)oxy)propyl)carbamoyl)piperidine -3-Butyl 1-carboxylate [Chem. 44]

Make (2S,4S)-4-azido-2-((3-((tert-butyldiphenylsilyl)oxy)propyl)aminoformyl)piperidine-1-carboxylic acid Tributyl ester (intermediate A-2-6; 362 mg, 0.64 mmol) was dissolved in methanol (6.4 mL), added palladium hydroxide (181 mg, 50 wt%), and stirred at room temperature under hydrogen atmosphere 2 hours. After the inside of the reaction system was replaced with a nitrogen atmosphere, Celite filtration was performed. The filtrate was concentrated under reduced pressure to obtain (2S,4S)-4-amino-2-((3-((tert-butyldiphenylsilyl)oxy)propyl)carbamoyl) Tri-butyl piperidine-1-carboxylate (345 mg, 97% yield). LCMS (LC-1); RT=1.93, m/z 540 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 7.64 (4H, dd, J = 6.4, 4.0 Hz), 7.46 - 7.34 (6H, m), 6.34 - 5.96 (1H, m), 4.90 - 4.63 (1H, m), 4.24 - 3.89 (1H, m), 3.75 - 3.64 (2H, m), 3.45 - 3.28 (3H, m) , 3.15 - 2.98 (0.5H, m), 2.92 - 2.64 (1.5H, m), 2.55 - 2.30 (1H, m), 1.79 - 1.68 (3.5H, m), 1.46 (9H, m), 1.32 - 1.13 (2.5H, m), 1.05 (9H, m).

[Chem.45] Method A-3

Intermediate A-3-1: (2S,4S)-4-((8-(benzyloxy)-7-bromoquinolin-2-yl)amino)-2-((3-((th Tributyldiphenylsilyl)oxy)propyl)aminoformyl)piperidine-1-carboxylic acid tert-butyl ester [Chem. 46]

Make (2S,4S)-4-amino-2-((3-((tert-butyldiphenylsilyl)oxy)propyl)aminoformyl)piperidine-1-carboxylic acid third Butyl ester (Intermediate A-2-7; 345 mg, 0.64 mmol) was dissolved in dimethylsulfene (5.8 mL), and 8-(benzyloxy)-7-bromo-2-chloroquinoline (Intermediate Substance A-1-7; 202 mg, 0.582 mmol), N,N-diisopropylethylamine (0.152 mL, 0.87 mmol), stirred at 120°C for 12 hours. After the reaction, water (30 mL) was added, extracted with ethyl acetate, and 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. Use silica gel column chromatography (eluent; chloroform:methanol=100:0-90:10) to purify the obtained crude product to obtain (2S,4S)-4-((8-(benzyloxy Base)-7-bromoquinolin-2-yl)amino)-2-((3-((tert-butyldiphenylsilyl)oxy)propyl)aminoformyl)piperidine- tert-butyl 1-carboxylate (147 mg, 27% yield). LCMS (LC-1); RT=2.31, m/z 852 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 8.24 - 8.18(1H, m), 7.68 - 7.57(6H, m) , 7.55 - 7.48 (2H, m), 7.45 - 7.29 (9H, m), 6.34 (1H, brs), 5.44 (1H, d, J = 10.8 Hz), 5.29 (1H, d, J = 10.8 Hz), 4.79 (1H, d, J = 8.0 Hz), 4.48 - 3.86 (1H, m), 3.67 (2H, t, J = 8.0 Hz), 3.48 - 3.26 (2H, m), 2.89 - 2.74 (1H, m) , 2.72 - 2.57 (1H, m), 2.29 (1H, d, J = 12.0 Hz), 1.75 - 1.65 (2H, m), 1.54 - 1.42 (10H, m), 1.34 - 1.18 (2H, m), 1.09 - 1.01 (10H, m).

Intermediate A-3-2: (2S,4S)-4-((8-(Benzyloxy)-7-bromoquinolin-2-yl)amino)-2-((3-hydroxypropyl )carbamoyl)piperidine-1-carboxylate tertiary butyl ester [Chemical 47]

Make (2S,4S)-4-((8-(benzyloxy)-7-bromoquinolin-2-yl)amino)-2-((3-((tertiary butyldiphenylsilane yl)oxy)propyl)carbamoyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate A-3-1; 147 mg, 0.172 mmol) was dissolved in tetrahydrofuran (0.86 mL), and tetrahydrofuran (0.86 mL) was added Butylammonium fluoride 1 M-tetrahydrofuran solution (0.863 mL, 0.863 mmol) was stirred at room temperature for 2 hours. After the reaction, the reaction mixture was directly purified by automatic silica gel column chromatography (eluent; chloroform:methanol=100:0-80:20) to obtain (2S,4S)-4-((8- (Benzyloxy)-7-bromoquinolin-2-yl)amino)-2-((3-hydroxypropyl)aminoformyl)piperidine-1-carboxylic acid tert-butyl ester (104 mg , yield 98%). LCMS (LC-1); RT=1.77, m/z 614 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 8.24 - 8.18 (1H, m), 7.61 (2H, d, J = 7.3 Hz), 7.55 - 7.48 (2H, m), 7.42 - 7.30 (3H, m), 6.51 (1H, brs), 5.43 (1H, d, J = 10.8 Hz), 5.30 (1H, d, J = 10.8 Hz), 5.02 - 4.82 (2H, m), 4.45 - 3.95 (1H, m), 3.60 - 3.51 (2H, m), 3.06 - 2.94 (2H, m), 2.93 - 2.64 (2H, m), 2.39 - 2.28 (1H, m), 1.86 - 1.73 (2H, m), 1.50 (9H, s), 1.44 - 1.21 (4H, m).

Intermediate A-3-3: (2S,4S)-2-((3-(Benzyloxy)propyl)aminoformyl)-4-((8-(Benzyloxy)-7- Bromoquinolin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester [Chem. 48]

Make (2S,4S)-4-((8-(benzyloxy)-7-bromoquinolin-2-yl)amino)-2-((3-hydroxypropyl)aminoformyl)piper Pyridine-1-carboxylic acid tert-butyl ester (intermediate A-3-2; 104 mg, 0.170 mmol) was dissolved in a mixed solvent of dichloromethane (0.85 mL) and pyridine (0.85 mL), and placed on ice at 0°C Add benzoyl chloride (0.024 mL, 0.20 mmol) and N,N-dimethylaminopyridine (2 mg, 0.017 mmol) under cooling in the bath, and stir at room temperature for 1 hour. After the reaction, the reaction mixture was directly purified by automatic silica gel column chromatography (eluent; chloroform:methanol=100:0-90:10) to obtain (2S,4S)-2-((3- (Benzyloxy)propyl)aminoformyl)-4-((8-(benzyloxy)-7-bromoquinolin-2-yl)amino)piperidine-1-carboxylic acid Tributyl ester (109 mg, 89% yield). LCMS (LC-1); RT=2.18, m/z 718 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 8.22 (1H, s), 8.02 (2H, d, J = 7.4 Hz ), 7.61 (2H, d, J = 8.0 Hz), 7.59 - 7.53 (1H, m), 7.51 (2H, d, J = 3.2 Hz), 7.44 (2H, t, J = 8.0 Hz), 7.33 (2H , t, J = 7.1 Hz), 6.66 - 6.32 (1H, m), 5.45 (1H, d, J = 10.8 Hz), 5.29 (1H, d, J = 10.8 Hz), 5.12 - 4.88 (1H, m) , 4.84 (1H, d, J = 6.8 Hz), 4.39 - 4.25 (3H, m), 3.46 - 3.35 (1H, m), 3.34 - 3.22 (1H, m), 2.95 - 2.66 (2H, m), 2.37 - 2.26 (1H, m), 1.97 - 1.88 (2H, m), 1.56 - 1.44 (11H, m), 1.37 - 1.27 (2H, m).

Intermediate A-3-4: 3-((2S,4S)-4-((7-bromo-8-hydroxyquinolin-2-yl)amino)piperidine-2-carboxamide)propyl Benzoate [Chem. 49]

Make (2S,4S)-2-((3-(benzoyloxy)propyl)aminoformyl)-4-((8-(benzyloxy)-7-bromoquinoline-2- Base) amino) piperidine-1-carboxylate tert-butyl ester (intermediate A-3-3; 108 mg, 0.12 mmol) was dissolved in dichloromethane (2.5 mL), and tribromide was added under ice-bath cooling Boronide 1 M-dichloromethane solution (0.742 mL, 0.74 mmol), followed by stirring for 30 minutes. After the starting material disappeared, methanol (2.5 mL) was added dropwise at 0°C to terminate the reaction. The obtained reaction mixture was directly purified by SCX to obtain 3-((2S,4S)-4-((7-bromo-8-hydroxyquinolin-2-yl)amino)piperidine-2 - formamide) propyl benzoate (77 mg, 97% yield). LCMS (LC-1); RT=1.52, m/z 528 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 8.87 (1H, brs), 8.18 (1H, s), 8.09 - 8.03 (2H, m), 7.66 - 7.59 (1H, m), 7.57 - 7.51 (1H, m), 7.48 - 7.40 (3H, m), 7.29 (1H, d, J = 8.4 Hz), 4.91 (1H, d , J = 5.6 Hz), 5.81 (2H, t, J = 5.6 Hz), 5.06 - 4.95(1H, m), 3.69 (1H, t, J = 3.9 Hz), 3.62 - 3.51 (2H, m), 3.21 (1H, d, J = 12.8 Hz), 3.08 (1H, dt, J = 4.4, 3.7 Hz), 2.92 - 2.80 (1H, m), 2.06 (2H, quint, J = 6.5 Hz), 1.94 - 1.88 ( 1H, m), 1.54 - 1.45 (2H, m), 1.27 (1H, ddd, J = 12.6, 10.0, 4.7 Hz).

Intermediate A-3-5: (2S,4S)-2-((3-(benzoyloxy)propyl)aminoformyl)-4-((7-bromo-8-hydroxyquinoline -2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester [Chemical 50]

3-((2S,4S)-4-((7-bromo-8-hydroxyquinolin-2-yl)amino)piperidine-2-carboxamide)propyl benzoate (intermediate A-3-4; 77 mg, 0.146 mmol) was dissolved in dichloromethane (7.4 mL), triethylamine (0.204 mL, 1.46 mmol), di-tert-butyl dicarbonate (240 mg, 1.10 mmol) were added, Stir at room temperature for 1 hour. Thereafter, the reaction mixture was purified directly using automatic silica gel column chromatography (eluent; chloroform:methanol=100:0-80:20), thereby obtaining (2S,4S)-2-((3-( Benzyloxy)propyl)carbamoyl)-4-((7-bromo-8-hydroxyquinolin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (77 mg, yield 84%). LCMS (LC-1); RT=1.98, m/z 628 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 9.28 - 8.76 (1H, m), 8.48 - 7.90 (3H, m) , 7.78 - 7.16 (4H, m), 6.92 - 5.92 (1H, m), 4.96 - 4.85 (1H, m), 4.49 - 4.01 (4H, m), 3.52 - 3.33 (2H, m), 2.98 (1H, d, J = 6.7 Hz), 2.10 - 1.88 (2H, m), 1.56 - 1.45 (11H, m), 1.37 - 1.18 (4H, m).

Intermediate A-3-6: (2S,4S)-4-((7-bromo-8-hydroxyquinolin-2-yl)amino)-2-((3-hydroxypropyl)carbamoyl Base) tert-butyl piperidine-1-carboxylate [Chemical 51]

Make (2S,4S)-2-((3-(benzoyloxy)propyl)aminoformyl)-4-((7-bromo-8-hydroxyquinolin-2-yl)amino ) tert-butyl piperidine-1-carboxylate (Intermediate A-3-5; 77 mg, 0.12 mmol) was dissolved in methanol (2.5 mL), and potassium carbonate (170 mg, 1.23 mmol) was added, and the Stir for 15 minutes. Thereafter, the reaction mixture was purified directly using automatic silica gel column chromatography (eluate; chloroform:methanol=100:0-60:40), thereby obtaining (2S,4S)-4-((7-bromo -8-Hydroxyquinolin-2-yl)amino)-2-((3-hydroxypropyl)carbamoyl)piperidine-1-carboxylic acid tert-butyl ester (45 mg, yield 70% ). LCMS (LC-1); RT=1.47, m/z 524 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 8.88 (1H, brs), 8.26 - 8.17(1H, m), 7.70 - 7.44 (1H, m), 7.33 - 7.28 (1H, m), 6.68 (1H, brs), 5.04 - 4.83 (2H, m), 4.45 - 4.00 (2H, m), 3.71 - 3.43 (5H, m) , 3.40 - 2.86 (2H, m), 1.96 (1H, d, J = 12.0 Hz), 1.82 - 1.67(2H, m), 1.66 - 1.45 (9H, m), 1.42 - 1.17 (2H, m).

Intermediate A-3-7: (3 ² S,3 ⁴ S)-1 ⁷ -bromo-4-oxo-9-oxa-2,5-diaza-1(2,8)-quinol Phyloline-3(4,2)-piperidina cyclononaphane-3 ¹ -carboxylic acid tert-butyl ester [Chem. 52]

Make (2S,4S)-4-((7-bromo-8-hydroxyquinolin-2-yl)amino)-2-((3-hydroxypropyl)carbamoyl)piperidine-1- Tertiary butyl carboxylate (intermediate A-3-6; 45 mg, 0.086 mmol) was dissolved in tetrahydrofuran (17.2 mL), and triphenylphosphine (56 mg, 0.22 mmol), azodicarboxylic acid dicarboxylate Tributyl ester 20% toluene solution (0.30 mL), stirred at room temperature for 12 hours. Thereafter, the reaction mixture was concentrated under reduced pressure. The obtained crude product was purified by automatic silica gel column chromatography (eluent; chloroform:methanol=100:0-90:10) to obtain (3 ² S,3 ⁴ S)-1 ⁷ -bromo -4-oxo-9-oxa-2,5-diaza-1(2,8)-quinoline-3(4,2)-piperidinecyclonona-3 ¹ -carboxylic acid third Butyl ester (26.3 mg, 61% yield). LCMS (LC-1); RT=1.56, m/z 506 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 8.22 (1H, d, J = 5.4 Hz), 7.60 - 7.52 (2H , m), 5.16 - 5.04 (1.5H, m), 4.91 - 4.85 (0.5H, m), 4.47 - 4.38 (1H, m), 4.35 - 4.26 (1.5H, m), 4.19 - 4.01 (1.5H, m), 3.86 - 3.71 (1.5H, m), 3.70 - 3.59 (0.5H, m), 3.13 (0.5H, dt, J = 16.0, 4.0 Hz), 2.95 (1.5H, dt, J = 16.0, 4.0 Hz), 2.24 - 2.03 (2H, m), 1.99 - 1.86 (1H, m), 1.75 - 1.62 (1H, m), 1.53 - 1.45 (9.5H, m), 1.39 - 1.18 (1.5H, m).

[Chemical 53] Method B-1

Intermediate B-1-2: (S)-4-oxopiperidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester [Chem. 54]

Dissolve (S)-1-(tert-butoxycarbonyl)-4-oxopiperidine-2-carboxylic acid (Intermediate B-1-1; 38.9 g, 160 mmol) in toluene (800 mL), To a mixed solvent of methanol (266 mL), trimethylsilyldiazomethane 2 M-diethyl ether solution (100 mL, 200 mmol) was added dropwise under cooling in an ice bath, and stirred at room temperature for 3 hours. After the reaction was completed, acetic acid (100 mL) was added under cooling in an ice bath, and concentrated under reduced pressure. Thereafter, water (200 mL) was added, followed by extraction with ethyl acetate, and 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 to obtain a crude product (41.1 g). It was used in the next reaction without purification. LCMS (LC-1); RT=1.12, m/z 258 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 5.18 - 5.08 (0.5H, m), 4.91 -4.82 (0.5H, m), 4.16 - 4.02 (1H, m), 3.75 (3H, s), 3.72 - 3.56 (1H, m), 2.78 (2H, d, J = 6.2 Hz), 2.55 - 2.46 (2H, m), 1.48 (9H, s).

Intermediate B-1-3: (2S,4R)-4-Hydroxypiperidine-1,2-dicarboxylic acid 1-(tert-butyl)2-methyl ester [Chem. 55]

(S)-4-Oxopiperidine-1,2-dicarboxylic acid 1-(tert-butyl)2-methyl ester (intermediate B-1-2; 11.1 g, 43.1 mmol) was dissolved in tetrahydrofuran ( 86 mL), at -78°C, add lithium tris-butylborohydride (L-selectride) 1 M-tetrahydrofuran solution (65 mL, 64.7 mmol) and stir for 2 hours. After the reaction, saturated aqueous ammonium chloride solution (200 mL) was added, extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and 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 (2S,4R)-4-hydroxypiperidine- 1-(tert-butyl)2-methyl 1,2-dicarboxylate (8.69 g, 78% yield). LCMS (LC-1); RT=0.77, m/z 260 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 5.07 - 4.57 (1H, m), 4.19 - 4.08 (1H, m) , 3.96 - 3.60 (4H, m), 3.47 - 3.21(1H, m), 2.42 (1H, d, J = 14.2 Hz), 1.92 (1H, ddd, J = 14.2, 6.8, 2.4 Hz), 1.79 - 1.62 (3H, m), 1.47 (9H, s).

Intermediate B-1-4: (2S,4R)-4-((methylsulfonyl)oxy)piperidine-1,2-dicarboxylic acid 1-(tert-butyl)2-methyl ester [Chem 56]

(2S,4R)-4-Hydroxypiperidine-1,2-dicarboxylic acid 1-(tert-butyl)2-methyl ester (intermediate B-1-3; 16.5 g, 63.6 mmol) was dissolved in di Add triethylamine (36 mL, 255 mmol) and methanesulfonyl chloride (9.85 mL, 127 mmol) to methyl chloride (127 mL) under cooling in an ice bath, and stir at room temperature for 1 hour. Thereafter, after extraction with ethyl acetate, the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product (21.5 g) was used in the next reaction without purification. LCMS (LC-1); RT=1.32, m/z 338 [M+H] ^＋

Intermediate B-1-5: (2S,4S)-4-Azidopiperidine-1,2-dicarboxylic acid 1-(tert-butyl)2-methyl ester [Chem. 57]

Make (2S,4R)-4-((methylsulfonyl)oxy)piperidine-1,2-dicarboxylic acid 1-(tert-butyl)2-methyl ester (intermediate B-1-4; 21.5 g, the crude product above) was dissolved in N,N-dimethylformamide (319 mL), sodium azide (8.29 g, 127 mmol) was added, and stirred at 80°C for 11 hours. After completion of the reaction, extraction was performed with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product (18.1 g) was used in the next reaction without purification. LCMS (LC-1); RT=1.53, m/z 285 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 5.12 - 4.60 (1H, m), 4.24 - 4.13 (0.5H, m ), 4.10 - 4.02 (0.5H, m), 3.81 - 3.72 (3H, m), 3.43 - 3.32 (1H, m), 3.11 - 2.89 (1H, m), 2.56 - 2.38 (1H, m), 2.04 - 1.85 (1H, m), 1.75 - 1.60 (2H, m), 1.52 - 1.39 (9H, m).

Intermediate B-1-6: (2S,4S)-4-aminopiperidine-1,2-dicarboxylic acid 1-(tert-butyl)2-methyl ester [Chem. 58]

Dissolving 1-(tert-butyl)2-methyl (2S,4S)-4-azidopiperidine-1,2-dicarboxylate (Intermediate B-1-5; 18.1 g, 63.7 mmol) Add palladium hydroxide (3.8 g, 20 wt%) to methanol (318 mL), and stir at room temperature for 21 hours under hydrogen atmosphere. After the inside of the reaction system was replaced with a nitrogen atmosphere, Celite filtration was performed. The filtrate was concentrated under reduced pressure to obtain (2S,4S)-4-aminopiperidine-1,2-dicarboxylic acid 1-(tert-butyl)2-methyl ester (15.0 g, three-stage yield 91%). LCMS (LC-1); RT=0.81, m/z 259 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 4.99 (0.5H, d, J = 4.8 Hz), 4.80 (0.5H , d, J = 4.8 Hz), 4.18 - 4.14 (0.5H, m), 4.12 - 3.94 (1H, m), 3.76 - 3.69 (4H, m), 3.37 - 3.30 (0.5H, t, J = 4.0 Hz ), 2.71 (1H, t, J = 11.3 Hz), 2.47 - 2.28 (1H, m), 2.26 - 2.14 (0.5H, m), 1.91 (0.5H, ddd, J = 14.4, 6.8, 2.6 Hz), 1.85 - 1.64 (2H, m), 1.56 - 1.40 (9H, m), 1.33 - 1.16 (1H, m).

Intermediate B-1-7: (2S,4S)-4-((8-(Benzyloxy)-7-bromoquinolin-2-yl)amino)piperidine-1,2-dicarboxylic acid 1-(tertiary butyl) 2-methyl ester [Chem. 59]

(2S,4S)-4-Aminopiperidine-1,2-dicarboxylic acid 1-(tert-butyl)2-methyl ester (intermediate B-1-6; 11.2 g, 43.2 mmol) was dissolved in In dimethylsulfoxide (79 mL), add 8-(benzyloxy)-7-bromo-2-chloroquinoline (intermediate A-1-7; 13.7 g, 39.3 mmol), N,N-di Isopropylethylamine (27.4 mL, 157 mmol), stirred at 100°C for 18 hours. Thereafter, water (300 mL) was added to the reaction mixture, extracted with ethyl acetate, and 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. Use silica gel column chromatography (eluent; chloroform:methanol=100:0-90:10) to purify the obtained crude product to obtain (2S,4S)-4-((8-(benzyloxy yl)-7-bromoquinolin-2-yl)amino)piperidine-1,2-dicarboxylic acid 1-(tert-butyl)2-methyl ester (11.7 g, 39% yield). LCMS (LC-1); RT=2.12, m/z 571 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 8.19 - 8.13 (1H, m), 7.63 - 7.50 (4H, m) , 7.44 - 7.28 (3H, m), 5.34 (2H, q, J = 10.6 Hz), 5.16 - 4.87 (1H, m), 4.79 (1H, d, J = 7.2 Hz), 4.23 - 4.12 (2H, m ), 3.65 (3H, s), 3.09 (1H, brs), 2.64 (1H, d, J = 12.6 Hz), 2.38 - 2.30 (1H, m), 1.72 (1H, dt, J = 12.6, 6.2 Hz) , 1.54 - 1.27 (10H, m).

Intermediate B-1-8: (2S,4S)-4-((8-(benzyloxy)-7-bromoquinolin-2-yl)amino)-1-(tert-butoxycarbonyl ) piperidine-2-carboxylic acid [chemical 60]

Make (2S,4S)-4-((8-(benzyloxy)-7-bromoquinolin-2-yl)amino)piperidine-1,2-dicarboxylic acid 1-(tert-butyl ) 2-methyl ester (intermediate B-1-7; 11.7 g, 20.6 mmol) was dissolved in methanol (680 mL), added 1 M-sodium hydroxide aqueous solution (206 mL), and stirred at 40°C for 1 hour. After completion of the reaction, 2 M-hydrochloric acid aqueous solution (103 mL) was added and extracted with chloroform, and 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. Use silica gel column chromatography (eluent; chloroform:methanol=100:0-80:20) to purify the obtained crude product to obtain (2S,4S)-4-((8-(benzyloxy yl)-7-bromoquinolin-2-yl)amino)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (8.97 g, 78% yield). LCMS (LC-1); RT=1.41, m/z 555 [MH] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 8.17 (1H, brs), 7.62 - 7.41 (5H, m), 7.40 - 7.27 (4H, m), 5.35 - 5.15 (3H, m), 5.12 - 4.84 (2H, m), 4.12 - 4.00 (1H, m), 3.20 - 3.12 (1H, m), 2.69 (2H, s), 1.47 (9H, s), 1.02 - 0.95 (1H, m).

Intermediate B-1-9: (2S,4S)-4-((7-bromo-8-hydroxyquinolin-2-yl)amino)piperidine-2-carboxylic acid [Chem. 61]

Make (2S,4S)-4-((8-(benzyloxy)-7-bromoquinolin-2-yl)amino)-1-(tertiary butoxycarbonyl)piperidine-2-carboxyl Acid (intermediate B-1-8; 8.97 g, 16.1 mmol) was dissolved in dichloromethane (161 mL), and boron tribromide 1 M-dichloromethane solution (96.7 mL , 96.7 mmol), followed by stirring for 2 hours. After the starting material disappeared, tert-butanol (160 mL) was added dropwise at 0°C to terminate the reaction. The obtained reaction mixture was directly purified by SCX to obtain (2S,4S)-4-((7-bromo-8-hydroxyquinolin-2-yl)amino)piperidine-2-carboxylic acid (6.13 g, 100% yield). LCMS (LC-1); RT=0.89, m/z 367 [M+H] ^＋ 1H-NMR (CD ₃ OD): δ (ppm) 8.00 (1H, d, J = 6.6 Hz), 7.46 -7.34 ( 2H, m), 7.26 - 7.09(2H, m), 4.32 - 4.24 (1H, m), 3.65 - 3.46 (2H, m), 3.24 - 3.07 (2H, m), 2.48 - 2.29 (1H, m), 2.15 - 1.94 (2H, m), 1.94 - 1.82 (1H, m), 1.81 - 1.68 (1H, m).

Intermediate B-1-10: (2S,4S)-4-((7-bromo-8-hydroxyquinolin-2-yl)amino)-1-(tert-butoxycarbonyl)piperidine- 2-Carboxylic acid [Chem. 62]

Make (2S,4S)-4-((7-bromo-8-hydroxyquinolin-2-yl)amino)piperidine-2-carboxylic acid (intermediate B-1-9; 5.31 g, 14.5 mmol ) was dissolved in N,N-dimethylformamide (725 mL), added triethylamine (6.05 mL, 43.5 mmol), di-tert-butyl dicarbonate (4.75 g, 21.8 mmol), at room temperature Stir for 1 hour. Thereafter, 1 M-hydrochloric acid aqueous solution was added and extracted with ethyl acetate, and 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 used in the next reaction without purification. LCMS (LC-1); RT=1.08, m/z 467 [M+H] ^＋

[Chem. 63] Method B-2

Intermediate B-2-1: (2S,4S)-4-((7-bromo-8-hydroxyquinolin-2-yl)amino)-2-((3-((tertiary butyldi Phenylsilyl)oxy)propyl)carbamoyl)piperidine-1-carboxylate tertiary butyl ester [Chemical 64]

Make (2S,4S)-4-((7-bromo-8-hydroxyquinolin-2-yl)amino)-1-(tertiary butoxycarbonyl)piperidine-2-carboxylic acid (intermediate B-1-10; 4.23 g, 9.07 mmol), 3-((tert-butyldiphenylsilyl)oxy)propan-1-amine (4.26 g, 13.6 mmol) dissolved in dichloromethane (45 mL ), add N-methyl ? . 1-Hydroxybenzotriazole (2.69 g, 19.9 mmol), stirred at room temperature for 2 hours. After completion of the reaction, the organic layer was extracted with dichloromethane and 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 used in the next reaction without purification. LCMS (LC-1); RT=2.56, m/z 764 [M+H] ^＋

Intermediate A-3-6: (2S,4S)-4-((7-bromo-8-hydroxyquinolin-2-yl)amino)-2-((3-hydroxypropyl)carbamoyl Base) tertiary butyl piperidine-1-carboxylate [Chemical 65]

Make (2S,4S)-4-((7-bromo-8-hydroxyquinolin-2-yl)amino)-2-((3-((tertiary butyldiphenylsilyl)oxy )Propyl)carbamoyl)piperidine-1-carboxylate tert-butyl ester (intermediate B-2-1; 4.64 g, 6.10 mmol) was dissolved in tetrahydrofuran (30 mL), and tetrabutyl fluoride was added Ammonium 1 M-tetrahydrofuran solution (30 mL, 30 mmol), stirred at room temperature for 1 hour. After the reaction, the reaction mixture was directly purified by automatic silica gel column chromatography (eluent; chloroform:methanol=100:0-60:40) to obtain (2S,4S)-4-((7- Bromo-8-hydroxyquinolin-2-yl)amino)-2-((3-hydroxypropyl)aminoformyl)piperidine-1-carboxylic acid tert-butyl ester (2.90 g, yield 91 %). LCMS (LC-1); RT=1.47, m/z 524 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 8.88 (1H, brs), 8.26 - 8.17 (1H, m), 7.70 - 7.44 (1H, m), 7.33 - 7.28 (1H, m), 6.68 (1H, brs), 5.04 - 4.83(2H, m), 4.45 - 4.00 (2H, m), 3.71 - 3.43 (5H, m) , 3.40 - 2.86 (2H, m), 1.96 (1H, d, J = 12.0 Hz), 1.82 - 1.67 (2H, m), 1.66 - 1.53 (8H, m), 1.50 - 1.45 (1H, m), 1.42 - 1.17 (2H, m).

Intermediate A-3-7: (3 ² S,3 ⁴ S)-1 ⁷ -bromo-4-oxo-9-oxa-2,5-diaza-1(2,8)-quinol tertiary butyl phen-3(4,2)-piperidine cyclononazone-3 ¹ -carboxylate [Chem. 66]

Make (2S,4S)-4-((7-bromo-8-hydroxyquinolin-2-yl)amino)-2-((3-hydroxypropyl)carbamoyl)piperidine-1- Tertiary butyl carboxylate (intermediate B-3-6; 2.90 g, 5.55 mmol) was dissolved in THF (1109 mL), triphenylphosphine (3.64 mg, 13.8 mmol), azodicarboxylic acid ditertiary 20% toluene solution (19.2 mL) of butyl ester was stirred at room temperature for 2 hours. Thereafter, the reaction mixture was concentrated under reduced pressure. The obtained crude product was purified by automatic silica gel column chromatography (eluent; chloroform:methanol=100:0-90:10) to obtain (3 ² S,3 ⁴ S)-1 ⁷ -bromo -4-oxo-9-oxa-2,5-diaza-1(2,8)-quinoline-3(4,2)-piperidinecyclonona-3 ¹ -carboxylic acid third Butyl ester (1.96 g, 70% yield). LCMS (LC-1); RT=1.56, m/z 506 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 8.22 (1H, d, J = 5.4 Hz), 7.60 - 7.52 (2H , m), 5.16 - 5.04 (1.5H, m), 4.91 - 4.85 (0.5H, m), 4.47 - 4.38 (1H, m), 4.35 - 4.26 (1.5H, m), 4.19 - 4.01 (1.5H, m), 3.86 - 3.71 (1.5H, m), 3.70 - 3.59 (0.5H, m), 3.13 (0.5H, dt, J = 16.0, 4.0 Hz), 2.95 (1.5H, dt, J = 16.0, 4.0 Hz), 2.24 - 2.03 (2H, m), 1.99 - 1.86 (1H, m), 1.75 - 1.62 (1H, m), 1.53 - 1.45 (9.5H, m), 1.39 - 1.18 (1.5H, m).

[Chem. 67] Method C-1

Intermediate C-1-1: (3 ² S,3 ⁴ S)-4-oxo-1 ⁷ -(2-(propoxymethyl)pyrimidin-5-yl)-9-oxa-2, tertiary butyl 5-diaza-1(2,8)-quinoline-3(4,2)-piperidinecyclonona-3 ¹ -carboxylate[Chemical 68]

Make (3 ² S,3 ⁴ S)-1 ⁷ -bromo-4-oxo-9-oxa-2,5-diaza-1(2,8)-quinoline-3(4,2 )-tert-butyl piperidinecyclonona-3 ¹ -carboxylate (Intermediate A-3-7; 51 mg, 0.099 mmol), (2-(propoxymethyl)pyrimidin-5-yl)boronic acid (165 mg, 45 wt%, 0.25 mmol) was dissolved in a mixed solvent of 1,4-dioxane (2.0 mL), water (0.50 mL), and potassium carbonate (40 mg, 0.30 mmol), [1,1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (20.2 mg, 0.020 mmol), stirred at 100°C for 4 hours under microwave irradiation. Thereafter, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by automatic amine silica gel column chromatography (eluent; chloroform:ethyl acetate=50:50) to obtain a crude purified product (313 mg). It was used in the next reaction without further purification. LCMS (LC-1); RT=1.44, m/z 578 [M+H] ^＋

Intermediate C-1-2: (3 ² S,3 ⁴ S)-1 ⁷ -(2-(propoxymethyl)pyrimidin-5-yl)-9-oxa-2,5-diazepine -1(2,8)-quinoline-3(4,2)-piperidincyclononafin-4-one[Chemical 69]

Make (3 ² S,3 ⁴ S)-4-oxo-1 ⁷ -(2-(propoxymethyl)pyrimidin-5-yl)-9-oxa-2,5-diaza-1 (2,8)-quinoline-3(4,2)-piperidincyclonona-3 ¹ -tert-butyl carboxylate (intermediate C-1-1; 313 mg, 0.54 mmol, crude product ) was dissolved in dichloromethane (1 mL), added trifluoroacetic acid (0.25 mL), and stirred at room temperature for 14 hours. The obtained reaction mixture was directly purified by SCX. Thereafter, use automatic amine silica gel column chromatography (eluent; chloroform:methanol=100:0-90:10) for purification to obtain (3 ² S,3 ⁴ S)-1 ⁷ -(2-(propane Oxymethyl)pyrimidin-5-yl)-9-oxa-2,5-diaza-1(2,8)-quinoline-3(4,2)-piperidinecyclonona-4 - Ketone (29.9 mg, 63% yield in two stages). LCMS (LC-1); RT=1.02, m/z 478 [M+H] ^＋

Example a-01-07 (final body C-1-3): (3 ² S,3 ⁴ S)-3 ¹ -methyl-1 ⁷ -(2-(propoxymethyl)pyrimidine-5- Base)-9-oxa-2,5-diaza-1(2,8)-quinoline-3(4,2)-piperidincyclononan-4-one[Chemical 70]

Make (3 ² S,3 ⁴ S)-1 ⁷ -(2-(propoxymethyl)pyrimidin-5-yl)-9-oxa-2,5-diaza-1(2,8) -quinoline-3(4,2)-piperidincyclononan-4-one (intermediate C-1-2; 29.9 mg, 0.063 mmol) was dissolved in dichloromethane (0.32 mL), methanol (0.32 mL ), add 37% formaldehyde aqueous solution (0.014 mL, 0.19 mmol), sodium triacetyloxyborohydride (20 mg, 0.094 mmol), and stir at room temperature for 1 hour. The obtained reaction mixture was directly purified by SCX, and then purified by reverse phase liquid chromatography to obtain (3 ² S,3 ⁴ S)-3 ¹ -methyl-1 ⁷ -( 2-(propoxymethyl)pyrimidin-5-yl)-9-oxa-2,5-diaza-1(2,8)-quinoline-3(4,2)-piperidine ring Nonafin-4-one (4.8 mg, 15% yield). LCMS (LC-1); RT=1.07, m/z 492 [M+H] ^＋ 1H-NMR (CD3OD): δ (ppm) 9.05 (2H, s), 8.20 (1H, s), 7.66 (1H, d, J = 8.4 Hz), 7.41 (1H, d, J = 8.4 Hz), 4.78 - 4.65 (3H, m), 4.20 - 4.10 (1H, m), 3.88 - 3.74 (3H, m), 3.62 (2H , t, J = 6.8 Hz), 3.57 - 3.48 (1H, m), 3.36 - 3.33 (2H, m), 2.93 - 2.73 (2H, m), 2.57 (4H, s), 2.26 (1H, d, J = 7.8 Hz), 2.01 - 1.93 (1H, m), 1.90 - 1.61 (5H, m), 0.98 (3H, t, J = 7.8Hz).

The compounds listed in the following table were synthesized by the same method. 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-01-01 Methods A-2, A-3, C-1 (LC-1); RT=1.04, m/z 425 [M+H] ⁺ a-01-02 Methods A-2, A-3, C-1 (LC-1); RT=0.90, m/z 481 [M+H] ⁺ a-01-03 Methods A-2, A-3, C-1 (LC-1); RT=0.89, m/z 446 [M+H] ⁺ a-01-04 Methods A-2, A-3, C-1 (LC-1); RT=1.13, m/z 518 [M+H] ⁺ a-01-05 Methods B-1, B-2, C-1 (LC-1); RT=1.11, m/z 510 [M+H] ⁺ a-01-06 Methods B-1, B-2, C-1 (LC-1); RT=1.39, m/z 511 [M+H] ⁺ a-01-07 Methods A-2, A-3, C-1 (LC-1); RT=1.08, m/z 492 [M+H] ⁺ a-01-08 Methods A-2, A-3, C-1 (LC-1); RT=0.96, m/z 456 [M+H] ⁺ a-01-09 Methods A-2, A-3, C-1 (LC-1); RT=0.83, m/z 420 [M+H] ⁺ a-01-10 Methods B-1, B-2, C-1 (LC-1); RT=1.16, m/z 546 [M+H] ⁺ a-01-11 Methods A-2, A-3, C-1 (LC-1); RT=0.83, m/z 455 [M+H] ⁺ a-01-12 Methods B-1, B-2, C-1 (LC-1); RT=1.20, m/z 520 [M+H] ⁺ a-01-13 Methods A-2, A-3, C-1 (LC-1); RT=1.10, m/z 504 [M+H] ⁺ a-01-14 Methods A-2, A-3, C-1 (LC-1); RT=1.03, m/z 425 [M+H] ⁺ a-01-15 Methods B-1, B-2, C-1 (LC-1); RT=1.38, m/z 493 [M+H] ⁺ a-01-16 Methods A-2, A-3, C-1 (LC-1); RT=0.86, m/z 469 [M+H] ⁺ a-01-17 Methods A-2, A-3, C-1 (LC-1); RT=0.94, m/z 522 [M+H] ⁺ a-01-18 Methods A-2, A-3, C-1 (LC-1); RT=0.85, m/z 469 [M+H] ⁺ a-01-19 Methods B-1, B-2, C-1 (LC-1); RT=0.90, m/z 452 [M+H] ⁺ a-01-20 Methods B-1, B-2, C-1 (LC-1); RT=1.14, m/z 453 [M+H] ⁺ a-01-21 Methods A-2, A-3, C-1 (LC-1); RT=1.08, m/z 504 [M+H] ⁺ a-01-22 Methods A-2, A-3, C-1 (LC-1); RT=0.93, m/z 491 [M+H] ⁺ a-01-23 Methods A-2, A-3, C-1 (LC-1); RT=1.20, m/z 528 [M+H] ⁺ a-01-24 Methods A-2, A-3, C-1 (LC-1); RT=0.87, m/z 434 [M+H] ⁺ a-01-25 Methods A-2, A-3, C-1 (LC-1); RT=0.93, m/z 460 [M+H] ⁺ a-01-26 Methods B-1, B-2, C-1 (LC-1); RT=1.16, m/z 510 [M+H] ⁺ a-01-27 Methods A-2, A-3, C-1 (LC-1); RT=1.25, m/z 520 [M+H] ⁺ a-01-28 Methods A-2, A-3, C-1 (LC-1); RT=0.98, m/z 470 [M+H] ⁺ a-01-29 Methods A-2, A-3, C-1 (LC-1); RT=1.01, m/z 460 [M+H] ⁺ a-01-30 Methods A-2, A-3, C-1 (LC-1); RT=0.88, m/z 434 [M+H] ⁺ a-01-31 Methods B-1, B-2, C-1 (LC-1); RT=1.16, m/z 524 [M+H] ⁺ a-01-32 Methods A-2, A-3, C-1 (LC-1); RT=0.74, m/z 450 [M+H] ⁺ a-01-33 Methods A-2, A-3, C-1 (LC-1); RT=1.23, m/z 461 [M+H] ⁺ a-01-34 Methods A-2, A-3, C-1 (LC-1); RT=0.88, m/z 434 [M+H] ⁺ a-01-35 Methods A-2, A-3, C-1 (LC-1); RT=1.11, m/z 506 [M+H] ⁺ a-01-36 Methods A-2, A-3, C-1 (LC-1); RT=0.88, m/z 434 [M+H] ⁺ a-01-37 Methods B-1, B-2, C-1 (LC-1); RT=1.29, m/z 534 [M+H] ⁺ a-01-38 Methods A-2, A-3, C-1 (LC-1); RT=1.12, m/z 506 [M+H] ⁺ a-01-39 Methods A-2, A-3, C-1 (LC-1); RT=0.99, m/z 448 [M+H] ⁺ a-01-40 Methods A-2, A-3, C-1 (LC-1); RT=1.00, m/z 448 [M+H] ⁺ a-01-41 Methods B-1, B-2, C-1 (LC-1); RT=0.94, m/z 452 [M+H] ⁺ a-01-42 Methods A-2, A-3, C-1 (LC-1); RT=0.92, m/z 448 [M+H] ⁺ a-01-43 Methods A-2, A-3, C-1 (LC-1); RT=1.24, m/z 506 [M+H] ⁺ a-01-44 Methods A-2, A-3, C-1 (LC-1); RT=1.01, m/z 495 [M+H] ⁺ a-01-45 Methods A-2, A-3, C-1 (LC-1); RT=0.85, m/z 464 [M+H] ⁺

[Chem. 71] Method D-1

Intermediate D-1-2: Quinolin-6-yl acetate [Chem. 72]

Dissolve quinolin-6-ol (intermediate D-1-1; 20.0 g, 138 mmol) in dichloromethane (222 mL), add pyridine (13.3 mL, 165 mmol), acetyl Chlorine (11.7 mL, 164 mmol), stirred at room temperature for 1 hour. After the reaction was completed, saturated sodium bicarbonate water (300 mL) was added, and stirred at room temperature for 45 minutes until no foaming occurred. Extraction was performed with chloroform, and 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 (26.1 g) was used in the next reaction without purification. LCMS (LC-1); RT=1.05, m/z 188 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 8.91 (1H, dd, J = 4.2, 1.7 Hz), 8.13 (2H , d, J = 1.7 Hz), 7.57 (1H, d, J = 2.6 Hz), 7.47 (1H, dd, J = 8.3, 2.6 Hz), 7.42 (1H, dd, J = 8.3, 4.2 Hz), 2.37 (3H, s).

Intermediate D-1-3: 3-bromoquinolin-6-yl acetate [Chem. 73]

Dissolve quinolin-6-yl acetate (intermediate D-1-2; 26.1 g, the crude product above) in carbon tetrachloride (500 mL), and add the Pyridine (28 mL, 343 mmol), bromine (50 g, 313 mmol). Thereafter, stirring was carried out at 90° C. for 3 hours. After the reaction was completed, dichloromethane (300 mL) and saturated sodium bicarbonate water (250 mL) were added, and stirred at room temperature for 15 minutes. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified using automatic silica gel column chromatography (eluate; chloroform:methanol=100:0-90:10) to obtain 3-bromoquinolin-6-yl acetate (25.9 g, yield 71%). LCMS (LC-1); RT=1.46, m/z 266 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 8.89 (1H, d, J = 2.1 Hz), 8.28 (1H, d , J = 2.1 Hz), 8.10 (1H, d, J = 8.9 Hz), 7.52 - 7.45 (2H, m), 2.37 (3H, s).

Intermediate D-1-4: 3-Bromoquinolin-6-ol [Chem. 74]

3-Bromoquinolin-6-yl acetate (Intermediate D-1-3; 25.9 g, 97.6 mmol) was dissolved in methanol (130 mL), water (78 mL), potassium carbonate (27.0 g, 195 mmol), stirred at room temperature for 1.5 hours. After the reaction, methanol was distilled off under reduced pressure. The crude product was washed three times with water (20 mL), and then dried under reduced pressure at 40° C. for 4 hours to obtain 3-bromoquinolin-6-ol (21.0 g, yield 96%). LCMS (LC-1); RT=1.19, m/z 224 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 8.75 (1H, d, J = 2.2 Hz), 8.16 (1H, d , J = 2.2 Hz), 7.99 (1H, d, J = 9.3 Hz), 7.32 (1H, dd, J = 9.3, 2.6 Hz), 7.03 (1H, d, J = 2.6 Hz), 5.24 (1H, brs ).

Intermediate D-1-5: 3-bromo-5-iodoquinolin-6-ol [Chem. 75]

3-Bromoquinolin-6-ol (intermediate D-1-4; 21.0 g, 93.8 mmol) was suspended in 2 M aqueous sodium hydroxide solution (204 mL), and iodine (28.6 g, 112 mmol) dissolved in 20% potassium iodide aqueous solution (potassium iodide 54 g/water 270 mL), and stirred at room temperature for 1 hour. After the reaction, acetic acid (27 mL) was added, stirred at room temperature for 1 hour, and then filtered. The crude product was washed three times with water (100 mL), and dried under reduced pressure at 40° C. for 12 hours to obtain 3-bromo-5-iodoquinolin-6-ol (33.6 g). LCMS (LC-1); RT=1.54, m/z 349 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 8.73 (1H, d, J = 2.1 Hz), 8.42 (1H, dd , J = 2.1, 0.6 Hz), 7.98 (1H, d, J = 9.2 Hz), 7.49 (1H, d, J = 9.2 Hz), 5.98 (1H, brs).

Intermediate D-1-6: 6-(benzyloxy)-3-bromo-5-iodoquinoline [Chem. 76]

3-Bromo-5-iodoquinolin-6-ol (Intermediate D-1-5; 33.6 g, 93.8 mmol) was dissolved in N,N-dimethylformamide (313 mL) and cesium carbonate was added (36.6 g, 112 mmol), benzyl bromide (12.3 mL, 103 mmol), stirred at room temperature for 2 hours. After the reaction, water (300 mL) was added, stirred at room temperature for 45 minutes, and then filtered. The crude product was dried under reduced pressure to obtain 6-(benzyloxy)-3-bromo-5-iodoquinoline (39.9 g, yield 96%). LCMS (LC-1); RT=2.32, m/z 440 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 8.73 (1H, d, J = 2.1 Hz), 8.64 (1H, d , J = 2.1 Hz), 8.02 (1H, d, J = 9.2 Hz), 7.53 (2H, d, J = 7.6 Hz), 7.47 - 7.39 (3H, m), 7.38 - 7.31(1H, m), 5.35 (2H, s).

Intermediate D-1-7: (6-(Benzyloxy)-3-bromoquinolin-5-yl)boronic acid [Chem. 77]

Dissolve 6-(benzyloxy)-3-bromo-5-iodoquinoline (intermediate D-1-6; 17.6 g, 40.0 mmol) in tetrahydrofuran (400 mL), add trimethyl borate at room temperature Ester (9.8 mL, 87.9 mmol). The reaction solution was cooled to -78°C, and isopropylmagnesium chloride 2 M tetrahydrofuran solution (50 mL, 100 mmol) was added dropwise over 15 minutes. Thereafter, it was warmed up to room temperature and stirred for 2 hours. After the reaction was completed, acetic acid (200 mL) and water (200 mL) were added, and stirred at room temperature for 30 minutes. Then, after extraction with ethyl acetate, the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product (11.7 g) was used in the next reaction without purification. LCMS (LC-1); RT=1.45, m/z 358 [M+H] ^＋

Intermediate D-1-8: 6-(Benzyloxy)-3-bromoquinolin-5-ol [Chem. 78]

Dissolve (6-(benzyloxy)-3-bromoquinolin-5-yl)boronic acid (Intermediate D-1-7; 11.5 g, crude product above) in acetone (400 mL) and add water (200 mL), potassium persulfate (oxone) (40.2 g, 65.6 mmol), and stirred at room temperature for 1 hour. After the reaction, saturated aqueous sodium thiosulfate solution (200 mL) was added, extracted with chloroform, and 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 (10.6 g) was used in the next reaction without purification. LCMS (LC-1); RT=1.69, m/z 330 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 8.76 (1H, d, J = 2.2 Hz), 8.65 - 8.60 (1H , m), 7.63 (1H, d, J = 9.3 Hz), 7.50 (1H, d, J = 9.3 Hz), 7.48 - 7.35 (5H, m), 6.09 (1H, s), 5.25 (2H, s) .

[Chem. 79] Method D-2

Intermediate D-2-2: (2S,4S)-4-((6-(benzyloxy)-5-((triisopropylsilyl)oxy)quinolin-3-yl)amino) Piperidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester [Chem. 80]

Make 6-(benzyloxy)-3-bromo-5-((triisopropylsilyl)oxy)quinoline (intermediate D-2-1; 3.60 g, 7.41 mmol), (2S,4S) -1-(tert-butyl)2-methyl 4-aminopiperidine-1,2-dicarboxylate (Intermediate B-1-6; 3.20 g, 12.4 mmol) was dissolved in toluene (22 mL) , add methanesulfonic acid [(2-di-tert-butylphosphine-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2 -(2'-Amino-1,1'-biphenyl)]palladium(II) (320 mg, 0.37 mmol), phosphazene base P ₂ -Et (5 mL, 15 mmol), stirred at room temperature 30 minutes. After the reaction, the reaction mixture was directly purified by automatic silica gel column chromatography (eluent; chloroform:methanol=100:0-80:20) to obtain (2S,4S)-4-((6-( Benzyloxy)-5-((triisopropylsilyl)oxy)quinolin-3-yl)amino)piperidine-1,2-dicarboxylic acid 1-(tert-butyl)2-methyl Ester (2.10 g, 43% yield). LCMS (LC-6); RT=2.10, m/z 664 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 8.24 (1H, d, J = 2.8 Hz), 7.52 - 7.28 (9H , m), 7.15 (1H, d, J = 9.2 Hz), 5.25 - 5.08 (0.5H, m), 4.93 (0.5H, brs), 4.18 (0.5H, d, J = 14.2 Hz), 4.05 (0.5 H, d, J = 14.2 Hz), 3.80 - 3.71 (3H, m), 3.47 - 3.30 (1H, m), 3.22 - 2.95 (1H, m), 2.58 (1H, brs), 2.41 - 2.16 (1H, m), 2.15 - 1.89 (1H, m), 1.80 - 1.61 (1H, m), 1.53 - 1.42 (9H, m), 1.36 - 1.17 (4H, m), 1.03 (18H, d, J = 7.3 Hz) .

Intermediate D-2-3: (2S,4S)-4-((6-(benzyloxy)-5-((triisopropylsilyl)oxy)quinolin-3-yl)amino) -1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid [Chem. 81]

Make (2S,4S)-4-((6-(benzyloxy)-5-((triisopropylsilyl)oxy)quinolin-3-yl)amino)piperidine-1,2- 1-(tert-butyl)2-methyl dicarboxylate (intermediate D-2-2; 2.10 g, 3.16 mmol) was dissolved in methanol (210 mL), and 1 M-sodium hydroxide aqueous solution (32 mL ), stirred at 40°C for 15 hours. After completion of the reaction, 1 M-hydrochloric acid aqueous solution (33 mL) was added, extracted with chloroform, and 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 (2.15 g) was used in the next reaction without purification. LCMS (LC-1); RT=1.95, m/z 650 [M+H] ^＋

Intermediate D-2-4: (2S,4S)-4-((6-(benzyloxy)-5-((triisopropylsilyl)oxy)quinolin-3-yl)amino) -2-((2-fluoro-3-hydroxypropyl)aminoformyl)piperidine-1-carboxylic acid tert-butyl ester [Chem. 82]

Make (2S,4S)-4-((6-(benzyloxy)-5-((triisopropylsilyl)oxy)quinolin-3-yl)amino)-1-(tertiary Oxycarbonyl)piperidine-2-carboxylic acid (Intermediate D-2-3; 2.15 g, 3.16 mmol), 3-amino-2-fluoropropan-1-ol (348 mg, 3.79 mmol) were dissolved in N , to N-dimethylformamide (16 mL), add N-methyl 𠰌line (0.87 mL, 7.90 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiamide Imine hydrochloride (2.45 g, 12.6 mmol), 1-hydroxybenzotriazole (1.01 g, 6.96 mmol), stirred at room temperature for 30 minutes. After completion of the reaction, extraction was performed with ethyl acetate, and 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 crude product was purified using automatic silica gel column chromatography (eluent; ethyl acetate:methanol=100:0-98:2) to obtain (2S,4S)-4-((6-(benzyloxy )-5-((triisopropylsilyl)oxy)quinolin-3-yl)amino)-2-((2-fluoro-3-hydroxypropyl)aminoformyl)piperidine-1 - Tertiary butyl carboxylate (886 mg, 39% yield). LCMS (LC-1); RT=2.35, m/z 725 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 8.27 - 8.23 (1H, m), 7.54 - 7.46 (1H, m) , 7.44 - 7.28 (6H, m), 7.14 (1H, d, J = 9.2 Hz), 5.16 (2H, s), 4.98 (1H, brs), 4.77 - 4.44 (1H, m), 4.12 (1H, q . J = 7.2 Hz), 3.71 (5H, m), 3.28 - 3.10 (1H, m), 2.96 (1H, brs), 2.75 - 2.49 (1H, m), 2.29 (1H, d, J = 10.8 Hz) , 2.05 (1H, s), 1.54 - 1.47 (1H, m), 1.35 - 1.17 (9H, m), 1.35 - 1.17 (5H, m), 1.03 (18H, d, J = 7.3 Hz).

Intermediate D-2-5: (2S,4S)-4-((6-(benzyloxy)-5-hydroxyquinolin-3-yl)amino)-2-((2-fluoro-3- Hydroxypropyl)carbamoyl)piperidine-1-carboxylate tertiary butyl ester[Chemical 83]

Make (2S,4S)-4-((6-(benzyloxy)-5-((triisopropylsilyl)oxy)quinolin-3-yl)amino)-2-((2- Fluoro-3-hydroxypropyl)carbamoyl)piperidine-1-carboxylate tert-butyl ester (intermediate D-2-4; 886 mg, 1.22 mmol) was dissolved in tetrahydrofuran (6.1 mL), and tetrahydrofuran was added Butylammonium fluoride 1 M-tetrahydrofuran solution (2.44 mL, 2.44 mmol) was stirred at room temperature for 30 minutes. After the reaction, the reaction mixture was directly purified by automatic silica gel column chromatography (eluate; chloroform:methanol=100:0-80:20) to obtain (2S,4S)-4-((6- (Benzyloxy)-5-hydroxyquinolin-3-yl)amino)-2-((2-fluoro-3-hydroxypropyl)aminoformyl)piperidine-1-carboxylic acid tert-butyl ester (660 mg, 95% yield). LCMS (LC-1); RT=1.46, m/z 569 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 8.29 (1H, d, J = 2.8 Hz), 7.55 - 7.28 (6H , m), 7.22 - 7.12 (2H, m), 6.92 - 6.37 (1H, m), 6.03 (1H, brs), 4.99 (1H, brs), 4.73 (0.5H, brs), 4.61 (0.5H, brs ), 4.46 - 4.06 (2H, m), 3.93 - 3.70 (3H, m), 3.66 (2H, brs), 3.10 - 2.95 (2H, m), 2.93 - 2.57 (2H, m), 2.10 (2H, d , J = 11.8 Hz), 1.53 - 1.48 (9H, m), 1.47 - 1.22 (2H, m).

Intermediate D-2-6: (3 ² S,3 ⁴ S)-1 ⁶ -(benzyloxy)-7-fluoro-4-oxo-9-oxa-2,5-diaza-1 (3,5)-quinoline-3(4,2)-piperidinecyclononazone-3 ¹ -tert-butyl carboxylate [Chem. 84]

Make (2S,4S)-4-((6-(benzyloxy)-5-hydroxyquinolin-3-yl)amino)-2-((2-fluoro-3-hydroxypropyl)aminoformyl Base) tert-butyl piperidine-1-carboxylate (intermediate D-2-5; 660 mg, 1.161 mmol) was dissolved in toluene (240 mL), and triphenylphosphine (773 mg, 2.90 mmol), A 20% solution of di-tert-butyl azodicarboxylate in toluene (4.16 mL, 3.48 mmol) was stirred at room temperature for 1 hour. Thereafter, the reaction mixture was concentrated under reduced pressure. The obtained crude product was purified by automatic silica gel column chromatography (eluate; chloroform:methanol=100:0-90:10) to obtain (3 ² S,3 ⁴ S)-1 ⁶ -( Benzyloxy)-7-fluoro-4-oxo-9-oxa-2,5-diaza-1(3,5)-quinoline-3(4,2)-piperidinecyclonona- 3 ^tert -Butyl 1-carboxylate (431 mg, 67% yield). LCMS (LC-1); RT=1.62, m/z 551 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 8.29 (1H, d, J = 2.8 Hz), 7.72 - 7.62 (1H , m), 7.53 - 7.28 (5H, m), 7.21 (1H, d, J = 9.4 Hz), 5.91 (1H, d, J = 7.2 Hz), 5.31 (1H, d, J = 12.0 Hz), 5.22 (1H, d, J = 12.0 Hz), 4.96 (0.5H, brs), 4.91 (0.5H, brs), 4.81 (0.5H, brs), 4.61 (1H, dd, J = 8.9, 3.5), 4.48 - 4.32 (1.5H, m), 4.07 - 3.99 (1H, m), 3.78 - 3.71 (2H, m), 3.68 - 3.57 (1H, m), 3.56 - 3.37 (2H, m), 2.72 (1H, d, J = 11.6 Hz), 1.99 - 1.92 (1H, m), 1.85 (2H, td, J = 6.8, 3.2 Hz), 1.73 - 1.59 (1H, m), 1.53 - 1.39 (9H, m).

[Chem. 85] Method D-3

Intermediate D-3-1: (3 ² S,3 ⁴ S)-7-fluoro- ^{1 6} -hydroxy-4-oxo-9-oxa-2,5-diaza-1(3,5 )-quinoline-3(4,2)-piperidinecyclononafin-3 ¹ -carboxylic acid tert-butyl ester[Chem.86]

Make (3 ² S,3 ⁴ S)-1 ⁶ -(benzyloxy)-7-fluoro-4-oxo-9-oxa-2,5-diaza-1(3,5)-quinone Phyloline-3(4,2)-piperidinecyclononafin-3 ¹ -carboxylic acid tert-butyl ester (intermediate D-2-6; 325 mg, 0.59 mmol) was dissolved in methanol (3 mL), tetrahydrofuran (3 mL) of the mixed solvent, was added palladium hydroxide (65 mg, 20 wt%), and stirred at room temperature for 18 hours under hydrogen atmosphere. After the inside of the reaction system was replaced with a nitrogen atmosphere, Celite filtration was performed. The filtrate was concentrated under reduced pressure to obtain (3 ² S,3 ⁴ S)-7-fluoro-1 ⁶ -hydroxy-4-oxo-9-oxa-2,5-diazepine as a crude product - tert-butyl 1(3,5)-quinoline-3(4,2)-piperidinecyclononazone-3 ¹ -carboxylate (330 mg, yield 92%). The crude product was used in the next reaction without purification. LCMS (LC-1); RT=1.13, m/z 461 [M+H] ^＋

Intermediate D-3-2: (3 ² S,3 ⁴ S)-7-fluoro-4-oxo-1 ⁶ -(((trifluoromethyl)sulfonyl)oxy)-9-oxa -2,5-Diaza-1(3,5)-quinoline-3(4,2)-piperidinecyclonona-3 ¹ -carboxylic acid tert-butyl ester [Chem. 87]

Make (3 ² S,3 ⁴ S)-7-fluoro-1 ⁶ -hydroxyl-4-oxo-9-oxa-2,5-diaza-1(3,5)-quinoline-3( 4,2)-tert-butyl piperidinecyclonona- ³¹ -carboxylate (intermediate D-3-1; 330 mg, 0.72 mmol) was dissolved in 1,4-dioxane (7.2 mL), Add N,N-dimethylformamide (6 drops), N,N-diisopropylethylamine (0.748 mL, 4.30 mmol), N-phenyl-bis(trifluoromethanesulfonylimide) (824 mg, 2.30 mmol), stirred at room temperature for 7 hours. After the reaction, the reaction mixture was directly purified by automatic silica gel column chromatography (eluent; chloroform:methanol=100:0-90:10) to obtain (3 ² S,3 ⁴ S)-7- Fluoro-4-oxo-1 ⁶ -(((trifluoromethyl)sulfonyl)oxy)-9-oxa-2,5-diaza-1(3,5)-quinoline-3 (4,2)-tert-butyl piperidinecyclonona-3 ¹ -carboxylate (420 mg, 99%). LCMS (LC-1); RT=1.65, m/z 593 [M+H] ^＋ 1H-NMR (DMSO-d ₆ ): δ (ppm) 8.55 (1H, d, J = 2.6 Hz), 8.18 (1H , d, J = 7.0 Hz), 7.75 (1H, d, J = 9.2 Hz), 7.23 (1H, d, J = 7.9 Hz), 7.05 (1H, s), 6.93 - 6.87 (1H, m), 5.14 (0.5H, brs), 5.08 - 4.93 (0.5H, m), 4.71 (0.5H, d, J = 2.4 Hz), 4.65 - 4.52 (0.5H, m), 4.46 - 4.22 (2H, m), 4.11 (1H, brs), 3.98 (1H, d, J = 9.0 Hz), 3.65 - 3.48 (3H, m), 3.29 - 3.11 (2H, m), 1.99 - 1.87 (1H, m), 1.59 (1H, d , J = 13.4 Hz), 1.42 - 1.23 (9H, m).

Intermediate D-3-3: (3 ² S,3 ⁴ S)-7-fluoro-4-oxo-1 ⁶ -(2-(propoxymethyl)pyrimidin-5-yl)-9-oxo Hetero-2,5-diaza-1(3,5)-quinoline-3(4,2)-piperidinecyclonona-3 ¹ -carboxylate tertiary butyl ester[Chem.88]

Make (3 ² S,3 ⁴ S)-7-fluoro-4-oxo-1 ⁶ -(((trifluoromethyl)sulfonyl)oxy)-9-oxa-2,5-diazepine Hetero-1(3,5)-quinoline-3(4,2)-piperidinecyclonona-3 ¹ -carboxylic acid tert-butyl ester (intermediate D-3-2; 420 mg, 0.71 mmol), 2-(propoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (1.30 g, 31 wt%, 1.77 mmol) was dissolved in a mixed solvent of 1,4-dioxane (2.8 mL), water (0.28 mL), cesium carbonate (705 mg, 2.12 mmol), [1,1'-bis(di Phenylphosphino)ferrocene]palladium(II) dichloromethane adduct (117 mg, 0.14 mmol) was stirred at 100°C for 2 hours under microwave irradiation. The reaction solution was filtered with diatomaceous earth, and the filtrate was concentrated under reduced pressure, and the crude product was purified by automatic silica gel column chromatography (eluate; chloroform:methanol=100:0-90:10) to obtain as (3 ² S,3 ⁴ S)-7-fluoro-4-oxo-1 ⁶ -(2-(propoxymethyl)pyrimidin-5-yl)-9-oxa-2, tert-butyl 5-diaza-1(3,5)-quinoline-3(4,2)-piperidinecyclonona- ³¹ -carboxylate (180 mg, 43% yield). The crude product was used in the next reaction without further purification. LCMS (LC-1); RT=1.44, m/z 595 [M+H] ^＋

Intermediate D-3-4: (3 ² S,3 ⁴ S)-7-fluoro-1 ⁶ -(2-(propoxymethyl)pyrimidin-5-yl)-9-oxa-2,5 -Diaza-1(3,5)-quinoline-3(4,2)-piperidincyclononafin-4-one[Chemical 89]

Make (3 ² S,3 ⁴ S)-7-fluoro-4-oxo-1 ⁶ -(2-(propoxymethyl)pyrimidin-5-yl)-9-oxa-2,5-di Aza-1(3,5)-quinoline-3(4,2)-piperidinecyclononazone-3 ¹ -carboxylic acid tert-butyl ester (Intermediate D-3-3; 180 mg, 0.30 mmol) Dissolve in dichloromethane (3.0 mL), add trifluoroacetic acid (0.75 mL), and stir at room temperature for 30 minutes. The obtained reaction mixture was crudely purified directly by SCX to obtain (3 ² S,3 ⁴ S)-7-fluoro-1 ⁶ -(2-(propoxymethyl)pyrimidin-5-yl)- 9-Oxa-2,5-diaza-1(3,5)-quinoline-3(4,2)-piperidincyclononan-4-one (148 mg, 98% yield). The crude product was used in the next reaction without further purification. LCMS (LC-1); RT=1.01, m/z 495 [M+H] ^＋

Example a-02-02 (final body D-3-5): (3 ² S,3 ⁴ S)-7-fluoro-3 ¹ -methyl-1 ⁶ -(2-(propoxymethyl) Pyrimidin-5-yl)-9-oxa-2,5-diaza-1(3,5)-quinoline-3(4,2)-piperidincyclononan-4-one[Chemical 90]

Make (3 ² S,3 ⁴ S)-7-fluoro- ^{1 6-} (2-(propoxymethyl)pyrimidin-5-yl)-9-oxa-2,5-diazepine-1( 3,5)-quinoline-3(4,2)-piperidincyclononan-4-one (intermediate D-3-4; 148 mg, 0.30 mmol) was dissolved in dichloromethane (1.5 mL), methanol (1.5 mL) of the mixed solvent, add 37% formaldehyde aqueous solution (0.068 mL, 0.91 mmol), sodium triacetyloxyborohydride (96 mg, 0.45 mmol), and stir at room temperature for 1 hour. The obtained reaction mixture was directly purified by SCX, and then purified by reverse phase liquid chromatography to obtain (3 ² S,3 ⁴ S)-7-fluoro-3 ¹ -methyl- 1 ⁶ -(2-(Propoxymethyl)pyrimidin-5-yl)-9-oxa-2,5-diaza-1(3,5)-quinoline-3(4,2)- Piperidincyclononafin-4-one (106 mg, 69% yield over two stages). LCMS (LC-1); RT=1.11, m/z 509 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 9.07 (2H, s), 8.43 (1H, d, J = 2.7 Hz ), 7.87 (1H, d, J = 8.7 Hz), 7.46 - 7.39 (2H, m), 6.64 (1H, brs), 5.20 - 4.87 (1H, m), 4.83 (2H, s), 4.23 - 4.10 ( 1H, m), 3.97 - 3.78 (3H, m), 3.74 - 3.62 (3H, m), 3.30 - 3.20 (2H, m), 2.84 - 2.76 (1H, m), 2.41 (3H, s), 2.34 ( 1H, brs), 2.21 (1H, d, J = 13.1 Hz), 2.03 (1H, d, J = 9.2 Hz), 1.80 - 1.63 (4H, m), 0.99 (3H, t, J = 7.4 Hz).

[Chemical 91] Method E-1

Intermediate E-1-1: 6-(benzyloxy)-3-bromo-5-(3-((tert-butyldiphenylsilyl)oxy)propoxy)quinoline [Chemical 92]

6-(Benzyloxy)-3-bromoquinolin-5-ol (Intermediate D-1-8; 3.00 g, 9.1 mmol) was dissolved in toluene (91 mL), and 3-((tert-butyl (diphenylsilyl)oxy)propan-1-ol (4.2 g, 18.2 mmol), triphenylphosphine (4.80 g, 18.2 mmol), tert-butyl azodicarboxylate (18.2 mmol), in Stir at room temperature for 1 hour. After the reaction was completed, the solvent was removed under reduced pressure, and the crude product was crudely purified using automatic silica gel column chromatography (eluate; hexane:ethyl acetate=100:0-70:30), and obtained as crude The purified 6-(benzyloxy)-3-bromo-5-(3-((tert-butyldiphenylsilyl)oxy)propoxy)quinoline (6.49 g). The crude product was used in the next reaction without further purification. LCMS (LC-6); RT=2.71, m/z 626 [M+H] ^＋

Intermediate E-1-2: 3-((6-(benzyloxy)-3-bromoquinolin-5-yl)oxy)propan-1-ol [Chem. 93]

Make 6-(benzyloxy)-3-bromo-5-(3-((tert-butyldiphenylsilyl)oxy)propoxy)quinoline (intermediate E-1-1; 6.49 g , 10.36 mmol) was dissolved in tetrahydrofuran (80 mL), added tetrabutylammonium fluoride (30 mL, 1 M-THF solution), and stirred at room temperature for 16 hours. After completion of the reaction, extraction was performed with ethyl acetate, and 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 crude product was purified using automatic silica gel column chromatography (eluent; chloroform:methanol=100:0-50:50) to obtain 3-((6-(benzyloxy)-3 -Bromoquinolin-5-yl)oxy)propan-1-ol (4.72 g). LCMS (LC-1); RT=1.66, m/z 388 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 8.77 (1H, d, J = 2.2 Hz), 8.58 (1H, dd , J = 2.2, 0.7 Hz), 7.93 - 7.75 (1H, m), 7.55 - 7.29 (6H, m), 5.27 (2H, s), 4.28 (2H, t, J = 5.8 Hz), 3.90 (2H, q, J = 5.8 Hz), 3.70 (1H, brs), 2.11 - 2.02 (2H, m).

Intermediate E-1-3: (2S,4S)-4-azidopiperidine-1,2-dicarboxylic acid 2-(3-((6-(benzyloxy)-3-bromoquinoline- 5-base) oxy)propyl) 1-(tertiary butyl) ester [chemical 94]

3-((6-(Benzyloxy)-3-bromoquinolin-5-yl)oxy)propan-1-ol (intermediate E-1-2; 4.02 g, 10.3 mmol), (2S, 4S)-4-azido-1-(tertiary butoxycarbonyl)piperidine-2-carboxylic acid (4.81 g, 17.8 mmol) was dissolved in dichloromethane (100 mL), and 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.06 g, 21.1 mmol), N,N-dimethylaminopyridine (2.70 g, 22.1 mmol), stirred at room temperature 3 hours. After completion of the reaction, extraction was performed with dichloromethane, and 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 crude product was purified by automatic silica gel column chromatography (eluate; hexane:ethyl acetate=90:10-0:100) to obtain (2S,4S)-4-azido as a crude product Piperidine-1,2-dicarboxylic acid 2-(3-((6-(benzyloxy)-3-bromoquinolin-5-yl)oxy)propyl)1-(tert-butyl)ester (5.69 g). The crude product was used in the next reaction without further purification. LCMS (LC-1); RT=2.36, m/z 640 [M+H] ^＋

Intermediate E-1-4: (2S,4S)-4-aminopiperidine-1,2-dicarboxylic acid 2-(3-((6-(benzyloxy)-3-bromoquinoline-5 -yl) oxy)propyl) 1-(tertiary butyl) ester [chemical 95]

Make (2S,4S)-4-azidopiperidine-1,2-dicarboxylic acid 2-(3-((6-(benzyloxy)-3-bromoquinolin-5-yl)oxy) Propyl) 1-(tert-butyl) ester (Intermediate E-1-3; 5.69 g, 8.88 mmol) was dissolved in THF (100 mL), triphenylphosphine (5.0 g, 19.0 mmol), water (5.0 mL), stirred at 70°C for 15 hours. After the reaction, the solvent was removed under reduced pressure, and the crude product was purified using automatic silica gel column chromatography (eluent; hexane:ethyl acetate=90:10-0:100) to obtain a crude purified product (2S,4S)-4-aminopiperidine-1,2-dicarboxylic acid 2-(3-((6-(benzyloxy)-3-bromoquinolin-5-yl)oxy)propane base) 1-(tert-butyl) ester (5.78 g). The crude product was used in the next reaction without further purification. LCMS (LC-1); RT=1.70, m/z 614 [M+H] ^＋

Intermediate E-1-5: (3 ² S,3 ⁴ S)-1 ⁶ -(benzyloxy)-4-oxo-5,9-dioxa-2-aza-1(3,5 )-quinoline-3(4,2)-piperidinecyclononafin-3 ¹ -carboxylic acid tert-butyl ester[Chemical 96]

Make (2S,4S)-4-aminopiperidine-1,2-dicarboxylic acid 2-(3-((6-(benzyloxy)-3-bromoquinolin-5-yl)oxy)propane base) 1-(tert-butyl) ester (intermediate E-1-4; 5.46 g, 8.89 mmol) was dissolved in 1,4-dioxane (90 mL), cesium carbonate (9.00 g, 27.6 mmol) was added ), methanesulfonic acid [(2-di-tert-butylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1 ,1'-biphenyl)] palladium (II) (1.10 g, 1.38 mmol), stirred at 120° C. for 3 days. After the reaction, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by automatic silica gel column chromatography (eluate; hexane:ethyl acetate=90:10-0:100) to obtain (3 ² S,3 ⁴ S)-1 ⁶ -(Benzyloxy)-4-oxo-5,9-dioxa-2-aza-1(3,5)-quinoline-3(4,2)-piperidinecyclononazone-3 ¹ - Tertiary butyl carboxylate (360 mg, 7% yield). LCMS (LC-1); RT=1.98, m/z 534 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 8.76 (1H, d, J = 2.3 Hz), 8.58 - 8.53 (1H , m), 7.79 (1H, d, J = 9.3 Hz), 7.53 - 7.30 (6H, m), 5.28 - 5.21 (0.5H, m), 4.97 (0.5H, d, J = 5.3 Hz), 4.46 - 4.34 (2H, m), 4.25 (2H, t, J = 6.2 Hz), 4.15 - 4.01 (0.5H, m), 3.95 (0.5H, d, J = 12.5 Hz), 3.06 - 2.84 (1H, m) , 2.66 (1H, dt, J = 11.4, 3.7 Hz), 2.31 (1H, t, J = 10.0 Hz), 2.23 - 2.12 (2H, m), 1.80 - 1.63 (1H, m), 1.50 - 1.37 (13H , m), 1.33 - 1.15 (1H, m).

[Chem.97] Method F-1

Intermediate F-1-1: tertiary butyl (3-((6-(benzyloxy)-3-bromoquinolin-5-yl)oxy)propyl)carbamate [Chemical 98]

6-(Benzyloxy)-3-bromoquinolin-5-ol (Intermediate D-1-8; 1.0 g, 3.03 mmol) was dissolved in toluene (15 mL) and (3-hydroxypropyl) Tert-butyl carbamate (1.59 g, 9.09 mmol), triphenylphosphine (1.99 g, 7.57 mmol), and finally 20% toluene solution of di-tert-butyl azodicarboxylate (10 mL, 9.09 mmol ), stirred at room temperature for 1 hour. The solvent of the reaction solution was distilled off, and purified using automatic silica gel column chromatography (eluate; hexane:ethyl acetate=1:1), thereby obtaining (3-((6-(benzyloxy)- tert-butyl 3-bromoquinolin-5-yl)oxy)propyl)carbamate (3.11 g, 99% yield). LCMS (LC-1); RT=2.11, m/z 487 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 8.76 (1H, d, J = 2.0 Hz), 8.56 (1H, d , J = 2.0 Hz), 7.80 (1H, d, J = 9.0 Hz), 7.53 (1H, s), 7.40 (5H, s), 5.29 (2H, s), 5.11 - 4.84 (2H, m), 4.26 - 4.17 (2H, m), 3.44 - 3.32 (2H, m), 2.04 - 1.97 (2H, m), 1.44 (9H, s).

Intermediate F-1-2: (3-((6-(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl) quinoline-5-yl) oxy) propyl) tertiary butyl carbamate [Chemical 99]

Make (3-((6-(benzyloxy)-3-bromoquinolin-5-yl)oxy)propyl)carbamate tert-butyl ester (intermediate F-1-1; 1.0 g, 3.03 mmol) was dissolved in 1,4-dioxane (15 mL), and bis(pinacolate) diboron (451 mg, 1.79 mmol), [1,1'-bis(diphenylphosphine) dioxane Iron] palladium(II) (175 mg, 0.24 mmol), potassium acetate (237 mg, 2.38 mmol), stirred at 100°C for 14 hours. The reaction solution was cooled to room temperature, and after removing the precipitated solid by filtration, the solvent was distilled off to obtain (3-((6-(benzyloxy)-3-(4,4, Tert-butyl 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-5-yl)oxy)propyl)carbamate. LCMS (LC-1); RT=2.14, m/z 534 [M+H] ^＋

Intermediate F-1-3: tert-butyl (3-((6-(benzyloxy)-3-hydroxyquinolin-5-yl)oxy)propyl)carbamate [Chem. 100]

Make (3-((6-(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline -5-yl)oxy)propyl) tert-butyl carbamate (intermediate F-1-2; 636 mg, 1.19 mmol) was dissolved in tetrahydrofuran (13 mL), and 1 M - Sodium hydroxide aqueous solution (520 μL), 20% hydrogen peroxide water (520 μL) and stirred at the same temperature for 2 hours. Add saturated aqueous sodium thiosulfate solution and 1 M-hydrochloric acid to the reaction mixture, extract with chloroform, dry with magnesium sulfate, remove the solvent by distillation, and use automatic silica gel column chromatography (eluate; hexane : ethyl acetate=50:50) for purification, thereby obtaining (3-((6-(benzyloxy)-3-hydroxyquinolin-5-yl)oxy)propyl)carbamic acid tertiary butyl Ester (678 mg, 99% yield). LCMS (LC-1); RT=1.68, m/z 425 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 8.65 - 8.48 (1H, m), 8.37 - 8.10 (1H, m) , 8.04 - 7.86 (1H, m), 7.85 - 7.69 (1H, m), 7.52 - 7.43 (2H, m), 7.43 - 7.27 (4H, m), 5.25 (2H, s), 4.18 - 4.13 (2H, m), 3.61 - 3.50 (2H, m), 1.96 - 1.86 (2H, m), 1.26 (2H, s), 1.24 (9H, s).

Intermediate F-1-4: 5-(3-aminopropoxy)-6-(benzyloxy)quinolin-3-ol [Chem. 101]

Make (3-((6-(benzyloxy)-3-hydroxyquinolin-5-yl)oxy)propyl)carbamate tert-butyl ester (intermediate F-1-3; 678 mg, 1.60 mmol) was dissolved in dichloromethane (17 mL), and trifluoroacetic acid (4.0 mL) was added at room temperature and stirred for 20 minutes. The reaction mixture was concentrated and processed with an SCX box to obtain 5-(3-aminopropoxy)-6-(benzyloxy)quinolin-3-ol (312 mg, yield 60%) . LCMS (LC-1); RT=0.96, m/z 325 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 8.64 (1H, d, J = 2.5 Hz), 7.83 - 7.76 (1H , m), 7.76 - 7.72 (1H, m), 7.49 - 7.44 (2H, m), 7.43 - 7.28 (4H, m), 5.25 - 5.20 (2H, m), 4.25 - 4.17 (2H, m), 3.09 - 2.99 (2H, m), 2.03 - 1.90 (2H, m).

Intermediate F-1-5: (2S,4R)-2-((3-((6-(benzyloxy)-3-hydroxyquinolin-5-yl)oxy)propyl)carbamoyl )-tert-butyl 4-hydroxypiperidine-1-carboxylate [Chem. 102]

5-(3-Aminopropoxy)-6-(benzyloxy)quinolin-3-ol (Intermediate F-1-4; 312 mg, 0.81 mmol) was dissolved in dichloromethane (4.0 mL) In, add N-methyl 𠰌line (222 μL, 2.01 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (627 mg, 3.22 mmol), 1-Hydroxybenzotriazole (239 mg, 1.77 mmol), (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypiperidine-2-carboxylic acid (376 mg, 1.45 mmol), Stir at room temperature for 3 hours. Water was added to the reaction mixture, extracted with chloroform, the solvent was distilled off, and purified by automatic silica gel column chromatography (lyotrope; chloroform:methanol=9:1) to obtain (2S,4R)- 2-((3-((6-(Benzyloxy)-3-hydroxyquinolin-5-yl)oxy)propyl)aminoformyl)-4-hydroxypiperidine-1-carboxylic acid third Butyl ester (122 mg, 27% yield). LCMS (LC-1); RT=1.43, m/z 552 [M+H] ^＋

Intermediate F-1-6: (3 ² S,3 ⁴ S)-1 ⁶ -(benzyloxy)-4-oxyl-2,9-dioxa-5-aza-1(3,5 )-quinoline-3(4,2)-piperidinecyclononafin-3 ¹ -tert-butyl carboxylate [Chem. 103]

Make (2S,4R)-2-((3-((6-(benzyloxy)-3-hydroxyquinolin-5-yl)oxy)propyl)carbamoyl)-4-hydroxypiperidine - tert-butyl 1-carboxylate (intermediate F-1-5; 122 mg, 0.22 mmol) was dissolved in toluene (20 mL), and triphenylphosphine (149 mg, 0.54 mmol), 20% azo A solution of di-tert-butyl dicarboxylate in toluene (780 μL, 0.65 mmol) was stirred for 1 hour and 30 minutes. The reaction mixture solution was concentrated and purified using automatic silica gel column chromatography (eluate; chloroform:methanol=90:10) to obtain (3 ² S,3 ⁴ S)-1 ⁶ -(benzyloxy )-4-Oxy-2,9-dioxa-5-aza-1(3,5)-quinoline-3(4,2)-piperidinecyclononacene-3 ¹ -carboxylic acid third Butyl ester (84 mg, 72%). LCMS (LC-1); RT=1.60, m/z 534 [M+H] ^＋

[Chem. 104] Method F-2

Intermediate F-2-1: (3 ² S,3 ⁴ S)-1 ⁶ -hydroxy-4-oxyl-2,9-dioxa-5-aza-1(3,5)-quinoline -3(4,2)-Piperidine cyclononazone-3 ¹ -tert-butyl carboxylate [Chem. 105]

Make (3 ² S,3 ⁴ S)-1 ^6- (benzyloxy)-4-oxyl-2,9-dioxa-5-aza-1(3,5)-quinoline-3( 4,2)-tert-butyl piperidinecyclononarone-3 ¹ -carboxylate (intermediate F-1-6; 84 mg, 0.15 mmol) was dissolved in methanol (0.8 mL), and tetrahydrofuran (0.8 mL) , palladium hydroxide (16.6 mg) was added under a nitrogen atmosphere, artificially replaced with hydrogen, and fully stirred at room temperature for 14 hours. After the insoluble matter in the reaction mixture was removed by filtration, the solvent was distilled off and purified by automatic silica gel column chromatography (eluate; chloroform:methanol=90:10) to obtain (3 ² S,3 ⁴ S)-1 ⁶ -Hydroxy-4-oxyl-2,9-dioxa-5-aza-1(3,5)-quinoline-3(4,2)-piperidinecyclonona- 3 ^tert -Butyl 1-carboxylate (31.2 mg, 46% yield). LCMS (LC-1); RT=1.12, m/z 444 [M+H] ^＋

Intermediate F-2-2: (3 ² S,3 ⁴ S)-1 ⁶ -(((trifluoromethyl)sulfonyl)oxy)-4-oxyl-2,9-dioxa- tertiary butyl 5-aza-1(3,5)-quinoline-3(4,2)-piperidinecyclononazone-3 ¹ -carboxylate[Chem. 106]

Make (3 ² S,3 ⁴ S)-1 ⁶ -hydroxy-4-oxyl-2,9-dioxa-5-aza-1(3,5)-quinoline-3(4,2) -Piperidinecyclonona-3 ¹ -tert-butyl carboxylate (intermediate F-2-1; 31.2 mg, 70 μmol) was dissolved in 1,4-dioxane (700 μL), and N,N -Bis(trifluoromethylsulfonyl)aniline (85 mg, 0.22 mmol), diisopropylethylamine (73 μL, 0.42 mmol), dimethylformamide (2 drops), and at room temperature Stirring was continued for 3 hours. The reaction mixture was concentrated and purified by automatic silica gel column chromatography (eluate; chloroform:methanol=90:10) to obtain (3 ² S,3 ⁴ S)-1 ⁶ -(((three Fluoromethyl)sulfonyl)oxy)-4-oxyl-2,9-dioxa-5-aza-1(3,5)-quinoline-3(4,2)-piperidine ring Tert-butyl nonafin-3 ¹ -carboxylate (44.3 mg, yield 99%). LCMS (LC-1); RT=1.68, m/z 576 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 8.80 (1H, d, J = 2.5 Hz), 8.01 (1H, s ), 7.93 (1H, d, J = 9.5 Hz), 7.84 - 7.79 (1H, m), 7.53 - 7.47 (1H, m), 7.43 - 7.34 (2H, m), 7.30 (3H, s), 5.76 - 5.59 (1H, m), 4.74 - 4.64 (1H, m), 4.42 - 4.22 (3H, m), 4.16 - 3.86 (4H, m), 3.43 - 3.26 (1H, m), 2.50 - 2.40 (1H, m ), 2.34 - 2.27 (1H, m), 2.21 - 2.13 (1H, m), 1.90 - 1.75 (4H, m), 1.46 (9H, s).

Intermediate F-2-3: (3 ² S,3 ⁴ S)-1 ⁶ -(2-(propoxymethyl)pyrimidin-5-yl)-4-oxyl-2,9-dioxa -tert-butyl 5-aza-1(3,5)-quinoline-3(4,2)-piperidinecyclononazone-3 ¹ -carboxylate[Chem. 107]

Make (3 ² S,3 ⁴ S)-1 ⁶ -(((trifluoromethyl)sulfonyl)oxy)-4-oxyl-2,9-dioxa-5-aza-1( 3,5)-quinoline-3(4,2)-piperidincyclononazone-3 ¹ -tert-butyl carboxylate (intermediate F-2-2; 44 mg, 76 μmol) was dissolved in 1,4 - Dioxane (600 μL), water (60 μL), add (2-(propoxymethyl)pyrimidin-5-yl)boronic acid (175 mg, 0.19 mmol), [1,1'-bis( Diphenylphosphine)ferrocene]palladium(II) (13 mg, 15 μmol), cesium carbonate (78 mg, 0.23 mmol), and irradiated by microwave at 100°C for 3 hours. After the insoluble matter in the reaction mixture solution was removed by filtration with diatomaceous earth, the solvent was distilled off and purified by automatic silica gel column chromatography (eluent; chloroform:methanol=90:10) to obtain (3 ² S ,3 ⁴ S)-1 ^6- (2-(propoxymethyl)pyrimidin-5-yl)-4-oxyl-2,9-dioxa-5-aza-1(3,5) - tert-butyl quinoline-3(4,2)-piperidincyclononafin-3 ¹ -carboxylate (22.8 mg, yield 52%). LCMS (LC-1); RT=1.42, m/z 578 [M+H] ^＋

Intermediate F-2-4: (3 ² S,3 ⁴ S)-1 ⁶ -(2-(propoxymethyl)pyrimidin-5-yl)-2,9-dioxa-5-aza -1(3,5)-quinoline-3(4,2)-piperidine cyclononaferone-4-one[Chem. 108]

Make (3 ² S,3 ⁴ S)-1 ^6- (2-(propoxymethyl)pyrimidin-5-yl)-4-oxyl-2,9-dioxa-5-aza-1 (3,5)-quinoline-3(4,2)-piperidincyclononazone-3 ¹ -tert-butyl carboxylate (intermediate F-2-3; 22.8 mg, 39 μmol) was dissolved in dichloro To methane (400 μL), trifluoroacetic acid (100 L) was added and stirred at room temperature for 20 minutes. The reaction mixture was treated with SCX to obtain (3 ² S,3 ⁴ S)-1 ⁶ -(2-(propoxymethyl)pyrimidin-5-yl)-2,9-dioxa- 5-Aza-1(3,5)-quinoline-3(4,2)-piperidincyclononafone-4-one (13.4 mg, 99% yield). LCMS (LC-1); RT=0.98, m/z 478 [M+H] ^＋

Example a-02-25 (final body F-2-5): (3 ² S,3 ⁴ S)-3 ¹ -methyl-1 ⁶ -(2-(propoxymethyl)pyrimidine-5- Base)-2,9-dioxa-5-aza-1(3,5)-quinoline-3(4,2)-piperidincyclononan-4-one[Chemical 109]

Make (3 ² S,3 ⁴ S)-1 ⁶ -(2-(propoxymethyl)pyrimidin-5-yl)-2,9-dioxa-5-aza-1(3,5) -Quinoline-3(4,2)-piperidincyclononan-4-one (Intermediate F-2-4; 13.4 mg, 39 μmol) was dissolved in dichloromethane (200 μL), methanol (200 μL) 37% aqueous formaldehyde solution (8.7 μL, 0.12 mmol) and triacetyloxyboron hydride (12.5 mg, 59 μmol) were added, and stirred at room temperature for 10 minutes. After the reaction mixture was treated with SCX, it was purified by preparative thin layer chromatography (eluate; chloroform: 2 M-ammonia methanol solution = 97:3), thereby obtaining (3 ² S,3 ⁴ S)- 3 ¹ -methyl-1 ⁶ -(2-(propoxymethyl)pyrimidin-5-yl)-2,9-dioxa-5-aza-1(3,5)-quinoline-3 (4,2)-Piperidincyclononafone-4-one (6.2 mg, 32% yield). LCMS (LC-1); RT=1.00, m/z 492 [M+H] ⁺ 1H-NMR (CD3OD): δ (ppm) 9.19 (2H, s), 8.82 (1H, d, J = 2.5 Hz) , 7.97 (1H, d, J = 9.0 Hz), 7.90 - 7.84 (2H, m), 4.78 (2H, s), 4.41 (1H, dd, J = 2.5, 2.5 Hz), 4.30 - 4.22 (1H, m ), 4.17 - 4.04 (1H, m), 3.86 - 3.69 (1H, m), 3.69 - 3.55 (4H, m), 3.40 (1H, d, J = 6.8 Hz), 3.29 - 3.11 (1H, m), 2.59 (3H, s), 2.35 - 2.25 (1H, m), 2.19 - 2.04 (3H, m), 1.98 - 1.84 (1H, m), 1.81 - 1.75 (1H, m), 1.75 - 1.67 (2H, m ), 1.17 (1H, t, J = 7.5 Hz), 0.98 (3H, t, J = 7.5 Hz.)

[Chem. 110] Method G-1

Intermediate G-1-3': (2S,4S)-4-azido-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid [Chem. 111]

(2S,4S)-4-azidopiperidine-1,2-dicarboxylic acid 1-(tert-butyl ) 2-methyl ester (5.3 g, 19 mmol) was dissolved in methanol (220 mL), added 1 M-sodium hydroxide aqueous solution (190 mL), and stirred at 40°C for 1 hour. 1 M-hydrochloric acid was added to the reaction mixture, neutralized, extracted with ethyl acetate, washed with saturated brine, dried with sodium sulfate, and the solvent was distilled off to obtain (2S,4S)-4-Azide The crude reaction mixture of 1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid. LCMS (LC-1); RT=0.89, m/z 269 [MH] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 5.07 (1H, brs), 4.92 (1H, brs), 4.24 - 3.97 (1H , m), 3.49 - 3.36 (1H, m), 3.18 - 2.92 (1H, m), 2.58 - 2.41 (1H, m), 2.01 - 1.88 (1H, m), 1.54 - 1.41 (9H, s).

Intermediate G-1-1: 2-(4-((1s,5s)-9-borabicyclo[3.3.1]non-9-yl)butyl)isoindoline-1,3-dione[ 112]

Dissolve 2-(but-3-en-1-yl)isoindoline-1,3-dione (2 g, 10 mmol) in 0.5 M 9-borabicyclo[3.3.1] under ice-bath cooling Nonane tetrahydrofuran solution (20 mL), stirred at the same temperature for 1.5 hours. The solvent of the reaction mixture was distilled off to obtain 2-(4-((1s,5s)-9-boronbicyclo[3.3.1]non-9-yl)butyl)isoindoline-1,3 - Crude reaction mixture of diketones.

Intermediate G-1-2: 2-(4-(6-(benzyloxy)-3-bromoquinolin-5-yl)butyl)isoindoline-1,3-dione [Chem. 113]

6-(Benzyloxy)-3-bromo-5-iodoquinoline (Intermediate D-1-8; 1.8 g, 4.1 mmol) was dissolved in 1,4-dioxane (8.2 mL), water (820 μL), add 2-(4-((1s,5s)-9-borabicyclo[3.3.1]non-9-yl)butyl)isoindoline-1,3-dione (intermediate G -1-1; 1.3 g, 4.1 mmol), 1,1'-bis(diphenylphosphino)ferrocene] palladium (Ⅱ) (600 mg, 820 μmol), potassium carbonate (1.7 g, 12 mmol), Heat and stir at 100°C for 14 hours. After the insoluble matter of the reaction mixture solution was removed by filtration through celite, the solvent was distilled off, and purified by automatic silica gel column chromatography (eluent; hexane:ethyl acetate=50:50) to obtain 2-(4-(6-(Benzyloxy)-3-bromoquinolin-5-yl)butyl)isoindoline-1,3-dione (340 mg, 16% yield). LCMS (LC-1); RT=2.29, m/z 440 [M+H] ^＋

Intermediate G-1-3: 4-(6-(benzyloxy)-3-bromoquinolin-5-yl)butane-1-amine [Chem. 114]

Make 2-(4-(6-(benzyloxy)-3-bromoquinolin-5-yl)butyl)isoindoline-1,3-dione (intermediate G-1-2; 553 mg , 1.07 mmol) was dissolved in ethanol (11 mL), hydrazine hydrate (105 μL, 2.15 mmol) was added, and heated and stirred at 85°C for 9 hours. The obtained crude reaction mixture was concentrated, and the insoluble matter was removed by filtration, and then the solvent was distilled off, and automatic silica gel column chromatography was used (eluent; hexane:ethyl acetate=50:50→chloroform: Methanol (90:10) was purified to obtain 4-(6-(benzyloxy)-3-bromoquinolin-5-yl)butane-1-amine (264 mg, yield 64%). LCMS (LC-1); RT=1.30, m/z 385 [M+H] ^＋

Intermediate G-1-4: (2S,4S)-4-azido-2-((4-(6-(benzyloxy)-3-bromoquinolin-5-yl)butyl)aminomethyl Acyl)piperidine-1-carboxylic acid tert-butyl ester [Chem. 115]

4-(6-(Benzyloxy)-3-bromoquinolin-5-yl)butan-1-amine (Intermediate G-1-3; 214 mg, 0.55 mmol) was dissolved in dimethylformamide Amine (2.8 mL), add N-methyl phospholine (150 μL, 1.39 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (638 mg , 3.33 mmol), 1-hydroxybenzotriazole (223 mg, 1.66 mmol), (2S,4S)-4-azido-1-(tertiary butoxycarbonyl)piperidine-2-carboxylic acid ( Intermediate G-1-3'; 150 mg, 0.55 mmol), stirred at room temperature for 14 hours. Water was added to the reaction mixture, extracted with chloroform, the solvent was distilled off, and purified by automatic silica gel column chromatography (eluent; chloroform:methanol=90:10) to obtain (2S,4R)-2 -((3-((6-(Benzyloxy)-3-hydroxyquinolin-5-yl)oxy)propyl)aminoformyl)-4-hydroxypiperidine-1-carboxylic acid tributyl Ester (220 mg, 62% yield). LCMS (LC-1); RT=2.23, m/z 637 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 8.85 - 8.72 (1H, m), 8.48 - 8.36 (1H, m) , 7.98 - 7.89 (1H, m), 7.60 - 7.30 (6H, m), 6.37 - 6.11 (1H, m), 5.34 - 5.20 (2H, m), 4.88 - 4.72 (1H, m), 4.05 - 3.90 ( 1H, m), 3.90 - 3.70 (1H, m), 3.38 - 3.00 (3H, m), 2.87 - 2.39 (3H, m), 1.91 - 1.76 (1H, m), 1.60 (1H, m), 1.51 - 1.40 (9H, m).

Intermediate G-1-5: (2S,4S)-4-amino-2-((4-(6-(benzyloxy)-3-bromoquinolin-5-yl)butyl)aminoformyl Base) tert-butyl piperidine-1-carboxylate [Chem. 116]

Make (2S,4R)-2-((3-((6-(benzyloxy)-3-hydroxyquinolin-5-yl)oxy)propyl)carbamoyl)-4-hydroxypiperidine tert-butyl-1-carboxylate (intermediate G-1-4; 190 mg, 298 μmol) was dissolved in tetrahydrofuran (1.2 mL), added triphenylphosphine (86 mg, 0.33 mmol), at 50°C Heat and stir for 5.5 hours. Add water to the obtained crude reaction mixture, use ethyl acetate to extract, use saturated brine to wash, use sodium sulfate to dry, remove the solvent by distillation, use automatic silica gel column chromatography (eluent; chloroform:methanol =95:5) was purified, whereby (2S,4S)-4-amino-2-((4-(6-(benzyloxy)-3-bromoquinolin-5-yl)butyl) was obtained Carbamoyl)piperidine-1-carboxylic acid tert-butyl ester (134 mg, yield 74%). LCMS (LC-1); RT=1.62, m/z 611 [M+H] ^＋

Intermediate G-1-6: (3 ² S,3 ⁴ S)-1 ⁶ -(Benzyloxy)-4-oxo-2,5-diaza-1(3,5)-quinoline- 3(4,2)-Piperidinecyclononazone-3 ¹ -tert-butyl carboxylate[Chem. 117]

Make (2S,4S)-4-amino-2-((4-(6-(benzyloxy)-3-bromoquinolin-5-yl)butyl)aminoformyl)piperidine-1- Tert-butyl carboxylate (intermediate G-1-5; 27 mg, 44 μmol) was dissolved in toluene (1.5 mL), and methanesulfonic acid [(2-di-tert-butylphosphine-3,6- Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (1.9 mg, 2.2 μmol), phosphazene base P ₂ -Et (29 μL, 88 μmol) and stirred at room temperature. The reaction mixture solution was purified by automatic silica gel column chromatography (eluent; chloroform:methanol=90:10) to obtain (3 ² S,3 ⁴ S)-1 ⁶ -(benzyloxy)-4 -Oxo-2,5-diaza-1(3,5)-quinoline-3(4,2)-piperidinecyclonona-3 ¹ -carboxylic acid tert-butyl ester (9 mg, yield 39%). LCMS (LC-1); RT=1.72, m/z 531 [M+H] ^＋

[Chem. 118] Method G-2

Intermediate G-2-1: (3 ² S,3 ⁴ S)-1 ⁶ -hydroxy-4-oxo-2,5-diaza-1(3,5)-quinoline-3(4, 2)-tert-butyl piperidine cyclonona-3 ¹ -carboxylate [Chem. 119]

Make (3 ² S,3 ⁴ S)-1 ⁶ -(benzyloxy)-4-oxo-2,5-diaza-1(3,5)-quinoline-3(4,2)- tert-butyl piperidinecyclonona-3 ¹ -carboxylate (intermediate G-1-6; 100 mg, 0.19 mmol) was dissolved in methanol (2.7 mL), ethyl acetate (4 mL), toluene (2.6 mL ), under a nitrogen atmosphere, palladium hydroxide (25 mg) was added, artificially replaced by hydrogen, and fully stirred at room temperature for 14 hours. After the insoluble matter in the reaction mixture was removed by filtration, the solvent was distilled off to obtain (3 ² S,3 ⁴ S)-1 ⁶ -hydroxyl-4-oxo-2,5-diazepine-1( tertiary butyl 3,5)-quinoline-3(4,2)-piperidinecyclononazone-3 ¹ -carboxylate (70 mg, 84% yield). LCMS (LC-1); RT=1.21, m/z 441 [M+H] ^＋

Intermediate G-2-2: (3 ² S,3 ⁴ S)-1 ⁶ -(((trifluoromethyl)sulfonyl)oxy)-4-oxo-2,5-diazepine- 1(3,5)-quinoline-3(4,2)-piperidinecyclonona-3 ¹ -tert-butyl carboxylate[Chem. 120]

Make (3 ² S,3 ⁴ S)-1 ⁶ -hydroxyl-4-oxo-2,5-diaza-1(3,5)-quinoline-3(4,2)-piperidinylcyclonone tertiary butyl fen-3 ¹ -carboxylate (intermediate G-2-1; 70 mg, 159 μmol) was dissolved in 1,4-dioxane (1.6 mL), and N,N-bis(trifluoro Methylsulfonyl)aniline) (181 mg, 0.51 mmol), diisopropylethylamine (170 μL, 0.95 mmol), dimethylformamide (6 drops), stirred at room temperature for 3 hours. The reaction mixture was concentrated and purified by automatic silica gel column chromatography (eluate; chloroform:methanol=90:10) to obtain (3 ² S,3 ⁴ S)-1 ⁶ -(((three Fluoromethyl)sulfonyl)oxy)-4-oxo-2,5-diaza-1(3,5)-quinoline-3(4,2)-piperidinecyclononazone-3 ¹ - Tertiary butyl carboxylate (88 mg, 97% yield). LCMS (LC-1); RT=1.76, m/z 573 [M+H] ^＋

Intermediate G-2-3: (3 ² S,3 ⁴ S)-1 ⁶ -(2-(propoxymethyl)pyrimidin-5-yl)-2,5-diaza-1(3, 5)-Tertiary butyl quinoline-3(4,2)-piperidinecyclononazone-3 ¹ -carboxylate[Chem. 121]

Make (3 ² S,3 ⁴ S)-1 ⁶ -(((trifluoromethyl)sulfonyl)oxy)-4-oxo-2,5-diazepine-1(3,5)- Quinoline-3(4,2)-piperidinecyclononafin-3 ¹ -carboxylate tert-butyl ester (intermediate G-2-2; 44 mg, 76 μmol) was dissolved in 1,4-dioxane ( 300 μL), water (30 μL), add (2-(propoxymethyl)pyrimidin-5-yl)boronic acid (175 mg, 0.19 mmol), [1,1'-bis(diphenylphosphine) Ferrocene]palladium (II) (32 mg, 38 μmol), cesium carbonate (150 mg, 0.46 mmol) and microwave irradiation at 100°C for 3 hours. After the insoluble matter in the reaction mixture solution was removed by filtration through celite, the solvent was distilled off, and purified by automatic silica gel column chromatography (lyotrope; chloroform:methanol=90:10) to obtain (3 ² S,3 ⁴ S)-1 ⁶ -(2-(propoxymethyl)pyrimidin-5-yl)-2,5-diaza-1(3,5)-quinoline-3(4,2 )-tert-butyl piperidinecyclonona-3 ¹ -carboxylate (44 mg, yield 99%). LCMS (LC-1); RT=1.46, m/z 575 [M+H] ^＋

Intermediate G-2-4: (3 ² S,3 ⁴ S)-1 ⁶ -(2-(propoxymethyl)pyrimidin-5-yl)-2,5-diaza-1(3, 5)-Quinoline-3(4,2)-piperidincyclononafin-4-one[Chem. 122]

Make (3 ² S,3 ⁴ S)-1 ⁶ -(2-(propoxymethyl)pyrimidin-5-yl)-2,5-diaza-1(3,5)-quinoline-3 (4,2)-Piperidinecyclononafin-31-carboxylic acid tert-butyl ester (intermediate G-2-3; 22.8 mg, 39 μmol) was dissolved in dichloromethane (400 μL), and trifluoroacetic acid was added (100 μL), stirred at room temperature for 20 minutes. The reaction mixture was treated with SCX to obtain (3 ² S,3 ⁴ S)-1 ⁶ -(2-(propoxymethyl)pyrimidin-5-yl)-2,5-diazepine- 1(3,5)-quinoline-3(4,2)-piperidincyclononofen-4-one (19 mg, 46% yield). LCMS (LC-1); RT=1.01, m/z 475 [M+H] ^＋

Example a-02-24 (final body G-2-5): (3 ² S,3 ⁴ S)-3 ¹ -methyl-1 ⁶ -(2-(propoxymethyl)pyrimidine-5- Base)-2,5-diaza-1(3,5)-quinoline-3(4,2)-piperidincyclononafin-4-one[Chemical 123]

Make (3 ² S,3 ⁴ S)-1 ⁶ -(2-(propoxymethyl)pyrimidin-5-yl)-2,5-diaza-1(3,5)-quinoline-3 (4,2)-Piperidincyclononafone-4-one (intermediate G-2-4; 19 mg, 39 μmol) was dissolved in dichloromethane (290 μL), methanol (290 μL), and 37% Aqueous formaldehyde (10 μL, 0.26 mmol) and triacetyloxyboron hydride (27.7 mg, 130 μmol) were stirred at room temperature for 35 minutes. The reaction mixture was treated with SCX and purified by HPLC to obtain (3 ² S,3 ⁴ S)-3 ¹ -methyl- ^{1 6} -(2-(propoxymethyl)pyrimidine-5 -yl)-2,5-diaza-1(3,5)-quinoline-3(4,2)-piperidincyclononofen-4-one (17.2 mg, 90% yield). LCMS (LC-1); RT=1.09, m/z 489 [M+H] ⁺ 1H-NMR (CD3OD): δ (ppm) 8.82 (2H, s), 8.43 (1H, d, J = 2.5 Hz) , 7.82 - 7.74 (1H, m, J = 8.5 Hz), 7.28 - 7.24 (1H, m), 7.05 (1H, d, J = 2.5 Hz), 4.79 (2H, s), 3.88 - 3.77 (2H, m ), 3.68 - 3.55 (4H, m), 3.12 - 3.02 (1H, m), 2.93 - 2.79 (2H, m), 2.57 (3H, s), 2.53 - 2.43 (1H, m), 2.07 - 2.01 (2H , m), 1.91 - 1.81 (1H, m), 1.78 - 1.66 (4H, m), 1.63 - 1.42 (2H, m), 0.99 (3H, t, J = 7.5 Hz).

[Chem. 124] Method H-1

Intermediate H-1-2: (S,E)-4-oxo-2-(tritylamino)hept-5-enoic acid methyl ester [Chem. 125]

(S)-5-(dimethoxyphosphininyl)-4-oxo-2-(trityl) prepared according to literature (J. Org. Chem., 2012, 77, 10001-10009) Amino)methyl valerate (17 g, 35.3 mmol) was dissolved in acetonitrile (200 mL), potassium carbonate (5.1 g, 37 mmol), acetaldehyde (5.92 mL, 106 mmol) were added and stirred at 40°C 48 hours. Cool the reaction mixture to room temperature, remove the solvent by distillation, add ethyl acetate, wash the organic layer with water and saturated brine, dry with magnesium sulfate, remove the solvent by distillation, and use automatic silica gel column chromatography (Eluent; Hexane:Ethyl acetate=75:25) for purification to obtain (S,E)-4-oxo-2-(tritylamino)hept-5-enoic acid methyl ester (11.5 g, 48% yield). 1H-NMR (CDCl ₃ ): δ (ppm) 7.55 - 7.41 (6H, m), 7.30 - 7.15 (9H, m), 6.80 - 6.72 (1H, m), 6.11 - 6.03 (1H, m), 3.79 - 3.63 (1H, m), 3.27 (3H, s), 2.90 - 2.72 (2H, m), 2.72 - 2.59 (1H, m), 1.89 (3H, dd, J = 7.0, 2.0 Hz).

Intermediate H-1-3: (S,E)-2-Amino-4-oxohept-5-enoic acid methyl ester trifluoroacetate [Chem. 126]

(S,E)-4-Oxo-2-(tritylamino)hept-5-enoic acid methyl ester (intermediate H-1-2; 11.5 g, 27.8 mmol) was dissolved in dichloromethane (92 mL), trifluoroacetic acid (92 mL) was added, and stirred at room temperature for 1 hour. The reaction mixture was concentrated, dissolved in water, washed with diethyl ether, and the solvent was distilled off to obtain (S,E)-2-amino-4-oxohept-5-enoic acid methyl ester trifluoroacetic acid Salt (8.49 g, 99% yield). 1H-NMR (DMSOd ₆ ): δ (ppm) 8.34 (3H, brs), 6.96 (1H, q, J = 7.0 Hz), 7.00 (1H, q, J = 7.0 Hz), 6.19 (1H, m), 4.37 (2H, m), 3.71 (3H, s), 3.31 - 3.17 (2H, m), 1.95 - 1.87 (3H, m).

Intermediate H-1-4: (2S)-1-Benzyl-6-methyl-4-oxopiperidine-2-carboxylic acid methyl ester [Chem. 127]

(S,E)-2-Amino-4-oxohept-5-enoic acid methyl ester trifluoroacetate (Intermediate H-1-3; 7.92 g, 27.8 mmol) was dissolved in THF (100 mL) Add molecular sieve 4A (8 g), triethylamine (3.87 mL, 27.8 mmol), benzaldehyde (2.83 mL, 27.8 mmol), and stir at room temperature for 30 minutes. After the insoluble matter in the reaction mixture was removed by filtration, the solvent was distilled off, dissolved in methanol (100 mL), added with sodium cyanoborohydride (27.8 mL, 27.8 mmol) and stirred at room temperature for 14 hours . Add saturated aqueous sodium bicarbonate solution to the reaction mixture, extract with dichloromethane, wash with saturated aqueous sodium bicarbonate and saturated brine, dry with magnesium sulfate, distill off the solvent, and use an automatic silica gel tube column layer Analysis method (eluent; hexane: ethyl acetate = 75:15) for purification, thereby obtaining (2S)-1-benzyl-6-methyl-4-oxopiperidine-2-carboxylic acid methyl ester (2.28 g, 31% yield). LCMS (LC-1); RT=1.54, m/z 262 [M+H] ^＋

Intermediate H-1-5: Methyl (2S)-6-methyl-4-oxopiperidine-2-carboxylate [Chem. 128]

Dissolve methyl (2S)-1-benzyl-6-methyl-4-oxopiperidine-2-carboxylate (Intermediate H-1-4; 100 mg, 0.38 mmol) in methanol (2.5 mL) , under a nitrogen atmosphere, palladium hydroxide (18 mg) was added, artificially replaced with hydrogen, and fully stirred at room temperature for 14 hours. After the insoluble matter in the reaction mixture was removed by filtration, the solvent was distilled off to obtain a crude product (64 mg, Yield 97%). 1H-NMR (DMSOd ₆ ): δ (ppm) 4.07 - 4.04 (1H, m), 3.78 (1.5H, s), 3.74 (1.5H, s), 3.27 - 3.23 (1H, m), 3.03 - 2.97 ( 1H, m), 2.73 - 2.59 (3H, m), 2.44 - 2.37 (3H, m), 2.17 - 2.07 (3H, m), 1.27 (1.5H, d, J = 6.0 Hz), 1.18 (1.5H, d, J = 6.0 Hz).

Intermediate H-1-6: Methyl (2S)-1,6-methyl-4-oxopiperidine-2-carboxylate [Chem. 129]

Dissolve methyl (2S)-6-methyl-4-oxopiperidine-2-carboxylate (Intermediate H-1-5; 1.54 g, 9.0 mol) in dichloromethane (70 mL) and add 37% aqueous formaldehyde solution (7 mL, 86 mmol), triacetyloxyboron hydride (2.28 g, 10.8 mmol), and stirred at room temperature for 1 hour. The reaction mixture was treated with SCX to obtain a crude product (1.48 g, yield 89%) containing methyl (2S)-1,6-methyl-4-oxopiperidine-2-carboxylate. LCMS (LC-1); RT=0.72, m/z 186 [M+H] ^＋

Intermediate H-1-7: Methyl (2S)-4-(benzylamino)-1,6-dimethylpiperidine-2-carboxylate [Chem. 130]

Dissolve (2S)-1,6-methyl-4-oxopiperidine-2-carboxylate (Intermediate H-1-6; 1.48 g, 7.99 mol) in methanol (19 mL) and add benzyl amine (4.4 mL, 40 mmol), titanium tetraisopropoxide (9.5 mL, 40 mmol), and stirred at room temperature for 14 hours. Sodium borohydride (1.04 g, 27.6 mmol) was added to the reaction mixture under cooling in an ice bath, and stirred at the same temperature for 1.5 hours. 25% ammonia water was added to the reaction mixture, and after stirring for 14 hours, the insoluble matter was removed by filtration with diatomaceous earth. After distilling off the solvent of the obtained organic layer, dilute with saturated brine, extract with chloroform-methanol (90:10), dry with magnesium sulfate, and evaporate the solvent to obtain (2S)-4-( The crude product of methyl benzylamino)-1,6-dimethylpiperidine-2-carboxylate (9.91 g, yield 99%).

Intermediate H-1-8: methyl (2S)-4-amino-1,6-dimethylpiperidine-2-carboxylate [Chem. 131]

Dissolve methyl (2S)-4-(benzylamino)-1,6-dimethylpiperidine-2-carboxylate (intermediate H-1-7; 2.21 g, 8.0 mmol) in methanol (50 mL), under a nitrogen atmosphere, add palladium hydroxide (2.21 g, 15.7 mmol), manually replace with hydrogen, and stir well at room temperature for 14 hours. After the insoluble matter of the reaction mixture was removed by filtration, the solvent was distilled off to obtain a crude product containing (2S)-4-amino-1,6-dimethylpiperidine-2-carboxylic acid methyl ester ( 2.52 g, yield 99%). LCMS (LC-1); RT=0.76, m/z 186 [M+H] ^＋

Intermediate H-1-9: methyl (2S)-4-((tert-butoxycarbonyl)amino)-1,6-dimethylpiperidine-2-carboxylate [Chem. 132]

Dissolve methyl (2S)-4-amino-1,6-dimethylpiperidine-2-carboxylate (Intermediate H-1-8; 1.4 g, 7.52 mmol) in dichloromethane (38 mL) In , di-tert-butyl dicarbonate (2.59 mL, 11.3 mmol) and triethylamine (2.1 mL, 15 mmol) were added, and stirred at room temperature for 3 hours. The reaction mixture was concentrated and purified using automatic silica gel column chromatography (eluate; chloroform:methanol:25% ammonia water=200:9:1) to obtain (2S)-4-((3-butyl Oxycarbonyl)amino)-1,6-dimethylpiperidine-2-carboxylic acid methyl ester (1.61 g, 75% yield). LCMS (LC-1); RT=1.23, m/z 287 [M+H] ^＋

Intermediate H-1-10: (2S)-4-((tert-butoxycarbonyl)amino)-1,6-dimethylpiperidine-2-carboxylic acid sodium salt [Chem. 133]

Make (2S)-4-((tertiary butoxycarbonyl)amino)-1,6-dimethylpiperidine-2-carboxylic acid methyl ester (intermediate H-1-9; 1.61 g, 11.2 mmol ) was dissolved in methanol (28 mL), 2 M-sodium hydroxide aqueous solution (5.6 mL, 11.3 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated to obtain (2S)-4-((tertiary butoxycarbonyl)amino)-1,6-dimethylpiperidine-2-carboxylic acid sodium salt (1.51 g, yield 99 %). LCMS (LC-1); RT=0.70, m/z 273 [M+H] ^＋

[Chem. 134] Method H-2

Intermediate H-2-2: (E)-2-(4-(6-(Benzyloxy)-3-bromoquinolin-5-yl)but-3-en-1-yl)isoindoline -1,3-Diketone [Chem. 135]

Dissolve 6-(benzyloxy)-3-bromo-5-iodoquinoline (Intermediate D-1-6; 2.0 g, 4.5 mmol) in toluene (50 mL) and add 10% tri-tert-butyl Phosphopentane solution (910 μL, 0.45 mmol), dicyclohexylmethylamine (2.6 g, 13.5 mmol), 2- (But-3-en-1-yl)isoindoline-1,3-dione (1.1 g, 5.5 mmol), tris(dibenzylideneacetone)dipalladium(0) (206 mg, 0.23 mmol) , and heated and stirred at 120° C. for 20 hours. After returning the reaction solution to room temperature, the solvent was concentrated and purified using silica gel column chromatography (eluate; hexane:ethyl acetate=86:14) to obtain (E)-2-(4 -(6-(Benzyloxy)-3-bromoquinolin-5-yl)but-3-en-1-yl)isoindoline-1,3-dione (1.4 g, 61% yield) .

Intermediate H-2-3: (E)-4-(6-(benzyloxy)-3-bromoquinolin-5-yl)but-3-en-1-amine [Chem. 136]

Make (E)-2-(4-(6-(benzyloxy)-3-bromoquinolin-5-yl)but-3-en-1-yl)isoindoline-1,3-dione (Intermediate H-2-2; 1.29 g, 2.51 mmol) was dissolved in ethanol (25 mL), added hydrazine hydrate (1.82 mL, 5.02 mmol), and heated to reflux for 4 hours. The reaction solution was cooled to room temperature, the solvent was distilled off, the residue was dissolved in water (25 mL), extracted with ethyl acetate, the organic layer was concentrated, and silica gel column chromatography (eluent; hexane : ethyl acetate=86:14) to purify, thereby obtaining (E)-4-(6-(benzyloxy)-3-bromoquinolin-5-yl)but-3-en-1-amine ( 680 mg, 39%).

Intermediate H-2-4: ((2S)-2-(((E)-4-(6-(benzyloxy)-3-bromoquinolin-5-yl)but-3-ene-1- Base) carbamoyl)-1,6-dimethylpiperidin-4-yl) tert-butyl carbamate [Chem. 137]

(E)-4-(6-(Benzyloxy)-3-bromoquinolin-5-yl)but-3-en-1-amine (Intermediate H-2-3; 193 mg, 0.50 mmol) Dissolve in dimethylformamide (5 mL), add 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (193 mg, 1.01 mmol), 1- Hydroxybenzotriazole (154 mg, 1.01 mmol), (2S)-4-((tert-butoxycarbonyl)amino)-1,6-dimethylpiperidine-2-carboxylic acid sodium salt (intermediate Substance H-1-10; 274 mg, 1.01 mmol), heated and stirred at 50°C for 14 hours. The reaction mixture was concentrated and purified using automatic silica gel column chromatography (eluent; hexane:ethyl acetate=50:50), thereby obtaining ((2S)-2-(((E)-4 -(6-(Benzyloxy)-3-bromoquinolin-5-yl)but-3-en-1-yl)aminoformyl)-1,6-dimethylpiperidin-4-yl) Tertiary butyl carbamate (353 mg, 99% yield). LCMS (LC-1); RT=1.95, m/z 638 [M+H] ^＋

Intermediate H-2-5: (2S)-4-amino-N-((E)-4-(6-(benzyloxy)-3-bromoquinolin-5-yl)but-3-ene -1-yl)-1,6-dimethylpiperidine-2-formamide [Chem. 138]

Make ((2S)-2-(((E)-4-(6-(benzyloxy)-3-bromoquinolin-5-yl)but-3-en-1-yl)carbamoyl) tert-butyl-1,6-dimethylpiperidin-4-yl)carbamate (intermediate H-2-4; 242 mg, 0.38 mmol) was dissolved in dichloromethane (3.8 mL), and tris Fluoroacetic acid (290 μL, 3.8 mmol), stirred at room temperature for 2 hours. The reaction solution was concentrated, neutralized with 25% ammonia water, extracted with chloroform, dried with magnesium sulfate, and the solvent was distilled off to obtain (2S)-4-amino-N-((E)-4- (6-(Benzyloxy)-3-bromoquinolin-5-yl)but-3-en-1-yl)-1,6-dimethylpiperidine-2-carboxamide (203 mg, yield rate 99%). LCMS (LC-1); RT=1.42, m/z 538 [M+H] ^＋

Intermediate H-2-6: (3 ² S,E)-1 ⁶ -(Benzyloxy)-3 ¹ ,3 ⁶ -Dimethyl-2,5-diaza-1(3,5)- Quinoline-3(4,2)-piperidinecyclononofen-8-en-4-one[Chem. 139]

Make (2S)-4-amino-N-((E)-4-(6-(benzyloxy)-3-bromoquinolin-5-yl)but-3-en-1-yl)-1 ,6-Dimethylpiperidine-2-carboxamide (Intermediate H-2-5; 210 mg, 0.38 mmol) was dissolved in 1,4-dioxane (3.9 mL), tris(dibenzylidene Dipalladium(0) (36 mg, 40 μmol), 2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl (36 mg, 80 μmol ), sodium phenoxide (90 mg, 0.78 mmol), and heated to reflux for 14 hours. After cooling the reaction mixture solution to room temperature, the solvent was distilled off, and purified using automatic silica gel column chromatography (eluate; chloroform:methanol=9:1), thereby obtaining (32S,E)-16-( Benzyloxy)-31,36-dimethyl-2,5-diaza-1(3,5)-quinoline-3(4,2)-piperidinecyclononacene-8-ene-4- Ketone (133 mg, 75% yield). LCMS (LC-1); RT=1.49, m/z 457 [M+H] ^＋

[Chem. 140] Method H-3

Intermediate H-3-1: (3 ² S,E)-1 ⁶ -Hydroxy-3 ¹ ,3 ⁶ -Dimethyl-2,5-diaza-1(3,5)-quinoline-3 (4,2)-Piperidinecyclononafone-8-en-4-one[Chem. 141]

Make (3 ² S, E)-1 ⁶ -(benzyloxy)-3 ¹ ,3 ⁶ -dimethyl-2,5-diaza-1(3,5)-quinoline-3(4, 2)-Piperidincyclononofen-8-en-4-one (intermediate H-2-6; 131 mg, 0.29 mmol) was dissolved in methanol (2.8 mL), and palladium on carbon (24 mg ), artificially replaced with hydrogen, and fully stirred at room temperature for 14 hours. After the insoluble matter in the reaction mixture was removed by filtration, the solvent was distilled off to obtain a compound containing (3 ² S,E)-1 ⁶ -hydroxyl-3 ¹ ,3 ⁶ -dimethyl-2,5-diazepine The crude product of hetero-1(3,5)-quinoline-3(4,2)-piperidincyclononofen-8-en-4-one (105 mg, 99% yield). LCMS (LC-1); RT=0.86, m/z 367 [M+H] ^＋

Intermediate H-3-2: Trifluoromethanesulfonic acid (3 ² S,E)-3 ¹ ,3 ⁶ -dimethyl-4-oxo-2,5-diaza-1(3,5) -Quinoline-3(4,2)-piperidinecyclononofen-8-en-1 ⁶ -yl ester[Chem. 142]

Make (3 ² S, E)-1 ⁶ -hydroxyl-3 ¹ ,3 ⁶ -dimethyl-2,5-diaza-1(3,5)-quinoline-3(4,2)-piper Pyridinecyclononof-8-en-4-one (intermediate H-3-1; 105 mg, 0.29 mmol) was dissolved in 1,4-dioxane (2.9 mL), and N,N-bis(tris Fluoromethylsulfonyl)aniline) (136 mg, 0.57 mmol), diisopropylethylamine (80 μL, 0.57 mmol), stirred at 70°C for 14 hours. The reaction mixture was concentrated to obtain trifluoromethanesulfonic acid (3 ² S, E)-3 ¹ ,3 ⁶ -dimethyl-4-oxo-2,5-diaza-1(3, The crude product of 5)-quinoline-3(4,2)-piperidincyclononofen-8-en-1 ⁶ -yl ester (143 mg, yield 99%). LCMS (LC-1); RT=1.61, m/z 499 [M+H] ^＋

Example a-02-17 (final body H-3-3): (3 ² S,E)-3 ¹ ,3 ⁶ -dimethyl-1 ⁶ -(2-methylpyrimidin-5-yl)- 2,5-Diaza-1(3,5)-quinoline-3(4,2)-piperidinecyclononofen-8-en-4-one[Chem. 143]

Make trifluoromethanesulfonic acid (3 ² S, E)-3 ¹ ,3 ⁶ -dimethyl-4-oxo-2,5-diaza-1(3,5)-quinoline-3(4 ,2)-Piperidincyclononofen-8-en- ^{1 6} -yl ester (Intermediate H-3-2; 120 mg, 0.24 mmol) was dissolved in 1,4-dioxane (2.4 mL), water ( 240 μL), add 2-methylpyrimidine-5-boronic acid pinacol ester (105 mg, 0.48 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium (Ⅱ) (17 mg, 20 μmol), cesium carbonate (156 mg, 0.48 mmol), microwave irradiation at 100°C for 3 hours. After the insoluble matter in the reaction mixture solution was removed by filtration through celite, the solvent was distilled off and purified by HPLC to obtain (3 ² S,E)-3 ¹ ,3 ⁶ -dimethyl-1 ⁶ - (2-Methylpyrimidin-5-yl)-2,5-diaza-1(3,5)-quinoline-3(4,2)-piperidincyclononofen-8-en-4-one (1.1 mg, yield 1%). LCMS (LC-1); RT=0.99, m/z 443 [M+H] ^＋ 1H-NMR (CD3OD): δ (ppm) 8.78 - 8.72 (2H, m), 8.57 - 8.54 (1H, m), 8.44 - 8.39 (1H, m), 7.88 - 7.83 (1H, m), 7.51 - 7.47 (1H, m), 7.38 - 7.33 (1H, m), 6.45 - 6.41 (1H, m), 6.40 - 6.36 (1H , m), 6.20 - 6.10 (2H, m), 3.93 - 3.85 (2H, m), 3.68 - 3.62 (2H, m), 3.52 - 3.44 (2H, m), 3.19 - 3.09 (2H, m), 2.76 (3H, s), 2.72 - 2.63 (2H, m), 2.54 (3H, s), 2.05 - 1.95 (2H, m), 1.62 - 1.41 (4H, m), 1.33 - 1.27 (2H, m), 1.17 (3H, d, J = 6.5 Hz).

[Chem. 144] Method I-1

Intermediate I-1-2: Methyl 1,2-dimethyl-4-oxopiperidine-2-carboxylate [Chem. 145]

1,2-dimethyl-4-oxo-1,2,3,4-tetrahydropyridine-2-carboxylic acid methyl ester ( 1.3 g, 7.3 mmol) was dissolved in tetrahydrofuran (8 mL), under nitrogen atmosphere, L-Selectride® (190 mL) was added at -78°C and stirred at the same temperature for 2 hours. Add methanol to the reaction mixture, quench the reaction, warm to room temperature, then concentrate the reaction mixture, and process it with an SCX box to obtain 1,2-dimethyl-4-oxopiperidine - Methyl 2-carboxylate reaction mixture. LCMS (LC-1); RT=0.94, m/z 186 [M+H] ⁺ .

Intermediate I-1-3: methyl 4-(benzylamino)-1,2-dimethylpiperidine-2-carboxylate [Chem. 146]

Dissolve methyl 1,2-dimethyl-4-oxopiperidine-2-carboxylate (intermediate I-1-2; 1.0 g, 5.47 mol) in methanol (13 mL) and add benzylamine (3.0 mL, 27.4 mmol), titanium tetraisopropoxide (6.5 mL, 21.9 mmol), and stirred at room temperature for 14 hours. Sodium borohydride (715 mg, 18.9 mmol) was added to the reaction mixture under cooling in an ice bath, and stirred at the same temperature for 2 hours. 25% aqueous ammonia was added to the reaction mixture, and after stirring for 14 hours, the insoluble matter was removed by filtration through celite. After distilling off the solvent of the obtained organic layer, dilute with saturated brine, extract with chloroform-methanol (90:10), dry with magnesium sulfate, and evaporate the solvent to obtain )- crude product of methyl 1,2-dimethylpiperidine-2-carboxylate (1.51 g, yield 99%).

Intermediate I-1-4: methyl 4-amino-1,2-dimethylpiperidine-2-carboxylate [Chem. 147]

Methyl 4-(benzylamino)-1,2-dimethylpiperidine-2-carboxylate (Intermediate 1-1-5; 1.51 g, 5.47 mmol) was dissolved in methanol (35 mL), Add palladium hydroxide (800 mg, 5.70 mmol) under nitrogen atmosphere, manually replace with hydrogen, and stir well at room temperature for 14 hours. After the insoluble matter in the reaction mixture was removed by filtration, the solvent was distilled off to obtain a crude product (1.02 g, produced rate 99%).

Intermediate I-1-5: methyl 4-((tert-butoxycarbonyl)amino)-1,2-dimethylpiperidine-2-carboxylate [Chem. 148]

4-Amino-1,2-dimethylpiperidine-2-carboxylic acid methyl ester (intermediate I-1-4; 1.02 g, 5.47 mmol) was dissolved in dichloromethane (38 mL) and di Di-tert-butyl carbonate (3.58 mL, 16.4 mmol), triethylamine (7.63 mL, 54.7 mmol) and stirred at room temperature for 3 hours. The reaction mixture was concentrated and purified using automatic silica gel column chromatography (eluate; hexane:ethyl acetate=20:80) to obtain 4-((tert-butoxycarbonyl)amino) - Methyl 1,2-dimethylpiperidine-2-carboxylate (205 mg, yield 13%). LCMS (LC-1); RT=1.26, m/z 287 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 4.53 - 4.32 (1H, m), 3.78 - 3.68 (3H, m) , 2.90 - 2.76 (1H, m), 2.64 - 2.45 (1H, m), 2.25 - 2.15 (2H, m), 1.98 - 1.84 (2H, m), 1.80 - 1.68 (1H, m), 1.43 (7H, s), 1.29 (2H, s).

Intermediate I-1-6: 4-((tert-butoxycarbonyl)amino)-1,2-dimethylpiperidine-2-carboxylic acid sodium salt [Chem. 149]

Dissolve methyl 4-((tert-butoxycarbonyl)amino)-1,2-dimethylpiperidine-2-carboxylate (Intermediate I-1-5; 687 mg, 2.40 mmol) in 1 M-sodium hydroxide aqueous solution (10 mL, 10 mmol), stirred at room temperature for 2 hours. The reaction mixture was concentrated to obtain 4-((tert-butoxycarbonyl)amino)-1,2-dimethylpiperidine-2-carboxylic acid sodium salt (853 mg, yield 99%).

[Chem. 150] Method I-2

Intermediate I-2-2: 3-((6-(benzyloxy)-3-bromoquinolin-5-yl)oxy)-2-fluoropropan-1-amine [Chem. 151]

Make (S)-(3-((6-(benzyloxy)-3-bromoquinolin-5-yl)oxy)-2-fluoropropyl)carbamic acid tertiary butyl ester (intermediate I- 2-1; 6.59 g, 13.0 mmol) was dissolved in dichloromethane (40 mL), added trifluoroacetic acid (10 mL), and stirred at room temperature for 3 hours. The reaction mixture was treated with SCX to obtain (S)-3-((6-(benzyloxy)-3-bromoquinolin-5-yl)oxy)-2-fluoropropan-1-amine (2.78 g, 53% yield). LCMS (LC-1); RT=1.38, m/z 405 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 8.84 - 8.76 (1H, m), 8.69 - 8.63 (1H, m) , 7.83 (1H, d, J = 9.3 Hz), 7.53 (1H, d, J = 9.3 Hz), 7.49 - 7.32 (5H, m), 5.32 - 5.18 (2H, m), 4.90 - 4.68 (1H, m ), 4.40 - 4.29 (2H, m), 3.08 - 2.97 (2H, m).

Intermediate I-2-3: (2-((3-((6-(benzyloxy)-3-bromoquinolin-5-yl)oxy-2-fluoropropyl)aminoformyl)- 1,2-Dimethylpiperidin-4-yl) tert-butyl carbamate [Chem. 152]

3-((6-(Benzyloxy)-3-bromoquinolin-5-yl)oxy)-2-fluoropropan-1-amine (Intermediate I-2-2; 1.02 g, 2.52 mmol) Dissolved in dichloromethane (20 mL), added N-methyl phenoline (695 μL, 2.52 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride salt (1.93 g, 10.1 mmol), 1-hydroxybenzotriazole (750 mg, 5.55 mmol), 4-((tert-butoxycarbonyl)amino)-1,2-dimethylpiperidine-2 -Carboxylic acid sodium salt (intermediate I-1-6; 687 mg, 2.52 mmol), stirred at room temperature for 14 hours. Water was added to the reaction mixture, extracted with chloroform, the solvent was distilled off, and purified using automatic silica gel column chromatography (eluate; hexane:ethyl acetate=30:70), thereby obtaining (2-( (3-((6-(Benzyloxy)-3-bromoquinolin-5-yl)oxy-2-fluoropropyl)aminoformyl)-1,2-dimethylpiperidine-4- base) tert-butyl carbamate (765 mg, yield 42%). LCMS (LC-1); RT=2.05, m/z 659 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ ( ppm) 8.77 (1H, d, J = 2.0 Hz), 8.67 - 8.63 (1H, m), 7.81 (1H, d, J = 9.0 Hz), 7.55 - 7.49 (1H, m), 7.49 - 7.35 (5H, m), 5.27 (2H, s), 4.98 (1H, dd, J = 10.0, 7.0 Hz), 4.92 - 4.64 (1H, m), 4.44 - 4.25 (3H, m), 4.12 (1H, dd, J = 7.0, 7.0 Hz), 3.83 - 3.67 (1H, m), 3.63 - 3.41 (2H, m), 2.89 - 2.63 (2H, m), 2.36 (3H, s), 2.34 - 2.22 (1H, m), 1.45 - 1.39 (9H, m), 1.29 - 1.24 (2H, m).

Intermediate I-2-4: 4-amino-N-(3-((6-(benzyloxy)-3-bromoquinolin-5-yl)oxy)-2-fluoropropyl)-1 ,2-Dimethylpiperidine-2-formamide[Chem. 153]

Make (2-((3-((6-(benzyloxy)-3-bromoquinolin-5-yl)oxy-2-fluoropropyl)aminoformyl)-1,2-dimethyl Piperidin-4-yl) tert-butyl carbamate (intermediate I-2-3; 765 mg, 1.16 mmol) was dissolved in dichloromethane (8 mL), added trifluoroacetic acid (2 mL), in Stir at room temperature for 20 minutes.Use SCX to treat the reaction mixture to obtain 4-amino-N-(3-((6-(benzyloxy)-3-bromoquinolin-5-yl)oxy yl)-2-fluoropropyl)-1,2-dimethylpiperidine-2-carboxamide (645 mg, yield 100%). LCMS (LC-1); RT=1.43, m/z 559 [M+H] ⁺

Intermediate I-2-5: 1 ⁶ -(Benzyloxy)-7-fluoro-3 ¹ ,3 ² -dimethyl-9-oxa-2,5-diaza-1(3,5) -Quinoline-3(4,2)-piperidincyclononafin-4-one[Chem. 154]

Make 4-amino-N-(3-((6-(benzyloxy)-3-bromoquinolin-5-yl)oxy)-2-fluoropropyl)-1,2-dimethylpiper Pyridine-2-carboxamide (intermediate I-2-4; 598 mg, 1.07 mmol) was dissolved in 1,4-dioxane (10 mL), and tris(dibenzylideneacetone)dipalladium (0 ) (98 mg, 107 μmol), dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl (102 mg, 214 μmol), sodium phenoxide (248 mg , 2.14 mmol), heated to reflux for 14 hours. After the reaction mixture solution was cooled to room temperature, the solvent was distilled off and purified by automatic silica gel column chromatography (eluate; ethyl acetate:methanol=90:10) to obtain 1 ⁶ -(benzyloxy )-7-fluoro-3 ¹ ,3 ² -dimethyl-9-oxa-2,5-diaza-1(3,5)-quinoline-3(4,2)-piperidinylcyclononyl Fan-4-one (179 mg, 32% yield). LCMS (LC-1); RT=1.39, m/z 479 [M+H] ^＋ 1H-NMR (CDCl ₃ ): δ (ppm) 8.32 (1H, d, J = 2.5 Hz), 8.00 (1H, d , J = 2.5 Hz), 7.67 (1H, d, J = 9.0 Hz), 7.52 - 7.29 (5H, m), 7.17 (1H, d, J = 9.0 Hz), 5.13 - 4.89 (1H, m), 4.27 (1H, dd, J = 11.5, 9.0 Hz), 4.17 - 4.04 (2H, m), 3.97 (1H, d, J = 4.4 Hz), 3.80 - 3.67 (1H, m), 3.54 - 3.26 (1H, m ), 3.18 (1H, d, J = 6.0 Hz), 2.92 (1H, td, J = 12.0, 4.0 Hz), 2.88 - 2.79 (1H, m), 2.69 (2H, s), 1.96 - 1.83 (2H, m), 1.50 (3H, s), 1.47 - 1.37 (1H, m).

[Chem. 155] Method I-3

Intermediate I-3-1: 7-fluoro- ^{1 6} -hydroxy- ^{3 1} ,3 ² -dimethyl-9-oxa-2,5-diaza-1(3,5)-quinoline- 3(4,2)-Piperidinecyclononafone-4-one[Chem. 156]

Make 1 ⁶ -(benzyloxy)-7-fluoro-3 ¹ ,3 ² -dimethyl-9-oxa-2,5-diaza-1(3,5)-quinoline-3(4 ,2)-Piperidincyclononafone-4-one (intermediate I-2-5; 180 mg, 0.38 mmol) was dissolved in methanol (8 mL), and 10% palladium on carbon (90 mg) was added under nitrogen atmosphere , artificially replaced with hydrogen, and fully stirred at room temperature for 14 hours. After the insoluble matter in the reaction mixture was removed by filtration, the solvent was distilled off to obtain 7-fluoro-1 ⁶ -hydroxyl-3 ¹ ,3 ² -dimethyl-9-oxa-2,5-diazepine - 1(3,5)-quinoline-3(4,2)-piperidincyclononofen-4-one (138 mg, 95% yield). LCMS (LC-1); RT=0.83, m/z 389 [M+H] ^＋ 1H-NMR (CD ₃ OD): δ (ppm) (1H, d, J = 3.0 Hz), 7.53 - 7.43 (1H , m), 7.33 - 7.20 (1H, m), 7.18 - 7.07 (1H, m), 7.01 (1H, d, J = 9.0 Hz), 6.89 - 6.85 (1H, m), 5.29 (1H, tdd, J = 9.0, 6.5, 3.0 Hz), 5.23 - 5.14 (1H, m), 5.12 - 4.94 (1H, m), 4.28 (1H, ddd, J = 17.5, 11.0, 7.5 Hz), 4.17 - 3.86 (3H, m ), 3.78 - 3.65 (1H, m), 3.51 - 3.39 (1H, m), 3.35 (3H, s), 3.13 - 3.01 (1H, m), 2.86 (1H, ddd, J = 11.0, 5.0, 2.0 Hz ), 2.62 - 2.56 (3H, m), 2.36 - 2.28 (1H, m), 1.99 (1H, d, J = 12.0 Hz), 1.75 (1H, dq, J = 12.0, 5.0 Hz), 1.46 - 1.41 ( 3H, m), 1.28 - 1.16 (2H, m).

Intermediate I-3-2: 7-fluoro-3 ¹ ,3 ² -dimethyl-9-oxa-2,5-diaza-1(3,5)-quinoline-trifluoromethanesulfonate 3(4,2)-Piperidine cyclononafin-1 ⁶ -yl ester [Chem. 157]

Make 7-fluoro- ^{1 6} -hydroxyl-3 ¹ ,3 ² -dimethyl-9-oxa-2,5-diaza-1(3,5)-quinoline-3(4,2)- Piperidinecyclononafone-4-one (intermediate I-3-1; 138 mg, 0.36 mmol) was dissolved in dichloromethane (4 mL), trifluoromethanesulfonic anhydride (72 μL, 0.43 mmol), pyridine (43 μL, 0.53 mmol), stirred at room temperature for 1 hour. ^The reaction ^mixture was concentrated to obtain the The crude product of phenoline-3(4,2)-piperidincyclononafran-1 ⁶ -yl ester (185 mg, yield 99%).

Example a-02-23 (final body I-3-3): 7-fluoro-3 ¹ ,3 ² -dimethyl-1 ⁶ -(2-methylpyrimidin-5-yl)-9-oxa -2,5-Diaza-1(3,5)-quinoline-3(4,2)-piperidincyclononan-4-one[Chem. 158]

Make trifluoromethanesulfonic acid 7-fluoro-3 ¹ ,3 ² -dimethyl-9-oxa-2,5-diaza-1(3,5)-quinoline-3(4,2)- Piperidine cyclononafin-1 ⁶ -yl ester (intermediate I-3-2; 185 mg, 0.36 mmol) was dissolved in 1,4-dioxane (4 mL), water (800 μL), and 2-methyl Pyrimidine-5-boronic acid pinacol ester (147 mg, 1.07 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(Ⅱ) (116 mg, 142 μmol), cesium carbonate ( 696 mg, 2.14 mmol), heated and stirred at 80°C for 2 hours. After removing the insoluble matter in the reaction mixture solution by filtration through celite, the solvent was distilled off and purified by HPLC to obtain 7-fluoro-3 ¹ ,3 ² -dimethyl-1 ⁶ as a low polar component -(2-Methylpyrimidin-5-yl)-9-oxa-2,5-diaza-1(3,5)-quinoline-3(4,2)-piperidinecyclononazone-4 - Ketone (43.7 mg, 26% yield). LCMS (LC-1); RT=1.03, m/z 465 [M+H] ⁺ 1H-NMR (CD ₃ OD): δ (ppm) 9.05 (2H, s), 8.42 (1H, d, J = 2.5 Hz), 7.77 (1H, d, J = 8.5 Hz), 7.50 (1H, d, J = 8.5 Hz), 7.03 (1H, d, J = 2.5 Hz), 5.25 (1H, d, J = 6.5 Hz) , 5.14 (1H, brs), 4.26 - 4.12 (1H, m), 4.08 (1H, dd, J = 12.0, 2.0 Hz), 3.93 - 3.77 (2H, m), 3.69 (1H, dt, J = 12.0, 3.5 Hz), 3.67 - 3.42 (1H, m), 2.96 - 2.81 (2H, m), 2.77 (3H, s), 2.57 (3H, s), 2.25 (1H, d, J = 13.2 Hz), 2.02 ( 1H, d, J = 12.0 Hz, 1H), 1.77 (1H, dq, J = 12.0, 5.0 Hz), 1.40 (3H, s), 1.34 - 1.20 (m, 1H).

[table 3] example structure Reference method LCMS data a-02-01 Methods H-1, I-2, I-3 (LC-1); RT=1.19, m/z 523 [M+H] ⁺ a-02-02 Method D-2, D-3 (LC-1); RT=1.11, m/z 509 [M+H] ⁺ a-02-03 Method D-3, E-1 (LC-1); RT=0.97, m/z 520 [M+H] ⁺ a-02-04 Method D-3, E-1 (LC-1); RT=1.20, m/z 534 [M+H] ⁺ a-02-05 Method D-3, E-1 (LC-1); RT=1.16, m/z 478 [M+H] ⁺ a-02-06 Method D-2, D-3 (LC-1); RT=1.09, m/z 512 [M+H] ⁺ a-02-07 Methods D-3, E-1, H-1 (LC-1); RT=1.24, m/z 448 [M+H] ⁺ a-02-08 Method D-3, E-1 (LC-1); RT=1.19, m/z 522 [M+H] ⁺ a-02-09 Methods H-1, I-2, I-3 (LC-1); RT=0.98, m/z 465 [M+H] ⁺ a-02-10 Method D-3, E-1 (LC-1); RT=1.40, m/z492 [M+H] ⁺ a-02-11 Method D-3, I-2 (LC-1); RT=0.96, m/z 465 [M+H] ⁺ a-02-12 Method D-3, E-1 (LC-1); RT=0.25, m/z 436 [M+H] ⁺ a-02-13 Method D-3, I-2 (LC-1); RT=1.00, m/z 479 [M+H] ⁺ a-02-14 Method D-2, D-3 (LC-1); RT=1.43, m/z 510 [M+H] ⁺ a-02-15 Method D-3, E-1 (LC-1); RT=0.98, m/z 450 [M+H] ⁺ a-02-16 Method D-2, D-3 (LC-1); RT=0.91, m/z 451 [M+H] ⁺ a-02-17 Methods H-1, H-2, H-3 (LC-1); RT=0.94, m/z 443 [M+H] ⁺ a-02-18 Method D-3, E-1 (LC-1); RT=0.97, m/z 420 [M+H] ⁺ a-02-19 Method D-2, D-3 (LC-1); RT=1.25, m/z 460 [M+H] ⁺ a-02-20 Method D-3, E-1 (LC-1); RT=1.16, m/z 434 [M+H] ⁺ a-02-21 Method D-2, D-3 (LC-1); RT=0.88, m/z433 [M+H] ⁺ a-02-22 Methods G-1, G-2, H-1 (LC-1); RT=0.96, m/z 445 [M+H] ⁺ a-02-23 Methods I-1, I-2, I-3 (LC-1); RT=0.92, m/z 465 [M+H] ⁺ nce Energy Tra-02-24 Method G-1, G-2 (LC-1); RT=1.12, m/z 489 [M+H] ⁺ a-02-25 Methods F-1, F-2 (LC-1); RT=1.06, m/z 492 [M+H] ⁺

<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) to determine the phosphorylation of IRAK-4 peptide substrate (biotin-KKKKRFSFKKSFKC). 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 prepared 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 calculated using the 4 Parameter Logistic Model of the software XLfit (ID Business Solutions Ltd.). In addition, about each operation and conditions in a measurement, it can change suitably within the range which a person in charge can understand and does not have a large influence on a measurement.

(2) Measurement results As shown below, a certain aspect of the compound of the present invention exhibits excellent IRAK-4 inhibitory activity. In addition, when measuring multiple times, the average value is shown.

[Table 4] example IC ₅₀ (nM) example IC ₅₀ (nM) a-01-01 1.63 a-01-21 2.29 a-01-02 0.89 a-01-22 0.89 a-01-03 2.11 a-01-23 1.21 a-01-04 4.24 a-01-24 2.48 a-01-05 1.37 a-01-25 4.43 a-01-06 2.53 a-01-26 1.41 a-01-07 1.49 a-01-27 4.25 a-01-08 1.47 a-01-28 4.04 a-01-09 1.28 a-01-29 4.14 a-01-10 43.44 a-01-30 2.8 a-01-11 0.79 a-01-31 3.42 a-01-12 1.75 a-01-32 1.59 a-01-13 2.95 a-01-33 4.79 a-01-14 1.73 a-01-34 4.19 a-01-15 2.77 a-01-35 2.84 a-01-16 1.25 a-01-36 8.86 a-01-17 3.04 a-01-37 4.52 a-01-18 1.84 a-01-38 6.73 a-01-19 1.6 a-01-39 5.12 a-01-20 1.15 a-01-40 14.78

[table 5] example IC ₅₀ (nM) example IC ₅₀ (nM) a-01-41 10.04 a-02-11 1.02 a-01-42 6.61 a-02-12 0.93 a-01-44 2.36 a-02-13 1.12 a-01-45 3.28 a-02-14 6.46 a-02-01 2.33 a-02-15 2.23 a-02-02 1.09 a-02-16 0.81 a-02-03 2.51 a-02-17 1.76 a-02-04 5.63 a-02-18 1.66 a-02-05 2.47 a-02-19 3.9 a-02-06 2 a-02-20 3.21 a-02-07 2.04 a-02-21 2.2 a-02-08 5.73 a-02-23 9.7 a-02-09 0.86 a-02-24 13.18 a-02-10 2.96

<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, about each operation and conditions in a measurement, it can change suitably within the range which a person in charge can understand and does not have a large influence on a measurement.

(2) Measurement results As shown below, a certain aspect of the compound of the present invention exhibits 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 6] example _IC50 (μM) example _IC50 (μM) a-01-01 0.028 a-01-21 0.117 a-01-02 0.044 a-01-22 0.118 a-01-03 0.045 a-01-23 0.124 a-01-04 0.048 a-01-24 0.140 a-01-05 0.048 a-01-25 0.141 a-01-06 0.050 a-01-26 0.142 a-01-07 0.057 a-01-27 0.145 a-01-08 0.063 a-01-28 0.149 a-01-09 0.064 a-01-29 0.150 a-01-10 0.068 a-01-30 0.162 a-01-11 0.073 a-01-31 0.163 a-01-12 0.075 a-01-32 0.165 a-01-13 0.076 a-01-33 0.170 a-01-14 0.080 a-01-34 0.177 a-01-15 0.081 a-01-35 0.178 a-01-16 0.092 a-01-36 0.182 a-01-17 0.099 a-01-37 0.189 a-01-18 0.104 a-01-38 0.199 a-01-19 0.113 a-01-39 0.204 a-01-20 0.113 a-01-40 0.253

[Table 7] example _IC50 (μM) example _IC50 (μM) a-01-41 0.293 a-02-11 0.045 a-01-42 0.246 a-02-12 0.047 a-01-43 0.237 a-02-13 0.048 a-01-44 0.210 a-02-14 0.058 a-01-45 0.227 a-02-15 0.064 a-02-01 0.012 a-02-16 0.065 a-02-02 0.013 a-02-17 0.066 a-02-03 0.013 a-02-18 0.081 a-02-04 0.023 a-02-19 0.102 a-02-05 0.023 a-02-20 0.117 a-02-06 0.024 a-02-21 0.135 a-02-07 0.033 a-02-22 0.324 a-02-08 0.036 a-02-23 0.716 a-02-09 0.036 a-02-24 0.378 a-02-10 0.043 a-02-25 0.500 [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.

Claims (19)

A compound or a salt thereof, the compound is represented by the following general formula (1): [Chem. 1] [In formula (1), R ¹ 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 ¹² , -S(O ₂ )R ¹² , -C(O)NR ¹¹ R ¹² , -C(O)OR ¹² , or a 3-7 membered saturated ring group, the above R ¹ can be Substituted by 1 to 3 identical or different substituents selected from group ^G1 ; the group ^G1 above is composed of -F, hydroxyl, cyano, halogenated _C1-6 alkyl, _C1-4 alkoxy, A group consisting of phenyl, 5-6 membered heteroaryl, and 3-7 membered saturated ring group, the phenyl ^group or 5-6 membered heteroaryl group in ^G1 group can be selected from 1～ Substituted by 3 identical or different substituents; the above G ^Ar group is composed of -F, -Cl, hydroxyl, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl, and -NH ₂ Group; R ¹¹ 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, or 3-7 membered saturated ring; R ¹² 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, 3-7 membered saturated ring group, phenyl, or 5-6 membered heteroaryl, the phenyl or 5-6 membered heteroaryl in ^R can be selected from 1 to 3 substituents in the above G ^Ar group are substituted by the same or different substituents; R ² is -H, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, C _{1 -6} alkoxy C _1-6 alkyl, or 3-7 membered saturated ring; R ³ is -H, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl , C _1-6 alkoxy C _1-6 alkyl, or 3-7 membered saturated ring; Ar is 6-10 membered aryl or 5-10 membered heteroaryl, the above Ar can be selected from ^G2 group 1 to 3 of them are substituted by the same or different substituents; the above-mentioned ^G2 group consists of -F, -Cl, hydroxyl, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxyl C _{1 -6} alkyl, R ^Ar1 -OC _1-3 alkyl, R ^Ar1 -NR ¹³ -C _1-3 alkyl, -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 , -NH ₂ , -S(O ₂ )NH ₂ , -NR ¹³ R ¹⁴ , and -NHC (O) A group consisting of NHR ¹⁵ ; R ^Ar1 is -H, C _1-6 alkyl, halogenated C _1-6 alkyl, or a 3-7 membered saturated ring group, and the above R ^Ar1 can be selected from G ³ 1 to 3 substituents in the group are substituted by the same or different substituents; the above-mentioned G ³ group consists of -F, hydroxyl, C _1-3 alkyl, halogenated C _1-3 alkyl, pendant oxy, C _1-3 A group consisting of alkoxy, halogenated C _1-3 alkoxy, and 3-7 membered saturated ring; R ¹³ is -H, C _1-3 alkyl, halogenated C _1-3 alkyl, C _1-3 alkoxy C _1-3 alkyl, halogenated C _1-3 alkoxy C _1-3 alkyl, or 3-7 membered saturated ring; R ¹⁴ is C _1-3 alkyl, halogenated C _1-3 alkyl, C _1-3 alkoxy C _1-3 alkyl, halogenated C _1-3 alkoxy C _1-3 alkyl, or 3-7 membered saturated ring group; R ¹⁵ is - H, phenyl, or 5-6 membered heteroaryl, the above R ¹⁵ can be substituted by 1 to 3 identical or different substituents selected from the G ⁴ group; the above G ⁴ group is composed of halogen, cyano, C A group consisting of _1-3 alkyl and halogenated C _1-3 alkyl; X ¹ is N or CH; X ² is NH or O; X ³ is the following general formula (1-1): ] Or the following general formula (1-2): [Chemical 3] Or the following general formula (1-3): [Chemical 4] (a, b represent the bonding orientation); R ²¹ and R ²² are independently -H, C _1-3 alkyl, halogenated C _1-3 alkyl; X ⁴ is the following general formula (2-1) : [Chemical 5] (b, c represent the bonding orientation); in formula (2-1), n is an integer of 1 to 3; Y is NR ⁵¹ , or O; R ³¹ and R ³² are independently -H, C _1-3 Alkyl, halogenated C _1-3 alkyl; or R ³¹ and R ³² can together form a 3-6 membered saturated ring; R ⁴¹ and R ⁴² are independently -H, -F, hydroxyl, C _1-3 alkane Base, halogenated C _1-3 alkyl, C _1-3 alkoxy, halogenated C _1-3 alkoxy; or R ⁴¹ and R ⁴² can together form a 3-6 membered saturated ring; R ⁵¹ is -H , C _1-3 alkyl, halogenated C _1-3 alkyl; or R ⁵¹ and the above R ³¹ can form a 4-6 membered saturated ring together; the above X ⁴ can be selected from 1 to 3 of the G ⁵ group Substituting with the same or different substituents; the above group ^G5 is selected from -F, hydroxyl, C _1-3 alkyl, halogenated C _1-3 alkyl, C _1-3 alkoxy, halogenated C _1-3 Groups consisting of alkoxy groups]. The compound or salt thereof as claimed in claim 1, wherein Ar is a 5-6 membered heteroaryl group. The compound or salt thereof as any one of claims 1 to 2, wherein R ¹ is -H, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, C _{1- 6} alkoxy C _1-6 alkyl, or 3-7 membered saturated ring group, the above R ¹ may be substituted by 1 to 3 identical or different ones selected from G ¹ group (G ¹ group has the same meaning as above) base substitution. The compound or salt thereof according to any one of claims 1 to 3, wherein X ² is NH. The compound or salt thereof as any one of claims 1 to 4, wherein X ³ is the following general formula (1-1): [Chemical 6] (R ²¹ and R ²² have the same meaning as above). The compound or salt thereof as any one of claims 1 to 5, wherein X ³ is the following general formula (1-1-1): [Chemical 7] . The compound or salt thereof according to any one of claims 1 to 6, wherein n is 1 in the general formula (2-1) of X ⁴ . The compound or salt thereof as any one of claims 1 to 7, wherein Ar is the following general formula (3-1): [Chemical 8] ; In formula (3-1), R ^Ar2 is -H, -F, -Cl, hydroxyl, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxyl C _1-6 alkyl, R ^Ar1 -OC _1-3 alkyl, or -NR ¹³ R ¹⁴ (R ^Ar1 , R ¹³ , and R ¹⁴ have the same meanings as above). The compound or salt thereof as any one of claims 1 to 8, wherein Ar is the general formula (3-1); in the formula (3-1), R ^Ar2 is -H, methyl, hydroxymethyl, -CH ₂ -OR ^Ar1 (R ^Ar1 has the same meaning as above). The compound or salt thereof according to any one of claims 1 to 9, wherein R ³ is -H. The compound or salt thereof according to any one of claims 1 to 10, wherein R ² is -H, or methyl. The compound or salt thereof according to any one of claims 1 to 11, wherein R ¹ is -H, or C _1-3 alkyl. A compound or a salt thereof, the compound is represented by the following formula: [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] .