RU2818822C1 - Macrocyclic compound - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: invention relates to a compound represented by general formula (1), or a pharmaceutically acceptable salt thereof, in formula (1) R¹ is -H or C_1-6 alkyl; R² is -H or C_1-6 alkyl; R³ is -H or C_1-6 alkyl; Ar is 6–10-membered aryl or 5–10-membered heteroaryl containing 2 heteroatoms selected from O, S and N, where Ar can be substituted with 1 substituent selected from group G²; group G² is a group of substitutes consisting of C_1-6 alkyl, hydroxy-C_1-6 alkyl, R^Ar1-OC_1-3 alkyl; R^Ar1 is -H, C_1-6 alkyl, or 3–7-membered saturated hydrocarbon ring, R^Ar1 can be substituted with 1–2 identical or different substitutes selected from group G³; group G³ is a group of substitutes consisting of a hydroxyl group and 3–7 membered saturated hydrocarbon ring group; X¹ is N or CH; X² is NH or O; X³ is a group represented by general formula (1-1), general formula (1-2) or formula (1-3) given below, a and b represent the direction of attachment; R²¹ and R²² independently represent -H; X⁴ is a group represented by general formula (2-1), b and c represent the direction of attachment; in formula (2-1), n is integer from 1 to 3; Y is NR⁵¹ or O; R³¹ and R³² independently represent -H, C_1-3 alkyl; R⁴¹ and R⁴² independently represent -H, -F, C_1-3 alkyl; or R⁴¹ and R⁴² can be combined to form 3–6 membered saturated hydrocarbon ring; R⁵¹ is H or C_1-3 alkyl; 1 or R⁵¹ and R³¹ can be combined to form 4–6-membered saturated heterocyclic ring containing one heteroatom selected from N.

EFFECT: novel compound which can be used in medicine for treating IRAK-4-mediated diseases is obtained.

11 cl, 7 tbl, 70 ex

Description

Field of technology to which the invention relates

[0001]

The present invention relates to a new macrocyclic compound and a medicinal product containing the said compound as an active ingredient.

State of the art

[0002]

Interleikin 1 receptor-associated kinase 4 (IRAK-4) is a protein phosphorylation enzyme that plays an important role in downstream signaling of Toll-like receptors (TLRs), the receptor interleukin 1 (interleukin 1 receptor - IL-1R), IL-18R and IL-33R (Non-Patent Document 1). Because the TLR/IL-1 family of receptors has an important function in inflammation and biological immunity, downstream signaling is thought to play an important role in many diseases, including inflammatory and autoimmune diseases.

[0003]

TLRs use pathogen-associated molecular patterns (PAMPs) produced by infectious microorganisms such as bacteria, fungi, parasites and viruses as ligands. They also recognize damage-associated molecular patterns (DAMPs) released from damaged or apoptotic cells and are activated. If a ligand binds to TLRs or members of the IL-1 receptor family, the adapter molecule, MyD88, is recruited to a common intracellular region called the TIR (Toll/IL-1 receptor) region. It is believed that IRAK-4 is recruited to receptors through interaction with MyD88, and downstream signaling begins (Non-Patent Document 2). IRAK-4 activates IRAK-1 and IRAK-2 and also controls the production of inflammatory mediators such as cytokines and chemokines through the downstream activation of signaling molecules such as NF-kB and MAPK.

[0004]

It has been reported that human cells deficient in the IRAK-4 gene do not respond to agonists for TLRs other than TLR3, IL-1β and IL-18 (Non-Patent Document 3). The IRAK-4 gene-deficient mouse also does not respond to agonists for TLRs other than TLR3, IL-1β and IL-18 (Non-Patent Document 4). On the other hand, mice deficient in the IRAK-1 gene and the IRAK-2 gene exhibit only partial suppression of these signals (Non-Patent Document 5). For this reason, IRAK-4, among the members of the IRAK family, is thought to play the most important role in these signal transductions. IRAK-4 knockout mice deficient in kinase activity have also been reported to have lower severity of arthritis, experimental autoallergic encephalomyelitis and atherosclerosis model compared to wild-type mice (Non-Patent Document 6). Thus, IRAK-4 kinase activity is essential for pathology signaling, and IRAK-4 inhibitors may demonstrate superior therapeutic efficacy in autoimmune diseases such as acute and chronic inflammation, rheumatoid arthritis and systemic erythrimatosis, metabolic disorders such as gout and diabetes, and diseases such as tumors.

[0005]

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

Previous Level Links

Patent documents

[0006]

Patent Document 1: International Patent Publication WO 2016/144846

Patent Document 2: International Patent Publication WO 2016/053771

Patent Document 3: International Patent Publication WO 2015/048281

Patent Document 4: International Patent Publication WO 2013/042137

Patent Document 5: International Patent Publication WO 2012/068546

Patent document b: International patent publication WO 2015/150995

Non-patent documents

[0007]

Non-Patent Document 1: Flannery S. & Bowie A.G., Biochemical Pharmacology, 80 (2010) 1981-1991

Non-Patent Document 2: Jain A. et al., Frontiters 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

The essence of the invention

Objectives of the present invention

[0008]

The object of the present invention is to provide a new compound that has inhibitory activity against IRAK-4. Another object of the present invention is to provide a new compound that can be used as an active ingredient of a drug for the prophylactic and/or therapeutic treatment of a disease associated with IRAK-4 inhibition. Another object of the present invention is to provide a medicament containing the specified compound.

Means of achieving these goals

[0009]

To achieve the above-described objectives, the inventors of the present invention have carried out extensive research. As a result, they discovered that the compounds of the present invention represented by formula (1) below have excellent IRAK-4 inhibitory activity and can be used for the prophylactic and/or therapeutic treatment of diseases associated with IRAK-4 inhibition, and filed the present invention .

[0010]

Thus, the present invention is implemented, for example, as follows.

[1] The compound represented by the following general formula (1):

[Formula 1]

[in formula (1)

R ¹ represents -H, C _1-6 alkyl, halogen-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, R ¹ may be substituted with 1-3 identical or different substituents selected from groups G ¹ ;

group G ¹ is a group of substituents consisting of -F, hydroxyl group, cyano group, halogen-C _1-6 alkyl, C _1-4 alkoxy, phenyl, 5- or 6-membered heteroaryl and 3-7-membered saturated ring group where phenyl and a 5- or 6-membered heteroaryl included in the group G ¹ may be substituted with 1-3 identical or different substituents selected from the group G ^Ar ;

the G ^Ar group is a substituent group consisting of -F, -Cl, hydroxyl group, cyano group, C _1-6 alkyl, halogen-C _1-6 alkyl and -NH ₂ ;

R ¹¹ is -H, C _1-6 alkyl, halo-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl, halo-C _1-6 alkoxy-C _1-6 alkyl or 3-7 -membered saturated ring group;

R ¹² represents C _1-6 alkyl, halo-C _1-6 alkyl, alkoxy-C _1-6 alkyl, halo-C _1-6 alkoxy-C _1-6 alkyl, 3-7 membered saturated ring group, phenyl or 5- or 6-membered heteroaryl, where phenyl and 5- or 6-membered heteroaryl as R ¹² may be substituted with 1-3 identical or different substituents selected from the group G ^Ar ;

R ² represents -H, C _1-6 alkyl, halogen-C _1-6 alkyl, hydroxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl or a 3-7 membered saturated ring group;

R ³ represents -H, C _1-6 alkyl, halogen-C _1-6 alkyl, hydroxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl or a 3-7 membered saturated ring group;

Ar is 6-10 membered aryl or 5-10 membered heteroaryl, where Ar may be substituted with 1-3 identical or different substituents selected from the group G ² ;

group G ² is a group of substituents consisting of -F, -Cl, hydroxyl group, cyano group, C _1-6 alkyl, halogen-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(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 ;

R ^Ar1 represents -H, C _1-6 alkyl, halo-C _1-6 alkyl or a 3-7 membered saturated ring group, where R ^Ar1 may be substituted with 1-3 identical or different substituents selected from the group G ³ ;

the G ³ group is a group of substituents consisting of -F, hydroxyl group, C _1-3 alkyl, halogen-C _1-3 alkyl, oxo group, C _1-3 alkoxy, halogen-C _1-3 alkoxy and 3-7- member of a saturated ring group;

R ¹³ represents -H, C _1-3 alkyl, halo-C _1-3 alkyl, C _1-3 alkoxy-C _1-3 alkyl, halo-C _1-3 alkoxy-C _1-3 alkyl or 3-7 -membered saturated ring group;

R ¹⁴ is C _1-3 alkyl, halo-C _1-3 alkyl, C _1-3 alkoxy-C _1-3 alkyl, halo-C _1-3 alkoxy-C _1-3 alkyl or a 3-7 membered saturated ring group;

R ¹⁵ represents -H, phenyl or 5- or 6-membered heteroaryl, R ¹⁵ may be substituted with 1-3 identical or different substituents selected from the group of substituents G ⁴ ;

the G ⁴ group is a substituent group consisting of halogen, cyano, C _1-3 alkyl and halogen-C _1-3 alkyl;

X ¹ represents N or CH;

X ² represents NH or O;

X ³ is a group represented by the following general formula (1-1):

[Formula 2]

given below by the general formula (1-2):

[Formula 3]

or

given below by the general formula (1-3):

[Formula 4]

(a and b represent the direction of attachment),

R ²¹ and R ²² independently represent -H, C _1-3 alkyl or halogen-C _1-3 alkyl;

X ⁴ is a group represented by the following general formula (2-1):

[Formula 5]

(b and c represent the direction of attachment); in formula (2-1),

n is an integer from 1 to 3;

Y represents NR ⁵¹ or O;

R ³¹ and R ³² independently represent -H, C _1-3 alkyl or halogen-C _1-3 alkyl; or

R ³¹ and R ³² can combine to form a 3-6 membered saturated ring;

R ⁴¹ and R ⁴² independently represent -H, -F, hydroxyl, C _1-3 alkyl, halogen-C _1-3 alkyl, C _1-3 alkoxy or halogen-C _1-3 alkoxy; or

R ⁴¹ and R ⁴² can combine to form a 3-6 membered saturated ring;

R ⁵¹ represents -H, C _1-3 alkyl or halogen-C _1-3 alkyl;

or

R ⁵¹ and R ³¹ can combine to form a 4-6 membered saturated ring;

X ⁴ may be substituted with 1-3 identical or different substituents selected from the group G ⁵ ; And

the G ⁵ group is a group of substituents consisting of -F, hydroxyl group, C _1-3 alkyl, halogen-C _1-3 alkyl, C _1-3 alkoxy and halogen-C _1-3 alkoxy].

or its salt.

[0011]

[2] The compound or salt thereof according to item [1], where Ar represents a 5- or 6-membered heteroaryl.

[2-2] A compound or a salt thereof as set forth in [1] above, wherein Ar is thienyl, thiazolyl, isothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl or pyrazinyl.

[2-3] A compound or a salt thereof as set forth in [1] above, wherein Ar is thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl or pyrazinyl.

[2-4] The compound or a salt thereof according to [1] above, where Ar represents thiazolyl, isothiazolyl, pyridyl or pyrimidinyl.

[2-5] The compound or a salt thereof according to [1] above, wherein Ar represents thiazolyl or pyrimidinyl.

[0012]

[3] A compound or a salt thereof according to item [1] or [2] above, where R ¹ represents -H, C _1-6 alkyl, halogen-C _1-6 alkyl, hydroxy-C _1-6 alkyl, a C _1-6 alkoxy-C _1-6 alkyl or 3-7 membered saturated ring group, and R ¹ may be substituted with 1-3 identical or different substituents selected from the group G ¹ (group G ¹ takes the meaning described above) .

[3-2] A compound or a salt thereof according to item [1] or [2] above, where R ¹ represents -H, C _1-6 alkyl, halogen-C _1-6 alkyl, C _1-6 alkoxy- C _1-6 alkyl or 3-7 membered saturated ring group, and R ¹ may be substituted with 1-3 identical or different substituents selected from the group of substituents G ¹ (the group of substituents G ¹ takes the meaning described above).

[3-3] A compound or a salt thereof as set forth in [1] or [2] above, wherein R ¹ represents -H, C _1-6 alkyl or a 3-7 membered saturated ring group, and R ¹ may be substituted with 1-3 identical or different substituents selected from the group G ¹ (the group of substituents G ¹ takes the meaning described above).

[0013]

[4] A compound or a salt thereof according to any one of [1] to [3-3] above, wherein X ² represents NH.

When referenced item numbers are specified using a range of values, such as "items [1] to [3-3] above" and a clause with an additional number, such as [3-2], is included in the specified range , this means that reference is also made to a clause with an additional number, such as [3-2]. The same applies to the descriptions presented below.

[0014]

[5] A compound or a salt thereof according to any one of [1] to [4] above, wherein X ³ is a group represented by the following general formula (1-1):

[Formula 6]

(R ²¹ and R ²² take the meanings described above).

[0015]

[6] A compound or a salt thereof according to any one of [1] to [5] above, wherein X ³ is a group represented by the following general formula (1-1-1):

[Formula 7]

[7] A compound or a salt thereof according to any of items [1] to [6] above, wherein in the general formula (2-1) for X ⁴ n is 1.

[0016]

[8] A compound or a salt thereof according to any one of [1] to [8] above, where Ar represents a group represented by the following general formula (3-1):

[Formula 8]

in formula (3-1)

R ^Ar2 is -H, -F, -Cl, hydroxyl group, cyano group, C _1-6 alkyl, halogen-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 take the meanings described above).

[8-2] A compound or a salt thereof according to any one of [1] to [7] above, where Ar is a group represented by the general formula (3-1), and in formula (3-1) R ^Ar2 represents -H, C _1-6 alkyl, hydroxy-C _1-6 alkyl or R ^Ar1 -OC _1-3 alkyl (R ^Ar1 takes the meaning described above).

[8-3] A compound or a salt thereof according to any one of [1] to [8] above, where Ar is a group represented by the general formula (3-1), and in formula (3-1) R ^Ar2 is R ^Ar1 -OC _1-3 alkyl (R ^Ar1 takes the meaning described above).

[0017]

[8-4] A compound or a salt thereof according to any one of items [1] to [8] above, where Ar represents a group represented by the general formula (3-1), in formula (3-1), R ^Ar2 represents is R ^Ar1 -OC _1-3 alkyl (R ^Ar1 takes the meaning described above), R ^Ar1 is a C _1-6 alkyl or 3-7 membered saturated ring group, and R ^Ar1 may be substituted with 1-3 identical or different substituents selected from the group G ³ (group G ³ takes the meaning described above).

[8-5] A compound or a salt thereof according to any one of items [1] to [8] above, where Ar represents a group represented by the general formula (3-1), in formula (3-1), R ^Ar2 represents is R ^Ar1 -OC _1-3 alkyl (R ^Ar1 takes the meaning described above), R ^Ar1 is C _1-6 alkyl, and R ^Ar1 may be substituted with 1-3 identical or different substituents selected from the group G ³ (group G ³ takes the values described above).

[8-6] A compound or a salt thereof according to any one of items [1] to [8] above, where Ar represents a group represented by the general formula (3-1), in formula (3-1), R ^Ar2 represents is R ^Ar1 -OC _1-3 alkyl (R ^Ar1 takes the meaning described above), R ^Ar1 is a 3-7 membered saturated ring group, and R ^Ar1 may be substituted with 1-3 identical or different substituents selected from group G ³ (group G ³ takes the meanings described above).

[8-7] A compound or a salt thereof according to any one of [1] to [7] above, where Ar represents a group represented by the general formula (3-1), in formula (3-1), R ^Ar2 represents is R ^Ar1 -OC _1-3 alkyl (R ^Ar1 takes the meaning described above), R ^Ar1 is C _3-7 cycloalkyl, and R ^Ar1 may be substituted with 1-3 identical or different substituents selected from the group G ³ (group G ³ takes the values described above).

[0018]

[9] A compound or a salt thereof according to any one of [1] to [8-7] above, where Ar represents a group represented by the general formula (3-1); And

in formula (3-1)

R ^Ar2 is -H, methyl, hydroxymethyl, -CH ₂ -OR ^Ar1 (R ^Ar1 takes the meaning described above).

[9-2] A compound or a salt thereof according to any one of [1] to [8-7] above, where Ar represents a group represented by the general formula (3-1), in formula (3-1), R ^Ar2 is R ^Ar1 -O-CH ₂ - (R ^Ar1 takes the meaning described above), R ^Ar1 is a C _1-6 alkyl or 3-7 membered saturated ring group, and R ^Ar1 may be substituted 1-3 identical or different substituents selected from the group G ³ (group G ³ takes the meaning described above).

[9-3] A compound or a salt thereof according to any one of items [1] to [8-7] above, where Ar represents a group represented by the general formula (3-1), in formula (3-1) R ^Ar2 is R ^Ar1 -O-CH ₂ - (R ^Ar1 takes the meaning described above), R ^Ar1 is C _1-6 alkyl, and R ^Ar1 may be substituted with 1-3 identical or different substituents selected from the group G ³ (group G ³ takes the meanings described above).

[0019]

[9-4] A compound or a salt thereof according to any one of items [1] to [8-7] above, where Ar represents a group represented by the general formula (3-1), in formula (3-1) R ^Ar2 is R ^Ar1 -O-CH ₂ - (R ^Ar1 takes the meaning described above), R ^Ar1 is a 3-7 membered saturated ring group, and R ^Ar1 may be substituted with 1-3 identical or different substituents selected from group G ³ (group G ³ takes the meanings described above).

[9-5] A compound or a salt thereof according to any one of [1] to [8-7] above, where Ar represents a group represented by the general formula (3-1), in formula (3-1), R ^Ar2 is R ^Ar1 -O-CH ₂ - (R ^Ar1 is as defined above), R ^Ar1 is C _3-7 cycloalkyl, and R ^Ar1 may be substituted with 1-3 identical or different substituents selected from the group G ³ (group G ³ takes the meanings described above).

[9-6] A compound or a salt thereof according to any one of [1] to [8-7] above, where Ar represents a group represented by the general formula (3-1), and in formula (3-1) R ^Ar2 is methyl or hydroxymethyl.

[9-7] A compound or a salt thereof according to any one of [1] to [8-7] above, where Ar represents a group represented by the general formula (3-1), and in formula (3-1) R ^Ar2 is methyl.

[9-8] A compound or a salt thereof according to any one of [1] to [8-7] above, where Ar represents a group represented by the general formula (3-1), and in formula (3-1) R ^Ar2 is hydroxymethyl.

[0020]

[10] A compound or a salt thereof according to any one of items [1] to [9-8] above, wherein R ³ represents -H.

[11] A compound or a salt thereof according to any one of [1] to [10] above, wherein R ² represents -H or methyl.

[12] A compound or a salt thereof according to any one of items [1] to [11] above, wherein R ¹ represents -H or C _1-3 alkyl.

[12-2] A compound or a salt thereof according to any one of [1] to [11] above, wherein R ¹ represents -H.

[12-3] A compound or a salt thereof according to any one of items [1] to [11] above, wherein R ¹ represents C _1-3 alkyl.

[12-4] A compound or a salt thereof according to any one of [1] to [11] above, wherein R ¹ represents methyl or ethyl.

[12-5] A compound or a salt thereof according to any one of [1] to [11] above, wherein R ¹ represents methyl.

[12-6] A compound or a salt thereof according to any one of [1] to [11] above, wherein R ¹ is ethyl.

[0021]

[13] The compound represented by the following formula:

[Formula 9]

or its salt.

[0022]

[14] The compound represented by the following formula:

[Formula 10]

or its salt.

[0023]

[15] The compound represented by the following formula:

[Formula 11]

or its salt.

[0024]

[16] The compound represented by the following formula:

[Formula 12]

or its salt.

[0025]

[17] The compound represented by the following formula:

[Formula 13]

or its salt.

[0026]

[18] The compound represented by the following formula:

[Formula 14]

or its salt.

[0027]

[19] The compound represented by the following formula:

[Formula 15]

or its salt.

[0028]

[20] A drug containing a compound according to any of [1] to [19] above, or a pharmaceutically acceptable salt thereof as an active ingredient.

[21] A drug as set forth in [20] above, which is a drug for the prophylactic and/or therapeutic treatment of a disease associated with IRAK4 inhibition.

[22] The drug according to item [20] above, which is a drug for the prophylactic and/or therapeutic treatment of rheumatism.

[23] An IRAK4 inhibitor containing a compound according to any one of [1] to [19] above, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0029]

[24] A pharmaceutical composition for the prophylactic and/or therapeutic treatment of rheumatism, which contains a compound according to any of items [1] to [19] above, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[25] A compound according to any one of [1] to [19] above, or a pharmaceutically acceptable salt thereof, which is used for the prophylactic and/or therapeutic treatment of rheumatism.

[26] A method of prophylactically and/or therapeutically treating rheumatism in a mammal, which includes the step of administering to the mammal an effective amount of a compound of any one of [1] to [19] above, or a pharmaceutically acceptable salt thereof.

Invention effect

[0030]

“The compounds represented by formula (1) or a salt thereof” (hereinafter referred to simply as “the compounds of the present invention”) have excellent IRAK-4 inhibitory activity. The compounds of the present invention, in accordance with a certain embodiment, exhibit significant selectivity in against other kinases, in particular FLT3. In addition, the compounds of the present invention, in accordance with a certain embodiment, show low genetic toxicity. The compounds of the present invention, in accordance with a certain embodiment, can also be used as an active ingredient of a drug. prophylactic and/or therapeutic treatment of a disease associated with IRAK-4 inhibition, for example for prophylactic and/or therapeutic treatment of an autoimmune disease. The compounds of the present invention, in accordance with a certain embodiment, can also be used as a reagent having inhibitory activity against. IRAK-4.

Methods for Carrying Out the Present Invention

[0031]

Next, the present invention will be explained in detail.

In the present specification, unless specifically stated otherwise, a carbon atom may be represented simply as "C", a hydrogen atom as "H", an oxygen atom as "O", a sulfur atom as "S", a nitrogen atom as "N". Further, a carbonyl group can be represented simply as “-C(O)-”, a carboxyl group as “-COO-”, a sulfinyl group as “-S(O)-”, a sulfonyl group as “-S(O) ₂ -", an ether bond - as "-O-", a thioether bond - as "-S-" (each sign in these groups shows a bond).

[0032]

As used herein, alkyl may be a straight, branched or cyclic saturated hydrocarbon group or a combination of such groups unless specifically stated otherwise. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, butyl, its isomers [normal (n), iso, secondary (sec), tertiary (tert), etc.] and cycloalkyl such as cyclopropyl and cyclobutyl. Examples of alkyl include alkyl having 1 to 6 carbon atoms. According to another embodiment, examples include alkyl having 1 to 3 carbon atoms. Alkyl containing from 1 to 6 carbon atoms may be referred to as C _1-6 alkyl.

[0033]

"Alkoxy" may be a linear, branched or cyclic saturated alkyloxy group or a combination of such groups unless specifically stated otherwise. Examples of such groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, its isomers [normal (n-), iso-, secondary (sec), tertiary (tert), etc.] and cycloalkyloxy, such as cyclopropoxy and cyclobutoxy. Examples of alkoxy include an alkoxy group containing from 1 to 6 carbon atoms. In another embodiment, examples include an alkoxy group containing from 1 to 3 carbon atoms. An alkoxy group containing from 1 to 6 carbon atoms may be referred to as C _1-6 alkoxy.

[0034]

"Alkylene" may be a linear or branched alkylene. Examples thereof include, but are not limited to, methylene, ethylene, propylene, butylene, methylmethylene, ethylmethylene, methylethylene, 1,2-dimethylethylene, 1,1,2,2-tetramethylethylene and 1-methylbutylene. Examples of alkylene include alkylene containing 1 to 6 carbon atoms. According to another embodiment, examples of alkylene include alkylene containing from 1 to 3 carbon atoms. Alkylene containing from 1 to 6 carbon atoms may be referred to as C _1-6 alkylene.

"Halogen" is fluorine (-F), chlorine (-Cl), bromine (-Br) or iodine (-I). According to another embodiment, examples of halogen include -F and -Cl. According to yet another embodiment, examples of halogen include -F. The term "halogen-" means substitution of 1-7 with the same or different halogens. According to another embodiment, it means replacing 1-5 with the same or different halogens. According to another embodiment, it means substitution with 1-3 halogens. According to another embodiment, it means the replacement of 1 halogen atom. Examples include -F substitution.

[0035]

The term “aromatic ring (aromatic ring)” is not particularly limited as long as the ring (ring) is aromatic, and examples thereof include a monocyclic tricyclic aromatic ring. Examples of the aromatic ring include an aromatic hydrocarbon ring and an aromatic heterocyclic ring. Specific examples of such groups include benzene, naphthalene, phenanthrene, thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, pyrrole, pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrimidinone, indole, isoindole, indazole, quinoline , isoquinoline, benzimidazole, benzotriazole, benzothiophene, benzofuran, benzothiazole, phthalazine, quinoxaline, pyrrolopyridine and carbazole.

Examples of an "aromatic ring group" include a monovalent group formed by the removal of one randomly selected hydrogen atom from an aromatic ring. The aromatic ring group may be a monocyclic to tricyclic aromatic group. Examples of such a group include, but are not limited to, aryl and heteroaryl.

[0036]

"Aryl" may be a monocyclic tricyclic aromatic hydrocarbon ring group. Aryl may also be an aromatic hydrocarbon ring group fused to a saturated hydrocarbon ring, as described below. Examples of aryl include 6-14 membered aryl. According to another embodiment, examples of aryl include 6-10 membered aryl. According to yet another embodiment, examples of aryl include 6-membered aryl. Specific examples of the aoid include phenyl, naphthyl, anthranyl, phenanthrenyl, florenyl, indanyl, and 1, 2, 3, 4-tetrahydronaphthalenyl. In accordance with another embodiment, examples of aryl include phenyl, and in accordance with yet another embodiment, examples of aryl include naphthyl. Indanyl and 1,2,3,4-tetrahydronaphthalenyl are 6-10 membered aryl.

[0037]

"Heteroaryl" may be a monocyclic tricyclic ring group containing 1 to 4 heteroatoms as ring-forming atoms. Examples of heteroatoms include O, S and N atoms. Examples of heteroaryl include 5-14 membered heteroaryl. According to another embodiment, examples of heteroaryl include 5-10 membered heteroaryl. According to yet another embodiment, examples of heteroaryl include 5- or 6-membered heteroaryl. Specific examples of heteroaryl include thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridonyl, pyrimidinonyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, zolyl, benzotriazolyl, benzothienyl, benzofuranyl, benzothiazolyl, phthalazinyl, quinoxalinyl, pyrrolopyridyl and carbazolyl.

[0038]

Examples of a "saturated ring" include a saturated hydrocarbon ring and a saturated heterocyclic ring. The saturated ring may be cross-linked or fused to an aromatic ring as described above.

A "saturated hydrocarbon ring" may contain from one to three hydrocarbon rings. Examples thereof include a 3-10 membered saturated hydrocarbon ring. According to another embodiment, examples thereof include a 3-7 membered saturated hydrocarbon ring. In yet another embodiment, examples thereof include a 5- or 6-membered saturated hydrocarbon ring. The saturated hydrocarbon ring may be cross-linked and may be fused to the aromatic ring described above. Specific examples of the saturated hydrocarbon ring include cyclopropane, cyclobutane, cyclopentane, cyclohexane and adamantane.

[0039]

A “saturated heterocyclic ring” may be a monocyclic-tricyclic saturated heterocyclic ring containing 1 to 4 heteroatoms as ring-forming atoms. Examples of the heteroatom include O, S and N atoms. Examples of the saturated heterocyclic ring include a 3-10 membered saturated heterocyclic ring. According to another embodiment, examples of the saturated heterocyclic ring include a 3-7 membered saturated heterocyclic ring. According to yet another embodiment, examples of the saturated heterocyclic ring include a 5- or 6-membered saturated heterocyclic ring. Such a saturated heterocyclic ring may contain a cross-link and may be fused to the aromatic ring described above. Specific examples of such a saturated heterocyclic ring include tetrahydropyran, tetrahydrofuran, piperidine, pyrrolidine, azetidine, oxetane, aziridine, oxirane, tetrahydrothiopyran, tetrahydrothiophene, morpholine, oxazepane and piperazine.

[0040]

Examples of a "fused ring" include a cyclic compound consisting of two or more rings bonded together such that the rings share two or more atoms, where two or more rings independently form a 3-7 membered saturated ring. The fused ring may contain from 1 to 3 heteroatoms selected from O, S and N atoms. Examples of the fused ring include a cyclic compound in which two adjacent atoms belong to both rings.

[0041]

Examples of a "spiro ring" include a cyclic compound consisting of two rings sharing one carbon atom, where the two rings independently form a 3-7 membered saturated ring. The spiro ring may contain from 1 to 3 heteroatoms selected from O, S and N atoms. When the spiro ring is formed by 7-11 atoms, such a ring may be called a 7-11 membered spiro ring. Examples of the spiro ring include a 7-13 membered spiro ring. According to another embodiment, examples of the spiro ring include a 7-11 membered spiro ring. According to yet another embodiment, examples of the spiro ring include a 7-9 membered spiro ring.

[0042]

Examples of the term “saturated ring group” include a monovalent group obtained by removing one randomly selected hydrogen atom from a saturated ring, and a divalent group obtained by removing one hydrogen atom each from two ring-forming atoms of a saturated ring. Examples of the saturated ring group include a saturated hydrocarbon ring group and a saturated heterocyclic ring group. Examples of such a group are 3-10 membered saturated ring groups. According to another embodiment, examples of such a group include a 3-7 membered saturated ring group. According to yet another embodiment, examples of such a group include a 5- or 6-membered saturated ring group.

[0043]

Examples of a “saturated hydrocarbon ring group” include a monovalent group formed by removing one randomly selected hydrogen atom from a saturated hydrocarbon ring, and a divalent group formed by removing one hydrogen atom each from two different ring-forming atoms of a saturated hydrocarbon ring. The saturated hydrocarbon ring group may be a monocyclic-tricyclic saturated hydrocarbon group. The saturated hydrocarbon ring group may be cross-linked and may be fused to the aromatic ring described above. Examples of such a group include a 3-10 membered saturated hydrocarbon ring group. According to another embodiment, examples of such a group include a 3-7 membered saturated hydrocarbon ring group. According to yet another embodiment, examples of such a group include a 5- or 6-membered saturated hydrocarbon ring group. Specific examples of the monovalent group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl. Specific examples of a divalent group include a divalent group obtained from any specific example of a monovalent group described above by further removing a hydrogen atom from a ring-forming atom other than the ring-forming atom from which the hydrogen atom was removed to form the monovalent group.

[0044]

Examples of a “saturated heterocyclic ring group” include a monovalent group obtained by removing a randomly selected hydrogen atom from a saturated heterocyclic ring, and a divalent group obtained by removing one hydrogen atom each from two different ring-forming atoms of a saturated heterocyclic ring. The saturated heterocyclic ring group may be a monocyclic-tricyclic saturated heterocyclic ring group containing 1 to 4 heteroatoms as ring-forming atoms. Such a saturated heterocyclic ring group may contain a cross-link and may be fused to an aromatic ring as described above. Examples of the heteroatom include O, S and N atoms. Examples of this group include a 3-10 membered heterocyclic ring group. According to another embodiment, examples of such a group include a 3-7 membered saturated heterocyclic ring group. According to yet another embodiment, examples of such a group include a 5- or 6-membered saturated heterocyclic ring group. Specific examples of the monovalent saturated heterocyclic ring group include tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, pyrrolidinyl, azetidinyl, oxetanyl, tetrahydrothiopyranyl, tetrahydrothienyl, morpholinyl and piperazinyl.

[0045]

A "partially unsaturated ring group" may be a saturated ring group of which a portion is unsaturated, and examples of such a group include a partially unsaturated hydrocarbon ring group and a partially unsaturated heterocyclic ring group. Examples of such a group include a 3-10 membered partially unsaturated ring group. According to another embodiment, examples of such a group include a 3-7 membered partially unsaturated ring group. According to yet another embodiment, examples of such a group include a 5- or 6-membered partially unsaturated ring group.

[0046]

A "partially unsaturated hydrocarbon ring group" may be a saturated hydrocarbon ring group of which a portion is unsaturated. Specific examples of such a group include cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl and bicyclooctatrienyl.

A "partially unsaturated heterocyclic ring group" may be a saturated heterocyclic ring group of which a portion is unsaturated. Specific examples of such a group include dihydropyranyl, dihydrofuranyl, dihydrothiopyranyl, dihydrothienyl, 1,2-dihydroquinolyl and 1,2,3,4-tetrahydroquinolyl.

[0047]

The present invention includes all isomers unless specifically stated otherwise. For example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylene, alkenylene and alkynylene include linear and branched groups. Furthermore, the scope of the present invention includes any of isomers of arrangement relative to a double bond, ring or fused ring (E- or Z-isomer or cis- or trans-isomer), isomers relative to an asymmetric carbon atom or the like (R- or S -isomer, isomers by α- or β-configuration, enantiomers, diastereomers, etc.), optically active substances having optical rotation (D- or L-isomer or d- or l-isomer), isomers by observed polarity during chromatographic separation (high polarity isomer or low polarity isomer), equilibrated compounds, conformational isomers, mixtures of these isomers in arbitrary ratios and racemates.

[0048]

In the present description, as is obvious to those skilled in the art, the symbol:

[Formula 16]

indicates that the bond is below the plane (i.e., α-configuration), the symbol:

[Formula 17]

shows that the bond is in front of the plane (i.e., β-configuration), and the symbol:

[Formula 18]

means the -configuration or the β-configuration, or a mixture thereof, unless specifically stated.

[0049]

In the following, the compounds represented by formula (1) and their salts will be described in detail.

[Formula 19]

[0050]

As used herein, the expression “may be substituted” means that, unless specifically stated, the corresponding group has no substituent or has 1 to 5 identical or different substituents. According to another embodiment, the expression means that the corresponding group has no substituent or 1 to 3 substituents. According to another embodiment, this expression means that the corresponding group has no substituent or 1 substituent. According to another embodiment, this expression means that the corresponding group does not have a substituent.

[0051]

Examples of R ¹ include -H, C _1-6 alkyl, halogen-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 and a 3-7 membered saturated ring group. According to another embodiment, examples thereof include -H, C _1-6 alkyl, halogen-C _1-6 alkyl, hydroxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl and 3-7- member saturated ring group. According to yet another embodiment, examples thereof include -H, C _1-6 alkyl, and a 3-7 membered saturated ring group. According to yet another embodiment, examples thereof include -H, methyl and ethyl. According to yet another embodiment, examples thereof include methyl.

R ¹ may be substituted with 1-3 identical or different substituents selected from the group G ¹ .

Examples of the G ¹ group include a group of substituents consisting of -F, hydroxyl group, cyano group, halogen-C _1-6 alkyl, C _1-4 alkoxy, phenyl, 5- or 6-membered heteroaryl and 3-7-membered saturated ring group . According to another embodiment, examples thereof include a G ¹¹ group consisting of -F, a hydroxyl group, a halogen-C _1-6 alkyl, a C _1-4 alkoxy and a 3-7 membered saturated ring group. According to yet another embodiment, examples include a G ¹² group consisting of -F, a hydroxyl group, a C _1-4 alkoxy and a 3-7 membered saturated ring group.

Phenyl and 5- or 6-membered heteroaryl included in the G ¹ group may be substituted with 1-3 identical or different substituents selected from the G ^Ar group.

[0052]

Examples of the G ^Ar group include a group consisting of -F, -Cl, hydroxyl group, cyano group, C _1-6 alkyl, halogen-C _1-6 alkyl and -NH ₂ . According to another embodiment, examples thereof include a G ^Ar1 group consisting of -F, -Cl, cyano, C _1-6 alkyl and halogen-C _1-6 alkyl.

Examples of R ¹¹ include -H, C _1-6 alkyl, halo-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl, halo-C _1-6 alkoxy-C _1-6 alkyl and 3-7 -membered saturated ring group. According to another embodiment, examples thereof include C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl, and a 3-7 membered saturated ring group.

Examples of R ¹² include C _1-6 alkyl, halo-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl, halo-C _1-6 alkoxy-C _1-6 alkyl, 3-7 membered saturated ring group, phenyl and 5- or 6-membered heteroaryl. According to another embodiment, examples thereof include C _1-6 alkyl, 3-7 membered saturated ring group, phenyl and 5- or 6-membered heteroaryl. According to yet another embodiment, examples thereof include a C _1-6 alkyl and a 3-7 membered saturated ring group.

Phenyl and 5- or 6-membered heteroaryl as R ¹² may be substituted with 1-3 identical or different substituents selected from the group G ^Ar .

In addition to the embodiment in which the G ^Ar group described above is used, there is also another embodiment in which the G ^Ar group is a G ^Ar1 group.

[0053]

Examples of R ² include -H, C _1-6 alkyl, halogen-C _1-6 alkyl, hydroxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl and a 3-7 membered saturated ring group. According to another embodiment, examples thereof include -H, C _1-6 alkyl and a 3-7 membered saturated ring group. According to yet another embodiment, examples thereof include -H, C _1-3 alkyl and cyclopropyl. According to yet another embodiment, examples thereof include -H and methyl. According to yet another embodiment, examples thereof include -H.

[0054]

Examples of R ³ include -H, C _1-6 alkyl, halogen-C _1-6 alkyl, hydroxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl and a 3-7 membered saturated ring group. According to another embodiment, examples thereof include -H, C _1-6 alkyl, and a 3-7 membered saturated ring group. According to yet another embodiment, examples thereof include -H, C _1-3 alkyl and cyclopropyl. According to yet another embodiment, examples thereof include -H and methyl. According to yet another embodiment, examples thereof include -H.

[0055]

Examples of Ar include 6-10 membered aryl and 5-10 membered heteroaryl. According to another embodiment, examples thereof include phenyl 5- or 6-membered heteroaryl. In yet another embodiment, examples thereof include 5- or 6-membered heteroaryl.

Examples of 6-10 membered aryl as Ar include phenyl, naphthyl and indanyl. According to yet another embodiment, examples thereof include phenyl.

[0056]

Examples of 5-10 membered heteroaryl Ar include thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridonyl, pyrimidinonyl, indolyl, isoindolyl, indazolyl, isoquinol, l , benzimidazolyl, benzotriazolyl, benzothienyl, benzofuranyl, benzothiazolyl, phthalazinyl, quinoxalinyl and pyrrolopyridyl. According to another embodiment, examples thereof include thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridon-yl and pyrimidinon-yl. According to yet another embodiment, examples thereof include thienyl, thiazolyl, isothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl and pyrazinyl. According to yet another embodiment, examples thereof include thienyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyridyl and pyrimidinyl. According to yet another embodiment, examples thereof include thiazolyl, isothiazolyl, pyridyl and pyrimidinyl. According to yet another embodiment, examples thereof include thiazolyl and pyrimidinyl. In yet another embodiment, examples thereof include pyrimidinyl.

[0057]

Ar may be substituted with 1-3 identical or different substituents selected from the group G ² .

Examples of the G ² group include a substituent group consisting of -F, -Cl, hydroxyl group, cyano group, C _1-6 alkyl, halo-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(O ₂ ) R ¹⁴ , S(O ₂ )NR ¹³ R ¹⁴ , -NH ₂ , -SO ₂ )NH ₂ , -NR ¹³ R ¹⁴ and -NHC(O)NHR ¹⁵ . According to another embodiment, examples thereof include the G ²¹ group consisting of C _1-6 alkyl, halogen-C _1-6 alkyl, hydroxy-C _1-6 alkyl and R ^Ar1 -OC _1-3 alkyl. According to yet another embodiment, examples thereof include the G ²² group consisting of C _1-6 alkyl, hydroxy-C _1-6 alkyl and R ^Ar1 -OC _1-3 alkyl. According to yet another embodiment, examples thereof include the G ²² group consisting of C _1-6 alkyl, hydroxy-C _1-6 alkyl and R ^Ar1 -OC _1-3 alkyl. According to yet another embodiment, examples thereof include R ^Ar1 -OC _1-3 alkyl. According to yet another embodiment, examples thereof include R ^Ar1 -O-methyl. According to yet another embodiment, examples thereof include methyl.

[0058]

Examples of R ^Ar1 include -H, C _1-6 alkyl, halogen-C _1-6 alkyl and a 3-7 membered saturated ring group. According to another embodiment, examples thereof include a C _1-6 alkyl and a 3-7 membered saturated ring group. According to yet another embodiment, examples thereof include C _1-6 alkyl. According to yet another embodiment, examples thereof include a normal cut. According to yet another embodiment, examples thereof include cyclobutyl and cyclopentyl. In yet another embodiment, examples thereof include cyclopentyl. In yet another embodiment, examples thereof include a 3-7 membered saturated ring group. Examples of the 3-7 membered saturated ring group include C _3-7 cycloalkyl and the 3-7 membered saturated heterocyclic ring group. Examples of the 3-7 membered saturated heterocyclic ring group include oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, morpholinyl and piperazinyl. According to another embodiment, examples thereof include tetrahydrofuranyl.

[0059]

R ^Ar1 may be substituted with 1-3 identical or different substituents selected from the group G ³ .

Examples of the G ³ group include a group of substituents consisting of -F, hydroxyl group, C _1-3 alkyl, halogen-C _1-3 alkyl, oxo, C _1-3 alkoxy, halogen-C _1-3 alkoxy and 3-7- member of a saturated ring group. According to another embodiment, examples thereof include a G ³¹ group consisting of -F, a hydroxyl group and a 3-7 membered saturated ring group. According to yet another embodiment, examples thereof include a G ³² group consisting of -F, hydroxyl, C _1-3 alkyl, halogen-C _1-3 alkyl, oxo, C _1-3 alkoxy and 3-7 membered saturated ring group. According to yet another embodiment, examples thereof include a G ³ 3 group consisting of -F, a hydroxyl group and a C _3-7 cycloalkyl. According to yet another embodiment, examples thereof include a G ³ 4 group consisting of -F, a hydroxyl group and cyclopropyl.

[0060]

Examples of R ¹³ include -H, C _1-3 alkyl, halo-C _1-3 alkyl, C _1-3 alkoxy-C _1-3 alkyl, halo-C _1-3 alkoxy-C _1-3 alkyl and 3-7 -membered saturated ring group. According to another embodiment, examples thereof include -H, C _1-3 alkyl, halogen-C _1-3 alkyl, C _1-3 alkoxy-C _1-3 alkyl and halogen-C _1-3 alkyl. In yet another embodiment, examples thereof include a 3-7 membered saturated ring group.

[0061]

Examples of R ¹⁴ include C _1-3 alkyl, halo-C _1-3 alkyl, C _1-3 alkoxy-C _1-3 alkyl, halo-C _1-3 alkoxy-C _1-3 alkyl and 3-7 membered saturated ring group. According to another embodiment, examples thereof include C _1-3 alkyl, halogen-C _1-3 alkyl, C _1-3 alkoxy-C _1-3 alkyl and halogen-C _1-3 alkyl. In yet another embodiment, examples thereof include a 3-7 membered saturated ring group.

Examples of the 3-7 membered saturated ring group as R ¹³ and R ¹⁴ include C _3-7 cycloalkyl and 3-7 membered saturated heterocyclic ring group. According to another embodiment, examples thereof include cyclopropyl, cyclobutyl and oxetanyl.

[0062]

Examples of R ¹⁵ include -H, phenyl and 5- or 6-membered heteroaryl. Examples of the 5- or 6-membered heteroaryl include thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl. According to another embodiment, examples of R ¹³ include phenyl and trifluoromethylphenyl.

[0063]

R ¹⁵ may be substituted with 1-3 identical or different substituents selected from the group G ⁴ .

Examples of the G ⁴ group include the substituent group consisting of halogen, cyano, C _1-3 alkyl and halogen-C _1-3 alkyl. According to another embodiment, examples thereof include the G ⁴¹ group consisting of -F, cyano, methyl and trifluoromethyl.

[0064]

Another embodiment of Ar is, for example, a group represented by formula (3-1).

[Formula 20]

[0065]

Examples of R ^Ar2 include -H, -F, -Cl, hydroxyl group, cyano group, C _1-6 alkyl, halogen-C _1-6 alkyl, hydroxy-C _1-6 alkyl, R ^Ar1 -OC _1-3 alkyl and - NR ¹³ R ¹⁴ (R ^Ar1 , R ¹³ and R ¹⁴ take the meanings described above). According to another embodiment, examples thereof include R ^Ar1 -OC _1-3 alkyl. According to yet another embodiment, examples thereof include -CH ₂ -OR ^Ar1 (R ^Ar1 takes the meaning described above). According to yet another embodiment, examples thereof include methyl and hydroxymethyl. According to yet another embodiment, examples thereof include methyl. According to yet another embodiment, examples thereof include hydroxymethyl.

Specific examples of R ^Ar1 -OC _1-3 alkyl include groups represented by the following formulas:

[Formula 21]

[0066]

According to another embodiment, specific examples of R ^Ar1 -OC _1-3 alkyl include groups represented by the following formulas.

[Formula 22]

[0067]

Examples of X ¹ include N and CH. According to another embodiment, examples thereof include N. According to another embodiment, examples thereof include CH.

Examples of X ² include NH and O. In another embodiment, examples thereof include NH.

Examples of X ³ include groups represented by formulas (1-1) through (1-3) (a and b indicate the direction of addition).

[Formula 23]

[0068]

According to another embodiment, examples thereof include the group represented by the general formula (1-1). According to yet another embodiment, examples thereof include the group represented by the following general formula (1-1-1).

[Formula 24]

[0069]

Examples of R ²¹ and R ²² independently include -H, C _1-3 alkyl and halogen-C _1-3 alkyl. According to another embodiment, examples thereof include -H and methyl. According to yet another embodiment, examples thereof include -H.

[0070]

Examples of X ⁴ include the group represented by the following formula (2-1) (b and c represent the direction of attachment).

[Formula 25]

[0071]

Examples of n include integers from 1 to 3. According to another embodiment, examples thereof include the integer 1.

Examples of Y include NR ⁵¹ and O. In another embodiment, examples thereof include NR ⁵¹ . According to yet another embodiment, examples thereof include O.

[0072]

Examples of R ³¹ and R ³² independently include -H, C _1-3 alkyl and halogen-C _1-3 alkyl. According to another embodiment, examples thereof include -H and methyl. According to yet another embodiment, examples include -H.

[0073]

R ³¹ and R ³² can also combine to form a 3-6 membered saturated ring. Examples of the 3-6 membered saturated ring include cyclopropyl, cyclobutyl, oxetanyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl and tetrahydropyranyl. According to another embodiment, examples thereof include cyclopropyl, cyclobutyl and oxetanyl. According to yet another embodiment, examples thereof include cyclopropyl and cyclobutyl.

[0074]

Examples of R ⁴¹ and R ⁴² independently include -H, -F, hydroxyl, C _1-3 alkyl, halogen-C _1-3 alkyl, C _1-3 alkoxy and halogen-C _1-3 alkoxy. According to another embodiment, examples thereof include -H, -F, C _1-3 alkyl, halogen-C _1-3 alkyl, C _1-3 alkoxy and halogen-C _1-3 alkoxy. According to yet another embodiment, examples thereof include -H, -F and C _1-3 alkyl. According to yet another embodiment, examples thereof include -H, -F and methyl. According to yet another embodiment, examples thereof include -H and -F.

[0075]

R ⁴¹ and R ⁴² can also combine to form a 3-6 membered saturated ring. Examples of the 3-6 membered saturated ring include cyclopropyl, cyclobutyl, oxetanyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl and tetrahydropyranyl. According to another embodiment, examples thereof include cyclopropyl, cyclobutyl and oxetanyl. According to yet another embodiment, examples thereof include cyclopropyl and cyclobutyl. According to yet another embodiment, examples thereof include cyclopropyl.

[0076]

Examples of R ⁵¹ include -H, C _1-3 alkyl and halogen-C _1-3 alkyl. According to another embodiment, examples thereof include -H and methyl. According to yet another embodiment, examples thereof include -H.

[0077]

R ⁵¹ and R ³¹ can also combine to form a 4-6 membered saturated ring. Examples of the 4-6 membered saturated ring include azetidinyl, pyrrolidinyl and piperazinyl. In yet another embodiment, examples thereof include pyrrolidinyl.

[0078]

X ⁴ may be substituted with 1-3 identical or different substituents selected from the group G ⁵ .

Examples of the G ⁵ group include a substituent group consisting of -F, hydroxyl group, C _1-3 alkyl, halogen-C _1-3 alkyl, C _1-3 alkoxy and halogen-C _1-3 alkoxy. According to another embodiment, examples of group G ⁵¹ include a substituent group consisting of -F, hydroxyl group and C _1-3 alkyl. According to another embodiment, examples of group G ⁵² include a substituent group consisting of -F and a hydroxyl group.

[0079]

Specific examples of X ⁴ include, for example, the groups represented by the following formulas:

[Formula 26]

[0080]

According to another embodiment, specific examples of X ⁴ include groups represented by the following formulas:

[Formula 27]

[0081]

Specific examples of compounds within the scope of the present invention include the following compounds. However, the scope of the present invention is not limited to them.

[0082]

As used herein, “compounds represented by formula (1)” generally refers to compounds represented by formula (1) in free form. Examples of their salts include the following salts.

The salt type of the compounds represented by formula (1) is not particularly limited, and it may be an acid addition salt or a base addition salt, and may be in the form of an intramolecular counterion. In particular, when a salt is used as an active ingredient of a drug, it is preferably a pharmaceutically acceptable salt. When a salt is presented herein for use as a drug, a salt of the compounds represented by formula (1) generally means a pharmaceutically acceptable salt. Acid addition salts include, for example, acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid, and acid addition salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, citric acid, malic acid, tartaric acid, dibenzoyltartaric acid, mandelic acid, maleic acid, fumaric acid, aspartic acid and glutamic acid . As examples of base addition salts, there may be mentioned base addition salts with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum hydroxide, base addition salts with an organic base such as methylamine, 2-aminoethanol, arginine, lysine, ornithine, etc. However, the type of salt is not limited to these types, and, of course, it can be suitably selected by one skilled in the art.

[0083]

The compounds of the present invention may be presented in hydrate form. The compounds of the present invention may also be presented in anhydrous form.

The compounds of the present invention may be presented in solvate form. The compounds of the present invention may also be presented in unsolvated form.

The compounds of the present invention may be presented in crystalline form. The compounds of the present invention may also be presented in amorphous form.

The compounds of the present invention may be labeled with any of various radioactive or non-radioactive isotopes.

More precisely, the compounds of the present invention include anhydrides and non-solvates of the “compounds represented by formula (1)”, their hydrates and/or solvates and crystals.

The compounds of the present invention also include anhydrides and non-solvates of the “salts of the compounds represented by formula (1)”, hydrates and/or solvates of salts and crystals thereof.

[0084]

The compounds of the present invention may also be pharmaceutically acceptable prodrugs of the “compounds represented by formula (1)”. A pharmaceutically acceptable prodrug is a compound containing a group that can be converted to an amino group, a hydroxyl group, a carboxyl group, or the like. as a result of solvolysis or under physiological conditions. For example, as a group that forms a prodrug for a hydroxyl group or an amino group, for example, an acyl group and an alkoxycarbonyl group can be mentioned. As the group that forms a prodrug for the carboxyl group, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, an s-butyl group, a tert-butyl group, an amino group may be mentioned. , methylamino group, ethylamino group, dimethylamino group and diethylamino group.

[0085]

Such a prodrug can generally be prepared, for example, by appropriately introducing a prodrug-forming group into any compound of the present invention into one or more groups arbitrarily selected from a hydroxyl group and an amino group, using a prodrug-forming reagent such as an appropriate halide, with followed, if necessary, by suitable isolation and purification of the compound in a convenient manner. A group that forms a prodrug can also suitably be introduced into the compounds of the present invention at the carboxyl group using a prodrug-forming reagent such as an appropriate alcohol or amine.

[0086]

<General methods of obtaining>

The compounds represented by formula (1) can be prepared according to known methods, such as the methods described below, similar methods, or the methods described in the examples. The compounds used in the following production methods as starting materials are available from commercial sources or can be prepared by known methods described, for example, in "Compendium of Organic Synthesis Methods, Vols. I to XII, Wiley InterScience".

[0087]

Certain intermediates may be used after the introduction of protecting groups or after deprotection according to known methods described, for example, in Peter G.M., Wuts, "Greene's Protective Groups in Organic Chemistry, John Wiley & Sons, 2014".

[0088]

The mixture of stereoisomers can be separated by a known method, for example the methods described in "E. L. Eloel, S. H. Wilen, Stereochemistry of Organic Compounds, John Wiley & Sons, 1994", similar methods and methods described in the examples. Multicomponent mixtures can be separated using the methods described above.

The synthesis reactions of the compounds of the present invention are carried out in suitable solvents selected in accordance with known methods. Suitable solvents are those that do not substantially react with the starting materials, intermediates or products at reaction temperatures (eg, temperatures ranging from the melting point to the boiling point of the solvent). Reactions can be carried out in a single type of solvent or in a mixture of solvents. A solvent suitable for each reaction is used.

[0090]

The progress of the reactions can be monitored using a suitable known method. For example, product formation can be monitored by spectroscopy using, for example, a nuclear magnetic resonance (NMR) machine using ¹ H, ¹³ C or the like, infrared spectrophotometer (IR), mass spectrometer (MS), high-speed liquid chromatography (HPLC), thin layer chromatography (TLC) or the like.

[0091]

The compounds of the present invention can be prepared by any methods other than those described herein with proper use of the methods described herein and general technical knowledge in the art. The reaction equations and examples are provided as typical examples only and do not limit the scope of the present invention.

[0092]

The abbreviations used in the diagrams described below are abbreviations commonly used in the art. The meanings of the abbreviations for the chemical terms used in this description, including examples, are defined as follows: DMF - N,N-dimethylformamide; DMSO - dimethyl sulfoxide; THF - tetrahydrofuran; DME - 1,2-dimethoxyethane; TFA - trifluoroacetic acid; hour - hours; RT - room temperature; RT - retention time; LG - group to be deleted.

[0093]

The compounds of the present invention represented by formula (1) can be prepared according to, for example, the following reaction schemes. In the following diagrams, "STAGE" means a process step, for example, "STAGE 1" means step 1.

[0094]

Macrocyclic compounds represented by formula (1) consist of four parts, i.e. a nitrogen-containing bicyclic heterocyclic ring mother core, a substituted piperidine, a linker linking moieties a and c, and an aromatic ring directly attached to the nitrogen-containing bicyclic heterocyclic ring mother core.

[0095]

Scheme 1 shows the first method for the synthesis of macrocyclic compounds. This method involves the first binding of a substituted piperidine and a linker connecting fragments a and c, the reaction of the resulting product with a nitrogen-containing bicyclic heterocyclic parent core to form the X ² bond, the subsequent formation of the X ³ bond to obtain a macrocycle, and finally the introduction of an aromatic ring that directly binds to nitrogen-containing bicyclic heterocyclic ring mother core.

[Formula 28]

SCHEME. 1

[0096]

The compounds represented by formula (1) can be prepared, for example, by the method shown in reaction scheme 1 (in the compound formulas, M represents, for example, a substituent that can interact through various types of coupling using ZnI, MgBr, boronic acid, complex boronic acid ester or the like, LG ¹ and LG ² represent a leaving group such as -Cl, -B -Br, -I, -OTf, -OMs, -OMs and -Ots, Q ¹ and Q ² represent such as a hydroxyl group, a leaving group such as -Cl, -Br, -I, -OTf, -OMs and -OTs, or a substituent capable of forming a C-O or C-C bond such as an alkenyl group and borane -derivative, and Q ³ is a substituent capable of forming a C-O or CN bond by reacting with an LG ² group such as a hydroxyl group and an amino group). The compounds represented by formulas (2)(6) are available from commercial sources or can be prepared according to known methods, such as the methods shown below or similar methods.

[0097]

STAGE 1

The compounds represented by formula (1) can be prepared by coupling the compound represented by formula (2) in the presence of a metal catalyst. More precisely, the compounds can be prepared, for example, by a Suzuki-Miyaura coupling reaction of a compound represented by formula (2) and a reagent represented by formula (6). For example, Pd(dppf)Cl ₂ , PdAmphos, Pd(PPh ₃ ) ₄ or the like can be used as a reaction catalyst. As the base, cesium carbonate, cesium fluoride, sodium carbonate or the like can be used. THF, 1,4-dioxane, DMF, acetonitrile or the like can be used as the reaction solvent. The reaction temperature is usually in the range from room temperature to 180°C.

[0098]

As the reagent represented by formula (6), commercially available boronic acid, pinacol esters and catechol esters can be used. It can also be prepared from available commercial sources of aryl bromide, aryl chloride and aryl iodide by metal-catalyzed coupling reaction or halogen-metal exchange reaction. More precisely, it can be obtained, for example, by a Suzuki-Miyaura coupling reaction with bis(pinacolate)diboron or the like. For example, Pd(dppf)Cl ₂ or the like can be used as a reaction catalyst. Potassium acetate or the like can be used as the base. As the reaction solvent, 1,4-dioxane or the like can be used. The reaction temperature may generally be in the range from 40 to 150°C. In addition to the two methods described above, the reagent represented by formula (6) can be prepared by a C-H bond activation boridation reaction in the presence of an iridium catalyst using an electron-donating bidentate ligand and a boron source such as bis(pinacolato)diboron without the addition of aryl halides.

[0099]

STAGE 2

The compound represented by formula (2) can be produced from the compound represented by formula (3) by a C-O bond formation reaction such as alkylation and Mitsunobu reaction, or a C-C bond formation reaction such as a metal-catalyzed coupling reaction. In the Mitsunobu reaction, OH groups are formed on the Q ¹ and Q ² moieties in formula (3), and the reaction is carried out by adding diethyl azodicarboxylate, diisopropyl azodicarboxylate or di-tert-butyl azodicarboxylate in the presence of triphenylphosphine. THF, toluene or the like can be used as the reaction solvent. In order for cyclization to proceed preferably as an intramolecular reaction rather than an intermolecular reaction, it is carried out under high dilution conditions from 0.1 to 0.001 mol/L. The reaction temperature may generally be in the range from room temperature to 80°C. The alkylation reaction can be accomplished through the formation of a hydroxyl group on the Q ¹ moiety and the removal of a group such as -Cl, -Br, -I, -OTf, -OMs, or -OTs on the Q ² moiety by performing the reaction under high dilution conditions in the presence of a base such as sodium hydride, potassium carbonate, cesium carbonate or diisopropylethylamine. THF, DMF, acetonitrile or the like can be used as the reaction solvent. The reaction temperature may generally be in the range from room temperature to 100°C.

[0100]

STAGE 3

The compound represented by formula (3) is synthesized by an alkylation reaction or metal-catalyzed coupling reaction of a substituted piperidine represented by formula (4) and a compound represented by formula (5). In particular, the alkylation reaction can be carried out in the presence of a base such as sodium hydride, potassium carbonate, cesium carbonate or diisopropylethylamine using THF, DMF, acetonitrile, DMF, acetonitrile or the like. as a reaction solvent at a temperature ranging from room temperature to 100°C to form a C-O or C-N bond.

Specifically, in a metal-catalyzed coupling reaction, a mixture of methanesulfonate [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2- (2'-amino-1,1'-biphenyl)] palladium(II) or tris(dibenzylideneacetone)dipalladium(0) as catalyst and dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl as the ligand, and phosphazene base P ₂ -Et or sodium phenoxide can be used as the base. THF, 1,4-dioxane, DMF, acetonitrile or the like can be used as the reaction solvent. The reaction temperature may generally be in the range from room temperature to 180°C. In addition, the compound represented by formula (3) can also be synthesized with a combination of reagents commonly used in the Buchwald-Hartwig cross-coupling reaction, thereby forming a C-O or C-N bond.

[0101]

[Formula 29]

SCHEME 2

[0102]

The compound represented by formula (4) can be prepared, for example, by the method shown in Reaction Scheme 2 (in compound formulas, Q ² represents, for example, a hydroxyl group, a leaving group such as -Cl, -Br, -I, - OTf, -OMs and -OTs, or a substituent capable of forming a C-O bond or a C-C bond, such as an alkenyl group and a borohydride derivative, and Q ³ is a substituent capable of forming a C-O bond or a C-C bond by reaction with the group LG ² such as hydroxyl group and amino group). The compounds represented by formulas (6) and (7) are available from commercial sources or can be prepared by known methods, such as those presented below, or similar.

[0103]

STAGE 4

The compound represented by formula (4) is synthesized by reducing the ketone moiety of the compound represented by formula (6). The reducing agent may be sodium borohydride, L-Selectolide or the like, which can only reduce the ketone moiety in the presence of an ester and an amide. The reaction is carried out using methanol, THF or the like as a solvent and usually occurs at a temperature in the range of -78°C to room temperature. When the Q ³ group is an amino group, the hydroxyl group formed by reduction undergoes conversion to a leaving group such as -Cl, -Br, -I, -OTf, -OMs and -OTs, then undergoes conversion to an azido group, and finally , in NH ₂ . For example, the secondary hydroxyl group may be converted to a leaving group by methanesulfonyl chloride, p-toluenesulfonyl chloride or the like. in the presence of a base such as triethylamine, in dichloromethane as solvent. The reaction usually takes place at a temperature in the range from 0 to 40°C. By reacting the resulting product with sodium azide in DMF, a Q ³ fragment-azidated compound can be obtained. The azido group can be reduced to the primary amino group by hydrogenation using palladium on carbon or palladium hydroxide or the Staudinger reaction using triphenylphosphine.

[0104]

STAGE 5

The compound represented by formula (6) is synthesized by amidation, esterification or acylation of the compound represented by formula (7). Specifically, a C _2-5 amino alcohol with a protected hydroxyl group or a C _2-5 diol with one protected hydroxyl group undergoes amide or ester bonding with the 4-oxopiperidine-2-carboxylic acid derivative represented by formula (7). As the condensing agent for amidation or esterification, 1-propanophosphoric anhydride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, HATU or the like can be used. HOBt, HOAt or the like can be used as the nucleophile for amidation. Diisopropylethylamine or the like can be used as the base. As the reaction solvent, for example, DMF, dichloromethane, THF or the like can be used. The reaction temperature may generally be in the range from 0 to 150°C. In the acylation reaction, the carboxylic acid moiety of the 4-oxopiperidine-2-carboxylic acid derivative may be activated with oxalyl dichloride, isobutyl chloroformate or the like. and then reacted with a _C2-5 protected amino alcohol or a single protected _C2-5 diol to form an amide or ester bond.

[0105]

Scheme 3 presents a second method for the synthesis of macrocyclic compounds, which is described below. First, the nitrogen-containing bicyclic heterocyclic ring mother core is reacted with a substituted piperidine to form an X ² bond, the resulting compound undergoes binding to the linker connecting fragments a and c. Further, as in Scheme 1, the final product is obtained through the formation of a macrocyclic ring and the introduction of an aromatic ring into a nitrogen-containing bicyclic heterocyclic ring mother core.

[0106]

The metal-catalyzed coupling reaction of the compound represented by formula (2) and the reagent represented by formula (6) (STEP 1) and the macrocycle formation reaction (STEP 2) using the compound represented by formula (3) as a starting material are common to the methods schemes 1 and 3.

[Formula 30]

scheme 3

[0107]

The compounds represented by formula (1) can be prepared, for example, by the method shown in reaction scheme 3 (in the compound formulas, M represents, for example, a substituent that can react with different types of coupling reactions using ZnI, MgBr, boronic acid, complex boronic acid ester or the like, LG ¹ and LG ² represent leaving groups such as -Cl, -Br, -I, -OTf, -OMs and -Ots, Q ¹ and Q ² represent, for example, hydroxyl a group, a leaving group such as -Cl, -Br, -I, -OTf, -OMs and -OTs, or a substituent capable of forming a C-O or C-C bond such as an alkenyl group and a borohydride derivative, and Q ³ is a substituent capable of forming a C-O or CN bond by the interaction of LG ² groups such as hydroxyl group and amino group). The compounds represented by formulas (2), (3), (5), (6), (8) and (9) are available from commercial sources or can be prepared according to known methods such as those shown below or the like.

[0108]

STAGE 6

The compound represented by formula (3) can be synthesized by amide or ester coupling of a C _2-5 amino alcohol with a protected hydroxyl group or a C _2-5 diol with a single hydroxyl group with a carboxylic acid represented by formula (8). The reaction used is an amidation reaction, an esterification reaction, an acylation reaction or the like. As the condensing agent for amidation or esterification, 1-propanephosphonic anhydride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, HATU or the like can be used. HOBt, HOAt or the like can be used as the nucleophile for amidation. Diisopropylethylamine or the like can be used as the base. As the reaction solvent, for example, DMF, dichloromethane, THF or the like can be used. The reaction temperature may generally be in the range from 0 to 150°C. In the acylation reaction, the carboxylic acid moiety may be activated using oxalyl dichloride, isobutyl chloroformate, or the like. and react with a _C2-5 protected amino alcohol or a single protected _C2-5 diol to form an amide or ester bond.

[0109]

STAGE 7

The compound represented by formula (8) is synthesized by alkylation or metal-catalyzed coupling reaction of the substituted piperidine represented by formula (9) with the compound represented by formula (5), and subsequent solvolysis of the resulting ester. The reaction conditions used for metal-catalyzed alkylation and coupling reactions are similar to those used in step 3 of Scheme 1. For ester hydrolysis, a base such as sodium hydroxide, potassium hydroxide and lithium hydroxide is used, and the reaction occurs at a temperature of 40 to 80 °C in a solvent such as methanol or ethanol. It is recommended to carry out reactions at 40°C to prevent isomerization at the chiral point at position 2 of piperidine. The compound represented by formula (9) can be synthesized by the method described in step 5 of Schemes 1 and 2. That is, it is synthesized from the 4-oxopiperidine-2-carboxylic acid derivative represented by formula (7) used as a starting material, methyl- esterification with trimethylsilyldiazomethane; or esterification using 1-propanephosphonic anhydride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidine, HATU or the like as a condensing agent.

[0110]

Scheme 4 shows the third method for the synthesis of macrocyclic compounds. In this method, a linker is first attached to link the substituted piperidine and moieties a and c, and then the resulting product is reacted with a nitrogen-containing bicyclic heterocyclic parent core to form an X ³ bond. After this, an X ² bond is formed to produce the macrocycle, and finally an aromatic ring is introduced, which must directly attach to the nitrogen-containing bicyclic heterocyclic parent core.

[Formula 31]

SCHEME4

[0111]

The compounds represented by formula (1) can be prepared, for example, by the method shown in reaction scheme 4 (in the compound formulas, M represents a substituent that can react through various types of coupling reactions using ZnI, MgBr, boronic acid, boronic ester acid or the like, LG ¹ and LG ² represent a leaving group such as -Cl, -Br, -I, -OTf, -OMs and -Ots, Q ¹ and Q ² represent, for example, a hydroxyl group, a leaving group such as -Cl, -Br, -I, -OTf, -OMs and -OTs, or or a substituent capable of forming a C-O or C-C bond, such as an alkenyl group or a borohydride derivative, and Q ³ represents is a substituent capable of forming a C-O or CN bond by interaction with an LG ² group, such as a hydroxyl group and an amino group). The compounds represented by formulas (2), (4)(b) and (10) are available from commercial sources or can be prepared according to known methods, such as those described below, or the like.

[0112]

STAGE 8

The compound represented by formula (11) is synthesized, for example, in a manner similar to that of step 10 of Scheme 3, through intramolecular alkylation or metal-catalyzed coupling reaction of the compound represented by formula (10). In this case, by carrying out the reaction under high dilution conditions where the substrate concentration is, for example, 0.1 to 0.001 mol/L to favor an intramolecular reaction rather than an intermolecular reaction, the compound represented by formula (11) can be synthesized.

[0113]

STAGE 9

The compound represented by formula (14) is synthesized by the intermolecular Mitsunobu reaction or the intermolecular alkylation reaction of the compound represented by formula (4) and the compound represented by formula (5). The reaction conditions are similar to those of step 2 of Scheme 1, but the reaction can be carried out under conditions where the substrate concentration is, for example, from 1.0 to 0.1 mol/l.

[0114]

Methods for preparing the compounds of the present invention are not limited to the methods described herein. For example, the compounds of the present invention can be prepared by modifying or converting substituents in the precursor compounds of the compounds of the present invention using one reaction or a combination of two or more reactions described in articles related to the field of chemistry and the like.

[0115]

Examples of the production method of compounds of the present invention that contain an asymmetric carbon atom include a production method based on asymmetric reduction, a method of using a commercially available starting material (or a starting material that can be prepared by a known method or the like) in which the moiety corresponding to the asymmetric carbon atom is already optically active, a method with optical separation, or a method for producing an optically active compound using an enzyme, etc. A method in which the compound of the present invention or its precursor is isolated as an optically active isomer by a conventional method can also be used. Examples of such a method include, for example, the method of using high performance liquid chromatography (HPLC) using a chiral column or supercritical fluid chromatography (SFC), classical fractional crystallization for the separation of optically active substances, including the formation of a salt with an optically active reagent, separation of fractional crystallization or the like and converting a salt into a compound in free base form, a method involving condensation with an optically active reagent to form a diastereomer, followed by separation, purification and decomposition of the resulting diastereomer, and the like. When the precursor is separated to obtain an optically active compound, the optically active compound of the present invention can then be produced by the above-described production methods with an optically active substance.

[0116]

When the compound of the present invention contains an acidic functional group such as a carboxyl group, a phenolic hydroxyl group or a tetrazole ring, the compound can be converted to a pharmaceutically acceptable salt (for example, inorganic sodium salts and the like, or organic triethylamine salts and the like .) using known methods. For example, when an inorganic salt is to be prepared, it is preferable to dissolve the compound of the present invention in water containing a hydroxide, carbonate, bicarbonate or the like corresponding to the desired inorganic salt. A water-miscible inactive organic solvent such as methanol, ethanol, acetone and dioxane may be added for the reaction. For example, by using sodium hydroxide, sodium carbonate or sodium bicarbonate, a sodium salt solution can be obtained.

[0117]

When the compound of the present invention contains an amino group, another basic functional group or an aromatic ring that already has basicity (for example, a pyridine ring, etc.), the compound can also be converted into a pharmaceutically acceptable salt (for example, a salt with an inorganic an acid such as hydrochloric acid, or a salt with an organic acid such as acetic acid) by known methods. For example, when a salt with an inorganic acid is to be prepared, it is preferable to dissolve the compound of the present invention in an aqueous solution containing the desired inorganic acid. A water-miscible inactive organic solvent such as methanol, ethanol, acetone and dioxane may be added for the reaction. For example, using hydrochloric acid can produce a hydrochloride solution.

[0118]

If a solid salt is needed, the solution can be evaporated or a water-miscible organic solvent of some polarity, such as n-butanol or ethyl methyl ketone, can be added to the solution to produce a solid salt.

The various compounds disclosed in the present invention can be purified by known methods, such as various chromatography techniques (column chromatography, flash column chromatography, thin layer chromatography, high performance liquid chromatography, supercritical fluid chromatography and the like).

[0119]

The compounds of the present invention, in accordance with a certain embodiment, have IRAK-4 inhibitory activity and can be used as an IRAK-4 inhibitor. That is, the compounds of the present invention, in accordance with a certain embodiment, can be used as a medicament for the prophylactic and/or therapeutic treatment of diseases associated with IRAK-4 inhibition. More precisely, a disease associated with IRAK-4 inhibition is a disease in which inhibition of IRAK-4 is effective, and more precisely, a disease associated with IRAK-4 inhibition is not particularly limited, provided that it can be prevented and/or treat by suppressing the production of inflammatory mediators, such as TNFα and IL-6, through inhibition of TLR or the IL-1 family of signal transduction system.

[0120]

IRAK-4 inhibitory activity can be quantified, for example, by the method described in Biological Assay Examples 1 and 2.

The disease associated with IRAK-4 inhibition is not particularly limited as long as it is a disease in which IRAK-4 inhibition is effective, and specific examples include, for example, acute or chronic inflammation, autoimmune diseases (rheumatoid arthritis, systemic erythematoses , lupus nephritis, etc.), autoinflammatory diseases (TNF receptor-associated periodic syndrome - TRAPS), familial Mediterranean fever, cryopyrine-associated periodic syndrome, high IgD syndrome, etc. ), metabolic disorders (gout, etc.), etc.

[0121]

In accordance with a certain embodiment, the compounds of the present invention have an inhibitory effect on TLR/IL-1β signaling and can be used as an active ingredient of a drug, as shown in the biological test examples presented below. In particular, the compounds of the present invention in accordance with a certain embodiment are preferably used for the prophylactic and/or therapeutic treatment of diseases in which IRAK-4 signaling is involved.

[0122]

The compounds of the present invention, in accordance with a certain embodiment, show significant selectivity for other kinases. Examples of other kinases include FLT3, ITK, CK2, IKKb, JAK1, Syk, PKC9 and p38. According to another embodiment, examples include, but are not limited to, FLT3.

The usefulness of a medicament of the present invention in accordance with a particular embodiment for the prophylactic and/or therapeutic treatment of a disease in which IRAK-4 signaling is involved in the pathological process can be confirmed, for example, by a cytokine production inhibition test using immunocytes or using a collagen model. induced arthritis. In particular, the method described in Biological Description Example 3 may be cited as a typical test example.

[0123]

The drug of the present invention according to a certain embodiment can be produced as a drug containing a compound represented by formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient, and the drug of the present invention also includes, for example, a drug containing a compound or a pharmaceutically acceptable salt thereof, which, when administered to a living body as a prodrug, is metabolized to produce the compound represented by formula (1) or a pharmaceutically acceptable salt thereof.

[0124]

Although the administration method of the drug of the present invention according to a certain embodiment is not particularly limited, the administration schedule may be suitably selected from, for example, oral administration, subcutaneous administration, intradermal administration, intramuscular injection, intravenous administration, perinasal administration, intravaginal administration, intrarectal injection, local injection into the affected part, etc.

[0125]

As the drug of the present invention, the compound represented by formula (1) or a pharmaceutically acceptable salt thereof can be used per se. However, it is preferable to add one or more kinds of pharmaceutically acceptable carriers to the compound represented by formula (1) or a pharmaceutically acceptable salt thereof to prepare a pharmaceutical composition and administer the composition. In addition, a hydrate or solvate of the compound represented by the general formula (1), or a pharmaceutically acceptable salt thereof, can be used as the active ingredient of the drug of the present invention.

[0126]

Examples of the dosage form used to prepare the above pharmaceutical composition include tablet, powder, granule, syrup, suspension, capsule, inhalation preparation, injection preparation and the like. For their production, various carriers suitable for obtaining drugs are used. Examples of the carrier of drugs for oral administration include excipients, binders, lubricants, fluidization accelerators and dyes. Examples of the method for using the composition as an inhalation drug include a method of inhaling a pharmaceutical composition in the form of a powder or a liquid dosage form obtained by dissolving or suspending the pharmaceutical composition in a solvent, a method of inhaling a mist of a pharmaceutical composition using a nebulizer called an atomizer or a nebulizer, and the like. When the composition is prepared in the form of an injection preparation, distilled water for injection, physiological saline solution, aqueous glucose solution, vegetable oil for injection, propylene glycol, polyethylene glycol and the like may generally be used as the diluent. If necessary, you can add disinfectants, antiseptics, stabilizers, isotonic agents, and emollients. A clathrate composition in which the compound of the present invention is clathrated into a cyclodextrin can also be prepared and used as a drug of the present invention.

[0127]

When administering the drug of the present invention in accordance with a certain embodiment, a suitable dosage form can be suitably selected and administered in an appropriate manner. For example, the drug may be administered orally in the form of a tablet, powder, granule, syrup, suspension, capsule or the like. The drug can also be administered through the respiratory tract in the form of an inhalation preparation. In addition, the drug may be administered subcutaneously, intradermally, intravascularly, intramuscularly, or intraperitoneally in the form of an injection, including drip infusion. In addition, the drug may be administered transmucosally in the form of a sublingual tablet, suppository, or the like, and may be administered transdermally in the form of a gel, lotion, ointment, cream, spray, or the like. The drug may also be administered in the form of a slow-release drug, for example, in the form of a sustained release injection and an injectable drug (eg, a film form drug, etc.).

[0128]

The administration period of the drug of the present invention according to a certain embodiment is not particularly limited. In general, the drug is administered during the period when the clinical symptoms of the disease are considered to be significant, and the administration usually continues for several weeks to one year. However, it is also possible to extend the administration period depending on the pathological conditions. The drug can also be administered prophylactically as prescribed by a doctor, even if clinical symptoms are not expressed. The dosage of the drug of the present invention according to a certain embodiment is not particularly limited. For example, when the drug of the present invention is administered orally, an adult may be prescribed from 0.01 to 1000 mg of the active ingredient per dose. As for the frequency of administration in the above case, administration may be carried out at a frequency of once every 6 months to daily administration, preferably once a day.

[0129]

The daily and/or once-daily dosage, administration period, and frequency of administration may be suitably increased or decreased depending on various conditions such as the age, body weight, physical health status of the patient, and the type and severity of the disease being treated. , method of administration and dosage form (possibility of delayed release of the active ingredient from the carrier, etc.).

[0130]

When the drug of the present invention according to a certain embodiment is used for the prophylactic and/or therapeutic treatment of the above-mentioned diseases, the drug of the present invention according to a certain embodiment can be used together with one or more kinds of drugs selected from the drugs described below, in the same thing or at different times. Moreover, the drug of the present invention according to a certain embodiment can be prepared in the form of a so-called combination drug together with drugs exemplified above and then administered. Such a combination preparation may be presented as a dosage form of a complete mixture of active ingredients, similar to typical compositions of this type, or in a dosage form, kit, or package comprising an unmixed combination of ingredients administered separately from two or more containers, each containing each active ingredient.

[0131]

Examples of drugs that can be used together with the drug of the present invention according to a certain embodiment include, for example, immunosuppressants (tacrolimus, cyclosporine, rapamycin, mycophenolate mofetil, interferon drugs, cyclophosphamide, azathioprine, methotrexate, etc.), antiphlogistics ( steroids (prednisolone, dexamethasone, betamethasone, cortisone, etc.) and nonsteroidal anti-inflammatory drugs (NSAIDs, ibuprofen, celecoxib, etc.), genetically engineered antirheumatic drugs (gold drugs, methotrexate, leflunomide, sulfasalazine, penicillamine, iguratimod, chloroquine, tofacitinib, etc.), antimalarials (hydroxychloroquine, etc.), therapeutic agents for the treatment of multiple sclerosis (interferon, drugs against α4-integrins, fingolimod, mitoxantrone, etc.) and anticytokine drugs (targeted drugs against TNFα, against IL-6, against IL-12/23, etc.). Examples also include biological drugs used as therapeutic agents for the treatment of autoimmune diseases (anti-CD20 drugs, CTLA-4-Ig, etc.), drugs for the treatment of disorders of uric acid metabolism (colchicine, probenecid, bucolom, benzbromarone, allopurinol etc.), hypoglycemic agents (alogliptin, nateglinide, acarbose, metformin, pioglitazone, insulin preparations, etc.), antihypertensive agents (imidapril, valsartan, candesartan, etc.), choleretic agents (ursodeoxycholic acid and etc.), bronchodilators (salmeterol and salbutamol, which are β2-agonists of adrenaline, ipratropium and tiotropium, which are anticholinergic drugs, etc.), therapeutic drugs for the treatment of allergic diseases (theophylline, etc. ), antiallergic drugs (fexoquinadine, epinastine, olopatadine, loratadine, cetirizine, bepotastine, ketotifen, sodium cromoglycate, pemirolast, chlorpheniramine, etc.), leukotriene antagonists (zafirlukast, montelukast, pranlukast, etc.), lipid-lowering drugs (atorvastatin, simvastatin, clinofibrate, bezafibrate, probucol, elastase, ethyl icosapentate, etc.), neurotransmitter control agents (donepezil, galantamine, memantine, etc.), antioxidants (vitamin E, acetylcysteine, carnitine, betaine, pentoxifylline and etc.) and antibiotics (various antibiotics of β-lactam type, macrolide type, tetracycline type, aminoglycoside type, quinolone type, etc., chloramphenicol, etc.). The drug of the present invention can also be used together with various types of drugs that will be developed in the future. These combination medicinal products are not limited in any way as long as they are clinically significant.

[0132]

The compounds of the present invention according to a certain embodiment include compounds exhibiting excellent safety (related to the absence of various toxicities and pharmacological safety) and excellent pharmacokinetic characteristics, etc., and the possibility of their use as an active ingredient of a drug can be confirmed, for example, using the methods described below.

[0133]

Examples of tests relating to safety include, but are not limited to, those described below. However, they are not limited to these examples. Examples include cytotoxicity tests (tests using HL60 cells, hepatocytes, etc.), genotoxicity tests (Ames test, mouse TK lymphoma test, chromosomal aberration test, micronucleus test, etc.), skin sensitivity tests (Bühler method, GPMT method, APT method, LLNA test, etc.), light sensitivity tests (adjuvant strip method, etc.), eye irritation tests (single instillation, short-term continuous instillation, repeated instillation, etc.) , pharmacological safety tests for the cardiovascular system (telemetry method, APD method, hERG inhibition assay, etc.), pharmacological safety tests for the central nervous system (FOB method, modified Irvine method, etc.), pharmacological safety tests for the respiratory system (method using a respiratory function measuring device, measurement method using a blood gas analyzer, etc.), general toxicity tests, reproductive toxicity and intrauterine toxicity tests, etc.

[0134]

Examples of tests relating to pharmacokinetic properties include, for example, the tests listed below. However, they are not limited to these examples. Examples include cytochrome P450 enzyme inhibition or induction tests, cell permeability tests (tests using CaCO-2 cells, MDCK cells, etc.), drug transporter ATPase assays, oral absorption tests, blood concentration transition tests, metabolism tests (stability test, molecular species test, reactivity test, etc.), solubility tests (turbidimetric solubility test, etc.), etc.

[0135]

The possibility of using the compounds of the present invention as an active ingredient of a drug according to a certain embodiment can be confirmed, for example, using a cytotoxicity test. Examples of the cytotoxicity test include methods using various cultured cells, for example, HL-60 cells, which are human preleukemia cells, primary isolated cultured hepatocyte cells, a neutrophil fraction prepared from human peripheral blood, and the like. Although the test may be performed using the procedure described below, it is not limited to the description provided. The cells are prepared in the form of a suspension with a concentration of 105 to 107 cells/ml, and the suspension is added to microtubes or microplates in a volume of 0.01 to 1 ml. A solution of the compound is added to the suspension in a volume of from 1/100 to 1 volume of the cell suspension, and the cells are cultured in cell culture medium with a final concentration of the compound from 0.001 to 1000 μM for 30 minutes to several days at 37°C at 5% _CO2 . After completion of incubation, cell survival is assessed using the MTT method, the WST-1 method (Ishiyama, M., et al., In Vitro Toxicology, 8, p. 187, 1995) or similar. By quantifying the cytotoxicity of a compound to cells, the potential for use of the compound as an active ingredient in a drug can be confirmed.

[0136]

The usefulness of the compounds of the present invention as an active ingredient of a drug according to a certain embodiment can be confirmed by, for example, a genotoxicity test. Examples of the genotoxicity test include the Ames test, mouse TK lymphoma test, chromosomal aberration test, micronucleus test and the like. The Ames test is a method for detecting reverse mutation by culturing certain species of Salmonella or Escherichia bacteria on microorganism culture plates or the like. and adding a compound thereto (see IYAKUSHIN (Notification by the chief of Evaluation and Licensing Division, Pharmaceutical and Medical Safety Bureau, Ministry of Health, Labor and Welfare, Japan), No. 1604, 1999, "Guideline for Genotoxicity Test", II-1. Genotoxicity Test, and the like). The Mouse Lymphoma TK Test is a test to detect the ability of a genetic mutation targeting the thymidine kinase gene of the L5178Y mouse lymphoma cell (see IYAKUSHIN No. 1604, 1999, "Guideline for Genotoxicity Test", 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, etc. .). The chromosomal aberration test is a method for determining the activity of initiating chromosomal aberration by

culturing mammalian cells in the presence of a compound, followed by cell fixation, staining and observation of cell chromosomes (see IYAKUSHIN No. 1604, 1999, "Guideline for Genotoxicity Test", II-2. Chromosomal Aberration Test Utilizing Mammalian Cultured Cells, and the like) . The micronucleus test, which is a method for assessing the ability to form micronuclei caused by chromosomal aberration, using a rodent method (in vivo test) can also be used (IYAKUSHIN No. 1604, 1999, "Guideline for Genotoxicity Test", II-4. Micronucleus Test Using Rodent; Hayashi M. et al., Mutat. Res., 312, pp. 293-304, 1994; Hayashi, M. et al., Mutagen., 35, pp. 234-252, 2000) , a method using cultured cells (in vitro test) (Fenech M., et al., Mutat. Res., 147, pp. 29-36, 1985; Miller, V., et al., Mutat. Res., 392, pp. 45-59, 1997), etc. Determining the genotoxicity of a compound using one or more of these methods can confirm the utility of the compound as an active ingredient in a drug.

[0137]

The possibility of using the compounds of the present invention as an active ingredient of a medicinal product according to a certain embodiment may be confirmed, for example, by a skin sensitivity test. Skin sensitivity tests include guinea pig skin sensitization tests, the Buehler method (Buehler, E.V., Arch. Dermatol., 91, pp. 171-177, 1965), the GPMT method (maximization method, Magnusson B., et al., J . Invest. Dermatol., 52, pp. 268-276, 1969), the APT method (adjuvant and patch test method (Sato, Y. et al., Contact Dermatitis, 7, pp. 225-237, 1981)), and etc. In addition, the LLNA (regional lymph node response assay) method can be used as a skin sensitivity test using a mouse (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., 25 (2), pp. 129-34, 2005) etc. Determining the ability of a compound to cause skin sensitization by one or more of these methods can confirm the utility of the compound as an active ingredient in a drug.

[0138]

The usefulness of the compounds of the present invention as an active ingredient of a medicinal product according to a particular embodiment can be confirmed, for example, by a skin photosensitivity test. Examples of the skin photosensitization test include the guinea pig skin photosensitization test (see "Drug Nonclinical Test Guideline Commentary 2002", Yakuji Nippo, published on 2002, 1-9: Skin Photosensitization Test, etc.) and the like. , other examples of methods include the "adjuvant and strip" method (Ichikawa, H. et al., J. Invest. Dermatol., 76, pp. 498-501, 1981), the Harber method (Harder, L.C., Arch. Dermatol., 96, pp. 646-653, 1967), Horio method (Horio, T., J. Invest. Dermatol., 67, pp.591-593, 1976), Jordan method ( Jordan (Jordan, W.P., Contact Dermatitis, 8, pp.109-116, 1982), Kochever's method (Kochever, I.E. et al., J. Invest. Dermatol., 73, pp. 14 4-14 6 , 1979), Maypepa (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. Determining the skin photosensitizing potential of a compound using one or more of these methods can confirm the utility of the compound as an active ingredient in a drug.

[0139]

In accordance with a certain embodiment, the use of the compounds of the present invention as an active ingredient of a drug can be confirmed, for example, by an ocular irritation test. Examples of the ocular irritation test include the single instillation test method (single instillation), the short-term continuous instillation test method (multiple instillations over a short period of time at equal intervals), the repeated (multiple) instillation test method over several days to several tens of days) using rabbit eyes, monkey eyes, etc., and a method for assessing symptoms of irritation of the ocular mucosa at certain time points after instillation in accordance with the refined Draize scale (Fukui, N. et al., Gendai no Rinsho) can be used , 4 (7), pp. 277-289, 1970), etc. Studying the eye irritant effect of a compound using one or more of these methods can confirm the utility of the compound as an active ingredient in a drug.

[0140]

The usefulness of the compounds of the present invention as an active ingredient of a medicinal product according to a particular embodiment may be confirmed by performing, for example, a cardiovascular pharmacological safety test. Examples of pharmacological safety tests for the cardiovascular system include the telemetry method (a method of quantifying the effect of administering a compound without anesthesia on the electrocardiogram, heart rate, blood pressure, blood flow, etc. (Electrocardiogram, Echocardiography, Blood Pressure and Pathological Tests of Animals Fundamental and Clinical Medicine, edited by Sugano S., Tsubone H., Nakada Y., published on 2003, Maruzen), APD method (measuring the action potential retention time of cardiac muscle cells (Muraki, K. et al., AM. J Physiol., 269, H524-532, 1995; Ducic, I. et al., J. Cardiovasc. Pharmacol., 30 (1), pp. 42-54, 1997), method for assessing hERG inhibition (potential clamp method). (patch clamp) (Chachin, M. et al., Nippon Yakurigaku Zasshi, 119, pp. 345-351, 2002), binding assay method (Gilbert, J. D. et al., J. Pharm. Tox. Methods, 50, pp. 187-199, 2004), Rb ⁺ efflex analysis method (Cheng, C.S. et al., Drug Develop. Indust. Pharm., 28, pp. 177-191, 2002), a method for assessing membrane potential (Dorn, A. et al., J. Biomol. Screen., 10, pp. 339-347, 2005)), etc. Determining the cardiovascular effects of a compound using one or more of these methods can confirm the utility of the compound as an active ingredient in a drug.

[0141]

The use of the compounds of the present invention as an active ingredient of a medicinal product according to a particular embodiment may be confirmed by performing, for example, a central nervous system pharmacological safety test. Examples of a pharmacological safety test for the central nervous system include the Functional Observational Battery (FOB) method (Functional Observational Battery, Mattson, J.L. et al., J. American College of Technology, 15 (3), pp. 239-254, 1996), modified Irwin method (method of assessment by observing general symptoms and behavior (Irwin, S., Comprehensive Observational Assessment (Berl.) 13, pp.222-257, 1968)), etc. Evaluating the effects of a compound on the central nervous system using one or more of these methods can confirm the utility of the compound as an active ingredient in a drug.

[0142]

The usefulness of the compounds of the present invention as an active ingredient of a medicinal product in accordance with a particular embodiment may be confirmed by performing, for example, a respiratory pharmacological safety test. Examples of a pharmacological safety test for the respiratory system include a method of quantitative determination using a respiratory function measuring device (a method for measuring respiratory rate, one-time 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), a method using a blood gas analyzer (a method for measuring the amount of gases in the blood, oxygen saturation of hemoglobin, etc.) p., Matsuo, S., Medicina, 40, pp. 188-, 2003), etc. Assessing the effect of a compound on the respiratory system using one or more of these methods can confirm the utility of the compound as an active ingredient in a drug.

[0143]

The possibility of using the compounds of the present invention as an active ingredient of a drug according to a certain embodiment may be confirmed, for example, by a general toxicity test. A general toxicity test is a method of single or repeated (over several days) oral or intravenous administration of a compound dissolved or suspended in a suitable solvent to a rodent such as rat and mouse, or non-rodent animal such as monkey and dog. with assessment through observation of general conditions, clinical and chemical changes, pathohistological changes, etc. in animals receiving the compound. Assessing the overall toxicity of a compound using these methods can confirm the utility of the compound as an active ingredient in a drug.

[0144]

The use of the compounds of the present invention as an active ingredient of a medicinal product according to a particular embodiment may be confirmed, for example, by a reproductive and intrauterine toxicity test. A reproductive and developmental toxicity test is a test examining the induction of harmful reproductive and developmental effects of a compound using rodents such as rats and mice, or non-rodent animals such as monkeys and dogs (see " Drug Nonclinical Test Guideline Commentary 2002", Yakuj i Nippo, published on 2002, 1-6: Reproductive and Developmental Toxicity Test, etc.). Examples of reproductive and intrauterine toxicity tests include tests related to fertility and early embryogenesis up to nidation, tests related to maternal development before and after birth, tests related to embryogenesis and fetal development (see IYAKUSHIN No. 1834, 2000, Appendix, "Guideline for Drug Toxicity Test", [3] Reproductive and Developmental Toxicity Test, etc.) etc. Assessing the reproductive and developmental toxicity of a compound using one or more of these methods can confirm the utility of the compound as an active ingredient in a drug.

[0145]

The possibility of using the compounds of the present invention as an active ingredient of a drug according to a particular embodiment can be confirmed, for example, by a cytochrome P450t enzyme inhibition or induction test (Gomez-Lechon, M.J. et al., Curr. Drug Metab., 5 (5), pp. . 443-462, 2004). Examples of a cytochrome P450 enzyme inhibition or induction test include, for example, a method for determining in vitro whether a compound inhibits the activity of a cytochrome P450 enzyme using a cytochrome P450 enzyme of each molecular species purified from cells or produced using a genetic recombinant or microsome of a human P450 expression system ( Miller, V.P. et al., Ann. N.Y. Acad. Sci., 919, pp. 26-32, 2000), a method for measuring changes in the expression of the cytochrome P450 enzyme of each molecular species using human liver microsomes or a suspension of destroyed cells ( Hengstler, J.G. et al., Drug Metab. Rev., 32, pp. 81-118, 2000), a method for extracting RNA from human hepatocytes exposed to a compound and comparing the amount of mRNA expression with a control to study the ability of the compound to induce enzymes (Kato , M. et al., Drug Metab. Pharmacokinet., 20 (4), pp. 236-243, 2005), etc. Evaluating the effect of a compound on the inhibition or induction of the cytochrome P450 enzyme using these methods can confirm the applicability of the compound in as an active ingredient in a drug.

[0146]

The usefulness of the compounds of the present invention as an active ingredient of a drug according to a particular embodiment may be confirmed, for example, by a reactive metabolite production test. Examples of a test that confirms the production of reactive metabolites include, for example, a method of incubating human liver microsomes in the presence of NADPH and fluorescently labeled glutathione using a dansyl group (dGSH), capturing the reactive metabolites as dGSH adducts, and completely detecting the peaks of reactive metabolites from the resulting quantities dGSH adducts based on fluorescence intensity used as an indicator (Junping Gan, et al., Chem. Res. Toxicol., 2005, 18, 896-903), a method of incubating an unlabeled compound with human liver microsomes in the presence of NADPH and measuring radioactivity carbon atom covalently bound to proteins (Baillie T.A., Drug Metabolizing Enzymes. Cytochrome P450 and Other Enzymes in Drug Discovery and Development, pp. 147-154, 2003), etc. Assessing a compound's risk of idiosyncratic drug toxicity, which is generated by the production of a reactive metabolite of the compound, using one or more of these methods can confirm the utility of the compound as an active ingredient in a drug.

[0147]

The possibility of using the compounds of the present invention as an active ingredient of a drug according to a certain embodiment may be confirmed, for example, by a cell permeability test. Examples of a cell permeability test include, for example, a method for measuring the permeability of a compound through a cell membrane in an in vitro cell culture system using CaCO-2 cells (Delie, F. et al., Crit. Rev. Ther. Drug Carrier Syst., 14, pp. 221-286, 1997; J. Pham Sci., 10, 2000; pp.1545-1558, 2003), a method for measuring the cell membrane permeability of a compound in an in vitro cell culture system using MDCK cells (Irvine, J.D. et al., J. Pham. Sci., 88, pp. 28-33, 1999 ) and so on. Assessing the cellular permeability of a compound using one or more of these methods can confirm the utility of the compound as an active drug ingredient.

[0148]

The utility of the compounds of the present invention as an active ingredient of a drug according to a particular embodiment can be confirmed by drug transporter ATPase assay for the ATP-binding cassette ABC. Examples of drug transporter ATPase assays include a method for determining whether a compound is a P-glycoprotein (P-gp) substrate using the baculovirus P-gp expression system (Germann, U.A., Methods Enzymol., 292, pp. 427-41, 1998) and so on. In addition, feasibility can also be confirmed by a transport test using oocytes collected from the African clawed frog (Xenopus laevis) for a solute carrier (SLC). Transfer assays include a method of testing whether a test compound is an OATP2 substrate using oocytes expressing OATP2 (Tamai I. et al., Pharm. Res., 2001 September; 18 (9), 1262-1269), and the like. Evaluating the effect of a compound on the ABC transporter or the SLC transporter using these methods can confirm the utility of the compound as an active ingredient in a drug.

[0149]

The possibility of using the compounds of the present invention as an active ingredient of a medicinal product according to a certain embodiment may be confirmed, for example, by an oral absorption test. Examples of the oral absorption test include a method of oral administration to a rodent, monkey, dog or the like. a specified amount of the compound dissolved or suspended in a suitable solvent, with the level of the compound in the blood after oral administration quantified over time using the LC-MS/MS method ("Newest Mass Spectrometry for Life Science", Kodansha Scientific, 2002, edited by Harada K. et al, etc.) to evaluate the transfer into the blood of a compound administered orally, etc. Estimates of the oral absorption of a compound using these methods can confirm the utility of the compound as an active ingredient in a drug.

[0150]

The usefulness of the compounds of the present invention as an active ingredient of a medicinal product according to a particular embodiment may be confirmed, for example, by a blood concentration transition test. Examples of a blood concentration transition test include a method of administering a compound orally or parenterally (eg, intravenously, intramuscularly, intraperitoneally, subcutaneously, transdermally, instillation, nasally, etc.) to a rodent, monkey, dog, or the like, and measuring the change in level the content of the compound in the blood over time after administration using the LC-MS/MS method ("Newest Mass Spectrometry for Life Science", Kodansha Scientific, 2002, edited by Harada K. et al, etc.) etc. Assessing the blood concentration transition of a compound using these methods can confirm the utility of the compound as an active ingredient in a drug.

[0151]

The possibility of using the compounds of the present invention as an active ingredient of a drug according to a certain embodiment may be confirmed, for example, by a metabolic test. Examples of a metabolic test include a method for assessing stability in blood (a method for predicting in vivo metabolic clearance based on the rate of metabolism of a compound in labeled microsomes of humans or other animal species (see 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.), method for determining molecular species of metabolites, method for determining reactive metabolites and etc. Evaluation of the metabolic profile of a compound using these methods can confirm the utility of the compound as an active ingredient in a drug.

[0152]

The possibility of using the compounds of the present invention as an active ingredient of a drug according to a certain embodiment can be confirmed, for example, by a solubility test. As a method for assessing water solubility, examples are given of methods to confirm solubility under acidic conditions, neutral conditions or basic conditions, as well as methods to confirm changes in solubility depending on the presence or absence of bile acid. Examples of a solubility test include a solubility test based on the turbidimetric method (Lipinski, C.A. et al., Adv. Drug Deliv. Rev., 23, pp. 3-26, 1997; Bevan, CD. et al., Anal. Chem., 72, pp. 17 81-17 87, 2000), etc. Assessing the solubility of a compound using these methods can confirm the utility of the compound as an active ingredient in a drug.

[0153]

The usefulness of the compounds of the present invention as an active ingredient of a drug according to a particular embodiment can be confirmed, for example, by examining upper gastrointestinal tract injury, renal dysfunction, and the like. As a pharmacological test for the upper gastrointestinal tract, a gastric mucosal study can be performed using a fasting rat gastric mucosal injury model. Examples of a pharmacological test of renal function include a method for measuring renal blood flow [Physiology, 18th edition, Bunkodo, 1986, Chapter 17] and the like. Assessing the effects of a compound on the upper gastrointestinal tract and renal function using these methods can confirm the utility of the compound as an active ingredient in a drug.

Examples

[0154]

Hereinafter, the present invention will be explained in more detail with reference to examples and biological test tests (hereinafter may be collectively referred to as “examples, etc.”). However, the scope of the present invention is not limited to the examples given.

All purchased reagents are used without additional purification. I use purchased anhydrous solvents without additional drying. For column chromatography, use a medium-pressure preparative purification system manufactured by YAMAZEN, SmartFlash, or a medium-pressure preparative purification system manufactured by BIOTAGE, Isolera ONE, to which a BIOTAGE Dalton is connected as an MS detector. The column used is SNAP Ultra from BIOTAGE or DispoPack AT from YMC. In some cases, purification is performed using BondElute SCX from Agilent as the ion exchange resin. BondElute SCX may be referred to simply as SCX from now on. An example of the SCX method is to flush the cartridge with methanol and dichloromethane, then adsorb the crude product dissolved in a minimal volume of solvent (e.g., a mixed solvent of dichloromethane and methanol, or the like), then flush the impurities with methanol under increasing pressure, and elute the product 2 .0 M ammonia solution in methanol. For thin layer chromatography (TLC), precoated silica gel 60 F254 (manufactured by Merck, product number 5715-1 M) was used. After developing chromatograms with a mixture of chloroform:methanol (1:0 to 1:1) or ethyl acetate:hexane (1:0 to 0:1), the presence of the compound is confirmed by UV irradiation (254 nm or 365 nm) or staining with iodine solution, aqueous solution potassium permanganate, phosphomolybdic acid (solution in ethanol), etc. Preparative thin layer chromatography (hereinafter also referred to as “PTLC”) is performed using one or more PLC Plate Silica Gel 60 F254 (20 × 20 cm, layer thickness 2 mm, including concentration zone (4 cm), manufactured by Merck, product number 13793- 1 M) depending on the amount of sample. Anhydrous magnesium sulfate or anhydrous sodium sulfate is used to dry organic solvents.

[0155]

NMR

For analysis using the 1H (4 00 MHz) nuclear magnetic resonance (hereinafter abbreviated as NMR) method, use AVANCE III HD-400MHz manufactured by Bruker or AVANCE III HD-600MHz manufactured by Bruker.

Known solvents or additives are used as internal standards. 1H NMR data are chemical shifts in parts per million (hereinafter abbreviated as ppm), integral values (described, for example, as 1H) and multiplets ("s" means singlet, "d" means doublet, "t" means triplet, "q" means quartet, "qui" means quintet, "m" means multiplet, "ush." means broadened, "dd" means doublet of doublets, etc.).

[0156]

For LCMS, the mass spectrum is obtained using liquid chromatography-mass spectrometry (LC-MS). Unless otherwise specified, the mass spectrometer used is a single quadrupole mass spectrometer SQD System (manufactured by Waters), and measurements are performed by electrospray ionization (ESI). The liquid chromatography apparatus used is Acquity Ultra Performance LC System manufactured by Waters. ACQUITY UPLC VEN C18 (2.1×50 mm, 1.7 µm) manufactured by Waters is used as a separation column.

[0157]

When LC conditions are specifically indicated in the Examples and Reference Examples, it means that the measurement is carried out with the specified solvent under the specified conditions, "m/z" means mass spectrum data (MH ⁺ or MH- are also indicated).

[0158]

(LC-1) Measurement is carried out under the following conditions: elution at a volumetric flow rate of 0.6 ml/minute using a linear gradient from 5 to 90% (v/v) solution B (acetonitrile) in solution A (10 mM aqueous acetate solution ammonium) from 0 to 2.0 minutes and then a linear gradient from 90 to 98% (v/v) solution B in solution A from 2.0 to 2.5 minutes.

[0159]

(LC-6) The measurement is carried out under the following conditions: elution is carried out at a volumetric flow rate of 0.6 ml/minute using a linear gradient from 70 to 90% (v/v) solution B (acetonitrile) in solution A (10 mM aqueous acetate ammonium) from 0 minutes to 2.0 minutes and then a linear gradient from 90 to 98% (v/v) solution B in solution A from 2.0 to 2.5 minutes.

[0160]

For HPLC purification, a preparative purification system manufactured by Waters Japan and a Triart C18 ExRS column (manufactured by YMC) or the like are used, and 10 mM aqueous ammonium acetate/acetonitrile is used as the eluent.

[0161]

The abbreviation “quantitative” indicated in the description of the following examples and methods for synthesizing intermediate compounds means that the target compound was obtained in quantitative yield.

[Formula 32]

Method A-1

[0162]

Intermediate A-1-2: 6-Bromo-3-fluoro-2-nitrophenol

[Formula 33]

[0163]

3-fluoro-2-nitrophenol (intermediate A-1-1, 30.9 g, 196 mmol) is dissolved in acetonitrile (20 ml) and concentrated sulfuric acid (44 ml) is added to the resulting solution, maintaining the temperature at 30° C or lower. Next, a solution of N-bromosuccinimide (35.4 g, 198 mmol) in acetonitrile (281 ml) was added dropwise to the reaction mixture over 1 hour 30 minutes under ice-cooling. The reaction mixture is then stirred for 12 hours, during which time the temperature of the mixture spontaneously rises from 0° C. to room temperature. After completion of the reaction, ice water (300 ml) was added to the reaction mixture, the resulting mixture was extracted with ethyl acetate, and then the organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The resulting crude product (62.1 g) was a mixture of the target compound and the bromine position isomer, but the resulting crude product was used in the next step without separation and purification.

LCMS (LC-1): RT=1.03, m/z 234 [M-H] ⁺ .

[0164]

Intermediate A-1-3: 2-(Benzyloxy)-1-bromo-4-fluoro-3-nitrobenzene

[Formula 3 4]

[0165]

b-Bromo-3-fluoro-2-nitrophenol (intermediate A-1-2, 62.1 g, mixture of bromine position isomers mentioned above) is dissolved in acetonitrile (1000 ml), benzyl bromide (2 4 .6 ml, 206 mmol) and potassium carbonate (95.0 g, 689 mmol) and stir the resulting mixture at 90°C for 1 hour. Water (300 ml) was added to the reaction mixture at room temperature, the resulting mixture was extracted with ethyl acetate, and then the organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, gradient elution: hexane:ethyl acetate = 100:0 to 40:60) to give 2-(benzyloxy)-1-bromo-4-fluoro-3-nitrobenzene (17.5 g , yield for 2 stages 2 7%).

LCMS (LC-1): RT=1.95 (determined only in UV).

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).

[0166]

Intermediate A-1-4: Methyl (3-(benzyloxy)-4-bromo-2-nitrophenyl)glycinate

[Formula 35]

[0167]

2-(Benzyloxy)-1-bromo-4-fluoro-3-nitrobenzene (intermediate A-1-3, 30.5 g, 93.5 mmol) and methylglycine hydrochloride hydrochloride (41.1 g, 327 mmol) are dissolved in acetonitrile (467 ml), N,N-diisopropylethylamine (95.0 ml, 542 mmol) and 4A molecular sieves (30.5 g) were added to the resulting solution and the resulting mixture was stirred at 50°C for 72 hours. The reaction mixture was then filtered through a pad of celite, the filtrate was extracted with ethyl acetate, and the organic layer was washed with water and brine. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, gradient elution, hexane:ethyl acetate = 100:0 to 50:50) to obtain a crude product (43.1 g). The resulting product is 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).

[0168]

Intermediate A-1-5: 8-(Benzyloxy)-7-bromo-3,4-dihydroquinoxalin-2(1H)-one

[Formula 3 6]

[0169]

Ethanol (550 ml) and water (550 ml) were added to methyl (3-(benzyloxy)-4-bromo-2-nitrophenyl) glycinate (intermediate A-1-4, 43.1 g, mentioned above as crude product), iron (97.5 g, 174 4 mmol) and ammonium chloride (58.3 g, 10 90 mmol) to obtain a suspension, which is stirred at 80°C for 4 hours. After completion of the reaction, ethanol (100 ml) and chloroform (100 ml) were added to the reaction mixture at room temperature, and the resulting mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to obtain crude product (29.6 g). The resulting product is used in the next reaction without further purification.

LCMS (LC-1): RT=1.51, m/z 331 [M-H] ⁺ .

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).

[0170]

Intermediate A-1-6: 8-(Benzyloxy)-7-bromoquinoxalin-2(1H)-one

Formula 37]

[0171]

8-(Benzyloxy)-7-bromo-3,4-dihydroquinoxalin-2(1H)-one (intermediate A-1-5, 2 9.6 g, mentioned above as crude product) was dissolved in tetrapidrofuran (592 ml) , manganese dioxide (27.0 g, 311 mmol) was added to the resulting solution and the resulting mixture was stirred at 70°C for 12 hours. After completion of the reaction, tetrapidrofuran (300 ml) was added to the reaction mixture at room temperature and the resulting mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure, then tetrapidrofuran (40 ml), ethyl acetate (250 ml) and hexane (250 ml) were added to the resulting solid residue, and the resulting mixture was stirred at room temperature for 30 minutes. The suspension is filtered and the recovered solid is dried under reduced pressure to give 8-(benzyloxy)-7-bromoquinoxalin-2(1H)-one (19.9 g, 64% yield over 3 steps).

LCMS (LC-1): RT=1.49, m/z 331 [M+H] ⁺ .

1H-NMR (CDCl ₃ ): δ (ppm) 9.05 (1H, br. s), 8.18 (1H, s), 7.55-7.48 (2H, m), 7, 47-7.36 (5H, m), 5.18 (2H, s).

[0172]

Intermediate A-1-7: 8-(Benzyloxy)-7-bromo-2-chloroquinoxaline

[Formula 38]

[0173]

8-(Benzyloxy)-7-bromoquinoxalin-2(1H)-one (intermediate A-1-6, 1.0 g, 3.02 mmol) was dissolved in thionyl chloride (10 ml) and N,N- was added to the solution. dimethylformamide (0.234 ml, 3.02 mmol) and stir the resulting mixture at 80°C for 1 hour. After completion of the reaction, water (30 ml) was added to the reaction mixture at room temperature, the resulting mixture was extracted with ethyl acetate, and then the organic layer was washed with water and brine. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, gradient elution, hexane:ethyl acetate = 100:0 to 60:40) to give 8-(benzyloxy)-7-bromo-2-chloroquinoxaline (644 mg, 61% yield).

LCMS (LC-1): RT=2.Q6, 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).

[0174]

[Formula 39]

Method A-2

[0175]

Intermediate A-2-3: tert-Butyl-(S)-2-((3-((tert-butyldiphenylsilyl)oxy)propyl)carbamoyl)-4-oxopiperidine-1-carboxylate

[Formula 40]

[0176]

(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), to the resulting solution While cooling with ice, add triethylamine (1.32 ml, 9.69 mmol) and isobutyl carbonochloridate (1.02 ml, 7.7 5 mmol) and stir the resulting mixture for 30 minutes. 3-((tert-Butyldiphenylsilyl)oxy)propan-1-amine (Intermediate A-2-2, 2.43 g, 7.76 mmol) was then added to the reaction mixture, and the resulting mixture was stirred at room temperature for 1 hour . After completion of the reaction, water (50 ml) was added to the reaction mixture, the resulting mixture was extracted with ethyl acetate, and then the organic layer was washed with water and brine. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, gradient elution: hexane:ethyl acetate = 100:0 to 70:30) to give tert-butyl-(S)-2-((3-((tert-butyldiphenylsilyl)oxy) propyl)carbamoyl)-4-oxopiperidine-1-carboxylate (2.15 g, 62% yield).

ZhKMS (ZhK-1): RT=2.26, t/z 539 [M+N] ⁺ .

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, br. s), 4.82 (1H, m), 3.96-3.80 (1H, m), 3.69 (2H, t, J=5.4 Hz), 3.55 (1Н, dd, J=13.3, 8.3, 5.0 Hz), 3.39 (2Н, m), 2.82 (1Н, dd, J=16.5, 2.8 Hz), 2.64-2.46 (2H, m), 2.45-2.35 (1H, m), 1.72 (1H, kV, J=6.3 Hz), 1.59-1.52 ( 1H, m), 1.47 (9H, s), 1.05 (9H, s).

[0177]

Intermediate A-2-4: tert-Butyl-(23,4R)-2-((3-((tert-butyldiphenylsilyl)oxy)propyl)carbamoyl)-4-hydroxypiperidine-1-carboxylate

[Formula 41]

[0178]

tert-Butyl-(S)-2-((3-((tert-butyldiphenylsilyl)oxy)propyl)carbamoyl)-4-oxopiperidine-1-carboxylate (intermediate A-2-3, 2.15 g, 4, 00 mmol) is dissolved in tetrahydrofuran (8 ml), a 1 M solution of L-Select, ride in tetrahydrofuran (6.0 ml, 6.00 mmol) is added to the resulting solution at -78°C and the resulting mixture is stirred for 1 hour. After completion of the reaction, a saturated aqueous ammonium chloride solution (20 ml) was added to the reaction mixture, the resulting mixture was extracted with ethyl acetate, and then the organic layer was washed with water and brine. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, gradient elution, hexane:ethyl acetate = 100:0 to 0:100) to give tert-butyl-(2S,4R)-2-((3-((tert-butyldiphenylsilyl) hydroxy)propyl)carbamoyl)-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, br. s), 5.75 (1H, br. s), 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).

[0179]

Intermediate A-2-5: tert-Butyl-(2S,4R)-2-((3-((tert-butyldiphenylsilyl)oxy)propyl)carbamoyl)-4-((methylsulfonyl)oxy)piperidine-1-carboxylate

[Formula 42]

[0180]

tert-Butyl-(2S,4R)-2-((3-((tert-butyldiphenylsilyl)oxy)propyl)carbamoyl)-4-hydroxypiperidine-1-carboxylate (intermediate A-2-4, 1.72 g, 3.19 mmol) was dissolved in dichloromethane (6.4 ml), triethylamine (0.80 ml, 5.74 mmol) and methanesulfonyl chloride (0.345 ml, 4.47 mmol) were added to the resulting solution while cooling with ice, and the resulting mixture was stirred at 0°C for 2 hours. Water (20 ml) was then added to the reaction mixture at room temperature, the resulting mixture was extracted with ethyl acetate, and then the organic layer was washed with water and brine. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude product (2.46 g) was used in the next reaction without further purification.

LCMS (LC-1): RT=2.25, t/z 619 [M+H] ⁺ .

[0181]

Intermediate A-2-6: tert-Butyl-(2S,4S)-4-azido-2-((3-((tert-butyldiphenylsilyl)oke)propyl)carbamoyl)piperidine-1-carboxylate

[Formula 43]

[0182]

tert-Butyl-(2S,4R)-2-((3-((tert-butyldiphenylsilyl)oxy)propyl)carbamoyl)-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (intermediate A-2-5 , 2.46 g, mentioned above as crude product) was dissolved in N,N-dimethylformamide (40 ml), sodium azide (388 mg, 5.79 mmol) was added to the resulting solution and the resulting mixture was stirred at 90°C for 6 hours. After completion of the reaction, water (20 ml) was added to the reaction mixture at room temperature, the resulting mixture was extracted with ethyl acetate, and then the organic layer was washed with water and brine. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, gradient elution, hexane:ethyl acetate = 100:0 to 80:20) to give tert-butyl-(2S,4S)-4-azido-2-((3-(( tert-butyldiphenylsilyl)oxy)propyl)carbamoyl)piperidine-1-carboxylate (362 mg, 20% yield for 2 steps).

LCMS (LC-1): RT=2.47, t/z 566 [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 (0.5N, 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, fifth, J=6.4 Hz), 1.49-1.23 (12H, m) , 1.05 (9H, s), 0.91-0.84 (1H, m).

[0183]

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

[Formula 44]

[0184]

tert-Butyl-(2S,4S)-4-azido-2-((3-((tert-butyldiphenylsilyl)oxy)propyl)carbamoyl)piperidine-1-carboxylate (intermediate A-2-6, 362 mg, 0 .64 mmol) was dissolved in methanol (6.4 ml), palladium hydroxide (181 mg, 50% by weight) was added to the solution and the resulting mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The atmosphere in the reaction system is replaced with nitrogen and then the reaction mixture is filtered through a pad of celite. The filtrate is concentrated under reduced pressure to give tert-butyl(2S,4S)-4-amino-2-((3-((tert-butyldiphenylsilyl)oxy)propyl)carbamoyl)piperidine-1-carboxylate (345 mg, yield 97 %).

LCMS (LC-1): RT=1.93, m/z 5 40 [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 (0.5N, 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).

[0185]

[Formula 45]

Method A-3

Method A-3

[0186]

Intermediate A-3-1: tert-Butyl-(2S,4S)-4-((8-(benzyloxy)-7-bromoquinoxalin-2-yl)amino)-2-((3-((tert-butyldiphenylsilyl )hydroxy)propyl)carbamoyl)piperidine-1-carboxylate

[Formula 46]

[0187]

tert-Butyl-(2S,4S)-4-amino-2-((3-((tert-butyldiphenylsilyl)oxy)propyl)carbamoyl)piperidine-1-carboxylate (intermediate A-2-7, 345 mg, 0 .64 mmol) is dissolved in dimethyl sulfoxide (5.8 ml), 8-(benzyloxy)-7-bromo-2-chloroquinoxaline (intermediate A-1-7, 202 mg, 0.5 82 mmol) is added to the resulting solution and N,N-diisopropylethylamine (0.15 2 ml, 0.87 mmol) and stir the resulting mixture at 120°C for 12 hours. After completion of the reaction, water (30 ml) was added to the reaction mixture, the resulting mixture was extracted with ethyl acetate, and then the organic layer was washed with water and brine. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, gradient elution, chloroform:methanol = 100:0 to 90:10) to give tert-butyl-(2S,4S)-4-((8-(benzyloxy)-7- bromoquinoxalin-2-yl)amino)-2-((3-((tert-butyldiphenylsilyl)oxy)propyl)carbamoyl)piperidine-1-carboxylate (147 mg, 27% yield).

LCMS (LC-1): RT=2.31, t/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, br. s), 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 (10N, m).

[0188]

Intermediate A-3-2: tert-Butyl-(2S,4S)-4-((8-(benzyloxy)-7-bromoquinoxalin-2-yl)amino)-2-((3-hydroxypropyl)carbamoyl)piperidine -1-carboxylate

[Formula 47]

[0189]

tert-Butyl-(2S,4S)-4-((8-(benzyloxy)-7-bromoquinoxalin-2-yl)amino)-2-((3-((tert-butyldiphenylsilyl)oxy)propyl)carbamoyl)piperidine -1-carboxylate (intermediate A-3-1, 147 mg, 0.172 mmol) is dissolved in tetrahydrofuran (0.86 ml), a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.863 ml, 0.863 mmol) is added to the resulting solution and the resulting solution is stirred mixture at room temperature for 2 hours. After completion of the reaction, the reaction mixture was purified using automated column chromatography (silica gel, gradient elution, chloroform:methanol = 100:0 to 80:20) to give tert-butyl-(2S,4S)-4-((8-( benzyloxy)-7-bromoquinoxalium-2-yl)amino)-2-((3-hydroxypropyl)carbamoyl)piperidine-1-carboxylate (104 mg, 98% yield).

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, br. s), 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).

[0190]

Intermediate A-3-3: tert-Butyl-(2S,4S)-2-((3-(benzoyloxy)propyl)carbamoyl)-4-((8-(benzyloxy)-7-bromoquinoxalin-2-yl) amino)piperidine-1-carboxylate

[Formula 48]

[0191]

tert-Butyl-(2S,4S)-4-((8-(benzyloxy)-7-bromoquinoxalium-2-yl)amino)-2-((3-hydrokeipropyl)carbamoyl)piperidine-1-carboxylate (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), benzoyl chloride (0.024 ml, 0.20 mmol) and N,N-dimethylaminepyridine (2 mp, 0.017 mmol) and stir the resulting mixture at room temperature for 1 hour. After completion of the reaction, the reaction mixture was purified using automated column chromatography (silica gel, gradient elution, chloroform:methanol = 100:0 to 90:10) to give tert-butyl-(2S,4S)-2-((3-( benzoyl oxide)propyl)carbamoyl)-4-((8-(benzyloxy)-7-bromoquinoxalin-2-yl)amino)piperidium-1-carboxylate (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).

[0192]

Intermediate A-3-4: 3-((2S,4S)-4-((7-Bromo-8-hydroxyquinoxalin-2-yl)amino)piperidin-2-carboxamido)propyl benzoate

[Formula 49]

[0193]

tert-Butyl-(2S,4S)-2-((3-(benzoyloxy)propyl)carbamoyl)-4-((8-(benzylocea)-7-bromoquinoxalin-2-yl)amino)piperidine-1-carboxylate ( intermediate A-3-3, 108 mg, 0.12 mmol) is dissolved in dichloromethane (2.5 ml), a 1 M solution of boron tribromide in dichloromethane (0.742 ml, 0.74 mmol) is added to the solution while cooling and then stirred the resulting mixture for 30 minutes. After the disappearance of the starting materials, methanol (2.5 ml) was added dropwise to the reaction mixture at 0°C to complete the reaction reaction. The resulting reaction mixture was purified by SCX to give 3-((2S,45)-4-((7-bromo-8-hydroxyquinoxalin-2-yl)amino)piperidin-2-carboxamido)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, br. s), 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, fifth, 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).

[0194]

Intermediate A-3-5: tert-Butyl-(2S,4S)-2-((3-(benzoyloxy)propyl)carbamoyl)-4-((7-bromo-8-hydroxyquinoxalin-2-yl)amino) piperidine-1-carboxylate

[Formula 50]

[0195]

3-((2S,4S)-4-((7-Bromo-8-hydroxyquinoxalin-2-yl)amino)piperidin-2-carboxamido)propyl benzoate (intermediate A-3-4, 77 mg, 0.146 mmol) dissolve in dichloromethane (7.4 ml), triethylamine (0.204 ml, 1.46 mmol) and di-tert-butyl dicarbonate (240 mg, 1.10 mmol) were added to the solution and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture is then purified directly using automated column chromatography (silica gel, gradient elution, chloroform:methanol = 100:0 to 80:20) to give tert-butyl-(2S,4S)-2-((3-(benzoyloxy ) propyl)carbamoyl)-4-((7-bromo-8-hydroxyquinoxalin-2-yl)amino)piperidine-1-carboxylate (77 mg, 84% yield).

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).

[0196]

Intermediate A-3-6: tert-Butyl-(2S,4S)-4-((7-bromo-8-hydroxyquinoxalin-2-yl)amino)-2-((3-hydroxypropyl)carbamoyl)piperidine-1 -carboxylate

[Formula 51]

[0197]

tert-Butyl-(2S,4S)-2-((3-(benzoyloxy)propyl)carbamoyl)-4-((7-bromo-8-hydroxyquinoxalin-2-yl)amino)piperidine-1-carboxylate (intermediate A-3-5, 77 mg, 0.12 mmol) is dissolved in methanol (2.5 ml), potassium carbonate (170 mg, 1.2 3 mmol) is added to the solution and the resulting mixture is stirred at room temperature for 15 minutes . The reaction mixture was then purified using automated column chromatography (silica gel, gradient elution, chloroform:methanol = 100:0 to 60:40) to give tert-butyl-(2S,4S)-4-((7-bromo-8 -Hydroxyquinox alium-2-yl)amino)-2-((3-hydroxypropyl)carbamoyl)piperidine-1-carboxylate (45 mg, 70% yield).

LCMS (LC-1): RT=1.47, t/z 524 [M+H] ⁺ .

1H-NMR (CDCl ₃ ): δ (ppm) 8.88 (1H, br. s), 8.26-8.17 (1H, m), 7.70-7.44 (1H, m ), 7.33-7.28 (1H, m), 6.68 (1H, br. s), 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).

[0198]

Intermediate A.-3-7: tert-Butyl-(3 ² S,3 ⁴ S)-1 ⁷ -bromo-4-oxo-9-oxa-2,5-diaza-1(2,8)-quinoxaline -3(4,2)-piperidium acyclononaphane-3 ¹ -carboxylate

[Formula 52]

[0199]

tert-Butyl-(2S,4S)-4-((7-bromo-8-hydrokeiquinoxalium-2-yl)amino)-2-((3-hydroxypropyl)carbamoyl)piperidine-1-carboxylate (intermediate A.- 3-6, 45 mg, 0.086 mmol) dissolved in tetrahydrofuran (17.2 ml), triphenylphosphine (56 mg, 0.22 mmol) and a 20% solution of di-tert-butyl azodicarboxylate in toluene (0.30 ml) were added to the solution. and stir the resulting mixture at room temperature for 12 hours. The reaction mixture is then concentrated under reduced pressure. The resulting crude product was purified using automated column chromatography (silica gel, gradient elution, chloroform:methanol = 100:0 to 90:10) to give tert-butyl-( ^32S , ^34S )-17-bromo-4 -oxo-9-oxa-2,5-diaza-1(2,8)-quinoxaline-3(4,2)-piperidinecyclonaphane-3 ¹ -carboxylate (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 (1.5N, m), 4.91-4.85 (0.5N, m), 4.47-4.38 (1H, m), 4.35-4.26 (1.5N, m ), 4.19-4.01 (1.5N, m), 3.86-3.71 (1.5N, m), 3.70-3.59 (0.5N, 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 (1.5N, m).

[0200]

[Formula 53]

Method B-1

[0201]

Intermediate B-1-2: 1-(tert-Butyl)-2-methyl-(S)-4-oxopiperidine-1,2-dicarboxylate

[Formula 54]

[0202]

(S)-1-[tert-Butoxycarbonyl)-4-oxopiperidine-2-carboxylic acid [intermediate E-1-1, 33.9 g, 160 mmol] was dissolved in a mixture of toluene (800 ml) and methanol (266 ml ), a 2 M solution of trimethylsilyldiazomethane 6 diethyl ether [100 ml, 200 mmol] was added dropwise to the solution while cooling with ice and the resulting mixture was stirred at room temperature for 3 hours. After completion of the reaction, acetic acid (100 ml) was added to the reaction mixture under ice-cooling, and the resulting mixture was concentrated under reduced pressure. Water [200 ml] was then added to the concentrated mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain crude product (41.1 g). The resulting product is used in the next reaction without further purification.

LCMS (LC-1): RT=1.12, t/ z 253 [M+H] ⁺ .

1H-NMR [CDCl ₃ ]: 5 (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).

[0203]

Intermediate B-1-3: 1-(tert-Butyl)-2-methyl-(2S,4R)-4-hydroxypiperidine-1,2-dicarboxylate

[Formula 55]

[0204]

1-(tert-Butyl)-2-methyl-(S)-4-oxopiperidine-1,2-dicarboxylate (intermediate B-1-2, 11.1 g, 43.1 mmol) was dissolved in tetrahydrofuran [8 6 ml), a 1 M solution of L-Selectride in tetrahydrofuran (65 ml, 64.7 mmol) was added to the solution at -78°C and the resulting mixture was stirred for 2 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (200 ml) was added to the reaction mixture, the resulting mixture was extracted with ethyl acetate, and then the organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, gradient elution, hexane:ethyl acetate = 100:0 to 0:100) to give 1-(tert-butyl)-2-methyl-(2S,4R)-4-hydroxypiperidine- 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).

[0205]

Intermediate B-1-4: 1-(tert-Butyl)-2-methyl-(2S,4R)-4-((methylsulfonyl)oxy)piperidine-1,2-dicarbokeylate

[Formula 56]

[0206]

1-(tert-Butyl)-2-methyl-(2S,4R)-4-hydroxypiperidine-1,2-dicarboxylate (intermediate B-1-3, 16.5 g, 63.6 mmol) was dissolved in dichloromethane ( 127 ml), triethylamine (36 ml, 255 mmol) and methanesulfonyl chloride (9.85 ml, 127 mmol) were added to the solution under ice-cooling, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then extracted with ethyl acetate, and the organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The resulting crude product (21.5 g) was used in the next reaction without further purification.

LCMS (LC-1): RT=1.32, m/z 338 [M+H] ⁺ .

[0207]

Intermediate B-1-5: 1-(tert-Butyl)-2-methyl-(2S,4S)-4-azidopiperidine-1,2-dicarboxylate

[Formula 57]

[0208]

1-(tert-Butyl)-2-methyl-(2S,4R)-4-((methylsulfonyl)oxy)piperidine-1,2-dicarboxylate (intermediate B-1-4, 21.5 g, mentioned above as crude product) was dissolved in N,N-dimethylformamide (319 ml), sodium azide (8.29 g, 127 mmol) was added to the resulting solution and the resulting mixture was stirred at 80°C for 11 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and then the organic layer was washed with water and brine. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product (18.1 g) was used in the next reaction without further 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).

[0209]

Intermediate B-1-6: 1-(tert-Butyl)-2-methyl-(2S,4S)-4-aminopiperidine-1,2-dicarboxylate

[Formula 58]

[0210]

1-(tert-Butyl)-2-methyl-(2S,4S)-4-azidopiperidine-1,2-dicarboxylate (intermediate B-1-5, 18.1 g, 63.7 mmol) was dissolved in methanol ( 318 ml), palladium hydroxide (3.8 g, 20% by weight) was added to the solution and the resulting mixture was stirred at room temperature for 21 hours under a hydrogen atmosphere. The atmosphere in the reaction system is replaced with nitrogen and then the reaction mixture is filtered through a pad of celite. The filtrate is concentrated under reduced pressure to give 1-(tert-butyl)-2-methyl-(2S,4S)-4-aminopiperidine-1,2-dicarboxylate (15.0 g, 91% yield over 3 steps).

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).

[0211]

Intermediate B-1-7: 1-(tert-Butyl)-2-methyl-(2S,4S)-4-((8-(benzyloxy)-7-bromoquinoxalin-2-yl)amino)piperidin-1, 2-dicarboxylate

[Formula 59]

[0212]

1-(tert-Butyl)-2-methyl-(2S,4S)-4-aminopiperidine-1,2-dicarboxylate (intermediate B-1-6, 11.2 g, 43.2 mmol) was dissolved in dimethyl sulfoxide ( 79 ml), 8-(benzyloxy)-7-bromo-2-chloroquinoxaline (intermediate A-1-7, 13.7 g, 39.3 mmol) and N,N-diisopropylethylamine (27.4 ml) were added to the solution , 157 mmol) and stir the resulting mixture at 100°C for 18 hours. Water (300 ml) was then added to the reaction mixture, the resulting mixture was extracted with ethyl acetate, and then the organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, gradient elution, chloroform:methanol = 100:0 to 90:10) to give 1-(tert-butyl)2-methyl-(2S,4S)-4-((8 -(benzyloxy)-7-bromoquinoxalin-2-yl)amino)piperidine-1,2-dicarboxylate (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, kV, 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, br. s), 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).

[0213]

Intermediate B-1-8: (2S,4S)-4-((8-(Benzyloxy)-7-bromoquinoxalin-2-yl)amino)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid

[Formula 60]

[0214]

1-(tert-Butyl)-2-methyl-(2S,4S)-4-((8-(benzyloxy)-7-bromoquinoxalin-2-yl)amino)piperidine-1,2-dicarboxylate (intermediate B- 1-7, 11.7 g, 20.6 mmol) was dissolved in methanol (680 ml), 1 M aqueous sodium hydroxide solution (206 ml) was added to the solution and the resulting mixture was stirred at 40°C for 1 hour. After completion of the reaction, 2 M aqueous hydrochloric acid (103 ml) was added to the reaction mixture, the resulting mixture was extracted with chloroform, and then the organic layer was washed with water and brine. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, gradient elution, chloroform:methanol = 100:0 to 80:20) to give (2S,4S)-4-((8-(benzyloxy)-7-bromoquinoxaline-2- yl)amino)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (8.97 g, 78% yield).

LCMS (LC-1): RT=1.41, m/z 555 [M-H] ⁺ .

1H-NMR (CDCl ₃ ): δ (ppm) 8.17 (1H, br.s), 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).

[0215]

Intermediate B-1-9: (2S,4S)-4-((7-Bromo-8-hydroxyquinoxalin-2-yl)amino)piperidine-2-carboxylic acid

[Formula 61]

[0216]

(2S,4S)-4-((8-(Benzyloxy)-7-bromoquinoxalin-2-yl)amino)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (intermediate B-1-8, 8 .97 g, 16.1 mmol) is dissolved in dichloromethane (161 ml), a 1 M solution of boron tribromide in dichloromethane (96.7 ml, 96.7 mmol) is added to the solution while cooling with ice to 0°C and the resulting mixture is stirred in within 2 hours. After the disappearance of the starting materials, tert-butanol (160 ml) was added dropwise to the reaction mixture at 0°C to complete the reaction. The resulting reaction mixture was purified directly by SCX to give (2S,4S)-4-((7-bromo-8-hydroxyquinoxalin-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).

[0217]

Intermediate B-1-10: (2S,4S)-4-((7-Bromo-8-hydroxyquinoxalin-2-yl)amino)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid

[Formula 62]

[0218]

(2S,4S)-4-((7-Bromo-8-hydroxyquinoxalin-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), triztylamine (6.05 ml, 43.5 mmol) and di-tert-butyl dicarbonate (4.75 g, 21.8 mmol) were added to the solution and the resulting mixture was stirred at room temperature within 1 hour. Then, 1 M aqueous hydrochloric acid was added to the reaction mixture, the resulting mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was used in the next reaction without further purification.

LCMS (LC-1): RT=1.08, m/z 467 [M+H] ⁺ .

[0219]

[Formula 63]

Method B-2

[0220]

Intermediate B-2-1: tert-Butyl-(2S,4S)-4-((7-bromo-8-hydroxyquinoxalin-2-yl)amino)-2-((3-((tert-butyldiphenylsilyl)oxy )propyl)carbamoyl)piperidine-1-carboxylate

[Formula 64]

[0221]

(2S,4S)-4-((7-Bromo-8-hydroxyquinoxalin-2-yl)amino)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (intermediate B-1-10, 4.23 g, 9.07 mmol) and 3-((tert-butyldiphenylsilyl)oxy)propan-1-amine (4.26 g, 13.6 mmol) were dissolved in dichloromethane (45 ml), N-methylmorpholine (2 .49 ml, 22.7 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.64 g, 36.3 mmol) and 1-hydroxybenzotriazole (2.69 g, 19.9 mmol) and Stir the resulting mixture at room temperature for 2 hours. After completion of the reaction, the reaction mixture was extracted with dichloromethane, and then the organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The resulting crude product was used in the next reaction without further purification.

LCMS (LC-1): RT=2.56, m/z 764 [M+H] ⁺ .

[0222]

Intermediate A-3-6: tert-Butyl-(23,4S)-4-((7-bromo-8-hydroxyquinoxalin-2-yl)amino)-2-((3-hydroxypropyl)carbamoyl)piperidine-1 -carboxylate

[Formula 65]

[0223]

tert-Butyl-(2S,4S)-4-((7-bromo-8-hydroxyquinoxalin-2-yl)amino)-2-((3-((tert-butyldiphenylsilyl)oxy)propyl)carbamoyl)piperidine-1 -carboxylate (intermediate B-2-1, 4.64 g, 6.10 mmol) is dissolved in uranium tetrahydrofuran (30 ml), a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (30 ml, 30 mmol) is added to the solution and the resulting mixture is stirred mixture at room temperature for 1 hour. After completion of the reaction, the reaction mixture was purified using automated column chromatography (silica gel, gradient elution, chloroform:methanol = 100:0 to 60:40) to give tert-butyl-(2S,4S)-4-((7-bromo -8-hydroxyquinoxalin-2-yl)amino)-2-((3-hydroxypropyl)carbamoyl)piperidine-1-carboxylate (2.90 g, 91% yield).

LCMS (LC-1): RT=1.47, m/z 524 [M+H] ⁺ .

1H-NMR (CDCl ₃ ): δ (ppm) 8.88 (1H, br. s), 8.26-8.17 (1H, m), 7.70-7.44 (1H, m ), 7.33-7.28 (1H, m), 6.68 (1H, br. s), 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).

[0224]

Intermediate A-3-7: tert-Butyl-(3 ² S,3 ⁴ S)-1 ⁷ -bromo-4-oxo-9-oxa-2,5-diaza-1(2,8)-quinoxaline- 3(4,2)-piperidinecyclonaphane-3 ¹ -carboxylate

[Formula 66]

[0225]

tert-Butyl-(2S,4S)-4-((7-bromo-8-hydroxyquinoxalin-2-yl)amino)-2-((3-hydroxypropyl)carbamoyl)piperidine-1-carboxylate (intermediate B-3 -6, 2.90 g, 5.55 mmol) was dissolved in THF (1109 ml), triphenylphosphine (3.64 mg, 13.8 mmol) and a 20% solution of di-tert-butyl azodicarboxylate in toluene (19, 2 ml) and stir the resulting mixture at room temperature for 2 hours. The reaction mixture is then concentrated under reduced pressure. The resulting crude product was purified using automated column chromatography (silica gel, gradient elution, chloroform:methanol = 100:0 to 90:10) to give tert-butyl-( ^32S , ^34S )-17 ^- bromo- 4-oxo-9-oxa-2,5-diaza-1(2,8)-quinoxaline-3(4,2)-piperidinecyclononaphane-3 ¹ -carboxylate (1.96 g, 70% yield).

LCMS (LC-1): RT=1.56, t/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 (1.5N, m), 4.91-4.85 (0.5N, m), 4.47-4.38 (1H, m), 4.35-4.26 (1.5N, m ), 4.19-4.01 (1.5N, m), 3.86-3.71 (1.5N, m), 3.70-3.59 (0.5N, 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).

[0226]

[Formula 67]

Method C-1

[0227]

Intermediate C-1-1: tert-Butyl-(3 ² S,3 ⁴ S)-4-oxo-1 ⁷ -(2-(propoxymethyl)pyrimidin-5-yl)-9-oxa-2,5- diaza-1(2,8)-quinoxaline-3(4,2)-piperidinecyclononaphane-3 ¹ -carboxylate

[Formula 68]

[0228]

tert-Butyl-(3 ² S,3 ⁴ S)-1 ⁷ -bromo-4-oxo-9-oxa-2,5-diaza-1(2,8)-quinoxaline-3(4,2)-piperidinecyclononaphane -3 ¹ -carboxylate (intermediate A-3-7, 51 mg, 0.099 mmol) and (2-(propoxymethyl)pyrimidin-5-yl)boronic acid (165 mg, 45 wt%, 0.25 mmol) are dissolved in a mixture of 1,4-dioxane (2.0 ml) and water (0.50 ml), add potassium carbonate (40 mg, 0.30 mmol) and dichloride complex [1,1'-bis(diphenylphosphino)ferrocene ]palladium(II) and dichloromethane (20.2 mg, 0.020 mmol) and stir the resulting mixture at 100°C for 4 hours under microwave irradiation. The reaction mixture is then filtered through a pad of celite and the filtrate is concentrated under reduced pressure. The crude product was purified using automated column chromatography (amino silica eluting, chloroform:ethyl acetate = 50:50) to give the crude product (313 mg). The resulting product is used in the next reaction without further purification.

LCMS (LC-1): RT=1.44, m/z 578 [M+H] ⁺ .

[0229]

Intermediate C-1-2: (3 ² S, 3 ⁴ S)-1 ⁷ -(2-(Propoxymethyl)pyrimidin-5-yl)-9-oxa-2,5-diaza-1(2,8) -quinoxaline-3(4,2)-piperidinecyclononaphan-4-one

[Formula 69]

[0230]

tert-Butyl-(3 ² S,3 ⁴ S)-4-oxo-1 ⁷ -(2-(propoxymethyl)pyrimidin-5-yl)-9-okea-2,5-diaza-1(2,8) -Quinoxaline-3(4,2)-piperidinecyclononaphane-3 ¹ -carboxylate (intermediate C-1-1, 313 mg, 0.54 mmol, crude product) was dissolved in dichloromethane (1 ml), trifluoroacetic acid was added to the solution (0.25 ml) and stir the resulting mixture at room temperature for 14 hours. The resulting reaction mixture is crudely purified by SCX. The resulting product is then purified using automated column chromatography (amino silica gel, gradient elution, chloroform:methanol = 100:0 to 90:10) to give (3 ² S,3 ⁴ S)-1 ⁷ -(2-(propoxymethyl) pyrimidin-5-yl)-9-oxa-2,5-diaza-1(2,8)-quinoxaline-3(4,2)-piperidinecyclononaphan-4-one (29.9 mg, yield for 2 steps 63% ).

LCMS (LC-1): RT=1.02, m/z 478 [M+H] ⁺ .

[0231]

Example a-01-07 (final product C-1-3): (3 ² S,3 ⁴ S)-3 ¹ -Methyl-1 ⁷ -(2-(propoxymethyl)pyrimidin-5-yl)-9-oxa -2,5-diaza-1(2,8)-quinoxaline-3(4,2)-piperidinecyclononaphan-4-one

[Formula 70]

[0232]

(3 ² S,3 ⁴ S)-1 ⁷ -(2-(Propoxymethyl)pyrimidin-5-yl)-9-oxa-2,5-diaza-1(2,8)-quinoxaline-3(4,2 )-piperidinecyclononaphan-4-one (intermediate C-1-2, 29.9 mg, 0.063 mmol) was dissolved in a mixture of dichloromethane (0.32 ml) and methanol (0.32 ml), 37% aqueous formaldehyde was added to the solution (0.014 ml, 0.19 mmol) and sodium triacetoxyborohydride (20 mg, 0.094 mmol) and stir the resulting mixture at room temperature for 1 hour. The resulting reaction mixture was first crudely purified by SCX and then purified using reverse phase liquid column chromatography to give ( ^32S , ^34S ) ^-31- methyl- ^17- (2-(propoxymethyl)pyrimidine-5- yl)-9-oxa-2,5-diaza-1(2,8)-quinoxaline-3(4,2)-piperidinecyclononaphan-4-one (4.8 mg, 15% yield).

LCMS (LC-1): RT=1.07, m/z 492 [M+H] ⁺ .

1H-NMR (CD ₃ OD): 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=7.8 Hz).

[0233]

The compounds presented in the tables below are synthesized by similar methods. In the tables below, the methods of acquisition referred to are listed in the Reference Methods column.

[0234]

[0235]

[Formula 71]

Method D-1

[0236]

Intermediate D-1-2: Quinoline-6-ylacetate

[Formula 72]

[0237]

Quinolin-6-ol (intermediate D-1-1, 20.0 g, 138 mmol) was dissolved in dichloromethane (222 mL), and pyridine (13.3 mL, 165 mmol) and acetyl chloride (11 .7 ml, 164 mmol) and stir the resulting mixture at room temperature for 1 hour. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution (300 ml) was added to the reaction mixture and the resulting mixture was stirred at room temperature for 45 minutes until foaming stopped. The reaction mixture is extracted with chloroform, then the organic layer is washed with water and brine. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude product (26.1 g) was used in the next reaction without further 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).

[0238]

Intermediate D-1-3: 3-Bromoquinoline-6-ylacetate

[Formula 73]

[0239]

Quinoline-6-ylacetate (intermediate D-1-2, 26.1 g, mentioned above as crude product) was dissolved in carbon tetrachloride (500 ml), and pyridine (28 ml) was added to the solution independently under ice-cooling using a dropping funnel , 343 mmol) and bromine (50 g, 313 mmol). The resulting mixture is then stirred at 90°C for 3 hours. After completion of the reaction, dichloromethane (300 ml) was added to the reaction mixture, and a saturated aqueous sodium hydrogen carbonate solution (250 ml) was added and the resulting mixture was stirred at room temperature for 15 minutes. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The crude product was purified using automated column chromatography (silica gel, gradient elution, chloroform:methanol = 100:0 to 90:10) to give 3-bromoquinoline-6-yl acetate (25.9 g, 71% yield).

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).

[0240]

Intermediate D-1-4: 3-Bromoquinolin-6-ol

[Formula 74]

[0241]

3-Bromoquinoline-6-ylacetate (intermediate D-1-3, 25.9 g, 97.6 mmol) was dissolved in methanol (130 ml), water (78 ml) and potassium carbonate (27.0 g) were added to the solution , 195 mmol) and stir the resulting mixture at room temperature for 1 hour 30 minutes. After completion of the reaction, the methanol is evaporated under reduced pressure. The crude product was washed 3 times with water (20 ml), then dried at 40°C for 4 hours under reduced pressure to obtain 3-bromoquinolin-6-ol (21.0 g, 96% yield).

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 (1Н, br. s).

[0242]

Intermediate D-1-5: 3-Bromo-5-iodoquinolin-6-ol

[Formula 75]

[0243]

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 the solution was added dropwise over 45 minutes. containing iodine (28.6 g, 112 mmol) dissolved in a 20% aqueous solution of potassium iodide (potassium iodide 54 g/water 270 ml), and stir the resulting mixture at room temperature for 1 hour. After completion of the reaction, acetic acid (27 ml) was added to the reaction mixture, the resulting mixture was stirred at room temperature for 1 hour and then filtered. The crude product was washed 3 times with water (100 ml) and dried at 40°C for 12 hours under reduced pressure 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, br. s).

[0244]

Intermediate D-1-6: 6-(Benzyloxy)-3-bromo-5-iodoquinoline

[Formula 76]

[0245]

3-Bromo-5-iodoquinolin-6-ol (intermediate D-1-5, 33.6 g, 93.8 mmol) was dissolved in N,N-dimethylformamide (313 ml), cesium carbonate (36, 6 g, 112 mmol) and benzyl bromide (12.3 ml, 103 mmol) and stir the resulting mixture at room temperature for 2 hours. After completion of the reaction, water (300 ml) was added to the reaction mixture, the resulting mixture was stirred at room temperature for 45 minutes and then filtered. The crude product was dried under reduced pressure to give 6-(benzyloxy)-3-bromo-5-iodoquinoline (39.9 g, 96% yield).

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).

[0246]

Intermediate D-1-7: (6-(Benzyloxy)-3-bromoquinolin-5-yl)boronic acid

[Formula 77]

[0247]

6-(Benzyloxy)-3-bromo-5-iodoquinoline (intermediate D-1-6, 17.6 g, 40.0 mmol) was dissolved in tetrahydrofuran (400 ml) and trimethyl borate (9 .8 ml, 87.9 mmol). The reaction mixture is cooled to -78°C and a 2 M solution of isopropylmapnium chloride in tetrahydrofuran (50 ml, 100 mmol) is added dropwise over 15 minutes. The resulting mixture is stirred for 2 hours, warming to room temperature. After completion of the reaction, acetic acid (200 ml) and water (200 ml) were added to the reaction mixture, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product (11.7 g) was used in the next reaction without further purification.

LCMS (LC-1): RT=1.45, m/z 358 [M+H] ⁺ .

[0248]

Intermediate D-1-8: 6-(Benzyloxy)-3-bromoquinolin-5-ol

[Formula 78]

[0249]

(6-(Benzyloxy)-3-bromoquinolin-5-yl)boronic acid (intermediate D-1-7, 11.5 g, mentioned above as crude product) was dissolved in acetone (400 ml), water was added to the solution ( 200 ml) and oxon (40.2 g, 65.6 mmol) and stir the resulting mixture at room temperature for 1 hour. After completion of the reaction, saturated aqueous sodium thiosulfate (200 ml) was added to the reaction mixture, the resulting mixture was extracted with chloroform, and the organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The resulting crude product (10.6 g) was used in the next reaction without further 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).

[0250]

[Formula 79]

Method D-2

[0251]

Intermediate D-2-2: 1-(tert-Butyl)-2-methyl-(2S,4S)-4-((6-(benzyloxy)-5-((triisopropylsilyl)oxy)quinolin-3-yl) amino)piperidine-1,2-dicarboxylate

[Formula 80]

[0252]

6-(Benzyloxy)-3-bromo-5-((triisopropylsilyl)oxy)quinoline (intermediate D-2-1, 3.60 g, 7.41 mmol) and 1-(tert-butyl)-2-methyl -(2S,4S)-4-aminopiperidine-1,2-dicarboxylate (intermediate B-1-6, 3.20 g, 12.4 mmol) was dissolved in toluene (22 ml), methanesulfonate was added to the solution [(2 -di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium( II) (320 mg, 0.37 mmol) and phosphazene base P ₂ -Et (5 ml, 15 mmol) and stir the resulting mixture at room temperature for 30 minutes. After completion of the reaction, the reaction mixture is purified using automated column chromatography (silica, gradient elution, chloroform:methanol = 100:0 to 80:20) to give 1-(tert-butyl)-2-methyl-(2S,4S) -4-((6-(benzyloxy)-5-((triisopropylsilyl)oxy)quinolin-3-yl)amino)piperidine-1,2-dicarboxylate (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 (0.5N, m), 4.93 (0.5N, br. s), 4.18 (0.5N, d, J= 14.2 Hz), 4.05 (0.5H, 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, br. s), 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).

[0253]

Intermediate D-2-3: (2S,4S)-4-((6-(Benzyloxy)-5-((triisopropylsilyl)oxy)quinolin-3-yl)amino)-1-(tert-butoxycarbonyl)piperidin- 2-carboxylic acid

[Formula 81]

[0254]

1-(tert-Butyl)-2-methyl-(2S,4S)-4-((6-(benzyloxy)-5-((triisopropylsilyl)oxy)quinolin-3-yl)amino)piperidin-1,2- dicarboxylate (intermediate D-2-2, 2.10 g, 3.16 mmol) was dissolved in methanol (210 ml), 1 M aqueous sodium hydroxide (32 ml) was added to the solution and the resulting mixture was stirred at 40 °C in within 15 hours. After completion of the reaction, 1 M aqueous hydrochloric acid (33 ml) was added to the reaction mixture, the resulting mixture was extracted with chloroform, and then the organic layer was washed with water and brine. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude product (2.15 g) was used in the next reaction without further purification.

LCMS (LC-1): RT=1.95, m/z 650 [M+H] ⁺ .

[0255]

Intermediate D-2-4: tert-Butyl-(2S,4S)-4-((6-(benzyloxy)-5-((triisopropylsilyl)oxy)quinolin-3-yl)amino)-2-((2 -fluoro-3-hydroxypropyl)carbamoyl)piperidine-1-carboxylate

[Formula 82]

[0256]

(2S,4S)-4-((6-(Benzyloxy)-5-((triisopropylsilyl)oxy)quinolin-3-yl)amino)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (intermediate D -2-3, 2.15 g, 3.16 mmol) and 3-amino-2-fluoropropan-1-ol (348 mg, 3.79 mmol) dissolved in N,N-dimethylformamide (16 ml), to solution add N-methylmorpholine (0.87 ml, 7.90 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.45 g, 12.6 mmol) and 1-hydroxybenzotriazole (1.01 g, 6.96 mmol) and stir the resulting mixture at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The crude product is purified using automated column chromatography (silica gel, gradient elution, ethyl acetate:methanol = 100:0 to 98:2) to give tert-butyl-(2S,4S)-4-((6-(benzyloxy)- 5-((triisopropylsilyl)oxy)quinolin-3-yl)amino)-2-((2-fluoro-3-hydroxypropyl)carbamoyl)piperidine-1-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, br. s), 4.77-4.44 (1H, m), 4.12 (1H, kV, J=7.2 Hz), 3.71 (5H, m), 3.28-3.10 (1H, m), 2.96 (1H, br. s ), 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).

[0257]

Intermediate D-2-5: tert-Butyl-(2S,4S)-4-((6-(benzyloxy)-5-hydroxyquinolin-3-yl)amino)-2-((2-fluoro-3-hydroxypropyl )carbamoyl)piperidine-1-carboxylate

[Formula 83]

[0258]

tert-Butyl-(2S,4S)-4-((6-(benzyloxy)-5-((triisopropylsilyl)oxy)quinolin-3-yl)amino)-2-((2-fluoro-3-hydroxypropyl)carbamoyl )piperidine-1-carboxylate (intermediate D-2-4, 886 mg, 1.22 mmol) was dissolved in tetrapidrofuran (6.1 ml), to the solution was added a 1 M solution of tetrabutylammonium fluoride in tetrapidrofuran (2.44 ml, 2 .44 mmol) and stir the resulting mixture at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was purified using automated column chromatography (silica gel, gradient elution, chloroform:methanol = 100:0 to 80:20) to give tert-butyl-(2S,4S)-4-((6-( benzyloxy)-5-hydroxyquinolin-3-yl)amino)-2-((2-fluoro-3-hydroxypropyl)carbamoyl)piperidine-1-carboxylate (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, br. s), 4.99 (1H, br. s), 4.73 (0.5H, br. s). s), 4.61 (0.5H, br. s), 4.46-4.06 (2H, m), 3.93-3.70 (3H, m), 3.66 (2H, br. s), 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).

[0259]

Intermediate D-2-6: tert-Butyl-(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)-piperidinecyclononaphane-3 ¹ -carboxylate

[Formula 84]

[0260]

tert-Butyl-(2S,4S)-4-((6-(benzyloxy)-5-hydroxyquinolin-3-yl)amino)-2-((2-fluoro-3-hydroxypropyl)carbamoyl)piperidine-1-carboxylate (intermediate D-2-5, 660 mg, 1.161 mmol) was dissolved in toluene (240 ml), triphenylphosphine (773 mg, 2.90 mmol) and a 20% solution of di-tert-butyl azodicarboxylate in toluene were added ( 4.16 ml, 3.48 mmol) and stir the resulting mixture at room temperature for 1 hour. The reaction mixture is concentrated under reduced pressure. The resulting crude product was purified using automated column chromatography (silica gel, gradient elution, chloroform:methanol = 100:0 to 90:10) to give tert-butyl-(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)-piperidinecyclononaphane-3 ^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, br. s), 4.91 (0.5H, br. s), 4.81 (0.5H, br. s), 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).

[0261]

[Formula 85]

Method D-3

[0262]

Intermediate D-3-1: tert-Butyl-(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)-piperidinecyclononaphen-3 ¹ -carboxylate

[Formula 86]

[0263]

tert-Butyl-(3 ² S,3 ⁴ S)-1 ⁶ -(benzyloxy)-7-fluoro-4-okeo-9-oxa-2,5-diaza-1(3,5)-quinoline-3( 4,2)-piperidinecyclononaphane-3 ¹ -carboxylate (intermediate D-2-6, 325 mg, 0.5 9 mmol) was dissolved in a mixture of methanol (3 ml) and tetrahydrofuran (3 ml), palladium hydroxide ( 65 mg, 20% wt.) and stir the resulting mixture at room temperature for 18 hours under a hydrogen atmosphere. The atmosphere in the reaction room is replaced with nitrogen and then the reaction mixture is filtered through a pad of celite. The filtrate is concentrated under reduced pressure to obtain tert-butyl-(3 ² S,3 ⁴ S)-7-fluoro-1 ⁶ -hydroxy-4-oxo-9-oxa-2,5-dmaz-1(3,5) -quinoline-3(4,2)-piperidinecyclononaphen-3 ¹ -carboxylate (330 mg, 92% yield) as crude product. The crude product is used in the next reaction without further purification.

LCMS (LC-1): RT=1.13, m/z 461 [M+H] ⁺ .

[0264]

Intermediate D-3-2: tert-Butyl-(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)-piperidinecyclononaphen-3 ¹ -carboxylate

[Formula 87]

[0265]

tert-Butyl-(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)-piperidinecyclononaphen-3 ¹ -carboxylate (intermediate D-3-1, 330 mg, 0.72 mmol) was dissolved in 1,4-dioxane (7.2 ml), N,N-dimethylformamide (6 drops), N,N-diisopropylethylamine (0.748 ml, 4.30 mmol) and N-phenyl-bis(trifluoromethanesulfonimide) (824 mg, 2.30 mmol) and stir the resulting mixture at room temperature for 7 hours. After completion of the reaction, the reaction mixture is purified using automated column chromatography (silica gel, gradient elution, chloroform:methanol = 100:0 to 90:10) to obtain tert-butyl-(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)-piperidinecyclononaphen-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 (0.5N, br. s), 5.08-4.93 (0.5N, m), 4.71 (0.5N, d, J=2.4 Hz), 4 .65-4.52 (0.5H, m), 4.46-4.22 (2H, m), 4.11 (1H, br. s), 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).

[0266]

Intermediate D-3-3: tert-Butyl-(3 ² S,3 ⁴ S)-7-fluoro-4-oxo-1 ⁶ -(2-(propoxymethyl)pyrimidin-5-yl)-9-oxa- 2,5-diaza-1(3,5)-quinoline-3(4,2)-piperidinecyclononaphane-3 ¹ -carboxylate

[Formula 88]

[0267]

tert-Butyl-(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)-piperidinecyclononaphen-3 ¹ -carboxylate (intermediate D-3-2, 420 mg, 0.71 mmol) and 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 mixture of 1,4-dioxane (2.8 ml) and water (0.28 ml), cesium carbonate (705 mg, 2.12 mmol) and a complex of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride and dichloromethane (117 mg, 0.14 mmol) were added to the solution ) and stir the resulting mixture at 100°C for 2 hours under microwave irradiation. The reaction mixture is filtered through a pad of celite, the filtrate is concentrated under reduced pressure and the crude product is purified using automated column chromatography (silica gel, gradient elution, chloroform:methanol = 100:0 to 90:10) to give tert-butyl-( ³² S,3 ⁴ S)-7-fluoro-4-oxo-1 ⁶ -(2-(propoxymethyl)pyrimidin-5-yl)-9-oxa-2,5-diaza-1(3,5)-quinoline- 3(4,2)-piperidinecyclononaphane-3 ¹ -carboxylate (180 mg, 43% yield) as a crude product. The crudely purified product is used in the next reaction without further purification.

LCMS (LC-1): RT=1.44, m/z 595 [M+H] ⁺ .

[0268]

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)-piperidinecyclononaphan-4-one

[Formula 89]

[0269]

tert-Butyl-(3 ² S,3 ⁴ S)-7-fluoro-4-oxo-1 ⁶ -(2-(propoxymethyl)pyrimidin-5-yl)-9-oxa-2,5-diaza-1( 3,5)-quinoline-3(4,2)-piperidinecyclononaphane-3 ¹ -carboxylate (intermediate D-3-3, 180 mg, 0.30 mmol) was dissolved in dichloromethane (3.0 ml) and added to the solution trifluoroacetic acid (0.75 ml) and stir the resulting mixture at room temperature for 30 minutes. The resulting reaction mixture was crudely purified by SCX to give (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)-piperidinecyclononaphan-4-one (148 mg, 98% yield). The crudely purified product is used in the next reaction without further purification.

LCMS (LC-1): RT=1.01, m/z 495 [M+H] ⁺ .

[0270]

Example a-02-02 (final product 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)-piperidinecyclononaphan-4-one

[Formula 90]

[0271]

(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)-piperidinecyclononaphan-4-one (intermediate D-3-4, 148 mg, 0.30 mmol) was dissolved in a mixture of dichloromethane (1.5 ml) and methanol (1.5 ml), and added to the solution 37% aqueous formaldehyde (0.068 ml, 0.91 mmol) and sodium triacetoxyborohydride (96 mg, 0.45 mmol) and stir the resulting mixture at room temperature for 1 hour. The resulting reaction mixture was crudely purified by SCX and then purified by reverse phase liquid column chromatography to give ( ^32S , ^34S )-7-fluoro- ³¹ -methyl- ^16- (2-(propoxymethyl)pyrimidine-5 -yl)-9-oxa-2,5-diaza-1(3,5)-quinolya-3(4,2)-piperidinecyclononaphan-4-one (106 mg, yield for 2 stages 69%).

LCMS (LC-1): RT=1.11, m/z 50 9 [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, br. s), 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, br. s), 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).

[0272]

[Formula 91]

Method E-1

[0273]

Intermediate E-1-1: 6-(Benzyloxy)-3-bromo-5-(3-((tert-butyldiphenylsilyl)oxy)propoxy)quinoline

[Formula 92]

[0274]

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-butyldiphenylsilyl) was added to the solution )oxy)propan-1-ol (4.2 g, 18.2 mmol), triphenylphosphine (4.80 g, 18.2 mmol) and di-tert-butyl azodicarboxylate (18.2 mmol) and stir the resulting mixture at room temperature for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure and the crude product was crudely purified using automated column chromatography (silica gel, gradient elution, hexane:ethyl acetate = 100:0 to 70:30) to give 6-(benzyloxy)-3-bromo- 5-(3-((tert-butyldiphenylsilyl)oxy)propoxy)quinoline (6.49 g) as crude product. The crudely purified product is used in the next reaction without further purification.

LCMS (LC-6): RT=2.71, m/z 626 [M+H] ⁺ .

[0275]

Intermediate E-1-2: 3-((6-(Benzyloxy)-3-bromoquinolin-5-yl)oxy)propan-1-ol

[Formula 93]

[0276]

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), tetrabutylammonium fluoride (30 ml, 1 M solution in THF) was added to the solution and the resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate and the organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The crude product is purified using automated column chromatography (silica gel, gradient elution, chloroform:methanol = 100:0 to 50:50) to give 3-((6-(benzyloxy)-3-bromoquinolin-5-yl)oxy) propan-1-ol (4.72 g) as a crude product.

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, kV, J=5.8 Hz), 3.70 (1H, br. s), 2.11-2.02 (2H, m).

[0277]

Intermediate E-1-3: 2-(3-((6-(Benzyloxy)-3-bromoquinolin-5-yl)oxy)propyl)-1-(tert-butyl)-(2S,4S)-4- Azidopiperidium-1,2-dicarboxylate

[Formula 94]

[0278]

3-((6-(Benzyloxy)-3-bromoquinolin-5-yl)oxy)propan-1-ol (intermediate E-1-2, 4.02 g, 10.3 mmol) and (2S,4S) -4-azido-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (4.81 g, 17.8 mmol) was dissolved in dichloromethane (100 ml), 1-(3-dimethylaminopropyl)-3 hydrochloride was added to the solution -ethylcarbodiimide (4.06 g, 21.1 mmol) and N,N-dimethylaminopyridine (2.70 g, 22.1 mmol) and stir the resulting mixture at room temperature for 3 hours. After completion of the reaction, the reaction mixture was extracted with dichloromethane and the organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The crude product is purified using automated column chromatography (silica gel, gradient elution, hexane:ethyl acetate = 90:10 to 0:100) to give 2-(3-((6-(benzyloxy)-3-bromoquinolin-5-yl )oxy)propyl)-1-(tert-butyl)-(2S,4S)-4-azidopiperidine-1,2-dicarboxylate (5.69 g) as a crude product. The crudely purified product is used in the next reaction without further purification.

LCMS (LC-1): RT=2.36, m/z 640 [M+H] ⁺ .

[0279]

Intermediate E-1-4: 2-(3-((6-(Benzyloxy)-3-bromoquinolin-5-yl)oxy)propyl)-1-(tert-butyl)-(2S,4S)-4- aminopiperidine-1,2-dicarboxylate

[Formula 95]

[0280]

2-(3-((6-(Benzyloxy)-3-bromoquinolin-5-yl)oxy)propyl)-1-(tert-butyl)-(2S,4S)-4-azidopiperidine-1,2-dicarboxylate ( intermediate E-1-3, 5.69 g, 8.88 mmol) was dissolved in tetrahydrofuran (100 ml), triphenylphosphine (5.0 g, 19.0 mmol) and water (5.0 ml) were added to the solution and stir the resulting mixture at 70°C for 15 hours. After completion of the reaction, the solvent was removed under reduced pressure and the crude product was purified using automated column chromatography (silica gel, gradient elution, hexane:ethyl acetate = 90:10 to 0:100) to give 2-(3-((6-(benzyloxy )-3-bromoquinolin-5-yl)oxy)propyl)-1-(tert-butyl)-(2S,4S)-4-aminopiperidine-1,2-dicarboxylate (5.78 g) as a crude product. The crudely purified product is used in the next reaction without further purification.

LCMS (LC-1): RT=1.70, m/z 614 [M+H] ⁺ .

[0281]

Intermediate E-1-5: tert-Butyl-(3 ² S,3 ⁴ S)-1 ⁶ -(benzyloxy)-4-oxo-5,9-dioxa-2-aza-1(3,5)- quinoline-3(4,2)-piperidinecyclononaphane-3 ¹ -carboxylate

[Formula 96]

[0282]

2-(3-((6-(Benzyloxy)-3-bromoquinolin-5-yl)oxy)propyl)-1-(tert-butyl)(2S,4S)-4-aminopiperidine-1,2-dicarboxylate (intermediate compound 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) and methanesulfonate [(2 -di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (1.10 g, 1.38 mmol) and stir the resulting mixture at 120°C for 3 days. After completion of the reaction, the reaction mixture is filtered through a pad of celite and the filtrate is concentrated under reduced pressure. The resulting crude product was purified using automated column chromatography (silica gel, gradient elution, hexane:ethyl acetate = 90:10 to 0:100) to give tert-butyl-(3 ² S,3 ⁴ S)-1 ⁶ -(benzyloxy )-4-oxo-5,9-dioxa-2-aza-1(3,5)-quinoline-3(4,2)-piperidinecyclononaphane-3 ¹ -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).

[0283]

[Formula 97]

Method F-1

[0284]

Intermediate F-1-1: tert-Butyl-(3-((6-(benzyloxy)-3-bromoquinolin-5-yl)oxy)propyl)carbamate

[Formula 98]

[0285]

6-(Benzyloxy)-3-bromoquinolin-5-ol (intermediate D-1-8, 1.0 g, 3.03 mmol) was dissolved in toluene (15 ml), tert-butyl-(3- pydroxypropyl)carbamate (1.59 g, 9.09 mmol), triphenylphosphine (1.99 g, 7.57 mmol) and finally a 20% solution of di-tert-butyl azodicarboxylate in toluene (10 ml, 9.09 mmol) and stir the resulting mixture at room temperature for 1 hour. The solvent was evaporated and the residue was purified using automated column chromatography (silica gel, eluent, hexane:ethyl acetate = 1:1) to give tert-butyl-(3-((6-(benzyloxy)-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) .

[0286]

Intermediate F-1-2: tert-Butyl-(3-((6-(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)quinolin- 5-yl)oxy)propyl)carbamate

[Formula 99]

[0287]

tert-Butyl-(3-((6-(benzyloxy)-3-bromoquinolin-5-yl)oxy)propyl)carbamate (intermediate F-1-1, 1.0 g, 3.03 mmol) dissolved in 1 ,4-dioxane (15 ml), add bis(pinacolato)diboron (451 mg, 1.79 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (175 mg, 0.24 mmol) and potassium acetate (237 mg, 2.38 mmol) and stir the resulting mixture at 100°C for 14 hours. The reaction solution was cooled to room temperature, the solid was removed by filtration, and the solvent was evaporated to give tert-butyl-(3-((6-(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaboran-2-yl)quinolin-5-yl)oxy)propyl)carbamate as a crude product.

LCMS (LC-1): RT=2.14, m/z 534 [M+H] ⁺ .

[0288]

Intermediate F-1-3: tert-Butyl-(3-((6-(benzyloxy)-3-hydroxyquinolin-5-yl)oxy)propyl)carbamate

[Formula 100]

[0289]

tert-Butyl-(3-((6-(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)quinolin-5-yl)oxy)propyl) carbamate (intermediate F-1-2, 636 mg, 1.19 mmol) was dissolved in tetrahydrofuran (13 ml), and 1 M aqueous sodium hydroxide (520 μl) and 20% aqueous hydrogen peroxide were added to the solution under ice-cooling ( 520 µl) and stir the resulting mixture at the same temperature for 2 hours. Saturated aqueous sodium thiosulfate and 1 M hydrochloric acid were added to the reaction mixture, the resulting mixture was extracted with chloroform, the organic layer was dried over magnesium sulfate, then the solvent was evaporated and the residue was purified using automatic column chromatography (silica gel, hexane:ethyl acetate = 50:50). ) to obtain tert-butyl-(3-((6-(benzyloxy)-3-hydroxyquinolin-5-yl)oxy)propyl)carbamate (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).

[0290]

Intermediate F-1-4: 5-(3-Aminopropoxy)-6-(benzyloxy)quinolin-3-ol

[Formula 101]

[0291]

tert-Butyl-(3-((6-(benzyloxy)-3-hydroxyquinolin-5-yl)oxy)propyl)carbamate (intermediate F-1-3, 678 mg, 1.60 mmol) was dissolved in dichloromethane (17 ml), trifluoroacetic acid (4.0 ml) was added to the solution at room temperature and the resulting mixture was stirred for 20 minutes. The reaction mixture was concentrated and the concentrated reaction mixture was processed using an SCX cartridge to obtain 5-(3-aminopropoxy)-6-(benzyloxy)quinolin-3-ol (312 mg, 60% yield).

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).

[0292]

Intermediate F-1-5: tert-Butyl-(2S,4R)-2-((3-((6-(benzyloxy)-3-hydroxyquinolin-5-yl)oxy)propyl)carbamoyl)-4-hydroxypiperidine -1-carboxylate

[Formula 102]

[0293]

5-(3-Aminopropoxy)-6-(benzyloxy)quinolin-3-ol (intermediate F-1-4, 312 mg, 0.81 mmol) was dissolved in dichloromethane (4.0 ml), N- methylmorpholine (222 μl, 2.01 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (627 mg, 3.22 mmol), 1-hydroxybenzotriazole (239 mg, 1.77 mmol) and (2S, 4R)-1-(tert-butoxycarbonyl)-4-hydroxypiperidine-2-carboxylic acid (376 mg, 1.45 mmol) and stir the resulting mixture at room temperature for 3 hours. Water was added to the reaction mixture and the resulting mixture was extracted with chloroform, the solvent was evaporated and the residue was purified using automatic column chromatography (silica gel, eluent, chloroform:methanol = 9:1) to obtain tert-butyl-(2S,4R)-2-(( 3-((6-(benzyloxy)-3-hydroxyquinolin-5-yl)oxy)propyl)carbamoyl)-4-hydroxypiperidine-1-carboxylate (122 mg, 27% yield).

LCMS (LC-1): RT=1.43, m/z 552 [M+H] ⁺ .

[0294]

Intermediate F-1-6: tert-Butyl-(3 ² S,3 ⁴ S)-1 ⁶ -(benzyloxy)-4-hydroxy-2,9-dioxa-5-aza-1(3,5)- quinoline-3(4,2)-piperidinecyclononaphane-3 ¹ -carboxylate

[Formula 103]

[0295]

tert-Butyl-(2S,4R)-2-((3-((6-(benzyloxy)-3-hydroxyquinolin-5-yl)oxy)propyl)carbamoyl)-4-hydroxypiperidine-1-carboxylate (intermediate F -1-5, 122 mg, 0.22 mmol) is dissolved in toluene (20 ml), triphenylphosphine (149 mg, 0.54 mmol) and a 20% solution of di-tert-butyl azodicarboxylate in toluene (780 μl, 0 .65 mmol) and stir the resulting mixture for 1 hour 30 minutes. The reaction mixture is concentrated and the residue is purified using automated column chromatography (silica gel, eluent, chloroform:methanol = 90:10) to give tert-butyl-(3 ² S,3 ⁴ S)-1 ⁶ -(benzyloxy)-4-oxy -2,9-dioxa-5-aza-1(3,5)-quinoline-3(4,2)-piperidinecyclononaphane-3 ¹ -carboxylate (84 mg, 72%).

LCMS (LC-1): RT=1.60, m/z 534 [M+H] ⁺ .

[0296]

[Formula 104]

Method F-2

[0297]

Intermediate F-2-1: tert-Butyl-(3 ² S,3 ⁴ S)-1 ⁶ -hydroxy-4-hydroxy-2,9-dioxa-5-aza-1(3,5)-quinoline- 3(4,2)-piperidinecyclononaphane-3 ¹ -carboxylate

[Formula 105]

[0298]

tert-Butyl-(3 ² S,3 ⁴ S)-1 ⁶ -(benzyloxy)-4-hydroxy-2,9-dioxa-5-aza-1(3,5)-quinoline-3(4,2) -piperidinecyclononaphane-3 ¹ -carboxylate (intermediate F-1-6, 84 mg, 0.15 mmol) is dissolved in methanol (0.8 ml), tetrahydrofuran (0.8 ml) and palladium hydroxide are added to the solution under nitrogen atmosphere (16.6 mg), the atmosphere in the reaction system was manually changed to hydrogen gas and the mixture was vigorously stirred at room temperature for 14 hours. Insoluble materials are removed from the reaction mixture by filtration, then the solvent is evaporated and the residue is purified using automated column chromatography (silica gel, eluent, chloroform:methanol = 90:10) to give tert-butyl-(3 ² S,3 ⁴ S)-1 ⁶ -Hydroxy-4-hydroxy-2,9-dioxa-5-aza-1(3,5)-quinoline-3(4,2)-piperidinecyclononaphane-3 ¹ -carboxylate (31.2 mg, 46% yield).

LCMS (LC-1): RT=1.12, m/z 444 [M+H] ⁺ .

[0299]

Intermediate F-2-2: tert-Butyl-(3 ² S,3 ⁴ S)-1 ⁶ -(((trifluoromethyl)sulfonyl)oxy)-4-hydroxy-2,9-dioxa-5-aza-1 (3,5)-quinoline-3(4,2)-piperidinecyclononaphane-3 ¹ -carboxylate

[Formula 106]

[0300]

tert-Butyl-(3 ² S,3 ⁴ S)-1 ⁶ -hydroxy-4-hydroxy-2,9-dioxa-5-aza-1(3,5)-quinoline-3(4,2)-piperidinecyclononaphane -3 ^1- carboxylate (intermediate F-2-1, 31.2 mg, 70 µmol) was dissolved in 1,4-dioxane (700 µl), N,N-bis(trifluoromethylsulfonyl)aniline (85 mg, 0.22 mmol), diisopropylethylamine (73 μl, 0.42 mmol) and dimethylformamide (2 drops) and stir the resulting mixture at room temperature for 3 hours. The reaction mixture is concentrated and the residue is purified using automated column chromatography (silica gel, eluent, chloroform:methanol = 90:10) to give tert-butyl-(3 ² S,3 ⁴ S)-1 ⁶ -(((trifluoromethyl)sulfonyl) oxy)-4-hydroxy-2,9-dioxa-5-aza-1(3,5)-quinoline-3(4,2)-piperidinecyclononaphane-3 ¹ -carboxylate (44.3 mg, 99% yield).

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).

[0301]

Intermediate F-2-3: tert-Butyl-(3 ² S,3 ⁴ S)-1 ⁶ -(2-(propoxymethyl)pyrimidin-5-yl)-4-hydroxy-2,9-dioxa-5- aza-1(3,5)-quinoline-3(4,2)-piperidinecyclononaphane-3 ¹ -carboxylate

[Formula 107]

[0302]

tert-Butyl-(3 ² S,3 ⁴ S)-1 ⁶ -(((trifluoromethyl)sulfonyl)oxy)-4-hydroxy-2,9-dioxa-5-aza-1(3,5)-quinoline- 3(4,2)-piperidinecyclononaphane-3 ¹ -carboxylate (intermediate F-2-2, 44 mg, 76 μmol) was dissolved in 1,4-dioxane (600 μl) and water (60 μl), and ( 2-(propoxymethyl)pyrimidin-5-yl)boronic acid (175 mg, 0.19 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (13 mg, 15 μmol) and cesium carbonate ( 78 mg, 0.23 mmol) and treated with microwave radiation at 100°C for 3 hours. Insoluble materials are removed by filtration through a pad of cellite, then the solvent is evaporated and the residue is purified using automated column chromatography (silica gel, eluent, chloroform:methanol = 90:10) to give tert-butyl-(3 ² S,3 ⁴ S)-1 ⁶ -(2-(propoxymethyl)pyrimidin-5-yl)-4-hydroxy-2,9-dioxa-5-aza-1(3,5)-quinoline-3(4,2)-piperidinecyclononaphane-3 ^1- carboxylate (22.8 mg, yield 52%).

LCMS (LC-1): RT=1.42, m/z 578 [M+H] ⁺ .

[0303]

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)-piperidinecyclononaphan-4-one

[0304]

tert-Butyl-(3 ² S,3 ⁴ S)-1 ⁶ -(2-(propoxymethyl)pyrimidin-5-yl)-4-hydroxy-2,9-dioxa-5-aza-1(3,5) -quinoline-3(4,2)-piperidinecyclononaphane-31-carboxylate (intermediate F-2-3, 22.8 mg, 39 µmol) was dissolved in 6 dichloromethane (400 µl), trifluoroacetic acid (100 µl) was added to the solution and Stir the resulting mixture at room temperature for 20 minutes. The reaction mixture is treated with SCX to give (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)-piperidinecyclononaphan-4-one (13.4 mg, 99% yield).

LCMS (LC-1): RT=0.98, m/z 478 [M+H] ⁺ .

[0305]

Example a-02-25 (final product F-2-5): (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)-piperidinecyclononaphan-4-one

[0306]

(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 )-piperidinecyclononaphan-4-one (intermediate F-2-4, 13.4 mg, 39 µmol) was dissolved in dichloromethane (200 µl) and methanol (200 µl), 37% aqueous formaldehyde (8.7 µl) was added to the solution , 0.12 mmol) and sodium triacetoxyborohydride (12.5 mg, 59 μmol) and stir the resulting mixture at room temperature for 10 minutes. The reaction mixture is treated with SCX and then purified using preparative thin layer chromatography (eluent, chloroform:2M ammonia in methanol = 97:3) to give (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)-piperidinecyclononaphan-4-one (6.2 mg, yield 32%).

LCMS (LC-1): RT=1.00, m/z 492 [M+H] ⁺ .

¹ H-NMR (CD ₃ OD): 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 (1Н, m), 4,17-4,04 (1Н, m), 3, 86-3, 69 (1Н, m), 3, 69-3, 55 (4Н, 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).

[0307]

[0308]

129

Intermediate G-1-3': (2S,4S)-4-Azido-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid

[030 9]

1-(tert-Butyl)-2-methyl-(2S,4S)-4-azidopiperidine-1,2-dicarboxylate (5.3 g, 19 mmol), prepared according to the method described in the literature (Eur. J . Org. Chem., 2004, 2928-2935), dissolved in methanol (220 ml), 1 M aqueous sodium hydroxide solution (190 ml) was added to the solution and the resulting mixture was stirred at 40°C for 1 hour. The reaction mixture was neutralized by adding 1 M hydrochloric acid and extracted with ethyl acetate, the organic layer was washed with brine, dried over sodium sulfate and the solvent was evaporated to obtain a crude reaction mixture containing (2S,4S)-4-azido-1-(tert-butoxycarbonyl) piperidine-2-carboxylic acid.

LCMS (LC-1): RT=0.89, m/z 269 [M-H] ⁺ .

1H-NMR (CDCl ₃ ): δ (ppm) 5.07 (1H, br.s), 4.92 (1H, br.s), 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).

[0310]

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

[0311]

2-(But-3-en-1-yl)isoindolin-1,3-dione (2 g, 10 mmol) was dissolved in a 0.5 M solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran (20) under ice cooling ml) and stir the resulting mixture at the same temperature for 1.5 hours. The solvent of the reaction mixture was evaporated to obtain a crude reaction mixture containing 2-(4-((1s,5s)-9-borabicyclo[3.3.1]nonan-9-yl)butyl)isoindoline-1,3-dione.

[0312]

Intermediate G-1-2: 2-(4-(6-(Benzyloxy)-3-bromoquinolin-5-yl)butyl)isoindoline-1,3-dione

[0313]

6-(Benzyloxy)-3-bromo-5-iodoquinoline (intermediate D-1-8, 1.8 g, 4.1 mmol) dissolved in 1,4-dioxane 8.2 ml) and water (82 0 µl ), 2-(4-((1s, 5s)-9-borabicyclo[3,3,1]nonan-9-yl)butyl)isoindoline-1,3-dione (intermediate G-1-1) is added to the solution , 1.3 g, 4.1 mmol), 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (60 0 mg, 820 μmol) and potassium carbonate (1.7 g, 12 mmol) and stir the resulting mixture at 100°C for 14 hours. Insoluble substances are removed from the reaction mixture by filtration through a pad of celite, then the solvent is evaporated and the residue is purified using automatic column chromatography (silica gel, 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, t/z 440 [M+H] ⁺

0314]

Intermediate G-1-3: 4-(6-(Benzyloxy)-3-bromoquinolin-5-yl)butan-1-amine

[0315]

2-(4-(6-(Benzyloxy)-3-bromoquinolin-5-yl)butyl)isoindoline-1,3-dione (intermediate G-1-2, 553 mg, 1.07 mmol) is dissolved in ethanol ( 11 ml), hydrazine hydrate (105 μl, 2.15 mmol) was added to the solution and the resulting mixture was stirred at 85°C for 9 hours. The resulting crude reaction mixture was concentrated, insoluble materials were removed by filtration, the solvent was further evaporated and the residue was purified using automated column chromatography (silica gel, eluent hexane:ethyl acetate = 50:50 → chloroform:methanol = 90:10) to give 4-(6- (benzyloxy)-3-bromoquinolin-5-yl)butan-1-amine (264 mg, 64% yield). LCMS (LC-1): RT=1.30, m/z 385 [M+H] ⁺ .

[0316]

Intermediate G-1-4: tert-Butyl-(2S,4S)-4-azido-2-((4-(6-(benzyloxy)-3-bromoquinolin-5-yl)butyl)carbamoyl)piperidine-1 -carboxylate

[0317]

4-(6-(Benzyloxy)-3-bromoquinolin-5-yl)butan-1-amine (intermediate G-1-3, 214 mg, 0.55 mmol) was dissolved in dimethylformamide (2.8 ml), to add N-methylmorpholine (150 μl, 1.39 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (638 mg, 3.33 mmol), 1-hydroxybenzotriazole (223 mg, 1.66 mmol) to the solution and (2S,4S)-4-azido-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (intermediate G-1-3', 150 mg, 0.55 mmol) and stir the resulting mixture at room temperature in within 14 hours. Water was added to the reaction mixture, the resulting mixture was extracted with chloroform, the solvent was evaporated and the residue was purified using automatic column chromatography (silica gel, eluent, chloroform:methanol = 90:10) to obtain tert-butyl-(2S,4R)-2-(( 3-((6-(benzyloxy)-3-hydroxyquinolin-5-yl)oxy)propyl)carbamoyl)-4-hydroxypiperidine-1-carboxylate (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).

[0318]

Intermediate G-1-5: tert-Butyl-(2S,4S)-4-amino-2-((4-(6-(benzyloxy)-3-bromoquinolin-5-yl)butyl)carbamoyl)piperidine-1 -carboxylate

[0319]

tert-Butyl-(2S,4R)-2-((3-((6-(benzyloxy)-3-hydroxyquinolin-5-yl)oxy)propyl)carbamoyl)-4-hydroxypiperidine-1-carboxylate (intermediate G -1-4, 190 mg, 2 98 µmol) was dissolved in tetrahydrofuran (1.2 ml), triphenylphosphine (86 mg, 0.33 mmol) was added to the solution and the resulting mixture was stirred at 50°C for 5.5 hours. Water was added to the resulting crude reaction mixture, the mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over sodium sulfate, the solvent was evaporated and the residue was purified using automatic column chromatography (silica gel, eluent, chloroform:methanol = 95:5) to obtain tert -butyl-[25,4S)-4-amino-2-((4-(6-(benzyloxy)-3-bromoquinolin-5-yl)butyl)carbamoyl)piperidine-1-carboxylate (134 mg, yield 7 4 %).

LCMS (LC-1): RT=1.62, m/z 611 [M+H] ⁺ .

[0320]

Intermediate G-1-6: tert-Butyl-(3 ² S,3 ⁴ S)-1 ⁶ -(benzyloxy)-4-oxo-2,5-diaza-1(3,5)-quinoline-3( 4,2)-piperidinecyclononaphane-3 ¹ -carboxylate

[0321]

tert-Butyl-(2S,4S)-4-amino-2-((4-(6-(benzyloxy)-3-bromoquinolin-5-yl)butyl)carbamoyl)piperidine-1-carboxylate (intermediate G-1 -5, 27 mg, 44 µmol) are dissolved in toluene (1.5 ml), methanesulfonate [(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) and phosphazene base P ₂ -Et (29 µl, 88 µmol) and stir the resulting mixture at room temperature. The reaction mixture is purified using automated column chromatography (silica gel, eluent, chloroform:methanol=90:10) to give tert-butyl-(3 ² S,3 ⁴ S)-1 ⁶ -(benzyloxy)-4-oxo-2, 5-diaza-1(3,5)-quinoline-3(4,2)-piperidinecyclononaphane-3 ¹ -carboxylate (9 mg, yield 3 9%).

LCMS (LC-1): RT=1.72, t/z 531 [M+H] ⁺

[0322]

[0323]

Intermediate G-2-1: tert-Butyl-(3 ² S,3 ⁴ S)-1 ⁶ -hydroxy-4-oxo-2,5-diaza-1(3,5)-quinoline-3(4, 2)-piperidinecyclononaphane-3 ¹ -carboxylate

[0324]

tert-Butyl-(3 ² S,3 ⁴ S)-1 ⁶ -(benzyloxy)-4-oxo-2,5-diaza-1(3,5)-quinoline-3(4,2)-piperidinecyclononaphane-3 ¹ -Carboxylate (intermediate G-1-6, 100 mg, 0.19 mmol) was dissolved in methanol (2.7 ml), ethyl acetate (4 ml) and toluene (2.6 ml), and added to the solution under nitrogen atmosphere palladium hydroxide (25 mg), the atmosphere is manually replaced with hydrogen gas and the resulting mixture is vigorously stirred at room temperature for 14 hours. Insoluble materials are removed from the reaction mixture by filtration and then the solvent is evaporated to obtain tert-butyl-(3 ² S,3 ⁴ S)-1 ⁶ -hydroxy-4-oxo-2,5-diaza-1(3,5)-quinoline -3(4,2)-piperidinecyclononaphane-3 ¹ -carboxylate (70 mg, yield 8 4%).

LCMS (LC-1): RT=1.21, m/z 441 [M+H] ⁺ .

[0325]

Intermediate G-2-2: tert-Butyl-(3 ² S,3 ⁴ S)-1 ⁶ -(((trifluoromethyl)sulfonyl)oxy)-4-oxo-2,5-diaza-1(3,5 )-quinoline-3(4,2)-piperidinecyclononaphane-3 ¹ -carboxylate

[0326]

tert-Butyl-(3 ² S,3 ⁴ S)-1 ⁶ -hydroxy-4-oxo-2,5-diaza-1(3,5)-quinoline-3(4,2)-piperidinecyclononaphane-3 ¹ - carboxylate (intermediate G-2-1, 70 mg, 159 µmol) was dissolved in 1,4-dioxane (1.6 ml), N,N-bis(trifluoromethylsulfonyl)aniline (181 mg, 0.51 mmol) was added to the solution ), diisopropylethylamine (170 μl, 0.95 mmol) and dimethylformamide (6 drops) and stir the resulting mixture at room temperature for 3 hours. The reaction mixture was concentrated and the residue was purified using automated column chromatography (silica gel, eluent, chloroform:methanol=90:10) to give tert-butyl-(3 ² S,3 ⁴ S)-1 ⁶ -(((trifluoromethyl)sulfonyl) oxy)-4-oxo-2,5-diaza-1(3,5)-quinoline-3(4,2)-piperidinecyclononaphane-3 ^1- carboxylate (88 mg, 97% yield).

LCMS (LC-1): RT=1.76, m/z 573 [M+H] ⁺

[0327]

Intermediate G-2-3: tert-Butyl-(3 ² S,3 ⁴ S)-1 ⁶ -(2-(propoxymethyl)pyrimidin-5-yl)-2,5-diaza-1(3,5) -quinoline-3(4,2)-piperidinecyclononaphane-3 ¹ -carboxylate

[0328]

tert-Butyl-(3 ² S,3 ⁴ S)-1 ⁶ -(((trifluoromethyl)sulfonyl)oxy)-4-oxo-2,5-diaza-1(3,5)-quinoline-3(4, 2)-piperidinecyclononaphane-3 ¹ -carboxylate (intermediate G-2-2, 44 mg, 76 μmol) was dissolved in 1,4-dioxane (300 μl) and water (30 μl), and (2-(propoxymethyl )pyrimidin-5-yl)boronic acid (175 mg, 0.19 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (32 mg, 3 8 µmol) and cesium carbonate (15 0 mg , 0.4 6 mmol) and treat the resulting mixture with microwave irradiation at 100°C for 3 hours. Insoluble substances are removed from the reaction mixture by filtration through a pad of celite, then the solvent is evaporated and the residue is purified using automatic column chromatography (silica eluent, chloroform:methanol = 9 0:10) to obtain tert-butyl-(3 ² S, 3 ⁴ S )-1 ⁶ -(2-(propoxymethyl)pyrimidin-5-yl)-2,5-diaza-1(3,5)-quinoline-3(4,2)-piperidinecyclononaphane-3 ^1- carboxylate (44 mg, yield 99%).

LCMS (LC-1): RT=1.46, m/z 575 [M+H] ⁺ .

[0329]

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)-piperidinecyclononaphan-4-one

[0330]

tert-Butyl-(3 ² S,3 ⁴ S)-1 ⁶ -(2-(propoxymethyl)pyrimidin-5-yl)-2,5-diaza-1(3,5)-quinoline-3(4,2 )-piperidinecyclononaphane-3 ¹ -carboxylate (intermediate G-2-3, 22.8 mg, 39 µmol) was dissolved in dichloromethane (400 µl), trifluoroacetic acid (100 µl) was added to the solution and the resulting mixture was stirred at room temperature in within 20 minutes. The reaction mixture is treated with SCX to give (3 ² S,3 ⁴ S)-1 ⁶ -(2-(propoxymethyl)pyrimidin-5-yl)-2,5-diaza-1(3,5)-quinoline-3 (4,2)-piperidinecyclononaphan-4-one (19 mg, yield 4 6%).

LCMS (LC-1): RT=1.01, m/z 475 [M+H] ⁺ .

[0331]

Example a-02-24 (final product G-2-5): (3 ² S,3 ⁴ S)-3 ¹ -Methyl-1 ⁶ -(2-(propoxymethyl)pyrimidin-5-yl)-2,5 -diaza-1(3,5)-quinoline-3(4,2)-piperidinecyclononaphan-4-one

[0332]

(3 ² S,3 ⁴ S)-1 ⁶ -(2-(Propoxymethyl)pyrimidin-5-yl)-2,5-diaza-1(3,5)-quinoline-3(4,2)-piperidinecyclononaphan- 4-one (intermediate G-2-4, 19 mg, 39 µmol) is dissolved in dichloromethane (290 µl) and methanol (290 µl), 37% aqueous formaldehyde (10 µl, 0.26 mmol) and triacetoxyborohydride are added to the solution sodium (27.7 mg, 130 μmol) and stir the resulting mixture at room temperature for 35 minutes. The reaction mixture is treated with SCX and then purified by HPLC to give (3 ² S,3 ⁴ S)-3 ¹ -methyl -1 ⁶ -(2-(propoxymethyl)pyrimidin-5-yl)-2,5-diaza-1(3,5)-quinoline-3(4,2)-piperidinecyclononaphan-4-one (17.2 mg, yield 9 0%).

LCMS (LC-1): RT=1.09, m/z 489 [M+H] ⁺ .

1H-NMR (CD ₃ OD): 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). [0333]

[0334]

Intermediate H-1-2: Methyl-(S,E)-4-oxo-2-(tritylamino)hept-5-enoate

[0335]

Methyl (S)-5-(dimethoxyphosphoryl)-4-oxo-2-(tritylamino)pentanoate (17 g, 35.3 mmol), prepared according to the method described in the scientific literature (J. Org. Chem., 2012, 77, 10001-10009), dissolved in acetonitrile

(200 ml), potassium carbonate (5.1 g, 37 mmol) and acetaldehyde (5.92 ml, 106 mmol) were added to the solution and the resulting mixture was stirred at 40°C for 4-8 hours. The reaction mixture was cooled to room temperature, the solvent was evaporated, then ethyl acetate was added, the organic layer was washed with water and brine, dried over magnesium sulfate, the solvent was evaporated and the residue was purified using automatic column chromatography (silica gel, eluent hexane:ethyl acetate=75:25 ) to give methyl (S,E)-4-oxo-2-(tritylamino)hept-5-enoate (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).

[0336]

Intermediate H-1-3: Methyl-(S,E)-2-amino-4-oxohept-5-enoate trifluoroacetic acid salt

[0337]

Methyl (S,E)-4-oxo-2-(tritylamino)hept-5-enoate (intermediate H-1-2, 11.5 g, 27.8 mmol) was dissolved in dichloromethane (92 ml), to trifluoroacetic acid (92 ml) is added to the solution and the resulting mixture is stirred at room temperature for 1 hour. The reaction mixture was concentrated, the residue was dissolved in water, then the solution was washed with diethyl ether and the solvent was evaporated to give methyl (S, E)-2-amino-4-oxohept-5-enoate trifluoroacetic acid salt (8.49 g, 99% yield ).

1H-NMR (DMSO d ₆ ): δ (ppm) 8.34 (3H, br. s), 6.96 (1H, sq, J=7.0 Hz), 7.00 (1H, sq , 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).

[0338]

Intermediate H-1-4: Methyl (2S)-1-benzyl-6-methyl-4-oxopiperidine-2-carboxylate

[0339]

Methyl (S, E)-2-amino-4-oxohept-5-enoate trifluoroacetic acid salt (intermediate H-1-3, 7.92 g, 27.8 mmol) was dissolved in tetrahydrofuran (100 ml), to 4A molecular sieves (8 g), triethylamine (3.87 mL, 27.8 mmol) and benzaldehyde (2.83 mL, 27.8 mmol) were added to the solution and the resulting mixture was stirred at room temperature for 30 minutes. Insoluble substances were removed from the reaction mixture by filtration, then the solvent was evaporated, the residue was dissolved in methanol (100 ml), sodium cyanoborohydride (27.8 ml, 27.8 mmol) was added to the solution and the resulting mixture was stirred at room temperature for 14 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, the resulting mixture was extracted with dichloromethane, the organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine, then dried over magnesium sulfate, the solvent was evaporated, and the residue was purified using automatic column chromatography (silica gel, eluent, hexane :ethyl acetate=75:15) to give methyl (2S)-1-benzyl-6-methyl-4-oxopiperidine-2-carboxylate (2.28 g, 31% yield).

LCMS (LC-1): RT=1.54, m/z 262 [M+H] ⁺ .

[0340]

Intermediate H-1-5: Methyl (2S)-6-methyl-4-oxopiperidine-2-carboxylate

[0341]

Methyl (2S)-1-benzyl-6-methyl-4-oxopiperidine-2-carboxylate (intermediate H-1-4, 100 mg, 0.38 mmol) was dissolved in methanol (2.5 ml), to solution Add palladium hydroxide (18 mg) under a nitrogen atmosphere, manually replace the atmosphere with hydrogen gas, and stir the mixture vigorously at room temperature for 14 hours. Insoluble materials were removed from the reaction mixture by filtration and then the solvent was evaporated to obtain a crude product containing methyl (2S)-6-methyl-4-oxopiperidine-2-carboxylate (64 mg, 97% yield).

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) .

[0342]

Intermediate H-1-6: Methyl (2S)-1,6-dimethyl-4-oxopiperidine-2-carboxylate

[0343]

Methyl (2S)-6-methyl-4-oxopiperidine-2-carboxylate (intermediate H-1-5, 1.54 g, 9.0 mol) was dissolved in dichloromethane (70 ml) and 31% aqueous was added to the solution. formaldehyde (7 ml, 86 mmol) and sodium triacetoxyborohydride (2.28 g, 10.8 mmol) and stir the resulting mixture at room temperature for 1 hour. The reaction mixture is treated with SCX to obtain a crude product containing methyl (2S)-1,6-dimethyl-4-oxopiperidine-2-carboxylate (1.48 g, 89% yield).

LCMS (LC-1): RT=0.72, t/z 186 [M+H] ⁺ .

[0344]

Intermediate H-1-7: Methyl (2S)-4-(benzylamino)-1,6-dimethylpiperidine-2-carboxylate

[0345]

Methyl (2S)-1,6-dimethyl-4-oxopiperidine-2-carboxylate (intermediate H-1-6, 1.48 g, 7.99 mol) was dissolved in methanol (19 ml), benzylamine was added to the solution (4.4 ml, 40 mmol) and titanium tetraisopropoxide (9.5 ml, 40 mmol) and stir the resulting mixture at room temperature for 14 hours. Sodium borohydride (1.04 g, 27.6 mmol) was added to the reaction mixture while cooling with ice, and the resulting mixture was stirred at the same temperature for 1.5 hours. A 25% aqueous ammonia solution is added to the reaction mixture, the resulting mixture is stirred for 14 hours, and then the insoluble precipitate is removed by filtration through a pad of celite. The solvent of the resulting organic layer was evaporated, the residue was diluted with brine, extracted with chloroform/methanol (90:10), the organic layer was dried over magnesium sulfate and the solvent was evaporated to dryness to obtain a crude product containing methyl (2S)-4-(benzylamino) -1,6-dimethylpiperidine-2-carboxylate (9.91 g, 99% yield).

[0346]

Intermediate H-1-8: Methyl (2S)-4-amino-1,6-dimethylpiperidine-2-carboxylate

[0347]

Methyl (2S)-4-(benzylamino)-1,6-dimethylpiperidine-2-carboxylate (intermediate H-1-7, 2.21 g, 8.0 mmol) was dissolved in methanol (50 ml), to solution Add palladium hydroxide (2.21 g, 15.7 mmol) under a nitrogen atmosphere, manually replace the atmosphere with hydrogen gas, and stir the mixture vigorously at room temperature for 14 hours. Insoluble materials were removed from the reaction mixture by filtration and the solvent was evaporated to give a crude product containing methyl (2S)-4-amino-1,6-dimethylpiperidine-2-carboxylate (2.52 g, 99% yield).

LCMS (LC-1): RT=0.76, m/z 186 [M+H] ⁺ .

[0348]

Intermediate H-1-9: Methyl (2S)-4-((tert-butoxycarbonyl)amino)-1,6-dimethylpiperidine-2-carboxylate

[0349]

Methyl (2S)-4-amino-1,6-dimethylpiperidine-2-carboxylate (intermediate H-1-8, 1.4 g, 7.52 mmol) was dissolved in dichloromethane (38 ml), to a solution in the atmosphere Add di-tert-butyl dicarbonate (2.59 mL, 11.3 mmol) and triethylamine (2.1 mL, 15 mmol) and stir the mixture at room temperature for 3 hours. The reaction mixture was concentrated and the residue was purified using automated column chromatography (silica gel, eluent, chloroform:methanol:2 5% aqueous ammonia=200:9:1) to give methyl-(2S)-4-((tert-butoxycarbonyl)amino) -1,6-dimethylpiperidine-2-carboxylate (1.61 g, 7 5% yield).

LCMS (LC-1): RT=1.23, m/z 287 [M+H] ⁺ .

[0350]

Intermediate H-1-10: Sodium salt of (2S)-4-((tert-butoxycarbonyl)amino)-1,6-dimethylpiperidine-2-carboxylic acid

[0351]

Methyl (2S)-4-((tert-butoxycarbonyl)amino)-1,6-dimethylpiperidine-2-carboxylate (intermediate H-1-9, 1.61 g, 11.2 mmol) was dissolved in methanol (28 ml), 2 M aqueous sodium hydroxide solution (5.6 ml, 11.3 mmol) was added to the solution and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give (2S)-4-((tert-butoxycarbonyl)amino)-1,6-dimethylpiperidine-2-carboxylic acid sodium salt (1.51 g, 99% yield).

LCMS (LC-1): RT=0.70, m/z 273 [M+H] ⁺ .

[0352]

[0353]

Intermediate H-2-2: (E)-2-(4-(6-(Benzyloxy)-3-bromoquinolin-5-yl)but-3-en-1-yl)isoindolin-1,3-dione

[0354]

6-(Benzyloxy)-3-bromo-5-iodoquinoline (intermediate D-1-6, 2.0 g, 4.5 mmol) was dissolved in toluene (50 ml), a 10% tri-tert solution was added to the solution. butylphosphine in pentane (910 μl, 0.4 5 mmol), dicyclohexylmethylamine (2.6 g, 13.5 mmol), 2-(but-3-en-1-yl)isoindolin-1,3-dione (1, 1 g, 5.5 mmol), obtained in accordance with the method described in the scientific literature (J. Org. Chem., 1974, 39, 1979-1980), and tris(dibenzylideneacetone) dipalladium (0) (206 mg, 0 .23 mmol) and stir the resulting mixture with heating at 120°C for 20 hours. The reaction solution was cooled to room temperature, then the solvent was evaporated and the residue was purified by column chromatography (silica gel, eluent, hexane:ethyl acetate=86:14) to obtain (E)-2-(4-(6-(benzyloxy)-3-bromoquinoline- 5-yl)but-3-en-1-yl)isoindolin-1,3-dione (1.4 g, 61% yield).

[0355]

Intermediate H-2-3: (E)-4-(6-(Benzyloxy)-3-bromoquinolin-5-yl)but-3-en-1-amine

[0356]

(E)-2-(4-(6-(Benzyloxy)-3-bromoquinolin-5-yl)but-3-en-1-yl)isoindolin-1,3-dione (intermediate H-2-2, 1.29 g, 2.51 mmol) was dissolved in ethanol (25 ml), hydrazine hydrate (1.82 ml, 5.02 mmol) was added to the solution and the resulting mixture was refluxed for 4 hours. The reaction solution was cooled to room temperature, the solvent was evaporated, the residue was dissolved in water (25 ml), the solution was extracted with ethyl acetate, the organic layer was concentrated and the residue was purified by column chromatography (silica gel, eluent hexane:ethyl acetate=86:14) to obtain (E)- 4-(6-(benzyloxy)-3-bromoquinolin-5-yl)but-3-en-1-amine (680 mg, 39%).

[0357]

Intermediate H-2-4: tert-Butyl-((2S)-2-(((E)-4-(6-(benzyloxy)-3-bromoquinolin-5-yl)but-3-ene-1- yl)carbamoyl)-1,6-dimethylpiperidin-4-yl)carbamate

[0358]

(E)-4-(6-(Benzyloxy)-3-bromoquinolin-5-yl)but-3-en-1-amine (intermediate H-2-3, 193 mg, 0.50 mmol) dissolved in dimethylformamide (5 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (193 mg, 1.01 mmol), 1-hydroxybenzotriazole (154 mg, 1.01 mmol) and sodium salt (2S)- 4-((tert-butoxycarbonyl)amino)-1,6-dimethylpiperidine-2-carboxylic acid (intermediate H-1-10, 274 mg, 1.01 mmol) and stir the resulting mixture with heating at 50°C for 14 hours. The reaction mixture was concentrated and the residue was purified using automated column chromatography (silica gel, eluent hexane:ethyl acetate=50:50) to give tert-butyl-((2S)-2-(((E)-4-(6-(benzyloxy )-3-bromoquinolin-5-yl)but-3-en-1-yl)carbamoyl)-1,b-dimethylpiperidin-4-yl)carbamate (353 mg, 99% yield).

LCMS (LC-1): RT=1.95, m/z 638 [M+H] ⁺ .

[0359]

Intermediate H-2-5: (2S)-4-Amino-N-((E)-4-(6-(benzyloxy)-3-bromoquinolin-5-yl)but-3-en-1-yl) -1,6-dime tilpiperidine-2-carboxamide

[0360]

tert-Butyl-((2S)-2-(((E)-4-(b-(benzyloxy)-3-bromoquinolin-5-yl)but-3-en-1-yl)carbamoyl)-1,6 -Dimethylpiperidin-4-yl)carbamate (intermediate H-2-4, 242 mg, 0.38 mmol) is dissolved in dichloromethane (3.8 ml), trifluoroacetic acid (2 90 μl, 3.8 mmol) is added to the solution. and stir the resulting mixture at room temperature for 2 hours. The reaction solution was concentrated, neutralized with 25% aqueous ammonia and extracted with chloroform, the organic layer was dried over magnesium sulfate and the solvent was evaporated to give (2S)-4-amino-N-((E)-4-(6-(benzyloxy)-3 -bromoquinolin-5-yl)but-3-en-1-yl)-1,6-dimethylpiperidin-2-carboxamide (203 mg, 99% yield).

LCMS (LC-1): RT=1.42, m/z 538 [M+H] ⁺ .

[0361]

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)-piperidanacyclononaphan-8-en-4-one

[0362]

(2S)-4-Amino-N-((E)-4-(6-(benzyloxy)-3-bromoquinolin-5-yl)but-3-en-1-yl)-1,6-dimethylgsperidin-2 -carboxamide (intermediate H-2-5, 210 mg, 0.38 mmol) is dissolved in 1,4-dioxane (3.9 ml), tris(dibenzylideneacetone)dipalladium(0) (36 mg, 40 μmol) is added to the solution ), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (36 mg, 80 µmol) and sodium phenoxide (90 mg, 0.78 mmol) and reflux the resulting mixture in within 14 hours. The reaction mixture is cooled to room temperature, then the solvent is evaporated and the residue is purified using automatic column chromatography (silica gel, eluent, chloroform:methanol=9:1) to give (3 ² S,E)-1 ⁶ -(benzyloxy)-3 ¹ ,3 ⁶ -dimethyl-2,5-diaza-1(3,5)-quinoline-3(4,2)-piperidinecyclononaphan-8-en-4-one (133 mg, 75% yield).

LCMS (LC-1): RT=1.4 9, m/z 457 [M+H] ⁺ .

[0363]

[0364]

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) -piperidinecyclononaphan-8-en-4-one

[03 65]

(3 ² S,E)-1 ⁶ -(Benzyloxy)-3 ^{1,3 6} -dimethyl-2,5-diaza-1 (3,5)-quinoline-3(4,2)-piperidinecyclononaphan-8-ene -4-one (intermediate H-2-6, 131 mg, 0.29 mmol) is dissolved in methanol (2.8 ml), palladium on carbon (24 mg) is added to the solution under nitrogen atmosphere, the atmosphere is manually replaced hydrogen gas and stir the resulting mixture vigorously at room temperature for 14 hours. Insoluble materials are removed from the reaction mixture by filtration and then the solvent is evaporated to obtain a crude product containing (3 ² S, E)-1 ⁶ -hydroxy-3 ¹ ,3 ⁶ -dimethyl-2,5-diaza-1(3,5) -quinoline-3(4,2)-piperidinecyclononaphan-8-en-4-one (105 mg, 99% yield).

LCMS (LC-1): RT=0.86, m/z 367 [M+H] ⁺ .

[0366]

Intermediate H-3-2: (3 ² S, E)-3 ¹ ,3 ⁶ -Dimethyl-4-oxo-2,5-diaza-1(3,5)-quinoline-3(4,2)- piperidinecyclononaphane-8-ene-1 ⁶ -yltrifluoromethanesulfonate

[0367]

(3 ² S, E)-1 ⁶ -Hydroxy-3 ^{1,3 6} -dimethyl-2,5-diaza-1(3,5)-quinoline-3(4,2)-piperidinecyclononaphane-8-ene-4 -one (intermediate H-3-1, 105 mg, 0.29 mmol) was dissolved in 1,4-dioxane (2.9 ml), N,N-bis(trifluoromethylsulfonyl)aniline) (136 mg, 0.57 mmol) and diisopropylethylamine (80 μl, 0.57 mmol) and stir the resulting mixture at 70°C for 14 hours. The reaction mixture is concentrated to obtain a crude product containing (3 ² S, E)-3 ¹ ,3 ⁶ -dimethyl-4-oxo-2,5-diaza-1(3,5)-quinoline-3(4,2) -piperidinecyclononaphan-8-ene-1 ⁶ -yltrifluoromethanesulfonate (143 mg, 99% yield).

LCMS (LC-1): RT=1.61, m/z 499 [M+H] ⁺ .

[0368]

Example a-02-17 (final product 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)-piperidinecyclononaphan-8-en-4-one

[0369]

(3 ² S, E)-3 ^{1,3 6} -Dimethyl-4-oxo-2,5-diaza-1(3,5)-quinoline-3(4,2)-piperidinecyclononaphan-8-ene-1 ⁶ -yltrifluoromethanesulfonate (intermediate H-3-2, 120 mg, 0.24 mmol) was dissolved in 1,4-dioxane (2.4 ml) and water (240 μl), pinacol ester 2-methylpyrimidine-5 was added to the solution -boronic acid (105 mg, 0.48 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (17 mg, 20 μmol) and cesium carbonate (156 mg, 0.48 mmol) and treated the resulting mixture was irradiated with microwaves at 100°C for 3 hours. Insoluble materials are removed from the reaction mixture by filtration through a pad of celite, then the solvent is evaporated and the residue is purified by HPLC to give (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)-piperidinecyclononaphan-8-en-4-one (1.1 mg, 1% yield).

LCMS (LC-1): RT=0.99, m/z 443 [M+H] ⁺ .

1H-NMR (CD ₃ OD): 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).

[0370]

[0371]

Intermediate I-1-2: Methyl 1,2-dimethyl-4-oxopiperidine-2-carboxylate

[0372]

Methyl 1,2-dimethyl-4-oxo-1,2,3,4-tetrahydropyridine-2-carboxylate (1.3 g, 7.3 mmol), prepared according to the method described in the literature (Org. Lett ., 2005, 435-437), dissolved in tetrahydrofuran (8 ml), L-Selectride(E) (190 ml) was added to the solution in a nitrogen atmosphere at -78°C and the resulting mixture was stirred at the indicated temperature for 2 hours. The reaction is quenched by adding methanol to the reaction mixture, then the reaction mixture is warmed to room temperature, concentrated and processed using an SCX cartridge to obtain a crude reaction mixture containing methyl 1,2-dimethyl-4-oxopiperidine-2-carboxylate.

LCMS (LC-1): RT=0.94, m/z 186 [M+H] ⁺ .

[0373]

Intermediate I-1-3: Methyl 4-(benzylamino)-1,2-dimethylpiperidine-2-carboxylate

[0374]

Methyl 1,2-dimethyl-4-oxopiperidine-2-carboxylate (intermediate 1-1-2, 1.0 g, 5.47 mol) was dissolved in methanol (13 ml), benzylamine (3.0 ml, 27.4 mmol) and titanium tetraisopropoxide (6.5 ml, 21.9 mmol) and stir the resulting mixture at room temperature for 14 hours. Sodium borohydride (715 mg, 18.9 mmol) was added to the reaction mixture while cooling with ice, and the resulting mixture was stirred at the same temperature for 2 hours. A 25% aqueous ammonia solution is added to the reaction mixture, the resulting mixture is stirred for 14 hours, and then insoluble substances are removed by filtration through a layer of celite. The solvent of the resulting organic layer was evaporated, the residue was diluted with brine and extracted with chloroform/methanol (90:10), the organic layer was dried over magnesium sulfate and the solvent was evaporated to dryness to obtain a crude product containing methyl 4-(benzylamino)-1,2 -dimethylpiperidine-2-carboxylate (1.51 g, 99% yield).

[0375]

Intermediate I-1-4: Methyl 4-amino-1,2-dimethylpiperidine-2-carboxylate

[0376]

Methyl 4-(benzylamino)-1,2-dimethylpiperidium-2-carboxylate (intermediate I-1-5, 1.51 g, 5.47 mmol) was dissolved in methanol (35 ml) and added to the solution under a nitrogen atmosphere palladium hydroxide (800 mg, 5.70 mmol), manually replace the atmosphere with hydrogen gas and stir the resulting mixture vigorously at room temperature for 14 hours. Insoluble materials were removed from the reaction mixture by filtration and then the solvent was evaporated to obtain a crude product containing methyl 4-amino-1,2-dimethylpiperidine-2-carboxylate (1.02 g, 99% yield).

[0377]

Intermediate I-1-5: Methyl 4-((tert-butoxycarbonyl)amino)-1,2-dimethylpiperidine-2-carboxylate

[0378]

Methyl 4-amino-1,2-dimethylpiperidine-2-carboxylate (intermediate I-1-4, 1.02 g, 5.47 mmol) was dissolved in dichloromethane (38 ml), di-tert-butyl dicarbonate was added to the solution (3.58 ml, 16.4 mmol) and triethylamine (7.63 ml, 54.7 mmol) and stir the resulting mixture at room temperature for 3 hours. The reaction mixture was concentrated and the residue was purified by automated column chromatography (silica gel, eluent, hexane:ethyl acetate = 20:80) to obtain methyl 4-((tert-butoxycarbonyl)amino)-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).

[0379]

Intermediate I-1-6: 4-((tert-butoxycarbonyl)amino)-1,2-dimethylpiperidine-2-carboxylic acid sodium salt

[0380]

Methyl 4-((tert-butoxycarbonyl)amino)-1,2-dimethylpiperidine-2-carboxylate (intermediate I-1-5, 68 7 mg, 2.4 0 mmol) is dissolved in 1 M aqueous sodium hydroxide ( 10 ml, 10 mmol) and stir the resulting solution at room temperature for 2 hours. The reaction mixture was concentrated to give 4-((tert-butoxycarbonyl)amino)-1,2-dimethylpiperidine-2-carboxylic acid sodium salt (853 mg, 99% yield).

[0381]

[0382]

Intermediate I-2-2: 3-((6-(Benzyloxy)-3-bromoquinolin-5-yl)oxy)-2-fluoropropan-1-amine

[0383]

tert-Butyl-(S)-(3-((6-(benzyloxy)-3-bromoquinolin-5-yl)oxy)-2-fluoropropyl)carbamate (intermediate I-2-1, 6.5 9 g, 13.0 mmol) was dissolved in dichloromethane (40 ml), trifluoroacetic acid (10 ml) was added to the solution and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture is treated with SCX to give (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).

[0384]

Intermediate I-2-3: tert-Butyl-(2-((3-((6-(benzyloxy)-3-bromoquinolin-5-yl)oxy-2-fluoropropyl)carbamoyl)-1,2-dimethylpiperidin- 4-yl)carbamate

[0385]

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), N-methylmorpholine (695 μl, 2.52 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodnimide hydrochloride (1.93 g, 10.1 mmol), 1-hydroxybenzotriazole ( 750 mg, 5.55 mmol) and 4-((tert-butoxycarbonyl)amino)-1,2-dimethylpiperidine-2-carboxylic acid sodium salt (intermediate 1-1-6, 687 mg, 2.52 mmol) and Stir the resulting mixture at room temperature for 14 hours. Water was added to the reaction mixture, the resulting mixture was extracted with chloroform, the solvent was evaporated and the residue was purified using automatic column chromatography (silica gel, eluent hexane:ethyl acetate=30:70) to obtain tert-butyl-(2-((3-((6 -(benzyloxy)-3-bromoquinolin-5-yl)oxy-2-fluoropropyl)carbamoyl)-1,2-dimethylpiperidin-4-yl)carbamate (765 mg, 42% yield).

LCMS (LC-1): RT=2.05, m/z 65 9 [M+H] ⁺ .

1H-NMR (CDCl ₃ ): δ (ppm) 8.7 7 (1H, d, J=2.Q 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 ( 1Н, dd, J=10, 0, 7.0 Hz), 4.92-4.64 (1Н, m), 4, 44-4, 25 (3Н, m), 4.12 (1Н, 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).

[0386]

Intermediate I-2-4: 4-Amino-N-(3-((6-(benzyloxy)-3-bromoquinolin-5-yl)oxy)-2-fluoropropyl)-1,2-dimethylpiperidine-2-carboxamide

[0387]

tert-Butyl-(2-((3-((6-(benzyloxy)-3-bromoquinolin-5-yl)oxy-2-fluoropropyl)carbamoyl)-1,2-dimethylpiperidin-4-yl)carbamate (intermediate 1-2-3, 765 mg, 1.16 mmol) was dissolved in dichloromethane (8 ml), trifluoroacetic acid (2 ml) was added to the solution and the resulting mixture was stirred at room temperature for 20 minutes. The reaction mixture was treated with SCX. producing 4-amino-N-(3-((6-(benzyloxy)-3-bromoquinolin-5-yl)oxy)-2-fluoropropyl)-1,2-dimethylpiperidine-2-carboxamide (645 mg, 100% yield ).

LCMS (LC-1): RT=1.4 3, m/z 55 9 [M+H] ⁺ .

[0388]

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)-piperidinecyclononaphan-4-one

[0389]

4-Amino-N-(3-((6-(benzyloxy)-3-bromoquinolin-5-yl)oxy)-2-fluoropropyl)-1,2-dimethylpiperidine-2-carboxamide (intermediate 1-2-4 , 598 mg, 1.07 mmol) dissolved in 1,4-dioxane (10 ml), tris(dibenzylideneacetone)dipalladium(0) (98 mg, 107 μmol), dicyclohexylphosphino-2',4',6' were added to the solution -triisopropyl-1,1'-biphenyl (102 mg, 214 µmol) and sodium phenoxide (248 mg, 2.14 mmol) and reflux the resulting mixture for 14 hours. The reaction mixture was cooled to room temperature, then the solvent was evaporated and the residue was purified by automated column chromatography (silica gel, eluent, ethyl acetate:methanol=90:10) to give 1 ⁶ -(benzyloxy)-7-fluoro-31,32-dimethyl- 9-oxa-2,5-diaza-1(3,5)-quinoline-3(4,2)-piperidinecyclononaphan-4-one (179 mg, 32% yield).

LCMS (LC-1): RT=1.39, m/z 479 [M+H] ⁺ .

1H-NMR (CDCl ₃ ): δ (m, d,) 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).

[0390]

[0391]

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) -piperidinecyclononaphan-4-one

[0392]

1 ⁶ -(Benzyloxy)-7-fluoro-3 ¹ ,3 ² -dimethyl-9-oxa-2,5-diaza-1(3,5)-quinoline-3(4,2)-piperidinecyclononaphan-4-one (intermediate 1-2-5, 180 mg, 0.38 mmol) dissolved in methanol (8 ml), 10% palladium on carbon (90 mg) was added to the solution under nitrogen atmosphere, the atmosphere was manually replaced with hydrogen gas and vigorously Stir the resulting mixture at room temperature for 14 hours. Insoluble materials are removed from the reaction mixture by filtration and then the solvent is evaporated to give 7-fluoro-1 ⁶ -hydroxy-3 ¹ ,3 ² -dimethyl-9-oxa-2,5-diaza-1(3,5)-quinoline-3 (4,2)-piperidinecyclononaphan-4-one (13 8 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, dkv, J=12.0, 5.0 Hz), 1.46-1.41 (3H, m), 1.28-1.16 (2H, m).

[0393]

Intermediate I-3-2: 7-Fluoro-3 ¹ ,3 ² -dimethyl-9-oxa-2,5-diaza-1(3,5)-quinoline-3(4,2)-piperidinecyclononaphane-1 ⁶ -yltrifluoromethanesulfonate

[0394]

7-Fluoro-1 ⁶ -hydroxy-3 ¹ ,3 ² -dimethyl-9-oxa-2,5-diaza-1(3,5)-quinoline-3(4,2)-piperidinacyclononaphan-4-one (intermediate compound 1-3-1, 138 mg, 0.36 mmol) was dissolved in dichloromethane (4 ml), trifluoromethanesulfonic anhydride (72 μl, 0.43 mmol) and pyridine (43 μl, 0.53 mmol) were added to the solution and Stir the resulting mixture at room temperature for 1 hour. The reaction mixture is concentrated to obtain a crude product containing (7-fluoro-3 ¹ ,3 ² -dimethyl-9-oxa-2,5-diaza-1(3,5)-quinoline-3(4,2)-piperidinecyclononaphane- 1 ⁶ -yltrifluoromethanesulfonate (185 mg, 99% yield) [0395]

Example a-02-23 (final product 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)-piperidinecyclononaphan-4-one

[0396]

7-Fluoro-3 ¹ ,3 ² -dimethyl-9-oxa-2,5-diaza-1(3,5)-quinoline-3(4,2)-piperidinecyclononaphan-1 ⁶ -yltrifluoromethanesulfonate (intermediate I-3 -2, 185 mg, 0.36 mmol) dissolved in 1,4-dioxane (4 ml) and water (800 μl), 2-methylpyrimidine-5-boronic acid pinacol ester (147 mg, 1.07 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (116 mg, 142 µmol) and cesium carbonate (696 mg, 2.14 mmol) and stir the resulting mixture while heating at 80°C for 2 hours. Insoluble materials are removed from the reaction mixture by filtration through a pad of celite, then the solvent is evaporated and the residue is purified by HPLC to give 7-fluoro-31,32-dimethyl-1 ⁶ -(2-methylpyrimidin-5-yl)-9-oxa-2 ,5-diaza-1(3,5)-quinoline-3(4,2)-piperidinecyclononaphan-4-one (43.7 mg, yield 2 6%) as a low-polarity fraction.

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, br. s), 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, dkv, J=12.0, 5.0 Hz), 1.40 (3H, s), 1.34-1.20 (m, 1H ).

[0397]

[0398]

<Biological Test Example 1: Measuring Inhibitory Activity Against Human IRAK-4>

(1) Change method

To measure human IRAK-4 activity (Invitrogen, Cat. PV33 62), phosphorylation of the IRAK-4 peptide substrate (biotin-KKKKRFSFKKSFKC) by the enzyme in the presence of 10 μM ATP (Sigma-Aldrich, Cat. A7699) is measured by TR-FRET. The enzymatic reaction is carried out in a reaction buffer containing 50 mM HEPES (pH 7.2), 1 mM DTT, 0.1 mM Na ₃ VO ₄ , 5 mM MgCl ₂ , 1 mM MnCl ₂ and 0.1% bovine serum albumin (BSA ). To measure IRAK-4 inhibitory activity, the test compound is added to a reaction buffer containing 1 nM IRAK-4, 0.5 μM peptide substrate and 10 μM ATP and incubate the mixture at 23°C for 30 minutes. Then a detection solution containing europium cryptate labeled antibody (0.3 μg/ml, antibody prepared using IRAK-4 peptide substrate as antigen), streptavidin-XL665 (2 μg/ml, CisBio, Cat. 610SAXLB), 50 mM HEPES (pH 7.2), 0.1% BSA, 120 mM KF and 66.7 mM EDTA (all reagent concentrations are final concentrations) were added to complete the reaction and the mixture was further incubated at 23°C for 60 minutes. Fluorescence intensities are measured at wavelengths of 665 nm and 620 nm using a microplate reader, and enzyme activity is calculated as the ratio of fluorescence intensities at 665 nm and 620 nm (665 nm/620 nm). The IRAK-4 inhibition ratio with the addition of 12.5 μM staurosporine (LC Laboratories, Cat. S-9300) was determined to be 100%, the IRAK-4 inhibition ratio without test compound addition was determined to be 0%, and the IC ₅₀ of the test compound was calculated using 4 -parametric logistic model of data analysis software XLfit (ID Business Solutions Ltd.).

The operations and conditions used for measurement may be varied accordingly within a range that can be understood by those skilled in the art and will not significantly affect the measurement results.

[0399]

(2) Measurement results

As shown below, the compounds of the present invention, in accordance with a certain embodiment, exhibit excellent inhibitory activities against IRAK-4.

When measurements are carried out several times, the results are presented as average values.

[0400]

[0402]

<Biological Test Example 2: LPS-stimulated TNFα Production Inhibition Test Using Human Acute Monocytic Leukemia Cell Line THP-1>

(1)Measurement method

The THP-1 assay evaluates the effect of a test compound on TNFα production induced by LPS stimulation. THP-1 cells (ATCC, Cat. TIB-202) are inoculated into a 96-well plate at a density of 1 x 105 cells/160 µl/well, the test compound is added in a volume of 20 µl and the plate is incubated at 37°C for 1 hour in incubator with 5% CO ₂ . Then add LPS in a volume of 20 μl (final concentration 2.5 ng/ml, Sigma, Cat. L2630) and incubate the plate for an additional 4 hours. After incubation, the plate is centrifuged, 100 μl of supernatant is collected from each well and used to estimate the amount of TNFα using HTRF (Cisbio, Cat. 62TNFPEB). When measuring the amount of TNFα, the supernatant is diluted twice with the medium, added to the wells of a 384-well plate in a volume of 10 μl, then anti-TNFα-cryptate (5 μl) and anti-TNFα-XL665 (5 μl) are added and the plate is left overnight. The fluorescence intensity ratio at wavelengths 620 and 665 nm (620 nm/665 nm) was measured using a microplate reader and the amount of TNFα in the supernatant was calculated using a calibration curve. The inhibition rate of TNFα production observed without the addition of LPS is determined as 100%, the inhibition rate of TNFα production observed without the addition of test compound is determined as 0%, and the IC ₅₀ of the test compound is calculated using the 4-parameter logistic model of XLfit data analysis software (ID Business Solutions Ltd.).

[0403]

Using a 96-well plate from which 100 μl of supernatant is collected, the cell survival rate is measured and the off-target effect of the test compound is assessed. CCK-8 (Dojindo, Cat. SK04-10) is added in a volume of 5 μl, the plate is incubated at 37°C for 1 hour and absorbance at 450 nm is measured using a microplate reader. The cell survival rate without LPS addition was determined to be 100%, and the IC ₅₀ of the test compound was calculated using XLfit.

The operations and conditions used for measurement may be varied accordingly within a range that can be understood by those skilled in the art and will not significantly affect the measurement results.

[0404]

(2) Measurement results

As shown below, the compounds of the present invention in accordance with a certain embodiment show excellent inhibitory activity against the production of TNFα.

When measurements are carried out several times, the results are presented as average values.

[0405]

Industrial applicability

[0407]

The compounds of general formula (1) and their salts have excellent inhibitory activity against IRAK-4 and, therefore, can be used as active drug ingredients for the prophylactic treatment and/or therapeutic treatment of diseases associated with IRAK-4 inhibition.

Claims (53)

1. A compound represented by the following general formula (1): in formula (1) R ¹ represents -H or C _1-6 alkyl; R ² represents -H or C _1-6 alkyl; R ³ represents -H or C _1-6 alkyl; Ar is a 6-10 membered aryl or 5-10 membered heteroaryl containing 2 heteroatoms selected from O, S and N, where Ar may be substituted with 1 substituent selected from the group G ² ; the G ² group is a substituent group consisting of C _1-6 alkyl, hydroxy-C _1-6 alkyl, R ^Ar1 -OC _1-3 alkyl; R ^Ar1 represents -H, C _1-6 alkyl or a 3-7 membered saturated hydrocarbon ring, R ^Ar1 may be substituted with 1-2 identical or different substituents selected from the group G ³ ; the G ³ group is a substituent group consisting of a hydroxyl group and a 3-7 membered saturated hydrocarbon ring group; X ¹ represents N or CH; X ² represents NH or O; X ³ is a group represented by the following general formula (1-1): given below by the general formula (1-2): the following formula (1-3): a and b represent the joining direction; R ²¹ and R ²² independently represent -H; X ⁴ is a group represented by the following general formula (2-1): b and c represent the direction of attachment; in formula (2-1), n is an integer from 1 to 3; Y represents NR ⁵¹ or O; R ³¹ and R ³² independently represent -H, C _1-3 alkyl; R ⁴¹ and R ⁴² independently represent -H, -F, C _1-3 alkyl; or R ⁴¹ and R ⁴² can combine to form a 3-6 membered saturated hydrocarbon ring; R ⁵¹ represents H or C _1-3 alkyl; or R ⁵¹ and R ³¹ can combine to form a 4-6 membered saturated heterocyclic ring containing one heteroatom selected from N; or a pharmaceutically acceptable salt thereof. 2. A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein Ar is a 5- or 6-membered heteroaryl containing two heteroatoms selected from O, S and N. 3. A compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R ¹ is -H, methyl or ethyl. 4. The compound or its pharmaceutically acceptable salt according to any one of paragraphs. 1-3, where X ² represents NH. 5. The compound or its salt according to any one of paragraphs. 1-4, where X ³ is a group represented by the following general formula (1-1-1): [Formula 7] 6. The compound or its pharmaceutically acceptable salt according to any one of paragraphs. 1-5, where in the general formula (2-1) for X ⁴ n is equal to 1. 7. The compound or its salt according to any one of paragraphs. 1-6, where Ar is a group represented by the following general formula (3-1): [Formula 8] in 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 is as defined above). 8. The compound or its salt according to any one of paragraphs. 1-7, where Ar is a group represented by the general formula (3-1), and in formula (3-1) R ^Ar2 is -H, methyl, hydroxymethyl or -CH ₂ -OR ^Ar1 , R ^Ar1 has the same meaning as above). 9. The compound or its pharmaceutically acceptable salt according to any one of paragraphs. 1-8, where R ³ represents -H. 10. The compound or its pharmaceutically acceptable salt according to any one of paragraphs. 1-9, where R ² represents -H or methyl. 11. The compound or its pharmaceutically acceptable salt according to any one of paragraphs. 1-10, where R ¹ represents -H or C _1-3 alkyl.