Novel pyrrole derivative and pharmaceutical composition for cancer treatment

Abstract

To provide a novel compound useful for cancer treatment.SOLUTION: Provided is a pyrrole derivative represented by the general formula (I): [In the formula, Aa and Ab represent a single bond, (CH=CH)m, or (Ra)p, where m and p are integers of 1 to 3, Ra represents CRb2, NRb, O, S, or C=O, Rb represents H, CnH2n+1, F, Cl, Br, or I, X1, X2, X3, X4, and X5 represent CH, CR1, or N, Y1, Y2, Y3, and Y4 represent CH, CR2, or N, R1 represents a substituent selected from CnH2n+1, CF3, Cl, OH, OCnH2n+1, CH2OH, and the like, R2 represents a substituent selected from CnH2n+1, OH, OCnH2n+1, and the like, where n is an integer of 1 to 3, and R3 represents H, F, Cl, or Br].SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to novel pyrrole derivatives and pharmaceutical compositions for cancer treatment.

Background Art

[0002] Acute T-lymphoblastic leukemia (T-ALL) is a rare cancer (Non-Patent Document 1) that often occurs in children. Its course is poor. Even if the symptoms are once improved by the treatment of ordinary leukemia, it is likely to deteriorate again. Moreover, when it deteriorates again, existing anti-leukemia drugs become ineffective. In addition, to date, anti-leukemia drugs specialized for T-ALL have not been developed, and the development of T-ALL-specific therapeutic agents is globally demanded.

[0003] Under such circumstances, the present inventors have identified, as compounds that suppress the growth of human T-ALL cell line CCRF-CEM but do not affect the growth of human B-lymphoma cell line Raji, by large-scale screening of natural compounds, the following structural formula:

Chemical formula

[0004] On the other hand, the present inventors have attempted the organic synthesis of related compounds having a structure similar to the above Auxarconjugatin B and have found compounds having selective growth inhibitory activity against T-ALL etc. (Patent Documents 1, 2).

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

[0006] [Non-Patent Document 1] Hunger SP, Mullighan CG. Acute Lymphoblastic Leukemia in Children. N Engl J Med. 2015; 373:1541-52. [Non-Patent Document 2] Miyashita, K, Yagi, T, Kagaya, N, et al. Identification of compounds that preferentially suppress the growth of T-cell acute lymphoblastic leukemia-derived cells. Cancer Sci. 2023; 114: 4032-4040. [Summary of the Invention] [Problems to be Solved by the Invention]

[0007] In addition to the above-mentioned acute T-lymphoblastic leukemia (T-ALL), various refractory cancers are known, and the development of therapeutic drugs specific to each cancer cell is globally demanded.

[0008] Therefore, an object of the present invention is to provide a novel compound useful for cancer treatment. Another object of the present invention is to provide a pharmaceutical composition for cancer treatment. [Means for Solving the Problems]

[0009] As a result of intensive studies to solve the above problems, the present inventors have found that a pyrrole derivative having a specific structure has a growth inhibitory effect on cancer cells, and have completed the present invention. That is, the gist of the pyrrole derivative of the present invention for solving the above problems and the pharmaceutical composition for cancer treatment is as follows.

[0010] [1] The following general formula (I): [Chemical formula] [In the formula, A a and A b are each independently a single bond, (CH=CH) m or (R a ) p and m is an integer from 1 to 3, p is an integer from 1 to 3, R a are each independently CR b 2 , NR b , O, S or C=O, and R b are each independently H, C n H 2n+1 , F, Cl, Br or I, where n is each independently an integer from 1 to 3, X 1 , X 2 , X 3 , X 4 and X 5 are each independently CH, CR 1 or N, provided that the number of those which are N among X 1 , X 2 , X 3 , X 4 and X 5 is 0 to 2, and the number of those which are CR 1 is 0 to 3, Y 1 , Y 2 , Y 3 and Y 4 are each independently CH, CR 2 or N, provided that the number of those which are N among Y 1 , Y 2 , Y 3 and Y 4 is 0 to 2, and the number of those which are CR 2 is 0 to 3, R1 is independently C n H 2n+1 、C 4 H 9 、CF 3 、F, Cl, Br, NHAc, OH, OC n H 2n+1 、OAc, CH 2 OH, CH 2 OC n H 2n+1 、CN, CONHC n H 2n+1 、CON(C n H 2n+1 ) 2 、COOH, and COOC n H 2n+1 and is a substituent selected from the group consisting of, where n is independently an integer from 1 to 3, provided that A a is (CH=CH) m and A b is a single bond and at least one R 1 is COOH or COOC n H 2n+1 in which case at least one other R 1 is other than COOH and COOC n H 2n+1 and when one or more R 1 is OH or OC n H 2n+1 in which case two or more R 1 containing said R 1 may be joined to each other to form a ring, R 2 is independently C n H 2n+1 、OH, OC n H 2n+1 、NH 2 、NHC n H 2n+1 、N(C n H 2n+1 ) 2 、and COOH and is a substituent selected from the group consisting of, where n is independently an integer from 1 to 3, R 3 is H, F, Cl or Br.], characterized by a pyrrole derivative. The pyrrole derivative of the present invention described in [1] above has a growth inhibitory effect on cancer cells.

[0011] [2] The following general formula (1):

Chemical formula

[0012] [3] The pyrrole derivative according to [2], wherein m is 1 or 2. The pyrrole derivative according to the above [3] is easy to synthesize.

[0013] [4] Y 1 Y 2 Y 3 and Y 4 are each independently CH or CR 2 The pyrrole derivative according to [2] or [3], which is The pyrrole derivative according to the above [4] is easy to synthesize.

[0014] [5] Y 1 、Y 2 、Y 3 and Y 4 is CH, the pyrrole derivative described in any one of [2] to [4]. The pyrrole derivative described in the above [5] is easy to synthesize.

[0015] [6] R 3 is H or Cl, the pyrrole derivative described in any one of [2] to [5]. The pyrrole derivative described in the above [6] is easy to synthesize.

[0016] [7] The following general formula (2):

Chemical formula

[0017] [8] The pyrrole derivative according to [7], wherein m is 1. The pyrrole derivative according to the above [8] is easy to synthesize.

[0018] [9] A b1 is NH, O, CH 2 -NH or CH 2 -O. The pyrrole derivative according to [7] or [8]. The pyrrole derivative according to the above [9] is easy to synthesize and has low lipophilicity.

[0019]

[10] Y 1 , Y 2 , Y 3 and Y 4 are CH. The pyrrole derivative according to any one of [7] to [9]. The pyrrole derivative according to the above

[10] is easy to synthesize.

[0020]

[11] The following general formula (3):

Chemical formula

[11] has an inhibitory effect on the growth of cancer cells and has low lipophilicity.

[0021]

[12] A a1 is CH 2 -NH, the pyrrole derivative according to

[11] . The pyrrole derivative according to the above

[12] is easy to synthesize and has low lipophilicity.

[0022]

[13] Y 1 、 Y 2 、 Y 3 and Y 4 is CH, the pyrrole derivative according to

[11] or

[12] . The pyrrole derivative according to the above

[13] is easy to synthesize.

[0023]

[14] A pharmaceutical composition for treating cancer, comprising the pyrrole derivative according to any one of [1] to

[13] or a pharmaceutically acceptable salt thereof. The pharmaceutical composition for treating cancer of the present invention according to the above

[14] has an inhibitory effect on the growth of cancer cells.

[0024]

[15] The pharmaceutical composition for treating cancer according to

[14] , which is used for treating cancer selected from leukemia, breast cancer, brain tumor, colorectal cancer, lung cancer, melanoma, ovarian cancer, kidney cancer, stomach cancer, and prostate cancer. The pharmaceutical composition for cancer treatment of the present invention described in the above

[15] is particularly useful for the treatment of cancers selected from leukemia, breast cancer, brain tumor, colorectal cancer, lung cancer, melanoma, ovarian cancer, kidney cancer, stomach cancer, and prostate cancer.

Effects of the Invention

[0025] According to the present invention, a novel pyrrole derivative useful for cancer treatment can be provided. Furthermore, according to the present invention, a pharmaceutical composition for cancer treatment containing such a pyrrole derivative or a pharmaceutically acceptable salt thereof can be provided.

Modes for Carrying Out the Invention

[0026] Hereinafter, the pyrrole derivative of the present invention and the pharmaceutical composition for cancer treatment will be exemplified and described in detail based on their embodiments.

[0027] <Pyrrole Derivative> The pyrrole derivative of the present invention has the following general formula (I):

Chemical Formula

[0028] The pyrrole derivative represented by the general formula (I) has a structure similar to Auxarconjugatin B, and has a growth inhibitory effect on various cancer cells including leukemia, and is excellent in selectivity. In the above general formula (I), A a and A b are each independently a single bond, (CH=CH) m or (R a ) p ; m is an integer from 1 to 3; p is an integer from 1 to 3. Since the pyrrole derivative represented by the general formula (I) does not have a site where 4 or more C=C bonds are consecutive, it is difficult to be oxidized and metabolized in the body, and it is easy to reach the target. Therefore, a pharmaceutical composition containing the pyrrole derivative represented by the general formula (I) or a salt thereof as an active ingredient is useful for the treatment of cancer.

[0029] In the general formula (I) above, A a and A b are each independently a single bond, (CH=CH) m or (R a ) p where m is an integer from 1 to 3 and p is an integer from 1 to 3. m represents the number of repeating vinylene units (-CH=CH-), and is preferably 1 or 2. At least one of A a and A b is (CH=CH) m . When m is 1 or 2, the pyrrole derivative represented by the general formula (1) is less likely to be further oxidized and metabolized, and is also easy to synthesize. R a are each independently CR b 2 , NR b , O, S or C=O, and R b are each independently H, C n H 2n+1 , F, Cl, Br or I, where n is each independently an integer from 1 to 3. "C n H 2n+1 " is a methyl group, an ethyl group, an n-propyl group, or an isopropyl group because n is an integer from 1 to 3.

[0030] In the general formula (I) above, X 1 , X 2 , X 3 , X 4 and X 5 are each independently CH, CR 1 or N, provided that the number of those which are N among X 1 , X 2 , X 3 , X 4 and X 5 is 0 to 2, and the number of those which are CR 1 is 0 to 3. In other words, among X 1 , X 2 , X 3 , X 4 and X 5 , three or more are CH or CR 1 , and also, X1 、X 2 、X 3 、X 4 and X 5 Among them, two or more are CH or N. That is, one carbon atom and X 1 、X 2 、X 3 、X 4 and X 5 Among the six atoms constituting the six-membered ring formed by and X, the number of carbon atoms is 4 to 6, and the number of nitrogen atoms is 0 to 2. Also, one carbon atom and X 1 、X 2 、X 3 、X 4 and X 5 The number of substituents R 1 introduced into the six-membered ring formed by and X is 0 to 3.

[0031] Regarding the CR 1 , R 1 are each independently C n H 2n+1 、C 4 H 9 、CF 3 、F, Cl, Br, NHAc, OH, OC n H 2n+1 、OAc, CH 2 OH, CH 2 OC n H 2n+1 、CN, CONHC n H 2n+1 、CON(C n H 2n+1 ) 2 、COOH, and COOC n H 2n+1 selected from the group consisting of. Here, n is each independently an integer from 1 to 3. However, when A a is (CH=CH) m , A b is a single bond, and at least one R 1 is COOH or COOC n H 2n+1 1 , at least one other Ris COOH and COOC n H 2n+1is other than. That is, A a is (CH=CH) m and when A b is a single bond, R 1 may be COOH or COOC n H 2n+1 In that case, there may be a plurality of R 1 (among X 1 , X 2 , X 3 , X 4 and X 5 two or more are CR 1 ). One or more other R 1 are each independently C n H 2n+1 , CF 3 , F, Cl, Br, NHAc, OH, OC n H 2n+1 , OAc, CH 2 OH, CH 2 OC n H 2n+1 , CN, CONHC n H 2n+1 , and CON(C n H 2n+1 ) 2 and are substituents selected from the group consisting of. Also, when one or more R 1 are OH or OC n H 2n+1 , two or more R 1 containing the R 1 may be bonded to each other to form a ring. Here, as the group formed by bonding two or more R 1 to each other, -O-O-, -OC n H 2n -O-, -OC n H 2n -C n H 2n O- and the like can be mentioned. Also, C n H 2n+1 , and OC n H 2n+1 , CH 2 OC n H 2n+1 , CONHC n H 2n+1, CON(C n H 2n+1 ), 2 and COOC n H 2n+1 in the "C n H 2n+1 ", since n is an integer from 1 to 3, it is a methyl group, an ethyl group, an n-propyl group, or an isopropyl group. Also, C 4 H 9 can be any of an n-butyl group, a sec-butyl group, an isobutyl group, and a tert-butyl group. Also, "Ac" in NHAc and OAc refers to an acetyl group, that is, NHAc represents an acetylamino group and OAc represents an acetoxy group.

[0032] In the above general formula (I), Y 1 , Y 2 , Y 3 and Y 4 are each independently CH, CR 2 or N, provided that the number of those which are N among Y 1 , Y 2 , Y 3 and Y 4 is 0 to 2, and the number of those which are CR 2 is 0 to 3. In other words, among Y 1 , Y 2 , Y 3 and Y 4 , two or more are CH or CR 2 , and among Y 1 , Y 2 , Y 3 and Y 4 , one or more are CH or N. That is, among the six atoms constituting the six-membered ring formed by two carbon atoms and Y 1 , Y 2 , Y 3 and Y 4 , the number of carbon atoms is 4 to 6, and the number of nitrogen atoms is 0 to 2. Also, the substituent R introduced into the six-membered ring formed by two carbon atoms and Y 1 , Y 2 , Y 3 and Y 4 2The number is from 0 to 3.

[0033] Regarding the above CR 2 R 2 is independently selected from the group consisting of C n H 2n+1 OH, OC n H 2n+1 NH 2 NHC n H 2n+1 N(C n H 2n+1 ) 2 and COOH, where n is independently an integer from 1 to 3. C n H 2n+1 and OC n H 2n+1 NHC n H 2n+1 and N(C n H 2n+1 ) 2 in "C n H 2n+1 " is a methyl group, an ethyl group, an n-propyl group, or an isopropyl group because n is an integer from 1 to 3.

[0034] In the above general formula (I), R 3 is H, F, Cl, or Br, preferably H or Cl. The bonding site of R 3 to the pyrrole ring is arbitrary and not particularly limited. Pyrrole derivatives in which R 3 is H or Cl are easy to synthesize.

[0035] (Pyrrole derivative represented by general formula (1)) The pyrrole derivative of the present invention is represented by the following general formula (1):

Chemical formula

[0036] The pyrrole derivative represented by the general formula (1) has a structure similar to Auxarconjugatin B, and has a growth inhibitory effect on various cancer cells including leukemia, and also has excellent selectivity. In addition, since the pyrrole derivative represented by the general formula (1) has m as an integer of 1 to 3 and does not have a site where 4 or more C=C bonds are consecutive, it is difficult to be oxidized and metabolized in the body, and it is easy to reach the target. Therefore, a pharmaceutical composition containing the pyrrole derivative represented by the general formula (1) or a salt thereof as an active ingredient is useful for the treatment of cancer.

[0037] In the above general formula (1), X 1 , X 2 , X 3 , X 4 and X 5 are each independently CH, CR 1 or N, provided that the number of those which are N among X 1 , X 2 , X 3 , X 4 and X 5 is 0 to 2, and the number of those which are CR 1 is 0 to 3. In other words, among X 1 , X 2 , X 3 , X 4 and X 5 , 3 or more are CH or CR 1 , and among X 1 , X 2 , X 3 , X 4 and X 5 , 2 or more are CH or N. That is, among the 6 atoms constituting the six-membered ring formed by one carbon atom and X 1 , X 2 , X 3 , X 4 and X 5 , there are 4 to 6 carbon atoms and 0 to 2 nitrogen atoms. Also, the substituent R introduced into the six-membered ring formed by one carbon atom and X 1 , X 2 , X 3 , X 4 and X 5 ​1 The number is from 0 to 3.

[0038] Regarding the CR 1 for R 1 are each independently C n H 2n+1 C 4 H 9 CF 3 F, Cl, Br, NHAc, OH, OCH n H 2n+1 OAc, CH 2 OH, CH 2 OCH n H 2n+1 CN, CONHCH n H 2n+1 CON(CH n H 2n+1 ) 2 COOH, and COOCH n H 2n+1 selected from the group consisting of, where n is each independently an integer from 1 to 3. Provided that when at least one R 1 is COOH or COOCH n H 2n+1 then at least one other R 1 is other than COOH and COOCH n H 2n+1 That is, R 1 may be COOH or COOCH n H 2n+1 1 1 2 3 4 5 1 1 n 2n+1 3 n 2n+1 2 2 n 2n+1 n H 2n+1 CF 3 F, Cl, Br, NHAc, OH, OCH n H 2n+1 OAc, CH 2 OH, CH 2 OCH n H 2n+1, CN, CONHC n H 2n+1 , and CON(C n H 2n+1 ) 2 is a substituent selected from the group consisting of. Also, one or more (preferably two or more) R 1 are OH or OC n H 2n+1 . In this case, the R 1 containing (i.e., OH or OC n H 2n+1 . The R 1 of at least one of) two or more R 1 may be bonded to each other to form a ring. Here, the group formed by bonding two or more R 1 to each other includes -O-O-, -OC n H 2n -O-, -OC n H 2n -C n H 2n O-, etc. Also, C n H 2n+1 , and OC n H 2n+1 , CH 2 OC n H 2n+1 , CONHC n H 2n+1 , CON(C n H 2n+1 ) 2 , and COOC n H 2n+1 In the "C n H 2n+1 ", since n is an integer from 1 to 3, it is a methyl group, an ethyl group, an n-propyl group, or an isopropyl group. Also, C 4 H 9 may be any of an n-butyl group, a sec-butyl group, an isobutyl group, and a tert-butyl group. Also, "Ac" in NHAc and OAc refers to an acetyl group, that is, NHAc represents an acetylamino group and OAc represents an acetoxy group.

[0039] In the above general formula (1), Y1 , Y 2 , Y 3 and Y 4 are each independently CH, CR 2 or N, provided that Y 1 , Y 2 , Y 3 and Y 4 among them, the number of those that are N is 0 to 2, and the number of those that are CR 2 is 0 to 3. In other words, Y 1 , Y 2 , Y 3 and Y 4 among them, two or more are CH or CR 2 , and Y 1 , Y 2 , Y 3 and Y 4 among them, one or more are CH or N. That is, among the six atoms constituting the six-membered ring formed by two carbon atoms and Y 1 , Y 2 , Y 3 and Y 4 the number of carbon atoms is 4 to 6, and the number of nitrogen atoms is 0 to 2. Also, the number of substituents R 1 , Y 2 , Y 3 and Y 4 introduced into the six-membered ring formed by and Y 2 is 0 to 3. In the general formula (1) above, Y 1 , Y 2 , Y 3 and Y 4 are each independently preferably CH or CR 2 , and more preferably CH. Y 1 , Y 2 , Y 3 and Y 4 is CH or CR 2 pyrrole derivatives, and Y 1 , Y 2 , Y 3 and Y 4 is CH pyrrole derivatives are easy to synthesize.

[0040] The CR 2Regarding R 2 is independently selected from the group consisting of C n H 2n+1 , OH, OC n H 2n+1 , NH 2 , NHC n H 2n+1 , N(C n H 2n+1 ) 2 , and COOH, where n is independently an integer from 1 to 3. C n H 2n+1 , as well as "C n H 2n+1 " in OC n H 2n+1 , NHC n H 2n+1 ), and N(C 2 is a methyl group, an ethyl group, an n-propyl group, or an isopropyl group because n is an integer from 1 to 3. n H 2n+1

[0041] In the general formula (1) above, m represents the repeating number of vinylene units (-CH=CH-), which is an integer from 1 to 3, and is preferably 1 or 2. When m is 1 or 2, the pyrrole derivative represented by the general formula (1) is less likely to be further oxidized and metabolized, and is also easy to synthesize.

[0042] In the general formula (1) above, R 3 is H, F, Cl, or Br, and is preferably H or Cl. The bonding site of R 3 to the pyrrole ring is arbitrary and not particularly limited. Pyrrole derivatives in which R 3 is H or Cl are easy to synthesize.

[0043] Examples of the pyrrole derivative represented by the general formula (1) above include the following general formula (1A):

Chemical formula

[0044] Examples of the pyrrole derivative represented by the above general formula (1) include the following general formula (1B): [Chemistry] Compounds represented by the formula and in which R in the general formula (1B) is OH or OMe are also preferred. Compounds represented by the general formula (1B) and in which R in the general formula (1B) is OH or OMe are also easy to synthesize, are hardly oxidized and metabolized, and further have excellent growth inhibitory activity and selectivity against cancer cells.

[0045] The pyrrole derivative represented by the above general formula (1) can be synthesized by any method. For example, first, a formyl compound having a pyrrole ring such as 2-formylpyrrole (also referred to as "pyrrole-2-carboxaldehyde"), 2-formyl-3-chloropyrrole, etc. is prepared. The formyl compound may be a commercially available reagent or can also be obtained by synthesis. For example, in the case of synthesis, an ester such as methyl 3-chloro-1H-pyrrole-2-carboxylate is used as a starting material and reduced with a reducing agent such as lithium aluminum hydride to obtain a hydroxy compound. Next, the obtained hydroxy compound is oxidized with an oxidizing agent such as 2-iodoxybenzoic acid (IBX) to obtain a formyl compound.

[0046] Next, the hydrogen of the pyrrole ring of the formyl compound is protected with di-tert-butyl dicarbonate to obtain a Boc-protected compound. For the obtained Boc-protected compound, a Wittig reaction is carried out using a phosphorus ylide such as (4-bromobenzyl)triphenylphosphonium bromide to obtain a Boc-protected bromo compound having a vinylene unit (-CH=CH-) and an aromatic ring (benzene ring, pyridine ring, pyrimidine ring, etc.). Deprotection is carried out on the obtained Boc-protected bromo compound using sodium methoxide or the like to obtain a bromo compound having a vinylene unit (-CH=CH-) and an aromatic ring (benzene ring, pyridine ring, pyrimidine ring, etc.).

[0047] Next, the pyrrole derivative represented by the general formula (1) can be synthesized by performing a Suzuki coupling of the bromo compound with an organoboron compound such as phenylboronic acid, methylphenylboronic acid, chlorophenylboronic acid, hydroxyphenylboronic acid, acetoxyphenylboronic acid, methoxyphenylboronic acid, dimethoxyphenylboronic acid, trimethoxyphenylboronic acid, pyridylboronic acid, pyrimidylboronic acid, etc.

[0048] As another method for the pyrrole derivative represented by the above general formula (1), for example, first, a monobromo compound having a vinylene unit (-CH=CH-) is prepared. The monobromo compound is mesyl (Ms) -protected with methanesulfonyl chloride with respect to a formyl compound such as 3-chloro-1H-pyrrole-2-carbaldehyde, and the obtained mesyl-protected compound is dibrominated using carbon tetrabromide and triphenylphosphine to obtain a dibromo compound, which can be obtained by performing debromination on the dibromo compound using dimethyl phosphite.

[0049] Next, a pyrrole derivative represented by the general formula (1) can be synthesized by the Suzuki-Miyaura cross-coupling of the monobromo compound and a boronic acid. Specifically, a biphenyl compound is obtained by the Suzuki-Miyaura cross-coupling of a starting material such as 5-bromo-2-chloroanisole or 5-bromo-2-chlorophenol and 4-methoxyphenylboronic acid, etc., and a boronic acid is obtained by reacting the biphenyl compound with bis(pinacolato)diboron. After performing the Suzuki-Miyaura cross-coupling reaction using the boronic acid and the monobromo compound, the pyrrole derivative represented by the general formula (1) can be synthesized by deprotecting the Ms group with tetrabutylammonium fluoride (TBAF).

[0050] (Pyrrole derivative represented by general formula (2)) The pyrrole derivative of the present invention is represented by the following general formula (2):

Chemical formula

[0051] The pyrrole derivative represented by the general formula (2) has a structure similar to Auxarconjugatin B, has a growth inhibitory effect on various cancer cells including leukemia, and also has excellent selectivity. In addition, the pyrrole derivative represented by the general formula (2) has m as an integer of 1 to 3 and does not have a site where 4 or more C=C bonds are consecutive. Therefore, it is difficult to be oxidized and metabolized in the body and can easily reach the target. Thus, a pharmaceutical composition containing the pyrrole derivative represented by the general formula (2) or a salt thereof as an active ingredient is useful for the treatment of cancer.

[0052] In the above general formula (2), A b1 is each independently (R a ) p where p is an integer of 1 to 3, and R a is each independently CR b 2 , NR b , O, S or C=O, and R b is each independently H, C n H 2n+1 , F, Cl, Br or I, where n is each independently an integer of 1 to 3. "C n H 2n+1 " is a methyl group, an ethyl group, an n-propyl group, or an isopropyl group because n is an integer of 1 to 3. A in the above general formula (2) b1 reduces the lipophilicity of the compound. Therefore, the pyrrole derivative represented by the general formula (2) has low lipophilicity, so the absorption rate in the intestinal tract is improved and it has excellent medicinal effects. A in the above general formula (2) b1 is preferably NH, O, CH 2 -NH or CH 2 -O. When A in the general formula (2) b1 is NH, O, CH 2 -NH or CH 2 -O, the compound has even lower lipophilicity and is also easy to synthesize.

[0053] In the above general formula (2), X 1 , X 2 , X 3 , X 4 and X 5 are each independently CH, CR 1 or N, provided that X 1 , X2 , X 3 , X 4 and X 5 Among them, the number of those that are N is 0 to 2, and the number of those that are CR 1 is 0 to 3. In other words, X 1 , X 2 , X 3 , X 4 and X 5 Among them, 3 or more are CH or CR 1 , and X 1 , X 2 , X 3 , X 4 and X 5 Among them, 2 or more are CH or N. That is, one carbon atom and X 1 , X 2 , X 3 , X 4 and X 5 Among the 6 atoms constituting the ring of the six-membered ring formed with, the number of carbon atoms is 4 to 6, and the number of nitrogen atoms is 0 to 2. Also, one carbon atom and X 1 , X 2 , X 3 , X 4 and X 5 The number of substituents R 1 introduced into the six-membered ring formed with is 0 to 3.

[0054] Regarding the above CR 1 , R 1 are each independently C n H 2n+1 , C 4 H 9 , CF 3 , F, Cl, Br, NHAc, OH, OC n H 2n+1 , OAc, CH 2 OH, CH 2 OC n H 2n+1 , CN, CONHC n H 2n+1 , CON(C n H 2n+1 ) 2 , COOH, and COOC n H 2n+1a substituent selected from the group consisting of, where n is an integer from 1 to 3, each independently. However, one or more R 1 is OH or OC n H 2n+1 in the case of, the two or more R 1 including the R 1 may be bonded to each other to form a ring. Here, the group formed by bonding two or more R 1 to each other includes -O-O-, -OC n H 2n -O-, -OC n H 2n -C n H 2n O-, etc. may be mentioned. Also, C n H 2n+1 , and OC n H 2n+1 , CH 2 OC n H 2n+1 , CONHC n H 2n+1 , CON(C n H 2n+1 ) 2 , and COOC n H 2n+1 in the "C n H 2n+1 " is a methyl group, an ethyl group, an n-propyl group, or an isopropyl group because n is an integer from 1 to 3. Also, C 4 H 9 may be any of an n-butyl group, a sec-butyl group, an isobutyl group, and a tert-butyl group. Also, "Ac" in NHAc and OAc refers to an acetyl group, that is, NHAc represents an acetylamino group and OAc represents an acetoxy group.

[0055] In the above general formula (2), Y 1 , Y 2 , Y 3 and Y 4 are each independently CH, CR 2 or N, provided that Y 1 , Y 2 , Y 3 and Y4 Among them, the number of those that are N is 0 to 2, and the number of those that are CR 2 is 0 to 3. In other words, Y 1 , Y 2 , Y 3 and Y 4 Among them, two or more are CH or CR 2 , and Y 1 , Y 2 , Y 3 and Y 4 Among them, one or more are CH or N. That is, two carbon atoms and Y 1 , Y 2 , Y 3 and Y 4 Among the six atoms constituting the six-membered ring formed by and, the number of carbon atoms is 4 to 6, and the number of nitrogen atoms is 0 to 2. Also, the substituent R 1 , Y 2 , Y 3 and Y 4 introduced into the six-membered ring formed by and is 0 to 3. 2 In the general formula (2) above, Y 1 , Y 2 , Y 3 and Y 4 are preferably CH. Y 1 , Y 2 , Y 3 and Y 4 The pyrrole derivative in which is CH is easy to synthesize.

[0056] Regarding the above CR 2 , R 2 are each independently a substituent selected from the group consisting of C n H 2n+1 , OH, OC n H 2n+1 , NH 2 , NHC n H 2n+1 , N(C n H 2n+1 ) 2 , and COOH, where n is each independently an integer from 1 to 3. C n H 2n+1 ​, and OC n H 2n+1 , NHC n H 2n+1 , and N(C n H 2n+1 ) 2 In, the "C n H 2n+1 " is a methyl group, an ethyl group, an n-propyl group, or an isopropyl group because n is an integer from 1 to 3.

[0057] In the above general formula (2), m represents the number of repetitions of the vinylene unit (-CH=CH-), is an integer from 1 to 3, is preferably 1 or 2, and particularly preferably 1. When m is 1, the pyrrole derivative represented by the general formula (2) is more difficult to be further oxidized and metabolized, and is also easy to synthesize.

[0058] In the above general formula (2), R 3 is H, F, Cl or Br, and preferably H or Cl. The bonding site of R 3 to the pyrrole ring is arbitrary and is not particularly limited. The pyrrole derivative in which R 3 is H or Cl is easy to synthesize.

[0059] As the pyrrole derivative represented by the above general formula (2), the following general formula (2A): [Chemical formula] represented by, and a compound in which R in the general formula (2A) is represented by NH or O is preferable. A compound represented by the general formula (2A) and in which R in the general formula (2A) is represented by NH or O is easy to synthesize, is difficult to be oxidized and metabolized, and further has excellent growth inhibitory activity and selectivity against cancer cells.

[0060] The pyrrole derivative represented by the above general formula (2) can be synthesized by any method. For example, first, a starting material such as 1H-pyrrole-2-carboxaldehyde is protected with mesyl (Ms) to obtain a mesyl protected product. On the other hand, a phosphonium ylide is obtained from a starting material such as 4-cyanobenzyl bromide using triphenylphosphine. Carbon chain elongation is carried out by a Wittig reaction using the mesyl protected product and the phosphonium ylide to obtain a nitrile product. The nitrile group of the nitrile product is reduced using diisobutylaluminum hydride (DIBAL) to obtain a formyl product. The formyl group of the formyl product is reduced using sodium borohydride (NaBH 4 ) to obtain a hydroxy product. The hydroxy group of the hydroxy product is chlorinated using thionyl chloride to obtain a chloro product.

[0061] Next, an S N 2 reaction is carried out between the chloro product and p-anisidine to obtain an amine product. Finally, the amine product is subjected to Ms deprotection using tetrabutylammonium fluoride (TBAF) to obtain a pyrrole derivative represented by the general formula (2). Alternatively, an S N 2 reaction is carried out between the chloro product and 4-methoxyphenol to obtain an ether product. Finally, Ms deprotection is carried out with TBAF to obtain a pyrrole derivative represented by the general formula (2).

[0062] (Pyrrole derivative represented by general formula (3)) The pyrrole derivative of the present invention is represented by the following general formula (3):

Chemical formula

[0063] The pyrrole derivative represented by the general formula (3) has a structure similar to Auxarconjugatin B, has a growth inhibitory effect on various cancer cells including leukemia, and is excellent in selectivity. In addition, since the pyrrole derivative represented by the general formula (3) does not have a site where four or more C=C bonds are consecutive, it is difficult to be oxidized and metabolized in the body and is likely to reach the target. Therefore, a pharmaceutical composition containing the pyrrole derivative represented by the general formula (3) or a salt thereof as an active ingredient is useful for the treatment of cancer.

[0064] In the above general formula (3), A a1 is each independently (R a ) p where p is an integer of 1 to 3, and R a is each independently CR b 2 , NR b , O, S or C=O, and R b is each independently H, C n H 2n+1 , F, Cl, Br or I, where n is each independently an integer of 1 to 3. "C n H 2n+1 " is a methyl group, an ethyl group, an n-propyl group or an isopropyl group because n is an integer of 1 to 3. A in the above general formula (3) a1 reduces the lipophilicity of the compound. Therefore, since the pyrrole derivative represented by the general formula (3) has low lipophilicity, its absorption rate in the intestinal tract is improved and it has excellent medicinal effects. A in the above general formula (3) a1 is preferably CH 2 -NH. A compound in which A in the general formula (3) a1 is CH 2 -NH has even lower lipophilicity and is also easy to synthesize.

[0065] In the above general formula (3), X 1 , X 2 , X 3 , X 4 and X 5 are each independently CH, CR 1 or N, provided that X 1 , X 2 , X 3 , X 4 and X 5Among them, the number of those that are N is 0 to 2, and the number of those that are CR 1 is 0 to 3. In other words, X 1 、X 2 、X 3 、X 4 and X 5 among them, 3 or more are CH or CR 1 and, X 1 、X 2 、X 3 、X 4 and X 5 among them, 2 or more are CH or N. That is, among the 6 atoms constituting the ring of the six-membered ring formed by 1 carbon atom and X 1 、X 2 、X 3 、X 4 and X 5 the number of carbon atoms is 4 to 6, and the number of nitrogen atoms is 0 to 2. Also, the number of substituents R 1 、X 2 、X 3 、X 4 and X 5 introduced into the six-membered ring formed with is 0 to 3. 1

[0066] Regarding the above CR 1 R 1 are each independently C n H 2n+1 、C 4 H 9 、CF 3 、F、Cl、Br、NHAc、OH、OC n H 2n+1 、OAc、CH 2 OH、CH 2 OC n H 2n+1 、CN、CONHC n H 2n+1 、CON(C n H 2n+1 ) 2 、COOH、and COOC n H 2n+1 selected from the group consisting of, where n is each independently an integer from 1 to 3. However, one or more R 1is OH or OC n H 2n+1 when it is, the R 1 two or more Rs containing 1 may be bonded to each other to form a ring. Here, two or more Rs 1 groups formed by bonding to each other include -O-O-, -OC n H 2n -O-, -OC n H 2n -C n H 2n O- and the like can be mentioned. Also, C n H 2n+1 , and OC n H 2n+1 CH 2 OC n H 2n+1 CONHC n H 2n+1 CON(C n H 2n+1 ) 2 and COOC n H 2n+1 in the "C n H 2n+1 " is a methyl group, an ethyl group, an n-propyl group, or an isopropyl group because n is an integer from 1 to 3. Also, C 4 H 9 can be any of an n-butyl group, a sec-butyl group, an isobutyl group, and a tert-butyl group. Also, "Ac" in NHAc and OAc refers to an acetyl group, that is, NHAc represents an acetylamino group, and OAc represents an acetoxy group.

[0067] In the above general formula (3), Y 1 , Y 2 , Y 3 and Y 4 are each independently CH, CR 2 or N, provided that the number of those that are N among Y 1 , Y 2 , Y 3 and Y 4 is 0 to 2, and the number of those that are CR 2 is 0 to 3. In other words, Y1 and Y 2 and Y 3 and Y 4 Among them, two or more are CH or CR 2 and Y 1 and Y 2 and Y 3 and Y 4 Among them, one or more are CH or N. That is, among the six atoms constituting the six-membered ring formed by two carbon atoms and Y 1 and Y 2 and Y 3 and Y 4 and Y, the number of carbon atoms is 4 to 6, and the number of nitrogen atoms is 0 to 2. Also, the substituent R 1 and Y 2 and Y 3 and Y 4 introduced into the six-membered ring formed with and Y 2 is 0 to 3. In the general formula (3) above, Y 1 and Y 2 and Y 3 and Y 4 are preferably CH. The pyrrole derivative in which Y 1 and Y 2 and Y 3 and Y 4 are CH is easy to synthesize.

[0068] Regarding the CR 2 R 2 are each independently C n H 2n+1 OH, OC n H 2n+1 NH 2 NHC n H 2n+1 N(C n H 2n+1 ) 2 and substituents selected from the group consisting of COOH, where n is each independently an integer from 1 to 3. C n H 2n+1 and OC n H 2n+1 NHC n H 2n+1 and N(Cn H 2n+1 ) 2 in the "C n H 2n+1 ", since n is an integer from 1 to 3, it is a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.

[0069] In the above general formula (3), R 3 is H, F, Cl or Br, and preferably H or Cl. The bonding site of R 3 to the pyrrole ring is arbitrary and not particularly limited. Pyrrole derivatives in which R 3 is H or Cl are easy to synthesize.

[0070] As the pyrrole derivative represented by the above general formula (3), the following structural formula (3A):

Chemical formula

[0071] The pyrrole derivative represented by the above general formula (3) can be synthesized by any method.

[0072] <Pharmaceutical composition for cancer treatment> The pharmaceutical composition for cancer treatment of the present invention (hereinafter, may be simply referred to as "pharmaceutical composition") is characterized by containing the pyrrole derivative of the present invention described above or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of the present invention has a growth inhibitory effect on cancer cells.

[0073] The pharmaceutically acceptable salts of the pyrrole derivatives represented by the above general formula (I) may be addition salts with acids or addition salts with bases. For example, as the acids in the addition salts of the pyrrole derivatives represented by the general formula (I) and acids, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, phosphorous acid, nitrous acid, citric acid, formic acid, acetic acid, oxalic acid, maleic acid, lactic acid, tartaric acid, fumaric acid, benzoic acid, mandelic acid, cinnamic acid, pamoic acid, stearic acid, glutamic acid, aspartic acid, methanesulfonic acid, ethanedisulfonic acid, p-toluenesulfonic acid, salicylic acid, succinic acid, trifluoroacetic acid, etc. may be mentioned. Also, as the acid addition salts, hydrochloride, hydrobromide, hydroiodide, sulfate, sulfamate, phosphate, nitrate, phosphite, nitrite, citrate, formate, acetate, oxalate, maleate, lactate, tartrate, fumarate, benzoate, mandelate, cinnamate, pamoate, stearate, glutamate, aspartate, methanesulfonate, ethanedisulfonate, p-toluenesulfonate, salicylate, succinate, trifluoroacetate, etc. may be mentioned. On the other hand, as the bases in the addition salts of the pyrrole derivatives represented by the general formula (I) and bases, sodium hydroxide, potassium hydroxide, calcium hydroxide, etc. may be mentioned. Also, as the base addition salts, sodium salt, potassium salt, calcium salt, etc. may be mentioned.

[0074] The pharmaceutical composition of the present invention can be used as an anticancer agent. The pharmaceutical composition of the present invention is particularly useful for the treatment of cancers selected from leukemia, breast cancer, brain tumor, colorectal cancer, lung cancer, melanoma, ovarian cancer, kidney cancer, stomach cancer, and prostate cancer. Therefore, in a preferred embodiment of the present invention, the pharmaceutical composition is used for the treatment of cancers selected from leukemia, breast cancer, brain tumor, colorectal cancer, lung cancer, melanoma, ovarian cancer, kidney cancer, stomach cancer, and prostate cancer. Here, as leukemia, more specifically, in addition to the above-mentioned acute T lymphoblastic leukemia (T-ALL), T lymphoblastic lymphoma (T-LBL), acute myeloid leukemia (AML) may be mentioned.

[0075] The pharmaceutical composition of the present invention may be in any dosage form for oral administration or parenteral administration. These dosage forms can be formulated according to conventional methods. The pharmaceutical composition of the present invention can contain, in addition to the pyrrole derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, additives, and the like.

[0076] Examples of the carrier and additives include water, acetic acid, pharmaceutically acceptable organic solvents, collagen, polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, sodium carboxymethyl cellulose, sodium polyacrylate, sodium alginate, water-soluble dextran, sodium carboxymethyl starch, pectin, methyl cellulose, ethyl cellulose, xanthan gum, gum arabic, casein, agar, polyethylene glycol, diglycerin, glycerin, propylene glycol, petrolatum, paraffin, stearyl alcohol, stearic acid, human serum albumin, mannitol, sorbitol, lactose, surfactants acceptable as pharmaceutical additives, and the like. The above additives can be used alone or in combination of two or more according to the dosage form of the pharmaceutical composition of the present invention.

[0077] Examples of the dosage form include tablets, capsules, fine granules, powders, granules, solutions, syrups, etc. in the case of oral administration. In the case of parenteral administration, dosage forms include injections, sprays, coatings, external preparations, etc. Here, in the case of an injection dosage form, for example, it can be administered systemically or locally by intravenous injection such as drip infusion, subcutaneous injection, intraperitoneal injection, etc. For example, in the case of an injectable preparation, the pharmaceutical composition of the present invention can be dissolved in a solvent (e.g., physiological saline, buffer solution, glucose solution, etc.), and further an appropriate additive (human serum albumin, polyethylene glycol, mannose-modified dendrimer, cyclodextrin conjugate, etc.) can be added and used. Also, in order to make it a dosage form that is dissolved before use, it may be lyophilized. As the excipient for lyophilization, for example, sugar alcohols and saccharides such as mannitol and glucose can be used.

[0078] The dosage of the pharmaceutical composition of the present invention, or the pyrrole derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, can be appropriately selected according to the age, sex, symptoms, administration route, number of administrations, dosage form, etc. of the subject. For example, in the case of an adult (60 kg), the dosage is usually 0.006 to 600 mg per day, preferably 0.06 to 60 mg, more preferably 0.6 to 6 mg. The administration method is preferably selected according to the age and symptoms of the patient. Also, the administration is preferably carried out once a day at intervals of several days, or divided into 2 to 4 times a day.

[0079] <Kit> The cancer treatment kit of the present invention is characterized by containing the pyrrole derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof as described above. Since the kit of the present invention contains the pyrrole derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, it is difficult to be oxidized and metabolized, and has an inhibitory effect on the growth of cancer cells.

[0080] In addition to the pyrrole derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, the kit of the present invention can contain pharmaceutically acceptable carriers, additives, reagents, adjuvants, special containers, other necessary accessories, instructions for use, etc. The kit of the present invention can also be used as a research reagent kit.

Examples

[0081] The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to the following examples at all.

[0082] <Synthesis of the compound according to the present invention> (1) Instrumental analysis, measuring devices · 1 H nuclear magnetic resonance spectrum ( 1 H-NMR) Measured using JEOL ECA 500 (500 MHz), and " 1The "1H-NMR (measurement frequency, measurement solvent) chemical shift value (multiplicity, spin coupling constant, number of hydrogens)" was described. The chemical shift value (δ) was expressed in ppm with tetramethylsilane (δ = 0) as the internal standard. The multiplicity was indicated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet or complex overlapping signals), and for broad signals, br was appended. The spin coupling constant (J) was described in Hz.

[0083] · 13 13C nuclear magnetic resonance spectrum ( 13 13C-NMR) Measured using a JEOL ECA 500 (126 MHz), and described as " 13 13C-NMR (measurement frequency, measurement solvent) chemical shift value (multiplicity, spin coupling constant, number of carbons)". The chemical shift value (δ) was expressed in ppm with tetramethylsilane (δ = 0) as the internal standard. The multiplicity was indicated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet or complex overlapping signals). The spin coupling constant (J) was described in Hz.

[0084] · Mass spectrum (MS): Electrospray ionization method (ESI) Measured by electrospray ionization method (ESI) using a JEOL JMS-T100LC type TOF mass spectrometer AccuTOF. The settings of the apparatus were: desolvation chamber temperature 250 °C, orifice 1 temperature 80 °C, needle voltage 2000 V, ring lens voltage 10 V, orifice 1 voltage 85 V, orifice 2 voltage 5 V. Sample feeding was performed by the infusion method at a flow rate of 30 mL / min. Described as "HR-ESI-MS: m / z: [M + adduct ion] + Calculated mass of the molecular formula; measured mass".

[0085] (2) Chromatography · Analytical thin layer chromatography (TLC) A TLC plate, silica gel 60F254 (Art. 5715) with a thickness of 0.25 mm, manufactured by E. Merck, was used. Detection of the compounds on the TLC was carried out by UV irradiation (254 nm or 365 nm) and by heating after dipping in a color-developing agent to develop color. As the color-developing agent, a solution prepared by dissolving p-anisaldehyde (9.3 mL) and acetic acid (3.8 mL) in ethanol (340 mL) and adding concentrated sulfuric acid (12.5 mL) was used.

[0086] ·Silica gel column chromatography It was carried out using silica gel 60N (spherical, neutral, 63 - 210 μm) manufactured by Kanto Chemical Co., Inc., as described in the "developing solvent".

[0087] (3) Basic operations Drying of the extraction solution after the reaction was carried out by washing with saturated brine and then adding anhydrous sodium sulfate. Concentration of the solution under reduced pressure was carried out using a rotary evaporator under the reduced pressure of an aspirator (20 - 30 mmHg). Removal of trace amounts of solvent was carried out using a vacuum pump (about 1 mmHg) equipped with a trap cooled in a liquid nitrogen bath. The mixing ratio of the solvents was all expressed as volume ratio.

[0088] (4) Solvents ·Distilled water Distilled and ion-exchanged water using an ADVANTEC TOYO GS-200 type distilled water production apparatus manufactured by ADVANTEC TOYO Co., Ltd. was used.

[0089] ·Toluene, methanol, ethanol, isopropanol, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile Dehydrated solvents for organic synthesis or special grade solvents manufactured by Kanto Chemical Co., Inc. were dried using molecular sieves (4A) and then used.

[0090] ·Solvents for NMR measurement The following were used as they were. Chloroform-d 1 : 99.7 ATOM%D, 0.03% TMS, manufactured by Kanto Chemical Co., Inc. Acetone-d 6 : Manufactured by Kanto Chemical Co., Inc., 99.7 ATOM%D, 0.03% TMS

[0091] <Synthesis method of compounds having the moiety of Structural Formulas (1a) to (1aj)> The synthesis scheme of the compound represented by the above general formula (1A) and in which R in the general formula (1A) is represented by the above structural formulas (1a) to (1aj) (in other words, the compound having the moiety of structural formulas (1a) to (1aj)) is as follows. [Chemical formula]

[0092] (Synthesis of hydroxy compound (5)) Commercially available methyl 3-chloro-1H-pyrrole-2-carboxylate (4) (4.12 g, 25.8 mmol) was dissolved in tetrahydrofuran (40 mL), cooled to 0 °C and stirred. Lithium aluminum hydride (2.16 g, 56.8 mmol) was added to this mixed solution and stirred for 5 minutes. The reaction mixture was warmed to room temperature and further stirred for 6 hours. Thereafter, a sufficient amount of saturated aqueous potassium sodium tartrate solution and ethyl acetate were added to the reaction mixture to decompose the excess reducing agent and stirred. The reaction treatment solution was filtered and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Thus, a crude product of hydroxy compound (5) was obtained. The crude product of hydroxy compound (5) was used as it was for the synthesis of the following formyl compound (6).

[0093] (Synthesis of formyl compound (6)) The hydroxy compound (5) crude product and sodium hydrogen carbonate (13.0 g, 154 mmol) were dissolved in DMSO (40 mL). To this mixed solution, 2-iodoxybenzoic acid (14.4 g, 51.6 mmol) was added, and the mixture was stirred for 20 hours. 15% Aqueous sodium hydroxide solution (50 mL) was added to the reaction mixture to quench it. Then, it was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue thus obtained was separated by column chromatography [hexane:ethyl acetate = 3:1] to obtain the formyl compound (6) (2.03 g, 15.6 mmol, 61% (two steps)).

[0094] · Identification results of the formyl compound (6) 1 H-NMR (500 MHz, chloroform-d 1 ) δ 9.67 (s, 1H), 9.30 (br, 1H), 7.02 (t, J = 2.6 Hz, 1H), 6.29 (t, J = 2.9 Hz, 1H). HR-ESI-MS: m / z: [M+H] + C 5 H 5 Calculated mass of ClNO 130.0060; measured mass 130.0042.

[0095] (Synthesis of the Boc-protected compound (7)) The formyl compound (6) (500 mg, 3.86 mmol), di-tert-butyl dicarbonate (1.26 g, 5.79 mmol), triethylamine (1.07 mL, 7.72 mmol) and 4-dimethylaminopyridine (47.0 mg, 386 μmol) were dissolved in methylene chloride (10 mL) and stirred for 5 minutes. Then, it was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue thus obtained was separated by column chromatography [hexane:ethyl acetate = 8:1] to obtain the Boc-protected compound (7) (803 mg, 3.50 mmol, 90%).

[0096] · Identification Results of Boc Protecting Group (7) 1 H-NMR (500 MHz, chloroform-d 1 ) δ 10.30 (s, 1H), 7.38 (d, J = 3.4 Hz, 1H), 6.29 (d, J = 3.4 Hz, 1H), 1.63 (s, 9H). HR-ESI-MS: m / z: [M+Na] + C 10 H 12 ClNO 3 Calculated mass of 252.04034; Measured mass of 252.03808.

[0097] (Synthesis of Boc Protected Bromo Compound (8)) Boc protecting group (7) (500 mg, 2.18 mg), (4-bromobenzyl) triphenylphosphonium bromide (1.67 g, 3.27 mmol), 18-crown 6-ether (14.0 μL, 65.4 μmol) and potassium carbonate (602 mg, 4.36 mmol) were dissolved in a mixed solution of methylene chloride (20 mL) and distilled water (20 mL), and stirred for 18 hours. Then, the reaction mixture solution was extracted with chloroform. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained therefrom was separated by column chromatography [hexane:ethyl acetate = 16:1] to obtain Boc protected bromo compound (8) (704 mg, 1.84 mmol, 84%).

[0098] · Identification Results of Boc Protected Bromo Compound (8) 1 H-NMR (500 MHz, acetone-d 6 ) δ7.65 (d, J = 16.8 Hz, 1H), 7.57 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 8.6 Hz, 2H), 7.38 (d, J = 3.6 Hz, 1H), 7.24 (d, J = 16.8 Hz, 1H), 6.32 (d, J = 3.6 Hz, 1H), 1.63 (s, 9H). HR-ESI-MS: m / z: [M+Na] + C 17 H 17 BrClNO 2 Calculated mass of 406.00084; measured mass of 406.00201.

[0099] (Synthesis of bromo compound (9)) Boc-protected bromo compound (8) (56.0 mg, 146 μmol) and sodium methoxide (approx. 5 mol / L methanol solution) (0.1 mL, 500 μmol) were dissolved in tetrahydrofuran (3 mL) and stirred for 20 minutes. The reaction mixture was diluted with distilled water, and saturated aqueous ammonium chloride was added to adjust the pH of the reaction solution to 8. Then, the reaction mixture was extracted with chloroform. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was separated by flash column chromatography (hexane:ethyl acetate = 95:5 → 74:26) to obtain bromo compound (9) (31.7 mg, 11.2 μmol, 76%).

[0100] · Identification results of bromo compound (9) 1 H-NMR (500 MHz, acetone-d 6 ) δ10.66 (br, 1H), 7.52 (dd, J = 6.6, 2.0 Hz, 2H), 7.46 (dd, J = 6.7, 1.9 Hz, 2H), 7.13 (d, J = 16.6 Hz, 1H), 6.95 (d, J = 16.6 Hz, 1H), 6.90 (t, J = 3.0 Hz, 1H), 6.15 (t, J = 2.7 Hz, 1H). HR-ESI-MS: m / z: [M+H] + C 12 H 10 Calculated mass of BrClN 281.96851; measured mass of 281.96903.

[0101] (General procedure for the synthesis of compounds having the moiety of structural formula (1a) to (1z) or (1aa) to (1aj)) Bromo compound (9) (30.0 mg, 106 μmol), various arylboronic acids (127 μmol), tetrakis(triphenylphosphine)palladium(0) (6.1 mg, 5.25 μmol) were dissolved in 1,4-dioxane (2 mL) and 1 mol / L aqueous sodium carbonate solution (2 mL), and heated under reflux. After confirming the disappearance of the starting materials by TLC, the reaction mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. Then it was concentrated under reduced pressure. The obtained residue was purified by flash column chromatography. For some different ones, they were described separately.

[0102] (Synthesis of the compound having the moiety of structural formula (1a)) Bromo compound (9) (109 mg, 387 μmol), phenylboronic acid (70.8 mg, 581 μmol), tetrakis(triphenylphosphine)palladium(0) (22.4 mg, 19.4 μmol), potassium carbonate (90.9 mg, 658 μmol) were dissolved in 1,4-dioxane (8 mL) and distilled water (2 mL), and heated under reflux for 15 hours. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. Then it was concentrated under reduced pressure. The obtained residue was separated by flash column chromatography (hexane:ethyl acetate = 82:8 → 61:29) to obtain the compound having the moiety of structural formula (1a) (45.6 mg, 163 μmol, 42%).

[0103] · Identification results of the compound having the moiety of structural formula (1a) 1 H-NMR (500 MHz, acetone-d 6) δ10.66 (s, 1H), 7.68 (t, J = 8.3 Hz, 4H), 7.60 (d, J = 8.6 Hz, 2H), 7.47 (t, J = 7.7 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.16 (d, J = 17.2 Hz, 1H), 7.04 (d, J = 16.6 Hz, 1H), 6.90 (t, J = 2.9 Hz, 1H), 6.16 (t, J = 2.3 Hz, 1H). HR-ESI-MS: m / z: [M+H] + C 18 H 15 Calculated mass of C + H 18 ClN: 280.08930; Measured mass: 280.08906.

[0104] (Synthesis of the compound having the moiety of structural formula (1b)) The obtained residue was purified by flash column chromatography (hexane:ethyl acetate = 100:0 → 79:21) to give the compound having the moiety of structural formula (1b) (25.7 mg, 87.5 μmol, 83%).

[0105] · Identification results of the compound having the moiety of structural formula (1b) 1 1H-NMR (500 MHz, acetone-d 6 ) δ10.66 (s, 1H), 7.64 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 9.2 Hz, 4H), 7.28 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 16.6 Hz, 1H), 7.03 (d, J = 16.6 Hz, 1H), 6.89 (t, J = 3.2 Hz, 1H), 6.16 (t, J = 2.9 Hz, 1H), 2.37 (s, 3H). HR-ESI-MS: m / z: [M+H] + C 19 H 17 Calculated mass of C + H 19 ClN: 294.10495; Measured mass: 294.10051.

[0106] (Synthesis of the compound having the moiety of structural formula (1c)) The obtained residue was purified by flash column chromatography (hexane:ethyl acetate = 98:2 → 77:23) to give the compound having the moiety of structural formula (1c) (22.9 mg, 77.9 μmol, 74%).

[0107] · Identification results of the compound having the moiety of structural formula (1c) 1 H-NMR (500 MHz, acetone-d 6 ) δ10.67 (s, 1H), 7.65 (d, J = 7.9 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.51 (s, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H), 7.19 - 7.14 (m, 2H), 7.03 (d, J = 16.6 Hz, 1H), 6.90 - 6.89 (m, 1H), 6.16 - 6.15 (m, 1H), 2.40 (s, 3H). HR-ESI-MS: m / z: [M+Na] + C 19 H 17 The calculated mass of C17H15NCl is 294.10440; the measured mass is 294.10061.

[0108] (Synthesis of the compound having the moiety of structural formula (1d)) The obtained residue was purified by flash column chromatography (hexane:ethyl acetate = 100:0 → 84:16) to give the compound having the moiety of structural formula (1d) (32.4 mg, 93.1 μmol, 88%).

[0109] · Identification results of the compound having the moiety of structural formula (1d) 1 H-NMR (500 MHz, chloroform-d 1) δ 8.32 (br, 1H), 7.71 (d, J = 9.2 Hz, 2H), 7.69 (d, J = 9.2 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 17.2 Hz, 1H), 6.76 (t, J = 2.9 Hz, 1H), 6.73 (d, J = 16.6 Hz, 1H), 6.22 (t, J = 2.9 Hz, 1H). HR-ESI-MS: m / z: [M+H] + C 19 H 14 ClF 3 Calculated mass of N: 348.07669; Measured mass: 348.07393.

[0110] (Synthesis of the compound having the moiety of structural formula (1e)) The bromo compound (9) (30 mg, 106 μmol), 4-chlorophenylboronic acid (24.9 mg, 159 μmol), and tetrakis(triphenylphosphine)palladium(0) (6.1 mg, 5.25 μmol) were dissolved in 1,4-dioxane (2 mL) and 1 mol / L aqueous sodium carbonate solution (2 mL), and heated to reflux for 30 minutes. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Then it was concentrated under reduced pressure. The obtained residue was subjected to flash column chromatography (hexane:ethyl acetate = 97:3 → 86:14) to isolate the crude product, and a compound having the moiety of structural formula (1e) (17.8 mg, 56.6 μmol, 53%) was obtained.

[0111] · Identification results of the compound having the moiety of structural formula (1e) 1 H-NMR (500 MHz, acetone-d 6) δ10.67 (s, 1H), 7.71 (dt, J = 9.2, 2.4 Hz, 2H), 7.67 (dt, J = 8.4, 2.0 Hz, 2H), 7.61 (d, J = 8.6 Hz, 2H), 7.49 (dt, J = 9.2, 2.4 Hz, 2H), 7.17 (d, J = 16.6 Hz, 1H), 7.04 (d, J = 16.6 Hz, 1H), 6.90 (t, J = 2.9 Hz, 1H), 6.16 (t, J = 2.9 Hz, 1H). HR-ESI-MS: m / z: [M+H] + C 18 H 14 Cl 2 Calculated mass of N: 314.05033; Measured mass: 314.05081.

[0112] (Synthesis of the compound having the moiety of structural formula (1f)) The obtained residue was purified by column chromatography (hexane:ethyl acetate = 0:100) to give the compound having the moiety of structural formula (1f) (27.2 mg, 80.9 μmol, 76%).

[0113] · Identification results of the compound having the moiety of structural formula (1f) 1 1H-NMR (500 MHz, acetone-d 6 ) δ10.65 (s, 1H), 9.23 (s, 1H), 7.74 (d, J = 8.6 Hz, 2H), 7.65 - 7.62 (m, 4H), 7.57 (d, J = 8.6 Hz, 2H), 7.14 (d, J = 16.6 Hz, 1H), 7.02 (d, J = 16.6 Hz, 1H), 6.89 (t, J = 2.9 Hz, 1H), 6.15 (t, J = 2.6 Hz, 1H), 2.10 (s, 3H). HR-ESI-MS: m / z: [M+Na] + C 20 H 17 ClN 2Calculated mass of NaO: 359.09271; Measured mass: 359.08860.

[0114] (Synthesis of the compound having the moiety of structural formula (1g)) The obtained residue was purified by flash column chromatography (hexane:ethyl acetate = 74:26 → 53:47) to give the compound having the moiety of structural formula (1g) (10.6 mg, 35.8 μmol, 34%).

[0115] · Identification results of the compound having the moiety of structural formula (1g) 1 H-NMR (500 MHz, chloroform-d 1 ) δ 8.27 (s, 1H), 7.54 - 7.47 (m, 6H), 7.07 (d, J = 16.6 Hz, 1H), 6.91 (dd, J = 6.6, 2.0 Hz, 2H), 6.74 (t, J = 3.2 Hz, 1H), 6.71 (d, J = 16.6 Hz, 1H), 6.21 (t, J = 2.9 Hz, 1H), 4.74 (s, 1H). HR-ESI-MS: m / z: [M+H] + C 18 H 15 Calculated mass of ClNO: 296.08422; Measured mass: 296.08761.

[0116] (Synthesis of the compound having the moiety of structural formula (1h)) The obtained residue was purified by flash column chromatography (hexane:ethyl acetate = 76:24 → 55:45) to give the compound having the moiety of structural formula (1h) (24.8 mg, 83.8 μmol, 80%).

[0117] · Identification results of the compound having the moiety of structural formula (1h) 1 H-NMR (500 MHz, chloroform-d 1) δ 8.30 (s, 1H), 7.57 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 8.6 Hz, 2H), 7.31 (t, J = 7.7 Hz, 1H), 7.19 (d, J = 7.4 Hz, 1H), 7.10 - 7.07 (m, 2H), 6.82 (dd, J = 8.0, 1.7 Hz, 1H), 6.75 (t, J = 2.9 Hz, 1H), 6.71 (d, J = 16.6 Hz, 1H), 6.21 (t, J = 2.6 Hz, 1H), 4.85 (d, J = 17.2 Hz, 1H). HR-ESI-MS: m / z: [M+H] + C 18 H 15 Calculated mass of C + H 18 ClNO: 298.08127; Measured mass: 298.08203.

[0118] (Synthesis of the compound having the moiety of structural formula (1k)) The obtained residue was purified by flash column chromatography (hexane:ethyl acetate = 91:9 → 70:30) to give the compound having the moiety of structural formula (1k) (28.3 mg, 91.3 μmol, 87%).

[0119] · Identification results of the compound having the moiety of structural formula (1k) 1 1H-NMR (500 MHz, chloroform-d 1 ) δ 8.29 (s, 1H), 7.56 - 7.54 (m, 4H), 7.51 (d, J = 8.6 Hz, 2H), 7.07 (d, J = 16.6 Hz, 1H), 6.98 (dd, J = 6.9, 1.7 Hz, 2H), 6.75 (t, J = 2.9 Hz, 1H), 6.71 (d, J = 16.6 Hz, 1H), 6.21 (t, J = 2.9 Hz, 1H), 3.81 (s, 3H). HR-ESI-MS: m / z: [M+H] + C 19 H 17Calculated mass of ClNO: 310.09987; Measured mass: 310.09685.

[0120] (Synthesis of the compound having the moiety of Structural Formula (1l)) The obtained residue was purified by flash column chromatography (hexane:ethyl acetate = 94:6 → 73:27) to give the compound having the moiety of Structural Formula (1l) (17.4 mg, 56.3 μmol, 53%).

[0121] · Identification results of the compound having the moiety of Structural Formula (1l) 1 1H-NMR (500 MHz, chloroform-d 1 ) δ 8.29 (s, 1H), 7.58 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.6 Hz, 2H), 7.36 (t, J = 8.0 Hz, 1H), 7.20 (d, J = 7.4 Hz, 1H), 7.14 (t, J = 2.0 Hz, 1H), 7.09 (d, J = 16.6 Hz, 1H), 6.90 (dd, J = 8.3, 2.6 Hz, 1H), 6.75 (t, J = 2.9 Hz, 1H), 6.72 (d, J = 16.6 Hz, 1H), 6.21 (t, J = 2.9 Hz, 1H), 3.88 (s, 3H). HR-ESI-MS: m / z: [M+H] + C 19 H 17 Calculated mass of ClNNaO: 310.09987; Measured mass: 310.09858.

[0122] (Synthesis of the compound having the moiety of Structural Formula (1m)) The obtained residue was purified by flash column chromatography (hexane:ethyl acetate = 89:11 → 68:32) to give the compound having the moiety of Structural Formula (1m) (23.6 mg, 76.1 μmol, 72%).

[0123] · Identification results of the compound having the moiety of Structural Formula (1m) 1 H-NMR (500 MHz, chloroform-d 1 ) δ 8.29 (s, 1H), 7.53 (dd, J = 6.3, 2.9 Hz, 2H), 7.50 (dd, J = 6.3, 2.9 Hz, 2H), 7.35 - 7.31 (m, 2H), 7.08 (d, J = 16.6 Hz, 1H), 7.04 (td, J = 7.4, 1.1 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.75 - 6.70 (m, 2H), 6.21 (t, J = 2.9 Hz, 1H), 3.83 (s, 3H). HR-ESI-MS: m / z: [M+H] + C 19 H 17 The calculated mass of ClNO is 310.09987; the measured mass is 310.10004.

[0124] (Synthesis of the compound having the moiety of structural formula (1n)) The obtained residue was purified by flash column chromatography (hexane:ethyl acetate = 66:34 → 45:55) to give the compound having the moiety of structural formula (1n) (27.8 mg, 89.7 μmol, 85%).

[0125] · Identification results of the compound having the moiety of structural formula (1n) 1 H-NMR (500 MHz, chloroform-d 1 ) δ 8.29 (s, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 16.6 Hz, 1H), 6.75 (t, J = 3.2 Hz, 1H), 6.72 (d, J = 16.6 Hz, 1H), 6.22 (t, J = 2.6 Hz, 1H), 4.75 (d, J = 5.7 Hz, 2H). HR-ESI-MS: m / z: [M+H] + C 19 H 17 Calculated mass of ClNO: 310.09987; Measured mass: 310.10120.

[0126] (Synthesis of the compound having the moiety of structural formula (1o)) The obtained residue was purified by flash column chromatography (hexane:ethyl acetate = 76:24 → 53:47) to give the compound having the moiety of structural formula (1o) (27.0 mg, 87.1 μmol, 83%).

[0127] · Identification results of the compound having the moiety of structural formula (1o) 1 H-NMR (500 MHz, chloroform-d 1 ) δ 8.29 (s, 1H), 7.63 (s, 1H), 7.61 - 7.59 (dd, J = 6.3, 1.8 Hz, 2H), 7.54 (m, 3H), 7.44 (t, J = 7.7 Hz, 1H), 7.35 (d, J = 7.4 Hz, 1H), 7.09 (d, J = 16.6 Hz, 1H), 6.75 (t, J = 2.9 Hz, 1H), 6.72 (d, J = 16.6 Hz, 1H), 6.21 (t, J = 2.9 Hz, 1H), 4.78 (d, J = 6.3 Hz, 2H). HR-ESI-MS: m / z: [M+H] + C 19 H 17 Calculated mass of ClNO: 310.09987; Measured mass: 310.10176.

[0128] (Synthesis of the compound having the moiety of structural formula (1p)) The obtained residue was purified by flash column chromatography (hexane:ethyl acetate = 88:12 → 67:33) to give the compound having the moiety of structural formula (1p) (29.4 mg, 90.8 μmol, 86%).

[0129] · Identification results of the compound having the moiety of Structural Formula (1p) 1 H-NMR (500 MHz, chloroform-d 1 ) δ 8.29 (s, 1H), 7.61 - 7.58 (m, 4H), 7.53 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 16.6 Hz, 1H), 6.75 (t, J = 3.2 Hz, 1H), 6.72 (d, J = 16.6 Hz, 1H), 6.21 (t, J = 2.9 Hz, 1H), 4.51 (s, 2H), 3.42 (s, 3H). HR-ESI-MS: m / z: [M+Na] + C 20 H 18 Calculated mass of C18H12ClNNaO: 346.09746; Measured mass: 346.09696.

[0130] (Synthesis of the compound having the moiety of Structural Formula (1q)) The obtained residue was purified by flash column chromatography (hexane:ethyl acetate = 0:100) to give the compound having the moiety of Structural Formula (1q) (15.3 mg, 45.4 μmol, 43%).

[0131] · Identification results of the compound having the moiety of Structural Formula (1q) 1 H-NMR (500 MHz, acetone-d 6 ) δ10.68 (s, 1H), 7.97 (d, J = 8.6 Hz, 2H), 7.77 (dd, J = 6.6, 2.0 Hz, 2H), 7.72 (m, 3H), 7.62 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 16.6 Hz, 1H), 7.04 (d, J = 16.6 Hz, 1H), 6.90 (t, J = 3.2 Hz, 1H), 6.17 (t, J = 2.6 Hz, 1H), 2.92 (d, J = 4.6 Hz, 3H). HR-ESI-MS: m / z: [M+H]+ C 20 H 18 ClN 2 Calculated mass of O: 337.11077; Measured mass: 337.11047.

[0132] (Synthesis of the compound having the moiety of structural formula (1r)) The obtained residue was purified by column chromatography (hexane:ethyl acetate = 0:100) to give the compound having the moiety of structural formula (1r) (13.4 mg, 38.1 μmol, 36%).

[0133] · Identification results of the compound having the moiety of structural formula (1r) 1 H-NMR (500 MHz, acetone-d 6 ) δ10.65 (s, 1H), 7.72 (dd, J = 6.6, 2.0 Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.50 (dd, J = 6.3, 2.5 Hz, 2H), 7.15 (d, J = 16.6 Hz, 1H), 7.01 (d, J = 16.6 Hz, 1H), 6.87 (t, J = 3.2 Hz, 1H), 6.13 (t, J = 2.6 Hz, 1H), 3.02 (s, 6H). HR-ESI-MS: m / z: [M+H] + C 21 H 20 ClN 2 Calculated mass of O: 351.12642; Measured mass: 351.12608.

[0134] (Synthesis of the compound having the moiety of structural formula (1s)) The obtained residue was purified by flash column chromatography (hexane:ethyl acetate = 88:12 → 67:33) to give the compound having the moiety of structural formula (1s) (28.4 mg, 83.6 μmol, 80%).

[0135] · Identification results of the compound having the moiety of structural formula (1s) 1 H-NMR (500 MHz, chloroform-d 1 ) δ 8.30 (s, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 7.12 (dd, J = 8.0, 8.0 Hz, 1H), 7.09 (d, J = 16.5 Hz, 1H), 6.97 (dd, J = 7.7, 1.4 Hz, 1H), 6.93 (dd, J = 8.3, 1.4 Hz, 1H), 6.75 (t, J = 3.0 Hz, 1H), 6.71 (d, J = 17.5 Hz, 1H), 6.21 (t, J = 2.9 Hz, 1H), 3.92 (s, 3H), 3.60 (s, 3H). HR-ESI-MS: m / z: [M+H] + C 20 H 19 ClNO 2 The calculated mass of 340.11043; the measured mass of 340.11017.

[0136] (Synthesis of the compound having the moiety of structural formula (1t)) The obtained residue was purified by flash column chromatography (hexane:ethyl acetate = 93:7 → 62:28) to give the compound having the moiety of structural formula (1t) (31.2 mg, 92.0 μmol, 87%).

[0137] · Identification results of the compound having the moiety of structural formula (1t) 1 H-NMR (500 MHz, acetone-d 6) δ10.63 (s, 1H), 7.51-7.49 (m, 2H), 7.49-7.47 (m, 2H), 7.26 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 17.2 Hz, 1H), 7.01 (d, J = 17.2 Hz, 1H), 6.88 (t, J = 2.9 Hz, 1H), 6.66 (d, J = 2.9 Hz, 1H), 6.62 (dd, J = 8.3, 2.6 Hz, 1H), 6.15 (t, J = 2.6 Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H). HR-ESI-MS: m / z: [M+H] + C 20 H 19 ClNO 2 Calculated mass of 342.10748; measured mass of 342.11106.

[0138] (Synthesis of the compound having the moiety of structural formula (1u)) The obtained residue was purified by flash column chromatography (hexane:ethyl acetate = 89:11 → 68:32) to give a compound (32.8 mg, 96.5 μmol, 90%) having the moiety of structural formula (1u).

[0139] · Identification results of the compound having the moiety of structural formula (1u) 1 1H-NMR (500 MHz, chloroform-d 1 ) δ 8.29 (s, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 7.08 (d, J = 16.6 Hz, 1H), 6.93-6.91 (m, 2H), 6.85 (dd, J = 8.9, 3.2 Hz, 1H), 6.74 (t, J = 2.9 Hz, 1H), 6.71 (d, J = 16.6 Hz, 1H), 6.21 (t, J = 2.9 Hz, 1H), 3.81 (s, 3H), 3.77 (s, 3H). HR-ESI-MS: m / z: [M+H]+ C 20 H 19 ClNO 2 Calculated mass: 340.11043; Measured mass: 340.11479.

[0140] (Synthesis of the compound having the moiety of Structural Formula (1v)) The obtained residue was purified by flash column chromatography (hexane:ethyl acetate = 91:9 → 70:30) to give the compound having the moiety of Structural Formula (1v) (15.4 mg, 45.3 μmol, 43%).

[0141] · Identification results of the compound having the moiety of Structural Formula (1v) 1 H-NMR (500 MHz, chloroform-d 1 ) δ 8.28 (s, 1H), 7.50 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.6 Hz, 2H), 7.29 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 16.6 Hz, 1H), 6.74 - 6.70 (m, 2H), 6.66 (d, J = 8.6 Hz, 2H), 6.20 (t, J = 2.9 Hz, 1H), 3.75 (s, 6H). HR-ESI-MS: m / z: [M+H] + C 20 H 19 ClNO 2 Calculated mass: 340.11043; Measured mass: 340.11102.

[0142] (Synthesis of the compound having the moiety of Structural Formula (1w)) The obtained residue was purified by flash column chromatography (hexane:ethyl acetate = 88:12 → 67:33). The obtained solid was suspended in methanol and filtered. The filtrate was collected to give the compound having the moiety of Structural Formula (1w) (12.1 mg, 35.6 μmol, 34%).

[0143] · Identification results of the compound having the moiety of Structural Formula (1w) 1 H-NMR (500 MHz, chloroform-d 1 ) δ 8.29 (s, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.17 (dd, J = 8.6, 2.3 Hz, 1H), 7.13 (d, J = 1.7 Hz, 1H), 7.07 (d, J = 16.6 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.75 (t, J = 3.2 Hz, 1H), 6.72 (d, J = 16.6 Hz, 1H), 6.21 (t, J = 2.9 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H). HR-ESI-MS: m / z: [M+Na] + C 20 H 18 ClNNaO 2 Calculated mass for 362.09238; Measured mass 362.08987.

[0144] (Synthesis of the compound having the moiety of structural formula (1x)) The obtained residue was purified by flash column chromatography (hexane:ethyl acetate = 85:15 → 64:36) to give the compound having the moiety of structural formula (1x) (26.3 mg, 77.3 μmol, 73%).

[0145] · Identification results of the compound having the moiety of structural formula (1x) 1 H-NMR (500 MHz, chloroform-d 1 ) δ 8.29 (s, 1H), 7.56 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 8.6 Hz, 2H), 7.08 (d, J = 16.6 Hz, 1H), 6.75 (m, 3H), 6.71 (d, J = 16.6 Hz, 1H), 6.47 (t, J = 2.3 Hz, 1H), 6.21 (t, J = 2.9 Hz, 1H), 3.86 (s, 6H). HR-ESI-MS: m / z: [M+H] + C 20 H 19 ClNO 2 Calculated mass 340.11043; measured mass 340.11030.

[0146] (Synthesis of the compound having the moiety of structural formula (1y)) The obtained residue was purified by flash column chromatography (hexane:ethyl acetate = 80:20 → 59:41) to give the compound having the moiety of structural formula (1y) (33.9 mg, 91.7 μmol, 87%).

[0147] · Identification results of the compound having the moiety of structural formula (1y) 1 H-NMR (500 MHz, chloroform-d 1 ) δ 8.29 (s, 1H), 7.55 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 8.6 Hz, 2H), 7.08 (d, J = 17.2 Hz, 1H), 6.80 (s, 2H), 6.75 (t, J = 3.2 Hz, 1H), 6.72 (d, J = 16.6 Hz, 1H), 6.22 (t, J = 2.9 Hz, 1H), 3.94 (s, 6H), 3.90 (s, 3H). HR-ESI-MS: m / z: [M+H] + C 21 H 21 ClNO 3 Calculated mass 370.12100; measured mass 370.12158.

[0148] (Synthesis of the compound having the moiety of structural formula (1z)) The obtained residue was purified by flash column chromatography (hexane:ethyl acetate = 92:8 → 61:29) to give the compound having the moiety of structural formula (1z) (32.8 mg, 102 μmol, 96%).

[0149] · Identification results of the compound having the moiety of structural formula (1z) 1 H-NMR (500 MHz, acetone-d 6 ) δ 10.62 (s, 1H), 7.59 (dd, J = 6.6, 2.0 Hz, 2H), 7.54 (dd, J = 6.3, 1.7 Hz, 3H), 7.42 (dd, J = 8.3, 2.0 Hz, 1H), 7.12 (d, J = 16.6 Hz, 1H), 7.01 (d, J = 16.6 Hz, 1H), 6.88 (t, J = 2.9 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.15 (t, J = 2.9 Hz, 1H), 4.59 (t, J = 8.9 Hz, 2H), 3.28 (t, J = 8.9 Hz, 2H). HR-ESI-MS: m / z: [M+H] + C 20 H 17 Calculated mass of ClNO 322.09987; Measured mass 322.09811.

[0150] (Synthesis of the compound having the moiety of structural formula (1aa)) The obtained residue was purified by flash column chromatography (hexane:ethyl acetate = 93:7 → 62:28) to give a compound having the moiety of structural formula (1aa) (34.2 mg, 101 μmol, 96%).

[0151] · Identification results of the compound having the moiety of structural formula (1aa) 1 H-NMR (500 MHz, chloroform-d 1) δ 8.29 (s, 1H), 7.52 (dd, J = 6.3, 2.3 Hz, 2H), 7.49 (dd, J = 6.3, 2.3 Hz, 2H), 7.13 (d, J = 2.3 Hz, 1H), 7.10 (dd, J = 8.0, 2.3 Hz, 1H), 7.06 (d, J = 16.6 Hz, 1H), 6.93 (d, J = 8.6 Hz, 1H), 6.74 (t, J = 3.2 Hz, 1H), 6.70 (d, J = 16.6 Hz, 1H), 6.20 (t, J = 2.9 Hz, 1H), 4.30 (s, 4H). HR-ESI-MS: m / z: [M+H] + C 20 H 17 ClNO 2 The calculated mass of 338.09478; the measured mass of 338.09388.

[0152] (Synthesis of the compound having the moiety of structural formula (1ab)) The obtained residue was purified by flash column chromatography (hexane:ethyl acetate = 97:3 → 62:28) to give the crude product. The obtained solid was suspended in methanol and filtered. The filtrate was collected to give the compound having the moiety of structural formula (1ab) (15.8 mg, 48.8 μmol, 46%).

[0153] · Identification results of the compound having the moiety of structural formula (1ab) 1 1H-NMR (500 MHz, acetone-d 6 ) δ10.62 (s, 1H), 7.61 (dd, J = 6.6, 2.0 Hz, 2H), 7.55 (dd, J = 6.6, 2.0 Hz, 2H), 7.50 - 7.48 (m, 2H), 7.12 (d, J = 16.6 Hz, 1H), 7.03 - 7.00 (m, 2H), 6.88 (t, J = 2.9 Hz, 1H), 6.15 (t, J = 2.9 Hz, 1H), 3.88 (s, 3H), 2.25 (s, 3H). HR-ESI-MS: m / z: [M+H] + C 20 H 17 The calculated mass of ClNO is 322.09987; the measured mass is 322.09811.

[0154] (Synthesis of the compound having the moiety of structural formula (1ac)) The obtained residue was purified by flash column chromatography (hexane:ethyl acetate = 67:33 → 46:54) to give the compound having the moiety of structural formula (1ac) (33.9 mg, 100 μmol, 94%).

[0155] · Identification results of the compound having the moiety of structural formula (1ac) 1 H-NMR (500 MHz, acetone-d 6 ) δ10.62 (s, 1H), 7.78 (d, J = 2.9 Hz, 1H), 7.63 (dd, J = 6.6, 2.0 Hz, 2H), 7.57-7.55 (m, 3H), 7.13 (d, J = 16.6 Hz, 1H), 7.05-7.00 (m, 2H), 6.88 (t, J = 3.2 Hz, 1H), 6.15 (t, J = 2.9 Hz, 1H), 4.71 (d, J = 6.9 Hz, 2H), 4.03 (t, J = 5.7 Hz, 1H), 3.88 (s, 3H). HR-ESI-MS: m / z: [M+H] + C 20 H 19 ClNO 2 The calculated mass of is 340.11043; the measured mass is 340.11201.

[0156] (Synthesis of the compound having the moiety of structural formula (1ad)) Bromo compound (9) (30 mg, 106 μmol), 3-hydroxy-4-methoxycarbonylphenylboronic acid (24.9 mg, 127 μmol), and tetrakis(triphenylphosphine)palladium(0) (6.1 mg, 5.3 μmol) were dissolved in 1,4-dioxane (4 mL) and 1 mol / L aqueous sodium carbonate solution (1 mL), and heated under reflux for 15 minutes. After the reaction mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Then, it was concentrated under reduced pressure. The obtained residue was separated by flash column chromatography (hexane:ethyl acetate = 91:9 → 70:30) to obtain the crude product. The obtained solid was suspended in methanol and filtered. The filtrate was collected to obtain a compound (20.0 mg, 56.6 μmol, 53%) having the moiety of structural formula (1ad).

[0157] · Identification results of the compound having the moiety of structural formula (1ad) 1 H-NMR (500 MHz, acetone-d 6 ) δ10.81 (s, 1H), 10.70 (br, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.74 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.30 (dd, J = 8.4, 1.1 Hz, 1H), 7.27 (d, J = 1.6 Hz, 1H), 7.20 (d, J = 16.6 Hz, 1H), 7.05 (d, J = 16.6 Hz, 1H), 6.91 (t, J = 3.0 Hz, 1H), 6.17 (t, J = 2.7 Hz, 1H), 3.99 (s, 3H). HR-ESI-MS: m / z: [M+Na] + C 20 H 17 NO 3 Cl calculated mass 354.08915; measured mass 354.09154.

[0158] (Synthesis of the compound having the moiety of structural formula (1ae)) Bromo compound (9) (30 mg, 106 μmol), 3-methoxy-4-methoxycarbonylphenylboronic acid (26.7 mg, 127 μmol), tetrakis(triphenylphosphine)palladium(0) (6.1 mg, 5.3 μmol) were dissolved in 1,4-dioxane (4 mL) and 1 mol / L aqueous sodium carbonate solution (0.1 mL), and heated under reflux for 1 hour. The reaction mixture solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Then it was concentrated under reduced pressure. The obtained residue was separated by flash column chromatography (hexane:ethyl acetate = 75:25 → 54:46) to obtain the crude product. Further purification by flash column chromatography (hexane:ethyl acetate = 70:30 → 49:51) gave the compound having the moiety of structural formula (1ae) (13.2 mg, 35.9 μmol, 34%).

[0159] · Identification results of the compound having the moiety of structural formula (1ae) 1 H-NMR (500 MHz, acetone-d 6 ) δ10.69 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 1.4 Hz, 1H), 7.33 (dd, J = 8.0, 1.7 Hz, 1H), 7.18 (d, J = 16.6 Hz, 1H), 7.05 (d, J = 16.6 Hz, 1H), 6.91 (t, J = 3.0 Hz, 1H), 6.17 (t, J = 2.8 Hz, 1H), 3.99 (s, 3H), 3.84 (s, 3H). HR-ESI-MS: m / z: [M+Na] + C 21 H 18 NO 3 Calculated mass of NaCl 390.08674; Measured mass 390.08231.

[0160] (Synthesis of the compound having the moiety of structural formula (1af)) Bromo compound (9) (27.2 mg, 96.3 μmol), 4-pyridylboronic acid (15.4 mg, 125 μmol), and tetrakis(triphenylphosphine)palladium(0) (5.5 mg, 4.8 μmol) were dissolved in 1,4-dioxane (2 mL) and 1 mol / L aqueous sodium carbonate solution (2 mL), and the mixture was heated under reflux for 2 hours. After the reaction mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Then, it was concentrated under reduced pressure. The obtained residue was subjected to flash column chromatography (hexane:ethyl acetate = 56:44 → 35:65) to separate the crude product. The obtained solid was washed with hexane to obtain a compound having the moiety of structural formula (1af) (12.6 mg, 44.8 μmol, 47%).

[0161] · Identification results of the compound having the moiety of structural formula (1af) 1 H-NMR (500 MHz, chloroform-d 1 ) δ 8.66 (d, J = 5.7 Hz, 2H), 8.33 (br, 1H), 7.64 (dd, J = 6.3, 1.7 Hz, 2H), 7.58 (dd, J = 6.3, 1.7 Hz, 2H), 7.52 (dd, J = 4.5, 2.0 Hz, 2H), 7.13 (d, J = 16.6 Hz, 1H), 6.77 (t, J = 2.9 Hz, 1H), 6.72 (d, J = 16.6 Hz, 1H), 6.23 (t, J = 2.9 Hz, 1H). HR-ESI-MS: m / z: [M+H] + C 17 H 14 ClN 2 Calculated mass 281.08455; Measured mass 281.08449.

[0162] (Synthesis of the compound having the moiety of structural formula (1ag)) Bromo compound (9) (34.1 mg, 121 μmol), 3-pyridylboronic acid (15.4 mg, 125 μmol), tetrakis(triphenylphosphine)palladium(0) (6.9 mg, 6.0 μmol) were dissolved in 1,4-dioxane (2 mL) and 1 mol / L aqueous sodium carbonate solution (2 mL), and heated under reflux for 6 hours. The reaction mixture solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Then it was concentrated under reduced pressure. The obtained residue was purified by flash column chromatography (hexane:ethyl acetate = 65:35 → 44:56) to obtain a compound (20.7 mg, 73.7 μmol, 61%) having the moiety of structural formula (1ag).

[0163] · Identification results of the compound having the moiety of structural formula (1ag) 1 H-NMR (500 MHz, chloroform-d 1 ) δ 8.88 (d, J = 2.3 Hz, 1H), 8.59 (dd, J = 4.9, 1.4 Hz, 1H), 8.32 (br, 1H), 7.89 (dt, J = 8.0, 2.0 Hz, 1H), 7.58 (m, 4H), 7.37 (dd, J = 7.4, 5.2 Hz, 1H), 7.11 (d, J = 16.6 Hz, 1H), 6.76 (t, J = 2.9 Hz, 1H), 6.73 (d, J = 16.6 Hz, 1H), 6.22 (t, J = 2.9 Hz, 1H). HR-ESI-MS: m / z: [M+H] + C 17 H 14 ClN 2 Calculated mass 281.08455; Measured mass 281.08538.

[0164] (Synthesis of the compound having the moiety of structural formula (1ah)) Bromo compound (9) (34.1 mg, 121 μmol), 5-pyrimidylboronic acid (17.9 mg, 144 μmol), and tetrakis(triphenylphosphine)palladium(0) (6.4 mg, 5.5 μmol) were dissolved in 1,4-dioxane (2 mL) and 1 mol / L aqueous sodium carbonate solution (2 mL), and the mixture was heated under reflux for 2 hours. After the reaction mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Then, it was concentrated under reduced pressure. The obtained residue was subjected to flash column chromatography (hexane:ethyl acetate = 62:38 → 41:59) to isolate the crude product. The obtained solid was washed with hexane to obtain a compound having the moiety of structural formula (1ah) (18.7 mg, 66.3 μmol, 60%).

[0165] · Identification results of the compound having the moiety of structural formula (1ah) 1 1H-NMR (500 MHz, chloroform-d 1 ) δ 9.20 (s, 1H), 8.98 (s, 2H), 8.33 (s, 1H), 7.61 (d, J = 8.6 Hz, 2H), 7.58 (dd, J = 6.3, 2.3 Hz, 2H), 7.13 (d, J = 16.6 Hz, 1H), 6.77 (t, J = 2.9 Hz, 1H), 6.73 (d, J = 16.6 Hz, 1H), 6.23 (t, J = 2.6 Hz, 1H). HR-ESI-MS: m / z: [M+H] + C 16 H 13 ClN 3 Calculated mass for 282.07980; Measured mass 282.08087.

[0166] (Synthesis of the compound having the moiety of structural formula (1ai)) The obtained residue was purified by flash column chromatography (hexane:ethyl acetate = 88:12 → 67:33) to obtain a compound having the moiety of structural formula (1ai) (32.2 mg, 104 μmol, 97%).

[0167] · Identification results of the compound having the moiety of Structural Formula (1ai) 1 H-NMR (500 MHz, acetone-d 6 ) δ10.65 (s, 1H), 8.47 (d, J = 2.9 Hz, 1H), 7.98 (dd, J = 8.6, 2.9 Hz, 1H), 7.64 (dd, J = 6.6, 2.0 Hz, 2H), 7.60 (dd, J = 6.3, 1.7 Hz, 2H), 7.16 (d, J = 16.6 Hz, 1H), 7.03 (d, J = 16.6 Hz, 1H), 6.89 (t, J = 2.9 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 6.16 (t, J = 2.6 Hz, 1H), 3.94 (s, 3H). HR-ESI-MS: m / z: [M+H] + C 18 H 16 ClN 2 The calculated mass of O is 311.09512; the measured mass is 311.09340.

[0168] (Synthesis of the compound having the moiety of Structural Formula (1aj)) The obtained residue was purified by flash column chromatography (hexane:ethyl acetate = 72:28 → 51:49) to obtain a compound (28.5 mg, 91.4 μmol, 86%) having the moiety of Structural Formula (1aj).

[0169] · Identification results of the compound having the moiety of Structural Formula (1aj) 1 H-NMR (500 MHz, acetone-d 6) δ10.64 (s, 1H), 8.84 (s, 2H), 7.67 (d, J = 8.6 Hz, 2H), 7.62 (d, J = 8.6 Hz, 2H), 7.15 (d, J = 16.6 Hz, 1H), 7.01 (d, J = 16.6 Hz, 1H), 6.88-6.87 (m, 1H), 6.14 (t, J = 2.6 Hz, 1H), 3.98 (s, 3H). HR-ESI-MS: m / z: [M+H] + C 17 H 15 ClN 3 Calculated mass of C + H 17 ClN 3 O is 312.09036; measured mass is 312.09051.

[0170] (Synthesis of the compound having the moiety of Structural Formula (1i)) The compound having the moiety of Structural Formula (1g) (15 mg, 50.7 μmol), acetic anhydride (5.7 μL, 60.8 μmol), 4-dimethylaminopyridine (4.6 mg, 37.6 μmol), and triethylamine (8.4 μL, 60.8 μmol) were dissolved in tetrahydrofuran (3 mL) and stirred. After two and a half hours, saturated aqueous sodium bicarbonate solution (2 mL) was added to quench the reaction. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Then it was concentrated under reduced pressure. The obtained residue was separated by flash column chromatography (hexane:ethyl acetate = 76:24 → 55:45) to obtain the compound having the moiety of Structural Formula (1i) (8.2 mg, 24.2 μmol, 48%).

[0171] · Identification results of the compound having the moiety of Structural Formula (1i) 1 H-NMR (500 MHz, chloroform-d 1) δ 8.29 (s, 1H), 7.61 (dd, J = 6.6, 2.0 Hz, 2H), 7.56 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.6 Hz, 2H), 7.16 (dd, J = 6.6, 2.0 Hz, 2H), 7.09 (d, J = 16.6 Hz, 1H), 6.75 (t, J = 2.9 Hz, 1H), 6.71 (d, J = 16.6 Hz, 1H), 6.22 (t, J = 2.9 Hz, 1H), 2.34 (s, 3H). HR-ESI-MS: m / z: [M+Na] + C 20 H 16 ClNNaO 2 Calculated mass of 360.07673; measured mass of 360.07499.

[0172] (Synthesis of the compound having the moiety of structural formula (1j)) The compound having the moiety of structural formula (1h) (24.8 mg, 83.7 μmol), acetic anhydride (9.5 μL, 100 μmol), 4-dimethylaminopyridine (5.1 mg, 4.2 μmol), and triethylamine (13.9 μL, 100 μmol) were dissolved in tetrahydrofuran (3 mL) and stirred. After two and a half hours, saturated aqueous sodium hydrogen carbonate solution (1 mL) was added to quench the reaction. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Then it was concentrated under reduced pressure. The obtained residue was separated by flash column chromatography (hexane:ethyl acetate = 83:17 → 62:38) to obtain the compound having the moiety of structural formula (1j) (17.8 mg, 52.7 μmol, 63%).

[0173] · Identification results of the compound having the moiety of structural formula (1j) 1 H-NMR (500 MHz, chloroform-d 1) δ 8.29 (s, 1H), 7.56 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H), 7.48 (dt, J = 7.8, 1.4 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.32 (t, J = 2.0 Hz, 1H), 7.10 - 7.05 (m, 2H), 6.75 (t, J = 2.9 Hz, 1H), 6.71 (d, J = 16.6 Hz, 1H), 6.21 (t, J = 2.9 Hz, 1H), 2.34 (s, 3H). HR - ESI - MS: m / z: [M + H] + C 20 H 17 ClNO 2 The calculated mass is 338.09478; the measured mass is 338.09160.

[0174] <Synthesis method of the compound represented by the general formula (1B)> The synthesis scheme of the compound represented by the above general formula (1B) and where R in the general formula (1B) is OH or OMe is as follows. [Chemical formula] [Chemical formula]

[0175] (Synthesis of the Ms protecting group (11)) Commercially available 3-chloro-1H-pyrrole-2-carbaldehyde (10) (606 mg, 4.68 mmol), sodium hydroxide (290 mg, 12.1 mmol) were dissolved in tetrahydrofuran (THF) (4 mL), cooled to 0 °C, and then methanesulfonyl chloride (435 μL, 5.56 mmol) was added dropwise, followed by stirring for one and a half hours. Water was added to quench the reaction, and the reaction mixture was warmed to room temperature. Then, the reaction mixture was extracted twice with 30 mL of ethyl acetate and concentrated under reduced pressure. This was purified by column chromatography [silica gel 60.8 g, hexane:ethyl acetate = 4:1] to obtain the Ms-protected product (11) (788 mg, 3.80 mmol, 81%).

[0176] · Identification results of the Ms-protected product (11) 1 H-NMR (500 MHz, CDCl 3 ) δ 3.69 (s, 3H), 6.38 (d, J = 3.5 Hz, 1H), 7.59 (d, J = 3.0 Hz, 1H), 9.88 (s, 1H).

[0177] (Synthesis of the dibromo product (12)) The Ms-protected product (11) (788 mg, 3.80 mmol), carbon tetrabromide (2.75 g, 8.31 mmol), and triphenylphosphine (4.35 g, 16.6 mmol) were dissolved in dichloromethane (simply dehydrated) (35 mL) and stirred at room temperature for 21 and a half hours. Then, the reaction mixture was purified by silica gel chromatography [silica gel 62.4 g, hexane:ethyl acetate = 4:1] to obtain the dibromo product (12) (713 mg, 1.96 mmol, 52%).

[0178] · Identification results of the dibromo product (12) 1 H-NMR (500 MHz, CDCl 3) δ 3.14 (s, 3H), 6.33 (d, J = 3.5 Hz, 1H), 7.19 (d, J = 3.5 Hz, 1H), 7.41 (s, 1H).

[0179] (Synthesis of monobromo compound (13)) Dibromo compound (12) (713 mg, 1.96 mmol) was dissolved in N,N-dimethylformamide (DMF) (simply dehydrated) (20 mL), dimethyl phosphite (1020 μL, 11.06 mmol) and triethylamine (1730 μL, 12.38 mmol) were added dropwise, and the mixture was stirred at room temperature for 24 hours. Then, the reaction mixture was extracted twice with 30 mL of ethyl acetate and concentrated under reduced pressure. This was purified by silica gel chromatography [silica gel 63.0 g, hexane:ethyl acetate = 4:1] to obtain a crude product of monobromo compound (13) (510 mg, 1.79 mmol, 91%) with a mixture of E / Z = 2 / 1.

[0180] · Identification results of monobromo compound (13) 1 H-NMR (500 MHz, CDCl 3 ) δ 3.33 (s, 3H), 6.33 (d, J = 3.5 Hz, 1H), 7.24 (s, 1H), 7.28(d, J = 3.5 Hz, 1H), 7.42 (d, 2H).

[0181] (Synthesis of biphenyl compound (15a)) Commercially available 5-bromo-2-chlorophenol (14a) (1.00 g, 4.82 mmol), 4-methoxyphenylboronic acid (1.10 g, 7.23 mmol), and tetrakis(triphenylphosphine)palladium (253 mg, 0.24 mmol) were dissolved in 1M aqueous sodium carbonate solution (5 mL) and 1,4-dioxane (5 mL), and the mixture was heated under reflux for 20 hours. Then, the reaction mixture was extracted twice with 30 mL of ethyl acetate and concentrated under reduced pressure. This was purified by silica gel chromatography [silica gel 61.7 g, hexane:ethyl acetate = 8:1] to obtain the biphenyl compound (15a) (1028 mg, 4.39 mmol, 91%).

[0182] · Identification results of biphenyl compound (15a) 1 H-NMR (500 MHz, CDCl 3 ) δ 3.87 (s, 3H), 5.54 (s, 1H), 6.97 (d, J = 8.5 Hz, 2H), 7.06 (d, J = 7.0 Hz, 2H), 7.21 (d, J = 2.0 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 8.5 Hz, 2H).

[0183] (Synthesis of boronic acid (16a)) The biphenyl compound (15a) (500 mg, 2.14 mmol), bis(pinacolato)diboron (1.42 g, 5.60 mmol), palladium acetate (27.5 mg, 0.11 mmol), X-Phos (93.7 mg, 0.19 mmol), and potassium acetate (638 mg, 6.41 mmol) were dissolved in 1,4-dioxane (7 mL), and the mixture was heated under reflux for 21 hours. Then, the reaction mixture was extracted twice with 30 mL of ethyl acetate and concentrated under reduced pressure. This was purified by flash chromatography [hexane:ethyl acetate = 10:0 to 21:4] to obtain the crude product of boronic acid (16a) (461 mg).

[0184] (Synthesis of Ms protecting group (17)) The crude boronic acid (16a) product (37.2 mg), monobromo compound (13) (52.4 mg, 0.18 mmol), and tetrakis(triphenylphosphine)palladium (8.5 mg, 0.0059 mmol) were dissolved in 1M aqueous sodium carbonate solution (2 mL) and 1,4-dioxane (2 mL), and heated under reflux for 20 hours. Then, tetra-n-butylammonium fluoride (331 μL, 0.35 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for one and a half hours. Thereafter, the reaction mixture was extracted twice with 30 mL of ethyl acetate and concentrated under reduced pressure. This was purified by flash chromatography [hexane:ethyl acetate = 4:1 to 1:1] to obtain the Ms protecting group (17) (20.6 mg, 0.051 mmol, 51%).

[0185] ·Identification results of Ms protecting group (17) 1 H-NMR (500 MHz, CDCl 3 ) δ 3.19 (s, 3H), 3.86 (s, 3H), 6.20 (t, J = 2.0 Hz, 1H), 6.74 (t, J = 2.0 Hz, 1H), 6.98 (m, 3H), 7.12 (d, J = 17 Hz, 1H), 7.53 (m, 4H), 7.75 (d, J = 8.0 Hz, 1H), 8.35 (b, 1H).

[0186] (Synthesis of the compound (1Ba) represented by the general formula (1B) where R is OH) The Ms protecting group (17) (20.6 mg, 0.051 mmol), KOH (50.8 mg, 0.91 mmol) were dissolved in distilled water (1 mL), methanol (1 mL), and ethanol (1.5 mL), stirred at room temperature for 22 hours, and then heated to reflux for one and a half hours. Thereafter, the reaction mixture was extracted twice with 30 mL of ethyl acetate and concentrated under reduced pressure. This was purified by flash chromatography [hexane:ethyl acetate = 7:3 to 1:1] to obtain the compound (1Ba) (4.8 mg, 0.015 mmol, 29%) represented by the general formula (1B) where R is OH.

[0187] · Identification results of the compound (1Ba) represented by the general formula (1B) where R is OH 1 H-NMR (500 MHz, CDCl 3 ) δ 3.86 (s, 3H), 4.96 (s, 1H), 6.20 (t, J = 2.0 Hz, 1H), 6.74 (t, J = 2.0 Hz, 1H), 6.97 (m, 4H), 7.10 (d, J = 17 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 2.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 1H), 8.34 (b, 1H).

[0188] (Synthesis of biphenyl compound (15b)) Commercially available 5-bromo-2-chloroanisole (14b) (1.18 g, 5.34 mmol), 4-methoxyphenylboronic acid (1.10 mg, 7.26 mmol), and tetrakis(triphenylphosphine)palladium (269.9 mg, 0.23 mmol) were dissolved in 1M aqueous sodium carbonate solution (6 mL) and 1,4-dioxane (6 mL), and heated under reflux for 1 hour. Then, the reaction mixture was extracted twice with 30 mL of ethyl acetate and concentrated under reduced pressure. This was purified by silica gel chromatography [60.0 g of silica gel, hexane:ethyl acetate = 8:1] to obtain the biphenyl compound (15b) (1.28 g, 5.13 mmol, 96%).

[0189] · Identification results of biphenyl compound (15b) 1 H-NMR (500 MHz, CDCl 3 ) δ 3.86 (s, 3H), 3.97 (s, 3H), 6.98 (d, J = 8.5 Hz, 2H), 7.07 (d, J = 7.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.5 Hz, 2H).

[0190] (Synthesis of boronic acid (16b)) The biphenyl compound (15b) (153 mg, 0.62 mmol), bis(pinacolato)diboron (461 mg, 1.81 mmol), palladium acetate (10.3 mg, 0.046 mmol), X-Phos (29.0 mg, 0.054 mmol), and potassium acetate (187 mg, 1.81 mmol) were dissolved in 1,4-dioxane (2.5 mL) and heated under reflux for 23 hours. Then, the reaction mixture was extracted twice with 30 mL of ethyl acetate and concentrated under reduced pressure. The resulting crude boronic acid (16b) product (485 mg) was used as it was in the synthesis of the following Ms-protected compound (18).

[0191] (Synthesis of Ms-protected compound (18)) Boric acid (16b) (486 mg), monobromo compound (13) (200.1 mg, 0.72 mmol), and tetrakis(triphenylphosphine)palladium (36.9 mg, 0.030 mmol) were dissolved in an aqueous solution of 1 M sodium carbonate (4 mL) and 1,4-dioxane (4 mL), and the mixture was heated under reflux for 20 hours. Then, the reaction mixture was extracted twice with 30 mL of ethyl acetate and concentrated under reduced pressure. This was purified by flash chromatography [hexane:ethyl acetate = 17:3 to 13:7] to obtain the Ms-protected product (18) (125 mg, 0.30 mmol, 59% (two steps)).

[0192] · Identification results of the Ms-protected product (18) 1 H-NMR (500 MHz, CDCl 3 ) δ 3.15 (s, 3H), 3.86 (s, 3H), 3.97 (s, 3H), 6.33 (d, J = 3.0 Hz, 1H), 6.99 (d, J = 8.5 Hz, 2H), 7.08 (d, J = 1.5 Hz, 1H), 7.16 (m, 2H), 7.73 (d, J = 16 Hz, 1H).

[0193] (Synthesis of the compound (1Bb) represented by the general formula (1B) where R is OMe) The Ms-protected product (18) (20.8 mg, 0.050 mmol) was dissolved in THF (3 mL), tetra-n-butylammonium fluoride (335 μL, 0.34 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Then, the reaction mixture was extracted twice with 30 mL of ethyl acetate and concentrated under reduced pressure. This was purified by flash chromatography [hexane:ethyl acetate = 9:1 to 7:3] to obtain the compound (1Bb) (8.9 mg, 0.026 mmol, 51% (two steps)) represented by the general formula (1B) where R is OMe.

[0194] · Identification results of the compound (1Bb) represented by the general formula (1B) where R is OMe 1H-NMR (500 MHz, CDCl 3 ) δ 3.87 (s, 3H), 3.95 (s, 3H), 6.19 (t, J = 3.0 Hz, 1H), 6.73 (t, J = 3.0 Hz, 1H), 7.00 (m, 4H), 7.10 (d, J = 17 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 7.5 Hz, 2H), 7.62 (d, J = 8.0 Hz, 1H), 8.36 (b, 1H). HR-ESI-MS (m / z): [M + H] + C 20 H 18 C l1 N 1 O 2 Calculated mass of C

[0195] <Synthesis method of the compound represented by the general formula (2A)> The synthesis scheme of the compound represented by the above general formula (2A) and where R in the general formula (2A) is NH or O is as follows.

Chemical formula

[0196] (Synthesis of the Ms-protected form (20)) Pyrrole-2-carboxaldehyde (19) (1.92 g, 20.2 mmol) was dissolved in tetrahydrofuran (simply dehydrated) (25 mL). Methanesulfonyl chloride (2.35 mL, 30.3 mmol) was added dropwise to this solution and cooled to 0 °C. Sodium hydride (1.62 g, 40.4 mmol) was added to this mixed solution and stirred for 2 hours. It was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography [silica gel 72 g, hexane:ethyl acetate = 2:1] to obtain the Ms-protected form (20) (2.67 g, 15.4 mmol, 76%).

[0197] · Identification results of Ms protecting group (20) 1 H-NMR (500 MHz, CDCl 3 ) δ 9.69 (d, J = 1.0 Hz, 1H), 7.61 (m, 1H), 7.21 (m, 1H), 6.42 (m, 1H), 3.63 (s, 3H). HR-MALDI-MS: m / z: [M+H] + C 6 H 8 NO 3 Calculated mass of S 174.02233; Measured mass 174.02194.

[0198] (Synthesis of phosphonium ylide (22)) 4-Cyanobenzyl bromide (21) (4.00 g, 20.4 mmol) and triphenylphosphine (8.03 g, 30.6 mmol) were dissolved in o-xylene (50 mL) and heated for 2 hours. After the reaction mixture was returned to room temperature, it was washed with toluene to obtain a crude product of phosphonium ylide (22) (9.20 g).

[0199] (Synthesis of nitrile (23)) Ms protecting group (20) (1.57 g, 9.10 mmol) and phosphonium ylide (22) (8.36 g, 18.2 mmol) were dissolved in tetrahydrofuran (simply dehydrated) (40 mL) and cooled to 0 °C. Sodium hydride (1.31 g, 31.8 mmol) was added to this solution and stirred at room temperature for two and a half hours. Then distilled water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography [silica gel 120 g, hexane:ethyl acetate = 2:1] to obtain nitrile (23) (995 mg, 3.65 mmol, 40%).

[0200] · Identification results of nitrile (23) 1 H-NMR (500 MHz, CDCl 3) δ 7.64 (d, J = 16.0Hz, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.5 Hz, 2H), 7.26 (m, 1H), 6.95 (d, J = 16 Hz. 1H), 6.73 (m, 1H), 6.37 (m, 1H), 3.14 (s, 3H). HR-MALDI-MS: m / z: [M] + C 14 H 12 N 2 O 2 Calculated mass of S: 272.05814; Measured mass: 272.06140.

[0201] (Synthesis of formyl compound (24)) The nitrile compound (23) (1.80 g, 6.60 mmol) was dissolved in methylene chloride (super dehydrated, 60 mL), and the solution was cooled to 0 °C and stirred under an argon atmosphere. 1.0 M diisobutylaluminum hydride-toluene solution (26.5 mL, 26.5 mmol) was added dropwise to this solution, and the mixture was stirred for 20 minutes. Then, a sufficient amount of acetone was added to decompose the excess reducing agent. Further, a sufficient amount of saturated aqueous potassium sodium tartrate solution and saturated aqueous ammonium chloride solution were added to this mixed solution, and the mixture was stirred for 19 hours. Then, the mixture was extracted with chloroform, and the organic layer was washed with saturated brine. Further, it was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography [silica gel 125 g, hexane:ethyl acetate = 4:1 to 1:1] to obtain the formyl compound (24) (1.42 g, 5.17 mmol, 78%).

[0202] · Identification results of formyl compound (24) 1 H-NMR (500 MHz, Acetone-d 6) δ 10.03 (s, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 16.0Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.29 (m, 1H), 7.24 (d, J = 16.5 Hz, 1H), 6.92 (m, 1H), 6.42 (m, 1H), 3.43 (s, 3H). HR-MALDI-MS: m / z: [M] + C 14 H 13 NO 3 Calculated mass for C H NO S: 275.05904; Measured mass: 275.06107.

[0203] (Synthesis of the hydroxy compound (25)) Sodium borohydride (412 mg, 10.9 mmol) was dissolved in methanol (simply dehydrated) (50 mL) and stirred for 5 minutes. The formyl compound (24) (1.00 g, 3.63 mmol) was dissolved in this solution and stirred for two and a half hours. Water was added to decompose the excess sodium borohydride. Then it was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the hydroxy compound (25) (999 mg, 3.60 mmol, 99%).

[0204] · Identification results of the hydroxy compound (25) 1 H-NMR (500 MHz, CDCl 3 ) δ 7.51 (d, J = 16.0Hz, 1H), 7.49 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 7.21 (m, 1H), 6.97 (d, J = 16.5 Hz, 1H), 6.64 (m, 1H), 6.33 (m, 1H), 4.71 (d, J = 6.0, 2H), 3.13 (s, 3H), 1.63 (t, J = 6.0, 1H). HR-MALDI-MS: m / z: [M] + C 14 H 15 NO3 Calculated mass of S: 277.07655; Measured mass: 277.07672.

[0205] (Synthesis of the chloro compound (26)) The hydroxy compound (25) (100 mg, 0.361 mmol) was dissolved in methylene chloride (simply dehydrated) (6 mL), cooled to 0 °C and stirred. Thionyl chloride (78.5 μL, 1.08 mmol) was added to this solution and stirred for 3 hours. Thereafter, extraction was performed with methylene chloride, the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography [silica gel 67.5 g, hexane:ethyl acetate = 3:1 to 2:1] to obtain the chloro compound (26) (90.0 mg, 0.305 mmol, 85%).

[0206] · Identification results of the chloro compound (26) 1 H-NMR (500 MHz, CDCl 3 ) δ 7.52 (d, J = 16.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.22 (m, 1H), 6.96 (d, J = 16.5 Hz, 1H), 6.65 (m, 1H), 6.34 (m, 1H), 4.60 (s, 2H), 3.12 (s, 3H). HR-MALDI-MS: m / z: [M] C 14 H 14 NO 2 Calculated mass of HNO SCl: 295.04300; Measured mass: 295.04283.

[0207] (Synthesis of the amine compound (27)) The chloro compound (26) (50.6 mg, 0.171 mmol), 4-dimethylaminopyridine (25.1 mg, 0.206 mmol), and p-anisidine (31.7 mg, 0.257 mmol) were dissolved in methylene chloride (15 mL) and stirred at room temperature for 1 hour. Then, the mixture was stirred at 40 °C for 19 hours. Thereafter, the mixture was extracted with chloroform, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography [silica gel 35.0 g, hexane:ethyl acetate = 2:1] to obtain the amine compound (27) (0.0699 mmol, 25.6 mg, 41%).

[0208] · Identification results of the amine compound (27) 1 H-NMR (500 MHz, CDCl 3 ) δ 7.48 (d, J = 16.5 Hz, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 7.21 (m, 1H), 6.96 (d, J = 16.5 Hz, 1H), 6.77 (d, J = 9.0Hz, 2H), 6.62 (m, 1H), 6.60 (d, J = 9.5, 2H), 6.32 (m, 1H), 4.30 (s, 2H), 3.83 (br, 1H), 3.74 (s, 3H), 3.11 (s, 3H).

[0209] (Synthesis of the compound (2Aa) represented by the general formula (2A) where R is NH) The amine compound (27) (25.6 mg, 0.0698 mmol) was dissolved in tetrahydrofuran (simply dehydrated) (1 mL), and 1.0 M tetrabutylammonium fluoride - tetrahydrofuran solution (140 μL, 0.140 mmol) was added dropwise to this solution. After stirring at room temperature for 3.5 hours, it was heated under reflux for 17 hours. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by flash chromatography [hexane:ethyl acetate = 4:1] to obtain the compound (2Aa) (10.9 mg, 0.0358 mmol, 51%) represented by the general formula (2A) where R is NH.

[0210] · Identification results of the compound (2Aa) represented by the general formula (2A) where R is NH 1 H-NMR (500 MHz, CDCl 3 ) δ 8.35 (br, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H), 6.96 (d, J = 16.5 Hz, 1H), 6.81 (m, 1H), 6.78 (d, J = 8.5 Hz, 2H), 6.65 (d, J = 16.5 Hz, 1H), 6.61 (d, J = 16.5 Hz, 2H), 6.34 (m, 1H), 6.25 (m, 1H), 4.27 (s, 2H), 3.74 (s, 3H), 3.51 (br, 1H). HR-ESI-MS: m / z: [M+H] + C 20 H 21 N 2 O 1 Calculated mass of 305.16539; Measured mass of 305.16469.

[0211] (Synthesis of the ether compound (28)) The chloro compound (26) (87.0 mg, 0.295 mmol) and 4-methoxyphenol (54.9 mg, 0.443 mmol) were dissolved in dimethylformamide (simply dehydrated) (10 mL). Potassium carbonate (122 mg, 0.885 mmol) was added to this mixed solution, and the mixture was stirred at 80 °C for 3 hours. The mixture was extracted with ethyl acetate, and the organic layer was washed with an aqueous potassium hydroxide solution and saturated brine. After drying the organic layer over anhydrous sodium sulfate, it was concentrated under reduced pressure. The obtained residue was purified by flash chromatography [hexane:ethyl acetate = 2:1] to obtain the ether compound (28) (63.4 mg, 0.165 mmol, 56%).

[0212] · Identification results of the ether compound (28) 1 H-NMR (500 MHz, CDCl 3 ) δ 7.51 (d, J = 17.0 Hz, 1H), 7.50 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.22 (m, 1H), 6.97 (d, J = 16.5 Hz, 1H), 6.91 (d, J = 9.0 Hz, 2H), 6.84 (d, J = 9.0 Hz, 2H), 6.64 (m, 1H), 6.33 (m, 1H), 5.02 (s, 2H), 3.77 (s, 3H), 3.12 (s, 3H).

[0213] (Synthesis of the compound (2Ab) represented by the general formula (2A) where R is O) The ether compound (28) (63.4 mg, 0.165 mmol) was dissolved in tetrahydrofuran (simply dehydrated) (5 mL), and 1.0 M tetrabutylammonium fluoride - tetrahydrofuran solution (331 μL, 0.331 mmol) was added dropwise to this solution, followed by stirring at room temperature for 22 hours. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by flash chromatography [hexane:ethyl acetate = 2:1] to obtain the compound (2Ab) (10.9 mg, 0.0358 mmol, 51.3%) represented by the general formula (2A) where R is O.

[0214] · Identification results of the compound (2Ab) represented by the general formula (2A) where R is O 1 H-NMR (500 MHz, CDCl 3 ) δ 8.35 (br, 1H), 7.44 (d, J = 8.0Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H), 6.98 (d, J = 16.5 Hz, 1H), 6.91 (d, J = 9.0Hz,2H), 6.84 - 6.82 (m, 1H), 6.83 (d, J = 10.0Hz, 2H), 6.66 (d, J = 16.5 Hz,1H), 6.36 (m, 1H), 6.25 (m, 1H), 5.00 (s, 2H), 3.77 (s, 3H). HR-ESI-MS: m / z: [M+H] + C 20 H 20 N 1 O 2 Calculated mass of 306.14940; Measured mass of 306.15109.

[0215] <Synthesis method of the compound represented by the structural formula (3A)> The compound represented by the following structural formula (3A) was synthesized by a general method.

Chemical formula

[0216] <Synthesis method of the compound represented by structural formula (2B)> The compound represented by structural formula (2B) was synthesized according to the following synthetic scheme.

Chemical formula

[0217] (Synthesis of silyl protected body (4)) Commercially available p-cresol (3) (1.94 ml, 18.5 mmol) and imidazole (1.94 ml, 18.5 mmol) were dissolved in N,N-dimethylformamide (DMF) (simply dehydrated) (8 mL) and cooled to 0 °C. To this mixed solution, tert-butyldimethylsilyl chloride (3.62 g, 24.0 mmol) was added and stirred for 1 hour. Hexane was added to the reaction mixture, and after washing with hydrochloric acid and saturated brine, it was dried over anhydrous sodium sulfate and concentrated to obtain a crude product (4.28 g) of silyl protected body (4).

[0218] ·Identification results of silyl protected body (4) 1 H-NMR (500 MHz, CDCl3) δ7.01 (d, J = 8.5 Hz, 2H), 6.75 (d, J = 8.5, 2H), 2.27 (s, 3H), 0.975 (s, 9H), 0.175 (s, 6H)

[0219] (Synthesis of phosphorus ylide body (5)) The silyl protecting group (4) (1.99 g), N-bromosuccinimide (1.75 g, 9.83 mmol), and azobisisobutyronitrile (368 mg, 2.24 mmol) were dissolved in carbon tetrachloride (30 ml) and heated under reflux for 30 minutes. The reaction mixture was suction filtered and washed with hexane. Distilled water was added to the filtrate, followed by extraction with hexane. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a pale yellow transparent oily product. This product and triphenylphosphine (3.52 g, 13.4 mmol) were dissolved in toluene (25 ml) and heated under reflux for 7 hours. The reaction mixture was washed with toluene to obtain a crude product of the phosphonium ylide (5) (5.39 g).

[0220] · Identification results of the phosphonium ylide (5) 1 H-NMR (500 MHz, CDCl 3 ) δ7.79-7.71 (m, 9H, 7.66-7.62 (m, 6H), 6.96 (dd, J=6.0, 2.5 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 5.33 (d, J=13.0, 2H), 0.946 (s, 9H), 0.136 (s, 6H)

[0221] (Synthesis of the Ms protecting group (6)) The Ms protecting group (2) (i.e., the Ms protecting group (20) in the synthesis of compound (2Ab)) (508 mg, 2.93 mmol) and the phosphonium ylide (5) (3.30 g) were dissolved in tetrahydrofuran (simply dehydrated) (40 mL) and cooled to 0°C. Sodium hydride (352 mg, 8.79 mmol) was added to this solution and stirred for 30 minutes, followed by stirring at room temperature for 21 hours. Then, distilled water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography [silica gel 88 g, hexane:ethyl acetate = 15:1 to 5:1] to obtain a crude product of the Ms protecting group (6) (386 mg).

[0222] · Identification result of Ms protecting group (6) 1 H-NMR (500 MHz, CDCl 3 ) δ7.38-7.34 (m, 3H), 7.19 (m, 1H), 6.91 (d, J=16.5 Hz, 1H), 6.83 (d, J=7.0 Hz, 2H), 6.57 (m, 1H), 6.31 (t, J=3.0 Hz, 1H), 3.12 (s, 3H), 0.916 (s, 9H), 0.097 (s, 1H)

[0223] (Synthesis of hydroxy compound (7)) Ms protecting group (6) (92.9 mg, 0.246 mmol) was dissolved in tetrahydrofuran (simply dehydrated) (3 mL), and 1.0 M tetrabutylammonium fluoride - tetrahydrofuran solution (492 μL, 0.492 mmol) was added dropwise to this solution, followed by stirring at room temperature for 1 hour. Distilled water was added to the reaction mixture, and the mixture was extracted with a mixed solution of ethyl acetate and hexane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product of hydroxy compound (7).

[0224] (Identification result of hydroxy compound (7)) 1 H-NMR (500 MHz, CDCl 3 ) δ7.39 (d, J=7.0 Hz, 2H), 7.35 (d, J=16.0 Hz, 1H), 7.19 (m, 1H), 6.92-6.82 (m, 3H), 6.58 (m, 1H), 6.32 (m, 1H), 3.11 (s, 3H),

[0225] (Synthesis of bromo compound (9)) 4-Methoxybenzyl alcohol (500 mg, 3.62 mmol) was dissolved in dichloromethane (5 ml), and the solution was cooled to 0 °C. Phosphorus tribromide (137 μl, 1.45 mmol) was added dropwise to this mixed solution, and the mixture was stirred at room temperature for 4.5 hours. Distilled water was added to the reaction mixture, and then the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product (670 mg) of the brominated compound (9).

[0226] (Identification results of the brominated compound (9)) 1 H-NMR (500 MHz, CDCl 3 ) δ7.33 (d, J = 9.0 Hz, 2H), 6.87 (d, J = 9.0 Hz, 2H), 4.51 (s, 2H), 3.81 (s, 3H)

[0227] (Synthesis of the ether compound (10)) The brominated compound (9) (108 mg, 0.537 mmol), the hydroxy compound (7) (53.4 mg, 0.203 mmol), and potassium carbonate (86.2 mg, 0.609 mmol) were dissolved in N,N-dimethylformamide, and the mixture was stirred at 80 °C for 15 hours. Distilled water was added to the reaction mixture, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel 27.0 g, hexane:ethyl acetate = 4:1] to obtain a crude product (56.4 mg) of the ether compound (10).

[0228] · Identification results of the crude product of the ether compound (10) 1 H-NMR (500 MHz, CDCl 3) δ7.42 (d, J=8.5 Hz, 2H), 7.36 (d, J=9.0 Hz, 2H), 7.36 (d, J=17.0 Hz, 1H), 7.19 (m, 1H), 6.96 (d, J=8.5 Hz, 2H), 6.93 (d, J=8.5, 2H), 6.91 (d, J=16.5, 1H), 6.58 (m, 1H), 6.31 (m,1H), 5.01 (s, 2H), 3.82 (s, 3H), 3.11 (s, 3H)

[0229] (Synthesis of the compound represented by structural formula (2B)) The crude product (53.6 mg) of the ether compound (10) was dissolved in tetrahydrofuran (simply dehydrated) (2 ml), and 1.0 M tetrabutylammonium fluoride - tetrahydrofuran solution (280 μl, 0.280 mmol) was added dropwise to this solution and heated under reflux for 6 hours. Distilled water was added to the reaction solution, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography [hexane:ethyl acetate = 91:9 → 72:28] to obtain the compound (17.3 mg, 0.0567 mmol) represented by structural formula (2B).

[0230] · Identification results of the compound represented by structural formula (2B) 1 H-NMR (500 MHz, CDCl 3 ) δ8.30 (br, 1H), 7.36 (d, J=9.0 Hz, 2H), 7.36 (d, J=9.0 Hz, 2H), 6.93 (t, J=8.5, 4H), 6.84 (d, J=16.5, 1H), 6.80 (m, 1H), 6.62 (d, J=16.5, 1H), 6.31 (m, 1H), 6.24 (m,1H), 5.01 (s, 2H), 3.82 (s, 3H)

[0231] <Synthesis method of the compound represented by structural formula (1C)> The compound represented by the following structural formula (1C) was synthesized by a general method.

Chemical formula

[0232] <Synthesis method of the compound represented by structural formula (1D)> The compound represented by the following structural formula (1D) was synthesized by a general method.

Chemical formula

[0233] <Synthesis method of the compound represented by structural formula (1E)> The compound represented by structural formula (1E) was synthesized according to the following synthetic scheme.

Chemical formula

[0234] (Synthesis of the compound represented by structural formula (1E)) Bromo compound (9) (same as bromo compound (9) in the synthesis of structural formula (1a), etc.) (50.0 mg, 0.177 mmol), 4-tert-butylphenylboronic acid (47.2 mg, 0.265 mmol), tetrakis(triphenylphosphine)palladium(0) (10.2 mg, 0.0885 mmol) were dissolved in 1,4-dioxane (2 mL) and 1 mol / L aqueous sodium carbonate solution (2 mL), and heated under reflux. After the reaction mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography [silica gel 25 g, hexane:ethyl acetate = 6:1]. The obtained residue was washed with methanol to obtain the compound represented by structural formula (1E) (30.0 mg, 0.0893 mmol, 50%).

[0235] · Identification results of the compound represented by structural formula (1E) 1 H-NMR (500 MHz, CDCl3 ) δ8.30 (broad, 1H), 7.61 - 7.52 (multiplet, 6H), 7.47 (doublet, J = 8.5 Hz, 2H), 7.08 (doublet, J = 17.0 Hz, 1H), 6.75 (triplet, J = 3.0 Hz, 1H), 6.72 (doublet, J = 16.5 Hz, 1H), 6.21 (triplet, J = 3.0 Hz, 1H), 1.37 (singlet, 9H)

[0236] <Synthesis method of the compound represented by Structural Formula (1F)> The compound represented by the following Structural Formula (1F) was synthesized by a general method.

Chemical formula

[0237] <Synthesis method of the compound represented by Structural Formula (1G)> The compound represented by the following Structural Formula (1G) was synthesized by a general method.

Chemical formula

[0238] <Synthesis method of the compound represented by Structural Formula (1H)> The compound represented by the following Structural Formula (1H) was synthesized by a general method.

Chemical formula

[0239] <Synthesis method of the compound represented by Structural Formula (2C)> The compound represented by Structural Formula (2C) was synthesized according to the following synthetic scheme.

Chemical formula

[0240] (Synthesis of Ether Form (11)) 4-Methoxyphenol (100 mg, 0.806 mmol), 4-bromophenylboronic acid (323 mg, 1.61 mmol), and copper(II) acetate (146 mg, 0.806 mmol) were dissolved in dichloromethane (2 ml). Triethylamine (221 μl, 1.61 mmol) was added dropwise to this mixed solution, and the mixture was stirred at 37 °C for 22 h under an oxygen atmosphere. The reaction mixture was filtered through celite with methylene chloride, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography [hexane:ethyl acetate = 100:0 → 94:6] to give the ether compound (11) (117 mg, 0.417 mmol, 52%).

[0241] · Identification results of ether compound (11) 1 H-NMR (500 MHz, CDCl 3 ) δ7.38 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 6.89 (d, J = 8.5 Hz, 2H), 6.82 (d, J = 9.0 Hz, 2H), 3.81 (s, 3H)

[0242] (Synthesis of boronic acid (12)) The ether compound (11) (100 mg, 0.358 mmol), bis(pinacolato)diboron (272 mg, 1.07 mmol), potassium acetate (105 mg, 1.07 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (14.6 mg, 0.0179 mmol) were dissolved in 1,4-dioxane (2 ml) under an argon atmosphere and heated to reflux for 28 h. Distilled water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography [hexane:ethyl acetate = 83:17 → 76:24] to give the crude product of boronic acid (12) (115 mg).

[0243] · Identification results of boronic acid (12) 1 H-NMR (500 MHz, CDCl 3 ) δ7.74 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 9.0 Hz, 2H), 6.91 (d, J = 9.0 Hz, 2H), 6.89 (d, J = 9.5 Hz, 2H), 3.81 (s, 3H), 1.33 (s, 12H)

[0244] (Synthesis of dibromo compound (13)) Carbon tetrabromide (3.80 g, 11.5 mmol) was dissolved in methylene chloride (5 ml). To the reaction solution, a methylene chloride solution (20 ml) of the Ms-protected compound (2) (i.e., the Ms-protected compound (20) in the synthesis of compound (2Ab)) (1.53 g, 8.82 mmol) and triphenylphosphine (6.01 g, 22.9 mmol) was gradually added dropwise, and the mixture was stirred for 90 minutes. Then, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography [200 g of silica gel, hexane:ethyl acetate = 4:1] to obtain dibromo compound (13) (2.39 g, 7.28 mmol, 83%).

[0245] · Identification results of dibromo compound (13) 1 H-NMR (500 MHz, CDCl 3 ) δ7.87 (s, 1H), 7.25 (m, 1H), 7.07 (m, 1H), 6.37 (t, J = 3.5 Hz, 1H), 3.13 (s, 3H)

[0246] (Synthesis of monobromo compound (14)) The dibromo compound (13) (2.45 g, 7.44 mmol) was dissolved in N,N-dimethylformamide (DMF) (simply dehydrated) (10 mL), dimethyl phosphite (2.48 mL, 29.8 mmol) and triethylamine (4.6 mL, 33.5 mmol) were added dropwise, and the mixture was stirred at room temperature for 24 hours. Then, the reaction mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography [85 g of silica gel, hexane:ethyl acetate = 4:1] to obtain the monobromo compound (14) (1.01 g, 7.28 mmol, 82%).

[0247] · Identification results of the monobromo compound (14) 1 H-NMR (500 MHz, CDCl 3 ) δ7.47 (d, J = 13.5 Hz, 1H), 6.68 (d, J = 14.0 Hz, 1H), 6.46 (m, 1H), 6.28 (t, J = 3.5 Hz, 1H), 3.12 (s, 3H)

[0248] (Synthesis of the methoxy compound (15)) The monobromo compound (14) (108 mg, 0.432 mmol), boronic acid (12) (93.8 mg), and tetrakis(triphenylphosphine)palladium(0) (16.7 mg, 0.0144 mmol) were dissolved in 1,4-dioxane (2 ml). 1M aqueous sodium carbonate solution (2 ml) was added dropwise to this mixed solution, and the mixture was heated to reflux for 1 hour. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography [hexane:ethyl acetate = 83:17 → 73:27] to obtain the methoxy compound (15) (61.8 mg, 0.167 mmol).

[0249] · Identification results of the methoxy compound (15) 1 H-NMR (500 MHz, CDCl 3) δ7.42 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 16.0 Hz, 1H), 7.20 (m, 1H), 7.00 (d, J = 9.5 Hz, 2H), 6.94 - 6.89 (m, 5H), 6.59 (m, 1H), 6.32 (t, J = 3.5 Hz, 1H), 3.82 (s, 3H), 3.12 (s, 3H)

[0250] (Synthesis of the compound represented by Structural Formula (2C)) The methoxy compound (15) (41.6 mg, 0.112 mmol) was dissolved in methanol (2 ml). To this mixed solution, 1 mL of an aqueous potassium hydroxide solution (32 mg, 0.570 mmol) was added dropwise, and the mixture was heated under reflux for 21 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (simply dehydrated) (2 ml). To this mixed solution, 1.0 M tetrabutylammonium fluoride - tetrahydrofuran solution (452 μl, 0.452 mmol) was added dropwise, and the mixture was heated under reflux for 19 hours. Distilled water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography [hexane:ethyl acetate = 83:17 → 73:27] to obtain the compound represented by Structural Formula (2C) (22.0 mg, 0.0755 mmol, 67%).

[0251] · Identification results of the compound represented by Structural Formula (2C) 1 H-NMR (500 MHz, CDCl 3 ) δ8.32 (br, 1H), 7.36 (d, J = 9.0 Hz, 2H), 6,.99 (d, J = 9.0, 2H), 6.91 - 6.85 (m, 5H), 6.81 (m, 1H), 6.63 (d, J = 16.0, 1H), 6.33 (m, 1H), 6.24 (m, 1H), 3.81 (s, 3H)

[0252] <Synthesis method of the compound represented by the structural formula (2D)> The compound represented by the structural formula (2D) was synthesized according to the following synthetic scheme.

Chemical formula

[0253] (Synthesis of amine compound (16)) p-Anisidine (463 mg, 3.76 mmol), 4-bromophenylboronic acid (1.51 g, 7.52 mmol), and copper acetate (683 mg, 3.76 mmol) were dissolved in methylene chloride (2 ml). Triethylamine (1.03 ml, 7.52 mmol) was added dropwise to this mixed solution, and the mixture was stirred at 37 °C for 22 hours under an oxygen atmosphere. The reaction mixture was filtered through celite with methylene chloride, distilled water was added to the filtrate, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel 90.0 g, hexane:ethyl acetate = 8:1 to 7:1] to obtain amine compound (16) (280 mg, 1.01 mmol, 27%).

[0254] · Identification results of amine compound (16) 1 H-NMR (500 MHz, CDCl 3 ) δ7.28 (d, 2H), 7.05 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 9.5 Hz, 2H), 6.76 (d, J = 8.5 Hz, 2H), 5.46 (br, 1H), 3.80 (s, 3H)

[0255] (Synthesis of boronic acid (17)) Amine compound (16) (150 mg, 0.539 mmol), bis(pinacolato)diboron (411 mg, 1.62 mmol), potassium acetate (159 mg, 1.62 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (22.0 mg, 0.0270 mmol) were dissolved in 1 ml of 1,4-dioxane under an argon atmosphere and heated to reflux for 19 hours. Distilled water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography [hexane:ethyl acetate = 84:16 → 76:24] to obtain boronic acid (17) (128 mg, 0.394 mmol, 73%).

[0256] · Identification results of boronic acid (17) 1 H-NMR (500 MHz, CDCl 3 ) δ7.65 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 9.5 Hz, 2H), 6.87 (d, J = 9.5 Hz, 2H), 6.84 (d, J = 9.0 Hz, 2H), 5.63 (br, 1H), 3.81 (s, 3H), 1.32 (s, 12H)

[0257] (Synthesis of methoxy compound (18)) Monobromo compound (14) (133 mg, 0.530 mmol), boronic acid (17) (144 mg, 0.442 mmol), tetrakis(triphenylphosphine)palladium(0) (25.6 mg, 0.0221 mmol) were dissolved in 1,4-dioxane (2 ml). A 1M aqueous sodium carbonate solution (2 ml) was added dropwise to this mixed solution, and the mixture was heated to reflux for 1 hour. The reaction mixture was extracted with methylene chloride, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography [hexane:ethyl acetate = 93:7 → 67:33] to obtain methoxy compound (18) (118 mg, 0.320 mmol, 72%).

[0258] · Identification result of the methoxy compound (18) 1 H-NMR (500 MHz, CDCl 3 ) δ 7.35 (d, J = 9.0, 2H), 7.31 (d, J = 16.0 Hz, 1H), 7.18 (m, 1H), 7.09 (d, J = 9.0 Hz, 2H), 6.90 - 6.86 (m, 5H), 6.55 (m, 1H), 6.30 (t, J = 3.5 Hz, 1H), 5.61 (br, 1H), 3.81 (a, 3H), 3.11 (s, 3H),

[0259] (Synthesis of the compound represented by Structural Formula (2D)) The methoxy compound (18) (118 mg, 0.320 mmol) was dissolved in tetrahydrofuran (simply dehydrated) (3 ml). To this mixed solution, 1.0 M tetrabutylammonium fluoride - tetrahydrofuran solution (1.28 ml, 1.28 mmol) was added dropwise and heated under reflux for 24 hours. 30 mL of chloroform was added to the reaction solution, and after washing with an aqueous ammonium chloride solution, the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with a small amount of chloroform to obtain the compound represented by Structural Formula (2D) (43.0 mg, 0.148 mmol, 46%).

[0260] · Identification result of the compound represented by Structural Formula (2D) 1 H-NMR (500 MHz, Acetone-d 6 ) δ10.3 (br, 1H), 7.29 (d, J = 8.5 Hz, 2H), 7.18 (br, 1H), 7.11 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 8.5 Hz, 2H), 6.90 - 6.87 (m, 3H), 6.79 - 6.76 (m, 2H), 6.20 (m, 1H), 6.08 (m, 1H), 3.77 (s, 1H)

[0261] <Anticancer test> (Test 1) The human leukemia-derived cell lines (CCRF-CEM (derived from T-ALL), Raji (derived from B lymphoma)) were cultured using RPMI-1640 Medium (Nacalai) containing 10% fetal bovine serum (Biosera), Penicillin-Streptomycin (Sigma), and 50 μM 2-mercaptoethanol (Sigma) at 37 °C - 5% CO 2 under the following conditions. In the growth inhibition assay, first, the cells were seeded into a 96-well plate at 3,000 cells / well, and each compound was added after serial dilution. After culturing for 3 days, Cell Counting Kit-8 (Dojin) was added and cultured for 4 hours, and the absorbance at 450 nm was measured using TriStar LB941 (Berthold) to comparatively quantify the number of viable cells and determine the IC50 value. The results are shown in Tables 1 to 3.

[0262] (Test 2) The compounds having the moieties of structural formulas (1a) to (1p), (1r) to (1ag), (1ai), (1aj) and the natural compound Auxarconjugatin B were examined for their cell growth inhibitory activity against human cultured cancer cells. As cancer cells, human cancer cell line 39 lines [7 lung cancer lines (NCI-H23, NCI-H226, NCI-H522, NCI-H460, A549, DMS273, DMS114), 6 gastric cancer lines (St-4, MKN1, MKN-B, MKN-A, MKN45, MKN74), 5 colorectal cancer lines (HCC2998, KM-12, HT-29, HCT-15, HCT-116), 5 ovarian cancer lines (OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8, SK-OV-3), 6 brain tumor lines (U251, SF-268, SF-295, SF-539, SNB-75, SNB-78), 5 breast cancer lines (HBC-4, BSY-1, HBC-5, MCF-7, MDA-MB-231), 2 renal cancer lines (RXF-631L, ACHN), 2 prostate cancer lines (DU-145, PC-3), and 1 melanoma line (LOX-IMVI)] were used. Each cell was seeded in a 96-well plate and cultured overnight. The next day, each serially diluted compound was added, and after culturing for 2 days, cell proliferation was measured by colorimetric quantification using sulforhodamine B. The 50% cell growth inhibitory concentration (GI50) was calculated from the cell growth curve. Here, the 50% cell growth inhibitory concentration (GI50) refers to the concentration that suppresses the increase in cell number by 50% by drug treatment when the increase in the sample cultured for 48 hours without drug treatment is set to 100% based on the number of cells before exposure to the compound (drug). In addition, for each compound, the average value (MG-MID) of log GI50 was determined. Furthermore, the difference (Delta) between the average value (MG-MID) of log GI50 and the minimum value (Best) of log GI50, and the difference (Range) between the maximum value (Worst) of log GI50 and the minimum value (Best) of log GI50 were determined. The results are shown in Table 1.

[0263] Note that in Table 1, CCRF-CEM, Raji, MG-MID, Delta, Range, and Best have the following meanings. CCRF-CEM: IC50 value for CCRF-CEM cells Raji: IC50 value for Raji cells MG-MID: Mean value of log GI50 Delta: Difference between MG-MID and Best Range: Difference between Worst and Best Best: Minimum value of log GI50

[0264] (Lipophilicity index (clogP)) For the compound represented by the general formula (2A) where R in the general formula (2A) is represented by NH or O, and the compound represented by the structural formula (3A), the lipophilicity index (clogP) was calculated using ChemBioDrawUltra 14.0.

[0265] (Reference Example 2) For reference, the following structural formula (a) described in JP 2021-138654 A (Patent Document 2): [Chemical formula] The results of Test 1 of the compound represented by the formula and the calculated value of the lipophilicity index (clogP) are shown in Table 2.

[0266] [Table 1]

[0267] [Table 2]

[0268] [Table 3]

[0269] From Tables 1, 2 and 3, it can be seen that the compounds represented by the general formula (I) have an inhibitory effect on the growth of cancer cells. In addition, the compounds represented by the general formula (I) inhibit the growth of the human T-ALL cell line CCRF-CEM at low concentrations and meet the criteria of not affecting the growth of the human B lymphoma cell line Raji at the same concentration, and it can be seen that they have the same tendency as the natural compound Auxarconjugatin B. Also, from Table 2, it can be seen that the compounds represented by the general formula (2) or the general formula (3) have low lipophilicity (high water solubility).

Industrial Applicability

[0270] The pyrrole derivative of the present invention or a pharmaceutically acceptable salt thereof can be used in a pharmaceutical composition for cancer treatment.

Claims

1. The following general formula (I): 【Chemistry 1】 [In the formula, A ａ and A ｂ are each independently a single bond, (CH=CH) ｍ Or (R ａ ) ｐ and m is an integer from 1 to 3; p is an integer from 1 to 3; R ａ are each independently CR ｂ ２ , N.R. ｂ , O, S or C=O, R ｂ are each independently H, C ｎ H ２ｎ＋１ , F, Cl, Br, or I, where each n is independently an integer from 1 to 3; X １ , X ２ , X ３ , X ４ and X ５ each independently represents CH, CR １ or N, where X １ , X ２ , X ３ , X ４ and X ５ The number of N is 0 to 2, and CR １ The number of is 0 to 3, Y １ , Y ２ , Y ３ and Y ４ each independently represents CH, CR ２ or N, where Y １ , Y ２ , Y ３ and Y ４ The number of N is 0 to 2, and CR ２ The number of is 0 to 3, R １ are each independently C ｎ H ２ｎ＋１ , C ４ H ９ , C.F. ３ , F, Cl, Br, NHAc, OH, OC ｎ H ２ｎ＋１ , OAc, CH ２ O.H., C.H. ２ O.C. ｎ H ２ｎ＋１ , C.N., C.O.N.C. ｎ H ２ｎ＋１ , CON(C ｎ H ２ｎ＋１ ) ２ , COOH, and COOC ｎ H ２ｎ＋１ where each n is independently an integer from 1 to 3, provided that A ａ (CH=CH) ｍ So, A ｂ is a single bond, and at least one R １ COOH or COOC ｎ H ２ｎ＋１ If R is at least one other １ COOH and COOC ｎ H ２ｎ＋１ and one or more R １ is OH or OC ｎ H ２ｎ＋１ In the case where R １ Two or more R １ may be bonded to each other to form a ring, R ２ are each independently C ｎ H ２ｎ＋１ , O.H., O.C. ｎ H ２ｎ＋１ , N.H. ２ , N.H.C. ｎ H ２ｎ＋１ , N(C ｎ H ２ｎ＋１ ) ２ and COOH, where each n is independently an integer from 1 to 3; R ３ is H, F, Cl or Br.

2. The following general formula (1): 【Chemistry 2】 [In the formula, X １ , X ２ , X ３ , X ４ and X ５ each independently represents CH, CR １ or N, where X １ , X ２ , X ３ , X ４ and X ５ The number of N is 0 to 2, and CR １ The number of is 0 to 3, Y １ , Y ２ , Y ３ and Y ４ each independently represents CH, CR ２ or N, where Y １ , Y ２ , Y ３ and Y ４ The number of N is 0 to 2, and CR ２ The number of is 0 to 3, m is an integer from 1 to 3; R １ are each independently C ｎ H ２ｎ＋１ , C ４ H ９ , C.F. ３ , F, Cl, Br, NHAc, OH, OC ｎ H ２ｎ＋１ , OAc, CH ２ O.H., C.H. ２ O.C. ｎ H ２ｎ＋１ , C.N., C.O.N.C. ｎ H ２ｎ＋１ , CON(C ｎ H ２ｎ＋１ ) ２ , COOH, and COOC ｎ H ２ｎ＋１ where n is independently an integer from 1 to 3, provided that at least one R １ COOH or COOC ｎ H ２ｎ＋１ If R is at least one other １ COOH and COOC ｎ H ２ｎ＋１ and one or more R １ is OH or OC ｎ H ２ｎ＋１ In the case where R １ Two or more R １ may be bonded to each other to form a ring, R ２ are each independently C ｎ H ２ｎ＋１ , O.H., O.C. ｎ H ２ｎ＋１ , N.H. ２ , N.H.C. ｎ H ２ｎ＋１ , N(C ｎ H ２ｎ＋１ ) ２ and COOH, where each n is independently an integer from 1 to 3; R ３ The pyrrole derivative according to claim 1 , wherein R is H, F, Cl or Br.

3. The pyrrole derivative according to claim 2 , wherein m is 1 or 2.

4. Y １ , Y ２ , Y ３ and Y ４ each independently represents CH or CR ２ The pyrrole derivative according to claim 2 ,

5. Y １ , Y ２ , Y ３ and Y ４ The pyrrole derivative according to claim 2, wherein is CH.

6. R ３ The pyrrole derivative according to claim 2, wherein is H or Cl.

7. The following general formula (2): 【Chemistry 3】 [In the formula, A ｂ１ are each independently (R ａ ) ｐ and p is an integer from 1 to 3; R ａ are each independently CR ｂ ２ , N.R. ｂ , O, S or C=O, R ｂ are each independently H, C ｎ H ２ｎ＋１ , F, Cl, Br, or I, where each n is independently an integer from 1 to 3; X １ , X ２ , X ３ , X ４ and X ５ each independently represents CH, CR １ or N, where X １ , X ２ , X ３ , X ４ and X ５ The number of N is 0 to 2, and CR １ The number of is 0 to 3, Y １ , Y ２ , Y ３ and Y ４ each independently represents CH, CR ２ or N, where Y １ , Y ２ , Y ３ and Y ４ The number of N is 0 to 2, and CR ２ The number of is 0 to 3, m is an integer from 1 to 3; R １ are each independently C ｎ H ２ｎ＋１ , C ４ H ９ , C.F. ３ , F, Cl, Br, NHAc, OH, OC ｎ H ２ｎ＋１ , OAc, CH ２ O.H., C.H. ２ O.C. ｎ H ２ｎ＋１ , C.N., C.O.N.C. ｎ H ２ｎ＋１ , CON(C ｎ H ２ｎ＋１ ) ２ , COOH, and COOC ｎ H ２ｎ＋１ where n is each independently an integer from 1 to 3, provided that one or more R １ is OH or OC ｎ H ２ｎ＋１ In the case where R １ Two or more R １ may be bonded to each other to form a ring, R ２ are each independently C ｎ H ２ｎ＋１ , O.H., O.C. ｎ H ２ｎ＋１ , N.H. ２ , N.H.C. ｎ H ２ｎ＋１ , N(C ｎ H ２ｎ＋１ ) ２ and COOH, where each n is independently an integer from 1 to 3; R ３ The pyrrole derivative according to claim 1 , wherein R is H, F, Cl or Br.

8. The pyrrole derivative according to claim 7 , wherein m is 1.

9. A ｂ１ NH, O, CH ２ -NH or CH ２ The pyrrole derivative according to claim 7, wherein the aryl group is —O.

10. Y １ , Y ２ , Y ３ and Y ４ The pyrrole derivative according to claim 7, wherein is CH.

11. The following general formula (3): 【Chemistry 4】 [In the formula, A ａ１ are each independently (R ａ ) ｐ and p is an integer from 1 to 3; R ａ are each independently CR ｂ ２ , N.R. ｂ , O, S or C=O, R ｂ are each independently H, C ｎ H ２ｎ＋１ , F, Cl, Br, or I, where each n is independently an integer from 1 to 3; X １ , X ２ , X ３ , X ４ and X ５ each independently represents CH, CR １ or N, where X １ , X ２ , X ３ , X ４ and X ５ The number of N is 0 to 2, and CR １ The number of is 0 to 3, Y １ , Y ２ , Y ３ and Y ４ each independently represents CH, CR ２ or N, where Y １ , Y ２ , Y ３ and Y ４ The number of N is 0 to 2, and CR ２ The number of is 0 to 3, R １ are each independently C ｎ H ２ｎ＋１ , C ４ H ９ , C.F. ３ , F, Cl, Br, NHAc, OH, OC ｎ H ２ｎ＋１ , OAc, CH ２ O.H., C.H. ２ O.C. ｎ H ２ｎ＋１ , C.N., C.O.N.C. ｎ H ２ｎ＋１ , CON(C ｎ H ２ｎ＋１ ) ２ , COOH, and COOC ｎ H ２ｎ＋１ where n is each independently an integer from 1 to 3, provided that one or more R １ is OH or OC ｎ H ２ｎ＋１ In the case where R １ Two or more R １ may be bonded to each other to form a ring, R ２ are each independently C ｎ H ２ｎ＋１ , O.H., O.C. ｎ H ２ｎ＋１ , N.H. ２ , N.H.C. ｎ H ２ｎ＋１ , N(C ｎ H ２ｎ＋１ ) ２ and COOH, where each n is independently an integer from 1 to 3; R ３ The pyrrole derivative according to claim 1 , wherein:

12. A ａ１ But, CH ２ The pyrrole derivative according to claim 11, which is -NH.

13. Y １ , Y ２ , Y ３ and Y ４ The pyrrole derivative according to claim 11, wherein is CH.

14. A pharmaceutical composition for cancer treatment, comprising the pyrrole derivative or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 13.

15. The pharmaceutical composition for cancer treatment according to claim 14, which is used to treat a cancer selected from leukemia, breast cancer, brain tumor, colon cancer, lung cancer, melanoma, ovarian cancer, renal cancer, gastric cancer, and prostate cancer.

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