KR101736387B1 - Thienopyridone derivative, method for preparing the same and pharmaceutical composition comprising the same - Google Patents

Thienopyridone derivative, method for preparing the same and pharmaceutical composition comprising the same Download PDF

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KR101736387B1
KR101736387B1 KR1020150190106A KR20150190106A KR101736387B1 KR 101736387 B1 KR101736387 B1 KR 101736387B1 KR 1020150190106 A KR1020150190106 A KR 1020150190106A KR 20150190106 A KR20150190106 A KR 20150190106A KR 101736387 B1 KR101736387 B1 KR 101736387B1
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formula
compound
nmr
aryl
rti
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이종석
박솔
이희승
신희재
이연주
이지훈
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한국해양과학기술원
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

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Abstract

The present invention relates to a thienopyridone derivative, a process for preparing the same, and a pharmaceutical composition containing the same, and more particularly, to a novel thienopyridone derivative containing various substituents and a process for producing the same, To a pharmaceutical composition for preventing or treating cancer.

Description

[0001] The present invention relates to a thienopyridone derivative, a method for preparing the same, and a pharmaceutical composition comprising the thienopyridone derivative,

The present invention relates to a thienopyridone derivative, a process for preparing the same, and a pharmaceutical composition containing the same, and more particularly, to a novel thienopyridone derivative containing various substituents and a process for producing the same, To a pharmaceutical composition for preventing or treating cancer.

Cancer is defined as "uncontrolled cell growth." These abnormal cell growths form a mass of cells called tumors that penetrate into surrounding tissues and, in severe cases, to other organs of the body.

Cancer is an intractable chronic disease that, even if treated with surgery, radiation, and chemotherapy, in many cases can not be cured, causes pain to the patient, and ultimately leads to death. More than 20 million people worldwide suffer from cancer, more than six million people die each year from cancer, and by 2020, 11 million people are expected to die of cancer, so cancer is urgently needed to find the cure Disease. Although cancer varies from country to country, it accounts for more than 20% of the total deaths in developed countries or Korea. However, despite many efforts, the precise cause and mechanism of cancer development is still unknown. There are many factors that cause cancer, but they are divided into internal factors and external factors. It is not known exactly how the normal cells transform into cancer cells through the mechanism, but at least 80-90% of them are known to be affected by external factors such as environmental factors. Internal factors include genetic factors, immunological factors, and external factors include chemicals, radiation, and viruses.

Cancer is widely classified into blood cancer and solid cancer, and it occurs in almost all parts of the body such as lung cancer, stomach cancer, breast cancer, oral cancer, liver cancer, uterine cancer, esophageal cancer and skin cancer. Among the methods used to treat these malignant tumors, chemotherapeutic agents other than surgery or radiation therapy are collectively referred to as anticancer agents, and most of them exhibit anticancer activity by inhibiting the synthesis of hexane.

On the other hand, aromatic heterocyclic compounds are one of the main chemical skeletons having a wide range of applications in chemical biology and medicinal chemistry research. Among them, 6-membered ring nitrogen hetero ring including pyridine, pyridine, pyrimidine, piperidine, piperazine and the like are often used as the main research theme in the development of new drugs because they exhibit pharmacological properties. In particular, 2-pyridone can act as a peptidomimetic skeleton due to the presence of an amide functional group in the 6-membered ring ring and can be used as a main chemical skeleton of various natural products showing antibacterial, antibacterial, antiinflammatory, antiviral, anti- It is one. In the current clinical trials, milrinone and amrinone, antibiotics pilicides and curlicides for the treatment of gram-negative bacterial infections, and perampanel, which shows applicability as a therapeutic agent for Parkinson's disease, include the 2-pyridone structure as a basic skeleton As can be seen, 2-pyridone is one of the major pharmacophore. In addition to its physiological activity, 2-pyridone is used in the manufacture of paints, pigments, fuel and lubricant additives, acid-base indicators, polymers and paint stabilizers. This study is concerned with the development of the 2-pyridone synthesis method which can be applied to various substrates in a different approach from the synthesis method reported so far and which facilitates the introduction of various substituents.

Recently, various pyridones have been developed. In particular, Korean Patent Registration No. 10-2010-0137563 discloses a compound of the formula (I) (see the publication): its pharmaceutical composition, its use in the treatment and / or prevention of diseases and disorders regulated by AMP agonists, , And Korean Patent Publication No. 10-2007-0047237 discloses a 5-HT receptor agonist and a partial agonist, which is a novel thienopyridine represented by the formula (I) Dinon compounds, and their synthesis and use for the treatment of diseases directly or indirectly mediated by 5-HT receptors.

Conventional methods for preparing thienopyridone derivatives are difficult to apply to various substrates and have difficulty in introducing various substituents. Thus, the present invention enables the introduction of various substituents into thienopyridone as a new approach to the preparation of the process.

In one embodiment of the invention,

The present invention provides a compound of formula 1, an enantiomer or diastereomer thereof, or a pharmaceutically acceptable acid or base addition salt thereof.

[Chemical Formula 1]

Figure 112015128997815-pat00001

In this formula,

R is H;

Linear or branched C 1 -C 10 alkyl; or

A linear or branched C 1 -C 10 alkyl, an amine, a 5 or 6 membered aromatic or unoriented heterocyclic amine containing 1 or 2 N, F 3 CO-, C 6 -C 10 aryl and C C 6 -C 10 aryl which is substituted or unsubstituted, at least one, selected from the group consisting of alkoxy of 1 - C 4 .

In one embodiment of the invention,

Group wherein R is consisting of an alkoxy amine, N one or with two 5-or 6-aromatic or non-aromatic heterocyclic amines of the circle, F 3 CO-, C 6 -C 10 aryl and C 1 -C 4 in the with at least one selected from the redundant enable a substituted or unsubstituted C 6 -C 10 aryl; it may be a.

In one embodiment of the invention,

The compound

One)

Figure 112015128997815-pat00002
;

2)

Figure 112015128997815-pat00003
;

3)

Figure 112015128997815-pat00004
;

4)

Figure 112015128997815-pat00005
;

5)

Figure 112015128997815-pat00006
;

6)

Figure 112015128997815-pat00007
;

7)

Figure 112015128997815-pat00008
; And

8)

Figure 112015128997815-pat00009
;

≪ / RTI >

In another embodiment of the present invention,

The present invention provides a compound of formula 2, an enantiomer or diastereomer thereof, or a pharmaceutically acceptable acid or base thereof.

(2)

Figure 112015128997815-pat00010

In this formula,

R is H;

Linear or branched C 1 -C 10 alkyl; or

A linear or branched C 1 -C 10 alkyl, an amine, a 5 or 6 membered aromatic or unoriented heterocyclic amine containing 1 or 2 N, F 3 CO-, C 6 -C 10 aryl and C C 6 -C 10 aryl which is substituted or unsubstituted, at least one, selected from the group consisting of alkoxy of 1 - C 4 .

In one embodiment of the invention,

Group wherein R is consisting of an alkoxy amine, N one or with two 5-or 6-aromatic or non-aromatic heterocyclic amines of the circle, F 3 CO-, C 6 -C 10 aryl and C 1 -C 4 in the with at least one selected from the redundant enable a substituted or unsubstituted C 6 -C 10 aryl; it may be a.

In one embodiment of the invention,

The compound

One)

Figure 112015128997815-pat00011
;

2)

Figure 112015128997815-pat00012
;

3)

Figure 112015128997815-pat00013
;

4)

Figure 112015128997815-pat00014
;

5)

Figure 112015128997815-pat00015
;

6)

Figure 112015128997815-pat00016
; And

7)

Figure 112015128997815-pat00017
;

≪ / RTI >

In another embodiment of the present invention,

Or a pharmaceutically acceptable acid or base thereof, wherein R < 1 >, R < 2 >, R < 3 >, R < 3 >

(3)

Figure 112015128997815-pat00018

In another embodiment of the present invention,

There is provided a process for preparing a compound represented by the following general formula (1).

[Reaction Scheme 1]

Figure 112015128997815-pat00019

In this formula,

R is H;

Linear or branched C 1 -C 10 alkyl; or

A linear or branched C 1 -C 10 alkyl, an amine, a 5 or 6 membered aromatic or unoriented heterocyclic amine containing 1 or 2 N, F 3 CO-, C 6 -C 10 aryl and C C 6 -C 10 aryl which is substituted or unsubstituted, at least one, selected from the group consisting of alkoxy of 1 - C 4 .

In one embodiment of the invention,

Group wherein R is consisting of an alkoxy amine, N one or with two 5-or 6-aromatic or non-aromatic heterocyclic amines of the circle, F 3 CO-, C 6 -C 10 aryl and C 1 -C 4 in the with at least one selected from the redundant enable a substituted or unsubstituted C 6 -C 10 aryl; it may be a.

In one embodiment of the invention,

The R

Figure 112015128997815-pat00020
,
Figure 112015128997815-pat00021
,
Figure 112015128997815-pat00022
,
Figure 112015128997815-pat00023
,
Figure 112015128997815-pat00024
,
Figure 112015128997815-pat00025
,
Figure 112015128997815-pat00026
or
Figure 112015128997815-pat00027
Lt; / RTI >

In one embodiment of the invention,

The compound of Formula 1-1 may be prepared by the following Reaction Scheme 1-1.

[Reaction Scheme 1-1]

Figure 112015128997815-pat00028

In another embodiment of the present invention,

(2), which is represented by the following Reaction Scheme 2: " (2) "

[Reaction Scheme 2]

Figure 112015128997815-pat00029

In this formula,

R is H;

Linear or branched C 1 -C 10 alkyl; or

A linear or branched C 1 -C 10 alkyl, an amine, a 5 or 6 membered aromatic or unoriented heterocyclic amine containing 1 or 2 N, F 3 CO-, C 6 -C 10 aryl and C C 6 -C 10 aryl which is substituted or unsubstituted, at least one, selected from the group consisting of alkoxy of 1 - C 4 .

In one embodiment of the invention,

Group wherein R is consisting of an alkoxy amine, N one or with two 5-or 6-aromatic or non-aromatic heterocyclic amines of the circle, F 3 CO-, C 6 -C 10 aryl and C 1 -C 4 in the with at least one selected from the redundant enable a substituted or unsubstituted C 6 -C 10 aryl; it may be a.

In one embodiment of the invention,

The R

Figure 112015128997815-pat00030
,
Figure 112015128997815-pat00031
,
Figure 112015128997815-pat00032
,
Figure 112015128997815-pat00033
,
Figure 112015128997815-pat00034
,
Figure 112015128997815-pat00035
or
Figure 112015128997815-pat00036
Lt; / RTI >

In another embodiment of the present invention,

(3), which is represented by the following Reaction Scheme (3).

[Reaction Scheme 3]

Figure 112015128997815-pat00037

In another embodiment of the present invention,

There is provided a pharmaceutical composition for preventing or treating cancer comprising as an active ingredient, the above compound, an enantiomer or diastereomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base.

The thienopyridone derivative of the present invention has a preventive and therapeutic effect on cancer, and its preparation method can introduce various aromatic rings into thienopyridone, and thus a novel thienopyridone derivative containing various substituents can be prepared can do.

Figure 1 shows a 1 H NMR graph of the chemical formula 1-1-2.
Fig. 2 shows a 13 C NMR graph of the chemical formula 1-1-2.
3 shows a 1 H NMR graph of the chemical formula 1-1-3.
4 shows a 13 C NMR graph of the chemical formula 1-1-3.
5 shows a 1 H NMR graph of the chemical formula 1-1.
6 shows a 13 C NMR graph of the chemical formula 1-1.
FIG. 7 is a graph showing the effect of the chemical formula 1-2

Figure 112015128997815-pat00038
It shows a graph of a 1 H NMR).
Figure 8 shows the chemical formula 1-2 (R)
Figure 112015128997815-pat00039
) ≪ 13 > C NMR graph.
Figure 9 shows the chemical formula 1-3 (R)
Figure 112015128997815-pat00040
It shows a graph of a 1 H NMR).
Figure 10 shows the chemical formula 1-3 (R)
Figure 112015128997815-pat00041
) ≪ 13 > C NMR graph.
Figure 11 shows the chemical formula (R)
Figure 112015128997815-pat00042
It shows a graph of a 1 H NMR).
Figure 12 shows the chemical formula (R < 1 >) (R &
Figure 112015128997815-pat00043
) ≪ 13 > C NMR graph.
FIG. 13 shows a comparison of the chemical formula 1-2
Figure 112015128997815-pat00044
It shows a graph of a 1 H NMR).
FIG. 14 shows a comparison of the chemical formula 1-2
Figure 112015128997815-pat00045
) ≪ 13 > C NMR graph.
FIG. 15 shows the chemical formula 1-3
Figure 112015128997815-pat00046
It shows a graph of a 1 H NMR).
FIG. 16 shows a comparison of the chemical formula 1-3
Figure 112015128997815-pat00047
) ≪ 13 > C NMR graph.
FIG. 17 shows a comparison of the chemical formula 1 (R =
Figure 112015128997815-pat00048
It shows a graph of a 1 H NMR).
Figure 18 shows the chemical formula 1 (R < RTI ID = 0.0 >
Figure 112015128997815-pat00049
) ≪ 13 > C NMR graph.
Fig.
Figure 112015128997815-pat00050
) ≪ / RTI > is the 1 H NMR graph of the chemistry of < RTI ID =
Fig.
Figure 112015128997815-pat00051
) ≪ 13 >
FIG.
Figure 112015128997815-pat00052
) ≪ / RTI > is the 1 H NMR graph of the chemistry of < RTI ID =
Fig. 22 is a schematic diagram showing the general formula (I)
Figure 112015128997815-pat00053
) ≪ 13 >
23 is a diagrammatic representation of a compound of formula
Figure 112015128997815-pat00054
) ≪ / RTI > is the 1 H NMR graph of the chemistry of < RTI ID =
Fig.
Figure 112015128997815-pat00055
) ≪ 13 >
25 shows a comparison of the chemical formula 2 (R =
Figure 112015128997815-pat00056
It shows a graph of a 1 H NMR).
Figure 26 shows a comparison of the chemical formula 2 (R < RTI ID = 0.0 >
Figure 112015128997815-pat00057
) ≪ 13 > C NMR graph.
27 shows a comparison of the chemical formula 2
Figure 112015128997815-pat00058
It shows a graph of a 1 H NMR).
28 shows the chemical formula (2) wherein R < RTI ID = 0.0 >
Figure 112015128997815-pat00059
) ≪ 13 > C NMR graph.
29 shows the chemical formula (R)
Figure 112015128997815-pat00060
It shows a graph of a 1 H NMR).
Figure 30 shows the chemical formula 2 (R < RTI ID = 0.0 >
Figure 112015128997815-pat00061
) ≪ 13 > C NMR graph.
31 shows a 1 H NMR graph of the chemical formula (3).
32 shows a 13 C NMR graph of the chemical formula (3).

Hereinafter, embodiments of the present invention will be described. However, the embodiments of the present invention can be modified into various other forms, and the scope of the present invention is not limited to the embodiments described below.

The term "linear alkyl" as used herein refers to straight chain alkyl having an alkyl chain length in a range of numbers. In an exemplary embodiment, the "alkyl" is 1, 2, 3, 4, 5, 6, 7, 8, 9, or containing a 10 carbon alkyl chain as defined above (i.e., C 1 -C 10 alkyl ). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl and the like.

The term "branched alkyl" as used herein refers to an alkyl chain in which branching points are present in the chain and the total number of carbon atoms in the chain is in a range of numbers. In an exemplary embodiment, "branched alkyl" refers to an alkyl chain as defined above containing 3, 4, 5, 6, 7, 8, 9 or 10 carbons (ie, branched C 3 -C 10 alkyl ). Examples of branched alkyl groups include, but are not limited to, iso-propyl, iso-butyl, sec-butyl and tert-butyl.

The term "alkoxy" as used herein refers to -O- (alkyl), wherein "alkyl" is as defined above.

The term " aryl ", as used herein, refers to cyclic hydrocarbons that characterize the non-stationary π electrons (aromatic) in which the ring is shared among the rings and represent the number of ring atoms in a range of numbers. In an exemplary embodiment, "aryl" refers to a cyclic hydrocarbon (i.e., C 6 -C 10 aryl) as described above containing 6, 7, 8, 9 or 10 ring atoms. Examples of the aryl group include, but are not limited to, benzene, naphthalene, tetralin, indene, and indane.

The term " heterocyclic amine ", as used herein, refers to cyclic amines in which one or two of the ring atoms are N and the number of ring atoms is in a range of numbers and refers to aromatic or non-aromatic amine. In an exemplary embodiment, "heterocyclic amine" refers to a cyclic amine (i. E., A 5 or 6 membered heterocyclic amine) as described above containing 5 or 6 ring atoms. Examples of heterocyclic amine groups include, but are not limited to, pyrrole, pyrazole, imidazole, pyridine, pyridazine, pyrimidine, piperidine and pyrrolidine.

The term "salt" as used herein embraces pharmaceutically acceptable salts which are commonly used to form alkali metal salts of free acids and to form addition salts of free bases. The nature of the salt is not critical as long as it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Exemplary pharmaceutical salts are described in Stahl, P. H., Wermuth, C. G., Eds. Handbook of Pharmaceutical Salts: Properties, Selection and Use; Verlag Helvetica Chimica Acta / Wiley-VCH: Zurich, 2002]. Specific non-limiting examples of inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid and phosphoric acid. Suitable organic acids include, without limitation, aliphatic, cycloaliphatic, aromatic, arylaliphatic, and heterocyclyl containing carboxylic and sulfonic acids, such as formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, But are not limited to, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesyl acid, stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, Methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, algenic acid, 3-hydroxybutyric acid, galactaric acid or galacturonic acid do. Suitable pharmaceutically acceptable salts of the free acid-containing compounds disclosed herein include, without limitation, metal salts and organic salts. Exemplary metal salts include, but are not limited to, suitable alkali metal (Ia family) salts, alkaline earth metal (IIa family) salts, and other physiologically acceptable metals. Such salts may be prepared from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Exemplary organic salts include, but are not limited to, primary amines, secondary amines, tertiary amines and quaternary ammonium salts such as tromethamine, diethylamine, tetra-N-methylammonium, N, Chloropropane, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.

Structural, chemical and stereochemical definitions are described in IUPAC Recommendations, more specifically in Physical Organic Chemistry (IUPAC Recommendations 1994) as summarized by Mueller, P. Pure Appl. Chem. 1994, 66, pp. 1077-1184 and Basic Terminology of Stereochemistry (IUPAC Recommendations 1996) as summarized by Moss, G.P. Pure

Appl. Chem. 1996, 68, pp. 2193-2222]. ≪ / RTI >

Enantiomers are defined as one of a pair of non-overlapping molecular entities that are mirror images of each other.

A diastereomer is defined as a stereoisomer that is not an enantiomer. A diastereomer is a stereoisomer that is not associated with an enantiomer. The diastereomers are characterized by differences in physical properties and some differences in chemical behavior for chiral reagents as well as for vikirals.

The present invention

The present invention provides a compound of formula 1, an enantiomer or diastereomer thereof, or a pharmaceutically acceptable acid or base addition salt thereof.

[Chemical Formula 1]

Figure 112015128997815-pat00062

In this formula,

R is H;

Linear or branched C 1 -C 10 alkyl; or

A linear or branched C 1 -C 10 alkyl, an amine, a 5 or 6 membered aromatic or unoriented heterocyclic amine containing 1 or 2 N, F 3 CO-, C 6 -C 10 aryl and C C 6 -C 10 aryl which is substituted or unsubstituted, at least one, selected from the group consisting of alkoxy of 1 - C 4 .

In one embodiment of the invention,

Group wherein R is consisting of an alkoxy amine, N one or with two 5-or 6-aromatic or non-aromatic heterocyclic amines of the circle, F 3 CO-, C 6 -C 10 aryl and C 1 -C 4 in the with at least one selected from the redundant enable a substituted or unsubstituted C 6 -C 10 aryl; it may be a.

In one embodiment of the invention,

The compound

One)

Figure 112015128997815-pat00063
;

2)

Figure 112015128997815-pat00064
;

3)

Figure 112015128997815-pat00065
;

4)

Figure 112015128997815-pat00066
;

5)

Figure 112015128997815-pat00067
;

6)

Figure 112015128997815-pat00068
;

7)

Figure 112015128997815-pat00069
; And

8)

Figure 112015128997815-pat00070
;

≪ / RTI >

The present invention

The present invention provides a compound of formula 2, an enantiomer or diastereomer thereof, or a pharmaceutically acceptable acid or base thereof.

(2)

Figure 112015128997815-pat00071

In this formula,

R is H;

Linear or branched C 1 -C 10 alkyl; or

A linear or branched C 1 -C 10 alkyl, an amine, a 5 or 6 membered aromatic or unoriented heterocyclic amine containing 1 or 2 N, F 3 CO-, C 6 -C 10 aryl and C C 6 -C 10 aryl which is substituted or unsubstituted, at least one, selected from the group consisting of alkoxy of 1 - C 4 .

In one embodiment of the invention,

Group wherein R is consisting of an alkoxy amine, N one or with two 5-or 6-aromatic or non-aromatic heterocyclic amines of the circle, F 3 CO-, C 6 -C 10 aryl and C 1 -C 4 in the with at least one selected from the redundant enable a substituted or unsubstituted C 6 -C 10 aryl; it may be a.

In one embodiment of the invention,

The compound

One)

Figure 112015128997815-pat00072
;

2)

Figure 112015128997815-pat00073
;

3)

Figure 112015128997815-pat00074
;

4)

Figure 112015128997815-pat00075
;

5)

Figure 112015128997815-pat00076
;

6)

Figure 112015128997815-pat00077
; And

7)

Figure 112015128997815-pat00078
;

≪ / RTI >

The present invention

Or a pharmaceutically acceptable acid or base thereof, wherein R < 1 >, R < 2 >, R < 3 >, R < 3 >

(3)

Figure 112015128997815-pat00079

The present invention

There is provided a process for preparing a compound represented by the following general formula (1).

[Reaction Scheme 1]

Figure 112015128997815-pat00080

In this formula,

R is H;

Linear or branched C 1 -C 10 alkyl; or

A linear or branched C 1 -C 10 alkyl, an amine, a 5 or 6 membered aromatic or unoriented heterocyclic amine containing 1 or 2 N, F 3 CO-, C 6 -C 10 aryl and C C 6 -C 10 aryl which is substituted or unsubstituted, at least one, selected from the group consisting of alkoxy of 1 - C 4 .

In one embodiment of the invention,

Group wherein R is consisting of an alkoxy amine, N one or with two 5-or 6-aromatic or non-aromatic heterocyclic amines of the circle, F 3 CO-, C 6 -C 10 aryl and C 1 -C 4 in the with at least one selected from the redundant enable a substituted or unsubstituted C 6 -C 10 aryl; it may be a.

In one embodiment of the invention,

The R

Figure 112015128997815-pat00081
,
Figure 112015128997815-pat00082
,
Figure 112015128997815-pat00083
,
Figure 112015128997815-pat00084
,
Figure 112015128997815-pat00085
,
Figure 112015128997815-pat00086
,
Figure 112015128997815-pat00087
or
Figure 112015128997815-pat00088
Lt; / RTI >

Hereinafter, the production method will be described in more detail.

The dried toluene solution dissolving a compound of formula 1-1, which is dissolved in EtOH and Na 2 CO 3 dissolved in H 2 O N, N -diethyl- 4- (4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl) aniline and tetrakis (triphenylphosphine) palladium (0) are sequentially added. When the reaction is completed, the reaction mixture is cooled and then extracted with distilled water and extracted with EtOAc to obtain the compound of Formula 1-2.

After the compound of formula (1-2) and mono-methyl fumarate are dissolved in DMF, benzotriazol-1-yloxy tris (dimethylamino) phosphonium hexafluorophosphate and N , N- diisopropylethylamine are added dropwise and stirred at room temperature. . LiCl is added and extracted with EtOAc to prepare the compound of Formula 1-3.

The compound of formula 1-3 is dissolved in dried DMF, potassium carbonate is added dropwise, stirred at room temperature and the reaction is completed. LiCl is added and extracted with EtOAc to give the compound of formula (1).

In one embodiment of the invention,

The compound of Formula 1-1 may be prepared by the following Reaction Scheme 1-1.

[Reaction Scheme 1-1]

Figure 112015128997815-pat00089

Hereinafter, the production method will be described in more detail.

The compound of Formula 1-1-1 is mixed with phenyltrimethylammonium tribromide and calcium carbonate in Dried EtOAc, MeOH and stirred to prepare the compound of Formula 1-1-2.

After dissolving the compound of formula 1-1-2 in ethanol, KOH was added dropwise, the mixture was heated at 100 to 150 ° C, stirred for 2 to 7 hours, adjusted to pH 3 to 6 using HCl, ≪ / RTI >

After the compound of formula (1-1-3) is dissolved in dried EtOAc, MeOH, silica gel is added and the mixture is heated to 50 to 90 ° C and stirred for 1 to 3 days to prepare a compound of formula (1-1).

The present invention

(2), which is represented by the following Reaction Scheme 2: " (2) "

[Reaction Scheme 2]

Figure 112015128997815-pat00090

In this formula,

R is H;

Linear or branched C 1 -C 10 alkyl; or

A linear or branched C 1 -C 10 alkyl, an amine, a 5 or 6 membered aromatic or unoriented heterocyclic amine containing 1 or 2 N, F 3 CO-, C 6 -C 10 aryl and C C 6 -C 10 aryl which is substituted or unsubstituted, at least one, selected from the group consisting of alkoxy of 1 - C 4 .

In one embodiment of the invention,

Group wherein R is consisting of an alkoxy amine, N one or with two 5-or 6-aromatic or non-aromatic heterocyclic amines of the circle, F 3 CO-, C 6 -C 10 aryl and C 1 -C 4 in the with at least one selected from the redundant enable a substituted or unsubstituted C 6 -C 10 aryl; it may be a.

In one embodiment of the invention,

The R

Figure 112015128997815-pat00091
,
Figure 112015128997815-pat00092
,
Figure 112015128997815-pat00093
,
Figure 112015128997815-pat00094
,
Figure 112015128997815-pat00095
,
Figure 112015128997815-pat00096
or
Figure 112015128997815-pat00097
Lt; / RTI >

Hereinafter, the production method will be described in more detail.

After dissolving the compound of formula (1) in dried DMF, the potassium carbonate and the iodomethane are added dropwise. When the reaction is completed, aq. LiCl is added and extracted with EtOAc to give the compound of formula (2).

The present invention

(3), which is represented by the following Reaction Scheme (3).

[Reaction Scheme 3]

Figure 112015128997815-pat00098

Hereinafter, the production method will be described in more detail.

After the compound of formula (2-1) is dissolved in dried DMF, potassium carbonate and an iodomethane are added dropwise. When the reaction is completed, aq. LiCl is added and extracted with EtOAc to give the compound of formula (3).

The present invention

There is provided a pharmaceutical composition for preventing or treating cancer comprising as an active ingredient, the above compound, an enantiomer or diastereomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base.

Hereinafter, preferred embodiments and the like are provided to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the examples.

Example 1. Compound of formula 1 (wherein R is

Figure 112015128997815-pat00099
)

Example 1-1. Preparation of Compound of Formula 1-1-2

After dissolving the compound of formula 1-1-1 (15.72 g, 0.1 mol, 1.0 equiv.) In dry DCM (150 mL) and MeOH (150 mL), phenyltrimethylammonium tribromide (112.78 g, 0.3 mol, 3 equiv.) and calcium carbonate (40.04 g, 0.4 mol, 4 equiv.) were added dropwise and the mixture was stirred at room temperature for 24 hours. When the reaction was complete, it was filtered and washed with EtOAc. The filtrate was dried over anhydrous Na 2 SO 4 , filtered, concentrated under reduced pressure and flash column chromatography to obtain the compound of formula 1-1-2 (Yield: 57%, 1 H NMR (500 MHz, CDCl 3 ) 隆 7 .26 (s, 1H), 5.59 (bs, 2H), 3.81 (s, 3H); 13 C NMR (125MHz, CDCl 3) δ164.1, 150.4, 128.1, 102.5, 100.4, 51.6; GC-MS m / z 238 (MH + ), 1 H NMR and 13 C NMR graphs are shown in Figures 1 and 2, respectively).

Figure 112015128997815-pat00100

Examples 1-2. Preparation of Compound of Formula 1-1-3

After dissolving the compound of Formula 1-1-2 (2.36 g, 10 mmol, 1.0 equiv.) In EtOH (10 mL), 1N aq KOH (2.80 g, 50 mmol, 5.0 equiv.) Was added dropwise, The mixture was heated and stirred for 5 hours. When the reaction was complete, the reaction mixture was cooled to 0 ° C and adjusted to pH 5 with 1N HCl. The filtered solid was washed with water and dissolved with acetone, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain a compound of formula 1-1-3 (Yield: 84%, 1 H NMR (CD 3 ) 2 CO)? 7.67 (s, 1H), 6.15 (bs, 2H); 13 C NMR (125 MHz, (CD 3 ) 2 CO)? 165.1, 152.0, 129.5, 102.7, m / z 224 (MH + ), 1 H NMR and 13 C NMR graphs are shown in Figures 3 and 4, respectively).

Figure 112015128997815-pat00101

Examples 1-3. Preparation of the compound of formula (1-1)

After dissolving the compound of Formula 1-1-3 (1.11 g, 5 mmol, 1 equiv.) In dry EtOAc (25 mL) and MeOH (25 mL), silica gel (3.33 g, 300% w / w) The mixture was heated to 70 DEG C and stirred for 2 days. When the reaction was completed, the silica gel was filtered off and the filtrate was dried over anhydrous Na 2 SO 4 , filtered, concentrated under reduced pressure, and subjected to silica column chromatography to obtain the compound of formula 1-1 ( 1 H NMR (500 MHz, CDCl 3 ) 隆 7.11 J = 3.0 Hz), 6.19 (d, 1H, J = 2.5 Hz), 3.50 (bs, 2H); 13 C NMR (125 MHz, CDCl 3 )? 142.5, 122.2, 104.3, 99.4; GC-MS m / z 180 (MH + ), 1 H NMR and 13 C NMR graphs are shown in Figures 5 and 6, respectively).

Figure 112015128997815-pat00102

Examples 1-4. Compounds of formula 1-2, wherein R is

Figure 112015128997815-pat00103
)

20.5 mmol) of Na 2 CO 3 (16.59 g, 20 mmol) dissolved in H 2 O (50 mL) was added to dried toluene (100 mL) having the compound of the formula 1-1 (3.561 g, 20 mmol, 1 equiv. 1 equiv.) And N , N- diethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (11.00 g, 40 mmol, 2 equiv.) And tetrakis (triphenylphosphine) palladium (0) (0.924 g, 0.80 mmol, 0.04 equiv.) Were sequentially added. After the reaction was completed, the reaction solution was cooled at room temperature and then extracted with EtOAc using distilled water. The organic layer was dried over anhydrous Na 2 SO 4 , filtered, concentrated under reduced pressure and flash column chromatography to obtain the compound of formula 1-2

Figure 112015128997815-pat00104
) To give (1 H NMR (500MHz, CDCl 3) δ 7.35 (d, 2H, J = 8.8 Hz), 7.00 (d, 1H, J = 3.5 Hz), 6.74 (d, 2H, J = 8.8 Hz), 6.22 (d, 1H, J = 3.5 Hz), 3.68 (bs, 2H), 3.40 (q, 4H, J = 7.0 Hz), 1.21 (t, 6H, J = 7.0 Hz); 13 C NMR (125MHz, CDCl 3) δ 147.1, 143.2, 135.1 , 129.3, 122.5, 120.9, 111.8, 100.0, 44.4, 12.7; Figs. 7 and 8 GC-MS m / z 247 (MH +), 1 H NMR and 13, the C NMR graph respectively Lt; / RTI >

Figure 112015128997815-pat00105

Wherein R is

Figure 112015128997815-pat00106
to be.

Examples 1-5. Compounds of formula 1-3, wherein R is

Figure 112015128997815-pat00107
) Preparation of

Dried DMF (10 mL) was added to a solution of a compound of formula 1-2

Figure 112015128997815-pat00108
) (246 mg, 1 mmol, 1 equiv.) And mono-methyl fumarate (130 mg, 1 mmol, 1 equiv.) Were dissolved. (Benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate was added dropwise (531 mg, 1.2 mmol, 1.2 equiv.) And N, N -diisopropylethylamine (0.44 mL, 2.5 mmol, 2.5 equiv.), Was stirred at room temperature . When the reaction is complete, aq. LiCl was added and extracted with EtOAc. The organic layer was separated and washed with brine dried, filtered over anhydrous Na 2 SO 4, concentrated under reduced pressure to flash column chromatography to afford the compound (of formula R 1-3
Figure 112015128997815-pat00109
) To give (1 H NMR (500MHz, CDCl 3) δ 7.47 (bs, 1H), 7.15 (d, 2H, J = 8.5 Hz), 6.98 (s, 1H), 6.68 (d, 2H, J = 8.5 Hz ), 4.06 (t, 1H, J = 7.3 Hz), 3.77 (s, 3H), 3.36 (q, 4H, 7.0 Hz), 3.03 (dd, 1H, J = 16.3, 7.8 Hz), 2.93 (dd, 1H J = 16.8, 6.8 Hz), 1.16 (t, 6H, J = 7.0 Hz); 13 C NMR (125 MHz, CDCl 3 ) δ 171.4, 168.3, 147.6, 134.3, 132.8, 129.0, 120.7, 119.9, 112.3, 112.1 , 52.8, 44.5, 39.1, 33.6, 12.6; GC-MS m / z 359 (MH + ), 1 H NMR and 13 C NMR graphs are shown in Figures 9 and 10, respectively).

Figure 112015128997815-pat00110

Wherein R is

Figure 112015128997815-pat00111
to be.

Examples 1-6. Compounds of formula 1 wherein R is

Figure 112015128997815-pat00112
) Preparation of

Compounds of formula 1-3, wherein R is

Figure 112015128997815-pat00113
) (36 mg, 0.1 mmol, 1.0 equiv.) Is dissolved in dried DMF (1 mL). Potassium carbonate (21 mg, 0.15 mmol, 1.5 equiv.) Was added dropwise and stirred at room temperature. When the reaction is complete, aq. LiCl was added and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous Na 2 SO 4 , filtered, concentrated under reduced pressure and flash column chromatography to obtain the compound of formula (1)
Figure 112015128997815-pat00114
) To give (1 H NMR (500MHz, CDCl 3) δ 10.52 (bs, 1H), 7.34 (s, 1H), 7.17 (s, 1H), 7.12 (d, 2H, J = 9.0 Hz), 6.44 (d , 2H, J = 8.5 Hz) , 3.97 (s, 3H), 3.24 (q, 4H, J = 7.0 Hz), 1.09 (t, 6H, J = 7.0 Hz); 13 C NMR (125MHz, CDCl 3) δ GC-MS m / z 357 (MH < + & gt ; ), 1 H NMR and < 13 & gt ; C NMR graphs 11 and 12, respectively).

Figure 112015128997815-pat00115

Wherein R is

Figure 112015128997815-pat00116
to be.

Example 2. A compound of formula 1 wherein R is

Figure 112015128997815-pat00117
)

All procedures were carried out in the same manner as in Example 1,

Figure 112015128997815-pat00118
) Was prepared in the same manner as in the preparation of R
Figure 112015128997815-pat00119
The 1 H NMR and 13 C NMR graphs of the compounds of Formulas 1-2, 1-3, and 1 are shown in FIGS. 13 to 18, respectively.

Example 3. A compound of formula 1 wherein R is

Figure 112015128997815-pat00120
)

All procedures were carried out in the same manner as in Example 1,

Figure 112015128997815-pat00121
) Was prepared in the same manner as in the preparation of R
Figure 112015128997815-pat00122
Of the formula 1-2, 1-3 and the compound exhibited 1 H NMR and 13 C NMR graph of the first to Figs. 19 to 24, respectively.

Example 4. A compound of formula 2 wherein R is

Figure 112015128997815-pat00123
)

Dried DMF (0.5 mL) was added to a solution of a compound of formula 1

Figure 112015128997815-pat00124
) (19 mg, 0.05 mmol, 1 equiv.) Was dissolved. Potassium carbonate (10.4 mg, 0.075 mmol, 1.5 equiv.) And Iodomethane (4.7 μL, 0.075 mmol, 1.5 equiv.) Were added dropwise. When the reaction is complete, aq. LiCl was added and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous Na 2 SO 4 , filtered, concentrated under reduced pressure and flash column chromatography to obtain the compound of formula 2
Figure 112015128997815-pat00125
) To give (1 H NMR (500MHz, CDCl 3) δ 7.41 (s, 1H), 7.24 (s, 1H), 7.11 (d, 2H, J = 8.0 Hz), 6.65 (d, 2H, J = 7.5 Hz ), 3.98 (s, 3H) , 3.40-3.36 (m, 7H), 1.18 (t, 6H, J = 6.5 Hz); 13 C NMR (125MHz, CDCl 3) δ 165.3, 163.3, 147.6, 142.7, 133.9, GC-MS m / z 371 (MH + ), 1 H NMR and 13 C NMR graphs are shown in FIGS. 25 and 26, respectively Lt; / RTI >

Figure 112015128997815-pat00126

Wherein R is

Figure 112015128997815-pat00127
to be.

Example 5. A compound of formula 2, wherein R is

Figure 112015128997815-pat00128
)

All the procedures are carried out in the same manner as in the above-mentioned Example 4,

Figure 112015128997815-pat00129
) Was prepared in the same manner as in the preparation of R
Figure 112015128997815-pat00130
≪ 1 > H NMR and < 13 > C NMR spectra of the compound of formula (2) are shown in FIGS. 27 and 28, respectively.

Example 6. Compound of formula 2 (wherein R is

Figure 112015128997815-pat00131
)

All the procedures are carried out in the same manner as in the above-mentioned Example 4,

Figure 112015128997815-pat00132
) Was prepared in the same manner as in the preparation of R
Figure 112015128997815-pat00133
≪ 1 > H NMR and < 13 > C NMR of the compound of formula (2) are shown in FIGS. 29 to 30, respectively.

Example 7:  3 < / RTI >

Dried DMF (0.5 mL) was added to a solution of the compound of formula (2-1)

Figure 112015128997815-pat00134
) (19 mg, 0.05 mmol, 1 equiv.) Was dissolved. Potassium carbonate (10.4 mg, 0.075 mmol, 1.5 equiv.) And Iodomethane (4.7 μL, 0.075 mmol, 1.5 equiv.) Were added dropwise. When the reaction is complete, aq. LiCl was added and extracted with EtOAc. The organic layer was separated, washed with brine anhydrous Na 2 SO 4 to the dry, filtered mixture was concentrated under reduced pressure, flash column chromatography to obtain a compound of the formula 3 (1 H NMR (500MHz, CDCl 3) δ 7.41 (s, 1H) , 7.24 (s, 1H), 7.11 (d, 2H, J = 8.0 Hz), 6.65 (d, 2H, J = 7.5 Hz), 3.98 (s, 3H), 3.40-3.36 t, 6H, J = 6.5 Hz ); 13 C NMR (125MHz, CDCl 3) δ165.3, 163.3, 147.6, 142.7, 133.9, 133.3, 132.3, 130.8, 122.6, 119.2, 117.4, 111.0, 53.2, 44.4, 34.3 , 12.7; GC-MS m / z 371 (MH + ), 1 H NMR and 13 C NMR graphs are shown in Figures 31 and 32, respectively).

Figure 112015128997815-pat00135

Experimental Example 1. Measurement of anti-cancer activity

(ATCC No.: CRL-1435 ™), Lung cancer: NCI-H23 (ATCC® Number: CRL-5800 ™), Breast cancer (ATCC® Number: HTB-26 ™), Colon cancer: HCT-15 (ATCC® Number: CCL-225 ™), Stomach cancer: NUGC-3, Renal cancer: CRL-1611 (TM)).

The mycoplasma test (MycoAlert Assay kit, Lonza) was used for the cell line used in the SRB experiment. The cell line was used one week after it was taken out of the nitrogen tank, after which passage number 10 was not exceeded. The number of cell lines used in the SRB assay did not exceed 20. The cells were cultured at the density of 70 ~ 80% in tissue culture flask (75cm 2 , BDFalcon353110) in a 5% CO 2 incubator at 37 ° C.

The concentration of the cell line was 4000 ~ 6000 cells / 200ml / well, and the medium contained 5% FBS. Each cell line was dispensed into a 96-well plate (96-well, flat-bottom with low evaporation lid, BD Falcon 353070) using an 8-channel pipette in 200 ml increments.

After 24 hours, the cells in the 96-well plate were homogenized and equilibrated under a microscope. The samples to be treated were dissolved in DMSO (100%) at concentrations of 30, 10, 3, 1 and 0.3 (mg / ml) Lt; / RTI > As a result, the stock solution was diluted 1000 times and the final concentration of DMSO was 0.1%. The stock solution is stored in the freezer after preparation (when the amount of sample to be treated is large, 20 ml of stock solution is dispensed to reduce the freezing / thawing cycle of the sample), and the diluted working solution is always ready for sample treatment . At this time, adriamycin was used as a positive control and drug treatment was performed within a concentration range in which GI50 value can be obtained.

The 96-well plate medium to be treated was removed using an 8-channel pipette. Now slowly remove the plate by tilting the bottom cells. The diluted samples 30, 10, 3, 1, and 0.3 (mg / ml) were dispensed in 200 μl aliquots and the number of wells in the control and sample groups was 4 (n = 4).

After 48 hours of treatment, the plate was fixed with 50% TCA in 50 ml / well. The fixed plate was left at 4 ° C for 60 minutes and then washed 4-5 times with tap water. The washed plate was dried, and 100 ml / well of SRB solution (0.4% sulforhodamine B in 1% acetic acid) was added and left for 30 minutes. The unbound dye reagent was washed with 0.1% acetic acid, dried again, and dissolved in 100 mM / well of 10 mM Tris base (pH 10.5). Absorbance was measured at 540 nm using a Versa max microplate reader (Molecular Devices), and the absorbance was calculated as a percentage of the solvent-treated group. The GI50 value of the test substance was calculated using Graphpad prism v4.0 software (n = 4, Sigmoidal dose-response (variable slope) equation).

The results of measurement of cell growth inhibitory activity are shown in Table 1 below.

Cancer cell line ACHN MDA-MB-231 HCT-15 NUGC-3 PC-3 NCI-H23

Figure 112015128997815-pat00136
16.2 20.4 26.3 24.0 15.5 21.7
Figure 112015128997815-pat00137
 81.4 81.4 81.4 81.4 81.4 81.4
Figure 112015128997815-pat00138
 84.6 84.6 84.6 84.6 84.6 84.6
Figure 112015128997815-pat00139
 95.1 95.1 95.1 95.1 95.1 95.1
Figure 112015128997815-pat00140
 10.2 12.3 9.6 12.7 21.5 9.0
Figure 112015128997815-pat00141
 105.1 105.1 105.1 105.1 105.1 105.1
Figure 112015128997815-pat00142
 83.0 83.0 83.0 83.0 83.0 83.0
Figure 112015128997815-pat00143
 81.2 81.2 81.2 81.2 81.2 81.2
Figure 112015128997815-pat00144
 81.0 81.0 81.0 81.0 81.0 81.0
Figure 112015128997815-pat00145
 7.4 6.7 5.6 7.1 8.4 8.7
Figure 112015128997815-pat00146
 28.9 24.2 45.1 44.0 40.3 35.1
Figure 112015128997815-pat00147
 14.9 9.4 10.5 18.0 14.8 15.4
Figure 112015128997815-pat00148
 100.2 100.2 100.2 100.2 100.2 100.2
Figure 112015128997815-pat00149
 79.9 79.9 79.9 79.9 79.9 79.9
Figure 112015128997815-pat00150
 78.3 78.3 78.3 78.3 78.3 78.3
Figure 112015128997815-pat00151
 76.6 76.6 76.6 76.6 76.6 76.6 Adriamycin 0.14 0.11 0.09 0.14 0.15 0.12

As shown in Table 1, it is confirmed that the above 16 compounds have anticancer activity.

Claims (16)

Or an enantiomer or diastereomer thereof, or a pharmaceutically acceptable acid or base thereof,
[Chemical Formula 1]
Figure 112017036690231-pat00152

In this formula,
Wherein R is selected from the group consisting of an amine, a 5 or 6 membered aromatic or non-aromatic heterocyclic amine containing 1 or 2 N, F 3 CO-, aryl of C 6 -C 10 and C 1 -C 4 alkoxy duplicate possibly substituted or unsubstituted by one or more selected from a C 6 -C 10 aryl. delete The compound according to claim 1, wherein the compound is
One)
Figure 112015128997815-pat00153
;
2)
Figure 112015128997815-pat00154
;
3)
Figure 112015128997815-pat00155
;
4)
Figure 112015128997815-pat00156
;
5)
Figure 112015128997815-pat00157
;
6)
Figure 112015128997815-pat00158
;
7)
Figure 112015128997815-pat00159
; And
8)
Figure 112015128997815-pat00160
;
≪ RTI ID = 0.0 > and / or < / RTI > Or an enantiomer or diastereomer thereof, or a pharmaceutically acceptable acid or base thereof,
(2)
Figure 112017036690231-pat00161

In this formula,
Wherein R is selected from the group consisting of an amine, a 5 or 6 membered aromatic or non-aromatic heterocyclic amine containing 1 or 2 N, F 3 CO-, aryl of C 6 -C 10 and C 1 -C 4 alkoxy duplicate possibly substituted or unsubstituted by one or more selected from a C 6 -C 10 aryl. delete 5. The compound according to claim 4, wherein the compound is
One)
Figure 112015128997815-pat00162
;
2)
Figure 112015128997815-pat00163
;
3)
Figure 112015128997815-pat00164
;
4)
Figure 112015128997815-pat00165
;
5)
Figure 112015128997815-pat00166
;
6)
Figure 112015128997815-pat00167
; And
7)
Figure 112015128997815-pat00168
;
≪ RTI ID = 0.0 > and / or < / RTI > Or an enantiomer or diastereomer thereof, or a pharmaceutically acceptable acid or base thereof,
(3)
Figure 112015128997815-pat00169
. 1. A process for preparing a compound of formula (1)
[Reaction Scheme 1]
Figure 112017036690231-pat00170

In this formula,
Wherein R is selected from the group consisting of an amine, a 5 or 6 membered aromatic or non-aromatic heterocyclic amine containing 1 or 2 N, F 3 CO-, aryl of C 6 -C 10 and C 1 -C 4 alkoxy with at least one selected from the redundant enable a substituted aryl or unsubstituted C 6 -C 10,
Wherein the compound of Formula 1-1 is prepared by the following Reaction Scheme 1-1;
[Reaction Scheme 1-1]
Figure 112017036690231-pat00221
. delete 9. The method of claim 8,
Figure 112015128997815-pat00171
,
Figure 112015128997815-pat00172
,
Figure 112015128997815-pat00173
,
Figure 112015128997815-pat00174
,
Figure 112015128997815-pat00175
,
Figure 112015128997815-pat00176
,
Figure 112015128997815-pat00177
or
Figure 112015128997815-pat00178
≪ RTI ID = 0.0 > 1. ≪ / RTI > delete A process for preparing a compound of formula (2)
[Reaction Scheme 2]
Figure 112017036690231-pat00180

In this formula,
Wherein R is selected from the group consisting of an amine, a 5 or 6 membered aromatic or non-aromatic heterocyclic amine containing 1 or 2 N, F 3 CO-, aryl of C 6 -C 10 and C 1 -C 4 alkoxy duplicate possibly substituted or unsubstituted by one or more selected from a C 6 -C 10 aryl. delete 13. The method of claim 12,
Figure 112015128997815-pat00181
,
Figure 112015128997815-pat00182
,
Figure 112015128997815-pat00183
,
Figure 112015128997815-pat00184
,
Figure 112015128997815-pat00185
,
Figure 112015128997815-pat00186
or
Figure 112015128997815-pat00187
Lt; RTI ID = 0.0 > (2) < / RTI > A process for preparing a compound of formula (3)
[Reaction Scheme 3]
Figure 112015128997815-pat00188
. delete
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WO2019107662A1 (en) * 2017-11-30 2019-06-06 한국해양과학기술원 Novel thieno[3,2-b]pyridine-5(4h)-one derivative compound, preparation method thereof and use thereof
KR20190064287A (en) * 2017-11-30 2019-06-10 한국해양과학기술원 Novel Thieno[3,2-b]pyridine-5(4H)-one Derivatives, method for preparing therefor and use of the same
KR102014077B1 (en) * 2017-11-30 2019-08-26 한국해양과학기술원 Novel Thieno[3,2-b]pyridine-5(4H)-one Derivatives, method for preparing therefor and use of the same
US11306103B2 (en) 2017-11-30 2022-04-19 Korea Institute Of Ocean Science & Technology Thieno[3,2-b]pyridine-5(4H)-one derivative compound, preparation method thereof and use thereof
KR20200020222A (en) 2018-08-16 2020-02-26 한국해양과학기술원 Synthesis method of thieno[3,2-b]pyridine-5(4H)-one derivatives using gold catalyst and use thereof
KR102179162B1 (en) 2018-08-16 2020-11-16 한국해양과학기술원 Synthesis method of thieno[3,2-b]pyridine-5(4H)-one derivatives using gold catalyst and use thereof

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