WO2018169360A1 - Quinoline-5,8-dione derivative as tgase 2 inhibitor, and pharmaceutical composition containing same - Google Patents

Abstract

The present invention relates to a quinoline-5,8-dione derivative compound represented by chemical formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The compound represented by chemical formula I, of the present invention, has a TGase 2 inhibitory effect, and a pharmaceutical composition containing the same can be useful for preventing or treating disorders or diseases which are mediated by TGase 2 or which react to TGase 2 inhibition.

Description

Quinoline-5,8-dione derivatives as TGase 2 inhibitors and pharmaceutical compositions comprising the same

The present invention relates to a quinoline-5,8-dione derivative compound having a transglutaminase 2 (TGase 2) inhibitory activity, an isomer thereof, a pharmaceutically acceptable salt thereof, and a composition containing the same.

Transglutaminase is a group of enzymes that form a covalent bond between a free amine group and the gamma-carboxamide group of glutamine inside a protein.It was first discovered in 1959, and its specific biochemical role was blood clotting in 1968. The protein was found in fibrin stabilizing factor (factor III).

Among them, type 2 glutaminase (TGase 2) is known to function mainly as a protein cross-linking enzyme by promoting the formation of lysine iso-dipeptide bonds, but recent studies have shown that TGase 2 expression is normally regulated. Not being found to play an important role in the pathological mechanism of many diseases.

Abnormally excessive expression of TGase 2 has been reported to play a major role in the development of diseases such as inflammatory diseases and autoimmune diseases. In addition, excessive expression of TGase 2 is known to induce neurodegenerative diseases, and recent studies have shown that tissue transglutaminase may have abnormally high levels in people with neurological diseases such as Huntington's and Parkinson's. .

In addition, it irreversibly binds to matrix proteins such as collagen, fibronectin, laminia, nidogen, and proteoglycan, or protease (extracellular matrix) Increasing resistance to proteolytic enzymes has been suggested to induce the deposition of severe extracellular matrix and to be involved in tissue fibrosis. In fact, it has been reported that TGase 2 plays a major role in experimental kidney and liver fibrosis, and the degree of fibrosis is reduced when the inhibitor is used to inhibit its activity.

An amine compound is known as a substance which suppresses TGase 2 activity, and typical examples thereof include cystamine and putrescine. In addition, chemical inhibitors such as monodansylcababerine, w-dibenzylaminoalkylamine, 3-halo-4,5-dihydroisooxazole and 2-[(2-oxopropyl) thio] imidazolium derivatives have been developed. However, all are known to cause nonspecific in vivo inhibition of other enzymes. In addition, although TGase 2 inhibitory activity of glucosamine derivatives, chlorogenic acid, epigallocatechin gallate, curcumin, sparparm and ethacrynic acid has been known recently, it is still unclear whether significant activity will be shown in the treatment of TGase 2 related diseases in animals. It is unknown.

Thus, there is a need for continued development of safe and effective transglutaminase inhibitors.

[Patent Documents]

United States Patent Application 2009-462554

Korean patent application 2008-0118688

Korean patent application 2009-0018388

Korean patent application 2014-0090500

[Non-Patent Documents]

Karpuj, Marcela V. et al., "Prolonged survival and decreased abnormal movements in transgenic model of Huntington disease, with administration of the transglutaminase inhibitor cystamine." Nature medicine 8.2 (2002): 143-149.

Soo-Youl Kim, ““ Transglutaminase 2 in inflammation. ”Frontier Bioscience 11 (2006): 3026-3035.

It is an object of the present invention to provide novel quinoline-5,8-dione derivative compounds, their stereoisomers or pharmaceutically acceptable salts thereof.

Another object of the present invention is to transglutaminase 2 (hereinafter referred to as TGase 2), which comprises a novel quinoline-5,8-dione derivative compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient. It is to provide a pharmaceutical composition for the prophylaxis or treatment of a disorder or disease mediated by or in response to inhibition of TGase 2.

However, the problem to be solved by the present application is not limited to the above-mentioned problem, another task that is not mentioned will be clearly understood by those skilled in the art from the following description.

The application provides a compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula I]

Where

R ₁ is hydrogen, halogen, —C _1-6 alkyl, or —OC _1-6 alkyl,

R ₂ is hydrogen, halogen or —NH ₂ , wherein one or more hydrogens of —NH ₂ may be optionally substituted with R ₄ ,

R ₃ is hydrogen, halogen, C _{6- 12} aryl, C _{3- 12} heteroaryl, C _{6- 12} arylaminocarbonyl, C _{3- 12} heteroaryl, amino, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkenyl, C _{3- 10,} and heterocycloalkyl, where said C _{6- 12} aryl, C _{3- 12} heteroaryl, C _{6- 12} arylaminocarbonyl, C _{3- 12} heteroaryl, amino, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkenyl, and C _{3- 10} heterocycloalkyl are unsubstituted or have at least one hydrogen may be substituted with R ₅ or = O,

R ₄ is halogen, C _{1- 6} alkyl, -C _{2- 6} alkenyl, - (C = O) - (C 1- 6 alkyl) or - (C = O) - ( C 2- 6 alkenylene), and ,

R ₅ is -CN, -NO _2, halogen, C _{1- 6} alkyl, C _{2- 6 alkenyl, -OH, -OR a, - (} C = O) -R b, - (C = O) OR b _{, -NR c R d, -SO 2} -R b, C 6-12 aryl, C _{3- 12} heteroaryl, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkenyl or C _{3- 10} heteroaryl cycloalkyl wherein the C _{1- 6} alkyl, C _{2- 6} alkenyl, C _6-12 aryl, C _3-12 heteroaryl, C _{3- 10} cycloalkyl, C _3- C ₁₀ cycloalkenyl and heterocycloalkyl _{3- 10} May be unsubstituted or one or more hydrogens may be substituted with R _e ,

R is _a C _{1- 6} alkyl, C _{2- 6} alkenyl, C _{6- 12} aryl, C _3-12 heteroaryl, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkenyl or C _{3- 10} heterocycloalkyl alkyl, wherein C _{1- 6} alkyl, C _{2- 6} alkenyl, C _{6- 12} aryl, C _3-12 heteroaryl, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkenyl and C _{3- 10} heteroaryl alkilneun cycloalkyl is unsubstituted or has at least one hydrogen of C _{1- 6} alkyl, C _{2- 6} alkenyl, -OH, -OC _{1- 6} can be substituted with alkyl, -O-CF ₃ or halogen,

R _b is _{hydrogen, -NR c R d, C 1-} 6 alkyl, C _{2- 6} alkenyl, C _{6- 12} aryl, C _3-12 heteroaryl, C _{3- 10} cycloalkyl, or C _{3- 10} heterocycloalkyl alkyl, wherein C _{1- 6} alkyl, C _{2- 6} alkenyl, C _{6- 12} aryl, C _3-12 heteroaryl, C _{3- 10} cycloalkyl and C _{3- 10} heteroaryl cycloalkyl or one or more unsubstituted and hydrogen may be substituted with C _{1- 6} alkyl, -OH or halogen,

R _c and R _d are each independently hydrogen, C _{1- 6} alkyl, C _{2- 6} alkenyl, - (C = O) - (C 1- 6 alkyl), - (C = O) - (C 2- ₆ alkenyl), - (C = O) - (C 3- 10 cycloalkyl), - (C = O) - (C 3- 10 heterocycloalkyl), or -SO ₂ - (C _2-6 alkyl) wherein the C _{1- 6} alkyl, C _{2- 6} alkenyl, - (C = O) - (C 1- 6 alkyl), - (C = O) - (C 2- 6 alkenyl), - (C = O) - (C _{3- 10} cycloalkyl), - (C = O) - (C 3- 10 heterocycloalkyl), and -SO ₂ - (C _{2- 6} alkyl) is a unsubstituted or at least one hydrogen of C _{1 - 6} alkyl, C _{2- 6} alkenyl, which may be substituted with -OH or halogen,

R _e is halogen, C _{1- 6} alkyl, C _{2- 6} alkenyl, -OH, -OC _{1- 6} alkyl, - (C = O) -R b, - (C = O) OR b, C 6- ₁₂ aryl, C _3-12 heteroaryl, C _{3- 10} cycloalkyl, C _3- C ₁₀ cycloalkenyl, or _{3- 10} heterocycloalkyl, wherein the C _{1- 6} alkyl, C _{2- 6} alkenyl, C _{6 - 12} aryl, C _3-12 heteroaryl, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkenyl and C _{3- 10} is heterocycloalkyl alkilneun unsubstituted or at least one hydrogen of C _1-6 alkyl, C _{2- 6} May be substituted with alkenyl, -OH or halogen,

The C _{3- 12} heteroaryl, and C _{3- 12} heteroaryl, amino, C _{3- 10} heterocycloalkyl contain 1 to 3 heteroatoms selected from O, N or S.

The present application is directed to a compound of Formula I, its stereoisomers or pharmaceutically acceptable salts thereof; And it provides a composition comprising a pharmaceutically acceptable carrier.

The present application provides a pharmaceutical composition for the prophylaxis or treatment of a disorder or disease mediated by or in response to inhibition of TGase 2, which is mediated by TGase 2 comprising a compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof as an active ingredient. to provide.

The novel quinoline-5,8-dione derivative compounds, stereoisomers or pharmaceutically acceptable salts thereof according to the present invention have little side effects and exhibit an effect of inhibiting TGase 2 effectively.

The novel quinoline-5,8-dione derivative compounds, stereoisomers or pharmaceutically acceptable salts thereof according to the present invention are for the treatment or prevention of disorders or diseases which are mediated by TGase 2 or in response to inhibitors of TGase 2 It can be usefully used.

1 is a graph showing the tumor volume of the control (CT) confirmed in Experimental Example 3, the compound of Formula I 5 mg / kg administration group, the compound of Formula I 10 mg / kg administration group and the compound of Formula I 20 mg / kg administration group.

Figure 2 is a graph showing the tumor weight of the control (CT) confirmed in Experimental Example 3, the compound of Formula I 5 mg / kg administration group, the compound of Formula I 10 mg / kg administration group and the compound of Formula I 20 mg / kg administration group.

Figure 3 is a photograph showing the tumor of the control group confirmed in Experiment 3, the compound of Formula I 5 mg / kg administration group, the compound of Formula I 10 mg / kg administration group and the compound of Formula I 20 mg / kg administration group.

Figure 4 is a graph showing the weight of the control group and the compound of Formula I 100 mg / kg administration group confirmed in Experimental Example 3.

Figure 5 is a graph showing the plasma concentration of the control group and the compound of Formula I 10 mg / kg administration group confirmed in Experimental Example 4.

Hereinafter, the present application will be described in detail so that those skilled in the art can easily practice the present application. However, the present application may be embodied in many different forms and should not be construed as limited to the specific embodiments described herein. The description of similar parts is omitted throughout the specification.

Throughout this specification, when a part is said to "include" a certain component, it means that it can further include other components, without excluding the other components unless otherwise stated.

As used throughout this specification, the terms “about”, “substantially”, and the like, are used at, or in close proximity to, numerical values when manufacturing and material tolerances inherent in the meanings indicated are provided, and an understanding of the present application may occur. Accurate or absolute figures are used to assist in the prevention of unfair use by unscrupulous infringers.

As used throughout this specification, the term “step of” or “step of” does not mean “step for”.

Throughout this specification, the term "combination (s) thereof" included in the expression of a makushi form refers to one or more mixtures or combinations selected from the group consisting of components described in the expression of makushi form, It means to include one or more selected from the group consisting of the above components.

Throughout this specification, the description of "A and / or B" means "A or B, or A and B."

Throughout this specification, "halo", "halogen" or "halo group" may be, but is not limited to, F, Cl, Br, or I.

Throughout this specification, “alkyl” or “alkyl group” may be a linear or branched, saturated or unsaturated, alkyl group having 1 to 10 carbon atoms, for example, methyl, ethyl, propyl, butyl, pentyl , Hexyl, heptyl, octyl, nonyl, decyl, or isomers thereof, but is not limited thereto.

Throughout this specification, the term “aryl” or “aryl group”, alone or as part of another group, refers to a monocyclic or bicyclic aromatic ring, eg, phenyl, substituted phenyl, as well as conjugated groups, Examples include, but are not limited to, naphthyl, phenanthrenyl, indenyl, tetrahydronaphthyl, indanyl, and the like. For example, the “aryl” or “aryl group” contains one or more rings having 5 or more atoms, and there may be 5 or fewer rings containing 22 or less atoms, and adjacent carbon atoms or Double bonds may be present alternately (resonance) between suitable heteroatoms. The "aryl" or "aryl group" is optionally halogen, such as F, Br, Cl or I, alkyl such as methyl, ethyl, propyl, alkoxy such as methoxy or ethoxy, hydroxy, carboxy, carbamoyl, alkyloxy Including but not limited to carbonyl, nitro, alkenyloxy, trifluoromethyl, amino, cycloalkyl, aryl, heteroaryl, cyano, alkyl S (O) m (m = O, 1, 2) or thiols It may be substituted with one or more groups that are not. For example, the "aryl" or "aryl group" may be phenyl, phenyl substituted as described above, phenyl, naphthyl, or naphthyl substituted as described above, but is not limited thereto.

Throughout this specification, the term “heteroaryl” or “heteroaryl group”, alone or as part of another group, means a monocyclic or bicyclic aromatic ring containing at least one atom other than a carbon atom, for example For example, furanyl, thiophenyl, pyrazolyl, pyrazinyl, pyridinyl, pyrimidinyl, benzothiazolyl, benzodioxyyl, andazolyl, isoindolinyl, indenyl, quinolinyl and benzothiophenyl And the like, but are not limited thereto. A “heteroaryl” or “heteroaryl group” contains one or more rings having five or more atoms, and may have up to five rings containing up to 22 atoms, and adjacent carbon atoms or suitable heteroatoms. There may be alternating (resonant) double bonds in between. In addition, "heteroaryl" or "heteroaryl group" may be substituted as described in the "aryl" or "aryl group".

Throughout this specification, "alkoxy" or "alkoxy group" may include, but is not limited to, an alkoxy group having an oxygen atom bonded to an "alkyl group" as defined above.

Throughout this specification, the term “amine” or “amine group”, alone or as part of another group, refers to —NH 2, wherein the “amine group” may refer to one or two substituents, which may be the same or different, Such as alkyl, aryl, arylalkyl, alkenyl, alkynyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, thioalkyl, Optionally substituted with carbonyl or carboxyl.

Quinoline-5,8- Dion  Derivative compounds

The application provides a compound represented by Formula II, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula I]

Where

R ₁ is hydrogen, halogen, -C _{1- 6} alkyl, -OC _{1- 6} alkyl,

R ₂ is hydrogen, halogen or —NH ₂ , wherein one or more hydrogens of —NH ₂ may be optionally substituted with R ₄ ,

R ₃ is hydrogen, halogen, C _{6- 12} aryl, C _{3- 12} heteroaryl, C _{6- 12} arylaminocarbonyl, C _{3- 12} heteroaryl, amino, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkenyl, C _{3- 10,} and heterocycloalkyl, where said C _{6- 12} aryl, C _{3- 12} heteroaryl, C _{6- 12} arylaminocarbonyl, C _{3- 12} heteroaryl, amino, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkenyl, and C _{3- 10} heterocycloalkyl are unsubstituted or have at least one hydrogen may be substituted with R ₅ or = O,

R ₄ is halogen, C _{1- 6} alkyl, -C _{2- 6} alkenyl, - (C = O) - (C 1- 6 alkyl) or - (C = O) - ( C 2- 6 alkenylene), and ,

R ₅ is -CN, -NO _2, halogen, C _{1- 6} alkyl, C _{2- 6 alkenyl, -OH, -OR a, - (} C = O) -R b, - (C = O) OR b _{, -NR c R d, -SO 2} -R b, C 6-12 aryl, C _{3- 12} heteroaryl, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkenyl or C _{3- 10} heteroaryl cycloalkyl wherein the C _{1- 6} alkyl, C _{2- 6} alkenyl, C _6-12 aryl, C _3-12 heteroaryl, C _{3- 10} cycloalkyl, C _3- C ₁₀ cycloalkenyl and heterocycloalkyl _{3- 10} May be unsubstituted or one or more hydrogens may be substituted with R _e ,

R is _a C _{1- 6} alkyl, C _{2- 6} alkenyl, C _{6- 12} aryl, C _3-12 heteroaryl, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkenyl or C _{3- 10} heterocycloalkyl alkyl, wherein C _{1- 6} alkyl, C _{2- 6} alkenyl, C _{6- 12} aryl, C _3-12 heteroaryl, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkenyl and C _{3- 10} heteroaryl cycloalkyl is unsubstituted or has one or more hydrogen may be substituted with C _{1- 6} alkyl, C _{2- 6} alkenyl, -OH, -OC _{1- 6} alkyl, -O-CF ₃ or halogen,

R _b is _{hydrogen, -NR c R d, C 1-} 6 alkyl, C _{2- 6} alkenyl, C _{6- 12} aryl, C _3-12 heteroaryl, C _{3- 10} cycloalkyl, or C _{3- 10} heterocycloalkyl alkyl, wherein C _{1- 6} alkyl, C _{2- 6} alkenyl, C _{6- 12} aryl, C _3-12 heteroaryl, C _{3- 10} cycloalkyl and C _{3- 10} heteroaryl cycloalkyl or one or more unsubstituted and hydrogen may be substituted with C _{1- 6} alkyl, -OH or halogen,

R _c and R _d are each independently hydrogen, C _{1- 6} alkyl, C _{2- 6} alkenyl, - (C = O) - (C 1- 6 alkyl), - (C = O) - (C 2- ₆ alkenyl), - (C = O) - (C 3- 10 cycloalkyl), - (C = O) - (C 3- 10 heterocycloalkyl), or -SO ₂ - (C _2-6 alkyl) wherein the C _{1- 6} alkyl, C _{2- 6} alkenyl, - (C = O) - (C 1- 6 alkyl), - (C = O) - (C 2- 6 alkenyl), - (C = O) - (C _{3- 10} cycloalkyl), - (C = O) - (C 3- 10 heterocycloalkyl), and -SO ₂ - (C _{2- 6} alkyl) is a unsubstituted or at least one hydrogen of C _{1 - 6} alkyl, C _{2- 6} alkenyl, which may be substituted with -OH or halogen,

R _e is halogen, C _{1- 6} alkyl, C _{2- 6} alkenyl, -OH, -OC _{1- 6} alkyl, - (C = O) -R b, - (C = O) OR b, C 6- ₁₂ aryl, C _3-12 heteroaryl, C _{3- 10} cycloalkyl, C _3- C ₁₀ cycloalkenyl, or _{3- 10} heterocycloalkyl, wherein the C _{1- 6} alkyl, C _{2- 6} alkenyl, C _{6 - 12} aryl, C _3-12 heteroaryl, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkenyl and C _{3- 10} is heterocycloalkyl alkilneun unsubstituted or at least one hydrogen of C _1-6 alkyl, C _{2- 6} May be substituted with alkenyl, -OH or halogen,

The C _{3- 12} heteroaryl, and C _{3- 12} heteroaryl, amino, C _{3- 10} heterocycloalkyl contain 1 to 3 heteroatoms selected from O, N or S.

In the compounds of formula I of the present disclosure, R ₁ is specifically hydrogen, -C _{1- 3} may be an alkyl or -OC _1-3 alkyl, preferably hydrogen, -CH ₃ or -O-CH _3, more preferably Preferably hydrogen or —O—CH ₃ .

In the compounds of formula (I) herein, R ₂ may specifically be hydrogen, Br or —NH ₂ .

In the compounds of formula (I) herein, R ₃ is specifically furanyl, thiophenyl, pyrazolyl, pyrazinyl, pyridinyl, pyrimidinyl, benzothiazolyl, benzothiophenyl, benzodioxyyl, indazolyl, Isoindolinyl, quinolinyl, pyridazinylamino, pyridinylamino, phenyl, indenyl, naphthalenyl, phenylamino, piperidinyl or cyclopropyl, more specifically furan-3-yl, thi Offen-2-yl, pyrazol-4-yl, pyrazin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, benzo [d] thiazole -5-yl, benzothiophen-2-yl, dihydrobenzo [1,4] dioxin-6-yl, indazol-6-yl, isoindolin-5-yl, 2-quinolinyl, 3 -Quinolinyl, 6-quinolinyl, pyridazin-3-ylamino, phenyl, inden-5-yl, naphthalen-2-yl, phenylamino, piperidin-1-yl, piperidin-2- Mono or cyclopropyl, preferably phenyl, pyrimidinyl or pyridinyl.

May be (C _2-3 alkenyl) - in compounds of formula (I) of the present disclosure, R ₄ is specifically - (C = O) - ( C 1- 3 alkyl) or - (C = O).

In the compounds of formula I of the present application, R _a may be specifically C _{1- 3} alkyl, phenyl or morpholino imidazol.

In the compounds of formula I of the present application, R _b may be specifically imidazol _{hydrogen, -NH 2, -NH (CH 3} ), C 1- 3 alkyl or C _{2- 3} alkenyl.

In the compound of formula (I) herein, R _c is specifically, hydrogen, C _{1- 3} alkyl, - (C = O) - (C 1-3 alkenyl), - (C = O) - (C 3- 6 cycloalkyl alkyl) or -SO ₂ - (C _{1- 3} alkyl), R _d may be specifically hydrogen or C _{1- 3} alkyl.

In the compounds of formula I of the present application, R _e may be specifically C _{1- 3} alkyl, -OH, -OC _{1- 3} alkyl, -COOH, -COOCH ₃ or morpholino imidazol.

According to one preferred embodiment of the present application, in the compound represented by the formula (I), stereoisomer or pharmaceutically acceptable salt thereof,

R ₁ is —OC _1-3 alkyl,

R ₂ is hydrogen,

R ₃ is furanyl, pyrazolyl, pyrazinyl, pyrimidinyl, benzothiazolyl, benzothiophenyl, indazolyl, isoindolinyl, quinolinyl or piperidinyl, and the furanyl, pyrazolyl, pyra Genyl, pyrimidinyl, benzothiazolyl, benzothiophenyl, indazolyl, isoindolinyl, quinolinyl or piperidinyl may be unsubstituted or one or more hydrogens may be replaced with R ₅ or = 0.

According to one preferred embodiment of the present application, in the compound represented by the formula (I), stereoisomer or pharmaceutically acceptable salt thereof,

R ₁ is —O—CH ₃ ,

R ₂ is hydrogen,

R ₃ is pyrimidinyl, the pyrimidinyl may be unsubstituted or one or more hydrogens may be substituted with R ₅ ,

R ₅ is -OR _a ,

R _a is phenyl, the phenyl may be unsubstituted or one or more hydrogens may be substituted with —O—CF ₃ .

According to one preferred embodiment of the present application, in the compound represented by the formula (I), stereoisomer or pharmaceutically acceptable salt thereof,

R ₁ is hydrogen, -C ₃ alkyl, -OC _{1- 1- 3} alkyl,

R ₂ is Br,

R ₃ is furanyl, thiophenyl, pyrazolyl, pyrimidinyl, benzothiazolyl, indazolyl, quinolinyl, phenyl, naphthalenyl or cyclopropyl and the furanyl, thiophenyl, pyrazolyl, pyrimidy Neyl, benzothiazolyl, indazolyl, quinolinyl, phenyl, naphthalenyl or cyclopropyl may be unsubstituted or one or more hydrogens may be replaced with R ₅ or ═O.

According to one preferred embodiment of the present application, in the compound represented by the formula (I), stereoisomer or pharmaceutically acceptable salt thereof,

R ₁ is hydrogen, halogen, -C _{1- 3} alkyl, -OC _{1- 3} alkyl,

R ₂ is —NH ₂ , wherein one or more hydrogens of —NH ₂ may be optionally substituted with R ₄ ,

R ₃ is quinolinyl, naphthalenyl, benzodioxinyl, benzothiazolyl, benzothiophenyl, cyclopropyl, isoindolinyl, indenyl, indazolyl, phenyl, phenylamino, pyrazine, pyridazine, pyridine, Pyridinylamino, pyrimidine or piperidine, wherein the quinolinyl, naphthalenyl, benzodioxinyl, benzothiazolyl, benzothiophenyl, cyclopropyl, isoindolinyl, indenyl, indazolyl, phenyl, Phenylamino, pyrazine, pyridazine, pyridine, pyridinylamino, pyrimidine and piperidine may be unsubstituted or one or more hydrogens may be substituted with R ₅ or = 0.

According to one preferred embodiment of the present application, in the compound represented by the formula (I), stereoisomer or pharmaceutically acceptable salt thereof,

R ₁ is hydrogen,

R ₂ is -NH ₂ ,

R ₃ is phenyl, the phenyl may be unsubstituted or substituted with R ₅ ,

R ₅ is -OR a or _a C _{1- 6} alkyl, wherein the C _{1- 6} alkyl in which one or more hydrogen may be substituted with R _e,

R _a is phenyl or piperidinyl, said phenyl or piperidinyl, and is unsubstituted or is at least one hydrogen may be substituted with C _{1- 3} alkyl,

R _e is morpholine.

According to one preferred embodiment of the present application, in the compound represented by the formula (I), stereoisomer or pharmaceutically acceptable salt thereof,

R ₁ is —O—CH ₃ ,

R ₂ is -NH ₂ ,

R ₃ is pyrimidinyl or pyridinyl, wherein pyrimidinyl or pyridinyl may be unsubstituted or substituted with R ₅ ,

R ₅ is halogen or C _{1- 3} alkyl, wherein C _{1- 3} alkyl is optionally substituted with R _e,

R _e is halogen.

According to one preferred embodiment of the present application, in the compound represented by the formula (I), stereoisomer or pharmaceutically acceptable salt thereof,

R ₁ is hydrogen, C _1-3 alkyl or —OC _1-3 alkyl,

R ₂ is hydrogen, Br or —NH ₂ ,

R ₃ is quinolinyl, naphthalenyl, indenyl, benzodioxyyl, benzothiazolyl, benzothiophenyl, isoindolinyl, indazolyl, phenylamino, pyrazinyl, pyridazinylamino, piperidinyl or Cyclopropyl, the quinolinyl, naphthalenyl, indenyl, benzodioxyyl, benzothiazolyl, benzothiophenyl, isoindolinyl, indazolyl, phenylamino, pyrazinyl, pyridazinylamino, piperididi Neyl and cyclopropyl may be unsubstituted or one or more hydrogens may be substituted with R ₅ or ═O.

R ₄ is - (C _{1- 3} alkenyl), - (C = O) - (C _{1- 3} alkyl) or - (C = O)

R ₅ is -CN, -NO _2, halogen, C _{1- 6} alkyl, C _{1- 6 alkenyl, -OH, -OR a, - (} C = O) -R b, - (C = O) OR b _{, -NR c R d, -SO 2} -R b, C 6-12 aryl, C _{3- 12} heteroaryl, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkenyl or C _{3- 10} heteroaryl cycloalkyl wherein the C _{1- 6} alkyl, C _{1- 6} alkenyl, C _6-12 aryl, C _3-12 heteroaryl, C _{3- 10} cycloalkyl, C _3- C ₁₀ cycloalkenyl and heterocycloalkyl _{3- 10} May be unsubstituted or one or more hydrogens may be substituted with R _e ,

R is _a C _{1- 6} alkyl, C _{1- 6} alkenyl, C _{6- 12} aryl, C _3-12 heteroaryl, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkenyl or C _{3- 10} heterocycloalkyl alkyl, wherein R _a is unsubstituted or has one or more hydrogen may be substituted with C _{1- 6} alkyl, C _{1- 6} alkenyl, -OH, -OC _{1- 6} alkyl, -O-CF ₃ or halogen,

R _b is _{hydrogen, -NR c R d, C 1-} 6 alkyl, C _{1- 6} alkenyl, C _{6- 12} aryl, C _3-12 heteroaryl, C _{3- 10} cycloalkyl, or C _{3- 10} heterocycloalkyl alkyl, wherein C _{1- 6} alkyl, C _{2- 6} alkenyl, C _{6- 12} aryl, C _3-12 heteroaryl, C _{3- 10} cycloalkyl and C _{3- 10} heteroaryl cycloalkyl or one or more unsubstituted and hydrogen may be substituted with C _{1- 6} alkyl, -OH or halogen,

R _c and R _d are each independently hydrogen, C _{1- 6} alkyl, C _{2- 6} alkenyl, - (C = O) - (C 1- 6 alkyl), - (C = O) - (C 2- ₆ alkenyl), - (C = O) - (C 3- 10 cycloalkyl), - (C = O) - (C 3- 10 heterocycloalkyl), or -SO ₂ - (C _2-6 alkyl) wherein the C _{1- 6} alkyl, C _{2- 6} alkenyl, - (C = O) - (C 1- 6 alkyl), - (C = O) - (C 2- 6 alkenyl), - (C = O) - (C _{3- 10} cycloalkyl), - (C = O) - (C 3- 10 heterocycloalkyl), and -SO ₂ - (C _{2- 6} alkyl) is a unsubstituted or at least one hydrogen of C _{1 - 6} alkyl, C _{2- 6} alkenyl, which may be substituted with -OH or halogen,

R _e is halogen, C _{1- 6} alkyl, C _{2- 6} alkenyl, -OH, -OC _{1- 6} alkyl, - (C = O) -R b, - (C = O) OR b, C 6- ₁₂ aryl, C _3-12 heteroaryl, C _{3- 10} cycloalkyl, C _3- C ₁₀ cycloalkenyl, or _{3- 10} heterocycloalkyl, wherein the C _{1- 6} alkyl, C _{2- 6} alkenyl, C _{6 - 12} aryl, C _3-12 heteroaryl, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkenyl and C _{3- 10} is heterocycloalkyl alkilneun unsubstituted or at least one hydrogen of C _1-6 alkyl, C _{2- 6} May be substituted with alkenyl, -OH or halogen,

The C _{3- 12} heteroaryl and C _{3- 10} heteroaryl cycloalkyl may contain a hetero atom of 1 to 3 selected from O, N or S.

According to one preferred embodiment of the present application, in the compound represented by the formula (I), stereoisomer or pharmaceutically acceptable salt thereof,

R ₁ is hydrogen or —O—CH ₃ ,

R ₂ is hydrogen or —NH ₂ ,

R ₃ is phenyl, pyrimidinyl or pyridinyl, wherein the phenyl, pyrimidinyl and pyridinyl may be unsubstituted or one or more hydrogens may be substituted with R ₅ ,

R ₅ is halogen, C _{1- 3} alkyl, -OR _a, wherein the C _{1- 3} alkyl is unsubstituted or substituted one or more hydrogen may be substituted with R _e,

R _a is phenyl or piperidinyl, said phenyl or piperidinyl, and is unsubstituted or is at least one hydrogen may be substituted with C _{1- 3} alkyl or O-CF _3,

R _e is halogen or morpholinyl.

In a specific embodiment of the present application, the compound represented by Formula I is a quinoline-5,8-dione derivative compound, a stereoisomer or a pharmaceutical thereof, selected from the group consisting of compounds of the formula shown in Table 1 below It may be a salt thereof, but is not limited thereto.

TABLE 1

In a preferred embodiment of the present invention, the compound represented by formula (I) is a quinoline-5,8-dione derivative compound, a stereoisomer or a pharmaceutical thereof, selected from the group consisting of compounds of the formula shown in the following [Table 2] It may be a salt thereof.

TABLE 2

As used herein, pharmaceutically acceptable salts refer to salts commonly used in the medical arts, for example inorganic ionic salts, hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodine, prepared from calcium, potassium, sodium and magnesium, and the like. Inorganic acid prepared with acid, perchloric acid and sulfuric acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid , Organic acid salts prepared with glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid And amino acid salts made with sulfonate, glycine, arginine, lysine and the like prepared with naphthalenesulfonic acid, and the like, trimethylamine, triethylamine, ammonia, pyridine, Although there are amine salts made of picoline and the like, the salts used in the present invention are not limited by these salts.

The compounds of formula (I) may contain one or more asymmetric carbons and may therefore exist as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and respective diastereomers. Such isomers can be separated by conventional techniques, for example, compounds of formula (I) by cleavage such as column chromatography or HPLC. Alternatively, the stereoisomers of each of the compounds of formula I can be stereospecifically synthesized using optically pure starting materials and / or reagents in known arrangements.

Quinoline-5,8- Dion  Compositions Comprising Derivative Compounds, Uses thereof, and Methods of Treatment Using the Same

The present application is directed to a compound of Formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof; And one or more pharmaceutically acceptable carriers.

The compound of formula (I) is as described above, and overlapping portions will not be described in detail.

The carrier can be used, for example, sugar, starch, microcrystalline cellulose, lactose (lactose monohydrate), glucose, di-mannitol, alginate, alkaline earth metal salt, clay, polyethylene glycol, phosphoric anhydride Calcium hydrogen, or a mixture thereof may be used, but is not limited thereto.

The composition may include, but is not limited to, for example, an additive such as a binder, a disintegrant, a lubricant, a pH adjuster, an antioxidant, and the like.

The binder is, for example, starch, microcrystalline cellulose, highly dispersible silica, mannitol, di-mannitol, sucrose, lactose monohydrate, polyethylene glycol, polyvinylpyrrolidone (povidone), polyvinylpyrrolidone copolymer (copovidone) , Hypromellose, hydroxypropyl cellulose, natural gums, synthetic gums, copovidone, gelatin, or mixtures thereof may be used, but is not limited thereto.

The disintegrating agent may include, for example, starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch; Clay such as bentonite, montmorillonite, or veegum; Celluloses such as microcrystalline cellulose, hydroxypropyl cellulose or carboxymethyl cellulose; Algins such as sodium alginate or alginic acid; Crosslinked celluloses such as croscarmellose sodium; Gums such as guar gum and xanthan gum; Crosslinked polymers such as crosslinked polyvinylpyrrolidone (crospovidone); Effervescent agents such as sodium bicarbonate, citric acid, or mixtures thereof may be used, but are not limited thereto.

The lubricant is, for example, talc, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monorate, glyceryl monostea Latex, glyceryl palmitostearate, colloidal silicon dioxide or mixtures thereof, and the like, but are not limited thereto.

The pH adjusting agent may include, for example, acidifying agents such as acetic acid, adipic acid, ascorbic acid, sodium ascorbate, sodium ether, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid (citric acid), precipitated calcium carbonate, ammonia water, Basic agents such as meglumine, sodium carbonate, magnesium oxide, magnesium carbonate, sodium citrate, calcium tribasic phosphate, and the like may be used, but are not limited thereto.

The antioxidant may be, for example, dibutyl hydroxy toluene, butylated hydroxyanisole, tocopherol acetate, tocopherol, propyl gallate, sodium hydrogen sulfite, sodium pyrosulfite and the like. The dissolution aid may be polyoxyethylene sorbitan fatty acid esters such as sodium lauryl sulfate, polysorbate, docusate sodium, poloxamer, and the like, but is not limited thereto.

Compounds of formula (I) have fewer side effects and exhibit an effect of effectively inhibiting TGase2, so the compositions herein can be used for the prophylaxis or treatment of disorders or diseases mediated by TGase 2 or in response to inhibition of TGase 2 have. However, the use of the compounds of formula (I) herein is not limited thereto.

The present application provides a pharmaceutical composition for the prophylaxis or treatment of a disorder or disease mediated by or in response to inhibition of TGase 2 comprising TGase 2 as an active ingredient comprising a compound of Formula I, a stereoisomer or a pharmaceutically acceptable salt thereof. to provide.

The compound of formula (I) is as described above, and description of overlapping portions will be omitted.

In one specific embodiment herein, said disorder or condition mediated by or reactive to inhibition of TGase 2 is in a group consisting of inflammatory disease, nervous system disease, cancer, renal parenchymal disease, fibrosis or a combination thereof. It may be selected, but is not limited thereto.

The inflammatory diseases include, for example, degenerative arthritis, diabetes mellitus, autoimmune myositis, arteriosclerosis, Crohn's disease, inflammatory gastric ulcer, stroke, liver cirrhosis, meningitis, rhinitis, conjunctivitis, asthma, inflammatory skin disease, inflammatory bowel disease, rheumatoid inflammatory disease Or glomerulonephritis, but is not limited thereto.

The nervous system disease may be, for example, Alzheimer's disease, dementia, Parkinson's disease, or Huntington's disease, but is not limited thereto.

The cancer may include, for example, colon cancer, small intestine cancer, rectal cancer, colon cancer, anal cancer, esophageal cancer, gastric cancer, pancreatic cancer, gallbladder cancer, uterine cancer, cervical cancer, breast cancer, ovarian cancer, lung cancer, lymph gland cancer, thyroid cancer, prostate cancer, and blood cancer. , Skin cancer, brain tumor, kidney cancer or bladder cancer, but is not limited thereto.

The fibrosis may be, for example, but not limited to pulmonary fibrosis or liver fibrosis.

In one preferred embodiment herein, the disorder or disease mediated by TGase 2 or in response to inhibition of TGase 2 is cancer, more preferably kidney cancer, brain cancer or gastric cancer.

In one aspect of the invention, there is provided a method of inhibiting TGase 2 activity in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I). Such subjects include, but are not limited to, mammals such as, for example, humans, monkeys, cattle, horses, dogs, cats, rabbits, rats, mice, and the like.

In one aspect of the invention, there is provided the use of a compound of formula (I) herein for the manufacture of a medicament for the treatment of a disorder or disease mediated by TGase 2 or in response to inhibition of TGase 2 in a subject.

Quinoline-5,8- Dion  Preparation of Derivative Compound

The application provides a process for the preparation of a compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof. However, the compounds of the formula (I), stereoisomers or pharmaceutically acceptable salts thereof described above are not limited to those prepared by the methods of preparation herein.

In one specific embodiment of the present application, the method for preparing the quinoline-5,8-dione derivative compound represented by Formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof is the same as in Scheme 1, which is obvious to those skilled in the art. This includes a manufacturing method that is modified to one level.

Scheme 1

) 또는 R-보레이트(

)를 사용하여 스즈키 반응(Suzuki reaction)으로 마이크로웨이브를 사용하여 화학식 1-7의 화합물을 합성한다. 최종적으로, 화학식 1-7의 화합물을 아세토니트릴(ACN)에 용해시킨 후, 질산세륨암모늄(Ceric ammonium nitrate, CAN) 수용액을 적가하여 화합식 1-8의 화합물을 합성할 수 있다.As shown in [Scheme 1], a compound of Formula 1-1 is reacted with nitric acid to synthesize a compound of Formula 1-2, and then a compound of Formula 1-3 is synthesized by a Pd / CH ₂ reduction reaction. . The compound of formula 1-3 is reacted with (E) -3-ethoxyacryloyl chloride to synthesize the compound of formula 1-4, and the compound of formula 1-4 is added dropwise to the sulfuric acid solution to react with formula 1-5 A compound of A compound of Formula 1-5 is synthesized by dissolving a compound of Formula 1-5 in a pyridine and dimethylformamide (DMF) solution and dropwise addition of phosphorus oxychloride (POCl ₃ ). And R-boronic acid pinacol ester (

) Or R-borate (

) To synthesize a compound of Formula 1-7 using a microwave in the Suzuki reaction. Finally, after dissolving the compound of Formula 1-7 in acetonitrile (ACN), the compound of Formula 1-8 may be synthesized by dropwise addition of an aqueous solution of cerium ammonium nitrate (CAN).

In addition, as shown in Scheme 1, the compound of Formula 1-9 may be synthesized by reacting bromine with the compound of Formula 1-8.

Further, as shown in Scheme 1, sodium azide (NaN ₃ ) was added dropwise to the compound of Formula 1-9 to synthesize the compound of Formula 1-10, and then the compound of Formula 1-10 was converted into Pd / C, Reduction of H ₂ or by reduction with sodium borohydride (NaBH ₄ ) can be synthesized a compound of Formula 1-11.

In one specific embodiment of the present application, the method for preparing the quinoline-5,8-dione derivative compound represented by Formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof is shown in Scheme 2, which is obvious to those skilled in the art. This includes a manufacturing method that is modified to one level.

Scheme 2

) 또는 R-보레이트(

)를 사용하여 스즈키 반응(Suzuki reaction)으로 마이크로웨이브를 사용하여 화학식 10-11의 화합물을 합성할 수 있다. As shown in Scheme 2, a compound of Formula 10-1 is reacted with nitric acid to synthesize a compound of Formula 10-2, and then a compound of Formula 10-3 is synthesized by a Pd / CH ₂ reduction reaction. . The compound of Formula 10-3 is reacted with acetyl chloride to synthesize the compound of Formula 10-4, and the compound of Formula 10-4 is reacted with H ₂ O to synthesize the compound of Formula 10-5. Is reacted with benzyl bromide (BnBr) a compound of formula 0-5 Synthesis of a compound of formula 10-6 and mCPBA was added dropwise to the compound of formula 10-6 by the after the synthesis of a compound of formula 10-7, POCl ₃ Dropwise to synthesize a compound of formula (10-8). Trichloroborane and dimethyl sulfan salt are added dropwise to synthesize a compound of Formula 10-9, and premi salt is added dropwise to synthesize a compound of Formula 10-10. Finally, R-boronic acid pinacol ester (

) Or R-borate (

) Can be used to synthesize the compound of formula 10-11 using a microwave in the Suzuki reaction.

In addition, as shown in Scheme 2, the compound of Formula 10-12 may be synthesized by desalting the compound of Formula 10-11.

Hereinafter, the present application will be described in more detail with reference to Preparation Examples, Examples, and Experimental Examples. However, the following Preparation Examples, Examples and Experimental Examples are provided only to help understanding of the present application, the contents of the present application is not limited to the following Preparation Examples, Examples and Experimental Examples.

[ Production Example ] Preparation of Intermediate Compounds

Production Example 1: 2 - Chloro -5,6,8- Trimethoxyquinoline  Preparation of (Compound of Formula 1-6)

step 1: 1 , 2,4- Trimethoxy -5-nitrobenzene 1-2 Preparation of the compound

Water (300 ml) in which 60% nitric acid (100 ml) is dissolved is cooled to 0 ° C., and then slowly added dropwise to 2,4,5-trimethoxybenzaldehyde (5 g, 25.5 mmol) and dissolved at the same temperature. Stir for 1 hour. After completion of the reaction, the reaction mixture was filtered and washed with water to give the following, a dry yellow solid compound (formula 1-2).

Step 2: 2,4,5-trimethoxyaniline 1-3 Preparation of the compound

1,2,4-trimethoxy-5-nitrobenzene (Formula 1-2 , 3.75 g, 17.6 mmol) synthesized in Step 1 was dissolved in ethyl acetate (EtOAc) / methanol (MeOH) (5/1). Then, Pd / C (0.2 eq) was added dropwise and stirred for 8 hours at room temperature under a hydrogen balloon. After completion of the reaction, the reaction mixture was filtered through celite, dried and the solvent under reduced pressure to give a beige solid compound (formula 1-3).

step 3: 3 - Ethoxy -N- (2,4,5- Trimethoxyphenyl Acrylamide 1-4 Preparation of the compound

2,4,5-trimethoxyaniline (Formula 1-3 , 3.22 g, 17.6 mmol) and pyridine (4.26 ml, 52.7 mmol) synthesized in Step 2 were dissolved in dichloromethane (300 ml) at room temperature and brought to 0 ° C. Cooled. Thereafter, (E) -3-ethoxyacryloylchloride (2.84 g, 21.1 mmol) dissolved in dichloromethane (3 ml) was slowly added dropwise. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was removed under reduced pressure. Isolated and purified by MPLC (hexanes / ethyl acetate), (5/1) to give a solid compound (formula 1-4).

step 4: 5 , 6,8- Trimethoxyquinoline -2 (1H) -one 1-5 Preparation of the compound

To sulfuric acid (33.7 ml, 633 mmol) was slowly added dropwise 3-ethoxy-N- (2,4,5-trimethoxyphenyl) acrylamide (Formula 1-4 , 3.55 g, 12.65 mmol) synthesized in Step 3. After melting, the mixture was stirred at room temperature for 2 hours. Ice water was added to terminate the reaction, and extracted with dichloromethane three times. Thereafter, the organic layer was washed with a saturated aqueous NaHCO ₃ solution, the organic layer was dried over anhydrous MgSO _4, and the solvent was removed under reduced pressure. The reaction mixture was purified by recrystallization using ethyl acetate and hexane to give a solid compound (formula 1-5).

step 5: 2 - Chloro -5,6,8- Trimethoxyquinoline  Formula 1-6 Preparation of the compound

5,6,8-trimethoxyquinolin-2 (1H) -one (Formula 1-5 , 2.3 g, 9.78 mmol), pyridine (0.791 ml, 9.78 mmol) and dimethylformamide (DMF) synthesized in step 4 (40 ml) was dissolved in chlorobenzene (100 ml), then phosphorus oxychloride (5.47 ml, 58.7 mmol) was added dropwise and the reaction mixture was stirred at reflux for 3 hours. After completion of the reaction, the mixture was extracted three times with ethyl acetate. The organic layer was washed sequentially with brine and saturated aqueous NaHCO ₃ solution, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. Purification by re-crystallization using ethyl acetate and hexane to yield a solid compound (formula 1-6).

Production Example  2: N- (3- (4,4,5,5- Tetramethyl -1,3,2- Dioxaborolan -2-yl) phenyl) Cyclopropanecarboxamide  Preparation of (Compound 2-3)

Step 1: N- (3- Bromophenyl ) Cyclopropanecarboxamide  Formula 2-2 Preparation of the compound

3-bromoaniline (Formula 2-1 , 1.5 g, 8.72 mmol) was dissolved in dichloromethane (20 ml) and then N, N-diisopropylethylamine (DIPEA) (3.05 ml, 17.44 mmol, 2 eq) Was added dropwise at 0 ° C. and stirred for 5 minutes at the same temperature. Then cyclopropanecarbonylchloride (0.912 g, 8.72 mmol, 1 eq) was added dropwise at 0 ° C. After the reaction mixture was stirred for 20 minutes at the same temperature, the solid compound to complete the reaction with H ₂ O, and the organic layer under reduced pressure to remove the solvent (Chemical Formula 2-2) was obtained.

Step 2: N- (3- (4,4,5,5- Tetramethyl -1,3,2- Dioxaborolan -2-yl) phenyl) Cyclopropanecarboxamide  Formula 2-3 Preparation of the compound

The N- (3- bromophenyl) synthesized in step 1, cyclopropane-carboxamide (formula 2 -2, 2.1 g, 8.73 mmol ), potassium acetate (2.57 g, 26.2 mmol, 3 eq), Pd (dppf) Cl ₂ -CH ₂ Cl ₂ (0.713 g, 0.873 mmol, 0.1 eq) and B ₂ Pin ₂ (6.65 g, 26.2 mmol, 3 eq) was dissolved in dimethyl sulfoxide (DMSO) (20 ml). The temperature was raised to 80 ° C and the reaction mixture was stirred for 12 hours. After completion of the reaction, the reaction mixture was filtered through celite and extracted with ethyl acetate. The organic layer was washed with H ₂ O, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture MPLC; in isolated and purified (hexane / ethyl acetate 70: 30) to give a solid compound (formula 2-3).

Production Example 3: 5 -(4,4,5,5- Tetramethyl -1,3,2- Dioxaborolan -2-yl) -2,3- Dehydro Preparation of -1H-inden-1-one (compound of Formula 3-2)

5-Bromo-2,3-dihydro -1H- inden-1-one (Formula 3 -1, 1 g, 4.74 mmol ), potassium acetate (1.37 g, 14.22 mmol, 3 eq), Pd (dppf) Cl ₂ -CH ₂ Cl ₂ (0.384 g, 0.47 mmol, 0.1 eq) and B ₂ Pin ₂ (2.41 g, 9.48 mmol, 3 eq) was dissolved in DMF (25 ml). The temperature was raised to 80 ° C and the reaction mixture was stirred for 12 hours. After completion of the reaction, the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture MPLC; in isolated and purified (hexane / ethyl acetate 70: 30) to give a solid compound (formula 3-2).

Production Example 4: 4 -(4,4,5,5- Tetramethyl -1,3,2- Dioxaborolan -2-yl) -2,3- Dehydro Preparation of -1H-inden-1-one (compound of Formula 4-2)

4-Bromo-2,3-dihydro -1H- inden-1-one (Formula 4 -1, 1 g, 4.74 mmol ), potassium acetate (1.37 g, 14.22 mmol, 3 eq), Pd (dppf) Cl ₂ -CH ₂ Cl ₂ (0.384 g, 0.47 mmol, 0.1 eq), B ₂ Pin ₂ (2.41 g, 9.48 mmol, 3 eq) was dissolved in DMF (25 ml). The temperature was raised to 80 ° C and the reaction mixture was stirred for 12 hours. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous Na ₂ SO ₄ , and the solvent was removed under reduced pressure. The reaction mixture MPLC; in isolated and purified (hexane / di-ethyl acetate 70: 30) to give a solid compound (formula 4-2).

Production Example 5: 2 - methyl -5- (4,4,5,5- Tetramethyl -1,3,2- Dioxaborolan -2 days) Isoindolin Preparation of -1-one (compound of formula 5-3)

step 1: 5 - Bromo -2- Methylisoindolin -1-one (Formula 5-2 Preparation of the compound

Methyl 4-bromo-2- (bromomethyl) benzoate (formula 5 -1, 2.5 g, 8.12 mmol ) of 2M methanamine reflux for 18 hours and then dissolved in (122 ml, 244 mmol, 30 eq) Stirred. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with H ₂ O, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture MPLC; in isolated and purified (hexane / ethyl acetate 70:30) to give the target compound (formula 5-2).

step 2: 2 - methyl -5- (4,4,5,5- Tetramethyl -1,3,2- Dioxaborolan -2 days) Isoindolin -1-one (Formula 5-3 Preparation of the compound

The 5-bromo-2-methyl synthesized in Step 1 sweep turned-1-one (Formula 5 -2, 2.1 g, 9.20 mmol ), potassium acetate (2.26 g, 23 mmol, 2.5 eq), Pd (dppf) Cl ₂ -CH ₂ Cl ₂ (0.225 g, 0.28 mmol, 0.03 eq) and B ₂ Pin ₂ (2.34 g, 9.20 mmol, 1 eq) was dissolved in 1,4-dioxane (20 ml). The temperature was raised to 100 ° C. and the reaction mixture was stirred for 5 hours. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. Thereafter, the reaction mixture was separated and purified by MPLC (hexane / ethyl acetate; 70:30) to obtain a target compound (Formula 5-3 ).

Production Example 6: 1 Isopropyl-6- (4,4,5,5- Tetramethyl -1,3,2- Dioxaborolan 2-yl) -1H-indazole (compound of formula 6-2) and 2-isopropyl-6- (4,4,5,5- Tetramethyl Preparation of -1,3,2-dioxaborolan-2-yl) -2H-indazole (compound of formula 6-3)

6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole (Formula 6-1 , 2 g, 8.19 mmol) was added DMF (20 ml), 2-bromopropane (2.3 ml, 24.58 mmol, 3 eq) and potassium carbonate (3.4 g, 24.58 mmol, 3 eq) were added dropwise and stirred at 85 ° C. After completion of the reaction, the mixture was extracted with ethyl acetate. The organic layer was washed with H ₂ O, dried over anhydrous Na ₂ SO ₄ , and the solvent was removed under reduced pressure. The reaction mixture MPLC; in isolated and purified (hexane / ethyl acetate 70: 30) target compound (formula 6-2, 6-3) to afford respectively.

Production Example 7: 2 - methyl -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2 days) Benzo [d] thiazole  Preparation of (Compound of Formula 7-2)

5-Bromo-2-methylbenzo [d] thiazole7 -One, 0.5 g, 2.19 mmol), potassium acetate (0.753 g, 7.67 mmol, 3.5 eq), Pd (dppf) Cl₂-CH₂Cl₂ (0.179 g, 0.22 mmol, 0.1 eq), B₂Pin₂ (0.612 g, 2.41 mmol, 1.1 eq) was dissolved in 1,4-dioxane (15 ml). The temperature was raised to 100 ° C and the reaction mixture was stirred for 12 hours. After completion of the reaction, the mixture was extracted with ethyl acetate. Organic layer₂Washed with O, followed by anhydrous MgSO₄Dried, and the solvent was removed under reduced pressure. Thereafter, the reaction mixture was separated and purified by MPLC (hexane / ethyl acetate; 70:30) to obtain the target compound7- 2) Was obtained.

Production Example  8: Cyclopropyl (3- (4,4,5,5- Tetramethyl -1,3,2- Dioxaborolan Preparation of -2-yl) phenyl) methanone (compound of formula 8-2)

(3-bromophenyl) (cyclopropyl) methanone (Formula 8 -1, 0.5 g, 2.22 mmol ), potassium acetate (0.654 g, 6.66 mmol, 3 eq), Pd (dppf) Cl 2 -CH 2 Cl 2 (91 mg, 0.11 mmol, 0.05 eq) and B ₂ Pin ₂ (0.621 g, 2.44 mmol, 1.1 eq) was dissolved in 1,4-dioxane (10 ml). The temperature was raised to 80 ° C and the reaction mixture was stirred for 12 hours. After completion of the reaction, the mixture was extracted with ethyl acetate. The organic layer was washed with H ₂ O and then dried over anhydrous MgSO ₄ to remove the solvent under reduced pressure. The reaction mixture MPLC; in isolated and purified (hexane / ethyl acetate 90:10) to give the target compound (formula 8-2).

Production Example 9: 2 -(3 ', 4'- Dimethoxybiphenyl -3-yl) -4,4,5,5- Tetramethyl -1,3,2- Dioxaborolan  Preparation of (Compound of Formula 9-3)

step 1: 3 '- Bromo -3,4- Dimethoxy -1,1'-biphenyl 9-2 Preparation of the compound

1-bromo-3-iodo-benzene (formula 9 -1, 1 g, 3.53 mmol ) was dissolved in toluene (10 ml), dissolved in ethanol (3 ml) (3,4- dimethoxyphenyl) boronic acid (1.29 g, 7.07 mmol, 2 eq) and 2M Na ₂ CO ₃ aqueous solution (3 eq) were added dropwise and stirred under a nitrogen stream for 10 minutes. Thereafter, Pd (dppf) Cl ₂ —CH ₂ Cl ₂ (144 g, 0.18 mmol, 0.05 eq) was dissolved. The reaction mixture was stirred at reflux for 12 hours. After completion of the reaction, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture MPLC; in isolated and purified (hexane / ethyl acetate 90:10) to give the target compound (formula 9-2).

step 2: 2 -(3 ', 4'- Dimethoxybiphenyl -3-yl) -4,4,5,5- Tetramethyl -1,3,2- Dioxaborolan  Formula 9-3 Preparation of the compound

3'-bromo-3,4-dimethoxy-1,1'-biphenyl synthesized in Step 1 (Formula 9-2 , 0.538 g, 1.84 mmol), potassium acetate (0.54 g, 5.51 mmol, 3 eq) , Pd (dppf) Cl ₂ -CH ₂ Cl ₂ (15 mg, 0.018 mmol, 0.01 eq), B ₂ Pin ₂ (0.699 g, 2.75 mmol, 1.5 eq) was dissolved in DMSO (10 ml). The temperature was raised to 80 ° C and the reaction mixture was stirred for 12 hours. After completion of the reaction, the mixture was extracted with ethyl acetate. The organic layer was washed with H ₂ O, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture MPLC; in isolated and purified (hexane / ethyl acetate 70:30) to give the target compound (formula 9-3).

Production Example 10: 1 - Cyclopropyl -4- (4- (4,4,5,5- Tetramethyl -1,3,2- Dioxaborolan Preparation of 2-yl) phenyl) piperidine (compound of Formula 10-3)

step 1: 4 -(4- (4,4,5,5- Tetramethyl -1,3,2- Dioxaborolan -2-yl) phenyl) piperidine 10-2 Preparation of the compound

tert-butyl 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperidine-1-carboxylate (Formula 10-1 , 2 g, 5.16 mmol) was dissolved in dichloromethane (20 ml), and trifluoroacetic acid (TFA) (7.96 ml, 103 mmol, 20 eq) was added dropwise at room temperature, and stirred at the same temperature for 2 hours. The reaction of the reaction mixture was terminated with H ₂ O and extracted with ethyl acetate. The organic layer was washed with H ₂ O, dried over anhydrous MgSO _4, and the organic layer under reduced pressure to remove the solvent to give the objective compound (10-2 formula).

step 2: 1 - Cyclopropyl -4- (4- (4,4,5,5- Tetramethyl -1,3,2- Dioxaborolan -2-yl) phenyl) piperidine 10-3 Preparation of the compound

Synthesized in Step 1, 4- (4- (4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl) phenyl) piperidine (Formula 10 -2, 953 mg , 3.28 mmol) in tetrahydrofuran (THF) (20 ml) and methanol (20 ml), followed by (1-ethoxycyclopropoxy) trimethylsilane (3.3 ml, 16.42 mmol, 5 eq) and acetic acid (0.376 ml, 26.2 mmol, 3 eq) was added dropwise at room temperature. After the reaction mixture was stirred for 10 minutes, sodium cyanoborohydride (0.516 g, 8.21 mmol, 2.5 eq) was added dropwise and stirred. After completion of the reaction with a saturated aqueous NaHCO ₃ solution, the mixture was extracted with ethyl acetate. After drying over anhydrous MgSO ₄ , the solvent was removed under reduced pressure. The reaction mixture MPLC; in isolated and purified (hexane / ethyl acetate 70: 30) to give a solid compound (Formula 10-3).

Production Example  11: potassium Trifluoro (2- (4- ( Trifluoromethoxy ) Phenoxy Preparation of Pyrimidin-5-yl) borate (Compound 11-4)

step 1: 5 - Bromo -2- (4- ( Trifluoromethoxy ) Phenoxy Pyrimidine 11-3 Preparation of the compound

5-bromo-2-iodopyrimidine (Formula 11-1 , 0.5 g, 1.76 mmol) was dissolved in DMSO (23 ml), and then 4- (trifluoromethoxy) phenol (Formula 11-2 , 0.341 ml) , 2.63 mmol, 1.5 eq) and K ₂ CO ₃ (485 mg, 3.51 mmol, 2 eq) were added dropwise at room temperature. The reaction mixture was stirred at 120 ° C. for 1 hour and then cooled to room temperature. The reaction of the reaction mixture was terminated with H ₂ O and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO ₄ , and the organic layer was depressurized to remove the solvent. The reaction mixture MPLC; in isolated and purified (hexane / ethyl acetate 90:10) to give the target compound (Formula 11-3).

Step 2: potassium Trifluoro (2- (4- ( Trifluoromethoxy ) Phenoxy Pyrimidin-5-yl) borate 11-4 Preparation of the compound

Was dissolved in a 5-bromo-2- (4- (trifluoromethoxy) phenoxy) pyrimidine (Formula 11-3, 386 mg, 1.15 mmol) prepared in Step 1 in THF (10 ml), -78 Cool to C and add 1.6M n-butyllithium (1.30 ml, 2.07 mmol, 1.8 eq) dropwise. Then, after stirring for 1 hour at the same temperature, triisopropylborate (0.535 ml, 2.30 mmol, 2 eq) was added dropwise at the same temperature. The reaction mixture was stirred at the same temperature for 1 hour, then raised to 0 ° C. and 4.5M potassium hydrogendifluoride aqueous solution (0.768 ml, 3.46 mmol, 3 eq) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure. Thereafter, the reaction mixture was dissolved in methanol and filtered, and the filtrate was reduced in pressure to obtain a target compound (Formula 11-4 ).

Production Example  12: Preparation of Potassium Trifluoro (2-phenoxypyrimidin-5-yl) borate (Compound of Formula 12-3)

step 1: 5 - Bromo -2- Phenoxypyrimidine  Formula 12-2 Preparation of the compound

5-bromo-2-iodopyrimidine (Formula 4-1 , 0.5 g, 1.76 mmol) was dissolved in DMSO (25 ml), followed by phenol (Formula 12-1 , 0.232 ml, 2.63 mmol, 1.5 eq) and K ₂ CO ₃ (485 mg, 3.51 mmol, 2 eq) was added dropwise at room temperature. The reaction mixture was stirred at 120 ° C. for 1 hour and then cooled to room temperature. The reaction of the reaction mixture was terminated with H ₂ O and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO ₄ , and the organic layer was depressurized to remove the solvent. The reaction mixture MPLC; in isolated and purified (hexane / ethyl acetate 90:10) to give the target compound (Formula 12-2).

Step 2: potassium trifluoro (2-phenoxypyrimidin-5-yl) borate 12-3 Preparation of the compound

5-Bromo-2-phenoxypyrimidine (Formula 12-2 , 412 mg, 1.64 mmol) synthesized in Step 1 was dissolved in THF (10 ml), cooled to -78 ° C, and 1.6M n-butyl Lithium (1.85 ml, 2.95 mmol, 1.8 eq) was added dropwise. Then, after stirring for 1 hour at the same temperature, triisopropylborate (0.762 ml, 3.28 mmol, 2 eq) was added dropwise at the same temperature. The reaction mixture was stirred at the same temperature for 1 hour, then raised to 0 ° C. and 4.5M aqueous potassium hydrogendifluoride solution (1.1 ml, 4.92 mmol, 3 eq) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure. After, the reaction mixture was dissolved in methanol, filtered, and concentrated under a reduced pressure to give the target compound (Formula 12-3).

Production Example  13: potassium Trifluoro (2-( Trifluoromethyl Pyridin-3-yl) Borate  Preparation of (Compound 13-2)

Using the same method as described in Step 2 of Preparation Example 12, but instead of 5-bromo-2-phenoxypyrimidine (Formula 12-2 ), 3-bromo-2- (trifluoromethyl) pyridine (Formula 12) 13-1) to give the objective compound (13-2) using the formula.

Production Example  14: potassium Trifluoro (quinolin-2-yl) borate  Preparation of (Compound of Formula 14-2)

2-bromoquinoline (Formula 14-1 , 1 g, 4.81 mmol) was dissolved in THF (20 ml), then cooled to -78 ° C and 1.6 M n-butyllithium (5.41 ml, 8.65 mmol, 1.8 eq) Was slowly added dropwise. Then, after stirring for 1 hour at the same temperature, triisopropylborate (2.23 ml, 9.61 mmol, 2 eq) was added dropwise at the same temperature. The reaction mixture was stirred at the same temperature for 1 hour, then the temperature was raised to 0 ° C. and 1M aqueous potassium hydrogendifluoride solution (14.42 ml, 14.42 mmol, 3 eq) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure. After, the reaction mixture was dissolved in methanol, filtered, and concentrated under a reduced pressure to give the target compound (Formula 14-2).

Production Example  15: Preparation of Potassium Trifluoro (5-methoxypyridin-2-yl) borate (Compound 15-2)

, Use the same method as that described for preparation 14 and 2-bromo-quinoline (Formula 14-1) instead of 2-bromo-5-methoxypyridine target compound was obtained (Formula 15-1) (Formula 15 2 ) was obtained.

Production Example 16: 2 - Methoxy -6- ( Tributylstannyl ) Pyrazine  Preparation of (Compound of Formula 16-2)

Was dissolved in 2-bromo-6-methoxy-pyrazine (Formula 16-1, 50 mg, 0.27 mmol) and _{Pd (Ph 3) 4 (15} mg, 0.013 mmol, 0.05 eq) in toluene (1 ml), Hexabutyldithianic acid (153 mg, 0.27 mmol, 1.0 eq) was added dropwise and stirred at 110 ° C. for 8 hours. The reaction mixture was cooled to room temperature, filtered through celite and extracted with dichloromethane. The organic layer was washed with H ₂ O, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. Then, the separation and purification of the reaction mixture by MPLC to give the target compound (Formula 16-2).

Production Example  17: N- (2- (2- Fluorophenyl ) -5,8- Dioxo -5,8- Dihydroquinoline -7-yl) acetamide (compound of formula 17-10)

step 1: 5 - Chloro -7- Nitroquinoline -8-ol (formula) 17-2 Preparation of the compound

The mixture of 5-chloroquinolin-8-ol (Formula 17-1 , 20 g, 111 mmol) dissolved in sulfuric acid (100 ml) was cooled to 0 ° C., followed by 70% nitric acid (8.53 ml, 134 mmol, 1.2 eq). Slowly added dropwise so that the internal temperature does not exceed 2 ℃. After stirring for 1 hour at the same temperature, the ice water was removed, the temperature was raised to room temperature and stirred for another 4 hours. After completion of the reaction, ice water was added dropwise and stirred for 4 hours. It was filtered and washed with water and the resulting yellow solid, and then dried to give the target compound (Formula 17-2).

step 2: 7 - Aminoquinoline -8-ol (formula) 17-3 Preparation of the compound

After the 5-chloro-7-nitro-quinolin-8-ol (Formula 17-2, 15 g, 68 mmol) prepared in Step 1 was dissolved in methanol (400 ml), dropwise with Pd / C (0.1 eq) and It was stirred for 3 days at room temperature under a hydrogen balloon. After completion of the reaction, the reaction mixture was filtered through celite, dried and the solvent under reduced pressure to give a solid compound (Formula 17-3).

step 3: 7 - Acetamidoquinoline -8-yl acetate 17-4 Preparation of the compound

Synthesized in step 2 7-aminoquinolin-8-ol (Formula 17-3 , 11 g, 68.7 mmol, 1 eq) was dissolved in THF (300 ml) and then N, N-diisopropylethylamine (48 ml, 275 mmol, 4 eq) was added dropwise and the reaction mixture was cooled to 0 ° C. Thereafter, acetylchloride (12 ml, 172 mmol, 2.5 eq) dissolved in THF (43 ml) was slowly added dropwise at the same temperature. The reaction mixture was stirred at rt for 8 h, the solvent was dried under reduced pressure, dissolved in dichloromethane and washed with water. The organic layer was dried over anhydrous MgSO ₄ and the solvent removed under reduced pressure to give the target compound (Formula 17-4).

Step 4: N- (8- Hydroxyquinoline -7 days) Acetamide  Formula 17-5 Preparation of the compound

Dissolve 7 -acetamidoquinolin-8-yl acetate (Formula 17-4 , 15 g, 62 mmol) synthesized in step 3 in methanol (400 ml), and then dropwise add H ₂ O (40 ml) to 1 The reflux was stirred for an hour. After completion of the reaction, the reaction mixture was dried under reduced pressure to give the target compound (Formula 17-5).

Step 5: N- (8- ( Benzyloxy ) Quinolin-7-yl) acetamide 17-6 Preparation of the compound

N- (8-hydroxyquinolin-7-yl) acetamide (Formula 17-5 , 14 g, 68 mmol) synthesized in step 4 was dissolved in DMF (200 ml), followed by potassium carbonate (14 g, 102 mmol, 1.5 eq) and benzylbromide (12 ml, 102 mmol, 1.5 eq) were added dropwise and stirred at 50 ° C. for 8 hours. After completion of the reaction, the mixture was dissolved in dichloromethane, filtered through celite, and the solvent was dried under reduced pressure. Thereafter, MPLC (hexanes / ethyl acetate) to separate and purify the target compound (Formula 17-6) was obtained.

step 6: 7 - Acetamido -8-( Benzyloxy Quinoline 1- Oxide  Formula 17-7 Preparation of the compound

Was dissolved in a - ((benzyloxy) quinolin-7-one 8) acetamide (Formula 17-6, 14 g, 47 mmol) in 1,2-dichloroethane (140 ml), the synthesis in step 5, N- Meta -chloroperoxybenzoic acid (mCPBA) (16 g, 95 mmol, 2 eq) was added dropwise and stirred at room temperature for 48 hours. After completion of the reaction, the mixture was filtered through celite and the solvent was dried under reduced pressure. Then, the isolated and purified by MPLC (dichloromethane / methanol) to give the target compound (Formula 17-7).

Step 7: N- (8- ( Benzyloxy )-2- Chloro  Quinolin-7-yl) acetamide 17-8 Preparation of the compound

7-acetamido-8- (benzyloxy) quinoline 1-oxide (Formula 17-7 , 13 g, 42 mmol) synthesized in step 6 was dissolved in chloroform (300 ml) and then in chloroform (3 ml). Melted POCl ₃ (4.7 ml, 50 mmol, 1.2 eq) was added dropwise and stirred for 15 minutes. The reaction mixture was refluxed and cooled for 2 hours, then ice was added and 6 N NaOH was slowly added dropwise until the pH was about 12. Extracted with dichloromethane, washed with water, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure to obtain the target compound (Formula 17-8 ).

Step 8: N- (2- Chloro -8- Hydroxyquinoline -7-yl) acetamide 17-9 Preparation of the compound

After dissolving N- (8- (benzyloxy) -2-chloroquinolin-7-yl) acetamide (Formula 17-8 , 6 g, 17 mmol) synthesized in step 7 in dichloromethane (100 ml), 2M trichloroborane dimethylsulfide (85 ml, 170 mmol, 10 eq) was added dropwise and stirred at room temperature for 8 hours. After completion of the reaction with a saturated aqueous NaHCO ₃ solution, the mixture was extracted with dichloromethane. The organic layer was washed with water and then dried over anhydrous MgSO ₄ and the solvent removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC (hexanes / ethyl acetate) to give the target compound (Formula 17-9).

Step 9: N- (2-chloro-5,8-dioxo-5,8-dihydro Quinolin-7-yl) Acetamide (Formula) 17-10 Compound of  Produce

After dissolving N- (2-chloro-8-hydroxyquinolin-7-yl) acetamide (Formula 17-9 , 3 g, 13 mmol) synthesized in step 8 in acetone (200 ml), NaH ₂ PO Premi salt (potassium nitrosodisulfonate) (5.57 g, 21 mmol, 1.6 eq) dissolved in ₄ buffer (0.3M, 200 ml) was added dropwise and stirred at room temperature for 8 hours. Acetone was removed under reduced pressure, and then extracted with dichloromethane. The organic layer was dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. Then, using ethyl acetate and hexane to give Solid Defining this to give a solid compound (formula 17-10).

Production Example 18: 4 , 4,5,5- Tetramethyl -2- (4- ( Tetrahydro -2H-pyran-4- Iloxy ) Phenyl) -1,3,2-dioxaborolane (compound of formula 18-3)

step 1: 4 -(4- Bromophenoxy ) Tetrahydro -2H-pyran (formula) 18-2 Preparation of the compound

4-bromophenol (Formula 18-1 , 500 mg, 2.89 mmol), 4-hydroxytetrahydropyran (0.4 ml, 4.34 mmol, 1.5 eq) and triphenylphosphine (PPh ₃ ) (1.1 g, 4.34 mmol , 1.5 eq) was dissolved in toluene (8 ml), then diethyl azodicarboxylate (DEAD) (1.4 ml, 3.18 mmol, 1.1 eq) was added dropwise at 0 ° C. The reaction mixture was stirred at room temperature for 45 minutes. After completion of the reaction, the solvent was removed under reduced pressure, dissolved in diethyl ether, and the resulting solid was filtered off. Ethyl acetate was added to the filtrate, washed with H ₂ O, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. Then, the separation and purification of the reaction mixture by MPLC to give the target compound (Formula 18-2).

step 2: 4 , 4,5,5- Tetramethyl -2- (4- ( Tetrahydro -2H-pyran-4- Iloxy ) Phenyl) -1,3,2-dioxaborolane (formula) 18-3 Preparation of the compound

4- (4-Bromophenoxy) tetrahydro-2H-pyran synthesized in Step 1 (Formula 18-2 , 638 mg, 2.48 mmol), potassium acetate (731 mg, 7.44 mmol, 3 eq), Pd (dppf Cl ₂ -CH ₂ Cl ₂ (203 mg, 0.25 mmol, 0.1 eq) and B ₂ Pin ₂ (756 mg, 2.98 mmol, 1.2 eq) was dissolved in 1,4-dioxane (15 ml). The temperature was raised to 100 ° C and the reaction mixture was stirred for 12 hours. After completion of the reaction, the reaction mixture was filtered through celite and extracted with ethyl acetate. The organic layer was washed with H ₂ O, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC (hexanes / ethyl acetate) to give the target compound (Formula 18-3).

Production Example 19: 1 Isopropyl-4- (4- (4,4,5,5- Tetramethyl -1,3,2- Dioxaborolan Preparation of -2-yl) phenoxy) piperidine (compound of formula 19-4)

Step 1: synthesized 1- (4- (4- Bromophenoxy Piperidin-1-yl) -2,2-dimethylpropan-1-one 19-1 Preparation of the compound

4-bromophenol (Formula 18-1 , 500 mg, 2.89 mmol), 4-hydroxypiperidine-1-carboxylate (0.87 g, 4.34 mmol, 1.5 eq) and triphenylphosphine (1.1 g, 4.34 mmol, 1.5 eq) was dissolved in anhydrous THF (8 ml), then DEAD (1.4 ml, 3.18 mmol, 1.1 eq) was added dropwise at 0 ° C. The reaction mixture was stirred at room temperature for 8 hours. After completion of the reaction, the solvent was removed under reduced pressure, dissolved in diethyl ether, and the resulting solid was filtered off. Ethyl acetate was added to the filtrate, washed with H ₂ O, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. Then, the separation and purification of the reaction mixture by MPLC to give the target compound (Formula 19-1).

step 2: 4 -(4- Bromophenoxy Piperidine 19-2 Preparation of the compound

1- (4- (4-bromophenoxy) piperidin-1-yl) -2,2-dimethylpropan-1-one (Formula 19-1 , 913 mg, 2.68 mmol) synthesized in Step 1 was prepared. After dissolving in dichloromethane (DCM) (10 ml), TFA (5.1 ml, 67.1 mmol, 25 eq) was slowly added dropwise at 0 ° C. The reaction mixture was stirred at room temperature for 2.5 hours and the solvent was removed under reduced pressure. By washing the reaction mixture as a saturated aqueous solution of NaHCO ₃ and brine, dissolved in ethyl acetate, in order, and then dried over anhydrous MgSO ₄ and the solvent removed under reduced pressure to give the target compound (Formula 19-2).

step 3: 4 -(4- Bromophenoxy )-One- Isopropylpiperidine  Formula 19-3 Preparation of the compound

4- (4-bromophenoxy) piperidine (Formula 19-2 , 200 mg, 0.78 mmol) synthesized in step 2 was dissolved in THF (1 ml) / 1,2-dichloroethane (2 ml) Then AcOH (3 drops), acetone (0.25 ml, 3.36 mmol, 4.3 eq) and sodium triacetoxyborohydride (331 mg, 1.56 mmol, 2 eq) were added dropwise at room temperature. The reaction mixture was stirred at 40 ° C. for 24 hours and the reaction was terminated with saturated aqueous NaHCO ₃ . Extracted with ethyl acetate, washed with water and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. Then, the separation and purification of the reaction mixture by MPLC to give the target compound (Formula 19-3).

step 4: 1 Isopropyl-4- (4- (4,4,5,5- Tetramethyl -1,3,2- Dioxaborolan -2-yl) phenoxy) piperidine 19-4 Preparation of the compound

4- (4-Bromophenoxy) -1-isopropylpiperidine synthesized in step 3 (Formula 19-3 , 145 mg, 0.49 mmol), potassium acetate (143 mg, 1.46 mmol, 3 eq), Pd (dppf) Cl ₂ -CH ₂ Cl ₂ (20 mg, 0.024 mmol, 0.05 eq) and B ₂ Pin ₂ (148 mg, 0.58 mmol, 1.2 eq) was dissolved in DMSO (3 ml). The reaction mixture was reacted at 85 ° C. for 2 hours in a Biotage microwave. The reaction was terminated with water and extracted with ethyl acetate. The organic layer was washed with H ₂ O, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. Then, the separation and purification of the reaction mixture by MPLC (dichloromethane / methanol) to give a solid compound (Formula 19-4).

Production Example 20: 4 -(4- (4,4,5,5- Tetramethyl -1,3,2- Dioxaborolan -2 days) Phenoxy Preparation of Pyridine (Compound of Formula 20-2)

step 1: 4 -(4- Bromophenoxy Pyridine 20-1 Preparation of the compound

4-bromophenol (Formula 18-1 , 150 mg, 0.87 mmol) was slowly added dropwise at 0 ° C. to DMF (3 ml) in which NaH (42 mg, 1 mmol, 1.2 eq) was dissolved. After stirring for 5 minutes at the same temperature, the mixture was stirred under reflux for 45 minutes at 180 ° C. After completion of the reaction, the mixture was cooled to room temperature, filtered through celite, and extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. Then, the separation and purification of the reaction mixture by MPLC to give the target compound (Formula 20-1).

step 2: 4 -(4- (4,4,5,5- Tetramethyl -1,3,2- Dioxaborolan -2 days) Phenoxy Pyridine 20-2 Preparation of the compound

4- (4-bromophenoxy) pyridine synthesized in step 1 (Formula 20-1 , 109 mg, 0.44 mmol), potassium acetate (128 mg, 1.31 mmol, 3 eq), Pd (dppf) Cl ₂ -CH ₂ Cl ₂ (11 mg, 0.013 mmol, 0.03 eq) and B ₂ Pin ₂ (133 mg, 0.52 mmol, 1.2 eq) was dissolved in DMSO (3 ml). The temperature was raised to 120 ° C and the reaction mixture was stirred for 12 hours. After completion of the reaction, the reaction mixture was filtered through celite and extracted with ethyl acetate. The organic layer was washed with H ₂ O, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC (hexanes / ethyl acetate) to give the target compound (Formula 20-2).

Production Example 21: 1 - methyl -4- (4- (4,4,5,5- Tetramethyl -1,3,2- Dioxaborolan -2 days) Phenoxy Preparation of Piperidine (Compound of Formula 21-2)

step 1: 4 -(4- Bromophenoxy )-One- Methylpiperidine  Formula 21-1 Preparation of the compound

4- (4-bromophenoxy) piperidine (Formula 19-2 , 150 mg, 0.59 mmol) synthesized in Step 2 of Preparation Example 19 was dissolved in formic acid (3 ml), and then formaldehyde (69 ul , 1.87 mmol, 3.2 eq) was added dropwise at room temperature. The reaction mixture was reacted at 150 ° C. for 5 minutes in a Biotage microwave. After the completion of the reaction, the solvent was removed under reduced pressure and dissolved in ethyl acetate. NaHCO ₃ and was washed with a saturated aqueous solution and brine, then dried over anhydrous MgSO ₄ and the solvent removed under reduced pressure to give the target compound (Formula 21-1).

step 2: 1 - methyl -4- (4- (4,4,5,5- Tetramethyl -1,3,2- Dioxaborolan -2 days) Phenoxy Piperidine 21-2 Preparation of the compound

Using the same method as described in step 4 of Preparation Example 19, but instead of 4- (4-bromophenoxy) -1-isopropylpiperidine (Formula 19-3 ), 4- (4-bromophenoxy ) -1-methyl-piperidine (using the formula 21-1) to give the target compound (formula 21-2).

Production Example 22: 1 -Ethyl-4- (4- (4,4,5,5- Tetramethyl -1,3,2- Dioxaborolan -2 days) Phenoxy Preparation of Piperidine (Compound of Formula 22-2)

step 1: 4 -(4- Bromophenoxy )-One- Ethyl piperidine  Formula 22-1 Preparation of the compound

A compound of Preparation 19, Step 2 4- (4-bromophenoxy) piperidine (Formula 19-2, 150 mg, 0.59 mmol) to THF (0.5 ml) / 1,2- dichloroethane (1 ml ), AcOH (3 drops), acetaldehyde (0.16 ml, 2.93 mmol, 5 eq) and sodium triacetoxyborohydride (248 mg, 1.17 mmol, 2 eq) were added dropwise at room temperature. The reaction mixture was stirred at 40 ° C. for 12 h and the reaction was terminated with saturated aqueous NaHCO ₃ . Extracted with ethyl acetate, washed with water and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. Then, the separation and purification of the reaction mixture by MPLC to give the target compound (Formula 22-1).

step 2: 1 -Ethyl-4- (4- (4,4,5,5- Tetramethyl -1,3,2- Dioxaborolan -2 days) Phenoxy Piperidine 22-2 Preparation of the compound

Using the same method as described in step 4 of Preparation Example 19, but instead of 4- (4-bromophenoxy) -1-isopropylpiperidine (Formula 19-3 ), 4- (4-bromophenoxy ) -1-methyl-piperidine (using the formula 22-1) to give the target compound (formula 22-2).

[ Example Quinoline-5,8- Dion  Preparation of Derivative Compounds

Example One: 2 -(3- Acetylphenyl ) -6- Methoxyquinoline -5,8- Dion of  Produce

Step 1: methyl  1- (3- (5,6,8- Trimethoxyquinoline -2 days) phenyl) Ethanon  Manufacture

2-chloro-5,6,8-trimethoxyquinoline (Formula 1-6 , 1eq) synthesized in Preparation Example 1 was dissolved in dimethyl ether (DME), and then Pd (dppf) Cl ₂ -CH ₂ Cl ₂ (10 mol%), 3-acetylphenylboronic acid (1.1eq) and 2M Na ₂ CO ₃ aqueous solution (4 eq) were added dropwise at room temperature and stirred for 10 minutes. The reaction mixture was reacted with Biotage microwave at 160 ° C. for 30 minutes. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give 1- (3- (5,6,8-trimethoxyquinolin-2yl) phenyl) ethanone.

step 2: 2 -(3- Acetylphenyl ) -6- Methoxyquinoline -5,8- Dion's  Produce

1- (3- (5,6,8-trimethoxyquinolin-2-yl) phenyl) ethanone (1 eq) synthesized in step 1 was dissolved in a small amount of acetonitrile (ACN), and then 0.6 M of cerium ammonium nitrate (CAN) (3 eq) aqueous solution was slowly added dropwise to 0 ° C. The reaction mixture was stirred at rt for 12 h. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.

1 H NMR (400 MHz, CDCl 3) δ 8.68 (s, 1H), 8.56 (d, J = 8.3 Hz, 1H), 8.48 (d, J = 7.8 Hz, 1H), 8.16 (d, J = 8.3 Hz, 1H) , 8.1 (d, J = 7.8 Hz, 1H), 8.48 (t, J = 7.7 Hz, 1H), 6.40 (s, 1H), 3.97 (s, 3H), 2.71 (s, 3H). MS 308 (M + 1).

Example  2 to Example  35

Using the same method as described in Example 1, but using R listed in Table 3 below in place 1 of 3-acetylphenylboronic acid to obtain the compounds of Examples 2 to 35.

TABLE 3

Example 36: 6 - Methoxy -2- (2- Methylpyrimidine -5-yl) quinoline-5,8- Dion's  Produce

step 1: 5 , 6,8- Trimethoxy -2- (2- Methylpyrimidine Preparation of -5-yl) quinoline

The 2-chloro -5,6,8- trimethoxy-quinoline (formula 1 -6, 1eq) synthesized in Preparation Example _{1 THF: H 2 O (4} : 1) was dissolved in, Pd (dppf) Cl ₂ -CH ₂ Cl ₂ (10 mol%), 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidine and K ₂ CO ₃ (3 eq) Was added dropwise at room temperature and stirred for 10 minutes. The reaction mixture was reacted for 30 minutes at 70 ° C. with a Biotage microwave. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give 5,6,8-trimethoxy-2- (2-methylpyrimidin-5-yl) quinoline.

step 2: 6 - Methoxy -2- (2- Methylpyrimidine -5-yl) quinoline-5,8- Dion's  Produce

5,6,8-trimethoxy-2- (2-methylpyrimidin-5-yl) quinoline (1 eq) synthesized in step 1 was dissolved in a small amount of ACN and then 0.6 M at 0 ° C. in the dark. CAN (3 eq) aqueous solution was slowly added dropwise. The reaction mixture was stirred at rt for 12 h. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.

1 H NMR (400 MHz, CDCl 3) δ 9.49 (s, 2H), 9.36 (s, 1H), 8.63 (d, J = 8.2 Hz, 1H), 8.13 (d, J = 8.2 Hz, 1H), 6.44 (s , 1H), 3.99 (s, 3H). MS 267.95 (M).

Example  37 to Example  39

Use the same method as described in Example 36, except that in Step 1, 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine The compounds of Examples 37-39 were obtained using R listed in Table 4 below instead of midine.

TABLE 4

Example 40: 2 -(3- Acryloylphenyl ) -6- Methoxyquinoline -5,8- Dion's  Produce

step 1: 1 -(3- (5,6,8- Trimethoxyquinoline -2-yl) phenyl) Prof Preparation of 2-en-1-one

1- (3- (5,6,8-trimethoxyquinolin-2-yl) phenyl) ethanone (1 eq) synthesized in step 1 of Example 1 was dissolved in tetrahydrofuran (THF), Paraformaldehyde (2 eq), diisopropylamine, 2,2,2-trifluoroacetic acid salt (1 eq) and trifluoroacetic acid (TFA) (0.1 eq) were added dropwise at room temperature. The reaction mixture was stirred at reflux for 3 days. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with H ₂ O, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC (hexane / ethylacetate; 70:30) to give 1- (3- (5,6,8-trimethoxyquinolin-2-yl) phenyl) prop-2-ene 1-one was obtained.

step 2: 2 -(3- Acryloylphenyl ) -6- Methoxyquinoline -5,8- Dion's  Produce

Using the same method as described in step 2 of Example 1, but instead of 1- (3- (5,6,8-trimethoxyquinolin-2-yl) phenyl) ethanone synthesized in Step 1 of this Example The title compound was synthesized using 1- (3- (5,6,8-trimethoxyquinolin-2-yl) phenyl) prop-2-en-1-one.

1 H NMR (400 MHz, CDCl 3) δ 8.67 (t, J = 1.6 Hz, 1H), 8.57 (d, J = 8.1 Hz, 1H), 8.50 (m, 1H), 8.17 (d, J = 8.3 Hz, 1H) , 8.10 (m, 1H), 7.68 (t, J = 7.7 Hz, 1H), 7.24 (m, 1H), 6.52 (dd, J = 17.1, 1.4 Hz, 1H), 6.41 (s, 1H), 6.02 ( dd, J = 10.6, 1.6 Hz, 1H), 3.98 (s, 3H). MS 320 (M + 1).

Example 41: 7 - Bromo -6- Methoxy -2- Phenylquinoline -5,8- Dion's  Produce

step 1: 5 , 6,8- Trimethoxy -2- Phenylquinoline  Produce

2-chloro-5,6,8-trimethoxyquinoline (Formula 1-6 , 1eq) synthesized in Preparation Example 1 was dissolved in DME, and then Pd (dppf) Cl ₂ -CH ₂ Cl ₂ (10 mol%) ), 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane (1.1eq) and 2M Na ₂ CO ₃ aqueous solution (4 eq) were added dropwise at room temperature, followed by 10 minutes Stirred. The reaction mixture was reacted with Biotage microwave at 160 ° C. for 30 minutes. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give 5,6,8-trimethoxy-2-phenylquinoline.

step 2: 6 - Methoxy -2- Phenylquinoline -5,8- Dion's  Produce

5,6,8-trimethoxy-2-phenylquinoline (1 eq) synthesized in Step 1 was dissolved in a small amount of ACN, and then slowly added dropwise 0.6 M of CAN (3 eq) solution at 0 ° C. in a dark place. It was. The reaction mixture was stirred at rt for 12 h. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give 6-methoxy-2-phenylquinoline-5,8-dione.

1 H NMR (400 MHz, DMSO) δ 8.83 (s, 1H), 8.51 (d, J = 6.8 Hz, 1H), 8.48 (s, 2H), 8.14 (d, J = 5.2 Hz, 1H), 7.75 (t , J = 7.8 Hz, 1H), 6.55 (s, 1H), 3.94 (s, 3H), 3.91 (s, 3H)

step 3: 7 - Bromo -6- Methoxy -2- Phenylquinoline -5,8- Dion's  Produce

6-methoxy-2-phenylquinoline-5,8-dione synthesized in step 2 After (1 eq) was dissolved in chloroform, bromine (Br ₂ ) (1.1 eq) was added dropwise at 0 ° C., and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.

1 H NMR (400 MHz, DMSO) δ 8.45 (d, J = 8.3 Hz, 1H), 8.19 (m, 2H), 8.09 (d, J = 8.2 Hz, 1H), 7.53 (m, 3H), 4.36 (s , 3H). MS 345.60 (M + 1).

Example  42 to Example  67

Using the same method as described in Example 41, but replacing in step 1 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane, R listed in Table 5 below Was used to obtain the compounds of Examples 42-67.

TABLE 5

Example 68: 7 - Bromo -6- Methoxy -2- (pyrimidin-5-yl) quinoline-5,8- Dion's  Produce

step 1: 5 , 6,8- Trimethoxy Preparation of 2- (pyrimidin-5-yl) quinoline

The 2-chloro -5,6,8- trimethoxy-quinoline (formula 1 -6, 1eq) synthesized in Preparation Example _{1 THF: H 2 O (4} : 1) was dissolved in, Pd (dppf) Cl ₂ -CH ₂ Cl ₂ (10 mol%), pyrimidin-5-ylboronic acid and K ₂ CO ₃ (3 eq) were added dropwise at room temperature and stirred for 10 minutes. The reaction mixture was reacted for 30 minutes at 70 ° C. with a Biotage microwave. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give 5,6,8-trimethoxy-2- (pyrimidin-5-yl) quinoline.

step 2: 6 - Methoxy -2- (pyrimidin-5-yl) quinoline-5,8- Dion's  Produce

5,6,8-trimethoxy-2- (pyrimidin-5-yl) quinoline (1 eq) synthesized in step 1 was dissolved in a small amount of ACN, and then 0.6 M of CAN (3 eq) aqueous solution was slowly added dropwise. The reaction mixture was stirred at rt for 12 h. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give 6-methoxy-2- (pyrimidin-5-yl) quinolin-5,8-dione.

step 3: 7 - Bromo -6- Methoxy -2- (pyrimidin-5-yl) quinoline-5,8- Dion's  Produce

6-methoxy-2- (pyrimidin-5-yl) quinolin-5,8-dione synthesized in step 2 (1 eq) was dissolved in chloroform, bromine (1.1 eq) was added dropwise at 0 ° C. and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.

1 H NMR (400 MHz, CDCl 3) δ 9.50 (s, 2H), 9.37 (s, 1H), 8.57 (d, J = 8.2 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 4.39 (s , 3H). MS 347.95 (M + 1).

Example  69 and Example  70

The compounds of Examples 69 and 70 were obtained using the same methods as described in Example 68, using R listed in Table 6 below in place 1 of pyrimidine-5-ylboronic acid.

TABLE 6

Example 71: 3 -(7- Bromo -6- Methoxy -5,8- Dioxo -5,8- Dihydroquinoline -2-yl) Preparation of Benzamide

Step 1: methyl  3- (7- Bromo -6- Methoxy -5,8- Dioxo -5,8- Dehydro  Preparation of Quinolin-2-yl) benzoate

Use the same method as described in Example 41, but with 3- (methoxycarbonyl) instead of 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane in Step 1 Phenylboronic acid was used to give methyl 3- (7-bromo-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl) benzoate.

step 2: 3 -(7- Bromo -6- Methoxy -5,8- Dioxo -5,8- Dihydroquinoline -2-yl) Preparation of Benzamide

Methyl 3- (7-bromo-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl) benzoate synthesized in step 1 was dissolved in 7M ammonia in methanol solution. After dissolution, sodium cyanide (0.1 eq) was added dropwise at room temperature. The reaction mixture was stirred for 3 days at room temperature. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by PTLC (dichloromethane / methanol; 98: 2) to afford the title compound.

1 H NMR (400 MHz, CDCl 3) δ 8.74 (s, 1H), 8.53 (d, J = 8.0 Hz, 1H), 8.46 (d, J = 8.2 Hz, 1H), 8.18 (d, J = 7.8 Hz, 1H ), 8.10 (d, J = 8.2 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 3.98 (s, 3H). MS 388.80 (M + 1).

Example 72: 7 - Bromo -6- Ethoxyquinoline -5,8- Dion's  Produce

step 1: 5 , 7- Dibromoquinoline Preparation of Compounds of -8-ol

Quinolin-8-ol (1 eq) was added dropwise to a methanol solution in which bromine (3 eq) was dissolved. Dropwise addition of methanol solution dissolved the NaHCO ₃ (2 eq) to the mixture and stirred for 5 minutes at room temperature (RT). Thereafter, Na ₂ SO ₃ (0.63 eq) was added dropwise to the reaction mixture and stirred at room temperature for 10 minutes. After completion of the reaction, the reaction solid was filtered, washed with H ₂ O and dried to give 5,7-dibromoquinolin-8-ol.

step 2: 7 - Bromoquinoline -5,8- Dion's  Produce

5,7-dibromoquinolin-8-ol synthesized in step 1 was slowly added dropwise to a sulfuric acid (20 eq) solution in which nitric acid (6 eq) was dissolved at 0 ° C. After stirring for 30 minutes at the same temperature, the reaction was terminated with ice water. Thereafter, the mixture was extracted with dichloromethane, the organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to afford 7-bromoquinoline-5,8-dione.

step 3: 7 - Bromo -6- Ethoxyquinoline -5,8- Dion's  Produce

7-Bromoquinoline-5,8-dione (1 eq) synthesized in step 2 was dissolved in methanol and cesium chloride (1.1 eq) and sodium ethoxide (2 eq) were added dropwise at 0 ° C. The reaction mixture was stirred for 30 minutes at room temperature. After completion of the reaction, the mixture was extracted with dichloromethane, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.

1 H NMR (400 MHz, CDCl 3) δ 9.05 (dd, J = 4.7, 1.72 Hz, 1H), 8.44 (dd, J = 7.9, 1.8 Hz, 1H), 7.71 (dd, J = 7.9, 4.7 Hz, 1H) , 4.68 (q, J = 7.0 Hz, 2H), 1.50 (t, J = 7.0 Hz, 3H). MS 283.50 (M + 1).

Example 73: 7 - Bromo -2- Phenylquinoline -5,8- Dion  Preparation of the compound

step 1: 2 - Phenylquinoline Preparation of 8-ol

After 2-bromoquinoline-8-ol was dissolved in dimethoxyethane, phenylboronic acid (1.5 eq) and 2M Na ₂ CO ₃ aqueous solution (3 eq) were added dropwise at room temperature and stirred for 10 minutes. Pd (PPh ₃ ) ₄ (0.1 eq) was added dropwise to the reaction mixture, followed by reaction for 30 minutes at 160 ° C. using a biotage microwave. After completion of the reaction, it was filtered through Celite and neutralized with 1M HCl aqueous solution. The mixture was extracted with ethyl acetate, and the organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to afford 2-phenylquinolin-8-ol.

step 2: 5 , 7- Dibromo -2- Phenylquinoline Preparation of 8-ol

After 2-phenylquinolin-8-ol (1 eq) synthesized in step 1 was dissolved in acetic acid, an acetic acid solution in which bromine (2.2 eq) was dissolved was slowly added dropwise. The reaction mixture was stirred at room temperature for 30 minutes, then ice water and Na ₂ S ₂ O ₃ were added dropwise and stirred for 10 minutes. After completion of the reaction, it was filtered and recrystallized with ethanol to give 5,7-dibromo-2-phenylquinolin-8-ol.

step 3: 7 - Bromo -2- Phenylquinoline -5,8- Dion's  Produce

5,7-dibromo-2-phenylquinolin-8-ol (1 eq) synthesized in step 2 was dissolved in ACN, and then CAN (2.2 eq) dissolved in H ₂ O was slowly added dropwise. After stirring for 2 hours the reaction mixture at room temperature, the reaction was terminated with H ₂ O. Extracted with ethyl acetate (EtOAc), dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.

1 H NMR (400 MHz, CDCl 3) δ 8.45 (d, J = 8.3 Hz, 1H), 8.22-8.17 (m, 2H), 8.13 (d, J = 8.3 Hz, 1H), 7.60 (s, 1H), 7.57 7.51 (m, 3 H). MS 316 (M + 2).

Example 74: 7 - Bromo -6- methyl -2- Phenylquinoline -5,8- Dion's  Produce

7-Bromo-2-phenylquinoline-5,8-dione (1 eq) synthesized in Example 73 was dissolved in ACN, followed by the dropwise addition of acetic acid (1.5 eq) and AgNO ₃ (0.5 eq). To the reaction mixture was slowly added dropwise an aqueous solution of ammonium persulfate (1.4 eq) and stirred at 80 ° C. for 4 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.

1 H NMR (400 MHz, CDCl 3) δ 8.49 (d, J = 8.3 Hz, 1H), 8.21-8.16 (m, 2H), 8.11 (d, J = 8.3 Hz, 1H), 7.56-7.51 (m, 3H) , 2.43 (s, 3 H). MS 330.05 (M + 1).

Example 75: 7 -Amino-6- Methoxy -2- (3- ( Trifluoromethoxy Preparation of Phenyl) quinoline-5,8-dione

step 1: 5 , 6,8- Trimethoxy -2- (3- ( Trifluoromethoxy Preparation of Phenyl) quinoline

2-chloro-5,6,8-trimethoxyquinoline (Formula 1-6, 1eq) synthesized in Preparation Example 1 was dissolved in DME, and then Pd (dppf) Cl ₂ -CH ₂ Cl ₂ (10 mol%) ), 3- (trifluoromethoxy) phenylboronic acid (1.1eq) and 2M Na ₂ CO ₃ aqueous solution (4 eq) were added dropwise at room temperature and stirred for 10 minutes. The reaction mixture was reacted with Biotage microwave at 160 ° C. for 30 minutes. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give 5,6,8-trimethoxy-2- (3- (trifluoromethoxy) phenyl) quinoline.

step 2: 6 - Methoxy -2- (3- ( Trifluoromethoxy ) Phenyl) quinoline-5,8- Dion's  Produce

5,6,8-trimethoxy-2- (3- (trifluoromethoxy) phenyl) quinoline (1 eq) synthesized in step 1 was dissolved in a small amount of ACN and then 0.6 M at 0 ° C. in the dark. CAN (3 eq) aqueous solution was slowly added dropwise. The reaction mixture was stirred at rt for 12 h. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to afford 6-methoxy-2- (3- (trifluoromethoxy) phenyl) quinoline-5,8-dione.

step 3: 7 - Bromo -6- Methoxy -2- (3- ( Trifluoromethoxy ) Phenyl) quinoline-5,8- Dion's  Produce

6-methoxy-2- (3- (trifluoromethoxy) phenyl) quinoline-5,8-dione synthesized in step 2 After (1 eq) was dissolved in chloroform, bromine (1.1 eq) was added dropwise at 0 ° C. and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give 7-bromo-6-methoxy-2- (3- (trifluoromethoxy) phenyl) quinoline-5,8-dione.

step 4: 7 - Ah-do -6- Methoxy -2- (3- ( Trifluoromethoxy ) Phenyl) quinoline-5,8- Dion's  Produce

7-Bromo-6-methoxy-2- (3- (trifluoromethoxy) phenyl) quinoline-5,8-dione synthesized in step 3 (1 eq) was dissolved in DMF / MeOH (1/1), then sodium azide (1.5 eq) was added dropwise and stirred at room temperature for 1 to 12 hours. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure to afford 7-azido-6-methoxy-2- (3- (trifluoromethoxy) phenyl). Quinoline-5,8-dione was obtained.

step 5: 7 -Amino-6- Methoxy -2- (3- ( Trifluoromethoxy ) Phenyl) quinoline-5,8- Dion's  Produce

Dissolve 7-azido-6-methoxy-2- (3- (trifluoromethoxy) phenyl) quinoline-5,8-dione (1 eq) synthesized in step 4 in EtOAc / MeOH (1/1) After addition, Pd / C (1 eq) was added dropwise and stirred under hydrogen stream for 12 hours. After completion of the reaction, the mixture was filtered through celite and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.

1 H NMR (400 MHz, CD3OD) δ 8.79 (s, 1H), 8.46 (d, J = 8.0 Hz, 1H), 8.41 (d, J = 8.2 Hz, 1H), 8.35 (d, J = 8.2 Hz, 1H ), 8.11 (d, J = 7.8 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 3.93 (s, 3H), 3.82 (s, 3H). MS 338.75 (M).

Example  76 to Example  108

Using the same method as described in Example 75, but using R listed in the following Table 7 in place of 3- (trifluoromethoxy) phenylboronic acid in Step 1 to obtain the compound of Examples 76 to 108 It was.

TABLE 7

Example 109: 7 -Amino-2- (4- Chloro -3- Fluorophenyl ) -6- Methoxyquinoline -5,8- Dion's  Produce

step 1: 7 - Ah-do -2- (4- Chloro -3- Fluorophenyl ) -6- Methoxyquinoline -5,8- Dion's  Produce

Using the same method as described in steps 1 to 4 of Example 75, but using 4-chloro-3-fluorophenylboronic acid instead of 3- (trifluoromethoxy) phenylboronic acid, 7-azido- 2- (4-chloro-3-fluorophenyl) -6-methoxyquinoline-5,8-dione was obtained.

step 2: 7 -Amino-2- (4- Chloro -3- Fluorophenyl ) -6- Methoxyquinoline -5,8- Dion's  Produce

Dissolve 7-azido-2- (4-chloro-3-fluorophenyl) -6-methoxyquinoline-5,8-dione (1 eq) synthesized in step 1 in THF / MeOH (5/1) After addition, sodium borohydride (10 eq) was added dropwise and stirred at room temperature for 3 hours. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.

1 H NMR (400 MHz, CDCl 3) δ 8.44 (d, J = 8.2 Hz, 1H), 7.99 (m, 2H), 7.86 (m, 1H), 7.54 (m, 1H), 5.22 (s, NH2), 4.10 (s, 3 H). MS 332.70 (M).

Example 110: 7 -Amino-6- Methoxy -2- (2- Methoxypyrimidine -5-yl) quinoline-5,8- Dion's  Produce

step 1: 5 , 6,8- Trimethoxy -2- (2- Methoxypyrimidine Preparation of -5-yl) quinoline

The 2-chloro -5,6,8- trimethoxy-quinoline (formula 1 -6, 1eq) synthesized in Preparation Example _{1 THF: H 2 O (4} : 1) was dissolved in, Pd (dppf) Cl ₂ -CH ₂ Cl ₂ (10 mol%), 2-methoxypyrimidin-5-ylboronic acid and K ₂ CO ₃ (3 eq) were added dropwise at room temperature and stirred for 10 minutes. The reaction mixture was reacted for 30 minutes at 70 ° C. with a Biotage microwave. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give 5,6,8-trimethoxy-2- (2-methoxypyrimidin-5-yl) quinoline.

step 2: 6 - Methoxy -2- (2- Methoxypyrimidine -5-yl) quinoline-5,8- Dion's  Produce

5,6,8-trimethoxy-2- (2-methoxypyrimidin-5-yl) quinoline (1 eq) synthesized in step 1 was dissolved in a small amount of ACN, and then 0.6 C at 0 ° C. in the dark. M aqueous solution of CAN (3 eq) was slowly added dropwise. The reaction mixture was stirred at rt for 12 h. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to afford 6-methoxy-2- (2-methoxypyrimidin-5-yl) quinolin-5,8-dione.

step 3: 7 - Bromo -6- Methoxy -2- (2- Methoxypyrimidine -5-yl) quinoline-5,8- Dion's  Produce

6-methoxy-2- (2-methoxypyrimidin-5-yl) quinolin-5,8-dione (1 eq) synthesized in step 2 was dissolved in chloroform and then bromine (1.1 eq) at 0 ° C. ) Was added dropwise and the reaction mixture was stirred at rt for 12 h. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give 7-bromo-6-methoxy-2- (2-methoxypyrimidin-5-yl) quinolin-5,8-dione.

step 4: 7 - Ah-do -6- Methoxy -2- (2- Methoxypyrimidine -5-yl) quinoline-5,8- Dion's  Produce

7-bromo-6-methoxy-2- (2-methoxypyrimidin-5-yl) quinolin-5,8-dione synthesized in step 3 (1 eq) was dissolved in DMF / MeOH (1/1), then sodium azide (1.5 eq) was added dropwise and stirred at room temperature for 1 to 12 hours. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure to afford 7-azido-6-methoxy-2- (2-methoxypyrimidin-5-yl. ) Quinoline-5,8-dione was obtained.

step 5: 7 -Amino-6- Methoxy -2- (2- Methoxypyrimidine -5-yl) quinoline-5,8- Dion's  Produce

7-azido-6-methoxy-2- (2-methoxypyrimidin-5-yl) quinolin-5,8-dione (1 eq) synthesized in step 4 was added to EtOAc / MeOH (1/1). After dissolving, Pd / C (1 eq) was added dropwise and stirred for 12 hours under hydrogen stream. After completion of the reaction, the mixture was filtered through celite and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.

1 H NMR (400 MHz, CDCl 3) δ 9.25 (s, 2H), 8.46 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 4.11 (s, 3H), 4.10 (s , 3H). MS 312.95 (M).

Example 111: 7 -Amino-6- Methoxy -2- (pyrimidin-5-yl) quinoline-5,8- Dion's  Produce

step 1: 7 - Ah-do -6- Methoxy -2- (pyrimidin-5-yl) quinoline-5,8- Dion's  Produce

Using the same method as described in step 1 to step 4 of Example 110, but using pyrimidine-5-ylboronic acid instead of 2-methoxypyrimidine-5-ylboronic acid in step 1, 7-azido-6 -Methoxy-2- (pyrimidin-5-yl) quinolin-5,8-dione was obtained.

step 2: 7 -Amino-6- Methoxy -2- (pyrimidin-5-yl) quinoline-5,8- Dion's  Produce

7-azido-6-methoxy-2- (pyrimidin-5-yl) quinolin-5,8-dione (1 eq) synthesized in step 1 was dissolved in THF / MeOH (5/1), Sodium borohydride (10 eq) was added dropwise and stirred at room temperature for 3 hours. After completion of the reaction, the mixture was extracted with dichloromethane.

The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.

1 H NMR (400 MHz, CDCl 3) δ 9.45 (s, 2H), 9.33 (s, 1H), 8.53 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 8.1 Hz, 1H), 4.12 (s , 3H). MS 282.95 (M).

Example  112 to Example  114

Using the same method as described in Example 118, but using R listed in Table 8 below instead of pyrimidine-5-ylboronic acid, the compounds of Examples 112 to 114 were obtained.

TABLE 8

Example  115: methyl  3- (3- (7-amino-6- Methoxy -5,8- Dioxo -5,8- Dihydroquinoline Preparation of 2-yl) phenyl) propanoate

Step 1: (E)- methyl  3- (3- (7- Ah-do -6- Methoxy -5,8- Dioxo -5,8- Dihydroquinoline Preparation of 2-yl) phenyl) acrylate

Use the same method as described in steps 1 to 4 of Example 75, except for (E) -3- (3-methoxy-3-oxo, instead of 3- (trifluoromethoxy) phenylboronic acid (1.1eq) (E) -3- (3- (7-azido-6-methoxy-5,8-dioxo-5,8-dihydroquinoline-2- using prop-1-enyl) phenylboronic acid I) phenyl) acrylate was obtained.

Step 2: methyl  3- (3- (7-amino-6- Methoxy -5,8- Dioxo -5,8- Dihydroquinoline Preparation of 2-yl) phenyl) propanoate

Methyl (E) -3- (3- (7-azido-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl) phenyl) acrylate synthesized in step 1 ( 1 eq) was dissolved in EtOAc / MeOH (1/1), then Pd / C (1 eq) was added dropwise and stirred under hydrogen stream for 12 hours. After completion of the reaction, the mixture was filtered through celite and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.

1 H NMR (400 MHz, CDCl 3) δ 8.41 (d, J = 7.8 Hz, 1H), 8.00 (m, 2H), 7.95 (d, J = 7.8 Hz, 1H), 7.44 (d, J = 7.7 Hz, 1H) , 7.33 (d, J = 7.5 Hz, 1H), 5.21 (brs, 2H, NH2), 4.09 (s, 3H), 3.70 (m, 3H) 3.07 (t, J = 7.8 Hz, 1H), 2.71 (t , J = 7.8 Hz, 1H). MS 366.80 (M).

Example 116: 7 -Amino-2- (3- (1-hydroxyethyl) phenyl) -6- Methoxyquinoline Preparation of -5,8-dione

step 1: 2 -(3- Acetylphenyl ) -7- Ah-do -6- Methoxyquinoline -5,8- Dion's  Produce

Use the same method as described in step 1 to step 4 of Example 75, using 2- (3-acetyl using 3-acetylphenylboronic acid instead of 3- (trifluoromethoxy) phenylboronic acid (1.1eq) Phenyl) -7-azido-6-methoxyquinoline-5,8-dione was obtained.

step 2: 7 -Amino-2- (3- (1-hydroxyethyl) phenyl) -6- Methoxyquinoline -5,8- Dion's  Produce

Methyl 2- (3-acetylphenyl) -7-azido-6-methoxyquinoline-5,8-dione (1 eq) synthesized in step 1 was dissolved in EtOAc / MeOH (1/1), and then Pd / C (1 eq) was added dropwise and stirred under hydrogen stream for 12 hours. After completion of the reaction, the mixture was filtered through celite and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.

1 H NMR (400 MHz, CDCl 3) δ 8.42 (d, J = 8.1 Hz, 1H), 8.14 (s, 1H), 8.04 (m, 2H), 7.50 (m, 2H), 5.21 (brs, 2H, NH 2), 4.09 (s, 3 H), 1.56 (s, 3 H). MS 325.00 (M + 1).

Example 117: 7 -Amino-2- (3- Aminophenyl ) -6- Methoxyquinoline -5,8- Dion's  Produce

step 1: 7 - Ah-do -6- Methoxy -2- (3- Nitrophenyl Quinoline-5,8- Dion's  Produce

Example 44, using the same method as described in step 4 of Example 75, but replacing 7-bromo-6-methoxy-2- (3- (trifluoromethoxy) phenyl) quinoline-5,8-dione 7-azido-6-methoxy-2- (3- using 7-bromo-6-methoxy-2- (3-nitrophenyl) quinoline-5,8-dione (1 eq) synthesized in Nitrophenyl) quinoline-5,8-dione was obtained.

step 2: 7 -Amino-2- (3- Aminophenyl ) -6- Methoxyquinoline -5,8- Dion's  Produce

Use the same method as described in step 5 of Example 75, except for 7-azido-6-methoxy-2- (3- (trifluoromethoxy) phenyl) quinoline-5,8-dione. The title compound was obtained using 7-azido-6-methoxy-2- (3-nitrophenyl) quinoline-5,8-dione (1 eq) synthesized in step 1.

1 H NMR (400 MHz, CDCl 3) δ 8.39 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.57 (m, 1H), 7.42 (d, J = 7.8 Hz, 1H) , 7.30 (m, 1H), 6.81 (dd, J = 7.9, 16 Hz, 1H), 5.21 (brs, 2H, NH 2), 4.09 (s, 3H), 3.85 (s, 2H). MS 296.05 (M + 1).

Example 118: 2 -(3- Acryloylphenyl ) -7-amino-6- Methoxyquinoline -5,8- Dion's  Produce

step 1: 2 -(3- Acetylphenyl ) -7-amino-6- Methoxyquinoline -5,8- Dion's  Produce

7-amino-2- (3- (1-hydroxyethyl) phenyl) -6-methoxyquinoline-5,8-dione synthesized in Example 116 was dissolved in dichloromethane, followed by des-martin periodi Egg-Martin Periodinane (2 eq) was added dropwise at 0 ° C. and stirred at room temperature for 4 hours. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with H ₂ O, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure to yield 2- (3-acetylphenyl) -7-amino-6-methoxyquinoline-5,8-dione. .

step 2: 2 -(3- Acryloylphenyl ) -7-amino-6- Methoxyquinoline -5,8- Dion's  Produce

Using the same method as described in step 1 of example 40, except that 1- (3- (5,6,8-trimethoxyquinolin-2-yl) phenyl) ethanone was synthesized in step 1 of this example. The title compound was obtained using 2- (3-acetylphenyl) -7-amino-6-methoxyquinoline-5,8-dione.

1 H NMR (400 MHz, CDCl 3) δ 8.63 (s, 1H), 8.46 (d, J = 8.2 Hz, 1H), 8.41 (d, J = 7.8 Hz, 1H), 8.10 (s, 1H), 8.05 (s, 1H), 7.66 (t, J = 7.7 Hz, 1H), 6.49 (d, J = 1.5 Hz, 1H), 6.00 (dd, J = 1.9, 1.5 Hz, 1H), 5.23 (brs, 2H, NH 2). MS 334.98 (M).

Example  119: N- (3- (7-amino-6- Methoxy -5,8- Dioxo -5,8- Dihydroquinoline Preparation of 2-yl) phenyl) acrylamide

7-amino-2- (3-aminophenyl) -6-methoxyquinoline-5,8-dione (1 eq) synthesized in Example 117 was dissolved in dichloromethane and then acryloylchloride (1.2 eq) , Triethylamine (1.2 eq) was added dropwise at 0 ° C., and stirred at room temperature for 8 hours. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with saturated NaHCO ₃ aqueous solution, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by PTLC (hexane / ethyl acetate; 40:60) to afford the title compound.

1 H NMR (400 MHz, CDCl 3) δ 8.40 (d, J = 8.1 Hz, 1H), 8.25 (s, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H) , 7.81 (d, J = 7.8 Hz, 1H), 7.76 (s, 1H), 7.47 (t, J = 7.9 Hz, 1H), 6.48 (dd, J = 16.8, 1.2 Hz, 1H), 6.32 (dd, J = 16.8 10.2 Hz, 1H), 5.81 (dd, J = 10.3, 1.2 Hz, 1H), 5.21 (brs, 2H, NH 2), 4.09 (s, 3H). MS 350.20 (M + 1).

Example 120: 7 -Amino-2- Phenylquinoline -5,8- Dion's  Produce

step 1: 7 - Ah-do -2- Phenylquinoline -5,8- Dion's  Produce

After dissolving 7-bromo-2-phenylquinoline-5,8-dione synthesized in Example 73 in THF, an aqueous solution of sodium azide (1.2 eq) was added dropwise and stirred at room temperature for 30 minutes. After completion of the reaction, the mixture was extracted with ethyl acetate. After drying over anhydrous MgSO ₄ , the solvent was removed under reduced pressure to give 7-azido-2-phenylquinoline-5,8-dione.

step 2: 7 -Amino-2- Phenylquinoline -5,8- Dion's  Produce

7-azido-2-phenylquinoline-5,8-dione (1 eq) synthesized in step 1 was dissolved in THF / H ₂ O (5/1), followed by sodium borohydride (10 eq). It was added dropwise and stirred at room temperature for 1 hour. After completion of the reaction, the mixture was extracted with ethyl acetate, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure to obtain the title compound.

1 H NMR (400 MHz, CDCl 3) δ 8.45 (d, J = 8.2 Hz, 1H), 8.14 (dd, J = 8.2, 1.9 Hz, 2H), 8.07 (d, J = 8.2 Hz, 1H), 7.55-7.48 (m, 3 H), 6.07 (s, 1 H), 5.30 (bs, 2 H). MS 251 (M + 1).

Example 121: 7 -Amino-6- methyl -2- Phenylquinoline -5,8- Dion's  Produce

Using the same method as described in Example 120, but replacing 7-bromo-2-phenylquinoline-5,8-dione in Step 1 with 7-bromo-6-methyl-2-phenyl Quinoline-5,8-dione (1 eq) was used to yield the title compound.

1 H NMR (400 MHz, CDCl 3) δ 8.46 (d, J = 8.2 Hz, 1H), 8.15-8.13 (m, 2H), 8.04 (d, J = 8.2 Hz, 1H), 7.53-7.46 (m, 3H) , 5.15 (bs, 2H), 2.06 (s, 3H). MS 265.20 (M + 1).

Example 122: 7 -Amino-2- (2- Chloropyridine -4-yl) -6- Methylquinoline -5,8- Dion's  Produce

step 1: 7 - Bromo -2- (2- Chloropyridine -4-yl) quinoline-5,8- Dion's  Produce

Using the same method as described in Example 73, but using 2-chloropyridin-4-ylboronic acid (1.5 eq) instead of phenylboronic acid in step 1, 7-bromo-2- (2-chloropyridine-4 -Yl) quinoline-5,8-dione was obtained.

step 2: 7 - Bromo -2- (2- Chloropyridine -4-yl) -6- Methylquinoline -5,8- Dion's  Produce

Using the same method as described in Example 74, but replacing 7-bromo-2- (2-chloropyridine synthesized in Step 1 instead of 7-bromo-2-phenylquinoline-5,8-dione (1 eq) 4-yl) quinolin-5,8-dione was used to give 7-bromo-2- (2-chloropyridin-4-yl) -6-methylquinoline-5,8-dione.

step 3: 7 -Amino-2- (2- Chloropyridine -4-yl) -6- Methylquinoline -5,8- Dion's  Produce

7-Bromo-2- (2-chloropyridin-4-yl synthesized in Step 2 instead of 7-bromo-2-phenylquinolin-5,8-dione using the same method as described in Example 120 ) -6-methylquinoline-5,8-dione to afford the title compound.

1 H NMR (400 MHz, CDCl 3) δ 8.57-8.53 (m, 2H), 8.10-8.07 (m, 2H), 7.94 (dd, J = 5.2, 1.5 Hz, 1H), 5.22 (bs, 2H), 2.08 ( s, 3H). MS 300.15 (M + 1)

Example 123: 7 -Amino-2- (3- ( Trifluoromethoxy ) Phenyl) quinoline-5,8- Dion's  Produce

step 1: 7 - Bromo -2- (3- ( Trifluoromethoxy ) Phenyl) quinoline-5,8- Dion's  Produce

Using the same method as described in Example 73, using 7-bromo-2- (3- (trifluoro) using 3- (trifluoromethoxy) phenylboronic acid (1.5 eq) instead of phenylboronic acid Methoxy) phenyl) quinoline-5,8-dione was obtained.

step 2: 7 -Amino-2- (3- ( Trifluoromethoxy ) Phenyl) quinoline-5,8- Dion's  Produce

Using the same method as described in Example 120, except for 7-bromo-2-phenylquinoline-5,8-dione, 7-bromo-2- (3- (triflo) synthesized in Step 1 of this Example Oromethoxy) phenyl) quinoline-5,8-dione to give the title compound.

1 H NMR (400 MHz, CDCl 3) δ 8.49 (d, J = 8.3 Hz, 1H), 8.07 (m, 2H), 8.00 (s, 1H), 7.55 (t, J = 7.9, 2H), 7.35 (d, J = 8.3, 1H), 6.09 (s, 2H), 5.34 (brs, 2H, NH 2). MS 334.70 (M)

Example  124 to Example  127

Using the same method as described in Example 123, but using R listed in Table 9 below instead of 3- (trifluoromethoxy) phenylboronic acid, the compounds of Examples 124 to 127 were obtained.

TABLE 9

Example  128: N- (6- Methoxy -2- (2- Methoxypyrimidine -5-day) -5,8- Dioxo -5,8- Dihydroquinoline Preparation of 7-yl) acetamide

7-amino-2- (2-fluoropyridin-4-yl) -6-methoxyquinoline-5,8-dione (1 eq) synthesized in Example 90 was dissolved in chloroform and then acryloylchloride (9 eq) and triethylamine (2 eq) were added dropwise and stirred under reflux for 2 days. After completion of the reaction, the mixture was extracted with dichloromethane, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by PTLC to give the title compound.

1 H NMR (400 MHz, CDCl 3) δ 8.57 (d, J = 8.1 Hz, 1H), 8.42 (d, J = 5.3 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 5.6 Hz, 1H), 7.70 (s, 1H), 7.61 (s, 1H), 6.43 (m, 2H), 5.91 (d, J = 9.36 Hz, 1H), 4.27 (s, 3H). MS 354.20 (M + 1).

Example  129: N- (5,8- Dioxo 2-phenyl-5,8- Dihydroquinoline Preparation of 7-yl) acetamide

7-amino-2-phenylquinoline-5,8-dione (1 eq) synthesized in Example 120 was dissolved in THF / CH ₂ Cl ₂ (1/1), followed by acetylchloride (2.5 eq), pyridine ( 3 eq) and N, N-dimethylpyridin-4-amine (0.1 eq) were added dropwise and stirred for 7 days. After completion of the reaction, the mixture was extracted with dichloromethane, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.

1 H NMR (400 MHz, CDCl 3) δ 8.46 (d, J = 8.3 Hz, 1H), 8.43 (bs, 1H), 8.17-8.12 (m, 2H), 7.96 (s, 1H), 7.56-7.51 (m, 3H), 2.34 (s, 3H). MS 293.20 (M + 1).

Example  130: N- (2- (2- Fluoropyridine -4-yl) -6- Methoxy -5,8- Dioxo -5,8- Dihydroquinoline Preparation of 7-yl) acrylamide

7-amino-6-methoxy-2- (2-methoxypyrimidin-5-yl) quinolin-5,8-dione (1 eq) synthesized in Example 110 was dissolved in chloroform, followed by acetylchloride ( 10 eq) and triethylamine (1 eq) were added dropwise and stirred under reflux for 12 hours. After completion of the reaction, the mixture was extracted with dichloromethane, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by PTLC to give the title compound.

1 H NMR (400 MHz, CDCl 3) δ 9.28 (s, 2H), 8.49 (d, J = 8.3 Hz, 1H), 8.02 (d, J = 8.3 Hz, 1H), 4.25 (s, 3H), 4.12 (s , 3H). MS 355.15 (M + 1).

Example  131 to Example  139

The compound of Examples 131 to 139 was obtained using the same method as described in Example 1, using R listed in Table 10 below in place 1 of 3-acetylphenylboronic acid.

TABLE 10

Example  140 to Example  144

Example 140 using the same method as described in Example 1, using R listed in Table 11 below instead of 3-acetylphenylboronic acid, and using 1,4-dioxane instead of dimethylether (DME) To the compound of Example 144 was obtained.

TABLE 11

Example  145 to Example  170

Use the same method as described in Example 36, except that in Step 1, 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine The compounds of Examples 145-170 were obtained using R listed in Table 12 below instead of midine.

TABLE 12

Example 171: 6 - Methoxy -2-( Pyrazine -2-yl) quinoline-5,8- Dion's  Produce

step 1: 5 , 6,8- Trimethoxy -2-( Pyrazine Preparation of 2-yl) quinoline

2-Chloro -5,6,8- trimethoxy-quinoline-1,4-dioxane (Formula 1 -6, 90 mg, 0.3 mmol ) and _{Pd (Ph 3) 4 (46} mg, 0.039 mmol, 0.1 eq) After dissolving in (8 ml), 2- (tributylstannyl) pyrazine (218 mg, 0.59 mmol, 2 eq) was added dropwise at room temperature. The reaction mixture was reacted at 130 ° C. for 2 hours in a Biotage microwave. After completion of the reaction, the reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give 5,6,8-trimethoxy-2- (pyrazin-2-yl) quinoline.

step 2: 6 - Methoxy -2-( Pyrazine -2-yl) quinoline-5,8- Dion  Manufacture

5,6,8-trimethoxy-2- (pyrazin-2-yl) quinoline (1 eq) synthesized in step 1 was dissolved in a small amount of ACN, and then 0.6 M of CAN (3 eq) aqueous solution was slowly added dropwise. The reaction mixture was stirred at rt for 12 h. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.

1 H NMR (400 MHz, CDCl 3) δ 9.90 (s, 1H), 8.77 (d, J = 8.2 Hz, 1H), 8.72-8.68 (m, 2H), 8.62 (d, J = 8.2 Hz, 1H), 6.43 (s, 1 H), 3.98 (s, 3 H). MS 268.2 (M + 1).

Example 172: 6 - Methoxy -2- (6- Methoxypyrazine -2-yl) quinoline-5,8- Dion's  Produce

Embodiments, use the same method as that described for example 171, In Step 1, a 2- (tributyl's taenil) pyrazine instead of 2-methoxy-6- (tributyltin's taenil) pyrazine (Formula 16-2), the title The compound was obtained.

1 H NMR (400 MHz, CDCl 3) δ 9.46 (s, 1H), 8.68 (d, J = 8.2 Hz, 1H), 8.58 (d, J = 8.2 Hz, 1H), 8.37 (s, 1H), 6.42 (s , 1H), 4.11 (s, 3H), 3.98 (s, 3H). MS 298.04 (M + 1).

Example  173: methyl  2- Methoxy -6- (5,6,8- Trimethoxyquinoline -2 days) Nicotinate  Produce

2-Chloro -5,6,8- trimethoxy-quinoline was dissolved in (Formula 1 -6, 0.3 g, 1.18 mmol ) to _{THF (4 ml) / H 2} O (1 ml), PdCl 2 (dtbpf) ( 116 mg, 0.18 mmol, 0.15 eq) and K ₂ CO ₃ (490 mg, 3.55 mmol, 3 eq) were added dropwise at room temperature. The reaction mixture was stirred at 70 ° C. for 8 hours and then cooled to room temperature. The reaction mixture was filtered through celite, and then the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC (hexane / ethylacetate; 70:30) to afford the title compound.

1 H NMR (400 MHz, DMSO) δ 8.77 (d, J = 8.2 Hz, 1H), 8.56 (d, J = 8.2 Hz, 1H), 8.39 (d, J = 7.8 Hz, 1H), 8.23 (d, J = 7.8 Hz, 1H), 6.55 (s, 1H), 4.10 (s, 3H), 3.92 (s, 3H), 3.86 (s, 3H). MS 355.20 (M + 1).

Example 174: 6 - Methoxy -2- (4- ( Trifluoromethyl Preparation of Piperidin-1-yl) quinoline-5,8-dione

step 1: 5 , 6,8- Trimethoxy Preparation of -2- (4- (trifluoromethyl) piperidin-1-yl) quinoline

2-Chloro -5,6,8- trimethoxy-quinoline (formula 1 -6, 0.4 g, 1.58 mmol ) was dissolved in toluene (2 ml), (trifluoromethyl) piperidin-4- (1 eq), Pd ₂ (dba) ₃ (0.05 eq), 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (BINAP) (0.1 eq) and sodium tert-butoxide (2.5 eq) was added dropwise at room temperature and stirred for 10 minutes. The reaction mixture was reacted at 125 ° C. for 1 hour in a Biotage microwave. After completion of the reaction, the reaction mixture was filtered through celite and the solvent was removed under reduced pressure. Extracted with ethyl acetate, washed with water, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give 5,6,8-trimethoxy-2- (4- (trifluoromethyl) piperidin-1-yl) quinoline.

step 2: 6 - Methoxy -2- (4- ( Trifluoromethyl ) Piperidin-1-yl) quinoline-5,8- Dion's  Produce

Dissolve 5,6,8-trimethoxy-2- (4- (trifluoromethyl) piperidin-1-yl) quinoline (0.098 g, 0.27 mmol) synthesized in step 1 in acetone (8 ml) After addition, premi salt (potassium nitrosodisulfonate) (0.114 g, 0.42 mmol, 1.6 eq) dissolved in NaH ₂ PO ₄ buffer (0.3 M / 8 ml, 2.4 mmol) was added dropwise. The reaction mixture was stirred at rt for 8 h and then extracted with dichloromethane. The organic layer was washed with H ₂ O, dried over anhydrous MgSO ₄ , and the organic layer was decompressed to remove the solvent. The reaction mixture was then separated and purified by PTLC to give the title compound.

1 H NMR (400 MHz, CDCl 3) δ 8.16 (d, J = 9.0 Hz, 1H), 6.85 (d, J = 9.0 Hz, 1H), 6.15 (s, 1H), 4.77 (d, J = 12.4 Hz, 2H ), 3.90 (s, 3H), 3.03 (t, J = 12.1 Hz, 1H), 2.37 (dd, J = 8.0, 4.0 Hz, 1H), 2.03 (d, J = 8.3 Hz, 2H), 1.65 (td , J = 12.7, 3.8 Hz, 1H). MS 341.20 (M + 1).

Example 175: 2 -(4,4- Difluoropiperidine -1-yl) -6- Methoxyquinoline -5,8- Dion's  Produce

Using the same method as described in Example 174, the title compound was obtained using 4,4-difluoropiperidine instead of 4- (trifluoromethyl) piperidine in step 1.

1 H NMR (400 MHz, CDCl 3) δ 8.19 (d, J = 9.0 Hz, 1H), 6.90 (d, J = 9.0 Hz, 1H), 6.16 (s, 1H), 3.98 (d, J = 5.1 Hz, 4H ), 3.90 (s, 3 H), 2.19-1.93 (m, 4 H). MS 309.20 (M + 1).

Example 176: 2 , 7- Dibromo -6- Isopropylquinoline -5,8- Dion's  Produce

After dissolving 2,7-dibromoquinoline-5,8-dione (200 mg, 0.63 mmol, 1 eq) and isobutyl acid (167 mg, 1.89 mmol, 3 eq) in acetonitrile (4 ml), Silver nitrate (54 mg, 0.32 mmol, 0.5 eq) and sulfuric acid diammonium peroxide (403 mg, 1.77 mmol, 2.8 eq) were added dropwise and reacted at 80 ° C. for 8 hours. The reaction was terminated with H ₂ O, extracted with ethyl acetate, dried over anhydrous MgSO _4, and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give 2,7-dibromo-6-isopropylquinoline-5,8-dione.

1 H NMR (400 MHz, CDCl 3) δ 8.23 (d, J = 8.2 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 3.64-3.57 (m, 1H), 1.40 (d, J = 7.0 Hz , 6H). MS 359.85 (M).

Example  177 to Example  180

Using the same method as described in Example 41, but replacing in step 1 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane, R listed in Table 13 below. Was used to obtain the compounds of Examples 177 to 180.

TABLE 13

Example  181 to Example  183

Using the same method as described in Example 41, but replacing in step 1 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane, R listed in Table 14 below. And 1,4-dioxane instead of dimethylether (DME) were used to obtain the compounds of Examples 181 to 183.

TABLE 14

Example  184 to Example  196

Using the same method as described in Example 68, but using R listed in Table 15 below instead of pyrimidine-5-ylboronic acid in Step 1, the compounds of Examples 184 to 196 were obtained.

TABLE 15

Example  197 to 203

Using the same method as described in Example 75, but using R listed in Table 16 below in place 1 of 3- (trifluoromethoxy) phenylboronic acid to obtain the compound of Examples 197 to 203 It was.

TABLE 16

Example 204: 7 -Amino-6- Methoxy -2- (2- Nitrophenyl Quinoline-5,8- Dion's  Produce

, Use the same method to that described in Example 109, using 4-chloro-3-flow Oro phenylboronic acid instead of 2-methoxy-6- (tributyltin's taenil) pyrazine (Formula 16-2), the title compound Obtained.

1 H NMR (400 MHz, DMSO) δδ 9.17 (s, 1H), 8.63 (d, J = 8.1 Hz, 1H), 8.46-8.43 (m, 2H), 7.01 (s, 2H), 4.07 (s, 3H) , 3.83 (s, 3 H). MS 313.2 (M + 1).

Example 205: 7 -Amino-6- Methoxy -2- (6- Methoxypyrazine -2-yl) quinoline-5,8- Dion's  Produce

Using the same method as described in Example 109, but instead of 4-chloro-3-fluorophenylboronic acid, 4,4,5,5-tetramethyl-2- (2-nitrophenyl) -1,3,2- Dioxaborolane was used to give the title compound.

1 H NMR (400 MHz, CDCl 3) δδ 8.46 (d, J = 8.0 Hz, 1H), 8.04 (dd, J = 7.8, 0.7 Hz, 1H), 7.71 (d, J = 7.9 Hz, 2H), 7.65-7.60 (m, 2 H), 4.10 (s, 3 H). MS 326.2 (M + 1).

Example  206 and Example  207

Use the same method as described in Example 75, but using R listed in Table 17 in place of 3- (trifluoromethoxy) phenylboronic acid in Step 1, and 1,4-di instead of dimethylether (DME) Oxane was used to obtain the compounds of Examples 206 and 207.

TABLE 17

Example  208 and Example  209

Using the same method as described in Example 109, using R of Table 18 instead of 4-chloro-3-fluorophenylboronic acid and 1,4-dioxane instead of dimethyl ether (DME), The compounds of Examples 208 and 209 were obtained.

TABLE 18

Example  210 to Example  214

Using the same method as described in Example 110, but using R listed in [Table 19] in step 1 instead of 2-methoxypyrimidine-5-ylboronic acid to obtain the compounds of Examples 210 to 214. .

TABLE 19

Example  215 to Example  237

Using the same method as described in Example 111, and using the R of [Table 20] instead of pyrimidine-5-ylboronic acid, the compounds of Examples 215 to 237 were obtained.

TABLE 20

Example 238: 2 -Amino-4- (7-amino-6- Methoxy -5,8- Dioxo -5,8- Dihydroquinoline 2-yl) benzoic acid

Methyl 2-amino-4- (7-amino-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl) benzoic acid (1 eq) synthesized in Example 210 was added MeOH / After dissolving in H ₂ O (1: 1), an aqueous solution of potassium hydroxide (35 eq) was added dropwise and reacted at 50 ° C. for 2.5 hours. After completion of the reaction, the mixture was neutralized with 1M aqueous hydrochloric acid, extracted with dichloromethane, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to afford the title compound as an orange solid.

1 H NMR (400 MHz, MeOD) δ 8.37 (d, J = 8.2 Hz, 1H), 8.10 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.58 (d, J = 1.7 Hz, 1H), 7.33 (dd, J = 8.3, 1.7 Hz, 1H), 3.81 (s, 3H). MS 341.10 (M + 2).

Example 239: 7 -Amino-6- Methoxy -2-( Pyrazine -2-yl) quinoline-5,8- Dion's  Produce

step 1: 7 - Bromo -6- Methoxy -2-( Pyrazine -2-yl) quinoline-5,8- Dion's  Produce

6-methoxy-2- (pyrazin-2-yl) quinolin-5,8-dione (1 eq) synthesized in Example 171 was dissolved in chloroform, and bromine (1.1 eq) was added dropwise at 0 ° C. The reaction mixture was stirred at rt for 12 h. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give 7-bromo-6-methoxy-2- (pyrazin-2-yl) quinolin-5,8-dione.

step 2: 7 - Ah-do -6- Methoxy -2-( Pyrazine -2-yl) quinoline-5,8- Dion's  Produce

7-Bromo-6-methoxy-2- (pyrazin-2-yl) quinolin-5,8-dione synthesized in step 1 (1 eq) was dissolved in DMF / MeOH (1/1), then sodium azide (1.5 eq) was added dropwise and stirred at room temperature for 1 to 12 hours. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure to give 7-azido-6-methoxy-2- (pyrazin-2-yl) quinoline-5, 8-dione was obtained.

step 3: 7 -Amino-6- Methoxy -2-( Pyrazine -2-yl) quinoline-5,8- Dion's  Produce

7 -azido-6-methoxy-2- (pyrazin-2-yl) quinolin-5,8-dione (1 eq) synthesized in step 2 was dissolved in THF / MeOH (5/1) and then sodium Borohydride (10 eq) was added dropwise and stirred at room temperature for 3 hours. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.

1 H NMR (400 MHz, CDCl 3) δ 9.83 (s, 1H), 8.71-8.66 (m, 3H), 8.52 (d, J = 8.2 Hz, 1H), 4.20 (s, 3H). MS 283.2 (M + 1).

Example 240: 6 -(7-amino-6- Methoxy -5,8- Dioxo -5,8- Dihydroquinoline Preparation of 2-yl) -2-methoxynicotinic acid

Methyl 6- (7-amino-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl) -2-methoxynicotinic acid (1 eq) synthesized in Example 214 was prepared using MeOH. / H ₂ O (5/1), NaOH (5 eq) was added dropwise and stirred at 70 ℃ for 3 hours, and then cooled to room temperature. After completion of the reaction, the mixture was neutralized with 1M aqueous hydrochloric acid. The organic layer was extracted with ethyl acetate, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC (dichloromethane / methanol; 90:10) to afford the title compound.

1 H NMR (400 MHz, CDCl 3) δ 8.64 (d, J = 8.1 Hz, 1H), 8.58 (d, J = 7.9 Hz, 1H), 8.50-8.37 (m, 2H), 5.19 (s, 2H), 4.28 (s, 3 H), 4.05 (s, 3 H). MS 356.20 (M + 1).

Example 241: 7 -Amino-2- (4- Chloro -3- Fluorophenyl Quinoline-5,8- Dion's  Produce

Step 1: N- (2- (4- Chloro -3- Fluorophenyl ) -5,8- Dioxo -5,8- Dihydroquinoline Preparation of 7-yl) acetamide

After dissolving N- (2-chloro-5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide (Formula 17-10 , 1 eq) synthesized in Preparation Example 17, Pd (dppf) Cl ₂ -CH ₂ Cl ₂ (10 mol%), 4-chloro-3-fluorophenylboronic acid (1.1 eq) and 2M aqueous solution of Na ₂ CO ₃ (4 eq) were added dropwise at room temperature and stirred for 10 minutes. The reaction mixture was reacted at 130 ° C. for 30 minutes in a Biotage microwave. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture is then separated and purified by MPLC to give N- (2- (4-chloro-3-fluorophenyl) -5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide. Obtained.

step 2: 7 -Amino-2- (4- Chloro -3- Fluorophenyl Quinoline-5,8- Dion's  Produce

N- (2- (4-chloro-3-fluorophenyl) -5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide (1 eq) synthesized in step 1 was added to methanol. After dissolving, 4M potassium hydroxide (1.1 eq) aqueous solution was added dropwise and stirred at 70 ° C for 30 minutes. After completion of the reaction, the mixture was extracted with dichloromethane, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.

1 H NMR (400 MHz, DMSO) δ 8.45 (d, J = 8.2 Hz, 1H), 8.35 (d, J = 8.2 Hz, 1H), 8.25 (dd, J = 10.8, 1.9 Hz, 1H), 8.14 (dd , J = 8.4, 1.7 Hz, 1H), 7.82 (dd, J = 8.1 Hz, 1H), 5.89 (s, 1H). MS 303.0 (M + 1).

Example  242 to Example  262

Using the same method as described in Example 241, but using R listed in the following Table 21 instead of 2-fluorophenylboronic acid in Step 1 of Example 249 to obtain a compound of Examples 242 to 262 It was.

TABLE 21

Example  263: N- (5,8- Dioxo -2-( Pyrazine 2-yl) -5,8- Dihydroquinoline Preparation of 7-yl) acetamide

N- (2-chloro-5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide synthesized in Preparation Example 17 (Formula 17-10 , 50 mg, 0.2 mmol) and Pd (Ph ₃ ) ₄ (23 mg, 0.02 mmol, 0.1 eq) is dissolved in 1,4-dioxane (4 ml), and then 2- (tributylstannyl) pyrazine (110 mg, 0.3 mmol, 2 eq) is added to room temperature. Dropped at The reaction mixture was reacted at 130 ° C. for 2 hours in a Biotage microwave. After completion of the reaction, the reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.

1 H NMR (400 MHz, CDCl 3) δ 9.86 (s, 1H), 8.81 (d, J = 8.2 Hz, 1H), 8.73 (d, J = 2.5 Hz, 1H), 8.70 (dd, J = 1.5 Hz, 1H ), 8.59 (d, J = 8.2 Hz, 1H), 8.45 (Broad s, 1H), 8.01 (s, 1H), 2.35 (s, 3H). MS 295.2 (M).

Example 264 Preparation of 7-amino-2- (5-methoxypyrazin-2-yl) quinoline-5,8-dione

Step 1: N- (2- (5- Methoxypyrazine 2-yl) -5,8- Dioxo -5,8- Dihydroquinoline Preparation of 7-yl) acetamide

Use the same method as described in Example 263, using N- (2- (5-methoxy) using 2-methoxy-5- (tributylstannyl) pyrazine instead of 2- (tributylstannyl) pyrazine Pyrazin-2-yl) -5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide was obtained.

Step 2: Preparation of 7-amino-2- (5-methoxypyrazin-2-yl) quinolin-5,8-dione

N- (2- (5-methoxypyrazin-2-yl) -5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide synthesized in step 1 was dissolved in methanol and then 4M. Aqueous solution of potassium hydroxide (1.1 eq) was added dropwise and stirred at 70 ° C for 30 minutes. After completion of the reaction, the mixture was extracted with dichloromethane, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.

1 H NMR (400 MHz, DMSO) δ 9.18 (s, 1H), 8.53 (d, J = 8.2 Hz, 1H), 8.47 (s, 1H), 8.40 (d, J = 8.2 Hz, 1H), 5.89 (s , 1H), 4.02 (s, 3H). MS 283.09 (M + 1).

Example  265: N- (2- (2- Fluorophenyl ) -5,8- Dioxo -5,8- Dihydroquinoline Preparation of 7-yl) acetamide

After dissolving N- (2-chloro-5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide (Formula 17-10 , 1 eq) synthesized in Preparation Example 17, Pd (dppf) Cl ₂ -CH ₂ Cl ₂ (10 mol%), 2-fluorophenylboronic acid (1.1 eq) and 2M Na ₂ CO ₃ aqueous solution (4 eq) were added dropwise at room temperature and stirred for 10 minutes. The reaction mixture was reacted at 130 ° C. for 30 minutes in a Biotage microwave. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.

1 H NMR (400 MHz, CDCl 3) δ 8.48 (d, J = 8.3 Hz, 1H), 8.42 (s, 1H), 8.22-8.16 (m, 2H), 7.98 (s, 1H), 7.51-7.46 (m, 1H), 7.34 (t, J = 7.4 Hz, 1H), 7.24-7.19 (m, 1H), 2.33 (s, 3H). MS 311.04 (M + 1).

Example  266: N- (5,8- Dioxo -2- (4- ( Trifluoromethyl ) Phenyl) -5,8- Dihydroquinoline Preparation of 7-yl) acetamide

Using the same method as described in Example 265, the title compound was obtained using 4- (trifluoromethyl) phenylboronic acid instead of 2-fluorophenylboronic acid.

1 H NMR (400 MHz, CDCl ₃ ) δ 8.54 (d, J = 8.2 Hz, 1H), 8.42 (s, 1H), 8.27 (d, J = 8.0 Hz, 2H), 8.17 (d, J = 8.2 Hz, 1H), 7.99 (s, 1H), 7.80 (d, J = 8.1 Hz, 2H), 2.34 (s, 3H). MS 360.93 (M).

Example 267: 7 -Amino-2- (4- ( Trifluoromethy ) Phenyl) quinoline-5,8- Dion's  Produce

N- (5,8-dioxo-2- (4- (trifluoromethyl) phenyl) -5,8-dihydroquinolin-7-yl) acetamide (1 eq) synthesized in Example 266 was methanol After dissolving in, 4M potassium hydroxide (1.1 eq) aqueous solution was added dropwise and stirred at 70 ° C for 30 minutes. After completion of the reaction, the mixture was extracted with dichloromethane and then anhydrous MgSO ₄ Dried, and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.

1 H NMR (400 MHz, CDCl 3) δ 8.51 (d, J = 8.3 Hz, 1H), 8.27 (d, J = 7.9 Hz, 2H), 8.11 (d, J = 8.1 Hz, 1H), 7.78 (d, J = 8.2 Hz, 2H), 6.10 (s, 1H), 5.33 (s, 2H). MS 319.00 (M + 1).

Example  268: N- (2- (4,4- Difluoropiperidine -1-yl) -5,8- Dioxo -5,8- Dihydroquinoline Preparation of 7-yl) acetamide

N- (2-chloro-5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide (Formula 17-10 , 1eq) synthesized in Preparation Example 17 was dissolved in DMF, and 4, 4-Difluoropiperidine (1.1eq) and DIPEA (1eq) were added dropwise at room temperature and reacted at 80 ° C for 3 hours. After completion of the reaction, the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with H ₂ O and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.

1 H NMR (400 MHz, CDCl 3) δ 8.28 (s, 1H), 8.15 (d, J = 8.7 Hz, 1H), 7.77 (s, 1H), 6.98 (d, J = 8.8 Hz, 1H), 3.96 (s , 4H), 2.29 (s, 32H), 2.10-2.07 (m, 4H). MS 336.03 (M + 1).

Example 269: Preparation of 7-amino-2- (phenylamino) quinoline-5,8-dione

Step 1: N- (5,8- Dioxo -2-( Phenylamino ) -5,8- Dihydroquinoline Preparation of 7-yl) acetamide

N- (2-chloro-5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide synthesized in Preparation Example 17 (Formula 17-10 , 10 mg, 0.04 mmol) and Aniline (4.4 ul, 0.048 mmol, 1.2 eq) in 1,4-dioxane (1 ml), followed by Pd (dppf) Cl ₂ -CH ₂ Cl ₂ (1 mg, 1.2 umol, 0.01 eq) and sodium tert-butoxide (4.6 mg, 0.048 mmol, 1.2 eq) were added dropwise at room temperature. The reaction mixture was reacted at 120 ° C. for 1 hour in a Biotage microwave. After completion of the reaction, the reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give N- (5,8-dioxo-2- (phenylamino) -5,8-dihydroquinolin-7-yl) acetamide.

Step 2: Preparation of 7-amino-2- (phenylamino) quinoline-5,8-dione

N- (5,8-dioxo-2- (phenylamino) -5,8-dihydroquinolin-7-yl) acetamide (1 eq) synthesized in step 1 was dissolved in methanol and then 4M potassium hydroxide A seed (1.1 eq) aqueous solution was added dropwise and stirred at 70 ° C for 30 minutes. After completion of the reaction, the mixture was extracted with dichloromethane, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.

1 H NMR (400 MHz, MeOD) δ 8.08 (d, J = 9.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.36 (t, J = 7.7 Hz, 2H), 7.10-7.06 (m , 2H), 5.84 (s, 1H). MS 266.1 (M + 1).

Example 270: 7 -Amino-2- (4- ( Trifluoromethyl ) Phenylamino Quinoline-5,8- Dion's  Produce

Using the same method as described in Example 269, the title compound was obtained using 4- (trifluoromethyl) aniline instead of aniline in step 1.

1 H NMR (400 MHz, CDCl 3) δ 8.24 (d, J = 8.7 Hz, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.59 (d, J = 8.6 Hz, 2H), 7.16 (d, J = 8.7 Hz, 1H), 5.97 (s, 1H), 5.17 (s, 2H). MS 333.90 (M).

Example 271: Preparation of 7-amino-2- (pyridin-2-ylamino) quinoline-5,8-dione

Step 1: N- (5,8- Dioxo -2- (pyridine-2- Monoamino ) -5,8- Dihydroquinoline Preparation of 7-yl) acetamide

N- (2-chloro-5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide synthesized in Preparation Example 17 (Formula 17-10 , 50 mg, 0.20 mmol) and pyridine-2 -Amine (23 mg, 0.24 mmol, 1.2 eq) in 1,4-dioxane (5 ml), followed by Pd (dba) ₃ (27 mg, 0.03 mmol, 0.15 eq), Cs ₂ CO ₃ (162 mg, 0.50 mmol, 2.5 eq) and xantphos (23 mg, 0.04 mmol, 0.2 eq) were added dropwise at room temperature. The reaction mixture was reacted at 140 ° C. for 1 hour in a Biotage microwave. After completion of the reaction, the reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by prep HPLC to give N- (5,8-dioxo-2- (pyridin-2-ylamino) -5,8-dihydroquinolin-7-yl) acetamide. .

Step 2: Preparation of 7-amino-2- (pyridin-2-ylamino) quinoline-5,8-dione

In step 1 N- (5,8-dioxo-2- (pyridin-2-ylamino) -5,8-dihydroquinolin-7-yl) acetamide (1 eq) was dissolved in methanol and then 4M Aqueous solution of potassium hydroxide (1.1 eq) was added dropwise and stirred at 70 ° C for 30 minutes. After completion of the reaction, the mixture was extracted with dichloromethane, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.

1 H NMR (400 MHz, MeOD) δ 8.18 (d, J = 3.8 Hz, 1H), 8.09 (d, J = 8.7 Hz, 1H), 7.86 (d, J = 8.6 Hz, 2H), 7.69-7.61 (m , 1H), 6.90 (dd, J = 6.8, 5.3 Hz, 2H), 5.76 (s, 1H). MS 266.97 (M).

Example 272: Preparation of 7-amino-2- (pyridazin-3-ylamino) quinoline-5,8-dione

Using the same method as described in Example 271, but using pyridazin-3-amine instead of pyridin-2-amine in step 1, the title compound was obtained.

1 H NMR (400 MHz, MeOD) δ 8.87 (d, J = 4.6 Hz, 1H), 8.54 (m, 1H), 8.37 (d, J = 8.5 Hz, 1H), 7.88 (m, 1H), 7.72 (d , J = 8.6 Hz, 1H), 5.94 (s, 1H). MS 267.97 (M).

Experimental Example

Experimental Example 1 Test of Cell Growth Inhibition Activity of Compound of Formula (I)

The sulforhodamine B (SRB) assay was used to test the anti-tumor activity of the compounds of formula (I) herein.

Renal cancer cell lines ACHN cells (containing 100 μl, containing 5,000 to 40,000 cells / well, adjusted according to the doubling time of each cell line) were incubated in 96-well microtiter plates. After 24 hours, 100 μl of the compound of Formula I herein were added to each well and the cultures were incubated at 37 ° C. for 48 hours. The cells were fixed with trichloroacetic acid (50 μl per well). Plates were incubated at 4 ° C. for at least 1 hour and up to 3 hours. The liquid was removed from the plate, washed five times with water and dried at room temperature for 12 to 24 hours. Immobilized cells were stained with 100 μl SRB for 5 minutes at room temperature and plates were washed three times with 1% glacial acetic acid. And dried at room temperature for about 12 to 24 hours. SRB stained cells were lysed in 10 mM Trizma base and absorbance was measured at 515 nm.

GI ₅₀ (Growth Inhibition of 50%), which represents 50% growth inhibition, was calculated from the following equation, which means that the number of control cells is reduced to 50%.

[(Ti-Tz) / (C-Tz)] × 100 = 50

In the above formula, Tz is the average cell number (cells / ml) at the start of the culture, Ti is the average cell number (cells / ml) 48 hours after drug treatment, C is the average cell number (cells / ml) after 48 hours of the control group.

As a result, it was found that the compound of Formula (I) of the present invention exhibits TGase 2 inhibitory activity, and specific results are shown in Tables 22 and 23 below.

Table 22

Table 23

Experimental Example 2: TGase 2 Inhibitory Activity Test of the Compound of Formula (I)

Transglutaminase measured the binding of [1,4, ^-14 C] putresin to succinated casein and observed that NDGA competes with putrescine to inhibit its response to the compounds of Formula I TGase 2 inhibitory activity was measured.

Specifically, succinylated casein (Calbiochem, Cat. No. 573464) was dissolved in 2% concentration in 0.1 M tris-acetic acid buffer (pH 8.0) containing 10 mM CaCl ₂ , 0.15 M NaCl, 1.0 mM EDTA. 5 mM DTT (1,4-dithiothritol) was also added immediately before use of the solution.

250 μCi / ml of [C- ¹⁴ C] putrescine dihydrochloride (Chemicals, Cat. No. ARC-245) was dissolved in 122.5 mL distilled water and adjusted to 2 μCi / ml. Transglutaminase (gpTG2, Zedia, Pro. No. T006) obtained from guinea pig liver was dissolved in Tris-HCl buffer (pH 7.5) containing 50 mM 1 mM EDTA. IX TEN buffer consists of 100 mM Tris-acetic acid buffer (pH 8.0), 1 mM EDTA, and 150 mM NaCl, and glass microfiber filters were purchased from Whatman GF / A (Cat. No. 1820-025).

To each vial was added 48.58 μl of TEN buffer and 0.42 μl of 25 ng / μl of gpTG2. Thereafter, the compounds of formula I prepared in the Examples were added to the assay vial at six different concentrations (100 μM, 200 μM, 300 μM, 400 μM, 500 μM, 600 μM) by 1 μl. After the assay vial was pre-incubated for 5 minutes at room temperature, 140 μl of 2% succinylation casein (5 mM DTT) and 10 μl of 2 μCi / ml putrescine were added to each assay vial and thermomixer) was incubated at 37 ° C. for 15 minutes. The reaction was terminated by the addition of 2 ml of cold 5% trichloroacetic acid (TCA). Assay vials were held at 4 ° C. for at least 1 hour to fix. The assay mixture was filtered through glass-fiber filter paper discs (Whatman GF / A) and washed with cold 5% TCA. The filter was placed in a counting vial and a scintillation cocktail solution was added. Counting vials were vortexed for 5 seconds and placed in the shaker for 30 minutes before counting.

As a result, it was found that the compound of formula (I) of the present application exhibited TGase 2 inhibitory activity, and specific results are shown in the following [Table 24] and [Table 25].

TABLE 24

TABLE 25

Experimental Example 3: Confirmation of the tumor suppressor effect of the compound of formula (I)

Renal cancer cells were transplanted to cause kidney cancer in the mouse, and the compound synthesized in Example 120 was added to a solution consisting of 7.5% poloxamer, 30% polyethylene glycol, 57.5% distilled water, and 5% soybean oil to give 5 mg. / kg, 10 mg / kg or 20 mg / kg was administered once a day for 6 days a week for 7 weeks, the negative control was 7.5% poloxamer, 30% polyethylene glycol, 57.5% distilled water and 5% soybean oil Solution was administered. The results are shown in [Fig. 1] to [Fig. 4] and [Table 26].

TABLE 26

As shown in FIGS. 1 to 3 and Table 26, it can be seen that the mice administered the compound of Formula I are much smaller in size and weight of the tumor than in the control group. In addition, as shown in Figure 4, it can be seen that the body weight of the mouse does not change significantly by the administration of the compound of formula (I), it can be seen that the compound of formula I is less toxic.

Experimental Example 4: Confirmation of the Pharmacokinetic Profile of the Compound of Formula (I)

Eight mice were orally administered with the compound synthesized in Example 120 at a 10 mg / kg dose, and blood was collected for 4 hours through the tail vein, and the concentration in blood was analyzed by LC-MS / MS. Quantitative results in blood are shown in [FIG. 5], and pharmacokinetic parameters are shown in [Table 27].

TABLE 27

As shown in FIG. 5, the compound of formula I synthesized in Example 120 had a rapid decrease in plasma concentration. As shown in Table 27, T _max was 8.1 minutes and the average half-life was 79.9 minutes. It can be expected to disappear quickly .

Claims (18)

A compound represented by formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: [Formula I]

Where R ₁ is hydrogen, halogen, —C _1-6 alkyl, or —OC _1-6 alkyl, R ₂ is hydrogen, halogen or —NH ₂ , wherein one or more hydrogens of —NH ₂ may be optionally substituted with R ₄ , R ₃ is hydrogen, halogen, C _6-12 aryl, C _3-12 heteroaryl, C _6-12 arylamino, C _3-12 heteroaryl, amino, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkene, C and _3-10 heterocycloalkyl, wherein said C _{6- 12} aryl, C _{3- 12} heteroaryl, C _{6- 12} arylaminocarbonyl, C _{3- 12} heteroaryl, amino, C _3-10 cycloalkyl, C _3-10 cycloalkyl alkenyl, C _{3- 10} and heterocycloalkyl are unsubstituted or have at least one hydrogen may be substituted with R ₅ or = O, R ₄ is halogen, C _{1- 6} alkyl, -C _{2- 6} alkenyl, - a (C _{2- 6} alkenyl), - (C = O) - (C _{1- 6} alkyl) or - (C = O) R ₅ is -CN, -NO _2, halogen, C _{1- 6} alkyl, C _{2- 6 alkenyl, -OH, -OR a, - (} C = O) -R b, - (C = O) OR b, and _{-NR c R d, -SO 2 -R} b, C 6-12 aryl, C _{3- 12} heteroaryl, C _{3- 10} cycloalkyl, C _3- C ₁₀ cycloalkene, or _{3- 10} heterocycloalkyl, wherein C _{1- 6} alkyl, C _{2- 6} alkenyl, C _6-12 aryl, C _{3- 12} heteroaryl, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkyl and C _3- alkene ₁₀ heterocycloalkyl is unsubstituted or One or more hydrogen may be substituted with R _e , R is _a C _{1- 6} alkyl, C _{2- 6} alkenyl, C _{6- 12} aryl, C _3-12 heteroaryl, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkyl and C _3- alkenyl or heterocycloalkyl ₁₀ , where R _a is an unsubstituted or at least one hydrogen of the beach may be substituted with C _{1- 6} alkyl, C _{2- 6} alkenyl, -OH, -OC _{1- 6} alkyl, -O-CF ₃ or halogen, R _b is _{hydrogen, -NR c R d, C 1-} 6 alkyl, C _{2- 6} alkenyl, C _{6- 12} aryl, C _3-12 heteroaryl, C _{3- 10} cycloalkyl, or C _{3- 10} heterocycloalkyl alkyl, wherein C _{1- 6} alkyl, C _{2- 6} alkenyl, C _{6- 12} aryl, C _3-12 heteroaryl, C _{3- 10} cycloalkyl and C _{3- 10} heteroaryl cycloalkyl or one or more unsubstituted and hydrogen may be substituted with C _{1- 6} alkyl, -OH or halogen, R _c and R _d are each independently hydrogen, C _{1- 6} alkyl, C _{2- 6} alkenyl, - (C = O) - (C 1- 6 alkyl), - (C = O) - (C 2-6 alkenyl), - (C = O) - (C 3- 10 cycloalkyl), - (C = O) - (C 3- 10 heterocycloalkyl), or -SO ₂ - and (C _2-6 alkyl), wherein C _{1- 6} alkyl, C _{2- 6} alkenyl, - (C = O) - (C 1- 6 alkyl), - (C = O) - (C 2- 6 alkenyl), - (C = O) - ( _3- C ₁₀ cycloalkyl), - (C = O) - (C 3- 10 heterocycloalkyl), and -SO ₂ - (C _{2- 6} alkyl) is a unsubstituted or at least one hydrogen of C _{1- 6} alkyl, C _{2- 6} can be substituted with alkenes, -OH or halogen, R _e is halogen, C _{1- 6} alkyl, C _{2- 6} alkenyl, -OH, - (C = O ) -R b, - (C = O) OR b, C 6- 12 aryl, C _3-12 heteroaryl aryl, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkene or C _{3- 10} cycloalkyl, and heteroaryl, wherein C _{1- 6} alkyl, C _{2- 6} alkenyl, C _{6- 12} aryl, C _3-12 heteroaryl, , C _{3- 10} cycloalkyl, C _{3- 10} cycloalkyl and C _3- alkenyl heterocycloalkyl alkilneun ₁₀ is unsubstituted or one or more hydrogen C _{1- 6} alkyl, C _{2- 6} may be substituted with alkenyl, -OH, or halogen, and , The C _{3- 12} heteroaryl, and C _{3- 12} heteroaryl, amino, C _{3- 10} heterocycloalkyl contain 1 to 3 heteroatoms selected from O, N or S. The method of claim 1, wherein, R ₁ is acceptable salts thereof with the compound, stereoisomer thereof, chemical or pharmaceutical agent represented by the general formula (I) is hydrogen or -OC _{1- 6} alkyl. The compound represented by formula (I), stereoisomer or pharmaceutically acceptable salt thereof, according to claim 1, wherein R ₂ is hydrogen, Br or —NH ₂ . The compound of claim 1, wherein R ₃ is furanyl, thiophenyl, pyrazolyl, pyrazinyl, pyridinyl, pyrimidinyl, benzothiazolyl, benzothiophenyl, benzodioxyyl, indazolyl, isoindolinyl , quinolinyl, with amino, pyridinyl, amino, phenyl, indenyl, naphthalenyl, phenyl, amino, piperidinyl or C _{3- 6-cyclopropyl} a compound of the formula I, its stereoisomer or pharmaceutically pyridazinyl Acceptable salts thereof. The compound represented by formula (I) according to claim 1, wherein R ₄ is-(C = O)-(C _1-3 alkyl) or-(C = O)-(C _2-3 alkene), or a stereoisomer thereof Pharmaceutically acceptable salts thereof. The method of claim 1, wherein, R is _a acceptable salt thereof C _{1- 3} alkyl, the compound represented by phenyl or morpholino carbonyl of the formula I, stereoisomers thereof, or a pharmaceutically. The method of claim 1 wherein, R _b is _{hydrogen, -NH 2, -NH (CH 3} ), C 1- 3 alkyl or C _2- alkenyl of ₃ acceptable compounds, stereoisomers thereof, chemical or pharmaceutical agent represented by the general formula (I) Salts thereof. The method of claim 1, wherein, R _c are each independently hydrogen, C _{1- 3} alkyl, - (C = O) - (C 1- 3 alkenyl), - (C = O) - (C 3-6 cycloalkyl) or -SO ₂ - (C _{1- 3} alkyl), R _d is hydrogen or an acceptable salt thereof in an C _{1- 3} alkyl represented by formula I, stereoisomers thereof, chemical or pharmaceutical agent. According to claim 1, R _e is acceptable salts thereof C _{1- 3} alkyl, -OH, -COOH, -COOCH _3, or a morpholino carbonyl compound, a stereoisomer thereof or a chemical agent of the formula I. The method of claim 1, And R ₁ is -OC _{1- 3} alkyl, R ₂ is hydrogen, R ₃ is furanyl, pyrazolyl, pyrazinyl, pyrimidinyl, benzothiazolyl, benzothiophenyl, indazolyl, isoindolinyl, quinoline or piperidinyl, R ₅ is -CN, -NO _2, halogen, C _{1- 6} alkyl, C _{1- 6 alkenyl, -OH, -OR a, - (} C = O) -R b, - (C = O) OR b, and _{-NR c R d, -SO 2 -R} b, C 6-12 aryl, C _{3- 12} heteroaryl, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkyl alkenyl or C _3-10 heterocycloalkyl, wherein C _{1- 6} alkyl, C _{1- 6} alkenyl, C _6-12 aryl, C _{3- 12} heteroaryl, C _3-10 cycloalkyl, C _{3- 10} cycloalkyl and C _3- alkene ₁₀ heterocycloalkyl is unsubstituted or One or more hydrogens may be substituted by R _e A compound represented by formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof. The method of claim 1, R ₁ is hydrogen, C _{1- 3} alkyl, -OC _{1- 3} alkyl, R ₂ is Br, R ₃ is furanyl, thiophenyl, pyrazolyl, pyrimidinyl, benzothiazolyl, indazolyl, quinoline, phenyl, naphthalenyl or cyclopropyl, the furanyl, thiophenyl, pyrazolyl, pyrimidinyl, Benzothiazolyl, indazolyl, quinoline, phenyl, naphthalenyl or cyclopropyl may be unsubstituted or one or more hydrogen may be substituted with R ₅ or ═O. A compound represented by formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof. The method of claim 1, R ₁ is hydrogen, halogen, -C _{1- 3} alkyl, -OC _{1- 3} alkyl, R ₂ is —NH ₂ , wherein one or more hydrogens of —NH ₂ may be optionally substituted with R ₄ , R ₃ is quinolinyl, naphthalenyl, benzodioxinyl, benzothiazolyl, benzothiophenyl, cyclopropyl, isoindolinyl, indenyl, indazolyl, phenyl, phenylamino, pyrazine, pyridazine, pyridine, Pyridinylamino, pyrimidine or piperidine, wherein the quinolinyl, naphthalenyl, benzodioxinyl, benzothiazolyl, benzothiophenyl, cyclopropyl, isoindolinyl, indenyl, indazolyl, phenyl, Phenylamino, pyrazine, pyridazine, pyridine, pyridinylamino, pyrimidine and piperidine may be unsubstituted or one or more hydrogen may be substituted with R ₅ or ═O. A compound represented by formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof. The method of claim 1, R ₁ is hydrogen, C _{1- 3} alkyl, -OC _{1- 3} alkyl, R ₂ is hydrogen, Br or —NH ₂ , R ₃ is quinoline, naphthalenyl, indenyl, benzodioxyyl, benzothiazolyl, benzothiophenyl, isoindolinyl, indazolyl, phenylamino, pyrazinyl, pyridazinylamino, piperidinyl or cyclopropyl ego, R ₄ is - (C _{1- 3} alkenyl), - (C = O) - (C _{1- 3} alkyl) or - (C = O) R ₅ is -CN, -NO _2, halogen, C _{1- 6} alkyl, C _{1- 6 alkenyl, -OH, -OR a, - (} C = O) -R b, - (C = O) OR b, and _{-NR c R d, -SO 2 -R} b, C 6-12 aryl, C _{3- 12} heteroaryl, C _{3- 10} cycloalkyl, C _3- C ₁₀ cycloalkene, or _{3- 10} heterocycloalkyl, wherein C _{1- 6} alkyl, C _{1- 6} alkenyl, C _6-12 aryl, C _{3- 12} heteroaryl, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkyl and C _3- alkene ₁₀ heterocycloalkyl is unsubstituted or One or more hydrogen may be substituted with R _e , R is _a C _{1- 6} alkyl, C _{1- 6} alkenyl, C _{6- 12} aryl, C _3-12 heteroaryl, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkyl and C _3- alkenyl or heterocycloalkyl ₁₀ , where R _a is an unsubstituted or at least one hydrogen of the beach may be substituted with C _{1- 6} alkyl, C _{1- 6} alkenyl, -OH, -OC _{1- 6} alkyl, -O-CF ₃ or halogen, R _b is hydrogen, -NR _c R _d, C _{1- 6} alkyl, C _{1- 6} alkenyl, C _3- C ₁₀ cycloalkyl or a _{3- 10,} and heterocycloalkyl, where R _b is unsubstituted or substituted one or more hydrogen C _{1- 6} can be substituted with alkyl, -OH or halogen, R _c and R _d are each independently hydrogen, C _{1- 6} alkyl, C _{1- 6} alkenyl, - (C = O) - (C 1- 6 alkyl), - (C = O) - (C 1-6 alkenyl), - (C = O) - (C 3- 10 cycloalkyl), - (C = O) - (C 3- 10 heterocycloalkyl), or -SO ₂ - and (C _1-6 alkyl), wherein R _c and R _d is an unsubstituted or substituted by one or more hydrogen may be substituted with C _{1- 6} alkyl, C _1-6 alkenyl, -OH or halogen, R _e is halogen, C _{1- 6} alkyl, C _{1- 6} alkenyl, -OH, - (C = O ) -R b, - (C = O) OR b, C 6- 12 aryl, C _3-12 heteroaryl aryl, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkene or C _{3- 10} heteroaryl and cycloalkyl, wherein R _e is unsubstituted or substituted one or more hydrogen is C _{1- 6} alkyl, C _{1- 6} alkenyl, -OH Or substituted with halogen, The C _{3- 12} heteroaryl and C _{3- 10} heteroaryl cycloalkyl containing 1 to 3 heteroatoms selected from O, N or S A compound represented by formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof. The compound according to claim 1, wherein the compound represented by formula (I) is selected from the group consisting of compounds of the formulas, stereoisomers or pharmaceutically acceptable salts thereof:

A composition comprising a compound according to any one of claims 1 to 14, a stereoisomer or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. A disorder or disease mediated by, or in response to, inhibition of TGase 2 comprising a compound according to any one of claims 1 to 14, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient. Pharmaceutical compositions for the prophylaxis or treatment. The method of claim 16, wherein the disorder or condition is mediated by or responds to inhibition of TGase 2, wherein the disorder or condition is selected from the group consisting of inflammatory diseases, neurological diseases, cancers, renal parenchymal diseases, fibrosis or combinations thereof. Pharmaceutical compositions for the prevention or treatment of a disorder or disease. The pharmaceutical composition of claim 17, wherein the cancer is selected from the group consisting of kidney cancer, brain cancer, and gastric cancer, or is mediated by TGase 2 or in response to inhibition of TGase 2.

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