KR102377102B1 - Method of preparing Quinoline-5,8-dione derivatives for TGase 2 inhibitor - Google Patents

Abstract

The present invention relates to a method for preparing a quinoline-5,8-dione derivative compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The compound represented by Formula I of the present invention has a TGase 2 inhibitory effect, and a pharmaceutical composition comprising the same is useful for preventing or treating disorders or diseases mediated by TGase 2 or responding to TGase 2 inhibition. can

Description

Method of preparing quinoline-5,8-dione derivatives as TGase 2 inhibitor {Method of preparing Quinoline-5,8-dione derivatives for TGase 2 inhibitor}

The present invention relates to a method for preparing a quinoline-5,8-dione derivative compound having transglutaminase 2 (TGase 2) inhibitory activity, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

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, and was first discovered in 1959. It was found in the protein fibrin stabilizing factor (factor XIII).

Among them, type 2 transglutaminase (TGase 2) is known to mainly function as a protein cross-linking enzyme by promoting the formation of a lysine iso-dipeptide bond. However, according to recent research results, the expression of TGase 2 is normally regulated It has been shown to play an important role in the pathological mechanisms of many diseases.

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

In addition, it irreversibly binds to matrix proteins such as collagen, fibronectin, laminia, nidogen or proteoglycan, or extracellular matrix protease ( It has been suggested that by increasing resistance to proteolytic enzyme), it induces severe extracellular matrix deposition and is involved in tissue fibrosis. In fact, it has been reported that TGase 2 plays a major role in experimental renal and liver fibrosis, and the degree of fibrosis decreases when its activity is inhibited using an inhibitor.

An amine compound is known as a substance that inhibits TGase 2 activity, and representative examples thereof include cystamine and putrescine. In addition, chemical inhibitors such as monodansilcadaverine, w-dibenzylaminoalkylamine, 3-halo-4,5-dihydroisoxazole, and 2-[(2-oxopropyl)thio]imidazolium derivatives have been developed. However, all of them are known to be toxic to induce inhibition of other enzymes non-specifically in vivo. In addition, recently, TGase 2 inhibitory activity of glucosamine derivatives, chlorogenic acid, epigallocatechin gallate, curcumin, sulpharem, and ethacrnic acid has been known. is undisclosed.

Therefore, there is a need for continuous development of safe and effective transglutaminase inhibitors.

US Patent Application No. 2009-462554 Korean Patent Application No. 2008-0118688 Korean Patent Application No. 2009-0018388 Korea Patent Application No. 2014-0090500

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 a method for preparing a novel quinoline-5,8-dione derivative compound, a stereoisomer or a pharmaceutically acceptable salt thereof.

The present application provides a method for preparing a compound represented by the following formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof:

[Formula I]

In the above formula,

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 heteroarylamino, C _3-10 cycloalkyl, C _3-10 cycloalkenyl, C _3-10 heterocycloalkyl, wherein said C _6-12 aryl, C _3-12 heteroaryl, C _6-12 arylamino, C _3-12 heteroarylamino, C _3-10 cycloalkyl C _3-10 Cycloalkenyl, and C _3-10 heterocycloalkyl may be unsubstituted or one or more hydrogens 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 alkenyl),

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 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 cycloalkenyl and C _3-10 heterocycloalkyl may be unsubstituted or one or more hydrogens may be substituted with R _e ,

R _a is 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 heterocyclo 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 hetero Cycloalkyl may be unsubstituted or one or more hydrogens 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 heterocyclo 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 heterocycloalkyl are unsubstituted or one or more 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 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) are unsubstituted or one or more hydrogens are C _{1 -6} alkyl, C _2-6 alkenyl, -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 _3-10 cycloalkenyl or C _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 cycloalkenyl and C _3-10 heterocycloalkyl are unsubstituted or one or more hydrogens are C _1-6 alkyl, C _2-6 may be substituted with alkenyl, -OH or halogen,

The C _3-12 heteroaryl, C _3-12 heteroarylamino and C _3-10 heterocycloalkyl include 1 to 3 heteroatoms selected from O, N or S.

The preparation method of the present application comprises the steps of preparing compound IMC2 by coupling compound IMC1 according to Scheme 1 below; and reacting compound IMC2 to prepare compound Q1.

[Scheme 1]

In Scheme 1,

Xa represents halogen,

Y, Y ₁ and Y ₂ are each independently C _1-6 alkyl,

A ₁ is C _6-12 aryl, C _3-12 heteroaryl, C _6-12 arylamino, C _3-12 heteroarylamino, C _3-10 cycloalkyl, C _3-10 cycloalkenyl, C _3-10 heterocycloalkyl, wherein C _6-12 aryl, C _3-12 heteroaryl, C _6-12 arylamino, C _3-12 heteroarylamino, C _3-10 cycloalkyl C _3-10 cycloalkenyl and C _3-10 heterocycloalkyl may be unsubstituted or one or more hydrogens may be substituted with R ₅ or =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 , -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 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 cycloalkenyl and C _3-10 heterocycloalkyl may be unsubstituted or one or more hydrogens may be substituted with R _e ,

R _a is 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 heterocyclo 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 hetero Cycloalkyl may be unsubstituted or one or more hydrogens 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 heterocyclo 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 heterocycloalkyl are unsubstituted or one or more 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 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) are unsubstituted or one or more hydrogens are C _{1 -6} alkyl, C _2-6 alkenyl, -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, C _3-10 cycloalkyl, C _3-10 cycloalkenyl or C _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 cycloalkenyl and C _3-10 heterocycloalkyl are unsubstituted or one or more hydrogens are C _1-6 alkyl, C _2-6 alkenyl, —OH or may be substituted with halogen,

The C _3-12 heteroaryl, C _3-12 heteroarylamino and C _3-10 heterocycloalkyl include 1 to 3 heteroatoms selected from O, N or S.

In the step of preparing compound Q1 from compound IMC2, compound Q1 may be prepared by dropwise adding an aqueous solution of ceric ammonium nitrate (CAN) to compound IMC2.

Herein, a method for preparing a quinoline-5,8-dione derivative includes: preparing compound IMC2 by coupling compound IMC1 according to Scheme 2 below; reacting compound IMC2 to prepare compound IMC3; and reacting compound IMC3 to prepare compound Q2.

[Scheme 2]

In Scheme 2,

Xa represents halogen,

Y, Y ₁ and Y ₂ are each independently C _1-6 alkyl,

A ₁ is any one of C6-12 aryl, C3-12 heteroaryl, C6-12 arylamino, C3-12 heteroarylamino, C3-10 cycloalkyl, C3-10 cycloalkenyl, and C3-10 heterocycloalkyl represents a functional group in which hydrogen of -(C=O)-(C1-6 alkyl) is substituted,

A ₂ is any one of C6-12 aryl, C3-12 heteroaryl, C6-12 arylamino, C3-12 heteroarylamino, C3-10 cycloalkyl, C3-10 cycloalkenyl, and C3-10 heterocycloalkyl represents a functional group in which hydrogen of -(C=O)-(C _2-6 alkenyl) is substituted.

, K⁺(BF₃(A₁))^-, (A₁)-Sn(n-Bu)₃, NH₂-(A₁) 또는

를 이용할 수 있다. 이때, (HO)₂-B-(A₁),

, K⁺(BF₃(A₁))^-, (A₁)-Sn(n-Bu)₃ 또는 NH₂-(A₁)에서의 A₁은 반응식 1 또는 반응식 2 각각에서 정의한 것과 동일하고,

에서 A₁은 R₅로 치환 또는 비치환된 C_3-12헤테로아릴을 나타낸다.In one embodiment of the present invention, in each of the coupling reactions of Schemes 1 and 2, (HO) ₂ -B-(A ₁ ),

, K ⁺ (BF ₃ (A ₁ )) ^- , (A ₁ )-Sn(n-Bu) ₃ , NH ₂ -(A ₁ ) or

is available. In this case, (HO) ₂ -B-(A ₁ ),

A 1 in , K ⁺ (BF ₃ (A ₁ )) ^- , (A ₁ )-Sn(n-Bu) ₃ or NH ₂ -(A ₁ ) is the same as defined in Scheme ₁ or Scheme 2, respectively,

In A ₁ represents C _3-12 heteroaryl substituted or unsubstituted with R ₅ .

The preparation method of the present invention may further include preparing compound Q3 by halogenating compound Q1 according to Scheme 3 below.

[Scheme 3]

In Scheme 3,

Y is C _1-6 alkyl,

B ₁ is halogen,

A ₁ is the same as defined in Scheme 1.

In one embodiment of the present invention, the method for preparing the quinoline-5,8-dione derivative may further include preparing compound Q4 from compound Q3 according to Scheme 4 below.

[Scheme 4]

In Scheme 4,

Y is C _1-6 alkyl,

B ₁ is halogen,

A ₁ is C _6-12 aryl, C _3-12 heteroaryl, C _6-12 arylamino, C _3-12 heteroarylamino, C _3-10 cycloalkyl, C _3-10 cycloalkenyl and C _3-10 In any one of heterocycloalkyl represents a functional group in which one hydrogen is substituted with -(C=O)-O(C _1-6 alkyl),

A ₃ is C _6-12 aryl, C _3-12 heteroaryl, C _6-12 arylamino, C _3-12 heteroarylamino, C _3-10 cycloalkyl C _3-10 cycloalkenyl, and C _3-10 In any one of heterocycloalkyl, one hydrogen represents a functional group substituted with -(C=O)-NH ₂ .

In one embodiment of the present invention, the method for preparing the quinoline-5,8-dione derivative may further include preparing compound Q5 from compound Q3 according to Scheme 5 below.

[Scheme 5]

In Scheme 5,

Y is C _1-6 alkyl,

B ₁ is halogen,

A ₁ is the same as defined in Scheme 1.

In one embodiment of the present invention, the method for preparing the quinoline-5,8-dione derivative may further include preparing compound Q6 from compound Q5 according to Scheme 6 below.

[Scheme 6]

In Scheme 6,

Y is C _1-6 alkyl,

A ₁ is the same as defined in Scheme 1,

A ₄ and A ₅ are each independently hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl, -(C=O)-(C _1-6 alkyl) or -(C=O)-(C _2-6 alkenyl), except when A ₄ and A ₅ are both hydrogen.

In one embodiment of the present invention, the method for preparing the quinoline-5,8-dione derivative includes preparing compound IMC3 from compound Q3 according to Scheme 7 below; and preparing compound Q7 through a reduction reaction of compound IMC3.

[Scheme 7]

In Scheme 7,

Y is C _1-6 alkyl,

A ₁ is C _6-12 aryl, C _3-12 heteroaryl, C _6-12 arylamino, C _3-12 heteroarylamino, C _3-10 cycloalkyl, C _3-10 cycloalkenyl, and C ₃ - a functional group in which at least one hydrogen in any of ₁₀ heterocycloalkyl is substituted with -(C=O)(C _1-6 alkyl), -NO ₂ or -(C=O)-O(C _1-6 alkyl) represents,

A ₆ is C _6-12 aryl, C _3-12 heteroaryl, C _6-12 arylamino, C _3-12 heteroarylamino, C _3-10 cycloalkyl C _3-10 cycloalkenyl, and C _3-10 In any one of the heterocycloalkyls at least one hydrogen represents a functional group substituted with -C(OH)(C _1-6 alkyl), -NH ₂ or -(C=O)-OH.

In one embodiment of the present invention, the method for preparing the quinoline-5,8-dione derivative may include preparing compound Q8 from compound Q7 according to Scheme 8 below.

[Scheme 8]

In Scheme 8,

Y is C _1-6 alkyl,

A ₆ is C _6-12 aryl, C _3-12 heteroaryl, C _6-12 arylamino, C _3-12 heteroarylamino, C _3-10 cycloalkyl, C _3-10 cycloalkenyl, and C ₃ - In any one of ₁₀ heterocycloalkyl represents a functional group in which one hydrogen is substituted with -C(OH)(C _1-6 alkyl) or -NH ₂ ,

A ₇ is C _6-12 aryl, C _3-12 heteroaryl, C _6-12 arylamino, C _3-12 heteroarylamino, C _3-10 cycloalkyl, C _3-10 cycloalkenyl and C _3-10 One hydrogen in any of the heterocycloalkyls is -(C=O)(C _1-6 alkyl), -(C=O)(C _2-6 alkenyl) or -NH(C=O)-CH= It represents a functional group substituted with CH ₂ .

The method for preparing a quinoline-5,8-dione derivative of the present application includes preparing compound Q9 according to Scheme 9 below.

[Scheme 9]

In Scheme 9,

Xb represents halogen.

In one embodiment of the present invention, the method for preparing the quinoline-5,8-dione derivative may further include preparing compound Q10 using compound Q9 according to Scheme 10 below.

[Scheme 10]

In Scheme 10,

Xb represents halogen,

Z ₁ represents halogen, C _1-3 alkyl or —O-(C _1-3 alkyl).

The method for preparing a quinoline-5,8-dione derivative of the present application includes preparing compound Q11 according to Scheme 11 below.

[Scheme 11]

In Scheme 11,

Xc and Xd each independently represent halogen,

A ₈ is C _6-12 aryl, C _3-12 heteroaryl, C _6-12 arylamino, C _3-12 heteroarylamino, C _3-10 cycloalkyl, C _3-10 cycloalkenyl, C _3-10 heterocycloalkyl, wherein C _6-12 aryl, C _3-12 heteroaryl, C _6-12 arylamino, C _3-12 heteroarylamino, C _3-10 cycloalkyl, C _3-10 cycloalkenyl and C _3-10 heterocycloalkyl may be unsubstituted or one or more hydrogens may be substituted with R ₅ or =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 , —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 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 cycloalkenyl and C _3-10 heterocycloalkyl may be unsubstituted or one or more hydrogens may be substituted with R _e ,

R _a is 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 heterocyclo 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 hetero Cycloalkyl may be unsubstituted or one or more hydrogens 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 heterocyclo 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 heterocycloalkyl are unsubstituted or one or more 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 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) are unsubstituted or one or more hydrogens are C _{1 -6} alkyl, C _2-6 alkenyl, -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, C _3-10 cycloalkyl, C _3-10 cycloalkenyl or C _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 cycloalkenyl and C _3-10 heterocycloalkyl are unsubstituted or one or more hydrogens are C _1-6 alkyl, C _2-6 alkenyl, —OH or may be substituted with halogen,

The C _3-12 heteroaryl, C _3-12 heteroarylamino and C _3-10 heterocycloalkyl include 1 to 3 heteroatoms selected from O, N or S.

In one embodiment of the present invention, in the method for preparing the quinoline-5,8-dione derivative, compound Q13 may be prepared using compound Q11 according to Scheme 12 below. For example, in Scheme 12, compound Q12 may be prepared by sequentially adding NaN ₃ and NaBH ₄ dropwise to compound Q11.

[Scheme 12]

In Scheme 12, Xd and A ₈ are the same as defined in Scheme 11, respectively.

In one embodiment of the present invention, the method for preparing the quinoline-5,8-dione derivative may further include preparing compound Q13 by reacting compound Q12 according to Scheme 13 below.

[Scheme 13]

In Scheme 13,

A ₈ is the same as in Scheme 12,

A ₉ and A ₁₀ are each independently hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl, -(C=O)-(C _1-6 alkyl) or -(C=O)-(C _2-6 alkenyl), except when A ₉ and A ₁₀ are hydrogen at the same time.

In one embodiment of the present invention, the method for preparing the quinoline-5,8-dione derivative may further include preparing compound Q14 by reacting compound Q11 according to Scheme 14 below.

[Scheme 14]

In Scheme 14,

Xd and A ₈ are each the same as defined in Scheme 11,

Z ₂ represents halogen, C _1-3 alkyl or —OC _1-3 alkyl.

In one embodiment of the present invention, the method for preparing the quinoline-5,8-dione derivative may further include preparing compound Q15 using compound Q14 according to Scheme 15 below. At this time, compound Q15 may be prepared by sequentially adding dropwise NaN ₃ and NaBH ₄ to compound 14.

[Scheme 15]

In Scheme 15,

Z ₂ , Xd and A ₈ are each the same as defined in Scheme 14 above.

In one embodiment of the present invention, the method for preparing the quinoline-5,8-dione derivative of the present application includes reacting compound Q16 according to Scheme 16 to prepare compound Q17.

[Scheme 16]

In Scheme 16,

Xf represents halogen,

Z ₃ represents halogen, C _1-3 alkyl or —OC _1-3 alkyl.

In one embodiment of the present invention, the method for preparing the quinoline-5,8-dione derivative may include preparing compound Q18 according to Scheme 17 below. In this case, premi salt may be used to prepare compound Q18.

[Scheme 17]

In Scheme 17,

Xg represents halogen.

In one embodiment of the present invention, the method for preparing the quinoline-5,8-dione derivative may further include preparing compound Q19 by reacting compound Q18 according to Scheme 18 below.

[Scheme 18]

In Scheme 18,

Xg represents halogen,

A ₁₃ is C _6-12 aryl, C _3-12 heteroaryl, C _6-12 arylamino, C _3-12 heteroarylamino, C _3-10 cycloalkyl, C _3-10 cycloalkenyl, C _3-10 heterocycloalkyl, wherein C _6-12 aryl, C _3-12 heteroaryl, C _6-12 arylamino, C _3-12 heteroarylamino, C _3-10 cycloalkyl, C _3-10 cycloalkenyl and C _3-10 heterocycloalkyl may be unsubstituted or one or more hydrogens may be substituted with R ₅ or =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 , —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 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 cycloalkenyl and C _3-10 heterocycloalkyl may be unsubstituted or one or more hydrogens may be substituted with R _e ,

R _a is 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 heterocyclo 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 hetero Cycloalkyl may be unsubstituted or one or more hydrogens 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 heterocyclo 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 heterocycloalkyl are unsubstituted or one or more 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 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) are unsubstituted or one or more hydrogens are C _{1 -6} alkyl, C _2-6 alkenyl, -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, C _3-10 cycloalkyl, C _3-10 cycloalkenyl or C _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 cycloalkenyl and C _3-10 heterocycloalkyl are unsubstituted or one or more hydrogens are C _1-6 alkyl, C _2-6 alkenyl, —OH or may be substituted with halogen,

The C _3-12 heteroaryl, C _3-12 heteroarylamino and C _3-10 heterocycloalkyl include 1 to 3 heteroatoms selected from O, N or S.

In one embodiment of the present invention, the method for preparing the quinoline-5,8-dione derivative may further include preparing compound Q20 by reacting compound Q19 according to Scheme 19 below.

[Scheme 19]

In Scheme 19,

A ₁₃ is the same as defined in Scheme 18 above.

The quinoline-5,8-dione derivative, a stereoisomer or a pharmaceutically acceptable salt thereof, prepared according to the preparation method of the present invention has few side effects and effectively inhibits TGase 2 .

The quinoline-5,8-dione derivative compound prepared according to the preparation method of the present invention, a stereoisomer or a pharmaceutically acceptable salt thereof, is mediated by TGase 2 or responds to a TGase 2 inhibitor. It can be usefully used for therapeutic or prophylactic purposes.

1 is a graph showing the tumor volume of the control group (CT), 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 confirmed in Experimental Example 3;
2 is a graph showing the tumor weights of the control group (CT), the compound of Formula I 5 mg/kg administered group, the compound of Formula I 10 mg/kg administration group, and the compound of Formula I 20 mg/kg administration group confirmed in Experimental Example 3;
Figure 3 is a photograph showing the appearance of tumors in the control group, the compound of formula I 5 mg / kg administration group, the compound of formula I 10 mg / kg administration group, and the compound 20 mg / kg administration group of the formula I confirmed in Experimental Example 3.
4 is a graph showing the body weight of the control group and 100 mg/kg administration group of the compound of Formula I confirmed in Experimental Example 3.
5 is a graph showing the plasma concentrations of the control group and the 10 mg/kg administration group of the compound of Formula I confirmed in Experimental Example 4.

Hereinafter, the present application will be described in detail so that those of ordinary skill in the art to which the present application pertains can easily implement it. However, the present application may be embodied in many different forms and is not limited to the specific embodiments described herein. In addition, descriptions of similar parts are omitted throughout the specification.

Throughout this specification, when a part "includes" a certain component, it means that other components may be further included, rather than excluding other components, unless otherwise stated.

As used throughout this specification, the terms "about," "substantially," and the like are used in a sense at or close to the numerical value when the manufacturing and material tolerances inherent in the stated meaning are presented, and are intended to enhance the understanding of this application. To help, precise or absolute figures are used to prevent unfair use by unconscionable infringers of the stated disclosure.

As used throughout this specification, the term "step for" or "step for" does not mean "step for".

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

Throughout this specification, reference to “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, respectively, for example, methyl, ethyl, propyl, butyl, pentyl. , hexyl, heptyl, octyl, nonyl, decyl, or an isomer thereof, but is not limited thereto.

Throughout this specification, the term "aryl" or "aryl group", alone or as part of another group, refers to monocyclic or bicyclic aromatic rings such as phenyl, substituted phenyl, as well as fused groups; Examples include, but are not limited to, naphthyl, phenanthrenyl, indenyl, tetrahydronaphthyl, and indanyl, and the like. For example, the term “aryl” or “aryl group” contains one or more rings having 5 or more atoms, and there may be up to 5 rings containing 22 or fewer atoms, adjacent carbon atoms or There may be alternating (resonance) double bonds between suitable heteroatoms. Said "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 limited to, carbonyl, nitro, alkenyloxy, trifluoromethyl, amino, cycloalkyl, aryl, heteroaryl, cyano, alkyl S(O) _m (m=O, 1, 2) or thiol may be substituted with one or more groups that are not For example, the "aryl" or "aryl group" may be, but is not limited to, phenyl, phenyl substituted as described above, phenyl, naphthyl, or naphthyl substituted as described above.

Throughout this specification, the term "heteroaryl" or "heteroaryl group", alone or as part of another group, refers to a monocyclic or bicyclic aromatic ring containing one or more atoms other than carbon atoms, e.g. For example, furanyl, thiophenyl, pyrazolyl, pyrazinyl, pyridinyl, pyrimidinyl, benzothiazolyl, benzodioxinyl, andazolyl, isoindolinyl, indenyl, quinolinyl and benzothiophenyl and the like, but are not limited thereto. A “heteroaryl” or “heteroaryl group” contains at least one ring having at least 5 atoms, and there may be up to 5 rings containing up to 22 atoms, contiguous carbon atoms or suitable heteroatoms There may be alternating (resonance) double bonds between them. In addition, "heteroaryl" or "heteroaryl group" may be substituted in the same manner as described for "aryl" or "aryl group".

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

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

Quinoline-5,8-dione derivative compound

The present application provides a compound represented by the following formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof:

[Formula I]

In the above formula,

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 heteroarylamino, C _3-10 cycloalkyl, C _3-10 cycloalkenyl, C _3-10 heterocycloalkyl, wherein said C _6-12 aryl, C _3-12 heteroaryl, C _6-12 arylamino, C _3-12 heteroarylamino, C _3-10 cycloalkyl C _3-10 Cycloalkenyl, and C _3-10 heterocycloalkyl may be unsubstituted or one or more hydrogens 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 alkenyl),

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 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 cycloalkenyl and C _3-10 heterocycloalkyl may be unsubstituted or one or more hydrogens may be substituted with R _e ,

R _a is 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 heterocyclo 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 hetero Cycloalkyl may be unsubstituted or one or more hydrogens 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 heterocyclo 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 heterocycloalkyl are unsubstituted or one or more 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 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) are unsubstituted or one or more hydrogens are C _{1 -6} alkyl, C _2-6 alkenyl, -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 _3-10 cycloalkenyl or C _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 cycloalkenyl and C _3-10 heterocycloalkyl are unsubstituted or one or more hydrogens are C _1-6 alkyl, C _2-6 may be substituted with alkenyl, -OH or halogen,

The C _3-12 heteroaryl, C _3-12 heteroarylamino and C _3-10 heterocycloalkyl include 1 to 3 heteroatoms selected from O, N or S.

In the compound of formula (I) herein, R ₁ may specifically be hydrogen, C _1-3 alkyl or -OC _1-3 alkyl, preferably hydrogen, -CH ₃ or -O-CH ₃ , more preferably is hydrogen or -O-CH ₃ .

In the compound 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, benzodioxinyl, 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.

In the compound of formula (I) herein, R ₄ may specifically be -(C=O)-(C _1-3 alkyl) or -(C=O)-(C _2-3 alkenyl).

In the compounds of formula (I) herein, R _a may specifically be C _1-3 alkyl, phenyl or morpholinyl.

In the compound of formula (I) herein, R _b may specifically be hydrogen, —NH ₂ , —NH(CH ₃ ), C _1-3 alkyl or C _2-3 alkenyl.

In the compounds of formula (I) herein, R _c is specifically hydrogen, C _1-3 alkyl, -(C=O)-(C _1-3 alkenyl), -(C=O)-(C _3-6 cyclo alkyl) or —SO ₂ —(C _1-3 alkyl), and R _d may specifically be hydrogen or C _1-3 alkyl.

In the compounds of formula (I) herein, R _e may specifically be C _1-3 alkyl, -OH, -OC _1-3 alkyl, -COOH, -COOCH ₃ or morpholinyl.

According to a preferred embodiment of the present application, in the compound represented by Formula I, a stereoisomer or a 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, the furanyl, pyrazolyl, pyra Zinyl, pyrimidinyl, benzothiazolyl, benzothiophenyl, indazolyl, isoindolinyl, quinolinyl or piperidinyl may be unsubstituted or one or more hydrogens may be substituted with R ₅ or =O.

According to a preferred embodiment of the present application, in the compound represented by Formula I, a stereoisomer or a 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, which phenyl may be unsubstituted or one or more hydrogens may be substituted with -O-CF ₃ .

According to a preferred embodiment of the present application, in the compound represented by Formula I, a stereoisomer or a pharmaceutically acceptable salt thereof,

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

R ₂ is Br,

R ₃ is furanyl, thiophenyl, pyrazolyl, pyrimidinyl, benzothiazolyl, indazolyl, quinolinyl, phenyl, naphthalenyl or cyclopropyl, the furanyl, thiophenyl, pyrazolyl, pyrimidi Nyl, benzothiazolyl, indazolyl, quinolinyl, phenyl, naphthalenyl or cyclopropyl may be unsubstituted or one or more hydrogens may be substituted with R ₅ or =O.

According to a preferred embodiment of the present application, in the compound represented by Formula I, a stereoisomer or a pharmaceutically acceptable salt thereof,

R ₁ is hydrogen, halogen, C _1-3 alkyl or —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, 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 =O.

According to a preferred embodiment of the present application, in the compound represented by Formula I, a stereoisomer or a 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 C _1-6 alkyl, _wherein one or more hydrogens may be substituted with R _e ;

R _a is phenyl or piperidinyl, which phenyl or piperidinyl may be unsubstituted or one or more hydrogens may be substituted with C _1-3 alkyl,

R _e is morpholine.

According to a preferred embodiment of the present application, in the compound represented by Formula I, a stereoisomer or a pharmaceutically acceptable salt thereof,

R ₁ is -O-CH ₃ ,

R ₂ is —NH ₂ ,

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

R ₅ is halogen or C _1-3 alkyl, wherein the C _1-3 alkyl may be substituted with R _e ,

Wherein R _e is halogen.

According to a preferred embodiment of the present application, in the compound represented by Formula I, a stereoisomer or a 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, benzodioxinyl, benzothiazolyl, benzothiophenyl, isoindolinyl, indazolyl, phenylamino, pyrazinyl, pyridazinylamino, piperidinyl or Cyclopropyl, the quinolinyl, naphthalenyl, indenyl, benzodioxinyl, benzothiazolyl, benzothiophenyl, isoindolinyl, indazolyl, phenylamino, pyrazinyl, pyridazinylamino, piperidi Nyl and cyclopropyl may be unsubstituted or one or more hydrogens may be substituted with R ₅ or =O.

R ₄ is -(C=O)-(C _1-3 alkyl) or -(C=O)-(C _1-3 alkenyl),

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 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 cycloalkenyl and C _3-10 heterocycloalkyl may be unsubstituted or one or more hydrogens may be substituted with R _e ,

R _a is 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 heterocyclo alkyl, wherein R _a is unsubstituted or one or more hydrogens 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 heterocyclo 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 heterocycloalkyl are unsubstituted or one or more 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 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) are unsubstituted or one or more hydrogens are C _{1 -6} alkyl, C _2-6 alkenyl, -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 _3-10 cycloalkenyl or C _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 cycloalkenyl and C _3-10 heterocycloalkyl are unsubstituted or one or more hydrogens are C _1-6 alkyl, C _2-6 may be substituted with alkenyl, -OH or halogen,

The C _3-12 heteroaryl and C _3-10 heterocycloalkyl may include 1 to 3 heteroatoms selected from O, N or S.

According to a preferred embodiment of the present application, in the compound represented by Formula I, a stereoisomer or a 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 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 C _1-3 alkyl may be unsubstituted or one or more hydrogens may be substituted with R _e ,

R _a is phenyl or piperidinyl, which phenyl or piperidinyl may be unsubstituted or one or more hydrogens 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 selected from the group consisting of compounds of the formula shown in Table 1 below, stereoisomers or pharmaceuticals thereof It may be an acceptable salt thereof, but is not limited thereto.

[Table 1]

In a preferred embodiment of the present application, the compound represented by Formula I is a quinoline-5,8-dione derivative compound selected from the group consisting of compounds of the formula shown in Table 2 below, a stereoisomer or a pharmaceutical thereof It may be an acceptable salt thereof.

[Table 2]

As used herein, the pharmaceutically acceptable salt means a salt commonly used in the pharmaceutical industry, for example, inorganic ionic salts prepared from calcium, potassium, sodium and magnesium, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodine Mineral 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 , glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc. organic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and sulfonic acid salts prepared with naphthalenesulfonic acid, etc., amino acid salts prepared with glycine, arginine, lysine, etc., and amine salts prepared with trimethylamine, triethylamine, ammonia, pyridine, picoline, etc., but these listed The type of salt in the present invention is not limited by the salt.

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 individual diastereomers. Such isomers can be separated by conventional techniques, for example, the compound of formula (I) by column chromatography or resolution such as HPLC. Alternatively, stereoisomers of each of the compounds of formula (I) can be synthesized stereospecifically using optically pure starting materials and/or reagents of a known configuration.

Composition comprising quinoline-5,8-dione derivative compound, use thereof, and treatment method using same

The present application relates to a compound of formula I, a set of stereoisomers or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable carrier.

The compound of Formula I is the same as described above, and overlapping parts will be omitted from detailed description.

As the carrier, for example, commonly used ones may be used, and sugar, starch, microcrystalline cellulose, lactose (lactose hydrate), 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 additives such as, for example, a binder, a disintegrant, a lubricant, a pH adjuster, and an antioxidant, but is not limited thereto.

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

The disintegrant is, for example, starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch; clays 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 sodium croscarmellose; gums such as guar gum and xanthan gum; crosslinked polymers such as crosslinked polyvinylpyrrolidone (crospovidone); An effervescent agent such as sodium bicarbonate or citric acid, or a mixture thereof may be used, but is 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 monostearate Late, glyceryl palmitostearate, colloidal silicon dioxide, or a mixture thereof may be used, but is not limited thereto.

The pH adjusting agent is, for example, an acidifying agent such as acetic acid, adipic acid, ascorbic acid, sodium ascorbate, sodium etherate, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid (citric acid) and precipitated calcium carbonate, aqueous ammonia, A basifying agent such as meglumine, sodium carbonate, magnesium oxide, magnesium carbonate, sodium citrate, and tribasic calcium phosphate may be used, but the present invention is not limited thereto.

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

Since the compound of formula (I) has few side effects and effectively inhibits TGase2, the composition of the present application can be used for preventing or treating disorders or diseases mediated by TGase 2 or responding to TGase 2 inhibition. there is. However, the use of the compounds of formula (I) herein is not limited thereto.

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

The compound of Formula I is the same as described above, and the description of overlapping portions will be omitted.

In one specific embodiment of the present application, the disorder or disease mediated by TGase 2 or responsive to inhibition of TGase 2 is selected from the group consisting of inflammatory disease, neurological disease, cancer, parenchymal disease, fibrosis, or a combination thereof. may be selected, but is not limited thereto.

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

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

The cancer is, for example, colon cancer, small intestine cancer, rectal cancer, colon cancer, anal cancer, esophageal cancer, stomach cancer, pancreatic cancer, gallbladder cancer, uterine cancer, cervical cancer, breast cancer, ovarian cancer, lung cancer, lymph gland cancer, thyroid cancer, prostate cancer, 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 of the present application, the disorder or disease mediated by TGase 2 or responsive to inhibition of TGase 2 is cancer, more preferably kidney cancer, brain cancer or stomach cancer.

In one aspect of the present application, there is provided a method of inhibiting TGase 2 activity in a subject, comprising administering to the subject a compound of formula (I) in a therapeutically effective amount. The subject includes, but is not limited to, mammals such as, for example, humans, monkeys, cattle, horses, dogs, cats, rabbits, rats, and mice.

In one aspect of the present application 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 or responsive to inhibition of TGase 2 in a subject.

Method for preparing quinoline-5,8-dione derivative compound

The present application provides a method for preparing the compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. However, the above-described compound of Formula I, a stereoisomer or a pharmaceutically acceptable salt thereof is not limited to those prepared by the preparation method of the present application.

In a specific embodiment of the present application, a method for preparing a quinoline-5,8-dione derivative compound represented by Formula I, an isomer thereof, or a pharmaceutically acceptable salt thereof is as shown in [Scheme a], and is apparent to those skilled in the art. This includes manufacturing methods that have been modified to a level.

[Scheme a]

) 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 a], 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 1-4 is synthesized by reacting the compound of Formula 1-3 with (E)-3-ethoxyacryloyl chloride, and the compound of Formula 1-4 is added dropwise to a sulfuric acid solution to react with the compound of Formula 1-5 synthesize the compound of A compound of Formula 1-5 is dissolved in a solution of pyridine and dimethylformamide (DMF), and phosphorus oxychloride (POCl ₃ ) is added dropwise to synthesize a compound of Formula 1-6. and R-boronic acid pinacol ester (

) or R-borate (

) using a Suzuki reaction to synthesize the compound of Formula 1-7 using microwaves. Finally, after dissolving the compound of Formula 1-7 in acetonitrile (ACN), an aqueous solution of ceric ammonium nitrate (CAN) may be added dropwise to synthesize the compound of Formula 1-8.

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

In addition, as shown in Scheme a, 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 added to Pd/C, The compound of Formula 1-11 may be synthesized by reducing H ₂ or reducing with sodium borohydride (NaBH ₄ ).

In a specific embodiment of the present application, a method for preparing a quinoline-5,8-dione derivative compound represented by Formula I, an isomer thereof, or a pharmaceutically acceptable salt thereof is as shown in [Scheme b], and is apparent to those skilled in the art. This includes manufacturing methods that have been modified to a level.

[Scheme b]

) 또는 R-보레이트(

)를 사용하여 스즈키 반응(Suzuki reaction)으로 마이크로웨이브를 사용하여 화학식 10-11의 화합물을 합성할 수 있다. As shown in [Scheme b], 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 . A compound of Formula 10-4 is synthesized by reacting a compound of Formula 10-3 with acetyl chloride, and a compound of Formula 10-5 is synthesized by reacting a compound of Formula 10-4 with H ₂ O. A compound of Formula 10-6 was synthesized by reacting a compound of Formula 10-5 with benzyl bromide (BnBr), and mCPBA was added dropwise to the compound of Formula 10-6 to synthesize a compound of Formula 10-7, POCl ₃ By dropwise addition, a compound of Formula 10-8 is synthesized. Then, trichloroborane and dimethyl sulfan salt are added dropwise to synthesize a compound of Formula 10-9, and a compound of Formula 10-10 is synthesized by dropwise addition of premi salt. Finally, R-boronic acid pinacol ester (

) or R-borate (

) can be used to synthesize the compound of Chemical Formula 10-11 by using a microwave in a Suzuki reaction.

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

Hereinafter, the present application will be described in more detail using Preparation Examples, Examples and Experimental Examples below. However, the following Preparation Examples, Examples and Experimental Examples are merely illustrative to aid the understanding of the present application, and the content of the present application is not limited to the following Preparation Examples, Examples and Experimental Examples.

[Preparation Example] Preparation of intermediate compound

Preparation Example 1: Preparation of 2-chloro-5,6,8-trimethoxyquinoline (Compound of Formula 1-6)

Step 1: 1,2,4-trimethoxy-5-nitrobenzene (formula 1-2 preparation of compounds)

After cooling water (300 ml) in which 60% nitric acid (100 ml) is dissolved to 0 °C, 2,4,5-trimethoxybenzaldehyde (5 g, 25.5 mmol) is slowly added dropwise to dissolve, and at the same temperature Stirred for 1 hour. After completion of the reaction, the reaction mixture was filtered, washed with water, and dried to obtain a yellow solid compound (Formula 1-2 ).

Step 2: 2,4,5-trimethoxyaniline (formula 1-3 preparation of compounds)

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 stream. After completion of the reaction, the reaction mixture was filtered through celite, and the solvent was dried under reduced pressure to obtain a beige solid compound (Formula 1-3 ).

Step 3: 3-ethoxy-N-(2,4,5-trimethoxyphenyl)acrylamide (formula 1-4 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 heated to 0 °C. cooled. Then, (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. Separation and purification by MPLC (hexane/ethyl acetate) (5/1) gave a solid compound (Formula 1-4 ).

Step 4: 5,6,8-trimethoxyquinolin-2(1H)-one (formula 1-5 preparation of compounds)

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

Step 5: 2-chloro-5,6,8-trimethoxyquinoline (formula 1-6 preparation of compounds)

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

Preparation 2: N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide (compound of formula 2-3 ) manufacturing

Step 1: N- (3-bromophenyl) cyclopropanecarboxamide (formula 2-2 preparation of compounds)

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

N-(3-bromophenyl)cyclopropanecarboxamide (Formula 2-2 , 2.1 g, 8.73 mmol) synthesized in step 1, 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) were 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. Thereafter, the reaction mixture was separated and purified by MPLC (hexane/ethyl acetate; 70:30) to obtain a solid compound (Formula 2-3 ).

Preparation 3: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (Formula Preparation of compound of 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) were 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, extraction was performed 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. Then, the reaction mixture was separated and purified by MPLC (hexane/ethyl acetate; 70:30) to obtain a solid compound (Formula 3-2 ).

Preparation 4: 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2,3-dihydro-1H-inden-1-one (Formula Preparation of compound of 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, extraction was performed 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. Then, the reaction mixture was separated and purified by MPLC (hexane/diethyl acetate; 70:30) to obtain a solid compound (Formula 4-2 ).

Preparation 5: 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoindolin-1-one (of Formula 5-3 compound) preparation

Step 1: 5-bromo-2-methylisoindolin-1-one (formula 5-2 preparation of compounds)

Methyl 4-bromo-2-(bromomethyl)benzoate (Formula 5-1 , 2.5 g, 8.12 mmol) was dissolved in 2M methanamine (122 ml, 244 mmol, 30 eq) and refluxed for 18 hours. stirred. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed with H ₂ O, 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 the target compound (Formula 5-2 ).

Step 2: 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (formula 5-3 preparation of compounds)

5-bromo-2-methylisoindolin-1-one synthesized in step 1 (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) were 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, extraction was performed 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 the target compound (Formula 5-3 ).

Preparation 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-1,3,2-dioxaborolan-2-yl)-2H-indazole (compound of formula 6-3) Produce

6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Formula 6-1 , 2 g, 8.19 mmol) was mixed with 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, followed by stirring at 85 °C. After completion of the reaction, extraction was performed 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. Thereafter, the reaction mixture was separated and purified by MPLC (hexane/ethyl acetate; 70:30) to obtain target compounds (Formula 6-2 , 6-3 ), respectively .

Preparation 7: 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzo [d] thiazole (compound of formula 7-2 ) manufacturing

5-bromo-2-methylbenzo[d]thiazole (Formula 7-1 , 0.5 g, 2.19 mmol), potassium acetate (0.753 g, 7.67 mmol, 3.5 eq), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (0.179 g, 0.22 mmol, 0.1 eq), B ₂ Pin ₂ (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, extraction was performed 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. Thereafter, the reaction mixture was separated and purified by MPLC (hexane/ethyl acetate; 70:30) to obtain the target compound (Formula 7-2 ).

Preparation 8: Preparation of cyclopropyl (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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) were 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, extraction was performed 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. Thereafter, the reaction mixture was separated and purified by MPLC (hexane/ethyl acetate; 90:10) to obtain the target compound (Formula 8-2 ).

Preparation Example 9: 2-(3',4'-dimethoxybiphenyl-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (of Formula 9-3 compound) preparation

Step 1: 3'-bromo-3,4-dimethoxy-1,1'-biphenyl (formula 9-2 of the compound)

1-bromo-3-iodobenzene (Formula 9-1 , 1 g, 3.53 mmol) was dissolved in toluene (10 ml), and then (3,4-dimethoxyphenyl) boronic acid dissolved in ethanol (3 ml) (1.29 g, 7.07 mmol, 2 eq) and 2M Na ₂ CO ₃ aqueous solution (3 eq) were added dropwise and stirred for 10 minutes under a nitrogen stream. Then, 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, extraction was performed with ethyl acetate. The organic layer was washed with 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; 90:10) to obtain the target compound (Formula 9-2 ).

Step 2: 2-(3',4'-dimethoxybiphenyl-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (formula 9-3 preparation of compounds)

3'-bromo-3,4-dimethoxy-1,1'-biphenyl (Formula 9-2 , 0.538 g, 1.84 mmol) synthesized in step 1, 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, extraction was performed 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 (hexane/ethyl acetate; 70:30) to obtain the target compound (Formula 9-3 ).

Preparation 10: 1-cyclopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (Formula 10- Preparation of compound of 3)

Step 1: 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (formula 10-2 preparation of compounds)

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), 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 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 solvent was removed by reducing the pressure of the organic layer to obtain the target compound (Formula 10-2 ).

Step 2: 1-Cyclopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine 10-3 preparation of compounds)

4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (Formula 10-2 , 953 mg) synthesized in step 1 , 3.28 mmol) was dissolved 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 solution of NaHCO ₃ , extraction was performed with ethyl acetate. After drying over anhydrous MgSO ₄ , 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 solid compound (Formula 10-3 ).

Preparation Example 11: Preparation of potassium trifluoro (2- (4- (trifluoromethoxy) phenoxy) pyrimidin-5-yl) borate (compound of formula 11-4)

Step 1: 5-bromo-2-(4-(trifluoromethoxy)phenoxy)pyrimidine (formula 11-3 preparation of compounds)

After dissolving 5-bromo-2-iodopyrimidine (Formula 11-1 , 0.5 g, 1.76 mmol) in DMSO (23 ml), 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 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. Thereafter, the reaction mixture was separated and purified by MPLC (hexane/ethyl acetate; 90:10) to obtain the target compound (Formula 11-3 ).

Step 2: Potassium trifluoro(2-(4-(trifluoromethoxy)phenoxy)pyrimidin-5-yl)borate 11-4 preparation of compounds)

After dissolving 5-bromo-2-(4-(trifluoromethoxy)phenoxy)pyrimidine (Formula 11-3 , 386 mg, 1.15 mmol) synthesized in step 1 in THF (10 ml), -78 After cooling to °C, 1.6M n-butyllithium (1.30 ml, 2.07 mmol, 1.8 eq) was added dropwise. Then, after stirring at the same temperature for 1 hour, triisopropylborate (0.535 ml, 2.30 mmol, 2 eq) was added dropwise at the same temperature. After the reaction mixture was stirred at the same temperature for 1 hour, the temperature was raised to 0 °C, and 4.5M aqueous potassium hydrogen difluoride 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, filtered, and the filtrate was reduced pressure to obtain the target compound (Formula 11-4 ).

Preparation 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 compounds)

5-bromo-2-iodopyrimidine (Formula 4-1 , 0.5 g, 1.76 mmol) was dissolved in DMSO (25 ml), and then 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 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. Thereafter, the reaction mixture was separated and purified by MPLC (hexane/ethyl acetate; 90:10) to obtain the target compound (Formula 12-2 ).

Step 2: Potassium trifluoro(2-phenoxypyrimidin-5-yl)borate (formula 12-3 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 at the same temperature for 1 hour, triisopropylborate (0.762 ml, 3.28 mmol, 2 eq) was added dropwise at the same temperature. After the reaction mixture was stirred at the same temperature for 1 hour, the temperature was raised to 0° C. and 4.5M aqueous potassium hydrogen difluoride 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. Thereafter, the reaction mixture was dissolved in methanol, filtered, and the filtrate was reduced to obtain the target compound (Formula 12-3 ).

Preparation 13: Preparation of potassium trifluoro (2- (trifluoromethyl) pyridin-3-yl) borate (compound of formula 13-2)

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

Preparation 14: Preparation of potassium trifluoro (quinolin-2-yl) borate (compound of formula 14-2)

2-Bromoquinoline (Formula 14-1 , 1 g, 4.81 mmol) was dissolved in THF (20 ml), cooled to -78 ° C, and 1.6M n-butyllithium (5.41 ml, 8.65 mmol, 1.8 eq) was slowly added dropwise. Then, after stirring at the same temperature for 1 hour, triisopropylborate (2.23 ml, 9.61 mmol, 2 eq) was added dropwise at the same temperature. After the reaction mixture was stirred at the same temperature for 1 hour, the temperature was raised to 0° C. and 1M aqueous potassium hydrogen difluoride 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. Thereafter, the reaction mixture was dissolved in methanol, filtered, and the filtrate was reduced pressure to obtain the target compound (Formula 14-2 ).

Preparation 15: Preparation of potassium trifluoro (5-methoxypyridin-2-yl) borate (compound of formula 15-2)

Using the same method as described in Preparation Example 14, but using 2-bromo-5-methoxypyridine (Formula 15-1 ) instead of 2-bromoquinoline (Formula 14-1 ), the target compound (Formula 15- 2 ) was obtained.

Preparation 16: Preparation of 2-methoxy-6-(tributylstannyl)pyrazine (Compound of Formula 16-2)

After dissolving 2-bromo-6-methoxypyrazine (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), Hexabutyldithianoic 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. Thereafter, the reaction mixture was separated and purified by MPLC to obtain the target compound (Formula 16-2 ).

Preparation 17: Preparation of N-(2-(2-fluorophenyl)-5,8-dioxo-5,8-dihydroquinolin-7-yl)acetamide (compound of formula 17-10)

Step 1: 5-chloro-7-nitroquinolin-8-ol (formula 17-2 preparation of compounds)

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

Step 2: 7-aminoquinolin-8-ol (formula 17-3 preparation of compounds)

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

Step 3: 7-acetamidoquinolin-8-yl acetate (formula 17-4 preparation of compounds)

synthesized in step 2 7-aminoquinolin-8-ol (Formula 17-3 , 11 g, 68.7 mmol, 1 eq) was dissolved in THF (300 ml), followed by N,N-diisopropylethylamine (48 ml, 275 mmol, 4 eq) was added dropwise and the reaction mixture was cooled to 0 °C. Then, acetyl chloride (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 room temperature for 8 hours, 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 was removed under reduced pressure to obtain the target compound (Formula 17-4 ).

Step 4: N-(8-hydroxyquinolin-7-yl)acetamide (formula 17-5 of the compound)

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

Step 5: N-(8-(benzyloxy)quinolin-7-yl)acetamide (formula 17-6 preparation of compounds)

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

Step 6: 7-acetamido-8-(benzyloxy)quinoline 1-oxide (formula 17-7 preparation of compounds)

After dissolving N-(8-(benzyloxy)quinolin - 7-yl)acetamide (Formula 17-6 , 14 g, 47 mmol) synthesized in step 5 in 1,2-dichloroethane (140 ml), 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. Thereafter, separation and purification by MPLC (dichloromethane/methanol) gave the target compound (Formula 17-7 ).

Step 7: N-(8-(benzyloxy)-2-chloroquinolin-7-yl)acetamide (formula 17-8 preparation of compounds)

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) Dissolved POCl ₃ (4.7 ml, 50 mmol, 1.2 eq) was added dropwise and stirred for 15 minutes. The reaction mixture was stirred under reflux for 2 hours and cooled, then ice was added and 6 N NaOH was slowly added dropwise until the pH reached 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-hydroxyquinolin-7-yl)acetamide (formula 17-9 preparation of compounds)

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 solution of NaHCO ₃ , extraction was performed with dichloromethane. The organic layer was washed with water, 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) to obtain the target compound (Formula 17-9 ).

Step 9: N-(2-chloro-5,8-dioxo-5,8-dihydroquinolin-7-yl)acetamide (formula 17-10 preparation of compounds)

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 ₄ Premisal salt (potassium nitrosodisulfonate) (5.57 g, 21 mmol, 1.6 eq) dissolved in a buffer (0.3M, 200 ml) was added dropwise, followed by stirring at room temperature for 8 hours. After removing the acetone under reduced pressure, it was extracted with dichloromethane. The organic layer was dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. Thereafter, it was purified by solidify using ethyl acetate and hexane to obtain a solid compound (Formula 17-10 ).

Preparation 18: 4,4,5,5-tetramethyl-2-(4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-1,3,2-dioxaborolane (Formula 18- Preparation of compound of 3)

Step 1: 4- (4-bromophenoxy) tetrahydro-2H-pyran (formula 18-2 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), and 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 reaction mixture was separated and purified by MPLC to obtain the target compound (Formula 18-2 ).

Step 2: 4,4,5,5-tetramethyl-2-(4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-1,3,2-dioxaborolane 18-3 preparation of compounds)

4-(4-bromophenoxy)tetrahydro-2H-pyran (Formula 18-2 , 638 mg, 2.48 mmol) synthesized in step 1, 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) were 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. Thereafter, the reaction mixture was separated and purified by MPLC (hexane/ethyl acetate) to obtain the target compound (Formula 18-3 ).

Preparation 19: 1-isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)piperidine (Formula 19 Preparation of compound of -4)

Step 1: Synthesized 1-(4-(4-bromophenoxy)piperidin-1-yl)-2,2-dimethylpropan-1-one (Formula 19-1 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 reaction mixture was separated and purified by MPLC to obtain the target compound (Formula 19-1 ).

Step 2: 4- (4-bromophenoxy) piperidine (formula 19-2 preparation of compounds)

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 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. The reaction mixture was dissolved in ethyl acetate, washed sequentially with a saturated aqueous solution of NaHCO ₃ and brine, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure to obtain the target compound (Formula 19-2 ).

Step 3: 4-(4-bromophenoxy)-1-isopropylpiperidine (formula 19-3 preparation of compounds)

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 quenched with a saturated aqueous solution of NaHCO ₃ . The mixture was extracted with ethyl acetate, washed with water 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 to obtain 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 (formula 19-4 of the compound)

4-(4-bromophenoxy)-1-isopropylpiperidine (Formula 19-3 , 145 mg, 0.49 mmol) synthesized in step 3, 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) were dissolved in DMSO (3 ml). The reaction mixture was reacted in a Biotage microwave at 85° C. for 2 hours. After completion of the reaction with water, extraction was performed 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. Thereafter, the reaction mixture was separated and purified by MPLC (dichloromethane/methanol) to obtain a solid compound (Formula 19-4 ).

Preparation 20: Preparation of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridine (compound of formula 20-2)

Step 1: 4- (4-bromophenoxy) pyridine (formula 20-1 of the compound)

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

Step 2: 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridine (formula 20-2 of the compound)

4-(4-bromophenoxy)pyridine (Formula 20-1 , 109 mg, 0.44 mmol) synthesized in step 1, 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) were 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 (hexane/ethyl acetate) to obtain the target compound (Formula 20-2 ).

Preparation 21: 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)piperidine (Formula 21- Preparation of compound of 2)

Step 1: 4-(4-bromophenoxy)-1-methylpiperidine (formula 21-1 of the compound)

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

Step 2: 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)piperidine (formula 21-2 of the compound)

Using the same method as described in step 4 of Preparation Example 19, 4-(4-bromophenoxy) instead of 4-(4-bromophenoxy)-1-isopropylpiperidine (Formula 19-3 ) )-1-methylpiperidine (Formula 21-1 ) was used to obtain the target compound (Formula 21-2 ).

Preparation 22: 1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)piperidine (Formula 22- Preparation of compound of 2)

Step 1: 4-(4-bromophenoxy)-1-ethylpiperidine (formula 22-1 of the compound)

4-(4-bromophenoxy)piperidine (Formula 19-2 , 150 mg, 0.59 mmol) synthesized in Step 2 of Preparation 19 was mixed with THF (0.5 ml)/1,2-dichloroethane (1 ml ), AcOH (3 drops), acetaldehyde (0.16 ml, 2.93 mmol, 5 eq), 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 hours, and the reaction was quenched with a saturated aqueous solution of NaHCO ₃ . The mixture was extracted with ethyl acetate, washed with water 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 to obtain the target compound (Formula 22-1 ).

Step 2: 1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)piperidine (formula 22-2 of the compound)

Using the same method as described in step 4 of Preparation Example 19, 4-(4-bromophenoxy) instead of 4-(4-bromophenoxy)-1-isopropylpiperidine (Formula 19-3 ) )-1-methylpiperidine (Formula 22-1 ) was used to obtain the target compound (Formula 22-2 ).

[Example] Preparation of quinoline-5,8-dione derivative compound

Example 1: 2-(3-acetylphenyl)-6-methoxyquinoline-5,8-dione manufacture of

Step 1: Preparation of methyl 1- (3- (5,6,8-trimethoxyquinolin-2yl) phenyl) ethanone

After dissolving 2-chloro-5,6,8-trimethoxyquinoline (Formula 1-6 , 1eq) synthesized in Preparation Example 1 in dimethyl ether (DME), 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, extraction was performed 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 to obtain 1-(3-(5,6,8-trimethoxyquinolin-2yl)phenyl)ethanone.

Step 2: Preparation of 2-(3-acetylphenyl)-6-methoxyquinoline-5,8-dione

After dissolving 1-(3-(5,6,8-trimethoxyquinolin-2-yl)phenyl)ethanone (1 eq) synthesized in step 1 in a small amount of acetonitrile (ACN), in a dark place A 0.6 M aqueous solution of cerium ammonium nitrate (CAN) (3 eq) was slowly added dropwise at 0°C. The reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, extraction was performed 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. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.

1H NMR (400MHz, CDCl3) 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).

Examples 2 to 35

The compounds of Examples 2 to 35 were obtained using the same method as that described in Example 1, but using R listed in Table 3 below instead of 3-acetylphenylboronic acid in Step 1.

[Table 3]

Example 36: Preparation of 6-methoxy-2-(2-methylpyrimidin-5-yl)quinoline-5,8-dione

Step 1: Preparation of 5,6,8-trimethoxy-2-(2-methylpyrimidin-5-yl)quinoline

After dissolving 2-chloro-5,6,8-trimethoxyquinoline (Formula 1-6 , 1eq) synthesized in Preparation Example 1 in THF:H ₂ O (4:1), 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 with Biotage microwave at 70° C. for 30 minutes. After completion of the reaction, extraction was performed 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 to obtain 5,6,8-trimethoxy-2-(2-methylpyrimidin-5-yl)quinoline.

Step 2: Preparation of 6-methoxy-2-(2-methylpyrimidin-5-yl)quinoline-5,8-dione

After dissolving 5,6,8-trimethoxy-2-(2-methylpyrimidin-5-yl)quinoline (1 eq) synthesized in step 1 in a small amount of ACN, 0.6 M in the dark at 0 °C CAN (3 eq) aqueous solution was slowly added dropwise. The reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, extraction was performed 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. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.

1H NMR (400 MHz, CDCl3) 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).

Examples 37-39

Using 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)pyri The compounds of Examples 37 to 39 were obtained by using R listed in Table 4 below instead of midine.

[Table 4]

Example 40: Preparation of 2-(3-acryloylphenyl)-6-methoxyquinoline-5,8-dione

Step 1: Preparation of 1-(3-(5,6,8-trimethoxyquinolin-2-yl)phenyl)prop-2-en-1-one

After dissolving 1-(3-(5,6,8-trimethoxyquinolin-2-yl)phenyl)ethanone (1 eq) synthesized in step 1 of Example 1 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, extraction was performed 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 reaction mixture was separated and purified by MPLC (hexane/ethyl acetate; 70:30) to 1-(3-(5,6,8-trimethoxyquinolin-2-yl)phenyl)prop-2-ene -1-one was obtained.

Step 2: Preparation of 2-(3-acryloylphenyl)-6-methoxyquinoline-5,8-dione

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

1H NMR (400MHz, CDCl3) 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: Preparation of 7-bromo-6-methoxy-2-phenylquinoline-5,8-dione

Step 1: Preparation of 5,6,8-trimethoxy-2-phenylquinoline

After dissolving 2-chloro-5,6,8-trimethoxyquinoline (Formula 1-6 , 1eq) synthesized in Preparation Example 1 in DME, Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (10 mol % ), 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolein (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, extraction was performed 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 to obtain 5,6,8-trimethoxy-2-phenylquinoline.

Step 2: Preparation of 6-methoxy-2-phenylquinoline-5,8-dione

After dissolving 5,6,8-trimethoxy-2-phenylquinoline (1 eq) synthesized in step 1 in a small amount of ACN, in the dark at 0 ° C, 0.6 M aqueous CAN (3 eq) solution was slowly added dropwise did. The reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, extraction was performed 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. Then, the reaction mixture was separated and purified by MPLC to obtain 6-methoxy-2-phenylquinoline-5,8-dione.

1H 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: Preparation of 7-bromo-6-methoxy-2-phenylquinoline-5,8-dione

6-methoxy-2-phenylquinoline-5,8-dione synthesized in step 2 (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, extraction was performed 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. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.

1H 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).

Examples 42 to 67

Using the same method as described in Example 45, except that in step 1, R listed in Table 5 instead of 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolein was used to obtain the compounds of Examples 42 to 67.

[Table 5]

Example 68: Preparation of 7-bromo-6-methoxy-2-(pyrimidin-5-yl)quinoline-5,8-dione

Step 1: Preparation of 5,6,8-trimethoxy-2-(pyrimidin-5-yl)quinoline

After dissolving 2-chloro-5,6,8-trimethoxyquinoline (Formula 1-6 , 1eq) synthesized in Preparation Example 1 in THF:H ₂ O (4:1), 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 with Biotage microwave at 70° C. for 30 minutes. After completion of the reaction, extraction was performed 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 to obtain 5,6,8-trimethoxy-2-(pyrimidin-5-yl)quinoline.

Step 2: Preparation of 6-methoxy-2-(pyrimidin-5-yl)quinoline-5,8-dione

After dissolving 5,6,8-trimethoxy-2-(pyrimidin-5-yl)quinoline (1 eq) synthesized in step 1 in a small amount of ACN, in the dark at 0 °C, 0.6 M CAN (3 eq) The aqueous solution was slowly added dropwise. The reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, extraction was performed 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 to obtain 6-methoxy-2-(pyrimidin-5-yl)quinoline-5,8-dione.

Step 3: Preparation of 7-bromo-6-methoxy-2-(pyrimidin-5-yl)quinoline-5,8-dione

6-methoxy-2-(pyrimidin-5-yl)quinoline-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, extraction was performed 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. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.

1H NMR (400 MHz, CDCl3) 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).

Examples 69 and 70

The compounds of Examples 69 and 70 were obtained using the same method as that described in Example 68, except that R listed in Table 6 below was used instead of pyrimidin-5-ylboronic acid in Step 1.

[Table 6]

Example 71: Preparation of 3-(7-bromo-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl)benzamide

Step 1: Preparation of methyl 3-(7-bromo-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl)benzoate

Using the same method as described in Example 41, except that in step 1, 3-(methoxycarbonyl) instead of 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolein Phenylboronic acid was used to give methyl 3-(7-bromo-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl)benzoate.

Step 2: Preparation of 3-(7-bromo-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl)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 at room temperature for 3 days. After completion of the reaction, extraction was performed 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. Then, the reaction mixture was separated and purified by PTLC (dichloromethane/methanol; 98:2) to obtain the title compound.

1H NMR (400 MHz, CDCl3) 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: Preparation of 7-bromo-6-ethoxyquinoline-5,8-dione

Step 1: Preparation of compound of 5,7-dibromoquinolin-8-ol

Quinolin-8-ol (1 eq) was added dropwise to a methanol solution in which bromine (3 eq) was dissolved. To this mixture, a methanol solution in which NaHCO ₃ (2 eq) was dissolved was added dropwise, followed by stirring at room temperature (RT) for 5 minutes. Then, 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 obtain 5,7-dibromoquinolin-8-ol.

Step 2: Preparation of 7-bromoquinoline-5,8-dione

5,7-dibromoquinolin-8-ol synthesized in step 1 was slowly added dropwise to a solution of sulfuric acid (20 eq) in which nitric acid (6 eq) was dissolved at 0 °C. After stirring at the same temperature for 30 minutes, the reaction was terminated with ice water. Then, extraction was performed with dichloromethane, 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. Thereafter, the reaction mixture was separated and purified by MPLC to obtain 7-bromoquinoline-5,8-dione.

Step 3: Preparation of 7-bromo-6-ethoxyquinoline-5,8-dione

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 at room temperature 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. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.

1H NMR (400 MHz, CDCl3) 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: Preparation of compounds of 7-bromo-2-phenylquinoline-5,8-dione

Step 1: Preparation of 2-phenylquinolin-8-ol

After 2-bromoquinolin-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, and then reacted at 160° C. for 30 minutes in a Biotage microwave. After completion of the reaction, the mixture 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, then dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. Thereafter, the reaction mixture was separated and purified by MPLC to obtain 2-phenylquinolin-8-ol.

Step 2: Preparation of 5,7-dibromo-2-phenylquinolin-8-ol

After dissolving 2-phenylquinolin-8-ol (1 eq) synthesized in step 1 in acetic acid, bromine (2.2 eq) in acetic acid solution was slowly added dropwise. After stirring the reaction mixture at room temperature for 30 minutes, 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 from ethanol to obtain 5,7-dibromo-2-phenylquinolin-8-ol.

Step 3: Preparation of 7-bromo-2-phenylquinoline-5,8-dione

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 the reaction mixture was stirred at room temperature for 2 hours, the reaction was quenched with H ₂ O. It was extracted with ethyl acetate (EtOAc), dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.

1H NMR (400 MHz, CDCl3) 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, 3H). MS 316 (M+2).

Example 74: Preparation of 7-bromo-6-methyl-2-phenylquinoline-5,8-dione

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

1H NMR (400 MHz, CDCl3) 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, 3H). MS 330.05 (M+1).

Example 75: Preparation of 7-amino-6-methoxy-2-(3-(trifluoromethoxy)phenyl)quinoline-5,8-dione

Step 1: Preparation of 5,6,8-trimethoxy-2-(3-(trifluoromethoxy)phenyl)quinoline

After dissolving 2-chloro-5,6,8-trimethoxyquinoline (Formula 1-6, 1eq) synthesized in Preparation Example 1 in DME, 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, extraction was performed 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 to obtain 5,6,8-trimethoxy-2-(3-(trifluoromethoxy)phenyl)quinoline.

Step 2: Preparation of 6-methoxy-2-(3-(trifluoromethoxy)phenyl)quinoline-5,8-dione

After dissolving 5,6,8-trimethoxy-2-(3-(trifluoromethoxy)phenyl)quinoline (1 eq) synthesized in step 1 in a small amount of ACN, 0.6 M in the dark at 0 °C CAN (3 eq) aqueous solution was slowly added dropwise. The reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, extraction was performed 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 to obtain 6-methoxy-2-(3-(trifluoromethoxy)phenyl)quinoline-5,8-dione.

Step 3: Preparation of 7-bromo-6-methoxy-2-(3-(trifluoromethoxy)phenyl)quinoline-5,8-dione

6-methoxy-2-(3-(trifluoromethoxy)phenyl)quinoline-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, extraction was performed 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 to obtain 7-bromo-6-methoxy-2-(3-(trifluoromethoxy)phenyl)quinoline-5,8-dione.

Step 4: Preparation of 7-azido-6-methoxy-2-(3-(trifluoromethoxy)phenyl)quinoline-5,8-dione

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), sodium azide (1.5 eq) was added dropwise and stirred at room temperature for 1 hour to 12 hours. After completion of the reaction, extraction was performed 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 remove 7-azido-6-methoxy-2-(3-(trifluoromethoxy)phenyl) Quinoline-5,8-dione was obtained.

Step 5: Preparation of 7-amino-6-methoxy-2-(3-(trifluoromethoxy)phenyl)quinoline-5,8-dione

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

1H NMR (400 MHz, CDOD) 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).

Examples 76 to 108

Using the same method as that described in Example 75, but using R listed in Table 7 below instead of 3-(trifluoromethoxy)phenylboronic acid in Step 1 to obtain the compounds of Examples 76 to 108 did

[Table 7]

Example 109: Preparation of 7-amino-2-(4-chloro-3-fluorophenyl)-6-methoxyquinoline-5,8-dione

Step 1: Preparation of 7-azido-2-(4-chloro-3-fluorophenyl)-6-methoxyquinoline-5,8-dione

7-azido-, 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. Obtained 2-(4-chloro-3-fluorophenyl)-6-methoxyquinoline-5,8-dione.

Step 2: Preparation of 7-amino-2-(4-chloro-3-fluorophenyl)-6-methoxyquinoline-5,8-dione

7-azido-2-(4-chloro-3-fluorophenyl)-6-methoxyquinoline-5,8-dione (1 eq) synthesized in step 1 was dissolved in THF/MeOH (5/1) After mixing, sodium borohydride (10 eq) was added dropwise and stirred at room temperature for 3 hours. After completion of the reaction, extraction was performed 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. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.

1H NMR (400 MHz, CDCl3) 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, 3H). MS 332.70 (M).

Example 110: Preparation of 7-amino-6-methoxy-2-(2-methoxypyrimidin-5-yl)quinoline-5,8-dione

Step 1: Preparation of 5,6,8-trimethoxy-2-(2-methoxypyrimidin-5-yl)quinoline

After dissolving 2-chloro-5,6,8-trimethoxyquinoline (Formula 1-6 , 1eq) synthesized in Preparation Example 1 in THF:H ₂ O (4:1), 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 with Biotage microwave at 70° C. for 30 minutes. After completion of the reaction, extraction was performed 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 to obtain 5,6,8-trimethoxy-2-(2-methoxypyrimidin-5-yl)quinoline.

Step 2: Preparation of 6-methoxy-2-(2-methoxypyrimidin-5-yl)quinoline-5,8-dione

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 in the dark at 0 °C. A CAN (3 eq) aqueous solution of M was slowly added dropwise. The reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, extraction was performed 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 to obtain 6-methoxy-2-(2-methoxypyrimidin-5-yl)quinoline-5,8-dione.

Step 3: Preparation of 7-bromo-6-methoxy-2-(2-methoxypyrimidin-5-yl)quinoline-5,8-dione

After dissolving 6-methoxy-2-(2-methoxypyrimidin-5-yl)quinoline-5,8-dione (1 eq) synthesized in step 2 in chloroform, bromine (1.1 eq) at 0 ° C. ) was added dropwise and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, extraction was performed 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 to obtain 7-bromo-6-methoxy-2-(2-methoxypyrimidin-5-yl)quinoline-5,8-dione.

Step 4: Preparation of 7-azido-6-methoxy-2-(2-methoxypyrimidin-5-yl)quinoline-5,8-dione

7-bromo-6-methoxy-2-(2-methoxypyrimidin-5-yl)quinoline-5,8-dione synthesized in step 3 (1 eq) was dissolved in DMF/MeOH (1/1), sodium azide (1.5 eq) was added dropwise and stirred at room temperature for 1 hour to 12 hours. After completion of the reaction, extraction was performed 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 7-azido-6-methoxy-2-(2-methoxypyrimidin-5-yl ) to obtain quinoline-5,8-dione.

Step 5: Preparation of 7-amino-6-methoxy-2-(2-methoxypyrimidin-5-yl)quinoline-5,8-dione

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

1H NMR (400 MHz, CDCl3) 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: Preparation of 7-amino-6-methoxy-2-(pyrimidin-5-yl)quinoline-5,8-dione

Step 1: Preparation of 7-azido-6-methoxy-2-(pyrimidin-5-yl)quinoline-5,8-dione

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

Step 2: Preparation of 7-amino-6-methoxy-2-(pyrimidin-5-yl)quinoline-5,8-dione

After dissolving 7-azido-6-methoxy-2-(pyrimidin-5-yl)quinoline-5,8-dione (1 eq) synthesized in step 1 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, extraction was performed 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. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.

1H NMR (400 MHz, CDCl3) 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).

Examples 112 to 114

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

[Table 8]

Example 115: Preparation of methyl 3-(3-(7-amino-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl)phenyl)propanoate

Step 1: Preparation of (E)-methyl 3-(3-(7-azido-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl)phenyl)acrylate

Using the same method as described in Steps 1 to 4 of Example 75, except that (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 1) phenyl) acrylate was obtained.

Step 2: Preparation of methyl 3-(3-(7-amino-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-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), Pd/C (1 eq) was added dropwise, and the mixture was stirred under a hydrogen stream for 12 hours. After completion of the reaction, the mixture was filtered through celite and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.

1H NMR (400MHz, CDCl3) 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: Preparation of 7-amino-2-(3-(1-hydroxyethyl)phenyl)-6-methoxyquinoline-5,8-dione

Step 1: Preparation of 2-(3-acetylphenyl)-7-azido-6-methoxyquinoline-5,8-dione

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

Step 2: Preparation of 7-amino-2-(3-(1-hydroxyethyl)phenyl)-6-methoxyquinoline-5,8-dione

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

1H NMR (400MHz, CDCl3) 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, NH2), 4.09 (s, 3H), 1.56 (s, 3H). MS 325.00 (M+1).

Example 117: Preparation of 7-amino-2-(3-aminophenyl)-6-methoxyquinoline-5,8-dione

Step 1: Preparation of 7-azido-6-methoxy-2-(3-nitrophenyl)quinoline-5,8-dione

Example 44 using the same method as described in step 4 of Example 75, but instead of 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: Preparation of 7-amino-2-(3-aminophenyl)-6-methoxyquinoline-5,8-dione

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

1H NMR (400MHz, CDCl3) 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, NH2), 4.09 (s, 3H), 3.85 (s, 2H). MS 296.05 (M+1).

Example 118: Preparation of 2-(3-acryloylphenyl)-7-amino-6-methoxyquinoline-5,8-dione

Step 1: Preparation of 2-(3-acetylphenyl)-7-amino-6-methoxyquinoline-5,8-dione

After dissolving 7-amino-2-(3-(1-hydroxyethyl)phenyl)-6-methoxyquinoline-5,8-dione synthesized in Example 116 in dichloromethane, Dess-Martin Periodi Egg (Dess-Martin Periodinane) (2 eq) was added dropwise at 0 °C and stirred at room temperature for 4 hours. After completion of the reaction, extraction was performed 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 obtain 2-(3-acetylphenyl)-7-amino-6-methoxyquinoline-5,8-dione. .

Step 2: Preparation of 2-(3-acryloylphenyl)-7-amino-6-methoxyquinoline-5,8-dione

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 2-(3-acetylphenyl)-7-amino-6-methoxyquinoline-5,8-dione was used to give the title compound.

1H NMR (400MHz, CDCl3) 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, NH2). MS 334.98 (M).

Example 119: Preparation of N-(3-(7-amino-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl)phenyl)acrylamide

After dissolving 7-amino-2-(3-aminophenyl)-6-methoxyquinoline-5,8-dione (1 eq) synthesized in Example 117 in dichloromethane, acryloyl chloride (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, extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous NaHCO ₃ solution, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. Thereafter, the reaction mixture was separated and purified by PTLC (hexane/ethyl acetate; 40:60) to obtain the title compound.

1H NMR (400MHz, CDCl3) 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, NH2), 4.09 (s, 3H). MS 350.20 (M+1).

Example 120: Preparation of 7-amino-2-phenylquinoline-5,8-dione

Step 1: Preparation of 7-azido-2-phenylquinoline-5,8-dione

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

Step 2: Preparation of 7-amino-2-phenylquinoline-5,8-dione

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

1H NMR (400 MHz, CDCl3) 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, 3H), 6.07 (s, 1H), 5.30 (bs, 2H). MS 251 (M+1).

Example 121: Preparation of 7-amino-6-methyl-2-phenylquinoline-5,8-dione

7-bromo-6-methyl-2-phenyl synthesized in Example 74 using the same method as that described in Example 120, but instead of 7-bromo-2-phenylquinoline-5,8-dione in Step 1 Quinoline-5,8-dione (1 eq) was used to give the title compound.

1H NMR (400 MHz, CDCl3) 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: Preparation of 7-amino-2-(2-chloropyridin-4-yl)-6-methylquinoline-5,8-dione

Step 1: Preparation of 7-bromo-2-(2-chloropyridin-4-yl)quinoline-5,8-dione

7-bromo-2-(2-chloropyridine-4) 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 -yl) quinoline-5,8-dione was obtained.

Step 2: Preparation of 7-bromo-2-(2-chloropyridin-4-yl)-6-methylquinoline-5,8-dione

7-bromo-2-(2-chloropyridine synthesized in step 1) using the same method as that described in Example 74, but instead of 7-bromo-2-phenylquinoline-5,8-dione (1 eq) -4-yl) quinoline-5,8-dione was used to obtain 7-bromo-2-(2-chloropyridin-4-yl)-6-methylquinoline-5,8-dione.

Step 3: Preparation of 7-amino-2-(2-chloropyridin-4-yl)-6-methylquinoline-5,8-dione

7-bromo-2-(2-chloropyridin-4-yl synthesized in step 2) using the same method as that described in Example 120, but instead of 7-bromo-2-phenylquinoline-5,8-dione )-6-methylquinoline-5,8-dione to give the title compound.

1H NMR (400 MHz, CDCl3) 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: Preparation of 7-amino-2-(3-(trifluoromethoxy)phenyl)quinoline-5,8-dione

Step 1: Preparation of 7-bromo-2-(3-(trifluoromethoxy)phenyl)quinoline-5,8-dione

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

Step 2: Preparation of 7-amino-2-(3-(trifluoromethoxy)phenyl)quinoline-5,8-dione

Using the same method as that described in Example 120, but instead of 7-bromo-2-phenylquinoline-5,8-dione, 7-bromo-2-(3-(triflo Oromethoxy)phenyl)quinoline-5,8-dione was used to give the title compound.

1H NMR (400MHz, CDCl3) 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, NH2). MS 334.70(M)

Examples 124 to 127

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

[Table 9]

Example 128: Preparation of N-(6-methoxy-2-(2-methoxypyrimidin-5-yl)-5,8-dioxo-5,8-dihydroquinolin-7-yl)acetamide

After dissolving 7-amino-2-(2-fluoropyridin-4-yl)-6-methoxyquinoline-5,8-dione (1 eq) synthesized in Example 90 in chloroform, acryloyl chloride (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. Then, the reaction mixture was separated and purified by PTLC to obtain the title compound.

1H NMR (400 MHz, CDCl3) 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: Preparation of N-(5,8-dioxo-2-phenyl-5,8-dihydroquinolin-7-yl)acetamide

After dissolving 7-amino-2-phenylquinoline-5,8-dione (1 eq) synthesized in Example 120 in THF/CH ₂ Cl ₂ (1/1), acetyl chloride (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. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.

1H NMR (400 MHz, CDCl3) 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: Preparation of N-(2-(2-fluoropyridin-4-yl)-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-7-yl)acrylamide

After dissolving 7-amino-6-methoxy-2-(2-methoxypyrimidin-5-yl)quinoline-5,8-dione (1 eq) synthesized in Example 110 in chloroform, acetyl chloride ( 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. Then, the reaction mixture was separated and purified by PTLC to obtain the title compound.

1H NMR (400 MHz, CDCl3) 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).

Examples 131 to 139

The compounds of Examples 131 to 139 were obtained using the same method as that described in Example 1, but using R listed in Table 10 below instead of 3-acetylphenylboronic acid in Step 1.

[Table 10]

Examples 140 to 144

Example 140 using the same method as described in Example 1, but using R listed in Table 11 below instead of 3-acetylphenylboronic acid, and using 1,4-dioxane instead of dimethyl ether (DME) to Example 144 were obtained.

[Table 11]

Examples 145-170

Using 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)pyri The compounds of Examples 145 to 170 were obtained by using R listed in Table 12 below instead of midine.

[Table 12]

Example 171: Preparation of 6-methoxy-2-(pyrazin-2-yl)quinoline-5,8-dione

Step 1: Preparation of 5,6,8-trimethoxy-2-(pyrazin-2-yl)quinoline

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

Step 2: Preparation of 6-methoxy-2-(pyrazin-2-yl)quinoline-5,8-dione

After dissolving 5,6,8-trimethoxy-2-(pyrazin-2-yl)quinoline (1 eq) synthesized in step 1 in a small amount of ACN, in the dark at 0 °C, 0.6 M CAN (3 eq) The aqueous solution was slowly added dropwise. The reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, extraction was performed 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. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.

1H NMR (400 MHz, CDCl3) 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, 1H), 3.98 (s, 3H). MS 268.2 (M+1).

Example 172: Preparation of 6-methoxy-2-(6-methoxypyrazin-2-yl)quinoline-5,8-dione

Using the same method as described in Example 171, but using 2-methoxy-6-(tributylstannyl)pyrazine (Formula 16-2 ) instead of 2-(tributylstannyl)pyrazine in step 1 The compound was obtained.

1H NMR (400 MHz, CDCl3) 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: Preparation of methyl 2-methoxy-6- (5,6,8-trimethoxyquinolin-2-yl) nicotinate

After dissolving 2-chloro-5,6,8-trimethoxyquinoline (Formula 1-6 , 0.3 g, 1.18 mmol) in 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. After the reaction mixture was filtered through celite, 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 title compound.

1H 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: Preparation of 6-methoxy-2-(4-(trifluoromethyl)piperidin-1-yl)quinoline-5,8-dione

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

After dissolving 2-chloro-5,6,8-trimethoxyquinoline (Formula 1-6 , 0.4 g, 1.58 mmol) in toluene (2 ml), 4-(trifluoromethyl)piperidine (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 in a Biotage microwave at 125° C. for 1 hour. After completion of the reaction, the reaction mixture was filtered through celite, and the solvent was removed under reduced pressure. It was extracted with ethyl acetate, washed with water, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. Thereafter, the reaction mixture was separated and purified by MPLC to obtain 5,6,8-trimethoxy-2-(4-(trifluoromethyl)piperidin-1-yl)quinoline.

Step 2: Preparation of 6-methoxy-2-(4-(trifluoromethyl)piperidin-1-yl)quinoline-5,8-dione

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 washing, premite (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 room temperature for 8 hours and then extracted with dichloromethane. The organic layer was washed with H ₂ O, dried over anhydrous MgSO ₄ , and the organic layer was reduced pressure to remove the solvent. Then, the reaction mixture was separated and purified by PTLC to obtain the title compound.

1H NMR (400 MHz, CDCl3) 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: Preparation of 2-(4,4-difluoropiperidin-1-yl)-6-methoxyquinoline-5,8-dione

The same method as described in Example 174 was used, except that 4,4-difluoropiperidine was used instead of 4-(trifluoromethyl)piperidine in Step 1 to obtain the title compound.

1H NMR (400 MHz, CDCl3) 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, 3H), 2.19 - 1.93 (m, 4H). MS 309.20 (M+1).

Example 176: Preparation of 2,7-dibromo-6-isopropylquinoline-5,8-dione

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

1H NMR (400 MHz, CDCl3) 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).

Examples 177 to 180

Using the same method as that described in Example 41, except that in Step 1, R listed in Table 13 instead of 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolein was used to obtain the compounds of Examples 177 to 180.

[Table 13]

Examples 181 to 183

Using the same method as that described in Example 41, except that in step 1, R listed in [Table 14] instead of 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolein was used, and 1,4-dioxane was used instead of dimethyl ether (DME) to obtain the compounds of Examples 181 to 183.

[Table 14]

Examples 184 to 196

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

[Table 15]

Examples 197 to 203

Using the same method as described in Example 75, but using R listed in Table 16 below instead of 3-(trifluoromethoxy)phenylboronic acid in Step 1 to obtain the compounds of Examples 197 to 203 did

[Table 16]

Example 204: Preparation of 7-amino-6-methoxy-2-(2-nitrophenyl)quinoline-5,8-dione

The title compound was prepared using the same method as described in Example 109, but using 2-methoxy-6-(tributylstannyl)pyrazine ( Formula 16-2 ) instead of 4-chloro-3-fluorophenylboronic acid. obtained.

1H NMR (400 MHz, DMSO) δ 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, 3H). MS 313.2 (M+1).

Example 205: Preparation of 7-amino-6-methoxy-2-(6-methoxypyrazin-2-yl)quinoline-5,8-dione

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

1H NMR (400 MHz, CDCl3) δ 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, 2H), 4.10 (s, 3H). MS 326.2 (M+1).

Examples 206 and 207

Using the same method as that described in Example 75, except that R listed in [Table 17] was used instead of 3-(trifluoromethoxy)phenylboronic acid in step 1, and 1,4-dimethylether (DME) was replaced with 1,4-dimethylether (DME). Oxane was used to give the compounds of Example 206 and Example 207.

[Table 17]

Examples 208 and 209

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

[Table 18]

Examples 210-214

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

[Table 19]

Examples 215 to 237

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

[Table 20]

Example 238: Preparation of 2-amino-4-(7-amino-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-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 dissolved in 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, it was neutralized with 1M aqueous hydrochloric acid solution, extracted with dichloromethane, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to give the title compound as an orange solid.

1H 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: Preparation of 7-amino-6-methoxy-2-(pyrazin-2-yl)quinoline-5,8-dione

Step 1: Preparation of 7-bromo-6-methoxy-2-(pyrazin-2-yl)quinoline-5,8-dione

After dissolving 6-methoxy-2-(pyrazin-2-yl)quinoline-5,8-dione (1 eq) synthesized in Example 171 in chloroform, bromine (1.1 eq) was added dropwise at 0 ° C. The reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, extraction was performed 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 to obtain 7-bromo-6-methoxy-2-(pyrazin-2-yl)quinoline-5,8-dione.

Step 2: Preparation of 7-azido-6-methoxy-2-(pyrazin-2-yl)quinoline-5,8-dione

7-bromo-6-methoxy-2-(pyrazin-2-yl)quinoline-5,8-dione synthesized in step 1 (1 eq) was dissolved in DMF/MeOH (1/1), sodium azide (1.5 eq) was added dropwise and stirred at room temperature for 1 hour to 12 hours. After completion of the reaction, extraction was performed 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 obtain 7-azido-6-methoxy-2-(pyrazin-2-yl)quinoline-5, 8-dione was obtained.

Step 3: Preparation of 7-amino-6-methoxy-2-(pyrazin-2-yl)quinoline-5,8-dione

After dissolving 7 -azido-6-methoxy-2-(pyrazin-2-yl)quinoline-5,8-dione (1 eq) synthesized in step 2 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, extraction was performed 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. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.

1H NMR (400 MHz, CDCl3) 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: Preparation of 6-(7-amino-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-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 mixed with MeOH Dissolved in /H ₂ O (5/1), NaOH (5 eq) was added dropwise, stirred at 70° C. for 3 hours, and then cooled to room temperature. After completion of the reaction, it was neutralized with a 1M aqueous hydrochloric acid solution. The organic layer was extracted with ethyl acetate, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC (dichloromethane/methanol; 90:10) to obtain the title compound.

1H NMR (400 MHz, CDCl3) 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, 3H), 4.05 (s, 3H). MS 356.20 (M+1).

Example 241: Preparation of 7-amino-2- (4-chloro-3-fluorophenyl) quinoline-5,8-dione

Step 1: Preparation of N-(2-(4-chloro-3-fluorophenyl)-5,8-dioxo-5,8-dihydroquinolin-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 in DME, Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (10 mol %), 4-chloro-3-fluorophenylboronic acid (1.1 eq) and 2M Na ₂ CO ₃ aqueous solution (4 eq) were added dropwise at room temperature, and 10 min. stirred. The reaction mixture was reacted in a Biotage microwave at 130° C. for 30 minutes. After completion of the reaction, extraction was performed 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. Then, the reaction mixture was 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: Preparation of 7-amino-2-(4-chloro-3-fluorophenyl)quinoline-5,8-dione

N-(2-(4-chloro-3-fluorophenyl)-5,8-dioxo-5,8-dihydroquinolin-7-yl)acetamide (1 eq) synthesized in step 1 was dissolved in methanol After dissolution, 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. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.

1H 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).

Examples 242 to 262

Using the same method as described in Example 241, but using R listed in Table 21 below instead of 2-fluorophenylboronic acid in Step 1 of Example 249 to obtain the compounds of Examples 242 to 262 did

[Table 21]

Example 263: Preparation of N-(5,8-dioxo-2-(pyrazin-2-yl)-5,8-dihydroquinolin-7-yl)acetamide

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

1H NMR (400 MHz, CDCl3) 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: Preparation of N-(2-(5-methoxypyrazin-2-yl)-5,8-dioxo-5,8-dihydroquinolin-7-yl)acetamide

Using the same method as described in Example 263, but 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)quinoline-5,8-dione

After dissolving N-(2-(5-methoxypyrazin-2-yl)-5,8-dioxo-5,8-dihydroquinolin-7-yl)acetamide synthesized in step 1 in methanol, 4M An 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. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.

1H 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: Preparation of N-(2-(2-fluorophenyl)-5,8-dioxo-5,8-dihydroquinolin-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 in DME, 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 in a Biotage microwave at 130° C. for 30 minutes. After completion of the reaction, extraction was performed 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. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.

1H NMR (400 MHz, CDCl3) 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: Preparation of N-(5,8-dioxo-2-(4-(trifluoromethyl)phenyl)-5,8-dihydroquinolin-7-yl)acetamide

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

1H 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: Preparation of 7-amino-2-(4-(trifluoromethi)phenyl)quinoline-5,8-dione

N-(5,8-dioxo-2-(4-(trifluoromethyl)phenyl)-5,8-dihydroquinolin-7-yl)acetamide (1 eq) synthesized in Example 266 was mixed with 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, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.

1H NMR (400 MHz, CDCl3) 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: Preparation of N-(2-(4,4-difluoropiperidin-1-yl)-5,8-dioxo-5,8-dihydroquinolin-7-yl)acetamide

After dissolving N- (2-chloro-5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide (Formula 17-10 , 1eq) synthesized in Preparation Example 17 in DMF 4, 4-Difluoropiperidine (1.1eq) and DIPEA (leq) were added dropwise at room temperature and reacted at 80°C for 3 hours. After completion of the reaction, extraction was performed 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. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.

1H NMR (400 MHz, CDCl3) 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: Preparation of N-(5,8-dioxo-2-(phenylamino)-5,8-dihydroquinolin-7-yl)acetamide

N-(2-chloro-5,8-dioxo-5,8-dihydroquinolin-7-yl)acetamide (Formula 17-10 , 10 mg, 0.04 mmol) and aniline (4.4 ul, 0.048 mmol, 1.2 eq) was dissolved 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-butoxy Seed (4.6 mg, 0.048 mmol, 1.2 eq) was added dropwise at room temperature. The reaction mixture was reacted in a Biotage microwave at 120 °C for 1 hour. After completion of the reaction, the reaction mixture was filtered through celite, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain N-(5,8-dioxo-2-(phenylamino)-5,8-dihydroquinolin-7-yl)acetamide.

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

After dissolving N-(5,8-dioxo-2-(phenylamino)-5,8-dihydroquinolin-7-yl)acetamide (1 eq) synthesized in step 1 in methanol, 4M potassium hydro 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. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.

1H 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: Preparation of 7-amino-2-(4-(trifluoromethyl)phenylamino)quinoline-5,8-dione

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

1H NMR (400 MHz, CDCl3) 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: Preparation of N-(5,8-dioxo-2-(pyridin-2-ylamino)-5,8-dihydroquinolin-7-yl)acetamide

N- (2-chloro-5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide (Formula 17-10 , 50 mg, 0.20 mmol) and pyridine-2 synthesized in Preparation Example 17 -Amine (23 mg, 0.24 mmol, 1.2 eq) was dissolved 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 in a Biotage microwave at 140° C. for 1 hour. After completion of the reaction, the reaction mixture was filtered through celite, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by prep HPLC to obtain 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, followed by 4M An 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. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound.

1H 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.

1H 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: Cell growth inhibitory activity test of the compound of Formula I

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

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

GI ₅₀ (Growth Inhibition of 50%) representing 50% growth inhibition was calculated from the following formula, and this value means a value that allows the number of control cells to be reduced to 50%.

[(Ti-Tz)/(C-Tz)] ㅧ100=50

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

As a result, it was found that the compound of Formula I of the present application exhibits TGase 2 inhibitory activity, and the specific results are shown in [Table 22] and [Table 23] below.

[Table 22]

[Table 23]

Experimental Example 2: TGase 2 inhibitory activity test of the compound of formula I

By measuring the binding of [1,4, ^-14 C]putrescine to succinylated casein by transglutaminase and observing that NDGA competes with putrescine to inhibit the reaction, TGase 2 inhibitory activity was measured.

Specifically, succinylated casein (Calbiochem, Cat. No. 573464) was dissolved in 0.1 M Tris-acetic acid buffer (pH 8.0) containing 10 mM CaCl ₂ , 0.15 M NaCl, and 1.0 mM EDTA at a concentration of 2%. In addition, 5 mM DTT (1,4-dithiothreitol) was 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 to adjust 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. 1X TEN buffer consisted of 100 mM Tris-acetic acid buffer (pH 8.0), 1 mM EDTA, and 150 mM NaCl, and a glass microfiber filter was 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 gpTG2 at 25 ng/μl. Thereafter, 1 μl of the compounds of formula I prepared in Examples were added to the assay vial at 6 different concentrations (100 μM, 200 μM, 300 μM, 400 μM, 500 μM, 600 μM). After the assay vials were pre-incubated at room temperature for 5 minutes, 140 μl of 2% succinylated casein (5 mM DTT) and 10 μl of 2 μCi/ml putrescine were added to each assay vial and added with a thermostatic mixer ( thermomixer) and incubated at 37 °C for 15 minutes. The reaction was quenched by addition of 2 ml of cold 5% trichloroacetic acid (TCA). The assay vials were placed at 4° C. for at least 1 hour and fixed. The assay mixture was filtered through a glass-fiber filter paper disc (Whatman GF/A) and washed with cold 5% TCA. The filter was placed in a counting vial and a scintillation cocktail solution was added. The counting vials were vortexed for 5 seconds and placed on a shaker for 30 minutes prior to counting.

As a result, it was found that the compound of Formula I of the present application exhibits TGase 2 inhibitory activity, and the specific results are shown in [Table 24] and [Table 25] below.

[Table 24]

[Table 25]

Experimental Example 3: Confirmation of the tumor suppressive effect of the compound of Formula I

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

[Table 26]

As shown in [FIG. 1] to [FIG. 3] and [Table 26], it can be seen that the mice administered with the compound of Formula I had much smaller tumor size and weight compared to the control group. In addition, as shown in FIG. 4 , it can be confirmed that the body weight of the mouse does not change significantly by administration of the compound of Formula I, and thus 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)

After oral administration of the compound synthesized in Example 120 at a dose of 10 mg/kg to 8 mice, blood was collected through the tail vein for up to 4 hours, and the concentration in the blood was analyzed by LC-MS/MS. The 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 plasma concentration of the compound of Formula I synthesized in Example 120 was rapidly reduced, and as shown in [Table 27], T _max was 8.1 minutes and the average half-life was 79.9 minutes, so that in vivo It can be expected to dissipate quickly .

Claims (20)

According to Scheme 1, preparing compound 1-3 by reducing compound 1-2 to Pd/CH ² ;
reacting compound 1-3 with (E)-3-ethoxyacryloyl chloride to prepare compound 1-4;
preparing compound 1-5 by adding compound 1-4 dropwise to a sulfuric acid solution and reacting;
preparing compound IMC 1 by dropwise adding compound 1-5 to phosphorus oxychloride (POCl ₃ );
preparing Compound IMC 2 using microwaves in a Suzuki reaction of compound IMC 1 using R-boronic acid pinacol ester or R-borate; and
After dissolving compound IMC 2 in acetonitrile (ACN), an aqueous solution of cerium ammonium nitrate (CAN) is added dropwise to prepare compound Q1,
a method for producing a quinoline-5,8-dione derivative;
[Scheme 1]

In Scheme 1,
A ₁ is C _6-12 aryl, C _3-12 heteroaryl, C _6-12 arylamino, C _3-12 heteroarylamino, C _3-10 cycloalkyl, C _3-10 cycloalkenyl, C _3-10 heterocycloalkyl, wherein C _6-12 aryl, C _3-12 heteroaryl, C _6-12 arylamino, C _3-12 heteroarylamino, C _3-10 cycloalkyl, C _3-10 cycloalkenyl or C _3-10 heterocycloalkyl may be unsubstituted or one or more hydrogens may be substituted with R ₅ or =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 , —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 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 cycloalkenyl or C _3-10 heterocyclo Alkyl may be unsubstituted or one or more hydrogens may be substituted with R _e ,
R _a is 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 heterocyclo 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 or C _3-10 Heterocycloalkyl may be unsubstituted or one or more hydrogens 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 heterocyclo alkyl, wherein 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 are unsubstituted or one More than one 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 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) is unsubstituted or one or more hydrogens are C may be substituted with _1-6 alkyl, C _2-6 alkenyl, -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, C _3-10 cycloalkyl, C _3-10 cycloalkenyl or C _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 cycloalkenyl or C _3-10 heterocycloalkyl is unsubstituted or one or more hydrogens are C _1-6 alkyl, C _2-6 alkenyl, —OH or may be substituted with halogen,
The C _3-12 heteroaryl, C _3-12 heteroarylamino and C _3-10 heterocycloalkyl include 1 to 3 heteroatoms selected from O, N or S. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete

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