WO2012169785A2

WO2012169785A2 - Symmetrically structured quinazoline derivatives

Info

Publication number: WO2012169785A2
Application number: PCT/KR2012/004475
Authority: WO
Inventors: In Hwan Bae; Ji Young Song; Eun Young Byun; Wha Il Choi; Ho Seok Kim; Seung Ah JUN; Young Gil Ahn
Original assignee: Hanmi Science Co Ltd
Current assignee: Hanmi Science Co Ltd
Priority date: 2011-06-07
Filing date: 2012-06-07
Publication date: 2012-12-13
Anticipated expiration: 2013-12-07
Also published as: WO2012169785A3; WO2012169785A9; KR20120135716A

Abstract

The present invention relates to a novel quinazoline derivative and a pharmaceutical composition for preventing or treating cancers, inflammatory diseases, autoimmune diseases, or neurodegenerative disorders comprising same as an active ingredient.

Description

DESCRIPTION

SYMMETRICALLY STRUCTURED QUINAZOLINE DERIVATIVES

FIELD OF THE INVENTION

The present invention relates to symmetrically structured quinazoline derivatives, more specifically, to novel quinazoline derivatives with a symmetrical structure and a pharmaceutical composition comprising same for preventing or treating cancers, inflammatory diseases, autoimmune diseases, or neurodegenerative disorders which are induced by the overexpression of apoptosis-inhibitory proteins (IAPs). BACKGROUND OF THE INVENTION

Apoptosis or programmed cell death plays an important role in homeostasis of multicellular organisms. This apoptosis maintains organisms by regulating the cell growth and death, however, if it is inhibited by some factors, there may result in pathological diversity including cancers, autoimmune diseases, neurodegenerative disorders, and others [see Thompson, C. B. Science, 267, 1456-1462 (1995) ; Hanahan, D. & Weinberg, R. A., Cell, 100, 57-70 (2000)].

Such regulatory step of apoptosis during the tumor development stages allows IAPs (apoptosis-inhibitory proteins) to accumulate within cells due to overexpression, to inhibit programmed cell death of mutant cancer cells undergoing an apoptotic stage, which leads to the inhibition of the natural apoptotic mechanism in the processes of development, growth, and metastasis of cancer cells by various apoptosis signals (e.g., stimuli such as DNA damage, chemical agents, and ultraviolet) [see George L. M, Biochemistry, 41, 7344-7349, (2002) ; Yigong Shi, Nature Rev. Mol. Cell. Bio., 5, 897- 907, (2004)].

IAPs bind to and incapacitate caspases, a class of cysteine proteases involved in programmed cell death. Caspases bind to BIR (baculovirus IAP repeat) domain of IAPs, an approximately 70 amino acid zinc-binding motif. XIAP (human X l chromosome encoded IAP), cIAPl (cellular IAP1) and cIAP2 (cellular IAP2) each consists of three tandem adjoined BIR domains at the N-terminus, and other mammalian IAPs have one BIR domain. XIAP is the most effective caspase inhibitor among the IAPs class, which binds to both caspase-9 (the initiator caspase) and caspase 3/7 (the effector caspase), respectively. Even though the roles of cIAPl and 2 in programmed cell death are still unknown, both bind to TNF-receptor 1 signaling complexes.

Smac/DIABLO (the second mitochondrial activator of caspase / direct IAP- binding protein with low pi), a polypeptide released from mitochondria during the apoptotic signal release, regulates the activities of IAPs by binding to the same sites to which IAPs bind. In addition, IAPs gene amplification and overexpression of IAPs have been found in many tumor cells.

For the above reasons, the resistance of tumor cells to apoptosis has been thought to be an important mechanism in tumor progression, and accordingly, there has been suggested that exploiting the difference between the mechanisms in tumor cells and those in normal cells may be as an effective anticancer therapeutic strategy.

Further, such drugs must act selectively on cancer cells, exerting no adverse side effects on normal cells.

Such drugs have been investigated by several international pharmaceutical manufacturers, as was disclosed in WO2008/073305A1, WO2008/073306A1,

WO2008/016893A2, WO2006/107963A1, WO2006/1 13376A1, and

WO2005/097791A1 by Novartis, WO2009/089502A1 and WO2008/079735A1 by

Genetech, WO2007/131366A1 by Aegera, WO2008/014252A2 by TetraLogic, and others.

As to the methods for inhibiting IAPs, studies on Smac/DIABLO, a natural

IAP inhibitory protein, structure mimetics are currently in progression. As a result, it has been found that the key sequence of alanine-valine-proline-isoleucine (Ala-Val- Pro-Ile, AVPI) is essential protein to bind with IAPs [see Yigong Shi, Nature structural biology, 8, 394-401, (2001)]. Caspase-9 and caspases-3, which are inhibited by IAP proteins such as XIAP, c-IAPl, C-IAP2, or survivin, are substituted by matured Smac proteins. Smac proteins form arch-shaped dimmers which can expand greater than 130 A in length during the substitution process [see Chai, J. et ah, Nature, 406, 855-862 (2000)]. This key sequence (AVPI or AVPF) of such structure shows pharmacological activity of 120-500 nM in an in vitro assay, but failed to overcome its low cell permeability.

The present inventors have endeavored to search for compounds having AVPI properties of a natural IAP inhibitory sequence having good cell permeability, and to evaluate the activities of the compounds on cancers, inflammatory diseases, autoimmune diseases and neurodegenerative disorders. As a result, we have successfully identified novel quinazoline derivatives with a symmetrically structure having excellent, selective efficacies on IAPs by studying activities and efficacies of structure mimetics.

SUMMARY OF THE INVENTION

Therefore, it is an object of the present invention to provide a novel quinazoline derivative.

It is further object of the present invention to provide a pharmaceutical composition comprising said compound as an active ingredient.

In accordance with one aspect of the present invention, there is provided a compound selected from the group consisting of a quinazoline derivative of formula (I), a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof, and a solvate thereof:

wherein,

R¹ and R² are each independently hydrogen, methyl, or ethyl;

R³ is hydrogen, Ci_-8alkyl, C_3-8cycloalkyl, C_2-salkenyl, C₂-5alkynyl, C_3- ₈cycloalkyl-Ci-3alkyl, C₃.₈heterocycloalkyl, C_3-8heterocycloalkyl-Ci_-3alkyl, C6-i₀aryl, C6-ioaryl-Ci_-3alkyl, Cs-toheteroaryl, or

wherein said R is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, thiol, amino, C_1-3alkoxy, Ci.₃alkylthio, mono(Ci. 3alkyl)amino, di(Ci_-3alkyl)amino, C_1-3acyl, C_1-3alkylsulfonyl, C_1-3alkoxycarbonyl, mono^i alky^aminocarboxy, di(C_1-3alkyl)aminocarboxy, Ci^acyloyl and Ci^alkyl;

R⁴ is hydrogen, C_1-6alkyl, C_2-6 alkenyl, C_2-6alkynyl, Ci- alkoxy, Ci_₆alkylthio, C3_-8cycloalkyl, C_6-1oaryl, or C5_-10heteroaryl, wherein said R⁴ is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, thiol, amino, Ci.₃alkoxy, C_1-3alkylthio, mono(Ci-3alkyl)amino, di(Ci. ₃alkyl)amino, Ci_-3acyl, C_1-3alkylsulfonyl, Q^alkoxycarbonyl, mono(C_1- 3alkyl)aminocarboxy, di(Ci_-3alkyl)aminocarboxy,

R⁵ is hydrogen, halogen, cyano, nitro, hydroxy, Ci^alkoxy, thiol, amino, carboxy, formyl, C_1- alkyl, C_3-8cycloalkyl, or C3- heterocycloalkyl;

Y is NH, NHCH₂, O or S;

Z is a substituent selected from the group consisting of:

wherein V is NH, NHC¾ or O; W is Ci_-8alkylene or C_2-8alkynylene; and Z' is N or CH;

6 7

R° and R are each independently hydrogen, methyl or phenyl, wherein said phenyl is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, thiol, amino, Ci_-3alkoxy, d alkylthio, mono(Ci. ₃alkyl)amino, di(C_1-3alkyl)amino, Ci_-3acyl, Ci_-3alkylsulfonyl, Cualkoxycarbonyl, mono(C_1-3alkyl)aminocarboxy, di(Ci_-3alkyl)aminocarboxy, Ci_-3acyloyl and Ci_-3alkyl;

o

R is hydrogen, halogen, cyano, nitro, hydroxy, thiol, amino, carboxy, formyl, Ci-3alkyl, C_1-3alkoxy, Ci_-3alkylthio, mono(Ci_-3alkyl)amino, d^Q.aalky amino, Q. ₃acyl, C_2-3alkenyl, C2_-3alkynyl, C_1-3alkylsulfonyl, Ci_-3alkoxycarbonyl, mono(Ci. ₃alkyl)aminocarboxy, di(C_1-3alkyl)aminocarboxy, Ci_-3acyloyl, or C_1-3acylamino;

m is an integer ranging from 2 to 12;

n is an integer ranging from 1 to 3;

o is an integer ranging from 0 to 6;

p is an integer ranging from 0 to 2;

q is an integer ranging from 0 to 5; and

r is an integer ranging from 0 to 3.

In accordance with a further aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating cancers, inflammatory diseases, autoimmune diseases, or neurodegenerative disorders, which comprises said compound as an active ingredient.

DETAILED DESCRIPTION OF THE INVENTION

Embodiments of the present invention are explained in detail hereinafter.

The term 'halogen' as used herein refers to fluorine, chlorine, bromine or iodine, unless otherwise indicated.

The term 'alkyl' as used herein refers to straight, cyclic, or branched hydrocarbon residues, unless otherwise indicated.

The term 'cycloalkyl' as used herein refers to cyclic alkyls including cyclopropyl, and others, unless otherwise indicated.

The term 'aryl' as used herein refers to monocyclic or bicyclic aromatic groups including phenyl, naphthyl, and others, unless otherwise indicated.

The term 'heterocycloalkyl' as used herein refers to cyclic alkyls including monocyclic, bicyclic alkyls, and others which contain heteroatoms selected from O, N and S, unless otherwise indicated. Examples of monoheterocycloalkyl include piperidinyl, morpholinyl, thiamorpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperazinyl and similar groups thereof, but not limited thereto.

The term 'heteroaryl' as used herein refers to aromatic groups including monocyclic or bicyclic groups, and others which contain heteroatoms selected from O, N and S, unless otherwise indicated. Examples of monocyclic heteroaryl include thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isooxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and similar groups thereof, but not limited thereto. Examples of bicyclic heteroaryl include indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, isoquinolinyl, purinyl, furopyridinyl and similar groups thereof, but not limited thereto.

The compound according to the present invention may also form a pharmaceutically acceptable salt. Such salt may be a pharmaceutically acceptable nontoxic acid addition salt containing anion, but not limited thereto. For example, the salt may include acid addition salts formed by inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydriodic acid, and others; organic carbonic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, and others; and sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulonic acid, naphthalensulfonic acid, and others. Among them, acid addition salts formed by hydrochloric acid, sulfuric acid, methanesulfonic acid or hydrohalogenic acid are preferred. Meanwhile, the compound of the present invention can have an asymmetric carbon center, and thus may be present in the form of R or S isomers, racemic compounds, diastereomeric mixtures, or individual diastereomers, such entire isomers and mixtures being included within the scope of the present invention.

In addition, solvates and hydrates of the compound of formula (I) are included within the scope of the present invention.

In the symmetrically structured quinazoline derivatives of formula (I), preferably, R¹ is hydrogen or methyl;

R is hydrogen, methyl or ethyl;

R is hydrogen, isopropyl, t-butyl or cyclohexyl;

R⁴ is hydrogen, C_1-6alkyl, Ci_-6alkoxy, C3_-8cycloalkyl, C_6-10aryl or C_5- _loheteroaryl, wherein said R⁴ is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, thiol, amino, C_1-3alkoxy, C_1-3alkylthio, mono(C_1-3alkyl)amino, di(Ci_-3alkyl)amino, Ci_-3acyl, C_1-3alkylsulfonyl, Ci_-3alkoxycarbonyl, mono(Ci_-3alkyl)aminocarboxy, di(C_1-3alkyl)aminocarboxy, Cj. ₃acyloyl and Ci_-3alkyl;

R⁵ is hydrogen, halogen, hydroxy, methoxy or ethoxy;

Y is NH, NHCH₂ or O;

Z is a substituent selected from the group consisting of:

wherein V is NH, NHCH₂ or O; W is Ci_-8alkylene or C_2-8alkynylene; and Z' is N or CH;

6 7

R° and R' are each independently hydrogen, methyl or phenyl;

8 ·

R is hydrogen, halogen, cyano, nitro, hydroxy, amino, carboxy, formyl, d- ₃alkyl, C_1-3alkoxy, C_1-3alkylthio, mono^^alky amino, di(C_1-3alkyl)amino, or d. m is an integer ranging from 2 to 12;

n is an integer ranging from 1 to 3;

o is an integer ranging from 0 to 6; p is an integer ranging from 0 to 2;

q is an integer ranging from 0 to 5; and

r is an integer ranging from 0 to 3.

More preferably, said Z is selected from the group consisting

Most preferred examples of the compound of formula (I) or its pharmaceutically acceptable salt are as follows. In addition to those compounds, a pharmaceutically acceptable salt, an isomer, a hydrate, or a solvate thereof may be used.

1) (S,S,2S,2'S)-N,N'-(4,4'-(((lS,4S)-cyclohexane-l,4- diylbis(methylene))bis(azandiyl))bis(7-methoxyquinazolin-6,4-diyl))bis(l-((S)-2- (methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride; 2) (S,S,2S,2'S)-N,N'-(4,4'-(hexa-2,4-dien-l,6-diylbis(oxy))bis(7 methoxyquinazolin-6,4-diyl))bis( 1 -((S)-3 ,3 -dimethyl-2-((S)-2- (methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride;

3) (S,S,2S,2' S)-N,N'-(4,4' -((( 1 R,4R)-cyclohexane- 1 ,4 diylbis(methylene))bis(azandiyl))bis(7-methoxyquinazolin-6,4-diyl))bis( 1 -((S)-3 ,3- dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride;

4) (S,S,2S,2'S)-N,N'-(4,4'-((lS,4S)-cyclohexane-l,4-diylbis(azandiyl))bis(7 methoxyquinazolin-6,4-diyl))bis( 1 -((S)-3 ,3 -dimethyl-2-((S)-2- (methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride;

5) (S,S,2S,2'S)-N,N'-(4,4'-((lR,4R)-cyclohexane-l,4-diylbis(azandiyl))bis(7 methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3-dimethyl-2-((S)-2- (methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride;

6) (S,S,2S,2'S)-N,N'-(4,4^,-(piperazin-l,4-diyl)bis(7-methoxyquinazolin-6,4- diyl))bis(l-((S)-3,3-dimethyl-2-((S)-2-

(methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride;

7) (S,S,2S,2'S)-N,N'-(4,4'-(((lS,4S)-cyclohexane-l,4- diylbis(methylene))bis(azandiyl))bis(7-methoxyquinazolin-6,4-diyl))bis(l-((S)-2- cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)pyrrolidine-2-carboxamide) dihydrochloride;

8) (S,S,2S,2'S)-N,N'-(4,4'-(((lS,4S)-cyclohexane-l,4- diylbis(methylene))bis(azandiyl))bis(7-methoxyquinazolin-6,4-diyl))bis( 1 -(3 -methyl- 2-((S)-2-(methylarnino)propanamido)butanoyl)pyrrolidine-2-carboxarnide)

dihydrochloride;

9) (S,S,2S,2'S)-N,N^,-(4,4'-((l,4-phenylenebis(methylene))bis(azandiyl))bis(7- methoxyquinazolin-6,4-diyl))bis( 1 -((S)-3,3-dimethyl-2-((S)-2- (methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride;

10) (S,S,2S,2'S)-N,N'-(4,4'-((l,3- phenylenebis(methylene))bis(azandiyl))bis(7-methoxyquinazolin-6,4-diyl))bis(l-((S)- 3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidine-2- carboxamide) dihydrochloride; 11) (S,S,2S,2'S)-N,N'-(4,4'-(((lS,2S)-l,2-diphenylethane-l,2- diyl)bis(azandiyl))bis(7-methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3-dimethyl-2-((S)-2- (methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride;

12) (S,S,2S,2'S)-N,N'-(4,4'-(butan-l,4-diylbis(azandiyl))bis(7- methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3-dimethyl-2-((S)-2- (methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride;

13) (S,S,2S,2'S)-N,N'-(4,4'-(hexane-l,6-diylbis(azandiyl))bis(7- methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3-dimethyl-2-((S)-2- (methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride;

14) (S,S,2S,2' S)-N,N' -(4,4' -(octan- 1 ,8-diylbis(azandiyl))bis(7- methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3-dimethyl-2-((S)-2- (methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride;

15) (S,S,2S,2'S)-N,N'-(4,4'-(decane-l,10-diylbis(azandiyl))bis(7- methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3-dimethyl-2-((S)-2- (methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride;

16) (S,S,2S,2'S)-N,N'-(4,4'-(((ethane-l,2-diylbis(oxy))bis(ethane-2,l- diyl))bis(azandiyl))bis(7-methoxyquinazolin-6,4-diyl))bis( 1 -((S)-3 ,3 -dimethyl-2-((S)- 2-(methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride;

17) (S,S,2S,2'S)-N,N'-(4,4'-([l,l'-biphenyl]-4,4'-diylbis(azandiyl))bis(7- methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3-dimethyl-2-((S)-2- (methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride;

18) (S,S,2S,2'S)-N,N'-(4,4'-(2-butyne-l,4-diylbis(oxy))bis(7- methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3-dimethyl-2-((S)-2- (methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride;

19) (S,S,2S,2'S)-N,N'-(4,4'-(hexa-2,4-dien-l,6-diylbis(oxy))bis(4,l- phenylene))bis(azandiyl))bis(7-methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3-dimethyl- 2-((S)-2-(methylarnino)propanamido)butanoyl)pyrrolidine-2-carboxamide)

dihydrochloride;

20) (S,S,2S,2'S)-N,N'-(4,4'-(hexa-l,3-diyne-l,4-diylbis(azandiyl))bis(7- methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3-dimethyl-2-((S)-2- (methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide;

21 ) (S,S,2S,2 ' S)-N,N' -(4,4'-(hexa-2,4-dien- 1 ,6-diylbis(oxy))bis(4, 1 - phenylene))bis(azandiyl))bis(7-methoxyquinazolin-6,4-diyl))bis(l-((S)-2-cyclohexyl- 2-((S)-2-(methylamino)propanamido)acetyl)pynOlidine-2-carboxamide)

dihydrochloride;

22) (S,S,2S,2'S)-N,N'-(4,4'-(((hexa-2,4-dien-l ,6-diylbis(oxy))bis(3-chloro- 4,l-phenylene))bis(azandiyl))bis(7-methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3- dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride; and

23) (S,S,2S,2'S)-N,N'-(4,4'-((6,6'-(hexa-2,4-dien-l ,6-diylbis(oxy))bis(pyridin- 6,3 -diyl))bis(azandiyl))bis(7-methoxyquinazolin-6,4-diyl))bis(l-((S)-3, 3 -dimethyl -2- ((S)-2-(methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide)

dihydrochloride.

Hereinafter, an exemplary method for preparing the compound of the present invention is explained.

Following abbreviations are used in preparation methods and Examples below:

Ala : alanine

Boc- : tert-butoxycarbonyl

Cbz- : 2-benzyloxycarbonylamino

Chg : cyclohexylglycine

CuCl : copper chloride

DIPEA : N,N-diisopropylethylamine

DMAP : N,N-dimethylaminopyridine

DMF : Ν,Ν-dimethyl formamide

DMSO : dimethyl sulfoxide

EA : ethyl acetate

EDCI : l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride HATU : [2-(lH-9-azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate]

HOBT : N-hydroxybenzotriazole

Mass : mass chromatogram

MC : methylene chloride MeAla : methylalanine

MeOH : methanol

-OBn : -O-benzyl

TEA : triethylamine

THF : tetrahydrofuran

TLC : thin layer chromatography

TMEDA : Ν,Ν,Ν',Ν'-tetramethylethylenediamine

Tie : t-butylglycine

Val : valine.

The compound of formula (I) of the present invention may be prepared by a synthetic method as shown in Reaction Schemes 1 , 2 and 3.

[Reaction Scheme 1]

wherein, R¹, R², R³, R⁴, R⁵, Y and Z have the same meanings as defined above.

Reaction Scheme 1 comprises the steps of:

(1) reacting a compound of formula (II) with a linker (Y-Z-Y) to obtain a compound of formula (III);

(2) reacting the compound of formula (III) with iron and reducing the resulting product to obtain a compound of formula (IV);

(3) reacting the compound of formula (IV) with three peptides to obtain a compound of formula (V); and

(4) reacting the compound formula (V) with hydrochloric acid to obtaining a compound of formula (1-1) to obtain a compound of formula (1-1).

The reaction processes of Reaction Scheme 1 are exemplified in following stepwise reaction.

Step (Ϊ)

A resulting compound obtained in Preparing Example 1 (1.0-1.1 equivalents), amine (0.48-0.52 equivalents) and TEA (4.0-4.5 equivalents) are mixed and dissolved in 2-propanol solvent (20-22 mL/g). The mixture is heated to a temperature of 70~90°C, and further stirred for 4-5 hours. After the mixture is cooled to room temperature, the resulting mixture is filtered and dried to obtain the desired compound as a solid. Step (ID

Iron (9.5-10.0 equivalents) and hydrochloric acid (0.7-0.8 equivalents) are mixed in 50% ethanol. The mixture is heated to a temperature of 90-1 10°C and heating is continued under reflux for 1 hour to activate iron. The resulting compound (1.0-1.2 equivalents) obtained in step (I) is added to activated iron and refluxed at 90-1 10°C for 2-3 hours. After completion of the reaction, the mixed solution is filtered through a Celite pad under reduced pressure, rinsed with a mixture of chloroform and isopropylalchol (4:1 (v/v), 80-90 mL/g), and the resulting filtrate is rinsed with an aqueous solution of sodium bicarbonate. The organic layer is dried over sodium sulfate, filtered and dried under reduced pressure to obtain the desired compound.

Step (IIP The compound (1 equivalent) obtained in step (II), Ala-Tie-Pro derivative (1.0-1.2 equivalents) and EDCI (9.5-10.0 equivalents) are dissolved in a solvent of pyridine (29-31 mL/g), and stirred. The mixture is heated to 50~60°C, further stirred for 4-5 hours, distilled under reduced pressure, dissolved in EA and rinsed with an aqueous solution of sodium bicarbonate. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the desired compound.

Step (IV)

The compound (1.0-1.1 equivalent) obtained in step (III) is dissolved in 4M HCl/dioxane (9-10 mL/g), and stirred for 3-4 hours at room temperature. After completion of the reaction, the resulting mixture is filtered and rinsed with diethyl ether to obtain the desired compound.

Alternatively, the compound of formula (I) of the present invention can also be prepared by the following reaction scheme.

[Reaction Scheme 2]

R¹, R², R³, R⁴, R⁵ and Y have the same meanings as defined above.

The reaction processes of Reaction Scheme 2 are exemplified in following stepwise reaction.

Step (I)

A resulting compound obtained in Preparing Example 1 (1.0-1.1 equivalents) and potassium carbonate (2.0-2.5 equivalents) are mixed in acetone. Bromate (1.5-1.7 equivalents) is added thereto and heated under reflux for 5 hours. After the mixture is cooled to room temperature, the resulting mixture is filtered, rinsed with acetone and dried under reduced pressure to obtain the desired compound as a solid.

Step (II)

Iron (4.9-5.2 equivalents) and hydrochloric acid (0.7-0.8 equivalents) are mixed in 50% ethanol. The mixture is heated to a temperature of 90-110°C and heating is continued under reflux for 1 hour to activate iron. The resulting compound (1.0-1.2 equivalents) obtained in step (I) is added to activated iron and refluxed at 90-1 10°C for 2-3 hours. After completion of the reaction, the mixed solution is filtered through a Celite pad under reduced pressure, rinsed with a mixture of chloroform and isopropylalchol (4: 1 (v/v), 80-90 mL/g), and the resulting filtrate is rinsed with an aqueous solution of sodium bicarbonate. The organic layer is dried over sodium sulfate, filtered and dried under reduced pressure to obtain the desired compound.

Step (III)

The compound (1.0-1.1 equivalents) obtained in step (II), Ala-Tie-Pro derivative (3.0-3.2 equivalents) and EDCI (5.0-5.3 equivalents) are mixed and dissolved in a solvent of pyridine (29-31 mL/g), and stirred. The mixture is heated to 50~60°C, further stirred for 4-5 hours, distilled under reduced pressure, dissolved in EA and rinsed with an aqueous solution of sodium bicarbonate. The organic layer is dried over sodium sulfate, distilled under reduced pressure, and purified by column chromatography to obtain the desired compound. Step (IV)

The compound (1.0-1.2 equivalents) obtained in step (III) is dissolved in dry acetone. TMEDA (1.2-2.0 equivalents) and CuCl (1.2-2.0 equivalents) are added, in sequence, thereto and the mixture is stirred for 5-6 hours at room temperature under oxidizing atmosphere. Subsequently, the mixture is concentrated under reduced pressure, dissolved in EA and rinsed with an aqueous solution of sodium bicarbonate. The organic layer is dried over sodium sulfate, filtered and distilled under reduced pressure, and purified by column chromatography to obtain the desired compound.

Step (V)

The compound (1.0-1.1 equivalents) obtained in step (IV) is dissolved in 4M HCl/dioxane (9-10 mL/g), and stirred for 3-4 hours at room temperature. After completion of the reaction, the resulting mixture is filtered and rinsed with diethyl ether to obtain the desired compound.

[Reaction Scheme 3]

wherein, A, R¹, R², R³, R⁴, R⁵ and Y have the same meanings as defined above.

The reaction processes of Reaction Scheme 3 are exemplified in following stepwise reaction.

Step (D

A resulting compound obtained in Preparing Example 1 (1.0-1.1 equivalents) and amine (2.0-2.2 equivalents) are mixed in 2-propanol solvent (20-22 mL/g). The mixture is heated to a temperature of 70~90°C, and further stirred for 4-5 hours. After the mixture is cooled to room temperature, the resulting mixture is filtered, rinsed with 2-propanol and dried to obtain the desired compounds as a solid.

Step (ID

Iron (4.9-5.2 equivalents) and hydrochloric acid (0.7-0.8 equivalents) are mixed in 50% ethanol. The mixture is heated to a temperature of 90-110°C and heating is continued under reflux for 1 hour to activate iron. The resulting compound (1.0-1.2 equivalents) obtained in step (I) is added to activated iron and refluxed at 90-100°C for 2-3 hours. After completion of the reaction, the mixed solution is filtered through a Celite pad under reduced pressure, rinsed with a mixture of chloroform and isopropylalcohol (4: 1 (v/v), 80-90 mL/g), and the resulting filtrate is rinsed with an aqueous solution of sodium bicarbonate. The organic layer is dried over sodium sulfate, distilled under reduced pressure, and purified by column chromatography to obtain the desired compound. Step (IIP

Step (V)

The synthesis of the mimetics of the present invention may be carried out using the general reaction scheme for preparing a library of Smac DIABLO structure mimetics as shown in Reaction Scheme 1, 2 and 3, and mass analysis may be performed using MicroMass ZQ™ (Waters).

The inventive compound including the quinazoline derivative of fornula (I), the pharmaceutically acceptable salt, the isomer, the hydrate, and the solvate thereof can selectively and effectively inhibit the growth of cancers, inflammatory diseases, autoimmune diseases, or neurodegenerative disorders induced by the overexpression of IAPs without showing any adverse side effect.

Accordingly, the present invention provides a use of the inventive compound for the manufacture of a medicament for preventing or treating cancers, inflammatory diseases, autoimmune diseases, or neurodegenerative disorders.

In addition, the present invention provides a pharmaceutical composition for preventing or treating cancers, inflammatory diseases, autoimmune diseases, or neurodegenerative disorders, which comprises the inventive compound as an active ingredient.

Further, the present invention provides a method for preventing or treating cancers, inflammatory diseases, autoimmune diseases, or neurodegenerative disorders, which comprises administering the inventive compound to a mammal in need thereof.

A proposed daily dose of the inventive compound for administration to a human may be in the range of 0.01 mg/kg(body weight) to 200 mg/kg(body weight), preferably 10 mg/kg(body weight) to 100 mg/kg(body weight). The inventive compound may be administered in a single dose or in divided doses per day. It is understood that the daily dose should be determined in light of various relevant factors including the condition, age, body weight and sex of the subject to be treated, administration route, and disease severity; and, therefore, the dosage suggested above should not be construed to limit the scope of the present invention in anyway.

The pharmaceutical composition of the present invention may be formulated in accordance with conventional methods, and may be prepared in the form of oral formulations such as tablets, pills, powders, capsules, syrups, emulsions, microemulsions, and others, or parenteral formulations such as intramuscular, intravenous, or subcutaneous administrations.

For oral formulations, carriers such as cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers, diluents, and others. For injectable formulations, carriers such as water, saline, glucose solution, glucose solution analogs, alcohols, glycols, ethers (e.g., polyethylene glycol 400), oils, fatty acids, fatty acid esters, glycerides, surfactants, suspending agents, emulsifiers, and others may be used.

Hereinafter, the present invention is described more specifically by the following examples, but these are provided only for illustration purposes, and the present invention is not limited thereto. Preparation Example 1: Preparation of 4-chloro-7-methoxy-6-nitroquinazoline

<Step 1> Preparation of 7-fluoro-3H-quinazolin-4-one 2-amino-4-fluorobenzoic acid (100 g, 0.64 mol) and formamide (154 mL, 3.87 mol) were mixed with a catalytic amount (1 mL) of Ν,Ν-dimethylformamide. The mixture was heated to 180°C and further stirred for 14 hours. The mixture was cooled to room temperature, and distilled water (1000 mL) was added thereto. The mixture was stirred for 30 min and filtered to obtain the title compound (86 g, 81.3%).

1H NMR(300 MHz, CDC1₃): δ 12.34(s, 1H), 8.19-8.12(m, 2H), 7.46-7.34(m,

2H)

MS(ESI⁺, m/z): 165 [M+H]⁺ <Step 2> Preparation of 7-fluoro-6-nitro-3H-quinazolin-4-one

7-fluoro-3H-quinazolin-4-one (25 g, 152 mmol) obtained in <Step 1> was added dropwise to a mixed solution of sulfuric acid (50 mL) and nitric acid (51 mL) at 0°C. The mixture was stirred at room temperature for 1 hour, and heated to 110°C, followed by stirring for 2 hours. The mixture was cooled to room temperature and ice water (300 mL) was added thereto. The resulting mixture was stirred for about 30 min and filtered to obtain the title compound (25 g, 79%).

1H NMR(300 MHz, CDC1₃): δ 12.83(br, 1H), 8.27(d, 1H), 8.32(s, 1H), 7.79(d,

1H)

MS(ESI⁺, m/z): 210 [M+H]⁺

<Step 3> Preparation of 7-methoxy-6-nitro-3H-quinazolin-4-one

7-fluoro-3H-quinazolin-4-one (25 g, 0.12 mol) obtained in <Step 2> was suspended in methanol (1.2 L). NaOMe (19.4 g, 0.36 mol) was added dropwise thereto and the mixture was stirred at 30°C or less. The mixture was heated to 65°C, further stirred for 2 hours. The mixture was cooled to room temperature and acidified into pH 5~6 using an aqueous hydrochloric acid (1 N). Water (300 mL) was added thereto, and the resulting mixture was stirred for 30 min and filtered to obtain the title compound (26 g, 98%).

1H NMR(300 MHz, DMSO-d⁶): δ 8.51(s, 1H), 8.22(s, 1H), 7.41(s, 1H), 4.03(s, 3H)

<Step 4> Preparation of 4-chloro-7-methoxy-6-nitroquinazoline To 7-methoxy-6-nitro-3H-quinazolin-4-one (26 g, 0.12 mol) obtained in <Step 3>, thionyl chloride (178 mL, 2.45 mol) and phosphorus oxychloride (35 mL, 0.38 mol) and N,N-dimethylformaldehyde (1 mL) were added. The solution was stirred and then heated to 100°C. When the compound is completely resolved, the solution was stirred for 2 hours. The solution was cooled to room temperature and solvents are distilled under reduced pressure. The resulting residue was mixed with toluene (300 mL), and distilled again under reduced pressure. The procedure was repeated three times to obtain the title compound (27 g, 85%).

Ή NMR(300 MHz, DMSO-d⁶): δ 9.12(s, 1H), 8.78(s, 1H), 7.79(s, 1H), 4.11(s, 3H)

Preparation Example 2: Preparation of (S)-l-((S)-2-((S)-2-(tert- butoxycarbonyI(methyl)amino)propanamido)-3,3-dimethylbutanoyl)pyrrolydine- 2-carboxylic acid

<Step 1> Preparation of (S)-2-benzyl 1-tert-butyl pyrrolidine- 1 ,2-dicarboxylate

Boc-Tle-OH (50.0 g, 0.23 mol) was dissolved in dichloromethane (500 mL), and EDCI (89.1 g, 0.46 mol), DMAP (5.7 g, 0.05 mol), DIPEA (162 mL, 0.932 mol), and benzyl alcohol (48 mL, 0.46 mol) were added dropwise. The mixture was stirred at room temperature for 12 hours. The mixture was washed several times with an aqueous solution of 5% citric acid. The organic layer was dried over sodium sulfate, and filtered and distilled under reduced pressure to obtain the title compound as yellow oil (70.0 g, 99%).

Ή NMPv(300 MHz, CDC1₃): δ 7.32 (m, 5H), 5.20 (m, 2H), 4.27 (d, 1H), 3.52 (m, 2H), 1.91 (m, 4H), 1.35 (s, 9H)

MS(ESI⁺, m/z): 306 [M+H]⁺

<Step 2> Preparation of (S)-benzyl pyrrolidine-2-carboxylate hydrochloride

(S)-2-benzyl 1-tert-butyl pyrrolidine- 1,2-dicarboxylate (70.0 g, 0.23 mol) obtained in <Step 1> was dissolved in a solution of 4M HCl/dioxane (175 mL) and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure and recrystallized with diethyl ether to obtain the title compound as a white solid (42.6 g, 77%). 1H NMR(300 MHz, CDC1₃): S 7.32 (m, 5H), 5.20 (m, 2H), 4.27 (d, 1H), 3.52 (m, 2H), 1.91 (m, 4H)

MS(ESf , m/z): 206 [M+H]⁺ <Step 3> Preparation of (S)-benzyl l-((S)-2-(tert-butoxycarbonylamino)-3,3- dimethylbutanovnpyrrolidine-2-carboxylate

(S)-benzyl pyrrolidine-2-carboxylate hydrochloride (30.0g, 0.12 mol) obtained in <Step 2> was dissolved in dichloromethane (300 mL), and Boc-Tle-OH (26.7g, 0.12 mol), HATU (56.6g, 0.15 mol) and DIPEA (43 mL, 0.25 mol) were added dropwise. The mixture was stirred at room temperature for 4 hours. Insoluble components were removed by filtration, and the filtrate was washed several times with an aqueous solution of 5% citric acid. The organic layer was dried over sodium sulfate, filtered and distilled under reduced pressure, and purified by column chromatography to obtain the title compound as transparent oil (47. Og, 91%).

Ή NMR(300 MHz, CDC1₃): δ 7.33 (m, 5H), 5.15 (m, 2H), 4.61 (m, 2H), 3.84 (m, 2H), 2.25 (m, 2H), 1.98 (m, 2H), 1.43 (s, 9H), 0.98 (s, 9H)

MS(ESI⁺, m/z): 419 [M+H]⁺

<Step 4> Preparation of (S)-benzyl l-((^"S)-2-amino-3,3-dimethylbutanoyl pyrrolidine- 2-carboxylate hydrochloride

(S)-benzyl l-((S)-2-(tert-butoxycarbonylamino)-3,3- dimethylbutanoyl)pyrrolidine-2-carboxylate (47.0 g, 0.1 1 mol) obtained in <Step 3> was dissolved in a solution of 4M HCl/dioxane (175 mL), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the title compound as transparent oil (39.0 g, 98%).

Ή NMR(300 MHz, CDC1₃): S 7.35 (s, 5H), 5.18 (q, 2H), 4.67 (t, 1H), 4.02 (m, 2H), 3.56 (m, 1H), 2.32 (m, 1H), 1.93 (m, 3H), 1.13 (s, 9H)

MS(ESI⁺, m/z): 319 [M+H]⁺

<Step 5> Preparation of (SVbenzyl . 1 -r(S -2-r(SV2-rtert- butoxycarbonyl(methyl amino)propanamido)-3,3-dimethylbutanoyl)pyrrolidine-2- carboxylate (S)-benzyl 1 -((S)-2-amino-3,3-dimethylbutanoyl)pyrrolidine-2-carboxylate hydrochloride (29.0 g, 0.08 mol) obtained in <Step 4> was dissolved in dichloromethane (300 mL), and Boc_MeAla-OH (24.9 g, 0.12 mol), EDCI (23.5 g, 0.12 mol) and DIPEA (43 mL, 0.25 mol) were added dropwise. The mixture was stirred at room temperature for 12 hours, and washed several times with an aqueous solution of 5% citric acid. The organic layer was dried over sodium sulfate, filtered and distilled under reduced pressure, and purified by column chromatography to obtain the title compound as transparent oil (30.0 g, 72%).

1H NMR(300 MHz, CDC1₃): S 7.33 (m, 5H), 5.16 (q, 2H), 4.76 (m, 1H), 4.54 (m, 1H), 3.84 (m, 1H), 3.66 (m, 1H), 2.77 (s, 3H), 2.18 (m, 1H), 1.95 (m, 3H), 1.47 (s, 9H), 1.29 (m, 5H), 0.96 (s, 9H)

MS(ESI⁺, m/z): 504 [M+H]⁺

<Step 6> Preparation of (SVl-((SV2-((SV2-(tert- butoxycarbonyl(methyl amino)propanamido)-3,3-dimethylbutanovnpyrrolidine-2- carboxylic acid

(S)-benzyl l-((S)-2-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)- 3,3-dimethylbutanoyl)pyrrolidine-2-carboxylate (28.0 g, 0.06 mol)obtained in <Step 5> was dissolved in methanol (300 mL), and 10% Pd/C (2.8 g) was added thereto, followed by stirring for 1.5 hours under hydrogenation conditions. Insoluble components were removed by filtration, and the filtrate was concentrated under reduced pressure, followed by purification using a column chromatography to obtain the title compound as a white solid (21.0 g, 91 %).

1H NMR(300 MHz, CDC1₃): δ 4.57 (m, 3H), 3.83 (m, 1H), 3.65 (m, 1H), 2.75 (s, 3H), 2.31 (m, 1 H), 2.01 (m, 3H), 1.46 (s, 9H), 1.29 (d, 3H), 0.98 (s, 9H)

MS(ESI⁺, m/z): 414 [M+H]⁺

Example 1: Preparation of (S,S,2S,2'S)-N,N'-(4,4'-(((lS,4S)-cyclohexane-l,4- diylbis(methylene))bis(azandiyI))bis(7-methoxyquinazolin-6,4-diyl))bis(l-((S)-2- (methylamino)propanamido)butanoyI)pyrroIidine-2-carboxamide)

dihydrochloride <Step 1> Preparation of nR,4R)cvclohexane-l,4-diylbis(methylene) dimethansulfonate

Trans- 1 ,4-cyclohexanedimethanol (10 g, 0.069 mol) was dissolved in MC, and methansulfonylchloride (13 mL, 0.166 mol) was added thereto at 0°C, followed by slow addition of triethylamine (23.2 mL, 0.166 mol) at the same temperature. The mixture was stirred at room temperature for 2 hours. The reaction was completed by adding ice thereto, and the mixture was diluted with MC. The organic layer was rinsed with an aqueous solution of sodium bicarbonate and salt, dried over sodium sulfate, filtered and dried under reduced pressure to obtain the title compound (14.0 g, 67%).

Ή NMR Spectrum (300 MHz, CDC1₃): δ 4.03(d, 4H), 2.99(s, 6H), 1.89(m, 4H), 1.72(m, 2H), 1.07(m, 4H)

<Step 2> Preparation of (lR,4R)-L4-bis(azidomethyl)cvclohexane

The compound (13.6 g, 0.045 mol) obtained in <Step 1> and sodium azide

(17.7 g, 0.271 mol) were dissolved in DMF (110 mL) by stirring at 120°C for 4 hours. The mixture was cooled to room temperature, ice was added thereto and then the solution was diluted with ethylacetate. The organic layer was rinsed with an aqueous solution of sodium hydroxide (1 N), water and salt water, dried over sodium sulfate, filtered and dried under reduced pressure to obtain the title compound (8.1 g, 92%).

1H NMR(300 MHz, CDC1₃): δ 3.19(d, 4H), 1.72(m, 4H), 1.44(m, 2H), 0.96(m,

4H)

<Step 3> Preparation of trans- 1 ,4-cyclohexanedimethanamine

The compound (3.7 g, 0.019 mol) obtained in <Step 2> and triphenylphosphine

(30.0 g, 0.114 mol) were dissolved in THF (40 mL), and water (7.0 mL, 0.381 mol) was added thereto. The mixture was stirred at 60°C for 4 hours. After completion of the reaction, the mixture was distilled under reduced pressure to remove THF. Hexane was added thereto, and resulting mixture was filtered to remove triphenyl phosphine. The procedure was repeated five times and then dried under reduced pressure to obtain the title compound (2.4 g, 90%).

1H NMR(300 MHz, CDC1₃): δ 2.33(d, 4H), 1.73(m, 4H), 1.04(m, 2H), 0.78(m,

4H) <Step 4> Preparation of N,N'-((lR,4RVcyclohexane-L4-diylbis(methylene))bis(7- methoxy-6-nitroquinazolin-4-amine

4-chloro-7-methoxy-6-nitroquinazoline (27 g, 0.098 mol) obtained in Preparation Example 1, trans- 1,4-cyclohexanedimethanamine (6.7 g, 0.047 mol) obtained in <Step 3> and triethylamine (53 mL, 0.38 mol) were dissolved in 2- propanol (1300 mL) and stirred. The mixture was heated to 60°C, further stirred for 4 hours and cooled to room temperature. The resulting mixture was filtered to obtain the title compound (19 g, 70%).

1H NMR(300 MHz, DMSO-d⁶): δ 9.00(s, 2H), 8.59(m, 2H), 8.45(s, 2H), 7.3 l(s,

2H), 3.99(s, 6H), 1.81(m, 4H), 1.66(br, 2H), 0.95(m, 4h)

<Step 5> Preparation of N4,N4^,-((lR.4RVcvclohexane-1.4-diylbis(methylene^'))bis(7- methoxyquinazolin-4,6-diamine)

Iron (4.6 g) was diluted in an aqueous solution of 50% ethanol (50 mL), added with hydrochloric acid (1.0 mL), and activated by heating to 100°C. Trans- 1,4- cyclohexanedimethanamine (4.5 g, 8.20 mmol) obtained in <Step 4> was added to the activated iron, followed by reflux at 100°C for 1 hour. After completion of the reaction, the mixed solution was filtered through a Celite pad, rinsed with a mixture of chloroform and isopropylalcohol (4:1 (v/v)), and the resulting filtrate was rinsed with an aqueous solution of sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and distilled under reduced pressure, and purified by column chromatography to obtain the title compound (0.6 g, 1 %).

1H NMR(300 MHz, DMSO-d⁶): δ 8.14(s, 2H), 7.48(m, 2H), 7.13(s, 2H), 6.93(s, 2H), 5.05(s,4H), 3.88(s, 6H), 1.78(m, 4H), 1.66(br, 2H), 0.91(m, 4H)

<Step 6> Preparation of di-tert-butyl r2S.2^,S (( 2S,2^,S r 2S,2^,S -2.2^,-( ('4.4^,- ((( 1 S,4S-cyclohexane- 1 ,4-diylbis(methylene )bis(azandiyl bis(7-methoxyquinazolin- 6,4-diyn)bis(azandiyl^'))bis(carbonyl))bis(pyrrolidin-2, 1 -diyl) bis(3,3-dimethyl- 1 - oxobutan-2, 1 -diyl)^')bis(azandiyl )bis( 1 -oxopropan-2, 1 -divD)bis(methylcarbamate)

The compound (1.0 g, 2.05 mmol) obtained in <Step 5>, (S)-l-((S)-2-((S)-2- (tert-butoxycarbonyl(methyl)amino)propanamido)-3,3-dimethylbutanoyl)pyrrolidine- 2-carboxylic acid (5.1 g, 12.28 mmol) obtained in Preparation Example 2 and EDCI (3.9 g, 20.47 mmol) were dissolved in a solvent of pyridine/DMF (50/5 mL), and stirred. The solution was heated to 60°C, further stirred for 4 hours, distilled under reduced pressure, and purified by column chromatography to obtain the title compound (1.7 g, 65%).

1H NMR(300 MHz, CDC1₃): S 9.68(s, 2H), 9.34(br, 2H), 8,79(s, 2H), 8,52(s,

2H), 7.16(s, 2H), 6.90(br, 2H), 5.70(m, 2H), 4.85(m, 2H), 4.71(m, 2H), 4.63(d, 2H), 3.98(s, 6H), 3.87(m, 2H), 3.71(m, 2H), 2.79(s, 6H), 2,54(m, 2H), 2.25-1.92(m, 2H), 2.16(br, 4H), 1.91(m, 2H), 1.68(br, 4H), 1.50(s, 18H), 1.34(d, 6H), 0.98(s, 18H) <Step 7> Preparation of rS.S^S^'S N.N'^^'-frri S^S cvclohexane-l^- diylbis(methylene )bis(azandiyl))bis(^'7-methoxyquinazolin-6,4-divn)bis(l-((S)-2- (methylamino)propanamido)butanovnpyrrolidine-2-carboxamide dihydrochloride

The compound (510 mg, 0.34 mmol) obtained in <Step 6> was dissolved in EA (10 mL), and a solution of 4M HCl/dioxane (2.0 mL, 7.97 mmol) was added thereto. The mixture was stirred for 3 hours at room temperature, filtered, and rinsed with diethyl ether to obtain the title compound as a light yellow solid (340 mg, 74%).

1H NMR(300 MHz, DMSO-d⁶): δ 9.98(m, 2H), 9.77(s,2H), 9.50(m, 2H), 8.88(s, 2H), 8.77(s, 2H), 8.61(d, 2H), 7.42(s, 2H), 4..78(m, 2H), 4.51(d, 2H), 4.01(s, 6H), 3.77(m, 2H), 3.69(m, 2H), 3.48(m, 2H), 2.13-1.89(m, 8H), 1.75(m, 8H), 1.33(d, 6H), 0.98(s, 18H)

Example 2: Preparation of (S,S,2S,2'S)-N,N'-(4,4'-(hexa-2,4-dien-l,6- diylbis(oxy))bis(7-methoxyquinazoIin-6,4-diyl))bis(l-((S)-3,3-dimethyl-2-((S)-2- (methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide)

dihydrochloride

<Step 1> Preparation of 7-methoxy-6-nitro-4-(propargyloxy)-quinazoline

7-methoxy-6-nitro-3H-quinazolin-4-one (1 g, 4.52 mmol) obtained in <Step 3> of Preparation Example 1 and potassium carbonate (1.25 g, 9.04 mmol) were dissolved in a solvent of acetone (15 mL), and stirred. Propargyl bromide (807 mg, 6.78 mmol) was added thereto and heated under reflux for 5 hours. The mixture was concentrated under reduced pressure and filtered to obtain the title compound (1 g, 85%). 1H NMR(300 MHz, DMSO-d⁶): δ 8.59(s, 2H), 7.48(s, 1H), 4.81(d, 2H), 4.06(s, 3H), 3.46(d, 1H)

MS(ESI⁺, m/z): 260 [M+H]⁺

<Step 2> Preparation of 6-amino-7-methoxy-4-(^'propargyloxyVquinazoline

Iron (1.1 g) was diluted in an aqueous solution of 50% ethanol (13 mL), one drop of hydrochloric acid solution was added thereto, and activated by heating the solution to 80°C. The compound (1 g, 3.85 mmol) obtained in <Step 1> was added thereto, followed by reflux at 80°C for 1 hour. After completion of the reaction, the mixed solution is filtered through a Celite pad under reduced pressure, rinsed with ethanol and the resulting filtrate was rinsed with sodium bicarbonate. The organic layer was dried over sodium sulfate, distilled under reduced pressure, and purified by silica gel column to obtain the title compound (410 mg, 46%).

1H NMR(300 MHz, CDC1₃): δ 8.12(s, 1H), 7.48(s, 1H), 7.04(s, 1H), 4.80(d, 2H), 4.19(br, 2H), 3.96(s, 3H), 2.46(d, 1H)

MS(ESI⁺, m/z): 230 [M+H]⁺

<Step 3> Preparation of tert-butyl fSVl((Sn-((SV2-(7-methoxy-4-(propargyloxyV quinazolin-6-ylcarbamo vDpyrrolidin- 1 -yl -3 ,3 -dimethyl- 1 -oxobutan-2- ylamino)- 1 - oxopropan-2-yl(methyl)carbamate

The compound (400 mg, 1.74 mmol) obtained in <Step 2>, (S)-l-((S)-2-((S)-2-

(tert-butoxycarbonyl(methyl)amino)propanamido)-3,3-dimethylbutanoyl)pyrrolidine-

2-carboxylic acid (858 mg, 2.62 mmol) obtained in Preparation Example 2, and EDCI (667 mg, 3.48 mmol) were dissolved in a solvent of pyridine (6 mL), and stirred. The mixture was heated to 50°C, and further stirred for 4 hours, distilled under reduced pressure, purified by column chromatography to obtain the title compound (1.02 g,

94%).

Ή NMR(300 MHz, CDC1₃): δ 9.48(br, 1H), 9.18(s, 1H), 8.23(s, 1H), 7.09(s, 1H), 6.90(brs, 1H), 4.85-4.82(m, 1H), 4.80(s, 2H), 4.64(d, 1H), 3.99(s, 3H), 3.88- 3.84(m, 1H), 3.70-3.67(m, 1H), 2.80(s, 3H), 2.56-2.53(m, 1H), 2.48(s, 1H), 2.30- 1.90(m, 3H), 1.58(s, 9H), 1.3(d, 3H), 0.98(s, 9H)

MS(ESI⁺, m/z): 625 [M+H]⁺ <Step 4> Preparation of di-tert-butylr2S_<2'SVl,l ^,-(2S.2^,S l .Γ-(^'(^'2S■2^,SV2,2^,-(4,4^,- (hexa-2,4-dien- ,6-diylbis(oxy) bis(7-methoxyquinazolin-6,4- diyl )bisfazandiyl)bis(oxomethylene)bis(py

oxobutan-2, 1 -diyl)bis(azandiynbis( 1 -oxopropan-2, 1 -diyPbismethylcarbamate

The compound (250 mg, 0.08 mmol) obtained in <Step 3>, CuCl(32 mg, 0.32 mmol) and TMEDA (48 μί, 0.32 mmol) were dissolved in acetone (1 mL) under oxidizing atmosphere, and stirred for 12 hours. The mixture was concentrated under reduced pressure, purified by silica gel column to obtain the title compound (80 mg, 80%).

Ή NMR(300 MHz, CDCl₃): δ 9.48(br, 2H), 9.16(s, 2H), 8.1 l(s, 2H), 7.08(s, 2H), 6.90(br, 2H), 4.88(s, 4H), 4.85-3.98(m, 6H), 3.98(s, 6H), 3.87-3.84(m, 2H), 3.70- 3.68(m, 2H), 2.80(s, 3H), 2.58-2.54(m, 2H), 2.16-1.90(m, 6H), 1.5 l(s, 18H), 1.33(d, 6H), 0.97(s, 18H)

MS(ESI⁺, m/z): 1247 [M+H]⁺

<Step 5> Preparation of (S,S,2S,2^,S)-N,N^,-(4,4^,-(hexa-2,4-dien-1.6- diylbis(oxy) bis(7-methoxyquinazolin-6.4-divn bis(l-((S)-3,3-dimethyl-2-((S)-2- (methylamino propanamido^')butanoyl)pyrrolidine-2-carboxamide) dihydrochloride

The compound (50 mg, 0.04 mmol) obtained in <Step 4> was dissolved in ethylacetate (1 mL), and a 4M-HCl/dioxane solution (0.1 mL) was added thereto, followed by stirring at room temperature for 1 hour. After completion of the reaction, the mixed solution was filtered to obtain the title compound as a light yellow solid (43 mg, 96%).

1H NMR(300 MHz, DMSO-d⁶): δ 9.61(br, 4H), 8.95(br, 2H), 8.84(s, 2H), 8.62 (d, 2H), 8.50 (s, 2H), 7.25 (s, 2H), 4.95(s, 4H), 4.75-4.73(m, 2H), 4.51(d, 2H), 4.13- 4.07(m, 2H), 4.03(s, 6H), 3.75-3.71(m, 4H), 2.45(s, 6H), 2.10-1.91(m, 8H), 1.34(d, 6H), 1.01(s, 18H)

MS(ESI⁺, m/z): 1047 [M+H]⁺

Example 3: Preparation of (S,S,2S,2'S)-N,N'-(4,4'-(((lR,4R)-cyclohexane-l,4- diyIbis(methylene))bis(azandiyl))bis(7-methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3- dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidine-2- carboxamide) dihydrochloride

The procedure of Example 1 was repeated except for using cis- 1,4- cyclohexanedimethanamine instead of trans- 1,4-cyclohexanedimethanamine in <Step 4> of Example 1 to obtain the title compound (13 mg, 2.3%).

MS(ESI⁺, m/z): 1079 [M+H]⁺

Example 4: Preparation of (S,S,2S,2'S)-N,N'-(4,4'-((lS,4S)-cyclohexane-l,4- diylbis(azandiyl))bis(7-methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3-dimethyl-2-((S)- 2-(methylamino)propanamido)butanoyI)pyrroIidine-2-carboxamide)

dihydrochloride

The procedure of Example 1 was repeated except for using trans- 1,4- cyclohexanediamine instead of trans- 1 ,4-cyclohexandimethanamine in <Step 4> of Example 1 to obtain the title compound (185 mg, 10%).

1H NMR(300 MHz, DMSO-d⁶): δ 9.79(s, 2H), 9.16(s, 2H), 8.88(s, 2H), 8.82(s, 2H), 8.6 l(d, 2H), 7.34(s, 2H), 4.77(m, 2H), 4.53(d, 2H), 4.44(br, 2H), 4.09(s, 6H), 3.71(m, 4H), 2.49(s, 6H), 2.27(s, 2H), 2.17(m, 4H), 2.08-1.91(m, 8H), 1.76(m, 4H), 1.34(d, 6H), 1.15(s, 6H), 0.95(s, 18H)

MS(ESI⁺, m/z): 1051 [M+H]⁺

Example 5: Preparation of (S,S,2S,2'S)-N,N'-(4,4'-((lR,4R)-cyclohexane-l,4- diylbis(azandiyl))bis(7-methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3-dimethyl-2-((S)- 2-(methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide)

dihydrochloride

The procedure of Example 1 was repeated except for using cis- 1,4- cyclohexanediamine instead of trans- 1,4-cyclohexanedimethanamine in <Step 4> of Example 1 to obtain the title compound (185 mg, 10%).

Ή NMR(300 MHz, DMSO-d⁶): δ 15.1 l(br, 2H), 9.80(s, 2H), 9.71(br, 2H), 9.52(br, 2H), 9.04(s, 4H), 8.85(s, 2H), 8.66(s, 2H), 7.50(s, 2H), 4.78(m, 2H), 4.52(d, 2H), 4.48(br, 2H), 4.02(s, 8H), 3.76(m, 4H), 2.49(s, 6H), 2.03(s, 16H), 1.36(d, 6H), 1.00(s, 18H)

MS(ESI⁺, m/z): 1051 [M+H]⁺

Example 6: Preparation of (S,S,2S,2'S)-N,N'-(4,4'-(piperazin-l,4-diyl)bis(7- methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3-dimethyl-2-((S)-2- (methyIamino)propanamido)butanoyl)pyrrolidine-2-carboxamide)

dihydrochloride

The procedure of Example 1 was repeated except for using piperazine instead of trans- 1,4-cyclohexandimethanamine in <Step 4> of Example 1 to obtain the title compound (2.5 mg, 1.5%).

MS(ESI⁺, m/z): 1022 [M+H]⁺

Example 7: Preparation of (S,S,2S,2'S)-N,N^,-(4,4'-(((lS,4S)-cyclohexane-l,4- diylbis(methyIene))bis(azandiyl))bis(7-methoxyquinazoIin-6,4-diyl))bis(l-((S)-2- cyclohexyl-2-((S)-2-(methylamino)propanamido)aceryl)pyrrolidine-2- carboxamide) dihydrochloride

The procedure of Example 1 was repeated except for using Boc-Chg-OH instead of Boc-Tle-OH in <Step 3> of Preparation Example 2 to obtain the title compound (60 mg, 10%).

MS(ESI⁺, m/z): 1 131 [M+H]⁺

Example 8: Preparation of (S,S,2S,2'S)-N,N'-(4,4'-(((lS,4S)-cyclohexane-l,4- diylbis(methylene))bis(azandiyl))bis(7-methoxyquinazolin-6,4-diyl))bis(l-(3- methyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidine-2- carboxamide) dihydrochloride

The procedure of Example 1 was repeated except for using Boc-Val-OH instead of Boc-Tle-OH in <Step 3> of Preparation Example 2 to obtain the title compound (50 mg, 9%).

MS(ESI⁺, m/z): 1051 [M+H]⁺ Example 9: Preparation of (S,S,2S,2^,S)-N,N'-(4,4'-((l,4- phenyIenebis(methylene))bis(azandiyl))bis(7-methoxyquinazolin-6,4-diyl))bis(l- ((S)-3,3-dimethyI-2-((S)-2-(methyIamino)propanamido)butanoyl)pyrroIidine-2- carboxamide) dihydrochloride

The procedure of Example 1 was repeated except for using 1,4- phenylenedimethylamine instead of trans- 1,4-cyclohexanedimethanamine in <Step 4> of Example 1 to obtain the title compound (1.5 mg, 1.3%).

MS(ESf , mix): 1073 [M+H]⁺

Example 10: Preparation of (S,S,2S,2'S)-N,N'-(4,4'-((l,3- phenylenebis(methylene))bis(azandiyI))bis(7-methoxyquinazolin-6,4-diyl))bis(l- ((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidine-2- carboxamide) dihydrochloride

The procedure of Example 1 was repeated except for using 1,3- phenylenedimethanamine instead of trans- 1 ,4-cyclohexandimethanamine in <Step 4> of Example 1 to obtain the title compound (65 mg, 10%).

MS(ESI⁺, m/z): 1073 [M+H]⁺

Example 11: Preparation of (S,S,2S,2'S)-N,N'-(4,4'-(((lS,2S)-l,2-diphenylethane- l,2-diyl)bis(azandiyl))bis(7-methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3-dimethyl-2- ((S)-2-(methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride

The procedure of Example 1 was repeated except for using (1S,2S)-1,2- diphenylethane- 1,2 -diamine instead of trans- 1,4-cyclohexanedimethanamine in <Step 4> of Example 1 to obtain the title compound (418.8 mg, 19%).

1H NMR(300 MHz, DMSO-d⁶): δ 9.72(s, 2H), 9.34(br, 2H), 9.04(s, 2H), 8.85(m, 4H), 8.57(d, 2H), 7.43(m, 4H), 7.38(s, 2H), 7.16(m, 6H), 6.34(m, 2H), 4.72(t, 2H), 4.48(d, 2H), 3.98(s, 6H), 3.18(m, 4H), 2.26(s, 6H), 2.02(m, 10H), 1.33(d, 6H), 0.90(s, 18H) MS(ESI⁺, m/z): 1149 [M+H]⁺

Example 12: Preparation of (S,S,2S,2'S)-N,N'-(4,4'-(butan-l,4- diylbis(azandiyI))bis(7-methoxyquinazolin-6,4-diyl))bis(l-((S)-3 -dimethyl-2-((S)- 2-(ntethyIamino)propanamido)butanoyl)pyrrolidine-2-carboxamide)

dihydrochloride

The procedure of Example 1 was repeated except for using 1 ,4-diaminobutane instead of trans- 1 ,4-cyclohexanedimethanamine in <Step 4> of Example 1 to obtain the title compound (217 mg, 1.8%).

Ή NMR(300 MHz, DMSO-d⁶): δ 9.48(br. s, 2H), 9.30(br. d, 2H), 8.59(s, 2H), 8.34(s, 2H), 7.14(s, 2H), 4.73(m, 2H), 4.51(m, 4H), 3.95(s, 6H), 3.68(m, 4H), 3.52(m, 4H), 2.75(s, 3H), 2.65(s, 3H), 1.99(m, 8H), 1.67(m, 4H), 1.21(d, 6H), 0.93(s, 18H)

MS(ESI⁺, m/z): 1026 [M+H]⁺

Example 13: Preparation of (S,S,2S,2'S)-N,N'-(4,4'-(hexane-l,6- diylbis(azandiyI))bis(7-methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3-dimethyl-2-((S)- 2-(methylamino)propanamido)butanoyI)pyrrolidine-2-carboxamide)

dihydrochloride

The procedure of Example 1 was repeated except for using 1 ,6-diaminopentane instead of trans- 1 ,4-cyclohexanedimethanamine in <Step 4> of Example 1 to obtain the title compound (384 mg, 9.2%).

1H NMR(300 MHz, DMSO-d⁶): δ 8.92(s, 2H), 8.64(s, 2H), 7.23(s, 2H), 4.80(t, 2H), 4.70(m, 2H), 4.13(s, 6H), 3.98(m, 4H), 3.80(m, 6H), 2.68(s, 6H), 2.17(m, 8H), 1.84(m, 4H), 1.49(m, 10H), 1.1 l(s, 18H)

MS(ESI⁺, m/z): 1053 [M+H]⁺

Example 14: Preparation of (S,S,2S,2'S)-N,N'-(4,4'-(octan-l,8- diyIbis(azandiyl))bis(7-methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3-dimethyl-2-((S)- 2-(methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide)

dihydrochloride The procedure of Example 1 was repeated except for using 1,8-diaminooctane instead of trans- 1,4-cyclohexanedimethanamine in <Step 4> of Example 1 to obtain the title compound (384 mg, 9.2%).

Ή NMR(300 MHz, DMSO-d⁶): δ 9.98(br, 2H), 9.80(s, 2H), 8.90(br, 2H), 8.87(s, 2H), 8.80(s, 2H), 8.64(d, 2H), 7.46(m, 2H), 4.79(m, 2H), 4.52(d, 2H), 4.04(m, 8H), 3.83(m, 2H), 3.68(m, 6H), 2.71(m, 2H), 2.46(s, 6H), 1.99(m, 10H), 1.65(m, 4H), 1.17(m, 14H), 1.00(s, 18H)

MS(ESI⁺, m/z): 1081 [M+H]⁺

Example 15: Preparation of (S,S,2S,2'S)-N,N'-(4,4'-(decane-l,10- diylbis(azandiyl))bis(7-methoxyquinazoIin-6,4-diyI))bis(l-((S)-3,3-dimethyI-2-((S)- 2-(methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide)

dihydrochloride

The procedure of Example 1 was repeated except for using 1 ,10- diaminodecane instead of trans- 1,4-cyclohexanedimethanamine in <Step 4> of Example 1 to obtain the title compound (507 mg, 12%).

MS(ESI⁺, m/z): 1 109 [M+H]⁺

Example 16: Preparation of (S,S,2S,2's)-N,N'-(4,4'-(((ethane-l,2- diyIbis(oxy))bis(ethane-2,l-diyl))bis(azandiyl))bis(7-methoxyquinazolin-6,4- diyI))bis(l-((S)-3,3-dimethyl-2-((S)-2-

(methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide)

dihydrochloride

The procedure of Example 1 was repeated except for using 2,2'- (ethylenedioxy)bis(ethylamine) instead of trans- 1,4-cyclohexanedimethanamine in <Step 4> of Example 1 to obtain the title compound (729 mg, 17%).

MS(ESI⁺, m/z): 1085 [M+H]⁺

Example 17: Preparation of (S,S,2S,2'S)-N,N'-(4,4^,-([l,l'-biphenyl]-4,4'- diylbis(azandiyl))bis(7-methoxyquinazoIin-6,4-diyl))bis(l-((S)-3,3-dimethyI-2-((S)- 2-(methylamino)propanaiiiido)butanoyl)pyrroIidine-2-carboxainide)

dihydrochloride

The procedure of Example 1 was repeated except for using benzidine instead of trans- 1 ,4-cyclohexanedimethanamine in <Step 4> of Example 1 to obtain the title compound (2 mg, 1.7%).

MS(ESr\ m/z): 1121 [M+H]⁺

Example 18: Preparation of (S,S,2S,2'S)-N,N'-(4,4'-(2-butyne-l,4- diylbis(oxy))bis(7-methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3-dimethyI-2-((S)-2- (methylaraino)propanamido)butanoyI)pyrrolidine-2-carboxamide)

dihydrochloride

The procedure of <Steps 5, 6, 7> of Example 1 was repeated except for using 2-butyn-l,4-diol instead of propargyl bromide in <Step 1> of Example 2 to obtain the title compound (1 15 mg, 15%).

MS(ESI⁺, m/z): 1023 [M+H]⁺

Example 19: Preparation of (S,S,2S,2'S)-N,N'-(4,4'-(hexa-2,4-dien-l,6- diylbis(oxy))bis(4,l-phenylene))bis(azandiyl))bis(7-methoxyquinazolin-6,4- diyl))bis(l-((S)-3,3-dimethyl-2-((S)-2-

(methyIamino)propanamido)butanoyl)pyrrolidine-2-carboxamide)

dihydrochloride

<Step 1> Preparation of l-nitro-4-(proparfiyloxy)benzen

4-nitrophenol (2.78 g, 19.98 mmol) and potassium carbonate (5.52 g, 39.96 mmol) were dissolved in a solvent of acetone (60 mL), and stirred. Propargyl bromide (3.57 mg, 29.98 mmol) was added thereto and heated under reflux for 5 hours. The mixture was concentrated under pressure and filtered to obtain the title compound (1 g, 85%).

1H NMR(300 MHz, DMSO-d⁶): δ 8.24(d, 2H), 7.21(d, 2H), 4.99(d, 2H), 3.68(t,

1H) <Step 2> Preparation of 4-(propargyloxy)benzenamine

Iron (5.5 g) was diluted in an aqueous solution of 50% ethanol (60 mL), added with one drop of hydrochloric acid solution, and activated by heating to 80°C. 1- nitro-4-(propargyloxy)benzene (3.5 g, 19.76 mmol) obtained in <Step 1> was added to the activated iron, followed by reflux at 80°C for 1 hour. After completion of the reaction, the mixed solution was filtered through a Celite pad under reduced pressure, rinsed with ethanol, and the resulting filtrate was rinsed with an aqueous solution of sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered under reduced pressure, and purified by silica gel column to obtain the title compound (2.6 g, 89%).

1H NMR(300 MHz, CDC1₃): δ 6.83(d, 2H), 6.64(d, 2H), 4.16(d, 2H), 3.47(br, 2H), 2.49(d, 1H)

<Step 3> Preparation of 7-methoxy-6-nitro-N-(4-propargyloxyphenyl quinazolin-4- amine

The compound (1.3 g, 8.82 mmol) obtained in <Step 2> and 4-chloro-7- methoxy-6-nitro-quinazoline (2.1 g, 8.82 mmol) were stirred in a solution of 2- propanol (30 mL). The mixture was heated to a temperature of 80°C, and further stirred for 4 hours. The mixture was cooled to room temperature, and the resulting mixture was filtered to obtain the title compound (3 g, 97%).

1H NMR(300 MHz, DMSO-d⁶): δ 11.84(br, 1H), 9.63(d, 1H), 8.87(s, 1H), 7.66(s, 1H), 7.63(d, 2H), 7.08(d, 2H), 4.81(s, 2H), 4.07(s, 3H), 3.60-3.57(m, 1H)

<Step 4> Preparation of 7-methoxy-N4-(4-propargyloxyphenyl)quinazoline-4,6- dimaine

Iron (2.4 g) was diluted in an aqueous solution of 50% ethanol (30 mL), added with one drop of hydrochloric acid solution, and activated by heating to 80°C. The compound (3 g, 8.56 mmol) obtained in <Step 3> was added to the activated iron, followed by reflux at 80°C for 1 hour. After completion of the reaction, the mixture solution was filtered through a Celite pad under reduced pressure, rinsed with ethanol, and the resulting filtrate was rinsed with aqueous solution of sodium bicarbonate. The organic layer was dried over sodium sulfate, distilled under reduced pressure, and purified by silica gel column to obtain the title compound (2 g, 70%). Ή NMR(300 MHz, CDC1₃): δ 9.15(br, 1H), 8.26(s, 1H), 7.74(d, 2H), 7.38(s, 1H), 6.99(d, 2H), 6.97(s, 1H), 5.26(br, 2H), 4.77(d, 2H), 3.94(s, 3H), 2.49(d, 1H)

<Step 5> Preparation of tert-butyl (5νΐ-((8 ΐ- 8 2-(7-ηΐ6ΐ1ιοχν-4-Γ4- (propargyloxy)phenylamino)quinazolin-6-ylcarbamoyl pyrrolidin- 1 -yl)-3 ,3 -dimethyl- 1 -oxobutan-2-ylamino)- 1 -oxopropan-2-yl(methyl carbamate

The compound (130 mg, 0.41 mmol) obtained in <Step 4>, (S)-l-((S)-2-((S)-2- (tert-butoxycarbonyl(methyl)amino)propanamido)-3,3-dimethylbutanoyl)pyrrolidine- 2-carboxylic acid (200 mg, 0.61 mmol) obtained in Preparation Example 2, and EDCI (157 mg, 0.82 mmol) were mixed in a solution of pyridine (2 mL), and dissolved. The mixture is heated to 50°C, and further stirred for 4 hours, distilled under reduced pressure, and purified by column chromatography to obtain the title compound (150 g, 51%).

1H NMR(300 MHz, CDC1₃): δ 9.72(s, 1H), 8.87 (brs, 1H), 8.57(s, 1H), 7.68(br, 1H), 7.59(d, 2H), 7.18(s, 1H), 7.01(d, 2H), 4.90-4.88(m, 1H), 4.73-4.63(m, 4H), 4.03- 3.87(m, 4H), 3.74-3.71(m, 1H), 2.80(s, 3H), 2.55-2.53(m, 2H), 2.21-2.02(m, 3H), 1.50(s, 9H), 1.34(d, 3H), 0.98(s, 9H)

<Step 6> Preparation of di-tert-butyl (2S,2^,SVl.l ^,- 2S■2'S l.Γ-((2S,2^,S 2,2^,- 4,4^,- (4,4'-(hexa-2,4-dien- 1 ,6-diylbis(oxy))bis(4, 1 -phenylene )bis(azandiyl)bis(7- methoxyquinazolin-6,4-diyl))bis(azandiyl)bis(oxomethylene)bis(pyrrolidin-2,l- diyl bis(3 ,3 -dimethyl- 1 -oxobutan-2, 1 -diyl)bis(azandiyl)bis( 1 -oxopropan-2, 1 - diyPbismethylcarbamate

The compound (264 mg, 0.089 mmol) obtained in <Step 5>, CuCl (35 mg, 0.36 mmol), TMEDA (54 μΐ, 0.36 mmol) were dissolved in acetone (1 mL) under oxidizing atmosphere, and stirred for 12 hours. The mixture was concentrated under reduced pressure, and purified by silica gel column to obtain the title compound (60 mg, 47%).

<Step 7> Preparation of rS,S,2S,2^,S -N.N^,-(4,4^,-(hexa-2.4-dien-1.6- diylbis(oxy) bis(4J-phenylene))bis(azandivn)bis(7-methoxyquinazolin-6,4- divO bis( 1 -((SV 3 ,3 -dimethyl-2-(TS V 2-

(methylamino propanamido butanoyl)pyrrolidine-2-carboxamide) dihydrochloride The compound (60 mg, 0.041 mmol) obtained in <Step 6> was dissolved in ethyl acetate (1 mL), a mixed solution of 4 HCl/dioxane (0.1 mL) added thereto, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was filtered to obtain the title compound as a yellow solid (45 mg, 83%).

1H NMR(300 MHz, DMSO-d⁶): δ 11.28(brs, 2H), 9.83(s, 2H), 9.46(brs, 2H), 9.12(s, 2H), 8.91(brs, 2H), 8.80(brs, 2H), 8.60(d, J=8.1Hz, 2H), 7.53(d, 4H), 7.09 (d, 4H), 5.04(s, 4H), 4.81-4.73(m, 2H), 4.53-4.50(m, 2H), 4.06(s, 6H), 3.99-3.63(m, 6H), 2.46(s, 6H), 2.17-1.91(m, 8H), 1.35(d, 6H), 1.00(s, 18H)

Example 20: Preparation of (S,S,2S,2'S)-N,N'-(4,4'-(hexa-l,3-diyne-l,4- diylbis(azandiyl))bis(7-methoxyquinazolin-6,4-diyl))bis(l-((S)-3^-dimethyI-2-((S)- 2-(methylamino)propanamido)butanoyI)pyrrolidine-2-carboxamide

The procedure of Example 19 was repeated except for using propargyl amine instead of 4-(propargyloxy)benzylamine in <Step 1> of Example 19 to obtain the title compound as a beige solid (187 mg, 1.2%).

Ή NMR(300 MHz, DMSO-d⁶): δ 9.64(s, 1H), 9.52(s, 1H), 9.15(s, 1H), 9.02(s, 1H), 8.62(s, 1H), 8.41(m, 2H), 7.87(br. d, 2H), 7.46(s, 1H), 7.36(s, 1H), 7.19(s, 1H), 4.76(m, 2H), 4.53(m, 2H), 4.33(m, 2H), 4.06(m, 2H), 4.01(s, 3H), 3.97(s, 3H), 3.73(m, 4H), 3.01(d, 2H), 2.19(s, 6H), 1.97(m, 8H), 1.1 l(d, 6H), 0.98(s, 9H), 0.96(s, 9H)

MS(ESf , m/z): 1046 [M+H]⁺

Example 21: Preparation of (S,S,2S,2'S)-N,N'-(4,4'-(hexa-2,4-dien-l,6- diylbis(oxy))bis(4,l-phenylene))bis(azandiyl))bis(7-methoxyquinazolin-6,4- diyl))bis(l-((S)-2-cyclohexyI-2-((S)-2-

(methylamino)propanamido)acetyl)pyrrolidine-2-carboxamide) dihydrochloride

The procedure of Example 19 was repeated except for using Boc-Chg-OH instead of Boc-Tle-OH in <Step 3> of Preparation Example 2 to obtain the title compound (72 mg, 10%).

MS(ESI⁺, m/z): 1281 [M+H]⁺ Example 22: Preparation of (S,S,2S,2'S)-N,N'-(4,4'-(((hexa-2,4-dien-l,6- diylbis(oxy))bis(3-chloro-4,l-phenylene))bis(azandiyI))bis(7-methoxyquinazoIin-

6,4-diyl))bis(l-((S)-3,3-dimethyI-2-((S)-2-

(methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide)

dihydrochloride

<Step 1> Preparation of 2-chloro-4-nitro-l-(prop-2-yn-l-yloxy)benzene

2-chloro-4-nitrophenyl (1.0 g, 5.76 mmol) was dissolved in acetone (20 mL), and potassium carbonate (1.5 g, 1 1.52 mmol) and propargyl bromide (0.65 mL, 8.64 mmol) were added thereto, followed by stirring for 4 hours. Sodium iodide (0.17 g, 1.15 mmol) was added thereto, and the mixture was further stirred for 1 hour at room temperature. The resulting mixture was filtered, rinsed with acetone. Subsequently, the filtrate was concentrated under reduced pressure, diluted with dichloromethane, and then rinsed with water. The organic layer was dried over sodium sulfate, filtered and distilled under reduced pressure to obtain the title compound (1.2 g, 98%).

Ή NMR(300 MHz, CDC1₃): δ 8.32(s, 1H), 8.19(d, 1H), 7.19(d, 1H), 4.90(s, 2H), 2.62(s, 1H)

<Step 2> Preparation of 3-chloro-4-(prop-2-yn-l-yloxy)aniline

Iron (1.76 g, 28.35 mmol) was diluted in an aqueous solution of 50% ethanol

(50 mL), added with hydrochloric acid (0.2 mL, 2.27 mmol), and activated by heating to 1 10°C for 1 hour. The compound (1.2 g, 5.67 mmol) obtained in <Step 1> was added thereto, followed by reflux at 110°C for 1 hour. After completion of the reaction, the mixed solution was filtered through a Celite pad under reduced pressure, rinsed with ethanol and the resulting filtrate was rinsed with a mixture of chloroform and isopropylalcohol (4:1 (v/v)), and the resulting filtrate was rinsed with an aqueous solution of sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and distilled under reduced pressure, purified by silica gel column using a mixed solution of ethylacetate and hexane (1 :2 (v/v)), to obtain the title compound (0.92 g, 89%).

Ή NMR(300 MHz, CDC1₃): δ 6.96(d, 1H), 6.74(s, 1H), 6.54(d, 1H), 4.67(s, 2H), 3.51(br, 2H), 2.5 l(m, 1H) <Step 3> Preparation of fS.S.2S.2'SVN.N^,-(4,4^,-((fhexa-2,4-dien-1.6- diylbis(oxy )bis(3-chloro-4,l-phenylene))bis(azandM^

divmbisri-((SV3.3-dimethyl-2-((^,SV2-

(methylarnino)propanamido)butanoyl^')pyrrolidine-2-carboxamide^') dihydrochloride

The procedure of Example 19 was repeated except for using 3-chloro-4-(prop- 2-yn-lyloxy)aniline obtained in <Step 2> of Example 22 instead of 4- (propargyloxy)benzenamine in <Step 1> of Example 19 to obtain the title compound (138 mg, 1.2 %)

Ή NMRQOO MHz, DMSO-d⁶): δ 1 1.19(br, 2H), 9.83(s, 2H), 9.21(br, 2H), 9.08(s, 2H), 8.81(s, 2H), 8.59(d, 2H), 7.79(s, 2H), 7.59(d, 2H), 7.39(s, 2H), 7.32 (d, 2H), 5.17(s, 4H), 4.80(m, 2H), 4.53(d, 2H), 4.07(s, 6H), 3.96(m, 2H), 3.77(m, 4H), 3.57(s, 6H), 2.03(m, 8H), 1.34(d, 6H), 1.00(s, 18H)

Example 23: Preparation of (S,S,2S,2'S)-N,N'-(4,4'-((6,6'-(hexa-2,4-dien-l,6- diylbis(oxy))bis(pyridin-6,3-diyl))bis(azandiyl))bis(7-methoxyquinazolin-6,4- diyl))bis(l-((S)-3,3-dimethyl-2-((S)-2-

(methylamino)propanamido)butanoyI)pyrroIidine-2-carboxamide)

dihydrochloride

<Step 1> Preparation of 5-nitro-2-(prop-2-yn-l-yloxy)pyridine

5-nitropyridin-2-ol (5.0 g, 0.0357 mol) was dissolved in acetone (120 mL), and potassium carbonate (9.87 g, 0.0714 mol) and propargyl bromide (4.04 mL, 0.0536 mol) were added thereto, followed by stirring for 2 hours at room temperature. The resulting mixture was filtered, rinsed with acetone. Subsequently, the filtrate was concentrated under reduced pressure, diluted with MC, and then rinsed with water. The organic layer was dried over sodium sulfate, concentrated under reduced pressure to obtain the title compound (6.2 g, 97%).

Ή NMR(300 MHz, CDC1₃): δ 9.04(d, 1H), 8.14(d, 1H), 6.60(d, 1H), 4.81(d,

2H), 2.73(t, 1H)

<Step 2> Preparation of 6-(prop-2-yn-l-yloxy)pyridin-3-amine

Iron (10.8 g, 0.174 mol) was diluted with in an aqueous solution of 50% ethanol (100 mL), added with hydrochloric acid (2.9 mL, 0.0348 mol), and activated by heating to 1 10°C for 1 hour. The compound (6.2 g, 0.0348 mol) obtained in <Step 1> was added thereto, followed by reflux at 1 10°C for 2 hours. After completion of the reaction, the mixed solution was filtered through a Celite pad under reduced pressure, rinsed with ethanol and the mixed solution was diluted with a mixture of chloroform and isopropylalcohol (4:1 (v/v)), rinsed with an aqueous solution of sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and distilled under reduced pressure, purified by silica gel column using a mixed solution of MC and MeOH (19: 1 (v/v)), to obtain the title compound (3.75 g, 73%).

1H NMR(300 MHz, MeOD): δ 7.27(d, 1H), 7.20(s, 1H), 6.47(d, 1H), 4.73(s, 2H), 2.87(t, 1H)

<Step 3> Preparation of (S.S.2S.2^,SVN,N^,-(4.4^,-r(6,6^,-(hexa-2,4-dien-1.6- diylbis(oxy) bis(pyridin-6,3-diyl))bis(azandiyl) bis(7-methoxyquinazolin-6,4- divmbisf 1 -((SV 3 ,3-dimethyl-2-((S V 2- (methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride

The procedure of Example 19 was repeated except for using 6-(prop-2-yn-l- yloxy)pyridin-3 -amine obtained in above <Step 2> of Example 23 instead of 4- (propargyloxy)benzenamine in <Step 1> of Example 19, and adding pyridine hydrochloride therein to obtain the title compound (48 mg, 1%).

1H NMR(300 MHz, DMSO-d⁶): δ 1 1.13(br, 2H), 9.86(s, 2H), 9.23(br, 2H),

9.06(s, 2H), 8.86(s, 2H), 8.58(d, 2H), 8.03(s, 2H), 7.70(d, 2H), 7.44(s, 2H), 6.55(d, 2H), 4.94(s, 4H), 4.81(m, 2H), 4.53(d, 2H), 4.07(s, 6H), 3.98(m, 2H), 3.76(m, 4H), 2.09(m, 8H), 1.34(d, 6H), 1.24(s, 6H), 1.00(s, 18H) The compounds obtained in Examples 1 to 23 are represented by the following structural formula, as shown in Table 1 below. <Table 1>

amino)propanamido)butanoyl)pyrrolidine-2-carboxamide) (S,S,2S,2'S)-N,N'-(4,4'-(hexa-2,4-dien-l,6-diylbis(oxy))bis(4,l- phenylene))bis(azandiyl))bis(7-methoxyquinazolin-6,4-diyl))bis(l-

21 ((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)

pyrrolidine-2-carboxamide) dihydrochloride

(S,S,2S,2'S)-N,N'-(4,4^,-(((hexa-2,4-dien-l,6-diylbis(oxy))bis(3- chloro-4,l-phenylene))bis(azandiyl))bis(7-methoxyquinazolin-6,4-

22

diyI))bis(l-((S)-3_rJ-dimethyl-2-((S)-2-(mcthylamino)propanamido) tow. butanoyl)pyrrolidine-2-carboxamide) dihydrochloride

(S.S^S^'S^N.N'^^'-We.e'-ihe aJ^-dien-l.e-diylbisioxyWbis

(pyridin-6,3-diyl))bis(azandiyl))bis(7-methoxyquinazolin-6,4-

23

diyl))bis(l-((S)-3,3-dimethyl-2^(S)-2-(methylamiiio)propanamido)

butanoyl)pyrrolidine-2-carboxamide) dihydrochloride

The compounds prepared in Examples were tested for biological assays as follows.

Experimental Example 1: Evaluation of inhibition on cell growth (in-vitro)

MDA-MB-231 breast cancer cell lines (ATCC # HTB-26) and BxPC-3 pancreas cancer cell lines (ATCC #CRL 1687), which have been reported to express XIAP, were obtained from ATCC (American type culture collection; Rockville, MD). MDA-MB-231 cell lines were incubated in L-15 medium supplemented with 10% FBS and 1% penicillin/streptomycin (Gibco BRL) at a T-75cm² growth flask. For experiments of toxicity to normal cells, fibroblasts Hs27 (ATCC #CRL 1634) and Balb/c3t3 (ATCC #CCL 163) were used. The various cell lines were transferred into 96-well plates at a density of 3,000-5,000 cells/100 μΐ, and cultured for 24 hours under conditions of 37°C, 5% C0₂, 95% air, and 100% relative humidity (MDA-MB-231 cells were cultured under atmospheric conditions). The cells were treated with 10 μ1~0.1 nM of test compounds, and MDA-MB-231 and normal cell lines were cultured for 120 and 72 hours, respectively. Cell viabilities of MDA-MB-231 cell lines were measured at an absorbance of 490 nm using using CellTiter 96TM Aqueous One Solution Cell proliferation Assay (MTS, Promega), and normal cell lines were measured by fixing cells with 10% TCA (trichloroacetic acid), staining with SRB (sulforhodamine B), and measuring at 540 nm. From the values, GI₅₀ values in which test compounds reduce the growth of cancer cells by 50% were calculated. The growth rates of cancer cells were calculated from following Equation 1 or 2.

[Equation 1]

[(Ti-Tx)/(C-Tz)] x 100 (for Ti>=Tz)

[Equation 2]

[(Ti-Tz/Tz) x 100 (for Ti<Tz)

In Equations 1 and 2, Tz refers to a density of untreated cells, which is an absorbance in 0% cell growth groups. C refers to a density of cells cultured by adding only medium, and Ti refers to a density of cells treated with test compounds.

GI₅₀ value is the concentration of a test compound when the value of Equation 1 is 50, which indicates the concentration test compound required to inhibit the cancer cells by 50%. On each measurement, test compounds were compared with a control.

The activity value of each compound (GIs₀ value) was shown in Table 2, and AEG-40730 (Human Genome Sciences) was used as a control.

As shown in Table 2, the compounds of the present invention inhibited more significantly the growth of MDA-MB-231 cell lines in which IAPs are overexpressed, even at a low concentration.

In contrast, the compounds of the present invention did not inhibit the growth of mouse normal cell line Balb/C and human normal cell line Hs27, even at a high concentration, which indicates that the compounds of the present invention has a high selectivity to the cell lines in which IAPs are overexpressed.

As evidenced above, the inventive compounds selectively act on IAPs to show no adverse side effects on normal cells and to allow normal apoptotic mechanism in tumor and abnormal cells. Thus, these compounds may be used in the prevention or treatment of cancers, inflammatory diseases, autoimmune diseases, and neurodegenerative disorders, alone or in combination, while exerting no adverse effects.

Claims

What is claimed is:

1. A compound selected from the group consisting of a quinazoline derivative of formula (I), a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof, and a solvate thereof:

wherein,

R and R are each independently hydrogen, methyl, or ethyl;

R is hydrogen, C_1-8alkyl, C_3-8cycloalkyl, C2-salkenyl, C^alkynyl, C_3-

8cycloalkyl-C_1-3alkyl, C_3-8heterocycloalkyl, C3.gheterocycloalkyl-Ci_-3alkyl, C _-10aryl, C_6-ioaryl-C_1-3alkyl, C_5-10heteroaryl, or Cs.[oheteroaryl-C_1-3alkyl, wherein said R³ is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, thiol, amino, C_1-3alkoxy, Ci_-3alkylthio, mono(C_1- ₃alkyl)amino, di(C_1-3alkyl)amino, C_1-3acyl, C_1-3alkylsulfonyl, Ci_-3alkoxycarbonyl, mono(C_1-3alkyl)aminocarboxy, di(Ci_-3alkyl)aminocarboxy, Ci_-3acyloyl and C_1-3alkyl;

R⁴ is hydrogen, Ci_-6alkyl, C_2-6 alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthio, C_3-8cycloalkyl,

or Cs_-10heteroaryl, wherein said R⁴ is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, thiol, amino, Cj_-3alkoxy, C_1-3alkylthio, mono(C_1-3alkyl)amino, di(Ci- ₃alkyl)amino, C_1-3acyl, Ci_-3alkylsulfonyl, C_1-3alkoxycarbonyl, mono(Ci. ₃alkyl)aminocarboxy, di(Ci_-3alkyl)aminocarboxy, Ci_-3acyloyl and Ci.₃alkyl;

R⁵ is hydrogen, halogen, cyano, nitro, hydroxy, C_1-3alkoxy, thiol, amino, carboxy, formyl, C_1-6alkyl, C_3-8cycloalkyl, or C_3-8heterocycloalkyl;

Y is NH, NHCH₂, O or S;

Z is a substituent selected from the group consisting of:

wherein V is NH, NHCH₂ or O; W is C_1-8alkylene or C_2-8alkynylene; and Z' is N or CH;

R⁶ and R⁷ are each independently hydrogen, methyl or phenyl, wherein said phenyl is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, thiol, amino, C_1-3alkoxy, Ci_-3alkylthio, mono(Ci- 3alkyl)amino, di(C_1-3alkyl)amino, C[_-3acyl, Ci_-3alkylsulfonyl, Ci_-3alkoxycarbonyl, mono(Ci_-3alkyl)aminocarboxy, di(C_1-3alkyl)aminocarboxy, Ci_-3acyloyl and Q^alkyl;

R is hydrogen, halogen, cyano, nitro, hydroxy, thiol, amino, carboxy, formyl, Ci_-3alkyl, Ci_-3alkoxy, C_1-3alkylthio, mono(Ci_-3alkyl)amino, di(C_1-3alkyl)amino, Ci. ₃acyl, C_2-3alkenyl, C_2-3alkynyl, Ci_-3alkylsulfonyl, C_1-3alkoxycarbonyl, mono(Ci. ₃alkyl)aminocarboxy, di(C_1-3alkyl)aminocarboxy, C_1-3acyloyl, or Ci_-3acylamino;

m is an integer ranging from 2 to 12;

n is an integer ranging from 1 to 3;

o is an integer ranging from 0 to 6;

p is an integer ranging from 0 to 2;

q is an integer ranging from 0 to 5; and

r is an integer ranging from 0 to 3.

2. The compound of claim 1, wherein R¹ is methyl.

3. The compound of claim 1, wherein R² is methyl.

4. The compound of claim 1 , wherein R³ is isopropy, t-butyl, or cyclohexyl.

5. The compound of claim 1, wherein R⁴ is hydrogen, C_1-6alkyl, C_1-6alkoxy, C3_-8cycloalkyl, C -i₀aryl, or Cs-^heteroaryl, wherein said R⁴ is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, thiol, amino, Ci_-3alkoxy, Ci-₃alkylthio, mono(C_1-3alkyl)amino, di(Ci. ₃alkyl)amino, Ci_-3acyl, C_1-3alkylsulfonyl, Ci_-3alkoxycarbonyl, mono(Ci. ₃alkyl)aminocarboxy, di(Ci_-3alkyl)aminocarboxy, C_1-3acyloyl and C_1-3alkyl.

6. The compound of claim 1, wherein R⁵ is methoxy.

7. The compound of claim 1 , wherein Y is NH, NHCH₂ or O.

8. The compound of claim 1 , wherein Z is selected from the group consisting of:

9. The compound of claim 1, wherein R is hydrogen, halogen, cyano, nitro, hydroxy, amino, carboxy, formyl, C_1-3alkyl, Ci_-3alkoxy, Ci_-3alkylthio, mono(Ci ₃alkyl)amino,

or C[.₃acyl.

10. The compound of claim 1, which is selected from the group consisting of:

1) (S,S,2S,2'S)-N,N'-(4,4'-(((lS,4S)-cyclohexane-l,4- diylbis(methylene))bis(azandiyl))bis(7-methoxyquinazolin-6,4-diyl))bis(l-((S)-2- (methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride;

2) (S,S,2S,2'S)-N,N'-(4,4'-(hexa-2,4-dien-l ,6-diylbis(oxy))bis(7- methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3-dimethyl-2-((S)-2- (methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride;

3) (S,S,2S,2' S)-N,N' -(4,4' -((( 1 R,4R)-cyclohexane- 1 ,4- diylbis(methylene))bis(azandiyl))bis(7-methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3- dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride;

4) (S,S,2S,2'S)-N,N'-(4,4'-((lS,4S)-cyclohexane-l,4-diylbis(azandiyl))bis(7- methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3-dimethyl-2-((S)-2- (methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride;

5) (S,S,2S,2'S)-N,N'-(4,4'-((lR,4R)-cyclohexane-l,4-diylbis(azandiyl))bis(7- methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3-dimethyl-2-((S)-2- (methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride;

6) (S,S,2S,2'S)-N,N'-(4,4'-(piperazin-l,4-diyl)bis(7-methoxyquinazolin-6,4- diyl))bis(l-((S)-3,3-dimethyl-2-((S)-2-

(methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride;

8) (S,S,2S,2'S)-N,N'-(4,4^,-(((lS,4S)-cyclohexane-l,4- diylbis(methylene))bis(azandiyl))bis(7-methoxyquinazolin-6,4-diyl))bis( 1 -(3 -methyl- 2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide)

dihydrochloride;

9) (S,S,2S,2'S)-N,N'-(4,4^,-((l,4-phenylenebis(methylene))bis(azandiyl))bis(7- methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3-dimethyl-2-((S)-2- (methylamino)propanamido)butanoyl)pyrrolidine-2-carboxaniide) dihydrochloride;

10) (S,S,2S,2'S)-N,N'-(4,4'-((l,3 phenylenebis(methylene))bis(azandiyl))bis(7-methoxyquinazolin-6,4-diyl))bis(l-((S)- 3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidine-2- carboxamide) dihydrochloride;

11) (S,S,2S,2'S)-N,N'-(4,4'-(((l S,2S)-l ,2-diphenylethane-l,2- diyl)bis(azandiyl))bis(7-methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3-dimethyl-2-((S)-2- (methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride;

12) (S,S,2S,2'S)-N,N'-(4,4'-(butan-l,4-diylbis(azandiyl))bis(7- methoxyquinazolin-6,4-diyl))bis( 1 -((S)-3 ,3 -dimethyl-2-((S)-2- (methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride;

14) (S,S,2S,2'S)-N,N'-(4,4'-(octane-l,8-diylbis(azandiyl))bis(7- methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3-dimethyl-2-((S)-2- (methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride;

15) (S,S,2S,2 ' S)-N,N'-(4,4'-(decane- 1 , 10-diylbis(azandiyl))bis(7- methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3-dimethyl-2-((S)-2- (methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride;

16) (S,S,2S,2'S)-N,N^,-(4,4'-(((ethane-l,2-diylbis(oxy))bis(ethane-2,l- diyl))bis(azandiyl))bis(7-methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3-dimethyl-2-((S)- 2-(methylaraino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride;

17) (S,S,2S,2'S)-N,N'-(4,4'-([l,l '-biphenyl]-4,4'-diylbis(azandiyl))bis(7- methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3-dimethyl-2-((S)-2- (methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride;

19) (S,S,2S,2'S)-N,N'-(4,4'-(hexa-2,4-dien-l,6-diylbis(oxy))bis(4,l- phenylene))bis(azandiyl))bis(7-methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3-dimethyl- 2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide)

dihydrochloride; 20) (S,S,2S,2'S)-N,N'-(4,4'-(hexa-l,3-diyne-l,4-diylbis(azandiyl))bis(7- methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3-dimethyl-2-((S)-2- (methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide;

21) (S,S,2S,2'S)-N,N'-(4,4'-(hexa-2,4-dien-l,6-diylbis(oxy))bis(4,l- phenylene))bis(azandiyl))bis(7-methoxyquinazolin-6,4-diyl))bis(l-((S)-2-cyclohexyl- 2-((S)-2-(methylamino)propanamido)acetyl)pyrrolidine-2-carboxamide)

dihydrochloride;

22) (S,S,2S,2'S)-N,N'-(4,4'-(((hexa-2,4-dien-l,6-diylbis(oxy))bis(3-chloro- 4,l-phenylene))bis(azandiyl))bis(7-methoxyquinazolin-6,4-diyl))bis(l -((S)-3,3- dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) dihydrochloride; and

23) (S,S,2S,2'S)-N,N'-(4,4'-((6,6'-(hexa-2,4-dien-l,6-diylbis(oxy))bis(pyridin- 6,3-diyl))bis(azandiyl))bis(7-methoxyquinazolin-6,4-diyl))bis(l-((S)-3,3-dimethyl-2- ((S)-2-(methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide)

dihydrochloride.

11. A use of the compound of claim 1 for the manufacture of a medicament for preventing or treating cancers, inflammatory diseases, autoimmune diseases, or neurodegenerative disorders.

12. A pharmaceutical composition for preventing or treating cancers, inflammatory diseases, autoimmune diseases, or neurodegenerative disorders, which comprises the compound of claim 1 as an active ingredient.

13. A method for preventing or treating cancers, inflammatory diseases, autoimmune diseases, or. neurodegenerative disorders, which comprises administering the compound of claim 1 to a mammal in need thereof.