KR101473453B1 - New compounds, the preparation thereof and pharmaceutical composition comprising the same - Google Patents

Abstract

The present invention relates to a hydroquinazoline derivative useful as an antagonist of T-type calcium channel for the treatment and prevention of disorders and diseases related to the function of T-type calcium channel. The present invention also encompasses compositions comprising such compound derivatives that are pharmaceutically acceptable and the use of such compounds.

Description

TECHNICAL FIELD The present invention relates to a novel compound, a process for producing the same, and a pharmaceutical composition comprising the compound.

The present invention relates to novel compounds, processes for their preparation and pharmaceutical compositions containing them.

Even though cancer research has been conducted for more than 30 years, the cancer incidence continues to increase worldwide due to changes in living conditions such as an increase in life expectancy, environmental pollution caused by industrialization, and erroneous eating habits. The World Health Organization (WHO) is one of the leading causes of death, and cancer is the leading cause of death in Korea, according to the Ministry of Health and Welfare It is known that about 100,000 cancer patients develop. Cancer is a middle-aged disease. It is inevitable that more than 70% of new clinical cases will be diagnosed at age 60 or older, and the incidence of cancer will increase as the world population ages.

Cancer is caused by the abnormal growth of cells, and cancer can be treated by inhibiting or killing cell growth. However, the conventional anticancer drugs have different treatment effects depending on the cancer organs, and the generation and action mechanisms of cancer are so varied that the therapeutic effect of various types of cancer can not be guaranteed.

Therefore, it is inevitable to develop a therapeutic agent capable of preventing or treating cancer more effectively by inhibiting the growth of cancer cells.

KR10-2008-0099108 KR10-2005-0003080 KR10-2005-0084739 KR10-0784195

It is an object of the present invention to provide a novel compound showing a calcium channel blocking effect and an anticancer effect, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

It is another object of the present invention to provide a process for preparing the novel compounds, their pharmaceutically acceptable salts or their hydrates or solvates.

It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating cancer, which comprises a novel compound, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient.

Still another object of the present invention is to provide a composition exhibiting a calcium channel blocking effect comprising the novel compound, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient.

It is still another object of the present invention to provide a method for treating cancer by administering the novel compound, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof to a subject.

It is still another object of the present invention to provide a method for blocking calcium channel by administering the novel compound, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof to a subject.

The present invention provides a compound represented by the following general formula (I), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof:

In the above formula (I)

X is -NR1R2 or a saturated or unsaturated five-, six- or seven-membered heterocycloamino group containing one to three heteroatoms selected from -N- and -O-,

R1 and R2 are independently -H; C1-C8 linear or branched alkyl; C2-C10 straight or branched chain carbamoyl alkyl, substituted or unsubstituted with C1-C6 straight or branched chain alkyl; A C2-C10 straight or branched chain carbamoyl amino alkyl substituted or unsubstituted with C1-C6 straight chain or branched alkyl; C2-C10 straight or branched chain amino alkyl substituted or unsubstituted with C1-C6 straight chain or branched alkyl; C2-C10 straight or branched chain piperidinyl ethyl, substituted or unsubstituted with C1-C6 straight chain or branched alkyl; Benzyl substituted or unsubstituted with C1-C6 straight chain or branched alkylamino; C5-C20 straight or branched chain piperazinyl oxo alkyl which is unsubstituted or substituted by C1-C6 straight-chain or branched alkyl,

The heterocyclic amino group may be unsubstituted or substituted by C1-C6 straight or branched alkyl; A straight chain or branched alkoxy of C1-C6; C1-C10 straight or branched chain aminoalkyl; Acetyl; Pyridyl, unsubstituted or substituted by C1-C6 straight or branched chain alkyl; Pyrimidyl substituted or unsubstituted with C1-C6 straight or branched chain alkyl; Piperazinyl substituted or unsubstituted with C1-C6 straight chain or branched alkyl; Morpholinyl substituted or unsubstituted with C1-C6 alkyl; Piperidinyl substituted or unsubstituted with C1-C6 straight chain or branched alkyl; C2-C10 straight or branched chain alkoxycarbonylamino; Or straight-chain or branched alkoxycarbonylamino of C2-C10,

Y is -NR3R4 or -OR5,

Wherein in the -NR3R4, R3 and R4 are independently -H; C1-C6 straight or branched chain alkoxy; C1-C6 straight or branched chain dialkylamino; C1-C6 straight or branched chain alkyl; A C 6 -C 10 pyridylalkyl unsubstituted or substituted with a C 1 -C 6 straight or branched chain alkyl; Substituted with straight or branched chain alkyl, C 1 -C 6 straight or branched chain alkoxy or C 1 -C 6 straight or branched chain alkyl, -F, -CF ₃ , -Cl, -Br, -I, Benzyl substituted or unsubstituted amino; Or C3-C10 cycloalkyl which is unsubstituted or substituted by C1-C6 straight-chain or branched alkyl,

Wherein -NR3R4 is a morpholinyl formed by connecting R3 and R4 together, wherein the morpholinyl is unsubstituted or substituted by C1-C6 straight or branched chain alkyl; Or C1-C6 straight chain or branched alkoxy,

Wherein R < 5 > is -H or C1-C6 straight chain or branched chain alkyl

R6 and R7 are independently -H; -F; -CF _3; -Cl; -Br; -I; Phenyl; C1-C6 straight or branched chain dialkylamino; A saturated or unsaturated 5-membered, 6-or 7-membered cycloalkyl optionally substituted by C1-C6 alkyl; Or a saturated or unsaturated five-, six- or seven-membered heterocyclic amino group containing one to three heteroatoms selected from N, O and S, wherein the phenyl or heterocyclic amino group is independently unsubstituted or substituted or _{-F, -CF 3, -Cl, -Br} , -I, and is substituted by alkoxy, alkyl, or a straight or branched-chain C1-C6 straight or branched chain C1-C6, or

R6 and R7 are connected to form a 6-membered heteroaryl comprising 1 to 3 N; Or wherein R6 and R7 form a cycloalkyl or aryl group of saturated or unsaturated 5 at connection 6 at or 7 atoms, the heteroaryl, cycloalkyl or aryl is unsubstituted or independently -F, -CF ₃ , -Cl, -Br, -I, C1-C6 straight chain or branched alkoxy, or C1-C6 straight chain or branched chain alkyl,

Wherein Z is _{-H, -F, -CF 3, -Cl} , -Br, -I, nitro, C1-C6 straight or branched alkyl, C1-C6 straight or branched chain alkyl amines, C1-C6 Substituted or unsubstituted amide, substituted or unsubstituted sulfonamide, straight or branched alkoxy of C1-C6, substituted or unsubstituted C3-C10 cycloalkyl, or substituted or unsubstituted C3 C10 cycloalkoxy,

When R6 is -H, then R7 is not -H

R7 is unsubstituted phenyl and X is -NR1R2, then R1 and R2 are not C2-C10 straight or branched chain amino alkyl unsubstituted or substituted with methyl or C1-C6 straight chain or branched alkyl; Or R < 7 > is unsubstituted phenyl, then X is not an unsubstituted piperidin-1-yl.

The compound represented by the above formula (I), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof of the present invention can inhibit the flow of calcium through the calcium channel and inhibit the growth of various kinds of cancer cells can do. Accordingly, the compound represented by the formula (I) of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof can be used as a calcium channel blocker and an anticancer agent.

In addition, the compound represented by the formula (I) of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is scarcely toxic. The compound represented by the above formula (I), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof of the present invention did not show any cytotoxicity even at a concentration of 100 μM when administered to cells.

In the above formula (I) of the present invention, X may be -NR < 1 > R < 2 >. When X is -NR1R2, R1 and R2 are independently -H; C1-C6 straight or branched chain alkyl; Straight or branched chain N, N-dialkylaminoalkyl of C2-C10; Piperidin-1-ylethyl; Benzyl substituted by straight or branched chain dialkylamino of C1-C6; - (CH ₂ ) n C (= O) -Ral; Or _{- (CH 2) m-NH} -C (= O) -Rb1 , wherein Ra1 and Rb1 are independently selected from 4-methyl-piperazin-1-yl, dimethylamino or alkoxy straight chain or branched chain C1-C6 And n and m are independently an integer of 1 to 6, and R 1 and R 2 may not be simultaneously -H.

Preferably, R 1 and R 2 are independently -H; methyl; ethyl; N, N-dimethylaminobenzyl; Dimethylaminoethyl; Dimethylaminopropyl; Dimethylaminobutyl; Dimethylaminopentyl; Dimethylaminohexyl; N-methylpiperazin-1-yl-4-oxobutyl; N-methylpiperazin-1-yl-3-oxopropyl; N-methylpiperazin-1-yl-5-oxopentyl; N, N-dimethylcarbamoylbutyl; N, N-dimethylcarbamoylpentyl; N, N-dimethylcarbamoylpropyl; (N, N-dimethylcarbamoyl) aminoethyl; (N, N-dimethylcarbamoyl) aminopropyl; (N, N-dimethylcarbamoyl) aminobutyl; Or (N, N-dimethylcarbamoyl) aminopentyl, and R 1 and R 2 may not be -H at the same time.

In the formula (I) of the present invention, X may be a heterocyclic amino group, preferably piperidin-1-yl; Piperidin-4-yl; Or piperazin-1-yl. The heterocyclic amino group piperadin-1-yl, piperidin-4-yl or piperazin-1-yl, which is unsubstituted or substituted by C1-C6 straight or branched chain alkyl; Acetyl; N, N-dialkylaminoalkyl of C3-C10; Pyridyl; Pyrimidyl; N-methylpiperidinyl; Piperidinyl; Piperazinyl; C2-C10 straight or branched chain piperidin-1-ylalkyl; - (CH ₂ ) n C (= O) -Ral; Or _{- (CH 2) p-NH} -C (= O) -Rb2 , wherein Ra2 and Rb2 are independently selected from 4-methyl-piperazin-1-yl, dimethylamino or alkoxy straight chain or branched chain C1-C6 And p and q may independently be an integer of 1 to 6.

When X is a heterocyclic amino group, X is preferably methyl; N, N-dimethylaminomethyl; N, N-dimethylaminoethyl; N, N-dimethylaminopropyl; N, N-dimethylaminobutyl; N, N-dimethylaminopentyl; methyl; ethyl; Pyridin-4-yl; N-methylpiperazin-1-yl; N-methylpiperidin-4-yl; Piperidin-1-yl; Acetyl; Tert-butoxycarbamoylamino; Ethoxycarbamoylamino; Methoxycarbamoylamino; Tertbutoxycarbonylamino; Ethoxycarbonylamino; Or methoxycarbonylamino. ≪ / RTI >

In Formula I of the present invention, Y may be -NR < 3 > R < 4 >. When Y is -NR < 3 > R < 4 >, the R3 and R4 are independently H; C1-C6 alkyl; Unsubstituted or substituted with _{-F, -CF 3, -Cl, -Br} , -I of, C1-C6 straight or branched alkyl, C1-C6 straight or branched C1-C6 alkoxy or a chain of the chain dialkylamino Benzyl; Pyridin-2-ylalkyl of C6-C10; Pyridin-4-yl-alkyl of C6-C10; C3-C6 cycloalkyl; Or R3 and R4 may be connected to form morpholin-4-yl.

Preferably R3 and R4 are independently H; benzyl; Benzyl substituted with _{-F, -CF 3, -Cl, -Br} , -I, methyl, methoxy or dimethylamino; Pyridin-2-ylmethyl; Pyridin-4-ylmethyl; Cyclopropyl; methyl; ethyl; Or R 3 and R 4 may be linked morpholin-4-yl, and R 3 and R 4 may not be simultaneously -H.

In the above formula (I) of the present invention, R6 and R7 are independently -H; C1 to C6 alkyl; -F; -CF _3; -Cl; -Br; -I; Dialkylamino of C1-C6; Cyclohexyl; Phenyl; Pyrrolidinyl-1-yl; Pyridyl-4-yl; Pyrrolidin-1-yl, pyridin-2-yl or morpholin-4-yl is unsubstituted or substituted by or -F, -CF _3, may be substituted with alkyl of -Cl, -Br, -I, alkoxy, or linear or branched C1-C6 straight or branched chain of C1-C6. Preferably, R6 and R7 are -H; -F; -CF _3; -Cl; -Br; -I; Dimethylamino; Phenyl, pyrrolidin-1-yl; Morpholin-4-yl; Or pyridin-2 may be in the phenyl, pyrrolidin-1-yl, morpholine-4-yl or 2-day unsubstituted or substituted by _{-F, -CF 3, -Cl, -Br} , - I, methoxy, methyl or ethyl.

In the above formula (I) of the present invention, R < 6 > and R < 7 >Pyridine; Or may form a cyclohexane, a benzene, pyridine or cyclohexane is unsubstituted or substituted by -F, -CF _3, -Cl, alkoxy of -Br, -I, straight-chain or branched-chain C1-C6, or C1 -C6 straight or branched chain alkyl.

In the formula (I) of the present invention Z is _{-H, -F, -CF 3, -Cl} , -Br, -I, nitro, C1-C6 straight or branched chain alkyl, straight or branched-chain C1-C6 Amine, or a substituted or unsubstituted C3-C10 cycloalkoxy.

The compound represented by the above formula (I) of the present invention may be a compound represented by the following formula (I-1):

R1A and R2A are independently -H; C1 to C6 alkyl; Piperidin-1-ethyl; N, N-dialkylaminoalkyl of C3-C10; Benzyl substituted by straight or branched chain dialkylamino of C1-C6; - (CH ₂ ) n C (= O) -Ral; Or _{- (CH 2) m-NH} -C (= O) -Rb1 , wherein Ra1 and Rb1 are independently selected from 4-methyl-piperazin-1-yl, dimethylamino or alkoxy straight chain or branched chain C1-C6 And n and m are independently an integer of 1 to 6,

R3A and R4A are independently -H; C1 to C6 alkyl; Unsubstituted or substituted with _{-F, -CF 3, -Cl, -Br} , -I of, C1-C6 straight or branched alkyl, C1-C6 straight or branched C1-C6 alkoxy or a chain of the chain dialkylamino Benzyl; Pyridin-2-ylalkyl of C6-C10; Pyridin-4-ylalkyl of C6-C10; C3-C6 cycloalkyl; Or R3A and R4A are linked morpholin-4-yl,

R6A and R7A are independently selected from the group consisting of -H; C1 to C6 alkyl; -F; -CF _3; -Cl; -Br; -I; Dialkylamino of C1-C6; Cyclohexyl; Pyridin-2-yl; Pyridin-4-yl; Pyrrolidin-1-yl; Or a phenyl, wherein cyclohexyl, phenyl, pyridin-4-yl, pyridin-2-yl or pyrrolidin-1-day independently unsubstituted or substituted by _{-F, -CF 3, -Cl, -Br} , -I , Straight or branched chain C1-C6 alkoxy, or C1-C6 straight chain or branched alkyl.

Z is as defined in the above formula (I).

The compound represented by the above formula (I) of the present invention may be a compound represented by the following formula (I-2):

In the formula (I-2)

X1 is C, N or O,

R1B is C1-C6 straight or branched chain alkyl; Acetyl; N, N-dialkylaminoalkyl of C3-C10; Pyridin-4-yl; Pyridin-2-yl; N-methyl-piperidin-1-yl; Piperidin-1-yl; N-methyl-piperazin-1-yl,

R3B and R4B are-H; C1 to C6 alkyl; Beach unsubstituted or _{-F, -CF 3, -Cl, -Br} , -I, alkoxy, or dialkylamino of C1-C6 straight or branched chain alkyl, C1-C6 straight or branched chain C1-C6 Substituted benzyl; Pyridin-2-ylalkyl of C6-C10; Pyridin-4-ylalkyl of C6-C10; C3-C6 cycloalkyl; Or morpholin-4-yl formed by linking R3B and R4B,

R6B and R7B are-H; C1 to C6 alkyl; -F; -CF _3; -Cl; -Br; -I; Phenyl; Pyridin-2-yl; Pyridin-4-yl; Dialkylamino of C1-C6; Pyrrolidin-1-yl; Morpholin-4-yl; And R < 7B > And R < 7B > is a 6-membered heteroaryl comprising 1 to 3 N linked together; Or R6B and R7B are linked 5-atom or 6-membered cycloalkyl, wherein said phenyl, pyridin-4-yl, pyridin- 2- yl, pyrrolidin- aryl, heteroaryl and cycloalkyl are independently unsubstituted or substituted by -F, -CF of _3, -Cl, -Br, -I, alkoxy, or C1-C6 straight or branched chain of C1-C6 straight or branched chain Lt; / RTI >

Z is as defined in the above formula (I).

The compound represented by the above formula (I) of the present invention may be a compound represented by the following formula (I-3):

In the above general formula (I-3)

X2 is C, N or O,

R1C is C1-C6 straight or branched chain alkyl; Acetyl; N, N-dialkylaminoalkyl of C3-C10; Pyridin-4-yl; Pyridin-2-yl; N-methyl-piperidin-4-yl; Piperidin-1-yl; N-methyl-piperazin-1-yl; Or -N-C (= O) -Ra3, wherein Ra3 is C1-C6 straight or branched chain alkoxy,

Wherein R3C is -H or a straight or branched chain alkyl of < RTI ID = 0.0 > Cl-C6 &

R6C and R7C are-H; C1 to C6 alkyl; -F; -CF _3; -Cl; -Br; -I; Phenyl unsubstituted or substituted with -F, -Cl, -Br, or -I; Pyridin-2-yl; Pyridin-l-yl; N, N-dimethylaminoalkyl of C3-C6; Pyrrolidin-1-yl; Morpholino-4-yl; Or R < 6C > and R < 7C > are 5 or 6 atoms saturated or unsaturated cycloalkyl formed together.

Z is as defined in the above formula (I).

The compounds represented by formula (I), (I-1), (I-2) or (I-3) of the present invention are as follows.

1. Preparation of 2- [2- (4-acetyl-piperazin-1-yl) -3-biphenyl-4-yl-3,4- dihydro- quinazolin- Benzyl) -acetamide < / RTI >

2. [2- (4-Acetyl-piperazin-1-yl) -3-biphenyl-4-yl-3,4- dihydro- quinazolin- 4-yl] -acetic acid methyl ester

3. [2- (4-Acetyl-piperazin-1-yl) -3-biphenyl-4-yl-3,4- dihydro- quinazolin-

4. Preparation of 2- [2- (4-acetyl-piperazin-1-yl) -3-biphenyl-4-yl-3,4- dihydro- quinazolin- Fluoromethyl-benzyl) -acetamide < / RTI >

5. Synthesis of 2- [2- (4-acetyl-piperazin-1-yl) -3-biphenyl-4-yl-3,4- dihydro- quinazolin- -Benzyl) -acetamide < / RTI >

6. Preparation of 2- [2- (4-acetyl-piperazin-1-yl) -3-biphenyl-4-yl-3,4- dihydro- quinazolin- Methoxy-benzyl) -acetamide < / RTI >

7. Preparation of 2- [2- (4-acetyl-piperazin-1-yl) -3-biphenyl-4-yl-3,4- dihydro- quinazolin-

8. Preparation of [3-biphenyl-4-yl-2- (4-t-butoxycarbonylamino-piperidin- 1 -yl) -3,4-dihydro- quinazolin- Thixed acid methyl ester

9. [3-Biphenyl-4-yl-2- (4-methyl-piperazin- 1 -yl) -3,4- dihydro- quinazolin- 4-yl] -acetic acid methyl ester

10. N-Benzyl-2- {3-biphenyl-4-yl-2- [4- (2- dimethylamino- ethyl) -piperazin- 1- yl] -3,4-dihydro- quinazoline Yl} -acetamide < / RTI >

11. Preparation of N-benzyl-2- [2- [5-dimethylamino-pentyl) -methyl-amino] -3- (4- pyridin- -4-yl] -acetamide

12. N-Benzyl-2- [2- [4- (2-dimethylamino-ethyl) -piperazin- Dihydro-quinazolin-4-yl] -acetamide < / RTI >

13. Preparation of 2- {3-biphenyl-4-yl-2- [4- (2-dimethylamino-ethyl) -piperazin- 1 -yl] -3,4-dihydro- quinazolin- } -N- (4-methyl-benzyl) -acetamide

14. Preparation of 2- {3-biphenyl-4-yl-2- [4- (2- dimethylamino- ethyl) -piperazin- 1-yl] -3,4- dihydro- quinazolin- } -N- (4-fluoro-benzyl) -acetamide

15. Preparation of 2- {3-biphenyl-4-yl-2- [4- (2- dimethylamino-ethyl) -piperazin- 1-yl] -3,4- dihydro- quinazolin- } -N- (4-methoxy-benzyl) -acetamide

16. Preparation of 2- {3-biphenyl-4-yl-2- [4- (2-dimethylamino-ethyl) -piperazin- 1- yl] -3,4- dihydro- quinazolin- } -N-pyridin-2-ylmethyl-acetamide

17. Preparation of 2- {3-biphenyl-4-yl-2- [4- (2- dimethylamino-ethyl) -piperazin- 1-yl] -3,4- dihydro- quinazolin- } -N-pyridin-4-ylmethyl-acetamide

18. N-Benzyl-2- {3-biphenyl-4-yl-2- [methyl- (2- piperidin- 1- yl- ethyl) -amino] -3,4- dihydro- quinazoline- 4-yl} -acetamide

Yl) -amino] -3,4-dihydro-quinazolin-4-yl} -2-methyl- -N- (4-fluoro-benzyl) -acetamide < / RTI >

20. N-Benzyl-2- [3-biphenyl-4-yl-2- (4-methyl-piperazin- 1 -yl) -3,4- dihydro- quinazolin-

21. Preparation of 2- [3-biphenyl-4-yl-2- (4-methyl-piperazin- 1 -yl) -3,4- dihydro- quinazolin- Benzyl) -acetamide < / RTI >

22. Preparation of 2- [3-biphenyl-4-yl-2- (4-methyl-piperazin- 1 -yl) -3,4- dihydro- quinazolin- Fluoromethyl-benzyl) -acetamide < / RTI >

23. Preparation of 2- [3-biphenyl-4-yl-2- (4-methyl-piperazin- 1 -yl) -3,4- dihydro- quinazolin- -Benzyl) -acetamide < / RTI >

24. Preparation of 2- [3-biphenyl-4-yl-2- (4-methyl-piperazin- l-yl) -3,4- dihydro- quinazolin- Methoxy-benzyl) -acetamide < / RTI >

Yl) -amino] -3,4-dihydro-quinazolin-4-yl} - (2-methyl-pyridin- -N- (4-trifluoromethyl-benzyl) -acetamide < / RTI >

26. 2- {3-Biphenyl-4-yl-2- [methyl- (2-piperidin- 1- yl- ethyl) -amino] -3,4- dihydro- quinazolin- -N- (4-methoxy-benzyl) -acetamide < / RTI >

27. 2- {3-Biphenyl-4-yl-2- [methyl- (2- piperidin- 1- yl- ethyl) -amino] -3,4- dihydro- quinazolin- -N- (4-methyl-benzyl) -acetamide < / RTI >

28. N-Benzyl-2- {3-biphenyl-4-yl-2 - [(4- dimethylamino- - acetamide

29. 2- {3-Biphenyl-4-yl-2 - [(4-dimethylamino-benzyl) -methyl-amino] -3,4- dihydro- quinazolin- 4-fluoro-benzyl) -acetamide < / RTI >

30. Preparation of 2- {3-biphenyl-4-yl-2 - [(4-dimethylamino-benzyl) -methyl-amino] -3,4- dihydro- quinazolin- 4-methoxy-benzyl) -acetamide < / RTI >

31. 2- [3-Biphenyl-4-yl-2- (4-methyl-piperazin- 1 -yl) -3,4-dihydro- quinazolin- Ylmethyl-acetamide

32. 2- {3-Biphenyl-4-yl-2- [methyl- (2-piperidin- 1- yl- ethyl) -amino] -3,4- dihydro- quinazolin- -N-pyridin-4-ylmethyl-acetamide < / RTI >

33. 2- {3-Biphenyl-4-yl-2 - [(4-dimethylamino-benzyl) -methyl-amino] -3,4- dihydro- quinazolin- -4-ylmethyl-acetamide < / RTI >

34. N-Benzyl-2- (3-biphenyl-4-yl-2- {methyl- [4- , 4-dihydro-quinazolin-4-yl) -acetamide

35. Preparation of 2- (3-biphenyl-4-yl-2- {methyl- [4- (4-methyl- piperazin- 1 -yl) -4-oxo- Dihydro-quinazolin-4-yl) -N- (4-fluoro-benzyl) -acetamide

36. 2- [3-Biphenyl-4-yl-2- (4-methyl-piperazin- 1 -yl) -3,4-dihydro-quinazolin- - Sun - Ethanone

37. 2- [3-Biphenyl-4-yl-2- (4-methyl-piperazin- 1 -yl) -3,4- dihydro-quinazolin- Ylmethyl-acetamide

38. 2- {3-Biphenyl-4-yl-2- [methyl- (2-piperidin- 1- yl- ethyl) -amino] -3,4- dihydro- quinazolin- -1-morpholin-4-yl-ethanone

39. 2- [3-Biphenyl-4-yl-2- (4-methyl-piperazin- 1 -yl) -3,4-dihydro-quinazolin- amides

40. 2- (3-Biphenyl-4-yl-2- {methyl- [4- (4-methyl- piperazin- 1 -yl) -4-oxo- Hydro-quinazolin-4-yl) -N- (4-methoxy-benzyl) -acetamide

41. 2- (3-Biphenyl-4-yl-2- {methyl- [4- (4-methyl- piperazin- 1- yl) -4-oxo- Hydro-quinazolin-4-yl) -N-pyridin-4-ylmethyl-acetamide

42. Preparation of 4 - {[3-biphenyl-4-yl-4- (2-morpholin-4-yl-2-oxo- ethyl) -3,4- dihydro-quinazolin- -Amino} -1- (4-methyl-piperazin-1-yl) -butan-

43. 2- (3-Biphenyl-4-yl-2- {methyl- [4- (4-methyl- piperazin- 1 -yl) -4-oxo- Hydro-quinazolin-4-yl) -N-cyclopropyl-acetamide

44. 5 - {[4- (Benzylcarbamoyl-methyl) -3- (4-dimethylamino-phenyl) -3,4-dihydro- quinazolin- Gt;

45. 5 - ({3- (4-Dimethylamino-phenyl) -4 - [(4-methyl- benzylcarbamoyl) -methyl] -3,4- dihydro- quinazolin- -Amino) -pentanyl < / RTI > acid dimethylamide

Dihydro-quinazolin-2-yl} - (4-fluoro-benzyl) Methyl-amino) -pentanone < / RTI > acid dimethylamide

Methyl} -3,4-dihydro-quinazolin-2-yl} - (3-methyl- Methyl-amino) -pentanone < / RTI > acid dimethylamide

48. 5 - {[4- (Benzylcarbamoyl-methyl) -3-biphenyl-4-yl-3,4- dihydro- quinazolin- 2-yl] -methyl-amino} -pentanone amides

49. 5 - ({3-Biphenyl-4-yl-4 - [(4- methyl- benzylcarbamoyl) -methyl] -3,4- dihydro- quinazolin- -Pentanylic acid dimethylamide

Dihydro-quinazolin-2-yl} -methyl-amino-lH-pyrrolo [2,3-c] ) -Pentanyl < / RTI > acid dimethylamide

51. 5 - ({3- (4-Dimethylamino-phenyl) -4 - [(4- methoxy- benzylcarbamoyl) -methyl] -3,4- dihydro- quinazolin- Methyl-amino) -pentanone < / RTI > acid dimethylamide

52. [2- (4-Pyridin-4-yl-piperazin-l-yl) -3- (4- pyrrolidin- 1 -yl- phenyl) -3,4- dihydro- quinazolin- Acetic acid methyl ester

53. [2- [4- (2-Dimethylamino-ethyl) -piperazin- 1-yl] -3- (4- pyrrolidin- 1 -yl- phenyl) -3,4- dihydro-quinna Zolin-4-yl] -acetic acid methyl ester

Dihydro-quinazolin-2-yl} -methyl-amino) - < / RTI > -Pentanylic acid dimethylamide

55. N-Benzyl-2- [2- [4- (2-dimethylamino-ethyl) -piperazin- 1 -yl] -3- (4- pyrrolidin- Dihydro-quinazolin-4-yl] -acetamide < / RTI >

56. 2- [2- [4- (2-Dimethylamino-ethyl) -piperazin- 1 -yl] -3- (4- pyrrolidin- 1 -yl- phenyl) -3,4- dihydro - quinazolin-4-yl] -N- (4-methyl-benzyl) -acetamide

57. 2- [2- [4- (2-Dimethylamino-ethyl) -piperazin- 1 -yl] -3- (4- pyrrolidin- 1 -yl- phenyl) -3,4-dihydro - quinazolin-4-yl] -N- (4-methoxy-benzyl) -acetamide

58. N-Benzyl-2- [2- (4-pyridin-4-yl-piperazin- 1 -yl) -3- (4- pyrrolidin- 1 -yl- -Quinazolin-4-yl] -acetamide < / RTI >

59. N- (4-Fluoro-benzyl) -2- [2- (4-pyridin-4-yl-piperazin- -3,4-dihydro-quinazolin-4-yl] -acetamide

60. N- (4-Methyl-benzyl) -2- [2- (4- pyridin-4-yl-piperazin- Dihydro-quinazolin-4-yl] -acetamide < / RTI >

61. N- (4-Methoxy-benzyl) -2- [2- (4- pyridin-4-yl-piperazin- -3,4-dihydro-quinazolin-4-yl] -acetamide

62. N-Benzyl-2- [2- [4- (2-dimethylamino-ethyl) -piperazin- 1 -yl] -3- (4- dimethylamino- phenyl) -3,4-dihydro -Quinazolin-4-yl] -acetamide < / RTI >

63. 2- [2- [4- (2-Dimethylamino-ethyl) -piperazin- 1 -yl] -3- (4- dimethylamino- phenyl) -3,4- dihydro- quinazoline- 4-yl] -N- (4-fluoro-benzyl) -acetamide

64. 2- [2- [4- (2-Dimethylamino-ethyl) -piperazin- 1 -yl] -3- (4- dimethylamino- phenyl) -3,4- dihydro- quinazoline- 4-yl] -N- (4-methyl-benzyl) -acetamide

65. 2- [2- [4- (2-Dimethylamino-ethyl) -piperazin- 1 -yl] -3- (4- dimethylamino- phenyl) -3,4- dihydro- quinazoline- 4-yl] -N- (4-methoxy-benzyl) -acetamide

66. 5 - [(3-Biphenyl-4-yl-4 - {[(4-dimethylamino- benzyl) -methyl-carbamoyl] -methyl} -3,4- dihydro- quinazolin- Yl) -methyl-amino] -pentanone < / RTI > acid dimethylamide

67. 2- [2 - [(5-Dimethylamino-pentyl) -methyl-amino] -3- (4- pyridin- 2- yl- phenyl) -3,4- dihydro- quinazolin- ] -N-pyridin-2-ylmethyl-acetamide

68. 2- [2- [5-Dimethylamino-pentyl) -methyl-amino] -3- (4-pyridin- 2- yl- phenyl) -3,4- dihydro- quinazolin- ] -N- (4-methyl-benzyl) -acetamide

69. N-Benzyl-2- (3-biphenyl-4-yl-2 - {[3- (3,3- dimethyl- ureido) -propyl] -methyl-amino} -3,4-dihydro -Quinazolin-4-yl) -acetamide < / RTI >

70. 2- {2- [4- (2-Dimethylamino-ethyl) -piperazin- 1 -yl] -3-naphthalen-2-yl-3,4- dihydro- quinazolin- -N- (4-methyl-benzyl) -acetamide < / RTI >

71. 2- {2- [4- (2-Dimethylamino-ethyl) -piperazin- 1 -yl] -3-naphthalen-2-yl-3,4- dihydro- quinazolin- -N- (4-methoxy-benzyl) -acetamide < / RTI >

72. 2- (3-Biphenyl-4-yl-2 - {[3- (3,3-dimethyl- ureido) -propyl] -methyl- amino} -3,4- dihydro- quinazoline- 4-yl) -N- (4-methyl-benzyl) -acetamide

73. 2- (3-Biphenyl-4-yl-2 - {[3- (3,3- dimethyl- ureido) -propyl] -methyl- amino} -3,4- dihydro- quinazoline- 4-yl) -N- (4-methoxy-benzyl) -acetamide

Yl)} - ({[(R) -1-phenyl-ethylcarbamoyl) -methyl] -3,4- dihydro- quinazolin- Methyl-amino) -pentanoic < / RTI > acid dimethylamide

75. {3-Biphenyl-4-yl-2- [4- (3-dimethylamino-propyl) -piperazin- 1- yl] -3,4- dihydro- quinazolin- Acetic acid methyl ester

76. N-Benzyl-2- {3-biphenyl-4-yl-2- [4- (3- dimethylamino- propyl) -piperazin- 1- yl] -3,4- dihydro- quinazoline Yl} -acetamide < / RTI >

77. 2- {3-Biphenyl-4-yl-2- [4- (3- dimethylamino- propyl) -piperazin- 1- yl] -3,4-dihydro-quinazolin- } -N- (4-fluoro-benzyl) -acetamide

78. 2- {3-Biphenyl-4-yl-2- [4- (3- dimethylamino- propyl) -piperazin- 1-yl] -3,4- dihydro- quinazolin- } -N- (4-methyl-benzyl) -acetamide

79. 2- {3-Biphenyl-4-yl-2- [4- (3- dimethylamino- propyl) -piperazin- 1-yl] -3,4- dihydro- quinazolin- } -N- (4-methoxy-benzyl) -acetamide

80. Preparation of {3-biphenyl-4-yl-2- [4- (1 -methyl- piperidin-4-yl) -piperazin- 1-yl] -3,4-dihydro-quinazoline- - yl} -acetic acid methyl ester

81. {3-Biphenyl-4-yl-2- [4- (4-methyl-piperazin- 1- yl) -piperidin- l-yl] -3,4- dihydro- quinazoline- - yl} -acetic acid methyl ester

82. 2- {3-Biphenyl-4-yl-2- [4- (3- dimethylamino- propyl) -piperazin- 1-yl] -3,4- dihydro- quinazolin- } -N, N-dimethyl-acetamide

83. 2- {3-Biphenyl-4-yl-2- [4- (3- dimethylamino- propyl) -piperazin- 1-yl] -3,4- dihydro- quinazolin- } -N-cyclopropyl-acetamide

84. [2- [4- (2-Dimethylamino-ethyl) -piperazin- 1 -yl] -3- (4- fluoro- phenyl) -3,4- dihydro- quinazolin- ] -Acetic acid methyl ester

85. [3- (4-Fluoro-phenyl) -2- (4-pyridin-4-yl-piperazin- 1 -yl) -3,4- dihydro- quinazolin- Acid methyl ester

86. [2- [4- (2-Dimethylamino-ethyl) -piperazin-1-yl] -3- (5,6,7,8-tetrahydro-naphthalen- - dihydro-quinazolin-4-yl] -acetic acid methyl ester

87. [2- (4-Pyridin-4-yl-piperazin-l-yl) -3- (5,6,7,8-tetrahydro-naphthalen- Quinazolin-4-yl] -acetic acid methyl ester

88. N-Benzyl-2- {3-biphenyl-4-yl-2- [4- (1- methyl- piperidin- 4- yl) -piperazin- Hydro-quinazolin-4-yl} -acetamide < / RTI >

89. 2- {3-Biphenyl-4-yl-2- [4- (1 -methyl- piperidin- 4- yl) -piperazin- 1- yl] -3,4-dihydro- quinazoline -4-yl} -N- (4-fluoro-benzyl) -acetamide

90. 2- {3-Biphenyl-4-yl-2- [4- (1 -methyl- piperidin- 4- yl) -piperazin- 1- yl] -3,4- dihydro- quinazoline -4-yl} -N- (4-methyl-benzyl) -acetamide

91. 2- {3-Biphenyl-4-yl-2- [4- (1 -methyl-piperidin- 4- yl) -piperazin- 1- yl] -3,4- dihydro- quinazoline -4-yl} -N- (4-methoxy-benzyl) -acetamide

92. (3- (4-Bromo-phenyl) -2- [4- (2-dimethylamino-ethyl) -piperazin- 1- yl] -3,4- dihydro- quinazolin- } -Acetic acid methyl ester

93. Preparation of [3- (4-bromo-phenyl) -2- (4-pyridin-4-yl- piperazin- 1 -yl) -3,4- dihydro- quinazolin- Acid methyl ester

94. N-Benzyl-2- {3-biphenyl-4-yl-2- [4- (4-methyl-piperazin- 1- yl) -piperidin- Hydro-quinazolin-4-yl} -acetamide < / RTI >

95. 2- {3-Biphenyl-4-yl-2- [4- (4-methyl-piperazin- 1- yl) -piperidin- 1 -yl] -3,4-dihydro-quinazoline -4-yl} -N- (4-fluoro-benzyl) -acetamide

96. 2- {3-Biphenyl-4-yl-2- [4- (4-methyl-piperazin- 1- yl) -piperidin- 1 -yl] -3,4-dihydro- quinazoline -4-yl} -N- (4-methyl-benzyl) -acetamide

97. 2- {3-Biphenyl-4-yl-2- [4- (4-methyl-piperazin- 1- yl) -piperidin- l-yl] -3,4-dihydro- quinazoline -4-yl} -N- (4-methoxy-benzyl) -acetamide

98. N-Benzyl-2- {2- [4- (2-dimethylamino-ethyl) -piperazin- 1 -yl] -3-quinolin-6-yl-3,4- dihydro- quinazoline- 4-yl} -acetamide

99. N-Benzyl-2- [3- (4-fluoro-phenyl) -2- (4- pyridin-4-yl- piperazin- 1 -yl) -3,4- dihydro- quinazoline- -Yl] -acetamide < / RTI >

100. 2- [3- (4-Fluoro-phenyl) -2- (4-pyridin-4- yl- piperazin- 1 -yl) -3,4- dihydro- quinazolin- N- (4-methoxy-benzyl) -acetamide

101. N-Benzyl-2- [2- [4- (2-dimethylamino-ethyl) -piperazin- 1 -yl] -3- (6- fluoro- Dihydro-quinazolin-4-yl] -acetamide < / RTI >

102. 2- [2- [4- (2-Dimethylamino-ethyl) -piperazin- 1 -yl] -3- (6- fluoro- naphthalen- 2-yl) -3,4-dihydro- Quinazolin-4-yl] -N- (4-fluoro-benzyl) -acetamide

103. 2- [2- [4- (2-Dimethylamino-ethyl) -piperazin- 1 -yl] -3- (6- fluoro- naphthalen- Quinazolin-4-yl] -N- (4-methyl-benzyl) -acetamide

104. 2- [2- [4- (2-Dimethylamino-ethyl) -piperazin- 1 -yl] -3- (6- fluoro- naphthalen- 2-yl) -3,4-dihydro- Quinazolin-4-yl] -N- (3-fluoro-benzyl) -acetamide

105. N-Benzyl-2- [3- (6-fluoro-naphthalen-2-yl) -2- (4- pyridin- Quinazolin-4-yl] -acetamide < / RTI >

106. N- (4-Fluoro-benzyl) -2- [3- (6-fluoro-naphthalen- Dihydro-quinazolin-4-yl] -acetamide < / RTI >

107. 2- [3- (6-Fluoro-naphthalen-2-yl) -2- (4- pyridin- - yl] -N- (4-methyl-benzyl) -acetamide

108. N-Benzyl-2- [2- [4- (2-dimethylamino-ethyl) -piperazin- 1-yl] -3- (4'- fluoro- , 4-dihydro-quinazolin-4-yl] -acetamide

109. 2- [2- [4- (2-Dimethylamino-ethyl) -piperazin-1-yl] -3- (4'-fluoro- Dihydro-quinazolin-4-yl] -N- (4-fluoro-benzyl) -acetamide

110. 2- [2- [4- (2-Dimethylamino-ethyl) -piperazin-1-yl] -3- (4'- fluoro- Dihydro-quinazolin-4-yl] -N- (4-methyl-benzyl) -acetamide

111. N-benzyl-2- [3- (4'-fluoro-biphenyl-4-yl) -2- (4- pyridin- Hydro-quinazolin-4-yl] -acetamide < / RTI >

112. N- (4-Fluoro-benzyl) -2- [3- (4'-fluoro-biphenyl- ) -3,4-dihydro-quinazolin-4-yl] -acetamide

113. N- (4-Chloro-benzyl) -2- [3- (4'-fluoro-biphenyl- -3,4-dihydro-quinazolin-4-yl] -acetamide

114. 2- [4-Fluoro-biphenyl-4-yl) -2- (4-pyridin- -4-yl] -N- (4-methyl-benzyl) -acetamide

115. N-Benzyl-2- [2- [4- (3-dimethylamino-propyl) -piperazin- 1-yl] -3- (4'- fluoro- , 4-dihydro-quinazolin-4-yl] -acetamide

116. 2- [2- [4- (3-Dimethylamino-propyl) -piperazin-l-yl] -3- (4'- fluoro- Dihydro-quinazolin-4-yl] -N- (4-fluoro-benzyl) -acetamide

117. N- (4-Chloro-benzyl) -2- [2- [4- (3-dimethylamino- propyl) -piperazin- 4-yl) -3,4-dihydro-quinazolin-4-yl] -acetamide

118. 2- [2- [4- (3-Dimethylamino-propyl) -piperazin-l-yl] -3- (4'- fluoro- Dihydro-quinazolin-4-yl] -N- (4-methyl-benzyl) -acetamide

119. N-Benzyl-2- [2- (4-pyridin-4-yl-piperazin-1-yl) -3- (5,6,7,8-tetrahydro-naphthalen- , 4-dihydro-quinazolin-4-yl] -acetamide

120. N- (4-Fluoro-benzyl) -2- [2- (4-pyridin-4-yl- piperazin- 1- yl) -3- (5,6,7,8-tetrahydro-naphthalene Yl) -3,4-dihydro-quinazolin-4-yl] - acetamide

121. N- (4-Methyl-benzyl) -2- [2- (4- pyridin-4-yl- piperazin- 1 -yl) -3- (5,6,7,8-tetrahydro- 2-yl) -3,4-dihydro-quinazolin-4-yl] -acetamide

122. N-Benzyl-2- [2- [4- (2-dimethylamino-ethyl) -piperazin- 1- yl] -3- (5,6,7,8-tetrahydro- Yl) -3,4-dihydro-quinazolin-4-yl] -acetamide

123. 2- [2- [4- (2-Dimethylamino-ethyl) -piperazin-1-yl] -3- (5,6,7,8-tetrahydro-naphthalen- Dihydro-quinazolin-4-yl] -N- (4-fluoro-benzyl) -acetamide

124. 2- [2- [4- (2-Dimethylamino-ethyl) -piperazin-1-yl] -3- (5,6,7,8-tetrahydro-naphthalen- Dihydro-quinazolin-4-yl] -N- (4-methyl-benzyl) -acetamide

125. N-Benzyl-2- [2- [4- (3-dimethylamino-propyl) -piperazin- 1 -yl] -3- (4- pyrrolidin- Dihydro-quinazolin-4-yl] -acetamide < / RTI >

126. 2- [2- [4- (3-Dimethylamino-propyl) -piperazin- 1-yl] -3- (4- pyrrolidin- 1 -yl- phenyl) -3,4- dihydro - quinazolin-4-yl] -N- (4-fluoro-benzyl) -acetamide

127. N- (4-Chloro-benzyl) -2- [2- [4- (3-dimethylamino-propyl) -piperazin- -Phenyl) -3,4-dihydro-quinazolin-4-yl] -acetamide

128. N- (3-Chloro-benzyl) -2- [2- [4- (3-dimethylamino-propyl) -piperazin- -Phenyl) -3,4-dihydro-quinazolin-4-yl] -acetamide

129. 2- [2- [4- (3-Dimethylamino-propyl) -piperazin- 1 -yl] -3- (4- pyrrolidin- 1 -yl- phenyl) -3,4- dihydro - quinazolin-4-yl] -N- (4-methyl-benzyl) -acetamide

130. 5 - {[4- (Benzylcarbamoyl-methyl) -3- (4-pyrrolidin- 1 -yl-phenyl) -3,4-dihydro- quinazolin- } -Pentanoic < / RTI > acid dimethylamide

131. 5 - {[4- [(4-Fluoro-benzylcarbamoyl) -methyl] -3- (4- pyrrolidin- 1 -yl- phenyl) -3,4- dihydro- quinazolin- -Yl] -methyl-amino} -pentanoic < / RTI > acid dimethylamide

132. 5 - {[4- [(4-Chloro-benzylcarbamoyl) -methyl] -3- (4- pyrrolidin- 1 -yl- phenyl) -3,4- dihydro- quinazolin- Yl] -methyl-amino} -pentanoic acid dimethylamide

133. 5- {Methyl- [4- [(4-methyl-benzylcarbamoyl) -methyl] -3- (4- pyrrolidin- 1 -yl- phenyl) -3,4- dihydro- quinazoline- 2-yl] -amino} -pentanoic acid dimethylamide

134. N-Benzyl-2- [2- [4- (2-dimethylamino-ethyl) -piperazin- 1-yl] -3- (4- Dihydro-quinazolin-4-yl] -acetamide < / RTI >

135. 2- [2- [4- (2-Dimethylamino-ethyl) -piperazin-l-yl] -3- (4- morpholin- Quinazolin-4-yl] -N- (4-fluoro-benzyl) -acetamide

136. N- (4-Chloro-benzyl) -2- [2- [4- (2-dimethylamino-ethyl) -piperazin- Phenyl) -3,4-dihydro-quinazolin-4-yl] -acetamide

137. 2- [2- [4- (2-Dimethylamino-ethyl) -piperazin- 1 -yl] -3- (4- morpholin- Quinazolin-4-yl] -N- (4-methyl-benzyl) -acetamide

138. 2- (3-Biphenyl-4-yl-2 - {[3- (3,3-dimethyl- ureido) -propyl] -methyl- amino} -3,4- dihydro- quinazoline- 4-yl) -N- (4-fluoro-benzyl) -acetamide

139. N-Benzyl-2- {2- [6-dimethylamino-hexyl) -methyl-amino] -3-naphthalen-2-yl-3,4- dihydro- quinazolin- Acetamide]

140. 2- {2- [(6- (6-Dimethylamino-hexyl) -methyl-amino] -3-naphthalen-2-yl-3,4- dihydro- quinazolin- - (4-methoxy-benzyl) -acetamide, or

141. N-Benzyl-2- {3- (4-cyclohexyl-phenyl) -2- [4- (2- dimethylamino- ethyl) -piperazin- 1- yl] -3,4- dihydro- Dihydro-quinazolin-4-yl} -acetamide

In the present invention, the pharmaceutically acceptable salt means a salt commonly used in the pharmaceutical industry. Examples of the salt include inorganic ion salts such as calcium, potassium, sodium and magnesium, hydrochloric acid, nitric acid, phosphoric acid, Acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, glutaric acid, Organic acid salts such as hydrochloric acid, hydrobromic acid, citric acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillyric acid and hydroiodic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and naphthalenesulfonic acid, amino acid salts prepared with glycine, arginine, lysine, and the like, and amino acid salts such as trimethylamine, triethylamine, Pyridine, picoline, and the like. However, the types of salts as defined in the present invention are not limited by the listed salts.

The present invention provides a process for preparing a compound represented by the above formula (I), a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.

The method of the present invention comprises the steps of: adding a compound represented by the following formula (II) to an organic solvent to prepare a solution; And

And then adding a compound represented by the following formula (III) to the solution to prepare a compound represented by the following formula (IV).

In the above formula (I-IV)

Wherein X to Z and R1 to R7 are as defined above.

When the diimide compound represented by the formula (II) is reacted with the amine compound represented by the formula (III), a guanidine intermediate is formed and the cyclization reaction is automatically carried out to prepare the hydroquinazoline compound represented by the formula (IV).

The compound represented by the formula (III) may be used at a ratio of 1 to 4 mol, preferably 1.5 to 2.5 mol, per mol of the compound represented by the formula (II).

The organic solvent may be an organic solvent commonly used for carrying out a cyclization reaction through a guanidine intermediate. Examples of the organic solvent include toluene, DMF (dimethylformamide), DMSO (dimethylsulfoxide), acetone Can be used, and toluene is more preferable.

The compound represented by the above formula (I) of the present invention may be a compound represented by the following formulas (I-1) to (I-3)

In the formulas (I-1) to (I-3)

R 1, R 2 A, R 3 A, R 4 A, R 6 A, R 6 B, R 1 B, R 3 B, R 4 B, R 6 B, R 7 B, R 1 C, R 3 C, R 6 C, R 7 C, Ra 1, Rb 1, Ra 3, Z, X 1, same.

In the method of the present invention, when Y of the compound represented by the above formula (I) is -NR 3 R 4, the method may further include reacting the compound represented by the formula (IV) with a compound represented by the following formula (V).

NHR < 3 > R <

In the above formula (V)

R3 and R4 are as defined above.

In the method of the present invention, when Y of the compound represented by Formula (I) is -OH, the method may further include reacting the compound represented by Formula IV with a metal hydroxide.

The metal hydroxide may be lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide or a mixture thereof, preferably lithium hydroxide.

In the process of the present invention, the compound represented by the formula (II) may be prepared by reacting a compound represented by the following formula (VI) with a phosphine compound represented by the following formula (VII).

In the above formulas VI and VII

Wherein R5, R6, R7 and Z are as defined above,

A is -Cl, -Br or -I.

In the present invention, the compound represented by the formula (VI) and the compound represented by the formula (VII) may be reacted in the presence of an amine compound and dichloromethane to prepare a compound represented by the formula (II).

The amine compound may be an amine compound generally used for synthesizing a diimide compound, preferably triethylamine.

In the present invention, the compound represented by the formula (VI) may be prepared by preparing a mixed solution comprising diphenylphosphoryl azide and a compound represented by the following formula (VIII); And

And adding a compound represented by the following formula (IX) to the mixed solution.

In the above formulas (VIII) and (IX)

R5 to R7 and Z are as defined above.

When the compound represented by the formula (VIII) is reacted by mixing diphenylphosphoryl azide, an isocyanate compound is formed through Curtis rearrangement reaction. When the aniline compound represented by the formula (IX) is sequentially introduced, the isocyanate compound the compound represented by the formula (VI) can be prepared in situ.

In the process of the present invention, the compound represented by the formula (II) can be produced by reacting a compound represented by the formula (IX) with a compound represented by the formula (X).

In Formulas IX and X,

Wherein R5, R6 and R7 and Z are as defined above.

In the present invention, the compound represented by the above formula (IX) can be purchased and used or synthesized through the reaction represented by the following reaction formula (I).

[Reaction Scheme I]

In the above Scheme I,

Wherein R5 and Z are as defined above,

R8 is formyl (-CHO) or methyl.

In Reaction Scheme I, the compound No. 1, which is 2-nitrobenzaldehyde, 2-nitrotoluene or a derivative thereof, is reacted with N, N-dimethylformaldehyde dimethyl acetal (DMFDMA) do. Thereafter, the enamine compound (2) is reacted with NaIO ₄ to obtain a benzaldehyde compound No. 3 compound. The benzaldehyde compound (3) and the malic acid are polymerized to synthesize cinnamic acid compound 4.

The cinnamic acid compound (4) is reacted with R 5 OH through an esterification reaction under an acid catalyst such as sulfuric acid to obtain an ester compound No. 5. Thereafter, the nitro group of the ester compound (5) can be reduced with an amine using zinc chloride dihydrate in an ethyl acetate solvent to obtain the compound represented by the above formula (IX).

The present invention provides a composition exhibiting a calcium channel blocking effect containing, as an active ingredient, a compound represented by the above-mentioned formula (I), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

The composition containing the compound represented by the above formula (I), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof may prevent the calcium from migrating through the calcium channel. Specifically, the composition can effectively block the T-type calcium channel.

The compound represented by the above formula (I) of the present invention may be a compound represented by the following formulas (I-1) to (I-3)

In the formulas (I-1) to (I-3)

R4A, R6A, R6B, R1B, R3B, R4B, R6B, R7B, R1C, R1A, R2A, R3A, R4A, R3C, R6C, R7C, Ra1, Rb1, Ra3, Z, X1, X2, n and m are as defined above.

The present invention provides a pharmaceutical composition for preventing or treating cancer comprising the compound represented by the above-mentioned formula (I), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient.

In the above formula (I)

X, Y, Z and R1 to R7 are as defined above.

It is possible to effectively inhibit the growth of cancer cells in a composition containing the compound represented by the above-mentioned formula (I) of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient, And can preferably exhibit excellent effects on prostate cancer, breast cancer, lung cancer, prostate cancer, colon cancer, pancreatic cancer, skin cancer or uterine cancer.

The compound represented by the above formula (I) of the present invention may be a compound represented by the following formulas (I-1) to (I-3)

In the formulas (I-1) to (I-3)

R 1, R 2 A, R 3 A, R 4 A, R 6 A, R 6 B, R 1 B, R 3 B, R 4 B, R 6 B, R 7 B, R 1 C, R 3 C, R 6 C, R 7 C, Ra 1, Rb 1, Ra 3, Z, X 1, same.

Such pharmaceutically acceptable salts are as described above for the pharmaceutically acceptable salts of the compounds of formula I of the present invention.

The pharmaceutical composition of the present invention may further comprise at least one pharmaceutically acceptable carrier in addition to the compound represented by the above-mentioned formula (I), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof for administration have. The pharmaceutically acceptable carrier may be a mixture of saline, sterilized water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components. If necessary, an antioxidant, , And other conventional additives such as a bacteriostatic agent may be added. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate into injectable solutions, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like. Accordingly, the composition of the present invention may be a patch, a liquid, a pill, a capsule, a granule, a tablet, a suppository, or the like. These formulations may be prepared by conventional methods used in the art for formulation or by methods disclosed in Remington's Pharmaceutical Science (recent edition), Mack Publishing Company, Easton PA, and may be formulated into a variety of formulations, .

The composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) depending on the intended method, and the dose may be appropriately determined depending on the body weight, age, sex, The range varies depending on diet, administration time, method of administration, excretion rate, and severity of the disease. The daily dose of the derivative compound of formula (I) of the present invention is about 1 to 1,000 mg / kg, preferably 10 to 500 mg / kg, more preferably once to several times a day.

The pharmaceutical composition of the present invention may further contain at least one active ingredient which exhibits the same or similar pharmaceutical activity besides the compound represented by the above-mentioned formula (I), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

The present invention provides a method for preventing or treating cancer by administering a compound represented by the above-mentioned formula (I), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof to a mammal including a human.

The present invention provides a method for blocking calcium channel by administering a compound represented by the above-mentioned formula (I), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof to a mammal including a human.

The compounds of formula (I), pharmaceutically acceptable salts thereof, or hydrates or solvates thereof according to the present invention can not only effectively block calcium channels but also inhibit the growth of cancer cells, Lt; / RTI >

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

The reagents and solvents mentioned below were purchased from Sigma-Aldrich Korea, TCI, Alfa Aesar unless otherwise noted, HLPC was 1100 Series from Agilent Technologies, and silica gel for column chromatography was purchased from Merk Silca gel 60 (0.040-0.063 mm ASTM) was used. ^{The 1} H NMR and ¹³ C NMR data were measured using a Varian Instrument (Varian) NMR 200 Spectrometer and a Bruker Avance III (400 MHz) mass spectrometer using an LCQ advantage-trap mass spectrometer equipped with an electrospray ionization source Finnigan, San Jose, CA, USA) and GC-2010 (Shimadzu) equipped with an electron ionization device.

Example  One

Synthesis of methyl 2-nitrocinnamate (Intermediate 2)

To methanol (2.0 mL) was added 2-nitroisocyanic acid (50 g, 0.26 mole) followed by saturated sulfuric acid (10.0 mL) and refluxed overnight. The reaction mixture was concentrated, diluted with ethyl acetate (2.0 L), washed with water (1.0 L), and the organic layer was dried over anhydrous MgSO ₄ and concentrated on a rotary evaporator to give methyl 2- Nitrosocyanate. ≪ / RTI > The methyl 2-nitrocinnamate was used as such in the next reaction without purification.

1H, NMR (CDCl3): 8.15-8.02 (m, 2H), 7.65-7.50 (m, 3H), 6.33 (d,

Example 2

Synthesis of methyl 2-aminocinamate (Intermediate 3)

The methyl 2-nitrocinnamate synthesized in Example 1 was used without further purification. Methyl 2-nitrocinnamate (52 g, 0.25 mole) and tin dichloride dihydrate (112 g, 0.5 mole) were added to ethyl acetate (2.0 mL) and the reaction mixture was heated to 70 <0> C for 1 h. After the reaction was completed, the reaction mixture was cooled to 20-30 DEG C and saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture to adjust the basicity of the solution to pH8. The mixture was filtered through celite (Celite 545) and the solid material was removed and the crude product was extracted with ethyl acetate three times. The combined organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified by column chromatography (hexane: ethyl acetate = 5: 1) to obtain methyl 2-amino cinnamate as a yellow crystal.

Yield: 60%, 1HNMR (200MHz, CDCl 3): 7.84 (d, 1H), 7.40 (d, 1H), 7.20 (t, 1H), 6.73 (m, 2H), 6.36 (d, 1H), 4.00 ( br, 2H) 3.81 (s, 3H)

Example  3

Urea Intermediate 1

(E) -3- {2- [3- (4-Fluoro- phenyl) -acrylic acid methyl ester ((E) phenyl) -ureido] -phenyl} -acrylic acid methyl ester)

To the toluene mixture was added diphenylphosphoryl azide (DPPA, 2.75 g, 10 mmole) and triethylamine (1.5 mmole) in toluene (100 mL) with the addition of 4-fluorobenzoic acid g, 15 mmole) was added at 20 degrees Celsius and stirred for 30 minutes. The reaction mixture was stirred at reflux until all dissolved. The reaction was cooled to 20 degrees Celsius and methyl 2-amino cinnamate (1.77 g, 10 mmole) was added to the reaction. The precipitated product was filtered and washed with ether to obtain (E) -3- {2- [3- (4-fluoro-phenyl) -ureido] -phenyl} -acrylic acid methyl ester as white crystals of the following formula Respectively.

1H NMR (200 MHz, DMSO): (DMSOd6) 9.00 (s, IH), 8.49 (s, IH), 7.87 , 3H), 7.11 (m, 3H), 6.57 (d, IH)

Example  4

Urea Intermediate 2

(E) -3- {2- [3 (4'-fluoro-biphenyl-4-yl) -ureido] -phenyl} -acrylic acid methyl ester - (4'-Fluoro-biphenyl-4-yl) -ureido] -phenyl} -acrylic acid methyl ester

(E) of the following formula was prepared by using the same reaction as in the above-mentioned preparation method of urea intermediate 1 (Example 3) using 4'-fluorophenylbenzoic acid (1.98 g, 10 mmole) instead of 4-fluorobenzoic acid, -3- {2- [3- (4'-fluoro-biphenyl-4-yl) -ureido] -phenyl} -acrylic acid methyl ester.

1H, NMR (200 MHz, DMSO): 9.09 (s, 1H), 8.56 (s, 1H), 7.94-7.27 (13H), 6.59 (d,

Example  5

Urea Intermediate 3

(E) -3- [2- (3-quinolin-6-yl-ureido) -phenyl] -acrylic acid methyl ester -phenyl] -acrylic acid methyl ester)

Using the same reaction as in the preparation of the above urea intermediate 1 (Example 3) using 5-quinoline-2-carboxylic acid (1.73 g, 10 mmole) instead of 4-fluorobenzoic acid, ) -3- [2- (3-quinolin-6-yl-ureido) -phenyl] -acrylic acid methyl ester.

1H, NMR (200MHz, DMSO): 8.81 (s, IH), 8.60 (s, IH), 7.98 ), 3.74 (s, 3H)

Example  6

Urea Intermediate 4

(E) -3- {2- [3- (2-fluoro-phenyl) -acrylic acid methyl ester 6-Fluoro-naphthalen-2-yl) -ureido] -phenyl} -acrylic acid methyl ester)

Using the same reaction as in the preparation of the urea intermediate 1 (Example 3), 6-fluoronaphthalene-2-carboxylic acid (1.90 g, 10 mmole) was used instead of 4-fluorobenzoic acid to obtain (E) -3- {2- [3- (6-Fluoro-naphthalen-2-yl) -ureido] -phenyl} -acrylic acid methyl ester.

1H, NMR (200 MHz, DMSO): 9.26 (s, 1H), 8.67 (s, 1H), 8.0-7.2 (m, 12H), 6.56 (d, 3H)

Example  7

Urea Intermediate 5

(E) -3- [2- (3-Naphthalen-2-yl-ureido) -phenyl] -acrylic acid methyl ester -phenyl] -acrylic acid methyl ester)

(E) - (4-fluoro-4-methylphenyl) -benzoic acid was obtained by using the same reaction as in the preparation method of the urea intermediate 1 (Example 3) using naphthalene-2-carboxylic acid 3- [2- (3-naphthalen-2-yl-ureido) -phenyl] -acrylic acid methyl ester.

1H NMR (200 MHz, DMSO): 9.26 (s, 1H), 8.67 (s, 1H), 8.0-7.1 (m, 12H), 6.61 3H)

Example  8

Urea Intermediate 6

(E) -3- {2- [3- (4-Pyridin-2-yl-phenyl) -ureido] -phenyl} -acrylic acid methyl ester -Pyridin-2-yl-phenyl) -ureido] -phenyl} -acrylic acid methyl ester)

(3.99 g, 10 mmole) was used instead of 4-pyridin-2-yl-benzoic acid instead of 4-fluorobenzoic acid to obtain the E) -3- {2- [3- (4-Pyridin-2-yl-phenyl) -ureido] -phenyl} -acrylic acid methyl ester.

1H, NMR (200 MHz, DMSO): 9.10 (s, 1H), 8.75 (s, 1H), 8.36 (s, 1H), 3.78 (s, 3H)

Example  9

Urea Intermediate 7

(E) -3- {2- [3- (4-Bromo-phenyl) -ureido] -phenyl} -acrylic acid methyl ester phenyl) -ureido] -phenyl} -acrylic acid methyl ester)

(E) -3 (trifluoromethyl) benzoate using the same reaction as in the above-mentioned preparation method of urea intermediate 1 (Example 3) using 4-bromobenzoic acid (1.99 g, 10 mmole) - {2- [3- (4-bromo-phenyl) -ureido] -phenyl} -acrylic acid methyl ester.

1H, NMR (200MHz, DMSO): 9.13 (s, IH), 8.58 (s, IH), 7.88 (m, 2H), 7.42 , 7.19 (m, 3 H), 6.57 (d, 1 H)

Example  10

Urea Intermediate 8

(E) -3- {2- [3- (4-fluoro-phenyl) -ureido] -phenyl} -acrylic acid methyl ester 4-Morpholin-4-yl-phenyl) -ureido] -phenyl} -acrylic acid methyl ester)

(2.07, 10 mmole) of 4-morpholin-4-yl-benzoic acid instead of 4-fluorobenzoic acid was used to synthesize ( E) -3- {2- [3- (4-Morpholin-4-yl-phenyl) -ureido] -phenyl} -acrylic acid methyl ester.

1H, NMR (200MHz, DMSO): 8.82 (s, IH), 8.41 (s, IH), 7.90 , 7.33 (d, 2H), 7.31 (t, 12H), 6.89 (d, 2H), 6.58 (d,

Example  11

Urea Intermediate 9

(E) -3- {2- [3- (4-Dimethylamino-phenyl) -ureido] -phenyl} -acrylic acid methyl ester -phenyl) -ureido] -phenyl} -acrylic acid methyl ester)

Using the same reaction as in the above-mentioned production method of urea intermediate 1 (Example 3), 4-N, N-dimethylaminobenzoic acid (1.61 g, 10 mmole) was used instead of 4-fluorobenzoic acid, (E) -3- {2- [3- (4-Dimethylamino-phenyl) -ureido] -phenyl} -acrylic acid methyl ester.

Yield: 1.05 g (31%), 1HNMR (200MHz, DMSO): 8.60 (s, IH), 8.25 (s, IH), 7.50-6.95 (m, 9H), 6.58 ), 2.93 (s, 3H), 2.85 (s, 3H)

Example  12

Urea Intermediate 10

(E) -3- [2- (3-Biphenyl-4-yl-ureido) -phenyl] -acrylic acid methyl ester ) -phenyl] -acrylic acid methyl ester)

(E) of the following formula was prepared by using the same reaction as the preparation method of the urea intermediate 1 (Example 3) using biphenyl-4-carboxylic acid (1.98 g, 10 mmole) instead of 4-fluorobenzoic acid, -3- [2- (3-biphenyl-4-yl-ureido) -phenyl] -acrylic acid methyl ester.

1H, NMR (200 MHz, DMSO): 9.11 (s, IH), 8.58 (s, IH), 7.91 (d, IH), 7.82-7.25 1H), &lt; / RTI &gt; 6.61 (d, 1H). 3.75 (s, 3 H)

Example  13

Urea Intermediate 11

(E) -3- {2- [3- (4-pyrrolidin-1-yl-phenyl) -ureido] -phenyl} -acrylic acid methyl ester (4-Pyrrolidin-1-yl-phenyl) -ureido] -phenyl} -acrylic acid methyl ester

(1.91 g, 10 mmole) was used instead of 4-fluorobenzoic acid in place of 4-fluorobenzoic acid to obtain the urea intermediate 1, Of (E) -3- {2- [3- (4-pyrrolidin-1-yl-phenyl) -ureido] -phenyl} -acrylic acid methyl ester.

(M, 2H), 7.40-7.10 (m, 4H), 3.74 (m, 2H), 1.93 g (53%), 1H NMR (200MHz, DMSO) s, 2H), 3.5-3.0 (br, 4H), 2.52.30 (br, 4H)

Example  14

Urea Intermediate 12

(E) -3- {2-benzyloxy-phenyl) -acrylic acid methyl ester, (E) -3- {2- [3- (5,6,7,8-tetrahydro-naphthalen- Synthesis of 2- [3- (5,6,7,8-Tetrahydro-naphthalen-2-yl) -ureido] -phenyl} -acrylic acid methyl ester

(1.76 g, 10 mmole) was used in place of 4-fluorobenzoic acid to obtain the urea intermediate 1 (Example 3) (E) -3- {2- [3- (5,6,7,8-tetrahydro-naphthalen-2-yl) -ureido] -phenyl} -acrylic acid methyl ester of the following formula:

1H, NMR (200MHz, DMSO): 8.80 (s, IH), 8.47 (s, IH), 7.86 , 7.18 (t, IH), 7.14 (s, IH), 7.12 (m, 2H), 6.97 (d, IH) 1.71 (br, 4H)

Example  15

Diimide Intermediate 1

(E) -3- [2- (4-Fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester ((E) acrylic acid methyl ester

(1.48 g, 5 mmole) and triethylamine (1.26 g, 12.5 mmole) were added to a solution of (E) -3- {2- [3- (4- fluoro-phenyl) -ureido] -phenyl} -acrylic acid methyl ester Dibromotriphenylphosphine (2.3 g, 5.5 mole) was slowly added dropwise to the mixture added to dichloromethane (25 mL) at 0 占 폚. The reaction mixture was stirred at 0 ° C for 1 hour, extracted three times with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrated material was purified by column chromatography (hexane: ethyl acetate = 20: 1) to obtain a white crystal of (E) -3- [2- (4-fluoro- phenyliminomethyleneamino) Phenyl] -acrylic acid methyl ester.

1H), 3.75 (s, 3H), 7.76 (d, IH), 7.76 (d, IH)

Example  16

Diimide Intermediate 2

(E) -3- [2- (4'-Fluoro-biphenyl-4-yliminomethyleneamino) -phenyl] -acrylic acid methyl ester -biphenyl-4-yliminomethyleneamino) -phenyl] -acrylic acid methyl ester)

(E) -3- {2- [3- (4'-fluoro-phenyl) -acrylic acid methyl ester in place of (E) -3- {2- [ (Example 15) using the above-prepared diimide intermediate 1 (1.85 g, 5 mmole) in the same manner as in Example 15, Crystalline (E) -3- [2- (4'-fluoro-biphenyl-4-yliminomethyleneamino) -phenyl] -acrylic acid methyl ester represented by the following formula was obtained.

Yield: 1.58 g (85%), 1HNMR (200MHz, CDCl3) 8.00-7.20 (m, 13H), 6.75 (d,

Example  17

Diimide Intermediate 3

(E) -3- [2- (Quinolin-6-yliminomethyleneamino) -phenyl] -acrylic acid methyl ester ((E) acid methyl ester

(E) -3- [2- (3-quinolin-6-yl) -phenyl] -acrylic acid methyl ester in place of (E) -3- {2- [ -Ureido) -phenyl] -acrylic acid methyl ester (1.74 g, 5 mmole) was subjected to the same reaction as the preparation method of diimide intermediate 1 (Example 15) to give (E ) -3- [2- (quinolin-6-yliminomethyleneamino) -phenyl] -acrylic acid methyl ester.

1H, NMR (200MHz, CDCl3) 8.90 (m, 1H), 8.76 (m, 1H), 8.21 (m, 2H), 7.99-7.45 ), 3.76 (s, 3H)

Example  18

Diimide Intermediate 4

(E) -3- [2- (6-Fluoro-naphthalen-2-ylmethoxy) phenyl] -acrylic acid methyl ester. 2-yliminomethyleneamino) -phenyl] -acrylic acid methyl ester)

(E) -3- {2- [3- (6-fluoro-phenyl) -acrylic acid methyl ester in place of (E) -3- {2- [ -Ureido] -phenyl} -acrylic acid methyl ester (1.82 g, 5 mmole) was used to synthesize the diimide intermediate 1 (Example 15). (E) -3- [2- (6-fluoro-naphthalen-2-yliminomethyleneamino) -phenyl] -acrylic acid methyl ester represented by the following formula was obtained.

Yield: 1.54 g (89%), 1HNMR (200MHz, CDCl3) 7.90-7.10 (m, 12H), 6.69

Example  19

Diimide Intermediate 5

(E) -3- [2- (Naphthalen-2-yliminomethyleneamino) -phenyl] -acrylic acid methyl ester acid methyl ester

(E) -3- [2- (3-naphthalen-2-yl) -phenyl] -acrylic acid methyl ester in place of (E) -3- {2- [ -Ureido) -phenyl] -acrylic acid methyl ester (1.73 g, 5 mmole), the title compound was obtained as white crystals of the following formula (E ) -3- [2- (naphthalen-2-yliminomethyleneamino) -phenyl] -acrylic acid methyl ester.

1H, NMR (200MHz, CDCl3) 8.0-7.1 (m, 12H), 6.74 (d,

Example  20

Diimide Intermediate 6

(E) -3- [2- (4-Pyridin-2-yl) -phenyl] -acrylic acid methyl ester -phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester)

(E) -3- {2- [3- (4-Pyridin-4-ylmethoxy) -phenyl] -acrylic acid methyl ester in place of (E) -3- {2- [ Using the same reaction as in the preparation of the diimide intermediate 1 (Example 15), the title compound was obtained as a white crystalline solid following the procedure for the preparation of the diimide intermediate 1 using 1.87 g (5 mmole) of 2- (E) -3- [2- (4-pyridin-2-yl-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester represented by the formula was obtained.

1H NMR (200MHz, CDCl3) 8.75 (s, 1H), 8.30-6.83 (m, 13H), 5.24

Example  21

Diimide Intermediate 7

(E) -3- [2- (4-Bromo-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester ((E) acrylic acid methyl ester

(E) -3- {2- [3- (4-bromo-phenyl) -acryloyl chloride instead of (E) -3- {2- [ -Methyl-phenyl) -ureido] -phenyl} -acrylic acid methyl ester (1.88 g, 5 mmole) was used in the same manner as the preparation of diimide intermediate 1 (Example 15) (E) -3- [2- (4-bromo-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester.

1H), 3.75 (s, 3H), 7.80 (d, IH), 7.80 (d, IH)

Example  22

Diimide Intermediate 8

(E) -3- [2- (4-morpholin-4-yl-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester yl-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester)

(E) -3- {2- [3- (4-fluoro-phenyl) -ureido] -phenyl} -acrylic acid methyl ester in place of (E) -3- {2- [ 4-yl-phenyl) -ureido] -phenyl} -acrylic acid methyl ester (1.97 g, 5 mmole) was used to prepare the diimide intermediate 1 (E) -3- [2- (4-morpholin-4-yl-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester represented by the following formula was obtained.

1H, NMR (CDCl3) 8.04 (d, 1H), 7.87 (d, 1H), 7.60 (m, 2H), 7.45 3H), 3.36 (m, 4H), 3.10 (m, 4H), 7.24 (d, IH)

Example  23

Diimide Intermediate 9

(E) -3- [2- (4-Methylamino-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester ((E) acrylic acid methyl ester

(E) -3- {2- [3- (4-Dimethyl (4-fluorophenyl) (Example 15) using the above-prepared diimide intermediate 1 (1.70 g, 5 mmole), the title compound was obtained as white crystals of the following formula (E) -3- [2- (4-dimethylamino-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester was obtained.

(S, 3H), 2.89 (s, 3H), 2.80 (s, 3H), 2.80 (s, 3H) ,

Example  24

Diimide Intermediate 10

(E) -3- [2- (Biphenyl-4-yliminomethyleneamino) -phenyl] -acrylic acid methyl ester ((E) acrylic acid methyl ester

(E) -3- [2- (3-biphenyl-4-fluoro-phenyl) -acrylic acid methyl ester in place of (E) -3- {2- [ Yl) -ureido) -phenyl] -acrylic acid methyl ester (1.87 g, 5 mmole) was used to prepare the diimide intermediate 1 (Example 15) E) -3- [2- (biphenyl-4-yliminomethyleneamino) -phenyl] -acrylic acid methyl ester.

1H, NMR (200MHz, CDCl3) 8.05 (d, 1H), 8.00-7.30 (m, 13H), 6.75

Example  25

Diimide Intermediate 11

(E) -3- [2- (4-Pyrrolidin-1-yl) -phenyl] -acrylic acid methyl ester -yl-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester)

(E) -3- {2- [3- (4-pyrrolidino-phenyl) -acrylic acid methyl ester in place of (E) -3- {2- [ (Example 15) using the above-prepared diimide intermediate 1 (1.83 g, 5 mmole), the title compound was obtained as white crystals (E) -3- [2- (4-pyrrolidin-1-yl-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester represented by the following formula was obtained.

(M, 3H), 7.40-7.10 (m, 3H), 6.6 (d, 2H), 3.76 (s, 3H), 3.37 (m, 3H) , 4H), &lt; / RTI &gt; 2.53 (br, 4H)

Example  26

Diimide Intermediate 12

(E) -3- [2- ((E) -3- [2- (4-fluoro- 5,6,7,8-Tetrahydro-naphthalen-2-yliminomethyleneamino) -phenyl] -acrylic acid methyl ester

(E) -3- {2- [3- (5,6-dihydroxy-phenyl) -acrylic acid methyl ester in place of (E) -3- {2- [ (Example 15) was prepared in the same manner as in the above-mentioned production method of diimide intermediate 1 (Example 15) using 1.75 g (5 mmole) of 2-methyl-7,8-tetrahydro-naphthalen- (E) -3- [2- (5,6,7,8-tetrahydro-naphthalen-2-yliminomethyleneamino) -phenyl] -acrylic acid methyl ester &Lt; / RTI &gt;

1H, NMR (200MHz, CDCl3) 8.04 (d, 1H), 7.55-7.00 (m, 7H), 3.73 (s, 3H), 2.70 (m, 4H), 1.71 )

Example  27

Ester Intermediate 1

Dihydro-quinazolin-4-yl] -acetic &lt; / RTI &gt; acid methyl ester Ester of (3- (4-Fluoro-phenyl) -2- (4-pyridin-4-yl-piperazin-1-yl) -3,4-dihydro-quinazolin-4-yl] -acetic acid methyl ester synthesis

To a solution of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester (509 mg, 1.72 mmole) in toluene (17 mL) was added 1- -Piperazine (457 mg, 3.36 mmole) was added, stirred for 2 hours and water (40 mL) was added. The organic layer was extracted three times with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated by rotary evaporation. Column chromatography was performed with silica and methanol: dichloromethane (5:95 by volume) developing solution to obtain [3- (4-fluoro-phenyl) -2- Yl-piperazin-l-yl) -3,4-dihydro-quinazolin-4-yl] -acetic acid methyl ester.

1H NMR (200 MHz, CDCl3) 8.28 (d, 2H), 7.25-6.94 (m, 8H), 6.62 (d, 2H), 5.02 (m, ), 3.56 (br, 4H), 3.21 (br, 4H), 2.80 (m,

Example  28

Ester Intermediate 2

Yl) -3- (4'-fluoro-biphenyl-4-yl) -3,4-dihydro-quinazoline -4-yl] -acetic acid methyl ester ([2- [4- (2-Dimethylamino-ethyl) -piperazin-1-yl] -3- (4'-fluoro-biphenyl- 4-dihydro-quinazolin-4-yl] -acetic acid methyl ester

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (505 mg, 1.36 mmole) and 1- [2- (dimethylamino) ethyl] piperazine (421 mg, 1.36 mmol) were added to a solution of 4- (2-dimethylamino-ethyl) -piperazin-1-yl (2-methylamino-ethyl) -piperazin-1- ] -3- (4'-fluoro-biphenyl-4-yl) -3,4-dihydro-quinazolin-4-yl] -acetic acid methyl ester.

1H NMR (400 MHz, CDCl3) 7.45 (m, 5H), 7.15 (m, 5H), 6.95 (m, 2H), 5.12 2H), 2.20 (s, 6H), 2.50 (m, 2H)

Example  29

Ester Intermediate 3

Yl] -3- (4'-fluoro-biphenyl-4-yl) -3,4-dihydro-quinazoline -4-yl] -acetic acid methyl ester ([2- [4- (3-Dimethylamino-propyl) -piperazin-1-yl] -3- (4'-fluoro-biphenyl- 4-dihydro-quinazolin-4-yl] -acetic acid methyl ester

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (500 mg, 1.34 mmole) and 1- [2- (dimethylamino) propyl] piperazine (459 mg, 2- [4- (3-dimethylamino-propyl) -piperazin-1-yl] -piperazin-1-yl ester represented by the formula below using the same reaction as in the above ester intermediate method 1 ] -3- (4'-fluoro-biphenyl-4-yl) -3,4-dihydro-quinazolin-4-yl] -acetic acid methyl ester.

(M, 2H), 5.15 (m, IH), 3.73 (s, 2H), 4.70-7.30 (m, 4H), 7.25-7.10 (M, 2H), 3.50 (br, 4H), 2.85 (m,

Example  30

Ester Intermediate 4

Yl) -3,4-dihydro-quinazolin-4-yl (4-fluoro-biphenyl- -Acetic acid methyl ester ([3- (4'-Fluoro-biphenyl-4-yl) -2- (4-pyridin- 4- yl- piperazin- 1 -yl) -3,4- dihydro- quinazolin- 4-yl] -acetic acid methyl ester

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (503 mg, 1.35 mmole) and 1-pyridin-4-yl-piperazine (437 mg, 2.68 mmole) were added to a solution of (4'- fluoro-biphenyl-4-yliminomethyleneamino) -phenyl] -acrylic acid methyl ester (4-fluoro-biphenyl-4-yl) -2- (4-pyridin-4-yl) Yl-piperazin-l-yl) -3,4-dihydro-quinazolin-4-yl] -acetic acid methyl ester.

1H NMR (400MHz, CDCl3) 7.47 (m, 7H), 7.30-6.95 (m, 9H), 5.16 , 8 H), 2.70 (m, 1 H), 2.56 (m, 1 H)

Example  31

Ester Intermediate 5

Yl) -3-quinolin-6-yl-3,4-dihydro-quinazolin-4-yl} -acetic acid Methyl ester ({2- [4- (3-Dimethylamino-propyl) -piperazin-1-yl] -3-quinolin-6-yl-3,4- dihydro- quinazolin- Synthesis of

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (506 mg, 1.54 mmole) and 1- [2- (dimethylamino) ethyl] piperazine (521 mg, 3.04 mmole) were added to a solution of Ester To a solution of {2- [4- (3-dimethylamino-propyl) -piperazin-1-yl] -3-quinolin- Yl-3,4-dihydro-quinazolin-4-yl} -acetic acid methyl ester.

2H), 8.00-7.80 (m, 2H), 7.60-7.10 (m, 2H), 8.00 (m, (M, 2H), 6.90 (m, 1H), 6.90 (m, )

Example  32

Ester Intermediate 6

Yl] -3- (6-fluoro-naphthalen-2-yl) -3,4-dihydro-quinazoline-4 -Acetic acid methyl ester ([2- [4- (3-Dimethylamino-propyl) -piperazin-1-yl] -3- (6- fluoro-naphthalen-2-yl) -3,4-dihydro -quinazolin-4-yl] -acetic acid methyl ester

((E) -3- [2 (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and (509 mg, 1.46 mmole) and 1- [2- (dimethylamino) ethyl] piperazine (454 mg, 2.88 mmol) were added to a solution of 2- 2- [4- (3-dimethylamino-propyl) -piperazin-1-yl] -methanone represented by the formula below was synthesized using the same reaction as the ester intermediate method 1 (Example 27) -3 - (6-fluoro-naphthalen-2-yl) -3,4-dihydro-quinazolin-4-yl] -acetic acid methyl ester.

1H, NMR (400MHz, CDCl3) 7.84 (m, 2H), 7.43-7.20 (m, 4H), 7.13 , 3.76 (s, 3H), 3.50 (br, 4H), 2.85 (m,

Example  33

Ester Intermediate 7

Yl) -3,4-dihydro-quinazolin-4-yl] - (4-fluoro-naphthalen- 4-yl-piperazin-1-yl) -3,4-dihydro-quinazolin-4-yl (4-pyrrolidin- ] -acetic acid methyl ester

((E) -3- [2 (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and (498 mg, 1.43 mmole) and 1-pyridin-4-yl-piperazine (470 mg, 2.88 mmole) were used in the same manner as in (3-fluoro-naphthalen-2-yl) -2- (4-pyridin-4-yl- Piperazin-l-yl) -3,4-dihydro-quinazolin-4-yl] -acetic acid methyl ester.

1H, NMR (400MHz, CDCl3) 8.23 (d, 2H), 7.50-6.90 (m, 10H), 6.58 (d, 2H), 5.16 ), 3.55 (br, 4H), 3.25 (br, 4H), 2.81 (m,

Example  34

Ester Intermediate 8

Yl} -3-naphthalen-2-yl-3,4-dihydro-quinazolin-4-yl} -acetic acid Methyl ester ({2- [4- (2-Dimethylamino-ethyl) -piperazin-1-yl] -3-naphthalen-2-yl-3,4- dihydro- quinazolin- Synthesis of

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (479 mg, 3.04 mmole) and 1- [2- (dimethylamino) ethyl] piperazine (50 mg, 2-yl) -3-naphthalene-2 (2-dimethylamino-ethyl) -piperazin-1 -yl ester shown in the following formula Yl-3,4-dihydro-quinazolin-4-yl} -acetic acid methyl ester.

Yield: 0.557 g (75%), 1HNMR (200MHz, CDCl3) .78-6.90 (m, 11H, aromatic), 6.45 (t, 1H), 5.34 (dd, J = 5.6 and 9.6 Hz, (M, 2H, -CO-CH2 (CH2CH2O)), 4.51-4.37 (m, 2H, PhCH2-NH-), 3.74 (Br, 4H), 2.18 (s, 6H, -N- (CH3) 2), 2.10

Example  35

Ester Intermediate 9

Yl) -3- (4-pyridin-2-yl-phenyl) -3,4-dihydro-quinazolin-4- Acetic acid methyl ester ([2- [4- (2-Dimethylamino-ethyl) -piperazin-1-yl] -3- (4- pyridin- quinazolin-4-yl] -acetic acid methyl ester

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (493 mg, 1.82 mmole) and 1- [2- (dimethylamino) ethyl] piperazine (443 mg, 2.82 mmole) in dichloromethane (2- [4- (2-dimethylamino-ethyl) -piperazin-1 -yl] -3, 3-dihydroxybenzene represented by the following formula, using the same reaction as in the above- - (4-pyridin-2-yl-phenyl) -3,4-dihydro-quinazolin-4-yl] -acetic acid methyl ester.

Yield: 0.344 g (48%), 1HNMR (200MHz, CDCl3) 8.59-6.84 (m, 12H, aromatic), 5.22 (dd, J = 5.6 and 10.0 Hz, (M, 2H, -CO-CH2-), 2.29 (br, 4H), 2.50-2.52 ), 2.16 (s, 6H, -N- (CH3) 2), 2.11 (br, 4H)

Example  36

Ester Intermediate 10

Dihydro-quinazolin-4-yl] -acetic &lt; / RTI &gt; (2-methyl-pyridin- (4-pyridin-2-yl-phenyl) -3,4-dihydro-quinazolin-4-yl] -acetic &lt; / RTI &gt; acid methyl ester

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (406 mg, 1.41 mmol) and N, N, N'-trimethyl-pentane-1,5-diamine (50 mg, Amino] -phenyl) -methyl-amino] -3- ((2-methylpiperazin-1 -yl) 4-pyridin-2-yl-phenyl) -3,4-dihydro-quinazolin-4-yl] -acetic acid methyl ester.

Yield: 0.521 g (74%), 1HNMR (200MHz, CDCl3) 8.67-6.89 (m, 12H, aromatic), 5.35 (dd, J = 5.6 and 9.6 Hz, 1H, J = 10.0 and 14.8, -CO-CH2-), 2.50-2.45 (dd, 1H, J = 5.2 and 14.4, -), 2.74 (br, (CH3) 2 (CH3) 2), 2.17 (s, 6H, N-CH3) )

Example  37

Ester Intermediate 11

Yl) -3,4-dihydro-quinazolin-4-yl} - (2-methylamino-ethyl) -piperazin- Acetic acid methyl ester ({3- (4-Bromo-phenyl) -2- [4- (2-dimethylamino-ethyl) -piperazin- 1- yl] -3,4- dihydro- quinazolin- acetic acid methyl ester

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (4-bromo-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester (510 mg, 1.36 mmole) and 1- [2- (dimethylamino) ethyl] piperazine (440 mg, 2.80 mmole) (4-bromo-phenyl) -2- [4- (2-dimethylamino-ethyl) -piperazine L-yl] -3,4-dihydro-quinazolin-4-yl} -acetic acid methyl ester.

1H, NMR (CDCl3) 7.32-6.85 (m, 8H), 5.00 (m, 1H), 3.71 (s, 3H), 3.40 (br, 4H), 2.75 ), 2.78 (m, 1H), 2.40-2.24 (m 8H), 2.19 (s, 6H)

Example  38

Ester Intermediate 12

Dihydro-quinazolin-4-yl] -acetic &lt; / RTI &gt; acid methyl ester Ester of (3- (4-bromo-phenyl) -2- (4-pyridin-4-yl-piperazin-1-yl) -3,4-dihydro-quinazolin-4-yl] -acetic acid methyl ester synthesis

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (4-bromo-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester (496 mg, 1.39 mmol) and 1-pyridin-4-yl-piperazine (457 mg, 2.80 mmole) The title compound was prepared from {3- (4-bromo-phenyl) -2- [4- (2-dimethylamino-ethyl) -piperazin- 1- Yl] -3,4-dihydro-quinazolin-4-yl} -acetic acid methyl ester.

1H), 3.79 (s, 3H), 3.60 (d, 2H), 3.40 (s, 3H) ), 3.61 (br, 4H), 3.25 (br, 4H), 2.80

Example  39

Ester Intermediate 13

Yl] - (4-fluoro-phenyl) -3,4-dihydro-quinazolin-4-yl] - Acetic acid methyl ester ([2- [4- (2-Dimethylamino-ethyl) -piperazin-1-yl] -3- (4-fluoro- phenyl) -3,4- dihydro- quinazolin- acetic acid methyl ester

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (498 mg, 1.67 mmole) and 1- [2- (dimethylamino) ethyl] piperazine (528 mg, 3.36 mmole) in the same manner as in (2- [4- (2-dimethylamino-ethyl) -piperazin-1 -yl] -3- (4 -Fluoro-phenyl) -3,4-dihydro-quinazolin-4-yl] -acetic acid methyl ester.

2H), 2.77 (m, 2H), 3.72 (s, 3H), 3.43 (br, , 2.49 (m, 1 H), 2.41 - 2.15 (m, 12 H)

Example  40

Ester Intermediate 14

Yl) -3- (4-morpholin-4-yl-phenyl) -3,4-dihydro-quinazoline-4 -Acetic acid methyl ester ([2- [4- (2-Dimethylamino-ethyl) -piperazin-1-yl] -3- (4-morpholin- -quinazolin-4-yl] -acetic acid methyl ester

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (505 mg, 1.39 mmole) and 1- [2- (dimethylamino) ethyl] piperazine (434 mg, 2.76 mmole) were added to a solution of 4- (4-morpholin- ) Was reacted with [2- [4- (2-dimethylamino-ethyl) -piperazin-1-yl] - 3- (4-morpholin-4-yl-phenyl) -3,4-dihydro-quinazolin-4-yl] -acetic acid methyl ester.

2H), 6.94 (m, 4H), 6.77 (d, 2H), 4.99 (m, 1H), 3.86 (m, 4H) (S, 3H), 3.46 (br, 4H), 3.08 (m, 4H), 2.79

Example  41

Ester Intermediate 15

Amino] -3,4-dihydro-quinazolin-4-yl} -acetic acid (prepared according to the procedure described for the synthesis of {3- (4-dimethylamino-phenyl) -2- Synthesis of methyl ester ({3- (4-Dimethylamino-phenyl) -2 - [(4-dimethylcarbamoyl-butyl) -methylamino] -3,4-dihydro-quinazolin-4-yl} -acetic acid methyl ester

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (503 mg, 1.64 mmole) and 5-methylamino-pentanobic acid dimethylamide (515 mg, 3.26 mmole) in the same manner as in step Synthesis of {3- (4-dimethylamino-phenyl) -2 - [(4-dimethylcarbamoyl-butyl) -methyl-amino ] -3,4-dihydro-quinazolin-4-yl} -acetic acid methyl ester.

2H), 6.85 (m, 4H), 6.52 (m, 2H), 4.85 (m, 1H), 3.71 (s, 3H) 2H), 2.51 (s, 3H), 2.89 (s, 3H), 2.83 (s,

Example  42

Ester Intermediate 16

Yl] -3- (4-dimethylamino-phenyl) -3,4-dihydro-quinazolin-4-yl] -Acetic acid methyl ester ([2- [4- (2-Dimethylamino-ethyl) -piperazin-1-yl] -3- (4-dimethylamino- phenyl) -3,4- dihydro- quinazolin- -acetic acid methyl ester

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (513 mg, 3.26 mmole) was used in the same manner as in the synthesis of the compound of Example 1 (2) using 2- (4-dimethylamino-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester (2- [4- (2-dimethylamino-ethyl) -piperazin-1 -yl] -3- ( 4-dimethylamino-phenyl) -3,4-dihydro-quinazolin-4-yl] -acetic acid methyl ester.

2H), 6.90 (m, 4H), 6.55 (d, 2H), 5.30 (m, 1H), 3.70 (s, 3H) 1H), 2.40 (m, 1H), 2.44 (m, 2H)

Example  43

Ester Intermediate 17

4-yl-3,4-dihydro-quinazolin-4-yl] -acetic acid methyl ester ([2- ( 4-Acetyl-piperazin-1-yl) -3-biphenyl-4-yl-3,4-dihydro-quinazolin-4-yl] -acetic acid methyl ester

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (507 mg, 1.43 mmole) and 1-acetylpiperazine (361 mg, 2.82 mmole) were used to synthesize the ester intermediate 1 (Example Yl) -3-biphenyl-4-yl-3,4-dihydro-quinazolin-4-ylcarbamate, represented by the formula: Yl] acetic acid methyl ester.

(M, 2H), 3.75 (s, 3H), 3.50-3.10 (m, 2H) (m, 5H), 2.6-2.4 (m, 2H), 1.71 (s, 3H)

Example  44

Ester Intermediate 18

(4-dimethylcarbamoyl-butyl) -methyl-amino] -3,4-dihydro-quinazolin-4-yl} -acetic acid methyl ester Synthesis of {3-Biphenyl-4-yl-2 - [(4-dimethylcarbamoyl-butyl) -methylamino] -3,4-dihydro-quinazolin-4-yl} -acetic acid methyl ester

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (516 mg, 1.41 mmole) and 5-methylamino-pentanobic acid dimethylamide (446 mg, 2.82 mmole) were added to a solution of the ester intermediate 1 - (4-dimethylcarbamoyl-butyl) -methyl-amino] -3, &lt; RTI ID = 0.0 & 4-dihydro-quinazolin-4-yl} -acetic acid methyl ester.

(S, 3H), 3.30 (m, 2H), 2.96 (s, H), 3.45 (m, 2H) ), 2.92 (s, 3H), 2.83 (s, 3H), 2.50-2. 20 (m, 4H)

Example  45

Ester Intermediate 19

(3-Biphenyl-4-yl-2- {[3- (3,3-dimethyl-ureido) -propyl] -methyl-amino} -3,4- dihydro- quinazolin- -Acetic acid methyl ester ((3-Biphenyl-4-yl-2- {[3- (3,3-dimethyl-ureido) -propyl] -methylamino} -3,4- dihydro- quinazolin- yl) -acetic acid methyl ester

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (500 mg, 1.41 mmole) and 1,1-dimethyl-3- (3-methylamino-propyl) -urea (450 mg, 2.82 mmol) in acetonitrile (3-Biphenyl-4-yl-2 - {[3- (3,3-dimethylpiperazin-1-ylmethyl) -Ureido) -propyl] -methyl-amino} -3,4-dihydro-quinazolin-4-yl) -acetic acid methyl ester.

J = 4.4 and 10.4 Hz, 1H, -CH2 (m, 13H, aromatic), 5.70 (br, (M, 2H), 2.85 (s, 6H), 3.45 (s, 3H) , 2.67-2.54 (m, 2H), 2.46-2.41 (m, 2H), 1.76-1.68 (br, 6H)

Example  46

Ester Intermediate 20

Yl} -3,4-dihydro-quinazolin-4-yl} - acetic acid 4-yl-2- [4- (2-dimethylamino-ethyl) -piperazin-1-yl] -3,4-dihydro-quinazolin- 4-yl} -acetic acid methyl ester ) Synthesis of

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (508 mg, 1.43 mmole) and 1- [2- (dimethylamino) ethyl] piperazine (359 mg, 2.82 mmole) in tetrahydrofuran 4-yl-2- [4- (2-dimethylamino-ethyl) -piperazine-1-carboxylic acid tert- butyl ester represented by the following formula, using the same reaction as in the above- Yl] -3,4-dihydro-quinazolin-4-yl} -acetic acid methyl ester.

2H), 7.45 (t, 2H), 7.40 (m, 1H), 7.18 (m, 2H), 7.58 (d, 2H), 6.94 (m, 2H), 5.13 (m, IH), 3.74 (s, 3H), 3.48 (br, m, 7 H), 2.22 (s, 6 H)

Example  47

Ester Intermediate 21

4-yl-2- [4- (4-methyl-piperazin-l-yl) -piperidin- l-yl] -3,4- dihydro- quinazolin- -Acetic acid methyl ester ({3-Biphenyl-4-yl-2- [4- (4-methyl-piperazin-1-yl) -piperidin- 1 -yl] -3,4-dihydro-quinazolin- -yl} -acetic &lt; / RTI &gt; acid methyl ester

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (507 mg, 1.43 mmole) and 1-methyl-4-piperidin-4-yl-piperazine (517 mg, 2.82 mmole) were added to a solution of Biphenyl-4-yl-2- [4- (4-methyl-piperazin-1-yl) -piperazin-1-yl ester represented by the following formula ) -Piperidin-l-yl] -3,4-dihydro-quinazolin-4-yl} -acetic acid methyl ester.

1H), 3.72 (s, 3H), 3.38 (s, 3H), 3.40 (m, 2H) (s, 2H), 2.90-2.70 (m, 3H), 2.70-2.30 (m, 5H)

Example  48

Ester Intermediate 22

(4-methyl-piperazin-1 -yl) -4-oxo-butyl] -amino} -3,4-dihydro- quinazoline -4-yl) -acetic acid methyl ester ((3-Biphenyl-4-yl-2- { -3,4-dihydro-quinazolin-4-yl) -acetic acid methyl ester

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (4-methyl-piperazin-l-yl) -butan-l-yl) -phenyl] -acrylic acid methyl ester (504 mg, 1.42 mmole) Biphenyl-4-yl-2- [4- (4 (trifluoromethyl) phenyl) -1,2,3,4-tetrahydroisoquinolin- -Piperidin-l-yl] -3,4-dihydro-quinazolin-4-yl} -acetic acid methyl ester.

(M, 3H), 3.50 (s, 3H), 2.85-2.70 (m, 3H) (m, 8 H), 2.40 - 1.9 (m, 12 H)

Example  49

Ester Intermediate 23

Dihydro-quinazolin-4-yl] -acetic acid methyl ester ([3-Biphenyl (4-methyl-piperazin- -4-yl-2- (4-methyl-piperazin-1-yl) -3,4-dihydro-quinazolin-4-yl] -acetic acid methyl ester

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (498 mg, 1.41 mmole) and 1-methylpiperazine (283 mg, 2.82 mmole) were used to synthesize the ester intermediate 1 (Example Yl) -3,4-dihydro-quinazolin-4-yl-2- (4-methyl-piperazin- Yl] acetic acid methyl ester.

2H), 6.80 (d, 2H), 6.15 (m, 4H), 7.28-7. 3H), 3.40-3.00 (m, 8H), 2.60-2.40 (m, 1H), 5.25 , &Lt; / RTI &gt; 2H), 1.72 (s, 3H)

Example  50

Ester Intermediate 24

Yl) -3,4-dihydro-quinazolin-4-yl (4-fluoro-phenyl) -Acetic acid methyl ester ({3-Biphenyl-4-yl-2- [4- (1 -methyl-piperidin-4-yl) -piperazin- 1 -yl] -3,4-dihydro-quinazolin- -yl} -acetic &lt; / RTI &gt; acid methyl ester

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (500 mg, 1.41 mmole) and 1- (1-methyl-piperidin-4-yl) -piperazine (517 mg, 2.82 mmole) in acetonitrile ) Was converted to [3-biphenyl-4-yl-2- (4-methyl-piperazin-1-yl) -3,4-dihydro-quinazolin-4-yl] -acetic acid methyl ester.

1H), 3.72 (s, 3H), 3.60 (s, 3H), 3.70 (m, 2H) 3H), 2.90-2.70 (m, 2H), 2.60-2.40 (m, 6H)

Example  51

Ester Intermediate 25

(4-dimethylamino-benzyl) -methyl-amino] -3,4-dihydro-quinazolin-4-yl} -acetic acid methyl ester { Synthesis of 3-Biphenyl-4-yl-2 - [(4-dimethylamino-benzyl) -methylamino] -3,4-dihydro-quinazolin-4-yl} -acetic acid methyl ester

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (507 mg, 1.43 mmole) and dimethyl- (4-methylaminomethyl-phenyl) -amine (463 mg, 2.82 mmole) (3-Biphenyl-4-yl-2- (4-methyl-piperazin-1 -yl) -3,4 -Dihydro-quinazolin-4-yl] -acetic acid methyl ester.

1H NMR (200 MHz, CDCl3) 7.55-6.90 (m, 16H), 6.67 (d, 1H), 5.15 (m, 1H), 3.64 (s, 3H), 3.0-2.7 , 8 H), 2.61 (m, 1 H), 1.6 (s 6 H)

Example  52

Ester Intermediate 26

(3-biphenyl-4-yl-2- [methyl- (2-piperidin- 1 -yl- ethyl) -amino] -3,4- dihydro- quinazolin- 4-yl} -acetic acid Methyl ester ({3-Biphenyl-4-yl-2- [methyl- (2-piperidin- 1- yl-ethyl) -amino] -3,4- dihydro- quinazolin- 4- yl} Synthesis of

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (2-piperidin-l-yl-ethyl) -amine (401 mg, 2.82 mmole) was added to a solution of 4- Biphenyl-4-yl-2- [methyl- (2-piperidin-l-yl) -methanone &lt; / RTI &gt; -Ethyl) -amino] -3,4-dihydro-quinazolin-4-yl} -acetic acid methyl ester.

1H, NMR (CDCl3): 7.70-7.10 (m, 13H), 5.15 (m, 1H), 3.80 (s, 3H), 3.20 ), 2.7-2.3 (m, 13H), 1.5 (m, 6H)

Example  53

Ester Intermediate 27

Yl} -3,4-dihydro-quinazolin-4-yl} - acetic acid 1-yl] -3,4-dihydro-quinazolin-4-yl} -acetic acid methyl ester &lt; RTI ID = 0.0 &gt; (3-Biphenyl- ) Synthesis of

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (503 mg, 1.43 mmole) and 1- [2- (dimethylamino) propyl] piperazine (483 mg, 2.82 mmole) (3-Biphenyl-4-yl-2- [4- (3-dimethylamino-propyl) -piperazine-1-carboxylic acid ethyl ester shown by the following formula: Yl] -3,4-dihydro-quinazolin-4-yl} -acetic acid methyl ester.

(M, 2H), 5.20-5.05 (m, 1H), 3.73 (s, 3H), 3.60 (m, 2H) 2H), 2.40-2.00 (m, 14H), 1.70-1. 50 (m, 2H)

Example  54

Ester Intermediate 28

Dihydro-quinazolin-4-yl] -acetic &lt; / RTI &gt; acid &lt; RTI ID = 0.0 &gt; Methyl ester (Synthesis of [3-Biphenyl-4-yl-2- (4-tert-butoxycarbonylamino-piperidin- 1 -yl) -3,4-dihydro- quinazolin- 4-yl] -acetic acid methyl ester

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (509 mg, 1.43 mmole) and 4- (N-tert-butoxy-amino) piperidine (559 mg, 2.82 mmole) 4-yl-2- (4-tert-butoxycarbamoylamino-piperidin-1-yl) -1- -Yl) -3,4-dihydro-quinazolin-4-yl] -acetic acid methyl ester.

Yield: 0.334 g (42%)

2H), 3.52 (s, 3H), 2.82 (m, 2H), 4.40 (d, 2.05 (m, 7H), 1.22 (s, 9H)

Example  55

Ester Intermediate 29

Dihydro-quinazolin-4-yl] - &lt; / RTI &gt; -Acetic acid methyl ester ([2- (4-Dimethylcarbamoyl-butyl) -methyl-amino] -3- (4- pyrrolidin- 1 -yl- phenyl) -3,4- dihydro- quinazolin- -acetic acid methyl ester

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (501 mg, 1.44 mmole) and 5-methylamino-pentanobic acid dimethylamide (456 mg, 2.88 mmole) were added to a solution of 4- (4-pyrrolidin- 1 -yl-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester (4-dimethylcarbamoyl-butyl) -methyl-amino] -3- (4-piperazin-1-yl) -methanone represented by the formula below using the same reaction as in the synthesis of the ester intermediate 1 L-yl-phenyl) -3,4-dihydro-quinazolin-4-yl] -acetic acid methyl ester.

(M, 6H), 6.43 (d, 2H), 5.23 (m, 1H), 3.7 (s, 3H), 3.24 (br, 4H 2H), 2.30 (br, 2H), 2.00 (s, 3H), 2.70 (s, 3H) , 1.45 (br, 4H)

Example  56

Ester intermediate 30

Yl) -3- (4-pyrrolidin-l-yl-phenyl) -3,4-dihydro-quinazolin- 4-yl] -acetic acid methyl ester ([2- [4- (2-Dimethylamino-ethyl) -piperazin-1-yl] -3- (4-pyrrolidin- dihydro-quinazolin-4-yl] -acetic acid methyl ester

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (497mg, 1.43mmole) and 1- [2- (dimethylamino) ethyl] piperazine (453mg, 2.88mmol) in acetonitrile 2- [4- (2-dimethylamino-ethyl) -piperazin-1-yl] -methanone represented by the formula below using the same reaction as in the above ester intermediate method 1 (Example 27) -3- (4-pyrrolidin- 1 -yl-phenyl) -3,4-dihydro-quinazolin-4-yl] -acetic acid methyl ester.

(M, 2H), 6.91 (d, 2H), 6.41 (d, 2H), 4.95 (dd, 1H), 3.73 (s, 3H), 3.45 (br 4H), 3.21 (m, 4H), 2.87-2.75 (m,

Example  57

Ester Intermediate 31

Yl] -3- (4-pyrrolidin-l-yl-phenyl) -3,4-dihydro-quinazoline- 4-yl] -acetic acid methyl ester ([2- [4- (3-Dimethylamino-propyl) -piperazin- dihydro-quinazolin-4-yl] -acetic acid methyl ester

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (503 mg, 1.45 mmole) and 1- [2- (dimethylamino) propyl] piperazine (493 mg, 2.88 mmol) in dichloromethane 2- [4- (3-dimethylamino-propyl) -piperazin-1-yl] -methanone represented by the formula below was synthesized using the same reaction as the ester intermediate method 1 (Example 27) -3- (4-pyrrolidin- 1 -yl-phenyl) -3,4-dihydro-quinazolin-4-yl] -acetic acid methyl ester.

(M, 2H), 3.86 (s, 2H), 3.75 (s, 3H), 3.65 (s, 2H) (M, 2H), 1.65 (m, 2H), 1.80 (m, 2H)

Example  58

Ester intermediate 32

(4-pyrrolidin-l-yl-phenyl) -3,4-dihydro-quinazolin-4-yl] 4-yl-piperazin-1-yl) -3- (4-pyrrolidin-1-yl-phenyl) -3,4- dihydroquinazolin- 4- yl] -acetic acid methyl ester

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (508 mg, 1.46 mmole) and 1-pyridin-4-yl-piperazine (470 mg, 2.88 mmole) were used in the same manner as in (4-pyridin-4-yl-piperazin-1-yl) -3- (4-pyrrolidone) Di-l-yl-phenyl) -3,4-dihydro-quinazolin-4-yl] -acetic acid methyl ester.

2H), 6.42 (d, 2H), 4.95 (d, 2H), 6.91 (d, 2H) (m, 2H), 1.96 (m, 4H), 3.70 (s, 3H)

Example  59

Ester intermediate 33

Yl] -3- (5,6,7,8-tetrahydro-naphthalen-2-yl) -3,4-di -Acetic acid methyl ester ([2- [4- (2-Dimethylamino-ethyl) -piperazin-1-yl] -3- (5,6,7,8-tetrahydro-quinazolin- naphthalen-2-yl) -3,4-dihydro-quinazolin-4-yl] -acetic acid methyl ester

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (500 mg, 1.50 mmole) and 1- [2- (dimethylamino) ethyl] piperazine were added to a solution of (5,6,7,8-tetrahydro-naphthalen-2-yliminomethyleneamino) -phenyl] -acrylic acid methyl ester 2- [4- (2-dimethylamino-ethyl) -piperazine &lt; / RTI &gt; represented by the formula below using the same reaction as in the above ester intermediate method 1 (Example 27) -1- yl] -3- (5,6,7,8-tetrahydro-naphthalen-2-yl) -3,4-dihydro- quinazolin-4-yl] -acetic acid methyl ester .

1H NMR (200MHz, CDCl3) 7.50-7.25 (m, 4H), 7.15-6.68 (m, 3H), 5.19 (br, 4H), 2.80 (m, 1H), 2.68 (br, 4H), 2.54

Example  60

Ester intermediate 34

3- (5,6,7,8-tetrahydro-naphthalen-2-yl) -3,4-dihydro-quinazoline 4-yl-piperazin-1-yl) -3- (5,6,7,8-tetrahydro-naphthalen-2- yl) -acetic acid methyl ester -3,4-dihydro-quinazolin-4-yl] -acetic acid methyl ester

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (50 mg, 1.51 mmole) and 1-pyridin-4-yl-piperazine (490 mg, (2-dimethylamino-ethyl) -piperazin-1-yl (3.0 g, 3.0 mmole), using the same reaction as the ester intermediate (1) ] -3- (5,6,7,8-tetrahydro-naphthalen-2-yl) -3,4-dihydro-quinazolin-4-yl] -acetic acid methyl ester.

Yield: 0.584 g (78%), 1HNMR (200MHz, CDCl3) 7.80-7.20 (m, 9H), 7.1-6.70 (m, 8H), 5.30-5.20 -3.20 (m, 12H), 2.50-2.30 (m, 6H), 1.90-1.6 (m, 6H)

Example  61

Dihydro-quinazolin-4-yl] -acetic acid ([2- (4-acetyl-piperazin- -piperazine-1-yl) -3-biphenyl-4-yl-3,4-dihydro-quinazoline-4-yl] -acetic acid

4-yl] -3,4-dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17: Example 43) (505 mg, 1.05 mmole) was added to a THF / water (1: 1) solution (10 mL). To this mixture was added lithium hydroxide (100 mg, 4.16 mmole) at room temperature and the reaction was heated to 60 &lt; 0 &gt; C and stirred for 2 hours. Thereafter, hydrochloric acid was added dropwise to adjust the pH to about 3 to 4, and the organic layer was extracted three times with dichloromethane. The collected organic layer was dried over anhydrous sodium sulfate and then concentrated using a rotavaporator to obtain [2- (4-acetyl-piperazin-1-yl) -3-biphenyl- 3,4-dihydro-quinazolin-4-yl] -acetic acid.

Yield: 463 mg, 94%, Mass: (M + H) &lt; ⁺ & gt ^; : 469

1H, NMR (200MHz, CDCl3) 7.55-7.30 (m, 4H), 7.29-7.10 (m, 5H), 7.19-6.90 2H), 3.50-3.10 (m, 8H), 2.6-2.4 (m, 2H), 1.71 (s, 3H)

Example  62

4-yl-3,4-dihydro-quinazolin-4-yl] -N- (4-fluoro- 4-yl] -N- (4-fluoro-benzyl) -acetamide ([2- (4-acetyl- piperazine- 1 -yl) -3-biphenyl-4-yl-3,4- dihydroquinazolin- ) -acetamide &lt; / RTI &gt;

4-yl] -3,4-dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17: Example 43) (105 mg, 0.22 mmole) and 1.1 equivalents of 1,5,7-triazabicyclo [4.4.0] dec-5-ene (1,5,7- Triazabicyclo [ ene (TBD) (32 mg, 0.23 mmole) was added to 2 equivalents of 4-fluorobenzylamine (0.2 mL) and stirred at 70 &lt; 0 &gt; C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the concentrate was diluted with ethyl acetate (5.0 mL), and then washed with a 0.5 M aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogencarbonate solution, water, and brine in this order. The organic layer was dried over anhydrous sodium sulfate, concentrated using a rotary evaporator, and purified by column chromatography with silica and a developing solution of methanol: ethyl acetate (1: 9) to obtain 2- [2- Yl) -3-biphenyl-4-yl-3,4-dihydro-quinazolin-4-yl] -N- (4-fluoro-benzyl) -acetamide.

Yield: 72 mg, 57%, Mass (M + H) &lt; ⁺ & gt ^; : 576

(M, 3H), 6.20 (br, IH), 5.31-5.30 (m, IH), 4.50 (m, 2H) 2H), 3.50-3.10 (m, 8H), 2.6-2.4 (m, 2H), 1.71 (s, 3H)

Example  63

4-yl-3,4-dihydro-quinazolin-4-yl] -N- (4-trifluoromethylpiperazin-1-yl) Methyl-benzyl) -acetamide ([2- (4-acetyl-piperazine-1-yl) -3-biphenyl-4-yl-3,4- dihydro- quinazolin- -benzyl) -acetamide &lt; / RTI &gt;

Dihydro-quinazolin-4-yl] -acetic acid (example 61) (101 mg, 0.21 mmole) and 1.1 equivalents of 1-hydroxybenzotriazole (HOBT) (31 mg, 0.23 mmole) were added to carbon dichloride (5.0 mL). 1.1 equivalents of 4-trifluoromethyl-benzylamine (40 mg, 0.23 mmole) was added dropwise to the mixture at 0 占 and stirred at 0 占 폚 for 1 hour. 1.1 eq. Of 1- [3- (dimethylamine) propyl] -3-ethylcarbodiimide hydrochloride (EDC) (44 mg, 0.23 mmole) was added to the reaction and stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the concentrated material was diluted with dichloromethane (5.0 mL), and then washed with an aqueous 0.5M hydrochloric acid solution, a saturated aqueous sodium hydrogencarbonate solution, water, and brine in this order. The organic layer was dried over anhydrous sodium sulfate, concentrated using a rotavaporator, and purified by column chromatography with silica and a developing solution of methanol: dichloromethane (1: 9) to obtain 2- [2- (4-acetyl Yl) -3-biphenyl-4-yl-3,4-dihydro-quinazolin-4-yl] -N- (4- trifluoromethyl- benzyl) -acetamide Respectively.

Yield: 85.4 mg, 65% Mass (M + H) &lt; ⁺ & gt ^; : 626

1H, NMR (200MHz, CDCl3) 7.60-7.30 (m, 10H), 7.26-7.15 (m, 6H), 6.98 (m, 2H), 6.35 ), 3.50-3.10 (m, 8H), 2.7-2.4 (m, 2H), 1.72 (s, 3H)

Example 64 (the same method as in Example 62)

Dihydro-quinazolin-4-yl] -N- (4-methyl-benzyl) -piperazin-1- 4-yl] -N- (4-methyl-benzyl) -acetamide ([2- (4-acetyl- piperazine- 1- yl) -3-biphenyl- -acetamide &lt; / RTI &gt;

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-3,4-dihydro-quinazolin-4-yl] -acetic acid was used in the place of 4-fluorobenzylamine in place of 4-fluorobenzylamine 2- [2- ((4-methyl-benzyloxy) -2,3-dihydro-2H- 4-yl] -N- (4-methyl-benzyl) -acetamide was obtained Respectively.

Yield: 94.0 mg, 81%, Mass (M + H) &lt; ⁺ & gt ^; : 572

1H, NMR (200MHz, CDCl3): 7.57-7.29 (m, 6H), 7.27-7.64 (m, 11H), 6.35 2H), 2.30 (s, 3H), 1.78 (s, 3H)

Example 65 . (Same method as in Example 62)

4-yl-3,4-dihydro-quinazolin-4-yl] -N- (4-methoxy- 4-yl] -N- (4-methoxy-benzyl) -acetamide ([ ) -acetamide &lt; / RTI &gt;

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-3,4-dihydro-quinazolin-4-yl] -acetic acid was used in the place of 4-fluorobenzylamine in place of 4-fluorobenzylamine 2- [2- (4-methoxy-benzyl) -2,3-dihydroisoquinolin-2-yl] -methanone represented by the following formula was obtained substantially in the same manner as in Example 62, Dihydro-quinazolin-4-yl] -N- (4-methoxy-benzyl) -acetamide &Lt; / RTI &gt;

Yield: 58.8 mg, 46%, Mass (M + H) &lt; ⁺ & gt ^; : 588

1H, NMR (200MHz, CDCl3) 7.56-7.33 (m, 4H), 7.28-7.10 (m, 6H), 7.17 (m, 2H), 6.80 3H), 3.40-3.00 (m, 8H), 2.60-2.40 (m, 2H), 1.72 (s, 3H) )

Example 66 . (Same method as in Example 62)

4-yl-3,4-dihydro-quinazolin-4-yl] -N-benzyl-acetamide (prepared from 2- [ Synthesis of 2- (4-acetyl-piperazine-1-yl) -3-biphenyl-4-yl-3,4-dihydro-quinazoline-4-yl] -N-benzyl-acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-3,4-dihydro-quinazolin-4-yl] -acetic acid was used in the place of 4-fluorobenzylamine in place of 4-fluorobenzylamine 2- [2- (4-acetyl-piperazin-1-yl) -piperidin-4-yl] -quinolinecarboxylic acid dihydrochloride represented by the following formula was obtained in substantially the same manner as in Example 62, Piperazin-l-yl) -3-biphenyl-4-yl-3,4-dihydro-quinazolin-4-yl] -N- benzyl-acetamide.

Yield: 60.4 mg, 52%, Mass (M + H) &lt; ⁺ & gt ^; : 558

1H, NMR (200MHz, CDCl3) 7.56-6.95 (m, 18H), 5.31 (m, IH), 4.70-4.55 (dd, IH), 4.50-4.35 1H), 1.87 (s, 3H), 3.80 (m, 8H)

Example 67 . (Same method as in Example 62)

4-yl-2- [4- (2-dimethylamino-ethyl) -piperazin-1-yl] -3,4- dihydro- quinazoline- - N-benzyl-2- {3- biphenyl-4-yl-2- [4- (2-dimethylamino-ethyl) -piperazine- 1 -yl] -3,4- dihydro- quinazoline- 4-yl} -acetamide &lt; / RTI &gt;

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2- [4- (2-dimethylamino-ethyl) -piperazin-l-yl] -3,4-dihydro- quinazoline- Was prepared in substantially the same manner as in Example 62, using (99 mg, 0.20 mmole) and benzylamine (0.2 mL) in a similar manner to that of 4-yl-2- [4- (2-dimethylamino-ethyl) -piperazin-1-yl] -3,4- dihydro- quinazoline- -Yl} -acetamide. &Lt; / RTI &gt;

Yield: 97 mg, 85%, Mass (M + H) &lt; ⁺ & gt ^; : 587

(1H, m, PhCH2-), 5.19 (1H, dd, J = 5.2 Hz and 9.6 Hz, COCH2CH), 4.38 (2H, s, NCH3), 2.14 (4H, br, -NCH2), 3.27 (4H, br, N-CH2), 2.59-2.33

Example 68 . (Same method as in Example 62)

N-Benzyl-2- [2- (5-dimethylamino-pentyl) -methyl-amino] -3- (4- pyridin-2-yl- phenyl) -3,4- dihydro- quinazoline- 2-yl-phenyl) -3,4-dihydroquinolin-2-yl] -pyrrolidin- 4-yl] -acetamide Synthesis of

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; Amino-3- (4-pyridin-2-yl-phenyl) -3,4-dihydro-quinazoline was used in the place of 4-fluorobenzylamine instead of 4- [ Pyridylmethylamine (0.2 mL) and 2-pyridylmethylamine (0.2 mL) in the same manner as in Example 62, the title compound was obtained as a white amorphous solid from the following Formula Benzyl-2- [2- (5-dimethylamino-pentyl) -methyl-amino] -3- (4- pyridin- - &lt; / RTI &gt; quinazolin-4-yl] -acetamide.

Yield: 81 mg, 71%, Mass (M + H) &lt; ⁺ & gt ^; : 575

1H, NMR (400MHz, CDCl3) 8.67-8.65 (m, 1H), 7.89 (d, 2H, J = 8.8), 7.76-7.71 1H, J = 1.2 and 7.6), 6.93-6.89 (m, IH), 6.73 (br, IH), 5.38-5.34 (dd 1H, J = 5.2 and 9.6), 4.53-4.43 (m, 2H), 3.46 (br, IH), 2.71 (br, 2H), 2.71-2.65 1H), 1.44 (br, 3H), 1.30 (br, 3H), 2.45 (d, 1H, J = 5.2 and 14.4), 2.25-2.20

Example 69. (The same method as in Example 62)

Yl) -3- (4-pyridin-2-yl-phenyl) -3,4-dihydro-pyrazol- Yl) -3- (4-pyridin-2-yl-acetamide) &lt; / RTI &gt; phenyl) -3,4-dihydroquinolin-4-yl] -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (2-dimethylamino-ethyl) -piperazin-1-yl] -3- (4-pyridin- Was prepared in substantially the same manner as in Example 62 by using (106 mg, 0.207 mmole) and benzylamine (0.2 mL) in the same manner as in Example 62, using 2- 2- [2- [4- (2-Dimethylamino-ethyl) -piperazin- 1 -yl] -3- (4- pyridin- 3,4-dihydro-quinazolin-4-yl] -acetamide.

Yield: 65.6 mg, 54%, Mass (M + H) &lt; ⁺ & gt ^; : 588

(D, J = 5.6 and 10.0 Hz, 1H, -CH2-CH-N-), 4.44-4.30 (m, 17H, aromatic) (m, 2H, PhCH2-NH-), 3.27 (br, 4H), 2.58-2.52, 2.40-2.35 N- (CH3) 2), 2.11 (br, 4H)

Example 70 . (Same method as in Example 62)

Yl} -3,4-dihydro-quinazolin-4-yl} - (2-methylamino-ethyl) -piperazin- 4-yl-2- [4- (2-dimethylamino-ethyl) -piperazine-1-yl] -3,4-dihydro- quinazoline-4-yl} -N- (4-methyl-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2- [4- (2-dimethylamino-ethyl) -piperazin-l-yl] -3,4-dihydro- quinazoline- 4-yl} -acetic acid methyl ester (ester intermediate 20: Example 46) (97 mg, 0.19 mmole) was reacted with 4-methyl-benzylamine (0.2 mL) 4-yl-2- [4- (2-dimethylamino-ethyl) -piperazin-1-yl] -3,4- dihydro- quinazoline-4 - yl} -N- (4-methyl-benzyl) -acetamide.

Yield: 97 mg, 85%, Mass (M + H) &lt; ⁺ & gt ^; : 601

1H, NMR (400MHz, CDCl3): 8.53-8.50 (t, IH, J = 6), 7.62-6.84 (m, 17H), 5.16-5.12 (dd, 1H, J = 4 and 10.4), 4.40-4.35 1H, J = 6 and 14.4), 4.18-4.13 (dd, 1H, J = 5.2 and 14.4), 2.61-2.55 (dd, 1H, 10.4 and 14.4), 2.28-2.25 (m, 4H) 3H), 2.17 (br, 2H), 2.09 (s, 6H)

Example 71 (the same method as in Example 62)

Yl} -3,4-dihydro-quinazolin-4-yl} - (2-methylamino-ethyl) -piperazin- 4-yl-2- [4- (2-dimethyl-ethyl) -piperazine-1-yl] -3,4-dihydro -quinazoline-4-yl} -N- (4-fluoro-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2- [4- (2-dimethylamino-ethyl) -piperazin-l-yl] -3,4-dihydro- quinazoline- 4-yl} -acetic acid methyl ester (Ester intermediate 20: Example 46) (100 mg, 0.195 mmole) was obtained by using substantially the same method as in Example 62, using 4-fluorobenzylamine 4-yl-2- [4- (2-dimethylamino-ethyl) -piperazin-1-yl] -3,4- dihydro- quinazoline-4 - yl} -N- (4-fluoro-benzyl) -acetamide.

Yield: 88 mg, 75%, Mass (M + H) &lt; ⁺ & gt ^; : 605

2H), 7.43-7.40 (m, 2H), 7.33-7.30 (m, 1H), 7.23-7.17 (m, 5H) 1H, J = 5.6 and 9.6), 4.44-4.40 (m, 1H), 7.12-7.10 (m, 2H), 3.46-3.33 (br, 4H), 2.61-2.55 (dd, 1H, J = 9.6 and 14.4), 2.45-2.40 (dd, 1H, J = 5.6 and 14.4) 2.21 (s, 8 H), 2.17 (br, 2 H)

Example 72 . (Same method as in Example 62)

Yl} -3,4-dihydro-quinazolin-4-yl} - (2-methylamino-ethyl) -piperazin- 4-yl-2- [4- (2-dimethylamino-ethyl) -piperazine-1-yl] -3,4-dihydro -quinazoline-4-yl} -N- (4-methoxy-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2- [4- (2-dimethylamino-ethyl) -piperazin-l-yl] -3,4-dihydro- quinazoline- 4-yl} -acetic acid methyl ester (ester intermediate 20: Example 46) (104 mg, 0.20 mmole) was obtained by using substantially the same method as in Example 62, using 4-methoxybenzylamine Piperazin-l-yl] -3,4-dihydro-quinazolin-4- &lt; / RTI &gt; Yl} -N- (4-methoxy-benzyl) -acetamide.

Yield: 93.7 mg, 76%, Mass (M + H) &lt; ⁺ & gt ^; : 617

J = 5.6 and 9.6), 4.44-4.40 (m, 2H), 3.46-3.33 (br, 4H), 2H), 2.17 (br, 2H), 2.35 (s, 2H), 2.45-2.55 (dd, 1H, J = 9.6 and 14.4), 2.45-2.40 (dd, 1H, J = 5.6 and 14.4)

Example 73 . (Same method as in Example 62)

Yl} -3,4-dihydro-quinazolin-4-yl} - (2-methylamino-ethyl) -piperazin- 4-yl-2- [4- (2-dimethylamino-ethyl) -piperazine-1-yl] -3,4-dihydro-quinazoline -4-yl} -N-pyridine-2-yl-methyl-acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2- [4- (2-dimethylamino-ethyl) -piperazin-l-yl] -3,4-dihydro- quinazoline- Was prepared in substantially the same manner as in Example 62, using (103 mg, 0.201 mmole) and pyridin-2-yl-methylamine (0.2 mL) 4-yl-2- [4- (2-dimethylamino-ethyl) -piperazin-1-yl] -3,4-dihydro-quinoline 4-yl} -N-pyridin-2-yl-methyl-acetamide.

Yield: 72 mg, 61%, Mass (M + H) &lt; ⁺ & gt ^; : 588

2H, PhCH2-NH (400 MHz, CDCl3) 8.51-6.97 (m, 17H, aromatic), 5.29 (dd, J = 4.8 and 10.4 Hz, 1H, -), 3.43 (br, 4H ), 2.78-2.71, 2.56-2.52 (dd, 2H, -CO-CH2-), 2.26 (br, 4H), 2.3 (s, 6H, -N- (CH 3) 2 ), 1.8 (br, 4H)

Example 74 (the same method as in Example 62)

Yl} -3,4-dihydro-quinazolin-4-yl} - (2-methylamino-ethyl) -piperazin- 4-yl-2- [4- (2-dimethylamino-ethyl) -piperazine-1-yl] -3,4-dihydro-quinazoline -4-yl} -N-pyridine-4-ylmethyl-acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2- [4- (2-dimethylamino-ethyl) -piperazin-l-yl] -3,4-dihydro- quinazoline- Was prepared in substantially the same manner as in Example 62, using 4-benzyloxy-4-pyrrolidin-4-yl} acetic acid methyl ester (Ester intermediate 20: Example 46) (96 mg, 0.188 mmole) and pyridin- 4-yl-2- [4- (2-dimethylamino-ethyl) -piperazin-l-yl] -3,4- dihydro- quinazoline -4-yl} -N-pyridin-4-ylmethyl-acetamide.

Yield: 48 mg, 43%, Mass (M + H) &lt; ⁺ & gt ^; : 588

(1H, m, PhCH2-), 8.86 (1H, CONH), 5.29 (1H, dd, J = 5.6 Hz and 9.2 Hz, COCH2CH) (4H, br, -NCH2), 3.46 (4H, br, N-CH2), 2.80-2.46

Example 75 . (Same method as in Example 62)

N-Benzyl-2- {3-biphenyl-4-yl-2- [methyl- (2- piperidin- 1- yl- ethyl) -amino] -3,4- dihydro- quinazolin- 4-yl-2- [methyl- (2-piperidin-1-yl-ethyl) -amino] -3,4-dihydro-quinazoline-4 -yl} -acetamide &lt; / RTI &gt;

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2- [methyl- (2-piperidin-l-yl-ethyl) -amino] -3,4-dihydro- quinazoline-4 instead of 4-fluorobenzylamine Was prepared in substantially the same manner as in Example 3, using (109 mg, 0.219 mmole) and benzylamine (100 mg) in the same manner as in Example 3, using N -Benzyl-2- {3-biphenyl-4-yl-2- [methyl- (2- piperidin- 1- yl- ethyl) -amino] -3,4-dihydro- quinazolin- } -Acetamide. &Lt; / RTI &gt;

Yield: 82.9 mg, 66%, Mass (M + H) &lt; ⁺ & gt ^; : 572

(M, 2H), 3.80-3.70 (m, IH), 7.30-7.30 (m, (m, 4H), 3.45-3.25 (br, 4H), 2.70-2.40 (m, 5H), 2.30-1.80

Example 76 : (Same method as in Example 62)

Yl) -2-methyl- (2-piperidin-l-yl-ethyl) -amino] -3,4-dihydro-quinazolin- 4-yl-2- [methyl- (2-piperidin-1-yl-ethyl) -amino] -3,4-dihydro- quinazoline-4-yl} -N- (4-fluoro-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2- [methyl- (2-piperidin-l-yl-ethyl) -amino] -3,4-dihydro- quinazoline-4 instead of 4-fluorobenzylamine -Acetic acid methyl ester (ester intermediate 26: Example 52) (100 mg, 0.20 mmole) and 4-fluorobenzylamine (0.2 mL) were used in the same manner as in Example 62 to give The title compound was prepared from 2- {3-biphenyl-4-yl-2- [methyl- (2-piperidin- 1 -yl- ethyl) -amino] -3,4- dihydro-quinazolin- Yl} -N- (4-fluoro-benzyl) -acetamide.

Yield: 52 mg, 44%, Mass (M + H) &lt; ⁺ & gt ^; : 590

(M, 2H), 3.80-3.70 (m, 2H), 7.30-7.30 (m, 2H) (m, 4H), 3.45-3.25 (br, 4H), 2.70-2.40 (m, 5H), 2.30-1.80

Example 77 . (Same method as in Example 62)

N-benzyl-2- [3-biphenyl-4-yl-2- (4- methyl- piperazin- 1 -yl) -3,4- dihydro-quinazolin- -benzyl-2- [3-biphenyl-4-yl-2- (4-methyl-piperazine- 1 -yl) -3,4-dihydro-quinazoline-4- yl] -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2- (4-methyl-piperazin-l-yl) -3,4-dihydro- quinazolin- 4-yl] -acetic acid was used in place of 4-fluorobenzylamine Benzyl-2- (3-methoxy-benzyl) -2,3-dihydro-2H-benzimidazole represented by the following structural formula was obtained substantially in the same manner as in Example 62, using the title compound (103 mg, 0.23 mmole) and benzylamine 4-yl-2- (4-methyl-piperazin-l-yl) -3,4-dihydro-quinazolin-4-yl] -acetamide.

Yield: 105.8 mg, 87%, Mass (M + H) &lt; ⁺ & gt ^; : 530

(M, 2H), 3.75 (m, 2H), 6.05 (m, 2H), 2.30 - 1.80 (m, 5H), &lt;

Example 78 (the same method as in Example 62)

Dihydro-quinazolin-4-yl] -N- (4-fluoro-pyridin-2- Benzyl) -acetamide (2- [3-biphenyl-4-yl-2- (4-methyl- piperazine- 1 -yl) -3,4- dihydro- quinazoline- 4- yl] -N- -benzyl) -acetamide &lt; / RTI &gt;

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2- (4-methyl-piperazin-l-yl) -3,4-dihydro- quinazolin- 4-yl] -acetic acid was used in place of 4-fluorobenzylamine Was prepared in substantially the same manner as in Example 62, using 2-fluoro-benzylamine (97 mg, 0.213 mmole) and 4-fluoro-benzylamine (0.2 mL) Dihydro-quinazolin-4-yl] -N- (4-fluoro-benzyl) -2,3- -Acetamide. &Lt; / RTI &gt;

Yield: 94 mg, 81%, Mass (M + H) &lt; ⁺ & gt ^; : 548

2H), 3.75 (m, IH), 5.25 (m, IH), 4.45-4.35 (m, (M, 4H), 2.30 (s, 3H), 2.45 (s, 3H)

Example 79 (the same method as in Example 62)

Dihydro-quinazolin-4-yl] -N- (4-trifluoromethyl-piperazin-l-yl) Methyl-piperazin-1-yl) -3,4-dihydro-quinazolin-4-yl] -N- (4-methyl- -trifluoromethyl-benzyl) -acetamide &lt; / RTI &gt;

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2- (4-methyl-piperazin-l-yl) -3,4-dihydro- quinazolin- 4-yl] -acetic acid was used in place of 4-fluorobenzylamine Was prepared in substantially the same manner as in Example 62, using 1-methyl-2-pyrrolidin-1-ylmethyl ester (Ester intermediate 23: Example 49) (101 mg, 0.22 mmole) and 4-trifluoromethyl- Dihydro-quinazolin-4-yl] -N- (4-trifluoromethyl-piperazin-l-yl) Methyl-benzyl) -acetamide. &Lt; / RTI &gt;

Yield: 104 mg, 79%, Mass (M + H) &lt; ⁺ & gt ^; : 598

1H, NMR (200MHz, CDCl3) 7.70-7.20 (m, 15H), 7.00-6.90 (m, 2H), 6.45 (br, IH), 5.25 ), 3.45-3.25 (br, 5H), 2.70-2.40 (m, 4H), 2.30 (s, 3H)

Example 80 . (Same method as in Example 62)

Dihydro-quinazolin-4-yl] -N- (4-methyl-benzyl) -piperazin-1- -Acetamide (2- [3-biphenyl-4-yl-2- (4-methyl-piperazine- 1 -yl) -3,4- dihydro- quinazolin- benzyl) -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; Dihydro-quinazolin-4-yl] -acetic acid was used in the place of 4-fluorobenzylamine instead of [[3-biphenyl- The title compound was prepared by a similar method to that of Example 62, using (94 mg, 0.207 mmole) and 4-methyl-benzylamine (0.2 mL) Dihydro-quinazolin-4-yl] -N- (4-methyl-benzyl) - Acetamide. &Lt; / RTI &gt;

Yield: 104 mg, 92.4%, Mass (M + H) &lt; ⁺ & gt ^; : 544

(M, 1H), 3.45-3.25 (m, 1H) (br, 4 [Eta]), 2.95 (m, IH), 2.40-1.80 (m,

Example 81 . (Same method as in Example 62)

Dihydro-quinazolin-4-yl] -N- (4-methoxy-pyridin-2- Benzyl) -acetamide (2- [3-biphenyl-4-yl-2- (4- methylpiperazin- 1 -yl) -3,4- dihydro- quinazolin- 4- yl] -N- -benzyl) -acetamide &lt; / RTI &gt;

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; Dihydro-quinazolin-4-yl] -acetic acid was used in the place of 4-fluorobenzylamine instead of [[3-biphenyl- The title compound was prepared by a similar method to that of Example 62, using the carboxylic acid ester (ester intermediate 23: Example 49) (101 mg, 0.22 mmole) and 4-methoxy-benzylamine Yl) -N- (4-methoxy-benzyl) -piperazin-1-yl] ) -Acetamide. &Lt; / RTI &gt;

Yield: 99 mg, 80%, Mass (M + H) &lt; ⁺ & gt ^; : 560

1H NMR (200 MHz, CDCl3) 8.25 (br, IH), 7.80-7.00 (m, 15H), 6.75 (d, 2H), 5.25 2H), 2.14 (s, 3H), 1.85 (m, 2H), 2.45 (m,

Example 82 (the same method as in Example 62)

Yl) -2-methyl- (2-piperidin-l-yl-ethyl) -amino] -3,4-dihydro-quinazolin- (2-piperidin-1-yl-ethyl) -amino] -3,4-dihydro- dihydro-quinazoline-4-yl} -N- (4-trifluoromethyl-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2- [methyl- (2-piperidin-l-yl-ethyl) -amino] -3,4-dihydro- quinazoline-4 instead of 4-fluorobenzylamine -Acetic acid methyl ester (ester intermediate 26: Example 52) (105 mg, 0.21 mmole) and 4-trifluoromethyl-benzylamine (0.2 mL) in substantially the same manner as in Example 62 4-yl-2- [methyl- (2-piperidin-l-yl-ethyl) -amino] -3,4-dihydro- quinazoline -4-yl} -N- (4-trifluoromethyl-benzyl) -acetamide.

Yield: 59.0 mg, 44%, Mass (M + H) &lt; ⁺ & gt ^; : 540

2H), 3.45-3.25 (m, 2H), 3.45-3.25 (br, 4H), 2.70 (m, 2H) -2.40 (m, 6H), 2.30-1.80 (m, 7H)

Example 83 (the same method as in Example 62)

Yl) -2-methyl- (2-piperidin-l-yl-ethyl) -amino] -3,4-dihydro-quinazolin- 4-yl-2- [methyl- (2-piperidin-yl-ethyl) -amino] -3,4-dihydro-quinazoline- 4-yl} -N- (4-methoxy-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2- [methyl- (2-piperidin-l-yl-ethyl) -amino] -3,4-dihydro- quinazoline-4 instead of 4-fluorobenzylamine -Acetic acid methyl ester (ester intermediate 26: Example 52) (98 mg, 0.197 mmole) and 4-methoxy-benzylamine (0.2 mL) were used in substantially the same manner as in Example 62, 4-yl-2- [methyl- (2-piperidin-l-yl-ethyl) -amino] -3,4-dihydro- quinazoline-4 - yl} -N- (4-methoxy-benzyl) -acetamide.

Yield: 47 mg, 40%, Mass (M + H) &lt; ⁺ & gt ^; : 602

2H), 3.80-3.70 (m, 5H), 3.45-3.25 (br, 4H), 2.70 (m, 2H) -2.40 (m, 6H), 2.30-1.80 (m, 7H)

Example  84. ( Example  62)

Yl) -2-methyl- (2-piperidin-l-yl-ethyl) -amino] -3,4-dihydro-quinazolin- (2-piperidin-1-yl-ethyl) -amino] -3,4-dihydro-quinazoline -4-yl} -N- (4-methyl-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2- [methyl- (2-piperidin-l-yl-ethyl) -amino] -3,4-dihydro- quinazoline-4 instead of 4-fluorobenzylamine -Acetic acid methyl ester (ester intermediate 26: Example 52) (107 mg, 0.215 mmole) and 4-methyl-benzylamine (0.2 mL) were used in the same manner as in Example 62 to give The title compound was prepared from 2- {3-biphenyl-4-yl-2- [methyl- (2-piperidin- 1 -yl- ethyl) -amino] -3,4- dihydro-quinazolin- Yl} -N- (4-methyl-benzyl) -acetamide.

Yield: 100.4 mg, 80%, Mass (M + H) &lt; ⁺ & gt ^; : 586

2H), 3.45-3.25 (m, 2H), 3.45-3.25 (br, 4H), 2.70 (m, 2H) -2.40 (m, 6H), 2.30-1.80 (m, 10H)

Example 85 . (Same method as in Example 62)

N-benzyl-2- {3-biphenyl-4-yl-2 - [(4-dimethylamino-benzyl) -methyl-amino] -3,4- dihydro- quinazolin- Synthesis of N-benzyl-2- {3-biphenyl-4-yl-2- [4-dimethylamino-benzyl) -methylamino] -3,4-dihydro-quinazoline-4-yl} -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; Benzyl-2- {3-biphenyl-4-yl-2 - [(4-dimethylamino-benzyl) -methyl- amino] -3,4- dihydro- quinazoline instead of 4-fluorobenzylamine 4-yl} -acetamide (Ester intermediate 25: Example 51) (103 mg, 0.199 mmole) and benzylamine (0.2 mL) were used in substantially the same manner as in Example 62, -Benzyl) -methyl-amino] -3,4-dihydro-quinazolin-4-yl} - acetamide &Lt; / RTI &gt;

Yield: 49.2 mg, 42%, Mass (M + H) &lt; ⁺ & gt ^; : 594

1H, NMR (200MHz, CDCl3) 7.70-6.90 (m, 2H), 6.60 (m, 2H), 6.05 ), 3.89 (s, 2H), 3.40 (br,

Example 86 . (Same method as in Example 62)

Amino] -3,4-dihydro-quinazolin-4-yl} -N- (4- (4-fluorobenzyl) 4-yl-2 - [(4-dimethylamino-benzyl) -methylamino] -3,4-dihydro-quinazolin- - (4-fluoro-benzyl) -acetamide Synthesis of

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; Benzyl-2- {3-biphenyl-4-yl-2 - [(4-dimethylamino-benzyl) -methyl- amino] -3,4- dihydro- quinazoline instead of 4-fluorobenzylamine 4-yl} -acetamide (Ester intermediate 25: Example 51) (105 mg, 0.20 mmol) and 4-fluoro-benzylamine (0.2 mL) The title compound was prepared from 2- {3-biphenyl-4-yl-2 - [(4-dimethylamino-benzyl) -methyl-amino] -3,4- dihydro- quinazolin- - (4-fluoro-benzyl) -acetamide. &Lt; / RTI &gt;

Yield: 42 mg, 35%, Mass (M + H) &lt; ⁺ & gt ^; : 597

1H NMR (200MHz, CDCl3) 7.70-6.90 (m, 19H), 6.60 (d, 2H), 5.80 (br, IH), 5.25 (m, IH), 4.8-4.60 (M, 2H), 1.75 (s, 3H), 2.45 (s, 3H)

Example 87 . (Same method as in Example 62)

Amino] -3,4-dihydro-quinazolin-4-yl} -N- (4- (4-fluorobenzyl) 4-yl} - (4-dimethylamino-benzyl) -methylamino] -3,4-dihydro-quinazolin- - (4-methoxy-bezyl) -acetamide Synthesis of

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; Benzyl-2- {3-biphenyl-4-yl-2 - [(4-dimethylamino-benzyl) -methyl- amino] -3,4-dihydro- quinacetaldehyde instead of 4-fluorobenzylamine (100 mg, 0.193 mmol) and 4-methoxy-benzylamine (0.2 mL) were used in substantially the same manner as in Example 62 to give the title compound Amino] -3,4-dihydro-quinazolin-4-yl} - (2-methylsulfanyl) N- (4-methoxy-benzyl) -acetamide was obtained.

Yield: 54.3 mg, 45%, Mass (M + H) &lt; ⁺ & gt ^; : 624

(M, 1H), 4.45-4.30 (m, 2H), 4.05 (br, 2H), 3.73 (s, 3H), 2.89 (s, 6H), 2.70-2.30

Example 88 (the same method as in Example 62)

Dihydro-quinazolin-4-yl] -N-pyridin-4-ylmethyl- 4-yl] -N-pyridin-4-ylmethyl-piperidine-1-yl) -3,4-dihydro-quinazolin- acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; Dihydro-quinazolin-4-yl] -acetic acid was used in the place of 4-fluorobenzylamine instead of [[3-biphenyl- Was prepared in substantially the same manner as in Example 62, using the carboxylic acid ester (ester intermediate 23: Example 49) (102 mg, 0.22 mmole) and pyridine-4-ylmethylamine (0.2 mL) Dihydro-quinazolin-4-yl] -N-pyridin-4-ylmethyl- -Acetamide. &Lt; / RTI &gt;

Yield: 37.2 mg, 32%, Mass (M + H) &lt; ⁺ & gt ^; : 531

(M, 2H), 3.40-3.30 (m, 2H), 7.90-7.80 (m, (m, 2H), 3.30-3.10 (m, 4H), 2.82 (s, 3H)

Example 89 (the same method as in Example 62)

Yl) -2-methyl- (2-piperidin-l-yl-ethyl) -amino] -3,4-dihydro-quinazolin- (2-piperidin-1-yl-ethyl) -amino] -3,4-dihydro-quinazoline- 4-yl} -N-pyridine-4-ylmethyl-acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2- [methyl- (2-piperidin-l-yl-ethyl) -amino] -3,4-dihydro- quinazoline-4 instead of 4-fluorobenzylamine -Acetic acid methyl ester (ester intermediate 26: Example 52) (97 mg, 0.195 mmole) and pyridin-4-ylmethylamine (0.2 mL), respectively, in substantially the same manner as in Example 62, The title compound was prepared from 2- {3-biphenyl-4-yl-2- [methyl- (2-piperidin- 1- yl- ethyl) -amino] -3,4- dihydro- quinazoline- 4-yl} -N-pyridin-4-ylmethyl-acetamide.

Yield: 42.4 mg, 38%, Mass (M + H) &lt; ⁺ & gt ^; : 573

2H), 3.45-3.25 (m, 2H), 3.45-3.25 (br, 4H), 2.70 (m, 2H) -2.40 (m, 6H), 2.30-1.80 (m, 7H)

Example 90 . (Same method as in Example 62)

Amino] -3,4-dihydro-quinazolin-4-yl} -N-pyridin-4-yl) -N- -Methyl-amino] -3,4-dihydro-quinazoline-4-yl} -N-pyridine &lt; / RTI &gt; -4-ylmethyl-acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; Benzyl-2- {3-biphenyl-4-yl-2 - [(4-dimethylamino-benzyl) -methyl- amino] -3,4-dihydro- quinacetaldehyde instead of 4-fluorobenzylamine 4-yl} -acetamide (ester intermediate 25: Example 51) (99 mg, 0.193 mmole) and pyridin-4-ylmethylamine (0.2 mL) Amino] -3,4-dihydro-quinazolin-4-yl} - (2-methylsulfanyl) N-pyridin-4-ylmethyl-acetamide.

Yield: 15.8 mg, 14%, Mass (M + H) &lt; ⁺ & gt ^; : 595

1H, NMR (200MHz, CDCl3) 8.50-6.80 (m, 17H), 6.85-6.55 (m, 4H), 6.30 (m, 2H), 4.10 (br, 2H), 3.74 (s, 3H), 2.75

Example 91 . (Same method as in Example 62)

4-yl-2- {methyl- [4- (4-methyl-piperazin- 1 -yl) -4-oxo- butyl] -amino} 4-yl-2- {methyl- [4- (4-methyl-piperazin-1-yl) - &lt; / RTI &gt; 4-oxo-butyl] -amino} -3,4-dihydro-quinazoline-4-yl) -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl) -2- {methyl- [4- (4-methyl-piperazin- 1 -yl) -4-oxo- butyl] -amino} -3, (106 mg, 0.19 mmole) and benzylamine (0.2 mL) in substantially the same manner as in Example 62, using 4-dihydro-quinazolin-4-yl) -acetic acid methyl ester Benzyl-2- (3-biphenyl-4-yl-2- {methyl- [4- (4-methyl-piperazin- Butyl] -amino} -3,4-dihydro-quinazolin-4-yl) -acetamide.

Yield: 32.4 mg, 27%, Mass (M + H) &lt; ⁺ & gt ^; : 629

(M, 2H), 2.90-2.50 (m, 8H), 2.50 (m, 2H) -1.90 (m, 10H)

Example 92 . (Same method as in Example 62)

4-yl-2- {methyl- [4- (4-methyl-piperazin- 1 -yl) -4-oxo- butyl] -amino} -3,4- dihydro- 4-yl-2- {methyl- [4- (4-methyl-piperazine-l- yl) -4-oxo-butyl] -amino} -3,4-dihydro-quinazoline-4-yl) -N- (4- fluoro-benzyl) -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl) -2- {methyl- [4- (4-methyl-piperazin- 1 -yl) -4-oxo- butyl] -amino} -3, (Example 42) (102 mg, 0.184 mmole) and 4-fluoro-benzylamine (0.2 mL) were used in the same manner as in Example The title compound was prepared in a manner substantially the same as 62, starting from 2- (3-biphenyl-4-yl-2- {methyl- [4- (4-methyl-piperazin- -Butyl] -amino} -3,4-dihydro-quinazolin-4-yl) -N- (4-fluoro-benzyl) -acetamide.

Yield: 9.6 mg, 8.1% Mass (M + H) &lt; ⁺ & gt ^; : 647

2H), 2.90-2.50 (m, 6H), 2.40 (m, 3H), 3.40-3.25 (m, -2.00 (m, 10H)

Example 93 . (Same method as in Example 62)

Dihydro-quinazolin-4-yl] -1-morpholin-4-yl (4-methyl-piperazin- 4-yl] -1-morpholin-4-yl-2- (4-methyl-piperazin- ethanone

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; Dihydro-quinazolin-4-yl] -acetic acid was used in the place of 4-fluorobenzylamine instead of [[3-biphenyl- The title compound was synthesized in substantially the same manner as in Example 62, using 2- (3-tert-butoxycarbonylamino) -thiazole-4-carboxylic acid (ester intermediates 23: Example 49) (100 mg, 0.22 mmole) and morpholine Dihydro-quinazolin-4-yl] -1-morpholin-4-yl-ethanone as an off-white solid .

Yield: 32.6 mg, 29%, Mass (M + H) &lt; ⁺ & gt ^; : 510

(M, 8H), 3.26-3.11 (m, 2H), 3.94 (m, 2H) , 6H), 2.80 (s, 3H), 2.33 (br, 2H), 2.26

Example 94 . (Example 62, the same method)

Dihydro-quinazolin-4-yl] -N-pyridin-2-ylmethyl- 4-yl] -N-pyridin-2-ylmethyl-piperidine-1-yl) -3,4-dihydro- quinazoline- acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; Dihydro-quinazolin-4-yl] -acetic acid was used in the place of 4-fluorobenzylamine instead of [[3-biphenyl- Using substantially the same method as in Example 62, the title compound was obtained as a white amorphous solid by the same procedure as in Example 62, using the acid methyl ester (Ester intermediate 23: Example 49) (101 mg, 0.22 mmole) and pyridin-2- Dihydro-quinazolin-4-yl] -N-pyridin-2-ylmethyl- -Acetamide. &Lt; / RTI &gt;

Yield: 18.2 mg, 16%, Mass (M + H) &lt; ⁺ & gt ^; : 531

2H), 3.81 (br, 2H), 3.45-3.40 (m, 2H), 4.30-4.30 (m, , 4H), 3.32-3.12 (m, 4H), 2.83 (s, 3H)

Example 95. (The same method as in Example 62)

Dihydro-quinazolin-4-yl} -1- (2-methyl-pyridin- 4-yl-2- [methyl- (2-piperidin-1-yl-ethyl) -amino] -3,4-dihydro-quinazoline- 4-yl} -1-morpholin-4-yl-ethanone)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2- [methyl- (2-piperidin-l-yl-ethyl) -amino] -3,4-dihydro- quinazolin- The title compound was prepared by a similar method to that of Example 62, using (102 mg, 0.205 mmole) and morpholine (0.2 mL) in the same manner as in Example 62, using 2-ethoxy- - {3-biphenyl-4-yl-2- [methyl- (2-piperidin- 1- yl- ethyl) -amino] -3,4- dihydro- quinazolin- Morpholin-4-yl-ethanone.

Yield: 38.6 mg, 34%, Mass (M + H) &lt; ⁺ & gt ^; : 552

2H), 3.80 (m, 2H), 3.20 (m, 4H), 2.80 (m, 4H) 2H), 1.43 (m, 2H), 1.54 (m, 2H), 1.43

Example 96 . (Same method as in Example 62)

4- [2- (4-methyl-piperazin-l-yl) -3,4-dihydro- quinazolin-4-yl] -N-cyclopropyl-acetamide Synthesis of 2- [3-biphenyl-4-yl-2- (4-methyl-piperazine-1-yl) -3,4-dihydro-quinazoline-4-yl] -N-cyclopropyl-acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; Dihydro-quinazolin-4-yl] -acetic acid was used in the place of 4-fluorobenzylamine instead of [[3-biphenyl- The title compound was prepared by a method substantially in the same manner as in Example 62, except that acetic acid (ester intermediate 23: Example 49) (99 mg, 0.22 mmole) and cyclopropylamine (0.2 mL) -Biphenyl-4-yl-2- (4-methyl-piperazin-1-yl) -3,4-dihydro-quinazolin-4-yl] -N- cyclopropyl-acetamide.

Yield: 90.6 mg, 86%, Mass (M + H) &lt; ⁺ & gt ^; : 480

(M, 2H), 6.40 (br, IH), 5.20 (m, IH), 3.47 (br, 4H), 2.71 (m, 1H), 7.53-7.14 2H), 0.47 (dd, 2H), 2.58-2.42 (m, 2H), 2.30-2.22 (m,

Example 97 . (Same method as in Example 62)

4-yl-2- {methyl- [4- (4-methyl-piperazin- 1 -yl) -4-oxo- butyl] -amino} -3,4- dihydro- 4-yl-2- {methyl- [4- (4-methyl-piperazine-l- yl) -4-oxo-butyl] -amino} -3,4-dihydro-quinazoline-4-yl) -N- (4-methoxy-benzyl) -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl) -2- {methyl- [4- (4-methyl-piperazin- 1 -yl) -4-oxo- butyl] -amino} -3, (106 mg, 0.19 mmole) and 4-methoxy-benzylamine (0.2 mL) were used, respectively, to give the title compound 4-yl-2- {methyl- [4- (4-methyl-piperazin-1-yl) -4- Oxo-butyl] -amino} -3,4-dihydro-quinazolin-4-yl) -N- (4-methoxy-benzyl) -acetamide.

Yield: 34.6 mg, 28%, Mass (M + H) &lt; ⁺ & gt ^; : 659

3H), 3.40-3.25 (m, 2H), 2.90-2.50 (m, 3H), 4.40-4.00 (m, 6 H), 2.40 - 2.80 (m, 10 H)

Example 98 (the same method as in Example 62)

4-yl-2- {methyl- [4- (4-methyl-piperazin- 1 -yl) -4-oxo- butyl] -amino} -3,4- dihydro- 4-yl-2- {methyl- [4- (4-methyl-piperazine-1-yl) -4-oxo-butyl] -amino} -3,4-dihydro-quinazoline-4-yl) -N-pyridine-4-ylmethyl-acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl) -2- {methyl- [4- (4-methyl-piperazin- 1 -yl) -4-oxo- butyl] -amino} -3, 4-yl) -acetic acid methyl ester (ester intermediate 22: example 48) (99 mg, 0.18 mmol) and N-pyridin-4-ylmethylamine (0.2 mL) 4-yl-2- {methyl- [4- (4-methyl-piperazin-1-yl) -4 -Oxo-butyl] -amino} -3,4-dihydro-quinazolin-4-yl) -N-pyridin-4- ylmethyl-acetamide.

Yield: 17.2 mg, 15%, Mass (M + H) &lt; ⁺ & gt ^; : 630

2H), 2.90-2.50 (m, 6H), 2.40 (m, 3H), 3.40-3.25 (m, -1.75 (m, 10H

Example 99 (the same method as in Example 62)

Dihydro-quinazolin-2-yl] -methyl-amino &lt; / RTI &gt; 4-yl-4- (2-morpholin-4-yl-2-oxo- ethyl) -3,4-dihydro-quinazolin-2-yl] -methylamino} -1- (4-methyl-piperazin-1-yl) -butan-

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl) -2- {methyl- [4- (4-methyl-piperazin- 1 -yl) -4-oxo- butyl] -amino} -3, (100 mg, 0.18 mmole) and morpholine (0.2 mL) in substantially the same manner as in Example 62, using 4-dihydro-quinazolin-4-yl) -acetic acid methyl ester There was obtained 4 - {[3-biphenyl-4-yl-4- (2- morpholin-4-yl-2-oxo- ethyl) -3,4- dihydro- quinazoline Yl] -methyl-amino} - l- (4-methyl-piperazin-l-yl) -butan-l-one.

Yield: 53.8 mg, 49%, (M + H) &lt; ⁺ & gt ^; : 609

(M, 8H), 2.96 (s, 3H), 2.40-1.90 (m, 3H) (m, 9H)

Example 100 . (Same method as in Example 62)

4-yl-2- {methyl- [4- (4-methyl-piperazin- 1 -yl) -4-oxo- butyl] -amino} -3,4- dihydro- 4-yl-2- {methyl- [4- (4-methyl-piperazine-1-yl) -4-oxo-quinazolin- -butyl] -amino} -3,4-dihydro-quinazoline-4-yl) -N-cyclopropyl-acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl) -2- {methyl- [4- (4-methyl-piperazin- 1 -yl) -4-oxo- butyl] -amino} -3, The title compound was obtained in substantially the same manner as in Example 62, using (97 mg, 0.175 mmole) and cyclopropylamine (0.2 mL) in the same manner as in Example 62 using 4-dihydro-quinazolin-4-yl) -acetic acid methyl ester In the same manner, the title compound was obtained from 2- (3-biphenyl-4-yl-2- {methyl- [4- (4-methyl-piperazin- Amino} -3,4-dihydro-quinazolin-4-yl) -N-cyclopropyl-acetamide.

Yield: 52 mg, 51%, Mass (M + H) &lt; ⁺ & gt ^; : 579

2H), 5.29 (m, 1H), 2.84-2.59 (m, 6H), 2.58-2.47 (m, 2H) (d, 2H), 0.30 (m, 2H), 1.43 (s, 3H)

Example 101 . (Same method as in Example 62)

Dihydro-quinazolin-2-yl] -methyl-amino} -pentanoic acid di (tert-butoxycarbonylamino) Synthesis of methyl amide (synthesis of 5 - {[4- (benzylcabamoyl-methyl) -3- (4-dimethylamino-phenyl) -3,4- dihydro- quinazoline-2- yl] -methyl- amino} -pentanoic acid dimethylamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-dimethylamino-phenyl) -2 - [(4-dimethylcarbamoyl-butyl) -methyl-amino] -3,4-dihydro- quinazoline-4 -Acetic acid methyl ester (ester intermediate 15: Example 41) (107 mg, 0.22 mmole) and benzylamine (0.2 mL) were used in the same manner as in Example 62 to obtain the title compound Dihydro-quinazolin-2-yl] -methyl-amino} -pentanoic acid di (tert-butoxycarbonylamino) Methyl amide.

Yield: 17.8 mg, 15%, Mass (M + H) &lt; ⁺ & gt ^; : 555

1H NMR (200 MHz, CDCl3) 7.60 (m, 1H), 7.35-6.82 (m, 10H), 6.58 (d, 2H), 5.22 , 6H), 3.00-2.61 (m, 11H), 2.45-2.20 (m, 6H)

Example 102. (The same method as in Example 62)

5 - ({3- (4-Dimethylamino-phenyl) -4 - [(4-methyl-benzylcarbamoyl) -methyl] -3,4- dihydro- quinazolin- ) -Pentanoic acid dimethylamide (5- (3- (4-dimethylamino-phenyl) -4 - [(4-methyl-benzylcarbamoyl) -methyl] -3,4- dihydro- quinazolin- methyl-amino) -pentanoic acid dimethylamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-dimethylamino-phenyl) -2 - [(4-dimethylcarbamoyl-butyl) -methyl-amino] -3,4-dihydro- quinazoline-4 -Acetic acid methyl ester (ester intermediate 15: Example 41) (100 mg, 0.21 mmole) and 4-methylbenzylamine (0.2 mL) were used in the same manner as in Example 62 to yield Methyl) -3,4-dihydro-quinazolin-2-yl} - (4-methyl-benzylcarbamoyl) Methyl-amino) -pentanoic acid dimethylamide.

Yield: 30.2 mg, 25%, Mass (M + H) &lt; ⁺ & gt ^; : 569

(D, 1H), 4.55-4.25 (m, 3H), 3.45-3.05 (m, 1H), 7.38-6.82 , 6H), 3.00-2.61 (m, 12H), 2.45-2.20 (m, 6H), 1.42 (s, 3H)

Example 103 (the same method as in Example 62)

Yl) -methyl-pyrimidin-4-yl] -methanone &lt; / RTI &gt; Amino) -pentanoic acid dimethylamide (5 - ({3- (4-dimethylamino-phenyl) -4 - [(4-fluoro- benzylcarbamoyl) -methyl] -3,4- dihydro- quinazoline- -methyl-amino) -pentanoic acid dimethylamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-dimethylamino-phenyl) -2 - [(4-dimethylcarbamoyl-butyl) -methyl-amino] -3,4-dihydro- quinazoline-4 -Acetic acid methyl ester (ester intermediate 15: Example 41) (101 mg, 0.21 mmole) and 4-fluoro-benzylamine (0.2 mL) were used in substantially the same manner as in Example 62, Methyl) -3,4-dihydro-quinazolin-2-yl] -2-methylpropionic acid ethyl ester was prepared from 5 - ({3- (4-dimethylamino- phenyl) -4 - [(4- fluoro-benzylcarbamoyl) Yl} -methyl-amino) -pentanoic acid dimethylamide was obtained.

Yield: 28.2 mg, 23%, Mass (M + H) &lt; ⁺ & gt ^; : 573

2H), 3.40-3.15 (m, 2H), 3.00-2.61 (m, 12H), 2.45 (m, 2H) -2.20 (m, 6H), 1.70-1. 50 (m, 2H), 1.42 (s, 3H)

Example 104 (the same method as in Example 62)

4-dihydro-quinazolin-2-yl} -methyl-carbamic acid tert-butyl ester as a colorless oil. Amino) -pentanoic acid dimethylamide (5 - ({3- (4-dimethylamino-phenyl) -4 - [(4- methoxy- -methyl-amino) -pentanoic acid dimethylamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-dimethylamino-phenyl) -2 - [(4-dimethylcarbamoyl-butyl) -methyl-amino] -3,4-dihydro- quinazoline-4 -Acetic acid methyl ester (ester intermediate 15: Example 41) (100 mg, 0.21 mmole) and 4-methoxy-benzylamine (0.2 mL) were used in substantially the same manner as in Example 62, 4 - [(4-methoxy-benzylcarbamoyl) -methyl] -3,4-dihydro-quinazolin-2- Yl} -methyl-amino) -pentanoic acid dimethylamide was obtained.

Yield: 22.6 mg, 18%, Mass (M + H) &lt; ⁺ & gt ^; : 585

1H NMR (200MHz, CDCl3) 7.40-6.50 (m, 13H), 5.22 (dd, 1H), 4.55-4.30 (m, 2H), 3.78 (s3H), 3.40-3.15 m, 12H), 2.45-2.20 (m, 6H), 1.70-1.50 (m, 2H), 1.42

Example 105 (the same method as in Example 62)

Dihydro-quinazolin-2-yl] -methyl-amino} -pentanoic acid dimethylamide (prepared from 5 - {[4- (benzylcarbamoylmethyl-3-biphenyl- Synthesis of 5 - {[4- (benzylcarbamoyl-methyl) -3-biphenyl-4-yl-3,4-dihydro- quinazoline-2-yl] -methyl- amino} -pentanoic acid dimethylamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2 - [(4-dimethylcarbamoyl-butyl) -methyl-amino] -3,4-dihydro-quinazolin- The title compound was obtained as a white amorphous solid by the same method as in Example 62, using the acetic acid methyl ester (Ester intermediate 18: Example 44) (102 mg, 0.198 mmole) and benzylamine (0.2 mL) Dihydro-quinazolin-2-yl] -methyl-amino} -pentanoic acid dimethylamide as a white solid.

Yield: 48.8 mg, 42%, Mass (M + H) &lt; ⁺ & gt ^; : 588

(M, 2H), 3.85 (s, 2H), 3.30-3.15 (m, 2H) (M, 2H), 2.87 (s, 3H), 2.77 (m, 2H)

Example 106 (the same method as in Example 62)

Dihydro-quinazolin-2-yl} -methyl-amino) -penta (4-methyl-benzylcarbamoyl) 4-yl-4 - [(4-methyl-benzylcarbamoyl) -methyl] -3,4-dihydro-quinazoline-2-yl} -methylamino) - pentanoic acid dimethylamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2 - [(4-dimethylcarbamoyl-butyl) -methyl-amino] -3,4-dihydro-quinazolin- -Acetic acid methyl ester (Ester intermediate 18: Example 44) (101 mg, 0.197 mmole) and 4-methyl-benzylamine (0.2 mL) were used in substantially the same manner as in Example 62, Dihydro-quinazolin-2-yl} -methyl-amino) - (4-methyl-benzylcarbamoyl) Pentanobic &lt; / RTI &gt; acid dimethylamide.

Yield: 45.4 mg, 38%, Mass (M + H) &lt; ⁺ & gt ^; : 602

(M, 2H), 3.80 (s, 2H), 3.30-3.15 (m, 2H) 2H), 2.87 (s, 3H), 2.77 (m5H), 2.55-2.20 (m, 5H)

Example 107. (In the same manner as in Example 62)

Dihydro-quinazolin-2-yl} -methyl-amino) - (4-fluoro-benzylcarbamoyl) Dihydro-quinazolin-2-yl} -methyl-amino) -propionic acid ethyl ester was prepared by the same procedure as described in Example 1, -pentanoic acid dimethylamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2 - [(4-dimethylcarbamoyl-butyl) -methyl-amino] -3,4-dihydro-quinazolin- -Acetic acid methyl ester (ester intermediate 18: Example 44) (100 mg, 0.195 mmole) and 4-fluoro-benzylamine (0.2 mL) were reacted in substantially the same manner as in Example 62 to give Dihydro-quinazolin-2-yl} -methyl-amino-lH-pyrrolo [2,3-c] ) -Pentanoic acid dimethylamide. &Lt; / RTI &gt;

Yield: 54.8 mg, 46%, Mass (M + H) &lt; ⁺ & gt ^; : 606

2H), 3.80 (s, 2H), 3.30-3.10 (m, 2H), 7.20 (m, 2H) (M, 2H), 2.87 (s, 3H), 2.77 (m, 2H)

Example 108. (In the same manner as in Example 62)

Dihydro-quinazolin-2-yl} -methyl-amino) - (4-methoxy-benzylcarbamoyl) 4-methoxy-benzylcarbamoyl) -methyl] -3,4-dihydro-quinazolin-2-yl} -methylamino) -pentanoic acid dimethylamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2 - [(4-dimethylcarbamoyl-butyl) -methyl-amino] -3,4-dihydro-quinazolin- -Acetic acid methyl ester (ester intermediate 18: Example 44) (97 mg, 0.189 mmole) and 4-methoxy-benzylamine (0.2 mL), respectively. The title compound was prepared from 5 - ({3-Biphenyl-4-yl-4 - [(4-methoxy-benzylcarbamoyl) -methyl] -3,4- dihydro- quinazolin- -Amino) -pentanoic &lt; / RTI &gt; acid dimethylamide.

Yields: 60.2 mg, 52%, Mass (M + H) &lt; ⁺ & gt ^; : 618

2H), 3.75 (m, 5H), 3.30-3.15 (m, 2H), 7.90 (m, (M, 2H), 2.87 (s, 3H), 2.77 (m, 2H)

Example 109. (Same procedure as in Example 62)

Dihydro-quinazolin-2-yl} -methyl-amino) -penta-quinazolin-2- 4-yl-4 - [(1-phenyl-ethylcarbamoyl) -methyl] -3,4-dihydro-quinazoline-2-yl} -methylamino) - pentanoic acid dimethylamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2 - [(4-dimethylcarbamoyl-butyl) -methyl-amino] -3,4-dihydro-quinazolin- -Acetic acid methyl ester (Ester intermediate 18: Example 44) (105 mg, 0.2045 mmole) and 4-methylbenzylamine (0.2 mL) was used in substantially the same manner as in Example 62 to obtain the title compound Dihydro-quinazolin-2-yl} -methyl-amino) -penta-quinazolin-2- Lt; / RTI &gt; acid dimethylamide.

Yield: 76.8 mg, 63%, Mass (M + H) &lt; ⁺ & gt ^; : 602

1H, NMR (200MHz, CDCl3) 8.00 (d, 1H), 7.60-7.10 (m, 16H), 7.10-6.80 (m, 2H), 5.30 2H), 2.95-2.60 (m, 8H), 2.50-2.10 (m, 4H), 1.90-1.60

Example 110. (Same procedure as in Example 62)

Yl) -3- (4-pyrrolidin-l-yl-phenyl) -3,4- dihydro- Dihydro-quinazolin-4-yl] - &lt; / RTI &gt; yl-phenyl) -3,4-dihydro-quinazoline-4-yl] -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-pyrrolidin-1-yl-phenyl) -3,4-dioxo-4- (107 mg, 0.212 mmole) and benzylamine (0.2 mL) were used in the same manner as in Example 62, respectively, to obtain substantially the same Benzyl-2- [2- [4- (2-dimethylamino-ethyl) -piperazin- 1 -yl] -3- (4- pyrrolidin- Yl-phenyl) -3,4-dihydro-quinazolin-4-yl] -acetamide.

Yield: 60.4 mg, 49%, Mass (M + H) &lt; ⁺ & gt ^; : 580

1H NMR (200MHz, CDCl 3) 7.60-7.10 (m, 11H), 7.10-6.80 (m 3H), 5.35 (m, m, 12H), 2.40-2.10 (m, 6H), 1.60 (br, 4H)

Example 111 (the same method as in Example 62)

Yl) -3- (4-pyrrolidin-l-yl-phenyl) -3,4-dihydro-quinoline (2-dimethylamino-ethyl) -piperazine-1-yl] -3- (4-pyrrolidine- 1-yl-phenyl) -3,4-dihydro-quinazoline-4-yl] -N- (4-methyl-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-pyrrolidin-1-yl-phenyl) -3,4-dioxo-4- (62 mg, 0.194 mmol) and 4-methyl-benzyl (0.2 mL) were used in the same manner as in Example 62, except that acetic acid Yl] -3- (4-pyrrolidin-1-yl-piperazin-1 -yl) -piperazin-1- Phenyl) -3,4-dihydro-quinazolin-4-yl] -N- (4-methyl- benzyl) -acetamide.

Yield: 29.4 mg, 26%, Mass (M + H) &lt; ⁺ & gt ^; : 594

1H NMR (200MHz, CDCl 3) 7.60-7.10 (m, 11H), 7.10-6.80 (m 2H), 5.35 (m, 5H), 3.02-2.70 (m, 12H), 2.40-2.10 (m, 9H), 1.60 (br, 4H)

Example 112 (the same method as in Example 62)

Yl) -3- (4-pyrrolidin-l-yl-phenyl) -3,4-dihydro-quinoline (2-Dimethylamino-ethyl) -piperazin-1-yl] -3- (4-pyrrolidin- -1-yl-phenyl) -3,4-dihydro-quinazolin-4-yl] -N- (4-methoxy-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-pyrrolidin-1-yl-phenyl) -3,4-dioxo-4- (62 mg, 0.10 mmol) and 4-methoxy-benzylamine (0.2 mL) were used in the same manner as in Example 62 (2-dimethylamino-ethyl) -piperazin-1 -yl] -3- (4-pyrrolidin- 1- Yl-phenyl) -3,4-dihydro-quinazolin-4-yl] -N- (4-methoxy-benzyl) -acetamide.

Yield: 15.2 mg, 12%, Mass (M + H) &lt; ⁺ & gt ^; : 610

2H), 4.35 (m, IH), 3.88 (s, 3H), 4.85 (m, IH) , 3.70-3.10 (m, 5H), 3.02-2.70 (m, 12H), 2.40-2.10 (m, 6H)

Example 113. (In the same manner as in Example 62)

(4-pyrrolidin-l-yl-phenyl) -3,4-dihydro-quinoline 4-yl-piperazine-1-yl) -3- (4-pyrrolidin-1-yl-phenyl) -3 , 4-dihydro-quinazoline-4-yl] -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-pyridin-4-yl-piperazin-l-yl) -3- (4- pyrrolidin- 1 -yl-phenyl) -3,4- dihydro- (100 mg, 0.196 mmole) and benzylamine (0.2 mL), respectively, in the same manner as in Example 62, using the compounds of the following formula (4-pyridin-4-yl-piperazin-1-yl) -3- -Dihydro-quinazolin-4-yl] -acetamide. &Lt; / RTI &gt;

Yield: 43.4 mg, 38%, Mass (M + H) &lt; ⁺ & gt ^; : 586

(M, 2H), 7.50-7.02 (m, 9H), 6.90 (d, 4H), 6.40 ), 3.77-3.40 (m, 2H), 3.20 (m, 8H), 2.00 (m, 4H)

Example 114 . (Same method as in Example 62)

Yl) -3- (4-pyrrolidin-1-yl-phenyl) -3, 4- 4-yl-piperazin-1-yl) -3- (4-fluoro-benzyl) -2- [ (4-pyrrolidin-1-yl-phenyl) -3,4-dihydro-quinazoline-4-yl] -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-pyridin-4-yl-piperazin-l-yl) -3- (4- pyrrolidin- 1 -yl-phenyl) -3,4- dihydro- (103 mg, 0.20 mmole) and 4-fluoro-benzylamine (0.2 mL) in substantially the same manner as in Example 62 (4-fluoro-benzyl) -2- [2- (4-pyridin-4-yl-piperazin- 1 -yl) -3- Yl-phenyl) -3,4-dihydro-quinazolin-4-yl] -acetamide.

Yield: 51.2 mg, 42%, Mass (M + H) &lt; ⁺ & gt ^; : 604

(M, 2H), 7.50 (m, 2H), 7.40-7.00 (m, 2H), 7.80 1H), 4.60 (m, 1H), 6.70 (d, 1H), 6.45 (d, (m, 4H),

Example 115 . (The same method as in Example 3)

Yl) -3- (4-pyrrolidin-1-yl-phenyl) -3, 4- 4-yl-piperazin-1-yl) -3- ((4-methyl-benzyl) -2- 4-pyrrolidine-1-yl-phenyl) -3,4-dihydro-quinazoline-4-yl] -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-pyridin-4-yl-piperazin-l-yl) -3- (4- pyrrolidin- 1 -yl-phenyl) -3,4- dihydro- Using substantially the same method as in Example 62, using (97 mg, 0.190 mmole) and 4-methyl-benzylamine (0.2 mL), the title compound (4-methyl-benzyl) -2- [2- (4-pyridin-4-yl-piperazin- 1 -yl) -3- Yl-phenyl) -3,4-dihydro-quinazolin-4-yl] -acetamide.

Yield: 35.2 mg, 31%, Mass (M + H) &lt; ⁺ &gt;: 600

(M, 3H), 6.50 (d, IH), 6.45 (d, IH), 7.80 (d, IH) 2H), 2.33 (s, 3H), 2.10-1.60 (m, 8H), 3.40-3. ),

Example 116 : (Same method as in Example 62)

Yl) -3- (4-pyrrolidin-1-yl-phenyl) -3, 4- 4-yl-piperazin-1-yl) -3- (4-methoxy-benzyl) -2- [ (4-pyrrolidin-1-yl-phenyl) -3,4-dihydro-quinazoline-4-yl] -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-pyridin-4-yl-piperazin-l-yl) -3- (4- pyrrolidin- 1 -yl-phenyl) -3,4- dihydro- (100 mg, 0.196 mmole) and 4-methoxy-benzylamine (0.2 mL) were used in the same manner as in Example 62, except that acetic acid (4-methoxy-benzyl) -2- [2- (4-pyridin-4-yl-piperazin- 1 -yl) -3- Yl-phenyl) -3,4-dihydro-quinazolin-4-yl] -acetamide.

Yield: 63.6 mg, 53%, Mass (M + H) &lt; ⁺ & gt ^; : 616

2H), 5.10 (m, 1H), 4.65-4.20 (m, 2H), 7.20-7.20 (m, (m, 2H), 3.90-3.60 (m, 5H), 3.50-3.20 (m, 6H), 3.30-3.10

Example 117 . (Same method as in Example 62)

Yl) -3- (4-dimethylamino-phenyl) -3,4-dihydro-quinolin-2- 2-dimethylamino-ethyl) -piperazine-1-yl] -3- (4-dimethylamino-phenyl) -3,4 -dihydro-quinazoline-4-yl] -acetamide Synthesis of

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-dimethylamino-phenyl) -3,4-dihydro-pyrazol-3-one Quinazolin-4-yl] -acetic acid methyl ester (ester intermediate 16: Example 42) (101 mg, 0.21 mmole) and benzylamine (0.2 mL) were reacted in substantially the same manner as in Example 62 to give 3- (4-dimethylamino-phenyl) -3,4-dihydro-2H-pyran-2- Dihydro-quinazolin-4-yl] -acetamide.

Yield: 33.8 mg, 29%, Mass (M + H) &lt; ⁺ & gt ^; : 554

2H), 3.44 (br, 4H), 2.90 (m, 2H), 3.25 (m, (m, 8H), 2.75 (m, 1H), 2.50 (m,

Example 118 . (Same method as in Example 62)

Yl) -3- (4-dimethylamino-phenyl) -3,4-dihydro-quinazolin-4- (2-dimethylamino-ethyl) -piperazine-1-yl] -3- (4-dimethylamino-phenyl) - 3,4-dihydro-quinazoline-4-yl] -N- (4-fluoro-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-dimethylamino-phenyl) -3,4-dihydro-pyrazol-3-one (98 mg, 0.20 mmole) and 4-fluoro-benzylamine (0.2 mL) were used in substantially the same manner as in Example 62, except that acetic acid (4-dimethylamino-phenyl) -3,4-dioxolan-4-ylmethyl) -piperazin-1-yl] Dihydro-quinazolin-4-yl] -N- (4-fluoro-benzyl) -acetamide.

Yield: 28.2 mg, 25%, Mass (M + H) &lt; ⁺ & gt ^; : 572

(M, 2H), 3.44 (br, 4H), 2.90 (m, 2H) (m, 8H), 2.75 (m, IH), 2.50 (m, IH), 2.37

Example 119 . (Same method as in Example 62)

Yl) -3- (4-dimethylamino-phenyl) -3,4-dihydro-quinazolin-4- (2-dimethylamino-ethyl) -piperazine-1-yl] -3- (4-dimethylamino-phenyl) -3 , 4-dihydro-quinazoline-4-yl] -N- (4-methyl-benzyl) -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-dimethylamino-phenyl) -3,4-dihydro-pyrazol-3-one (101 mg, 0.21 mmole) and 4-methyl-benzylamine (0.2 mL) were used in the same manner as in Example 62, respectively, to obtain substantially the same (4-dimethylamino-phenyl) -3,4-dioxolan-4-ylmethyl) -piperazin-1-yl] - dihydro-quinazolin-4-yl] -N- (4-methyl-benzyl) -acetamide.

Yield: 43.8 mg, 38%, Mass (M + H) &lt; ⁺ & gt ^; : 568

2H), 3.44 (br, 4H), 2.90 (m, 2H), 2.32 (m, (m, 2H), 2.75 (s, 3H), 2.20 (s, 6H)

Example 120. (Same procedure as in Example 62)

Yl) -3- (4-dimethylamino-phenyl) -3,4-dihydro-quinazolin-4- (2-dimethylamino-ethyl) -piperazine-1-yl] -3- (4-dimethylamino-phenyl) - 3,4-dihydro-quinazoline-4-yl] -N- (4-methoxy-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17 and 4 &lt; RTI ID = 0.0 &gt; (2-dimethylamino-ethyl) -piperazin-1-yl] -3- (4-dimethylamino-phenyl) -3,4-dihydro-quinoline (104 mg, 0.22 mmole) and 4-methoxy-benzylamine (0.2 mL) were used in the same manner as in Example 62, respectively, to obtain substantially the same (4-dimethylamino-phenyl) -3,4-dioxolan-4-ylmethyl) -piperazin-1-yl] -Dihydro-quinazolin-4-yl] -N- (4-methoxy-benzyl) -acetamide.

Yield: 46.2 mg, 36%, Mass (M + H) &lt; ⁺ & gt ^; : 584

(M, 2H), 3.72 (s, 3H), 3.40 (s, 3H) (S, 6H), 2.24 (s, 6H), 2.45 (m, 2H)

Example 121. (In the same manner as in Example 62)

Methyl] -3,4-dihydro-quinazolin-2-yl) - &lt; / RTI & -Methyl-amino] -pentanoic acid dimethylamide (5 - [(3-biphenyl-4-yl-4 - {[4- -quinazoline-2-yl) -methyl-amino] -petanoic acid dimethylamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2 - [(4-dimethylcarbamoyl-butyl) -methyl-amino] -3,4-dihydro-quinazolin- -Acetic acid methyl ester (ester intermediate 18: Example 44) (100 mg, 0.195 mmole) and (4-dimethylamino-benzyl) -methylamine (0.2 mL) were used in substantially the same manner as in Example 62 4 - {[(4-dimethylamino-benzyl) -methyl-carbamoyl] -methyl} -3,4-dihydro- Quinazolin-2-yl) -methyl-amino] -pentanoic acid dimethylamide.

Yield: 65.6 mg, 52%, Mass (M + H) &lt; ⁺ & gt ^; : 645

(M, 2H), 3.77 (m, 2H), 3.30-3.15 (m, 2H), 7.90 (m, 1H) 2H), 2.87 (s, 3H), 2.77 (m, 5H), 2.60-2.20 (m, 8H)

Example 122 . (Same method as in Example 62)

2-yl-phenyl) -3,4-dihydro-quinazolin-4-yl] - (2-methyl-pyridin- 4-pyridin-2-yl-phenyl) -3, 4-dihydro (2-methyl- -quinazoline-4-yl] -N-pyridine-2-ylmethyl-acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; Amino-3- (4-pyridin-2-yl-phenyl) -3,4-dihydro-quinazoline was used in the place of 4-fluorobenzylamine instead of 4- [ (10 mg, 0.21 mmol) and N-pyridin-2-ylmethylamine (0.2 mL) in substantially the same manner as in Example 62 The title compound was prepared from 2- [2 - [(5-dimethylamino-pentyl) -methyl-amino] -3- (4- pyridin- -Quinazolin-4-yl] -N-pyridin-2-ylmethyl-acetamide.

Yields: 21 mg, 17%, Mass (M + H) &lt; ⁺ & gt ^; : 576

1H, NMR (200MHz, CDCl3) 8.65-8.64 (m, IH), 8.50-8.48 (m, IH), 7.86 (d, 2H, J = 8.8), 7.75-7.71 2H), 7.51 (t, 1H, J = 4.4), 7.27-7.17 (m, 6H), 6.99 (d, 1H, J = 6.8), 6.92-6.90 (Dd, 1H, J = 4.8 and 10), 4.66-4.53 (m, 2H), 2.81-2.75 (dd, 1H, J = 10 and 14.4), 2.56-2.51 and 14.4), 2.35 (s, 3H), 2.28 (s, 6H), 1.52 (br, 4H)

Example 123. (In the same manner as in Example 62)

2-yl-phenyl) -3,4-dihydro-quinazolin-4-yl] - (2-methyl-pyridin- 4-pyridine-2-yl-phenyl) -3,4-dihydro- &lt; / RTI &gt; dihydro-quinazoline-4-yl] -N- (4-methyl-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; Amino-3- (4-pyridin-2-yl-phenyl) -3,4-dihydro-quinazoline was used in the place of 4-fluorobenzylamine instead of 4- [ 4-yl] -acetic acid methyl ester (ester intermediate 10: Example 36) (99 mg, 0.198 mmole) and 4-methylbenzylamine (0.2 mL) were used in substantially the same manner as in Example 62, Amino-3- (4-pyridin-2-yl-phenyl) -3,4-dihydro-quinazolin- 4-yl] -N- (4-methyl-benzyl) -acetamide.

Yields: 35 mg, 30%, Mass (M + H) &lt; ⁺ & gt ^; : 589

1H, NMR (400 MHz, CDCl3) 8.67-6.89 (m, 16H, aromatic), 6.65 (br, IH, Bn-NHCO), 5.35 (dd, J = 5.6 and 9.6 Hz, (Dd, 1H, J = 10.0 and 14.8, -CO-CH2-), 2.50-2.45 (d, 2H, J = 5.6, PhCH2- (s, 3H, Ph-CH3), 2.17 (s, 6H, -N- (CH3) 2), 1.8 (br, 4H) 1.57-1.27 (m, 6H, -CH2-CH2-CH2-CH2-N- (CH3) 2)

Example 124 . (Same method as in Example 62)

N-Benzyl-2- (3-biphenyl-4-yl-2 - {[3- (3,3- dimethyl- ureido) -propyl] -methyl- amino} -3,4-dihydro- 4-yl-2 - {[3- (3,3-dimethyl-ureido) -propyl] -methyl- amino} -3H-benzyl- , 4-dihydro-quinazoline-4-yl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (3-Biphenyl-4-yl-2 - {[3- (3,3-dimethyl-ureido) -propyl] -methyl-amino} -3,4-dihydro- (Tert-butoxycarbonylamino) quinazolin-4-yl) -acetic acid methyl ester (ester intermediate 19: Example 45) (103 mg, 0.20 mmole) and benzylamine The title compound was prepared from N-benzyl-2- (3-biphenyl-4-yl-2 - {[3- (3,3- Dihydro-quinazolin-4-yl) -acetamide.

Yield: 45 mg, 38%, Mass (M + H) &lt; ⁺ & gt ^; : 589

(Dd, J = 4.4 and 10.4 Hz, 1H, -CH2-CH-N-), 4.55-7.27 (m, 18H, aromatic) 2H), 2.46-2.41 (m, 2H), 2.38 (m, 2H) 2H), 1.76-1.68 (br, 6H)

Example 125 . (Same method as in Example 62)

3-Naphthalen-2-yl-3,4-dihydro-quinazolin-4-yl} -N- (2-methyl-ethyl) -piperazin- 2-yl-3,4-dihydro-quinazoline (2-dimethylamino-ethyl) -piperazine-1-yl] -3-naphthalene- -4-yl} -N- (4-methyl-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; The title compound was prepared from {2- [4- (2-dimethylamino-ethyl) -piperazin-1-yl] -3-naphthalen-2-yl-3,4-dihydro-quinazoline- -Acetic acid methyl ester (ester intermediate 8: Example 34) (100 mg, 0.21 mmole) and 4-methyl-benzylamine (0.2 mL) were used in the same manner as in Example 62, Piperazin-1-yl] -3-naphthalen-2-yl-3,4-dihydro-quinazoline-4 - yl} -N- (4-methyl-benzyl) -acetamide.

Yields: 48 mg, 40%, Mass (M + H) &lt; ⁺ & gt ^; : 575

(D, J = 5.6 and 9.6 Hz, 1H, -CH2-CH-N-), 4.51-4.37 (m, 15H, aromatic), 6.42 2H, PhCH2-NH-), 3.69 (br, 4H), 2.63-2.57, 2.46-2.42 2.18 (s, 6H, -N- (CH3) 2), 2.10 (br, 4H)

Example 126 . (Same method as in Example 62)

3-Naphthalen-2-yl-3,4-dihydro-quinazolin-4-yl} -N- (2-methyl-ethyl) -piperazin- Yl) -3-naphthalene-2-yl-3,4-dihydro-quinolin-2- quinazoline-4-yl} -N- (4-methoxy-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; Yl) -3-naphthalen-2-yl-3,4-dihydro-quinazoline-1-carboxylic acid was used in the place of 4-fluorobenzylamine instead of 4- {2- [4- Was prepared in substantially the same manner as in Example 62, using 4-methoxy-benzylamine (0.2 mL) and 4-methoxybenzylamine (102 mg, 0.21 mmole) The title compound was prepared as described in the preparation of the title compound from 2- {2- [4- (2-dimethylamino-ethyl) -piperazin-1-yl] -3-naphthalen-2-yl-3,4-dihydro- quinazoline -4-yl} -N- (4-methoxy-benzyl) -acetamide.

Yields: 37 mg, 30%, Mass (M + H) &lt; ⁺ & gt ^; : 591

2H, PhCH2-NH (400 MHz, CDCl3) 7.75-6.72 (m, 15H, aromatic), 5.33 (dd, J = 5.2 and 9.6 Hz, 1H, (M, 2H, -CO-CH2-), 2.34 (br, 4H), 2.6 (s, 6H, -) N- (CH3) 2), 2.10 (br, 4H)

Example 127. 7- (Same method as in Example 62)

-Propyl] -methyl-amino} -3,4-dihydro-quinazolin-4- &lt; / RTI & (3-Biphenyl-4-yl-2 - {[3- (3,3-dimethyl-ureido) -propyl] -methyl- amino} -3,4-dihydro-quinazoline-4-yl) -N- (4-methyl-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (3-Biphenyl-4-yl-2 - {[3- (3,3-dimethyl-ureido) -propyl] -methyl-amino} -3,4-dihydro- (100 mg, 0.195 mmole) and 4-methyl-benzylamine (0.2 mL) were used in substantially the same manner as in Example 62, except that acetic acid methyl ester (3-Biphenyl-4-yl-2 - {[3- (3,3-dimethyl-ureido) -propyl] -methyl- Dihydro-quinazolin-4-yl) -N- (4-methyl-benzyl) -acetamide.

Yield: 29 mg, 25%, Mass (M + H) &lt; ⁺ & gt ^; : 603

(Dd, J = 5.2 and 10.0 Hz, 1H, -CH2-CH-N-), 4.49 (br, 1H) 2H), 2.53 (s, 3H), 2.35 (s, 3H), 2.35 (m, 2H) , 2.44 (br, 2H), 1.75 - 1.64 (br, 2H)

Example 128 . (Same method as in Example 62)

-Propyl] -methyl-amino} -3,4-dihydro-quinazolin-4- &lt; / RTI & (3-biphenyl-4-yl-2 - {[3- (3,3-dimethyl-ureido) -propyl] -methyl-amino } -3,4-dihydro-quinazoline-4-yl) -N- (4-methoxy-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (3-Biphenyl-4-yl-2 - {[3- (3,3-dimethyl-ureido) -propyl] -methyl-amino} -3,4-dihydro- -Acetic acid methyl ester (ester intermediate 19: Example 45) (107 mg, 0.208 mmole) and 4-methoxy-benzylamine (0.2 mL) In the same manner, the title compound was obtained from 2- (3-biphenyl-4-yl-2 - {[3- (3,3-dimethyl-ureido) Dihydro-quinazolin-4-yl) -N- (4-methoxy-benzyl) -acetamide.

Yields: 42 mg, 33%, Mass (M + H) &lt; ⁺ & gt ^; : 619

(D, J = 4.8 and 10.8 Hz, 1H, -CH2-CH-N-), 4.47-4.32 (m, 2H, PhCH2 2H), 2.44 (s, 3H), 3.74 (s, 3H) 2H), 1.72 (br, 2H)

Example 129. (In the same manner as in Example 62)

Yl) -methyl-pyrimidin-4-yl] -pyridin-2-yl} -5- ({3-biphenyl- Amino) -pentanoic acid dimethylamide (5 - ({3-biphenyl-4-yl-4 - [((R) -1- phenyl- ethylcarbamoyl) -methyl] -3,4- dihydro- quinazoline- 2- yl} -methyl-amino) -pentanoic &lt; / RTI &gt; aicd dimethylamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2 - [(4-dimethylcarbamoyl-butyl) -methyl-amino] -3,4-dihydro-quinazolin- -Acetic acid methyl ester (ester intermediate 18: Example 44) (101 mg, 0.197 mmole) and (R) -alpha methylbenzylamine (0.2 mL), respectively, The title compound was prepared from 5- ({3-biphenyl-4-yl-4 - [((R) -1- phenyl- ethylcarbamoyl) -methyl] -3,4- dihydro-quinazolin- } -Methyl-amino) -pentanoic acid dimethylamide.

Yield: 44.0 mg, 37%, Mass (M + H) &lt; ⁺ & gt ^; : 602

(M, 2H), 2.40 (m, 2H), 2.40 (m, 2H) 2H), 2.50 (m, 3H), 2.26 (s, 3H), 2.10 (s,

Example 130. (In the same manner as in Example 62)

4-yl-2- [4- (3-dimethylamino-propyl) -piperazin-1-yl] -3,4-dihydro- quinazoline-4 -Benzyl-2- {3-biphenyl-4-yl-2- [4- (3-dimethylamino- propyl) -piperazine- 1- yl] -3,4- dihydro- quinazoline- 4-yl} -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2- [4- (3-dimethylamino-propyl) -piperazin-l-yl] -3,4- dihydro- quinazoline- Was prepared in substantially the same manner as in Example 62, using (109 mg, 0.207 mmole) and benzylamine (0.2 mL), in the same manner as in Example 62, using the title compound Yl] -3,4-dihydro-quinazoline-2-carboxylic acid ethyl ester was prepared from N-benzyl-2- {3- 4-yl} -acetamide. &Lt; / RTI &gt;

Yield: 82.6 mg, 67%, Mass (M + H) &lt; ⁺ & gt ^; : 601

(M, 2H), 3.40-3.20 (m, 2H), 5.40-7. 20 (m, , 2.95-2.60 (m, 8H), 2.50-2.30 (m, 12H), 1.50 (m, 2H)

Example 131. (In the same manner as in Example 62)

Yl} -3,4-dihydro-quinazolin-4-yl} - [4- (3-dimethylamino-propyl) -piperazin- 4-yl-2- [4- (3-dimethyl-propyl) -piperazin-1-yl] -3,4-dihydro (2- {3-biphenyl- -quinazoline-4-yl} -N- (4-fluoro-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2- [4- (3-dimethylamino-propyl) -piperazin-l-yl] -3,4- dihydro- quinazoline- (100 mg, 0.19 mmole) and 4-fluorobenzylamine (0.2 mL) were used in the same manner as in Example 62, respectively, to obtain the title compound 4-yl-2- [4- (3-dimethylamino-propyl) -piperazin-1-yl] -3,4-dihydro- quinazoline -4-yl} -N- (4-fluoro-benzyl) -acetamide.

Yield: 37 mg, 31%, Mass (M + H) &lt; ⁺ & gt ^; : 619

2H), 3.80-3.60 (m, 2H), 3.50-2.80 (m, 8H), 4.80-4.40 (m, , 2.60-1.90 (m, 12H)

Example 132. (In the same manner as in Example 62)

Yl} -3,4-dihydro-quinazolin-4-yl} - [4- (3-dimethylamino-propyl) -piperazin- 4- (3-dimethylamino-propyl) -piperazine-1-yl] -3,4-dihydro- quinazoline-4-yl} -N- (4-methyl-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2- [4- (3-dimethylamino-propyl) -piperazin-l-yl] -3,4- dihydro- quinazoline- Was prepared by substantially the same method as in Example 62, using 4-methoxybenzylamine (104 mg, 0.198 mmole) and 4-methylbenzylamine (0.2 mL), respectively, 4-yl-2- [4- (3-dimethylamino-propyl) -piperazin-l-yl] -3,4- dihydro- quinazoline- 4-yl} -N- (4-methyl-benzyl) -acetamide.

Yield: 71.2 mg, 58%, Mass (M + H) &lt; ⁺ & gt ^; : 615

(M, 2H), 3.80-3.60 (m, 2H), 3.50-3.2 (br, 8H) , 2.40 - 1.80 (m, 12H)

Example 133. (In the same manner as in Example 62)

Yl} -3,4-dihydro-quinazolin-4-yl} - [4- (3-dimethylamino-propyl) -piperazin- 4-yl-2- [4- (3-dimethylamino-propyl) -piperazine-1-yl] -3,4-dihydro -quinazoline-4-yl} -N- (4-methoxy-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2- [4- (3-dimethylamino-propyl) -piperazin-l-yl] -3,4- dihydro- quinazoline- Was prepared in substantially the same manner as in Example 62 by using 4-methoxybenzylamine (97 mg, 0.185 mmole) and 4-methoxybenzylamine (0.2 mL), respectively, 4-yl-2- [4- (3-dimethylamino-propyl) -piperazin-1-yl] -3,4-dihydro- quinazoline -4-yl} -N- (4-methoxy-benzyl) -acetamide.

Yield: 74.9 mg, 64%, Mass (M + H) &lt; ⁺ & gt ^; : 631

(M, 2H), 3.80-3.20 (m, 10H), 2.3-1.80 (m, 12H)

Example 134. (In the same manner as in Example 62)

Yl} -3,4-dihydro-quinazolin-4-yl} - [4- (3-dimethylamino-propyl) -piperazin- 4-yl-2- [4- (3-dimethylamino-propyl) -piperazine-1-yl] -3,4-dihydro-quinazoline-4 -yl} -N, N-dimethyl-acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2- [4- (3-dimethylamino-propyl) -piperazin-l-yl] -3,4- dihydro- quinazoline- Was prepared in substantially the same manner as in Example 62 by using 2-methyl-4-pyrrolidin-4-yl} acetic acid methyl ester (Ester intermediate 27: Example 53) (98 mg, 0.186 mmole) 4-yl-2- [4- (3-dimethylamino-propyl) -piperazin-1-yl] -3,4-dihydro- quinazoline -4-yl} -N, N-dimethyl-acetamide.

Yields: 25 mg, 25%, Mass (M + H) &lt; ⁺ & gt ^; : 539

2H), 3.60-3. 35 (br, 2H), 3.30 (m, 2H) 2.70 (m, 12H), 2.60-2.40 (m, 2H), 2.40-1.70 (m, 12H)

Example 135. (The same method as in Example 3)

Yl} -3,4-dihydro-quinazolin-4-yl} - [4- (3-dimethylamino-propyl) -piperazin- 4-yl-2- [4- (3-dimethylamino-propyl) -piperazine-1-yl] -3,4-dihydro-quinazoline-4-yl } -N-cyclopropyl-acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2- [4- (3-dimethylamino-propyl) -piperazin-l-yl] -3,4- dihydro- quinazoline- 4-yl} -acetic acid methyl ester (ester intermediate 27: Example 53) (101 mg, 0.19 mmole) and cyclopropylamine (0.2 mL) were used in the same manner as in Example 62, The title compound was prepared from 2- {3-biphenyl-4-yl-2- [4- (3-dimethylamino-propyl) -piperazin- 1- yl] -3,4- dihydro- quinazolin- } -N-cyclopropyl-acetamide. &Lt; / RTI &gt;

Yield: 35 mg, 33%, Mass (M + H) &lt; ⁺ & gt ^; : 551

2H), 3.30-3.10 (m, 5H), 3.60-3.30 (m, 2H) , 2.80-2.60 (m, 2H), 2.50-2.10 (m, 11H), 1.98 (s, 2H), 1.50-0.80

Example 136. (In the same manner as in Example 62)

N-benzyl-2- {3-biphenyl-4-yl-2- [4- (1- methyl- piperidin- 4- yl) -piperazin- 1- yl] -3,4-dihydro- 4-yl) -piperazin-1-yl] - (2-methyl-piperazin- 3,4-dihydro-quinazoline-4-yl} -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2- [4- (1 -methyl-piperidin-4-yl) -piperazin- 1-yl] -3,4- dihvdro- -Acetic acid methyl ester (ester intermediate 24: Example 50) (100 mg, 0.186 mmole) and benzylamine (0.2 mL) were reacted in substantially the same manner as in Example 62 to give the title compound Benzyl-2- {3-biphenyl-4-yl-2- [4- (1- methyl- piperidin- 4- yl) -piperazin- 4-dihydro-quinazolin-4-yl} -acetamide.

Yields: 24 mg, 21%, Mass (M + H) &lt; ⁺ & gt ^; : 613

2H), 3.50-3.20 (m, 10H), 7.30-7.10 (m, 10H), 7.0-6.70 (m, 8H) , 2.50-2.30 (m, 5H), 1.90-1.6 (m, 6H)

Example 137. (In the same manner as in Example 62)

4-yl-2- [4- (1-methyl-piperidin-4-yl) -piperazin- 1-yl] -3,4-dihydro-quinazoline- 4-yl) -piperazine-l- (4-fluoro-benzyl) - &lt; / RTI & yl] -3,4-dihydro-quinazolin-4-yl} -N- (4-fluoro-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2- [4- (1 -methyl-piperidin-4-yl) -piperazin- 1-yl] -3,4- dihvdro- (108 mg, 0.20 mmol) and 4-fluorobenzylamine (0.2 mL) were used in the same manner as in Example 62, except that acetic acid The title compound was prepared from 2- {3-biphenyl-4-yl-2- [4- (1-methyl- piperidin- Dihydro-quinazolin-4-yl} -N- (4-fluoro-benzyl) - cetamide.

Yield: 31 mg, 25%, Mass (M + H) &lt; ⁺ & gt ^; : 631

1H, NMR (200MHz, CDCl3) 7.80-7.20 (m, 9H), 7.1-6.70 (m, 8H), 5.30-5.20 (m, , 2.50-2.30 (m, 6H), 1.90-1.6 (m, 6H)

Example 138. (In the same manner as in Example 62)

4-yl-2- [4- (1-methyl-piperidin-4-yl) -piperazin- 1-yl] -3,4-dihydro-quinazoline- 4-yl) -piperazine-1-yl (2-methyl-piperazin- ] -3,4-dihydro-quinazolin-4-yl} -N- (4-methyl-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2- [4- (1 -methyl-piperidin-4-yl) -piperazin- 1-yl] -3,4- dihvdro- (Substantially the same procedure as in Example 62) was carried out using (99 mg, 0.184 mmole) and 4-methylbenzylamine (0.2 mL) in the same manner as in Example 62 4-yl) -2- [4- (1-methyl-piperidin-4-yl) -piperazin- 1 -yl] - dihydro-quinazolin-4-yl} -N- (4-methyl-benzyl) -acetamide.

Yield: 38 mg, 32%, Mass (M + H) &lt; ⁺ & gt ^; : 627

2H), 3.80 (m, 4H), 3.50 (m, 2H), 7.80-7.20 (m, 9H), 7.1-6.70 -3.20 (m, 6H), 2.50-2.30 (m, 5H), 1.90-1.6 (m, 6H)

Example 139 . (Same method as in Example 62)

4-yl-2- [4- (1-methyl-piperidin-4-yl) -piperazin- 1-yl] -3,4-dihydro-quinazoline- 4-yl) -piperazine-l- (4-methoxy-benzyl) -acetamide. yl] -3,4-dihydro-quinazoline-4-yl} -N- (4-methoxy-benzyl) -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2- [4- (1 -methyl-piperidin-4-yl) -piperazin- 1-yl] -3,4- dihvdro- -Acetic acid methyl ester (ester intermediate 24: Example 50) (101 mg, 0.186 mmole) and 4-methoxybenzylamine (0.2 mL) In the same manner, the title compound was obtained as a colorless oil from 2- (3-biphenyl-4-yl-2- [4- (1-methyl-piperidin- , 4-dihydro-quinazolin-4-yl} -N- (4-methoxy-benzyl) -acetamide.

Yield: 39 mg, 33%, Mass (M + H) &lt; ⁺ & gt ^; : 643

(M, 2H), 3.90 (s, 3H), 3.50 (m, 2H) -3.20 (m, 12H), 2.50-2.30 (m, 5H), 1.90-1.6 (m, 6H)

Example 140. (In the same manner as in Example 62)

4-yl-2- [4- (4-methyl-piperazin-l-yl) -piperidin- l-yl] -3,4- dihydro- 4-yl-2- [4- (4-methyl-piperazine-1-yl) -piperidine-1-yl] - 3,4-dihydro-quinazoline-4-yl} -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2- [4- (4-methyl-piperazin-l-yl) -piperidin- l-yl] -3,4-dihydro -Acetic acid methyl ester (ester intermediate 21: Example 47) (104 mg, 0.193 mmole) and benzylamine (0.2 mL) were used in the same manner as in Example 62, Benzyl-2- {3-biphenyl-4-yl-2- [4- (4-methyl-piperazin- 1- yl) -piperidin- 4-dihydro-quinazolin-4-yl} -acetamide.

Yields: 28 mg, 24%, Mass (M + H) &lt; ⁺ & gt ^; : 612

2H NMR (400 MHz, CDCl3)? 7.70-7.00 (m, 14H), 5.20-5.10 (m, 1H), 4.80 (m, 2H), 4.50 , 16H), &lt; / RTI &gt; 2.90-2.70 (m, 2H),

Example 141 . (Same method as in Example 62)

4-yl-2- [4- (4-methyl-piperazin-l-yl) -piperidin- l-yl] -3,4- dihydro- quinazoline- 4-yl-2- [4- (4-methyl-piperazine-1-yl) -piperidine-l- yl] -3,4-dihydro-quinazolin-4-yl} -N- (4-fluoro-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2- [4- (4-methyl-piperazin-l-yl) -piperidin- l-yl] -3,4-dihydro (100 mg, 0.186 mmole) and 4-fluorobenzylamine (0.2 mL) in substantially the same manner as in Example 62, except that acetic acid The title compound was prepared from 2- {3-biphenyl-4-yl-2- [4- (4-methyl-piperazin- 1 -yl) -piperidin- Dihydro-quinazolin-4-yl} -N- (4-fluoro-benzyl) -acetamide.

Yields: 31 mg, 26%, Mass (M + H) &lt; ⁺ & gt ^; : 631

4H), 4.30-4.00 (m, 2H), 4.10 (m, 2H), 3.20 (m, 2H) -2.50 (m, 14H), 2.20 (m, 2H),

Example 142 . (Same method as in Example 62)

4-yl-2- [4- (4-methyl-piperazin-l-yl) -piperidin- l-yl] -3,4- dihydro- quinazoline- 4-yl-2- [4- (4-methyl-piperazin-1-yl) -piperidine-1-yl &lt; / RTI &gt; ] -3,4-dihydro-quinazolin-4-yl} -N- (4-methyl-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2- [4- (4-methyl-piperazin-l-yl) -piperidin- l-yl] -3,4-dihydro (97 mg, 0.180 mmole) and 4-methylbenzylamine (0.2 mL) were used in the same manner as in Example 62, respectively, to obtain substantially the same The title compound was prepared from 2- {3-biphenyl-4-yl-2- [4- (4-methyl-piperazin- 1 -yl) -piperidin- Dihydro-quinazolin-4-yl} -N- (4-methyl-benzyl) -acetamide.

Yields: 29 mg, 26%, Mass (M + H) &lt; ⁺ & gt ^; : 627

(M, 2H), 4.30 (m, 2H), 3.00 (m, 2H), 4.00-4 -2.50 (m, 16H), 2.20 (m, 2H),

Example 143 . (Same method as in Example 62)

4-yl-2- [4- (4-methyl-piperazin-l-yl) -piperidin- l-yl] -3,4- dihydro- quinazoline- 4-yl-2- [4- (4-methyl-piperazine-1-yl) -piperidine-l- yl] -3,4-dihydro-quinazoline-4-yl} -N- (4-methoxy-benzyl) -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 4-yl-2- [4- (4-methyl-piperazin-l-yl) -piperidin- l-yl] -3,4-dihydro (109 mg, 0.20 mmole) and 4-methoxybenzylamine (0.2 mL) were used in the same manner as in Example 62, except that acetic acid The title compound was prepared from 2- {3-biphenyl-4-yl-2- [4- (4-methyl-piperazin- 1 -yl) -piperidin- Dihydro-quinazolin-4-yl} -N- (4-methoxy-benzyl) -acetamide.

Yields: 41 mg, 32%, Mass (M + H) &lt; ⁺ & gt ^; : 643

(M, 2H), 4.13 (m, 2H), 3.75 (s, 3H), 4.75 (m, 2H) ), 3.60-3.00 (m, 16H), 2.90-2.70 (m, 2H)

Example 144. Synthesis of (Same method as in Example 62)

N-Benzyl-2- {2- [4- (2-dimethylamino-ethyl) -piperazin- 1 -yl] -3-quinolin- 6-yl-3,4- dihydro- quinazolin- 2-dimethylamino-ethyl) -piperazine-1-yl] -3-quinoline-6-yl-3,4-dihydro-quinazoline-4 -yl} -acetamide &lt; / RTI &gt;

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; The title compound was prepared from {2- [4- (3-dimethylamino-propyl) -piperazin-l-yl] -3-quinolin-6-yl-3,4-dihydro-quinazoline- -Acetic acid methyl ester (ester intermediate 5: Example 31) (100 mg, 0.20 mmol) and benzylamine (0.2 mL) were used in the same manner as in Example 62 to obtain the title compound N-Benzyl-2- {2- [4- (2-dimethylamino-ethyl) -piperazin- 1 -yl] -3-quinolin- 6-yl-3,4- dihydro- quinazolin- Yl} -acetamide. &Lt; / RTI &gt;

Yield: 19 mg, 17%, Mass (M + H) &lt; ⁺ & gt ^; : 562

(M, 2H), 7.60-7.10 (m, 6H), 7.00-6.90 (m, 2H), 8.00 (M, 4H), 3.45-3.20 (m, 8H), 2.95-2.65 (m, 4H)

Example 145 . (Same method as in Example 62)

Yl-piperazin-l-yl) -3,4-dihydro-quinazolin-4-yl 4-yl-piperazine-1-yl) -3,4-dihydro-quinazoline-4- yl] -acetamide &lt; / RTI &gt;

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-fluoro-phenyl) -2- (4-pyridin-4-yl-piperazin-1-yl) -3,4- dihydro- quinazolin- Substantially the same method as in Example 62 was used, except that acetic acid methyl ester (ester intermediate 1: Example 27) (106 mg, 0.23 mmole) and benzylamine (0.2 mL) Yl-piperazin-l-yl) -3,4-dihydro-quinazolin-4-yl ] -Acetamide. &Lt; / RTI &gt;

Yield: 22 mg, 18%, Mass (M + H) &lt; ⁺ & gt ^; : 535

(M, 2H), 3.70-3. 45 (m, 2H), 5.13 (m, , &Lt; / RTI &gt; 4H), 3.47-3.20 (m, 6H)

Example 146 . (Same method as in Example 62)

Dihydro-quinazolin-4-yl] -N- (4-fluoro-phenyl) (4-fluoro-phenyl) -2- (4-pyridin-4-yl-piperazine- 1 -yl) -3,4-dihydro-quinazoline -4-yl] -N- (4-methoxy-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-fluoro-phenyl) -2- (4-pyridin-4-yl-piperazin-1-yl) -3,4- dihydro- quinazolin- Was prepared in substantially the same manner as in Example 62, using (101 mg, 0.22 mmole) and acetic acid methyl ester (ester intermediate 1: Example 27) and methoxybenzylamine (0.2 mL) Yl) -3,4-dihydro-quinazolin-4-yl] -N- (4-fluorophenyl) - (4-methoxy-benzyl) -acetamide.

Yield: 35 mg, 30%, Mass (M + H) &lt; ⁺ & gt ^; : 565

(D, 2H), 5.15 (m, 1H), 4.52-4.31 (m, 2H) 2H), 3.75 (s, 3H), 3.70-3.50 (br, 4H), 3.47-3.20 (m, 6H)

Example 147 . (Same method as in Example 62)

Yl) -3- (6-fluoro-naphthalen-2-yl) -3,4-di 2-dimethylamino-ethyl) -piperazine-1-yl] -3- (6-fluoro-naphthalene-2 -yl) -3,4-dihydro-quinazoline-4-yl] -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 3- (6-fluoro-naphthalen-2-yl) -3,4-dihydro-benzoic acid was used in the place of 4-fluorobenzylamine instead of 4- [ The title compound was prepared in substantially the same manner as in Example 62, using (104 mg, 0.206 mmole) and benzylamine (0.2 mL) instead of dihydro-quinazolin-4-yl] -acetic acid methyl ester The title compound was prepared by the same procedure as described in the preparation of N-benzyl-2- [2- [4- (2-dimethylamino-ethyl) -piperazin- 1 -yl] -3- (6-fluoro-naphthalen- ) -3,4-dihydro-quinazolin-4-yl] -acetamide.

Yield: 39.4 mg, 33%, Mass (M + H) &lt; ⁺ & gt ^; : 579

1H, NMR (400MHz, CDCl3) 8.30-8.20 (m, 3H), 7.80-7.60 (m, 2H), 7.40-7.20 (m, 8H), 7.00 2H), 3.1 (m, 4H), 2.90-2.50 (m, 7H), 3.40 (m,

Example 148 (the same method as in Example 62)

3- (6-fluoro-naphthalen-2-yl) -3,4-dihydro-quinazoline &lt; / RTI &gt; 4-yl] -N- (4-fluoro-benzyl) -acetamide. 2-yl) -3,4-dihydro-quinazolin-4-yl] -N- (4-fluoro-benzyl) -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 3- (6-fluoro-naphthalen-2-yl) - (4-fluorophenyl) (100 mg, 0.20 mmole) and 4-fuluroobenzylamine (0.2 mL) were used in the same manner as in the synthesis of the intermediate In substantially the same manner as in Example 62, the title compound was obtained by the reaction of 2- [2- [4- (2-dimethylamino-ethyl) -piperazin-1-yl] -3- (6- Yl) -3,4-dihydro-quinazolin-4-yl] -N- (4-fluoro-benzyl) -acetamide.

Yield: 21.0 mg, 18%, Mass (M + H) &lt; ⁺ & gt ^; : 597

1H, NMR (400MHz, CDCl3) 8.30-8.20 (br, 2H), 7.80-7.00 (m, 10H), 6.70-6.50 (m, 2H), 5.30 3H), 3.40 (m, 4H), 3.3 (br, 2H), 3.1 (m, 4H), 2.90-2.50

Example 149 . (Same method as in Example 62)

3- (6-fluoro-naphthalen-2-yl) -3,4-dihydro-quinazoline &lt; / RTI &gt; (2-dimethylamino-ethyl) -piperazine-1-yl] -3- (6-fluoro-naphthalene -2-yl) -3,4-dihydro-quinazolin-4-yl] -N- (4-methyl-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 3- (6-fluoro-naphthalen-2-yl) -3,4-dihydro-benzoic acid was used in the place of 4-fluorobenzylamine instead of 4- [ (62 mg, 0.194 mmol) and 4-methylbenzylamine (0.2 mL) were used in the same manner as in Example 62, except that the compound Yl) -3- (6-fluoro-naphthalen-2-yl) -piperazin-1-yl ) -3,4-dihydro-quinazolin-4-yl] -N- (4-methyl-benzyl) -acetamide.

Yield: 36.0 mg, 31%, Mass (M + H) &lt; ⁺ & gt ^; : 593

2H), 7.39-7.32 (m, 4H), 7.14-6.95 (m, 4H), 6.64-6.62 (m, 2H), 7.26-8.19 (m, , 4.30 (m, 4H), 3.10 (m, 4H), 2.40-2.30 (m, , 8H)

Example 150 (the same method as in Example 62)

3- (6-fluoro-naphthalen-2-yl) -3,4-dihydro-quinazoline &lt; / RTI &gt; 4-yl] -N- (3-fluoro-benzyl) -acetamide. 2-yl) -3,4-dihydro-quinazoline-4-yl] -N- (3-fluoro-benzyl) -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; 3- (6-fluoro-naphthalen-2-yl) -3,4-dihydro-benzoic acid was used in the place of 4-fluorobenzylamine instead of 4- [ (62 mg, 0.21 mmol) and 3-fluorobenzylamine (0.2 mL) were used in the same manner as in Example 62 and using 2-fluorobenzylamine In a substantially similar manner, the title compound is obtained by reacting the titled compound of 2- [2- [4- (2-dimethylamino-ethyl) -piperazin-1 -yl] -3- (6-fluoro- Yl) -3,4-dihydro-quinazolin-4-yl] -N- (3-fluoro-benzyl) -acetamide.

Yield: 21.0 mg, 17%, Mass (M + H) &lt; ⁺ & gt ^; : 597

2H), 4.20 (m, 2H), 4.70 (m, 2H), 4.70 (m, 4H), 3.10 (m, 4H), 2.40-2.30 (m, 5H)

Example 151 . (Same method as in Example 62)

(4-pyridin-4-yl-piperazin-l-yl) -3,4-dihydro-quinazoline 4-yl-piperazin-1-yl) -3, 4-dihydro-naphthalen-2- 4-dihydro-quinazoline-4-yl] -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-pyridin-4-yl-piperazin-l-yl) -3,4-dihydro-quinoline (100 mg, 0.196 mmole) and benzylamine (0.2 mL) were used in the same manner as in Example 62, respectively, to give the title compound as a white amorphous solid The title compound was prepared from N-benzyl-2- [3- (6-fluoro-naphthalen-2-yl) -2- (4- pyridin- Dihydro-quinazolin-4-yl] -acetamide.

Yield: 25.6 mg, 22%, Mass (M + H) &lt; ⁺ & gt ^; : 585

(M, 2H), 3.57 (br, 4H), 5.17 (m, 2H), 4.60 (d, 3.23 (br, 4H), 2.81 (m, IH), 2.58 (m, IH)

Example 152 ; (Same method as in Example 62)

(4-Fluoro- benzyl) -2- [3- (6-fluoro-naphthalen- (4-fluoro-benzyl) -2- [3- (6-fluoro-naphthalene-2-yl) -2- (4-pyridine- 4-yl-piperazin-1-yl) -3,4-dihydro-quinazoline-4-yl] -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-pyridin-4-yl-piperazin-l-yl) -3,4-dihydro-quinoline (Tert-butoxycarbonylamino) -thiazol-4-yl] -acetic acid methyl ester (ester intermediate 7: Example 33) (99 mg, 0.194 mmole) and 4-fluorobenzylamine (4-Fluoro-benzyl) -2- [3- (6-fluoro-naphthalen-2-yl) -2- Yl) -3,4-dihydro-quinazolin-4-yl] -acetamide.

Yield: 14.4 mg, 12%, Mass (M + H) &lt; ⁺ & gt ^; : 602

(M, 2H), 3.57 (br, 4H), 4.75 (d, 2H) 3.23 (br, 4H), 2.81 (m, IH), 2.45 (m, IH)

Example 153 . (Same method as in Example 61)

2-yl) -2- (4-pyridin-4-yl-piperazin-l-yl) -3,4-dihydro-quinazolin- 4-yl-piperazin-1-yl) - (4-methyl-benzyl) 3,4-dihydro-quinazoline-4-yl] -N- (4-methyl-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-pyridin-4-yl-piperazin-l-yl) -3,4-dihydro-quinoline Was prepared in substantially the same manner as in Example 62, using 4-methylbenzylamine (0.29 mmole) and (107 mg, 0.21 mmole) of 4- 2- (4-pyridin-4-yl-piperazin-l-yl) -3,4-dihydro-pyrazol- Quinazolin-4-yl] -N- (4-methyl-benzyl) -acetamide.

Yield: 13.0 mg, 10%, Mass (M + H) &lt; ⁺ & gt ^; : 599

(M, 2H), 3.57 (br, 4H), 5.18 (d, 2H) 2H), 2.45 (s, 3H), 3.23 (br, 4H)

Example 154. (In the same manner as in Example 62)

Yl) -3- (4'-fluoro-biphenyl-4-yl) -3,4-dihydro- 2-dimethylamino-ethyl) -piperazine-1-yl] -3- (4 ' -fluoro-quinazolin- biphenyl-4-yl) -3,4-dihydro-quinazoline-4-yl] -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4'-fluoro-biphenyl-4-yl) -3, 4-fluorobenzylamine in place of 4- (95 mg, 0.179 mmole) and benzylamine (0.2 mL) in substantially the same manner as in Example 62, using 4-dihydro-quinazolin-4-yl] -acetic acid methyl ester (4'-fluoro-biphenyl-2-yl) -3- (4-fluoro-biphenyl- -4-yl) -3,4-dihydro-quinazolin-4-yl] -acetamide.

Yield: 82.0 mg, 76%, Mass (M + H) &lt; ⁺ & gt ^; : 605

2H), 7.41 (d, 2H), 7.28 (m, 5H), 7.20 (m, 3H), 7.12 (m, (m, 2H), 2.50 (m, 2H), 2.50 (m, , 4H), 2.22 (s, 6H), 2.16 (br, 3H)

Example 155 . (Same method as in Example 62)

3- (4'-Fluoro-biphenyl-4-yl) -3,4-dihydro-pyrazol- 2-dimethylamino-ethyl) -piperazine-1-yl] -3- (4 ' -fluoro-biphenyl-4-yl) -3,4-dihydro-quinazolin-4-yl] -N- (4- fluoro-benzyl) -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4'-fluoro-biphenyl-4-yl) -3, 4-fluorobenzylamine in place of 4- Using Example 101 (0.15 g, 0.19 mmole) and 4-fluorobenzylamine (0.2 mL), the title compound was obtained as white crystals from 4-dihydro-quinazolin-4-yl] -acetic acid methyl ester Yl] -3- (4'-fluoro-biphenyl) -piperazin-1 -yl] -piperazin-1- Yl) -3,4-dihydro-quinazolin-4-yl] -N- (4-fluoro-benzyl) -acetamide.

Yield: 60.5 mg, 51%, Mass (M + H) &lt; ⁺ & gt ^; : 623

2H), 7.41 (d, 2H), 7.30-7.20 (m, 5H), 7.11 (m, 3H), 7.10 (br, (M, 2H), 3.30 (br, 4H), 2.76 (br, 4H), 2.58 (s, 6 H)

Example 156 . (Same method as in Example 62)

3- (4'-Fluoro-biphenyl-4-yl) -3,4-dihydro-pyrazol- 2-dimethylamino-ethyl) -piperazine-1-yl] -3- (4 ' -methyl- yl) -3,4-dihydro-quinazolin-4-yl] -N- (4-methyl-benzyl) -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4'-fluoro-biphenyl-4-yl) -3, 4-fluorobenzylamine in place of 4- (100 mg, 0.188 mmole) and 4-methylbenzylamine (0.2 mL) were used in the same manner as in Example 62, except that 4-hydroxy-4-dihydro-quinazolin- In substantially the same manner, the title compound was obtained as a colorless solid of 2- [2- [4- (2-dimethylamino-ethyl) -piperazin-1-yl] -3- (4'- Yl) -3,4-dihydro-quinazolin-4-yl] -N- (4-methyl- benzyl) -acetamide.

Yield: 84.1 mg, 72%, Mass (M + H) &lt; ⁺ & gt ^; : 618

1H NMR (400 MHz, CDCl3) 7.50 (m, 2H), 7.41 (m, 2H), 7.25-7.10 (m, 10H), 6.99-6.93 ), 3.31 (br, 4H), 2.56 (m, IH), 2.30 (m, 5H)

Example 157. 7- (Same method as in Example 62)

4-yl-piperazin-l-yl) -3,4-dihydro-pyrazol- 4-yl-piperazin-1-yl) - quinazolin-4-yl] -acetamide. -3,4-dihydro-quinazoline-4-yl] -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-fluoro-biphenyl-4-yl) -2- (4-pyridin-4-yl- piperazin- 1 -yl) -3,4- dihydro (102 mg, 0.19 mmole) and benzylamine (0.2 mL) were reacted in substantially the same manner as in Example 62 to give the title compound as a white amorphous solid. (4-Fluoro-biphenyl-4-yl) -2- (4-pyridin- 4-dihydro-quinazolin-4-yl] -acetamide.

Yield: 56.2 mg, 48%, Mass (M + H) &lt; ⁺ & gt ^; : 611

(D, 2H), 5.13 (m, 1H), 4.30 (m, 2H), 8.13 (d, 2H), 7.33-7.15 (m, 11H), 7.10-6.93 (m, 8H) , 3.70-3.50 (br, 4H), 3.47-3.20 (m, 4H), 2.71 (m,

Example 158. 7- (Same method as in Example 62)

Yl) -2- (4-pyridin-4-yl-piperazin-1-yl) - (4-fluoro-benzyl) -2- [3- (4'-fluoro-biphenyl-4-yl) -2- -pyridine-4-yl-piperazine-1-yl) -3,4-dihydro-quinazoline-4-yl] -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-fluoro-biphenyl-4-yl) -2- (4-pyridin-4-yl- piperazin- 1 -yl) -3,4- dihydro (105 mg, 0.196 mmole) and 4-fluorobenzylamine (0.2 mL) in substantially the same manner as in Example 62, except that acetic acid methyl ester (4-fluoro-biphenyl-4-yl) -2- (4-pyridin-4-yl -Piperazin-l-yl) -3,4-dihydro-quinazolin-4-yl] -acetamide.

Yield: 61.0 mg, 50%, Mass (M + H) &lt; ⁺ & gt ^; : 629

1H NMR (400MHz, CDCl3) 8.13 (d, 2H), 7.75-7.30 (m, 10H), 7.20-7.01 (m, 8H), 6.83 2H), 3.70-3.50 (br, 4H), 3.47-3.20 (m, 4H), 2.71 (m,

Example 159 . (Same method as in Example 62)

(4-chloro-benzyl) -2- [3- (4'-fluoro-biphenyl- (4-chloro-benzyl) -2- [3- (4'-fluoro-biphenyl-4-yl) -2- pyridine-4-yl-piperazine-1-yl) -3,4-dihydro-quinazoline-4-yl] -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-fluoro-biphenyl-4-yl) -2- (4-pyridin-4-yl- piperazin- 1 -yl) -3,4- dihydro (Substantially the same procedure as in Example 62) was carried out using (101 mg, 0.188 mmole) and 4-chlorobenzylamine (0.2 mL) in the same manner as in Example 62 (4-chloro-benzyl) -2- [3- (4'-fluoro-biphenyl-4-yl) -2- L-yl) -3,4-dihydro-quinazolin-4-yl] -acetamide.

Yield: 52.1 mg, 43%, Mass (M + H) &lt; ⁺ & gt ^; : 645

1H, NMR (400MHz, CDCl3) 8.11 (d, 2H), 7.65-7.30 (m, 10H), 7.18-6.98 (m, 8H) 2H), 3.70-3.50 (br, 4H), 3.47-3.20 (m, 4H), 2.71 (m,

Example 160 . (Same method as in Example 62)

2- (4-Pyridin-4-yl-piperazin-l-yl) -3,4-dihydro-quinazoline-4 4-yl) -2- (4-pyridin-4-yl-piperazine-l- yl) -3,4-dihydro-quinazolin-4-yl] -N- (4-methyl-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-fluoro-biphenyl-4-yl) -2- (4-pyridin-4-yl- piperazin- 1 -yl) -3,4- dihydro (100 mg, 0.186 mmole) and 4-methylbenzylamine (0.2 mL) were used in substantially the same manner as in Example 62, except that acetic acid methyl ester (ester intermediate 4: 2- (4-pyridin-4-yl-piperazin-1-yl) -3,4- - dihydro-quinazolin-4-yl] -N- (4-methyl-benzyl) -acetamide.

Yield: 56.2 mg, 48%, Mass (M + H) &lt; ⁺ & gt ^; : 625

2H), 5.15 (m, IH), 4.25 (m, 2H), 6.80 (d, IH) , 3.70-3.50 (br, 4H), 3.47-3.20 (m, 4H), 2.60 (m,

Example 161. 7- (The same method as in Example 3)

Yl] -3- (4'-fluoro-biphenyl-4-yl) -3,4-dihydro- -Dihydro-quinazolin-4-yl] - &lt; / RTI &gt; biphenyl-4-yl) -3,4-dihydro-quinazoline-4-yl] -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4'-fluoro-biphenyl-4-yl) -3, 4-dihydro- (101 mg, 0.186 mmole) and benzylamine (0.2 mL) in substantially the same manner as in Example 62, using 4-dihydro-quinazolin-4-yl] -acetic acid methyl ester Benzyl-2- [2- [4- (3-dimethylamino-propyl) -piperazin-1-yl] -3- (4'- fluoro-biphenyl -4-yl) -3,4-dihydro-quinazolin-4-yl] -acetamide.

Yields: 46.8 mg, 41%, Mass (M + H) &lt; ⁺ & gt ^; : 619

(M, 2H), 3.49 (m, 2H), 4.49 (m, 2H) 2H), 2.75 (m, 2H), 2.78 (m, 2H)

Example 162 . (Same method as in Example 62)

3- (4'-Fluoro-biphenyl-4-yl) -3,4-dihydro-pyrazol- 4-yl] -N- (4-fluoro-benzyl) -acetamide. -fluoro-biphenyl-4-yl) -3,4-dihydro-quinazolin-4-yl] -N- (4- fluoro-benzyl) -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4'-fluoro-biphenyl-4-yl) -3, 4-dihydro- Using Example 103 (103 mg, 0.189 mmole) and 4-fluorobenzylamine (0.2 mL), the title compound was obtained as white crystals from 2-bromo-4-fluoroaniline Was prepared in substantially the same manner as 2- [2- [4- (3-dimethylamino-propyl) -piperazin-l-yl] -3- (4'-fluoro- Yl) -3,4-dihydro-quinazolin-4-yl] -N- (4-fluoro-benzyl) -acetamide.

Yield: 41.0 mg, 34%, Mass (M + H) &lt; ⁺ & gt ^; : 637

(M, 2H), 3.49 (br, 4H), 4.30 (m, 2H) 2H), 2.77 (m, 2H), 2.78 (m, 2H)

Example 163. (The same method as in Example 62)

Yl] -3- (4'-fluoro-biphenyl-4- (4-fluoro-benzyl) -2- (4-chloro-benzyl) -2- [2- [4- (3-dimethylamino-propyl) -piperazine-1 -yl] -3- (4'-fluoro-biphenyl-4-yl) -3,4-dihydro-quinazoline-4-yl] -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4'-fluoro-biphenyl-4-yl) -3, 4-dihydro- The title compound was obtained by following the same procedure as that of Example 62 and using 4-chlorobenzylamine (0.2 mL) and 4-dihydro-quinazolin-4-yl] -acetic acid methyl ester (Ester intermediate 3: Example 29) (98 mg, 0.180 mmole) (4-chloro-benzyl) -2- [2- [4- (3-dimethylamino-propyl) -piperazin- 1 -yl] -3- (4'-fluoro-biphenyl-4-yl) -3,4-dihydro-quinazolin-4-yl] -acetamide.

Yield: 33.5 mg, 29%, Mass (M + H) &lt; ⁺ & gt ^; : 653

(M, 2H), 3.49 (br, 4H), 4.30 (m, 2H) 2H), 2.78 (m, 2H), 2.78 (m, 2H)

Example 164. (The same manner as in Example 62)

3- (4'-Fluoro-biphenyl-4-yl) -3,4-dihydro-pyrazol- 4-yl] -N- (4-methyl-benzyl) -acetamide (2- [2- [4- (3-dimethylamino- propyl) -piperazine- yl) -3,4-dihydro-quinazolin-4-yl] -N- (4-methyl-benzyl) -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4'-fluoro-biphenyl-4-yl) -3, 4-dihydro- (62 mg, 0.188 mmol) and 4-methylbenzylamine (0.2 mL) were used in the same manner as in Example 62 and using 4-dihydro-quinazolin-4-yl] -acetic acid methyl ester In substantially the same manner, the title compound was obtained from 2- [2- [4- (3-dimethylamino-propyl) -piperazin-l-yl] -3- (4'- Yl) -3,4-dihydro-quinazolin-4-yl] -N- (4-methyl- benzyl) -acetamide.

Yield: 54.2 mg, 46%, Mass (M + H) &lt; ⁺ & gt ^; : 633

2H), 3.50 (m, 2H), 3.50 (m, 2H), 3.50 (m, 2H), 2.80 (m, 2H), 2.85 (s, 3H), 2.85 (m,

Example 165 : (Same method as in Example 62)

N-benzyl-2- [2- (4-pyridin-4-yl-piperazin-1-yl) -3- (5,6,7,8-tetrahydro- 4-yl-piperazin-1-yl) -3- (5,6,7,8-dihydro- quinazolin- -tetrahydro-naphthalene-2-yl) -3,4-dihydro-quinazoline-4-yl] -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (5,6,7,8-tetrahydro-naphthalen-2-yl) -3, 5-dihydro-pyrazol- (100 mg, 0.20 mmole) and benzylamine (0.2 mL) in substantially the same manner as in Example 62 using 4-dihydro-quinazolin-4-yl] -acetic acid methyl ester Benzyl-2- [2- (4-pyridin-4-yl-piperazin-1-yl) -3- (5,6,7,8- tetrahydro-naphthalene -2-yl) -3,4-dihydro-quinazolin-4-yl] -acetamide.

Yield: 35.4 mg, 31%, Mass (M + H) &lt; ⁺ & gt ^; : 571

(M, 2H), 5.22 (m, IH), 4.60 (m, 2H), 7.90-7.16 (M, 2H), 2.45 (m, 2H), 2.45 (m, IH) )

Example 166. &lt; (Same method as in Example 62)

3- (5,6,7,8-tetrahydro-naphthalen-2-yl) -piperazin-1- 4-yl-piperazine-l- (4-fluoro-benzyl) -2- [2- yl) -3- (5,6,7,8-tetrahydro-naphthalene-2-yl) -3,4-dihydro-quinazoline-4-yl] -acetamid e)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (5,6,7,8-tetrahydro-naphthalen-2-yl) -3, 5-dihydro-pyrazol- (97 mg, 0.196 mmole) and 4-fluorobenzylamine (0.2 mL) were used in the same manner as in Example 62, except that 4-dihydro-quinazolin-4-yl] -acetic acid methyl ester (4-pyridin-4-yl-piperazin-1-yl) -3- (5 , 6,7,8-tetrahydro-naphthalen-2-yl) -3,4-dihydro-quinazolin-4-yl] -acetamide.

Yield: 60.8 mg, 53%, Mass (M + H) &lt; ⁺ & gt ^; : 589

1H, NMR (400MHz, CDCl3) 8.33 (s, 1H), 8.26 (m, 2H), 7.76 (m, 2H), 7.29-6.78 (M, 2H), 4.52 (m, 1H), 4.30 (m, 1H), 3.29 (br, 4H), 2.97 (br,

Example 167. &lt; (Same method as in Example 62)

3- (5,6,7,8-tetrahydro-naphthalen-2-yl) - N- (4-methyl- (4-methyl-benzyl) -2- [2- (4-pyridin-4-yl-piperazine-1- yl) -acetamide ) -3- (5,6,7,8-tetrahydro-naphthalene-2-yl) -3,4-dihydro-quinazoline-4-yl] -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (5,6,7,8-tetrahydro-naphthalen-2-yl) -3, 5-dihydro-pyrazol- The title compound was obtained by following the same procedure as described in example 62 and using 4-methyl-benzylamine (0.2 mL) and 4-dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester intermediate 34: (4-methyl-benzyl) -2- [2- (4-pyridin-4-yl-piperazin- 1 -yl) -3- , 7,8-tetrahydro-naphthalen-2-yl) -3,4-dihydro-quinazolin-4-yl] -acetamide.

Yield: 30.2 mg, 26%, Mass (M + H) &lt; ⁺ & gt ^; : 585

1H, NMR (400MHz, CDCl3) 8.23 (m, 2H), 7.79-7. 65 (m, 1H,), 7.40-6.83 2H), 2.47 (m, 1H), 2.35 (m, 3H), 2.45 (m, ), 1.76 (m, 4H)

Example 168. &lt; (Same method as in Example 62)

Yl) -3- (5,6,7,8-tetrahydro-naphthalen-2-yl) - &lt; / RTI & Dihydro-quinazolin-4-yl] - &lt; / RTI &gt; , 6,7,8-tetrahydro-naphthalene-2-yl) -3,4-dihydro-quinazoline-4-yl] -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (5,6,7,8-tetrahydro-naphthalen-2-yl) -3, 5-dihydro-pyrazol- (104 mg, 0.21 mmole) and benzylamine (0.2 mL) in substantially the same manner as in Example 62, using 4-dihydro-quinazolin-4-yl] -acetic acid methyl ester Benzyl-2- [2- [4- (2-dimethylamino-ethyl) -piperazin-1-yl] -3- (5,6,7,8- Tetrahydro-naphthalen-2-yl) -3,4-dihydro-quinazolin-4-yl] -acetamide.

Yield: 68.4 mg, 58%, Mass (M + H) &lt; ⁺ & gt ^; : 565

(M, 2H), 3.50 (br, 6H), 6.30-7.30 (m, 2.68 (br, 4H), 2.39 (br, 4H), 2.28-2.20 (m,

Example 169. &lt; (Same method as in Example 62)

Yl) -3- (5,6,7,8-tetrahydro-naphthalen-2-yl) -3,4-dihydro- 2-dimethylamino-ethyl) -piperazine-1-yl] - 3 - (2-methylsulfanyl) - (5,6,7,8-tetrahydro-naphthalene-2-yl) -3,4-dihydro-quinazoline-4- yl] -N- (4-fluoro-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (5,6,7,8-tetrahydro-naphthalen-2-yl) -3, 5-dihydro-pyrazol- Using Example 100 (100 mg, 0.20 mmole) and 4-fluorobenzylamine (0.2 mL), the title compound was obtained as white crystals from 2-bromo-4-fluoroaniline (2-dimethylamino-ethyl) -piperazin-1-yl] -3- (5,6,7,8- Yl) -3,4-dihydro-quinazolin-4-yl] -N- (4-fluoro-benzyl) -acetamide.

Yield: 74.2 mg, 64%, Mass (M + H) &lt; ⁺ & gt ^; : 583

(M, 2H), 3.50 (br, 6H), 2.82 (m, 2H) 2H), 2.68 (br, 6H), 2.54 (m, IH), 2.39 (br,

Example 170. 7- (Same method as in Example 62)

Yl) -3- (5,6,7,8-tetrahydro-naphthalen-2-yl) -3,4-dihydro- 2-dimethylamino-ethyl) -piperazine-1-yl] - 3- (4-methyl-benzyl) (5,6,7,8-tetrahydro-naphthalene-2-yl) -3,4-dihydro-quinazolin-4-yl] -N- (4-methyl-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (5,6,7,8-tetrahydro-naphthalen-2-yl) -3, 5-dihydro-pyrazol- The title compound was obtained by following the same procedure as described in example 62 and using (101 mg, 0.20 mmole) and 4-methylbenzylamine (0.2 mL), and using 4-dihydro- In substantially the same manner, the title compound was obtained from 2- [2- [4- (2-dimethylamino-ethyl) -piperazin-1-yl] -3- (5,6,7,8- Dihydro-quinazolin-4-yl] -N- (4-methyl-benzyl) -acetamide. .

Yield: 50.3 mg, 43%, Mass (M + H) &lt; ⁺ & gt ^; : 579

(M, 2H), 3.50 (br, 6H), 2.80 (m, 2H) (m, 4H), 2.28-2.20 (m, 15H), 1.76 (m, 4H)

Example 171. &lt; (Same method as in Example 62)

Yl) -3- (4-pyrrolidin-1-yl-phenyl) -3,4- dihydro- Dihydro-quinazolin-4-yl] - &lt; / RTI &gt; acetamide was prepared from N-benzyl-2- [2- [4- (3- dimethylamino- propyl) -piperazine- yl-phenyl) -3,4-dihydro-quinazoline-4-yl] -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; Yl) -3- (4-pyrrolidin-1-yl-phenyl) - 3,4-dihydro- Using substantially the same procedure as in Example 62, using (98 mg, 0.189 mmole) and benzylamine (0.2 mL), the title compound was obtained as a white amorphous solid by the same method as in Example 62 Benzyl-2- [2- [4- (3-dimethylamino-propyl) -piperazin- 1 -yl] -3- (4- pyrrolidin- -Phenyl) -3,4-dihydro-quinazolin-4-yl] -acetamide.

Yield: 45 mg, 40%, Mass (M + H) &lt; ⁺ & gt ^; : 594

1H NMR (400 MHz, CDCl3) 7.82 (m, 1H), 7.45-7.00 (m, 10H), 6.39 (m, 2H) 4H), 1.60 (m, 2H), 2.60 (m, 2H)

Example 172. 7- (Same method as in Example 62)

Yl) -3- (4-pyrrolidin-l-yl-phenyl) -3,4-dihydro-quinoline 4-yl] -N- (4-fluoro-benzyl) -acetamide (2- [2- [4- (3- dimethylamino- propyl) -piperazine- -1-yl-phenyl) -3,4-dihydro-quinazoline-4-yl] -N- (4- fluoro-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; Yl) -3- (4-pyrrolidin-1-yl-phenyl) - 3,4-dihydro- (102 mg, 0.197 mmol) and 4-fluoro-benzylamine (0.2 mL) were used in the same manner as in Example 62 Piperazin-1-yl] -3- (4-pyrrolidin-l- Yl-phenyl) -3,4-dihydro-quinazolin-4-yl] -N- (4-fluoro-benzyl) -acetamide.

Yield: 54 mg, 45%, Mass (M + H) &lt; ⁺ & gt ^; : 612

(M, 2H), 2.59 (m, 2H), 2.54 (m, 2H) 2H), 1.99 (m, 4H), 1.60 (m, 2H), 2.27-2.18 (m,

Example 173. (Same procedure as in Example 62)

Yl) -3- (4-pyrrolidin-1-yl-phenyl) -piperazin-1- ) -3,4-dihydro-quinazolin-4-yl] -acetamide (N- (4-chloro-benzyl) -2- [2- [4- (3- dimethylamino- propyl) -piperazine- 1- yl] -3- (4-pyrrolidin-1-yl-phenyl) -3,4-dihydro-quinazoline-4-yl] -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; Yl) -3- (4-pyrrolidin-1-yl-phenyl) - 3,4-dihydro- -Acetic acid methyl ester (Ester intermediate 31: Example 57) (99 mg, 0.191 mmol) and 4-chloro-benzylamine (0.2 mL) (4-chloro-benzyl) -2- [2- [4- (3-dimethylamino-propyl) -piperazin- 1 -yl] -3- (4-pyrrolidin-1-yl-phenyl) -3,4-dihydro-quinazolin-4-yl] -acetamide.

Yield: 67 mg, 56%, Mass (M + H) &lt; ⁺ & gt ^; : 629

(M, 2H), 2.59 (m, 2H), 3.74-3.01 (m, 2H) 1H), 1.45 (m, 4H), 1.60 (m, 2H), 2.45-2.2.39

Example 174 . (Same method as in Example 62)

3- (4-pyrrolidin-1-yl-phenyl) -piperazin-1 -yl] ) -3,4-dihydro-quinazolin-4-yl] - acetamide (N- (3- yl] -3- (4-pyrrolidine-1-yl-phenyl) -3,4-dihydro-quinazoline-4-yl] -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; Yl) -3- (4-pyrrolidin-1-yl-phenyl) - 3,4-dihydro- (100 mg, 0.193 mmole) and 3-chloro-benzylamine (0.2 mL) were used in the same manner as in Example 62, except that acetic acid (3-chloro-benzyl) -2- [2- [4- (3-dimethylamino-propyl) -piperazin- 1 -yl] -3- (4-pyrrolidin-1-yl-phenyl) -3,4-dihydro-quinazolin-4-yl] -acetamide.

Yield: 46 mg, 38%, Mass (M + H) &lt; ⁺ & gt ^; : 629

(M, 2H), 2.62 (m, 2H), 3.52-3.30 (m, 2H) 2H), 1.99 (m, 4H), 1.60 (m, 2H), 2.43-2.39 (m, 4H)

Example 175. 7- (Same method as in Example 62)

Yl) -3- (4-pyrrolidin-l-yl-phenyl) -3,4-dihydro-quinoline 4-yl] -3- (4-pyrrolidine-2-carboxylic acid ethyl ester) 1-yl-phenyl) -3,4-dihydro-quinazoline-4-yl] -N- (4-methyl-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; Yl) -3- (4-pyrrolidin-1-yl-phenyl) - 3,4-dihydro- -Acetic acid methyl ester (ester intermediate 31: Example 57) (104 mg, 0.20 mmol) and 4-methyl-benzylamine (0.2 mL) In a substantially similar manner, the title compound is obtained by reacting the titled compound of 2- [2- [4- (3-dimethylamino-propyl) -piperazin-1-yl] -3- (4-pyrrolidin- -Phenyl) -3,4-dihydro-quinazolin-4-yl] -N- (4-methyl-benzyl) -acetamide.

Yield: 63 mg, 51%. Mass (M + H) &lt; ⁺ & gt ^; : 608

(M, 2H), 2.62 (m, 2H), 3.52-3.30 (m, 2H) (M, 4H), 1.60 (m, 2H), 1.60 (m, 2H)

Example 176. &lt; (Same method as in Example 62)

Dihydro-quinazolin-2-yl] -methyl-amino} - (3-methylsulfanyl) 4-dihydro-quinazolin-2-yl] -methyl-amino} -propionic acid ethyl ester was prepared from 5- -pentanoic acid dimethylamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-dimethylcarbamoyl-butyl) -methyl-amino] -3- (4-pyrrolidin- 1 -yl-phenyl) -3,4-dihydro- Quinazolin-4-yl] -acetic acid methyl ester (ester intermediate 29: Example 55) (101 mg, 0.20 mmol) and benzylamine (0.2 mL) The title compound was prepared from 5 - {[4- (benzylcarbamoyl-methyl) -3- (4-pyrrolidin- 1 -yl-phenyl) -3,4- dihydro- quinazolin- -Amino} -pentanoic acid dimethylamide. &Lt; / RTI &gt;

Yields: 52 mg, 45%, Mass (M + H) &lt; ⁺ & gt ^; : 581

1H, NMR (400MHz, CDCl3) 7.44-6.86m, 11H), 6.43 (m, 2H) 5.15 2H), 1.98 (m, 6H), 1.81 (m, 1H), 1.57-1.27 (m, 4H)

Example 177. &lt; (Same method as in Example 62)

Methyl-3- (4-pyrrolidin-l-yl-phenyl) -3,4-dihydro-quinazolin-2-yl ] -Methyl-amino} -pentanoic acid dimethylamide (5 - {[4 - [(4-fluoro-benzylcarbamoyl) -methyl] -3- dihydro-quinazoline-2-yl] -methyl-amino} -pentanoic acid dimethylamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-dimethylcarbamoyl-butyl) -methyl-amino] -3- (4-pyrrolidin- 1 -yl-phenyl) -3,4-dihydro- (100 mg, 0.197 mmole) and 4-fluoro-benzylamine (0.2 mL) in substantially the same manner as in Example 62, using (4-fluoro-benzylcarbamoyl) -methyl] -3- (4-pyrrolidin-l-yl-phenyl) -3,4- Dihydro-quinazolin-2-yl] -methyl-amino} -pentanoic acid dimethylamide.

Yield: 46 mg, 40%, Mass (M + H) &lt; ⁺ & gt ^; : 589

1H, NMR (400MHz, CDCl3) 7.44-6.86 m, 10H), 6.40 (m, 2H) 5.13 (m, 1H), 4.53 2H), 2.80 (s, 2H), 2.72-2.60 (m, 4H), 2.40-2.36 (m, 3H), 2.00

Example 178 . (Same method as in Example 62)

(4-chloro-benzylcarbamoyl) -methyl] -3- (4-pyrrolidin-l-yl-phenyl) -3,4- dihydro- quinazolin- -Methyl-amino} -pentanoic acid dimethylamide (5 - {[4 - [(4-chloro-benzylcarbamoyl) -methyl] -3- (4- pyrrolidin- -quinazoline-2-yl] -methyl-amino} -pentanoic acid dimethylamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-dimethylcarbamoyl-butyl) -methyl-amino] -3- (4-pyrrolidin- 1 -yl-phenyl) -3,4-dihydro- (62 mg, 0.20 mmol) and 4-chloro-benzylamine (0.2 mL) in substantially the same manner as in Example 62 Was added to a suspension of 5 - {[4- [(4-chloro-benzylcarbamoyl) -methyl] -3- (4- pyrrolidin- 1 -yl- phenyl) -3,4- dihydro -Quinazolin-2-yl] -methyl-amino} -pentanoic acid dimethylamide.

Yield: 37 mg, 30%, Mass (M + H) &lt; ⁺ & gt ^; : 616

1H, NMR (400MHz, CDCl3) 7.40-6.86m, 10H), 6.41 (m, 2H) 5.14 , 2.90 (s, 2H), 2.80 (s, 2H), 2.74-2.70 (m, 4H), 2.40-2.36

Example 179 : (Same method as in Example 62)

Methyl-3- (4-pyrrolidin-l-yl-phenyl) -3,4-dihydro-quinazolin-2- Amino] -pentanoic acid dimethylamide (5- {methyl- [4- [4-methyl-benzylcarbamoyl) -methyl] -3- (4- pyrrolidin- -dihydro-quinazoline-2-yl] -amino} -pentanoic acid dimethylamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-dimethylcarbamoyl-butyl) -methyl-amino] -3- (4-pyrrolidin- 1 -yl-phenyl) -3,4-dihydro- (4-methyl-benzylamino) quinazolin-4-yl] -acetic acid methyl ester (ester intermediate 29: Example 55) (105 mg, 0.208 mmole) Methyl-3- (4-pyrrolidin-l-yl-phenyl) -3,4-dihydro- Dihydro-quinazolin-2-yl] -amino} -pentanoic acid dimethylamide.

Yield: 63 mg, 51%, Mass (M + H) &lt; ⁺ & gt ^; : 595

1H, NMR (400MHz, CDCl3) 7.40-6.86m, 10H), 6.43 (m, 2H) 5.14 (m, 1H), 4.53 2H), 2.80 (s, 2H), 2.74-2.70 (m, 4H), 2.40-2.36 (m, 6H)

Example 180. 7- (Same method as in Example 62)

(4-morpholin-4-yl-phenyl) -3,4-di (4-morpholin-4-yl) -methanone was prepared according to the procedure described for the synthesis of N-benzyl-2- [2- [4- -phenyl) -3,4-dihydro-quinazoline-4-yl] -acetamide Synthesis of

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-morpholin-4-yl-phenyl) -3,4-dihydro-2H-pyran-2- (100 mg, 0.192 mmole) and benzylamine (0.2 mL) in substantially the same manner as in Example 62 to give the title compound The title compound was prepared by the same procedure as described in the preparation of N-benzyl-2- [2- [4- (2-dimethylamino-ethyl) -piperazin- ) -3,4-dihydro-quinazolin-4-yl] -acetamide.

Yield: 69 mg, 60%, Mass (M + H) &lt; ⁺ & gt ^; : 596

(M, 6H), 3.87 (m, 4H), 4.82 (m, 2H) 2H), 2.29 (s, 3H), 2.00 (s, 3H), 3.36 (m, 2H)

Example 181. 7- (Same method as in Example 62)

(4-morpholin-4-yl-phenyl) -3,4-dihydro-quinazoline 4-yl] -N- (4-fluoro-benzyl) -acetamide (2- [2- [4- (2-dimethylamino- ethyl) -piperazine- 4-yl-phenyl) -3,4-dihydro-quinazolin-4-yl] -N- (4- fluoro-benzyl) -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-morpholin-4-yl-phenyl) -3,4-dihydro-2H-pyran-2- (95 mg, 0.182 mmol) and 4-fluoro-benzylamine (0.2 mL) were used in the same manner as in Example 3, except that dihydro-quinazolin-4-yl] -acetic acid methyl ester In substantially the same manner, the title compound was obtained as a colorless oil from 2- [2- [4- (2-dimethylamino-ethyl) -piperazin- 1 -yl] -3- (4- Phenyl) -3,4-dihydro-quinazolin-4-yl] -N- (4-fluoro-benzyl) -acetamide.

Yield: 76 mg, 68%, Mass (M + H) &lt; ⁺ & gt ^; : 614

1H, NMR (400MHz, CDCl3) 7.95 (m, 2H), 7.30 (m, 2H), 7.20-7.00 (m, 8H) 3.37 (m, 9H), 3.20-3.06 (m, 5H), 2.60 (s, 3H), 2.00

Example 182 : (Same method as in Example 62)

Yl) -3- (4-morpholin-4-yl-phenyl) -piperazin-1- (4-chloro-benzyl) -2- [2- [4- (2-dimethylamino-ethyl) -piperazine-1- yl ] -3- (4-morpholin-4-yl-phenyl) -3,4-dihydro-quinazoline-4-yl] -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-morpholin-4-yl-phenyl) -3,4-dihydro-2H-pyran-2- The same procedure as described in Example 62 was repeated using (101 mg, 0.194 mmole) and 4-chloro-benzylamine (0.2 mL) in the same manner as in Example 62, except that dihydro-quinazolin-4-yl] -acetic acid methyl ester (4-chloro-benzyl) -2- [2- [4- (2-dimethylamino-ethyl) -piperazin- 4-morpholin-4-yl-phenyl) -3,4-dihydro-quinazolin-4-yl] -acetamide.

Yield: 75 mg, 61%, Mass (M + H) &lt; ⁺ & gt ^; : 631

(M, 4H), 3.32 (m, 9H), 3.21-3.08 (m, 5H) ), 2.70 (s, 3H), 2.33 (s, 3H)

Example 183 : (Same method as in Example 62)

(4-morpholin-4-yl-phenyl) -3,4-dihydro-quinazoline 4-yl] -N- (4-methyl-benzyl) -acetamide (2- [2- [4- (2-dimethylamino- ethyl) -piperazine- -yl-phenyl) -3,4-dihydro-quinazoline-4-yl] -N- (4-methyl-benzyl) -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-morpholin-4-yl-phenyl) -3,4-dihydro-2H-pyran-2- (103 mg, 0.198 mmole) and 4-methyl-benzylamine (0.2 mL) were used in the same manner as in Example 62, except that the compound Yl) -3- (4-morpholin-4-yl-phenyl) -piperazin-1- ) -3,4-dihydro-quinazolin-4-yl] -N- (4-methyl-benzyl) -acetamide.

Yield: 84 mg, 70%, Mass (M + H) &lt; ⁺ & gt ^; : 610

4H), 3.32 (m, 9H), 3.21-3.08 (m, 5H), 4.40 (m, 2H) ), 2.60 (s, 3H), 2.30 (s, 3H), 2.00 (s, 3H)

Example  184

Urea  Intermediate 13

(E) -3- {2- [3- (4-Cyclohexyl-phenyl) -ureido] -phenyl} -acrylic acid methyl ester. phenyl) -ureido] -phenyl} -acrylic acid methyl ester)

(E) -3 (trifluoromethyl) benzoate using the same reaction as in the above-mentioned preparation method of urea intermediate 1 (Example 3) using 4-cyclohexylbenzoic acid (2.04 g, 10 mmole) - {2- [3- (4-cyclohexyl-phenyl) -ureido] -phenyl} -acrylic acid methyl ester.

Yield: 2.65g, 70%, Mass ( M + H) +: 379, 1HNMR (400MHz, DMSO): 8.89 (s, 1H), 8.49 (s, 1H), 7.90 (d, 1H), 7.75 (m, 2H), 7.37 (m, 3H), 7.14 (m, 3H), 6.59 (d,

Example  185

Diimide  Intermediate 13

(E) -3- [2- (4-Cyclohexyl-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester ((E) acrylic acid methyl ester

(E) -3- {2- [3- (4-cvclohexyl) -phenyl] -acrylic acid methyl ester in place of (E) -3- {2- [ -Methyl-phenyl) -ureido] -phenyl} -acrylic acid methyl ester (1.90 g, 5 mmole) was used in the same manner as the preparation of diimide intermediate 1 (Example 15) (E) -3- [2- (4-cyclohexyl-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester.

Yield: 1.41g, 78%, Mass ( M + H) +: 361 1HNMR (400MHz, DMSO): 8.03 (d, 1H), 7.89 (d, 1H), 7.45 (m, 3H), 7.24 (m, 6H ), 6.72 (d, IH), 3.73 (s, 3H), 1.77 (m5H), 1.36

Example  186

Ester intermediate 35

Yl} -3,4-dihydro-quinazolin-4-yl} - (2-methylamino-ethyl) -piperazin- Acetic acid methyl ester ({3- (4-Cyclohexyl-phenyl) -2- [4- (2-dimethylamino-ethyl) -piperazin- 1- yl] -3,4- dihydro- quinazolin- acetic acid methyl ester

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (509 mg, 1.39 mmol) and 2-dimethylaminoethyl-piperazine (439 mg, 2.78 mmole) in the same manner as in the synthesis of the ester intermediate 1 Methyl-amino] -3-naphthalen-2-yl-3,4-dihydro-quinolin-2-one hydrochloride -Quinazolin-4-yl} -acetic acid methyl ester.

Yield: 682 mg, 85%, Mass (M + H) &lt; ⁺ &gt;: 578

(M, 2H), 2.35 (s, 4H), 2.23 (m, 2H) (m, 2H), 2.17 (br, 4H), 1.85-1.80 (m, 4H), 1.74-1.71

Example  187

Ester intermediate 36

Dihydro-quinazolin-4-yl} -acetic acid methyl ester ({2 - [(6-dimethylamino-hexyl) - [(6-Dimethylamino-hexyl) -methyl-amino] -3-naphthalen-2-yl-3,4-dihydro-quinazolin-4-yl} -acetic acid methyl ester

Instead of (E) -3- [2- (4-fluoro-phenyliminomethyleneamino) -phenyl] -acrylic acid methyl ester and 1-pyridin- (484 mg, 3.06 mmole) and 1- [6- (dimethylamino-hexyl) -methylamine (502 mg, 1.53 mmole) Methyl-amino] -3-naphthalen-2-yl-3 (3-naphthalen-2-yl) , 4-dihydro-quinazolin-4-yl} -acetic acid methyl ester.

Yield: 559 mg (75%), Mass (M + H) &lt; ⁺ & gt ^; : 487

1H, NMR (400 MHz, CDCl3)? 7.78-7.17 (m, 10H, aromatic), 6.98 (Dd, -CO-CH2-), 2.23 (br, &lt; RTI ID = 0.0 &gt; (br, 2H), 2.17 (s, 6H, -N- (CH3) 2), 1.48 (br, 2H)

Example 188 (the same method as in Example 62)

-Propyl] -methyl-amino} -3,4-dihydro-quinazolin-4- &lt; / RTI & (3-Biphenyl-4-yl-2 - {[3- (3,3-dimethyl-ureido) -propyl] -methyl-amino } -3,4-dihydro-quinazolin-4-yl) -N- (4-fluoro-benzyl) -acetamide)

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester intermediate 17) instead of [2- (4-acetyl-piperazin- (3-Biphenyl-4-yl-2- {[3- (3,3-dimethyl-ureido) -propyl] -methyl-amino} -3,4- dihydro- quinazolin- -Acetic acid methyl ester (ester intermediate 19: Example 45) (107 mg, 0.208 mmole) and 4-fluorobenzylamine (0.2 mL) were used in the substantially the same manner as in Example 62, -Propyl] -methyl-amino} -3,4-dihydro-quinazoline-4-carboxylic acid -Yl) -N- (4-fluoro-benzyl) -acetamide.

Yields: 107 mg, 86%, Mass (M + H) &lt; ⁺ & gt ^; : 607

(Br, IH, Bn-NHCO), 5.28 (dd, J = 4.4 and 10.4 Hz, IH, -CH2-CH-N 2H), 3.83 (s, 3H, -NHCH3), 3.40 (br, (Dd, 1H, J = 4.8 and 14.8, - (CH3) 2) 2.60-2.53 CO-CH2-), 1.77 (br, 2H)

Example 189. &lt; (Same method as in Example 62)

N-benzyl-2- {2- [(6-dimethylamino-hexyl) -methyl-amino] -3-naphthalen-2-yl-3,4- dihydro- quinazolin- Synthesis of (N-Benzyl-2- {2 - [(6-dimethylamino-hexyl) -methylamino] -3-naphthalen-2-yl-3,4-dihydro-quinazolin-

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; Amino-3-naphthalen-2-yl-3,4-dihydro-quinazolin-4-yl} - (2-methyl- Benzyl (4-fluorobenzyl) benzyl ester shown in the following formula, in substantially the same manner as in Example 62, using acetic acid methyl ester (ester intermediate 36: Example 187) (103 mg, 0.21 mmole) and benzylamine -2 - [(6-dimethylamino-hexyl) -methyl-amino] -3-naphthalen-2-yl-3,4- dihydro- quinazolin-4-yl} -acetamide .

Yields: 105 mg, 89%, Mass (M + H) &lt; ⁺ & gt ^; : 562

1H NMR (400 MHz, CDCl3)? 7.77-7.70 (m, 3H, aromatic), 7.45-7.17 (m, 11H, aromatic), 6.96 , 6.21 (br, 1H, Bn-NHCO), 5.36 (dd, J = 4.0 and 8.8 Hz, 1H, (Br, 1H), 2.74-2.64 (dd, 1H, J = 8.8 and 14.0, -CO-CH2-), 2.54-2.48 (dd, 1H, J = 6.4 and (Br, 2H), 1.39 (br, 2H), 1.23 (br, 4H) )

Example 190 (the same method as in Example 62)

3-Naphthalen-2-yl-3,4-dihydro-quinazolin-4-yl} -N- (2-methyl- 3-naphthalen-2-yl-3,4-dihydro-quinazolin-4-yl) -acetamide (2- {2 - [(6-Dimethylamino-hexyl) Synthesis of N- (4-methoxy-benzyl) -acetamide

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; Amino-3-naphthalen-2-yl-3,4-dihydro-quinazolin-4-yl} - (2-methyl- Using substantially the same method as in Example 62, using acetic acid methyl ester (ester intermediate 36: Example 187) (101 mg, 0.21 mmole) and 4-methoxybenzylamine (0.2 mL) Amino-3-naphthalen-2-yl-3,4-dihydro-quinazolin-4-yl} -N- (2-methyl- (4-methoxy-benzyl) -acetamide.

Yields: 103 mg, 83%, Mass (M + H) &lt; ⁺ & gt ^; : 592

4H, aromatic), 7.22-7.14 (m, 4H, aromatic), 6.97-6.79 (m, 4H, aromatic), 7.45-7.35 (d, J = 6.4 and 8.8 Hz, 1H, -CH2-CH-N-), 4.42-4.38 (m, 2H), 3.78 (Br, 2H), 2.74-2.67 (dd, 1H, J = 9.2 and 14.4, -CO-CH2-), 2.53-2.48 (br, 2H), 1.43 (br, 2H), 1.25 (br, 2H)

Example 191 : (Same method as in Example 62)

N-benzyl-2- {3- (4-cyclohexyl-phenyl) -2- [4- (2- dimethylamino- ethyl) -piperazin- 1- yl] -3,4- dihydro- quinazoline -4-yl} -acetamide, the title compound was obtained as colorless crystals from N-benzyl-2- {3- (4-cyclohexyl- dihydro-quinazolin-4-yl} -acetamide Synthesis of

Dihydro-quinazolin-4-yl] -acetic acid methyl ester (ester Intermediate 17) and &lt; RTI ID = 0.0 &gt; (4-cyclohexyl-phenyl) -2- [4- (2-dimethylamino-ethyl) -piperazin- (101 mg, 0.18 mmole) and benzylamine (0.2 mL) were used in the same manner as in Example 62, respectively, to give the title compound as a white amorphous solid The title compound was prepared from N-benzyl-2- {3- (4-cyclohexyl-phenyl) -2- [4- (2- dimethylamino- ethyl) -piperazin- Hydro-quinazolin-4-yl} -acetamide.

Yields: 80.1 mg, 75%, Mass (M + H) &lt; ⁺ & gt ^; : 593

(1H, d, J = 4.8 Hz and 10.8 Hz, COCH2 CH), 4.47-4.39 (2H, m), 5.18 m, PhCH2-) 3.31 (4H, br, N-CH2), 2.58-2.33 (2H, m), 2.34 ), 1.82-1.80 (4H, m), 1.74-1.71 (1H, d), 1.36-1.34 (4H, m), 1.28-1.21

Hereinafter, preferred examples for the understanding of the present invention will be described. However, it should be understood that the present invention is not limited to the above-described exemplary embodiments.

Experimental Example 1: Determination of calcium channel blocking effect

The T-type calcium channel blocking effect was evaluated by electrophysiological cell patch clamp method using HEK293 cell line (derived from human kidney cancer cells) of mammalian 1 G-selectively expressing T-type calcium channel gene, Korea Patent No. 0610731 and Monteil, A., et al., J. Biol . Chem . 2000 , 275, 6090-6100.

1) inhibition measurement

HEK293 cells were prepared by adding 10% fetal bovine serum (FBS), 1% penicillin / streptomycin (v / v) to Dulbecco's modified Eagle's medium (DMEM) And cultured in a culture solution in a humidified condition of 95% air / 5% CO ₂ at a temperature of 36.5 ° C. The culture solution was changed once to 3-4 days with fresh medium, and the cells were subcultured every week. At this time, the culture solution was treated with a solution of G-418 (0.5 mg / ml) to grow only 1G T-type calcium channel-expressing cells (HEK 293). Cells used in the T-type calcium channel activity assay were cultured on cover slips coated with poly-L-lysine (0.5 mg / ml) at each time of the cycle, and the calcium channel activity was recorded between 2-7 days Respectively.

At the single cell level, the T-type calcium channel current was measured by electrophysiologic whole cell patch clamp method using an EPC-9 amplifier (HEKA, German). At this time, an extracellular solution [NaCl 140 mM, CaCl 2 2 mM, N- (2-hydroxyethyl) piperazine-N '- (2'-ethanesulfonic acid) (HEPES) 10 mM Solution [KCl 130 mM, HEPES 10 mM, EGTA (ethylene glycol tetraacetic acid) 11 mM, MgATP 5 mM (pH 7.4) was used. The T-type calcium channel activation protocol, which is activated at a low voltage, is a method in which a micro-glass electrode having a resistance of 3-4 MΩ in which the above-mentioned cell internal solution is placed is stuck in a single cell to become a whole-cell recording mode, The magnitude of the inward current due to T-type calcium channel activity was measured when the potential was fixed at -100 mV and then depolarized at -30 mV every 10 seconds (50 ms duration). On the other hand, the inhibition percentage was measured and compared with that before the treatment with 1 μM of the compound of the present invention after addition of the intracellular solution, followed by hypo-polarization. The results are shown in Table 1 below.

2) IC50 measurement

HEK293 cells were prepared by adding 10% fetal bovine serum (FBS), 1% penicillin / streptomycin (v / v) to Dulbecco's modified Eagle's medium (DMEM) And cultured in a culture solution in a humidified condition of 95% air / 5% CO ₂ at a temperature of 36.5 ° C. The culture solution was changed once to 3-4 days with fresh medium, and the cells were subcultured every week. At this time, the culture solution was treated with a solution of G-418 (0.5 mg / ml) to grow only 1G T-type calcium channel-expressing cells (HEK 293). Cells used in the T-type calcium channel activity assay were cultured on cover slips coated with poly-L-lysine (0.5 mg / ml) at each time of the cycle, and the calcium channel activity was recorded between 2-7 days Respectively.

At the single cell level, the T-type calcium channel current was measured by electrophysiologic whole cell patch clamp method using an EPC-9 amplifier (HEKA, German). At this time, an extracellular solution [NaCl 140 mM, CaCl 2 2 mM, N- (2-hydroxyethyl) piperazine-N '- (2'-ethanesulfonic acid) (HEPES) 10 mM Solution [KCl 130 mM, HEPES 10 mM, EGTA (ethylene glycol tetraacetic acid) 11 mM, MgATP 5 mM (pH 7.4) was used. The T-type calcium channel activation protocol, which is activated at a low voltage, is a method in which a micro-glass electrode having a resistance of 3-4 MΩ in which the above-mentioned cell internal solution is placed is stuck in a single cell to become a whole-cell recording mode, The magnitude of the inward current due to T-type calcium channel activity was measured when the potential was fixed at -100 mV and depolarized at -30 mV every 10 seconds (50 ms duration). After the addition of the intracellular solution, the compounds of the present invention were added at concentrations of 0.625, 1.25, 2.5, 5, 10 and 20 μM, respectively, and then the magnitude of the inward current due to T- (IC50) inhibiting 50% of the calcium channel was determined. The results are shown in Table 2 below.

Table 1: Inhibition

Table 2: IC50

Experimental Example 2: Confirmation of Growth Inhibitory Effect on Cancer Cell Lines

Growth inhibitory effects on cancer cell lines are described by Skehan, P. et al., J. Natl Cancer Inst . 1990 , 82, 1107-1112, the sulforhodaimine B (SRB) essay method was used.

The prostate cancer (prostate cancer (DU 145)], colon cancer (HT-29), ovarian cancer [A-549] human ovarian cancer (SK-OV-3)] was measured by SRB assay (sulforhodamine B assay).

All cell lines of the cancer cells 10% (V / V) heat inactivated fetal bovine serum (heat inactivated fetal bovine serum: FBS ) in RPMI 1640 humid conditions of 5% CO ₂ in a culture solution (Gibco BRL) containing And cultured at 37 ° C. These cells were transferred to 96-well plates and planted. Various concentrations of the compound of the above example were treated in triplicate to each well and incubated for 72 hours at 37 ° C in 5% CO ₂ conditions to allow cancer cells to grow sufficiently. After incubation, 100 μL of formalin solution was slowly added to each well of the microplate. The microplate was allowed to stand at room temperature for 30 minutes and then washed five times with tap water. 100 μL of 0.4% SRB (sulforhodamine B) solution was added to the wells of each plate and kept at room temperature for 30 minutes. The SRB solution was removed and the plate was washed 5 times with 1% acetic acid before drying in air. The bound SRB was dissolved in 100 μL of a 10 mM non-buffered Tris-base solution (Sigma) and the plate was placed on a plate shaker for at least 10 minutes. The optical density was measured at a wavelength of 520 nm using a microplate reader (Versamax, Molecular Devices) and the growth inhibition concentration was expressed as GI 50 (μM).

The T-type calcium channel blocking effect and the cancer cell growth inhibitory effect of the compounds of the present invention are shown in Table 3.

Table 3. Anticancer effect of compounds (GI50: mu M)

Claims (24)

The following compounds, their pharmaceutically acceptable salts, or their hydrates or solvates:
4-yl-2- [4- (4-methyl-piperazin-l-yl) -piperidin- l-yl] -3,4- dihydro- quinazolin- } -Acetic acid methyl ester;
Yl} -3,4-dihydro-quinazolin-4-yl} - acetic acid Acid methyl ester;
Yl} -3,4-dihydro-quinazolin-4-yl} - (2-methylamino-ethyl) -piperazin- N- (4-methyl-benzyl) -acetamide;
Yl} -3,4-dihydro-quinazolin-4-yl} - (2-methylamino-ethyl) -piperazin- N- (4-fluoro-benzyl) -acetamide;
Yl} -3,4-dihydro-quinazolin-4-yl} - (2-methylamino-ethyl) -piperazin- N- (4-methoxy-benzyl) -acetamide;
4-yl-2- [4- (4-methyl-piperazin-l-yl) -piperidin- l-yl] -3,4- dihydro- quinazoline- -Yl} -N- (4-fluoro-benzyl) -acetamide;
4-yl-2- [4- (4-methyl-piperazin-l-yl) -piperidin- l-yl] -3,4- dihydro- quinazoline- - yl} -N- (4-methyl-benzyl) -acetamide;
Yl) -3- (4'-fluoro-biphenyl-4-yl) -3,4-dihydro- - dihydro-quinazolin-4-yl] -acetamide;
3- (4'-Fluoro-biphenyl-4-yl) -3,4-dihydro-pyrazol- Quinazolin-4-yl] -N- (4-fluoro-benzyl) -acetamide; And
3- (4'-Fluoro-biphenyl-4-yl) -3,4-dihydro-pyrazol- Quinazolin-4-yl] -N- (4-methyl-benzyl) -acetamide. delete delete delete delete delete delete delete delete delete delete 2. The compound according to claim 1,
Yl} -3,4-dihydro-quinazolin-4-yl} - (2-methylamino-ethyl) -piperazin- N- (4-fluoro-benzyl) -acetamide; Yl] -3,4-dihydro-quinazolin-4-yl} - (2-methyl-piperazin- -N- (4-methoxy-benzyl) -acetamide, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. delete delete delete delete delete delete delete delete A pharmaceutical composition for preventing or treating cancer comprising, as an active ingredient, at least one compound selected from the group consisting of: a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof;
4-yl-2- [4- (4-methyl-piperazin-l-yl) -piperidin- l-yl] -3,4- dihydro- quinazolin- } -Acetic acid methyl ester;
Yl} -3,4-dihydro-quinazolin-4-yl} - acetic acid Acid methyl ester;
Yl} -3,4-dihydro-quinazolin-4-yl} - (2-methylamino-ethyl) -piperazin- N- (4-methyl-benzyl) -acetamide;
Yl} -3,4-dihydro-quinazolin-4-yl} - (2-methylamino-ethyl) -piperazin- N- (4-fluoro-benzyl) -acetamide;
Yl} -3,4-dihydro-quinazolin-4-yl} - (2-methylamino-ethyl) -piperazin- N- (4-methoxy-benzyl) -acetamide;
4-yl-2- [4- (4-methyl-piperazin-l-yl) -piperidin- l-yl] -3,4- dihydro- quinazoline- -Yl} -N- (4-fluoro-benzyl) -acetamide;
4-yl-2- [4- (4-methyl-piperazin-l-yl) -piperidin- l-yl] -3,4- dihydro- quinazoline- - yl} -N- (4-methyl-benzyl) -acetamide;
Yl) -3- (4'-fluoro-biphenyl-4-yl) -3,4-dihydro- - dihydro-quinazolin-4-yl] -acetamide;
3- (4'-Fluoro-biphenyl-4-yl) -3,4-dihydro-pyrazol- Quinazolin-4-yl] -N- (4-fluoro-benzyl) -acetamide; And
3- (4'-Fluoro-biphenyl-4-yl) -3,4-dihydro-pyrazol- Quinazolin-4-yl] -N- (4-methyl-benzyl) -acetamide. The pharmaceutical composition according to claim 21, wherein the cancer is prostate cancer, breast cancer, lung cancer, colon cancer, pancreatic cancer, skin cancer or uterine cancer. 22. The pharmaceutical composition according to claim 21, wherein the cancer is lung cancer, colon cancer, pancreatic cancer or ovarian cancer. 22. The compound of claim 21, wherein said compound is 2- {3-biphenyl-4-yl-2- [4- (2- dimethylamino- ethyl) -piperazin- - quinazolin-4-yl} -N- (4-fluoro-benzyl) - acetamide; Yl] -3,4-dihydro-quinazolin-4-yl} - (2-methyl-piperazin- -N- (4-methoxy-benzyl) -acetamide. &Lt; / RTI &gt;