BRPI0714035A2 - irreversible protein tyrosine kinase inhibitors and their methods of preparation and use - Google Patents

Abstract

IRREVERSIBLE INHIBITORS OF TYROSINE KINASE PROTEINS AND METHODS OF PREPARATION AND USES OF THE SAME. Compounds that could inhibit protein tyrosine kinase activity or pharmaceutically acceptable salts or hydrates thereof. The uses of compounds in the treatment or prevention of physiological abnormalities induced by overexpression of protein tyrosine kinase in mammals. The methods of preparing the compounds.

Description

1

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DESCRIPTIVE REPORT IRREVERSIBLE INHIBITORS OF TYROSINE KINASE PROTEINS AND THE METHODS OF PREPARATION AND USES OF THEM

DESCRIPTION

The invention relates to quinazoline or quinoline derivatives, a method of

its preparation and a method of using it as pharmaceutical agents.

As a cell surface receptor, protein tyrosine kinase (PTK) can transmit signals to cells. During mutation, however, PTK can be activated even without ligand binding. Consequently, false signals of cell growth and reproduction are transferred. Additionally, overexpression of PTK in cells may cause a certain weak signal to be amplified inappropriately. Also, during many steps of the cellular signal transfer chain, the occurrence of PTK mutation or overexpression can generate false signals. These false signals still take unregulated cell reproduction effectively, and 15 can cause cellular carcinogenesis.

EGFR is a typical example. EGFR belongs to epidermal growth factor receptor tyrosine kinase (EGFR-TK) cell surface receptors. The receptor family comprises the EGF receptor (an erbB-1 oncogene protein product), erbB-2 receptor (Neu or HER2), erbB-3 tumor protein mutant receptor and erbB-4 receptor. EGF and alpha transforming growth factor (TGFα) are the two most important ligands of EGFR. Although the receptor plays a minor role in healthy adults, it is closely related to the pathological process of most types of cancer, especially colon cancer and breast cancer. An EGFR-TK inhibitor can therefore block the transfer of these receptor signals and be used to treat cancer caused by EGFR overexpression, such as colorectal cancer, breast cancer, kidney cancer, lung cancer, and head cancer. neck.

In addition, an EGFR-TK inhibitor may be used to treat other diseases caused by EGFR overexpression, such as psoriasis, nephritis and pancreatitis, described below.

There is currently no effective way to treat proliferative skin diseases such as psoriasis. Conventionally, anticancer drugs such as methotrexate are used, but the drug has strong side effects and the response is poor within the limited dosage required. In psoriasis tissues, TGFα is the major growth factor that is overexpressed. In animal experiments, 50% of TGFÎ ± -expressed transgenic mice produce psoriasis, suggesting that a good inhibitor of the EGFR signal transfer mechanism may

/ 2/46

inhibit psoriasis, ie the EGFR-TK inhibitor can alleviate psoriasis symptoms.

EGF is an effective mitogen of renal tubular cells. In mice with streptozotocin-induced diabetes, urine secretion and EGF mRNA are increased fourfold. Additionally, EGFR expression is enhanced in 5 patients with proliferative glomerulonephritis (Roychaudhury et al Pathology). These findings indicate that blocking EGF signal transfer can be used to treat and prevent renal damage. Therefore, it is postulated that an EGFR-TK inhibitor can be used to treat proliferative glomerulonephritis and diabetes-induced kidney disease. In patients with chronic pancreatitis, EGFR and TGFa 10 expression is reported to be much higher than in healthy adults (Korc et al Gut 1994, 35, 1468). In patients with severe chronic pancreatitis, erbB-2 receptor overexpression has been confirmed (Friess et al Ann.Surg. 1994, 220, 183). It is therefore postulated that an EGFR inhibitor could potentially be used to treat pancreatitis.

During the embryonic cell maturation process, embryonic cell implantation in the endometrium and other peripheral implantation, EGF and TGFα are synthesized in uterine tissues (Taga Nippon Sanka Fujinka Gakkai Zasshi 1992, 44, 939) and EGFR increased (Brown et al Endocrinology 1989, 124, 2882). In the meantime, heparin-bound EGF is induced due to the approach of embryonic cells that are developing but not yet captured (Das et al Development 1994, 20 120, 1071). TGFα and EGFR expression have a high level in embryonic cells (Adamson, Moi reprod. Dev. 1990, 27, 16). Surgical removal of the submandibular gland, an important organ in internal secretion, and treatment with monoclonal antibody against EGFR can greatly reduce mouse fertility by reducing the success of embryonic cell implantation (Tsutsumi et al 25 J.Endocrinlogy 1993, 138, 437). These results indicate that an EGFR-TK inhibitor may function as a contraceptive.

WO 92/078844 dated May 14, 1992 and WO 92/14716 dated September 3, 1992 disclose 2,4-diamino quinazoline, used as enhancers of chemotherapeutic agents in the treatment of cancer.WO 92/20642 dated 26 November 30, 1992 discloses bicyclic bis mono- and / or aryl and / or heteroaryl compounds which may inhibit EGF and / or PDGF receptor tyrosine kinase.

European patents 520722A1, 566226A1, 635498A1, 602851A1, WO 95/19774 and WO 95/15758 refer to reversible EGF receptor tyrosine kinase inhibitors. These inhibitors belong to 4-anilinoquinazoline derivatives and some have a high inhibitory activity against EGF receptor tyrosine kinase, but in an animal pathological model these inhibitors demonstrate low activity. The reason for this lies in the fact that PTK is a catalyst that catalyses

a phosphate group to transfer AJP to a protein tyrosine residue, and the EGF receptor reversible tyrosine kinase inhibitors mentioned above compete with ATP to bind EGF receptor tyrosine kinase, but in cells ATP concentration It is much higher (mM grade), so reversible EGF receptor tyrosine kinase inhibitors that demonstrate high in vitro activity have difficulty showing a high effect in animal pathological models. Irreversible EGF receptor tyrosine kinase inhibitors, however, do not compete with ATP, so they are expected to perform better in vivo.

In 1997 a US patent disclosed a new irreversible EGF receptor tyrosine 10 kinase inhibitor. In the inhibitor, a Michael acceptor is introduced in the sixth position of quinazoline so that a Michael addition reaction can occur between the inhibitor and cysteine sulfhydryl at the small active central tyrosine kinase wall of the EGF receptor. In addition, inhibitor activity has a positive correlation with the activation energy of Michael's addition reaction between inhibitor and cysteine sulfhydryl. So both American Wyeth Pharmaceutical Co., Ltd. Pfizer Pharmaceuticals Co. Ltd. choose to develop high-reactivity, high-activity EGF receptor tyrosine kinase inhibitors.

The present invention discloses an irreversible EGF receptor tyrosine kinase inhibitor representing a unique chemical structure and high inhibitory activity and low reactivity against EGF receptor tyrosine kinase. Research has found that the compound demonstrates good inhibitory activity against EGF-stimulated A431 cell autophosphorylation, and demonstrates some growth inhibitory activity against the cell strain, has a good antitumor effect on the pathological animal model of the A431 tumor.

In view of the problems described above, it is an object of the invention to promote a

compound or pharmaceutically acceptable salts or hydrates thereof which may exhibit protein tyrosine kinase activity.

Another object of the invention is to provide a preparation comprising at least one pharmaceutically acceptable compound or salts or hydrates thereof which may exhibit protein tyrosine kinase activity.

Another object of the invention is also to provide a method for preparing a compound that inhibits protein tyrosine kinase activity.

To achieve the stated objectives, in accordance with one embodiment of the invention, a compound of formula (I) is provided.

where X represents N1 C-CN or CH; Y represents CH 2, S, O or N-R 9; R11 R31 R7 and R8 independently represent H1 CF3 or C1-4 alkyl; R2 represents a group selected from formula (II), (III), (IV), (V), (VI), (VII) or (VIII);

uVD OVIO Π VIID DVIIID

R41 R6 independently represents H, C1-4 alkyl, OC1-4 alkyl, OH1 F, Cl, Br, OCF3 or trifluoromethyl;

R5 at each occurrence is independently chosen from H, F, C1. Alkyl, OH, OC1 -fifif1 OCF3, OCF2CH3, NH2, NH (C1f-afififa) 1 N (C1-afkyl) 2L-1-pyrrolinyl, 1-piperidyl, 4-morpholine, Cl1 Br, trifluoromethyl, O (CH2) 2 ^ OCF 3 O (CH 2) 2 · OC 1. Alkyl, O (CH 2) 2 N NH (C 1-4 alkyl), O (CH 2) 2 N 4 N (C 1 -C 4 alkyl) 21 (1-pyrrolinyl) (CH 2) 2.40, (1-piperidyl) (CH 2) 2 O, (4-morpholine) (CH 2) 2 O, NHC (O) H, NHC (O) (C 1-6 alkyl) 1 NiCl. 6 alkyl) C (O) (C 1-6 alkyl), O (CH 2) 2 N OH, N (C 1-4 alkyl) C (O) 0 (C 1-4 alkyl), N (C 1-6 alkyl) C (0 ) 0H, NHC (O) O) C 1-6 alkyl), OC (O) NH (C 1-4 Alkyl) 1 OC (O) N (C 1-4 Alkyl) 2, (1-piperidyl) (CH 2) 2_40C (0), (4-morpholine) (CH 2) 2 ^ OC (0)> (1-pyrrolinyl) (CH 2) MOC (0), (1-imidazolyl) (CH 2) 2 ^ 0, (4-imidazolyl) (CH 2) 2 ^ OC (O), (pyrazolyl) (CH 2) 2.40, (triazolyl) (CH 2) 2 O (C) or Ar (CH 2) 1 O;

R9 at each occurrence is independently chosen from H, C16al 5/46

CF 3, CF 2 CH 3, (CH 2) 2 -OH 1 (CH 2 K 4 OC 1 -alkyl (CH 2 NH 1 -C 4 alkyl), (CH 2) 1- 4N (C 1-6 alkyl) 2, (1-pyrrolinyl) (CH 2) 1.4, (I- Piperidyl) (CH 2) 1 ', 4'-morpholine (CH 2) 4, C (O) C, 6a here) a, C (O) (CHr) 1'OH (C) (CH 2)', .. O) (CH 2) 1 N (C 1-6 alkyl) r, (I-Pyrrolidin) (CH 2) 1 C (O), (1-piperidyl) (CH 2) 1.6 C (O), H-morpholine (CH 2 C 10 O) , C (O) OC1 alkyl, C (O) 0 (CH2) 2.40C3 alkyl, C (O) 0 (CH2) 2 N (C2 alkyl) 2 C (O) O (CH2) 2 NH (C1-C31-alkyl) 1- (1-pyrrolinyl) (CH2) 2 ^ OC (O) 1- (1-piperidyl) (CH2) 2.40C (0), (4-morpholine) (CH2) 2.40C (0), ( CH 2) 14 C (O) C 1-6 alkyl, Ar (CH 2) 1 H;

R10 represents H1 C1-4 alkyl or one or two F;

R111 R12 independently represent H, 1 to 4 same from different groups chosen from F, Cl1 Br1 I1 CN1 NO2 1 CF3, OH1 NH2, C1-4 alkylal OC1. 4alkyl, OCF 31, OCF 2 CH 3, NH (C 1 -C 3 alkyl) 1 N (C 1 -C 3 alkyl) 2, OC (O) C 1 -C 3 alkyl NHC (O) H 1 NHC (0) C 1 -C 4 alkyl N 2 CO 3 alkylO, C (O) OC 1 C (O) N (C1) alkylC (O) N (C 1 -C 6 alkyl) 2 1 COOH 1 C (O) C 1 -C 6 alkyl S (O) C 1 -C 6 alkyl SO 2 Cl 2 C 2 O 1 alkylO 2 SO 2 NHC 1. 4alkyl or SO 2 N (C 1-4 alkyl) 2,

A1 B independently represent aromatic ring; Ar is phenyl, phenyl or substituted pyridyl; D represents O1 S1 NH or methyl; and m, η independently represent an integral from 0 to 4.

In the embodiments of the invention, C1-4 alkyl and C1-4 alkyl may be straight chain alkyl, branched chain alkyl or cyclic alkyl, saturated or unsaturated alkyl, optionally substituted by F1 OH1 COOH1 CO2 (C1-4 alkyl) 1 C (O) NH2 , C (O) NH (C1-4 alkyl), C (O) N (C1-4 alkyl) 2, NHC (O) (C1-4 alkyl), NH2, NH (C1-4 alkyl), N (C1-4 alkyl) 2l NHC (O) NH2, NHC (NH) NH2, O (C1-4 alkyl) or S (C1-4 alkyl).

When A, B independently represent an aromatic ring, the ring may be numbered from 5 to 7 and contain from 0 to 4 heteroatoms such as N 1 O or S and so on. A, B may also independently represent a polycyclic aromatic group consisting of two or three joined rings numbered from 5 to 7.

In the embodiments of the invention, the connection position of group R2 connected to the amino group of the fourth position of the mother core is not limited to the position displayed by the broken line, another position also applies.

When the compound of formula (I) is defined as an E / Z isomer, it may be an E isomer or a Z isomer or a mixture of an E isomer and a Z isomer.

When the compound of formula (I) is defined as an R / S isomer, it may be an R isomer or an S isomer or a mixture of an R isomer and an S isomer.

The uniqueness of the compound of the invention can be clearly visualized by comparing the structure and property of the compound of Example 33 with 6/46.

comparison compound A of Example 84, B of Example 85 and C

10

15

20

Comparison Compound C

.Example 33

Comparison Compound B (Example

Comparison Compound A (Example 84) 85)

Comparison compound C is a small irreversible molecular inhibitor of EGFR-TK that has the highest activity among all compounds reported in the literature. At the molecular level, the EC50 value of Comparison Compound C against EGFR-TK is 10 7 Mm1 whereas in the same test, EC50 value of Comparison Compound B is merely about 0.5 pm, which means that the activity of the compound Comparison B is five million times lower than that of Comparison Compound C. The difference between the two compounds in the chemical structure is merely the difference in the steric hindrance of the substituted branch of the sixth position. invention is lower than that of comparison compound B.

In an EGFR-TK inhibitory activity test, however, at the cellular level, the activity of the compound of the invention is several orders of magnitude higher than that of comparison compound B. For example, the activity of the compound in Example 33 is not only very high. higher than that of comparison compound B, but also very close to that of contrast compound A (also shown in Tables 3, 4). However, the ECso value of the EGFR-TK comparison compound AeC is equivalent to

at the molecular level, which means that the activity of compound 7/46

Example 33 is equivalent to that of comparison compound C, and is one million times greater than that of comparison compound B.

There are reports in the literature that the irreversible EGFR-TK inhibitor activity is ten times higher than that of the irreversible EGFR-TK inhibitor in the A431 animal tumor model, but their activity is equivalent at the molecular level. The compound of the present invention proved to be an irreversible EGFR-TK inhibitor by a cell model assay (as shown in Table 5), while high activity comparison compound A was shown to be a reversible inhibitor in the same test, which is according to the result by a direct test using EGFR-TK described 10 in some literatures.

The compound of the invention has Heract-2 TK1 inhibition bioactivity and part of the results are listed in Table 6.

The compound of the invention has some degree of growth inhibition against the A431 epidermal cancer cell strain, colorectal cancer cell strain 15 LoVo1 BT 474 breast cancer cell strain and SK-Br breast cancer cell strain -3. A portion of the test results are listed in Tables 7, 8, and 9. Some compounds have growth inhibition activity 30 times greater against A431 than Tarceva (as shown in Table 7). Some have equivalent growth inhibiting activity against Lapatinib breast cancer (as shown in Table 8). Some have better growth inhibiting activities against LoVo colorectal cancer cell compared to adriamycin (as shown in Table 9).

Accordingly, the invention teaches a method of inhibiting cancer cell growth in mammals which comprises administering to a mammal in need of the compound of formula (J) or saJ or a pharmaceutically acceptable hydrate thereof, characterized in that the cancer includes but not limited to breast cancer, skin cancer, colorectal cancer, head and neck cancer, lung cancer, kidney cancer, bladder cancer, ovarian cancer, oral cancer, laryngeal cancer, esophageal cancer, gastric cancer, cervical cancer and 30 liver cancer.

The compound of formula (I) suitable for use as a medical active ingredient comprises the compounds wherein R1 represents H1 CH3 or CH2CH3, more particularly R1 represents H.

The compound of formula (I) suitable for use as a medical active ingredient comprises those compounds wherein R 3 represents H, CH 3 or CH 2 CH 3, more particularly R 3 represents H.

The compound of formula (I) suitable for use as an active ingredient.

The medical composition comprises the compounds wherein R7 represents H1 CH3 or CH2CH3, more particularly R7 represents H.

The compound of formula (!) Suitable for use as a medical active ingredient comprises those compounds wherein R 8 represents H, CH 35 or CH 2 CH 3, more particularly R 8 represents H.

The compound of formula (I) suitable for use as a medical active ingredient comprises the compounds wherein R 4 represents H 1 F, CH 3, CH 2 CH 3, CH 2 CH 2 CH 3, OCH 3 or OCH 2 CH 3, more particularly R 4 represents H 1 F, CH 3 CH 2 CH 3 or OCH 3, and even more particularly, R4 represents H, F1 CH3 or 10 OCH3.

The compound of formula (I) suitable for use as a medical active ingredient comprises those compounds wherein R 6 represents H, F, CH 3 CH 2 CH 3, CH 2 CH 2 CH 3 1 OCH 3 1 OCF 3 or more particularly R 6 represents H 1 F1 CH 3, CH 2 CH 3 or OCH 3 1 and even more particularly, R6 represents 15 H1F1CH3OuOCH3.

The compound of formula (I) suitable for use as a medical active ingredient comprises those compounds wherein A represents the benzene, pyridine, pyrimidine, pyrazine, 4-nitrogen heterocyclic pyridine ring, pyrrol, furan, thiophene, pyrazole, thiazole, indole, benzofuran, benzothiophene or naphthalene ring, more particularly A represents benzene, pyridine, thiophene, pyrazole, thiazole, indole or naphthalene ring.

The compound of formula (I) suitable for use as a medical active ingredient comprises the compounds wherein B represents ring benzene, pyridine, pyrimidine, pyrazine, 4-nitrogen heterocyclic pyridine, pyrrol, furan, thiophene, pyrazol, thiazole, indole, benzofuran, benzothiophene or naphthalene ring, more particularly B represents benzene, pyridine, thiophene, pyrazole, thiazole, indole or naphthalene ring.

The compound of formula (I) suitable for use as a medical active ingredient comprises those compounds wherein D represents O, S or 30 NH, more particularly D represents O.

The compound of formula (I) suitable for use as a medical active ingredient comprises the compounds wherein R10 represents H, one or two F, CH3. CF3 or Et, more particularly R10 represents H, two F1 CH3 or CF3, and even more particularly R10 represents H. The compound of formula (I) suitable for use as an active ingredient

The physician understands the compounds characterized by the fact that R11 represents the same or different H1 1 to 4 F1 Cl, Br1 CN1 NO2. CF3 OH1 CH3, CH2CH3, CH2CH2CH3, 9/46

alkynyl, OCH3, OCH2CH3, OCF3, CO2CH3, CO2CH2CH3, NH2l NHCH3l NHCH2CH3, N (CH3) 2l NHC (O) H1 NHC (O) CH3l NHC (O) CH2CH3, N (CH3) C (O) CH3, C (O ) NHCH 3 C (O) NHCH 2 CH 3 or C (O) N (CH 3) ', more particularly R 11 represents H 1 one or two same or different F1 Cl 1 Br 1 CN 1 CF 3 OH, ethinyl, OCH 3 1 OCH 2 CH 3 1 OCF 3, CO 2 CH 3 1 CO 2 CH 2 CH 3. N (CH 3) 2 or NHC (O) CH 3, even more particularly R 11 represents H 1 one or two of the same or different F1 Cl 1 Br 1 CN 1 CF 3, CH 3 1 CH 2 CH 3, ethynyl, OCH 3, OCH 2 CH 3 1 OCF 3, CO2 CH 2 CH 3, NH 2 1 NHCH 3, NH 2 N (CH 3) 2 or NHC (O) CH 3.

The compound of formula (I) suitable for use as a medical active ingredient comprises the compounds wherein R 12 represents the same or different H 1 1 to 4 F1 Cl, Br 1 CN 1 NO 2 1 CF 3, OH 1 CH 3 1 CH 2 CH 3 1 CH 2 CH 2 CH 3 1 alkynyl, OCH 3, OCH 2 CH 3 1 OCF 3 1 CO 2 CH 3, CO 2 CH 2 CH 3 NH 2, NHCH 3, NHCH 2 CH 3, N (CH 3) 2 1 NHC (O) H 1 NHC (O) CH 3 1 NHC (O) CH 2 CH 3. N (CH 3) C (O) CH 3 C (O) NHCH 3 C (O) NHCH 2 CH 3 or C (O) N (CH 3) 2, more particularly R 12 represents H1 one or two same or different F, Cl 1 Br, CN, CF 3, OH 1 CH 3 I ethinyl CH 2 CH 3, OCH 3 1 OCH 2 CH 3, OCF 3, CO 2 CH 3, CO 2 CH 2 CH 3, NH 2, NHCH 3, NHCH 2 CH 3, N (CH 3) 2 or NHC (O) CH 3.

The compound of formula (I) suitable for use as a medical active ingredient comprises the compounds wherein R5 represents H1 F, OH CH3, CH2 CH3, CH2 CH2 CH3, OCH3, OCH2 CH3, OCF3, OCF2 CH3, NH2, NHCH3 20 N (CH3). 21-1-pyrrolinyl, 1-piperidyl, 4-morpholine, trifluoromethyl, O (CH 2) 2 OH 1 O (CH 2) 3 OH, O (CH 2) 4 OH, O (CH 2) 2 OCH 3, O (CH 2) 3 OCH 3, O (CH 2) 4 OCH 3, O (CH2) 2OCH2CH3, O (CH2) 3OCH2CH3, O (CH2) 4OCH2CH3, O (CH2) 2N (CH3) 2, O (CH2) 3N (CH3) 2, O (CH2) 4N (CH3) 2, O ( CH 2) 2 N (CH 2 CH 3) 2 O (CH 2) 3 N (CH 2 CH 3) 2 O (CH 2) 4 N (CH 2 CH 3) 2 O (CH 2) 2 N (CH 3) CH 2 CH 3 O (CH 2) 3 N CH 2 CH 3

25 O (CH 2) 4 N (CH 3) CH 2 CH 3, O (CH 2) 2 NH (CH 3), O (CH 2) 3 NH (CH 3), O (CH 2) 4 NH (CH 3) 1 (1-pyrrolinyl) (CH 2) 20, (1 - pyrrolinyl) (CH2) 30, (1-pinrolinyl) (CH2) 40, (1-piperidyl) (CH2) 20, (1-piperidyl) (CH2) 3O, (1-piperidyl) (CH2) 40, (4 -morpholine) (CH 2) 20, (4-morpholine) (CH 2) 30, (4-morpholine) (CH 2) 40, NHC (O) H, NHC (O) CH 3. NHC (O) CH 2 CH 3, NHC (O) CH 2 CH 2 CH 3 1 N (CH 3) C (O) H 1 N (CH 3) C (O) CH 3 1 N (CH 3) C (O) CH 2 CH 3 1 30 N (CH 3) C (O) CH 2 CH 2 CH 3 1 NHC ( O) OCH3, NHC (O) OCH2CH3l N (CH3) C (O) OCH3l N (CH3) C (O) OCH2CH3l N (CH3) C (O) OCH2CH2CH3, OC (O) NHCH3, OC (O) NHCH2CH3l OC ( O) N (CH3) 2 or OC (O) N (CH3) CH2CH3

The compound of formula (I) suitable for use as a medical active ingredient comprises the compounds wherein R 9 represents H 1 CH 3, 35 CH 2 CH 3, CH 2 CH 2 CH 3 1 CF 3, CF 2 CH 3 1 (CH 2) 2 OH 1 (CH 2) 3 OH 1 (CH 2) 4 OH 1 (CH 2) 2 OCH 3 1 (CH2) 3OCH31 (CH2) aOCH3, (CH2) 2OCH2CH3, (CH2) 3OCH2CH3l (CH2) 4OCH2CH3l (CH2) 2N (CH3) 2l (CH2) 3N (CH2) 4N (CH3) 2, (CH2 ) 2N (CH2CH3) 2l (CH2) 3N (CH2CH3) 2l 10/46

(CH 2) 4 N (CH 2 CH 3) 2, (CH 2) 2 N (CH 3) CH 2 CH 3, (CH 2) 3 N (CH 3) CH 2 CH 3,

(CH2) 4N (CH3) CH2CH3, (CH2) 2NH (CH3), (CH2) 3NH (CH3) 1 (CH2) 4NH (CH3) 1 (1- Pi (TolinylXCH2) 2-, (I-Pyrrolinyl) (CH2 ) 3-, (1-pyrrolyryl) (CH2) 4-, (1-piperidyl) (CH2) 2-, (1-piperidyl) (CH2) 3, (1-piperidyl) (CH2) 4, (4-morpholine ) (CH 2) 2, (4-morpholine) (CH 2) 3, (4-5 morpholine) (CH 2) 4, C (O) CH 3, C (O) CH 2 CH 3, C (O) CH 2 CH 2 CH 3, C (O) ( CH 2) 4 OH 1 C (O) CH 2 OH 1 C (O) (CH 2) 2 OH, C (O) (CH 2) 3 OH, C (O) CH 2 OCH 3, C (O) (CH 2) 2 OCH 3 C (O) (CH 2) 3 OCH 3 C ( O) (CH 2) 4 OCH 3 C (O) CH 2 OCH 2 CH 3 C (O) CH 2 N (CH 3) 2, C (O) (CH 2) 2 N (CH 3) 2, C (O) (CH 2) 3 N (CH 3) 2 C (O) (CH 2) 4 N (CH 3) 2, C (O) CH 2 N (CH 3) CH 2 CH 3, C (O) (CH 2) 2 N (CH 3) CH 2 CH 3, C (O) (CH 2) 3 N (CH 3) CH 2 CH 3, C (O) ( CH2) 4N (CH3) CH2CH3, C (O) CH2NHCH2CH3, C (O) (CH2) 2NHCH2CH3, C (O) (CH2) 3NHCH2CH3l

C (O) (CH2) 4NHCH2CH3, C (O) CH2NHCH3, C (O) (CH2) 2NHCH3, C (O) (CH2) 3NHCH3, C (O) (CH2) 4NHCH3, C (O) CH2NHPr, C ( O) (CH2) 2NHPr1 C (O) (CH2) 3NHPr1 C (O) (CH2) 4NHPr, C (O) CH2N (CH2CH3) 2, C (O) (CH2) 2N (CH2CH3) 2l

C (O) (CH 2) 3 N (CH 2 CH 3) 2, C (O) (CH 2) 4 N (CH 2 CH 3) 2, (1-pyrrolinHa) CH 2 C (0), (1-15 pyrrolinyl) (CH 2) 2 C (0). (I-Pyrrolidin) (CH 2) 3 C (O) 1- (1-pyrrolinyl) (CH 2) 4 C (0), (1-piperidyl (CH 2 Cl 2)). (1-piperidyl) (CH 2) 2 C (0), (1-piperidyl) (CH 2) 3 C (0), (1-piperidyl) (CH 2) 4 C (0), (4-morpholine) (CH 2) 4 C (0), (4-morpholine) (CH 2) 3 C (0), (4-morpholine) CH 2 C (0). (4-morpholine) (CH 2) 2 C (0), C (O) OCH 3, C (O) OCH 2 CH 3, C (O) OPr, C (O) OPr-1 C (O) O (CH 2) 2 OCH 3, C ( O) O (CH 2) 3 OCH 3, C (O) O (CH 2) 4 OCH 3, 20 C (O) O (CH 2) 2 OCH 2 CH 3, C (O) O (CH 2) 2 N (CH 3) 2, C (O) O (CH 2 ) 3N (CH3) 2,

C (O) O (CH 2) 4 N (CH 3) 2, (I-Pyrrormyl) (CH 2) 2OC (O), 0-pyrro) inyl) (CH 2) 3OC (O), (1-pyrrolinyl) (CH 2) 4OC (0), (1-piperidyl) (CH 2) 20 C (0). (1-piperidyl) (CH2) 30C (0), (1-piperidyl) (CH2) 40C (0), (4-morpholine) (CH2) 2OC (0), (4-morpholine) (CH2) 3OC (C )), (4-morpholine) (CH2) 4OC (0), CH2C (O) OCH3, (CH2) 2C (O) OCH3, (CH2) 3C (O) OCH3, 25 CH2C (O) OCH2CH3, (CH2) 2C (O) OCH2CH3 or (CH2) 3C (O) OCH2CH3

The compound of formula (I) suitable for use as a medical active ingredient comprises the compounds characterized in that m, η independently represent 0.1 or 2. Table 1

Examples of R91 R11 in the compound of formula (I) suitable for use

as a medical active ingredient.

R9 Rt1 R3 r * -

H H "H 3 ^ C $ ~~

H 3-H H 3-F

H 3-CH3 H 3-CF3

H 3-Alkyne H 3-CN H 3-ΝΟζ H 3-C (0) CH3 H 3-S (0) CH3 H 3-SO2NHCH3 H 3-SO2IM (CH3) 2 H 3-CON (CH3) 2 H 3 -1 H 4-Br H 4-CH 3 H 4-alkynyl H 4-NOz H 4-C (0) CH 3 H 4-S (0) CH 3 H 4-SO 2 NHCH 3 H 4-SO 2 N (CH 3) 2 H 4-F -3-Br H 4-F-3-CH3 H 4-F-3-alkynyl H 4-F-3-NO2 H 4-F-3-C (0) CH3 H 4-F-3-S (0 ) CH 3 H 4-F-3-SO 2 NHCH 3 H 4-F-3-SO 2 N (CH 3) 2 H 4-F-3-CON (CH 3) 2 H 4-F-3-CI CH 3 H CH 3 3-Br CH 3 3 -CH3 CH3 3-alkynyl CH3 3 -N02 CH3 3-C (0) CH3 CH3 3-S (0) CHj CH3 3-S02NHCH3 CH3 S-SO2N (CH3) 2 CH3 3-CON (CH3) 2 CH3 3-1

1/46

H 3-OCH3 H 3-SO2CH3 H 3-CO2CH3 H 3-CO02CH2CH3 H 3-CONHCH3 H 4-CON (CH3) 2 H 4-CI H 4-FH 4-CF3 H 4-CN H 4-OCH3 H 4- SO2CH3 H 4-CO02CH3 H 4-CO02CH2CH3 H 4-CONHCH3 H 4-F-3-IH 4-F-3-CF3 H 4-F-3-CN H 4-F-3-OCH3 H 4-F-3 -S02CH3 H 4-F-3-C02CH3 H 4-F-3-C02CH2CH H 4-F-3-CONHCH3 H 3-F-4-F CH3 3-CI CH3 3-F CH3 3-CF3 CH3 3-CN CH3 3-OCH3 CH3 3-SO2CH3 CH3 3-CO02CH3 CH3 3-CO02CH2CH3 CH3 3-CONHCH3 CH3 4-CON (CH3) 2 CH3 4-CI 12/46

CH3 4-Br CH3 4-F CH3 4-CH3 CH3 4-CF3 CH3 4-alkyl CH3 4-CN CH3 4-SO2N (CH3) 2 CH3 4-CONHCH3 CH3 4-F-3-Br CH3 4-F-3 -I CH3 4-F-3-CH3 CH3 4-F-3-CF3 CH3 4-F-3-alkynyl CH3 4-F-3-CN CH3 4-F-3-NÜ2 CH3 4-F-3-OCH3 CH3 4-F-3-C (0) CH3 CH3 4-F-3-S02CH3 CH3 4-F-3-S (0) CH3 CH3 4-F-3-C02CH3 CH3 4-F-3-S02NHCH3 CH3 4 -F-3-CO2 CH2 CH 4-F-3-SO2N (CH3) 2 CH3 4-F-3-CONHCH3 CH3 4-F-3-CON (CH3) 2 CH3 4-F-3-CON (CH3) 2 CH3 4-F-3-CI CH3 3-F-4-F CH3 2-SO2CH3 CH3 3-COOH CH3 4-COOH CH3 2-C (0) 0CH3 CH3 2-1 CH3 2-CI CH3 2-Br CH3 2 -F CH3 2-CH3 CH3 2-CH3 CH3 2-alkynyl CH3 2-CN CH3 2-N02 CH3 2-OCH3 CH3 2-C (0) CH3 Et 3-CI Et 3-Br Et 3-F Et 3-CH3 Et 3-CF3 Et 3-alkynyl Et 3-CN Et 3-NO 2 Et 3-OCH 3 Et 3-C (0) CH 3 Et 3-SO 2 CH 3 Et 3-S (0) CH 3 Et 3-CO 2 CH 3 Et 3-SO 2 NHCH 3 Et 3 -C02CH2C H3 Et 3 -SO2N (CH3) 2 Et 3-CONHCH3 Et 3-CON (CH3) 2 Et 4-CON (CH3) 2 Et 3-1 Et 4-C1 Et 4-Br Et 4-F Et 4- CH3 Et A-CF3 Et 4-alkynyl Et 4-CN Et 4-NO * Et 4-OCH3 13/46

Et 4-C (0) CH 3 Et 4 SO 2 CH 3 Et 4 -S (0) CH 3 Et 4-CO 2 CH 3 Et 4-SO 2 NHCH 3 Et 4-CO 2 CH 2 CH 3 Et 4-SO 2 N (CH 3) 2 Et 4-CONHCH 3 Et 4-F-3- Br Et 4-F-3-I Et 4-F-3-CH3 Et 4-F-3-CF3 Et 4-F-3-alkynyl Et 4-F-3-CN Et 4-F-3-NO2 Et 4-F-3-OCH3 Et 4-F-3-C (0) CH3 Et 4-F-3-SO2 CH3 Et 4-F-3-S (0) CH3 Et 4-F-3-CO2 CH3 Et 4- F-3-SO 2 NHC H 3 Et 4-F-3-CO 2 CH 2 <Et 4-F-3-SO 2 N (CH 3) 2 Et 4-F-3-CONHC Et 4-F-3-CON (CH 3) 2 Et H Et 4-F-3-CI Et 3-F-4-F Et 2-SO 2 CH 3 Et 3-COOH Et 4-COOH Et 2-C (0) 0CH3 Et 2-1 Et 2-C1 Et 2-Br Et 2- F Et 2 -CH 3 Et 2 -CH 3 Et 2-alkynyl Et 2-CN Et 2-NO * Et 2-OCH 3 Et 2-C (0) CH 3 O (CH 2) 2OM 3-CON (CH 3) 2 O (CH 2) 2OMe H O (CH2) 2OMe 3-CI O (CH2) 2OMe 3-Br O (CH2) 2OMe 3-FO (CH2) 2OMe 3-CHa O (CH2) 2OMe 3-CF3 O (CH2) 2OMe 3-alkynyl O (CH2) 2OMe 3-CN O (CH2) 2OMe 3-NO2 O (CH2) 2OMe 3-OCH3 O (CH2) 2OMe 3-C (0) CH3 O (CH2) 2OMe 3-SO2CH3 O (CH2) 2OMe 3- S (0) CH3 O (CH2) 2OMe 3-CO02CH3 O (CH2) 2OMe S-SO2NHCH3 O (CH2) 2OMe 3-CO02CH2CH3 O (CH2) 2OMe S-SO2N (CH3) 2Oe (CH2) 2OMe 3-CONHCH3 O (CH2) 2OMe 3-JO (CH2) 2OMe 4-CIO (CH2) 2OMe 4-Br O (CH2) 2OMe 4-FO (CH2) 2OMe 4-CH3 O (CH2) 2OMe 4-C F3 O (CH2) 2OM 4-alkynyl O (CH2) 2OM 4-CN O (CH2) 2OM 4-NO2 O (CH2) 2OM 4-OCH3 14/46

O (CH2) 2OM 4-C (0) CH3 O (CH2) 2OMe 4-SO2CH3 O (CH2) 2OMe 4-S (0) CH3 O (CH2) 2OMe 4-CO2O3 O (CH2) 2OMe 4-SO2NHCH3 O ( CH2) 2OMe 4-CO2 CH2CH3 O (CH2) 2OMe 4-SO2N (CH3) 2O (CH2) 2OMe 4-CONHCH3 O (CH2) 2OMe 4-CON (CH3) O (CH2) 2OMe 4-F-3-CON ( CH3) 2O (CH2) 2OMe 4-F-3-Br O (CH2) 2OMe 4-F-3-IO (CH2) 2OMe 4-F-3-CH3 O (CH2) 2OMe 4-F-3-CF3 O (CH2) 2OM 4-F-3-alkynyl O (CH2) 2OMe 4-F-3-CN O (CH2) 2OMe 4-F-3-NO2 O (CH2) 2OMe 4-F-3-OCH3 O ( CH2) 2OM 4-F-3-C (0) CH3 O (CH2) 2OMe 4-F-3-SO2CH3 O (CH2) 2OMe 4-F-3-S (0) CH3 O (CH2) 2OMe 4-F -3-CO 2 CH 3 O (CH 2) 2OM 4-F -3-SO 2 NHCH 3 O (CH 2) 2OM 4-F-3-CO 2 CH 2 CH 3 O (CH 2) 2OM 4-F-3-SO 2 N (C H 3) 2 O (CH 2) 2OM 4-F-3-CONHCH3 O (CH2) 2OMe 4-F-3-CJ O (CH2) 2OMe 3-F-4-FO (CH2) 2OMe 2-SO2CH3 O (CH2) 2OMe 3-COOH O (CH2) 2OMe 4-COOH O (CH2) 2OMe 2-C (0) 0CH3 O (CH2) 2OMe 2-1 O (CH2) 2OMe 2-CI O (CH2) 2OMe 2-Br O (CH2) 2OMe 2-FO (CH2 ) 2OMe 2-CH3 O (CH2) 2OMe 2-CH3 O (CH2) 2OMe 2-alkynyl O (CH2) 2OMe 2-CN O (CH2) 2OMe 2-NO2 O (CH2) 2OMe 2-OCH3 O (CH2) 2OMe 2-C (0) CH3 O (CH2) 2OMe 3-CI O (CH2) 2OMe 3-Br O (CH2) 2OMe 3-FO (CH2) 2OMe 3-CH3 O (CH2) 2OMe 3-CF3 O (CH2) 2OMe 3-a Iquinyl O (CH2) 2OMe 3-CN O (CH2) 2OMe 3-NO2 O (CH2) 2OMe 3-OCH3 O (CH2) 2OMe 3-C (0) CH3 O (CH2) 2OMe 3-SO2CH3 O (CH2) 2OMe 3-S (0) CH3 O (CH2) 2OMe 3-CO2 CH3 O (CH2) 2OMe 3-SO2NHCH3 O (CH2) 2OMe 3-CO2H2CH3 O (CH2) 2OMe 3-SO2N (CH3) 2O (CH2) 2OMe 3- COIMHCH3 O (CH2) 2OMe S-CON (CH3) 2O (CH2) 2OMe 4-CON (CH3) 2O (CH2) 2OMe 3-1 O (CH2) 2OMe 4-CI O (CH2) 2OMe 4-Br O (CH2) 2OM 4-FO (CH2) 2OM 4-CH3 O (CH2) 2OM 4-CF3 O (CH2) 2OM 4-alkynyl O (CH2) 2OM 4-CN O (CH2) 2OM 4-NO2 O (CH2) 2OMe 4-OCH3 15/46

O (CH2) 2OM 4-C (0) CH3 O (CH2) 2OMe ^ SO2CH3 O (CH2) 2OMe 4-S (0) CH3 O (CH2) 2OMe 4-CO02CH3 O (CH2) 2OMe 4-SO2NHCH3 O (CH2 ) 2OM 4-CO 2 CH 2 CH 3 O (CH 2) 2OM 4-SO 2 N (CH 3) 2 O (CH 2) 2OM 4-CONHCH 3 O (CH 2) 2OM 4-F-3-alkynyl O (CH 2) 2OM 4-F-3-CN O (CH2) 2OMe 4-F-3-Br O (CH2) 2OMe 4-F-3-IO (CH2) 2OMe 4-F-3-CH3 O (CH2) 2OMe 4-F-3-CF3 O (CH2) 2OMe 4-F-3-NO2 O (CH2) 2OMe 4-F-3-OCH3 O (CH2) 2OMe 4-F-3-C (0) CH3 O (CH2) 2OMe 4-F-3-SO2CH3 O ( CH2) 2OM 4-F-3-S (0) CH3 O (CH2) 2OMe 4-F-3-CO02CH3 O (CH2) 2OMe 4-F-3-SO2NHCH3 O (CH2) 2OMe 4-F-3-CO02CH2CH3 O (CH2) 2OMe 4-F-3-SO2N (CH3) 2 O (CH2) 2OMe 4-F-3-CONHCH3 O (CH2) 2OMe 4-F-3-CON (CH3) 2O (CH2) 2OMe 4 -F-3-CI O (CH2) 2OMe 3-F-4-FO (CH2) 2OMe 2-SO2CH3 O (CH2) 2OMe HO (CH2) 2OMe 3-COOH O (CH2) 2OMe 4-COOH O ( CH2) 2OMe 2-C (0) 0CH3 O (CH2) 2OMe 2-1 O (CH2) 2OMe 2-CI O (CH2) 2OMe 2-Br O (CH2) 2OMe 2-FO (CH2) 2OMe 2-CH3 O (CH2) 2OMe 2-CF3 O (CH2) 2OMe 2-alkynyl O (CH2) 2OMe 2-CNO (CH2) 2OMe 2-NO2 O (CH2) 2OMe 2-OCH3 O (CH2) 2OMe 2C (0) CH 3 O (CH 2) 2 OH 3-1 O (CH 2) 2 OH H O (CH 2) 2 OH 3-Cl O (CH 2) 2 OH 3-Br O (CH 2) 2 OH 3-FO (CH 2) 2 OH 3-CH, O (CH 2 ) 2OH 3-CF3 O (CH2) 2OH 3-a Iquini I O (CH 2) 2 OH 3-CN O (CH 2) 2 OH 3-NOz O (CH 2) 2 OH 3-OCH 3 O (CH 2) 2 OH 3-C (0) CH 3 O (CH 2) 2 OH 3-CO 2 CH 3 O (CH 2) 2 OH 3-S (0) CH 3 O (CH 2) 2 OH 3-CO 2 CH 2 C H 3 O (CH 2) 2 OH 3-SO 2 NHCH 3 O (CH 2) 2 OH 3-CONHCH 3 O (CH 2) 2 OH 3-SO 2 N (CH 3) 2 O (CH 2) 2 OH 4-CON (CH 3) 2 O (CH 2) 2 OH S-CON (CH 3) 2 O (CH 2) 2 OH 4-C O (CH 2) 2 OH 4-Br O (CH 2) 2 OH 4-FO (CH 2) 2OH 4-CH3 O (CH2) 2OH 4-C F3 O (CH2) 2OH 4-Alkynyl O (CH2) 2OH 4-CN O (CH2) 2OH 4-NO2 O (CH2) 2OH 4-OCH3 16/46

O (CH 2) 2 OH AC (O) CH 3 O (CH 2) 2 OH 4-SO 2 CH 3 O (CH 2) 2 OH 4-S (0) CH 3 O (CH 2) 2 OH 4-CO 2 CH 3 O (CH 2) 2 OH 4-SO 2 NHCH 3 O (CH 2) 2OH 4-CO 2 CH 2 CH 3 O (CH 2) 2 OH ^ SO 2 N (CH 3) 2 O (CH 2) 2 OH 4-CONHCH 3 O (CH 2) 2 OH 4-CON (CH 3) 2 O (CH 2) 2 OH 4-F-3-CON (CH 3) 2 O (CH2) 2OH 4-F-3-Br O (CH2) 2OH 4-F-3-IO (CH2) 2OH 4-F-3-CH3 O (CH2) 2OH 4-F-3-CF3 O ( CH2) 2OH 4-F-3-alkynyl O (CH2) 2OH 4-F-3-CN O (CH2) 2OH 4-F-3-NO2 O (CH2) 2OH 4-F-3-OCH3 O (CH2) 2OH 4-F-3-C (0) CH 3 O (CH 2) 2 OH 4-F-3-SO 2 CH 3 O (CH 2) 2 OH 4-F-3-SO 2 NHCH 3 O (CH 2) 2 OH 4-F-3-CO 2 CH 2 CH 3 O ( CH 2) 2OH 4-F -3-SO 2 N (CH 3) 2 O (CH 2) 2 OH 4-F-3-CONHCH 3 O (CH 2) 2 OH 4-F-3-CI O (CH 2) 2 OH 3-F-4-FO (CH2) 2OH H O (CH2) 2OH 3-COOH O (CH2) 2OH 4-COOH O (CH2) 2OH 2-C (0) 0CH3 O (CH2) 2OH 2-IO (CH7) 2OH 2-CI O (CH2) 2OH 2-Br O (CH2) 2OH 2-FO (CH2) 2OH 2-CHa O (CH2) 2OH 2-CH3 O (CH2) 2OH 2-alkynyl O (CH2) 2OH 2-CN O (CH2) 2OH 2-NOz O (CH2) 2OH 2-OCH3 O (CH2) 2OH 2-C (0) CH3 O (CH2) 2OH 2-SO2CH3 CH3 4-NO2 CH3 4-OCH3 CH3 4-C (0) CH3 CH3 4 -SO2CH3 CH3 4-S (0) CH3 CH3 4-CO2 CH3 CH3 4-SOTNHCH3 CH3 4-CO2 CH2 CH3 Table 2 Examples of R5 in the compound of formula (J) suitable for be used as medical active ingredient R5 Ri Rb F OH OCH3 OCH2CH3 O (CH2) 2OMe O (CH2) 3OMe O (CH2) 2OH OPr-n OPr-i O (CH2) 3OH O (CH2) 4OMe OBu-n O (CH2 ) 3NMe2 O (CH2) 2NMe2 O (CH2) 3NEt2 O (CH2) 2NEt2

O (CH2) 30-

0 (CH2) 3 (1-pyrrolinyl 0 (CH2) 2 (1-

0 (CH2) 2 (1-17/46

10

15

morpholine)

0 (CH2) 3 (1-

imidazolyl)

0 (CH2) 4 (1-

morpholine)

0 (CH2) 4 (1-

piperidyl)

N (Me) C (O) Me

0 (CH2) 3 (1-pyridyl) 0 (CH2) 4 (1-pyrrolinyl) CH3

OCF3

morpholine)

0 (CH2) 2 (1-

imidazoliJa)

0 (CH2) 4 (1-

imidazolyl)

NMe2

OCF2CH3

pyrrolinyl) 0 (CH2) 2 (1-imidazolyl) H

NHC (O) Me

The invention further relates to an application of a compound of formula (I), R8 R7

(!)

characterized in that X represents N, C-CN or CH; Y represents CH 2, S 1 O or N-R 9; R1, R3, R7 and R8 independently represent H, CF3 O1 C1-4 alkyl;

R2 represents a group selected from formula (II), (I "), (JV) ■ (V) - (V1) 1 (VII) or (VIII);

R12 R10

Ά I

R12

Hello

DLiD

D — B-

DlVo

R

11

10

R

11

>

IIHV

IVII

Free

\ /

Vllli

R 4, R 6 independently represent H, C 1-6 alkylalkylC 1-4 alkyl, OH 1 F1 Cl, Br, OCF 3 or trifluoromethyl;

R5 at each occurrence is independently chosen from H, F, C1. Alkyl, OH, C 1-4 Alkyl, OCF 3, O (CH 2) 2 -OCF 3, OCF 2 CH 3, NH 2, NH (C 1-4 alkyl), NiCl. 6alkyl) 2,1-pyrrolinyl, 1-piperidyl. 4-morpholine, F, Cl. Br, trifluoromethyl, O (CH 2) 2 · OC 1. δalkyl, O (CH2) 2 NH3 (C1-6 alkyl). O (CH 2) 2 N (C 1-6 alkyl) 2. (1-pyrrolinyl) (CH2) 2.40, (1-18/46

piperidyl) (CH2) 2-40, (A-VnorfoWna) (CH2) 2-AO, NHC (O) H, NHC (O) (C1-6 alkyl) C (0) (C1-6 alkyl) ), O (CH 2) 2 N-OH 1 N (C 1-6 alkyl) C (O) 0 (C 1-6 alkyl), N (C 1-6 alkyl) C (O) OH, NHC (O) O (C 1-6 alkyl) 1 OC (O) NH (C 1-4 alkyl) 1 OC (O) N (C 1-4 alkyl) 2, (1-piperidyl) (CH 2) 2 OCO (0), (4-morpholine) (CH 2) 2 ^ OC ( O), (1-pyrrelinyl) (CH 2) 2.40C (0), (I-Imidazoyl) (CH 2) 2 O, (4-imidazolyl) (CH 2) 2 O (C), Ar (CH 2) 4 O (pyrazolyl) (CH 2) 2.40 or (triazolyl) (CH 2) 2 40 ° C (0);

R 9 at each occurrence is independently selected from H, C 1-4 alkyl CF 3, CF 2 CH 3, (CH 2) 2 ^ OH 1 (CH 2) 1 ^ OC 1 -Salkyl, (CH 2 NH 1 -C 4 alkyl), (CH 2) 1 N C 1-6 alkyl) 2, (I-Pyrrolidine) (CH 2) 1 j, (I-Piperidyl) (CH 2) 1 H -1 -morpholineXCH 3,), C (O) C 1. 6alkyl, C (O) (CH 2) 1 H OH 1 C (O) (CH 2) 1 HOC 1 -Salkyl C (O) (CH 2) 1 H N (C 1 -Salkyl) 2, (1-pyrrolinylXCH 2 -eCP), (1-Piperidyl) (CH 2) 1 (C (O) -1-morpholine (CH 2 Cl 2), C (O) OC 1. 6alkyl, C (O) O (CH 2) 2 N 2 O 1 -C 1 -alkyl C (O) O (CH 2) 2 N (C 1 -C 7 Alkyl) 2 C (0) 0 (CH 2) 2.4NH (C 1 6 alkyl), (I (Pyrrolidine) (CH 2) 2 O (O) 1- (1-piperidyl) (CH 2) 2.40C (0), (4-morpholine) (CH 2) 2. * C (O), (CH 2) 1 C (O) C 1 -C 4 here Ar or (CH 2) 1 H;

R10 represents H, C1-4 alkyl or one or two F;

R 11, R 12 independently represent H1 one to four equal from different groups selected from F1 Cl, Br, I, CN, NO 2, CF 3, OH NH 2, C 1 alkyl, OC 1 alkyl, OCF 3, OCF 2 CH 3, NH (CM alkyl) , N (C 1-4 alkyl) 2, OC (O) C 1-4 alkyl, NHC (O) H 1 NHC (O) C 1-6 alkyl, N (C 1-4 alkyl) C (O) C 1-6 alkyl, C (O) OC 1. , alkyl, C (O) NHC1 alkyl, C (O) N (C4 alkyl), COOH1 C (O) C1 alkyl, S (O) C1., alkyl, SO2 C • 1-4 alkyl, SO2 NHC1- * alkyl or SO2 N (C1-4 alkyl);

A1 B independently represent aromatic ring; Ar is phenyl, phenyl or substituted pyridyl; D represents O, S, NH or methoxy; and m, η independently represent an integral from 0 to 4.

The application concerns the treatment or prevention of physiological disorder caused by EGFR or Her-2 overexpression in mammals, the disorder includes but is not limited to breast cancer, kidney cancer, bladder cancer, oral cancer, laryngeal cancer, cancer. esophageal, gastric cancer, colorectal cancer, ovarian cancer, lung cancer, and head and neck cancer; In addition, the application relates to the treatment or prevention of physiological disorder by inhibiting EGFR-TK activity in mammals, the disorder includes but is not limited to psoriasis, pneumonia, hepatitis, nephritis, pancreatitis, diabetes.

To achieve the above objectives, in accordance with another embodiment of the invention, a preparation comprising at least one compound of formula (I) or pharmaceutically acceptable salts or hydrates thereof is provided.

n rj

(I)

characterized in that X represents N1 C-CN or CH; Y represents CH 2, S, O or N-R 9; R11 R31 R7 and R8 independently represent H, CF3 or C1-6 alkyl;

R 2 represents a group selected from formula (II), (III), (IV), (V), (VI), (VII) or (VIII);

~ r \

R12 R10

nllo

12

R10 π IIlD

• R11

Rii

»12

IV

D>

p11

ÇvillD

Λ

V. //

R41 R6 independently represent H1 C1-4 alkyl, OC1-4 alkyl, OH, F, Cl, Br, OCF3 or trifluoromethyl;

R5 at each occurrence is independently selected from H1 F, C1-4 alkyl, OH1 OC1-4 alkyl, OCF3, O (CH2) 2 ^ OCF3, OCF2CH3, NH2, NH (C1-4 alkyl), N (C1-4 alkyl) 2l 1-pyrrolinyl, 1-piperidyl, 4-morpholine. F1 Cl1 Br, trifluoromethyl, O (CH2) 2. 4OC 1 alkyl, O (CH 2) 2 NH (C 1 -Salkyl) 10 (CH 2) 2 N (C 1 -C 6 alkyl) 2, (1-pyrrolinyl) (CH 2) 2.40, (1-piperidyl) (CH 2) 2 O, (4-morpholine) (CH 2) 2 O, NHC (O) H, NHC (O) (C 1-6 alkyl), N (C 1-6 alkylC 1-10 alkyl). O (CH 2) 2 N OH (N 1 -C 4 alkyl (C 1 O 10 C 8 alkyl), N (C 1-6 alkyl) Ja (C) O, NHC (O) O (C 1-6 alkyl) 1 O (O) NH (C 1-6 alkyl) 1 OC (O) N (C 1 H 3) 2. (1-piperidyl) (CH 2) 2 · 0C (0). (4-morpholine) (CH 2) 2 · OC (0). (1-pyrrolinyl) (CH 2) 2 O (O), (1-imidazolyl) (CH 2) 2.40, (4-imidazolyl) (CH 2) 2 O (0). Ar (CH 2) 1 O, (Pyrazolyl) (CH 2) 2 O or (triazolyl) (CH 2) MOC (O);

R9 at each occurrence is independently chosen from H, C1. 6alkyl, CF3 CF2 CH3, (CH2) 2 ^ 1 OH, (CH2 H2 O4 alkyl) (CH2) 1 NH (C1-C1 alkyl), (CH2) 1.

4N (C 1-6 alkyl) 2> (I-Pyrrolinyl) (CH 2) 1 H, (1-piperidyl) (CH 2) 1-4, (4-morpholine) (CH 2) V 4, C (O) C 1-1 alkylH, C (O) (CH2) 1-OH1 C (O) (CH2) 1-OC1-C1 -C6 alkyl C (O) (CH2) 1-N (C1-C4 alkyl) 2, (I-Pyrrolidine) (CH2) t-C ( O) 1- (1-piperidyl) (CH 2), C (O), (4-morpholine) (CH 2) 1.4 C (O), C (O) OC 1 alkyl, C 1 O 6 CH 2 OC 4 alkyl, C (O) 0 (CH 2) 2-4 N (C 1-6 alkyl) 2, C (0) 0 (CH 2) 2-4 NH (C 6 -alkyl), (I-Pyrrolidin) (CH 2) 2 O (O), (1-piperidyl ) (CH 2) 2 O (C), (4-morpholine) (CH 2) 2 O (O), (CH 2) 1X (O) OC 1 Alkyl or Ar (CH 2) 1 O;

R10 represents H, C1-4 alkyl or one or two F;

R111 R12 independently represent H11 to 4 same from different groups chosen from F, Cl1 Br, I, CN1 NO2, CF3, OH1 NH2, C1-4 alkylal OC1. 4alkyl, OCF3, OCF2CH3, NH (C1-4 alkyl), N (C1-4 alkyl) 2, OC (O) C1-4 alkyl NHC (O) H1 NHC (O) C1-4 alkyl NC4 alkylC1O4C4 alkyl, C (O) C1 ^qui C C C C C C C (((((((((((,,,,,, C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C Cllllllll.............. 4alkyl or SO 2 N (C 1-6 alkyl) 2;

A1 B independently represent aromatic ring, Ar is phenyl, phenite or substituted pyridyl; D represents O1 S1 NH or methylene; and m, η independently represent an integral from 0 to 4.

The preparation comprises at least the compound of formula (I) or pharmaceutically acceptable salts or hydrates thereof which is used as a medical active ingredient and processed with required or pharmaceutically acceptable excipients to the appropriate dosage form. The method of administration of the dosage form includes, but is not limited to oral administration, intravenous injection, intraperitoneal injection, subcutaneous injection, intramuscular injection, nasal drip, eye drops, inhalation, anal administration, vaginal administration or epidermal administration.

The preparation comprises at least the compound of formula (I) or pharmaceutically acceptable salts or hydrates thereof may treat or prevent physiological disorder caused by EGFR or Her-2 overexpression in mammals, the disorder includes, but is not limited to breast cancer , kidney cancer, bladder cancer, oral cancer, laryngeal cancer, esophageal cancer, gastric cancer, colorectal cancer, ovarian cancer, lung cancer, head and neck cancer, psoriasis, pneumonia, hepatitis, nephritis, pancreatitis and diabetes.

To achieve the above objectives, in accordance with yet another embodiment of the invention, a method of preparing a compound of formula (I) is provided.

N R3

Ο)

characterized in that X represents N, C-CN or CH; Y represents CH 2, S, O or N-R 9; R11 R3, R7 and R8 independently represent H1 CF3 or C1-6 alkyl;

R 2 represents a group selected from formula (II), (III), (IV), (V), (VI), (VII) or (VIII);

10

rV8 ^ »

R12 R10 π IIG

I read Vg

11

V / 12

R1

R

11

R10 Ill

R11

R

12

\

-N H

! Vile

g Vlii

IVr

R

11

> -4

.H

* /

f VIIIa

15

20

25

R41 R6 independently represent H1 C1-4 alkyl, OC1-4 alkyl, OH1 F1 Cl, Br, OCF3 or trifluoromethyl;

R5 at each occurrence is independently selected from H, F, C1-Galchyl, OH, OC1 ^ alkyl, OCF3, O (CH2) 2 ^ OCF31 OCF2 CH3 NH2, NH (C1 ^ alkyl) 1 N (C1 ^ alkyl) 2 , 1-pyrrolinyl, 1-piperidyl. 4-morpholine, F, Cl, Br, trifluoromethyl, O (CH 2) 2. 4OC1 ^ alkyl, O (CH2) 2 ^ NH (C1-4 alkyl) 1 O (CH2) JMN (C1-4 alkyl) 2, (I-Pyrrolidine) (CH2) 2 ^ O1 (1-piperidyl) (CH2) 2 ^ O, (4-morpholine) (CH 2) 2 O, NHC (O) H 1 NHC (O) (C 1-6 alkyl) 1 NiCl. 6 alkyl) C (O) (C 1-6 alkyl), O (CH 2) 2 ^ 4 OH 1 N (C 1-6 alkyl) C (O) 0 (C 1-6 alkyl), N (C 1-6 alkyl) C (0) OH, NHC (O) O (C1-4 alkyl) 1 OC (O) NH (C1-4 alkyl) 1 OC (O) N (C1-4 alkyl) 2. (1-piperidyl) (CH 2) 2 O (C), (4-morpholine) (CH 2) 2 O (0), (1-pyrrolinyl) (CH 2) 2.4OC (0), (I-Imidazoyl) ( CH 2) 2 O (4-imidazolyl) (CH 2) 2 O (0). Ar (CH 2) 1 O, (pyrazolyl) (CH 2) M 0 or (Wazoyl) (CH 2) 2 O (O);

R9 at each occurrence is independently chosen from H1 C1. 22/46

10

15

6alkyl, CF3, CF2CH3, (CH2) 2 ^ OH1 (CH2 OC4 alkyl), (CH2 NH4 C1 alkyl), (CH2) 1. ,, N (C1-4 alkyl) 2l (I-Pyrrolidine) (CH2) 1 (1-Piperidyl) (CH 2) 1 -1- (4-morpholine) (CH 2) 1-4, C (O) C 1-4 alkyl (C 2) (CH 2) f OHOH C (O) (CH 2) 1 C 1 -C 6 alkyl, C (O) (CH 2) MN (C 1 a) qui) 2, (I-Pyrrolidine) (CH 2) 1 C (O), (1-piperidyl) (CH 2) 4 C ( O), (4) morpholineKCH 2 K 4 C (O) 1 C (O) OC 1 alkyl 3 C (0) 0 (CH 2) 2 4 O 4 alkyl, C (0) 0 (CH 2) 2 ^ N (C 3 alkyl) 2, C (0) O (CH 2) 2 N NH (C 1 alkyl), (1-pyrrolinyl) (CH 2) 2 O (0), (1-piperidyl) (CH 2) 2.40C (0), (4-morpholine) (CH2) 2.4OC (O), (CH2) 1X (O) OC1 Alkyl or Ar (CH2) 1.

R10 represents H, C1-4 alkyl or one or two F;

R 11, R 12 independently represent H 1 to 4 same from different groups selected from F1 Cl, Br, I, CN, NO 2, CF 3, OH 1 NH 2, C 1-4 alkylal OC 1. 4alkyl, OCF3, OCF2CH3, NH (C1-4 alkyl), N (C1-4 alkyl) 2l OC (O) C1-4 alkyl, NHC (O) H, NHC (O) C1-4 alkyl N (C1-4 alkyl) C (0 ) C1-4 alkyl, C (O) OC1-4 alkyl, C1-4 NHC4 alkyl, C (O) N (C1-4 alkyl) 2, COOH1 C (O) C1-4 alkylSOC4-4 alkyl, SO2 C1-4 alkyl SO2NHC1. 4alkyl or SO 2 N (C 1-4 alkyl) 2l

A, B independently represent aromatic ring; Ar is substituted phenyl, phenyl or pyridyl; D represents O, S, NH or methylene; and m, η independently represent an integral from 0 to 4.

The method comprises the steps of: 1) contacting a compound of formula (XI)

20 n (XO

with (R 15) (R 13) P (O) CH (R 8) COOR 14 or Ar 3 P = CR 8 CO 2 R 14 to yield a compound of formula (IX)

R8

vW:

25 (fX)

characterized in that Y represents CH2, S, O1 or N-R9 except ΝΗ; R 8 independently represent H 1 CF 3, or C 1-4 alkylal R 9 is independent at each occurrence chosen from H 1 C 1-4 alkylal CF 3. CF 2 CH 31 (CH 2) 2.4 OH, (CH 2) 1 HCl. (CH 2) 1 N-NH 1 Cl 1 (alkyl), (CH 2) 1 N (C 1 -C 4) (2) (I-Pyroxy) (CH 2) 4 4, (1-23/46)

piperidyl) (CH 2) 1-4, (4-morpholine) (CH 2) 1.4, C (O) C, 6a alkyl, C (O) (CH 2) v 4 OH 1 C (O) (CH 2) 1. 40C 16 alkyl, C (O) (CH 2) 1 N (C 1 alkyl) 21 (I-Pyroxy) (CH 2) 1 C (O), (I-Piperidyl) (CH 2) 1. C (O), (4 -) (CH 2), C (O), C (O) OC 1 alkyl, C (O) O (CH 2) 2 O 2 alkyl, C (O) O (CH 2) )2. 4N (C1-6 alkyl) 2, (1-pyrrolinyl) (CH2) 2.4OC (0), (1-piperidyl) (CH2) 2 ^ 0C (0), (4-morpholine) (CH2) 2 ^ OC (0 ), (C 1-4 alkyl), or Ar (CH 2) n; R 13 and R 15 are independently C 1-6 alkyl, C 1-4 alkyl, phenyl, substituted phenyl, phenoxy, or substituted phenoxy; R 14 represents C 1-6 alkyl; Ar is phenyl or substituted phenyl, and η independently represent an integral from 0 to 4.

2) Contact the compound of formula (IX) with the compound of formula (X) to obtain the compound of formula (I) (except that Y represents NH). The definitions of R11 R21 R3, R4, R51 R61 R7 and R8 for formula (IX), (X) are the same as for formula (I). During the reaction, the compound of formula (IX) may first be transformed into an active ester, acyl chloride, acyl imidazole or mixed anhydride and then contacted with the compound of formula (X), and tertiary amines such as triethylamine, N- Substituted methylmorpholine, trimethylamine, pyridine or pyridine may be used to accelerate the reaction. When the compound of formula (IX) is transformed into thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride or danuric chloride it may be used as chlorinating agents. Optionally, the compound of formula (IX) may first be transformed into anhydride and then contacted with the compound of formula (X), and substituted pyridine or pyridine such as DMAP may be used as a catalyst to accelerate the reaction.

3) Transforming the compound of formula (J) characterized in that Y represents (CH3) 3COC (O) N into the compound of formula (XII) under acidic or pyrolysis condition, characterized by the fact that the definitions of R11 R21 R31 R41 R5 R 6, R 7 and R 8 for formula (XII) is the same as for formula (I). The acidic condition may be trifluoroacetate acid, hydrochloric acid, sulfonic acid or an acetyl chloride plus alcoholic system. 24/46

R4

X. .............................. Xll

4) Contacting the compound of formula (XII) with XR9 to obtain the compound of formula (I) characterized in that Y represents NR9 and the definition of R9 is the same as that for formula (I) (except that R9 represents Η ), X represents Cl1 Br1 I, Oms or Ots. During the reaction, the organic base such as triethylamine, trimethylamine, pyridine, substituted pyridine or inorganic base such as sodium carbonate, potassium carbonate may be used to accelerate the reaction, and suitable reaction solvent includes acetonitrile, dimethylformamide, dimethylacetamide, tetrahydrofuran or dimethyl glycol ethylene ether.

Cellular epidermal growth factor receptor (EGFR-TK) tyrosine kinase inhibition experiment

1) A431 cells were cultured in a medium prepared by adding 10% FCS in another medium comprising 50% DMEM and 50% F12.

2) A431 cells grown in six-well plates were cultured in serum free medium for 24 hours, and over the 24 hour period, the medium was replenished once after 12 hours.

3) A solution containing a compound to be evaluated was added to A431 cells and the cells were cultured for 2 hours, supplemented twice by a free medium of the compound, and then EGF (100 ng / well) was added, and cultured for 5 hours. minutes

4) A431 cell homogenate was prepared by Laemili buffer, which comprises 2% sodium dodecyl sulfonate (SDS), 5% 2-mercaptoethanol, 10% glycerol, pH value was 6.8.

5) The A431 cell homogenate was heated for 5 minutes at 100 ° C.

6) Proteins in A431 cell homogenates were separated by the PAGE method and transferred to a nitrocellulose membrane, and an infrared reading was obtained.

7) The formula for calculating the inhibition percentage.

% inhibition = 100 - {infrared reader reading (sample) / infrared reader reading (empty)] χ 100 25/46

The previous partial measurement results for a single concentration are listed in Table 3 (preliminary selection). EC50 measurement results for some compounds are listed in Table 4. Table 3

Inhibitory activity (percentage inhibition) of some compounds of the Examples with 3μΜ concentration against EGF-TK phosphorylation of EGF-stimulated A431 cells

Percent Percent Percent Percent Inhibiting Compound (%) Inhibiting Compound (%) Inhibiting Compound (%) Example 1 NA Example 3 85 Example 4 78 Example 5 73 Example 6 24 Example 7 65 Example 8 NA Example 30 55 Example 31 33 Example 32 87 Example 33 94 Example 34 68 Example 35 23 Example 36 57 Example 37 82 Example 38 94 Example 40 89 Example 41 71 Example 43 91 Example 50 95 Example 51 94 Example 72 97 Example 73 82 Example 105 44 Example 107 52 Example 110 59 Example 118 41 Example 132 64 Example 134 59 Example 141 91 Example 143 96 Example 144 89 Example 150 46

Note: NA = No Activity Table 4

Inhibitory activity (ECs0) of some compounds of the Examples against EGF-stimulated EGFR-TK phosphorylation of A431 cells

EC50 Compound (M) EC50 Compound (MM) EC50 Compound (MM) Example 3 0.15 Example 4 0.58 Example 7 0.4 26/46

Example 32 0.09 Example 33 0.033 Example 34 0.76

Example 36 0.98 Example 41 0.30 Example 65 0.23

Example 82 0.013 Example 83 13 Example 110 0.9

Example 141 0.28 Example 143 0.16

The irreversible inhibition of cell epidermal growth factor receptor tyrosine kinase (EGFR-TK) experiment

1) A431 cells were cultured in a medium prepared by adding 10% FCS in another medium comprising 50% DMEM and 50% F12.

2) A431 cells grown in six well plates were grown in a

serum free medium for 24 hours, and over the 24 hour period, the medium was replenished once after 12 hours.

3) A solution containing a compound to be evaluated was added to A431 cells and cultured for 2 hours, supplemented twice by a medium free from the

10 compound, and then EGF (100ng / well) was added, and grown for 5 minutes.

4) A431 cell homogenate was prepared by Laemili buffer, which comprises 2% sodium dodecyl sulfonate (SDS), 5% 2-mercaptoethanol, 10% glycerol, pH value was 6.8.

5) The A431 cell homogenate was heated for 5 minutes at 100 ° C.

6) Proteins in A431 cell homogenates were separated by

PAGE method and transferred to a nitrocellulose membrane, and an infrared reading was obtained.

7) The formula for calculating the inhibition percentage:

% inhibition = 100 - [reading by infrared reader (medicine) / reading by reader

20 infrared (empty)] * 100D

8) Formula for calculating the recovery percentage. % recovery = 100 -% inhibition

Part of the results are listed in Table 5. Table 5

The Irreversible Property of Some Compounds of the Examples Against EGF-stimulated EGFR-TK Forforylation of A431 Cells

Percent Percentage of Recovery Inhibition Compound EC50 (HM) Property (%) (%) Example 32 0.09 78 22 Irreversible Inhibitor Example 33 0.038 89 11 Irreversible Inhibitor Example 82 0.013 74 86 Reversible Inhibitor 27/46

After the literature procedure, the inhibitory activity of some compounds of the Examples against Her-2-stimulated Her-2 receptor TK phosphorylation of BT474 cells was measured, and part of the results are listed in Table 6. Table 6

The inhibitory activity of some compounds of the Examples against Her-2-stimulated Her-2 receptor TK phosphorylation of BT474 cells

Compound Εθ5ο (μΜ) Compound EC50 (MM) Compound ECso (MM) Example 43 0.35 Example 72 0.82 Example 73 1.7 Example 105 0.48 Example 108 0.18 Example 150 0.26

Cell Growth Inhibition Assay (MTS Assay) 1. Cell strain and reagents

A431: human epithelial adenocarcinoma cell strain; LoVo: strain of

I The human colorectal cancer cell; BT474: breast cancer; SK-Br-3: breast cancer; SIT solution (SIGMA); RPM11640 culture solution; phosphoric acid buffer; Dimethyl Sulfoxide (DMSO); MTS Solution (Promega), 96-well cell culture plate, anti-cancer compounds. 2. Measurement

The above cells were cultured for several days (RPM1 1640, 10% of

bovine serum) collected and suspended in serum-free RPMI1640-SIT medium, implanted in a 96-well cell culture dish with each well containing 20,000 cells / 100 microliter. Cells were cultured overnight under 5% CO2 and 37 ° C conditions. The next day, anti-cancer compounds (between 3 and 10 mM) were dissolved by Dimethyl Sulfoxide (DMSO) as a stock solution, and Adriamycin was used as a control. positive, DMSO as negative control. According to the experimental design, the stock solution was diluted and added to the 96-well cell culture plate grown for 48 hours under 5% CO2 and 37IL conditions. Subsequently, 20 DL of the MTS solution was added to each well of the stock plate. 25-well cell culture and grown for an additional 2 to 4 hours under 5% CO 2 and 37 ° C conditions. Absorbance was read at 490 nm wavelength, and converted to cell survival rate.

Percent inhibition calculation formula:% inhibition = 100 - [infrared reader reading (medicine) / infrared reader reading 30 (empty) J HOO

For each concentration, these two measurements were made and the mean was obtained. Part of the results are listed in Tables 7, 8 and 9. Table 7 28/46

Growth inhibiting activity (EC50) of some compounds of the Examples against A43 cells

Compound EC50 ^ M) Compound EC50 ^ M) Compound EC50 ^ M) Example 3 2 Example 4 1.8 Example 7 5 Example 32 0.6 Example 33 0.10 Example 34 13 Example 36 30 Example 38 0.014 Example 41 1.5 Example 42 0.12 Example 43 0.11 Example 50 0.15 Example 51 OJ 2 Example 72 0.09 Example 73 0.63 Example 82 0.30 Example 83 35 Example 108 3.0 Example 118 1.9 Example 134 0.9 Example 143 0.25 Example 154 0.11 Tarceva 0.45 Lapatinibe 1.19

Table 8

Growth inhibition activity (EC50) (in μΜ) of some compounds of the 5 Examples against BT474 and SK-Br-3 cells

Compound BT474 SK-Br-3 Example 48 0.61 0.52 Example 72 1.31 0.80 Example 73 21.48 2.31 Example 108 1.57 0.53 Lapatinibe 0.12 0.07

Table 9

Growth inhibiting activity (EC50) of some compounds of the Examples against colorectal cancer LoVo cells

EC50 Compound (MM) EC50 Compound (MM) EC50 Compound (MM)

Example 42 3 Example 43 T ~ 5 Example 38 ΪΤβ

Example 51 7.6 Example 72 1.8 Example 73 8.0

Example 108 Example 154 Adriamici-

7.0 3.1 1.5

at

Preparation of 1a: tert-Butyl 4-oxopiperidine-1-carboxylate Piperidone hydrochloride hydrate 4- (8.65 g), BOC2O (12.2 g), NaHCO3 (8.8 g)

and NaCl (11.2 g) were dissolved separately in a mixture of tetrahydrofuran (80 ml) and water (80 ml), mixed at room temperature and allowed to stand overnight for separation of the layers. The water layer was extracted once with chloroform. The organic phases were combined, washed once with 29/46

saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to form a white solid (11.35 g).

Preparation of 1b. tert-butyl 3-oxopyrroJidine-1-carboxylate

After the procedure of preparing 1a except that piperidone A-5 hydrochloride was replaced by 3-oxopyrrolidine hydrochloride, the title compound was prepared.

Preparation of 1c: 1- (2-Methoxyethyl) piperidine-4-one

hydrated A-piperidone hydrochloride (8.65 g), CH 3 OCH 2 CH 2 I (12.58 g) and K 2 CO 3 (15.55 g) were dissolved separately in a mixture of tetrahydrofuran (80 ml) and water (80 ml), mixed at room temperature. room and allowed to stand overnight at 10 ° C for separation into layers. The water layer was extracted once with chloroform. The organic phase was combined, washed once with saturated brine, dried over anhydrous magnesium sulfate and filtered. Finally, the filtrate was evaporated in vacuo to form an oleaginous product.

Preparation of 2a. tert-butyl 4- (2-methoxy-2-oxoethylidene) piperidine-1-carboxylate Sodium hydroxide (4.56 g, 0.114 mol) was dissolved in alcohol (210 ml), and

Alcohol solution containing methyl dimethoxy phosphoryl acetate (11.4g, 0.062mol) added with stirring. The mixture was stirred for 30 min at room temperature. 1- (tert-Butoxycarboxyl) piperidyl-4-one (11.35g, 0.057mol) was added with stirring at room temperature, and the reaction was allowed to stand overnight. Then the mixture was acidified with dilute hydrochloric acid until the pH value reached 4, filtered, concentrated, dissolved with water and chloroform. The chloroform phase was obtained after layer separation. The water phase was extracted once with chloroform. The chloroform phase was combined, washed once with saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated in vacuo to form the title compound.

Preparation of 2b: methyl 2- (1- (2-methoxyethyl) piperidin-4-ylidene) acetate

After the procedure of preparing 2a except that tert-butyl A-oxopiperidine 1-carboxylate was replaced by (1- (2-methoxy) ethyl-4-oxopiperidine), the title compound was prepared.

Preparation of 2c: (E / Z) -tert-butyl 3- (2-methoxy-2-oxoethylidene) pinrolidine -1-

carboxylate

After the procedure of preparing 2a except that tert-butyl 4-oxopiperidine 1-carboxylate was replaced with tert-butyl 3-oxopyrroline 1-carboxylate, the title compound was prepared.

Preparation of 3a: 2- (1- (tert-Butoxycarbonyl) piperidin-4-ylidene) acetic acid

The 4- (2-methoxy-2-oxoethylidene) piperidine-1-carboxylate tert-butyl obtained above was added to tetrahydrofuran (60ml), methanol (60ml) and 1N lithium hydroxide (60ml), 30/46

stirring at room temperature and resting overnight. Then the mixture was extracted three times with dichloromethane. The organic phase was removed and the water phase was acidified with 1N hydrochloric acid until the pH reached 4, extracted three times with dichloromethane and then to combine the organic phase. The organic phase was washed 5 times with saturated brine, dried over anhydrous magnesium sulfate and filtered. Finally the filtrate was evaporated in vacuo to form the title compound.

Preparation of 3b: 2- (1- (2-Methoxyethyl) piperidin-4-ylidene) acetic acid

After the preparation procedure 3a except that tert-butyl 4- (2-methoxy-2-oxoethylidene) piperidine-1-carboxylate1 was replaced by 2- (1- (2- 10-methoxyethyl) piperidin-4-ylidene) methyl acetate , the title compound was prepared.

Preparation of 3c: (E) -2- (1- (tert-Butoxycarbonyl) pyrrolidin-3-acetic acid)

ilidene)

After the procedure of preparing 3a except that tert-butyl 4- (2-methoxy-2-oxoethylidene) piperidine-1-carboxy) was replaced by (E / Z) -tert-butyl 3- (2-methoxy-2- 15 oxoethylidene) pyrrolidine-1-carboxylate, the title compound was prepared.

Preparation of 4a: N4- (3-Ethinylphenyl) quinazoline-4,6-diamine

2 g of the iron powder was immersed in dilute hydrochloric acid for 30 min, filtered and washed with water. Subsequently, the iron powder obtained, 0.1 g of N- (3-acetylene-phenyl) -6-nitroquinazoline-4-amine, 25 ml of alcohol-water solution (water: alcohol = 1: 2), and 0.3 20 ml. of acetic acid were added to a four-necked flask with mechanical stirring and heating reflux for one hour. After the reaction, the mixture was cooled to room temperature, filtered, concentrated and added ethyl acetate, washed three times with hydrochloric acid. The hydrochloric acid layer was combined and alkalized with Na 2 CO 3 until the pH value reached 9, extracted three 25 times with ethyl acetate and then to combine the organic phase. The organic phase was washed once with saturated brine, dried over anhydrous magnesium sulfate and filtered. Finally the filtrate was evaporated in vacuo to form the title compound.

After the procedure of preparing 4a, the compounds of 4b-4r were prepared.

Preparation of 4b: N4- (4- (benzyloxy) -3-chlorophenyl) quinazoline-4,6-diamine

Preparation of 4c: N4- (4- (3-chlorobenzyloxy) -3-chlorophenyl) quinazoline-4,6-diamine Preparation of 4d: N '1- (4- (3-bromobenzyloxy) -3-chlorophenyl) quinazoline-4 Preparation of 4e: N4- (4- (3-Methoxybenzyloxy) -3-chlorophenyl) quinazoline-4,6-diamine

Preparation of 4f: N4- (4- (3-Ethoxybenzyloxy) -3-chlorophenyl) quinazoline-4,6-diamine 35 Preparation of 4g: N4- (3-Chloro-4- (pyridin-2-ylmethoxy) phenyl) quinazoline -4, 6-

diamine

Preparation of 4h: N4- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -7-fluoroquinazoline-31/46

4,6-diamine

Preparation of 4i. N4- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -7-methoxyquinazoline-4,6-diamine

Preparation of 4j: N4- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -7-ethoxyquinazoline-4,6,5-diamine

Preparation of 4k: N4- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -7- (2-methoxyethoxy) quinazoline-4,6-diamine

Preparation of 41: N ', - (4- (3-chlorobenzyloxy) -3-chlorophenyl) -7-methoxyquinazoline-4,6-diamine

Preparation of 4m: N4- (3-chloro-4- (pyridine-2-i) methoxy) phenyl) -7-methoxyquinazoline-

4,6-diamine

Preparation of 4n: N4- (1-Benzyl-1H-indol-5-yl) quinazoline-4,6-diamine Preparation of 4th: N4- (1- (3-fluorobenzyl) -1H-indol-5-yl) - 7-methoxyquinazoline-4,6-diamine

Preparation of 4p: N4- (1-benzyl-1H-indol-5-yl) -7- (2-methoxyethoxy) quinazoline-4,6-one

diamine

Preparation of 4q: 7-Ethoxy-N4- (3-methoxy-4-phenoxyphenyl) quinazoline-4,6-diamine Preparation of 4-7-ethoxy-N4- (4- (4-fluorophenoxy) -3-methoxyphenyl) quinazoline- 4,6-diamine 20 Example 1

tert-butyl 4- (2- (4- (3-ethynylphenylamino) quinazolin-6-ylamino) -2-

oxoethylidene) piperidine-1-carboxylate

1 g 2- (1- (tert-Butoxycarbonyl) piperidin-4-ylidene) acetic acid was added to 20 ml of anhydrous THF in a one-neck flask (100 ml). The solution was dissolved with stirring and resined with an ice-salt bath. Then 0.6 ml of isobutylchloroformate and 0.5 ml of N-methylmorpholine were added with stirring for 20 min. 1,046 g of N 4- (3-ethynyl phenyl) quinazoline-4,6 diamine was dissolved in 10 ml of pyridine (dried over molecular sieve) and 0.4 ml of added N-methylmorpholine. The mixture was added to the flask under ice bath with stirring. After the reaction, the solvent was evaporated in vacuo and separated with chloroform and water. The chloroform layer was washed once with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated in vacuo to form a crude product which was recrystallized from isopropanol, MS (electron impact) 482M +. Example 2

N- (4- (3-Ethinylphenylamino) quinazolin-6-yl) -2- (piperidin-2-yl) acetamide trifluoroacetate

4-ylidene)

Tert-Butyl - ((4- (3-ethynylphenylamino) quinazolin-6-yl-aminocarbonyl) carboxylic ester - 32/46

methylene) piperidine-1- (92 mg, 0.38 mmol) was dissolved in 10 mL of 20% anhydrous TFA / DCM solution and stirred at room temperature for 2 hours, evaporated in vacuo, vacuum dried to form an off-white foam solid, MS: 384 (M + 1). Example 3

N- (4- (3-Ethinylphenylamino) quinazolin-6-yl) -2- (piperidin-4-ylidene) acetamide

Acetamide trifluoroacetate N- (4- (3-ethynylphenylamino) quinazolin-6-yl) -2- (piperidin-4-ylidene) was dissolved in ethyl acetate. The mixture was washed once separately with saturated Na 2 CO 3 and saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated in vacuo to form a product, MS (10 electron impact) 384 (M + 1). Example 4

N- (4- (3-Ethiniphenylamino) quinazolin-6-yl) -2- (1-methoxypendin-4-ylidene) acetamide N- (4- (3-ethynylphenylamino) quinazolin-6-yl acetamide ) -2- (piperidin-4-ylidene) (20 mg, 0.046 mmol), methyl iodide (8.0 mg, 0.056 mmol), anhydrous potassium carbonate (17 15 mg) and acetonitrile (5 mL) were added in one vial (50 ml) with stirring at room temperature for 24 hours. After the reaction, the solution was filtered, evaporated in vacuo to form a solid. The solid was purified by TLC (500 µm thick silica gel plate, chloroform to methanol developer 95: 5), MS: 398 (M + 1).

Following the procedure of Example 4, the compounds of Example 5-8 were

prepared. Example 5

2- (1-ethylpipendin-4-ylidene) -N- (4- (3-ethynylphenylam MS: 412 (M + 1)) 25 Example 6

2- (1-benzylpiperidin-4-ylidene) -N- (4- (3-ethynylphenylamino) quinazolin-6-yl) acetamide MS: 474 (M + 1) Example 7

N- (4- (3-Ethinylphenylamino) quinazolin-6-yl) -2- (1- (2-methoxyethyl) piperidin-4-30ylidene) acetamide MS: 440 (M-1) Example 8

Methyl 2- (4- (2- (4- (3-ethynylphenylamino) quinazolin-6-ylamino) -2-oxoethylidene) piperidin-1-yl) acetate MS: 454 (M +) Example 9

N- (4- (3-Ethinylphenylamino) quinazolin-6-yl) -2- (1-isopropylpiperidin-4-one)

ylidene) acetamide MS. 426 (M + 1) Example 10 33/46

N- (4- (3-Ethinitphenylamino) quinazolin-6-yl) -2- (1- (2-hydroxyethyl) pipericlin-4-ylidene) acetamide MS: 428 (M + 1)

Following the procedure of Example 1, the compounds of Example 11-29 were prepared.

5 Example 11

tert-butyl 4- (2-oxo-2- (4- (phenylamino) quinazolin-6-ylamino) ethylidene) piperidine-1-arboxylate MS: 459 (M +) Example 12

tert-butyl 4- (2- (4- (3-chloro-4-fluorophenylamino) quinazolin-6-ylamino) -2-10 oxoethylidene) piperidine-1-carboxylate MS: 511 (M +) Example 13

tert-butyl 4- (2- (4- (3-bromophenylamino) quinazolin-6-ylamino) -2-

oxoethylidene) piperidine-1-carboxylate MS: 539 (M + 1) Example 14

(S) - tert-Butyl 4- (2-oxo-2- (4- (1-phenylethylamino) quinazolin-6-ylamino) ethylidene)

piperidine-1-carboxylate MS: 487 (M +) Example 15

(R) - tert-Butyl 4- (2-oxo-2- (4- (1-phenylethylamino) quinazolyl-6-ylamino) ethylidene) piperidine-1-carboxylate MS: 487 (M +) 20 Example 16

tert-butyl 4- (2- (4- (3-chlorophenylamino) quinazolin-6-ylamino) -2-oxoetifidene) piperidine-1-carboxylate MS: 493 (M +) Example 17

tert-butyl 4- (2- (4- (3-chlorophenylamino) -7-fluoroquinazolin-6-ylamino) -2,25-oxoethyldeno) piperidine-1-carboxylate MS: 511 (M +) Example 18

tert-butyl 4- (2- (4- (3-bromophenylamino) -7-methoxyquinazolin-6-ylamino) -2-

oxoethylidene) piperidine-1-carboxylate MS: 568 (M + 1) Example 19

Tert-Butyl 4- (2- (4- (3-bromophenylamino) -7-ethoxyquinazolin-6-ylamino) -2-

oxoethylidene) piperidine-1-carboxylate MS: 582 (M + 1) Example 20

tert-butyl 4- (2- (4- (3-bromophenylamino) -7- (2-methoxyethoxy) quinazolin-6-ylamino) -2-oxoethylidene) pipendin-1-carboxylate MS: 612 (M +1) 35 Example 21

tert-butyl 4- (2- (4- (1H-indol-5-ylamino) quinazolin-6-ylamino) -2-oxoethylidene) piperidine-1-carboxylate MS: 498 (M +) 34/46

Example 22

tert-butyl 4- (2- (4- (3-ethynitphenylamino) -7-methoxyquinazolin-6-ylamino) -2-

oxoethylidene) piperidine-1-carboxylate MS. 512 (M ') Example 23

tert-butyl 4- (2- (4- (3-chloro-4-fluorophenylamino) -7-methoxyquinazolin-6-ylamino) -2-oxoethylidene) piperidine-1-carboxylate MS: 541 (M +) Example 24

tert-butyl 4- (2- (4- (1H-indol-5-ylamino) -7-methoxyquinazolin-6-ylamino) -2-

oxoethylidene) piperidine-1-carboxylate MS: 528 (M +) Example 25

tert-butyl 4- (2- (4- (3-bromophenylamino) -7- (3-methoxypropoxy) quinazolin-6-ylamino) -2-oxoethylidene) piperidine-1-carboxylate MS: 626 (M +) Example 26

tert-butyl 4- (2- (4- (3-bromophenylamino) -7- (3-morpholinopropoxy) quinazolin-6-ylamino) -2-oxoethylidene) piperidine-1-carboxylate MS: 681 (M +) Example 27

tert-butyl 4- (2- (4- (3-ethynylphenylamino) -7- (2-methoxyethoxy) quinazolin-6-ylamino) -2-oxoethylidene) piperidine-1-carboxylate 27 MS: 557 (M + 1) Example 28

tert-butyl 4- (2- (4- (3-chloro-4-fluorophenylamino) -7- (2-methoxyethoxy) quinazolin-6-ylamino) -2-oxoethylidene) piperidine-1-cart> oxylate MS: 585 ( M +) Example 29

tert-butyl 4- (2- (4- (1H-incyl-5-ylamino) -7- (2-methoxyethoxy) quinazolin -6-ylamino) -2-oxoethylidene) piperidine-1-carboxylate MS: 572 (M +)

Following the procedure of Example 2, 3, the compounds of Example 30-50 were prepared. Example 30

N- (4- (3-chlorophenylamino) -7-fluoroquinazolin-6-yl) -2- (piperidin-4-ylidene) acetamide MS: 411 (M + 1) Example 31

N- (4- (phenylamino) quinazolin-6-yl) -2- (piperidin-4-ylidene) acetamide MS: 359 (M + 1) Example 32

N- (4- (3-chloro-4-fluorophenylamino) quinazolin-6-yl) -2- (piperidin-4-ylidene) acetamide MS. 410 (M +) Example 33

N- (4- (3-bromophenylamino) quinazolin-6- [1] -2- (piperidin-4-ylidene) acetamide MS. 438 (M +) 35/46

Example 34

(S) -N- (4- (1-phenylethylamino) quinazolin-6-yl) -2- (piperidin-4-ylidene) acetamide MS:

387 (M +) Example 35

(R) -N- (4- (1-phenylethylamino) quinazolin-6-yl) -2- (piperidin-4-ylidene) acetamide MS:

387 (M +) Example 36

N- (4- (3-chlorophenylamino) quinazolin-6-yl) -2- (piperidin-4-ylidene) acetamide MS: 393 (M +) 10 Example 37

N- (4- (3-bromophenylammonium) -7- (3-morpholinopropoxy) quinazolin-6-yl) -2- (piperidin-4-hydroxy) acetamide MS: 581 (M +) Example 38

N- (4- (3-bromophenylamino) -7-methoxyquinazolin-6-yl) -2- (piperidin-4-itidene) 15 acetamide MS: 467 (M +) Example 39

N- (4- (3-bromophenylamino) -7-ethoxyquinazolin-6-yl) -2- (piperidin-4-ylidene) acetamide MS: 482 (M +) Example 40

20 N- (4- (3-bromophenylamino) -7- (2-methoxyethoxy) quinazoliri-6-ii) -2- (piperidin-4-

ylidene) acetamide MS: 512 (M + 1) Example 41

N- (4- (1H-indol-5-amino) quinazorin-6-yl) -2- (pipendin-4-ylidene) acetamide MS: 398 (M + 1) 25 Example 42

N- (4- (3-Ethinylphenylamino) -7-methoxyquinazolin-6-yl) -2- (piperidin-4-ylidene) acetamide MS: 413 (M +) Example 43

N- (4- (3-chloro-4-fluorophenylamino) -7-methoxyquinazolin-6-yl) -2- (piperidin-4-30-ylidene) acetamide MS: 441 (M + 1) Example 44

N- (4- (1H-indol-5-y) amino) -7-methoxyquinazorin-6-O-2- (piperidin-4-ylidene) acetamide MS: 428 (M + 1) Example 45

(S) -N- (7-Methoxy-4- (1-phenylethylamino) quinazolin-6-yl) -2- (piperidin-4-

ylidene) acetamide MS. 417 (M +) Example 46 36/46

(R) -N- (7-Methoxy-4- (1-phenylethyl / lamino) quinazolin-6-yl) -2- (w / perid / n-4-ylidene) acetamide MS: 417 (M +) Example 47

N- (4- (3-Ethinylphenylamino) -7- (2-methoxyethoxy) quinazolin-6-yl) -2- (piperidin-4-5-ylidene) acetamide MS: 457 (M +) Example 48

N- (4- (3-chloro-4-fluorophenylamino) -7- (2-methoxyethoxy) quinazolin-6-yl) -2- (piperidin-4-ylidene) acetamide MS: 485.5 (M +) Example 49

10 N- (4- (3-ethenipheniphamirx)) 7- (3-morpholinopropoxy) quinazolin-6-yl) -2- (pi

ylidene) acetamide MS: 526 (M + 1) Example 50

N- (4- (3-Ethinylphenylamino) -7- (3-methoxypropoxy) quinazolin-6-yl) -2- (piperidin-4-ylidene) acetamide MS: 471 (M + 1) 15 After the procedure of Example 4 , the compounds of Example 51-83 were

prepared. Example 51

N- (4- (3-Ethinylphenylamino) -7-methoxyquinazolin-6-yl) -2- (1-methylpiperidin-4-ylidene) acetamide MS: 427 (M + 1) 20 Example 52

N- (7-ethoxy-4- (3-ethynylphenylamino) quinazolin-6-yl) -2- (1-ethylpiperidin-4-ylidene) acetamide MS: 455 (M +) Example 53

2- (1-ethylpiperidin-4-ylidene) -N- (4- (3-ethynitphenylamino) -7-methoxyquinazolin-6-25 yl) acetamide MS: 441 (M +) Example 54

N- (7-ethoxy-4- (3-ethynylphenylamino) quinazolyr) -6-yl) -2- (1-methylpiperidin-4-ylidene) acetamide MS: 441 (M +) Example 55

30 N- (4- (3-bromophenylamino) quinazolin-6-yl) -2- (1-methylpiperidin-4-ylidene) acetamide

MS: 452 (M +) Example 56

N- (4- (3-bromophenylamino) quinazolin-6-yl) -2- (1-ethylpipendin-4-ylidene) acetamide MS: 466 (M + 1) 35 Example 57

N- (4- (3-bromophenylamino) quinazolin-6-yl) -2- (1- (2-methoxyethyl) piperidin-4-ylidene) acetamide MS: 496 (M + 1) 37/46

Example 58

N- (4- (3-bromophenylamino) -7-methoxyquinazolin-6-yl) -2- (1-methylpiperidin-4-ylidene) acetamide MS. 482 (M + 1) Example 59

5 N- (4- (3-bromophenylamino) -7-methoxyquinazol-6-yl) -2- (1-ethylpiperidin-4-one)

ylidene) acetamide MS: 496 (M + 1) Example 60

N- (4- (3-bromophenylamino) -7-methoxyquinazolin-6-n-ylidene) acetamide MS: 526 (M +) 10 Example 61

N- (4- (3-bromophenylamino) -7-methoxyquinazolin-6-yl) -2- (1- (3-methoxypropyl) piperidin-4-ylidene) acetamide MS: 540 (M +) Example 62

N- (4- (3-bromophenitamino) -7-ethoxyquinazolin-6-yl) -2- (1-methylpiperidin-4-15-ylidene) acetamide MS: 496 (M + 1) Example 63

N- (4- (3-bromophenylamyrK)) - 7-ethoxyquinazolin-6-yl) -2- (1-ethylpiperidin-4-ylidene) acetamide MS: 510 (M +) Example 64

20 N- (4- (3-bromophenylamino) -7-ethoxyquinazolin-6-yl) -2- (1- (2-methoxyethyl) piperidin-4-

ylidene) acetamide MS: 540 (M +) Example 65

N- (4- (3-bromophenylamino) -7- (2-methoxyethoxylidene) acetamide MS: 526 (M +) 25 Example 66

N- (4- (3-bromophenylamiroxy) 7- (3-methoxypropoxy) quinazolin-4-yl) -2- (1-methylpiperyl-4-ylidene) acetamide MS: 540 (M +) Example 67

N- (4- (3-bromophenylamino) -7- (3- (dimethylamino) propoxy) quinazolin-6-yl) -2- (1-30 methylpiperidin-4-ylidene) acetamide MS: 552 (M +) Example 68

N- (4- (3-bromophenyl] amino) -7- (3-morpholinopropoxy) quinazo) in-6-i)) -2- (1-methylpiperidin-4-ylidene) acetamide MS: 595 (M + 1) Example 69

N- (4- (3-chlorophenylamino) -7-fluoroquinazolin-6-yl) -2- (1-methylpiperidin-4-one)

ylidene) acetamide MS. 425 (M +) Example 70 38/46

N- (4- (3-chlorophenylamino) -7-fluoroquinazole] 6- (1) -2- (1-et / lp / peridin-4-ylidene) acetamide MS: 439 (M +) Example 71

N- (4- (3-chlorophenylamino) -7-fluoroquinazolin-6-yl) -2- (1- (2-methoxyethyl) piperidin-4-5-ylidene) acetamide MS: 469 (M +) Example 72

N- (4- (3-chloro-4-fluorophenylamino) -7-methoxyquinazolin-6-yl) -2- (1-methylpiperidin-4-ylidene) acetamide MS: 455 (M +) Example 73

10 N- (4- (3-chloro-4-fluorophenylamino) -7-methoxyquinazolin-6-yl) -2- (1- (2-

methoxyethyl) piperidin-4-ylidene) acetamide MS: 499 (M +) Example 74

N- (4- (3-chloro-4-fluorophenylamino) quinazolin-6-yl) -2- (1- (2-methoxyethyl) piperidin-4-ylidene) acetamide MS: 469 (M +) 15 Example 75

N- (4- (1H-indol-5-ylamide) quinazolin-6-yl) -2- (1-methylpiperidin-4-ylidene) acetamide MS: 412 (M + 1) Example 76

N- (4- (1H-indol-5-ylamino) quinazolyl-MS-MS: 426 (M + 1) Example 77

N- (4- (1H-indol-5-ylamino) quinazolin-6-yl) -2- (1- (2-methoxyethyl) piperidin-4-ylidene) acetamide MS: 456 (M +) Example 78

25 (S) -2- (1-methylpiperidin-4-lidene) -N- (4- (14-enetylamino) quinazoKn-6-yl) acetamide

MS: 401 (M +) Example 79

(S) -2- (1-Ethylpiperidinylphenyl) -N- (4- (1-phenylethyl) MS: 415 (M +) 30 Example 80

(S) -2- (1- (2-Methoxyethyl) piperidin-4-ylidene) -N- (4- (1-phenylethylamino) quinazolin-6-yl) acetamide MS: 445 (M +) Example 81

(S) -N- (7- (2-methoxyethoxy) -4- (1-phenylethylamino) quinazo-vin-6-yl) -2- (piperidin-4-35-ylidene) acetamide MS: 537 (M +) Example 82

N- (4- (1H-indol-5-ylamino) -7- (2-methoxyethoxy) quinazolin-6-yl) -2- (piperidin-4-39/46

ylidene) acetam MS: 472 (M + 1) Example 83

N- (4- (3-bromophenylamino) quinoline-6-yl) -2- (pyrrhoxy-3-yl) o) acetamide MS: 423 (M + 1) 5 Example 84

Comparison Compound A: N- (4- (3-bromophenylamino) quinazolin-6-yl) propionamide

N * - (3-acetylenylphenyl) quinazoline -4,6-diamine (100 mg, 0.32 mmol) pyridine (0.3 mL) and DMAP (20 mg) were dissolved in 10 mL of anhydrous THF solution and 10 added in a flask. drip reaction. The solution was resin at 5n, propionyl chloride (33 mg, 0.35 mmol) was added, ice bath was removed, the solution was stirred at room temperature and filtered. The filtrate was evaporated in vacuo to form a yellow solid which was dissolved with ethyl acetate, washed once separately with saturated Na 2 CO 3, 10% acetic acid and saturated brine. The organic phase was dried, filtered, centrifuged to form a crude product which was purified with TLC to form an off-white product. Example 85

Comparison Compound B: N- (4- (3-bromophenylamino) quinazolin-6-yl) acrylamide

After the procedure of Example 84 except that propionyl chloride was

replaced by acryloyl chloride, the title compound was prepared. Example 86

Comparison Compound C: N- (4- (3-bromophenylamino) quinazotin-6-yl) -3-methylbut-2-enamide

25 Following the procedure of Example 84 except that propionyl chloride was

replaced by 3-methylbutyl-2-en-acyl chloride, the title compound was prepared. Example 87

N- (7-Methoxy-4- (2-phenylcyclopropylamino) quinazolin-6-yl) -2- (1- (2-methoxyethyl) piperidin-4-ylidene) acetamide 1) Preparation of 2- acyl chloride hydrochloride (1- (2-methoxyethyl) piperidin-4-

ilidene)

2.4 g of 2- (1- (2-methoxyethyl) piperidin-4-ylidene) acetic acid was dissolved in 20 ml of thionyl chloride, with a 2 hour flow-back, evaporated under reduced pressure to remove thionyl chloride and form. a solid product. 2) Preparation of N- (7-Methoxy-4- (2-phenylcyclopropylamino) quinazolin-6-yl) -2- (1-

(2-methoxyethyl) piperidin-4-lidene) acetamide

Following the procedure of Example 84, the title compound was prepared by 40/46

2- (1- (2-Methoxyethyl) piperidin-4-ylidene) acetyl chloride hydrochloride contact with N4- (7-methoxy-4- (2-phenylcyclopropylamino) quinazolin-4,6-diamine.

N1- (4- (3-bromophenylamino) quinazolin-6-yl) -N4- (2- (2- (dimethylamino) ethoxy) ethyl) fumaramide

79 mg of N1- (4- (3-bromophenyl) quinazolin-4,6-diamine, 39 mg of maleic anhydride and 15 ml of THF were added to a refluxing one-mouth flask (50 ml). , the solution was evaporated in vacuo and purified by thin layer chromatography.The pure product was dissolved with anhydrous THF, ethoxyamino alcohol added and cooled in a geto bath.Then the DCC-containing THF solution was added dropwise, ice bath removed and heating reflux was followed for one day.After reaction, the solution was resined at room temperature, filtered, evaporated in vacuo to form a crude product 105 mg of the crude product was dissolved with 20 mL of pyridine 400 mg of p-methylbenzene sulfonic chloride added with stirring at room temperature After reaction, the solvent was removed and the residue dissolved with ethyl acetate, washed once separately with saturated Na 2 CO 3, 1 N HCl and saturated NaCl, dried with magnesium sulfate The anhydrous, filtered, evaporated in vacuo to form a product. The product was dissolved with 10 ml of pyridine, dimethylamine added with stirring at room temperature. After the reaction, the solvent was evaporated in vacuo and purified by thin layer chromatography, MS (electron impact) 528 M +. Example 89

N- (4- (3-bromophenylamino) quinazolin-6-yl) -2- (1- (2- (2- (2- (2-hydroxyethoxy) ethylamino) acetyl) piperidin-4-ylidene) acetamide

40 mg of N- (4- (3-bromophenylamirv3) chyrazoUrvG-yl) -2- (piperidin-4-ylidene) acetamide and 10 ml of THF were added in a one-neck flask (50 ml), resins in a 1-liter bath. ice, 0.01 ml chloroacetic chloride and 0.02 ml triethylamine (dried over molecular sieve) added with stirring at room temperature. After the reaction, the solvent was evaporated in vacuo, the residue was dissolved with ethyl acetate, washed three times with water and once with saturated brine, dried with anhydrous magnesium sulfate, filtered, evaporated in vacuo to form a crude product. (30 mg). The crude product was dissolved with 10 ml acetonitrile, 7.3 mg (0.07 mmol) ethoxy amine alcohol and 0.02 ml triethylamine (dried over molecular sieve) added with stirring at room temperature. After the reaction, the solvent was evaporated in vacuo and purified by thin layer chromatography, MS (electron impact) 581 M +.

Following the literature procedure, the compounds of Example 90-101 were prepared. 41/46

Example 90

N4- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -7- (3-morpholinopropoxy) quinazoline-4,6-diamine Example 91

5 N4- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -7- (3-methoxypropoxy) quinazoline-4,6-one

diamine Example 92

N4- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -7-ethoxyquinazoline-4,6-diamine Example 93

10 N4- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -7-methoxyquinazoline-4,6-diamine

Example 94

N4- (3-chloro-4- (pyridin-2-imephoxy) phenyl) -7-forooroquinazoline-4,6-diamine Example 95

N4- (3-chloro-4- (pyrid »n-2-ylmethoxy> phen« a) qumazol »na-4,6-diamine 15 Example 96

7-Methoxy-N4- (3-methoxy-4-phenoxyphenyl) quinazoline-4,6-djamine Example 97

7-Methoxy-N4- (4- (3-methoxyphenoxy) phenyl) quinazoline-4,6-diamine Example 98

N4- (2-chloro-4- (pyridin-2-ylmethoxy) phenyl) -7-methoxyquinazoline-4,6-diamine

Example 99

N4- (4- (benzyloxy) -3-chlorophenyl) -7-methoxyquinazoline-4,6-diamine

Example 100

N4- (4- (3-chlorobenzyloxy) -3-fluorophenyl) -7-methoxyquinazoline-4,6-diamine

25 Example 101

N4- (4- (3-chloro-4-fluorobenzyloxy) phenyl) -7-methoxyquinazoline-4,6-diamine

Example 102

tert-butyl 4- (2- (4- (3-chloro-4- (pyridin-2-ylmethoxy) feriylamino) quinazolin-6-ylamino) -2-oxoethylidene) piperidine-1-carboxylate 30 1 g of 2- ( 1- (tert-butyloxycarbonyl) piperidin-4-ylidene) acetic acid, 20 ml of

Anhydrous THF were added in a one-neck flask (100 ml), dissolved with stirring and resins with an ice-salt bath, then 0.6 ml of isobutylchloroformate and 0.5 ml of N-methylmorpholine added, stirring for 20 mins. 1.046 g of N4- (4-3-chloro- (pyridin-2-ylmethoxy) phenyl) quinazoline-4,6 diamine was dissolved with 10 ml of pyridine 35 (dried over a molecular sieve), 0.4 ml of N-methylmorpholine added, and the mixture was added to the flask under ice bath with stirring. After the reaction, the solvent was evaporated in vacuo and partitioned with chloroform and water. The chloroform layer 42/46

It was washed once with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated in vacuo to form a crude product, which was recrystallized from isopropanol, MS (electron impact) 601M +. Example 103

Acetamide N- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) quinazolin-6-yl) -2- (piperidin-4-ylidene) trifluoroacetate

tert-butyl-4 - ((4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) quinazolin-6-yl-aminocarbonyl) -methylene) piperidine-1-carboxylic ester (92 mg, 0.38 mmol) was dissolved in 10 ml of 20% anhydrous TFA / DCM solution with stirring at room temperature for 2 hours, evaporated in vacuo, vacuum dried to form an off-white foam solid, MS: 501 (M + 1). Example 104

N- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) quinazolin-6-yl) -2- (piperidin-4-ylidene) acetamide

15 N- (4- (3-chloromethyl- (pyridin-2-ylmethoxy) phenylamino) quinazolin-6-yl) -2- (piperidin-4-

Acetamide ylidene) trifluoroacetate was dissolved with ethyl acetate, washed once with saturated Na 2 CO 3 and once with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated in vacuo to form a product, MS (electron impact) 501 (M + 1).

Following the procedure of Example 104, compounds of 105-115 were

prepared. Example 105

N- (4- (4- (3-fluorobenzyloxy) -3-dorophenylamino) -7-methoxyquinazin-6-yl) -2- (piperidin-4-ylidene) acetamide MS: 548 (M + 1) 25 Example 106

N- (4- (4- (3-fluorobenzyloxy) -3-chlorophenylamino) -7- (3-methoxypropoxy) quinazolin-6-yl) -2- (piperidin-4-ylidene) acetamide MS: 605 (M +) Example 107

N- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) -7-ethoxyquinazolin-6-yl) -2- (piperidin-30 4-ylidene) acetamide MS: 544 (M +) Example 108

N- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) -7-methoxyquinazolin-6-yl) -2- (piperidin-4-ylidene) acetamide MS: 531 (M + 1) Example 109

N- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) -7-fluoroquinazolin-6-yl) -2-

(piperidin-4-ylidene) acetamide MS: 519 (M + 1) Example 110 43/46

N- (7-methoxy-4- (4-methoxy-44enoxyphenylamino) quinazolin-6-yl) -2- (p-pentlin-4-ylidene) acetamide MS: 512 (M + 1) Example 111

N- (7-methoxy-4- (4- (3-methoxyphenoxy) phenylamino) quinazolin-6-yl) -2- (piperidylidene) acetamide MS: 511 (M +) Example 112

N- (4- (2-chloro-4- (pyridin-2-ylmethoxy) phenylamino) -7-methoxyquinazolin-6-yl) -2- (piperidin-4-ylidene) acetamide MS: 531 (M + 1) Example 113

N- (4- (4- (benzyloxy) -3-chlorophenylamino) -7-methoxyquinazin) -6-i)) -2- (piperidin-4-ylidene) acetamide MS: 531 (M + 1) Example 114

N- (4- (4- (3-chlorobenzyloxy) -3-fluorophenylamino) -7-methoxyquinazolin-6-yl) -2-

(piperidin-4-ylidene) acetamide MS: 547 (M +) Example 115

N- (4- (4- (3-chloro-4-fluorobenzyloxy) phenylamino) -7-methoxyquinazolin-6-yl) -2- (piperidin-4-ylidene) acetamide MS: 548 (M + 1) Example 116

N- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamin-4-ylidene) acetamide

N- (4- (3-chloro-4- (pyridin-2H-methoxy) phenj (amino) quinazolyl-6-yl) -2- (1-pyridene) acetamide (20 mg, 0.046mmol), methyl iodide (8.0 mg, 0.056 mmol), anhydrous potassium carbonate (17 mg) and acetonitrile (5 ml) were added in a one-neck flask (50 ml) and mixed at room temperature for 24 hours.After the reaction, the solution was filtered, evaporated vacuum to form a solid The solid was purified by TLC (500 µm thick silica gel plate, developer: chloroform to methanol 95: 5), MS: 515M +

Following the procedure of Example 116, the compounds of Example 117-118 were prepared. Example 117

N- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) -7-methoxyquinazolin-6-yl) -2- (1-ethylpiperidin-4-ylidene) acetamide MS: 558 (M +) Example 118

N- {4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) -7-methoxyethyl) piperidin-4-ylidene) acetamide MS: 588 (M +)

Following the literature procedure, the compounds of Example 119-131 were prepared. 44/46

Example 119

6-amino-4- (3-chlorophenylamino) -7-methoxyquinoline-3-carbonitrile Example 120

6-amino-4- (3-chloro-4-fluorophenylamino) -7-methoxyquinoline-3-carbonitrile 5 Example 121

6-amino-4- (3-ethynylphenylamino) -7-methoxyquinoline-3-carbonitrile Example 122

6-amino-4- (3-bromophenylamino) -7-methoxyquinoline-3-carbonitrile Example 123

10 6-amino-4- (3-chloro-4-fluorophenylamino) -7-e (oxyquinoline-3-carbonitrile

Example 124

6-amino-7-ethoxy-3- (3-n-ifenylammo) quinoline-3-carbonitrile Example 125

6-amino-4- (3-bromophenylamino) -7-ethoxyquinoline-3-carbonitrile Example 126

6-amino-4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) -7-methoxyquinoline-3-carbonitrile Example 127

6-amino- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) -7-ethoxyquinoline-3-20 carbonitrile Example 128

4- (4- (3-fluorobenzyloxy) -3-chlorophenylamino) -6-amino-7-methoxyquinoline-3-carbonitride Example 129

4- (4- (3-fluorobenzyl-oxo-3-dorophenylamino) -6-amino-7-ethoxyquinoline-3-

carbonitrile Example 130

6-amino-4- (4- (3-fluorophenoxy) -3-methoxyphenylamino) -7-methoxyquinoline-3-carbonitrile Example 131

6-amino-7-ethoxy-4- (4- (3-fluorophenoxy) -3-methoxyphenylamino) quinoline-3-carbonitrib

Following the procedure of Example 104, compounds of 132-145 were prepared. Example 132

35 N- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) -3-damage-7-methoxyquinolin-6-yl) -2-

(piperidin-4-ylidene) acetamide MS: 554 (M + 1) Example 133 45/46

N- (4- (3-chlorophenylamino) -3-cyano-7-ethoxyquinolin-6-yl) -2- (piperidin-4-ylidene) acetamide MS: 461 (M +) Example 138

N- (4- (3-chlorophenylamino) -3-cyano-7-methoxyquinolin-6-yl) -2- (piperidin-4-5-ylidene) acetamide MS: 448 (M + 1) Example 139

N- (4- (3-chloro-4-fluorophenylamino) -3-cyano-7- (2-methoxyethoxy) quinolin-6-yl) -2- (piperidin-4-ylidene) acetamide MS: 510 (M + 1 ) Example 140

10 N- (4- (3-chloro-4-fluorOphenylamino) -3-cyano-7-ethoxyquinolin-6-yl) -2- (piperidin-4-

ylidene) acetamide MS: 480 (M + 1) Example 141

N- (4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxyquinolin-6-yl) -2- (piperidin-4-ylidene) acetamide MS: 466 (M + 1) 15 Example 142

N- (3-cyano-7-ethoxyM- (3-ethynylphenylamino) quinolin-6-yl) -2- (piperidin-4-ylidene) acetamide MS: 452 (M + 1) Example 143

N- (3-cyano-4- (3-ethynylphenylamino) -7-methoxyquinolin-6-yl) -2- (piperidin-4-20 ylidene) acetamide MS: 438 (M + 1) Example 144

N- (4- (3-bromophenylamirium) -3-cyano-7-ethoxyquinolin-6-yl) -2- (piperidin-4-ylidene) acetamide MS: 506 (M +) Example 145

25 N- (4- (3-bromophenylamino) -3-cyano-7-methoxyquiniol-6-yl) -2- (piperidin-4-

ylidene) acetamide MS: 493 (M + 1)

Following the procedure of Example 116, compounds of 146-154 were prepared. Example 146

30 N- (4- (3-chloro-4-fluorophenylamino) -3-cyano-7-ethoxyquinolin-6-yl) -2- (1-methylpiperidine)

4-ylidene) acetamide MS: 494 (M + 1) Example 147

N- (4- (3-chloro-4-fluorophenylamino) -3-cyano-7-ethoxyquinolin-6-yl) -2- (1- (2-methoxyethyl) piperidin-4-ylidene) acetamide MS: 537 (M + ) 35 Example 148

N- (3-cyano-7-ethoxy-4- (3-ethynylphenylamino) quinolin-6-yl) -2- (1-methylpiperidin-4-ylidene) acetamide MS: 466 (M + 1) 46/46

ylidene) acetamide MS: 493 (M + 1)

Following the procedure of Example 116, compounds of 146-154 were prepared. Example 146

5 N- (4- (3-doro-4-fluorophenylamino) -3-cyano-7-ethoxyquinolin-6-yl) -2- (1-methylpiperidine)

4-ylidene) acetamide MS: 494 (M + 1) Example 147

N- (4- (3-chloro-4-fluorophenylamino) -3-cyano-7-ethoxyquinolin-6-yl) -2- (1- (2-methoxyethyl) piperidin-4-ylidene) acetamide MS: 537 (M + ) 10 Example 148

N- (3-cyano-7-ethoxy-4- (3-ethynylphenylamino) quinolin-6-yl) -2- (1-methylpiperidin-4-ylidene) acetamide MS: 466 (M + 1) Example 149

N- (3-cyano-7-ethoxy-4- (3-ethoxyphenylamino) quinoJin-6-yl) -2- (1- (2-15 methoxyethyl) piperidin-4-ylidene) acetamide MS: 510 (M + 1 ) Example 150

N- (4- (3-dorcH4- (pyridin-2-ylmethoxy) phenylamino) -3-damage-7-ethoxyquinolin-6-yl) -2- (1-methylpiperidin-4-ylidene) acetamide MS: 582 (M +1) Example 151

N- (4- (3-doro-4- (pyridin-2-ylmethoxy) phenylamino) -3-cyano-7-ethoxyquinolin-6-yl) -2- (1-

(2-methoxyethyl) piperidin-4-ylidene) acetamide MS: 626 (M + 1) Example 152

N- (4- (4- (3-fluoro-benzoxy) -3-dorophenylamino) -3-cyano-7-ethoxyquinolin-6-yl) -2- (1-methylpiperidin-4-ylidene) acetamide MS: 600 (M + 1) 25 Example 153

N- (4- (4- (3-fluorobenzyloxy) -3-chlorophenylamino) -3-cyano-7-ethoxyquinolin-6-yl) -2- (1- (2-methoxyethyl) piperidin-4-ylidene) acetamide MS : 643 (M +) Example 154

N- (4- (3-Ethinylphenylamino) -7-methoxyquinazol-4-ylidene) acetamide MS: 471 (M +)

While some particular embodiments of the invention have been exhibited and described, it will be obvious to those skilled in the art that changes and modifications can be made without departing from the invention in its broadest aspects, and therefore, the purpose of the appended claims is to cover all such changes and modifications. modifications because they are within the true spirit and scope of the invention.

Claims (16)

1. IRREVERSIBLE INHIBITORS OF PROTEIN TYROSIN KINASES composed of the formula (I) or pharmaceutically acceptable salts or hydrates thereof which may inhibit protein tyrosine kinase activity; an application of said compound in the treatment or prevention of physiological disorder caused by protein tyrosine kinase overexpression or inhibition of protein tyrosine kinases activity in mammals; and a method of preparing it; <formula> formula see original document page 48 </formula> (I) characterized by the fact that X represents N1 C-CN or CH; Y represents CH 2, S 1 O or N-R 9; R11 R31 R7 and R8 independently represent H, CF3, C1-4 alkyl; R2 represents a group selected from formula (II), (HI) 7 (IV), (V), (VI), (VII) or (VIII); <formula> formula see original document page 48 </formula> R41 R6 independently represent H, C1-4 alkyl, OC1-4 alkyl, OH1 F, Cl, Br, OCF3 or trifluoromethyl; R5 at each occurrence is independently selected from H, F, C1-4 alkyl, OH, OC1-4 alkyl, OCF3, OCF2CH3, NH2, NH (C1-4 alkyl), N (C1-4 alkyl) 2,1-pyrrolinyl, 1 - piperidyl, 4-morpholine, Cl, Br, trifluoromethyl, O (CH 2) 2 OCl-C 1-1 O, (CH 2) 2 OCOF 3 O (CH 2) 2 NH (C 1 -Balyl) 10 (CH 2) MN ( C 1-6 alkyl) 2. (1-pyrrolinyl) (CH 2) 2 O, (1-piperidyl) (CH 2) 2-40, (4-morpholine) (CH 2) M 0, NHC (O) H 1 NHC (O) (C 1-6 alkyl) 1 NiC 1 . 6 (alkyl) C (O) (C 1-6 alkyl), O (CH 2) 2 N-OH 1 N (C 1-4 alkyl), (C) O (C 1-6 alkyl), N (C 1-6 alkyl) C (O ) OH, NHC (0) 0) C1-6 alkyl), OC (O) NH (C1-4 alkyl) 1 OC (O) N (C1-4 alkyl) 2L (1-piperidyl) (CH2) 2-40C (0), ( 4-morpholine) (CH 2) 2 O (O) t (I-Pyrrolidine) (CH 2) 2 O (O), (I-Imidazoyl) (CH 2) 2 O (Pyrazoyl) (CH 2) 2 O (1) triazolyl) (CH 2) 2 X> C (O) or Ar (CH 2) 1 O; R 9 at each occurrence is independently selected from H 1 C 1-4 alkyl, CF 3, CF 2 CH 3, (CH 2) 2 ^ OH 1 (CH 2 J 3 OC 4 alkyl, (CH 2) 1 NH (C 1 -C 4 Alkyl) 1 (CH 2) 1 3 NiC 1-6 alkyl) 21 (I-Pyrrolidine) (CH 2) 1., (I-Piperidyl) (CH 2) 1 4, 4-morpholine (CH 2) 4, C (O) C 1. and real. C (O) (CH 2) 1 ^ OH 1 C 1 OHCH 2 O 2 alkyl, C (O) (CH 2) 1 N (C 1 -C 6 alkyl) 2l (1-pyrrolinylC 1 H 2 O 4), (I-Piperidyl) (CH 2) (C (O) -1 morpholine (CH 2) (C 10). C (O) OC1. alkyl, C (O) O (CH 2) 2 W 1 CO 1 -Salkyl C (O) O (CH 2) 2 N (C 1 SaIquHa) 2, (1 pyrrolinyl) (CH 2) 2. 40 ° C (0), (1-piperidyl) (CH 2) 2 ° C (0), (4-morpholine) (CH 2) 2 ° C OC (0), (CH 2) 1 ° C (O) OC 1. 6 alkyl, Ar (CH 2) 1 -V, R 10 represents H 1 C 1-4 alkyl or one or two F; R11. R 12 independently represent H, 1 to 4 the same or different groups chosen from F1 Cl, Br, I 1 CN 1 NO 21 CF 3, OH 1 NH 21 C 1 alkylalkyl OC 1 Alkyl OCF 3, OCF 2 CH 31 NH (C 1-4 Alkyl), N (C 1-4 Alkyl) 21C (O) C 1-6 alkyl NHC (O) H 1 NHC (O) C 1-6 alkyl N 1 -C 4 alkylC 1 O 4 C 4 alkyl. C (O) C 1-6 alkyl C (O) NHC 1-4 alkyl C (O) N (C 1-4 alkyl) 2 1 COOH 1 C (O) C 1-4 alkyl S (O) C 1-4 alkyl 2 SO 2 Cl 2 SO 2 NHC 1. 4 afchiia or SO 2 N (C 1-4 afchiIa) 2; A1 B independently represent aromatic ring; Ar is phenyl or substituted phenyl; D represents O 1 S, NH or methylene; and m, η independently represent an integer from 0 to 4. The compound of formula (I) according to claim 1, characterized in that R 1, R 31 R 4, R 6 and R 7 independently represent H, R 8 represents H, CH 3 or CH 2 CH 3. The compound of formula (I) 1 according to claim 1, characterized in that R 5 at each occurrence is independently selected from H, F, OCF 3, OC 1 O 3 CH 2) 2 -OCAL 1 OCH 2 O 3. Alkyl, 2- (1-pyrrolinyl) ethoxyl, 2- (1-piperidyl) ethoxyl, 2- (4-morpholine) ethoxyl, 3- (1-pyrrolinyl) propyloxy, 3- (1-piperidyl) propyloxy, 3- ( 4-morpholine) propyloxy, Ph (CH 2) 1 O or Py (CH 2) 1 O. 4 The compound of formula (I) according to claim 1, wherein Y represents N-R91 R9 at each occurrence is independently selected from H1 CF3 C1 -C1 alkylal (CH2) 2 ^ OH1 (CH2) 2 ^ OC1. (C1-Alkyl) 2, (1-pyrrolinyl) - (CH2) 2 ', (1-piperidyl) - (CH2) 2', (4-morpholine) - (CH2) 2- 4, C (O) OC1 -alkyl, (CH2) 1X (O) OC1 -alkyl, Ph (CH2) 11 or Py (CH2) n4. 5 The compound of formula (I) according to claim 1, characterized in that m, η independently represent 0,1 or 2. 6 The protein tyrosine kinase of claim 1, wherein said protein tyrosine kinase represents EGFα tyrosine kinase. 7 The protein tyrosine kinase of claim 1, characterized in that said protein tyrosine kinase represents Her-2 tyrosine kinase. 8 The compound of the formula (!) Or pharmaceutically acceptable salts or hydrates thereof which may inhibit the growth of cancer cells <formula> formula see original document page 50 </formula> characterized in that X represents N, C -CN or CH; Y represents CH 2, S 1 O or N-R 9; R11 R31 R7 and R8 independently represent H1 C1-4 alkyl; R2 represents a group selected from formula (II), (III), (IV), (V), (VI), (VII) or (VIU); R4, R6 independently represent H, C1-4 alkyl, OC1-4 alkyl, OH, F, Cl, Br, OCF3 or trifluoromethyl; R5 at each occurrence is independently selected from H, F1 C1-4 alkyl, OH1 OC1 ^ alkyl1 OCF3. OCF 2 CH 3, NH 2, NH (C 1-6 alkyl). N (C 1-6 alkyl) 21-pyrrolinyl, 1-piperidyl, 4-morpholine. Cl1 Br1 trifluoromethyl, O (CH2) 2 ^ OC, ^ alkyl1 O (CH2) 2 ^ OCF310 O (CH2) 1 MNH (C1-4 alkyl), O (CH2) 2 ^ N (C1-Alkyl) 2l (1-pyrrolinyl) (CH 2) 2 O, (1-piperidyl) (CH 2) 2 O, (4-morpholine) (CH 2) 2 N 1 O NHC (O) H 1 NHC (O) (C 1-6 alkyl), N (C 1-6 alkyl) C (O) (C 1-6 alkyl), O (CH 2) 2 OH, N (C 1-6 alkyl) C (O) O (C 1-6 alkyl) 1 N (C 1-6 alkyl) C (O) OH, NHC (O) O) C 1-6 alkyl), OC (O) NH (C 1-4 alkyl), OC (O) N (C 1-4 alkyl) 2 '(1-piperidyl) (CH 2) 2 O (C), (4-morpholine) ( CH 2) 2 O (O) 1- (1-pyrrolinyl) (CH 2) MOC (O), (I-Imidazoyl) (CH 2) 2 ^ O 1 (Pyrazolyl) (CH 2) 2 O, (triazolyl) (CH 2) 2 OC (O) or Ar (CH 2) 1 O; R9 at each occurrence is independently selected from H1 C1-4 alkyl, CF3l CF2CH3l (CH2) 2j1OH, (CH2 OC4 alkyl), (CH2) ^ NH (C1-6 alkyl), (CH2) 1 ^ NiC1.6 alkyl) 2, ( I-Pyrrolidin) (CH 2) 1- (1-piperidyl) (CH 2) 4. (4-morpholin) (CH 2) 14.4, C (O) C1. alkyl, C (O) (CH 2) 1 ^ OH 1 C (0) (CH 2) ^ 0 C ^ alkyl, C (O) (CH 2) 1 jNN (C 3 alkyl) 2l (1-ρίΓΓθΙίηίΐ3) (ΟΗ2) ^ 0 (0 ), (1-ptperidyl) (CH 2) 4 C (O), (4-morphophen) (CH 2) 4 C (O), C (O) OC 1. Alkyl, C (O) 0 (CH 2) 2 C 10 C 4 alkyl, C (O) O (CH 2) 2 N (C 1-4 alkyl) 2 '(1-pyrrolinyl) (CH 2) 2. 40C (0), (1-piperidyl) (CH 2) 2X> C (0). (4-morpholine) (CH 2) 2 · OC (0), (CH 2) 1 · C (O) OC 1. ealkyl or Ar (CH 2) 1 4; R10 represents H, C1-4 alkyl or one or two F; R111 R12 independently represent H1 to 4 equal to or from different groups selected from F, Cl, Br, I, CN, NO2, CF3 OH1 NH2, C1-4 alkyl1 OC1-4 alkyl, OCF3, OCF2CH3, NH (C1-4 alkyl) , N (C 1 -C 6 alkyl) 2 1 OC (O) C 1 -C 7 alkyl NHC (O) H 1 NHC (O) C 1 -C 6 alkyl N 1 -C 4 alkylC 1 O 6 C 4 alkyl, C (O) C 1 -C 6 alkyl C (O) NHC 1 C 3 C ) N (C 1 -C 6 alkyl) 1 COOH 1 C (O) C 1 -C 6 alkyl, S (O) C 1 -C 3 alkylal SO 2 Cl 1 4 alkylal 2 SO 2 NHCl. 4alkyl or SO 2 N (C 1-6 alkyl); A, B independently represent aromatic ring; Ar is phenyl, substituted phenyl or pyridyl; D represents O1 S1 NH or methylene; in, η independently represent an integer from 0 to 4. 9. Cancer cells according to claim 8, characterized by the fact that EGFR is overexpressed in said cancers. 10. Cancer cells according to claim 8, characterized by fact that Her-2 is overexpressed in those cancers. A preparation comprising at least one compound of formula (I) or pharmaceutically acceptable salts or hydrates thereof, characterized in that said compound or pharmaceutically acceptable salts or hydrates thereof is used as a medical active ingredient and processed with necessary and pharmaceutically acceptable excipients for a suitable dosage form, and said compound or pharmaceutically acceptable salts or hydrates thereof used as a medical active ingredient may treat or prevent disease by oral administration, intravenous injection, intraperitoneal injection, subcutaneous injection, intramuscular injection. , nasal drip, eye drops, inhalation, anal administration, vaginal administration, or epidermal administration, (I) X represents N1 C-CN or CH; Y represents CH 2, S, O or N-R 9; R11 R31 R7 and R8 independently represent H1 C1-4 alkyl; R 2 represents a group selected from formula (II), (III), (IV), (V), (VI), (VII) or (VIII); <formula> formula see original document page 52 </formula> R, Re independently represent H1 C1-4 alkyl1 OC1-4 alkyl, OH1 F1 Cl1 Br, OCF3 or trifluoromethyl; R5 at each occurrence is independently selected from H1 F1 C1-alkylalkyl OH1 OC1 -alkyl OCF3 OCF2CH3l NH2, NH (C1-4 alkyl) 1 N (C1-4 alkyl) 2l 1-pyrrolinyl, 1-piperidyl, 4-morpholine, Cl Br, trifluoromethyl, O (CH 2) 2 C 10 C 4 alkyl, O (CH 2) 2 40 CF 3 O (CH 2) 2 NH (C 1-6 alkyl). O (CH 2) 2 N (C 1-6 alkyl) 2L (1-pyrrolinyl) (CH 2) 2 O (0-pipendyl) (CH 2) 2 O (4-morpholine) (CH 2) 2 O, NHC (O) H 1 NHC (O) (C 1-6 alkyl), N (C 1-6 alkyl) C (O) (C 1-6 alkyl), O (CH 2) 2 N-OH 1 N (C 1-6 alkyl) C (O) O (C 1-6 alkyl) 1 NiCl. .6 alkyl) C (O) 0H, NHC (O) O) C 1-6 alkyl), 0C (0) NH (C 1-6 alkyl), OC (O) N (C 1-6 alkyl) 2, (1-piperidyl) (CH 2) 2 [Deg.] C (0), (4-morpholine) (CH 2) 2. (I-Pyrrolidin) (CH 2) 2 O (O) 1- (1-imidazolyl) (CH 2) 2 O. (Pyrazolyl) (CH 2) 2 O, (triazolyl) (CH 2) 2 O (0) or Ar (CH 2) 4) 0; R 9 at each occurrence is independently selected from H, C1-4 alkyl, CF3, CF2CH3, (CH2) 2 ^ OH1 (CH2) 1 ^ OC, .alkyl, (CH2) ^ NH (C1-4 alkyl), (CHz (NtC, 6alkyl) 2, (1-pyrrolinyl) (CH 2) M. (I-Piperidyl) (CH 2) 1. (4-morpholine) (CH 2) 1 C (O) C 1. and real. C (O) (CH 2) mOH 1 C (O) (CH 2) 4 O 4 alkylHa, C (O) (CH 2) 4 N (C 2 alkyl) 2 1 (1-pITlinyl) (CH 2) 4 C (0), ( 1-piperidyl) (CH 2) (C (O), 4-morpholine (CH 2 Cl 2). C (O) OC1. Alkyl, C (O) O (CH 2) 21 C 14 H 14 Cl 2, C (O) 0 (CH 2) 2 N (C 1-6 alkyl) 2, (1-pyrrolinyl) (CH 2) 2. 40 ° C (0), (1-piperidyl) (CH 2) 2 ° C (0), (4-morpholine) (CH 2) 2 ° C OC (0), (CH 2) 1 ° C (O) OC 1. ealkyl or Ar (CH 2) 1%; R10 represents H, C1-4 alkyl or one or two F; R111 R12 independently represent H1 to 4 equal or from the groups thereof from F, Cl, Br, 1, CN, NO2, CF3, OH, NH2, C1-4 alkyl, OC4 alkyl, OCF3, OCF2CH3, NH (C1-4 alkyl) 1 N (C1-4 alkyl) 2, OC (O) C1-4 alkyl, NHC (O) H1 NHC (O) C1-4 alkyl N (C1-4 alkyl) C (O) alkyl, C (O) OC1 ^ Alkyl, C (O) NHCl1 Alkyl, C (O) N (C1 ^-Alkyl) 1 COOH1 C (O) C1qui-Alkyl1 S (O) C1-Alkyl, SO2ClC Alkyl, SO2NHCl. 4 alkyl or SO 2 N (C 1-6 alkyl); A, B independently represent aromatic ring; Ar is phenyl, substituted phenyl or pyridyl; D represents O1 S1 NH or methylphene; and independently represent an integer from 0 to 4. The preparation comprising at least one compound of formula (J) or pharmaceutically acceptable salts or hydrates thereof as claimed in claim 11, wherein said preparation may be used to treat cancer. The types of cancer of claim 8 or 12, characterized in that they comprise breast cancer, kidney cancer, bladder cancer, oral cancer, Iaringeo cancer1 esophageal cancer, gastric cancer, colorectal cancer, ovarian cancer, lung cancer and head and neck cancer. The preparation comprising at least one compound of formula (I) or the pharmaceutically acceptable salts or hydrates thereof of claim 11, wherein said preparation may be used to treat or prevent physiological disorder caused by inhibition of protein activity. tyrosine kinase in mammals. The physiological disorder of claim 1 or 14, characterized in that said physiological disorder comprises psoriasis, pneumonia, hepatitis, nephritis, pancreatitis, diabetes and the types of cancer. A method of preparing a compound of formula (I) of claims 1, 8 or 11, wherein X represents N, C-CN or CH; Y represents CH 21 S 1 O or N-R 9; R1. R3, R7 and R8 independently represent H, C1-4 alkyl; R2 represents a group selected from formula (II), (III) 1 (IV) 1 (V), (VI) 1 (VII) or (VIII); <41> formula see original document page 54 </b> R41 R6 independently represent H1 C1-4 alkyl, OClJ6 alkyl, OH1 F, Cl1 Br, OCF3 or trifluoromethyl; R5 at each occurrence is independently selected from H1 F1 C1-4 alkylalkyl OH1 OC1-4 alkyl OCF31 OCF2CH3l NH2l NH (C1-6 alkyl) 1 N (C1-6 alkyl) 2l 1-pyrrolinyl, 1-piperidyl, 4-morpholine, Cl1 Br, trifluoromethyl . O (CH2) 2jOCOC1alkyl O (CH2) 2 ^ OCF3.0 (CH2) 2 ^ NH (C1 -C4 alkyl), 0 (CH2) 2 ^ N (C1 -C4 alkyl) 2, (1-pyrrolinyl) (CH2) 2 O, (1-piperidyl) (CH 2) 2 O (4-morpholine) (CH 2) 2 O, NHC (O) H 1 NHC (O) (C 1 -C 6 Alkyl) -1 NiCl. 6 alkyl) C (O) (C 1-6 alkyl), O (CH 2) 4 OH 1 N (C 1-6 alkyt) C (O) 0 (C 1-6 alkyl), N (C 1-6 alkyl) C (O) OH, NHC (O ) O) C 1-6 alkyl), OC (O) NH (C 1-4 alkyl), OC (O) N (C 1-6 alkyl) 2, (1-piperidyl) (CH 2) 2 O (C), (4-morpholine ) (CH 2) 4 OC (0), (I-Pyrrolidine) (CH 2) 4 OC (O), (1-imidazolyl) (CH 2) 2 JO (pyrazolyl) (CH 2) 2 JO (triazolyl) ( CH 2) 2., OC (O) or Ar (CH 2) 1 O; R 9 at each occurrence is independently selected from H 1 C 4 alkyl, CF 3, CF 2 CH 3, (CH 2) 2 H OH (CH 2 O 3 alkyl), (CH 2 NH 1 C 4 alkyl). 6 (alkyl) 2 -1- (1-pyrrolinj) a) (CH 2) (4, (1-piperidyl) (CH 2) f (4-morpholine) (CH 2), 1 C (O) Cl. CH 2) 1 H 2 O 1 CH 2 CH 2 O 2 alkyl C (O) (CH 2) 1 N (C 1 -C 4 alkyl) 2 1 (1-pyrrolinyl) (CH 2) 1 C (O). (I-Piperidyl) (CH 2) 1 4 C (O) 1'-morpholine (CH 2 X 1 O), C (O) OC 1. is alkyl, C (O) 0 (CH 2) 2 O 4 C 4 alkyl. C (0) 0 (CH 2) 2 J, N (Cl 1 6 alkyl) 2 -1 (1-pyrrolinyl) (CH 2) 2-40C (0), (1-piperidyl) (CH 2) 2 O (0), (4-morpholine) (CH 2) 2 · OC (0). (CH 2) 1 C (O) OC 1 C 6 alkyl or Ar (CH 2) 1 H; R10 represents H1 C1-4 alkyl or one or two F; R111 R12 independently represent H1 to 4 equal or from different groups selected from F1 Cl, Br, I, CN1 NO2 1 CF3 OH OH1 NH2 C1 C1 alkyl1 OC1 alkylalkyl OCF3CH3 NH (C1-5 alkyl), N (C1-5 alkyl) ) 2, OC (O) C 1-6 alkyl, NHC (O) H, NHC (O) C 1-6 alkyl N 1 -C 4 alkylC 1-10 alkyl. C (O) C 1-6 alkyl, C (O) NHC 1-6 alkyl C (O) N (C 1-4 alkyl) 1 COOH 1 C (O) C 1-6 alkylS S (O) C 1-4 alkylalkyl SO 2 Cl 1 ^ alkylal SO 2 NHC 1. 4 alkyl or SO 2 N (C 1 -C 10 Alkyl) A, B independently represent aromatic ring; Ar is phenyl, substituted phenyl or pyridyl; D represents O1 S1 NH or methylene; and m, η independently represent an integer from 0 to 4; and the method comprises the steps of: c1) hydrolyzing the reaction product containing the compound of formula (Xi) with Ri5 (R13) P (O) CH (R8) COOR14 or Ar3P = CR8CO2R14 to obtain the compound of (IX) Characterized in that R131 R15 independently is C1-4 alkyl, OC1-4 alkyl, phenyl, substituted phenyl, phenoxy or substituted phenoxy, R14 represents C1-4 alkyl, and the definition of Y is the same as in claim 1 except that Y represents ΝΗ ; <formula> formula see original document page 55 </formula> 2. contacting the compound of formula (X), postponed chloride or anhydride thereof with the compound of formula (IX) in the presence of condensing agent to obtain the compound of formula (I) transforming the compound of formula (I) from step 2) wherein Y represents N-R 9 and R 9 represents (CH 3) 30 (C (0)) into the compound of formula (XII) under acidic conditions, characterized in that the definitions of R11 R21 R31 R41 R51 R51 R61 R71 R81 R101 R111 R121 A1 B1 D1 X. Y1 m and η are the same as in claim 1; <formula> formula see original document page 56 </formula> 4. contacting the compound of formula (XII) with XR9 to obtain the compound of formula (I), characterized in that the definition of R9 is the same as that for formula (I), and X represents Cl1 Br, I1 OMs or Ots.