MXPA06007284A

MXPA06007284A - Novel phenylalanine derivative

Info

Publication number: MXPA06007284A
Application number: MXPA/A/2006/007284A
Authority: MX
Inventors: Hajime Ito; Yasuhiro Tanaka; Noriyasu Kataoka; Tatsuya Okuzumi; Kazuyuki Sagi; Tadakiyo Nakagawa; Tatsuhiro Yamada; Shunsuke Kageyama; Yoichiro Shima; Masayuki Sugiki; Itsuya Tanabe; Tamotsu Suzuki; Akira Narayama; Kazuyuki Ubukata; Kenji Shinkai; Misato Noguchi; Ayatoshi Andou; Yoriko Yamamoto; Koichi Futa; Tokumasu Munetaka
Original assignee: Ajinomoto Co Inc
Priority date: 2003-12-22
Filing date: 2006-06-22
Publication date: 2006-12-13

Abstract

A specific phenylalanine derivative or its analog showing an activity of inhibiting alpha4 inntegrin is used as a remedy for various diseases in which alpha4 inntegrin participates.

Description

BY, KG, KZ, - • BG, cp, CY, 1E.1S, IT. LT, OAPI (BF, BJ MR, NE, SN, * tt &H? #S: NOVEDOUS DERIVATIVES OF FEN1LALAN1NA FIELD OF THE INVENTION The present invention relates to novel phenylalanine derivatives and the use of phenylalanine derivatives as medicines. The present invention also relates to compounds useful as therapeutic agents or preventive agents of inflammatory diseases in which the adhesion process dependent on integrin a 4 participates in the pathology. It was reported that integrins 4 participate in rheumatoid arthritis, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), systemic lupus erythematosus, multiple sclerosis, Sjögren's syndrome, asthma, psoriasis, allergy, diabetes mellitus, cardiovascular diseases, sclerosis arterial pressure, restenosis, tumor proliferation, tumor metastasis and transplant rejection. The compounds of the present invention which have an antagonistic effect on integrins a 4 are useful as therapeutic agents or preventive agents for the diseases described above. In addition, it has been reported that integrins at 4 have the potential to participate in preeclampsia, cerebral ischemic disorders (including cerebral infarction), systemic sclerosis, ankylosing spondylitis, psoriatic arthritis, sarcoidosis, giant cell arteritis, uveitis, fibroid lung, lung disease chronic obstructive disease, osteoarthritis, Alzheimer's, spinal cord injury, traumatic brain injury, primary sclerosing cholangitis, liver cirrhosis caused by hepatitis C, chronic active hepatitis, sacroiliitis, ankylosing spondylitis, episcleritis, iritis, uveitis, erythema nodosum, pyoderma gangrenosum and autoimmune hepatitis. The compounds of the present invention are also useful as therapeutic agents or preventive agents for the diseases described above. In addition, the compounds of the present invention are useful as therapeutic agents or preventive agents not only for the aforementioned diseases but also for diseases in which intakes to 4 are impotent to participate in the pathology. The present invention also relates to the methods for the production of the novel phenylalanine derivatives mentioned above and the intermediates of the synthesis thereof.

BACKGROUND OF THE INVENTION In inflammatory reactions, it is generally understood that when a microorganism invades a tissue or when the tissue of the injured, the leukocytes play an important role for the exclusion of the microorganism or for the repair of the injured tissue. It is also widely understood that in such cases, usually leukocytes in Circulation in the blood must pass through the vascular wall and must again supply the injured tissue. It has been elucidated that the infiltration of leukocytes from the blood vessel into the tissue is carried out by integrin molecules which are a group of heterodimeric proteins that are expressed in leukocytes. The integrin molecules are classified in at least 8 subfamilies (subfamilies ß 1 to ßd) depending on the β chains of them. Typical known subfamilies are the β1 and β3 subfamilies involved in the adhesion of cellular ingredients to the extracellular matrix such as collagen and fibronectin; subfamily ß 2 involved in cell-cell adhesion in the immune system; and subfamily ß 7 which mainly participates in the infiltration of leukocytes into mucosal tissues (non-patent literature 1). As for the integrins a 4 described above, two types of molecules thereof are known. There is the molecule VLA-4 (very late antigen 4) that belongs to the subfamily ß 1 and that includes the chain 4 ß 1 and the molecule LPAM-1 (adhesion molecule HEV of the Peyer's plate of lymphocyte-1) that belongs to subfamily ß 7 and comprising the chain at 4 ß 7. Usually the majority of circulating leukocytes in the blood have only a few adhesion affinities for vascular endothelial cells and can not move out of blood vessels . However, the lymphocytes that mainly comprise the T cells and the B cells are able to move out of the blood vessels through a phenomenon called lymphocyte self-direction where these move from the blood to the lymphoid tissue through the wall of the blood vessels and subsequently these can return to the blood through the lymphatic vessels under physiological conditions. It is known that LPAM-1 molecules participate in lymphocyte autodirection towards the lymphoid tissue of an intestinal tract such as Peyer's plaque (non-patent literature 2). On the other hand, when inflammation occurs, vascular endothelial cells are activated by cytokines and chemokines released from inflamed tissue, the expression of a group of cell surface antigens (adhesion molecules) involved in the adhesion of the leukocytes to the vascular endothelial cells, and many leukocytes infiltrate out of the blood vessel into the inflamed tissue through the adhesion molecules. Since cell surface antigens in vascular endothelial cells participate in the adhesion of leukocytes, it is known that E-selectin (adhesion molecule that participates mainly in the adhesion of neutrophils), ICAM-1 and VCAM-1 which mainly participate in the adhesion of lymphocytes, and MAdCAM-1 which mainly participates in the adhesion of lymphocytes in the lymphoid tissue of an intestinal tract such as Peyer's plaque (non-patent literature 1). It was reported that in those adhesion molecules, VCAM-1 acts as a ligand for both VLA-4 and LPAM-1 and that MAdCAM-1 acts as the ligand for LPAM-1. As a ligand of both VLA-4 and LPAM-1, fibronectin is also known, which is a type of extracellular matrix (non-patent literature 1). The subfamily of β 1 integrin to which VLA-4 belongs comprises at least 6 integrins (VLA-1 to VLA-6) using extracellular matrices such as fibronectin, collagen and laminin as the ligands. Many of the integrins use extracellular matrices as ligands, such as VLA.5, the subfamily β3 and the subfamily β5, recognize the sequence arginine-glycine-aspartic acid (RGD) in fibronectin, vitronectin, tenascin and osteopontin . On the other hand, in the interaction of VLA.4 and fibronectin, the RGD sequence participates only as a CS.1 peptide segment comprising leucine-aspartic acid-valine (LDV) as the participating core sequence (non-patent literature 3) . Clemens et al. found a sequence similar to the LDV in the amino acid sequence of VCAM-1 and MAdCAM-1. It has been elucidated that a variant obtained by partially modifying the CS.1-like sequence of the molecules VCAM.1 and MAdCAM.1 can not interact with VLA-4 or with LPAM-1 (non-patent literatures 4 to 7) . Therefore, it was found that the sequence similar to CD-1 is important for the interaction of VLA-4 / LPAM-1 and VCAM-1 / MAdCAM-1. It was also reported that the cyclic peptide having the structure similar to CS-1 is antagonistic to both the interaction of VLA-4 or LPAM-1 with VCAM-1, MAdCAM or the peptide CS-1 (non-patent literature 8). The aforementioned facts indicate that all interactions of integrin to 4 and VCAM-1. MAdCAM-1 or fibronectin can be blocked by the use of an integrin ce 4 antagonist (the term "antagonist" of integrin at 4"in the specification indicates an antagonistic substance to integrin a4ß1 and / or a4ß7.) It is also known that the expression of VCAM-1 in vascular endothelial cells is caused by inflammatory factors such as LPS, TNF -a or IL-1 and that when inflammation occurs, the infiltration of leukocytes from the blood vessel into the tissue is carried out by the adhesion mechanism of VLA-4A CAM-1 (non-patent literature 9 a 11) Because VLA-4 is expressed on the surface of activated lymphocytes, monocytes, eosinophils, mast cells and neutrophils, the adhesion mechanism of VLA-4V / CAM-1 plays an important role for the infiltration of those cells towards inflamed tissue It was reported that VLA-4 is expressed in various sarcoma cells such as melanoma cells, and it was also elucidated that the adhesion mechanism of VLA-4 / VCAM-1 participates in the metastasis of these tumors. By investigating the expression of VCAM-1 in various pathological tissues, it became evident that the adhesion mechanisms of this VLA-4A / CAM-1 participate in various pathological stages. That is, it was reported that in addition to the activated cells of the vascular endothelium, the expression of VCAM-1 is increased in inflamed tissues in patients with autoimmune diseases such as in the rheumatoid synovium (literature no 12 and 13), lungs and epithelium of the respiratory tract in asthma (non-patent literature 14) and allergic diseases (non-patent literature 15), systemic lupus erythematosus (non-patent literature 16), Sjogren's syndrome (non-patent literature) patent 17), multiple sclerosis (non-patent literature 18) and psoriasis (non-patent literature a 19); atherosclerotic plaques (non-patent literature 20), intestinal tissues of patients with inflammatory bowel diseases such as Crohn's disease and ulcerative colitis (non-patent literatures 21 and 22), inflamed tissue of the Langerhans islet of patients with diabetes ( non-patent literature 23) and implants during the rejection of heart or kidney transplantation (non-patent literatures 24 and 25). The adhesion mechanism of VLA-4A CAM-1 participates in these various diseases. There are many reports that show that in vivo administration of the VLA-4 or VCAM-1 antibody was effective in the improvement of the diseases of the animal models with those inflammatory diseases. Specifically, Yednock et al. and Barón et al. reported that in vivo administration of an antibody against integrins to 4 was effective in controlling the incidence ratio or in the control of encephalomyelitis in experimental autoimmune encephalomyelitis models, for example multiple sclerosis models (non-literature Patent 26 and 27). Zeidler et al. reported that in vivo administration of an antibody against integrin a 4 was effective in controlling the incidence ratio of arthritis by mouse collagen (rheumatoid models) (non-patent literature 28). The therapeutic effect of an antibody against integrin a 4 in asthma models was reported by Abraham et al. and SAgara et al. (Literatures not of patent 21 and 30). The effect of an antibody against the Integrin at 4 in inflammatory bowel disease models was reported by Podolsky et al. (non-patent literature 31). The effect of an antibody against integrin was reported to 4 and that against. VCAM antibody in models of insulin-dependent diabetes by Barón et al. (non-patent literature to 32). It was evident with baboon models that restenosis of a blood vessel after angioplasty is carried out because arteriosclerosis can be inhibited by administration of the integrin antibody to 4 (non-patent literature 33). It was also reported that the integrin a 4 or the VCAM antibody is effective in inhibiting the rejection of an implant or in the inhibition of cancer metastasis (non-patent literatures 34 and 35). The therapeutic effect of an antibody against V.CAM-1 in inflammatory bowel disease models was reported by Sans et al. (non-patent literature 44). As described above, unlike VCAM-1, MAdCAM-1 which is a ligand of LPAM-1 is constitutively expressed in elevated endothelial venules (HEV) in the intestinal mucosa, mesenteric lymph nodes, Peyer's plaque and spleen and participates in the self-direction of mucosal lymphocytes. It is also known that the mechanism of adhesion by LPAM-1 / MAdCAM-1 not only has physiological roles in the self-direction of lymphocytes but also participates in some pathological processes. Briskin et al reported an increase in the expression of MAdCAM-1 in inflamed regions in intestinal tracts of patients with inflammatory bowel diseases such as Crohn's disease and Ulcerative colitis (non-patent literature 36). Hanninen et al. reported that induction of expression is observed in inflamed tissue of the Langerhans islet of the NOD mouse which is a model of insulin-dependent diabetes (non-patent literature 37). The fact that the adhesion mechanism by LPAM-1 / MAdCAM participates in the progression of diseases is evident from the fact that the conditions of the mouse models with inflammatory bowel disease (non-patent literature 38) and the NOD mouse models described above are improved by the live administration of the antibody to MAdCAM or to the antibody to β-7 integrin (non-patent literatures 39 and 40). The aforementioned facts indicate that the possibility of using the blocking of the adhesion mechanism by VLA-4? / CAM-1, LPAM-1? / CAM-1 or LPAM-1 / MAdCAM-1 by a suitable antagonist is effective in the treatment of the chronic inflammatory diseases described above. With respect to the therapeutic effects of the appropriate antagonist (s), these can be ensured by the animal models described in the aforementioned literatures or the other literatures such as non-patent literature 45 and 46. The use of the antibody in against VLA-1 as the VLA-4 antagonist is described in patent literatures 1 to 4. Peptide compounds such as VLA-4 antagonists are described in patent literature 5 to 8. Useful amino acid derivatives such as VLA-4 antagonists are described in patent literature 9 to 13. The integrin inhibitor a 4 of low molecular weight which can be administered orally is described in patent literatures 14 and 15. [Patent Literature 1] WO93 / 13798 [Patent Literature 2] WO93 / 15764 [Patent Literature 3] WO94 / 16094 [Literature Patent 4] WO95 / 19790 [Patent Literature 5] WO94 / 15958 [Patent Literature 6] WO95 / 15973 [Patent Literature 7] WO96 / 00581 [Patent Literature 8] WO96 / 06108 [Patent Literature 9] WO99 / 10312 [Patent Literature 10] WO99 / 10313 [Patent Literature 11] WO99 / 36393 [Patent Literature 12] W099 / 37618 [Patent Literature 13] WO99 / 43642 [Patent Literature 14] WO02 / 16329 [Literature of patent 15] WO03 / 070709 [Non-Patent Literature 1] Shimidzu et al. Adv. Immunol. 72: 325-380, 1999 [Non-Patent Literature 2] Butcher et al. Adv.

Immunol. 72: 209-253, 1999 [Non-Patent Literature 3] Pulido et al. J. Biol. Chem. 266: 10241-10245, 1991 [Non-patent literature 4] Clements et al. J. Cell Sci. 107: 2127-2135, 1994 [Non-Patent Literature 5] Vonderheide et al. J. Cell Biol. 125: 215-222, 1994 [Non-patent literature 6] Renz et al. J. Cell Biol. 125: 1395-1406, 1994 [Non-Patent Literature 7] Kilger et al. Int. Immunol. 9: 219-226, 1997 [Non-Patent Literature 8] Valderslice et al. Immunol. 158: 1710-1718, 1997 [Non-Patent Literature 9] Elices, Celi 60: 577-584, 1990 [Non-Patent Literature 10] Osborn et al. Cell 59: 1203-1211, 1989 [Non-patent literature 11] Issekutz et al. J. Exp. Med. 183: 2175-2184, 1996 [Non-patent literature 12] van Dinther-Janssen, Immunol. 147: 4207-4210, 1991 [Non-Patent Literature 13] Morales-Ducret et al. J. Immunol. 149: 1424-1431, 1992 [Non-Patent Literature 14] ten Hacken et al. Clin. Exp. Allergy 12: 1518-1525, 1998 [Non-patent literature 15] Randolph et al. J. Clin. Invest. 104: 1021-1029, 1999 [Non-patent literature 16] Takeuchi et al. J. Clin. Invest. 92: 3008-3016, 1993 [Non-Patent Literature 17] Edwards et al. Ann. Rheum.

Dis. 52: 806-811, 1993 [Non-patent literature 18] Steffen et al. Am. J. Pathol. 145: 189-201, 1994 [Non-Patent Literature 19] Graves et al. J. Am. Acad. Dermatol. 29: 67-72, 1993 [Non-patent literature 20] O'Brien et al. J. Clin. Invest. 92: 945-951, 1993 [Non-patent literature 21] Koizumi et al. Gastroenterol. 103: 840-847, 1992 [Non-patent literature 22] Nakamura et al. Lab. Invest. 69: 77-85, 1993 [Non-patent literature 23] Martin et al. J. Autoimmun. 9: 637-643, 1996 [Non-patent literature 24] Herskowitz et al. Am. J. Pathol. 145: 1082-1094, 1994 [Non-Patent Literature 25] Hill et al. Kidney Int. 47: 1383-1391, 1995 [Non-patent literature 26] Yednock et al. Nature 356: 63-66, 1992 [Non-patent literature 27] Baron et al. J. Exp. Med. 177: 57-68, 1993 [Non-patent literature 28] Zeidler et al. Autoimmunity 21: 245-252, 1995 [Non-Patent Literature 29] Abraham et al. J. Clin. Invest. 93: 776-787, 1994 [Non-patent literature 30] Sagara et al. Int. Arch. Allergy Immunol. 112: 287-294, 1997 [Non-patent literature 31] Podoisky et al. J. Clin. Invest. 92: 372-380, 1993 [Non-patent literature 32] Barón et al. J. Clin. Invest. 93: 1700-1708, 1994 [Non-patent literature 33] Lumsden et al. J. Vasc. Surg. 26: 87-93, 1997 [Non-Patent Literature 34] Isobe et al. J. Immunol. 153: 5810-5818, 1994 [Non-patent literature 35] Okahara et al. Cancer Res. 54: 3233-3236, 1994 [Non-patent literature 36] Briskin et al. Am. J. Pathol. 151: 97-110, 1997 [Non-patent literature 37] Hanninen et al. J. Immunol. 160: 6018-6025, 1998 [Non-patent literature 38] Picarella et al. J. Immunol. 158: 2099-2106, 1997 [Non-patent literature 39] Hanninen et al. J. Immunol. 160: 6018-6025, 1998 [Non-Patent Literature 40] Yang et al. Diabetes 46: 1542-1547, 1997 [Non-Patent Literature 41] Prog. Med. 5: 2157-2161, 1985 [Non-patent Literature 42] lyakuhin no kaihatsu (Hirokawa Shoten) vol. 7: 163-138, 1990 [Non-patent literature 43] Saishin Soyakkagaku (Technomics, Inc.) Gekan: 271-298, 1999 [Non-Patent Literature 44] Sans, M. et al. Gastroenterology 116: 874-883, 1999 [Non-Patent Literature 45] Leone, D.R. et al. J. Pharmacol. Exp. Ther 305: 1150-1162, 2003 [Non-patent literature 46] Kudlacz E. et al. J. Pharmacol. Exp. Ther 301: 747-752, 2002 [Non-Patent Literature 47] Gordon, F.H. et al.

Gastroenterology 121: 268-274, 2001 DETAILED DESCRIPTION OF THE INVENTION An object of the present invention is to provide novel compounds that have integrin antagonistic effects at 4. Another objective of the present invention is to provide compounds that have an antagonistic effect to integrin a 4, which can be administered orally. Yet another objective of the present invention is to provide a pharmaceutical composition comprising said novel compounds and a pharmaceutically acceptable carrier thereof. A further objective of the present invention is to provide a medicament containing said novel compounds. A further objective of the present invention is to provide integrin antagonists at 4. Even a further objective of the present invention is to provide therapeutic agents or preventive agents for diseases in which an adhesion process dependent on integrin a4 participates in the pathology , such as inflammatory diseases, rheumatoid arthritis, inflammatory bowel diseases (including Crohn's disease and ulcerative colitis), systemic lupus erythematosus, multiple sclerosis, Sjögren's syndrome, asthma, psoriasis, allergy, diabetes mellitus, cardiovascular diseases, arterial sclerosis, restenosis , tumor proliferation, tumor metastasis and rejection of transplants.

A further objective of the present invention is to provide therapeutic agents or preventive agents for diseases such as preeclampsia, ischemic cerebrovascular disorders (including cerebral infarction), systemic sclerosis, ankylosing spondylitis, psoriatic arthritis, sarcoidosis, giant cell arteritis, uveitis, fibroid lung, chronic obstructive pulmonary disease, osteoarthritis, Alzheimer's disease, spinal cord injury, traumatic brain injury, primary sclerosing cholangitis, liver cirrhosis caused by hepatitis C, active chronic hepatitis, sacroiliitis, ankylosing spondylitis, episcleritis, iritis, uveitis, erythema nodosum, pyoderma gangrenosum and autoimmune hepatitis. Furthermore, a further objective of the present invention is to provide therapeutic agents or preventive agents not only for the aforementioned diseases but also for diseases in which integrins a 4 have the potential to participate in the pathology. Even a further objective of the present invention is to provide the methods for the production of the aforementioned novel compounds and the synthesis of the intermediates thereof. For the purpose of solving the problems described above, the inventors have synthesized various phenylalanine derivatives and have found that the novel specific phenylalanine derivatives have excellent antagonistic activity for integrin a 4 under the presence of serum and in the total elimination of them in the Body is low. The inventors have also found that the derivatives of phenylalanine, specific, show a high area under the curve concentration in blood plasma-time (AUC) and a high bioavailability when administered orally. They also found additionally that said derivatives have an excellent activity antagonistic to integrin at 4 in vivo when administered orally.

The present invention has also been completed based on this finding. The term of the present invention makes it possible to decrease its dose and number of dose. That is, the present invention is described as follows: [1] phenylalanine derivatives of the following formula (1) or pharmaceutically acceptable salts thereof: [1] wherein R 11 represents a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms which may have a substituent (s), a morpholinoethyloxy group or a benzyloxy group which may be substituted with a methyl group (s) or a methoxy group (s), R12 and R13 each independently represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an acetyl group or a group methyloxycarbonyl, or N (R12) R13 represents a 1-pyrroiidinyl group, 1-piperidinyl group, 4-morphoiinyl group, 4-thiomorpholinyl group, 3-tetrahydrothiazolyl group or 1-piperazinyl group of which the fourth position can be substituted with a alkyl group having from 1 to 3 carbon atoms, R14 represents a methyl group or an ethyl group, Ri 'represents a hydrogen atom, a fluorine atom or a chlorine atom, Xi represents -CH (R1a) -, - CH (R1a) CH (R1b) -, CH (R1a) CH (R1b) CH (R1c) -, -CH (R1a) CH (R1b) CH (R1c) CH (R1d) -, N (R1a) CH (R1b) CH (R1c) -, -OCH (R1a) CH (R1b) -, OCH (R1a) CH (R1b) CH (R1c) - or 1,3-pyrrolidinylene, wherein R1a, R1b, R1c and R1d each independently represents a hydrogen atom or a methyl group, and Y11 and Y12 represent any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and ( F, Me). The phenylalanine derivatives of the following formula (2) or pharmaceutically acceptable salts thereof: (2) wherein R21 represents a hydroxyl group, an alkoxy group having from 1 to 6 carbon atoms, a morpholinoethyloxy group or a benzyloxy group which may be substituted with a methyl group (s) or a methoxy group (s), R22 represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms, R24 represents a methyl group or an ethyl group, R2 'represents a hydrogen atom, a fluorine atom or a chlorine atom, X2 represents -CH (R2a) -, -CH2CH2- or -N (R2a) CH2CH2-, wherein R2a represents a hydrogen atom or a methyl group, and Y2-? and Y22 represent any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me). The phenylalanine derivatives of the following formula (3) or pharmaceutically acceptable salts thereof: wherein R 31 represents a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, a morpholinoethyloxy group or a group benzyloxy which can be substituted with a methyl group (s) or a methoxy group (s), R34 represents a methyl group or an ethyl group, R3 'represents a hydrogen atom or a fluorine atom, Formula (3-1) represents a 4-morpholinyl group, a 4-thiomorpholinyl group, a 3-tetrahydrothiazolyl group, a 1-piperazinyl group of which the fourth position can be substituted with an alkyl group having from 1 to 3. carbon atom, or a 1-imidazolyl group which may be substituted with a methyl group, an ethyl group or an amino group, wherein X3 represents an oxygen atom, a hydrogen atom which may be substituted with an alkyl group which has 1 to 3 carbon atoms, or a sulfur atom, and Y3-1 and Y32 represent any of the combinations, (Cl, Cl), (CI, Me), (CI, F)) (F, F) and (F) Me). The phenylalanine derivatives of the following formula (4) or pharmaceutically acceptable salts thereof: where R? represents a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, a morpholinoethyloxy group or a benzyloxy group which may be substituted with a methyl group (s) or a methoxy group (s), the ring represents a ring benzene, a pyridine ring, a thiophene ring, a piperidine ring of which the first position can be substituted with an alkyl group having from 1 to 3 carbon atoms, a piperazine ring of which the first and / or fourth position may be substituted with an alkyl group having from 1 to 3 carbon atoms, or a pyrrolidine ring of which the first position may be substituted with an alkyl group having from 1 to 3 carbon atoms, R44 represents a methyl group or a ethyl group, and Y41 and Y42 represent any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me). The phenylalanine derivatives of the following formula (5) or pharmaceutically acceptable salts thereof: wherein R51 represents a hydroxyl group, an alkoxy group having from 1 to 6 carbon atoms, a morpholinoethyloxy group or a benzyloxy group which may be substituted with a methyl group (s) or a methoxy group (s), R54 represents a methyl group or an ethyl group, R5 'represents a hydrogen atom or a fluorine atom, R5a and R5b each independently represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms, or N (R5a ) R5b represents a 1-pyrrolidinyl group or a 1-piperidinyl group, and Y51 and Y52 represent any combination, (Cl, Cl), (CI, Me), (CI, F), (F, F) and ( F, Me). The phenylalanine derivatives of the following formula (6) or pharmaceutically acceptable salts thereof: where R6? represents a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, a morpholinoethyloxy group or a benzyloxy group which may be substituted with a methyl group (s) or a methoxy group (s), A6 represents any of the following formulas (6-1) to (6-6): . { ß-, > (-2: ^ -3.}. Te- *? (6 - 5) (6-6) and Y6-? and Yß2 represent any of the combinations, (Cl, Cl), (CllMe), (Clf F) I (F, F) and (FIMe). The phenylalanine derivatives of the following formula (7) or pharmaceutically acceptable salts thereof: 171 wherein R71 represents a hydroxyl group, an alkoxyl group having 1 to 6 carbon atoms, a morpholinoethyloxy group or a group benzyloxy which can be substituted with a methyl group (s) or a methoxy group (s), R74 represents a methyl group or an ethyl group, R7 represents an alkynyl group having from 3 to 5 carbon atoms, a cycloalkylmethyl group which has from 4 to 6 carbon atoms, a cycloalkyl group having from 3 to 6 carbon atoms, or a propyl group, and Y71 and Y 2 represent any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F ) and (F, Me). The phenylalanine derivatives of the following formula (8) or pharmaceutically acceptable salts thereof: ífi) where R8? represents a hydroxyl group, an alkoxy group having from 1 to 6 carbon atoms, a morpholinoethyloxy group or a benzyloxy group which may be substituted with a methyl group (s) or a methoxy group (s), or a hydroxyethyl group, R82 represents a methyl group or an ethyl group, Rs4 represents a methyl group or an ethyl group, n8 represents an integer from 0 to 2, and Yβ? and d2 represent any of the combinations, (Cl, Cl), (CI, Me), (CI, F), (F, F) and (F, Me). The phenylalanine derivatives of the following formula (9) or pharmaceutically acceptable salts thereof: (9) wherein R91 represents a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, a morpholinoethyloxy group or a benzyloxy group which may be substituted with a methyl group (s) or a methoxy group (s) , R92 represents a hydroxyl group, an alkoxy group having from 1 to 6 carbon atoms, an amino group or a benzyloxy group which may be substituted with a methyl group (s) or a methoxy group (s), Rg4 represents a methyl group or an ethyl group, X9 represents an atomic bond, -CH2-, -CH2CH2- or -CH = CH-, and Y91 and Y92 represent any combination, (Cl, Cl), (Cl, I ), (CI, F), (F, F) and (F, Me). The phenylalanine derivatives of the following formula (10) or pharmaceutically acceptable salts thereof: (10.) wherein R-101 represents an alkoxy group having from 2 to 6 carbon atoms or a morpholinoethyloxy group, R10 represents a methyl group or an ethyl group, R104 represents a methyl group or an ethyl group, and Y101 and Y102 represent any of the combinations, (Cl, Cl), (Cl, Me), (CI, F), (F, F) and (F, Me) The phenylalanine derivatives of the following formula (11) or pharmaceutically acceptable salts thereof: (ID wherein Rm represents an alkoxy group having from 1 to 6 carbon atoms or a morpholinoethyloxy group, R114 represents a methyl group or an ethyl group, and Yin and Y112 represent any combination, (Cl, Cl), (CI, Me), (Cl, F), (F, F) and (F, Me). The phenylalanine derivatives of the following formula (12) or pharmaceutically acceptable salts thereof: (12) wherein R12 represents an alkoxy group having from 1 to 6 carbon atoms or a morpholinoethyloxy group, R? 24 represents a methyl group or an ethyl group, and A represents any of the following formulas (12-1) and (12-2): p? _? ) (1 2 -2 - The phenylalanine derivatives of the following formula (13) or pharmaceutically acceptable salts thereof: wherein R131 represents a hydroxyl group, an alkoxy group having from 1 to 6 carbon atoms, a morpholinoethyloxy group or a benzyloxy group which may be substituted with a methyl group (s) or a methoxy group (s), R13a and R13b each independently represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or N (R13a) R13b represents a 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group, 4-thiomorpholinyl group , 3-tetrahydrothiazolyl group or 1-piperazinyl group of which the fourth position can be substituted with an alkyl group having from 1 to 3 carbon atoms, and Y13? and Y132 represent any of the combinations, (Cl, Cl), (CI, Me), (CI, F), (F, F) and (F, Me). The phenylalanine derivatives of the following formula (14) or pharmaceutically acceptable salts thereof: wherein R141 represents a hydroxyl group, an alkoxy group having from 1 to 6 carbon atoms or a morpholinoethyloxy group, R144 represents a methyl group or an ethyl group, a hydroxyl group in a quinazolinedione ring is located in the sixth or seventh position of the ring, and Y? 4? and Y? 42 represent any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me). A pharmaceutical composition comprising a pharmaceutically acceptable phenylalanine derivative or sai thereof according to any of the aforementioned [1] to [50] as a pharmaceutically acceptable active ingredient and vehicle thereof. An α4 integrin antagonist comprising a phenylalanine derivative or a pharmaceutically acceptable salt thereof according to any of the aforementioned [1] to [50] as an active ingredient. A therapeutic agent or preventive agent for inflammatory diseases in which the adhesion process depends on the integrin to 4 participates in the pathology, which comprises a phenylalanine derivative or a pharmaceutically acceptable sai thereof in accordance with any of the aforementioned [1] to [50] as an active ingredient. A therapeutic agent or preventive agent for rheumatoid arthritis, inflammatory bowel diseases (including Crohn's disease and ulcerative colitis), systemic lupus erythematosus, multiple sclerosis, Sjogren's syndrome, asthma, psoriasis, allergy, diabetes mellitus, cardiovascular diseases, arterial sclerosis, restenosis, tumor proliferation, tumor metastasis and rejection of transplants, which contain a phenylalanine derivative or a pharmaceutically acceptable salt thereof according to any of the aforementioned [1] to [50] as an active ingredient. A therapeutic agent or preventive agent for preeclampsia, ischemic cerebrovascular disorders (including cerebral infarction), systemic sclerosis, ankylosing spondylitis, psoriatic arthritis, sarcoidosis, giant cell arteritis, uveitis, fibroid lung, chronic obstructive pulmonary disease, osteoarthritis, Alzheimer's disease, spinal cord injury, traumatic brain injury, primary sclerosing cholangitis, liver cirrhosis caused by hepatitis C, chronic active hepatitis, sacroiliitis, ankylosing spondylitis, episcleritis, iritis, uveitis, erythema nodosum, pyoderma gangrenosum and autoimmune hepatitis, which comprise a derivative of phenylalanine or a pharmaceutically acceptable salt thereof conformance with any of the aforementioned [1] to [50] as an active ingredient. A therapeutic agent or preventive agent for diseases in which integrins a 4 have the potential to participate in the pathology, which comprise a phenylalanine derivative or a pharmaceutically acceptable salt thereof in accordance with any of the aforementioned [1 ] to [50] as an active ingredient. The present invention also provides the following compounds, which are the intermediates in the synthesis of the phenylalanine derivatives of the formula (1): isopropyl (S) -2- (2,6-dichlorobenzoylamino) -3- (4-nitrophenyl) ) propionate, isopropyl (S) -2- (2,6-dichlorobenzoylamino) -3- (4-aminophenyl) propionate, isopropyl (S) -3- [4- (2-amino-5-iodo-benzoylamino) -phenyl ] -2- (2,6-dichlorobenzoylamino) propionate, isopropyl (S) -2- (2,6-dichlorobenzoylamino) -3- [4- (6-iodo-2,4-dioxo-1, 2,3, 4-tetrahydro-2H-quinazolin-3-yl) phenyl] propionate, isopropyl (S) -2- (2,6-dichlorobenzoylamino) -3- [4- (6-iodo-1-methyl-2,4-dioxo -1, 2,3,4-tetrahydro-2H-quinazolin-3-yl) phenyl] propionate, (S) -3- acid. { 4- [2- (2,6-dichlorobenzoyamino) -2-isopropy-picarboxiiethyl] phenyl} -1-methyl-2,4-dioxo-1, 2,3,4-tetrahydroquinazoline-6-carboxylic acid, isopropyl (S) -2- (2,6-dichlorobenzoxylamino) -3- [4- (6- hydroxymethyl-1-methyl-2,4-dioxo-1, 2,3,4-tetrahydro-2H-quinazolin-3-yl) phenyl] propionate, isopropyl (S) -3- [4- (6-chloromethyl-1 -methyl-2,4-dioxo-1, 2,3,4-tetrahydro-2H-quinazolin-3-yl) phenyl] -2- (2,6-dichlorobenzoylamino) propionate, and isopropyl (S) -2- ( 2,6-dichlorobenzoylamino) -3- [4- (6-hydroxy-1-methyl-2,4-dioxo-1, 2,3,4-tetrahydro-2H-quinazolin-3-yl) phenyl] propionate.

PREFERRED MODALITY OF THE INVENTION An "alkyl group having 1 to 6 carbon atoms" is any straight, branched or cyclic chain group, examples are methyl, ethyl, propyl and isopropyl groups, a butyl group, an isobutyl group, a sec- butyl, a tert-butyl group, a cyclopropylmethyl group, a cyclobutyl group, a pentyl group, an isopentyl group, a hexyl group, a 1-methyl-butyloxy group, a 1, 1-dimethyl-propyl group, a cyclopropyl group, In addition, an "alkyl group having 1 to 3 carbon atoms" is any straight or branched chain group and denotes a methyl, ethyl, propyl and isopropyl group. C 1 -C 6"denotes those of which an alkyl portion is either straight, branched or cyclic, examples being methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy groups. , pentyloxy, isopentyloxy, 1-methyl-1-butyloxy, 1-1-dimethyl- propyloxy, 2-methyl-butyloxy, neopentyloxy, hexyloxy, isohexyloxy, 1-methyl-pentyloxy, 1,1-dimethyl-butyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy. An "alkoxy group having 2 to 6 carbon atoms" indicates those of which an alkyl part is either a straight chain, branched or cyclical. Examples thereof are ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, pentyloxy, isopentyloxy, 1-methyl-1-butyloxy, 1-1-dimethyl-propyloxy, 2-methyl-butyloxy, neopentyloxy, hexyloxy, isohexyloxy, 1-methyl-pentyloxy, 1,1-dimethyl-butyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyioxy. A "branched alkoxy group having from 3 to 6 carbon atoms" indicates those of which an alkyl portion is either a branched or cyclic chain. These can be substituted with a methoxy group or a hydroxyl group. Examples thereof are isopropyloxy, sec-butyloxy, tert-butyloxy, 1-methyl-1-butyloxy, 1-1-dimethyl-propyloxy, 2-methyl-butyloxy, neopentyloxy, 1-methyl-pentyloxy, 1,1-dimethyl groups. -butyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy. Among these, an isopropyloxy group, a sec-butyloxy group, a 1-methyl-1-butyloxy group, a cyclopentyloxy group and a cyclohexyloxy group, and an isopropyloxy group is particularly preferable. In an "alkynyl group having 3 to 5 carbon atoms", a carbon atom (s) having a free radical (s) is not limited to an SP atom (s). Examples thereof are 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentyl and 2-pentyl groups. In "cycloalkylmethyl group having 4 to 6 carbon atoms" denotes the cyclopropylmethyl, cyclobutylmethyl and cyclopentylmethyl groups. In "cycloalkyl group having 3 to 6 carbon atoms" denotes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.

A "piperazinyl group of which the fourth position can be substituted with an alkyl group having from 1 to 3 carbon atoms" indicates the piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-propylpiperazinyl and N-isopropylpiperazinyl groups. In a "piperazine ring of which the first and / or fourth position can be substituted with an alkyl group having from 1 to 3 carbon atoms", a substituent (s) in the nitrogen of the first and / or fourth position thereof It can be the same or it can be different from each other. Examples of the combination of substituents are (H, H), (H, Me), (H, Et), (H, Pr), (H, isoPr), (Me, Me), (Me, Et) , (Me, Pr), (Me, isoPr), (Et, Et), (Et, Pr), (Et, isoPr), (Pr, Pr), (Pr, isoPr) e (isoPr, isoPr). The fifth, sixth, seventh and eighth positions of a quinazolinedione ring indicate the following formulas: CH, -CO-R11, -COR21, -CO-R31, -CO-R41, -CO-R51, -CO-R61, -CO-R71, -CO-R81, -CO-R91, -CO-R101, -CO -R111, -CO-R121, -CO-R131, and -CO-R141 in the formulas (1) to (14) of the present invention indicate a carboxyl group or a carboxyl group in a modification of the prodrug which is converted to a carboxyl group in vivo. That is, R11, R21, R31, R41, R51, R61, R71, R81, R91, R101, R111, R121, R131, R141 (hereinafter referred to as R11 to R141) indicate a hydroxyl group or a group which is substituted with a hydroxyl group in vivo. Concrete examples of a carboxyl group in a modification of the prodrug are described in, for example, non-patent literatures 41 to 43. R11 to R141 include, for example, an alkoxy group having from 1 to 8 carbon atoms which may have a substituent (s), an aryloxy group which may have a substituent (s), an arylalkyloxy group which may have a substituent (s), a heteroaryloxy group which may have a substituent (s) and a heteroarylalkyl group of which may have a substituent (s). An alkoxy group having from 1 to 8 carbon atoms in the present invention indicates those of which an alkyl part is either a straight, branched or cyclic chain. Examples thereof are methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, pentyloxy, isopentyloxy, 1-methyl-1-butyloxy, 1-1-dimethyl-propyloxy, 2-methyl-butyloxy, neopentyloxy. , hexyloxy, isohexyloxy, 1-methyl-pentyloxy, 1,1-dimethyl-butyloxy, heptyloxy, octyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy. An alkoxy group having from 1 to 8 carbon atoms is preferably an alkoxy group having from 1 to 6 carbon atoms. Specifically, these include a methoxy group, an ethoxy group, an isopropyloxy group, a butyloxy group, a butyloxy group, a sec-benzyloxy group, a pentyloxy group and a cyclopentyloxy group. Preferably in a particular way, these include a methoxy group, an ethoxy group, an isopropyloxy group and a butyloxy group. An alkoxy group having 1 to 6 carbon atoms which has a substituent (s) preferably includes a morpholinoethyloxy group, a 2-methoxy-ethoxy group and a 1-methyl-2-methoxy-hexoxy group; an arylalkyloxy group which may have a substituent (s) preferably includes a benzyloxy group; an aryloxy group which may have a substituent (s) preferably includes a phenyloxy group and a 2-methoxy-phenyloxy group; and a heteroaryloxy group which may have a substituent (s) preferably includes a furanyloxy group. The term "aryl" in an "aryloxy group" denotes phenyl and naphthyl. The term "heteroaryl" in a "heteroaryloxy group" denotes a 5- to 8-membered mono-, bi- or tri-cyclic aromatic ring group containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of atoms of oxygen, sulfur and nitrogen as a ring atom. For example, these include pyridyl, pyridazinyl, pyrimidyl (= pyrimidinyl), pyrazinyl, furyl, thienyl, pyrrolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazoyl, tetrazolyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, purinyl, quinolyl (= quinolinyl) , isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, pteridinyl, imidazoxazolyl, imidazothiazolyl, imidazoimidazolyl, dibenzofuranyl, dibenzothienyl, carbazolyl and acridinyl.

A substituent (s) in "an alkoxy group which may have a substituent (s)" includes, for example, a morpholinyl group, a piperidinyl group, a pyrrolidinyl group, a dimethylamino group, a diethylamino group, a methoxy group, a pivaloyloxy group, an ethoxycarbonyloxy group, a cyclohexyloxycarbonyloxy group, a (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl group, a 0.2-benzoyloxyrene group and a hydroxy group. A methoxy group having a 0.2-benzoyloxyrene group as a substituent (s) denotes a 3-oxo-1,3-dihydro-2-benzofuran-1-yloxy group. A substituent (s) in "an aryloxy group which may have a substituent (s)" includes methoxy group and a methyl group. A substituent (s) in "a heteroaryloxy group which may have a substituent (s)" includes a methoxy group and a methyl group. The phenylalanine derivatives of the formulas (1) to (14) can be considered to be optical isomers and the compounds indicated in the present invention include all said optical isomers. Additionally, both the compounds formed by a particular optical isomer and the mixture of several optical isomers were included in the compounds of the present invention. Additionally, with respect to the stereochemistry of the phenylalanine portion explicitly indicated in formulas (1) to (14), the L-form is preferable. The phenylalanine derivatives of the formulas (1) to (14) can be considered to be diastereomers, and the diastereomer and the mixture of diastereomers are included in the compounds of the present invention.

When the phenylalanine derivatives of the formulas (1) to (14) of the present invention include a mobile hydrogen atom, it can be considered that the phenylalanine derivatives of the formulas (1) to (14) of the present invention include a variety of tautomeric forms and the compounds indicated in the present invention include said tautomeric forms.

Preferable examples of each sign in formula (1) R11 preferably is a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms or a benzyloxy group, and more preferably a hydroxyl group, a isopropyloxy group, a butyloxy group , a pentyloxy group, a benzyloxy group, a sec-butyl group, a tert-butyl group, a 1-methyl-butyloxy group, a 1,1-dimethyl-propyl group, a 1-methyl-pentyloxy group, a group 1 , 1-dimethyl-butyloxy, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group. A hydroxyl group and an isopropyloxy group are particularly preferable among these. An alkyl group in R12 and R13 preferably is an alkyl group having from 1 to 3 carbon atoms. R 12 is preferably a hydrogen atom, a methyl group or an ethyl group, and particularly preferably a methyl group or an ethyl group. R13 is preferably a hydrogen atom or a methyl group, and particularly preferably it is a hydrogen atom.

Among the aforementioned, N (R12) R13 is preferably a dimethylamino group, an ethylamino group or a methylamino group, or, N (R12) R13 is also preferably a 1-pyrrolidinyl group, a 1-piperidinyl group or a 4- group morpholinyl. R 14 is preferably a methyl group. R-T preferably is a hydrogen atom or a fluorine atom and particularly preferably it is a hydrogen atom. The substituent position of R-i 'is preferably the sixth or seventh position of a quinazolinedione ring. X preferably is -CH (R1a) -, -CH (R1a) CH (R1b) -, - CH (R1a) CH (R1b) CH (R1c) -, -OCH (R1a) CH (R1b) - or 1 , 3-pyrrolidinylene, and particularly preferably -CH2-. The substituting position of Xi is preferably the sixth, seventh or eighth position of a quinazolinedione ring in preferably the sixth or seventh position thereof, and particularly preferably the sixth position thereof. R1a, R1b, R1c and R1d are preferably a hydrogen atom. Both Y11 and Y12 are preferably a chlorine atom. Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [1], wherein, in formula (1), R 11 represents a hydroxyl group, an alkoxyl group having from 1 to 6 carbon atoms. carbon, a morpholinoethyloxy group or a benzyloxy group which may be substituted with a methyl group (s) or a methoxy group (s), an alkyl group at R12 and R13 represents an alkyl group having from 1 to 3 carbon atoms, and Xi represents -CH (R1a) -, -CH (R1a) CH (R1b) -, -CH (R1a) CH (R1b) CH (R1c) -, -OCH (R1 a) CH (R1b) - or 1, 3 -pyrrolidinylene. Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [2], wherein, in formula (1), Xi represents -CH (R1a) -, -CH2CH2-, -N (R1a ) CH2CH2-, or 1,3-pyrrolidinylene. Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [2], wherein, in formula (1), Xi represents -CH (R1a) -, -CH2CH2-, -N (R1a CH2CH2-, or 1,3-pyrrolidinylene, wherein R1a represents a hydrogen atom or a methyl group. Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [3], wherein, in the formula (1), R12 and R13 each independently represents a hydrogen atom, an alkyl group having from 1 to 3 carbon atoms, or N (R12) R13 represents a 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group, 4-thiomorpholinyl group, 3-tetrahydrothiazolyl group or 1-piperazinyl group of which the fourth position can be substituted with an alkyl group having 1 to 3 carbon atoms.

Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [3], wherein, in the formula (1), R 12 represents a methyl group or an ethyl group, R 13 represents a hydrogen atom, a methyl group or an ethyl group, or N (R12) R13 represents a 1-pyrrolidinyl group, a 1-piperidinyl group or a 4-morpholinyl group, R14 represents a methyl group, Ri 'represents a hydrogen atom, XT represents - CH2-, which is located in the sixth, seventh or eighth position of the quinazolinedione ring, and Y ?? and Y12 represents any of the combinations, (Ci, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me). In addition, phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [5] are preferred, wherein, in formula (1), both Yn and Y-? 2 represents a chlorine atom. Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [3], wherein, in formula (1), R 13 represents a hydrogen atom, a methyl group or an ethyl group, X? ' represents -CH2-, which is located in the sixth, seventh or eighth position of the quinazolinedione ring, and Y-n and Y? 2 represents the combination of (Cl, Cl). Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [6], wherein, in formula (1), R 13 represents a hydrogen atom, a methyl group or an ethyl group, and Xi represents -CH2-, which is located in the sixth position of the quinazolinedione ring. Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [6], wherein, in formula (1), R 13 represents a hydrogen atom, a methyl group or an ethyl group, and Xi represents -CH2-, which is located in the seventh position of the quinazolinedione ring. Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [3], wherein, in the formula (1), R 12 and R 13 each independently represent a methyl group or an ethyl group, R 14 represents a methyl group, RT represents a hydrogen atom or a fluorine atom, which is located in the sixth or seventh position of the quinazolinedione ring, Xi represents -N (CH3) CH2CH2- or 1,3-pyrrolidinium, which is located in the sixth or seventh position of the quinazolinedione ring, and Y11 and Y-12 represents the combination of (Cl, Cl). Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the ementioned [2], wherein, in the formula (1), R12 and R13 each independently represents a hydrogen atom, a methyl group or a ethyl group, or N (R12) R13 represents a 1-pyrrolidinyl group, a 1-piperidinyl group or a 4-morpholinyl group, R14 represents a methyl group or an ethyl group, Ri 'represents a hydrogen atom, Xi represents -OCH (R1a) CH (R1 b) -, wherein R1 a and R1 b each independently represents a hydrogen atom or a methyl group, and Yii and Y12 represents any combination of (Cl, Cl), (CI, Me), (Cl, F), (F, F) and (F, Me). Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [10], wherein, in the formula (1), R12 and R13 each independently represents a hydrogen atom, a methyl group or a ethyl group, R14 represents a methyl group, and Yn and Y12 represents the combination of (Cl, Cl).

Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [1], wherein, in formula (1), R 11 represents a hydroxyl group or an alkoxyl group having from 1 to 6 carbon atoms. carbon which may have a methoxy group (s) a substituent (s), R12 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R13 represents a hydrogen atom, a methyl group or a group ethyl, or N (R12) R13 represents a 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group, 4-thiomorpholinyl group, 3-tetrahydrothiazolyl group or 1-piperazinyl group of which the fourth position can be substituted with a alkyl group having from 1 to 3 carbon atoms, R14 represents a methyl group, Ri 'represents a hydrogen atom, Xi represents -CH (R1a) -, -CH (R1a) CH (R1b) -, CH (R1a) CH (R1b) CH (R1c) -, or -OCH (R1a) CH (R1b) -, which is located in the sixth position of the quinazolinedione ring, wherein each of R1a, R1 by R1c represents a hydrogen atom, and Y11 and Y12 represents the combination of (Cl, Cl). Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [1], wherein, in formula (1), R 11 represents a hydroxyl group or an alkoxyl group having from 1 to 6 carbon atoms. carbon, R12 represents an alkyl group having 1 to 6 carbon atoms, R13 represents a hydrogen atom, a methyl group or an ethyl group, R14 represents a methyl group, R ^ represents a hydrogen atom, Xi represents -CH (R1a ) - or -CH (R1a) CH (R1b) -, which is located in the sixth position of the quinazolinedione ring, wherein each of R1a and R1b represents a hydrogen atom, and Y11 and Y12 represents the combination of ( Cl, Cl). Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [1], wherein, in formula (1), R 11 represents a hydroxyl group or an alkoxyl group having from 1 to 6 carbon atoms. carbon, R12 represents an alkyl group having from 1 to 5 carbon atoms, R13 represents a hydrogen atom, R14 represents a methyl group, Ri 'represents a hydrogen atom, Xi represents -CH (R1a) -, -CH ( R1a) CH (R1b) - or - CH (R1a) CH (R1b) CH (R1c) -, which is located in the sixth position of the quinazolinedione ring, wherein each of R1a, R1 by R1 c represents an atom of hydrogen, and Y11 and Y12 represents the combination of (Cl, Cl). Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [1], wherein, in formula (1), R 11 represents a hydroxyl group or an alkoxyl group having from 1 to 6 carbon atoms. carbon, R12 represents a methyl group or an ethyl group, R13 represents a hydrogen atom, R14 represents a methyl group, Ri 'represents a hydrogen atom, XT represents -CH (R1a) -, -CH (R1a) CH (R1b ) - or CH (R1a) CH (R1b) CH (R1c) -, which is located in the sixth position of the quinazolinedione ring, wherein each of R1a, R1b and R1c represents a hydrogen atom, and Y11 and Y12 represents the combination of (Cl, Cl). Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [1], wherein, in formula (1), R 11 represents a hydroxyl group or an alkoxyl group having from 1 to 6 carbon atoms. carbon, R12 represents a methyl group, an ethyl group, an isobutyl group, a cyclopropylmethyl group, a cyclobutyl group, a sec-butyl group or an isopentyl group. R13 represents a hydrogen atom, R14 represents a methyl group, Ri 'represents a hydrogen atom, Xi represents -CH (R1a) -, which is located in the sixth position of the quinazolinedione ring, where R1a represents a hydrogen atom, and Y11 and Y12 represents the combination of (Cl, Cl ). Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [1], wherein, in formula (1), R 11 represents a hydroxyl group or an alkoxyl group having from 1 to 6 carbon atoms. carbon, R12 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R13 represents a hydrogen atom, a methyl group or an ethyl group, or N (R12) R13 represents a 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group, 4-thiomorpholinyl group, 3-tetrahydrothiazolyl group or 1-piperazinyl group of which the fourth position can be substituted with an alkyl group having from 1 to 3 carbon atoms, R 14 represents a methyl group, Ri 'represents a hydrogen atom, XT represents -O-CH (R1a) CH (R1b) - or -O-CH (R1a) CH (R1b) CH (R1c) -, which is located in the sixth position of the quinazolinedione ring, wherein each of R1a, R1 by R1 c represents a hydrogen or a methyl group, and Y11 and Y12 represents the combination of (Cl, Cl).

Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to one of the above-mentioned [1] to [17], wherein, in the formula (1), R 11 represents a branched alkoxy group having from 3 to 6 carbon atoms. Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to one of the aforementioned [1] represented by the following formulas: Preferable examples of each sign in formula (2) R21 preferably is a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms or a morpholinoethyloxy group, and particularly preferably a hydroxyl group, a methoxy group, a group ethoxy, an isopropyloxy group, a butyloxy group or a morpholinoethyloxy group. R22 is preferably a methyl group or an ethyl group. R24 is preferably a methyl group. R2 'is preferably a hydrogen atom or a fluorine atom. The substituting position of R2 'is preferably the sixth or seventh position of a quinazolinedione ring. X2 preferably is -CH2-, -NHCH2CH2- or -N (Me) CH2CH2-. The substituting position of X2 is preferably the sixth, seventh or eighth position of a quinazolinedione ring and more preferably the seventh or eighth position thereof. Both Y21 and Y22 preferably are a chlorine atom.

Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [20], wherein, in the formula (2), R22 represents a methyl group or an ethyl group, R24 represents a methyl group, R2 'represents a hydrogen atom, X2 represents -CH2-, which is located at the sixth, seventh or eighth position of the quinazolinedione ring, and Y21 and Y22 represents the combination of (Cl, Cl). Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [20], wherein, in the formula (2), R 22 represents a hydrogen atom, a methyl group or an ethyl group, R 24 represents a methyl group, R2 'represents a hydrogen atom or a fluorine atom, which is located in the sixth or seventh position of the quinazolinedione ring, X2 represents -N (CH3) CH2CH2- or -NHCH2CH2-, which is located in the sixth or seventh position of the quinazolinedione ring, and Y21 and Y22 represents the combination of (Cl, Cl).

Preferable examples of each sign in formula (3) R31 preferably is a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, a morpholinoethyloxy group or a benzyloxy group, and particularly preferably a hydroxyl group, a methoxy group, an ethoxy group, an isopropyloxy group, a butyloxy group, a pentyloxy group, a morpholinoethyloxy group or a benzyloxy group. R34 is preferably a methyl group. R3 'is preferably a hydrogen atom. The aforementioned formula (3-1) is preferably a 4-morpholinyl group, a 1-piperazinyl group of which the fourth position can be substituted with an alkyl group having from 1 to 3 carbon atoms, or a 1-imidazolyl group which can be substituted with a methyl group, an ethyl group or an amino group. The bonds in the formula (3-1) may be saturated or unsaturated. X3 in the formula (3-1) is preferably an oxygen atom or a nitrogen atom. The aforementioned formula (3-1) is preferably in particular a 4-morpholinyl group, a 4-methyl-1-piperazinyl group or a 2-amino-1-imidazolyl group. Both Y3? as Y32 are preferably a chlorine atom. Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [23], wherein the formula (3-1) represents a group 4-morpholinyl, a 4-thiomorpholinyl group, a 3-tetrahydrothiazolyl group, a group 1 - . 1-piperazinyl of which the fourth position can be substituted with a alkyl group having 1 to 3 carbon atoms, or a 1-imidazolyl group which may be substituted with a methyl group or an amino group, wherein X 3 represents an oxygen atom, a nitrogen atom which may be substituted with an alkyl group having from 1 to 3 carbon atoms, or a sulfur atom. Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [24], wherein, in the formula (3), R34 represents a methyl group, R3 'represents a hydrogen atom, the formula ( 3-1) represents a 4-morpholinyl group or a 1-piperazinyl group of which the fourth position can be substituted with an alkyl group having from 1 to 3 carbon atoms, and Y31 as Y32 represent the combination of (Ci, Cl ). Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [24], wherein, in the formula (3), R3 represents a methyl group, R3 'represents a hydrogen atom, the formula ( 3-1) represents a 2-amino-1-imidazolyl group, and Y3? as Y32 represent the combination of (Cl, Cl).

Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [23], wherein, in the formula (3), R34 represents a methyl group, R3 'represents a hydrogen atom or a hydrogen atom. fluorine, the formula (3-1) represents a 1-imidazolyl group from which the second position can be substituted with a methyl group or an ethyl group, and Y31 as Y32 represent the combination of (Cl, Cl).

Preferable examples of each sign in the formula (4) The ring is preferably a benzene ring, a pyridine ring, a thiophene ring, a piperidine ring of which the first position can be substituted with an alkyl group having from 1 to 3 carbon atoms. carbon or a piperazine ring of which the first and / or fourth position can be substituted with an alkyl group having from 1 to 3 carbon atoms. R41 preferably is a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, a morpholinoethyloxy group or a benzyloxy group, and particularly preferably a hydroxyl group, a methoxy group, an ethoxy group, an isopropyloxy group, a butyloxy group, a pentyloxy group, a morpholinoethyloxy group or a benzyloxy group. The ring is preferably a benzene ring, a piperidine ring of which the first position can be substituted with an alkyl group having 1 to 3 carbon atoms, or a piperazine ring of which the first and / or fourth position can be substituted with an alkyl group having from 1 to 3 carbon atoms, and particularly preferably a piperazine ring from which the first and / or fourth positions can be substituted with a methyl group. R44 is preferably a methyl group. So much and ? as Y42 are preferably a chlorine atom. Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [28], wherein, in the formula (4), the ring represents a piperazine ring of which the first and / or fourth position may be substituted with a methyl group, R44 represents a methyl group, and Y? and Y 2 represents the combination of (Cl, Cl).

Preferable examples of each sign in the formula (5) R51 preferably is a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms or a morpholinoethyloxy group, and particularly preferably a hydroxyl group, a methoxy group, a group ethoxy, an isopropyl group, a butyloxy group or a morpholinoethyloxy group. R54 is preferably a methyl group. Rs' is preferably a hydrogen atom. N (R5a) R5b is preferably an ethylamino group or a 1-pyrrolidinyl group.

Both Y51 and Y52 are preferably a chlorine atom. Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [30], wherein, in the formula (5), R54 represents a methyl group. R5 'represents a hydrogen atom. N (R5a) R5b represents an ethylamino group or a 1-pyrrolidinyl group, and Y51 and Y52 represent the combination of (Cl, Cl).

Preferable examples of each sign in the formula (6) RI preferably is a hydroxyl group, an alkoxyl group having from 1 to 6 carbon atoms, a morpholinoethyloxy group, or a benzyloxy group, and particularly preferably a hydroxyl group, a methoxy group, an ethoxy group, an isopropyloxy group, a butyloxy group, a group, pentyloxy, a morpholinoethyloxy group or a benzyloxy group. A is preferably any of the formulas (6-1) to (6-6). Both Y6-? as Y62 preferably they are a chlorine atom. Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [32], wherein, in the formula (6), A6 represents any of the aforementioned formulas (6-1) to (6-) 4).

Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [32], wherein, in the formula (6), R6? represents a hydroxyl group, and Y6? and Yß2 represents the combination of (Cl, Cl).

Preferred examples of each sign in formula (7) R7? preferably it is a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms or a morpholinoethyloxy group, and particularly preferably a hydroxyl group, a methoxy group, an ethoxy group, a isopropyl group, a butyloxy group or a morpholinoethyloxy group. R 4 is preferably a methyl group. R7 is preferably a 2-propynyl group, a cyclopropylmethyl group, a propyl group or a cyclopentyl group. So much and ? as Y72 preferably they are a chlorine atom. Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [35], wherein, in the formula (7), R 4 represents a methyl group. R7 represents a 2-propynyl group or a cyclopropylmethyl group, and Y71 and Y72 represent the combination of (Cl, Cl).

Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [35], wherein, in the formula (7), R74 represents a methyl group. R7 represents a propyl group, and Y71 and Y72 represent the combination of (Cl, Cl).

Preferable examples of each sign in formula (8) Rai preferably is a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms or a morpholinoethyloxy group, and particularly preferably a hydroxyl group, a methoxy group, a group ethoxy, an isopropyloxy group, a butyloxy group or a morpholinoethyloxy group. R82 is preferably a methyl group. R84 preferably is a methyl group. n8 preferably is any of the integers 0 or 2, and particularly preferably is 0. preferably it is a methylthio group or a methanesulfonyl group. The substituent position of S is preferably the sixth position of a quinazolinedione ring. Both Y8? as Y82 they are preferably a chlorine atom.

Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [38], wherein, in the formula (8), R81 represents a hydroxyl group, an alkoxyl group having from 1 to 6 carbon atoms. carbon, a morpholinoethyloxy group or a benzyloxy group of which may be substituted with a methyl group (s) or a methoxy group (s). Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [38], wherein, in the formula (8), R82 represents a methyl group. R8 represents a methyl group. n8 represents any of the integers 0 or 2, S is located in the sixth position of a quinazolinedione ring, and Yßi and Yß2 represent the combination of (Cl, Cl).

Preferable examples of each sign in formula (9) R91 preferably is a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, a morpholinoethyloxy group or a benzyloxy group, and particularly preferably a hydroxyl group, a group methoxy, an ethoxy group, an isopropyloxy group, a butyloxy group, a pentyloxy group, a morpholinoethyloxy group or a benzyloxy group. Rg2 preferably is a hydroxyl group, a benzyloxy group, a methoxy group or an amino group. CO-Rg2 can be a carboxyl group in a modification of the prodrug which is converted to a carboxyl group in vivo. That is, R92 is preferably a hydroxyl group or a group which is substituted with a hydroxyl group in vivo. Specific examples of the group (s) which is substituted with a hydroxyl group in vivo were mentioned above. R94 preferably is a methyl group. X9 is preferably an atomic bond. The substituent position of Xg is preferably the sixth position of a quinazolinedione ring. Both Y91 and Y92 preferably are a chlorine atom. Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the above-mentioned [41], wherein, in the formula (9), Xg represents -CH2CH2- or -CH = CH- and Rg2 represents a hydroxyl group , or Xg represents an atomic bond and R92 represents a benzyloxy group, X9 is located at the sixth position of the quinazolinedione ring, Rg4 represents a methyl group, and Y91 and Y92 represents the combination of (Cl, Cl). Phenylalanine derivatives or pharmaceutically acceptable salts thereof are preferred in accordance with. previously mentioned [41], where, in formula (9), X9 represents an atomic bond and Rg2 represents a hydroxyl group, a methoxy group or an amino group, Xg is located in the sixth position of the quinazolinedione ring, Rg4 represents a methyl group, and Ygi and Yg2 represents the combination of (Cl, Cl) .

Preferred examples of each sign in the formula (10) R? O? preferably it is an alkoxy group having from 2 to 4 carbon atoms or a morpholinoethyloxy group, and particularly preferably an ethoxy group, an isopropyloxy group, a butyloxy group or a morpholinoethyloxy group. R10 is preferably a methyl group or an ethyl group, and particularly preferably an ethyl group. R104 preferably is a methyl group. Both Y101 and Y102 preferably are a chlorine atom. Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [44], wherein, in the formula (10), R10 represents an ethyl group Preferable examples of each sign in the formula (11) R-m preferably is an alkoxy group having from 1 to 4 carbon atoms or a morpholinoethyloxy group, and particularly in an preferably a methoxy group, an ethoxy group, an isopropyloxy group, a butyloxy group or a morpholinoethyloxy group. R114 is preferably a methyl group. Both Y111 and Y112 are preferably a chlorine atom.

Preferable examples of each sign in formula (12) R121 preferably is an alkoxy group having 1 to 4 carbon atoms or a morpholinoethyloxy group, and particularly preferably a methoxy group, an ethoxy group, an isopropyloxy group, a group butyloxy or a morpholinoethyloxy group. Ri2 is preferably a methyl group. A is preferably formula (12-1).

Preferable examples of each sign in formula (13) Ri3-? preferably it is an alkoxy group having 1 to 6 carbon atoms or a benzyloxy group which may be substituted with a methyl group (s) or a methoxy group (s), and particularly preferably an ethoxy group or a benzyloxy group . The substituent position of an ammonium side chain is preferably the sixth, seventh or eighth position of a quinazolinedione ring and more preferably the eighth position thereof. R13a and R13b preferably are a methyl group or, N (R13a) R13b preferably is a 1-pyrrolidinyl group.

Y131 and Y-I32 are preferably (Cl, Cl), (Cl, Me) or (Cl, F).

Preferable examples of each sign in formula (14) R-141 preferably is a hydroxyl group, an alkoxyl group having 1 to 6 carbon atoms or a morpholinoethyloxy group, and particularly preferably an ethoxy group or a benzyloxy group. R-I44 is preferably a methyl group or an ethyl group. The substituent position of a hydroxy group on a quinazolinedione ring is preferably the sixth or seventh position of the ring, and more preferably the eighth position thereof. Y141 and Y-I42 are preferably (Cl, Cl), (Cl, Me), (Cl, F), (F, F) or (F, Me), and particularly preferably (Cl, Cl), (Cl , Me) or (Cl, F). Preferred are phenylalanine derivatives or pharmaceutically acceptable salts thereof according to the aforementioned [49], wherein, in the formula (14), R144 represents a methyl group, a hydroxyl group is located in the sixth position of the ring quinazolinedione, and Y? ? and Y? 42 represent the combination of (Cl, Cl). The preferable compounds in formulas (1) to (14) are those described in the examples. Particularly preferable compounds are those in Examples 7, 8, 12, 21, 28, 30, 34, 37, 40, 46, 54, 59, 90, 91, 92, 99, 103, 106, 111, 116, 124, 136, 138, 139, 141, 142, 143, 144, 145, 147, 148, 149, 150, 151, 153, 154, 155, 156, 157, 159, 162, 163, 164, 165, 166, 170, 171, 172, 173, 174, 176, 179, 181, 184, 185, 189, 191, 193, 196, 198, 201, 210, 213, 214, 216, 217, 218, 219, 220, 222, 223, 224, 225, 226, 229, 207, 230, 232, 233, 234 and 235. Among the compounds of formulas (1) to (14), the compound of formula (1) is particularly preferable, and especially those wherein R 11 represents a hydroxyl group not only exhibits excellent activity antagonistic against the a4 ß1 binding but also exhibits an extremely low body elimination (CLtot). Therefore, the compounds have excellent characteristics as an active form for an orally administered integrin a4 antagonist (prodrug) which is effective at the lower doses and lower number of doses. Particularly, the compounds wherein R 11 represents a branched alkoxy group having 3 to 6 carbon atoms exhibit excellent durability of effect when administered orally. When the compounds of formulas (1) to (14) of the present invention can form salts thereof, it is suitable for the salts to be pharmaceutically acceptable. When the compound has an acidic group such as a carboxyl group in the formulas, the salts may be ammonium salts, or salts thereof with alkali metals, for example sodium and potassium, salts thereof with alkaline earth metals, for example calcium and magnesium, salts thereof with aluminum, salts thereof with zinc, salts thereof with organic amines, for example triethylamine, ethanolamine, morpholine, piperidine and dicyclohexylamine, and salts thereof with basic amino acids, for example arginine and lysine. When the compound has a basic compound in the formulas, the salts can be those with inorganic acids, for example hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and hydrobromic acid; those with organic carboxylic acids, for example acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, tannic acid, butyric acid, hybenic acid, pamico acid, enanthic acid, decanoic acid, theoclic acid, salicylic acid, lactic acid, oxalic acid, mandelic acid, and malic acid; and those with organosulfonic acids, for example methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid. The salts can be formed by mixing a compound of the formulas (1) to (14) with an acid as a necessary base in a suitable ratio in a solvent or dispersant or by the reaction of cation exchange or anion exchange with another salt. The compounds of the present invention also include solvates of the compounds of formulas (1) to (14) such as hydrates and alcohol adducts thereof. The compounds of the present invention can be modified into prodrug forms. The prodrug in the present invention means a compound (s) which is converted to the compounds of the present invention in vivo. For example, when an active compound contains a carboxyl group, a phosphoric group and the like, the compounds in a Prodrug modification include esters, amides and the like thereof. When an active compound contains an amino group, the compounds in a modification of the prodrug include the amides, r-carbamates and the like thereof. When an active compound contains a hydroxyl group, the compounds in a modification of the prodrug include the esters, carbonates, carbamates and the like thereof. When the compounds of the present invention are modified into prodrug forms, the compounds can connect with amino acids or saccharides. The present invention also includes metabolites of the compounds of the present invention. The metabolites of the compounds of the present invention mean compounds towards which the compounds of the present invention have been converted by metabolic enzymes and so forth in vivo. Their examples are compounds wherein a hydroxyl group have been introduced into a benzene ring by metabolism; the compounds wherein an alkoxy group has been converted to a hydroxyl group by metabolism; and compounds wherein an alkyl group on a nitrogen atom has been dealkylated by metabolism. In addition, these include compounds wherein a glucuronic acid, glucose, an amino acid or a sulfuric acid has been connected with a carboxylic acid moiety of the compounds of the present invention, a portion of the hydroxyl group of the compounds of the present invention or a portion of the hydroxyl group introduced by the metabolism.

The compounds of the present invention have an excellent antagonistic effect against cell adhesion via integrins at 4 and excellent bioavailability and durability after oral administration. In addition, they have excellent durability even by parenteral administration. These characteristics reflect an excellent affinity for proteins at 4, plasma protein binding, solubility, hepatic elimination, total elimination of the body or permeability of the intestinal tract membrane. Especially, since the compounds of the present invention have excellent antagonistic activity for integrin a4 even under the existence of plasma protein, low dose of the compound of the present invention can be effective when administered in vivo. In addition, the total removal of the body from the compounds of the present invention is low and, therefore, they are excellent in a sustained profile in the blood plasma. These characteristics make it possible to reduce your dose and number of doses. In addition, the blood plasma level of the compounds of the present invention can be maintained and therefore adhesion of the cells via integrin a 4 can be effectively inhibited. The compounds of the present invention have a high membrane permeability, and a high area under the blood plasma concentration-time curve (AUC) and bioavailability when administered orally.

In addition, the compounds of the present invention have excellent safety. Particularly, the compound of the formula (1) in the compounds of the formulas (1) to (14) exhibits a high solubility and is useful. Therefore, the novel phenylalanine derivatives of the present invention and the salts thereof provide excellent integrin a 4 antagonists and therapeutic agents or agents for prevention for diseases in which the adhesion-dependent adhesion process a 4 participates in pathology, such as inflammatory diseases, rheumatoid arthritis, inflammatory bowel diseases (including Crohn's disease and ulcerative colitis), systemic lupus erythematosus, multiple sclerosis, Sjögren's syndrome, asthma, psoriasis, allergy, diabetes mellitus, cardiovascular diseases, sclerosis arterial, restenosis, tumor proliferation, tumor metastasis and rejection of transplants. They also provide therapeutic agents or preventive agents for diseases such as preeclampsia., cerebral ischemic disorders (including cerebral infarction), systemic sclerosis, ankylosing spondylitis, psoriatic arthritis, sarcoidosis, giant cell arteritis, uveitis, fibroid lung, chronic obstructive pulmonary disease, osteoarthritis, Alzheimer's disease, spinal cord injury, brain injury traumatic, primary sclerosing cholangitis, liver cirrhosis caused by hepatitis C, chronic active hepatitis, sacroiliitis, spondylitis ankylosing, episcleritis, iritis, uveitis, erythema nodosum, pyoderma gangrenosum and autoimmune hepatitis. In addition, they provide therapeutic agents or preventive agents not only for the aforementioned diseases but also for diseases in which the integrins at 4 have the potential to participate in the pathology. The dose of the compounds of the present invention or salt thereof used for the purpose described above varies depending on the compound used, the intended therapeutic effect, the method of administration, the period of treatment, and the age and body weight of the patient. The dose is usually from 1 μg to 5 g daily for adults on oral administration, and 0.01 μg to 1 g daily for adults on parenteral administration (eg, intravenously, subcutaneously, intramuscularly, by suppository, barium enema, ointment, adhesive patch to the skin, sublingually, and eye drops). The compounds of the present invention have a high stability in acid or alkaline solution and are useful since it is possible to apply them to various dosage forms. The compounds of the present invention or salts thereof are administered as they are or in the form of various pharmaceutical compositions having a pharmaceutically acceptable carrier to patients.

Pharmaceutically acceptable carriers include, for example, various commonly used organic or inorganic carrier materials as materials for drug preparation. Examples thereof are diluents, lubricants, binders, disintegrants, water-soluble polymer and basic inorganic salts in solid preparation; and solvents, solubilizing agents, suspending agents, agents for the formation of isotonic solutions, pH regulating agents and sedative agents in liquid solution. In addition, additives may be used, if necessary, such as antiseptic agents, antioxidant substances, coloring agents, sweetening agents, acidic agents, foaming agents and fragrant materials. The dosage forms of the pharmaceutical compositions are, for example, tablets, powders, pills, granules, capsules, suppositories, solutions, sugar-coated tablets, reservoirs, syrups, suspending agents, emulsions, troches, sublingual agents, adhesive patches to skin, oral disintegrating agents (tablets), respiratory agents, barium enema, ointments, skin-adhesive patches, adhesives and eye drops. These can be prepared with auxiliaries for ordinary preparation, by an ordinary method. The pharmaceutical compositions of the present invention can be produced by methods commonly used in the field of the art for preparation and, for example, by the methods described in Japanese Pharmacopoeia The methods for preparation are described below in detail. For example, when preparing the compounds of the present invention as oral preparations, diluents and, if necessary, binders, disintegrating agents, lubricants, coloring agents, flavoring agents are also added. These are subsequently formed as, for example, tablets, powders, pills, granules, capsules, suppositories, solutions, sugar coated tablets, reservoirs, syrups, suspending agents, emulsions, troches, sublingual agents, oral disintegrating agents (tablets) and Respiratory agents by ordinary methods. As the diluents, for example, lactose, corn starch, sucrose, glucose, sorbit and crystalline cellulose are used; as the binders, there are used, for example, polyvinyl alcohol, polyvinyl ether, ethylcellulose, methylcellulose, acacia, tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropylstarch and polyvinylpyrrolidone; as the disintegrating agents are used, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium acid carbonate, calcium citrate, dextran and pectin; as lubricants, magnesium stearate, tare, polyethylene glycol, silica, hydrogenated vegetable oil and the like are used; The materials that can be allowed to be added to the drugs are used as the coloring agents; and as flavoring agents, for example, cocoa powder, menthol, aromatic acid, peppermint oil, borneol and cinnamon powder.

These tablets or granules can be coated, if necessary, with sugar, gelatin and the like. When injectable agents are prepared, pH adjusters, pH adjusting agents, stabilizing and preservative agents are also added, if necessary, and subsequently these are prepared as subcutaneous agents, intramuscularly and intravenously, administered by ordinary methods. The phenylalanine derivatives (1) of the present invention can be produced, for example, by methods described below. The phenylalanine derivatives (2) to (14) can be produced by the same methods as those described below. ÍS -'i ^ -2j ~ 'Vehicle for solid phase A suitably protected carboxylic acid (S-1) is loaded into a resin by a usual method. The Q substituent of the carboxylic acid (S-1) has a structure of 2-Yn-6-Y? 2-Ph-CO as described above with reference to formula (1), this is a substituent which can be converted in 2-Yn-6-Y? 2-Ph-CO at any stage of the synthesis or is a protecting group of an amino group. The R substituent of the carboxylic acid (S-1) has a structure of a substituent which is they can convert NH2 or a properly protected form of the NH2 group. As for the charge reaction conditions, the reaction can be carried out by the use, if necessary, of a suitable additive such as HOAt (1-hydroxy-7-azabenzotriazole), HOBt (1-hydroxybenzotriazole) or DMAP ( dimethylaminopyridine) and a condensing agent such as DIC (diisopropylcarbodiimide), DCC (dicyclohexylcarbodiimide) or EDC (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide) in an organic solvent such as dichloromethane, DMF (N, N-dimethylformamide) or NMP (N-methyl-2-pyrrolidine). For example, when the Wang resin is used, the reaction is carried out in the presence of DIC and DMAP in DMF to obtain an ester (S-2).

When Q is, for example, a protecting group E (S-3) of an amino group, the protecting group can be removed depending on the protecting group E under suitable conditions to obtain the amine (S-4). For example, in the case where the Fmoc group (9-fluorenylmethoxycarbonyl group) is used as the protecting group Ei, it can be removed with a base such as piperidine in a solvent such as DMF. The amide (S-5) can be had by reacting the amine (S-4) with a suitable carboxylic acid by using a condensing agent such as DIC and, if necessary, a suitable additive such as HOAt or HOBt in an organic solvent such as DMF, NMP or dichloromethane. The amide (S-5) can also be obtained by the reaction of a suitable hydrochloric acid under the presence of a base.

IS 2 IS_d) The ester (S-2) can be charged to an amine (S-6) under suitable conditions depending on the substituent R. For example, when a nitro group is used as R, the ester (S-2) is it can charge the amine (S-6) in the presence of a reducing agent such as SnCl 2 or hydrates thereof in a solvent such as NMP, DMF or ethanol. In the case of an amine protected with the Fmoc group (9-fluorenylmethoxycarbonyl group) (FmocNH), the protecting group can be removed with a base such as piperidine in a solvent such as DMF to obtain the amine (S-6). -7J (S- * i IS-K A quinazolinedione (S-9) can be synthesized by the following method. First, an amide (S-7) can be obtained by reaction of the amine (S-6) with a benzoic acid halide having a nitro group in the ortho position under the existence of the 2,6-lutidine base in a solvent such as NMP, or by reacting it with a carboxylic acid having a nitro group in the activated ortho position by the use of a condensing agent such as DIC and, if necessary, a suitable additive such as HOAt or HOBt in an organic solvent such as DMF, NMP or dichloromethane. Later, an amine (S-8) is obtained by reducing the nitro group with SnCl 2 or hydrates thereof and is cycled by reagents such as CDl (carbonyldiimidazole), triphosgene or p-nitrophenylchloroformate to obtain the quinazolinedione (S-9) . Like the other methods for synthesis, quinazolinedione (S-9) can also be obtained by the following method. First, an amide (S-8) can be obtained by reacting the amine (S-6) with a carboxylic acid from which an amino group in the ortho position activated by the use of a condensing agent such as DIC and, if it is necessary, a suitable additive such as HOAt or HOBt in an organic solvent such as DMF, NMP or dichloromethane. Subsequently, an amide (S-8) is formed in cycle by the same process mentioned above to obtain the quinazolinedione (S-9). The substituents R 'and R "' in the formulas (S-7) to (S-9) are groups which are derived from benzoic acid derivatives used in the aforementioned reaction, these are R1 'or -XrN (R12 ) R13 described in formula (1), or groups which can be converted to R11 or X N (R12) R13 at any stage of the synthesis. < S- «(S-105) In the formula (S-10), compounds can be obtained wherein R" is represented by a methyl group by the reaction of Mitsunobu with the quinazolinedione (S-9) using methanol, diisopropylazodicarboxylic acid and The similar ones can be obtained by the reaction of methyl iodide under the existence of a base such as potassium carbonate.

The ester (S-10) thus obtained is cleaved from a resin under suitable conditions to obtain a carboxylic acid (S-11). For example, when the Wang resin is used, in the ester (S-10), each of Q, R1, R "and R '" are converted, if necessary, to 2-Yn-6- Y? 2 -Ph-CO, -XrN (R12) R13, a methyl group or R ^, or groups which can be converted to 2-Yp-6-Y12-Ph-CO, -XrN (R? 2) Ri3, a group methyl or R-i 'under the conditions of removal of the resin. Subsequently, the ester (S- ) is treated with an acid solution that includes TFA (trifluoroacetic acid) to obtain a solution of the carboxylic acid (1: R1 = OH) wherein, in the formula (1), R1 is represented by a hydroxyl group. In addition, the pure carboxylic acid (1: R1 = OH) can be obtained by applying well known isolation and purification methods such as concentration, extraction, crystallization, column chromatography, HPLC and recrystallization to the carboxylic acid thus obtained (1: R1 = OH). In addition, the carboxylic acid (1: R1 = OH) can also be obtained by applying the methods for solid phase synthesis to the liquid phase method where the appropriate protective group is selected and well-known methods of isolation and purification are used. . In the carboxylic acid (S-11), each of Q, R ', R "and R'" represent 2-Yn-6-Y-? 2-Ph-CO, -XrN (R12) R? 3, a methyl group or R ^, or groups which can be converted to 2-Yn-6 ?? 2-Ph-CO, -XrN (R- | 2) R? 3, a methyl group or R? ' in subsequent processes. The carboxyl group in the formula (S-11) can be converted to the group -CO-R11 (wherein R11 represents an alkoxy group) by a well-known esterification. More specifically, the methods are as follows. The carboxyl group is treated with a suitable alcohol under the conditions of dehydration under an acid catalyst; if necessary, it is treated with O-alkylating agents such as an alkyl halide under the existence of a base or an acid; if necessary, it is treated with an adequate alcohol under the existence of a base, after the conversion to the acid halide with thionyl chloride and the like; more specifically, it is treated with, for example, ethyl chloroformate under the existence of a base to convert it to acid anhydride. Subsequently, if necessary, the substance of the reaction was treated with a suitable alcohol under the existence of a base. Further, if necessary, it was also treated with a suitable alcohol under the existence of a condensing agent such as dicyclohexylcarbodiimide and a catalyst such as dimethylaminopyridine. After these processes, the compounds of the present invention (1: R1 is an alkoxy group) can be obtained by the conversion of Q, R ', R "and R'", if necessary. In formula (1), for example, a compound of (S-15) wherein Xi represents CH 2 can be synthesized as follows. In the formula, R11a represents R11 or functional groups which can be converted to R11 at any stage of the synthesis.

A nitro compound (S-12), which is a raw material, can be obtained, for example, by the synthesis process such as that of (S) -2- (2,6-dichlorobenzoylamino) -3-hydropropyl ester. - (4-nitrophenyl) propionate in process 1 of reference example 4. The nitro compound (S-12) is reduced to an aniline compound by reaction with SnCl 2, the hydrogenation reaction in the presence of catalysts metals, and Similar. More specifically, the corresponding aniline compounds can be obtained, for example, by the synthesis process such as that of the (S) -2- (2,6-dichlorobenzoylamino) -3- (4-aminophenyl) propionic acid isopropylester in process 2 of reference example 4. After the condensation thus obtained, the compounds of aniline and an anthranilic acid substituted with Xa (Xa represents a halogen atom, a triflate group and the like) by the use of an agent (s) ) suitable condenser, cycle formation is carried out by reagents such as CDl (carbonyldiimidazole), ethyl chloroformate and triphosgene to obtain (S-13). Other methods for obtaining (S-13) is as follows: the aforementioned aniline compounds are reacted with 2-nitrobenzoic acid chloride substituted with Xa under the existence of a suitable base; and subsequently, a nitro group is reduced by SnCl 2, the hydrogenation reaction in metal catalysts, and the like and formed in cycle by the reagents such as CD 1, ethyl chloroformate and triphosgene. The other additional method for obtaining (S-13) is as follows: The urea linkage is formed between the above-mentioned aniline compounds and the ester of an anthranilic acid substituted with Xa by the use of CDl, ethyl chloroformate, triphosgene and the like; and subsequently, if necessary, the reaction mixture is cycled by reaction with a suitable base. Next, R14 is introduced by methods such as reaction of the compound (S-13) with alkyl halide under the existence of a suitable base, and the reaction of Mitsunobu using alcohol. Subsequently, Xa is converted to a carboxylic acid by, for example, a conversion reaction using a palladium and carbon monoxide catalyst. The carboxylic acid is converted to an alcohol compound (S-14, Xb = OH) by the method such as the reactive reaction via mixed acid anhydride. In addition, Xb is converted to a residual group (Xb = a halogen group, a triflate group, a mesylate group, a tosylate group, etc.) using a suitable acid halide, sulfonium halide, thionyl halide, phosphoryl halide and the Similar. Subsequently, the substitution reaction is carried out using a suitable substituted amine to obtain the objective compound (S-15). The present invention provides compounds having an antagonistic activity for integrin a 4 or a pharmaceutically acceptable salt thereof. The present compounds are useful for the treatment or prevention of diseases in which the process dependent adhesion integrin 4 participates in the pathology, such as inflammatory diseases, rheumatoid arthritis, disease inflammatory bowel (including Crohn's disease and ulcerative colitis ), systemic lupus erythematosus, multiple sclerosis, Sjogren's syndrome, asthma, psoriasis, allergy, diabetes, cardiovascular diseases, arterial sclerosis, restenosis, tumor proliferation, tumor metastasis and transplantation rejection. The present compounds are also useful for the treatment or prevention of preeclampsia, ischemic cerebrovascular disorders (Including cerebral infarction), systemic sclerosis, ankylosing spondylitis, psoriatic arthritis, sarcoidosis, giant cell arteritis, uveitis, fibroid lung, chronic obstructive pulmonary disease, osteoarthritis, Alzheimer's disease, spinal cord injury, traumatic brain injury, sclerosing cholangitis primary, liver cirrhosis caused by hepatitis C, active chronic hepatitis, sacroiliitis, ankylosing spondylitis, episcleritis, iritis, uveitis, erythema nodosum, pyoderma gangrenosum and autoimmune hepatitis. In addition, the present compounds are useful for the treatment or prevention not only of the aforementioned diseases but also for diseases in which integrins at 4 have the potential to participate in the pathology.

EXAMPLES The following examples will further illustrate the present invention, which are only preferred embodiments of the invention and which in no way limit the invention. In the following examples, although the salts of the intended compounds are not described, they were obtained as trifluoroacetic acid (TFA) salts in the case of compounds that are capable of forming TFA salts. This is because the intended compounds were obtained by being purified by a solvent containing 0.1% TFA and dried by freezing in the final process.

EXAMPLE 1 Synthesis of the compound of the following formula (E-1) which has a substituent (s) of example 1 of table 1 Process 1 Charge to the resin Fmoc-Phe (4-nitro) -OH (25 g), DIC (8.9 mL), DMAP (281 mg) and DMF (193 mL) were added to the Wang resin (1.2 mmol / g) , 19.3 g) and stirred at room temperature for 3 hours. After removal of the excess solvent, the resin was washed with DMF, methanol, dichloromethane and DMF three times each. In order to carry out the protection of an unreacted hydroxyl group in the resin, the resin is treated with acetic anhydride (19.6 mL), pyridine (16.8 mL) and DMF (193 mL) for 2 hours. After removal of the excess solvent, the resin was washed with DMF, methanol and dichloromethane three times each, and dried under reduced pressure.

Process 2 Removal of the Fmoc group A DMF solution of 20% piperidine (200 mL) was added to the resin obtained in process 1 and reacted for 15 minutes. The reaction mixture was further reacted with a DMF solution of 20% piperidine (200 mL) for 15 minutes. After solvent removal, the resin was washed with NMP, methanol and dichloromethane three times each, and dried under reduced pressure.

Process 3 Acylation reaction 2,6-Dichlorobenzoyl chloride (10.3 mL), 2,6-lutidine (13.7 mL) and NMP (120 mL) were added to the resin obtained in process 2 and reacted for 14 hours. After removal of the excess solvent, the resin was washed with NMP, methanol and dichloromethane three times each, and dried under reduced pressure.

Process 4 Reduction of the nitro group SnCl2.2H2O (150 g), NMP (300 mL) and EtOH (15 mL) were added to the resin obtained in process 3 and reacted for 14 hours.

After removal of the excess solvent, the resin was washed with NMP, methanol and dichloromethane three times each, and dried under reduced pressure.

Process 5 Acylation reaction 5-Fluoro-2-nitrobenzoic acid (1.63 g), DIC (675 μL), HOAt (1.2 g) and NMP (25 L) were mixed and stirred for 1 hour, and subsequently added to 1 g of the resin obtained in process 4 and reacted for 14 hours. After removal of the excess solvent, the resin was washed with NMP, methanol and dichloromethane three times each, and dried under reduced pressure.

Process 6 Substitution of the fluoro group with amine Morpholine (400 μL) and NMP (2 mL) were added to 200 mg of the resin obtained in process 5 and reacted for 14 hours.

Process 7 Reduction of the nitro group The reduction of the nitro group was carried out with the resin obtained in process 6 by the same procedure as that used by process 4 in example 1.

Process 8 Construction of a quinazolinedione ring by carbonyldiimidazole The carbonyldiimidazole (400 mg) and NMP (2 mL) were added to the resin obtained in process 7 and stirred at 95 ° C for 14 hours. After removal of the excess solvent, the resin was washed with NMP, methanol and dichloromethane three times each, and dried under reduced pressure.

Process 9 Alkylation Triphenylphosphine (520 mg), methane! (80 μL), 40% toluene (1 mL), diisopropylazodicarboxylic acid solution (1 mL) and dichloromethane (2 mL) to the resin obtained in process 8 and stirred for 14 hours. After removal of the excess solvent, the resin was washed with NMP, methanol and dichloromethane three times each, and dried under reduced pressure.

Process 10 Excision from resin The resin obtained in process 9 was treated with trifluoroacetic acid containing 5% water for 1 hour. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 61 mg of the intended compound. MS (ESI MH +): 597 EXAMPLES 2 to 6 synthesis of the compounds of the following formula (E-1) which has a substituent (s) of examples 2 to 6 of Table 1 The compounds of the following formula (E-1) which has a substituent (s) of examples 2 to 6 of Table 1 were synthesized by the same procedure as that of Example 1 except that the corresponding amines were used in the process 6. of example 1.

EXAMPLE 7 Synthesis of the compound of the following formula (E-2) which has a substitute (s) of Example 7 of Table 2 Process 1 Acylation reaction 1 g of the resin obtained in process 4 of example 1 was acylated by the same procedure as that of process 5 in example 1 except that 2-amino-5-nitrobenzoic acid was used in the process.

Process 2 Construction of the quinazolinedione ring The construction of the quinazolinedione ring was carried out to the resin obtained in process 1 by the same procedure as that of process 8 in example 1.

Process 3 Alkylation Methyl iodide (1 mL), diisopropylethylamine (1 mL) and NMP (5 mL) were added to the resin obtained in process 2 and stirred for 14 hours. After removal of the solvent, the resin was washed with NMP, methanol and dichloromethane three times each, and dried under reduced pressure.

Process 4 Reduction of the nitro group The reduction of the nitro group was carried out to the resin obtained in process 1 by the same procedure as that of process 4 in example 1.

Process 5 2-nitrosulfonylation 2-Nitrosulfonyl chloride (1 g), 2,6-di-t-butyl-4-methylpyridine (1 mL) and dichloromethane (15 mL) were added to the resin obtained in the process 4 and stirred at 4 ° C for 24 hours. After removal of the solvent, the resin was washed with NMP, methanol and dichloromethane three times each, and dried under reduced pressure.

Process 6 Alkylation Propyl iodide (400 μL), diisopropylethylamine (400 μL) and NMP (2 mL) were added to 200 mg of the resin obtained in process 5 and stirred for 14 hours. After removal of the solvent, the resin was washed with NMP, methanol and dichloromethane three times each, and dried under reduced pressure.

Process 7 Removal of the 2-nitro sulfonyl group 2-mercaptoethanol (200 μL), 1,8-diazabicyclo [5.4.0] undec-7-ene (100 μL) and NMP (2 mL) were added to the resin obtained in the process 6 and stirred for 1 hour. After the removal of the solvent, the resin washed with NMP, methanol and dichloromethane three times each, and dried under reduced pressure.

Process 8 Cleavage from the resin, purification Cleavage from the resin and purification thereof was carried out on the resin obtained in process 7 by the same procedure as that of process 10 in example 1 to obtain 38 mg of the intended compound. MS (ESI MH +): 569 EXAMPLES 8 to 12 Synthesis of the compounds of the following formula (E-2) which has a substituent (s) of examples 8 to 12 of Table 2 The compounds of the following formula (E-2) which has a substituent (s) of Examples 8 to 12 of Table 2 were synthesized by the same procedure as that of Example 7 except that the corresponding halides were used in process 6 of Example 7.

EXAMPLE 13 Synthesis of the compound of the following formula (E-3) which has a substituent (s) of example 13 of table 3 Process 1 acylation reaction 1 g of the resin obtained in process 4 of example 1 was acylated by the same procedure as that of process 5 in example 1 except that 2-amino-4,5-difluorobenzoic acid was used in the process.

Process 2 Construction of the quinazolinedione ring Carbonyldiimidazole (3 g) and NMP (15 mL) were added to the resin obtained in process 1 and stirred for 14 hours. After removal of the excess solvent, the resin was washed with NMP, methanol and dichloromethane three times each, and dried under reduced pressure.

Process 3 Substitution of the fluoro group with amine N.N'-trimethylethylenediamine (400 μL) and NMP (2 mL) were added to 200 mg of the resin obtained in process 2 and stirred at 90 ° C for 14 hours. After removal of the excess solvent, the resin was washed with NMP, methanol and dichloromethane three times each, and dried under reduced pressure.

Process 4 Alkylation The resin obtained in process 3 was alkylated by the same procedure as that of process 9 in example 1.

Process 5 Cleavage from the resin, purification Cleavage from the resin and purification thereof was carried out to the resin obtained in process 4 by the same procedure as that of process 10 in example 1 to obtain mg of the intended compound. MS (ESI MH +): 630 EXAMPLES 14 to 15 Synthesis of the compounds of the following formula (E-3) which has a substituent (s) of the examples 14 to 15 of table 3. The compounds of the following formula (E-3) which has a substituent (s) of examples 14 to 15 of table 3 were synthesized by the same procedure as that of example 13 except that the corresponding amines were used in process 3 of example 13.

EXAMPLE 16 Synthesis of the compound of the following formula (E-4) Process 1 acylation reaction 200 mg of the resin obtained in process 4 of example 1 were acylated by the same procedure as that of process 5 in example 1 except that 2-nitro-4,5-difluorobenzoic acid was used in the process.

Process 2 Substitution of the fluoro group with amine Substitution of the fluoro group with amine was carried out to the resin obtained in process 1 by the same procedure as that of process 6 in example 1 except that 2-methoxy-N- was used. methiletialmine in the process.

Process 3 Reduction of the nitro group, construction of the quinazolinedione ring, alkylation, cleavage from the resin, purification The reduction of the nitro group was carried out to the resin obtained in process 2 by the same procedure as that of process 4 in the Example 1; the construction of the quinazolinedione ring was carried out to the resin by the same procedure as that of process 8 in example 1; the alkylation was carried out to the resin by the same procedure than that of process 9 in example 1; and subsequently the cleavage from the resin and purification thereof was carried out to the resin by the same procedure as that of process 10 in Example 1 to obtain 59 mg of the intended compound. MS (ESI MH +): 617 EXAMPLE 17 Synthesis of the compound of the following formula (E-5) Process 1 Substitution of the fluoro group with amine Substitution of two fluoro groups with amines was carried out at 200 mg of the resin obtained in process 1 of example 16 by the same procedure as that of process 3 in example 13 except that used N, N'-dimethylethylenediamine in the process.

Process 2 Reduction of the nitro group, construction of the quinazolinedione ring, alkylation, cleavage from the resin, purification The reduction of the nitro group was carried out to the resin obtained in process 1 by the same procedure as that of process 4 in the Example 1; the construction of the quinazolinedione ring was carried out to the resin by the same procedure as that of process 8 in example 1; the alkylation was carried out to the resin by the same procedure than that of process 9 in example 1; and subsequently the cleavage from the resin and purification thereof was carried out to the resin by the same procedure as that of process 10 in Example 1 to obtain 16 mg of the intended compound. MS (ESI MH +): 596 EXAMPLE 18 Synthesis of the compound of the following formula (E-6) Process 1 acylation reaction 200 mg of the resin obtained in process 4 of example 1 were acylated by the same procedure as that of process 5 in example 1 except that 1-methyl-5-nitro-1H-pyrazole was used -4-carboxylic acid in the process.

Process 2 Reduction of the nitro group, construction of the quinazolinedione ring, alkylation, cleavage from the resin, purification The reduction of the nitro group was carried out to the resin obtained in process 1 by the same procedure as that of process 4 in the Example 1; the construction of the quinazolinedione ring was carried out to the resin by the same procedure as that of process 8 in example 1; the alkylation was carried out to the resin by the same procedure than that of process 9 in example 1; and subsequently the cleavage from the resin and purification thereof was carried out to the resin by the same procedure as that of process 10 in example one to obtain 15 mg of the intended compound. MS (ESI MH +): 516 EXAMPLE 19 Synthesis of the compound of the following formula (E-7) Process 1 Acylation reaction 1 g of the resin obtained in process 4 of example 1 was acylated by the same procedure as that of process 5 in example 1 except that 2-amino-4-nitrobenzoic acid was used in the process.

Process 2 Construction of the quinazolinedione ring, alkylation. reduction of the nitro group The construction of the quinazolinedione ring was carried out to the resin obtained in process 1 by the same procedure as that of process 8 in example 1; the alkylation was carried out to the resin by the same procedure as that of process 3 in example 7; and subsequently the reduction of the nitro group was carried out to the resin by the same procedure as that of process 4 in example 1.

Process 3 Alkylation Ethyl iodide (200 μL), potassium carbonate (200 mg) and NMP (4 mL) were added to 400 mg of the resin obtained in process 2 and stirred at 80 ° C for 9 hours. After removal of the solvent, the resin was washed with NMP, methanol and dichloromethane three times each, and dried under reduced pressure.

Process 4 Cleavage from the resin, purification Cleavage from the resin and purification thereof was carried out on the resin obtained in process 3 by the same procedure as that of process 10 in example 1 to obtain 43 mg of the intended compound. MS (ESI MH +): 555 EXAMPLE 20 Synthesis of the compound of the following formula (E-8) Process 1 Substitution of the fluoro group with amine Substitution of the fluoro group with amine was carried out at 200 mg of the resin obtained in process 5 of example 1 by the same procedure as that of process 6 in example 1 except that it was used 2- (methylamino) ethanol in the process.

Process 2 Protection of the hydroxyl group with acetyl group Acetic anhydride (200 μL), pyridine (200 μL) and NMP were added (2 mL) to the resin obtained in process 1 and stirred for 14 hours.

After removal of the solvent, the resin was washed with NMP, methanol and dichloromethane three times each, and dried under reduced pressure.

Process 3 Reduction of the nitro group, construction of the quinazolinedione ring, alkylation The reduction of the nitro group was carried out to the resin obtained in process 2 by the same procedure as that of process 4 in example 1; the construction of the quinazolinedione ring was carried out to the resin by the same procedure as that of process 8 in example 1; and subsequently the alkylation was carried out on the resin by the same procedure as that of process 9 in example 1.

Process 4 Excision from the resin, cleavage of the acetyl group from the protecting group The resin obtained in process 3 was treated with trifluoroacetic acid containing 5% water for 1 hour. After filtration, the filtrate was concentrated under reduced pressure. A solution of 4M dioxane acid chloride (3 mL) and water (600 μL) was added to the obtained residue and stirred at 90 ° C for 1.5 hours. Subsequently the residue was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 42 mg of the intended compound. MS (ESI MH +): 585 EXAMPLE 21 Synthesis of the compound of the following formula (E-9) which has a substituent (s) of example 21 of table 4 Process 1 Methyl esterification A 2M hexane solution (4.5 mL) of trimethylsilyldiazomethane was added to the mixture of 2-nitro-3-methylbenzoic acid (1.6 g) and acetone (15 mL) and stirred for 3 hours. After removal of the solvent, the residue was diluted with ethyl acetate and washed with an aqueous solution of 1 M sodium hydrate, water and a saturated aqueous solution of sodium chloride respectively. Subsequently, the obtained substance was concentrated and dried to obtain methyl-2-nitro-methylbenzoate.

Process 2 Bromination Benzoyl peroxide was added to the mixture of methyl-2-nitro-3-methylbenzoate (1.6 g), N-bromosucciimide (2.0 g) and benzene (15 mL) and stirred at 90 ° C throughout the night. After removal of the solvent, the residue was diluted with ethyl acetate and washed with aqueous sodium thiosulfate, aqueous solution of 1 M sodium hydrate, water and saturated aqueous solution of sodium chloride respectively. Subsequently, the obtained substance was concentrated and dried, and the unpurified material obtained was purified by silica gel column chromatography to obtain methyl-3-bromomethyl-2-nitrobenzoate.

Process 3 Amination Methyl 3-bromomethyl-2-nitrobenzoate (1.6 g) was dissolved in methanol (5 mL). Methanol solution (6 mL) of 2 M dimethylamine was added thereto and stirred overnight. After removal of the solvent, the residue was diluted with 1 M hydrochloric acid and washed with ethyl acetate. The water layer was made alkaline with aqueous sodium hydrate solution and extracted with ethyl acetate. The usual work procedure was carried out to obtain methyl 3-dimethylaminomethyl-2-nitrobenzoate.

Process 4 Ester hydrolysis The mixture of methyl 3-dimethylaminomethyl-2-nitrobenzoate (0.72 g) and 6M hydrochloric acid was stirred at 100 ° C overnight. After cooling the mixture to room temperature, the precipitated crystals were filtered, washed with diethyl ether and dried under reduced pressure to obtain 3-dimethylaminomethyl-2-nitrobenzoic acid hydrochloride. H-NMR (DMSO) d 2.70 (s, 6H), 4.31 (s, 2H), 7.84 (m, 1 H), 8.07 (1H, d, J = 7.8 Hz), 8.32 (1H, d, J = 7.5 Hz) Process 5 Formation of acid chloride The mixture of 3-dimethiaminomethyl-2-nitrobenzoic acid hydrochloride (0.1 g) and thionyl chloride (5 mL) was stirred at 80 ° C for 3 hours. The solvent was removed and the residue was dried to obtain 3-dimethylamino-methyl-2-nitrobenzoyl chloride.

Process 6 Reaction of reaction 3-dimethylaminomethyl-2-nitrobenzoyl chloride (0.69 g), 0.11 g of the resin obtained in process 4 of example 1, 2,6-lutidine (0.04 ml) and NMP (1.5 ml) were mixed. and they reacted throughout the night. After removal of the solvent process, the residue was washed with NMP, methanol and dichloromethane three times each, and dried under reduced pressure.

Process 7 Reduction of the nitro group The reduction of the nitro group was carried out to the resin obtained in process 6 by the same procedure as that of process 7 in example 1.

Process 8 Construction of the quinazolinedione ring by carbonyldiimidazole The construction of the quinazolinedione ring was carried out to the resin obtained in process 7 by the same procedure as that of process 8 in example 1.

Process 9 Alkylation The resin obtained in process 8 was alkylated by the same procedure as that of process 9 in example 1.

Process 10 Excision from the resin The cleavage from the resin was carried out to the resin obtained in process 9 by the same procedure as that of process 10 in example 1 to obtain 12 mg of the intended compound. MS (ESI MH +): 569 EXAMPLE 22 Synthesis of the compound of the following formula (E-9) which has a substituent (s) of example 22 of Table 4 Methyl 3- (1-pyrrolidinylmethyl) -2-nitrobenzoate was obtained by the use of pyrrolidine in place of dimethylamino in process 3 of example 21.

Subsequently, the intended compound was obtained by the same procedures as those of processes 4 to 10 in example 21. MS (ESI MH +): 595 EXAMPLE 23 Synthesis of the compound of the following formula (E-9) which has a substituent (s) of example 23 of Table 4 The mixture of 4 mg of the compound of example 21, ethanol (3 mL) and 4M hydrogen chloride solution / dioxane (2 mL) was stirred at 85 ° C for 5 hours. After removal of the solvent, the residue was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 3.6 mg of the intended compound. MS (ESI MH +): 597 EXAMPLE 24 Synthesis of the compound of the following formula (E-9) which has a substituent (s) of example 24 of table 4 The mixture of 4 mg of the compound of example 21, dichloromethane (2 mL), triethylamine (10 μL), isopropanol (1 L), HOBt (15 mg) and EDC hydrochloride (20 mg) was stirred overnight. After removal of the solvent, the residue was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 3.6 mg of the intended compound. MS (ESI MH +): 611 EXAMPLES 25 to 27 Synthesis of the compounds of the following formula (E-9) which has a substituent (s) of examples 25 to 27 of table 4 The compounds were synthesized by the same procedure as that of example 24 except that the corresponding alcohols were used instead of isopropanol.

EXAMPLE 28 Synthesis of the compound of the following formula (E-10) which has a substituent (s) of example 28 of Table 5 The intended compound was obtained by the same procedure as that of Example 21 except that 2-nitro-5-acid was used -methylbenzoic as a raw material. MS (ESI MH +): 569 EXAMPLES 29 to 33 Synthesis of the compounds of the following formula (E-10) which has a substituent (s) of examples 29 to 33 of Table 5 The intended compounds were obtained by the same procedure as that of example 23 or 24 except that it was used the compound of Example 28 as a raw material.

EXAMPLE 34 Synthesis of the compound of the following formula (E-11) which has a substituent (s) of example 34 of Table 6: synthesis of N- (2,6-dichlorobenzoyl) -4- [7 - [(dimethylamino) trifluoroacetate methyl] -1-methyl-2,4-quinazolinedione-3-yl] -L-phenylalanine Process 1 Synthesis of 4- (hydroxymethyl-2-nitrobenzoic acid methyl ester 0.51 ml (5.36 mmol) ethyl chloroformate was added to the mixture of 1.0 g (4.46 mmol) of 4-methyloxycarbonyl-3-nitrobenzoic acid, 15 ml of tetrahydrofuran and 1.55 mL (11.2 mmol) of triethylamine under cooling with ice.After stirring for 30 minutes, the precipitated salts were filtered and 0.17 g (4.46 mmol) of sodium borohydride and 2 g of ice were added to the filtrate. of stirring at room temperature during the whole night, the solvent was removed and the usual work procedure was carried out on the residue. Subsequently, the material obtained was purified with silica gel column chromatography (30% ethyl acetate / hexane) to obtain the title compound. Yield: 0.64 g (3.04 millimoles) at 68% Process 2 Synthesis 4-f (dimethylamino) methyl-1-nitrobenzoyl chloride hydrochloride 0.64 g (3.04 mmol) of the compound obtained in process 1 were dissolved in 10 mL of methylene chloride and 0.635 mL (4.56 mmol) of triethylamine, and 0.282 mL (3.64 mmol) of methanesulfonyl chloride was added dropwise under ice-cooling. After stirring for 2 hours, the usual work procedure was carried out to the mixture in accordance with the usual method to obtain an unpurified material. The obtained unpurified material was treated by the same procedures as those of processes 3, 4 and 5 in Example 21 to obtain the title compound. Yield: 0.64 g (2.20 millimoles) at 75% Process 3 The same procedures were carried out sequentially as those of process 6 in example 21 and processes 7, 8, 9 and 10 in example 1 using the acid chloride obtained in process 2 and the resin obtained in process 4 of Example 1 to obtain the title compound. MS (ESI MH +): 569 EXAMPLE 35 Synthesis of the compound of the following formula (E-11) which has a substituent (s) of example 35 of Table 6: synthesis of N- (2,6-dichlorobenzoyl) -4- [1-methyl-7- (pyrrolidine -1-methylmethyl) 2,4-quinazoline-dione-3-yl] -L-phenylalanine trifiuoroacetate Process 1 Synthesis of 2-nitro-4- (pyrrolidin-1-ylmethyl) benzoyl chloride hydrochloride The title compound was obtained by the same procedure as that of example 34 except that pyrrolidine was used as amine instead of dimethylamine in the process 2 of example 34.

Process 2 Synthesis of N- (2,6-dichlorobenzoyl) -4- 1-methyl-7- (pyrrolidin-1-ylmethyl) -2,4-quinananedinedione-3-yl] -L-phenylalanine trifluoroacetate carried out sequentially the same procedures as those of process 6 in example 21 and processes 7, 8, 9 and 10 in example 1 using the acid chloride obtained in process 1 and the resin obtained in process 4 of Example 1 to obtain the title compound. MS (ESI MH +): 595 EXAMPLE 36 Synthesis of the compound of the following formula (E-12): synthesis of N- (2,6-dichlorobenzoyl) -4- (1-methyl-2,4-dioxo-1, 2,3,4-tetrahydrobenzo [g] quinazoline-3 (2H) -yl) -L-phenylalanine The title compound was obtained by the same procedures as those of processes 5, 8, 9 and 10 in Example 1 except that 3-amino-2-acid was used. Naphthalene carboxylic acid and the resin obtained in process 4 of Example 1, raw materials. MS (ESI MH +): 562 EXAMPLE 37 Synthesis of the compound of the following formula (E-13) which has a substituent (s) of example 37 of table 7: synthesis of N- (2,6-dichlorobenzoyl) -4- [1-methyl-6- (methylthio ) -2,4-quinazoline-dione-3-iI] -L-phenylalanine Process 1 Synthesis of 5-methylthio-2-nitrobenzoyl chloride 2.5 mL of 15% sodium methylmercaptan aqueous solution were added to the mixture of 1.0 g (5.40 miiimoles) of 5-fluoro-2-nitrobenzoic acid and 5 mL of ethanol and they were shaken for 2 days. Subsequently, 10 mL of water was added and the pH thereof was adjusted to be 1 by concentrated hydrochloric acid. After filtering the precipitated compound, it was washed with water, ether and hexane and dried to obtain an unpurified material of 5-methylthio-2-nitrobenzoic acid. 3 mL of thionyl chloride was added to the unpurified material obtained and stirred for 5 hours. The thionyl chloride was removed to obtain the title compound.

Process 2 Synthesis of N- (2,6-dichlorobenzoyl) -4-f1-methyl-6- (methylthioV2,4-quinazoline-dione-3-in-L-phenylalanine The title compound was obtained by the same procedures as those of process 6 in example 21 and processes 7, 8, 9 and 10 in example 1 except that acid chloride obtained in process 1 and the resin obtained in process 4 of example 1 were used as raw materials EM (ESI MH + ): 558 EXAMPLE 38 Synthesis of the compound of the following formula (E-13) which has a substituent (s) of example 38 of Table 7: synthesis of N- (2,6-dichlorobenzoyl) -4- [1-methyl-6- (methanesulfonyl) -2,4-quinazoline-dione-3-yl] -L-phenylalanine Process 1 Oxidation The mixture of 130 mg of the resin in process 2 of example 37 before carrying out the same procedure as that of process 10 in example 1 (cleavage from resin), 1.5 ml of methylene chloride and 0.20 g of meta-chloro perbenzoic acid was reacted for 24 hours. The obtained resin was washed with NMP, the mixed aqueous solution of sodium hydrogen carbonate and sodium thiosulfate, methanol and methylene chloride three times each and dried under reduced pressure.

Process 2 Synthesis of N- (2,6-dichlorobenzoyl) -4-H-methyl-6- (methylsulfoniD-2,4-quinazoline-dione-3-ip-L-phenylalanine The resin obtained in process 1 was treated by the same procedure as that of process 10 in example 1 to obtain the title compound. MS (ESI MH +): 590 EXAMPLE 39 Synthesis of the compound of the following formula (E-14) which has a substituent (s) of example 39 of table 8: synthesis of N- (2,6-dichlorobenzoyl) -4- [1-methyl-7- (morpholine -4-yl) -2,4-quinazoline-dione-3-yl] -L-phenylalanine trifluoroacetate Process 1 Synthesis of 4-fluoro-2-nitrobenzoyl chloride 5 mL of thionyl chloride were added to 0.5 g of 4-fluoro-2-nitrobenzoic acid and stirred overnight. The thionyl chloride was removed to obtain the title compound.

Process 2 Synthesis of N- (2,6-dichlorobenzoyl) -4- [1-methyl-7- (morpholine-4-yl) -2,4-quinazoline-dione-3-ip-L-phenylalanine trifluoroacetate The compound of title was obtained by the same procedures as those of process 6 in example 21 and processes 6, 7, 8, 9 and 10 in example 1 using the acid chloride obtained in process 1 and the resin obtained in process 4 of the example 1 as raw materials. MS (ESI MH +): 596 EXAMPLE 40 Synthesis of the compound of the following formula (E-14) which has a substituent (s) of example 40 of Table 8: synthesis of N- (2,6-dichlorobenzoyl) -4- [1-methyl-7- (pyrrolidin-1-yl) -2,4-quinazoline-dione-3-yl] -L-phenylalanine trifluoroacetate The title compound was obtained by the same procedure as that of example 39 except that pyrrolidine was used in place of morpholine for carry out the same procedure as that of process 6 in example 1 in process 2 of example 39. MS (ESI MH +): 581 EXAMPLES 41 to 42 Synthesis of the compounds of the following formula (E-15) which has a substituent (s) of examples 41 to 42 of Table 9. Compounds of the following formula (E-15) which has a substituent (s) of examples 41 to 42 of table 9 were synthesized by the same procedure as that of example 1 except that the corresponding amines were used in process 6 of example 1.

EXAMPLE 43 Synthesis of the compound of the following formula (E-16) which has a substituent (s) of example 43 of table 10 Process 1 Methyl ester of N- (2,6-dichlorobenzoyl) -4 - [(2-amino-5-iodobenzoyl) amino-1-L-phenylalanine The mixture of methyl ester of N- (2,6-dichlorobenzoyl) -4 -amino-L-phenylalanine (2.22 g), EDC / HCl (960 mg), HOBT (675 mg), triethylamine (834 μL), 2-amino-5-iodobenzoic acid (1.3 g) and dichloromethane (100 mL) were He stirred all night. The mixture was extracted with styling acetate and treated in accordance with the usual method to obtain an unpurified material of the intended compound.

Process 2 N- (2,6-dichlorobenzoyl) -4- [6-iodo-2,4-quinazoline-dione-3-irj-L-phenylalanine methyl ester The mixture of the unpurified material obtained in process 1, DMF (120 mL) and carbonyldiimidazole (4.5 g) was stirred at 80 ° C for 4 hours. The mixture was extracted with ethyl acetate and treated according to the usual method to obtain the title compound.

Process 3 N- (2,6-dichlorobenzoyl) -4-f1-methyl-6-iodo-2,4-quinazoline-dione-3-n-L-phenylalanine methyl ester DMF (20 mL), potassium carbonate (648 mg) and methyl iodide (176 μL) were added to the unpurified material obtained in process 2 and stirred at room temperature overnight. The mixture was extracted with ethyl acetate and treated according to the usual method.

Process 4 N- (2,6-dichlorobenzoii) -4-ri-methyl-6-iodo-2,4-quinazoline-dione-3-yl "l-phenylalanine The mixture of the unpurified material obtained in process 3 (20). mg), 4M dioxane acid chloride solution (1 mL) and water (100 μL) were stirred at 90 ° C for 4 hours.After removal of the solvent, the residue was purified by high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 3 mg of the intended compound MS (ESI MH +): 638 EXAMPLE 44 Synthesis of the compound of the following formula (E-16) which has a substituent (s) of Example 44 of Table 10 Process 1 N- (2,6-dichlorobenzoyl) -4- [1-methyl-6-cyano-2,4-q? Inazoline-dione-3-in-L-phenylalanine methyl ester The mixture of the unpurified material obtained in process 3 of Example 43 (220 mg), DMF (2 mL), tetrakis (triphenylphosphine) palladium (5 mg) and zinc cyanide (79 mg) were stirred at 90 ° C for 4 hours. The mixture was extracted with ethyl acetate and treated according to the usual method to obtain the title compound.

Process 2 N- (2,6-dichlorobenzoyl) -4- [1-methyl-6-cyano-2,4-quinazoline-dione-3-in-L-phenylalanine The unpurified material obtained in process 1 (60 mg ) was treated by the same procedure as that of process 4 in Example 43 to obtain the title compound. MS (ESI MH +): 537 EXAMPLES 45 and 46 Synthesis of the compounds of the following formula (E-16) which has a substituent (s) of examples 25 to 46 of Table 10 Process 1 N- (2,6-dichlorobenzoyl) -4-f1-methyl-6-benzyloxycarbonyl-2,4-quinazoline-dione-3-yl] -L-phenylalanine methyl ester The mixture of the unpurified material obtained in process 3 of Example 43 (311 mg), DMF (5 mL), palladium acetate (10 mg), benzyl alcohol (99 μL) and triethylamine (143 μL) were stirred under the presence of carbon monoxide at 100 ° C. C for 3 hours. The mixture was extracted with ethyl acetate and treated according to the usual method to obtain an unpurified material of the title compound.

Process 2 N- (2,6-dichlorobenzoyl) -4- [1-methyl-6-benzyloxycarbonyl-2,4-quinazoline-dione-3-yl] -L-phenylalanine and N- (2,6-dichlorobenzoyl) -4- [1-methyl-6-carboxyl-2,4-quinazoline-dione-3-yl] -L-phenylalanine The mixture of the unpurified material obtained in process 1 (60 mg), dioxane acid chloride solution 4M (1 mL) and water (100 μL) were stirred at 90 ° C for 4 hours. After removal of the solvent, the residue was purified by high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain the intended compound, 6-carboxyl compound (5 mg) and 6-benzyloxycarbonyl compound ( 1 mg). MS (ESI MH +): 556 (compound 6-carboxyl) MS (ESI MH +): 646 (compound 6-benzyloxycarbonyl) EXAMPLE 47 Synthesis of the compound of the following formula (E-17) Process 1 Methyl ester of N- (2,6-dichlorobenzoyl) -4- [2,4-dioxo-1, 2,3,4-tetrahydro-3- (2H) pyrido [3,2-d] pyrim Dinyl] -L-phenylalanine The title compound was obtained by the same procedures as those of process 1 in Example 43 except that 2-carboxy-3-aminopyridine was used in place of 2-amino-5-iodobenzoic acid, and then process 2 in example 43.

Process 2 N- (2,6-dichlorobenzoyl) -4- [1-methyl-2,4-dioxo-1, 2,3,4-tetrahydro-3- (2H) pyridof3,2-dlpyrimidinyl) methyl ester - L-phenylalanine The mixture of the unpurified material obtained in process 1, triphenylphosphine (60 mg), methanol (15 μL), 40% toluene solution (118 mg) of diisopropylazodicarboxylic acid and dichloromethane (2 mL) was stirred throughout the night. The mixture was extracted with ethyl acetate and treated according to the usual method to obtain the title compound.

Process 3 N- (2,6-dichlorobenzoyl) -4- [1-methyl-2,4-dioxo-1, 2,3,4-tetrahydro-3- (2H) p ridor o 3, 3-d] pyrimidine pL-phenylalanine The unpurified material obtained in process 2 (20 mg) was treated by the same procedure as that of process 4 in example 43 to obtain the title compound. MS (ESI MH +): 513 EXAMPLE 48 Synthesis of the compound of the following formula (E-18) The compound was obtained by the same procedure as that of example 47 except that 3-amino-4-carboxypyridine was used in place of 2-carboxy-3-aminopyridine in process 1 of example 47.

EXAMPLE 49 Synthesis of the compound of the following formula (E-19) which has a substituent (s) of example 49 of table 11 Process 1 Methyl ester of N- (2,6-dichlorobenzoyl) -4- [1-methyl-6- (2-t-butoxycarbonyletenyl) -2,4-quinazoline-dione-3-yl] -L-phenylalanine The mixture of the unpurified material obtained in process 3 of Example 43 (630 mg), DMF (5 mL), palladium acetate (22 mg), t-butyl acrylate (283 μL) and triethiamine (270 μL) was stirred at 70 ° C for 3 hours. The mixture was extracted with ethyl acetate and treated according to the usual method to obtain the title compound.

Process 2 The mixture of the unpurified material obtained in process 1, dichloromethane and TFA was stirred at room temperature for 1 hour. After removal of the solvent, the mixture of the unpurified material obtained, 4M dioxane acid chloride solution and water was stirred at 90 ° C for 4 hours. After removal of the solvent, the residue was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 10 mg of the intended compound. MS (ESI MH +): 582 EXAMPLE 50 Synthesis of the compound of the following formula (E-19) which has a substituent (s) of example 50 of table 11 Process 1 N- (2,6-dichlorobenzoyl) -4- [1-methyl-6- (trimethylsilylethoxycarbonyl) -2,4-quinazoline-dione-3-ill-L-phenylalanine methyl ester The mixture of the crude material obtained in the process 3 of Example 43 (6.58 mg), DMF (5 mL), palladium acetate (226 mg), trimethylsilyl ethanol (2.9 mL) and triethylamine (2.8 mL) was stirred under the existence of carbon monoxide at 50 ° C overnight. The mixture was extracted with ethyl acetate and treated according to the usual method to obtain the title compound.

Process 2 N- (2,6-dichlorobenzoyl) -4- [1-methyl-6-carboxy-2,4-quinazoline-dione-3-yl] -L-phenylalanine methyl ester Unpurified material obtained in process 1 (4.2 g), tetrahydrofuran (100 ml) and tetrabutylammonium fluoride (3.3 g) was stirred at room temperature for 2 hours. The mixture was extracted with ethyl acetate and treated according to the usual method to obtain the title compound.

Process 3 Triethylamine (70 μL) and ethyl chloroformate (20 μL) were added to the mixture of the unpurified material obtained in process 2 (142 mg) and tetrahydrofuran (50 mL) under ice-cooling and stirring for 30 minutes. After the addition of water with ammonia (1 mL) to the solvent of reaction and heating it to room temperature, the reaction mixture was stirred for 2 hours. Subsequently, the mixture was extracted with ethyl acetate and treated according to the usual method. The mixture of the crude material obtained, 4M dioxane acid chloride solution (2 mL) and water (200 μL) was stirred at 90 ° C for 4 hours. After removal of the solvent, the residue was purified by high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 7 mg of the intended compound. MS (ESI MH +): 555 EXAMPLE 51 Synthesis of the compound of the following formula (E-19) which has a substituent (s) of example 51 of table 11 Process 1 Methyl ester of N- (2,6-dichlorobenzoyl) -4-f1-methyl-6- (2-t-butoxycarbonyl-ethyl) -2,4-quinazoline-dione-3-yl] -L-phenylalanine mixture of the amount of five sixths of the unpurified material obtained in process 1 of example 49, methanol (10 mL), 6-hydrate of nickel chloride (191 mg) and sodium borohydride (62 mg) was stirred at room temperature for 6 hours. hours. The mixture was extracted with ethyl acetate and treated according to the usual method to obtain the intended compound.

Process 2 N- (2,6-dichlorobenzoyl) -4- [1-methyl-6- (2-carbonylethyl) -2,4-quinazoline-na-dione-3-yl] -L-phenylalanine methyl ester The mixture from the unpurified material obtained in process 1, dichloromethane (2 mL) and TFA (2 mL) was stirred at room temperature for 1 hour. The solvent was removed to obtain an unpurified material of the intended compound.

Process 3 The mixture of the unpurified material obtained in process 2, 4M dioxane acid chloride solution and water was stirred at 90 ° C for 4 hours.

After removal of the solvent, the residue was purified by high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain the intended compound. MS (ESI MH +): 584 EXAMPLE 52 Synthesis of the compound of the following formula (E-19) which has a substituent (s) of example 52 of table 11 Triethylamine (190 μL) and ethyl chloroformate (80 μL) were added to the mixture of the amount of five sixths of the unpurified material obtained in process 2 of example 51 and tetrahydrofuran (20 mL) under ice-cooling and stirred for 30 minutes. After the addition of two or three Pieces of ice and sodium borohydride (20 mg) were added to the reaction mixture and heating thereof to room temperature, the reaction mixture was stirred for 2 hours. Subsequently, the mixture was extracted with ethyl acetate and treated according to the usual method. The unpurified material obtained was dissolved in 4M dioxane acid chloride solution (2 mL) and water (200 μL) and stirred at 90 ° C for 4 hours. After removal of the solvent, the residue was purified by high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 7 mg of the intended compound. EM (ESI MH +): 570 EXAMPLE 53 Synthesis of the compound of the following formula (E-20) which has a substituent (s) of example 53 of table 12 Process 1 N- (2,6-dichlorobenzoyl) -4- [1-methyl-6-hydroxymethyl-2,4-quinazoline-dione-3-yl] -L-phenylalanine methyl ester Triethylamine (970 μL) was added and ethyl chloroformate (400 μL) to the mixture of the unpurified material obtained in process 2 of the example 50 (142 mg) and tetrahydrofuran (100 mL) were cooled under ice and stirred for 30 minutes. After filtration, two or three pieces of ice and sodium borohydride (160 mg) were added to the filtrate. After warming from this to room temperature, the reaction mixture was stirred for 2 hours. Subsequently, the mixture was extracted with ethyl acetate and treated according to the usual method to obtain the intended compound.

Process 2 N- (2,6-dichlorobenzoiD-4-f1-methyl-6-chloromethyl-2,4-quinazoline-dione-3-ill-L-phenylalanine The mixture of the unpurified material obtained in process 1, solution of 4M dioxane acid chloride (4 mL) and water (400 μL) were stirred at 80 ° C for 2 hours. After removal of the solvent, the residue was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain the intended compound.

Process 3 The mixture of the substance obtained in process 2 (20 mg), acetonitrile (1 mL) and morpholine (6 μL) was stirred at room temperature for 2 hours. After removal of the solvent, the residue was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 3 mg of the intended compound. MS (ESI MH +): 611 EXAMPLES 54 to 58 Synthesis of the compounds of the following formula (E-20) which has a substituent (s) of examples 54 to 58 of table 12 The compounds were synthesized by the same procedure as that of process 3 in example 53 except that they used the corresponding amines instead of the morpholine in the process. NMR data of the compound of Example 54: 1 H-NMR (DMSO-d 6) 9.13 (d, 1 H, J = 8.4 Hz), 8.69-8.97 (br, 2H), 8.23 (d, 1 H, J = 2.1 Hz ), 7.86 (dd, 1 H, J = 8.6, 2.1 Hz), 7.57 (d, 1 H, J = 8.7 Hz), 7.34-7.43 (m, 6H), 7.18 (d, 2H, J = 8.4 Hz) , 4.70-4.78 (m, 1 H), 4.22-4.26 (m, 2H), 3.53 (s, 3H), 3.22 (dd, 1H, J = 14.2, 4.3 Hz), 2.91-3.00 (m, 3H), 1.19 (t, 3H, J = 7.3 Hz).

EXAMPLE 59 Synthesis of the compound of the following formula (E-21) Process 1 The mixture of the unpurified material obtained in process 3 of Example 43, DMSO (2 mL), copper iodide (11 mg), potassium carbonate (273 mg) and aminoimidazole (273 mg) was stirred at 130 ° C for 2 days. The mixture was extracted with ethyl acetate and treated according to the usual method.

After removal of the solvent, the residue was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) and the ester hydrolysis was carried out by the same procedure as that of process 4 in the Example 43 to obtain the title compound. MS (ESI MH +): 593 EXAMPLE 60 Synthesis of the compound of the following formula (E-22) which has a substituent (s) of example 60 of Table 13 The mixture of methyl ester of N- (2,6-dichlorobenzoyl) -4- [1-methyI-6 -hydroxymethyl-2,4-quinazoIina-dione-3-yl] -L-phenylalanine (7 mg) which was obtained by the same procedure as that of process 1 in example 53 and subsequently the purification with high performance liquid chromatography , tetrahydrofuran (1 mL), water (1 mL) and lithium hydroxide (1.2 mg) were stirred at room temperature for 2 hours. The mixture was extracted with ethyl acetate, treated according to the usual method and purified by high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 1 mg of the intended compound. MS (ESI MH +): 542 EXAMPLE 61 Synthesis of the compound of the following formula (E-22) which has a substituent (s) of example 61 of table 13 The mixture of the substance obtained in process 2 of the example 53 (40 mg), methanol (1 mL) and 40% methanol solution (1 mL) of sodium methoxide was stirred at room temperature for 2 hours. The mixture was treated according to the usual method and purified by high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 4 mg of the intended compound. MS (ESI MH +): 556 EXAMPLE 62 Synthesis of the compound of the following formula (E-23) which has a substituent (s) of Example 62 of Table 14 Process 1 Acylation reaction 3-Methoxymethyl-2-nitrobenzoic acid (160 mg), DIC (58 μL), HOAt (101 mg) and NMP (1.5 mL) were mixed and stirred for 3 hours.

Subsequently, the mixture was added to 200 mg of the resin obtained in process 4 in example 1 and reacted for 17 hours. After Removal of the excess solvent, the resin was washed with NMP, methanol and dichloromethane three times each, and dried under reduced pressure.

Process 2 Reduction of the nitro group SnCl2-2H2O (1.5 g), NMP (3 mL) and EtOH (150 μL) were added to the resin obtained in process 1 and reacted at room temperature for 16 hours. After removal of the solvent, the resin was washed with NMP, methanol and dichloromethane three times each, and dried under reduced pressure.

Process 3 Construction of the quinazolinedione ring with carbonyldiimidazole Carboniidiimidazole (400 mg) and NMP (2 mL) were added to the resin obtained in process two and stirred at 90 ° C for 21 hours. After removal of the excess solvent, the resin was washed with NMP, methanol and dichloromethane three times each time, and dried under reduced pressure.

Process 4 Alkylation Methyl iodide (200 μL), tetramethyl guanidine (200 μL) and NMP (2.5 mL) were added to the resin obtained in process 3, stirred for 1 hour, and washed with methanol and NMP three times each once after the removal of excess solvent. After repeating these three processes At times, the resin was washed with methanol and dichloromethane three times each time, and dried under reduced pressure.

Process 5 Excision from resin The resin obtained in process 4 was treated with trifluoroacetic acid containing 5% water for 1 hour. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 16 mg of the intended compound. MS (ESI MH +): 556 EXAMPLE 63 Synthesis of the compound of the following formula (E-23) which has a substituent (s) of example 63 of table 14 The intended compound was obtained by the same procedure as that of example 62 except that 4-methoxymethyl-2 acid was used -nitrobenzoic acid instead of 3-methoxymethyl-2-nitrobenzoic acid. MS (ESI MH +): 556 EXAMPLE 64 Synthesis of the compound of the following formula (E-24) Process 1 nitration ß-picoline-N-oxide (10 g) was added slowly to the mixed acid of the concentrated sulfuric acid (35 mL) and concentrated nitric acid (27.5 mL) at 0 ° C, gradually heated to 105 ° C and It stirred for 4 hours. The reaction solvent which was cooled to room temperature was poured into ice (100 g) and sodium carbonate (60 g) was added thereto. After filtering the precipitate, the reaction mixture was washed with water and dried under reduced pressure to obtain 5.83 g of 3-methyl-4-nitropyridine-N-oxide.

Process 2 Oxidation The substance obtained in process 1 (5.83 g) and the dehydrating sodium dichromate (11.4 g) were slowly added to the concentrated sulfuric acid (39.5 mL) at 0 ° C and reacted at room temperature for 4 hours. The reaction solvent was poured into ice (80 g) and slowly water (100 mL) was added thereto. Additionally, sodium acid sulfite was added thereto until the orange color of the hexavalent chromium vanished and the precipitate was filtered. The ethyl acetate and 1 N hydrochloric acid were added to the filtered, extracted and washed solid substance. The layer of Ethyl acetate was concentrated under reduced pressure to obtain the powder of 4-nitronicotinic acid N-oxide (3.23 g).

Process 3 Catalytic reduction Water (75 mL), 28% ammonia in water (1.2 mL) and 10% Pd / C (0.8 g) were added to the substance obtained in process 2 (1.5 g) and stirred in an atmosphere. of hydrogen (3.8 kg / cm2) for 8 hours. The reaction solvent was filtered and the filtrate was concentrated under reduced pressure so that the measurement of the liquid was 15 mL. 1 N Hydrochloric acid was added to adjust the pH of the solvent so that the precipitated insoluble materials were filtered off to become slightly acidic. The residue was washed with water and dried under reduced pressure to obtain the powder of 4-aminonicotinic acid (620 mg).

Process 4 Acylation reaction The substance obtained in process 3 (207 mg), DIC (116 μL), HOAt (204 mg), DIEA (131 μL) and DMP (3 mL) were mixed and stirred for 10 hours. Subsequently, the mixture was added to 200 mg of the resin obtained in process 4 in example 1 and reacted for 14 hours. After removal of the excess solvent, the resin was washed with NMP, methanol and dichloromethane three times each, and dried under reduced pressure.

Process 5 Construction of the quinazolinedione ring with carbonyldiimidazole Carbonyldiimidazole (400 mg) and NMP (2 mL) were added to the resin obtained in process 4 and stirred at 90 ° C for 18 hours. After removal of the excess solvent, the resin was washed with NMP, methanol and dichloromethane three times each, and dried under reduced pressure.

Process 6 Alkylation Triphenylphosphine (520 mg), methanol (80 μL), 40% toluene solution (1 mL) of diisopropylazodicarboxylic acid and dichloromethane (2 mL) were added to the resin obtained in process 5 and stirred for 19 hours . After removal of the excess solvent, the resin was washed with NMP, methanol and dichloromethane three times each, and dried under reduced pressure.

Process 7 Excision from resin The resin obtained in process 6 was treated with trifluoroacetic acid containing 5% water for 1 hour. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 28 mg of the intended compound. MS (ESI MH +): 513 EXAMPLES 61 to 81 Synthesis of the compounds of the following formula (E-25) which has a substituent (s) of the examples at 65 to 81 of tables 15-1 and 15-2. The intended compounds were obtained by the following methods, A to C: A (Methylesterification) The corresponding carboxylic acids were added to the mixture of methanol and thionyl chloride and stirred overnight.

After removal of the solvent, the residue was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain the intended compound (s).

B The mixture of the corresponding carboxylic acids, suitable solvent (s) such as DMF and dichloromethane, combined organic base (s) such as triethylamine and diisopropylethylamine, corresponding alcohols, HOBt if necessary, and EDC hydrochloride was stirred overnight. After concentration, the mixture was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain the intended compound (s).

C The mixture of the corresponding carboxylic acids, corresponding alcohols and 4M dioxane acid chloride solution were stirred at 90 ° C for several hours. After removal of the solvent, the unpurified material was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain the intended compound (s).

EXAMPLES 82 to 86 Synthesis of the compounds of the following formula (E-26) which has a substituent (s) of Examples 82 to 86 of Table 16 The intended compounds were obtained by the same procedure as that of either A, B, or C in the aforementioned examples.

EXAMPLES 87 to 88 Synthesis of the compounds of the following formula (E-27) which has a substituent (s) of examples 87 to 88 of Table 17 EXAMPLE 87 The substance obtained in process 2 of Example 50 was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain the intended compound. EM (ESI MH +): 570 EXAMPLE 88 Methanol (2 mL) and 2M hexane solution (1 mL) of trimethylsilyldiazomethane were added to the substance obtained in process 2 of Example 50 and stirred for 3 hours. After removing the solvent, the obtained substance was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain the intended compound. MS (ESI MH +): 584 EXAMPLE 89 Synthesis of the compound of the following formula (E-28) Process 1 Methyl ester of N- (2,6-dichlorobenzoyl) -4-f1-methyl-6- (2-hydroxyethylamino) -2,4-quinazoline-dione-3-yl] -L-phenylalanine The mixture of the material without purify obtained in the process 3 of Example 43 (100 mg), dimethylacetoamide (2 mL), copper iodide (3 mg), aminoethanol (0.011 mL) and potassium carbonate (41 mg) were mixed at 80 ° C overnight . After extracting the mixture with ethyl acetate and removing the solvent, the residue was purified by high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain the intended compound.

Process 2 The mixture of the unpurified material obtained in process 2, 4M dioxane acid chloride solution (2 mL) and water (200 μL) were stirred at 90 ° C for 4 hours. After removal of the solvent, the residue was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain the intended compound. MS (ESI MH +): 571 EXAMPLE 90 Synthesis of the compound of the following formula (E-29) The mixture of 40 mg of the carboxylic acid obtained in Example 34, 5 mL of ethanol and 5 mL of dioxane solution containing 4M acid chloride was stirred at 90 ° C for 2 hours. hours. After removal of the solvent, the residue was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain the intended compound. MS (ESI MH +): 597 H-NMR (DMSO) d 1.20 (3H, t), 2.80 (6H, s), 2.95-3.25 (2H,), 3.55 (3H, s), 4.15 (2H, q), 4.45 (2H, s), 4.80 (1H, d), 7.20 (2H, d), 7.35-7.50 (6H, m), 7.70 (1H, s), 8.15 (1H, d), 9.25 (1H , d).

EXAMPLE 91 Synthesis of the compound of the following formula (E-30) The mixture of 50 mg of the carboxylic acid obtained in Example 54, 0.5 mL of benzyl alcohol and 1 mL of dioxane solution containing 4M acid chloride was stirred at 90 ° C. 4 hours. After concentration of the reaction solvent, the mixture was purified by high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain the intended compound.

MS (ESI MH +): 659 H-NMR (DMSO) d 1.20 (3H, t), 2.90-3.40 (4H, m), 3.55 (3H, s), 4.25 (2H, t), 4.90 (1H, m ), 5.20 (2H, s), 7.20 (2H, d), 7.30-7.50 (10H, m), 7.60 (1H, d), 7.90 (1H, d), 8.25 (1H, d), 8.80 (2H, br), 9.30 (1 H, d).

EXAMPLE 92 Synthesis of the compound of the following formula (E-31) Process 1 Acylation reaction The mixture of 600 mg of N- (2, 6-dichlorobenzoyl) -4-amino-L-phenylalanine obtained in process 4 of example 1 wherein the carboxyl group was bound with Wang resin, 730 mg of 2-amino-4,5-difluorobenzoic acid, 320 μL of DIC (diisopropylcarbodiimide), 570 mg of HOAt (1-hydroxy-7-azabenzotriazole) and 6 mL of NMP (N-methyl-pyrroiidone) were stirred at room temperature overnight. After removal of the solvent, the residue was washed with NMP, methanol, dichloromethane and diethyl ether, and dried under reduced pressure.

Process 2 Construction of the quinazolinedione ring with carbonyldiimidazole Carbonyldiimidazole (600 mg) and NMP (4.9 mL) were added to the resin obtained in process 1 and stirred at room temperature for 13 minutes. hours. After removal of the excess solvent, the resin was washed with NMP, methanol and dichloromethane four times each time, and dried under reduced pressure. Carbonyldiimidazole (600 mg) and NMP (4.9 mL) were added back to the resin and stirred at room temperature for 16 hours. After removal of the excess solvent, the resin was washed with NMP, methanol and dichloromethane four times each, and dried under reduced pressure.

Process 3 Substitution of the fluoro group with amine Imidazole (600 mg), diisopropylethylamine (600 μL) and NMP (3 mL) were added to 340 mg of the resin obtained in process 2 and reacted for 14.5 hours. After removal of the excess solvent, the resin was washed with NMP, methanol and dichloromethane four times each, and dried under reduced pressure.

Process 4 Alkylation Triphenylphosphine (780 mg), methanol (120 μL), 40% toluene solution (1.5 mL) of diisopropylazodicarboxylic acid and dichloromethane (3 mL) were added to the resin obtained in process 3 and stirred for 18.5 hours. . After removal of the excess solvent, the resin was washed with NMP, methanol and dichloromethane four times each, and dried under reduced pressure.

Process 5 Cleavage from the resin, purification Cleavage from the resin and purification thereof was carried out on the resin obtained in process 4 by the same procedure as that of process 10 in example 1 to obtain 95 mg of the intended compound. MS (ESI MH +): 596 1 H-NMR (SO-D 6 D): d 2.94-3.04 (1 H, m), 3.20-3.27 (1H, m), 4.71-4.80 (1H, m), 7.23 (2H, d, J = 8.4 Hz), 7.39-7.47 (5H, m), 7.58 (1H, s), 7.87 (1H, d, J = 6.0 Hz), 8.04-8.10 (2H, m), 8.96 (1H, s), 9.15 (1 H, d, J = 8.1 Hz), 12.80 (1 H, brs).

EXAMPLE 93 Synthesis of the compound of the following formula (E-32) Process 1 Synthesis of N- (t-butoxycarbonyl) -4- (6-dimethylamino-2,4-quinazoline-dione-3-iO-L-phenylalanine methyl ester 3 g of N- (t-butoxycarbonyl) methyl ester 4-amino-L-phenylalanine, 2.73 g of methyl 2-amino-5- (dimethylamino) benzoate dihydrochloride, 1.65 g of CDl (carbonyldiimidazole) and 50 mL of acetonitrile were stirred at room temperature, then 2.8 mL were added. of triethylamine thereto and stirred at 60 ° C overnight, after removal of the solvent, the residue obtained was extracted ethyl acetate, washed with water and with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After removal of the solvent, the obtained residue was purified with silica gel column chromatography to obtain 2 g of the title compound.

Process 2 Synthesis of 4- (6-dimethylamino-1-methyl-2,4-quinazoline-dione-3-yl) -L-phenylalanine methyl ester dihydrochloride The 500 mg mixture of the quinazolinedione obtained in process 1, 0.3 mL of methanol, 0.4 g of triphenylphosphine, 0.7 mL of 45% toluene solution of diisopropydiazodicarboxylic acid and dichloromethane were stirred overnight. After removal of the solvent, the residue was treated according to the usual method using dichloromethane as a solvent for extraction to obtain an unpurified material of N- (t-butoxycarbonyl) -4- (6-dimethylamino-1) methyl ester -methyl-2,4-quinazoline-dione-3-yl) -L-phenylalanine. Mixing the unpurified material, 5 mL of the dioxane solution containing 4M acid chloride and 5 mL of dichloromethane was stirred at room temperature for 5 hours. After removal of the solvent, the obtained residue was washed with dichloromethane to obtain an unpurified material of the title compound.

Process 3 Synthesis of N- (2-chloro-6-fluorobenzoyl) -4- (6-dimethylamino-1-methyl-2,4-quinazoline-dione-3-yl-L-phenylalanine trifluoroacetate) The mixture of 100 mg of the unpurified amine material obtained in process 2, 80 mg of 2-chloro-6-fluorobenzoyl chloride, 100 μL of triethylamine and 4 mL of DMF (dimethylformamide) was stirred at room temperature and treated in accordance with the usual method using ethyl acetate as a solvent for extraction for obtain an unpurified material. The unpurified material obtained was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 51 mg of the intended compound. MS (ESI MH +): 553 Process 4 Synthesis of N- (2-chloro-6-fluorobenzoyl) -4- (6-dimethylamino-1-methyl-2,4-quinazoline-dione-3-yl-phenylalanine trifluoroacetate The mixture of 15 mg of the compound of the methyl ester obtained in process 3 of Example 93, 3 mL of dioxane solution containing 4M acid chloride and 2 mL of water was stirred at 80 ° C for 2 hours.After removal of the solvent, the residue was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA (trifluoroacetic acid)) to obtain the intended compound MS (ESI MH +): 539 EXAMPLE 94 Synthesis of the compound of the following formula (E-33) Process 1 Acylation reaction The mixture of 50 mg of the amine compound obtained in process 2 of example 93, 38 mg of 2,4-dichloropyridine-2-carboxylic acid obtained by the same procedure as that of Eur. J. Org. Chem. 2001, 1371-1376, 30 mg of HOAt, 38 mg of EDC / HCl (1-dimethylaminopropinium-3-ethylcarbodiimide hydrochloride), 560 μL of triethylamine and 2 mL of DMF were stirred at 40 ° C. The reaction solvent was purified by high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA (trifluoroacetic acid)) to obtain the intended compound. EM (ESI MH +): 570 Process 2 Ester hydrolysis The intended compound was obtained by the same procedure as that of process 4 in example 93 using the ester obtained in process 1. MS (ESI MH +): 556 EXAMPLE 95 Synthesis of the compound of the following formula (E-34) The intended compound was obtained by the same procedure as that of process 4 in example 92, using the resin obtained by the same procedure as that of process 2 in example 92. EM (ESI MH +): 548 EXAMPLE 96 Synthesis of the compound of the following formula (E-35) Lithium hydroxide (7 mg), methanol (3.5 mL), tetrahydrofuran (0.5 mL) and acetone (2.0 mL) were added to the compound obtained in Example 88 (60 mg). and were stirred at room temperature for 30 minutes. After removal of the excess solvent, the residue was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 6.3 mg of the intended compound. EM (ESI MH +): 570 EXAMPLE 97 Synthesis of the compound of the following formula (E-36) Process 1 N- (2,6-dichlorobenzoon-4- (1-methyl-2,4-dioco-1, 2,3,4-tetrahydro-pyrimido [4,5-d] pyrimidine-3- (2H ) -l) -L-phenylalanine The mixture of the compound obtained in Example 131 (15 mg), 4M dioxane acid chloride solution (1 mL) and water (200 μL) was stirred at 90 ° C for 2 hours. After removal of the solvent, the residue was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain the intended compound. MS (ESI MH +): 514 EXAMPLES 98 to 99 Synthesis of the compounds of the following formula (E-37) which has a substituent (s) of the examples 98 to 99 of Table 18 The compounds were synthesized by the same procedure as that of process 3 in Example 53 except that they used the corresponding amines instead of the morpholine. MS data (ESI MH +) of the compound of example 99: 555 NMR data of the compound of example 99: 1 H NMR (DMSO-d 6): d 2.58 (3 H, t, J = 5.1 Hz), 2.98 (1 H, dd, J = 14.1, 10.5 Hz), 3.24 (1H, dd, J = 14.1, 4.5 Hz), 3.55 (3H, s), 4.22-4.28 (1H, m), 4.61-4.80 (1 H, m), 7.20 ( 2H, d, J = 8.4 Hz), 7.39-7.46 (5H, m), 7.60 (1H, d, J = 9.0 Hz), 7.88 (1 H, d, J = 6.9 Hz), 8.24 (1H, d, J = 1.5 Hz), 8.80 (2H, brs), 9.15 (1H, d, J = 8.7 Hz), 12.90 (1H, brs) EXAMPLE 100 Synthesis of the compound of the following formula (E-38) Process 1 Alkylation Methyl iodide (200 μL), potassium carbonate was added (200 mg) and NMP (4 mL) to the resin obtained in process 2 of example 19 (400 mg) and stirred at 60 ° C for 9 hours. After removal of the solvent, the resin was washed with NMP, methanol and dichloromethane three times each, and dried under reduced pressure.

Process 2 Excision from the resin, purification The cleavage from the resin and purification thereof was carried out on the resin obtained in process 1 by the same procedure as that of process 10 in example 1 to obtain 31 mg of the intended compound. MS (ESI MH +): 555 EXAMPLES 101 to 121 Synthesis of the compounds of the following formula (E-39) which has a substituent (s) of Examples 101 to 121 of Tables 19-1, 19-2 and 19-3 The intended compounds were obtained from the following methods, A to E: A (methylesterification) The corresponding carboxylic acids were added to the mixture of methanol and thionyl chloride and stirred overnight.

After removal of the solvent, the residue was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain the intended compound (s). B The mixture of the corresponding carboxylic acids, suitable solvent (s) such as DMF and dichloromethane, combined organic base (s) such as triethylamine and diisopropylethylamine, corresponding alcohols, HOBt if necessary, and EDC hydrochloride was stirred overnight. After concentration, the mixture was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain the intended compound (s). C The mixture of the corresponding carboxylic acids, corresponding alcohols and 4M dioxane acid chloride solution was stirred at 90 ° C for several hours. After the removal of the solvent, the material without purify was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain the intended compound (s). D. The mixture of the corresponding carboxylic acids, methylalcohol and 2.0M hexane solution of trimethylsilyldiazomethane was stirred at room temperature for a few minutes. After removal of the solvent, the unpurified material obtained was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain the desired compound (s). E The mixture of the corresponding carboxylic acids, ethylene glycol, EDC / HCl, HOAt and dichloromethane was stirred. After removal of the solvent, the unpurified material obtained was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain the intended compound (s). NMR data of the compound of Example 111: 1 H-NMR (DMSO-de): d 9.23 (d, 1H, J = 8.1 Hz), 8.64-8.79 (br, 2H), 8.23 (d, 1 H, J = 2.2 Hz), 7.86 (dd, 1H, J = 2.1 Hz, J = 8.7 Hz), 7.57 (d, 1H, J = 8.7 Hz), 7.35-7.45 (m, 6H), 7.19 (d, 2H, J = 8.3 Hz), 4.93 (sep, 1 H, J = 6.3 Hz), 4.75 (m, 1 H), 4.24 (m, 2H), 3.53 (s, 3H), 3.17 (dd, 1 H, J = 5.0 Hz, J = 14.5 Hz), 2.94-3.00 (m, 3H), 1.21 (d, 3H, J = 6.2 Hz), 1.19 (t, 3H, J = 7.3 Hz), 1.17 (d, 3H, J = 6.2 Hz). The corresponding carboxylic acid which is the unpurified synthetic material of the compound of Example 111 is the compound of Example 54.

In addition, the compound of example 111 was obtained by the same procedure as that of process 3 in example 53 except that the compound of process 1 in example 174 was used as an unpurified material and ethylamine was used in place of morpholine .

EXAMPLES 122 to 123 Synthesis of the compounds of the following formula (E-40) which has a substituent (s) of example 122 to 123 of Table 20 The intended compounds were obtained by the same procedure as that of C or D in the aforementioned examples.

EXAMPLE 124 Synthesis of the compounds of the following formula (E-41) The intended compound was obtained by the same procedure as that of D in the aforementioned examples 101 to 121. MS (ESI MH +): 610 EXAMPLE 125 Synthesis of the compounds of the same formula (E-42) The intended compounds were obtained by the same procedure as that of D in the aforementioned examples 101 to 121. MS (ESI MH +): 530 EXAMPLES 125 to 127 Synthesis of the compounds of the following formula (E-43) which has a substituent (s) of examples 126 to 127 of Table 21 EXAMPLE 126 The unpurified material obtained in process 2 of example 47 was treated according to the usual method to obtain the title compound.

EXAMPLE 127 Isopropanol (2 mL) and concentrated sulfuric acid (0.1 mL) were added to the substance obtained in example 47 (50 mg) and heated and refluxed for 2 hours. After removal of the solvent, the reaction mixture was treated according to the usual method to obtain the title compound.

EXAMPLE 128 Synthesis of the compounds of the following formula (E-44) The intended compound was obtained by the same procedure as that of D in the aforementioned examples 101 to 121. MS (ESI MH +): 527 EXAMPLE 129 Synthesis of the compounds of the following formula (E-45) Process 1 Methyl ester of 4-f (4-aminopyrimidine-5-ipcarbonyl-amino- N- (2,6-dichlorobenzoyl) -L-phenylalanine The mixture of methyl ester of N- (2,6-dichlorobenzoyl) -4-amino- L-phenylalanine (1.0 g), EDC / HCl (783 mg), HOAt (555 mg), triethylamine (747 μL), 4-aminopyrimidine-5-carboxylic acid (417 mg) and dichloromethane (15 mL) were stirred throughout After diluting the mixture with dichloromethane and washing it with water saturated with sodium bicarbonate, the aqueous layer of the it was dried over sodium sulfate and concentrated. The residue was washed with dichloromethane to obtain 125 mg of an unpurified material of the title compound.

Process 2 Methyl ester of N- (2,6-dichlorobenzoi-4- (2,4-dioxo-1, 2,3,4-tetrahydropyrimido [4,5-dlpyrimidine-3- (2H) -yl) -L- phenylalanine The mixture of the unpurified material obtained in process 1 (145 mg), DMF (10 mL) and carbonyldiimidazole (482 mg) was stirred at 110 ° C for 24 hours.The mixture was extracted with ethyl acetate and treated with ethyl acetate. according to the usual method to obtain an unpurified material of the title compound.

Process 3 N- (2,6-dichlorobenzoyl) -4- (1-methyl-2,4-dioxo-1, 2,3,4-tetrahydropyrimido [4,5-dlpyrimidine-3 (2H) -yl) methyl ester ) -L-phenylalanine DMF (2 mL), potassium carbonate (62 mg) and methyl iodide (40 μL) were added to the unpurified material obtained in process 2 and stirred at room temperature for 3 hours. The mixture was extracted with ethyl acetate and purified by high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 61 mg of the intended compound (s). MS (ESI MH +): 528 EXAMPLE 131 Synthesis of the compounds of the following formula (E-46) The intended compound was obtained by the same procedure as that of D in the aforementioned examples 101 to 121. MS (ESI MH +): 583 EXAMPLE 132 Synthesis of the compounds of the following formula (E-47) The intended compound was obtained by the same procedure as that of C in the aforementioned examples 101 to 121. EM (ESI M +): 624 EXAMPLES 133 to 134 Synthesis of the compounds of the following formula (E-48) which has a substituent (s) of examples 133 to 134 of Table 22 EXAMPLE 133 The mixture of the compound of Example 54 (19 mg), acetonitrile (3 mL), triethylamine (18 μL) and methyl chloroformate (5 μL) was stirred at room temperature for 5 minutes. After removal of the solvent, the residue was purified by high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 17 mg of the intended compound (s). MS (ESI MH +): 641 EXAMPLE 134 The mixture of the compound of Example 54 (26 mg), aeetonitrile (3 mL), triethylamine (20 μL) and acetyl chloride (6 μL) was stirred at room temperature for 10 minutes. After removal of the solvent, the residue was purified by high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 22 mg of the intended compound (s). MS (ESI MH +): 625 REFERENCE EXAMPLE 1 Synthesis of 3-methoxymethyl-2-nitrobenzoic acid Process 1 Methoxylation The methanol solution (4.7 mL) of sodium methoxide (197 mg) was added dropwise to the mixture of methyl 3-bromomethyl-2-nitrobenzoate (1 g) and methanol (7 mL) under heating and reflux. Two minutes later, the mixture was cooled with ice and 1.82 mL of 4M dioxane acid chloride solution was added dropwise thereto. After removal of the solvent, diethyl ether and water were added and the organic layer thereof was dried over sodium sulfate. After removal of the solvent, the obtained residue was purified with silica gel column chromatography to obtain 621 mg of methyl 3-methoxymethyl-2-nitrobenzoate Process 2 Hydrolysis of the methyl ester The mixture of 582 mg of the substance obtained in the process 1, 10 mL of 1,4-dioxane and 10 mL of 6M hydrochloric acid was stirred at 80 ° C for two nights. After the addition of ethyl acetate and 1 N hydrochloric acid to the reaction mixture and extraction thereof, the organic layer was washed with aqueous sodium hydroxide solution. In addition, the aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. After the Removal of the solvent, the residue was dried under reduced pressure to obtain 288 mg of the title compound.

REFERENCE EXAMPLE 2 Synthesis of 4-methoxymethyl-2-nitrobenzoic acid Process 1 Reduction of the carboxylic acid Tetrahydrofuran solution of the 1.0 M borane-tetrahydrofuran complex was added dropwise to the solution tetrahydrofuran (45 mL) of 2.25 g of 4-methyloxycarbonyl-3-nitrobenzoic acid and stirred at room temperature for 48 hours . Methylalcohol (2 mL) and 1 N hydrochloric acid (10 mL) were added thereto and concentrated. After the addition of ethyl acetate and water, liquid separation was carried out. The organic layer was washed with saturated sodium hydrogen carbonate and dried over sodium sulfate. After removal of the solvent, the unpurified material obtained was purified with silica gel column chromatography to obtain 1.33 g of methyl 4-hydroxymethyl-2-nitrobenzoate.

Process 2 Chlorination The mixture of 1.33 g of benzyl alcohol obtained in the process 1, 18 mL of tetrahydrofuran, 60 mL of diethyl ether, 1.8 mL of thionyl chloride and 91 μL of pyridine were stirred at room temperature overnight.

After the addition of ethyl acetate and 10 mL of 1N hydrochloric acid, the liquid separation was carried out. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. After removal of the solvent, the mixture was dried under reduced pressure to obtain 1.29 g of methyl 4-chloromethyl-2-nitrabenzoate Process 3 Methoxylation, hydrolysis of methyl ester 40 ml of methylalcohol and 1.22 g of sodium methoxide were added to 1.29 g of benzyl chloride obtained in process 2 and stirred at 80 ° C for 1.5 hours, after cooling of the solution at room temperature, 10 mL of water was added and stirred overnight. Ethyl acetate and water, an aqueous solution of 0.1 N sodium hydroxide and a saturated aqueous solution of sodium chloride were added thereto and liquid separation was carried out. The water layer was made acidic by hydrochloric acid and extracted with ethyl acetate. After removal of the solvent, the unpurified material obtained was purified by high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 450 mg of the title compound.

REFERENCE EXAMPLE 3 Synthesis of methyl 2-amino-5- (dimethylamino) benzoate / dihydrochloride Process 1: 30.0 g (148 millimoles) of 5-chloro-2-nitrobenzoic acid were dissolved in 78 mL (744 millimoles) of a 50% aqueous solution of dimethiamine under cooling in the ice bath. The solution was heated to 60 ° C in a sealed tube for 23 hours. The reaction solution was completely cooled and the internal pressure was released from it. After monitoring the term of the reaction by HPLC analysis, the reaction solution was placed in another container (using approximately 50 mL of water), and 49.6 mL of concentrated hydrochloric acid was added thereto and subsequently 200 mL of water was added thereto. The yellow crystals were precipitated by the addition of hydrochloric acid. The crystal solution was aged at 10 ° C overnight, filtered and dried under reduced pressure to obtain 30.95 g of 5-dimethylamino-2-nitrobenzoic acid. (99% yield). 1 H NMR (400 MHz, DMSO-d 6): 8.88 (bs, 1 H), 7.97 (d, 1 H, J = 9.4 Hz, aryl coupling = 1.76 Hz), 6.78 (d, 1 H, J = 9.4 Hz, aryl coupling = 2.84 and 1.92 Hz), 6.71 (s, 1 H, aryl coupling = 2.88 and 1.60 Hz), 3.08 (s, 6H). 13 C NMR (100 MHz, DMSO-d 6): 168.58, 153.86, 133.94, 132.85, 127.03, 111.44, 109.69, 40.24. MS (ESI MH +): m / z 211.17 (M + H) +, 209.27 (M-H).

Process 2: 40.0 g (190.30 millimoles) of 5-dimethylamino-2-nitrobenzoic acid were suspended in 160 ml of methanol at 25 ° C. The suspension was cooled in the ice bath and 53.6 mL of concentrated sulfuric acid was added thereto. After the addition of the concentrated sulfuric acid, the temperature of the solution was increased to about 30 ° C. The solution in that condition was placed in a 60 ° C bath and stirred under heating for 20 hours. After monitoring the progress of the reaction by CLAR and confirming the disappearance of the raw material, 400 mL of toluene was added thereto and diluted. Additionally, 200 mL of water and aqueous sodium hydroxide solution (where 38.06 g of sodium hydroxide were dissolved in 200 mL of water) were added thereto. In addition, the aqueous layer was extracted with 200 mL of toluene and the solution with toluene was combined. The toluene layer was washed with 300 mL of water saturated with sodium bicarbonate. Subsequently the toluene layer was concentrated under reduced pressure (where the temperature in the bath can 50 ° C) so that the intended compound became approximately 20% by weight. After removal of the solvent under reduced pressure, the crystals of the intended compound were precipitated and matured at room temperature for 1 hour. 220 mL of n-heptane was added and further stirred at 5 ° C overnight. The crystals were separated by suction filtration and washed with 100 mL of n-heptane. The wet crystals were dried under reduced pressure at 60 ° C for 3 hours to obtain 34.82 g of a yellow crystalline powder of methyl 5-dimethylamino-2-nitrobenzoate. (Yield of 82%). 1 H NMR (400 MHz, DMSO-d 6): 8.02 (d, 1 H, J = 9.4 Hz), 6.82 (d, 1 H, J = 9.36 Hz, aryl coupling = 2.56 Hz), 6.78 (s, 1 H , coupling to aryl = 2.4 Hz), 3.83 (s, 3H), 3.10 (s, 6H). 13 C NMR (100 MHz, DMSO-d 6): 167.70, 153.92, 132.71, 132.34, 127. 24, 111.87, 110.07, 53.21, 40.28. MS (ESI MH +): m / z 224.24 (M) +. HR EM (FAB): m / z 224.0830 (M) + Process 3: 10.06 g (44.9 millimoles) of methyl 5-dimethylamino-2-nitrobenzoate were added to 50 mL of methanol and suspended, and 9.0 mL of 10M hydrochloric acid and 1.96 g (wet, 1 mol% per substrate) were added. of activated carbon with palladium at 5%. The reaction vessels were replaced with nitrogen gas and stirred at room temperature overnight. After filtering the palladium catalyst by filtration with Celite, the filtrate was concentrated under reduced pressure to make it about half the original amount. 80 mL of acetone was added to the solution and it was concentrated under reduced pressure three times to precipitate the compound of the formula (12). After the compound matured below -10 ° C, the compound was dried under reduced pressure to obtain 11.16 g of methyl 2-amino-5- (dimethylamino) benzoate / dihydrochloride. (Yield of 93%). 1 H NMR (400 MHz, DMSO-d 6): 8.09 (s, 1 H), 7.72 (d, 1 H, J = 9.0 Hz), 6.96 (d, 1 H, 9.08 Hz), 5.50 (bs), 3.83 (s, 6H). 13 C NMR (-100 MHz, DMSO-d 6): 167.12, 131.64, 126.66, 123.29, 118.7, 108.7, 108.88, 52.18, 45.84. MS (FAB): m / z 195.3 (M + H) + HR EM (FAB) ): m / z 195.1122 (M + H) + EXAMPLE 135 Synthesis of the compound of the following formula (E-49) which has a substituent (s) of example-135 of table 23 Process 1 N- (t-Butoxycarbonyl) -4- (6-iodo-1-methyl-2,4-quinazoline-dione-3-yl) -L-phenylalanine methyl ester The mixture of N- (t-methyl ester -butoxycarbonyl) -4-amino-L-phenylalanine (10.25 g), 2-amino-5-iodobenzoic acid (9.18 g), EDC / HCl (6.8 g), HOBT (4.8 g), triethylamine (6.6 mL) and tetrahydrofuran (300 mL) was stirred at 40 ° C throughout the night. The solution where approximately one-half of the solvent was removed, diluted with water and ethyl acetate and taken out the liquid separation. The organic layer was washed with water, saturated aqueous solution of ammonium chloride, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed to obtain 22 g of the unpurified material. Unpurified material (22 g), CDl (carbonyldiimidazole) (17 g) and DMF (200 mL) were stirred at 80 ° C overnight. The reaction solution was diluted with water and ethyl acetate, and liquid separation was carried out. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed to obtain 23.4 g of the unpurified material. Unpurified material (23.4 g), methyl iodide (3 mL), potassium carbonate (10.0 g) and DMF (100 mL) were stirred at room temperature overnight. The reaction solution was diluted with water and ethyl acetate, and liquid separation was carried out. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed to obtain 15 g of the intended compound.

Process 2 N- (2-chloro-6-fluorobenzoyl) -4- (6-iodo-1-methyl-2,4-quinazoline-dione-3-yl) -L-phenylalanine methyl ester The substance obtained in the process 1 (5 g), trifluoroacetic acid (3 mL) and dichloromethane (100 mL) were stirred at room temperature for 3 hours. In addition, trifluoroacetic acid (10 mL) was added and stirred at room temperature for 2 hours. After removal of the solvent, 4M dioxane acid chloride solution was added and concentrated. The residue is Diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was removed to obtain an unpurified material. Unpurified material, 2-chloro-6-fluorobenzoyl chloride (2.5 g), triethylamine (5 mL) and dichloromethane (100 mL) were stirred at room temperature overnight. The reaction solution was diluted with water and dichloromethane, and liquid separation was carried out. The organic layer was washed with dilute hydrochloric acid, aqueous sodium hydroxide solution and dried over anhydrous sodium sulfate. The solvent was removed to obtain an unpurified material. The unpurified material was purified with silica gel column chromatography (hexane / ethyl acetate) to obtain 2.7 g of the intended compound.

Process 3 N- (2-chloro-6-fluorobenzoyl) -4- (1-methyl-6-chloromethyl-2,4-quinazoline-dione-3-yl) -L-phenylalanine methyl ester The substance obtained in the process 2 was treated by the same procedures as those of process 1 and 2 in example 50, and process 1 and 2 in example 53 respectively to obtain the title compound.

Process 4 The mixture of the substance obtained in process 3 (300 mg), tetrahydrofuran (20 mL) and 2M ethylamine-tetrahydrofuran solution (14 mL) was stirred at room temperature overnight. After the Removal of the solvent, the residue was purified by high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 70 mg of the intended compound. MS (ESI MH +): 553 EXAMPLE 136 Synthesis of the compound of the following formula (E-49) which has a substituent (s) example 136 of table 23 The substance obtained in process 3 in example 135 was reacted by the same procedure as that of process 4 in Example 135 using dimethylamine 2M-tetrahydrofuran solution to obtain the intended compound. MS (ESI MH +): 539 EXAMPLE 137 Synthesis of the compound of the following formula (E-49) which has a substituent (s) of example 137 of table 23 Process 1 N- (2-Chloro-6-methoxybenzoyl) -4- (6-odo-1-methyl-2,4-quinazoline-dione-3-yl) -L-phenylalanine methyl ester The substance obtained in the Process 1 of Example 135 (5 g), trifluoroacetic acid (10 mL) and dichloromethane (100 mL) were stirred at room temperature for 2 hours. After the removal of the solventThe residue was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was removed to obtain an unpurified material. The mixture of the unpurified material, 2-chloro-6-methylbenzoic acid (2.2 g), EDC / HCl (2.7 g), HOBT (2.1 g) and DMF (20 mL) was stirred at room temperature overnight. The reaction solution was added to water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed to obtain an unpurified material. The unpurified material was purified with silica gel column chromatography (hexane / ethyl acetate) to obtain 1.1 g of the intended compound.

Process 2 The substance obtained in process 1 was reacted by the same procedures as those of process 3 and 4 in example 135 to obtain 90 mg of the intended compound. MS (ESI MH +): 549 EXAMPLE 138 Synthesis of the compound of the following formula (E-51) which has a substituent (s) of example 138 of Table 25: N- (2,6-dichlorobenzoyl) -4- [6-ethylmethylamino-1 -] - isopropyl ester methyl-2, 4-quinazoIina-dione-3-yl] -L-phenylalanine The mixture of the substance obtained in the process 2 of Example 53 (250 mg), isopropanol (6 mL) and 4M dioxane chloride solution ( 6 mL) was stirred at 70 ° C for 3 hours. After removal of the solvent, isopropanol (5 mL), acetonitrile (2 mL) and methylethylamine (0.4 mL) were added and stirred at room temperature for two days. After removal of the solvent, the residue was purified by high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 138 mg of the intended compound. MS (ESI MH +): 625 EXAMPLE 139 Synthesis of the compound of the following formula (E-49) which has a substituent (s) of example 139 of Table 23: N- (2,6-dichlorobenzoyl) -4- [6-ethylmethylamino-1-methyl-2, 4-quinazoline-dione-3-yl] -L-phenylalanine 4M dioxane acid chloride solution (2 mL) and water (200 μL) were added to the compound of Example 138 (30 mg) and stirred at 80 ° C. 2 hours. After removal of the solvent, the residue was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 15 mg of the intended compound. MS (ESI MH +): 583 EXAMPLE 140 Synthesis of the compound of the following formula (E-49) which has a substituent (s) of example 140 of Table 23: N- (2,6-dichlorobenzoyl) -4- [6-hydroxy-1-methyl-2, 4-quinazoline-dione-3-IL] -L-phenylalanine The mixture of 2-nitro-5-methoxybenzoic acid (4 g), tetrahydrofuran (200 mL), N- (2,6-dichlorobenzoyl) -4-methyl ester -amino-L-phenylalanine (6 g), EDC / HCl (3.6 g), HOBT (3.0 g) and triethylamine (4.4 mL) was added and stirred at 40 ° C overnight. The mixture was extracted with ethyl acetate and treated according to the usual method. The crude material obtained was dissolved in ethyl acetate (20 mL) and 1 g of activated charcoal with 10% parydate was added and stirred under a hydrogen atmosphere at room temperature overnight. After filtration on Celite, the residue was treated according to the usual method. DMF (200 mL) and carbonyldiimidazole (5.2 g) were added to the unpurified material obtained and stirred at 80 ° C for 4 hours. The mixture was extracted with ethyl acetate and treated according to the usual method. DMF (200 mL), potassium carbonate (4.4 g) and methyl iodide (1.2 mL) were added to the material without purifying obtained and stirred at room temperature overnight. The mixture was extracted with ethyl acetate and treated according to the ordinary method. A solution of 1 M-dichloromethane boron tribromide (50 mL) was added to the obtained crude material and stirred at room temperature for 3 days. The mixture was extracted with dichloromethane and treated according to the usual method. The unpurified material obtained was added to water / acetonitrile (1: 1) and the precipitates were filtered to obtain 2.2 g of an unpurified material of the intended compound. The filtrate was concentrated and purified by high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 510 mg of the intended compound. MS (ESI MH +): 528 EXAMPLE 141 Synthesis of the compound of the following formula (E-49) which has a substituent (s) of example 141 of Table 23: N- (2,6-dichlorobenzoyl) -4- [6 - ((2S) isopropyl ester) 2-aminopropoxy) -1-methyl-2,4-quinazoline-dione-3-yl] -L-phenylalanine Process 1 t-Butyl (1S) -2-hydroxy-1-methylethylcarbamate Di-t-butyldicarbonate (17 g), triethylamine (9 mL) and dichloromethane (100 mL) were added to L-alaninol (5 g) and stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane and washed with water, and the organic layer was dried over anhydrous magnesium sulfate. After removal of the solvent, the unpurified material obtained was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain 5.9 g of the title compound.

Process 2 t-Butyl (1S) -2-chloro-1-methylethylcarbamate Methanesulfonyl chloride (3.1 mL), triethylamine (9.0 mL) and dichloromethane (150 mL) were added to the compound obtained in process 1 (5.9 g) and stirred at 0 ° C for 2 hours. The mixture was diluted with dichloromethane and washed with water, and the organic layer was dried over anhydrous magnesium sulfate. After removal of the solvent, lithium chloride (2.8 g) and DMF (100 mL) were added to the unpurified material obtained and stirred at 40 ° C overnight. The mixture was diluted with ethyl acetate and washed with water, and the organic layer was dried over anhydrous magnesium sulfate. After removal of the solvent, the unpurified material obtained was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain 3.6 g of the title compound.

Process 3 The compound obtained in process 2 (15 mg), DMF (2 mL) and potassium carbonate (14 mg) were added to the compound of Example 154 (30 mg) and stirred at 90 ° C overnight. The mixture was extracted with acetate of ethyl and treated in accordance with the usual method. The unpurified material obtained was dissolved in 4M dioxane acid chloride solution (2 mL) and stirred at room temperature for 2 hours. It was added to water (200 μL) and stirred at 80 ° C for 2 hours. After removal of the solvent, the residue was purified by high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 10 mg of the intended compound. MS (ESI MH +): 528 EXAMPLE 142 Synthesis of the compound of the following formula (E-51) which has a substituent (s) of example 142 of Table 23: N- (2,6-dichlorobenzoyl) -4- [6- (2-dimethylaminoethoxy) -1- methyl-2,4-quinazoline-dione-3-yl] -L-phenylalanine. t-Butyl 2-chloroethylcarbamate (157 mg), DMF (3 mL) and potassium carbonate (1384 mg) were added to the compound of Example 154 ( 450 mg) and stirred at 90 ° C overnight. The mixture was extracted with ethyl acetate and treated according to the usual method. The unpurified material obtained was dissolved in 4M dioxane acid chloride solution (2 mL) and stirred at room temperature for 2 hours. After removal of the solvent, the residue was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 350 mg of a purified material. Acetonitrile (5 mL), formalin (37 μL), acetic acid (26 μL) and sodium triacetoxy boron (98 mg) were added to the purified material. obtained (170 mg) and stirred at room temperature for 2 hours. After removal of the solvent, the residue was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 150 mg of a purified material. 4M Dioxane acid chloride solution (1 mL) and water (200 μL) were added to the obtained purified material (20 mg) and stirred at 90 ° C for 2 hours. After removal of the solvent, the residue was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 11 mg of a purified material. EM (ESI MH +): 599 EXAMPLE 143 Synthesis of the compound of the following formula (E-50) which has a substituent (s) of example 143 of Table 24: N- (2,6-dichlorobenzoyl) -4- [7-ethylaminomethyl-1-methyl-2, 4-quinazoline-dione-3-yl] -L-phenylalanine Process 1 Methyl 4-f (t-butoxycarbonylethylamino) met.p-2-nitrobenzoate Triethylamine (1.9 mL) and ethyl chloroformate (1.0 mL) were added to the mixture of 1-methyl-2-nitroterephthalate (2.0 g) and tetrahydrofuran. (120 mL) under cooling with ice and stirred for 30 minutes. Sodium borohydride (500 mL) was added and then three pieces of ice to the solution of reaction and stirred at room temperature for 2 hours. The mixture was extracted with ethyl acetate and treated according to the usual method. The unpurified material obtained (565 mg) was dissolved in dichloromethane (10 mL). Triethylamine (0.74 mL) and methanesulfonyl chloride (0.25 mL) were added under cooling with ice and stirred for 2 hours. The mixture was extracted with dichloromethane and treated according to the usual method. The unpurified material obtained was dissolved in acetonitrile (20 mL) and 2.0M-monoethylamine-tetrahydrofuran solution (2.68 mL) and stirred at room temperature overnight. The mixture was extracted with ethyl acetate and treated according to the usual method. The unpurified material obtained was dissolved in dichloromethane (10 mL). Triethylamine (0.74 mL) and di-t-butyldicarbonate (700 mg) were added under cooling with ice and stirred for 2 hours. The mixture was extracted with dichloromethane and treated according to the usual method to obtain 520 mg of the title compound.

Process 2 The substance obtained in process 1 (520 mg) was dissolved in tetrahydrofuran (20 mL), aqueous solution of 1M sodium hydroxide (5 mL) and methanol (10 mL) and stirred at room temperature for 2 hours and subsequently at 40 ° C for 2 hours. The mixture was extracted with ethyl acetate and treated according to the usual method. Tetrahydrofuran (20 mL), N- (2,6-dichlorobenzoyl) -4-amino-L-phenylalanine methyl ester (563 mg), EDC / HCl (352 mg), HOBT (248 mg) and triethylamine (425) were added. μL) and stirred to 40 ° C throughout the night. The mixture was extracted with ethyl acetate and treated according to the usual method. The unpurified material obtained was dissolved in ethyl acetate (20 mL) and 20 mg of activated carbon with 10% palladium and stirred under the presence of hydrogen at room temperature overnight. After filtration on Celite, the residue was treated according to the usual method. DMF (10 mL) and carbonyldiimidazole (364 mg) were added to the obtained crude material and stirred at 80 ° C for 4 hours. The mixture was extracted with ethyl acetate and treated according to the usual method. DMF (10 mL), potassium carbonate (212 mg) and methyl iodide (58 μL) were added to the unpurified material obtained and stirred at room temperature overnight. The mixture was extracted with ethyl acetate and treated according to the usual method. The unpurified material obtained was dissolved in 4N dioxane acid chloride solution (2 mL) and water (200 μL) and stirred at 80 ° C for 2 hours. After removal of the solvent, the residue was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 40 mg of the intended compound.

EXAMPLE 144 Synthesis of the compound of the following formula (E-50) which has a substituent (s) of example 144 of Table 24: N- (2,6-dichlorobenzoyl) -4- [7-methylaminomethyl] -1-methyl-2 , 4-quinazoline-dione-3-yl] -L-phenylalanine The intended compound was obtained by the same procedures as those of process 1 and 2 in example 143 except that the monomethylamine 2.0M-tetrahydrofuran solution was used to remove the monoethylamine 2.0M-tetrahydrofuran site. MS (ESI MH +): 555 EXAMPLE 145 Synthesis of the compound of the following formula (E-50) which has a substituent (s) of example 145 of Table 24: N- (2,6-dichlorobenzoyl) -4- [1-methyl-7-propylaminomethyl-2, 4-quinazoline-dione-3-yl] -L-phenylalanine The intended compound was obtained by the same procedures as those of process 1 and 2 in example 143 except that propylamine was used in place of the 2.0 M monoethylamine solution tetrahydrofuran. MS (ESI MH +): 583 EXAMPLE 146 Synthesis of the compound of the following formula (E-50) which has a substituent (s) of example 146 of Table 24: N- (2,6-dioriorobenzoyl) -4- [1-methyl-7-diethylaminomethyl-2, 4-quinazoline-dione-3-yl] -L-phenylalanine The intended compound was obtained by the same procedures as those of process 1 and 2 in Example 143 except that the diethylamine was used in place of the 2.0 M monoethylamine-tetrahydrofuran solution. MS (ESI MH +): 597 EXAMPLE 147 Synthesis of the compound of the following formula (E-51) which has a substituent (s) of example 147 of Table 25 The intended compound was obtained by the same procedure as that of C in the aforementioned examples 101 to 121 using the compound from example 54. MS (ESI MH +): 625 EXAMPLE 148 Synthesis of the compound of the following formula (E-51) which has an example substituent (s) 148 of Table 25 The intended compound was obtained by the same procedure as that of C in the aforementioned examples 101 to 121 using the compound from example 54. MS (ESI MH +): 625 EXAMPLE 149 Synthesis of the compound of the following formula (E-51) which has an example substituent (s) 149 of Table 25 The intended compound was obtained by the same procedure as that of C in the aforementioned examples 101 to 121 using the compound from example 54. MS (ESI MH +): 597 EXAMPLE 150 Synthesis of the compound of the following formula (E-51) which has an example substituent (s) 150 of Table 25 The intended compound was obtained by the same procedure as that of C in the aforementioned examples 101 to 121 using the compound from example 99. MS (ESI MH +): 583 EXAMPLE 151 Synthesis of the compound of the following formula (E-51) which has a substituent (s) of example 151 of Table 25 The intended compound was obtained by the same procedure as that of C in the aforementioned examples 101 to 121 using the compound of example 99. MS (ESI MH +): 597 5 1 H-NMR (DMSO-d 6): d 1.19 (3H, d, J = 6.3 Hz), 1.23 (3H, d, J = 6.3 Hz), 2.57 (3H, t, J = 5.1 Hz), 3.01 (1H, dd, J = 14.1, 9.9 Hz), 3.19 (1H, dd, J = 14.1, 5.1 Hz), 3.55 (3H, s), 4.24 (2H, t, J = 5.4 Hz), 4.72-4.82 (1H, m), 4.95 (1 H, sep, J = 6.3 Hz), 7.21 (2H, d, J = 8.4 Hz), 7.37-7.48 ( 5H, m), 7.59 (1 H, d, J = 8.7 Hz), 7.88 (1 H, dd, J = 8.7, 2.1 Hz), 8.24 (1 H, d, J = 2.1 Hz), 8.58 (2H, 10 brs), 9.25 (1 H, d, J = 8.1 Hz). In addition, the compound of example 151 was obtained by the same procedure as that of process 3 in example 53 except that the compound of process 1 in example 174 was used as a raw material and methylamino was used in place of morpholine. -15 EXAMPLE 152 Synthesis of the compound of the following formula (E-51) which has a substituent (s) of example 152 of Table 25 The intended compound was obtained by the same procedure as that of C in the aforementioned examples 101 to 121 using the compound of example 99. MS (ESI MH +): 611 EXAMPLE 153 Synthesis of the compound of the following formula (E-51) which has a substituent (s) of example 153 of Table 25 The intended compound was obtained by the same procedure as that of C in the aforementioned examples 101 to 121 using the compound of example 140. MS (ESI MH +): 556 EXAMPLE 154 Synthesis of the compound of the following formula (E-51) which has a substituent (s) of example 154 of Table 25 The intended compound was obtained by the same procedure as that of C in the aforementioned examples 101 to 121 using the compound from example 140. MS (ESI MH +): 570 EXAMPLE 155 Synthesis of the compound of the following formula (E-51) which has a substituent (s) of example 155 of Table 25: N-isopropyl ester (2,6-dichlorobenzoyl) -4- [6- (2-dimethylaminoethoxy) -1-methyl-2,4-quinazoline-dione-3-yl] -L-phenylalanine. T-Butyl 2-chloroetheylcarbamate ( 157 mg), DMF (3 mL) and potassium carbonate (1384 mg) a! compound of Example 154 (450 mg) and stirred at 90 ° C overnight. The mixture was extracted with ethyl acetate and treated according to the usual method. The unpurified material obtained was dissolved in 4M dioxane acid chloride solution (2 mL) and stirred at room temperature for 2 hours. After the removal of the solvent, the residue was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 350 mg of a purified material. Acetonitrile (5 mL), formalin (37 μL), acetic acid (26 μL) and sodium triacetoxy boron (98 mg) were added to the obtained purified material (170 mg) and stirred at room temperature for 2 hours. After removal of the solvent, the residue was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 150 mg of the intended compound. MS (ESI MH +): 641 EXAMPLE 156 Synthesis of the compound of the following formula (E-52) which has a substituent (s) of example 156 of Table 26: N-isopropyl ester (2,6-dichlorobenzoyl) -4- [7-ethylaminomethyl-1-methyl-2,4-quinazoline-dione-3-yl] -L-phenylalanine. 4M dioxane acid chloride solution (2 mL) was added.

Sodium propane (2 mL) was added to the compound of Example 143 (20 mg) and stirred at 80 ° C for 2 hours. After removal of the solvent, the residue was purified by high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 10 mg of the intended compound. MS (ESI MH +): 611 EXAMPLE 157 Synthesis of the compound of the following formula (E-52) which has a substituent (s) of example 157 of Table 26: cyclopentyl ester of N- (2,6-dichlorobenzoyl) -4- [7-methylaminomethyl-1-methyl- 2,4-quinazo-Iina-dione-3-yl] -L-phenylalanine.4M dioxane chloride solution (2 mL) and cyclopentanol (2 mL) were added to the compound of Example 144 (20 mg) and stirred at 80 ° C for 2 hours. After removal of the solvent, the residue was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 15 mg of the intended compound. MS (ESI MH +): 623 EXAMPLE 158 Synthesis of the compound of the following formula (E-52) which has a substituent (s) of example 158 of Table 26: isobutyl ester of N- (2,6-dichlorobenzoyl) -4- [7-methylaminomethyl-1-methyl] -2,4-quinazoline-dione-3-yl] -L-phenylalanine 4M dioxane acid chloride solution (2 mL) and isobutanol (2 mL) were added to the compound of Example 144 (20 mg) and stirred at 80 ° C by 2 hours. After removal of the solvent, the residue was purified by high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 12 mg of the intended compound. MS (ESI MH +): 611 EXAMPLE 159 Synthesis of the compound of the following formula (E-52) which has a substituent (s) of example 159 of Table 26: N- (2,6-dioriorobenzoyl) -4- [1-methyl-7-propylaminomethyl] isopropyl ester -2,4-quinazoline-dione-3-yl] -L-phenylalanine 4M dioxane acid chloride solution (2 mL) and isopropanol (2 mL) were added to the compound of example 145 (50 mg) and stirred at 80 ° C for 3 hours. After removal of the solvent, the residue was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 25 mg of the intended compound. MS (ESI MH +): 625 EXAMPLE 160 Synthesis of the compound of the following formula (E-53) which has a substituent (s) of example 160 of Table 27 The intended compound was obtained by the same procedure as that of Example 92 except that 2-methylimidazole was used instead of imidazole MS (ESI MH +): 610 EXAMPLE 161 Synthesis of the compound of the following formula (E-53) which has a substituent (s) of example 161 of Table 27 The intended compound was obtained by the same procedure as that of example 92 except that 2-ethylimidazole was used instead of imidazole MS (ESI MH +): 624 EXAMPLE 162 Synthesis of the compound of the following formula (E-53) which has a substituent (s) of example 162 of Table 27 The intended compound was obtained by the same procedure as that of C in the aforementioned examples 101 to 121 using the compound from Example 92. MS (ESI MH +): 638 1 H-NMR (DMSO-d 6): d 1.19 (3 H, d, J = 6.3 Hz), 1.23 (3 H, d, J = 6.3 Hz), 3.02 (1 H, dd , J = 14.1, 9.9 Hz), 3.20 (1H, dd, J = 14.1, 5.4 Hz), 3.59 (3H, s), 4. 72-4.82 (1H, m), 4.95 (1 H, sep, J = 6.3 Hz), 7.24 (2H, d, J = 8.1 Hz), 7.38-7.48 (5H, m), 7.69 (1H, s), 7.91 (1 H, d, J = 6.0 Hz), 8.07-8.14 (2H, m), 9.15 (1 H, s), 9.25 (1 H, d, J = 7.8 Hz).

EXAMPLES 163 to 173 Synthesis of the compounds of the following formula (E-54) which has substituents of Examples 163 to 173 of Table A. The compounds obtained in Examples 163 to 173 were synthesized by the same procedure as that of C in Examples 65 to 81.

EXAMPLE 174 Synthesis of the compound of the following formula (E-55) which has a substituent (s) of example 174 of Table B Process 1 synthesis of the isopropyl ester of 4- [6- (chloromethyl) -1-methyl-2,4- oxox-1, 2,3,4-tetrahydroquinazoline-3 (2H) -yl] -N- (2,6-dichlorobenzoyl) -L-phenylalanine A mixed solvent of methylene chloride (140 mL) and dimethylformamide (140 mL) was cooled to 0 ° C. Phosphorus oxychloride (4.1 mL) was added and stirred for 30 minutes. The compound of Example 234 (25.7 g) was added at 0 ° C and was stirred at room temperature for 1 hour. Additionally, phosphorus oxychloride (0.4 mL) was added and stirred for 1 hour. Subsequently, ethyl acetate (500 mL) and water saturated with sodium bicarbonate were added. (100 mL) and stirred vigorously. After the ethyl acetate (500 mL) and water (200 mL) were added to separate it into layers, the organic layer was washed with water saturated with sodium bicarbonate (200 mL), aqueous 1 N sodium hydroxide solution (100 mL) and saturated aqueous sodium chloride solution (200 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain an unpurified material. The title compound was obtained by crystallization from methylene chloride and hexane. Yield: 20.32 g MS (ESI MH +): 602 Process 2 Isopropyl (2S) -3- [4- (6- (azidomethyl) -1-methyl-2,4-dioxo-1, 2,3,4-tetrahydro-3 (2H) -quinazolinyl) phenyl] -2-f (2,6-dichlorobenzoiPaminolpropanoate) Sodium azide (56 mg) and dimethylsulfoxide (5 mL) were added to the compound (400 mg) obtained in process 1 and stirred for 2.5 hours after dilution with ethyl acetate and washing with water, the organic layer was dried over anhydrous sodium sulfate.The solvent was removed under reduced pressure and the residue was purified with silica gel chromatography (hexane-ethyl acetate) to obtain the title compound (350 mg) ".

Process 3 Isopropyl (2S) -3- [4- (6- (aminomet-p-1-methylene-2,4-dioxo-1, 2,3,4-tetrahydro-3 (2HVquinazolinyl) phenyl-2 - [( 2,6-dioxo-1, 2,3,4-tetrahydro-3 (2H) -quinazolinyl) phenyl1-2-f (2,6-dichlorobenzoyl) amino] propanoate Triphenylphosphine (52 mg) and tetrahydrofuran (2 mL) were added. ) to the compound (100 mg) obtained in process 2 and stirred for 30 minutes Water (200 μL) was added to the reaction solution and further stirred overnight, after the solvent was removed, the residue it was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 76 mg of the intended compound.

EXAMPLES 175 to 183 Synthesis of the compounds of the following formula (E-55) which has substituents of examples 175 to 183 of table B. The compounds were synthesized by the same procedure as that of process 3 in example 53 except that the compound of the process 1 in Example 174 was used as a raw material and the corresponding amines were used in place of morpholine.

EXAMPLE 184 Synthesis of the compound of the following formula (E-56) which has a substituent (s) of Example 184 of Table C.

Process 1 Isopropyl (2S) -2-r (2,6-dichlorobenzoyl) amino1-3-f4- (7-fluoro-6-iodo-1-methyl-2,4-dioxo-1, 2,3,4- tetrahydro-3 (2HY quinazolinyl) phennprapanoate The title compound was synthesized by the same procedures as those of processes 1 to 3 in Example 43 except that N- (2,6-dichlorobenzoyl) -4 isopropyl ester was used - [(2-amino-5-iodobenzoyl) amino] -L-phenylalanine obtained in process 1 of Example 234 in place of the N- (2,6-dichlorobenzoyl) -4 - [(2-amino-5-methyl) methyl ester - iodobenzoyl) amino] -L-phenylalanine; and 2-amino-4-fiuoro-5-iodobenzoic acid was used in place of 2-amino-5-iodobenzoic acid.

Process 2 Isopropyl (2S) -2 - [(2,6-dichlorobenzoyl) amino1-3-f4- (7-fluoro-1-methyl-6 - [(methylamino) methyl] -2,4-dioxo-1, 2 , 3,4-tetrahydra-3 (2H) -quinazolinyl) phenylpropanoate The compound obtained in process 1 was treated by the same procedures as those of processes 4 and 5 in example 234, process 1 in example 174, and Example 175 to obtain the title compound.

EXAMPLE 185 and 186 Synthesis of the compounds of the following formula (E-56) which has substituents of examples 185 and 186 of table C. The compounds were synthesized by the same procedure as that of example 184 except that the corresponding amines were used in the process 2 of example 184.

EXAMPLE 187 Synthesis of the compound of the following formula (E-57) which has a substituent (s) of example 187 of Table D.

Process 1 Methyl (2S) -2-amino-3- [4- (6-iodo-1-methyl-2,4-dioxo-1, 2,3,4-tetrahydro-3 (2H) -quinazolinyl) hydrochloride phenyl] propanoate 4M Dioxane acid chloride solution was added to methyl (2S) -2 - [(tert-butoxycarbonyl) amino] -3- [4- (6-iodo-1-methyl-2,4-dioxo-1, 2, 3,4-tetrahydro-3- (2H) -quinazolinyl) phenyl] propanoate (5 g) obtained in process 1 of the example 125 and stirred for 3 hours. The solvent was removed to obtain the title compound (4.2 g).

Process 2 Methyl (2SV2-α (2-chloro-6-methylbenzoyl) amino1-3-r4- (6-iodo-1-methyl-2,4-dioxo-112,3,4-tetrahydro-3 (2H) - quinazolinyl) feninpropanoate 2-Chloro-6-methyl benzoic acid (1.7 g), EDC / HCl (1.9 g), HOAt (1.4 g), triethylamine (2.2 mL) and dichloromethane (42 mL) were added to the compound obtained in the process 1 (2.1 g) and stirred overnight After the reaction mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid, water saturated with sodium bicarbonate and saturated aqueous sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate The solvent was removed to obtain an unpurified material of the title compound.

Process 3 Isopropyl (2S -2 - [(2-chloro-6-methylbenzoyl) amino] -3- [4- (6-iodo-1-methyl-2,4-dioxo-1, 2,314-tetrahydro-3 (2H ) -quinazolinyl) phenyl] propanoate 4M dioxane acid chloride solution (30 mL) and water (6 mL) were added to the compound obtained in process 2 and stirred at 90 ° C overnight after removal of the solvent , 4M dioxane acid chloride solution (25 mL) and isopropyl alcohol (25 mL) were added to the residue and stirred at 90 ° C for 3.5 hours After the reaction mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid, water saturated with sodium bicarbonate and saturated aqueous sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate.The solvent was removed to obtain an unpurified material of the title compound.

Process 4 Isopropyl (2S) -2-((2-chloro-6-methylbenzoyl) amino] -3-r4- (1-methyl-6-r (methylamino) metin-2,4-dioxo-1, 2,3 , 4-tetrahydro-3 (2H) -quinazolinyl) phenyl] propanoate The compound obtained in process 3 was treated by the same procedures as those of processes 4 and 5 in example 234, process 1 in example 174, and example 175 to obtain the title compound.

EXAMPLE 188 Synthesis of the compound of the following formula (E-57) which has a substituent (s) of example 188 of Table D. The compound was synthesized by the same procedure as that of example 187 except that a corresponding amine was used in the process 4 of example 187.

EXAMPLE 189 Synthesis of the compound of the following formula (E-57) which has a substituent (s) of example 189 of table D. The compound obtained in process 2 of example 135 was treated by the same procedures as those of processes 4 and 5 in example 234, process 1 in example 174, and example 175 to obtain the title compound.

EXAMPLE 190 Synthesis of the compound of the following formula (E-57) which has a substituent (s) of Example 190 of Table D.

The compound was synthesized by the same procedure as that of Example 189 except that a corresponding amine was used in Example 189.

EXAMPLES 191 to 206 Synthesis of the compound of the following formula (E-58) which has a substituent (s) of example 191 and 206 of table E. The compounds were synthesized by the same procedure as that of process 4 in example 43 except that they were used the compounds of Examples 174 to 188 and 190 as raw materials.

EXAMPLE 207 Synthesis of the compound of the following formula (E-59) which has a substituent (s) of example 207 of Table F. Methanesulfonyl chloride (30 μL), triethylamine (80 μL) and dichloromethane (3 mL) were added to methyl (2S) -2 - [(2,6-dichlorobenzoyl) amino] -3- [4- (6- (3-hydroxypropyl) -1-methyl-2,4-dioxo-1, 2,3,4-tetrahydro -3 (2H) -quinazolinyl) phenyl] propanoate (150 mg) which is a synthetic intermediate of example 52, and was stirred at 0 ° C for 2.5 hours. After the reaction solvent was diluted with ethyl acetate and washed with 1 N hydrochloric acid, water saturated with sodium bicarbonate and saturated aqueous sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The obtained residue was dissolved in acetonitrile (6 mL), added dropwise to a solution of methylamine 2M-tetrahydrofuran (9 mL) and stirred at 50 ° C overnight. After removing the solvent, the residue was purified by high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 70 mg of the intended compound.

EXAMPLE 208 and 209 Synthesis of the compounds of the following formula (E-59) which has substituents of examples 208 and 209 of table F The compounds were synthesized by the same procedure as that of example 207 except that a tetrahydrofuran solution of each amine was used corresponding to the methylamine 2M-tetrahydrofuran solution.

EXAMPLE 210 Synthesis of the compounds of the following formula (E-59) which has a substituent (s) of Example 210 of Table F 4M Dioxane acid chloride solution (2 mL) and isopropanol (2 mL) were added to the compound of Example 207 (65 mg) and stirred at 90 ° C for 3.5 hours. After removal of the solvent, the residue was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain 60 mg of the intended compound.

EXAMPLES 211 and 212 Synthesis of the compounds of the following formula (E-59) which has substituents of examples 211 and 212 of table F The compounds were synthesized by the same procedure as that of example 210 using the compounds obtained in examples 208 and 209.

EXAMPLES 213 to 218 Synthesis of the compounds of the following formula (E-60) which has substituents of examples 213 to 218 of Table G Process 1 The unpurified material of the compound of example 140 (2.49 g), 4M dioxane acid chloride solution (50 mL) and isopropyl alcohol (50 mL) were stirred at 80 ° C for 1.5 hours and the solvent was removed therefrom. A mixture of the unpurified material obtained, 1-bromo-2- Chloroethane (3.91 mL), potassium carbonate (6.51 g) and acetone (100 mL) was stirred at 50 ° C for 3 days. After removal of the solvent, the residue was diluted with water and ethyl acetate, and liquid separation was carried out. After the organic layer was washed with saturated aqueous sodium chloride solution, the solvent was removed to obtain the unpurified material (2.85 g).

Process 2 The intended compounds were obtained by the following methods A, B or CA A mixture of alkyl halide in process 1, a corresponding amine and a suitable solvent (s) such as acetonitrile were stirred at 80 ° C. all night to 3 days. After removal of the solvent, the residue was purified by high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain the intended compound. B. A mixture of alkyl halide in process 1, a corresponding amine (or, corresponding amine hydrochloride and a base (s) such as triethylamine) and a suitable solvent (s) such as acetonitrile were stirred in a deep tube at 80 ° C all night to 3 days. After removal of the solvent, the residue was purified by high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain the intended compound.

C. A mixture of alkyl halide in process 1, a corresponding amine and a suitable solvent (s) such as acetonitrile were stirred at 50 ° C overnight to 3 days. After removal of the solvent, the residue was purified by high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain the intended compound.

EXAMPLES 219 to 224 Synthesis of the compounds of the following formula (E-60) which has substituents of examples 219 to 224 of Table G A mixture of a corresponding ester, 4M dioxane acid chloride solution and water was stirred at 80 ° C of few hours to all night. After removal of the solvent, the residue was purified by high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain the intended compound.

EXAMPLE 225 Synthesis of the compound of the following formula (E-61) which has a substituent (s) of Example 225 of Table H The intended compound was obtained by the same procedures as those of Examples 213 to 218 except that 1-bromo-3-chloropropane was used in place of 1-bromo-2-chloroethane.

EXAMPLES 226 and 227 Synthesis of the compounds of the following formula (E-61) which has substituents of Examples 226 and 227 of Table H The intended compounds were obtained by the same procedure as those of Examples 219 to 224.

EXAMPLE 228 Synthesis of the compound of the following formula (E-62) Process 1 Synthesis of isopropyl ester of N- (2,6-dichlorobenzoyl) -4-r7-fluoro-6- (2-hydroxyethyl) -1-methyl-2,4-dioxo-1, 2,3,4-tetrahydroquinazoline -3 (2H) -yl1-L-phenylalanine Under argon, palladium acetate (6.5 mg) and triphenylphosphine (30 mg) were suspended in 5 mL of diethyl ether and stirred for 10 minutes.

After the decantation was carried out twice with diethyl ether, N- (2,6-dichlorobenzoyl) -4- [7-fiuoro-1-nnetyl-2,4-dioxo-1, 2 isopropyl ester was added, 3,4-tetrahydroquinazoline-3 (2H) -yl) -L-phenylalanine (374 mg), complex of 2,4,6-trivinylcyclotriboroxane-pyridine (138 mg), dimethylformamide (5 mL) and 2M aqueous sodium carbonate solution (1.15 mL) and stirred at 90 ° C for 1.5 hours. After removing the insoluble materials by filtration with Celite, the usual processing was carried out to obtain an unpurified material (0.36 g). The unpurified material obtained was dissolved in tetrahydrofuran (3 mL) and cooled to 0 ° C. Subsequently, sodium borohydride (35 mg) and trifluoroboran diethyl ether complex (81 μL) were added and stirred at 0 ° C for 1 hour. The reaction mixture was further stirred at room temperature for 1 hour and cooled again to 0 ° C and water (0.26 mL) was slowly added. After the reaction mixture was stirred at room temperature for 1 hour and cooled again to 0 ° C, an aqueous solution (5 mL) of Oxone (registered trademark) (1.3 g, obtained from Sigma- Aldrich) and stirred at room temperature for 3.5 hours. Sodium bisulfite was further added, extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate to obtain an unpurified material. The unpurified material obtained was purified by silica gel column chromatography (chloroformate: methanol = 49: 1 to 4: 1, gradient) to obtain the title compound. Yield: 0.197 g (0.32 mmol, 60%) MS (ESI MH +): 616 Process 2 Synthesis of isopropyl ester of N- (2 -6-dichlorobenzo-IV4-. {7-fluoro-1-methyl-6-r2- (methylamino) et p-2,4-dioxo-1, 2,3, 4-tetrahydroquinazoline-3 (2H) -yl.}. -L-phenylalanine The compound obtained in the process (0.197 g) was dissolved in methylene chloride (2 mL), and triethylamine (67 μL) and methanesulfonyl chloride were added. (32 μL) at 0 ° C. After stirring the mixture for 2 hours, the usual procedure was carried out to obtain an unpurified material, A tetrahydrofuran solution (10 mL) of 2M methylamine and acetonitrile (6 mL) were heated. to 50 ° C, and a solution of acetonitrile (6 mL) of the unpurified material was slowly added dropwise and stirred overnight.After removal of the solvent under reduced pressure, the residue was purified with liquid chromatography of high resolution (water / acetonitrile, each containing 0.1% TFA) to obtain the title compound Yield: 51.7 mg MS (ESI MH +): 629 EXAMPLE 229 Synthesis of the compound of the following formula (E-63) Synthesis of N- (2,6-dichlorobenzoyl) -4-. { 7-Fluoro-1-methyl-6- [2- (methylamino) ethyl] -2,4-dioxo-1, 2,3,4-tetrahydroquinazoline-3 (2H) -yl} -L-phenylalanine 4M dioxane acid chloride solution (4 mL) and water (0.8 mL) were added to the compound of Example 228 (10 mg) and stirred at 90 ° C for 2 hours. After removal of the solvent under reduced pressure, the residue was purified by high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain the title compound. Yield: 5.3 mg MS (ESI MH +): 587 EXAMPLE 230 Synthesis of the compound of the following formula (E-64) Synthesis of N- (2,6-dichlorobenzoyl) -4-. { 1-Methyl-6- [2- (methylamino) ethyl] -2,4-dioxo-1, 2,3,4-tetrahydroquinazoline-3 (2H) -yl} -L-phenylalanine The title compound was obtained by the same procedures as those of processes 1 and 2 in Example 228, and then Example 229 except that N- (2,6-dichlorobenzoyl) -4- (1-) methyl ester was used. methyl-2,4-dioxo-6-iodo-1, 2,3,4-tetrahydroquinazoline-3 (2H) -yl) -L-phenylalanine as a raw material. MS (ESI MH +): 559 EXAMPLE 231 Synthesis of the compound of the following formula (E-65) The compound of example 52 (351 mg) was dissolved in dichloromethane (10 mL) and triethylamine (0.167 L, 1.2 mmol). Methanesulfonyl chloride (0.116 mL, 1.2 mmol) was added dropwise under ice cooling and stirred for 2 hours. The usual processing was carried out to obtain an unpurified material. Acetonitrile (5 mL), potassium carbonate (170 mg) and 2M-dimethylamine-tetrahydrofuran solution (616 μL) were added to the unpurified material and stirred at room temperature overnight. After removal of the solvent, the residue was purified by high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain the title compound. MS (ESI MH +): 611 EXAMPLE 232 Synthesis of the compound of the following formula (E-66) 4M dioxane acid chloride solution of iopropanol was added to the compound of example 144 and stirred at 80 ° C for 2 hours.

After removal of the solvent, the residue was purified with high performance liquid chromatography (water / acetonitrile, each containing 0.1% TFA) to obtain the intended compound.

MS (ESI MH +): 597 EXAMPLE 233 Synthesis of the compound of the following formula (E-67) The intended compound was obtained by the same procedure as that of C in the aforementioned examples 101 to 121 using an unpurified material of the compound of Example 140. MS (ESI MH +): 542 EXAMPLE 234 Synthesis of the compound of the following formula (E-68) Process 1 synthesis of 4-f (2-amino-5-odobenzoyl) amino] -N- (2,6-dichlorobenzoyl) -L-phenylalanine isopropyl ester 4-amino-N- isopropyl ester ( 2,6-dichlorobenzoyl) -L-phenylalanine, 1-hydroxybenzothiazole monohydrate (11.5 g) and 5-iodoantranilic acid (17.8 g) in dimethylformamide (200 mL) and cooled to 0 ° C. 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (13.7 g) was added and the ambient temperature was stirred for 16 hours. The organic chart in which ethyl acetate (1 L) was added was washed with 0.1 N sodium hydroxide aqueous solution (200 mL, 100 mL), water (100 mL), 0.1-N hydrochloric acid (200 mL) and saturated aqueous solution of sodium chloride (200 mL, 100 mL), respectively. After removing the organic layer over anhydrous sodium sulfate and removing the solvent, a solid material obtained from a mixed solvent of methylene chloride and hexane was filtered to obtain the title compound. Yield: 37.06 g (57.88 mmol) MS (ESI MH +): 640 Process 2 Synthesis of isopropyl ester of 4- (2,6-dichlorobenzoyl) -4- (6-iodo-2,4-dioxo-1, 2,3,4-tetrahydroquinazoline-3- (2H) -yl-L- phenylalanine N, N-carbonyldiimidazole (28.16 g) was dissolved in 150 ml of dimethylformamide and heated to 80 [deg.] C. A dimethylformamide solution (150 ml) of the compound obtained in process 1 (37.06 g) was added dropwise and stirred overnight, after cooling the mixture to room temperature, ethyl acetate (1 L) and water (500 mL) were added and extraction was continued. The organic layer obtained was washed with water (300 mL, 200 mL, 200 mL) and saturated aqueous sodium chloride solution (100 mL) and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the solid material obtained was suspended in methylene chloride and hexane. The solid material obtained was filtered and dried to obtain the title compound. Yield: 33.06 g EM (ESI MH +): 666 Process 3 Synthesis of isopropylester of 4- (2,6-dichlorobenzoyl) -4- (6-iodo-1-methyl-2,4-dioxo-1, 2,3,4-tetrahydroquinazoline-3- (2H) -il -L-phenylalanine The compound obtained in process 2 (33.06 g) and potassium carbonate (14.5 g) were added to dimethylformamide (200 mL), and then iodomethane (10 mL) was further added and stirred at room temperature for 4 hours After removal of the insoluble materials by filtration on Celite, ethyl acetate (1 L) and water (300 mL) were added to the filtrate and the extraction was continued The organic layer obtained was washed with 1 N hydrochloric acid (250 ml). mL), water saturated with sodium bicarbonate (250 mL) and saturated aqueous solution of sodium chloride (200 mL), respectively.After the removal of the solvent, the solid material obtained was suspended in methylene chloride and hexane. The obtained solid was filtered and dried to obtain the title compound Yield: 37.85 g MS (ESI MH +): 680 Process 4 Synthesis of isopropyl ester of N- (2,6-dichlorobenzoyl) -4- (6-carboxyl-1-methyl-2,4-dioxo-1, 2,3,4-tetrahydroquinazoline-3- (2H) - il-L-phenylalanine The compound obtained in process 3 was dissolved in dimethyl formamide (140 mL) and triethylamine (13.1 mL) and water (8.5 mL) were added.After bubbling carbon monoxide, palladium acetate (52%) was added. mg) and stirred under a carbon monoxide atmosphere at 70 ° C for 11 hours.

After removal of the insoluble materials by filtration on Celite, dimethylformamide (approximately 100 mL) was removed under reduced pressure. Subsequently, ethyl acetate (1 L) and 1 N hydrochloric acid (300 mL) were added and extraction was continued. The organic layer obtained was washed with 1 N hydrochloric acid (250 mL) and saturated aqueous sodium chloride solution (200 mL, 200 mL), and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the solid material obtained was suspended in methylene chloride and hexane. The solid material obtained was filtered and dried to obtain the title compound. Yield: 27.23 g EM (ESI MH +): 598 - - - Process 5 Synthesis of isopropyl ester of N- (2,6-dichlorobenzoyl) -4- (6-hydroxymethyl) -1-methyl-2,4-dioxo-1, 2,3,4-tetrahydroquinazoline-3- (2H) -yl-L-phenylalanine The compound obtained in process 4 was dissolved in tetrahydrofuran (200 mL). Triethylamine (9.51 mL) was added and cooled to 0 ° C. Ethyl chloroformate (4.56 mL) was added dropwise and stirred for 30 minutes. After filtering the insoluble materials, the filtrate was cooled to 0 ° C and sodium borohydride (2.58 g) and ice (5 pieces) were added and stirred for 1 hour. Subsequently, sodium borohydride (0.25 g) was further added and stirred for 20 minutes. 1 N hydrochloric acid (74.8 mL), ethyl acetate and water were added respectively and extraction was continued. The layer organic was washed with 0.3 N hydrochloric acid, water, water saturated with sodium bicarbonate and saturated aqueous solution of sodium chloride. After removal of the solvent, the solid material obtained was suspended in methylene chloride and hexane. The solid material obtained was filtered and dried to obtain the title compound. Yield: 25.69 g EM (ESI MH +): 584 EXAMPLE 235 Synthesis of the compound of the following formula (E-69) The intended compound was obtained as a by-product material of the compound of example 228. MS (ESI MH +): 609 EXAMPLE 236 Synthesis of the compound of the following formula (E-70) The intended compound was obtained as a by-product material of the compound of example 228. MS (ESI MH +): 567 REFERENCE EXAMPLE 4 Synthesis of isopropyl ester of 4-amino-N- (2,6-dichlorobenzoyl) -L-phenylalanine (ie synthesis of isopropyl (S) -2- (2,6-dichlorobenzoylamino) -3- (4-nitrophenyl) propionate Process 1: Synthesis of isopropyl ester of 4-nitro-N- (2,6-dichlorobenzoyl) -L-phenylalanine Isopropanol (130 mL), tetrahydrofuran (50 mL) and sulfuric acid (0.44 mL) were added to 4-nitro- N- (2,6-dichlorobenzoyl) -L-phenylalanine (2.95 g, 7. 70 mmol) and stirred at 50 ° C for 5 days. After removal of the solvent under reduced pressure, the solid material obtained was washed with water and dried to obtain 3.28 g of a white solid material. MS (ESI) m / z 425 (MH +) Process 2 Synthesis of isopropyl ester of 4-amino-N- (2,6-dichlorobenzoiO-L-phenylalanine (ie synthesis of isopropyl (S) -2- (2,6-dichlorobenzoylamine) -3- (4 -amniphenyl) propionate Isopropanol (6 mL), tetrahydrofuran (3 mL) and 3% Pt-S / C (20 mg) were added to the solid material obtained in Process 1 (98 mg) and stirred under an Hydrogen, room temperature overnight After filtering the reaction solution, the filtrate was washed with isopropanol and was removed under reduced pressure to obtain 92 mg of the title compound. MS (ESI) m / z 395 (MH +) The structural formulas of the compounds in the examples are shown below.

TABLE 1 TABLE 2 TABLE 3 The compounds of examples 16 to 20 TABLE 4 PICTURE TABLE 6 The compound of example 36 TABLE 7 TABLE 8 fifteen TABLE 9 TABLE 10 The compounds of examples 47 and 48 TABLE 11 fifteen TABLE 12 The compound of example 59 TABLE 13 TABLE 14 The compound of formula 64 (E-24) TABLE 15-1 TABLE 15-2 TABLE 16 TABLE 17 The compounds of examples 89 to 97 TABLE 18 . s-i H (E-37) The compound of example 100 TABLE 19-1 EXAMPLE 19-2 EXAMPLE 19-3 TABLE 20 The compounds of examples 124 to 125 TABLE 21 The compounds of examples 128 to 132 TABLE 22 TABLE 23 TABLE 24 TABLE 25 TABLE 27 TABLE A TABLE B 15 TABLE C TABLE D TABLE E-1 Ra or l c. H TABLE F TABLE G N. 1 '0 TABLE H The compounds of examples 228 to 236 In addition, compounds which indicate the following structural chemical formulas are easily produced by the same methods as in those above-mentioned examples or methods for synthesis, or by the application of some modifications which themselves explain themselves to one skilled in the art. who knows these methods.

TABLE 28 tES-n TABLE 29 (ES-2) TABLE 30 ÍES-3) -R -Me -Et Ma A Me -AA 10 \ / TABLE 31 ÍES-4) -R -Me -Et MO Ma twenty - . 20 -AA * ^ o TABLE 32 TABLE 33 R Me TABLE 34 twenty TABLE 35 TABLE 36 TABLE 37 TABLE 38 TABLE 39 EXAMPLE PROOF 1 Test of antagonistic activity to the integrin VCAM-1 / a4ß1 binding under the existence of blood serum The ability of a substance antagonistic test to bind the cell strain of human T cells, Jurkat (ATCC TIB-152), was determined to express the integrin a4β1, to VCAM-1. Fifty μl / well of a solution (500 ng / ml) of recombinant human VACM-1 / Fc (R & D systems) was added with pH A regulator (0.1 M NaHCO3, pH 9.6) to a microtiter plate of 96 wells (Nunc Maxisorp). After incubation at 4 ° C overnight and washed once with PBS, a pH regulator (pH regulator B) obtained by dissolving Block Ace (Snow Brand Milk Products Co., Ltd.) with PBS at 1/2 concentration was added in an amount of 150 μl / well. After incubation at room temperature for 2 hours, the pH regulator was removed and the plate was washed with PBS once. Jurkat cells were washed with modified Eagle's medium by Dulbecco (SIGMA, hereinafter referred to as "DMEM") once. Subsequently, the cells again felt in a pH regulator for binding (DMEM containing 20 mM HEPES, 0.1% BSA, 2 mM MnCl2 and 50% human blood serum (Sigma)) to obtain 1 x 106 cells / mL Sixty μl of a test substance was added at various concentrations obtained by dissolving it with the pH regulator for attachment to a 96 well, round bottom plate (IWAKI). Immediately afterwards, 60 μl of the Jurkat cells (1x 106 cells / ml) were added and shaken on a plate stirrer (IKA-Labortechnik, IKA-SCHUTTLER MTS-4) at 1000 rpm for 10 seconds. In 120 μL of the cell suspension to which the test substance had been added, each 100 μL of it was transferred to a plate coated with VCAM-1 / Fc and incubated in a dark place at room temperature for 60 minutes. After stirring on the plate stirrer at 1000 rpm for 30 seconds, the solution was removed immediately. Subsequently unbound cells were removed by washing with PBS once. A pH C regulator (PBS containing 0.82% Triton X-100) was added to the plate in an amount of 70 μL / well. After stirring on the plate stirrer at 1000 rpm for 5 minutes, bound Jurkat cells were used. After centrifugation of the cells on a plate for centrifugation (SIGMA 4-15C) at room temperature at 2500 rpm for 5 minutes, 50 μL of the supernatants were transferred to a 96-well microtiter plate (Nunc Maxisorp). Each 50 μL of the pH regulator for substrate (Promega non-radioactive cytotoxicity assay, CytoTox 96) was added thereto, stirred on a plate shaker at 1000 rpm for 10 seconds and reacted in a dark place at room temperature for 30 minutes. Subsequently, each 50 μL of the stop solution (Promega non-radioactive cytotoxicity assay, CytoTox 96) was added to the same and was stirred on a plate agitator at 1000 rpm for 10 seconds. Its absorbance at 490 nm was determined with a plate reader (Molecular Devices, Vmax). The absorbance thus obtained - detects an activity of lactate dehydrogenase (LDH) dissolved in the supernatant of each well. That is, the absorbance is proportional to the number of Jurkat cells remaining in the plate via binding to VCAM-1. The test was carried out in duplicate and the binding rate of each test substance was determined at various concentrations while the absorbance of free well test substance was determined to be 100% and the absorbance of free well Jurkat cells was determined That was 0%. The concentration for the 50% inhibition of the binding, IC 50, was calculated. The results obtained show in the results table 1.

TABLE OF RESULTS 1 Assay of antagonistic activity to binding by integrin VCAM-1 / a4β1 (IC50, nM) is a compound of Example 1 in WO 02/16329 (patent literature 14).

EXAMPLE PROOF 2 Pharmacokinetic study by intravenous administration to the rat After all the compounds of the present invention wherein R11 to R141 are a hydroxyl group, which were active forms, they were weighed on a scale; these were adjusted by dimethyl sulfoxide to be 10 mg / mL. Polyethylene glycol 400 and distilled water were added to prepare 1 mg / mL of a solution for administration. A 1 mg / mL solution was intravenously administered as a particular dose to a Wistar rat in an amount of 1 mL / kg. 1, 5, 10, 20, 60 and 180 minutes later, the concentration of the drug in blood plasma obtained by taking a blood sample from the cervical vein during the time under anesthesia was determined with LC / MS. From the results obtained, the area under the plasma-time concentration curve was calculated from time zero to infinity (AUCinf (iv)) in accordance with the trapezoidal method of the pharmacokinetic analysis. The total elimination in the body (CLtot, [L / hr / kg]) was calculated as an index of disappearance of the drug in the blood plasma from a dose [mg / kg] and AUC [μgxhr / mL] in accordance with the formula: CLtot = Dose + AUCinf (ív). The results obtained show in the results table 2.

TABLE OF RESULTS 2 Total body elimination in intravenous administration to a rat (CLtot, fL / hr / kgl) is a compound of Example 1 in WO 02/16329 (patent literature 14).

EXAMPLE PROOF 3 Pharmacokinetic study by oral administration to the rat After all the compounds of the present invention in which R11 to R141 are different from a hydroxyl group, which were prodrugs, were weighed on a scale, they were adjusted by dimethyl sulfoxide to be 100 mg / mL. The solution mixture of polyethylene glycol 400: polyethylene glycol = 1: 1 was added thereto to prepare 2.5 mg / mL of a solution for administration. 2.5 mg / mL of the administration solution was administered orally to a male Wistar rat (7 to 9 weeks of age) in an amount of 4 mL / kg. 0.25, 0.5, 1, 2, 4, 6 or 8 hours later, the blood was withdrawn from the cervical vein under anesthesia with a syringe treated with dichlorvos in which an esterase inhibitor. Subsequently, the blood was transferred to a tube treated with heparin and centrifuged, and blood plasma was obtained. The acetonitrile containing the internal standard substance was added in two parts thereto to the blood plasma obtained and the concentration of the corresponding active form was determined wherein R11 to R141 are hydroxyl groups by LC / MS / MS. From the results obtained, the area under the plasma-time concentration curve was calculated from the zero to infinity time of the active form, that is, (AUCinf (po)). The bioavailability (BA) was calculated from AUCinf (iv) of the active form in the intravenous administration obtained from example test 2 by the following formula: BA (%) = [AUCinf (po) / dose (po)] / [AUCinf (iv) / dose (iv)] x 100 AUCinf: the area under the plasma concentration-time curve from time zero to infinity of the active form in oral or intravenous administration Dosage: oral or intravenous dose (as the active form) The results obtained show in the results table 3 TABLE OF RESULTS 3 Pharmacokinetic studies in oral administration to a rat * is a compound of example 190 in WO02 / 16329 (patent literature 14) and corresponds to a methyl ester compound of example 1 in WO02 / 16329 (patent literature 14).

EXAMPLE OF TEST 4 Activity to raise the number of lymphocytes in the peripheral blood in a rat After the inhibitory substance of the bond between integrin at 4 and VCAM-1 is administered in vivo, in the case where this inhibitory activity works effectively, it suggests that the number of lymphocytes in the peripheral blood is increased by inhibiting the adhesion of lymphocytes to blood vessels or organs (non-patent literatures 45 and 47). The activity of the compounds of the present invention was examined to raise the number of lymphocytes in the rat. A dose solution was prepared by dissolving the compounds of the present invention in dimethyl sulfoxide, adding the mixed solution of polyethylene glycol 400: polyethylene glycol = 1: 1 and reversing repeatedly. The final concentration of DMSO was adjusted to be 2.5%. The solution for dosing a test substance (3 mg / kg, 10 mg / kg or 30 mg / kg) was orally administered to a male Wistar rat (6 to 8 weeks of age) in an amount of 4 mL / kg. After the time points were fixed after the administration, the blood was withdrawn from the long abdominal vein under anesthesia and shaken in a container coated with EDTA-2K for blood collection. Subsequently, the number of lymphocytes in the peripheral blood was determined by means of an automated comprehensive hematology analyzer (SF-3000, Sysmex). The test was run at n = 5, and the ratio (%) of the number of lymphocytes in the peripheral blood in a group to which the test substance was administered compared to a group treated with the vehicle (a control group) of calculated, while the average value of the number of lymphocytes in the peripheral blood in a control group was determined to be 100%. The results obtained are shown in the table of results TABLE OF RESULTS 4 (No. 1) Assay of elevation of lymphocyte activity in the peripheral blood by oral administration to a rat O: pass (measurement criteria or more) X: failure (less than the measurement criterion) -: not evaluated TABLE OF RESULTS 4 (No. 2) by an oral administration to a rat O: pass (measurement criteria or more) X: failure (less than the measurement criterion) -: not evaluated TABLE OF RESULTS 4 (NO.3) O: pass (measurement criteria or more) X: failure (less than the measurement criterion) -: not evaluated

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - Pharmaceutical derivatives of the following formula (1) or pharmaceutically acceptable salts thereof: p) wherein R 11 represents a hydroxyl group, an akoxyl group having 1 to 6 carbon atoms which may have a substituent (s), a morpholinoethyloxy group or a benzyloxy group which may be substituted with a group (s) methyl or a methoxy group (s), R12 and R13 each independently represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an acetyl group or a methyloxycarbonyl group, or N (R12) R13 represents a group 1-pyrrolidinyl, 1-piperidinyl group, 4-morpholinyl group, 4-thiomorpholinyl group, 3-tetrahydrothiazolyl group or 1-piperazinyl group of which the fourth position can be substituted with an alkyl group having from 1 to 3 carbon atoms. carbon, R14 represents a methyl group or an ethyl group, Ri 'represents a hydrogen, a fluorine atom or a chlorine atom, Xi represents -CH (R1a) -, - CH (R1a) CH (R1b) -, -CH (R1a) CH (R1b) CH (R1c) -, CH (R1a) ) CH (R1 b) CH (R1c) CH (R1d) -, -N (R1a) CH (R1 b) CH (R1c) -, OCH (R1a) CH (R1b) -, -OCH (R1a) CH (R1b) CH (R1c) - or 1,3-pyrrolidinylene, wherein R1a, R1b, R1c and R1d each independently represent a hydrogen atom or a methyl group, and Yn and Y-? 2 represent any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).

2. The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 1, further characterized in that, in the formula (1), R11 represents a hydroxyl group, an alkoxy group having from 1 to 6 carbon atoms , a morpholinoethyloxy group or a benzyloxy group which may be substituted with a methyl group (s) or a methoxy group (s), an alkyl group in R12 and R13 represents an alkyl group having from 1 to 3 carbon atoms, and ^ represents -CH (R1a) -, -CH (R1a) CH (R1b) -, -CH (R1a) CH (R1b) CH (R1c) -, - OCH (R1a) CH (R1b) - or 1 , 3-pyrroidinylene.

3. The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 2, further characterized in that, in the formula (1), Xi represents -CH (R1a) -, - CH2CH2-, -N (R1a) CH2CH2-, or 1,3-pyrrolidinylene, wherein R1a represents a hydrogen atom or a methyl group.

4. The phenylalanine derivatives or pharmaceutically-acceptable salts thereof according to claim 3, further characterized in that, in formula (1), R12 and R13 each independently represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or N (R12) R13 represents a 1-pyrrolidinyl group, 1-piperidinyl, 4-morpholinyl group, 4-thiomorpholinyl group, 3-tetrahydrothiazolyl group or 1-piperazinyl group of which the fourth position can be substituted with an alkyl group having from 1 to 3 carbon atoms.

5. The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 3, further characterized in that, in the formula (1), R12 represents a methyl group or an ethyl group, R13 represents a hydrogen atom, a methyl group or an ethyl group, or N (R12) R13 represents a 1-pyrrolidinyl group, a 1-piperidinyl group or a 4-morpholinyl group, R14 represents a methyl group, R ^ represents a hydrogen atom, X- '; represents -CH2-, which is located in the sixth, seventh or eighth position of the quinazolinedione ring, and YH and Y? 2 represents any of the combinations, (Cl, Cl), (Cl, Me), (CI, "F ), (F, F) and (F, Me)

6. The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 3, further characterized in that, in the formula (1), R13 represents an atom of hydrogen, a methyl group or an ethyl group, XT represents -CH2-, which is located in the sixth, s optimal or eighth position of the quinazolinedione ring, and Y11 and Y12 represents the combination of (Cl, Cl).

7. - The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 6, further characterized in that, in the formula (1), R 13 represents a hydrogen atom, a methyl group or an ethyl group, and Xi represents -CH 2 -, which is located in the sixth position of the quinazolinedione ring.

8. The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 6, further characterized in that, in the formula (1), R13 represents a hydrogen atom, a methyl group or an ethyl group, and Xi represents -CH2-, which is located in the seventh position of the quinazolinedione ring.

9. The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 3, further characterized in that, in the formula (1), R12 and R13 each independently represents a methyl group or an ethyl group, R14 represents a methyl group, Ri 'represents a hydrogen atom or a fluorine atom, which is located in the sixth or seventh position of the quinazolinedione ring, Xi represents -N (CH3) CH2CH2- or 1,3-pyrrolidinylene, which is localized in the sixth or seventh position of the quinazolinedione ring, and Yp and Y12 represents the combination of (Cl, Cl).

10. The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 2, further characterized in that, in the formula (1), R12 and R13 each independently represents a hydrogen atom, a methyl group or a ethyl group, or N (R12) R13 represents a 1-pyrrolidinyl group, a 1-piperidinyl group or a 4-morpholinyl group, R14 represents a methyl group or an ethyl group, Ri 'represents a hydrogen atom, Xi represents -OCH (R1a) CH (R1b) -, wherein R1a and R1b each independently represents a hydrogen atom or a methyl group, and Yn and Y-? 2 represents any combination of (Cl, Cl), (Cl, Me ), (Cl, F), (F, F) and (F, Me).

11. The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 10, further characterized in that, in the formula (1), R12 and R13 each independently represents a hydrogen atom, a methyl group or a group ethyl, R14 represents a methyl group, and Yn and Y-? 2 represents the combination of (Cl, Cl).

12. The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 1, further characterized in that, in the formula (1), R11 represents a hydroxyl group or an alkoxy group having from 1 to 6 carbon atoms which may have a methoxy group (s) a substituent (s), R12 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R13 represents a hydrogen atom, a methyl group or an ethyl group , or N (R12) R13 represents a 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group, 4-thiomorpholinyl group, 3-tetrahydrothiazolyl group or 1-piperazinyl group of which the fourth position can be substituted with a group alkyl having 1 to 3 carbon atoms, R14 represents a group methyl, Ri 'represents a hydrogen atom, Xi represents -CH (R1a) -, -CH (R1a) CH (R1b) -, -CH (R1a) CH (R1b) CH (R1c) -, or -OCH (R1a) CH (R1b) -, which is located in the sixth position of the quinazolinedione ring, where each of R1a, R1b and R1c represents a hydrogen atom, and Yn and Y12 represents the combination of (Cl, Cl) .

13. The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 1, further characterized in that, in the formula (1), R11 represents a hydroxyl group or an alkoxy group having from 1 to 6 carbon atoms , R12 represents an alkyl group having from 1 to 6 carbon atoms, R13 represents a hydrogen atom, a methyl group or an ethyl group, - R14 represents a methyl group, RT represents a hydrogen atom, Xi represents -CH ( R1 a) - or -CH (R1a) CH (R1b) -, which is located in the sixth position of the quinazolinedione ring, where each of R1a and R1b represents a hydrogen atom, and Y-p and Y12 represents the combination of (Cl, Cl).

14. Phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 1, further characterized in that, in the formula (1), R11 represents a hydroxyl group or an alkoxy group having from 1 to 6 carbon atoms , R12 represents an alkyl group having from 1 to 5 carbon atoms, R13 represents a hydrogen atom, R14 represents a methyl group, Ri 'represents a hydrogen atom, Xi represents -CH (R1a) -, - CH (R1a) CH (R1b) - or -CH (R1a) CH (R1b) CH (R1c) -, which is located in the sixth position of the quinazolinedione ring, wherein each of R1a, R1b and R1c represents a hydrogen atom, and Yn and Y? 2 represents the combination of (Cl, Cl).

15. The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 1, further characterized in that, in the formula (1), R11 represents a hydroxyl group or an alkoxy group having from 1 to 6 carbon atoms , R12 represents an alkyl group having from 1 to 5 carbon atoms, R13 represents a hydrogen atom, R14 represents a methyl group, RT represents a hydrogen atom, X ^ represents -CH (R1a) -, -CH (R1a CH (R1b) - or -CH (R1a) CH (R1b) CH (R1c) -, which is located in the sixth position of the quinazolinedione ring, wherein each of R1a, R1b and R1c represents a hydrogen atom, and Yp and Y? 2 represents the combination of (Cl, Cl).

16. The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 1, further characterized in that, in the formula (1), R11 represents a hydroxyl group or an alkoxy group having from 1 to 6 carbon atoms , R12 represents a methyl group, an ethyl group, an isobutyl group, a cyclopropylmethyl group, a cyclobutyl group, a sec-butyl group or an isopentyl group, R13 represents a hydrogen atom, R14 represents a methyl group, RT represents an atom of hydrogen, Xi represents -CH (R1a) -, the which is located in the sixth position of the quinazolinedione ring, where R1a represents a hydrogen atom, and Yn and Y12 represents the combination of (Cl, Cl).

17. The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 1, further characterized in that, in the formula (1), R11 represents a hydroxyl group or an alkoxyl group having from 1 to 6 carbon atoms , R12 represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms, R13 represents a hydrogen atom, a methyl group or an ethyl group, or N (R12) R13 represents a 1-pyrrolidinyl group, 1-piperidinium, 4-morpholinyl group, 4-thiomorpholinyl group, 3-tetrahydrothiazolyl group or 1-piperazinyl group of which the fourth position can be substituted with an alkyl group having from 1 to 3 carbon atoms-, R 14 represents a methyl group, Ri 'represents a hydrogen atom, Xi represents -O-CH (R1 a) CH (R1 b) - or -O-CH (R1a) CH (R1 b) CH (R1c) -, which is localized in the sixth position of the quinazolinedione ring, wherein each of R1a, R1 by R1c represents an atom d and hydrogen or a methyl group, and Yn and Y-? 2 represents the combination of (Cl, Cl).

18. The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to any of claims 1 to 17, further characterized in that, in the formula (1), R11 represents a branched alkoxy group having from 3 to 6 carbon atoms. carbon.

19. - The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 1, further characterized in that they are represented by the following formulas: C.VN. "- .. O .." fl - i -. - '< - ... G O: I i « < -. n ? r-. r and H i

20. - Phenylalanine derivatives of the following formula (2) or pharmaceutically acceptable salts thereof: (Z) wherein R21 represents a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, a morpholinoethyloxy group or a benzyloxy group which may be substituted with a methyl group (s) or a methoxy group (s) , R22 represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms, R24 represents a methyl group or an ethyl group, R2 'represents a hydrogen atom, a fluorine atom or a chlorine atom, X2 represents -CH (R2a) -, -CH2CH2- or -N (R2a) CH2CH2-, wherein R2a represents a hydrogen atom or a methyl group, and Y2? and Y22 represent any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).

21. The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 20, further characterized in that, in formula (2), R22 represents a methyl group or an ethyl group, R24 represents a methyl group, R2 'represents a hydrogen atom, X2 represents -CH2-, which is located in the sixth, seventh or eighth position of the quinazolinedione ring, and Y2? and Y22 represents the combination of (Cl, Cl).

22. The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 20, further characterized in that, in the formula (2), R22 represents a hydrogen atom, a methyl group or an ethyl group, R24 represents a methyl group, R2 'represents a hydrogen atom or a fluorine atom, which is located in the sixth or seventh position of the quinazolinedione ring, X2 represents -N (CH3) CH2CH2- or -NHCH2CH2-, which is located in the sixth or seventh position of the quinazolinedione ring, and Y21 and Y22 represents the combination of (Cl, Cl).

23.- Phenylalanine derivatives of the following formula (3) or pharmaceutically acceptable salts thereof: wherein R31 represents a hydroxyl group, an alkoxy group having from 1 to 6 carbon atoms, a morpholinoethyloxy group or a benzyloxy group which may be substituted with a methyl group (s) or a methoxy group (s), R3 represents a methyl group or an ethyl group, R3 'represents a hydrogen atom or a fluorine atom, Formula (3-1) represents a 4-morpholinyl group, a 4-thiomorpholinyl group, a 3-tetrahydrothiazolyl group, a 1-piperazinyl group of which the fourth position can be substituted with an alkyl group having from 1 to 3 carbon atom, or a 1-imidazolyl group which may be substituted with a methyl group, an ethyl group or an amino group, wherein X 3 represents an oxygen atom, a hydrogen atom which may be substituted with a group alkyl which has from 1 to 3 carbon atoms, or a sulfur atom, and Y3? and Y32 represent any of the combinations, (Cl; Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).

24. The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 23, further characterized in that, in the formula (3), formula (3-1) represents a 4-morpholinyl group, a 4-thiomorpholinyl group , a 3-tetrahydrothiazolyl group, a 1-piperazinyl group of which the fourth position may be substituted with an alkyl group having 1 to 3 carbon atoms, or a 1-imidazolyl group which may be substituted with a methyl group or an amino group, wherein X3 represents an oxygen atom, a nitrogen atom which may be substituted with an alkyl group having from 1 to 3 carbon atoms, or a sulfur atom.

25. The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 24, further characterized in that, in the formula (3), R34 represents a methyl group, R3 'represents a hydrogen atom, the formula (3) -1) represents a 4-morpholinyl group or a 1-piperazinyl group of which the fourth position can be substituted with an alkyl group having from 1 to 3 carbon atoms, and Y31 as Y32 represent the combination of (Cl, Cl) .

26. The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 24, further characterized in that, in the formula (3), R34 represents a methyl group, R3 'represents a hydrogen atom, the formula (3) -1) represents a 2-amino-1-imidazolyl group, and Y31 as Y32 represents the combination of (Cl, Cl).

27. The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 23, further characterized in that, in the formula (3), R3 represents a methyl group, R3 'represents a hydrogen atom or a fluorine atom , the formula (3-1) represents a 1-imidazolyl group from which the second position can be substituted with a methyl group or an ethyl group, and Y31 as Y32 represent the combination of (Cl, Cl).

28. - Phenylalanine derivatives of the following formula (4) or pharmaceutically acceptable salts thereof: wherein R i represents a hydroxyl group, an alkoxy group having from 1 to 6 carbon atoms, a morpholinoethyloxy group or a benzyloxy group which may be substituted with a methyl group (s) or a methoxy group (s), ring represents a benzene ring, a pyridine ring, a thiophene ring, a piperidine ring of which the first position can be substituted with an alkyl group having from 1 to 3 carbon atoms, a piperazine ring of which the first and / or or the fourth position can be substituted with an alkyl group having from 1 to 3 carbon atoms, or a pyrrolidine ring from which the first position can be substituted with an alkyl group having from 1 to 3 carbon atoms, R44 represents a methyl group or an ethyl group, and Y41 and Y42 represent any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).

29. The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 28, further characterized in that, in the formula (4), the ring represents a piperazine ring of which the first and / or fourth position can be substituted with a methyl group, R44 represents a methyl group, and Y -? and Y42 represents the combination of (Cl, Cl).

30. Phenylalanine derivatives of the following formula (5) or pharmaceutically acceptable salts thereof: wherein R51 represents a hydroxyl group, an alkoxy group having from 1 to 6 carbon atoms, a morpholinoethyloxy group or a benzyloxy group which may be substituted with a methyl group (s) or a methoxy group (s), R54 represents a methyl group or an ethyl group, R5 'represents a hydrogen atom or a fluorine atom, R5a and R5b each independently represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms, or N (R5a) R5b represents a 1-pyrrolidinyl group or a 1-piperidinyl group, and Y51 and Y52 represent any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).

31. The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 30, further characterized in that, in the formula (5), R54 represents a methyl group, R5 'represents a hydrogen atom, N (R5a) R5b represents a ethylamino group or a 1-pyrrolidinyl group, and Y5-? and Y52 represent the combination of (Cl, Cl).

32. Phenylalanine derivatives of the following formula (6) or pharmaceutically acceptable salts thereof: where R6? represents a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, a morpholinoethyloxy group or a benzyloxy group which may be substituted with a methyl group (s) or a methoxy group (s), A6 represents any of the following formulas (6-1) to (6-6): Í6- 1) (6- 2: < d-3 > (6-5; í6"63 and Yßi and Yß2 represent any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).

33. - The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 32, further characterized in that, in the formula (6), A6 represents any of the aforementioned formulas (6-1) to (6-4).

34. The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 32, further characterized in that, in the formula (6), R61 represents a hydroxyl group, and Y6-? and Y? 2 represents the combination of (Cl, Cl).

35.- Phenylalanine derivatives of the following formula (7) or pharmaceutically acceptable salts thereof: R7? represents a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, a morpholinoethyloxy group or a benzyloxy group which may be substituted with a methyl group (s) or a methoxy group (s), R74 represents a methyl group or an ethyl group, R7 represents an alkynyl group having from 3 to 5 carbon atoms, a cycloalkylmethyl group having from 4 to 6 carbon atoms, a cycloalkyl group having from 3 to 6 carbon atoms, or a propyl group , and Y7-? and Y72 represent any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).

36. - The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 35, further characterized in that, in the formula (7), R7 represents a methyl group, R7 represents a 2-propynyl group or a cyclopropylmethyl group, and Y7 ? Y - 5 AND 2 represent the combination of (Cl, Cl).

37. The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 35, further characterized in that, in the formula (7), R7 represents a methyl group, R7 represents a propyl group, and Y1 and Y72 represent the combination 10 of (Cl, Cl).

38.- Phenylalanine derivatives of the following formula (8) or pharmaceutically acceptable salts thereof: m where R8? represents a hydroxyl group, an alkoxy group having from 1 to 6 carbon atoms, a morpholinoethyloxy group or a benzyloxy group which Can be substituted with a methyl group (s) or a methoxy group (s), or a hydroxyethyl group, R82 represents a methyl group or an ethyl group, R84 represents a methyl group or an ethyl group, n8 represents an integer of 0 to 2, and Y81 and Y82 represent any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).

39. The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 38, further characterized in that, in the formula (8), R8? represents a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, a morpholinoethyloxy group or a benzyloxy group of which may be substituted with a methyl group (s) or a methoxy group (s).

40.- The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 38, further characterized in that, in the formula (8), R82 represents a methyl group, R84 represents a methyl group, n8 represents any of the integers 0 or 2, S is located in the sixth position of a quinazolinedione ring, and Y8? Y Y82 represent the combination of (Cl, Cl).

41.- Phenylalanine derivatives of the following formula (9) or pharmaceutically acceptable salts thereof: (9) wherein R9 represents a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, a morpholinoethyloxy group or a benzyloxy group which may be substituted with a methyl group (s) or a methoxy group (s), Rg2 represents a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, an amino group or a benzyloxy group which may be substituted with a methyl group (s) or a methoxy group (s), Rg represents a methyl group or an ethyl group, Xg represents an atomic bond, -CH2-, -CH2CH2- or -CH = CH-, and Y91 and Y92 represent any of the combinations, (Cl, Cl), (Cl, Me), (CI, F), (F, F) and (F, Me).

42. The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 41, further characterized in that, in the formula (9), Xg represents -CH2CH2- or -CH = CH- and R92 represents a hydroxyl group, or X9 represents an atomic bond and Rg2 represents a benzyloxy group, Xg is located at the sixth position of the quinazolinedione ring, R9 represents a methyl group, and Y91 and Y92 represents the combination of (Cl, Cl).

43.- The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 41, further characterized in that, in the formula (9), Xg represents an atomic bond and R92 represents a hydroxyl group, a methoxy group or a group amino, X9 is located in the sixth position of the quinazolinedione ring, Rg represents a methyl group, and Y91 and Y92 represents the combination of (Cl, Cl).

44.- Phenylalanine derivatives of the following formula (10) or pharmaceutically acceptable salts thereof: (10) wherein R101 represents an alkoxy group having from 2 to 6 carbon atoms or a morpholinoethyloxy group, R10 represents a methyl group or an ethyl group, R4 represents a methyl group or an ethyl group, and Y101 and Y102 represent any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F. Me).

45.- The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 44, further characterized in that, in the formula (10), R10 represents an ethyl group.

46.- Phenylalanine derivatives of the following formula (11) or pharmaceutically acceptable salts thereof: £ 11) wherein Rm represents an alkoxy group having 1 to 6 carbon atoms or a morpholinoethyloxy group, Rn4 represents a methyl group or an ethyl group, and Ym and Yn2 represent any combination, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F. Me).

47.- Phenylalanine derivatives of the following formula (12) or pharmaceutically acceptable salts thereof: (12) wherein R- represents an alkoxy group having 1 to 6 carbon atoms or a morpholinoethyloxy group, R 2 represents a methyl group or an ethyl group, and A represents any of the following formulas (12-1) and (12- : i 2 - t í Í T 2 -2

48. - Phenylalanine derivatives of the following formula (13) or pharmaceutically acceptable salts thereof: wherein R131 represents a hydroxyl group, an alkoxy group having from 1 to 6 carbon atoms, a morpholinoethyloxy group or a benzyloxy group which may be substituted with a methyl group (s) or a methoxy group (s), R13a and R13b each independently represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or N (R13a) R13b represents a 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group, 4-thiomorpholinyl group , 3-tetrahydrothiazolyl group or 1-piperazinyl group of which the fourth position can be substituted with an alkyl group having 1 to 3 carbon atoms, and Y13-1 and Y132 represent any combination, (Cl, Cl) , (Cl, Me), (Cl, F), (F, F) and (F, Me).

49.- Phenylalanine derivatives of the following formula (14) or pharmaceutically acceptable salts thereof: wherein R141 represents a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms or a morpholinoethyloxy group, R144 represents a group methyl or an ethyl group, a hydroxyl group in a quinazolinedione ring is located in the sixth or seventh position of the ring, and Yw and Y? represent any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).

50.- The phenylalanine derivatives or pharmaceutically acceptable salts thereof according to claim 49, further characterized in that, in the formula (14), R144 represents a methyl group, a hydroxyl group is located in the sixth position of the quinazolinedione ring , and Y-? 4 and Y-? 42 represent the combination of (Cl, Cl).

51. A pharmaceutical composition comprising a phenylalanine derivative or a pharmaceutically acceptable salt thereof according to any of claims 1 to 50 as an active ingredient and a pharmaceutically acceptable carrier thereof.

52. An α4 integrin antagonist comprising a phenylalanine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 50 as an active ingredient.

53.- A therapeutic agent or preventive agent for inflammatory diseases in which a adhesion process dependent on integrin a4 participates in the pathology, which comprises a phenylalanine derivative or a pharmaceutically acceptable salt thereof according to any of the claims 1 to 50 as an active ingredient.

54. - A therapeutic agent or preventive agent for rheumatoid arthritis, inflammatory bowel diseases, systemic lupus erythematosus, multiple sclerosis, Sjögren's syndrome, asthma, psoriasis, allergy, diabetes mellitus, cardiovascular diseases, arterial sclerosis, restenosis, tumor proliferation, tumor metastasis and transplant rejection, which comprises a phenylalanine derivative or a pharmaceutically acceptable salt thereof according to any of claims 1 to 50 as an active ingredient.