WO2003089410A1 - Phenylalanine derivative - Google Patents

Phenylalanine derivative

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Publication number
WO2003089410A1
WO2003089410A1 PCT/JP2003/004970 JP0304970W WO03089410A1 WO 2003089410 A1 WO2003089410 A1 WO 2003089410A1 JP 0304970 W JP0304970 W JP 0304970W WO 03089410 A1 WO03089410 A1 WO 03089410A1
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Prior art keywords
hz
ih
substituted
unsubstituted
compound
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PCT/JP2003/004970
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French (fr)
Japanese (ja)
Inventor
Yoshisuke Nakasato
Kiminori Ohta
Eri Arai
Osamu Saku
Hiroko Kusaka
Satoshi Nakanishi
Haruhiko Manabe
Akira Ogawa
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Kyowa Hakko Kogyo Co., Ltd.
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with heteroatoms or with carbon atoms having three bonds to hetero atoms, with at the most one to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72Nitrogen atoms
    • C07D213/74Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D241/00Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06Dipeptides
    • C07K5/06139Dipeptides with the first amino acid being heterocyclic
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides

Abstract

A phenylalanine derivative represented by the formula (I): (I) (wherein m and n are the same or different and each is 1 or 2; R2 represents (un)substituted lower alkyl, etc.; R1 represents (un)substituted lower alkyl, etc.; and R3, R4, R5, and R6 are the same or different and each is hydrogen, (un)substituted lower alkyl, oxo, etc.) or a pharmacologically acceptable salt of the derivative. They are useful as an α4 integrin inhibitor.

Description

Specification

Fe two Ruarayun derivatives

Technical field

The present invention relates to alpha 4 Lee Nteguri emission inhibitor and to useful Feniruaranin derivative or a pharmacologically acceptable salt thereof.

BACKGROUND

Adhesion between cells and cells or extracellular Matrigel Ttasu the migration into inflamed position of leukocyte adhesion and, plays an important role in mobilization of stem cells during ontogeny. Although the various adhesion molecules in these processes is interposed and summer clarified, Integurin interacts with a ligand expressed on the cell, which is one of particular adhesion molecules, cells and cell or cell outer Matrix Li Ttasu and adjust important is the work [a Dohijon 'Mo Rekyunorezu' Lee emissions adhesion - the Noresu ■ § emissions de ■ di seeds (adhesion Molecules in Health and Disease); Ponore (Paul, LC ), Ishukutsu

(Issekutz, T. Ζ.) Author; Masenore Dekker: New York (Marcel Dekker: New York), pp. 297-300 (1997)].

Non-4 Lee Nteguri down, terrorist dimer to the J3 1 Lee Nteguri down (α 4] 3 1) ¾ VLA-4 (very late antigeN -4) and] S 7 terrorist dimer to the Integurin (α 4 | 37) the Development $ formed to LPAM - 1 (lymphocyte Peyer's patch HEV adhesion molecule- 1) of two types of molecules there has been known. VLA- 4 is lymphocytes, monocytes, eosinophils and expressed mast on cells, Kiwamugen on vascular endothelial VCAM- 1 (Vascular Cell Adhesion Molecule- 1) and Fuibu port nectin is in its ligand is there. The LPAM- 1 is lymphocytes, monocytes, eosinophils, and expressed on the basophils, intestinal mucosa VCAM-1 and fibronectin sequence, mesenteric lymph nodes, Peyer's patches Contact Yopi spleen MadCAM expressed in high endothelial Hososei artery (layer) - 1 (mucosal addressin cell adhesion molecule) is at its ligands.

The inflammatory response date temple and VLA- 4 and LPAM- 1, VCAM-1 or MadCAM- by a 1 and the † th interactions, inflammatory cells and vascular endothelial cells are known to adhere firmly [A Dohijo down 'mode Rekyunorezu' Lee 'Noresu to' emissions Anne de • Disease (Adhesion Molecules In Health And Disease); Ponore (Paul, LC), Ishukutsu (Issekutz, T. Ζ.) Author; Marcel 'dead car: New York (Marcel Dekker: New York), 297- 300 pp (1997) adhesion through the alpha 4 integrin in a variety of pathological processes are known and child involved, is a pathological process example, experimental autoimmune encephalomyelitis (Ipushiron'arufaipushiron), multiple sclerosis (MS), inflammatory brain disorders, such as brain inflammation [Nechiya one (Nature), 356 Certificates, 63 (1992), Jananore 'O Bed' E task Peri mental ■ Medicine (J. Exp. Med.), 177 Certificates, 5 7 (1993)], asthma [Journal 'O Bed' Ekusuperi mental 'Medeishin, 180 Certificates, 795 (1994), Jananore-O Bed (J. Exp Med..) -. Click linear force Honoré Investor (.. J. Clin Invest) Sutigeshiyo down, 93 Certificates, 776 (1994), journal - O Bed - Imunoroji (J. Immunology), 0.99, pp. 2407 (1993)], inflammatory bowel disease (ulcerative including colitis and Crohn's disease) journal. O blanking. Imuno biology (J. Immunology), 152 Certificates, pp 3238 (1994)], chronic rheumatoid Umachi [journal O blanking. Imunoroji (J. Immunology), (. Annals Rheumatic Dis) 147 Certificates, p. 4207 (1991), Anarusu 'O Breakfast' Liu Matty click 'Deijiizu, 52 Certificates, 672 (1993), Jananore ■ O Bed-click linear force Norre - fin downy Sutigesho down (J. Clin. Invest.), 93 Certificates, 405 (1994), the journal 'O Breakfast -. (.. J. Clin Invest) click Rinikaru Investor Sutigeshiyo down, 89 Certificates, pp 1445 (1S91_nen)], (including acute juvenile diabetes) Diabetes [Proceedings Dinh grayed ■ O blanking ■ the National Academy · O blanking ■ Sciences ■ O blanking YOU SA, (Proc. Nat. Acad. Sciences of US A), 90 Certificates, page 10494 (1993), die-Bee tee's (Diabetes), 43 Certificates, 529 page (1994), Jananore, O blanking ■ click the linear force Norre - (.. J. Clin Invest) Inbe Sutigesho down, 93 Certificates, 1700 (1994)], tumor metastasis [Canon capacitors one 'research ( Can. Res.), 54 Certificates, 233 (1994), Intana relational, Jananore, O blanking-Kiyansa (Int. J. Can.), 58 Certificates, 298 (1994), The 'Jananore' O Breakfast 'Pathology (J. Path.), 170 Certificates, 429 (1993), diffusion Ellen Shi er to emissions (Diff.), 52 Certificates 239 (1993), Pretty Mesh 'Jananore ■ O Breakfast' Cancer (British J. Cancer), 68 Certificates, 862 (1993), Japanese 'journal - O Breakfast - Cancer Research (Japanese J. Cancer Res. ), 83 Certificates, 1304 (1992)], Ateromu sclerosis [Science (Science), 251 Certificates, 788 (1991),, Ateriosuta Les opening cis ■ collected by filtration Nboshisu

(Arterioscler. Thromb.), 13 Certificates, 197 (1993)], tissue transplantation [trans plantation try to down-Proceedings (Transpl. Proceed.), 25 Certificates, 813 (1993)], dementia [§ main Rika emissions. journals ■ O blanking ■ Pas Soroji (Am. J. Path.), 144 Certificates, 27 (1994)], atopic dermatitis journal 'O Bed' allergies. click Li two force Norre 'Imuno biology (J. Allergy Clin. Immunol.), 102 Certificates, 461 (1998)], Anoretsuno ヽ one more disease, AIDS, meningitis, encephalitis, stroke and other brain disorders, nephritis, retinitis , psoriasis, such as acute leukocyte-mediated lung injury, such as occurs in myocardial ischemia and adult respiratory distress syndrome, and the like.

Anti-inflammatory effects of a 4 Integuri emission inhibitor, using an anti-alpha 4 antibody inhibits the interaction between a 4 Integuri ting its Li ligand, it has been studied in a variety of inflammatory model. For example, experimental autoimmune encephalomyelitis (Ipushiron'arufaipushiron), multi sclerosis (MS) [Nechiya one (Nature), 356 Certificates, 63 (1992), two euros Biology (Neurology), 47 Certificates, 1053 page (1996)], asthma [journal O blanking ■ Arerugi one 'click Rinikaru. Imunoroji (J. Allergy Clin. Immunol.) 100 Certificates, 242 pp. (1997), Lee centers nationalist nano les. Akai Buss ■ (... Int Arch allergy Immunol) O Bed 'allergy and Imuno Logie, 112 Certificates, 287 pp. (1997)], rheumatoid rheumatism [journal Honoré - O Bed Liu Mato biology, (J. Rheumatol.) 23 Certificates, pp 2086 (1996), Imuno biology (Immunology), 88 Certificates, 569 (1996)], diabetes [Jananore ■ O Bed 'click linear force Honoré ■ Investor Sutigeshiyo emission (J. Clin. Invest. ), 93 Certificates, 1700 (1994)], nephritis [journal 'O drive. I-time Noroji (J. Immu nol.), 162 Certificates, p. 5519 (1999)], tissue transplantation [di Yananore ■ O Bed-click re-two force Norre. Lee Nbe Sutigesho down (J. Clin. Invest.), 95 Certificates, 2601, pp. ( 1995)], inflammatory bowel disease [journal. O blanking. click linear force Honoré 'Lee Nbe Sutigeshiyo emission (J. Clin. Invest.), 92 Certificates, 372 (1993)], contact hypersensitivity [European 'journal O Breakfast - (.. Eur J. Immunol) Imunoroji one, 23 Certificates, 682 (1993)], and the like [this your Rere Te α 4 Lee Nteguri down inhibitors are effective.

Tilia two Ruara Nin skeleton a compound having in its structure is, W098 / 53814, W098 / 53817, W099 / 20272, discussions 9/25685, W099 / 26922, W099 / 26923,

W099 / 64395, US6291511, leakage 1/12183, W001 (c) 4328, W098 / 58902, discussions 9/36393, W002 / 18320, orchid 9/06390, Xie 9/06431, W099 / 06435, discussions 0/43354, ■ 0 / 43369, the field 0/43371, picture 0/43372, W000 / 43413,

■ 0/43415, ■ 0/51974, ■ 2/08202, picture 9/10312, ff099 / 10313, the field 0/48994, picture 1/42215, W001 / 42225, W099 / 37618, W099 / 64390,

■ 0/18759, WO00 / 73260, W001 / 47867, W002 / 04426, easy 9/67230, picture 0/35855, W000 / 37444, J 01/163802, W001 / 21584, W001 / 32610, W002 / 14272, ■ 1 / 36376, discussions 2/16329, DE19962936, W001 / 68586, W002 / 02556, W001 / 47868, W002 / 20522, W002 / 28830, W002 / 57242, 0 02/42264, α 4 Lee Nteguri on to the W002 / 68398, US6410781 It has been described as an inhibitor Hitoshi IJ.

However, not the actual that is used to treat "4 integrin inhibitor present in these compounds, the more active compounds having strong, more oral absorbability good compounds, therapeutic contact Yopi used for prophylaxis development of alpha 4 Lee Nteguri emission inhibitor is desired to have a preferred nature to.

Disclosure of the Invention

Eyes' manner of the present invention is useful as a shed 4 integrin inhibitors, non 4 I Nteguri down the various diseases bonding mechanism involving over (e.g., multiple hard sclerosis, asthma, inflammatory bowel disease , rheumatoid rheumatic, diabetes, tumor metastasis, arteriosclerosis, atopic dermatitis, nephritis, psoriasis, myocardial ischemia, treatment and Ζ or useful for the prevention or the like for full Nirua cellular rejection, etc.) at the time of organ transplantation Ru near providing alanine derivative or a pharmacologically acceptable salt thereof. The present invention relates to the following (1) (1 1)

(1) (I)

{Wherein, m and n are the same or different, 1 or 2 represents, R 2 is substitution or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, a substituted or unsubstituted cycloalkyl, substituted or unsubstituted Shikuroarukeyuru, if substituted Ku represents unsubstituted Ariru, substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted alicyclic heterocyclic group,

R 1 is a substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Ariru, substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted alicyclic heterocyclic group, - C (= Y) NR 9 R 10 ( wherein, Y represents an oxygen atom or a sulfur atom, R 9 and R ie the same or different, a hydrogen atom, a substituted or unsubstituted lower alk kill, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or is unsubstituted Ariru, substituted or an unsubstituted aromatic heterocyclic group, or a substitution or unsubstituted alicyclic heterocyclic group), one C (= 0) R 9a (wherein, R 9a has the same meaning as the R 9), one C (= 0) 0R 9b (wherein, R 9b are the same as those obtained by removing a hydrogen atom from the definition of the R 9) or in one S0 2 R u [wherein, R 11 is synonymous with the R 9b some force or, represents an NR 9e R 1Q c (wherein, R 9e and R 1Q e is their respective same meanings as defined above and R 1 Q) represents a], R 3, R 4, R 5 and R 6 may be the same or different, a hydrogen atom, or represents a lower alkyl or Okiso substituted or unsubstituted, R 3, R 4, of R 5 and R 6, are two present on the same carbon atom, the connexion such together with the carbon atoms, or form a saturated monocyclic hydrocarbon ring, or, R 3, R 4, may form a two are together a connexion lower alkylene of R 5 and R 6 , R 7 and R 8 are identical or different dates, a hydrogen atom, a halogen, two Toro, substituted or unsubstituted Amino, substitution or unsubstituted lower Al Kokishi, substituted or unsubstituted lower Al Kiruchio, substituted or unsubstituted lower Arukanoiru, substituted or unsubstituted lower alkyl, substituted or is unsubstituted Ariru, substituted or aromatic heterocyclic group, or a substituted unsubstituted or phenylene Ruaranin derivative or a pharmacologically salt permissible represented by represents} unsubstituted alicyclic heterocyclic group.

(2) R 2 is R 2A <wherein although R 2A have the same meanings as the R 2,

(A) as a substituent on the nitrogen atom,

(a) - C (= Y 1A) NR 12A R 13A ( wherein, Y 1A is an oxygen atom or a sulfur atom, R 12A and R 13A are the same or different, a hydrogen atom, a substituted or unsubstituted lower alkyl , substituted or unsubstituted lower alkenyl - represents Le, lower alkynyl also properly unsubstituted or substituted or unsubstituted consequent opening alkyl le),

(b) - C (= 0 ) R 12Aa ( wherein, R 12Aa is as defined above R 12A),

(c) - C (= 0 ) 0R 12Ab ( wherein, R 12Ab is as defined above R 12A) or

(d) - S0 2 in R 13A [wherein, R 13A is added to the definition of the R 12A, one NR 12A. R 13Ae (wherein, R 12A. And R 13A. Each wherein R 12A and R 13A is as defined above) with a representative of, a substituted or unsubstituted 2-pyrrolyl or 4-substituted 4 Ichipi Perijiniru,

(B) 4 of one NR "[in the formula the substituents (R 2 to the 1-position of the bonding site to the adjacent carbonyl), R 14 one C (two Y 1A) NR 12A R 13A ( wherein, Y 1A, R 12A and

R 13A is the same meanings as defined above, respectively), one C (= 0) R 12Aa (wherein, R 12Aa is as defined above), in one C (== 0) 0R 12Ab (wherein, R 12Ab is the synonymous a is) or in one S0 2 R 13A (wherein a, is R 13A lower alkyl substituted by] represents the same meaning as defined above), even lower alkenyl properly has a lower alkyl, substitution or unsubstituted Ariru, substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted alicyclic heterocyclic group,

(C) having a 3-position substituent, 2, 2-dimethyl-cyclopentyl, 1, 2, 2 - Application Benefits Mechinoreshiku port pentyl, 2, 2, 3 - Application Benefits Mechinoreshiku b Penchinore or 1, 2, 2, 3- Te Torame Chino les cyclopentyl Honoré,

(D) as a substituent,

(a) - NR 15 S0 2 R 16 ( wherein, R 15 and R 16 are as defined defined above R 12A the same or different),

(b) 1-position of the ring structure (the 1-position of the bonding position to the carbonyl adjacent to the R 2) is to first place the bonding site to the 2-position moiety (carbonyl adjacent to R 2 is nitrogen atom ) gar S0 2 - properly be substituted composed monocyclic 5-7 membered ring of the unsubstituted alicyclic heterocyclic group,

(c) 2-position of the ring structure (bonding position to the 1-position of the carbonyl adjacent to the R 2) (wherein, R 16 has the same meaning as defined above) is _ S0 2 R 16 nitrogen substituted with properly be substituted composed monocyclic 5-7 membered ring atom is unsubstituted alicyclic heterocyclic group, or,

(d) 1-position of the ring structure (the 1-position of the bonding position to the carbonyl adjacent to the R 2) gar NR 15 S0 2 R 16 (wherein, R 15 and R 16 are each as defined above ) substituted or unsubstituted lower alkyl having been unsubstituted alicyclic heterocyclic group or a substituted or unsubstituted cycloalkyl Le is substituted or the configured monocyclic 5-7 membered ring with a carbon atom substituted with or

(E) (the 1-position of the binding positions of the adjacent carbonyl) 2- and 3-position portion of the ring structure gar C (= 0) negation one or - consists of a C (= S) NH- that a monocyclic 5- to 7-membered substituted or ring not a unsubstituted alicyclic heterocyclic group>, wherein R 1 is R 1A [wherein, although R 1A has the same meaning as R 1, R when 2A is the properly be substituted with one or two atoms selected from oxygen atom and a sulfur atom which is unsubstituted alicyclic heterocyclic group, R 1A is a substituted or unsubstituted lower alkyl, substituted or unsubstituted substituted Ariru, substituted or unsubstituted aromatic heterocyclic group, substituted or is properly unsubstituted alicyclic heterocyclic group or a C (=

0) 0R 9b (wherein, R 9b is has the same meaning as defined above) and not], R 3, R 4, R 5 and R 6 are each R 3A, R 4A, R 5A and R 6A (wherein among, R 3A, R 4A, but R 5A Oyo Pi R 6A have the same meanings as R 3, R 4, R 5 and R 6, respectively, 1 or 2 R 2A is selected from oxygen atom Oyo Pi sulfur atom when a substituted or unsubstituted alicyclic heterocyclic group having a number of atoms, is R 3A, R 4A, not a lower alkyl or Okiso of any of substitution or unsubstituted R 5A and R 6A) (1) Hue two Ruaranin derivative or a pharmacologically acceptable salt thereof.

(3) R 2 is R 2B [wherein, although R 2B has the same meaning as the R 2,

(A) a substituted 2 - 4 Ichipiperi Jiniru having pyrophosphoric Li Le or 1-position and 4-position substituents,

(B) 4-position substituent and a substituted lower alkyl, substituted lower alkenyl If Ku has substituted lower alkynyl, substituted or unsubstituted Ariru, substituted or is laid also aromatic heterocyclic group, or a substituted unsubstituted unsubstituted alicyclic heterocyclic group,

(C) replacement consequent opening pentyl,

(D) as a substituent,

(a) - NR 15 S0 2 R 16 ( wherein, R 15 and R 16 each have the same meanings as defined above),

(b) 1-position of the ring structure (the 1-position of the bonding position to the carbonyl adjacent to the R 2) is located at nitrogen atom 2 of part one S0 2 - monocyclic 5-7 membered composed of substituted ring is properly unsubstituted alicyclic heterocyclic group,

(c) 2-position of the ring structure (the 1-position of the bonding position to the carbonyl adjacent to the R z) gar S0 (wherein, R 16 is as defined above) 2 R 16 nitrogen substituted with a substituted or unsubstituted alicyclic heterocyclic group monocyclic 5-7 membered ring consisting of atom or,

(d) 1-position of the ring structure (the 1-position of the bonding position to the carbonyl adjacent to the R 2) gar NR 15 S0 2 R 16 (wherein, R 15 and R 16 are each as defined above ) has been in properly be substituted composed monocyclic 5-7 membered ring of carbon atoms of the substituted or unsubstituted having an alicyclic heterocyclic group or a substituted or unsubstituted consequent opening alkyl Le unsubstituted substituted with lower alkyl or,

(E) (to join position 1-position of the carbonyl adjacent to the R 2) 2 and 3 position part of the ring structure is one C (= 0) negation - or one C (= S) NH- a that is configured not a monocyclic 5-7 membered substituted or unsubstituted alicyclic heterocyclic ring group, in which R 1 is R 1A (wherein, R 1A is as defined above) There, R 3, R 4, R 5 and R 6 are each R 3A, in R 4 \ R 5A and R 6A (wherein, R 3A, R 4A, Contact R 5A, the preliminary R 6A is respectively as defined above phenylene Ruaranin derivative or a pharmacologically acceptable salt thereof) in the above (1), wherein.

(4) R 1 is a substituted or unsubstituted lower alkyl, substituted or non-substitution Ariru, substituted or unsubstituted aromatic heterocyclic group, also is properly substituted unsubstituted alicyclic heterocyclic group, One Ci ^ S NR 9! ^ (wherein, R 9 and R 1 () is as defined, respectively therewith the), (wherein, R 9a is as defined above) Single C (== 0) R 9a or one S0 2 (wherein, R u has the same meaning as defined above) R u phenylene Ruaranin derivative or a pharmacologically acceptable salt of a above (1), wherein.

(5) R 2 is a substituted or unsubstituted Ariru, substituted or unsubstituted aromatic heterocyclic group, or formula (II)

The - (it represents or sulfur atom, R 17 represents a substituted or unsubstituted lower alkyl, substituted or is unsubstituted Ariru or a substituted or unsubstituted aromatic heterocyclic group wherein, Q is one CH 2) Fueniruara Nin derivative or a pharmacologically acceptable salt thereof of (1) or (4) wherein represents.

(6) R 3, R 4, R 5 and above (1) R 6 is a hydrogen atom, it is allowed Fuweniruaranin derivative or its pharmacological according to any one of (4) and (5) salt.

(7) above (1) to Hue two Ruaranin derivative conductor or pharmaceuticals containing as an active ingredient a pharmacologically acceptable salt thereof according to any one of (6).

(8) above (1) to Hue two Ruaranin derivative conductor or flight 4 I Nteguri emission inhibitor containing as its pharmacologically acceptable salt thereof as an active ingredient according to any one of (6).

(9) above (1) to Hue two Ruaranin derivative conductors or anti-inflammatory agent comprising as an active ingredient a pharmacologically acceptable salt thereof according to any one of (6).

(1 0) shed 4 I Nteguri down inhibitor for the manufacture of (1) to (6) Noi use of phenylene Ruaranin derivative or a pharmacologically acceptable salt thereof according to any misalignment.

(1 1) anti-inflammatory agent for the preparation of (1) to according to any one of (6) Fuweniruaranin derivative or use t of a pharmaceutically acceptable salt thereof

(1 2) (1) to full two Ruaranin inducing member or flight 4 Integuri down, characterized in that it comprises the step of administering an effective amount of a pharmacologically acceptable salt thereof according to any one of (6) method of treating adhesive mechanisms you mediated diseases through inhibition agent.

(1 3) (1) to full two Ruaranin inducing member or method of treating inflammation comprising the step of administering an effective amount of a pharmacologically acceptable salt thereof according to any one of (6) .

In the definitions of the groups in Formula (I) and (II),

(I) is a lower alkyl, e.g., straight-chain or branched alkyl of from 1 to 10 carbon atoms, specifically methyl, Echiru, propyl, isopropyl, Puchinore, sec Buchinore, tert- Puchinore, Penchinore , Lee Sopenchinore, neopentyl pentyl, hexyl, heptyl, Okuchiru, Isookuchinore, Noel, de Sil, and the like. Lower alkoxy, lower alkylthio, lower alk force Noiru and mono also are properly lower alkyl portion content of di-lower Arukiruami Roh has the same meaning as defined above lower alkyl, the two lower alkyl moieties of the di-lower Arukiruami Roh is either the same or different it may be. Moreover, as the two are lower alkylene are together such connexion formation of R 3, RR 5 and R 6, such as those formed by removing one hydrogen atom from the lower alkyl is exemplified et be.

(Ii) is a lower alkenyl include straight-chain or branched Aruke two Honoré carbon atoms 2-8, specifically Bininore, Arinore, 1 one propenyl, butenyl two Honoré, pent two Norre, Kiseninore, Heputeninore, Okute two Norre, Okutaji Eniru and the like to.

(Iii) is a lower alkynyl include linear or 芬枝 shaped Anorekininore having 2 to 8 carbon atoms, specifically Echininore, 1 one Puropininore, Buchuru, Petit two Honoré to Kishunore, pliers two Honoré to, , Okuchi two Norre, Puropanoreginore, and the like.

And a (iv) cycloalkyl is, for example carbon number 3-10, a saturated monocyclic carbon hydrocarbon radical or bicyclic system three also are properly ring systems saturated bridged cyclic hydrocarbon group, the concrete Sik port pro Pinore, Shikurobuchinore, cyclopentyl Honoré, Kishinore cyclohexane, Puchinore cyclohexane, Shikurookuchinore, Shikurono two Honoré, Shikurode Shinore, Puchinore bicyclo [2.2. 1], Bruno Noreadamanchiru, Adama pentyl and the like. R 3, RR 5 and of R 6, are two present on the same carbon atom, is a carbon atom together such connexion, a saturated monocyclic hydrocarbon ring formed, for example, 3 carbon are mentioned those 10, specifically, Shikuropurono, "down, sik Robutan, cyclopentane, hexa down to consequent opening, cycloheptane, cyclooctane, cyclononene, cyclodecane, and the like.

(V) is a consequent opening alkenyl, such as unsaturated monocyclic carbon hydrocarbon group having 3 to 8 carbon atoms, specifically Shikuropurope - le, cyclobutenyl, cyclopentyl Nteninore, the consequent opening Kiseninore, cyclohexylene Puteninore, consequent opening Okute two Honoré, cyclopentadiene Jefferies two Honoré, Kisajeninore cyclohexane, Putajeni Le like cyclohexane and the like.

(Vi) is a Ariru, for example 6-14 membered monocyclic Kaoru Kowamoto or bicyclic ~ pentacyclic condensed aromatic ring group having ring carbon atoms 6-30, the preferred properly 6 to 14 carbon atoms bicyclic ~ pentacyclic condensed aromatic ring group which monocyclic aromatic groups or 3-8 membered rings are fused 6-8 membered ring mentioned in, fused aromatic ring group may include a saturated carbocyclic ring well, specifically phenylalanine, Nafuchinore, pentalenyl, Lee Ndeyuru, a down Application Benefits Honoré, full Henin Application Benefits Honoré, Lee Ndaninore, Lee Ndaseninore, 1, 2,

3, 4-Te Torahi Doronafuchiru, 6, 7, 8, heptyl and the like to the 9-Te Torahi draw 5 H- base Nzoshikuro.

(Vi i) is an aromatic heterocyclic group, for example a nitrogen atom, a 5- or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from oxygen atom and sulfur atom, nitrogen atom, 'oxygen atom and including fused ring aromatic and at least one atom selected from nitrogen atom a heterocyclic group, and the like in the bicyclic or tricyclic, which 3- to 8-membered rings are fused , specifically pyridyl, Piraji alkenyl, pyridinium Mijiniru, pin Ridajiniru, benzoyl Midazori Le, 2-O key Sobenzoi formidacillin, sledding / Les, Benzoto Riazorinore, Benzofurinore, benzo Choi two Honoré, pre two Honoré, Benzookisazori Honoré, benzothiazolyl Honoré, Ben Zojiokisorinore, Lee Ndazori Le, Lee down drill, Lee Soi down Dorinore, pre alkenyl, keno Rinore, Lee Sokino Rinore, Futaraju / Les, naphthyl Jininore, Kinokisarininore, pyrosulfate Lil, pyrazolyl, quinazolinyl, Niino Li two Le, Application Benefits Azorinore, preparative Riajiniru, Te Torazori Le, i imidazolyl, O Kisazorinore, Isookisazori Le, thiazol Le, i Sochiazori Le, Choi alkenyl, furyl, Okisajiazoriru, thiadiazolyl, and the like.

(Vi ii) it is in the aliphatic heterocyclic group, for example a nitrogen atom, an oxygen atom and a 5- or 6-membered monocyclic alicyclic heterocyclic groups containing at least one atom selected from nitrogen atom , nitrogen atom, at least selected from oxygen atom and a sulfur atom such as one atom including condensed ring alicyclic heterocyclic groups are mentioned bicyclic or tricyclic, which 3- to 8-membered rings are fused , specifically pyrrolidinyl, 2,

5 Jiokisopiro Li Jiniru, thiazol Jiniru, Okisazorijiniru, pin Perijiru, piperidino, piperidines Rajunore, Homopi Bae Rajunore, Homopi Bae Rijinore, Homopiperi Gino, Monorehorininore, Monorehori Roh, Chiomonorehori alkenyl, Chiomonorehori Roh, Biraniru, Chiobiraniru, Te Torahi Doropiri Jinore , Te Torahi mud Villa two Norre, Te Torahi Dorofuraninore, Te Torahi mud Kino Li Le, Te Torahi Doroisokino Lil, Okutahi Dorokino Li Le, Yi down drill nil, hurry down drilling two / Les, Bae Norehi mud Azepininore, Peruhi mud A Zoshiniru , 1, 3 - Jiokisaniru, and the like. .

(Ix) halogen represents fluorine, chlorine, each atom of bromine and ® © iodine.

(X) substituted lower alkyl, substituted lower alkenyl, substituted lower alkynyl, substituted lower alkoxy, is a substituent in the substituted lower alkylthio and substituted lower alk force Roh I le, the same or different, such 1 to 3 substituents, halogen, human Dorokishi, two Toro, Shiano, Okiso, Menorekaputo, azide, § Mi Roh, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkylthio, lower alk force of also properly unsubstituted substituted Noi Le, mono- Moshiku di-lower Arukiruami Bruno, substituted or non-substituted consequent opening alkyl, substituted or non-substituted Sik Roarukeniru, substituted or is unsubstituted Ariru, substituted or is unsubstituted Ariruokishi , is rather to be substituted unsubstituted aromatic heterocyclic group, a substituted or unsubstituted alicyclic heterocyclic group, - CC ^ Y ^ NR ^ R13 (wherein, Y 1 represents an oxygen atom or a sulfur atom, R 12 and R 13 are the same or different, a hydrogen atom, a substituted or unsubstituted lower § alkyl, substituted or is unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or non-substituted a cycloalkyl, also rather it is unsubstituted Ariru substituted, substituted or aromatic heterocyclic group or substituted or non-substituted or an unsubstituted alicyclic heterocyclic group, R 12 and R 13 may form a connexion heterocyclic group together with the nitrogen atom you neighbor), one C (= 0) R 12a (wherein among, R 12a is a hydrogen atom, a substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower Arukini Le, substituted or unsubstituted cycloalkyl, substituted § reel is also properly unsubstituted, also is properly substituted Unsubstituted aromatic heterocyclic group, or substituted or represents unsubstituted alicyclic heterocyclic group), one C (= 0) 0R 12b (wherein, R 12b is as defined above R 12a) one S0 2 R 14 [wherein, R 14 is either the same as defined above R 12 a, or an NR 12e R 13 e (wherein, R 12. and R 13e are each the R 12 and R 13 as defined in a) represents a] one NH S0 2 R 12d (wherein, R 12 d is as defined above R 12 a), - NHC ( = S) NHR 12e ( wherein, R 12e is the R 12 a synonymous a is) or a NHC (= 0) (CH 2 ) in p 0 R 12f (wherein a, p is an integer of. 1 to 8, R 12f is the R 12 a is as defined above), and the like It is.

Lower alkoxy, lower alkylthio, lower alkyl moiety of the lower Arukanoi Le Contact Yopi mono- Moshiku di-lower Arukiruamino, shea click Roanorekinore, consequent lower / Rekeninore, § Li Nore and Ariru portion of § Li Ruokishi, aromatic indicated here heterocyclic group, aliphatic heterocyclic group and halogen, each of said lower alkyl (i), a cycloalkyl (iv), Shikuroaruke two Le (v), § 'reel (vi), an aromatic Hajime Tamaki (vi i ), it has the same meanings as alicyclic Hajime Tamaki (vi ii) and halogen (ix), 2 one low-grade alkyl ^^ part of di-lower Arukiruami Roh may be the same or different.

Here at the indicated substituted lower alkoxy, substituted lower alkylthio, substituted lower grade Al force Noiru, is a substituent definitive substituted consequent opening Arukinore Contact Yopi substituted consequent opening alkenyl, same or different, such 1 to 3 substituents of , Nono androgenic and the like, substituted Ariru, substituted Ariruokishi, is a substituent in the substituted aromatic heterocyclic group and the substituted alicyclic heterocyclic group, the same or different One in example 1 to 3 substituents, halogen, human Dorokishi, two Toro, Shiano, old Kiso, mercapto, azido, Amino, carboxy, substitutions also properly is a substituent in the lower alkyl [the substituted lower alkyl unsubstituted, identical or different, such substitution number 1 3, human Dorokishi, halo Gen, and the like], properly be substituted unsubstituted lower alkoxy [該置 換低 grade alkoxy Is a definitive substituents, same or different 1 to 3 substituents For example, halogen and the like], lower alkylthio, lower grade Arukanoiru, mono also is properly dilower Arukiruami Bruno, sik Roaruki Le, consequent opening alkenyl, Ariru, Ariruokishi, aromatic heterocyclic group, aliphatic heterocyclic group and the like.

Further, where lower alkyl shown, lower alkoxy, lower alkyl Chio, lower alk force Noiru Oyobi things also properly lower alkyl moiety of the di-lower Arukiruami Bruno, a cycloalkyl, sik Roarukeniru, § Li Lumpur Contact and § Li Ruokishi § reel portion, an aromatic heterocyclic group, aliphatic heterocyclic group and halogen, each of said lower alkyl (i), cycloalkyl Le (iv), consequent Roarukeniru (v), § Li Lumpur (vl), aromatic group a Hajime Tamaki (vii), have the same meanings as alicyclic Hajime Tamaki (viii) and halogen (ix), 2 two lower alkyl moieties of the di-lower alk Kiruami Roh is but it may also be the same or different.

Also, here shown as a heterocyclic group and R 12 and R 13 are connexion formed such together with the adjacent nitrogen atom, for example at least monocyclic 5-membered or 6-membered containing one nitrogen atom a Hajime Tamaki (the monocyclic heterocyclic groups, other nitrogen atom may contain an oxygen atom or a sulfur atom), less at 3-8 membered ring is bicyclic or tricyclic condensed both condensed bicyclic double heterocyclic group containing one nitrogen atom (the fused heterocyclic group may contain other nitrogen atom, may contain an oxygen atom or a sulfur atom) and the like, specifically the pyrrolidinyl, piperidine Gino, Piperajininore, Monoreho Li Bruno, Chiomonorehori Bruno, Homopiperi Gino, Homopiperaji - Le, Te tiger arsenide mud pyridinium Jiniru, Te tiger arsenide Doroki Roh Li sulfonyl, Te tiger arsenide Doroisokino Li sulfonyl, and the like.

(Xi) substituted cycloalkyl, substituted cycloalkenyl, a substitutable Ariru, substituted aromatic heterocyclic group, a substituted aliphatic heterocyclic group, substituted 2-pyrophosphoric Lil, 4-substituted 4-Piberiji - Le, 3-position substituent a, 2, 2-Jimechirushi click Ropenchinore, 1, 2, 2-Application Benefits Mechinoreshiku Ropenchinore, 2, 2, 3 one Application Benefits Mechirushiku port pentyl and 1, 2, 2, 3 - Te Toramechirushi click port pentyl, 1- and as the substituent in the substituted consequent opening pentyl 4 Ichipipe lysinyl of Rapi with 4-position substituent, in addition to the groups mentioned in the definition of the substituents (X) in the substituted lower alkyl, substituted or unsubstituted lower alkyl and substituted and the like.

Lower alkyl shown here, the synonymous with lower alkyl (i), is a substituent in the substituted lower alkyl, the same or different 1 to 3 substituents For example, human Dorokishi, halogen (the halogen is the a halogen (ix) synonymous) and the like.

It is a (xi i) substitutions in substituted Amino groups, same or different substituents having 1 to 2 lower alkyl, lower Arukanoiru and the like. Lower alkyl moiety of the lower alkyl and lower § Le force Noiru shown here is the same as defined in the lower alkyl (i).

Hereinafter, the compound of the compound of formula (I) called (I). The same applies to the reduction compounds of other formula numbers.

Compounds as a pharmacologically acceptable salt of (I), non-toxic, water soluble ones are preferable, for example, acid addition salts, metal salts, Anmoniumu salts, organic § Mi emissions addition salts, amino acid addition salts and the like.

Is the acid addition salts such as hydrochloride, hydrobromide, nitrate, sulfate, inorganic salts such as phosphates, benzenesulfonate, benzoate, Kuen, fumarate, Darukon , lactate, maleate, malate, oxalic acid, methanesulfonic acid, there are up and organic salts such as tartrate.

Is a metal salt, for example sodium Umushio, alkali metal Shokushio such potassium salts, magnesium salts, alkaline earth metal salts such as calcium salts, Al Miniumu salts, zinc salts, and the like.

Is a Anmoniumu salts such Anmoniumu, are exemplified tetramethylammonium Moniumu etc., is an organic Amin addition salts such Moruhori emissions addition salt, piperidine addition salt, and the like, and Amino acid addition salts is then, for example, glycine addition salt, phenylene Ruaranin addition salts, lysine addition salt, § aspartic acid addition salt, glutamate addition salts, and the like.

It will be described for compound preparation of (I).

In the production method shown below, when groups as defined are inappropriate for carrying or change under the reaction conditions, or methods, methods for atmospheric organic synthetic chemistry, for example, functional group protection, deprotection protection, etc. [for example, Purotekute i blanking group scan 'in' organic synthesis, third Edition (protective groups in organic synthesis, third edition), green (TWGreene) Author, the job down. Wai Lee 'Anne de' Sands' Lee down it can be carried out easily prepared by subjecting the means Koporeite' de (John Wiley & Sons Inc.) (1999 years) reference. It is also possible to change the order of reaction steps such as introduction substituent optionally.

Compound (I) can be obtained by the production method shown below, for example. Production Method 1:

Step 2

<Wherein, X is a halogen (the halogen of the halogen (a) as synonymous) or single 0S0 2 W {W is lower alkyl [said lower Al kill also properly unsubstituted substituted the lower alkyl (i) have the same meaning as, is a substituent that put in the substituted lower alkyl, same or different halogen 1 to 3 substituents (該Ha androgenic the halogen (a) as synonymous) and the like] or substituted Moshiku is unsubstituted Ariru [the Ariru has the same meaning as the Ariru (vi), the substitution § is a substituent at re Lumpur, same or different halogen substituents having 1 to 3 (the halogen wherein the halogen (a) as synonymous), lower alkyl (said lower alkyl is a lower alkyl (i) represents a} represents the same meaning as) and the like], P 1 is lower alkyl (said lower Al Kir same as the lower alkyl (i) Represents at that), m, n, RRR 3 , RR 5, RR 7 and R 8 each have the same meanings as defined above>

[Step 1]

This reaction is a known method [for example, Journal O Bed 'candy Rican Chemie Cal Society, 118 Certificates, pp 7215 (1996), Doron to Te tiger. (J. Am Chem Soc...) - Letters (Tetrahedron Lett .), 38, 6363 H (1997 years), the journal off ,, Oge two click 'ChemStation Doo Lee (J. Org. Chem.),

66 Certificates, can be carried out according to page 2498 (2001)], and the like. For example the compound (III), in a solvent inert to the reaction, a catalytic amount to 1 equivalent of the path Rajiumu complex, a catalytic amount to 1 equivalent of Li down ligand and one equivalent to 10 equivalents of a salt group presence, 1 eq by reacting with to an excess amount of the compound (IV), to give compound (V).

If R 7 or R 8 is an electron withdrawing group such as a two preparative port also that the compound (III), without solvent or in a solvent inert to the reaction, is reacted with one equivalent to an excess amount of the compound (IV) Accordingly, it is also possible to obtain the compound (V).

Reaction inert solvent, the reaction in rather good any as long as it is inert and is not particularly limited, for example, Te Torahi Dorofuran, preparative Noreen, xylene, 1, 4 one Jiokisan, dimethyl Tokishetan, or in alone dimethylcarbamoyl Ruhorumuami de like can be used as a mixture thereof, among others Te Torahi Dorofuran or toluene are preferred.

Is a palladium complex, for example palladium acetate, tri scan (self - supplied Jiri Den'ase tons) dipalladium, may be used te tetrakis Application Benefits Fueniruhosufi down palladium, and among them palladium acetate or Application Benefits scan (dibenzylidene acetone tons) dipalladium are preferred.

The re down ligands, e.g. triphenyl phosphinite down, tri one t ert over butyrate Honoré phosphinothricin down, preparative rie 0 preparative Rinorehosufi emissions, 1, 1, One-bis (diphenyl Eni Honoré phosphine b Roh) Hue mouth Sen, 2, 2, one-bis (Jifue two Norre Hosufui Roh) _ 1, 1 '- binaphthyl (BINAP), 2 - [di (t ert- Breakfast chill) Hosufui Roh] Bifue two Norre, 2 - to Jishiku Russia Kishinorehosufi Bruno bi-phenylene Honoré, 2 - Jishiku b Kishinorehosufi node on 2 'to - (N, N-dimethyl Chiruamino) Bifue two Le, or the like can be used, among others 2 - [di (t ert one butyl) Hosufui Bruno] biphenyl is preferred.

Is a base, for example cesium carbonate, Li phosphate potassium, sodium t Ert- butoxide, hydrogenated sodium © beam can and Mochiiruko the Toryechiruamin like, among which cesium carbonate or sodium © beam t Ert- butoxy de but good Masui.

The reaction is carried out at a temperature between a temperature, preferably 60 ° (~ 100 ° C between room temperature ~ 120 ° C, is a generally completed in 5 minutes to 48 hours. Compound (III) W098 / 53817 , W099 / 36393. or the like can be used as the synthesized according to the method described in. compounds (IV) and the commercially available products or are new experimental chemistry course, 14 Certificates, the chemical Society of Japan (1978) it can be optionally used those synthesized according to the method described in equal.

[Step 2]

The compound obtained in step 1 (V), for example, Protective - group scan Yi emissions -. Organic Synthesis, Third Edition (Protective Groups in Organic Synthesis, third edition), click rie down, 丄 'W. Greene Li Pride goes, by treatment in accordance with the job down. Wye rie Ann de 'Sons' Lee Nkoporeitetsu de (John Wiley & Sons Inc.) a method of deprotecting a protecting group of a carboxylic acid according to (1999), etc. , to give compound (I). For example, if P 1 is methyl, Echiru like, in a solvent inert to the reaction, for example, hydroxide sodium © beam, to hydrolysis treatment with Al force in Li in aqueous solution such as potassium hydroxide © beam or lithium hydroxide by, if P 1 is a tert- butyl, and the like, in an inert solvent or without a solvent, for example it is possible to obtain a compound (I) by acid treatment with tri Furuo mouth acid, hydrochloric acid .

Reaction inert solvent, the reaction in rather good any as long as it is inert but are not particularly limited, for example, Te Torahi Dorofuran, di Okisan, 1, 2-dimethyl Tokishetan, benzene, Tonoreen, xylene, dimethylformamidine de, Jimechiruase Toami de, N- Mechirupiro Li pyrrolidone, methanol, ethanol, N- propanol, or in alone Lee Sopuro pills alcohol can be used as a mixture thereof. The aforementioned compound (V) is leaving in also be obtained cowpea to the method shown below, for example.

Production Method 2:

Wherein, P 2 is lower alkyl O alkoxycarbonyl (lower alkyl has the same meaning as the lower alkyl (i)), and display the protecting group § Mi amino group such as benzyl, X 1 is the X as defined in and, m, n, R \ R 2, R 3, R 4, R 5, R 6, R 7, R 8 Contact and P 1 each have the same meanings as defined above]

[Step 3]

In a similar manner to Step 1, Ri by the reacting the compound (IV) to the compound (VI), to give compound (VII). Is a compound (VI) for example 098/53817, it can arbitrarily use it those synthesized according to the method described in such as W099 / 36393.

[Step 4]

The compound obtained in step 3 (VII), for example, Protective Groups in - Organic Synthesis Third Edition (Protective Groups in Organic Synthesis, third edition), click rie down (TW Greene) Pride goes Moulton down 'Wai rie. Ann de 'Sons. Lee Nkoporeitetsu de subjected to (John Wi 1 ey & Sons Inc.) (1999 years) how deprotecting the protecting group of the Amino group described in such as the compound (VIII) it is possible to obtain.

If for example, when P 2 is tert- butoxycarbonyl, in an inert solvent or without a solvent, for example Application Benefits Furuoro acetate, Ri by the fact that acid treatment with hydrochloric acid or the like, also the P 2 Gabe Njiru etc. an inert solvent, a catalytic amount W

The presence of such palladium one activated carbon, it is possible by Ri deprotection to hydrogenolysis.

Reaction inert solvent, the reaction in rather good any as long as it is inert and is not particularly limited, for example Jikurorome Tan, black hole Holm, Te Torahi Dorofuran, Toruen, acetic Echiru, § Se Toni Application Benefits Le, Te Torahi Dorofuran, Jiokisan, 1, 2-dimethyl Tokishetan, benzene, Tonoreen, xylene, dimethylcarbamoyl Honoré phosphono REM A mi de, Jimechinorea cell store Mi de, N- Mechirupiro Li pyrrolidone, methanol, E data Nord , or N one propanol, isopropyl alcohol alone may be used those combined mixed.

[Step 5]

The compound obtained in Step 4 (VI II), in a solvent inert to the reaction, 1 the presence of equivalents to 10 equivalents of condensing agent, by Rukoto reacted with 1 to 5 equivalents of the carboxylic acid (IX), compound (V) can be obtained.

Solvent inert to the reaction, the reaction in rather good any as long as it is inert and is not particularly limited, for example Jikurorome Tan, black hole Holm, dichloroethylene b Roetan dimethylol Honoré phosphono REM ami de, Jimechinorease Ta Mi de, N _ Mechirupiro Li pyrrolidone, dimethyl sulfoxide, Te tiger arsenide mud furan, Jiokisan, Jefferies Chino Les ether Honoré, diisopropyl Seo prop Honoré ether Honoré, benzene, Tonoreen, xylene, acetic Echinore, § Se Toni DOO the Rinore like also in alone can be used as a mixture thereof, among others Jimechiruhoru Muami de also properly is preferred Te Torahi Dorofuran or a mixed solvent thereof arbitrariness.

Is a condensing agent, for example Kishirukarubojii mi de to Jishiku port, Jie Seo pro Pinot les Kano levo diisopropyl Mi de, N- Echinore N '- (3 - Jimechinoreami Bruno propyl) Karubojii mi de, or its hydrochloride salt, benzo preparative Riazoru 1 one Inore Application Benefits scan (dimethyl Chiruami Roh) Kisafunoreo port Li down halide salt to Hosuhoniumu, di Hue El azide or the like is used, among them N- E Chiru N 'i (3 Jimechiruami Nopuro pills) Karubojii Mi de or arbitrariness preferred hydrochloride salt. Further, the reaction is carried out in the presence of 1 to 5 equivalents of an additive as necessary.

Is an additive, for example, N- arsenate Dorokishikohaku acid imide, 1 - arsenide de Rokishibenzoto Riazonore, 3-arsenide Dorokishi one 4 _ Okiso one 3, 4 - dihydric draw 1, 2, 3 - base Nzoto triazine or the like is used are, among others 1 - human Dorokishibenzo DOO Riazo Ichiru are preferred.

Temperature during the reaction is 0 ° C~150 ° C, preferably at a temperature between room temperature ~ 80 ° C, generally completed in 5 minutes to about 48 hours.

Also besides the above-described method, using a reactive equivalent of the corresponding carboxylic acid (IX), for example, acid Kurorai de carboxylic acid (IX), an active ester or mixed acid anhydride or the like in place of the carboxylic acid (IX) , the reaction also inert solvent in the absence of a solvent in the presence or absence of a base, by Rukoto reacted with a compound (VI II), it is also possible to obtain a compound (V).

Reaction inert solvent, the reaction in rather good any as long as it is inert but are not particularly limited, for example dichloromethane, black hole Holm, Te Torahi Dorofuran, Jiokisan, Tonoreen, acetic Echiru, § Se Tonito Rinore, pyridine or the like is used, among others dichloromethane or arbitrarily favored Te Torahi Dorofuran.

It is a base, for example preparative Ryechiruamin, pyridine, diisopropyl pin Ruechiruamin, organic bases such Jimechiruami Roh pyridinium Jin, diisopropyl Pinot Les aminomethylol Honoré polystyrene, poly Bininorepirijin, Monorehori drink chill polystyrene solid phase supported on a base such as is used, among others preparative Riechiruamin or pyridine is preferred, if the reaction is carried out in parallel synthesis method (Konbinato real ■ ChemStation Application Benefits Chief) is Jiisopuropirua amino methyl polystyrene are preferred.

Temperature during the reaction is 0 ° C~100 ° C, preferably at a temperature between room temperature ~ 80 ° C, generally completed in 5 minutes to about 48 hours.

As the compound (IX) is commercially available or Shin Jikken Kagaku Koza, 14 Certificates, Japan Chemical Society (1978), or the like can be optionally used those synthesized in accordance with the method described in. Some of the compounds of the aforementioned compound (VII) can also be obtained by the method described below.

Production Method 3:

Wherein, P 2a is a lower alkyl O alkoxycarbonyl (lower alkyl has the same meaning as the lower alkyl (i)), and display the protecting group § Mi amino group such as benzyl, m, n, RR 4, R 5, R 6, R 7 , R 8 and P 1 each have the same meanings as defined above]

[Step 6]

Compound (X), for example Protective 'group scan' Lee emissions - auger two click - Synthesis Second Edition (Protective Groups in Organic Synthesis, third edition), green (TW Greene) Author, the job down - Wai Li sitting - § It is subjected to a method for removing the protective group of § Mi Roh group described in emissions de Sands fin Incorporated Rei Tetsu de (John Wiley & Sons Inc.) (1999 years), and the like, of compounds with (XI) it is possible to obtain.

For example, if P 2a is tert- butoxycarbonyl, in an inert solvent or without a solvent, for example Application Benefits Furuoro acetate, Ri by the fact that acid treatment with hydrochloric acid or the like, and if P 2a is benzyl, etc. , in an inert solvent in the presence of such palladium one activated carbon of a catalytic amount, by hydrogenolysis, or 2 - Kuroroechiruku every mouth Horume preparative and inert solvent or without a solvent, after the reaction, methanol by refluxing at medium [Shinre' preparative (Synlett.), 195 (1993)] can be deprotected.

Reaction inert solvent, the reaction in rather good any as long as it is inert and is not particularly limited, for example dichloromethane, black hole Holm, Te preparative La arsenide Dorofuran, toluene, acetic Echiru, § Se Toni Application Benefits Honoré, Te preparative La arsenide mud furan, Jiokisan, 1, 2-dimethyl Tokishetan, benzene, Tonoreen, xylene, dimethylcarbamoyl Honoré phosphono REM A mi de, Jimechinorea cell Toami de, N- Mechirupiro Li pyrrolidone, meta Nord , E data Nord, N- propanol, or isopropyl alcohol alone may be used those combined mixed.

Compound (X) can be synthesized according methods or in described in step 3 of the above-mentioned production method 2.

[Step 7]

Among the compounds (VII), wherein R 1 is R la [wherein, R la one C (= 0) R 9a (wherein, R 9a is as defined above), one C (= 0) 0R 9b ( wherein, R 9b is in the same meaning as defined above) or a S0 2 R "(wherein compound R 11 is that a 'represents the same meaning as defined above) (Vila) is obtainable by the following method it can.

(Wherein, m, n, R la, R 3, R 4, R 5, R 6, R 7, R 8, P 1 and P 2 are as defined before SL, respectively)

Compound (Vila), the compound obtained in Step 6 (XI), the reaction in an inert solvent or without a solvent, in 1-5 equivalents of R 9a C (= 0) X 2 ( wherein, R 9a is wherein a is synonymous, X 2 are as defined above X), in R 9b 0C (= 0) X 2a ( wherein, R 9b are as defined above, X 2a is as defined above X) or R ^ SO 211 (wherein, R 11 are as defined above, X 2b is as defined above X) and from 1 to 5 equivalents of a base in the presence or absence, be obtained by reacting it can.

Reaction inert solvent, the reaction in rather good any as long as it is inert and is not particularly limited, for example dichloromethane, black hole Holm, Te preparative La arsenide Dorofuran, Jiokisan, toluene, acetic acid Echinore , § Se Toni DOO Lil, or pyridine, and the like alone can be used as a mixture thereof, preferable among them dichloromethane or Te Torahi Dorofuran arbitrariness.

As a base, for example preparative Ryechiruamin, pyridine, carried diisopropyl Sopuropi Ruechiruami down, Jimechirua Mi Bruno organic bases pyridinium gin etc., diisopropyl Sopuro Pinoreami Roh main Chinorepori styrene, poly Bininorepiri Jin, to a solid phase such as Monorehori drink Chirupori styrene bases and the like are used, lay preferred among them bets Riechiruami down or pyridine, in the case where the reaction is carried out in parallel synthesis method (convenor real 'ChemStation Application Benefits Chief) is diisopropyl Sopuropirua Mi Roh methylpoly styrene is preferred.

The reaction at a temperature between 0 ° C~100 ° C, preferably at a temperature between room temperature ~ 80 ° C, generally completed in 5 minutes to 48 hours.

[Step 8]

Among the compounds (VI I), [wherein, R lb one C (= Y) NHR ie (in the formula, Y Contact and R l fl each have the same meanings as defined above) an represents] R 1 is R lb in a compound (Vl lb) can be obtained by the following method.

(Wherein, m, n, R lb, R 3, R 4, R 5, R 6, R 7, R 8, P 1 and P 2 are as defined before SL, respectively)

Compound (Vl lb) is, in the compounds obtained in step 6 (XI), the reaction in inert solvents, in the 1-5 equivalents of R ie NC (= Y) (wherein, R ie and Y are each the and a is) synonymous can 1-5 equivalents of a base in the presence or absence, to obtain Ri particular good reacting. Reaction inert solvent, the reaction in rather good any as long as it is inert and is not particularly limited, for example, water, methanol, Etano Lumpur, Te preparative La arsenide mud furan, Jiokisan, Jimechinoreho / Remuami de, di methylsulfamoyl O dimethylsulfoxide, or alone N- Mechirubiperi Don like can be used as a mixture thereof, among others Te Torahi Dorofuran are preferred. Is a base, for example, supported carbonate potassium, inorganic salts groups such as hydrogenated isocyanatomethyl Li © beam, preparative Ryechiruami emissions, organic bases such as pyridine, diisopropyl amine Nomechirupori styrene, poly Bininorepirijin, to a solid phase such Monorehori Nomechinorepori styrene bases or the like is used, if among them Application Benefits Echiru § Mi emissions or pyridinium Jin verses preferred, the reaction is carried out in parallel synthesis method (co Nbina preparative real 'ChemStation Application Benefits Chief) is diisopropyl Sopuropiruami Nomechi Lupori styrene is preferred.

Temperature during the reaction is 0 ° C~150 ° C, preferably at a temperature between room temperature ~ 80 ° C, generally completed in 5 minutes to 48 hours.

[Step 9]

Among the compounds (VI I), wherein R 1 is R le [wherein, R le is among the definitions above R 1, substituted Moshiku is unsubstituted lower alkyl, substituted or is unsubstituted lower alkenyl Le, substituted lower alkynyl also properly unsubstituted, substituted or is unsubstituted cyclo alkyl, substituted or is unsubstituted Ariru, substituted or unsubstituted aromatic heterocyclic group, or substituted or the unsubstituted fat cyclic represents a heterocyclic group], compound (VI I c) may be obtained cowpea to the following method.

(Wherein, m, n, R lc s R 3, R 4, R 5, R 6, R 7, R 8, P 1 and P 2 are as defined before SL, respectively) Compound (VI I c) the compound obtained in step 6 (XI), in a solvent inert to the reaction, 1:. 10 in equivalents of R le X 2 e (wherein, R le is as defined above der Ri, X 2c is wherein X and is synonymous), it is possible to obtain 15 equivalents of a base in the presence or absence, the Rukoto reacted.

Reaction inert solvent, the reaction in rather good any as long as it is inert and is not particularly limited, for example acetone, Te Torahi mud furan, Jiokisan, dimethylformamidine de, Jimechirusuruo Kishido, N- Mechirubiperi also Don like alone can be used as a mixture thereof, among others Te Torahi Dorofuran are preferred.

Is a base, for example potassium carbonate um, inorganic salts groups such as hydrogenated isocyanatomethyl Li © beam, preparative Ryechiruamin, organic bases such as pyridinium Jin, diisopropyl amine Nomechirupori styrene, poly Binirupiri Jin, to a solid phase such as Monorehori Nomechirupori styrene supported bases like are used, and among them potassium carbonate © beam or hydrogenated sodium © beam are preferred, parallel synthesis - when the reaction is carried out in (Konbinatoria Le ChemStation Application Benefits Chief) include diisopropyl § amino methyl polystyrene It is preferred.

The reaction temperatures between 0 ° C~150 ° C, is favored properly carried out at a temperature between room temperature ~ 80 ° C, generally completed in 5 minutes to about 48 hours.

[Step 1 0]

Among the compounds (VI I c), R 1 . There (wherein, R ld is the properly be substituted that put in the definition of R 1 is a non-one to a lower alkyl end substituted CH 2 - represents a one except groups) one CH 2 R ld, compound ( vl ld) can be obtained by the following method.

Compound (Vl ld), the compound obtained in Step 6 (XI), in a solvent inert to the reaction, the presence 1 to 10 equivalents of a reducing agent, in 1-3 equivalents of R ld CH0 (wherein, R ld it can be obtained by reacting a are as defined before SL).

Reaction inert solvent, the reaction in rather good any as long as it is inert and is not particularly limited, for example methanol, Etanoru, dichloromethane, Kurorohonoremu, dichloroethane, Te Torahi Dorofura down, Jiokisan, GETS Chinoreetenore, diisopropyl Seo prop Honoré ether Honoré, benzene, Tonoreen, xylene, dimethylformamidine de like can be used alone or as a mixture of them, arbitrarily favored among them methanol or Te tiger arsenide Dorofuran.

Is a reducing agent, for example, preparative Riase butoxy borohydride isocyanatomethyl Li um borohydride isocyanatomethyl Li um, hydrogenated Shianohou Motona Application Benefits um etc. using et al are, among others preparative Riase butoxy hydride Hou Motona Application Benefits Umm is preferable.

The reaction temperatures between 0 ° C~100 ° C, preferred properly in our row at a temperature between 0 ° C~50 ° C, ends at about the normal 5 minutes to 48 hours.

Among the foregoing compounds (V), m and n is 1, is in the R 3 is 6-position of the piperazine ring (piperidines Rajin ring is the 1-position of the binding site for the adjacent benzene ring), R 4 site and R 5 5-position of the piperazine ring is in the (piperazine ring is the 1-position of the binding site for the adjacent benzene ring), R 6 is to bind to 3-position (benzene ring piperazine ring is adjacent the piperazine ring which is a Okiso present to) the 1-position compound (Va) can be obtained by the following method.

Process 4:

Step 12

(Wherein, RR 2, R 3, R 4, R 5, R 7, R 8 and P 1 are as defined above, respectively) The reaction is, for example, Doron to Te tiger 'Letters (Tetrahedron Lett.), 41 Certificates, it is a child that is in accordance with the method described in 6309, pp. (2000), and the like.

[Step 1]

Compound (XI I), in a solvent inert to the reaction, the presence a reducing agent from 1 to 10 equivalents, Ri by the reacted with 1-3 equivalents of (XI II), to obtain a compound (XIV) it can.

Reaction inert solvent, the reaction in rather good any as long as it is inert and is not particularly limited, for example, methanol, ethanol, dichloromethane, Kurorohonoremu, Jikuroroetan, Te Torahi Dorofura down, Jiokisan, GETS Chirueteru, Jie Seo prop Honoré ether Honoré, benzene, can be used by mixing toluene, xylene, alone or their dimethyl formamidine de, and among them methanol or Te tiger arsenide Dorofuran are preferred.

Is a reducing agent, for example, preparative Riase butoxy borohydride isocyanatomethyl Li um borohydride isocyanatomethyl Li um, hydrogenated Shianohou Motona Application Benefits um etc. using et al are, among others preparative Riase butoxy hydride Hou Motona Application Benefits © beam is preferable.

Further, the reaction can also be carried out in the presence of molecular sieves, if necessary.

The reaction temperatures between 0 ° C~ 100 ° C, preferred properly in our row at a temperature between 0 ° C ~ 50 ° C, generally completed in 5 minutes to 48 hours.

Is a compound (XI I) may optionally be used that form if according to the method described in example W099 / 10312 or the like. Compound (XI II) and to the example, if Te Bok Rahedoron - (. Tetrahedron Lett) Letters, 41 Certificates can arbitrarily use it those synthesized according to the method described in 6309, pp. (2000) and the like.

[Step 1 2]

Step 1 1 The compound obtained in the (XIV), in a solvent inert to the reaction, Ri by the treatment with 1-10 equivalents of a base to give compound (Va). Reaction inert solvent, the reaction in rather good any as long as it is inert and is not particularly limited, for example acetone, Te Torahi mud furan, Jiokisan dimethylol Honoré phosphono REM Ami de dimethylol / Resuruokishido,

Or in alone N- Mechirubiperi Don, or the like can be used as a mixture thereof, among others Te Torahi Dorofuran are preferred.

Is a base, for example, carbonate force Li um, Toryechirua Mi emissions, pyridine, hydrogenated sodium or the like is used, among others carbonate potassium or hydrogen Kana bird © beam is preferred.

Temperature during the reaction is 0 ° C~150 ° C, preferably at a temperature between room temperature ~ 80 ° C, generally completed in 5 minutes to 48 hours.

Further, among the compounds of the above (V), m and n are 1, R 3 is 5- or 6-position of the piperazine down ring (piperazine ring is the 1-position of the binding site for the adjacent benzene ring) There, R 4 and R 5 3-position of piperidines Rajin ring is in the (piperidines radio emissions ring is the 1-position of the binding site for the adjacent benzene ring), R 6 is 2-position of piperidines Rajin ring ( compound is a Okiso present a site for binding with the benzene ring to which piperazine ring is adjacent to) the 1-position (Vb) can be obtained by the following method.

Production Method 5:

Step 14

(Wherein, RR 2, R 3, R 4, R 5, R 7, R 3 and P 1 are as defined above) This reaction is, for example Te Bok Rahedoron - Letters (Tetrahedron Lett.)

Vol. 41, can be carried out according to the method described in 8735 (1998) and the like. [Step 1 3]

Step 1 1 in the same manner as, Ri by the reacting the compound (XV) to the compound (XI I), to give compound (XVI). Is a compound (XI I) may optionally be used that form if according to the method described in example W099 / 10312 or the like. Compound (XV) and to Delon example to Te tiger - (. Tetrahedron Lett) Letters, 41 Certificates, Ru can be arbitrarily used that those synthesized according to the method described in 8735, pp. (2000) and the like.

[Step 1 4]

Step 1 3 with a compound obtained by (XVI), in a solvent inert to the reaction, Ri by the treatment with a base the presence of 1 to 10 equivalents, leaving in it to obtain the compound (Vb).

Solvent inert to the reaction, the reaction in rather good any as long as it is inert and is not particularly limited, for example methanol, Etanoru, Te Torahi Dorofuran, Jiokisan dimethylol Honoré phosphono REM A mi de, Jimechinore Suruokishido, N- Mechirubiperi also Don like alone can be used as a mixture thereof, among which methanol or Te Torahi Dorofuran are preferred.

It is a base, for example mosquitoes Li um tert- Putokishi de, hydrogenated diisocyanato Li U beam, Richiumujii Sopuro Piruami de or the like is used, among others potassium tert- butoxide or hydrogen Kana Application Benefits um are preferred.

The reaction temperatures between 0 ° C~150 ° C, preferred properly takes place at a temperature between room temperature ~ 80 ° C, generally completed in 5 minutes to 48 hours.

Further, depending on conditions, Ru mower that P 1 is a carboxylic acid off to produce.

Et al. Of the compound (1), the conversion of functional groups contained in the conversion and substituents of each functional group in the starting compounds and intermediate compounds, For example a known method [, Nshibu 'Organic Transformation sucrose to completion lens one liR (Comprehens i ve Organ ic Transiormat ions, second edi ti on), Rarokku (RC Larock) Author, job down 'Wai Lee ■ Anne de. Sands • fin Incorporated Leyte head (John Wi l ey & Sons. Inc .) (which can be carried out by 1999)], and the like.

By implemented in appropriate combination of the above methods or the like to obtain a compound having the desired functional group at the desired position (I).

Isolation of products and intermediates in the above process, purification methods used in conventional organic synthesis, for example, filtration, extraction, washing, drying, concentration, in combination forming crystallized, the various chroma Togurafi Chief appropriate It can be carried out. Further purification methods conventionally used in general parallel synthesis method (combinatorial 'ChemStation Application Benefits Chief), for example, base Nzoiruku port Lai de polymers Bowne de, poly (4 one Bulle pyridine), a polyamine, benzaldehyde de pointes Rimabaun de, DOO Richiruku b Li de polymer bound etc. Waals force base Nji Yarejin, e.g. AG1- X80H- resin can be performed by purification method using (Baiora' de Co.) resin ion exchange resins such as. The intermediates as possible out also be subjected to the next reaction without purification.

To the compound (I), positional isomers, but isomers such as geometrical isomers or optical isomers are also those which may exist, the mixture in any ratio of all possible isomers including and said isomers also it wrapped containing the compounds of the present invention.

If you want to get the salt of compound (I), Compound (I) can and salts are obtained may be purified as it is, also can the compound (I) is obtained in the form of the free compound (I) was dissolved or suspended in a suitable solvent, it is sufficient to form a salt by adding an acid or a base.

The compound (I) or a pharmaceutically acceptable salt, water or the species solvents (e.g., Etanoru, Te Torahi Dorofuran, Jiokisan etc.) may exist in the form of adducts with them adducts are also included in the compounds of the present invention.

Compound Specific examples of (I) shown in Table 3 one third Table one 3. A part of the groups R 1 and R 2 of the compounds described in Table 3 one third Table one 3, their respective a separately as shown in Tables 1 and 2. However, Gobutsu of the present invention is not limited thereto.

Table 1

R 1 R 1

-n-

L6t0 / £ 0d £ / ΣJd 0 680 / εθ OAV E

: 0 Engineering z E z

A5 o

E

-98-

- - - -

2 Table More

B-09 B-10 B-11 B-12

B-22 B-23 B-24

B-25 -88- ef-a

6e-a

- a

L6 0 / £ 0dT / 13d 0 680 / £ 0 OAV 94 A - 06 B-04 623 (M + H) +

95 A - 06 562 (M + H) +

96 A - 06 B - 06 594 (M + H) +

97 A - 06 B - 07 594 (M + H) +

98 A - 06 B - 08 589 (M + H) +

99 A - 07 B-01 581 (M + H) +

100 A - 07 B - o 0 O2 595 (M + H) +

101 A - 07 B-03 613 (M + H) +

102 A - 07 B-04 545 (M + H) +

103 A - 07 B-05 484 (M + H) +

104 A - 07 B - 06 516 (M + H) +

105 A - 07 B-07 516 (M + H) +

106 A- 07 B - 08 509 (M - H) +

107 A - 08 B-01 616 (+ H) +

108 A - 08 B - 02 630 (M + H) +

109 A - 08 B-03 648 (M + H) +

110 A - 08 578 (MH)

111 A - 08 B-05 517 (MH) +

112 A - 08 B-06 549 (MH) + t

170 A- 15 B - 08 571 (M + H)

171 A - 16 B-01 657 (M + H) +

172 A- 16 B - 02 671 ( M + H) +

>

173 A - 16 689 (M + H) +

174 A - 16 621 (M + H) +

175 A - 16 B-05 560 (M + H) +

176 A- 16 B - oo O o 0 o6 592 (M + H) +

Dimensions OO dimensions CO L

177 A- 16 592 (M + H) +

178 A- 16 B - 08 587 ( M + H) +

179 A - 17 B-01 661 (M + H) +

180 A - 17 B-02 675 (M + H) +

181 A - 17 · 693 (M + H) +

182 A - 17 625 (M + H) +

183 A - 17 564 (M + H) +

184 A- 17 B - 06 596 ( M + H) +

185 A - 17 B-07 596 (M + H) +

186 B ​​- 08 591 (M + H)

187 A - 18 B-01 607 (M + H) +

188 A - 18 B-02 621 (M + H) + 227 Α - 23 B-01 594 (M + H)

228 A - 23 B - 02 608 (M + H)

229 A - 23 B - 03 626 (Μ + Η)

230 A - 23 B-04 558 (Μ + Η)

231 A - 23 B - 05 497 (Μ + Η)

232 A - 23 B-06 529 (Μ + Η) +

233 A - 23 B - 07 529 (Μ + Η) +

234 A - 23 B 08 524 ( Μ + Η) +

235 A - 24 B-01 701 (Μ + Η) +

236 A - 24 B - 02 714 (Μ + Η) +

237 A - 24 B - 03 732 (Μ + Η) +

238 A - 24 B-04 665 (Μ + Η) +

239 A - 24 B - 05 604 (Μ + Η)

240 A - 24 B-06 636 (Μ + Η)

241 A - 24 B - 07 63b (Μ + Η)

242 A - 24 B - 08 631 (Μ + Η)

B-01

244 A - 25 B-02 620 (Μ + Η) +

245 A-25 B - 03 638 (Μ + Η) +

284 A - 30 696 (M + H) +

285 A- 30 714 (M + H ) +

286 A - 30 B-04 646 (M + H) +

287 A- 30 B - 05 585 ( M + H) +

288 A- 30 B-06 617 ( M + H) +

289 A- 30 617 (M + H ) +

290 A - 30 B - O ooooo 0 o o8 610 (MH) +

Dimensions OC

291 A-31 B-01 642 (M + H) +

292 A-31 B-02 656 (M + H) +

293 A-31 B-03 674 (M + H) +

294 A-31 606 (M + H) +

295 A-31 B - 05 545 (M + H) +

296 A-31 575 (MH) +

297 A-31 577 (M + H) +

298 A-31 B - 08 570 (MH) +

299 A - 32 B-01 640 (M + H) +

300 A- 32 B-02 654 ( M + H) +

301 A- 32 672 (M + H ) +

302 A- 32 604 (M + H ) +

Table one 2 o

Of

MASS

Object R 2 R 1 R 3 R 4 R 5 R 6 R 7 R 8

(M / z) No.

381 Ph Me Me Me Me HH 554 (M) +

382 B-27 Ph Me Me Me Me HH 555 (M) +

383 Ph Me Me HHHH 526 (+ H) +

384 B-27 Ph Me Me HHHH 527 (M + H) +

385 B-27 Ph Et Et HHHH 599 (M + H) +

386 B-06 Ph HHHH N0 2 H 543 () + benzene ring bonded under formula

Roh F

387 B-06 N0 2 H 573 (M) +

~

388 Ph Me Me HH N0 2 H 571 (M + H) +

Table 3 one 3

R2 H o

In the above table, M e represents methyl, E t represents Echinore, P h denotes the full Eniru, A c represents Asechiru.

Next, specifically described with reference to Test Examples for the pharmacological activities of representative compounds (I).

Test Example 1: VLA-4 / VCAM- 1 binding inhibition (cell adhesion) test

Human recomb inant so lubl e VCAM-1 (R & D System Inc.) 50 mmol / L-phosphate sodium buffer (PBS, pH 6. 0) to adjust the concentration of 0. 25 g / mL at 96 and dispensed at 50 ZL per well in well Ti coater plate min, 4 was left standing overnight at ° C (solid phase of VCAM- 1). The supernatant was removed from the solution in each well was aliquoted this amount, 1 washed once with 100 L of PBS per well, RPMI-1640 medium (S i gma Inc.) test drug solution 90 mu per well and diluted in L was added. VLA - 4 human Τ cell line Jurkat known to be expressing (ATCC, TIB- 152) and, RPMI-1640 medium (S i gma Co.) in a 2 x 10 7 eel 1 s / mL to adjust the concentration, aliquoted 10 / z L per well min. 1 hour at 37 ° C, after allowed to attach these cells (VLA- 4 / VCAM- 1 was bonded by bonds), RPMI-1640 medium (Gibco Co., Fuenoruretsu de free) plate was washed with a non-adhesive the cells were removed. Here the 100 mu of L per well RPMI-1640 medium (Gibco Co., Fuenonoreretsu de free) was added, further 10 mmo l / L WST-1 (Dojindo) solution and 0. 4 mmo l / L Fuenajinme preparative sulphate the (S i gma Inc.) aqueous solution was mixed with an equal volume of a solution, was dispensed in 10 / z L per well min. In 5% C0 2 incubator and cultured for 2-4 hours to cause a color adherent cells, measuring the absorbance with a microplate spectrophotometer 450 nm using (EL 340, BI 0-TEK, Inc.) (reference wavelength 630 nm) It was boss. Cell adhesion ratio was calculated from the following equation. Incidentally, the group overlaid with Jurkat cells without immobilized a VCAM- 1 - a (VCAM 1 non-immobilized group) was background. Further, the compound concentration that inhibits cell adhesion by 50% and 50% inhibitory concentration was calculated using Al l 205 Expressions Exce l Fit. Cell adhesion inhibition rate (%) =

The 100 X {1- (test agent addition group absorbance one VCAM- 1 non-immobilized group absorbance) Pas test agent non-addition group of absorbance one VCAM- 1 non-immobilized group absorbance)} As a result, the 4 shows one tables 1 and 4 one 2 tables. 4 one Table 1

50% inhibitory concentration Compound No. (mnol / L)

110

2 120

16 84

18 240

21 230

24 390

26 140

41 1100

42 76

50 28

The fourth one in Table 2

50% inhibitory concentration Compound No. (nmol / L)

355 28

356 31

357 570 363 42 366 29 379 22 393 86

405 30

406 39

Test Example 2: LPAM- 1 / VCAM- 1 binding inhibition test

Human Bok recombinant soluble VCAM - 1 (R & D Systeraf ±) were prepared at a concentration of 2 mu g / mL in 50 mmol / L-phosphate isocyanatomethyl Li um buffer (pH 6.0), 96 you Ita one plates by dispensing 50 minutes per hole, and allowed to stand overnight at 4 ° C

(Solid phase of VCAM-1). The supernatant was removed from the solution in each well was aliquoted this amount, after once washed with 1 Anaa or 100 L of PBS, mediation Si buffer [25 mraol / L HEPES

(2- [4- (2-nydroxy ethyl) -1-piperazinylJ ethane sulfonic acid), 150 mraol / L NaCl, 3 mraol / L KCl, 2 mmol / L click ,, glucose, 0.1% BSA (bovine serum albumin) , lmmol / L MnCl 2> pH 7.3] test drug solution diluted to 90 L added per well to a. Human to be expressing LPAM- 1 is known

B cell line JY (ECACC, 94022533) was prepared at a concentration of 2 x 10 7 cells / mL in Atsusei Bruno Ffa was dispensed 10 L min per well. 30 minutes 37 ° C, After adhering the cells were washed plates in RPMI-1640 medium (Fuenorure' de free), non-adherent cells were removed. XTT solution of 50 L per hole to here

(Cell proliferation KitII s Roche - Daiagunosuti box Co., Ltd.) was dispensed a 50 // L min. 5% Ji by 2-3 hours at 0 2 Inkyubeta one allowed to develop adhesion cells, the absorbance of the microplate spectrophotometer 450 nm using (EL 340, BI0-TEK, Inc.) (reference wavelength 630 nm) It was measured. Cell adhesion ratio was calculated from the following equation. Incidentally, the JT cells without immobilization with VCAM- 1 heavy layers were group (VCAM- 1 non-immobilized group) as a background. Further, the fine 胞接 adhesion to the compound concentration that inhibits 50% and 50% inhibitory concentration was calculated using the All 205 Expressions Excel Fit.

Cell adhesion inhibition rate (%) =

100X {1-(test agent addition group absorbance one VCAM- 1 non-immobilized group absorbance) Pas test agent non-addition group of absorbance one VCAM- 1 non-immobilized group absorbance)}

The results are shown in the fourth one Table 3.

The fourth one in Table 3

50% inhibitory concentration Compound No. (, nraol / L)

41 22

357

393 1.9 406 0.53

Incidentally, besides the above test examples, for example, Journal O Bed 'Pharma Koroji one-and, Ekusuperi Mentanore' Sera Pyuti box (

Journal of Pharmacology and Experimental Therapeutics), 278 Certificates, guinea pig asthma model described in 847 (1996), a journal. O blanking Immunology (Journal of Immunology), 163 Certificates, mouse respiratory tract as described in 403 pages (1999) . hypersensitivity model, journal O-flops' Imunoroji (journal of Immunology), 167 Certificates, delayed-type hypersensitivity Modenore described on pages 3980 (2001), Jananore - Saibu - Imuno biology (journal of Immunology), 167 Certificates, 1004, pp collagen-induced arthritis model as described in (2001), Ja Nanore-O Breakfast - Imuno biology (Journal of Immunology) ヽ 163 Certificates ヽ 1265 pages Okisazoron-induced contact dermatitis model described in (1999), jar Nanore ' O Bed - Investor stay gAME Restorative 'Derma Toroji (Journal of Investigative Dermatology), 111 Certificates, according to page 86 (1998) O key Sazoron-induced § atopic skin Flame models, etc., by various evaluation models commonly used to assess the anti-inflammatory effect, can exhibit excellent come pharmacological action of the compounds of the present invention.

Applications of these compounds provided by the present invention is not limited to the use of an effective ingredient of the medicament of the present invention, intermediates such as for the preparation of the active ingredient and other compounds of other pharmaceutical It can also be used in applications. The use of the compounds of the present invention, nor Iuma is that such other applications are included.

'Medicament of the present invention, to include in the compound (I) and a pharmacologically acceptable salt thereof, a hydrate thereof and substances active ingredient selected from the group consisting of solvates Rabbi and features. As the medicament of the present invention may be administered as an active ingredient the compound (I) as alone, in general, as an active ingredient the compound (I) and additive one or more formulation it is desirable to be administered in the form of a pharmaceutical composition comprising a thing.

Pharmaceutical compositions according to the present invention, compounds as the active ingredient (I) or alone pharmacologically acceptable salt thereof or any by containing as a mixture of an active ingredient for other treatments, can. They also pharmaceutical compositions mixed together with one or more responsible bodies are allowed to active ingredient pharmacologically be prepared by any methods well known in the technical field of pharmaceutics. Incidentally, the drug of the present invention is applicable to a mammal including human.

Administration route of the medicament of the present invention is not particularly limited, it can be appropriately selected the most effective route of administration for treatment Contact Yopi Z or preventing from either parenteral administration, such as oral or intravenous administration .

The production of liquid preparations suitable for oral administration are, for example, water, sucrose, Sol Bi Tsu bets, sugars fructose, etc., polyethylene glycol, Dali calls such as pro Pirenguri call, sesame oil, Oribu oil, oils such as soybean oil s, preservatives such as P- arsenide de proxy benzoic acid esters, be sampled Roberifu Laver, also can be used pharmaceutical additives of flavors such as Bae Pami down bets, the production of solid preparations such as tablets is, for example, lactose, excipients such Man'ni' bets, starch disintegrants, lubricants such as magnesium stearate, Po Li Bulle § Bruno l'Ecole, binders such as human Dorokishipuro Pirusenorerosu, moon effect fatty acid esters surfactants, plasticizers such as glycerin, and the like can be used.

Intravascular administration preparation such as injection of formulations suitable for parenteral administration may be formulated with an aqueous medium of good Mashikuwahi preparative isotonic with blood. For example, injections, saline solution, Budu sugar solution, and an aqueous medium selected from a mixture of salt water and Pudou sugar dissolved solution, both solutions, suspensions, or a dispersion, a suitable auxiliaries according to conventional methods it can be prepared Te. The preparation of formulations for parenteral administration, e.g., diluents, fragrances, preservatives, excipients, collapse 壌剤, lubricants, binders, surfactants, or one to three substituents selected from plasticizers 2 it can be used more pharmaceutical additives.

The amount and frequency of administration of the medicament of the present invention is not particularly limited, the type of the substance as an active ingredient, route of administration, the therapeutic and Z or purpose of prevention, the patient's age and weight, the nature and severity of the condition, etc. It can be appropriately selected depending on various conditions. For example, is preferably administered by dividing adult per L~50mgZ kg 3-4 times. However, these dosing amount and frequency of administration will vary depending on various conditions described above.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, will be specifically described by al by the present invention through examples and reference examples, the scope of the present invention is not limited to these examples. In addition, the numbers of the compounds in the following Examples and Reference Examples correspond to the numbers of the compounds shown by the examples in Table 3. Further, the compound obtained mass spectrometry (MS), were identified by pro ton nuclear magnetic resonance (¾- NMR) or the like. The results of mass spectrometry of the compound, described in conjunction with Table 3 above.

Pro ton nuclear magnetic resonance scan Bae-vector data representative compounds are shown in the fifth to Table 6 and examples.

Physicochemical data of each compound in the following Examples were measured Te cowpea the following equipment.

- Anonymous: JEOL JNM-EX270 (270 MHz) or JE0L Door - GX270 (270 MHz) MS: Micromass LCT or Micromass Quatro (measured at APCI method or ESI method)

Reference Example 1: N-(toluene one 4 _ sulfonyl) Single L- prolyl one O- (preparative Rifunoreo port main Tansuruhoniru) Single L Chiroshin tert- Buchiruesu ether (Compound a)

W099 / 06.39 thousand obtained according to the method described in N- (toluene one 4-scan Norehoninore) - L-Pro Li Honoré _ L Chiroshin tert- butyl ester Honoré (32.9 g, 67.3 mmol) in dichloromethane (200 mL) dissolved in, under cooling, pyridine (16.0 raL, 198 mmol) and anhydrous bets Rifunoreo port methanesulfonic acid (14.6 mL, 86.8 mmol) and the mixture was stirred at room temperature for 4 hours. Dilute hydrochloric acid and dichloro Rometan added to the reaction solution, after extraction, the organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica force gel strength Ramukuroma preparative chromatography (hexane / acetic acid Echiru = 3/1 to), the title compound as colorless crystals 87% (36.5 g, 58.8 mraol) obtained in It was.

- NMR (CDC1 3) δ ( ppm): 7.84 (d, J two 8.3 Hz, 2H), 7.36-7.28 ( m, 6H), 7.17 (d, J = 8.4 Hz, 2H), 4.78-4.70 (m, 1H), 4.08-4.03 (m, 1H), 3.38-3.03 (m, 4H), 2.21 (s, 3H), 2.05-2.00 (m, 1H), 1.56-1.40 (m, 3H), 1.45 (s, 9H).

Reference Example 2: N-benzene scan Honoré Honi Honoré one L one pro reroute 〇 one (G Li full Orofume chest Honoré Honi Honoré) Single L- Tyrosine tert- Petit Honoré Este Honoré (of compound b)

In the same manner as in Reference Example 1, from N- benzenesulfonyl L- pro re Honoré one L Chiroshin tert- Bed Chiruesuteru obtained according to the method described in W099 / 06 390, to give the title compound.

NMR (CDC1 3) δ (ppra ): 7.84 (d, J = 7.8 Hz, 2H), 7.67-7.52 (m, 3H), 7.37-7.26 (m, 3H), 7.19 (d, J = 8.4 Hz, 2H ), 4.78-4.70 (m, 1H), 4.09-4.05 (m, 1H), 3.39-3.03 (m, 4H), 2.04-2.00 (m, 1H), 1.57 - 1.39 (m, 3H), 1.46 (s , 9H).

Reference Example 3: N - (3, 5- Axis port opening benzenesulfonyl two Honoré) - L one pro re Nore O- (Application Benefits Funoreorofume chest Honoré Hoyu Honoré) Single L Chiroshin tert one-butyl ester (Compound c)

In the same manner as in Reference Example 1, W099 / 06390 obtained according to the method described in N- (3, 5- Axis port opening benzenesulfonyl two Honoré) Single L- pro re Honoré _ L- Tyrosine tert- Petit glycol ester Achieved ', to give the title compound.

- thigh (CDC1 3) S (ppra) : 7.73 (d, J = 1.8 Hz, 2H), 7.61 (t, J = 1.8 Hz, 1H), 7.31 (t, J = 8.6 Hz, 2H), 7.21 (d , J = 8.6 Hz, 2H), 4.80-4.70 (m, 1H), 4.15-4.05 (m, 1H), 3.43-3.05 (m, 4H), 2.13-2.05 (m, 1H), 1.70 - 1.50 (m , 3H), 1.46 (s, 9H).

Reference Example 4: 4 - (4-phenylene Rubiperajin one 1 - I le) Single L one-phenylene Rua La Nin methyl ester (Compound d)

Step 1

W099 / 36393 was obtained according to the method described in N-(tert Putokishika Lupo two Honoré) _ O-(Application Benefits Funoreorofume Tansunorehoniru) - L-tyrosine Thin methylate Honoré ester (5.0 g, 12 mraol) and 1 - dissolved phenylene Honoré piperazine (2.3 g, 14 trnnol) to Te Torahi Dorofuran (50 mL), carbonate Seshiumu (5.3 g, 16 mmol), 2- [di (tert- Puchinore) phosphine Bruno] Bifeninore (263 mg , 0.88 Ramol) and Application Benefits scan (dibenzylidene § seton) dipalladium (266 mg, 0.29 mmol) and the mixture was stirred for 3 hours at 60 ° C. The reaction solution saturated chloride § Nmoniumu solution and acetic Echiru was added and after extraction, the organic layer was washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica force gel strength Ramuku chromatography (hexane / acetic acid E chill = 3/1 to) of colorless crystals N- (tert- butoxycarbonyl) - 4 - ( 4 one Hue Nino Levi prochlorperazine one 1 over I Honoré) 60% of an L one Fueninorearani emission methyl ester (3.1 g, obtained in 7.1 mmol).

-丽(CDC1 3) δ (ppm) : 7.30 (t, J = 7.6 Hz, 2H), 7.04 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 7.6 Hz, 2H), 6.92-6.86 (m, 3H), 3.72 (s, 3H), 3.33 (s, 8H), 3.01 (m, 2H), 1.42 (s, 9H).

Step 2

Obtained in Step 1 N-(tert-butoxycarbonyl) Single 4- (4-Fe two Honoré piperazine one 1 - I le) Single L over phenylene Honoré alanine methylate Honoré Es ether (2.4 g, 5.5 mmol) and Axis B Lome was dissolved in Tan (40 mL), Application Benefits Funore O b acetate (15 mL) and the mixture was stirred for 30 minutes at room temperature. The reaction solution was concentrated under reduced pressure, the resulting residue was diluted with acetic acid Echiru. The solution was added to saturated sodium hydrogen isocyanatomethyl Li © anhydrous solution, after separated, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the title of compound of colorless crystals 99% (1.8 g, 5.4 mmol) obtained in.

1 H-NMR (CDC1 3) δ (ppm): 7.29 (dt, J = 1.8 Hz, 6.9 Hz, 2H), 7.11 (d, J = 8. 6 Hz, 2H), 7.00-6.86 (m, 5H) , 3.72 (s, 3H), 3.70 (dd, J = 5.1 Hz, 7.7 Hz), 3.33 (s, 8H), 3.03 (dd, J = 5.1 Hz, 14 Hz, 1H), 2.80 (dd, J = 7.7 Hz, 14 Hz, 1H).

Reference Example 5: N-(tert-butoxycarbonyl) Single 4- (piperazin-one 1 - I le) one L- phenylene Ruaraninme Chiruesuteru (Compound e) Step 1

Analogously to Step 1 of Reference Example 4, N- (tert Butokishikaru Boniru) - from O- (Application Benefits Funoreorofume chest Honoré Honi Honoré) _ L-tyrosine methylate Honoré Este Honoré and benzylidene Honoré piperazine, N- ( tert- Butokishika Noreponinore) - 4 - (4 one base Njinorepi Bae Rajin one 1 Inore) to give an L- phenylene Rua La Nin methyl ester.

- NMR (CDC1 3) δ ( ppm): 7.42-7.22 (m, 5H), 6.99 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 4.95-4.85 (m, 1H), 4.60-4.50 (m, 1H), 3.71 (s, 3H), 3.56 (s, 2H), 3.19-3.15 (m, 4H), 3.05-2.95 (m, 2H),

2.65-2.58 (m, 4H), 1.41 (s, 9H).

Step 2

Obtained in Step 1 N-(tert-butoxycarbonyl) - 4 - (4 one Benjinorepi Bae Rajin one 1 Inore) Single L- Hue Nino les alanine methylate Honoré Es ether (12.2 g, 27 mmol) and Axis Rorometan (120 mL It was dissolved in), under ice-cooling, 2-black port e chill chloro phosphono Les Mae preparative (4 mL, 38 mmol) to give a force [pi, and stirred between at 2 at room temperature. Brine was added to the reaction solution, and extracted twice with acetic acid Echiru. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and purified by resulting residue (hexane / acetate Echiru = 3 to) silica force gel strength Ramukuroma preparative chromatography to yield a brown oil. The resulting compound having conducted the dissolved heated under reflux for 1 hour in methanol (0.99 mL). The reaction solution was concentrated under reduced pressure, the residue saturated sodium hydrogen isocyanatomethyl Li um resulting aqueous solution was added thereto, followed by extraction with acetic acid Echiru. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the title of compound of colorless crystals 78 ° /. (7.7 g, 21.2 mraol) was obtained in.

- negation R (CDC1 3) δ (ppm ): 7.02 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 4.96-4.90 (m, 1H), 4.60-4.50 (m , 1H), 3.82-3.74 (m, 4H),

3.71 (s, 3H), 3.16- 3.10 (m, 4H), 3.03-3.00 (ra, 2H), 1.31 (s, 9H) Reference Example 6:. N- (2, 6- dichloro base Nzoinore) Single 3- two Toro one 4-O i (Application Benefits Funoreoro meth Nsunorehoninore) Single L- off e - Norearani Nechinore ester (compound)

Step 1

3 - Two collected by filtration - L-tyrosine E chill Este Honoré hydrochloride (10.0 g, 36.9 mmol) and carbonate Na Application Benefits um (5.87 g, 55.4 mmol) and water (100 mL) and § Se tons (100 mL) mixture is dissolved in a solvent, under ice-cooling for 2, 6-dichloro port base Nzoi Rukuro Li de (9.25 g, 44.3 mmol) and the mixture was stirred for 1 hour at room temperature. 2.0 mo'1 / L was neutralized with hydrochloric acid, collected by filtration resulting solid, a yellow solid N-(2, 6- dichlorobenzoyl every mouth base Nzoinore) - 3 twelve Toro one L over tyrosine E Chino les Este Honoré a 100% (16. Og, 36.9 mmol) was obtained in.

Step 2

The resulting N- (2, 6- Axis B port base Nzoiru) in step 1 one 3 two by filtration over L- tyrosine E Chino Les Este Honoré (15.0 g, 35.1 mmol) and pyridinium Jin (11. O g, the 140 mmol) was dissolved in Axis Rorometan (140 mL), under ice-cooling anhydrous Application Benefits Funoreorome Tansunorehon acid (14.8 g, 52.7 mmol) force [[e, and stirred at room temperature for 1 hour. The black hole Holm added to the reaction solution, washed with water 2.0 mol / L hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, the resulting residue was purified by silica force gel strength Ramuku chromatography (click throat Holm), was obtained in the title compound as a white solid 100% (5.71 g, 10.0 mmol). Reference Example 7: 4- (3, 3-dimethyl-2- Okiso one 4- Fuenirupi Pera gin _ 1 one I le) Single L- phenylene Rua la Yun methyl ester (Compound g) Step 1 -

N- § Li Ruaniri down (19 mL, 140 mmol) was dissolved in dimethicone Honoré phosphono REM § mi de (190 mL), carbonate mosquito Li um (29 g, 210 ramol) and methyl bromoacetate (16 mL, 168 mmol ), and the mixture was stirred for 2 hours at 70 ° C. Saturated chloride Anmoniumu solution and acetic acid Echiru added to the reaction solution, the organic layer was extracted, washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the resulting residue was purified by silica Kagerukuroma preparative chromatography (hexa on / acetic Echiru = 1/20 to), a pale yellow liquid N- Ariru N- Fe Niruami Bruno methyl acetate It was obtained in 89% (26 g, 125 mmol).

- image R (CDC1 3) δ (ppm ): 7.25-7.17 (ra, 2H), 6.73 (t, J = 7.3 Hz, 1H), 6.65 (dd, J = 0.91 Hz, 8.8 Hz, 2H), 5.96- 5.82 (m, 1H), 5.22 (dt, J = 1.6 Hz, 15 Hz, 1H), 5.18 (dt, J = 1.6 Hz, 8.5 Hz, 1H), 4.03 (s, 2H), 4.02 (dt, J = 1.6 Hz, 6.4 Hz, 2H), 3.73 (s, 3H).

Step 2

Resulting N- § Lil in Step 1 - N- Fenirua Mi Roh methyl acetate (4.0 g, 19 mmol) was dissolved in Te Torahi Dorofuran (30 mL), - 78 ° Kisamechirujishira to Richiumu cooled to C disilazide (29% Te Torahi Dorofuran solution, 55 m, 95 mmol) was added, and the mixture was stirred .30 min. Thereafter ® chromatography Dometan (5.9 m L, 95 mmol) was added and stirred for 30 minutes to 0 ° C. The reaction solution saturated chloride ammonium Niumu solution and acetic Echiru added, the organic layer was extracted and washing with saturated brine and dried over anhydrous magnesium sulfate. Filtration. After over, the filtrate was concentrated under reduced pressure, the resulting residue was purified by Shirikageruku chromatography (hexane / acetic acid Echiru = 1/20 to), a pale yellow liquid 2-(N-§ Li Le _N- off Nirua Mino) was obtained in an 2-Mechirupuro acid methyl 75% (3.4 g, 15 mmol).

X HN R (CDC1 3) δ (ppm): 7.19 (t, J = 8.0 Hz, 2H), 6.90 ", J = 8.0 Hz, 1H), 6.88 (d, J = 8.0 Hz, 2H), 5.91-5.80 (m, 1H), 5.24 (dd, J = 1.8 Hz, 17 Hz, 1H), 5.06 (dd, J = 1.8 Hz, 10 Hz, 1H), 3.93 (dt, J = 1.8 Hz, 4.4 Hz, 2H) , 3.70 (s, 3H), 1.48 (s, 6H).

Step 3

Obtained in Step 2 2-(N- § Li Nore N- Fuenirua Mi Roh) - 2 - methylcarbamoyl Honoré acid Mechinore (2.4 g, 10 mmol) and Te Torahi Dorofuran (25 mL) and water (25 mL) mixture is dissolved in a solvent, after cooling to 0 ° C, tetroxide O scan Mi © beam (25 mg, 0.10 mmol) was added and stirred. Added over meth Cayo U periodate Na Application Benefits U beam (4.36 g, 20 mmol) for 4 0 minutes, and stirred for 2 hours to room temperature. Acetic acid Echiru added to the reaction solution, the organic layer was extracted and washing with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the resulting residue was purified by silica force Geruku chromatography (hexane / acetic acid Echiru = 1/9 to) of colorless liquid 2-(N- formyl amino-les-methylcyclohexyl N- Hue Niruami Roh) one 2 - Mechirupuro acid Mechinore a 60% (1.4 g, obtained in 6.0 mmol).

NMR (CDC1 3) δ (ppm ): 9.71 (ΐ, J = 1.6 Hz, 1H), 7.25 (t, J = 7.7 Hz, 2H), 7.06, J two 7.7 Hz, 1H), 7.02 ( d, J = 7.7 Hz, 2H), 4.04 (d, J = 1.6 Hz, 2H), 3.73 (s, 3H), 1. 4 (s, 6H).

Step 4

2 one obtained in Step 3 (N-formylmethyl one N - Fenirua Mi Roh) Single 2- Mechirupuro acid methyl (1.4 g, 6.0 mmol) and 4 Ichia Mi node on N - (tert-butoxy force Rubo sulfonyl) Single L- Hue Nino les alanine methylate Honoré es ether (1.8 g, a 6.0 mmol) 1, and 2-Axis b Roetan (30 mL) 溶角 Army, after cooling to 0 ° C, acetic acid (lO Ral, 18 mmol), molecular sieves 4 a (1.5 g) and preparative Riase butoxy borohydride Na Application Benefits um (1.9 g, 9.0 mmol) and the mixture was stirred for 2 hours to room temperature. The reaction solution a saturated carbon. Oxyhydrogen isocyanatomethyl Li c anhydrous solution of acetic acid Echiru added, the organic layer was extracted, washed with saturated brine and dried over anhydrous magnesium sulfate. After over, the filtrate was concentrated under reduced pressure, and purified to give al the residue by silica force Geruku port Conclusions chromatography (hexane / acetic acid Echiru = 1/9 to), a yellow solid N- (tert- butoxycarbonyl) - 4 one {2- [N- (1- main Tokishikanorepo two / laser 1 over main switch / Reechinore) Single N- Hue Nirua Mi Bruno] Echiruami Bruno} an L- Hue Nino les-alanine methyl ester Honoré 55% (1.7 g, 3.3 obtained in mmol).

- NMR (CDC1 3) δ ( ppm): 7.29-7.24 (m, 2H), 7.19-7.12 (m, 3Η), 6.87 (d, J = 8.5 Hz, 2H), 6.47 (d, J = 8.5 Hz, 2H), 4.91 (brd, J = 8.2 Hz, 1H), 4.49 (brs, 1H), 3.75 (s, 3H), 3.69 (s, 3H), 3.31 (t, J = 5.6 Hz, 2H), 2.94 ( d, J = 5.9 Hz, 211), 2.84 (t, J = 5.6 Hz, 2H), 1.41 (s, 9H), 1.30 (s, 6H). step 5

Obtained in Step 4 N- (tert script butoxycarbonyl) one 4- {2- [N i (1 - main butoxy carbonitrile Nino rate 1 over main Chinoreechinore) Single N- Fueninorea amino] Echinorea Mi Roh} _ one Hue Nino-les-alanine methylate Norre Este Norre (960 mg,

The 1.9 mmol) was dissolved in methanol (20 mL), diisocyanato Li Umume Tokishido (1.0 g; the 19 mmol) was added and stirred for 12 hours at 60 ° C. The reaction solution was concentrated under reduced pressure, water (10 mL) was added dropwise 0. 2 mol / L hydrochloric acid while stirring, the pH of the solution was adjusted to about 3. Acetic acid Echiru added, the organic layer was extracted, washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, a white solid of N-(tert butoxide deer Lupo sulfonyl) Single 4 one (3, 3 one Dimethicone / rate 2 _ Okiso one 4 one Hue Nino les piperazine one 1 one Inore) Single L

- phenylene Ruaranin 99% (8 § 0 mg, 1.9 mraol) was obtained in. The obtained compound was used in the next step without any more purification.

Step 6

Step resulting N-(tert-butoxy-carbonitrile el) 5 one 4- (3, 3 one Jimechinore one 2- Okiso one 4 one Hue Nino les piperazine one 1 Inore) Single L - Hue Nino Les alanine (870 mg / 1.9 mmol ) was dissolved in dimethicone Honoré phosphono REM a mi de (9.0 Ral), carbonate mosquito Li um (280 mg, 2.1 mraol) Oyopi ® over domain data emission (0.13 mL, 2.1 mmol) was added, stirred for 1 hour at room temperature did. Saturated chloride Anmoniumu solution and acetic acid Echiru added to the reaction solution, the organic layer was extracted, washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the resulting residue was purified by silica gel chroma preparative chromatography (hexa on / acetic Echiru = 1/3 to), N_ colorless crystals (tert- Butokishika Ruponiru) - 4 - (3 3- Jimechinore one 2- Okiso one 4- Feninorepi Bae Rajin one 1 one I le) Single L one Hue Nino les alanine main Chiruesutenore a 82% (730 mg, obtained in 1.5 mmol).

1H-NMR (CDC1 3) δ (ppm): 7.35- 7.29 (m, 3H), 7.20 - 7.14 (m, 6H), 4.97 (br d, J = 8.1 Hz, 1H), 4.58 (brd, J = 7.4 Hz, 1H), 3.75 (t, J = 5.3 Hz, 2H), 3.73 (s, 3H), 3.51 (t, J = 5.3 Hz, 2H), 3.10 (brs, 2H), 1.43 (s, 9H.) , 1.42 (s, 6H).

Step 7

Step resulting N-(tert script butoxycarbonyl) 6 one 4- (3, 3 Jimechinore 2- Okiso one 4 one Hue Nino les piperazine one 1 over I Honoré) - L one Hue Nino les alanine methylate Honoré Este Honoré (150 mg, a 0.31 mmol) was dissolved in Axis b Lome Tan (3 mL), collected by Rifuruoro acetate. (1 mL) was added and stirred for 30 minutes at room temperature. The reaction solution was concentrated under reduced pressure, the resulting residue Dilute with acetic Echiru was added to saturated bicarbonate Na Application Benefits um aqueous solution. The organic layer was extracted, washed with saturated Japanese brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the title compound as colorless crystals 99% (120 mg, 0.31 mraol) was obtained in.

δ (ppm): 7.37-7.13 (m, 9H), 3.77-3.73 (m, 6Η),

3.51 (t, J = 5.1 Hz, 2H), 3.12 (dd, J = 4.9 Hz, 14 Hz, 1H), 2.86 (dd, J two 8.1 Hz, 14 Hz, 1H), 1.42 (s, 6H). Implementation example 1: N-(Tonoreen one 4- Sunorehoninore) Single L- pro re Nore 4 one [4 one (2- Shianofueniru) piperidines Rajin one 1 one I le] one L- phenylene Norearani down

Step 1

Compound a (623 mg, 1.00 tnmol) obtained in Reference Example 1 and 1 i (2-Xia Nofue two Honoré) piperazine (229 mg, 1.22 mmol) was dissolved in Te Torahi Dorofuran (2.0 mU, cesium carbonate (462 mg, 1.42 tnmol), 2 - [di (tert- Puchinore) phosphite Huy Bruno] Bifue two Honoré (23.0 mg, 0.0771 mmol) and acetic acid Parajiumu (11.0 mg, 0.0490 mmol) and Ka卩E, 4 6 0 ° C time was stirred. the reaction solution was added a saturated aqueous sodium chloride and acetic acid Echiru, and the organic layer was extracted and dried with anhydrous magnesium sulfate. the solvent was distilled off, silica gel and the resulting residue was Rukaramukuroma preparative chromatography (hexane / acetic acid purification by Echiru = 1/1), colorless crystals of N- (Tonoreen one 4 one sulfonyl Honoré) Single L one pro Rinore 4 one [4- (2-Shianofueniru) piperidines Rajin one 1 one I le] one L - phenylene Norearani down tert- butyl Honoré Este Honoré a 35% (230 mg, 0.350 mmol) In was obtained.

- NMR (CDC1 3) δ ( ppm): 7.72 (d, J = 8.4 Hz, 2H), 7.58 (dd, J = 0.8 Hz, 8. 1 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H ), 7.32 (d, J = 8.4 Hz, 2H), 7.31-7.30 (m, 1H), 7.09 (d, J = 8.4 Hz, 2H), 7.07-7.01 (m, 2H), 6.89 (d, J = 8.4 Hz, 2H), 4.72-4.65 (m, 1H), 4.09-4.07 (m, 1H), 3.36-3.35 (m, 9H), 3.16 (dd, J = 5.7 Hz, 13.8 Hz, 1H), 3.13- 3.07 (m, 1H), 2.98 (dd, J = 7.0 Hz, 14.0 Hz, 1H), 2.43 (s, 3H), 1.48 (s, 9H), 1.47-1.42 (m, 4H).

Step 2

Obtained in Step 1 N-(toluene one .4 one sulfonyl) Single L- Pro Li Lu 4- [4 one (2- Shianofueniru) piperidines Rajin one 1 - Inore] one L one Hue Nino les alanine tert- butyl ester (230 mg, 0.350 mmol) was dissolved in di chloromethane (5 mL), collected by Li Furuoro acetate (1 raL, 13.0 mmol), and the mixture was stirred at room temperature for 12 hours. The solvent and Application Benefits Furuoro acetate was distilled off under reduced pressure, the residue 1 mol / L hydroxide Na tri © anhydrous solution was added to completely dissolve. Acetic acid was added to the solution, the precipitated crystals were collected by filtration and was obtained in the target title compound as colorless crystals 71% (149 mg, 0. 248 mmo l).

- NMR (CDC1 3) δ ( ppm): 7. 69 (d, J = 7. 3 Hz, 2H), 7. 55 (d, J = 7. 6 Hz, 2H), 7. 49 (t, J = 8. 1 Hz, 1H), 7. 19 (d, J = 6. 5 Hz, 2H), 7. 08-6. 98 (ra, 4H), 6. 81 (d, J = 7. 6 Hz , 2H), 4. 74-4. 64 (m, 1H), 4. 10-4. 05 (ra, 1H), 3. 28-3. 25 (m, 10H), 2. 98-2. 77 (m, 2H), 2. 33 (s, 3H), 1. 78- 1. 75 (ra, 1H), 1. 37-1. 33 (m, 2H), 1. 17-1. 14 (m , 1H).

In the same manner as in Example 1, it was form if Compound 2-3 6 and Example 2-3 6. Pro 1 of the resulting compound, the emission nuclear magnetic resonance scan Bae-vector data, shown in Table 5.

Table 5

Compound determination

- Ί opening

■ m solvent

8.00 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 8.3

Hz, 2H), 7.40 (d, J = 8.3 Hz, 2H), 7.24 (t,

J = 8.5 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H),

7.00 (d, J = 7.9 Hz, 2H), 6.94 (d, J = 8.5

2 DMSO- d 6

Hz, 2H), 6.82 (t, J = 7.9 Hz, 1H),

4.38-4.50 (m, 1H), 4.10-4.15 (m, 1H), 3.26

(Brs, 8H), 3.60-2.85 (m, 4H), 2.40 (s, 3H),

1.70-1.35 (m, 4H)

7.73 (d, J = 7.9 Hz, 2H), 7.38-7.26 (m,

3H), 7.14 (d, J = 8.2 Hz, 2H), 7.06-6.86

(M, 6H), 4.90-4.65 (m, 1H), 4.20-4.05 (m,

3 CDCls

1H), 3.87 (s, 3H), 3.32-3.21 (m, 8H),

3.20-2.90 (m, 4H), 2.40 (s, 3H), 2.05- 1.85

(M, 1H), 1.60- 1.35 (m, 3H) 7.68 (d, J = 8.1 Hz, 2H), 7.50 (m, IH),

7.41-7.25 (m, 6H), 6.89-6.86 (m, 2H), 6.72

(D, J = 8.1 Hz, 2H), 4.85-4.78 (, 1H),

CDCla 4.09-4.06 (m, 1H), 3.80-3.74 (m, 8H),

3.44-3.41 (m, 1H), 3.33-3.05 (m, 3H), 2.43

(S, 3H), 1.60-1.53 ​​(m, 3H), 1.27-1.26 (m,

IH)

7.72 (d, J = 7.6 Hz, 2H), 7.37 (d, J = 7.3

Hz, III), 7.30 (d, J = 8.1 Hz, 2H), 7.13 (d, J

= 7.6 Hz, 2H), 6.99 (d, J = 9.2 Hz, 2H),

CDCls 6.91-6.84 (m, 4H), 4.75-4.72 (m, IH),

4.11-4.08 (m, IH), 3.78 (s, 3H), 3.38-3.15

(M, 10H), 3.15-2.95 (m, 2H), 2.41 (s, 3H),

1.99-1.96 (m, 1H), 1.52-1.47 (m, 3H)

7.71-7.66 (m, 4H), 7.57 (d, J = 8.1 Hz, 1H),

7.46-7.11 (m, 8H), 4.85-4.78 (m, 1H),

CDCla 4.11-4.06 (m, 1H), 3.69 3.68 (m, 8H),

3.41-3.07 (m, 4H), 2.42 (s, 3H), 2.35 (s,

3H), 2.00-1.96 (m, IH), 1.57-1.49 (m, 3H)

7.70 (d, J = 8.3 Hz, 2H), 7.39-6.92 (m,

10H), 4.82-4.75 (m, 1H), 4.09-4.07 (m, IH),

CDCla 3.44-3.13 (m, 12H), 2.42 (s, 3H), 2.27 (s,

3H), 2.23 (s, 3H), 2.02-2.01 (m, 1H),

1.55-1.52 (m, 3H) 7.70 (d, J = 7.8 Hz, 2H), 7.49 (d, J = 8.6 Hz, 2H), 7.30-7.26 (m, 2H), 7.12 (d, J = 8.1 Hz, 2H), 6.94 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.4

CD Cls Hz, 2H), 4.77-4.73 (m, 1H), 4.08-4.03 (m,

1H), 3.39-3.37 (m, 4H), 3.26-3.25 (m, 6H), 3.07-2.91 (m, 2H), 2.40 (s, 3H), 1.89.1.85 (m, 1H), 1.49-1.25 ( m, 3H)

7.72 (d, J = 7.8 Hz, 2H), 7.65 (d, J = 5.7 Hz, 1H), 7.40 (d, J = 8.1 Hz, 2H), 7.23 (d, J = 8.9 Hz, 2H), 6.99- 6.96 (m, 4H), 6.79 (d, J = 8.6

DMSO - d 6 Hz, 2H), 3.98-3.94 (m, 2H), 3.24-3.21 (m,

4H), 3.17-3.15 (m, 4H), 3.10-2.93 (m, 4H), 2.38 (s, 3H), 1.77- 1.71 (m, 1H), 1.37- 1.33 (m, 3H)

7.70 (d, J = 8.2 Hz, 2H), 7.57-7.51 (m, 4H), 7.43-7.37 (m, 2H), 7.31 -7.25 (m, 4H), 7.14 (d, J = 8.2 Hz, 2H) , 7.02 (d, J = 8.9 Hz, 2H),

CD Cls 6.93 (d, J = 8.6 Hz, 2H), 4.81 -4.74 (m, 1H),

4.11 -4.09 (m, 1H), 3.35-3.23 (m, 10H), 3.14-3.08 (m, 2H), 2.40 (s, 3H), 2.04-2.02 (m, 1H), 1.51 - 1.43 (m, 3H )

8.11 (d, J = 9.7 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 7.6 Hz, IH), 7.32 (d, J = 7.8 Hz, 2H), 7.15 ( d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 9.7 Hz, 2H),

CDCls

4.82-4.75 (m, 1H), 4.09 -4.06 (m, 1H), 3.58-3.54 (m, 4H), 3.40-3.30 (m, 6H), 3.23-3.09 (m, 2H), 2.43 (s, 3H ), 2.04-2.03 (m, IH), 1.50- 1.47 (m, 3H)

7.69 (d, J = 8.3 Hz, 2H), 7.42 -7.11 (m, 8H), 7.02 (d, J = 8.3 Hz, 2H), 4.82-4.77 (m, 1H),

CDCls 4.08-4.06 (m, 1H), 3.49-3.39 (m, 9H),

3.31 -3.12 (m, 3H), 2.43 (s, 3H), 2.05-2.03 (m, IH), 1.54- 1.48 (m, 3H)

7.70 (d, J = 8.2 Hz, 2H), 7.38-7.35 (m, IH), 7.32 (d, J = 7.9 Hz, 2H), 7.19-7.01 (m, 8H),

CDCls 4.82-4.75 (m, IH), 4.09 4.07 (m, IH),

3.40-3.26 (m, 11H), 3.16-3.09 (m, 1H), 2.43 (s, 3H), 2.06-2.04 (m, IH), 1.54-1.51 (m, 3H)

8.12 (d, J = 7.6 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 7.8 Hz, 4H), 6.90 (d, J = 8.9 Hz, 2H), 4.54- 4.49 (m, IH), 4.11-4.08

CDaOD

(M, IH), 3.32-3.29 (m, 8H), 3.22-3.02 (m, 3H), 2.42 (s, 3H), 1.88-1.81 (m, 1H), 1.65-1.51 (m, 4H)

8.18 (d, J = 4.9 Hz, IH), 7.70 7.68 (m, 2H),

7.50-7.45 (m, 2H), 7.17-7.13 (m, 2H),

7.05- 7.01 (m, 2H), 6.79 6.75 (m, 2H), 6.67-6.60 (m, 2H), 4.65-4.60 (m, IH),

CDCls

4.06- 4.03 (m, 1H), 3.62-3.60 (m, 4H), 3.31-3.26 (m, 2H), 3.14-3.12 (m, 4H), 2.94-2.90 (m, 2H), 2.31 (s, 3H ), 1.77-1.73 (m, 1H), 1.33-1.25 (m, 3H)

8.20 (br s, 1H), 8.13 (br s, 1H), 7.88 (br s, IH), 7.69 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 7.6 Hz, 1H), 7.32 ( d, J = 7.9 Hz, 2H), 7.17 (d, J = 8.2 Hz, 2H), 7.08 (d, J = 8.2 Hz, 2H),

CDCls

4.84-4.76 (m, 1H), 4.09-4.07 (m, 1H), 3.87-3.86 (m, 4H), 3.36 3.23 (m, 7H), 3.16-3.11 (m, 1H), 2.43 (s, 3H) , 2.06-2.03 (m, IH), 1.58-1.53 ​​(m, 3H) 8.35 (d, J = 4.9 Hz, 2H), 7.71 (d, = 8.6 Hz, 2H), 7.38 (d, J = 6.9 Hz, IH), 7.32 (d, J two 8.2 Hz, 2H), 7.12 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H), 6.54 (t, J = 4.9

CDCls

Hz, 1H), 4.81-4.74 (m, 1H), 4.11-4.09 (m, 1H), 3.95-3.91 (m, 4H), 3.42-3.36 (m, 1H), 3.27-3.06 (m, 7H), 2.42 (s, 3H), 2.09-2.05 (m, IH), 1.53- 1.46 (m, 3H)

7.71 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 8.6 Hz, 2H), 6.75 (d, J = 8.6 Hz, 2H), 4.60- 4.55 (m, 1H),

CDCls

4.11-4.08 (m, IH), 3.50-2.90 (m, 12H), 2.65 (s, 3H), 2.42 (s, 3H), 2.15-2.08 (m, IH), 1.68- 1.58 (m, 3H)

7.94 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.1 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 6.83 ( d, J = 8.9 Hz, 2H), 4.42-4.36

DMSO- d 6

(M, 1H), 4.13-4.11 (m, 1H), 3.13-3.11 (m, 6H), 3.01-2.84 (m, 2H), 2.73-2.72 (m, IH), 2.40 (s, 3H), 1.86 -1.82 (m, 2H)

8.03 (d, J = 8.1 Hz, IH), 7.69 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.6 Hz, 2H), 6.90 ( d, J = 8.6 Hz, 2H), 4.43-4.33

DMSO - d 6

(M, IH), 4.14-4.12 (m, IH), 3.33 -3.30 (m, 2H), 3.19-3.12 (m, 8H), 3.11 -2.85 (m, 2H), 2.40 (s, 3H), 1.60 - 1.44 (m, 4H)

7.90 (d, J = 7.8 Hz, IH), 7.70 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H), 7.40-7.20 (m, 5H), 7.04 (d, J = 8.7 Hz, 2H), 6.80 (d, J = 8.7

DMSO -. D 6 Hz, 2H), 4.34-4.31 (m, IH), 4.09-4 11 (m,

1H), 3.50 (s, 2H), 3.31 (brs, 4H), 3.07 (brs, 4H), 3.05 -2.79 (m, 4H), 2.40 (s, 3H), 1.70- 1.35 (m, 4H)

8.51 (d, J = 5.9 Hz, 2H), 7.97 (d, J = 7.6 Hz, 1H), 7.69 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 7.8 Hz, 2H), 7.34 ( d, J = 5.4 Hz, 2H), 7.07 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.1 Hz, 2H),

DMSO - d 6

4.42-4.38 (m, IH), 4.14-4.11 (m, 1H), 3.57-3.55 (m, IH), 3.32-3.30 (m, 4H), 3.11 -3.09 (m, 4H), 3.08-2.89 (m , 3H), 2.40 (s, 3H), 1.74- 1.38 (m, 4H)

8.01 (d, J = 7.8 Hz, IH), 7.69 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 7.8 Hz, 2H), 7.13 (d, J = 8.6

DMS O - d 6 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 4.46-4.38

(M, 1H), 4.15-4.07 (m, 1H), 3.40-2.90 (m, 14H), 2.40 (s, 3H), 1.62- 1.41 (m, 4H)

(H

<ra) 88 Ϊ-89 Τ '(Η8' s) 68 2 '(Η' ^) Z6 Z-S02

'(Η8' ^) 8 '(ΗΧ' ^) SO t-Zl f '(Ηΐ

9 Ρ -OS顧9Ζ

28 f-0 ^ f '( Hg' Ζ Η 68 = Γ ΊΡ) 989 UZ 'Ζ Η

^ "8 = f 'Ρ) 80 ·' (H ^ 'Ζ Η 9 L = f' Ρ) 68 · '(UZ

'Ζ Η Τ · 8 = f ' Ρ) 697, '(ΗΤ' ^ Η 89 = f 'Ρ) 96

(Hf

<τπ) Of ΐ- ^ 9'Ι ' (Η8' s) OfZ '(ΗΖ) 98 ^ -f08

'(Hf' ^) 908-8Χ 8 '(Η' m) 888-A8 8

'(HS 898- 8 "8' (HT 'm) TT ^ -Sl' ^ '(HI

9 P -OSHQ 9Z

'M) 6 -f-Lft' (UZ 'ZH 98 = f ΊΡ) 069' (HZ

'Z H fS = f' P ) ZYL '(HT' ZH fSX = f 'P) OS i,

'(HS e' L-lfL £ (HT 'Z H ST = f' P) IL

'(m S9'L-fL-L ' (HT '2 H 97, two' ρ) 66 · arm

'(H8) Z m <tn ) 8' (HI

8g 8-S88 m SS S -L '2' (HI 0l - Y

9 P -OSHQ

C (HI 88 -5 ^ '( HZ' Z H f8 = f 'Ρ) T69

'(HS' 9 · 8 = Γ 'Ρ) ZYL' (HZ 'Z H 8 · = f' Ρ) 687- C (HZ 'Z H 8 = Γ' Ρ) 69 · '(Ηΐ' Ζ Η 9 ' L = Γ 'Ρ) 66 ·

0 680 / £ 0 OAV 7.81 (d, J = 7.1 Hz, 2H), 7.66-7.47 (m, 6H), 7.35 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 7.3 Hz, 2H) , 7.15-7.03 (m, 2H), 4.85-4.77 (m, 1H),

CDCla

4.12-4.09 (m, IH), 3.66 (brs, 4H), 3.53-3.06 (m, 4H), 3.34 (brs, 4H), 2.31 (s, 3H), 2.10-2.00 (m, 1H), 1.45- 1.65 (m, 3H)

8.07 (d, J = 7.9 Hz, IH), 7.82 (d, J = 6.9 Hz, 2H), 7.71 (t, J = 7.6 Hz, IH), 7.60 (t, J = 7.9 Hz, 2H), 7.43 ( d, J = 7.9 Hz, 2H), 7.32 (t, J =

DMSO- d 6 7.9 Hz, 2H), 7.21-7.17 (m, 3H), 7.10-7.04 (m,

3H), 4.50-4.40 (m, IH), 4.17-4.13 (m, IH), 3.33 (brs, 6H), 3.18 (brs, 4H), 3.10-2.88 (m, 2H), 1.70-1.40 (m, 4H)

7.96 (d, J = 7.3 Hz, IH), 7.82 (d, J = 6.5 Hz, 2H), 7.80 (s, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.60 (t, J = 7.8 Hz, 3H), 7.37 (d, J = 8.1 Hz, 1H), 7.15 (t, J = 7.3 Hz, 1H), 7.09 (d, J =

DMSO- d 6 8.4Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H),

4.40-4.33 (m, 1H), 4.12-4.08 (m, 1H), 3.36-3.34 (m, 2H), 3.16-3.14 (m, 4H), 3.13-3.09 (m, 4H), 3.04-2.87 (m , 2H), 1.66-1.41 (m, 4H) 7.93 (d, J = 7.6 Hz, IH), 7.83 (d, J = 6.8 Hz, 2H), 7.71 (t, J = 7.3 Hz, 2H), 7.65 - 7.58 (m, 3H), 7.20 (d, J = 8.1 Hz, 1H), 7.14- 7.11 (m, IH), 7.10

DMSO - d 6

(D, J = 8.6 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 4.34-4.30 (m, IH), 4.16-4.13 (m, IH), 3.27 (m, 8H), 3.20- 2.89 (m, 4H), 1.69 1.37 (m, 4H)

7.92- 7.60 (m, 9H), 7.34 (m, 1H), 7.06 (d, J = 7.8 Hz, 2H), 6.85 (d, J = 7.6 Hz, 2H), 4.22-4.12 (m,

DMSO - d 6

2H), 3.33-3.28 (m, 4H), 3.20-3.16 (m, 4H), 3.02-2.97 (m, 4H), 1.30- 1.26 (m, 4H)

8.37 (s, 1H), 8.10 (s, IH), 8.02 (d, J = 5.4 Hz, 1H), 7.86-7.80 (m, 3H), 7.69 (d, J = 5.4 Hz, IH), 7.60 (t , J two 8.4 Hz, 2H), 7.13 (d, J = 8.1 Hz,

DMSO - d 6

2H), 6.93 (d, J = 8.9 Hz, 2H), 4.40-4.37 (m, 1H), 4.20-4.16 (m, 1H), 3.72 3.69 (m, 8H), 3.21-3.19 (m, 4H), 1.18- 1.13 (m, 4H)

7.92 (d, J = 7.0 Hz, IH), 7.83 (d, J = 7.6 Hz, 2H), 7.70 (t, J = 7.0 Hz, 1H), 7.60 (t, J = 7.8 Hz, 2H), 7.08 ( d, J = 8.1 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.6 Hz, 1H), 6.71 (d, J =

DMSO - d 6

2.2 Hz, IH), 6.38 (dd, J = 2.2 Hz, 8.4 Hz, IH), 5.91 (s, 2H), 4.33-4.28 (, IH), 4.14 (d, J = 4.9 Hz, 1H), 3.29 - 3.26 (m, 2H), 3.20-3.17 (m, 4H), 3.13-2.87 (m, 6H), 1.68- 1.24 (m, 4H) 8.04 (br s, 1H), 7.82-7.51 (m, 7H), 7.20-7.12 (m,

3H), 6.86 (d, J = 7.6 Hz, 2H), 4.82-4.78 (m, IH),

34 CDCls

4.16-4.14 (m, 1H), 3.38-3.25 (m, 10H), 3.11-3.08 (m, 2H), 1.95-1.93 (m, IH), 1.43-1.23 (m, 3H)

8.45 (s, 2H), 7.87 (d, J = 7.3 Hz, 2H), 7.71-7.60 (m, 4H), 6.96 (d, J = 8.6 Hz, 2H), 6.79 (d, J =

35 DMSO- d 6 8.4 Hz, 2H), 4.02-3.98 (m, 1H), 3.83-3.78 (m,

1H), 3.45-3.40 (m, 4H), 3.21-3.16 (m, 4H), 3.09-2.98 (m, 4H), 1.38-1.24 (m, 4H)

8.43 (dd, J = 1.6 Hz, 5.1 Hz, 1H), 8.09 (dd, J = 1.6 Hz, 7.6 Hz, IH), 8.00 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 7.0 Hz , 2H), 7.70 (t, J = 7.0 Hz, IH), 7.60 (t, J = 7.6 Hz, 2H), 7.11 (d, J = 8.4

36 DMSO- d 6 Hz, 2H), 6.95 (dd, J = 4.6 Hz, 7.6 Hz, IH),

6.90 (d, J = 8.9 Hz, 2H), 4.43-4.37 (m, 1H), 4.18-4.14 (m, 1H), 3.75-3.73 (m, 4H), 3.33-3.22 (m, 6H), 3.03- 2.86 (m, 2H), 1.63-1.35 (m, 4H)

Example 3 7: N-(toluene - 4 one sulfo - Le) _ L- Pro Li Le one 4 one (4 Mechinorehomopi Bae Rajin one 1 Inore) Ri by the same method as one L- Hue Nino les-alanine Example 1 , a compound a obtained in reference example 1 1 - from the main Chiruhomopi Bae Rajin to give the title compound.

- Orchid (DMSO- d 6) δ (ppm ):. 1. 38- 1. 59 (m, 3H), 1. 67-1 80 (m, IH),

1. 91 - 2. 05 (m, 2H), 2. 40 (s, 3H), 2. 45 (s, 3H), 2. 74 (brs, IH), 2. 83

(Brs, IH), 2. 85-3. 29 (m, 8H), 3. 35 (brs, IH), 3. 46 (brs, 1H), 4. 04

(M, IH), 4. 21 (ra, IH), 6. 57 (d, J = 8. 4 Hz, 2H), 6. 98 (d, J = 8. 4

Hz, 2H), 7. 41 (d, J = 8. 2 Hz, 2H), 7. 72 (d, J = 8. 2 Hz, 2H), 7. 80 (d, J = 6.8 Hz, 1H) . 'eXAMPLE 3 8: N-(toluene one 4 one sulfonyl) Single L one pro reroute 4 one [4 i (3 main Tokishifueniru) Single 3 Mechirubiperajin one 1 - I Honoré] one L one Hue Nino les alanine

Ri by the same method as in Example 1, from the resulting compound a and 1 one (3-main Tokishifueniru) Single '2 Mechirubiperajin in Reference Example 1 to give the title compound.

'H- MRCDMSO-de) 8 (ppm): 1.04 (d, J = 6.6 Hz, 3H), 1.33-1.77 (m, 4H), 2.40 (s, 3H), 2.70-2.85 (m, 1H), 2.85 -3.15 (ra, 4H), 3.20-3.48 (m, 4H), 3.48-3.62 (m, 1H), 3.71 (s, 3H), 4.00-4.16 (m, 2H), 4.21-4.38 (m, 1H) , 6.36 (d, J - 7.9 Hz, 1H), 6.43 (s, 1H), 6.52 (d, J = 8.9 Hz, 1H), 6.86 (d, J = 8.2 Hz, 2H), 7.05-7.15 (m, . 3H), 7.41 (d, J = 7.9 Hz, 2H), 7.72 (d, J = 7.9 Hz, 2H), 7.91 (d, J = 6.3 Hz, 1H) example 3 9: N- (3, 5 - Axis port opening benzenesulfonyl) Single L-loop port Rinore 4 one [4 one (2- Shiano phenylene Honoré) piperidines Rajin one 1- Inore] one L one-phenylene Ruaranin

In the same manner as in Example 1, from the compound c obtained in Reference Example 3 1 i (2 Shiano phenyl) piperidines Rajin to give the title compound.

- image R (CDC1 3) δ (ppm ): 7.71 (d, J = 1.8 Hz, 2H), 7.61 (t, J = 1.8 Hz, 1H), 7.58-7.48 (m, 2H), 7.19-7.03 (m , 7H), 4.85 - 4.78 (m, 1H), 4.12-4.09 (ra, 1H), 3.45-3.40 (m, 10H), 3.35-3.12 (ra, 2H), 2.13-2.11 (ra, 1H), 1.68 -1.57 (m, 3H).

Example 4 0: N-benzenesulfonyl L one prolyl one 4 one (3-O Kiso one 4 one Hue Nino les piperazine one 1 - Inore) with one L one Hue Nino Les similar manner to alanine in Example 1, Reference Example from compound b and 1 one-phenylene Rubiperajin one-2-one obtained in 2 to give the title compound.

- Keio R (DMS0 - d 6) δ (ppm): 8.02 (d, J = 7.9 Hz, 1H), 7.82 (d, J = 7.3

Hz, 2H), 7.71 (t, J = 7.3 Hz, 1H), 7.60 (t, J = 7.3 Hz, 2H), 7.44-7.33

(M, 3H), 7.28-7.22 (m, 2H), 7.14 (d, J = 8.7 Hz, 2H), 6.90 (d, J

= 8.7 Hz, 2H), 4.41 (dd, J = 7.9 Hz, 13 Hz, 1H), 4.15 (ra, 1H), 3.91 (s, 2H), 3.80 (t, J = 5.3 Hz, 2H), 3.57 ( t, J = 5.3 Hz, 2H), 3.16-3.05 (m, 2H), 3.03-2.87 (m, 2H), 1.63-1.42 (m, 4H).

Example 4 1: N- (2, 6- Axis B B base Nzoiru) Single 4- (4 one phenylene Rubiperajin one 1 Inore) Single L one-phenylene Ruaranin

Step 1

Compound d (926 mg, 2.7 raraol) obtained in Reference Example 4 was dissolved in dichloromethane (15 mL), cooled to 0 ° C, collected by Ryechirua Mi emissions (1.1 mL, 8.2 raraol) and 2, 6-Axis b port base Nzoinoreku b Rye-de (0.46 mL, 3.3 mmol) and the mixture was stirred for 30 minutes at room temperature. The Then, 1 mol / L hydrochloric acid and acetic acid Echiru added to the reaction solution, and separated. The organic layer was washed with saturated bicarbonate isocyanatomethyl Li um aqueous solution followed by washing with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (hexane / acetate Echiru = 3/1) to obtain colorless crystals N-(2, 6- dichloro port Ben Zoinore) - 4 - ( 4 _ Hue Nino les piperazine one 1 Inore) Single L one Fuee Ruaraninme Chiruesutenore a 78% (1.1 g, obtained in 2.1 mmol).

- negation R (CDC1 3) δ (ppm ): 7.33-7.21 (m, 5H), 7.12 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 8.2 Hz, 2H), 6.91-6.87 (m , 3H), 6.25 (d, J = 8.1 Hz, 1H), 5.16 (dt, J = 5.4 Hz, 8.1 Hz, 1H), 3.77 (s, 3H), 3.31 (s, 8H), 3.21 (d, J = 5. 4 Hz, 2H).

Step 2

Obtained N- in step 1 (2, 6-dichloro port base Nzoiru) Single 4 one (4 one Hue Nino les piperazine one 1 Izure) Single L- Hue Nino les alanine methylate Honoré et Sutenore (1.1 g, 2.1 mmol) Te a tiger heat mud francs (20 m L) and methanol

Was dissolved in a mixed solvent of (8.0 mL), water (8.0 mL) lithium hydroxide was dissolved in © arm 'monohydrate (134 mg, 3.2 mmol) and the mixture was stirred for 2 hours at room temperature. Reaction solution was concentrated under reduced pressure and, after addition of water (10 mL), dropwise with stirring 0.2 mol / L hydrochloric acid to adjust the pH value of the solution to about 5. The precipitated crystal was filtrated

, The title compound as colorless crystals was obtained in 93% (981 mg, 2.0 mmol).

- Flame (DMS0 - d 6) δ ( ppm): 8.83 (d, J = 8.7 Hz, 1H), 7.46-7.34 (m, 3H),

7.24 (t, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8. 0 Hz, 2H), 6. 90 (d, J = 8. 0 Hz , 2H), 6. 81 (t, J = 8. 0 Hz, IH), 4. 55 (dd, J = 5. 3 Hz, 8. 6Hz, IH), 3. 24 (s, 8H), 3 . 04 (dd, J = 5. 3 Hz, 14 Hz, IH), 2. 87 (dd, J = 8. 7 Hz, 14. 0 Hz, IH).

In the same manner as in Example 4 1, was synthesized Compound 4 2-5 0 and that of Example 4 2-5 0. Pro-ton nuclear magnetic resonance scan Bae click Torude data of the obtained compound are shown in Table 6.

Table 6

Compound determination

sc.

solvent

1.38- 1.73 (m, 4H), 2.80- 3.18 (m, 4H), 3.24 (s, 8H), 4.15-4.17 (m, 1H), 4,40-4.43 (m, 1H), 6.80 (t, J = 7.8 Hz, 2H), 6.91 (d, J = 7.8 Hz, 2H), 6.98 (d, J = 7.8 Hz,

42 clothes SO - d 6

2H), 7.12 (d, J = 7.8 Hz, 2H), 7.23 (t, J = 7.8 Hz, 2H), 7.60 (t, J = 7.2 Hz, 2H), 7.71 (t, J = 7.2 Hz, 2H) , 7.82 (d, J = 7.2 Hz, 2H), 8.01 (d, J = 7.9 Hz, IH)

2.86 (dd, J = 8.6 Hz, 14 Hz, IH), 3.05 (dd, J = 4.9 Hz, 14 Hz, 1H), 3.23 (s, 8H), 4.53 (dd, J = 4.9 Hz, 8.6 Hz, IH ), 6.80 (t, J = 7.6 Hz, IH), 6.89 (d, J = 8.6 Hz, 2H),

43 DMSO- d 6

6.99 (d, J = 7.6 Hz, 2H), 7.15 (d, J = 8.6 Hz, 2H), 7.24 (t, J = 7.6 Hz, 2H), 7.66 (s, 2H), 8.81 (d, J = 7.2 Hz, IH)

2.93 (dd, J = 9.6 Hz, 14 Hz, IH), 3.08 (dd, J = 4.6 Hz, 14 Hz, IH), 3.25 (s, 8H), 4.51 (m, IH), 6.80 (t, J = 7.6 Hz, IH), 6.92 (d, J = 8.6 Hz, 2H), 6.99 (d, J

DMSO- d 6

= 7.6 Hz, 2H), 7.15 (d, J = 8.6 Hz, 2H), 7.23 (m, 3H), 7.33 (t, J = 9.9 Hz, IH), 7.56 (ild, J = 9.9 Hz, 15 Hz, 1H), 8.44 (d, J = 11 Hz, IH)

2.40 (s, 3H) '2.62 ​​(dd, J = 7.6 Hz, 11 Hz, IH), 2.88-3.04 (m, 3H), 3.24 (s, 8H), 4.22 (d, J = 11 Hz, IH), 4.40 (dd, J = 7.7 Hz, 13 Hz, IH), 4.73 (d, J = 11 Hz, IH), 4.79 (m, 1H), 6.80 (t, J = 7.6 Hz, IH),

DMSO- d 6

6.90 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 7.6 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 7.23 (t, J = 7.6 Hz, 2H), 7.40 ( d, J = 8.2 Hz, 2H), 7.77 (d, J = 8.2 Hz, 2H), 8.08 (d, J = 7.7 Hz, IH)

1.71 1.79 (m, 1H), 2.02-2.39 (m, 3H), 2.78 (dd, J = 10 Hz, 14 Hz, IH), 3.06 (dd, J = 4.7 Hz, 14 Hz, IH), 3.22 (s , 8H), 3.33 (d, J = 15 Hz, IH), 3.90 (dd, J = 3.1 Hz, 8.7 Hz, IH), 4.51 (dt, J = 4.7 Hz, 10

DMSO- d 6

Hz, IH), 4.73 (d, J = 15 Hz, IH), 6.80 (t, J = 7.3 Hz, IH), 6.92 (d, J = 8.6 Hz, 2H), 7.00 (m, 4H), 7.10 ( d, J = 8.6 Hz, 2H), 7.20-7.33 (m, 5H), 8.44 (d, J = 8.2 Hz IH), 12.78 (brs, IH) 2.87 (dd, J = 8.2 Hz, 14 Hz, IH) , 2.98 (dd, J = 4.9 Hz, 14 Hz, IH), 3.26 (s, 8H), 3.67 (s, 6H), 4.51 (dd, J = 8.2 Hz, 14 Hz, IH), 6.63 (d, J =

DMSO - d 6 8.2 Hz, 2H), 6.80 (t, J = 7.4 Hz, IH), 6.93 (d, J

= 8.6 Hz, 2H) '6.99 (d, J = 7.4 Hz, 2H), 7.16 (d, J = 8.6 Hz, 2H), 7.25 (m, 3H), 8. 10 (d, J = 8.2 Hz, IH )

2.86 (dd, J = 9.4 Hz, 14 Hz, IH), 3.04 (dd, J = 4.9 Hz, 14 Hz, IH), 3.27 (s, 8H), 4.53 (m, 1H), 6.8 l (t, J = 7.6 Hz, IH), 6.93 (d, J = 8.6 Hz,

DMSO - d 6

2H), 7.01 (d, J = 7.6 Hz, 2H), 7. 14 (m, 4H), 7.24 (t, J = 7.6 Hz, 2H), 7.49 (m, IH), 9.06 (d, J = 7.9 Hz, IH)

2.85 (dd, J = 8.7 Hz, 14 Hz, 1H), 3.00 (dd, J = 5.4 Hz, 14 Hz, IH), 3.26 (s, 8H), 4.58 (dd, J = 8.1 Hz, 14 Hz, IH ), 6.81 (t, J = 7.6 Hz, IH),

CD Cla 6.92 (d, J = 8.7 Hz, 2H), 7.00 (d, J = 7.6 Hz,

2H), 7. 14 (d, J = 8.7 Hz, 2H), 7.24 (t, J = 7.6 Hz, 2H), 7.58- 7.71 (m, 3H), 9. 12 (d, J = 8.1 Hz, IH )

1.46- 1.65 (m, IH), 1.65 - 1.85 (m, 3H), 2.84- 3.01 (m, 2H), 3.24 (s, 8H), 3.30- 3.40 (m, 2H), 4.31 (d, J = 7.4 Hz, IH), 4.41 (dd, J = 7.3 Hz, 13 Hz, 1H), 6.79 (t, J = 7.6 Hz, IH), 6.91 (d, J = 8.6

DMSO - d 6

Hz, 2H), 6.98 (d, J = 7.6 Hz, 2H), 7.12 (d, J = 8.6 Hz, 2H), 7.22 (t, J = 7.6 Hz, 2H), 7.82 (d, J = 1.8 Hz, 2H), 8.00 (t, J = 1.8 Hz, IH), 8.16 (d, J = 8.1 Hz, IH), 12.77 (brs, III) example 5 1

Compound 5 1-3 3 8 were obtained in the following manner.

Preparation of Step 1 compound (Vile)

Wherein, R le is one C (= 0) R 9a (where R 9a is as defined above), (wherein, the R u has the same meaning as defined above) one S0 2 R u or a C (= 0) (wherein, R 1. has the same meaning as before SL) negation R ie represents a]

Te Torahi Dorofuran solution of compound e obtained in Reference Example 5 (0.100 raol / L, 0.500 mL, 0.050 mtnol) in, R 9a C (= 0) Cl ( wherein, R 9a is Ru as defined above der) , R 12 S0 2 C1 (wherein, R 12 is as defined above) or R 1Q NC (= 0) (wherein, R 10 has the same meaning as defined above) click throat Holm solution (1.000 mol / L, and 0.075 m, 0.075 mol) Oyopi Jie Sopuro Pinoreami Bruno methylpoly styrene - (Argonaut Corporation, about 3.72 ramol / g, 0.03 mg) and the mixture was stirred at room temperature for 12 hours and sealed. The reaction solution poly A Mi emissions (Novabiochem Corp., about 3 mraol / g, 33 mg) and Kurorohonoremu (0.20 mL) and the mixture was stirred at room temperature for 24 hours and sealed. The resin in the reaction mixture was filtered off, the solvent was distilled off. The resulting residue was dissolved in click every mouth Holm (0.70 nil), Benzoirukurori Doporima one bounce de (about 2.5 mmol / g, 33 mg) and poly (4 - Byurupiri Jin) (Al Dori pitch Co., 33 rag , 0. 31 mmol) was sealed and the mixture was stirred for 20 hours at room temperature. After filtration the resin, the filtrate concentrated to dryness to give Compound (Vile).

Preparation process 2 compounds (Vllle)

(Wherein, R le is as defined above)

The compound obtained in Step 1 (Vile), Torifuruoro acetate (0.25 mL, 3.24 mmol) and dichloromethane (0.25 ml) was added, followed by stirring at room temperature for 5 hours. After distilling off the solvent and Torifuruoro acetate, Jiokisan solution of hydrogen chloride (4 raol / L, 0.5 ml) and was Karoe.

The solvent was distilled off, the same operation again, to give the compound (Vllle).

Step 3 1 Preparation of Compound (Ve)

(Wherein, R le are as defined above, R 2e is selected Bareru group from group according to Table 2 above)

Compound obtained in Step 2 (Vllle) was dissolved in dimethylformamide § mi de (0.2 mL), N-Echiru _Ν '- (3 - Jimechirua Mi Nopuropiru) carboxamide diisopropyl Mi de of dimethylformamide A mi de solution (0.075 mL , 1 mol / L, 0.075 mol ), 1 over human Dorokishibenzo Application Benefits azole dimethylformamide § mi de solution (0.075 mL, 1 mol / L , 0.075 mol), and R 2e - C00H (wherein, R 2e is the dimethylformamidine de solution as synonymous) (0.075 mL, 1 mol / L, 0.075 mol) was added, sealed and stirred at room temperature for 12 hours. After distilling off the reaction solvent, an aqueous hydrochloric acid solution to give et the residue (1 mol / L, 0.20 mL) was added and extracted twice with black port Holm (0.50 mL). The organic layer was washed with saturated bicarbonate isocyanatomethyl Li um solution, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain of compound a (Ve). Incidentally, some of the compounds (Ve) are also those obtained by the following method.

Step 3 2 Compound alternative preparation of (Ve)

Compound obtained in Step 2 (Vllle) was dissolved in Te Torahi Dorofura emissions (0.50 mL), R 2e - C0C1 ( wherein, R 2e is as defined above) black port Holm solvent solution (1.0 mol / L, 0.075 mL, 0.075 mol) and di-isopropylidene Honoré amino methylation polystyrene (33 mg) and the mixture was stirred at room temperature for 12 hours and sealed. The reaction solution was added a Poriami emissions (33 mg) and clients every mouth Holm (0.20 mL) in and over 晚 stirred at room temperature tightly closed. The resin in the reaction mixture was filtered off, the solvent was distilled off. The resulting residue was dissolved in black port Holm (0.70 mL), sealed by adding Benzoi torque B Li Dopori Mabaun de (33 mg) and poly (4 Binirupiri Jin) (33 mg), and stirred over 晚 at room temperature . After filtration the resin, the filtrate concentrated to dryness to give compound (Ve).

Step 4

The compound obtained in Step 3-1 or 3-2 and (Ve) was dissolved in a mixed solvent of methanol (0.20 mL) and as tetrahydrofuran (0.10 ml), hydroxide lithium © anhydrous solution (1 mol / L, 0.20 mL ) and the mixture was stirred at room temperature for 4 hours. After distilling off the reaction solvent, aqueous hydrochloric acid to the resulting residue (1 mol / L, 0.20 mL) was added, chloroform (0.40 mL), to Kisafuruoroi Sopuro Piruarukonore (0.20 mL) and a mixed solvent of methanol (0.04 mL) in was extracted. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give compound 5 1-3 3 8 respectively.

Pro tons nuclear magnetic resonance scan Bae-vector data of representative compounds are shown below. Compound 1 4 0

- NMR (DMS0 - d 6) 8 (ppm): 8.01 (d, J = 7.9 Hz, 1H), 7.82-7.79 (m, 2H), 7.73-7.57 (m, 3H), 7.11 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 4.45-4.37 (m, 1H), 4.16-4.13 (m, 1H), 3.79 (brs, 2H), 3.58 (brs, 2H), 3.35 -3.30 (m, 2H), 3.15-2.85 (m, 6H), 2.05-1.95 (m, 1H), 1.65-1.38 (m, 4H), 0. 74-0.70 (m, 4H).

Compound 1 4 5

-删R (DMS0 - d 6) δ (ppm): 8.99 (d, J = 8.7 Hz, 1H), 7.46-7.34 (m, 3H), 7.15 (d, J = 8.6 Hz, 2H), 6.88 (d , J = 8.6 Hz, 2H), 4.64-4.56 (m, 1H), 3.80 (brs, 2H), 3.60 (brs, 2H), 3.15-3.00 (m, 5H), 2.84 (dd, J = 9.4 Hz, 14.0 Hz, 1H), 2.05- 1.97 (ra, 1H), 0.77-0.71 (m, 4H). compound 2 2 8

- Orchid (DMS0-d 6) δ ( ppm): 8.01 (d, J two 7.9 Hz, 1H), 7.82-7.79 ( ra, 2H), 7.73-7.57 (m, 3H), 7.11 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 4.44-4.36 (ra, 1H), 4.17-4.13 (m, 1H), 3.31-3.24 (m, 6H), 3.17-3.12 (m, 4H), 3.03-2.83 (m, 2H), 2.78 (s, 6H), 1.65-1.41 (m, 4H).

Compound 2 3 3

- NMR (CDC1 3) δ ( ppm): 8.01 (brs, 1H), 7.30-7.23 (m, 3H), 7.18 (d, J = 8. 4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 6.41 (d, J = 7.8 Hz, 1H), 5.18-5.09 (m, 1H), 3.40-3.37 (m, 4H), 3.27-3.10 (m, 6H), 2.85 (s, 6H).

Compound 3 0 7

7.9 Hz, 1H), 7.82-7.79 (m, 2H), 7.75-7.57 (m, 3H), 7.11 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 6.52 ( t, J = 5.3 Hz, 1H), 4.45-4.37 (m, 1H), 4.16-4.13 (m, 1H), 3.40-3.30 (m, 6H), 3.18-2.85 (m, 6H), 1.65-1.40 ( ra, 4H), 1.02 (t, J = 7.2 Hz, 3H).

Compound 3 1 2

- image R (DMSO - d 6) δ (ppm): 8.94 (d, J = 7.9 Hz, 1H), 7.45-7.35 (ra, 3H), 7.14 (d, J = 8.6 Hz, 2H), 6.87 (d , J = 8.6 Hz, 2H), 6.55 (t, J = 5.2 Hz, 1H), 4.62-4.54 (m, 1H), 3.42-3.38 (m, 4H), 3.10-3.00 (m, 7H), 2.84 ( dd, J = 9.0 Hz, 14.1 Hz, 1H), 1.02 (t, J = 7.2 Hz, 3H). in the same manner as in example 4 1, compound 3 3 9-3 7 9 3 8 1-3 8 5 was synthesized as in example 3 3 9-3 7 9 3 8 1-3 8 5. Pro tons nuclear magnetic resonance scan Bae-vector data of the obtained compound, are shown in Table 7 below. EXAMPLE 3 8 0: N - (4- force Norebokishi one 2, 6 - Axis B B base Nzoinore) - 4 - (4-dimethylcarbamoyl Roh-less zone Reho Nino lepidocrocite Bae Rajin one 1 - I / Les) - L-Hue Ninorearanin

Step 1

4 - (4 one dimethylsulfoxide Nino les piperazine one 1 - I le) one L- phenylene Honoré § La Nin methylate Honoré Este Honoré (175 mg, 0.492 mmol) and 2, 6 - Axis Rollo phenyl one 4 - (1, 3 - Jiokisan one 2 - I le) benzoic acid (186 mg, was dissolved 0.702 mmol) in dimethyl formamidine de (10 ml), N-Echiru one N '- (3- dimethyl § amino propyl) Karupojii Mi de (191 mg , 0.994 mmol), 1 over human Dorokishibenzo preparative Riazonore (154 mg, 1.00 mmol) and Toryechiruamin (0.140 ml, 1.00 mmol) and the mixture was stirred overnight at room temperature. Saturated bicarbonate isocyanatomethyl Li © anhydrous solution of acetic acid Echiru added to the reaction solution, and the organic layer was extracted twice, washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the resulting residue was purified by Shirikageruku chromatography (hexane / acetic acid Echiru = 1/1 to), N _ [2, 6 - dichloro 4 one (1, 3 - Jiokisan one 2 - Inore) Benzoinore] - 4 - (4-dimethylcarbamoyl Roh less Honoré Honi Honoré piperazine one 1 Inore) Single L one-phenylene Rua La Nin methyl ester 82% (254 mg, was obtained in 0.403 mmol).

- negation R (CDC1 3) δ (ppm ): 7.42 (s, 2H), 7.11 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 6.64-6.61 (m, 1H ), 5.42 (s, 1H), 5.13-5.05 (ra, 1H), 4.24 (dd, J = 4.9 Hz, 10.5 Hz, 2H), 3.96 (t, J = 12.2 Hz, 2H), 3.74 (s, 3H ), 3.39-3.35 (m, 4H), 3.19-3.16 (m, 6H), 2.86 (s,

6H), 2.24-2.10 (m, 2H).

Step 2

Compound obtained in Step 1 (254 mg, 0.403 mmol) was dissolved in § seton (10 mL), and stirred for 4 hours at room temperature was added a 6 mol / L hydrochloric acid (5 mL). 4 was neutralized by adding mol / L hydroxide isocyanatomethyl Li © anhydrous solution, a saturated sodium hydrogen isocyanatomethyl Li c anhydrous solution of acetic acid Echiru added, the organic layer was extracted twice, washed with saturated brine Kiyoshigo, anhydrous and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, N-(2, 6- dichloro 4 Honoreminore base Nzoinore) - 4 - (4 - dimethyl Chino less Honoré e Nino lepidocrocite Bae Rajin one 1 over I / LES) Single L- Fuenia Norearaninme Chiruesutenore a 76% (188 mg, 0.306 mmol) obtained in.

- NMR (CDC1 3) δ ( ppm): 9.91 (s, 1H), 7.78 (s, 2H), 7.10 (d, J = 8.6

Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 6.42 (d, J = 7.3 Hz, 1H), 5.18-5.07

(M, 1H), 3.77 (s, 3H), 3.39-3.35 (m, 4H), 3.20-3.16 (ra, 6H), 2.85

(S, 6H).

Step 3

Compound obtained in Step 2 (188 rag, 0.306 mmol) was dissolved in methanol (5 raL), hydroxide force Li © beam (52 ​​mg, 0.918 mmol) and iodine (58 mg, 0.459 mmol) at room temperature was added a and the mixture was stirred for 2 hours. Chloride Anmoniumu aqueous solution and acetic acid E chill added, the organic layer was extracted twice, washed with saturated brine and dried over anhydrous sulfate Ma Guneshiumu. After filtration, the filtrate was concentrated under reduced pressure, N-(2, 6 - dichloro b _ 4-menu Tokishikanorepo two Norebe Nzoinore) Single 4 one (4 Jimechinore sulfo Nino les piperazine one 1 Inore) Single Mr - Hue Nino Rare la ene the main Chinoree Sutenore 60 ο / ο (114 mg, 0.216 mmol) obtained in.

8.6 Hz, 2H), 6.83 (d, J = 8.9 Hz, 2H), 6.41-6.39 (m, 1H), 5.17-5.10 (ra, 1H), 3.94 (s, 3H), 3.76 (s, 3H), 3.39-3.35 (ra, 4H), 3.20-3.16 (m, 6H), 2.86 (s, 6H).

Step 4

The compound obtained in Step 3 (7δ.7 mg, 0.119 mmol) was dissolved in a mixed solvent of a Te Torahi Dorofura emissions (5 mL) and water (3 ml), lithium monohydrate (51.0 mg hydroxide, 1.22 mmol) was added and the mixture was stirred for 5 hours at room temperature. After a l mol / L hydrochloric acid Caro e solution acidic, acetate Echiru was added and the organic layer was extracted twice, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, N_ (4 Ichiriki Norepokishi one 2, 6-dichloro b base Nzoinore) Single 4 one (4 one Jimechinore Sunorehoninorepi Bae Rajin one 1 - Inore) Single L one Hue Nino les alanine 67% (49.6 mg, 0.0865 mmol) was obtained.

-讀(CD 3 0D) δ (ppm ): 7.90 (s, 2H), 7.20 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 7.6 Hz, 2H), 4.80-4.74 (m, 1H .), 3.35-3.34 (m, 4H), 3.16-3.15 (m, 4H), 2.99-2.73 (m, "211), 2.85 (s, 6H) example 3 8 6: N - (2, 6 Jiku mouth opening base Nzoiru) - 3 - two Toro one 4 - (4 one Hue Nino Levi prochlorperazine one 1 Inore) one L- Hue Nino-les-alanine E Chino Les Este Norre

Step 1

Compound f (5.59 g, 10.0 mmol) obtained in Reference Example 6 in 1 - phenylene ruby ​​Perazine (8.1 g, 50 mmol) was added and over 晚攪 stirred at room temperature. Papermaking seminal The reaction night Shi Li force gel strength Ramuku chromatography (hexane / acetic acid Echiru = 2/1 to), a yellow solid N-(2, 6 - Axis B port base Nzoiru) over 3 two Toro one 4 was obtained in one (4 monounsaturated Eni Bruno Levi prochlorperazine one 1 over I Honoré) 100% of an L- full Eninorearani Ne Chino Les Este Honoré (5.71 g, 10.0 mmol).

Step 2

Obtained in Step 1 N-(2, 6- dichlorobenzoyl every mouth base Nzoiru) - 3 - Two filtrated over 4 one (4 one Hue Nino Levi prochlorperazine one 1 Inore) - L-Fueninoreara nin E Chino les Este Honoré (100 mg, 0.180 mmol) was dissolved in a mixed solvent of Metanonore (1 mL) and Te preparative La arsenide Dorofuran (1 mL), 5% lithium hydroxide aqueous solution (1 mL) was added and stirred at room temperature for 1 hour . The reaction mixture was neutralized with 2 mol / mL hydrochloric acid, the solvent was distilled off, it was collected by filtration the resulting solid was obtained in the title of compound as a yellow solid 92% (90 mg, 0.166 mmol). In the same manner as in Example 3 8 6, to synthesize a compound 3 8 7-3 9 1 and Example 3 8 7-3 9 1. Pro ton nuclear magnetic resonance space-vector data of the obtained compound are shown in Table 7 below. Example 3 9 2: 3 - amino-N-(2, 6- Axis B port base Nzoiru) one 4 - (4 one Hue Nino les piperazine one 1 - Inore) Single L- Hue Nino les alanine Step 1

EXAMPLE 3 8 Step 1 in the resulting N- 6 (2, 6-dichloro port base Nzoi Honoré) Single 3 - Two filtrated one 4 one (4 one Hue Nino Levi prochlorperazine one 1 - Inore) Single L one phenylene Rua La Nin E chill ester (3.00 g, 5.25 mmol) was dissolved in a mixed solvent of concentrated hydrochloric acid (10 mL) and methanol (40 mL), and zinc (3.00 g, 46.2 mmol) was added at room temperature and stirred for 1 hour did. Ammonia water was added to the reaction solution, followed by extraction with click every mouth Holm, the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica force gel strength Ramukuroma preparative chromatography (hexane / acetate Echiru = 2/1), a white solid .3 - amino No N-(2, 6- dichloro port base Nzoinore) Single 4 one (4 Hue Nino les piperazine one 1 one I Le) 85% of an L- Hue Nino les alanine E Chino Les Este Honoré (2.41 g, obtained in 4.45 mmol).

Step 2

Step obtained in 1 3-Amino _ N- (2, 6- dichlorobenzoyl every mouth base Nzoiru) - 4 - (4 one Hue Nino les piperazine one 1 - Inore) Single L one Fueninorearani Nechiruesuteru (100 mg, 0. 180 mmol ) was dissolved in methanol mixed solvent one Honoré (1 Ral) and Te tiger arsenide Dorofuran (1 mL), was added a 5% aqueous lithium hydroxide solution (1 mL), and stirred at room temperature for 1 hour. The reaction mixture was neutralized with 2 mol / tiiL hydrochloride, the solvent was distilled off, it was collected by filtration resulting solid, the title compound as a white solid 89% (85 mg, 0.166 mmol) obtained in.

In the same manner as in Example 3 9 2, to synthesize a compound 3 9 3-3 9 5 in Example 3 9 3 to 3 9 5. Pro ton nuclear magnetic resonance space-vector data of the obtained compound are shown in Table 7 below. Example 3 9 6: 3- bromo-N-(2, 6- Axis B port base Nzoiru) one 4 - (4 one Hue Nino Levi prochlorperazine one 1 Inore) Single L one Hue Nino rare la ene Step 1

Example 3 9 obtained in 2 steps 1 3 amino No N-(2, 6- Axis B B base Nzoinore) - 4 - (4 - Fueninorepipera gin one 1 Inore) - L

- was dissolved in a mixed solvent of Fe two / Les alanine E Chino Les Este Honoré (271 mg, 0.500 mmol) '48% Nioii 匕水 Motomi (1 mL) and ethanol (3 mL), - at 10 ° C nitrite tert Buchinore (62 mg, 0.600 mraol) was added to the Etanonore (1 mL) of was also this 溶角 Army, the temperature was raised to 0 ° C, copper bromide (I) (143 mg, 1.00 ramol) and the mixture was stirred for 2 hours at room temperature. The reaction solution of 28% ammonia water was added and extracted with click Loloho Lum, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off and the resulting residue was purified by silica force gel column chroma Togurafi one (the key San / acetic Echiru = 4/1), the white solid 3 - bromo one N-(2, 6 - Axis B mouth base Nzoinore) Single 4 i (4 - Hue Nino les piperazine one 1 - I le) one L- Hue Nino les alanine E Chino Les ester 93% (280 mg, was obtained in 0.463 mmol).

Step 2

Obtained in Step 1 3 - promoter N-(2, 6- Axis B port base Nzoinore) - 4 - (4 - Hue Nino Levi prochlorperazine one 1 Inore) Single L- Fueninorearani Ne Chino Les Este Honoré (180 mg, 0.298 mmol) was dissolved in a mixed solvent of the main Tano one Honoré (2 mL) and Te bets la arsenide Dorofura emissions (2 mL), 5% hydroxide lithium. anhydrous solution (1 mL) was added stirring 1 hour at room temperature did. The reaction mixture was neutralized with 2 mol / mL hydrochloric acid, the solvent was distilled off, it was collected by filtration resulting solid, the title compound as a white solid 84% (145 mg, 0.251 mmol) obtained in.

In the same manner as in Example 3 9 6, to synthesize a compound 3 9 7-3 9 9 with Example 3 9 7-3 9 9. Pro ton nuclear magnetic resonance space-vector data of the obtained compound are shown in Table 7 below. Example 4 0 0: N - (2, 6 - Axis B B base Nzoinore) - 4 - (4 one Hue Ninorebiperajin one 1 Inore) - 3 - (pyrrol one Norre one 1- Inore) Single L one Hue Ninorearanin

Step 1

Example 3 9 2 steps 1 obtained in 3 - amino No N-(2, 6 - Axis B B base Nzoinore) - 4 - (4 - Hue Nino Levi prochlorperazine one 1 - Inore) - L one Feninore alanine E Chino Les Este Honoré (271 mg, 0.500 mraol) was dissolved in acetic acid (1 mL), 2, 5- dimethyl Tokishite Torahi Dorofuran (0.0600 mL, 0.922 ramol) was stirred for 1 hour at the mixture 60 ° C. Acetic acid Echiru added to the reaction solution, washed with saturated sodium hydrogen na Application Benefits © anhydrous solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica Kagerukaramuku Roma Togura fee (hexane / acetate Echiru = 2/1 to), the white solid N-(2, 6 Jiku port mouth base Nzoinore) one 4 - ( 4 monounsaturated Eni Norre piperazine _ 1 Inore) - 3 - (pyro one Norre one 1-I Norre) one l- off Eninorearayu Ne Chino Les Este Norre a 58% (127 mg, was obtained in 0.245 mmol).

Step 2

Obtained in Step 1 N-(2, 6 - Axis B port base Nzoinore) - 4 - (4 - Hue Nino les piperazine one 1 Inore) Single 3 - (pyrrol one Norre one 1 unique thread) Single L - phenylene Rua La Nin E chill Este Honoré (127 mg, 0.245 mmol) was dissolved in a mixed solvent of methanol (1 nil) and Te Torahi Dorofuran (1 mL), 5% hydroxide of lithium solution (1 mL) was added at room temperature in the mixture was stirred for 2 hours. The reaction mixture was neutralized with 2 mol / L hydrochloric acid, the solvent was distilled off, it was collected by filtration the resulting solid to give a white solid material the title compound in 78% (108 mg, 0. 192 mmol). Example 4 0 1: 3 - Asechinorea mi Roh one N-(2, 6 - Axis B B base emission zone Isure) - 4 - (3, 3 one Jimechinore one 4 - Hue Nino Levi prochlorperazine one 1 - I le) one L one Hue Nino-les-alanine

Step 1

Example 3 9 3, compound 3 9 3 intermediate with the obtained 3 - § Mi Bruno

- N - (2, 6 - dichloro b base Nzoinore) Single 4 one (3, 3-Jimechinore

4 one full et Nino les piperazine one 1 unique thread) - L-full et Ninorearani Nechinore ester (496 mg, 1.0 mmol) and N, N-diisopropyl Piruechiruami emissions (516 mg, 4.0 mmol) the black port Holm (10 mL) was dissolved in acetic anhydride (306 mg, 3.0 ramol) was added at room temperature and over 晚攪 拌. The reaction mixture was concentrated and one 晚攪 拌 added E ethanol (4 mL) and 4 mol / L hydrochloric acid Jiokisan solution (4 mL). After the added neutralizing the reaction solution to 28% ammonia water, and extracted twice with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off and the resulting residue was purified by a silica gel column chroma preparative chromatography (Black. Neck Holm / methanol = 50/1), the white solid 3- Asechiruami Roh one N-(2, 6 - Axis b port base Nzoinore) 4 - (3, 3 - Jimechinore

4 - off Est - Norepi Bae Rajin one 1 over I Honoré) Single L monounsaturated Eninorearani Nechinore ester 95% (418 mg, was obtained in 0.95 mmol).

Step 2

Step 1 obtained in 3 - Asechinorea mi node on N-(2, 6 - Axis B port base Nzoiru) one 4 - (3, 3 - Jimechinore 4 one Hue Nino les piperazine one 1 - I le) one L- phenylene Rua la Ri nin E chill Este Honoré, the title compound was obtained by a similar manner to step 2 of example 4 1 method. In the same manner as in Example 4 0 1 to form if the compound 4 0 2 and Example 4 0 2. Pro tons nuclear magnetic resonance scan Bae-vector data of the obtained compound are shown in Table 7 below. Example 4 0 3: N - (2, 6 - Axis B port base Nzoiru) Single 3 - dimethyl § Mi Bruno one 4 - (3, 3 - dimethyl Chiru 4 - Hue Nino Levi prochlorperazine one 1 over I Honoré) Single L- Hue Nino rare La ene

Example 3 9 3, compound 3 9 3 intermediate and to the obtained 3 § Mi Bruno - N-(2, 6 - Axis B B base Nzoinore) - 4 - (3, 3 - Jimechinore 4 one Hue Nino Les piperazine one 1 Inore) Single L one Hue Nino les alanine E Chino Les Esutenore (500 mg, 0.879 mmol), 37 ο / 0 phosphono Rem § Roh Rede arsenide de water ί night (1 mL, 12.3 mmol) and acetic acid (1 the mL) was dissolved in § Se Tonito Lil (10 mL), under ice-cooling Toriase butoxy borohydride Na Application Benefits © beam (746 mg, 3.52 mmol) and the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated, the resulting residue acetic acid Echiru added to and washed with saturated sodium hydrogen isocyanatomethyl Li © beam solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off. The resulting residue were added and dissolved in methanol (4 mL) and Te Torahi Dorofuran (4 mL), was added 5% aqueous lithium hydroxide solution (4 mL), and stirred at room temperature for 4 hours. The reaction mixture was neutralized with concentrated hydrochloric acid, the solvent was distilled off, it was collected by filtration and the precipitate produced by adding water to the resulting residue, the title compound as a white solid 28% (142 mg, 0.250 mmol) obtained in . In the same manner as in Example 4 0 3 and forms if the compound 4 0 4 Example 4 0 4. Pro ton nuclear magnetic resonance scan Bae-vector data of the obtained compound,

• shown in Table 7 below. Example 4 0 5: 3-click Rollo over N-[2, 6- Axis Rollo over 4- (Te Torazo Honoré one 5- Inore) Benzoinore] - 4 _ [4 - (3, 5-Axis Rorofue two Honoré) piperidines Rajin - 1-Inore] one l one Hue Nino-les-alanine

Step 1

N-(2, 6- dichloro - 4 one Shianobenzoiru) Single 4- (4 one Application Benefits Funoreoro polypropylfumerate chest Honoré Honi Honoré) Single 3 twelve preparative port one L monounsaturated Eninorearanin E Chino Les Este Honoré (518 mg, 0.887 mmol ) and N- (2, 6 - dichloro Rofue sulfonyl) piperidines Rajin (504 mg, a 2.18 mmol) was dissolved in Jikurorome Tan (5 ml), collected by Ryechiruami emissions (0.150 ral, 1.07 mmol) was added, followed at room temperature final night and the mixture was stirred. Water and acetic acid Echiru was added to the reaction solution, the organic layer out 2 Kai抽, washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the resulting residue was purified by silica force Geruku Kuchma preparative chromatography (hexane / acetate Echiru = 3/1), N- (2, 6- Axis B port one 4- Xia Bruno benzo I Honoré) - 4 - [4 - (3, 5-Axis b port phenylene Honoré) piperazinyl Rajin one 1 Inore] - 3 twelve filtrated one L one Hue Nino les alanine E Chino les S. Tenore 72 0 / 0 (423 mg, 0.636 mraol ) was obtained in.

- negation R (CDC1 3) δ (ppm ): 7.68 (s, 1H), 7.63 (s, 2H), 7.42 (d, J = 8. 1 Hz, 1H), 7.25 (s, 1H), 7. 13 (d, J = 8.4 Hz, 1H), 6.85 (s, 2H), 6.43 (d, J = 7.2 Hz, 1H), 5. 15-5.09 (ra, 1H), 4.27 (q, J = 7.2 Hz, 2H), 3.37-3.35 (m, 4H), 3.33-3.26 (m, 2H), 3.23-3. 19 (m, 4H), 1.32 (t, J = 7.2 Hz, 3H).

Step 2

Compound obtained in Step 1 (423 tng, 0.636 mmol) was dissolved in methanol (5 ml), concentrated hydrochloric acid (1 ml) and zinc / copper powder (426 mg) was added, then stirred at room temperature for 2 hours. Under ice-cooling, nitrite Na door Li Umm to the reaction solution (65.6 rag,

0.951 mmol) and the mixture was stirred for 2 hours at room temperature. To the reaction solution, copper (I) chloride

(131 mg, 1.33 mmol) and copper chloride (Π) (160 mg, 1. 19 mmol) was added, and after stirring for 2 hours al, an aqueous ammonia solution and acetic acid Echiru added, the organic layer was extracted twice, saturated It washed 3 times with brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the resulting residue was purified by silica gel chroma preparative chromatography (hexane / acetate Echiru = 2/1), 3 - chloro over N-(2, 6- dichloro - 4 one Xia Nobenzoinore) Single 4 _ [4 - (3, 5 Jikurorofue two Honoré) piperidines Rajin one 1- Inore] - l-Fueyuanoreara nin E Chino Les ester 29% (119 mg, was obtained in 0.182 mmol).

'H-NMRCCDClj) δ (ppm): 7.60 (s, 2H), 7.14-7.07 (m, 2H), 6.97 (d, J = 8.1 Hz, 1H), 6.83 (s, 1H), 6.79 (s, 2H ), 6.37 (d, J = 7.8 Hz, 1H), 5.15-5.06 (m, 1H), 4.11 (q, J = 7.3 Hz, 2H), 3.40-3. 12 (m, 10H), 1.26 (t, J = 7.0 Hz, 3H).

Step 3

Compound obtained in Step 2 (119 rag, 0.182 mmol) was dissolved in dimethylformamide completion mi de (5 ral), azide Na tri um (59 mg, 0.908 ramol) and § chloride Nmoyuumu (50.9 mg, 0.952 mmol ), and the mixture was 8 hours stirred at subsequent 1 0 0 ° C. The reaction solution was allowed to cool, was acidified by adding 1 niol / L hydrochloric acid, acetic E chill was added and the organic layer was extracted twice, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the resulting residue was purified by silica dim chromatography (viii b port Holm / methanol = 8/2), 3 - click B port one N - (2, 6 - Axis b b one 4-Te preparative La sledding Honoré benzo i le) one 4- [4 - (3, 5 - Axis b port phenylene Honoré) piperazine one 1 - Lee thread] an L one Fueninorearani Ne chill Este Honoré 29 It was obtained in% (127 mg, 0. 182 mmol).

Step 4 '

The compound obtained in Step 3 (127 mg, 0.182 mmol) was dissolved in a mixed solvent of a Te Torahi Dorofura emissions (5 ml) and water (3 ml), lithium hydroxide monohydrate (61.0 rag, 1.45 nrnol ) and the mixture was stirred at room temperature for 7 hours. The reaction solution was concentrated, the resulting residue of acetic acid was added, was collected by filtration and the resulting crystals of the title compound 81% (98.4 rag, 0.147 ramol) was obtained in.

NMR (DMS0- d 6) δ ( ppm): 9.20-9.14 (m, 1H), 8.03 (s, 2H), 7.28-7.12

(M, 2H), 7.00 (s, 2H), 6.92 (d, J = 8.6 Hz, 1H), 6.89 (s, 1H), 4.75-4.65 (m, 1H), 3.24-3.20 (m, 4H), 3.14-2.84 (m, 2H), 3.07-3.02 (m, 4H) example 4 0 6:. N- (2, 6- dichloro port base Nzoinore) - 4 - (3, 3 - Jimechinore 2- Okiso one 4 one Hue Nino les piperazine one 1 - I le) one L- Hue Nino les alanine.

Ri by the same method as in Example 4 1, was obtained target title compound from the compound g obtained in Reference Example 7. Pro tons nuclear magnetic resonance scan Bae click Torude chromatography data of the obtained compound are shown in Table 8 below.

In the same manner as in Example 4 0 6, the synthesized of compounds in accordance with the method of Reference Example 7, the I 匕合 product 4 0 7-4 2 4 Example 4 0 7-4 2 4 synthesized. Pro ton nuclear magnetic resonance scan Bae-vector data of the obtained compound are shown in Table 8 below.

Table 7

Compound ^ -NMR δ (ppm):

Measurement solvent

W ¾

7.89 (d, J = 7.2 Hz, 1H), 7.71-7.25 (m,

339 CDCls 14H), 4.86-4.76 (m, 1H), 3.97-3.67 (m,

8H), 2.42-2.12 (m, 4H), 1.86-1.44 (m, 4H).

7.83-7.23 (m, 14H), 7.09 (d, J = 6.5 Hz,

1H), 4.86 (m, 1H), 4.14-3.74 (m, 8H),

340 CDCls

3.35-3.28 (m, 2H), 3.03 (s, 3H), 2.37 2.32 (m, 2H), 1.75-1.44 (m, 6H).

8.32 (d, J = 6.9 Hz, 1H), 7.69 (d, J = 6.8

Hz, 2H), 7.58 (d, J = 6.8 Hz, 1H),

7.44-7.15 (m, 11H), 4.73 (m, 1H),

341 CDCls

3.76-3.60 (m, 8H), 3.21 (dd, J = 4.9, 12.7

Hz, 1H), 3.11 (dd, J = 6.2, 12.7 Hz, 1H),

1.85-1.53 ​​(m, 4H). 7.37 (d, J = 7.3 Hz, 2H), 7.29 (t, J = 7.6 Hz, IH), 7.14-6.94 (m, 11H), 4.42 (m, 1H), 3.29 (m, 8H), 2.91 (dd, J = 5.1, 14.0

342 CDCls

Hz, IH), 2.81 (dd, J = 7.0, 14.0 Hz, 1H), 1.79-1.52 (m, 4H), 0.67 (t, J = 7.3 Hz, 3H), 0.58 (t, J = 7.3 Hz, 3H ).

7.85 (d, J = 7.2 Hz, IH), 7.58-7.00 (m, 14H), 4.81-4.75 (m, 1H), 3.46-3.33 (m,

343 CDCls 10H), 3.30 (dd, J = 4.2, 13.8 Hz, IH),

3.13 (dd, J = 6.9, 13.8 Hz, IH), 2.30-1.48 (m, 4H), 1.57 (s, 3H).

7.80 (d, J = 7.2 Hz, 1H), 7.66-7.24 (m, 14H), 4.94-4.91 (m, IH), 4.61 (d, J = 9.3

344 CDCls Hz, 1 * H), 4.29 (d, J = 9.3 Hz, IH),

4.37-3.71 (m, 8H), 3.26-3.18 (m, 2H), 1.21 (s, 3H), 1.00 (s, 3H).

7.06-6.63 (m, 11H), 6.60 (t, J = 7.3 Hz, IH), 6.45 (d, J = 7.8 Hz, IH), 4.46 (d, J = 6.5 Hz, IH), 4.28 (d, J = 4.9 Hz, IH), 4.18

345 CDCla (s, 2H), 3.12 (m, 8H), 2.86 (dd, J = 4.9,

13.8 Hz, 1H), 2.70 (dd, J = 5.7, 13.8 Hz, 1H), 1.97 (s, 3H), 1.38-1.24 (m, 3H), 0.57 (s, 3H), 0.56 (s, 3H).

■ in- 7.30 (t, J = 8.1 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 8.1 Hz, 2H),

6.96-6.91 (m, 3H), 6.62 (d, J = 7.8 Hz, IH), 4.82-4.80 (m, IH), 3.41 3.33 (m,

346 CDCls

12H), 3.11 (dd, J = 5.1, 14.1 Hz, 1H), 2.93 (dd, J = 8.4, 14.1 Hz, 1H), 1.96- 1.71 (m, 8H), 0.74 (t, J = 7.5 Hz, 3H ), 0.62 (t, J = 7.5 Hz, 3H).

7.38-7.03 (m, 9H), 6.67 (d, J = 7.8 Hz, IH), 4.89-4.59 (m, 4H), 3.46 (m, 8H), 3.18

347 CDCls (dd, J = 4.9, 13.5 Hz, IH), 3.06 (dd, J =

8.4, 13.5 Hz, 1H), 2.03 (s, 3H), 1.51 (s, 3H), 1.18 (s, 3H).

7.27 (t, J = 7.6 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H),

6.92-6.87 (m, 3H), 6.47 (d, J = 6.8 Hz,

348 CDCls IH), 4.81 (m, 1H), 4.59 (s, 2H), 4.09 (s,

IH), 3.65 (s, 3H), 3.30 3.28 (m, 8H), 3.16-3.03 (m, 2H), 1.48 (s, 3H), 1.17 (s, 3H).

7.30-7.06 (m, 8H), 6.89 (t, J = 7.2 Hz, 2H), 4.63-4.50 (m, 4H), 3.53-3.45 (m, 8H),

349 CDCla 3.15-3.12 (m, 2H), 2.87 (t, J = 10.8 Hz,

IH), 1.62 (s, 3H), 1.29 (s, 3H), 1.15 (s, 3H), 1.02 (s, 3H). 8.98 (d, J = 5.9 Hz, IH), 7.27-6.99 (m, 8H ), 6.83 (t, J = 6.5 Hz, 1H), 4.48 (m, IH), 4.37 (d, J = 8.9 Hz, 1H), 4.31 (d, J =

350 DMSO-de

8.9 Hz, IH), 3.52 (m, 8H), 3.02 (dd, J = 4.6, 12.7 Hz, 1H), 2.92 (dd, J = 7.6, 12.7 Hz, IH), 1.61 (s, 3H), 1.27 ( s, 3H).

7.92 (d, J = 7.5 Hz, IH), 7.20 (d, J = 7.2 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 6.87 ( d, J = 8.4 Hz, 2H), 6.77 (t, J = 8.4 Hz, IH), 4.69 (d, J = 9.0

351 DMSO-de Hz, IH), 4.52 (d, J = 9.0 Hz, IH), 4.33

(M, IH), 3.22 (m, 8H), 2.93 (dd, J = 5.4, 13.8 Hz, 1H), 2.82 (dd, J = 8.1, 13.8 Hz, IH), 2.69 (s, 6H), 1.43 ( s, 3H), 1.24 (s, 3H).

7.66 (d, J = 6.6 Hz, IH), 7.08-6.83 (m, 9H), 5.23 (d, J = 15.0 Hz, 1H), 4.88 (d, J = 15.0 Hz, IH), 4.59-4.50 (m , IH),

352 CDCla

4.44-4.30 (m, 1H), 3.42-3.31 (m, 8H), 2.95-2.82 (m, 2H), 1.29 (s, 3H), 0.97 (s, 3H).

7.39-7.00 (m, 9H), 4.85-4.73 (m, 1H), 4.64 (s, 2H), 4.13 (s, IH), 3.48 (m, 8H),

353 CDCla

3.18-3.08 (m, 2H), 2.20 (s, 3H), 1.55 (s, 3H), 1.31 (s, 3H). 03

7.54 (t, J = 8.4 Hz, 2H), 7.39 (t, J = 8.1 Hz, 2H), 7.30 (d, J = 7.8 Hz, 2H), 7.2 1 (d, J = 6.8 Hz, 2H), 7.11 (t, J = 7.0 Hz, IH),

354 DMSO-de 5.14-5.09 (m, 1H), 5.06 5.00 (m, 1H), 4.77

(D, J = 9.5 Hz, IH), 4.69 (m, IH), 4.54 (d, J = 9.5 Hz, 1H), 3.65-3.44 (m, 8H), 3.36 (s, 3H), 3.32 -3.06 ( m, 2H).

7.98 (t, J = 1.9 Hz, 1H), 7.79 (d, J = 1.9 Hz, 2H), 7.22 (t, J = 7.3 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 6.98 ( d, J = 8. 1 Hz, 2H), 6.87 (d, J = 8. 1 Hz, 2H), 6.79 (t, J = 7.3

355 DMSO-de

Hz, IH), 4.28 -4.25 (m, IH), 4.03 (s, 2H), 3.50-3.21 (m, 10H), 3.04 (dd, J = 5.1, 13.5 Hz, 1H), 2.96 (dd, J = 7.0, 13.5 Hz, 1H), 1.60 (d, J = 6.2 Hz, 2H).

8.22 (m, IH), 7.95 (s, 1H), 7.79 (s, 2H), 7.22 (t, J = 7.8 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.1 Hz, 2H), 6.79 (t,

356 DMSO-de

J = 7.3 Hz, IH), 4.36 -4.28 (m, 2H), 4.16 (m, 1H), 3.36-3.23 (m, 10H), 2.99 -2.85 (m, 2H), 1.88 - 1.80 (m, 2H) .

9.23 (d, J = 8.1 Hz, IH), 8.64 (s, 2H),

7.24 (t, J = 8.4 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 7.8 Hz, 2H), 6.93 (d,

357 DMSO-de

J = 8.6 Hz, 2H), 6.81 (t, J = 7.3 Hz, 1H), 4.70-4.62 (m, IH), 3.33 3.24 (m, 8H), 3.11-2.80 (m, 2H). -9ΐτ-

N 6 Meng Odf / IDd 0 680 / C0 ΟΛ \ 7.88 (s, 2H), 7.72-7.65 (m, IH), 7.26 7.20 (m, 2H), 7.13 (d, J = 8.6 Hz, 2H), 6.98 ( d, J = 8.1 Hz, 2H), 6.84-6.77 (m, 3H),

362 DMSO-de

4.46-4.38 (m, IH), 3.28-3.20 (m, 8H), 3.06 (dd, J = 5.3, 14.0 Hz, IH), 2.90 (dd, J = 9.2, 14.0 Hz, IH).

9.13 (d, J = 7.4 Hz, IH), 7.82 (s, 2H), 7.29-7.21 (m, 2H), 7.15 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 8.1 Hz, 2H ), 6.94 (d, J =

363 DMSO-de 8.6 Hz, 2H), 6.80 (t, J = 7.3 Hz, IH),

4.69-4.59 (m, IH), 3.25 3.15 (m, 8H), 3.05 (dd, J = 5.3, 14.0 Hz, IH), 2.85 (dd, J = 9.2, 14.0 Hz, IH).

9.01 (d, J - 7.4 Hz, IH), 8.18 (s, IH), 7.87 (s, 2H), 7.70 (s, 1H), 7.26-7.14 (m, 4H), 6.99 (d, J = 8.1 Hz, 2H), 6.91 (d, J =

364 DMSO-de 8.6 Hz, 2H), 6.81 (t, J = 7.3 Hz, 1H),

4.64-4.56 (m, IH), 3.40-3.20 (m, 8H), 3.06 (dd, J = 5.3, 14.0 Hz, 1H), 2.86 (dd, J = 9.2, 14.0 Hz, IH).

9.05 (d, J = 7.4 Hz, IH), 7.81 (s, 2H), 7.52 (d, J = 15.7 Hz, IH), 7.28-7.21 (m, 4H), 7.05-6.97 (m, 4H), 6.85 (t, J = 7.3

365 DMSO-de Hz, IH), 6.70 (d, J = 15.7 Hz, IH), 4.92

(Brs, IH), 4.70-4.60 (m, 1H), 3.31 (s, 8H),

3.06 (dd, J = 5.3, 14.0 Hz, IH), 2.85 (dd, J = 9.2, 14.0 Hz, IH). W

9.16 (d, J = 7.4 Hz, IH), 8.03 (s, 2H), 7.26-7.15 (m, 4H), 7.00-6.94 (m, 4H), 6.80

366 DMSO-de (t, J two 7.3 Hz, 1H), 4.69-4.61 (m, IH),

3.25 (s, 8H), 3.06 (dd, J = 5.3, 14.0 Hz, IH), 2.85 (dd, J = 9.2, 14.0 Hz, IH).

9.18 (d, J = 7.4 Hz, IH), 7.81 (s, 2H), 7.26-7.14 (m, 4H), 6.98 (d, J = 8.1 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H ), 6.80 (t, J =

367 DMSO-de

7.3 Hz, 1H), 4.68-4.60 (m, IH), 3.35 3.24 (m, 8H), 3.06 (dd, J = 5.3, 14.0 Hz, IH), 2.85 (dd, J = 9.2, 14.0 Hz, IH) .

9.16 (d, J two 7.4 Hz, IH), 7.93 (s, 2H), 7.26-7.14 (m, 4H), 6.98 (d, J = 8.1 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H ), 6.81 (t, J =

368 DMSO-de

7.3 Hz, 1H), 4.70-4.60 (m, 1H), 3.35-3.25 (m, 8H), 3.06 (dd, J = 5.3, 14.0 Hz, IH), 2.85 (dd, J = 9.2, 14.0 Hz, IH ).

8.70 (d, J = 7.7 Hz, 1H), 7.25-7.12 (m, 4H), 6.98 (d, J = 8.1 Hz, 2H), 6.88 (d, J two 8.4 Hz, 2H), 6.81 (t, J = 7.3 Hz, 1H), 6.77

369 DMSO-de

(S, 2H), 4.57-4.49 (m, IH), 3.26-3.20 (m, 8H), 3.00 (dd, J = 5.3, 14.0 Hz, IH), 2.84 (dd, J = 9.2, 14.0 Hz, IH ).

8.83 (d, J = 7.4 Hz, 1H), 7.81 (s, 2H),

7.26-7.13 (m, 4H), 7.00-6.88 (m, 4H), 6.92 (s, 1H), 6.79 (t, J = 7.3 Hz, IH), 4.60 4.50

370 DMSO-de

(M, 1H), 4.52 (s, 2H), 3.26-3.20 (m, 8H), 3.02 (dd, J = 5.3, 14.0 Hz, 1H), 2.84 (dd, J = 9.2, 14.0 Hz, IH). 8.58 (d, J = 7.7 Hz, IH), 7.25-7.13 (m, 4H), 7.08 (s, 2H), 6.98 (d, J = 8.1 Hz,

371 DMSO-de 2H), 6.87 (d, J = 8.6 Hz, 2H), 6.79 (t, J =

7.3 Hz, IH), 4.53-4.45 (m, IH), 3.26 3.20 (m, 8H), 3.06-2.82 (m, 2H), 2.98 (s, 3H).

8.92 (d, J = 8.3 Hz, IH), 7.81 (d, J = 8.2 Hz, 2H), 7.68-7.58 (m, 3H), 7.25-7.20 (m, 2H), 7.10 (d, J = 8.4 Hz , 2H), 7.05 (s, 2H), 6.98 (d, J = 8.1 Hz, 2H), 6.87 (d, J =

372 DMSO-de

8.6 Hz, 2H), 6.79 (t, J = 7.3 Hz, IH), 4.57-4.50 (m, 1H), 3.25 3.20 (m, 8H), 2.98 (dd, J = 5.3, 14.0 Hz, IH), 2.77 (dd, J = 9.2, 14.0 Hz, IH).

8.92 (d, J = 7.9 Hz, IH), 7.31 7.20 (m, 4H), 7.05 (s, 2H), 7.09 7.02 (m, 4H), 6.88

373 DMSO-de (t, J = 7.3 Hz, IH), 4.63-4.55 (m, IH),

3.35 (s, 8H), 3.05 (dd, J = 5.3, 14.0 Hz, IH), 2.85 (dd, J = 9.2, 14.0 Hz, IH).

10.10 (brs, 1H), 8.86 (d, J = 7.9 Hz, IH), 8.33 (brs, IH), 7.61 (s, 2H), 7.27-7.15 (m, 4H), 6.99 (d, J = 8.1 Hz , 2H), 6.91 (d, J =

374 DMSO-de 8.4 Hz, 2H), 6.81 (t, J = 7.3 Hz, IH),

4.61-4.53 (m, IH), 3.32 (s, 8H), 3.06 (dd, J = 5.3, 14.0 Hz, IH), 2.91 (d, J = 4.1 Hz, 3H), 2.86 (dd, J = 9.2, 14.0 Hz, IH). 8.03 (d, J = 7.8 Hz, 2H), 7.83 (d, J = 6.9 Hz, 2H), 7.71 (t, J = 7.2 Hz, 1H), 7.61 (t, J = 7.8 Hz , 2H), 7.26 (t, J = 7.8 Hz, IH), 7.11 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.7

375 DMSO-de

Hz, 2H), 4.38-4.34 (m, IH), 4.16-4.13 (m, IH), 3.60-3.58 (m, 4H), 3.29 3.27 (m, 5H), 3.16-3.08 (m, 1H), 3.06 2.89 (m, 2H), 1.67- 1.41 (m, 4H).

12.66 (s, IH), 9.02 (d, J = 8.4 Hz, 1H),

8.03 (d, J = 7.8 Hz, 2H), 7.46-7.38 (m, 3H), 7.27 (t, J = 7.8 Hz, IH), 7.17 (d, J =

376 DMSO-de

8.4 Hz, 2H), 6.93 (d, J = 8.6 Hz, 2H), 4.67-4.59 (m, IH), 3.63-3.59 (m, 4H), 3.32-3.28 (m, 4H), 3.08-2.81 (m , 2H).

9.24 (d, J = 8.4 Hz, IH), 8.64 (s, 2H), 8.04 (d, J = 7.8 Hz, 2H), 7.27 (t, J = 7.5 Hz, IH), 7.17 (d, J = 8.4 Hz, 2H), 6.95 (d,

377 DMSO-de

J = 8.7 Hz, 2H), 4.70-4.63 (m, IH),

3.61-3.60 (m, 4H), 3.32 3.31 (m, 4H), 3.11-2.8 l (m, 2H).

8.17 (d, J = 9.0 Hz, IH), 7.91-7.88 (m, 3H), 7.61 (d, J = 8.4 Hz, IH), 7.53-7.50

DMSO-de (m, 2H), 7.45 (t, J = 7.5 Hz, IH),

378

7.19-7.16 (m, 3H), 6.94 6.91 (m, 2H), 4.62-4.56 (m, IH), 3.31-3.17 (m, 8H), 3.05-2.92 (m, 2H). 9.17-9.14 (m, 1H), 7.85 (s, 2H), 7.16 (d, J = 8.1 Hz, 2H), 7.01 (s, 2H), 6.93 6.90

379 DMSO-de

(M, 3H), 4.65-4.61 (m, 1H), 3.33 3.20 (m, 8H), 2.89-2.50 (m, 2H).

7.90 (s, 2H), 7.20 (d, J two 8.4 Hz, 2H), 6.92 (d, J = 7.6 Hz, 2H), 4.80-4.74 (m,

380 CD 3 OD

1H), 3.35-3.34 (m, 4H), 3.16-3.15 (m, 4H), 2.99-2.73 (m, 2H), 2.85 (s, 6H).

9.06 (d, J = 8.1 Hz, IH), 7.78-7.19 (m, 5H), 7.47-7.36 (m, 3H), 7.20 (d, J = 7.3 Hz, 2H), 6.99 (d, J = 7.3 Hz , 2H),

381 DMSO-de 4.69-4.61 (m, 1H), 3.90 3.82 (m, 4H),

3.06 (dd, J = 4.6, 13.8 Hz, 1H), 2.87 (dd, J = 9.7, 13.8 Hz, IH), 1.73 (s, 6H), 1.24 (s, 6H).

9.26 (d, J = 8.4 Hz, IH), 8.65 (s, 2H), 7.77-6.98 (m, 5H), 7.15 (d, J two 8.1 Hz,

382 DMSO-de 2H), 6.89 (d, J = 8.1 Hz, 2H), 4.69-4.68

(M, IH), 3.90-3.84 (m, IH), 3.51 3.40 (m, 1H), 3.05 (m, 4H), 1.06 (s, 12H).

7.76 (bs, IH), 7.49-7.48 (m, 3H),

7.30-7.22 (m, 5H), 7.20 (d, J = 8.1 Hz,

383 CDCls 2H), 6.81 (d, J = 8.1 Hz, 2H), 6.57 (d, J =

7.6 Hz, IH), 5.07-5.00 (m, IH), 3.59-3.48 (m, 6H), 3.22-3.21 (m, 2H), 1.41 (s, 6H).

8.40 (brs, 2H), 7.39-7.26 (m, 5H), 7.20 (d, J = 7.3 Hz, 2H), 6.76 (d, J = 7.3 Hz,

384 CDCls

2H), 4.99-4.93 (m, IH), 3.53-3.47 (m, 2H), 3.36-3.24 (m, 6H), 1.25 (s, 6H) Z, 6l70 / C0df / X3d 0 680 / εθ OAV L6t0 / £ 0d / 13d 0 680 / £ 0 OAV 9.02 (d, J = 8.1 Hz, 1H), 7.46-7.34 (m, 6H), 7.24-7.14 (m, 2H), 6.88 (d, J = 7.8 Hz , IH), 6.64 (d, J = 1.4 Hz, IH), 6.54 (d,

394 DMSO-de

J = 7.8 Hz, 1H), 4.66-4.58 (m, IH),

3.02-2.72 (m, 8H), 1.81-1.77 (m, 4H), 1.43-1.42 (m, 2H), 1.26-1.24 (m, 2H).

8.98 (d, J = 7.9 Hz, 1H), 7.46-7.36 (m, 3H), 7.23 (t, J = 2.8 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 6.79 (t, J = 7.2 Hz, 1H),

395 employment SO-d 6

5.87 (s, 2H), 4.61-4.54 (m, IH),

3.33-3.10 (m, 8H), 2.80 (dd, J = 5.7, 13.4 Hz, IH), 2.60 (dd, J = 8.6, 13.6 Hz, IH).

7.52 (s, 1H), 7.37 (d, J = 9.0 Hz, 2H), 7.27-7.19 (m, 5H), 6.95 (d, J = 8.1 Hz,

396 CDCls IH), 6.86 (d, J = 9.0 Hz, 2H), 6.49 (brs,

1H), 5.08 (m, IH), 3.29 (m, 8H), 3.11 (m, 2H).

12.8 (brs, 1H), 9.06 (d, J = 8.4 Hz, IH), 7.44-7.35 (m, 4H), 7.25 7.20 (m, 3H), 7.13 (d, J = 8.1 Hz, 1H), 6.99 ( d, J = 7.8

397 DMSO-de Hz, 2H), 6.79 (t, J = 7.2 Hz, IH),

4.70-4.62 (m, IH), 3.32-3.26 (m, 4H), 3.15-3.06 (m, 5H), 2.85 (dd, J = 13.2, 16.8 Hz, IH) -. Zl-

.6fO / COdf / 13d 0 680 / CO OAV -9ZI-

L6 0 / £ 0d £ / ΣJd 0 680 / £ 0 OAV 3 Table

Compound determination

solvent

9.07 (d, J = 8.3 Hz, 1H), 7.46-7.32 (m, 7H), 7.26-7.20 (m, 4H), 7.15 (t, J = 7.1 Hz, IH), 4.70

406 DMSO- d 6 (m, IH), 3.67 (t, J = 5.3 Hz, 2H), 3.47 (t, J = 5.3

Hz, 2H), 3.16 (dd, J = 4.9 Hz, 14 Hz, IH), 2.93 (dd, J = 9.9 Hz, 14 Hz), 1.29 (s, 6H).

9.28 (d, J = 8.3 Hz, 1H), 8.63 (s, 2H), 7.36-7.12 (m, 9H), 4.74 (m, IH), 3.67 (t, J = 5.3 Hz, 2H),

407 DMSO- d 6 3.47 (t, J = 5.3 Hz, 2H), 3.20 (dd, J = 4.5 Hz,

14Hz, IH), 2.92 (dd, J = 10 Hz, 14 Hz, IH), 1.29 (s, 6H).

9.07 (d, J = 8.2 Hz, 1H), 7.46-7.23 (m, 10H), 4.70 (m, 1H), 3.68 (t, J = 5.3 Hz, 2H), 3.51 (t, J

408 DMSO- d 6

= 5.3 Hz, 2H), 3.17 (dd, J = 4.6 Hz, 14 Hz, IH), 2.93 (dd, J = 10 Hz, 14Hz, IH), 1.36 (s, 6H).

9.29 (d, J = 8.2 Hz, IH), 8.64 (s, 2H), 7.35 (t, J = 1.6 Hz, 1H), 7.33 (d, J = 8.9 Hz, 2H), 7.25 (d, J = 8.9 Hz, 2H), 7.24 (d, J = 1.6 Hz, 2H), 4.75

409 DMSO- d 6

(M, IH), 3.68 (t, J = 5.1 Hz, 2H), 3.51 (t, J = 5.1 Hz, 2H), 3.20 (dd, J = 4.6 Hz, 14 Hz, 1H), 2.92 (dd, J = 9.9 Hz, 14 Hz, 1H), 1.36 (s, 6H).

9.04 (d, J = 8.7 Hz, 1H), 7.46-7.37 (m, 3H), 7.33 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 6.99-6.90 (m , 3H), 4.69 (m, IH), 3.68 (t, J = 5.0

410 DMSO- d 6

Hz, 2H), 3.50 (t, J = 5.0 Hz, 2H), 3.17 (dd, J = 4.6 Hz, 14 Hz, IH), 2.93 (dd, J = 10 Hz, 14 Hz, IH), 1.38 (s , 6H). 9.29 (d, J = 8.2 Hz, IH), 8.64 (s, 2H), 7.33 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 8.3 Hz, 2H), 6.96 (t , J = 9.3 Hz, IH), 6.91 (d, J = 7.6 Hz, 2H), 4.75

411 DMSO- d 6

(M, IH), 3.69 (t, J = 4.9 Hz, 2H), 3.51 (t, J two 4.9 Hz, 2H), 3.20 (dd, J = 4.4 Hz, 14 Hz, IH), 2.92 (dd, J = 10 Hz, 14 Hz, IH), 1.38 (s, 6H).

9.08 (d, J = 8.4 Hz, IH), 7.46-7.31 (m, 7H), 7.26-7.21 (m, 4H), 4.71 (m, IH), 3.66 (t, J = 5.3

412 DMSO- d 6 Hz, 2H), 3.45 (t, J = 5.3 Hz, 2H), 3.16 (dd, J =

4.7 Hz, 14Hz, 1H), 2.93 (dd, J = 9.8 Hz, 14 Hz, IH), 1.29 (s, 6H).

9.30 (d, J = 8.4 Hz, IH), 8.64 (s, 2H), 7.39-7.21 (m, 8H), 4.75 (m, 1H), 3.67 (t, J = 5.1 Hz, 2H),

413 DMSO- d 6 3.46 (t, J = 5.1 Hz, 2H), 3.21 (dd, J = 4.5 Hz, 14

Hz, 1H), 2.92 (dd, J = 10 Hz, 14 Hz, IH), 1.29 (s, 6H).

7.37-7.21 (m, 6H), 6.80 (d, J = 4.1 Hz, 4H), 5.12-5.07 (m, IH), 3.70 (t, J = 5.4 Hz, 2H), 3.46

414 DMSO- d 6

(T, J = 5.4 Hz, 2H), 3.32-3.29 (m, 2H), 2.31 (s, 6H), 1.39 (s, 6H).

7.31-7.12 (m, 12H), 6.67 (dd, J = 3.8 Hz, 8.1 Hz, IH), 5.23-5.16 (m, IH), 3.68 (t, J = 5.4 Hz, 2H), 3.54 (t, J = 5.1 Hz, 2H), 3.27 (dd, J = 5.1 Hz, 14.3

415 DMSO- d 6

Hz, 1H), 3.21 (dd, J = 5.1 Hz, 14.3 Hz, IH), 2.43-2.34 (m, 2H), 2.01 1.97 (m, 2H), 1.77- 1.61 (m, 4H). 9.07 (d, J = 8.2 Hz, 1H), 7.45-7.22 (m, 8H), 7.29 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 8.6 Hz, 2H), 4.68 (m, IH), 3.63 ( s, 2H), 3.44 (t, J = 5.3 Hz,

416 DMSO - d 6

2H), 3.14 (dd, J = 4.8 Hz, 14 Hz, IH), 2.91 (dd, J = 9.7 Hz, 14 Hz, 1H), 2.73 (t, J = 5.3 Hz, 2H), 1.42 (s, 6H ).

9.28 (d, J = 8.2 Hz, IH), 8.63 (s, 2H), 7.41 - 7.22 (m, 5H), 7.29 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 8.6 Hz, 2H ), 4.73 (m, 1H), 3.63 (s, 2H), 3.45 (t,

417 DMSO- d 6

J = 5.4 Hz, 2H), 3.18 (dd, J = 4.4 Hz, 14 Hz, IH), 2.90 (dd, J = 9.9 Hz, 14 Hz, IH), 2.73 (t, J = 5.4 Hz, 2H), 1.42 (s, 6H).

9.07 (d, J = 8.2 Hz, IH), 7.45- 7.35 (m, 3H), 7.30 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.4 Hz,

418 DMSO- d 6 2H), 4.69 (m, IH), 3.56 (t, J = 5.6 Hz, 2H),

3. 14 (dd, J = 4.9 Hz, 14 Hz, 1H), 2.96 -2.87 (m, 3H), 2.33 (s, 3H), 1.28 (s, 6H).

8.82 (d, J = 8.3 Hz, 1H), 7.42 - 7.34 (m, 3H), 7.3 1 (d, J = 8.7 Hz, 2H), 7.19 (d, J = 8.7 Hz, 2H), 4.73 (m, IH), 3.60 (brs, 2H), 3.16 (dd, J =

419 DMSO- d 6 5.1 Hz, 14 Hz, IH), 3.07 (brs, 2H), 2.97 (dd, J

= 9.3 Hz, 14 Hz, IH), 2.33 (brs, 2H), 1.36 (s, 6H), 1.03 0.79 (m, 1H), 0.66 0.45 (m, 2H), 0.34 0.12 (m, 2H). 12.8 ( brs, IH), 9.08 (d, J = 8.4 Hz, 1H),

7.45-7.35 (m, 3H), 7.29 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.3 Hz, 2H), 4.69 (m, IH), 3.52 (t, J = 5.1 Hz, 2H ), 3.14 (dd, J = 4.7 Hz, 14 Hz,

420 DMSO- d 6 IH), 2.91 (dd, J = 9.9 Hz, 14 Hz, IH), 2.82 (t, J

= 5.1 Hz, 2H), 2.20 (d, J = 6.8 Hz, 2H),

1.86- 1.74 (m, 2H), 1.74- 1.58 (m, 3H), 1.48- 1.41 (m, IH), 1.40 1.09 (m, 3H), 1.23 (s, 6H),

0.94-0.78 (m, 2H).

9.07 (d, J = 8.2 Hz, 1H), 7.45-7.18 (m, 9H), 6.98 (d, J = 8.1 Hz, 2H), 6.82 (t, J = 7.3 Hz, IH), 4.71 (m, 1H ), 3.95 (s, 2H), 3.79 (t, J = 5.2

421 DMSO- d 6

Hz, IH), 3.62 (t, J = 5.2 Hz, IH), 3.17 (dd, J =

4.8 Hz, 14 Hz, 1H), 2.93 (dd, J = 10 Hz, 14 Hz, IH).

9.05 (d, J = 8.1 Hz, IH), 7.45-7.21 (m, 9H), 6.93 (d, J = 8.1 Hz, 2H), 6.76 (t, J = 7.3 Hz, IH), 4.70 (m, IH ), 4.45 (q, J = 6.8 Hz, 1H),

422 DMSO- d 6 3.88-3.81 (m, 1H), 3.75 3.67 (m, 2H), 3.54-3.44

(M, IH), 3.16 (dd, J = 4.8 Hz, 14 Hz, 1H), 2.93 (dd, J = 9.9 Hz, 14 Hz, 1H), 1.36 (d, J = 6.8 Hz, 3H). 9.27 ( d, J = 8.3 Hz, IH), 8.63 (s, 2H), 7.34-7.21

(M, 6H), 6.94 (d, J = 8.1 Hz, 2H), 6.76 (t, J = 7.2 Hz, 1H), 4.74 (m, 1H), 4.46 (q, J = 7.0 Hz,

423 DMSO- d 6 1H), 3.89-3.81 (m, IH), 3.76-3.66 (m, 2H),

3.54-3.44 (m, 1H), 3.20 (dd, J = 4.7 Hz, 14 Hz, 1H), 2.92 (dd, J = 9.9 Hz, 14 Hz, IH), 1.36 (s, 6H).

9.06 (d, J = 8.1 Hz, IH), 7.47-7.27 (m, 12H), 4.70 (m, IH), 4.09 (t, J = 6.1 Hz, 2H), 4.07 (t, J

424 DMSO- d 6

= 6.1 Hz, 2H), 3.18 (dd, J = 4.9 Hz, 14 Hz, IH), 2.95 (dd, J = 9.9 Hz, 14 Hz, IH).

Formulation Example 1: Tablets

Conventional manner, for preparing tablets having the following composition.

Prescription Compound 4 1 20 mg

Lactose 143. 4 mg

Potato starch 30. Mg

Hydroxycarboxylic professional Pinot receptacle Norre loin 6 mg

- Sutari _ phosphate Maguneshiumu 0. 6 mg_

200 rag

Formulation Example 2: Injection

Conventional manner, an injection is prepared having the following composition

Prescription Compound 4 1 2 mg

Purified soybean oil 200 rag

Purified egg yolk lecithin 24 mg

Injection for glycerin 50 mg

Distilled water for injection 1. 72 mL

2. The availability of on 00 raL industry

Ri by the present invention are useful as a shed 4 Lee Nteguri emission inhibitor, various diseases through a 4 I Nteguri emissions were bonding mechanism is involved (e.g., multiple hard sclerosis, asthma, inflammatory bowel disease, rheumatoid rheumatic, diabetes, tumor metastasis, arteriosclerosis, Conclusions P. dermatitis, nephritis, useful psoriasis, myocardial ischemia, treatment and Z or preventing such cells rejection, etc.) at the time of organ transplantation off Nirua alanine derivative or a drug but pharmacologically acceptable provided.

Claims

The scope of the claims
1. Formula (I)
{Wherein, m and n are the same or different, represent 1 or 2, R 2 is substitution also properly is unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted also properly unsubstituted a cycloalkyl, substituted or non-substituted Sik Roarukeniru, rather also substituted unsubstituted Ariru, substituted or is laid also aromatic heterocyclic group or substituted unsubstituted represents the unsubstituted alicyclic heterocyclic group,
R 1 is substituted or unsubstituted lower alkyl, substituted or is unsubstituted lower Arukeyuru, substituted or unsubstituted lower alkynyl, 'substituted or non-substituted a cycloalkyl, substituted or unsubstituted of Ariru, substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted alicyclic heterocyclic group, - C (= Y) NR 9 R 1. (Wherein, Y represents an oxygen atom or a sulfur atom, and R ie are the same or different, a hydrogen atom, a substituted or is lower alk kill unsubstituted substituted or unsubstituted lower alkenyl, lay be substituted the unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or is unsubstituted Ariru, substituted or unsubstituted aromatic heterocyclic group, or substitution also properly unsubstituted alicyclic a heterocyclic group), one C (= 0) R 9a (wherein, R 9a has the same meaning as the R 9), one C (== 0) 0R 9b (wherein, R 9b are the R 9 the same meaning as the group formed by removing a hydrogen atom from a) or in one S 0 2 R u [wherein defined, R 11 is force the same meanings as defined above R 9b or one NR 9c R 1 () c (wherein, It represents R 9c and R 1 () c represents the, respectively that R 9 and R 1 () synonymous)], R 3, R 4 , R 5 and R 6 are the same or different A hydrogen atom, or substituted or represents a lower alkyl or Okiso unsubstituted Further, among R 4, R 5 and R 6, are two present on the same carbon atom, together with the carbon atom It turned to either form a saturated monocyclic hydrocarbon ring, or, R 3, R 4, two cormorants Chino of R 5 and R 6 may form a lower alkylene become Ichi緖, R 7 and R 8 is turned same or different, a hydrogen atom, a halogen, di- Toro, substituted or unsubstituted Amino, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower § alkylthio, lower substituted or unsubstituted Arukanoiru , mono also properly di-lower Arukiruamino, substituted or unsubstituted lower alkyl, substituted or is unsubstituted Ariru, S substituted or unsubstituted aromatic heterocyclic group or properly be substituted unsubstituted alicyclic heterocyclic Phenyl Aranin derivative or a pharmacologically acceptable salt thereof represented by} represents a ring group.
2. During R 2 is R 2A <formula, but R 2A have the same meanings as the R 2,
(A) as a substituent on the nitrogen atom,
(a) - C (= Y 1A) NR 12A R 13A ( wherein, Y 1A is an oxygen atom or a sulfur atom, R 12A and R 13A are the same or different, a hydrogen atom, a substituted or unsubstituted lower alkyl , substituted or unsubstituted lower alkenyl, also properly substituted represents a lower alkynyl, or substituted or unsubstituted cycloalkyl Honoré unsubstituted),
(b) - C (= 0 ) R 12Aa ( wherein, R 12Aa is as defined above R 12A),
(c) - C (= 0 ) 0R 12Ab ( wherein, R 12Ab is as defined above R 12A) or
(d) - S0 2 in R 13A [wherein, R 13A is added to the definition of the R 12A, one NR 12Ae R 13A. (Wherein, R 12Ac and R 13Ae each said R 12A and R 13A is as defined above) with a representative of, a substituted or unsubstituted 2-pyro Lil or 4-substituted 4-pin Perijiniru,
(B) 4 of one NR 14 [wherein as the substituent (R 2 and 1 of the coupling position with the adjacent carbonyl), R 14 one C (= Y 1A) NR 12A R 13A ( wherein, Y 1A, R 12A and
R 13A each have the same meanings as defined above), - C (= 0) in H 12Aa (wherein, R 12Aa is as defined above), one C (= 0) 0R 12Ab (wherein, R 12Ab is said during synonymous a is) or an S0 2 R 13A (wherein, R 13A is as defined above;) lower alkyl substituted by a representative, lower alkenyl properly has a lower alkynyl, substitution or non substituted Ariru, substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted alicyclic heterocyclic group,
(C) having a 3-position substituent, 2, 2-dimethyl-cyclopentyl, 1, 2, 2 - Application Benefits Mechirushiku Ropenchiru, 2, 2, 3 - Application Benefits Mechinoreshiku b pentyl or 1, 2, 2, 3 - Te door Ramechirushiku Ropenchinore,
(D) as a substituent,
(a) - NR 15 S0 2 R 16 ( wherein, R 15 and R 16 are as defined defined above R 12A the same or different),
(b) 1-position of the ring structure (the 1-position of the bonding position to the carbonyl adjacent to the R 2) is to first place the bonding site to the 2-position moiety (carbonyl adjacent to R 2 is nitrogen atom ) gar S0 2 - properly be substituted composed monocyclic 5-7 membered ring of the unsubstituted alicyclic heterocyclic group,
(c.) 2-position of the ring structure (the 1-position of the bonding position to the carbonyl adjacent to the R 2) gar S0 (wherein, R 16 is as defined above) 2 R 16 substituted by composed ChissoHara child monocyclic 5-7 membered ring substituted or unsubstituted alicyclic heterocyclic group, or,.
(1-position of the ring structure (the 1-position of the bonding position to the carbonyl adjacent to the R 2) gar NR 15 S0 2 R 16 (wherein, R 15 and R 16 each have the same meanings as defined above) a substituted or unsubstituted lower alkyl properly be substituted monocyclic 5-7 membered ring consisting of substituted carbon atoms having an alicyclic heterocyclic group or a substituted or unsubstituted consequent opening alkyl Le unsubstituted or
(E) (to join position 1-position of the carbonyl adjacent to the R 2) 2 and 3 position part of the ring structure gar C (= 0) negation one or a C (two S) NH- in also substituted configured that monocyclic 5- to 7-membered ring properly is not a unsubstituted alicyclic heterocyclic group>, wherein R 1 is R 1A [wherein, R 1A is R 1 as defined some, but when the properly be substituted with one or two atoms which R 2A is selected from oxygen atom and a sulfur atom which is unsubstituted alicyclic heterocyclic group, R 1A is a substituted or unsubstituted lower alkyl , substituted or unsubstituted Ariru, substituted or unsubstituted aromatic heterocyclic group, in a substituted or unsubstituted alicyclic heterocyclic group or a C (= 0) 0R 9b (wherein, R 9b is as defined above a present) and not], R 3, R 4, R 5 and R 6 are each R 3A, R 4A, in R 5A and R 6A (wherein, R 3A, R 4A, R 5A and R 6A each of R 3 Although the same meaning as R \ R 5 and R 6, when R 2A is substituted or unsubstituted alicyclic heterocyclic group having an oxygen atom and a sulfur chosen from atoms' one or two atoms , R 3A, R 4A, is phenylene Ruaranin derivative or a pharmacologically allowable according to claim 1, wherein the both are not a replacement or unsubstituted lower alkyl or Okiso) of R 5A and R 6A salt that.
3. During R 2 is R 2B [wherein, although R 2B has the same meaning as the R 2,
(A) a substituted 2 - 4 Ichipiperi Gieres with pyro lil or 1-position and 4-position substituents,
(B) 4-position substituent and a substituted lower alkyl, substituted lower alkenyl If Ku has substituted lower alkynyl, substituted or unsubstituted Ariru, substituted or unsubstituted aromatic heterocyclic group or substituted or are properly non substituted alicyclic heterocyclic group,
(C) replacement consequent opening pentyl,
(D) as a substituent,
(a) - NR 15 S0 2 R 16 ( wherein, R 15 and R 16 each have the same meanings as defined above),
(b) 1-position of the ring structure (the 1-position of the bonding position to the carbonyl adjacent to the R 2) monocyclic 5-7 membered composed is one S0 2 _ 2-position moiety is nitrogen atom a substituted or unsubstituted alicyclic heterocyclic ring group,
(c) 2-position of the ring structure (the 1-position of the bonding position to the carbonyl adjacent to the R 2) gar S0 (wherein, R 16 is as defined above) 2 R 16 nitrogen substituted with a substituted or unsubstituted alicyclic heterocyclic group monocyclic 5-7 membered ring consisting of atom or,
(d) 1-position of the ring structure (the 1-position of the bonding position to the carbonyl adjacent to the R 2) gar NR 15 S0 2 R 16 (wherein, R 15 and R 16 are each as defined above
) Unsubstituted or having been monocyclic 5 substituted or is unsubstituted 7-membered alicyclic heterocyclic group or substituted or is unsubstituted consequent opening alkyl Le consists of carbon atoms substituted with unsubstituted lower alkyl, or (E) (to join position 1-position of the carbonyl adjacent to the R 2) 2 and 3 position part of the ring structure is _ C (= 0) Comeau or a C ( = S) negation is an not a substituted or unsubstituted alicyclic heterocyclic group monocyclic 5- to 7-membered ring that is composed of, in R 1 is R 1A (wherein, R 1A is the and a synonymous), R 3, R 4, R 5 and R 6 are each R 3A, R 4A, in R 5A and R 6A (wherein, R 3A, R 4A, R 5A and R 6A are the respective off Eniruaranin derivative or a pharmacologically acceptable salt of claims 1, wherein the a same meaning) and.
4. R 1 is a substituted or unsubstituted lower alkyl, substituted or unsubstituted Ariru, substituted or unsubstituted aromatic heterocyclic group, substituted or is properly of Hi置conversion alicyclic heterocyclic group, one C (= S) NR 9 R 1C (wherein, R 9 and R ie have the same meanings as before SL respectively), one C (= 0) in R 9a (wherein, R 9a is as defined above) or an SC ^ R 11 (wherein, R 11 has the same meaning as defined above) Fueniruaranin derivative or a pharmacologically acceptable salt thereof according to claim 1, wherein a.
5. R 2 is a substituted or unsubstituted Ariru, substituted or unsubstituted aromatic heterocyclic group, or formula (II)
The (wherein, Q represents an CH 2 _ or a sulfur atom, R 17 represents a substituted or unsubstituted lower alkyl, substituted or unsubstituted Ariru or substituted or unsubstituted aromatic heterocyclic group) Fueniruaranin derivative or a pharmacologically acceptable salt thereof in the range 1 or 4 according representing.
6. R 3, R 4, R 5 and R 6 Fuyuniruara nin derivative or a pharmacologically acceptable salt thereof according to any one of claims 1, 4 and 5 according to a hydrogen atom.
7. Claims either was or full two Ruara Nin derivative according to claim 1 to 6 of a medicament containing in its pharmacologically acceptable salt as an active ingredient.
8. The Suruhi 4 in integrin inhibitors containing as its pharmacologically acceptable salt thereof as an active ingredient Feniruaranin derivative or according to any one of claims 1-6 claims.
9. Billing was or Feniruaranin derivative according to any one of claims 1 to 6 antiinflammatory agent comprising in a pharmacologically acceptable salt thereof as an active ingredient,
1 0. Alpha 4 Using Lee Nteguri emission inhibitor range 1-6, whichever is phenylene Ruaranin derivative or a pharmacologically acceptable Ru salt according to claims for the manufacture of.
1 1. Use of phenylene Ruarayun derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 6 claims for the manufacture of an anti-inflammatory agent.
1 2. Claims 1-6 full We two Ruaranin derivative or features and Suruhi 4 Lee Nteguri down and this includes the step of administering an effective amount of a pharmacologically acceptable salt thereof according to any one of the method of treating a disease bonding mechanism via inhibition agent is involved.
1 3. Method of treating inflammation characterized that you comprising administering a phenylene Ruaranin derivative or effective amount of a pharmacologically acceptable salt thereof according to any one of claims 1 to 6 claims.
PCT/JP2003/004970 2002-04-19 2003-04-18 Phenylalanine derivative WO2003089410A1 (en)

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WO2007060408A2 (en) * 2005-11-23 2007-05-31 Astrazeneca Ab L-phenylalanine derivatives and their use as integrin antagonists
WO2007088041A1 (en) * 2006-01-31 2007-08-09 Jerini Ag Compounds for the inhibition of integrins and use thereof
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