TW200951122A - Carboxylic acid compound or the salt - Google Patents

Carboxylic acid compound or the salt Download PDF

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Publication number
TW200951122A
TW200951122A TW098103153A TW98103153A TW200951122A TW 200951122 A TW200951122 A TW 200951122A TW 098103153 A TW098103153 A TW 098103153A TW 98103153 A TW98103153 A TW 98103153A TW 200951122 A TW200951122 A TW 200951122A
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Taiwan
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esi
nmr
compound
brs
salt
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TW098103153A
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Chinese (zh)
Inventor
Tadashi Terasaka
Hiroshi Matsuda
Shinji Ito
Mamoru Tasaki
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Astellas Pharma Inc
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Publication of TW200951122A publication Critical patent/TW200951122A/en

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/29—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/75—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
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    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
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    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C275/36—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with at least one of the oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. N-aryloxyphenylureas
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    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C317/00—Sulfones; Sulfoxides
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    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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Abstract

Provided is a compound having a CRTH2 antagonism and being useful as a preventive and/or remedy for inflammatory diseases (for example, asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, urticaria, eosinophilic bronchitis, food allergy, sinusitis, angiitis, chronic obstructive pulmonary disease, etc.) or multiple sclerosis. As the results of studies on compounds having a CRTH2 antagonism, it has been confirmed that a carboxylic acid compound or a salt thereof has a CRTH2 antagonism. The above-described carboxylic acid compound or a salt thereof has a CRTH2 antagonism and is usable as a preventive and/or remedy for inflammatory diseases (for example, asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, urticaria, eosinophilic bronchitis, food allergy, sinusitis, angiitis, chronic obstructive pulmonary disease, etc.) or multiple sclerosis.

Description

200951122 六、發明說明： 【發明所屬之技術領域】 本發明係關於可使用作爲醫藥組成物、尤其是炎症性 疾病或多發性硬化症治療用醫藥組成物之有效成分之羧酸 化合物或其鹽。 【先前技術】[Technical Field] The present invention relates to a carboxylic acid compound or a salt thereof which can be used as an active ingredient of a pharmaceutical composition, particularly an inflammatory disease or a pharmaceutical composition for treating multiple sclerosis. [Prior Art]

已知爲過敏性炎症誘導細胞之肥胖細胞係透過其細胞 表面之Fc ε RI與抗原特異之IgE結合。侵入生體內之抗 原藉由與該細胞表面上之特異IgE結合且使肥胖細胞活性 化，產生各種炎症性介體，誘發過敏性炎症（Current Opinion in Immunolo gy, 2 002 年，1 4 ( 6 )卷，p · 688-693 前列腺素D2 ( PGD2 )爲活化性肥胖細胞所產生之主 要類前列腺素（prostanoid )»迄今爲止認爲於氣喘患者 ^ 呼吸道因抗原暴露引起PGD2在數分鐘以內顯著產生亢進 • (新英格蘭醫藥期刊（New England Journal of Medicine )，1986年，315(13)卷，p80 0-804;美國呼吸道疾病回 顧（American Review of Respiratory Disease)，1 983 年， 128 ( 4 )卷，ρ· 5 97-602 )，或報導有若過敏性鼻炎患者 之鼻黏膜或異位性皮膚炎患者之皮虜暴露於抗原時，於炎 症局部引起PGD2產生之亢進（免疫學期刊（Journal ofAn obese cell line known as an allergic inflammation-inducing cell binds to antigen-specific IgE through Fc ε RI on its cell surface. An antigen that invades a living body binds to specific IgE on the surface of the cell and activates obese cells to produce various inflammatory mediators, which induces allergic inflammation (Current Opinion in Immunolo gy, 2 002, 14 (6) Volume, p · 688-693 Prostaglandin D2 ( PGD2 ) is the main prostaglandin produced by activating obese cells » It has been considered so far in asthmatic patients that the respiratory tract is significantly induced to produce PGD2 within a few minutes due to antigen exposure. • (New England Journal of Medicine, 1986, 315(13), p80 0-804; American Review of Respiratory Disease, 1 983, 128 (4), ρ· 5 97-602 ), or reported that if the skin of patients with nasal mucosa or atopic dermatitis in patients with allergic rhinitis is exposed to antigen, it causes hyperproliferation of PGD2 in the local area of inflammation (Journal of Immunology)

Immunology ) , 19 91 年，146 ( 2)卷，ρ·671 -676 )。另外 ，過去已報導有對人類皮內投與PGD2時引發紅斑，於大 200951122 鼠中使血管透過性亢進而形成浮腫（英國免疫學期刊（ British Journal of Immunology) , 1 976 年，56 ( 2)卷，p 229-233 )、對狗氣管中PGD2亦引發嗜酸血球累積（應 用生理學期刊（Journal of Applied Physiology)，1989 年 ，67(3)卷，P 959-962) 。Fujitani等人報導有使用抗原Immunology ), 19 91, 146 (2), ρ·671 -676). In addition, it has been reported in the past that erythema is induced by intradermal administration of PGD2 in humans, and vascular permeability is formed in large 200951122 mice to form edema (British Journal of Immunology, 1 976, 56 (2) Volume, p 229-233), also causes accumulation of eosinophils in PGD2 in the dog's trachea (Journal of Applied Physiology, 1989, 67(3), P 959-962). Fujitani et al reported using antigen

誘發氣喘模型，於相較於正常小鼠PGD2產生增加之 PGD2合成酵素轉基因小鼠於呼吸道中嗜酸血球浸潤及 Th2細胞素產生受到亢進（免疫學期刊（Journal of Immunology )，2002 年，168(1)卷，p. 443-449)，提示 PGD2促進過敏性炎症。如此PGD2於過敏性炎症部位之 產生受到亢進，促進過敏反應，因此認爲與過敏疾病之發 病及惡化有密切關聯。Induced asthma model, in the PGD2 synthetase transgenic mice with increased production of PGD2 compared to normal mice, eosinophil infiltration and Th2 cytokine production were hyperactive in the respiratory tract (Journal of Immunology, 2002, 168 ( 1) Volume, p. 443-449), suggesting that PGD2 promotes allergic inflammation. As a result, PGD2 is hyperactive in the area of allergic inflammation and promotes allergic reactions. Therefore, it is considered to be closely related to the onset and deterioration of allergic diseases.

最初作爲PGD2受體已知有爲G蛋白共軛型受體（ GPCR )之一之DP(D型類前列腺素受體）。然而，於豚 鼠中PGD2雖顯示眼壓降低作用及於結膜中顯示炎症誘發 作用（尤其是是酸性白血球浸潤），但爲DP選擇性促效 劑之BW245C雖顯示眼壓降低作用但未誘發嗜酸血球對結 膜之浸潤，提示PGD2之嗜酸血球浸潤誘發作用並非透過 DP ( Investigate Opthlmology & Visual Science, 1 990 年， 1卷，p. 138-146)。再者，於200 1年Monneret等人使用 自人類單離之嗜酸血球，由於PGD2使嗜酸血球活性化或 爲DP選擇性促效劑之BW245C不使嗜酸血球活性化以及 爲DP拮抗劑之BWA86C不阻礙因PGD2引起嗜酸血球活 性化，故而提倡PGD2之嗜酸血球活性化作用係透過新穎 -6- 200951122A DP (D-type prostaglandin receptor) which is one of G protein-conjugated receptors (GPCRs) is known as a PGD2 receptor. However, in guinea pigs, PGD2 showed a decrease in intraocular pressure and an inflammation-inducing effect in the conjunctiva (especially acidic leukocyte infiltration), but BW245C, a DP selective agonist, showed an effect of reducing intraocular pressure but did not induce acidophilus. The infiltration of blood cells into the conjunctiva suggests that the eosinophil infiltration induced by PGD2 is not transmitted through DP (Investigate Opthlmology & Visual Science, 990, Vol. 1, p. 138-146). Furthermore, in 2001, Monnetet et al. used eosinophils isolated from humans, and BW245C, which activates eosinophils or is a DP selective agonist, does not activate eosinophils and is a DP antagonist. BWA86C does not hinder the activation of eosinophils due to PGD2, so it is recommended to activate the eosinophilic activity of PGD2 through novel-6-200951122

之 PGD2 受體(Blood, 2001 年，98(6)卷，p. 1942-1948 )。於同時期Hirai等人報導PGD係藉由作爲CRTH2 ( 於Th2細胞上表現之化學引誘劑受體-同源分子）之配位 體之作用，而誘發Th2細胞、嗜酸血球、嗜鹼血球之趨化 (實驗醫藥期刊（The Journal of Experimental Medicine )，2001 年，193(2)卷，p. 255-261)。同時，報導有 CRTH2不認爲於Thl細胞中表現，而係作爲Th2細胞選 擇性表現之化學引誘劑類受體加以選殖之G蛋白共軛型 之孤兒受體，於活性化之肥胖細胞之培養上清液中，存在 有其配位體活性以及除Th2細胞以外亦於與嗜酸血球、嗜 鹼血球之過敏性反應有關之炎症性細胞中表現（免疫學期 干[J ( Journal of Immunology )，199 9 年，162(3)卷，p. 1278-1286，FEBS Letter, 1999 年，8 卷，459 ( 2 ) , p. 195-199 )。由此到目前，均認爲PGD2係透過CRTH2及DP 之兩種受體而發揮其生物活性。 CRTH2爲使cAMP上升之Gs偶合型GPCR，DP爲阻 礙cAMP上升之Gi偶合型GPCR，故細胞內訊號傳達系統 不同，具有不同機能。迄今使用對於CRTH2及DP之促 效劑、拮抗劑進行探討，故而報導作爲CRTH2之機能有 細胞趨化活性化（Th2細胞、嗜酸血球、嗜鹼血球）、黏 著分子表現促進（Th2細胞、嗜酸血球）、Th2細胞素產 生促進（Th2細胞）等。另一方面，作爲DP之機能有血 小板凝集抑制、血管擴張、平滑肌鬆驰、細胞趨化抑制（ DP表現細胞、嗜酸血球、樹枝狀細胞）、嗜酸血球細胞 200951122The PGD2 receptor (Blood, 2001, 98(6), p. 1942-1948). At the same time, Hirai et al. reported that PGD induces Th2 cells, eosinophils, and basophilic blood cells by acting as a ligand for CRTH2 (a chemoattractant receptor-homologous molecule expressed on Th2 cells). Chemotherapy (The Journal of Experimental Medicine, 2001, 193(2), p. 255-261). At the same time, it is reported that CRTH2 is not considered to be expressed in Th1 cells, but is a G protein-conjugated orphan receptor that is selected as a chemoattractant receptor selectively expressed by Th2 cells, and is activated by an obese cell. In the culture supernatant, there is a ligand activity and expression in inflammatory cells related to allergic reactions of eosinophils and basophilic blood cells in addition to Th2 cells (J (Journal of Immunology) , 199, 162(3), p. 1278-1286, FEBS Letter, 1999, Vol. 8, 459 (2), p. 195-199). From this point of view, it is considered that PGD2 exerts its biological activity through both receptors of CRTH2 and DP. CRTH2 is a Gs-coupled GPCR that raises cAMP, and DP is a Gi-coupled GPCR that blocks cAMP rise, so the intracellular signal transmission system is different and has different functions. As far as the use of CRTH2 and DP agonists and antagonists has been investigated, it has been reported that as a function of CRTH2, cell chemotactic activation (Th2 cells, eosinophils, basophils) and adhesion molecules are promoted (Th2 cells, hobby) Acid cell), Th2 cytokine production promotion (Th2 cell), and the like. On the other hand, as a function of DP, platelet aggregation inhibition, vasodilation, smooth muscle relaxation, cell chemotaxis inhibition (DP expression cells, eosinophils, dendritic cells), eosinophils 200951122

凋亡誘導、睡眠誘導等。認爲PGD2係藉由DP之作用於 局部引發血管擴張使血管透過性亢進，而另一方面藉由 CRTH2之作用引起炎症性細胞浸潤及活性化，而促進過 敏性炎症。有關該等方面，Nagata等人及Pettipher等人 之總論中已有詳細描述（前列腺素白三烯及必須胺基酸（ Prostaglandins Leukotrienes & Essential Fatty Acids )， 2003年，69(2-3)卷，p. 169-177;天然回顧藥物發現（ Natural Review Drug Discovery)，2007 年，6 ( 4)卷，p. 313-325) ° 由以上，認爲因抗原刺激而產生活性化肥胖細胞之主 要類前列腺素之PGD2係透過CRTH2使Th2細胞或嗜酸 血球等之炎症性細胞活性化，促進朝炎症部位之趨化，進 而促進自Th2細胞產生Th2配位體藉此於過敏性炎症中 扮演主要角色，熱切期望開發CRTH2拮抗藥作爲對於過 敏性炎症之治療藥。Apoptosis induction, sleep induction, and the like. It is considered that PGD2 promotes vascular hyperpermeability by locally causing vasodilation by DP, and on the other hand, inflammatory cell infiltration and activation by action of CRTH2 promotes allergic inflammation. These aspects have been described in detail in the generals of Nagata et al. and Pettipher et al. (Prostaglandins Leukotrienes & Essential Fatty Acids, 2003, 69 (2-3) Vol. p. 169-177; Natural Review Drug Discovery, 2007, 6(4), p. 313-325) ° From above, it is believed that activated fat cells are produced by antigen stimulation. PGD2, a major prostaglandin, activates inflammatory cells such as Th2 cells or eosinophils through CRTH2, promotes chemotaxis toward inflammation sites, and promotes the production of Th2 ligands from Th2 cells to play a role in allergic inflammation. The main role, eager to develop CRTH2 antagonists as a therapeutic drug for allergic inflammation.

例如，具有CRTH2拮抗作用、具有抗氣喘作用之化 合物已知有以下述式（A) 、（B) 、（C) 、（D) 、( E )表示之化合物（分別爲專利文獻1、2、3、4、5)。 -8 - 200951122 [化l]For example, a compound having the anti-asthmatic effect of CRTH2 antagonism is known as a compound represented by the following formulas (A), (B), (C), (D), (E) (Patent Documents 1, 2, respectively) 3, 4, 5). -8 - 200951122 [化l]

(B) (D) % [式中各符號分別參見該公報， . 其中，專利文獻2中（B)之W表示 爲 0、1、2) 、NR13、CRi〇R2、CRiR2， 專利文獻3中，（C)之L表示CR6R7 CS， 專利文獻4中，（D)之A表示與B糸 至14員環雜環]。 專利文獻5公開日在本申請案之優先曰 又例如，專利文獻6、7及8中揭示們 〇、S(0)n (η 、CO、CNR6、 I合或鍵結之5 之後。 :爲製造中間體 -9- 200951122 之以（F)表示之化合物。 [化2](B) (D) % [In the above, each symbol of the formula is referred to in the publication, wherein W of the (B) of Patent Document 2 is represented by 0, 1, 2), NR13, CRi〇R2, CRiR2, and Patent Document 3 L of (C) represents CR6R7 CS, and in Patent Document 4, A of (D) represents a ring heterocyclic ring with B 糸 to 14 members. Patent Document 5 discloses the priority of the present application. For example, Patent Documents 6, 7, and 8 disclose that 〇, S(0)n (n, CO, CNR6, I, or bond 5): The compound represented by (F) is manufactured as an intermediate-9-200951122. [Chemical 2]

H〇v Ο R001 R002 R003 F -CF 3 -OCH,CH, • -CF 3 -〇ch3 • -CF 3 F CI CI -OCH2CH3 CI CI -och3 CI CI [專利文 獻 1]國 際 公 開 第 W02004/058164 說 明 書 [專利文 獻 2]國 際 公 開 第 W02006/005909 說 明 書 [專利文 獻 3]國 際 公 開 第 W02007/1 43745 說 明 書 [專利文 獻 4]國 際 公 開 第 W02007/1 46838 說 明 書 [專利文 獻 5]國 際 公 開 第 W02008/024746 說 明 書 [專利文 獻 6]國 際 公 開 第 W02006/0 14012 說 明 書 [專利文 獻 7]國 際 公 開 第 W02008/066784 說 明 書 [專利文 獻 8]特 開 2007-231005 號H〇v Ο R001 R002 R003 F -CF 3 -OCH,CH, -CF 3 -〇ch3 • -CF 3 F CI CI -OCH2CH3 CI CI -och3 CI CI [Patent Document 1] International Publication No. WO2004/058164 [Patent Document 2] International Publication No. WO2006/005909 Specification [Patent Document 3] International Publication No. WO2007/1 43745 Specification [Patent Document 4] International Publication No. WO2007/1 46838 Specification [Patent Document 5] International Publication No. WO2008/024746 Specification [Patent Document 6] International Publication No. WO2006/0 14012 Specification [Patent Document 7] International Publication No. WO2008/066784 Specification [Patent Document 8] Special Opening 2007-231005

【發明內容】 [發明欲解決之課題] 本發明者基於CRTH2拮抗作用，而以提供炎症性疾 病（例如，氣喘、過敏性鼻炎、過敏性皮膚炎、結膜炎、 -10- 200951122 蓴麻疼、嗜酸血球性支氣管炎、食物過敏、副鼻腔炎、血 管炎、慢性阻塞性肺疾病等）或多發性硬化症等之預防及 /或治療有用之醫藥組成物，進而以提供含有該等之醫藥 作爲目的進行硏究。 [解決課題之手段] 本發明者對於具有CRTH2拮抗作用之化合物積極檢 ^ 討之結果，發現式（I)之化合物可作爲CRTH2拮抗作用 而完成本發明。 亦即，本發明係關於式（I)化合物或其鹽，以及含 有式（I)化合物或其鹽、以及賦形劑之醫藥組成物。 [化3]SUMMARY OF THE INVENTION [Problems to be Solved by the Invention] The present inventors provide an inflammatory disease based on CRTH2 antagonism (for example, asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, -10-200951122 ricin pain, hobby a pharmaceutical composition useful for the prevention and/or treatment of sclerosing bronchitis, food allergy, paranasal sinusitis, vasculitis, chronic obstructive pulmonary disease, etc., or multiple sclerosis, and further providing a medicine containing the same Purpose to conduct research. [Means for Solving the Problems] The present inventors have actively examined the compounds having CRTH2 antagonism, and found that the compound of the formula (I) can be used as the CRTH2 antagonistic action to complete the present invention. That is, the present invention relates to a compound of the formula (I) or a salt thereof, and a pharmaceutical composition comprising the compound of the formula (I) or a salt thereof, and an excipient. [Chemical 3]

[式中， R1爲-(Cu伸烷基）-COOH或-H， 1)當R1爲-(C^-6伸烷基）-COOH時， R2爲鹵素或-H， R3爲鹵素、Cu烷基、-o-ccu烷基）或- η, 2 )當R1爲-H時， R2與R3與其等所鍵結之苯環一起形成以下式（Π) -11 - 200951122 表示之基， [化8]Wherein R1 is -(Cualkyl)-COOH or -H, 1) When R1 is -(C^-6alkyl)-COOH, R2 is halogen or -H, and R3 is halogen, Cu Alkyl, -o-ccualkyl) or - η, 2) When R1 is -H, R2 and R3 together with the benzene ring to which they are bonded form a base represented by the following formula (Π) -11 - 200951122, [ 8]

R V 爲=CH-或=N-， m表示1至6之整數， R4爲鹵素或-H， 但，R3爲_H時，R4爲鹵素， R5爲-H、_素或Cu院基， R爲可分別以由以尺^表不之相同或不同之基取代之芳 基、雜芳基、雜環烷基或-N(R6a)(R6b)， RXA爲鹵素、Ci-6院基、齒基Ci.6院基、-〇-(Ci.6院基） 、-0-(_基 Ci.6 院基、-S-(Ci.6 院基）、-N-(Ci-6 烷基）2、 芳基、經鹵素取代之芳基、經-〇-(<：! _6烷基）取代之芳基、 經烷基）2取代之芳基、鹵芳基、-OH、-CN、-8( = 0)2-((^-6烷基）、-NHSpOh^Cu烷基）或環狀胺基， R6a爲-((^6伸烷基）-芳基、-(Cu伸烷基）·雜芳基、或-(Cm伸烷基）-雜環烷基， R6b爲-H或Cm烷基， A 爲-Ο -或-S -， D 爲-C( = 〇)-、或-S( = 0)2-， -12- 200951122 E爲鍵結、Cu伸烷基或C2_6伸烯基， Y 爲-C(R5a) =或-N=， R5a爲-Η、鹵素、或Cm烷基，〕 Z 爲=CH-、或=N-， U 爲-C(R5b) =或-N=， R5b爲-Η、鹵素或Cu烷基， 但，下列化合物除外，RV is =CH- or =N-, m represents an integer from 1 to 6, and R4 is halogen or -H. However, when R3 is _H, R4 is halogen, and R5 is -H, _ or Cu, R An aryl group, a heteroaryl group, a heterocycloalkyl group or a -N(R6a)(R6b) which may be substituted by the same or different substituents, respectively, in the range of R^A, halogen, Ci-6, and teeth. Base Ci.6 yard base, -〇-(Ci.6 yard base), -0-(_基Ci.6院基, -S-(Ci.6院基), -N-(Ci-6 alkyl 2, an aryl group, a halogen-substituted aryl group, an aryl group substituted with -〇-(<:! -6 alkyl group), an alkyl group substituted with an alkyl group 2, a halogen aryl group, -OH, -CN , -8 ( = 0) 2-((^-6 alkyl), -NHSpOh^Cu alkyl) or cyclic amine, R6a is -((^6alkyl)-aryl, -(Cu Alkyl)-heteroaryl, or -(Cmalkyl)-heterocycloalkyl, R6b is -H or Cm alkyl, A is -Ο- or -S-, D is -C(=〇)- , or -S( = 0)2-, -12- 200951122 E is a bond, Cu alkyl or C2_6 extended alkenyl, Y is -C(R5a) = or -N=, R5a is -Η, halogen, Or Cm alkyl,] Z is =CH-, or =N-, U is -C(R5b) = or -N=, R5b is -Η, halogen or Cu alkyl, except for the following compounds,

3-{3-氟-4-[ ( 5-{[4-(三氟甲基）苯甲醯基]胺基}吡 啶-2-基）氧基]苯基}丙酸， 3-{3-乙氧基-4-[(5-{[4-(三氟甲基）苯甲醯基]胺基 }吡啶-2-基）氧基]苯基}丙酸， 3·{3-甲氧基-4-[ ( 5-{[4-(三氟甲基）苯甲醢基]胺基 }吡啶-2-基）氧基]苯基}丙酸， 3-[4- ( {5-[ ( 3,4-二氯苯甲醯基）胺基]吡啶-2-基}氧 基）-3-氟苯基]丙酸， 3-[4-({5-[(3,4-二氯苯甲醯基）胺基]吡啶-2-基}氧 基）-3-乙氧基苯基]丙酸， 3-[4-({5-[(3,4-二氯苯甲醯基）胺基]吡啶-2-基}氧 基）-3-甲氧基苯基]丙酸，及 [4-{4-[ (3,4-二氯苯甲醯基）胺基]苯氧基卜3-甲氧基 苯基）乙酸]。 再者，若未特別說明，則本說明書中之化學式中$胃 號用於其他化學式時，相同的符號表示相同之意義° 另外，本發明係關於含有式（I)化合物或其鹽 -13- 200951122 症性疾病或多發性硬化症之治療用醫藥組成物，亦即，含 有式（I)之化合物或其鹽之炎症性疾病或多發性硬化症 治療劑。 另外’本發明係關於式（I)化合物或其鹽用以製造 炎症性疾病或多發性硬化症之治療用醫藥組成物之用途， 以及對患者投予有效量之式（I )化合物或其鹽之炎症性 疾病或多發性硬化症之治療方法。 [發明效果] 式（I)化合物或其鹽具有CRTH2拮抗作用，可使用 作爲炎症性疾病（例如，氣喘、過敏性鼻炎、過敏性皮虜 炎、結膜炎、奪麻疹、嗜酸血球性支氣管炎、食物過敏、 副鼻腔炎、血管炎、慢性阻塞性肺疾病等）或多發性硬化 症等之預防及/或治療劑。 【實施方式】 以下，詳細說明本發明。 「鹵素」爲、Cl、Br、或I。至於其他樣態爲F或C1 〇 「（^_6烷基」爲直鏈或分支狀之碳數1至6之烷基， 例如，甲基、乙基、正丙基、異丙基、正丁基、異丁基、 第二丁基、第三丁基、正戊基、正己基等。至於其他樣態 爲Ci-4烷基。又其他樣態爲甲基或乙基。 「鹵基CL6烷基」爲經1個以上鹵素取代之Ci-6烷 -14- 200951122 基。其它樣態爲經1至5個鹵素取代之Ci-6烷基，又其 他樣態爲-cf3、-cf2h、-chf2、或-CH2CH2F。 ^ c!.6伸烷基」爲直鏈或分支狀之碳數1至6之伸烷 ~ 基，例如亞甲基 '伸乙基、三亞甲基、伸丙基、四亞甲基 、五亞甲基、或六亞甲基等。至於其他樣態爲山.4伸烷 基，又其他樣態爲亞甲基或伸乙基。 「C2_6伸烯基」爲直鏈或分支狀之碳數2至6之伸烯 ^ 基’例如伸乙烯基、伸丙烯基、伸丁烯基、伸戊烯基、或 伸己烯基等。其他樣態爲C2_4伸烯基。 「芳基」爲C6_14之單環至三環芳香族烴環基，例如 苯基、或萘基，其他樣態爲苯基。 「雜芳基」意指具有一個以上選自氮、氧及硫組成之 群組之相同或不同雜原子之5或6員環芳香族雜環，該等 亦可爲與環戊烷環或苯環縮合。其他樣態爲亦可與苯環縮 合之5或6員芳香族雜環，又其他樣態爲噻吩基、三唑基 Q 、吡啶基、吲哚基、苯并呋喃基、苯并噻吩基、苯并噁唑 I 基、苯并噻唑基、苯并咪唑基、咪唑吡啶基、異喹啉基、 或喹啉基等。其他樣態爲吲哚基。 「雜環烷基」意指具有一個以上選自由氮、氧及硫組 成之群組之相同或不同之雜原子之5至7員非芳香族雜環 ，該等可具有部分不飽和鍵，亦可與苯環縮合。其他樣態 爲哌啶基、異茚滿基、四氫喹啉基、四氫異喹啉基、 2,3,4,5-四氫-1H-3-苯并吖庚因基等。至於其他樣態爲可 與苯環縮合之5至7員非芳香族雜環，又其他樣態爲四氫 -15- 200951122 異喹啉基。 「環狀胺」意指上述「雜環院基」中，具有至少一個 氮原子之單環〜三環式「雜環烷基」。亦可具有部分不飽 和鍵。其他樣態爲環貝數爲4〜9員之環，又其他樣態舉例 爲卩比略陡基、峨陡基、嗎啉基、或均哌陡基。 本說明書中’所謂「可經取代」意指未經取代、或具 有1至6個取代基者’其他樣態意指具有1至5個者。另 外’具有複數個取代基時’該等取代基可相同亦可彼此不 本說明書中’所謂「經取代」意指具有1至6個取代 基，其他樣態意指具有1至5個取代基。另外，具有複數 個取代基時，該等取代基可相同亦可彼此不同。3-{3-Fluoro-4-[(5-{[4-(trifluoromethyl)benzylidenyl]amino}pyridin-2-yl)oxy]phenyl}propanoic acid, 3-{3 -ethoxy-4-[(5-{[4-(trifluoromethyl)benzylidenyl]amino}pyridin-2-yl)oxy]phenyl}propanoic acid, 3·{3-A Oxy-4-[(5-{[4-(trifluoromethyl)benzylidenyl]amino}pyridin-2-yl)oxy]phenyl}propanoic acid, 3-[4- ( {5 -[ ( 3,4-dichlorobenzhydryl)amino]pyridin-2-yl}oxy)-3-fluorophenyl]propionic acid, 3-[4-({5-[(3,4) -dichlorobenzhydryl)amino]pyridin-2-yl}oxy)-3-ethoxyphenyl]propionic acid, 3-[4-({5-[(3,4-dichlorobenzene) Mercapto)amino]pyridin-2-yl}oxy)-3-methoxyphenyl]propionic acid, and [4-{4-[(3,4-dichlorobenzylidene)amino) ]phenoxybu 3-methoxyphenyl)acetic acid]. Further, unless otherwise specified, in the chemical formula of the present specification, when the stomach number is used in other chemical formulae, the same symbols indicate the same meaning. Further, the present invention relates to the compound containing the formula (I) or its salt-13- 200951122 A pharmaceutical composition for the treatment of a disease or multiple sclerosis, that is, an inflammatory disease or a multiple sclerosis therapeutic agent containing the compound of the formula (I) or a salt thereof. Further, the present invention relates to the use of a compound of the formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for the treatment of an inflammatory disease or multiple sclerosis, and an effective amount of the compound of the formula (I) or a salt thereof for administration to a patient. The treatment of inflammatory diseases or multiple sclerosis. [Effect of the Invention] The compound of the formula (I) or a salt thereof has a CRTH2 antagonistic action and can be used as an inflammatory disease (for example, asthma, allergic rhinitis, atopic dermatitis, conjunctivitis, measles, eosinophilic bronchitis, A preventive and/or therapeutic agent for food allergy, paranasal sinusitis, vasculitis, chronic obstructive pulmonary disease, or the like, or multiple sclerosis. [Embodiment] Hereinafter, the present invention will be described in detail. "Halogen" is, Cl, Br, or I. As for the other forms, F or C1 〇 "(^_6 alkyl group) is a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl Base, isobutyl, second butyl, tert-butyl, n-pentyl, n-hexyl, etc. As for other forms, it is Ci-4 alkyl. Other forms are methyl or ethyl. "Halo-based CL6 The alkyl group is a Ci-6 alkane-14-200951122 group substituted by one or more halogens. The other forms are Ci-6 alkyl groups substituted with 1 to 5 halogens, and other forms are -cf3, -cf2h, -chf2, or -CH2CH2F. ^ c!.6alkylene" is a linear or branched carbon number of 1 to 6 alkyl, such as methylene 'extended ethyl, trimethylene, propyl , tetramethylene, pentamethylene, or hexamethylene, etc. As for the other forms, it is a methylene group, and the other forms are methylene or ethyl. "C2_6 extended alkenyl" is A linear or branched carbon number of 2 to 6 is, for example, a vinyl group, a propylene group, a butenyl group, a pentenyl group, or a hexenylene group. Other forms are C2_4 olefins. "Aryl" is a monocyclic to tricyclic aromatic hydrocarbon of C6_14 a group such as phenyl or naphthyl, and other forms are phenyl. "Heteroaryl" means a 5 or 6 membered ring having one or more identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. An aromatic heterocyclic ring, which may also be condensed with a cyclopentane ring or a benzene ring. Other forms are 5 or 6-membered aromatic heterocyclic rings which may also be condensed with a benzene ring, and other forms are thienyl, triazole Base Q, pyridyl, fluorenyl, benzofuranyl, benzothienyl, benzoxazole I, benzothiazolyl, benzimidazolyl, imidazolidinyl, isoquinolinyl, or quinolinyl Other forms are fluorenyl. "Heterocycloalkyl" means a 5- to 7-membered non-aromatic heterocyclic ring having one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, These may have a partially unsaturated bond and may also be condensed with a benzene ring. Other forms are piperidinyl, isoindolyl, tetrahydroquinolyl, tetrahydroisoquinolinyl, 2,3,4,5- Tetrahydro-1H-3-benzoazepine or the like. As for other forms, it is a 5 to 7 member non-aromatic heterocyclic ring which can be condensed with a benzene ring, and other forms are tetrahydro-15-200951122 "Crystalline" means a monocyclic to tricyclic "heterocycloalkyl" group having at least one nitrogen atom in the above "heterocyclic compound". It may also have a partially unsaturated bond. The ring number is a ring of 4 to 9 members, and other examples are 卩 slightly steep, 峨 steep, morpholinyl, or homopiped. In the present specification, 'so-called "may be substituted" means not 'Substituted, or having 1 to 6 substituents, 'other forms mean 1 to 5. When 'with multiple substituents', the substituents may be the same or may not be the same as the 'so-called' in this specification. Substituted" means having 1 to 6 substituents, and other forms means having 1 to 5 substituents. Further, when there are a plurality of substituents, the substituents may be the same or different from each other.

「RXA」之其他樣態爲RXB，又其他樣態爲Rxc 〇 RXB爲鹵素、Cu烷基、鹵基Cl-6烷基、_〇_(Cl_6烷 基）、-〇-(鹵基Cu烷基）、-S^Cu烷基）、-Ν-γυ烷基 )2、芳基 '經烷基）取代之芳基、或經-N-iCu烷 基）2取代之芳基。The other form of "RXA" is RXB, and other forms are Rxc 〇RXB is halogen, Cu alkyl, haloCl-6 alkyl, _〇_(Cl_6 alkyl), -〇-(halo cumane An aryl group substituted with an alkyl group substituted with an alkyl group or an aryl group substituted with an -N-iCualkyl group 2 or an aryl group substituted with an alkyl group.

Rxc 爲 C1、_CH3、-CF3、-〇CH3、_OCF3、_SCH3、-N(CH3)2、苯基、經-0CH3取代之苯基、或經-N(CH3)2取 代之苯基。 以下顯示本發明之樣態： (1) R1爲- (C!-6伸烷基）-COOH之式（I)化合物。 至於其他樣態，R1爲- CH2-COOH之式（I)化合物。 又其他樣態，Ri爲-H之式（I )化合物。 16 - 200951122 (2) R2爲-Η之式（I)化合物。 (3 ) R3爲鹵素、Cm烷基、或- 0-((^-6烷基）之式（I)化 合物。 至於其他樣態，R3爲鹵素之式（I )化合物。 又其他樣態，R3爲F、Br或C1之式（I )化合物。 (4) R4爲-H之式（I)化合物。 (5) R5爲-H之式（I)化合物。Rxc is C1, _CH3, -CF3, -〇CH3, _OCF3, _SCH3, -N(CH3)2, phenyl, phenyl substituted by -CH3, or phenyl substituted by -N(CH3)2. The mode of the present invention is shown below: (1) A compound of the formula (I) wherein R1 is -(C!-6alkylene)-COOH. As for the other forms, R1 is a compound of the formula (I) of -CH2-COOH. In still other instances, Ri is a compound of formula (I) of -H. 16 - 200951122 (2) R2 is a compound of the formula (I). (3) R3 is a halogen, a Cm alkyl group, or a compound of the formula (I) of -0-((^-6 alkyl). As for the other forms, R3 is a halogen compound of the formula (I). R3 is a compound of the formula (I) wherein F, Br or C1. (4) A compound of the formula (I) wherein R4 is -H. (5) A compound of the formula (I) wherein R5 is -H.

(6 ) R6爲可經相同或彼此不同之RXA分別取代之雜芳基 或雜環烷基之式（I)化合物。 至於其他樣態，R6爲可經相同或彼此不同之RXA取 代之苯基之式（I)化合物， 又其他樣態，R6爲可經相同或彼此不同之rXB取代 之苯基之式（I)化合物， 又再其他樣態’ R6爲可經相同或彼此不同之RXc取 代之苯基之式（I)化合物。 Q (7) A爲-0-之式（I)化合物。 . (8) D爲- C( = 0)-之式（I)化合物。 ^ (9) E爲鍵結之式（I)化合物。 (1〇) Y爲-CH =或- CF =之式（1)化合物。 至於其他樣態，Y爲-Ν·=之式（1)化合物。 (11) Ζ爲=CH-之式（I)化合物° (12) U爲- CH =之式（I)化合物。 (13) m爲1之式（I)化合物° (Μ) V爲=N-之式（I)化合物° -17- 200951122 (15) R6a爲-((^.6伸烷基）-芳基，且R6b爲-H之式（I) 化合物。 (16) 上述（1)至（15)中所述之基中，藉由組合兩種 以上成爲互不矛盾之構造之式（I)化合物。 具體而言，舉例爲例如以下之化合物。 (A) R1 爲- (Cm 伸烷基）-COOH，R2 爲-H，R3 爲 F、C1 或Br之式（I )化合物。(6) R6 is a compound of the formula (I) which may be substituted with a heteroaryl or heterocycloalkyl group which are respectively substituted by RXA which are the same or different from each other. As for the other forms, R6 is a compound of the formula (I) which may be substituted with the same or different RXA phenyl groups, and other forms, R6 is a formula (I) which may be substituted by the same or different RXB. Compounds, yet other forms 'R6 are compounds of formula (I) which may be substituted with the same or different RXc phenyl groups. Q (7) A is a compound of the formula (I) in the form of -0. (8) D is a compound of the formula (I) wherein -C(=0)-. ^ (9) E is a compound of formula (I) bonded. (1〇) Y is a compound of the formula (1) wherein -CH = or -CF =. As for the other forms, Y is a compound of the formula (1) of -Ν·=. (11) The compound of the formula (I) wherein Ζ is =CH- (12) U is - CH = the compound of the formula (I). (13) Compound of formula (I) wherein m is 1 ° (Μ) V is a compound of formula (I) = N-° -17- 200951122 (15) R6a is -((^.6alkyl)-aryl (6) A compound of the formula (I) wherein R6b is -H. (16) A compound of the formula (I) wherein two or more of the groups described above are incompatible with each other in the above-mentioned (1) to (15). Specifically, for example, the following compounds are exemplified: (A) A compound of the formula (I) wherein R1 is -(Cm alkylene)-COOH, R2 is -H, and R3 is F, C1 or Br.

(B) R1爲- CH2-COOH之上述（A)所述之化合物。 以下列出本發明之又其他樣態。 [1] 式[I]化合物或其鹽，其中R6爲可經相同或彼此不同 之以RXB表示之基分別取代之芳基、雜芳基、雜環烷基 或-N(R6a)(R6b)。 [2] 如[1]所述之化合物或其鹽，其中 R1 爲-CH2-COOH 或 _h， m爲1，(B) The compound of the above (A) wherein R1 is -CH2-COOH. Still other aspects of the invention are listed below. [1] A compound of the formula [I], wherein R6 is an aryl group, a heteroaryl group, a heterocycloalkyl group or a —N(R6a)(R6b) which may be respectively substituted with the same or different substituents represented by RXB. . [2] The compound according to [1] or a salt thereof, wherein R1 is -CH2-COOH or _h, m is 1,

R6a爲-(Cm伸烷基）_芳基， R6b 爲-H， 但，Y 爲-N =時，u__ch=， Y 爲-CH =或-CF =時，z 爲=CH_ [3]如[2]所述之化合物或其鹽，其中 r3爲鹵素、Cl·6烷基或-0-Cl-6烷基 R4 爲-H。 [4]如[3]所述之化合物或其鹽，其中 Y 爲-N=， -18- 200951122 Z 爲=CH-。 [5] 如[4]所述之化合物或其鹽，其中e爲鍵結。 [6] 如[5]所述之化合物或其鹽，其中R6爲可經相同或彼 ' 此不同之以rxb表示之基取代之苯基。 [7] 如[6]所述之化合物或其鹽，其中 A 爲 _ Ο -， D 爲-C ( =0 )-， 〇 R2 爲-η， R3爲鹵素。 [8] 如[7]所述之化合物或其鹽，其中 R6爲可經相同或彼此不同之以Rxc表示之基取代之 苯基， [9] 如[2]所述之化合物或其鹽，其中γ爲_CH =或_CF=。 [10] 如[9]所述之化合物或其鹽，其φ A 爲-0-， D 爲- C(=0) • r6爲可經相同或彼此不同之以rxb表示之基取代之 苯基。 [1 1]如[2]所述之化合物或其鹽，其中R1爲-H。 Π2]如[11]所述之化合物或其鹽，其中V爲=N… 本發明中包含之具體化合物之例舉例爲以下之化合物 或其鹽： (3-氯- 4-{4-[(3,4-二氯苯甲醯基）胺基]苯氧基丨苯基乙 酸）， -19- 200951122 (4-{4·[ ( 1-苯并呋喃-2-基羰基）胺基]苯氧基卜3-氯苯基 )乙酸， [3-氯-4-({4-[(3,4-二氯苯甲醯基）胺基]苯基}磺醯基） 苯基]乙酸， (3-氯-4-{4-[(3,4-二氫異喹啉-2(1Η)-基羰基）胺基] 苯氧基}苯基）乙酸， [4-(4-{[(2£)-3-(3,4-二氯苯基）丙-2-烯醯基]胺基} 苯氧基）-2-甲基-1Η-苯并咪唑-1-基]乙酸， [3-氯-4-(4-{[4-(三氟甲基）苯甲醯基]胺基}苯氧基）苯 基]乙酸， (3-氯-4- ( 2-氟-4-[ ( 1Η-吲哚-2-基羰基）胺基]苯氧基） 苯基）乙酸， [3-氯-4- ( 4-{[ ( 1-甲基-1Η-吲哚-2-基）羰基]胺基}苯氧 基）苯基]乙酸， [3-氯-4- ( 4-{[ ( 6-氟-1Η-苯并咪唑-2-基）胺甲醯基]胺基 }苯氧基）苯基]乙酸， 0 {3·氯-4-[ ( 5-{[ ( 5-氟-1Η-吲哚-2-基）羰基]胺基}吡啶-2- . 基）氧基]苯基}乙酸， [3-溴-4- (4-{ [4-(三氟甲氧基）苯甲醯基]胺基}苯氧基） 苯基]乙酸，及 {3·氯-4-[(5-{[4-(三氟甲氧基）苯甲醯基]胺基}吡啶-2-基）氧基]苯基}乙酸。 式（I)之化合物係依據取代基之種類而存在有互變 異構物或幾何異構物。本說明書中’僅敘述式（1)之化 -20- 200951122 合物之異構物之一種型態，但本發明亦包含該等以外之異 構物、異構物經分離者、或亦包含該等之混合物。 * 又，式（I)之化合物具有不對稱碳原子時，存在有 ' 基於此之光學異構物。本發明包含式（I)化合物之光學 異構物之經分離者，或者該等之混合物。 另外，本發明亦包含以式（I)表示之化合物之製藥 學上可接受性前驅藥。製藥學上可接受性前驅藥爲具有可 藉由溶劑分解或在生理條件下轉化成胺基、羥基、羧基等 之基之化合物。形成前驅藥之基舉例爲例如Prog. Med.， 5, p.2 1 5 7-2 1 6 1 ( 1985)或「醫藥品之開發」（廣川書店 、1990年），第7巻、分子設計163-198中所述之基。 又，式（I)化合物之鹽爲式（I)化合物之製藥學上 可接受性鹽，且依據取代基種類而有形成酸加成鹽或與鹼 之鹽之情況。具體而言，舉例爲與鹽酸、氫溴酸、氫碘酸 、硫酸、硝酸、磷酸等無機酸、或與甲酸、乙酸、丙酸、 ^ 草酸、丙二酸、琥珀酸、富馬酸、馬來酸、乳酸、蘋果酸 . 、扁桃酸、酒石酸、二苯甲醯基酒石酸、二甲苯醯基酒石 ^ 酸、檸檬酸、甲烷磺酸、乙烷磺酸、苯磺酸、對-甲苯磺 酸、天門冬胺酸、榖胺酸等有機酸之加成鹽，與鈉、鉀、 鎂、鈣、鋁等無機鹼，與甲基胺、乙基胺、乙醇胺、離胺 酸、鳥胺酸等有機鹼等之鹽，乙醯基亮胺酸等各種胺基酸 及氨基酸衍生物之鹽或銨鹽等。 再者，本發明亦包含式（I)之化合物及其鹽之各種 水合物或溶劑化物，及結晶多型之物質。又，本發明亦包 -21 - 200951122 含以各種放射線或非放射線同位素標記之化合物。 本說明書中有時使用下列簡寫符號。R6a is -(Cmalkyl)-aryl, R6b is -H, but when Y is -N =, u__ch=, Y is -CH = or -CF =, z is =CH_ [3] as [ 2] The compound or a salt thereof, wherein r3 is halogen, Cl.6 alkyl or -0-Cl-6alkyl R4 is -H. [4] The compound or a salt thereof according to [3], wherein Y is -N=, and -18-200951122 Z is =CH-. [5] The compound according to [4] or a salt thereof, wherein e is a bond. [6] The compound according to [5], wherein R6 is a phenyl group which may be substituted by the same or the same as the group represented by rxb, or a salt thereof. [7] The compound according to [6] or a salt thereof, wherein A is _ Ο -, D is -C ( =0 )-, 〇 R 2 is -η, and R 3 is a halogen. [8] The compound according to [7] or a salt thereof, wherein R6 is a phenyl group which may be substituted with the same or different substituents represented by Rxc, [9] the compound according to [2] or a salt thereof, Where γ is _CH = or _CF=. [10] The compound according to [9] or a salt thereof, wherein φ A is -0-, and D is -C(=0) • r6 is a phenyl group which may be substituted by the same or different radicals represented by rxb . [1] The compound according to [2], wherein R1 is -H, or a salt thereof. The compound or a salt thereof according to [11], wherein V is =N. The specific compound contained in the present invention is exemplified by the following compound or a salt thereof: (3-chloro-4-{4-[( 3,4-Dichlorobenzhydryl)amino]phenoxypurine phenylacetic acid), -19- 200951122 (4-{4·[(1-benzofuran-2-ylcarbonyl)amino)benzene Oxybu 3-chlorophenyl)acetic acid, [3-chloro-4-({4-[(3,4-dichlorobenzhydryl)amino]phenyl}sulfonyl)phenyl]acetic acid, (3-Chloro-4-{4-[(3,4-dihydroisoquinolin-2(1Η)-ylcarbonyl)amino]phenoxy}phenyl)acetic acid, [4-(4-{[ (2£)-3-(3,4-dichlorophenyl)prop-2-enyl]amino}phenoxy)-2-methyl-1indole-benzimidazol-1-yl]acetic acid, [3-Chloro-4-(4-{[4-(trifluoromethyl)benzylidenyl]amino}phenoxy)phenyl]acetic acid, (3-chloro-4-(2-fluoro-4) -[ (1Η-indol-2-ylcarbonyl)amino]phenoxy)phenyl)acetic acid, [3-chloro-4-(4-{[(1-methyl-1Η-吲哚-2-) (carbonyl)amino]phenoxy)phenyl]acetic acid, [3-chloro-4-(4-{[(6-fluoro-1Η-benzoimidazol-2-yl)aminecarboxylidene]amino }Phenoxy)phenyl]acetic acid, 0 {3·chloro-4-[( 5-{[( 5-fluoro-1Η-) Indole-2-yl)carbonyl]amino}pyridin-2-yloxy]phenyl}acetic acid, [3-bromo-4-(4-{[4-(trifluoromethoxy)benzoquinone) Amino]phenoxy)phenyl]acetic acid, and {3·chloro-4-[(5-{[4-(trifluoromethoxy)benzylidene]amino}pyridin-2-yl )oxy]phenyl}acetic acid. The compound of the formula (I) is a tautomeric or geometric isomer depending on the kind of the substituent. In the present specification, 'only one type of the isomer of the formula (1) -20-200951122 is described, but the present invention also includes the isomers, isomers, or the like. a mixture of these. * Further, when the compound of the formula (I) has an asymmetric carbon atom, there is an optical isomer based on this. The present invention comprises an isolated optical isomer of a compound of formula (I), or a mixture thereof. Further, the present invention also encompasses a pharmaceutically acceptable prodrug of a compound represented by the formula (I). The pharmaceutically acceptable prodrug is a compound having a group which can be converted into an amine group, a hydroxyl group, a carboxyl group or the like by solvolysis or under physiological conditions. Examples of the base for forming a prodrug are, for example, Prog. Med., 5, p. 2 1 5 7-2 1 6 1 (1985) or "Development of Pharmaceuticals" (Guangchuan Bookstore, 1990), No. 7, Molecular Design The group described in 163-198. Further, the salt of the compound of the formula (I) is a pharmaceutically acceptable salt of the compound of the formula (I), and depending on the kind of the substituent, an acid addition salt or a salt with a base may be formed. Specifically, it is exemplified by inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, or with formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, and horse. Acid, lactic acid, malic acid, mandelic acid, tartaric acid, benzoyl tartaric acid, xylylene tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluene Acid, aspartic acid, valine and other organic acid addition salts, and sodium, potassium, magnesium, calcium, aluminum and other inorganic bases, and methylamine, ethylamine, ethanolamine, lysine, ornithine A salt such as an organic base or the like, a salt or an ammonium salt of various amino acids such as ethionyl leucine and an amino acid derivative. Further, the present invention also encompasses various hydrates or solvates of the compound of the formula (I) and salts thereof, and a crystalline polymorph. Further, the present invention also encompasses -21 - 200951122 compounds containing various radioactive or non-radiographic isotopes. The following abbreviations are sometimes used in this manual.

AcOEt或EtOAc:乙酸乙酯，brine:飽和食鹽水， BuOH : 丁醇，Cs2C03 :碳酸鉋，CHC13 :氯仿，CuCl2 : 氯化銅，DCM:二氯甲烷，DCC:二環己基碳二醯亞胺， DEAD :偶氮二羧酸乙酯，DMSO :二甲基亞颯，DMF : Ν,Ν-二甲基甲醯胺，DMAP : 4-二甲胺基吡啶，DIPEA : 二異丙基乙胺，DPPA :二苯基磷酸疊氮化物，EtOH :乙 醇，HOBt : N-羥基苯并三唑，IPE:二異丙基醚、K2C03 :碳酸鉀，KOH :氫氧化鉀，mCPBA :間氯過氧苯甲酸、 MeCN :乙腈，MeOH :甲醇，MgS04 :無水硫酸鎂， Na2C03 :碳酸鈉，NaHC03 ··碳酸氫鈉’ NaOH ·氫氧化鈉 ，NMM : N-甲基嗎啉，TEA :三乙胺，THF :四氫呋喃， PdCl2(PPh3)2 ··二氯雙（三苯基膦）鈀，Pd(PPh3)4 :肆（ 三苯基膦）鈀（〇)，冒8(：.11(：1:>1-乙基-：^’-(3-二甲胺 基丙基）-碳二醯亞胺鹽酸鹽，Zn(CN)2:氰化鋅，ESI-MS :電子噴佈離子化法質量分析，mp:熔點。 (製造法） 式（I)化合物及其鹽可利用基於其基本構造或依據 取代基種類之特徵，使用各種習知之合成方法製造。此時 ，依據官能基之種類，有在自原料至中間物之階段中以適 當保護基（可易於轉化成該官能基之基）取代該官能基之 製造技術上效果之情況。至於該等保護基，可舉例爲例如 -22- 200951122AcOEt or EtOAc: ethyl acetate, brine: saturated brine, BuOH: butanol, Cs2C03: carbonic acid planer, CHC13: chloroform, CuCl2: copper chloride, DCM: dichloromethane, DCC: dicyclohexylcarbodiimide , DEAD: Ethyl azodicarboxylate, DMSO: dimethyl hydrazine, DMF: hydrazine, hydrazine-dimethylformamide, DMAP: 4-dimethylaminopyridine, DIPEA: diisopropylethylamine , DPPA: diphenylphosphoric acid azide, EtOH: ethanol, HOBt: N-hydroxybenzotriazole, IPE: diisopropyl ether, K2C03: potassium carbonate, KOH: potassium hydroxide, mCPBA: m-chloroperoxy Benzoic acid, MeCN: acetonitrile, MeOH: methanol, MgS04: anhydrous magnesium sulfate, Na2C03: sodium carbonate, NaHC03 · sodium bicarbonate 'NaOH · sodium hydroxide, NMM: N-methylmorpholine, TEA: triethylamine, THF: tetrahydrofuran, PdCl2(PPh3)2 ··dichlorobis(triphenylphosphine)palladium, Pd(PPh3)4: 肆(triphenylphosphine)palladium(〇), 8 (:.11(:1: >1-Ethyl-:^'-(3-dimethylaminopropyl)-carbodiimide hydrochloride, Zn(CN)2: zinc cyanide, ESI-MS: Electrospray ionization Method for mass spectrometry, mp: melting point. (Manufacturing method) Compounds of formula (I) and salts thereof Manufactured using a variety of conventional synthetic methods based on their basic structure or depending on the type of substituent. In this case, depending on the type of functional group, there is a suitable protecting group in the stage from the raw material to the intermediate (which can be easily converted into The functional group) is substituted for the technical effect of the functional group. As for the protecting groups, for example, -22-200951122

Wut s ( P. G. M. Wuts )及 Greene ( T. W· Greene )著之「 Greene’s有機合成保護基（第4版，2006年）」中所述 之保護基，只要依據該等反應條件適當選擇即可。該等方 ' 法在導入該保護基進行反應後，可依據需要去除保護基藉 此獲得所需之化合物。 另外，式（I)化合物之前驅藥係與上述保護基同樣 ，可於自原料至中間物之階段中導入特定之基，或者使用 Q 所得之式（I)化合物進行反應製造。反應可經由使用一 般之酯化、醯胺化、脫水等熟悉本技藝者習知之方法進行 〇 以下說明式（I)化合物之代表性製造方法。各製造 方法亦可參照該說明書中附加之參考文獻進行。另外，本 發明之製造方法並不限於以下所示之例。 (第一製造方法） ^ 式（I)之化合物可使經保護之碳酸脫保護而製造。 . 該脫保護可藉由水解、氫解或觸媒之脫保護等製造。鹼水 解時，可使用無機鹸（NaOH、KOH、NaHC03、Cs2C〇3等 )。酸水解時，可使用鹽酸。任一反應溫度均可在冰冷至 回流條件下，於不使基質分解之條件下進行反應。至於溶 劑可使用醇類（MeOH、EtOH等）、DMF或DMSO等有 機溶劑，或水或該等之混合溶劑。氫解時，通常可在鈀觸 媒存在下，於氫氣氛圍氣體中反應。在DMF、MeOH等溶 劑中，可於室溫至回流之反應溫度下製造。觸媒脫保護之 -23- 200951122 情況下可使用鈀等觸媒，在鹼性條件下製造。 (原料合成） [化5]The protecting groups described in "Greene's Organic Synthetic Protection Group (4th edition, 2006)" by Wut s (P. G. M. Wuts) and Greene (T. W. Greene) may be appropriately selected depending on the reaction conditions. After the introduction of the protecting group to carry out the reaction, the protecting group can be removed as needed to obtain the desired compound. Further, the compound of the formula (I) may be introduced into a specific group from the stage of the raw material to the intermediate, or may be produced by reacting the compound of the formula (I) obtained by Q, similarly to the above-mentioned protecting group. The reaction can be carried out by a method known to those skilled in the art using general esterification, amide amination, dehydration, etc. 〇 A representative production method of the compound of the formula (I) will be explained below. Each method of manufacture can also be carried out with reference to additional references in this specification. Further, the manufacturing method of the present invention is not limited to the examples shown below. (First Manufacturing Method) ^ The compound of the formula (I) can be produced by deprotecting the protected carbonic acid. The deprotection can be produced by hydrolysis, hydrogenolysis or deprotection of a catalyst. In the case of alkaline hydrolysis, inorganic hydrazine (NaOH, KOH, NaHC03, Cs2C〇3, etc.) can be used. When acid hydrolysis, hydrochloric acid can be used. Either reaction temperature can be carried out under ice-cold to reflux conditions without decomposing the substrate. As the solvent, an organic solvent such as an alcohol (MeOH, EtOH, etc.), DMF or DMSO, or water or a mixed solvent of these may be used. In the case of hydrogenolysis, it is usually reacted in a hydrogen atmosphere in the presence of a palladium catalyst. In a solvent such as DMF or MeOH, it can be produced at a reaction temperature from room temperature to reflux. Catalyst deprotection -23- 200951122 In the case of a catalyst such as palladium, it can be produced under alkaline conditions. (Material synthesis) [Chemical 5]

[R1’、R2’及R3’分別表示對R1、R2及R3分別所具有[R1', R2', and R3' respectively indicate that each of R1, R2, and R3 has

之羧基保護之基]。The base of the carboxyl group].

化合物（2a)可藉由使化合物（1)之胺基與相對應 之羧酸（R6-E-COOH)反應製造。羧酸（R6-E-COOH)係 (i)直接於同一反應系統內，在縮合劑存在下與化合物 (1)反應之方法，及（ii)衍生成反應性衍生物後，與 化合物（1)反應之方法（步驟1-1)。 (i)之使羧酸直接於同一系統內反應之方法係使化 合物（1)與對應之羧酸以等量或其一者過量使用，使該 等之混合物在縮合劑存在下，於對反應惰性之溶劑中，自 冷卻至加熱下’較好在-20°C至60 t下攪拌0.1小時至5 -24- 200951122 天。至於溶劑之例並無特別限制，但可舉例爲芳香族烴類 (苯、甲苯或二甲苯等）、鹵化烴類（DCM、1,2-二氯乙 烷或氯仿等）、醚類（二乙基醚、THF或二噁烷等）、 ' DMF、DMS0、Et0Ac、MeCN或水，以及該等之混合溶劑 。縮合劑之例舉例爲WSC、DCC、DPPA、磷醯氯，但並 不限於該等。若使用添加劑（例如HOBt等）有時對反應 較佳。在有機鹼（例如TEA、DIPEA或NMM等）、或無 Q 機鹼（例如’ K2C〇3或KOH等）之存在下進行反應，有 於使反應順利進行方面有利之情況。The compound (2a) can be produced by reacting an amine group of the compound (1) with a corresponding carboxylic acid (R6-E-COOH). The carboxylic acid (R6-E-COOH) is a method in which (i) is directly reacted with the compound (1) in the presence of a condensing agent, and (ii) is derivatized into a reactive derivative, and the compound (1) The method of reaction (step 1-1). (i) a method of reacting a carboxylic acid directly in the same system by using compound (1) in an equivalent amount or in an excess amount with the corresponding carboxylic acid, such that the mixture is reacted in the presence of a condensing agent. In an inert solvent, it is preferably stirred from -20 ° C to 60 t for 0.1 hour to 5 -24 to 200951122 days from cooling to heating. The solvent is not particularly limited, but examples thereof include aromatic hydrocarbons (benzene, toluene or xylene), halogenated hydrocarbons (DCM, 1,2-dichloroethane or chloroform, etc.) and ethers (two). Ethyl ether, THF or dioxane, etc.), 'DMF, DMS0, Et0Ac, MeCN or water, and mixtures of such solvents. Examples of the condensing agent are WSC, DCC, DPPA, and phosphonium chloride, but are not limited thereto. If an additive (e.g., HOBt, etc.) is used, the reaction is sometimes preferred. The reaction is carried out in the presence of an organic base (e.g., TEA, DIPEA or NMM, etc.) or a Q-free base (e.g., 'K2C〇3 or KOH, etc.), which is advantageous in that the reaction proceeds smoothly.

(Π)之羧酸轉變成反應性衍生物之後，與化合物（ 1)反應獲得化合物（2)之方法，羧酸之反應性衍生物之 例舉例爲與鹵化劑（例如，磷醯氯、亞硫醯氯等）反應獲 得之酸鹵化物，與氯甲酸異丁酯等反應獲得之混合酸酐， 與HOBt等縮合獲得之活性酯等。化合物（1 )與反應性 衍生物之反應可在鹵化烴類、芳香族烴類、醚類等之對反 〇 應惰性之溶劑中，自冷卻至加熱下，較好在-20°c至60°C . 下進行。而且，反應時於鹼（例如，NMM、TEA、DIPEA 、DMAP、吡啶、甲基吡啶、二甲基吡啶等）之存在下反 應有使反應順利進行方面有利之情況。另外，耻啶亦可兼 用作溶劑。 [文獻]S.R. Sandler及W. Karo著「有機官能基製備 」’第2版，第1卷，學院出版公司，1991年 曰本化學會編「實驗化學講座（第5版）」16卷（ 2005年）（九善） -25- 200951122 化合物（2b)可援用步驟1-1之條件製造。亦即，可 經由使用磺酸之游離酸或其反應性衍生物代替使用試藥之 羧酸游離酸或其反應性衍生物，藉此製造化合物（2b)( 步驟1-2)。 化合物（2c)可使化合物（1)與三碳醯氯等與HN( R6a) ( R6b )反應而製造。反應通常係在鹼（例如，NMM 、TEA、DIPEA、DMAP、吡啶、甲基吡啶、二甲基吡啶 等）之存在下進行。溶劑係使用鹵化烴類、芳香族烴類、 醚類、酯類、MeCN、DMF或DMSO等之對反應惰性之有 機溶劑，或該等之混合溶劑。另外，反應係在冷卻下、冷 卻至室溫下，或室溫至加熱下進行。 [化6]After the carboxylic acid of (Π) is converted into a reactive derivative, a compound (2) is obtained by reacting the compound (1), and a reactive derivative of the carboxylic acid is exemplified by a halogenating agent (for example, phosphonium chloride, argon). An acid anhydride obtained by the reaction of thiopurine or the like, an acid anhydride obtained by a reaction with isobutyl chloroformate or the like, an active ester obtained by condensation with HOBt or the like, or the like. The reaction of the compound (1) with the reactive derivative may be carried out in a solvent inert to the reaction of a halogenated hydrocarbon, an aromatic hydrocarbon or an ether, from cooling to heating, preferably from -20 ° C to 60. °C. Under proceed. Further, the reaction in the presence of a base (e.g., NMM, TEA, DIPEA, DMAP, pyridine, picoline, lutidine, etc.) is advantageous in that the reaction proceeds smoothly. In addition, dioxin can also be used as a solvent. [Document] SR Sandler and W. Karo, "Organic Functional Group Preparation", 2nd Edition, Volume 1, College Publishing Company, 1991, "The Experimental Chemistry Lecture (5th Edition)", 16 volumes (2005) Year) (Jiushan) -25- 200951122 Compound (2b) can be produced by using the conditions of Step 1-1. Namely, the compound (2b) (Step 1-2) can be produced by using a free acid of a sulfonic acid or a reactive derivative thereof instead of using a carboxylic acid free acid or a reactive derivative thereof. The compound (2c) can be produced by reacting the compound (1) with trimethyl chlorochloride or the like with HN(R6a)(R6b). The reaction is usually carried out in the presence of a base (e.g., NMM, TEA, DIPEA, DMAP, pyridine, picoline, lutidine, etc.). The solvent is an organic solvent inert to the reaction such as a halogenated hydrocarbon, an aromatic hydrocarbon, an ether, an ester, MeCN, DMF or DMSO, or a mixed solvent thereof. Further, the reaction is carried out under cooling, cooling to room temperature, or room temperature to heating. [Chemical 6]

(1) [式中，X意指鹵素等離去基]。 化合物（5)可藉由使烷醇或硫醇之化合物（3)與化 合物（4)偶合而製造（步驟2-1)。作爲鹼係使用無機 鹼（例如 NaOH、KOH、NaHC03、Cs2C03 等），反應溶 200951122 劑係使用鹵化烴類、芳香族烴類、醚類、EtOAc等酯類、 MeCN、DMF或DMS0等之對反應惰性之有機溶劑，或該 等之混合溶劑。另外，反應係在室溫至加熱下進行。 化合物（1)可由將化合物（4)之硝基還原而製造（ 步驟2-2)。反應可使用芳香族硝基之還原方法，且通常 在鹽酸條件下使鐵粉反應，或者可藉由接觸還原等製造。(1) [wherein, X means a halogen isobaric group]. The compound (5) can be produced by coupling an alkyl alcohol or a compound (3) of a mercaptan with the compound (4) (step 2-1). An inorganic base (for example, NaOH, KOH, NaHC03, Cs2C03, etc.) is used as the base, and the reaction solution 200951122 is a reaction using a halogenated hydrocarbon, an aromatic hydrocarbon, an ether, an ester such as EtOAc, MeCN, DMF or DMS0. An inert organic solvent, or a mixed solvent of these. Further, the reaction is carried out at room temperature to under heating. Compound (1) can be produced by reducing the nitro group of Compound (4) (Step 2-2). The reaction can be carried out by a method of reducing an aromatic nitro group, and the iron powder is usually reacted under a hydrochloric acid condition, or can be produced by contact reduction or the like.

另外，在製造上述之製造法及中間物製造法中所述以 外之實施例化合物及中間物時，可採用本說明書之製造例 或者實施例中所述之方法，或者以該等爲準之方法，而且 ，可藉由已知方法、熟悉本技藝者本身已瞭解之方法製造 再者，以式（I)表示之若干化合物可由如上述般製 造之本發明化合物’藉由任意組合習知之烷化、醯化、取 代反應、氧化、還原、水解、脫保護等熟悉本技藝者慣用 之步驟而製造。 〇 式（I )之化合物係經單離、純化成游離化合物、其 • 鹽、水合物、溶劑化物、或結晶多型物質。式（I)化合 _ 物之鹽可藉由施加慣用方法之造鹽反應而製造。 單離、純化係使用萃取、分段結晶、各種區分層析法 等慣用之化學操作進行。 各種異構物可藉由選擇適當之原料製造，或者可利用 異構物間之物理化學性質之差異分離。例如，光學異構物 係藉由消旋體之一般光學解析法（例如，藉由與光學活性 鹼或酸之非對映異構物鹽導致之分段結晶或使用對掌性管 -27- 200951122 柱等之層析儀）獲得，又，亦可自適當之光學活性原料製 造。 式（I)化合物之藥理活性係以下列之試驗確認。 試驗例1-1 :膜標本之調製Further, in the case of producing the compound of the example and the intermediates other than those described in the above-mentioned production method and intermediate production method, the method described in the production example or the examples of the present specification, or the method based on the above, may be employed. Further, it can be produced by a known method, a method known to those skilled in the art, and a plurality of compounds represented by the formula (I) can be alkylated by any combination of the compounds of the present invention as described above. , deuteration, substitution reaction, oxidation, reduction, hydrolysis, deprotection, and the like, which are familiar to those skilled in the art. The compound of the formula (I) is isolated, purified to a free compound, a salt, a hydrate, a solvate or a crystalline polymorph. The salt of the compound of the formula (I) can be produced by applying a salt-forming reaction by a conventional method. The separation and purification are carried out by conventional chemical operations such as extraction, fractional crystallization, and various differential chromatography. The various isomers may be produced by selecting an appropriate starting material or may be separated by the difference in physicochemical properties between the isomers. For example, optical isomers are by general optical resolution of the racemate (for example, by fractional crystallization with a diastereomeric salt of an optically active base or acid or using a pair of palms-27- 200951122 Columns and other chromatographs are obtained, and can also be made from suitable optically active materials. The pharmacological activity of the compound of formula (I) is confirmed by the following tests. Test Example 1-1: Modulation of membrane specimens

對人類CRTH2 cDNA持續表現之HEK293細胞，在緩 衝液（10mM BES(N，N-雙（2-羥基乙基）-2-胺基-乙烷-磺酸）、1 mM EDTA、1 OmM MnCl2，ρΗ = 7·0，以下稱爲 分析緩衝液）中，於26G注射針筒內快速通過並使其破 碎所調製之含細胞膜脂懸浮液作爲模標本，保存於-80 °C 。之後，於使用時融解進行試驗。 試驗例1-2 : CRTH2結合試驗HEK293 cells stably expressing human CRTH2 cDNA in buffer (10 mM BES (N, N-bis(2-hydroxyethyl)-2-amino-ethane-sulfonic acid), 1 mM EDTA, 1 OmM MnCl2, In the ρΗ = 7·0, hereinafter referred to as the analysis buffer, the cell-containing membrane lipid suspension prepared by rapidly passing through the 26G syringe and being disrupted was used as a model specimen and stored at -80 °C. After that, the test was carried out by melting at the time of use. Test Example 1-2: CRTH2 binding test

將膜標本（每一分析使用以蛋白量計爲50微克）、 受檢化合物及以氚標記之PGD2(最終濃度：2nM )於0.2 毫升分析緩衝液中在4°C培育2小時後，將反應液吸引過 濾至GF/B板（Perkin Elmer)之濾紙上，以洗淨用緩衝 液（lOmM BES、0.01% BSA )洗淨三次後，以 TopCount (Perkin Elmer )測定吸附在濾紙上之放射活性。又， CRTH2特異結合係以添力口 1 〇μΜ之DK-PGD2時所被抑制 之放射活性部分加以求得。 其結果，例如本發明化合物之以下實施例化合物（Ex )顯示分別如下之活性値（IC5〇値）。Exl : 9. InM ; Ex6 :1 InM ； Exl 8 ： 14nM ； Ex3 0 ： 2,9nM ； Ex34 ： 1 OnM ； -28- 200951122The membrane samples (50 micrograms in protein per assay), the test compound and PGD2 labeled with hydrazine (final concentration: 2 nM) were incubated in 0.2 ml of assay buffer for 2 hours at 4 ° C. The liquid was suction-filtered onto a filter paper of GF/B plate (Perkin Elmer), washed three times with a washing buffer (10 mM BES, 0.01% BSA), and then the radioactivity adsorbed on the filter paper was measured by a TopCount (Perkin Elmer). Further, the CRTH2-specific binding system was obtained by adding a radioactive portion which was inhibited when DK-PGD2 of 力-Μ1Μ was added. As a result, for example, the following example compound (Ex) of the compound of the present invention shows the following active oxime (IC5〇値). Exl : 9. InM ; Ex6 : 1 InM ; Exl 8 : 14nM ; Ex3 0 : 2,9nM ; Ex34 : 1 OnM ; -28- 200951122

Ex3 5 : 5,6nM ； Ex3 7 : 4.8nM ； Ex43 ： 9.9nM ； Ex5 5 : 4.1 nM ； Ex56 ： 8.7nM ； Ex94 : 4.8nM ； Ex 1 09 ： 4.9nM ； Exl40: 0.53nM; Ex 15 1 ： l.OnM; Exl52 ： 20nM。 試驗例2:天竺鼠抗原誘發呼吸道反應性亢進模型 本發明化合物之抗氣喘作用除對Burgess等人之方法 (Agent Actions, 1 992 年，37 ( 3-4)卷，第 162-1 64 頁 0 )些許變更以外藉由天竺鼠抗原誘發呼吸道反應性亢進模 型加以評價。 亦即，對雄性Hartley系天竺鼠經腹腔投與1毫升之 20毫克/毫升之蛋白蛋白（以下稱爲OVA)生理食鹽水（ 初次敏化，作爲第0天），進而於第2天經腹腔投與1毫 升之1毫克/毫升之OVA生理食鹽水，藉此進行動態抗原 敏化。自第14天至第21天使用超音波氣霧發生器（ OMRON公司），對動物每日一次每次10分中吸入暴露至 〇 0.5% OVA生理食鹽水（生理食鹽水對照組則吸入暴露至 . 生理食鹽水）。於抗原吸入暴露開始1小時前或4小時前 _ 經口投與受檢化合物。又，爲防止過敏反應，於吸入暴露 開始之30分鐘前，以10毫克/公斤經腹腔投與吡拉明（ pyrilamine ) ° 於第22天，以胺基甲酸酯（1.5克/公斤腹腔投與） 麻醉下，對動物氣管插入接續於人工呼吸器（型號683, Harvard公司）之導管，以加拉明（gallamine) (6毫克/ 公斤，腹腔內投與）使自發呼吸停止，在機械換氣（換氣 -29- 200951122 速度：每分鐘60下，換氣量：體重每loo克1毫升）以 3分鐘間隔依序靜脈內投與乙醯甲膽鹼（methacholine ) (0、2、4、6、8、10、12、14微克/公斤）。藉由壓力傳 導器測定呼吸道內壓之上升，算出對乙醯甲膽驗投與量與 呼吸道內壓上升作圖時之濃度曲線下面積（AUC )。 其結果’判定本發明化合物中，例如以下表示之實施 例化合物顯示有效活性。Ex3 5 : 5,6nM ; Ex3 7 : 4.8nM ; Ex43 : 9.9nM ; Ex5 5 : 4.1 nM ; Ex56 : 8.7nM ; Ex94 : 4.8nM ; Ex 1 09 : 4.9nM ; Exl40 : 0.53nM ; Ex 15 1 : l.OnM; Exl52: 20nM. Test Example 2: guinea pig antigen-induced respiratory hyperactivity model The anti-asthmatic effect of the compound of the present invention is in addition to the method of Burgess et al. (Agent Actions, 1973, 37 (3-4), vol. 162-1 64, page 0) A few changes were evaluated by a model of the guinea pig antigen-induced respiratory hyperactivity. That is, male Hartley guinea pigs were intraperitoneally administered with 1 ml of 20 mg/ml protein protein (hereinafter referred to as OVA) physiological saline (primary sensitization as day 0), and then intraperitoneally on day 2 Dynamic antigen sensitization was carried out with 1 ml of 1 mg/ml of OVA physiological saline. From the 14th day to the 21st day, the ultrasound aerosol generator (OMRON) was used to inhale and expose the animal to 0.5% OVA physiological saline once every 10 minutes (the physiological saline control group was inhaled and exposed to . Physiological saline). The test compound was orally administered 1 hour before or 4 hours before the start of antigen inhalation exposure. In addition, in order to prevent allergic reactions, the pyrilamine was administered intraperitoneally at 10 mg/kg 30 minutes before the start of inhalation exposure, and the urethane (1.5 g/kg was administered intraperitoneally). And under anesthesia, the trachea was inserted into the catheter of the artificial respirator (model 683, Harvard), and the spontaneous breathing was stopped by gallamine (6 mg/kg, intraperitoneal administration). Gas (ventilation -29- 200951122 speed: 60 per minute, ventilation: 1 ml per loo), intravenously administered methacholine (0, 2, 4) at 3 minute intervals , 6, 8, 10, 12, 14 μg / kg). The increase in the pressure in the respiratory tract was measured by a pressure transducer, and the area under the concentration curve (AUC) when the test for the amount of the acetaminophen was plotted against the increase in the pressure in the airway was calculated. As a result, it was judged that, for example, the compound of the example shown below showed an effective activity in the compound of the present invention.

Ex 抑制率 Ex 抑制率 1 66% (3毫克/公斤） (1小時前投與） 43 100% (3毫克/公斤） (4小時前投與） 6 61% (3毫克/公斤） (4小時前投與） 56 90% (1毫克/公斤） (4小時前投與） 1 8 46% (1毫克/公斤） (4小時前投與） 152 70% (3毫克/公斤） (4小時前投與） 34 76% (3 mg/kg) (1小時前投與） [表1] 上述實驗結果，確認式（I)化合物對CRTH2具有掊 抗活性。因此，可使用於炎症性疾病（例如，氣喘、過敏 性鼻炎、過敏性皮膚炎、結膜炎、奪麻疹、嗜酸血球性支 氣管炎、食物過敏、副鼻腔炎、血管炎、慢性阻塞性肺疾 病等）或多發性硬化症等之治療。 又，本案中，例如實施例化合物之羧酸成爲酯之製造 力化合物並未顯示活性。可定本發明中實施例化合物之羧 -30- 200951122 酸之酸性質子對於CRTH2展現拮抗活性具重要性。 含有式（I)化合物或其鹽之一種或兩種以上作爲有 效成分之醫藥組成物可使用該領域通常使用之賦形劑亦即 ' 藥劑用賦形劑或藥劑溶介質等，藉由通常使用之方法加以 調製。 投與可藉錠劑、九劑、膠囊、顆粒劑、散劑、液劑等 經口投與，或亦可藉關節內、靜脈內、肌肉內等之注射劑 ◎ 、栓劑、點眼劑、眼軟膏、經皮用液劑、軟膏劑、經皮用 貼附劑、經黏膜液劑、經黏膜貼附劑、吸入劑等之非經口 投與之任一種形態。 至於用於經口投與之固體組成物係使用錠劑、散劑、 顆粒劑等。於該等固體組成物，係使1種或2種以上之有 效成分與至少一種惰性賦形劑例如乳糖、甘露糖、葡萄糖 、羥丙基纖維素、微晶纖維素、澱粉、聚乙烯吡咯啶酮及 /或偏矽酸鋁酸鎂等混合而成。組成物亦可依據一般方法 Ο 含有惰性添加劑如如硬脂酸鎂之潤滑劑或如羧甲基澱粉鈉 - 等之崩解劑、安定化劑、溶解助劑。錠劑或九劑可依據需 . 要以糖衣或胃溶性或腸溶性物質之膜加以被膜。 用以經口投與之液體組成物包含藥劑上可容許之乳濁 劑、溶液劑、懸浮劑、糖漿劑或酊劑，可含有一般使用之 惰性稀釋劑例如純化水或乙醇。該液體組成物除惰性稀釋 劑以外’亦可含有如可溶化劑、濕潤劑、懸浮劑之輔助劑 、甜味劑、矯味劑、芳香劑、防腐劑。 用於非經口投與之注射劑含有無菌水性或非水性溶液 -31 - 200951122Ex inhibition rate Ex inhibition rate 1 66% (3 mg/kg) (administered 1 hour ago) 43 100% (3 mg/kg) (administered 4 hours ago) 6 61% (3 mg/kg) (4 hours) Pre-administration) 56 90% (1 mg/kg) (administered 4 hours ago) 1 8 46% (1 mg/kg) (administered 4 hours ago) 152 70% (3 mg/kg) (4 hours ago Administration 34 76% (3 mg/kg) (administered 1 hour ago) [Table 1] The above experimental results confirmed that the compound of the formula (I) has an antagonistic activity against CRTH2. Therefore, it can be used for inflammatory diseases (for example, asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, measles, eosinophilic bronchitis, food allergy, paranasal vaginitis, vasculitis, chronic obstructive pulmonary disease, etc. ) or treatment of multiple sclerosis. Further, in the present invention, for example, a compound having a carboxylic acid as an ester of the compound of the example does not exhibit activity. The carboxylic acid proton of the compound of the present invention can be determined to exhibit an antagonistic activity for CRTH2. The pharmaceutical composition containing one or two or more compounds of the compound of the formula (I) or a salt thereof as an active ingredient can be used by using an excipient which is generally used in the field, that is, a pharmaceutical excipient or a drug solution medium, etc., by usual use. The method is modulated. Injectable tablets, nine doses, capsules, granules, powders, liquids, etc., or injectables such as intra-articular, intravenous, intramuscular, etc. ◎, suppositories, eye drops, eye ointments , a percutaneous solution, an ointment, a transdermal patch, a mucosal solution, a mucosal patch, an inhalant, or the like, which is administered orally. As for the solid composition for oral administration, a tablet, a powder, a granule, or the like is used. In the solid composition, one or more active ingredients are combined with at least one inert excipient such as lactose, mannose, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidine. A mixture of a ketone and/or magnesium metasilicate aluminate. The composition may also be in accordance with a general method Ο an inert additive such as a lubricant such as magnesium stearate or a disintegrant such as sodium carboxymethyl starch, a stabilizer, and a dissolution aid. Lozenges or nine doses may be applied as needed. The film is applied as a film of sugar-coated or stomach-soluble or enteric material. The liquid composition for oral administration contains a pharmaceutically acceptable emulsion, solution, suspension, syrup or elixir, and may contain an inert diluent such as purified water or ethanol which is generally used. The liquid composition may contain, in addition to the inert diluent, an adjuvant such as a solubilizing agent, a wetting agent, a suspending agent, a sweetener, a flavoring agent, a flavoring agent, and a preservative. Injection for parenteral administration containing sterile aqueous or non-aqueous solution -31 - 200951122

劑、懸浮劑或乳濁劑。至於水性溶劑，包含例如注射用蒸 餾水或生理食鹽水。至於非水性溶劑，有例如丙二醇、聚 乙二醇或如橄欖油之植物油、如乙醇之醇類、或聚山梨糖 醇酯80 (藥典名）等。此種組成物亦可進而含有等張化 劑、防腐劑、濕潤劑、乳化劑、分散劑、安定化劑或溶解 助劑。該等可例如通過保留細菌之過濾膜加以過濾、配合 殺菌劑或藉由照射加以無菌化。又，亦可製造該等無菌固 體組成物，於使用前溶解或懸濁於無菌水或無菌注射用溶 劑中後加以使用。A suspending agent or an opacifying agent. As the aqueous solvent, for example, distilled water for injection or physiological saline is contained. As the nonaqueous solvent, there may be mentioned, for example, propylene glycol, polyethylene glycol or a vegetable oil such as olive oil, an alcohol such as ethanol, or a polysorbate 80 (Pharmacopoeia). Such a composition may further contain an isotonic agent, a preservative, a wetting agent, an emulsifier, a dispersing agent, a stabilizer, or a dissolution aid. These may be sterilized, for example, by filtration through a filter membrane that retains bacteria, in combination with a bactericide, or by irradiation. Further, the aseptic solid composition may be produced and dissolved or suspended in sterile water or a sterile injectable solvent before use.

作爲外用劑，包含軟膏劑、硬膏劑、乳霜劑、凍膏劑 、外敷軟膏劑、噴霧劑、洗劑、點眼劑、眼軟膏等。含有 一般使用之軟膏基劑、洗劑基劑、水性或非水性液劑、懸 濁劑、乳劑等。例如作爲軟膏或洗劑基劑，舉例有聚乙二 醇、丙二醇、白色凡士林、白色蜜孅、聚氧乙烯硬化篦麻 油、單硬脂酸甘油酯、硬脂醇、鯨孅醇、月桂聚乙二醇（ Lauromacrogol)、倍半油酸山梨糖醇酐酯等。 吸收劑或經鼻劑等之經黏膜劑係使用液體或半固體狀 者，可依據以往已知方法製造。例如可適當添加習知賦形 劑或進而添加pH調節劑、防腐劑、界面活性劑、潤滑劑 、安定劑或增黏劑等。投與可使用用以適當吸入或吹送之 裝置。例如使用計量投與吸入裝置等之習知裝置或噴霧器 ，化合物作以單獨或經處方之混合物之粉末或與醫藥容許 之擔體組合而成之溶液或懸濁液予以投與。乾燥粉末吸入 器等，亦可爲單次或多次投予用者，可利用乾燥粉末或含 -32- 200951122 有粉末之膠囊。或者，亦可爲使用適當推進劑例如氯氟烷 、氫氟院或二氧化碳等之適當氣體之加壓氣溶膠噴霧器等 之形態。 ' 通常經口投與時，每日投與量，適宜爲每體重約爲 0.001至100毫克/公斤，較好爲0J至30毫克/公斤，更 好爲0.1至10毫克/公斤，其可每日投與—次或分2至4 次投與。靜脈內投與時，每日投與量，適宜爲每體重約爲 _ 0.0001至10毫克/公斤，每日投與一次或分數次投與。又 ，作爲經黏膜劑，適宜爲每體重約爲0.001至100毫克/ 公斤，每日投與一次或分數次，投與。投與量係依據症狀、 年齡、性別等加以考慮而對應個別情況適當決定。 式（I)化合物可倂用對於認爲上述式（I)化合物顯 示爲有效之疾病之各種治療劑或預防劑。該併用可同時投 與或個別連續投與或亦可間隔所需時間間隔投與。同時投 與製劑可爲配合劑亦可經各別製劑化。 . [實施例] 以下，依據實施例更詳細說明式（Ο化合物之製造 方法。又，本發明不限定於下列實施例中所述化合物。又 ，製造例中分別顯示原料化合物之製造方法。又，式（I )化合物之製造方法並不僅限於以下所示之具體實施例之 製造方法，式（I)化合物亦可藉由該等製造方法之組合 ，或以熟悉本技藝者本身已知之方法製造。 又，實施例、製造例及後續表中係使用下列簡寫。Pr -33- 200951122 :製造例編號，Ex :實施例編號，structure :構造式， Data :物理化學數據，NMR : W-NMR ( d6-DMSO )， NMR ( CDC13 ) ： *H-NMR ( CDC13 ) ，ESI : ESI-MS。 製造例1As the external preparation, an ointment, a plaster, a cream, a cream, an external ointment, a spray, a lotion, an eye drop, an eye ointment and the like are contained. It contains an ointment base, a lotion base, an aqueous or non-aqueous liquid agent, a suspending agent, an emulsion, and the like which are generally used. For example, as an ointment or lotion base, polyethylene glycol, propylene glycol, white petrolatum, white candied fruit, polyoxyethylene hardened castor oil, glyceryl monostearate, stearyl alcohol, whale sterol, and laurel A diol (lauromacrogol), sorbitan oleate, and the like. The transmucosal agent such as an absorbent or a nasal spray can be produced by a conventionally known method using a liquid or semi-solid. For example, a conventional excipient or a pH adjusting agent, a preservative, a surfactant, a lubricant, a stabilizer or a tackifier may be added as appropriate. The device can be used for proper inhalation or insufflation. For example, a compound or a nebulizer for metering an inhalation device or the like is used, and the compound is administered as a solution or a suspension of a mixture of a single or a prescribed mixture or a drug-supported carrier. A dry powder inhaler or the like may be used for single or multiple administrations, and may be a dry powder or a capsule containing -32-200951122 powder. Alternatively, it may be in the form of a pressurized aerosol sprayer or the like using a suitable propellant such as a chlorofluorocarbon, a hydrofluorocarbon or a carbon dioxide gas. 'When usually administered orally, the daily dose is suitably from 0.001 to 100 mg/kg per body weight, preferably from 0 J to 30 mg/kg, more preferably from 0.1 to 10 mg/kg. The daily investment is divided into two or four times. When administered intravenously, the daily dose is suitably about 0.00101 to 10 mg/kg per body weight, administered once daily or in divided doses. Further, as a transmucosal agent, it is suitably administered at a dose of about 0.001 to 100 mg/kg per body weight, administered once or several times a day, and administered. The amount of administration is determined based on symptoms, age, gender, etc., and is determined appropriately for individual cases. The compound of the formula (I) can be administered with various therapeutic or prophylactic agents for diseases which are considered to be effective for the compound of the above formula (I). The combined use may be administered simultaneously or individually in succession or may be administered at intervals required. At the same time, the preparation can be formulated as a compounding agent or can be separately formulated. [Examples] Hereinafter, the formula (the method for producing a ruthenium compound) will be described in more detail based on the examples. Further, the present invention is not limited to the compounds described in the following examples. Further, in the production examples, the production methods of the raw material compounds are respectively shown. The method for producing the compound of the formula (I) is not limited to the production method of the specific examples shown below, and the compound of the formula (I) may be produced by a combination of the methods of production or by a method known per se to those skilled in the art. In addition, the following abbreviations are used in the examples, the production examples, and the subsequent tables. Pr - 33 - 200951122 : Manufacturing example number, Ex : Example number, structure : Structural formula, Data : Physical and chemical data, NMR : W-NMR ( d6-DMSO), NMR (CDC13): *H-NMR (CDC13), ESI: ESI-MS.

於含3-氯-4-羥基苯基乙酸乙酯（5.66克）之DMF ( 100毫升）溶液中添加K2C03 (4.74克）及二甲基硫代胺 基甲醯氯（3.75克），在50 °C下攪拌5小時。將反應混 合物注入水（500毫升）中，以EtOAc(300毫升）萃取 。有機層以水（200毫升）、飽和食鹽水（200毫升）洗 淨後，以MgS04乾燥後，濾液經減壓濃縮，藉此獲得3-氯-4-(二甲基胺基碳亞硫醯氧基）苯基乙酸乙酯（7.69 克）之橙色油。 製造例2 使3-氯-4-(二甲基胺基碳亞硫醯氧基）苯基乙酸乙 〇 酯（7.6克）在外溫240°C下攪拌3小時。反應物以矽膠 . 管柱層析儀（正己烷/EtOAc )純化，獲得（3-氯-4-(( 二甲基胺基甲醯基）磺胺醯基）苯基）乙酸乙酯（1.65克 )之橙色油。 製造例3 使（3-氯-4-((二甲基胺基甲醯基）磺胺醯基）苯 基）乙酸乙酯（1.64克）溶於Me OH(16_4毫升）中，添 -34- 200951122 加ΚΟΗ (1·52克）之水（8.2毫升）溶液，在50°C下攪拌 2小時。減壓濃縮反應混合物，使殘留物溶解於水（10毫 升）中，在室溫攪拌下滴加1M鹽酸（40毫升）。經攪拌 ' 30分鐘以上後，過濾收集析出物。乾燥過濾物，獲得（ 3-氯-4-磺胺醯基苯基）乙酸（0.93克）之淡黃色粉末。 如製造例3般，使用對應之原料製造下表所示之製造 例3 -1至3 - 2之化合物。 〇 製造例4 於含{4- (4-胺基苯氧基）-3-氯苯基}乙酸乙酯（1.50 克）之DCM ( 30毫升）溶液中添加3,4-二氯苯甲酸（ 1.12 克）、WSC.HC1(1.13 克）、HOBt(795 毫克）， 且在室溫下攪拌6小時。將反應溶液注入水（150毫升） 中後，以EtOAc (300毫升）萃取。有機層以水（150毫 升）、飽和食鹽水洗淨後，以MgS04乾燥後’減壓濃縮 φ 濾液。殘留物使用矽膠管柱層析純化，獲得3-氯-4-{4-( . 3，4-二氯苯甲醯基胺基）苯氧基}苯基乙酸乙酯（1.90克 )之淡黃色固體。 如製造例4般，使用對應之原料製造下表所示之製造 例4-1至4-136之化合物。 製造例5 於含{4- ( 6-胺基吡啶-3 -基氧基）-3-氯苯基丨乙酸乙 酯（150毫克）之DCM( 3毫升）溶液中添加3，4_二氯苯 -35- 200951122 甲醯氯（108 毫克）、TEA ( 82μί ) 、DMAP ( 12 毫克） ，且在室溫下攪拌隔夜。將反應混合物注入水中，以 EtOAc萃取。有機層依序以飽和NaHC03水溶液、水、飽 · 和食鹽水洗淨後，經MgS04乾燥後，減壓濃縮濾液。使 ， 所得殘留物經矽膠管柱層析（正己烷：EOAc = 3 : 1 )純化 ，獲得[3-氯-4- ( {6-[ ( 3,4-二氯苯甲醯基）胺基]吡啶- 3-基}氧基）苯基]乙酸乙酯（209.5毫克）之無色膠狀物。 〇 製造例6 在冰冷卻下，於含[4-(4-胺基苯氧基）-3-氯苯基]乙 酸乙酯（300毫克）之THF (6毫升）溶液中添加TEA ( 410微升）及三碳醯氯（146毫克）且攪拌1小時後，添 加1，2,3,4-四氫異喹啉（137微升），在室溫下攪拌隔夜 。以EtOAc稀釋反應溶液後，依序以1M鹽酸、飽和食鹽 水洗淨，以MgS04乾燥後，減壓濃縮濾液。使所得殘留 物經矽膠管柱層析純化，獲得（3-氯-4-{4-[ ( 3,4-二氫異 〇 喹啉-2(1H)-基羰基）胺基]苯氧基}苯基）乙酸乙酯（ _ 243毫克）之淡褐色無定型物。 如製造例6般，使用對應之原料製造下表所示之製造 例6 -1至6 - 8之化合物。 製造例7 在冰冷卻下，於含[3 -氯- 4-( 4-{( 4 -硝基苯氣基羰基 )胺基}苯氧基）苯基]乙酸乙酯（25〇毫克）與TEA( -36 - 200951122 148微升）之THF (5毫升）溶液中添加苯乙胺（80.4微 升），在室溫下攪拌1小時。將反應溶液注入水中後，以 EtOAc萃取。有機層依序以飽和NaHC03 7欠溶液、水、飽 和食鹽水洗淨後，經MgS04乾燥後，減壓濃縮濾液。使 用IPE洗淨殘留物，獲得[3-氯-4- ( 4-{[2-苯基乙基]胺甲 醯基}胺基）苯氧基]苯基]乙酸乙酯（203毫克）之白色粉 末。 0 如製造例7般，使用對應之原料製造下表所示之製造 例7-1及7-2之化合物。 製造例8 於含（3-氯-4-羥基苯基）乙酸（3.00克）之EtOH ( 30毫升）溶液中添加濃硫酸（89.3微升），且在室溫下 攪拌隔夜。將反應溶液注入水中後，以EtOAc萃取。有 機層依序以水、飽和NaHC03水溶液、水、飽和食鹽水洗 〇 淨後，經MgS04乾燥後，減壓濃縮濾液，獲得（3-氯-4-. 羥基苯基）乙酸乙酯（3.30克）之褐色油狀物質。 如製造例8般，使用對應之原料製造下表所示之製造 例8-1及8-5之化合物。 製造例9 在冰冷卻下於含[3-氯-4- ( 4-胺基苯氧基）苯基]乙酸 乙酯（1.50克）之DCM(30毫升）溶液中添加吡啶（ 1.31毫升），攪拌10分鐘，且緩慢添加氯甲酸（4-硝基 -37- 200951122 苯基）酯（1.19克）’在室溫下攪拌2小時。將水（ι〇〇 毫升）添加於反應溶液中攪拌10分鐘後，以EtOAc萃取 。有機層以飽和食鹽水洗淨後，經MgS04乾燥後，減壓 濃縮濾液。使殘留物經矽膠管柱層析（正己烷：Et0Ac = 3 :2-0 : 1 )純化，以混合溶劑（DCM : IPE=1 : 4 )洗淨所 得之粗製結晶，獲得[3 -氯-4-( 4-{[( 4 -硝基苯氧基）擬 基]胺基}苯氧基）苯基]乙酸乙酯（2.36克）之白色粉末 製造例1 0 於[4- ( 4-{[ ( 5-溴·1-苯并呋喃-2-基）羰基]胺基}苯 氧基）-3-氯苯基]乙酸乙酯之DMF ( 5毫升）溶液中添加 Zn(CN) 2(133 毫克）及 Pd( PPh3 ) 4 ( 175 毫克），且 在微波照射下於1 5 0 °C反應1小時。濾除不溶物，將水（ 50毫升）加於濾液中，以EtO Ac ( 40毫升）萃取。有機 層依序以水、飽和食鹽水洗淨，以MgS04乾燥，減壓濃 〇 縮濾液。獲得褐色油（ 570毫克）。使殘留物經矽膠管柱 . 層析（正己烷：EtOAc = 2: 1)純化’獲得[3 -氯-4-(4-{[ (5-氰基-1-苯并呋喃-2-基）羰基]胺基}苯氧基）苯基]乙 酸乙酯（199.3毫克）之白色固體。 製造例11 於含{3-氯-4-(4-硝基苯氧基）苯基}乙酸乙酯（300 毫克）之DCM ( 6毫升）溶液中添加吡啶（95.2微升）及 -38- 200951122 苯磺醯氯（138微升），且在室溫下攪拌隔夜。將反應溶 液注入水中後，使用EtO Ac萃取。有機層依序以水、飽 和食鹽水洗淨後，經MgS04乾燥，且減壓濃縮濾液，使 • 殘留物經矽膠管柱層析純化，獲得（3-氯-4-{4-[(苯基磺 醯基）胺基]苯氧基}苯基）乙酸乙酯（410毫克）之白色 粉末。 如製造例11般，使用對應之原料製造下表所示之製 造例1 1 -1之化合物。 製造例12 在冰冷卻下於硼烷-THF錯合物（1.17M，12.8毫升） 中添加環己烯（3.04毫升）且攪拌5分鐘後，添加含 {[2,5-二氯- 4-(4-硝基苯氧基）苯基]乙烯基}(三甲基） 矽烷（1.63克）之THF ( 25毫升）溶液，且在相同溫度 下攪拌2小時。於反應溶液中添加iM NaOH水溶液（ Ο 10.7毫升）及Me〇H(12.5毫升）後，添加過氧化氫水溶 • 液（30%，4.86毫升）且在相同溫度下攪拌1小時。將反 . 應溶液注入水中後，以EtOAc萃取，有機層以飽和食鹽 水洗淨後’以MgS04乾燥，減壓濃縮濾液。使殘留物溶 解於EtOH (5毫升）中’添加一滴濃硫酸，加熱回流4 小時。將反應溶液冷卻至室溫後，注入水中，以EtOAc 萃取。有機層以飽和食鹽水洗淨，以MgS04乾燥，且減 壓濃縮濾液。殘留物經矽膠管柱層析純化，獲得[2,5_二 氯-4- (4 -硝基苯氧基）苯基]乙酸乙酯（51〇毫克）之茶 -39- 200951122 色油狀物質。 製造例13 於含1-溴-2,5-二氯-4- ( 4-硝基苯氧基）苯（1.85克 )與TEA (1·07毫升）之MeCN(10毫升）溶液中添加二 氯雙（三苯基膦）鈀（358毫克）、碘化酮（I) (194毫 克）、（三甲基矽烷基）乙炔（2_12毫升），且在微波照 射下於80°C下反應2小時。將反應溶液注入水中後，以 EtOAc萃取。有機層以飽和食鹽水洗淨後，以MgS04乾 燥，且減壓濃縮濾液。殘留物經矽膠管柱層析純化，獲得 {[2,5-二氯-4- ( 4-硝基苯氧基）苯基]乙烯基}(三甲基） 矽烷（1.63克）之茶色油狀物質。 製造例1 4Add K2C03 (4.74 g) and dimethylthioaminomethylguanidinium chloride (3.75 g) to a solution of ethyl 3-chloro-4-hydroxyphenylacetate (5.66 g) in DMF (100 mL) Stir at ° C for 5 hours. The reaction mixture was poured into EtOAc (EtOAc) The organic layer was washed with water (200 ml) and saturated brine (200 ml), and dried over Mg.sub.4. Ethyl phenyl phenylacetate (7.69 g) in orange oil. Production Example 2 3-Chloro-4-(dimethylaminocarbazosulfinyloxy)phenylacetate (7.6 g) was stirred at an external temperature of 240 ° C for 3 hours. The reaction was purified by column chromatography (hexanehexane /EtOAc) toield (3-chloro-4-((dimethylaminocarbamoyl)sulfonyl)phenyl)ethyl acetate (1.65 g) ) orange oil. Production Example 3 Ethyl (3-chloro-4-((dimethylaminocarbamimidino)sulfonyl)phenyl)acetate (1.64 g) was dissolved in Me OH (16-4 ml). 200951122 A solution of hydrazine (1.52 g) in water (8.2 ml) was stirred at 50 ° C for 2 hours. The reaction mixture was concentrated under reduced vacuol. After stirring for '30 minutes or more, the precipitate was collected by filtration. The filtrate was dried to give (3-chloro-4-sulfonamidophenyl)acetic acid (0.93 g) as a pale yellow powder. As in Production Example 3, the compounds of Production Examples 3-1 to 3-2 shown in the following Table were produced using the corresponding raw materials. 〇Production Example 4 To a solution of ethyl 4-(4-aminophenoxy)-3-chlorophenyl}acetate (1.50 g) in DCM (30 mL) 1.12 g), WSC.HC1 (1.13 g), HOBt (795 mg), and stirred at room temperature for 6 hours. The reaction solution was poured into water (150 ml) The organic layer was washed with water (150 ml) and a saturated aqueous solution of sodium chloride, and dried with MgSO 4 and then concentrated. The residue was purified using EtOAc EtOAc EtOAc EtOAc (EtOAc (EtOAc) Yellow solid. As in Production Example 4, the compounds of Production Examples 4-1 to 4-136 shown in the following Table were produced using the corresponding raw materials. Preparation Example 5 To a solution of ethyl 4-(6-aminopyridin-3-yloxy)-3-chlorophenylhydrazine (150 mg) in DCM (3 mL) Benzene-35- 200951122 formazan chloride (108 mg), TEA (82 μί), DMAP (12 mg), and stirred at room temperature overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with a saturated aqueous solution of NaHCO.sub.3, water, sat. and brine, and dried over EtOAc. The residue obtained was purified by hydrazine column chromatography (hexane: EOAc = 3: 1) to give [3-chloro-4-({6-[(3,4-dichlorobenzhydryl)) Pyridine-3-yl}oxy)phenyl]acetate (209.5 mg) as a colorless gum. 〇Production Example 6 TEA (410 μm) was added to a solution of [4-(4-aminophenoxy)-3-chlorophenyl]acetate (300 mg) in THF (6 mL). After stirring for 1 hour with trichlorophosphonium chloride (146 mg), 1,2,3,4-tetrahydroisoquinoline (137 μL) was added and stirred at room temperature overnight. The reaction solution was diluted with EtOAc, and washed with 1M hydrochloric acid and brine. The obtained residue was purified by hydrazine column chromatography to give (3-chloro-4-{4-[(3,4-dihydroisoindolequinolin-2(1H)-ylcarbonyl)amino]phenoxy }Phenyl)acetate ( _ 243 mg) of pale brown amorphous material. As in Production Example 6, the compounds of Production Examples 6-1 to 6-8 shown in the following Table were produced using the corresponding raw materials. Production Example 7 Under the cooling of ice, [3-chloro-4-(4-{(4-nitrophenyl)carbonyl)amino}phenoxy)phenyl]acetate (25 mg) To a solution of TEA (-36 - 200951122 148 liters) in THF (5 mL) was added phenethylamine (80.4 liters) and stirred at room temperature for 1 hour. After the reaction solution was poured into water, it was extracted with EtOAc. The organic layer was washed successively with saturated NaHC03 7 under solution, water and saturated brine, dried over MgSO 4 , and evaporated. The residue was washed with IPE to give [3-chloro-4-(4-{[2-phenylethyl]aminocarbamoyl}amino)phenoxy]phenyl]acetate (203 mg). White powder. 0 As in Production Example 7, the compounds of Production Examples 7-1 and 7-2 shown in the following Table were produced using the corresponding raw materials. Production Example 8 Concentrated sulfuric acid (89.3 μl) was added to a solution of (3-chloro-4-hydroxyphenyl)acetic acid (3.00 g) in EtOH (30 ml), and stirred overnight at room temperature. After the reaction solution was poured into water, it was extracted with EtOAc. The organic layer was washed with water, saturated aqueous NaHCO3, water, and brine, and dried over EtOAc EtOAc. Brown oily substance. As in Production Example 8, the compounds of Production Examples 8-1 and 8-5 shown in the following Table were produced using the corresponding raw materials. Preparation Example 9 To a solution of [3-chloro-4-(4-aminophenoxy)phenyl]acetate (1.50 g After stirring for 10 minutes, chloroformic acid (4-nitro-37-200951122 phenyl) ester (1.19 g) was slowly added and stirred at room temperature for 2 hours. Water (ι 毫升) was added to the reaction solution and stirred for 10 minutes, and then extracted with EtOAc. The organic layer was washed with brine, dried over MgSO 4 , and evaporated. The residue was purified by column chromatography (hexane: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: White powder of ethyl 4-(4-{[(4-nitrophenoxy)methyl]amino}phenoxy)phenyl]acetate (2.36 g). Add Zn(CN) 2 to a solution of {[( 5-bromo-l-benzofuran-2-yl)carbonyl]amino}phenoxy)-3-chlorophenyl]acetate in DMF (5 mL) (133 mg) and Pd(PPh3) 4 (175 mg), and reacted at 150 ° C for 1 hour under microwave irradiation. The insoluble material was filtered, and water (50 ml) was added to the filtrate and extracted with EtO Ac (40 ml). The organic layer was washed successively with water and saturated brine, dried over MgSO 4 , and evaporated. Obtained brown oil (570 mg). The residue was purified by column chromatography eluting with EtOAc (hexane: EtOAc = 2:1) to afford [3-chloro-4-(4-{[(5-cyano-1-benzofuran-2-yl) Ethyl carbonyl]amino}phenoxy)phenyl]acetate (199.3 mg) as a white solid. Preparation Example 11 To a solution of ethyl 5-(4-chloro-4-(4-nitrophenoxy)phenyl}acetate (300 mg) in EtOAc (m. 200951122 Benzene sulfonium chloride (138 μL) and stirred at room temperature overnight. After the reaction solution was poured into water, it was extracted with EtO Ac. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride, and dried over MgSO4, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain (3-chloro-4-{4-[(benzene) A white powder of ethyl sulfonyl)amino]phenoxy}phenyl)acetate (410 mg). As in Production Example 11, the compound of Production Example 1 1-1 shown in the following Table was produced using the corresponding raw materials. Production Example 12 After adding cyclohexene (3.04 ml) to a borane-THF complex (1.17 M, 12.8 ml) under ice cooling and stirring for 5 minutes, the addition of {[2,5-dichloro-4- A solution of (4-nitrophenoxy)phenyl]vinyl}(trimethyl)decane (1.63 g) in THF (25 mL). After adding iM NaOH aqueous solution (Ο 10.7 ml) and Me〇H (12.5 ml) to the reaction solution, hydrogen peroxide aqueous solution (30%, 4.86 ml) was added and stirred at the same temperature for 1 hour. After the solution was poured into water, the mixture was extracted with EtOAc. EtOAc was evaporated. The residue was dissolved in EtOH (5 mL). After cooling the reaction solution to room temperature, it was poured into water and extracted with EtOAc. The organic layer was washed with saturated brine, dried over MgSO 4 and evaporated. The residue was purified by silica gel column chromatography to give [2,5-dichloro-4-(4-nitrophenoxy)phenyl]acetic acid ethyl ester (51 mg) of tea-39-200951122 substance. Preparation Example 13 Addition of a solution of 1-bromo-2,5-dichloro-4-(4-nitrophenoxy)benzene (1.85 g) and TEA (1.07 ml) in MeCN (10 ml) Chlorobis(triphenylphosphine)palladium (358 mg), iodinated ketone (I) (194 mg), (trimethyldecyl) acetylene (2-12 ml), and reacted at 80 ° C under microwave irradiation 2 hour. After the reaction solution was poured into water, it was extracted with EtOAc. The organic layer was washed with saturated brine, dried over MgSO 4 and evaporated. The residue was purified by hydrazine column chromatography to give brown oil of [[2,5-dichloro-4-(4-nitrophenoxy)phenyl]vinyl}(trimethyl) decane (1.63 g). Shaped matter. Manufacturing Example 1 4

於含{3-氯-4- (4-硝基苯氧基）苯基}乙酸乙酯（2.30 克）之EtOH ( 46毫升）-水（11.5毫升）溶液中添加氯 化銨（3.66克）及鐵粉（3.83克），加熱回流3小時。 以矽藻土過濾反應溶液後，減壓濃縮，添加飽和NaHC03 後，以EtOAc萃取。有機層以飽和食鹽水洗淨後，以 MgS04乾燥，減壓濃縮濾液，獲得{4- (4-胺基苯氧基）-3-氯苯基}乙酸乙酯（2.30克）之褐色油狀物質。 如製造例1 4般，使用對應之原料製造下表中所列製 造例14-1至14-15之化合物。 -40- 200951122 製造例15 在冰冷卻下，於含（2-溴·4-甲氧基苯基）乙酸乙酯 (4.4克）之DCM(44毫升）溶液中滴力卩1M BBr3之 ' DCM溶液（24.1毫升）。在5°C下攪拌5小時後，在冰冷 卻下於反應混合物中滴加EtOH (30毫升），終止反應， 且減壓濃縮，以EtO Ac ( 150毫升）萃取所得殘留物。有 機層依序以水（1〇〇毫升）、飽和食鹽水（100毫升）洗 Q 淨，以MgS04乾燥，且減壓濃縮濾液。使殘留物經正己 烷/IPE粉末化後過濾收集，藉由減壓乾燥，獲得（2-溴-4-羥基苯基）乙酸乙酯（2.56克）之白色固體。 製造例16 於含（3-氯-4-羥基苯基）乙酸乙酯（2.00克）之 DMF(30毫升）溶液中添加K2C03(2.58克）及4-硝基 氟苯（1.03毫升），且在60°C下攪拌2小時。將反應混 〇 合物冷卻至室溫後，注入水中，使用EtOAc萃取。有機 • 層以飽和食鹽水洗滁兩次後，以MgS04乾燥，且減壓濃 縮濾液。殘留物經矽膠管柱層析（正己烷·· EtOAc = 4 : 1 )純化，獲得{3-氯-4- (4-硝基苯氧基）苯基}乙酸乙酯（ 2.30克）之褐色油狀物質。 如製造例16般，使用對應之原料製造下表中所列製 造例16-1至16-15之化合物。 製造例17 -41 - 200951122 在室溫下攪拌含 4-苄氧基-1-吲哚（2.98克）與 K2C03 ( 1.12克）之DMF ( 30毫升）懸浮液，且逐次添 加溴乙酸乙酯（1.9毫升），且在室溫下攪拌隔夜。追加 K2C03 (1.12克）及溴乙酸乙酯（1.9毫升），且於室溫 下再攪泮8小時。將水加於反應混合物中且以EtO Ac萃 取’有機層以飽和食鹽水洗淨後，以MgS04乾燥，減壓 濃縮濾液。所得殘留物經矽膠管柱層析（甲苯）純化，獲 得（4-苄氧基-1H-吲哚-1-基）乙酸乙酯（1.66克）之白 色固體。 製造例18Add ammonium chloride (3.66 g) to a solution of ethyl <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Iron powder (3.83 g) was heated and refluxed for 3 hours. The reaction solution was filtered with EtOAc (EtOAc)EtOAc. The organic layer was washed with brine, dried over EtOAc EtOAcjjjjjjjjj substance. The compound of the production examples 14-1 to 14-15 shown in the following table was produced using the corresponding raw materials as in Production Example 14. -40- 200951122 Production Example 15 In a solution of ethyl 2-(bromo- 4-methoxyphenyl)acetate (4.4 g) in DCM (44 mL) Solution (24.1 ml). After stirring for 5 hours at 5 ° C, EtOAc (30 mL) was evaporated. The organic layer was washed with water (1 ml) and saturated brine (100 ml), dried over MgSO 4 and concentrated. The residue was crystallized from n-hexane / EtOAc (EtOAc)EtOAc. Preparation Example 16 To a solution of (3-chloro-4-hydroxyphenyl)acetic acid ethyl ester (2.00 g) in DMF (30 ml), K2C03 (2.58 g) and 4-nitrofluorobenzene (1.03 ml), Stir at 60 ° C for 2 hours. After cooling the reaction mixture to room temperature, it was poured into water and extracted with EtOAc. The organic layer was washed twice with saturated brine, dried over MgSO 4 and concentrated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) Oily substance. The compound of the production examples 16-1 to 16-15 shown in the following table was produced using the corresponding raw materials as in Production Example 16. Production Example 17 -41 - 200951122 A suspension of 4-benzyloxy-1-indole (2.98 g) and K2C03 (1.12 g) in DMF (30 ml) was stirred at room temperature, and ethyl br 1.9 ml) and stirred overnight at room temperature. K2C03 (1.12 g) and ethyl bromoacetate (1.9 ml) were added, and the mixture was further stirred at room temperature for 8 hours. Water was added to the reaction mixture and the organic layer was washed with a saturated aqueous solution of sodium chloride. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) Manufacturing Example 18

在冰冷卻下於含吲哚-2-羧酸乙酯（1克）之DMF ( 10毫升）溶液中添加60%氫化鈉（240毫克），在室溫下 攪拌10分鐘後，添加1-溴-2-氟乙烷（1克），在室溫下 攪拌2小時。以EtO Ac稀釋反應溶液後依序以1M鹽酸、 飽和食鹽水洗淨，以MgS04乾燥，且減壓濃縮濾液。殘 留物經矽膠管柱層析純化，獲得1- ( 2-氟乙基）吲哚-2-羧酸乙酯（1.1克）之無色油。 製造例19 將（4-苄氧基·1Η-吲哚-1-基）乙酸乙酯（1.75克） 溶於EtOH ( 17.5毫升）及THF (17.5毫升）之混合溶 劑中，且添加10%鈀碳（含50%水）（1.2克），在氫氣 氛圍氣體中，在室溫、常壓下接觸還原4小時。使用矽藻 -42- 200951122 土過濾反應混合物，且減壓濃縮濾液。獲得（4-羥基-1H-吲哚-1-基）乙酸乙酯（1·37克）之淡茶色油。 • 製造例20 於含2-溴-Ν,Ν_二甲基苯胺（ 500毫克）及3-乙氧基 羰基苯基硼酸（582毫克）之1,4-二噁烷（10毫升）溶液 中添加2Μ Na2C03水溶液（2.75毫升）及[1,1’-雙（二苯 ^ 基膦基）芴]二氯鈀（2 04毫克），且在氮氣氛圍氣體中 於90°C下攪拌4小時。將反應混合物冷卻至室溫後注入水 中，以 EtOAc萃取。有機層以飽和食鹽水洗淨後，以 MgS04乾燥，且減壓濃縮濾液。殘留物經矽膠管柱層析純 化，獲得2’-(二甲胺基）聯苯-3-羧酸乙酯（620毫克） 之淡黃色油狀物質。 表2至表34列出製造例化合物之構造及物理化學數 據。 〇 . 實施例1 於含（3-氯-4·{4-[(3,4-二氯苯甲醯基）胺基]苯氧基 }苯基）乙酸乙酯（210毫克）之EtOH ( 4.2毫升）溶液 中添加2M NaOH水溶液（ 43 9微升），在室溫下攪拌4 小時。於反應溶液中添加1M鹽酸，將pH調整爲3至4 後，以水稀釋，且以EtOAc萃取。有機層以飽和食鹽水 洗淨後，以MgS04乾燥，減壓濃縮濾液。殘留物經IPE 粉末化後乾燥，獲得（3-氯-4-{4-[(3,4-二氯苯甲醯基） •43- 200951122 胺基]苯氧基}乙酸（182毫克）之白色粉末。 如實施例1般’使用對應之原料製造以下表35至75 中所示之實施例2至實施例153之化合物。表35至表61 中分別表示實施例化合物之構造，且表62至表75分別表 示物理化學數據。 [表2]Add 60% sodium hydride (240 mg) to a solution of ethyl hydrazine-2-carboxylate (1 g) in DMF (10 mL). 2-Fluoroethane (1 g) was stirred at room temperature for 2 hours. The reaction solution was diluted with EtO Ac, and then washed with 1M hydrochloric acid and brine, dried over Flor. The residue was purified by silica gel column chromatography toield ethyl 1-(2-fluoroethyl)indole-2-carboxylate (1.1 g). Preparation Example 19 Ethyl (4-benzyloxy·1Η-indol-1-yl)acetate (1.75 g) was dissolved in a mixed solvent of EtOH (17.5 ml) and THF (17.5 ml), and 10% palladium was added. Carbon (containing 50% water) (1.2 g) was contact-reduced at room temperature under normal pressure for 4 hours in a hydrogen atmosphere. The reaction mixture was filtered using celite - 42 - 200951122, and the filtrate was concentrated under reduced pressure. A pale brown oil of (4-hydroxy-1H-indol-1-yl)acetate (1·37 g) was obtained. • Production Example 20 in a solution of 2-bromo-indole, hydrazine-dimethylaniline (500 mg) and 3-ethoxycarbonylphenylboronic acid (582 mg) in 1,4-dioxane (10 ml) An aqueous solution of 2ΜNa2C03 (2.75 ml) and [1,1'-bis(diphenylphosphino)phosphonium]dichloropalladium (2,04 mg) were added, and the mixture was stirred at 90 ° C for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO 4 , and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) Tables 2 to 34 list the structures and physicochemical data of the compounds of the production examples. 〇. Example 1 Ethyl acetate (210 mg) containing (3-chloro-4·{4-[(3,4-dichlorobenzylidenyl)amino]phenoxy}phenyl)acetate (210 mg) A solution of 2M NaOH (43 9 μl) was added to the solution (4.2 ml) and stirred at room temperature for 4 hours. After adding 1 M hydrochloric acid to the reaction solution, the pH was adjusted to 3 to 4, diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO 4 and evaporated. The residue was pulverized by IPE and dried to give (3-chloro-4-{4-[(3,4-dichlorobenzhydryl)-43-200951122-amino]phenoxy}acetic acid (182 mg) White powder. The compounds of Examples 2 to 153 shown in the following Tables 35 to 75 were produced using the corresponding raw materials as in Example 1. The structures of the example compounds are shown in Tables 35 to 61, respectively, and Table 62 Table 75 shows the physicochemical data. [Table 2]

Pr 1 Structure Cl CH3 Data MS(ESI) ·· 324(M+Na)+ 2 Cl CH3 MS(ESI)： 324(M+Na)+ 3 H〇^0rSH MS(ESI)： 201(M-H)_ 3-1 h3c ch3 MS(ESI)： 242(M+H)+Pr 1 Structure Cl CH3 Data MS (ESI) ·· 324 (M+Na)+ 2 Cl CH3 MS (ESI): 324 (M+Na) + 3 H 〇^0rSH MS (ESI): 201 (MH) _ 3 -1 h3c ch3 MS(ESI): 242(M+H)+

-44 - 200951122 [表3]-44 - 200951122 [Table 3]

Pr Structure Data 3-2 MS(ESI)： 206(M-H)' 4 H 广。 MS(ESI)： 500(M+Na)+ 4-1 MS(ESI)： 466(M+Na)+. 4-2 ch3 MS(ESI)： 446(M+Na)+ 4-3 H^0xjS°a^ MS(ESI)： 462(M+Na)+ 4-4 MS(ESI)： 483(M+Na)+ 4-5 h3c-〇X^〇^n\〇^ MS(ESI)： 472(M+Na)+ -45- 200951122 [表4]Pr Structure Data 3-2 MS (ESI): 206 (M-H)' 4 H broad. MS (ESI): MH (MH): °a^ MS(ESI): 462 (M+Na) + 4-4 MS (ESI): 48 (M+Na) + 4-5 h3c-〇X^〇^n\〇^ MS(ESI): 472 (M+Na)+ -45- 200951122 [Table 4]

Pr Structure Data 4-6 MS(ESI)： 483(M+Na)+ 4-7 H 广 MS(ESI)： 472(M+Na)+ 4-8 MS(ESI)： 483(M+Na)+ 4-9 S^CI MS(ESI)： 501(M+Na)+ 4-10 MS(ESI)： 479,481(M+H)+ 4-11 Η 广。 MS(ESI): 496,498(M+Na)+ -46 - 200951122 m 5]Pr Structure Data 4-6 MS (ESI): 483 (M+Na) + 4-7 H. MS (ESI): 472 (M+Na) + 4-8 MS (ESI): 483 (M+Na)+ 4-9 S^CI MS (ESI): 501 (M+Na) + 4-10 MS (ESI): 479, 481 (M+H) + 4-11 。 广. MS (ESI): 496, 498 (M+Na) + -46 - 200951122 m 5]

Pr Structure Data 4-12 MS(ESI): 484,486(M+Na)+ 4-13 H 广 MS(ESI)： 478,480(M-H)· 4-14 MS(ESI): 451(M+H)+ 4-15 MS(ESI)： 452(M+H)+ 4-16 MS(ESI)： 468(M+Na)+ 4-17 HsC、x^aNVh 3 h MS(ESI): 434(M+H)+ -47- 200951122 [表6]Pr Structure Data 4-12 MS (ESI): 484, 486 (M+Na) + 4-13 H MS (ESI): 478, 480 (MH) · 4-14 MS (ESI): 451 (M+H) + 4- 15 MS (ESI): 452 (M+H) + 4-16 MS (ESI): 468 (M+Na) + 4-17 HsC, x^aNVh 3 h MS (ESI): 434 (M+H)+ -47- 200951122 [Table 6]

Pr Structure Data 4-18 h3c-〇^^S^n^0：c' MS(ESI): 516(M+Na)+ 4-19 h3c-〇^^〇^nVi Hc丨丨 MS(ESI): 500,502(M+Na)+ 4-20 MS(ESI): 466,468(M+Na)+ 4-21 kSsi^^〇.CH3 MS(ESI): 496,498(M+Na)+ 4-22 H 广 MS(ESI): 488(M+Na)+ 4-24 H 广 MS(ESI): 484,486(M+Na)+Pr Structure Data 4-18 h3c-〇^^S^n^0:c' MS(ESI): 516(M+Na)+ 4-19 h3c-〇^^〇^nVi Hc丨丨MS(ESI): 500,502 (M+Na)+ 4-20 MS (ESI): 466,468 (M+Na)+ 4-21 kSsi^^〇.CH3 MS (ESI): 496,498 (M+Na)+ 4-22 H ESI): 488 (M+Na)+ 4-24 H broad MS (ESI): 484,486 (M+Na)+

-48- 200951122 [表7]-48- 200951122 [Table 7]

Pr Structure Data 4-23 Cl MS(ESI)： 500,502(M+Na)+ 4-24 MS(ESI)： 484,486(M+Na)+ 4-25 Cl h3C 八 MS(ESI)： 496,498(M+Na)+ 4-26 h3c-〇W^〇1^n^QCs&gt; MS(ESI)： 489(M+Na)+ 4-27 h3c-〇X^〇^n\^ MS(ESI): 471(M+Na)+ 4-28 H 广。uS^O^X) MS(ESI) ·· 508(M+Na)+ -49- 200951122 m siPr Structure Data 4-23 Cl MS (ESI): 500, 502 (M+Na) + 4-24 MS (ESI): 484, 486 (M+Na) + 4-25 Cl h3C s. MS (ESI): 496, 498 (M+Na ) + 4-26 h3c-〇W^〇1^n^QCs&gt; MS(ESI): 489(M+Na)+ 4-27 h3c-〇X^〇^n\^ MS(ESI): 471(M +Na)+ 4-28 H wide. uS^O^X) MS(ESI) ·· 508(M+Na)+ -49- 200951122 m si

Pr Structure Data 4-29 ^ °'ch3 MS(ESI)： 538(M+Na)+ 4-30 MS(ESI)： 472,474(M+Na)+ 4-31 MS(ESI)： 461(M+H)+ 4-32 ViCH3 MS(ESI)： 524(M+Na)+. 4-33 H^0uS°x&gt;，v，F MS(ESI)： 489(M+Na)+ 4-34 H广 H MS(ESI)： 478(M+H)+ -50- 200951122 [表9]Pr Structure Data 4-29 ^ °'ch3 MS (ESI): 538 (M+Na) + 4-30 MS (ESI): 472, 474 (M+Na) + 4-31 MS (ESI): 461 (M+H + 4-32 ViCH3 MS (ESI): 524(M+Na)+. 4-33 H^0uS°x&gt;,v,F MS(ESI): 489(M+Na)+ 4-34 H wide H MS (ESI): 478 (M+H) + -50 - 200951122 [Table 9]

Pr Structure Data 4-35 CF3 MS(ESI)： 500(M+Na)+ 4-36 人 CF3 MS(ESI): 501(M+Na)+ 4-37 MS(ESI)： 487(M+Na)十 4-38 H 广。xjVxxv^ H ^ch3 MS(ESI)： 501(M+Na)+ 4-39 H3C、i^r χχχ^Α 3 H U 0 0 MS(ESI): 525(M+Na)+ 4-40 MS(ESI): 468(M+Na)+ -51 - 200951122 m ι〇]Pr Structure Data 4-35 CF3 MS (ESI): 500 (M+Na) + 4-36:::::::::::::::::: Ten 4-38 H wide. XjVxxv^ H ^ch3 MS(ESI): 501(M+Na)+ 4-39 H3C, i^r χχχ^Α 3 HU 0 0 MS(ESI): 525(M+Na)+ 4-40 MS (ESI) ): 468(M+Na)+ -51 - 200951122 m ι〇]

Pr Structure Data 4-41 H MS(ESI)： 471(M+Na)+ 4-42 MS(ESI)： 485(M+Na)+ rF~ -^ 4-43 MS(ESI)： 489(M+Na)+ 4-44 H ^Asxh3 MS(ESI): 478(M+Na)+ 4-45 MS(ESI)： 518(M+Na)+ 4-46 H 广。uVxxv^ H砂。| MS(ESI)： 481(M-H)· -52- 200951122 [表 11]Pr Structure Data 4-41 H MS (ESI): 471 (M+Na) + 4-42 MS (ESI): 485 (M+Na) + rF~ -^ 4-43 MS (ESI): 489 (M+ Na) + 4-44 H^Asxh3 MS (ESI): 478 (M+Na) + 4-45 MS (ESI): 518 (M+Na) + 4-46 H. uVxxv^ H sand. MS (ESI): 481(M-H)· -52- 200951122 [Table 11]

Pr Structure Data 4-47 MS(ESI)： 480(M+Na)+ 4-48 h 广。 ch3 MS(ESI)： 464(M+Na)+ 4-49 HZC XCH3 MS(ESI)： 529(M+H)+ 4-50 MS(ESI)： 500(M+Na)+ 4-51 MS(ESI)： 471(M+Na)+ 4-52 (Λ^χχν^ H H 心 ch3 MS(ESI)： 485(M+Na)+ -53- 200951122 m i2]Pr Structure Data 4-47 MS (ESI): 480 (M+Na) + 4-48 h wide. Ch3 MS (ESI): 464 (M+Na) </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; ESI): 471(M+Na)+ 4-52 (Λ^χχν^ HH heart ch3 MS(ESI): 485(M+Na)+ -53- 200951122 m i2]

Pr Structure Data 4-53 ch3 MS(ESI)： 460(M+Na)+ 4-54 MS(ESI): 472(M+Na)+ 4-55 Cl ο Ιί&quot;&quot;^γ0γΝ，o h3c 八 MS(ESI)： 459(M+Na)+ 4-56 Cl ch3 MS(ESI)： 490(M-H)' 4-57 Cl ch3 MS(ESI)： 461(M-H)· 4-58 MS(ESI)： 506,508(M+Na)+Pr Structure Data 4-53 ch3 MS(ESI): 460(M+Na)+ 4-54 MS(ESI): 472(M+Na)+ 4-55 Cl ο Ιί&quot;&quot;^γ0γΝ,o h3c 八MS (ESI): 459 (M+Na) </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; (M+Na)+

-54- 200951122 m i3]-54- 200951122 m i3]

Pr Structure Data 4-59 MS(ESI)： 505,507(M+Na)+ 4-60 h3c-〇^^〇^nV^ MS (ESI)： 506,508(M+Na)+ 4-61 h3c-〇W^〇^nVvx MS(ESI)： 486(M+Na)+ 4-62 MS(ESI)： 490,492(M+Na)+ 4-63 VNi n^J^ch3 MS(ESI): 464(M+H)+ 4-64 Η3〇^〇υ5〇Χλ,Α^Ρ CF3 MS (ESI) 518(M+Na)+ -55- 200951122 m η]Pr Structure Data 4-59 MS(ESI): 505,507(M+Na)+ 4-60 h3c-〇^^〇^nV^ MS (ESI): 506,508(M+Na)+ 4-61 h3c-〇W^ 〇^nVvx MS (ESI): 486 (M+Na) + 4-62 MS (ESI): 490, 492 (M+Na) + 4-63 VNi n^J^ch3 MS (ESI): 464 (M+H) + 4-64 Η3〇^〇υ5〇Χλ,Α^Ρ CF3 MS (ESI) 518(M+Na)+ -55- 200951122 m η]

Pr Structure Data 4-65 3 H以叭％ ch3 MS(ESI): 475(M+Na)+ 4-66 h 广 MS(ESI): 472(M+Na)+ 4-67 MS(ESI)： 490(M+Na)+ 4-68 H3C-〇^r MS(ESI): 506,508(M+Na)+ 4-69 MS(ESI)： 505,507(M+Na)+ 4-70 H ^/^〇，CF3 MS(ESI)： 516(M+Na)+ -56- 200951122 m i5]Pr Structure Data 4-65 3 H in 5% % ch3 MS (ESI): 475 (M+Na) + 4-66 h MW (ESI): 472 (M+Na) + 4-67 MS (ESI): 490 (M+Na)+ 4-68 H3C-〇^r MS (ESI): 506, 508 (M+Na) + 4-69 MS (ESI): 505,507 (M+Na) + 4-70 H^/^〇, CF3 MS (ESI): 516 (M+Na)+ -56- 200951122 m i5]

Pr Structure Data 4-71 h3c^\=/ MS(ESI)： 486(M+Na)+ 4-72 H N^ya MS(ESI)： 506(M+Na)+ 4-73 H3C、u5^aNVh MS(ESI)： 480(M+H)+ 4-74 ch3 NMR (CDC13)： 1.28(3H,t, J=7.1Hz), 2.45(3H,s), 3.58(2H,s), 4.18(2H,q, J=7.1Hz), 6.90-7.90 (llH’m) 4-75 h3c、U^ ^C^X^ch3 MS(ESI)： 480(M+Na)+ -57- 200951122 m i6]Pr Structure Data 4-71 h3c^\=/ MS(ESI): 486(M+Na)+ 4-72 HN^ya MS(ESI): 506(M+Na)+ 4-73 H3C, u5^aNVh MS (ESI): 480 (M+H) + 4-74 ch3 NMR (CDC13): 1.28 (3H, t, J = 7.1 Hz), 2.45 (3H, s), 3.58 (2H, s), 4.18 (2H, q, J=7.1Hz), 6.90-7.90 (llH'm) 4-75 h3c, U^^C^X^ch3 MS(ESI): 480(M+Na)+ -57- 200951122 m i6]

Pr Structure Data 4-76 MS(ESI)： 484(M+Na)+ 4-77 MS(ESI)： 464(M+H)+ 4-78 MS(ESI)： 490(M+Na)+ 4-79 MS(ESI)： 460(M+Na)+ 4-80 MS(ESI)： 458(M+Na)+ 4-81 MS(ESI): 526(M+Na)+Pr Structure Data 4-76 MS (ESI): 484 (M+Na) + 4-77 MS (ESI): 464 (M+H) + 4-78 MS (ESI): 490 (M+Na)+ 4- 79 MS (ESI): 460 (M+Na) + 4- 80 MS (ESI): 459 (M+Na) + 4-81 MS (ESI): 526 (M+Na)+

-58- 200951122 [表 17]-58- 200951122 [Table 17]

Pr Structure Data 4-82 MS(ESI): 509(M+Na)+ 4-83 H 广。 MS(ESI)： 493(M+H)+ 4-84 s MS(ESI): 515(M+Na)+ 4-85 H3C^0XjS°^Xn /=. ηη3ΛνΛ^ MS(ESI)： 513(M+Na)+ 4-86 H 广。 MS(ESI): 489(M+Na)+ 4-87 CF3 MS(ESI)： 479,481(M+H)+ -59- 200951122 m is]Pr Structure Data 4-82 MS (ESI): 509 (M+Na) + 4-83 H. MS (ESI): 495 (M+H) + 4- s s (ESI): 515 (M+Na) + 4-85 H3C^0XjS°^Xn /=. ηη3ΛνΛ^ MS(ESI): 513 (M +Na)+ 4-86 H wide. MS (ESI): 489 (M+Na) + 4-87: ???::::::::::::::::::

Pr Structure Data 4-88 MS(ESI)： 464,466(M+H)+ 4-89 MS(ESI)： 505(M+Na)+ 4-90 MS(ESI)： 477(M+Na)+ 4-91 H 广。 MS(ESI)： 464(M+H)+ 4-92 MS(ESI)： 503(M+Na)+ 4-93 Cl ch3 MS(ESI)： 499(M+Na)+Pr Structure Data 4-88 MS (ESI): 464, 466 (M+H) + 4-89 MS (ESI): 505 (M+Na) + 4-90 MS (ESI): 477 (M+Na)+ 4- 91 H wide. MS (ESI): 464 (M+H) + 4-495 MS (ESI): 503 (M+Na) + 4-93 Cl ch3 MS (ESI): 499 (M+Na)+

-60- 200951122 m i9]-60- 200951122 m i9]

Pr Structure Data 4-94 h3c MS(ESI)： 498(M+H)+ 4-95 h3c 〇xNlV0ri x H3c^ 0 ^ MS(ESI)： 478(M+Na)+ 4-96 h3c H3C^ ^ MS(ESI)： 546(M+Na)+ 4-97 MS(ESI)： 485(M+Na)+ 4-98 MS(ESI)： 490(M+Na)+ 4-99 〇XNrV°Y^ 〇 H H〆。U MS(ESI)： 476(M+Na)+ -61 - 200951122 m 2〇]Pr Structure Data 4-94 h3c MS (ESI): 498 (M+H) + 4-95 h3c 〇xNlV0ri x H3c^ 0 ^ MS (ESI): 478 (M+Na) + 4-96 h3c H3C^ ^ MS (ESI): 546 (M+Na) + 4-97 MS (ESI): 495 (M+Na) + 4-98 MS (ESI): 490 (M+Na) + 4-99 〇XNrV°Y^ 〇 HH〆. U MS (ESI): 476 (M+Na) + -61 - 200951122 m 2〇]

Pr Structure Data 4-100 MS(ESI)： 476(M+Na)+. 4-101 MS(ESI)： 469,471 (M+H)+ 4-102 MS(ESI): 485,487(M+H)+ 4-103 MS(ESI)： 516,518(M+Na)+ 4-104 MS(ESI): 529,531(M+Na)+ 4-105 MS(ESI)： 477(M+Na)+Pr Structure Data 4-100 MS (ESI): 476 (M+Na) +. 4-101 MS (ESI): 469, 471 (M+H) + 4-102 MS (ESI): 485, 487 (M+H) + 4 - 103 MS (ESI): 516, 518 (M+Na) + 4-104 MS (ESI): 529, 531 (M+Na) + 4-105 MS (ESI): 477 (M+Na)+

-62- 200951122 [表 21]-62- 200951122 [Table 21]

Pr Structure Data 4- 106 MS(ESI)： 463(M+Na)+ 4- 107 MS(ESI)： 544,546(M+Na)+ 4- 108 η3ο^Ν^〇^ν^ MS(ESI)： 505(M+Na)+ 4- 109 MS(ESI): 466(M-H)· 4- 110 MS(ESI): 515,517(M+Na)+ 4- 111 Br Η MS(ESI)： 544,546(M+Na)+ -63- 200951122 m 22]Pr Structure Data 4-106 MS (ESI): 463 (M+Na) + 4-107 MS (ESI): 544, 546 (M+Na) + 4- 108 η3ο^Ν^〇^ν^ MS(ESI): 505 (M+Na)+ 4-109 MS (ESI): 466 (MH)············· + -63- 200951122 m 22]

Pr Structure Data 4- 112 MS(ESI)： 515,517(M+Na)+ 4- 113 MS(ESI): 489(M+Na)+ 4- 114 H 〇'~'0~Br MS(ESI): 550,552(M+Na)+ 4- 115 Cl MS(ESI)： 488(M+Na)+ 4- 116 H^0u5rV，Vrc, 0H3 MS(ESI): 514(M+Na)+ 4- 117 MS(ESI)： 485(M+Na)+Pr Structure Data 4- 112 MS (ESI): 515, 517 (M+Na) + 4- 113 MS (ESI): 489 (M+Na) + 4-114 H 〇 '~'0~Br MS (ESI): 550,552 (M+Na)+ 4-115 Cl MS (ESI): 488 (M+Na) + 4-116 H^0u5rV, Vrc, 0H3 MS (ESI): 514 (M+Na) + 4- 117 MS (ESI) ): 485 (M+Na)+

-64 - 200951122-64 - 200951122

m 23] Pr Structure Data 4-118 MS(ESI)： 437(M+H)+ 4-119 MS(ESI)： 473(M+Na)+ 4-120 hh7^f MS(ESI)： 503(M+Na)+ 4-121 MS(ESI)： 499(M+Na)+ 4-122 MS(ESI)： 519(M+Na)+ 4-123 H^0^r°aNV H MS(ESI)： 533,535(M+Na)+ -65- 200951122 m 24]m 23] Pr Structure Data 4-118 MS (ESI): 437 (M+H) + 4-119 MS (ESI): 473 (M+Na) + 4-120 hh7^f MS (ESI): 503 (M +Na)+ 4-121 MS (ESI): 499 (M+Na) + 4-122 MS (ESI): 519 (M+Na) + 4-123 H^0^r°aNV H MS (ESI): 533,535 (M+Na)+ -65- 200951122 m 24]

Pr Structure Data 4-124 MS(ESI)： 490(M+Na)+ 4-125 ci MS(ESI): 506(M+Na)+ 4-126 η3〇χ \=/ F MS(ESI)： 482(M+H)+ 4-127 Hv^ MS(ESI)： 520(M+Na)+ 4-128 γΛ^χΧν^ MS(ESI)： 500(M+Na)+ 4-129 MS(ESI)： 500(M+Na)+ -66 - 200951122Pr Structure Data 4-124 MS (ESI): 490 (M+Na) + 4-125 ESI MS (ESI): 506 (M+Na) + 4-126 η3〇χ \=/ F MS (ESI): 482 (M+H)+ 4-127 Hv^ MS (ESI): 520 (M+Na) + 4-128 γΛ^χΧν^ MS (ESI): 500 (M+Na) + 4-129 MS (ESI): 500(M+Na)+ -66 - 200951122

m 25] Pr Structure Data 4-130 MS(ESI)： 518(M+Na)+ 4-131 H 以 CH3 MS(ESI)： 462(M-H)· 4-132 ^^^〇'CF3 MS(ESI)： 517(M+Na)+ 4-133 ^^ocf3 MS(ESI)： 560,562(M+Na)+ 4-134 MS(ESI)： 466(M+H)+ 4-135 MS(ESI): 487(M+Na)+ -67- 200951122 m 26]m 25] Pr Structure Data 4-130 MS (ESI): 518 (M+Na) + 4-131H EtOAc (ESI): 462 (MH) 517(M+Na)+ 4-133^^ocf3 MS (ESI): 560, 562 (M+Na) + 4-134 MS (ESI): 466 (M+H) + 4-135 MS (ESI): 487 (M+Na)+ -67- 200951122 m 26]

Pr Structure Data 4-136 CF3 MS(ESI): 519(M+Na)+ 5 MS(ESI)： 501(M+Na)+ 6 γΛ^α，Ν〇〇 MS(ESI)： 487(M+Na)+ 6-1 H七 MS(ESI)： 473(M+Na)+ 6-2 Η广。对 MS(ESI): 487(M+Na)+ 6-3 H^0w5r°aNXn H °Ό MS(ESI)： 515(M+Na)+ -68- 200951122Pr Structure Data 4-136 CF3 MS (ESI): 519 (M+Na) + 5 MS (ESI): 501 (M+Na) + 6 γΛ^α, Ν〇〇MS (ESI): 487 (M+Na ) + 6-1 H-seven MS (ESI): 473 (M+Na) + 6-2 Η Guang. MS (ESI): 487 (M+Na)+ 6-3 H^0w5r°a NXn H Ό MS (ESI): 515 (M+Na) + -68- 200951122

m 27] Pr Structure Data 6-4 Cl o 〇 OH MS(ESI): 565(M+Na)+ 6-5 h3c」 β NC〇 MS(ESI)： 492(M+Na)+ 6-6 义① MS(ESI)： 505(M+Na)+ 6-7 h3c-〇^^〇^/n0Q MS(ESI): 521，523(M+Na)+ 6-8 H 广。xjS^a，N〇〇 MS(ESI)： 509,511(M+H)+ 7 H3C、XJ0&quot;U，N』 3 Η H MS(ESI): 475,477(M+Na)+ -69- 200951122 m 28]m 27] Pr Structure Data 6-4 Cl o 〇OH MS (ESI): 565(M+Na)+ 6-5 h3c" β NC〇MS(ESI): 492(M+Na)+ 6-6 MS (ESI): 505 (M+Na) + 6-7 s, s, s, s, s, s, s, s, s, s. xjS^a, N〇〇 MS(ESI): 509,511(M+H)+ 7 H3C, XJ0&quot;U,N』 3 Η H MS(ESI): 475,477(M+Na)+ -69- 200951122 m 28]

Pr Structure Data 7-1 H广。 3 Η 1 ch3 MS(ESI)： 489(M+Na)+ 7-2 H 广 H ^ MS(ESI)： 501,503(M+Na)+ 8 H3C~/ 0 Cl MS(ESI): 237(M+Na)+ 8-1 H3C」0 F MS(ESI): 221(M+Na)+ 8-2 〇^Q-〇H H3c j 0 o-ch3 MS(ESI)： 233(M+Na)+ 8-3 jhT^sh H3C j 0 Cl MS(ESI): 229(M-H)' 8-4 H3C —^ 0 Br MS(ESI): 281,283(M+Na)+ 8-5 CH3 〇^-Q-〇/ h3c」0 MS(ESI): 295,297(M+Na)+Pr Structure Data 7-1 H wide. 3 Η 1 ch3 MS (ESI): 489 (M+Na) + 7-2 H H H (MH): 501, 503 (M+Na) + 8 H3C~/ 0 Cl MS (ESI): 237 (M+ Na)+ 8-1 H3C”0 F MS (ESI): 221 (M+Na)+ 8-2 〇^Q-〇H H3c j 0 o-ch3 MS (ESI): 233 (M+Na)+ 8 -3 jhT^sh H3C j 0 Cl MS (ESI): 229(MH)' 8-4 H3C -^ 0 Br MS (ESI): 281, 283 (M+Na) + 8-5 CH3 〇^-Q-〇/ H3c”0 MS(ESI): 295,297(M+Na)+

-70- 200951122-70- 200951122

m 29] Pr Structure Data 9 3 H NMR(CDC13): 1.28(3H,t,J=7.1 Hz),3.58(2H,s), 4.18(2H,q,J=7.1 Hz),6.93(lH,d, J=8.4Hz)，6.95-7.00(3H，m), 7.14(lH,dd,J= 2.1,8.4Hz),7.37-7.44(5H,m),8.27-8.31(2H,m) 10 H MS(ESI) ·· 497(M+Na)+ 11 H 广。 MS(ESI)： 468,470(M+Na)+ 11- 1 H认 MS(ESI)： 536,53 8(M+Na)+ 12 H^〇u&gt;0^aN〇2 Cl MS(ESI)： 368(M-H)_ 13 HCf C， 3 ch3 MS(ESI): 402,404(M+Na)+ -71 - 200951122 m 3〇]m 29] Pr Structure Data 9 3 H NMR (CDC13): 1.28 (3H, t, J = 7.1 Hz), 3.58 (2H, s), 4.18 (2H, q, J = 7.1 Hz), 6.93 (lH, d , J=8.4Hz), 6.95-7.00(3H,m), 7.14(lH,dd,J=2.1,8.4Hz),7.37-7.44(5H,m),8.27-8.31(2H,m) 10 H MS (ESI) ·· 497(M+Na)+ 11 H wide. MS (ESI): 468, 470 (M+Na) + &lt;1&&&&&&&&&&&&&&&&&&&&&&&& (MH)_ 13 HCf C, 3 ch3 MS (ESI): 402,404 (M+Na)+ -71 - 200951122 m 3〇]

Pr Structure Data 14 MS(ESI): 328(M+Na)+ 14-1 MS(ESI)： 307(M+H)+ 14-2 H 广。Λ^αΝΗ2 MS(ESI): 324(M+Na)+ 14-3 MS(ESI): 290(M+H)+ 14-4 S jf^T〇丫l Nv^nh2 MS(ESI)： 308(M+H)+ 14-5 H^0l^rsUNH2 MS(ESI)： 344(M+Na)+ 14-6 Cl F 0 iT^T〇yS h3c 八 ^^nh2 MS(ESI)： 346(M+Na)+ 14-7 Cl Cl 〇 H3C 八 k^NH2 MS(ESI)： 362,364(M+Na)+Pr Structure Data 14 MS (ESI): 328 (M+Na) + 14-1 MS (ESI): 307 (M+H) + 14-2 H. Λ^αΝΗ2 MS (ESI): 324 (M+Na) + 14-3 MS (ESI): 290 (M+H) + 14-4 Sjf^T〇丫l Nv^nh2 MS (ESI): 308 ( M+H)+ 14-5 H^0l^rsUNH2 MS(ESI): 344(M+Na)+ 14-6 Cl F 0 iT^T〇yS h3c 八^^nh2 MS(ESI): 346(M+ Na)+ 14-7 Cl Cl 〇H3C 八k^NH2 MS(ESI): 362,364(M+Na)+

-72- 200951122 [表 31]-72- 200951122 [Table 31]

Pr Structure Data 14-8 Cl ch3 MS(ESI)： 320(M+H)+ 14-9 H3c^ NH2 MS(ESI)： 311(M+H)+ 14-10 H^0^°UNH2 Cl MS(ESI)： 340,342(M+H)+ 14-11 h3c h3c^ 0 ^ ^nh2 MS(ESI): 326(M+H)+ 14-12 MS(ESI)： 372,374(M+Na)+ 14-13 Br MS(ESI)： 372,374(M+Na)+ 14-14 CH3 MS(ESI)： 342(M+Na)+ -73- 200951122 m 32]Pr Structure Data 14-8 Cl ch3 MS (ESI): 320 (M+H) + 14-9 H3c^NH2 MS (ESI): 311 (M+H) + 14-10 H^0^°UNH2 Cl MS ( ESI): 340, 342 (M+H) + 14-11 h3c h3c^ 0^^nh2 MS (ESI): 326 (M+H) + 14-12 MS (ESI): 372,374 (M+Na) + 14-13 Br MS (ESI): 372, 374 (M+Na) + 14-14 CH3 MS (ESI): 342 (M+Na) + -73 - 200951122 m 32]

Pr Structure Data 14-15 H^〇w5r〇^NH2 MS(ESI)： 307(M+H)+ 15 h^〇W?〇h Br MS(ESI)： 281，283(M+Na)+ 16 H^0u5°aN〇2 MS(ESI): 334(M-H)· 16-1 Cl 〇 h3c 八 ^^no2 MS(ESI)： 359(M+Na)+ 16-2 h3c、〇 H广。wyix2 MS(ESI)： 354(M+Na)+ 16-3 H3CaA^X2 MS(ESI)： 342(M+Na)+ 16-4 s iV A h3c 八 n^^no2 MS(ESI)： 338(M+H)+ 16-5 h^0xAsUn〇2 MS(ESI)： 374(M+Na)+Pr Structure Data 14-15 H^〇w5r〇^NH2 MS(ESI): 307(M+H)+ 15 h^〇W?〇h Br MS(ESI): 281,283(M+Na)+ 16 H ^0u5°aN〇2 MS (ESI): 334(MH)· 16-1 Cl 〇h3c 八^^no2 MS(ESI): 359(M+Na)+ 16-2 h3c, 〇H wide. Wyix2 MS (ESI): 354 (M+Na) + 16-3 H3CaA^X2 MS (ESI): 342 (M+Na) + 16-4 s iV A h3c 八 n^^no2 MS (ESI): 338 ( M+H)+ 16-5 h^0xAsUn〇2 MS(ESI): 374(M+Na)+

-74- 200951122 m 33]-74- 200951122 m 33]

Pr Structure Data 16-6 η^0χ^°Λν〇2 MS(ESI): 376(M+Na)+ 16-7 Η^0υ5τ°ΛΝ〇2 MS(ESI)： 392,394(M+Na)+ 16-8 Cl NMR(CDC13) ：6.98-7.02(2H, m),7.27(lH,s), 7.79(lH,s),8.23 -8.27(2H,m) 16-9 Cl ch3 H广。！jytX〇2 MS(ESI): 372(M+Na)+ 16-10 MS(ESI)： 363(M+Na)+ 16-11 h3c h3c^ 0 ^ ^no2 MS(ESI)： 356(M+H)+ 16-12 H3C、^aN〇2 MS(ESI)： 402,404(M+Na)+ -75- 200951122 m 34]Pr Structure Data 16-6 η^0χ^°Λν〇2 MS(ESI): 376(M+Na)+ 16-7 Η^0υ5τ°ΛΝ〇2 MS (ESI): 392,394 (M+Na)+ 16- 8 Cl NMR (CDC13): 6.98-7.02 (2H, m), 7.27 (1H, s), 7.79 (1H, s), 8.23 - 8.27 (2H, m) 16-9 Cl ch3 H. ! jytX 〇 2 MS (ESI): 372 (M+Na) + 16-10 MS (ESI): 363 (M+Na) + 16-11 h3c h3c^ 0 ^ ^no2 MS (ESI): 356 (M+H ) + 16-12 H3C, ^aN〇2 MS (ESI): 402,404 (M+Na)+ -75- 200951122 m 34]

Pr Structure Data 16-13 Br MS(ESI)： 402,404(M+Na)+ 16-14 ch3 MS(ESI)： 372(M+Na)+ 16-15 MS(ESI): 359(M+Na)+. 17 h3c^ MS(ESI)： 310(M+H)+ 18 0 h3c^oAy：；\=x f〜n^O MS(ESI): 258(M+Na)+ 19 h3c」 MS(ESI)： 242(M+Na)+ 20 H3C^〇JS0f^ h3c’N、ch3 MS(ESI)： 270(M+H)+ -76- 200951122 [表 35]Pr Structure Data 16-13 Br MS (ESI): 402, 404 (M+Na) + 16 - 14 (3) (3) (ESI): 372 (M+Na) + 16-15 MS (ESI): 359 (M+Na)+ 17 h3c^ MS(ESI): 310(M+H)+ 18 0 h3c^oAy:;\=xf~n^O MS(ESI): 258(M+Na)+ 19 h3c" MS (ESI): 242(M+Na)+ 20 H3C^〇JS0f^ h3c'N, ch3 MS(ESI): 270(M+H)+ -76- 200951122 [Table 35]

-77- 200951122 [表 36]-77- 200951122 [Table 36]

Ex Structure 7 8 Ssi^ci 9 10 11 12 h3c Η0^Ex Structure 7 8 Ssi^ci 9 10 11 12 h3c Η0^

-78- 200951122 [表 37]-78- 200951122 [Table 37]

-79- 200951122 [表 38]-79- 200951122 [Table 38]

Ex Structure 19 20 h 21 22 H 23 HC1从丨 24Ex Structure 19 20 h 21 22 H 23 HC1 from 丨 24

-80- 200951122 [表 39]-80- 200951122 [Table 39]

-81 - 200951122 m 4〇]-81 - 200951122 m 4〇]

Ex Structure 31 32 33 ch3 34 ΗΟΐΛ°αΛΝ〇〇 35 36 -82- 200951122 [表 41]Ex Structure 31 32 33 ch3 34 ΗΟΐΛ°αΛΝ〇〇 35 36 -82- 200951122 [Table 41]

-83- 200951122 m 42]-83- 200951122 m 42]

Ex Structure 43 CF3 44 人 CF3 45 H U 〇/Nb 46 ηοΛ^ 47 H0US 48 ηΛ^Ί^ΟEx Structure 43 CF3 44 person CF3 45 H U 〇/Nb 46 ηοΛ^ 47 H0US 48 ηΛ^Ί^Ο

-84- 200951122 m 43]-84- 200951122 m 43]

Ex Structure 49 50 51 52 ηΛ^Ά 53 Cl 54 Cl 〇 r\°Y^i -85- 200951122 m 44]Ex Structure 49 50 51 52 ηΛ^Ά 53 Cl 54 Cl 〇 r\°Y^i -85- 200951122 m 44]

Ex Structure 55 56 57 Η 58 59 κ 60 -86- 200951122 m 45]Ex Structure 55 56 57 Η 58 59 κ 60 -86- 200951122 m 45]

-87- 200951122 m 46]-87- 200951122 m 46]

Ex Structure 67 68 H l^Ls/CH3 69 HOuS°ia^cH3 ch3 70 H K^h3 71 72Ex Structure 67 68 H l^Ls/CH3 69 HOuS°ia^cH3 ch3 70 H K^h3 71 72

-88- 200951122 m 47]-88- 200951122 m 47]

-89- 200951122 m 48]-89- 200951122 m 48]

Ex Structure 79 80 81 82 ch3 83 HOwS°aNv H也。、 84 -90- 200951122 m 49]Ex Structure 79 80 81 82 ch3 83 HOwS°aNv H also. , 84 -90- 200951122 m 49]

-91 - 200951122 [表 50]-91 - 200951122 [Table 50]

ExEx

Structure 91Structure 91

-92- 200951122 [表 51]-92- 200951122 [Table 51]

Ex Structure 97 98 Η iH3 99 Η Α 100 101 Η0^ ^ Η ου 102 houS°iQni^ Η ^〇^CF3 -93- 200951122 m 52]Ex Structure 97 98 Η iH3 99 Η Α 100 101 Η0^ ^ Η ου 102 houS°iQni^ Η ^〇^CF3 -93- 200951122 m 52]

Ex Structure 103 h3c^\=/ 104 105 H0^ ^ 106 H0^ ^ CF3 107 Cl ch3 H0XJ^°^^T 108 H〇wS°^\T -94- 200951122 m 53]Ex Structure 103 h3c^\=/ 104 105 H0^ ^ 106 H0^ ^ CF3 107 Cl ch3 H0XJ^°^^T 108 H〇wS°^\T -94- 200951122 m 53]

Ex Structure 109 110 111 CF3 112 113 H0^〇aNW H ΐο 114 ΗΟχ^ά°αΝν H i^_Br -95- 200951122 m 55]Ex Structure 109 110 111 CF3 112 113 H0^〇aNW H ΐο 114 ΗΟχ^ά°αΝν H i^_Br -95- 200951122 m 55]

Ex Structure 115 116 ch3 117 118 119 120 -96- 200951122 m 56]Ex Structure 115 116 ch3 117 118 119 120 -96- 200951122 m 56]

ΟΟ

Ex Structure 121 122 123 ηλΛ°Λ/ν〇〇 124 H N-〇 125 HOiA0TiNv H 126 H0^°txNv H ^c- -97- 200951122 m 57]Ex Structure 121 122 123 ηλΛ°Λ/ν〇〇 124 H N-〇 125 HOiA0TiNv H 126 H0^°txNv H ^c- -97- 200951122 m 57]

Ex Structure 127 128 Η〇^°'α,χ〇：〇ι 129 130 131 132 H O^O-CN -98- 200951122 [表 58]Ex Structure 127 128 Η〇^°'α,χ〇:〇ι 129 130 131 132 H O^O-CN -98- 200951122 [Table 58]

Ex Structure 133 ΟΙ 134 H〇xJ^ 135 H0X^r°UNV 136 Hj^aNv^ 137 138 -99- 200951122 m 59]Ex Structure 133 ΟΙ 134 H〇xJ^ 135 H0X^r°UNV 136 Hj^aNv^ 137 138 -99- 200951122 m 59]

Ex Structure 139 HOwya，NC〇 140 141 142 143 h3c w 144 h3〇^C1Ex Structure 139 HOwya, NC〇 140 141 142 143 h3c w 144 h3〇^C1

-100- 200951122 m 6〇]-100- 200951122 m 6〇]

Ex Structure 145 146 147 148 149 ηΛ^Ά 150 -101 - 200951122 [表 61]Ex Structure 145 146 147 148 149 ηΛ^Ά 150 -101 - 200951122 [Table 61]

Ex Structure 151 H Ul〇XF3 152 H ^〇XF3 153 CF3 -102- 200951122 m 62]Ex Structure 151 H Ul〇XF3 152 H ^〇XF3 153 CF3 -102- 200951122 m 62]

Ex Data 1 NMR ： 3.61 (2H,s),6.99(2H,d,J=9.0Hz),7.02(lH,d,J=8.4Hz),7.24( lH,dd,J=2.1,8.4Hz),7.50(lH,d,J=2.0Hz),7.76(2H,d,J=9.0Hz),7.83(lH ,d,J=8.3Hz),7.94(lH,dd,J=2.1,8.4Hz),8.21(lH,d,J=2.1Hz),10.42(lH,s ),12.47(lH,brs). MS(ESI) ： 448(M-H)·. mp ： 220-222 °C. 2 NMR : 3.61(2H,s)，6.98(2H，d，J=8.9Hz),7.01(lH，d，J=8.3Hz)，7.24( lH,dd，J=2.0,8.4Hz)，7.50(lH，d，J=1.9Hz)，7.61(2H，d,J=8.6Hz)，7.77(2H ,d，J=8.9Hz),7.98(2H，d,J=8.4Hz)，10.34(lH，s)，12_48(lH，brs). MS(ESI) ： 438(M+Na)+. 3 NMR : 2_39(3H,s),3.61(2H，s)，6.97(2H，d，J=8.9Hz),7.00(lH,d，J= 8.3Hz),7.23(lH，dd,J=2.0,8.4Hz)，7.33(2H，d，J=8.2Hz)，7.50(lH,d，J= 2.0Hz)，7.78(2H,d,J=9.0Hz)，7.87(2H，d，J=8.2Hz)，10.19(lH，s), 12.46( lH，brs)_ MS(ESI) ： 418(M+Na)+. 4 NMR ： 3.61(2H,s),3.84(3H,s),6.97(2H,d,J=9.1Hz),7.00(lH,d,J= 8.3Hz),7.06(2H,d,J=8.8Hz),7.23(lH,dd9J=2.1,8.4Hz),7.49(lH,d,J= 2.0Hz),7.77(2H,d,J=9.0Hz),7-95(2H,(U=8.4Hz),10.12(lH,s),12.46( lH’brs) MS(ESI) ： 434(M+Na)+. 200951122 m 63Ex Data 1 NMR : 3.61 (2H, s), 6.99 (2H, d, J = 9.0 Hz), 7.02 (1H, d, J = 8.4 Hz), 7.24 (1H, dd, J = 2.1, 8.4 Hz), 7.50 (lH, d, J = 2.0 Hz), 7.76 (2H, d, J = 9.0 Hz), 7.83 (lH, d, J = 8.3 Hz), 7.94 (lH, dd, J = 2.1, 8.4 Hz), 8.21 (lH, d, J = 2.1 Hz), 10.42 (1H, s), 12.47 (1H, brs). MS (ESI): 448 (MH)·. mp: 220-222 ° C. 2 NMR: 3.61 ( 2H, s), 6.98 (2H, d, J = 8.9 Hz), 7.01 (lH, d, J = 8.3 Hz), 7.24 (lH, dd, J = 2.0, 8.4 Hz), 7.50 (lH, d, J) = 1.9 Hz), 7.61 (2H, d, J = 8.6 Hz), 7.77 (2H, d, J = 8.9 Hz), 7.98 (2H, d, J = 8.4 Hz), 10.34 (lH, s), 12_48 ( lH, brs). MS (ESI): 438 (M+Na) +. 3 NMR: 2_39 (3H, s), 3.61 (2H, s), 6.97 (2H, d, J = 8.9 Hz), 7.00 (lH) , d, J = 8.3 Hz), 7.23 (lH, dd, J = 2.0, 8.4 Hz), 7.33 (2H, d, J = 8.2 Hz), 7.50 (lH, d, J = 2.0 Hz), 7.78 (2H) , d, J = 9.0 Hz), 7.87 (2H, d, J = 8.2 Hz), 10.19 (lH, s), 12.46 (lH, brs) _ MS (ESI): 418 (M+Na) +. 4 NMR : 3.61 (2H, s), 3.84 (3H, s), 6.97 (2H, d, J = 9.1 Hz), 7.00 (lH, d, J = 8.3 Hz), 7.06 (2H, d, J = 8.8 Hz) , 7.23 (lH, dd9J=2.1, 8.4 Hz), 7.49 (lH, d, J = 2.0 Hz), 7.77 (2H, d, J = 9.0 Hz), 7-95 (2H, (U = 8.4 Hz), 10.12 (lH, s), 12.46 ( lH'brs) MS (ESI): 434 (M+Na)+. 200951122 m 63

Ex Data 5 NMR : 3.62(2H，s)，7.02(2H，d，J=9.0Hz)，7.05(lH，d，J=8.4Hz)，7.26( lH,d,J=2.0,8.4Hz),7.51(lH,d,J-2.0Hz),7.76(lH,t,J=7.5Hz),7.90-7.94 (lH,m),7.96(2H,d,J=9.1Hz),8.13(lH,d,J=8.2Hz),8.25(lH,d,J=8.4Hz), 8.26(lH,d,J=8.3Hz),8.63(lH,d,J=8.6Hz),10.79(lH5s),12.48(lH,brs). MS(ESI) ： 455(M+Na)+. 6 NMR : 3.62(2H,s)，6.99(2H，d，J=9.0Hz)，7.03(lH，d，J=8.4Hz)，7.55( lH，dd，J=2_l,8.4Hz)，7.37(lH，t，J=7_5Hz)，7.49-7.53(2H，m)，7_72(lH，d， J=8.3Hz)，7.76(lH，s)，7.80-7.84(3H，m)，10.58(lH，s)，12.46(lH，brs)· MS(ESI) ： 444(M+Na)+. mp ： 240-240.5 °C. 7 NMR ： 3.61(2H，s)，6.98-7.03(3H，m)，7.24(lH，dd，J=2.1，8.3Hz)，7_26-7.40(2H，m),7.50(lH，d，J=2.0Hz),7_53-7.65(lH，m)，7_74-7.85(lH，m)，7.93-7.96(2H，m)，10.97(lH，s)，12.49(lH，brs)， 13.44(lH,brs). MS(ESI) ： 444(M+Na)+. 8 NMR : 3.62(2H，s)，6.98-7.01(2H，m)，7.03(lH，d，J=8.3Hz)，7.25( lH，dd，J=2.1，8.5Hz)，7.51(lH，d,J=2.1Hz),7.73-7.77(2H，m)，8.62 (lH，d，J=2.1Hz)，8.90(lH，d，J=2_2Hz)，10.57(lH，s)，12.48(lH，brs). MS(ESI) ： 473,475(M+Na)+. 9 NMR ： 3.62(2H,s),7.00-7.05(3H,m),7.25(lH,dd,J=2.1,8.4Hz),7.51( lH,d,J=2.1Hz),7.73(lH,t,J=8.0Hz),7.83(2H,d,J=9.0Hz),7.90(lH,dt,J =1.4,7.6Hz)，8.12(lH，d，J=8.5Hz),8.16(lH，d，J=7.6Hz)，8.96(lH,d，J=2. 0Hz)，9.36(lH，d，J=2.3Hz)，10.65(lH,s)，12.48(lH，brs)· MS(ESI) ： 455(M+Na)+. 10 NMR ： 3.62(2H,s),6.99-7.04(3H,m),7.25(lH,dd,J=2.1,8.4Hz),7.51( lH,d,J=2.1Hz),7.85(lH,dt,J=1.2,7.6Hz),7.90-7.94(lH,m),7.96-8.00 (2H,m)，8.26(lH，d,J=8.1Hz)，8.31(lH，d，J=7.6Hz)，8.71(lH，s)，9.48(lH， s),10.83(lH,s),12.49(lH,brs). MS(ESI) ： 455(M+Na)+. 11 NMR ： 3.62(2H,s),7.00-8.30(9H,m),11.09(lH,s),12.43(lH,br). MS(ESI) ： 473(M+Na)+ 12 NMR ： 2.45(3H,s),5.08(2H,s),6.65-8.30(10H,m),10.39(lH,s),13.33 (lH,brs). MS(ESI) : 492(M+Na)+ 13 NMR ： 2.45(3H,s),5.08(2H,s),6.60-7.75(14H,m),l〇.21(lH,s), 13.32(lH,brs). MS(ESI) ： 450(M+Na)+ 14 NMR ： 3.65(2H,s),7.15(lH,d,J=8.8Hz),7.24(lH,d,J=8.2Hz),7.29 (lH,dd,J=1.9,8.3Hz),7.49(lH,d,J=1.9Hz),7.84(lH,d,J=8.3Hz),7.94( lH,dd,J=2.1,8.5Hz),8.20-8.23(2H,m),8.41(lH9d,J=2.6Hz), 10.56(lH,s),12.50(lH,brs). MS(ESI) ： 449,45 l(M-H)·. 15 NMR ： 3.58(2H,s),3.74(3H,s),6.83-6.87(3H,m)56.96(lH,d,J=8.0Hz), 7.08(lH，d，J=1.8Hz)，7.67(2H，d，J=9.0Hz)，7.82(lH，d,J=8.3Hz)，7.93( lH，dd，J=2.0,8.4Hz),8.20(lH，d，J=2.1Hz)，10.35(lH，s)，12.37(lH,brs). MS(ESI) ： 468,470(M+Na)+. 200951122Ex Data 5 NMR: 3.62 (2H, s), 7.02 (2H, d, J = 9.0 Hz), 7.05 (1H, d, J = 8.4 Hz), 7.26 (1H, d, J = 2.0, 8.4 Hz), 7.51 (lH, d, J-2.0 Hz), 7.76 (lH, t, J = 7.5 Hz), 7.90-7.94 (lH, m), 7.96 (2H, d, J = 9.1 Hz), 8.13 (lH, d , J = 8.2 Hz), 8.25 (lH, d, J = 8.4 Hz), 8.26 (lH, d, J = 8.3 Hz), 8.63 (lH, d, J = 8.6 Hz), 10.79 (lH5s), 12.48 ( lH, brs). MS (ESI): 455 (M+Na) +. 6 NMR: 3.62 (2H, s), 6.99 (2H, d, J = 9.0 Hz), 7.03 (1H, d, J = 8.4 Hz ), 7.55 ( lH, dd, J = 2_l, 8.4 Hz), 7.37 (lH, t, J = 7_5 Hz), 7.49-7.53 (2H, m), 7_72 (lH, d, J = 8.3 Hz), 7.76 ( lH, s), 7.80-7.84 (3H, m), 10.58 (lH, s), 12.46 (lH, brs) MS (ESI): 444 (M+Na)+. mp: 240-240.5 ° C. 7 NMR: 3.61 (2H, s), 6.98-7.03 (3H, m), 7.24 (1H, dd, J = 2.1, 8.3 Hz), 7_26-7.40 (2H, m), 7.50 (lH, d, J = 2.0) Hz), 7_53-7.65 (lH, m), 7_74-7.85 (lH, m), 7.93-7.96 (2H, m), 10.97 (lH, s), 12.49 (lH, brs), 13.44 (lH, brs) MS (ESI): 444 (M+Na) +. 8 NMR: 3.62 (2H, s), 6.98-7.01 (2H, m), 7.03 (1H, d, J = 8.3 Hz), 7.25 (lH, dd , J = 2.1, 8.5 Hz), 7.51 (lH, d, J = 2.1 Hz), 7.73 - 7.77 (2H, m), 8.62 (l H, d, J = 2.1 Hz), 8.90 (lH, d, J = 2_2 Hz), 10.57 (lH, s), 12.48 (lH, brs). MS (ESI): 473, 475 (M+Na) +. 9 NMR : 3.62 (2H, s), 7.00-7.05 (3H, m), 7.25 (lH, dd, J = 2.1, 8.4 Hz), 7.51 (lH, d, J = 2.1 Hz), 7.73 (lH, t, J = 8.0 Hz), 7.83 (2H, d, J = 9.0 Hz), 7.90 (lH, dt, J = 1.4, 7.6 Hz), 8.12 (lH, d, J = 8.5 Hz), 8.16 (lH, d, J) = 7.6 Hz), 8.96 (lH, d, J = 2. 0 Hz), 9.36 (lH, d, J = 2.3 Hz), 10.65 (lH, s), 12.48 (lH, brs) MS (ESI): 455 (M+Na)+. 10 NMR : 3.62 (2H, s), 6.99-7.04 (3H, m), 7.25 (lH, dd, J = 2.1, 8.4 Hz), 7.51 (1H, d, J = 2.1 Hz) ), 7.85 (lH, dt, J = 1.2, 7.6 Hz), 7.90-7.94 (lH, m), 7.96-8.00 (2H, m), 8.26 (lH, d, J = 8.1 Hz), 8.31 (lH, d, J = 7.6 Hz), 8.71 (lH, s), 9.48 (lH, s), 10.83 (lH, s), 12.49 (lH, brs). MS (ESI): 455 (M+Na) +. NMR: 3.62 (2H, s), 7.0-8.30 (9H, m), 11.09 (1H, s), 12.43 (1H, br). MS (ESI): 473 (M+Na) + 12 NMR: 2.45 (3H) , s), 5.08 (2H, s), 6.65-8.30 (10H, m), 10.39 (1H, s), 13.33 (1H, brs). MS (ESI): 492 (M+Na) + 13 NMR : 2.45 (3H, s), 5.08 (2H, s), 6.60-7.75 (14H, m), l.21. (lH, s), 13.32 (lH, brs). MS (ESI): 450 (M+Na) + 14 NMR : 3.65 (2H, s), 7.15 (lH, d, J = 8.8 Hz), 7.24 (lH, d, J = 8.2 Hz), 7.29 (lH, dd, J = 1.9, 8.3 Hz), 7.49 (lH, d, J = 1.9 Hz), 7.84 (lH, d, J = 8.3 Hz), 7.94 (lH, dd, J = 2.1, 8.5 Hz), 8.20-8.23 (2H, m), 8.41 (lH9d, J = 2.6 Hz), 10.56 (lH, s), 12.50 (lH, </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 8.0 Hz), 7.08 (lH, d, J = 1.8 Hz), 7.67 (2H, d, J = 9.0 Hz), 7.82 (lH, d, J = 8.3 Hz), 7.93 (lH, dd, J = 2.0, 8.4 Hz), 8.20 (lH, d, J = 2.1 Hz), 10.35 (lH, s), 12.37 (lH, brs). MS (ESI): 468,470 (M+Na)+. 200951122

Ο m 64 Ex Data 16 NMR ： 3.66(2H,s),7.3l(lH,dd,J=l.9,8.4Hz),7.35(lH,d5J=8.2Hz), 7.51(lH，d，J=1.8Hz)，7.87(lH，d，J=8.5Hz)，7.96(lH，dd，J=2_l，8_5Hz)， 8.23(lH，d，J=2_lHz)，8.94(2H，s),10.75(lH，s),12.53(lH，brs)· MS(ESI) : 474,476(M+Na)+. 17 NMR : 3.62(2H，s),6.98-7.02(2H,m),7.07-7.13(2H，m)，7.31(lH，d，J= 12.8Hz),7.73-7.77(2H,m),7.82(lH,d,J=8.3Hz),7.94(lH,dd5J=2.1, 8.4Hz),8.21(lH,cU=2.1Hz),10.42(lH,s),12.47(lH5brs). MS(ESI) ： 456,458(M+Na)+. 18 NMR ： 3.58(2H,s),6.84-6.86(lH,m),7.14-7.16(lH,m),7.44-7.50(3H, m)，7.83-7.96(4H，m)，8.22-8.23(lH，m)，10.59(lH，s)，12.46(lH，brs). MS(ESI) ： 488(M+Na)+. 19 NMR ： 3.62(2H,s),7.00-7.04(2H,m),7.06-7.12(2H,m),7.28-7.40( 3H,m),7.55-7.63(lH,m),7.77-7.84(lH,m),7.91-7.95(2H,in),10.96( lH,s),12.46(lH,brs),13.44(lH,brs). MS(ESI) : 404(M-H)·. 20 NMR : 3.59(2H，s)，3.75(3H，s)，6.85-6.88(3H，m)，6.96(lH，d，J=8.0Hz)， 7.08(lH,d,J=1.8Hz),7.27-7.39(2H,m),7.55-7.62(lH,m),7.74-7.82 (lH,m),7.83-7.87(2H,m),10.86(lH,s),12.38(lH,brs),13.41(lH,brs). MS(ESI) : 416(M_H)·. 21 NMR : 3.67(2H，s)，7.32(lH，dd，J=1.9,8.4Hz)，7.36(lH，d，J=8.2Hz), 7.29-7.43(2H,m),7.52(lH,d,J=1.8Hz),7.55-7.63(lH,m),7.75-7.85 (lH,m),9.10(2H,s),11.39(lH,s),12.53(lH,brs),13.57(lH,brs). MS(ESI) ： 422(M-H)·. 22 NMR ： 3.65(2H,s),7.18(lH,d,J=8.9Hz),7.25(lH,d,J=B.2Hz),7.29 (lH,dd,J=2.0,8.4Hz),7.30-7.40(2H,m),7.49(lH,d,J=1.9Hz),7.55-7.62(lH,m),7.76-7.83(lH,m),8.37(lH,dd,J=2.7,8.9Hz), 8.61(1 H,d, J=2.5Hz), 11.17( 1 H,s), 12.51 (1 H,brs), 13.50(1 H,brs). MS(ESI) ： 421(M-H)'. 23 NMR ： 3.61(2H,s),6.99(2H,d,J=9.0Hz),7.00(lH,d,J=8.4Hz),7.23( lH,dd,J=2.0,8.4Hz),7.50(lH,d,J=1.9Hz),7.56(lH,dd,J=1.8,8.2Hz), 7.63(lH,d,J=8.2Hz),7.71(2H,d,J=8.9Hz),7.77(lH,d,J=19Hz),10.57(1 H，s)，12.47(lH，brs). MS(ESI) : 472,474(M+Na)' 24 NMR : 3.61(2H，s)，6.96-7_00(2H，m)，7.02(lH，d，J=8.3Hz)，7_24( lH，dd，J=2.1,8.4Hz)，7.50(lH，d，J=2.2Hz)，7_57(lH，t，J=7.9Hz)，7.65-7.68(lH，m),7_75-7.79(2H，m)，7.91(lH，dt，J=1.2,7_9Hz)，8.00(lH，t，J= 1.8Hz)，10.38(lH,s)，12.48(lH，brs). MS(ESI) : 438,440(M+Na)+. 25 NMR : 3_61(2H，s)，3.95(3H，s)，6.95-6.99(2H，m)，7.01(lH，d,J=8.4Hz)， 7.24(lH，dd，J=2.1，8.4Hz)，7.30(lH，d，J=8.8Hz)，7.50(lH，d，J=2.0Hz)， 7.74-7.78(2H，m),7.97(lH，dd，J=2.2,8.8Hz)，8.08(lH,d，J=2.2Hz)， 10.22(lH,s),12.48(lH,brs). MS(ESI) ： 468,470(M+Na)+. -105- 200951122 [表65 Ex Data 26 NMR ： 3.58(2H,s),6.85-6.88(lH,m),7.14-7.20(lH,m),7.31-7.60 (5H,m),7.64-7.66(lH,m),7.81-7.83(lH,m),8.06-8.12(2H,m),11-17 nH,s),12.46nH,brs),13.5HlH,s).MS(ESI) ： 46〇CM+Na)+ 27 NMR ： 3.61(2H,s),6.96-7.00(2H,m),7.02(lH,d,J=8.4Hz),7.24(lH, dd，J=2.1，8.4Hz)，7.50(lH，d，J=2.1Hz),7.74-7.78(2H，m)，7.87(lH，t，J= 1.9Hz),7.98(2H,d,J=1.9Hz),10.45(lH,s),12.47(lH,brs). MS(ESI) ： 448,450(M-H)'. 28 NMR ： 3.62(2H,s),6.96-7.00(2H,m),7.02(lH,d,J=8.4Hz),7.24( lH，dd,J=2_l，8.5Hz),7.50(lH，d，J=2.1Hz)，7.60(lH，t,J=8.9Hz)， 7.74-7.78(2H，m)，7.97-8.01(lH，m)，8.20(lH，dd，J=2.2,7.2Hz)， 10.38 (lH,s),12.46(lH,brs). MS(ESI) ： 456,458(M+Na)+. 29 NMR ： 3.61(2H,s),3.96(3H,s),6.97-7.00(2H5m),7.02(lH,d5J=8.4Hz), 7.24(lH,dd,J=2.1,8.5Hz),7.50(lH,cU=2.1Hz),7.57(lH,dd,J=2.1,8.2 Hz)，7.60(lH，d，J=8.2Hz)，7.65(lH，d，J=1.6Hz)，7.73-7.78(2H，m)， 10.32(lH,s),12.49(lH,brs). MS(ESI) ： 468,470(M+Na)+. 30 NMR ： 3.62(2H,s),6.99-7.09(4H,m),7.20-7.26(2H,m),7.41-7.51(3H,m),7-67-7.69(lH,m),7.80-7.84(2H,m),10.26(lH,s), 11.75(lH,s),12.47(lH,brs). MS(ESI) ： 443(M+Na)+. 31 NMR ： 3.62(2H,s),6.93-7.03(3H,m),7.23-7.26(lH,m),7.48-7.51(lH,m),7.76-7.84(2H,m),8.10-8.13(lH,m),8.21-8.23(lH,m), 8.78-8.79(lH,m),9.58(lH,s),10.47(lH,s),12.47(lH,brs). MS(ESI) ： 461(M+Na)+. 32 NMR ： 3.60(2H,s),6.97-7.03(3H,m),7.23-7.25(lH,m),7.40-7.95(1 lH,m),8.22-8.23(lH,m),10.39(lH,s),12.50(lH,brs). MS(ESI) ： 480(M+Na)+. 33 NMR ： 3.59(2H,s),3.80(3H,s),6.96-8.04(15H,m),10.31(lH,s), 12.47(lH,brs). MS(ESI) ： 510(M+Na)+. 34 NMR ： 2.85(2H,t,J=5.9Hz),3.59(2H,s),3.69(2H,t,J=5.9Hz), 4.63(2H，s)，6.87-6.91(2H，m),6.93(lH，d，J=8.4Hz),7.15-7.22(5H,m),7.45-7.50(3H,m),8.60(lH,s),12.45(lH,brs). MS(ESI) : 459(M+Na)+. mp : 167-169 °C. 35 NMR ： 3.61(2H,s),6.70-7.80(14H,m),10.26(lH,s),12.47(lH,brs). MS(ESI) : 430(M+Na)+· 36 NMR ： 3.61(2H,s),6.80-7.95(12H,m),10.29(lH,s),12.48(lH,brs). MS(ESI) ： 474(M-H)·. 37 NMR ： 2.45(3H,s),5.08(2H,s),6.60-8.00(12H,m),10.24(lH,s), 13.30(lH,brs). MS(ESI) ： 496(M+H)+. 38 NMR ： 1.12(3H,U=7.3Hz),3.35-3.41(2H,m),3.62(2H,s)56.98-7.03(3H,m),7.23-7.26(lH,m),7.50-7.51(lH,m),7.77-7.81(2H,m)s 8.03-8.06(2H,m),8.17-8.19(2H,m),10.55(lH,s),12.47(lH,brs). MS(ESI) ： 496(M+Na)+.Ο m 64 Ex Data 16 NMR : 3.66 (2H, s), 7.3 l (lH, dd, J = 1.9, 8.4 Hz), 7.35 (lH, d5J = 8.2 Hz), 7.51 (lH, d, J = 1.8Hz), 7.87 (lH, d, J=8.5Hz), 7.96 (lH, dd, J=2_l, 8_5Hz), 8.23 (lH, d, J=2_lHz), 8.94 (2H, s), 10.75 (lH) , s), 12.53 (lH, brs)· MS (ESI): 474,476 (M+Na)+. 17 NMR: 3.62 (2H, s), 6.98-7.02 (2H, m), 7.07-7.13 (2H, m ), 7.31 (lH, d, J = 12.8 Hz), 7.73 - 7.77 (2H, m), 7.82 (lH, d, J = 8.3 Hz), 7.94 (lH, dd5J = 2.1, 8.4 Hz), 8.21 (lH) , cU=2.1 Hz), 10.42 (lH, s), 12.47 (lH5brs). MS (ESI): 456, 458 (M+Na)+. 18 NMR: 3.58 (2H, s), 6.84-6.86 (1H, m) , 7.14 - 7.16 (lH, m), 7.44 - 7.50 (3H, m), 7.83 - 7.96 (4H, m), 8.22 - 8.23 (lH, m), 10.59 (lH, s), 12.46 (lH, brs) MS (ESI): 488 (M+Na)+. 19 NMR: 3.62 (2H, s), 7.00-7.04 (2H, m), 7.06-7.12 (2H, m), 7.28-7.40 (3H, m) , 7.55-7.63 (lH, m), 7.77-7.84 (lH, m), 7.91-7.95 (2H, in), 10.96 (lH, s), 12.46 (lH, brs), 13.44 (lH, brs). MS (ESI): 404(MH)·. 20 NMR: 3.59 (2H, s), 3.75 (3H, s), 6.85-6.88 (3H, m), 6.96 (1H, d, J = 8.0 Hz), 7.08 ( lH,d,J=1.8Hz), 7.27-7.39(2H,m), 7.55-7.62(lH,m),7.74-7.82 (lH,m),7.83-7.87 (2H, m), 10.86 (lH, s), 12.38 (1H, brs), 13.41 (1H, brs). MS (ESI): 416 (M_H)·. 21 NMR: 3.67 (2H, s), 7.32 ( lH, dd, J = 1.9, 8.4 Hz), 7.36 (lH, d, J = 8.2 Hz), 7.29-7.43 (2H, m), 7.52 (lH, d, J = 1.8 Hz), 7.55-7.63 (lH , m), 7.75-7.85 (lH, m), 9.10 (2H, s), 11.39 (lH, s), 12.53 (lH, brs), 13.57 (lH, brs). MS (ESI): 422 (MH) · 22 NMR : 3.65 (2H, s), 7.18 (lH, d, J = 8.9 Hz), 7.25 (lH, d, J = B. 2 Hz), 7.29 (lH, dd, J = 2.0, 8.4 Hz) , 7.30-7.40 (2H, m), 7.49 (lH, d, J = 1.9 Hz), 7.55-7.62 (lH, m), 7.76-7.83 (lH, m), 8.37 (lH, dd, J = 2.7, 8.9 Hz), 8.61 (1 H, d, J = 2.5 Hz), 11.17 ( 1 H, s), 12.51 (1 H, brs), 13.50 (1 H, brs). MS (ESI): 421 (MH) '. 23 NMR : 3.61 (2H, s), 6.99 (2H, d, J = 9.0 Hz), 7.00 (1H, d, J = 8.4 Hz), 7.23 (1H, dd, J = 2.0, 8.4 Hz), 7.50 (lH, d, J = 1.9 Hz), 7.56 (lH, dd, J = 1.8, 8.2 Hz), 7.63 (lH, d, J = 8.2 Hz), 7.71 (2H, d, J = 8.9 Hz), 7.77 (1H, d, J = 19 Hz), 10.57 (1H, s), 12.47 (1H, brs). MS (ESI): 472, 474 (M+Na)' 24 NMR: 3.61 (2H, s), 6.96- 7_00(2H,m), 7.02(lH,d,J=8.3Hz), 7_24( lH,dd,J=2.1,8.4Hz), 7.50 (lH,d,J=2.2Hz),7_57(lH,t , J = 7.9 Hz), 7.65-7.68 (lH, m), 7_75-7.79 (2H, m), 7. 91(lH,dt,J=1.2,7_9Hz), 8.00(lH,t,J=1.8Hz), 10.38(lH,s),12.48(lH,brs). MS(ESI) : 438,440(M+Na) +. 25 NMR: 3_61 (2H, s), 3.95 (3H, s), 6.95-6.99 (2H, m), 7.01 (1H, d, J = 8.4 Hz), 7.24 (lH, dd, J = 2.1, 8.4 Hz), 7.30 (lH, d, J = 8.8 Hz), 7.50 (lH, d, J = 2.0 Hz), 7.74-7.78 (2H, m), 7.97 (lH, dd, J = 2.2, 8.8 Hz) , 8.08 (lH, d, J = 2.2 Hz), 10.22 (lH, s), 12.48 (lH, brs). MS (ESI): 468, 470 (M+Na) +. -105 - 200951122 [Table 65 Ex Data 26 NMR: 3.58 (2H, s), 6.85-6.88 (lH, m), 7.14-7.20 (1H, m), 7.31-7.60 (5H, m), 7.64-7.66 (lH, m), 7.81-7.83 (lH , m), 8.06-8.12 (2H, m), 11-17 nH, s), 12.46nH, brs), 13.5HlH, s). MS (ESI): 46〇CM+Na)+ 27 NMR: 3.61 ( 2H, s), 6.96-7.00 (2H, m), 7.02 (lH, d, J = 8.4 Hz), 7.24 (lH, dd, J = 2.1, 8.4 Hz), 7.50 (lH, d, J = 2.1 Hz) ), 7.74-7.78 (2H, m), 7.87 (lH, t, J = 1.9 Hz), 7.98 (2H, d, J = 1.9 Hz), 10.45 (lH, s), 12.47 (lH, brs). MS (ESI): 448,450 (MH)'. 28 NMR: 3.62 (2H, s), 6.96-7.00 (2H, m), 7.02 (1H, d, J = 8.4 Hz), 7.24 ( lH, dd, J = 2 _ l , 8.5 Hz), 7.50 (lH, d, J = 2.1 Hz), 7.60 (lH, t, J = 8.9 Hz), 7.74-7.78 (2H, m ), 7.97-8.01 (lH, m), 8.20 (lH, dd, J = 2.2, 7.2 Hz), 10.38 (lH, s), 12.46 (lH, brs). MS (ESI): 456, 458 (M+Na) +. 29 NMR: 3.61 (2H, s), 3.96 (3H, s), 6.97-7.00 (2H5m), 7.02 (1H, d5J = 8.4 Hz), 7.24 (lH, dd, J = 2.1, 8.5 Hz), 7.50 (lH, cU = 2.1 Hz), 7.57 (lH, dd, J = 2.1, 8.2 Hz), 7.60 (lH, d, J = 8.2 Hz), 7.65 (lH, d, J = 1.6 Hz), 7.73 7.78 (2H, m), 10.32 (1H, s), 12.49 (1H, brs). MS (ESI): 468, 470 (M+Na) +. 30 NMR: 3.62 (2H, s), 6.99-7.09 (4H, m), 7.20-7.26 (2H, m), 7.41-7.51 (3H, m), 7-67-7.69 (lH, m), 7.80-7.84 (2H, m), 10.26 (lH, s), 11.75 ( lH, s), 12.47 (lH, brs). MS (ESI): 443 (M+Na) +. 31 NMR: 3.62 (2H, s), 6.93-7.03 (3H, m), 7.23-7.26 (lH, m), 7.48-7.51 (lH, m), 7.76-7.84 (2H, m), 8.10-8.13 (lH, m), 8.21-8.23 (lH, m), 8.78-8.79 (lH, m), 9.58 ( lH, s), 10.47 (lH, s), 12.47 (1H, brs). MS (ESI): 461 (M+Na) +. 32 NMR: 3.60 (2H, s), 6.97-7.03 (3H, m) , 7.23-7.25 (lH, m), 7.40-7.95 (1 lH, m), 8.22-8.23 (lH, m), 10.39 (lH, s), 12.50 (lH, brs). MS (ESI): 480 ( M+Na)+. 33 NMR: 3.59 (2H, s), 3.80 (3H, s), 6.96-8.04 (15H, m), 10.31 (1H, s), 12.47 (lH, brs). MS (ESI) : 510(M+Na)+. 34 NMR : 2.85 (2H, t, J = 5.9 Hz), 3.59 (2H, s), 3.69 (2H, t, J = 5.9 Hz), 4.63 (2H, s), 6.87-6.91 (2H, m), 6.93 (lH, d, J=8.4 Hz), 7.15-7.22 (5H, m), 7.45-7.50 (3H, m), 8.60 (lH, s), 12.45 (lH, brs). MS (ESI): 459 (M+Na + mp : 167-169 ° C. 35 NMR : 3.61 (2H, s), 6.70-7.80 (14H, m), 10.26 (lH, s), 12.47 (lH, brs). MS (ESI): 430 (M+Na)+· 36 NMR: 3.61 (2H, s), 6.80-7.95 (12H, m), 10.29 (1H, s), 12.48 (lH, brs). MS (ESI): 474 (MH)· 37 NMR : 2.45 (3H, s), 5.08 (2H, s), 6.60-8.00 (12H, m), 10.24 (1H, s), 13.30 (1H, brs). MS (ESI): 496 (M+ H) +. 38 NMR : 1.12 (3H, U = 7.3 Hz), 3.35-3.41 (2H, m), 3.62 (2H, s) 56.98-7.03 (3H, m), 7.23-7.26 (lH, m), 7.50-7.51 (lH, m), 7.77-7.81 (2H, m)s 8.03-8.06 (2H, m), 8.17-8.19 (2H, m), 10.55 (lH, s), 12.47 (lH, brs). MS (ESI): 496 (M+Na)+.

-106- 200951122 [表66-106- 200951122 [Table 66

Ex Data 39 NMR:3.62(2H，s),7.00-7.04(3H，m)，7.24-7.26(lH，m)，7.51- 7.52(lH,m),7.64-7.67(lH,m),7.82-7.87(2H,m),8.13-8.16(lH,m),8.25- 8.28(lH,m),8.54-8.56(lH,m),8.63-8.64(lH,m),9.01- 9.03(lH,m),10.56(lH,s),12.52(lH,brs). MS(ESI) ： 433(M+H)+. 40 NMR ： 3.60(2H,s),6.96-7.03(3H,m),7.06-7.11(lH,m),7.23- 7.25(lH,m),7.39-7.40(lH,m),7.44-7.51(3H,m),7.77- 7.83(2H,m),10.33(lH,s),11.91(lH,s). MS(ESI) ： 461(M+Nar. 41 NMR ： 3.60(2H,s),6.95-6.99(2H,m),7.02(lH,d,J=8.4Hz),7.24(lH, dd,J=2.1,8.4Hz),7.27(lH,d,J=4.1Hz),7.50(lH,d,J=2.1Hz), 7.67-7.71(2H,m),7.90(lH,d,J=4.2Hz),10.34(lH,s). MS(ESI) ： 444,446(M+Na)+. 42 NMR ： 3.09-3.13(2H,m),3.36-3.39(2H,m),3.62(2H,s),6.89-6.95 (3H,m),7.19-7.22(lH,m),7.47-7.59(5H,m),7.73- 7.78(2H,m),10.34(lH,s),12.46(lH,brs),14.85(lH,brs). MS(ESI) ： 450(M+H)+. 43 NMR ： 3.53(2H,s)56.94-7.01(3H,m),7.21-7.24(lH,m),7.48-7.49 (lH,m),7.74-7.80(2H,m),7.90-7.92(2H,m),8.14-8.16(2H,m), 10.53(lH,s). MS(ESI) ： 472(M+Na)+. mp ： 238-240 °C. 44 NMR ： 3.57(2H,s),6.96-7.03(3H,m),7.23-7.25(lH,m),7.49-7.50 (1H,m)，7.74-7.80(2H, m)，8.10-8.12(lH,m),8.56-8.58(lH，m), 9.24-9.25(lH,m),10.70(lH,s). MS(ESI) ： 473(M+Na)+. 45 NMR ： 3.04(3H,s),3.61(2H,s),6.96-7.02(3H,m),7.22-7.25 (lH,m),7.40-7.51(3H,m),7.67-7.78(4H,m),9.97(lH,brs), 10.32(lH,s),12.50(lH,brs). MS(ESI) ： 497(M+Na)+. 46 NMR ： 2.58(3H,s),3.62(2H,s),6.90-8.20(12H,m),10.44(lH,s), 12.49(lH,brs). MS(ESI) ： 485(M+Na)+. 47 NMR ： 3.61(2H,s),6.90-8.20(12H,m),8.48(lH,s),10.30(lH,s), 12.49(lH,brs) MS(ESI) ： 487(M+Na)+. 48 NMR ： 1.50-1.70(6H,m),3.1〇-3.35(4H,m),3.59(2H,s),6.90-7.80(1 lH,m),10.17(lH,s),12.55(lH,br). MS(ESI) ： 465(M+H)+. 49 NMR ： 3.62(2H,s),6.90-8.35(llH,m),11.19(lH,s),12.49(lH5brs). MS(ESI) ： 461(M+Na)+. 50 NMR ： 3.61(2H,s),6.90-7.90(12H,m),8.56(lH,t,J=2.1Hz),9.00-9.15 (2H,m), 10.54( 1 H,s), 12.48( 1 H,brs). MS(ESI) ： 481(M+Na)+. 51 NMR ： 3.62(2H,s),3.78(3H,s),6.86-6.89(lH,m),6.98-7.03 (3H,m),7.13-7.14(lH,m),7.23-7.25(lH,m),7.31-7.36(2H,m),7.50-7.51(lH,m),7.79-7.83(2H,m),10.21(lH,s),11.60(lH,s),12.48(lH,brs). MS(ESI) ： 473(M+Na)+. 52 NMR ： 3.57(2H,s),6.82-6.85(lH,m),7.06-7.26(3H,m),7.43-7.52 (5H,m),7.68-7.70(lH,m),7.94- 7.97(2H,m),10.44(lH,s),11.83(lH,s),12.57(lH,brs). MS(ESI) : 459(M+Na)' -107- 200951122 m 67 Ex Data 53 NMR ： 3.59(2H,s),6.83-6.86(2H,m),6.92(lH,d,J=8.4Hz),7.04-7.08 (2H,m),7.20(lH,dd,J=2.1,8.5Hz),7.46(lH,d,J=2.0Hz),7.53-7.57 (2H,m),7.60-7.64(lH,m),7.71-7.73(2H,m),10.18(lH,brs), 12.45(lH,brs). MS(ESI) ： 440(M+Na)+. 54 NMR ： 3.60(2H,s),6.87-6.90(2H,m),6.96(lH,d,J=8.3Hz),7.05-7.08 (2H,m),7.22(lH,dd,J=2.1,8.5Hz),7.48(lH,d,J=2.2Hz),7.64(lH,dd,J= 2.2,8.5Hz),7.85(lH,d,J=2.1Hz),7.86(lH,d,J=8.5Hz),10.31(lH,brs), 12.45(lH,brs). MS(ESI) ： 508,510(M+Na)+. 55 NMR ： 3.60(2H,s),6.89-6.91(lH,m),7.06-7.08(lH,m),7.10-7.26 (3H,m),7.43-7.50(3H,m),7.59-7.62(lH,m),7.69-7.71(lH,m),7.98-8.02(lH,m),10.45(lH,s),11.82 (lH,s),12.50(lH,brs). MS(ESI) ： 461(M+Na)+. mp ： 220-221 °C. 56 NMR ： 3.62(2H,s),4.00,4.02(3H,s),6.97-7.02(3H,m),7.12-7.16 (lH,m),7.23-7.25(lH,m),7.30-7.34(2H,m),7.50-7.51(lH,m),7.56-7.58 (lH,m),7.69-7.71(lH,m),7.78-7.82(2H,m),10.37(lH,s), 12.47(1 H,brs). MS(ESI) ： 435(M+H)+. mp ： 215-216°C. 57 NMR ： 3.61(2H,s),6.58-6.59(lH,m),6.96-7.00(3H,m),7.22-7.25 (lH,m),7.46-7.50(3H,m),7.72-7.75(lH,m),7.80-7.84(2H,m),8.26-8.25 (1 H,m), 10.16(1 H,s), 11.40(1 H,s), 12.46(1 H,brs). MS(ESI) ： 443(M+Na)+. 58 NMR ： 3.62(2H,s),6.97-7.03(3H,m),7.23-7.26(lH,m),7.50-7.51 (lH,m),7.59-7.66(lH,m),7.74-7.78(2H,m),7.85-7.88(lH,m),8.01- 8.06(lH,m),10.35(lH,s),12.48(lH,brs). MS(ESI) ： 440(M+Na)+. 59 NMR ： 3.61(2H,s),6.95-7.00(3H,m),7.12-7.24(3H,m),7.46-7.50 (2H,m),7.76-7.80(2H,m),8.18-8.20(lH,m),8.27- 8.28(lH,m),9.77(lH,s),11.73(lH,s),12.47(lH,brs). MS(ESI) ： 421(M+H)+. 60 NMR ： 3.60(2H,s),6.89-6.91(lH,m),7.10-7.24(2H,m),7.50-7.58 (2H，m)，7.84-7.95(3H,m),8.21-8.22(lH，m)，10.61(lH，s)， 12.46(lH,brs). MS(ESI) ： 490(M+Na)+. 61 NMR ： 3.62(2H,s),6.99-7.03(3H,m),7.21-7.26(2H,m),7.40-7.51 (3H,m),7.78-7.83(3H,m),10.35(lH,s),11.98(lH,s),12.51(lH,brs). MS(ESI) ： 453(M-H)'. 62 NMR ： 3.58(2H,s),3.93(3H,s),6.95-7.01(3H,m),7.22-7.34(2H,m), 7.49-7.50(lH,m),7.74-7.86(4H,m),10.19(lH,s). MS(ESI) ： 452(M+Na)+. 63 NMR ·· 2.32(3H，s),3.61(2H，s)，6_96-7.02(3H，m)，7.23-7.25(lH，m)， 7.44-7.50(2H，m),7.72-7.79(4H，m)，10.26(lH，s),12.47(lH，brs). MS(ESI) ： 436(M+Na)+. 64 NMR ： 3.62(2H,s),6.98-7.04(3H,m),7.24-7.26(lH,m),7.50-7.51 (lH,m),7.76-7.81(3H,m),7.96-7.98(lH,m),8.26-8.29(2H,m), 10.51(lH,s),12.47(lH,brs). MS(ESI) : 448(M-H)_Ex Data 39 NMR: 3.62 (2H, s), 7.00-7.04 (3H, m), 7.24-7.26 (lH, m), 7.51- 7.52 (lH, m), 7.64-7.67 (lH, m), 7.82 7.87(2H,m), 8.13-8.16(lH,m), 8.25- 8.28(lH,m),8.54-8.56(lH,m),8.63-8.64(lH,m),9.01- 9.03(lH,m ), 10.56 (lH, s), 12.52 (1H, brs). MS (ESI): 433 (M+H) +. 40 NMR: 3.60 (2H, s), 6.96-7.03 (3H, m), 7.06- 7.11(lH,m), 7.23- 7.25(lH,m), 7.39-7.40(lH,m),7.44-7.51(3H,m),7.77- 7.83(2H,m),10.33(lH,s), 11.91 (1H, s). MS (ESI): 461 (M+N. NMR: 3.60 (2H, s), 6.95-6.99 (2H, m), 7.02 (1H, d, J = 8.4 Hz), 7.24 (lH, dd, J=2.1, 8.4 Hz), 7.27 (lH, d, J = 4.1 Hz), 7.50 (lH, d, J = 2.1 Hz), 7.67-7.71 (2H, m), 7.90 (lH, d, J = 4.2 Hz), 10.34 (1H, s). MS (ESI): 444, 446 (M+Na) +. 42 NMR: 3.09-3.13 (2H, m), 3.36-3.39 (2H, m), 3.62 (2H, s), 6.89-6.95 (3H, m), 7.19-7.22 (lH, m), 7.47-7.59 (5H, m), 7.73- 7.78 (2H, m), 10.34 (lH, s), 12.46 (lH, brs), 14.85 (1H, brs). MS (ESI): 450 (M+H) +. 43 NMR: 3.53 (2H, s) 56.94-7.01 (3H, m), 7.21 - 7.24 (lH, m), 7.48-7.49 (lH, m), 7.74-7.80 (2H, m), 7.90-7.92 (2H, m), 8.14-8.16 (2H, m), 10.53 (lH, s). MS (ESI) : 472(M+Na)+. mp : 238-240 °C. 44 NMR : 3.57(2H, s), 6.96-7.03 (3H, m), 7.23-7.25 (lH, m), 7.49-7.50 (1H, m), 7.74-7.80 (2H, m), 8.10-8.12 (lH, m), 8.56- 8.58 (lH, m), 9.24-9.25 (1H, m), 10.70 (1H, s). MS (ESI): 473 (M+Na)+. 45 NMR: 3.04 (3H, s), 3.61 (2H, s), 6.96-7.02 (3H, m), 7.22-7.25 (lH, m), 7.40-7.51 (3H, m), 7.67-7.78 (4H, m), 9.97 (lH, brs), 10.32 (lH, s), 12.50 (lH, brs). MS (ESI): 495 (M+Na) +. 46 NMR: 2.58 (3H, s), 3.62 (2H, s), 6.90-8.20 (12H, m), 10.44 (lH, s), 12.49 (1H, brs). MS (ESI): 495 (M+Na) +. 47 NMR: 3.61 (2H, s), 6.90-8.20 (12H, m), 8.48 (lH, s ), 10.30 (lH, s), 12.49 (1H, brs) MS (ESI): 487 (M+Na) +. 48 NMR: 1.50-1.70 (6H, m), 3.1 〇 - 3.35 (4H, m), 3.59 (2H, s), 6.90-7.80 (1 lH, m), 10.17 (lH, s), 12.55 (1H, br). MS (ESI): 465 (M+H)+. 49 NMR: 3.62 (2H , s), 6.90-8.35 (llH, m), 11.19 (lH, s), 12.49 (lH5brs). MS (ESI): 461 (M+Na)+. 50 NMR: 3.61 (2H, s), 6.90- 7.90 (12H, m), 8.56 (lH, t, J = 2.1 Hz), 9.00-9.15 (2H, m), 10.54 ( 1 H, s), 12.48 ( 1 H, brs). MS (ESI) : 481 (M+Na)+. 51 NMR: 3.62 (2H, s), 3.78 (3H, s), 6.86-6.89 (lH, m), 6.98-7.03 (3H, m), 7.13-7.14 (lH, m) , 7.23 - 7.25 (lH, m), 7.31 - 7.36 (2H, m), 7.50-7. 51 (lH, m), 7.79-7.83 (2H, m), 10.21 (lH, s), 11.60 (lH, s), 12.48 (lH, brs). MS (ESI): 473 (M+Na)+. 52 NMR : 3.57 (2H, s), 6.82-6.85 (lH, m), 7.06-7.26 (3H, m), 7.43-7.52 (5H, m), 7.68-7.70 (lH, m), 7.94 - 7.97 ( 2H,m), 10.44 (lH, s), 11.83 (lH, s), 12.57 (lH, brs). MS (ESI): 459 (M+Na)' -107- 200951122 m 67 Ex Data 53 NMR : 3.59 (2H, s), 6.83-6.86 (2H, m), 6.92 (lH, d, J = 8.4 Hz), 7.04-7.08 (2H, m), 7.20 (lH, dd, J = 2.1, 8.5 Hz), 7.46 (lH, d, J = 2.0 Hz), 7.53-7.57 (2H, m), 7.60-7.64 (lH, m), 7.71-7.73 (2H, m), 10.18 (lH, brs), 12.45 (lH, MS (ESI): 440 (M+Na)+. 54 NMR: 3.60 (2H, s), 6.87-6.90 (2H, m), 6.96 (lH, d, J = 8.3 Hz), 7.05-7.08 (2H, m), 7.22 (lH, dd, J = 2.1, 8.5 Hz), 7.48 (lH, d, J = 2.2 Hz), 7.64 (lH, dd, J = 2.2, 8.5 Hz), 7.85 (lH, d, J = 2.1 Hz), 7.86 (lH, d, J = 8.5 Hz), 10.31 (lH, brs), 12.45 (lH, brs). MS (ESI): 508, 510 (M+Na) +. 55 NMR: 3.60 (2H, s), 6.89-6.91 (lH, m), 7.06-7.08 (lH, m), 7.10-7.26 (3H, m), 7.43-7.50 (3H, m), 7.59-7.62 (lH, m ), 7.69-7.71 (lH, m), 7.98-8.02 (lH, m), 10.45 (lH, s), 11.82 (lH, s), 12.50 (lH, brs). MS (ESI): 461 (M+ Na)+. mp : 220-221 ° C. 56 NMR : 3.62 (2H, s), 4.00, 4.02 (3H, s), 6.97-7.02 (3H, m), 7.12-7.16 (lH, m), 7.23-7.25 (lH, m), 7.30-7.34 (2H, m), 7.50-7.51 (lH, m), 7.56- 7.58 (lH, m), 7.69-7.71 (lH, m), 7.78-7.82 (2H, m), 10.37 (lH, s), 12.47 (1H, brs). MS (ESI): 435 (M+H +. mp : 215-216 ° C. 57 NMR : 3.61 (2H, s), 6.58-6.59 (lH, m), 6.96-7.00 (3H, m), 7.22-7.25 (lH, m), 7.46- 7.50(3H,m), 7.72-7.75(lH,m), 7.80-7.84(2H,m),8.26-8.25 (1 H,m), 10.16(1 H,s), 11.40(1 H,s) , MS (ESI): 443 (M+Na) +. 58 NMR: 3.62 (2H, s), 6.97-7.03 (3H, m), 7.23 - 7.26 (lH, m), 7.50-7.51 (lH, m), 7.59-7.66 (lH, m), 7.74-7.78 (2H, m), 7.85-7.88 (lH, m), 8.01 - 8.06 (lH, m), 10.35 (lH, s ), 12.48 (1H, brs). MS (ESI): 440 (M+Na) +. 59 NMR: 3.61 (2H, s), 6.95-7.00 (3H, m), 7.12-7.24 (3H, m), 7.46-7.50 (2H,m), 7.76-7.80(2H,m), 8.18-8.20(lH,m), 8.27- 8.28(lH,m),9.77(lH,s),11.73(lH,s), 12.47 (1H, brs). MS (ESI): 422 (M+H) +. 60 NMR: 3.60 (2H, s), 6.89-6.91 (1H, m), 7.10-7.24 (2H, m), 7.50- 7.58 (2H, m), 7.84-7.95 (3H, m), 8.21-8.22 (1H, m), 10.61 (lH, s), 12.46 (1H, brs). MS (ESI): 490 (M+Na) +. 61 NMR: 3.62 (2H, s), 6.99-7.03 (3H, m), 7.21-7.26 (2H , m), 7.40-7.51 (3H, m), 7.78-7.83 (3H, m), 10.35 (lH, s), 11.98 (lH, s), 12.51 (lH, brs). MS (ESI): 453 ( MH)'. 62 NMR: 3.58 (2H, s), 3.93 (3H, s), 6.95-7.01 (3H, m), 7.22-7.34 (2H, m), 7.49-7.50 (lH, m), 7.74 7.86(4H,m), 10.19(lH,s). MS(ESI): 452(M+Na)+. 63 NMR ·· 2.32 (3H, s), 3.61 (2H, s), 6_96-7.02 (3H , m), 7.23-7.25 (lH, m), 7.44-7.50 (2H, m), 7.72-7.79 (4H, m), 10.26 (lH, s), 12.47 (lH, brs). MS (ESI): 436(M+Na)+. 64 NMR : 3.62 (2H, s), 6.98-7.04 (3H, m), 7.24-7.26 (lH, m), 7.50-7.51 (lH, m), 7.76-7.81 (3H , m), 7.96-7.98 (lH, m), 8.26-8.29 (2H, m), 10.51 (lH, s), 12.47 (lH, brs). MS (ESI): 448 (MH) _

-108- 200951122 m 68-108- 200951122 m 68

Ex 65 Data NMR ： 2.50(6H,s),3.70(2H,s),6.96-7.02(3H,m),7.14-8.09(1 lH,m), 8.09-8.10(lH,m),10.34(lH,s). MS(ESI) ： 501(M+H)+. 66 NMR ： 3.59(2H,s),4.76(4H,s),6.89-6.92(2H,m),6.94(lH,d,J=8.4Hz), 7.21(lH,dd,J=2.1,8.5Hz),7.30-7.38(4H,m),7.48(lH,d,J=2.0Hz), 7.55-7.59(2H,m),8.39(lH,s),12.46(lH,brs). MS(ESI) ： 445,447(M+Na)+. 67 NMR ： 1.86-1.93(2H,m),2.74(2H,t,J=6.5Hz),3.59(2H,s),3.70 (2H,t,J=6.1Hz),6.89-6.98(4H,m),7.09-7.14(2H,m),7.21(lH,dd,J= 2.0,8.4Hz),7.36(lH,d,J=7.6Hz),7.46-7.50(3H,m),8.88(lH,s), 12.46(1 H,brs). MS(ESI) ： 459,461(M+Na)+. 68 NMR ： 2.54(3H,s),3.61(2H,s),6.96-6.99(2H,m),7.00(lH,d,J=8.3Hz), 7.23(lH,dd,J=2.0,8.4Hz),7.38(2H,d,J=8-5Hz),7.50(lH,d,J=2.1Hz),7. 75-7.79(2H,m),7.92(2H,d,J=85Hz),10.22(lH,s),12.47(lH,brs). MS(ESI) ： 450,452(M+Na)+. 69 NMR ： 2.30(3H,s),2.3l(3H,s),3.61(2H,s),6.95-7.01(3H,m),7.22-7.29 (2H,m),7.49-7.50(lH,m),7.68-7.80(4H,m),10.16(lH,s), 12.46(lH,brs). MS(ESI) ： 432(M+Na)+. 70 NMR ： 2.38(3H,s),3.62(2H,s),6.98-7.06(4H,m),7.23-7.25 (lH,m), 7.31-7.5 l(4H,m),7.79-7.83(2H,m),10.22(lH,s), 11.63(lH,s),12.48(lH,brs). MS(ESI) ： 457(M+Na)+. 71 NMR ： 2.61(2H,t,J=7.7Hz),2.91(2H,t,J=7.7Hz),3.59(2H,s),6.80-7.65 (12H,m),9.94(lH,s),12.46(lH,brs). MSiESI) ： 432(M+Na)+. 72 NMR ： 3.61(2H,s),6.80-7.10(4H,m),7.23(lH,dd,J=2.1,8.4Hz),7.40-8.10(6H,m),8.59(lH,dd,J=1.6,4.8Hz),8.82(lH,d,J=2.1Hz),10.33(lH,s ),12.46( lH,brs). MS(ESI) : 431(M+Na)+. 73 NMR ： 3.60(2H,s),6.90-8.05(10H,m),10.40(lH,s),12.53(lH,brs). MS(ESI) ： 456(M+Na)+. 74 NMR ： 2.42(3H,s),3.61(2H,s),6.90-8.00(10H,m),10.31(lH,s), 12.47(lH,brs). MS(ESI) : 452(M+Na)+. 75 NMR ： 3.61(2H,s),6.90-8.00(10H,m),11.00(lH,s),12.49(lH,brs), 13.57(lH,brs). MS(ESI) ： 462(M+Na)+. 76 NMR ： 2.45(3H,s),3.59(2H,s),6.90-8.00(10H,m),10.92(lH,s), 13.30(lH,brs). MS(ESI) ： 434(M-HV. 77 NMR ： 2.20(3H,s),3.54(2H,s),6.76-6.84(2H,m),7.16-7.18(lH,m), 7.46-7.47(lH,m),7.57-7.60(lH,m),7.73-7.74(lH,m),7.81-7.85 (lH,m),7.93-7.95(lH,m),8.21-8.22(lH,m),10.40(lH,s). MS(ESI) ： 486(M+Na)+. 78 NMR ： 2.20(3H,s),3.59(2H,s),6.76-6.88(2H,m),7.05-7.09(lH,m) ,7.16-7.24(2H,m),7.41-7.49(3H,m)57.65-7.69(2H,m),7.76-7.77 (lH,m),10.21(lH,s),11.73(lH,s),12.46(lH,brs). MS(ESI) : 457(M+Na)+. -109- 200951122 m 69 Ex Data 79 NMR : 3.64(2H,s)，6.81(lH，d，J=15.8Hz)，7.13(lH，d，J=8.8Hz)， 7.22(lH，d，J=8.3Hz)，7.28(lH，dd，J=2.1,8.3Hz)，7.40-7.48(4H，m),7.59-7.65(3H,m),8.21(lH,dd9J=2.7,8.9Hz),8.35(lH,d,J=2.6Hz),10.39(lH,s ),12.50(lH,brs). MS(ESI) : 431(M+Na)+. 80 NMR ： 3.65(2H,s),7.07(lH,t,J=7.4Hz),7.16(lH,d,J=8.8Hz),7.21-7.30 (3H,m),7.40(lH,d,J=1.5Hz),7.46(lH,d,J=8.2Hz),7.49(lH,&lt;U=1.8Hz), 7.68(lH，d，J=8.0Hz)，8.25(lH，dd，J=2.7,8.9Hz)，8.48(lH，d，J=2.7Hz)，10 .40(lH，s)，11.80(lH，s)，12.50(lH，brs). MS(ESI) ： 444(M+Na)+. 81 NMR : 3.61(2H，s)，6.87(lH，d，J=8.3Hz),7.07(lH，d，J=8.9Hz)， 7.22(lH，dd,J=2.1，8.4Hz)，7.39(lH，dt，J=0.8,8.0Hz)，7.50-7.55(2H,m),7.74(lH,d,J=8.5Hz),7.78(lH,dd,J=1.6,8.8Hz),7.79(lH,s), 7.85(lH，d，J=7.6Hz)，8.16(lH，d，J=2.5Hz)，10.76(lH,s)，12.46(lH，brs). MS(ESI) ： 478,480(M+Na)+. 82 NMR : 2.33(3H，s)，3.61(2H,s)，6.90-8.10(10H，m)，10.31(lH，s)， 12.50(lH，br). MS(ESI) ： 452(M+Na)+. 83 NMR : 3.61(2H,s)，3.82(3H，s)，6.90-8.00(10H，m)，10.86(lH，s)， 12.50(lH，brs)，13.30(lH，br). MS(ESI) ： 452(M+H)+. 84 NMR ： 3.61(2H，s)，6.85(lH，d，J=8.4Hz)，7.09(2H，d，J=9.0Hz)，7.20-7.26(2H,m)，7.43(lH，d，J=1.5Hz)，7.47(lH，d，J=8.2Hz)，7.51(lH，d，J=2.1 Hz)，7_69(lH，d，J=7.9Hz)，7.76(lH,dd，J=2.5,9.0Hz),8.16(lH,d，J=2.4Hz )，10.40(lH，s),11.79(lH,s)，12.45(lH，brs)· MS(ESI) ： 477,479(M+Na)+. 85 NMR ： 2.75(2H,U=7.1Hz),3.31-3.36(2H,m),3.58(2H,s),6.08(lH,t,J= 5.7Hz),6.85-6.90(3H,m),7.17-7.25(4H,m),7.29-7.33(2H,m),7.37- 7.41(2H,m),7.46(lH,d,J=2.0Hz),8.50(lH,s),12.43(lH,brs). MS(ESI) ： 447,449(M+Na)+. 86 NMR ： 1.51-1.81(4H,m),2.67-2.90(3H,m),3.59(2H,s),4.25-4.28 (2H,m),6.86-6.93(3H,m),7.18-7.32(6H,m)s7.46-7.50(3H,m), 8.55(lH,s),12.45(lH,brs). MS(ESI) ： 487(M+Na)+. 87 NMR ： 3.57(2H,s),6.97-7.03(3H,m),7.22-7.25(lH,m),7.49-7.50 (lH,m),7.73-7.78(2H,m),7.96-8.07(3H,m),10.56(lH,s), 12.50(lH,brs). MS(ESI) ： 490(M+Na)+. 88 NMR ： 2.3l(3H,s),3.61(2H,s),6.95-7.00(3H,m),7.22-7.28 (2H,m),7.49-7.59(2H,m),7.89-7.93(2H,m),8.43-8.48(2H,m), 10.33(lH,s),12.45(lH,s). MS(ESI) : 436(M+H)+. 89 NMR ： 3.59(2H,s),6.97-7.01 (2H,m),7.03(lH,d,J=8.3Hz), 7.24(lH,dd,J=2.1,8.4Hz),7.50(lH,d,J=2.0Hz),7.53(lH,dd,J=2.3,8.8 Hz),7.75-7.78(2H,m),7.79-7.83(2H,m),7.94(lH,cU=2.1Hz), 10.65(lH,s). MS(ESI) ： 478,480(M+Na)+.Ex 65 Data NMR : 2.50 (6H, s), 3.70 (2H, s), 6.96-7.02 (3H, m), 7.14-8.09 (1 lH, m), 8.09-8.10 (lH, m), 10.34 (lH) MS (ESI): 501 (M+H)+. 66 NMR: 3.59 (2H, s), 4.76 (4H, s), 6.89-6.92 (2H, m), 6.94 (1H, d, J = 8.4 Hz), 7.21 (lH, dd, J = 2.1, 8.5 Hz), 7.30-7.38 (4H, m), 7.48 (lH, d, J = 2.0 Hz), 7.55-7.59 (2H, m), 8.39 (lH, s), 12.46 (1H, brs). MS (ESI): 445,447 (M+Na) +. 67 NMR: 1.86-1.93 (2H, m), 2.74 (2H, t, J = 6.5 Hz), 3.59 (2H, s), 3.70 (2H, t, J = 6.1 Hz), 6.89-6.98 (4H, m), 7.09-7.14 (2H, m), 7.21 (lH, dd, J = 2.0, 8.4 Hz) , 7.36 (lH, d, J = 7.6 Hz), 7.46-7.50 (3H, m), 8.88 (1H, s), 12.46 (1H, brs). MS (ESI): 459,461 (M+Na)+. 68 NMR : 2.54 (3H, s), 3.61 (2H, s), 6.96-6.99 (2H, m), 7.00 (1H, d, J = 8.3 Hz), 7.23 (lH, dd, J = 2.0, 8.4 Hz ), 7.38 (2H, d, J = 8-5 Hz), 7.50 (lH, d, J = 2.1 Hz), 7. 75-7.79 (2H, m), 7.92 (2H, d, J = 85 Hz), 10.22 (lH, s), 12.47 (1H, brs). MS (ESI): 450, 452 (M+Na) +. 69 NMR: 2.30 (3H, s), 2.3l (3H, s), 3.61 (2H, s) , 6.95-7.01 (3H, m), 7.22-7.29 (2H, m), 7.49-7.50 (lH, m), 7.68-7.80 (4H, m), 10.16 (lH, s), 12.46 (lH, brs) MS (ESI): 432 (M+Na) +. 70 NMR: 2.38 (3H, s), 3.62 (2H, s), 6.98-7.06 (4H, m), 7.23-7.25 ( lH,m), 7.31-7.5 l(4H,m), 7.79-7.83(2H,m), 10.22(lH,s), 11.63(lH,s), 12.48(lH,brs). MS(ESI): 457(M+Na)+. 71 NMR: 2.61 (2H, t, J = 7.7 Hz), 2.91 (2H, t, J = 7.7 Hz), 3.59 (2H, s), 6.80-7.65 (12H, m) , 9.94 (lH, s), 12.46 (lH, brs). MSiESI): 432 (M+Na) +. 72 NMR: 3.61 (2H, s), 6.80-7.10 (4H, m), 7.23 (lH, dd , J = 2.1, 8.4 Hz), 7.40-8.10 (6H, m), 8.59 (lH, dd, J = 1.6, 4.8 Hz), 8.82 (lH, d, J = 2.1 Hz), 10.33 (lH, s) , </ RTI> <RTIgt; MS (ESI): 456 (M+Na) +. 74 NMR: 2.42 (3H, s), 3.61 (2H, s), 6.90-8.00 (10H, m), 10.31 (lH, s), 12.47 (1H, brs). MS (ESI): 452 (M+Na) +. 75 NMR: 3.61 (2H, s), 6.90-8.00 (10H, m), 11.00 (lH, s), 12.49 (lH, Brs), 13.57 (1H, brs). MS (ESI): 462 (M+Na) +. 76 NMR: 2.45 (3H, s), 3.59 (2H, s), 6.90-8.00 (10H, m), 10.92 (lH, s), 13.30 (1H, brs). MS (ESI): 434 (M-HV. 77 NMR: 2.20 (3H, s), 3.54 (2H, s), 6.76-6.84 (2H, m), 7.16-7.18(lH,m), 7.46-7.47(lH,m),7.57-7.60(lH,m),7.73-7.74(lH,m),7.81-7.85 (lH,m),7.93-7.95(lH , m), 8.21 - 8.22 (lH, m), 10.40 (lH, s). MS (ESI): 486 (M+ Na)+. 78 NMR: 2.20 (3H, s), 3.59 (2H, s), 6.76-6.88 (2H, m), 7.05-7.09 (lH, m), 7.16-7.24 (2H, m), 7.41 7.49 (3H, m) 57.65-7.69 (2H, m), 7.76-7.77 (lH, m), 10.21 (lH, s), 11.73 (lH, s), 12.46 (lH, brs). MS (ESI): 457(M+Na)+. -109- 200951122 m 69 Ex Data 79 NMR : 3.64 (2H, s), 6.81 (lH, d, J = 15.8 Hz), 7.13 (lH, d, J = 8.8 Hz), 7.22 (lH, d, J = 8.3 Hz), 7.28 (lH, dd, J = 2.1, 8.3 Hz), 7.40-7.48 (4H, m), 7.59-7.65 (3H, m), 8.21 (lH, dd9J= 2.7, 8.9 Hz), 8.35 (lH, d, J = 2.6 Hz), 10.39 (lH, s), 12.50 (lH, brs). MS (ESI): 431 (M+Na)+. 80 NMR: 3.65 ( 2H, s), 7.07 (lH, t, J = 7.4 Hz), 7.16 (lH, d, J = 8.8 Hz), 7.21-7.30 (3H, m), 7.40 (lH, d, J = 1.5 Hz), 7.46 (lH, d, J = 8.2 Hz), 7.49 (lH, &lt; U = 1.8 Hz), 7.68 (lH, d, J = 8.0 Hz), 8.25 (lH, dd, J = 2.7, 8.9 Hz), 8.48 (lH,d,J=2.7 Hz), 10.40 (lH, s), 11.80 (lH, s), 12.50 (lH, brs). MS (ESI): 444 (M+Na)+. 81 NMR : 3.61 (2H, s), 6.87 (lH, d, J = 8.3 Hz), 7.07 (lH, d, J = 8.9 Hz), 7.22 (lH, dd, J = 2.1, 8.4 Hz), 7.39 (lH, Dt, J = 0.8, 8.0 Hz), 7.50-7.55 (2H, m), 7.74 (lH, d, J = 8.5 Hz), 7.78 (lH, dd, J = 1.6, 8.8 Hz), 7.79 (lH, s ), 7.85(lH,d,J= 7.6 Hz), 8.16 (lH, d, J = 2.5 Hz), 10.76 (lH, s), 12.46 (1H, brs). MS (ESI): 478, 480 (M+Na)+. 82 NMR: 2.33 (3H, s), 3.61 (2H, s), 6.90-8.10 (10H, m), 10.31 (1H, s), 12.50 (1H, br). MS (ESI): 452 (M+Na)+. 83 NMR: 3.61 (2H, s), 3.82 (3H, s), 6.90-8.00 (10H, m), 10.86 (lH, s), 12.50 (lH, brs), 13.30 (lH, br). MS (ESI): 452 ( M+H)+. 84 NMR: 3.61 (2H, s), 6.85 (1H, d, J = 8.4 Hz), 7.09 (2H, d, J = 9.0 Hz), 7.20-7.26 (2H, m), 7.43 (lH, d, J = 1.5 Hz), 7.47 (lH, d, J = 8.2 Hz), 7.51 (lH, d, J = 2.1 Hz), 7_69 (lH, d, J = 7.9 Hz), 7.76 (lH) , dd, J = 2.5, 9.0 Hz), 8.16 (lH, d, J = 2.4 Hz), 10.40 (lH, s), 11.79 (lH, s), 12.45 (lH, brs) · MS (ESI): 477,479 (M+Na)+. 85 NMR: 2.75 (2H, U = 7.1 Hz), 3.31-3.36 (2H, m), 3.58 (2H, s), 6.08 (1H, t, J = 5.7 Hz), 6.85- 6.90 (3H, m), 7.17-7.25 (4H, m), 7.29-7.33 (2H, m), 7.37- 7.41 (2H, m), 7.46 (lH, d, J = 2.0 Hz), 8.50 (lH, s), 12.43 (lH, brs). MS (ESI): 447, 449 (M+Na) +. 86 NMR: 1.51-1.81 (4H, m), 2.67-2.90 (3H, m), 3.59 (2H, s) , 4.25-4.28 (2H, m), 6.86-6.93 (3H, m), 7.18-7.32 (6H, m) s7.46-7.50 (3H, m), 8.5 5(lH, s), 12.45 (lH, brs). MS (ESI): 487 (M+Na) +. 87 NMR: 3.57 (2H, s), 6.97-7.03 (3H, m), 7.22-7.25 ( lH, m), 7.49-7.50 (lH, m), 7.73-7.78 (2H, m), 7.96-8.07 (3H, m), 10.56 (lH, s), 12.50 (lH, brs). MS (ESI) : 490(M+Na)+. 88 NMR : 2.3l (3H, s), 3.61 (2H, s), 6.95-7.00 (3H, m), 7.22-7.28 (2H, m), 7.49-7.59 (2H , m), 7.89-7.93 (2H, m), 8.43-8.48 (2H, m), 10.33 (lH, s), 12.45 (lH, s). MS (ESI): 436 (M+H)+. NMR: 3.59 (2H, s), 6.97-7.01 (2H, m), 7.03 (1H, d, J = 8.3 Hz), 7.24 (lH, dd, J = 2.1, 8.4 Hz), 7.50 (lH, d, J = 2.0 Hz), 7.53 (lH, dd, J = 2.3, 8.8 Hz), 7.75-7.78 (2H, m), 7.79-7.83 (2H, m), 7.94 (lH, cU = 2.1 Hz), 10.65 ( lH, s). MS (ESI): 478, 480 (M+Na)+.

-110- 200951122 m 7〇]-110- 200951122 m 7〇]

Ex 90 Data NMR : 2.43(3H，s)，3.61(2H，s)，6.97-7.00(2H，m)，7.03(lH,d,J=8.4Hz)， 7.24(lH，dd，J=2.1，8.3Hz)，7.32(lH,dd，J=1.4,8.6Hz)，7.50(lH，d，J=2.0 Hz),7.59-7.62(2H,m),7.68(lH,d,J=0.8Hz),7.80-7.84(2H,m), 10.54(lH,s),12.48(lH,brs). MS(ESI) ： 458,460(M+Na)+. 91 NMR ： 3.62(2H,s),6.97-7.01(2H,m),7.03(lH,d,J=8.3Hz), 7.25(lH,dd,J=2.1,8.5Hz),7.36(lH,dt,J=2.7,9.3Hz),7.51(lH,d,J=2.1 Hz)，7.66(lH，dd，J=2.7,8.7Hz)，7.75-7.78(2H，m)，7.79-7.83(2H，m)， 10.62(lH，s)，12.47(lH，brs). MS(ESI) ： 462,464(M+Na)+. 92 NMR ： 1.59-1.62(2H,m),1.82-1.90(2H,m),3.17-3.23(2H,m), 3.59(2H，s)，4.02-4.05(2H,m)，5.21(lH，s)，6.87-6.93(3H，m)，7.19-7.22 (lH，m)，7.36-7.39(2H，m),7.47· 7.54(5H,m),8.53(lH,s),12.50(lH,brs). MS(ESI) ： 513(M-H)·. 93 NMR ： 3.00(6H,s),3.61(2H,s),6.75-6.77(2H,m),6.93-6.99(3H,m), 7.21-7.24(lH,m),7.48-7.49(lH,m),7.75-7.79(2H,m),7.85-7.87(2H,m), 9.90(lH,s),12.45(lH,brs). MS(ESI) ： 425(M+H)+. 94 NMR ： 3.61(2H,s),6.90-8.00(10H,m),11.04(lH,s),12.48(lH,brs), 13.63(lH,brs). MS(ESI) ： 478(M+Na)+. mp ： &gt;300 °C. 95 NMR ： 2.19(3H,s),3.51(2H,s),6.76(lH,dd,J=2.8,8.6Hz), 6.89(lH,d,J=2.8Hz),7.06(lH,d,J=8.3Hz),7-24(lH,dd,J=2.1,8.4Hz), 7.28(lH,d,J=8.6Hz),7.49(lH,d,J=2Hz),7.82(lH,d,J=8.4Hz), 7.94(lH,dd,J=2,8.5Hz),8.20(lH,d,J=1.9Hz),10.05(lH,s). MS(ESI) ： 486(M+Na)+. 96 NMR ： 2.24(3H,s),3.63(2H,s),6.70-7.70(1 lH,m),9.85(lH,s), 11.71(lH,s),12.49(lH,brs). MS(ESI) ： 457(M+Na)+. 97 NMR ： 2.11(3H,s),3.61(2H,s),6.94-7.00(3H,m),7.22-7.37(3H,m), 7.43-7.50(5H,m),7.71-7.73(2H,m),9.97(lH,s),12.50(lH,brs). MS(ESI) ： 444(M+Na)+. 98 NMR ： 2.78-2.82(2H,m),2.91(3H,s),3.50-3.55(2H,m),3.55(2H,s), 6.84-6.89(2H,m),6.91(lH,d,J=8.4Hz),7.18-7.22(2H,m),7.24-7.32 (4H,m),7.42-7.46(2H,m),7.46(lH,d,J=2.2Hz),8.23(lH,s). MS(ESI) ： 439,441(M+H)+. 99 NMR ： 2.88-2.92(4H,m),3.59(2H,s),3.59-3.62(4H,m),6.87-6.91 (2H,m),6.93(lH,d,J=8.3Hz),7.10-7.18(4H,m), 7.20(lH,dd,J=2.1,8.3Hz),7.46-7.50(3H,m),8.54(lH,s),12.42(lH,brs). MS(ESI) ： 451,453(M+H)+. 100 NMR ： 4.02(3H,s),5.03(2H,s),6.27-6.28(lH,m),6.56-6.58(lH,m), 7.02-7.23(5H,m),7.28-7.33(3H,m),7.56-7.58(lH,m),7.69-7.70(lH,m) ,7.75-7.79(2H,m),10.34(lH,s),13.04(lH,brs). MS(ESI) ： 462(M+Na)+. -111 - 200951122 [表 71]Ex 90 Data NMR: 2.43 (3H, s), 3.61 (2H, s), 6.97-7.00 (2H, m), 7.03 (1H, d, J = 8.4 Hz), 7.24 (lH, dd, J = 2.1, 8.3 Hz), 7.32 (lH, dd, J = 1.4, 8.6 Hz), 7.50 (lH, d, J = 2.0 Hz), 7.59-7.62 (2H, m), 7.68 (lH, d, J = 0.8 Hz) , 7.80-7.84 (2H, m), 10.54 (1H, s), 12.48 (1H, brs). MS (ESI): 458, 460 (M+Na) +. 91 NMR : 3.62 (2H, s), 6.97-7.01 (2H, m), 7.03 (lH, d, J = 8.3 Hz), 7.25 (lH, dd, J = 2.1, 8.5 Hz), 7.36 (lH, dt, J = 2.7, 9.3 Hz), 7.51 (lH, d, J = 2.1 Hz), 7.66 (lH, dd, J = 2.7, 8.7 Hz), 7.75-7.78 (2H, m), 7.79-7.83 (2H, m), 10.62 (lH, s), 12.47 (lH MS(ESI): 462,464 (M+Na)+. 92 NMR: 1.59-1.62 (2H, m), 1.82-1.90 (2H, m), 3.17-3.23 (2H, m), 3.59 (2H) , s), 4.02-4.05 (2H, m), 5.21 (lH, s), 6.87-6.93 (3H, m), 7.19-7.22 (lH, m), 7.36-7.39 (2H, m), 7.47· 7.54 (5H, m), 8.53 (1H, s), 12.50 (1H, brs). MS (ESI): 513 (MH)·. 93 NMR: 3.00 (6H, s), 3.61 (2H, s), 6.75- 6.77(2H,m), 6.93-6.99(3H,m), 7.21-7.24(lH,m),7.48-7.49(lH,m),7.75-7.79(2H,m),7.85-7.87(2H,m ), 9.90 (lH, s), 12.45 (1H, brs). MS (ESI): 425 (M+H) +. 94 NMR: 3.61 (2H, s), 6.90-8.00 (10H, m), 1 1.04 (lH, s), 12.48 (1H, brs), 13.63 (1H, brs). MS (ESI): 478 (M+Na) +. mp : &gt; 300 ° C. 95 NMR : 2.19 (3H, s ), 3.51 (2H, s), 6.76 (lH, dd, J = 2.8, 8.6 Hz), 6.89 (lH, d, J = 2.8 Hz), 7.06 (lH, d, J = 8.3 Hz), 7-24 (lH, dd, J = 2.1, 8.4 Hz), 7.28 (lH, d, J = 8.6 Hz), 7.49 (lH, d, J = 2 Hz), 7.82 (lH, d, J = 8.4 Hz), 7.94 ( lH, dd, J=2, 8.5 Hz), 8.20 (lH, d, J = 1.9 Hz), 10.05 (1H, s). MS (ESI): 486 (M+Na) +. 96 NMR : 2.24 (3H , s), 3.63 (2H, s), 6.70-7.70 (1 lH, m), 9.85 (lH, s), 11.71 (lH, s), 12.49 (lH, brs). MS (ESI): 457 (M +Na)+. 97 NMR: 2.11 (3H, s), 3.61 (2H, s), 6.94-7.00 (3H, m), 7.22-7.37 (3H, m), 7.43-7.50 (5H, m), 7.71 - 7.73 (2H, m), 9.97 (1H, s), 12.50 (1H, brs). MS (ESI): 444 (M+Na)+. 98 NMR: 2.78-2.82 (2H, m), 2.91 (3H , s), 3.50-3.55 (2H, m), 3.55 (2H, s), 6.84-6.89 (2H, m), 6.91 (lH, d, J = 8.4 Hz), 7.18-7.22 (2H, m), 7.24-7.32 (4H, m), 7.42-7.46 (2H, m), 7.46 (lH, d, J = 2.2 Hz), 8.23 (lH, s). MS (ESI): 439,441 (M+H)+. 99 NMR : 2.88-2.92 (4H, m), 3.59 (2H, s), 3.59-3.62 (4H, m), 6.87-6.91 (2H, m), 6.93 (lH, d, J = 8.3 Hz), 7.10 -7.18 (4H, m), 7.20 (lH, dd, J = 2.1, 8.3 Hz), 7.46-7.50 (3H, m), 8.54 (lH, s), 12.42 (lH, brs). MS (ESI):451,453(M+H)+. 100 NMR : 4.02 (3H, s), 5.03 (2H, s), 6.27-6.28 (lH, m), 6.56-6.58 (lH, m), 7.02-7.23 (5H, m ), 7.28-7.33 (3H, m), 7.56-7.58 (lH, m), 7.69-7.70 (lH, m), 7.75-7.79 (2H, m), 10.34 (lH, s), 13.04 (lH, brs MS(ESI): 462(M+Na)+. -111 - 200951122 [Table 71]

Ex Data __ 101 NMR : 2.83-2.88(2H，m)，3.68-3.71(2H，m)，4.63(2H，s),5.02(2H，s)， 6.27-6.28(lH,m),6.49-6.51(lH,m),6.90-6.96(2H,m),7.03-7.09 (lH,m),7.14-7.22(5H,m),7.27-7.28(lH,m),7.43-7.48(2H,m), 8.57(lH,s),12.99(lH,brs). MS(ESI) ： 464(M+Na)+. 102 NMR ： 3.61(2H,s),6.90-8.10(1 lH,m),10.39(lH,s),12.47(lH,brs). MS(ESI) : 488(M+Na)+. 103 NMR ： 2.60(3H,s),3.62(2H,s),6.90-7.90(1 lH,m),10.46(lH,s), 12.46(lH,brs). MS(ESI) ： 458(M+Na)+. 104 NMR ： 3.62(2H,s),4.17(3H,s),6.97-7.04(3H,m),7.23-7.26(lH,m), 7.34-7.51(3H,m),7.72-7.74(lH,m),7.80-7.82(lH,m),7.89-7.93 (2H,m),10.93(lH,s),12.50(lH,brs). MS(ESI) : 436(M+H)+. 105 NMR 5.03(2H,s),6.27-6.28(lH,m),6.58-6.60(lH,m),7.00-7.13 (3H,m),7.19-7.25(lH,m),7.30-7.31(lH,m),7.35-7.39(lH,m),7.48-7.53(lH，m),7.69-7.84(5H,m)，10.56(lH，s)，13.05(lH，brs). MS(ESI) ： 449(M+Na)+. 106 NMR ： 5.01(2H,s),6.25-6.26(lH,m),6.57-6.61(lH,m),7.00-7.21 (4H,m),7.27-7.30(lH,m),7.73-7.82(2H,m),7.91-7.98(2H,m), 8.14-8.19(2H,m), 10.48(1 H,s), 13.10(1 H,brs). MS(ESI) ： 477(M+Na)+. 107 NMR ： 2.19(3H,s),3.59(2H,s),4.02(3H,s),6.75-6.77(lH,m),6.85-6.87(lH,m),7.12-7.20(2H,m),7.30-7.34(2H,m),7.48-7.49(lH,m), 7.55-7.71(3H,m),7.79-7.80(lH,m),l〇.32(lH,s),12.50(lH,brs). MS(ESI) ： 471(M+Na)+. 108 NMR ： 3.60(2H,s),4.02(3H,s),6.88-6.90(lH,m),7.13-7.22(3H,m), 7.31-7.35(2H,m),7.49-7.50(lH,m),7.58-7.61(2H,m),7.71-7.73 (lH,m),7.94-7.98(lH,m),10.55(lH,s),12.46(lH,brs). MS(ESI) ： 475(M+Na)+. 109 NMR : 3_66(2H,s)，7.05-7.09(3H，m)，7.36-7.40(lH，m)，7.51(lH，dt,J= 1.3,7.8Hz)，7.68(lH，s)，7.73(lH，d，J=8.3Hz)，7.78(lH，d,J=0.8Hz)， 7.83(lH,d,J=7.7Hz),7.85-7.89(2H,m),10.63(lH,s). MS(ESI) : 478,480(M+Na)+. 110 NMR : 3.67(2H，s)，6.98-7.01(4H,m)，7.20.7.24(lH，m),7.41(lH，d，J= 1.5Hz)，7.47(lH，d，J=8.3Hz),7.66-7.69(2H,m),7.83-7.87(2H，m)， 10.35(lH,s),11.83(lH,s). MS(ESI) ： 477,479(M+Na)+. 111 NMR ： 3.65(2H,s),7.16(lH,d,J=8.8Hz),7.24(lH,d,J=8.3Hz), 7.29(lH,dd,J=2.0,8.3Hz),7.49(lH,d,J=1.9Hz),7.93(2H,d,J=8.3Hz), 8.16(2H,d,J=8.2Hz),8.24(lH,dd,J=2.7,8.9Hz),8.43(lH,d,J=2.5Hz), 10.63(lH,s),12.49(lH,brs). MS(ESI) ： 449,45 l(M-H)·. 200951122Ex Data __ 101 NMR : 2.83-2.88 (2H, m), 3.68-3.71 (2H, m), 4.63 (2H, s), 5.02 (2H, s), 6.27-6.28 (lH, m), 6.49-6.51 (lH, m), 6.90-6.96 (2H, m), 7.03-7.09 (lH, m), 7.14-7.22 (5H, m), 7.27-7.28 (lH, m), 7.43-7.48 (2H, m) , 8.57 (lH, s), 12.99 (lH, brs). MS (ESI): 464 (M+Na)+. 102 NMR: 3.61 (2H, s), 6.90-8.10 (1 lH, m), 10.39 ( lH, s), 12.47 (lH, brs). MS (ESI): 488 (M+Na)+. 103 NMR: 2.60 (3H, s), 3.62 (2H, s), 6.90-7.90 (1 lH, m ), 10.46 (lH, s), 12.46 (1H, brs). MS (ESI): 458 (M+Na)+. 104 NMR: 3.62 (2H, s), 4.17 (3H, s), 6.97-7.04 ( 3H,m),7.23-7.26(lH,m), 7.34-7.51(3H,m),7.72-7.74(lH,m),7.80-7.82(lH,m),7.89-7.93 (2H,m), 10.93 (lH, s), 12.50 (1H, brs). MS (ESI): 436 (M+H)+. 105 NMR 5.03 (2H, s), 6.27-6.28 (lH, m), 6.58-6.60 (lH , m), 7.00-7.13 (3H, m), 7.19-7.25 (lH, m), 7.30-7.31 (lH, m), 7.35-7.39 (lH, m), 7.48-7.53 (lH, m), 7.69 -7.84 (5H, m), 10.56 (1H, s), 13.05 (1H, brs). MS (ESI): 449 (M+Na) +. 106 NMR : 5.01 (2H, s), 6.25-6.26 (lH , m), 6.57-6.61 (lH, m), 7.00-7.21 (4H, m), 7.27-7.30 (lH, m), 7.73-7.82 (2H, m), 7.91-7.98 (2H, m), 8.14 -8.19(2H,m), 10.48(1 H,s), 13.10 (1H, brs). MS (ESI): 437 (M+Na) +. 107 NMR: 2.19 (3H, s), 3.59 (2H, s), 4.02 (3H, s), 6.75-6.77 (lH, m), 6.85-6.87 (lH, m), 7.12-7.20 (2H, m), 7.30-7.34 (2H, m), 7.48-7.49 (lH, m), 7.55-7.71 (3H, m), 7.79- 7.80(lH,m), l〇.32(lH, s), 12.50 (lH, brs). MS (ESI): 471 (M+Na)+. 108 NMR: 3.60 (2H, s), 4.02 (3H , s), 6.88-6.90 (lH, m), 7.13-7.22 (3H, m), 7.31-7.35 (2H, m), 7.49-7.50 (lH, m), 7.58-7.61 (2H, m), 7.71 - 7.73 (lH, m), 7.94-7.98 (1H, m), 10.55 (1H, s), 12.46 (1H, brs). MS (ESI): 475 (M+Na) +. 109 NMR : 3_66 (2H , s), 7.05-7.09 (3H, m), 7.36-7.40 (lH, m), 7.51 (lH, dt, J = 1.3, 7.8 Hz), 7.68 (lH, s), 7.73 (lH, d, J = 8.3 Hz), 7.78 (lH, d, J = 0.8 Hz), 7.83 (lH, d, J = 7.7 Hz), 7.85-7.89 (2H, m), 10.63 (lH, s). MS (ESI): 478,480 (M+Na)+. 110 NMR: 3.67 (2H, s), 6.98-7.01 (4H, m), 7.20.7.24 (lH, m), 7.41 (lH, d, J = 1.5 Hz), 7.47 ( lH,d,J=8.3Hz), 7.66-7.69(2H,m),7.83-7.87(2H,m), 10.35(lH,s),11.83(lH,s). MS(ESI) : 477,479(M +Na)+. 111 NMR : 3.65 (2H, s), 7.16 (lH, d, J = 8.8 Hz), 7.24 (lH, d, J = 8.3 Hz), 7.29 (lH, dd, J = 2.0, 8.3 Hz), 7.49 (lH, d, J = 1.9 Hz), 7.93 (2H, d, J = 8.3 Hz), 8.16 (2H, d, J = 8.2 Hz), 8.24 (lH, dd, J = 2.7, 8.9 Hz), 8.43 (lH, d, J = 2.5 Hz), 10.63 (lH, s), 12.49 ( lH,brs). MS(ESI) : 449,45 l(MH)·. 200951122

m 721 Ex Data 112 NMR : 3.65(2H，s)，4.02(3H，s)，7.12-7.16(2H，m),7.24(lH,d，J=8.2Hz)， 7.29(1 H，dd,J=2.0,8.4Hz)，7.30-7.35(2H，m)，7.49(lH,d,J=1.9Hz)， 7.58(lH,d,J=8.2Hz),7.70(lH,d,J=7.9Hz),8.25(lH,dd,J=2.7,8.8Hz), 8.44(lH,d,J=2.6Hz),10.47(lH,s),12.50(lH,brs). MS(ESI) ： 458,460(M+Na)+. 113 NMR ： 3.61(2H,s),6.80-7.90(1 lH5m),l〇.32(lH,s),12.10(lH,s), 12.48(lH,brs). MS(ESI) ： 461(M+Na)+. 114 NMR ： 3.61(2H,s),6.90-8.15(1 lH,m),10.64(lH,s),12.48(lH,brs). MS(ESI) ： 522,524(M+Na)+. 115 NMR ： 3.62(2H,s),6.90-8.10(1 lH,m),8.35(lH,s),10.56(lH,s), 12.48(lH,brs). MS(ESI) : 460(M+Na)+. 116 NMR : 3.61(2H，s)，3.83(3H,s)，6.57-6.59(lH，m)，6.96-7.01(3H，m)， 7.22-7.25(lH,m),7.43-7.56(3H,m),7.79-7.84(3H,m),8.26-8.27(lH,m),10.17(lH,s),12.50(lH,brs). MS(ESI) ： 457(M+Na)+. 117 NMR ： 3.60(2H,s),6.90-6.92(lH,m),7.13-7.24(2H,m),7.37-7.41 (lH,m),7.50-7.58(2H,m),7.64-7.86(4H,m),7.96- 8.00(lH，m)，10.79(lH，s)，12.45(lH,brs). MS(ESI) ： 462(M+Na)+. 118 NMR ： 5.03(2H,s),6.28-6.29(lH,m),6.57-6.59(lH,m),7.03-7.13 (4H,m),7.18-7.25(2H5m),7.29-7.30(lH,m),7.38-7.41(lH,m), 7.46-7.48(lH,m),7.66-7.70(lH,m),7.76- 7.81 (2H,m), 10.23 (1 H,s), 11.74( 1 H,s), 13.00( 1 H,brs) MS(ESI) ： 448(M+Na)+. 119 NMR ： 2.84-2.87(2H,m),3.58-3.72(4H,m),4.64(2H,s),6.79-6.81 (lH,m),7.03-7.08(lH,m),7.15-7.23(5H,m),7.29-7.32(lH,m),7.46- 7.47(lH,m),7.64-7.68(lH,m),8.82(lH,s),12.44(lH,brs). MS(ESI) ： 477(M+Na)+. 120 NMR ： 3.59(2H,s),6.79-6.89(2H,m),7.1 l-7.21(2H,m),7.38-7.49 (5H,m),7.61-7.66(3H,m),7.91-7.95(lH,m),10.47(lH,s), 12.45(lH,brs). MS(ESI) ： 448(M+Na)+. 121 NMR ： 3.62(2H,s),6.97-7.01(3H,m),7.27-7.30(lH,m),7.35-7.39 (lH,m),7.49-7.53(lH,m),7.64-7.65(lH,m),7.71-7.76(2H,m), 7.80-7.84(3H,m),10.57(lH,s),12.54(lH,brs). MS(ESI) ： 488,490(M+Na)+. 122 NMR ： 3.61(2H,s),4.02(3H,s),6.97-7.00(3H,m),7.12-7.20 (lH,m),7.27-7.34(3H,m),7.55-7.58(lH,m),7.64-7.71(2H,m), 7.78-7.82(2H,m),10.35(lH,s),12.50(lH,brs). MS(ESI) ： 501,503(M+Na)+. 123 NMR ： 2.86(2H,t,J=5.9Hz),3.58(2H,s),3.70(2H,t,J=5.9Hz), 4.64(2H,s),6.74(lH,d,J-8.4Hz),6.99(lH,d,J=8.8Hz),7.16-7.21(5H,m),7.45-7.48(2H,m),7.83(lHid,J=2.4Hz), 8.78(lH,s),12.43(lH,brs). MS(ESI) ： 493,495(M+Na)+. -113- 200951122 m 731 Ex Data 124 NMR ： 5.03(2H,s),6.28-6.29(lH,m),6.57-6.59(lH,m),7.03-7.15 (3H，m)，7.19-7.25(lH，m)，7.30-7.38(3H，m)，7.57-7.59(lH，m)， 7.79-7.83(lH，m)，7_90-7_94(2H，m)，10.92(lH，s)，12.98(lH，brs)， 13.42(lH,s). MS(ESI) ： 449(M+Na)+. 125 NMR ： 3.65(2H,s),7.16(lH,d,J=8.8Hz),7.25(lH,cU=8.2Hz), 7.29(lH,dd,J=1.9,8.3Hz),7.37(lH,dt,J=2.7,9.3Hz),7.49(lH,d,J=1.9 Hz),7.66(lH,dd,J=2.7,8.7Hz),7.74-7.78(2H,m),8.27(lH,dd,J= 2.7,8.9Hz)，8.46(lH，d，J=2.7Hz)，10.79(lH，s),12.50(lH，brs). MS(ESI) ： 463,465(M+Na)+. 126 NMR ： 3.65(2H,s),7.16(lH,d,J=8.8Hz),7.25(lH,d,J=8.2Hz), 7.29(lH,dd,J=2.0,8.3Hz),7.49(lH,d,J=1.9Hz),7.54(lH,dd,J=2.2,8.8 Hz),7.74(lH,d,J=0.9Hz),7-77(lH,d,J=9.0Hz),7.94(lH,d,J=2.2Hz), 8.26(lH,dd,J=2.7,8.9Hz),8.46(lH,d,J=2.6Hz),10.81(lH,s),12.51(lH ,brs). MS(ESI) : 479,481(M+Na)+. 127 NMR ： 3.53(2H,s),6.94-6.98(3Hsm),7.25-7.27(lH,m),7.62-7.63 (lH,m),7.74-7.83(3H,m),7.93-7.95(lH,m)58.21-8.22(lH,m), 10.45(lH,s). MS(ESI) ： 516,518(M+Na)+. 128 NMR ： 5.03(2H,s),6.25-6.26(lH,m),6.57-6.59(lH,m),7.00-7.30 (5H,m),7.71-7.95(4H,m),8.19-8.22(lH,m),l〇.39(lH,s), 13.00(lH,brs). MS(ESI) : 477(M+Na)+. 129 NMR : 3.60(2H,s),6.88-6.90(lH,m),7.15-7.22(2H,m),7.32-7.38 (2H,m),7.50(lH,m),7.59-7.60(lH,m),7.80-7.85(2H,m), 8.05-8.09(lH,m),11.21(lH,s),12.44(lH,brs),13.49(lH,s). (ESI) ： 440(M+H)+. 130 NMR ： 5.03(2H,s),6.27-6.28(lH,m),6.55-6.56(lH,m),6.81-6.85 (lH,m),6.98-7.10(3H,m),7.17-7.22(lH,m),7.29-7.30(lH,m), 7.39-7.47(3H,m),7.60-7.71(5H,m),10.22(lH,s),13.05(lH,brs). MS(ESI) ： 435(M+Na)+. 131 NMR ： 3.61 (2H,s),6.98-7.09(4H,m),7.20-7.29(2H,m),7.41-7.48 (2H,m),7.64-7.68(2H,m),7.79-7.83(2H,m),10.25(lH,s),11.73(lH,s), 12.44( lH,brs). MS(ESI) ： 487,489(M+Na)+. 132 NMR ： 3.60(2H,s),6.90-8.00(10H,m),8.44(lH,d,J=1.4Hz), 10.70(lH,s),12.50(lH,br). MS(ESI) : 469(M+Na)+. 133 NMR ： 3.69(2H,s),6.90-8.30(10H,m),10.45(lH,s),12.48(lH,brs). MS(ESI) ： 515.8,517.9(M+Na)+. 134 NMR ： 3.69(2H,s),6.90-7.90(12H,m),10.28(lH,s),11.75(lH,s), 12.48(lH,brs). MS(ESI) ： 487,489(M+Na)+. 135 NMR ： 3.62(2H,s),4.01(3H,s),6.97-7.02(3H,m),7.15-7.28 (3H,m),7.48-7.51(2H,m),7.59-7.63(lH,m),7.77- 7.81(2H,m),10.40(lH,s),12.47(lH,brs). MS(ESI) ： 475(M+Na)+.m 721 Ex Data 112 NMR: 3.65 (2H, s), 4.02 (3H, s), 7.12-7.16 (2H, m), 7.24 (1H, d, J = 8.2 Hz), 7.29 (1 H, dd, J =2.0, 8.4 Hz), 7.30-7.35 (2H, m), 7.49 (lH, d, J = 1.9 Hz), 7.58 (lH, d, J = 8.2 Hz), 7.70 (lH, d, J = 7.9 Hz) ), 8.25 (lH, dd, J = 2.7, 8.8 Hz), 8.44 (lH, d, J = 2.6 Hz), 10.47 (lH, s), 12.50 (lH, brs). MS (ESI): 458,460 (M +Na)+. 113 NMR: 3.61 (2H, s), 6.80-7.90 (1 lH5m), l.32 (lH, s), 12.10 (lH, s), 12.48 (lH, brs). MS (ESI) 461(M+Na)+. 114 NMR: 3.61 (2H, s), 6.90-8.15 (1 lH, m), 10.64 (lH, s), 12.48 (lH, brs). MS (ESI): 522,524 (M+Na)+. 115 NMR: 3.62 (2H, s), 6.90-8.10 (1 lH, m), 8.35 (lH, s), 10.56 (lH, s), 12.48 (lH, brs). MS ( ESI): 460 (M+Na)+. 116 NMR: 3.61 (2H, s), 3.83 (3H, s), 6.57-6.59 (lH, m), 6.96-7.01 (3H, m), 7.22-7.25 ( lH, m), 7.43-7.56 (3H, m), 7.79-7.84 (3H, m), 8.26-8.27 (lH, m), 10.17 (lH, s), 12.50 (lH, brs). MS (ESI) : 457(M+Na)+. 117 NMR: 3.60 (2H, s), 6.90-6.92 (1H, m), 7.13-7.24 (2H, m), 7.37-7.41 (lH, m), 7.50-7.58 ( 2H, m), 7.64-7.86 (4H, m), 7.96-8.00 (lH, m), 10.79 (1H, s), 12.45 (lH, brs). MS (ESI): 462 (M+Na)+. 118 NMR : 5.03(2H, s), 6.28-6.29 (lH, m), 6.57-6.59 (lH, m), 7.03-7.13 (4H, m), 7.18-7.25 (2H5m), 7.29-7.30 (lH, m) , 7.38-7.41 (lH, m), 7.46-7.48 (lH, m), 7.66-7.70 (lH, m), 7.76- 7.81 (2H, m), 10.23 (1 H, s), 11.74 ( 1 H, s), 13.00 ( 1 H, brs) MS (ESI): 448 (M+Na) +. 119 NMR: 2.84-2.87 (2H, m), 3.58-3.72 (4H, m), 4.64 (2H, s) , 6.79-6.81 (lH, m), 7.03-7.08 (lH, m), 7.15-7.23 (5H, m), 7.29-7.32 (lH, m), 7.46- 7.47 (lH, m), 7.64-7.68 ( lH, m), 8.82 (lH, s), 12.44 (1H, brs). MS (ESI): 477 (M+Na)+. 120 NMR: 3.59 (2H, s), 6.79-6.89 (2H, m) , 7.1 l-7.21(2H,m), 7.38-7.49 (5H,m), 7.61-7.66(3H,m),7.91-7.95(lH,m),10.47(lH,s), 12.45(lH,brs MS (ESI): 448 (M+Na)+. 121 NMR: 3.62 (2H, s), 6.97-7.01 (3H, m), 7.27-7.30 (lH, m), 7.35-7.39 (lH, m ), 7.49-7.53 (lH, m), 7.64-7.65 (lH, m), 7.71-7.76 (2H, m), 7.80-7.84 (3H, m), 10.57 (lH, s), 12.54 (lH, brs) MS(ESI): 488,490 (M+Na)+. 122 NMR: 3.61 (2H, s), 4.02 (3H, s), 6.97-7.00 (3H, m), 7.12-7.20 (lH, m), 7.27-7.34(3H,m), 7.55-7.58(lH,m), 7.64-7.71(2H,m), 7.78-7.82(2H,m), 10.35(lH,s),12.50(lH,brs). MS (ESI): 501, 503 (M+Na) +. 123 NMR: 2.86 (2H, t, J=5.9 Hz), 3.58 (2H, s), 3.70 (2H, t, J = 5.9 Hz), 4.64 (2H, s), 6.74 (lH, d, J-8.4 Hz), 6.99 (lH, d, J = 8.8 Hz), 7.16-7.21 (5H, m), 7.45-7.48 (2H, m), 7.83 (lHid, J = 2.4 Hz), 8.78 (lH, s), 12.43 (lH, brs). MS ( ESI): 493,495 (M+Na)+. -113- 200951122 m 731 Ex Data 124 NMR: 5.03 (2H, s), 6.28-6.29 (lH, m), 6.57-6.59 (lH, m), 7.03-7.15 (3H,m), 7.19-7.25(lH,m), 7.30-7.38(3H,m),7.57-7.59(lH,m), 7.79-7.83(lH,m),7_90-7_94(2H,m) , 10.92 (lH, s), 12.98 (1H, brs), 13.42 (1H, s). MS (ESI): 449 (M+Na)+. 125 NMR: 3.65 (2H, s), 7.16 (lH, d , J=8.8Hz), 7.25 (lH, cU=8.2Hz), 7.29 (lH, dd, J=1.9, 8.3Hz), 7.37 (lH, dt, J=2.7, 9.3Hz), 7.49(lH,d , J = 1.9 Hz), 7.66 (lH, dd, J = 2.7, 8.7 Hz), 7.74 - 7.78 (2H, m), 8.27 (lH, dd, J = 2.7, 8.9 Hz), 8.46 (lH, d, J = 2.7 Hz), 10.79 (lH, s), 12.50 (1H, brs). MS (ESI): 463,465 (M+Na)+. 126 NMR: 3.65 (2H, s), 7.16 (lH, d, J = 8.8 Hz), 7.25 (lH, d, J = 8.2 Hz), 7.29 (lH, dd, J = 2.0, 8.3 Hz), 7.49 (lH, d, J = 1.9 Hz), 7.54 (lH, dd, J) =2.2, 8.8 Hz), 7.74 (lH, d, J = 0.9 Hz), 7-77 (lH, d, J = 9.0 Hz), 7.94 (lH, d, J = 2.2 Hz), 8.26 (lH, dd , J = 2.7, 8.9 Hz), 8.46 (lH, d, J = 2.6 Hz), 10.81 (lH, s ), 12.51 (lH, brs). MS (ESI): 479, 481 (M+Na)+. 127 NMR: 3.53 (2H, s), 6.94-6.98 (3Hsm), 7.25-7.27 (lH, m), 7.62 7.63 (lH, m), 7.74-7.83 (3H, m), 7.93-7.95 (lH, m) 58.21-8.22 (lH, m), 10.45 (1H, s). MS (ESI): 516, 518 (M+Na +. 128 NMR : 5.03 (2H, s), 6.25-6.26 (lH, m), 6.57-6.59 (lH, m), 7.00-7.30 (5H, m), 7.71-7.95 (4H, m), 8.19 -8.22 (lH, m), δ.39 (1H, s), 13.00 (1H, brs). MS (ESI): 477 (M+Na)+. 129 NMR: 3.60 (2H, s), 6.88- 6.90 (lH, m), 7.15-7.22 (2H, m), 7.32-7.38 (2H, m), 7.50 (lH, m), 7.59-7.60 (lH, m), 7.80-7.85 (2H, m), 8.05-8.09 (lH, m), 11.21 (lH, s), 12.44 (lH, brs), 13.49 (lH, s). (ESI): 440 (M+H) +. 130 NMR : 5.03 (2H, s ), 6.27-6.28 (lH, m), 6.55-6.56 (lH, m), 6.81-6.85 (lH, m), 6.98-7.10 (3H, m), 7.17-7.22 (lH, m), 7.29-7.30 (lH,m), 7.39-7.47(3H,m), 7.60-7.71(5H,m), 10.22(lH,s),13.05(lH,brs). MS(ESI) : 435(M+Na)+ 131 NMR : 3.61 (2H, s), 6.98-7.09 (4H, m), 7.20-7.29 (2H, m), 7.41-7.48 (2H, m), 7.64-7.68 (2H, m), 7.79-7.83 (2H, m), 10.25 (1H, s), 11.73 (1H, s), 12.44 (1H, brs). MS (ESI): 487, 489 (M+Na)+. 132 NMR: 3.60 (2H, s), 6.90-8.00 (10H, m), 8.44 (lH, d, J = 1.4 Hz), 10.7 0 (lH, s), 12.50 (1H, br). MS (ESI): 469 (M+Na)+. 133 NMR: 3.69 (2H, s), 6.90-8.30 (10H, m), 10.45 (lH, s), 12.48 (1H, brs). MS (ESI): 515.8, 517.9 (M+Na)+. 134 NMR: 3.69 (2H, s), 6.90-7.90 (12H, m), 10.28 (lH, s) , 11.75 (lH, s), 12.48 (1H, brs). MS (ESI): 487, 489 (M+Na)+. 135 NMR: 3.62 (2H, s), 4.01 (3H, s), 6.97-7.02 (3H , m), 7.15-7.28 (3H, m), 7.48-7.51 (2H, m), 7.59-7.63 (lH, m), 7.77- 7.81 (2H, m), 10.40 (lH, s), 12.47 (lH , brs). MS (ESI) : 475 (M+Na)+.

-114- 200951122-114- 200951122

m 741 I Ex Data 136 NMR : 2.40(3H，s)，3.43(2H，s)，3.98(3H，s)，6.93-6.98(3H，m)， 7.13-7.15(1 H,m),7.19-7.22(2H,m),7.44-7.46(3H,m),7.75-7.79 (2H,m),10.32(lH,s). MS(ESI) ： 471(M+Na)+. 137 NMR ： 3.62(2H,s),4.01(3H,s),6.97-7.02(3H,m),7.23-7.33 (3H,m),7.50-7.51(lH,m),7.61-7.64(lH,m),7.77-7.81(3H,m), 10.44(lH,s),12.46(lH,brs). MS(ESI) : 491(M+Na)+. 138 NMR ： 3.61(2H,s),6.98-7.02(3H,m),7.06-7.1 l(lH,m),7.27-7.29 (lH,m),7.40-7.48(3H,m),7.64-7.65(lH,m),7.79-7.83(2H,m), 10.30(lH,s),11.86(lH,s),12.46(lH,brs). MS(ESI) ： 505,507(M+Na)+. 139 NMR ： 2.83-2.86(2H,m&gt;,3.59-3.71 (4H,m),4.63(2H,s),6.86-6.91 (3H,m),7.15-7.25(5H,m),7.46-7.50(2H,m),7.61-7.62(lH,m), 8.59(lH,s),13.5(lH,brs). MS(ESI) ： 503,505(M+Na)+. 140 NMR ： 3.66(2H,s),7.06-7.52(8H,m),8.25(lH,dd,J=2.7,8.9Hz), 8.48(lH,d,J=2.7Hz),10.47(lH,s),11.93(lH,s).12.48(lH,brs) MS(ESI) ： 462(M+Na)+. mp ： 227-228 °C. 141 NMR : 3.66(2H，s)，7.14-7.32(4H，m),7.38-7.52(3H,m)，7.79(lH，d，J= 2.1Hz)，8.25(lH，dd，J=2.7,8.9Hz)，8.48(lH，d，J=2.7Hz)，10.49(lH，s)， 12.02(lH，s)，12.51(lH，brs). MS(ESI) ： 478(M+Na)+. 142 NMR : 2.38(3H,s),3.65(2H，s)，7.04-7.51(8H，m)，8.25(lH,dd，J= 2.7,8.9Hz)，8.48(lH，d，J=2.7Hz)，10.36(lH，s)，11.67(lH，s)， 12.52(lH，brs). MS(ESI) ： 434(M-H)'. 143 NMR ： 3.65(2H,s),4.02(3H,s),7.12-7.32(5H,m),7.47-7.53 (2H,m),7.62(lH,dd,J=4.5,8.9Hz),8.24(lH,dd,J=2.7,8.9Hz), 8.44(lH，d，J=2.7Hz)，10.53(lH，s)，12_53(lH，brs). MS(ESI) ： 476(M+Na)+. 144 NMR : 3.65(2H，s)，4.01(3H，s)，7.14-7.34(5H，m)，7.49(lH，d，J=1.9Hz)， 7.63(lH，d，J=8.9Hz)，7.80(lH,d，J=1.9Hz)，8.25(lH，dd,J=2.7,8.9Hz)， 8.44(lH，d，J=2.7Hz)，10.58(lH，s)，12.51(lH，brs). MS(ESI) ： 492(M+Na)+. 145 NMR ： 2.40(3H，s),3.65(2H，s)，3_99(3H，s)，7.12-7_18(2H，m)，7_24- 7.32(3H,m),7.43-7.50(3H,m),8.24(lH,dd,J=2.7,8.9Hz), 8.43(lH,d,J=2.7Hz),l〇.43(lH,s),12.49(lH,brs). MS(ESI) ： 472(M+Na)+. 146 NMR ： 1.31(3H,t),3.66(2H,s),4.59(2H,q),7.12-7.17(2H,m), 7.22-7.36(4H，m),7.49(lH，d，J=1.9Hz)，7.60(lH，d，J=7.9Hz), 7.71(lH，d，J=7.9Hz)，8.27(lH，dd，J=2.7,8.9Hz)，8.44(lH，d，J=2.7Hz)， 10_48(lH，s)，12.49(lH，brs). MS(ESI) : 472(M+Na)+. 147 NMR : 3.65(2H，s)，4.21-4.96(4H，m)，7.12-7.74(9H，m)，8.25(lH，dd，J= 2.7,8.9Hz)，8.42(lH,d，J=2.7Hz)，10.53(lH，s),12.49(lH，s). MS(ESI) : 468(M+H)+. -115- 200951122 m 75]m 741 I Ex Data 136 NMR : 2.40 (3H, s), 3.43 (2H, s), 3.98 (3H, s), 6.93-6.98 (3H, m), 7.13-7.15 (1 H, m), 7.19- 7.22 (2H, m), 7.44-7.46 (3H, m), 7.75-7.79 (2H, m), 10.32 (1H, s). MS (ESI): 471 (M+Na)+. 137 NMR: 3.62 ( 2H, s), 4.01 (3H, s), 6.97-7.02 (3H, m), 7.23-7.33 (3H, m), 7.50-7.51 (lH, m), 7.61-7.64 (lH, m), 7.77- 7.81 (3H, m), 10.44 (1H, s), 12.46 (1H, brs). MS (ESI): 491 (M+Na)+. 138 NMR: 3.61 (2H, s), 6.98-7.02 (3H, m), 7.06-7.1 l(lH, m), 7.27-7.29 (lH, m), 7.40-7.48 (3H, m), 7.64-7.65 (lH, m), 7.79-7.83 (2H, m), 10.30 (1H, s), 11.86 (lH, s), 12. , m), 4.63 (2H, s), 6.86-6.91 (3H, m), 7.15-7.25 (5H, m), 7.46-7.50 (2H, m), 7.61-7.62 (lH, m), 8.59 (lH , s), 13.5 (1H, brs). MS (ESI): 503, 505 (M+Na) +. 140 NMR: 3.66 (2H, s), 7.06-7.52 (8H, m), 8.25 (lH, dd, J =2.7, 8.9 Hz), 8.48 (lH, d, J = 2.7 Hz), 10.47 (lH, s), 11.93 (lH, s). 12.48 (lH, brs) MS (ESI): 462 (M+Na) +. mp: 227-228 ° C. 141 NMR: 3.66 (2H, s), 7.14-7.32 (4H, m), 7.38-7.52 (3H, m), 7.79 (lH, d, J = 2.1 Hz), 8.25 (lH, dd J = 2.7, 8.9 Hz), 8.48 (lH, d, J = 2.7 Hz), 10.49 (lH, s), 12.02 (lH, s), 12.51 (lH, brs). MS (ESI): 478 (M+ Na)+. 142 NMR: 2.38 (3H, s), 3.65 (2H, s), 7.04-7.51 (8H, m), 8.25 (lH, dd, J = 2.7, 8.9 Hz), 8.48 (lH, d, J = 2.7 Hz), 10.36 (lH, s), 11.67 (1H, s), 12.52 (1H, brs). MS (ESI): 434 (MH)'. 143 NMR: 3.65 (2H, s), 4.02 ( 3H, s), 7.12-7.32 (5H, m), 7.47-7.53 (2H, m), 7.62 (lH, dd, J = 4.5, 8.9 Hz), 8.24 (lH, dd, J = 2.7, 8.9 Hz) , 8.44 (lH, d, J = 2.7 Hz), 10.53 (1H, s), 12-53 (1H, brs). MS (ESI): 476 (M+Na)+. 144 NMR: 3.65 (2H, s), 4.01 (3H, s), 7.14 - 7.34 (5H, m), 7.49 (lH, d, J = 1.9 Hz), 7.63 (lH, d, J = 8.9 Hz), 7.80 (lH, d, J = 1.9 Hz) ), 8.25 (lH, dd, J = 2.7, 8.9 Hz), 8.44 (lH, d, J = 2.7 Hz), 10.58 (lH, s), 12.51 (lH, brs). MS (ESI): 492 (M) +Na)+. 145 NMR: 2.40 (3H, s), 3.65 (2H, s), 3_99 (3H, s), 7.12-7_18 (2H, m), 7_24- 7.32 (3H, m), 7.43-7.50 (3H, m), 8.24 (lH, dd, J = 2.7, 8.9 Hz), 8.43 (lH, d, J = 2.7 Hz), l〇.43 (lH, s), 12.49 (lH, brs). MS (ESI): 472 (M+Na)+. 146 NMR: 1.31 (3H, t), 3.66 (2H, s), 4.59 (2H, q), 7.1 2-7.17(2H,m), 7.22-7.36(4H,m), 7.49(lH,d,J=1.9Hz), 7.60(lH,d,J=7.9Hz), 7.71(lH,d,J= 7.9 Hz), 8.27 (lH, dd, J = 2.7, 8.9 Hz), 8.44 (lH, d, J = 2.7 Hz), 10_48 (lH, s), 12.49 (lH, brs). MS (ESI): 472 (M+Na)+. 147 NMR: 3.65 (2H, s), 4.21-4.96 (4H, m), 7.12-7.74 (9H, m), 8.25 (lH, dd, J = 2.7, 8.9 Hz), 8.42 (lH,d,J=2.7 Hz), 10.53 (lH, s), 12.49 (lH, s). MS (ESI): 468 (M+H) +. -115 - 200951122 m 75]

Ex 148 Data NMR : 2.74(3H，s)，2.95-3.04(lH，m)，3.28-3.39(lH，m)，3.64(2H，s)， 4.00-4.07(lH，m),6,54-6.68(2H,m)，7.01-7.34(5H，m)，7.47(lH，d，J= 2.1Hz)，8.19(lH，dd，J=2.7,8.9Hz)，8.34(lH，d，J=2.7Hz)，10.20(lH,s)， 12_47(lH，s). MS(ESI) : 460(M+Na)+_ 149 NMR : 2.74(3H，s)，2_95-3.04(lH,m)，3.28-3.38(lH，m),3.60(2H，s)， 4.00-4.07(lH,m),6.53-6.68(2H,m),6.92-7.09(5H,m),7.22(lH,dd,J= 2.1,8.4Hz),7.49(lH,d,J=2.1Hz),7.76-7.73(2H,m),10.06(lH,s), 12.44( lH,brs). MS(ESI) ： 459(M+Na)+. 150 NMR ： 3.61(2H,s),6.90-8.10(llH,m),11.25(lH,s),12.50(lH,brs). MS(ESI) ： 445(M+Na)+ 151 NMR ： 3.60(2H,s),6.94-7.02(3H,m),7.27(lH,dd,J=2,8.4Hz), 7.53(2H,d,J=8Hz),7.64(lH,d,J=2Hz),7.77(2H,d,J=9.2Hz),8.08(2H,d, J=9.2Hz),10.38(lH,s),12.49(lH,brs). MS(ESI) ： 532,534(M+Na)+. mp ： 252-254 °C. 152 NMR ： 3.64(2H,s),7.15(lH,d,J=8.8Hz),7.23(lH,d,J=8.4Hz), 7.28(lH，dd，J=2,8.4Hz)，7.48(lH，d，J=2Hz)，7.55(2H，d，J=8Hz)， 8.09(2H，d,J=8.8Hz)，8.22(lH，dd,J=2.6,9.2Hz)，8.41(lH，d,J=2.4Hz)， 10.52(lH，s)，12.56(lH,brs). MS(ESI) ： 489(M+Na)+. mp ： 178-180 °C. 153 NMR ： 3.64(2H,s),7.17(lH,d,J=8.8Hz),7.20-7.35(2H,m)5 7.49(lH,d,J=2Hz),7.90-8.10(3H,m),8.23(lH,dd,J=2.8,8.8Hz), 8.42(lH,d,J=2.8Hz),10.68(lH,s),12.49(lH,brs). MS(ESI) ： 491(M+Na)+.Ex 148 Data NMR: 2.74 (3H, s), 2.95-3.04 (lH, m), 3.28-3.39 (lH, m), 3.64 (2H, s), 4.00-4.07 (lH, m), 6, 54- 6.68(2H,m), 7.01-7.34(5H,m), 7.47(lH,d,J=2.1Hz), 8.19(lH,dd,J=2.7,8.9Hz),8.34(lH,d,J= 2.7 Hz), 10.20 (lH, s), 12_47 (1H, s). MS (ESI): 460 (M+Na) + 149 NMR: 2.74 (3H, s), 2_95-3.04 (lH, m), 3.28-3.38(lH,m), 3.60(2H,s), 4.00-4.07(lH,m),6.53-6.68(2H,m),6.92-7.09(5H,m),7.22(lH,dd,J = 2.1, 8.4 Hz), 7.49 (lH, d, J = 2.1 Hz), 7.76-7.73 (2H, m), 10.06 (lH, s), 12.44 (lH, brs). MS (ESI): 459 (M +Na)+. 150 NMR: 3.61 (2H, s), 6.90-8.10 (llH, m), 11.25 (1H, s), 12.50 (1H, brs). MS (ESI): 445 (M+Na)+ 151 NMR: 3.60 (2H, s), 6.94-7.02 (3H, m), 7.27 (1H, dd, J = 2, 8.4 Hz), 7.53 (2H, d, J = 8 Hz), 7.64 (lH, d, J = 2 Hz), 7.77 (2H, d, J = 9.2 Hz), 8.08 (2H, d, J = 9.2 Hz), 10.38 (lH, s), 12.49 (lH, brs). MS (ESI): 532,534 ( M+Na)+. mp: 252-254 ° C. 152 NMR: 3.64 (2H, s), 7.15 (lH, d, J = 8.8 Hz), 7.23 (lH, d, J = 8.4 Hz), 7.28 ( lH, dd, J=2, 8.4 Hz), 7.48 (lH, d, J = 2 Hz), 7.55 (2H, d, J = 8 Hz), 8.09 (2H, d, J = 8.8 Hz), 8.22 (lH, Dd, J=2.6, 9.2 Hz), 8.41 (lH, d, J = 2.4 Hz), 10.52 (lH, s), 12.56 (lH, brs). MS (ESI): 489 (M+Na)+. mp: 178-180 °C 153 NMR : 3.64 (2H, s), 7.17 (lH, d, J = 8.8 Hz), 7.20-7.35 (2H, m) 5 7.49 (lH, d, J = 2 Hz), 7.90-8.10 (3H, m ), 8.23 (lH, dd, J = 2.8, 8.8 Hz), 8.42 (lH, d, J = 2.8 Hz), 10.68 (lH, s), 12.49 (lH, brs). MS (ESI): 491 (M) +Na)+.

[產業上之可能利用性] 式（I)之化合物或其鹽具有CRTH2掊抗作用，可使 用作爲炎症性疾病（例如，氣喘、過敏性鼻炎、過敏性皮 膚炎、結膜炎、蓴麻疹、嗜酸血球性支氣管炎、食物過敏 -116- 200951122 、副鼻腔炎、血管炎、慢性阻塞性肺疾病等）或多發性硬 化症等之預防及/或治療劑。[Industrial Applicability] The compound of the formula (I) or a salt thereof has a CRTH2 inhibitory action and can be used as an inflammatory disease (for example, asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, urticaria, acidophilus) A preventive and/or therapeutic agent for hemorrhagic bronchitis, food allergy-116-200951122, paranasal rhinitis, vasculitis, chronic obstructive pulmonary disease, etc. or multiple sclerosis.

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Claims (1)

200951122 七、申請專利範圍： 1. 一種式（I)之化合物、其鹽或其前驅藥， [化7]200951122 VII. Patent application scope: 1. A compound of formula (I), a salt thereof or a precursor thereof, [Chem. 7] [式中， R1爲- (Cm伸烷基）-COOH或-H, 1)當R1爲-(Cm伸烷基）-COOH時， R2爲鹵素或-H， R3爲鹵素、Cu烷基、-CMCu烷基）或-H， 2 )當R1爲-H時， R2與R3與其等所鍵結之苯環一起形成以下式（II 表不之基’ [化8]Wherein R1 is -(Cmalkyl)-COOH or -H, 1) When R1 is -(Cmalkyl)-COOH, R2 is halogen or -H, and R3 is halogen, Cu alkyl, -CMCu alkyl) or -H, 2) When R1 is -H, R2 and R3 together with the benzene ring bonded thereto form the following formula (II) V 爲=CH-或=N-， m表示1至6之整數 R4爲鹵素或-H， -118- 200951122 但，R3爲-Η時，R4爲鹵素， R5爲-Η、鹵素或C!-6烷基， ' R6爲可分別以由以RXA表示之基所選擇之基取代之芳基 - 、雜芳&quot;^基、雜環烷基或-N(R6a)(R6b)， RXA爲鹵素' Cb6烷基、鹵基Cm烷基、-CKCm烷基） 、-〇-(鹵基 C!_6 烷基、-SJC! —6 烷基）、-N-iCu 烷基）2、 芳基、經鹵素取代之芳基、經-〇-(山-6烷基）取代之芳基、 ^ 經-N-CCy烷基）2取代之芳基、鹵芳基、-OH、-CN、-s ( = 0)2-((^-6 烷基）、-NHS ( = 0)2-((^-6 烷基）或環狀胺基， R6a爲-((^-6伸烷基）-芳基、-(Ci-6伸烷基）-雜芳基、-(Ci.6伸烷基）-雜環烷基， R6b爲Η或Cu烷基， A 爲-Ο-或-S-， D 爲-C( = 0)-、或-S( = 0)2-， E爲鍵結、（^.6伸烷基或C2_6伸烯基， % Y 爲-C(R5a) =或-N=， • R5b爲-Η、鹵素或Ci.6烷基； m Z 爲=CH-、或=N-， u 爲-C(R5b) =或-N=， R5b爲-Η、鹵素或Cu烷基] 但，下列化合物除外， 3·{3-氟-4-[(5-{[4-(三氟甲基）苯甲醯基]胺基}吡啶-2-基）氧基]苯基}丙酸， 3-{3-乙氧基-4-[(5-{[4-(三氟甲基）苯甲醯基]胺基}吡 -119- 200951122 啶-2-基）氧基]苯基}丙酸， 3-{3-甲氧基-4-[(5-{[4-(三氟甲基）苯甲醯基]胺基}吡 啶-2-基）氧基]苯基}丙酸， 3-[4- ( {5-[ ( 3,4-二氯苯甲醯基）胺基]吡啶-2-基ί氧基 )-3-氟苯基]丙酸， 3-[4-({5-[(3,4-二氯苯甲醯基）胺基]吡啶-2-基}氧基 )-3-乙氧基苯基]丙酸， 3-[4-({5-[(3,4-二氯苯甲醯基）胺基]吡啶-2-基}氧基 )-3-甲氧基苯基]丙酸，及 [4-{4-[(3,4-二氯苯甲醯基）胺基]苯氧基}-3-甲氧基苯基 )乙酸]。 2. 如申請專利範圍第1項之式（I)化合物或其鹽， 其中 R6爲可分別經相同或彼此不同之以RXB表示之基取代之 芳基、雜芳基、雜環烷基或-N(R6a)(R6b)， RXB爲鹵素、C!-6烷基、鹵基Cu烷基、-〇-(C丨-6烷基） 、-〇-(幽基 Cb6 烷基、-S-(Cb6 烷基）、-N^Cu 烷基）2、 芳基、經-CMCu烷基）取代之芳基、或經-N-iCu烷基）2 取代之芳基。 3. 如申請專利範圍第2項之化合物或其鹽，其中 R1 爲-CH2-COOH 或-H， m爲1， R6a爲-(Cm伸烷基）-芳基， R6b 爲-H， -120- 200951122 但，γ爲-N =時，U爲-CH=， Y 爲 _CH =或-CF =時，Z 爲=CH-。 ; 4.如申請專利範圍第3項之化合物或宜鹽，其中r3 爲鹵素、Ci.6院基或-〇.-Ci.6院基’ R4爲- JJ。 5. 如申請專利範圍第4項之化合物或其鹽，其中γ 爲-N=，Z 爲=CH-。 6. 如申請專利範圍第5項之化合物或其鹽，其中e爲 鍵結。 7. 如申請專利範圍第6項之化合物或其鹽，其中R6 爲可經相同或彼此不同之以11^表示之基取代之苯基。 8. 如申請專利範圍第7項之化合物或其鹽，其中 Α 爲-Ο ， D 爲- C( = 〇)-， R2 爲-Η， R3爲鹵素。 9. 如申請專利範圍第8項之化合物或其鹽，其中 • R6爲可經相同或彼此不同之以Rxe表示之基取代之苯基 Rxc 爲 C1、-CH3、-CF3、-OCH3、-ocf3、-SCH3、_ N(CH3)2、苯基、經-〇CH3取代之苯基、或經-N(CH3)2取 代之苯基。 1〇_如申請專利範圍第3項之化合物或其鹽，其中 γ 爲-CH =或-CF=。 11.如申請專利範圍第10項之化合物或其鹽，其中 -121 - 200951122 A 爲-Ο-， D 爲- C( = 0)·， R6爲可經相同或彼此不同之以Rxb表示之基取代之苯基 〇 12. 如申請專利範圍第3項之化合物或其鹽，其中Ri 爲·Η。 13. 如申請專利範圍第12項之化合物或其鹽，其中ν 爲。 14. 如申請專利範圍第2項之化合物或其鹽，其係如 下所示之化合物： (3-氯-4-{4-[(3,4-二氯苯甲醯基）胺基]苯氧基}苯基） 乙酸， (4-{4-[ ( 1-苯并呋喃-2-基羰基）胺基]苯氧基}-3-氯苯基 )乙酸， [3-氯-4-({4-[(3,4-二氯苯甲醯基）胺基]苯基}磺醯基） 苯基]乙酸， (3-氯-4-{4-[(3,4-二氫異唾啉-2(1«[)-基羰基）胺基] 苯氧基}苯基）乙酸， [4-(4-{[(2£)-3-(3,4-二氯苯基）丙-2-烯醯基]胺基} 苯氧基）-2-甲基-1Η-苯并咪唑-1-基]乙酸， [3-氯-4-(4-{[4-(三氟甲基）苯甲醯基]胺基}苯氧基）苯 基]乙酸， (3-氯-4- ( 2-氟-4-[ ( 1Η-吲哚-2·基羰基）胺基]苯氧基） 苯基）乙酸， -122- 200951122 [3 -氯-4- ( 4-{[ ( 1-甲基-1H-吲哚-2 -基）羰基]胺基}苯氧 基）苯基]乙酸， [3-氯-4- ( 4-{[ ( 6-氟-1H-苯并咪唑-2-基）胺甲醯基]胺基 }苯氧基）苯基]乙酸， {3 -氯-4- [ ( 5-{[ ( 5 -氣-1H_D引哄-2-基）鑛基]妝基}卩比卩疋-2_ 基）氧基]苯基}乙酸， [3_溴·4- ( 4-{[4-(三氟甲氧基）苯甲醯基]胺基}苯氧基） ^ 苯基]乙酸，及 {3-氯-4-[(5-{[4-(三氟甲氧基）苯甲醯基]胺基}吡啶-2-基）氧基]苯基}乙酸。 16. —種醫藥組成物，其特徵爲含有申請專利範圍第1 項之化合物或其鹽及製藥學上可接受性賦型劑。 17· —種用以治療或預防炎症性疾病或多發性硬化症 之醫藥組成物，其特徵爲含有申請專利範圔第1項之化合 物或其鹽。 '% 18.—種申請專利範圍第1項之化合物或其鹽之使用 ’其特徵係用於製造炎症性疾病或多發性硬化症之預防或 治療用醫藥組成物。 19. 一種申請專利範圍第丨項之化合物或其鹽之使用 ’其特徵係用於炎症性疾病或多發性硬化症之預防或治療 〇 20. —種炎症性疾病或多發性硬化症之預防或治療方 法’其特徵係對患者投予有效量之申請專利範圍第1項之 化合物或其鹽。 -123- 200951122 四、指定代表圖： (一） 本案指定代表圖為：無。 (二） 本代表圖之元件符號簡單說明：無V is =CH- or =N-, m represents an integer of 1 to 6 R4 is halogen or -H, -118- 200951122 However, when R3 is -Η, R4 is halogen, and R5 is -Η, halogen or C!- 6 alkyl, 'R6 is an aryl group, a heteroaryl group, a heterocycloalkyl group or a -N(R6a)(R6b) which may be substituted with a group selected from the group represented by RXA, and RXA is a halogen. 'Cb6 alkyl, halo Cm alkyl, -CKCm alkyl), -〇-(halo C!_6 alkyl, -SJC!-6 alkyl), -N-iCu alkyl), aryl, Halogen-substituted aryl group, aryl group substituted with -〇-(san-6-alkyl), aryl substituted with -N-CCyalkyl)2, haloaryl, -OH, -CN, -s ( = 0) 2-((^-6 alkyl), -NHS ( = 0)2-((^-6 alkyl) or cyclic amine, R6a is -((^-6alkyl)- Aryl, -(Ci-6alkyl)-heteroaryl, -(Ci.6alkyl)-heterocycloalkyl, R6b is hydrazine or Cu alkyl, A is -Ο- or -S-, D is -C( = 0)-, or -S( = 0)2-, E is a bond, (^.6 alkyl or C2_6 extended alkenyl, % Y is -C(R5a) = or -N =, • R5b is -Η, halogen or Ci.6 alkyl; m Z is =CH-, or =N-, u is -C(R5b) = or -N=, R5b is -Η, halogen or Cu However, except for the following compounds, 3·{3-fluoro-4-[(5-{[4-(trifluoromethyl)benzylidenyl]amino}pyridin-2-yl)oxy]phenyl }propionic acid, 3-{3-ethoxy-4-[(5-{[4-(trifluoromethyl)benzylidenyl]amino}pyr-119- 200951122 pyridine-2-yl)oxy Phenyl}propionic acid, 3-{3-methoxy-4-[(5-{[4-(trifluoromethyl)benzylidenyl]amino}pyridin-2-yl)oxy]benzene Propionate, 3-[4-({5-[(3,4-dichlorobenzhydryl)amino]pyridin-2-ylmethoxy)-3-fluorophenyl]propanoic acid, 3 -[4-({5-[(3,4-Dichlorobenzylidenyl)amino]pyridin-2-yl}oxy)-3-ethoxyphenyl]propionic acid, 3-[4- ({5-[(3,4-Dichlorobenzhydryl)amino]pyridin-2-yl}oxy)-3-methoxyphenyl]propionic acid, and [4-{4-[( 3,4-Dichlorobenzhydryl)amino]phenoxy}-3-methoxyphenyl)acetic acid] 2. A compound of the formula (I) or a salt thereof according to the first aspect of the patent application, wherein R6 is an aryl group, a heteroaryl group, a heterocycloalkyl group or a -N(R6a)(R6b) which may be substituted with the same or different substituents represented by RXB, and RXB is halogen, C!-6 alkyl, halogen. Base Cu alkyl, -〇-(C丨-6 alkyl), -〇-(幽Cb6 alkyl, -S-(Cb6 alkyl), -N^Cu alkyl)2, aryl, aryl substituted with -CMCu alkyl), or substituted with -N-iCualkyl)2 . 3. The compound of claim 2 or a salt thereof, wherein R1 is -CH2-COOH or -H, m is 1, R6a is -(Cmalkyl)-aryl, and R6b is -H, -120 - 200951122 However, when γ is -N =, U is -CH=, Y is _CH = or -CF =, and Z is =CH-. 4. A compound or salt as claimed in claim 3, wherein r3 is halogen, Ci.6, or -〇.-Ci.6, and R4 is -JJ. 5. A compound of claim 4 or a salt thereof, wherein γ is -N= and Z is =CH-. 6. The compound of claim 5 or a salt thereof, wherein e is a bond. 7. The compound of claim 6 or a salt thereof, wherein R6 is a phenyl group which may be substituted with the same or different substituents represented by 11^. 8. The compound of claim 7 or a salt thereof, wherein Α is -Ο, D is -C(=〇)-, R2 is -Η, and R3 is halogen. 9. The compound of claim 8 or a salt thereof, wherein R6 is a phenyl group Rxc which may be substituted by the same or different substituents represented by Rxe, C1, -CH3, -CF3, -OCH3, -ocf3 , -SCH3, _N(CH3)2, phenyl, phenyl substituted by -CH3, or phenyl substituted by -N(CH3)2. 1〇_ The compound of claim 3 or a salt thereof, wherein γ is -CH= or -CF=. 11. The compound of claim 10 or a salt thereof, wherein -121 - 200951122 A is -Ο-, D is -C(=0), and R6 is a group which may be the same or different from each other and represented by Rxb Substituted phenyl hydrazine 12. The compound of claim 3 or a salt thereof, wherein Ri is Η. 13. The compound of claim 12 or a salt thereof, wherein ν is. 14. A compound of the formula 2 or a salt thereof, which is a compound shown below: (3-chloro-4-{4-[(3,4-dichlorobenzhydryl)amino]benzene Oxy}phenyl)acetic acid, (4-{4-[(1-benzofuran-2-ylcarbonyl)amino]phenoxy}-3-chlorophenyl)acetic acid, [3-chloro-4- ({4-[(3,4-Dichlorobenzhydryl)amino]phenyl}sulfonyl)phenyl]acetic acid, (3-chloro-4-{4-[(3,4-dihydro) Isopipelin-2(1«[)-ylcarbonyl)amino]phenoxy}phenyl)acetic acid, [4-(4-{[(2£)-3-(3,4-dichlorophenyl) )prop-2-enyl]amino}phenoxy)-2-methyl-1indole-benzimidazol-1-yl]acetic acid, [3-chloro-4-(4-{[4-(three) Fluoromethyl)benzhydryl]amino}phenoxy)phenyl]acetic acid, (3-chloro-4-(2-fluoro-4-[(1Η-吲哚-2.ylcarbonyl)amino]] Phenoxy)phenyl)acetic acid, -122- 200951122 [3-chloro-4-(4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenoxy)benzene Acetic acid, [3-chloro-4-(4-{[(6-fluoro-1H-benzimidazol-2-yl)aminecarboxy]amino}phenoxy)phenyl]acetic acid, {3 -chloro-4-[( 5-{[(5-气-1H_D引哄-2-yl)mine base] makeup base}卩比卩疋-2_ yloxy]phenyl}acetic acid, [3_bromo-4-(4-{[4-(trifluoromethoxy)benzylidenyl]amino}phenoxy)^phenyl] Acetic acid, and {3-chloro-4-[(5-{[4-(trifluoromethoxy)benzylidenyl]amino}pyridin-2-yl)oxy]phenyl}acetic acid. A pharmaceutical composition characterized by comprising a compound of the first aspect of the patent application or a salt thereof and a pharmaceutically acceptable excipient. A pharmaceutical composition for treating or preventing an inflammatory disease or multiple sclerosis, which comprises the compound of claim 1 or a salt thereof. '% 18. The use of a compound or a salt thereof according to claim 1 ' is characterized by the manufacture of a pharmaceutical composition for the prevention or treatment of an inflammatory disease or multiple sclerosis. 19. Use of a compound or a salt thereof according to the scope of the patent application 'characteristics for the prevention or treatment of inflammatory diseases or multiple sclerosis 〇20. Prevention of inflammatory diseases or multiple sclerosis or The method of treatment is characterized in that an effective amount of the compound of claim 1 or a salt thereof is administered to a patient. -123- 200951122 IV. Designated representative map: (1) The representative representative of the case is: None. (2) A brief description of the symbol of the representative figure: none -3- 200951122 五、本案若有化學式時，請揭示最能顯示發明特徵的化學式：無-3- 200951122 V. If there is a chemical formula in this case, please reveal the chemical formula that best shows the characteristics of the invention: none -4- 200951122 773343 發明專利說明書 #；月修正補充 (本申請瓣式L言物任意麵，※言彌·靑 C07D 401/12 2006. 01 C07D 213/60 2006.01 C07C 233/24 2006. 01 A61K 31/343 2006. 01 A61K 31/404 2006. 0! A61K 31/4184 2006. 01 A61K 31/423 2006.01 A61K 31/44 2006.01丨 A61P 29/00 2006.01 A61P 37/02. 2006. 01； 分麪： ※申請案號：98103153 ※申請日：98年01月23日 ， 一、 發明名稱：（中文/英文） 羧酸化合物或其鹽 Carboxylic acid compound or the salt 二、 中文發明摘要： 本發明提供一種化合物，其具有CRTH2拮抗作用， 可使用作爲炎症性疾病（例如，氣喘、過敏性鼻炎、過敏 性皮膚炎、結膜炎、蓴麻疹、嗜酸血球性支氣管炎、食物 過敏、gil鼻腔炎、血管炎、慢性阻塞性肺疾病等）或多發 性硬化症等之預防及/或治療劑。 -本發明者針對具有CRTH2拮抗作用之化合物進行探 討’確認竣酸化合物或其鹽具有CRTH2拮抗作用，因而 完成本發明。本發明之羧酸化合物或其鹽具有CRTH2拮 抗作用’可使用作爲炎症性疾病（例如，氣喘、過敏性鼻 炎、過敏性皮膚炎 '結膜炎、奪麻疹、嗜酸血球性支氣管 炎、食物過敏、副鼻腔炎、血管炎、慢性阻塞性肺疾病等） 或多發性硬化症等之預防及/或治療劑。 200951122 六、發明說明： 【發明所屬之技術領域】 本發明係關於可使用作爲醫藥組成物、尤其是炎症性 疾病或多發性硬化症治療用醫藥組成物之有效成分之羧酸 化合物或其鹽。 【先前技術】-4- 200951122 773343 Invention Patent Specification #; Month Correction Supplement (This application has a petal L language on any side, ※言弥·靑C07D 401/12 2006. 01 C07D 213/60 2006.01 C07C 233/24 2006. 01 A61K 31 /343 2006. 01 A61K 31/404 2006. 0! A61K 31/4184 2006. 01 A61K 31/423 2006.01 A61K 31/44 2006.01丨A61P 29/00 2006.01 A61P 37/02. 2006. 01; Facet: ※Application Case No.: 98103153 ※Application date: January 23, 1998, I. Name of the invention: (Chinese/English) Carboxylic acid compound or the salt thereof. Abstract: The present invention provides a compound which It has CRTH2 antagonism and can be used as an inflammatory disease (for example, asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, urticaria, eosinophilic bronchitis, food allergies, gil nasal inflammation, vasculitis, chronic obstructive A prophylactic and/or therapeutic agent for lung disease or the like, or multiple sclerosis, etc. - The present inventors conducted a discussion on a compound having CRTH2 antagonistic action to confirm that a citrate compound or a salt thereof has CRTH2 The present invention has been completed. The carboxylic acid compound of the present invention or a salt thereof has CRTH2 antagonism' can be used as an inflammatory disease (for example, asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, measles, eosinophils) Prophylactic and/or therapeutic agent for bronchitis, food allergy, paranasal sinusitis, vasculitis, chronic obstructive pulmonary disease, etc., or multiple sclerosis. 200951122 VI. Description of the Invention: [Technical Field of the Invention] The present invention A carboxylic acid compound or a salt thereof which can be used as an active ingredient of a pharmaceutical composition, particularly an inflammatory disease or a pharmaceutical composition for treating multiple sclerosis. 已知爲過敏性炎症誘導細胞之肥胖細胞係透過其細胞 表面之Fc ε RI與抗原特異之IgE結合。侵入生體內之抗 原藉由與該細胞表面上之特異IgE結合且使肥胖細胞活性 化，產生各種炎症性介體，誘發過敏性炎症（Current Opinion in Immunology, 2002 年，14 ( 6)卷，p. 688-693 前列腺素D2 ( PGD2 )爲活化性肥胖細胞所產生之主 要類前列腺素（prostanoid )。迄今爲止認爲於氣喘患者 ^ 呼吸道因抗原暴露引起PGD2在數分鐘以內顯著產生亢進 (新英格蘭醫藥期刊（New England Journal of Medicine )，1986年，315(13)卷，p800-804;美國呼吸道疾病回 顧(American Review of Respiratory Disease ) , 1 9 8 3 年， 128 ( 4 )卷，ρ· 597-602 )，或報導有若過敏性鼻炎患者 之鼻黏膜或異位性皮膚炎患者之皮膚暴露於抗原時，於炎 症局部引起PGD2產生之充進（免疫學期刊（Journal of Immunology )，1 99 1 年，1 4 6 ( 2 )卷，p · 67 1 -6 76 )。另外 ，過去已報導有對人類皮內投與PGD2時引發紅斑，於大 200951122 鼠中使血管透過性亢進而形成浮腫（英國免疫學期刊（ British Journal of Immunology) , 1 976 年，56 ( 2)卷，P 229-233)、對狗氣管中PGD2亦引發嗜酸血球累積（應 用生理學期刊（Journal of Applied Physiology)，1989 年 ,67(3)卷，p 959-962) 。Fuj it ani等人報導有使用抗原An obese cell line known as an allergic inflammation-inducing cell binds to antigen-specific IgE through Fc ε RI on its cell surface. An antigen that invades a living body binds to specific IgE on the surface of the cell and activates obese cells to produce various inflammatory mediators, which induce allergic inflammation (Current Opinion in Immunology, 2002, 14 (6), p 688-693 Prostaglandin D2 ( PGD2 ) is a major prostanoid produced by activating obese cells. It has been considered so far that patients with asthma have respiratory tracts that cause PGD2 to be significantly hyperactive within minutes due to antigen exposure (New England) New England Journal of Medicine, 1986, 315(13), p800-804; American Review of Respiratory Disease, 1989, 128(4), ρ·597 -602), or reported that if the skin of patients with nasal mucosa or atopic dermatitis in patients with allergic rhinitis is exposed to antigen, localization of PGD2 is caused by inflammation (Journal of Immunology, 1 99) 1 year, 1 4 6 ( 2 ) volume, p · 67 1 -6 76 ). In addition, it has been reported in the past that erythema is caused by intradermal administration of PGD2 in humans, and blood vessels are transmitted through the large 200951122 mouse. The formation of edema (British Journal of Immunology, 1 976, 56 (2), P 229-233) also causes eosinophil accumulation in PGD2 in the trachea of dogs (Applied Physiology Journal) Of Applied Physiology, 1989, 67(3), p 959-962). Fujit ani et al. reported the use of antigens 誘發氣喘模型，於相較於正常小鼠PGD2產生增加之 PGD2合成酵素轉基因小鼠於呼吸道中嗜酸血球浸潤及 Th2細胞素產生受到亢進（免疫學期刊（Journal of Immunology )，2002 年，16 8 ( 1)卷，p. 443-449 ) ’ 提不 PGD2促進過敏性炎症。如此PGD2於過敏性炎症部位之 產生受到亢進，促進過敏反應，因此認爲與過敏疾病之發 病及惡化有密切關聯。Induced asthma model, in the PGD2 synthetase transgenic mice with increased production of PGD2 compared to normal mice, eosinophil infiltration and Th2 cytokine production are hyperactive in the respiratory tract (Journal of Immunology, 2002, 16 8 (1) Volume, p. 443-449) 'Pg2 does not promote allergic inflammation. As a result, PGD2 is hyperactive in the area of allergic inflammation and promotes allergic reactions. Therefore, it is considered to be closely related to the onset and deterioration of allergic diseases. 最初作爲PGD2受體已知有爲G蛋白共軛型受體（ GPCR)之一之DP(D型類前列腺素受體）。然而，於豚 鼠中PGD2雖顯示眼壓降低作用及於結膜中顯示炎症誘發 作用（尤其是是酸性白血球浸潤），但爲DP選擇性促效 劑之BW24 5 C雖顯示眼壓降低作用但未誘發嗜酸血球對結 膜之浸潤，提示PGD2之嗜酸血球浸潤誘發作用並非透過 DP ( Investigate Opthlmology &amp; Visual Science, 1 990 年， 1卷，ρ· 1 3 8-146 )。再者，於2001年Monneret等人使用 自人類單離之嗜酸血球，由於PGD 2使嗜酸血球活性化或 爲DP選擇性促效劑之BW245 C不使嗜酸血球活性化以及 爲DP拮抗劑之BWA86C不阻礙因PGD2引起嗜酸血球活 性化，故而提倡PGD2之嗜酸血球活性化作用係透過新穎 -6- 200951122A DP (D-type prostaglandin receptor) which is one of G protein-conjugated receptors (GPCRs) is known as a PGD2 receptor. However, in guinea pigs, PGD2 showed a decrease in intraocular pressure and an inflammation-inducing effect in the conjunctiva (especially acidic leukocyte infiltration), but BW24 5 C, a DP selective agonist, showed an effect of reducing intraocular pressure but did not induce The infiltration of eosinophils into the conjunctiva suggests that the eosinophil infiltration induced by PGD2 is not transmitted through DP (Investigate Opthlmology &amp; Visual Science, 990, Vol. 1, p. 1 3 8-146). Furthermore, in 2001, Monnetet et al. used eosinophils isolated from humans, and BW245 C, which activates eosinophils or is a DP selective agonist due to PGD 2, does not activate eosinophils and is antagonistic to DP. BWA86C does not hinder the activation of eosinophils due to PGD2, so it is recommended to activate the eosinophils of PGD2 through novel-6-200951122 之 PGD2 受體(Blood, 2001 年，98(6)卷，p. 1 942-1 948 )。於同時期Hirai等人報導PGD係藉由作爲CRTH2 ( 於Th2細胞上表現之化學引誘劑受體-同源分子）之配位 體之作用，而誘發Th2細胞、嗜酸血球、嗜鹼血球之趨化 (實驗醫藥期刊（The Journal of Experimental Medicine )，2001 年，193(2)卷，p. 255-261)。同時，報導有 CRTH2不認爲於Thl細胞中表現，而係作爲Th2細胞選 擇性表現之化學引誘劑類受體加以選殖之G蛋白共軛型 之孤兒受體，於活性化之肥胖細胞之培養上清液中，存在 有其配位體活性以及除Th2細胞以外亦於與嗜酸血球、嗜 鹼血球之過敏性反應有關之炎症性細胞中表現（免疫學期 刊（Journal of Immunology ) ， 1 999 年，162(3)卷，p. 1 278- 1 286, FEBS Letter, 1 999 年，8 卷，459 ( 2 ) , p. 195-199)。由此到目前，均認爲PGD2係透過CRTH2及DP 之兩種受體而發揮其生物活性。 CRTH2爲使cAMP上升之Gs偶合型GPCR，DP爲阻 礙cAMP上升之Gi偶合型GPCR，故細胞內訊號傳達系統 不同，具有不同機能。迄今使用對於CRTH2及DP之促 效劑、拮抗劑進行探討，故而報導作爲CRTH2之機能有 細胞趨化活性化（Th2細胞、嗜酸血球、嗜鹼血球）、黏 著分子表現促進（Th2細胞、嗜酸血球）、Th2細胞素產 生促進（Th2細胞）等。另一方面，作爲DP之機能有血 小板凝集抑制、血管擴張、平滑肌鬆弛、細胞趨化抑制（ DP表現細胞、嗜酸血球、樹枝狀細胞）、嗜酸血球細胞 200951122The PGD2 receptor (Blood, 2001, 98(6), p. 1 942-1 948). At the same time, Hirai et al. reported that PGD induces Th2 cells, eosinophils, and basophilic blood cells by acting as a ligand for CRTH2 (a chemoattractant receptor-homologous molecule expressed on Th2 cells). Chemotherapy (The Journal of Experimental Medicine, 2001, 193(2), p. 255-261). At the same time, it is reported that CRTH2 is not considered to be expressed in Th1 cells, but is a G protein-conjugated orphan receptor that is selected as a chemoattractant receptor selectively expressed by Th2 cells, and is activated by an obese cell. In the culture supernatant, there is a ligand activity and expression in inflammatory cells related to allergic reactions of eosinophils and basophilic blood cells in addition to Th2 cells (Journal of Immunology, 1 999, 162(3), p. 1 278- 1 286, FEBS Letter, 1 999, 8 volumes, 459 (2), p. 195-199). From this point of view, it is considered that PGD2 exerts its biological activity through both receptors of CRTH2 and DP. CRTH2 is a Gs-coupled GPCR that raises cAMP, and DP is a Gi-coupled GPCR that blocks cAMP rise, so the intracellular signal transmission system is different and has different functions. As far as the use of CRTH2 and DP agonists and antagonists has been investigated, it has been reported that as a function of CRTH2, cell chemotactic activation (Th2 cells, eosinophils, basophils) and adhesion molecules are promoted (Th2 cells, hobby) Acid cell), Th2 cytokine production promotion (Th2 cell), and the like. On the other hand, as a function of DP, platelet aggregation inhibition, vasodilation, smooth muscle relaxation, and cell chemotaxis inhibition (DP expression cells, eosinophils, dendritic cells), eosinophils 200951122 凋亡誘導、睡眠誘導等。認爲PGD2係藉由DP之作用於 局部引發血管擴張使血管透過性亢進，而另一方面藉由 CRTH2之作用引起炎症性細胞浸潤及活性化，而促進過 敏性炎症。有關該等方面，Nagata等人及Pettipher等人 之總論中已有詳細描述（前列腺素白三烯及必須胺基酸（ Prostaglandins Leukotrienes &amp; Essential Fatty Acids )， 2003年，69(2-3)卷，p. 169-177;天然回顧藥物發現（ Natural Review Drug Discovery)，2007 年，6 ( 4)卷，ρ· 313-325) ° 由以上，認爲因抗原刺激而產生活性化肥胖細胞之主 要類前列腺素之PGD2係透過CRTH2使Th2細胞或嗜酸 血球等之炎症性細胞活性化，促進朝炎症部位之趨化，進 而促進自Th2細胞產生Th2配位體藉此於過敏性炎症中 扮演主要角色，熱切期望開發CRTH2拮抗藥作爲對於過 敏性炎症之治療藥。 〇 例如，具有CRTH2拮抗作用、具有抗氣喘作用之化 合物已知有以下述式（A) 、( B ) 、( C ) 、( D) 、( E )表示之化合物（分別爲專利文獻1、2、3、4、5 )。 -8 - 200951122 [化i]Apoptosis induction, sleep induction, and the like. It is considered that PGD2 promotes vascular hyperpermeability by locally causing vasodilation by DP, and on the other hand, inflammatory cell infiltration and activation by action of CRTH2 promotes allergic inflammation. These aspects have been described in detail in the generals of Nagata et al. and Pettipher et al. (Prostaglandins Leukotrienes & Essential Fatty Acids, 2003, 69 (2-3) Vol. p. 169-177; Natural Review Drug Discovery, 2007, 6(4), ρ·313-325) ° From above, it is believed that activated fat cells are produced by antigen stimulation. PGD2, a major prostaglandin, activates inflammatory cells such as Th2 cells or eosinophils through CRTH2, promotes chemotaxis toward inflammation sites, and promotes the production of Th2 ligands from Th2 cells to play a role in allergic inflammation. The main role, eager to develop CRTH2 antagonists as a therapeutic drug for allergic inflammation. For example, a compound having the anti-asthmatic effect of CRTH2 antagonism is known as a compound represented by the following formulas (A), (B), (C), (D), and (E) (Patent Documents 1 and 2, respectively) , 3, 4, 5). -8 - 200951122 [化i] (E)(E) [式中各符號分別參見該公報， 其中，專利文獻2中（B)之W表示0、S(0)n ( η 爲 0、1、2) 、NR13、CR'OR2、cWr2， 專利文獻3中，（C)之L表示CR6R7、CO、CNR6、 cs， 專利文獻4中，（D )之A表示與B縮合或鍵結之5 至14員環雜環]。 專利文獻5公開日在本申請案之優先日之後。 又例如，專利文獻6、7及8中揭示作爲製造中間體 -9- 200951122 之以（F)表示之化合物。 [化2] R001 R002 r003 F - -cf3 -och2ch3 _ -cf3 -och3 - -cf3 F Cl Cl -och2ch3 Cl Cl -och3 Cl Cl[In the above, each symbol of the formula is referred to in the publication, wherein W of the (B) of Patent Document 2 represents 0, S(0)n (η is 0, 1, 2), NR13, CR'OR2, cWr2, Patent Document 3 In the case of (C), L represents CR6R7, CO, CNR6, cs, and in Patent Document 4, A of (D) represents a 5- to 14-membered ring heterocyclic ring condensed or bonded with B]. The patent document 5 publication date is after the priority date of the present application. Further, for example, Patent Documents 6, 7, and 8 disclose a compound represented by (F) as a production intermediate -9-200951122. R001 R002 r003 F - -cf3 -och2ch3 _ -cf3 -och3 - -cf3 F Cl Cl -och2ch3 Cl Cl -och3 Cl Cl [專利文獻1]國際公開第W02004/058 1 64說明書 [專利文獻2]國際公開第W02006/005909說明書 [專利文獻3]國際公開第WO20 07/1 43 745說明書 [專利文獻4]國際公開第WO2007/1 46838說明書 [專利文獻5]國際公開第W02008/024746說明書 [專利文獻6]國際公開第W02006/0 140 1 2說明書 [專利文獻7]國際公開第W02007/066784說明書 [專利文獻8]特開2007-23 1 00 5號 【發明內容】 [發明欲解決之課題] 本發明者基於CRTH2拮抗作用，而以提供炎症性疾 病（例如，氣喘、過敏性鼻炎、過敏性皮膚炎、結膜炎、 -10- 200951122 奪麻疹、嗜酸血球性支氣管炎、食物過敏、副鼻腔炎、血 管炎、慢性阻塞性肺疾病等）或多發性硬化症等之預防及 /或治療有用之醫藥組成物，進而以提供含有該等之醫藥 作爲目的進行硏究。 [解決課題之手段][Patent Document 1] International Publication No. WO2004/058 1 64 Specification [Patent Document 2] International Publication No. WO2006/005909 Specification [Patent Document 3] International Publication No. WO20 07/1 43 745 Specification [Patent Document 4] International Publication No. WO2007 [1] [Patent Document 5] International Publication No. WO2008/024746 Specification [Patent Document 6] International Publication No. WO2006/0 140 1 2 Specification [Patent Document 7] International Publication No. WO2007/066784 Specification [Patent Document 8] 2007-23 1 00 5 [Summary of the Invention] [Problems to be Solved by the Invention] The present inventors provide an inflammatory disease based on CRTH2 antagonism (for example, asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, -10 - 200951122 Medications for the prevention and/or treatment of measles, eosinophilic bronchitis, food allergies, paranasal sinusitis, vasculitis, chronic obstructive pulmonary disease, etc., or multiple sclerosis, and further The purpose of including such medicines is to investigate. [Means for solving the problem] 本發明者對於具有CRTH2拮抗作用之化合物積極檢 討之結果’發現式（I )之化合物可作爲CRTH2拮抗作用 而完成本發明。 亦即’本發明係關於式（I )化合物或其鹽，以及含 有式（I )化合物或其鹽、以及賦形劑之醫藥組成物。 [化3]The present inventors have actively examined the results of compounds having CRTH2 antagonism. It has been found that the compound of the formula (I) can be used as the CRTH2 antagonistic effect to complete the present invention. That is, the present invention relates to a compound of the formula (I) or a salt thereof, and a pharmaceutical composition comprising the compound of the formula (I) or a salt thereof, and an excipient. [Chemical 3] [式中， R爲-(Cm伸院基）-C〇〇H或-H， 1)當R1爲-(Cu伸烷基）-c〇〇H時， R2爲_素或-H， R3爲鹵素、CU6烷基、( Cl-6烷基）或-H， 2 )當R1爲-Η時， R2與R3與其等所鍵結之苯環—起形成以下式（π) -11 - 200951122 表示之基， [化4]Wherein R is -(Cm stretching)-C〇〇H or -H, 1) When R1 is -(Cu alkyl)-c〇〇H, R2 is _ or -H, R3 Is halogen, CU6 alkyl, (Cl-6 alkyl) or -H, 2) When R1 is -Η, R2 and R3 together with the benzene ring bonded thereto form the following formula (π) -11 - 200951122 Base of representation, [Chemical 4] V 爲= CH -或=N-， m表示1至6之整數， R4爲鹵素或-H， 但，R3爲-H時，R4爲鹵素， R5爲-H、鹵素或C丨_6烷基， R6爲可分別以由以RXA表示之相同或不同之基取代之芳 基、雜芳基、雜環烷基或-N(R6a)(R6b)， RXA爲鹵素、Ci.6院基、鹵基Ci.6院基、_〇_(Ci-6焼基） 、-0-(鹵基 Ci.6 院基、-S-iCu 院基）、-N-fC]—6 院基）2、 芳基、經鹵素取代之芳基、經-Ο - (C 6烷基）取代之芳基、 經-N-CCi.6烷基）2取代之芳基、鹵芳基、-OH、-CN、-S( = 0)2-(Ci-6 院基）、_NHS( = 0)2-(Ci-6 院基）或環狀胺基’ R6a爲-((^-6伸烷基）-芳基、-((^-6伸烷基）-雜芳基、或-(Cm伸烷基）-雜環烷基， R6b爲-H或Cu烷基， A 爲-0-或-S-， D 爲-C( = 0)-、或-S( = 0)2- ’ -12- 200951122 E爲鍵結、Cm伸烷基或C2-6伸烯基， Y 爲-C(R5a) =或-N=， R5a爲-Η、鹵素、或Cm烷基， Z 爲=CH-、或=N-， U 爲-C(R5b) =或-N=， R5b爲-Η、鹵素或Cm烷基， 但，下列化合物除外，V is =CH - or =N-, m represents an integer from 1 to 6, and R4 is halogen or -H, but when R3 is -H, R4 is halogen, and R5 is -H, halogen or C丨_6 alkyl And R6 is an aryl group, a heteroaryl group, a heterocycloalkyl group or -N(R6a)(R6b) which may be substituted by the same or different groups represented by RXA, and RXA is a halogen, a Ci.6 yard group, a halogen. Base Ci.6 yard base, _〇_(Ci-6 焼 base), -0-(halogen-based Ci.6 yard base, -S-iCu yard base), -N-fC]-6 yard base) Aryl, halogen-substituted aryl, Ο-(C 6 alkyl) substituted aryl, -N-CCi.6 alkyl) 2 substituted aryl, haloaryl, -OH, -CN , -S( = 0)2-(Ci-6), _NHS(=0)2-(Ci-6) or cyclic amine 'R6a is -((^-6alkyl)- Aryl, -((^-6alkyl)-heteroaryl, or -(Cmalkyl)-heterocycloalkyl, R6b is -H or Cu alkyl, A is -0- or -S- , D is -C( = 0)-, or -S( = 0)2- ' -12- 200951122 E is a bond, Cm alkyl or C2-6 extended alkenyl, Y is -C(R5a) = Or -N=, R5a is -Η, halogen, or Cm alkyl, Z is =CH-, or =N-, U is -C(R5b) = or -N=, R5b is -Η, halogen or Cm alkane Base, but Except for the following compounds, 3-{3-氟-4-[(5-{[4-(三氟甲基）苯甲醯基]胺基}吡 啶-2-基）氧基]苯基}丙酸， 3-{3-乙氧基-4-[(5-{[4-(三氟甲基）苯甲醯基]胺基 }吡啶-2-基）氧基]苯基}丙酸， 3-{3-甲氧基-4-[(5-{[4-(三氟甲基）苯甲醯基]胺基 }吡啶-2-基）氧基]苯基}丙酸， 3-[4- ( {5-[ ( 3,4-二氯苯甲醯基）胺基]吡啶-2-基}氧 基）-3-氟苯基]丙酸， 3-[4- ( {5-[ ( 3,4-二氯苯甲醯基）胺基]吡啶_2-基}氧 基）-3-乙氧基苯基]丙酸， 3-[4- ( {5-[ ( 3,4-二氯苯甲醯基）胺基]吡啶_2_基}氧 基）-3-甲氧基苯基]丙酸，及 [4-{4-[(3,4-二氯苯甲醯基）胺基]苯氧基}_3_甲氧基 苯基]乙酸]。 再者，若未特別說明，則本說明書中之化學式中之符 號用於其他化學式時’相同的符號表示相同之意義。 另外’本發明係關於含有式（I)化合物或其鹽之炎 -13- 200951122 症性疾病或多發性硬化症之治療用醫藥組成物，亦即，含 有式（I)之化合物或其鹽之炎症性疾病或多發性硬化症 治療劑。 另外，本發明係關於式（I )化合物或其鹽用以製造 炎症性疾病或多發性硬化症之治療用醫藥組成物之用途， 以及對患者投予有效量之式（I )化合物或其鹽之炎症性 疾病或多發性硬化症之治療方法。3-{3-Fluoro-4-[(5-{[4-(trifluoromethyl)benzylidenyl]amino}pyridin-2-yl)oxy]phenyl}propanoic acid, 3-{3 -ethoxy-4-[(5-{[4-(trifluoromethyl)benzylidenyl]amino}pyridin-2-yl)oxy]phenyl}propionic acid, 3-{3-A Oxy-4-[(5-{[4-(trifluoromethyl)benzylidenyl]amino}pyridin-2-yl)oxy]phenyl}propanoic acid, 3-[4- ( {5 -[ ( 3,4-dichlorobenzhydryl)amino]pyridin-2-yl}oxy)-3-fluorophenyl]propionic acid, 3-[4- ( {5-[ ( 3,4) -Dichlorobenzhydryl)amino]pyridin-2-yl}oxy)-3-ethoxyphenyl]propionic acid, 3-[4-({5-[(3,4-dichlorobenzene) Mercapto)amino]pyridin-2-yl}oxy)-3-methoxyphenyl]propionic acid, and [4-{4-[(3,4-dichlorobenzhydryl)amino) ]phenoxy}_3_methoxyphenyl]acetic acid]. Further, unless otherwise stated, the symbols in the chemical formulas in the present specification are used in the other chemical formulas, and the same symbols denote the same meanings. Further, the present invention relates to a pharmaceutical composition for the treatment of a disease of the formula (I) or a salt thereof, which comprises a compound of the formula (I) or a salt thereof, which comprises a compound of the formula (I) or a salt thereof. An inflammatory disease or a therapeutic agent for multiple sclerosis. Further, the present invention relates to the use of a compound of the formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for the treatment of an inflammatory disease or multiple sclerosis, and an effective amount of the compound of the formula (I) or a salt thereof for administration to a patient The treatment of inflammatory diseases or multiple sclerosis. [發明效果] 式（I)化合物或其鹽具有CRTH2拮抗作用，可使用 作爲炎症性疾病（例如，氣喘、過敏性鼻炎、過敏性皮膚 炎、結膜炎、蓴麻疹、嗜酸血球性支氣管炎、食物過敏、 副鼻腔炎、血管炎、慢性阻塞性肺疾病等）或多發性硬化 症等之預防及/或治療劑。[Effect of the Invention] The compound of the formula (I) or a salt thereof has CRTH2 antagonism and can be used as an inflammatory disease (for example, asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, urticaria, eosinophilic bronchitis, food) A prophylactic and/or therapeutic agent for allergy, paranasal sinusitis, vasculitis, chronic obstructive pulmonary disease, etc. or multiple sclerosis. 【實施方式】 •以下’詳細說明本發明。 「鹵素」爲、Cl、Br、或I。至於其他樣態爲F或C1 「C!_6烷基」爲直鏈或分支狀之碳數1至6之烷基， 例如，甲基、乙基、正丙基、異丙基、正丁基、異丁基、 第一 丁基、弟二丁基、正戊基、正己基等。至於其他樣態 爲C i ·4烷基。又其他樣態爲甲基或乙基。 「鹵基C,-6烷基」爲經i個以上鹵素取代之Ci 6烷 -14- 200951122 基。其它樣態爲經1至5個鹵素取代之Ci-6烷基’又其 他樣態爲- CF3、-CF2H、或- CH2CH2F。 「c!_6伸烷基」爲直鏈或分支狀之碳數1至6之伸烷 基，例如亞甲基、伸乙基、三亞甲基、伸丙基、四亞甲基 、五亞甲基、或六亞甲基等。至於其他樣態爲C!-4伸烷 基，又其他樣態爲亞甲基或伸乙基。[Embodiment] The present invention will be described in detail below. "Halogen" is, Cl, Br, or I. As for the other forms, F or C1 "C!_6 alkyl" is a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl. , isobutyl, first butyl, dibutyl, n-pentyl, n-hexyl and the like. As for the other forms, it is C i ·4 alkyl. Still other forms are methyl or ethyl. "Halo-C, -6-alkyl" is a Ci 6 alkane-14-200951122 group substituted by i or more halogens. Other aspects are Ci-6 alkyl' substituted with 1 to 5 halogens and other forms - CF3, -CF2H, or -CH2CH2F. "c!_6 alkylene" is a linear or branched alkyl group having 1 to 6 carbon atoms, such as methylene, ethyl, trimethylene, propyl, tetramethylene, penta. Base, or hexamethylene group, etc. As for the other forms, it is a C!-4 alkylene group, and other forms are methylene or ethyl. 「c2.6伸烯基」爲直鏈或分支狀之碳數2至6之伸烯 基，例如伸乙烯基、伸丙烯基、伸丁烯基、伸戊烯基、或 伸己烯基等。其他樣態爲C 2 - 4伸烯基。 「芳基」爲C6-14之單環至三環芳香族烴環基，例如 苯基、或萘基，其他樣態爲苯基。 「雜芳基」意指具有一個以上選自氮、氧及硫組成之 群組之相同或不同雜原子之5或6員環芳香族雜環，該等 亦可爲與環戊烷環或苯環縮合。其他樣態爲亦可與苯環縮 合之5或6員芳香族雜環，又其他樣態爲噻吩基、三唑基 、吡啶基、吲哚基、苯并呋喃基、苯并噻吩基、苯并噁唑 基、苯并噻唑基、苯并咪唑基、咪唑吡啶基、異喹啉基、 或喹啉基等。其他樣態爲吲哚基。 「雜環烷基」意指具有一個以上選自由氮、氧及硫組 成之群組之相同或不同之雜原子之5至7員非芳香族雜環 ，該等可具有部分不飽和鍵，亦可與苯環縮合。其他樣態 爲哌啶基、異茚滿基、四氫喹啉基、四氫異喹啉基、 2,3,4,5-四氫-1H-3-苯并吖庚因基等。至於其他樣態爲可 與苯環縮合之5至7員非芳香族雜環，又其他樣態爲四氫 -15- 200951122 異喹啉基。 「環狀胺」意指上述「雜環烷基」中，具有至少一個 氮原子之單環〜三環式「雜環院基」。亦可具有部分不飽 和鍵。其他樣態爲環員數爲4〜9員之環，又其他樣態舉例 爲卩比咯 Π定基、峨U定基、嗎琳基、或均哌陡基。 本說明書中’所謂「可經取代」意指未經取代、或具 有1至6個取代基者，其他樣態意指具有1至5個者。另 外，具有複數個取代基時’該等取代基可相同亦可彼此不 同。 本說明書中’所謂「經取代」意指具有1至6個取代 基’其他樣態意指具有1至5個取代基。另外，具有複數 個取代基時，該等取代基可相同亦可彼此不同。 「RXA」之其他樣態爲Rxb，又其他樣態爲Rxc。 RXB爲鹵素、Cm烷基、鹵基Cu烷基、烷 基）、-〇-(鹵基C丨-6烷基）、-SJC!—6烷基）、-N-(Cl_6烷基 )2、芳基 '經-0-((:,-6烷基）取代之芳基、或經-NjCu烷 基）2取代之芳基。 RXC 爲 C1、_CH3、-CF3、-OCH3、-〇CF3、_SCH3、- N(CH3)2、苯基、經_〇ch3取代之苯基、或經-N(CH3)2取 代之苯基。 以下顯示本發明之樣態： (1) Rl爲- (Cu伸烷基）_C00H之式（I)化合物。 至於其他樣態，R1爲- CH2-CO〇H之式（1)化合物。 又其他樣態，R!爲-H之式（I )化合物。 -16 - 200951122 (2) R2爲-Η之式（I)化合物。 (3) R3爲幽素、Cu烷基、或- CKCu烷基）之式（I)化 合物。 至於其他樣態，R3爲鹵素之式（I )化合物。 又其他樣態，R3爲F、Br或C1之式（I )化合物。 (4 ) R4爲-H之式（I )化合物。 (5) R5爲-H之式（I)化合物。"c2.6 an alkenyl group" is a linear or branched alkenyl group having 2 to 6 carbon atoms, such as a vinyl group, a propenyl group, a butenyl group, a pentenyl group, or a hexenyl group. . Other forms are C 2 -4 extended alkenyl groups. The "aryl group" is a monocyclic to tricyclic aromatic hydrocarbon ring group of C6-14, such as a phenyl group or a naphthyl group, and the other form is a phenyl group. "Heteroaryl" means a 5- or 6-membered ring aromatic heterocyclic ring having one or more identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, which may also be with a cyclopentane ring or a benzene. Ring condensation. Other forms are 5 or 6-membered aromatic heterocycles which may also be condensed with a benzene ring, and other forms are thienyl, triazolyl, pyridyl, indolyl, benzofuranyl, benzothienyl, benzene. And oxazolyl, benzothiazolyl, benzimidazolyl, imidazolidinyl, isoquinolyl, or quinolyl. Other forms are sulfhydryl groups. "Heterocycloalkyl" means a 5- to 7-membered non-aromatic heterocyclic ring having one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, which may have partially unsaturated bonds, It can be condensed with a benzene ring. Other examples are piperidinyl, isoindanyl, tetrahydroquinolyl, tetrahydroisoquinolinyl, 2,3,4,5-tetrahydro-1H-3-benzazepine and the like. As for the other forms, it is a 5- to 7-membered non-aromatic heterocyclic ring which can be condensed with a benzene ring, and other forms are tetrahydro-15-200951122 isoquinolyl. The "cyclic amine" means a monocyclic to tricyclic "heterocyclic compound" having at least one nitrogen atom in the above "heterocycloalkyl group". It can also have partial unsaturated keys. Other forms are rings with a ring number of 4 to 9 members, and other examples are 卩 咯 Π Π, 峨 U 基, 吗 基, or 哌 陡. In the present specification, 'so-called "substitutable" means unsubstituted or has 1 to 6 substituents, and other forms mean 1 to 5. Further, when there are a plurality of substituents, the substituents may be the same or different from each other. The term "substituted" in the present specification means having 1 to 6 substituents. The other forms mean having 1 to 5 substituents. Further, when there are a plurality of substituents, the substituents may be the same or different from each other. The other aspect of "RXA" is Rxb, and the other aspect is Rxc. RXB is halogen, Cm alkyl, halo-C-alkyl, alkyl), -〇-(halo C丨-6 alkyl), -SJC!-6 alkyl), -N-(Cl_6 alkyl)2 An aryl group in which an aryl group is substituted with an -O-((:,-6-alkyl)-substituted aryl group or a -NjCualkyl group). RXC is C1, _CH3, -CF3, -OCH3, -〇CF3, _SCH3, -N(CH3)2, phenyl, phenyl substituted by _〇ch3, or phenyl substituted by -N(CH3)2. The mode of the present invention is shown below: (1) A compound of the formula (I) wherein R1 is -(Cu alkylene)_C00H. As for the other forms, R1 is a compound of the formula (1) of -CH2-CO〇H. In still other forms, R! is a compound of formula (I) of -H. -16 - 200951122 (2) R2 is a compound of the formula (I). (3) A compound of the formula (I) wherein R3 is a ghrelin, a Cu alkyl group or a - CKCu alkyl group. As for the other forms, R3 is a halogen compound of the formula (I). In still other instances, R3 is a compound of formula (I) of F, Br or C1. (4) A compound of the formula (I) wherein R4 is -H. (5) A compound of the formula (I) wherein R5 is -H. (6 ) R6爲可經相同或彼此不同之RXA分別取代之雜芳基 或雜環烷基之式（I)化合物。 至於其他樣態，R6爲可經相同或彼此不同之RXA取 代之苯基之式（I)化合物， 又其他樣態，R6爲可經相同或彼此不同之RXB取代 之苯基之式（I )化合物， 又再其他樣態，R6爲可經相同或彼此不同之RXc取 代之苯基之式（I)化合物。 (7) A爲- Ο-之式（I)化合物。 (8) D爲- C( = 0) -之式（I)化合物。 (9) E爲鍵結之式（I)化合物。 (10) Y爲- CH =或-CF =之式（I)化合物。 至於其他樣態，Y爲_N =之式（〇化合物。 (1 1 ) Z爲=CH-之式（I )化合物。 (12) U爲- CH =之式（I)化合物。 (13) m爲1之式（I)化合物。 (14 ) V爲=N-之式（I )化合物。 -17- 200951122 (15) R6a爲_((：1-6伸烷基）-芳基，且R6b爲-Η之式（I) 化合物。 (16) 上述（1)至（15)中所述之基中，藉由組合兩種 以上成爲互不矛盾之構造之式（I)化合物。 具體而言，舉例爲例如以下之化合物。 (A) R1 爲-(Cm 伸烷基）-COOH，R2 爲-H，R3 爲 F、C1 或Br之式（I )化合物。(6) R6 is a compound of the formula (I) which may be substituted with a heteroaryl or heterocycloalkyl group which are respectively substituted by RXA which are the same or different from each other. As for the other forms, R6 is a compound of the formula (I) which may be substituted with the same or different RXA phenyl groups, and other forms, R6 is a phenyl group which may be substituted by the same or different RXB (I) Compounds, yet other forms, R6 is a compound of formula (I) which may be substituted with the same or different RXc phenyl groups. (7) A is a compound of the formula (I). (8) D is -C(=0) - a compound of formula (I). (9) E is a compound of the formula (I) bonded. (10) Y is a compound of formula (I) wherein -CH = or -CF =. As for the other states, Y is a formula of _N = (〇 compound. (1 1 ) Z is a compound of the formula (I) = CH-. (12) U is - CH = a compound of the formula (I). A compound of the formula (I) wherein m is 1. (14) A compound of the formula (I) wherein V is =N-. -17- 200951122 (15) R6a is _((:1-61-6 alkyl)-aryl, and R6b is a compound of the formula (I) of the formula (I). (16) A compound of the formula (I) which is a structure which is not contradicted by two or more types in the groups described in the above (1) to (15). For example, the following compounds are exemplified. (A) A compound of the formula (I) wherein R1 is -(Cm alkylene)-COOH, R2 is -H, and R3 is F, C1 or Br. (B) R1爲- CH2-COOH之上述（A)所述之化合物。 以下列出本發明之又其他樣態。 [1] 式Π]化合物或其鹽，其中R6爲可經相同或彳皮Λ $胃 之以RXB表示之基分別取代之芳基、雜芳基、雜環 或-N(R6a)(R6b)。 [2] 如[1]所述之化合物或其鹽，其中 R1 爲-CH2-COOH 或-H， m爲1，(B) The compound of the above (A) wherein R1 is -CH2-COOH. Still other aspects of the invention are listed below. [1] A compound of the formula: or a salt thereof, wherein R6 is an aryl group, a heteroaryl group, a heterocyclic ring or a -N(R6a)(R6b) which may be substituted by the same or a scorpion 胃 $ stomach represented by RXB. . [2] The compound or a salt thereof according to [1], wherein R1 is -CH2-COOH or -H, m is 1, R6a爲-(Cm伸烷基μ芳基， R6b 爲-Η， 但，Y爲-N =時，u爲- CH=， Y 爲-CH =或-CF =時，z 爲=CH-。 [3] 如[2]所述之化合物或其鹽，其中 R3爲鹵素、Cu烷基或_〇_Ci6烷基， R4 爲-H。 [4] 如[3]所述之化合物或其鹽，其中 Y 爲， -18- 200951122 Z 爲=CH-。 [5] 如[4]所述之化合物或其鹽，其中E爲鍵結。 [6] 如[5]所述之化合物或其鹽，其中r6爲可經相同或彼 此不同之以RXB表示之基取代之苯基。 [7] 如[6]所述之化合物或其鹽，其中 A 爲-Ο - ’ D 爲-C ( =0 )-， C) R2 爲-H， R3爲鹵素。 [8 ]如[7 ]所述之化合物或其鹽，其中 R6爲可經相同或彼此不同之以Rxc表示之基取代之 苯基， [9] 如[2]所述之化合物或其鹽，其中γ爲-CH =或-CF=。 [10] 如[9]所述之化合物或其鹽，其中 A 爲-0- ’ D 爲-C ( =0 )- ’ R6爲可經相同或彼此不同之以RXB表示之基取代之 苯基。 [1 1]如[2]所述之化合物或其鹽，其中R1爲-H。 [12]如[11]所述之化合物或其鹽，其中V爲=N-。 本發明中包含之具體化合物之例舉例爲以下之化合物 或其鹽： (3-氯-4-{4-[(3,4-二氯苯甲醯基）胺基]苯氧基}苯基） 乙酸， -19- 200951122 (4-{4-[ ( 1-苯并呋喃-2-基羰基）胺基]苯氧基}-3-氯苯基 )乙酸， [3-氯-4- ( {4-[ ( 3,4-二氯苯甲醯基）胺基]苯基}磺醯基） 苯基]乙酸， (3 -氯-4-{4-[ ( 3,4 -二氫異喹啉-2 ( 1H)-基羰基）胺基] 苯氧基}苯基）乙酸， [4-(4-{[(2£)-3-(3,4-二氯苯基）丙-2-烯醯基]胺基} 苯氧基）-2-甲基-1H-苯并咪唑-1-基]乙酸’R6a is -(Cmalkylalkyl-aryl, R6b is -Η, but when Y is -N=, u is -CH=, Y is -CH= or -CF=, z is =CH-. The compound or a salt thereof, wherein R3 is a halogen, a Cu alkyl group or a _〇_Ci6 alkyl group, and R4 is -H. [4] The compound according to [3] or a salt thereof, Wherein Y is a compound of the formula [4] or a salt thereof, wherein E is a bond. [6] The compound according to [5] or a salt thereof, Wherein r6 is a phenyl group which may be substituted with the same or different substituents represented by RXB. [7] The compound according to [6] or a salt thereof, wherein A is -Ο - 'D is -C (=0) -, C) R2 is -H and R3 is halogen. [8] The compound according to [7] or a salt thereof, wherein R6 is a phenyl group which may be substituted with the same or different substituents represented by Rxc, [9] the compound according to [2] or a salt thereof, Where γ is -CH= or -CF=. [10] The compound according to [9] or a salt thereof, wherein A is -0-'D is -C(=0)-'R6 is a phenyl group which may be substituted by the same or different substituents represented by RXB . [1] The compound according to [2], wherein R1 is -H, or a salt thereof. [12] The compound or a salt thereof according to [11], wherein V is =N-. Examples of the specific compound contained in the present invention are exemplified by the following compounds or salts thereof: (3-chloro-4-{4-[(3,4-dichlorobenzylidene)amino]phenoxy}phenyl Acetic acid, -19- 200951122 (4-{4-[(1-benzofuran-2-ylcarbonyl)amino]phenoxy}-3-chlorophenyl)acetic acid, [3-chloro-4- ( {4-[(3,4-Dichlorobenzhydryl)amino]phenyl}sulfonyl)phenyl]acetic acid, (3-chloro-4-{4-[(3,4-dihydroiso) Quinoline-2(1H)-ylcarbonyl)amino]phenoxy}phenyl)acetic acid, [4-(4-{[(2£)-3-(3,4-dichlorophenyl)propane- 2-ethylindenyl]amino}phenoxy)-2-methyl-1H-benzimidazol-1-yl]acetic acid' [3-氯-4-(4-{[4-(三氟甲基）苯甲醯基]胺基}苯氧基）苯 基]乙酸， (3-氯-4- ( 2-氟-4-[ ( 1H-吲哚-2-基羰基）胺基]苯氧基） 苯基）乙酸， [3-氯-4- ( 4-{[ ( 1-甲基-1H-吲哚-2-基）羰基]胺基}苯氧 基）苯基]乙酸，[3-Chloro-4-(4-{[4-(trifluoromethyl)benzylidenyl]amino}phenoxy)phenyl]acetic acid, (3-chloro-4-(2-fluoro-4) -[(1H-indol-2-ylcarbonyl)amino]phenoxy)phenyl)acetic acid, [3-chloro-4-(4-{[(1-methyl-1H-indole-2-) Carbonyl]amino}phenoxy)phenyl]acetic acid, [3-氯-4- ( 4-{[ ( 6-氟-1H-苯并咪唑-2-基）胺甲醯基]胺基 }苯氧基）苯基]乙酸， {3-氯-4-[ ( 5-{[ ( 5-氟-1H-吲哚-2-基）羰基]胺基}吡啶- 2- 基）氧基]苯基}乙酸’ [3 -溴-4- ( 4-{[4-(三氟甲氧基）苯甲醯基]胺基}苯氧基） 苯基]乙酸，及 {3-氯-4-[ ( 5-{[4·(三氟甲氧基）苯甲醯基]胺基}吡啶-2- 基）氧基]苯基}乙酸。 式（I)之化合物係依據取代基之種類而存在有互變 異構物或幾何異構物。本說明書中’僅敘述式（Ϊ )之化 -20- 200951122 合物之異構物之一種型態，但本發明亦包含該等以外之異 構物、異構物經分離者、或亦包含該等之混合物。 又，式（I)之化合物具有不對稱碳原子時，存在有 基於此之光學異構物。本發明包含式（I)化合物之光學 異構物之經分離者，或者該等之混合物。[3-Chloro-4-(4-{[(6-fluoro-1H-benzimidazol-2-yl)aminecarboxy]amino}phenoxy)phenyl]acetic acid, {3-chloro-4 -[ ( 5-{[(5-fluoro-1H-indol-2-yl)carbonyl]amino}pyridine-2-yl)oxy]phenyl}acetic acid '[3 -bromo-4-(4- {[4-(Trifluoromethoxy)benzylidenyl]amino}phenoxy)phenyl]acetic acid, and {3-chloro-4-[( 5-{[4·(trifluoromethoxy) Benzomethylene]amino}pyridin-2-yl)oxy]phenyl}acetic acid. The compound of the formula (I) is a tautomeric or geometric isomer depending on the kind of the substituent. In the present specification, it is a type of the isomer of the formula -20-200951122, but the present invention also includes the isomers, isomers, or the like. a mixture of these. Further, when the compound of the formula (I) has an asymmetric carbon atom, there is an optical isomer based thereon. The present invention comprises an isolated optical isomer of a compound of formula (I), or a mixture thereof. 另外，本發明亦包含以式（I)表示之化合物之製藥 學上可接受性前驅藥。製藥學上可接受性前驅藥爲具有可 藉由溶劑分解或在生理條件下轉化成胺基、羥基、羧基等 之基之化合物。形成前驅藥之基舉例爲例如Prog. Med., 5, p.2 1 5 7-2 1 6 1 ( 1 9 8 5 )或「醫藥品之開發」（廣川書店 、1990年），第7巻、分子設計163-198中所述之基。 又，式（I)化合物之鹽爲式（I)化合物之製藥學上 可接受性鹽’且依據取代基種類而有形成酸加成鹽或與鹼 之鹽之情況。具體而言’舉例爲與鹽酸、氫溴酸、氫碘酸 、硫酸、硝酸、磷酸等無機酸、或與甲酸、乙酸、丙酸、 ^ 草酸、丙二酸、琥珀酸、富馬酸、馬來酸、乳酸、蘋果酸 、扁桃酸、酒石酸、二苯甲醯基酒石酸、二甲苯醯基酒石 酸、檸檬酸、甲烷磺酸、乙烷磺酸、苯磺酸、對-甲苯磺 酸、天門冬胺酸、榖胺酸等有機酸之加成鹽，與鈉、鉀、 鎂、鈣、鋁等無機鹼，與甲基胺、乙基胺、乙醇胺、離胺 酸、鳥胺酸等有機鹼等之鹽，乙醯基亮胺酸等各種胺基酸 及氨基酸衍生物之鹽或銨鹽等。 再者’本發明亦包含式（I)之化合物及其鹽之各種 水η物或溶劑化物’及結晶多型之物質。又，本發明亦包 -21 - 200951122 含以各種放射線或非放射線同位素標記之化合物。 本說明書中有時使用下列簡寫符號。 AcOEt或EtOAc:乙酸乙酯，brine:飽和食鹽水， BuOH : 丁醇，Cs2C03 :碳酸鉋，CHC13 :氯仿，CuCl2 : 氯化銅，DCM :二氯甲烷，DCC :二環己基碳二醯亞胺， DEAD :偶氮二羧酸乙酯，DMSO :二甲基亞碾，DMF : Ν,Ν-二甲基甲醯胺，DMAP : 4-二甲胺基吡啶，DIPEA : 二異丙基乙胺，DPPA :二苯基磷酸疊氮化物，EtOH :乙 醇，HOBt : N-羥基苯并三唑，IPE :二異丙基醚、K2C03 :碳酸鉀，KOH :氫氧化鉀，mCPBA :間氯過氧苯甲酸、 MeCN :乙腈，MeOH :甲醇，MgS04 :無水硫酸鎂， Na2C〇3:碳酸鈉，NaHC〇3:碳酸氫鈉，NaOH:氫氧化鈉 ，NMM : N-甲基嗎啉，TEA :三乙胺，THF :四氫呋喃， PdCl2(PPh3)2 :二氯雙（三苯基膦）鈀，Pd(PPh3)4 :肆（ 三苯基膦）鈀（〇) ，WSC· HC1: N-乙基-N，-(3-二甲胺 基丙基）-碳二醯亞胺鹽酸鹽，Zn(CN)2 :氰化鋅，ESI-MS :電子噴佈離子化法質量分析，mp:熔點。 (製造法） 式（I)化合物及其鹽可利用基於其基本構造或依據 取代基種類之特徵，使用各種習知之合成方法製造。此時 ’依據官能基之種類，有在自原料至中間物之階段中以適 當保護基（可易於轉化成該官能基之基）取代該官能基之 製造技術上效果之情況。至於該等保護基，可舉例爲例如 -22-Further, the present invention also encompasses a pharmaceutically acceptable prodrug of a compound represented by the formula (I). The pharmaceutically acceptable prodrug is a compound having a group which can be converted into an amine group, a hydroxyl group, a carboxyl group or the like by solvolysis or under physiological conditions. Examples of the base for forming a prodrug are, for example, Prog. Med., 5, p. 2 1 7 7-2 1 6 1 (1 9 8 5 ) or "Development of Pharmaceuticals" (Guangchuan Bookstore, 1990), No. 7 , the basis described in Molecular Designs 163-198. Further, the salt of the compound of the formula (I) is a pharmaceutically acceptable salt of the compound of the formula (I) and may form an acid addition salt or a salt with a base depending on the kind of the substituent. Specifically, 'exemplified by inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, or with formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, horse Acid, lactic acid, malic acid, mandelic acid, tartaric acid, benzoyl tartaric acid, xylyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartame An addition salt of an organic acid such as aminic acid or lysine, and an inorganic base such as sodium, potassium, magnesium, calcium or aluminum, and an organic base such as methylamine, ethylamine, ethanolamine, lysine or ornithine The salt, the salt or ammonium salt of various amino acids and amino acid derivatives such as ethionyl leucine. Further, the present invention also encompasses various water η or solvate' of the compound of the formula (I) and a salt thereof, and a crystalline polymorph. Further, the present invention also encompasses -21 - 200951122 compounds containing various radioactive or non-radiographic isotopes. The following abbreviations are sometimes used in this manual. AcOEt or EtOAc: ethyl acetate, brine: saturated brine, BuOH: butanol, Cs2C03: carbonic acid planer, CHC13: chloroform, CuCl2: copper chloride, DCM: dichloromethane, DCC: dicyclohexylcarbodiimide , DEAD : Ethyl azodicarboxylate, DMSO : dimethyl submilling, DMF : hydrazine, hydrazine-dimethylformamide, DMAP: 4-dimethylaminopyridine, DIPEA: diisopropylethylamine , DPPA: diphenylphosphoric acid azide, EtOH: ethanol, HOBt: N-hydroxybenzotriazole, IPE: diisopropyl ether, K2C03: potassium carbonate, KOH: potassium hydroxide, mCPBA: m-chloroperoxy Benzoic acid, MeCN: acetonitrile, MeOH: methanol, MgS04: anhydrous magnesium sulfate, Na2C〇3: sodium carbonate, NaHC〇3: sodium hydrogencarbonate, NaOH: sodium hydroxide, NMM: N-methylmorpholine, TEA: three Ethylamine, THF: tetrahydrofuran, PdCl2(PPh3)2: dichlorobis(triphenylphosphine)palladium, Pd(PPh3)4: 肆(triphenylphosphine)palladium(〇), WSC· HC1: N-ethyl -N,-(3-dimethylaminopropyl)-carbodiimide hydrochloride, Zn(CN)2: zinc cyanide, ESI-MS: mass spectrometry by electron spray, mp: melting point . (Manufacturing method) The compound of the formula (I) and a salt thereof can be produced by using various conventional synthetic methods based on the basic structure or the characteristics depending on the kind of the substituent. At this time, depending on the kind of the functional group, there is a technically advantageous effect of substituting the functional group with a suitable protecting group (a group which can be easily converted into the functional group) from the stage of the raw material to the intermediate. As for such protecting groups, for example, -22- 200951122 Wuts ( P. G. M. Wuts )及 Greene ( r Greene’s有機合成保護基（第4版 之保護基’只要依據該等反應條件連 法在導入該保護基進行反應後，可任 此獲得所需之化合物。 另外’式（I)化合物之前驅藥 ，可於自原料至中間物之階段中導7 所得之式（I)化合物進行反應製造 般之酯化、醯胺化、脫水等熟悉本g 以下說明式（I )化合物之代表 方法亦可參照該說明書中附加之參考 發明之製造方法並不限於以下所示之 (第一製造方法） 式（I )之化合物可使經保護之 該脫保護可藉由水解、氫解或觸媒之 解時，可使用無機鹼（NaOH、KOH -)。酸水解時，可使用鹽酸。任一反 回流條件下，於不使基質分解之條件 劑可使用醇類（MeOH、EtOH等）、 機溶劑，或水或該等之混合溶劑。氫 媒存在下，於氫氣氛圍氣體中反應。 劑中，可於室溫至回流之反應溫度下 W. Greene )著之「 ，2006年）」中所述 當選擇即可。該等方 據需要去除保護基藉 係與上述保護基同樣 特定之基，或者使用 。反應可經由使用一 藝者習知之方法進行 性製造方法。各製造 文獻進行。另外，本 例。 碳酸脫保護而製造。 脫保護等製造。鹼水 NaHC03、Cs2C03 等 應溫度均可在冰冷至 下進行反應。至於溶 DMF或DMSO等有 解時，通常可在鈀觸 在DMF、MeOH等溶 製造。觸媒脫保護之 -23- 200951122 情況下可使用鈀等觸媒，在鹼性條件下製造。 (原料合成） [化5]200951122 Wuts ( PGM Wuts ) and Greene ( r Greene 's organic synthetic protecting group (protective group of the 4th edition can be obtained by simply introducing the protective group according to the reaction conditions, and then obtaining the desired compound. The compound of the formula (I) is pre-drug-extracted, and the compound of the formula (I) obtained from the stage of the raw material to the intermediate can be subjected to reaction-like esterification, amide amination, dehydration, etc. I) Representative methods of the compounds can also be referred to the manufacturing method of the referenced invention in the specification, and are not limited to the following (first manufacturing method). The compound of the formula (I) can be protected by the deprotection by hydrolysis. For the solution of hydrogenolysis or catalyst, an inorganic base (NaOH, KOH -) can be used. In the case of acid hydrolysis, hydrochloric acid can be used. Under any reflux conditions, an alcohol can be used as a condition agent without decomposing the substrate (MeOH). , EtOH, etc.), organic solvent, or water or a mixture of these solvents. In the presence of a hydrogen medium, it is reacted in a hydrogen atmosphere. In the agent, it can be used at room temperature to reflux reaction temperature (W. Greene) , 2006)" can be selected when you choose. These methods require removal of the protecting group by the same specific base as the above protecting group, or use. The reaction can be carried out by a method which is conventionally known by a person skilled in the art. Each manufacturing document was carried out. In addition, this example. Made by deprotection of carbonic acid. Deprotection and other manufacturing. Alkaline water NaHC03, Cs2C03, etc. should be allowed to react under ice cooling. As for the dissolution of DMF or DMSO, it is usually produced by dissolving palladium in DMF, MeOH or the like. Catalyst deprotection -23- 200951122 In the case of a catalyst such as palladium, it can be produced under alkaline conditions. (Material synthesis) [Chemical 5] R3·R3· [R1 ’、R2’及R3’分別表示對R1、R2及R3分別所具有 之羧基保護之基]。 化合物（2a )可藉由使化合物（1 )之胺基與相對應 之羧酸（R6-E-COOH)反應製造。羧酸（R6-e-cooh)係 (i)直接於同一反應系統內，在縮合劑存在下與化合物 (1 )反應之方法，及（ii )衍生成反應性衍生物後，與 化合物（1)反應之方法（步驟1-1)。 (i )之使羧酸直接於同一系統內反應之方法係使化 合物（1)與對應之羧酸以等量或其一者過量使用，使該 等之混合物在縮合劑存在下，於對反應惰性之溶劑中，自 冷卻至加熱下，較好在-20°C至60°C下攪拌〇.1小時至5 -24- 200951122 天。至於溶劑之例並無特別限制，但可舉例爲芳香族烴類 (苯、甲苯或二甲苯等）、鹵化烴類（DCM、1,2-二氯乙 烷或氯仿等）、醚類（二乙基醚、THF或二噁烷等）、 DMF、DMSO、EtOAc、MeCN或水，以及該等之混合溶劑 。縮合劑之例舉例爲WSC、DCC、DPPA、磷醯氯，但並 •不限於該等。若使用添加劑（例如HOBt等）有時對反應 較佳。在有機驗（例如TEA、DIPEA或NMM等）、或無 ^ 機鹼（例如’ K2C〇3或KOH等）之存在下進行反應，有 於使反應順利進行方面有利之情況。 (i i )之羧酸轉變成反應性衍生物之後，與化合物（ 1)反應獲得化合物（2)之方法，羧酸之反應性衍生物之 例舉例爲與_化劑（例如，磷醯氯、亞硫醯氯等）反應獲 得之酸鹵化物，與氯甲酸異丁酯等反應獲得之混合酸酐， 與HOBt等縮合獲得之活性酯等。化合物（1 )與反應性 衍生物之反應可在鹵化烴類、芳香族烴類、醚類等之對反 ^ 應惰性之溶劑中’自冷卻至加熱下，較好在-20°C至60°C 下進行。而且，反應時於鹼（例如，NMM、TEA、DIPEA 、DMAP、吡啶、甲基吡啶、二甲基吡啶等）之存在下反 應有使反應順利進行方面有利之情況。另外，吡啶亦可兼 用作溶劑。 [文獻]S.R，Sandler及W. Karo著「有機官能基製備 」，第2版，第1卷，學院出版公司，i 99 1年 曰本化學會編「實驗化學講座（第5版）」16卷（ 2005年）（九善） -25- 200951122 化合物（2b )可援用步驟1 - 1之條件製造。亦即，可 經由使用磺酸之游離酸或其反應性衍生物代替使用試藥之 羧酸游離酸或其反應性衍生物，藉此製造化合物（2b)( 步驟1-2 )。[R1', R2' and R3' respectively represent a group which protects the carboxyl group which each of R1, R2 and R3 has. The compound (2a) can be produced by reacting an amine group of the compound (1) with a corresponding carboxylic acid (R6-E-COOH). The carboxylic acid (R6-e-cooh) is a method in which (i) is directly reacted with the compound (1) in the presence of a condensing agent, and (ii) is derivatized into a reactive derivative, and the compound (1) The method of reaction (step 1-1). (i) a method of reacting a carboxylic acid directly in the same system by using compound (1) in an equivalent amount or in an excess amount with the corresponding carboxylic acid, such that the mixture is reacted in the presence of a condensing agent. In an inert solvent, it is preferably stirred at -20 ° C to 60 ° C for 1 hour to 5 - 24 to 2009 51122 days from cooling to heating. The solvent is not particularly limited, but examples thereof include aromatic hydrocarbons (benzene, toluene or xylene), halogenated hydrocarbons (DCM, 1,2-dichloroethane or chloroform, etc.) and ethers (two). Ethyl ether, THF or dioxane, etc.), DMF, DMSO, EtOAc, MeCN or water, and a mixed solvent of these. Examples of the condensing agent are WSC, DCC, DPPA, and phosphonium chloride, but are not limited to these. If an additive (e.g., HOBt, etc.) is used, the reaction is sometimes preferred. The reaction is carried out in the presence of an organic test (e.g., TEA, DIPEA or NMM, etc.) or a non-organic base (e.g., 'K2C〇3 or KOH, etc.), which is advantageous in that the reaction proceeds smoothly. After the carboxylic acid of (ii) is converted into a reactive derivative, the compound (2) is obtained by reacting with the compound (1), and examples of the reactive derivative of the carboxylic acid are exemplified by a phosphating agent (for example, phosphonium chloride, The acid halide obtained by the reaction of sulfoxide, etc., the mixed acid anhydride obtained by the reaction with isobutyl chloroformate or the like, the active ester obtained by condensation with HOBt or the like, and the like. The reaction of the compound (1) with the reactive derivative can be carried out by self-cooling to heating in a solvent inert to a halogenated hydrocarbon, an aromatic hydrocarbon or an ether, preferably at -20 ° C to 60 ° C. Perform at °C. Further, the reaction in the presence of a base (e.g., NMM, TEA, DIPEA, DMAP, pyridine, picoline, lutidine, etc.) is advantageous in that the reaction proceeds smoothly. Further, pyridine can also be used as a solvent. [Documents] SR, Sandler and W. Karo, "Organic Functional Group Preparation", 2nd Edition, Volume 1, College Publishing Company, i 99 1 year, Sakamoto Chemical Society, "Experimental Chemistry Lecture (5th Edition)" 16 Volume (2005) (Jiushan) -25- 200951122 Compound (2b) can be produced by using the conditions of Step 1-1. Namely, the compound (2b) (Step 1-2) can be produced by using a free acid of a sulfonic acid or a reactive derivative thereof instead of using a carboxylic acid free acid or a reactive derivative thereof. 化合物（2c)可使化合物（1)與三碳醯氯等與HN( R6a) ( R6b )反應而製造。反應通常係在鹼（例如，NMM 、TEA、DIPEA、DMAP、吡啶、甲基吡啶、二甲基吡啶 等）之存在下進行。溶劑係使用鹵化烴類、芳香族烴類、 醚類、酯類、MeCN、DMF或DMSO等之對反應惰性之有 機溶劑，或該等之混合溶劑。另外，反應係在冷卻下、冷 卻至室溫下，或室溫至加熱下進行。 [化6]The compound (2c) can be produced by reacting the compound (1) with trimethyl chlorochloride or the like with HN(R6a)(R6b). The reaction is usually carried out in the presence of a base (e.g., NMM, TEA, DIPEA, DMAP, pyridine, picoline, lutidine, etc.). The solvent is an organic solvent inert to the reaction such as a halogenated hydrocarbon, an aromatic hydrocarbon, an ether, an ester, MeCN, DMF or DMSO, or a mixed solvent thereof. Further, the reaction is carried out under cooling, cooling to room temperature, or room temperature to heating. [Chemical 6] (1) [式中，X意指鹵素等離去基]。 化合物（5 )可藉由使烷醇或硫醇之化合物（3 )與化 合物（4)偶合而製造（步驟2-1)。作爲鹼係使用無機 鹼（例如 NaOH、KOH、NaHC03、Cs2C03 等），反應溶 -26- 200951122 劑係使用鹵化烴類、芳香族烴類、醚類、EtOAc等酯類、 MeCN、DMF或DMSO等之對反應惰性之有機溶劑，或該 等之混合溶劑。另外，反應係在室溫至加熱下進行。 化合物（1)可由將化合物（4)之硝基還原而製造（ 步驟2-2)。反應可使用芳香族硝基之還原方法，且通常 在鹽酸條件下使鐵粉反應，或者可藉由接觸還原等製造。(1) [wherein, X means a halogen isobaric group]. The compound (5) can be produced by coupling an alkyl alcohol or a compound (3) of a mercaptan with the compound (4) (step 2-1). An inorganic base (for example, NaOH, KOH, NaHC03, Cs2C03, etc.) is used as the base, and a halogenated hydrocarbon, an aromatic hydrocarbon, an ether, an ester such as EtOAc, MeCN, DMF or DMSO is used as the reaction solution -26-200951122. An organic solvent inert to the reaction, or a mixed solvent thereof. Further, the reaction is carried out at room temperature to under heating. Compound (1) can be produced by reducing the nitro group of Compound (4) (Step 2-2). The reaction can be carried out by a method of reducing an aromatic nitro group, and the iron powder is usually reacted under a hydrochloric acid condition, or can be produced by contact reduction or the like. 另外，在製造上述之製造法及中間物製造法中所述以 外之實施例化合物及中間物時，可採用本說明書之製造例 或者實施例中所述之方法，或者以該等爲準之方法，而且 ，可藉由已知方法、熟悉本技藝者本身已瞭解之方法製造 再者，以式（I)表示之若干化合物可由如上述般製 造之本發明化合物，藉由任意組合習知之烷化、醯化、取 代反應、氧化、還原、水解、脫保護等熟悉本技藝者慣用 之步驟而製造。 式（I )之化合物係經單離、純化成游離化合物、其 鹽、水合物、溶劑化物、或結晶多型物質。式（I )化合 物之鹽可藉由施加慣用方法之造鹽反應而製造。 單離、純化係使用萃取、分段結晶、各種區分層析法 等慣用之化學操作進行。 各種異構物可藉由選擇適當之原料製造，或者可利用 異構物間之物理化學性質之差異分離。例如，光學異構物 係藉由消旋體之一般光學解析法（例如，藉由與光學活性 鹼或酸之非對映異構物鹽導致之分段結晶或使用對掌性管 -27- 200951122 柱等之層析儀）獲得，又，亦可自適當之光學活性原料製 造。 式（I)化合物之藥理活性係以下列之試驗確認。 試驗例1-1 :膜標本之調製Further, in the case of producing the compound of the example and the intermediates other than those described in the above-mentioned production method and intermediate production method, the method described in the production example or the examples of the present specification, or the method based on the above, may be employed. Further, it can be produced by a known method, a method known to those skilled in the art, and a plurality of compounds represented by the formula (I) can be obtained by the above-described compound of the present invention, by any combination of conventional alkylation. , deuteration, substitution reaction, oxidation, reduction, hydrolysis, deprotection, and the like, which are familiar to those skilled in the art. The compound of the formula (I) is isolated, purified to a free compound, a salt, a hydrate, a solvate or a crystalline polymorph. The salt of the compound of the formula (I) can be produced by applying a salt-forming reaction by a conventional method. The separation and purification are carried out by conventional chemical operations such as extraction, fractional crystallization, and various differential chromatography. The various isomers may be produced by selecting an appropriate starting material or may be separated by the difference in physicochemical properties between the isomers. For example, optical isomers are by general optical resolution of the racemate (for example, by fractional crystallization with a diastereomeric salt of an optically active base or acid or using a pair of palms-27- 200951122 Columns and other chromatographs are obtained, and can also be made from suitable optically active materials. The pharmacological activity of the compound of formula (I) is confirmed by the following tests. Test Example 1-1: Modulation of membrane specimens 對人類CRTH2 cDNA持續表現之HEK29 3細胞，在緩 衝液（10mM BES(N，N-雙（2-羥基乙基）-2-胺基-乙烷-擴酸）、1 mM EDTA、1 OmM MnCl2，ρΗ = 7·0，以下稱爲 分析緩衝液）中，於26G注射針筒內快速通過並使其破 碎所調製之含細胞膜脂懸浮液作爲模標本，保存於-80°C 。之後，於使用時融解進行試驗。 試驗例1-2 : CRTH2結合試驗HEK29 3 cells that continue to be expressed in human CRTH2 cDNA in buffer (10 mM BES (N,N-bis(2-hydroxyethyl)-2-amino-ethane-propionic acid), 1 mM EDTA, 1 OmM MnCl2 , ρΗ = 7·0, hereinafter referred to as the analysis buffer), the cell membrane lipid suspension prepared by rapidly passing through the 26G syringe and being disrupted was used as a model specimen and stored at -80 °C. After that, the test was carried out by melting at the time of use. Test Example 1-2: CRTH2 binding test 將膜標本（每一分析使用以蛋白量計爲50微克）、 受檢化合物及以氚標記之PGD2 (最終濃度：2nM)於0.2 毫升分析緩衝液中在4°C培育2小時後，將反應液吸引過 濾至GF/B板（Perkin E丨mer )之濾紙上，以洗淨用緩衝 液（l〇mM BES、0.01% BSA )洗淨三次後，以 TopCount (Perkin Elmer )測定吸附在濾紙上之放射活性。又， CRTH2特異結合係以添加1〇μΜ之DK-PGD2時所被抑制 之放射活性部分加以求得。 其結果，例如本發明化合物之以下實施例化合物（Ex )顯示分別如下之活性値（IC5〇値）。Exl : 9. InM ; Ex6 :1 InM ； Exl B ·· 14nM ； Ex3 0 ： 2.9nM ； Ex34 : 1 OnM ； -28- 200951122 Εχ3 5 ： 5.6ηΜ ； Εχ3 7 ： 4.8ηΜ ； Εχ43 ： 9.9ηΜ ； Εχ55 ： 4.1 ηΜ ； Εχ56 ： 8.7ηΜ ； Εχ94 : 4.8ηΜ ； Εχΐ 09 ： 4.9ηΜ ； Εχ140 ： 0.53ηΜ ； Ex 15 1 ： Ι.ΟηΜ; Εχ152 ： 20ηΜ° 試驗例2:天竺鼠抗原誘發呼吸道反應性亢進模型The membrane samples (50 micrograms in protein per assay), the test compound and PGD2 labeled with hydrazine (final concentration: 2 nM) were incubated in 0.2 ml of assay buffer for 2 hours at 4 ° C. The solution was suction-filtered onto a filter paper of GF/B plate (Perkin E丨mer), washed three times with a washing buffer (10 mM BES, 0.01% BSA), and adsorbed on a filter paper by TopCount (Perkin Elmer). Radioactivity. Further, the CRTH2-specific binding system was obtained by adding a radioactive portion which was inhibited when 1 〇μΜ of DK-PGD2 was added. As a result, for example, the following example compound (Ex) of the compound of the present invention shows the following active oxime (IC5〇値). Exl : 9. InM ; Ex6 : 1 InM ; Exl B · · 14nM ; Ex3 0 : 2.9nM ; Ex34 : 1 OnM ; -28- 200951122 Εχ 3 5 : 5.6ηΜ ; Εχ 3 7 : 4.8ηΜ ; Εχ 43 : 9.9ηΜ ; Εχ 55 : 4.1 ηΜ ; Εχ 56 : 8.7ηΜ ; Εχ 94 : 4.8ηΜ ; Εχΐ 09 : 4.9ηΜ ; Εχ 140 : 0.53ηΜ ; Ex 15 1 : Ι.ΟηΜ; Εχ 152 : 20ηΜ° Test Example 2: guinea pig antigen-induced respiratory hyperactivity model 本發明化合物之抗氣喘作用除對Burgess等人之方法 (Agent Actions, 1 992 年，37 ( 3-4)卷，第 1 62- 1 64 頁 )些許變更以外藉由天竺鼠抗原誘發呼吸道反應性亢進模 型加以評價。 亦即，對雄性Hartley系天竺鼠經腹腔投與1毫升之 20毫克/毫升之蛋白蛋白（以下稱爲OVA)生理食鹽水（ 初次敏化，作爲第0天），進而於第2天經腹腔投與1毫 升之1毫克/毫升之OVA生理食鹽水，藉此進行動態抗原 敏化。自第14天至第21天使用超音波氣霧發生器（ OMRON公司），對動物每日一次每次10分中吸入暴露至 0.5°/。OVA生理食鹽水（生理食鹽水對照組則吸入暴露至 生理食鹽水）。於抗原吸入暴露開始1小時前或4小時前 經口投與受檢化合物。又，爲防止過敏反應，於吸入暴露 開始之3 0分鐘前，以1 〇毫克/公斤經腹腔投與吡拉明（ pyrilamine ) 〇 於第22天’以胺基甲酸酯（1.5克/公斤腹腔投與） 麻醉下’對動物氣管插入接續於人工呼吸器（型號683， Harvard公司）之導管，以加拉明（gaUamine ) ( 6毫克/ 公斤’腹腔內投與）使自發呼吸停止，在機械換氣（換氣 -29- 200951122 速度：每分鐘60下’換氣量：體重每1〇〇克1毫升）以 3分鐘間隔依序靜脈內投與乙醯甲膽鹼（methach〇Hne ) (0、2、4、6、8、10、12、14微克/公斤）。藉由壓力傳 導器測定呼吸道內壓之上升，算出對乙酿甲膽驗投與量與 呼吸道內壓上升作圖時之濃度曲線下面積（AUC )。 其結果’判定本發明化合物中，例如以下表示之實施 例化合物顯示有效活性。The anti-asthmatic effects of the compounds of the present invention are induced by guinea pig antigens in addition to a slight change in the method of Burgess et al. (Agent Actions, 1973, 37 (3-4), pp. 1 62- 1 64). The model is evaluated. That is, male Hartley guinea pigs were intraperitoneally administered with 1 ml of 20 mg/ml protein protein (hereinafter referred to as OVA) physiological saline (primary sensitization as day 0), and then intraperitoneally on day 2 Dynamic antigen sensitization was carried out with 1 ml of 1 mg/ml of OVA physiological saline. From the 14th day to the 21st day, the animal was exposed to 0.5°/ inhalation by using an ultrasonic aerosol generator (OMRON) once a day for 10 minutes. OVA physiological saline (physiological saline control group was inhaled and exposed to physiological saline). The test compound was orally administered 1 hour before or 4 hours before the start of antigen inhalation exposure. Also, in order to prevent allergic reactions, the pyrilamine was administered intraperitoneally at 1 mg/kg before the inhalation exposure, and on the 22nd day, the urethane (1.5 g/kg) was used. Intraperitoneal administration] Under anesthesia, the trachea was inserted into a catheter connected to a respirator (model 683, Harvard), and spontaneous breathing was stopped with gaUamine (6 mg/kg 'intraperitoneal administration). Mechanical ventilation (ventilation -29- 200951122 speed: 60 times per minute 'ventilation volume: 1 ml per 1 gram of body weight) intravenously administered with methotrexate (methach〇Hne) at 3 minute intervals (0, 2, 4, 6, 8, 10, 12, 14 μg/kg). The pressure channel was used to measure the increase in the pressure in the airway, and the area under the concentration curve (AUC) when the test dose and the increase in the intraventricular pressure were plotted. As a result, it was judged that, for example, the compound of the example shown below showed an effective activity in the compound of the present invention. Ex 抑制率 Ex 抑制率 1 66% (3毫克/公斤） (1小時前投與） 43 100% (3毫克/公斤） (4小時前投與） 6 61% (3毫克/公斤） (4小時前投與） 5 6 90% (1毫克/公斤） (4小時前投與） 18 46% (1毫克/公斤） (4小時前投與） 152 70% (3毫克/公斤） (4小時前投與） 34 76% (3 mg/kg) U小時前投與）Ex inhibition rate Ex inhibition rate 1 66% (3 mg/kg) (administered 1 hour ago) 43 100% (3 mg/kg) (administered 4 hours ago) 6 61% (3 mg/kg) (4 hours) Pre-administered) 5 6 90% (1 mg/kg) (administered 4 hours ago) 18 46% (1 mg/kg) (administered 4 hours ago) 152 70% (3 mg/kg) (4 hours ago To be administered) 34 76% (3 mg/kg) U hour before the administration) 上述實驗結果，確認式（I )化合物對CRTH2具有拮 抗活性。因此，可使用於炎症性疾病（例如，氣喘、過敏 性鼻炎、過敏性皮膚炎、結膜炎、蓴麻疹、嗜酸血球性支 氣管炎 '食物過敏、副鼻腔炎、血管炎、慢性阻塞性肺疾 病等）或多發性硬化症等之治療。 又’本案中，例如實施例化合物之羧酸成爲酯之製造 力化合物並未顯示活性。可定本發明中實施例化合物之羧 -30- 200951122 酸之酸性質子對於CRTH2展現拮抗活性具重要性。 含有式（I)化合物或其鹽之一種或兩種以上作爲有 效成分之醫藥組成物可使用該領域通常使用之賦形劑亦即 藥劑用賦形劑或藥劑溶介質等，藉由通常使用之方法加以 調製。 投與可藉錠劑、九劑、膠囊、顆粒劑、散劑、液劑等As a result of the above experiment, it was confirmed that the compound of the formula (I) has an antagonistic activity against CRTH2. Therefore, it can be used for inflammatory diseases (for example, asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, urticaria, eosinophilic bronchitis) food allergy, paranasal sinusitis, vasculitis, chronic obstructive pulmonary disease, etc. ) or treatment of multiple sclerosis. Further, in the present invention, for example, a compound having a carboxylic acid as an ester of the compound of the example does not exhibit activity. The carboxylic acid proton of the compound of the present invention can be determined to exhibit an antagonistic activity for CRTH2. The pharmaceutical composition containing one or two or more compounds of the compound of the formula (I) or a salt thereof as an active ingredient can be used by using an excipient which is usually used in the field, that is, a pharmaceutical excipient or a drug solution medium, etc., by usual use. The method is modulated. Injectable tablets, nine doses, capsules, granules, powders, liquids, etc. 經口投與，或亦可藉關節內、靜脈內、肌肉內等之注射劑 、栓劑、點眼劑、眼軟膏、經皮用液劑、軟膏劑、經皮用 貼附劑、經黏膜液劑、經黏膜貼附劑、吸入劑等之非經口 投與之任一種形態。 至於用於經口投與之固體組成物係使用錠劑、散劑、 顆粒劑等。於該等固體組成物，係使1種或2種以上之有 效成分與至少一種惰性賦形劑例如乳糖、甘露糖、葡萄糖 、羥丙基纖維素、微晶纖維素、澱粉、聚乙烯吡咯啶酮及 /或偏矽酸鋁酸鎂等混合而成。組成物亦可依據一般方法 ^ 含有惰性添加劑如如硬脂酸鎂之潤滑劑或如羧甲基澱粉鈉 等之崩解劑、安定化劑、溶解助劑。錠劑或九劑可依據需 要以糖衣或胃溶性或腸溶性物質之膜加以被膜。 用以經口投與之液體組成物包含藥劑上可容許之乳濁 劑、溶液劑、懸浮劑、糖漿劑或酊劑，可含有一般使用之 惰性稀釋劑例如純化水或乙醇。該液體組成物除惰性稀釋 齊！I以外’亦可含有如可溶化劑、濕潤劑、懸浮劑之輔助劑 、甜味劑、矯味劑、芳香劑、防腐劑。 用於非經口投與之注射劑含有無菌水性或非水性溶液 -31 - 200951122Oral administration, or intra-articular, intravenous, intramuscular, etc. injections, suppositories, eye drops, eye ointments, transdermal solutions, ointments, transdermal patches, transmucosal agents Any form of non-oral administration of mucosal patch, inhalant, etc. As for the solid composition for oral administration, a tablet, a powder, a granule, or the like is used. In the solid composition, one or more active ingredients are combined with at least one inert excipient such as lactose, mannose, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidine. A mixture of a ketone and/or magnesium metasilicate aluminate. The composition may also contain an inert additive such as a lubricant such as magnesium stearate or a disintegrant such as sodium carboxymethyl starch, a stabilizer, and a dissolution aid according to a general method. The lozenge or the nine doses may be coated with a film of a sugar-coated or stomach-soluble or enteric material as needed. The liquid composition for oral administration contains a pharmaceutically acceptable emulsion, solution, suspension, syrup or elixir, and may contain an inert diluent such as purified water or ethanol which is generally used. The liquid composition is diluted in inertia! Other than I may also contain adjuvants such as solubilizing agents, wetting agents, suspending agents, sweeteners, flavoring agents, flavoring agents, and preservatives. Injection for parenteral administration containing sterile aqueous or non-aqueous solution -31 - 200951122 劑、懸浮劑或乳濁劑。至於水性溶劑，包含例如注射用蒸 餾水或生理食鹽水。至於非水性溶劑，有例如丙二醇、聚 乙二醇或如橄欖油之植物油、如乙醇之醇類、或聚山梨糖 醇酯80 (藥典名）等。此種組成物亦可進而含有等張化 劑、防腐劑、濕潤劑、乳化劑、分散劑、安定化劑或溶解 助劑。該等可例如通過保留細菌之過濾膜加以過濾、配合 殺菌劑或藉由照射加以無菌化。又，亦可製造該等無菌固 體組成物，於使用前溶解或懸濁於無菌水或無菌注射用溶 劑中後加以使用。A suspending agent or an opacifying agent. As the aqueous solvent, for example, distilled water for injection or physiological saline is contained. As the nonaqueous solvent, there may be mentioned, for example, propylene glycol, polyethylene glycol or a vegetable oil such as olive oil, an alcohol such as ethanol, or a polysorbate 80 (Pharmacopoeia). Such a composition may further contain an isotonic agent, a preservative, a wetting agent, an emulsifier, a dispersing agent, a stabilizer, or a dissolution aid. These may be sterilized, for example, by filtration through a filter membrane that retains bacteria, in combination with a bactericide, or by irradiation. Further, the aseptic solid composition may be produced and dissolved or suspended in sterile water or a sterile injectable solvent before use. 作爲外用劑，包含軟膏劑、硬膏劑、乳霜劑、凍膏劑 、外敷軟膏劑、噴霧劑、洗劑、點眼劑、眼軟膏等。含有 一般使用之軟膏基劑、洗劑基劑、水性或非水性液劑、懸 濁劑、乳劑等。例如作爲軟膏或洗劑基劑，舉例有聚乙二 醇、丙二醇、白色凡士林、白色蜜蠟、聚氧乙烯硬化篦麻 油、單硬脂酸甘油酯、硬脂醇、鯨蠟醇、月桂聚乙二醇（ Lauromacrogol)、倍半油酸山梨糖醇酐酯等。 吸收劑或經鼻劑等之經黏膜劑係使用液體或半固體狀 者，可依據以往已知方法製造。例如可適當添加習知賦形 劑或進而添加pH調節劑、防腐劑、界面活性劑、潤滑劑 、安定劑或增黏劑等。投與可使用用以適當吸入或吹送之 裝置。例如使用計量投與吸入裝置等之習知裝置或噴霧器 ’化合物作以單獨或經處方之混合物之粉末或與醫藥容許 之擔體組合而成之溶液或懸濁液予以投與。乾燥粉末吸入 器等’亦可爲單次或多次投予用者，可利用乾燥粉末或含 -32- 200951122 有粉末之膠囊。或者，亦可爲使用適當推進劑例如氯氟烷 、氫氟院或一氧化碳等之適當氣體之加壓氣溶膠噴霧器等 之形態。As the external preparation, an ointment, a plaster, a cream, a cream, an external ointment, a spray, a lotion, an eye drop, an eye ointment and the like are contained. It contains an ointment base, a lotion base, an aqueous or non-aqueous liquid agent, a suspending agent, an emulsion, and the like which are generally used. For example, as an ointment or lotion base, polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hardened castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, and laurel A diol (lauromacrogol), sorbitan oleate, and the like. The transmucosal agent such as an absorbent or a nasal spray can be produced by a conventionally known method using a liquid or semi-solid. For example, a conventional excipient or a pH adjusting agent, a preservative, a surfactant, a lubricant, a stabilizer or a tackifier may be added as appropriate. The device can be used for proper inhalation or insufflation. For example, a conventional device such as a metered administration inhalation device or a nebulizer&apos; compound is administered as a solution or a suspension of a powder of a mixture, either alone or in a prescribed mixture, or a combination with a pharmaceutically acceptable carrier. The dry powder inhaler or the like can also be used for single or multiple administrations, and can be used as a dry powder or a capsule containing -32-200951122 powder. Alternatively, it may be in the form of a pressurized aerosol sprayer or the like using a suitable propellant such as a chlorofluorocarbon, a hydrofluorocarbon or a carbon monoxide. 通常經口投與時，每日投與量’適宜爲每體重約爲 0.001至100晕克/公斤’較好爲0」至30毫克/公斤，更 好爲〇_1至10晕克/公斤’其可每日投與一次或分2至4 次投與。靜脈內投與時’每日投與量’適宜爲每體重約爲 0.0001至10鼋克/公斤，每日投與—次或分數次投與。又 ，作爲經黏膜劑’適宜爲每體重約爲〇,001至10〇毫克/ 公斤’每日投與一次或分數次投與。投與量係依據症狀、 年齡、性別等加以考慮而對應個別情況適當決定。 式（I)化合物可倂用對於認爲上述式（I)化合物顯 示爲有效之疾病之各種治療劑或預防劑。該倂用可同時投 與或個別連續投與或亦可間隔所需時間間隔投與。同時投 與製劑可爲配合劑亦可經各別製劑化。 [實施例] 以下’依據實施例更詳細說明式（I )化合物之製造 方法。又，本發明不限定於下列實施例中所述化合物。又 ，製造例中分別顯示原料化合物之製造方法。又，式（1 )化合物之製造方法並不僅限於以下所示之具體實施例之 製造方法，式（I)化合物亦可藉由該等製造方法之組合 ，或以熟悉本技藝者本身已知之方法製造。 又，實施例、製造例及後續表中係使用下列簡寫。Pr -33- 200951122 :製造例編號’ Ex:實施例編號，structure:構造式， Data :物理化學數據，NMR : W-NMR ( d6-DMSO )， NMR ( CDC13 ) : W-NMR ( CDC13 ) ，ESI : ESI-MS。 製造例1 於含3-氯-4-羥基苯基乙酸乙酯（5.66克）之DMF(Usually, when administered orally, the daily dose is suitably 0.001 to 100 gram/kg per body weight, preferably 0 to 30 mg/kg, more preferably 〇_1 to 10 gram/kg. 'It can be administered once or twice or four times a day. When administered intravenously, the 'daily dose' is suitably about 0.0001 to 10 g/kg per body weight, and is administered daily or in divided doses. Further, as a transmucosal agent, it is suitable to be administered once or several times per day for a body weight of about 〇, 001 to 10 mg/kg. The amount of administration is determined based on symptoms, age, gender, etc., and is determined appropriately for individual cases. The compound of the formula (I) can be administered with various therapeutic or prophylactic agents for diseases which are considered to be effective for the compound of the above formula (I). The application may be administered simultaneously or individually or may be administered at intervals required. At the same time, the preparation can be formulated as a compounding agent or can be separately formulated. [Examples] Hereinafter, the production method of the compound of the formula (I) will be explained in more detail based on the examples. Further, the present invention is not limited to the compounds described in the following examples. Further, in the production examples, the production methods of the raw material compounds are respectively shown. Further, the method for producing the compound of the formula (1) is not limited to the production method of the specific examples shown below, and the compound of the formula (I) may be a combination of the production methods or a method known per se to those skilled in the art. Manufacturing. Further, the following abbreviations are used in the examples, the manufacturing examples, and the subsequent tables. Pr -33- 200951122 : Manufacturing Example No. 'Ex: Example No., structure: Structural Formula, Data: Physical Chemistry Data, NMR: W-NMR (d6-DMSO), NMR (CDC13): W-NMR (CDC13), ESI: ESI-MS. Production Example 1 DMF containing ethyl 3-chloro-4-hydroxyphenylacetate (5.66 g) ( 1 〇〇毫升）溶液中添加K2CO3 ( 4.74克.）及二甲基硫代胺 基甲醯氯（3.75克），在50 °C下攪拌5小時。將反應混 合物注入水（500毫升）中，以EtOAc ( 3 00毫升）萃取 。有機層以水（200毫升）、飽和食鹽水（200毫升）洗 淨後，以MgS04乾燥後，濾液經減壓濃縮，藉此獲得3-氯-4-(二甲基胺基碳亞硫醯氧基）苯基乙酸乙酯（7.69 克）之橙色油。 製造例2K 2 CO 3 ( 4.74 g.) and dimethyl thiocarbamidine chloride (3.75 g) were added to the solution, and the mixture was stirred at 50 ° C for 5 hours. The reaction mixture was poured into EtOAc (3 mL). The organic layer was washed with water (200 ml) and saturated brine (200 ml), and dried over Mg.sub.4. Ethyl phenyl phenylacetate (7.69 g) in orange oil. Manufacturing Example 2 使3-氯-4-(二甲基胺基碳亞硫醯氧基）苯基乙酸乙 酯（7.6克）在外溫24 0°C下攪拌3小時。反應物以矽膠 管柱層析儀（正己烷/EtO Ac )純化，獲得（3-氯-4-(( 二甲基胺基甲醯基）磺胺醯基）苯基）乙酸乙酯（1.65克 )之橙色油。 製造例3 使（3-氯-4-((二甲基胺基甲醯基）磺胺醯基）苯 基）乙酸乙酯（1.64克）溶於MeOH(16.4毫升）中，添 -34- 200951122 加KOH (1.52克）之水（8.2毫升）溶液，在50°C下攪拌 2小時。減壓濃縮反應混合物，使殘留物溶解於水（1 0毫 升）中，在室溫攪拌下滴加1M鹽酸（40毫升）。經攪拌 3 0分鐘以上後，過濾收集析出物。乾燥過濾物，獲得（ ' 3-氯-4-磺胺醯基苯基）乙酸（0.93克）之淡黃色粉末。 如實施例1般，使用對應之原料製造下表所示之製造 例3-1至3-2之化合物。 〇 製造例4 於含{4-(4-胺基苯氧基）-3-氯苯基}乙酸乙酯（1.50 克）之DCM ( 30毫升）溶液中添加3,4-二氯苯甲酸（ 1.12 克）、WSC.HC1(1.13 克）、HOBt(795 毫克）， 且在室溫下攪拌6小時。將反應溶液注入水（150毫升） 中後，以EtOAc (300毫升）萃取。有機層以水（150毫 升）、飽和食鹽水洗淨後，以MgS04乾燥後，減壓濃縮 ^ 濾液。殘留物使用矽膠管柱層析純化，獲得3-氯-4-{4-( 3，4-二氯苯甲醯基胺基）苯氧基}苯基乙酸乙酯（1.90克 )之淡黃色固體。 如製造例4般，使用對應之原料製造下表所示之製造 •例4 -1至4 -1 3 6之化合物。 製造例5 於含{4- (6-胺基吡啶-3-基氧基）-3-氯苯基}乙酸乙 酯（150毫克）之DCM(3毫升）溶液中添加3,4 -二氯苯 -35- 200951122 甲醯氯（108 毫克）、ΤΕΑ(82Α) 、DMAP(12 毫克） ，且在室溫下攪拌隔夜。將反應混合物注入水中’以 EtOAc萃取。有機層依序以飽和NaHC03水溶液、水、飽 和食鹽水洗淨後’經MgS〇4乾燥後’減壓濃縮濾：液。使 所得殘留物經砂膠管柱層析（正己院·· E0Ac = 3: 〇純化 ，獲得[3-氯-4-( {6-[( 3，4-二氯苯甲醯基）胺基]吡啶-3-基}氧基）苯基]乙酸乙酯（209.5毫克）之無色膠狀物。3-Chloro-4-(dimethylaminocarbazosulfinyloxy)phenylacetate (7.6 g) was stirred at an external temperature of 24 ° C for 3 hours. The reaction was purified by a silica gel column chromatography (hexane/EtOAc) to afford (3-chloro-4-((dimethylaminocarbazinyl)sulfonyl)phenyl) ethyl acetate (1.65 g) ) orange oil. Preparation Example 3 Ethyl (3-chloro-4-((dimethylaminocarbamimidino)sulfonyl)phenyl)acetate (1.64 g) was dissolved in MeOH (16.4 ml), and then -34-200951122 A solution of KOH (1.52 g) in water (8.2 ml) was added and stirred at 50 ° C for 2 hours. The reaction mixture was concentrated under reduced vacuol. After stirring for 30 minutes or more, the precipitate was collected by filtration. The filtrate was dried to give (3-chloro-4-sulfonamidophenyl)acetic acid (0.93 g) as a pale yellow powder. As in Example 1, the compounds of Production Examples 3-1 to 3-2 shown in the following Table were produced using the corresponding raw materials. 〇Production Example 4 To a solution of ethyl 4-(4-aminophenoxy)-3-chlorophenyl}acetate (1.50 g) in DCM (30 mL) 1.12 g), WSC.HC1 (1.13 g), HOBt (795 mg), and stirred at room temperature for 6 hours. The reaction solution was poured into water (150 ml) The organic layer was washed with water (150 ml) and brine, dried over MgSO 4 and evaporated. The residue was purified using EtOAc EtOAc EtOAc EtOAc (EtOAc) solid. As in Production Example 4, the compounds of Examples 4 -1 to 4 -1 3 6 were produced using the corresponding raw materials. Preparation Example 5 Addition of 3,4-dichlorobenzene to a solution of ethyl 4-(6-aminopyridin-3-yloxy)-3-chlorophenyl}acetate (150 mg) in DCM (3 mL) Benzene-35- 200951122 formazan chloride (108 mg), hydrazine (82 Α), DMAP (12 mg), and stirred at room temperature overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed successively with a saturated aqueous solution of NaHCO.sub.3, water and saturated brine. The obtained residue was subjected to silica gel column chromatography (Zhenghexi·E0Ac = 3: hydrazine to obtain [3-chloro-4-({6-[(3,4-dichlorobenzhydryl)amino]] Pyridine-3-yl}oxy)phenyl]acetate (209.5 mg) as a colorless gum. 製造例6Manufacturing Example 6 在冰冷卻下，於含[4- ( 4-胺基苯氧基）-3-氯苯基]乙 酸乙酯（3 00毫克）之THF ( 6毫升）溶液中添加TEA ( 410微升）及三碳醯氯（146毫克）且攪拌1小時後，添 加1，2,3,4-四氫異喹啉（137微升），在室溫下攪拌隔夜 。以EtOAc稀釋反應溶液後，依序以1M鹽酸、飽和食鹽 水洗淨，以MgS04乾燥後，減壓濃縮濾液。使所得殘留 物經矽膠管柱層析純化，獲得（3-氯-4-{4-[ ( 3,4-二氫異 喹啉-2 (1H)-基羰基）胺基]苯氧基}苯基）乙酸乙酯（ 243毫克）之淡褐色無定型物。 如製造例6般，使用對應之原料製造下表所示之製造 例6 -1至6 - 8之化合物。 製造例7 在冰冷卻下，於含[3-氯-4-(4-{(4-硝基苯氧基羰基 )胺基}苯氧基）苯基]乙酸乙酯（250毫克）與TEA( -36- 200951122 148微升）之THF (5毫升）溶液中添加苯乙胺（80.4微 升），在室溫下攪拌1小時。將反應溶液注入水中後，以 EtOAc萃取。有機層依序以飽和NaHC03水溶液、水、飽 和食鹽水洗淨後，經MgS04乾燥後，減壓濃縮濾液。使 用IPE洗淨殘留物，獲得[3-氯-4- ( 4-{[2-苯基乙基]胺甲 醯基}胺基）苯氧基]苯基]乙酸乙酯（203毫克）之白色粉 末。TEA (410 μL) was added to a solution of ethyl 4-[4-(4-aminophenoxy)-3-chlorophenyl]acetate (3 mg) in THF (6 mL) After trichlorophosphonium chloride (146 mg) and stirring for 1 hour, 1,2,3,4-tetrahydroisoquinoline (137 μL) was added and stirred at room temperature overnight. The reaction solution was diluted with EtOAc, and washed with 1M hydrochloric acid and brine. The residue thus obtained was purified by silica gel column chromatography to give (3-chloro-4-{4-[(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)amino]phenoxy} Phenyl)acetate (243 mg) of pale brown amorphous material. As in Production Example 6, the compounds of Production Examples 6-1 to 6-8 shown in the following Table were produced using the corresponding raw materials. Production Example 7 Ethyl acetate containing [3-chloro-4-(4-{(4-nitrophenoxycarbonyl)amino}phenoxy)phenyl] (250 mg) and TEA under ice-cooling Add phenethylamine (80.4 μL) to a solution of THF (5 mL) (m.). After the reaction solution was poured into water, it was extracted with EtOAc. The organic layer was washed with a saturated aqueous solution of NaHCO.sub.3, water and saturated aqueous sodium chloride, and dried over EtOAc. The residue was washed with IPE to give [3-chloro-4-(4-{[2-phenylethyl]aminocarbamoyl}amino)phenoxy]phenyl]acetate (203 mg). White powder. 如製造例7般，使用對應之原料製造下表所示之製造 例7-1及7-2之化合物。 製造例8 於含（3-氯-4-羥基苯基）乙酸（3.00克）之EtOH ( 3〇毫升）溶液中添加濃硫酸（89.3微升），且在室溫下 攪拌隔夜。將反應溶液注入水中後，以EtOAc萃取。有 機層依序以水、飽和NaHC03水溶液、水、飽和食鹽水洗 ^ 淨後’經MgS04乾燥後，減壓濃縮濾液，獲得（3_氯-4_ 羥基苯基）乙酸乙酯（3.30克）之褐色油狀物質。 如製造例8般，使用對應之原料製造下表所示之製造 例8-1及8-5之化合物。 製造例9 在冰冷卻下於含[4- ( 4-胺基苯氧基）-3-氯苯基]乙酸 乙酯（1.50克）之DCM ( 30毫升）溶液中添加吡啶（ 1.31毫升）’攪拌10分鐘，且緩慢添加氯甲酸（4-硝基 -37- 200951122 苯基）酯（1.19克），在室溫下攪拌2小時。將水（100 毫升）添加於反應溶液中攪拌10分鐘後，以Eto Ac萃取 。有機層以飽和食鹽水洗淨後，經MgS04乾燥後，減壓 濃縮濾液。使殘留物經矽膠管柱層析（正己烷：EtOAc = 3 :2-0 : 1 )純化，以混合溶劑（DCM : IPE=1 : 4 )洗淨所 得之粗製結晶，獲得[3-氯-4- ( 4-{[ ( 4-硝基苯氧基）羰 基]胺基}苯氧基）苯基]乙酸乙酯（2.36克）之白色粉末 製造例1 0 於[4- ( 4-{[ ( 5-溴-1-苯并呋喃-2-基）羰基]胺基}苯 氧基）-3-氯苯基]乙酸乙酯之DMF ( 5毫升）溶液中添加 Zn(CN) 2(133 毫克）及 Pd(PPh3 )4(175 毫克），且 在微波照射下於1 5 0 °C反應1小時。濾除不溶物，將水（ 50毫升）加於濾液中，以EtOAc(40毫升）萃取。有機 層依序以水、飽和食鹽水洗淨，以M g S 0 4乾燥，減壓濃 縮濾液。獲得褐色油（5 7 0毫克）。使殘留物經矽膠管柱 層析（正己烷：EtOAc = 2 : 1 )純化，獲得[3_氯-4_ ( 4_{[ (5 -氰基-1-苯并咲喃-2 -基）锻基]胺基}苯氧基）苯基]乙 酸乙酯（199.3毫克）之白色固體。 製造例1 1 於含[4- (4 -胺基苯氧基）-3 -氯苯基]乙酸乙醋（3〇〇 毫克）之DCM (6毫升）溶液中添加耻陡（95.2微升）及 -38-As in Production Example 7, the compounds of Production Examples 7-1 and 7-2 shown in the following Table were produced using the corresponding raw materials. Production Example 8 Concentrated sulfuric acid (89.3 μl) was added to a solution of (3-chloro-4-hydroxyphenyl)acetic acid (3.00 g) in EtOH (3 mL), and stirred overnight at room temperature. After the reaction solution was poured into water, it was extracted with EtOAc. The organic layer was washed with water, saturated aqueous NaHCO.sub.3, water, and brine, and then dried over <RTI ID=0.0> Oily substance. As in Production Example 8, the compounds of Production Examples 8-1 and 8-5 shown in the following Table were produced using the corresponding raw materials. Preparation Example 9 To a solution of [4-(4-aminophenoxy)-3-chlorophenyl]acetic acid ethyl acetate (1.50 g) in EtOAc. After stirring for 10 minutes, chloroformic acid (4-nitro-37-200951122 phenyl) ester (1.19 g) was slowly added, and stirred at room temperature for 2 hr. Water (100 ml) was added to the reaction solution and stirred for 10 minutes, and then extracted with Eto Ac. The organic layer was washed with brine, dried over MgSO 4 , and evaporated. The residue was purified by column chromatography (hexanes: EtOAc = EtOAc: EtOAc: EtOAc: EtOAc: 4-(4-{[(4-Nitrophenoxy)carbonyl]amino}phenoxy)phenyl]acetate (2.36 g) as a white powder. Add Zn(CN) 2 to a solution of [(5-bromo-1-benzofuran-2-yl)carbonyl]amino}phenoxy)-3-chlorophenyl]acetate in DMF (5 mL) 133 mg) and Pd(PPh3)4 (175 mg) were reacted at 150 ° C for 1 hour under microwave irradiation. Insoluble material was filtered, and water (50 ml) was evaporated. The organic layer was washed with water and saturated brine, dried over MgSO 4 , Obtained a brown oil (5 70 mg). The residue was purified by column chromatography (n-hexane:EtOAc = 2:1) to afford [3 </ RTI> Ethyl]amino}phenoxy)phenyl]acetate (199.3 mg) as a white solid. Production Example 1 1 Adding a shame (95.2 μl) to a solution of [4-(4-aminophenoxy)-3-chlorophenyl]acetic acid ethyl acetate (3 mg) in DCM (6 ml) And -38- 200951122 苯磺醯氯（138微升），且在室溫下攪拌隔夜。將 液注入水中後，使用EtOAc萃取。有機層依序以 和食鹽水洗淨後，經MgS04乾燥，且減壓濃縮濾 殘留物經矽膠管柱層析純化，獲得（3-氯-4-{4-[( 醯基）胺基]苯氧基}苯基）乙酸乙酯（410毫克） 粉末。 如製造例11般，使用對應之原料製造下表所 造例1 1 -1之化合物。 製造例1 2 在冰冷卻下於硼烷- THF錯合物（1.17M，12.8 中添加環己烯（3.04毫升）且攪拌5分鐘後， {[2,5-二氯-4_ ( 4-硝基苯氧基）苯基]乙烯基}(三 矽烷（1_63克）之THF (25毫升）溶液，且在相 下攪拌2小時。於反應溶液中添加1M NaOH水 10.7毫升）及MeOH(12.5毫升）後，添加過氧化 液（3 0 %，4.8 6毫升）且在相同溫度下攪拌1小時 應溶液注入水中後，以EtOAc萃取，有機層以飽 水洗淨後，以MgS04乾燥，減壓濃縮濾液。使殘 解於EtOH ( 5毫升）中，添加一滴濃硫酸，加熱 小時。將反應溶液冷卻至室溫後，注入水中，以 萃取。有機層以飽和食鹽水洗淨，以MgS04乾燥 壓濃縮濾液。殘留物經矽膠管柱層析純化，獲得 氯-4-(4-硝基苯氧基）苯基]乙酸乙酯（510毫克 反應溶 水、飽 液，使 苯基磺 之白色 示之製 毫升） 添加含 甲基） 同溫度 溶液（ 氫水溶 。將反 和食鹽 留物溶 回流4 EtOAc ，且減 [2,5-二 )之茶 -39- 200951122 色油狀物質。 製造例13 於含1-溴-2,5-二氯-4- (4-硝基苯氧基）苯（1.85克 )與TEA (1.07毫升）之MeCN( 10毫升）溶液中添加二 氯雙（三苯基膦）鈀（358毫克）、碘化嗣（I) (194毫 克）、（三甲基矽烷基）乙炔（2.12毫升），且在微波照 射下於80°C下反應2小時。將反應溶液注入水中後，以 EtOAc萃取。有機層以飽和食鹽水洗淨後，以MgS04乾 燥，且減壓濃縮濾液。殘留物經矽膠管柱層析純化，獲得 {[2,5-二氯-4- ( 4-硝基苯氧基）苯基]乙烯基}(三甲基） 矽烷（1.63克）之茶色油狀物質。 製造例1 4 於含{3-氯-4-(4-硝基苯氧基）苯基}乙酸乙酯（2.30 克）之EtOH(46毫升）-水（11.5毫升）溶液中添加氯 化銨（3.66克）及鐵粉（3.83克），加熱回流3小時。 以矽藻土過濾反應溶液後，減壓濃縮，添加飽和NaHC03 後，以EtOAc萃取。有機層以飽和食鹽水洗淨後，以 1^3 04乾燥，減壓濃縮濾液，獲得{4-(4-胺基苯氧基）-3-氯苯基}乙酸乙酯（2.30克）之褐色油狀物質。 如製造例1 4般，使用對應之原料製造下表中所列製 造例14-1至14-15之化合物。 200951122 製造例15200951122 Benzene sulfonium chloride (138 μL) and stirred at room temperature overnight. After the solution was poured into water, it was extracted with EtOAc. The organic layer was washed successively with brine, dried over MgSO4, and concentrated under reduced pressure and purified by silica gel column chromatography to afford (3-chloro-4-{4-[(decyl)amino]benzene Ethyloxy}phenyl)acetate (410 mg) powder. As in Production Example 11, the compound of the above Example 11-1 was produced using the corresponding raw materials. Production Example 1 2 After adding cyclohexene (3.04 ml) to a borane-THF complex (1.17 M, 12.8) under ice cooling and stirring for 5 minutes, {[2,5-dichloro-4_(4-nitrate) a solution of benzyloxy)phenyl]vinyl}(trioxane (1_63 g) in THF (25 mL), and then stirred for 2 hr under the phase. 1 M NaOH water (10.7 mL) and MeOH (12.5 ml) After the addition of a peroxidizing solution (30%, 4.8 6 ml) and stirring at the same temperature for 1 hour, the solution was poured into water, and then extracted with EtOAc. The organic layer was washed with water and dried over MgSO. The filtrate was dissolved in EtOH (5 ml), and a portion of concentrated sulfuric acid was added and heated for a few hours. The reaction solution was cooled to room temperature and then poured into water for extraction. The organic layer was washed with saturated brine and concentrated with MgS04. The filtrate was purified by hydrazine column chromatography to obtain ethyl chloro-4-(4-nitrophenoxy)phenyl]acetate (510 mg of the reaction solution was dissolved in water, and the phenyl sulfonate was white. ML) Add methyl group) with temperature solution (hydrogen water solution. Resolve salt and salt residue) 4 EtOAc, and Save [2,5) of the color of tea -39-200951122 oily substance. Preparation Example 13 To a solution of 1-bromo-2,5-dichloro-4-(4-nitrophenoxy)benzene (1.85 g) and TEA (1.07 ml) in MeCN (10 ml) (Triphenylphosphine)palladium (358 mg), ruthenium iodide (I) (194 mg), (trimethyldecyl) acetylene (2.12 ml), and reacted at 80 ° C for 2 hours under microwave irradiation. After the reaction solution was poured into water, it was extracted with EtOAc. The organic layer was washed with saturated brine, dried over MgSO 4 and evaporated. The residue was purified by hydrazine column chromatography to give brown oil of [[2,5-dichloro-4-(4-nitrophenoxy)phenyl]vinyl}(trimethyl) decane (1.63 g). Shaped matter. Production Example 1 4 Addition of ammonium chloride to a solution of ethyl {O-chloro-4-(4-nitrophenoxy)phenyl}acetate (2.30 g) in EtOH (46 ml)-water (11.5 ml) (3.66 g) and iron powder (3.83 g) were heated under reflux for 3 hours. The reaction solution was filtered with EtOAc (EtOAc)EtOAc. The organic layer was washed with brine, dried over EtOAc EtOAc EtOAc. Brown oily substance. The compound of the production examples 14-1 to 14-15 shown in the following table was produced using the corresponding raw materials as in Production Example 14. 200951122 Manufacturing Example 15 在冰冷卻下，於含（2 -溴-4 -甲氧基苯基）乙酸乙醋 (4.4克）之DCM ( 44毫升）溶液中滴加1M ΒΒγ3之 DCM溶液（24.1毫升）。在5°C下攪拌5小時後，在冰冷 卻下於反應混合物中滴加EtOH ( 30毫升），終止反應， 且減壓濃縮’以EtOAc ( 150毫升）萃取所得殘留物。有 機層依序以水（1〇〇毫升）、飽和食鹽水（1〇〇毫升）洗 淨，以MgS04乾燥，且減壓濃縮濾液。使殘留物經正己 烷/IPE粉末化後過濾收集，藉由減壓乾燥，獲得（2-溴-4-羥基苯基）乙酸乙酯（2.56克）之白色固體。 製造例16 於含（3-氯-4-羥基苯基）乙酸乙酯（2.00克）之 DMF(30毫升）溶液中添加K2C03 (2.58克）及4-硝基 氟苯（1.03毫升），且在601：下攪拌2小時。將反應混 ^ 合物冷卻至室溫後，注入水中，使用EtOAc萃取。有機 層以飽和食鹽水洗滌兩次後，以MgS04乾燥’且減壓濃 縮濾液。殘留物經矽膠管柱層析（正己烷：Et0Ae = 4 : 1 )純化，獲得{3-氯-4- ( 4-硝基苯氧基）苯基丨乙酸乙醋（ 2.30克）之褐色油狀物質。 如製造例1 6般，使用對應之原料製造下表Φ m % # 造例1 6 -1至1 6 -1 5之化合物。 製造例1 7 -41 - 200951122A 1 M solution of ΒΒγ3 in DCM (24.1 mL) was added dropwise to a solution of &lt;RTI ID=0.0&gt;0&gt; After stirring for 5 hours at 5 ° C, EtOAc (EtOAc)EtOAc. The organic layer was washed with water (1 mL) and saturated brine (1 mL), dried over MgSO 4 and evaporated. The residue was crystallized from n-hexane / EtOAc (EtOAc)EtOAc. Preparation Example 16 To a solution of (3-chloro-4-hydroxyphenyl)acetic acid ethyl ester (2.00 g) in DMF (30 ml), K2C03 (2.58 g) and 4-nitrofluorobenzene (1.03 ml), Stir at 601: for 2 hours. After cooling the reaction mixture to room temperature, it was poured into water and extracted with EtOAc. The organic layer was washed twice with saturated brine, dried over MgSO 4 and concentrated. The residue was purified by silica gel column chromatography (hexanes: EtOAc: EtOAc: EtOAc) Shaped matter. The compound of the following Table Φ m % # 造例1 6 -1 to 16 -1 5 was produced using the corresponding raw materials as in Production Example 16. Manufacturing Example 1 7 -41 - 200951122 在室溫下攪拌含 4-苄氧基·1-吲哚（2.98克）與 K2C03 ( 1_12克）之DMF (30毫升）懸浮液，且逐次添 加溴乙酸乙酯（1.9毫升），且在室溫下攪拌隔夜。追加 K2C03(1.12克）及溴乙酸乙酯（1.9毫升），且於室溫 下再攪抻8小時。將水加於反應混合物中且以Et〇Ac萃 取，有機層以飽和食鹽水洗淨後，以Mg S04乾燥，減壓 濃縮濾液。所得殘留物經矽膠管柱層析（甲苯）純化，獲 得（4-苄氧基-1H-吲哚-1-基）乙酸乙酯（1.66克）之白 色固體。 製造例18A suspension of 4-benzyloxy·1-indole (2.98 g) and K2C03 (1-12 g) in DMF (30 ml) was stirred at room temperature, and ethyl bromoacetate (1.9 ml) Stir under temperature overnight. K2C03 (1.12 g) and ethyl bromoacetate (1.9 ml) were added, and the mixture was further stirred at room temperature for 8 hours. Water was added to the reaction mixture and the mixture was extracted with EtOAc (EtOAc). The residue was purified by EtOAc EtOAc EtOAc (EtOAc) Manufacturing Example 18 在冰冷卻下於含吲哚-2-羧酸乙酯（1克）之DMF ( 10毫升）溶液中添加60%氫化鈉（240毫克），在室溫下 攪拌1〇分鐘後，添加1-溴-2-氟乙烷（1克），在室溫下 擾拌2小時。以E10 A c稀釋反應溶液後依序以1 Μ鹽酸、 飽和食鹽水洗淨’以MgS04乾燥’且減壓濃縮濾液。殘 留物經矽膠管柱層析純化’獲得1 - ( 2 -氟乙基）吲哚-2 · 羧酸乙酯（1」克）之無色油。 製造例19 將（4-苄氧基-1Η-吲哚-1-基）乙酸乙酯（1.75克） 溶於EtOH ( 17.5毫升）及THF (17.5毫升）之混合溶 劑中，且添加1 0 %钯碳（含5 0 %水）（1.2克）’在氫氣 氛圍氣體中，在室溫、常壓下接觸還原4小時。使用砂藻 -42- 200951122 土過濾反應混合物，且減壓濃縮濾液。獲得（4-羥基-1H-吲哚-1-基）乙酸乙酯（1.37克）之淡茶色油。 製造例2060% sodium hydride (240 mg) was added to a solution of ethyl hydrazine-2-carboxylate (1 g) in DMF (10 ml), and the mixture was stirred at room temperature for 1 min. Bromo-2-fluoroethane (1 g) was scrambled for 2 hours at room temperature. The reaction solution was diluted with E10 A c, and then washed with aq. The residue was purified by hydrazine gel column chromatography to afford ethyl 1-(2-fluoroethyl)indole-2-carboxylate (1 g). Preparation Example 19 Ethyl (4-benzyloxy-1Η-indol-1-yl)acetate (1.75 g) was dissolved in a mixed solvent of EtOH (17.5 ml) and THF (17.5 ml), and 10% was added. Palladium carbon (containing 50% water) (1.2 g) was contact-reduced for 4 hours at room temperature under normal pressure in a hydrogen atmosphere. The reaction mixture was filtered using celite-42-200951122, and the filtrate was concentrated under reduced pressure. A pale brown oil of (4-hydroxy-1H-indol-1-yl)acetate (1.37 g) was obtained. Manufacturing Example 20 於含2-溴-Ν,Ν-二甲基苯胺（ 500毫克）及3-乙氧基 羰基苯基硼酸（582毫克）之1，4-二噁烷（1〇毫升）溶液 中添加2Μ Na2C03水溶液（2.75毫升）及[1，1’_雙（二苯 基膦基）芴]二氯鈀（2 04毫克），且在氮氣氛圍氣體中 於90°C下攪拌4小時。將反應混合物冷卻至室溫後注入水 中，以 EtOAc萃取。有機層以飽和食鹽水洗淨後，以 M gS04乾燥，且減壓濃縮濾液。殘留物經矽膠管柱層析純 化，獲得2’-(二甲胺基）聯苯-3-羧酸乙酯（ 62 0毫克） 之淡黃色油狀物質。 表2至表34列出製造例化合物之構造及物理化學數Add 2Μ Na2C03 to a solution of 2-bromo-indole, hydrazine-dimethylaniline (500 mg) and 3-ethoxycarbonylphenylboronic acid (582 mg) in 1,4-dioxane (1 mL) Aqueous solution (2.75 ml) and [1,1'-bis(diphenylphosphino)phosphonium]dichloropalladium (2 04 mg) were stirred at 90 ° C for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) Tables 2 to 34 list the structures and physicochemical numbers of the compounds of the manufacturing examples. 實施例1 於含（3-氯-4-{4-[(3,4-二氯苯甲醯基）胺基]苯氧基 }苯基）乙酸乙酯（210毫克）之EtOH(4.2毫升）溶液 中添加2M NaOH水溶液（439微升），在室溫下攪拌4 小時。於反應溶液中添加1Μ鹽酸，將p Η調整爲3至4 後，以水稀釋，且以EtOAc萃取。有機層以飽和食鹽水 洗淨後’以MgS04乾燥’減壓濃縮濾液。殘留物經IPE 粉末化後乾燥，獲得（3 -氯-4- {4-[(3,4 -二氯苯甲醯基） -43- 200951122 胺基]苯氧基}乙酸（182毫克）之白色粉末。 如實施例1般，使用對應之原料製造以下表3 5至74 中所示之實施例2至實施例153之化合物。表35至表60 中分別表示實施例化合物之構造，且表61至表74分別表 示物理化學數據。 [表2] Pr Structure Data 1 Cl 〒h3 1 j0r〇TN、CH3 MS(ESI)： 324(M+Na)+ 2 Cl 〒h3 兄（^YSYN、ch3 h3c八。人人1 0 MS(ESI)： 324(M+Na)+ 3 MS(ESI)： 201(M-H)' 3-1 ηΛ〇Ϊ h3c ch3 MS(ESI)： 242(M+H)+Example 1 EtOH (4.2 ml) of ethyl (3-chloro-4-{4-[(3,4-dichlorobenzylidyl)amino]phenoxy}phenyl)acetate (210 mg) A 2M aqueous NaOH solution (439 μL) was added to the solution, and stirred at room temperature for 4 hours. After adding 1 Μ hydrochloric acid to the reaction solution, p Η was adjusted to 3 to 4, diluted with water, and extracted with EtOAc. The organic layer was washed with a saturated aqueous solution of sodium chloride and then evaporated. The residue was powdered by IPE and dried to give (3-chloro-4-{4-[(3,4-dichlorobenzhydryl)-43-200951122 amino]phenoxy}acetic acid (182 mg) White powder. The compounds of Examples 2 to 153 shown in the following Tables 35 to 74 were produced using the corresponding raw materials as in Example 1. The structures of the example compounds are shown in Tables 35 to 60, respectively. 61 to 74 show physical and chemical data, respectively. [Table 2] Pr Structure Data 1 Cl 〒h3 1 j0r〇TN, CH3 MS (ESI): 324 (M+Na)+ 2 Cl 〒h3 Brother (^YSYN, ch3 h3c 8. Everyone 1 0 MS (ESI): 324 (M+Na) + 3 MS (ESI): 201 (MH)' 3-1 η Λ〇Ϊ h3c ch3 MS (ESI): 242 (M+H)+ -44 - 200951122 [表3]-44 - 200951122 [Table 3] Pr Structure Data 3-2 MS(ESI)： 206(M-H)· 4 MS(ESI)： 500(M+Na)+ 4-1 H 广 MS(ESI)： 466(M+Na)+. 4-2 ch3 MS(ESI): 446(M+Na)+ 4-3 H 广 MS(ESI): 462(M+Na)+ 4-4 MS(ESI): 483(M+Na)+ 4-5 MS(ESI)： 472(M+Na)+ -45- 200951122 m 4] Pr Structure Data 4-6 MS(ESI)： 483(M+Na)+ 4-7 H3C、^CXVh 3 H Ν^Λ MS(ESI): 472(M+Na)+ 4-8 MS(ESI)： 483(M+Na)+ 4-9 Sj^ci MS(ESI)： 501(M+Na)+ 4-10 MS(ESI)： 479,481(M+H)+ 4-11 MS(ESI): 496,498(M+Na)+ -46- 200951122 [表5]Pr Structure Data 3-2 MS (ESI): 206 (MH)· 4 MS (ESI): 500 (M+Na) + 4-1 H MS (ESI): 466 (M+Na)+. 4-2 Ch3 MS (ESI): 446 (M+Na) </RTI> &lt;RTI ID=0.0&gt;&gt; ESI): 472(M+Na)+ -45- 200951122 m 4] Pr Structure Data 4-6 MS(ESI): 483(M+Na)+ 4-7 H3C, ^CXVh 3 H Ν^Λ MS (ESI) 472(M+Na)+ 4-8 MS (ESI): 483 (M+Na) + 4-9 Sj^CI MS (ESI): 501 (M+Na) + 4-10 MS (ESI): 479,481(M+H)+ 4-11 MS(ESI): 496,498(M+Na)+ -46- 200951122 [Table 5] Pr Structure Data 4-12 MS(ESI)： 484,486(M+Na)+ 4-13 h3Ca 人☆ MS(ESI): 478,480(M-H)· 4-14 H3C、w5r〇xXVh H MS(ESI)： 451(M+H)+ 4-15 H 广 Η I心 MS(ESI)： 452(M+H)+ 4-16 H 广。x2r°XXVh 3 H ν^Λ MS(ESI)： 468(M+Na)+ 4-17 H ^ MS(ESI) ·· 434(M+H)+ -47- 200951122 [表6] Pr Structure Data 4-18 MS(ESI)： 516(M+Na)+ 4-19 MS(ESI)： 500,502(M+Na)+ 4-20 MS(ESI)： 466,468(M+Na)+ 4-21 η 广 MS(ESI)： 496,498(M+Na)+ 4-22 Η^0^Λ8αΝν H MS(ESI)： 488(M+Na)+ -48- 200951122 [表7]Pr Structure Data 4-12 MS (ESI): 484, 486 (M+Na) + 4-13 h3Ca ☆ MS (ESI): 478, 480 (MH) · 4-14 H3C, w5r〇xXVh H MS (ESI): 451 ( M+H)+ 4-15 H Hirose I Heart MS (ESI): 452 (M+H) + 4-16 H wide. X2r°XXVh 3 H ν^Λ MS(ESI): 468(M+Na)+ 4-17 H ^ MS(ESI) ·· 434(M+H)+ -47- 200951122 [Table 6] Pr Structure Data 4 -18 MS (ESI): 516 (M+Na) + 4-19 MS (ESI): 500, 502 (M+Na) + 4-20 MS (ESI): 466,468 (M+Na)+ 4-21 η wide MS (ESI): 496,498 (M+Na)+ 4-22 Η^0^Λ8αΝν H MS (ESI): 488 (M+Na)+ -48- 200951122 [Table 7] Pr Structure Data 4-23 Cl MS(ESI)： 500,502(M+Na)+ 4-24 H 广 MS(ESI)： 484,486(M+Na)+ 4-25 h3c-〇^^〇^n^0；-ch3 MS(ESI): 496,498(M+Na)+ 4-26 MS(ESI)： 489(M+Na)+ 4-27 MS(ESI)： 471(M+Na)+ 4-28 H广 MS(ESI): 508(M+Na)+ -49- 200951122 [表8] Pr Structure Data 4-29 H 广。 ^ °'ch3 MS(ESI): 538(M+Na)+ 4-30 Cl MS(ESI)： 472,474(M+Na)+ 4-31 MS(ESI): 461(M+H)+ 4-32 VCCH3 MS(ESI): 524(M+Na)+. 4-33 MS(ESI): 489(M+Na)+ 4-34 Η MS(ESI): 478(M+H)+Pr Structure Data 4-23 Cl MS (ESI): 500, 502 (M+Na) + 4-24 H broad MS (ESI): 484, 486 (M+Na) + 4-25 h3c-〇^^〇^n^0; -ch3 MS (ESI): 495, 498 (M+Na) + 4-26 MS (ESI): 495 (M+Na) + 4-27 MS (ESI): 471 (M+Na)+ 4-28 H MS (ESI): 508 (M+Na)+ -49- 200951122 [Table 8] Pr Structure Data 4-29 H wide. ^ ° 'ch3 MS (ESI): 538 (M+Na) + 4-30 Cl MS (ESI): 472, 474 (M+Na) + 4-31 MS (ESI): 461 (M+H) + 4-32 VCCH3 MS (ESI): 524 (M+Na) +. 4-33 MS (ESI): 495 (M+Na) + 4-34 Η MS (ESI): 478 (M+H)+ -50- 200951122 [表9]-50- 200951122 [Table 9] Pr Structure Data 4-35 CF3 MS(ESI)： 500(M+Na)+ 4-36 H 广 、人 cf3 MS(ESI)： 501(M+Na)+ 4-37 MS(ESI)： 487(M+Na)+ 4-38 Η ch3 MS(ESI)： 501(M+Na)+ 4-39 Cl H3cA(A^0&quot; 3 Η U 〇〇 MS(ESI): 525(M+Na)+ 4-40 MS(ESI): 468(M+Na)+ -51 - 200951122 m ι〇] Pr Structure Data 4-41 H MS(ESI)： 471(M+Na)+ 4-42 MS(ESI)： 485(M+Na)+ 4-43 MS(ESI)： 489(M+Na)+ 4-44 H^0uir〇XiHVi CH3 MS(ESI)： 478(M+Na)+ 4-45 MS(ESI)： 518(M+Na)+ 4-46 MS(ESI): 481(M-H)· -52- 200951122 m ii]Pr Structure Data 4-35 CF3 MS (ESI): 500 (M+Na) + 4-36 H, cf3 MS (ESI): 501 (M+Na) + 4-37 MS (ESI): 487 (M +Na)+ 4-38 Η ch3 MS(ESI): 501(M+Na)+ 4-39 Cl H3cA(A^0&quot; 3 Η U 〇〇MS(ESI): 525(M+Na)+ 4- 40 MS (ESI): 468 (M+Na) + -51 - 200951122 m ι〇] Pr Structure Data 4-41 H MS (ESI): 471 (M+Na) + 4-42 MS (ESI): 485 ( M+Na)+ 4-43 MS (ESI): 495 (M+Na) + 4-44 H^0u 〇 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> ESI (ESI): 478 (M+Na) + 4-45 MS (ESI): 518 (M+Na)+ 4-46 MS(ESI): 481(MH)· -52- 200951122 m ii] Pr Structure Data 4-47 H^0u5r°^VrF MS(ESI)： 480(M+Na)+ 4-48 H 广 ch3 MS(ESI)： 464(M+Na)+ 4-49 h3c&quot; nch3 MS(ESI)： 529(M+H)+ 4-50 ^N^^cp3 MS(ESI): 500(M+Na)+ 4-51 H^0wS°iaN\p K MS(ESI)： 471(M+Na)+ 4-52 H^0w5r°aNv， H取％ MS(ESI)： 485(M+Na)+ -53- 200951122 m π] Pr Structure Data 4-53 ch3 MS(ESI)： 460(M+Na)+ 4-54 MS(ESI)： 472(M+Na)+ 4-55 Cl o ff^Y°YN^ 0 MS(ESI)： 459(M+Na)+ 4-56 Cl ch3 MS(ESI)： 490(M-H)· 4-57 Cl ch3 MS(ESI): 461(M-H)· 4-58 MS(ESI): 506,508(M+Na)+ -54- 200951122 m π]Pr Structure Data 4-47 H^0u5r°^VrF MS(ESI): 480(M+Na)+ 4-48 H wide ch3 MS(ESI): 464(M+Na)+ 4-49 h3c&quot; nch3 MS( ESI): 529(M+H)+ 4-50^N^^cp3 MS(ESI): 500(M+Na)+ 4-51 H^0wS°iaN\p K MS(ESI): 471 (M+ Na)+ 4-52 H^0w5r°aNv, H% MS (ESI): 485(M+Na)+ -53- 200951122 m π] Pr Structure Data 4-53 ch3 MS(ESI): 460(M+ Na)+ 4-54 MS (ESI): 472 (M+Na) + 4-55 Cl o ff^Y°YN^ 0 MS (ESI): 459 (M+Na) + 4-56 Cl ch3 MS (ESI) 490(MH)· 4-57 Cl ch3 MS (ESI): 461 (MH)· 4-58 MS (ESI): 506, 508 (M+Na) + -54- 200951122 m π] Pr Structure Data 4-59 H广 MS(ESI)： 505,507(M+Na)+ 4-60 H 广 MS(ESI)： 506,508(M+Na)+ 4-61 MS(ESI)： 486(M+Na)+ 4-62 MS(ESI)： 490,492(M+Na)+ 4-63 H^0〇ir0tiV H N^^cH3 MS(ESI)： 464(M+H)+ 4-64 CF3 MS(ESI)： 518(M+Na)+ -55- 200951122 m η] Pr Structure Data 4-65 3 H UyCH3 ch3 MS(ESI)： 475(M+Na)+ 4-66 MS(ESI)： 472(M+Na)+ 4-67 MS(ESI): 490(M+Na)+ 4-68 MS(ESI)： 506,508(M+Na)+ 4-69 MS(ESI)： 505,507(M+Na)+ 4-70 MS(ESI)： 516(M+Na)+Pr Structure Data 4-59 H-G (MS): 505,507 (M+Na) + 4-60 H MS (ESI): 506, 508 (M+Na) + 4-61 MS (ESI): 486 (M+Na + 4-62 MS (ESI): 490, 492 (M+Na) + 4-63 H^0〇ir0tiV HN^^cH3 MS (ESI): 464 (M+H) + 4-64 CF3 MS (ESI): 518(M+Na)+ -55- 200951122 m η] Pr Structure Data 4-65 3 H UyCH3 ch3 MS (ESI): 475 (M+Na) + 4-66 MS (ESI): 472 (M+Na) + 4-67 MS (ESI): 495 (M+Na) + 4- 68 MS (ESI): 506, 508 (M+Na) + 4-69 MS (ESI): 505,507 (M+Na) + 4-70 MS (ESI): 516(M+Na)+ -56- 200951122 m i5]-56- 200951122 m i5] Pr Structure Data 4-71 h3c^\=/ MS(ESI)： 486(M+Na)+ 4-72 H3C、iA°uNVh 3 H N^yc. MS(ESI)： 506(M+Na)+ 4-73 H 广 H把V MS(ESI)： 480(M+H)+ 4-74 ch3 NMR (CDC13)： 1.28(3H,t, J=7.1Hz), 2.45(3H,s), 3_58(2H，s), 4.18(2H,q, J=7.1Hz), 6.90-7.90 (llH’m) 4-75 H3CA〇^ji&quot; X^X^CH3 MS(ESI): 480(M+Na)+ -57- 200951122 m i6] Pr Structure Data 4-76 MS(ESI)： 484(M+Na)+ 4-77 H n^-ch3 MS(ESI)： 464(M+H)+ 4-78 3 H MS(ESI)： 490(M+Na)+ 4-79 Η3^0^Λ°χ&gt;^ MS(ESI)： 460(M+Na)+ 4-80 MS(ESI): 458(M+Na)+ 4-81 H3C^〇A^〇XX,A^^c, MS(ESI)： 526(M+Na)+ -58- 200951122 m π]Pr Structure Data 4-71 h3c^\=/ MS(ESI): 486(M+Na)+ 4-72 H3C, iA°uNVh 3 HN^yc. MS(ESI): 506(M+Na)+ 4- 73 H 广H V MS (ESI): 480 (M+H) + 4-74 ch3 NMR (CDC13): 1.28 (3H, t, J = 7.1 Hz), 2.45 (3H, s), 3_58 (2H, s), 4.18(2H,q, J=7.1Hz), 6.90-7.90 (llH'm) 4-75 H3CA〇^ji&quot; X^X^CH3 MS(ESI): 480(M+Na)+ -57 - 200951122 m i6] Pr Structure Data 4-76 MS (ESI): 484 (M+Na) + 4-77 H n^-ch3 MS (ESI): 464 (M+H) + 4-78 3 H MS ( ESI): 490(M+Na)+ 4-79 Η3^0^Λ°χ&gt;^ MS(ESI): 460(M+Na)+ 4-80 MS(ESI): 458(M+Na)+ 4 -81 H3C^〇A^〇XX, A^^c, MS(ESI): 526(M+Na)+ -58- 200951122 m π] Pr Structure Data 4-82 MS(ESI)： 509(M+Na)+ 4-83 MS(ESI)： 493(M+H)+ 4-84 H 广 λΛΎά s MS(ESI): 515(M+Na)+ 4-85 MS(ESI)： 513(M+Na)+ 4-86 MS(ESI)： 489(M+Na)+ 4-87 CF3 MS(ESI): 479,481(M+H)+ -59- 200951122 m is] Pr Structure Data 4-88 MS(ESI)： 464,466(M+H)+ 4-89 MS(ESI): 505(M+Na)+ 4-90 MS(ESI)： 477(M+Na)+ 4-91 H 广 H化 MS(ESI): 464(M+H)+ 4-92 MS(ESI): 503(M+Na)+ 4-93 Cl ch3 MS(ESI)： 499(M+Na)+Pr Structure Data 4-82 MS (ESI): 509 (M+Na) + 4-83 MS (ESI): 493 (M+H) + 4-84 H λ ΛΎά s MS (ESI): 515 (M+Na + 4-85 MS (ESI): 513 (M+Na) + 4-86 MS (ESI): 484 (M+Na) + 4-87 CF3 MS (ESI): 479,481 (M+H) + -59 - 200951122 m is] Pr Structure Data 4-88 MS (ESI): 464,466 (M+H) + 4-89 MS (ESI): 505 (M+Na) + 4-90 MS (ESI): 477 (M+ Na)+ 4-91 H OH (ESI): 464 (M+H) + 4-92 MS (ESI): 503 (M+Na) + 4-93 Cl ch3 MS (ESI): 499 (M +Na)+ -60- 200951122 m i9]-60- 200951122 m i9] Pr Structure Data 4-94 h3c MS(ESI)： 498(M+H)+ 4-95 h3c 〇^NlV0ri x h3c^ 0 ^ MS(ESI)： 478(M+Na)+ 4-96 h3c MS(ESI): 546(M+Na)+ 4-97 MS(ESI): 485(M+Na)+ 4-98 H3C、wS°成 MS(ESI)： 490(M+Na)+ 4-99 〇^NxV°n ? h MS(ESI)： 476(M+Na)+ -61 - 200951122 m 2〇] Pr Structure Data 4-100 MS(ESI)： 476(M+Na)+. 4-101 H^0u5r°^V^F MS(ESI): 469,471 (M+H)+ 4-102 MS(ESI)： 485,487(M+H)+ 4-103 MS(ESI): 516,518(M+Na)+ 4-104 MS(ESI): 529,531(M+Na)+ 4-105 H ν^Λ MS(ESI)： 477(M+Na)+Pr Structure Data 4-94 h3c MS (ESI): 498 (M+H) + 4-95 h3c 〇^NlV0ri x h3c^ 0 ^ MS (ESI): 478 (M+Na) + 4-96 h3c MS (ESI) ): 546(M+Na)+ 4-97 MS(ESI): 485(M+Na)+ 4-98 H3C, wS° to MS (ESI): 490(M+Na)+ 4-99 〇^NxV °n ? h MS(ESI): 476(M+Na)+ -61 - 200951122 m 2〇] Pr Structure Data 4-100 MS(ESI): 476(M+Na)+. 4-101 H^0u5r° ^V^F MS (ESI): 469, 471 (M+H) + 4-102 MS (ESI): 485, 487 (M+H) + 4-103 MS (ESI): 516, 518 (M+Na) + 4-104 MS (ESI): 529,531 (M+Na)+ 4-105 H ν^Λ MS (ESI): 477 (M+Na)+ -62- 200951122 [表 21]-62- 200951122 [Table 21] Pr Structure Data 4- 106 Η〆。u MS(ESI)： 463(M+Na)+ 4- 107 MS(ESI)： 544,546(M+Na)+ 4- 108 Hz0^° ^ ^K^0；CI MS(ESI)： 505(M+Na)+ 4- 109 3 H n-^Q, MS(ESI)： 466(M-H)* 4- 110 MS(ESI): 515,517(M+Na)+ 4- 111 Br MS(ESI)： 544,546(M+Na)+ -63- 200951122 m 22] Pr Structure Data 4- 112 MS(ESI)： 515,517(M+Na)+ 4- 113 MS(ESI)： 489(M+Na)+ 4- 114 MS(ESI) ·· 550,552(M+Na)+ 4- 115 h3Ca〇aJ^ MS(ESI)： 488(M+Na)+ 4- 116 H^0wSvKvci CH3 MS(ESI): 514(M+Na)+ 4- 117 H3C^〇A^ MS(ESI): 485(M+Na)+Pr Structure Data 4- 106 Η〆. u MS (ESI): 463 (M+Na) + 4- 107 MS (ESI): 544, 546 (M+Na) + 4-108 Hz0^°^^K^0; CI MS (ESI): 505 (M+ Na)+ 4-109 3 H n-^Q, MS (ESI): 466 (MH)* 4- 110 MS (ESI): 515, 517 (M+Na) + 4- 111 Br MS (ESI): 544, 546 (M +Na)+ -63- 200951122 m 22] Pr Structure Data 4- 112 MS (ESI): 515,517 (M+Na) + 4- 113 MS (ESI): 489 (M+Na) + 4-114 MS (ESI) ··· 550,552(M+Na)+ 4- 115 h3Ca〇aJ^ MS(ESI): 488(M+Na)+ 4-116 H^0wSvKvci CH3 MS(ESI): 514(M+Na)+ 4- 117 H3C^〇A^ MS(ESI): 485(M+Na)+ -64 - 200951122-64 - 200951122 m 23] Pr Structure Data 4-118 MS(ESI)： 437(M+H)+ 4-119 H 广 jTXVh 3 H n^Q) MS(ESI)： 473(M+Na)+ 4-120 H^0^°UNVx h &gt;^&gt;yF h3c w MS(ESI)： 503(M+Na)+ 4-121 hh/^ MS(ESI)： 499(M+Na)+ 4-122 H 广 MS(ESI)： 519(M+Na)+ 4-123 MS(ESI)： 533,535(M+Na)+ -65- 200951122 m 24] Pr Structure Data 4-124 MS(ESI)： 490(M+Na)+ 4-125 H 广 MS(ESI): 506(M+Na)+ 4-126 h3c/ \=/ F MS(ESI): 482(M+H)+ 4-127 ηη；%- MS(ESI)： 520(M+Na)+ 4-128 H 广。 MS(ESI)： 500(M+Na)+ 4-129 MS(ESI): 500(M+Na)+ -66 - 200951122m 23] Pr Structure Data 4-118 MS (ESI): 437 (M+H) + 4-119 H sssssssssssssssssssssssssssssssss 0^°UNVx h &gt;^&gt;yF h3c w MS(ESI): 503(M+Na)+ 4-121 hh/^ MS(ESI): 499(M+Na)+ 4-122 H Wide MS ( ESI): 519 (M+Na) + 4-123 MS (ESI): 533, 535 (M+Na) + -65 - 200951122 m 24] Pr Structure Data 4-124 MS (ESI): 490 (M+Na)+ 4-125 H broad MS (ESI): 506 (M+Na) + 4-126 h3c / \=/ F MS (ESI): 482 (M+H) + 4-127 ηη; %- MS (ESI): 520 (M+Na) + 4-128 H wide. MS (ESI): 500 (M+Na) + 4-129 MS (ESI): 500 (M+Na) + -66 - 200951122 m 25] Pr Structure Data 4-130 MS(ESI)： 518(M+Na)+ 4-131 H必％ MS(ESI)： 462(M-H)' 4-132 MS(ESI): 517(M+Na)+ 4-133 ^〇cf3 MS(ESI)： 560,562(M+Na)+ 4-134 MS(ESI)： 466(M+H)+ 4-135 H 广。 MS(ESI): 487(M+Na)+ -67- 200951122 m 26] Pr Structure Data 4-136 H 广。 CF3 MS(ESI)： 519(M+Na)+ 5 MS(ESI)： 501(M+Na)+ 6 H3C、u5m，N〇〇 MS(ESI)： 487(M+Na)+ 6-1 H 广 H七 MS(ESI)： 473(M+Na)+ 6-2 H^0u5r°X&gt;A^ MS(ESI)： 487(M+Na)+ 6-3 Η^0ιΛ°αΝΑΝ^ Η ^ MS(ESI)： 515(M+Na)+m 25] Pr Structure Data 4-130 MS (ESI): 518 (M+Na)? + 4-133 ^〇cf3 MS (ESI): 560, 562 (M+Na) + 4-134 MS (ESI): 466 (M+H) + 4-135 H. MS (ESI): 487 (M+Na) + -67 - 200951122 m 26] Pr Structure Data 4-136 H wide. CF3 MS (ESI): 519 (M+Na) + 5 MS (ESI): 501 (M+Na) + 6 H3C, u5m, N〇〇MS (ESI): 487 (M+Na) + 6-1 H广 H7 MS(ESI): 473(M+Na)+ 6-2 H^0u5r°X&gt;A^ MS(ESI): 487(M+Na)+ 6-3 Η^0ιΛ°αΝΑΝ^ Η ^ MS (ESI): 515 (M+Na)+ -68- 200951122-68- 200951122 m 27] Pr Structure Data 6-4 OH MS(ESI): 565(M+Na)+ 6-5 ¥ H 00 MS(ESI)： 492(M+Na)+ 6-6 MS(ESI)： 505(M+Na)+ 6-7 h3c-〇^^〇^/nQQ MS(ESI)： 521,523(M+Na)+ 6-8 h 广 aA°u，nC〇 MS(ESI)： 509,511 (M+H)+ 7 H3C、w5r〇UA』 3 Η H MS(ESI): 475,477(M+Na)+ -69- 200951122 m 28] Pr Structure Data 7-1 3 Η 1 ch3 MS(ESI)： 489(M+Na)+ 7-2 H MS(ESI): 501，503(M+Na)+ 8 H3C」0 Cl MS(ESI): 237(M+Na)+ 8-1 H3C-7 0 F MS(ESI)： 221(M+Na)+ 8-2 jhT^0H H3c」0 0-CH3 MS(ESI): 233(M+Na)+ 8-3 0^-Q-sh h3c」0 Cl MS(ESI)： 229(M-H)' 8-4 jhT^0H H3C j 0 Br MS(ESI): 281，283(M+Na)+ 8-5 CH3 〇^-^〇/ H3C」0 MS(ESI): 295,297(M+Na)+m 27] Pr Structure Data 6-4 OH MS (ESI): 565 (M+Na) + 6-5 OH 00 MS (ESI): 492 (M+Na) + 6-6 MS (ESI): 505 ( M+Na)+ 6-7 h3c-〇^^〇^/nQQ MS(ESI): 521,523(M+Na)+ 6-8 h broad aA°u, nC〇MS(ESI): 509,511 (M+H ) + 7 H3C, w5r〇UA』 3 Η H MS(ESI): 475,477(M+Na)+ -69- 200951122 m 28] Pr Structure Data 7-1 3 Η 1 ch3 MS(ESI): 489 (M+ Na)+ 7-2 H MS (ESI): 501, 503 (M+Na) + 8 H3C : 221(M+Na)+ 8-2 jhT^0H H3c"0 0-CH3 MS (ESI): 233 (M+Na) + 8-3 0^-Q-sh h3c"0 Cl MS (ESI): 229(MH)' 8-4 jhT^0H H3C j 0 Br MS (ESI): 281, 283 (M+Na) + 8-5 CH3 〇^-^〇/ H3C"0 MS (ESI): 295,297 (M +Na)+ -70- 200951122-70- 200951122 [表 29: Pr Structure Data 9 H 广 λΛααχτ。2 3 Η NMR(CDC13): 1.28(3H，t，J=7.1 Hz)，3.58(2H，s), 4.18(2H,q,J=7.1 Hz),6.93(lH,d, J=8.4Hz),6.95-7.00(3H,m), 7.14(lH,dd,J= 2.1,8.4Hz),7.37-7.44(5H,m),8.27-8.31(2H,m) 10 η广 Η MS(ESI): 497(M+Na)+ 11 MS(ESI)： 468,470(M+Na)+ 11- 1 H广 Η认 MS(ESI)： 536,538(M+Na)+ 12 h^0u&gt;°x^n〇2 Cl MS(ESI): 368(M-H)' 13 HCi Cl 3 ch3 MS(ESI)： 402,404(M+Na)+ -71 - 200951122 [表 30] Pr Structure Data 14 H^0WS°UNH2 MS(ESI)： 328(M+Na)+ 14-1 MS(ESI)： 307(M+H)+ 14-2 H广。士久 MS(ESI)： 324(M+Na)+ 14-3 H 广。uVxx2 MS(ESI): 290(M+H)+ 14-4 H 广 λΛί MS(ESI)： 308(M+H)+ 14-5 η^0ιΛ8χ&gt;ΝΗ2 MS(ESI)： 344(M+Na)+ 14-6 Cl F 0 (f\〇YS MS(ESI)： 346(M+Na)+ 14-7 Cl Cl 0 ffV°YS h3c 八。人'•人^ ^^nh2 MS(ESI)： 362,364(M+Na)+ -72- 200951122 [表 31][Table 29: Pr Structure Data 9 H λλααχτ. 2 3 Η NMR (CDC13): 1.28 (3H, t, J = 7.1 Hz), 3.58 (2H, s), 4.18 (2H, q, J = 7.1 Hz), 6.93 (lH, d, J = 8.4 Hz) , 6.95-7.00 (3H, m), 7.14 (lH, dd, J = 2.1, 8.4 Hz), 7.37-7.44 (5H, m), 8.27-8.31 (2H, m) 10 η Η MS (ESI): 497(M+Na)+ 11 MS(ESI): 468,470 (M+Na)+ 11- 1 H Η MS (ESI): 536,538 (M+Na)+ 12 h^0u&gt;°x^n〇2 Cl MS (ESI): 368 (MH) </RTI> </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 328 (M+Na) + 14-1 MS (ESI): 307 (M+H) + 14-2 H. Shijiu MS (ESI): 324 (M+Na) + 14-3 H wide. uVxx2 MS (ESI): 290 (M+H) + 14-4 H λ Λ MS (ESI): 308 (M+H) + 14-5 η^0ιΛ8χ&gt;ΝΗ2 MS(ESI): 344(M+Na) + 14-6 Cl F 0 (f\〇YS MS(ESI): 346(M+Na)+ 14-7 Cl Cl 0 ffV°YS h3c 八人'•人^ ^^nh2 MS(ESI): 362,364 (M+Na)+ -72- 200951122 [Table 31] Pr Structure Data 14-8 Cl CH. 〇 H3C 八 ^^nh2 MS(ESI)： 320(M+H)+ 14-9 rCWlX H3c」 NH2 MS(ESI)： 311(M+H)+ 14-10 Cl MS(ESI): 340,342(M+H)+ 14-11 h3c」0 ^ MS(ESI)： 326(M+H)+ 14-12 H3C、wS°tX2 MS(ESI)： 372,374(M+Na)+ 14-13 H3C、u/xXH2 Br MS(ESI)： 372,374(M+Na)+ 14-14 ,c、Xi5rVNH2 ch3 MS(ESI)： 342(M+Na)+ -73- 200951122 m 32] Pr Structure Data 14-15 MS(ESI)： 307(Μ+Η)+ 15 h^〇U7〇H Br MS(ESI)： 281,283(M+Na)+ 16 H 广 λΛα MS(ESI)： 334(M-H)· 16-1 〇 Ιί^γΟγΝ, |~13(：八0^^^^ ^^no2 MS(ESI)： 359(M+Na)+ 16-2 H 广。 MS(ESI)： 354(M+Na)+ 16-3 Η3^0^ΛοαΝ〇2 MS(ESI)： 342(M+Na)+ 16-4 9 Λ〇γΝ1 Νν^νΝ02 MS(ESI)： 338(M+H)+ 16-5 &lt;λΛ3χχ2 MS(ESI)： 374(M+Na)+ -74- 200951122 [表 33]Pr Structure Data 14-8 Cl CH. 〇H3C 八^^nh2 MS(ESI): 320(M+H)+ 14-9 rCWlX H3c" NH2 MS(ESI): 311(M+H)+ 14-10 Cl MS (ESI): 340, 342 (M+H) + 14-11 s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, + 14-13 H3C, u/xXH2 Br MS (ESI): 372, 374 (M+Na) + 14-14, c, Xi5rVNH2 ch3 MS (ESI): 342 (M+Na) + -73- 200951122 m 32] Pr Structure Data 14-15 MS (ESI): 307 (Μ+Η)+ 15 h^〇U7〇H Br MS (ESI): 281, 283 (M+Na) + 16 H λλΛα MS (ESI): 334 (MH) · 16-1 〇Ιί^γΟγΝ, |~13(:八0^^^^ ^^no2 MS(ESI): 359(M+Na)+ 16-2 H Wide MS (ESI): 354(M+ Na)+ 16-3 Η3^0^ΛοαΝ〇2 MS(ESI): 342(M+Na)+ 16-4 9 Λ〇γΝ1 Νν^νΝ02 MS(ESI): 338(M+H)+ 16-5 &lt;λΛ3χχ2 MS (ESI): 374 (M+Na)+ -74- 200951122 [Table 33] Pr Structure Data 16-6 H广 MS(ESI)： 376(M+Na)+ 16-7 η^0^τ°Λν〇2 MS(ESI): 392,394(M+Na)+ 16-8 b々Un〇2 Cl NMR(CDC13) ：6.98-7.02(2H, m),7.27(lH,s), 7.79(lH,s),8.23 -8.27(2H,m) 16-9 Cl ch3 H广。以。成。2 MS(ESI): 372(M+Na)+ 16-10 h3c^ 0 ^ MS(ESI)： 363(M+Na)+ 16-11 h3c^ 0 ^ ^no2 MS(ESI): 356(M+H)+ 16-12 h 广 λΛ°χχ2 MS(ESI): 402,404(M+Na)+ -75- 200951122 m 34] Pr Structure Data 16-13 H3C、^aN〇2 Br MS(ESI)： 402,404(M+Na)+ 16-14 η^Λ^°^ν〇2 ch3 MS(ESI)： 372(M+Na)+ 16-15 Cl o 、人 N02 MS(ESI)： 359(M+Na)+. 17 身。力 h3c」 MS(ESI)： 310(M+H)+ 18 MS(ESI)： 258(M+Na)+ 19 h3c」 MS(ESI): 242(M+Na)+ 20 h3c-〇^9 h3c’、ch3 MS(ESI): 270(M+H)+ -76- 200951122 [表 35]Pr Structure Data 16-6 H-wide MS (ESI): 376(M+Na)+ 16-7 η^0^τ°Λν〇2 MS(ESI): 392,394(M+Na)+ 16-8 b々Un 〇2 Cl NMR (CDC13): 6.98-7.02 (2H, m), 7.27 (1H, s), 7.79 (1H, s), 8.23 - 8.27 (2H, m) 16-9 Cl ch3 H. To. to make. 2 MS (ESI): 372 (M+Na) + 16 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - H) + 16-12 h λ Λ ° 2 MS (ESI): 402, 404 (M+Na) + -75- 200951122 m 34] Pr Structure Data 16-13 H3C, ^aN〇2 Br MS (ESI): 402,404 ( M+Na)+ 16-14 η^Λ^°^ν〇2 ch3 MS(ESI): 372(M+Na)+ 16-15 Cl o , human N02 MS(ESI): 359(M+Na)+ 17 body. Force h3c" MS (ESI): 310 (M+H) + 18 MS (ESI): 258 (M+Na) + 19 h3c MS MS (ESI): 242 (M+Na) + 20 h3c-〇^9 h3c ', ch3 MS (ESI): 270 (M + H) + -76 - 200951122 [Table 35] -77- 200951122 [表 36]-77- 200951122 [Table 36] -78- 200951122 [表 37]-78- 200951122 [Table 37] Ex Structure 13 h3c H〇^ 14 15 16 17 18 h〇XJ0^ Xi^A^ci -79- 200951122 [表 38]Ex Structure 13 h3c H〇^ 14 15 16 17 18 h〇XJ0^ Xi^A^ci -79- 200951122 [Table 38] -80- 200951122 [表 39]-80- 200951122 [Table 39] 200951122 m 4〇]200951122 m 4〇] -82- 200951122 [表 41]-82- 200951122 [Table 41] -83- 200951122 m 42]-83- 200951122 m 42] -84- 200951122 m 43]-84- 200951122 m 43] -85- 200951122 m 44]-85- 200951122 m 44] -86- 200951122 m 45]-86- 200951122 m 45] -87- 200951122 m 46]-87- 200951122 m 46] -88- 200951122 m 47]-88- 200951122 m 47] -89- 200951122 m 48]-89- 200951122 m 48] -90- 200951122 m 49]-90- 200951122 m 49] -91 - 200951122 m 5〇]-91 - 200951122 m 5〇] -92- 200951122 [表 51]-92- 200951122 [Table 51] Ex Structure 97 98 H iH3 99 HOuS°aNxN^ h ^ 100 101 H OU 102 H WA〇/CF3 -93- 200951122 m 52] Ex Structure 103 h3c/ w/ 104 HOwS°aNvv; H ^ 105 H0^ ^ 106 H ^^CF3 107 Cl ch3 108 -94- 200951122 m 53]Ex Structure 97 98 H iH3 99 HOuS°aNxN^ h ^ 100 101 H OU 102 H WA〇/CF3 -93- 200951122 m 52] Ex Structure 103 h3c/ w/ 104 HOwS°aNvv; H ^ 105 H0^ ^ 106 H ^^CF3 107 Cl ch3 108 -94- 200951122 m 53] Ex Structure 109 110 111 ηλΛ。^^ CF3 112 113 H奶 114 Η0^Λ°αΝν H i)^_Br -95- 200951122 m 54] Ex Structure 115 λ j0&quot;〇Xi X/s H0 H 116 ch3 117 118 119 ΗΛ^ά，Ν〇〇 120 ΗΟιΛοΛκχ^ -96- 200951122 m 55]Ex Structure 109 110 111 ηλΛ. ^^ CF3 112 113 H milk 114 Η0^Λ°αΝν H i)^_Br -95- 200951122 m 54] Ex Structure 115 λ j0&quot;〇Xi X/s H0 H 116 ch3 117 118 119 ΗΛ^ά,Ν〇〇 120 ΗΟιΛοΛκχ^ -96- 200951122 m 55] Ex Structure 121 122 123 124 Η N心 125 H0^°^v，F 126 ΗΟιΛ°χ&gt;Νν H -97- 200951122 m 56] Ex Structure 127 128 129 130 131 132 H °^&gt;CNEx Structure 121 122 123 124 Η N-heart 125 H0^°^v,F 126 ΗΟιΛ°χ&gt;Νν H -97- 200951122 m 56] Ex Structure 127 128 129 130 131 132 H °^&gt;CN -98- 200951122 m 57]-98- 200951122 m 57] Ex Structure 133 01 134 Η0Λ^°Χλ,Λ^ 135 hoiA°unv :办 136 hA^XXV^ 137 h3c \=r 138 ^〇Ία«ν -99- 200951122 [表 58] Ex Structure 139 140 141 142 143 h3c w 144 η/备Ex Structure 133 01 134 Η0Λ^°Χλ,Λ^ 135 hoiA°unv : 136 hA^XXV^ 137 h3c \=r 138 ^〇Ία«ν -99- 200951122 [Table 58] Ex Structure 139 140 141 142 143 h3c w 144 η/备 -100- 200951122 m 59]-100- 200951122 m 59] Ex Structure 145 H0^r°^V^ 心％ 146 147 148 ηΛ^Ά 149 ηΛ^Ά 150 H -101 - 200951122 m 6〇] Ex Structure 151 H0Xj5r°aN^ H ΙΛ〇^Ρ3 152 H 153 CF3 -102- 200951122 [表 61] Ex Data 1 NMR ： 3.61(2H,s),6.99(2H,d,J=9.0Hz),7.02(lH,d,J=8.4Hz),7.24( lH,dd,J=2.1,8.4Hz),7.50(lH,d,J=2.0Hz),7.76(2H,d,J=9.0Hz),7.83(lH ,d,J=8.3Hz),7.94(lH,dd,J=2.1,8.4Hz),8.21(lH,d,J=2.1Hz),10.42(lH,s ),12.47(lH,brs). MS(ESI) ： 448(M-H)·. mp ： 220-222 °C. 2 NMR ： 3.61(2H,s),6.98(2H,d,J=8.9Hz),7.01(lH,d,J=8.3Hz),7.24( lH,dd,J=2.0,8.4Hz),7.50(lH,d,J=1.9Hz),7.61(2H,d,J=8.6Hz),7.77(2H ，d，J=8.9Hz)，7.98(2H,d，J=8.4Hz),10.34(lH，s),12.48(lH,brs). MS(ESI) ： 438(M+Na)+. 3 NMR ： 2.39(3H,s),3.61(2H,s),6.97(2H,d,J=8.9Hz),7.00(lH,d,J= 8.3Hz),7.23(lH,dd,J=2.0,8.4Hz),7.33(2H,d,J=8.2Hz),7.50(lH,d,J= 2.0Hz),7.78(2H,d,J=9.0Hz),7.87(2H,d,J=8.2Hz),10.19(lH,s),12.46( lH,brs). MS(ESI) ： 418(M+Na)+. 4 NMR ： 3.61(2H,s),3.84(3H,s),6.97(2H,d,J=9.1Hz),7.00(lH,d,J= 8.3Hz),7.06(2H,d,J=8.8Hz),7.23(lH,dd,J=2.1,8.4Hz),7.49(lH,d,J= 2.0Hz),7.77(2H,d,J=9.0Hz),7.95(2H,d,J-8.4Hz),10.12(lH,s),12.46( lH’brs) MS(ESI) ： 434(M+Na)+. 103- 200951122 m 62] Ex Data 5 NMR : 3.62(2H，s)，7.02(2H,d，J=9.0Hz)，7.05(lH,d，J=8.4Hz)，7.26( lH，d，J=2.0,8.4Hz)，7.51(lH，d，J=2.0Hz),7.76(lH,t，J=7.5Hz)，7.90-7.94 (lH,m),7.96(2H,d,J=9.1Hz),8.13(lH,d,J=8.2Hz),8.25(lH,d,J=8.4Hz), 8.26(lH,d,J=8.3Hz),8.63(lH,d,J=8.6Hz),10.79(lH,s),12.48(lH,brs). MS(ESI) ： 455(M+Na)+. 6 NMR ： 3.62(2H,s),6.99(2H,d,J=9.0Hz),7.03(lH,d,J=8.4Hz),7.55( lH,dd,J=2.1,8.4Hz),7.37(lH,t,J=7.5Hz),7.49-7.53(2H,m),7.72(lH,d, J=8.3Hz),7.76(lH,s),7.80-7.84(3H,m),10.58(lH,s), 12.46(lH,brs). MS(ESI) ： 444(M+Na)+. mp ： 240-240.5 °C. 7 NMR ： 3.61(2H,s),6.98-7.03(3H,m),7.24(lH,dd,J=2.1,8.3Hz),7.26-7.40(2H,m),7.50(lH,d,J=2.0Hz),7.53-7.65(lH,m),7.74-7.85(lH,m),7.93-7.96(2H,m),10.97(lH,s),12.49(lH,brs), 13.44(lH,brs). MS(ESI) ： 444(M+Na)+. 8 NMR ： 3.62(2H,s),6.98-7.01(2H,m),7.03(lH,d,J=8.3Hz),7.25( 1 H，dd,J=2.1，8.5Hz)，7.51 (1 H，d，J=2.1Hz)，7.73-7.77(2H，m)，8.62 (lH，d,J=2.1Hz)，8.90(lH，d,J=2.2Hz)，10.57(lH,s)，12.48(lH,brs). MS(ESI) ： 473,475(M+Na)+. 9 NMR ： 3.62(2H,s),7.00-7.05(3H,m),7.25(lH,dd,J=2.1,8.4Hz),7.51( lH,d,J=2.1Hz),7.73(lH,t,J=8.0Hz),7.83(2H,d,J=9.0Hz),7.90(lH,dt,J =1.4,7.6Hz),8.12(lH,d,J=8.5Hz),8.16(lH,cU=7.6Hz),8.96(lH,d,J=2. 0Hz),9.36(lH,d,J=2.3Hz),10.65(lH,s),12.48(lH,brs). MS(ESI) ： 455(M+Na)+. 10 NMR ： 3.62(2H,s),6.99-7.04(3H,m),7.25(lH,dd,J=2.1,8.4Hz),7.51( lH,d,J=2.1Hz),7.85(1 H,dt,J=l.2,7.6Hz),7.90-7.94(lH,m),7.96-8.00 (2H,m),8.26(lH,d,J=8.1Hz),8.31(lH,d,J=7.6Hz),8.71(lH,s),9.48(lH, s),10.83(lH,s),12.49(lH,brs). MS(ESI) : 455(M+Na)+. 11 NMR ： 3.62(2H,s),7.00-8.30(9H,m),11.09(lH,s),12.43(lH,br). MS(ESI) : 473(M+Na)+ 12 NMR ： 2.45(3H,s),5.08(2H,s),6.65-8.30(10H,m),10.39(lH,s),13.33 (lH,brs). MS(ESI) ： 492(M+Na)+ 13 NMR ： 2.45(3H,s),5.08(2H,s),6.60-7.75(14H,m),10.21(lH,s), 13.32(lH,brs). MS(ESI) ： 450(M+Na)+ 14 NMR ： 3.65(2H,s),7.15(lH,d,J=8.8Hz),7.24(lH,d,J=8.2Hz),7.29 (lH,dd,J=1.9,8.3Hz),7.49(lH,d,J=1.9Hz),7.84(lH,d,J=8.3Hz),7.94( lH,dd，J=2.1，8.5Hz),8.20-8.23(2H,m)，8.41(lH,d,J=2.6Hz)， 10.56(lH,s),12.50(lH,brs). MS(ESI) ： 449,45 l(M-H)*. 15 NMR ： 3.58(2H,s),3.74(3H,s),6.83-6.87(3H,m),6.96(lH,d,J=8.0Hz), 7.08(lH,d,J=1.8Hz),7.67(2H,d,J=9.0Hz),7.82(lH,d,J=8.3Hz),7.93( lH,dd,J=2.0,8.4Hz),8.20(lH,d,J=2.1Hz),10.35(lH,s),12.37(lH,brs). MS(ESI) ： 468,470(M+Na)+.Ex Structure 145 H0^r°^V^ Heart% 146 147 148 ηΛ^Ά 149 ηΛ^Ά 150 H -101 - 200951122 m 6〇] Ex Structure 151 H0Xj5r°aN^ H ΙΛ〇^Ρ3 152 H 153 CF3 -102 - 200951122 [Table 61] Ex Data 1 NMR: 3.61 (2H, s), 6.99 (2H, d, J = 9.0 Hz), 7.02 (1H, d, J = 8.4 Hz), 7.24 ( lH, dd, J = 2.1, 8.4 Hz), 7.50 (lH, d, J = 2.0 Hz), 7.76 (2H, d, J = 9.0 Hz), 7.83 (lH, d, J = 8.3 Hz), 7.94 (lH, dd, J = 2.1, 8.4 Hz), 8.21 (lH, d, J = 2.1 Hz), 10.42 (lH, s), 12.47 (lH, brs). MS (ESI): 448 (MH)·. mp : 220-222 °C 2 NMR : 3.61 (2H, s), 6.98 (2H, d, J = 8.9 Hz), 7.01 (lH, d, J = 8.3 Hz), 7.24 (1H, dd, J = 2.0, 8.4 Hz), 7.50 (lH, d, J = 1.9 Hz), 7.61 (2H, d, J = 8.6 Hz), 7.77 (2H, d, J = 8.9 Hz), 7.98 (2H, d, J = 8.4 Hz), 10.34 (lH , s), 12.48 (lH, brs). MS (ESI): 438 (M+Na) +. 3 NMR: 2.39 (3H, s), 3.61 (2H, s), 6.97 (2H, d, J = 8.9 Hz), 7.00 (lH, d, J = 8.3 Hz), 7.23 (lH, dd, J = 2.0, 8.4 Hz), 7.33 (2H, d, J = 8.2 Hz), 7.50 (lH, d, J = 2.0) Hz), 7.78 (2H, d, J = 9.0 Hz), 7.87 (2H, d, J = 8.2 Hz), 10.19 (lH, s), 12.46 (lH, brs). MS (ESI): 418 (M+ Na)+. 4 NMR: 3.61 (2H, s), 3.84 (3H, s), 6.97 (2H, d, J = 9.1 Hz), 7.00 (1H, d, J = 8.3 Hz), 7.06 (2H, d , J=8.8H z), 7.23 (lH, dd, J = 2.1, 8.4 Hz), 7.49 (lH, d, J = 2.0 Hz), 7.77 (2H, d, J = 9.0 Hz), 7.95 (2H, d, J-8.4) Hz), 10.12 (lH, s), 12.46 ( lH'brs) MS (ESI): 434 (M+Na)+. 103- 200951122 m 62] Ex Data 5 NMR : 3.62 (2H, s), 7.02 (2H , d, J = 9.0 Hz), 7.05 (lH, d, J = 8.4 Hz), 7.26 (lH, d, J = 2.0, 8.4 Hz), 7.51 (lH, d, J = 2.0 Hz), 7.76 (lH , t, J = 7.5 Hz), 7.90-7.94 (lH, m), 7.96 (2H, d, J = 9.1 Hz), 8.13 (lH, d, J = 8.2 Hz), 8.25 (lH, d, J = 8.4 Hz), 8.26 (lH, d, J = 8.3 Hz), 8.63 (lH, d, J = 8.6 Hz), 10.79 (lH, s), 12.48 (lH, brs). MS (ESI): 455 (M) +Na)+. 6 NMR: 3.62 (2H, s), 6.99 (2H, d, J = 9.0 Hz), 7.03 (1H, d, J = 8.4 Hz), 7.55 (1H, dd, J = 2.1, 8.4 Hz), 7.37 (lH, t, J = 7.5 Hz), 7.49-7.53 (2H, m), 7.72 (lH, d, J = 8.3 Hz), 7.76 (lH, s), 7.80-7.84 (3H, m ), 10.58 (lH, s), 12.46 (1H, brs). MS (ESI): 444 (M+Na)+. mp: 240-240.5 ° C. 7 NMR: 3.61 (2H, s), 6.98-7.03 (3H,m), 7.24 (lH, dd, J=2.1, 8.3 Hz), 7.26-7.40 (2H, m), 7.50 (lH, d, J = 2.0 Hz), 7.53-7.65 (lH, m), 7.74-7.85 (lH, m), 7.93-7.96 (2H, m), 10.97 (1H, s), 12.49 (lH, brs), 13.44 (lH, brs). MS (ESI): 444 (M+Na) +. 8 NMR : 3.62 (2H, s), 6.98-7.01 (2H, m), 7.03 (1H, d, J = 8.3 Hz), 7.25 ( 1 H Dd, J = 2.1, 8.5 Hz), 7.51 (1 H, d, J = 2.1 Hz), 7.73 - 7.77 (2H, m), 8.62 (lH, d, J = 2.1 Hz), 8.90 (lH, d, J = 2.2 Hz), 10.57 (lH, s), 12.48 (1H, brs). MS (ESI): 473, 475 (M+Na) +. 9 NMR: 3.62 (2H, s), 7.00-7.05 (3H, m ), 7.25 (lH, dd, J = 2.1, 8.4 Hz), 7.51 (lH, d, J = 2.1 Hz), 7.73 (lH, t, J = 8.0 Hz), 7.83 (2H, d, J = 9.0 Hz) ), 7.90 (lH, dt, J = 1.4, 7.6 Hz), 8.12 (lH, d, J = 8.5 Hz), 8.16 (lH, cU = 7.6 Hz), 8.96 (lH, d, J = 2. 0 Hz) , </ RTI> </ RTI> <RTIgt; 6.99-7.04(3H,m), 7.25(lH,dd,J=2.1,8.4Hz), 7.51( lH,d,J=2.1Hz), 7.85(1 H,dt,J=l.2,7.6Hz ), 7.90-7.94 (lH, m), 7.96-8.00 (2H, m), 8.26 (lH, d, J = 8.1 Hz), 8.31 (lH, d, J = 7.6 Hz), 8.71 (lH, s) , 9.48 (lH, s), 10.83 (lH, s), 12.49 (1H, brs). MS (ESI): 455 (M+Na) +. 11 NMR : 3.62 (2H, s), 7.00-8.30 (9H , m), 11.09 (lH, s), 12.43 (1H, br). MS (ESI): 473 (M+Na) + 12 NMR: 2.45 (3H, s), 5.08 (2H, s), 6.65-8.30 (10H, m), 10.39 (1H, s), 13.33 (1H, s), MS (ESI): 492 (M+Na) + 13 NMR: 2.45 (3H, s), 5.08 (2H, s), 6.60 - 7.75 (14H, m), 10.21 (1H, s), 13.32 (1H, brs). MS (ESI): 450 (M+Na) + 14 NMR: 3. 65(2H, s), 7.15 (lH, d, J = 8.8 Hz), 7.24 (lH, d, J = 8.2 Hz), 7.29 (lH, dd, J = 1.9, 8.3 Hz), 7.49 (lH, d , J = 1.9 Hz), 7.84 (lH, d, J = 8.3 Hz), 7.94 (lH, dd, J = 2.1, 8.5 Hz), 8.20-8.23 (2H, m), 8.41 (lH, d, J = 2.6 Hz), 10.56 (lH, s), 12.50 (1H, brs). MS (ESI): 449, 45 l (MH)*. 15 NMR: 3.58 (2H, s), 3.74 (3H, s), 6.83 -6.87(3H,m), 6.96(lH,d,J=8.0Hz), 7.08(lH,d,J=1.8Hz), 7.67(2H,d,J=9.0Hz),7.82(lH,d, J = 8.3 Hz), 7.93 (lH, dd, J = 2.0, 8.4 Hz), 8.20 (lH, d, J = 2.1 Hz), 10.35 (lH, s), 12.37 (lH, brs). MS (ESI) : 468,470(M+Na)+. -104- 200951122-104- 200951122 m 63] Ex Data 16 NMR : 3.66(2H，s)，7.31(lH，dd,J=1.9,8.4Hz)，7.35(lH,d，J=8.2Hz), 7.51(lH,d,J=1.8Hz),7.87(lH,d,J=B.5Hz),7.96(lH,dd,J=2.158.5Hz), 8.23(lH,d,J=2.1Hz),8.94(2H,s),10.75(lH,s),12.53(lH,brs). MS(ESI) : 474,476(M+Na)+. 17 NMR : 3.62(2H，s)，6.98-7.02(2H，m)，7.07-7.13(2H，m),7.31(lH，d，J= 12.8Hz)，7.73-7.77(2H，m)，7.82(lH，d，J=8.3Hz)，7.94(lH,dd，J=2.1， 8.4Hz)，8.21(lH，d，J=2.1Hz)，10.42(lH，s)，12.47(lH,brs). MS(ESI) ： 456,458(M+Na)+. 18 NMR ： 3.58(2H,s),6.84-6.86(lH,m),7.14-7.16(lH,m),7.44-7.50(3H, m)，7.83-7.96(4H，m)，8.22-8.23(lH,m)，10.59(lH，s)，12.46(lH，brs). MS(ESI) : 488(M+Na)+. 19 NMR : 3.62(2H，s)，7.00-7.04(2H,m)，7.06-7.12(2H，m)，7.28-7.40( 3H，m)，7.55-7.63(lH,m)，7.77-7.84(lH，m)，7.91-7.95(2H,m)，10.96( lH，s)，12.46(lH,brs),13.44(lH，brs). MS(ESI) ： 404(M-H)·. 20 NMR : 3.59(2H,s)，3.75(3H,s)，6.85-6.88(3H，m)，6.96(lH,d，J=8.0Hz)， 7.08(lH，d，J=1.8Hz)，7.27-7.39(2H,m)，7.55-7.62(lH，m)，7.74-7.82 (lH，m)，7.83-7.87(2H，m),10.86(lH,s)，12.38(lH，brs)，13.41(lH，brs). MS(ESI) ： 416(M-H)·. 21 NMR : 3.67(2H,s),7.32(lH，dd，J=1.9,8.4Hz)，7.36(lH，d，J=8.2Hz)， 7.29-7.43(2H,m),7.52(lH,d,J=1.8Hz),7.55-7.63(lH,m),7.75-7.85 (lH,m),9.10(2H,s),11.39(lH,s),12.53(lH,brs),13.57(lH,brs). MS(ESI) ： 422(M-H)·. 22 NMR ： 3.65(2H,s),7.18(lH,d,J=8.9Hz),7.25(lH,d,J=8.2Hz),7.29 (lH,dd,J=2.0,8.4Hz),7.30-7.40(2H,m),7.49(lH,d,J=1.9Hz),7.55-7.62(lH,m),7.76-7.83(lH,m),8.37(lH,dd,J=2.7,8.9Hz), 8.61(lH,d,J=2.5Hz),11.17(lH,s),12.51(lH,brs),13.50(lH,brs). MS(ESI) ： 421(M-H)'. 23 NMR ： 3.61(2H,s),6.99(2H,d,J=9.0Hz),7.00(lH,d,J=8.4Hz),7.23( lH,dd,J=2.0,8.4Hz),7.50(lH,d,J=1.9Hz),7.56(lH,dd,J=1.8,8.2Hz), 7.63(lH,d,J=8.2Hz),7.71(2H,d,J=8.9Hz),7.77(lHscU=1.9Hz),10.57(l H,s),12.47(lH,brs). MS(ESI) ： 472,474(M+Na)+. 24 NMR ·· 3.61(2H,s),6.96-7.00(2H,m),7.02(lH,d,J=8.3Hz),7.24( lH,dd,J=2.1,8.4Hz),7.50(lH,d,J=2.2Hz),7.57(lH,t,J=7.9Hz),7.65-7.68(lH,m),7.75-7.79(2H,m),7.91(lH,dt,J=1.2,7.9Hz),8.00(lH,t,J= 1.8Hz),10.38(lH,s),12.48(lH,brs). MS(ESI) ： 438,440(M+Na)+. 25 NMR ： 3.61(2H,s),3.95(3H,s),6.95-6.99(2H,m),7.01(lH,d,J=8.4Hz), 7.24(lH,dd,J=2.1,8.4Hz),7.30(lH,d,J=8.8Hz),7.50(lH,d,J=2.0Hz), 7.74-7.78(2H,m),7.97(lH,dd,J=2.2,8.8Hz),8.08(lH,d,J=2.2Hz), 10.22(lH,s),12.48(lH,brs). MS(ESI) ： 468,470(M+Na)+. -105- 200951122 m 641 Ex Data 26 NMR ： 3.58(2H,s),6.85-6.88(lH,m),7.14-7.20(lH,m),7.31-7.60 (5H,m),7.64-7.66(1 H,m),7-81 -7.83(lH,m),8.06-8.12(2H,m), 11.17 (lH,s),12.46(lH,brs),13.51(lH,s).MS(ESI) ： 460(M+Na)+ 27 NMR ： 3.61(2H,s),6.96-7.00(2H,m),7.02(lH,d,J=8.4Hz),7.24(lH5 dd,J=2.1,8.4Hz),7.50(lH,d,J=2.1Hz)57.74-7.78(2H,m),7.87(lH,t,J= 1.9Hz),7.98(2H,d,J=1.9Hz),10.45(lH,s),12.47(lH,brs). MS(ESI) : 448,450(M-HV. 28 NMR ： 3.62(2H,s),6.96-7.00(2H,m),7.02(lH,d,J=8.4Hz),7.24( lH,dd,J=2.1,8.5Hz),7.50(lH,d,J=2.1Hz),7-60(lH,t,J=8.9Hz), 7.74-7.78(2H,m),7.97-8.01(lH,m),8.20(lH,dd,J=2.2,7.2Hz), 10.38 (lH,s),12.46(lH,brs). MS(ESI) ： 456,458(M+Na)+. 29 NMR ： 3.61(2H,s),3.96(3H,s),6.97-7.00(2H,m),7.02(lH,d,J=8.4Hz), 7.24(lH,dd,J=2.1,8.5Hz),7.50(lH,d,J=2.1Hz),7.57(lH,dd,J=2.1,8.2 Hz),7.60(lH,d,J=8.2Hz),7.65(lH,d,J=1.6Hz),7.73-7.78(2H,m), 10.32(lH,s),12.49(lH,brs). MS(ESI) ： 468,470(M+Na)+. 30 NMR ： 3.62(2H,s),6.99-7.09(4H,m),7.20-7.26(2H,m),7.41-7.51(3H,m),7.67-7.69(lH,m),7.80-7.84(2H,m),10.26(lH,s), 11.75(lH,s),12.47(lH,brs). MS(ESI) : 443(M+Na)+. 31 NMR ： 3.62(2H,s),6.93-7.03(3H,m),7.23-7.26(lH,m),7.48-7.51(lH,m),7.76-7.84(2H,m)58.10-8.13(lH,m),8.21-8.23(lH,m), 8.78-8.79(lH,m),9.58(lH,s),10.47(lH,s),12.47(lH,brs). MS(ESI) ： 461(M+Na)+. 32 NMR ： 3.60(2H,s),6.97-7.03(3H,m),7.23-7.25(lH,m),7.40-7.95(1 lH,m),8.22-8.23(lH,m),10.39(lH,s),12.50(lH,brs). MS(ESI) : 480(M+Na)+. 33 NMR ： 3.59(2H,s),3.80(3H,s),6.96-8.04(15H,m),10.31(lH,s), 12.47(lH,brs). MS(ESI) ： 510(M+Na)+. 34 NMR ： 2.85(2H,U=5.9Hz),3-59(2H,s),3.69(2H,t,J=5.9Hz), 4.63(2H,s),6.87-6.91(2H,m),6.93(lH,d,J=B.4Hz),7.15-7.22(5H,m),7.45-7.50(3H,m),8.60(lH,s),12.45(lH,brs). MS(ESI) ： 459(M+Na)+. mp ： 167-169 °C. 35 NMR ： 3.61(2H,s),6.70-7.80(14H,m),10.26(lH,s),12.47(lH,brs). MS(ESI) ： 430(M+Na)+. 36 NMR ： 3.61(2H,s),6.80-7.95(12H,m),l〇.29(lH,s),12.48(lH,brs). MS(ESI) ： 474(M-H)*. 37 NMR ： 2.45(3H,s),5.08(2H,s),6.60-8.00(12H,m),10.24(lH,s), 13.30(lH,brs). MS(ESI) ： 496(M+H)+. 38 NMR ： 1.12(3H,t,J=7.3Hz),3.35-3.41(2H,m),3.62(2H,s),6.98-7.03(3H,m),7.23-7.26(lH,m),7.50-7.51(lH,m),7.77-7.81(2H,m), 8.03-8.06(2H,m),8.17-8.19(2H,m),10.55(lH,s),12.47(lH,brs). MS(ESI) ： 496(M+Na)+. -106- 200951122m 63] Ex Data 16 NMR : 3.66 (2H, s), 7.31 (lH, dd, J = 1.9, 8.4 Hz), 7.35 (lH, d, J = 8.2 Hz), 7.51 (lH, d, J = 1.8) Hz), 7.87 (lH, d, J = B. 5 Hz), 7.96 (lH, dd, J = 2.158.5 Hz), 8.23 (lH, d, J = 2.1 Hz), 8.94 (2H, s), 10.75 ( lH, s), 12.53 (1H, brs). MS (ESI): 474, 476 (M+Na) +. 17 NMR: 3.62 (2H, s), 6.98-7.02 (2H, m), 7.07-7.13 (2H, m), 7.31 (lH, d, J = 12.8 Hz), 7.73 - 7.77 (2H, m), 7.82 (lH, d, J = 8.3 Hz), 7.94 (lH, dd, J = 2.1, 8.4 Hz), 8.21 (lH, d, J = 2.1 Hz), 10.42 (1H, s), 12.47 (1H, brs). MS (ESI): 456, 458 (M+Na) +. 18 NMR : 3.58 (2H, s), 6.84 -6.86(lH,m),7.14-7.16(lH,m),7.44-7.50(3H,m),7.83-7.96(4H,m),8.22-8.23(lH,m),10.59(lH,s) MS (ESI): 488 (M+Na) +. 19 NMR: 3.62 (2H, s), 7.00-7.04 (2H, m), 7.06-7.12 (2H, m), 7.28 -7.40( 3H,m), 7.55-7.63(lH,m),7.77-7.84(lH,m),7.91-7.95(2H,m),10.96(lH,s),12.46(lH,brs),13.44 (lH, brs). MS (ESI): 404 (MH)·. 20 NMR: 3.59 (2H, s), 3.75 (3H, s), 6.85-6.88 (3H, m), 6.96 (lH, d, J =8.0Hz), 7.08(lH,d,J=1.8Hz), 7.27-7.39(2H,m),7.55-7.62(l H, m), 7.74-7.82 (lH, m), 7.83-7.87 (2H, m), 10.86 (1H, s), 12.38 (lH, brs), 13.41 (lH, brs). MS (ESI): 416 (MH)· 21 NMR: 3.67 (2H, s), 7.32 (lH, dd, J = 1.9, 8.4 Hz), 7.36 (lH, d, J = 8.2 Hz), 7.29-7.43 (2H, m), 7.52 (lH, d, J = 1.8 Hz), 7.55-7.63 (lH, m), 7.75-7.85 (lH, m), 9.10 (2H, s), 11.39 (lH, s), 12.53 (lH, brs) , 13.57 (1H, brs). MS (ESI): 422 (MH). 22 NMR: 3.65 (2H, s), 7.18 (lH, d, J = 8.9 Hz), 7.25 (lH, d, J = 8.2 Hz), 7.29 (lH, dd, J=2.0, 8.4 Hz), 7.30-7.40 (2H, m), 7.49 (lH, d, J = 1.9 Hz), 7.55-7.62 (lH, m), 7.76-7.83 (lH,m), 8.37 (lH, dd, J=2.7, 8.9 Hz), 8.61 (lH, d, J = 2.5 Hz), 11.17 (lH, s), 12.51 (lH, brs), 13.50 (lH, MS (ESI): 421 (MH)'. 23 NMR: 3.61 (2H, s), 6.99 (2H, d, J = 9.0 Hz), 7.00 (1H, d, J = 8.4 Hz), 7.23 ( lH, dd, J = 2.0, 8.4 Hz), 7.50 (lH, d, J = 1.9 Hz), 7.56 (lH, dd, J = 1.8, 8.2 Hz), 7.63 (lH, d, J = 8.2 Hz), 7.71 (2H, d, J = 8.9 Hz), 7.77 (lHscU = 1.9 Hz), 10.57 (l H, s), 12.47 (lH, brs). MS (ESI): 472, 474 (M+Na) +. 24 NMR · · 3.61 (2H, s), 6.96-7.00 (2H, m), 7.02 (lH, d, J = 8.3 Hz), 7.24 (lH, dd, J = 2.1, 8.4 Hz), 7.50 (lH, d, J=2.2 Hz), 7.57 (lH, t, J=7.9 Hz), 7.65-7.68 (lH, m), 7.75-7.79 (2H, m), 7 .91 (lH, dt, J = 1.2, 7.9 Hz), 8.00 (lH, t, J = 1.8 Hz), 10.38 (lH, s), 12.48 (lH, brs). MS (ESI): 438,440 (M+ Na)+. 25 NMR: 3.61 (2H, s), 3.95 (3H, s), 6.95-6.99 (2H, m), 7.01 (1H, d, J = 8.4 Hz), 7.24 (lH, dd, J = 2.1, 8.4 Hz), 7.30 (lH, d, J = 8.8 Hz), 7.50 (lH, d, J = 2.0 Hz), 7.74-7.78 (2H, m), 7.97 (lH, dd, J = 2.2, 8.8 Hz), 8.08 (lH, d, J = 2.2 Hz), 10.22 (lH, s), 12.48 (lH, brs). MS (ESI): 468,470 (M+Na)+. -105- 200951122 m 641 Ex Data 26 NMR : 3.58 (2H, s), 6.85-6.88 (lH, m), 7.14-7.20 (lH, m), 7.31-7.60 (5H, m), 7.64-7.66 (1 H, m), 7-81 -7.83 (lH, m), 8.06-8.12 (2H, m), 11.17 (lH, s), 12.46 (lH, brs), 13.51 (lH, s). MS (ESI): 460 (M+Na)+ 27 NMR : 3.61 (2H, s), 6.96-7.00 (2H, m), 7.02 (1H, d, J = 8.4 Hz), 7.24 (lH5 dd, J = 2.1, 8.4 Hz), 7.50 (lH, d, J = 2.1 Hz) 57.74-7.78 (2H, m), 7.87 (lH, t, J = 1.9 Hz), 7.98 (2H, d, J = 1.9 Hz), 10.45 (lH, s), 12.47 (lH, brs MS (ESI): 448, 450 (M-HV. 28 NMR: 3.62 (2H, s), 6.96-7.00 (2H, m), 7.02 (1H, d, J = 8.4 Hz), 7.24 (1H, dd, J=2.1, 8.5 Hz), 7.50 (lH, d, J=2.1 Hz), 7-60 (lH, t, J=8.9 Hz), 7.74-7.78 (2H, m), 7.97-8.01 (lH, m ), 8.20 (lH, dd, J = 2.2, 7.2 Hz), 10.38 (lH, s), 12.46 (lH, brs). MS (ESI): 456, 458 ( M+Na)+. 29 NMR: 3.61 (2H, s), 3.96 (3H, s), 6.97-7.00 (2H, m), 7.02 (1H, d, J = 8.4 Hz), 7.24 (lH, dd, J = 2.1, 8.5 Hz), 7.50 (lH, d, J = 2.1 Hz), 7.57 (lH, dd, J = 2.1, 8.2 Hz), 7.60 (lH, d, J = 8.2 Hz), 7.65 (lH, d, J = 1.6 Hz), 7.73 - 7.78 (2H, m), 10.32 (lH, s), 12.49 (1H, brs). MS (ESI): 468, 470 (M+Na) +. 30 NMR : 3.62 (2H , s), 6.99-7.09 (4H, m), 7.20-7.26 (2H, m), 7.41-7.51 (3H, m), 7.67-7.69 (lH, m), 7.80-7.84 (2H, m), 10.26 (lH, s), 11.75 (lH, s), 12.47 (1H, brs). MS (ESI): 443 (M+Na) +. 31 NMR: 3.62 (2H, s), 6.93-7.03 (3H, m ), 7.23-7.26 (lH, m), 7.48-7.51 (lH, m), 7.76-7.84 (2H, m) 58.10-8.13 (lH, m), 8.21-8.23 (lH, m), 8.78-8.79 ( lH, m), 9.58 (lH, s), 10.47 (lH, s), 12.47 (1H, brs). MS (ESI): 461 (M+Na)+. 32 NMR: 3.60 (2H, s), 6.97 -7.03 (3H, m), 7.23-7.25 (lH, m), 7.40-7.95 (1 lH, m), 8.22-8.23 (lH, m), 10.39 (lH, s), 12.50 (lH, brs). MS (ESI): 480 (M+Na) +. 33 NMR: 3.59 (2H, s), 3.80 (3H, s), 6.96-8.04 (15H, m), 10.31 (lH, s), 12.47 (lH, MS (ESI): 510 (M+Na)+. 34 NMR: 2.85 (2H, U=5.9 Hz), 3-59 (2H, s), 3.69 (2H, t, J = 5.9 Hz), 4.63 (2H, s), 6.87-6.91 (2H, m), 6.93 (lH, d, J = B. 4 Hz), 7.15-7.22 (5H, m), 7.45-7.50 (3H, m), 8. 60 (lH, s), 12.45 (1H, brs). MS (ESI): 459 (M+Na)+. mp: 167-169 ° C. 35 NMR: 3.61 (2H, s), 6.70-7.80 (14H , m), 10.26 (lH, s), 12.47 (1H, brs). MS (ESI): 430 (M+Na)+. 36 NMR: 3.61 (2H, s), 6.80-7.95 (12H, m), l 〇.29(lH, s), 12.48 (lH, brs). MS (ESI): 474 (MH)*. 37 NMR: 2.45 (3H, s), 5.08 (2H, s), 6.60-8.00 (12H , m), 10.24 (lH, s), 13.30 (1H, brs). MS (ESI): 496 (M+H) +. 38 NMR: 1.12 (3H, t, J = 7.3 Hz), 3.35-3.41 ( 2H, m), 3.62 (2H, s), 6.98-7.03 (3H, m), 7.23-7.26 (lH, m), 7.50-7.51 (lH, m), 7.77-7.81 (2H, m), 8.03- 8.06(2H,m), 8.17-8.19(2H,m), 10.55(lH,s),12.47(lH,brs). MS(ESI) : 496(M+Na)+. -106- 200951122 m 65 Ex Data 39 NMR ： 3.62(2H,s),7.00-7.04(3H,m),7.24-7.26(lH,m),7.51-7.52(lH,m)，7.64-7.67(lH，m)，7.82-7.87(2H，m)，8.13-8.16(lH，m)，8.25-8.28(lH,m),8.54-8.56(lH，m)，8.63-8.64(lH,m)，9.01-9.03(lH，m)，10.56(lH，s)，12.52(lH,brs)· MS(ESI) ： 433(M+H)+. 40 NMR ： 3.60(2H,s),6.96-7.03(3H,m),7.06-7.11(lH,m),7.23- 7.25(lH,m),7.39-7.40(lH,m),7.44-7.51(3H,m),7.77- 7.83(2H,m),10.33(lH,s),11.91(lH,s). MS(ESI) ： 461(M+Na)i. 41 NMR ： 3.60(2H,s),6.95-6.99(2H,m),7.02(lH,d,J=8.4Hz),7.24(lH, dd,J=2.1，8.4Hz)，7.27(lH，d,J=4.1Hz)，7.50(lH，d，J=2.1Hz), 7.67-7.71(2H,m),7.90(lH,d,J=4.2Hz),10.34(lH,s). MS(ESI) ： 444,446(M+Na)+. 42 NMR ： 3.09-3.13(2H,m),3.36-3.39(2H,m),3.62(2H,s),6.89-6.95 (3H,m),7.19-7.22(lH,m),7.47-7.59(5H,m),7.73- 7.78(2H,m),10.34(lH,s),12.46(lH,brs),14.85(lH,brs). MS(ESI) ： 450(M+H)+. 43 NMR ： 3.53(2H,s),6.94-7.01(3H,m),7.21-7.24(lH,m),7.48-7.49 (lH,m),7.74-7.80(2H,m),7.90-7.92(2H,m),8.14-8.16(2H,m), 10.53(lH,s). MS(ESI) ： 472iM+Na)+. mp ： 238-240 °C. 44 NMR ： 3.57(2H,s),6.96-7.03(3H,m),7.23-7.25(lH,m),7.49-7.50 (lH,m),7.74-7.80(2H,m),8.10-8.12(lH,m),8.56-8.58(lH,m), 9.24-9.25(lH,m),10.70(lH,s). MS(ESI) ： 473(M+Na)+. 45 NMR ： 3.04(3H,s),3.61(2H,s),6.96-7.02(3H,m),7.22-7.25 (lH,m),7.40-7.51(3H,m),7.67-7.78(4H,m),9.97(lH,brs), 10.32(lH,s),12.50(lH,brs). MS(ESI) ： 497(M+Na)+. 46 NMR ： 2.58(3H,s),3.62(2H,s),6.90-8.20(12H,m),10.44(lH,s), 12.49(lH,brs). MS(ESI) : 485(M+Na)+. 47 NMR ： 3.61(2H,s),6.90-8.20(12H,m),8.48(lH,s),10.30(lH,s), 12.49(lH,brs) MS(ESI) ： 487(M+Na)+. 48 NMR ： 1.50-1.70(6H,m),3.10-3.35(4H,m),3.59(2H,s),6.90-7.80(1 lH,m),10.17(lH,s),12.55(lH,br). MS(ESI) ： 465(M+H)+. 49 NMR : 3.62(2H，s),6.90-8.35(1 lH，m),11.19(lH，s)，12.49(lH,brs). MS(ESI) ： 461(M+Na)+. 50 NMR ： 3.61(2H,s),6.90-7.90(12H,m),8.56(lH,t,J=2.1Hz),9.00-9.15 (2H,m),10.54(lH,s),12.48(lH,brs). MS(ESI) ： 481(M+Na)+. 51 NMR : 3.62(2H，s),3.78(3H，s),6.86-6.89(lH,m),6.98-7.03 (3H,m),7.13-7.14(lH,m),7.23-7.25(lH,m),7.31-7.36(2H,m),7.50-7.51(lH,m),7.79-7.83(2H,m),10.21(lH,s),11.60(lH,s),12.48(lH,brs). MS(ESI) ： 473(M+Na)+. 52 NMR ： 3.57(2H,s),6.82-6.85(lH,m),7.06-7.26(3H,m),7.43-7.52 (5H,m),7.68-7.70(lH,m),7.94- 7.97(2H,m),l〇.44(lH,s),11.83(lH,s),12.57(lH,brs). MS(ESI) : 459(M+Na)' -107- 200951122 [表66 Ex Data 53 NMR ： 3.59(2H,s),6.83-6.86(2H,m),6.92(lH,d,J=8.4Hz),7.04-7.08 (2H,m),7.20(lH,dd,J=2.1,8.5Hz),7.46(lH,d,J=2.0Hz),7.53-7.57 (2H,m),7.60-7.64(lH,m),7.71-7.73(2H,m),10.18(lH,brs), 12.45(lH,brs). MS(ESI) ： 440(M+Na)+. 54 NMR ： 3.60(2H,s),6.87-6.90(2H,m),6.96(lH,d,J=8.3Hz),7.05-7.08 (2H,m),7.22(lH,dd,J=2.1,8.5Hz),7.48(lH,d,J=2.2Hz),7.64(lH,dd,J= 2.2,8.5Hz),7.85(lH,d,J=2.1Hz),7.86(lH,d,J=8.5Hz),10.31(lH,brs), 12.45(lH,brs). MS(ESI) ： 508,510(M+Na)+. 55 NMR ： 3.60(2H,s),6.89-6.91(lH,m),7.06-7.08(lH,m),7.10-7.26 (3H,m),7.43-7.50(3H,m),7.59-7.62(lH,m),7.69-7.71(lH,m),7.98-8.02(lH,m),10.45(lH,s),11.82 (lH,s),12.50(lH,brs). MS(ESI) ： 461(M+Na)+. mp ： 220-221 °C. 56 NMR ： 3.62(2H,s),4.00,4.02(3H,s),6.97-7.02(3H,m),7.12-7.16 (lH,m),7.23-7.25(lH,m),7.30-7.34(2H,m),7.50-7.51(lH,m),7.56-7.58 (lH,m),7.69-7.71(lH,m),7.78-7.82(2H,m),10.37(lH,s), 12.47(lH,brs). MS(ESI) ： 435(M+H)+. mp ： 215-216 °C. 57 NMR ： 3.61(2H,s),6.58-6.59(lH,m),6.96-7.00(3H,m),7.22-7.25 (lH,m),7.46-7.50(3H,m),7.72-7.75(lH,m),7.80-7.84(2H,m),8.26-8.25 (lH,m),10.16(lH,s),11.40(lH,s),12.46(lH,brs). MS(ESI) ： 443(M+Na)+. 58 NMR ： 3.62(2H,s),6.97-7.03(3H,m),7.23-7.26(lH,m),7.50-7.51 (lH,m),7.59-7.66(lH,m),7.74-7.78(2H,m),7.85-7.88(lH,m),8.01- 8.06(lH,m),10.35(lH,s),12.48(lH,brs). MS(ESI) ： 440(M+Na)+. 59 NMR ： 3.61(2H,s),6.95-7.00(3H,m),7.12-7.24(3H,m),7.46-7.50 (2H,m),7.76-7.80(2H,m),8.18-8.20(lH,m),8.27- 8.28(lH,m),9.77(lH,s),11.73(lH,s),12.47(lH,brs). MS(ESI) : 421(M+H)+. 60 NMR ： 3.60(2H,s),6.89-6.91(lH,m),7.10-7.24(2H,m),7.50-7.58 (2H,m),7.84-7.95(3HJm),8.21-8.22(lH!m),10.61(lH,s), 12.46(lH,brs). MS(ESI) : 490(M+Na)+. 61 NMR ： 3.62(2H,s),6.99-7.03(3H,m),7.21-7.26(2H,m),7.40-7.51 (3H,m),7.78-7.83(3H,m),10.35(lH,s),11.98(lH,s),12.51(lH,brs). MS(ESI) : 453(M-H)_. 62 NMR ： 3.58(2H,s),3.93(3H,s),6.95-7.01(3H,m),7.22-7.34(2H,m), 7.49-7.50(lH,m),7.74-7.86(4H,m),10.19(lH,s). MS(ESI) ： 452(M+Na)+. 63 NMR ： 2.32(3H,s),3.61(2H,s),6.96-7.02(3H,m),7.23-7.25(lH,m), 7.44-7.50(2H,m),7.72-7.79(4H,m),10.26(lH,s),12.47(lH,brs). MS(ESI) ： 436(M+Na)+. 64 NMR ： 3.62(2H,s),6.98-7.04(3H,m),7.24-7.26(lH,m),7.50-7.51 (lH,m),7.76-7.81(3H,m),7.96-7.98(lH,m),8.26-8.29(2H,m), 10.51(lH,s),12.47(lH,brs). MS(ESI) ： 448(M-H)' -108- 200951122m 65 Ex Data 39 NMR : 3.62 (2H, s), 7.00-7.04 (3H, m), 7.24-7.26 (1H, m), 7.51-7.52 (1H, m), 7.64-7.67 (lH, m), 7.82-7.87(2H,m), 8.13-8.16(lH,m), 8.25-8.28(lH,m),8.54-8.56(lH,m),8.63-8.64(lH,m),9.01-9.03(lH m), 10.56 (lH, s), 12.52 (1H, brs). 7.06-7.11(lH,m),7.23- 7.25(lH,m),7.39-7.40(lH,m),7.44-7.51(3H,m),7.77- 7.83(2H,m),10.33(lH,s ), 11.91 (1H, s). MS (ESI): 461 (M+Na) i. 41 NMR: 3.60 (2H, s), 6.95-6.99 (2H, m), 7.02 (1H, d, J=8.4 Hz), 7.24 (lH, dd, J=2.1, 8.4 Hz), 7.27 (lH, d, J = 4.1 Hz), 7.50 (lH, d, J = 2.1 Hz), 7.67-7.71 (2H, m), 7.90 (1H, d, J = 4.2 Hz), 10.34 (1H, s). MS (ESI): 444, 446 (M+Na) +. 42 NMR: 3.09-3.13 (2H, m), 3.36-3.39 (2H, m), 3.62 (2H, s), 6.89-6.95 (3H, m), 7.19-7.22 (lH, m), 7.47-7.59 (5H, m), 7.73- 7.78 (2H, m), 10.34 (lH, s), 12.46 (lH, brs), 14.85 (1H, brs). MS (ESI): 450 (M+H) +. 43 NMR : 3.53 (2H, s), 6.94-7.01 (3H, m), 7.21. -7.24(lH,m), 7.48-7.49 (lH,m),7.74-7.80(2H,m),7.90-7.92(2H,m),8.14-8.16(2H,m), 10.53(lH,s) MS (ESI) : 472iM+Na)+. Mp : 238-240 ° C. 44 NMR : 3.57 (2H, s), 6.96-7.03 (3H, m), 7.23 - 7.25 (lH, m), 7.49-7.50 (lH, m), 7.74-7.80 (2H , m), 8.10-8.12 (lH, m), 8.56-8.58 (lH, m), 9.24-9.25 (lH, m), 10.70 (lH, s). MS (ESI): 473 (M+Na)+ 45 NMR : 3.04 (3H, s), 3.61 (2H, s), 6.96-7.02 (3H, m), 7.22-7.25 (lH, m), 7.40-7.51 (3H, m), 7.67-7.78 (4H , m), 9.97 (lH, brs), 10.32 (1H, s), 12.50 (1H, brs). MS (ESI): 497 (M+Na)+. 46 NMR: 2.58 (3H, s), 3.62 ( 2H, s), 6.90-8.20 (12H, m), 10.44 (1H, s), 12.49 (1H, brs). MS (ESI): 485 (M+Na)+. 47 NMR: 3.61 (2H, s) , 6.90-8.20 (12H, m), 8.48 (lH, s), 10.30 (lH, s), 12.49 (1H, brs) MS (ESI): 487 (M+Na) +. 48 NMR: 1.50-1.70 ( 6H, m), 3.10-3.35 (4H, m), 3.59 (2H, s), 6.90-7.80 (1 lH, m), 10.17 (lH, s), 12.55 (lH, br). MS (ESI): 465(M+H)+. 49 NMR: 3.62 (2H, s), 6.90-8.35 (1 lH, m), 11.19 (1H, s), 12.49 (lH, brs). MS (ESI): 461 (M +Na)+. 50 NMR: 3.61 (2H, s), 6.90-7.90 (12H, m), 8.56 (lH, t, J = 2.1 Hz), 9.00-9.15 (2H, m), 10.54 (lH, s ), 12.48 (lH, brs). MS (ESI): 481 (M+Na)+. 51 NMR: 3.62 (2H, s), 3.78 (3H, s), 6.86-6.89 (lH, m), 6.98- 7.03 (3H, m), 7.13 - 7.14 (lH, m), 7.23-7. 25 (lH, m), 7.31-7.36 (2H, m), 7.50-7.51 (lH, m), 7.79-7.83 (2H, m), 10.21 (lH, s), 11.60 (lH, s), 12.48 ( lH,brs). MS (ESI): 473 (M+Na)+. 52 NMR: 3.57 (2H, s), 6.82- 6.85 (lH, m), 7.06-7.26 (3H, m), 7.43-7.52 ( 5H,m), 7.68-7.70(lH,m),7.94- 7.97(2H,m), l〇.44(lH,s), 11.83(lH,s),12.57(lH,brs). MS (ESI) ) : 459(M+Na)' -107- 200951122 [Table 66 Ex Data 53 NMR : 3.59 (2H, s), 6.83-6.86 (2H, m), 6.92 (1H, d, J = 8.4 Hz), 7.04 -7.08 (2H,m), 7.20 (lH,dd,J=2.1,8.5Hz), 7.46 (lH,d,J=2.0Hz),7.53-7.57 (2H,m), 7.60-7.64 (lH,m ), 7.71-7.73 (2H, m), 10.18 (1H, brs), 12.45 (1H, brs). MS (ESI): 440 (M+Na)+. 54 NMR: 3.60 (2H, s), 6.87- 6.90 (2H, m), 6.96 (lH, d, J = 8.3 Hz), 7.05-7.08 (2H, m), 7.22 (lH, dd, J = 2.1, 8.5 Hz), 7.48 (lH, d, J = 2.2 Hz), 7.64 (lH, dd, J = 2.2, 8.5 Hz), 7.85 (lH, d, J = 2.1 Hz), 7.86 (lH, d, J = 8.5 Hz), 10.31 (lH, brs), 12.45 (lH, brs). MS (ESI): 508, 510 (M+Na) +. 55 NMR: 3.60 (2H, s), 6.89-6.91 (1H, m), 7.06-7.08 (lH, m), 7.10-7.26 (3H, m), 7.43-7.50 (3H, m), 7.59-7.62 (lH, m), 7.69-7.71 (lH, m), 7.98-8.02 (lH, m), 10.45 (lH, s), 11.82 (lH, s), 12.50 (lH, brs). MS (ESI): 461 (M+Na)+. mp: 220-221 °C 56 NMR : 3.62 (2H, s), 4.00, 4.02 (3H, s), 6.97-7.02 (3H, m), 7.12-7.16 (lH, m), 7.23-7.25 (lH, m), 7.30-7.34 (2H, m), 7.50-7.51 (lH, m), 7.56-7.58 (lH, m), 7.69-7.71 (lH, m), 7.78-7.82 (2H, m), 10.37 (lH, s), 12.47 (lH, brs). MS (ESI): 435 (M+H) +. mp: 215-216 ° C. 57 NMR: 3.61 (2H, s), 6.58-6.59 (lH, m), 6.96-7.00 ( 3H,m),7.22-7.25 (lH,m), 7.46-7.50(3H,m),7.72-7.75(lH,m),7.80-7.84(2H,m),8.26-8.25 (lH,m), 10.16 (lH, s), 11.40 (1H, s), 12.46 (1H, brs). MS (ESI): 443 (M+Na)+. 58 NMR: 3.62 (2H, s), 6.97-7.03 (3H, m), 7.23-7.26 (lH, m), 7.50-7.51 (lH, m), 7.59-7.66 (lH, m), 7.74-7.78 (2H, m), 7.85-7.88 (lH, m), 8.01 8.06 (lH, m), 10.35 (lH, s), 12.48 (1H, brs). MS (ESI): 440 (M+Na)+. 59 NMR: 3.61 (2H, s), 6.95-7.00 (3H, m), 7.12-7.24 (3H, m), 7.46-7.50 (2H, m), 7.76-7.80 (2H, m), 8.18-8.20 (lH, m), 8.27- 8.28 (lH, m), 9.77 ( lH, s), 11.73 (lH, s), 12.47 (1H, brs). MS (ESI): 421 (M+H) +. 60 NMR: 3.60 (2H, s), 6.89-6.91 (lH, m) , 7.10-7.24 (2H, m), 7.50-7.58 (2H, m), 7.84-7.95 (3HJm), 8.21-8.22 (lH!m), 10.61 (lH, s), 12.46 (lH, brs). MS (ESI): 490 (M+Na)+. 61 NMR: 3.62 (2H, s), 6.99-7.03 (3H, m), 7.21-7.26 (2H, m), 7.40-7.51 (3H, m), 7.78-7.83 (3H, m), 10.35 (lH, s), 11.98 (lH, s), 12.51 (lH, brs) MS (ESI): 453 (MH) _. 62 NMR: 3.58 (2H, s), 3.93 (3H, s), 6.95-7.01 (3H, m), 7.22-7.34 (2H, m), 7.49-7. (lH, m), 7.74-7.86 (4H, m), 10.19 (1H, s). MS (ESI): 452 (M+Na)+. 63 NMR: 2.32 (3H, s), 3.61 (2H, s ), 6.96-7.02 (3H, m), 7.23-7.25 (lH, m), 7.44-7.50 (2H, m), 7.72-7.79 (4H, m), 10.26 (lH, s), 12.47 (lH, brs MS(ESI): 436(M+Na)+. 64 NMR: 3.62 (2H, s), 6.98-7.04 (3H, m), 7.24-7.26 (lH, m), 7.50-7.51 (lH, m ), 7.76-7.81 (3H, m), 7.96-7.98 (lH, m), 8.26-8.29 (2H, m), 10.51 (lH, s), 12.47 (lH, brs). MS (ESI): 448 ( MH)' -108- 200951122 m 67 Ex Data 65 NMR : 2.50(6H，s)，3.70(2H,s)，6.96-7.02(3H，m)，7.14-8.09(llH，m)， 8.09-8.10(lH,m),10.34(lH,s). MS(ESI) ： 501(M+H)+. 66 NMR ： 3.59(2H,s),4.76(4H,s),6.89-6.92(2H,m),6.94(lH,d,J=8.4Hz), 7.21(lH,dd,J=2.1,8.5Hz),7.30-7.38(4H,m)57.48(lH,d,J=2.0Hz), 7.55-7.59(2H,m),8.39(lH,s),12.46(lH,brs). MS(ESI) ： 445,447(M+Na)+. 67 NMR ： 1.86-1.93(2H,m),2.74(2H,t,J=6.5Hz),3.59(2H,s),3.70 (2H,t,J=6.1Hz),6.89-6.98(4H,m),7.09-7.14(2H,m),7.21(lH,dd,J-2.0,8.4Hz)，7.36(lH，d，J=7.6Hz)，7.46-7.50(3H，m)，8_88(lH，s), 12.46(lH,brs). MS(ESI) ： 459,461(M+Na)+. 68 NMR : 2_54(3H,s)，3.61(2H，s)，6.96-6.99(2H，m),7_00(lH，d,J=8.3Hz), 7.23(lH，dd，J=2.0,8.4Hz)，7.38(2H，d，J=8.5Hz),7.50(lH,d,J=2.1Hz)，7. 75-7.79(2H,m)，7.92(2H,d，J=8.5Hz)，10.22(lH，s)，12.47(lH,brs). MS(ESI) : 450,452(M+Na)+. 69 NMR ： 2.30(3H,s),2.31(3H,s),3.61(2H,s),6.95-7.01(3H,m),7.22-7.29 (2H,m),7.49-7.50(lH,m),7.68-7.80(4H,m), 10.16(lH,s), 12.46(lH,brs). MS(ESI) ： 432(M+Na)+. 70 NMR ： 2.38(3H,s),3.62(2H,s),6.98-7.06(4H,m),7.23-7.25 (lH,m), 7.31-7.51(4H,m),7.79-7.83(2H,m),10.22(lH,s), 11.63(lH,s),12.48(lH,brs). MS(ESI) ： 457(M+Na)+. 71 NMR : 2.61(2H，t，J=7.7Hz)，2.91(2H,t,J=7.7Hz)，3.59(2H,s)，6.80-7.65 (12H，m)，9.94(lH，s),12.46(lH,brs). MS(ESI) ： 432(M+Na)+. 72 NMR ： 3.61(2H,s),6.80-7.10(4H,m),7.23(lH,dd,J=2.1,8.4Hz),7.40- 8.10(6H,m),8.59(lH,dd,J=1.6,4.8Hz),8.82(lH,d,J=2.1Hz),10.33(lH,s ),12.46(lH,brs). MS(ESI) ： 431(M+Na)+. 73 NMR ： 3.60(2H,s),6.90-8.05(10H,m),10.40(lH,s),12.53(lH,brs). MS(ESI) ： 456(M+Na)+. 74 NMR ： 2.42(3H,s),3.61(2H,s),6.90-8.00(10H,m),10.31(lH,s), 12_47(lH，brs). MS(ESI) ： 452(M+Na)+. 75 NMR ： 3.61(2H,s),6.90-8.00(10H,m),11.00(lH,s),12.49(lH,brs), 13.57(lH,brs). MS(ESI) ： 462(M+Na)+. 76 NMR ： 2.45(3H,s),3.59(2H,s),6.90-8.00(10H,m),10.92(lH,s), 13.30(lH,brs). MS(ESI) ： 434(M-H)·. 77 NMR : 2.20(3H,s)，3.54(2H,s),6.76-6.84(2H，m),7.16-7.18(lH,m)， 7.46-7.47(lH,m),7.57-7.60(lH,m),7.73-7.74(lH,m),7.81-7.85 (lH,m),7.93-7.95(lH,m),8.21-8.22(lH,m),10.40(lH,s). MS(ESI) ： 486(M+Na)+. 78 NMR ： 2.20(3H,s),3.59(2H,s),6.76-6.88(2H,m),7.05-7.09(lH,m) ,7.16-7.24(2H,m),7.41-7.49(3H，m),7.65-7.69(2H，m),7.76-7.77 (lH,m),10.21(lH,s),11.73(lH,s),12.46(lH,brs). MS(ESI) ： 457(M+Na)+. -109- 200951122 m 681 Ex Data 79 NMR : 3.64(2H，s)，6.81(lH，d，J=15.8Hz)，7.13(lH，d，J=8.8Hz)， 7.22(lH，d，J=8.3Hz)，7.28(lH，dd，J=2.1，8_3Hz)，7.40-7.48(4H，m)，7.59-7.65(3H，m),8.21(lH,dd，J=2.7,8.9Hz)，8.35(lH，d，J=2.6Hz),10.39(lH，s )，12.50(lH，brs). MS(ESI) ： 431(M+Na)+. 80 NMR ： 3.65(2H,s),7.07(lH,t,J=7.4Hz),7.16(lH,d,J=8.8Hz),7.21-7.30 (3H，m)，7.40(lH，d，J=1.5Hz)，7.46(lH，d，J=8.2Hz)，7.49(lH，d，J=l_8Hz)， 7.68(lH，d，J=8.0Hz)，8.25(lH，dd，J=2.7,8.9Hz)，8.48(lH,d，J=2.7Hz)，10 •40(lH，s)，11.80(lH，s)，12.50(lH，brs). MS(ESI) : 444(M+Na)+. 81 NMR : 3.61(2H，s)，6.87(lH，d，J=8.3Hz)，7.07(lH，d，J=8.9Hz)， 7.22(lH,dd,J=2.1,8.4Hz)，7_39(lH，dt，J=0.8,8.0Hz)，7.50-7.55(2H，m)，7.74(lH，d,J=8.5Hz)，7.78(lH，dd，J=1.6,8.8Hz)，7.79(lH,s)， 7.85(lH,d，J=7.6Hz)，8.16(lH，d,J=2.5Hz)，10.76(lH，s)，12.46(lH，brs). MS(ESI) ： 478,480(M+Na)+. 82 NMR ： 2.33(3H,s),3.61(2H,s),6.90-8.10(10H,m),10.3l(lH,s), 12.50(lH,br). MS(ESI) : 452(M+Na)+. 83 NMR ： 3.61(2H,s),3.82(3H,s),6.90-8.00(10H,m),10.86(lH,s), 12.50(lH,brs),13.30(lH,br). MS(ESI) : 452(M+H)+. 84 NMR ： 3.61(2H，s)，6.85(lH，d，J=8.4Hz),7.09(2H,d,J=9.0Hz)，7.20-7.26(2H,m)，7.43(lH,d，J=1.5Hz)，7.47(lH，d，J=8.2Hz)，7.51(lH，d，J=2.1 Hz)，7.69(lH,d，J=7.9Hz)，7.76(lH,dd，J=2.5,9.0Hz)，8.16(lH，d,J=2.4Hz ),10.40(lH,s),11.79(lH,s),12.45(lH,brs). MS(ESI) ： 477,479(M+Na)+. 85 NMR ： 2.75(2H,t5J=7.1Hz),3.31-3.36(2H,m),3.58(2H,s),6.08(lH,t,J= 5.7Hz),6.85-6.90(3H,m),7.17-7.25(4H,m),7.29-7.33(2H,m),7.37- 7.41(2H,m),7.46(lH,d,J=2.0Hz),8.50(lH,s),12.43(lH,brs). MS(ESI) ： 447,449(M+Na)+. 86 NMR ： 1.51-1.81(4H,m),2.67-2.90(3H,m),3.59(2H,s),4.25-4.28 (2H,m),6.86-6.93(3H,m),7.18-7.32(6H,m),7.46-7.50(3H,m), 8.55(lH,s),12.45(lH,brs). MS(ESI) ： 487(M+Na)+. 87 NMR ： 3.57(2H,s),6.97-7.03(3H,m),7.22-7.25(lH,m),7.49-7.50 (lH,m),7.73-7.78(2H,m),7.96-8.07(3H,m),10.56(lH,s), 12.50(lH,brs). MS(ESI) ： 490(M+Na)+. 88 NMR ： 2.31(3H,s),3.61(2H,s),6.95-7.00(3H,m),7.22-7.28 (2H,m),7.49-7.59(2H,m),7.89-7.93(2H,m),8.43-8.48(2H,m), 10.33(lH,s),12.45(lH,s). MS(ESI) ： 436(M+H)+. 89 NMR ： 3.59(2H,s),6.97-7.01(2H,m),7.03(lH,cU=8.3Hz), 7.24(lH，dd，J=2.1,8.4Hz)，7.50(lH,d，J=2.0Hz)，7.53(lH，dd,J=2.3,8-8 Hz),7.75-7.78(2H,m),7.79-7.83(2H,m),7.94(lH,d,J=2.1Hz), 10.65(lH,s). MS(ESI) ： 478,480(M+Na)+. -110- 200951122m 67 Ex Data 65 NMR : 2.50 (6H, s), 3.70 (2H, s), 6.96-7.02 (3H, m), 7.14-8.09 (llH, m), 8.09-8.10 (lH, m), 10.34 ( lH, s). MS (ESI): 501 (M+H) +. 66 NMR: 3.59 (2H, s), 4.76 (4H, s), 6.89-6.92 (2H, m), 6.94 (lH, d, J = 8.4 Hz), 7.21 (lH, dd, J = 2.1, 8.5 Hz), 7.30-7.38 (4H, m) 57.48 (lH, d, J = 2.0 Hz), 7.55-7.59 (2H, m), 8.39 (lH, s), 12.46 (1H, brs). MS (ESI): 445,447 (M+Na) +. 67 NMR: 1.86-1.93 (2H, m), 2.74 (2H, t, J = 6.5 Hz), 3.59 (2H, s), 3.70 (2H, t, J = 6.1 Hz), 6.89-6.98 (4H, m), 7.09-7.14 (2H, m), 7.21 (lH, dd, J-2.0, 8.4 Hz) , 7.36 (lH, d, J = 7.6 Hz), 7.46-7.50 (3H, m), 8_88 (lH, s), 12.46 (lH, brs). MS (ESI): 459,461 (M+Na)+. NMR: 2_54 (3H, s), 3.61 (2H, s), 6.96-6.99 (2H, m), 7_00 (lH, d, J = 8.3 Hz), 7.23 (lH, dd, J = 2.0, 8.4 Hz) , 7.38 (2H, d, J = 8.5 Hz), 7.50 (lH, d, J = 2.1 Hz), 7. 75-7.79 (2H, m), 7.92 (2H, d, J = 8.5 Hz), 10.22 ( lH, s), 12.47 (lH, brs). MS (ESI): 450,452 (M+Na) +. 69 NMR: 2.30 (3H, s), 2.31 (3H, s), 3.61 (2H, s), 6.95 -7.01 (3H, m), 7.22-7.29 (2H, m), 7.49-7.50 (lH, m), 7.68-7.80 (4H, m), 10.16 (lH, s), 12.46 (lH, brs). MS (ESI) : 432(M+Na)+. 70 NMR : 2.38 (3H, s), 3.62 (2H, s), 6.98-7.06 (4H, m), 7.23-7.25 (1H, m), 7.31-7.51 (4H, m), 7.79-7.83 (2H, m), 10.22 (lH, s), 11.63 (1H, s), 12.48 (1H, brs). MS (ESI): 457 (M+Na) +. 71 NMR: 2.61 (2H, t, J = 7.7 Hz ), 2.91 (2H, t, J = 7.7 Hz), 3.59 (2H, s), 6.80-7.65 (12H, m), 9.94 (lH, s), 12.46 (lH, brs). MS (ESI): 432 (M+Na)+. 72 NMR: 3.61 (2H, s), 6.80-7.10 (4H, m), 7.23 (lH, dd, J=2.1, 8.4 Hz), 7.40- 8.10 (6H, m), 8.59 (lH, dd, J = 1.6, 4.8 Hz), 8.82 (lH, d, J = 2.1 Hz), 10.33 (lH, s), 12.46 (lH, brs). MS (ESI): 431 (M+Na) +. 73 NMR: 3.60 (2H, s), 6.90-8.05 (10H, m), 10.40 (1H, s), 12.53 (1H, brs). MS (ESI): 456 (M+Na)+. 74 NMR : 2.42 (3H, s), 3.61 (2H, s), 6.90-8.00 (10H, m), 10.31 (lH, s), 12_47 (lH, brs). MS (ESI): 452 (M+Na)+ 75 NMR : 3.61 (2H, s), 6.90-8.00 (10H, m), 11.00 (1H, s), 12.49 (1H, brs), 13.57 (1H, brs). MS (ESI): 462 (M+ Na)+. 76 NMR: 2.45 (3H, s), 3.59 (2H, s), 6.90-8.00 (10H, m), 10.92 (1H, s), 13.30 (1H, brs). MS (ESI): 434 (MH)·. 77 NMR: 2.20 (3H, s), 3.54 (2H, s), 6.76-6.84 (2H, m), 7.16-7.18 (lH, m), 7.46-7.47 (lH, m), 7.57 -7.60(lH,m),7.73-7.74(l H, m), 7.81-7.85 (lH, m), 7.93-7.95 (lH, m), 8.21 - 8.22 (lH, m), 10.40 (lH, s). MS (ESI): 486 (M+Na) +. 78 NMR: 2.20 (3H, s), 3.59 (2H, s), 6.76-6.88 (2H, m), 7.05-7.09 (lH, m), 7.16-7.24 (2H, m), 7.41-7.49 ( 3H, m), 7.65-7.69 (2H, m), 7.76-7.77 (lH, m), 10.21 (lH, s), 11.73 (lH, s), 12.46 (lH, brs). MS (ESI): 457 (M+Na)+. -109- 200951122 m 681 Ex Data 79 NMR: 3.64 (2H, s), 6.81 (lH, d, J = 15.8 Hz), 7.13 (lH, d, J = 8.8 Hz), 7.22 (lH, d, J = 8.3 Hz), 7.28 (lH, dd, J = 2.1, 8_3 Hz), 7.40-7.48 (4H, m), 7.59-7.65 (3H, m), 8.21 (lH, dd, J = 2.7, 8.9 Hz), 8.35 (lH, d, J = 2.6 Hz), 10.39 (lH, s), 12.50 (lH, brs). MS (ESI): 431 (M+Na)+. 80 NMR: 3.65 ( 2H, s), 7.07 (lH, t, J = 7.4 Hz), 7.16 (lH, d, J = 8.8 Hz), 7.21-7.30 (3H, m), 7.40 (lH, d, J = 1.5 Hz), 7.46 (lH, d, J = 8.2 Hz), 7.49 (lH, d, J = l_8 Hz), 7.68 (lH, d, J = 8.0 Hz), 8.25 (lH, dd, J = 2.7, 8.9 Hz), 8.48 (lH,d,J=2.7 Hz), 10 •40 (lH, s), 11.80 (lH, s), 12.50 (lH, brs). MS (ESI): 444 (M+Na)+. 81 NMR: 3.61(2H,s), 6.87(lH,d,J=8.3Hz),7.07(lH,d,J=8.9Hz), 7.22(lH,d d, J = 2.1, 8.4 Hz), 7_39 (lH, dt, J = 0.8, 8.0 Hz), 7.50 - 7.55 (2H, m), 7.74 (lH, d, J = 8.5 Hz), 7.78 (lH, dd , J=1.6, 8.8 Hz), 7.79 (lH, s), 7.85 (lH, d, J = 7.6 Hz), 8.16 (lH, d, J = 2.5 Hz), 10.76 (lH, s), 12.46 (lH) MS (ESI): 478, 480 (M+Na) +. 82 NMR: 2.33 (3H, s), 3.61 (2H, s), 6.90-8.10 (10H, m), 10.3 (lH, s) , MS (ESI): 452 (M+Na) +. 83 NMR: 3.61 (2H, s), 3.82 (3H, s), 6.90-8.00 (10H, m), 10.86 (lH) , s), 12.50 (lH, brs), 13.30 (1H, br). MS (ESI): 452 (M+H) +. 84 NMR: 3.61 (2H, s), 6.85 (1H, d, J = 8.4 Hz), 7.09 (2H, d, J = 9.0 Hz), 7.20-7.26 (2H, m), 7.43 (lH, d, J = 1.5 Hz), 7.47 (lH, d, J = 8.2 Hz), 7.51 ( lH, d, J = 2.1 Hz), 7.69 (lH, d, J = 7.9 Hz), 7.76 (lH, dd, J = 2.5, 9.0 Hz), 8.16 (lH, d, J = 2.4 Hz), 10.40 ( lH, s), 11.79 (lH, s), 12.45 (1H, brs). MS (ESI): 477, 479 (M+Na) +. 85 NMR: 2.75 (2H, t5J = 7.1 Hz), 3.31-3.36 (2H , m), 3.58 (2H, s), 6.08 (lH, t, J = 5.7 Hz), 6.85-6.90 (3H, m), 7.17-7.25 (4H, m), 7.29-7.33 (2H, m), 7.37- 7.41 (2H, m), 7.46 (lH, d, J = 2.0 Hz), 8.50 (1H, s), 12.43 (1H, brs). MS (ESI): 447, 449 (M+Na) +. 86 NMR : 1.51-1.81(4H,m) , 2.67-2.90 (3H, m), 3.59 (2H, s), 4.25-4.28 (2H, m), 6.86-6.93 (3H, m), 7.18-7.32 (6H, m), 7.46-7.50 (3H, m), 8.55 (1H, s), 12.45 (1H, s). MS (ESI): 487 (M+Na)+. 87 NMR: 3.57 (2H, s), 6.97-7.03 (3H, m), 7.22 -7.25 (lH, m), 7.49-7.50 (lH, m), 7.73-7.78 (2H, m), 7.96-8.07 (3H, m), 10.56 (lH, s), 12.50 (lH, brs). MS (ESI): 490 (M+Na)+. 88 NMR: 2.31 (3H, s), 3.61 (2H, s), 6.95-7.00 (3H, m), 7.22-7.28 (2H, m), 7.49-7.59 (2H,m), 7.89-7.93(2H,m), 8.43-8.48(2H,m), 10.33(lH,s), 12.45(lH,s). MS(ESI) : 436(M+H)+ 89 NMR : 3.59 (2H, s), 6.97-7.01 (2H, m), 7.03 (1H, cd = 8.3 Hz), 7.24 (1H, dd, J = 2.1, 8.4 Hz), 7.50 (lH, d, J = 2.0 Hz), 7.53 (lH, dd, J = 2.3, 8-8 Hz), 7.75-7.78 (2H, m), 7.79-7.83 (2H, m), 7.94 (lH, d, J = 2.1 Hz) ), 10.65(lH,s). MS(ESI) : 478,480(M+Na)+. -110- 200951122 m 69] Ex Data 90 NMR : 2.43(3H，s)，3.61(2H，s)，6_97-7.00(2H，m)，7.03(lH，d，J=8_4Hz)， 7.24(lH，dd，J=2.1，8.3Hz)，7.32(lH,dd，J=1.4,8.6Hz)，7.50(lH，d，J=2.0 Hz)，7.59-7.62(2H，m)，7.68(lH,d，J=0.8Hz),7.80-7.84(2H，m)， 10.54(lH，s)，12.48(lH，brs). MS(ESI) ： 458,460(M+Na)+. 91 NMR ： 3.62(2H,s),6.97-7.01(2H,m),7.03(lH,d,J=8.3Hz), 7.25(lH,dd,J=2.1,8.5Hz),7.36(lH,dt,J=2.7,9.3Hz),7.51(lH,d,J=2.1 Hz),7.66(lH,dd,J=2.7,8.7Hz),7.75-7.78(2H,m),7.79-7.83(2H,m), 10.62(lH,s),12.47(lH,brs). MS(ESI) ： 462,464(M+Na)+. 92 NMR ： 1.59-1.62(2H,m),1.82-1.90(2H,m),3.17-3.23(2H,m), 3.59(2H，s)，4.02-4.05(2H，m)，5.21(lH，s)，6.87-6.93(3H，m)，7.19-7.22 (lH,m),7.36-7.39(2H,m),7.47-7.54(5H,m),8.53(lH,s),12.50(lH,brs). MS(ESI) ： 513(M-H)'. 93 NMR ： 3.00(6H,s),3.61(2H,s),6.75-6.77(2H,m),6.93-6.99(3H,m), 7.21-7.24(lH,m),7.48-7.49(lH,m),7.75-7.79(2H,m),7.85-7.87(2H,m), 9.90(lH,s),12.45(lH,brs). MS(ESI) ： 425(M+H)+. 94 NMR ： 3.61(2H,s),6.90-8.00(10H,m),11.04(lH,s),12.48(lH,brs), 13.63(lH,brs). MS(ESI) ： 478(M+Na)+. mp ： &gt;300 °C. 95 NMR ： 2.19(3H,s),3.51(2H,s),6.76(lH,dd,J=2.8,8.6Hz), 6.89(lH,d,J=2.8Hz),7.06(lH,d,J=8.3Hz),7.24(lH,dd,J=2.1,8.4Hz), 7.28(lH,d,J=8.6Hz),7.49(lH,dJ=2Hz),7.82(lH,d,J=8.4Hz), 7.94(lH,dd,J=2,8.5Hz)，8.20(lH，d，J=1.9Hz)，10.05(lH，s). MS(ESI) ： 486(M+Na)+. 96 NMR ： 2.24(3H,s),3-63(2H,s),6.70-7.70(1 lH,m),9.85(lH,s), 11.71(lH,s),12.49(lH,brs). MS(ESI) ： 457(M+Na)+. 97 NMR ： 2.11(3H,s),3.61(2H,s),6.94-7.00(3H,m),7.22-7.37(3H,m), 7.43-7.50(5H,m),7.71-7.73(2H,m),9.97(lH,s),12.50(lH,brs). MS(ESI) ： 444(M+Na)+. 98 NMR ： 2.78-2.82(2H,m),2.91(3H,s),3.50-3.55(2H5m),3.55(2H,s), 6.84-6.89(2H,m),6.91(lH,cU=8.4Hz),7.18-7.22(2H,m),7.24-7.32 (4H,m),7.42-7.46(2H,m),7.46(lH,d,J=2.2Hz),8.23(lH,s). MS(ESI) : 439,441(M+H)+_ 99 NMR : 2.88-2.92(4H，m)，3.59(2H，s)，3.59-3.62(4H，m)，6.87-6.91 (2H，m),6.93(lH，d，J=8.3Hz)，7.10-7.18(4H，m)， 7.20(lH，dd，J=2.1，8.3Hz)，7.46-7.50(3H,m),8.54(lH，s),12.42(lH，brs). MS(ESI) ·· 451，453(M+H)+. 100 NMR : 4.02(3H，s),5.03(2H，s),6_27-6.28(lH，m)，6.56-6.58(lH，m)， 7.02-7.23(5H，m)，7.28-7.33(3H,m)，7.56-7.58(lH，m)，7.69-7.70(lH，m) ,7·75-7.79(2H，m),1034(lH,s)，13.04(lH,bΓS)· MS(ESI) : 462(M+Na)+. -111 - 200951122 m 7〇] Ex Data 101 NMR ： 2.83-2.88(2H,m),3.68-3.71(2H,m),4.63(2H,s),5.02(2H,s), 6.27-6.28(lH,m),6.49-6.51(lH,m),6.90-6.96(2H,m),7.03-7.09 (lH,m),7.14-7.22(5H,m),7.27-7.28(lH,m),7.43-7.48(2H,m), 8.57(lH，s),12.99(lH,brs). MS(ESI) ： 464(M+Na)+. 102 NMR ： 3.61(2H,s),6.90-8.10(1 lH,m),10.39(lH,s),12.47(lH,brs). MS(ESI) ： 488(M+Na)+. 103 NMR ： 2.60(3H,s),3.62(2H,s),6.90-7.90(1 lH,m),10.46(lH,s), 12.46(1 H,brs). MS(ESI) ： 458(M+Na)+. 104 NMR ： 3.62(2H,s),4.17(3H,s),6.97-7.04(3H,m),7.23-7.26(lH,m), 7.34-7.51(3H,m),7.72-7.74(lH,m),7.80-7.82(lH,m),7.89-7.93 (2H5m),10.93(lH,s),12.50(lH,brs). MS(ESI) ： 436(M+H)+. 105 NMR ： 5.03(2H,s),6.27-6.28(lH,m),6.58-6.60(lH,m),7.00-7.13 (3Hsm),7.19-7.25(lH,m),7.30-7.31(lH,m),7.35-7.39(lH,m),7.48- 7.53(lH,m),7.69-7.84(5H,m),10.56(lH,s),13.05(lH,brs). MS(ESI) : 449(M+Na)+. 106 NMR ： 5.01(2H,s),6.25-6.26(lH,m),6.57-6.61(lH,in),7.00-7.21 (4H,m),7.27-7.30(lH,m),7.73-7.82(2H,m),7.91-7.98(2H,m), 8.14-8.19(2H,m)，10.48(lH,s),13.10(lH，brs). MS(ESI) : 477(M+Na)+. 107 NMR:2.19(3H，s)，3.59(2H，s)，4.02(3H，s)，6.75-6.77(lH，m)，6.85-6.87(lH，m)，7.12-7_20(2H，m)，7.30-7.34(2H，m),7.48-7.49(lH,m)， 7.55-7.71(3H,m)，7.79-7.80(lH,m),10.32(lH,s)，12.50(lH，brs). MS(ESI) ： 471(M+Na)+. 108 NMR : 3.60(2H，s)，4.02(3H，s),6.88-6.90(lH，m)，7.13-7.22(3H，m)， 7.31-7.35(2H,m),7.49-7.50(lH,m),7.58-7.61(2H,m),7.71-7.73 (lH，m)，7.94-7.98(lH，m)，10.55(lH,s)，12.46(lH，brs). MS(ESI) : 475(M+Na)+. 109 NMR : 3.66(2H，s),7.05-7.09(3H，m)，7.36-7.40(lH，m)，7.51(lH，dt，J= 1.3,7.8Hz)，7.68(lH，s)，7.73(lH，d,J=8.3Hz),7.78(lH，d，J=0_8Hz)， 7.83(lH，d，J=7.7Hz),7.85-7.89(2H，xn)，10.63(lH，s)_ MS(ESI) ： 478,480(M+Na)+. 110 NMR ： 3.67(2H,s),6.98-7.01(4H,m),7.20-7.24(lH,m),7.41(lH,d,J= 1.5Hz),7.47(lH,d,J=8.3Hz),7.66-7.69(2H,m),7.83-7.87(2H,m), 10.35(lH,s),11.83(lH,s). MS(ESI) ： 477,479(M+Na)+. 111 NMR ： 3.65(2H,s),7.16(lH,d,J=8.8Hz),7.24(lH,d,J=8.3Hz), 7.29(lH,ddJ=2.0,8.3Hz),7.49(lH,d,J=1.9Hz),7.93(2H,d,J=8.3Hz), 8.16(2H,d,J=8.2Hz),8.24(lH,dd,J=2.7,8.9Hz),8.43(lH,d,J=2.5Hz), 10.63(lH,s),12.49(lH,brs). MS(ESI) ： 449,451(M-H)·.m 69] Ex Data 90 NMR : 2.43 (3H, s), 3.61 (2H, s), 6_97-7.00 (2H, m), 7.03 (1H, d, J = 8_4 Hz), 7.24 (lH, dd, J = 2.1, 8.3 Hz), 7.32 (lH, dd, J = 1.4, 8.6 Hz), 7.50 (lH, d, J = 2.0 Hz), 7.59-7.62 (2H, m), 7.68 (lH, d, J = 0.8) Hz), 7.80-7.84 (2H, m), 10.54 (1H, s), 12.48 (1H, brs). MS (ESI): 458, 460 (M+Na)+. 91 NMR: 3.62 (2H, s), 6.97 -7.01 (2H, m), 7.03 (lH, d, J = 8.3 Hz), 7.25 (lH, dd, J = 2.1, 8.5 Hz), 7.36 (lH, dt, J = 2.7, 9.3 Hz), 7.51 ( lH,d,J=2.1 Hz), 7.66 (lH, dd, J=2.7, 8.7 Hz), 7.75-7.78 (2H, m), 7.79-7.83 (2H, m), 10.62 (lH, s), 12.47 (lH, brs). MS (ESI): 462, 464 (M+Na) +. 92 NMR: 1.59-1.62 (2H, m), 1.82-1.90 (2H, m), 3.17-3.23 (2H, m), 3.59 (2H, s), 4.02-4.05 (2H, m), 5.21 (lH, s), 6.87-6.93 (3H, m), 7.19-7.22 (lH, m), 7.36-7.39 (2H, m), 7.47 - 7.5 (MH). 6.75-6.77(2H,m), 6.93-6.99(3H,m), 7.21-7.24(lH,m),7.48-7.49(lH,m),7.75-7.79(2H,m),7.85-7.87(2H , m), 9.90 (lH, s), 12.45 (1H, brs). MS (ESI): 425 (M+H) +. 94 NMR: 3.61 (2H, s), 6.90-8.00 (10H, m), 11.04 (lH, s), 12.48 (1H, brs), 13.63 (1H, brs). MS (ESI): 478 (M+Na) +. mp : &gt; 300 ° C. 95 NMR : 2.19 (3H, s ), 3.51 (2H, s), 6.76 (lH, dd, J = 2.8, 8.6 Hz), 6.89 (lH, d, J = 2.8 Hz), 7.06 (lH, d, J = 8.3 Hz), 7.24 (lH) , dd, J = 2.1, 8.4 Hz), 7.28 (lH, d, J = 8.6 Hz), 7.49 (lH, dJ = 2 Hz), 7.82 (lH, d, J = 8.4 Hz), 7.94 (lH, dd, J = 2, 8.5 Hz), 8.20 (lH, d, J = 1.9 Hz), 10.05 (1H, s). MS (ESI): 486 (M+Na)+. 96 NMR: 2.24 (3H, s), 3-63 (2H, s), 6.70-7.70 (1 lH, m), 9.85 (1H, s), 11.71 (lH, s), 12.49 (lH, brs). MS (ESI): 457 (M+Na +. 97 NMR: 2.11 (3H, s), 3.61 (2H, s), 6.94-7.00 (3H, m), 7.22-7.37 (3H, m), 7.43-7.50 (5H, m), 7.71-7.73 (2H, m), 9.97 (lH, s), 12.50 (1H, brs). MS (ESI): 444 (M+Na) +. 98 NMR: 2.78-2.82 (2H, m), 2.91 (3H, s ), 3.50-3.55 (2H5m), 3.55 (2H, s), 6.84-6.89 (2H, m), 6.91 (lH, cU = 8.4 Hz), 7.18-7.22 (2H, m), 7.24-7.32 (4H, m), 7.42-7.46 (2H, m), 7.46 (1H, d, J = 2.2 Hz), 8.23 (1H, s). MS (ESI): 439,441 (M+H) + _ 99 NMR: 2.88-2.92 (4H, m), 3.59 (2H, s), 3.59-3.62 (4H, m), 6.87-6.91 (2H, m), 6.93 (lH, d, J = 8.3 Hz), 7.10-7.18 (4H, m ), 7.20 (lH, dd, J = 2.1, 8.3 Hz), 7.46-7.50 (3H, m), 8 .54 (lH, s), 12.42 (lH, brs). MS (ESI) · 451,453 (M+H) +. 100 NMR : 4.02 (3H, s), 5.03 (2H, s), 6_27- 6.28 (lH, m), 6.56-6.58 (lH, m), 7.02-7.23 (5H, m), 7.28-7.33 (3H, m), 7.56-7.58 (lH, m), 7.69-7.70 (lH, m ),7·75-7.79(2H,m),1034(lH,s),13.04(lH,bΓS)· MS(ESI) : 462(M+Na)+. -111 - 200951122 m 7〇] Ex Data 101 NMR : 2.83-2.88 (2H, m), 3.68-3.71 (2H, m), 4.63 (2H, s), 5.02 (2H, s), 6.27-6.28 (lH, m), 6.49-6.51 (lH, m), 6.90-6.96 (2H, m), 7.03-7.09 (lH, m), 7.14-7.22 (5H, m), 7.27-7.28 (lH, m), 7.43-7.48 (2H, m), 8.57 ( lH, s), 12.99 (lH, brs). MS (ESI): 464 (M+Na) +. 102 NMR: 3.61 (2H, s), 6.90-8.10 (1 lH, m), 10.39 (lH, s ), 12.47 (lH, brs). MS (ESI): 488 (M+Na) +. 103 NMR: 2.60 (3H, s), 3.62 (2H, s), 6.90-7.90 (1 lH, m), 10.46 (lH, s), 12.46 (1H, brs). MS (ESI): 458 (M+Na) +. 104 NMR: 3.62 (2H, s), 4.17 (3H, s), 6.97-7.04 (3H, m), 7.23-7.26 (lH, m), 7.34-7.51 (3H, m), 7.72-7.74 (lH, m), 7.80-7.82 (lH, m), 7.89-7.93 (2H5m), 10.93 (lH, s), 12.50 (lH, brs). MS (ESI): 436 (M+H)+. 105 NMR: 5.03 (2H, s), 6.27-6.28 (lH, m), 6.58-6.60 (lH, m) , 7.00-7 .13 (3Hsm), 7.19-7.25 (lH, m), 7.30-7.31 (lH, m), 7.35-7.39 (lH, m), 7.48- 7.53 (lH, m), 7.69-7.84 (5H, m) , 10.56 (lH, s), 13.05 (1H, brs). MS (ESI): 449 (M+Na)+. 106 NMR: 5.01 (2H, s), 6.25-6.26 (lH, m), 6.57-6.61 (lH,in), 7.00-7.21 (4H,m), 7.27-7.30(lH,m),7.73-7.82(2H,m),7.91-7.98(2H,m), 8.14-8.19(2H,m) , 10.48 (lH, s), 13.10 (1H, brs). MS (ESI): 437 (M+Na)+. 107 NMR: 2.19 (3H, s), 3.59 (2H, s), 4.02 (3H, s ), 6.75-6.77 (lH, m), 6.85-6.87 (lH, m), 7.12-7_20 (2H, m), 7.30-7.34 (2H, m), 7.48-7.49 (lH, m), 7.55-7.71 (3H, m), 7.79-7.80 (lH, m), 10.32 (lH, s), 12.50 (1H, brs). MS (ESI): 471 (M+Na)+. 108 NMR: 3.60 (2H, s ), 4.02 (3H, s), 6.88-6.90 (lH, m), 7.13-7.22 (3H, m), 7.31-7.35 (2H, m), 7.49-7.50 (lH, m), 7.58-7.61 (2H , m), 7.71-7.73 (lH, m), 7.94-7.98 (lH, m), 10.55 (lH, s), 12.46 (lH, brs). MS (ESI): 475 (M+Na)+. NMR: 3.66 (2H, s), 7.05-7.09 (3H, m), 7.36-7.40 (lH, m), 7.51 (lH, dt, J = 1.3, 7.8 Hz), 7.68 (lH, s), 7.73 ( lH,d,J=8.3Hz), 7.78(lH,d,J=0_8Hz), 7.83(lH,d,J=7.7Hz), 7.85-7.89(2H,xn), 10.6 3(lH, s)_ MS(ESI): 478, 480 (M+Na)+. 110 NMR: 3.67 (2H, s), 6.98-7.01 (4H, m), 7.20-7.24 (lH, m), 7.41 ( lH,d,J=1.5Hz), 7.47(lH,d,J=8.3Hz), 7.66-7.69(2H,m),7.83-7.87(2H,m), 10.35(lH,s),11.83(lH MS(ESI): 477,479 (M+Na)+. 111 NMR: 3.65 (2H, s), 7.16 (lH, d, J = 8.8 Hz), 7.24 (lH, d, J = 8.3 Hz) , 7.29 (lH, ddJ=2.0, 8.3 Hz), 7.49 (lH, d, J = 1.9 Hz), 7.93 (2H, d, J = 8.3 Hz), 8.16 (2H, d, J = 8.2 Hz), 8.24 (lH, dd, J = 2.7, 8.9 Hz), 8.43 (lH, d, J = 2.5 Hz), 10.63 (lH, s), 12.49 (lH, brs). MS (ESI): 449, 451 (MH). -112- 200951122-112- 200951122 『表川 Ex Data 112 NMR : 3.65(2H，s),4.02(3H，s)，7.12-7.16(2H，m)，7.24(lH,d，J=8.2Hz)， 7.29(lH,dd,J=2.0,8.4Hz),7.30-7.35(2H,m),7.49(lH,d,J=1.9Hz), 7.58(lH,d,J=8.2Hz),7.70(lH,d,J=7.9Hz),8.25(lH,dd,J=2.7,8.8Hz), 8.44(lH,d,J=2.6Hz),10.47(lH,s),12.50(lH,brs). MS(ESI) ： 458,460(M+Na)+. 113 NMR ： 3.61(2H,s),6.80-7.90(1 lH,m),10.32(lH,s),12.10(lH,s), 12.48(lH,brs). MS(ESI) ： 461(M+Na)+. 114 NMR ： 3.61(2H,s),6.90-8.15(1 lH,m),10.64(lH,s),12.48(lH,brs). MS(ESI) ： 522,524(M+Na)+. 115 NMR ： 3.62(2H,s),6.90-8.10(llH,m),8.35(lH,s),10.56(lH,s), 12.48(lH,brs). MS(ESI) ： 460(M+Na)+. 116 NMR ： 3.61(2H,s),3.83(3H,s),6.57-6.59(lH,m),6.96-7.01(3H,m), 7.22-7.25(lH,m),7.43-7.56(3H,m),7.79-7.84(3H,m),8.26- 8.27(lH,m),10.17(lH,s),12.50(lH,brs). MS(ESI) ： 457(M+Na)+. 117 NMR ： 3.60(2H,s),6.90-6.92(lH,m),7.13-7.24(2H,m),7.37-7.41 (lH,m),7.50-7.58(2H,m),7.64-7.86(4H,m),7.96- 8.00(lH，m),10.79(lH,s),12.45(lH,brs)_ MS(ESI) : 462(M+Na)+. 118 NMR ： 5.03(2H,s),6.28-6.29(lH,m),6.57-6.59(lH,m),7.03-7.13 (4H,m),7.18-7.25(2H,m),7.29-7.30(lH,m),7.38-7.41(lH,m), 7.46-7.48(lH,m),7.66-7.70(lH,m),7.76-7.81(2H,m),10.23(lH,s),11.74(lH,s),13.00(lH,brs) MS(ESI) ： 448(M+Na)+. 119 NMR ： 2.84-2.87(2H,m),3.58-3.72(4H,m),4.64(2H,s),6.79-6.81 (lH,m),7.03-7.08(lH,m),7.15-7.23(5H,m),7.29-7.32(lH,m),7.46-7.47(lH,m),7.64-7.68(lH,m),8.82(lH,s),12.44(lH,brs). MS(ESI) ： 477(M+Na)+. 120 NMR ： 3.59(2H,s),6.79-6.89(2H,m),7.11-7.21(2H,m),7.38-7.49 (5H,m),7.61-7.66(3H,m),7.91-7.95(lH,m)510.47(lH,s), 12.45(lH,brs). MS(ESI) ： 448(M+Na)+. 121 NMR ： 3.62(2H,s),6.97-7.01(3H,m),7.27-7.30(lH,m),7.35-7.39 (lH,m),7.49-7.53(lH,m),7.64-7.65(lH,m),7.71-7.76(2H,m), 7.80-7.84(3H,m),10.57(lH,s),12.54(lH,brs). MS(ESI) ： 488,490(M+Na)+. 122 NMR ： 3.61(2H,s),4.02(3H,s),6.97-7.00(3H,m),7.12-7.20 (lH,m),7.27-7.34(3H,m),7.55-7.58(lH,m),7.64-7.71(2H,m), 7.78-7.82(2H,m),10.35(lH,s),12.50(lH,brs). MS(ESI) : 501,503(M+Na)' 123 NMR : 2.86(2H,t,J=5.9Hz),3.58(2H，s),3.70(2H,t，J=5.9Hz)， 4.64(2H,s),6_74(lH，d，J=8.4Hz)，6.99(lH，d，J=8.8Hz)，7.16-7.21(5H,m),7.45-7.48(2H,m),7.83(lH,d,J=2.4Hz), 8.78(lH,s),12.43(lH,brs). MS(ESI) ： 493,495(M+Na)+. -113- 200951122 m 721 Ex Data 124 NMR ： 5.03(2H,s),6.28-6.29(lH,m),6.57-6.59(lH,m),7.03-7.15 (3H,m),7.19-7.25(lH,m),7.30-7.38(3H,m),7.57-7.59(lH,m), 7.79-7.83(lH,m),7.90-7.94(2H,m),10.92(lH,s),12.98(lH,brs), 13.42(lH,s). MS(ESI) ： 449(M+Na)+. 125 NMR ： 3.65(2H,s),7.16(lH,d,J=8.8Hz),7.25(lH,d,J=8.2Hz), 7.29(lH,dd,J=1.9,8.3Hz),7.37(lH,dt,J=2.7,9.3Hz),7.49(lH,iU=1.9 Hz),7.66(lH,dd,J=2.7,8.7Hz),7.74-7.78(2H,m),8.27(lH,dd,J= 2.7,8.9Hz),8.46(lH,d,J=2.7Hz),10.79(lH,s),12.50(lH,brs). MS(ESI) ： 463,465(M+Na)+. 126 NMR ： 3.65(2H,s),7-16(lH,d,J=8.8Hz),7.25(lH,d,J=8.2Hz), 7.29(lH,dd,J-2.0,8.3Hz),7.49(lH,d,J=1.9Hz),7.54(lH,dd,J=2.2,8.8 Hz)，7.74(lH，d,J=0.9Hz)，7.77(lH,d，J=9.0Hz)，7.94(lH，d,J=2.2Hz)， 8.26(lH,dd,J=2.7,8.9Hz),8.46(lH,cU=2.6Hz),10.81(lH,s),12.51(lH ,brs). MS(ESI) ·· 479,481(M+Na)+. 127 NMR ： 3.53(2H,s),6.94-6.98(3H,m),7.25-7.27(lH,m),7.62-7.63 (lH5m),7.74-7.83(3H,m),7.93-7.95(lH,m),8.21-8.22(lH,m), 10.45(lH,s). MS(ESI) ： 516,518(M+Na)+. 128 NMR ： 5.03(2H,s),6.25-6.26(lH,m),6.57-6.59(lH,m),7.00-7.30 (5H,m),7.71-7.95(4H,m),8.19-8.22(lH,m),10.39(lH,s), 13.00(lH,brs). MS(ESI) ： 477(M+Na)+. 129 NMR : 3.60(2H,s),6.88-6.90(lH,m),7.15-7.22(2H,m),7.32-7.38 (2H,m),7.50(lH,m),7.59-7.60(lH,m),7.80-7.85(2H,m), 8.05-8.09(lH,m),11.21(lH,s),12.44(lH,brs),13.49(lH,s). (ESI) : 440(M+H)+. 130 NMR ： 5.03(2H,s),6.27-6.28(lH,m),6.55-6.56(lH,m),6.81-6.85 (lH,m),6.98-7.10(3H,m),7.17-7.22(lH,m),7.29-7.30(lH,m), 7.39-7.47(3H,m),7.60-7.71(5H,m),10.22(lH,s),13.05(lH,brs). MS(ESI) : 435(M+Na)+. 131 NMR : 3.61(2H,s)，6.98-7.09(4H,m)，7.20-7.29(2H，m)，7.41-7.48 (2H，m),7.64-7.68(2H，m)，7.79-7.83(2H，m)，10.25(lH,s)，11.73(lH，s), 12.44( lH,brs). MS(ESI) ： 487,489(M+Na)+. 132 NMR ： 3.60(2H,s),6.90-8.00(10H,m),8.44(lH,d,J-1.4Hz), 10.70(lH,s),12.50(lH,br). MS(ESI) ： 469(M+Na)+. 133 NMR ： 3.69(2H,s),6.90-8.30(10H,m),10.45(lH,s),12.48(lH,brs). MS(ESI) ： 515.8,517.9(M+Na)+. 134 NMR ： 3.69(2H,s),6.90-7.90(12H,m),l〇.28(lH,s),11.75(lH,s), 12.48(lH,brs)_ MS(ESI) ： 487,489(M+Na)+. 135 NMR ： 3.62(2H,s),4.01(3H,s),6.97-7.02(3H,m),7.15-7.28 (3H,m),7.48-7.51(2H,m),7.59-7.63(lH,m),7.77- 7.81(2H,m),10.40(lH,s),12.47(lH,brs). MS(ESI) ： 475(M+Na)+. -114- 200951122『表川Ex Data 112 NMR: 3.65 (2H, s), 4.02 (3H, s), 7.12-7.16 (2H, m), 7.24 (lH, d, J = 8.2 Hz), 7.29 (lH, dd, J =2.0, 8.4 Hz), 7.30-7.35 (2H, m), 7.49 (lH, d, J = 1.9 Hz), 7.58 (lH, d, J = 8.2 Hz), 7.70 (lH, d, J = 7.9 Hz) ), 8.25 (lH, dd, J = 2.7, 8.8 Hz), 8.44 (lH, d, J = 2.6 Hz), 10.47 (lH, s), 12.50 (lH, brs). MS (ESI): 458,460 (M +Na)+. 113 NMR: 3.61 (2H, s), 6.80-7.90 (1 lH, m), 10.32 (1H, s), 12.10 (1H, s), 12.48 (lH, brs). MS (ESI) 114(M+Na)+. 114 NMR: 3.61 (2H, s), 6.90-8.15 (1 lH, m), 10.64 (lH, s), 12.48 (lH, brs). MS (ESI): 522,524 ( M+Na)+. 115 NMR: 3.62 (2H, s), 6.90-8.10 (llH, m), 8.35 (1H, s), 10.56 (lH, s), 12.48 (lH, brs). MS (ESI) 460(M+Na)+. 116 NMR : 3.61 (2H, s), 3.83 (3H, s), 6.57-6.59 (lH, m), 6.96-7.01 (3H, m), 7.22-7.25 (lH, m), 7.43-7.56 (3H, m), 7.79-7.84 (3H, m), 8.26- 8.27 (lH, m), 10.17 (lH, s), 12.50 (lH, brs). MS (ESI): 457 NMR: 3.60 (2H, s), 6. m), 7.64-7.86 (4H, m), 7.96-8.00 (lH, m), 10.79 (lH, s), 12.45 (lH, brs)_ MS (ESI): 462 (M+Na)+. 118 NMR : 5.03(2H,s), 6.28-6.29 (lH , m), 6.57-6.59 (lH, m), 7.03-7.13 (4H, m), 7.18-7.25 (2H, m), 7.29-7.30 (lH, m), 7.38-7.41 (lH, m), 7.46 -7.48 (lH, m), 7.66-7.70 (lH, m), 7.76-7.81 (2H, m), 10.23 (lH, s), 11.74 (lH, s), 13.00 (lH, brs) MS (ESI) : 448 (M+Na)+. 119 NMR: 2.84-2.87 (2H, m), 3.58-3.72 (4H, m), 4.64 (2H, s), 6.79-6.81 (1H, m), 7.03-7.08 ( lH, m), 7.15-7.23 (5H, m), 7.29-7.32 (lH, m), 7.46-7.47 (lH, m), 7.64-7.68 (lH, m), 8.82 (lH, s), 12.44 ( lH,brs). MS (ESI): 477 (M+Na)+. 120 NMR: 3.59 (2H, s), 6.79-6.89 (2H, m), 7.11-7.21 (2H, m), 7.38-7.49 ( 5H, m), 7.61-7.66 (3H, m), 7.91-7.95 (lH, m) 510.47 (lH, s), 12.45 (lH, brs). MS (ESI): 448 (M+Na)+. NMR: 3.62 (2H, s), 6.97-7.01 (3H, m), 7.27-7.30 (lH, m), 7.35-7.39 (lH, m), 7.49-7.53 (lH, m), 7.64-7.65 (lH) , m), 7.71-7.76 (2H, m), 7.80-7.84 (3H, m), 10.57 (lH, s), 12.54 (lH, brs). MS (ESI): 488,490 (M+Na)+. NMR: 3.61 (2H, s), 4.02 (3H, s), 6.97-7.00 (3H, m), 7.12-7.20 (lH, m), 7.27-7.34 (3H, m), 7.55-7.58 (lH, m ), 7.64-7.71 (2H, m), 7.78-7.82 (2H, m), 10.35 (1H, s), 12.50 (1H, brs). MS (ESI): 501, 503 (M+Na)' 123 NMR: 2.86 (2H, t, J = 5.9 Hz), 3.58 (2H, s), 3.70 (2H, t, J = 5.9 Hz), 4.64 (2H, s), 6_74 (lH, d, J = 8.4 Hz), 6.99 (lH, d, J = 8.8 Hz), 7.16-7.21 (5H, m), 7.45-7.48 (2H, m), 7.83 (lH,d,J=2.4 Hz), 8.78 (lH, s), 12.43 (lH, brs). MS (ESI): 493,495 (M+Na) +. -113 - 200951122 m 721 Ex Data 124 NMR : 5.03 (2H, s), 6.28-6.29 (lH, m), 6.57-6.59 (lH, m), 7.03-7.15 (3H, m), 7.19-7.25 (lH, m), 7.30-7.38 (3H, m) , 7.57-7.59 (lH, m), 7.79-7.83 (lH, m), 7.90-7.94 (2H, m), 10.92 (lH, s), 12.98 (lH, brs), 13.42 (lH, s). MS (ESI): 449 (M+Na)+. 125 NMR: 3.65 (2H, s), 7.16 (1H, d, J = 8.8 Hz), 7.25 (lH, d, J = 8.2 Hz), 7.29 (lH, Dd, J = 1.9, 8.3 Hz), 7.37 (lH, dt, J = 2.7, 9.3 Hz), 7.49 (lH, iU = 1.9 Hz), 7.66 (lH, dd, J = 2.7, 8.7 Hz), 7.74 7.78 (2H, m), 8.27 (lH, dd, J = 2.7, 8.9 Hz), 8.46 (lH, d, J = 2.7 Hz), 10.79 (lH, s), 12.50 (lH, brs). MS (ESI) : 463,465 (M+Na)+. 126 NMR: 3.65 (2H, s), 7-16 (1H, d, J = 8.8 Hz), 7.25 (lH, d, J = 8.2 Hz), 7.29 (lH, Dd, J-2.0, 8.3 Hz), 7.49 (lH, d, J = 1.9 Hz), 7.54 (lH, dd, J = 2.2, 8.8 Hz), 7.74 (lH, d, J = 0.9 Hz), 7.77 ( lH, d, J = 9.0 Hz), 7.94 (lH, d, J = 2.2 Hz), 8.26 (lH, dd, J = 2.7, 8.9 Hz), 8.46 (lH, cU = 2.6 Hz), 10.81 (lH, s),12.51(lH,brs). MS(ESI) ·· 479,481(M+Na)+. 127 NMR : 3.53(2H,s),6.94-6.98(3H,m),7.25-7.27(lH,m),7.62-7.63 (lH5m),7.74-7.83(3H,m),7.93-7.95(lH,m) , 8.21 - 8.22 (lH, m), 10.45 (1H, s). MS (ESI): 516, 518 (M+Na) +. 128 NMR : 5.03 (2H, s), 6.25-6.26 (lH, m), 6.57 -6.59 (lH, m), 7.00-7.30 (5H, m), 7.71 - 7.95 (4H, m), 8.19-8.22 (lH, m), 10.39 (lH, s), 13.00 (lH, brs). MS (ESI): 477(M+Na)+. 129 NMR: 3.60 (2H, s), 6.88-6.90 (lH, m), 7.15-7.22 (2H, m), 7.32-7.38 (2H, m), 7.50 (lH, m), 7.59-7.60 (lH, m), 7.80-7.85 (2H, m), 8.05-8.09 (lH, m), 11.21 (lH, s), 12.44 (lH, brs), 13.49 (lH) , s). (ESI): 440 (M+H)+. 130 NMR: 5.03 (2H, s), 6.27-6.28 (lH, m), 6.55-6.56 (lH, m), 6.81-6.85 (lH, m), 6.98-7.10 (3H, m), 7.17-7.22 (lH, m), 7.29-7.30 (lH, m), 7.39-7.47 (3H, m), 7.60-7.71 (5H, m), 10.22 ( lH, s), 13.05 (1H, brs). MS (ESI): 435 (M+Na)+. 131 NMR: 3.61 (2H, s), 6.98-7.09 (4H, m), 7.20-7.29 (2H, m), 7.41-7.48 (2H, m), 7.64-7.68 (2H, m), 7.79-7.83 (2H, m), 10.25 (lH, s), 11.73 (lH, s), 12.44 (lH, brs) MS (ESI): 487, 489 (M+Na) +. 132 NMR: 3.60 (2H, s), 6.90-8.00 (10H, m), 8.44 (lH, d, J-1.4 Hz), 10.70 (lH, s ), 12.50 (lH, br). MS (ESI): 469 ( M+Na)+. 133 NMR: 3.69 (2H, s), 6.90-8.30 (10H, m), 10.45 (1H, s), 12.48 (1H, brs). MS (ESI): 515.8, 517.9 (M+ Na)+. 134 NMR: 3.69 (2H, s), 6.90-7.90 (12H, m), l.28 (lH, s), 11.75 (lH, s), 12.48 (lH, brs) _ MS (ESI : 487,489 (M+Na)+. 135 NMR: 3.62 (2H, s), 4.01 (3H, s), 6.97-7.02 (3H, m), 7.15-7.28 (3H, m), 7.48-7.51 (2H , m), 7.59-7.63 (lH, m), 7.77- 7.81 (2H, m), 10.40 (lH, s), 12.47 (lH, brs). MS (ESI): 475 (M+Na)+. 114- 200951122 Γ表 73] Ex Data 136 NMR : 2.40(3H，s)，3.43(2H，s)，3.98(3H，s)，6.93-6.98(3H，m)， 7.13-7.15(lH,m),7.19-7.22(2H,m),7.44-7.46(3H,m),7.75-7.79 (2H,m),10.32(lH,s). MS(ESI) ： 471(M+Na)+. 137 NMR ： 3.62(2H,s),4.01 (3H,s),6.97-7.02(3H,m),7.23-7.33 (3H,m),7.50-7.51(lH,m),7.61-7.64(lH,m),7.77-7.81(3H,m), 10.44(lH,s),12.46(lH,brs). MS(ESI) : 491(M+Na)+. 138 NMR ： 3.61(2H,s),6.98-7.02(3H,m),7.06-7.1 l(lH,m),7.27-7.29 (lH,m),7.40-7.48(3H,m),7.64-7.65(lH,m),7.79-7.83(2H,m), 10.30(lH,s),11.86(lH,s),12.46(lH,brs). MS(ESI) ： 505,507(M+Na)+. 139 NMR ： 2.83-2.86(2H,m),3.59-3.71(4H,m),4.63(2H,s),6.86-6.91 (3H，m)，7.15-7.25(5H，m)，7.46-7.50(2H，m)，7.61-7.62(lH，m)， 8.59(lH,s),13.5(lH,brs). MS(ESI) : 503,505(M+Na)+. 140 NMR ： 3.66(2H,s),7.06-7.52(8H,m),8.25(lH,dd,J=2.7,8.9Hz), 8.48(lH,d,J=2.7Hz),10.47(lH,s),11.93(lH,s).12.48(lH,brs) MS(ESI) ： 462(M+Na)+. mp ： 227-228 °C. 141 NMR ： 3.66(2H,s),7.14-7.32(4H,m),7.38-7.52(3H,m),7.79(lH,d,J= 2.1Hz),8.25(lH,dd,J=2.7,8.9Hz),8.48(lH,d,J=2.7Hz),10.49(lH,s), 12.02(lH,s),12.51(lH,brs). MS(ESI) : 478(M+Na)+. 142 NMR ： 2.38(3H,s),3.65(2H,s),7.04-7.51(8H,m),8.25(lH,dd,J= 2.7,8.9Hz),8.48(lH,d,J=2.7Hz),10.36(lH,s),11.67(lH,s), 12.52(lH,brs). MS(ESI) : 434(M-HV. 143 NMR ： 3.65(2H,s),4.02(3H,s),7.12-7.32(5H,m),7.47-7.53 (2H,m),7.62(lH,dd,J=4.5,8.9Hz),8.24(lH,dd,J=2.7,8.9Hz), 8.44(lH,d,J=2.7Hz),10.53(lH,s),12.53(lH,brs). MS(ESI) ： 476(M+Na)+. 144 NMR ： 3.65(2H,s),4.01(3H,s)57.14-7.34(5H,m),7.49(lH,d,J=1.9Hz), 7.63(lH,d,J=8.9Hz),7.80(lH,d,J=1.9Hz),8.25(lH,dd,J=2.7,8.9Hz), 8.44(lH,d,J=2.7Hz),10.58(lH,s),12.51(lH,brs). MS(ESI) ： 492(M+Na)+. 145 NMR : 2.40(3H,s),3.65(2H,s),3.99(3H,s),7.12-7.18(2H,m),7.24- 7.32(3H,m),7.43-7.50(3H,m),8.24(lH,dd,J=2.7,8.9Hz), 8.43(lH,d,J=2.7Hz),10.43(lH,s),12.49(lH,brs). MS(ESI) : 472(M+Na)+· 146 NMR ： 1.31(3H,t),3.66(2H,s),4.59(2H,q),7.12-7.17(2H,m)! 7.22-7.36(4H，m)，7.49(lH,d,J=L9Hz)，7.60(lH，d，J=7.9Hz)， 7.71(lH，d,J=7.9Hz)，8_27(lH,dd，J=2.7,8.9Hz)，8_44(lH,d，J=2_7Hz), 10.48(lH,s),12.49(lH,brs). MS(ESI) : 472(M+Na)+. 147 NMR : 3.65(2H，s)，4.21-4.96(4H，m)，7.12-7.74(9H，m)，8.25(lH，dd，J= 2.7,8.9Hz),8.42(lH,d,J=2.7Hz),10.53(lH,s),12.49(lH,s). MS(ESI) ： 468(M+H)+. -115- 200951122 m 74] Ex 148 Data NMR ： 2.74(3H,s),2.95-3.04(lH,m),3.28-3.39(lH,m),3.64(2H,s), 4.00-4.07(lH,m),6.54-6.68(2H,m),7.01-7.34(5H,m),7.47(lH,d,J= 2.1Hz)，8.19(lH,dd,J=2_7,8.9Hz)，8.34(lH,d，J=2.7Hz),10.20(lH，s), 12.47(lH,s). MS(ESI) ： 460(M+Na)+. 149 NMR : 2.74(3H,s),2.95-3.04(lH，m)，3.28-3.38(lH，m),3.60(2H，s)， 4.00-4.07(lH，m)，6.53-6.68(2H，m)，6.92-7.09(5H，m),7.22(lH，dd，J= 2.1,8.4Hz),7.49(lH,d,J=2.1Hz),7.76-7.73(2H,m),10.06(lH,s), 12.44(lH，brs). MS(ESI) : 459(M+Na)+. 150 NMR : 3.61(2H，s)，6.90-8.10(llH，m),11.25(lH,s),12.50(lH,brs). MS(ESI) ： 445(M+Na)+ 151 NMR ： 3.60(2Hss),6.94-7.02(3H,m),7.27(lH,dd,J=2,8.4Hz), 7.53(2H,d,J=8Hz),7.64(lH,d,J=2Hz),7.77(2H,d,J=9.2Hz),8.08(2H,d, J=9.2Hz),l〇.38(lH,s),12.49(lH,brs). MS(ESI) ： 532,534(M+Na)+. mp ： 252-254 °C. 152 NMR ： 3.64(2H,s),7.15(lH,d,J=8.8Hz),7.23(lH,d,J=8.4Hz), 7.28(lH,dd,J=2,8.4Hz),7.48(lH,d,J=2Hz),7.55(2H,d,J=8Hz), 8.09(2H,d,J=8.8Hz),8.22(lH,dd,J=2.6,9.2Hz),8.41(lH,d,J=2.4Hz), 10.52(lH,s),12.56(lH,brs). MS(ESI) ： 489(M+Na)+. mp ： 178-180 °C. 153 NMR ： 3.64(2H,s),7.17(lH,d,J=8.8Hz),7.20-7.35(2H,m), 7.49(1H,d,J=2Hz),7.90-8.10(3H,m),8.23(lH,dd,J=2.8,8.8Hz), 8.42(lH,d,J=2.8Hz),10.68(lH,s),12.49(lH,brs). MS(ESI) : 491(M+Na)+.73 Table 73] Ex Data 136 NMR: 2.40 (3H, s), 3.43 (2H, s), 3.98 (3H, s), 6.93-6.98 (3H, m), 7.13-7.15 (lH, m), 7.19- 7.22 (2H, m), 7.44-7.46 (3H, m), 7.75-7.79 (2H, m), 10.32 (1H, s). MS (ESI): 471 (M+Na)+. 137 NMR: 3.62 ( 2H, s), 4.01 (3H, s), 6.97-7.02 (3H, m), 7.23-7.33 (3H, m), 7.50-7.51 (lH, m), 7.61-7.64 (lH, m), 7.77- 7.81 (3H, m), 10.44 (1H, s), 12.46 (1H, brs). MS (ESI): 491 (M+Na)+. 138 NMR: 3.61 (2H, s), 6.98-7.02 (3H, m), 7.06-7.1 l(lH, m), 7.27-7.29 (lH, m), 7.40-7.48 (3H, m), 7.64-7.65 (lH, m), 7.79-7.83 (2H, m), 10.30 (lH, s), 11.86 (lH, s), 12.46 (1H, brs). MS (ESI): 505, 507 (M+Na)+. 139 NMR: 2.83-2.86 (2H, m), 3.59-3.71 (4H , m), 4.63 (2H, s), 6.86-6.91 (3H, m), 7.15-7.25 (5H, m), 7.46-7.50 (2H, m), 7.61-7.62 (lH, m), 8.59 (lH , s), 13.5 (1H, brs). MS (ESI): 503, 505 (M+Na) +. 140 NMR: 3.66 (2H, s), 7.06-7.52 (8H, m), 8.25 (lH, dd, J =2.7, 8.9 Hz), 8.48 (lH, d, J = 2.7 Hz), 10.47 (lH, s), 11.93 (lH, s). 12.48 (lH, brs) MS (ESI): 462 (M+Na) +. mp: 227-228 ° C. 141 NMR: 3.66 (2H, s), 7.14-7.32 (4H, m), 7.38-7.52 (3H, m), 7.79 (lH, d, J = 2.1 Hz), 8.25 (lH, dd, J= 2.7, 8.9 Hz), 8.48 (lH, d, J = 2.7 Hz), 10.49 (lH, s), 12.02 (lH, s), 12.51 (lH, brs). MS (ESI): 478 (M+Na) +. 142 NMR: 2.38 (3H, s), 3.65 (2H, s), 7.04-7.51 (8H, m), 8.25 (lH, dd, J = 2.7, 8.9 Hz), 8.48 (lH, d, J = 2.7 Hz), 10.36 (lH, s), 11.67 (1H, s), 12.52 (1H, brs). MS (ESI): 434 (M-HV. 143 NMR: 3.65 (2H, s), 4.02 (3H, s), 7.12-7.32 (5H, m), 7.47-7.53 (2H, m), 7.62 (lH, dd, J = 4.5, 8.9 Hz), 8.24 (lH, dd, J = 2.7, 8.9 Hz), 8.44 (lH, d, J = 2.7 Hz), 10.53 (lH, s), 12.53 (1H, brs). MS (ESI): 476 (M+Na)+. 144 NMR: 3.65 (2H, s), 4.01 ( 3H, s) 57.14-7.34 (5H, m), 7.49 (lH, d, J = 1.9 Hz), 7.63 (lH, d, J = 8.9 Hz), 7.80 (lH, d, J = 1.9 Hz), 8.25 (lH, dd, J = 2.7, 8.9 Hz), 8.44 (lH, d, J = 2.7 Hz), 10.58 (lH, s), 12.51 (lH, brs). MS (ESI): 492 (M+Na) +. 145 NMR: 2.40 (3H, s), 3.65 (2H, s), 3.99 (3H, s), 7.12 - 7.18 (2H, m), 7.24 - 7.32 (3H, m), 7.43-7.50 (3H, m), 8.24 (lH, dd, J = 2.7, 8.9 Hz), 8.43 (lH, d, J = 2.7 Hz), 10.43 (lH, s), 12.49 (lH, brs). MS (ESI): 472 ( M+Na)+· 146 NMR: 1.31 (3H, t), 3.66 (2H, s), 4.59 (2H, q), 7.12-7.17 (2H, m)! 7.22-7.36 (4H, m), 7.49 ( lH,d,J=L9Hz), 7.60 (lH,d,J=7.9Hz), 7.71(lH,d,J=7.9Hz),8_27(lH,dd,J=2.7,8.9H z), 8_44 (lH, d, J = 2_7 Hz), 10.48 (lH, s), 12.49 (lH, brs). MS (ESI): 472 (M+Na)+. 147 NMR: 3.65 (2H, s) , 4.21-4.96 (4H, m), 7.12-7.74 (9H, m), 8.25 (lH, dd, J = 2.7, 8.9 Hz), 8.42 (lH, d, J = 2.7 Hz), 10.53 (lH, s ), 12.49 (lH, s). MS (ESI): 468 (M+H) +. -115 - 200951122 m 74] Ex 148 Data NMR: 2.74 (3H, s), 2.95-3.04 (lH, m), 3.28-3.39(lH,m), 3.64(2H,s), 4.00-4.07(lH,m),6.54-6.68(2H,m),7.01-7.34(5H,m),7.47(lH,d,J = 2.1 Hz), 8.19 (lH, dd, J = 2_7, 8.9 Hz), 8.34 (lH, d, J = 2.7 Hz), 10.20 (lH, s), 12.47 (lH, s). MS (ESI): 460(M+Na)+. 149 NMR: 2.74 (3H, s), 2.95-3.04 (1H, m), 3.28-3.38 (1H, m), 3.60 (2H, s), 4.00-4.07 (lH, m ), 6.53-6.68 (2H, m), 6.92-7.09 (5H, m), 7.22 (lH, dd, J = 2.1, 8.4 Hz), 7.49 (lH, d, J = 2.1 Hz), 7.76-7.73 ( 2H,m), 10.06 (lH, s), 12.44 (1H, brs). MS (ESI): 459 (M+Na)+. 150 NMR: 3.61 (2H, s), 6.90-8.10 (llH, m) , 11.25 (lH, s), 12.50 (1H, brs). MS (ESI): 445 (M+Na) + 151 NMR: 3.60 (2Hss), 6.94-7.02 (3H, m), 7.27 (lH, dd, J=2, 8.4 Hz), 7.53 (2H, d, J=8 Hz), 7.64 (lH, d, J=2 Hz), 7.77 (2H, d, J=9.2 Hz), 8.08 (2H, d, J= 9.2Hz), l〇.38 (lH , s), 12.49 (lH, brs). MS (ESI): 532, 534 (M+Na) +. mp: 252-254 ° C. 152 NMR: 3.64 (2H, s), 7.15 (lH, d, J = 8.8 Hz), 7.23 (lH, d, J = 8.4 Hz), 7.28 (lH, dd, J = 2, 8.4 Hz), 7.48 (lH, d, J = 2 Hz), 7.55 (2H, d, J = 8 Hz) ), 8.09 (2H, d, J = 8.8 Hz), 8.22 (lH, dd, J = 2.6, 9.2 Hz), 8.41 (lH, d, J = 2.4 Hz), 10.52 (lH, s), 12.56 (lH) MS(ESI): 489 (M+Na)+. mp: 178-180 ° C. 153 NMR: 3.64 (2H, s), 7.17 (lH, d, J = 8.8 Hz), 7.20-7.35 (2H,m), 7.49(1H,d,J=2Hz), 7.90-8.10(3H,m), 8.23(lH,dd,J=2.8,8.8Hz), 8.42(lH,d,J=2.8Hz ), 10.68 (lH, s), 12.49 (lH, brs). MS (ESI): 491 (M+Na)+. [產業上之可能利用性] 式（I)之化合物或其鹽具有CRTH2拮抗作用，可使 用作爲炎症性疾病（例如，氣喘、過敏性鼻炎、過敏性皮 膚炎、結膜炎、奪麻疹、嗜酸血球性支氣管炎、食物過敏 -116- 200951122 、副鼻腔炎、血管炎、慢性阻塞性肺疾病等）或多發性硬 化症等之預防及/或治療劑。[Industrial Applicability] The compound of the formula (I) or a salt thereof has a CRTH2 antagonistic action and can be used as an inflammatory disease (for example, asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, measles, eosinophils) A preventive and/or therapeutic agent for bronchitis, food allergy-116-200951122, paranasal rhinitis, vasculitis, chronic obstructive pulmonary disease, etc. or multiple sclerosis. -117 200951122 773343 發明專利說明書 #；月修正補充 (本申請瓣式L言物任意麵，※言彌·靑 C07D 401/12 2006. 01 C07D 213/60 2006.01 C07C 233/24 2006. 01 A61K 31/343 2006. 01 A61K 31/404 2006. 0! A61K 31/4184 2006. 01 A61K 31/423 2006.01 A61K 31/44 2006.01丨 A61P 29/00 2006.01 A61P 37/02. 2006. 01； 分麪： ※申請案號：98103153 ※申請日：98年01月23日 ， 一、 發明名稱：（中文/英文） 羧酸化合物或其鹽 Carboxylic acid compound or the salt 二、 中文發明摘要： 本發明提供一種化合物，其具有CRTH2拮抗作用， 可使用作爲炎症性疾病（例如，氣喘、過敏性鼻炎、過敏 性皮膚炎、結膜炎、蓴麻疹、嗜酸血球性支氣管炎、食物 過敏、gil鼻腔炎、血管炎、慢性阻塞性肺疾病等）或多發 性硬化症等之預防及/或治療劑。 -本發明者針對具有CRTH2拮抗作用之化合物進行探 討’確認竣酸化合物或其鹽具有CRTH2拮抗作用，因而 完成本發明。本發明之羧酸化合物或其鹽具有CRTH2拮 抗作用’可使用作爲炎症性疾病（例如，氣喘、過敏性鼻 炎、過敏性皮膚炎 '結膜炎、奪麻疹、嗜酸血球性支氣管 炎、食物過敏、副鼻腔炎、血管炎、慢性阻塞性肺疾病等） 或多發性硬化症等之預防及/或治療劑。 200951122 三、英文發明摘要： 200951122 七、申請專利範圍： 1.一種式（I)之化合物、其鹽或其前驅藥，-117 200951122 773343 Invention patent specification#; monthly correction supplement (this application flap L language arbitrary face, ※言弥·靑C07D 401/12 2006. 01 C07D 213/60 2006.01 C07C 233/24 2006. 01 A61K 31/ 343 2006. 01 A61K 31/404 2006. 0! A61K 31/4184 2006. 01 A61K 31/423 2006.01 A61K 31/44 2006.01丨A61P 29/00 2006.01 A61P 37/02. 2006. 01; Facet: ※Application No.: 98103153 ※Application date: January 23, 1998, I. Name of the invention: (Chinese / English) Carboxylic acid compound or the salt thereof. Abstract: The present invention provides a compound having CRTH2 antagonism, can be used as an inflammatory disease (for example, asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, urticaria, eosinophilic bronchitis, food allergies, gil nasal inflammation, vasculitis, chronic obstructive pulmonary disease A disease or the like, or a prophylactic and/or therapeutic agent for multiple sclerosis, etc. - The present inventors conducted a discussion on a compound having CRTH2 antagonistic action to confirm that a citrate compound or a salt thereof has CRTH2 The present invention has been completed. The carboxylic acid compound of the present invention or a salt thereof has CRTH2 antagonism' can be used as an inflammatory disease (for example, asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, measles, eosinophils) Prevention and/or treatment of bronchitis, food allergies, paranasal sinusitis, vasculitis, chronic obstructive pulmonary disease, etc. or multiple sclerosis. 200951122 III. English Abstract: 200951122 VII. Patent Application Range: 1 a compound of formula (I), a salt thereof or a precursor thereof, [式中， R1爲- (Cu伸烷基）-COOH或-H, 1)當R1爲-((^.6伸烷基）-COOH時， R2爲鹵素或-H， R3爲鹵素、Cu烷基、-CMCu烷基）或-H， 2 )當R1爲-H時， R2與R3與其等所鍵結之苯環一起形成以下式（II) 表不之基*Wherein R1 is -(Cu alkyl)-COOH or -H, 1) when R1 is -((^.alkyl)-COOH, R2 is halogen or -H, and R3 is halogen, Cu Alkyl, -CMCualkyl) or -H, 2) When R1 is -H, R2 and R3 together with the benzene ring to which they are bonded form a base of the following formula (II)* [化8][化8] V 爲=C Η-或=N -， m表示1至6之整數， R4爲鹵素或-H， -118- 200951122 但，R3爲-Η時，R4爲鹵素， R5爲-Η、鹵素或C!-6烷基， R6爲可分別以由以RXA表示之基所選擇之基取代之芳基 、雜芳基、雜環烷基或_N(R6a)(R6b)， RXA爲鹵素、C丨-6烷基、鹵基C丨-6烷基、-〇-(C丨·6烷基） 、-〇-(鹵基 Cu 烷基、-SJCm 烷基）、-N-(C!.6 烷基）2、 芳基、經鹵素取代之芳基、經- 烷基）取代之芳基、V is =C Η- or =N -, m represents an integer from 1 to 6, R4 is halogen or -H, -118- 200951122 However, when R3 is -Η, R4 is halogen and R5 is -Η, halogen or C -6 alkyl, R6 is an aryl group, a heteroaryl group, a heterocycloalkyl group or a _N(R6a)(R6b) which may be substituted with a group selected from the group represented by RXA, and RXA is a halogen, C丨. -6 alkyl, halo C丨-6 alkyl, -〇-(C丨.6 alkyl), -〇-(halo-Cu alkyl, -SJCm alkyl), -N-(C!.6 Alkyl) 2, aryl, halogen-substituted aryl, alkyl-substituted aryl, 經-N-(Ci-6院基）2取代之方基、歯#S、-OH、-CN、_ s ( = 0)2-((^-6 烷基）、-NHS( = 0)2-(Cl_6 烷基）或環狀胺基， R6a爲-丨^^伸烷基）-芳基、-(Cu伸烷基）-雜芳基、-(Cu6伸烷基）-雜環烷基， R6b爲Η或Cu烷基， A 爲· 〇 -或-S - ’ D 爲-C( = 0)-、或-S( = 0)2-， E爲鍵結' Cu伸烷基或C2-6伸烯基， Y 爲-C(R5a) =或-N=， R5b爲-Η、鹵素或C,-6烷基； Z 爲=CH-、或=N-， U 爲-C(R5b) =或-N=， R5b爲-Η、鹵素或Cm烷基， 但，下列化合物除外， 3-{3-氟-4-[(5-{[4-(三氟甲基）苯甲醯基]胺基}吡啶-2-基）氧基]苯基}丙酸， 3-{3-乙氧基-4-[ ( 5-{[4-(三氟甲基）苯甲醯基]胺基}吡 -119- 200951122 啶-2-基）氧基]苯基}丙酸， 3-{3-甲氧基-4-[(5-{[4-(三氟甲基）苯甲醯基]胺基}吡 啶-2-基）氧基]苯基}丙酸， 3-[4-({5-[(3,4-二氯苯甲醯基）胺基]吡啶-2-基}氧基 )-3-氟苯基]丙酸， 3-[4-({5-[(3,4-二氯苯甲醯基）胺基]吡啶-2-基}氧基 )-3-乙氧基苯基]丙酸， 3- [4-({5-[(3,4-二氯苯甲醯基）胺基]吡啶-2-基}氧基 )-3 -甲氧基苯基]丙酸，及 4- {4-[(3,4-二氯苯甲醯基）胺基]苯氧基}-3-甲氧基苯基 乙酸]。 2.如申請專利範圍第1項之式（I )化合物或其鹽， 其中 R6爲可分別經相同或彼此不同之以RXB表示之基取代之 芳基、雜芳基、雜環烷基或-N(R6a)(R6b)， RXB爲鹵素、C丨-6烷基、鹵基Cu烷基、烷基） 、-0-(鹵基Cm烷基、-SdCM烷基）、-NJCm烷基）2、 芳基、經-0-((^-6烷基）取代之芳基、或經-NJCu烷基）2 取代之芳基。 3 .如申請專利範圍第2項之化合物或其鹽，其中 R1 爲-CH2-COOH 或-H， m爲1， R6a爲-(Cm伸烷基）-芳基， R6b 爲-H， -120- 200951122 但’ Y爲-N =時，U爲·CH=， Y 爲- CH =或- CF =時，Z 爲=CH-。 4. 如申請專利範圍第3項之化合物或其鹽，其中R3 爲鹵素、Cu烷基或-O-Cw烷基，R4爲-η。 5. 如申請專利範圍第4項之化合物或其鹽，其中γ 爲-Ν= ’ Ζ 爲=CH-。 6·如申請專利範圍第5項之化合物或其鹽，其中E爲 鍵結。 7·如申請專利範圍第6項之化合物或其鹽，其中R6 爲可經相同或彼此不同之以RXB表示之基取代之苯基。 8-如申請專利範圍第7項之化合物或其鹽，其中 A 爲-0-， D 爲-C( = 0)-， R1 2 爲-Η， R3爲鹵素。 9.如申請專利範圍第8Square group substituted by -N-(Ci-6) based 2, 歯#S, -OH, -CN, _ s ( = 0)2-((^-6 alkyl), -NHS( = 0) 2-(Cl_6 alkyl) or cyclic amine, R6a is -alkyl, aryl, -(Cu alkyl)-heteroaryl, -(Cu6alkyl)-heterocycloalkane a group, R6b is a hydrazine or a Cu alkyl group, A is · 〇- or -S - ' D is -C( = 0)-, or -S( = 0)2-, E is a bond 'Cu alkyl group or C2-6 is an alkenyl group, Y is -C(R5a) = or -N=, R5b is -Η, halogen or C, -6 alkyl; Z is =CH-, or =N-, U is -C( R5b) = or -N=, R5b is -Η, halogen or Cm alkyl, except for the following compounds, 3-{3-fluoro-4-[(5-{[4-(trifluoromethyl))benzene Indenyl]amino}pyridin-2-yl)oxy]phenyl}propionic acid, 3-{3-ethoxy-4-[(5-{[4-(trifluoromethyl))benzyl) Amino}pyr-119- 200951122 pyridin-2-yl)oxy]phenyl}propionic acid, 3-{3-methoxy-4-[(5-{[4-(trifluoromethyl)benzene) Mercapto]amino}pyridin-2-yl)oxy]phenyl}propionic acid, 3-[4-({5-[(3,4-dichlorobenzhydryl)amino]pyridine-2 -yl}oxy)-3-fluorophenyl]propionic acid, 3-[4-({5-[(3,4-dichlorobenzylidyl)amino]pyridine-2- }oxy)-3-ethoxyphenyl]propionic acid, 3-[4-({5-[(3,4-dichlorobenzylidinyl)amino]pyridin-2-yl}oxy) -3 -Methoxyphenyl]propionic acid, and 4-{4-[(3,4-dichlorobenzhydryl)amino]phenoxy}-3-methoxyphenylacetic acid]. 2. The compound of the formula (I) or a salt thereof according to the first aspect of the invention, wherein R6 is an aryl group, a heteroaryl group, a heterocycloalkyl group or a group which may be substituted with the same or different substituents represented by RXB, respectively. N(R6a)(R6b), RXB is halogen, C丨-6 alkyl, halo-C-alkyl, alkyl), -0-(halo Cm alkyl, -SdCM alkyl), -NJCm alkyl) 2. An aryl group, an aryl group substituted with an -0-((^-6 alkyl)-substituted aryl group, or substituted with -NJCualkyl)2. 3. The compound of claim 2 or a salt thereof, wherein R1 is -CH2-COOH or -H, m is 1, R6a is -(Cmalkyl)-aryl, and R6b is -H, -120 - 200951122 But when 'Y is -N =, U is ·CH=, Y is -CH = or -CF =, Z is =CH-. 4. The compound of claim 3 or a salt thereof, wherein R3 is halogen, Cu alkyl or -O-Cw alkyl, and R4 is -η. 5. A compound of claim 4 or a salt thereof, wherein γ is -Ν= Ζ = is =CH-. 6. The compound of claim 5 or a salt thereof, wherein E is a bond. 7. A compound according to claim 6 or a salt thereof, wherein R6 is a phenyl group which may be substituted with the same or different substituents represented by RXB. 8-A compound according to claim 7 or a salt thereof, wherein A is -0-, D is -C(=0)-, R1 2 is -Η, and R3 is halogen. 9. If the scope of patent application is 8 項之化合物或其鹽，其中a compound or a salt thereof, wherein -OCH3 、- -〇cf3、_sch3、- 、或經-N(CH3)2取 Rxc 爲 Cl、-CH3、-CF3、 N(CH3)2、苯基、經- 〇CH3取代之苯基 代之苯基。 項之化合物或其鹽，其中γ 1 1 .如申請專利範圍第 10項之化合物或其鹽，其中 -121 - 1 0 ·如申請專利範圍第 2 爲-CH =或-CF = 200951122 A 爲-Ο -， D 爲-C( = 0)·， R6爲可經相同或彼此不同之以RXB表示之基取代之苯基 〇 12. 如申請專利範圍第3項之化合物或其鹽，其中R1 爲-H。 13. 如申請專利範圍第12項之化合物或其鹽，其中v 爲=N-。 1 4.如申請專利範圍第2項之化合物或其鹽，其係如 下所示之化合物： (3 -氯-4-{4-[ ( 3,4 -二氯苯甲酿基）胺基]苯氧基}苯基） 乙酸， (4-{4-[(1-苯并呋喃-2-基羰基）胺基]苯氧基}-3-氯苯基 )乙酸， [3-氯-4-({4-[(3,4-二氯苯甲醯基）胺基]苯基}磺醯基） 苯基]乙酸， (3-氯-4-{4-[(3,4-二氫異喹啉-2(1H)-基羰基）胺基] 苯氧基}苯基）乙酸， [4-(4-{[(2£)-3-(3,4-二氯苯基）丙-2-燒醯基]胺基} 苯氧基）-2-甲基-1H-苯并咪唑-卜基]乙酸’ [3-氯-4-(4-{[4-(三氟甲基）苯甲醯基]胺基}苯氧基）苯 基]乙酸， (3 -氯-4- ( 2 -氟-4-[ ( ΙΗ-卩引哄-2-基鑛基）胺基]苯氧基） 苯基）乙酸， -122- 200951122 [3 -氯-4- (4-{[(卜甲基-1H -吲哚-2 -基）羰基]胺基}苯氧 基）苯基]乙酸， [3-氯-4- ( 4-{[ ( 6-氟-1H-苯并咪唑-2-基）胺甲醯基]胺基 }苯氧基）苯基]乙酸， {3 -氯-4- [ ( 5-{[ ( 5 -氟-1H -吲哚-2-基）羰基]胺基}吡啶-2- 基）氧基]苯基}乙酸， [3-溴-4- ( 4-{[4-(三氟甲氧基）苯甲醯基]胺基}苯氧基） @ 苯基]乙酸，及 {3-氯- 4-[ ( 5-{[4-(三氟甲氧基）苯甲醯基]胺基}吡啶- 2- 基）氧基]苯基}乙酸。 15. —種醫藥組成物，其特徵爲含有申請專利範圍第1 項之化合物或其鹽及製藥學上可接受性賦型劑。 1 6 · —種用以治療或預防炎症性疾病或多發性硬化症 之醫藥組成物，其特徵爲含有申請專利範圍第1項之化合 物或其鹽。 ^ 17.—種申請專利範圍第1項之化合物或其鹽之使用 ’其特徵係用於製造炎症性疾病或多發性硬化症之預防或 治療用醫藥組成物。 18.—種申請專利範圍第1項之化合物或其鹽之使用 ’其特徵係用於炎症性疾病或多發性硬化症之預防或治療 〇 19_ 一種炎症性疾病或多發性硬化症之預防或治療方 法’其特徵係對患者投予有效量之申請專利範圍第1項之 化合物或其鹽。 -123- 200951122 四、指定代表圖： (一） 本案指定代表圖為：無。 (二） 本代表圖之元件符號簡單說明：無 200951122 五、本案若有化學式時，請揭示最能顯示發明特徵的化學式：無-OCH3, - -〇cf3, _sch3, -, or phenyl substituted by -N(CH3)2 with Rxc as Cl, -CH3, -CF3, N(CH3)2, phenyl, substituted by -CH3 . A compound or a salt thereof, wherein γ 1 1 is a compound of the formula 10 or a salt thereof, wherein -121 - 1 0 - if the scope of the patent application is 2 -CH = or -CF = 200951122 A - Ο -, D is -C( = 0)·, R6 is a phenyl hydrazine which may be substituted by the same or different substituents represented by RXB. 12. The compound of claim 3 or a salt thereof, wherein R1 is -H. 13. The compound of claim 12 or a salt thereof, wherein v is =N-. 1 . The compound of claim 2 or a salt thereof, which is a compound shown below: (3-chloro-4-{4-[(3,4-dichlorobenzyl)amino] Phenoxy}phenyl)acetic acid, (4-{4-[(1-benzofuran-2-ylcarbonyl)amino]phenoxy}-3-chlorophenyl)acetic acid, [3-chloro-4 -({4-[(3,4-Dichlorobenzhydryl)amino]phenyl}sulfonyl)phenyl]acetic acid, (3-chloro-4-{4-[(3,4-di) Hydrogen isoquinoline-2(1H)-ylcarbonyl)amino]phenoxy}phenyl)acetic acid, [4-(4-{[(2£)-3-(3,4-dichlorophenyl)) Prop-2-pyrene]amino}phenoxy)-2-methyl-1H-benzimidazole-buki]acetic acid '[3-chloro-4-(4-{[4-(trifluoromethyl) Benzomethylene]amino}phenoxy)phenyl]acetic acid, (3-chloro-4-(2-fluoro-4-[(ΙΗ-卩卩哄-2-ylidene))] Phenoxy)phenyl)acetic acid, -122- 200951122 [3-chloro-4-(4-{[(imethyl-1H-indol-2-yl)carbonyl]amino}phenoxy)phenyl]acetic acid , [3-chloro-4-(4-{[(6-fluoro-1H-benzimidazol-2-yl)aminecarboxy]amino}phenoxy)phenyl]acetic acid, {3-chloro- 4-[( 5-{[(5-fluoro-1H-indol-2-yl)carbonyl]amino}pyrr -2-yl)oxy]phenyl}acetic acid, [3-bromo-4-(4-{[4-(trifluoromethoxy)benzylidenyl]amino}phenoxy)@phenyl] Acetic acid, and {3-chloro-4-[(5-{[4-(trifluoromethoxy)benzylidenyl]amino}pyridin-2-yl)oxy]phenyl}acetic acid. A pharmaceutical composition comprising a compound of the first aspect of the patent application or a salt thereof and a pharmaceutically acceptable excipient. A pharmaceutical composition for treating or preventing an inflammatory disease or multiple sclerosis, which comprises the compound of the first aspect of the patent application or a salt thereof. ^ 17. Use of a compound or a salt thereof according to claim 1 ' is characterized by the manufacture of a pharmaceutical composition for the prevention or treatment of an inflammatory disease or multiple sclerosis. 18. Use of a compound or a salt thereof according to claim 1 'characteristics for the prevention or treatment of inflammatory diseases or multiple sclerosis 〇19_ Prevention or treatment of an inflammatory disease or multiple sclerosis The method 'is characterized by administering to a patient an effective amount of a compound of claim 1 or a salt thereof. -123- 200951122 IV. Designated representative map: (1) The representative representative of the case is: None. (II) Simple description of the symbol of the representative figure: None 200951122 V. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: none
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