TW200827349A

TW200827349A - 5-(1H-1,2,3-triazole-4-yl)-1H-pyrazole derivatives

Info

Publication number: TW200827349A
Application number: TW096141231A
Authority: TW
Inventors: Naoki Kanaya; Yuichi Ochiai
Original assignee: Daiichi Sankyo Co Ltd
Priority date: 2006-11-02
Filing date: 2007-11-01
Publication date: 2008-07-01
Also published as: JP2009184925A; WO2008053602A1

Abstract

Disclosed are: a compound represented by the formula (I), a salt thereof, or a solvate of the compound or the salt; and a pharmaceutical agent comprising the compound, the salt or the solvate. The compound has an inhibitory activity on platelet aggregation, and is therefore excellent in safety and in vivo kinetics.

Description

200827349 九、發明說明：【發明所屬之技術領域】本發明係關於一種具有抑制血小板凝集作用之吡唑衍生物。【先前技術】 •血小板起到血管損傷時凝集、形成止血血栓而防止出血的重要作用，然而另一方面，於血管内之血管内皮受到損 r 傷之部位、狹窄之部位等，會由於凝集而誘導血栓或栓 ‘塞。由於該等血栓或栓塞而引起心肌梗塞、心絞痛、缺血月自血官病、末梢血管病等缺血性疾病。因此，於缺血性疾病之預防及治療中使用抑制血小板凝集藥。#中低用量之阿司匹林自先前就用作抑制血小板凝集藥，其效果可由 APT(Antiplatelet Trialist’s c〇llab〇mi〇n ;抗血小板試驗聯口報告）设明（翏照非專利文獻1}，Αρτ係統合分析對⑺萬患者投與之複數個臨床試驗結果。而，眾所周知阿司匹林具有引起腸胃等出司匹林潰瘍之副作用， ’該副作用與投與量無關 100個人中會有1人有該副作用（參照非專利文獻2)。眾所周知阿司匹林抑制血小板凝集之作200827349 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD The present invention relates to a pyrazole derivative having a platelet aggregation inhibiting action. [Prior Art] • Platelets play an important role in agglutination during blood vessel damage and form hemostatic thrombus to prevent hemorrhage. On the other hand, in the blood vessel endothelium where the vascular endothelium is damaged or injured, it may be agglomerated. Inducing a thrombus or a plug. Ischemic diseases such as myocardial infarction, angina pectoris, ischemic month, blood stasis, and peripheral vascular disease due to such thrombus or embolism. Therefore, inhibition of platelet aggregation is used in the prevention and treatment of ischemic diseases. #中低低素素素 has been used as a platelet aggregation inhibitor since its effect, and its effect can be ascertained by APT (Antiplatelet Trialist's c〇llab〇mi〇n; anti-platelet test joint report) (see Non-Patent Document 1), Αρτ Systematic analysis of the results of a number of clinical trials administered by (7) million patients. However, it is well known that aspirin has the side effects of causing ulcers in the stomach and in the stomach. 'The side effects are not related to the amount of administration. One in 100 people has this side effect. (Refer to Non-Patent Document 2). It is well known that aspirin inhibits platelet aggregation.

4)。再者，眾所周知非類固醇性抗炎症藥選擇性地抑制 126365.doc 200827349 COX-2而起到抗炎症作用。眾所周知至今為止具有抗血栓作用之吼唑衍生物有化合物(A)(參照專利文^及非專利文獻”及化合物 (B)(參照專利文獻2)。 [化1]4). Furthermore, it is well known that non-steroidal anti-inflammatory drugs selectively inhibit 126365.doc 200827349 COX-2 and have an anti-inflammatory effect. The carbazole derivative having an antithrombotic effect so far is known as a compound (A) (see Patent and Non-Patent Literature) and Compound (B) (see Patent Document 2).

CHF, 然而’化合物（A)對膠廊讀道 )了胗原誘蜍血小板凝集之IC5G值為 5.3 X 1 〇 Μ，對於C〇x_2顯示出強於前者之抑制活性⑻5。值為2.術、)。同樣，化合物(B)之抑制血小板凝集作用與其對COX-2之抑制活性相比亦並不強。另-方面，專利文獻3揭示抑制血小板凝集藥之化合物 (C)等，然、而將構成本化合物之㈣環上之*位的二氣基轉換為甲氧基而獲得之化合物(D)顯示出腎毒性，故而專利文獻3所揭示之抑制血小板凝㈣在安全性方面無法稱得上係確實優良者。 [化2] ΜβΟ 1NJ jHTnv (C) MeO 入*〆CHF, however, 'Compound (A) reads on the capsule) The IC5G value of the platelet agglutination induced by sputum is 5.3 X 1 〇 Μ, which shows stronger inhibition activity for C 〇 x 2 (8) 5 . The value is 2. surgery,). Similarly, the inhibition of platelet aggregation by the compound (B) is not as strong as the inhibitory activity against COX-2. On the other hand, Patent Document 3 discloses a compound (C) or the like which inhibits a platelet aggregation drug, and the compound (D) obtained by converting a divalent group at the * position on the (IV) ring of the present compound into a methoxy group is shown. Since the nephrotoxicity is caused, the inhibition of platelet aggregation (IV) disclosed in Patent Document 3 cannot be said to be superior in terms of safety. [Chemical 2] ΜβΟ 1NJ jHTnv (C) MeO into *〆

Me—Me—

〇Me (D) [專利文獻1]日本專利第2586713號說明書 126365.doc 200827349 [專利文獻2]國際公開97/29774號手冊 [專利文獻3]國際公開2006/0 14005號手冊 [非專利文獻1]BMJ，3 08卷、8 1-1 06頁、1994年 [非專利文獻2]BMJ，321 卷、1 1 83-1 1 87 頁、2000年 [非專利文獻 3]Neurology、57 卷、Suppl.2、S5-S7 頁 [非專利文獻4]Drugs Today、35卷、25 1-265 頁、1999年 [非專利文獻 5]Chem.Pharm_Bull.、45 卷、987-995 頁、 1997 年【發明内容】 [發明所欲解決之問題] 本發明係提供一種安全性較高之較強之抑制血小板凝集藥。本發明者們為尋求上述抑制血小板凝集藥而專心研究之結果發現，以下述通式（I)表示之吡唑衍生物可較強地抑制 COX-1及COX-2，且並不顯示出腎毒性，起到較強之抑制血小板凝集作用，從而完成本發明。即，本發明提供一種化合物、其鹽或彼等之溶劑合物，該化合物係以通式（I)表示， [化3]〇Me (D) [Patent Document 1] Japanese Patent No. 2586713 Specification 126365.doc 200827349 [Patent Document 2] International Publication No. 97/29774 Manual [Patent Document 3] International Publication No. 2006/0 14005 No. [Non-Patent Document 1 BMJ, Vol. 3, Vol. 8, pp. 1-1, 2006, 1994 [Non-Patent Document 2] BMJ, 321 volumes, 1 1 83-1 1 87 pages, 2000 [Non-Patent Document 3] Neurology, 57 volumes, Suppl .2, S5-S7 [Non-Patent Document 4] Drugs Today, Vol. 35, 25 1-265, 1999 [Non-Patent Document 5] Chem. Pharm_Bull., Volume 45, 987-995, 1997 [Invention [Contents] [Problems to be Solved by the Invention] The present invention provides a stronger platelet aggregation-inhibiting drug with higher safety. The present inventors have found that the pyrazole derivative represented by the following general formula (I) can strongly inhibit COX-1 and COX-2 without exhibiting a kidney, as a result of intensive studies for the above-mentioned platelet-inhibiting drug. Toxicity, which plays a strong role in inhibiting platelet aggregation, thereby completing the present invention. That is, the present invention provides a compound, a salt thereof or a solvate thereof, which is represented by the formula (I), [Chemical 3]

126365.doc 200827349 (式中’ R2表示選自氫原子、有時亦經取代之低碳數烧基、低碳數炔基、有時亦經取代之胺甲醯基、氰基、有時亦經取代之胺基、有時亦唑取代之低碳數烷氧基及低碳數烧醯基中之基或原子；戎中― 式中X表不以通式（II)表示之基， [化4] —V>Rl (II) 式中之環狀結構表示除了式中所記載之氮原子以外有時亦將其他氮原子或氧原子作為構成原子之4〜7員之脂環式雜％ R表不4 %狀結構亦可由選自有時亦經取代之低碳數烧基有時亦經取代之胺甲酿基、有時亦經取代之胺基、經基、低碳數燒氧基、側氧基、低碳數㈣基、低碳數烷基磺醯基及鹵素原子中之丨〜2個基或原子取代。本發明又提供-種含有上述化合物、其鹽或彼等之溶劑合物之醫藥組合物；一種含有上述化合物、其鹽或彼等之溶劑合物之醫藥；以上述化合物、其鹽或彼等之溶劑合物作為有效成分之抑制血小板凝集藥；以上述化合物、其鹽或彼等之溶劑合物作為有效成分之缺血性疾病之預防及/ 或治療藥。本發明又提供一種缺血性疾病之預防及/或治療方法，其特徵在於，投與上述化含物、其鹽或彼等之溶劑合物之有效量。 126365.doc 200827349 本發明進而提供上述化合物、其鹽或彼等之溶劑合物的用途，其用於醫藥製造；上述化合物、其鹽或彼等之溶劑合物的用途’其用於缺血性疾病之預防及/或治造。、 [發明之效果]126365.doc 200827349 (wherein R 2 represents a low carbon number alkyl group selected from a hydrogen atom, sometimes substituted, a low carbon number alkynyl group, a substituted amino amidino group, a cyano group, and sometimes a substituted amino group, sometimes a lower alkoxy group substituted with a azole, and a group or atom in a lower carbon number; wherein X is not represented by the formula (II), [ 4] —V> Rl (II) The cyclic structure in the formula represents an alicyclic heteropoly group of 4 to 7 members which may have other nitrogen atoms or oxygen atoms as constituent atoms in addition to the nitrogen atom described in the formula. R may not have a 4%-like structure or may be selected from a low-carbon alkyl group which is sometimes substituted or sometimes substituted, an amine group which is sometimes substituted, an amine group which is sometimes substituted, a base group, and a low carbon number. a base, a pendant oxy group, a lower carbon number (tetra) group, a lower alkyl alkylsulfonyl group, and a fluorene atom or a halogen atom. The present invention further provides a compound containing the above compound, a salt thereof or the like. a pharmaceutical composition of a solvate; a medicament comprising the above compound, a salt thereof or a solvate thereof; the above compound, a salt thereof or a solvent thereof The agent for inhibiting platelet aggregation as an active ingredient; the preventive and/or therapeutic agent for ischemic diseases comprising the above compound, a salt thereof or a solvate thereof as an active ingredient. The present invention further provides prevention of ischemic diseases And/or a method of treatment characterized by administering an effective amount of the above-mentioned compound, a salt thereof or a solvate thereof. 126365.doc 200827349 The present invention further provides the above compound, a salt thereof or a solvate thereof Use for the manufacture of a drug; use of the above compound, a salt thereof or a solvate thereof for the prevention and/or treatment of an ischemic disease. [Effect of the invention]

本發明之化合物⑴、其鹽或彼等之溶劑合物具有保持較高之安全性、且較強地抑制也小板凝集、抑制血栓形成之作用°因&’可有效地詩預防及/或治療心肌梗塞、心絞痛（慢性穩定心絞痛、不穩定心絞痛等）、缺血性腦血管病（TIA(transient ischemic attack ;短暫性腦缺血發作）、腦梗塞等）、末梢血管病、人工血管置換後閉塞、冠狀動脈介入術（CABG(Coronary artery bypass grafUng surgery ;冠狀動脈繞道手術）、PTCA(percutane〇us transluminai coronary angioplasty ;經皮腔内冠狀動脈成形術）、支架置放術等）後之血栓性閉塞、糖尿病性視網膜病•腎病、心臟人工瓣膜置換時閉塞、急性冠狀動脈綜合症等由血栓•栓塞所引起之缺血性疾病。又，可有效用於預防及/或治療血管手術、血液體外循環等所伴隨之血栓·栓塞。進而，可有效地改善慢性動脈閉塞症所伴隨之潰瘍、疼痛、冷感等缺血性症狀。【實施方式】以下就通式（I)加以說明。 R2表示選自1)有時亦經取代之低碳數烷基、2)低碳數炔基、3)有時亦經取代之胺曱醯基、4)氰基、5)有時亦經取 126365.doc -10- 200827349 代之胺基、6)有時亦經取代之低碳數烷氧基及7)低碳數烷醯基之基。、本σ兒明書中之「低碳數烷基」係表示碳數1〜6之直鏈狀支鏈狀或環狀之烷基。具體而言可列舉：甲基、乙基、正丙基、異丙&、正丁基'異丁基、第三丁基、正戊基異戊基、正已基、環丙基、環丁基、環戊基、環已基、環丙基甲基、環戊基甲基。本Λ明書中之「低碳數烷氧基」係表示其結構中包含低碳數烷基之烷氧基。具體而言可列舉：甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基、第三丁氧基、正戊氧基、環戊基氧基。況月曰中之低石厌數炔基」係表示碳數2〜6之直鏈狀、支鏈狀或環狀之炔基。具體而言可列舉：乙炔基、^ 丙炔基、2-丙炔基、丨_丁炔基、2_ 丁炔基、丨_戊炔基、2_ 戊炔基。本說明書中之「低碳數烷醯基」係表示碳數卜6之直鏈狀或支鏈狀的烷醯基。具體而言可列舉：曱醯基、乙醯基、正丙醯基、正丁醯基、異丁醯基。本說明書中之「低碳數烧基磺醯基」係表示以低碳㈣基取代之績酿基。具體而言可列舉：甲基磺醯基、乙基磺酿基、正丙基確酿基、異丙基續酿基、正丁基磺醯基、異丁基％酿基、第三丁基績酿基、正戊基磺醯基、異戊基磺醯基、環丙基磺醯基、環己基磺醯基。進而，就上述1)〜7)加以說明。 126365.doc -11 - 200827349 )有時亦經取代之低碳㈣基」係表示可由選自包含以下所料之a)〜e)之料基群中的1個、或者㈣或不同之2〜3個取代基或原子所取代之低碳錢基。該等取代基或原子只要可取代’則既可取代為低碳數烷基中之相同碳原子，亦可取代為Μ碳原子。作為有時亦經取代之低碳數烧基，較好的是甲基、乙基或正丙基，尤好的是甲基。The compound (1) of the present invention, a salt thereof or a solvate thereof has a function of maintaining high safety and strongly inhibiting agglomeration of small plates and inhibiting thrombus formation, and can effectively prevent poetry prevention and/or Or treatment of myocardial infarction, angina pectoris (chronic stable angina, unstable angina, etc.), ischemic cerebrovascular disease (TIA (transient ischemic attack), cerebral infarction, etc.), peripheral vascular disease, artificial vascular replacement Thrombosis after posterior occlusion, coronary intervention (CABG (Coronary artery bypass grafUng surgery; coronary bypass surgery), PTCA (percutane〇us transluminai coronary angioplasty; percutaneous transluminal coronary angioplasty), stent placement, etc. Ischemic diseases caused by thrombosis and embolism, such as occlusion, diabetic retinopathy, nephropathy, occlusion during cardiac prosthetic valve replacement, and acute coronary syndrome. Further, it can be effectively used for preventing and/or treating thrombus and embolism accompanying vascular surgery, blood extracorporeal circulation and the like. Further, it is possible to effectively improve ischemic symptoms such as ulcers, pain, and cold sensation accompanying chronic arterial occlusive disease. [Embodiment] Hereinafter, the general formula (I) will be described. R2 represents a lower alkyl group selected from 1) and sometimes substituted, 2) a lower alkynyl group, 3) an amine group which is sometimes substituted, 4) a cyano group, and 5) sometimes Take 126365.doc -10- 200827349 substituted amino group, 6) sometimes substituted lower alkoxy group and 7) lower alkyl alkoxy group. The "lower alkyl group" in the present specification means a linear branched or cyclic alkyl group having 1 to 6 carbon atoms. Specific examples thereof include methyl, ethyl, n-propyl, isopropyl & n-butyl 'isobutyl, tert-butyl, n-pentylisopentyl, n-hexyl, cyclopropyl, and ring. Butyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl. The "lower alkoxy group" in the present specification means an alkoxy group having a lower alkyl group in its structure. Specific examples thereof include a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a third butoxy group, a n-pentyloxy group, and a cyclopentyloxy group. . The low-stone anodized alkynyl group in the state of the moon is a linear, branched or cyclic alkynyl group having a carbon number of 2 to 6. Specific examples thereof include an ethynyl group, a propynyl group, a 2-propynyl group, a fluorenyl-butynyl group, a 2-butynyl group, a fluorenyl-pentynyl group, and a 2-pentynyl group. The "lower alkyl alkane group" in the present specification means a linear or branched alkane group of carbon number. Specific examples thereof include an anthracenyl group, an ethyl fluorenyl group, a n-propyl group, an n-butyl group, and an isobutyl group. The "low carbon number sulfonyl sulfonyl group" in the present specification means a base which is substituted with a low carbon (tetra) group. Specific examples thereof include a methylsulfonyl group, an ethylsulfonic acid group, a n-propyl acylate group, an isopropyl thioglycol group, a n-butyl sulfonyl group, an isobutyl hexanyl group, and a third butyl group. Base, n-pentylsulfonyl, isopentylsulfonyl, cyclopropylsulfonyl, cyclohexylsulfonyl. Further, the above 1) to 7) will be described. 126365.doc -11 - 200827349 ) The low carbon (tetra) group which is sometimes substituted may mean one, or (four) or different 2~ selected from the group of materials including a) to e) A low carbon carbon group substituted with three substituents or atoms. The substituent or the atom may be substituted with the same carbon atom in the lower alkyl group as long as it can be substituted, or may be substituted with a fluorene carbon atom. As the low carbon number base which is sometimes substituted, a methyl group, an ethyl group or a n-propyl group is preferred, and a methyl group is particularly preferred.

a)有時亦由⑽、或者相同或不同之2個低碳數烧基所取代之胺甲醯基：該胺甲醢基係表示未經取代之胺甲醢基或由1〜2個低碳數烷基取代之胺甲醯基。具體而言可列舉：甲基胺甲酿基、乙基胺甲醯基、二甲基胺甲醯基、N—甲基-N-乙基胺甲醯基。該等之中，較好的是未經取代之胺甲醯基、甲基胺甲醯基或二甲基胺甲醯基。 b)有時亦由選自低碳數烷基、低碳數烷醯基及低碳數烷基磺醯基中的1個、或者相同或不同之2個取代基取代之胺基：該胺基係表示未經取代之胺基、或者由選自低碳數烷基、低碳數烷醯基及低碳數烷基磺醯基中之1個、或者相同或不同之2個取代基取代之胺基。具體而言可列舉：甲基胺基、乙基胺基、正丙基胺基、異丙基胺基、環丙基胺基、正丁基胺基、異丁基胺基、環戊基甲基胺基、二甲基胺基、二乙基胺基、二正丙基胺基、二正丁基胺基、N-甲基-N-乙基胺基、N-乙基-N-正丙基胺基、N-甲基-N-環戊基甲基胺基、甲驢基胺基、乙醢基胺基、正丙酿基胺基、 N-甲基-N-乙醯基胺基、N-乙基乙醯基胺基、甲基磺醯基胺基、乙基磺醯基胺基、異丙基磺醯基胺基、正丁基磺 126365.doc -12- 200827349 醯基胺基、環丙基績醯基胺基、環丁確醯基胺基、队甲基-N-甲基續醯基胺基、N.乙基_N_甲基續醯基胺基。 C)羥基：的是 d)低碳數烷氧基：較好的是甲氧基或乙氧基，尤好甲氧基。溴及碘，較好的是氟或 e)鹵素原子：可列舉氟、氣氯，尤好的是氟。a) Aminomethyl group which is sometimes substituted by (10) or two lower carbon number groups which are the same or different: the amine formamidine group represents an unsubstituted amine carbenyl group or is composed of 1 to 2 low Aminoalkyl substituted by a C number alkyl group. Specific examples thereof include a methylamine methyl alcohol group, an ethylamine methyl sulfonyl group, a dimethylamine methyl fluorenyl group, and an N-methyl-N-ethylamine methyl fluorenyl group. Among these, an unsubstituted amine methyl sulfonyl group, a methylamine methyl fluorenyl group or a dimethylamine fluorenyl group is preferred. b) an amine group which is sometimes substituted by one or a same or different two substituents selected from the group consisting of a lower alkyl group, a lower alkyl alkano group and a lower alkyl alkylsulfonyl group: the amine The base system represents an unsubstituted amine group, or is substituted by one substituent selected from the group consisting of a lower alkyl group, a lower alkyl alkano group and a lower alkyl alkylsulfonyl group, or the same or different two substituents. Amino group. Specific examples thereof include methylamino group, ethylamino group, n-propylamino group, isopropylamino group, cyclopropylamino group, n-butylamino group, isobutylamino group, cyclopentyl group Amino group, dimethylamino group, diethylamino group, di-n-propylamino group, di-n-butylamino group, N-methyl-N-ethylamino group, N-ethyl-N-positive Propylamine, N-methyl-N-cyclopentylmethylamino, decylamino, ethylamino, n-propylamino, N-methyl-N-ethinylamine , N-ethylethenylamino, methylsulfonylamino, ethylsulfonylamino, isopropylsulfonylamino, n-butylsulfide 126365.doc -12- 200827349 Amino, cyclopropyl decylamino, cyclobutyl decylamino, benzyl-N-methyl decylamino, N. ethyl-N-methyl decylamino. C) Hydroxy: is d) lower alkoxy: preferably methoxy or ethoxy, especially methoxy. Bromine and iodine are preferably fluorine or e) halogen atoms: fluorine or chlorine, and particularly preferably fluorine.

2) 作為低碳數炔基，較好的是乙炔其』足〇厌丞、丨-丙炔基或2_丙炔基’尤好的是乙炔基。 3) 「有時亦經取代之胺甲醯基」係表示未經取代之胺甲醯基，或者由丨個、或相同或者不同之2個低碳數烷基取代之胺甲醯基。具體而言可列舉：甲基胺甲醯基、乙基胺甲醯基、正丙基胺甲醯基、二甲基胺甲醯基、二乙基胺曱醯基、N-甲基乙基胺甲醯基。 4) 「氰基」 5) 「有時亦經取代之胺基」係表示未經取代之胺基，或者由1個、或相同或者不同之2個低碳數烷基取代之胺基。具體而言可列舉：甲基胺基、乙基胺基、正丙基胺基、二甲基胺基、二乙基胺基、N-甲基乙基胺基。其中較好的是未經取代之胺基、甲基胺基或二甲基胺基。 6) 「有時亦經取代之烷氧基」係表示未經取代之烷氧基、或者由選自包含上述1)之a)〜e)之取代基群中的1個、或相同或者不同之2〜3個取代基或原子所取代之烷氧基。作為有時亦經取代之烷氧基，較好的是未經取代之低碳數 126365.doc -13- 200827349 2氧基^由胺甲醮基取代之低碳數炫氧基，更好的是甲氧基、乙氧基或胺f醯基^ 基甲氧基。土甲乳基，攻好的是甲氧基或胺f醢 7)作為「低碳數烷醯基曰其，+ 乂的疋乙酿基或正丙醯基，尤好的是乙醯基。作為R2，該等1)〜7)之戈基中，較好的是有時亦代之低碳數烷基，更好# Up & 另卞力、工取更好的疋未經取代之低碳數烷基，其中最好的是甲基。其就X力口以言兒明〇 V Φ — ⑴、主月X表不以通式（Π)表示之基，通式 (II)表不除了通式（π)中¥ # )甲口己载之鼠原子以外、亦可將其他氮原子或氧原子作為構成肩早的再攻原子的可具有取代基的4〜7員之脂環式雜環基。曰作為4〜7貝之脂環式雜户| 衣式雜％基，可列舉：氮雜環丁基…比 ( =絲、吼唾咬基"辰°定基”底嗪基、六氫噠嗪基、六氫疋基、味㈣基、高旅嗪基、嗎琳基"号吐咬基、氧氮雜環庚燒基。該等之中較好的是氮雜環丁基、対咬基、口比唾啶基、哌啶基、哌丄蚕I ，、虱噠嗪基、嗎啉基、唠唑啶基或氧氮雜環庚烷基，尤好的 T j疋农嗪基、哌啶基、嗎啉基”号唑啶基、氧氮雜環庚烷基或吡咯啶基。 R係取代為構成上述4〜7員之炉s ^ 貝之月曰娘式複索環基之脂環式雜環的碳原子或氮原子之基表丞衣不選自以下之⑴〜（ix)中之基。 ⑴有時亦經取代之低碳數院基：表示與上述尺2之有時亦故取代之低碳數烷基相同之某。 N心丞即，表示可由選自包含上 126365.doc -14- 200827349 述a)〜e)之取代基群中的1個、或者相同或不同之2〜3個取代基或原子取代之低碳數烷基。進而，有時亦經取代之低碳數烷基亦可為以側氧基單獨取代之低碳數烷基。又，有時亦經取代之低碳數烷基亦可為與選自上述a)〜e)中之基或原子組合而取代之低碳數烷基。作為低碳數烷基，較好的是甲基或環丙基。進而，作為取代為低碳數烷基之基或原子，較好的是鹵素原子、羥基、低碳數烷氧基及胺基。因此，作為取代為式（II)中之環狀結構之經取代的低碳數烷基，較好的是函素低碳數烷基、羥基低碳數烷基、低碳數烷氧基低碳數烷基或胺基低碳數烷基。函素低碳數烷基係表示以_素原子取代之低碳數烷基。作為_素低碳數烷基可列舉：氟甲基、二氟甲基、三氟甲基、氯甲基、二氣曱基、二氯甲基，該等之中，較好的是氟甲基、二氟甲基或二氣甲基’尤好的是氟甲基。羥基低碳數烷基係表示以羥基取代之低碳數烷基。作為羥基低碳數烷基可列舉：羥基甲基、1-羥基乙基、2-羥基乙基、丨-羥基丙基、2_羥基丙基、3-經基丙基。低碳數烷氧基低碳數烷基係表示以低碳數烷氧基取代之低碳數烷基，可例示：甲氧基甲基、乙氧基曱基、甲氧基乙基、乙氧基乙基。其中較好的是甲氧基甲基。胺基低碳數烷基係表示以胺基取代之低碳數烷基，具體而言可列舉：胺基甲基、胺基乙基、丨_胺基環丙基’其中較好的是1-胺基環丙基。 (11)有時亦經取代之胺甲醯基：有時亦經取代之胺曱醯基係表示與上述R2中之有時亦經取代之胺曱醯基相同之 126365.doc -15- 200827349 基。作為有時亦經取代之胺甲醯基，較好的是未經取代之胺甲醢基、甲基胺甲醯基或二甲基胺甲醯基，尤好的是未經取代之胺甲醯基。㈣有時亦經取代之胺基：有時亦經取代之胺基係表示與上述R2中之有時亦經取代之胺基相同之基。作為有時亦經取代之胺基，較好的是未經取代之胺基、甲基胺基、二甲基胺基、乙基胺基或二乙基胺基，尤好的是未經取代之胺基或二甲基胺基。 (iv)羥基 (V)低碳數烷氧基：作為低碳數烷氧基，較好的是甲氧基或乙氧基，尤好的是甲氧基。 (vi) 側氧基， (vii) 低碳數烷醯基··作為低碳數烷醯基，可列舉：甲醯基、乙醯基、正丙醯基、正丁醯基、異丁醯基、三甲基乙醯基，該等之中尤好的是甲醯基。 (viii) 低碳數烷基磺醯基：作為低碳數烷基磺醯基，可列舉：曱基磺醯基、乙基磺醯基、正丙基磺醯基、異丙基磺醯基、正丁基磺醯基、異丁基磺醯基、第三丁基磺醯基、正戊基磺醯基、異戊基磺醯基、環丙基磺醯基、環己基磺醯基。該等之中較好的是甲基磺醯基、乙基磺醯基或正丙基石黃醢基。 (ix) 鹵素原子：作為鹵素原子，較好的是氟或氯。選自該等（1)〜(IX)之基或原子可將1個取代為上述脂環式雜環基’若可取代則亦可將相同或不同之2〜4個取代為上 126365.doc -16- 2008273492) As the lower carbon alkynyl group, it is preferred that acetylene has an acetylene group, particularly a hydrazine, a fluorenyl-propynyl group or a 2-propynyl group. 3) "Aminomethyl group which is sometimes substituted" means an unsubstituted aminomethyl group or an amine carbenyl group which is substituted by one, or the same or different two lower alkyl groups. Specific examples thereof include methylamine methyl sulfonyl group, ethylamine methyl sulfonyl group, n-propylamine methyl fluorenyl group, dimethylamine carbhydryl group, diethylamino fluorenyl group, and N-methylethyl group. Aminomethyl thiol. 4) "Cyano" 5) "Amino group which is sometimes substituted" means an unsubstituted amino group or an amine group substituted by one or two of the same or different two lower alkyl groups. Specific examples thereof include a methylamino group, an ethylamino group, a n-propylamino group, a dimethylamino group, a diethylamino group, and an N-methylethylamino group. Of these, an unsubstituted amino group, a methylamino group or a dimethylamino group is preferred. 6) "Alkoxy group which is sometimes substituted" means an unsubstituted alkoxy group, or one, or the same or different from a group of substituents selected from the group a) to e) above) 2 to 3 substituents or alkoxy groups substituted by an atom. As the alkoxy group which is sometimes substituted, it is preferably an unsubstituted low carbon number 126365.doc -13-200827349 2 oxy group; a lower decyloxy group substituted by an amine mercapto group, more preferably It is a methoxy group, an ethoxy group or an amine group. The base is based on the methoxy group or the amine propyl group. The methoxy group or the amine group )7) is used as the "low carbon number alkyl group", and the 乂酿酿正 or n- propyl group is particularly preferred. As R2, in the group of 1) to 7), it is preferred that the lower alkyl group is sometimes replaced by a lower alkyl group, and more preferably, it is better, and the work is better. a lower alkyl group, the most preferred of which is a methyl group. The X-port is clearly expressed as V Φ — (1), the main month X is not represented by the formula (Π), and the formula (II) is given. Except for the mouse atom contained in the general formula (π), the other nitrogen atom or oxygen atom may be used as the alicyclic ring of the 4 to 7 member which may have a substituent. Heterocyclic group. 曰 as a 4 to 7 shell alicyclic type of miscellaneous | clothing heteropoly group, can be cited: azetidinyl ... ratio (= silk, 吼咬 & & & & & & & & & & & 底a hexahydropyridazinyl group, a hexahydroindolyl group, a benzoic acid group, a sulphate group, a high carbazide group, a morphine group, a chlorinated group, and an oxazepine group. Among these, aza is preferred. Cyclobutyl, indole, oral succinyl, piperidinyl, piperazine I , pyridazinyl, morpholinyl, oxazolidinyl or oxazepanyl, especially preferably T j oxazinyl, piperidinyl, morpholinyl oxazolidinyl, oxy nitrogen heterocycle a heptyl group or a pyrrolidinyl group. The R group is substituted with a carbon atom or a nitrogen atom of the alicyclic heterocyclic ring constituting the above-mentioned 4 to 7 member furnaces. It is a group selected from the following (1) to (ix). (1) Low-carbon number base which is sometimes substituted: It is the same as the low-carbon alkyl group which is sometimes substituted with the above-mentioned ruler 2. N heart 丞That is, it is represented by a lower alkyl group which may be substituted with one or a same or different 2 to 3 substituents or atoms selected from the group consisting of a) to e) of 126365.doc -14-200827349. Further, the lower alkyl group which may be substituted may be a lower alkyl group which is substituted by a pendant oxy group. Further, the substituted lower alkyl group may be selected from the above a lower alkyl group substituted by a group or a combination of atoms in a) to e). A methyl group or a cyclopropyl group is preferred as the lower alkyl group. Further, as a group substituted with a lower alkyl group Or atom, Preferred are a halogen atom, a hydroxyl group, a lower alkoxy group and an amine group. Therefore, as the substituted lower alkyl group substituted by the cyclic structure in the formula (II), it is preferred that the element is low. a C number alkyl group, a hydroxy lower alkyl group, a lower alkoxy a lower alkyl group or an amine lower alkyl group. A lower alkyl group of a functional group means a lower carbon number substituted with a _ atom The alkyl group may, for example, be a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dihalomethyl group or a dichloromethyl group. The fluoromethyl group, the difluoromethyl group or the di-halomethyl group is particularly preferably a fluoromethyl group. The hydroxy-lower alkyl group means a lower alkyl group substituted with a hydroxy group. : hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, hydrazine-hydroxypropyl, 2-hydroxypropyl, 3-propylidene. The lower alkoxy alkoxy lower alkyl group means a lower alkyl group substituted with a lower alkoxy group, and is exemplified by methoxymethyl, ethoxylated, methoxyethyl, and B. Oxyethyl. Of these, a methoxymethyl group is preferred. The amine-based lower alkyl group means a lower alkyl group substituted with an amine group, and specific examples thereof include an aminomethyl group, an aminoethyl group, and an anthracene-aminocyclopropyl group. - Aminocyclopropyl. (11) Aminomethyl group which is sometimes substituted: the amine sulfhydryl group which is sometimes substituted is the same as the sometimes substituted amine sulfhydryl group in the above R 2 126365.doc -15- 200827349 base. As the amine methyl sulfhydryl group which is sometimes substituted, it is preferably an unsubstituted amine carbhydryl group, a methylamine carbaryl group or a dimethylamine carbhydryl group, particularly preferably an unsubstituted amine group.醯基. (4) Amine groups which are sometimes substituted: The amine group which is sometimes substituted also represents the same group as the sometimes substituted amino group in the above R2. As the amine group which is sometimes substituted, an unsubstituted amino group, a methylamino group, a dimethylamino group, an ethylamino group or a diethylamino group is preferred, and it is preferably unsubstituted. Amino or dimethylamino. (iv) Hydroxy (V) lower alkoxy group: As the lower alkoxy group, a methoxy group or an ethoxy group is preferred, and a methoxy group is particularly preferred. (vi) a pendant oxy group, (vii) a lower alkyl alkano group. As a lower alkyl alkane group, a methyl group, an ethyl group, a n-propyl group, a n-butyl group, an isobutyl group, a trimethyl group Base ethyl sulfhydryl, especially among these ones is the thiol group. (viii) lower alkyl alkylsulfonyl group: as a lower alkylsulfonyl group, a mercaptosulfonyl group, an ethylsulfonyl group, a n-propylsulfonyl group, an isopropylsulfonyl group , n-butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl, cyclopropylsulfonyl, cyclohexylsulfonyl. Preferred among these are methylsulfonyl, ethylsulfonyl or n-propylxanthene. (ix) Halogen atom: As the halogen atom, fluorine or chlorine is preferred. The substituent or the atom selected from the above (1) to (IX) may be substituted with one of the above alicyclic heterocyclic groups. If it is substituted, the same or different 2 to 4 may be substituted as the upper 126365.doc -16- 200827349

述·脂環式雜提A 該脂環式又，複數個基進行取代時，既可取代為作為=同一元素，亦可取代為不同元素。的是㈣環…環、州…雜環，較好咬環或嗎料。錢雜環㈣環、啦略作為X ’較好的是哌嗪基、哌嗪基、4-環丙基•奉基、2·氣…：琳基、4_甲基辰哌唪美、”蚕丞2氣甲基吡咯啶基、2,4-二甲基 ”土 I氟甲基吡咯啶基、氧氮雜俨鬼、卜甘基今唑啶其、”衣庚燒基、4,4-二甲可上疋基、2_胺甲醯基哌啶基或的是2-脸田破甘飞4甲虱基-哌啶基，尤好私甲δώ基口辰σ定基、4-甲氧美说基、土辰啶基、4_甲基-哌嗪 4_娘丙基-哌嗪基、嗎啉基、氣f f ^ , 乳虱雜裱庚烷基、4,4-二 Τ基τ唑义基或2_氟甲基吡咯啶基。作為本發明之化合物’較好的是r、甲基；X為哌唪二：:基，基、4_甲基·娘嗪基，丙基+秦土 2 -鼠甲基口比洛口定某、24- - w «· 定基2,4 —甲基娘嗪基、2·敗甲基吡 h基、K氮雜環庚烧基、4,4_二甲基十坐咬基、2_胺甲酉进基哌啶基或4_甲氧基_哌啶基 .^ ^ ^ 化口物。進而尤好的是R2 為甲基；X為2·胺甲醯基錢基、4-甲氧基_錢基、4_甲 ^秦基、4·環丙基4嗪基、嗎琳基、氧氮雜環庚燒土、4,4.—甲基料咬基或n甲基対唆基之化合物。並不限於本發明之所有化合物均形成鹽，本發明之化人物具有縣或胺基時等有時亦形成鹽。進而，亦有其鹽形成浴劑合物之情形。此處之鹽可列舉鹽酸、氫溴酸、硫酸、硝酸等無機酸之鹽；甲錢、對甲苯續酸、反丁稀二 126365.doc -17- 200827349 之鹽；與鈉、鉀、鈣等鹼金屬或鹼酸、三氤醋酸等有機酸土類金屬之離子之鹽。本發明之化合物每I 士一意之 >谷劑合物中之溶劑合物，除了附加有用於結晶之拚ψ隹 + 啊出4之 >谷劑的溶劑合物以外，亦包含，收空氣中之水分而形成之水合物。作為溶劑之例，例如可列舉：水、甲醇或乙醇等低碳數醇、丙綱或乙猜等有機溶劑。The alicyclic type A is alicyclic, and when a plurality of groups are substituted, it may be substituted as the same element or may be substituted for a different element. It is (four) ring... ring, state...heterocyclic ring, better bite ring or material. The heterocyclic ring of tetrahydrogen (tetra) is similar to X', preferably piperazinyl, piperazinyl, 4-cyclopropyl-Fan-based, 2·gas...: Lin-based, 4-methyl-methylpyrazine, Silkworm pupa 2 gas methyl pyrrolidinyl, 2,4-dimethyl" soil I fluoromethyl pyrrolidinyl, oxazepine, bromo-methyl oxazide, "gumene, 4,4-two A can be a thiol group, a 2-aminomethylmercaptopiperidinyl group or a 2-face field broken Ganfei 4 mercapto-piperidinyl group, especially a private ώ ώ ώ 口口 σ σ 、、, 4-methoxy Said base, tert-butyl group, 4-methyl-piperazine 4_n-propyl-piperazinyl, morpholinyl, gas ff ^, chyloin, heptyl, 4,4-didecylrazole Alkyl or 2-fluoromethylpyrrolidinyl. As the compound of the present invention, preferred is r, methyl; X is piperidine::yl, benzyl, 4-methylanthionyl, propyl+ Qin soil 2 - mouse methyl mouth than Luokou Ding, 24--w «· Dingji 2,4-methyl-nylazinyl, 2·-methylpyryl, K azepan, 4, 4_dimethyl dimethyl sittan, 2-aminomethyl hydrazino-piperidinyl or 4-methoxy-piperidinyl. ^ ^ ^ </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Aminomethylmercapto 4-methoxy-kengyl, 4-methylthiol, 4·cyclopropyl-4-azinyl, morphinyl, oxazepine, 4,4.-methyl chinyl or n-methyl The compound of the present invention is not limited to the case where all of the compounds of the present invention form a salt, and when a person of the present invention has a county or an amine group, a salt is sometimes formed. Further, there is a case where a salt forms a bath composition. The salt herein may be a salt of a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or nitric acid; a salt of acetaminophen, p-toluene acid, anti-butyl 126365.doc -17-200827349; and sodium, potassium and calcium. a salt of an organic acid earth metal such as an alkali metal or an alkali acid or a triterpene acetic acid. The solvate of the compound of the present invention per gram of the granule of the present invention is added to the crystallization of the compound. In addition to the solvate of the granules, the hydrate of the granules is also contained in the solvate of the granules, and examples of the solvent include low-carbon alcohols such as water, methanol or ethanol. Organic solvents such as C-class or B-guess.

作為本發明之化合物、其鹽或彼等之溶劑合物，較好地可列舉由下述式（ia)〜(ik) [化5]The compound of the present invention, a salt thereof or a solvate thereof is preferably exemplified by the following formula (ia) to (ik) [Chemical 5]

中任一式表示之化合物、其鹽或彼等之溶劑合物。進而， 126365.doc -18- 200827349 最好地可例示以上述式（Ib)表示之化合物、其鹽或彼溶劑合物。之〜，廿和口奶+會較強地抑制COX-1及COX-2，且不顯示腎毒 ' I陡顯不出較強之抑制血小板凝集作用，就主要藥效、安. 王〖生、經口吸收性、内處置、溶解性之觀點而言’作為醫藥品極為優，本發明之化合物、其鹽或彼等之溶：法製造。」稽由下述方A compound represented by any of the formulae, a salt thereof or a solvate thereof. Further, 126365. doc -18 to 200827349 is preferably exemplified by the compound represented by the above formula (Ib), a salt thereof or a solvate thereof. ~, 廿 and mouth milk + will strongly inhibit COX-1 and COX-2, and does not show nephrotoxicity 'I steepness does not show strong inhibition of platelet aggregation, the main drug effect, An. Wang〗 From the viewpoints of oral absorption, internal treatment, and solubility, 'the pharmaceutical product is extremely excellent, and the compound of the present invention, the salt thereof, or the like thereof are produced by the method. The following party

以下就本發明之化合物⑴之代异 [化6] 表“方法加以說明The following is a description of the compound (1) of the present invention.

化合_可藉…方法而製造:將化合物⑴溶解於 126365.doc -19- 200827349 四氫呋喃等惰性溶劑中烧基）酿胺鐘等驗進行處酯或草酸二乙酯）（2)， -7 8 °C〜室溫。，於-78°C冷卻下，以雙（三甲基矽理，添加草酸二烷基酯（草酸二甲並進行攪拌。反應溫度較好地是貌醇鋼(甲醇納或乙醇納)存在下 =了:基醋(草酸二甲醋或草酸二乙醋)⑺於醇(甲(醇) (好二液中加以處理，亦可獲得化合物(3)。反應溫度較好的疋-10〜1〇〇°C。再者’芳香族嗣⑴藉由8鳥等人（chem ph瞻咖 =:5(7)，114°)之方法、或參考例所記載之方法或基於该方法之方法進行製造即可。芳香族酮⑴具有經基、胺基等官能基時，有時必須事 =適！，保護基保護該等官能基。作為經基之保護基 1 +·第二丁基、节基等’作為胺基之保護基可列舉·· 三氟乙醯基、第三丁氧基幾基、节氧幾基等。該等保護基於適於各保護基之條件下可脫離。接著’將化合物（3)與肼衍生物（⑷w〇 2〇〇4/〇69824)溶解於醇（甲醇或乙醇）中，升溫授拌3G分鐘〜5小時後，向反 :中"“口適罝之醋酸’進而升溫攪拌i晚，藉此可製造化合物（5)。反應溫度較好地是心抓。此時，會副生位置異構物’但藉由石夕膠管柱層析法或結晶化可容易地將化合物（5)分離精製。 ( 接著，甲醇或酯體（6)可藉由升溫攪拌化合物（5)與雷氏鎳之醇乙醇）懸濁液而製造。反應溫度較好的是 126365.doc -20- 200827349 機化學之通常知 50〜110°C。該反應條件或試劑等可根據有識而適當選擇。又，酯體（6a)亦可由下述化合物（8)衍生而成 [化7]The compound can be produced by the method: the compound (1) is dissolved in an inert solvent such as 126365.doc -19-200827349 tetrahydrofuran, and the amine or the oxalate is added to the amine (2), -7 8 °C ~ room temperature. Under cooling at -78 ° C, bis (trimethyl hydrazine, add dialkyl oxalate (dimethyl oxalate and stir. The reaction temperature is better in the presence of methanol (methanol or ethanol) =: base vinegar (dimethyl oxalate or oxalic acid) (7) in alcohol (methyl (alcohol) (treated in a good solution, can also obtain compound (3). The reaction temperature is better 疋-10~1 〇〇°C. Further, 'aromatic 嗣(1) is carried out by the method of 8 birds et al. (chem ph = 5 (7), 114°), or the method described in the reference example or the method based on the method. When the aromatic ketone (1) has a functional group such as a trans group or an amine group, it may be necessary to protect the functional group. The protecting group serves as a protecting group for the base group. Examples of the protecting group for the amino group and the like include a trifluoroethenyl group, a third butoxy group, an oxygenoxy group, etc. These protections are detachable under conditions suitable for each protecting group. The compound (3) and the anthracene derivative ((4)w〇2〇〇4/〇69824) are dissolved in an alcohol (methanol or ethanol), and the mixture is heated for 3G minutes to 5 hours, then reversed to the middle " The acetic acid of the mouth is further heated and stirred for a night, whereby the compound (5) can be produced. The reaction temperature is preferably a heart-carrying. At this time, the by-position isomer is 'but but by the Shixi rubber column chromatography The compound (5) can be easily isolated and purified by a method or crystallization. (Next, the methanol or the ester (6) can be produced by stirring a suspension of the compound (5) and the alcohol of Raney nickel). Preferably, 126365.doc -20- 200827349 is generally known as machine temperature 50 to 110 ° C. The reaction conditions, reagents, etc. can be appropriately selected according to knowledge. Further, the ester body (6a) can also be composed of the following compound (8) Derived

R2表示與上述R2相同之基 r3表示甲基或乙 (上述式中基）。於烧醇鈉（甲醇鈉或乙醇鈉）存扃 )仔在下，將化合物（8)與草酸二烧基醋（草酸二甲酯或草酸 G酉曰）（2)於醇（甲醇或乙醇）溶液中加以處理，藉此可猶组儿人心精此Τ獲仔化合物（9)。反應溫度較好的是-10〜100°c。R2 represents the same group as the above R2, and r3 represents a methyl group or a group B (the group in the above formula). In the case of sodium alkoxide (sodium methoxide or sodium ethoxide), the compound (8) and oxalic acid dialkyl vinegar (dimethyl oxalate or G oxalate) (2) in alcohol (methanol or ethanol) solution It can be treated in this way, so that it can be used by the children to get the compound (9). The reaction temperature is preferably -10 to 100 ° C.

又，化合物w亦可藉由下述方法製造：將化合物⑻溶解於四氫吱喃等惰性溶劑中，於_78t冷卻下，以雙（三甲基石夕烧基）醯㈣等驗進行處理，添加草酸4基醋（草酸二甲醋或草酸二乙醋)(2)，且進行攪拌。反應溫度較好的是-78t：〜室溫。接著將化合物（9)與肼衍生物（(4)w〇 2〇〇4/〇6982句溶解於醇（甲醇或乙醇）中，升溫㈣3G分鐘〜5小時後，向反應液中添加適量夕細^ ^ 之醋I，進而升溫攪拌丨晚，藉此可製造口物(6a)在匕日寸’ |副生位置異構物，但藉由矽膠管柱 126365.doc 21 200827349 層析法或結晶化可容易地將化合物（6a)分離精製。再者’务香族_(8)可由下述化合物（ia)衍生而成。又，亦可應用文獻記載之方法（Erik Van der Eycken等人、〇rgFurther, the compound w can also be produced by dissolving the compound (8) in an inert solvent such as tetrahydrofuran, and cooling it under _78 t cooling, and treating it with bis(trimethyl sulphide) ruthenium (iv). Oxalic acid 4-based vinegar (dimethyl oxalate or oxalic acid diethyl vinegar) (2), and stirred. The reaction temperature is preferably -78t: ~ room temperature. Next, the compound (9) and the anthracene derivative ((4) w〇2〇〇4/〇6982 are dissolved in an alcohol (methanol or ethanol), and the temperature is raised (4) for 3 G minutes to 5 hours, and then an appropriate amount is added to the reaction solution. ^ ^ vinegar I, and then warmed to stir in the evening, whereby the mouth (6a) can be made in the next day's | by-product position isomer, but by the ruthenium column 126365.doc 21 200827349 Chromatography or crystallization Further, the compound (6a) can be easily isolated and purified. Further, the 'Fragxiang_(8) can be derived from the following compound (ia). Further, the method described in the literature can also be applied (Erik Van der Eycken et al. 〇rg

Lett· 2004、6(23)、4223-4225)，以使用市銷之乙炔衍生物 (10或12)與叠氮化合物之***環形成反應而製造。 [化8]Lett. 2004, 6(23), 4223-4225) was prepared by reacting a commercially available acetylene derivative (10 or 12) with a triazole ring of an azide compound. [化8]

(η)(η)

藉由加熱回流化合物（la)與雷氏鎳之醇 < 甲醇或乙醇）懸濁液可製造化合物（8)。該反應條件或試劑等可根據有機化學之通常知識而適當選擇。 ®鼠化納、二甲美合懸濁液，可製造L 。該反應條件或試劑選擇。藉由於室溫下攪拌3-丁炔-2-醇（10) 石爪酸、及礙化銅之第三丁醇與水之混 (卜甲基-1Η-1，2,3·***-4_基）乙醇（11) 等可根據有機化學之通常知識而適當向化合物(11)之二氯甲烷溶液中添加二氧化錳，且於室溫下攪拌’藉此可製造化合物（8)。該反應條件或試劑等二 126365.doc -22- 200827349 根據有機化學之通常知識而適當選擇。進而，藉由於室溫下攪採^ τα 1 m 見拌3-丁炔丄酮⑽、疊氮化鈉、 :二“酸、及猶之第三丁醇與水之混合懸濁液，亦化合物（8)°該反應條件或試料可根據有機化學之通吊知識而適當選擇。接著’可藉由通常方法# 使®曰體（6)水解，而衍生為羧酸體（7) 〇 [化9]Compound (8) can be produced by heating a compound (la) and a Raney nickel alcohol <methanol or ethanol) suspension. The reaction conditions, reagents and the like can be appropriately selected in accordance with the usual knowledge of organic chemistry. ® Mouse Nasal, Metformin suspension can be used to make L. The reaction conditions or reagents are selected. By mixing 3-butyn-2-ol (10) stearic acid at room temperature, and mixing the third butanol of copper with water (bu methyl-1Η-1,2,3·triazole-4_ Ethyl alcohol (11) or the like can be added to a dichloromethane solution of the compound (11) as appropriate according to the general knowledge of organic chemistry, and stirred at room temperature to thereby produce the compound (8). The reaction conditions or reagents, etc., are appropriately selected according to the usual knowledge of organic chemistry. Further, by stirring at room temperature, τα 1 m is mixed with 3-butynyl ketone (10), sodium azide, and two "acids, and a mixture of third butanol and water, also a compound. (8) ° The reaction conditions or samples can be appropriately selected according to the knowledge of organic chemistry. Next, 'the steroid body (6) can be hydrolyzed by the usual method # to be derivatized into a carboxylic acid (7) 〇 9]

驗可列舉：鹼金屬（例如，鐘、納、卸等）之氯氧化物。又，作為路易斯酸，例如可列舉：三漠化硼。反應溫度較好的疋-20〜l〇〇C，更好的是_5。〇〜5〇。〇。對由上述製造法而獲得之羧酸體⑺實施下述處理，藉此可獲得本發明之化合物〇)。 [化 10]The test may exemplify the oxychloride of an alkali metal (for example, a clock, a nano, a discharge, etc.). Further, examples of the Lewis acid include boron trioxide. The reaction temperature is preferably 疋-20~l〇〇C, more preferably _5. 〇~5〇. Hey. The carboxylic acid body (7) obtained by the above production method is subjected to the following treatment, whereby the compound 本) of the present invention can be obtained. [化10]

•R， 126365.doc -23- 200827349 (上述式中，R1及R2分別表示與上述…及汉2相同之基）藉由使羧酸體（7)與胺基體（13)縮合，可製造本發明之化合物⑴。上述縮合反應亦可應用一般使用之方法作為肽合成法。作為一般使用之肽合成法，例如可列舉：疊氮化物法、醯氯法、酸酐法、DCC(dicyclohexylcarb〇diimide ;二環己基• R, 126365.doc -23- 200827349 (In the above formula, R1 and R2 respectively represent the same groups as described above and Han 2) By condensing the carboxylic acid body (7) with the amine matrix (13), the present invention can be produced. Inventive compound (1). The above condensation reaction can also be applied as a peptide synthesis method by a generally used method. Examples of the peptide synthesis method generally used include an azide method, a hydrazine method, an acid anhydride method, and DCC (dicyclohexylcarb〇diimide; dicyclohexyl group).

石反化一亞胺）法、活性酯法、叛基二味。坐法、DCC/HOSTStone-reverse imine) method, active ester method, rebel base. Sitting method, DCC/HOST

(hydroxybenzotriazole ; 1-羥基苯幷***）法、使用水溶性碳化二亞胺之方法、使用氰基磷酸二乙酯之方法等，該等方法。己载於 M· Bodanszky，Y. S，Klausner及 M. A. Ondetti 著 "Peptide Synthesis'- (A Wiley-interscience Publication, New(hydroxybenzotriazole; 1-hydroxybenzotriazole) method, method using water-soluble carbodiimide, method using diethyl cyanophosphate, and the like. It is contained in M. Bodanszky, Y. S, Klausner and M. A. Ondetti "Peptide Synthesis'- (A Wiley-interscience Publication, New

York，1976 年）、G. R. pettit 著"Synthetic Peptides，' (Elsevier Scientific Publication Company, New York, 1976 年）、曰本化學會編"第4版實驗化學講座22卷，有機合成 IV”（丸善股份有限公司、㈣年）等中。作為用於該縮合反應之溶劑，可列舉·· Ν，Ν-二f基甲醯胺"比„定、氯仿、二氯甲烧、四氫口夫喃、-口罢@ ，士》一 7烷、乙腈等溶劑，或該等之混合溶劑。反應溫度較好的是口 & sue，更好的是_1〇〜3〇°c。胺體（13)可使用市銷之化入口物，又，亦可使用按照文獻記載之方法或製造例所— 、 … 製造者。 °栽之方法、或者組合該等方法所根據有機化學之通常知識的化合物（I)進一步加以修飾化合物（I)。對由上述方法製造之本發明藉此可衍生為本發明之其他 126365.doc *24- 200827349 本發明之化合物⑴、其鹽或彼等之溶劑合物具有較強之抗血小板作用，即使於高剪應力誘導之血栓症模式下亦可較強地抑制血栓形成。又，本發明之化合物較之上述專利文獻3記載之化合物（B)，腎毒性極其微弱，安全性方面尤其優良。考慮到抑制血小板凝集藥之長期投與，該安全性極其重要。因此，本發明之化合物⑴、其鹽或彼等之溶劑合物對於包含人在内之哺乳類，可有效用作心肌梗塞、1 絞痛（慢性敎獨心症、不敎心絞痛等）、缺血性:血二York, 1976), GR Pettit "Synthetic Peptides,' (Elsevier Scientific Publication Company, New York, 1976), Sakamoto Chemical Society, "4th Edition Experimental Chemistry Lecture 22, Organic Synthesis IV" (Maruzen Co., Ltd., (four) years), etc. As a solvent used for the condensation reaction, Ν, Ν-di-f-carbamamine " „定, chloroform, chloroform, tetrahydromanol喃, - 口口@,士》 A solvent such as acetylene or acetonitrile, or a mixed solvent of these. The reaction temperature is preferably port & sue, more preferably _1 〇 ~ 3 〇 °c. The amine (13) may be a commercially available inlet or a manufacturer or a manufacturer according to the methods described in the literature. The compound (I) is further modified by the method of planting or the combination of the methods (I) according to the general knowledge of organic chemistry. The present invention produced by the above method can be derived from the other 126365.doc *24- 200827349 of the present invention, the compound (1) of the present invention, a salt thereof or a solvate thereof has a strong anti-platelet effect even if it is high Shear stress-induced thrombosis can also strongly inhibit thrombosis. Further, the compound of the present invention is extremely weak in nephrotoxicity and particularly excellent in safety in comparison with the compound (B) described in the above Patent Document 3. This safety is extremely important in view of inhibiting the long-term administration of platelet aggregation drugs. Therefore, the compound (1), a salt thereof or a solvate thereof of the present invention can be effectively used for myocardial infarction, 1 colic (chronic sputum monocentric disorder, angina pectoris, etc.), ischemia for mammals including humans. Sex: Blood II

病（短暫性腦缺血發作（TIA)、腦梗塞等）、末梢血管病、I 工A官置換後閉塞、冠狀動脈介人術（冠狀動脈繞道手術 (CABG)、經皮腔内冠狀動脈成形術（pTcA)、支架置放術等）後之血栓性閉塞、糖尿病性視網膜病病、:臟人瓣膜置換時閉塞等由血栓•栓塞所引起之缺血性疾病之預防及/或治療劑。又，可有效用作血管手術、血液體外循環等所伴隨之血栓·栓塞之預防及/或治療劑。進而，亦有效用於改善慢性動脈閉塞症所伴隨之潰瘍、疼痛、冷感等缺血性症狀。將本發明之化合物⑴、其鹽或彼等之溶劑合物用作醫藥日π ’投與買根據患者之年齡、性別、症狀等而不同，成人每人之日用量較好的是(U叫〜丨g，尤好的是Q5叫〜5〇〇叫。該情形時，亦可將1日量分為數次進行投與，必要時’亦可超過上述1日量進行投與。將本發明之化合物⑴、其鹽或彼等之溶劑合物作為有效成分之醫藥可根據需要之投與法及劑型而加以使用，其製 126365.doc -25- 200827349 劑利用通常所#用> & % # _ “使用之各種製劑的製傷法，根據f要調予上允許之_，選擇與投與法—致之劑型即可，投= 及劑型並無特別限制。〆作為經口用製劑，例如除了錠劑、散劑、顆粒劑、膠囊劑等固體製劑以外’亦可列舉液劑、糖聚劑、醜劑、懸浮劑、乳劑等液體製劑。作為注射劑’既可將本發明之化合物⑴、其鹽或彼等之溶劑合物溶解而填充至容器中，x，亦可藉由冷床乾燥等使之成為固體，製成用時製備之製劑。製備該等製劑時，可根據需要選擇使用製劑學上允許之添加物，例如黏合劑、崩解劑、溶解促進劑、潤滑劑、填充劑、賦形劑等。接著，列舉參考例、實施例及試驗例詳細說明本發明。參考例1 W6-甲氧基吼咬_3_基）-5-[1_甲基_5·(苯硫基三唾-4_基]-1Η_σ比峻-3-叛酸乙酯 [化 11]Disease (transient ischemic attack (TIA), cerebral infarction, etc.), peripheral vascular disease, occlusion after I-A replacement, coronary intervention (coronary bypass surgery (CABG), percutaneous transluminal coronary angioplasty) Thrombotic occlusion, diabetic retinopathy after surgery (pTcA), stent placement, etc.: prevention and/or treatment of ischemic diseases caused by thrombosis and embolism, such as occlusion during visceral valve replacement. Further, it can be effectively used as a prophylactic and/or therapeutic agent for thrombus and embolism accompanying vascular surgery and extracorporeal blood circulation. Furthermore, it is also effective for improving ischemic symptoms such as ulcers, pain, and cold sensation associated with chronic arterial occlusive disease. The compound (1) of the present invention, a salt thereof or a solvate thereof is used as a medical day π's investment and purchase differs according to the age, sex, symptom, etc. of the patient, and the daily dosage of each adult is better (U is called ~丨g, especially preferably Q5 is called ~5 squeaking. In this case, the amount of one day can be divided into several times for administration, and if necessary, it can be administered more than the above-mentioned one-day amount. The medicinal compound (1), a salt thereof or a solvate thereof as an active ingredient can be used according to the required administration method and dosage form, and the 126365.doc -25-200827349 agent can be used as usual. % # _ "Injury method for the preparation of various preparations, according to f, it is necessary to adjust the dosage form, and the dosage form is selected and administered. There is no particular limitation on the dosage form and dosage form. 〆 as an oral preparation For example, in addition to a solid preparation such as a tablet, a powder, a granule, or a capsule, a liquid preparation such as a liquid preparation, a sugar polymerization agent, an ugly agent, a suspending agent, or an emulsion may be mentioned. As the injection, the compound of the present invention (1) can be used. , the salt or their solvate is dissolved and filled into the container In the middle, x may be made into a solid by drying in a cold bed or the like to prepare a preparation prepared at the time of use. When preparing the preparation, an additive which is pharmaceutically acceptable, such as a binder, disintegration may be selected as needed. The agent, the dissolution promoter, the lubricant, the filler, the excipient, etc. The following is a detailed description of the present invention by reference to the examples, examples and test examples. Reference Example 1 W6-methoxybite_3_yl)-5 -[1_methyl_5·(phenylthiotris-s--4-yl)-1Η_σ ratio Jun-3-etreic acid ethyl ester [Chemical 11]

i) 4-Π-曱基-5-(苯硫基）-1比1，2,3-***-4-基]_2,4_二側氧基丁酸乙酯於氬氣環境下，於_78°C冷卻下，向1-[卜甲基_5_(苯硫 126365.doc -26 - 200827349 基）-1仏1，2,3_***-4-基]乙酮（1.84吕，3.01^等人，（：1^111·i) 4-Π-mercapto-5-(phenylthio)-1 to 1,2,3-triazol-4-yl]_2,4-dioxybutyric acid ethyl ester under argon atmosphere Under cooling at _78 ° C, to 1-[Bu methyl_5_(phenylsulfonate 126365.doc -26 - 200827349)-1仏1,2,3-triazol-4-yl]ethanone (1.84 L, 3.01) ^等人, (:1^111·

Pharm，Bull·，1997, 45 (7)，1140)之四氫呋喃（3 7 ml)溶液中滴加雙（三甲基矽烷基）醯胺鋰（i .0 Μ之四氫呋喃溶液， 8.68 ml)，且攪拌80分鐘。於同溫下向反應液中滴加草酸二乙醋（2.14 ml)且攪拌15分鐘，於0°C攪拌30分鐘。進而於室溫下攪拌3小時。向反應液中添加水與二乙鱗實施分液，向水層添加飽和氣化銨水溶液，以氯仿進行萃取。以無水硫酸鈉乾燥有機層。過濾後，於減壓下餾去溶劑，獲得固體4-[1-甲基_5-(苯硫基）-1Η·ΐ，2,3-***-4-基]-2,4-二侧氧基丁酸乙酯（1.60 g，61%)。 ]H-NMR (400 MHz5 CDC13) δ: 1.38-1.42 (3Η? m)5 3.95 (3Η5 s)，4.36-4.42 (2Η，m)，7.22-7.35 (5Η，m)，7·52(1Η，s)。 MS (El) m/z: 333 (Μ+) 〇 2)標題化合物將4-[1_甲基-5_(本硫基）_ni，2,3-三〇坐-4-基]·2,4·二側氧基丁酸乙酯（1.59 g)與5-肼基-2-甲氧基吡啶（〇73〇 g，w〇 2004/069824)之乙醇（32 ml)懸濁液加熱回流仏分鐘。向反應液中添加醋酸（1.37 ml)，進而加熱回流18小時。空氣冷卻後，向反應液中添加飽和碳酸氫鈉與氯仿實施分液，以無水硫酸鈉乾燥有機層。過濾後，於減壓下餾去溶劑，以矽膠管柱層析法（己烷_醋酸乙酯）精製所獲得之殘渣，獲得固體標題化合物（1.08 g，52%)。 ^H-NMR (400 MHz, CDC13) δ: 1.39-1.43 (3Η, m), 3.93 (3Η, m)，3.96 (3Η，s)，4.41_4.47 (2Η，m)，6.72 (ιη，d，Η』Hz)， 126365.doc -27- 200827349 7·66-7.69 (m， -***基Ml 6.90-6.93 (2H，m)，7.21-7.26 (4H，m) m)，8.10 (1H，d，J=2.7 Hz)。 MS (El) m/z: 436 (M+)。參考例2 i_(6-甲氧基吡啶-3-基）-5-(1-甲基2 3 吡唑-3-羧酸 [化 12]Pharm, Bull, 1997, 45 (7), 1140) in tetrahydrofuran (37 ml) solution was added dropwise lithium bis(trimethyldecyl) guanamine (i.0 四 tetrahydrofuran solution, 8.68 ml), and Stir for 80 minutes. Oxalic acid diethylacetate (2.14 ml) was added dropwise to the reaction mixture at the same temperature and stirred for 15 minutes, and stirred at 0 ° C for 30 minutes. Further, the mixture was stirred at room temperature for 3 hours. Water and diethyl squama were added to the reaction mixture for liquid separation, and a saturated aqueous solution of ammonium carbonate was added to the aqueous layer, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give solid 4-[1-methyl_5-(phenylthio)-1 Η·ΐ, 2,3-triazol-4-yl]-2,4-di Ethyl acetobutyrate (1.60 g, 61%). ]H-NMR (400 MHz5 CDC13) δ: 1.38-1.42 (3Η? m)5 3.95 (3Η5 s), 4.36-4.42 (2Η,m), 7.22-7.35 (5Η,m),7·52(1Η, s). MS (El) m/z: 333 (Μ+) 〇2) The title compound is 4-[1_methyl-5_(methionyl)_ni,2,3-tris-yt-4-yl]·2, 4. Ethyl 2-butoxybutyrate (1.59 g) and 5-mercapto-2-methoxypyridine (〇73〇g, w〇2004/069824) in ethanol (32 ml) suspension heated to reflux 仏minute. Acetic acid (1.37 ml) was added to the reaction mixture, followed by heating under reflux for 18 hours. After the air was cooled, a saturated sodium hydrogencarbonate solution and chloroform were added to the mixture, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated to drynessjjjjjjjjjjjj ^H-NMR (400 MHz, CDC13) δ: 1.39-1.43 (3Η, m), 3.93 (3Η, m), 3.96 (3Η, s), 4.41_4.47 (2Η, m), 6.72 (ιη, d ,Η』Hz), 126365.doc -27- 200827349 7·66-7.69 (m, -triazolyl Ml 6.90-6.93 (2H,m), 7.21-7.26 (4H,m) m),8.10 (1H, d, J = 2.7 Hz). MS (El) m/z: 436 (M+). Reference Example 2 i_(6-Methoxypyridin-3-yl)-5-(1-methyl 2 3 pyrazole-3-carboxylic acid [Chemical 12]

1) 1-(6-甲氧基吼咬_3_基）-5_(1_甲基 1Η-°比唑-3-羧酸乙酯基）醇，進行向雷氏鎖（NIKKO RICA R-100，2〇 g)中添加乙清洗（實施傾析法去除乙醇），於氬翁、虱％ i兄下，向所獲得 ( 殘液的乙醇（40 ml)懸濁液中添加κ(6_曱氧基吨咬3 [1-甲基-5-(苯硫基）·1Η-1，2,3-三K基>1Η“比嗤冬缓酸乙醋（1·〇7 g)之乙醇（60 ml)懸濁液，加熱回流3·5小時。: 氣冷卻後，以矽藻土過濾反應液中之固體。於減壓下餾去所獲得之濾液之溶劑，以矽膠管柱層析法（氯仿_丙_)精製所獲得之殘渣，獲得固體1-(6-甲氧基吡啶·3•基）-5-(1_甲基-111_1，2,3-三吐-4-基）-111-吼唑-3-羧酸乙龍（〇.6〇7§， 75%) °1) 1-(6-methoxy octazone _3_yl)-5_(1_methyl 1 Η-°biazole-3-carboxylate ethyl ester) alcohol, subjected to Reyes lock (NIKKO RICA R- Add 100 to 200,2〇g) (to carry out decantation to remove ethanol), and add κ (6_ to the obtained liquid (40 ml) suspension under the argon and 虱% si brothers.曱 oxy ton bite 3 [1-methyl-5-(phenylthio)·1Η-1,2,3-three K group>1Η" 嗤嗤缓缓缓 ( (1·〇7 g) Ethanol (60 ml) suspension, heated to reflux for 3.5 hours.: After cooling with air, the solid in the reaction solution was filtered with diatomaceous earth. The solvent of the obtained filtrate was distilled off under reduced pressure. The residue obtained by the purification method (chloroform_propyl_) was purified to give 1-(6-methoxypyridin-3-yl)-5-(1_methyl-111_1,2,3-tris-4- Base) -111-carbazole-3-carboxylic acid ethyl ester (〇.6〇7§, 75%) °

iH-NMR (400 MHz，CDC13) δ·· 1.40-1.44 (3H，m) 3·99 (3H 126365.doc • 28 · 200827349 s)，4.07 (3H，s)，4.42-4.48 (2H，m)，6·83 (1H，d，j = 8.8 Hz)， 7·21 (1H，s)，7.31 (1H，s)，7.70 (1H，dd5 J=8.8, 2.7 Hz)， 8·22 (1H，d，J=2.7 Hz)。 MS (El) m/z: 328 (M+)。 2)標題化合物於室溫下向1-(6-曱氧基吡啶_3-基）_5-(l-甲基-1H-1，2,3-***-4-基）-1Η-吡唑-3-羧酸乙酯（0.600 g)之甲醇（12 ml)及四氫呋喃（12 ml)混合溶液中添加1N氫氧化鈉水溶液（4·5 7 ml)，攪拌1小時。向反應液中添加1N鹽酸水溶液（4.57 ml) 實施中和後，添加水、及氯仿與甲醇（10比1)混合溶劑，實施分液。於減壓下餾去有機層之溶劑，獲得固體標題化合物（0.540 g，98%) ° W-NMR (400 MHz，DMSO-d6) δ: 3·93 (3H，m)，4.04 (3H， m)，6.94 (1Η，d，J=8.8 Ηζ)，7·16 (1Η，m)，7.80-7.83 (1Η， m)，8.09 (1H，m)，8·27 (1H，d，J = 2.7 Hz)，13.03 (1H，br)。 MS (El) m/z: 300 (M+) 〇參考例3 1-(6-甲氧基吡啶-3_基）-5-(1-甲基_ih-1，2,3-***_4-基）-1Η- 吡唑-3-羧酸乙酯 1) 1-(1·甲基-1H-1，2,3-三唾-4-基）乙酉同以乙醇清洗雷氏鎳（NIKKO RICA R_l〇〇，50 g)(實施傾析法去除乙醇），於氬氣環境下，向所獲得之殘渣的乙醇（1〇〇 ml)懸濁液中添加1·[1-甲基- 5-(苯硫基）·ιη·1，2,3_***_4· 基]乙酮（5.00 g，S. Ohta等人，Chem· pharm Bull·，1997, 126365.doc -29- 200827349 45 (7)，1140)之乙醇（100 ml)懸濁液，加熱回流4小時。空氣冷卻後’以矽藻土過濾反應液中之固體。於減壓下餾去所獲得之濾液溶劑，以矽膠管柱層析法（己烷-醋酸乙酯）精製所獲得之殘渣，獲得固體之l-(i_甲基基）乙酮（0.685 g，26%)。 !H-NMR (400 MHz，CDC13) δ: 2·69 (3H，s)，4.16 (3H，s)， 8·05 (1Η，s) 〇 MS (ESI) m/z: 126 (Μ+Η)+。 2) 4-(1-曱基-1H-1，2,3-***-4-基）-2,4-二側氧基丁酸乙酯於氬氣環境下，於室溫下向乙醇鈉（20%乙醇溶液，3.70 g) 之乙醇（6.8 ml)溶液中添加草酸二乙酯（ι·48 ml)，攪拌15 分鐘。向反應液中添加1-(1-甲基-1H-1，2,3-***-4-基）乙酉同 (0.6 80 g)之乙醇（13·6 ml)溶液，攪拌2小時。向反應液中添加水與二***實施分液，向水層添加飽和氯化銨水溶液，以氯仿加以萃取。以無水硫酸鈉乾燥有機層。過濾後，於減壓下餾去溶劑，獲得固體之4-(1-甲基-1H-1，2,3-***-4-基）-2,4-二側氧基丁酸乙酯（0.904 g，74%)。 ^-NMR (400 MHz5 CDC13) δ: 1.39-1.42 (3Η, m)? 4.20 (3Η5 s)，4·37_4·42 (2Η，m)5 7·42 (1Η，s)，8·16 (1Η，s) 〇 MS (El) m/z·· 225 (M+) 〇 3) 標題化合物將4-(1-甲基-1H_1，2,3 -三。坐-4-基）-2，4 -二側氧基丁酸乙西旨 (0.896 g)與5·肼基-2-甲氧基吡啶（0.554 g，WO 2004/069824)之乙醇（18 ml)懸濁液加熱回流30分鐘。向反 126365.doc •30- 200827349 應液中追加5-肼基-2-甲氧基吼咬(0.lu g)，加熱回流叫、時。進而，向反應液中添加醋酸（1,14 ml)，加熱回流叫、時。空氣冷卻後，向反應液中添加飽和碳酸氯納與氣仿實施分液，以無水硫酸納乾燥有機層。過滤後，於減壓下館 h容劑’以石夕膠管柱層析法（甲苯·丙酮）精製所獲得之殘邊’獲得固體之標題化合物（〇 881 g，67%>。參考例4 f ； 2-甲氧基-5-[3-[(4·甲氧基哌唆-1-基m基]-5-(ι-甲基-1H_ 1，2,4-***-3_基）-1Η-吡唑_1-基]吡啶 [化 13]iH-NMR (400 MHz, CDC13) δ·· 1.40-1.44 (3H,m) 3·99 (3H 126365.doc • 28 · 200827349 s), 4.07 (3H, s), 4.42-4.48 (2H, m) ,6·83 (1H,d,j = 8.8 Hz), 7·21 (1H, s), 7.31 (1H, s), 7.70 (1H, dd5 J=8.8, 2.7 Hz), 8·22 (1H, d, J = 2.7 Hz). MS (El) m/z: 328 (M+). 2) The title compound is 1-(6-methoxypyridine-3-yl)-5-(1-methyl-1H-1,2,3-triazol-4-yl)-1Η-pyridin at room temperature To a mixed solution of oxazole-3-carboxylic acid ethyl ester (0.600 g) in methanol (12 ml) and tetrahydrofuran (12 ml) was added 1N sodium hydroxide aqueous solution (4·7 7 ml), and the mixture was stirred for 1 hour. After adding 1N aqueous hydrochloric acid solution (4.57 ml) to the reaction mixture, the mixture was neutralized, and water and a mixed solvent of chloroform and methanol (10:1) were added thereto to carry out liquid separation. The solvent of the organic layer was evaporated to dryness crystals crystals crystalsssssssssssssssssssssssssssssssssssss ), 6.94 (1Η, d, J=8.8 Ηζ), 7·16 (1Η, m), 7.80-7.83 (1Η, m), 8.09 (1H, m), 8·27 (1H, d, J = 2.7 Hz), 13.03 (1H, br). MS (El) m/z: 300 (M+) 〇 Reference Example 3 1-(6-methoxypyridin-3-yl)-5-(1-methyl-ih-1,2,3-triazole_ 4-yl)-1Η-pyrazole-3-carboxylic acid ethyl ester 1) 1-(1·methyl-1H-1,2,3-tris-7-yl)acetamidine with the cleaning of Raney nickel with ethanol ( NIKKO RICA R_l〇〇, 50 g) (to carry out decantation to remove ethanol), and add 1·[1-methyl- to the suspension of ethanol (1〇〇ml) of the obtained residue under argon atmosphere. 5-(phenylthio)·ιη·1,2,3_triazole_4·yl]ethanone (5.00 g, S. Ohta et al., Chem. pharm Bull·, 1997, 126365.doc -29- 200827349 A suspension of 45 (7), 1140) in ethanol (100 ml) was heated to reflux for 4 hours. After air cooling, the solid in the reaction solution was filtered with diatomaceous earth. The obtained filtrate solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (hexane-ethyl acetate) to give a solid l-(i-methyl) ethyl ketone (0.685 g). , 26%). !H-NMR (400 MHz, CDC13) δ: 2·69 (3H, s), 4.16 (3H, s), 8·05 (1Η, s) 〇MS (ESI) m/z: 126 (Μ+Η )+. 2) 4-(1-Mercapto-1H-1,2,3-triazol-4-yl)-2,4-dioxyacetic acid ethyl ester in ethanol under argon at room temperature To a solution of sodium (20% ethanol solution, 3.70 g) in ethanol (6.8 ml) was added diethyl oxalate (1·4 ml) and stirred for 15 min. A solution of 1-(1-methyl-1H-1,2,3-triazol-4-yl)acetamidine (0.680 g) in ethanol (13·6 ml) was added to the mixture and stirred for 2 hr. Water and diethyl ether were added to the reaction mixture to carry out liquid separation, and a saturated aqueous ammonium chloride solution was added to the aqueous layer, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give ethyl 4-(1-methyl-1H-1,2,3-triazol-4-yl)-2,4-diethyloxybutanoate as a solid. (0.904 g, 74%). ^-NMR (400 MHz5 CDC13) δ: 1.39-1.42 (3Η, m)? 4.20 (3Η5 s), 4·37_4·42 (2Η,m)5 7·42 (1Η,s),8·16 (1Η ,s) 〇MS (El) m/z·· 225 (M+) 〇3) The title compound will be 4-(1-methyl-1H_1,2,3 -3.sup.4-yl)-2,4 - A suspension of dioxyl acetobutyrate (0.896 g) and 5·mercapto-2-methoxypyridine (0.554 g, WO 2004/069824) in ethanol (18 ml) was heated and refluxed for 30 minutes. Add a 5-mercapto-2-methoxy bite (0.lu g) to the solution 126365.doc •30- 200827349, and heat it back. Further, acetic acid (1,14 ml) was added to the reaction liquid, and the mixture was heated under reflux. After air cooling, saturated sodium carbonate was added to the reaction mixture, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the residue obtained by refining the residue obtained by purifying the column chromatography (toluene·acetone) under reduced pressure gave the title compound (〇881 g, 67%). Reference Example 4 f 2-methoxy-5-[3-[(4.methoxypiperazin-1-yl)]-(i-methyl-1H-1 1,2,4-triazole-3-yl )-1Η-pyrazole-1-yl]pyridine [Chemical 13]

於室溫下將1-(6-甲氧基吡啶基）-5·(1_甲基“仏丨，^ ***-3-基）-1Η-吡唑-3-羧酸（184 mg，W〇 2〇〇6/〇14〇()5)、各甲氧基哌啶鹽酸鹽（185 mg，w〇 2〇〇4/〇944〇7)、丨_羥基苯幷***（16 mg)、三乙胺（425 μ1)、及3_(3_二甲基胺基丙基）-ι·乙基碳化二亞胺鹽酸鹽（176 mg)之二氯甲烷（3〇 mi) 溶液攪拌一整夜。向反應液中添加水與1〇%甲醇_氯仿，實鈿为液。以無水硫酸鈉乾燥有機層。過濾後，於減壓下餾去溶劑，以矽膠薄層層析法（氯仿_甲醇）精製所獲得之殘〉查’獲得固體標題化合物（1〇9 mg，45%)。 ^-NMR (400 MHz, CDC13) δ: 1.66 (2Η, brs), 1.93 (2Η, 126365.doc •31 · 200827349 brs)，3.37 (3H，s)，3·49 (2H，brs)5 3.69 (1H，brs)，3·9〇 (3H， s)，3.98 (3H，s)，4·07 (1H，s)，4.23 (1H，s)，6·8〇 (1H，d， J=8.79 Hz)，7·22 (1H，d，J=0.49 Hz)，7.71 (1H，dd，J = 8 79, 2.20 Hz)，7·99 (1H，s)，8.23 (1H，d，J=2.69 Hz)。 MS (ESI) m/z: 398 (M+H)+ o 參考例5 1-(1-甲基-1H-1，2,3-三吐-4_基）乙酮 A法） (' 卜向第三丁醇（1.5 ml)與水（1.5 ml)溶液中添加3-丁炔-2__ (82 μΐ)、疊氮化鈉（65 mg)、二甲基硫酸（97 μΐ)、及碘化銅 (1)(38 mg)，於室溫下攪拌17小時。過濾反應液之固體後，於減壓下餾去濾液之溶劑。以矽膠薄層層析法（二氯甲烷-甲醇）精製所獲得之殘渣，獲得固體標題化合物 (21 mg) 〇 MS (El) m/z: 125 (M+)。1-(6-Methoxypyridyl)-5·(1-methyl-oxime, triazol-3-yl)-1Η-pyrazole-3-carboxylic acid (184 mg, at room temperature W〇2〇〇6/〇14〇()5), each methoxypiperidine hydrochloride (185 mg, w〇2〇〇4/〇944〇7), 丨_hydroxybenzotriazole (16 Methyl chloride (3 〇mi) solution of mg), triethylamine (425 μl), and 3-(3-dimethylaminopropyl)-ι·ethylcarbodiimide hydrochloride (176 mg) The mixture was stirred overnight, and water and 1% by mole of methanol-chloroform were added to the reaction mixture, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give a solvent. The residue obtained by the purification of (chloroform-methanol) was obtained to give the title compound (1 〇 9 mg, 45%). NMR (400 MHz, CDC13) δ: 1.66 (2 Η, brs), 1.93 (2 Η, 126365 .doc •31 · 200827349 brs), 3.37 (3H, s), 3·49 (2H, brs) 5 3.69 (1H, brs), 3·9〇 (3H, s), 3.98 (3H, s), 4 · 07 (1H, s), 4.23 (1H, s), 6·8 〇 (1H, d, J = 8.79 Hz), 7.22 (1H, d, J = 0.49 Hz), 7.71 (1H, dd, J = 8 79, 2.20 Hz), 7·99 (1H, s), 8.23 (1H d, J = 2.69 Hz) MS (ESI) m/z: 398 (M+H) + o Reference Example 5 1-(1-methyl-1H-1,2,3-tris--4-yl) Ethyl ketone A method) (' Addition of 3-butyne-2__ (82 μΐ), sodium azide (65 mg), dimethyl sulfate to a solution of tributanol (1.5 ml) and water (1.5 ml) (97 μΐ), and copper iodide (1) (38 mg), stirred at room temperature for 17 hours. After filtering the solid of the reaction mixture, the solvent of the filtrate was evaporated under reduced pressure. The residue obtained was purified by methylene chloride-methanol (EtOAc)

Ci 6法） 1) 1-(1-甲基-111-1，2,3-三嗤-4-基）乙醇向第三丁醇（1.5 ml)與水（1·5 ml)溶液中添加3_ 丁炔_2_醇 (81 μΐ)、疊氮化鈉（65 mg)、二曱基硫酸（97 μ1)、及碘化銅 (1)(3 8 mg)，於室溫下攪拌。過濾反應液之固體後，於減壓下餾去濾液之溶劑。以矽膠薄層層析法（二氣甲烷_甲醇）精製所獲得之殘渣，獲得油狀物質之1-(1•甲基 ***_4_基）乙醇（54 mg)。 'H-NMR (400 MHz, CDC13) δ: 1.59 (3Η, d3 J=6.62 Hz), 2.38 126365.doc -32 · 200827349 (1H，d，J=4.17 Hz)，4.09 (3H，s)，5.〇9 (1H，dt，J=12.01， 5·21 Hz)，7·46 (1H，s)。 13C-NMR (400 MHz，CDC13) δ: 23.1，36.6，62.9，121.1， 152.7。 MS (ESI) m/z: 128 (M+H)+。 2)標題化合物向1-(1-曱基-1H-1，2,3-***-4-基）乙醇（635 mg)之二氣曱烷（10 ml)溶液中添加二氧化錳（4.9 g)，於室溫下攪拌15小時。以矽藻土過濾反應液，於減壓下餾去濾液之溶劑。以石夕膠管柱層析法（二氣甲烧-甲醇）精製所獲得之殘潰，獲得標題化合物（627 mg)。參考例6 (3R)-3-甲基嗎啉鹽酸鹽 [化 14]Ci 6 method) 1) Add 1-(1-methyl-111-1,2,3-trimethyl-4-yl)ethanol to a solution of tert-butanol (1.5 ml) and water (1.5 ml) 3_butyne-2-alcohol (81 μΐ), sodium azide (65 mg), dimercaptosulfate (97 μl), and copper iodide (1) (38 mg) were stirred at room temperature. After filtering the solid of the reaction liquid, the solvent of the filtrate was distilled off under reduced pressure. The residue obtained was purified by silica gel thin-layer chromatography (di-methane-methanol) to afford 1-(1-methyltriazole-4-yl)ethanol (54 mg) as an oil. 'H-NMR (400 MHz, CDC13) δ: 1.59 (3Η, d3 J=6.62 Hz), 2.38 126365.doc -32 · 200827349 (1H,d,J=4.17 Hz),4.09 (3H,s),5 .〇9 (1H, dt, J=12.01, 5·21 Hz), 7.46 (1H, s). 13C-NMR (400 MHz, CDC13) δ: 23.1, 36.6, 62.9, 121.1, 152.7. MS (ESI) m/z: 128 (M+H)+. 2) The title compound was added to a solution of 1-(1-mercapto-1H-1,2,3-triazol-4-yl)ethanol (635 mg) in dioxane (10 ml). g), stir at room temperature for 15 hours. The reaction liquid was filtered through celite, and the solvent of the filtrate was evaporated under reduced pressure. The residue obtained was purified by silica gel column chromatography (yield of methylene chloride-methanol) to give the title compound (627 mg). Reference Example 6 (3R)-3-methylmorpholine hydrochloride [Chem. 14]

H〇 -HCI 1)第三丁基（3R)-3-甲基嗎啉-4-羧酸酉旨使（R)-2-胺基丙醇（3.4 ml)溶解於四氫呋喃（2〇〇 ml)中，添加鼠化納（5 5 % i η礦物油、2 · 1 g )，於室溫下擾掉3 〇分鐘。向反應液中添加氯醋酸乙酯（4·7 ml)，加熱回流7小日。於減壓下餾去反應溶劑後，使所獲得之殘渣懸浮於醋酸乙酯中。藉由矽藻土過濾去除不溶物，於減壓下餾去濾液浴劑’獲得粗物質之（R)-5-甲基嗎琳酮（3.5 g)。將其溶解於四氫呋喃（250 ml)中，添加氫化鋁鋰（23 g)，加熱 126365.doc -33- 200827349 回抓7小時。冷卻至室溫，添加甲醇使反應結束後，添加矽藻土（30 g)、硫酸鈉十水合物（3〇 g)，攪拌2小時。以矽藻土過濾反應液，向濾液中添加二碳酸二第三丁酯（6·6 g)，攪拌17小時。於減壓下餾去反應溶劑，以矽膠管柱層析法（己烷-醋酸乙酯）精製所獲得之殘渣，獲得油狀物質之第三丁基（3S)-3 -甲基嗎琳·4_羧酸酯（15 g、25%)。 !H-NMR (400 MHz, CDC13) δ: 1.24 (3H5 d5 J=6.6 Hz)5 I.47 ( (9H，s)，3.11-3.19 (1H，m)，3.40-3.46 (1H，m)，3.56-3.70 (3H，m)，3.82-3.87 (1H，m)，4·08-4·01 (1H，m)。 MS (ESI) m/z: 202 (M+H)+。 2)標題化合物將上述弟二丁基（3S)-3 -甲基嗎淋-4-魏酸g旨（1 ·5 g)溶解於醋酸乙酯（30 ml)中，添加4 N之鹽酸-醋酸乙醏溶液（5 ml)，攪拌1 8小時。濾取析出物，獲得固體標題化合物 (0.82 g、80〇/〇) 〇 ( ^-NMR (400 MHz, DMSO-D6) δ: 1.16 (3Η5 d5 J - 6.6 Hz) 2.97-3.04 (1Η，m)，3.14-3.19 (1Η，m)，3.21-3.29 (1Η 3·42 (1H，dd，J=12.3，10.0 Hz)，3.65-3.72 (1H，m)，3 83 3.89 (2H，m)，9.56 (2H，brs)。 MS (ESI) m/z: 102 (M+H)+。參考例7 (3S)-3-甲基嗎啉鹽酸鹽 [化 15] 126365.doc -34- 200827349H〇-HCI 1) tert-butyl(3R)-3-methylmorpholine-4-carboxylic acid hydrazine to dissolve (R)-2-aminopropanol (3.4 ml) in tetrahydrofuran (2 〇〇 ml) In the middle, add ratified sodium (5 5 % i η mineral oil, 2 · 1 g) and disturb for 3 〇 minutes at room temperature. Ethyl chloroacetate (4·7 ml) was added to the reaction mixture, and the mixture was heated under reflux for 7 days. After distilling off the reaction solvent under reduced pressure, the obtained residue was suspended in ethyl acetate. The insoluble matter was removed by filtration through celite, and the filtrate bath was distilled off under reduced pressure to obtain crude material (R)-5-methylmorphinone (3.5 g). This was dissolved in tetrahydrofuran (250 ml), lithium aluminum hydride (23 g) was added, and heated to 126365.doc -33 - 200827349 for 7 hours. After cooling to room temperature and adding methanol to the end of the reaction, diatomaceous earth (30 g) and sodium sulfate decahydrate (3 〇 g) were added, and the mixture was stirred for 2 hours. The reaction liquid was filtered through celite, and dibutyl succinate (6·6 g) was added to the filtrate, followed by stirring for 17 hours. The reaction solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the tributyl(3S)-3-methyl-m-line of the oily substance. 4-carboxylic acid ester (15 g, 25%). !H-NMR (400 MHz, CDC13) δ: 1.24 (3H5 d5 J=6.6 Hz) 5 I.47 ( (9H, s), 3.11-3.19 (1H, m), 3.40-3.46 (1H, m), 3.56-3.70 (3H,m), 3.82-3.87 (1H,m),4·08-4·01 (1H,m) MS (ESI) m/z: 202 (M+H)+. The compound was dissolved in ethyl acetate (30 ml) by the above-mentioned di-butyl (3S)-3-methyloxalin-4-weilic acid g (1. 5 g), and 4 N hydrochloric acid-acetic acid acetate was added. The solution (5 ml) was stirred for 18 hours. The precipitate was collected by filtration to give the title compound (yield::::::::::::::::::::::::::::::: , 3.14 - 3.19 (1Η, m), 3.21-3.29 (1Η 3·42 (1H, dd, J = 12.3, 10.0 Hz), 3.65-3.72 (1H, m), 3 83 3.89 (2H, m), 9.56 (2H, brs) MS (ESI) m/z: 102 (M+H) +. Reference Example 7 (3S)-3-methylmorpholine hydrochloride [Chem. 15] 126365.doc -34- 200827349

MeMe

HN^ -HCI 1) 弟-—丁基（3S)-3 -甲基嗎琳-4-竣酸酉旨利用與參考例6之1}相同之方法，由〇2-胺基丙醇（3·4 ml)獲得油狀物質之第三丁基（3s)-3-曱基嗎啉-4-羧酸酯 (3.9 g，76%) 〇 1H-NMR (400 MHz，CDC13) δ: 1·24 (3H，d，J=6.6 Hz)，1.47 (9H，s)，3·11_3·19 (1H，m)，3.40-3.46 (1H, m)，3.56-3.70 (3H，m)，3·83-3·87 (1H，m)，4.08-4.01 (1H，m)。 MS (ESI) m/z: 202 (M+H)+。 2) 標題化合物利用與參考例6之2)相同之方法，由上述第三丁基（3S) 3-甲基嗎啉-4-羧酸酯（3.9 g)獲得固體之標題化合物6 g，60%) 〇 'H-NMR (400 MHz, DMSO-D6) δ: 1.18 (3Η, d, J=6.6 Hz) 2.96-3.03 (1H，m)，3.13-3.18 (1H，m)，3·2㈡·29 〇H，叫 3.42-3.47 (1H，m)，3.68-3.74 (1H，m)5 3·83_3·89 (2H，^ 9.72 (2H，brs)。 ’ MS (ESI) m/z: 102 (M+H)+ 〇參考例8 1，3-二甲基哌嗪鹽酸鹽 [化 16]HN^-HCI 1) Di-butyl(3S)-3-methylmorphin-4-decanoate was used in the same manner as in Reference Example 6}, from 〇2-aminopropanol (3) · 4 ml) Obtained the tert-butyl (3s)-3-mercaptomorpholine-4-carboxylate (3.9 g, 76%) of the oily substance 〇1H-NMR (400 MHz, CDC13) δ: 1· 24 (3H,d,J=6.6 Hz), 1.47 (9H, s), 3·11_3·19 (1H, m), 3.40-3.46 (1H, m), 3.56-3.70 (3H, m), 3· 83-3·87 (1H, m), 4.08-4.01 (1H, m). MS (ESI) m/z: 202 (M+H)+. 2) The title compound was obtained from the titled compound (6 g, EtOAc, m. %) 〇'H-NMR (400 MHz, DMSO-D6) δ: 1.18 (3Η, d, J=6.6 Hz) 2.96-3.03 (1H,m), 3.13-3.18 (1H,m),3·2(2)· 29 〇H, called 3.42-3.47 (1H,m), 3.68-3.74 (1H,m)5 3·83_3·89 (2H,^ 9.72 (2H,brs). ' MS (ESI) m/z: 102 ( M+H)+ 〇Reference Example 8 1,3-Dimethylpiperazine hydrochloride [Chemical 16]

MeMe

-2HCI SMe 126365.doc -35- 200827349 1) 2，4 - 一甲基派σ秦酸节g旨於〇C向2-甲基哌嗪酸苄酯（w〇 2003/022214，1.8 g)之甲醇（40 ml)溶液中添加三乙醯氧基硼氫化鈉（21 g)、醋酸 (0.43 ml)及3 7%甲醛水溶液（2.0 mi)。於室溫下攪拌j小時後’添加飽和碳酸氫鈉水溶液與二氯甲烷，實施分液。於減壓下餾去有機層，以矽膠管柱層析法（氣仿_甲醇）精製所獲得之殘渣，獲得油狀物質之2,4_二甲基哌嗪酸苄酯（18 g，94%) 〇 W-NMR (400 MHz，CDC13) δ: 1·27 (3H，d，J=6.6 Hz)，h89· 1·96 (1H，m)，2·09-2·13 (1H, m)，2·24 (3H，s)，2.57-2.61 (1H，m)，2.70-2.74 (1H，m)，3.14-3.22 (1H，m)，3·88-3·93 (1H，m)，4.27-4.34 (1H，m)5 5.10-5.17 (2H，m)，7·37·73〇 (5H，m) 〇 MS (ESI) m/z: 249 (M+H)十。 2) 標題化合物使上述2,4-二甲基哌嗪酸苄酯（1·8 g)及鈀碳（1〇 g)懸浮於乙醇（10 ml)及1 N之鹽酸-乙醇溶液（2〇以）中，於氫氣琴境下擾拌7小時。藉由石夕藻土過濾去除鈀，於減壓下顧去慮液 >谷劑’獲付油狀物質之標題化合物（1.3 g，1％。 H-NMR (400 MHz，DMSO_D6) δ: 1·29_1·30 (3H，m) 2 8〇 (3H，s)，3.09-4.15 (7H，m)，10 07 (2H，brs)，1185 ⑽ m) 〇 5 實施例1 2-甲氧基_5-[3·[(4-甲氧基哌啶小基）羰基甲基“Η 126365.doc -36 - 200827349 1，2，3 -二嗤 _4-基）_ 1 η_ σ比嗤-1 -基]。比口定 [化 17]-2HCI SMe 126365.doc -35- 200827349 1) 2,4 - monomethylpyrazine acid g is intended for 〇C to 2-methylpiperazine benzyl ester (w〇2003/022214, 1.8 g) To a solution of methanol (40 ml) was added sodium triethoxysulfonate hydride (21 g), acetic acid (0.43 ml) and a 3 7% aqueous solution of formaldehyde (2.0 mi). After stirring at room temperature for 1 hour, a saturated aqueous solution of sodium hydrogencarbonate and dichloromethane were added, and liquid separation was carried out. The organic layer was evaporated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (methanol) to give the oily substance of benzyl 2, 4-dimethylpiperazine (18 g, 94). %) 〇W-NMR (400 MHz, CDC13) δ: 1·27 (3H, d, J=6.6 Hz), h89·1·96 (1H, m), 2·09-2·13 (1H, m ), 2·24 (3H, s), 2.57-2.61 (1H, m), 2.70-2.74 (1H, m), 3.14-3.22 (1H, m), 3·88-3·93 (1H, m) , 4.27-4.34 (1H,m)5 5.10-5.17 (2H,m),7·37·73〇(5H,m) 〇MS (ESI) m/z: 249 (M+H)10. 2) The title compound was prepared by suspending the above 2,4-dimethylpiperazine benzyl ester (1·8 g) and palladium carbon (1 〇g) in ethanol (10 ml) and 1 N hydrochloric acid-ethanol solution (2〇) In the middle, it was disturbed for 7 hours under the hydrogen atmosphere. The palladium was removed by filtration through celite, and the title compound (1.3 g, 1%. H-NMR (400 MHz, DMSO_D6) δ: 1 · 29_1·30 (3H, m) 2 8〇 (3H, s), 3.09-4.15 (7H, m), 10 07 (2H, brs), 1185 (10) m) 〇 5 Example 1 2-methoxy _ 5-[3·[(4-methoxypiperidinyl)carbonylmethyl"Η 126365.doc -36 - 200827349 1,2,3 -diindole_4-yl)_ 1 η_ σ 嗤-1 -基]. 比口定[化17]

於室溫下向參考例2之ΐ-(6-甲氧基。比啶-3-基）-5-(1-甲基-1Η·1，2,3-***-4-基）-ih-吡唑-3-羧酸（〇·254 g)、4-曱氧基旅啶鹽酸鹽（〇·192 g，WO 2004/094407)、3_(3_二甲基胺基丙基）-1-乙基碳化二亞胺鹽酸鹽（0·178 g)、及1-羥基苯幷三。坐（0.126 g)之二氯甲烷mi)溶液中，添加三乙胺 (0·307 ml)，擾拌21小時。向反應液中添加水與氣仿，實施分液，於減壓下餾去有機層之溶劑。以矽膠管柱層析法 (氣仿甲醇）精製所獲得之殘渣，獲得固體之標題化合物 (0.239 g，71%) 〇 'H-NMR (400 MHz, CDC13) δ: 1.71 (3Η, m)5 1.94 (2Η m) 3·38 (3H，s)，3.47-3.56 (2H，m)，3.68-3.74 (1H，m)，3·98 (3H，s)，4.09 (3H，s)，4.21-4.26 (1H，m)，6·81 (1H，d，J=8 5Ϊ́-(6-Methoxy.pyridin-3-yl)-5-(1-methyl-1Η·1,2,3-triazol-4-yl)- to Reference Example 2 at room temperature Ih-pyrazole-3-carboxylic acid (〇·254 g), 4-decyloxy traveller hydrochloride (〇·192 g, WO 2004/094407), 3-(3-dimethylaminopropyl) 1-ethyl carbodiimide hydrochloride (0·178 g), and 1-hydroxyphenyl hydrazine. After sitting in a solution of (0.126 g) dichloromethane m), triethylamine (0·307 ml) was added and the mixture was stirred for 21 hours. Water and a gas mixture were added to the reaction liquid, and liquid separation was carried out, and the solvent of the organic layer was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography (methanol) toield of the title compound (0.239 g, 71%) 〇 'H-NMR (400 MHz, CDC13) δ: 1.71 (3Η, m)5 1.94 (2Η m) 3·38 (3H, s), 3.47-3.56 (2H, m), 3.68-3.74 (1H, m), 3·98 (3H, s), 4.09 (3H, s), 4.21 4.26 (1H,m),6·81 (1H,d,J=8 5

Hz)，7.07 (1H，s)，7·32 (1H，s)，7.68-7.70 (ih，m)，8 22 (1H，d，J=2.4 Hz)。MS (ESI) m/z: 397 (M+)。實施例2 4-{[1-(6-甲氧基吡啶-3-基）-5-(1-甲基-111_152,3_三唾_4_基）-1H-吡唑-3-基]羰基}嗎啉 126365.doc -37- 200827349 [化 18]Hz), 7.07 (1H, s), 7.32 (1H, s), 7.68-7.70 (ih, m), 8 22 (1H, d, J = 2.4 Hz). MS (ESI) m/z: 397 (M+). Example 2 4-{[1-(6-Methoxypyridin-3-yl)-5-(1-methyl-111-152,3-tris-7-yl)-1H-pyrazol-3-yl ]carbonyl}morpholine 126365.doc -37- 200827349 [Chemical 18]

於室溫下，向參考例2之1·(6-甲氧基吡啶_3-基）-5-(1-甲基-1H-1，2,3-***-4-基）-1Η-吡唑 _3_ 羧酸（0.260 g)、3_(3-二甲基胺基丙基）-1-乙基碳化二亞胺鹽酸鹽（〇183 g)、及b 經基苯幷***（0.:129 g)之二氯甲烷（5·2 ml)溶液中添加嗎啉 (90.5 μΐ)與三乙胺（〇·133 ml)，攪拌17小時。向反應液中添加水與氣仿，實施分液，於減壓下餾去有機層之溶劑。以矽膠管柱層析法（氯仿_甲醇）精製所獲得之殘渣，獲得固體之標題化合物（0.277 g，87%)。 H-NMR (400 MHz，CDC13) δ: 3.73-3.82 (6H，m)，3.98 (3H， 0, 4.09 (3H，s)，4.10 (2H，m)，6.82 (1H，d，J=8.8 Hz)，7·ΐ4 (1H，s)，7.33 (1H，s)，7·66-7·69 (1H，m)，8·22 (1H，d，J=2 4To the reference example 2, 1·(6-methoxypyridine-3-yl)-5-(1-methyl-1H-1,2,3-triazol-4-yl)-1Η at room temperature -pyrazole_3_carboxylic acid (0.260 g), 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride (〇183 g), and b-phenylbenzotriazole (0.: 129 g) of methylene chloride (5. 2 ml) was added morpholine (90.5 μM) and triethylamine (〇·133 ml), and stirred for 17 hours. Water and a gas mixture were added to the reaction liquid, and liquid separation was carried out, and the solvent of the organic layer was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting elut elut elut elut elut H-NMR (400 MHz, CDC13) δ: 3.73-3.82 (6H, m), 3.98 (3H, 0, 4.09 (3H, s), 4.10 (2H, m), 6.82 (1H, d, J = 8.8 Hz ),7·ΐ4 (1H,s),7.33 (1H,s),7·66-7·69 (1H,m),8·22 (1H,d,J=2 4

Hz) 〇 · MS (El) m/z: 369 (M+)。 (B法）於室溫下，向參考例2之l-(6-曱氧基吡啶_3_基）—5、（1_曱基韻-1，2,3-二唑-4-基）_ιη·吡唑-3·羧酸（9.00 g)、3、（3 二甲基私：基丙基）-i-乙基碳化二亞胺鹽酸鹽（6·32 g)、及1 _ 基苯幷三。坐(4.45 g)之二氯甲烷⑽叫溶液中添加嗎： 126365.doc •38- 200827349 ml)與二乙胺（4.60 ml)，擾拌17小時。向反應液中添加水與氯仿，實施分液，以無水硫酸鈉乾燥有機層。過濾後，於減壓下餾去溶劑，以矽膠管柱層析法（氣仿_甲醇）精製所獲彳于之殘邊’獲得固體之標題化合物。於加熱回流下溶解所獲得之固體甲醇懸濁液。於冰浴冷卻下攪拌反應液，濾取析出晶體。進而，於減壓下餾去濾液之溶劑，向所獲知之固體中添加甲醇，於加熱回流下溶解該反應液。於冰浴冷卻下攪拌反應液，濾取析出晶體，與先前所獲得之口P刀合併’從而獲得標題化合物（1 〇·2 g，92%) 〇實施例3 1-{[1_(6-甲氧基吡啶_3_基）_5_(1_甲基_111_1，2,3_***_心基）_ m-吡唑-3—基]羰基}_4_甲基旅嘻 [化 19]Hz) 〇 · MS (El) m/z: 369 (M+). (Method B) To 1-(6-decyloxypyridine-3-yl)-5, (1_fluorenyl-1,2,3-oxadiazol-4-yl) of Reference Example 2 at room temperature )_ιη·pyrazole-3·carboxylic acid (9.00 g), 3, (3 dimethyl private: propyl)-i-ethylcarbodiimide hydrochloride (6·32 g), and 1 _ Benzoquinone III. Sitting (4.45 g) of dichloromethane (10) is added as a solution: 126365.doc •38- 200827349 ml) and diethylamine (4.60 ml), stir-fed for 17 hours. Water and chloroform were added to the reaction liquid, and liquid separation was carried out, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the title compound was obtained from the residue obtained from EtOAc (methanol). The obtained solid methanol suspension was dissolved under reflux with heating. The reaction solution was stirred under ice cooling, and crystals were separated by filtration. Further, the solvent of the filtrate was distilled off under reduced pressure, methanol was added to the obtained solid, and the mixture was dissolved under reflux with heating. The reaction solution was stirred under ice-cooling, and crystals were separated by filtration, and then combined with the previously obtained P-knife to obtain the title compound (1 〇·2 g, 92%) 〇 Example 3 1-{[1_(6- Methoxypyridine _3_yl)_5_(1_methyl_111_1,2,3_triazole_heart group)_m-pyrazole-3-yl]carbonyl}_4_methyl 嘻[[19]

於室溫下，向參考例2之ι_(6_曱氧基吡啶-3-基）基·1Η-1，2,3-二唑-4-基）_1H_ 吡唑·3_ 羧酸（0.200 g)、3_(3_二甲基fe基丙基）-1·乙基碳化二亞胺鹽酸鹽（〇14〇 g)、及1 羥基苯幷二唑（99.0 mg)之二氯甲烷（4 ml)溶液中添加i•曱基♦嗓（0.111 ml)與三乙胺（〇1〇2 ml),攪拌15小時。向反應液中添加水與氯仿，實施分液，於減壓下餾去有機層之溶劑。以矽膠管柱層析法（氣仿_甲醇）精製所獲得之殘涪， 126365.doc •39- 200827349 獲得固體之標題化合物（0.176 g，69%)。 W-NMR (400 MHz，CDC13) δ: 2.34 (3H，s)，2.47-2.53 (4H， m)，3·86 (2Η，m)5 3.98 (3Η，s)，4·07 (2Η，m)，4.09 (3Η，s)， 6.80-6.82 (1H，m)，7·10 (1H，s)，7·32 (1H，s)，7.67-7.70 (1H，m)，8·22 (1H，m) 〇 MS (El) m/z: 382 (M+) 〇實施例4 f ^環丙基-4-{Π-(6-甲氧基吡啶-3-基）-5-(l-甲基-lH-l，2,3- ***-4-基）lH_吡唑-3基]羰基}哌嗪 [化 20]To the reference example 2, iota(6-fluorenylpyridin-3-yl)yl-1Η-1,2,3-oxadiazol-4-yl)_1H-pyrazole·3_carboxylic acid (0.200 g) , 3_(3_Dimethylfepropyl)-1·ethylcarbodiimide hydrochloride (〇14〇g), and 1 hydroxybenzodiazepine (99.0 mg) of dichloromethane (4 To the solution, add i•indenyl 嗓(0.111 ml) and triethylamine (〇1〇2 ml) and stir for 15 hours. Water and chloroform were added to the reaction mixture, and liquid separation was carried out, and the solvent of the organic layer was evaporated under reduced pressure. Residues obtained by purifying the column chromatography (methanol-methanol), 126 365. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> W-NMR (400 MHz, CDC13) δ: 2.34 (3H, s), 2.47-2.53 (4H, m), 3·86 (2Η, m) 5 3.98 (3Η, s), 4·07 (2Η, m ), 4.09 (3Η, s), 6.80-6.82 (1H, m), 7·10 (1H, s), 7·32 (1H, s), 7.67-7.70 (1H, m), 8.22 (1H , m) 〇MS (El) m/z: 382 (M+) 〇 Example 4 f ^cyclopropyl-4-{Π-(6-methoxypyridin-3-yl)-5-(l-A --lH-l,2,3-triazol-4-yl)lH-pyrazol-3-yl]carbonyl}piperazine [Chemical 20]

向參考例2之1-(6-甲氧基吡啶基）-甲基_m_i，2,3-三唾-4-基）-1Η-η比唑_3_羧酸（25〇〇叫）之队义二甲基甲醯 (5 ml)’谷液中添加環丙基旅嗓鹽酸鹽（245·$ mg，WO 2004/069824)、3-(3-二甲基胺基丙基卜^乙基碳化二亞胺鹽酸鹽（192.2 mg)、ι_羥基苯幷***（112,9 mg)、及三乙胺 (0.3 50 ml) ’擾拌15小時。向反應液中添加飽和碳酸氫鈉水浴液與氣仿，實施分液，以水清洗有機層後，以無水硫酉欠鈉乾爍。過濾後，於減壓下餾去有機溶劑，以矽膠薄層層析法（氯仿-甲醇）精製所獲得之殘渣，獲得固體之標題化合物（250.7 mg，74%)。 126365.doc 200827349 W-NMR (400 MHz，CDC13) δ: 0.46 (4H，m)，1·62·1·67 (1H， m)，2.64-2.72 (4H，m)，3.75-3.81 (2H，m)，3·94-4·〇ι (5H， m)，4.09 (3H，s)，6.81 (1H，d，J=8.8 Hz)，7·10 (1H，s)，7 32 (1H，s)，7·69 (1H，dd，J=8.8，2.7 Hz)，8.22 (1H，d，j=2 7 Hz) 〇 MS (ESI) m/z: 409 (M+H)+。實施例5 4-{[1-(6-甲氧基吡啶_3-基）-5-(1-甲基-1!^-1，2,3-***_4_基）_ 1H-吡唑-3-基]羰基}嗎啉 1) 1-曱基-1Η-1，2,3-*** 於冷卻至0°C之條件下，花費2小時向1Η]，2,3-***（150 g)及碘代甲烷（189 ml)之四氫呋喃（2·25 1)溶液中滴加n 二氮雜雙環[5·4·0]-7-十一烯（389 ml)。將反應液於室溢下攪拌16小時。過濾分離反應液之不溶物，於減壓下餾去澹液之溶劑’減壓蒸顧（6 mmHg，72°C )所獲得之殘渣，獲得油狀物之1 -甲基-1H-1，2,3-三唾（11 7 g，65%)。 W-NMR (400 MHz，CDC13) δ: 4·13 (3H，s)，7.56-7.56 (1H， m)，7.7 0 - 7.71 (1Η，m) 〇 2) 1-甲基-5_(苯硫基）-ιη·1，2,3-三嗤於冷卻至-50°C之條件下，花費1.5小時向丨_甲基_1Η_ 1，2,3-***（117 g)之無水四氫呋喃（1.2 1}溶液中滴加正丁基鋰（1.59 Μ之正乙烷溶液，1〇6 1}後，攪拌2小時。花費2小時向反應液中滴加二苯二硫醚（369 g)之無水四氫呋喃（ι·2 1)溶液後，將反應液於室溫下攪拌18小時。向反應液中添 126365.doc •41 - 200827349 加水（1 1)，以醋酸乙酯萃取4次，以無水硫酸鈉乾燥經合併之有機層。過濾分離後，於減壓下餾去有機溶劑，以矽膠層析法（己烷-醋酸乙酯）精製所獲得之殘渣，獲得油狀物之 1-曱基-5-(苯硫基）-1Η-1，2,3-***（224 g，83%)。 ^H-NMR (400 MHz5 CDC13) δ： 3.97 (3Η? s)5 7.11-7.14 (2Η? m)，7·23·7·32 (3Η，m)，7.86 (ιΗ，s)。 ’ MS (ESI) m/z: 192 (Μ+Η)+。 3) 1-[1-甲基-5-(苯硫基）-lH-l，2,3-***-4-基]乙酮於冷卻至-50°C之條件下，花費3〇分鐘向2,2,6,6_四曱基哌啶（237 ml)之無水四氫呋喃（2丨）溶液中滴加正丁基鋰 (1·60 Μ之正乙烷溶液，878 ml)。進而，花費15小時向反應液中滴加1 -甲基- 5-(苯硫基）_ iH-1，2,3-三唾（224 g)之無水四氫呋喃（1.5 1)溶液後，攪拌2小時。向反應液中添加冰甲氧基甲基乙醯胺（133 g)，於室溫下攪拌3小時。向反應液中添加水（1·3 1)與醋酸乙酯（5 1}實施分液，以水（1·3丨）清洗有機層。以無水硫酸鈉乾燥有機層。過濾分離後，於減壓下餾去有機溶劑，以矽膠層析法（己烷_醋酸乙酯）精製所獲得之殘潰，獲得油狀物甲基-5_(苯硫基）-1Η-1，2,3-***-4-基]乙酮（236 g，86%)。 !H-NMR (4〇〇 MHz，CDC13) δ·· 2.72 (3H，s)，3.92 (3H，s)， 7.2 1 -7.33 (5Η，m)。 4) 4 [1甲基_5_(苯硫基）_11^-1，2,3-三嗤-4-基]-2,4-二側氧基丁酸乙酯向乙鮮納（82·6 g)之乙醇（1丨）溶液中添加草酸二乙醋（177 126365.doc -42 - 200827349 g)。花費15分鐘向反應溶液中滴加甲基_5_(苯硫基）_ 1仏1，2,3-***_4-基]乙酮（23 6 §)之乙醇（75〇1111)溶液，攪拌 2· 5小時。向反應液中添加1N鹽酸水溶液（1 ·2 1)進行中和，濾取析出固體，獲得4-[1-甲基-5-(苯硫基唑_ 4-基]-2,4-二側氧基丁酸乙酯（254 g，76%)。 1H-NMR (400 MHz，CDC13) δ: 1·40 (3H，t，J = 7.1 Ηζ)，3·95 (3H，s)，4.39(2H，q，J = 7.1Hz)，7.21-7.25(2H，m)，7.29- 7·34 (3H，m)，7.52 (1H，s)。 5) 1-(6-甲氧基。比啶-3-基）-5-[l-甲基·5_(苯硫基）_ih-1，2,3- 三ο坐-4-基]-1 Η·ϋ比唾-3 -魏酸乙酉旨將4-[1-甲基- 5-(苯硫基）-1Η-1，2,3-三唾-4 -基]-2,4-二側氧基丁酸乙酯（147 g)及5-肼基-2-甲氧基。比唆（67·8 g，WO 2004/069824)之乙醇（1·48 1)懸濁液於内溫75。(：下攪拌4.5小時。花費10分鐘向反應液中滴加醋酸（133 g)，進而，於内溫75°C下攪拌4·5小時。空氣冷卻後，向反應液中添加乙醇 (1 1)實施攪拌，濾取析出晶體，獲得1-(6-甲氧基吼啶-3-基）-5-[1-甲基- 5-(苯硫基）-1Η-1，2,3-***-4-基]-1H-吡唑-3-羧酸乙酯（152 g，79%)。 !H-NMR (400 MHz, CDC13) δ: 1.41 (3H? t5 J=7.1 Hz)5 3.93 (3H，s)，3.96 (3H，s)，4.44 (2H，q，J=7.1 Hz)，6.72 (1H，d， J = 8.8 Hz)，6.89-6.93 (2H，m)，7.21-7.27 (4H，m)，7.68 (1H， dd，J=8.8, 2.7 Hz)，8.10 (1H，d，J=2.7 Hz)。 6) 1-(6-曱氧基吡啶-3-基）-5-(1-曱基-1H-1，2,3-***-4-基）-1H-吡唑-3_羧酸乙酯 126365.doc -43- 200827349 向1-(6-甲氧基11比咬-3 -基）-5-[l -甲基-5-(笨硫基）1只 1，2,3-***-4-基]-1H-吡唑-3-羧酸乙酯（152 g)中添加带田八鎳To Reference Example 2, 1-(6-methoxypyridyl)-methyl_m_i, 2,3-trisept-4-yl)-1Η-η-pyrazole-3-carboxylic acid (25 〇〇) Addition of cyclopropyl guanidine hydrochloride (245·$ mg, WO 2004/069824), 3-(3-dimethylaminopropyl b) to the solution of dimethyl dimethyl hydrazine (5 ml) ^Ethylcarbodiimide hydrochloride (192.2 mg), iota-hydroxybenzotriazole (112,9 mg), and triethylamine (0.3 50 ml) 'scrambled for 15 hours. Add saturation to the reaction solution. The sodium bicarbonate water bath and the air were mixed, and the liquid layer was separated. After washing the organic layer with water, the sodium sulphate was dried with anhydrous sulphur. After filtration, the organic solvent was distilled off under reduced pressure to obtain a thin layer chromatography (chloroform). - Methanol) The residue obtained was purified to give the title compound (250.7 mg, 74%). 126365.doc 200827349 W-NMR (400 MHz, CDC13) δ: 0.46 (4H, m),1·62·1· 67 (1H, m), 2.64-2.72 (4H, m), 3.75-3.81 (2H, m), 3·94-4·〇ι (5H, m), 4.09 (3H, s), 6.81 (1H, d, J = 8.8 Hz), 7·10 (1H, s), 7 32 (1H, s), 7·69 (1H, dd, J = 8.8, 2.7 Hz), 8.22 (1H, d, j=2 7 Hz) 〇MS (ESI) m/z: 409 (M +H)+. Example 5 4-{[1-(6-Methoxypyridine-3-yl)-5-(1-methyl-1!^-1,2,3-triazole_4_ Base) _ 1H-pyrazol-3-yl]carbonyl}morpholine 1) 1-indolyl-1Η-1,2,3-triazole, after cooling to 0 ° C, takes 2 hours to 1 Η], Add n-diazabicyclo[5·4·0]-7-undecene (389) to a solution of 2,3-triazole (150 g) and methyl iodide (189 ml) in tetrahydrofuran (2·25 1). Ml). The reaction solution was stirred in a chamber for 16 hours. The insoluble matter of the reaction mixture was separated by filtration, and the residue obtained by distilling off the solvent of the mash liquid under reduced pressure (6 mmHg, 72 ° C) was obtained to obtain an oily 1-methyl-1H-1. 2,3-three saliva (11 7 g, 65%). W-NMR (400 MHz, CDC13) δ: 4·13 (3H, s), 7.56-7.56 (1H, m), 7.7 0 - 7.71 (1Η,m) 〇2) 1-methyl-5_(phenylsulfonate) Base)-ιη·1,2,3-triterpene was cooled to -50 ° C for 1.5 hours to 丨_methyl_1Η_ 1,2,3-triazole (117 g) of anhydrous tetrahydrofuran ( 1.2 1} Add n-butyllithium (1.59 Μ of n-ethane solution, 1〇6 1} to the solution and stir for 2 hours. It takes 2 hours to add diphenyl disulfide (369 g) to the reaction solution. After the anhydrous tetrahydrofuran (1·1 1) solution was stirred, the reaction mixture was stirred at room temperature for 18 hours. To the reaction mixture was added 126365.doc •41 - 200827349 water (1 1), extracted with ethyl acetate 4 times, anhydrous The combined organic layer was dried over sodium sulfate, and the organic solvent was evaporated under reduced pressure, and the residue obtained was purified by silica gel chromatography (hexane-ethyl acetate). -5-(phenylthio)-1Η-1,2,3-triazole (224 g, 83%). ^H-NMR (400 MHz5 CDC13) δ: 3.97 (3Η? s)5 7.11-7.14 (2Η m),7·23·7·32 (3Η,m),7.86 (ιΗ,s). MS (ESI) m/z: 192 (Μ+Η)+. 3) 1-[1-methyl - 5-(phenylthio)-lH-l,2,3-triazol-4-yl]ethanone, after cooling to -50 ° C, takes 3 〇 minutes to 2, 2, 6, 6 4 Add n-butyllithium (1·60 Μ of n-ethane solution, 878 ml) to a solution of hydrazinopiperidin (237 ml) in anhydrous tetrahydrofuran (2 Torr). Further, add 15 hours to the reaction solution. -Methyl 5-(phenylthio)_iH-1,2,3-tris-sal (224 g) in anhydrous tetrahydrofuran (1.5 1), stirred for 2 hours. Add ice methoxy group to the reaction mixture Ethyl acetamide (133 g) was stirred at room temperature for 3 hours. Water (1·3 1) and ethyl acetate (5 1} were added to the reaction solution for liquid separation and washed with water (1.3 丨). The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the organic solvent was evaporated under reduced pressure and purified by silica gel chromatography (hexane-ethyl acetate). -5_(phenylthio)-1Η-1,2,3-triazol-4-yl]ethanone (236 g, 86%).H-NMR (4 〇〇MHz, CDC13) δ·· 2.72 ( 3H, s), 3.92 (3H, s), 7.2 1 -7.33 (5Η, m). 4) 4 [1methyl_5_(phenylthio)_11^-1,2,3-trim-4- Base]-2,4-two side oxygen Oxalic acid diethyl acetate butyrate to fresh sodium acetate (82 · 6 g) with ethanol (1 Shu) solution (177 126365.doc -42 - 200827349 g). A solution of methyl _5_(phenylthio)_1仏1,2,3-triazol-4-yl]ethanone (23 6 §) in ethanol (75〇1111) was added dropwise to the reaction solution over 15 minutes. Stir for 2 hours. A 1N aqueous hydrochloric acid solution (1·2 1) was added to the reaction mixture for neutralization, and a solid was collected by filtration to obtain 4-[1-methyl-5-(phenylthiozolyl-4-yl)-2,4-di Ethyl acetobutanoate (254 g, 76%). 1H-NMR (400 MHz, CDC13) δ: 1·40 (3H, t, J = 7.1 Ηζ), 3·95 (3H, s), 4.39 (2H, q, J = 7.1 Hz), 7.21-7.25 (2H, m), 7.29-7.34 (3H, m), 7.52 (1H, s). 5) 1-(6-methoxy. Pyridin-3-yl)-5-[l-methyl·5_(phenylthio)_ih-1,2,3-tris--4-yl]-1 Η·ϋ than saliva-3-propionate 4-[1-Methyl-5-(phenylthio)-1Η-1,2,3-tris-7-yl]-2,4-dioxyacetate (147 g) And 5-mercapto-2-methoxy. The ethanol (1·48 1) suspension of 唆 (67·8 g, WO 2004/069824) was at an internal temperature of 75. (: stirring for 4.5 hours. To the reaction liquid, acetic acid (133 g) was added dropwise over 10 minutes, and further stirred at an internal temperature of 75 ° C for 4 hours. After air cooling, ethanol was added to the reaction liquid (1 1 Stirring is carried out, and crystals are precipitated by filtration to obtain 1-(6-methoxyacridin-3-yl)-5-[1-methyl-5-(phenylthio)-1Η-1,2,3- Ethyl triazol-4-yl]-1H-pyrazole-3-carboxylate (152 g, 79%).H-NMR (400 MHz, CDC13) δ: 1.41 (3H? t5 J=7.1 Hz)5 3.93 (3H, s), 3.96 (3H, s), 4.44 (2H, q, J = 7.1 Hz), 6.72 (1H, d, J = 8.8 Hz), 6.89-6.93 (2H, m), 7.21-7.27 (4H, m), 7.68 (1H, dd, J = 8.8, 2.7 Hz), 8.10 (1H, d, J = 2.7 Hz). 6) 1-(6-decyloxy-3-yl)-5 -(1-Mercapto-1H-1,2,3-triazol-4-yl)-1H-pyrazole-3-carboxylic acid ethyl ester 126365.doc -43- 200827349 to 1-(6-methoxy 11-bite-3-yl)-5-[l-methyl-5-(phenothionyl)-1 1,2,3-triazol-4-yl]-1H-pyrazole-3-carboxylic acid Adding eight nickel to the ester (152 g)

(1 kg)之乙醇（1·5 1)懸濁液，於内溫74°C下攪拌1小時。* 氣冷卻後，向反應液中添加氯仿且實施攪拌後，以石夕藻土過濾反應液。以水將濾液之有機溶劑清洗2次。以無水石危酸鈉乾燥有機層。過濾分離後，於減壓下餾去有機溶1，以矽膠管柱層析法（丙酮-氯仿）精製所獲得之殘渣，獲得固體之1-(6-甲氧基吡啶-3-基）-5-(1-曱基·1Η-1，2,3-三唾一4 基比唑-3-羧酸乙酯（101 g，88%)。 ^-NMR (400 MHz5 CDC13) δ: 1.42 (3Η5 t5 J=7.1 Ηζ)? 3 99 (3Η，s)，4.07 (3Η，s)，4.45 (2Η，q，J=7.1 Ηζ)，6·83 (1Η d J = 8.8 Hz)，7.21 (1H，s)，7.30 (1H，s)，7.71 (1H，dd，卜8 8 2·7 Hz)，8.22 (1H，d，J=2.7 Hz)。 ’ MS (ESI) m/z: 329 (M+H)、 7) 1-(6-曱氧基吡啶-3-基）-5-(1-曱基-1H_1，2,3_***_4·基）_ ΙΗ-吼嗤-3-緩酸於室溫下向1-(6-甲氧基咄啶基）_5_(1_甲基2弘 ***-4-基）-1Η-吡唑-3-羧酸乙酯（1〇1 g)之甲醇（1丨）與四氫咬喃（H)之混合懸濁液中添加1Nfl氧化鈉水溶液（768 mi)’攪拌2.5小時。於減壓下顧去反應液之溶劑，達到約 -半量後’過濾分離不溶物。向濾液中添加酸（768 mi)，滤取所生成之固體，獲得if甲氧基。比〇基）·5_ (1-甲基-1Η-1，2,3·三唾-4-基）-ιη 96%) ° g -°比°坐_3_羧酸（8 8.4 126365.doc • 44 - 200827349 04 (3H, S)3 dd，J=8.8, 13.05 (1H， i-NMR (400 MHz，DMSO-d6) δ: 3·93 (3H，s)，4 6.96 (1H，d，J=8_8 Hz)，7.17 (1H，s)，7.83 (1H， 2.7 Hz)，8.12 (1H，s)，8·28 (1H，d，J=2.7 Hz)， brs) o MS (ESI) m/z: 301 (M+H)+。 8)標題化合物於冰浴冷卻下，向1-(6-甲氧基吡啶-3_基）_5_(1_甲美 1，2,3-***-4-基）-1Η_ 吡唑-3-羧酸（88.4 g)、3-A - V -一甲基胺基丙基）-1_乙基碳化二亞胺鹽酸鹽（62·1幻及丨·羥美苯幷一唾（43.8 g)之二氣甲院（ι·8 1)懸濁液中添加嗎琳$幻與三乙胺（32.8 g)，攪拌15分鐘後，將反應液於室溫下攪拌 23小時。向反應液中添加飽和碳酸氫鈉水溶液（1 ·$ 1)實施分液後，進而，以二氯甲烷萃取水層。合併有機層後，以無水硫酸鈉乾燥。過濾分離後，於減壓下餾去有機溶劑，以矽膠管柱層析法（甲醇_氯仿）精製所獲得之殘渣，獲得固體之標題化合物。於加熱回流下溶解所獲得之固體甲醇懸濁液。於熱時過濾反應液，將濾液空氣冷卻放置，濾取析出晶體’獲得標題化合物（58.8 g，54%)。實施例6 5_[3-U(2S)-2-(氟甲基）吼咯啶基]羰基}-5_(1_甲基·1H_ 1，2,3-***_4_基）_1Η_σ比唑·卜基]_2_甲氧基吡啶 [化 21] 126365.doc -45- 200827349(1 kg) of ethanol (1·5 1) suspension was stirred at an internal temperature of 74 ° C for 1 hour. * After cooling with air, chloroform was added to the reaction mixture and stirred, and the reaction liquid was filtered through Shixia. The organic solvent of the filtrate was washed twice with water. The organic layer was dried over anhydrous sodium sulfate. After filtration and separation, the organic solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (acetone-chloroform) to give solid 1-(6-methoxypyridin-3-yl)- Ethyl 5-(1-decyl·1Η-1,2,3-tris-tetramethylbutyrazole-3-carboxylate (101 g, 88%). ^-NMR (400 MHz5 CDC13) δ: 1.42 ( 3Η5 t5 J=7.1 Ηζ)? 3 99 (3Η, s), 4.07 (3Η, s), 4.45 (2Η, q, J=7.1 Ηζ), 6.83 (1Η d J = 8.8 Hz), 7.21 (1H , s), 7.30 (1H, s), 7.71 (1H, dd, Bu 8 8 2·7 Hz), 8.22 (1H, d, J = 2.7 Hz). ' MS (ESI) m/z: 329 (M +H), 7) 1-(6-decyloxypyridin-3-yl)-5-(1-indolyl-1H_1,2,3-triazole-4-yl)_ΙΗ-吼嗤-3- Evaporation of 1-(6-methoxyacridinyl)-5-(1-methyl-2-oxatriazol-4-yl)-1Η-pyrazole-3-carboxylate (1〇1) at room temperature g) A mixed suspension of methanol (1 Torr) and tetrahydroanion (H) was added with 1 Nfl of an aqueous sodium oxide solution (768 mi) and stirred for 2.5 hours. The solvent of the reaction liquid was taken under reduced pressure to obtain about -half amount, and the insoluble matter was separated by filtration. Acid (768 mi) was added to the filtrate, and the resulting solid was collected by filtration to give an methoxy. Bisyl)·5_(1-methyl-1Η-1,2,3·tris-s--4-yl)-ιη 96%) ° g -° ratio ° sitting _3_carboxylic acid (8 8.4 126365.doc • 44 - 200827349 04 (3H, S)3 dd, J=8.8, 13.05 (1H, i-NMR (400 MHz, DMSO-d6) δ: 3·93 (3H, s), 4 6.96 (1H, d, J=8_8 Hz), 7.17 (1H, s), 7.83 (1H, 2.7 Hz), 8.12 (1H, s), 8·28 (1H, d, J=2.7 Hz), brs) o MS (ESI) m /z: 301 (M+H)+. 8) The title compound was cooled in an ice bath to 1-(6-methoxypyridin-3-yl)-5-(1-methyl-1,2,3-triazole 4-yl)-1Η_pyrazole-3-carboxylic acid (88.4 g), 3-A-V-monomethylaminopropyl)-1_ethylcarbodiimide hydrochloride (62·1 illusion)吗············································································· After stirring for 23 hours at room temperature, a saturated aqueous solution of sodium hydrogencarbonate (1·$1) was added to the reaction mixture, and the aqueous layer was extracted with dichloromethane. The organic layer was combined and dried over anhydrous sodium sulfate. After separation by filtration, the organic solvent is distilled off under reduced pressure to obtain a silica gel column chromatography. (Methanol-chloroform), the residue obtained was purified to give the title compound as a solid. The solid methanol suspension obtained was dissolved under reflux with heating. The reaction mixture was filtered while hot, and the filtrate was air-cooled and filtered to obtain crystals. The title compound (58.8 g, 54%). Example 6 5-[3-U(2S)-2-(fluoromethyl)pyridinyl]carbonyl}-5-(1_methyl·1H_ 1,2,3 -triazole_4_yl)_1Η_σbazole·buki]_2_methoxypyridine [Chem. 21] 126365.doc -45- 200827349

於室溫下向參考例2之1-(6-甲氧基吡啶-3-基甲基_ 1Η-1，2,3·***-4-基）-1Η-吡唑-3-羧酸（〇_2〇〇 g)、（2S)·氟甲基吡咯啶鹽酸鹽（0.139 g，WO 2006/004027)、3-(3-二甲基胺基丙基）-1-乙基碳化二亞胺鹽酸鹽（0.140 g)、及L經基苯幷三嗤（99·0 rng)之二氯甲烷（4 ml)溶液中添加三乙胺 (0·241 ml) ’授拌63小時。向反應液中添加水與氯仿，實施分液，於減壓下餾去有機層之溶劑。以矽膠管柱層析法 (氣仿-甲醇）精製所獲得之殘渣，獲得固體標題化合物 (0.178 g，69%) 〇 ^-NMR (400 MHz, CDC13) δ: 1.88-2.15 (4H, m), 3.67-4.16 (8H，m)，4.36-5.18 (3H，m)，6.80-6.82 (1H，m)，7·2ΐ-7·23 (1H，m)，7·35-7·40 (1H，m)，7.66-7.71 (1H，m)，8.21-8.24 (1H，m) o MS (El) m/z: 385 (M+)。實施例7 (3R)-4-{[l-(6-甲氧基吼啶-3-基甲基***-4·基）_ 1H-吡唑-3-基]羰基}_3_甲基嗎啉 [化 22] 126365.doc -46- 200827349To 1-(6-methoxypyridin-3-ylmethyl-1 Η-1,2,3·triazol-4-yl)-1 Η-pyrazole-3-carboxylic acid of Reference Example 2 at room temperature (〇_2〇〇g), (2S)·fluoromethylpyrrolidine hydrochloride (0.139 g, WO 2006/004027), 3-(3-dimethylaminopropyl)-1-ethylcarbylation Diethylamine (0·241 ml) was added to a solution of diimine hydrochloride (0.140 g) and L-formyl hydrazine tris(99·0 rng) in dichloromethane (4 ml). . Water and chloroform were added to the reaction liquid, and liquid separation was carried out, and the solvent of the organic layer was evaporated under reduced pressure. The residue obtained was purified by silica gel column chromatography (methanol-methanol) to give the title compound (0.178 g, 69%) 〇^-NMR (400 MHz, CDC13) δ: 1.88-2.15 (4H, m) , 3.67-4.16 (8H, m), 4.36-5.18 (3H, m), 6.80-6.82 (1H, m), 7·2ΐ-7·23 (1H, m), 7·35-7·40 (1H , m), 7.66-7.71 (1H, m), 8.21-8.24 (1H, m) o MS (El) m/z: 385 (M+). Example 7 (3R)-4-{[l-(6-methoxyacridin-3-ylmethyltriazol-4yl)-1H-pyrazol-3-yl]carbonyl}_3_methyl Morpholine [Chem. 22] 126365.doc -46- 200827349

向參考例2之1-(6-甲氧基吡啶-3·基）_5_(卜甲基-1H-1，2,3- ***-4-基）-1Η_吡唑·3-羧酸（13〇 mg)之Ν，Ν·二甲基甲醯胺 (4 ml)溶液中添加參考例6之（3R)-3-甲基嗎啉（120 mg)、4- (4,6-二甲氧基-1，3,5-三嗪_2-基）-4-甲基氣化嗎啉（155 fTo the 1-(6-methoxypyridin-3-yl)-5-(p-methyl-1H-1,2,3-triazol-4-yl)-1Η-pyrazole-3-carboxylic acid of Reference Example 2 (13) 〇mg), Ν·dimethylformamide (4 ml) was added to the solution of Reference Example 6 (3R)-3-methylmorpholine (120 mg), 4-(4,6-dimethoxy Base-1,3,5-triazine_2-yl)-4-methyl vaporized morpholine (155 f

mg)、及三乙胺（1δ〇 μΐ)，於室温下攪拌4小時。向反應溶液中添加水、醋酸乙酯實施分液，於減壓下餾去有機層，以石夕膠管柱層析法（氯仿-甲醇）精製所獲得之_，獲得固體之標題化合物（121 mg，73%)。 lH-NMR(4〇〇MHZ，CDCl3)S:1.43(3H，d,J=6.6Hz)，3.38- 3.21 (1H，m)，3.53·3.76 (3H，m)，3 84 3 96 (ih，蛛 3 98 (3H，S)，4.09(3H，s)’4.40-4.62 (1H，m)，4 74-4 95 (iHm)， 6.82 (1H，d，J=9.0 Hz)，7.11(1H，s) 7 33 (ih,s)，7 66 7 69 (1H，m)，8.22 (1H，d，J = 2.7 Hz) 〇 MS (ESI) m/z·· 384 (M+H)+。實施例8 (3SM_{[1_(6.甲氧基e比咬_3_基）_5仆甲基^+2,3-三嗤 4-基）-1Η-σΛ。坐·3_基]幾基}-3 -甲基嗎琳 [化 23] 126365.doc 47· 200827349(mg), and triethylamine (1δ〇 μΐ), stirred at room temperature for 4 hours. Water and ethyl acetate were added to the reaction solution to carry out liquid separation, and the organic layer was evaporated under reduced pressure, and purified by silica gel column chromatography (chloroform-methanol) to give the title compound (121 mg , 73%). lH-NMR (4〇〇MHZ, CDCl3) S: 1.43 (3H, d, J = 6.6 Hz), 3.38- 3.21 (1H, m), 3.53·3.76 (3H, m), 3 84 3 96 (ih, Spider 3 98 (3H, S), 4.09 (3H, s) '4.40-4.62 (1H, m), 4 74-4 95 (iHm), 6.82 (1H, d, J = 9.0 Hz), 7.11 (1H, s) 7 33 (ih, s), 7 66 7 69 (1H, m), 8.22 (1H, d, J = 2.7 Hz) 〇MS (ESI) m/z·· 384 (M+H)+ Example 8 (3SM_{[1_(6. methoxye is more than bite_3_yl)_5 servoyl^^2,3-trisyl-4-yl)-1Η-σΛ. Sit·3_基] }-3 -Methylline [Chem. 23] 126365.doc 47· 200827349

利用與實施例7相同之方法，由參考例2之1ββ(6_甲氧基吡啶-3_基）-5_(1·曱基-1Η-1，2,3-***-4-基）_1Η_吡唑-3·羧酸 (12〇 mg)及參考例7之（3S)-3_甲基嗎啉（11〇 mg)獲得固體之標題化合物（112 mg，73%)。In the same manner as in Example 7, 1ββ(6-methoxypyridin-3-yl)-5-(1·indolyl-1Η-1,2,3-triazol-4-yl) of Reference Example 2 was used. </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt;

!Η.ΝΜΚ (400 MHz, CDC13) δ: 1.43 (3Η5 d5 J = 6.6 Ηζ)5 3.20- 3.38 (1Η，m)，3·53-3.74 (3Η，m)，3.85-3.94 (1Η，m)，3.98 (3H，s)，4.10 (3H，s)，4.40-4.63 (1H，m)，4.73-4.93 (1H，m)， 6.82 (1H，d，J-9.0 Hz)，7·12 (1H，s)，7.32 (1H，s)，7.68 (1H， dd? J = 9.0?2.7Hz)58.22(1H5 d5 J^2.7 Hz) 〇 MS (ESI) m/z: 384 (M+H)、實施例9 {[ (6甲氧基基^」，^•三吐_心基）_ 心比嗤-3-基浪基卜&氧氮雜環庚燒 [化 24]!Η.ΝΜΚ (400 MHz, CDC13) δ: 1.43 (3Η5 d5 J = 6.6 Ηζ)5 3.20- 3.38 (1Η,m),3·53-3.74 (3Η,m),3.85-3.94 (1Η,m) , 3.98 (3H, s), 4.10 (3H, s), 4.40-4.63 (1H, m), 4.73-4.93 (1H, m), 6.82 (1H, d, J-9.0 Hz), 7·12 (1H , s), 7.32 (1H, s), 7.68 (1H, dd? J = 9.0? 2.7 Hz) 58.22 (1H5 d5 J^2.7 Hz) 〇MS (ESI) m/z: 384 (M+H), implementation Example 9 {[(6-methoxy group^", ^•三吐_心基)_心比嗤-3-基浪基卜&oxazepine[化24]

刊用與實施例7相同之啶基甲基]H_ ，由參考例2之1-(6-甲氧基吡二11 坐-4 -基）-1Η-^峻-3 -叛酸 126365.doc -48- 200827349 (130 mg)與1，4·氧氮雜環庚烷鹽酸鹽（w〇 2004/94407，120 mg)獲得固體之標題化合物（92.7 mg，56%)。 ^-NMR (400 MHz5 CDC13) δ: 2.00-2.10 (2Η5 m)5 3.79-3.89 (6Η，m)，3.98 (3Η，s)，4.04-4.13 (2Η，m)，4.09 (3Η，s)，6.81 (1H，d，J=9.0 Hz)，7.13 (1H，d，J=4.3 Hz)，7.34-7.36 (1H， m)，7.65-7.69 (1H，m)，8.23-8.20 (1H，m)。 MS (ESI) m/z: 384 (M+H)+。實施例10 5_{3-[(4,4-二甲基-1，3-噚唑啶_3_基）羰基]_5_(1_甲基_1^1- 1，2,3-***-4_基）-111-吡唑-1-基}_2_甲氧基吡啶 [化 25]The same pyridinemethyl]H_ as in Example 7 was used, and 1-(6-methoxypyridin-11--4-yl)-1Η-^Jun-3-Resin 126365.doc of Reference Example 2 -48-200827349 (130 mg). ^-NMR (400 MHz5 CDC13) δ: 2.00-2.10 (2Η5 m)5 3.79-3.89 (6Η,m),3.98 (3Η,s),4.04-4.13 (2Η,m),4.09 (3Η,s), 6.81 (1H,d,J=9.0 Hz), 7.13 (1H,d,J=4.3 Hz),7.34-7.36 (1H, m), 7.65-7.69 (1H,m), 8.23-8.20 (1H,m) . MS (ESI) m/z: 384 (M+H)+. Example 10 5_{3-[(4,4-Dimethyl-1,3-oxazolidine-3-yl)carbonyl]_5_(1_methyl_1^1- 1,2,3-triazole -4_yl)-111-pyrazol-1-yl}_2-methoxypyridine [Chemical 25]

利用與實施例7相同之方法，由參考例2之甲氧基外匕口疋-3-基）-5-(1-甲基-1H-1，2,3-三。坐 _4-基）_1H-口比吐-3-叛酸 (13〇 mg)與4，心二甲基嘮唑啶（75%水溶液，12〇 μ1)獲得固體之標題化合物（124 mg，75%)。 H-NMR (400 MHz，CDC13) δ: 1.62 (6H，s)，3.79 (2H，s)， 3.98 (3Η，s)，4.10 (3Η，s)，5.47 (2Η，s)，6·81 (1Η，d，J=9.〇In the same manner as in Example 7, the methoxy oxime oxime-3-yl)-5-(1-methyl-1H-1,2,3-tri. </ RTI> </ RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; H-NMR (400 MHz, CDC13) δ: 1.62 (6H, s), 3.79 (2H, s), 3.98 (3Η, s), 4.10 (3Η, s), 5.47 (2Η, s), 6·81 ( 1Η,d,J=9.〇

Hz)，7.21(lH，s)，7.38(lH，s)，7.66-7.69 (lH，m)，8.22- 8· 1 8 (1H，m)。 MS (ESI) m/z: 384 (M+H)+。 126365.doc -49- 200827349 實施例11 1-UW6-甲氧基甲基·⑴^义三士心基）-1Η-吼唑-3-基]羰基）旅啶甲醯胺 [化 26]Hz), 7.21 (lH, s), 7.38 (lH, s), 7.66-7.69 (lH, m), 8.22 - 8·1 8 (1H, m). MS (ESI) m/z: 384 (M+H)+. 126365.doc -49- 200827349 Example 11 1-UW6-methoxymethyl·(1)^islysine)-1Η-oxazol-3-yl]carbonyl)-benzamidamide [Chem. 26]

利用與實施例7相同之方法，由參考例2之1-(6•甲氧基吡啶-3_基）-5·(1_甲基***_4_基）_1Η-吡唑_3-羧酸 (120 mg)與哌啶-2-甲醯胺鹽酸鹽（WO 2006/4027，132 mg) 獲得固體之標題化合物（130 mg，85%)。 'H-NMR (400 MHz, CDC13) δ: 1.52-1.85 (5Η? m)5 2.29-2.41 (1Η，m)，2.78-2.86 (1/2Η，m)，3.13-3.21 (1/2Η，m)，3.98 (3H，s)，4·10 (3H，s)，4.68-4.73 (1H，m)5 5.32-5.45 (2H，m)， 6.34-6.39 (1/2H，m)，6·80-6·84 (1H，m)，7.02-7.07 (1/2H， m)，7.12-7.16 (1H，m)，7.28-7.36 (1H，m)，7.63-7.70 (1H， m)5 8·23_8.18 (1H，m)。實施例12 1-{[1-(6_甲氧基吡啶-3-基）_5_(1-甲基-111-1，2,3-***-4-基）- 1Η_ϋ比唑-3·基]羰基}-2,4-二甲基哌嗪 [化 27] 126365.doc -50- 200827349In the same manner as in Example 7, 1-(6•methoxypyridin-3-yl)-5·(1-methyltriazole_4_yl)_1Η-pyrazole-3-3 was used in Reference Example 2. Carboxylic acid (120 mg) and piperidin-2-carbamide hydrochloride (WO 2006/4027, 132 mg) 'H-NMR (400 MHz, CDC13) δ: 1.52-1.85 (5Η? m)5 2.29-2.41 (1Η,m), 2.78-2.86 (1/2Η,m),3.13-3.21 (1/2Η,m ), 3.98 (3H, s), 4·10 (3H, s), 4.68-4.73 (1H, m) 5 5.32-5.45 (2H, m), 6.34-6.39 (1/2H, m), 6·80 -6·84 (1H, m), 7.02-7.07 (1/2H, m), 7.12-7.16 (1H, m), 7.28-7.36 (1H, m), 7.63-7.70 (1H, m)5 8· 23_8.18 (1H, m). Example 12 1-{[1-(6-Methoxypyridin-3-yl)-5-(1-methyl-111-1,2,3-triazol-4-yl)- 1Η-indoleazole-3· Carbonyl]-2,4-dimethylpiperazine [Chem. 27] 126365.doc -50- 200827349

利用與實施例7相同之方法，由參考例2之ι_(6_甲氧基吡啶-3-基）-5_(1-甲基-1H_1，2,3-***·4-基）_1H-吡唑-3-羧酸 (120 mg)及參考例8之1，3-二甲基派嗪鹽酸鹽（149 mg)獲得非晶形之標題化合物（11 5 mg，73°/〇)。 1H-NMR(400 MHZ，CDCl3)8:1.42(3H，d，J=6.3Hz)，2.01· 2.08 (1H，m)，2·20-2·24 (1H，m)，2.27 (3H，s)，2.59-2.88 (2H，m)，3·43_3·58 (1H，m)，3.98 (3H，s)，4·09 (3H，s)， 4.53-4.58 (1H，m)，4.90 (1H，brs)，6·80·6·83 (1H，m)，7.07 (1H，s)，7·32 (1H，s)，7_67_7·70 (1H，m)，8.23-8.22 (1H， m) 〇 MS (ESI) m/z: 397 (M+H)、 [試驗例1 ]抑制血小板凝集作用使用1/10容積之3.8%檸檬酸納作為抗血凝劑，採集人體血液，以1 80 g離心1 〇分鐘，分離富血小板血漿（pRp， platelet rich plasma)。分離取出上層之PRP後，將下層以 1600 g離心1〇分鐘，分離取出上層之貧血小板血漿（ppp ; platelet-poor Plasma)。向 2〇〇 μ12ΡΙιρ 中添加 1 …之被試驗化a物之/谷液，於3 7 C升溫2分鐘後，添加2 μΐ之膠原，誘導血小板凝集。血小板凝集率使用PAM-12C(MC Medical) 進行測定。將PPP之透光率設為1〇〇%凝集值，求得化合物之各濃度的凝集率，算出1(：5()值。結果示於表1。 126365.doc -51 - 200827349 [試驗例2]環加氧酶· 1 (COX-1)及環加氧酶-2(COX-2)之抑制作用抑制被試驗化合物之COX-1及COX-2活性的測定係使用 Cayman Chemical Company 之 COX抑制劑 Screening Assay Kit(目錄編號 560 101，560121)。測定前，準備反應緩衝液、原血紅素、花生四稀酸、 SnCl2、EIA緩衝液、清洗緩衝液、***素（PG ; prostaglandin)篩查EIA標準液、PG篩查乙醯膽驗酉旨酶 (AchE ; acetylcholine esterase)、示縱劑（呈色酵素 HRP Conjugate)、PG 篩查 EIA抗血清。 (1) 藉由 COX-1 或 COX_2產生 PGF2a 將包含被試驗化合物（50 μΜ)及COX-1或COX-2之反應液於37°C下靜置10分鐘後，添加10 μΐ之花生四烯酸，於37°C 下靜置2分鐘。反應後，添加50 μΐ之IN-鹽酸，停止反應後，添加1 00 μΐ之SnCl2溶液，於室溫靜置5分鐘。 (2) 利用ELISA(酵素免疫分析法，Enzyme-linked 111111111110 33 8 37)所進行之？0卩2〇1之定量向以小鼠抗兔IgG加以塗佈之96孔（well)培養孤的各孔中添加50 μΐ之抗血清（兔抗PGF2a抗體）後，順次添加50 μΐ之將上述PGF2a產生反應液稀釋2000倍之溶液、50 μΐ之AchE 示蹤劑，於室溫下靜置1 8小時。以清洗緩衝液將各孔清洗 5次，去除過剩之AchE示縱劑後，添加200 μΐ愛耳門 (Ellman)試劑。於暗室靜置60分鐘後，以405 nm測定吸光度。 126365.doc -52- 200827349 (3)被試驗化合物之抑制活性之計算使用PG篩查EIA標準液製作標準曲線，根據上述吸光度求得PGF2a之產生量。算出被試驗化合物各濃度之COX-1 或C.OX-2之抑制率，求得IC5G。結果示於表1。再者，抑制率之計算中，將使用不含被試驗化合物之反應液而獲得之PGF2a之產生量作為100%。 [表1] [結果1]Using the same method as in Example 7, m_(6-methoxypyridin-3-yl)-5-(1-methyl-1H-1,2,3-triazol-4-yl)_1H- from Reference Example 2 Pyrazole-3-carboxylic acid (120 mg) and 1,3-dimethylpyrazine hydrochloride (149 mg) of Reference Example 8 gave the title compound (11 5 mg, 1H-NMR (400 MHZ, CDCl3) 8: 1.42 (3H, d, J = 6.3 Hz), 2.01· 2.08 (1H, m), 2·20-2·24 (1H, m), 2.27 (3H, s ), 2.59-2.88 (2H, m), 3·43_3·58 (1H, m), 3.98 (3H, s), 4·09 (3H, s), 4.53-4.58 (1H, m), 4.90 (1H ,brs),6·80·6·83 (1H,m),7.07 (1H,s),7·32 (1H,s),7_67_7·70 (1H,m),8.23-8.22 (1H, m) 〇MS (ESI) m/z: 397 (M+H), [Test Example 1] Inhibition of platelet aggregation Using a 1/10 volume of 3.8% sodium citrate as an anticoagulant, human blood was collected at 1 80 g. Platelet-rich plasma (pRp, platelet rich plasma) was separated by centrifugation for 1 minute. After the upper layer of PRP was separated and removed, the lower layer was centrifuged at 1600 g for 1 minute, and the upper platelet-poor plasma (ppp; platelet-poor plasma) was separated and taken out. To the 2 〇〇 μ12 ΡΙιρ, 1 / of the test a substance / gluten solution was added, and after heating at 37 C for 2 minutes, 2 μ of collagen was added to induce platelet aggregation. Platelet aggregation rate was measured using PAM-12C (MC Medical). The light transmittance of PPP was set to 1 〇〇% agglutination value, and the aggregation rate of each concentration of the compound was determined, and a value of 1 (:5 () was calculated. The results are shown in Table 1. 126365.doc -51 - 200827349 [Test Example 2] Inhibition of cyclooxygenase 1 (COX-1) and cyclooxygenase-2 (COX-2) The inhibition of COX-1 and COX-2 activity of the test compound was carried out using COX of Cayman Chemical Company. Inhibitor Screening Assay Kit (Catalog No. 560 101, 560121). Prepare reaction buffer, protohemoglobin, arachidonic acid, SnCl2, EIA buffer, wash buffer, prostaglandin (PG; prostaglandin) before assay. EIA standard solution, PG screening for AchE acetylcholine esterase, Illustrator (HRP Conjugate), PG screening EIA antiserum. (1) Produced by COX-1 or COX_2 PGF2a After the reaction mixture containing the test compound (50 μM) and COX-1 or COX-2 was allowed to stand at 37 ° C for 10 minutes, 10 μM of arachidonic acid was added and allowed to stand at 37 ° C for 2 minutes. After the reaction, add 50 μM of IN-hydrochloric acid, stop the reaction, add 100 μM of SnCl 2 solution, and let stand at room temperature for 5 minutes. (2) Quantification of 0卩2〇1 by ELISA (Enzyme-linked 111111111110 33 8 37) to 96-well cultured mouse anti-rabbit IgG After adding 50 μM antiserum (rabbit anti-PGF2a antibody) to each well, 50 μM of the above solution of the PGF2a production reaction solution was diluted 2000 times, 50 μM of AchE tracer was added, and the mixture was allowed to stand at room temperature for 1 8 . Hour. Wash the wells 5 times with wash buffer, remove excess AchE extender, add 200 μl Ellman reagent, and let stand for 60 minutes in the dark room, then measure the absorbance at 405 nm. 126365.doc - 52- 200827349 (3) Calculation of inhibitory activity of test compound A standard curve was prepared using PG screening EIA standard solution, and the amount of PGF2a produced was determined based on the above absorbance. COX-1 or C.OX- of each concentration of the test compound was calculated. The inhibition rate of 2 was found to be IC5G. The results are shown in Table 1. In addition, in the calculation of the inhibition rate, the amount of PGF2a produced by using the reaction solution containing no test compound was used as 100%. [Table 1] [ Result 1]

被試驗物質膠原刺激血小板凝集抑制 Ι〇50(μΜ) COX_l抑制活性 IC50_ COX-2抑制活性 Ι<35〇(μΜ) 實施例1 0.21 >300 >300 實施例2 0.19 >300 >300 參考例4* 0.21 >50 NT * : WO 2006/014005之申請專利範圍所包含之化合物（D) NT :不測試 [試驗例3]雄性大白鼠經口單次投與毒性試驗分別將被試驗物質（實施例1、2、及參考例4)以200 mg/kg向雄性大白鼠經口投與，第二日宰殺，調查毒性。向對照群同樣投與0.5% methylcellulose(甲基纖維素）(20 ml/kg) 〇 <方法> (1)大白鼠使用雄性大白鼠（Crl : CD(SD)，6週齡，日本CHARLES RICER股份有限公司）進行試驗。動物之餌食及水之攝取自 126365.doc -53 - 200827349 由，但自投與前一日傍晚至投與約2小時後實施禁食。動物於投與前一日，藉由以體重為基準之分層隨機分配而以群間平均體重近似之方式，劃分為每群5隻[安全性試驗電腦系統（富士通）]。 (2) 使用之試劑 1) 0.5% w/v Methyl Cellulose 400cP Solution， Sterilized(0.5%MC、和光純藥股份有限公司） η) 1 0%中性緩衝福爾馬林液（和光純藥股份有限公司） (3) 試驗設計向大白鼠經口單次投與被試驗物質，於第二日宰殺，調查毒性。 (4) 薬液之製備薬液為用時製備。以達到1〇 mg/ml之濃度之方式，使被试驗物質（實施例i、2、及參考例4)懸濁於〇·5% mc中。 (5) 對照群向對照群經口投與（20 ml/kg)0.5% MC。 (6) 投與方法 1)投與路徑：經口 ii)頻率：單次 iU)投與液量：20 ml/kg i v)用於投鱼之哭藍· 又”之為具·大白鼠用一次性胃管（Fuchigami器械店）及一次性人從左射裔（泰爾茂） )向對照群投與溶劑：以同樣之方法投與（2〇 ml/kg)(K5% 。 126365.doc -54· 200827349Platelet aggregation inhibition by test substance collagen Ι〇50 (μΜ) COX_1 inhibitory activity IC50_COX-2 inhibitory activity Ι<35〇(μΜ) Example 1 0.21 >300 > 300 Example 2 0.19 > 300 > 300 Reference Example 4* 0.21 > 50 NT * : Compound (D) included in the patent application scope of WO 2006/014005 NT: Not tested [Test Example 3] Male rats were tested by oral single-dose toxicity test The substances (Examples 1, 2, and 4) were orally administered to male rats at 200 mg/kg, and slaughtered on the second day to investigate toxicity. The control group was also administered with 0.5% methylcellulose (methylcellulose) (20 ml/kg) 〇<Method> (1) Rats were used with male rats (Crl: CD (SD), 6 weeks old, Japanese CHARLES RICER Co., Ltd.) conducted the test. Feeding of animals and water intake from 126365.doc -53 - 200827349 by, but self-injection from the previous day evening to about 2 hours after the implementation of fasting. The animal was divided into five groups per group [safety test computer system (Fujitsu)] by the stratified random distribution based on body weight and approximated by the average weight between groups on the day before the administration. (2) Reagents used 1) 0.5% w/v Methyl Cellulose 400cP Solution, Sterilized (0.5% MC, Wako Pure Chemical Co., Ltd.) η) 10% neutral buffered formalin solution (Wako Pure Chemical Co., Ltd.) (3) The test design was applied to the rats in a single dose to the test substance, and slaughtered on the second day to investigate the toxicity. (4) Preparation of mash The mash is prepared for use. The test substances (Examples i, 2, and Reference Example 4) were suspended in 〇·5% mc at a concentration of 1 〇 mg/ml. (5) Control group The control group was orally administered (20 ml/kg) of 0.5% MC. (6) Method of administration 1) Route of administration: Oral ii) Frequency: Single iU) Dosing amount: 20 ml/kg iv) For crying blue for fish, and for use with rats The disposable gastric tube (Fuchigami equipment store) and the disposable person from the left-handed (Termao) to the control group were given the solvent: in the same way (2〇ml/kg) (K5%. 126365.doc -54· 200827349

Vi)禁食處理：自投與前一日傍晚至投與約2小時後，使所有動物禁食。 (7)檢查 i) 症狀觀察··觀察自投與後至宰殺時有無死亡及腎毒性。 ii) 體重·於投與鈾與宰殺時，使用天平（Lp_42〇〇、 Sartorius)測定體重。 ni)剖檢：切斷頸動脈使動物放血致死後，以肉眼觀察胸腹腔内之主要内臟器官。 W)病理組織學性檢查··採集肝、脾、腎、心、肺及消化管，以10%中性緩衝福爾馬林液固定後，於病態組織學方面觀察HE(Hematoxylin and eosin;蘇木紫_伊紅）染色標本0 <結果> Ο症狀觀察：被試驗物質（實施例丨、2、及參考例4)投與群中並未發現死亡及毒性症狀。 ⑴體重··被試驗物質（實施例！、2、及參考例4)投與群中並未發現變化。 in)剖檢：被試驗物質（實施例！、2、及參考例4)投與群中’並未發現與投藥相關之變化。 iv)病理組織學性檢查： 126365.doc -55- 200827349 [表2] 被試驗物質月臟之組織學性檢杳其他内臟器官之組織學性檢杳實施例1 無與投藥相關之變化無與投藥相關之變化實施例2 無與投藥~ 無與投藥相關之變化參考例4 Γ腎髓質内帶集合肝上皮之變性、以及細胞質内之玻璃小滴沈積(I/5例）無與投藥相關之變化根據表2結果瞭解到，本發明化合物較之具有1，2,4_三峻環之WO 2006/014005所記載之化合物，腎毒性更弱，安全性更高。 [試驗例4]實施例2之雄性大白鼠經口單次投與毒性試驗（高用量）將被試驗物質（實施例2)以500、1〇〇〇及2000 mg/kg向雄大白鼠經口投與，於第二日宰殺，調查毒性。向對照群同樣投與 0.5% methylcellulose(20 ml/kg)。 <方法> (1) 大白鼠使用雄性大白鼠（Crl : CD(SD)，6週齡，日本CHARLES RICER股份有限公司）進行試驗。動物之餌食及水之攝取自由，但自投與前一日傍晚至投與約2小時後，實施禁食。動物於投與前一日，藉由以體重為基準之分層隨機分配而以群間平均體重近似之方式，劃分為每群5隻[安全性試驗電腦系統（富士通）]。 (2) 使用之試劑 126365.doc -56- 200827349 i) 0.5% w/v Methyl Cellulose 400cP Solution ^ Stenhzed(〇.5% MC、和光純藥股份有限公司） π) 1 0%中性緩衝福爾馬林液（和光純藥股份有限公司） (3) 试驗設計向大白鼠經口單次投與被試驗物質，於第二日宰殺，調查毒性。 (4) 薬液之製備薬液為用時製備。以達到25、5〇及1〇〇 mg/ml2濃度之方式’使被試驗物質（實施例2)懸濁於〇·5% MC中。 (5) 對照群向對照群經口投與（20 ml/kg)〇.5% MC。 (6) 投與方法 i) 投與路徑：經口 ii) 頻率：單次Vi) Fasting: All animals were fasted from the previous day's evening to about 2 hours after the cast. (7) Examination i) Symptom observation·· Observe whether there is death or nephrotoxicity from the time of administration to slaughter. Ii) Weight • When applying uranium and slaughter, use a balance (Lp_42〇〇, Sartorius) to measure body weight. Ni) necropsy: After cutting off the carotid artery and letting the animal bleed to death, the main internal organs in the chest and abdomen were observed with the naked eye. W) Histopathological examination. · Collect liver, spleen, kidney, heart, lung and digestive tract. After fixation with 10% neutral buffered formalin, observe HE (Hematoxylin and eosin; Su in pathological histology) Wood Violet_Eosin) stained specimen 0 <Results> Symptom observation: No death and toxicity symptoms were observed in the test substance (Examples 丨, 2, and Reference Example 4). (1) Weight/· The test substance (Examples!, 2, and Reference Example 4) was not found in the administration group. In) necropsy: The test substance (Examples!, 2, and Reference Example 4) was administered to the group. No changes related to drug administration were found. Iv) Histopathological examination: 126365.doc -55- 200827349 [Table 2] Histological examination of the test substance and histological examination of other internal organs Example 1 No change related to administration Changes related to administration Example 2 No administration and no change related to administration Reference Example 4 Degeneration of the hepatic epithelium in the medullary medulla and the deposition of glass droplets in the cytoplasm (I/5 cases) Correlation changes According to the results of Table 2, it is understood that the compound of the present invention has less nephrotoxicity and higher safety than the compound described in WO 2006/014005 having 1,2,4_tricycle. [Test Example 4] Oral single-dose toxicity test of male rats of Example 2 (high dosage) The test substance (Example 2) was administered to male rats at 500, 1 〇〇〇 and 2000 mg/kg. Investigated and slaughtered on the second day to investigate the toxicity. 0.5% methylcellulose (20 ml/kg) was administered to the control group. <Method> (1) Rats Male rats (Crl: CD (SD), 6 weeks old, Japan CHARLES RICER Co., Ltd.) were used for the test. The animal's bait and water intake are free, but the fasting is carried out from the evening of the previous day to about 2 hours after the administration. On the day before the administration, the animals were divided into 5 groups per group [safety test computer system (Fujitsu)] by stratified random distribution based on body weight and approximated by the average weight between groups. (2) Reagents used 126365.doc -56- 200827349 i) 0.5% w/v Methyl Cellulose 400cP Solution ^ Stenhzed (〇.5% MC, Wako Pure Chemical Co., Ltd.) π) 1 0% Neutral Buffer Ma Linye (Wako Pure Chemical Co., Ltd.) (3) The test design was applied to the rats in a single dose to the test substance, and slaughtered on the second day to investigate the toxicity. (4) Preparation of mash The mash is prepared for use. The test substance (Example 2) was suspended in 〇·5% MC in such a manner as to reach concentrations of 25, 5 Torr and 1 〇〇 mg/ml2. (5) Control group The control group was orally administered (20 ml/kg) 〇.5% MC. (6) Method of administration i) Investment path: oral ii) Frequency: single time

Hi)投與液量：20 ml/kg iv)用於投與之器具：大白鼠用一次性胃管器械店）及一次性注射器（泰爾茂） V)向對照群投與溶劑：以同樣之方法投與（2〇 ml/kg)〇.5% MC。 vi)禁食處理：自投與前一日傍晚至投與約2小時後，使所有動物禁食。 (7) 檢查 i)症狀觀察：觀察自投與後至宰殺時有無死亡及腎毒性。 126365.doc -57- 200827349 ii) 體重：於投與前與宰殺時，使用天平（LP-4200、 Sartorius)測定體重。 iii) 剖檢：切斷頸動脈使動物放血致死後，以肉眼觀察胸腹腔内之主要内臟器官。 iv) 病理組織學性檢查：採集肝、脾、腎、心、肺及消化管，以1 0%中性緩衝福爾馬林液固定後，於病態組織學方面觀察HE(Hematoxylin and eosin ;蘇木紫-伊紅）染色標本。再者，消化管（盲腸）除外之組織中，於2〇〇〇 mg/kg2 群中並未發現投藥所引起之變化，故而並未對5〇〇及1〇〇〇 mg/kg之群實施檢查。消化管（盲腸）於1〇〇〇 mg/kg之群中並未發現投藥所引起之變化，故而並未對5〇〇 mg/kg之群實施檢查。 <結果> 1)症狀觀察：被試驗物質（實施例2)投與群中並未發現死亡。500 mg/kg之群之i例中，除了觀察到暫時之流涎以外’並未發現毒性症狀。 ϋ)體重：被試驗物質（實施例2)投與群巾並未發現㈣化。 X吏Hi) dosage: 20 ml/kg iv) instruments for administration: disposable gastric tube equipment for rats) and disposable syringes (Termao) V) solvent to control group: same The method was administered (2〇ml/kg) 〇.5% MC. Vi) Fasting treatment: All animals were fasted from the previous day's evening to about 2 hours after the administration. (7) Examination i) Observation of symptoms: Observe whether there is death or nephrotoxicity from the time of administration to the time of slaughter. 126365.doc -57- 200827349 ii) Weight: The weight was measured using a balance (LP-4200, Sartorius) before and during the slaughter. Iii) Anatomy: After cutting off the carotid artery and letting the animal bleed to death, the main internal organs in the chest and abdomen were observed with the naked eye. Iv) Histopathological examination: liver, spleen, kidney, heart, lung and digestive tract were collected and fixed in 10% neutral buffered formalin solution. HE (Hematoxylin and eosin; Su was observed in pathological histology) Wood Violet - Eosin) stained specimens. Furthermore, in the tissues other than the digestive tract (caecal), no changes were observed in the 2〇〇〇mg/kg2 group, so the group of 5〇〇 and 1〇〇〇mg/kg was not implemented. an examination. The digestive tract (caecal) was not found in the group of 1 〇〇〇 mg/kg, and the group of 5 〇〇 mg/kg was not examined. <Results> 1) Symptom observation: No death was observed in the test substance (Example 2). In the case of i in the 500 mg/kg group, no signs of toxicity were observed except for the temporary hooliganism observed. ϋ) Weight: The test substance (Example 2) was not found (4). X吏

Hi)剖檢：被試驗物質（實施例2)投與群中，並投藥相關之變化。 X見與 iv)病理組織學性檢查： 126365.doc -58- 200827349Hi) necropsy: The test substance (Example 2) was administered to the group and the drug-related changes were made. X see and iv) histopathological examination: 126365.doc -58- 200827349

[表3] 被試驗物質(實施例 2)之投與量(mg/kg) 腎臟之組織學性檢查其他内臟器官之組織學性檢查 1000 未實施無與投藥相關之變化(僅對盲腸實施） 2000 無與投藥相關之變化盲腸之糜爛及細胞浸潤 (2/5 例） 126365.doc -59-[Table 3] Administration amount of the test substance (Example 2) (mg/kg) Histological examination of the kidneys Histological examination of other internal organs 1000 No drug-related changes were performed (only for the cecum) 2000 No change in cecal erosion and cell infiltration associated with drug administration (2/5 cases) 126365.doc -59-

Claims

200827349 十、申請專利範圍： 1. -種化合物、其鹽或彼等之溶劑合物，該化合物係以通式（I)表示，200827349 X. Patent application scope: 1. A compound, a salt thereof or a solvate thereof, which is represented by the general formula (I).

X 式中’ R2表示自氫原子、有時亦經取代之低碳數烧基、低碳數炔基、有時亦經取代之胺甲醯基、氰基、有時亦經取代之胺基、有時亦經取代之低碳數烧氧基及低碳數烧醯基中選擇之基團或原子；式中χ表示以通式⑻ 表不之基，In the formula, R 2 represents a low carbon number alkyl group, a low carbon number alkynyl group, a sometimes substituted aminomethyl group, a cyano group, and sometimes an amine group, which are also substituted with a hydrogen atom. a group or atom selected from the group consisting of a low carbon number alkoxy group and a low carbon number ruthenium group; wherein χ represents a group represented by the formula (8),

(II) 式:之環狀結構表示除式中所記載之氮原子以外有時产、，：二原子或氧原子作為構成原子之4〜7員之脂環式雜 :表不㈣狀結構亦可由選自下述之卜2個基團或 '、、子所取代m經取代之低碳數縣、有時亦經取代之知·甲酿基、有時亦經取获之脸其 T7J、，工取代之胺基、羥基、低碳數烷 :“基、低碳數烷醯基、低碳數烷基磺素原子。土入 126365.doc 200827349 2·如請求項1之化合物、其鹽或彼等之溶劑合物，其中R2 係有時亦經取代之低碳數烷基。 3 ·如請求項1之化合物、其鹽或彼等之溶劑合物，其中R2 為曱基。 4 ·如明求項1之化合物、其鹽或彼等之溶劑合物，其中X係亦T由選自下述之1〜2個基團或原子所取代之派嗓基、旅咬基、噚唑啶基、氧氮雜環庚烷基、吡咯啶基或嗎啉基：有時亦經取代之低碳數烷基、有時亦經取代之胺甲醯基、有時亦經取代之胺基、羥基、低碳數烷氧基、側氧基、低碳數烷醯基、低碳數烷基磺醯基及_素原子。 5·如清求項1之化合物、其鹽或彼等之溶劑合物，其中又為哌嗪基、哌啶基、噚唑啶基、嗎啉基、氧氮雜環庚烷基、吡咯啶基、4-甲基-哌嗪基、4_環丙基_哌嗪基、2仁甲基-派嗪基、4-甲氧基-派咬基、胺甲酿基旅咬基’、 4,4_二甲基嘮唑啶基或2-氟甲基吼咯啶基。 6·如請求項1之化合物、其鹽或彼等之溶劑合物，其中… 為甲基；Xt号钱基、嗎琳基、氧氮雜環庚&基4 咯咬基、4_甲基-哌嗪基、4_環丙基_哌嗪基、甲基-哌嗪基、4-曱氧基-哌啶基、2-胺甲醯基哌啶芙、4 4 一甲基噚唑啶基或2-氟甲基吡咯啶基。 ’ 7. 一種化合物、其鹽或彼等之溶劑合物，其係以下述式 (la)〜（Ik) 126365.doc 200827349(II) Formula: The cyclic structure indicates that it is produced in addition to the nitrogen atom described in the formula, and: a diatomic or oxygen atom is used as an alicyclic impurity of 4 to 7 members constituting an atom: It may be a low carbon number county selected from two groups selected from the following, or a substituting m, a sub-substituted m, and sometimes a substituted t-J, and sometimes a T7J, Amine, a hydroxy group, a lower alkane: a "lower alkyl alkane group, a lower alkyl sulfonate atom. Into 126365.doc 200827349 2. A compound of claim 1, a salt thereof Or a solvate thereof, wherein R2 is a lower alkyl group which is sometimes substituted. 3. The compound of claim 1, a salt thereof or a solvate thereof, wherein R2 is a fluorenyl group. The compound of claim 1, a salt thereof or a solvate thereof, wherein the X system is also a T group substituted by a group of 1 to 2 groups or atoms selected from the group consisting of a thiol group, a tether base, and a carbazole. Pyridyl, oxazepine, pyrrolidinyl or morpholinyl: sometimes substituted, lower alkyl, sometimes substituted, formazan, sometimes also taken An amine group, a hydroxyl group, a lower alkoxy group, a pendant oxy group, a lower alkyl alkano group, a lower alkyl alkyl sulfonyl group, and a _ atom. 5. The compound of claim 1, a salt thereof or The solvates thereof, which are again piperazinyl, piperidinyl, oxazolidinyl, morpholinyl, oxazepanyl, pyrrolidinyl, 4-methyl-piperazinyl, 4_ Cyclopropyl-piperazinyl, 2-merylmethyl-pyrazinyl, 4-methoxy-trans- butyl, amine-branched butyl base, 4,4-dimethyloxazolidinyl or 2- A fluoromethyl-pyridinyl group. The compound of claim 1, a salt thereof or a solvate thereof, wherein... is a methyl group; Xt-hydroxyl, morphinyl, oxazepine & 4 octyl, 4-methyl-piperazinyl, 4-cyclopropyl-piperazinyl, methyl-piperazinyl, 4-decyloxy-piperidinyl, 2-amine-mercaptopiperidyl 4 4 -Methyloxazolidinyl or 2-fluoromethylpyrrolidinyl. ' 7. A compound, a salt thereof or a solvate thereof, which is represented by the following formula (la)~(Ik) 126365. Doc 200827349

(Id) (le) (If)(Id) (le) (If)

中之任一式表示之化合物、其鹽或彼等之溶劑合物。 8. 一種化合物、其鹽或彼等之溶劑合物，其係以下述式 (lb)A compound represented by any of the formulae, a salt thereof or a solvate thereof. A compound, a salt thereof or a solvate thereof, which is represented by the following formula (lb)

(lb) 表示之化合物、其鹽或彼等之溶劑合物。 9. 一種化合物、其鹽或彼等之溶劑合物，其係4-{[1_(6-曱氧基吡啶-3-基）-5-(1-甲基-1H-1，2,3-***-4-基）-1Η-吡唑-3-基]羰基}嗎啉。 10. —種醫藥，其含有如請求項1至9中任一項之化合物、其 126365.doc 200827349 鹽或彼等之溶劑合物。 11(lb) A compound, a salt thereof or a solvate thereof. A compound, a salt thereof or a solvate thereof, which is 4-{[1_(6-decyloxypyridin-3-yl)-5-(1-methyl-1H-1,2,3 -Triazol-4-yl)-1 Η-pyrazol-3-yl]carbonyl}morpholine. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, a 126365.doc 200827349 salt or a solvate thereof. 11

缺血性疾病之預防及/或治療劑，其將如請求 -項之化合物、其鹽或彼等之溶劑合物作為項1至9 有效成 12. 一種抑制血小板凝集藥化合物、其鹽或彼等之 ’其將如請求項…中任溶劑合物作為有效成分。一項之 126365.doc 200827349 七、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：八、本案若有化學式時，請揭示最能顯示發明特徵的化學式：A prophylactic and/or therapeutic agent for ischemic diseases which is effective as a compound of claim 1 , a salt thereof or a solvate thereof as item 1 to 9. 12. A compound for inhibiting platelet aggregation, a salt thereof or the like Etc. 'It will be as a solvate as the active ingredient in the request. 126365.doc 200827349 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please reveal the best display. Chemical formula of the inventive feature:

MeO ^ 126365.docMeO ^ 126365.doc