TW200804294A

TW200804294A - A pyrazole compound

Info

Publication number: TW200804294A
Application number: TW95138705A
Authority: TW
Inventors: Yasunori Moritani; Ritsuo Imashiro; Atsushi Sato
Original assignee: Tanabe Seiyaku Co
Priority date: 2005-10-21
Filing date: 2006-10-20
Publication date: 2008-01-16
Also published as: TWI378922B

Abstract

The present invention relates to a pyrazole compound having potent CB1-antagonizing activity, having the following formula [I]: wherein R1and R2 are the same or different and an optionally substituted aryl group etc., R3 is an alkyl group etc., E is one of the following groups of the formula (i) to (iv): Q1 is a single bond, an alkylene group or a group of the formula: -N(R7)-, R7 is a hydrogen atom or an alkyl group, Q2 is a single bond, an oxygen atom or an alkylene group, R4 is a cycloalky1 group, a group of the formula: -N(R5)(R6) etc., one of R5 and R6 is a hydrogen atom or an alky1 group and the other is an alkyl group, a group of the formula: -N(R8)(R9) etc., D is an oxygen atom etc., RA1 is an amino group etc., RA2 is an optionally substituted aliphatic heterocyclic group, R is an alkyl group optionally substituted by one to three halogen atom(s) etc., one of R8 and R9 is a hydrogen atom or an alkyl group and the other is an alkyl group etc., or a pharmaceutically acceptable salt thereof.

Description

200804294 九、發明說明：【發明所屬之技術領域】本發明係關於新穎吼唑化合物或其醫藥上可接受之鹽類，4化合物具有強力之中枢大麻鹼受體（CB1)拮抗活性，因此可作為醫藥用途。【先前技術】士眾所悉知吸食大麻會產生各種精神或神經反應，諸如 %，感或空間感迷失、陶醉感、記憶改變、痛覺喪失、幻覺等。通常稱為「大麻驗」之化合物包括△ 9 —四氫大麻酚（△ 9-MC)與許多此等反應有關連。一般認為大麻鹼作用係由於忒化合物與其内生專一性/高親力受體間之交互作用所造成。已經辨識與複製大麻鹼受體的兩種亞型（CB1與 CB2)。CB1受體分佈於包括腦之中樞神經系統（CNs)區域中 &見非專利文獻1 )，而CB2受體則分佈於包括脾臟之免疫系統中（見非專利文獻2)。、對此等大麻鹼受體具有親和力之物質（促效劑、拮抗劑或逆促效劑）可產生類似大麻之各種藥理作用。尤其是，對中樞CB1受體具有親和力之物質可用於治療中植神經系統疾病，諸如精神疾病、神經疾病等。已知有各種化合物為對此等大麻鹼受體具有親和力之物質，包括吡唑-3-曱醯胺化合物如SR141716(見非專利文獻3)、4,5-二氫吡唑化合物如SLV—319(見非專利文獻4)、二氫吡唑并[3, 4-c]吼啶-7-酮化合物、2H—吡唑并[4, 3一d] 嘧啶-7(6H)-酮（見專利文獻1)等。其中，至少SR14m6 318695 6 200804294 與SLV-319已進行作為食慾抑制劑（an〇rexigenics)G^& 胖劑）效果之臨床研究。 -專利文獻 1 : W02004/094417 -非專利文獻 1 ·· Nature，第 346 卷，561-564 頁（1 990 年）非專利文獻2 : Nature，第365卷，61-65頁（1993年）非專利文獻 3: Life Science，第 63 卷，PL113-PL117( 1998 年）非專利文獻 4 · Journal of Medicinal Chemistry，第 47 卷，3 期，627-643 頁（2004 年）【發明内容】本發明之目的在提供具有強力CB1受體拮抗活性之新穎吼唑化合物，因而可作為醫藥之用途。本發明係關於式[I ]之吡唑化合物或其醫藥上可接受之鹽類：200804294 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD The present invention relates to a novel carbazole compound or a pharmaceutically acceptable salt thereof, and the compound 4 has a strong central cannabinoid receptor (CB1) antagonistic activity, and thus can be used as Medical use. [Prior Art] It is known to the public that smoking marijuana can produce various mental or neurological reactions such as %, feeling or spatial distraction, intoxication, memory change, pain loss, illusion, and the like. Compounds commonly referred to as "cannabis test" include △ 9 - tetrahydrocannabinol (Δ 9-MC) associated with many of these reactions. It is generally believed that the action of cannabinoids is caused by the interaction between the guanidine compound and its endogenous/high affinity receptor. Two subtypes of the cannabinoid receptor (CB1 and CB2) have been identified and replicated. The CB1 receptor is distributed in the region including the central nervous system (CNs) of the brain & see Non-Patent Document 1), and the CB2 receptor is distributed in the immune system including the spleen (see Non-Patent Document 2). Substances with affinity for these cannabinoid receptors (agonists, antagonists or inverse agonists) can produce various pharmacological effects similar to cannabis. In particular, substances having affinity for the central CB1 receptor can be used for the treatment of diseases of the planting nervous system such as mental diseases, neurological diseases and the like. Various compounds are known which have affinity for such cannabinoid receptors, including pyrazole-3-guanamine compounds such as SR141716 (see Non-Patent Document 3), 4,5-dihydropyrazole compounds such as SLV- 319 (see Non-Patent Document 4), dihydropyrazolo[3,4-c]acridin-7-one compound, 2H-pyrazolo[4,3-d]pyrimidin-7(6H)-one ( See Patent Document 1) and the like. Among them, at least SR14m6 318695 6 200804294 and SLV-319 have been clinically studied as an appetite suppressant (an 〇rexigenics) G^& fat agent. - Patent Document 1: W02004/094417 - Non-Patent Document 1 · Nature, Vol. 346, pp. 561-564 (1 990) Non-Patent Document 2: Nature, Vol. 365, pp. 61-65 (1993) Patent Document 3: Life Science, Vol. 63, PL113-PL117 (1998) Non-Patent Document 4 · Journal of Medicinal Chemistry, Vol. 47, No. 3, pp. 627-643 (2004) [Invention] The object is to provide a novel carbazole compound having potent CB1 receptor antagonistic activity, and thus can be used as a medicine. The present invention relates to a pyrazole compound of the formula [I] or a pharmaceutically acceptable salt thereof:

[I] 式中， R與R2相同或不同，為視需要經取代之芳基或視需要經取代之雜芳基； R、為（a)氫原子，（b)視需要經一至三個選自下列之基團取代$院基：_素原子、氰基、烷基氧基、烷基氧基羰基、視=要經—至二個烷基取代之胺基、醯胺基、烷基胺甲醯基胺基、烷磺醯基胺基、二（烷基）胺磺醯基胺基、視需要 318695 7 200804294 經一至二個烷基取代之胺甲醯基'烷基氧基羰基、烷基硫基、烷亞磺醯基、烷磺醯基與視需要經取代之飽和或不飽和雜環基，（C)視需要經一至二個烷基取代之胺磺醯基，^ (d)視需要經取代之飽和或不飽和雜環基，或（幻F與。相結合，並與R1，鄰接之氧原子和吡唑環一起形成下式之環In the formula, R and R2 are the same or different, and are optionally substituted aryl or optionally substituted heteroaryl; R, (a) hydrogen atom, (b) one to three as needed Substituting the following from the group: _ atom, cyano, alkyloxy, alkyloxycarbonyl, amide = to two alkyl substituted amine, guanamine, alkylamine Mercaptoamine, alkanesulfonylamino, di(alkyl)amine sulfonylamino, 318695 7 200804294 Aminocarbonyl substituted by one to two alkyl groups, alkyloxycarbonyl, alkane a thiol group, an alkylsulfinyl group, an alkanesulfonyl group and optionally a saturated or unsaturated heterocyclic group, (C) an amine sulfonyl group substituted by one to two alkyl groups as required, ^ (d) a substituted saturated or unsaturated heterocyclic group, or a combination of R1, an adjacent oxygen atom and a pyrazole ring, may form a ring of the following formula.

環A為視需要經取代之芳基（或雜芳基），為式 -（CH2)m-〇-、一〇—(CH2)n一〇—或—N(R〇) —(CH2)n—〇一之基團，r〇為氫原子或烷基，m為1至3之整數，11為2至3之整數· 以及正， E為下列式（i)至式（iv)基團中之一者··Ring A is an optionally substituted aryl (or heteroaryl) group of the formula -(CH2)m-〇-, 〇-(CH2)n-〇- or -N(R〇)-(CH2)n a group of one, wherein r is a hydrogen atom or an alkyl group, m is an integer from 1 to 3, 11 is an integer from 2 to 3, and is positive, and E is a group of the following formula (i) to formula (iv) One of them··

〇^q2~r4, Λν： ι ⑴ ⑻ (iii) Q1為單鍵、伸烷基或式—N(R7) —之基團， R為虱原子或烧基， Q為單鍵、氧原子或伸烧基， R、為環烷基、式-N(R )(R6)之基團、視需要經取代之芳基或視需要經取代之飽和或不飽和雜環基， R5與R6之-者為氫原子或烧基且另—者為（a)視需要經下列基團取代之烧基：i素原子、胺基、烧基硫基、烧亞石黃 318695 8 200804294 醯基、烷磺醯基與視需要經取代之芳基，（b)視需要經取代之環烧基，（c)式-N(R8)(R9)基團，（d)視需要經取代之芳 -基或（e)視需要經取代之飽和或不飽和雜環基， R與R之一者為氫原子或烧基且另一者為（a)視需要經一至二個選自下列之基團取代之烷基··侧氧基、氰基、烷基氧基、醯基與視需要經取代之芳基，（幻環烷基，（c)醯基， (d)視需要經取代之芳基或（e)視需要經取代之飽和或不飽和雜環基， D為氧原子或式基團， RA1為胺基或下式之基團：〇^q2~r4, Λν: ι (1) (8) (iii) Q1 is a single bond, an alkyl group or a group of the formula -N(R7)-, R is a halogen atom or a burnt group, and Q is a single bond, an oxygen atom or Stretching group, R, is a cycloalkyl group, a group of the formula -N(R)(R6), an optionally substituted aryl group or an optionally substituted saturated or unsaturated heterocyclic group, R5 and R6- Those which are hydrogen atoms or alkyl groups and which are (a) substituted by the following groups as needed: i atom, amine group, alkylthio group, pyrophyllite 318695 8 200804294 sulfhydryl, alkane sulfonate a fluorenyl group and an optionally substituted aryl group, (b) a substituted cycloalkyl group, (c) a formula -N(R8)(R9) group, (d) an optionally substituted aryl group or (e) a saturated or unsaturated heterocyclic group which may be substituted as required, one of R and R being a hydrogen atom or a burnt group and the other being (a) optionally substituted by one or two groups selected from the group consisting of Alkyl·sideoxy, cyano, alkyloxy, fluorenyl and optionally substituted aryl, (phantom cycloalkyl, (c) fluorenyl, (d) optionally substituted aryl or (e) a saturated or unsaturated heterocyclic group which is optionally substituted, and D is an oxygen atom or Group, RA1 is a group or a group of the formula:

式中，k為3至5之整數， R為視需要經取代之脂肪族雜環基，視需要經一至三個鹵素原子取代之烷基、烷基氧基烷基幾，、職硫基、視f要經取代之環縣、視需要經取代之芳基或視需要經取代之飽和或不飽和雜環基。【實施方式】卜關於本發明之化合物[I]，在R1(或環A)與R2為芳基之此芳基之實例包括6至則單環或雙環芳基，例如本奈基。其中’較佳之此芳基實例為苯基。，^或環A)與雜芳基之情況，此雜芳基實例包 •貝含氧雜芳基，例如吱喃基或派喃基（阶咖）；貝含硫雜芳基，例如嗟吩基（thienyl)或5至6員含 31S695 9 200804294 氮雜芳基，例如Π比啶基。其中，較佳之此雜芳基實例為噻吩基或吡啶基。環Α為芳基及/或雜芳基時，上述R1與R2可經一至三個選自下列之基團取代：（a)鹵素原子，（b)氰基，（c)視需要經一至三個函素原子取代之烧基，（d)視需要經一至三個鹵素原子取代之烷基氧基及（e)烷磺醯基。 R、R3、R4、R5、R6、R8或R9中芳基之實例，包括6至 10員單環或雙環芳基，例如苯基、萘基等，其中，以苯基為佳。此外，此芳基可經一至三個選自以下之基團取代： (a)鹵素原子，（b)羥基，（c)氰基，（d)側氧基，（e)視需要經一至三個鹵素原子取代之烷基，（f)烷基氧基烷基，（g) 胺基烧基’（h)環烷基，（i)芳基烷基，（j)視需要經一至三個鹵素原子取代之烷基氧基，（k)視需要經一至二個烷基取代之胺基，（1)視需要經一至二個烷基取代之胺甲醯基，（m) 1基’（η)烧基硫基’（0)烧亞石黃酸基，（p)烧石黃醯基，（^) 視需要經一至二個烷基取代之胺磺醯基，（r)芳磺醯基，（s) 芳基，該芳基視需要可經一至三個選自_素原子、氰基、視需要經一至三個鹵素原子取代之烷基、烷基氧基與烷磺醯基之基團取代，以及（〇雜芳基。在R、R、R、R5、R6、R8或R9為飽和或不飽和雜環基之h況，此雜環基實例包括（a)飽和或不飽和4至7員雜單 %基，该雜單環基含有一至四個選自氧原子、硫原子與氮原子之雜原子；（b)飽和或不飽和8至15員含氮雙環或三環雜環基，該雜環基係稠合（fusing)前述該雜單環基與=Wherein k is an integer of from 3 to 5, and R is an optionally substituted aliphatic heterocyclic group, optionally substituted with one to three halogen atoms, an alkyloxyalkyl group, a thiol group, A ring or a substituted or substituted aryl group or a substituted or unsaturated heterocyclic group which is optionally substituted. [Embodiment] With respect to the compound [I] of the present invention, examples of the aryl group in which R1 (or ring A) and R2 are an aryl group include 6 to a monocyclic or bicyclic aryl group such as Bennaki. Among the preferred examples of such aryl groups are phenyl groups. , or ring A) with a heteroaryl group, examples of this heteroaryl group • shellfish oxygen-containing heteroaryl group, such as fluorenyl or pyranyl (step coffee); shell sulfur-containing heteroaryl, such as porphin The thienyl or 5 to 6 member contains 31S695 9 200804294 azaaryl, such as a hydrazinyl group. Among them, preferred examples of the heteroaryl group are a thiophenyl group or a pyridyl group. When the ring is aryl and/or heteroaryl, the above R1 and R2 may be substituted by one to three groups selected from the group consisting of: (a) a halogen atom, (b) a cyano group, and (c) one to three as needed. a calcinin-substituted alkyl group, (d) an alkyloxy group substituted with one to three halogen atoms, and (e) an alkanesulfonyl group. Examples of the aryl group in R, R3, R4, R5, R6, R8 or R9 include 6 to 10 membered monocyclic or bicyclic aryl groups such as phenyl, naphthyl and the like, of which phenyl is preferred. Further, the aryl group may be substituted with one to three groups selected from the group consisting of: (a) a halogen atom, (b) a hydroxyl group, (c) a cyano group, (d) a pendant oxy group, and (e) one to three as needed. a halogen-substituted alkyl group, (f) alkyloxyalkyl group, (g) an amine alkyl group '(h) cycloalkyl group, (i) an arylalkyl group, (j) one to three as needed Alkoxy group substituted by a halogen atom, (k) an amine group substituted by one to two alkyl groups as needed, (1) an amine formazan group substituted by one to two alkyl groups, (m) 1 group '( η) alkylthio '(0) pyrolitic acid group, (p) pyrithion xanthyl group, (^) optionally substituted with one to two alkyl groups, (r) arylsulfonyl group, (s) an aryl group which may optionally have one to three groups selected from the group consisting of a sulfonium atom, a cyano group, an alkyl group substituted with one to three halogen atoms, an alkyloxy group and an alkanesulfonyl group, as needed. Substituted, and (doped aryl). In the case where R, R, R, R5, R6, R8 or R9 is a saturated or unsaturated heterocyclic group, examples of the heterocyclic group include (a) saturated or unsaturated 4 to 7 members of the mono-unit, the heteromonocyclic group contains one to four a hetero atom of an oxygen atom, a sulfur atom and a nitrogen atom; (b) a saturated or unsaturated 8 to 15 member nitrogen-containing bicyclic or tricyclic heterocyclic group, which is fused to the aforementioned heteromonocyclic group and =

318695 10 200804294 或一個遥自C3-8環烧基、5至6員單 A $ 7 Μ ^ ^ ^ ^ 貝早％方基及飽和或不飽和4至7貝雜早裱基之其他環其 ^ , 衣基團而形成，該雜單環基含有1至4個選自氧原子、硫原平衣土 s .w ，,L屬子與虱原子之雜原子；以及 (C)飽和或不飽和之8至u M含氮螺雜環 heterocyclic)基。 R、R3、R4、R5、R6、r8 戋 R9 中 κ ; κ τ飽和或不飽和雜環基之實例有： (A) 飽和或不飽和之選自下列基團之含氧或含硫雜環基：呋喃基、四氫呋喃基、哌喃基、四氫哌喃基、噻吩基、四氫噻吩基、硫代哌喃基、四氫硫代哌喃基、苯并呋喃基、一氫苯并呋喃基、異苯并呋喃基、色滿基（chr〇manyl)、異色滿基、色烯基（chromeny 1)、異色烯基、苯并噻吩基與二氫苯并噻吩基；或 (B) 飽和或不飽和選自下列基團之含氮雜環基··氮σ旦基 (azetidyl)、吡咯啶基（pyrroiidinyi)、吡咯啉基 (pyrrolinyl)、咪唑啶基（imidazolidinyl)、咪唑啉基 (imidazolinyl)、吡唑啶基（pyraz〇ii(iinyl)、吡唑啉基 (pyrazolinyl)、吡咯基（pyrrolyl)、2H-吡咯基、咪唑基 (imidazoly 1)、口比口坐基（pyrazoly 1)、二氳口比口坐基、口塞口坐口定基（thiazolidinyl)、異嗟嗤咬基、異曙嗤基 (isoxazolyl)、曙嗤咬基（oxazolidinyl)、噚二嗤基 (oxadiazolyl)、三嗤基（triazolyl)、吼咬基、二氫σ比口定基、四氫u比唆基、六氫σ比咬基、σ比哄基（pyraz i ny 1)、六氫吼畊基、嘴咬基、四氫°密唆基、塔哄基（？71：丨(1&2丨1^1)、嗎 11 318695 200804294 福啉基（morpholinyl)、氮辛基（azocinyl)、氮雜環庚基、吲哄基（i ndo 1 i z iny 1)、苯并咪唑基、苯并三唑基、叫丨π朵基、異口引11朵基、3Η-,ϋ朵基、1H-叫卜坐基（lH-indazolyl)、四哇基、嘌吟基、嗓咬基（pteridinyl)、4H-嗅哄基 (4H-quinolizinyl)、喹啉基（quinolyl)、二氫喹啉基、四氫喹啉基、異喹啉基、二氫異喹啉基、四氫異啥琳基、二氫呔畊基（dihydrophthalazinyl)、萘啶基 (naphthyridinyl)、喹喏啉基（qUinoxaiinyi)、啥嗤琳基 (quinazolinyl)、二氫喹唑啉基、二氫苯并噻哄基、二氫苯并―哄基（dihydrobenzoxazinyl)、嗜琳基 (cinnol iny 1)、咕噸基（xantheny 1)、咔唑（carbazoly 1)、 yS-^ISC/S-carbolinyD'—^SCphenanthridinyl)、吖啶基（acridinyl)、5H-二氫-二苯并氮呼基 dihydro-dibenzazepinyl)與下式之螺雜環基，318695 10 200804294 or a remote from C3-8 ring-burning base, 5 to 6 members single A $ 7 Μ ^ ^ ^ ^ shell early % square and saturated or unsaturated 4 to 7 shells of other early ring bases ^ Forming a group of 1,5-containing heterocyclic groups containing an oxygen atom, a sulfur-containing plain soil s.w, a hetero atom of a L-gen and a ruthenium atom; and (C) a saturated or unsaturated 8 to u M nitrogen-containing spiro heterocyclic heterocyclic). R, R3, R4, R5, R6, r8 κR9 κ; Examples of κτ saturated or unsaturated heterocyclic groups are: (A) a saturated or unsaturated oxygen-containing or sulfur-containing heterocyclic ring selected from the following groups Base: furyl, tetrahydrofuranyl, piperidyl, tetrahydropyranyl, thienyl, tetrahydrothiophenyl, thiopiperidyl, tetrahydrothiopiperidyl, benzofuranyl, monohydrobenzofuran , isobenzofuranyl, chr〇manyl, heterochroman, chromenyl 1, isoalkenyl, benzothienyl and dihydrobenzothienyl; or (B) saturated Or unsaturated nitrogen-containing heterocyclic group selected from the group consisting of azetidyl, pyrroiidinyi, pyrrolinyl, imidazolidinyl, imidazolinyl ), pyrazirii (iinyl), pyrazolinyl, pyrrolyl, 2H-pyrrolyl, imidazoly 1, pyrazolly 1,氲氲比 thia thia thia thia thia thia thia thia thia thia thia thia thia thia thia thia thia thia thia thia thia thia thia thia thia thia thia thia thia thia thia thia thia thia thia thia thia thia (thiazolidinyl) Lidinyl), oxadiazolyl, triazolyl, bite base, dihydro σ specific base, tetrahydrou thiol, hexahydro σ ratio, σ 哄 base (pyraz i Ny 1), hexahydroquinone cultivating base, mouth biting base, tetrahydro thiol thiol, sulfonyl group (?71: 丨 (1& 2丨1^1), 1111 318695 200804294 morpholinyl, Azocinyl, azacycloheptyl, oxime (i ndo 1 iz iny 1), benzimidazolyl, benzotriazolyl, 丨π-moleyl, heterologous 11-mer, 3Η -, ϋ 基 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , dihydroquinolyl, tetrahydroquinolyl, isoquinolyl, dihydroisoquinolyl, tetrahydroisoindolyl, dihydrophthalazinyl, naphthyridinyl, quinacrid U 基 (qUinoxaiinyi), quinazolinyl, dihydroquinazolinyl, dihydrobenzothiazinyl, dihydrobenzoxazinyl, cinnol iny 1, 咕Tonyl (xantheny 1), carbazole carbazoly 1), yS- ^ ISC / S-carbolinyD '- ^ SCphenanthridinyl), acridinyl (acridinyl), 5H- dihydro - dibenzazepine group call dihydro-dibenzazepinyl) of the spiro-heterocyclic group of the formula,

式中，RA與RB相同或不同且為氳原子或烷基，而卩與厂為 1或2之整數。當中，R、R3、R4、R5、R6、壤基之較佳實例，包括餉釦邊、R6、R8或R9中飽和或不餘和雜硫之雜單環基，例如氮σ旦基、啶基、吡啶基、六氫吡畊基、包括飽和或不飽和5至7員含氮、氧或基、呋喃基、四，例如氮咀基、吡咯基、吡咯啶基、、六氫吡Π井基、嘧π定基、。比哄基、葡四氫哌喃基、四氫硫代哌喃基、嗎福氮。旦基、吡咯基、吡咯啶基、六氫吡吨D井基、U唆基、。比哄基、氮雜環庚、四氫硫代旅喃基、嗎福琳基、 318695 12 200804294 硫代嗎福琳基、嘆吩基、四氫σ塞吩基、噻嗤基、異嘆唑基、口琴唑基、異噚唑基、噚二唑基、四唑基或吼啶基。此外，上述R、R3、R4、R5、R6、R8與R9中飽和或不飽和含氮雜環基可經一至四個選自下列之基團取代：（a)鹵素原子’（b)經基，（c)氰基，（d)側氧基，（e)視需要經一至三個素原子取代之烷基，（f)烷基氧基烷基，（g)胺基烷基，（h)烷亞磺醯基烷基，（i)烷磺醯基烷基，（j)環烷基， (k)芳基烷基，（1)視需要經一至三個鹵素原子取代之烧基氧基，（m)羧基，（n)視需要經一至二個選自烷基與醯基之基團取代之胺基’（0)視需要經一至二個烧基取代之胺甲醯基’（p)fc基，（q)烧基硫基，（r)烧亞;5黃酸基，（s)烧石黃醯基，（Ό視需要經一至二個烷基取代之胺磺醯基，（u)芳磺酸基’（v)芳基，該芳基視需要可經一至三個選自齒素原子、氰基、視需要經一至三個鹵素原子取代之烷基、烷基氧基與烷磺醯基之基團取代，以及（w)雜芳基，該雜芳基視需要可經一至三個選自視需要經一至三個齒素原子取代之烧基、i素原子與氰基之基團取代。 R、R、R4、R5、R6、R8與r9中醯基之實例，包括由式 R-C00H [Ac-Ι]之羧酸化合物移去羥基所構成之基團，換言之即式Rx-C0-之基團，式中，^為彳“氫原子，（b)視需要經一至二個選自齒素原子、氰基與烷磺醯基之基團取代之烷基，（c)視需要經芳基取代之烷基氧基，（们環烷基， (e)視需要經-至二個選自齒素原子、氰基、烧基、三齒素烷基與烷基氧基之基團取代之芳基，（f)視需要經一至二個 318695 13 200804294 烷基取代之胺基，或（g)視需要經一至二個選自鹵素原子、氰基、烷基與三齒素烷基之基團取代之飽和或不飽和雜環 -基。此醯基之具體實例可為（al)曱醯基，（bl)Ci_6烷基一羰 .基，例如乙醯基、丙醯基等；三鹵素一Ch烷基—羰基，例Λ 如一氟乙a&基專，或氰基—Ci-e烧基—幾基，例如氰乙酿基， (cUCh烷基氧基-羰基，例如曱氧羰基、乙氧羰基、三級丁氧羰基等；或芳基-Ch烷基氧基—羰基，例如苯曱氧基罗厌基，（dl)C3-8環烧基—羰基，例如環丙基幾基、環戊基幾基等，（el)芳基-羰基，例如苯甲醯基；單或二_芳基一羰基，例如氯苯曱醯基、氟苯甲醯基、二氟苯甲醯基等；氰基-芳基-羰基，例如氰苯甲醯基；三鹵素—Ci6烷基—芳基一羰基，例如三氟甲基苯甲醯基；或三鹵素一Ci 6烷基氧基— 芳基-羰基，例如三氟曱氧基苯甲醯基，（fl)胺甲醯基、 N-(Ch烷基）胺甲醯基，或（gl)呋喃甲醯基、噻吩甲醯基、溴噻吩甲醯基、氰噻吩甲醯基、σ比啶基羰基、氯吼啶基羰基、氰吡啶基羰基、三氟甲基σ比啶基羰基或吡哄基羰基。本叙明之化合物[I ]當中，較佳之化合物實例包括化合物[I]中，、口 R1與R2相同或不同且為視需要經一至二個選自鹵素原子、氰基、三i素烷基、烷基氧基、烷基硫基、烷亞磺醯基與烷石黃醯基之基團取代之苯基； R3為（a)氫原子，（b)視需要經一至三個選自下列之基團取代之烷基··齒素原子、氰基、烷基氧基、烷基硫基、醯基、胺基、醯胺基、胺甲醯基、烷基胺，醯基胺基、烷 31S695 14 200804294 石黃醯基胺基、二（烧基）胺石黃酸基胺基與餘和或不飽和5至 6員雜環基（該雜環基視需要可經一至二個選自側氧基與烧基之基團取代），⑷視需要經一至二個统基取代之胺續醯基，或⑷飽和或不飽和a 6員雜環基（該雜環基視需要可經-至二個選自側氧基與烷基之基團取代）；以及 E為式（i)之基團中， Q1為單鍵或式-NH-之基團， Q為皁鍵、氧原子或伸烧基， R4為(a)視需要經一至三個選自鹵素原子、氰基與烷碏醯基之基團取代之芳基，（13)環烷基，（c)視需要經一至二個選自下列基團取代之飽和或不飽和5至7員雜單環基：鹵素原子、側氧基、氰基、視需要經一至三個函素原子取代之烷基、視需要經一至二個烷基取代之胺基、胺甲醯基與醯基，（d)式-n(r5)(r6)之基團，或（e)下式之螺雜環基： rb 4>、 R5為氫原子或烧基， R6為（1)視需要經一至三個選自卣素原子、胺基、烷基氧基、烷基硫基、烷亞磺醯基、烷磺醯基與芳基之基團取代之烧基’（2)視需要經胺甲酿基取代之環烧基，（3)式 -N(R8)(R9)之基團，（4)醯基，（5)視需要經一至三個選自鹵素原子、氰基、三鹵素烷基與烷基氧基之基團取代之芳 318695 15 200804294 基’或（6)視需要經一至四個選自下列基團取代之飽和或不乾矛5至7員雜單環基··鹵素原子、側氧基、視需要經一 •至三個鹵素原子取代之烷基、烷基氧基烷基、芳基烷基、 •視需要經-至三㈣素原子取代之絲氧基、㈣、緩土基、胺甲酿基、垸石黃酿基、視需要經一至二個炫基取代之胺福 «、芳石黃酿基、視需要經一至二個選自烧基與酿基之基團取代之胺基、視需要經一至二個齒素原子取代之芳基以及視需要經一至二個選自··視需要經一至三個鹵素原子取代之烷基、齒素原子與氰基之基團取代之雜芳基， R為虱原子，R為烧基，q與r為1之整數， R8為氫原子或烧基，及 R9為視需要經一至二個選自側氧基、氰基與芳基之基團取代之烧基’·醯基；芳基或雜芳基。此外，本發明之化合物[ί]當中，其他較佳化合物之實例包括： ⑴化合物⑴巾’ y相同或不同且為由素苯基；只3為烧基或院基氧基烧基；E為式（ii)之基團，式巾，R為⑷ 視需要經-至三個鹵素原子取代之院基，⑻烧基氧基烷基’（c)視而要經選自羥基與烷基之基團取代之環烷基，（d) 烷基硫基，（e)視需要經一至二個選自鹵素原子與氰基之基團取代之芳基，或（f)視需要經烷磺醯基、醯基或雜芳基取代之飽和或不飽和雜環基； ⑵化合物⑴巾m2相同或不同且為函素苯基；^為烷基或烷基氧基烷基；E為式（iii)之基團，式中，rA1為胺 16 318695 200804294 基或下式之基團：，让為3至4之整數； (3)化合物[I]中，R1與R2相同或不同且為鹵素苯基；y為火元基或烧基氧基烧基；E為式（iv)之基團，式中，rA2為視需要經嘧啶基或鹵素嘧啶基取代之4至7員含氮脂肪族雜環基。 §中’更仏之化合物貫例包括化合物[I ]中， R為經一至二個選自鹵素原子與三鹵素一匕^烷基之基團取代之苯基； R2為經一至二個齒素原子取代之苯基； R為視需要經一至三個鹵素原子取代之Ci-4烷基、Cw 烷基氧基-Ch烷基、氰基—Cl_4烷基氧基、胺基—Ci4烷基（該基團之胺基部份可視需要經選自醯基、二（烷基）胺磺醯基與Cl-4烧基-胺曱醯基之基團取代）、胺甲酸基一Ch烧基、噚唑基-Ch烷基（該基團之噚唑基部份可視需要經一至二個Ch院基取代）、噻唑基—Ci 4烷基；以及 E為式（i)之基團， Q1為單鍵， Q2為單鍵或Ch伸烷基， R4為視需要經一至三個選自侧氧基、胺甲醯基與Ci 4 丈元基胺基之基團取代之飽和或不飽和5至6員雜單環基，或為式-NH(R6)之基團，及 318695 17 200804294 R6為（aWH烷基，（b)視需要經胺曱醯基取代之c5 8 環烷基，（c)視需要經一至二個齒素原子取代之苯基，（d) 、視需要經一至三個選自下列之基團取代之飽和或不飽和5 .至7員雜單環基：鹵素原子、側氧基、視需要經一至三個鹵素原子取代之Cr_4烷基、視需要經一至二個鹵素原子取代之本基、氣本基、Ci-4烧基氧基-苯基、酿基、苯基—a 4 烷基、羧基、視需要經一至二個選自Ch烷基與氰基之基團取代之胺基、胺曱醯基以及視需要經一至二個選自鹵素原子、Ci-4烷基與三鹵素-C!-4烷基之基團取代之吡σ定基，或（e)視需要經一至二個選自Cw烷基與吡啶基之基團取代之胺基。當中，其他更佳之化合物實例包括： (1)化合物[I]中’ R與R2相同或不同且為鹵素苯基，· R為Cl _4烧基、二鹵素-Cl-4烧基或Cl _4烧基氧基一 Cl-4烧基； E為式（ii)之基團，式中，R為（a)視需要經一至三個齒素原子取代之Ch烷基，（b)視需要經選自羥基與Cl_4烷基之基團取代之Cw環烷基，（cOC!-4烷基硫基，（们視需要經— 至二個選自鹵素原子與氰基之基團取代之芳基，或（e)視需要經選自Cw烷磺醯基、醯基與雜芳基之基團取代之飽和或不飽和雜環基； (2)化合物[I]中，R1與R2相同或不同且為鹵素苯基；尺為〇1-4$元基或〇1-4燒基氧基-(]1-4烧基；£為式（；[；[；[)之基團，式中，RA1為胺基或下式之基團·· 318695 18 200804294 • ，k為3至4之整數；或 (33)化。物⑴中’R1R2相同或不同且為鹵素苯基； R為Ch烧基aCh烧基氧基一Ci 4燒基；e為式（ιν)之基團，式中，RA2為視需要經t定基或三由素_Ci4烧基十定基取代之4至7員脂肪族雜環基。 1、田中又更佳之化合物實例包括化合物[I ]中， R為、、工自氣原子與二函素—c"垸基之基團取代之苯基； R32為經一至二個選自氯原子或氟原子之基團取代之苯基； Μ為視需要經一至三個選自下列之基團取代之CH烷基：氟原子、氰基、Ch烷基氧基、胺基—Ci 3烷基、Ci 3烷基一羰基胺基、C1_3烷基—胺甲磺醯基胺基、C1_3烷基—磺醯基胺基一（C1-3烷基）胺續醯基胺基、噻唑基與視需要經一至二個Ch烷基取代之噚唑基；以及 E為式（i)之基團， Q為早鍵， Q2為單鍵或Ch伸烷基， R為視需要經一至二個選自側氧基、c"烷基胺基與胺甲基基團取代之飽和或不飽和5至6員雜單環基，或為式-NH(R6)之基團，及 R6為（a)!：!-3烷基，（b)視需要經胺甲醯基取代之C3 6 環烷基，（c)視需要經一至二個選自氯原子、氟原子、氰基與Cm烷基氧基之基團取代之苯基，（d)視需要經一至三個 318695 19 200804294 選自下列之基團取代之飽和或不飽和5至7員雜單環基：氟原子、侧氧基、視需要經一至三個氟原子取代之Cm烷基、二氟-Cl-3烧基-幾基、Cl-3烧基氧基-Cl-3烧基-幾基、氰基-C!-3烷基-羰基、胺曱醯基、視需要經一至二個選自 C!-3烷基、三氟-Cm烷基-羰基與苯甲醯基之基團取代之胺基、視需要經一至二個選自氯原子、氟原子、氰基、Ο」烷基氧基與三氟-匕-3烷基之基團取代之苯曱醯基、羧基、苯甲基、視需要經一至二個選自氣原子與氟原子之基團取代之苯基以及視需要經一至二個選自氯原子、氟原子、氰基、CH烷基與三氟-Cl_3烷基之基團取代之吡啶基，或經一至二個選自Cm烷基與吡啶基之基團取代之胺基。畜中，其他又更佳之化合物[j ]之實例包括： ⑴化3合物[I]中，R1為氯苯基或三氟甲基苯基；R2為氣苯基；R3為Ch烧基；E為式（ii)之基團，式中，R為三氣— 為氯笨基；R3g Cm烷 1為5至6員脂肪族雜写 (2)化合物[I]中，R1為氯苯基基；E為式（iii)之基團，式中基；或 ⑶化合物m中，以氣苯基；R2為氯笨基；“ci 3燒為广之基團’式中，R、視需要經三… 基-嘴欠基取代之5至6員脂肪族雜環基。本發明之化合物⑴#中，制佳化合物 ==Γ之化合物或其醫藥上可接受之鹽ί 卜d本基）-5-u-氯苯基）_4_τ氧基_3善（卜氮 318695 20 200804294 庚基）胺甲醯基]-1H-吡唑； 1-(2-氯苯基）-5_(4_氯苯基）_4_曱氧基_3_[n_(4_四氫哌 .喃基）胺曱醯基]— 吡唑；二又 1-(2-氯苯基）-5-(4_氯苯基）_4_乙氧基—3七鲁嗎福琳基）胺曱酸基]-1 Η-π比嗤； 1-（2-氯苯基）-5-（4-氯苯基）-4- 甲氧基—3一[N-(2, 2 二氟乙基）胺曱酿基]-1 Η—π比嗤； 1-(2-氯苯基）-5-(4-氯苯基）-4-甲氧基一3一[N-(N一六气响 ϋ定基）胺曱酿基]-1H-。比唾； 1 -（2-氯苯基）-5 -（4一氯苯基）一 4一甲氧基—3-[ν—(Ν—嗎福啉基）胺曱醯基]- 1Η-吡唑； 1-（2-氯苯基）-5-（4-氯苯基）-4-甲氧基—3-[Ν-(1一各咬基）胺曱醯基]- 1Η-吡唑； 1-(2 -氯苯基）-5-(4-氯苯基）-4-乙氧基—3-[Ν~(Ν-六氣口比啶基）胺曱醯基;ΜΗ-吡唑； 1 -（2-氯苯基）-5-（4-氯苯基）_4-(2 -甲氧乙氧基）一3一 (Ν-六氫吡啶基）胺甲醯基]- 1Η-吡唑； 1 -（2-氯苯基）-5_(4-氯苯基）-4-曱氧基-3-[ 1 一（ν—嗎福琳基）乙醯基]-1Η-吡唑； 1-(2, 4-二氯苯基）-5-（4-氯苯基）-4-曱氧基一3 - [Ν-（Ν-六氫σ比唆基）胺甲酸基]-1 Η-ϋ比峻； 1 -（2, 4-二氣苯基）-5-（4-氯苯基）-4-甲氧基一3-[N-(l-口比咯啶基）胺甲醯基]-1Η-吡唑； 1 -（2, 4-二氯苯基）-5-（4-氯苯基）-4-甲氧基-3-[Ν-（Ν-嗎 21 ·.， r«·· 318695 200804294 福啉基）胺曱醯基]-1H-吡唑； 1-（2, 4-二氯苯基）-5 -（4-氯苯基）- 4-甲氧基一 3- [(ν' -二甲基肼基）羰基]- 1Η-吡唑； 1-(2-氯苯基）-5-（4-氣苯基）-4-甲氧基一3-（Ν-環戊基胺甲酿基）-1Η -吼哇； 1-(2-氯苯基）-5-（4-氯苯基）-4-甲氧基一3-（Ν-異丙基胺甲酉篮基）-1Η -吼σ坐； 1 -（2, 4-二氯苯基）-5-（4-氯苯基）-4-二氟甲氧基 -3-[Ν-(1-吡咯啶基）胺曱醯基]-1Η-吡唑； 1-（2-氯-4-氟苯基）-5-(4-氯苯基）-4-曱氧基一3-[Ν-（Ν-嗎福淋基）胺曱酿基]-1Η -17比哇； 1-(2 -氯苯基）-5 -（4-三曱基苯基）-4-甲氧基一 3 一 [(ν' γ -二曱基骄基）幾基]-1Η_σ比σ坐； 1-(2-氯苯基）-5-(4-三氟甲基苯基）-4 -甲氧基—3 —[ν-(1一。比口各ϋ定基）胺曱酸基]-1Η - °比唾； 1-(2-氯苯基）-5-(4-三氟甲基苯基）一4-甲氧基一3—[ν-(Ν-嗎福琳基）胺曱酸基]—1Η -σ比嗤； 1-(2-氯本基）-5-（4_三氟曱基苯基）一4-甲氧基一3-[Ν-（4 - 四氫旅σ南基）胺曱酸基]-1 Η-σ比唾； 1 -（2-氯苯基）-5-（4-氯苯基）-4-甲氧基一3-{Ν-[1-（4-氟苯甲醯基）六氳吡畊-4-基]胺甲醯基} — 1Η 一吡唑； 1-(2-氯苯基）-5-(4-三氟甲基苯基）_4_二氟甲氧基一3一 [(r，ir-二曱基肼基）羰基]_1H—吡唑； 1-(2-氯苯基）-5-(4-三氟曱基苯基）_4一二氟甲氧基_3_[n_ 318695 22 200804294 (4 -四氯旅喃基）胺甲酿基]一 1 Η - σ比唾； 1-(2-氯本基）- 5-（4二氟甲基苯基）—4 —二氟曱氧基—3 一 [ν_ (1 -ϋ比洛σ定基）胺曱酸基]-1Η -σ比唾； 1 -（2-氯本基）-5-（4-氯本基）-4-甲氧基—3—[ν一（ 1 一^比嘻口定基）胺曱醯基]- 1Η-吡唑； 1-(2-氯苯基）-5-(4-氯苯基）-4-甲氧基[Ν—(順一2, 6一二曱基-Ν-嗎福啉基）胺曱醯基]—1Η-吡唾； 1-(2-氯苯基）-5-(4-氯苯基）-4-曱氧基—3一[Ν—(4, 4一二氟 -Ν-六氫^比咬基）胺曱酿基]-1 η-°比唾； 1 -（2-氯苯基）-5-（4-氯苯基）-4-甲氧基〜3一[Ν一（4一三氟曱基-Ν-六氫吡啶基）胺曱醯基]— 1Η—吡唑； 1-（2-氯苯基）-5-(4-氯苯基）-4-甲氧基—3—[(Γ，一二甲基肼基）幾基]-1 Η-吼唾； 1 -（2-氯苯基）-5-（4-氯苯基）-4-乙氧基—3—[Ν-(4一四氫哌喃基）胺曱酿基]-1 Η-σ比嗤；甲基月井基）参炭基]-1Η -。比σ坐； 1-（2-氯苯基）-5-（4-三氟甲基苯基）一4—乙氧基— 3_[(fr， 1-(2-氯苯基）-5-（4-氯苯基）-4-(2-曱氧基乙氧基）—3一[ν一 (4-四氫哌喃基）胺曱醯基]— 1Η—吡唑；卜（2-氯苯基）-5 -（4-三氟曱基苯基）—4-(2-曱氧基乙氧基〕 -3-[N-（1-吡咯啶基）胺曱醯基]—1H一吡唑； 1-（2-氯苯基）-5-(4-三氟曱基苯基）-4 -（2-曱氧基乙氧基〕 -3-[N -（N-嗎福啉基）胺曱醯基]-1H-吡唑；》 1一（2一氯苯基）一5一（4一氯苯基）-4-甲氧基-3-[N-(l，1〜二側 318695 23 200804294 氧基硫代嗎福啉基-4-基）胺曱醯基]η—TJ比哇； 1-（2-氯苯基）-5-（4-氯苯基）-4-甲氧基「N f 土 υ UN -〔四氫π夫口南 -3 -基）胺曱隨基]-1Η -。比哇； 1-(2-氯苯基）-5-(4-氯苯基）-4-甲氧基-3_[ν__(4_笨甲辨基六氫吡哄-卜基）胺甲醯基]—1Η-吡唑； 1 1-（2-氯苯基）—5-(4-氣苯基）-4-正丙氧基ν' 一曱基骄基）幾基]-1Η -σ比。坐； 1-（2-氯苯基）—5-(4-氯苯基）-4-甲氧基-3-{1[4—(4一氯# 曱醯基）六氫吡畊—1 一基]胺甲醯基卜1Η—吡唑；氣笨 1 (2-氯本基）一 5-(4-氯苯基）-4-甲氧基—3-{N-- & 曱基本甲酸基）六氫σ比畊—1 一基]胺曱酿基丨—1 η—〇比嗤· 一 1-(2-氯苯基）一5-（4-氯苯基）-4-甲氧基一3一{1^[4一（3—氟# 甲醯基）六氳吡畊-卜基]胺甲醯基卜1Η—吡唑；氟苯 1 -（2-氯苯基）一5-(4-氯苯基）-4-曱氧基一3—「η ^ 一 L、丄’ 1 ——側氧基硫代嗎福淋- 4 -基）乙驢基]-1Η-σ比唾；〜口比Wherein RA and RB are the same or different and are a ruthenium atom or an alkyl group, and the ruthenium is an integer of 1 or 2. Among them, preferred examples of R, R3, R4, R5, R6, and a soil base include a heterocyclic monocyclic group which is saturated or unsatisfiable with a sulfur in R6, R8 or R9, such as a nitrogen sigma group, a pyridine. Base, pyridyl, hexahydropyridinyl, including saturated or unsaturated 5 to 7 members containing nitrogen, oxygen or a group, furyl, tetra, such as a nitrogen-based, pyrrolyl, pyrrolidinyl, hexahydropyridinium Base, pyrimidine π, Compared with mercapto, glucohydropyranyl, tetrahydrothiopyranyl, and phoranyl. Danyl, pyrrolyl, pyrrolidinyl, hexahydropyridinium D, U 唆,.哄哄, azepine, tetrahydrothio-branyl, wheylinyl, 318695 12 200804294 thiofenoflavinyl, stilbene, tetrahydro σ thiophene, thiazide, isoxazole Base, oroxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl or acridinyl. Further, the above saturated or unsaturated nitrogen-containing heterocyclic group of R, R3, R4, R5, R6, R8 and R9 may be substituted with one to four groups selected from the group consisting of: (a) a halogen atom '(b) via a group , (c) cyano, (d) pendant oxy, (e) alkyl optionally substituted with one to three prime atoms, (f) alkyloxyalkyl, (g) aminoalkyl, (h Alkylsulfinylalkyl, (i) alkanesulfonylalkyl, (j) cycloalkyl, (k) arylalkyl, (1) optionally substituted with one to three halogen atoms a group, (m) a carboxyl group, (n) an amine group which is substituted with one to two groups selected from an alkyl group and a fluorenyl group, and optionally substituted with one to two alkyl groups. p) fc group, (q) alkylthio group, (r) calcined; 5 xanthate group, (s) calcined xanthine group, (defectively required to be substituted with one to two alkyl groups of amidoxime, (u Arylsulfonyl '(v)aryl, which may optionally have one to three alkyl groups selected from the group consisting of a dentate atom, a cyano group, optionally substituted with one to three halogen atoms, an alkyloxy group and an alkane Substituted with a sulfonyl group, and (w) a heteroaryl group, as desired Substituting one to three groups selected from the group consisting of an alkyl group substituted with one to three dentate atoms, an atom of an atom and a cyano group. Examples of the fluorenyl group in R, R, R4, R5, R6, R8 and r9, Including a group consisting of a hydroxyl group removed from a carboxylic acid compound of the formula R-C00H [Ac-Ι], in other words, a group of the formula Rx-C0-, wherein ^ is a "hydrogen atom, (b) as needed An alkyl group substituted with one to two groups selected from the group consisting of a dentate atom, a cyano group and an alkanesulfonyl group, (c) an alkyloxy group optionally substituted with an aryl group, (cycloalkyl, (e) An aryl group substituted with two groups selected from the group consisting of a dentate atom, a cyano group, a decyl group, a tridentate alkyl group and an alkyloxy group, (f) one to two 318695 13 200804294 alkyl groups as needed a substituted amine group, or (g) a saturated or unsaturated heterocyclic group substituted with one to two groups selected from a halogen atom, a cyano group, an alkyl group and a tridentate alkyl group as needed. Examples may be (al) fluorenyl, (bl) Ci_6 alkyl-carbonyl group, such as acetamyl, propyl hydrazino, etc.; trihalogen-Ch alkyl-carbonyl, such as, for example, fluoroethyl a& Or cyano-Ci-e An alkyl group, such as a cyanoacetyl group, (cUCh alkyloxy-carbonyl, such as an anthraceneoxycarbonyl group, an ethoxycarbonyl group, a tertiary butoxycarbonyl group, etc.; or an aryl-Chalkyloxy-carbonyl group, for example Phenyloxy oxalyl, (dl) C3-8 cycloalkyl-carbonyl, such as cyclopropyl, cyclopentyl, etc., (el) aryl-carbonyl, such as benzhydryl; mono- or Di-aryl-carbonyl, such as chlorophenyl fluorenyl, fluorobenzhydryl, difluorobenzhydryl, etc.; cyano-aryl-carbonyl, such as cyanobenzyl; trihalo-Ci6 alkyl- An aryl-carbonyl group, such as a trifluoromethylbenzylidene group; or a trihalogen-Ci 6 alkyloxy-aryl-carbonyl group, such as a trifluoromethoxybenzyl fluorenyl group, (fl) an amine carbaryl group, N-(Ch alkyl)amine mercapto, or (gl) furanyl, thiophenemethyl, bromothiophene, cyanothiomethane, σ-pyridylcarbonyl, chloropyridylcarbonyl, Cyanopyridylcarbonyl, trifluoromethyl σ-pyridylcarbonyl or pyridylcarbonyl. Among the compounds [I] of the present invention, preferred examples of the compound include the compound [I], and the R1 and R2 are the same or different and are optionally selected from one or two selected from the group consisting of a halogen atom, a cyano group, and a tri-alkyl group. a phenyl group substituted with a group of an alkyloxy group, an alkylthio group, an alkylsulfinyl group and an alkyl sulfonium group; R3 is (a) a hydrogen atom, and (b) is optionally one to three groups selected from the group consisting of Substituted alkyl dentate atom, cyano group, alkyloxy group, alkylthio group, decyl group, amine group, decylamino group, amine carbaryl group, alkylamine, decylamino group, alkane 31S695 14 200804294 Phytoretrienyl, bis(alkyl)amine phosphatidylidene amine and residual or unsaturated 5 to 6 membered heterocyclic group (the heterocyclic group may be optionally oxidized by one or two groups) a group substituted by a group, (4) an amine thiol group substituted by one to two substituents, or (4) a saturated or unsaturated a 6 member heterocyclic group (the heterocyclic group may be optionally selected from two to two) a group in which the pendant oxy group is substituted with an alkyl group; and wherein E is a group of the formula (i), Q1 is a single bond or a group of the formula -NH-, and Q is a soap bond, an oxygen atom or a stretching group, R4 is (a) an aryl group optionally substituted with one to three groups selected from a halogen atom, a cyano group and an alkano group, (13) a cycloalkyl group, (c) optionally one to two selected from the following a saturated or unsaturated 5 to 7 membered heteromonocyclic group substituted by a group: a halogen atom, a pendant oxy group, a cyano group, an alkyl group optionally substituted with one to three functional atoms, optionally substituted with one to two alkyl groups An amine group, an amine carbenyl group and a fluorenyl group, (d) a group of the formula -n(r5)(r6), or (e) a spiroheterocyclic group of the formula: rb 4>, R5 is a hydrogen atom or a burnt And R6 is (1) substituted by one to three groups selected from the group consisting of a halogen atom, an amine group, an alkyloxy group, an alkylthio group, an alkylsulfinyl group, an alkanesulfonyl group and an aryl group, as needed. The alkyl group (2) is optionally substituted with an amine ketone group, (3) a group of the formula -N(R8)(R9), (4) a thiol group, and (5) one to three as needed. Aromatic 318695 substituted with a group selected from a halogen atom, a cyano group, a trihaloalkyl group and an alkyloxy group. </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; 5 to 7 members of heteromonocyclic group · halogen atom, side An oxy group, an alkyl group substituted with one to three halogen atoms, an alkyloxyalkyl group, an arylalkyl group, a silk group which is optionally substituted with a to-tetra(tetra) atom, (iv), a mild soil a base, an amine-based base, a vermiculite yellow base, an amine bromide substituted by one or two leuco groups, and an aromatic stone base, if necessary, substituted with one or two groups selected from the group consisting of a base and a base An amine group, an aryl group substituted with one to two dentate atoms as needed, and optionally one or two alkyl groups selected from one to three halogen atoms, a dentate atom and a cyano group, if necessary a substituted heteroaryl group, R is a halogen atom, R is an alkyl group, q and r are integers of 1, R8 is a hydrogen atom or a burnt group, and R9 is optionally one to two selected from the group consisting of a pendant oxy group and a cyano group. An alkyl group substituted with an alkyl group; an aryl group or a heteroaryl group. Further, among the compounds of the present invention, examples of other preferred compounds include: (1) The compound (1) is the same or different and is a phenyl group; only 3 is a burnt group or a siloxane group; a group of the formula (ii), a formula, R is (4) a group substituted with three halogen atoms as required, and (8) an alkyloxyalkyl group (c) is optionally selected from a hydroxyl group and an alkyl group. a group substituted with a cycloalkyl group, (d) an alkylthio group, (e) an aryl group substituted with one to two groups selected from a halogen atom and a cyano group, or (f) an alkanesulfonate if necessary a saturated or unsaturated heterocyclic group substituted with a thiol or a heteroaryl group; (2) a compound (1) wherein the m2 is the same or different and is a phenyl group; the alkyl group is an alkyl group or an alkyloxy group; a group wherein rA1 is an amine 16 318695 200804294 or a group of the formula: wherein is an integer from 3 to 4; (3) in the compound [I], R1 and R2 are the same or different and are halogen benzene a y is a pyrenyl group or a pyrenyloxy group; E is a group of the formula (iv), wherein rA2 is a 4 to 7 member nitrogen-containing aliphatic group substituted by a pyrimidinyl group or a halogen pyrimidinyl group as needed. Ring baseIn the compound [I], R is a phenyl group substituted with one or two groups selected from a halogen atom and a trihalogen-alkyl group; R2 is one to two dentates. An atom-substituted phenyl group; R is a Ci-4 alkyl group, a Cw alkyloxy-Ch alkyl group, a cyano-Cl_4 alkyloxy group, an amine group-Ci4 alkyl group substituted with one to three halogen atoms as needed ( The amine moiety of the group may be optionally substituted with a group selected from the group consisting of a fluorenyl group, a di(alkyl)amine sulfonyl group and a Cl-4alkyl-amino group, a urethane group, a chromic group, oxazolyl-Chalkyl (the carbazole moiety of the group may be substituted by one to two Ch-yard groups), thiazolyl-Ci 4 alkyl; and E is a group of formula (i), Q1 is a single bond, Q2 is a single bond or a Ch alkyl group, and R4 is a saturated or unsaturated 5 to be substituted with one to three groups selected from the group consisting of a pendant oxy group, an amine carbaryl group and a Ci 4 aryl group. a 6-membered heteromonocyclic group, or a group of the formula -NH(R6), and 318695 17 200804294 R6 is (aWH alkyl, (b) optionally substituted by an amine thiol group, c5 8 cycloalkyl, (c ) one to two odontogens as needed Substituted phenyl, (d), optionally saturated or unsaturated with one to three groups selected from the group consisting of: 5 to 7 membered heteromonocyclic groups: halogen atom, pendant oxy group, optionally one to three a halogen atom-substituted Cr_4 alkyl group, optionally substituted with one to two halogen atoms, a gas group, a Ci-4 alkyloxy-phenyl group, a phenyl group, a phenyl-a 4 alkyl group, a carboxyl group, An amine group, an amine sulfhydryl group substituted with one to two groups selected from a C alkyl group and a cyano group, and optionally one to two selected from a halogen atom, a Ci-4 alkyl group and a trihalogen-C!-4 a pyridyl group substituted with an alkyl group, or (e) an amine group optionally substituted with one or two groups selected from the group consisting of a Cw alkyl group and a pyridyl group. Among other examples of preferred compounds include: (1) a compound In [I], R is the same as or different from R2 and is a halogen phenyl group, and R is a Cl _4 alkyl group, a dihalogen-Cl-4 alkyl group or a Cl -4-alkyloxy group-Cl-4 alkyl group; (ii) a group wherein R is (a) a Ch alkyl group substituted with one to three dentate atoms, and (b) a Cw ring substituted with a group selected from a hydroxyl group and a C 4 alkyl group, if necessary. alkyl , (cOC!-4 alkylthio, (optionally - to two aryl groups substituted with a halogen atom and a cyano group, or (e) optionally selected from a Cw alkanesulfonyl group, a saturated or unsaturated heterocyclic group substituted with a group of a fluorenyl group and a heteroaryl group; (2) In the compound [I], R1 and R2 are the same or different and are a halogen phenyl group; 〇1-4 Alkyloxy-(]1-4 alkyl group; £ is a group of the formula (;[;[;[), wherein RA1 is an amine group or a group of the following formula: 318695 18 200804294 • , k is an integer from 3 to 4; or (33). In the compound (1), 'R1R2 is the same or different and is a halogen phenyl group; R is a calcinyl aCh-alkyloxy-Ci 4 alkyl group; and e is a group of the formula (ιν), wherein RA2 is optionally a fixed group. Or a 4- to 7-membered aliphatic heterocyclic group substituted with a _Ci4 alkyl group. 1. A better example of a compound in Tanaka includes a compound in the compound [I], R is a phenyl group substituted with a group derived from a gas atom and a difunctional element-c" fluorenyl group; and R32 is one or two selected from a chlorine atom. a phenyl group substituted with a group of a fluorine atom; hydrazine is a CH alkyl group substituted with one to three groups selected from the group consisting of: a fluorine atom, a cyano group, a Ch alkyl group, an amine group - a Ci 3 alkyl group. , Ci 3 alkyl-carbonylamino group, C1_3 alkyl-amine methylsulfonylamino group, C1_3 alkyl-sulfonylamino-(C1-3 alkyl)amine hydrazino group, thiazolyl group An oxazolyl group substituted with one to two Ch alkyl groups; and E is a group of the formula (i), Q is an early bond, Q2 is a single bond or a Ch alkyl group, and R is optionally selected from one to two A pendant or oxyalkyl group and an amine methyl group substituted with a saturated or unsaturated 5 to 6 membered heteromonocyclic group, or a group of the formula -NH(R6), and R6 is (a)! :!-3 alkyl, (b) C3 6 cycloalkyl substituted with an aminomethyl thiol group as desired, (c) optionally one to two selected from a chlorine atom, a fluorine atom, a cyano group and a Cm alkyloxy group. Substituted phenyl group, (d) as needed One to three 318695 19 200804294 A saturated or unsaturated 5 to 7 membered heteromonocyclic group substituted with a group selected from the group consisting of a fluorine atom, a pendant oxy group, a Cm alkyl group substituted by one to three fluorine atoms, and a difluoride. -Cl-3alkyl-aryl, Cl-3alkyloxy-Cl-3alkyl-yl, cyano-C!-3 alkyl-carbonyl, amine thiol, optionally one to two An amine group substituted with a group selected from a C.-3 alkyl group, a trifluoro-Cm alkyl-carbonyl group and a benzamidine group, optionally containing one or two selected from a chlorine atom, a fluorine atom, a cyano group, and an anthracene group. a phenyl fluorenyl group substituted with a group of a oxy group and a trifluoro-inden-3-alkyl group, a carboxy group, a benzyl group, a phenyl group optionally substituted with one or two groups selected from a gas atom and a fluorine atom, and a pyridyl group substituted with one to two groups selected from a chlorine atom, a fluorine atom, a cyano group, a CH alkyl group and a trifluoro-Cl_3 alkyl group, or a group selected from one to two groups selected from a Cm alkyl group and a pyridyl group Substituted amine group. Examples of other and more preferred compounds [j] in the animal include: (1) in the compound [I], R1 is chlorophenyl or trifluoromethylphenyl; R2 is a gaseous phenyl group; and R3 is a Ch-alkyl group; E is a group of the formula (ii), wherein R is a tri-gas - a chlorophenyl group; R3g Cm alkane 1 is a 5- to 6-membered aliphatic hetero- (2) compound [I], and R1 is a chlorophenyl group. E is a group of formula (iii), a group of formula; or (3) compound m is a gas phenyl group; R2 is a chlorophenyl group; "ci 3 is a broad group", R, as needed a 5- to 6-membered aliphatic heterocyclic group substituted by a hydrazide group. In the compound (1)# of the present invention, a compound of the compound == a compound of hydrazine or a pharmaceutically acceptable salt thereof ί db base) -5-u-chlorophenyl)_4_τoxy_3 善(卜氮318695 20 200804294 heptyl)aminemethanyl-1H-pyrazole; 1-(2-chlorophenyl)-5-(4-chloro Phenyl)_4_decyloxy_3_[n_(4_tetrahydropeperyl)aminoindolyl]-pyrazole; di-l-(2-chlorophenyl)-5-(4-chlorobenzene Base)_4_ethoxy-3-7-rufofen-based) aminic acid]-1 Η-π 嗤; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4 - methoxy-3-[N-(2, 2 difluoro Ethyl)amine oxime]-1 Η-π 嗤; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-[N-(N- Six gas ϋ ) ) ) ) ) ] ] ] ] ] ] ] ] ] ] ] ] ] ] ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; Ν-?-fosfolinyl)aminoguanidino]- 1 Η-pyrazole; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-[Ν-( 1 各 ) ) ) ) ) ) ) ) 1- 1- ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- -hexafluoropyridyl)amine hydrazino; hydrazine-pyrazole; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-(2-methoxyethoxy)-1-3 (Ν-hexahydropyridyl)amine-carbamoyl]- 1Η-pyrazole; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-[1 ν 吗吗琳 ) ) ) ] ] ] ] ] ] ] ] ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; -(Ν-hexahydroσ-pyridyl)carbamic acid]-1 Η-ϋ比峻; 1 -(2, 4-diphenyl)-5-(4-chlorophenyl)-4-methoxy 3-I-(N-(l-propylpyrrolidyl)aminemethanyl]-1Η-pyrazole; 1-(2,4-dichlorophenyl)-5-( 4-chlorophenyl)-4-methoxy-3-[Ν-(Ν-?21·., r«·· 318695 200804294 porinyl) amidino]-1H-pyrazole; 1-( 2,4-Dichlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-[(ν'-dimethylindenyl)carbonyl]- 1Η-pyrazole; 1-( 2-Chlorophenyl)-5-(4-phenylphenyl)-4-methoxy-l-(indolyl-cyclopentylamineyl)-1Η-吼w; 1-(2-chlorophenyl) -5-(4-chlorophenyl)-4-methoxy-3-(indole-isopropylaminemethanthine)-1Η-吼σ sitting; 1 -(2,4-dichlorophenyl) -5-(4-chlorophenyl)-4-difluoromethoxy-3-[indole-(1-pyrrolidinyl)amine fluorenyl]-1 Η-pyrazole; 1-(2-chloro- 4-fluorophenyl)-5-(4-chlorophenyl)-4-decyloxy-l-[Ν-(Ν-吗福淋基)amine 曱基 ]]-1Η -17 比哇; 1- (2-Chlorophenyl)-5-(4-trimethylphenyl)-4-methoxy-3-[(ν' γ-dimercapto-yl)-yl]-1Η_σ ratio σ sitting; 1 -(2-Chlorophenyl)-5-(4-trifluoromethylphenyl)-4-methoxy-3-[ν-(1. Alkyl decanoyl group -1 Η - ° than saliva; 1-(2-chlorophenyl)-5-(4-trifluoromethylphenyl)- 4-methoxy-3-[ Ν-(Ν-moffolinyl)amine decanoic acid]-1 Η-σ 嗤; 1-(2-chlorobenzyl)-5-(4-trifluorodecylphenyl)-4-methoxy a 3-[Ν-(4 - tetrahydro sulphate sulphonyl) aminic decanoic acid group]-1 Η-σ ratio saliva; 1 -(2-chlorophenyl)-5-(4-chlorophenyl)-4 -methoxy-3-{Ν-[1-(4-fluorobenzylidenyl)hexafluoropyridin-4-yl]aminecarboxylidene}- 1Η-pyrazole; 1-(2-chlorophenyl) -5-(4-Trifluoromethylphenyl)_4-difluoromethoxy-1,3- [[r,ir-didecylfluorenyl)carbonyl]_1H-pyrazole; 1-(2-chlorobenzene -5-(4-Trifluorodecylphenyl)_4-difluoromethoxy_3_[n_ 318695 22 200804294 (4-tetrachloro-branyl) amine-based] 1 Η - σ than saliva ; 1-(2-chlorobenzyl)-5-(4-difluoromethylphenyl)-4-difluoromethoxy-3-[v_(1-indolylpyrazine) aminic acid]- 1Η-σ ratio saliva; 1 -(2-chlorobenzyl)-5-(4-chlorobenzyl)-4-methoxy-3-[ν一(1一^比嘻口基基)amine sulfhydryl ]- 1Η-pyrazole; 1-(2-chlorophenyl)-5-(4-chlorobenzene ))-4-methoxy[Ν-(cis-2,6-didecyl-fluorenyl-norfosfyl) amidino]-Η-pyrrole; 1-(2-chlorophenyl)-5 -(4-chlorophenyl)-4-methoxy-3-[Ν-(4,4-difluoro-indole-hexahydro^bitryl)amine oxime]-1 η-° than saliva; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy~3-[indenyl(4-trifluorodecyl-fluorenyl-hexahydropyridinyl)amine fluorenyl ]-1 Η-pyrazole; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-[(indole, dimethylhydrazino) group]- 1 Η-吼 ;; 1 -(2-chlorophenyl)-5-(4-chlorophenyl)-4-ethoxy-3-[Ν-(4-tetrahydropyranyl)amine broth ]-1 Η-σ ratio ; methyl month well base) ginseng base]-1Η -. Sitting σ; 1-(2-chlorophenyl)-5-(4-trifluoromethylphenyl)-4-ethoxy-3_[(fr, 1-(2-chlorophenyl)-5- (4-chlorophenyl)-4-(2-decyloxyethoxy)-3-[v-(4-tetrahydropyranyl)amine fluorenyl]-1 Η-pyrazole; Chlorophenyl)-5-(4-trifluorodecylphenyl)-4-(2-decyloxyethoxy)-3-[N-(1-pyrrolidinyl)amine fluorenyl]-1H 1-pyrazole; 1-(2-chlorophenyl)-5-(4-trifluorodecylphenyl)-4-(2-decyloxyethoxy)-3-[N-(N-?啉 ) 曱醯 ] ] ] ] ] ] 》》》》》一一一一一一一一一一一一一一一一一一一一一一一一一一一一一一~ two sides 318695 23 200804294 oxythiomorpholinyl-4-yl)amine fluorenyl] η-TJ than wow; 1-(2-chlorophenyl)-5-(4-chlorophenyl)- 4-methoxy "N f υ UN - [tetrahydro π 夫口南-3 -yl)amine oxime with a group]-1 Η -. Biwa; 1-(2-chlorophenyl)-5-(4 -Chlorophenyl)-4-methoxy-3_[ν__(4_ 笨辨六六六六六 ) ) )) 醯 ] ] ; ; ; ; ; ; ) 5-(4-(phenyl)-4-n-propoxy ν' ]-1Η -σ ratio. Sit; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-{1[4-(4-chloro- fluorenyl)六氢耕 — — 1 一 1 ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; N-- & 曱 basic formic acid) hexahydro σ ratio tillage - 1 - base] amine 丨丨 - 1 η - 〇嗤一 · 1- 1-(2-chlorophenyl)-5-(4-chloro Phenyl)-4-methoxy-3-{1^[4-(3-fluoro#methylmercapto)hexa-pyrene-p-ki]amine-methylpyridylpyrazine-pyrazole; fluorobenzene 1 -( 2-Chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3 - "η ^ - L, 丄' 1 - oxo-thio-thiopentaline - 4 -yl)驴基]-1Η-σ than saliva;

1-（2-氯苯基）-5-（4-氯苯基）-4-二氟甲氧基— 34^0 17各咬基）胺甲酸基]一 1 Η-σ比嗤； 1 -（2-氯笨基）-5-（4-氯苯基）-4-二氟甲氧基—3— 一甲基骄基）幾基]-1 Η-σ比嗤； 1-（2-氯苯基）—5-（4-氯苯基）-4-二氟甲氧基— 氫哌喃基）胺甲醯基]—1H-吡唑；四 1-（2-氯苯基）-5一（4-氯苯基）-4-乙氧基—3—# 甲醯基）六氬吡畊-1 一基]胺甲醯基卜1Η 一吡唑；鼠求 1 -（2-氟本基）-5-（4-三氟曱基苯基）-4-乙氧其q ίλ 平l丞— 318695 24 200804294 (4-氟苯曱醯基）六氫吡哄—}-基]胺曱醯基卜ih—吡唑； 1 (2氯苯基）—5 —(4〜氯苯基）-4-二氟甲氧基-3-[N -（1，1-▲一侧氧基硫代嗎福啉—4—基）胺曱醯基]-1H—吡唑； -1一（2一乳苯基）—5 —(4'氣苯基）-4-曱氧基-3-{N-[4-（3-氣苯甲酿基）六氮吼D井基]胺甲醯基} — 1H—吡唑； (氣本基）5 (4-氣苯基）一4一曱氧基—3- {N-[ 4-（2-氣苯甲酿基）六氮吨哄〜:^基]胺曱醯基}— 1H 一吡唑； ^(2—氣苯基）一5一（4'氣苯基）-4-曱氧基-3-{N-[4-（3, 4-二氟苯甲醯基）六氳吡啡一丨一基]胺曱醯基} — 1H-吡唑；卜（2一氯苯基）—5一（4一氯苯基）-4-曱氧基-3-{N-[4-（2, 4-二氟苯甲醯基）六氫吡啡一丨一基]胺甲醯基卜1H__吡唑； 1-（2-氯苯基）-5-(4-氣苯基）一4一曱氧基—3一{N—[4一（3, 5一二氟苯甲醯基）六氫吡哄一丨—基]胺甲醯基卜1H—吡唑； 1 -（2-氯苯基）- 5一（4—氯苯基）一 4一甲氧基—3 一 [2一（1-曱磺醯基六氫吡啶-4-基）-1，3,4-_二唑—5-基]-111—吡唑；’、 1-（2, 4-二氯苯基）—5一（4一氯苯基）一4一甲氧基一3 — [n—(4一氟苯基）胺甲醯基]- 1H-吡唑； 1 -（2-氯苯基）—5-(4一氯苯基）一4一曱氧基—3-{n—[4 — (4一氟苯基）六氫呲畊-1-基]胺甲醯基卜1H 一吡唑； 1 -（2-氯苯基）—5一（4一氯苯基）一4一甲氧基—3—[N—(3一三氟甲基吡咯啶-1-基）胺甲醯基]—1H 一吡唑； 1 一（2, 4一二氯苯基）-5-（4-三氟甲基苯基）一4一甲氧基-3 — [(N , N ~ 一 T基骄基）绩基]比哇； 1 -（2, 4-二氯苯基）一5 —(4-三氟甲基苯基）_4一甲氧基—3 —[Ν- 318695 25 200804294 (N-嗎福琳基）胺曱醯基]-1 Η-0比唾； 1 -（2，4-二氯苯基）- 5-（4-二氟甲基苯基）- 4-甲氧基一 3—[Ν- (1，1-二側氧基-2-四氫噻吩基）胺甲醯基]- 1Η-吡唑； 1 -（2-氣-4-氣本基）-5 -（4-二氣曱基苯基）-4 -甲氧基-3 -[Ν-（4-四氳哌喃基）胺甲醯基]一 1Η-吡唑； 1 -（2-氯-4-氟苯基）-5-（4-三氟甲基苯基）-4-曱氧基一3一 [Ν-（Ν-嗎福啉基）胺甲醯基]-1Η-吡唑； 1 -（2-氯苯基）-5-(4-三氟甲基苯基）-4-曱氧基一3-[Ν- (1 ’ 1 " 一側氧基~~ Ν -硫代嗎福琳基）胺甲酿基]—1 - π比唾； 1 -（2-氯苯基）-5-(4-氯苯基）-4-曱氧基-3-[N-（4-氟-N-六氫口比σ定基）胺曱醯基]一；[Η-σ比峻； 1-(2, 4-一氯苯基）一5-（4-氣苯基）-4-曱氧基—3-[Ν-(4-苯曱醯基六氫吼哄—l —基）胺甲醯基]一 1 Η—π比唾；卜（2, 4一二氯苯基）-5-（4-氯苯基）-4-曱氧基-3-{N-[4- (2, 4-二氟苯甲醯基）六氫口比哄一卜基]胺曱醯基卜1H一吡哇； 5-(4-氯苯基）—1 —(2一氟苯基）一4一甲氧基一3一[.(4, 4一二氟一六氳"比啶基）胺甲醯基]- 1H-吡唑； 1 -（2-氯苯基）—5 —(4一三氟甲基苯基）一 4一甲氧基—3—[n— (4, 4-二氟六氫吡啶基）胺曱醯基]一1Ή—吡唑； 1 -（2, 4-二氯苯基）一5一（4一三氟甲基苯基）—4-甲氧基一 3一 (4, 4一二氟—Ν一六氫吡啶基）胺甲醯基]-1Η-吡唑； 5-（4-氯苯基）—卜（2一氟苯基）一4一甲氧基—3一丨.[3一（三氟甲基）吡咯啶-1-基]胺甲醯基丨一 1Η -口比口坐；卜（2一風苯基）—5一（4一氯苯基）一4-曱氧基-3-{Ν-[4-（5-氰基 318695 26 200804294 °比σ定-2 -基）六氮σ比哄-1 -基]胺曱酿基} -1Η -ϋ比嗤； 1-(2-氯苯基）-5-（4-氯苯基）-4-曱氧基-3-{Ν-[4-（5-二氟曱基吡啶-2-基）六氫吡哄-1-基]胺曱醯基丨-1Η-吡唑； 1-(2-氣苯基）-5-（4-氯苯基）-4-二氟甲氧基-3-[Ν-（4, 4- 二氟-N-六氫吡啶基）胺曱醯基]- 1H-吡唑； 1 -（2 -氯苯基5-(4-三氟甲基苯基）- 4-甲氧基-3 - [5-(2，2，2 -二氣乙基）-1，3，4 -卩萼二嗤-2 -基]-1H -σ 比 °坐； 5 -（4 -氣苯基）-1-(2-氟苯基）- 4-甲氧基-3 - {Ν- [4 -（4 -氣苯1-(2-Chlorophenyl)-5-(4-chlorophenyl)-4-difluoromethoxy- 34^0 17 each bite) urethane)-1 Η-σ 嗤; 1 - (2-chlorophenyl)-5-(4-chlorophenyl)-4-difluoromethoxy-3-methoxymethyl aryl)]-1 Η-σ 嗤; 1-(2- Chlorophenyl) 5-(4-chlorophenyl)-4-difluoromethoxy-hydropiperidyl)amine-mercapto]-1H-pyrazole; tetra-l-(2-chlorophenyl)- 5-(4-chlorophenyl)-4-ethoxy-3-#methylamino)hexafluoropyrazine-1-yl]amine-methylpyridyl 1Η-pyrazole; mouse 1-(2-fluoro Benzo)-5-(4-trifluorodecylphenyl)-4-ethoxylated q ίλ flat l丞 — 318695 24 200804294 (4-fluorophenylindenyl)hexahydropyridinium-}-yl]amine曱醯基卜ih-pyrazole; 1 (2chlorophenyl)-5-(4~chlorophenyl)-4-difluoromethoxy-3-[N-(1,1-▲ one-oxyl) Thiomorpholine-4-yl)aminoindenyl]-1H-pyrazole; -1-(2-butylphenyl)-5-(4'-phenylphenyl)-4-oxime-3- {N-[4-(3- gas benzoyl) hexanitroindole D] carbamoyl} - 1H-pyrazole; (gas base) 5 (4-phenylphenyl) - 4 曱Oxy-3-{N-[ 4-(2- gas benzene酿 ) ) 六 ) : : : : : : : : : : : : : : : — — — — — — ; ; ; ; ; ; ; ; ^ ; ; ^ ^ ; ; ; ; ; ; -{N-[4-(3, 4-difluorobenzylidene)hexa-pyridinyl-indenyl]-amine hydrazino} — 1H-pyrazole; Bu (2-chlorophenyl)-5 (4-chlorophenyl)-4-methoxy-3-(N-[4-(2,4-difluorobenzhydryl)hexahydropyridinyl]-aminomethyl hydrazide 1H__ Pyrazole; 1-(2-chlorophenyl)-5-(4-phenylphenyl)- 4-indolyloxy-3-{N-[4-(3,5-difluorobenzhydryl)-6 Hydropyridinium-yl]amine-methylpyridyl 1H-pyrazole; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-tetramethyl--[1] 1-nonylsulfonylhexahydropyridin-4-yl)-1,3,4-oxadiazol-5-yl]-111-pyrazole; ', 1-(2, 4-dichlorophenyl)- 5-(4-chlorophenyl)-tetramethyloxy-3-[n-(4-fluorophenyl)amine-carbamoyl]- 1H-pyrazole; 1-(2-chlorophenyl)-5 -(4-chlorophenyl)- 4-indolyloxy-3-{n-[4-(4-fluorophenyl)hexahydroindol-1-yl]amine-methylpyridyl 1H-pyrazole; -(2-chlorophenyl)-5-(4-chlorobenzene一4-methoxy-3-(N-(3-trifluoromethylpyrrolidin-1-yl)aminemethanyl]-1H-pyrazole; 1-(2,4-dichlorophenyl) -5-(4-Trifluoromethylphenyl)-tetramethyloxy-3 — [(N , N ~ a T-based argyryl) kei] 1 - (2, 4-dichlorobenzene )) 5-(4-trifluoromethylphenyl)_4-methoxy-3 —[Ν- 318695 25 200804294 (N-moffolinyl)amine thiol]-1 Η-0 than saliva; 1-(2,4-dichlorophenyl)-5-(4-difluoromethylphenyl)-4-methoxy-3-[Ν-(1,1-di-oxo-2-ene-4 Hydrothienyl)amine-mercapto]- 1Η-pyrazole; 1-(2-gas-4-carbyl)-5-(4-dimethylnonylphenyl)-4-methoxy-3 [Ν-(4-tetrahydropyranyl)amine-carbamoyl]-indolyl-pyrazole; 1-(2-chloro-4-fluorophenyl)-5-(4-trifluoromethylphenyl)- 4-decyloxy-3-31[Ν-(Ν-morpholinyl)aminemethanyl]-1Η-pyrazole; 1-(2-chlorophenyl)-5-(4-trifluoromethylbenzene ))-4-oxooxy-3-[Ν-(1 '1 " one-side oxy~~ Ν-thio-fosfosinyl) amine-based]-1 - π than saliva; 1 -( 2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3 -[N-(4-fluoro-N-hexahydroport to sigma) amine sulfhydryl]-; [Η-σ ratio; 1-(2,4-chlorophenyl)-5-(4- Phenyl phenyl)-4-decyloxy-3-(Ν-(4-phenylhydrazinylhexahydroindole-1-yl)amine carbaryl]-1 Η-π than saliva; Bu (2, 4 Monodichlorophenyl)-5-(4-chlorophenyl)-4-oximeoxy-3-{N-[4-(2,4-difluorobenzhydryl)hexahydroport Amine oxime 1H-pyrva; 5-(4-chlorophenyl)-1-(2-fluorophenyl)- 4-methoxy-l-[[(4,4-difluoro]氲氲 quot 比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比[n-(4,4-difluorohexahydropyridinyl)amine fluorenyl]-indolyl-pyrazole; 1-(2,4-dichlorophenyl)-5-(4-trifluoromethylphenyl) - 4-methoxy-3-tris(4,4-difluoro-indolylhexahydropyridinyl)amine-mercapto]-indole-pyrazole; 5-(4-chlorophenyl)-b (2) Fluorophenyl)-1,4-methoxy-3-indan. [3-(Trifluoromethyl)pyrrolidin-1-yl]amine-carboxamidine- 1 Η - mouth than mouth; Bu (2 benzene) Base)—5-(4-chlorobenzene ) 4- 4-oxo-3-{Ν-[4-(5-cyano 318695 26 200804294 ° σ定-2-yl) hexaza σ 哄-1 -yl]amine hydrazine} -1Η - ϋ 嗤; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4- methoxy-3-{Ν-[4-(5-difluorodecylpyridine-2- Hexahydropyridin-1-yl]amine fluorenyl-1丨-pyrazole; 1-(2-phenylphenyl)-5-(4-chlorophenyl)-4-difluoromethoxy- 3-[Ν-(4,4-difluoro-N-hexahydropyridyl)amine fluorenyl]-1H-pyrazole; 1-(2-chlorophenyl 5-(4-trifluoromethylphenyl) )- 4-methoxy-3 -[5-(2,2,2-dioxaethyl)-1,3,4-quinone-2-yl]-1H-σ ratio ° sitting; 5 -(4-oxophenyl)-1-(2-fluorophenyl)-4-methoxy-3 - {Ν- [4- (4- gas benzene)

基）六氫吡哄-1-基]胺曱醯基丨-ΙΗ-吡唑； 5-（4-氣苯基）-1-（2-氟苯基）-4-甲氧基-3-{Ν-[4-（4-氟苯基）六氫吡哄-1-基]胺甲醯基丨-ΙΗ-吡唑； 4-胺甲醯基甲氧基一1一（2-氯苯基）一5一（4-氣苯基）一3-[Ν-(4-胺甲酿基-4-苯基-Ν-六氫吡啶基）胺甲醯基]-1Η一吡唾； 4-(2-胺乙氧基）曱氧基-卜^—氯苯基）_5_(4_氣苯基）—3_ [N-(吡咯啶-1-基）胺曱醯基]_1H -口比哇； 4-[2-(乙醯基胺基）乙氧基—（2 —氯苯基）—5 —(4—氯苯基）一 3—[N—(吡咯啶-1-基）胺甲醯基]- 1H-吡唑； 1 (2氯苯基）—5-(4-氯苯基）-4-[2-(甲磺醯基胺基）乙氧基;1-3-[N-(吡咯啶-；[一基）胺甲醯基]— 1H—吡唑，·以及 =2-氯苯基）—5_(4_氯苯基）_4_{2_[(n，n_:甲基胺石黃酿基）胺基]乙氧基卜3 —[N十比㈣+基）胺甲酸基]鲁吼口坐〇時==== = == 318695 27 200804294 =、光學異構物），本發明亦包括其立體異構物之一種及其混合物。本發明化合物對CB1受體具有強力拮抗活性，可作 •為藥劑用於預防及/或治療⑶受體轉介之疾病，例如精神疾病包括精神分裂症、焦慮症、麼力、憂營症、癲癇、神 =退化症、脊髓小腦病症、認知失常、大腦創傷、恐慌發、週邊神經病變、青光眼、偏頭痛、帕金森氏心出则^) 症、阿⑽默（Alzheimer、）症、杭了頓氏（HuntingWs) 症、雷諾氏（RaynaU(Ts)症候群、顫抖症、 t人輸；胸腺病症、妥瑞氏(一、)症候二孓不自主運動、躁營症、癌症、藥物引發之不自主運動、肌張力不全、敗血性休克、出血性休克、低血堡、失眠、免疫學疾病包括發炎、多發性硬化症、唱吐、腹篇、氣喘、食慾疾病例如厭/暴食交替症、厭食症#、肥胖症、非= 素依賴型糖尿病⑽DM)、記憶障礙、泌尿疾病、心血管二病、不孕症、感染、與去_化有關之疾病、神經發炎、、病毒性腦炎、中風、肝硬化或腸胃道疾病包括腸道運送症（disorder) 〇此外’本發明化合物⑴可作為藥劑用於戒除慢性户療、酒精依賴或藥物濫用[例如，鴉片類藥物、巴比妥‘ (barbiturate)、大麻、古柯鹼化⑻以时）、安非他入文现 (amphetandne)、天使塵（phencycUdine)、迷幻越 °、P 二氮呼化合物等]。 ^ 丰开再者，本發明化合物Π]可作為藥劑用於提高止痛藥物 318695 28 200804294 尼古丁或麻醉藥物之止痛活性等；或作為戒煙（戒除吸煙或依賴）藥劑。此外，本發明化合物[丨]能用於治療與代謝疾病有關之症狀，包括：肥胖症、糖尿病、葡萄糖耐受不良、高胰島 =血症、高脂血症、高膽固醇血症、高三酸甘油脂血症: 脂肪代謝病症、動脈硬化、高血壓、心血管疾病、冠心病、憂鬱症、焦慮症、藥物成癮與物質成癮。本發明化合物[I ]能以游離型式或其醫藥上可接受之鹽類型式供臨床使用。化合物[i]之醫藥上可接受之鹽類包括：無機酸鹽，例如鹽酸鹽、硫酸鹽、磷酸鹽或氫溴酸鹽；有機酸鹽，例如乙酸鹽、反式丁烯二酸鹽、草酸鹽、；檬酸鹽、甲錢鹽、苯俩鹽、對甲苯賴鹽或順丁稀二酸鹽。此外，當本發明化合物⑴於分子内具有叛基等時，該醫藥上可接受之鹽類之實例包括：與鹼，例如驗金屬（例如納*鉀鹽）或驗土金屬（例如，飼鹽）所成之鹽類。化口物[I]或其醫藥上可接受之鹽類包括其分子内鹽 ’八加成物（additive) ’以及其溶劑合物或其水合物。 ^月化σ物⑴或其醫藥上可接受之鹽類可口服或 =投予’且能調配成慣用醫藥製劑，例如疑劑、顆粒、膠晨、粉末、注射劑或吸入劑。本&明化合物⑴或其醫藥上可接受之鹽類所使用」 ^可㈣投予途徑與患者年齡、體重、病況而加以⑼ 二:又予’主射製劑時’通常劑量範圍為約0. 0001至: 毫克/公斤/日’較佳為約0.001至01毫克/公斤/日。 318695 29 200804294 予口服製劑時，通常劑量範圍為約〇〇〇1幻〇〇毫克& /日，較佳為約〇· 01至10毫克/公斤/日。本發明化合物[Π亦可料料上述疾病/病症治療之、附加或補充之治療。該輔助、附加或補充之 ::::發明化合物伴隨地或依序地投予已接受、正心會用於病況治療之—或多種附加治療劑，例如—或多種白知之抗憂f劑、抗精神病劑或抗焦慮劑之患者。本發明化合物[I ]能以下列方制限於該等方法。 ]方式-備，惟不應解釋成受Hexahydropyridin-1-yl]amine fluorenyl-indole-pyrazole; 5-(4-phenylphenyl)-1-(2-fluorophenyl)-4-methoxy-3- {Ν-[4-(4-Fluorophenyl)hexahydropyridin-1-yl]aminecarboxylidene-indole-pyrazole; 4-aminecarboxymethylmethoxy-1-one (2-chlorobenzene) 5-) 4-(4-phenylphenyl)-3-[indolyl-(4-amine-bromyl-4-phenyl-indole-hexahydropyridyl)amine-methylhydrazino]-1Η-pyrrole; 4 -(2-Aminoethoxy)decyloxy-bromo-chlorophenyl)_5_(4-hydrophenyl)-3_[N-(pyrrolidin-1-yl)amine fluorenyl]_1H-port ratio Wow; 4-[2-(ethylideneamino)ethoxy-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(N-(pyrrolidin-1-yl)amine Methyl hydrazide]- 1H-pyrazole; 1 (2 chlorophenyl)-5-(4-chlorophenyl)-4-[2-(methylsulfonylamino)ethoxy; 1-3-[ N-(pyrrolidine-;[monoylaminocarbazinyl]-1H-pyrazole, and =2-chlorophenyl)-5-(4-chlorophenyl)_4_{2_[(n,n_: A Alkyl yellow wine base) ethoxy] ethoxy b 3 - [N ten (4) + yl) urethane) 吼吼 mouth ==== = == 318695 27 200804294 =, optical isomers The invention also includes stereoisomers thereof One and a mixture thereof. The compound of the present invention has potent antagonistic activity against the CB1 receptor, and can be used as a medicament for preventing and/or treating (3) receptor-transferred diseases, such as mental disorders including schizophrenia, anxiety, dysentery, sorrow, Epilepsy, God = degenerative disease, spinal cord cerebellum, cognitive disorders, brain trauma, panic attacks, peripheral neuropathy, glaucoma, migraine, Parkinson's heart is ^), A (10) silent (Alzheimer), Hangzhou HuntingWs disease, Rayna U (Ts) syndrome, trembling, t-human transmission; thymic disease, Tourette's syndrome, involuntary movement, involuntary disease, cancer, drug-induced Self-exercise, dystonia, septic shock, hemorrhagic shock, hypo-blood, insomnia, immunological diseases including inflammation, multiple sclerosis, vomiting, abdominal, asthma, appetite diseases such as anaxia/albiosis, anorexia Disease #, obesity, non-dependent diabetes (10) DM), memory disorders, urinary diseases, cardiovascular disease, infertility, infection, diseases associated with de-inflammation, neuroinflammation, viral encephalitis, Wind, cirrhosis or gastrointestinal diseases include intestinal disorders. In addition, the compound of the present invention (1) can be used as a medicament for quitting chronic family therapy, alcohol dependence or drug abuse [eg, opiates, barbital' ( Barbiturate), marijuana, coca basification (8) time, amphetamine (amphetandne), angel dust (phencycUdine), psychedelic phlegm, P diazepane compound, etc.]. ^ 丰开 Further, the compound of the present invention can be used as an agent for analgesic drugs 318695 28 200804294 Analgesic activity of nicotine or anesthetic drugs; or as a smoking cessation (quit smoking or dependence) agent. In addition, the compound of the present invention [丨] can be used for the treatment of symptoms associated with metabolic diseases, including: obesity, diabetes, glucose intolerance, high islet=hyperemia, hyperlipidemia, hypercholesterolemia, high triglyceride Grevixemia: Fat metabolism disorders, arteriosclerosis, hypertension, cardiovascular disease, coronary heart disease, depression, anxiety, drug addiction and substance addiction. The compound [I] of the present invention can be used clinically in the form of a free form or a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salts of the compound [i] include: inorganic acid salts such as hydrochlorides, sulfates, phosphates or hydrobromides; organic acid salts such as acetates, trans-butenedioates, Oxalate, citrate, methic acid salt, benzene salt, p-toluene lysate or cis-succinate. Further, when the compound (1) of the present invention has a repressive group or the like in the molecule, examples of the pharmaceutically acceptable salt include: with a base such as a metal test (for example, a sodium salt) or a soil test metal (for example, a feed salt) ) The salt formed. The hydration compound [I] or a pharmaceutically acceptable salt thereof includes the intramolecular salt 'eight-additive' and a solvate thereof or a hydrate thereof. The compounded sigma (1) or a pharmaceutically acceptable salt thereof can be administered orally or in the form of a conventional pharmaceutical preparation such as a suspect, granule, gelatin, powder, injection or inhalation. This & Ming compound (1) or its pharmaceutically acceptable salt is used. (4) The route of administration and the patient's age, body weight, and condition are added. (9) 2: When the main injection preparation is used, the usual dose range is about 0. 0001 to: mg/kg/day' is preferably about 0.001 to 01 mg/kg/day. 318695 29 200804294 When administered orally, the usual dosage range is about 〇〇〇1 〇〇〇〇 mg & / day, preferably about 〇 01 to 10 mg / kg / day. The compounds of the invention [Π may also be treated with the treatment, addition or supplementation of the above mentioned diseases/disorders. The auxiliary, additional or supplemental:::: The inventive compound is administered concomitantly or sequentially to an acceptable therapeutic agent that is accepted for use in the treatment of the condition, or a plurality of additional therapeutic agents, for example, or a plurality of anti-anxiety agents, A patient with an antipsychotic or an anxiolytic agent. The compound [I] of the present invention can be limited to these methods in the following manner. Mode-prepared, but should not be interpreted as

方法A 本發明化合物[I ]中，E 或氧原子之化合物，換言之Process A In the compound [I] of the present invention, a compound of E or an oxygen atom, in other words

為式（i)之基團，且q2為單鍵，即具有下式[I-A]者·· 式中，Q為羊鍵或氧原子能藉由以下方式製備·· 而其他符號係如以上所定義，應： (1)使式[II-A]之化合物與式[ΠΙ-a]之醇類化合物反Is a group of the formula (i), and q2 is a single bond, that is, a formula having the following formula [IA], wherein Q is a sheep bond or an oxygen atom can be prepared by the following means, and other symbols are as defined above , (1) Reversing the compound of formula [II-A] with the alcohol compound of formula [ΠΙ-a]

[Π-Α] 而其他符號係如以上式中，Γ為氫原子、烷基或苯甲基所定義； 30 s 31S695 200804294 HO-R41 [III-a] 式中’ R41為環烧基或視需要經取代之飽和或不飽和雜環基，或 (2)使式[II-A]化合物與式[in-b]之胺類或胼化合物或其鹽類反應： HN(R42)(R43) [II 卜 b] 式中’R與R43之一者為氫原子或烧基，而另一者為（&)視需要經選自鹵素原子、胺基、烷基硫基、烷亞磺醯基、烧磺醯基與視需要經取代之芳基之基團取代之烷基，（b)環烧基，（c)式-N(R8)(R9)之基團，（d)視需要經取代之芳基，或（e)視需要經取代之飽和或不飽和雜環基；或！^42與R43 一者彼此以其終端結合’而與鄰接之氮原子一起形成視需要可經取代之飽和或不飽和含氨雜環基，其他符號係如以上所定義。[Π-Α] and other symbols are as defined above, wherein Γ is a hydrogen atom, an alkyl group or a benzyl group; 30 s 31S695 200804294 HO-R41 [III-a] where R41 is a cycloalkyl group or a ring A substituted or unsaturated heterocyclic group is required, or (2) a compound of the formula [II-A] is reacted with an amine or an anthracene compound of the formula [in-b] or a salt thereof: HN(R42)(R43) [II 卜b] wherein one of 'R and R43 is a hydrogen atom or a burnt group, and the other is (&) optionally selected from a halogen atom, an amine group, an alkylthio group, a methanesulfinium group. a group substituted with a sulfonyl group and an alkyl group optionally substituted with an aryl group, (b) a cycloalkyl group, (c) a group of the formula -N(R8)(R9), (d) as needed Substituted aryl, or (e) a saturated or unsaturated heterocyclic group which is optionally substituted; or ^42 and R43, which are bonded to each other by their terminal', together with the adjacent nitrogen atom, form a saturated or unsaturated amino-containing heterocyclic group which may be optionally substituted, and other symbols are as defined above.

Ra為氳原子時，上述反應（1)與反應（2)能在含縮合劑以及含或不含活化劑與鹼之溶劑中進行。溶劑之實例包括任何不影響反應之溶劑，例如二氣曱烷、三氯甲烧 (chloroform)、二曱基曱醯胺、二曱基乙醯胺、四氳咬喃、一卩亏烧（dioxane)、曱本、本、1，2-二氯乙烧、1 一曱基σ比口各唆酮、1，2-二甲氧基乙烧等。縮合劑可為例如：二環己基碳二亞胺（dicyclohexylcarbodiimide，DCC)、1-乙基-3 - (3-二曱基胺基丙基）碳二亞胺鹽酸鹽（WSC HC1)、疊氮鱗酸二苯酯（diphenylphosphoryl azide，DPPA)、幾基二口米唑 (CDI)、鼠膦酸一乙酯（diethyl cyanophosphonate， 318695 31 200804294 DEPC)、二異丙基碳二亞胺（DIpCi)、六氟鱗酸苯并三唑 -1-基氧基參啦咯啶基鱗（PyB〇p)、羰基二（三唑）、N—環己 -基碳二亞胺-Γ-丙基氧曱基、聚苯乙烯（PS—碳二亞胺）、N— 乙氧羰基-2-乙氧基-ι，2-二氫喹啉（EEDQ)、六氟磷酸2-(7-氮雜苯并三唑—1一基I 3, 3一四曱基脲鏽（2一（7一 azabenzotriazol-l-yi)-1，1，3, 3-tetramethyluronium hexaf luorophosphate，HATU)、六氟磷酸 2-(1H-苯并三唑 —卜基）-1，1，3, 3-四甲基脲鏽（HBTU)、六氟磷酸溴參吼咯啶基鱗（PyBroP)、四氟硼酸2-(1H-苯并三唑-1-基）-1，1， 3, 3-四甲基脲鏽（TBTU)、六氯銻酸氯—丨，丨，3, 3一四甲基脲麵I (ACTU)等。活化劑之實例包括··卜羥基苯并三唑（Η〇Βΐ)、 1-羥基琥珀醯亞胺（H〇Su)、二曱胺基吡啶（DMAp)、卜羥基 - 7-氮雜苯并三唑（Η〇Αΐ)、羥基呔醯亞胺（H〇pht)、五氟酚 (Pfp OH)、1 -輕基苯并三嗤—石黃酿胺基甲基聚苯乙稀 (PS-HOBt)等。鹼包括例如··吡啶、三乙胺、二異丙基乙基月女4甲基嗎福啉、l 8一二氮雜雙環[5, 〇]一7一十一烯⑺別) 等。上述製程中，化合物[Π-A]之使用量為每一莫耳化合物[III-a]或化合物[ni-b]可使用〇· 33至1· 5莫耳，較佳為0· 5至1 · 2莫耳。縮合劑之使用量為每一莫耳化合物 [Η A]、化合物[hi—a]或化合物[hi—b]可使用1〇至3 〇莫耳較佳為1·〇至1.2莫耳。鹼之使用量為每一莫耳化合物[Π-A]、化合物[in—a]或化合*[ni-b]可使用i 〇 3 · 〇莫耳，較佳為1 · 〇至1 · 2莫耳。活化劑之使用量為 318695 32 200804294 母莫耳化5物[II-A]、化合物[π I-a]或化合物[11 υ] 可使用0.01至2.0莫耳，較佳為〇」至10莫耳。反應能在0至150°C進行，較佳為2〇至8(TC。化合物[II-A]之ΪΤ為氫原子時，化合物[丨_幻能藉由將化合物[I Ι-A]轉變成對應之反應性衍生物（例如，酸鹵化物、混合酸酐），然後在鹼存在下，於溶劑中或無溶劑下使此反應性衍生物與化合物[ln_a]或化合物^丨卜…反應而予以製備。 “ 化合物[II-A]之Ra為烷基或苯甲基時，本方法A亦能藉由習知方式進行，例如以水解、使用鹽酸、曱酸、三氟乙酸等之酸解或氫化反應，將化合物[Π_Α]轉變成對應之下式[II-Aa]之羧酸化合物··When Ra is a halogen atom, the above reaction (1) and reaction (2) can be carried out in a solvent containing a condensing agent and with or without an activator and a base. Examples of the solvent include any solvent which does not affect the reaction, such as dioxane, chloroform, dimethyl decylamine, dimercaptoacetamide, tetraterpene, and dioxane. ), transcript, bis, 1,2-dichloroethane, 1 fluorenyl σ, ketone, 1,2-dimethoxyethane, and the like. The condensing agent may be, for example, dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-didecylaminopropyl)carbodiimide hydrochloride (WSC HC1), stacked Diphenylphosphoryl azide (DPPA), dibasic bis-imidazole (CDI), diethyl cyanophosphonate (318695 31 200804294 DEPC), diisopropyl carbodiimide (DIpCi) , benzotriazol-1-yloxy-salrrolidinyl scale (PyB〇p), carbonyl bis(triazole), N-cyclohexylcarbodiimide-Γ-propyl oxygen Sulfhydryl, polystyrene (PS-carbodiimide), N-ethoxycarbonyl-2-ethoxy-m,2-dihydroquinoline (EEDQ), 2-(7-azabenzene hexafluorophosphate) And triazole-l-yl I 3,3-tetradecylurea rust (2-azabenzotriazol-l-yi-1,1,3,3-tetramethyluronium hexaf luorophosphate, HATU), hexafluorophosphate 2- (1H-benzotriazol-bu)-1,1,3,3-tetramethylurea rust (HBTU), bromopyridinium hexafluorophosphate (PyBroP), tetrafluoroborate 2-(1H -benzotriazol-1-yl)-1,1,3,3-tetramethylurea rust (TBTU), hexachloroantimonate chloride - , hydrazine, 3, 3-tetramethylurea surface I (ACTU), etc. Examples of activators include hydroxybenzotriazole (Η〇Βΐ), 1-hydroxysuccinimide (H〇Su), Di-guanidinopyridine (DMAp), hydroxy- 7-azabenzotriazole (Η〇Αΐ), hydroxy quinone imine (H〇pht), pentafluorophenol (Pfp OH), 1-light benzene And triterpene-stone yellow amino-polystyrene (PS-HOBt), etc. The base includes, for example, pyridine, triethylamine, diisopropylethyl virgin 4 methylmorpholine, l 8 A diazabicyclo[5, fluorene]-7 undene (7), etc. In the above process, the compound [Π-A] is used in an amount of from 33 33 to 1.5 moles per mole of the compound [III-a] or the compound [ni-b], preferably from 0.5 to 5. 1 · 2 moules. The condensing agent is used in an amount of from 1 Torr to 3 Torr, preferably from 1 Torr to 1.2 moles per mole of the compound [Η A], the compound [hi-a] or the compound [hi-b]. The amount of the base used may be i 〇 3 · 〇 Mo Er, preferably 1 · 〇 to 1 · 2 per mole of the compound [Π-A], the compound [in-a] or the compound *[ni-b] Moor. The activator is used in an amount of 318695 32 200804294. The mother molybdenum 5 [II-A], the compound [π I-a] or the compound [11 υ] may be used in an amount of 0.01 to 2.0 mol, preferably 〇" to 10 mol. The reaction can be carried out at 0 to 150 ° C, preferably 2 to 8 (TC.) When the compound [II-A] is a hydrogen atom, the compound [丨_幻幻 can be converted by converting the compound [I Ι-A] Corresponding to a reactive derivative (for example, an acid halide, a mixed acid anhydride), and then reacting the reactive derivative with the compound [ln_a] or the compound in the presence or absence of a solvent in a solvent or without a solvent. When the Ra of the compound [II-A] is an alkyl group or a benzyl group, the method A can also be carried out by a conventional method, for example, hydrolysis, hydrolysis using hydrochloric acid, citric acid, trifluoroacetic acid or the like. Or a hydrogenation reaction, converting the compound [Π_Α] into a carboxylic acid compound corresponding to the following formula [II-Aa]·

式中’符號係如以上所定義，然後使羧酸化合物[n—Aa] 與化合物[III-a]或化合物[Πΐ-b]以如上述相同之方式反應而進行。本發明化合物[I ]中，E為式（i)之基團，Q2為伸烷基，且R4為式-N(R42)(R43)基團之化合物，換言之，即下式[I一B] 之化合物： 33 318695 200804294The symbol in the formula is as defined above, and then the carboxylic acid compound [n-Aa] is reacted with the compound [III-a] or the compound [Πΐ-b] in the same manner as described above. In the compound [I] of the present invention, E is a group of the formula (i), Q2 is an alkylene group, and R4 is a compound of the formula -N(R42)(R43) group, in other words, the following formula [I-B] Compound: 33 318695 200804294

式中，Q22為伸烷基，而其他符號係如以上所定義，能藉由使下式[II-B]之化合物與化合物[ln-b]4其鹽類反應來製備：Wherein Q22 is an alkylene group, and the other symbols are as defined above, which can be prepared by reacting a compound of the following formula [II-B] with a salt of the compound [ln-b]4:

[Π-Β] 式中，X為鹵素原子，而其他符號係如以上所定義。化合物[II-B]與化合物[IH-b]之反應能在含或不含鹼之/合剎中進行。溶劑之實例包括任何不影響反應之溶劑’例如二氯甲烷、三氯甲烷、=曱基曱醯胺、二甲基乙醯胺、二甲亞砜（dimethyl sulf〇xide)、四氳呋喃、二口琴文兀甲笨笨、1，2-一氯乙烧、1-甲基π比略咬酮、1，2 —二甲氧基乙烷等。鹼包括例如：吡啶、彡乙胺、二異丙基：基胺、4-甲基嗎福啉、18一二氮雜雙環[5, 4, 〇]—卜十一 (DBU)、碳酸鉀等。上述製程中，化合物[ΙΠ-b]之使用量為每一莫耳化^ 物[II-B]可使用丨^至別莫耳，較佳為1〇至3 〇莫耳1 驗之使用量為每—莫耳化合物[ΙΠ-b]或化合物[Π_Β] 使用0。至20莫耳，較佳為1〇至3 〇莫耳。反應能在—2 至100 C進行，較佳為〇至5〇。〇。[Π-Β] wherein X is a halogen atom, and other symbols are as defined above. The reaction of the compound [II-B] with the compound [IH-b] can be carried out in the presence or absence of a base. Examples of the solvent include any solvent which does not affect the reaction, such as dichloromethane, chloroform, decyl decylamine, dimethyl acetamide, dimethyl sulfoxixide, tetrahydrofuran, The harmonica is stupid, 1,2-chloroethane, 1-methyl π, ketone, 1,2-dimethoxyethane, and the like. The base includes, for example, pyridine, guanylamine, diisopropyl: amine, 4-methylmorpholine, 18-diazabicyclo [5, 4, fluorene]-b eleven (DBU), potassium carbonate, etc. . In the above process, the compound [ΙΠ-b] is used in an amount of from 丨^ to 别莫耳, preferably from 1〇 to 3 〇莫耳1, per mole of the compound [II-B]. Use 0 for each mole compound [ΙΠ-b] or compound [Π_Β]. Up to 20 moles, preferably 1 to 3 moles. The reaction can be carried out at from -2 to 100 C, preferably from 〇 to 5 Torr. Hey.

方法C 318695 34 200804294 ⑴本發明化合物⑴中，E為式⑴之基目，Q1為式 -Ν(ί〇-之基團，Q2為單鍵，且R4為式_w(r42)(r43)基團之化合物，換言之，即下SU-C]之化合物：Method C 318695 34 200804294 (1) In the compound (1) of the present invention, E is a group of the formula (1), Q1 is a group of the formula -Ν(〇〇-, Q2 is a single bond, and R4 is a formula of _w(r42)(r43) a compound of a group, in other words, a compound of SU-C]:

式中，符號係如以上所定義，能藉由使下如卜G]之化合物兵化合物[III-13]在式[a]化合物存在τ反應來製備：In the formula, the symbol is as defined above, and can be produced by reacting a compound of the compound [III-13] of the following formula (a) in the presence of τ in the compound of the formula [a]:

[n-c] 式中，符號係如以上所定義， W1-C0-W2 [&] 式中，W與W2相同或不同，且為脫離基團。 ^物[a]中，W]與W2之實例包括：σ米唑基、_素原子與苯氧基。此化合物之具體實例包括：L广羰基—二咪唾、光氣（ph〇sgene)、三光氣等。反應所用溶劑^實例包括任何不影響反應之溶劑，例如乙腈、二氯甲n氯甲烷三1，2-二氯乙烷、四氫呋喃等。化合*[Ιπ—^之使用量為每-莫耳化合物[n_c]可使用1G至莫耳，較佳為 1.0至1.2莫耳。化合物[a]之使用量為每—莫耳化人物 [ιι-c]或化合物[m_b]可使用1〇至5 〇莫耳，較^為乂〇至2. 0莫耳。反應能在_2〇至1〇〇〇c進行，較佳為〇至 318695 35 200804294 (2)此外，化合物[I-C]亦能藉由使化合物[η—c]與化合物[a ]反應而產生式[IV ]之化合物：[n-c] wherein the symbol is as defined above, W1-C0-W2 [&] wherein W is the same as or different from W2 and is a leaving group. In the object [a], examples of W] and W2 include: σ-mizozolyl, _-primary and phenoxy. Specific examples of the compound include: L-polycarbonyl-dimethine, ph〇sgene, triphosgene, and the like. The solvent used in the reaction is exemplified by any solvent which does not affect the reaction, such as acetonitrile, m-chlorochloromethane, 1,2-dichloroethane, tetrahydrofuran, and the like. The amount of compounding *[Ιπ-^ used may be from 1 G to mol, preferably from 1.0 to 1.2 mol per mol% of the compound [n_c]. The compound [a] is used in an amount of from 1 to 5 moles per mole of the character [ιι-c] or the compound [m_b], and is more than 2. 0 moles. The reaction can be carried out at _2 Torr to 1 〇〇〇c, preferably 〇 318 695 35 200804294 (2) Further, the compound [IC] can also be produced by reacting the compound [η-c] with the compound [a]. a compound of the formula [IV]:

式中’符號係如以上所定義，然後使該產物或其反應性衍生物與化合物[III-b]反應，或使化合物[ΙΠ—|3]與化合物 [a ]反應產生式[V ]之化合物：Wherein the symbol is as defined above, and then the product or its reactive derivative is reacted with the compound [III-b], or the compound [ΙΠ-|3] is reacted with the compound [a] to give the formula [V] Compound:

式中，符號係如以上所定義，然後使該產物[v]或其反應性衍生物與化合物[n—c]反應而製備。化合物[IV]或化合物[V]之反應性衍生物之實例包括該等W2經轉變成下式基團之化合物··In the formula, the symbol is as defined above, and then the product [v] or a reactive derivative thereof is reacted with the compound [n-c] to prepare. Examples of the reactive derivative of the compound [IV] or the compound [V] include the compounds in which the W2 is converted into a group of the following formula.

而此等反應性衍生物能藉由使W2為咪唑基之化合物[v]與碘曱烷反應而得到。，、化a物[Π -c ]或化合物[I π -b ]與化合物[a ]之反應能在’合劑中進行。溶劑之實例包括任何不影響反應之溶劑， J如乙腈一氯甲烧、1，2-二氣乙烧、苯、甲苯、四氫咬南人丨’2 —甲氧基乙烷等。化合物[a]之使用量為每一莫耳一物[II ◦]或化合物[ΙΠ-b]可使用ΐ·〇至3.0莫耳，較 318695 36 200804294 佳為1 · 〇至1 · 2莫耳為 20 至 8〇t：。。本反應能在0至15〇°C進行較佳將化合物[IV]或化合物⑺轉變成其反應性衍生物之心广b藉由例如使该化合物“”或化合物[v]肖齒化燒如 /、甲烷在,奋μ彳中反應來進行。本反應能在〇至艺進行，較佳為20至80。(：。化合物[IV](或其反應性衍生物）與化合物[Η 之反應或化合物[v](或其反應性衍生物）與化合物[丨卜c]之反應能在含驗之溶财進行。溶劑之實例包括任何不影塑/應之溶劑，例如二氯甲烷、三氯甲烷、二甲基甲醯胺、二甲基^醯胺、二甲亞砜、四氫呋喃、二Π萼烷、甲苯、苯、— =氯乙烧、卜甲基料㈣、U—二甲氧基乙烧等。驗之實例包括··吡啶、三乙胺、二異丙基乙基胺、4—曱基嗎福琳、二氮雜雙環[5,4，Q] —7—十—稀（_等。此等反應性何生物之使用量為每—莫耳化合物[ΙΠ—邮化合物 [Π-C]可使用〇·33至3·〇莫耳，較佳為〇.5至i2莫耳。反應能在-30至lOOt：進行，較佳為〇至5〇t：。 (3)再者，化合物[丨—c]中，R?為氫原子之化合物，換吕之即下式[I-Ca]之化合物：These reactive derivatives can be obtained by reacting a compound [v] having an imidazolyl group with iodonane. The reaction of the a substance [Π -c ] or the compound [I π -b ] with the compound [a] can be carried out in a mixture. Examples of the solvent include any solvent which does not affect the reaction, such as acetonitrile-chloromethane, 1,2-diethylene b-ethene, benzene, toluene, tetrahydro-n-butyl phthalate, and 2-methoxyethane. The compound [a] can be used in an amount of one mole per compound [II ◦] or a compound [ΙΠ-b] can be used from ΐ·〇 to 3.0 moles, compared to 318695 36 200804294 preferably 1 · 〇 to 1 · 2 moles For 20 to 8 〇t:. . The reaction can be carried out at 0 to 15 ° C to preferably convert the compound [IV] or the compound (7) into a reactive derivative, by, for example, causing the compound "" or the compound [v] to be oscillated. /, methane in the reaction, to react. The reaction can be carried out at a temperature of from 20 to 80. (: The reaction of the compound [IV] (or its reactive derivative) with the compound [Η or the compound [v] (or its reactive derivative) and the compound [丨卜c] can be dissolved in the test. Examples of the solvent include any solvent which is not plasticized/supplemented, such as dichloromethane, chloroform, dimethylformamide, dimethylamine, dimethyl sulfoxide, tetrahydrofuran, dioxane, Toluene, benzene, - = chloroethene, methyl (4), U-dimethoxyethane, etc. Examples include pyridine, triethylamine, diisopropylethylamine, 4-mercapto Lin, diazabicyclo[5,4,Q]-7-d-lean (_ et al. The use of these reactive organisms is per-mole compound [ΙΠ-mail compound [Π-C] can be used 〇·33 to 3·〇莫耳, preferably 〇.5 to i2 mol. The reaction energy can be carried out at -30 to 100 t: preferably 〇 to 5 〇 t: (3) Further, the compound [丨In -c], R? is a compound of a hydrogen atom, and the compound of the formula [I-Ca] is replaced by the following:

式中，符號係如以上所定義’能藉由使下式[χχιν]之異氰酸醋化合物與化合物[ni—b]或其鹽類反應來製備： 37 318695 [XXIV] 200804294 式中’符號係如以上所定義。㈣、能在含驗而含或不含活化劑之溶劑。溶叙貫例包括任何不影響反應之溶割，例如峰喃、二噚烷、三氯甲烷、二氯甲烷、H : γ ^ ^ ，—甲氣基乙炫、其：’。欢之貫例包括：三乙胺、二異丙基乙基胺、Ν-甲基嗎褐嚇等。活化劑可為4_二甲基胺基_+料唆基吼唆等。化合物[m-b]或其鹽類之使用量為每物[XXIV]可使用以至5^莫耳，較佳為u至u莫耳°。本反應能在-50至5(TC進行，較佳為_1〇至3〇t：。Wherein the symbol is as defined above, which can be prepared by reacting an isocyanate compound of the formula [χχιν] with a compound [ni-b] or a salt thereof: 37 318695 [XXIV] 200804294 where the symbol Is as defined above. (4) A solvent capable of containing or not containing an activator. Examples of dissolution include any dissolution which does not affect the reaction, such as peak, dioxane, chloroform, methylene chloride, H: γ ^ ^, -methyl carbyl, which: '. Examples of joy include: triethylamine, diisopropylethylamine, guanidine-methyl chlorophene. The activator may be 4-dimethylamino group _ + hydrazinyl hydrazine or the like. The compound [m-b] or a salt thereof is used in an amount of 5 μmol, preferably u to u mole, per [XXIV]. The reaction can be carried out at -50 to 5 (TC, preferably from _1 Torr to 3 Torr).

方法D "本發明化合物[I]中，E為式⑴之基團，到2為單鍵或氧原子之化合物，換言之，即下式门-^之化合物： r2)^n【q21_r4 _ 式中，符號係如以上所定義，能藉由使化合物[n-C]與羧酸化合物[1 ]或其反應性衍生物反應來製備： R4-Q21-C〇〇h [i] 式中，符號係如以上所定義。本反應能以如方法A之方式進行。Process D " In the compound [I] of the present invention, E is a group of the formula (1), and a compound having a single bond or an oxygen atom to 2, in other words, a compound of the following formula: r2)^n[q21_r4 _ In the above, the symbol is as defined above, and can be prepared by reacting the compound [nC] with the carboxylic acid compound [1 ] or a reactive derivative thereof: R4-Q21-C〇〇h [i] where As defined above. This reaction can be carried out in the same manner as in Process A.

方法E 38 318695 200804294 方法E-(i) 本發明化合物Π]中，E為式（11)基團之化合物，換言之’即下式[I-E]之化合物：Process E 38 318695 200804294 Process E-(i) In the compound Π] of the present invention, E is a compound of the group of the formula (11), in other words, a compound of the following formula [I-E]:

[I-E] 式中，符號係如以上所定義，能藉由使式n—Ea]之化合物與脫水劑在含驗之溶劑中反應來製備：[I-E] wherein the symbol is as defined above, which can be prepared by reacting a compound of the formula n-Ea] with a dehydrating agent in a solvent to be tested:

式中，符號係如以上所定義。溶劑之實例包括任何不影響反應之溶劑，例如二氯甲烷、三氯甲烷、四氫呋喃、二氯乙烷、甲苯、乙腈等。鹼之實例包括··三乙胺、二異丙基乙基胺、二甲基胺基吡啶等。脫水劑可為氯化2一氯—丨，3一一曱基咪嗤鏽、五氣化石粦、聚石粦酸（p〇lyph〇spholic acid)、鱗醯氯（phosphorus oxychloride)、亞硫酸氯 (thionyl chloride)等。本反應能在-1〇至80°C進行，較佳為10至50°C。方法E-(ii) 本發明化合物[I ]中，Q1與Q2為單鍵，且E為式（i i i ) 基團之化合物，能依據例如以下反應式E-(i i)來製備：反應式E-(ii) 39 318695 200804294Wherein the symbols are as defined above. Examples of the solvent include any solvent which does not affect the reaction, such as dichloromethane, chloroform, tetrahydrofuran, dichloroethane, toluene, acetonitrile and the like. Examples of the base include triethylamine, diisopropylethylamine, dimethylaminopyridine and the like. The dehydrating agent may be chlorinated 2-chloro-hydrazine, 3-indan-carbyl rust, five-gas fossil mites, p〇lyph〇spholic acid, phosphorous oxychloride, chlorine sulfite. (thionyl chloride) and the like. The reaction can be carried out at from -1 to 80 ° C, preferably from 10 to 50 ° C. Process E-(ii) In the compound [I] of the present invention, a compound in which Q1 and Q2 are a single bond and E is a group of the formula (iii) can be produced, for example, according to the following reaction formula E-(ii): -(ii) 39 318695 200804294

1 OR3 步驟 EM ι R w'^vw11 r2/n、i/ h 人J 飞阳] [I-EA2] \^) 上述反應式中，Boc為三級丁氧基羰基，wh與？"為_ 素原子，環A’為4至6員含氮雜環基，而其他符號係如以上所定義。反應步驟E1 -1 : 化合物[II-Ea]與化合物[2E]之反應能以如方法A之方式進行。反應步驟E1-2 : —化合物[3E]與化合物[5Ea]或其鹽類之反應，能在含鹼 =/合d中進行。化合物[5Ea ]之鹽類實例包括鹽酸鹽等。溶劑之實例包括任何不影響反應之溶劑，例如甲醇、乙醇、異丙醇、四氫呋喃、二噚烷、N，N_二甲基甲醯胺、二石風、二衰审、— _ . 山分、二氣甲烷、苯、甲苯等。鹼之實例包括：仄酉欠鉀、妷酸氫鈉、碳酸鈉、磷酸氫鈉、甲醇鈉、乙三級丁醇細、=7 ^ 甲二乙胺、吡啶等。此外，化合物[3E ]與化合 31869 40 200804294 物[5Eb]之反應亦能以如上述之方式進行反應步驟E1- 3 : 方式（例如，酸處移除化合物[4E]之B〇c基可依據習知理）來進行。反應步驟E1-4 : 化合物[卜則與化合物_之反應，能在含驗之溶^ 中進行。溶劑之實例包括任何不影響反應之溶劑，例如二腈、N，N-二甲基甲醯胺、四氫呋喃、二氯甲烷、三氯甲烷、一虱乙烷、二噚烷、二曱氧基乙烷等。鹼之實例包括··碳酸鉀、碳酸氫鈉、碳酸鈉、磷酸氳鈉、三乙胺、吡啶人方法E-(iii) 疋本發明化合物[I]中，Q1與Q2為單鍵，且E為式（iv) 基團之化合物，例如能依據以下反應式E—(iii)來反應式E-(iii) " ·1 OR3 Step EM ι R w'^vw11 r2/n, i/ h Person J Feiyang] [I-EA2] \^) In the above reaction formula, Boc is a tertiary butoxycarbonyl group, wh and ? " is a _ atom, ring A' is a 4 to 6 member nitrogen-containing heterocyclic group, and other symbols are as defined above. Reaction step E1 -1 : The reaction of the compound [II-Ea] with the compound [2E] can be carried out in the same manner as in the method A. Reaction Step E1-2: The reaction of the compound [3E] with the compound [5Ea] or a salt thereof can be carried out in the presence of a base = / d. Examples of the salt of the compound [5Ea] include a hydrochloride and the like. Examples of the solvent include any solvent which does not affect the reaction, such as methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, N,N-dimethylformamide, two stone wind, two failure test, - _. , two gas methane, benzene, toluene, etc. Examples of the base include: potassium hydride, sodium hydrogen hydride, sodium carbonate, sodium hydrogen phosphate, sodium methoxide, ethylene tertiary butanol, = 7 ^ methyl diethylamine, pyridine, and the like. Further, the reaction of the compound [3E] with the compound 31869 40 200804294 [5Eb] can also be carried out in the same manner as described above in the reaction step E1 - 3 : (for example, the acid removal of the compound [4E] B 〇 c group can be based on Xi Zhili) to carry out. Reaction Step E1-4: The reaction of the compound [Bu] with the compound _ can be carried out in the test solution. Examples of the solvent include any solvent which does not affect the reaction, such as dinitrile, N,N-dimethylformamide, tetrahydrofuran, dichloromethane, chloroform, monoethyl ethane, dioxane, dimethoxyl Alkane, etc. Examples of the base include potassium carbonate, sodium hydrogencarbonate, sodium carbonate, sodium citrate, triethylamine, and pyridine human method E-(iii). In the compound [I] of the present invention, Q1 and Q2 are single bonds, and E A compound of the formula (iv), for example, can be reacted according to the following reaction formula E-(iii): E-(iii) "

步驟E2-4 RA2C0C1 [12E]Step E2-4 RA2C0C1 [12E]

41 318695 200804294 上述反應式中，符號係如以上所定義。反應步驟E2-1 : 化合物[11—Ea]與化合物[7E]之反應能以與方法a所述之相同方式進行。反應步驟E2-2 : 將化合物[8E]轉變成化合物[9E]能在含硫化劑之溶劑中進行。溶劑之實例包括任何不影響反應之溶劑，例如曱苯、苯、二甲苯、四氫呋喃、二-烷、二氯甲烷、三氯曱烷等。硫化劑之實例包括：拉威森氏（Lawess〇n/s)試劑、五硫化二磷等。反應步驟E2-3 : 、士化合物[9E]與化合物[10幻或其鹽的反應能在含鹼之溶劑中進行。化合物[105:]之鹽可為鹽酸鹽等。溶劑之實例包括任何不影響反應之溶劑，例如乙醇、甲醇、異丙醇、 :氫吱鳴、二嗜烧、二甲基甲醯胺、二m二氯甲烧、氯仿$甲笨等。驗之貫例包括碳酸鉀、碟酸氫納、碳酸鈉、磷酸氫鈉、曱醇鈉、乙醇鈉'第三丁醇鉀、三乙胺、吡啶等。一反應步驟E2-4 : 、—化合物[11E]與化合物[12E]之反應能在含驗之溶劑中進行。溶劑之實例包括任何不影響反應之溶劑，例如二氯甲烷、二甲基曱醯胺、四氫呋喃、二氯乙⑥、二噚烷、1 〒氧基乙烧專。驗之貫例包括：二，脸山 —乙月女、吡啶、碳酸鉀、碳酸氫納、碳酸納、構酸氫納等。 318695 42 20080429441 318695 200804294 In the above reaction formula, the symbols are as defined above. Reaction step E2-1: The reaction of the compound [11-Ea] with the compound [7E] can be carried out in the same manner as the method a. Reaction step E2-2: Conversion of the compound [8E] to the compound [9E] can be carried out in a solvent containing a vulcanizing agent. Examples of the solvent include any solvent which does not affect the reaction, such as benzene, benzene, xylene, tetrahydrofuran, di-alkane, dichloromethane, trichloromethane or the like. Examples of the vulcanizing agent include: Lawessen(R)/s. reagent, phosphorus pentasulfide, and the like. Reaction Step E2-3: The reaction of the compound [9E] with the compound [10 phantom or its salt can be carried out in a solvent containing a base. The salt of the compound [105:] may be a hydrochloride or the like. Examples of the solvent include any solvent which does not affect the reaction, such as ethanol, methanol, isopropanol, hydroquinone, diacetoin, dimethylformamide, m-dichloromethane, chloroform, and chloroform. Examples of the test include potassium carbonate, sodium hydrogencarbonate, sodium carbonate, sodium hydrogen phosphate, sodium decoxide, sodium ethoxide, potassium t-butoxide, triethylamine, pyridine, and the like. A reaction step E2-4: - the reaction of the compound [11E] with the compound [12E] can be carried out in a solvent. Examples of the solvent include any solvent which does not affect the reaction, such as methylene chloride, dimethyl decylamine, tetrahydrofuran, dichloroethane 6, dioxane, and methoxy ethene. The examples include: 2, face mountain - female, pyridine, potassium carbonate, sodium bicarbonate, sodium carbonate, acid hydrogen hydride and so on. 318695 42 200804294

方法F 且y為伸乙本發明化合物[I]中，E為式⑴之基團，基之化合物，換言之，即下式[I-F]之化合物Process F and y are exoethyl. In the compound [I] of the present invention, E is a group of the formula (1), a compound of the group, in other words, a compound of the following formula [I-F]

能藉由例如使下式[Π-F]之鹽類反應來製備：式中’符號係如以上所定義，化合物與化合*[In—b]或其It can be prepared, for example, by reacting a salt of the formula [Π-F]: wherein the symbol is as defined above, the compound and the compound *[In-b] or

[II-F] 式中，符號係如以上所定義。夫许f — 本反應能在含驗之溶劑中In the formula [II-F], the symbols are as defined above.夫许f — This reaction can be in the solvent of the test

灯。洛劑之實例包括任何 ^ T 里而醢 ^ + 仃不衫響反應之溶劑，例如乙醇呉丙知、四氣呋喃、二曙俨吁風寺。鹼之貫例包括：三乙 _田 r ，萨嗞笙几人仏「了 —兴丙基乙基胺、N-甲馬子田啉專。化合物[III-b]或发鴎初 | 入私「ΤΤΡΊ 風矢員之使用量為每一草耳 a物[II-F]可使用1.0至3』 =莫耳 i 夭十旱乂佳為1·1至耳。本反應能在20至200tit ].5 方法G 丁 1 乂么為50至i00t:。本發明化合物[I ]中，E為彳Γ 且R4為經側氧基取代之飽和5 : j團:^為單鍵’ 物，換言之，即下式[卜G]之化合物貝,3輯單環基之化合 318695 43 200804294light. Examples of the agent include any solvent which is in the range of ^ T and 醢 ^ + does not react, such as ethanol, propylene, tetrahydrofuran, and Erqi Yufeng Temple. Examples of alkalis include: Sanyi _ Tian r, Saji several people 仏 "-- propyl propylamine, N-methyl methine porphyrin. Compound [III-b] or hairpinchu | private" ΤΤΡΊ The amount of use of the wind stalker is 1.0 to 3 for each turf abundance [II-F] = 1 to 1 ear to the ear. The reaction can be between 20 and 200 tit. 5 Method G 11 乂 is 50 to i00t: In the compound [I] of the present invention, E is 彳Γ and R4 is saturated by a side oxy group 5: j group: ^ is a single bond', in other words, Compound of the following formula [Bu G], compound of 3 series of monocyclic groups 318695 43 200804294

[I-G] 來製備[I-G] to prepare

W5—(CH2)P-CO-W6 [10] 式中W與W為鹵素原子，而其他符號係如以上所定義。本反應⑽在含驗之_中進行。溶劑之實例包括任何 !影響反應之溶劑，例如m、三氯μ、乙腈、四W5—(CH2)P-CO-W6 [10] wherein W and W are halogen atoms, and other symbols are as defined above. This reaction (10) is carried out in the test. Examples of the solvent include any solvent that affects the reaction, such as m, trichloro-, acetonitrile, tetra

虱吱喃、二H琴烧、Ν Ν- -田I m你A • 一 5兀丨N，iN —甲基甲醯胺、乙醇等。鹼之實例包括·二乙胺、二異丙基乙基胺、N-甲基嗎福琳等。化合物[ίο]之使用里為每_莫耳化合物[h—g]可使们· 〇至。· 〇莫耳較么為1· 1至2. 〇莫耳。本反應能在—1〇至 C進行，較佳為3〇至8〇它。方法Η 4本發明化合物[1]中，Ε為式⑴之基目，Q2為單鍵，且R為1，1-二側氧基—!^_硫代嗎福啉基之化合物，換言之，即下式[Ι-Η]之化合物：、 44 31S695 200804294虱吱、, 二 H 琴, Ν Ν - - 田 I m you A • a 5 兀丨 N, iN — methyl carbamide, ethanol, etc. Examples of the base include diethylamine, diisopropylethylamine, N-methylionine, and the like. The compound [ίο] can be used in every _ mole compound [h-g]. · 〇莫耳是为1·1 to 2. 〇莫耳. The reaction can be carried out at -1 to C, preferably from 3 to 8 . Method Η 4 In the compound [1] of the present invention, hydrazine is a group of the formula (1), Q2 is a single bond, and R is a 1,1-di- oxy-!^-thiomorpholinyl compound, in other words, That is, the compound of the following formula [Ι-Η]: , 44 31S695 200804294

[I-H] 式中’其他符號係如以上物[n—G]與二乙_在含驗之二：：由例如使上述化合甲苯、N，N-二甲基甲醯胺曱亞石風等。驗之實例實例包括任何不影響反應之來製備。溶劑之噚烷、田例如乙醇、異丙醇、二包括·二乙胺、二異丙基乙基、、一美σ比哈耸^ ^ 甲基嗎福啉、二曱胺土專。一乙烯颯之使用量為每一草耳#人铷「TT rl # 1 η 5 ^ Π - ^ 莫耳化合物[II-G]可[IH] In the formula, the other symbols are as follows [n-G] and diethyl _ in the second test: by, for example, the above-mentioned compound toluene, N,N-dimethylformamide, slate, etc. . EXAMPLES Examples include any preparation that does not affect the reaction. Solvents of decane, fields such as ethanol, isopropanol, di-diethylamine, diisopropylethyl, and a sigma- sulphate ^ ^ methyl porphyrin, diammonium. The amount of ethylene used is 1 铷 TT TT rl # 1 η 5 ^ Π - ^ More compound [II-G]

便用1· 0至3. 0旲耳，較佳為J .pn q 玍U旲耳。本反應能在60至20(TC進行，較佳為8〇至16吖。It is preferably from 1.0 to 3. 0 ears, preferably J.pn q 玍U ears. The reaction can be carried out at 60 to 20 (TC, preferably 8 to 16 Torr).

方法I 4本發明化合物[I]中’ E為式⑴之基團，q2為單鍵，且R4為經飽和之5至7貞含氮雜單環絲狀胺基，而該含氮雜單環基I經侧氧基取代者，換言之，即下式[H] 之化合物： V2 [Μ] (ch2〆式中’Z為酿基，q為2至3之整數，r為1至2之整數，而其他符號係如以上所定義，能藉由例如使下式— 之化合物進行分子内環化反應來製備： 45 318695 200804294 [I-Ia]Process I 4 In the compound [I] of the present invention, 'E is a group of the formula (1), q2 is a single bond, and R4 is a saturated 5- to 7-inch nitrogen-containing monocyclic filamentous amine group, and the nitrogen-containing simple single Ring group I is substituted by a pendant oxy group, in other words, a compound of the following formula [H]: V2 [Μ] (wherein 'Z is a brewing group, q is an integer of 2 to 3, and r is 1 to 2 Integers, and other symbols, as defined above, can be prepared, for example, by intramolecular cyclization of a compound of the formula: 45 318695 200804294 [I-Ia]

(CH2)rW5 (CH2)rH^HZ 式中，符號係如以上所定義。本反應能在含鹼之溶劑中進行。溶劑之實例包括任何不影響反應之溶劑，例如二氯甲烷、亞颯、二曱基咪唑啶酮（dimethyl imidazolidone)、乙腈、四氫呋喃、1，2-二曱氧基乙烷、i，2-二氯乙烷等。驗之實例包括：氫化鈉、氳化鉀、碳酸鉀、碳酸鉋、乙醇麵等。驗之使用量為每一莫耳化合物[I — Ia]可使用1〇至5 〇莫耳’較佳為1.1至1·5莫耳。本反應能在4〇至200 °C進行，較佳為80至12〇。(：。(CH2)rW5 (CH2)rH^HZ wherein the symbol is as defined above. This reaction can be carried out in a solvent containing a base. Examples of the solvent include any solvent which does not affect the reaction, such as dichloromethane, hydrazine, dimethyl imidazolidone, acetonitrile, tetrahydrofuran, 1,2-dimethoxy ethane, i, 2-di Ethyl chloride and the like. Examples of the test include sodium hydride, potassium telluride, potassium carbonate, carbonic acid planing, and ethanol surface. It can be used in an amount of from 1 Torr to 5 Torr, preferably from 1.1 to 1.5 moles per mole of the compound [I - Ia]. The reaction can be carried out at 4 to 200 ° C, preferably 80 to 12 °. (:.

方法J 本發明化合物[I]中，下式[I-J]之化合物： [I-J]Process J In the compound [I] of the present invention, the compound of the following formula [I-J]: [I-J]

卜NBu N

^RX 式中’符就係如以上所定義，能藉由例如使化合物[π 一 G] ”下式[Ac-Ι ]之羧酸化合物或其反應性衍生物（例如，對應之酸齒化物、酸酐）起反應來製備··^RX is a carboxylic acid compound or a reactive derivative thereof (for example, a corresponding acid dentate) as defined above, which can be obtained, for example, by the compound [π-G]"[Ac-Ι] , anhydride) reacted to prepare ··

Rx~C00H [Ac-1] 式中符就係如以上所定義。本反應能以與上述方法a相同之方式進行。本毛明化合物[I]中，下式[I-K]之化合物： 46 318695 200804294 [I-K]Rx~C00H [Ac-1] is the same as defined above. This reaction can be carried out in the same manner as in the above method a. In the present compound [I], the compound of the following formula [I-K]: 46 318695 200804294 [I-K]

RVC R2/ "N Jr-O-K44 式中，R44為視需要經取代之飽和或不飽和雜單環基，而其他符號係如以上所定義，能藉由例如使化合或其反應性衍生物與下式[11 ]之醇類化合物起反應來製備： & R44 - 0H [11] 式中’符號係如以上所定義。本反應能以如上述方法C ( 2 ) 之相同方式進行。本發明之標的化合物[I ]亦能藉由例如使以上所得之化合物[I]中之RVR2等取代基進行分子内轉變成為所期望之取代基來製備。分子内轉變之製程能依據標的取代基之種類予以選擇，並可例如以下列方法（a)至（f)來進行。方法（a) : RVR2之取代基為氰基（或含氰基之基團）之化合物[I]，能藉由使rW為鹵素原子（或含卣素之基團）之對應化合物[I]與氰化物（例如，氰化辞、氰化銅、氰化三甲基矽烷、氰化鉀等）在催化劑、鹼與添加劑之存在或不存在下起反應而製得。鹼之實例包括··三乙胺、N—甲基六虱《比咬、二異丙基乙基胺等。催化劑之實例包括：把催化劑’例如乙酸鈀、參（二苯亞甲基丙酮）二鈀、反式二氯雙（三環己膦）鈀、肆（三苯膦）鈀等，或鎳催化劑，例如二漠雙（三苯膦）銻等。添加劑之實例包括：膦化合物，例如三^膦、 1，广-雙（二苯膦基）二（環戊二埽）鐵、消旋2，r_雙（二苯 318695 47 200804294 膦基）—1，1 —聯萘、2 -（- -一你丁 I 一二級丁膦基）聯苯、2-(二環己膦基）聯苯、2 -二環己膦基—2 M m 獅丞2 -（N，N-二甲胺基）聯苯或三一二級丁膦等。 —— 方法⑻.具有燒基胺基或環烧基胺基（或含烧基胺或環烧基胺基之基團）之化合物⑴，能藉由使具函素原子之對應化σ物[1]與單或：垸基胺或環絲胺在催化劑、驗與添加劑之存在下歧應而製得。催化劑之實例可為用於方法⑷之妹合物與銅化合物等。添加劑之實例可為用於方法(a)之膦化合物等。鹼之實例包括：乙酸鉀、碳酸鉀、碳酸铯、三級丁醇鉀等。方法（c):具有烷基氧基（或含烷基氧基之基團）之化人物[1]’能藉由使具經基（或含經基之基團）之對應化合物[口^ 與鹵化烧在溶射起反應；或使具祕（或含烧基氧基之基團k對應化合物[I]與醇類在含鹼（例如，碳酸钟、碳酸鉋、氫化鈉等）或含活化劑（例如，偶氮二，酸二乙酯等）之溶;=)彳中，在經二取代之膦存在下起反應而製得。方法（d):具有烷亞磺醯基或烷磺醯基（或含烷亞磺醯基或院〜S&基之基團）之化合物⑴，能藉由在溶劑中以氧化劑，例如間氯過苯甲酸，處理具有烷基硫基（或含烷基硫基之基團）之對應化合物[丨]而製得。方法（e):具有醯胺基（或含醯胺基之基團）之化合物 [1]#，能藉由使具胺基（或含胺基之基團）之對應化合物與醯化劑，例如羧酸化合物[Ac — 川或反應性衍生物（例如，相應之酸南化物、對應之酸酐），起反應而製得。本反應能 318695 48 200804294 在3釦（例如，三乙胺）或含縮之溶劑中，在活化劑(例如，卜經可溶破二亞胺) •在下起反應而製得。土开一唑）存在或不存物[1]方二(二)由1有”酿基(或含胺甲酿基之基團)之化合其氧其Λ之其園讀中以氨處理具燒基氧基幾基（或含炫土乳基叛基之基團)之對應化合物⑴而製得。若有必要’前述製程所得之本發明化合物⑴，能以習知方式轉變成其醫藥上可接受鹽類。立1_間化合物之寧借 1)本發明中間化合物中，Q1為單鍵或伸烷基之化合物 [II Α]此以下列反應式Ai、Α2或A3所述之方式來製備。反應式A1RVC R2/ "N Jr-O-K44 wherein R44 is a saturated or unsaturated heteromonocyclic group which is optionally substituted, and the other symbols are as defined above, and can be derived, for example, by chemical combination or its reactivity. The compound is prepared by reacting with an alcohol compound of the following formula [11]: & R44 - 0H [11] wherein the 'symbol' is as defined above. This reaction can be carried out in the same manner as in the above method C ( 2 ). The subject compound [I] of the present invention can also be produced by, for example, subjecting a substituent such as RVR2 in the compound [I] obtained above to intramolecular conversion to a desired substituent. The process of intramolecular transformation can be selected depending on the type of the substituent, and can be carried out, for example, by the following methods (a) to (f). Process (a): a compound [I] wherein the substituent of RVR2 is a cyano group (or a group containing a cyano group), and the corresponding compound [I] capable of making rW a halogen atom (or a group containing a halogen) It is prepared by reacting with cyanide (for example, cyanide, copper cyanide, trimethyldecane cyanide, potassium cyanide, etc.) in the presence or absence of a catalyst, a base and an additive. Examples of the base include triethylamine, N-methylhexanene, specific biting, diisopropylethylamine and the like. Examples of the catalyst include: a catalyst such as palladium acetate, bis(methylenemethyleneacetone) dipalladium, trans dichlorobis(tricyclohexylphosphine)palladium, ruthenium (triphenylphosphine)palladium or the like, or a nickel catalyst, For example, Ermobi (triphenylphosphine) ruthenium and the like. Examples of the additive include: a phosphine compound such as tris(phosphine), 1, broad-bis(diphenylphosphino)di(cyclopentadienyl) iron, racemic 2, r-bis (diphenyl 318695 47 200804294 phosphino)- 1,1 -binaphthyl, 2 -(- -1-butyl I-dibutylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl, 2 -dicyclohexylphosphine- 2 M m Griffin 2 - (N, N-dimethylamino) biphenyl or tri- or di-butylphosphine. - Method (8). Compound (1) having an alkylamino group or a cycloalkylamino group (or a group containing a decylamine or a cycloalkylamine group) can be obtained by constituting a corresponding element of the sigma atom [ 1] is prepared by reacting with mono- or decylamine or cyclosamine in the presence of a catalyst, an additive, and an additive. Examples of the catalyst may be a sister compound for use in the method (4), a copper compound or the like. Examples of the additive may be a phosphine compound or the like used in the method (a). Examples of the base include potassium acetate, potassium carbonate, cesium carbonate, potassium tert-butoxide, and the like. Process (c): a person having an alkyloxy group (or an alkyloxy group-containing group) [1]' can be made by a corresponding compound having a trans group (or a group containing a radical) Reacting with a halogenated fire in a solution; or reacting a compound having a secret (or a group containing a calcinyloxy group k) with an alcohol in an alkali-containing (eg, carbonic acid clock, carbonic acid planer, sodium hydride, etc.) or activated Dissolving (for example, azodicarbonate, diethyl ester, etc.); =) hydrazine, obtained by reacting in the presence of a disubstituted phosphine. Process (d): Compound (1) having an alkylsulfinyl group or an alkanesulfonyl group (or a group containing a sulfinyl group or a sulfonate group), which can be used as an oxidizing agent such as m-chloro in a solvent Perbenzoic acid is prepared by treating a corresponding compound [丨] having an alkylthio group (or an alkylthio group-containing group). Process (e): a compound [1]# having a mercaptoamine group (or a group containing a mercapto group) capable of reacting a corresponding compound having an amine group (or an amine group-containing group) with a deuteration agent, For example, a carboxylic acid compound [Ac- or a reactive derivative (for example, a corresponding acid amide, a corresponding acid anhydride) is reacted. The reaction energy 318695 48 200804294 is obtained by reacting in an activator (for example, a bromide-soluble diimine) in a 3 button (for example, triethylamine) or a solvent containing a shrinkage. Soil-opening azole) presence or absence of material [1] square two (two) from the 1 "brewed base (or amine-containing base group) combination of its oxygen, its garden read with ammonia treatment The compound (1) of the present invention, which is obtained by the above-mentioned process, can be converted into its medicinal form in a conventional manner. Acceptable salts. 1) The compound of the present invention 1) In the intermediate compound of the present invention, the compound wherein Q1 is a single bond or an alkyl group [II Α] is as described in the following reaction formula Ai, Α 2 or A3 Preparation. Reaction Formula A1

RR

[vq 反應 m\[vq reaction m\

反應式A2 318695 49 200804294Reaction formula A2 318695 49 200804294

[d][d]

反應式A3 步驟疫〜11 i$rz™ -2 [χνη 去酯化反應 [XIV] [XV]Reaction Formula A3 Steps Epidemic ~11 i$rzTM -2 [χνη Deesterification [XIV] [XV]

上述反應式A1、Α2與A3中，R11為視需要經取代之芳 50 318695 200804294 基或視需要經取代之雜芳基；R31為視需要經選自鹵素原子、胺基、單烷基胺基與二烷基胺基基團取代之烷基；Raa 為氮原子或烧基；R為烧基；Rd為烧基或苯甲基；χ1、χ2 與X3為鹵素原子；W3為反應性殘基；W4為反應性殘基，而其他符號係如以上所定義。反應步驟A1-1 : 自化合物[VI ]產生化合物[V11 ]之反應能在含驗之溶劑中進行。鹼之實例包括：乙酸鈉、乙酸鉀、碳酸鈉、碳酸鉀、碳酸氫鈉、碳酸氫鉀、甲醇鈉、乙醇鈉等。溶劑之貫例包括任何不影響反應之溶劑，例如水、乙醇、甲醇、二噚烷、二曱基曱醯胺、二曱基乙醯胺等。鹼之使用量為母一莫耳化合物[VI]可使用1·0至20莫耳，較佳為1〇至3.0莫耳。本反應能在3〇至200 °C進行，較佳為60至 100〇C。反應步驟A1 -2 : 化合物[VII]與化合物[vi Π]之反應能在含鹼之溶劑中進行。鹼之實例包括：氳化鈉、氫化鉀、疊氮化鈉、二異丙胺基鋰、雙（三甲基矽烷基）胺基鋰、碳酸鉀、甲醇鈉、乙醇鈉等。溶劑之實例包括任何不影響反應之溶劑，例如一氯甲烷、苯、甲苯、四氫呋喃、二甲氧基乙烷、二噚烷、一甲基甲月女、二甲亞石風等。化合物[VIII]之使用量為每一莫耳化合物[VII]可使用！·〇至10莫耳，較佳為1()至 3· 0莫耳。鹼之使用量為每一莫耳化合物[VII]可使用I 〇至20莫耳，較佳為L0至5· 〇莫耳。本反應能在-30至100 318695 51 200804294 °C進行，較佳為20至60°C。同時，化合物[11 - A ]亦能在含活化劑（例如，偶氮二甲酸一乙酯）之溶劑中藉由使化合物[V11 ]與醇類化合物 .[VI11-a]反應來製備： R31-0H [VIII - a] 式中’符號係如以上所定義。溶劑之實例包括任何不影響反應之溶劑，例如二氯曱烷、三氯曱烷、二甲基曱醯胺、二甲基乙醯胺、二曱亞颯、四氫呋喃、二噚烷、曱苯、苯、 1，2-一氯乙烧、1一甲基σ比洛唆酮、1，2 —二甲氧基乙烧等。反應步驟Α2-1 : 以習知方式可使化合物[II—All]轉變成相應之反應性衍生物（化合物[IX ])。此反應性衍生物之實例包括相應之酉文鹵化物（化合物[IX]中γ為鹵素原子）或相應之混合酸酐 (化合物[IX]中W3為烷基氧基羰基氧基等）。相應之酸鹵化物能藉由例如使化合物[Π-Α11]與鹵化劑（例如，亞硫醯氯、磷醯氯、五氣化磷、草醯氯等）在含或不含催化劑量二甲基甲醯胺之溶劑或無溶劑中起反應來製備。此外，相應之混合酸酐能藉由例如使化合物[II-All]與氯甲酸烷酯 (例如氣甲酉文乙酯專）在驗（例如，三乙胺、二異丙基乙基胺等）存在下起反應來製備。溶劑之實例包括任何不影響反應之’谷釗，例如二氯甲烧、三氯甲烧、四氫°夫喃、苯、甲苯等。本反應能在-60至l〇(TC進行，較佳為—4〇至8(rc。反應步驟A2-2 : 匕曰物[IX ]轉、交成化合物[X ]能在含重氮甲烧化合物 318695 52 200804294 m’重w炫、三甲基钱基重氮甲燒等）。溶劑之實列!任何不影響反應之溶劑，例如乙醚、二噚烷、苯、 f氮甲烷化合物之使用量為每-莫耳化：物™ 可使用1·0至10莫耳，較佳為丨 .,η 5 0Λ〇旲斗权彳土為丨.0至3.〇莫耳。本反應能至8〇C進行’較佳為-10至50。(：。反應步驟A2-3 : 化合物⑴轉變成化合物[H-A12]之反應能在含或不 2銀鹽之溶财加熱予以進行。溶劑之實例包括任何不影曰^應之溶劑’例如水、醇（例如，f醇、乙醇）等。銀鹽之貫例包括：氧化銀、苯甲酸銀等。銀鹽之使用量為每一莫耳化合物[X]使用L0至2〇莫耳，較佳為ι 〇至5 〇莫耳。本反應能在50至20(rc進行，較佳為8〇至15吖。、反應步驟A2-4 : 化合物[XI]能藉由在含還原劑（例如，氫化㈣溶劑中還原化合物[叫⑴而得到。溶劑之實例包括任何不影響反應之溶劑，例如乙驗、四氫咬喃等。還原劑之用量為每一莫耳化合物[II-A11]可使用1.0至20莫耳，，佳為2.0S5.0莫耳。本反應能在_50幻〇rc進行：為-10 至 4(TC。化合物[XI]亦能藉由還原Rag烷基之化合物[丨卜A 而製得。本反應能在含還原劑例如简化鈉等之溶劑行。溶劑之實例包括任何不影響反應之溶劑，例如: 喃與曱醇之混合物等。還原劑之使用量為每一莫耳化人 [II-A1]可使用1.0至20莫耳，較佳為2 〇至5 〇莫^。 318695 53 200804294 本反應能在30至l〇0t進行，較佳為5〇至⑽。C。反應步驟A2-5 ·· 以習知方式可使化合物[XI]轉變成相應物（化合物[ΠΙ])。例如，r4“原子錢心轉^生藉由個別使Μ硫㈣例如亞硫氯⑽化丈元碩fe例如Τ磺醯氯來處理化合物[Χί]而予以製備。反應步驟A 2 - 6 : 化合物[ΧΙΠ與化合物⑷或其鹽類之反應能在含驗之洛劑中進行。化合物[d]之鹽類實例包括：金屬冑，例如卸鹽:溶劑之實例包括任何不影響反應之溶劑，例如乙鍵、四氫呋喃、苯、二甲基甲醯胺、二甲基乙醯胺、甲醇、乙。鹼貫例包括··氫化鈉、氫化鉀、甲醇鈉、乙醇鈉、二異丙胺基鋰、雙（三甲基矽烷基）胺基鋰等。化合物[d] 或其鹽類之使用量為每一莫耳化合*[χπ]可使用丨.〇至 10.0莫耳，較佳為1.5至3·〇莫耳。鹼之使用量為每一莫耳化合物[XII]可使用^至10·0莫耳，較佳為15至3 〇莫耳本反應此在-20至200°C進行，較佳為20至i〇〇°c。若有需要，Q1為6伸烷基之化合物[π—A]能藉由例如將上述步驟A2-3(或步驟A2-6)所得之標的化合物，利用去酯化反應轉變成相應之羧酸化合物，然後使此羧酸化合物進行步驟A2-1、A2-2與A2-3(或步驟A2-4、A2-5與Δ2-6) 一系列反應，重複以上製程至所欲次數而製得。 Q1為式-N(R7)-之化合物[π-A]能藉由例如使化合物 [II-Ae]或化合物[II-Af ](參見以下反應步驟（：卜4)進行 318695 54 200804294 習知去酯化反應而予以製備。反應步驟A3-1 : 化合物[XIV ]與化合物[χν ]之反應能在含驗之溶劑中進行。鹼之實例包括：碳酸鈉、碳酸鉀、碳酸氫鈉、碳酸氫鉀、氫化鈉、氫化鉀、二異丙胺基鋰、雙（三曱基矽烷基）胺基鋰、碳酸鉋等。溶劑之實例包括任何不影響反應之溶劑，例如二氯甲烷、三氯甲烷、二曱基曱醯胺、二曱基乙醯胺、二曱亞砜、四氳呋喃、二噚烷、曱苯、苯、I 2一二氣乙烷、1-甲基吡咯啶酮、丨’2一二曱氧基乙烷等。化合物 [XV]或其鹽類之使用量為每一莫耳化合物[χιν]可使用 1· 0至5· 0莫耳，較佳為h丨至2· 〇莫耳。鹼之使用量為母一莫耳化合物[XIV]可使用ι·〇至5·〇莫耳，較佳為1 1 至2.0莫耳。本反應能在-1〇至1〇(rc進行，較佳為2〇至 80t：。反應步驟A3-2 : 化合物[XVI]之去酯化反應能藉由使此化合物進行習知水解反應來進行。反應步驟A3-3 : 化合物[XVII]之分子内環化反應能在含函化劑及含不含活化劑之溶劑中進行。_化劑之實例包括：亞硫酿磷酿氯、五氯化碟、草酿氯等。活化劑之實例包括：^仆鋁、士化鐵(III)、三氯化硼、三氟化硼、四氯化鈦、四化錫等。溶劑之實例包括任何不影響反應之溶劑，例= 硫化碳、二氯甲烷、硝基曱烷、三氯曱烷、四氫呋喃、： 318695 55 200804294 口等烷、曱苯、苯、硝基苯、12-二氯乙烷、一二曱氧基乙烷等。鹵化劑之使用量為每一莫耳化合物[χνπ]可使用 1.0至5.0莫耳，較佳為hl至2 〇莫耳。本反應能在3〇至200C進行，較佳為8〇至i50°C。反應步驟A3-4 : 化合物[XVIII]與化合物[χιχ]之反應能在含鹼之溶劑中進行。鹼之貫例包括：鹼金屬醇鹽，例如甲醇鈉丨鹼金屬胺化物，例如二異丙胺基鋰；鹼金屬氫化物，例如氫化鈉等。溶劑之實例包括任何不影響反應之溶劑，例如乙醇、 :醇、四氫呋喃、二-烷、甲苯、苯、I 2一二甲氧基乙烷等。化合物[XIX]或其鹽類之使用量為每一莫耳化合物 [XVIII]使用1· 〇至3· 〇莫耳，較佳為I 〇至L 5莫耳。鹼之使用量為每一莫耳化合物[χνιπ]可使用h 〇至5· 〇莫耳，較佳為1· 1至3·〇莫耳。本反應能在-70至1501進行，較佳為-50至50。〇。反應步驟A 3 - 5 : 〜化合物[XX]與化合物[XXI]之反應能在含或不含鹼之岭剡中進仃。鹼之實例包括：吡啶、三乙胺、二異丙基乙，胺、4-甲基嗎福啉、I 8—二氮雜雙環[5, 4, 〇]十一烯等。溶劑之實例包括任何不影響反應之溶劑，例如乙醇、甲醇、四氣咬喃、二嗜垸、甲苯、苯、1，2-二曱氧基乙院等。化合物[XXI]之使用量為每一莫耳化合物[χχ]可使用1· 〇至莫耳，較佳為^至h5莫耳。本反應能在—1()至1〇〇 c進行，較佳為20至6〇艺。 318695 56 200804294In the above reaction formulas A1, Α2 and A3, R11 is an optionally substituted aryl 50 318695 200804294 group or an optionally substituted heteroaryl group; and R31 is optionally selected from a halogen atom, an amine group, a monoalkylamine group. An alkyl group substituted with a dialkylamino group; Raa is a nitrogen atom or a burnt group; R is an alkyl group; Rd is an alkyl group or a benzyl group; χ1, χ2 and X3 are halogen atoms; and W3 is a reactive residue. ; W4 is a reactive residue, and other symbols are as defined above. Reaction Step A1-1: The reaction of the compound [V11] from the compound [VI] can be carried out in the solvent to be tested. Examples of the base include sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium methoxide, sodium ethoxide and the like. Examples of the solvent include any solvent which does not affect the reaction, such as water, ethanol, methanol, dioxane, dimethyl decylamine, dimethyl acetamide, and the like. The amount of the base used is from 1 to 0 to 20 moles, preferably from 1 to 3.0 moles, of the mother-mole compound [VI]. The reaction can be carried out at 3 to 200 ° C, preferably 60 to 100 ° C. Reaction Step A1 - 2: The reaction of the compound [VII] with the compound [vi Π] can be carried out in a solvent containing a base. Examples of the base include sodium hydride, potassium hydride, sodium azide, lithium diisopropylamide, lithium bis(trimethyldecyl)amine, potassium carbonate, sodium methoxide, sodium ethoxide and the like. Examples of the solvent include any solvent which does not affect the reaction, such as methyl chloride, benzene, toluene, tetrahydrofuran, dimethoxyethane, dioxane, monomethyl methacrylate, dimethyl sulphur, and the like. The compound [VIII] is used in an amount per mole of the compound [VII]! • 〇 to 10 moles, preferably 1 () to 3.0 moles. The base is used in an amount of from 1 Torr to 20 mol, preferably from L0 to 5 mol, per mol of the compound [VII]. The reaction can be carried out at -30 to 100 318695 51 200804294 ° C, preferably 20 to 60 ° C. Meanwhile, the compound [11 - A ] can also be produced by reacting the compound [V11 ] with an alcohol compound [VI11-a] in a solvent containing an activator (for example, monoethyl azodicarboxylate): R31 -0H [VIII - a] where the 'symbol' is as defined above. Examples of the solvent include any solvent which does not affect the reaction, such as dichloromethane, trichlorodecane, dimethylamine, dimethylacetamide, diterpenoid, tetrahydrofuran, dioxane, toluene, Benzene, 1,2-chloroethane, 1-methyl σ-poicone, 1,2-dimethoxyethane, and the like. Reaction step Α2-1: The compound [II-All] can be converted into the corresponding reactive derivative (compound [IX]) in a conventional manner. Examples of the reactive derivative include the corresponding oxime halide (wherein γ is a halogen atom in the compound [IX]) or a corresponding mixed acid anhydride (W3 in the compound [IX] is an alkyloxycarbonyloxy group or the like). Corresponding acid halides can be obtained, for example, by reacting a compound [Π-Α11] with a halogenating agent (for example, sulfinium chloride, phosphonium chloride, phosphorus pentoxide, grass mash, etc.) with or without a catalyst amount of dimethyl It is prepared by reacting a solvent of carbamide or a solvent. Further, the corresponding mixed acid anhydride can be tested by, for example, the compound [II-All] and an alkyl chloroformate (for example, acetaminophen) (for example, triethylamine, diisopropylethylamine, etc.) There is a reaction to prepare. Examples of the solvent include any of the gluten which does not affect the reaction, such as methylene chloride, trichloromethane, tetrahydrofuran, benzene, toluene and the like. The reaction can be carried out at -60 to 1 Torr (TC, preferably -4 Torr to 8 (rc. Reaction step A2-2: oxime [IX] conversion, crosslinking into compound [X] can be in the presence of diazo Burning compound 318695 52 200804294 m' heavy w Hyun, trimethyl ketone diazepine, etc.) Solvent list! Any solvent that does not affect the reaction, such as the use of ether, dioxane, benzene, f nitrogen compounds The amount is per-mole: TM can be used from 1 to 0 to 10 m, preferably 丨., η 5 0 Λ〇旲彳彳丨 0 0 0 0 0 0 0 。。。。。。。。。。。。。 8 〇 C is carried out 'preferably from -10 to 50. (:. Reaction step A2-3: The reaction of converting the compound (1) into the compound [H-A12] can be carried out by heating with or without a silver salt. Examples include any solvent that does not affect the solution, such as water, alcohol (for example, f alcohol, ethanol), etc. Examples of silver salts include: silver oxide, silver benzoate, etc. The amount of silver salt used is The ear compound [X] is used in an amount of from 0 to 2 mol, preferably from 1 to 5 mol. The reaction can be carried out at 50 to 20 (rc, preferably 8 to 15). Reaction step A2-4 : Compound [XI] can be A reducing agent (for example, a hydrogenated (tetra) solvent is obtained by reducing a compound [referred to as (1). Examples of the solvent include any solvent which does not affect the reaction, such as an assay, tetrahydroanthracene, etc. The amount of the reducing agent is each mole compound [II] -A11] can be used with 1.0 to 20 moles, preferably 2.0S5.0 moles. This reaction can be carried out at _50 illusion rc: -10 to 4 (TC. Compound [XI] can also be reduced by Rag The compound of the alkyl group is prepared by using A. The reaction can be carried out in a solvent containing a reducing agent such as sodium or the like. Examples of the solvent include any solvent which does not affect the reaction, for example, a mixture of meranol and decyl alcohol, etc. The amount of use can be from 1.0 to 20 moles, preferably from 2 Torr to 5 Torr per mole of human [II-A1]. 318695 53 200804294 The reaction can be carried out at 30 to 10 Torr, preferably. 5〇至(10).C. Reaction Step A2-5 ·· In a conventional manner, the compound [XI] can be converted into a corresponding compound (compound [ΠΙ]). For example, r4 "atomic money" is made by individual Sulphur (4), such as sulfite (10), is prepared by treating the compound [Χί] with sulfonium chloride, for example, in the reaction step A 2 - 6 : The compound [ΧΙΠ and the compound (4) or a salt thereof can be reacted in the test agent. Examples of the salt of the compound [d] include: metal ruthenium, for example, salt removal: examples of the solvent include any reaction which does not affect the reaction. Solvents, such as ethyl bond, tetrahydrofuran, benzene, dimethylformamide, dimethylacetamide, methanol, B. Basic examples include sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, diisopropylamino Lithium, bis(trimethyldecyl)amino lithium, and the like. The compound [d] or a salt thereof is used in an amount of from 莫.〇 to 10.0 mol, preferably from 1.5 to 3 mol, per mol% of the compound [χπ]. The amount of the base used is from 0 to 10·0 moles, preferably from 15 to 3 moles per mole of the compound [XII]. This is carried out at -20 to 200 ° C, preferably 20 to i. 〇〇°c. If desired, the compound [π-A] wherein Q1 is a 6-alkyl group can be converted into the corresponding carboxylic acid by a de-esterification reaction by, for example, the above-obtained compound obtained in the above step A2-3 (or step A2-6). a compound, which is then subjected to a series of reactions of steps A2-1, A2-2 and A2-3 (or steps A2-4, A2-5 and Δ2-6), and the above process is repeated to the desired number of times. . The compound [π-A] wherein Q1 is a formula -N(R7)- can be carried out, for example, by subjecting the compound [II-Ae] or the compound [II-Af] (see the following reaction step (: Bu 4) 318695 54 200804294 The esterification reaction is carried out to prepare. Step A3-1: The reaction of the compound [XIV] with the compound [χν] can be carried out in a solvent containing the test. Examples of the base include sodium carbonate, potassium carbonate, sodium hydrogencarbonate, and carbonic acid. Potassium hydrogen hydride, sodium hydride, potassium hydride, lithium diisopropylamide, lithium bis(tridecyl decyl) alkoxide, carbonic acid planing, etc. Examples of the solvent include any solvent which does not affect the reaction, such as dichloromethane, chloroform. , dimethyl decylamine, dimercaptoacetamide, disulfoxide, tetrahydrofuran, dioxane, toluene, benzene, I 2 dioxaethane, 1-methylpyrrolidone, anthracene '2-dimethoxyethane, etc. The compound [XV] or its salt is used in an amount of from 1.0 to 5.0 moles per mole of the compound [χιν], preferably from h to 2 · 〇莫耳. The amount of base used is 1 - to 2.0 moles, preferably 1 to 2.0 moles. (arc, preferably 2 to 80 t: Reaction Step A3-2: Deesterification of Compound [XVI] can be carried out by subjecting the compound to a conventional hydrolysis reaction. Reaction Step A3-3: Compound [ The intramolecular cyclization reaction of XVII] can be carried out in a solvent containing a functionalizer and a solvent containing no activator. Examples of the chemical agent include: sulphur, phosphorus, chlorine, sulphuric acid, chlorine, etc. Examples of the agent include: servant aluminum, iron (III), boron trichloride, boron trifluoride, titanium tetrachloride, tin tetrachloride, etc. Examples of the solvent include any solvent which does not affect the reaction, for example, vulcanization Carbon, dichloromethane, nitrodecane, trichlorodecane, tetrahydrofuran,: 318695 55 200804294 Oral alkane, toluene, benzene, nitrobenzene, 12-dichloroethane, monodecyloxyethane, etc. The halogenating agent is used in an amount of 1.0 to 5.0 moles, preferably hl to 2 moles per mole of the compound [χνπ]. The reaction can be carried out at 3 to 200 C, preferably 8 to i50. °C. Reaction step A3-4: The reaction of the compound [XVIII] with the compound [χιχ] can be carried out in a solvent containing a base. Is alkoxide, such as sodium methoxide metal aminide, such as lithium diisopropylamide; alkali metal hydride, such as sodium hydride, etc. Examples of the solvent include any solvent that does not affect the reaction, such as ethanol, alcohol, tetrahydrofuran, two - alkane, toluene, benzene, I 2 -dimethoxyethane, etc. The compound [XIX] or a salt thereof is used in an amount of from 1 Torr to 3 Torr per mole of the compound [XVIII]. Preferably, the amount of the base is from 0 to · mol, preferably from 1 to 3 〇 mol, per mole of the compound [χνιπ]. The reaction can be carried out at from -70 to 1501, preferably from -50 to 50. Hey. Reaction Step A 3 - 5 : The reaction of the compound [XX] with the compound [XXI] can be carried out in the presence or absence of a base. Examples of the base include pyridine, triethylamine, diisopropylethyl, amine, 4-methylmorpholine, I 8-diazabicyclo[5,4,fluorenyl]undecene and the like. Examples of the solvent include any solvent which does not affect the reaction, such as ethanol, methanol, tetrachatopyrene, dioxins, toluene, benzene, 1,2-dimethoxyoxyl, and the like. The compound [XXI] is used in an amount of from 1 Torr to Mohr per mole of the compound [χχ], preferably from ^ to h5. The reaction can be carried out at from -1 () to 1 〇〇 c, preferably from 20 to 6 Å. 318695 56 200804294

i i)化合物[11〜B ]能藉由例如使用化合物[Π - Aa ]或相應之一烧基醯胺化合物或相應之N-烧基-N-烧基氧基酿胺 .化合物依據下列反應式B來製備：反應式BIi) the compound [11~B] can be used, for example, by using the compound [Π-Aa] or the corresponding one of the decylamine compound or the corresponding N-alkyl-N-alkyloxylanamine. Preparation by B: Reaction Formula B

ΡΙ·Β] 上述反應式中，Rc為烷基，γ為鹵素原子，而其他符號係如以上所定義。反應步驟Β1-1 : 化合物[II-Aa]與化合物[bl ]或化合物[b2]之反應能在溶劑中進行。溶劑之實例包括任何不影響反應之溶劑，，如乙醚、四氫呋喃、二噚烷、二甲氧基乙烷、苯、甲笨等。化合物[bl]或化合物[1)2]之使用量為每一莫耳化合物 [Π-Aa]可使用2.0至3 〇莫耳，較佳為2 〇至2 5莫耳。本反應能在-50至8(TC進行，較佳為_1〇至4〇。〇。反應步驟B1-2 : 制中進行。齒化劑之 (—甲基乙醯胺）二演 ^化合物[χΧΙΙ]之鹵化反應能在溶例包括. >臭、Ν-溴號j白醯亞胺、雙 318695 57 200804294 /臭酸等。溶劑之實例包括任何不影響反應之溶劑，例如乙醚、二氯甲烷、1，2-二氯乙烷、三氯曱烷、四氯化碳等。鹵化劑之使用量為每一莫耳化合物[χχπ]可使用丨· 〇至。3.〇莫耳，較佳為1〇至2〇莫耳。本反應能在“ο至μ C進行，較佳為〇至3〇°c。 111)化合物[Ιΐ-c]例如能以下列反應式C1所述之方式來製備：反應式C1 OR3r1Vvco〇h tui ^ τ>2 疊氮化反應 [II-Ac ] (azidation) OR3ΡΙ·Β] In the above reaction formula, Rc is an alkyl group, γ is a halogen atom, and other symbols are as defined above. Reaction step Β1-1: The reaction of the compound [II-Aa] with the compound [b1] or the compound [b2] can be carried out in a solvent. Examples of the solvent include any solvent which does not affect the reaction, such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, benzene, methyl bastene and the like. The compound [bl] or the compound [1) 2] is used in an amount of 2.0 to 3 moles per mole of the compound [Π-Aa], preferably 2 to 25 moles. The reaction can be carried out at -50 to 8 (TC, preferably 1-1 Torr to 4 Torr. 反应. Reaction step B1-2: carried out in the process. Toothing agent (-methylethyl oxime) [χΧΙΙ] The halogenation reaction can be included in the solution: > odor, Ν-bromine, leucomine, 318695 57 200804294 / odor acid, etc. Examples of the solvent include any solvent which does not affect the reaction, such as diethyl ether, Methyl chloride, 1,2-dichloroethane, trichlorodecane, carbon tetrachloride, etc. The amount of halogenating agent used is 每一· 〇 to each mole compound [χχπ]. 3. 〇莫耳, Preferably, the reaction is carried out at "o to μ C, preferably from 〇 to 3 ° C. 111.) The compound [Ιΐ-c] can be, for example, represented by the following reaction formula C1. By way of preparation: Reaction formula C1 OR3r1Vvco〇h tui ^ τ>2 Azidation reaction [II-Ac] (azidation) OR3

CON3 步驟 Cl-2 庫爾提斯(Curtius) [xxm ]重排 R1^rNco ϋCON3 Step Cl-2 Curtius [xxm] Rearrangement R1^rNco ϋ

步驟 [2 Cl-4 RStep [2 Cl-4 R

R2 酸處理 {… 烷化反應 [XXIV] R rTT„ , R2 [n_Ca] [II-Cb] 上述反應式中，R71為烷基，而其他符號係如以上所定義。反應步驟C1 -1 : 化合物[11 -Ac]與疊氮化劑之反應能在含鹼之溶劑中 $行。溶劑之實例包括任何不影響反應之溶劑，例如丙酮、苯、甲苯、四氫呋喃、乙醚等。疊氮化劑之實例包括：疊氮磷酸二苯酯（DPPA)、疊氮化鈉等。鹼之實例包括：吡啶、 :乙胺、二異丙基乙基胺、4_甲基嗎福啉、U—二氮雜雙 %[5, 4, 0]十一烯等。疊氮化劑之使用量為每一莫耳化合物R2 acid treatment {... alkylation reaction [XXIV] R rTT„ , R2 [n_Ca] [II-Cb] In the above reaction formula, R71 is an alkyl group, and other symbols are as defined above. Reaction step C1 -1 : Compound The reaction of [11 -Ac] with an azide can be carried out in a solvent containing a base. Examples of the solvent include any solvent which does not affect the reaction, such as acetone, benzene, toluene, tetrahydrofuran, diethyl ether, etc. azide Examples include: diphenylphosphoryl azide (DPPA), sodium azide, etc. Examples of the base include: pyridine, : ethylamine, diisopropylethylamine, 4-methylmorpholine, U-diazepine Miscellaneous double % [5, 4, 0] undecene, etc. The amount of azide is used per mole of compound

318695 58 200804294 [II-Ac]可使用1· 〇至5· 〇莫耳，較佳Λ 干乂 ι 土与1 · 1至2 η 鹼之使用量為每一莫耳化合物[n—Ac]可使用·莫耳。 -莫耳，較佳為1. 1至3. 〇莫耳。本及廉^ ·〇至10·0 寸奉反應旎在〜3〇行，較佳為-10至lot。王M c進反應步驟C1-2 : 化合物[XXIV]能藉由在溶劑中加熱進行庫爾 (curtius)重排反應予以製備。溶劑之實例包括不反應之溶劑，例如苯、甲苯、二噚烷、三氯甲产應能在40至200〇c進行，較佳為60至12(rc。兀、本反反應步驟C1 -3 : 化合物[xm]之酸處理能在有或無溶劑中進行。之實例包括任何不影響反應之溶劑，例如水等。酸之^ =括：強酸，例如硫酸、鹽酸、硝酸、三氧乙酸、氫二酉欠之使用畺為母一莫耳化合物[XXIV]可使用£ 〇至。10.、0莫耳，較佳為3 0至5 〇莫耳。本反應能在〇至2⑽ C進行，較佳為4〇至12〇。〇。反應步驟C1 -4 : 化合物[II-Ca]之烷化反應能在溶劑中於下列丨）至3) “件下進行，例如1 )於驗（例如，氫化鈉、碳酸钾、吼疋—乙胺、一異丙基乙基胺、4-曱基嗎福琳、1，二气雜雙環[5,4, 0]十一烯等）以及式[χχν]之烷基^化物存在 —卜~ · R72-X4 [XXV] 式中，R2為烷基，χ4為鹵素原子；或2)於還原劑（例如， 318695 59 200804294 氯化減、蝴氫化納、氰基•化納、三乙ϋ氧基獨氫化鋼等）、酸（例如，乙酸、甲酸等）以㈣化合物[mi]存在 73 - cho [mi] 為烷基；<3)於活化劑(例如，偶氮二甲酸二乙 >73 式中苯膦丁膦等）以及式酯等）、經三取代之膦（例如 [XXV11 ]之醇化合物存在下·· R74 - OH [XXVII] ιΛϋ/4域基。溶劑之實例包括任何不影響反應4 = 二氯甲统、三氯甲垸、二甲基甲醯胺、二甲! 二胺、二甲亞砜、四氫呋喃、二0¥烷、甲苯、苯、^ 2_ 二氯乙烷、1 —甲基吡咯啶酮、1 一，應能在-20至loot；進行▲ ’ — ^*土乙燒等。本反 1UU b進仃，較佳為0至4〇〇c。 ^引5入、Γ有义要’可在化合物[n—Ca]進行燒化反應則，引入適當保護基（例如，烷基氧基，芳錢基氧基狀如如二級丁氧基幾土我丞叛基如本甲虱基羰基等）至3 保護基能依據該伴考其磁半土、㈣保4基種類’利用習知方式予以引入或去 I示化口物[ΙΙ-Cb]亦能藉由在式㈤之醇化合物中： r-Oif fej 式中’ R為三級丁基或！甲其應(反應步驟㈣而得到彻斯重排反 318695 60 200804294 ORe [II-Ae ] 然後使此化合物[11 -Ae ]與烷基鹵化物[]或醇化合物 [XXVII]反應，產生式[π-Af]之化合物：318695 58 200804294 [II-Ac] can be used from 1·〇 to 5· 〇莫耳, preferably Λ dry 乂 soil and 1 · 1 to 2 η alkali is used in the amount of each mole compound [n-Ac] Use · Mo Er. - Moore, preferably from 1. 1 to 3. 〇莫耳. This and the cheap ^ · 〇 to 10 · 0 inch of the reaction 旎 in the ~ 3 〇 line, preferably -10 to lot. The reaction of the compound M XX can be carried out by subjecting the compound [XXIV] to a curtius rearrangement reaction by heating in a solvent. Examples of the solvent include a solvent which does not react, for example, benzene, toluene, dioxane, and trichloromethane should be produced at 40 to 200 ° C, preferably 60 to 12 (rc. 兀, the present reaction step C1 -3) The acid treatment of the compound [xm] can be carried out in the presence or absence of a solvent. Examples include any solvent which does not affect the reaction, such as water, etc. Acids include: strong acids such as sulfuric acid, hydrochloric acid, nitric acid, trioxoacetic acid, The use of hydrazine as a parent-mole compound [XXIV] can be used up to 10. 0, 0 摩尔, preferably 30 to 5 〇 mol. The reaction can be carried out at 〇 to 2 (10) C, Preferably, it is 4 Torr to 12 Torr. 反应 Reaction step C1 -4 : The alkylation reaction of the compound [II-Ca] can be carried out in a solvent in the following 丨) to 3) ", for example, 1) in the test (for example) , sodium hydride, potassium carbonate, hydrazine-ethylamine, monoisopropylethylamine, 4-mercapto-florin, 1, di-heterobicyclo[5,4,0]undecene, etc.) The alkyl group of χχν] is present - b~ · R72-X4 [XXV] wherein R2 is an alkyl group, χ4 is a halogen atom; or 2) is a reducing agent (for example, 318695 59 200804294 chlorination reduction, butterfly hydrogenation , cyano group, sodium triethoxy hydride, etc.), acid (eg, acetic acid, formic acid, etc.) in the presence of (iv) compound [mi] 73 - cho [mi] is alkyl; <3) in activation a reagent (for example, phenylphosphonium azodicarboxylate), a phenylphosphine, etc., a trisubstituted phosphine (for example, an alcohol compound of [XXV11] in the presence of R74-OH [XXVII] Λϋ / 4 domain. Examples of solvents include any reaction 4 = dichloromethane, trichloromethane, dimethylformamide, dimethyl! diamine, dimethyl sulfoxide, tetrahydrofuran, dioxin , toluene, benzene, ^ 2_ dichloroethane, 1-methylpyrrolidone, 1 one, should be able to be in -20 to loot; ▲ '- ^ * earthy sulphur, etc. This anti-1UU b into the 仃Preferably, it is 0 to 4〇〇c. ^Introduction to 5, Γ有要要' can be carried out in the compound [n-Ca], and a suitable protecting group (for example, an alkyloxy group, an aryloxy group) Such as, for example, two-stage butoxy-based soils, such as thiol-based carbonyl groups, etc.) to 3, the protective group can be introduced or removed according to the magnetic semi-soil, (4) I The oral substance [ΙΙ-Cb] can also be obtained from the alcohol compound of the formula (5): r-Oif fej where 'R is a tertiary butyl group or a methicone (the reaction step (4) is obtained by the gas reversal reaction 318695 60 200804294 ORe [II-Ae ] This compound [11 -Ae ] is then reacted with an alkyl halide [] or an alcohol compound [XXVII] to give a compound of the formula [π-Af]:

式中，付號係如以上所定義，接著移除式Re〇c〇_醯基部份而予以製備。醯基部份之移除能利用（1)以酸例如鹽酸、三氟乙酸、氫溴酸等進行處理；或（2)在約15{rc加熱處理；或（3)進行催化性氫化反應。化合物[ΙΙ-F]能藉由使化合物⑴士]與化合物叫 (例如，烧基鐘如甲基旬在溶劑（例如，四氣咬喃）中反應然後使產物與『為乙婦基之化合物⑽（例如，溴化乙稀基鎂）反應來製備。化口物[11 G ]月匕藉由以如方法A所述之相同方式，使與式[12]之肼化合物或其鹽類反應，產物中移除醯基（Z)而製得·· 式中，Z為酿基。本發明之說明鱼Φ ^主* U々々丄 r .^ /、甲σ月專利乾圍中，「鹵素原子丨；贶、氯、蛾或溴原子。「烧美立共目女1 ^ A 1 5 A J 土」思扣具有Ϊ至6個碳原子 “、 _原子之直鏈或支鏈絲。「環烧基」意 318695 61 200804294 具有3至8個碳原子，較佳烧基」意指具有丨以個^^ 7個&原子之城基。「伸之直鏈或支鏈伸燒基。^，Μ為1至3個碳原子實施例本务明化合物藉由以下眚又處妒您Λ、W丄下只轭例予以更詳細地說明，但不應解釋成將本發明限制於此。實施例1 將嗎福琳(1.47克)、水可溶碳二亞胺鹽酸鹽 (.克上、1:經基苯并三哇水合物仙克)加至3,基 + (2 —乳本基)—5~(4'氯苯基)+甲氧基-1Η-爾5 克，芬相1⑻所得之化合物）之二氯甲烧αοο毫升）溶液中’於室溫㈣混合物一夜。然後將碳酸氣納水溶液加至反應混t物巾簡拌，接著用三㈣料取。有機層以硫酸鎮乾無後過遽。濾、液經真空濃縮後粗產物时膝管柱層析（溶劑：己烧/乙酸乙酯=40/60至20/80)進行純化，得二卜（2-氯苯基）-5-(4_氯苯基）_4_甲氧基_3|(n_嗎福琳基）胺甲醯基]-11{-吡唑（3.49克，產率81%)呈粉末。質譜（MS)數據： MS(大氣壓化學游離，APCI)m/z : 447/449[M+HJ + 實施例2 至溫下，將草醯氯（21微升）與一滴二甲基甲醯胺加至夢考例1(6)所得化合物（73毫克）之二氯甲烷（2毫升）溶液中，並在相同溫度下攪拌混合物丨小時。然後濃縮反應混合物，殘留物以四氫呋喃（2毫升）稀釋。接著加入N-胺基 318695 62 200804294 吡咯啶鹽酸鹽（123毫克）與三乙胺（279微升），室溫攪拌2 小時。加入IN HC1溶液（800微升）並攪拌。加入乙酸乙酯， -有機層用矽藻土（diatomaceous earth)管柱（CHEM ELUTE， VAR I AN公司製造）萃取。萃取液經真空濃縮後所得粗產物用矽膠管柱層析（Chr⑽atorex NH-矽膠，Fuji Silicia Chem·公司製造，溶劑：己烷/乙酸乙酯=50/50至30/70) 進行純化，得到1-(2-氯苯基）-5-(4-氯苯基）-4-甲氧基 -3-[N-(1_吡咯啶基）胺甲醯基]-1H-吡唑（43毫克，產率 50%)呈粉末。 MS(APCI)m/z ： 431/433[M+H]+ 貫施例3 (1) 在0°C、氮氣環境下，將甲基鋰（ι· 〇4M乙醚溶液， 13· 9毫升）逐滴加至參考例1(6)所得化合物（2· 5克）之四氫呋喃（100毫升）溶液中，並在相同溫度下攪拌混合物分鐘’然後室溫擾拌3小時。接著在冰冷卻下將水與乙酸乙酯加至反應混合物中並攪拌。有機層以碳酸氫鈉水溶液清洗，以硫酸鎂乾燥後過濾。濾液經真空濃縮後所得粗產物用矽膠管柱層析（溶劑：己烷/乙酸乙酯=9〇/1〇至85/15) 進行純化，得到3-乙醢基-1-(2-氯苯基）-5-(4-氯苯基） -4-曱氧基-1H-吡唑（1· 1克，產率43%)呈固體。 MS(APCI)m/z ： 361/363[M+H]+ (2) 將溴（8· 5微升）逐滴加至上述步驟（1)所得化合物 (6 0毫克）之三氯甲烷（3宅升）溶液中，室溫攪拌混合物3 小時。然後濃縮反應混合物，殘留物以二甲基甲酿胺（3毫In the formula, the pay is as defined above, and then the formula Re〇c〇_醯 is removed to prepare. The removal of the thiol moiety can be carried out by (1) treatment with an acid such as hydrochloric acid, trifluoroacetic acid, hydrobromic acid or the like; or (2) heat treatment at about 15 {rc; or (3) catalytic hydrogenation. The compound [ΙΙ-F] can be obtained by reacting the compound (1) with a compound (for example, a pyridyl group such as methyl ketone in a solvent (for example, tetracha) to form a compound with the compound. (10) (for example, ethyl bromide) is prepared by reacting. The compound [11 G ] is reacted with the hydrazine compound of the formula [12] or a salt thereof in the same manner as described in the method A. In the product, the thiol group (Z) is removed and the formula is obtained. In the formula, Z is a brewing base. The description of the invention is Φ ^ main * U々々丄r .^ /, A σ 专利 patent circumstance, " A halogen atom; a ruthenium, a chlorine, a moth or a bromine atom. "Smoke the beautiful female 1 ^ A 1 5 AJ soil" has a chain of up to 6 carbon atoms ", _ atoms of straight or branched wire." Cycloalkyl" 318695 61 200804294 having 3 to 8 carbon atoms, preferably alkyl" means having a group of ^^7 & atoms. "Stretching a straight chain or a branched chain." , Μ is 1 to 3 carbon atoms. The present invention is described in more detail by the following yoke, but it should not be construed as limiting the invention thereto. Example 1 Adding whallin (1.47 g), water-soluble carbodiimide hydrochloride (. gram, 1: benzotrizal hydrate) to 3, yl + (2 - Milk base) - 5 ~ (4 'chlorophenyl) + methoxy-1 Η - er 5 g, the compound obtained from the fen phase 1 (8)) in a solution of dichloromethane (αοοοοοοοοοοο Then, the aqueous solution of carbonic acid gas is added to the reaction mixture, and then mixed with three (four) materials. The organic layer is dried with sulfuric acid and dried without sputum. The filtrate is concentrated in vacuo and the crude product is subjected to knee column chromatography. Purification by solvent: hexane/ethyl acetate = 40/60 to 20/80) to give di(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy_3|(n _ 福琳 ) ) 胺 ] ] ] ] ] ] 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 [M+HJ + Example 2 To a solution of dichloromethane (21 μL) and a drop of dimethylformamide added to the compound (73 mg) of Dream Test 1 (6) to dichloromethane (2). (ml) in solution and stir the mixture at the same temperature for a few hours. Then concentrate the reaction mixture, residual Diluted with tetrahydrofuran (2 mL) followed by N-amino 318695 62 200804294 pyrrolidine hydrochloride (123 mg) and triethylamine (279 μL), stirred at room temperature for 2 hours. Add IN HC1 solution (800 micron) Ethyl acetate was added, and the organic layer was extracted with a diatomaceous earth column (CHEM ELUTE, manufactured by VAR I AN). The extract was concentrated in vacuo and the crude product was chromatographed with a silica gel column. (Chr(10)atorex NH-raycene, manufactured by Fuji Silicia Chem., solvent: hexane/ethyl acetate = 50/50 to 30/70) Purification to obtain 1-(2-chlorophenyl)-5-(4-chloro Phenyl)-4-methoxy-3-[N-(1-pyrrolidinyl)aminemethanyl]-1H-pyrazole (43 mg, yield 50%) was obtained as a powder. MS (APCI) m/z : 431/433 [M+H] + Example 3 (1) Methyl lithium (1·4M diethyl ether solution, 13.9 ml) at 0 ° C under nitrogen atmosphere It was added dropwise to a solution of the compound (2.5 g) obtained in Reference Example 1 (6) in tetrahydrofuran (100 ml), and the mixture was stirred at the same temperature for a minute and then stirred at room temperature for 3 hours. Water and ethyl acetate were then added to the reaction mixture under ice cooling and stirred. The organic layer was washed with aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give a crude product which was purified using EtOAc EtOAc EtOAc EtOAc Phenyl)-5-(4-chlorophenyl)-4-methoxy-1H-pyrazole (1.1 g, 43% yield) was obtained as a solid. MS (APCI) m/z : 361 / 363 [M+H] + (2) bromine (8.5 μl) was added dropwise to the compound (60 mg) of chloroform ( The mixture was stirred at room temperature for 3 hours. The reaction mixture was then concentrated and the residue was taken from dimethylamine (3 m

318695 63 200804294 升）稀釋。加入嗎福啉（146微升），然後室溫攪拌2小時。接著將水與乙酸乙酯加至反應混合物中並攪拌。有機層用 .石夕藻土管柱（CHEM ELUTE，VARIAN公司製造）萃取。萃取液 •經真空濃縮後所得粗產物用矽膠管柱層析（Chr⑽atorex NH-矽膠，Fuji Silicia chem.公司製造，溶劑：己烷/乙酉夂乙g曰80/20至65/35)進行純化，流出之區分液經真空濃备百所彳于產物以三級丁醇溶解後進行冷凍乾燥，得到3_ [(N，馬私琳基）乙酿基]-1-(2-氯苯基）-5-(4-氯笨基） 4甲氧基-1H-吡唑（26· 8毫克，產率36%乂呈粉末。 MS(APCI)m/z ： 446/448[M+H]+ 實施例4至13 、相應之起始物以如實施例1至3之一者中所述之相同方去處理，知到如下表1所示之化合物。 64 318695 200804294 表 1(1) 實施例號碼 R3 -N(R5)(R6) 物化性質等 4 ch3 H /N^CF3 | 固體 MS(APCI》444/446 [M+H]十 5 ch3 固體 MS(APCI): 445/447 [M+H]+ 6 ch3 固體 MS(電灑游離，ESI): 444 [M+H]+ 7 c2h5 固體 MS(APCI): 459/461 [M+H]+ 8 CH30(CH2)2- 固體 MS(APCI): 489/491 [M+H]+ 9 C2H5 HN-N 0 / \«f 固體 MS(APCI): 461/463 [M^-H]4* 65 318695 200804294 表 1(2)318695 63 200804294 liters) diluted. Add morphine (146 μl) and stir at room temperature for 2 hours. Water and ethyl acetate were then added to the reaction mixture and stirred. The organic layer was extracted with a stone column (CHEM ELUTE, manufactured by VARIAN Co., Ltd.). The extract was purified by vacuum chromatography on a silica gel column chromatography (Chr (10) atorex NH- phthalocyanine, manufactured by Fuji Silicia chem., solvent: hexane / acetonitrile 曰 80/20 to 65/35). The separated liquid is condensed in a vacuum and concentrated in a third-stage butanol, and then lyophilized to obtain 3_[(N, 玛琳琳) ethoxy] -1-(2-chlorophenyl)- 5-(4-chlorophenyl) 4methoxy-1H-pyrazole (26·8 mg, yield 36% 乂 as a powder. MS (APCI) m/z: 446/448 [M+H]+ Examples 4 to 13 and the corresponding starting materials were treated in the same manner as described in one of Examples 1 to 3, and the compounds shown in the following Table 1 were known. 64 318695 200804294 Table 1 (1) Example No. R3 -N(R5)(R6) Physicochemical properties, etc. 4 ch3 H /N^CF3 | Solid MS (APCI) 444/446 [M+H] 十 5 ch3 Solid MS (APCI): 445/447 [M+H] + 6 ch3 solid MS (electrospray free, ESI): 444 [M+H]+ 7 c2h5 solid MS (APCI): 459/461 [M+H]+ 8 CH30(CH2)2-solid MS (APCI): 489/491 [M+H]+ 9 C2H5 HN-N 0 / \«f Solid MS (APCI): 461/463 [M^-H]4* 65 318695 200804294 Table 1(2)

實施例14 將4-四氫硫代哌喃基胺（140毫克，參考例12(2)所得化合物）、水可溶碳二亞胺鹽酸鹽（230毫克）與1-羥基苯并三嗤水合物（184毫克）加至3 -叛基-1-(2 -氣苯基）-5-(4-氯苯基）-4-曱氧基-lH-u比唑（290毫克，參考例1(6)所得化 66 318695 200804294 基甲酿胺(6毫升/°.5毫升)之溶液 0、θ人&Λ 5物一仪。然後將碳酸氫鈉水溶液加至反、曲用二氣甲烷萃取。萃取液經真空粗產物时膠管柱層析（溶劑：己烧/乙酸乙酉旨= 基）+= = )進行純化’得到卜（2-氯苯基）-5-(4-氣苯土虱土 3 [N—(4-四氫硫代哌喃基）胺甲醯基]_1H一 t坐（323亳克，產率87%)呈無色固體。 MS(APCI)m/z ： 462/464[M+H]+ 實施例15 在〇 C將二氟乙酸（77微升）加至實施例14所得化合物（116毛克）之一氯甲烷毫升）溶液中，室溫攪拌混合物 30刀1里接著加入3 —氯過苯甲酸（58毫克，水含量2⑽），在相同溫度下攪拌1小時，室溫攪拌2小時。添加碳酸氫鈉水/合液至反應混合物中並攪拌，然後以三氯甲烷萃取。萃取液經真空濃縮後粗產物用矽膠管柱層析（溶劑··己烷/ 乙酸乙酯=50/50至30/70—三氯甲烷/甲醇= ι〇〇/〇至95/5) 進行純化，得到1-(2-氯苯基）—5 —(4-氯苯基）-4—甲氧基 -3-{N-[4-(1-側氧基四氫硫代哌喃基）]胺f醢基卜lfJ一吡唾（28· 5毫克，產率24%)呈無色固體。 MS(APCI)m/z ： 478/480[M+H]+ 實施例16 除3 -氯過本甲酸係使用115毫克外，將實施例14所得化合物（116毫克）以如實施例15相同之方法處理，得到卜（2-氯苯基）-5-（4-氯苯基）-4-甲氧基-3-[4-（1，1—二 318695 67 200804294 侧氧基四氫硫代哌喃基）]胺甲醯基丨_1H—吡唑（69毫克，產率56%)呈無色固體。 MS(APCI)m/z ： 494/496[M+H]+ 實施例17 將4-四氫硫代哌喃醇（61毫克）與扣二甲胺基吡啶（2〇毫克）加至參考例1(6)所得化合物（73毫克）之二氯甲烷宅升）溶液中並攪拌混合物。然後在〇。〇添加二環己基碳二亞胺（45毫克）至混合物中並室溫攪拌—夜。將碳酸氫納水溶液加至反應混合物中並擾拌，接著用三氯甲烧萃取。萃取液經真空濃縮後粗產物用矽膠管柱層析（溶劑··己烷/乙酸乙酯=77/23至53/47)進行純化，得到^(2-氯苯基） -5-（4-氯苯基）-4-甲氧基—3-(4-四氫硫代哌喃基氧基）羰基-1H-u比唑（53毫克，產率59%)呈無色固體。 MS(APCI)m/z ： 447/449[M+H]+ 實施例18 在〇c、氮氣環境下，將疊氮磷酸二苯酯（47微升）與三乙胺（33微升）加至參考例1(6)所得化合物（73毫克）之甲苯（3毫升）溶液中，然後在__混合物—夜。接著在冰冷卻下將4_四氫哌喃基胺（36毫克）與4-二甲胺基吼啶（2. 4毫克）加至反應混合物中’在8〇。〇攪拌一夜。接著加入碳酸氫鈉水溶液並攪拌，然後用矽藻土管柱（chem ELUTE VAR IAN公司製造）萃取。萃取液經真空濃縮後所得粗產物用矽膠官柱層析（溶劑：己烷/乙酸乙酯=⑽至 20/80)進行純化，得到卜（2_氯苯基）_5_([氯苯基經 318695 68 200804294 基-3-[Γ-(4-四氫哌喃基）脲基]—ι H-吡唑（1〇毫克，產去 —11%)呈無色固體。卞。MS(APCI)m/z : 461/463[M+H]+ 實施例19 (1) 將參考例17所得化合物（513毫克）與3 —胺基一工一二級丁氧羰基氮哩以如實施例；[所述之相同々到卜α4-二氣苯基）-5-(4一氣笨基）一4_甲格3=_= (1-三級丁氧羰基）氮哩基]胺甲醯基卜1Η-吡唑（59〇毫克，產率83%)呈固體。 MS(APCI)m/z ·· 551/553[Μ+Η] + (2) 將4NHC1-乙酸乙酯（2毫升）加至上述步驟（1)所得化合物（590毫克）之三氯甲則5毫升）溶液中，室溫授掉混合物一夜。然後真空濃縮反應混合物，添力口乙酸乙醋與碳酸氫納水錄至殘㈣巾並㈣。有機層以硫賴乾燥後過濾。濾液經真空濃縮後殘留物以二氯曱烷（2毫升）稀釋。接著加入三乙胺（30毫升）與對氯苯甲醯氯（35毫克）並室溫攪拌一夜。然後加入檸檬酸水溶液並攪拌。有機層以飽和碳酸氫納水溶液、鹽水清洗，以硫_乾燥後過遽曰。濾液經真空濃縮後殘留物以二甲基甲酸胺（1毫升）稀釋。接著加入氫化鈉（4毫克）並在8crc攪拌2日。冷卻至室溫後加入水與乙酸乙酯，有機層以乙酸乙醋萃取。萃取液經真空濃縮後所得粗產物用石夕膠管柱層析（溶劑：己烧/乙酸 ^旨=〇/_)進行純化，得到卜（m苯基）_5_(4_氯苯基）4 i基-3-{N-[3-(4-氯苯甲醯基）氮。旦基]胺甲醯基} 318695 69 200804294 -1 Η-吡唑（30毫克，產率52%)呈粉末。 MS(APCI)m/z： 589/591[M+H]+ .實施例20 (1)將1-二級丁氧羰基—3-胺基吡咯啶（279毫克）、水可溶碳二亞胺鹽酸鹽（288毫克）與1 —羥基苯并三唑水合物 (230毫克）加至3-羧基-1-(2-氯苯基）-5 — (4-氯苯基）一\-曱氧基-1H-吡唑（363毫克，參考例1(6)所得化合物）之二氯甲烧（5毫升）溶液中，室溫攪拌混合物一夜。然後將碳酸氫鈉水溶液加至反應混合物中並攪拌，接著用三氯甲烧萃取。萃取液經真空濃縮後粗產物用矽膠管柱層析（溶劑1 己烧/乙酸乙酯=75/25至55/45)進行純化，然後以三級丁醇溶解。溶液經冷凍乾燥得到3-{N-[3-(卜三級丁氧羰美）吼咯啶基]胺曱醯基}-1-（2-氯苯基）-5-(4〜氯苯基）—4一甲氧基-1Η-σ比唑（516毫克，產率97%)呈無色粉末。 MS(APCI)m/z · 431/433[M+H-Boc] + (Boc :三級丁氧幾美） (2)在0C，將4N HC1-二卩等烷（3毫升）加至上述步驟 (1)所得化合物（425毫克）之二曙烷（2毫升）溶液中，在相同溫度下攪拌混合物2小時，室溫攪拌2小時。接著將破酸氫鈉水溶液加至反應混合物中進行鹼化。攪拌混合物然後用矽藻土管柱（CHEMELUTE，VARIAN公司製造）萃取。萃取液經真空濃縮，得到1-(2-氯苯基）—5-(4—氯苯基）〜4-甲氧基-3-[N-( 3-吡咯啶基）胺曱醯基]-in-吡唑（344毫克，產率100%)呈無色黏稠物。 MS(APCI)m/z ： 431/433[M+H]+ 318695 70 200804294 (3)在Ot，將三乙胺（112微升）與三氟乙酸酐（56微升）加至上述步驟（2)所得化合物（86亳克）之罗醇（3毫升）溶液卜室溫授拌混合物一夜。接著將石炭酸氯納水溶液加至反應混合物中並攪拌，然後用矽藻土管柱ELUTE， VARIAN公司製造）萃取。萃取液經真空濃縮，得到^(2 — 氯苯基）-5-(4-氯苯基）—4 一甲氧基一 3_0_[3_(1_三氟乙醯基）吡咯啶基]胺甲醯基卜1H_吡唑（9〇毫克，產率86%)呈無色粉末。 MS(APCI)m/z ： 527/529[M+H]1 實施例21 (1)將N-二級丁氧羰基肼（297毫克）、水可溶碳二亞胺 1酉文鹽（431笔克）與1 —羥基苯并三唑水合物（345亳克）加至3-缓基+ (2 —氯苯基）„5_(4一氯苯基）一4_甲氧基嗤（3.5克’參考们⑻所得化合物）之二氯甲院（2〇毫升）溶液中，室溫攪拌混合物4小時。然後將碳酸氫納水溶液加至反應混合物巾關拌，接著用三氯f料取。萃取液經真空濃縮後粗產物时膠管柱層析（溶劑：己烧/乙酸乙酉旨，/20至60/40)進行純化，然後以三級丁醇溶解。溶液經冷滚乾燥得到3-[(r-三級丁氧幾基肼基）胺曱醯基] 克，產率100%)無色粉末。 MS(APCI)m/z ： 477/479[M+H]+ n/2)在，將4NHC1 —二嗜烧（25毫升）加至上述步驟 ⑴所得化合物（3.43克）C⑴毫升）溶液中，然後 318695 71 200804294 在5 Q C攪拌混合物3日。冷卻後，將碳酸氫納水溶液與乙 .酸乙酯加至反應混合物中。攪拌混合物後以乙酸乙酯萃取。有機層以硫酸鎂乾燥後過濾。濾液經真空濃縮，所得粗產物以三級丁醇溶解，經冷凍乾燥後得到3-肼基幾基 -1 -（2-氣苯基）-5-(4-氣苯基）-4-甲氧基-1Η-吼唑（2. 64 克’產率100%)淡黃色粉末。 MS(APCI)m/z ： 377/379[M+H]+ (3)將1-曱磺醯基六氫吡啶_4_甲酸（62毫克）、水可溶碳二亞胺鹽酸鹽（58亳克）與1-羥基苯并三唑水合物（46亳克）加至上述步驟（2)所得化合物（76毫克）之二氯曱烷（3 笔升谷液中，室溫攪拌混合物一夜。接著將碳酸氫鈉水溶液加至反應混合物中並攪拌，然後以三氯曱烷萃取。萃取液經真空濃縮後所得粗產物用矽膠管柱層析（溶劑：己烷/ 乙酸乙酯=92/8至90/10)進行純化，得到卜。—氯苯基） -5-(4-氯苯基）-3-({r_[(卜甲石黃醯基六i比咬_4—基）羰基]肼基}幾基）+甲氧基_1Η_«(85δ亳克，產率呈無色粉末。 MS(APCI)m/z ： 566/568[M+H]+ 實施例22 =將1 基-4-三級丁氧#炭基六氣吼哄基⑽毫 (V〇=了 16i2)所得化合物)、水可溶碳二亞胺鹽酸鹽 =至二其唾水合物⑽毫克)與三崎 U升）加至3-祕+ (2_氯苯基）_ 基鲁㈣，參考们⑻所得化 318695 72 200804294 T毫升你液中’室㈣摔混合物—夜。然後將碳酸氣納士浴液加至反應混合物中並攪拌’接著用三氯甲烷萃取。卒取液經真空濃縮後粗產物用㈣管柱層析（溶劑：己统/ 乙酸乙酉旨=60/40至40/60)進行純化，得至3普（4 一三2 了氧幾基六氫叫-1-基）胺甲醯基]+ (2_氯苯基氯苯基）-4-甲氧基鲁対（1.56克，產率79%)呈無色固 MSCAPCI)m/z ： 546/548[M+H]+ (2)在室溫，將4NHC1-二噚烷（20毫升）加至上述步驟 (1)所得化合物（1.56克）之二噚烷（1〇亳升）溶液中，然後在5(TC授拌混合物-夜。冷卻至室溫後，將碳酸氣納水溶液加至反應混合物中進行鹼化。攪拌混合物然後以三氯曱烷萃取。萃取液以硫酸鎂乾燥後過濾。濾液經真空濃縮，得到1-（2-氯苯基）一 5_(4_氣苯基）_4_曱氧基_3_[N_(六氫吡哄-1-基）胺曱醯基]— 1H-吡唑（1. 26克，產率99%)呈盔色固體。 … MS(APCI)m/z ： 446/448[M+H]+ (3)將二乙胺（39微升）與苯甲醯氯（丨6微升）加至上述步驟（2)所得化合物（38毫克）之二氯曱烷（1毫升）溶液中，室溫攪拌混合物一夜。接著將碳酸氫鈉水溶液加至反應混合物中並攪拌，然後以三氯甲烷萃取。萃取液經真空濃縮後所得粗產物用矽膠管柱層析（溶劑：己烷/乙酸乙酯 = 40/60至〇/；[〇〇)進行純化，得到3—[N—(4_苯曱醯基六氫吼畊-卜基）胺曱醯基]—卜^一氯苯基）一5一（4一氯苯基）一4一甲 318695 73 200804294 氧基-1H-吡唑（20毫克，產率53%)呈無色固體。 _ MS(APCI)m/z： 550/552[M+H]+ 實施例2 3 在0 C ’將HC1-二曙烷（6毫升）加至實施例2i(i) 所得化合物（95毫克）之二卩琴烷（5毫升）溶液中，然後在5〇 °C攪拌混合物2小時。冷卻後，將碳酸氫鈉水溶液加至反應混合物中進行鹼化。有機層用矽藻土管柱（C{JEM ， VAR IAN公司製造）萃取。萃取液經真空濃縮，得到3 —肼基羰基-1-(2-氣苯基）一5-(4一氯苯基）_4一曱氧基一 1Η—σ比唑 (1.26克，產率99%)粗產物。接著加入乙醇（2毫升）、三乙胺（28微升）與二乙烯砜（24微升），在氮氣環境下加熱廻流混合物5小時。冷卻後，加水至反應混合物中並攪拌。有機層用矽藻土管柱（CHEM ELUTE，VARIAN公司製造）萃取，萃取液經真空濃縮。所得粗產物依序用矽膠管柱層析 (溶劑·二氯甲烧/曱醇=1〇〇/〇至g6/4)與隨一矽膠管柱層析（Chromatorex NH-矽膠，Fuji Si liciaChem·公司製造曰，溶劑：己烷/乙酸乙酯=40/60至20/80)進行純化，得到 1-（2-氯苯基）-5-(4-氯苯基）-3-[N-(1，1-二側氧基硫代 N-嗎福啉基）胺甲醯基]一4—甲氧基—1H 一吡唑（43毫克，產率 50%)無色固體。 ~ MS(APCI)m/z ： 495/497[M+H]+Example 14 4-tetrahydrothiopipetanylamine (140 mg, compound obtained in Reference Example 12 (2)), water-soluble carbodiimide hydrochloride (230 mg) and 1-hydroxybenzotriazine Hydrate (184 mg) was added to 3-remediate-1-(2-(phenylphenyl)-5-(4-chlorophenyl)-4-methoxy-lH-u-pyrazole (290 mg, reference example) 1(6) Achieved 66 318695 200804294 A solution of keto-amine (6 ml / °. 5 ml) 0, θ human & Λ 5 一 one instrument. Then add sodium bicarbonate aqueous solution to the reverse, curved two gas Extraction of methane. Purification of the extract by vacuum column chromatography (solvent: calcined / acetic acid ethyl acetate = base) + = = ) to obtain 'bu (2-chlorophenyl)-5-(4-benzene Soil (3) (NPCI) m/z: /464[M+H]+ Example 15 To a solution of the compound obtained in Example 14 (116 g) in chloromethane (m. 1 followed by 3-chloroperbenzoic acid (58 mg, water content 2 (10)), at the same temperature Stir for 1 hour and stir at room temperature for 2 hours. Sodium bicarbonate water/liquid mixture was added to the reaction mixture and stirred, followed by extraction with chloroform. The extract was concentrated in vacuo and the crude product was chromatographed with EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc Purification to give 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-{N-[4-(1-trioxytetrahydrothiopiperidyl) )] Amine f 醢卜 lfJ-pyrazine (28.5 mg, yield 24%) was a colorless solid. MS (APCI) m/z: 478 / 480 [M+H] + Example 16 The compound obtained in Example 14 (116 mg) was obtained in the same manner as in Example 15 except that the solvent was used. The method is carried out to obtain di(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-[4-(1,1—di 318695 67 200804294 side oxytetrahydrothio Piperidyl)]aminocarbazinyl-1H-pyrazole (69 mg, yield 56%) was obtained as a colorless solid. MS (APCI) m/z: 494 / 496 [M+H] + Example 17 4-tetrahydrothiopentanol (61 mg) and dimethylaminopyridine (2 mg) were added to the reference. 1 (6) The obtained compound (73 mg) in dichloromethane (methanol) was stirred and stirred. Then hey.二 Add dicyclohexylcarbodiimide (45 mg) to the mixture and stir at room temperature overnight. A solution of sodium hydrogencarbonate in water was added to the reaction mixture and scrambled, followed by extraction with trichloromethane. The extract was concentrated in vacuo and the crude product was purified using EtOAc EtOAc EtOAc EtOAc EtOAc -Chlorophenyl)-4-methoxy-3-(4-tetrahydrothiopiperanyloxy)carbonyl-1H-u-biazole (53 mg, yield 59%) was obtained as a colourless solid. MS (APCI) m / z: 447 / 449 [M + H] + Example 18 In a 〇c, nitrogen atmosphere, diphenyl azide (47 μl) and triethylamine (33 μl) To a solution of the compound (73 mg) obtained in the title compound (3) (3 ml), Next, 4-tetrahydropyranylamine (36 mg) and 4-dimethylaminopyridine (2.4 mg) were added to the reaction mixture under ice-cooling at 8 Torr. Stir it overnight. Then, an aqueous sodium hydrogencarbonate solution was added and stirred, followed by extraction with a diatomaceous earth column (manufactured by Chem ELUTE VAR IAN). The crude product obtained by concentration in vacuo was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = (10) to 20/80) to give (2-chlorophenyl)_5_([chlorophenyl] 318695 68 200804294 -3-[Γ-(4-tetrahydropiperidyl)ureido]-ι H-pyrazole (1 〇 mg, yield - 11%) as a colorless solid. 卞 MS (APCI) m /z: 461/463 [M+H] + Example 19 (1) The compound obtained in Reference Example 17 (513 mg) and 3-amino-based mono- ortho-butoxycarbonyl hydrazine as in the Example; The same as described to αα4-diphenyl)-5-(4-a gas-based)- 4-methyl 3=_= (1-tertiary butoxycarbonyl)azinyl]amine-methyl sulfonyl Pyrazole (59 mg, yield 83%) was solid. MS (APCI) m / z · 551 / 553 [Μ + Η] + (2) 4NHC1-ethyl acetate (2 ml) was added to the compound obtained in the above step (1) (590 mg) of trichloromethane 5 In a solution of ML), the mixture was allowed to pass overnight at room temperature. The reaction mixture was then concentrated in vacuo, and ethyl acetate and sodium hydrogencarbonate were added to the residual (iv) towel and (iv). The organic layer was dried over sulfur and filtered. The filtrate was concentrated in vacuo and the residue was purified eluted eluted eluted Then triethylamine (30 ml) and p-chlorobenzoguanidine chloride (35 mg) were added and stirred at room temperature overnight. Then an aqueous citric acid solution was added and stirred. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and then evaporated. The filtrate was concentrated in vacuo and EtOAcqqqqqq Sodium hydride (4 mg) was then added and stirred at 8crc for 2 days. After cooling to room temperature, water and ethyl acetate were added and the organic layer was extracted with ethyl acetate. The crude product obtained by concentration in vacuo was purified by silica gel column chromatography (solvent: hexane/acetic acid = 〇 / _) to give b (m phenyl)_5_(4- chlorophenyl) 4 i Base-3-{N-[3-(4-chlorobenzylidene) nitrogen. Danyl]Aminomethyl hydrazino} 318695 69 200804294 -1 Η-pyrazole (30 mg, yield 52%) is a powder. MS (APCI) m/z: 589 / 591 [M+H] + . Example 20 (1) 1-1-butoxycarbonyl- 3-aminopyrrolidine (279 mg), water-soluble carbon Amine hydrochloride (288 mg) and 1-hydroxybenzotriazole hydrate (230 mg) were added to 3-carboxy-1-(2-chlorophenyl)-5-(4-chlorophenyl)-\- A solution of the decyloxy-1H-pyrazole (363 mg, the compound obtained in Reference 1 (6)) in methylene chloride (5 ml) was stirred at room temperature overnight. Then, an aqueous sodium hydrogencarbonate solution was added to the reaction mixture and stirred, followed by extraction with trichloromethane. The extract was concentrated in vacuo and the crude product was purified using silica gel column chromatography (solvent 1 hexane/ethyl acetate = 75/25 to 55/45) and then dissolved in THF. The solution was freeze-dried to obtain 3-{N-[3-(b-tert-butoxycarbonyl) oxazolidinyl]aminoindenyl}-1-(2-chlorophenyl)-5-(4- chlorobenzene 4-Methoxy-1Η-σ-rhizozolium (516 mg, yield 97%) was obtained as a colorless powder. MS (APCI) m/z · 431/433 [M+H-Boc] + (Boc: tris-butoxybutyric acid) (2) at 0C, 4N HCl-dioxane (3 ml) was added to the above The solution of the obtained compound (425 mg) in dioxane (2 ml) was stirred for 2 hr. Next, an aqueous sodium hydrogencarbonate solution was added to the reaction mixture for alkalization. The mixture was stirred and then extracted with a diatomaceous earth column (CHEMELUTE, manufactured by VARIAN Co., Ltd.). The extract is concentrated in vacuo to give 1-(2-chlorophenyl)-5-(4-chlorophenyl)~4-methoxy-3-[N-(3-pyrrolidinyl)amine fluorenyl] -in-pyrazole (344 mg, yield 100%) was a colorless viscous material. MS (APCI) m/z: 431/433 [M+H]+ 318695 70 200804294 (3) In Ot, triethylamine (112 μl) and trifluoroacetic anhydride (56 μl) were added to the above procedure ( 2) A solution of the obtained compound (86 g) in hexane (3 ml) was stirred at room temperature overnight. Next, an aqueous solution of sodium chlorate was added to the reaction mixture and stirred, followed by extraction with a diatomaceous earth column ELUTE, manufactured by VARIAN. The extract is concentrated in vacuo to give (2-(chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-0_[3_(1-trifluoroethyl)pyrrolidinyl]amine Indole 1H_pyrazole (9 mg, yield 86%) was obtained as a colorless powder. MS (APCI) m/z: 527 / 529 [M+H] 1 Example 21 (1) N-??-butoxycarbonyl oxime (297 mg), water-soluble carbodiimide 1 酉 salt (431) Pg) with 1-hydroxybenzotriazole hydrate (345 gram) added to 3-sulfoyl + (2-chlorophenyl) „5_(4-chlorophenyl)- 4-methoxy hydrazine (3.5 The solution was stirred at room temperature for 4 hours in a solution of the compound obtained in Reference (8). The aqueous sodium hydrogencarbonate solution was then added to the reaction mixture, followed by extraction with trichlorof. The extract is concentrated in vacuo and the crude product is purified by a column chromatography (solvent: hexane/acetic acid, /20 to 60/40), then dissolved in tri-butyl alcohol. The solution is subjected to cold-roll drying to obtain 3-[ (r-tertiary butoxymethylhydrazino) amidino] gram, yield 100%) colorless powder. MS (APCI) m/z: 477/479 [M+H]+ n/2) 4NHC1 - diasterophilic (25 ml) was added to the solution of the compound obtained in the above step (1) (3.43 g) C (1 ml), then 318 695 71 200804294 was stirred at 5 ° C for 3 days. After cooling, sodium bicarbonate solution and B were added. Ethyl acetate is added to the reaction mixture The mixture was stirred and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo, and the obtained crude product was dissolved in tri-butyl alcohol and lyophilized to give 3-mercapto-1 -(2-Phenylphenyl)-5-(4-phenylphenyl)-4-methoxy-1indole-indazole (2. 64 g, yield 100%) pale yellow powder. MS (APCI) m/ z : 377/379[M+H]+ (3) 1-indolesulfonylhexahydropyridine_4_carboxylic acid (62 mg), water-soluble carbodiimide hydrochloride (58 g) and 1 - Hydroxybenzotriazole hydrate (46 g) was added to the compound obtained in the above step (2) (76 mg) in dichloromethane (3 liters of the solution, and the mixture was stirred overnight at room temperature. Add to the reaction mixture and stir, then extract with trichloromethane. The extract is concentrated in vacuo and the crude product is purified by column chromatography (solvent: hexane / ethyl acetate = 92/8 to 90/10) Purification, to obtain b.-chlorophenyl)-5-(4-chlorophenyl)-3-({r_[( 甲甲醯六六 i i i _ _ 4 ) ) 羰羰羰)) Base_1Η_«(85δ亳克, the yield is colorless powder. MS (APCI) m/z : 566 / 568 [M+H] + Example 22 = compound of 1 - 4 - 3 - 3 -butoxy # carbon hexafluorenyl (10) mM (V 〇 = 16i2) ), water soluble carbodiimide hydrochloride = to two of its salic acid (10) mg) and Sansaki U liter) added to 3- secret + (2_ chlorophenyl) _ kuru (four), reference (8) 318695 72 200804294 T ml your liquid 'room (four) drop mixture - night. The carbonic acid naphtha bath was then added to the reaction mixture and stirred' followed by extraction with chloroform. The crude product is concentrated in vacuo and purified by (4) column chromatography (solvent: hexane / acetic acid acetonitrile = 60/40 to 40/60) to obtain 3 pu (4 1-3 oxa groups) Hydrogen is called 1-yl)amine-methylmercapto]+(2-chlorophenylchlorophenyl)-4-methoxyr-ruthenium (1.56 g, yield 79%) is colorless solid MSCAPCI) m/z : 546 /548[M+H]+ (2) 4HCI 1-dioxane (20 ml) was added to a solution of the compound obtained in the above step (1) (1.56 g) in dioxane (1 liter). Then, at 5 (TC mixture mixture - night. After cooling to room temperature, an aqueous solution of sodium carbonate was added to the reaction mixture for alkalization. The mixture was stirred and then extracted with trichloromethane. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 1-(2-chlorophenyl)-5-(4-phenylphenyl)-4-yloxy_3_[N_(hexahydropyridin-1-yl)amine fluorenyl]- 1H-pyrazole (1.26 g, yield 99%) was a viscous solid. MS (APCI) m/z: 446/448 [M+H] + (3) diethylamine (39 μl) The compound obtained in the above step (2) (38 mg) was dissolved in dichloromethane (1 ml) with benzamidine chloride (6 μL). The mixture was stirred overnight at room temperature, then aqueous sodium hydrogencarbonate solution was added to the reaction mixture and stirred, and then extracted with chloroform. The extract was concentrated in vacuo and the crude product was purified by column chromatography (solvent: hexane / Ethyl acetate = 40/60 to 〇/; [〇〇] was purified to give 3-[N-(4-benzoinylhexahydroindole-pyl)amine sulfhydryl]-bromo-chlorobenzene Ethyl 5-(4-chlorophenyl)- 4-methoxy 318695 73 200804294 Oxy-1H-pyrazole (20 mg, yield 53%) was obtained as a colorless solid. MS (APCI) m/z: 550 / 552 [M+H] + Example 2 3 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> In a solution of dioxane (5 ml), the mixture was stirred at 5 ° C for 2 hours. After cooling, an aqueous solution of sodium hydrogencarbonate was added to the reaction mixture for alkalization. The organic layer was extracted with a diatomaceous earth column (C{JEM, manufactured by VAR IAN). The extract was concentrated in vacuo to give <RTI ID=0.0>>&&&&&&&&&&&&& %) crude product. Then, ethanol (2 ml), triethylamine (28 μl) and divinyl sulfone (24 μL) were added, and the turbulent mixture was heated under a nitrogen atmosphere for 5 hours. After cooling, water was added to the reaction mixture and stirred. The organic layer was extracted with a diatomaceous earth column (CHEM ELUTE, manufactured by VARIAN), and the extract was concentrated in vacuo. The obtained crude product was sequentially chromatographed on a silica gel column (solvent·dichloromethane/decyl alcohol = 1 〇〇/〇 to g6/4) and chromatographic column chromatography (Chromatorex NH-gelatin, Fuji Si liciaChem· Purification by the company, solvent: hexane / ethyl acetate = 40 / 60 to 20 / 80) to give 1-(2-chlorophenyl)-5-(4-chlorophenyl)-3-[N- (1,1-di-side oxythio N-norfosfosyl) Aminomethyl hydrazide] 4-methoxy- 1H-pyrazole (43 mg, yield 50%) as a colorless solid. ~ MS(APCI)m/z : 495/497[M+H]+

實施例24A 將水可溶碳二亞胺鹽酸鹽（44毫克）與丨-羥基苯并三唑水合物（35毫克）加至實施例22(2)所得化合物（67毫克） 318695 74 200804294 之二氯甲烷（2毫升）溶液中，室溫攪拌混合物一夜。然後將碳酸氫鈉水溶液加至反應混合物中並攪拌，接著用二氯 -甲烷萃取。萃取液經真空濃縮後粗產物用矽膠管柱層析（溶劑··己烷/乙酸乙酯=40/60至〇/1〇〇)進行純化，得到3—丨^ [4-（5-溴-2-噻吩曱醯基）六氫吡哄-i—基]胺曱醯基卜卜 (2-氯苯基）-5 -（4-氯苯基）-4-曱氧基-1H-吼唑（79毫克，產率79%)固體。 MS(APCI)m/z ： 634/636[M+H]+Example 24A Water-soluble carbodiimide hydrochloride (44 mg) and hydrazine-hydroxybenzotriazole hydrate (35 mg) were added to the compound obtained in Example 22 (2) (67 mg) 318695 74 200804294 The mixture was stirred at room temperature overnight in dichloromethane (2 mL). Then, an aqueous sodium hydrogencarbonate solution was added to the reaction mixture and stirred, followed by extraction with dichloromethane. The extract was concentrated in vacuo and the crude product was purified using EtOAc EtOAc EtOAc EtOAc EtOAc -2-thiopheninyl)hexahydropyridinium-i-yl]amine oxime bromide (2-chlorophenyl)-5-(4-chlorophenyl)-4-decyloxy-1H-indole Azole (79 mg, yield 79%) solid. MS (APCI) m/z : 634/636 [M+H]+

實施例24B 將氰化鋅（6毫克）、參（二苯亞甲基丙酮）二鈀（1· 5毫克）與1，1 -雙（二苯膦基）二（環戊二烯）鐵（DppF，I 8毫克）加至實施例24A所得化合物（49毫克）之二甲基曱醯胺耄升）溶液中，然後在微波反應器中於18〇。〇攪拌混合物^ 5 分鐘。冷卻至室溫後，將水與乙酸乙酯加至反應混合物中並攪拌。有機層用矽藻土管柱（CHEM ELUTE，VARIM公司製造）卒取，萃取液經真空濃縮，所得粗產物用矽膠管柱層析（溶劑··己烷/乙酸乙酯=30/70至〇/100)進行純化，得^ 3-{N-[4-（5-氰基-2嗟吩曱醯基）六氫^比哄—1 —基]胺曱醯基卜1-（2-氯苯基）-5-（4-氯苯基）-4一曱氧基—1H—吼唑（79 毫克，產率83%)無色固體。 MS(APCI)m/z ： 581/583[M+H]+ 實施例25 (1)將溴（15微升）逐滴加至參考例7所得化合物（72 耄克）之三氯甲烷（3毫升）溶液中，室溫攪拌混合物1小 318695 75 200804294 時。然後真空濃縮反應混合物，殘留物以二曱基甲醯胺（3 毫升）稀釋。加入嗎福啉（87微升），然後室溫攪拌2小時。 -接著將碳酸氫鈉水溶液加至反應混合物中。攪拌後，混合物用矽藻土管柱（CHEMELUTE，VARIAN公司製造）處理以萃取有機層。萃取液經真空濃縮，所得粗產物用矽膠管柱層析（溶劑：己烷/乙酸乙酯=60/40至40/60)進行純化，得到 1 (2-氣本基）-5-(4-氯苯基）-4-曱氧基-3 - [2-(N-嗎福琳基）乙酿基]-1Η -。比σ坐。 (2)將一甲基甲酿胺（3毫升）加至上述步驟（1)所得化 5物中，然後在〇 C加入氫化納（8 · 8毫克）。在氮氣環境下室溫攪拌混合物1小時。接著將碳酸氫鈉水溶液加至反應此合物中。攪拌後，混合物用上述之石夕藻土管柱處理以萃取有機層。萃取液經真空濃縮，所得粗產物依序用矽膠管柱層析（溶劑：己烷/乙酸乙酯=60/40至4〇/6〇)與凝膠滲透層析（管柱·· JAIGEL-1H與2Η，流動相：三氣甲烷）進行純化，件到1-（2-氯苯基）-5 -（4-氯苯基）一4一甲氧基—3—[2 一 (Ν-嗎福啉基）丙醯基；I —1Η—吼唑（1〇· 3毫克，步驟（υ至（？）總產率11 %)無色粉末。 MS(APCI)m/z ： 581/583[M+H]+ 實施例2 6 將參考例5(2)與1-胺基吡咯啶以如實施例丨所述之相同方法處理，得到丨一（2 一氣苯基）一 5 —(4—氯苯基）-4一甲氧羰基曱氧基-3-[N-(l-吡咯啶基）胺甲醯基]-1H—吡唑（71 3 毫克，產率73%)固體。 318695 76 200804294 MS(APCI)m/z ： 489/491[M+H]+ 實施例27 將6N氨_甲醇U毫升）加至實施例26所得化合物（5〇毫克）之曱醇（5毫升）溶液中，室溫攪拌混合物一夜。然後將乙酸乙酯與水加至反應混合物中並攪拌。分離出有機' 層，有機層經真空濃縮後所得粗產物用矽膠管桂層析（冰劑：己烷/乙酸乙酯=50/50至30/70)進行純化，^到4+胺甲醯基曱氧基-1 -（2-氣苯基）-5-（4-氯苯基卜吼# 咯啶基）胺曱醯基]-111-吡唑（1〇.2毫克，產率11%)淡普色固體。 ” MS(APCI)m/z ： 474/476[M+H] 實施例28 將氯化2-氯-1，3-二甲基咪唑啉（4〇毫克）與三乙胺 (62微升）加至實施例21 (3)所得化合物（884亳克）之二氯甲烧（2毫升）溶液中’室溫攪拌混合物一夜。然後將碳酸氳鈉水溶液加至反應混合物中並攪拌，接著以三氯甲烧萃取。萃取液經真空濃縮後粗產物用矽膠管柱層析（溶劑：己烷/乙酸乙酯=40/60至10/90)進行純化，得到ι — (2 —氯苯基）-5-（4-氯苯基）-4-甲氧基-3-[2-(1-曱磺醯基六氫σ比啶 -4-基）-1，3, 4-噚二唑-5-基]-1Η-吡唑（21· 8毫克，產率 26%)無色固體。 MS(APCI)m/z ： 548/550[M+H]+ 實施例29 3-胺基-1 -（2-氯苯基）-5-（4-氯苯基）-4-甲氧基一 iH- 318695 77 200804294 。比哇⑶毫克，參相6所得化合物）舆環己Μ酸⑴毫克)以如實施例1所述之相同方法處理’得到卜(2一氯苯基) -5-(4-氣苯基）-3-環己幾基胺基+甲氧基_1Η♦坐（28 、毫克，產率63%)固體。 MS(APCI)ra/z ： 444/446[M+H]+ 實施例30 在〇°c、氮氣環境下，將疊氮磷酸二苯酯（47微升）與三乙胺（33微升）加至參考例1(6)所得化合物（73毫克）之曱苯（3毫升）溶液中，並在相同溫度下攪拌混合物如分鐘，然後室溫攪拌1小時，801攪拌2小時。接著在冰冷卻下將4-四氫哌喃醇（37毫克）與4_二曱胺基吡啶（2./4 2 克）加至反應混合物中，然後在8〇它攪拌一夜。在〇它將碳酸氫鈉水溶液加至反應混合物中並攪拌，混合物用矽藻土管柱（CHEMELUTE，VARIAN公司製造）萃取。萃取液經^空濃縮後所得粗產物用矽膠管柱層析（溶劑：己烷/乙酸乙 = 70/30至60/40)進行純化，得到ι_(2-氯苯基）_5_(4_氯苯基）-3-{[(四氫哌喃-4-基氧基）羰基]胺基卜4_甲氧基 -1H-吡唑（16毫克，產率17%)無色固體。 MS(APCI)m/z ： 462/464[M+H]+ 實施例31 將相應之起始物以如實施例1所述之相同方法處理，付到1，5-雙（4 -氯苯基）-4 -曱氧基-3 - [Ν-(σ比嘻π定基）胺甲酸基：ΜΗ—比唑（32毫克，產率74%)粉末。 MS(電灑游離，ESI)m/z : 431· 05[Μ+Η] + 318695 78 200804294 實施例32 將三乙胺（112微升）與乙醯氯（28微升）加至實施例20 ^ (2)所得化合物（86毫克）之二氯曱烷（3毫升）溶液中，室溫授拌混合物一夜。接著在將碳酸氫鈉水溶液加至反應混合物中並攪拌，混合物用矽藻土管柱（CHEM ELUTE， VAR I AN公司製造）萃取。萃取液經真空濃縮後所得粗產物用矽膠管柱層析（溶劑：三氯曱烷/甲醇=1〇〇/〇至94/6)進行純化’得到1-(2-氣苯基）-5-(4-氣苯基）-4-曱氧基—3-[N-(l-乙醯基-3-吡咯啶基）胺曱醯基]一1{|一吡唑（86毫克，產率91%)粉末。 MSCAPCI)m/z ： 473/475[M+H]+ 實施例33 貫施例20(2)所得化合物（86毫克）與甲磺醯氣以如實施例32所述之相同方法處理，得到i — Q —氣苯基氯苯基）-4-甲氧基-3-[N-（1-甲磺醯基—吡咯啶基）胺甲醯基]-1H-吡唑（84毫克，產率8 3%)粉末。 MS(APCI)ra/z ： 509/511[M+H]+ 實施例34 實施例20(2)所得化合物（86亳克）與N，N_二甲基胺磺醯氣以如實施例32所述之相同方法處理，得到丨_(2〜氯苯基）-5-(4-氯苯基）+曱氧基_3_{n_[卜（n，n_二曱基胺碌本醯基）-3-吡咯啶基]胺曱醯基卜1H_吡唑（62毫克，產率57%) 粉末。 MS(APCI)m/z ： 538/540[M+H]+ 318695 79 200804294 實施例3 5 對應之起始物以如實施例2 5 (1)所述之相同方、去卢 .理’得到1一（2-氯苯基）- 5-（4-氯苯基）-甲氧基—3 一 [1 一 (順-2,6-二甲基1^-六氫吡啶基）乙醯基]-1恥吡唾（46毫克，產率49%)固體。 MS(APCI)m/z ： 472/474[M+H]+ 實施例36 對應之起始物以如實施例25(1)所述之相同方法處理’得到1 一（2-氯苯基）-5 -（4-氯苯基）-4-甲氧基-3—[1 一 (1，1-二侧氧基硫代N-嗎福啉基）乙醯基]—ιΗ—坐（73毫克，產率74%)固體。 MS(APCI)m/z ： 472/474[M+H]+ 實施例37 在〇 C ’將4N HC1 -二曙烧（3毫升）加至實施例21 (1) 所付化合物（9 5毫克）之二卩琴烧（1毫升）溶液中，然後4 〇攪拌混合物2小時。冷卻至室溫後，將碳酸氳鈉水溶液加至反應混合物中並攪拌，混合物用石夕藻土管柱 ELUTE ’ VAR IAN公司製造）萃取。萃取液經真空濃縮後所得粗產物用矽膠管柱層析（溶劑：三氯曱烷/甲醇=19/1)進行純化，得到1-(2-氯苯基）-5 — (4-氯苯基）-4-甲氧基-3-{N-[1-(2-側氧基）六氫吼啶基]胺甲醯基卜1Η—σ比唑毫克’產率62%)無色固體。 MS(APCI)m/z ： 459/461[M+H]+ 實施例3 8 80 318695 200804294 ，^將嗎福啉（21微升）與三乙胺（28微升）加至參考例8 戶 =化合物（75毫克）之甲醇（2毫升）溶液巾，然後加熱避 •流混合物2小時。冷卻至室溫後，將水與乙酸乙醋加至反應此δ物中並攪拌，混合物用矽藻土管柱（， VARIAN公司製造）萃取。萃取液經真空濃縮後所得粗產物用石夕膠管柱層析（溶劑：三氯甲垸/甲醇=1〇〇/〇至95/5)進行、’、屯化得到1一（2-氯苯基）-5-(4-氣苯基）—4-甲氧基_3_ [3-(N-嗎福啉基）丙醯基；|_1H_吡唑（8〇5毫克，產率π%) 無色固體。 MS(APCI)m/z ： 460/462[M+H]+ 實施例3 9 在，將三乙胺（42微升）與三光氣（89毫克）加至參考例9⑵所得化合物（50毫克氯乙烧（3毫升）溶液中’然後6(TC授拌混合物2. 5小時。冷卻反應混合物至〇°C後將水加入並擾拌，接著以三氯甲烧萃取。萃取液經真空濃縮後，殘留物以二氯甲烷稀釋。接著加入丨，卜二氧化硫代嗎福啉（41毫克），室溫攪拌混合物4小時。’然= 將石反酸氩鈉水溶液加至反應混合物中並攪拌，混合物以三氣曱烧萃取。萃取液經真空濃縮後所得粗產物用石夕膠管柱層析（溶劑：己烷/乙酸乙酯=45/55至2〇/8〇)進行純化，得到1-(2-氯苯基）-5-(4-氯苯基一二側氧基硫代 N-嗎福啉基）羰基]胺基-4-曱氧基_1H_吡唑（23. 4毫克，產率31%)無色固體。 MS(APCI)m/z ： 495/497[M+H]+ 318695 81 200804294 實施例40至192 對應之起始物以如實施例1至3之一者中所述之相同 ':方法處理，得到如下表2所示化合物。表 2(1) αχΚ^。 n-r5 cliX j 實施例號碼 R3 -N(R5)(R6) 物化性質等 40 ch3- 粉末 MS(APCI):479/481 [M+H]+ 41 CHr 粉末 MS(APCI):465/467[M+Hf 42 ch3- HN-N^O / \/ 粉末 MS(APCI):481/483 [M+H]+ 43 ch3· ψ-〇° 粉末 MS(APCI):480/482[M+H]+ 44 ch3- -NH-N(CH3)2 粉末 MS(APCI):439/441 [M+H]+ 45 f2ch- HN-N^O / \—/ 粉末 MS(APCI):517/519[M+H]+ 46 f2ch- ψ-Ν〕粉末 MS(APCI):501/503[M+H]+ 82 318695 200804294 表 2(2) n-r5 c1J3-ci r' 實施例號瑪 R3 -N(R5)(R6) 物化性質等 47 CF3CH2- 粉末 MS(APCI):533/535[M+H]+ 48 CF3CH2- HN-N^O / \^/ 粉末 MS(APCI):549/551[M+H]+ 49 CF3CH2- 粉末 MS(APCI):548/550[M+H]+ 50 CF3CH2- 〒-N^y 粉末 MS(APCI):547/549[M+H]+ 51 CF3CHr -NH-N(CH3)2 粉末 MS(APCI):507/509[M+H]+ 52 ch3- H XX 固體 MS(APCI);540/542[M+H]+ 53 ch3- KN—^^-cf3 固體 MS(APCI):541/543[M+H]+ 54 ch3- cf3 固體 MS(APCI):490/492[M+H]+ 83 318695 200804294 表 2(3) P n-r5 O-ci R' 實施例號碼 R3 -N(R5)(R6) 物化性質等 55 CH3· 粉末 MS(APCI):430/432[M+H]+ 56 CHr 粉末 MS(APCI);402/404[M+H]+ 57 ch3· ch3 ^N〇粉末 MS(APCI):467/469[M+H]+ 58 ch3_ hn-<CH3 / ch3 粉末 MS(APCI):404/406[M+H]+ 59 ch3- YCH3 H CH3 粉末 MS(APCI):418/420[M+H]+ 60 ch3: 、SXi 粉末 MS(APCI):452/454[M+H]+ 61 ψ<2° 粉末 MS(APCI):517/519[M+H]+ 62 粉末 MS(APCI):501/503[M+H]+ 63 粉末 MS(APCI):515/517[M+H]+ 84 318695 200804294 表 2(4)Example 24B Zinc cyanide (6 mg), bis(dibenzylideneacetone) dipalladium (1.5 mg) and 1,1 -bis(diphenylphosphino)bis(cyclopentadienyl)iron ( DppF, I 8 mg) was added to a solution of the compound obtained in Example 24A (49 mg) in dimethylamine (m.p.) and then in a microwave reactor at 18 Torr. Stir the mixture for 5 minutes. After cooling to room temperature, water and ethyl acetate were added to the reaction mixture and stirred. The organic layer was drawn with a diatomaceous earth pipe column (CHEM ELUTE, manufactured by VARIM Co., Ltd.), and the extract was concentrated in vacuo. The obtained crude product was chromatographed on a silica gel column (solvent··hexane/ethyl acetate=30/70 to 〇/ 100) Purification to obtain 3-{N-[4-(5-cyano-2indolyl)hexahydropyranyl-1 -yl]amine sulfhydryl 1-(2-chlorobenzene) 5-(4-Chlorophenyl)-4-methoxy- 1H-indazole (79 mg, yield 83%) as a colorless solid. MS (APCI) m/z: 581 / 583 [M+H] + Example 25 (1) bromine (15 μl) was added dropwise to the compound of Reference Example 7 (72 g) of chloroform (3) In a solution of ML), stir the mixture at room temperature for 1 small 318695 75 200804294. The reaction mixture was then concentrated in vacuo. Add morphine (87 μl) and stir at room temperature for 2 hours. - An aqueous solution of sodium hydrogencarbonate is then added to the reaction mixture. After the stirring, the mixture was treated with a diatomaceous earth column (CHEMELUTE, manufactured by VARIAN Co., Ltd.) to extract an organic layer. The extract was concentrated in vacuo, and the obtained crude product was purified by chromatography (solvent: hexane/ethyl acetate=60/40 to 40/60) to give 1 (2-carbyl)-5-(4) -Chlorophenyl)-4-decyloxy-3 - [2-(N-homofolinyl)ethidyl]-1Η-. Sit more than σ. (2) Monomethylamine (3 ml) was added to the obtained product of the above step (1), and then sodium hydride (8·8 mg) was added to 〇C. The mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. An aqueous solution of sodium hydrogencarbonate is then added to the reaction mixture. After stirring, the mixture was treated with the above-mentioned Shixiazao column to extract an organic layer. The extract was concentrated in vacuo, and the obtained crude product was purified by column chromatography (solvent: hexane/ethyl acetate=60/40 to 4 〇/6 〇) and gel permeation chromatography (column · JAIGEL- Purification of 1H and 2Η, mobile phase: tri-gas methane, to 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-[2-(Ν-吗啉基 ) 醯 ; ; ; ; ; ; ; ; ; ; ; ; ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( M+H]+ Example 2 6 Reference Example 5(2) was treated with 1-aminopyrrolidine in the same manner as described in Example , to give hydrazine (2-hydroxyphenyl)-5-(4- Chlorophenyl)-4-methoxycarbonylcarbonyloxy-3-[N-(l-pyrrolidinyl)aminemethanyl]-1H-pyrazole (71 3 mg, yield 73%) solid. 318 695 76 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The mixture was stirred at room temperature overnight. Ethyl acetate and water were then added to the reaction mixture and stirred. The organic layer was separated, and the organic layer was concentrated in vacuo to give purified crude product (yield: hexane/ethyl acetate = 50/50 to 30/70). Alkyloxy-1 -(2-phenylphenyl)-5-(4-chlorophenyldiindole #rrolidyl)amine hydrazino]-111-pyrazole (1 〇.2 mg, yield 11 %) Light color solid. MS (APCI) m/z: 474/476 [M+H] Example 28 2-Chloro-1,3-dimethylimidazolium chloride (4 mg) and triethylamine (62 μL) The mixture was stirred in a solution of the obtained compound ( 384 g) in methylene chloride (2 ml), and the mixture was stirred at room temperature overnight. Then, aqueous sodium hydrogen carbonate solution was added to the reaction mixture and stirred, followed by three Extraction with chloroform. The extract was concentrated in vacuo and purified using EtOAc EtOAc (EtOAc:EtOAc:EtOAc -5-(4-chlorophenyl)-4-methoxy-3-[2-(1-oxasulfonylhexahydro-pyridin-4-yl)-1,3,4-oxadiazole- 5-yl]-1 -pyrimazole (21.8 mg, yield 26%) as a colorless solid. MS (APCI) m/z: 548 / 550 [M+H] + Example 29 3-amino-1 (2-Chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-iH- 318695 77 200804294. Biwa (3) mg, the compound obtained as the phase 6) 舆cyclohexanoic acid (1) mg) The same method as described in Example 1 was carried out to obtain '(i-chlorophenyl)-5-(4-phenylphenyl)-3-cyclohexylamino + methoxy_1 Η ♦ (28, Milli , yield 63%) solid. MS (APCI) / s: 444 / 446 [M + H] + Example 30 Diphenyl azide (47 μL) with 〇 ° C, under nitrogen atmosphere Triethylamine (33 μL) was added to a solution of the compound (73 mg) obtained in the title compound (3) (3 ml), and the mixture was stirred at the same temperature for one minute, then stirred at room temperature for 1 hour, 801 Stir for 2 hours. Then add 4-tetrahydropipetanol (37 mg) and 4-diamidinopyridine (2./4 2 g) to the reaction mixture under ice-cooling, then stir overnight at 8 Torr. In the crucible, an aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and stirred, and the mixture was extracted with a diatomaceous earth column (CHEMELUTE, manufactured by VARIAN Co., Ltd.). The extract was concentrated by vacuum distillation to obtain a crude product by a silica gel column chromatography (solvent) Purification by hexane/acetic acid B = 70/30 to 60/40) gave i-(2-chlorophenyl)-5-(4-chlorophenyl)-3-{[(tetrahydropyran-4-yloxy) Alkyl carbonyl]amino-4-bromo-1H-pyrazole (16 mg, yield 17%) as a colorless solid. MS (APCI) m/z: 462 / 464 [M+H] + Example 31 Corresponding starting materials are as described in Example 1. Treated in the same way, to 1,5-bis(4-chlorophenyl)-4-decyloxy-3 - [Ν-(σ 嘻π定基) urethane: ΜΗ-by-azole (32 mg, produced) Rate 74%) powder MS (electrospray free, ESI) m/z : 431 · 05 [Μ + Η] + 318695 78 200804294 Example 32 Triethylamine (112 μl) with ethyl chloroform (28 μl The mixture was added to a solution of the obtained compound (m. Then, an aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and stirred, and the mixture was extracted with a column of diatomaceous earth (CHEM ELUTE, manufactured by VAR I AN). The crude product obtained by concentration in vacuo was purified by silica gel column chromatography (solvent: trichloromethane / methanol = 1 / / / / / / / / / / / / / / / / / / / / / -(4-Phenylphenyl)-4-methoxy-3-[N-(l-ethylidene-3-pyrrolidinyl)amine fluorenyl]- 1{|-pyrazole (86 mg, produced Rate 91%) powder. MSCAPCI) m/z: 473 / 475 [M+H] + Example 33 The compound obtained from Example 20 (2) (86 mg) was treated with methanesulfonium gas in the same manner as described in Example 32 to give i —Q—Oxophenylchlorophenyl)-4-methoxy-3-[N-(1-methylsulfonyl-pyrrolidinyl)amine-methylmethyl]-1H-pyrazole (84 mg, yield 8 3%) powder. MS (APCI) / / / / / / / / / / The same method is used to obtain 丨_(2~chlorophenyl)-5-(4-chlorophenyl)+decyloxy_3_{n_[b (n, n-didecylamine sulfenyl) -3-Pyrrolidinyl]amine sulfhydryl 1H-pyrazole (62 mg, yield 57%) powder. MS (APCI) m/z: 538/540 [M+H]+ 318695 79 200804294 Example 3 5 The corresponding starting material was obtained in the same manner as described in Example 2 5 (1). 1-(2-chlorophenyl)-5-(4-chlorophenyl)-methoxy-3-[1 -(cis-2,6-dimethyl 1^-hexahydropyridinyl)ethenyl ]-1 spirulina (46 mg, yield 49%) solid. MS (APCI) m/z: 472 / 474 [M+H] + Example 36 The corresponding starting material was treated in the same manner as described in Example 25 (1) to give 1-(2-chlorophenyl). -5-(4-chlorophenyl)-4-methoxy-3-[1 -1,1-di-oxythio N-norfosyl)ethinyl]-methane-sit (73 Milligram, yield 74%) solid. MS (APCI) m/z: 472 / 474 [M+H] + </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 4N HCl - diterpene (3 ml) was added to the compound of Example 21 (1) (9 5 mg) The second is in a solution of the simmered meat (1 ml), and then the mixture is stirred for 4 hours. After cooling to room temperature, an aqueous solution of sodium bismuth carbonate was added to the reaction mixture and stirred, and the mixture was extracted with a celite column manufactured by ELUTE' VAR IAN. The crude product was purified by vacuum column chromatography (solvent: trichloromethane / methanol = 19 / 1) to give 1-(2-chlorophenyl)-5 - (4-chlorobenzene). 4-Methoxy-3-{N-[1-(2-o-oxy)hexahydroacridinyl]amine-methylpyridyl 1 Η-σ-pyrazole mg' yield 62%) as a colorless solid. MS (APCI) m/z: 459/461 [M+H] + Example 3 8 80 318695 200804294 , ^ Add morpholine (21 μl) and triethylamine (28 μL) to Reference Example 8 = Compound (75 mg) in methanol (2 mL) solution, then heat to avoid mixture for 2 hours. After cooling to room temperature, water and ethyl acetate were added to the reaction and stirred, and the mixture was extracted with a diatomaceous earth column (manufactured by VARIAN Co., Ltd.). The crude product obtained by concentration in vacuo was subjected to chromatography on silica gel column (solvent: trichloromethane/methanol = 1 〇〇/〇 to 95/5), and hydrazine was obtained to obtain 1-(2-chlorobenzene). -5-(4-Phenylphenyl)-4-methoxy_3_[3-(N-morpholinyl)propanyl;|_1H_pyrazole (8〇5 mg, yield π%) ) Colorless solid. MS (APCI) m/z: 460 / 462 [M+H] + </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Ethylene (3 ml) in the solution 'then 6 (TC mixed mixture for 2.5 hours. After cooling the reaction mixture to 〇 ° C, the water was added and scrambled, and then extracted with trichloromethane. The extract was concentrated in vacuo. The residue was diluted with methylene chloride. Then, hydrazine, thiophenoxaline (41 mg) was added, and the mixture was stirred at room temperature for 4 hours. 'Right = aqueous solution of sodium arsenate was added to the reaction mixture and stirred. The mixture was extracted with a three-gas mixture. The crude product was purified by vacuum chromatography (solvent: hexane/ethyl acetate = 45/55 to 2 〇 /8 〇) to give 1-( 2-chlorophenyl)-5-(4-chlorophenyl-di-oxo-oxythio N-morpholinyl)carbonyl]amino-4-methoxy-1H-pyrazole (23. 4 mg, Yield 31%) colorless solid. MS (APCI) m/z: 495 / 497 [M+H] + 318 695 81 200804294 Examples 40 to 192 corresponding starting materials in one of the examples 1 to 3 Said the same ': square The compound shown in the following Table 2 was obtained. Table 2 (1) αχΚ^. n-r5 cliX j Example No. R3 -N(R5)(R6) Physicochemical properties, etc. 40 ch3- Powder MS (APCI): 479/481 [M+H]+ 41 CHr Powder MS (APCI): 465/467 [M+Hf 42 ch3- HN-N^O / \/ Powder MS (APCI): 481/483 [M+H]+ 43 ch3· Ψ-〇° Powder MS (APCI): 480/482 [M+H]+ 44 ch3- -NH-N(CH3)2 Powder MS (APCI): 439/441 [M+H]+ 45 f2ch- HN- N^O / \—/ Powder MS (APCI): 517/519 [M+H]+ 46 f2ch- ψ-Ν] Powder MS (APCI): 501/503 [M+H]+ 82 318695 200804294 Table 2 ( 2) n-r5 c1J3-ci r' Example No. R3 -N(R5)(R6) Physicochemical properties, etc. 47 CF3CH2- Powder MS (APCI): 533/535 [M+H]+ 48 CF3CH2- HN-N ^O / \^/ Powder MS (APCI): 549/551 [M+H]+ 49 CF3CH2- Powder MS (APCI): 548/550 [M+H]+ 50 CF3CH2- 〒-N^y Powder MS ( APCI): 547/549 [M+H]+ 51 CF3CHr -NH-N(CH3)2 powder MS (APCI): 507/509 [M+H]+ 52 ch3-H XX solid MS (APCI); 542[M+H]+ 53 ch3- KN—^^-cf3 Solid MS (APCI): 541/543[M+H]+ 54 ch3- cf3 Solid MS (APCI): 490/492[M+H]+ 83 318695 200804294 Table 2(3) P n-r5 O-ci R' Example Number R 3 -N(R5)(R6) Physicochemical properties, etc. 55 CH3· Powder MS (APCI): 430/432 [M+H]+ 56 CHr powder MS (APCI); 402/404 [M+H]+ 57 ch3· Ch3 ^N〇 powder MS (APCI): 467/469 [M+H]+ 58 ch3_ hn-<CH3 / ch3 powder MS (APCI): 404/406 [M+H]+ 59 ch3- YCH3 H CH3 powder MS (APCI): 418/420 [M+H] + 60 ch3: , SXi powder MS (APCI): 452/454 [M+H] + 61 ψ < 2 ° powder MS (APCI): 517/519 [M +H]+ 62 Powder MS (APCI): 501/503 [M+H]+ 63 Powder MS (APCI): 515/517 [M+H]+ 84 318695 200804294 Table 2(4)

Ck 如5 n-r5 Ο-Cl R' Boc:三級丁氧基羰基實施例號碼 R3 -N(R5)(R6) 物化性質等 64 -(CH2)2SCH3 HN-N^O / \^J 粉末 MS(APCI):507/509[M+H]+ 65 / \1 粉末 MS(APCI):546/548[M+H]+ 66 粉末 MS(APCI):545/547[M+H]+ 67 -ch3 甲㈣二)-OCH3 粉末 MS(APCI):475/477[M+H]+ 68 -ch3 HN-N^ 粉末 MS(APCI):461/463[M+H]+ 69 -ch3 hn-On-so2 / ^ fc2H5 粉末 MS(APCI):537/539[M+H]+ 70 -ch3 hn-^n-so2 ’ ^ N(CH3)2 粉末 MS(APCr):552/554[M+H]+ 71 細ch3 粉末 MS(APCI):545/547[M+H]+ 85 318695 200804294 表 2(5) P N-R5 實施例號碼 R3 -N(R5)(R6) 物化性質等 72 ch3 ψ-〇°2 粉末 MS(APCI):480/482[M+H]+ 73 ch3 粉末 MS(APCI):463/465[M+H]+ 74 ch3 hn-^isH； / b ch3 粉末 MS(APCI):487/489[M+H]+ 75 ch3 H /N、n〜〇ch3 ch3 黏稠物 MS(APCI):449/451 [M+H]+ 76 ch3 h ch3 ，n、n 气 H3C 人^ 粉末 MS(APCI):473/475[M+H]+ 77 〇 ψ-〇粉末 MS(APCI):533/535[M+H]+ 78 ch3 Η ，Nv^sch3 黏稠物 MS(APCI):436/438[M+H]+ 79 CHr ch3 固體 MS(APCI):468/470[M+H]+ 86 318695 200804294 表 2(6) 厂^N-R5 0^cl R6’ 實施例號碼 R3 _n(r5)(r6) 物化性質等 80 ch3- ψ-Ν(02Η5)2 粉末 MS(APCI):433/435[M+H]+ 81 ch3- ch3 ch3 粉末 MS(APCI):475/477[M+H]+ 82 CHr h3c 平-n^Z) h3c 粉末 MS(APCI):473/475[M+H]+ 83 ch3- ψ-ΚΙ)ζ 粉末 MS(APCI):481/483 [M+H]+ 84 CHr ™-N^^CF3 固體 MS(APCI) :513/515 [M+H]+ 85 C2H5- ψ-Ν(ΟΗ3)2 固體 MS(APCI):419/421 [M+H]+ 86 C2H5- 固體 MS(APCI):445/447[M+H]+ 87 C2H5- ψ-〇固體 MS(APCI):460/462[M+H]+ 87 318695 200804294 表 2(7) Ν-Ν n_r5 ex〆，實施例號碼 R3 -N(R5)(R6) 物化性質等 88 CH30(CH2)2- 固體 MS(APCI):490/492[M+H；T 89 CH30(CH2)2- HN-N(CH3)2 粉末 MS(APCI):449/451 [M+H]+ 90 CH30(CH2)2- 粉末 MS(APCI):475/477[M+H]+ 91 ch3- 00 固體 MS(APCI):432/434[M+H]+ 92 CH3(CH2)2- 固體 MS(APCI):459/461 [M+H]+ 93 ch3(ch2)2- HN-N(CH3)2 固體 MS(APCI):433/435[M+H]+ 94 ch3(ch2)2- ψ-〇固體 MS(APCI):474/476[M+H]+ 95 ch3- ^nCn~0 固體 MS(APCI):522/524[M+H]+ 96 CHr 平-〇-〇固體 MS(APCI):523/525[M+Hf 88 318695 200804294 表 2(8) αχχτ^。 tAci ^ 實施例 5虎石馬 R3 ^N(R5)(R6) 物化性質等 97 ch3- ην·νΓ? 1 一、och3 固體 MS(APCI):475/477[M+H]+ 98 ch3- hn^Nx\ 1 S)ch3 固體 MS(APCI):475/477[M+H]+ 99 CHr 固體 MS(APCI):524/526[M+H]+ 100 ch3- 固體 MS(APCI):524/526[M+H]+ 101 CH3(CH2)2- ψ^-fQ 固體 MS(APCI):586/588[M+H]+ 102 F2CH- 甲固體 MS(APCI):467/469[M+H]+ 103 f2ch- k^-n(ch3)2 固體 MS(APCI):441/443[M+H]+ 104 CH3OCOCH2- mi-N(CH3)2 固體 MS(APCI):463/465[M+H]+ 105 f2ch- 甲Ό 固體 MS(APCI):482/484[M+Hf 89 318695 200804294 表 2(9) n-r5 (X ^ 實施例號碼 R3 _N(R5)(R6) 物化性質等 106 (CH3)2NS〇2- 固體 MS(APCI):524/526[M+H]+ 107 (ch3)2nso2- m^-N(CH3)2 固體 MS(APCI):498/500[M+H]+ 108 (CH3)2NS〇2- ψ-Ο 固體 MS(APCI):539/541[M+H]+ 109 ch3- 固體 MS(APCI):540/542[M+H]+ 110 CHr 固體 MS(APCI):540/542[M+H]+ 111 CHr /^cf3 甲，Cr 固體 MS(APCI):499/50I [Μ+Η]+ 112 ψ^Ο 固體 MS(APCI):514/516[Μ+Η]+ 113 m^-N(CH3)2 固體 MS(APCI):488/490[M+H]+ 114 固體 MS(APCI):529/531 [M+H]+ 90 318695 200804294 表 2(10) 游5 實施例號碼 R3 -N(R5)(R6) 物化性質等 115 固體 MS(APCI):526/528[M+H]+ 116 1>CH3 ψ-〇固體 MS(APCI):527/529[M+H]+ 117 ^V/CH3 HsC-^ζΙί ψ-Ν(ΟΗ3)2 固體 MS(APCI):500/502[M+H]+ 118 ch3- 固體 MS(APCI):439/441 [M+H]+ 119 ch3- 固體 MS(APCI):439/441[M+H]+ 120 ch3- 』ijrCN 固體 MS(APCI):463/465[M+H]+ 121 ch3- H 固體 MS(APCI):468/470[M+H]+ 91 318695 200804294 表 2(11) Ν·Ν N-R5 (X, ^ 實施例號碼 R, -N(R5)(R6) 物化性質等 122 F ψ^Ο 粉末 MS(APCI):415/417[M+H]+ 123 F 粉末 MS(APGI):429/431 [M+H]+ 124 ch3o 中-N〕固體 MS(APCI):427/429[M+H]+ 125 ch3o- 固體 MS(APCI):441/443 [M+H]+ 126 ch3o- r~\ HN-N 0 / 固體 MS(APCI):443/445[M+H]+ 127 ch3o- 固體 MS(APCI):442/444[M+H]+ 128 NC- 固體 MS(APCI):422/424[M+H]+ 92 318695 200804294 表 2(12) faXci R' 實施例號碼 -N(R5)(R6) 物化性質等 129 IW-N(CH3)2 f 粉末 MS(APCI):423/425[M+H]+ 130 粉末 MS(APCI):449/451 [M+H]+ 131 粉末 MS(APCI):463/465[M+H]+ 132 ηνη/~\) / 粉末 MS(APGI):465/467[M+H]+ 133 粉末 MS(APCI):464/466[M+H]+ 93 318695 200804294 表 2(13) F3C^ n-r5 (X〆實施例號碼 R3 _n(r5)(r6) 物化性質等 134 CHr m-N(CH3)2 固體 MS(APCI):439/441 [Μ+Η]+ 135 ch3- 固體 MS(APCI):465/467[M+H]+ 136 CHr 固體 MS(APCI):479/481 [M+H]+ 137 CHr HN-N~\ / \f 固體 MS(APCI):481/483[M+H]+ 138 ch3- 固體 MS(APCI):480/482[M+H]+ 139 f2ch- i^-n(ch3)2 粉末 MS(APCI):475/477[M+H]+ 140 f2ch· ψ-〇粉末 MS(APCI):516/518 [M+H]+ 141 f2ch· 粉末 MS(APCI):501/503[M+H]+ 142 c2h5 靡平-n(ch3)2 固體 MS(APCI):453/455[M+H]+ 94 318695 200804294 表 2(14) F3C^〇 SF-R5 Ο-Cl R" 實施例號碼 R3 -N(R5)(R6) 物化性質等 143 c2h5- 固體 MS(APCI):479/481 [M+H]+ 144 c2h5- HN-N^ t \^f 固體 MS(APCI):493/495[M+H]+ 145 c2h5- HN-N^O / N^/ 固體 MS(APCI):495/497[M+H]+ 146 c2h5_ 固體 MS(APCI)494/496[M+H]+ 147 ch3o(ch2)2- Ψ谭 h3)2 粉末 MS(APCI):483/485[M+H]+ 148 ch3o(ch2)2_ 〒- 固體 MS(APCI):509/511 [M+H]+ 149 CH30(CH2)2. 固體 MS(APCI):523/525[M+H]+ 150 CH30(CH2)2- Γ^\ HN-N Ο / \^f 固體. MS(APCI):525/527[M+H]+ 151 CH30(CH2)2- 粉末 MS(APCI):524/526[M+H]+ 95 318695 200804294 表 2(15) C1^5 n-r5 實施例號碼 R” -N(R5)(R6) 物化性質等 152 CFr 固體 MS(APCI):465/467[M+H]+ 153 CFr 固體 MS(APCI):479/481 [M+H]+ 154 CFr r~\ HN — N O / V—/ 固體 MS(APCI):481/483[M+H]+ 155 cf3- 固體 MS(APCI)480/482[M+H]+ 156 NC- 粉末 MS(ESI):422.10[M+H]+ 157 F m^(cu3)2 粉末 MS(ESI):389.09[M+H]+ 158 F 粉末 MS(ESI):415.11[M+H]+ 159 F 甲"KZ)0 粉末 MS(ESI):430.10[M+H]+ 96 318695 200804294 表 2(16) n-r5 實施例號碼 R” -N(R5)(R6) 物化性質等 160 Cl 粉末 MS(APGI):514/516[M+H]+ 161 Cl roi-N(CH3)2 粉末 MS(APCI):473/475[M+H]+ 162 Cl 粉末 MS(APCI):515/517[M+H]+ 163 Cl 粉末 MS(APCI):548/550[M+H]+ 164 Cl ch3 粉末 MS(APCI):536/538[M+H]+ 165 F 甲-〇粉末 MS(APCI):498/500[M+H]+ 166 F m^(CH3)2 粉末 MS(APCI):457/459[M+H]十 167 F 〒_〇粉末 MS(APCI):499/501 [M+H]+ 168 F ^-〇〇2 粉末 MS(APCI):532/534[M+H]+ 169 F ch3 粉末 MS(APCI):520/522[M+H]+ 97 318695 200804294 表 2(17) C，^〇 (X a 實施例號碼 R3 -N(R5)(R6) 物化性質等 170 ο 粉末 MS(APCI):516/518[M+H]+ 171 ch3 HN-N^SO / U 粉末 MS(APCI):479/481 [M+H]+ 172 粉末 MS(APCI):532/534[M+H]+ 173 ch3 A η3<^〇、οι3 粉末 MS(APCI):460/462[M+H]+ 174 ch3 -Op 固體 MS(APCI):466/468[M+H]+ 98 318695 200804294 表 2(18) R’xx^ n-r5 R,，iX a 實施例號碼 R， R” _N(R5)(R6) 物化性質等 175 F H -NH-N(CH3)2 粉末 MS(APCI):389/391 [M+H]+ 176 F H HN-N^O / U 粉末 MS(APCI):431/433[M+H]+ 177 F H ™-C° 粉末 MS(APCI):430/432[M+H]+ 178 ch3o H •nh-n(ch3)2 固體 MS(APCI):401/403[M+H]+ 179 CH3SO2 H -NH-N(CH3>2 固體 MS(APCI):449/451 [M+H]+ 180 CH3SO2 H 固體 MS(APCI):475/477[M+H]+ 181 CH3SO2 H τΌ 固體 MS(APCI):490/492[M+H]+ 182 CN H -NH-N(CH3)2 / 固體 MS(APCI):396/398[M+H]+ 183 CN H ψ<2° 固體 MS(APCI):437/439[M+H]+ 184 Cl Cl HNH0KCF3 固體 MS(APCI):540/542[M+H]+ 99 318695 200804294 表 2(19) CI^5 n_r5 CX” a 實施例號瑪 R” _N(R5)(R6) 物化性質等 185 cf3 -NH-N(CH3)2 固體 MS(APCI):439/441 [M+H]+ 186 ch3o _nh_n(ch3)2 粉末 MS(ESI):40L09[M+H]+ 187 ch3o 粉末 MS(ESI):427.13[M+H]+ 188 ch3o 粉末 MS(ESI):442.12[M+H]+ 189 CN -NH-N(CH3>2 粉末 MS(ESI):396.09[M+H]+ 190 CN ，〇粉末 MS(ESI):437.10[M+H]+ 100 318695 200804294 表 2(20) XL· och3 n -r5 JJ 實施例號碼 -N(R5)(R6) 物化性質等 191 -NH-N(CH3)2 粉末 MS(ESI):405.03[M+H]+ 192 甲-^o 粉末 MS(ESI):446.04[M+H]^ 實施例193至218 對應之起始物以如實施例2 2 (3)中所述之相同方法處理，得到如下表3所示化合物。 101 318695 200804294 表 3(1) HN-N^JSHET 實施例號碼 Rm 物化性質等 193 固體 MS(APCI):568/570fM+H]+ 194 固體 MS(APCI):576/578[M+H]+ 195 〇々ci 固體 MS(APCI):585/587[M+H]4 196 固體 MS(APCI):575/577[M+H]+ 197 固體 MS(ESI):583.99[M+Hf 198 -COCH3 固體 MS(ESI):487.97[M+Hf 199 ^-〇-cf3 固體 MS(ESI):618.03[M+H]+ 200 粉末 MS(ESI):568.01[M+H]+ 201 K) 粉末 MS(ESI):539.98[M+H]+ 202 (^-〇-〇ch3 粉末 MS(ESI):580.05[M+H]+ 102 318695 200804294 表 3(2) 實施例號碼 R， R3 R”，物化性質等 203 Cl ch3 粉末 MS(ESI):542.04[M+H]+ 204 Cl CH3 粉末 MS(ESI):551.00[M+H]+ 205 Cl ch3 固體 MS(ESI):568.01[M+H]+ 206 Cl CH3 固體 MS(ESI):618.99[M+H]+ 207 Cl ch3 H3 固體 MS(ESI):552.01[M+H]+ 208 Cl c2h5 固體 MS(APCI):582/584[M+H]+ 209 cf3 C2H5 固體 MS(APCI):616/618[M+H]+ 103 318695 200804294 表 3(3) HN~N N-R … H3c?~/ 實施例號碼 R”，物化性質等 210 °hO 固體 MS(APCI):578/580[M+H]+ 211 Q jT\ 固體 ny-F MS(APCI):596/598[M+H]+ 表 3(4) HNRs^^HT，實施例號碼 R”，物化性質等 212 固體 MS(APCI):575/577[M+H]+ 213 VC1 固體 MS(APCI):584/586[M+H]+ 214 固體 MS(APCI):584/586[M+H]+ 104 318695 200804294 215 VF 固體 MS(APCI):586/58B[M+H]+ 216 ίίλρ 固體 MS(APCI):586/588[M+Hf 217 F 固體 MS(APCI):586/588[M+H]+ 218 〇币 NC 固體 MS(APGI):575/577[M+H]+ 實施例219至224 對應之起始物以如實施例1或22(3)中所述之相同方法處理，得到如下表4所示化合物。 105 318695 200804294 表4 σΧΧ jocri (X KJ m^-R6 實施例號碼 R6 物化性質等 219 固體 MS(APCI):549/551 [M+H]+ 220 固體 MS(APCI):567/569[M+H]+ 221 ~°-y〇粉末 MS(APCI)535/537[M+H]+ 222 七A 粉末 MS(APCI):553/555[M+H]+ 223 ^Y〇"F 粉末 MS(APCI):553/555[M+H]+ 224 <\crcl 粉末 MS(APCI):569/571 [M+H]+ 實施例225至231 對應之起始物以如實施例2 8中所述之相同方法處 106 318695 200804294 理，得到如下表5所示化合物。表5 於x 實施例號碼 R”，物化性質等 225 固體 MS(APCI):455/457[M+H]+ 226 -ch2-cf3 固體 MS(APCI):469/471 [M+H]+ 227 固體 MS(APCI):47!/473[M+H]+ 228 固體 MS(APCI):574/576[M+H]+ 229 固體 MS(APCI):54B/550[M+H]+ 230 ^Q-cn 固體 MS(APCI):488/490[M+H]+ 231 -ο 固體 MS(APCI):463/465[M+H]+ 實施例232至238 對應之起始物以如實施例19中所述之相同方法處理，得到如下表6所示化合物。 107 318695 200804294 表6 ζΧτ% —<^N-Rm R"/ 實施例號碼 R， R” R”，物化性質等 232 C1 Cl 粉末 MS(APCI):555/557[M+H]+ 233 C1 Cl V 粉末 MS(APCI):573/575[M+H]+ 234 C1 Cl 粉末 MS(APCI);573/575[M+H]+ 235 cf3 H 粉末 MS(APCI):555/557 [M+H]+ 236 cf3 H ^rF 粉末 MS(APCI):573/575[M+H]+ 237 cf3 H 粉末 MS(APCI):573/575[M+Hf 238 cf3 H 粉末 MS(APCI):589/591 [M+H]+ 實施例239至248 對應之起始物以如實施例23中所述之相同方法處理，得到如下表7所示化合物。 108 318695 200804294 表7 HN-N S02 實施例號碼 R， R，， R3 物化性質等 239 C1 H -c2h5 固體 MS(APCI):509/511 [M+Hf 240 C1 H -(ch2)2och3 固體 MS(APCI):539/541 [M+H]+ 241 C1 H -chf2 固體 MS(APCI):531/533[M+H]+ 242 C1 Cl 響ch3 固體 MS(APCI);529/531 [M+H]+ 243 cf3 H _c2h5 固體 MS(APCI):543/545[M+H]+ 244 cf3 H -(CH2)2〇CH3 固體 MS(APCI):573/575[M+H]+ 245 Cl Cl -CH2-CF3 粉末 MS(APCI):597/599[M+H]+ 246 CFs Cl ch3 粉末 MS(APCI):563/565[M+H]+ 247 cf3 F -ch3 粉末 MS(APCI):547/549[M+H3+ 248 cf3 H -ch3 粉末 MS(APCD：529/531 [M+H]+ 實施例249至254 對應之起始物以如實施例30中所述之相同方法處理，得到如下表8所示化合物。 109 318695 200804294 表8 (X。〜實施例號碼 _N(R5)(R6) 物化性質等 249 CH3 ^n^^och3 固體 MS(APCI):449/451 [Μ+Η]+ 250 一N 0 \^/ 固體 MS(APCI):447/449[M+H]+ 251 固體 MS(APCI):445/447[M+H]+ 252 -N(CH3)2 固體 MS(APCI):405/407[M+H]+ 253 〇^nh2 固體 MS(APCI):531/533 [M+H]+ 254 ι^\ 一Ν S02 Ν^/ 1 固體 MS(APO):495/497[M+H]+ 實施例255至260 對應之起始物以如實施例29中所述之相同方法處理，得到如下表9所示化合物。 110 318695 200804294 表9 aXXj^3 (X。實施例號碼物化性質等 255 -ο 固體 MS(APCI):438/440[M+H]+ 256 固體 MS(APCI):463/465[M+H]+ 257 固體 MS(APCI):439/44! [M+H]+ 258 \=r[si 固體 MS(APCI):464/466[M+H]+ 259 固體 MS(APCI):507/509[M+H]+ 260 —so2ch3 固體 MS(APCI):516/518[M+H]+ 實施例261至262 對應之起始物以如實施例3 7中所述之相同方法處理，得到如下表10所示化合物。 111 318695 200804294 表ίοCk such as 5 n-r5 Ο-Cl R' Boc: tertiary butoxycarbonyl group number R3 -N(R5)(R6) physicochemical properties, etc. 64 -(CH2)2SCH3 HN-N^O / \^J powder MS (APCI): 507/509 [M+H] + 65 / \1 Powder MS (APCI): 546/548 [M+H] + 66 Powder MS (APCI): 545/547 [M+H]+ 67 -ch3 A (4) 2)-OCH3 Powder MS (APCI): 475/477 [M+H] + 68 -ch3 HN-N^ Powder MS (APCI): 461/463 [M+H]+ 69 -ch3 hn- On-so2 / ^ fc2H5 powder MS (APCI): 537/539 [M+H] + 70 -ch3 hn-^n-so2 ' ^ N(CH3)2 powder MS (APCr): 552/554 [M+H ]+ 71 Fine ch3 powder MS (APCI): 545/547 [M+H]+ 85 318695 200804294 Table 2(5) P N-R5 Example number R3 -N(R5)(R6) Physicochemical properties, etc. 72 ch3 ψ -〇°2 Powder MS (APCI): 480/482 [M+H]+ 73 ch3 Powder MS (APCI): 463/465 [M+H]+ 74 ch3 hn-^isH; / b ch3 Powder MS (APCI) ): 487/489[M+H]+ 75 ch3 H /N, n~〇ch3 ch3 Viscous MS (APCI): 449/451 [M+H]+ 76 ch3 h ch3 , n, n gas H3C person ^ Powder MS (APCI): 473/475 [M+H] + 77 〇ψ-〇 powder MS (APCI): 533/535 [M+H] + 78 ch3 Η , Nv^sch3 Viscous MS (APCI): 436 /438[M+H]+ 79 CHr ch3 Solid MS (APCI): 468/470 [M+H]+ 86 318695 200804294 Table 2(6) Plant ^N-R5 0^cl R6' Example number R3 _n(r5)(r6) Physicochemical properties, etc. 80 ch3- ψ-Ν(02Η5)2 Powder MS (APCI): 433/435 [M+H]+ 81 ch3- ch3 ch3 powder MS (APCI): 475/477 [M+H]+ 82 CHr h3c flat-n^Z) h3c powder MS (APCI): 473/475 [M+H] + 83 ch3- ψ-ΚΙ)ζ Powder MS (APCI): 481/483 [M+H]+ 84 CHr TM-N^^CF3 Solid MS (APCI):513/515 [M+H]+ 85 C2H5- ψ-Ν(ΟΗ3)2 Solid MS (APCI): 419/421 [M+H]+ 86 C2H5- Solid MS (APCI): 445/447 [M+H]+ 87 C2H5- ψ-〇 solid MS (APCI) ): 460/462[M+H]+ 87 318695 200804294 Table 2(7) Ν-Ν n_r5 ex〆, Example No. R3 -N(R5)(R6) Physicochemical Properties, etc. 88 CH30(CH2)2-Solid MS (APCI): 490/492 [M+H; T 89 CH30(CH2)2-HN-N(CH3)2 powder MS (APCI): 449/451 [M+H]+ 90 CH30(CH2)2- powder MS (APCI): 475 / 477 [M+H] + 91 ch3- 00 solid MS (APCI): 432 / 434 [M+H] + 92 CH3 (CH2) 2 - solid MS (APCI): 459/461 [ M+H]+ 93 ch3(ch2)2-HN-N(CH3)2 Solid MS (APCI): 433/435 [M+H]+ 94 ch3(ch2)2- ψ-〇 solid MS (APCI): 474/476[M+H]+ 95 ch3- ^nCn~0 Solid MS (APCI): 522/524 [M+H]+ 96 CHr Flat - -〇 solid MS (APCI): 523/525 [M + Hf 88 318695 200804294 Table 2 (8) αχχτ ^. tAci ^ Example 5 Tiger stone horse R3 ^ N (R5) (R6) Physicochemical properties, etc. 97 ch3- ην·νΓ? 1 I. och3 solid MS (APCI): 475/477 [M+H]+ 98 ch3- hn^ Nx\ 1 S)ch3 solid MS (APCI): 475/477 [M+H] + 99 CHr solid MS (APCI): 524/526 [M+H] + 100 ch3-solid MS (APCI): 524/526 [M+H]+ 101 CH3(CH2)2- ψ^-fQ Solid MS (APCI): 586/588 [M+H]+ 102 F2CH- A solid MS (APCI): 467/469 [M+H] + 103 f2ch- k^-n(ch3)2 Solid MS (APCI): 441/443 [M+H]+ 104 CH3OCOCH2- mi-N(CH3)2 Solid MS (APCI): 463/465 [M+H ]+ 105 f2ch- formazan solid MS (APCI): 482/484 [M+Hf 89 318695 200804294 Table 2 (9) n-r5 (X ^ Example No. R3 _N(R5)(R6) Physicochemical properties, etc. 106 ( CH3) 2NS〇2-solid MS (APCI): 524/526[M+H]+ 107 (ch3)2nso2- m^-N(CH3)2 Solid MS (APCI): 498/500[M+H]+ 108 (CH3)2NS〇2- ψ-Ο Solid MS (APCI): 539/541 [M+H]+ 109 ch3- Solid MS (APCI): 540/542 [M+H]+ 110 CHr Solid MS (APCI) ):540/542[M+H]+ 111 CHr /^cf3 A, Cr Solid MS (APCI): 499/50I [Μ+Η]+ 112 ψ^Ο Solid MS (APCI): 514/516 [Μ+ Η]+ 113 m^-N(CH3)2 Solid MS (APCI): 488/490 [M+H]+ 114 solid MS (APCI): 529/531 [M+H]+ 90 318695 200804294 Table 2(10) Tour 5 Example number R3 -N(R5)(R6) Physical and chemical properties, etc. 115 Solid MS (APCI): 526/528 [ M+H]+ 116 1>CH3 ψ-〇 solid MS (APCI): 527/529 [M+H]+ 117 ^V/CH3 HsC-^ζΙί ψ-Ν(ΟΗ3)2 Solid MS (APCI): 500 /502[M+H]+ 118 ch3-solid MS (APCI): 439/441 [M+H]+ 119 ch3-solid MS (APCI): 439/441 [M+H]+ 120 ch3- 』ijrCN solid MS (APCI): 463/465 [M+H]+ 121 ch3-H solid MS (APCI): 468/470 [M+H]+ 91 318695 200804294 Table 2(11) Ν·Ν N-R5 (X, ^ Example No. R, -N(R5)(R6) Physicochemical properties, etc. 122 F ψ^Ο Powder MS (APCI): 415/417 [M+H] + 123 F Powder MS (APGI): 429/431 [M +H]+ 124 ch3o Medium-N] Solid MS (APCI): 427/429 [M+H]+ 125 ch3o- Solid MS (APCI): 441/443 [M+H]+ 126 ch3o- r~\ HN -N 0 /solid MS (APCI): 443 / 445 [M+H] + 127 ch3o - solid MS (APCI): 442 / 444 [M+H] + 128 NC - solid MS (APCI): 422 / 424 [ M+H]+ 92 318695 200804294 Table 2(12) faXci R' Example number-N(R5)(R6) Physicochemical properties, etc. 129 IW-N(CH3)2 f Powder MS (APCI): 423/425 [M +H]+ 130 Powder MS (APCI): 4 49/451 [M+H]+ 131 Powder MS (APCI): 463/465 [M+H]+ 132 ηνη/~\) / Powder MS (APGI): 465/467 [M+H]+ 133 Powder MS (APCI): 464/466[M+H]+ 93 318695 200804294 Table 2(13) F3C^n-r5 (X〆Example No. R3 _n(r5)(r6) Physicochemical Properties, etc. 134 CHr mN(CH3)2 Solid MS (APCI): 439/441 [Μ+Η]+ 135 ch3-solid MS (APCI): 465/467[M+H]+ 136 CHr solid MS (APCI): 479/481 [M+H]+ 137 CHr HN-N~\ / \f Solid MS (APCI): 481/483 [M+H]+ 138 ch3- Solid MS (APCI): 480/482[M+H]+ 139 f2ch- i^-n (ch3)2 Powder MS (APCI): 475/477 [M+H] + 140 f2ch· ψ-〇 powder MS (APCI): 516/518 [M+H]+ 141 f2ch· Powder MS (APCI): 501 /503[M+H]+ 142 c2h5 靡平-n(ch3)2 Solid MS (APCI): 453/455[M+H]+ 94 318695 200804294 Table 2(14) F3C^〇SF-R5 Ο-Cl R" Example number R3 -N(R5)(R6) Physicochemical properties, etc. 143 c2h5- Solid MS (APCI): 479/481 [M+H]+ 144 c2h5- HN-N^ t \^f Solid MS (APCI ): 493/495[M+H]+ 145 c2h5-HN-N^O / N^/ Solid MS (APCI): 495/497 [M+H]+ 146 c2h5_ Solid MS (APCI) 494/496 [M +H]+ 147 ch3o(ch2)2- Ψ谭h3)2 Powder MS (APCI): 483/48 5[M+H]+ 148 ch3o(ch2)2_ 〒- Solid MS (APCI): 509/511 [M+H]+ 149 CH30(CH2)2. Solid MS (APCI): 523/525 [M+H ]+ 150 CH30(CH2)2- Γ^\ HN-N Ο / \^f solid. MS(APCI): 525/527[M+H]+ 151 CH30(CH2)2- Powder MS (APCI): 524 /526[M+H]+ 95 318695 200804294 Table 2(15) C1^5 n-r5 Example number R" -N(R5)(R6) Physicochemical properties, etc. 152 CFr solid MS (APCI): 465/467 [ M+H]+ 153 CFr Solid MS (APCI): 479/481 [M+H]+ 154 CFr r~\ HN — NO / V—/ Solid MS (APCI): 481/483 [M+H]+ 155 Cf3-solid MS (APCI) 480/482 [M+H]+ 156 NC- powder MS (ESI): 422.10 [M+H] + 157 F m^ (cu3) 2 powder MS (ESI): 389.09 [M+ H]+ 158 F powder MS (ESI): 415.11 [M+H]+ 159 F A "KZ)0 powder MS (ESI): 430.10 [M+H]+ 96 318695 200804294 Table 2 (16) n-r5 Example No. R"-N(R5)(R6) Physicochemical Properties, etc. 160 Cl Powder MS (APGI): 514/516 [M+H]+ 161 Cl roi-N(CH3)2 Powder MS (APCI): 473/ 475[M+H]+ 162 Cl powder MS (APCI): 515/517 [M+H]+ 163 Cl powder MS (APCI): 548/550 [M+H]+ 164 Cl ch3 powder MS (APCI): 536/538[M+H]+ 165 F A-Plutonium Powder MS (APCI): 498/500[M+H]+ 166 F m^(CH3)2 Powder MS (APCI): 457/459 [M+H] 十167 F 〒_〇 Powder MS (APCI): 499/501 [M+H]+ 168 F ^-〇〇2 Powder MS (APCI): 532/534 [M+H] + 169 F ch3 Powder MS (APCI): 520/522 [M+H] + 97 318695 200804294 Table 2 (17) C, ^〇 (X a Example) No. R3 - N(R5)(R6) Physicochemical properties, etc. 170 ο Powder MS (APCI): 516/518 [M+H] + 171 ch3 HN-N^SO / U Powder MS (APCI): 479/481 [M +H]+ 172 Powder MS (APCI): 532/534 [M+H]+ 173 ch3 A η3<^〇, οι3 Powder MS (APCI): 460/462[M+H]+ 174 ch3 -Op Solid MS (APCI): 466/468 [M+H] + 98 318695 200804294 Table 2 (18) R'xx^ n-r5 R,, iX a Example number R, R" _N(R5)(R6) Physicochemical properties, etc. 175 FH -NH-N(CH3)2 Powder MS (APCI): 389/391 [M+H]+ 176 FH HN-N^O / U Powder MS (APCI): 431/433 [M+H]+ 177 FH TM-C° Powder MS (APCI): 430/432 [M+H]+ 178 ch3o H •nh-n(ch3)2 Solid MS (APCI): 401/403[M+H]+ 179 CH3SO2 H - NH-N (CH3>2 solid MS (APCI): 449/451 [M+H]+ 180 CH3SO2 H solid MS (APCI): 475 / 477 [M+H] + 181 CH3SO2 H τΌ solid MS (APCI): 490/492[M+H]+ 182 CN H -NH-N(CH3)2 / solid MS (APCI): 396/398 [M+H] + 183 CN H ψ < 2° solid MS (APCI): 437/439 [M+H] + 184 Cl Cl HNH0KCF3 solid MS (APCI): 540/542 [M+H]+ 99 318695 200804294 Table 2(19) CI^5 n_r5 CX” a Example No. R R _N(R5)(R6) Physicochemical Properties, etc. 185 cf3 -NH-N(CH3)2 Solid MS ( APCI): 439/441 [M+H]+ 186 ch3o _nh_n(ch3)2 Powder MS (ESI): 40L09[M+H]+ 187 ch3o powder MS (ESI): 427.13 [M+H]+ 188 ch3o powder MS (ESI): 442.12 [M+H] + 189 CN -NH-N (CH3 > 2 powder MS (ESI): 396.09 [M+H] + 190 CN, 〇 powder MS (ESI): 437.10 [M+H ] + 100 318695 200804294 Table 2 (20) XL· och3 n -r5 JJ Example No. -N(R5)(R6) Physicochemical properties, etc. 191 -NH-N(CH3)2 Powder MS (ESI): 405.03 [M+ H]+ 192 A-^o powder MS (ESI): 446.04 [M+H]^ The corresponding starting materials of Examples 193 to 218 were treated in the same manner as described in Example 2 2 (3), The compounds shown in Table 3. 101 318695 200804294 Table 3(1) HN-N^JSHET Example number Rm Physical and chemical properties, etc. 193 Solid MS (APCI): 568/570fM+H]+ 194 Solid MS (APCI): 576/578 [M+H]+ 195 〇々 ci Solid MS (APCI): 585/587 [M+H] 4 196 mp. MS (APCI): 575 / 577 [M+H] + 197 solid MS (ESI): 583.99 [M+Hf 198 -COCH3 Solid MS (ESI): 487.97 [M+H.sup..sup.ss.ssssssssssssssssssssssssssssssssssssssssssss ESI): 539.98 [M+H]+ 202 (^-〇-〇ch3 powder MS (ESI): 580.05 [M+H] + 102 318695 200804294 Table 3(2) Example No. R, R3 R", physicochemical properties </RTI> </RTI> </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> </RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; <RTI ID=0.0></RTI> 209 cf3 C2H5 Solid MS (APCI): 616/618 [M+H]+ 103 318695 200804294 Table 3(3) HN~N NR ... H3c?~/ Example No. R", Physicochemical Properties, etc. 210 °hO Solid MS ( APCI): 578/580[M+H]+ 211 Q jT\ Solid ny-F MS (APCI): 5 96/598[M+H]+ Table 3(4) HNRs^^HT, Example No. R", Physicochemical Properties, etc. 212 Solid MS (APCI): 575/577 [M+H]+ 213 VC1 Solid MS (APCI) ): 584/586[M+H]+ 214 Solid MS (APCI): 584/586 [M+H]+ 104 318695 200804294 215 VF Solid MS (APCI): 586/58B[M+H]+ 216 ίίλρ Solid MS (APCI): 586/588 [M+Hf 217 F solid MS (APCI): 586/588 [M+H] + 218 NC NC NC solid MS (APGI): 575/577 [M+H]+ Example The corresponding starting materials of 219 to 224 were treated in the same manner as described in Example 1 or 22 (3) to give the compound shown in Table 4 below. 105 318695 200804294 Table 4 σΧΧ jocri (X KJ m^-R6 Example No. R6 Physicochemical Properties, etc. 219 Solid MS (APCI): 549/551 [M+H]+ 220 Solid MS (APCI): 567/569 [M+ H]+ 221 ~°-y〇 Powder MS(APCI)535/537[M+H]+ 222 Seven A Powder MS(APCI): 553/555[M+H]+ 223 ^Y〇"F Powder MS (APCI): 553/555 [M+H] + 224 <\crcl powder MS (APCI): 569/571 [M+H]+ Examples 225 to 231 corresponding starting materials as in Example 28 The same method was used to obtain the compound shown in Table 5 below. Table 5 at x Example No. R", physicochemical properties, etc. 225 Solid MS (APCI): 455/457 [M+H] + 226 - Ch2-cf3 solid MS (APCI): 469/471 [M+H]+ 227 solid MS (APCI): 47!/473[M+H]+ 228 solid MS (APCI): 574/576 [M+H] + 229 Solid MS (APCI): 54B/550[M+H]+ 230^Q-cn Solid MS (APCI): 488/490[M+H]+ 231 -ο Solid MS (APCI): 463/465 [ M+H]+ The corresponding starting materials of Examples 232 to 238 were treated in the same manner as described in Example 19 to give the compound shown in the following Table 6. 107 318695 200804294 Table 6 ζΧτ% —<^N-Rm R"/ real Example number R, R" R", physicochemical properties, etc. 232 C1 Cl powder MS (APCI): 555/557 [M+H] + 233 C1 Cl V powder MS (APCI): 573/575 [M+H] + 234 C1 Cl powder MS (APCI); 573/575 [M+H]+ 235 cf3 H powder MS (APCI): 555/557 [M+H]+ 236 cf3 H ^rF powder MS (APCI): 573/575 [ M+H]+ 237 cf3 H powder MS (APCI): 573/575 [M+Hf 238 cf3 H powder MS (APCI): 589/591 [M+H]+ Examples 239 to 248 corresponding starting materials The same procedure as described in Example 23 gave the compound shown in Table 7 below. 108 318695 200804294 Table 7 HN-N S02 Example No. R, R,, R3 Physicochemical Properties, etc. 239 C1 H -c2h5 Solid MS (APCI): 509/511 [M+Hf 240 C1 H -(ch2)2och3 Solid MS ( APCI): 539/541 [M+H]+ 241 C1 H -chf2 Solid MS (APCI): 531/533 [M+H]+ 242 C1 Cl Ring ch3 Solid MS (APCI); 529/531 [M+H ]+ 243 cf3 H _c2h5 Solid MS (APCI): 543/545 [M+H]+ 244 cf3 H -(CH2)2〇CH3 Solid MS (APCI): 573/575 [M+H]+ 245 Cl Cl - CH2-CF3 powder MS (APCI): 597/599 [M+H]+ 246 CFs Cl ch3 powder MS (APCI): 563/565 [M+H]+ 247 cf3 F -ch3 powder MS (APCI): 547/ 549 [M+H3+ 248 cf3 H -ch3 powder MS (APCD: 529/531 [M+H] + the corresponding starting materials of Examples 249 to 254 were treated in the same manner as described in Example 30, and the following table was obtained. Compounds shown in 8. 109 318695 200804294 Table 8 (X.~ Example No. _N(R5)(R6) Physicochemical properties, etc. 249 CH3 ^n^^och3 Solid MS (APCI): 449/451 [Μ+Η]+ 250 A N 0 \^/ Solid MS (APCI): 447/449 [M+H]+ 251 Solid MS (APCI): 445/447 [M+H]+ 252 -N(CH3)2 Solid MS (APCI) :405/407[M+H]+ 253 〇^nh2 Solid MS (APCI): 531/533 [M+H]+ 254 ι ^\一Ν S02 Ν^/ 1 Solid MS (APO): 495/497 [M+H]+ The corresponding starting materials of Examples 255 to 260 were treated in the same manner as described in Example 29, and the following table was obtained. Compounds shown in Figure 11. 110 318695 200804294 Table 9 aXXj^3 (X. Example No. Physicochemical Properties, etc. 255 - o Solid MS (APCI): 438/440 [M+H] + 256 Solid MS (APCI): 463/465 [M+H]+ 257 Solid MS (APCI): 439/44! [M+H]+ 258 \=r[si Solid MS (APCI): 464/466 [M+H]+ 259 Solid MS (APCI) : 507 / 509 [M + H] + 260 - so2ch3 solid MS (APCI): 516 / 518 [M + H] + Examples 261 to 262 corresponding starting materials in the same manner as described in Example 37 The compound shown in the following Table 10 was obtained by the treatment. 111 318695 200804294 Table ίο

實施例263 在0°C，將3 -氯過苯曱酸（90毫克，水含量25%)加至實施例64所得化合物（127毫克）之二氣曱烷（2毫升）溶液中，然後在相同溫度下攪拌混合物30分鐘。接著將碳酸氫鈉水溶液加至反應混合物中並攪拌。分離有機層，有機層經真空濃縮。所得粗產物用矽膠管柱層析（溶劑：三氯曱烷 /甲醇= 100/0至95/5)進行純化，得到1-(2-氯苯基）-5-(4-氯苯基）-4-[2-(甲亞磺醯基）乙氧基]-3-[N-(l-吼咯啶基）胺曱醯基]-1H-吼唑（92毫克，產率70%)粉末。 MS(APCI)m/z ： 523/525[M+H]+ 實施例264 參考例9(2)所得化合物（33毫克）以如實施例29所述 112 318695 200804294 -之相同方法處理，得到1_(2-氯笨基）-5〜（4—氯苯基）—4一甲 .氧基-3-[(1-苯甲醯基六氫吼啶-4-基）羰基]胺基-1H—吼唑 \ (40毫克，產率74%)固體。 • MS(APCI)m/z ： 549/551[M+H]+ 實施例2 6 5 實施例172所得化合物（160毫克）以如實施例15所述之相同方法處理，得到氯苯基）_5_(4_氯苯基）_4一 (卜側氧基―4—四氫硫代哌喃基）氧基-3-[N-(4_四氫哌喃基）胺甲醯基]-1H-吡唑（15毫克，產率1〇%)粉末。 MS(APCI)m/z： 548/550[M+H]+ 實施例2 6 6 實施例172所得化合物（160毫克）以如實施例16所述之相同方法處理，得到1-(2—氯苯基）—5 —(4—氯苯基）一4一 (1，I —一側氧基—4-四氫硫代旅喃基）氧基—3-[n-(4-四氫口底喃基）胺甲醯基]-1H-吡唑（73毫克，產率45%)固體。 MS(APCI)m/z ： 564/566[M+H]+ 實施例267 (1) 芩考例18所得化合物（155毫克）以如實施例1所述之相同方法處理，得到丨―（2-氯苯基）—5 —(4—氯苯基）—4 一 (4-四氫硫代哌喃基）氧基-3 —[N—(N-嗎福啉基）胺曱醯基] - 1H-吡唑（170毫克，產率92%)粉末。 MS(APCI)m/z ： 533/535[M+H]+ (2) 上述步驟（1)所得化合物（152毫克）以如實施例15 所述之相同方法處理，得到丨―（2 —氯苯基）—(4_氯苯基） 113 318695 200804294 --4-(1-側氧基-4-四氫硫代哌喃基）氧基—3—[n_(n—嗎福啉 -基）胺甲醯基]-1 Η-吼峻（97毫克，產率62%)粉末。 MS(APCI)m/z ： 549/551[M+H]+ 實施例2 6 8 實施例78所得化合物（65毫克）以如實施例1 5所述之相同方法處理’得到1-(2-氯苯基）-5-(4-氯苯基）-4-甲氧基-3-{N-[2-（甲亞磺醯基）乙基]胺甲醯基卜1Η_σ比唑（62 毫克，產率92%)粉末。 MS(APCI)m/z ： 452/454[M+H]+ 實施例269 實施例78所得化合物（65毫克）以如實施例16所述之相同方法處理，得到1-(2-氯苯基）-5-(4-氣苯基）—4—甲氧基-3-{N-[2-（曱磺醯基）乙基]胺曱醯基卜1H-吡嗤（68毫克，產率96%)粉末。 MS(APCI)m/z ： 468/470[M+H]+ 實施例270 對應之起始物以如實施例29所述之相同方法處理，得到1-(2-氯苯基）-5-(4-氯苯基）-4-甲氧基〜3〜（2-吼啶基乙酸基）胺基-1H-吼嗤（31毫克，產率69%)粉末。 MS(APCI)m/z ： 453/455[M+H]+ 實施例271 對應之起始物以如實施例27所述之相同方法處理，得到4-(胺曱醯基）甲氧基-；ι_(2-氯苯基）一5〜（4〜 =亍 [〇r，ίΓ-二曱肼基）羰基]一1H-吡唑（26· 7亳$ 女七、 &見，產率30%) 114 318695 200804294 粉末。 MS(APCI)m/z ： 448/451[M+H]+ 實施例272至273 對應之起始物以如實施例1，然後以參考例14中所述之相同方法處理，得到如下表11所示化合物。表11 hn-n 實施例號碼 -n(r5)(r6) 物化性質等 272 、ϊ^^802(：Η3 粉末 MS(APCI):509/511 [M+H]+ 273 一也固體 MS(APCI):503/505[M+H]+ 實施例274 (1)參考例1(6)所得化合物（109毫克）與參考例48所得化合物（105毫克）以如實施例1所述之相同方法處理，得到1-(2-氯苯基）-5-(4-氯苯基）-4-曱氧基-3-[N-(4-苯曱基-4-乙氧羰基六氫吡啶-1-基）胺曱醯基]-1H-吡唑（152 毫克，產率83%)呈無色固體。 MS(APCI)m/z ： 607/609[M+H]+ 115 318695 200804294 ·'⑵將2N氫氧化納水溶液（25()微升）加至上述步驟⑴ 所侍化合物(150宅克)之乙醇(3亳升)溶液中，然後於 .C攪拌混合物-夜。接著再將⑽氫氧化納水溶液（_微 .^加至反應混合物中，於9Gt攪拌混合物2日。冷卻至室溫，’加人1N鹽酸水溶液簡拌，混合物以三氣甲烧萃取取液心真空浪縮後所得粗產物用石夕膠管柱層析（溶劑：三氯甲炫/甲醇，/2至95/5)與石夕勝薄層層析（溶劑：三氯甲烧/甲醇=95/5)進行純化，得到卜（2_氯苯基）_卜 (4-氣苯基）+甲氧基_3餐（4_苯甲基+羧基六氯吼咬一 1一基)胺甲酿基"I-1H-口e古士士士」11比主Cb5·5耄克，產率38%)呈淡音色固體。 /' MS(APCI)m/z ： 579/581[M+H]+ > (3)將氯化叙（5. 5 t克）、水可溶碳二亞胺鹽酸鹽（2〇毛克）、1羥基苯并二唑水合物（16毫克）與三乙胺（2〇微升）加至上述步驟（2)所得化合物（29 4毫克）之二曱基曱醯胺〇毫升）溶液中，室溫㈣混合物_夜。接著將碳酸氫納水溶液加至反應混合物中並㈣，混合物用三氯甲烧萃 ^有機層用水清洗後經真空濃縮。所得粗產物用_矽膠管柱層析（Chr_atorex^-矽膠，溶劑：己烷/乙酸乙酯 = 5/65至0/100)進行純化，得到丨_(2_氯苯基）_5_(4_氯苯基）-4-甲氧基-3-[N-(4-苯曱基〜4_胺甲醯基六氫〇比啶 -卜基）胺甲醯基]-1H-吡唑（23.6毫克，產率8〇%)呈無色固體。 MS(APCI)m/z ： 578/580[M+H]+ 318695 116 200804294 實施例275 (1)參考例1(6)所得化合物（545毫克）與參考例45(3) 所得化合物（292毫克）以如實施例1所述之相同方法處理，得到1-(2-氣苯基）-5-（4-氯苯基）-4-曱氧基—3—[N-(4-曱氧羰基四氫硫代哌喃—4-基）胺曱醯基]-1 η-吡唑（48〇毫克，產率92%)無色固體。 MS(APCI)m/z ： 520/522[M+H]+ (2)冰冷卻下，將三氟乙酸（163微升）加至上述步驟（l) 所得化合物（275毫克）之二氣甲烷（5毫升）溶液中，然後室溫攪拌混合物30分鐘。接著在冰冷卻下將間氯過苯曱酸 (244耄克）加至反應混合物中，室溫攪拌混合物】小時。再加入間氯過苯曱酸（61毫克），室溫攪拌混合物3〇分鐘。然後反應混合物以如實施例丨5所述之相同方法萃取與純化，得到1-(2-氣苯基）—5 -（4-氯苯基）一4一甲氧基—3 一 [N-(4-甲氧羰基-1，1-二側氧基四氫硫代哌喃一4 —基）胺甲醯基]-ll·吡唑（272.1毫克，產率93%)之淡黃色固體。脈 MS(APCI)m/z ： 552/554[M+H]+ (3)將2N氳氧化鈉水溶液（49〇微升）加至上述步驟（？) 所得化合物⑽毫克）之乙醇（3毫升）溶液中，然後室溫擾拌混合物一夜。接著將狀鹽酸水溶液（5〇〇微升）加至反應混合物中並授拌，混合物以三氯甲料取。萃取液經直: 濃縮後所得粗產物用石夕膠管柱層析（溶劑：三氯曱烧艸 = 99/1至90/10)進行純化，得到基）-〇氧基-3鲁㈣基—本/) = (4 —氯苯 ’ 侧氧基四虱硫代娘喃 318695 117 200804294 ,-4-基）胺甲酿基]-坐（224.7毫克，產率85%) .色固體。 ^ ；MS(APCI)m/z ： 538/540[M+H]+ (4)將氯化銨（7· 5宅克）、水可溶碳二亞胺鹽酸鹽（28 -毫克）、卜經基苯并三峻水合物（21冑克）與三乙胺（29微升）加至上述步驟⑶所得化合物（38毫克）之二甲基甲酿胺（ι 毫升）溶液中’室溫授拌混合物2日。接著將碳酸氫納水溶液加至反應混合物中並授拌，混合物用三氯甲院萃取。有機層用水清洗後經真空濃縮。所得粗產物用NH_矽膠管柱層析（ChromatorexNH-矽膠，溶劑··己烷/乙酸乙酯=2〇/8〇至0/100)進行純化’得到^(2 —氯苯基）_5_(4_氯苯基）_4_ 曱氧基-3-[N-(4-胺甲醯基-i，卜二側氧基四氯硫代派喃 -4-基）胺甲醯基]-1H_吡唑（33.9毫克，產率85%)無色固體。 MS(APCI)m/z： 537/539[M+H]+ 實施例276 (1) 參考例5 (2)所得化合物（16 8毫克）與參考例4 7 (2) 所知化合物（7 0耄克）以如實施例1所述之相同方法處理，知到1-（2-氯苯基）-5-(4-氯苯基）-4-曱氧羰基甲氧基一3一 [N-（4-甲氧羰基-4-苯基六氫吡啶-1 一基）胺甲醯基]—1H一吡唾（1〇8.1毫克，產率57%)之無色固體。 MS(APCI)m/z ： 637/639[M+H]+ (2) 將2 N鼠氧化納水溶液（3 3 6微升）加至上述步驟（1) 所得化合物（107毫克）乙醇（2毫升）溶液中，然後於8(rc 318695 118 200804294 攪拌混合物2小時。接著再將2N氫氧化納水溶液⑽微加至反應混合物巾，10{rc授拌混合物}小時。添加四虱呋喃（1宅升）至反應混合物中，1〇〇〇c攪拌3日。冷卻至室溫後，亡入2N鹽酸水溶液（500微升）並攪拌，混:二以三氯甲烷萃取。萃取液經真空濃縮後殘留物以二甲基甲醯胺（2宅升）稀釋。然後加入氣化銨（27毫克）、水可溶碳二亞胺鹽酸鹽（97毫克）、1-羥基苯并三唑水合物（77毫克）與三乙胺（140微升），室溫攪拌混合物4小時。接著將碳酸氫鈉水溶液加至反應混合物中並攪拌，混合物用三氯曱烷萃取。有機層用水清洗後經真空濃縮。所得粗產石夕膠管柱層析（Chr⑽atorexNH-矽膠，溶劑：己烧/乙酸乙酯=20/80至0/100)進行純化，得到丨―（2-氯苯基）—5 —(夂4一氯苯基）-4-胺甲醯基甲氧基—3一[N-(4 —胺甲醯基一4一苯基六氫吡啶-卜基）胺甲醯基]吡唑（59. 2毫克，產率58%) 呈無色固體。 MS(APCI)ra/z ： 607/609[M+H]1 實施例277 (1)冰冷卻下，將二曱酸二-三級丁酯（21·82克）之四氫呋喃溶液（100毫升）逐滴加至含S-甲硫脲硫酸鹽 (S-methylthiourea sulfate，15· 31 克）與碳酸鉀（3〇 4 克）之水（300毫升）溶液中，然後於室溫攪拌混合物一夜。反應混合物以乙酸乙酯萃取。萃取液以硫酸鎂乾燥後經真空濃縮，得到N-三級丁氧羰基-S-甲硫脲（18· 85克，產率 99%)呈白色固體。 318695 119 200804294 MS(APCI)m/z : 191[M+H]+ ☆ (2)在室溫，將水可溶碳二亞胺鹽酸鹽（2· 克）加至含參考例1(6)所得化合物（3·63克）、上述步驟⑴所得化 -合物（2·85克）、卜羥基苯并三唑（2·28克）與三乙胺（ι·5ι 克）之Ν，Ν 一甲基甲醯胺（1〇〇毫升）溶液中，然後攪拌混合物夜。接著將水加至反應混合物中，以過遽法收集所產生之沉澱物，然後用三氣甲烷溶解。溶液用水清洗，以硫酸鎂乾燥後經真空濃縮，得到^(2 —氯苯基）—5 —(4-氯苯基）-4-甲氧基-3-(N-{[(三級丁氧羰基胺基）甲硫基]亞甲基}胺甲醯基）-1H-吡唑（5· 20毫克，產率97%)呈白色固體。 MS(APCI)m/z : 535/537[M+H]+ (3) 在室溫，將肼鹽酸鹽（6·85克）加至含上述步驟（2) 所得化合物（1· 07克）與碳酸鉀（6· 91克）之甲醇（2〇毫升）邊浮液中，然後8 0 C攪拌混合物一夜。冷卻後，將水加至反應混合物中，混合物以三氯甲烷萃取。萃取液以硫酸鎂乾燥後經真空濃縮。所得粗產物用矽膠管柱層析（溶劑：己烷/乙酸乙酯=65/35至45/55)進行純化，得到ΐ-(2-氯苯基）-5-(4-氯苯基）-4-曱氧基-3-[5-(三級丁氧羰基胺基） -1，2, 4-三唑-3-基]-1H-吡唑（814毫克，產率81%)呈白色固體。 MS(APCI)m/z ： 501/503[M+H]+ (4) 在室溫，將4N HC1-二卩等烷（2· 0毫升）加至上述步驟（3)所得化合物（〇· 80克）之甲醇（10毫升）溶液中，攪拌混合物一夜。接著將碳酸氫鈉水溶液加至反應混合物中， 120 318695 200804294 -混合物用三氯甲烷萃取。萃取液以硫酸鎂乾燥後經真空濃，細，付到1-(2-氯苯基）-5-(4-氯苯基）-4-▼氧基—3-(5-胺基-1，2, 4-三唑-3-基）-1Η-σ比峻（390毫克，產率61%)呈白人色固體。 MS(APCI)m/z ： 401/403[M+H]+ (5)在室溫，將1，4-二溴丁烷（215毫克）加至含上述步驟（4)所得化合物（ι〇0毫克）與碳酸鉀（276毫克）之乙腈（3 毫升）懸浮液中，然後使混合物在14〇t微波反應器中攪拌 9〇分鐘。接著將水加至反應混合物中，混合物用乙酸乙酯萃取。萃取液以硫酸鎂乾燥後經真空濃縮。所得粗產物用矽膠管柱層析（溶劑··三氯甲烷/甲醇=1〇〇/〇至92/8)進行純化，得到1-(2-氯苯基）-5-(4-氯苯基）-4—曱氧基一3一 [5-（1-吡咯啶基）—；[，2, 4-三唑-3-基]-1H-吡唑（33· 4毫克，產率29%)呈淡黃色固體。 MS(APCI)m/z ： 455/457[M+H]+ 實施例278 (1)在室溫’將羥胺鹽酸鹽（6.95克）加至實施例277(2) 所得化合物（1.07克）與碳酸鉀（6. 91克）之甲醇（2〇毫升）懸浮液中，8CTC擾拌混合物-夜。冷卻後，將水加至反應混合物中，混合物用三氯甲烧萃取。萃取液以硫酸鎂乾燥後經真空濃縮。所得粗產物用矽膠管柱層析（溶劑：己烷/ 乙酸乙酉旨=80/20至60/40)進行純化，得至|U_(2—氣苯基） -5-(4-氣苯基）-4-甲氧基-3-[3七級了氧録胺基）一1，2,4一曙二吐-5 —基比唾（194毫克，產率19%)呈白 318695 121 200804294 I色固體。，MS(APCI)m/z : 502/504[Μ+ΗΓ (2) 在室溫，將4Ν HC卜二噚烷（1·〇毫升）加至上述步驟（1)所得化合物（〇 · 17克）之甲醇（5毫升）溶液中，授拌混 —合物一夜。接著將碳酸氫鈉水溶液加至反應混合物中，混合物用三氯甲烷萃取。萃取液以硫酸鎂乾燥後經真空濃縮’得到1-(2-氣苯基）-5-(4-氯苯基）-4-甲氧基-3~(3-胺基-1，2, 4-嘿二唑-5-基）-1Η-吼唑（104毫克，產率76%)呈白色固體。 MS(APCI)m/z： 402/404[M+H]+ (3) 在至温，將1，4-二溴丁炫（1毫升）加至含上述步驟 (2)所得化合物（8〇毫克）與碳酸鉀（276毫克）之乙腈（3毫升）懸浮液中，然後使混合物在14〇。(：微波反應器中攪拌 210分鐘。接著將水加至反應混合物中，混合物用乙酸乙酯萃取。萃取液以硫酸鎂乾燥後經真空濃縮。所得粗產物用矽膠管柱層析（溶劑：己烷/乙酸乙酯=95/5至〇/1〇〇)進行純化，得到1-(2-氯苯基）—5-(4—氯苯基）—4—甲氧基一 3一 [3-(1-比咯啶基）—丨，2, 4-噚二唑—5-基]—1H-吡唑（8· j毫克，產率9%)呈白色固體。 MS(APCI)m/z : 456/458[M+H]+ 實施例279 (1)將2N氫氧化鈉水溶液（1〇毫升）加至參考例1(4) 所得化合物（3. 77克）之乙醇（30毫升）溶液中，室溫擾拌混口物5小4。接著再將2f\f氫氧化鈉水溶液（5毫升）加至反 318695 122 200804294 應/m合物中，6 0 C祝拌混合物一夜。冷卻至室溫後，加入 2N鹽酸水溶液（20毫升）並攪拌混合物。接著將水加至混合物中並繼續攪拌混合物。所產生沉澱物以過濾法收集，然後乾燥，得到3-羧基-1 —(2-氯苯基）-5 —(4-氯苯基）—4 一羥基-1H-吡唑（3· 07克，產率88%)呈無色固體。 MS(APCI)m/z ： 349/351[M+H]+ (2)上述步驟（1)所得化合物（52毫克）與參考例53(3) 所得化合物（34毫克）以如實施例丨所述之相同方法處理，知到1-(2-氯苯基）-5-（4-氣苯基）—4-羥基一3一丨[4一胺甲醯基-4-(乙胺基）-N-六氫吡啶基]羰基卜1H-吡唑（33 7毫克’產率45%)呈淡黃色固體。 MS(APCI)m/z ： 502/504[M+H]+ 實施例280 ⑴參考例1(6)所得化合物（145毫克）舆參考例料所得化合物(77毫克)以如實施例！所述之相同方法處理，得到1-(2-氯苯基）-5-(4_氯苯基）_4_甲氧基羰基環己烷-1-基）胺甲醯基]-1H_吡唑（175毫克，產呈無色粉末。〇 MS(APCI)m/z ： 502/504[M+H]+ ⑵上述㈣⑴所得化合物（174毫克）以如實施例 275⑶所述之相同方法處理，得到卜（2、氯苯基）: 苯基）-4-甲氧基-3-[Ν-(Μ基環己院—卜基）胺甲齡 -1Η-吡唑（171毫克，產率1〇〇%)呈無色固體。土 MS(APCI)m/z ： 488/490[M+H]+ 318695 123 200804294 (3)上述步驟（2)所得化合物（34毫克）以如實施例275 (4)所述之相同方法處理，得到卜（2 —氯苯基5 —(4-氯苯基）-4-曱氧基—3—[N—(卜胺曱醢基環己烧]—基）胺曱酸基] …-1H-吡唑（26· 1毫克，產率77%)呈無色固體。 MS(APCI)m/z ： 487/489[M+H]+ 實施例281 (1) ί考例1 (6)所得化合物（145毫克）與參考例46所得化合物（78毫克）以如實施例1所述之相同方法處理，得到1-（2-氯苯基）—5 —(4一氯苯基）一4一甲氧基一3-[Ν—(4-曱氧羰基四氫哌喃-4-基）胺甲醯基]—1Η-^4(15〇毫克，產率 74%)呈無色固體。 MS(APCI)m/z ： 504/506[M+H]+ (2) 上述步驟（i)所得化合物（15〇毫克）以如實施例 275(3)所述之相同方法處理，得到丨兴卜氯苯基）-5 —(4 一氯苯基）-4-甲氧基—3-[N-（4-羧基-四氫哌喃—4-基）胺甲醯基]-1H-吡唑（137· 3毫克，產率93%)呈無色固體。 MS(APCI)m/z ： 490/492[M+H]+ (3) 上述步驟（2)所得化合物（34毫克）以如實施例275 (4)所述之相同方法處理，得到丨―（2-氯笨基）—5 —(4—氯苯基）-4-甲氧基-3-[N-（4-胺甲醯基-四氫哌喃—4一基）胺甲醯基]-1H-吡唑（31毫克，產率90%)呈固體。 MS(APCI)m/z ： 489/491[M+H]+ 實施例282 (1)實施例275(1 )所得化合物（200毫克）以如實施例 318695 124 200804294 275⑶所述之相时法處理，得到卜（2'氯苯基）_5_(4'氯苯基）-4-甲氧基|[N_(4_叛基_四氯硫代呢喃—4_基）胺甲 -·醯基]-1H-吡唑（146毫克，產率76%)呈無色固體。 MS(APCI)m/z ： 506/508[M+H]+ (2)上述步驟（1)所得化合物（π毫克）以如實施例275 (4)所述之相同方法處理，得到丨兴卜氯苯基氯苯基）-4-曱虱基-3-[Ν-(4-胺曱醯基-四氫硫代哌喃_4_基）胺甲醯基]— 1Η—吡唑（31· 1毫克，產率88%)呈固體。 MS(APCI)m/z： 505/507[M+H]+ 實施例283 (1) 參考例1(6)所得化合物（1〇9毫克）與參考例47所得化合物（94毫克）以如實施例丨所述之相同方法處理，得到1 -（2-氯苯基）一5一（4一氯苯基）一4一甲氧基一3-[N一（4一曱氧羰基-4-苯基六氫吡啶—丨—基）胺甲醯基卜1H—吡唑（142· 8 笔克’產率82%)呈無色固體。 MS(APCI)m/z ： 579/581[M+H]+ (2) 將2N氫氧化鈉水溶液（250微升）加至上述步驟（1) 所奋化合物（140毫克）之乙醇（3毫升）溶液中，然後5〇。〇授掉混合物2小時。接著將四氫呋喃（2毫升）加至反應混 b物中，80 C攪拌混合物2日。冷卻至室溫後，加入2N 鹽酸水溶液（250微升）並攪拌，混合物以三氯甲烷萃取。卒取液以硫酸鎂乾燥後過濾。濾液經真空濃縮，所得殘留物以二甲基甲酿胺（2毫升）稀釋。接著加入氯化銨（18毫克）、水可溶碳二亞胺鹽酸鹽（65毫克）、1_羥基苯并三唑 125 318695 200804294 水合物（52笔克）與二乙胺（95微升），室溫攪拌混合物一夜。然後將飽和碳酸氳鈉水溶液加至反應混合物中並攪 -拌，混合物用三氯甲烷萃取。有機層用水清洗後濃縮。所 …得粗產物用二異丙醚清洗，得到丨―（2—氯苯基）—5 —(4—氯笨基）-4-曱氧基-3-[N-（4-胺甲醯基一4-苯基六氫吡啶q一基）胺甲醯基]-111-吡唑（25.5毫克，產率19%)呈無色固體。 MS(APCI)m/z ： 564/566[M+H]+ 實施例284 (1)冰冷卻下，將2· 2N偶氮二甲酸二乙酯—曱苯溶液 (4. 5毫升）逐滴加至含參考例丨（4)所得化合物（3· 77克）、 N-（2-羥乙基）胺曱酸三級丁酯（1·61克）與三苯膦（2· 62克）之四氫呋喃（100毫升）溶液中，室溫攪拌混合物一夜。接著將水加至反應混合物中，混合物用乙酸乙g旨萃取。萃取液以硫酸錤乾燥後經真空濃縮。所得粗產物用石夕膠管柱層析（溶劑··己烷/乙酸乙酯=80/20至60/40)進行純化，得到 4一[2-(二級丁氧幾基胺基）乙氧基]-1-(2-氯苯基）-5-(4-氯苯基）-3-乙氧羰基-1H-吼唑（3.37克，產率6 5%)呈固體。 MS(APCI)m/z ： 520/522[M+H]+ (2)將IN氫氧化納水溶液（15毫升）加至上述步驟（i) 所得化合物（2· 60克）之乙醇（20毫升）溶液中，室溫攪拌混合物一夜。所產生沉澱物以過濾法收集，以水—乙醇清洗後乾燥’得到4-[2-(三級丁氧羰基胺基）乙氧基-3-羧基-1 - (2-氯苯基）-5-(4-氯苯基）-111-°比唑（2.47克，產率99%) 呈固體。 126 318695 200804294 MS(APCI)m/z ： 490/492[M+H]+ (3)在室溫，將水可溶碳二亞胺鹽酸鹽（1· 92克）加至含上述步驟（2)所得化合物（2· 47克）、1-羥基苯并三唑 (1· 53克）與二乙胺（2· 2〇克）之N，N一二甲基甲醯胺（5〇毫升） /谷液中，然後攪拌混合物一夜。接著將水加至反應混合物中，以乙酸乙酯萃取。萃取液以硫酸鎂乾燥後經真空濃縮。所得粗產物用矽膠管柱層析（溶劑：己烷/乙酸乙酯=65/35 至45/55)進行純化，得到4—[2-(三級丁氧羰基胺基）乙氧基-1-(2-氣苯基）—5 —(4—氯苯基）_3-[N—(卜吼咯啶基）胺甲醯基]-1H-吡唑（2· 〇7克，產率74%)呈固體。 MS(APCI)ra/z ： 560/562[M+H]+ (4)在室溫，將4N HC卜二噚烷加至上述步驟（3)所得化δ物（1 · 6 8克）之一曙烧（4毫升）溶液中，攪拌混合物一夜。反應混合物經真空濃縮後，殘留物以乙醚—乙醇清洗然後乾燥後，得到4-(2-胺基乙氧基兴卜㈡―氯苯基）—卜（4〜' 氯苯基）-3-[N-(1-吡咯啶基）胺甲醯基]—1H—吡唑鹽酸鹽 (1.55克，產率97%)呈固體。疏 MS(APCI)m/z ： 460/462[M+H]+ (5)上述步驟（4)所得化合物（1〇〇毫克）用ΝΗ_矽膠管柱層析（溶劑：三氯甲烷/甲醇=1〇〇/〇至94/6)處理，得 4-(2-胺基乙氧基）-1-(2-氯笨基）_5_(4_氯苯基 (1-吡咯啶基）胺甲醯基]-1Η_吡唑（57毫克，產率66%)呈粉末。 1 MS(APCI)m/z ： 460/462[M+H]+ 318695 127 200804294 .實施例285 將乙醯氯（79耄克）與三乙胺（π〗毫克）加至參考例 …284(4)所得化合物（99毫克）之二氯甲烷毫升）溶液中，然後稅拌混合物一仪。接著將飽和碳酸氫鈉水溶液加至反 •應混合物中，混合物以三氯甲烷萃取。萃取液以硫酸鎂乾煉後經真空濃縮。所得粗產物用矽膠管柱層析（溶劑··三氯甲烷/甲醇= 100/0至94/6)進行純化，得到4-[2一（乙醯基胺基）乙氧基]-1-(2-氣苯基）—5 —(4—氯苯基）—3—[N—(卜吼咯啶基）胺曱醯基]-1H-吡唑（20毫克，產率2〇%)呈粉末。 MS(APCI)m/z ： 502/504[M+H]+ 實施例286 實施例284(4)所得化合物（99毫克）與曱磺醯氯（ιΐ5 毫克）以如實施例285所述之相同方法處理，得到^^一氯苯基）- 5-(4-氯苯基）-4-[2-(甲磺醯基胺基）乙氧基]一3一 [N-(l-吡咯啶基）胺曱醯基]-1H—吡唑（83毫克，產率呈粉末。 MS(APCI)m/z ： 538/540[M+H]+ 實施例287 實施例284(4)所得化合物（99毫克）與二甲基胺石备醯氯（144毫克）以如實施例285所述之相同方法處理，得到 1-(2-氯苯基）-5-(4-氯苯基）-4-[2 —(二甲基胺續酿基）乙氧基]- 3-[Ν-(1-吼洛唆基）胺甲醯基；μ1Η〜吡唾（7丨毫克，產率63%)呈粉末。 & MS(APCI)m/z ： 567/569[M+H]+ 318695 128 200804294 實施例288 貫施例284(4)所得化合物（99毫克）與異氰酸乙酯（η 宅克）以如實施例285所述之相同方法處理，得到^^一氯苯基）-5-(4-氯苯基）-4-[2-ατ-乙基脲基）乙氧基]—3 一[Να-吡咯啶基）胺甲醯基；Μη—吡唑（79 毫克，產率 74%) 呈粉末。 MS(APCI)m/z ： 531/533[M+H]+ 實施例289 (1) 在室溫，將水可溶碳二亞胺鹽酸鹽（3· 83克）加至含參考例1(6)所得化合物（3· 63克）、7N氨-甲醇（6毫升）、卜羥基苯并三唑（3· 06克）與三乙胺（ι·〇；[克）之& N一二甲基甲醯胺（100毫升）溶液中，然後攪拌混合物一夜。接著將飽和碳酸氫鈉水溶液加至反應混合物中，混合物以三氯曱烷萃取。萃取液以硫酸鎂乾燥後經真空濃縮。所得粗產物用乙醚清洗後乾燥，得到1 —(2—氯苯基）—5 一氯苯基） - 4-甲氧基-3-胺甲醯基-1Η-σ比唾（2· 04克，產率56%)呈固體。 MS(APCI)m/z ： 362/364[M+H]+ (2) 將含上述步驟（1)所得化合物（ι·8ΐ克）與拉威森氏試劑（2 · 0 2克）之甲苯（1 〇毫升）溶液加熱题流擾拌2小時。冷卻後，將丽-矽膠（2克）加至反應混合物中然後過遽混合物。濾液經真空濃縮後所得粗產物用矽膠管柱層析（溶劑··己烷/乙酸乙酯=85/15至65/35)進行純化，得到丨一^一氯苯基）-5-（4-氯苯基）-4-甲氧基-3-硫代胺甲醯基一ifj-吼 318695 129 200804294 唑（0.69克，產率37%)呈固體。 MS(APCI)m/z ： 378/380[M+H]+ (3)將含上述步驟（2)所得化合物（7〇毫克）與肼水合 …物（125毫克）之乙醇（2· 5毫升）溶液加熱廻流攪拌2小時。冷卻後，將反應混合物真空濃縮，然後加水至殘留物中。混合物以三氯甲烷萃取，萃取液以硫酸鎂乾燥後經真空濃縮。然後在所得粗產物與三乙胺（151毫克）之二氯甲燒 (2.5宅升）>谷液中，加入；[一 [4一（三氟甲基）定—2 —基]六氣吡啶_4-羰基氯（293毫克），室溫攪拌混合物一夜。然後2 入飽和碳酸氫鈉水溶液，混合物用三氯曱烷萃取。萃取液以硫酸鎂乾燥後經真空濃縮。所得粗產物用矽膠管柱層析 (溶劑：己烷/乙酸乙酯=50/50至3〇/7〇)進行純化，得9到 1-(2-氯苯基）-5-（4-氯苯基）-4-甲氧基—3一 {5一[;1一（4 一三氟甲基嘧啶-2-基）吡咯啶一4一基]2, 4一三唑〜3一基卜唑（19毫克，產率12%)呈固體。 MS(APCI)m/z ： 615/617[M+H]+ 實施例290至308 相應物質以如實施例1中所述之相 < <邳丨小方法處理，得到如下表12所示化合物。 318695 130 200804294 表 12(1) °ΧΧτ% I X N-R5 R‘ 實施例號碼 -N(R5)(R6) 物化性質等 290 Ar-F 粉末 MS(APCI):481/483 [M+H]+ 291 F 粉末 MS(APCI):463/465 [M+H]+ 292 I^shN^-F 粉末 MS(APCI):463/465 [M+H]+ 293 Ν=ν 粉末 MS(APCI):440/442 [M+H]+ 294 Η C^H5 粉末 MS(APCI):456/458 [M+H]+ 295 Μ Η 粉末 MS(APCI):454/456 [M+H]+ 131 318695 200804294 表 12(2) ση^。 n -r5 (X.〆實施例號碼 R” -N(R5)(R6) 物化性質等 296 Cl 粉末 MS(APCI):521/523 [M+H]+ 297 Cl 粉末 MS(APCI):522/524 [M+H]+ 298 Cl och3 och3 粉末 MS(APCI):500/502 [M+Hf 299 Cl 粉末 MS(APCI):443/445 [M+H]+ 300 F /^CF3 粉末 MS(APCI):483/485 [M+H]+ 301 F 固體 MS(APCI):465/467 [M+H]+ 132 318695 200804294 表 12(3) 實施例號碼 R, R” R3 物化性質等 302 cf3 H Cl ch3 固體 MS(APCI):515/517 [M+H]+ 303 cf3 F Cl ch3 固體 MS(APCI):533/535[M+H]+ 304 cf3 Cl Cl ch3 固體 MS(APCI):549/551 [M+H]+ 305 cf3 H Cl chf2 固體 MS(APCI):551/553 [M+H]+ 306 cf3 F Cl chf2 固體 MS(APCI):569/571 [M+H]+ 307 Cl H Cl chf2 固體 MS(APCI):517/519 [M+H]+ 308 cf3 Cl Cl chf2 固體 MS(APCI):585/587 [M+H]+ 實施例309至324 133 318695 200804294 相應物質以如實施例22(3)中所述之相同方法處理，得到如下表13所示化合物。表 13(1) RP-…χ 實施例 5虎碼 R” R5 物化性質等 309 Η \xCF3 粉末 MS(APCI): 556/558 [M+H]+ 310 Η v^0CH3 粉末 MS(APCI): 518/520 [M+H]+ 311 Η -s/CN 粉末 MS(APCI): 513/515 [M+H]+ 312 Cl 粉末 MS(APCI): 584/586 [M+H]+ 313 Cl fOlf 粉末 MS(APCI): 620/622 [M+Hf 314 Cl OC；粉末 MS(APCI): 620/622 [M+H]+ 315 Cl 粉末 MS(APCI): 627/629 [M+H]+ 316 Cl cf3 粉末 MS(APCI): 576/578 [M+H]+ 317 Cl \^cf3 粉末 MS(APCI): 590/592 [M+H]+ 134 318695 200804294 表 13(2) CCF w rx 實施例號碼 Rx 物化性質等 318 令1 粉末 MS(APCI): 568/570 [M+H]+ 319 XXc, 粉末 MS(APCI): 568/570 [M+H]+ 320 αΧ) 粉末 MS(APCI): 568/570 [M+H]+ 321 粉末 MS(APCI): 552/554 [M+H]+ 322 ~0^CF3 粉末 MS(APCI): 602/604 [M+H]+ 323 粉末 MS(APCI): 559/561 [M+H]+ 324 -^-och3 粉末 MS(APCI): 564/566 [M+H]+ 實施例325至335 相應物質以如實施例21中所述之相同方法處理，然後所得產物以如實施例28中所述之相同方法處理，得到如下表14所示化合物。 135 318695 200804294 表 14(1) 實施例號碼 R 物化性質等 325 ch3 ^ch3 固體 MS(APCI): 429/431 [M+H]+ 326 \/〇CH3 固體 MS(APCI): 431/433 [M+H]+ 327 cf3 粉末 MS(APCI): 455/457 [M+H]+ 328 n^CH3 固體 MS(APCI): 503/505 [M+H]+ 329 ^〇H 固體 MS(APCI): 443/445 [M+H]+ 330 VC1 h3c ch3 固體 MS(APCI): 463/465 [M+H]+ 331 \^SCH3 固體 MS(APCI): 433/435 [M+H]+ 136 318695 200804294 表 14(2)Example 263 To a solution of the compound obtained in Example 64 (127 mg) in dioxane (2 mL) The mixture was stirred at the same temperature for 30 minutes. Next, an aqueous sodium hydrogencarbonate solution was added to the reaction mixture and stirred. The organic layer was separated and the organic layer was concentrated in vacuo. The obtained crude product was purified by silica gel column chromatography (solvent: trichlorohexane / methanol = 100/0 to 95/5) to give 1-(2-chlorophenyl)-5-(4-chlorophenyl). 4-[2-(methylsulfinyl)ethoxy]-3-[N-(l-fluorenyl)aminoindolyl]-1H-indazole (92 mg, yield 70%) powder. MS (APCI) m/z: </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; (2-Chlorophenyl)-5~(4-chlorophenyl)-4-ylmethoxy-3-[(1-benzylidylhexahydroacridin-4-yl)carbonyl]amino-1H - carbazole \ (40 mg, yield 74%) solid. MS (APCI) m/z: 549 / 551 [M+H] + Example 2 6 5 The compound obtained in Example 172 (160 mg) was treated in the same manner as described in Example 15 to give chlorophenyl)_5_ (4_Chlorophenyl)_4-(p-oxy-4-tetrahydrothiopiperidyl)oxy-3-[N-(4-tetrahydropyranyl)aminecarboxyl]-1H- Pyrazole (15 mg, yield 1%) powder. MS (APCI) m/z: 548 / 550 [M+H] + Example 2 6 6 The compound obtained in Example 172 (160 mg) was treated in the same manner as described in Example 16 to give 1-(2-chloro Phenyl)-5-(4-chlorophenyl)-4-iso(1,I-one-oxy-4-tetrahydrothioholanyloxy)-3-[n-(4-tetrahydro port) Aminomethyl)-1H-pyrazole (73 mg, yield 45%) solid. MS (APCI) m/z: 564/566 [M+H] + </RTI> </RTI> 267 (1) The compound (155 mg) obtained in Example 18 was treated in the same manner as described in Example 1. -Chlorophenyl)-5-(4-chlorophenyl)-4-(4-tetrahydrothiopiperidyl)oxy-3-[N-(N-morpholinyl)amine fluorenyl] - 1H-pyrazole (170 mg, yield 92%) powder. MS (APCI) m/z: 533 / 535 [M+H] + (2) The compound obtained in the above step (1) (152 mg) was treated in the same manner as described in Example 15 to give bis-(2-chloro Phenyl)-(4-chlorophenyl) 113 318695 200804294 --4-(1-Sideoxy-4-tetrahydrothiopiperidyl)oxy-3-[n_(n-morpholine-yl) Aminomethyl hydrazide]-1 Η-吼 ( (97 mg, yield 62%) powder. MS (APCI) m/z: 549 / 551 [M+H] + Example 2 6 8 The compound obtained in Example 78 (65 mg) was treated in the same manner as described in Example 15. Chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-{N-[2-(methylsulfinyl)ethyl]aminecarboxamido 1Η_σ-biazole (62 mg , yield 92%) powder. MS (APCI) m/z: 452 / 454 [M+H] + </RTI> </RTI> -5-(4-Phenylphenyl)-4-methoxy-3-{N-[2-(oxasulfonyl)ethyl]amine sulfhydryl 1H-pyridinium (68 mg, yield 96%) powder. MS (APCI) m/z: 468 / 470 [M+H] + </RTI> (4-Chlorophenyl)-4-methoxy~3~(2-acridinylacetoxy)amino-1H-indole (31 mg, yield 69%) powder. MS (APCI) m/z: 453 / 455 [M+H] + </RTI> </ RTI> </ RTI> The corresponding starting material was treated in the same manner as described in Example 27 to give 4-(amine fluorenyl) methoxy- ;ι_(2-chlorophenyl)-5~(4~=亍[〇r,ίΓ-diinyl)carbonyl]-1H-pyrazole (26·7亳$ female seven, & see, yield 30%) 114 318695 200804294 Powder. MS (APCI) m/z: 448/451 [M+H]+ The corresponding starting materials of Examples 272 to 273 were treated as in Example 1, and then treated in the same manner as described in Reference Example 14 to give the following Table 11 The compound shown. Table 11 hn-n Example No. -n(r5)(r6) Physicochemical properties, etc. 272, ϊ^^802(:Η3 Powder MS(APCI): 509/511 [M+H]+ 273 A solid MS (APCI) 503/505 [M+H] + Example 274 (1) The compound (109 mg) obtained from the compound of the formula (1), and the compound (105 mg) obtained in the referenced Example 48 were treated in the same manner as described in Example 1. , 1-(2-Chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-[N-(4-phenylhydrazin-4-ethoxycarbonylhexahydropyridine-1) -Aminoguanidino]-1H-pyrazole (152 mg, yield 83%) as a colorless solid. MS (APCI) m/z: 607/609 [M+H]+ 115 318695 200804294 · '(2) A 2N aqueous solution of sodium hydroxide (25 (1 μL) was added to the solution of the compound (1) in the above step (1) in ethanol (3 liters), and then the mixture was stirred at -C. Then, (10) Aqueous sodium solution (_micro.) was added to the reaction mixture, and the mixture was stirred at 9 Gt for 2 days. Cooled to room temperature, and the mixture was mixed with 1N aqueous hydrochloric acid, and the mixture was extracted with trimethylamine to extract the liquid core and vacuumed. The product was chromatographed with Shixi rubber column (solvent: trichloromethane/methanol, /2 to 95/5) and Shi Xisheng thin Purification by chromatography (solvent: trichloromethane/methanol = 95/5) afforded (2-dichlorophenyl)-bu (4-phenylphenyl) + methoxy _3 (4 benzyl) +Carboxy hexachloropurine bite 1 -1 base) Amine-based "I-1H-mouth e Gulisters" 11 is slightly softer than the main Cb5·5 gram, yield 38%) /' MS (APCI) m/z : 579/581 [M+H]+ > (3) Chlorination (5.5 tg), water-soluble carbodiimide hydrochloride (2 〇克), 1 hydroxybenzobisazole hydrate (16 mg) and triethylamine (2 〇 microliter) were added to the solution of the compound obtained in the above step (2) (29 4 mg) in dimethylidene amidoxime), room Warm (four) mixture _ night. Next, an aqueous solution of sodium hydrogencarbonate was added to the reaction mixture (4), and the mixture was subjected to trichloromethane. The organic layer was washed with water and concentrated in vacuo. The obtained crude product was purified by column chromatography (Chr_atorex^-gel, solvent:hexane/ethyl acetate = 5/65 to 0/100) to give 丨_(2_chlorophenyl)_5_(4_ Chlorophenyl)-4-methoxy-3-[N-(4-benzoinyl~4-aminocarbamoylhexahydroindolepyridinyl-byl)amine-methylmethyl]-1H-pyrazole (23.6 Mg, yield 8 % by weight) as a colorless solid. MS (APCI) m/z: 578 / 580 [M+H] + 318 695 116 200804294 Example 275 (1) Compound (545 mg) obtained in Reference Example 1 (6) and the compound obtained in Reference Example 45 (3) (292 mg) Processed in the same manner as described in Example 1 to give 1-(2-phenylphenyl)-5-(4-chlorophenyl)-4-methoxy-3-[N-(4-oxo) Carbonyltetrahydrothiopyran-4-yl)aminoindenyl]-1 η-pyrazole (48 mg, yield 92%) was obtained as a colorless solid. MS (APCI) m/z: 520 / 522 [M+H] + (2) Trifluoromethane (163 liters) was added to the compound (275 mg) of the above-mentioned step (1). (5 ml) in the solution, then the mixture was stirred at room temperature for 30 minutes. Then, m-chloroperbenzoic acid (244 g) was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for an hour. Further, m-chloroperbenzoic acid (61 mg) was added, and the mixture was stirred at room temperature for 3 minutes. The reaction mixture was then extracted and purified in the same manner as described in Example 5 to give 1-(2-phenylphenyl)-5-(4-chlorophenyl)-4-methoxy-3-[N- (4-Methoxycarbonyl-1,1-di-oxytetrahydrothiopyran-4-yl)amine-carbamoyl]-ll.pyrazole (272.1 mg, yield 93%) as pale yellow solid. Pulse MS (APCI) m/z : 552/554 [M+H] + (3) 2N sodium hydroxide aqueous solution (49 〇 microliter) was added to the above step (?) compound (10 mg) ethanol (3 ml) In solution, the mixture was then spoiled overnight at room temperature. Next, an aqueous hydrochloric acid solution (5 μL) was added to the reaction mixture and the mixture was stirred, and the mixture was taken as a trichloromethane. The extract is passed through: After concentration, the crude product obtained is purified by Shih-Hybrid column chromatography (solvent: trichlorosulfonium oxime = 99/1 to 90/10) to give the base)-methoxy-3-(tetra)- This /) = (4 - chlorobenzene ' side oxytetrazepine thiophenanthrene 318695 117 200804294, -4-yl) amine mercapto] - sitting (224.7 mg, yield 85%). ^ ;MS(APCI)m/z : 538/540[M+H]+ (4) Ammonium chloride (7.5 mil), water-soluble carbodiimide hydrochloride (28-mg), Benzyl benzotrisin (21 g) and triethylamine (29 μl) were added to the solution of the compound (38 mg) obtained in the above step (3) in dimethyl amide (1 ml). The mixture was 2 days. Next, an aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and the mixture was stirred, and the mixture was extracted with a trichloromethane. The organic layer was washed with water and concentrated in vacuo. The obtained crude product was purified by NH-purine gel column chromatography (Chromatorex NH-phthalic acid, solvent·hexane/ethyl acetate=2〇/8〇 to 0/100) to obtain ^(2-chlorophenyl)_5_( 4-Chlorophenyl)_4_decyloxy-3-[N-(4-aminomethylindolyl-i, bis-oxo-oxytetrachlorothiopyran-4-yl)amine-methylmethyl]-1H_ Pyrazole (33.9 mg, yield 85%) was a colorless solid. MS (APCI) m/z: 537 / 539 [M+H] + Example 276 (1) Reference Example 5 (2) Compound (16 8 mg) and Reference Example 4 7 (2) Known compound (7 0 The product was treated in the same manner as described in Example 1 to give 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-indoleoxycarbonylmethoxy-3-one [N. -(4-Methoxycarbonyl-4-phenylhexahydropyridine-1 -yl)aminemethanyl]-1H-pyrrolidine (1 〇 8.1 mg, yield 57%) as a colorless solid. MS (APCI) m/z: 637/639 [M+H]+ (2) 2 N aqueous sodium oxide solution (3 36 μL) was added to the compound obtained in the above step (1) (107 mg) ethanol (2) ML) solution, then stir the mixture for 2 hours at 8 (rc 318695 118 200804294. Then add 2N aqueous sodium hydroxide solution (10) to the reaction mixture towel, 10{rc mixing mixture for 1 hour. Add tetrahydrofuran (1 house)升) to the reaction mixture, stirring at 1 °c for 3 days. After cooling to room temperature, 2N aqueous hydrochloric acid solution (500 μl) was added and stirred, and the mixture was extracted with chloroform. The extract was concentrated in vacuo. The residue was diluted with dimethylformamide (2 liters), then ammonium hydride (27 mg), water soluble carbodiimide hydrochloride (97 mg), 1-hydroxybenzotriazole hydrate (77 mg) and triethylamine (140 μl), the mixture was stirred at room temperature for 4 hours. Then aqueous sodium hydrogen carbonate solution was added to the reaction mixture and stirred, and the mixture was extracted with trichloromethane. Concentration. Obtained crude gemstone column chromatography (Chr(10)atorexNH-矽, solvent: hexane/B Purification with ethyl acetate = 20/80 to 0/100) gives 丨-(2-chlorophenyl)-5-(indolyl-4-chlorophenyl)-4-aminemethyl methoxy-3-[ N-(4-Aminomethylphenyl-4-ylphenylhexahydropyridinyl)-pyridinyl]pyrazole (59.2 mg, yield 58%) as a colorless solid. MS (APCI). 607/609[M+H]1 Example 277 (1) A solution of di-tert-butyl phthalate (21·82 g) in tetrahydrofuran (100 ml) was added dropwise to the mixture containing A solution of sodium thiourea sulfate (15. 31 g) and potassium carbonate (3 〇 4 g) in water (300 ml) was then stirred at room temperature overnight. The mixture was extracted with ethyl acetate. The extract was dried over MgSO.sub.sub.sub.sub.sub.sub.sub.sub.sub.ssssssssssssssssssssssssssssssssssss : 191 [M+H]+ ☆ (2) Water-soluble carbodiimide hydrochloride (2 g) was added to the compound (3·63 g) containing Reference Example 1 (6) at room temperature, The compound obtained in the above step (1) (2·85 g), hydroxybenzotriazole (2·28 g) and three Ethylamine (Ig 5 gram), hydrazine in a solution of methylformamide (1 ml), and then the mixture was stirred overnight. Water was then added to the reaction mixture to collect the precipitate by the hydrazine method. The solution is then dissolved in tri-methane. The solution is washed with water, dried over magnesium sulfate and concentrated in vacuo to give (2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3- (N-{[(Tri-Butoxycarbonylamino)methylthio]methylidene)-carbamoyl)-1H-pyrazole (5·20 mg, yield 97%) as a white solid. MS (APCI) m/z: 535 / 537 [M+H] + (3) 肼 HCl (6·85 g) was added to the compound obtained in the above step (2) at room temperature (1·7 g) The mixture was stirred with a solution of potassium carbonate (6.99 g) in methanol (2 mL) and then stirred at room temperature overnight. After cooling, water was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was dried over magnesium sulfate and concentrated in vacuo. The obtained crude product was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = 65/35 to 45/55) to give bis-(2-chlorophenyl)-5-(4-chlorophenyl). 4-methoxy-3-[5-(tertiary butoxycarbonylamino)-1,2,4-triazol-3-yl]-1H-pyrazole (814 mg, yield 81%) White solid. MS (APCI) m/z: 501/503 [M+H]+ (4) 4N HCl-dioxane and the like (2·0 ml) were added to the compound obtained in the above step (3) at room temperature (〇·· In a solution of 80 g) in methanol (10 ml), the mixture was stirred overnight. An aqueous solution of sodium bicarbonate was then added to the reaction mixture, 120 318 695 200804294 - the mixture was extracted with chloroform. The extract was dried over magnesium sulfate, concentrated in vacuo, and then applied to 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-hyloxy-3-(5-amino-1) , 2, 4-Triazol-3-yl)-1Η-σ ratio (390 mg, yield 61%) was a white solid. MS (APCI) m/z: 401 / 403 [M+H] + (5) 1,4-dibromobutane (215 mg) was added to the compound obtained in the above step (4) at room temperature ( 0 mg) in a suspension of potassium carbonate (276 mg) in acetonitrile (3 mL), then the mixture was stirred in a 14 〇t microwave reactor for 9 min. Water was then added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated in vacuo. The obtained crude product was purified by silica gel column chromatography (solvent···················· ))-4-methoxyl-3-[5-(1-pyrrolidinyl)-;[,2,4-triazol-3-yl]-1H-pyrazole (33·4 mg, yield 29 %) is a pale yellow solid. MS (APCI) m/z: 455 / 457 [M+H] + 278 (1) </ RTI> </ RTI> hydroxyamine hydrochloride (6.95 g) was added to the compound obtained in Example 277 (2) (1.07 g) In a suspension of potassium carbonate (6.91 g) in methanol (2 ml), 8 CTC was used to scramble the mixture - night. After cooling, water was added to the reaction mixture, and the mixture was extracted with trichloromethane. The extract was dried over magnesium sulfate and concentrated in vacuo. The obtained crude product was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 80/20 to 60/40) to give||||| )-4-methoxy-3-[3-7-oxo-oxoamine)-1,2,4-dioxapyrene-5-based ratio saliva (194 mg, yield 19%) is white 318695 121 200804294 I color solid. , MS (APCI) m / z : 502 / 504 [Μ + ΗΓ (2) at room temperature, 4 Ν HC dioxane (1 · 〇 ml) was added to the compound obtained in the above step (1) (〇 · 17 g In a solution of methanol (5 ml), the mixture was mixed overnight. Next, an aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was dried over magnesium sulfate and concentrated in vacuo to give 1-(2-phenylphenyl)-5-(4-chlorophenyl)-4-methoxy-3~(3-amino-1,2, 4-oxadiazol-5-yl)-1 - oxazole (104 mg, yield 76%) as a white solid. MS (APCI) m / z: 402 / 404 [M + H] + (3) 1,4-dibromobutane (1 ml) was added to the compound obtained in the above step (2) at room temperature (8 〇) In a suspension of potassium acetate (276 mg) in acetonitrile (3 ml), then the mixture was taken at 14 Torr. (The mixture was stirred for 210 minutes in a microwave reactor. Water was then added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated in vacuo. Purification by alkane/ethyl acetate = 95/5 to 〇/1 〇〇) to give 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3. -(1-pyrrolidyl)-indole, 2,4-oxadiazole-5-yl]-1H-pyrazole (8·j mg, yield 9%) as a white solid. MS (APCI) m/ z: 456/458 [M+H] + Example 279 (1) EtOAc (3 mL) In the solution, stir the mixture at room temperature for 5 small 4. Then add 2f\f aqueous sodium hydroxide solution (5 ml) to the compound 318695 122 200804294, and mix the mixture for 60 ° C overnight. After room temperature, 2N aqueous hydrochloric acid (20 ml) was added and the mixture was stirred. Then water was added to the mixture and the mixture was stirred. The resulting precipitate was collected by filtration and then dried to give 3-carboxy-1 - (2) -chlorophenyl -5-(4-Chlorophenyl)-4 monohydroxy-1H-pyrazole (3.07 g, yield 88%) as colorless solid. MS (APCI) m/z: 349/351 [M+H] (2) The compound obtained in the above step (1) (52 mg) and the compound obtained in Reference Example 53 (3) (34 mg) were treated in the same manner as described in Example ,, and 1-(2-chlorophenyl) was obtained. -5-(4-Phenylphenyl)- 4-hydroxy-3-indan[4-aminocarbazin-4-(ethylamino)-N-hexahydropyridyl]carbonyl b 1H-pyrazole (33 7 mg (yield 45%) as a pale yellow solid. MS (APCI) m/z: 502 / 504 [M+H] + Example 280 (1) Compound (145 mg) of Reference Example 1 (6) 舆 Reference Example The obtained compound (77 mg) was treated in the same manner as described in Example to give 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxycarbonylcyclohexane-1- Aminomethylmercapto]-1H-pyrazole (175 mg, produced as a colorless powder. 〇MS (APCI) m/z: 502/504 [M+H] + (2) Compound (174 mg) obtained as described above (4) (1) Treated in the same manner as described in Example 275 (3) to give bis(2, chlorophenyl): phenyl)-4-methoxy-3-[indole-(fluorenylcyclohexyl)-yl-amine-1 - Pyrazole (171 mg, yield 1%) was a colorless solid. Soil MS (APCI) m/z: 488 / 490 [M+H] + 318695 123 200804294 (3) The compound obtained in the above step (2) (34 mg) was treated in the same manner as described in Example 275 (4). Obtained (2-chlorophenyl 5-(4-chlorophenyl)-4-methoxy-3-[N-(iminomethylcyclohexyl)-yl)amine decanoic acid] ...-1H -pyrazole (26.1 mg, yield 77%) as a colorless solid. MS (APCI) m/z: 487 / 489 [M+H] + Example 281 (1) ί Test Example 1 (6) (145 mg) and the compound obtained in Reference Example 46 (78 mg) were treated in the same manner as described in Example 1 to give 1-(2-chlorophenyl)-5-(4-chlorophenyl)- 4-? Oxyl 3-(indo-(4-indoleoxytetrahydropyran-4-yl)aminecarboxylidene]-l-[upsilon]^(15 mg, yield 74%) was obtained as a colorless solid. m/z: 504/506 [M+H] + (2) The compound obtained in the above step (i) (15 mg) was treated in the same manner as described in Example 275 (3) to give the chlorobenzene. 5-(4-chlorophenyl)-4-methoxy-3-(N-(4-carboxy-tetrahydropyran-4-yl)aminemethanyl]-1H-pyrazole (137) · 3 mg, yield 93%) Solid. MS (APCI) m/z: 490 / 492 [M+H] + (3) The compound obtained in the above step (2) (34 mg) was treated in the same manner as described in Example 275 (4) to give 丨-( 2-Chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-[N-(4-aminocarbamimido-tetrahydropyran-4-yl)aminecarbamyl] -1H-pyrazole (31 mg, yield 90%) was obtained as a solid. MS (APCI) m/z: </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> </RTI> </RTI> </RTI> </RTI> </RTI> </RTI> </RTI> , obtained b (2' chlorophenyl)_5_(4' chlorophenyl)-4-methoxy | [N_(4_ 基基_tetrachlorothiopyran-4-yl)amine methyl--indenyl] -1H-pyrazole (146 mg, yield 76%) was obtained as a colorless solid. MS (APCI) m/z: 506 / 508 [M+H] + (2) The compound obtained in the above step (1) (π mg) was treated in the same manner as described in Example 275 (4). Chlorophenyl chlorophenyl)-4-mercapto-3-[indolyl-(4-aminoindolyl-tetrahydrothiopyran-4-yl)aminecarboxylidene]- 1 oxime-pyrazole (31 · 1 mg, yield 88%) as a solid. MS (APCI) m/z: 505 / 507 [M+H] + Example 283 (1) The compound obtained in Reference Example 1 (6) (1 〇 9 mg) and the compound obtained in Reference Example 47 (94 mg) were carried out as Treated in the same manner as described in the above, to give 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-[N-(4-indolyloxy-4- Phenylhexahydropyridine-fluorenyl-aminocarboxamide 1H-pyrazole (142. 8 gram yield 82%) was obtained as a colorless solid. MS (APCI) m/z: 579 / 581 [M+H] + (2) 2N aqueous sodium hydroxide (250 μL) was added to the above step (1) of the compound (140 mg) of ethanol (3 ml) ) in the solution, then 5 〇.授 The mixture was given for 2 hours. Then, tetrahydrofuran (2 ml) was added to the reaction mixture, and the mixture was stirred at 80 ° for 2 days. After cooling to room temperature, 2N aqueous hydrochloric acid (250 μL) was added and stirred, and the mixture was extracted with chloroform. The stroke liquid was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was crystalljjjjjjj Then add ammonium chloride (18 mg), water soluble carbodiimide hydrochloride (65 mg), 1-hydroxybenzotriazole 125 318695 200804294 hydrate (52 g) and diethylamine (95 μl The mixture was stirred at room temperature overnight. Saturated sodium carbonate aqueous solution was then added to the reaction mixture and stirred, and the mixture was extracted with chloroform. The organic layer was washed with water and concentrated. The crude product was washed with diisopropyl ether to give bis-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-[N-(4-aminecarboxamidine). Base-4-phenylhexahydropyridine q-yl) Aminomethylidene]-111-pyrazole (25.5 mg, yield 19%) was obtained as a colorless solid. MS (APCI) m / z: 564 / 566 [M + H] + Example 284 (1) 2, 2 N diethyl azodicarboxylate - benzene solution (4.5 ml) was dropped by ice cooling Addition to the compound (3·77 g) obtained in Reference Example (4), N-(2-hydroxyethyl)amine decanoate (1·61 g) and triphenylphosphine (2.62 g) The mixture was stirred at room temperature overnight in tetrahydrofuran (100 mL). Water was then added to the reaction mixture and the mixture was extracted with acetic acid. The extract was dried over barium sulfate and concentrated in vacuo. The obtained crude product was purified by silica gel column chromatography (solvent·hexane/ethyl acetate=80/20 to 60/40) to give 4-[2-(2,2-butoxyamino) ethoxylate. 1-[2-Chlorophenyl)-5-(4-chlorophenyl)-3-ethoxycarbonyl-1H-indazole (3.37 g, yield 65%) was obtained as a solid. MS (APCI) m/z: 520 / 522 [M+H] + (2) EtOAc (20 mL) of EtOAc (20 mL) The solution was stirred at room temperature overnight. The resulting precipitate was collected by filtration, washed with water-ethanol and dried to give 4-[2-(tertiary butoxycarbonylamino)ethoxy-3-carboxy-1-(2-chlorophenyl)- 5-(4-Chlorophenyl)-111-° azole (2.47 g, yield 99%) was obtained as a solid. 126 318695 200804294 MS(APCI)m/z : 490/492[M+H]+ (3) Add water-soluble carbodiimide hydrochloride (1.92 g) to the above step at room temperature ( 2) The obtained compound (2.47 g), 1-hydroxybenzotriazole (1.53 g) and diethylamine (2.2 g) N,N-dimethylformamide (5 ml) ) / in the trough, then stir the mixture overnight. Water was then added to the reaction mixture and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated in vacuo. The obtained crude product was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = 65/35 to 45/55) to give 4-[2-(tris-butyloxycarbonylamino)ethoxy-1 -(2-Phenylphenyl)-5-(4-chlorophenyl)_3-[N-(b-pyridinyl)amine-carbamoyl]-1H-pyrazole (2·7 g, yield 74 %) is solid. MS (APCI)ra/z : 560/562 [M+H] + (4) 4N HC-dioxane was added to the above-mentioned step (3) to obtain a δ (1·68 g) The mixture was stirred overnight in a simmer (4 mL) solution. After the reaction mixture was concentrated in vacuo, the residue was purified eluting with diethyl ether-ethyl ether and then dried to give 4-(2-aminoethyloxyb (b)-chlorophenyl)-b (4~' chlorophenyl)-3- [N-(1-Pyrrolidinyl)aminemethanyl]-1H-pyrazole hydrochloride (1.55 g, yield 97%) was obtained as a solid. MS (APCI) m / z : 460 / 462 [M + H] + (5) The compound obtained in the above step (4) (1 mg) was chromatographed on a ΝΗ_矽 rubber column (solvent: chloroform/methanol) Treatment with =1〇〇/〇 to 94/6) gives 4-(2-aminoethoxy)-1-(2-chlorophenyl)-5-(4-chlorophenyl(1-pyrrolidinyl)amine Methyl hydrazide]-1 Η-pyrazole (57 mg, yield 66%) was obtained as a powder. 1 MS (APCI) m/z: 460/462 [M+H] + 318 695 127 200804294. Example 285 (79 g) and triethylamine (π mg) were added to a solution of the compound (99 mg) in m.p. A saturated aqueous solution of sodium hydrogencarbonate was then added to the mixture and the mixture was extracted with chloroform. The extract was dried over magnesium sulfate and concentrated in vacuo. The obtained crude product was purified by silica gel column chromatography (solvent················· (2-Phenylphenyl)-5-(4-chlorophenyl)-3-(N-(azeridyl)aminoindolyl]-1H-pyrazole (20 mg, yield 2%) In powder. MS (APCI) m/z: 502 / 504 [M+H] + </RTI> </RTI> Example 286 The compound obtained from Example 284 (4) (99 mg) and sulfonium chloride (m. Process to give ^^-chlorophenyl)-5-(4-chlorophenyl)-4-[2-(methylsulfonylamino)ethoxy]- 3-amino[N-(l-pyrrolidine) Aminoguanidino]-1H-pyrazole (83 mg, yield in powder. MS (APCI) m/z: 538 / 540 [M+H] + Example 287 Example 284 (4) 99 mg) was treated with dimethylamine sulfonium chloride (144 mg) in the same manner as described in Example 285 to give 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4. -[2 -(dimethylamine aryl)ethoxy]- 3-[indole-(1-indolyl)aminemethanyl; μ1Η~pyrazine (7丨 mg, yield 63%) </ RTI> <RTIgt; The compound was treated in the same manner as described in Example 285 to give chlorophenyl)-5-(4-chlorophenyl)-4-[2-?? 3 a [Να-pyrrolidinyl) Methyl acyl; Μη- pyrazole (79 mg, 74% yield) as a powder. MS (APCI) m/z: 531 / 533 [M+H] + Example 289 (1) Water-soluble carbodiimide hydrochloride (3·83 g) was added to Reference Example 1 at room temperature (6) The obtained compound (3·63 g), 7N ammonia-methanol (6 ml), hydroxybenzotriazole (3.66 g) and triethylamine (ι·〇; [克克的& N In a solution of dimethylformamide (100 ml), the mixture was stirred overnight. A saturated aqueous solution of sodium hydrogencarbonate was then added to the mixture and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated in vacuo. The obtained crude product was washed with diethyl ether and dried to give 1-(2-chlorophenyl)-5-chlorophenyl)-4-methoxy-3-aminecarbazin-1Η-σ than saliva (2. 04 g) The yield was 56%) as a solid. MS (APCI) m / z : 362 / 364 [M + H] + (2) Toluene containing the compound obtained in the above step (1) (1·8 g) and Lavison's reagent (2 · 2 2 g) (1 〇 ml) solution heating problem flow mixing for 2 hours. After cooling, ruthenium (2 g) was added to the reaction mixture and the mixture was passed through. The filtrate was concentrated in vacuo to give a crude product which was purified by EtOAc EtOAc EtOAc EtOAc EtOAc -Chlorophenyl)-4-methoxy-3-thioaminemethanyl-ifj-吼318695 129 200804294 Azole (0.69 g, yield 37%) as a solid. MS (APCI) m / z : 378 / 380 [M + H] + (3) The compound obtained in the above step (2) (7 mg) was hydrated with hydrazine (125 mg) in ethanol (2.5 ml) The solution was heated and stirred for 2 hours. After cooling, the reaction mixture was concentrated in vacuo then water was added to residue. The mixture was extracted with chloroform. The extract was dried over magnesium sulfate and then concentrated in vacuo. Then, the obtained crude product is added with triethylamine (151 mg) in dichloromethane (2.5 liter) > trough solution; [一[4一(trifluoromethyl)- 2 -yl] 6 gas Pyridine- 4-carbonyl chloride (293 mg) was stirred at room temperature overnight. Then a saturated aqueous solution of sodium hydrogencarbonate was added and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated in vacuo. The obtained crude product was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 50/50 to 3 〇 / 7 〇) to give 9 to 1-(2-chlorophenyl)-5-(4- Chlorophenyl)-4-methoxy-3-{5-[;1-(4-trifluoromethylpyrimidin-2-yl)pyrrolidine-4-yl]2,4-triazole~3-yl Buzol (19 mg, yield 12%) was solid. MS (APCI) m/z: 615/617 [M+H] + Examples 290 to 308 The corresponding materials were treated in a <<<>> Compound. 318695 130 200804294 Table 12(1) °ΧΧτ% IX N-R5 R' Example No. -N(R5)(R6) Physicochemical Properties, etc. 290 Ar-F Powder MS (APCI): 481/483 [M+H]+ 291 F Powder MS (APCI): 463/465 [M+H]+ 292 I^shN^-F Powder MS (APCI): 463/465 [M+H]+ 293 Ν=ν Powder MS (APCI): 440 /442 [M+H]+ 294 Η C^H5 Powder MS (APCI): 456/458 [M+H]+ 295 Μ 粉末 Powder MS (APCI): 454/456 [M+H]+ 131 318695 200804294 12(2) ση^. n -r5 (X.〆Example number R" -N(R5)(R6) Physicochemical properties, etc. 296 Cl Powder MS (APCI): 521/523 [M+H]+ 297 Cl Powder MS (APCI): 522/ 524 [M+H]+ 298 Cl och3 och3 Powder MS (APCI): 500/502 [M+Hf 299 Cl Powder MS (APCI): 443/445 [M+H]+ 300 F /^CF3 Powder MS (APCI ): 483/485 [M+H]+ 301 F Solid MS (APCI): 465/467 [M+H]+ 132 318695 200804294 Table 12(3) Example No. R, R" R3 Physicochemical Properties, etc. 302 cf3 H Cl ch3 solid MS (APCI): 515 / 517 [M+H] + 303 cf3 F Cl ch3 solid MS (APCI): 533/535 [M+H] + 304 cf3 Cl Cl ch3 solid MS (APCI): 549/ 551 [M+H]+ 305 cf3 H Cl chf2 solid MS (APCI): 551/553 [M+H]+ 306 cf3 F Cl chf2 solid MS (APCI): 569/571 [M+H]+ 307 Cl H Cl chf2 solid MS (APCI): 517/519 [M+H]+ 308 cf3 Cl Cl chf2 solid MS (APCI): 585/587 [M+H]+ Examples 309 to 324 133 318695 200804294 The same procedure as described in Example 22 (3) gave the compound shown in Table 13 below. Table 13 (1) RP-...χ Example 5 Tiger code R" R5 Physicochemical properties, etc. 309 Η \xCF3 Powder MS (APCI) : 556/558 [M+H]+ 310 Η v^0CH 3 Powder MS (APCI): 518/520 [M+H]+ 311 Η -s/CN Powder MS (APCI): 513/515 [M+H]+ 312 Cl Powder MS (APCI): 584/586 [M +H]+ 313 Cl fOlf Powder MS (APCI): 620/622 [M+Hf 314 Cl OC; Powder MS (APCI): 620/622 [M+H]+ 315 Cl Powder MS (APCI): 627/629 [M+H]+ 316 Cl cf3 Powder MS (APCI): 576/578 [M+H]+ 317 Cl \^cf3 Powder MS (APCI): 590/592 [M+H]+ 134 318695 200804294 Table 13 ( 2) CCF w rx Example number Rx Physicochemical properties, etc. 318 Order 1 Powder MS (APCI): 568/570 [M+H]+ 319 XXc, Powder MS (APCI): 568/570 [M+H]+ 320 αΧ Powder MS (APCI): 568/570 [M+H]+ 321 Powder MS (APCI): 552/554 [M+H]+ 322 ~0^CF3 Powder MS (APCI): 602/604 [M+H ]+ 323 Powder MS (APCI): 559/561 [M+H]+ 324 -^-och3 Powder MS (APCI): 564/566 [M+H]+ Examples 325 to 335 corresponding materials as in Example 21 Treatment was carried out in the same manner as described above, and then the obtained product was treated in the same manner as described in Example 28 to give the compound shown in Table 14 below. 135 318695 200804294 Table 14(1) Example number R Physical and chemical properties, etc. 325 ch3 ^ch3 Solid MS (APCI): 429/431 [M+H]+ 326 \/〇CH3 Solid MS (APCI): 431/433 [M +H]+ 327 cf3 Powder MS (APCI): 455/457 [M+H]+ 328 n^CH3 Solid MS (APCI): 503/505 [M+H]+ 329 ^〇H Solid MS (APCI): 443/445 [M+H]+ 330 VC1 h3c ch3 Solid MS (APCI): 463/465 [M+H]+ 331 \^SCH3 Solid MS (APCI): 433/435 [M+H]+ 136 318695 200804294 Table 14 (2)

Rtf 實施例號碼 R, R” 物化性質等 332 C1 Cl 固體 MS(APCI): 503/505 [M+H]+ 333 cf3 H 粉末 MS(APCI): 503/505 [M+H]+ 334 cf3 F 粉末 MS(APCI): 521/523 [M+Hf 335 cf3 Cl 粉末 MS(APCI): 537/539 [M+H]+ 實施例336 (1)在氮氣環境下，將草醯氣（1· 92毫升）之二氯曱烷 (70毫升）溶液冷卻至-74°C，然後將二曱亞砜（3· 22毫升）以超過15分鐘之時間逐滴加入。在相同溫度下攪拌混合物 20分鐘，然後將1-二苯曱基-3-羥基氮咀（1-benzhydryl - 3-hydroxy azeti dine，5克）之二氯曱烧（25毫升）溶液以超過45分鐘之時間逐滴加入。在相同溫度下攪拌混合物 75分鐘。接著將三乙胺（11. 6毫升）以超過20分鐘之時間逐滴加入，在相同溫度下攪拌混合物150分鐘。將反應混合物回溫至0°C後，逐滴加入1NHC1水溶液（64毫升）。室 137 318695 200804294 溫攪拌混合物，然後分離水層。將1NHC丨水溶液加至有機層並撥拌，然後分離水層（重複該萃取步驟三次）。合併水層並邊攪拌邊以2N氫氧化納水溶液中和（ph9)，接著以乙酸乙酯萃取。萃取液以鹽水清洗，以硫酸鎮乾燥後過遽。濾液經真空濃縮後所得粗產物用矽膠管柱層析（溶劑··己烷 /乙酸乙酯= 100/0至90/10)進行純化，得到卜二苯曱基氮咀-3-酮（4· 57克，產率92%)呈白色固體。 MS(APCI)m/z ： 238[M+H]+ (2)將二甲胺鹽酸鹽（4·89克）、乙酸（3·42毫升）與氰化鉀（3· 92克）加至上述步驟所得化合物（1〇· 76克）之甲醇（110毫升）溶液中，55t:攪拌混合物115分鐘。冷卻至室溫後，將飽和碳酸氫鈉水溶液（15〇毫升）加至反應混合物中，室溫攪拌混合物45分鐘。混合物以乙酸乙酯萃取，有機層依序用碳酸氫鈉水溶液、鹽水清洗，以硫酸鎂乾加後過濾。濾液經真空濃縮後所得粗產物用矽膠管柱層析（溶劑：己烷/乙酸乙酯=5/1至4/1)進行純化，得到^ 二苯甲基-4-氰基-4-二甲胺基氮0旦（13 55克，產率1〇〇%) 呈黃色黏稠物。 MS(APCI)m/z ： 292[M+H]+ (3)冰冷卻下，將濃硫酸（25. 5毫升）以超過ι〇分鐘之時間逐滴加至上述步驟（2)所得化合物（13. 5克）之二氯甲烷（275毫升）溶液中，室溫攪拌混合物41小時。然後將反應混合物逐滴加至冰冷卻之水中，接著邊攪拌邊以2n氫氧化鈉水溶液鹼化（PH11)。混合物以二氯曱烷萃取，有機層 138 318695 200804294 以碳酸氫財溶液清洗，以歧鎂乾燥後㈣。濾液經真空濃縮後殘留物以乙酸乙酯再結晶，得到卜二苯曱基一4一胺曱酿基胺基氮以9.47克，產率圆）呈無色固體。 MS(APCI)ra/z ： 310[M+H]+ (4) 將IN HC卜二噚烷（12· 8毫升）與10%鈀—碳（1β 36 克）加至上述步驟（3)所得化合物（3· 95克）之曱醇（8〇毫升）溶液中，在氮氣環境下室溫攪拌混合物3小時。過濾反應混合物，濾液經真空濃縮。接著將乙醚加至殘留物中並攪拌。過濾收集所產生晶體，然後真空乾燥，得到胺甲醯基-4-二甲胺基氮。旦鹽酸鹽（22〇克，產率96%)呈無色固體。 MS(APCI)m/z: 144[Μ+Η]+ (5) 將2Ν氫氧化鈉水溶液（5〇〇微升）加至上述步驟（4) 所得化合物（180毫克）之水（2毫升）溶液中，室溫攪拌混合物30分鐘。冰冷卻下，將亞硝酸鈉（138毫克）與乙酸（93 微升）加至反應混合物中，室溫攪拌混合物一夜。接著加入飽和碳酸氫鈉水溶液。攪拌後，混合物經真空濃縮，所得粗產物用矽膠管柱層析（溶劑··己烷/乙酸乙酯=3〇/7〇至 0/100)進行純化，然後真空乾燥，得到4 —胺甲醯基-4一二甲胺基-1-亞硝基氮哩（137亳克，產率79%)呈淡黃色固體。 MSCAPCI)m/z ： 173[M+H]+ (6)將氯化亞錫（π)二水合物（316毫克）加至上述步驟（5)所得化合物（69毫克）之乙醇（2毫升;)溶液中，混合物 318695 139 200804294 •加熱廻流攪拌1日。冷卻至室溫後，真空濃縮反應混合物。接著將三氯甲烷加至殘留物中並攪拌，然後用矽藻土 y (cel ite)過濾。濾液經真空濃縮後將殘留物溶解在n，n一二 -甲基甲醯胺（3毫升）中。接著加入參考例1(6)所得化合物 (145宅克），然後混合物以如實施例丨中所述之相同方法處理，得到1-(2-氯苯基）一5 一（4 一氯苯基）—4—甲氧基-3 一 {N_ [3-胺甲醯基-3-(二甲胺基）氮咀—；[一基]胺甲醯基卜1H一吡唑（化合物a，4· 7毫克，產率2· 7%)呈淡黃色固體與1 —(2一氯笨基）-5-（4-氯苯基）-3-{[3-胺甲醯基-3-（二甲胺基）氮口旦-1-基]胺甲醯基丨一4-甲氧基-1H-吡唑（化合物b，45. 5 毫克，產率27%)呈無色固體。化合物 a，MS(APCI)m/z : 448/490[M+H] + 化合物 b，MS(APCI)m/z ·· 503/505[M+H] + 實施例337 (1)將碳酸鉀（3.73克）與六氫吼畊（1.16克）加至2,5-二氯°比咬（2克）二曱基曱醯胺（3〇毫升）之溶液中，然後於 11 〇°C攪拌混合物4小時。反應混合物冷卻後，加入乙酸乙酯與飽和碳酸氫鈉水溶液，混合物以乙酸乙酯萃取。有機層用水清洗，以硫酸鎂乾燥後過濾。濾液經真空濃縮後所付粗產物用NH-石夕膠管柱層析（Chromatorex NH-石夕膠，溶劑：三氣甲烷/曱醇=1〇〇/〇至99/1)進行純化，得到5-氯 -2-（1-六氫吡哄基）吡啶（〇. 28克，產率100%)呈淡黃色固體。 MS(APCI)m/z ： 198/200[M+H]+ 140 318695 200804294 (2) 上述步驟（1)所得化合物（27〇毫克）以如實施例 336(5)中所述之相同方法處理，得到5-氯-2-(4-亞硝基六氫吡畊-1-基）吡啶呈淡黃色固體。 (3) 將上述步驟（2)所得化合物之四氫呋喃（4毫升）溶液冷部至〇°C，接著逐漸加入氳化鋁鋰（91毫克），攪拌混 &物1小日$。然後將飽和碳酸氫納水溶液逐漸加至反應混合物中，混合物以三氯曱烷萃取。有機層以硫酸鎂乾燥後過濾。濾液經真空濃縮，得到2 —(4—胺基六氫吡哄―丨-基） -5-氯^比啶（276毫克）呈淡黃色固體。 MS(APCI)m/z： 213/215[M+H]+ (4) 將參考例ι(6)所得化合物（1〇()毫克）與上述步驟 (3 )所得化合物（5 9毫克）以如實施例1中所述之相同方法處理，得到1-(2-氯苯基）—5 —(4-氯苯基）-3-{N-[4-(5-氯吼唆-2-基）六氫吡啡—1 一基]胺甲醯基卜4一甲氧基一 1Η—σ比嗤 (96毫克’產率63%)呈無色粉末。 MS(APCI)m/z ： 557/559[M+H]+ 實施例338 將碳酸鉀（5 0宅克）與6 -氯於驗腈 (6-chloronicotinnitrile，50 毫克）加至參考例 22(2)所得化合物（60毫克）二曱基甲醯胺（1· 2毫升）溶液中，然後在170°C微波加熱器中攪拌混合物1小時。反應混合物冷卻後，加入乙酸乙酯與水，混合物以乙酸乙酯萃取。有機層用水清洗，以硫酸鎂乾燥後過濾。濾液經真空濃縮後所得粗產物用矽膠管柱層析（溶劑··己烷/乙酸乙酯=50/50至 318695 141 200804294 30/70)進行純化，得到1-(2-氯苯基）—5〜（4-氯笨基）一 3-.{N-[4-(5-氰基吡啶-2-基）六氫。比哄―1 —基]胺曱醯基卜4-…曱氧基-1H-吼唑（20. 8毫克，產率28%)呈無色粉末。 'MS(APCI)m/z ： 548/550[M+H]+ 實施例339 相應物質以如實施例338中所述之相同方法處理，得到1-(2-氯苯基）-5-（4-氯苯基）一3 (N [4〜（5 —二氟曱基口比啶-2-基）六氫吡哄-1-基]胺曱醯基丨一4一曱氧基-1H-吡哇呈無色粉末。 MS(APCI)m/z· 573/575[M+H]+ 實施例340至351 相應物質以如實施例337中所述之相同方法處理，得到如下表15所示化合物。 318695 142 200804294 表 15(1) ax)rQn 實施例號碼 R”” 物化性質等 340 Cl N=\ ~"0"CF3 粉末 MS(APCI): 591/593 [M+H]+ 341 F 粉末 MS(APCI): 540/542 [M+H]+ 342 F J〇icl 粉末 MS(APCI): 540/542 [M+H]+ 343 F 粉末 MS(APCI): 540/542 [M+H]+ 344 F 粉末 MS(APCI): 524/526 [Μ+ΗΓ 345 F J〇Lp 粉末 MS(APCI): 524/526 [M+H]+ 346 F On 粉末 MS(APCI): 524/526 [M+H]+ 347 Cl cPO 粉末 MS(APCI): 556/558 [M+H]+ 143 318695 200804294 表 15(2) ΗΝ-Ν N-R,Mt 實施例號碼 R” R抑物化性質等 348 Cl 粉末 MS(APCI): 556/558 [M+H]+ 349 Cl ♦ 粉末 MS(APCI): 556/558 [M+H]+ 350 Cl j〇lf 粉末 MS(APCI): 540/542 [M+H]+ 351 Cl N=\ 粉末 MS(APCI): 537/539 [M+H]+ 實施例352 (1)在室溫，將1N氫氧化鈉水溶液（5毫升）加至參考例1(6)所得化合物（750毫克）之甲醇（10毫升）溶液中，攪拌混合物一夜。然後將2N HC1水溶液加至反應混合物中’ 混合物以三氯甲烷萃取。萃取液以硫酸鎂乾燥後經真空濃縮。所得粗產物以甲醇清洗，然後乾燥，得到3-羧基-1-(2-氯苯基）-5-(4_氯苯基）-4-羥基-1H-吼唑（626毫克，產率 90%)呈固體。 MS(APCI)m/z ： 349/351[M+H]+ 144 318695 200804294 (2)在室溫’將水可溶碳二亞胺鹽酸鹽（57〇毫克）加至含上述步驟（1)所得化合物（62〇毫克）、4—胺基四氫哌喃 (300毫克）、1—羥基苯并三唑（46〇毫克）與三乙胺（3〇〇毫克）之N，N-二甲基甲醯胺（15毫升）溶液中，然後攪拌混合物一夜。接著將飽和碳酸氫鈉水溶液加至反應混合物中，此合物以二氯甲烷萃取。萃取液以硫酸鎂乾燥後經真空濃縮。所得粗產物用矽膠管柱層析（溶劑··己烷/乙酸乙酯= 75/25至0/100)進行純化，得到1-(2-氯苯基）-5-(4-氯苯基）-4-羥基-3-[N-（4-四氫哌喃基）胺甲醯基]—1H 一吡唑 (272毫克，產率35%)呈固體。 MS(APCI)m/z ： 432/434[M+H]+ (3)在室溫，將溴乙腈（18〇毫升）加至上述步驟（幻所得化合物（129毫克）與碳酸鉋（163毫克）之N，N一二甲基甲醯胺（3毫升）懸浮液中，在相同溫度下攪拌混合物6 =時。接著將水加至反應混合物中’混合物以乙酸乙酯萃取。萃取液以硫祕乾難經真空濃縮。㈣粗產物时膠管S 層析（溶劑：己烷/乙酸乙酯=60/40至40/60)進行純化，得到卜（2-氯苯基）-5-(4-氯苯基）-4-氰基甲氧基—3—[N—(4 — 四氫旅喃基）胺曱醯基]-1H-吼唾（I%毫克，產率95%)呈固 MS(APCI)m/z ： 471/473[M+H]+ 實施例353至355 同方法處理，得到相應物質以如實施例23中所述之相如下表16所示化合物。 318695 145 200804294 表16 F3CV^s 9^2 心。2 實施例號碼 R” 物化性質等 353 Η 固體 MS(APCI): 565/567 [M+H]+ 354 Cl 固體 MS(APCI): 599/601 [M+H]+ 355 F 固體 MS(APCI): 583/585 [M+H]+ 實施例356至359 相應物質以如實施例1中所述之相同方法處理，得到如下表17所示化合物。 146 318695 200804294 表17 HN-N V~Rm, 實施例號碼 R”” 物化性質等 356 ^"nh2 固體 MS(APCI): 488/490 [M+H]+ 357 〇、nIcf3 H 固體 MS(APCI): 570/572 [M+H]+ 358 固體 MS(APCI): 564/566 [M+H]+ 359 〇^cf3 固體 MS(APCI): 584/586 [M+H]+ 實施例360 相應物質以如實施例22(1)至22(2)中所述之相同方法處理，得到5-(4-氯苯基）-1-(2, 4-二氯苯基）-4-曱氧基 -3-[N-（1_六氫吡畊基）胺曱醯基]-1H-吡唑（560毫克，產率81%)呈粉末。 MS(APCI)m/z ： 480/482[M+H]+ 實施例361 相應物質以如實施例22(3)中所述之相同方法處理’ 147 318695 200804294 得到1-（2-氣苯基）-5-（4-氯笨基）一4一曱氧基-3一入[2-（曱颯基）乙醯基]六氫吡哄—丨—基]胺甲醯基]——吡唑 (28毫克，產率63%)呈粉末。 MS(APCI)m/z ： 566/568[M+H]+ _ 實施例362 在室溫，將溴二氟乙酸乙酯（3〇5毫克）加至實施例352 (2)所付化合物（129宅克）與碳酸鉋（163毫克）之N，N-二甲基甲醯胺（3毫升）懸浮液中，室溫攪拌混合物6小時。接者將水加至反應混合物中’混合物以乙酸乙酯萃取。萃取液以硫酸鎂乾燥後經真空濃縮。所得粗產物用石夕膠管柱層析（溶劑··己烷/乙酸乙酯=60/40至40/60)進行純化，得到 1 -（2-氯苯基）-5-(4-氯苯基）-4-（乙氧羰基）（二就）甲氧基 -3-[N-(4-四氫痕喃基）胺曱龜基]-1H-°比唾（74毫克，產率 44%)呈粉末。 MS(APCI)m/z ： 554/556[M+H]+ 實施例363至364 相應物質以如實施例2 7 9中所述之相同方法處理，^ 到如下表18所示化合物。 318695 148 200804294 表18Rtf Example No. R, R" Physicochemical Properties, etc. 332 C1 Cl Solid MS (APCI): 503/505 [M+H]+ 333 cf3 H Powder MS (APCI): 503/505 [M+H]+ 334 cf3 F Powder MS (APCI): 521/523 [M+Hf 335 cf3 Cl powder MS (APCI): 537/539 [M+H]+ Example 336 (1) Under a nitrogen atmosphere, grass 醯 gas (1·92) A solution of methylene chloride (70 ml) was cooled to -74 ° C, then disulfoxide (3 · 22 mL) was added dropwise over 15 minutes. The mixture was stirred at the same temperature for 20 minutes. A solution of 1-benzhydryl-3-hydroxy azeti dine (5 g) in dichlorohydrazine (25 ml) was then added dropwise over a period of 45 minutes. The mixture was stirred at a temperature for 75 minutes, then triethylamine (11.6 ml) was added dropwise over a period of 20 minutes, and the mixture was stirred at the same temperature for 150 minutes. The reaction mixture was warmed to 0 ° C, followed by dropwise Add 1 NHC1 aqueous solution (64 ml). Room 137 318695 200804294 Warmly stir the mixture, then separate the aqueous layer. Add 1 NHC hydrazine aqueous solution to the organic layer and mix, then separate The aqueous layer was repeated (the extraction step was repeated three times). The aqueous layer was combined and neutralized with a 2N aqueous sodium hydroxide solution (ph9) with stirring, followed by extraction with ethyl acetate. The extract was washed with brine, dried over sulfuric acid and dried. The filtrate was concentrated in vacuo to give a crude product which was purified by silica gel column chromatography (hexane / ethyl acetate = 100/0 to 90/10) to afford · 57 g, yield 92%) as a white solid. MS (APCI) m/z: 238 [M+H] + (2) dimethylamine hydrochloride (4·89 g), acetic acid (3·42) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; An aqueous solution of sodium hydrogencarbonate (15 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 45 minutes. The mixture was extracted with ethyl acetate. The organic layer was washed sequentially with aqueous sodium hydrogen carbonate and brine, dried over magnesium sulfate and filtered. The crude product obtained after concentration in vacuo was purified by silica gel column chromatography (solvent: hexane/ethyl acetate = 5/1 to 4/1). Purification afforded diphenylmethyl-4-cyano-4-dimethylamino nitrogen (13 g, yield 1%) as a yellow viscous material. MS (APCI) m/z: 292 [ M+H]+ (3) Under ice cooling, concentrated sulfuric acid (25. 5 ml) was added dropwise to the compound obtained in the above step (2) (1. The mixture was stirred at room temperature for 41 hours in 275 ml). Then, the reaction mixture was added dropwise to ice-cooled water, followed by alkalization (pH 11) with 2 n aqueous sodium hydroxide solution with stirring. The mixture was extracted with dichloromethane, and the organic layer was washed with a hydrogen carbonate solution and dried over magnesium (4). The filtrate was concentrated in vacuo and the residue was crystallised from ethyl acetate to give the desired product. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; MS(APCI)ra/z : 310[M+H]+ (4) Add IN HC dioxane (12·8 ml) and 10% palladium-carbon (1β 36 g) to the above step (3) The mixture of the compound (3.95 g) in methanol (8 mL) was stirred at room temperature under nitrogen for 3 hr. The reaction mixture was filtered and the filtrate was concentrated in vacuo. Then diethyl ether was added to the residue and stirred. The resulting crystals were collected by filtration, and then dried in vacuo to give the amidomethyl-4-dimethylamino nitrogen. The hydrochloride salt (22 g, 96% yield) was a colorless solid. MS (APCI) m/z: 144 [Μ + Η] + (5) A solution of the compound (180 mg) obtained in the above step (4) (2 ml) The solution was stirred at room temperature for 30 minutes in the solution. Sodium nitrite (138 mg) and acetic acid (93 μL) were added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature overnight. Then a saturated aqueous solution of sodium hydrogencarbonate was added. After stirring, the mixture was concentrated in vacuo, and the obtained crude product was purified by EtOAc EtOAc EtOAc EtOAc EtOAc Mercapto-4-dimethylamino-1-nitrosoazepine (137 g, yield 79%) was a pale yellow solid. MSCAPCI) m/z: 173 [M+H] + (6) EtOAc (EtOAc) (m. In solution, mixture 318695 139 200804294 • Heated and stirred for 1 day. After cooling to room temperature, the reaction mixture was concentrated in vacuo. Trichloromethane was then added to the residue and stirred, followed by filtration with celite. The filtrate was concentrated in vacuo and the residue was crystalljjjjjjjjj Next, the compound obtained in Reference Example 1 (6) (145 gm) was added, and then the mixture was treated in the same manner as described in Example to give 1-(2-chlorophenyl)-5-(4-chlorophenyl). -4-methoxy-3-{N_[3-aminoformamido-3-(dimethylamino)nitrogen--[monoyl]amine-methylpyridyl 1H-pyrazole (compound a, 4 · 7 mg, yield 6.7 %) as a pale yellow solid with 1-(2-chlorophenyl)-5-(4-chlorophenyl)-3-{[3-amine-carbazin-3-( Dimethylamino)azin-1-yl]aminecarboxylidene 4-methoxy-1H-pyrazole (Compound b, 45.5 mg, yield 27%) was obtained as a colorless solid. Compound a, MS (APCI) m/z: 448/490 [M+H] + Compound b, MS (APCI) m/z ·· 503/505 [M+H] + Example 337 (1) Potassium carbonate (3.73 g) and hexahydroquinone (1.16 g) were added to a solution of 2,5-dichloropyrine (2 g) dimethyl decylamine (3 ml) and then stirred at 11 ° C. The mixture was 4 hours. After the reaction mixture was cooled, ethyl acetate and aq. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the crude product was purified by NH-Dish-gel column chromatography (Chromatorex NH-shixi gum, solvent: tri-gas methane / decyl alcohol = 1 〇〇 / 〇 to 99 / 1) to obtain 5 -Chloro-2-(1-hexahydropyridinyl)pyridine (〇 28 g, yield 100%) was obtained as a pale yellow solid. MS (APCI) m/z: 198 / 200 [M+H] + 140 318695 200804294 (2) The compound obtained in the above step (1) (27 mg) was treated in the same manner as described in Example 336 (5). 5-Chloro-2-(4-nitrosohexahydropyrylene-1-yl)pyridine was obtained as a pale yellow solid. (3) The tetrahydrofuran (4 ml) of the compound obtained in the above step (2) was cooled to 〇 ° C, and then lithium aluminum hydride (91 mg) was gradually added thereto, and the mixture was stirred for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was then gradually added to the reaction mixture, and the mixture was extracted with trichloromethane. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 2-(4-aminohexahydropyridinium-fluorenyl)-5-chloropyridinium (276 mg) as a pale yellow solid. MS (APCI) m/z: 213 / 215 [M+H] + (4) The compound (1 〇() mg) of the compound of the formula (1) and the compound (5 9 mg) obtained in the above step (3) are Treatment in the same manner as described in Example 1 gave 1-(2-chlorophenyl)-5-(4-chlorophenyl)-3-{N-[4-(5-chloroindole-2- The hexahydropyrimidin-1 mono-amino]aminopyridinium 4-methoxy-1 Η-σ ratio (96 mg 'yield 63%) is a colorless powder. MS (APCI) m/z: 557 / 559 [M+H] + Example 338. Potassium carbonate (5 0 gram) and 6-chloronic acid (6-chloronicotinnitrile, 50 mg) were added to Reference Example 22 ( 2) A solution of the obtained compound (60 mg) of dimercaptocaramine (1.2 ml) was then stirred for one hour in a microwave oven at 170 °C. After the reaction mixture was cooled, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give a crude product which was purified using EtOAc EtOAc EtOAc EtOAc EtOAc 5-(4-Chlorophenyl)-3--{4-(5-cyanopyridin-2-yl)hexahydro.哄哄 1 1 ] ] ] 4- 4- 4- 4- 4- 4- 4- 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 'MS (APCI) m/z: 548 / 550 [M+H] + Example 339 The corresponding material 4-chlorophenyl)-3 (N [4~(5-difluoroindolyl)pyridin-2-yl)hexahydropyridin-1-yl]amine-based fluorenyl-4-yloxy-1H -Pytha is a colorless powder. MS (APCI) m / z · 573 / 575 [M + H] + Examples 340 to 351 The corresponding materials were treated in the same manner as described in Example 337 to give the following Table 15 Compound 318695 142 200804294 Table 15(1) ax)rQn Example number R"" Physicochemical properties, etc. 340 Cl N=\~"0"CF3 Powder MS (APCI): 591/593 [M+H]+ 341 F Powder MS (APCI): 540/542 [M+H]+ 342 FJ〇icl Powder MS (APCI): 540/542 [M+H]+ 343 F Powder MS (APCI): 540/542 [M+H] + 344 F Powder MS (APCI): 524/526 [Μ+ΗΓ 345 FJ〇Lp Powder MS (APCI): 524/526 [M+H]+ 346 F On Powder MS (APCI): 524/526 [M+ H]+ 347 Cl cPO powder MS (APCI): 556/558 [M+H]+ 143 318695 200804294 Table 15(2) ΗΝ-Ν NR, Mt Example number R" R inhibitory property, etc. 348 Cl powder MS ( APCI): 556/558 [M +H]+ 349 Cl ♦ Powder MS (APCI): 556/558 [M+H]+ 350 Cl j〇lf Powder MS (APCI): 540/542 [M+H]+ 351 Cl N=\ Powder MS ( APCI): 537/539 [M+H] + 352 (1) (1) EtOAc (1 EtOAc) The solution was stirred overnight. Then a 2N aqueous HCl solution was added to the mixture. The mixture was extracted with chloroform. The extract was dried over magnesium sulfate and concentrated in vacuo. The crude product was washed with methanol and then dried to give 3 -Carboxy-1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-hydroxy-1H-indazole (626 mg, yield 90%) was obtained as a solid. MS (APCI) m/z : 349/351 [M+H]+ 144 318695 200804294 (2) Add water-soluble carbodiimide hydrochloride (57 mg) at room temperature to the above step (1) The obtained compound (62 mg), 4-aminotetrahydropyran (300 mg), 1-hydroxybenzotriazole (46 mg) and triethylamine (3 mg) of N, N-di Methylformamide (15 ml) was added and the mixture was stirred overnight. A saturated aqueous solution of sodium hydrogencarbonate was then added to the mixture and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated in vacuo. The obtained crude product was purified by silica gel column chromatography (solvent·hexane/ethyl acetate = 75/25 to 0/100) to give 1-(2-chlorophenyl)-5-(4-chlorophenyl). 4-Hydroxy-3-[N-(4-tetrahydropyranyl)aminecarbamyl]-1H-pyrazole (272 mg, yield 35%) was obtained as a solid. MS (APCI) m/z: 432 / 434 [M+H] + (3) bromoacetonitrile (18 mL) was added to the above step at room temperature (magic compound (129 mg) and carbonated (163 mg) In a suspension of N,N-dimethylformamide (3 ml), the mixture was stirred at the same temperature for 6 = time. Then water was added to the reaction mixture. The mixture was extracted with ethyl acetate. The secret is difficult to concentrate in vacuo. (4) The crude product is purified by H-chrome chromatography (solvent: hexane/ethyl acetate = 60/40 to 40/60) to give bis(2-chlorophenyl)-5-(4) -Chlorophenyl)-4-cyanomethoxy-3-(N-(4-tetrahydromethane) amidino]-1H-indole (I% mg, yield 95%) is solid MS (APCI) m/z: 471 / 473 [M+H] + </ RTI> </ </ </ > </ </ > </ </ > </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 16 F3CV^s 9^2 heart. 2 Example number R” Physicochemical properties, etc. 353 固体 Solid MS (APCI): 565/567 [M+H]+ 354 Cl Solid MS (APCI): 599/601 [M+H ]+ 355 F solid MS (APCI): 583/585 [M+H]+ Examples 356 to 359 Corresponding substances Treatment in the same manner as described in Example 1 gave the compound shown in the following Table 17. 146 318695 200804294 Table 17 HN-N V~Rm, Example No. R"" Physicochemical Properties, etc. 356 ^"nh2 Solid MS ( APCI): 488/490 [M+H]+ 357 〇, nIcf3 H Solid MS (APCI): 570/572 [M+H]+ 358 Solid MS (APCI): 564/566 [M+H]+ 359 〇 ^cf3 Solid MS (APCI): 584/586 [M+H] + Example 360 The corresponding material was treated in the same manner as described in Examples 22(1) to 22(2) to give 5-(4-chloro Phenyl)-1-(2,4-dichlorophenyl)-4-methoxy-3-[N-(1_hexahydropyrrole)amine sulfhydryl]-1H-pyrazole (560 mg) , yield 81%) as a powder. MS (APCI) m/z: 480 / 482 [M+H] + Example 361 The corresponding material was treated in the same manner as described in Example 22 (3) '147 318695 200804294 1-(2-Phenylphenyl)-5-(4-chlorophenyl)-tetramethyloxy-3-[2-(indolyl)ethenyl]hexahydropyridinium-fluorenyl-based Aminomethyl hydrazide] - pyrazole (28 mg, yield 63%) is a powder. MS (APCI) m/z: 566 / 568 [M+H] + </RTI> <RTIgt; </RTI> </RTI> </ RTI> </ RTI> </ RTI> The mixture was stirred in a suspension of N.N-dimethylformamide (3 ml) with EtOAc (EtOAc) (EtOAc) The water was added to the reaction mixture. The mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated in vacuo. The obtained crude product was purified by silica gel column chromatography (solvent·hexane/ethyl acetate=60/40 to 40/60) to give 1-(2-chlorophenyl)-5-(4-chlorobenzene. ))-4-(ethoxycarbonyl)(di)methoxy-3-[N-(4-tetrahydroindolyl)amine thiol base]-1H-° than saliva (74 mg, yield 44 %) is a powder. MS (APCI) m/z: 554 / 556 [M+H] + </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 318695 148 200804294 Table 18

參考例1 (1)將氯化鎂（26克）與三乙胺（48· 6克）加至丙二酸單乙酯鉀鹽（39克）之乙腈（100毫升）溶液中，室溫攪拌混合物2小時（溶液A)。在室溫，將羰基二咪唑（19· 5克）加至 4-氯苯基乙酸（18. 6克）之乙腈（100毫升）溶液中’在相同溫度下攪拌混合物1· 5小時。然後在室溫，加入上述所製備溶液A，在相同溫度下攪拌混合物30分鐘，接著在80 °C攪拌2小時。冷卻反應混合物至室溫後，加入2N HC1 溶液（260毫升）並攪拌。有機層以碳酸氫鈉水溶液、鹽水清洗，以硫酸鎂乾燥後過濾。濾液經真空濃縮後所得粗產 149 318695 200804294 物用矽膠管柱層析（溶劑··己烷/乙酸乙酯=8/1至6/1)進行純化’得到4-(4-氯苯基）-3-側氧基丁酸乙酯（25克，產率 95%)呈液體。 MS(APCI)m/z ： 241/243[M+H]+ (2)冰冷卻下，將亞硝酸鈉（7· 9克）水溶液以超過j 〇分鐘之時間逐滴加至含2-氯苯胺（13· 3克）之2Ν HC1溶液中’在相同溫度下攪拌混合物2小時（溶液b)。在室溫，將乙酸鈉（27. 2克）加至上述步驟（1)所得化合物（25克）之乙醇（300毫升）溶液中，然後冰冷卻混合物，接著加入上述所製備溶液B，在相同溫度下擾拌混合物3 〇分鐘，在室溫攪拌1小時。用玻璃過濾器以過濾法收集所產生之固體物質，然後以水清洗，以三氯甲烷溶解。溶液以鹽水清洗，有機層以硫酸鎂乾燥後過濾。濾液經真空濃縮，所得固體物質以己烷清洗後經真空乾燥，得到4-(4-氯苯基）—2一 [(2-氯苯基）亞肼基]—3-側氧基丁酸乙酯（32· 3克，產率 82%)呈粉末。卞 MS(APCI)m/z： 379/381[M+H]+ (3)將溴（4· 37毫升）逐滴加至上述步驟（2)所得化合物（32· 2克）之三氯曱烷（500毫升）溶液中，室溫攪拌^合物1小時。再添加溴（1毫升）後，混合物室溫攪拌丨小時。反應混合物經真空濃縮，殘留物以乙醚稀釋後以鹽水清洗。有機層以硫酸鎂乾燥後過溏。濾液經真空濃縮，得到 4-溴-4-(4-氯苯基）—2-[ (2-氯苯基）亞肼基]—3〜側氧基丁酸乙酯（39克，產率1〇〇%)呈固體。 318695 150 200804294 MS(APCI)m/z ： 457/459[M+H]+ (4)將乙酸鈉（35克）加至上述步驟（3)所得化合物（39 克）之乙醇/水（300毫升/100亳升）溶液中，於9〇。〇攪拌混合物3小時。反應混合物濃縮後，將乙酸乙酯與水加至: 留物中並攪拌混合物。有機層以鹽水清洗，以硫酸鎂乾燥後過濾。濾液經真空濃縮，所得固體物質以異丙醚及乙二清洗，得到1-(2-氯苯基）-5-(4-氯苯基）-3_乙氧羰基-4_ 經基-1H-吡唑（26克，產率81%)呈粉末。 MS(APCI)m/z ： 377/379[M+H]+ ^ (5)冰冷卻下，將氫化鈉（2· 54克）加至上述步驟（4)所得化合物（20克）之二甲基甲醯胺（15〇毫升）溶液中，在相同μ度下攪拌混合物3〇分鐘，接著在室溫攪拌1小時。將碘甲烷（4· 95耄升）加至反應混合物中，室溫攪拌混合物工 J日守。接著反應混合物中加入水與乙酸乙酯並授拌混合物。有機層以鹽水清洗，以石荒酸鎂乾燥後過溏。濾液經直空濃縮，所得固體物質以異丙醚清洗，得到1K2 —氯苯基、) 5 (4氯笨基）一3一乙氧羰基一4—甲氧基一1 η一吼唾（15. 7 克’產率76%)呈粉末。 MS(APCI)m/z ： 391/393[M+H]+ 、（6)冰冷卻下，將2N氫氧化鈉水溶液（24毫升）加至上述步驟（5)所得化合物（15·7克）之乙醇（2〇〇毫升）溶液中，室溫攪拌混合物一夜。將2Ν fiCI水溶液（30毫升）加至反應混合物中，攪拌混合物後濃縮。過濾收集所產生固體物貝，以水清洗，得到3-羧基-1-(2-氯苯基）-5-(4-氯 318695 151 200804294 苯基）-4-甲氧基-1H-响唾（14·4克，產率99%)呈粉末。 MS(APCI)m/z： 363/365[M+H]+ 參考例2 將三苯膦（208毫克）與2-(N—嗎福啉基）乙醇（96微升）加至1-(2-氯苯基）-5-(4-氯苯基）-3-乙氧羰基—4 —經基 - 1H-吡唑（200毫克，參考例1(4)所得化合物）之四氫呋喃 (4宅升）溶液中並攪拌。纟（TC、氮氣環境下，逐滴加入偶氮二羧酸二異丙酯（154微升），然後室溫攪拌混合物一夜。反應混合物經真空濃縮後粗產物用劑:己烧/乙酸乙一至助。)進行純二：氯苯基）-5-(4-氯苯基）-3-乙氧幾基_4_[2_(N_嗎福淋基）乙氧基]-1H-吡唑（463毫克，產率100%)呈無色黏稠物。 MS(APCI)m/z ： 490/492[M+H]+ 參考例3 (1)相應起始物以如參考例1(1)至1(4)中所述之相同方法處理’得到5-(4_氯苯基氯苯基）_3_乙氧羰基-4-羥基-1H-吡唑（6· 2克）。 MS(APCI)m/z ： 411/413[M+H]+ (2)在虱氣環境下，將氫化鈉（118毫克，6〇%礦油释诗液）力:至上述步驟⑴所得化合物（1.1克）之二甲基甲酿胺 (一 12/升）溶液中，在相同溫度下擾掉混合物15分鐘。將氟曱A 2, 2, 2-二氟乙g旨（L 18毫升）加至反應混合物中1然後於6rc_混合物15分鐘。冷卻至室溫後，加入袴松酸水溶液與乙酸乙酯。混合物以乙酸乙酯萃取，有 318695 152 200804294 機層以硫酸鎂乾燥後過濾。濾液經真空濃縮後所得粗產物用NH-石夕膠管柱層析（Chr⑽at〇rex丽-矽膠，心卩Silicia Chem·公司製造，溶劑··己烷/乙酸乙酯=9〇/1〇至8〇/2〇) 進行純化’得到5-(4-氯苯基）-l-(2, 4-二氯苯基）-3-乙氧罗厌基-4-(2, 2, 2-三氟乙氧基）— ih-吼唑（1.28克，產率97%) 呈無色固體。 MS(APCI)m/z ： 493/495[M+H]+ 參考例4 (1) 相應起始物以如參考例Id)至丨（4)中所述之相同方法處理，得到丨―（2—氯苯基）—3-乙氧羰基—4-羥基—5-(4一三氟甲基苯基）一 1H一 π比唑（4〇克）。 MS(APCI)m/z ： 411/413[M+H]+ (2) 將氯二氟乙酸（丨· 3〇克）與碳酸鉀（2· 76克）加至上述步驟（1)所得化合物（82〇毫克）之二甲基曱醯胺（1〇毫升） /谷液中，然後於。〇攪拌混合物2日。冷卻至室溫後，將稀釋之HC1水溶液加至反應混合物中。攪拌後，混合物以二氯甲烷萃取，萃取液經真空濃縮。殘留物以甲醇（1◦毫升）稀釋，然後在室溫加入1Ν氫氧化鈉水溶液（4毫升），在相同溫度下攪拌混合物一夜。將稀釋之HC1水溶液加至反應混合物中。攪拌後，混合物以三氣曱烷萃取，萃取液經真空濃縮。所得粗產物以甲醇清洗，乾燥後得到卜（2一氯苯基）-4-二就曱氧基—3—乙氧羰基—5一（4一三氟甲基苯基） - 1H-比哇（504毫克，產率58%)呈無色固體。 MS(APCI)m/z ： 433/435[M+H]+ 318695 153 200804294 參考例5 (Ο在室溫’將氫化鈉（0· 40克，6〇%礦油懸浮液）加至麥考例1(4)所得化合物u· 39克）之二曱基曱醯胺（1()毫升）溶液中’在相同溫度下攪拌混合物15分鐘。將溴乙腈（1· 2〇克）加至反應混合物中，然後室溫攪拌混合物一夜。加入檸檬酸水溶液與乙酸乙酯至反應混合物中。攪拌後，混合物以乙酸乙酯萃取，有機層以硫酸鎂乾燥後過濾。濾液經真工/辰縮後所得粗產物用矽膠管柱層析（溶劑··己烷/乙酸乙酷=50/50至30/70)進行純化，得到卜（2—氯苯基）—5 —(4一氯苯基）-3-乙氧羰基—4—氰基曱氧基—1Η—吼唑（1·28克，產率61%)呈白色粉末。 MS(APCI)m/z ： 416/418[M+H]+ 、（2)冰冷卻下，將IN氫氧化鈉水溶液（2毫升）加至上驟⑴所％化合物甲醇（5毫升）溶液中，然後室溫擾掉 =合f 2小時一。㈣HC1轉液(4毫升)加至反應混合物此合物以二軋甲料取。有機層以硫酸鎂乾燥後過濾。真空濃縮濾液，3-羧基一;[一一畜玫悉1 U乳本基）—5 —(4 —氯苯基）一4一 (甲氧羰基）甲氧基一1H-吡唑真古太、方nn、毛克’產率99%)呈白色粉末0 MS(APCI)m/z ： 421/423[M+H]+ 參考例6 在〇 °C、氮氣環境下，將-贫| 田鱼一 ^ / 將—本基磷《氮化物（250微升: -、一乙月女（17 0微升）加至參考例1 ( 亏例1(6)所得化合物（363毫克夂甲本（30笔升）溶液中，然後 πReference Example 1 (1) Magnesium chloride (26 g) and triethylamine (48·6 g) were added to a solution of potassium monoethyl malonate (39 g) in acetonitrile (100 ml), and the mixture was stirred at room temperature 2 Hour (solution A). The carbonyldiimidazole (19.5 g) was added to a solution of 4-chlorophenylacetic acid (18.6 g) in acetonitrile (100 ml) at room temperature. The mixture was stirred at the same temperature for 1.5 hours. Then, the above-prepared solution A was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes, followed by stirring at 80 ° C for 2 hours. After cooling the reaction mixture to room temperature, 2N HCl solution (260 mL) was added and stirred. The organic layer was washed with aqueous sodium hydrogen carbonate solution and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give a crude material (yield: 149, 318, s, s, s, s, s, s, s, s, s, s Ethyl 3-oxobutanoate (25 g, 95% yield) was a liquid. MS (APCI) m/z : 241/243 [M+H] + (2) Under ice cooling, an aqueous solution of sodium nitrite (7.9 g) was added dropwise to the 2-chloro group over a period of j 〇 min. The mixture of aniline (13. 3 g) in 2 Ν HC1 solution was stirred at the same temperature for 2 hours (solution b). Sodium acetate (27.2 g) was added to a solution of the compound obtained in the above step (1) (25 g) in ethanol (300 ml) at room temperature, and then the mixture was ice-cooled, followed by the solution B prepared above, in the same The mixture was spoiled at temperature for 3 minutes and stirred at room temperature for 1 hour. The solid matter produced was collected by filtration using a glass filter, then washed with water and dissolved in chloroform. The solution was washed with brine, and the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo, and the obtained solid material was washed with hexane and dried in vacuo to give 4-(4-chlorophenyl)-2-[[2-chlorophenyl] fluorenyl]- 3-oxobutyric acid Ethyl ester (32. 3 g, yield 82%) was obtained as a powder.卞MS(APCI)m/z: 379/381[M+H]+ (3) bromine (4·37 ml) was added dropwise to the compound obtained in the above step (2) (32·2 g) of trichloropurine The solution was stirred at room temperature for 1 hour in a solution of hexane (500 mL). After additional bromine (1 ml) was added, the mixture was stirred at room temperature for a few hours. The reaction mixture was concentrated in vacuo. The organic layer was dried over magnesium sulfate and dried. The filtrate was concentrated in vacuo to give ethyl 4-bromo-4-(4-chlorophenyl)-2-[(2-chlorophenyl)hydrazinyl]-3-butoxyacetate (39 g, yield 1〇〇%) is solid. 318695 150 200804294 MS(APCI)m/z : 457/459[M+H]+ (4) Add sodium acetate (35 g) to the compound obtained in the above step (3) (39 g) in ethanol/water (300 ml) /100 liters) in solution, at 9 〇. The mixture was stirred for 3 hours. After the reaction mixture was concentrated, ethyl acetate and water were added to the residue and the mixture was stirred. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo, and the obtained solid material was purified eluting with diethyl ether and diethyl ether to give 1-(2-chlorophenyl)-5-(4-chlorophenyl)-3-ethoxycarbonyl-4-yl-1H- Pyrazole (26 g, yield 81%) was in powder. MS (APCI) m/z: 377 / 379 [M+H] + (5) EtOAc (2. 54 g). The solution was stirred at the same μ degree for 3 hrs in a solution of carbamide (15 mM), followed by stirring at room temperature for 1 hour. Methyl iodide (4.95 liters) was added to the reaction mixture, and the mixture was stirred at room temperature. Water and ethyl acetate were then added to the reaction mixture and the mixture was combined. The organic layer was washed with brine and dried over magnesium sulphate. The filtrate was concentrated in a straight space, and the obtained solid substance was washed with isopropyl ether to give 1K2-chlorophenyl, (5, 4-chlorophenyl)- 3-ethoxycarbonyl- 4-methoxy- 1 η- 吼吼 (15 7 g 'yield 76%) is a powder. MS (APCI) m/z: 391 / 393 [M+H]+, (6) 2N sodium hydroxide aqueous solution (24 ml) was added to the compound obtained in the above step (5) (15·7 g) under ice cooling. The mixture was stirred in a solution of ethanol (2 mL) at room temperature overnight. A 2 Ν solution of fiCI (30 ml) was added to the reaction mixture, and the mixture was stirred and concentrated. The resulting solid shells were collected by filtration and washed with water to give 3-carboxy-1-(2-chlorophenyl)-5-(4-chloro 318695 151 200804294 phenyl)-4-methoxy-1H-salt (14·4 g, yield 99%) was a powder. MS (APCI) m/z: 363/365 [M+H] + Reference Example 2 Triphenylphosphine (208 mg) and 2-(N-norfosinyl)ethanol (96 μL) were added to 1-( 2-Chlorophenyl)-5-(4-chlorophenyl)-3-ethoxycarbonyl-4-yl-yl-1H-pyrazole (200 mg, compound obtained in Reference Example 1 (4)) tetrahydrofuran (4 house) l) the solution and stir.纟 (TC, nitrogen atmosphere, diisopropyl azodicarboxylate (154 μl) was added dropwise, then the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. Assisted.) Pure two: chlorophenyl)-5-(4-chlorophenyl)-3-ethoxyxoyl_4_[2_(N_fofofyl) ethoxy]-1H-pyrazole (463 Mg, yield 100%) is a colorless viscous material. MS (APCI) m/z : 490 / 492 [M+H] + Reference Example 3 (1) The corresponding starting materials were treated in the same manner as described in Reference Examples 1 (1) to 1 (4). -(4_Chlorophenylchlorophenyl)_3_ethoxycarbonyl-4-hydroxy-1H-pyrazole (6.2 g). MS (APCI) m/z : 411/413 [M+H]+ (2) Sodium hydride (118 mg, 6〇% mineral oil) in a helium atmosphere: to the compound obtained in the above step (1) In a solution of (1.1 g) of dimethylamine (12/L), the mixture was disturbed at the same temperature for 15 minutes. Fluoroxime A 2, 2, 2-difluoroethane (L 18 ml) was added to the reaction mixture 1 and then to the 6rc_ mixture for 15 minutes. After cooling to room temperature, an aqueous solution of decanoic acid and ethyl acetate were added. The mixture was extracted with ethyl acetate. 318 695 152. The filtrate was concentrated in vacuo and the crude product was purified by NH------------------- 〇/2〇) Purification' yields 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-3-ethoxyoxapin-4-(2, 2, 2-three Fluoroethoxy)-ih-carbazole (1.28 g, yield 97%) was obtained as a colorless solid. MS (APCI) m/z: 493/495 [M+H] + Reference Example 4 (1) The corresponding starting materials were treated in the same manner as described in Reference Examples Id) to (4) to obtain 丨-( 2-Chlorophenyl)-3-ethoxycarbonyl-4-hydroxy-5-(4-trifluoromethylphenyl)-1H-pyrazole (4 g). MS (APCI) m/z : 411/413 [M+H] + (2) chlorodifluoroacetic acid (丨·3 g) and potassium carbonate (2.66 g) were added to the compound obtained in the above step (1) (82 〇 mg) of dimethyl decylamine (1 〇 ml) / gluten solution, then at. The mixture was stirred for 2 days. After cooling to room temperature, the diluted aqueous HCl solution was added to the reaction mixture. After stirring, the mixture was extracted with dichloromethane and the mixture was concentrated in vacuo. The residue was diluted with MeOH (1 mL), and then aqueous sodium hydroxide (4 ml) was added at room temperature, and the mixture was stirred overnight at the same temperature. A diluted aqueous solution of HCl was added to the reaction mixture. After stirring, the mixture was extracted with trioxane and the extract was concentrated in vacuo. The obtained crude product was washed with methanol and dried to give bis(2-chlorophenyl)-4-di- methoxyoxy-3-ethoxycarbonyl-5-(4-trifluoromethylphenyl)-1H-biwa (504 mg, yield 58%) as a colorless solid. MS (APCI) m/z : 433/435 [M+H]+ 318695 153 200804294 Reference Example 5 (Ο at room temperature 'Add sodium hydride (0·40 g, 6〇% mineral oil suspension) to McCaw The compound obtained in Example 1 (4) was obtained by stirring the mixture at the same temperature for 15 minutes in the solution of dimethyl decylamine (1 ml) in a solution. Bromoacetonitrile (1.2 g) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. An aqueous citric acid solution and ethyl acetate were added to the reaction mixture. After stirring, the mixture was extracted with EtOAc. The crude product obtained by real work/shrinking of the filtrate was purified by silica gel column chromatography (solvent·hexane/acetic acid=50/50 to 30/70) to obtain di(2-chlorophenyl)-5. —(4-Chlorophenyl)-3-ethoxycarbonyl-4-cyanomethoxy- 1 Η-carbazole (1·28 g, yield 61%) was obtained as a white powder. MS (APCI) m / z: 416 / 418 [M + H] +, (2) EtOAc (2 mL) was added to a solution of the compound (1) in methanol (5 ml). Then room temperature is disturbed = f f 2 hours. (4) HC1 transfusion (4 ml) was added to the reaction mixture. The compound was taken as a two-rolled material. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo, 3-carboxy-[1]-[1] (4-chlorophenyl)- 4-(methoxycarbonyl)methoxy-1H-pyrazole , square nn, gram' yield 99%) is white powder 0 MS (APCI) m / z: 421/423 [M + H] + reference example 6 in 〇 ° C, nitrogen environment, will - poor | Fish a ^ / will - the base phosphorus "nitride (250 microliters: -, one month female (17 0 microliters) was added to the reference example 1 (deficient 1 (6) compound (363 mg of armor ( 30 pens in the solution, then π

交在相同 >里度下攪拌混合物3G 318695 154 200804294 分鐘，於80 C攪拌混合物2小時。接著將βΝ HC1水溶液加至反應混合物中，於lOOt：攪拌混合物一夜。冷卻至室溫後，將碳酸氫鈉水溶液加至反應混合物中。攪拌後，混合物以三氯甲烷萃取，萃取液以硫酸鎂乾燥後過濾。濾液經真空濃縮，所得粗產物用矽膠管柱層析（溶劑：己烷/乙酸乙酯=80/20至40/60)進行純化，得到3-胺基-1 —(2-氯苯基）-5-（4-氯苯基）一4-甲氧基—1H 一吼唑（43毫克，產率 50%)呈淡黃色固體。 MS(APCI)m/z： 334/336[M+H]+ 茶考例7 在〇°C、氮氣環境下，將曱基鋰（13· 9毫升，i 〇倾乙醚溶液）逐滴加至參考例丨（6)所得化合物（2· 5克）之四氫呋喃（100耄升）溶液中，並在相同溫度下攪拌混合物3〇分釦，然後於室溫攪拌3小時。接著在冰冷卻下將水與乙酸乙酯加至反應混合物中並攪拌。有機層以碳酸氫鈉水溶液清洗，以硫酸鎂乾燥後過濾。濾液經真空濃縮，所得粗產物用矽膠官柱層析（溶劑··己烷/乙酸乙酯=9〇/1〇至進行純化，得到3—乙醯基—丨―（2—氯苯基）—5 —(4—氯苯基）一 4-甲氧基-1H-吡唑（1」克，產率43%)呈淡黃色固體。 MS(APCI)m/z ： 361/363[M+H]+ 參考例8 在-78°C、氮氣環境下，將甲基鋰（29毫升，1〇指乙醚溶液）逐滴加至3_羧基氯苯基）_5_(4_氣苯基） 4甲氧基-1H-吡唑（1· 〇9克）之四氫呋喃（3〇毫升）溶液 318695 155 200804294 •中，並在相同溫度下攪拌混合物3〇分鐘。回溫至 •將漠化（乙烯基）鎂（7·7毫升，〇.97M四氫吱d南溶液）逐滴加至反應混合物中，室溫攪拌混合物3小時。將水與水溶液加至反應混合物中。㈣後，混合物以乙酸乙_ 取。有機層以硫酸鎂乾燥後過濾。濾液經真空濃縮，所二粗產物用矽膠管柱層析（溶劑：己烷/乙酸乙酯=9〇/ι〇至于 85/15)進行純化，得到^(2 —氯苯基）_5_(4_氯苯基）_4_甲氧基-3-乙烯羰基-1H-吡唑（78〇毫克，產率7〇%)呈無色固 MS(APCI)m/z ： 373/375[M+H]+ 參考例9 (1)在o°c、氮氣環境下，將二苯基磷疊氮化物（2·37 耄升）與二乙胺（1·67毫升）加至3-叛基-1-(2-氯苯基）-5 -(4-氯苯基）-4-曱氧基一 1Η-η比嗤（3· 63克）之甲苯（30毫升）溶液中，然後在相同溫度下攪拌混合物30分鐘，於80°C 撥掉混合物3小時。冷卻至〇後，將苯曱醇（1 · 8 6毫升）與4 - 一曱胺基ϋ比咬（61毫克）加至反應混合物中，於8 0 °C 攪拌混合物一夜。冷卻至室溫後，將碳酸氫鈉水溶液加至反應混合物中。攪拌後，混合物以乙酸乙酯萃取，萃取液以硫酸鎂乾燥後過濾。濾液經真空濃縮，所得粗產物用矽膠管柱層析（溶劑：己烷/乙酸乙酯=80/20至60/40)進行純化’得到3 -苯曱氧幾基胺基-1-(2 -氯苯基）-5-(4 -氯苯基） -甲氧基-1H-吡唑（4. 15克，產率89%)呈淡黃色黏稠物。 MS(APCI)m/z ： 468/470[M+H]+ 156 318695 200804294 (2)將10%鈀-碳（400毫克）加至上述步驟（1)所得化人 H1幻之甲醇（5〇毫升）溶液中，在氫氣環境下室温i 二此:物7小時。過濾反應混合物，濾液經真空濃縮。接著將一氯甲烷與碳酸氫鈉水溶液加至殘留物中。攪拌後，混合物以三氯甲烷萃取，萃取液以硫酸鎂乾燥後過濾。濾液經真空濃縮’所得粗產物以乙醇再結晶，然後過遽除^ 所產生之無色沉澱物質。濾液經真空濃縮，所得粗產物用矽膠管柱層析（溶劑：己烷/乙酸乙酯=7〇/3〇至5〇/5〇)進行純化，得到3-胺基-1-(2-氯苯基氣苯基）_4_甲氧基-1H-吡唑（31〇毫克，產率11%)呈淡黃色固體。平 MS(APCI)m/z ： 334/336[M+H]+The mixture was stirred at the same > 3G 318695 154 200804294 minutes, and the mixture was stirred at 80 C for 2 hours. Next, an aqueous solution of βΝ HC1 was added to the reaction mixture, and the mixture was stirred overnight at 100 °C. After cooling to room temperature, an aqueous solution of sodium hydrogencarbonate was added to the reaction mixture. After stirring, the mixture was extracted with chloroform, and the extract was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo, and the obtained crude material was purified using EtOAc EtOAc EtOAc EtOAc EtOAc 5-(4-Chlorophenyl)-4-methoxy-lH-carbazole (43 mg, yield 50%) was obtained as pale yellow solid. MS (APCI) m / z: 334 / 336 [M + H] + tea test 7 曱 ° C, nitrogen atmosphere, the sulfhydryl lithium (13 · 9 ml, i 〇乙醚 ether solution) was added dropwise Refer to the solution of the obtained compound (2.5 g) in tetrahydrofuran (100 liter), and the mixture was stirred at the same temperature for 3 〇, and then stirred at room temperature for 3 hours. Water and ethyl acetate were then added to the reaction mixture under ice cooling and stirred. The organic layer was washed with aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo, and the obtained crude product was purified by chromatography (solvent hexane/ethyl acetate = 9 〇 / 〇〇 , , , , , , , , ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( —5 —(4-Chlorophenyl)-4-methoxy-1H-pyrazole (1 g, yield 43%) as a pale yellow solid. MS (APCI) m/z: 361/363 [M+ H]+ Reference Example 8 Methyl lithium (29 ml, 1 〇 diethyl ether solution) was added dropwise to 3-carboxylated phenylphenyl)_5_(4- phenylphenyl) 4 at -78 ° C under nitrogen atmosphere. A solution of methoxy-1H-pyrazole (1·〇9 g) in tetrahydrofuran (3 mL) 318695 155 200804294 • and the mixture was stirred at the same temperature for 3 minutes. The temperature was warmed to. • Desertified (vinyl) magnesium (7.7 ml, 〇.97 M tetrahydroanthracene d-solution) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. Water and an aqueous solution were added to the reaction mixture. (4) After the mixture is taken as acetic acid. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo, and the crude material was purified using silica gel column chromatography (solvent: hexane / ethyl acetate = 9 〇 / 〇〇 </ </ </ _Chlorophenyl)_4_methoxy-3-vinylcarbonyl-1H-pyrazole (78〇mg, yield 7〇%) as colorless solid MS (APCI) m/z : 373/375[M+H] + Reference Example 9 (1) Add diphenylphosphoric azide (2·37 liters) and diethylamine (1·67 ml) to 3-reactive -1- in o °c under nitrogen atmosphere (2-Chlorophenyl)-5-(4-chlorophenyl)-4-hydroxyl- 1 Η-η than hydrazine (3·63 g) in toluene (30 ml) solution, then stirred at the same temperature The mixture was allowed to stand for 30 minutes at 80 ° C for 3 hours. After cooling to hydrazine, phenyl decyl alcohol (1·86 6 ml) was added to the reaction mixture with 4-aminoamine hydrazine (61 mg), and the mixture was stirred at 80 ° C overnight. After cooling to room temperature, an aqueous solution of sodium hydrogencarbonate was added to the reaction mixture. After stirring, the mixture was extracted with ethyl acetate. The filtrate was concentrated in vacuo, and the obtained crude material was purified using EtOAc EtOAc EtOAc EtOAc EtOAc -Chlorophenyl)-5-(4-chlorophenyl)-methoxy-1H-pyrazole (4.15 g, yield 89%) as a pale yellow viscous material. MS (APCI) m/z: 468/470 [M+H]+ 156 318695 200804294 (2) 10% palladium-carbon (400 mg) was added to the above-mentioned step (1) to obtain human H1 phantom methanol (5 〇 In a solution of HCl), under a hydrogen atmosphere at room temperature i: 7 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. Then, methyl chloride and an aqueous solution of sodium hydrogencarbonate were added to the residue. After stirring, the mixture was extracted with chloroform, and the extract was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The obtained crude product was recrystallized from ethanol, and then the colorless precipitated material was obtained. The filtrate was concentrated in vacuo, and the obtained crude material was purified using EtOAc EtOAc EtOAc EtOAc EtOAc Chlorophenyl phenylphenyl)_4-methoxy-1H-pyrazole (31 mg, yield 11%) was obtained as a pale yellow solid. Flat MS (APCI) m/z : 334/336 [M+H]+

參考例1Q U)冰冷卻下，將氫化鈉（360毫升）加至卜苯甲氧羰基 —4-羥基六氫吡啶（1·3克）二甲基曱醯胺（1〇毫升）溶液人土中，在氮氣環境下室溫攪拌混合物丨小時。冰冷卻^，將碘甲烷（374微升）加至反應混合物中，在相同溫度下攪拌混合物1小時，室溫攪拌2小時。將水與乙酸乙酯加至反應混合物中並攪拌混合物。有機層以鹽水清洗，以硫酸鎂乾燥後過濾。濾液經真空》辰縮，所得粗產物用石夕膠管柱展析（溶劑：己烷/乙酸乙酯=88/12至70/30)進行純化，得到卜苯甲氧羰基-4-甲氧基六氫吼啶（622毫克，產率45⑽呈淡黃色油狀物。 MS(APCI)m/z ： 250[M+H]+ (2)將10%Ιε-碳（80毫克）加至上述步驟（i)所得化人 318695 157 200804294 物（620毫克）之甲醇（20毫升）溶液中，在氫氣環境下室溫攪拌混合物3小時。以膜過濾器過濾反應混合物，濾液經真空濃縮，得到4-甲氧基六氫吡啶（29〇毫克，產率1〇〇%) 呈淡黃色油狀物。 MS(APCI)m/z ·· 116[M+H] + 參考例11 (1) 冰冷卻下，將二羧酸三級丁酯（68· 8克）加至丨一苯曱基-4-胺基六氫吡啶（57·丨克）之二氯曱烷（3〇〇毫升）溶液中，室溫攪拌混合物3日。反應混合物經真空濃縮，將乙酸乙酯與碳酸氫鈉水溶液加至殘留物中。攪拌混合物，有機層以鹽水清洗，以硫酸鎂乾燥後過濾。濾液經真空濃縮，所得粗晶體以異丙醚清洗，然後過濾收集。濾液經真空浪縮，所得粗晶體以異丙醚清洗，然後過濾收集。合併所收集粗晶體，乾燥後得到卜苯曱基—4—(三級丁氧羰胺基六氳吡啶（83.2克，產率96%)呈淡黃色固體。 MS(APCI)m/z : 291[M+H]+ (2) 將20%鈀-碳（17· 5克）加至上述步驟（丨）所得化人物（72· 6克）之甲醇（350毫升）溶液中，在氫氣環境下室"溫攪拌混合物一夜。以膜過濾器過濾反應混合物，濾液經直空濃縮，得到4-(三級丁氧羰基）胺基六氫吡啶（48 3克了產率96%)呈淡黃色固體。 MS(APCI)m/z ： 201[M+H]+ (3) 將三乙胺（5· 23毫升）加至上述步驟（2)所得化合物（5· 0克）之二氯曱烷（50毫升）溶液中，接著在冰冷^下 318695 ㉓ 158 200804294 加入乙磺醯氯（2. 36毫升）。在相同溫度下攪拌混合物3〇，分麵。回/JHL至至溫後，真空濃縮反應混合物，將三氯甲烧與碳酸氫鈉水溶液加至殘留物中。攪拌後，有機層以硫酸鎂乾燥，然後過濾。濾液經真空濃縮，所產生晶體以異丙醚再結晶，得到4-(三級丁氧羰基）胺基-丨-乙磺醯基六氫口比11疋（6·99克’產率96%)呈淡黃色固體。 MS(APCI)m/z ： 291[M+H]+ (4)將4NHC1-二D弓烷（23·3毫升）與甲醇（5毫升）加至上述步驟（3)所得化合物中，室溫攪拌混合物一夜。將四氳呋喃與2Ν氫氧化鈉水溶液加至反應混合物中進行中和。加入碳酸鉀使混合物飽和，以四氫呋喃萃取。萃取液經真空濃縮，殘留物以三級丁醇溶解，然後冷凍乾燥，得到4一胺基-1-乙磺醯基六氫吡啶（4· 20克，產率94%)呈淡紅色粉末。 MS(APCI)m/z ： 193[M+H]+ 參考例12 (1)在室溫，將乙酸鈉（3·28克）與羥胺鹽酸鹽（1.81 克）加至4-四氫硫代哌喃酮（2· 32克）之乙醇（1〇〇毫升）溶液中，在相同溫度下攪拌混合物2小時。反應混合物經^ 空濃縮，將乙酸乙酯與碳酸氫鈉水溶液加至殘留物中。攪拌後，混合物以乙酸乙酯萃取，有機層以鹽水清洗，以硫酸鎂乾燥後過濾。濾液經真空濃縮，得到4 —四氫硫代哌喃肟（4-tetrahydrothiopyrane 0Xime)(2.53 克，產率 96%) 呈無色固體。 318695 159 200804294 MS(APCI)m/z ： 132[M+H]+ (2)冰冷卻下、氮氣環境中，將氫化鋁鋰（289毫克）加至上述步驟（1)所得化合物（5〇〇毫克）之乙醚（10毫升）溶 •液中’在相同溫度下混合物30分鐘，接著在室溫授摔 1小時。再將氫化鋁鋰（72毫克）加至反應混合物中，4〇它授拌混合物2小時。將水（1毫升）與2N氫氧仙水溶液（1 毫升）加至反應混合物巾。㈣後，时藻JL(Gelite)過遽混合物，濾、液經真空濃縮，得到4_四氫硫代㈣基胺（15〇晕克’產率34%)呈黃色液體。 MS(APCI)m/z ： 118[M+H]+ 參考例13 將20%二氯化鈦水溶液（413毫升）加至4_亞硝基硫代嗎福琳（17. 6克）之水（5毫升）溶液中，室溫㈣混合物35 小時。將碳酸鉀加至反應混合物中進行鹼化，然後過濾混合物。將三氯甲烷加至濾液中，攪拌混合物。有機層以鹽水清洗，以硫酸鎂乾燥後過遽。濾液經真空濃縮，得到4_ 胺基硫代嗎福啉（10. 14克，產率64. 5%)呈淡黃色黏稠物。在该產物（7. 57克）三氯甲烷（1〇毫升）溶液中，加入 ΗΠ-二Df烧（Π. 6毫升）錢拌。真空濃縮反應混合物，所產生晶體以異丙趟-己烧清 >先，乾燥後得到4_胺基硫代嗎福啉鹽酸鹽（6· 3克，產率63· 6%)呈粉末。 MS(APCI)m/z ： 119[M-HC1]+ 參考例14 (1)將2N氫氧化納水溶液（7· 6毫升）加至4, 4-二氟六 318695 160 200804294 ^比唆鹽酸鹽（2.0克）之水（32毫升）溶液中，室溫攪拌混 1^、時。冰冷卻下，將亞硝酸納（1.75克）加至反應混 ° +，/然後加入乙酸（1.27毫升）。室溫攪拌混合物2小時。接著加入碳酸氫鈉水溶液並攪拌，混合物以三氯甲烷萃^萃取液Μ酸鎂賴，然後過濾。濾液經真空濃縮所付粗產物用石夕膠管柱層析（溶劑：己烧/乙酸乙醋W1) 進行，’’屯化得到4, 4-二氟-1-亞硝基六氫吡啶（丨.89克，產率99%)呈淡黃色固體。 MS(APCI)m/z ·· 151 [Μ+ΗΓ (2)冰冷卻下，將氫化鋁鋰（837毫克）逐漸加至上述步驟⑴所得化合物（1.89克）之四氫吱喃溶液中，然後加熱迴流混合物1小時。冰冷卻下’將水加至反應混合物中，然後加熱廻流混合物30分鐘。冷卻至室溫後，用矽藻土過濾反應混合物。濾液經真空濃縮，將碳酸氫鈉水溶液與三氯甲烧加至殘留物中。_後，有機層以硫酸納乾燥，、然後過濾。濾液經真空濃縮，得到卜胺基_4,4_二氟六氫吼啶（500毫克，產率29%)呈淡黃色油狀物。 MS(APCI)ra/z ： 137[M+H]+ 參考例15 將/臭化氫水溶液（1 〇毫升）加至參考例9 (1)所得化合物（1· 9克）之乙酸（1〇毫升）溶液中，於8〇。〇攪拌混合物2 小時。將2N氫氧化鈉水溶液（13〇毫升）加至反應混合物中並攪拌，混合物以三氯甲烷萃取。混合物以三氯甲烷萃取。萃取液以1k鎂乾燥，然後過滤。濾液經真空濃縮，所得 318695 161 200804294 粗產物用矽膠管杈層析（溶劑：己烷/乙酸乙酯=70/30至 0/100)與NH-石夕膠管柱層析（chromatorex NH-石夕膠，Fuji Silicia Chem.公司製造，溶劑：己烷/乙酸乙酯=7〇/3〇至 60/40)進行純化，得到3-胺基―丨―（2-氯苯基）-5-(4-氯笨基）-4-甲氧基-ΙΗ-呢唑（353毫克，產率26%)呈淡黃色固體。 MS(APCI)m/z ： 334/336[M+H]+ 參考例16 (1) 將亞硝酸三級丁酯（3· 5毫升）加至4-三級丁氧羰基/、氫σ比哄（1 · 3克）之二氣曱烧（5 〇毫升）溶液中，然後加熱廻流混合物一夜。反應混合物經真空濃縮，所得粗產物用砍膠管柱層析（>谷劑·己燒/乙酸乙g旨：=4 /1至2 /1)進行純化，得到4-三級丁氧羰基-1-亞硝基六氫吡啡（758毫克，產率50%)呈黃色固體。 MS(APCI)m/z : 216[M+H]+ (2) 在室溫，將鋅粉（1· 1克）加至上述步驟（1)所得化合物（730耄克）之甲醇（10毫升）溶液中，然後冰冷卻下，將乙酸（10毫升）逐滴加入，室溫攪拌混合物2小時。過濾反應混合物，將碳酸氫鈉水溶液加至濾液中進行鹼化。攪拌後’混合物以二氯甲纟元卒取。有機層以硫酸納乾燥，然後過濾。漉液經真空濃縮，得到1 —胺基-4-三級丁氧幾美六氫吼啡（730毫克，產率100%)呈淡黃色油狀物。參考例17 參考例3(1)所得化合物以如參考例1(5)至1(6)中所 162 318695 200804294 述之相同方法處理，得到3 —羧基〜〗-(2扣—友# (4-氯苯基）一 4 -甲氧基一；[H-口比唾（2只古太广才土）5 MS(APCI)m/z ： 397/399[M+H]+ 89%)王固體參考例18 參考例1(4)所得化合物（321奢卜一參寺謂所述之相同;f二:= 苯基）5 (4-氣苯基）-3-乙氧羰基〜4-(4—四 … 氧基，然後該產物以如參考例i⑻γ所二基) 處理，得到3,基-Η2'氣苯基 =四虱硫代娘喃基）氧基普対（351毫克，產率_) MS(APCI)m/z ： 449/451[M+H]+ 參考例19 相應起始物以如參考例丨中所述之相同方法處理，得到1，5雙（4-氯苯基）一4 一甲氧基一 lfJ—吡唑一3 一羧酸（3〇克，產率67%)呈固體。 MS(APCI)m/z ： 363/365[M+H]+ 參考例20至43 相應起始物以如參考例1至5之一者中所述之相同方法處理’得到如下表B1所示化合物。 318695 163 200804294 表 Bl(l) :说參考例號碼 R1 R2 物化性質等 20 〇c 固體 MS(APCI):347/349 [M+H]+ 21 ci~〇- 固體 MS(APCI):381/383 [M+H]+ 22 h3coh^— acl 固體 MS(APCI):359/361 [M+H]+ 23 aCF3 固體 MS(APCI):397/399 [M+H]+ 24 cc 固體 MS(APCI):354/356 [M+H]+ 25 aF 固體 MS(APCI):347/349 [M+H]+ 26 nchQ- acl 固體 MS(APCI):354/356 [M+H]+ 164 318695 200804294 表 Bl(2) :说參考例號碼 R1 R2 物化性質等 27 clj〇^ 固體 MS(ESI):429/431 [Μ-ΗΓ 28 双固體 MS(ESI):413/415 [Μ-ΗΓ 29 OCh3 固體 MS(APCI):359/361 [M+H]+ 30 H3C02S-^l·- (Xa 固體 MS(APCI):407/409 [M+Hf 165 318695 200804294 表 Bl(3) R1 PR3 VC/ Ο-α 參考例號碼 R1 R3 物化性質等 31 ci-〇- o 固體 MS(APCI):433/435 [M+H]+ 32 丨α普 -(CH2)2SCH3 粉末 MS(APCI):423/425 [M+H]+ 33 F3CHW^ -chf2 粉末 MS(APCI):433/435 [M+H]+ 34 Cl~ -c2h5 固體 MS(APCI):377/379 [M+H]+ 35 F3CH〇- -C2H5 固體 MS(APCI):411/413 [M+H]+ 36 ci^Q~ <CH2)2OCH3 固體 MS(APCI):407/409 [M+H]+ 37 p3c-〇^ -(CH2)2OCH3 固體 MS(APCI):441/443 [M+HJ+ 38 ChH0~ _c3h7 固體 MS(APCI):391/393 [M+H]+ 166 318695 200804294 表 Bl(4) ^^n"n/dh Ο-α 參考例 3虎碼 R3 物化性質等 39 9 ,ch3 iv 固體 MS(APCI):456/458 [M+H]+ 40 -chf2 下列步驟中，各化合物作為起始物使用而未經進一步純化。 41 42 -\/CH3 h3c4> 43 hT3 參考例44 冰冷卻下，攪拌1-胺基環己基羧酸（600毫克）之四氫咬σ南-曱醇溶液。然後逐滴加入（三曱基石夕烧基）重氮曱烧溶液（4. 2毫升），攪拌混合物一夜。真空濃縮反應混合物，將乙醚-己烷（1 /1)加至殘留物中。接著加入4Μ HC1 -乙酸乙酯（1.05毫升），過濾收集沉澱物，然後乾燥，得到1-胺基-1-曱氧羰基環己烷。（423毫克，產率52%)呈白色粉末。 167 318695 200804294 MS(APCI)m/z ： 158[M+H]+ .參考例45 (1)將四氫硫代哌喃-4-酮（l〇克）之甲醇（22亳升）溶 …液加至氰化鉀（5· 6克）與氯化銨（5· 06克）之水（17毫升）溶液中’然後混合物加熱避流一夜。冷卻至室溫後，將1N 氫氧化鈉水溶液加至反應混合物中。混合物以乙醚萃取，有機層以硫酸鎂乾燥後過濾。濾液經真空濃縮，然後在殘留物之乙醚溶液中加入4N ΗΠ-乙酸乙酯。過濾收集沉澱物，得到4-胺基-4-氰基四氫硫代哌喃鹽酸鹽（丨3· 6克，產率88%)呈無色固體。 MS(ESI)m/z ： 143[M+H]+ (2) 使上述步驟（1)所得化合物（ι〇· 5克）之jjCl水溶液（500毫升）加熱廻流一夜。冷卻至室溫後，真空濃縮反應混合物。殘留物經乾燥，得到4-胺基四氫硫代哌喃一4一羧酸根鹽酸鹽（10· 6克）呈粗產物。 MS(ESI)m/z : 162[M+H]+ (3) 將亞硫醯氯（5 · 7毫升）逐漸滴加至上述步驟（2)所得化合物（10· 6克）之曱醇（70毫升）溶液中，然後加熱廻流混合物一夜。冷卻至室溫後，真空濃縮反應混合物。殘留物以乙酸乙酯-乙醚清洗，然後加入1Ν氫氧化鈉水溶液。混合物以二氣曱烧萃取，有機層以硫酸鎂乾燥，然後過慮。濾液經真空、/辰縮，得到4-胺基-4-曱氧幾基四氫疏代派喃 (3· 83克，產率39%)呈棕色油狀物。 MS(ESI)m/z ： 176[M+H]+ 318695 168 200804294 - (4)將間氯過苯甲酸（394毫克）逐漸加至上述步驟（3) -所得化合物（100毫克）之二氯f烷（4毫升）溶液中，室溫授拌混合物30分鐘。將甲醇（4毫升）加至反應混合物中級^ •後逐漸加入PL-HCOsMP(巨多孔性聚合物鍵結等當量HC(r3) -樹脂（0· 9克），攪拌混合物一夜。過濾反應混合物，濾液經真空濃縮。所得粗產物用矽膠管柱層析（溶劑··己烷/乙酸乙酯=30/70至0/100)進行純化，得到4-胺基-4—甲氧羰基-1，1-二側氧基四氫硫代哌喃（38毫克，產率32%)呈無色固體。 … MS(ESI)m/z ： 208[M+H]+ 參考例46 相應物質以如參考例45(1)至45(3)中所述之相同方法處理，得到4-胺基-4-甲氧羰基四氫哌喃呈白色晶體。 MS(ESI)ra/z ： 160[M+H]+ 參考例47 (1)在室溫，將2N(三甲基矽烷基）重氮甲烷—乙醚溶液 (8· 8耄升）滴加至丨―三級丁氧羰基—4—羧基_4—苯基六氫吡唆（1.53克）之四氫呋喃（2毫升）一曱醇（2亳升）溶液中，在相同/m度下攪拌混合物3小時。將飽和碳酸氫鈉水溶液加至反應混合物中並攪拌，混合物以三氯曱烷萃取。萃取液以硫酸鎮乾燥，然後過濾。濾液經真空濃縮，所得粗產物用石夕膠管柱層析（溶劑：己烷/乙酸乙酯=90/10至85/15) 進行純化，得到卜三級丁氧羰基—4—甲氧羰基—4—苯基六氫吡啶（1· 31克，產率82%)呈無色固體。 169 318695 200804294 MS(APCI)m/z ： 220[M+H]' _ (2)將4N HC1 -二嗜烧（3毫升）加至上述步驟（i )所得化合物之二噚烷（2毫升）溶液中，室溫攪拌混合物丨小時。再將4N HC1 -二_院（2毫升）加至反應混合物中，室溫攪拌混合物2小時。冰冷卻下，將飽和碳酸氫鈉水溶液加至反應混合物中並攪拌，混合物以三氯曱烷萃取。萃取液以硫酸鎂乾燥，然後過濾。濾液經真空濃縮，將水（5毫升）、亞硝酸鈉（276毫克）與乙酸d 72微升）加入殘留物中，室溫攪拌混合物一夜。將飽和碳酸氫鈉水溶液加至反應混合物中並棍拌，混合物以三氯甲炫萃取。萃取液經真空濃縮，所得粗產物用矽膠管柱層析（溶劑··己烷/乙酸乙酯=85/15 至75/25)進行純化，然後所得產物以曱醇（3毫升）稀釋。冰冷部下’加入鋅粉（654毫克），然後滴加乙酸（3毫升），室溫攪拌混合物2小時。過濾反應混合物，將飽和碳酸氳鈉水溶液加至濾液中。攪拌後，混合物以三氯甲烷萃取，萃取液以硫酸鎂乾燥，然後過濾。濾液經真空濃縮，得到卜胺基-4-甲氧羰基-4-苯基六氫π比啶（389毫克，產率83%) 呈無色固體。 MS(APCI)ra/z ： 235[M+H]+ 參考例48 將亞硝酸鈉（276毫）與乙酸（201微升）加至4-乙氧羰基一 4-苯甲基六氫吼啶（495毫克）之水（5毫升）溶液中，室溫擾拌混合物一夜。將飽和碳酸氫鈉水溶液加至反應混合物中並攪拌混合物，混合物以三氯甲烷萃取。萃取液經真 170 318695 200804294 空濃縮，所得粗產物用石夕膠管柱層析（溶劑：己烧/乙酸乙酯=85/15至80/20)進行純化，然後乾燥，得到[乙氧羰基4苯甲基-卜亞硝基六氫吼咬（565毫克，產率⑽％)呈無色固體。冰冷卻下，將鋅粉（654毫克）加至該產物（565 亳克）之甲醇（3毫升）溶液中，然後加入乙酸（3毫升），室溫攪拌混合物3小時。過濾反應混合物，濾液經真空濃縮。將飽和碳酸氫納水溶液與三氯甲燒加至殘留物中並授摔混 α物犯σ物以：氯甲烧萃取。萃取液以硫酸鎮乾燥，然 :過濾：濾液經真空濃縮，得到卜胺基_4_苯甲基_4_乙氧羰基六氫吡啶（5〇8亳克，產率97%)呈無色黏稠物。 MS(APCI)m/z ： 263[M+H]+ 參考例49 麥考例4(1)所得化合物以如參考例1(5)至ι(6)中所述之相同方法處理，得到3-縣+ (2_氯苯基）_5 —(4二氟甲基苯基）-41氧基鲁_αι克，產率一固體。 …Ε MS(APCI)m/z ： 397/399[M+H]+ 參考例50至52 相應物質以如參考例i⑴至！⑷中所述之相處理，，然後所得產物以如參相4⑵巾所述之 ^ 理，得到如下表B2所示化合物。 / ； 318695 171 200804294 表B2Reference Example 1Q U) Sodium hydride (360 ml) was added to a solution of benzoyloxycarbonyl-4-hydroxyhexahydropyridine (1.3 g) dimethyl decylamine (1 mM) under ice cooling. The mixture was stirred at room temperature under a nitrogen atmosphere for a few hours. After ice cooling, methylene iodide (374 μl) was added to the reaction mixture, and the mixture was stirred at the same temperature for 1 hour and at room temperature for 2 hours. Water and ethyl acetate were added to the reaction mixture and the mixture was stirred. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was subjected to vacuum distillation, and the obtained crude product was purified by a celite column (solvent: hexane/ethyl acetate = 88/12 to 70/30) to obtain benzyloxycarbonyl-4-methoxy. Hexahydroacridine (622 mg, yield 45 (10) as a pale yellow oil. MS (APCI) m/z: 250 [M+H] + (2) Add 10% Ιε-carbon (80 mg) to the above steps (i) A solution of the obtained product 318695 157 200804294 ( MeOH (MeOH) (MeOH) (MeOH) Methoxy hexahydropyridine (29 〇 mg, yield 〇〇%) was obtained as a pale yellow oil. MS (APCI) m/z ·· 116 [M+H] + Reference Example 11 (1) Under ice cooling Adding a third butyl carboxylic acid ester (68·8 g) to a solution of indolinyl-4-aminopyridinium (57·g) in dichlorodecane (3 mL). The mixture was stirred at room temperature for 3 days. The mixture was evaporated. The liquid was concentrated in vacuo, and the obtained crude crystals were washed with isopropyl ether and then collected by filtration. The filtrate was subjected to vacuum filtration, and the obtained crude crystals were washed with isopropyl ether and then collected by filtration. The collected crude crystals were combined and dried to give —4—(Tri-tert-butyloxycarbonylaminopyridinium pyridine (83.2 g, yield 96%) as a pale yellow solid. MS (APCI) m/z: 291 [M+H]+ (2) 20% palladium - Carbon (17.5 g) was added to a solution of the above-mentioned step (丨) of the obtained character (72·6 g) in methanol (350 ml), and the mixture was stirred under a hydrogen atmosphere for one night. Filtered with a membrane filter. The reaction mixture was concentrated with EtOAc (EtOAc m.) +H]+ (3) Triethylamine (5. 23 ml) was added to a solution of the compound obtained in the above step (2) (5.0 g) in dichloromethane (50 ml). 23 158 200804294 Add ethanesulfonyl chloride (2. 36 ml). Stir the mixture at the same temperature for 3 〇, face the dough. Return / JHL to the temperature, concentrate in a vacuum and mix. To the residue, trichloromethane and aqueous sodium hydrogencarbonate were added to the residue. After stirring, the organic layer was dried over magnesium sulfate and then filtered. The filtrate was concentrated in vacuo and crystals were crystallised from isopropyl ether to give 4-( The tertiary butyloxycarbonyl)amino-indole-ethanesulfonyl hexahydro port was light yellow solid at 11 疋 (6·99 g 'yield 96%). MS (APCI) m/z: 291 [M+H [+4] To a compound obtained in the above step (3), 4NHC1-di-D-hexane (23·3 ml) and methanol (5 ml) were added, and the mixture was stirred overnight at room temperature. Tetrahydrofuran and 2 Torr aqueous sodium hydroxide solution were added to the reaction mixture for neutralization. The mixture was saturated with potassium carbonate and extracted with tetrahydrofuran. The extract was concentrated in vacuo, and the residue was crystallised eluted eluted with EtOAc (EtOAc) MS (APCI) m/z : 193 [M+H] + Reference Example 12 (1) sodium acetate (3·28 g) and hydroxylamine hydrochloride (1.81 g) were added to 4-tetrahydrogen In a solution of heptanone (2.22 g) in ethanol (1 mL), the mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated in vacuo to give ethyl acetate and aqueous sodium hydrogen sulfate. After the mixture was stirred, the mixture was extracted with ethyl acetate. The filtrate was concentrated in vacuo to give 4-tetrahydrothiopyrane 0Xime (2.53 g, yield 96%) as a colourless solid. 318695 159 200804294 MS(APCI)m/z : 132[M+H]+ (2) Lithium aluminum hydride (289 mg) was added to the compound obtained in the above step (1) under ice cooling under nitrogen atmosphere (5 〇〇) (Mg) of diethyl ether (10 ml) dissolved in a solution of the mixture at the same temperature for 30 minutes, followed by a drop of 1 hour at room temperature. Further, lithium aluminum hydride (72 mg) was added to the reaction mixture, and the mixture was stirred for 2 hours. Water (1 ml) and 2N aqueous solution of hydroxyhydrogen (1 ml) were added to the reaction mixture. (4) After the algae JL (Gelite) was passed through the mixture, the filtrate and the solution were concentrated in vacuo to give 4-tetrahydrothio(tetra)amine (15% sm. yield: 34%) as a yellow liquid. MS (APCI) m/z: 118 [M+H] + Reference Example 13 A 20% aqueous solution of titanium dichloride (413 ml) was added to the water of 4 nitroso-thio- phenofoline (17.6 g) (5 ml) solution, room temperature (tetra) mixture for 35 hours. Potassium carbonate was added to the reaction mixture for alkalization, and then the mixture was filtered. Trichloromethane was added to the filtrate and the mixture was stirred. The organic layer was washed with brine, dried over magnesium sulfate and dried. The filtrate was concentrated in vacuo to give 4-amine thiophenoline (10. 14 g, yield 64.5%) as pale yellow viscous. Into a solution of this product (7.51 g) in chloroform (1 ml), ΗΠ-di Df (Π. 6 ml) was added and mixed. The reaction mixture was concentrated in vacuo, and the crystals obtained were purified by isopropyl hexane-hexane. <RTI ID=0.0>>&&&&&&&&&&&&&&& . MS (APCI) m/z : 119 [M-HC1] + Reference Example 14 (1) 2N aqueous sodium hydroxide solution (7.6 mL) was added to 4, 4-difluoro-6318695 160 200804294 ^ A solution of salt (2.0 g) in water (32 ml) was stirred at room temperature for 1 °. Under ice cooling, sodium nitrite (1.75 g) was added to the reaction mixture, and then acetic acid (1.27 ml) was added. The mixture was stirred at room temperature for 2 hours. Next, an aqueous solution of sodium hydrogencarbonate was added and stirred, and the mixture was extracted with chloroform, and the mixture was filtered. The filtrate was concentrated in vacuo and the crude product was chromatographed on silica gel column (solvent: hexanes/ethyl acetate EtOAc), and sulphurized to give 4, 4-difluoro-1-nitrosodium hexahydropyridine (丨) .89 g, yield 99%) was a pale yellow solid. MS (APCI) m/z ·· 151 [Μ+ΗΓ (2) Lithium aluminum hydride (837 mg) was gradually added to the tetrahydrofuran solution of the compound obtained in the above step (1) (1.89 g) under ice cooling, and then The mixture was heated to reflux for 1 hour. Water was added to the reaction mixture under ice cooling, and then the turbulent mixture was heated for 30 minutes. After cooling to room temperature, the reaction mixture was filtered through Celite. The filtrate was concentrated in vacuo, and aqueous sodium bicarbonate and trichloromethane were added to the residue. After _, the organic layer was dried over sodium sulfate and then filtered. The filtrate was concentrated in vacuo to give EtOAc EtOAc (EtOAc: EtOAc) MS (APCI)ra/z : 137 [M+H] + Reference Example 15 An aqueous solution of hydrogen peroxide (1 mL) was added to the acetic acid (1 9) of the compound (1·9 g) obtained in Reference Example 9 (1). In ML) solution, at 8 〇. The mixture was stirred for 2 hours. A 2 N aqueous sodium hydroxide solution (13 ml) was added to the reaction mixture and stirred, and the mixture was extracted with chloroform. The mixture was extracted with chloroform. The extract was dried over 1 k of magnesium and then filtered. The filtrate was concentrated in vacuo to give 318 695 161 200804294 crude product eluted with hydrazine gel (solvent: hexane / ethyl acetate = 70/30 to 0/100) and NH-Shixi gum column chromatography (chromatorex NH-Shi Xi Glue, manufactured by Fuji Silicia Chem., solvent: hexane/ethyl acetate = 7 〇 / 3 Torr to 60 / 40), purified to give 3-amino-indole-(2-chlorophenyl)-5-( 4-Chlorophenyl)-4-methoxy-indole-triazole (353 mg, yield 26%) was obtained as a pale yellow solid. MS (APCI) m/z : 334 / 336 [M + H] + Reference Example 16 (1) Adding butyl nitrite (3.5 ml) to 4-tertiary butoxycarbonyl/hydrogen σ ratio哄 (1 · 3 g) in a gas-burning (5 〇 ml) solution, then heat the turbulent mixture overnight. The reaction mixture is concentrated in vacuo, and the obtained crude product is purified by <RTI ID=0.0>>&&&&&&&&&&&&&&&&&&&&&&&&&&&& 1-Nitrosohexahydropyridin (758 mg, yield 50%) was obtained as a yellow solid. MS (APCI) m/z: 216 [M+H] + (2) Zn (1·1 g) was added to the compound obtained in the above step (1) (730 g) methanol (10 ml) The solution was then added dropwise with ice-cooling, and acetic acid (10 ml) was added dropwise, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered, and an aqueous sodium hydrogencarbonate solution was added to the filtrate to be basified. After the agitation, the mixture was drawn with methylene chloride. The organic layer was dried over sodium sulfate and then filtered. The mash was concentrated in vacuo to give 1-amino-4-tris-butoxy hexahydroquinone (730 mg, yield 100%) as a pale yellow oil. Reference Example 17 The compound obtained in Reference Example 3 (1) was treated in the same manner as described in Reference Example 1 (5) to 1 (6), 162 318695 200804294, to give 3-carboxyl----(2-cluster-you# (4) -Chlorophenyl)-4-methoxy-one; [H-port than saliva (2 Gutaiguangcai) 5 MS(APCI)m/z: 397/399[M+H]+ 89%) Wang Solid Reference Example 18 The compound obtained in Reference Example 1 (4) (321 is the same as that described in the first step; f 2: = phenyl) 5 (4-phenylphenyl)-3-ethoxycarbonyl~4-( 4-tetra(oxy), then the product is treated as the reference i (8) γ-diyl group to give 3, benzyl-hydrazine 2' phenyl phenyl = tetrathracene thio- yloxy) oxime (351 mg, yield _) MS (APCI) m/z: 449 / 451 [M+H] + Reference Example 19 The corresponding starting material was treated in the same manner as described in the Reference Example to give 1,5 bis(4-chlorophenyl). A 4-methoxy-l-pyrazole-3-carboxylic acid (3 g, yield 67%) was solid. MS (APCI) m/z: 363/365 [M+H] + Reference Examples 20 to 43 The corresponding starting materials were treated in the same manner as described in one of Reference Examples 1 to 5 to obtain the following Table B1. Compound. 318695 163 200804294 Table Bl(l): Refer to reference number R1 R2 Physicochemical properties, etc. 20 〇c Solid MS (APCI): 347/349 [M+H]+ 21 ci~〇- Solid MS (APCI): 381/383 [M+H]+ 22 h3coh^— acl Solid MS (APCI): 359/361 [M+H]+ 23 aCF3 Solid MS (APCI): 397/399 [M+H]+ 24 cc Solid MS (APCI) :354/356 [M+H]+ 25 aF Solid MS (APCI): 347/349 [M+H]+ 26 nchQ- acl Solid MS (APCI): 354/356 [M+H]+ 164 318695 200804294 Bl(2): said reference example number R1 R2 physicochemical properties, etc. 27 clj〇^ Solid MS (ESI): 429/431 [Μ-ΗΓ 28 Double solid MS (ESI): 413/415 [Μ-ΗΓ 29 OCh3 solid MS (APCI): 359/361 [M+H]+ 30 H3C02S-^l·- (Xa Solid MS (APCI): 407/409 [M+Hf 165 318695 200804294 Table Bl(3) R1 PR3 VC/ Ο-α Reference example number R1 R3 Physicochemical properties, etc. 31 ci-〇- o Solid MS (APCI): 433/435 [M+H]+ 32 丨α普-(CH2)2SCH3 Powder MS (APCI): 423/425 [M+ H]+ 33 F3CHW^ -chf2 Powder MS (APCI): 433/435 [M+H]+ 34 Cl~ -c2h5 Solid MS (APCI): 377/379 [M+H]+ 35 F3CH〇- -C2H5 Solid MS (APCI): 411/413 [M+H]+ 36 ci^Q~ <CH2)2OCH3 Solid MS (APCI): 407/409 [M+H]+ 37 p3c-〇^ -(CH2)2OCH3 solid MS (APCI):441/443 [M+HJ+ 38 ChH0~ _c3h7 solid MS (APCI):391/393 [M+H] + 166 318695 200804294 Table Bl(4) ^^n"n/dh Ο-α Reference Example 3 Tiger Code R3 Physicochemical Properties, etc. 39 9 ,ch3 iv Solid MS (APCI): 456/458 [M+H]+ 40 - Chf2 In the following procedure, each compound was used as a starting material without further purification. 41 42 -\/CH3 h3c4> 43 hT3 Reference Example 44 A solution of 1-aminocyclohexylcarboxylic acid (600 mg) in tetrahydron sigma-nonanol was stirred under ice cooling. Then, a solution of diazonium hydride (4.2 ml) was added dropwise (trimethyl sulfonate), and the mixture was stirred overnight. The reaction mixture was concentrated in vacuo and diethyl ether-hexane (1 /1) Then, 4 Μ of HCl-acetic acid ethyl ester (1.05 ml) was added, and the precipitate was collected by filtration, and then dried to give 1-amino-1- yloxycarbonylcyclohexane. (423 mg, yield 52%) as a white powder. 167 318695 200804294 MS (APCI) m / z : 158 [M + H] + . Reference Example 45 (1) tetrahydrothiopiperazin-4-one (l gram) of methanol (22 liters) dissolved ... The solution was added to a solution of potassium cyanide (5.6 g) and ammonium chloride (5.06 g) in water (17 ml) and the mixture was heated to avoid overnight. After cooling to room temperature, 1 N aqueous sodium hydroxide solution was added to the reaction mixture. The mixture was extracted with diethyl ether. The filtrate was concentrated in vacuo and then 4N EtOAc-EtOAcEtOAc. The precipitate was collected by filtration to give 4-amino-4-cyanotetrahydrothiopyran hydrochloride (3. 6 g, yield 88%) as a colorless solid. MS (ESI) m/z: 143 [M+H] + (2) The compound of the above step (1) (1 gram) of jjCl aqueous solution (500 ml) was heated and turbulent overnight. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was dried to give 4-aminotetrahydrothiopyran-4-carboxylate hydrochloride (10.6 g) as crude. MS (ESI) m/z: 162 [M+H] + (3) thiol chloride (5·7 ml) was gradually added dropwise to the compound obtained in the above step (2) (10·6 g) of sterol ( In a solution of 70 ml), the turbulent mixture was then heated overnight. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was washed with ethyl acetate-diethyl ether and then 1 aqueous sodium hydroxide. The mixture was extracted with a gas purge, and the organic layer was dried over magnesium sulfate and then evaporated. The filtrate was vacuumed to give 4-amino-4-indoleoxytetrahydropyran (3·83 g, yield 39%) as a brown oil. MS (ESI) m / z: 176 [M+H] + 318 695 168 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> The mixture was stirred at room temperature for 30 minutes in a solution of f-hexane (4 mL). Methanol (4 ml) was added to the intermediate of the reaction mixture. Then, PL-HCOsMP (macroporous polymer bond equivalent of HC(r3)-resin (0.9 g) was gradually added, and the mixture was stirred overnight. The reaction mixture was filtered. The filtrate was concentrated in vacuo, and the obtained crude material was purified eluting with EtOAc EtOAc EtOAc EtOAc 1-Di-tertiary oxytetrahydrothiopyran (38 mg, yield 32%) was obtained as a colorless solid. MS (ESI) m/z: 208 [M+H] + Reference Example 46 Treatment with the same method as described in 45 (1) to 45 (3) gave 4-amino-4-methoxycarbonyltetrahydropyran as a white crystal. MS (ESI) / s: 160 [M+H] + Reference Example 47 (1) 2N (trimethyldecyl)diazomethane-diethyl ether solution (8·8 liter) was added dropwise to 丨-tertiary butoxycarbonyl-4-carboxyl_4 at room temperature. To a solution of phenylhexahydropyridinium (1.53 g) in tetrahydrofuran (2 ml) in decyl alcohol (2 liters), the mixture was stirred for 3 hours at the same /m. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture. Stir, the mixture is three Extraction with decane. The extract was dried with sulphuric acid and then filtered. The filtrate was concentrated in vacuo and the crude product was purified using EtOAc (EtOAc: EtOAc/EtOAc: The third-order butoxycarbonyl-4-methoxycarbonyl-4-phenylhexahydropyridine (1.31 g, yield 82%) was obtained as a colorless solid. 169 318695 200804294 MS (APCI) m/z : 220 [M +H]' _ (2) To a solution of the compound obtained in the above step (i) in dioxane (2 ml) was added 4N EtOAc (2 mL). - __ (2 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Under ice cooling, a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and stirred, and the mixture was extracted with trichloromethane. The mixture was dried with MgSO4, EtOAc. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and the mixture was stirred, and the mixture was extracted with trichloromethane. The extract was concentrated in vacuo, and the obtained crude material was purified by EtOAc EtOAc EtOAc EtOAc Zinc powder (654 mg) was added under ice cooling, then acetic acid (3 ml) was added dropwise, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered, and a saturated aqueous solution of sodium carbonate was added to the filtrate. After stirring, the mixture was extracted with chloroform, and the extract was dried over magnesium sulfate and then filtered. The filtrate was concentrated in vacuo to give EtOAc (EtOAc: EtOAc) MS (APCI)ra/z: 235 [M+H] + Reference Example 48 Sodium nitrite (276 s) and acetic acid (201 liters) were added to 4- ethoxycarbonyl- 4-phenylmethylhexahydroacridine (495 mg) in water (5 ml) was stirred at room temperature overnight. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and the mixture was stirred, and the mixture was extracted with chloroform. The extract was concentrated by vacuum at 170 318695 200804294, and the obtained crude product was purified by chromatography on silica gel column (solvent: hexane/ethyl acetate = 85/15 to 80/20), and then dried to give [ethoxycarbonyl 4 Benzyl-bunitrosohexahydropurine (565 mg, yield (10%)) was a colorless solid. Zinc powder (654 mg) was added to a solution of the product (565 g) in methanol (3 ml), and then acetic acid (3 ml) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. A saturated aqueous solution of sodium hydrogencarbonate and trichloromethane were added to the residue and the mixture was allowed to be mixed with α. The extract was dried with sulphuric acid, then: filtered: the filtrate was concentrated in vacuo to give <RTI ID=0.0>> Things. MS (APCI) m/z : 263 [M+H] + Reference Example 49 The compound obtained in the study of Example 4 (1) was treated in the same manner as described in Reference Examples 1 (5) to (6) to obtain 3 - County + (2_chlorophenyl)_5 - (4 difluoromethylphenyl)-41oxylu_αι克, yield one solid. ...Ε MS(APCI)m/z : 397/399[M+H]+ Reference Examples 50 to 52 The corresponding substances are as in Reference Example i(1) to! The phase treatment described in (4), and then the obtained product is obtained as described in the reference phase 4 (2), to give the compound shown in the following Table B2. / ; 318695 171 200804294 Table B2

Rl 严2 參考例號碼 R1 R2 50 C办〇ς 51 F3CHQ- λ 52 F3c^T ^---；-- XX 白色固體 MS(APCI):399/401 [Μ+Η]+ 白色固體 MS(APCI):467/469 [M+Hf 淡黃色固體 MS(APCI):451/453 [Μ十 H]+ 物化性質等參考例53 (1)冰冷卻下，將乙胺鹽酸鹽（2· 69克）之水（3毫升）溶液滴加至卜苯曱基六氫咄啶—4—嗣（5· 69克）之乙醇（4· 2 毫升）溶液中’然後滴加入氰化卸（2· 〇4克）之水（7毫升）溶液’室溫攪拌混合物一夜。將異丙醇（1 〇毫升）與水（3〇毫升）加至反應混合物中，攪拌混合物然後萃取。將水（3〇毫升）加至有機層，攪拌混合物然後萃取。有機層以二氯甲烷（30毫升）稀釋，以鹽水清洗，以硫酸鎂乾燥後過濾。濾液經真空濃縮，將異丙醇（1〇〇毫升）加至殘留物中，濾去沉殿物。濾液經真空濃縮，得到卜苯甲基—4-氰基—4-乙胺基六氫吡啶（7· 3克，產率99· 7%)呈黃色油狀物。 172 31S695 200804294 MS(APCI)m/z ： 244[M+H]+ (2 )冰冷卻下，以超過2 〇公籍夕n士 m • _ , λ 刀知之妆間’將濃硫酸（4. ί 宅升）滴，至上述步驟（1)所得化合物（138克）之二氯甲燒（4.8毫升）溶液中，室溫授掉混合物—夜物中萃取出有機層，然後冰冷卻下，以超W小時之二夺間口，將28%氨水溶液滴加至有機層中。將水（12亳升）加至反應混合物中，混合物以m萃取。有機層以鹽水清洗y 以硫酸鎂乾燥後過濾。濾液經真空濃縮，得到卜苯甲基—4 一胺甲醯基-4-(乙胺基）六氫t定（1·44克，產率97%)呈淡普色固體。 ^ MS(APCI)m/z ： 262[M+H]+ (3)將20%風氧化纪-碳加至上述步驟（2)所得化合物 (1.4克）之曱醇（19毫升）溶液中，然後在氮氣環境下室溫攪拌混合物一夜。用矽藻土過濾反應混合物，濾液經真空濃縮。將異丙醚（30毫升）加至濃縮液中，過濾收集所沉澱晶體，乾燥後得到4-胺甲醯基-4-乙胺基六氫吡啶（〇.84 克，產率91%)呈淡黃色固體。 MS(APCI)m/z ： 172[M+H]+ 試驗例1 人類CB1受體結合分析 (1)人類CB1受體製備（膜部分）材料：人類CB1表現細胞株：hCBl/CH0#C3(Euroscreen公司）培養基：F-12(GIBCO#1 1765_062)，10%胎牛血清，抗 318695 173 200804294 生素[400微克’遺傳黴素 (GIBC0#1181卜031) 缓衝溶液A : 50毫莫耳濃度tris—HCUpH7 5)，含有伸乙基二胺四乙酸（2.5毫莫耳濃度）、％(：12(5毫3莫耳濃度）與蔗糖（200毫莫耳濃度）步驟：培養在上述培養基中之受體表現細胞以鱗酉复緩衝溶液 (χ2)清洗，然後在冰冷卻或4它（以下步驟亦在相同溫度下進行）下添加緩衝溶液Α(2毫升）。用細胞刮棒收集細胞，用微吸取官型超音波振盪器振盪2〇秒（脈衝開：2秒，脈衝關：1秒），然後離心（500 xg，15分鐘）。分離上清液，然後離心（43000 x g，60分鐘）。將產生之沉澱小粒懸浮在緩衝溶液A中，用波特氏（Potter)型均質器均質化。將等體積之80%丙三醇加至均質液中，然後在_8〇。〇保存。 (2)CB1受體結合分析步驟材料：緩衝溶液B : 50毫莫耳濃度tris-HCl(pH7· 5)，含有伸乙基二胺四乙酸（2· 5毫莫耳濃度）、MgCl2(5毫莫耳濃度）與牛血清白蛋白（2毫克/毫升，無脂肪酸， SIGMA-A7030) 緩衝溶液C : 50毫莫耳濃度tris-HCl(pH7. 5)，含有伸乙基二胺四乙酸（2· 5毫莫耳濃度）、MgCl2(5毫莫耳濃度）與牛血清白蛋白（2毫克/毫升，無脂肪酸， SIGMA-A7906) 174 318695 200804294 塗佈溶液：0. 3%乙亞胺聚合物放射性配位子：[3H]-CP55940 [30奈莫耳濃度 (nM)/7992每分鐘衰變數/微升（dpm/ // 1)]，係以緩衝溶液B稀釋8· 3微莫耳濃度（// M)放射性配位子溶液而製得方法：使分析盤（96格孔，Costar編號#3371 )之每一格孔裝有緩衝溶液B (14 0微升）、每一試驗化合物二曱亞;5風溶液 (20微升，終濃度〇· 1%)、放射性配位子（2〇微升）與膜製劑（20微升，〇· 5微克/20微升），然後30°C培養混合物9〇分鐘，以進行結合反應。將反應混合物收集至預先用上述塗佈溶液浸泡之分析盤（Packard Unifilter GF/B， #6005177)每一格孔中。以緩衝溶液（；（200微升}(1〇)清洗分析盤，然後於50°C乾燥1小時，將Microscinti40(40 微升）加至每一格孔中。經結合之放射性標記以閃爍計數器 (TopCount NXT，Packard製造）定量。每一試驗化合物對放射性配位子結合至CB1受體之lC5〇值，係使用Graphpad Prism3.02依據量化之放射標記活性來計算。 (3)結果母试驗化合物之IC5〇值顯示在表C1。當中，表中符號定義如下： + · 1〇〇奈莫耳濃度<IC5。<500奈莫耳濃度 + + : 10奈莫耳濃度<IC5()<i〇〇奈莫耳濃度 + + + :IC5Q<10奈莫耳濃度 318695 175 200804294 表ci 試驗化合物 IC5〇(毫莫耳濃度）實施例4化合物 + + 實施例36化合物 + + 實施例54化合物 + + 實施例5 5化合物 + + 實施例18化合物 ++ 實施例134化合物 + + 實施例148化合物 + + 實施例216化合物 + + 實施例276化合物 + + 實施例279化合物 + + 實施例288化合物 + 實施例307化合物 + + + 實施例339化合物 + + 工業上應用本lx月化5物[I ]可用於治療及/或預防各種eg〗受邀媒介之疾病’例如精神病句莊掉# “甲届包括精神分裂症。本發明化合彩 1=合=曼性治療:酒精依賴或藥物濫用。而且劑。° 用於作為止痛活性料_或戒煙藥 318695 176Rl strict 2 reference example number R1 R2 50 C office 51 F3CHQ- λ 52 F3c^T ^---;-- XX white solid MS (APCI): 399/401 [Μ+Η]+ white solid MS (APCI ): 467/469 [M+Hf Light yellow solid MS (APCI): 451/453 [Μ10H]+ Physicochemical properties, etc. Reference Example 53 (1) Ethylamine hydrochloride (2·69 g) under ice cooling ) water (3 ml) solution was added dropwise to the solution of phenylene sulfhydryl hexahydroacridine 4-(嗣) (5·69 g) in ethanol (4.2 ml) and then added dropwise to cyanide (2· 〇 4 g) of water (7 ml) solution The mixture was stirred at room temperature overnight. Isopropanol (1 ml) and water (3 ml) were added to the reaction mixture, and the mixture was stirred and then extracted. Water (3 ml) was added to the organic layer, and the mixture was stirred and then extracted. The organic layer was diluted with methylene chloride (30 mL), brine and evaporated. The filtrate was concentrated in vacuo and isopropyl alcohol (1 mL) was applied to residue and filtered. The filtrate was concentrated in vacuo to give phenylmethyl- 4-cyano-4-ethylamine hexahydropyridine (7.3 g, yield: 99.7%) as a yellow oil. 172 31S695 200804294 MS(APCI)m/z : 244[M+H]+ (2) Under ice cooling, with more than 2 〇〇 n n m m • _ , λ Knife know the makeup room 'to concentrate sulfuric acid (4. ί 宅)), to the above-mentioned step (1) of the compound (138 g) in a solution of methylene chloride (4.8 ml), the mixture was extracted at room temperature - the organic layer was extracted, and then cooled under ice to The W-hour was taken over the second hour, and a 28% aqueous ammonia solution was added dropwise to the organic layer. Water (12 liters) was added to the reaction mixture, and the mixture was extracted with m. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give the crystals of <RTI ID=0.0>>>>> ^ MS(APCI)m/z: 262 [M+H] + (3) 20% of the oxidized carbon-carbon was added to the solution of the compound obtained in the above step (2) (1.4 g) in methanol (19 ml). The mixture was then stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was filtered through celite, and filtrate was concentrated in vacuo. Diisopropyl ether (30 ml) was added to the concentrate, and the precipitated crystals were collected by filtration, and dried to give 4-amine-carbazyl-4-ethylamine hexahydropyridine (yield: 84 g, yield 91%). Light yellow solid. MS (APCI) m/z : 172 [M+H]+ Test Example 1 Human CB1 receptor binding assay (1) Human CB1 receptor preparation (membrane fraction) Material: Human CB1 expression cell line: hCBl/CH0#C3 ( Euroscreen) Medium: F-12 (GIBCO #1 1765_062), 10% fetal bovine serum, anti-318695 173 200804294 Biotin [400 micrograms of 'geneticmycin (GIBC0#1181 031) buffer solution A: 50 millimoles Concentration tris-HCUpH7 5), containing ethylenediaminetetraacetic acid (2.5 millimolar concentration), % (: 12 (5 mM molar concentration) and sucrose (200 millimolar concentration) Step: Culture in the above medium The receptor-expressing cells were washed with a squamous buffer solution (χ2), and then buffer solution (2 ml) was added under ice cooling or 4 (the following steps were also carried out at the same temperature). The cells were collected with a cell scraper. , oscillate with a micro-absorbent ultrasonic oscillator for 2 sec seconds (pulse on: 2 seconds, pulse off: 1 second), then centrifuge (500 xg, 15 minutes). Separate the supernatant, then centrifuge (43000 xg, 60 Minutes). The precipitated pellets are suspended in buffer solution A, using a Potter type homogenizer. Add an equal volume of 80% glycerol to the homogenate, then store at _8〇.〇 (2) CB1 receptor binding assay step Materials: Buffer solution B: 50 millimolar concentration tris-HCl ( pH7·5), containing ethylenediaminetetraacetic acid (2.5 millimolar concentration), MgCl2 (5 millimolar concentration) and bovine serum albumin (2 mg/ml, no fatty acid, SIGMA-A7030) buffer Solution C: 50 millimolar concentration of tris-HCl (pH 7.5) containing exoethyldiaminetetraacetic acid (2.5 millimolar concentration), MgCl2 (5 millimolar concentration) and bovine serum albumin (2) Mg/ml, no fatty acid, SIGMA-A7906) 174 318695 200804294 Coating solution: 0.3% ethylimine polymer radioactive ligand: [3H]-CP55940 [30 Namol concentration (nM) / 7992 per minute Decay number / microliter (dpm / // 1)], prepared by diluting 8.3 micromolar (//M) radioactive ligand solution with buffer solution B: Method of making analysis plate (96 cells, Each well of Costar No. #3371) is filled with buffer solution B (140 μl), each test compound diterpenoid; 5 wind solution (20 μl, final concentration 〇·1%), radioligand 2〇 microliters) membrane preparations (20 [mu] L, 1.5 billion mu] g / 20 [mu] l), and the mixture is incubated 30 ° C 9〇 minutes to binding reaction. The reaction mixture was collected into each well of an assay disk (Packard Unifilter GF/B, #6005177) previously soaked with the above coating solution. The assay plate was washed with a buffer solution (; (200 μl) (1 μL), then dried at 50 ° C for 1 hour, and Microscinti 40 (40 μL) was added to each well. The combined radioactive label was used as a scintillation counter. (TopCount NXT, manufactured by Packard) Quantitative. The lC5 enthalpy of each test compound binding to the CB1 receptor for the radioligand was calculated using Graphpad Prism 3.02 based on the quantified radiolabeling activity. (3) Results test The IC5 enthalpy of the compound is shown in Table C1, wherein the symbols in the table are defined as follows: + · 1 〇〇 Nemour concentration < IC5. <500 Naimer concentration + + : 10 nmer concentration <IC5( <i〇〇Nemo concentration + + + : IC5Q < 10 Nymol concentration 318695 175 200804294 Table ci Test compound IC5 〇 (mole concentration) Example 4 compound + + Example 36 compound + + Example 54 compound + + Example 5 5 compound + + Example 18 compound ++ Example 134 compound + + Example 148 compound + + Example 216 compound + + Example 276 compound + + Example 279 compound + + Example 288 Compound + Example 307 + + + Example 339 compound + + industrial application of this lx monthly 5 [I] can be used to treat and / or prevent a variety of diseases of the invited media 'such as mental illness sentence Zhuang off # "A session including schizophrenia The invention has the same color: 1 = combined = mann treatment: alcohol dependence or drug abuse. Moreover, the agent is used as an analgesic active material _ or smoking cessation drug 318695 176

Claims

200804294 X. Patent application scope: • 1 · A compound of the formula [I ]11 is a specific compound or a pharmaceutically acceptable salt thereof:

Wherein R1 and R2 are the same or different and are optionally substituted aryl or optionally substituted heteroaryl; R is (a) a hydrogen atom, (b) optionally one to three selected from the group consisting of Alkyl substituted by a group: an atom, a cyano group, an alkyloxy group, an alkyloxycarbonyl group, an amine group substituted with one to two alkyl groups as needed, a decylamino group, an alkylamine-methylamino group, Alkylsulfonylamino, di(alkyl)aminesulfonylamino, optionally substituted with one to two alkyl groups, alkyloxycarbonyl, alkylthio, alkylsulfinyl Alkanesulfonyl and optionally substituted saturated or unsaturated heterocyclic groups, (c) optionally substituted by one to two alkyl groups, or optionally substituted saturated or unsaturated heterocyclic groups Or (e) R3 is bonded to R1 and together with R1, an adjacent oxygen atom and a pyrazole ring form a cyclic group of the formula:

The aryl (or heteroaryl) '-Z-0- is ring A is an optionally substituted group - 〇-(cH〇n-〇- or -N(RG)-(CH2)n+ group R is a gas atom or an alkyl group, an integer of mg! to 3, η is an integer from 2 to 177 318695 200804294 3; and E is one of the following formulas (i) to (iv):

Q1 is a single bond, an alkyl group or a group of the formula -N(R7)-, R7 is a hydrogen atom or an alkyl group, Q2 is a single bond, an oxygen atom or an alkylene group, - R4 is a cycloalkyl group, and the formula -n (r5) a group of (r6), optionally substituted aryl or optionally substituted saturated or unsaturated heterocyclic group, one of R and R6 being a hydrogen atom or an alkyl group and the other being (a An alkyl group which is substituted by the following groups, such as a halogen atom, an amine group, an alkylthio group, an alkylsulfinyl group, an alkanesulfonyl group, and an optionally substituted aryl group, (1)) a substituted cycloalkyl group, (c) a group of the formula -N(R8)(R9), ((1) optionally substituted aryl or (e) optionally substituted saturated or unsaturated heterocyclic group, One of R8 and R9 is a hydrogen atom or an alkyl group and the other is (a) an alkyl group optionally substituted with one or two groups selected from the group consisting of a pendant oxy group, a cyano group, an alkyloxy group, and an anthracene group. And optionally substituted aryl, (b) cycloalkyl ', (C) ii, (4) aryl to be substituted or (e) optionally substituted saturated or unsaturated heterocyclic group, D is an oxygen atom or a group of the formula -NH-, and R is an amine group or the following formula Group: 318695 178 200804294 -lQ:H2)k wherein k is an integer from 3 to 5, RA2 is an optionally substituted aliphatic heterocyclic group, and R is an alkane substituted by one to three halogen atoms as needed a group, an alkyloxy-alkyl group, a decylthio group, an optionally substituted cycloalkyl group, an optionally substituted aryl group or an optionally substituted saturated or unsaturated heterocyclic group. 2. A compound according to claim 1, wherein R1 and R2 are the same or different and (i) 6 to 1 member aryl group substituted by one to three groups selected from the group consisting of halogen atoms. , cyano, alkyl, tris-alkyl, alkyloxy, tri-alkyloxy and alkanesulfonyl, or (丨1) optionally substituted with one to three groups selected from the group consisting of An oxygen-containing, sulfur- or nitrogen-containing heteroaryl group of 6 members: a halogen atom, a cyano group, an alkyl group, a trihaloalkyl group, an alkyloxy group, a trihaloalkyloxy group and an alkanesulfonyl group. 3. The compound of claim 1, wherein the saturated or unsaturated heterocyclic group of r, R3, R4, R, R, R or R9 is (a) a saturated or unsaturated 4S 7 member heterocyclic ring. a heteromonocyclic group containing one to four hetero atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom; (b) a saturated or unsaturated = 8 to 15 membered nitrogen-containing bicyclic or tricyclic heterocyclic group, the hetero The ring system will be a heteromonocyclic group with - or two other ring groups selected from the group consisting of a C38 cycloalkyl group, a 5 to 6 membered monocyclic aryl group, and a saturated or unsaturated 4 to 7 member. '成' the heteromonocyclic group contains! Up to 4 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms; or (c) saturated or unsaturated 8 to 11 318695 179 200804294 nitrogen-containing spiroheterocyclyl. 4. The compound of claim 3, wherein the aryl group of R, R3, R4, RR, R 4R9 is a 6 to 10 membered monocyclic ring which is optionally substituted with one to three groups selected from the group consisting of Bicyclic aryl: (a) dentate atom, (b) #工基, (c) cyano, (d) pendant oxy, (e) alkyl substituted with one to three halogen atoms as desired, (f) Alkyloxyalkyl, (g) aminoalkyl '(h)cycloalkyl, (indenyl)arylalkyl, (j.), if desired, substituted by one to three halogen atoms, k) Fee group substituted by one to two alkyl groups as needed, (1) Amine group substituted by one to two alkyl groups as needed, (m) mercapto group, (n) alkylthio group, (〇) Alkylsulfinyl, (p) alkanesulfonyl, (q) an aminesulfonyl group substituted by one to two alkyl groups, (r) aragonite yellow, (s) aryl, the aryl group It is optionally substituted with one to three groups selected from a halogen atom, a cyano group, an alkyl group substituted with one to three halogen atoms, an alkyloxy group and an alkanesulfonyl group, and (t) a heteroaryl group. 5. A compound according to claim 3, wherein the saturated or unsaturated heterocyclic group of R, R3, R4, R5, R6, R8 or R9 is optionally substituted by one to four groups selected from the group consisting of the following: a saturated or unsaturated heterocyclic group: (a) an S atom, (b) a hydroxyl group, (c) a cyano group, (d) a pendant oxy group, (e) an alkyl group substituted with one to three halogen atoms as required, f) alkyloxyalkyl, (g) aminoalkyl, (h) alkylsulfinylalkyl, (i) alkanesulfonylalkyl, (j) cycloalkyl, (k) aryl An alkyl group, (1) an alkyloxy group substituted with one to three halogen atoms, (m) a carboxyl group, and (η) an amine group optionally substituted with one or two groups selected from an alkyl group and an anthracenyl group, (〇) Aminomercapto group substituted by one to two alkyl groups, (Ρ) fluorenyl group, (q) alkylthio group, (r) 180 318695 200804294 Acrylonitrile, (S) alkane sulfonate The base, (t) is optionally substituted with one to two alkyl groups, and the (V) is optionally one to three k from a halogen atom, a chaotic base, or one to three as needed. a halogen-substituted alkyl group, an alkyloxy group and An aryl group substituted with a group of an alkanesulfonyl group, and (W) a heteroaryl group optionally substituted with one to three alkyl groups selected from the group consisting of an alkyl group substituted with one to three halogen atoms, a halogen atom and a cyano group. . 6. A compound according to claim 5, wherein the fluorenyl group in R, R3, R4, R5, R6, R8 or R9 is a group of the formula RX-C0-, and RX is a hydrogen atom (a), b) an alkyl group substituted with one to three groups selected from the group consisting of a halogen atom, a cyano group, a decyloxy group and an alkane sulfonyl group, (c) an alkyl group optionally substituted with an aryl group, (d) a cycloalkyl group, (e) optionally substituted with one to three aryl groups selected from the group consisting of a halogen atom, a cyano group, an alkyl group, a trihalogen group and a decyloxy group, (f) one to two as needed An alkyl-substituted amine group, or (g) a saturated or unsaturated heterocyclic group substituted with one to two groups selected from the group consisting of a halogen atom, a cyano group, a alkyl group and a tri-silyl group, as needed. 7. The compound of claim 3, wherein the saturated or unsaturated heterocyclic group in r, R3, R4, R5, R6, R8 or R9 is: (A) saturated or not selected from the group consisting of A saturated oxygen-containing or sulfur-containing heterocyclic group: furyl, tetrahydrofuranyl, piperidyl, tetrahydropyranyl, porphinyl, tetradecyl, thiopyranyl, tetrathracenethiopyran Base, benzofuranyl, diargon benzofuranyl, isobenzofuranyl, chromanyl, heterochromyl, fluorenyl, heterochromatic, benzo. a saturated or unsaturated nitrogen-containing heterocyclic group selected from the group consisting of the following groups: Nitrogen 318695 181 200804294 base, π ratio σ Π 基, Π ratio Slightly leaching base, Weijun bite base, miso base, bite base, σ than 嗤基 base, ^ 洛洛基, 2 Η-° than rotyl, miso base, ° ratio. Sitrate, dihydropyrazolyl, thiazole, thiazole, isothiazolyl, iso-oxazolyl, oxime sigma, hydrazine, triterpene, σ-bite, dihydro-sigma , tetrahydrogen ratio σ-based, hexahydropurine 17-based, σ-pyridyl, hexahydroindenyl, sigma-based, tetrahydropyrimidinyl, hydrazine, morpholinyl, azinyl, nitrogen Heterocyclic heptyl, hydrazine, benzimidazolyl, benzotriazolyl, fluorenyl, iso-.朵基,3Η-σ?|σ朵基,1Η-° 唾, 17, 17, 嗓呤, 嗓定, 4Η-啥哄, 啥, 二, 二, tetrahydrogen喧琳基, iso-linyl, dihydroisoindolyl, tetrahydroisoindolyl, dihydropyridinyl, naphthalene, base, wow, base, diterpene, Dihydrobenzothiophenyl, dihydrobenzhydrazine, porphyrin, xanthene, fluorenyl, /5-mercapto, morphine, sulfhydryl, 5Η-dihydrodibenzo a nitrogen group and a spiroheterocyclic group of the formula

/-(CHA wherein, 1^ is the same or different and is a hydrogen atom or a burnt group, and q and r are integers of 1 or 2. 8. A compound according to claim 3, wherein R, The saturated or unsaturated heterocyclic group in R3, R4, R5, R6, R8 or R9 is a nitrogen fluorenyl group, a pyridyl group, a σ ratio succinic group, a hexahydroquinone sigma group, a tetrahydro 11 decyl group, and a tetra Hydrogenthio 11 decyl, hexahydroindenyl, whufyl, thiotropine, thiophene, tetrahydrothiophenyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazole 182 318695 200804294 A base, a triacetin or a bite base. 9 A compound according to claim 1 wherein R and R are the same or different and are optionally selected from one or two selected from the group consisting of a halogen atom, a cyano group, and three a phenyl group substituted with a group of an alkyl group, an alkyloxy group, an alkylthio group, an alkylsulfinyl group and an alkanesulfonyl group; R is a (&) hydrogen atom, (b) one to three as needed An alkyl group selected from the group consisting of a cyano group, a cyano group, an alkyloxy group, an alkylthio group, an anthracene group, an amine group, an anthranyl group, an amine group, an alkylamine group Amino group An amine group, a di(alkyl)amine sulfonylamino group and a saturated or unsaturated 5 to 6 membered heterofluorenyl group (the heterocyclic group is optionally substituted with one or two groups selected from a pendant oxy group and an alkyl group) And (c) an amine sulfonyl group substituted by one to two alkyl groups, (d) a saturated or unsaturated 5 to a β-membered heterocyclic group (the heterocyclic group is optionally selected from the group consisting of pendant oxy groups and a group substituted with an alkyl group), or (e) a spiroheterocyclic group of the formula:

In the gas, R is a nitrogen atom 'RB is an alkyl group, and q and r are integers of 1; E is a group of formula (i), Q is a single bond or a group of the formula -NH-, and Q is a single bond, an oxygen atom or An alkyl group, R is (a) an aryl group optionally substituted with one to three groups selected from a halogen atom, a cyano group and a fluorenyl group, (b) a cycloalkyl group, (c) as required 318695 183 200804294 One to two saturated or unsaturated 5 to 7 membered heteromonocyclic groups selected from the group consisting of a halogen atom, a pendant oxy group, a cyano group, an alkyl group optionally substituted with one to three halogen atoms, and optionally a two alkyl substituted amino group, an amine carbenyl group and a fluorenyl group, or (d) a group of the formula -N(R5)(R6), wherein R is a halogen atom or a burnt group, 1"^ 6 R And (1) an alkyl group substituted with one to three groups selected from a halogen atom, an amine group, a decyloxy group, an alkylthio group, an alkylsulfinyl group, an alkanesulfonyl group and an aryl group, if necessary ( 2) a cycloalkyl group substituted with an amine thiol group as required, (3) a group of the formula -N(R8)(R9), (4) a fluorenyl group, and (5) optionally one to three selected from a sulfhydryl atom , cyano, trihaloalkyl and alkyloxy a substituted aryl group, or (6) a saturated or unsaturated 5 to 7 membered heteromonocyclic group substituted by one to four groups selected from the group consisting of: a stimulating atom, a pendant oxy group, and optionally one to three An alkyl group substituted with a halogen atom, an alkyloxyalkyl group, an alkyloxy group substituted with one to three halogen atoms, an anthracenyl group, an alkanesulfonyl group, and an amine sulfonium group substituted by one to two alkyl groups as necessary. a arylsulfonyl group, an amine group optionally substituted with one or two groups selected from an alkyl group and a fluorenyl group, an aryl group optionally substituted with one to three _ atoms, and optionally one to two Self-respecting a heteroaryl group substituted with an alkyl group substituted with one to three functional atoms, a group substituted with an atom of an im group and a cyano group, R is a halogen atom or a leuco group, and R9 is optionally added to two An alkyl group substituted with a pendant oxy group, an aryl group and an aryl group; an anthracenyl group; an aryl group or a heteroaryl group. The compound of claim 1, wherein R1 and R2 are the same or different and are halogen phenyl; R3 is alkyl or alkyloxyalkyl; and E is a group of formula (ii) In the formula, R is (a) an alkyl group which is substituted with one to three halogen atoms as needed, (b) an alkyloxy group, and (c) is optionally substituted with a group selected from a hydroxyl group and an alkyl group. a cycloalkyl group, (d) an alkylthio group, (e) an aryl group substituted with one to two groups selected from a halogen atom and a cyano group, or (f) an alkanesulfonyl group or a fluorenyl group, if necessary Or a heteroaryl substituted saturated or unsaturated heterocyclic group. 11. A compound according to claim 1 wherein r1 is the same or different and is a halogen phenyl group; R3 is an alkyl or alkyloxyalkyl group; and E is a group of formula (iii) Wherein, R1 is an amino group or a group of the following formula: 〇12. A compound according to claim 1, wherein ri is the same as or different from r2 and is a halogen phenyl group; and R3 is an alkyl group or an alkyloxy group. An alkyl group; and E is a group of the formula (iv), wherein, in the formula, a 4 to 7 member nitrogen-containing aliphatic heterocyclic group substituted with a pyrimidinyl group or a halogenpyrimidinyl group is required. 13. A compound according to claim 9 wherein R is a phenyl group substituted with one to two groups selected from the group consisting of a halogen atom and a trihalogen-Ci4 alkyl group; R is substituted with one to two ι | Phenyl; R3 is an alkyl group substituted with one to three halogen atoms, a Ci_4 alkyloxy-Ch alkyl group, a cyano-Cl_4 alkyloxy group, an amine group-Ci 4 alkyl group (this group) The amine moiety may optionally be substituted with a group selected from the group consisting of fluorenyl, di(alkyl) 185 318695 200804294 sulfonamide and C!-4 alkyl-amine carbaryl, and the amine mercapto-Ch alkyl group. , carbazolyl-Ch alkyl (the nf azole moiety of the group may be optionally substituted with one to two Ch alkyl groups), thiazolyl-CH alkyl; Q1 is a single bond; Q2 is a single bond or Cl-4 a stretching group; R4 is a saturated or unsaturated 5 to 6 membered heteromonocyclic group substituted by one to three groups selected from the group consisting of a pendant oxy group, an amine fluorenyl group and a Ci-4 alkyl-amino group, or a group of the formula -NH(R6); and R6 is (a) a Cw alkyl group, (b) a C5 8 cycloalkyl group substituted with an amine sulfhydryl group as desired, (c) one to two dentivins as needed Atomic substituted phenyl, ( d) a saturated or unsaturated 5 to 7 membered heteromonocyclic carbene atom, a pendant oxy group, optionally substituted with one to three halogen atoms, optionally substituted with one or three halogen atoms, optionally substituted with the following groups: a phenyl group, a cyanophenyl group, a fluorenyl group, a phenyl group, a phenyl group, a carboxy group, a phenyl group, a phenyl group, a carboxyl group, and optionally one or two selected from the group consisting of one or two halogen atoms. An alkyl group substituted with a group of a murine group, an amine methyl group, and optionally a pyridyl group substituted with one or two groups selected from a halogen atom, a C4 alkyl group and a trihalogen-Cw alkyl group, or (e) an amine group substituted with one to two groups selected from the group consisting of a C alkyl group and a hydrazinyl group, as needed. 14. The compound of claim 1, wherein the compound is the same or different and is a halogen group, and R is a Cl-4 alkyl group, a trihalogen-Ci_4 alkyl group or a Ci-4 alkyloxy-Cw alkane. And R is (a) a Ch alkyl group substituted with one to three mesoid atoms as desired, (b) a C5-8 cycloalkyl group optionally substituted with a group selected from a hydroxyl group and a Cw alkyl group, (c) ChCh alkyl 318695 186 200804294 base, (d) an aryl group substituted with one to two groups selected from a halogen atom and a cyano group, or (e) optionally selected from aCh alkanesulfonyl group, hydrazine A saturated or unsaturated heterocyclic group substituted with a group of a heteroaryl group. _15. The compound of claim 11, wherein Ri is the same or different and is a halogen phenyl group; 1 is a Cw alkyl group or a Ci-4 alkyloxy-Ch alkyl group; and RA1 is an amine group. Or a group of the following formula:

16. The compound of claim 12, wherein ^ is the same as or different from R2 and is a halogen phenyl group; R3 is a Ci-4 alkyl group; and RA2 is optionally a pyrimidinyl group or a trihalogen-Chalkyl group - A 4- to 7-membered aliphatic heterocyclic group substituted with a pyrimidinyl group. 17. The compound of claim 13, wherein R is a phenyl group substituted with a group selected from a chlorine atom and a trifluoro-Ci-3 alkyl group; and R2 is one or two selected from a chlorine atom or fluorine. a phenyl group substituted with an atom; R3 is a Cl_4 group, a fluoro group, a cyano group, a Cl-4 alkyloxy group, an amine group, a Ci-3 alkyl group, optionally substituted with one to three groups selected from the group consisting of , 匕_3 alkyl-carbonylamino group, Ch alkyl-amine-methylamino group, Ch alkyl-sulfoyl thiol, one (C 1 ~3 alkyl) amine aryl amine group, 17 stopper a sulphonyl group substituted with one to two C1_3 alkyl groups as desired; and E is a group of formula (i), Q1 is a single bond, 318695 187 200804294 Q2 is a single bond or a Cl-4 alkyl group, R a saturated or unsaturated 5 to 6 membered heteromonocyclic group substituted with one to two groups selected from the group consisting of a pendant oxy group, a Ch alkylamino group and an amine methyl group, or a formula-leg (R6) a group, and R6 is (a) a Ci-3 alkyl group, (b) a c3_6 cycloalkyl group substituted by an amine mercapto group as needed (c) optionally one to two selected from the group consisting of a chlorine atom, a fluorine atom, and a rat Substituted with a group of 〇1_3 methoxyl groups Phenyl, (d) optionally substituted with one to three saturated or unsaturated 5 to 7 membered heteromonocyclic amino groups selected from the group consisting of the following aryl groups, optionally substituted with one to three fluorine atoms Ci-3 alkyl, trifluoro-Ci-s alkyl-aryl, Ci-3 alkyloxy-Ch alkyl-carbonyl, cyano-C!-3 alkyl-carbonyl, amine mercapto, If necessary, an amine group substituted with a group derived from a Cl-3 alkyl group, a digas-Cl-3 alkyl group and a benzoic acid group, if necessary, one to two selected from a chlorine atom and a fluorine atom a benzyl group, a carboxy group, a benzyl group substituted with a group of a cyano group, an anthracene-3 alkyloxy group and a trifluoro-G-3 alkyl group, optionally having one or two selected from a chlorine atom and a fluorine atom. a phenyl group substituted with a group and, if necessary, one or one bite group substituted with a group selected from a chlorine atom, a fluorine atom, a cyano group, a Cl-3 alkyl group and a trifluoro-Ch alkyl group, or (e) Two amine groups selected from the group consisting of a c1-3 alkyl group and an acridinyl group. 18. A compound according to claim 14 wherein R1 is chlorophenyl or trifluoromethylphenyl; R2 is chlorophenyl; R3 is C!-3 alkyl; and r is difluoro-Cl- 3 burning base. 19. A compound according to claim 15 wherein chlorophenyl; R2 is chlorophenyl; R3*Cualkyl; and RA1 is 5 to 6 membered aliphatic 188 318695 200804294 - a heterocyclic group. 20) The compound of claim 16 wherein pi is chlorobenzene, R is a gas radical, R3 is a Ci_3 alkyl group; and RA2 is a diterpene-Ci-3 alkyl group as desired. The pyrimidine group is substituted with 5 to 6 members of the aliphatic heterocyclic ring. _ 21 · A compound selected from the group consisting of the following or a pharmaceutically acceptable salt thereof · Jiu 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methyl Oxy-cycloheptylheptyl)amine hydrazino]- 1H-pyrazole; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-[N -(4-14 tetrahydropyranyl)amine hydrazino]- 1H-pyrazole; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-ethoxy-3 [1^(1^?folinyl)aminecarboxylidene]- 1H-pyrazole; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3- [N-(2 2 trifluoroethyl)aminemethanyl]-1H-pyrazole; ' 1 -(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3 —[n—六氖11 ratio bite base) amine broth base]-1Η - ° ratio σ sitting; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy- 3-[Ν—(Ν一吗福琳基)amine 曱基 base]-1Η -17 嗤; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-decyloxy 3-(Ν-(1-π-pyridyl)amine fluorenyl]-1Η-pyrazole; 1-(2-chlorophenyl)-5-(4-phenylphenyl)-4-ethoxy —3-[Ν-(Ν-hexaazinyl)amine fluorenyl]-1Η-pyrazole; 1-(2-Phenylphenyl)-5-(4-chlorophenyl)-4-(2-methoxyethoxy)-3-amino[N-(N-hexahydropyridinyl)amine fluorenyl] -1H-pyrazole; 318695 189 200804294 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-[1-(Ν-?福•琳基)乙Stiff base]-1H-^ ratio σ sitting; 1 -(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-[N-(N-26) Hydropyridyl)aminemethanyl]-1Η-pyrazole; • 1 -(2,4-dichlorophenyl)-5-(4-phenylphenyl)-4-oxime-3-[Ν- (1 - pyrrolidinyl)aminemethanyl]-1Η-pyrazole; 1-(2,4-diphenyl)-5-(4-chlorophenyl)-4-methoxy-3-[ Ν-(Ν-homofolinyl)amine fluorenyl]- 1 Η-pyrazole; 1 -(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methoxy- 3-[or, r-dimercapto)carbonyl]-1Η-pyrazole; 1-(2-phenylphenyl)-5-(4-chlorophenyl)-4-indolyl-3-(N -cyclopentylaminecarbamyl)-1H-pyrazole; 1-(2-chlorophenyl)-5-(4-phenylphenyl)-4-methoxy-3-(N-isopropylamine Mercapto)-1H-pyrazole; 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-difluorodecyloxy-3-31 [N- 1-pyrrolidinyl)amine-mercapto]-1H-pyrazole; 1-(2-chloro-4-fluorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-[ N-(N-moffipyl)amine decanoate]-1 Η - ° ratio. 1-(2-phenylphenyl)-5-(4-trifluoromethylphenyl)- 4-indolyloxy-l-[(ν' Γ-diindenyl)carbonyl]- 1Η-pyridyl Azole; 1-(2-phenylphenyl)-5-(4-tri-diphenylphenyl)-tetramethyloxy-1,3-hydroxyl-[1-pyridinyl]aminoindenyl]- 1Η -pyrazole; 1-(2-chlorophenyl)-5-(4-trifluoromethylphenyl)-4-yloxy-3-[^-(Ν-morpholinyl)amine fluorenyl ]-1Η-pyrazole; 318695 190 200804294 1-(2-Phenylphenyl)-5-(4-trifluorodecylphenyl)- 4-indolyloxy-3-[N-(4-tetrahydroperylene)喃 ) 胺胺 ] ] ] ] ; ; ; 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- Fluorobenzoic acid) hexahydropyridin-4-yl]aminocarboxylic acid]-111-° azole; 1-(2-phenylphenyl)-5-(4-trifluoromethylphenyl)-4 -Difluoromethoxy-3 -[(N,N-甲朋1基))]-lH-外匕唆; 1 (2 gas-based)-5-(4-trifluorodecylphenyl) 1-4-Denylmethoxy-3-(N-(4-tetrahydropyranyl)amine sulfhydryl]-1H-pyrazole; 1-(2-chlorophenyl)-5-(4-tri Fluoromethylphenyl)-4-difluoromethoxy-3 [N-(1-pyrrolidinyl)amine-carbamoyl]-iH-pyrazole; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-[ 1^-(1-11 σ 定 ) ) ) ) ) ) ] ] ] ] ] ] 1 1 1 1 1 1 1 1 1 1 1 - (2-chlorophenyl)-5 -(4-chlorophenyl)-4-methoxy Base ~3 - [Ν-(cis-2 6-'-methyl-oxime-moffolinyl)amine aryl]-1 H-吼嗤; 1-(2-chlorophenyl)-5-( 4-chlorophenyl)-4-methoxy-3-[indole-(4f-fluoro-N-hexahydropyridinyl)amine fluorenyl]-1H-pyrazole; 1-(2-chlorophenyl) -5-(4-chlorophenyl)-4-methoxy-3-[N-(4-di-methyl-N-hexanitroindole-12-decyl)amine-based]-1Η-σ than saliva ; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-carbamoyl)carbonyl]- 1Η-pyrazole; — 1-(2-chlorophenyl)- 5-(4-Chlorophenyl)_4-ethoxy~3 - UN4-tetrahydro-branyl)amine-mercapto]- 1H-pyrazole; 1-(2-chlorophenyl)-5-(4 -Trifluoromethylphenyl)~4-ethoxyl~3 N,dimethylidene)yl]-111-° ratio σ; ' 318695 (S 191 200804294 1-(2-chlorophenyl)- 5-(4-chlorophenyl)-4-(2-methoxyethoxy)-3-[N-(4-tetrahydro) Piperidyl)amine-mercapto]-1H-pyrazole; 1-(2-chlorophenyl)-5-(4-trifluoromethylphenyl)~4-(2-methoxyethoxy)- 3-[N-(1-pyrrolidinyl)aminemethanyl]-1H-pyrazole; soil 1-(2-chlorophenyl)-5-(4-trifluoromethylphenyl)-4 2-methoxyethoxyx)-3-[N-(N-morpholino)aminecarboxylidene]-1H-pyrazole; soil 1 -(2-chlorophenyl)-5-(4-chloro Phenyl)-4-methoxy-3-[1(1, bis-oxo-oxythiofenofyl-4-yl)aminemethanyl]-1 {{-吼唾· 1 -(2 -Chlorophenyl)-5-(4-carbophenyl)-4-methoxy-3-[N~(tetrahydrofuran-3-yl)amine-branthyl]-[η-口比唾; 1 - (2-Chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-1,3-indolyl-(4-benzoic acid hexamethylene-1-yl)amine fluorenyl] —1Η—η-razole; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-(n-propoxy)-fluorenyl-dimethylhydrazino)carbonyl]-1Η-pyrazole ; 1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-4-yloxy-3-[NU-gasbenzhydryl)hexahydropyridinium-i-yl]amine hydrazine Mercapto]-1}1-0 azole; 1-(2-chlorophenyl)-5-(4-chlorophenyl — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — 2-chlorophenyl)-5-(4-monophenyl)-4-yloxy-3-[N-[4-(3-fluorophenylindenyl)hexahydropyrazine-i-yl]amine oxime醯]]-1H-pyrazole; 1 mono(2-chlorophenyl)-5-(4-phenylphenyl)-4-methoxy-3-[(1, bis-oxothio thiofolf) Porphyrin-4-yl)ethinyl]-hydrazine-pyrazole; monochlorophenyl)-5-(4-monophenyl)-4-difluoromethoxy-

318695 192 200804294 °pyrrolidyl)amine hydrazinyl]-1H-pyrazole; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-difluoromethoxyl-3~ [(^ fT-dimethylhydrazino)carbonyl]-1H-pyrazole; '1-(2-phenylphenyl)-5-(4-chlorophenyl)-4-difluorodecyloxy-tetrahydro brig喃 )) amine 基 ]] -1Η-13 than saliva; ί-(2-chlorophenyl)-5-(4-chlorophenyl)-4-ethoxyfluorobenzyl) hexahydroindole -1 -yl]amine-branthyl]- 1 Η-^ than saliva 1 -(2-chlorophenyl)-5-(4-trifluorodecylphenyl)-4-ethoxy-[4-( 4-fluorobenzhydryl)hexahydropyrazine-1-1-yl]aminocarbazyl]-ιη-carbazole; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4- Difluoromethoxy-3-[Ν1-(L 1-di-oxythio-norporphyrin-4-yl)amine fluorenyl]-Η-pyrazole; chlorophenyl)-5-(4 Chlorophenyl)-4-methoxy-3-[indole-[4-(3-chlorobenzinomethyl)hexahydropyrylene-1-yl]aminemethanyl]-1Η-pyva; ^ — Chlorophenyl)-5-<monochlorophenyl)-4-methoxy-3-[indole-[4-(2-chloroacylmethyl)hexahydropyridin-1-yl]amine formazan Base]- 1 Η-pyrazole; 1 (2~gasphenyl)-5-(4-chlorophenyl)-4-methoxy-3-[indole-[4-^,4~difluorobenzhydryl)hexahydropyrazole-indole Amino]aminomethane]-u-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3 - [N - [4 -saphthyl]-fluorobenzidine Hexahydropyrazole 11 well-l-yl]amine-mercapto]-1H-pyridyl, 3(g-decyl)-5-(4-chlorophenyl)-4-methoxy-3-[N -[4-,,~difluorobenzhydryl)hexahydropyridin-1-yl]aminecarboxylidene]-1H-pyridyl 31Ε695 193 200804294 1-(2-chlorophenyl)-5-(4- Chlorophenyl)-4-decyloxy-3-[2~(i-曱石醯醯基六氢吼-4-yl)-1,3,4-,disita-5-yl]-ΐΗ -π than saliva; 1 -(2,4-"-gas-based)-5-(4-propenyl)-4-methoxy-1,3-hydroxy[n-(4-fluorophenyl)amine oxime -1H-pyrazole; 1 -(2-chlorobenzyl)-5-(4-chlorophenyl)-4-methoxy-3 -[Ν-[Κ4·~fluorophenyl)hexahydropyridyl耕-卜基]Aminomercapto]-1 Η-pyrazole; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-oxime-3-[Ν~(3 - tris(hydrazinylpyrrolidin-1-yl)aminemethanyl]-l-pyrazole; 1 one (2,4-dichloro 5-(4-trifluorodecylphenyl)-4-methoxy-1,3-[[indole, fluorenyl-dimethylhydrazino)carbonyl]- 1 Η-pyrazole; 1 (2, 4- Dichlorophenyl)-5-(4-tri-lalylmethylphenyl)-4-methoxy-3-[Ν-(Ν-morpholinyl)amine fluorenyl]-1Η-pyrazole; Mono(2,4-dichlorophenyl)-5-(4-trifluorodecylphenyl)-4-methoxy-3-[Ν-( 1,1-di-oxy-2-tetraindole) σ 吩 ) ) ) ) ] ] ] — — ; ; ; ; ; ; ; ; ; ; ; 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 3-[indolyl-(4-tetrahydropyranyl)amine fluorenyl]-1 Η-pyrazole; 1-(2-chloro-4-fluorophenyl)-5-(4-trifluoromethyl Phenyl)- 4-methoxy-3-[indolyl-(indolyl-norfosyl)aminoindenyl]-1Η-pyrazole; 1-(2-phenylene)-5-(4-tri Fluoromethylphenyl)-4-methoxy-3 - [indolyl-(1,1-di- oxythio-norfosyl) carbamic acid]-1 Η-吼嗤; 1 -(2-gas Phenyl)-5-(4-chlorophenyl)-4-methoxy-3-[indolyl-(4-fluoro-indolyl-hexahydropyridinyl)aminecarboxylidene-1-pyridazole; 318695 194 200804294 1-(2,4-Dichlorophenyl)-5-(4- Phenyl)- 4-oxooxy-3-[N-(4-benzylidene hexahydropyrylene-1-yl)amine-methylglycolyl]-1H-pyrazole; 1 (2,4 - gas 5-(4-phenylene)-4-yloxy-3-[N-[4-(2,4-difluoro-capto-methyl)hexahydropyrazine-j-yl]amine A醯基]一吡口坐; 5-(4-Phenylphenyl)4-(2-fluorophenyl)-4-methoxy-l-[n-(4,4-difluoro-N-hexaquinone Pyridyl)amine hydrazinyl]-indolepyrazole; 1-(2-chlorophenyl)-5-(4-trifluoromethylphenyl)- 4-indolyloxy-3-[n- (4 , 4-difluorohexahydropyridyl)amine-carbamoyl]-1 Η-pyrazole; 1-(2,4-dichlorophenyl)-5-(4-trifluorodecylphenyl)-4-曱一一 3 一 Ν ( ( ( ( ( ( ( ( ( ( ( ; ; ; 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 ( 4--4-oxo-3-[indolyl-[3-(trimethylmethylisopyridin-1-yl)amineindolyl]-1Η-pyrazole; 1 mono(2-chlorophenylchlorophenyl) )-4-methoxy-3-[N-[4~(5-it-based 疋2-yl)hexahydro-portion 哄-l-yl]amine decanoic acid group]_ 1 η-oral ratio saliva; 1 One (2-one phenyl)~5~(4-chlorophenyl)-4- Oxy-3-[[[4~(5-monomethylpyridyl~2~yl)hexahydropyrylene-1-yl]aminoindolyl]-1H-pyrazole; oxime (2-chlorobenzene) ~5~(4-Chlorophenyl)-4-difluorodecyloxy-3-[N-(4,4-di-N-hexahydropyridyl)amine-methylmethyl]-1H-pyridyl Azole; 1 mono(2-chlorophenyl)~5~(4-trifluoromethylphenyl)-4-methoxy-3-[5-(2, 2, 2 dihexyl)-1, 3,4-oxadiazol-2-yl]-1H-pyrazole; gas-based) 1~(2-(phenylphenyl)-4-decyloxy-3-[N-[4-(4-chloro) Phenyl) hexa- oxan-1-yl]amine carbaryl]-1H-pyrazole; 318695 195 200804294 5-(4-chlorophenyl)4-(2-fluorophenyl)-4-methoxy 3-[n-[4-(4-fluorophenyl)hexahydropyridinium-p-butyryl]-amino]-1H-pyrazole; 4-amine-mercaptomethoxy-b (b)-chloro Phenyl)-5-(4-chlorophenyl)-3-amino[N-(4-aminoindenyl-4-ylphenyl-N-hexahydropyridinyl)amine fluorenyl]-1{1 - mouth比 σ; 4-(2-Aminoethoxy)methoxy-chlorophenyl)-5-(4-chlorophenyl)-3-(N-(pyrrolidin-1-yl)aminecarboxamide ]-1H-pyrazole; 4 [2 (ethylamine) Ethoxy]-1 - (2-chlorophenyl)-5-(4-chlorophenyl)-3-[N-(pyrrolidin-1-yl)amine fluorenyl]-1H-pyrazole; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-[2-(methylglycosylamino)ethoxy]-3-[N-(pyrrolidin-1-yl) Aminomethyl]-1H-pyrazole; and 1-(2-chlorophenyl)-5-(4-phenylphenyl)-4-[2-[(N,N-didecylamine sulfonate) Amino]ethoxy]-3-[N-(indol-1-yl)aminecarboxylidene] -1Η-ϋ is more than a mouth. A pharmaceutical composition comprising an oxazole compound of the formula [I] or a pharmaceutically acceptable salt thereof as an active ingredient:

Wherein R and R are the same or different and are optionally substituted aryl or optionally substituted heteroaryl; R3 is (a) an argon atom, (b) optionally one to three selected from the group consisting of Alkyl substituted by a group: halogen atom, cyano group, alkyloxy group, alkyloxy group 196 318695 200804294 Carbonyl group, optionally substituted with one to two alkyl groups, anthranyl group, alkylamine formamylamine Alkylsulfonylamino, di(alkyl)aminesulfonylamino, optionally substituted with one to two alkyl groups, alkyloxycarbonyl, alkylthio, alkylsulfin a thiol, alkanesulfonyl and optionally substituted saturated or unsaturated heterocyclic group, (c) an amine sulfonyl group substituted with one to two alkyl groups, or (d) optionally substituted or saturated An unsaturated heterocyclic group, or (e) R3 is bonded to R1, and then forms a ring group of the following formula together with r1, an adjacent oxygen atom and a fluorene ring:

Ring A is an optionally substituted aryl (or heteroaryl) group, -z-〇 is a formula -(CH2)m-〇-, -〇-(CH2)n-〇- or -N(R.) —(CH2)n—〇—The group 'R is a hydrogen atom or a burnt group, 111 is an integer from 1 to 3, η is an integer from 2 to 3; and Ε is the following formula (i) to formula (iv) One of the regiments: Office, office...do rA2 (1) (8) (m) H (iv) Ql is a single bond, an alkyl group or a group of the formula -N(R7)-, R7 is a hydrogen atom or an alkyl group, Q2 a single bond, an oxygen atom or an alkylene group, a cycloalkyl group, a group of the formula -N(r5)(r6), an optionally substituted aryl group or an optionally substituted saturated or unsaturated heterocyclic group, 318695 197 200804294 - R4R6 is a hydrogen atom or a burnt group and the other is (4) as required. The base to be substituted by the following base: atom, amine, thiol, ^ sulfinyl , alkanesulfonyl and optionally substituted aryl, (...requires substituted cycloalkyl, (c) formula N(R8)(R9) fine', (4) depending on the need to be substituted a group or (e) a saturated or unsaturated heterocyclic group which is optionally substituted, and a hydrogen atom of r8 and r And (4) an alkyl group substituted with one or two groups selected from the group consisting of a pendant oxy group, a cyano group, an alkyloxy group, a fluorenyl group and an optionally substituted aryl group, (b) a cycloalkyl group, (C) anthracenyl group, (d) an optionally substituted aryl group or (6) a substituted or unsaturated heterocyclic group optionally substituted, and D is an oxygen atom or a group of the formula -NH-, RA1 is an amino group or a group of the formula: wherein k is an integer of from 3 to 5, R is an optionally substituted aliphatic heterocyclic group, and R is an alkyl group substituted by one to three atoms, if necessary, Alkyloxyalkylcarbonyl, alkylthio, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted saturated or unsaturated heterocyclic group. A pharmaceutical composition of 22, which is a prophylactic and/or therapeutic agent for a CB1 receptor vector disease. 24) A pharmaceutical composition as claimed in claim 23, wherein the ϋβ1 318695 198 200804294 has a wide range of susceptibility ^Psychiatric disorders include schizophrenia, anxiety, 丽1, epilepsy, neurodegenerative, spinal cord cerebellum Cognitive bias; pain: panic attack, peripheral neuropathy, glaucoma, letter i, Alzheimer's disease, Huntington's disease, Raynaud's cancer, drug lead = main = sexual involuntary movement, disease, Gushan & involuntary movement, muscle tension, septic rest ^ ^ ^ ^ t ^ ^ # ^ Liu Wei Feng, rolling %, appetite diseases including anaesthesia / (; 1 brain, sputum 2 'sickness, obesity , non-cedidin-dependent diabetes, memory disorders, urinary diseases, cardiovascular diseases, infertility, = infection, demyelination, social diseases, neuroinflammation, viral encephalitis, sputum, cirrhosis or Gastrointestinal diseases include intestinal transit disorders. 25. The pharmaceutical composition of claim 22, which is used as a remedy for chronic treatment, alcohol dependence or drug abuse. 26. The pharmaceutical composition of claim 22, which is an agent for increasing the analgesic activity of an analgesic or anesthetic. 27. A pharmaceutical composition as claimed in claim 22, which is an agent for quitting smoking (except smoking or nicotine dependence). 318695 199 200804294 VII. Designated representative map·· None (1) The representative representative of the case is: (). • (2) A brief description of the symbol of the representative figure: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention:

5 318695