TWI378922B

TWI378922B - A pyrazole compound

Info

Publication number: TWI378922B
Application number: TW95138705A
Authority: TW
Inventors: Yasunori Moritani; Ritsuo Imashiro; Atsushi Sato
Original assignee: Mitsubishi Tanabe Pharma Corp
Priority date: 2005-10-21
Filing date: 2006-10-20
Publication date: 2012-12-11
Also published as: TW200804294A

Description

1378922 .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，該化合物具有強力之中枢***鹼受體（CB1)拮抗活性， -因此可作為醫藥用途。 •【先前技術】 +所悉知吸食***會產生各種精神或神經反應，諸如時間感或空間感逑失、陶醉感、記憶改變、痛覺喪失、幻 •覺等。通常稱為「***鹼」之化合物包括△ 9_四氫 9-THC)與許多此等反應有關連。一般認為***鹼作用係由於該化合物與其内生專一性/高親力受體間之交互作用所 k成。已經辨識與複製***驗受體的兩種亞型（CM與 CB2)。CB1丈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)。 φ 對此等***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***之各種藥理作用。尤其是，對中抱CB1受體具有親和力之物f可用於治療中樞神經系統疾病’諸如精神疾病、神經疾病等。已知有各種化合物為對此等***鹼受體具有親和力之物質，包括吡唑-3-甲醯胺化合物如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)、 =氫吡唑并[3,4-c]吡啶-7-酮化合物、2H_吡唑并[4,3_d] 嘧啶-7(611)-酮（見專利文獻1)等。其中，至少SR14ni6 318695 6 1378922 -與SLV-319已進行作為食慾抑制劑（anorexigenics)(抗肥胖劑）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（1990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 籲卷 ’ 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吡唑化合物，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：139. The invention relates to a novel carbazole compound or a pharmaceutically acceptable salt thereof, which has strong central cannabinoid receptor (CB1) antagonistic activity, and thus Can be used as a medicine. • [Prior Art] + Knowing that smoking marijuana can produce a variety of mental or neurological reactions, such as loss of time or sense of space, intoxication, memory changes, loss of pain, illusion. Compounds commonly referred to as "cannabinoids" including Δ 9_tetrahydro 9-THC are associated with many of these reactions. It is generally believed that the action of cannabinoids is due to the interaction between the compound and its endogenous/high affinity receptor. Two subtypes (CM and CB2) have been identified and replicated for cannabin receptors. The CB1 receptor is distributed in the region including the central nervous system (CNS) & see Non-Patent Document 1), and the CB2 receptor is distributed in the immune system including the spleen (see Non-Patent Document 2). φ A substance (afficking agent, antagonist or inverse agonist) having affinity for such cannabinoid receptors can produce various pharmacological effects similar to cannabis. In particular, the substance f having an affinity for the CB1 receptor can be used for the treatment of central nervous system diseases such as mental diseases, neurological diseases and the like. Various compounds are known which have affinity for such cannabinoid receptors, including pyrazole-3-carbamamine compounds such as SR141716 (see Non-Patent Document 3), 4, 5-dihydropyrazole compounds such as SLV_319 ( See Non-Patent Document 4), = Hydropyrazolo[3,4-c]pyridine-7-one compound, 2H-pyrazolo[4,3_d]pyrimidin-7(611)-one (see Patent Document 1) Wait. Among them, at least SR14ni6 318695 6 1378922 - and SLV-319 have been clinically studied as effects of anorexigenics (anti-fat agents). Patent Document 1: W02004/094417 Non-Patent Document 1: Nature, Vol. 346, pp. 561-564 (1990) • Non-Patent Document 2: Nature, Vol. 365, pp. 61-65 (1993) • Non-patent literature 3: Life Science, Vol. 63, PL113-PL117 (1998) Non-Patent Document 4: Journal of Medicinal Chemistry, 47th, Vol. 3, pp. 627-643 (2004) [Summary of the Invention] The novel pyrazole compound having potent CB1 receptor antagonistic activity is provided, 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:

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之烧基：i素原子、氰基、烷基氧基、烷基氧基羰基、視需要經一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 7 318695 1378922 經一至二個烷基取代之胺甲醯基、烷基氧基羰基、烷基硫基、烷亞碩醯基、烷磺醯基與視需要經取代之飽和或不飽和雜垓基’（C)視需要經一至二個烷基取代之胺磺醯基，或 (d)視需要經取代之飽和或不飽和雜環基，或（e)R3與^相結合，並與R1，鄰接之氧原子和吡唑環一起形成下式之基團：Wherein R 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 a group substituted by a group: an atom of a cyano group, 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, if desired 7 318695 1378922 Aminomethyl substituted by one to two alkyl groups, alkyloxycarbonyl, alkylthio, alkylene A sulfhydryl group, an alkane sulfonyl group and optionally substituted saturated or unsaturated heterofluorenyl group '(C) optionally substituted with one to two alkyl groups, or (d) saturated as desired Or an unsaturated heterocyclic group, or (e) R3 and ^, and together with R1, an adjacent oxygen atom and a pyrazole ring form a group of the formula:

環A為視需要經取代之芳基（或雜芳基），_z_〇_為式 ^H2)m-〇-、-〇-(CH2)n—〇_或一N(R〇)_(CH2)n_〇_之基團，r。為氫原子或烧基，m為i至3之整數，n為2至3之整數以及 ’ E為下列式（丨）至式（iv)基團中之一者： • h2' 办R，AV: η1 ⑴ (ii> (iii) H (iv) Q為早鍵、伸烷基或式_N(R7)_2基團， R為虱原子或烧基， Q2為單鍵、氧原子或伸烷基， R4為環烧基、式-NUW)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， R與R6之-者為氫原子或絲且另—者為⑷視需要經下列基團取代之烧基：齒素原子、胺基、燒基硫基、烧亞石黃 318695 8 1378922 .醯基、烷磺醯基與視需要經取代之芳基，（b)視需要經取代之環烷基，（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餘和雜環基， R8與R9之一者為氫原子或烷基且另一者為（a)視需要經一至二個選自下列之基團取代之烷基：側氧基、氰基、烷基氧基、醯基與視需要經取代之芳基，（…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-NH-基團， RA1為胺基或下式之基團：式中，k為3至5之整數，尺為視需要經取代之脂肪族雜環基，需要經一至三㈣素原子取代之烷基、统基氧基院基疏基 '視需要經取代之環貌基、視需要經取代之方基或視需要經取代之飽和或不飽和雜環基。【實施方式】Ring A is an optionally substituted aryl (or heteroaryl), _z_〇_ is of the formula ^H2)m-〇-, -〇-(CH2)n-〇_ or one N(R〇)_( CH2) n_〇_ group, r. Is a hydrogen atom or a burnt group, m is an integer from i to 3, n is an integer from 2 to 3, and 'E is one of the following formulas (丨) to (iv): • h2' R, AV : η1 (1) (ii) (iii) H (iv) Q is an early bond, an alkyl group or a _N(R7)_2 group, R is a ruthenium atom or a burnt group, and Q2 is a single bond, an oxygen atom or an alkylene a group wherein R 4 is a cycloalkyl group, a group of the formula -NUW), an optionally substituted aryl group or an optionally substituted saturated or unsaturated heterocyclic group, wherein R and R 6 are a hydrogen atom or a silk and the other - (4) An alkyl group substituted by the following groups as needed: dentate atom, amine group, alkylthio group, pyrophyllite 318695 8 1378922. mercapto group, alkanesulfonyl group and optionally substituted aryl group , (b) optionally substituted cycloalkyl, (c) a formula -N(R8)(R9) group, (d) optionally substituted aryl or (e) as desired saturated or not substituted And a 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, Alkyloxy, fluorenyl and optionally substituted aryl, (...cycloalkyl, c) a fluorenyl group, (d) an optionally substituted aryl group or (e) a substituted or unsaturated heterocyclic group optionally substituted, _D is an oxygen atom or a formula -NH- group, and RA1 is an amine group or A group of the formula: wherein k is an integer of from 3 to 5, the aliquot is an optionally substituted aliphatic heterocyclic group, an alkyl group substituted with one to three (tetra) atoms, and a sulfhydryl group A saturated or unsaturated heterocyclic group which is substituted as needed, optionally substituted or optionally substituted with a heterocyclic group.

關於本發明之化合物⑴，在R 基:實例包括6…單環或雙環芳=如本基或蔡基。其中’較佳之此芳基實例為笨基。在R C或環A)與R2為雜芳A _ 括5至6員含氧雜芳A ::基之清況，此雜芳基實例包 5至”二it f ]如Μ基或Μ的™1); 方基’例如嗟吩基（tMenyl)或5至6員含 31S695 9 1378922 .氮雜芳基，例如吡啶基。其中，較佳之此雜芳基實例為噻吩基或π咬基。環Α為芳基及/或雜芳基時，上述^與^可經一至三個選自下列之基團取代：（a)鹵素原子，氰基，（c)視需要經一至三個|素原子取代之烷基，（d)視需要經一至三個鹵素原子取代之烧基氧基及（e)烧確酿基。 R、R3、R4、R5、R6、尺8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)侧氧基，（〇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) 胺基烷基，（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，（ra) 酉血基，（η)院基硫基，（〇)烷亞磺醯基，（p)烧續醯基，（q) •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鹵素原子、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（t)雜芳基。在R、R3、R4 ' R5、R6、R8或R9為飽和或不飽和雜環基之情況’此雜環基實例包括（a)飽和或不飽和4至7員雜單衰基’該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)前述該雜單環基與一 10 318695 1378922 ，或二個選自C3-8環燒基、5至6員單環芳基及飽和或不飽和4至7員雜單環基之其他環基團而形成，該雜美人有i至4個選自氧原子、硫原子與氮原子之雜原子二： (C)飽和或不飽和之8至11員含氮螺雜環（spir〇_ heterocyclic)基。 R、R3、R4、R5、R6、R8 戎 r9 Φ τ- & κf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、二氫苯并吱D南基、異苯并呋喃基、色滿基（chr〇many丨）、異色滿基、色烯基（chromenyl)、異色烯基、苯并π塞吩基與二氮苯弁σ塞吩基；或 (Β)飽和或不飽和選自下列基團之含氮雜環基：氮π旦基 (azetidyl)、吡 17各咬基（pyrrolidinyl)、《»比洛琳基鲁（pyrrolinyl)、咪唑啶基（imidazolidinyl)、咪唑琳基〇11^(1&2〇1111丫1)、11比唑咬基（0丫『&2〇11(^1171)、'»比《坐琳基 (pyrazolinyl)、吡咯基（pyrrolyl)、2H-吡口各基、咪唑基 (imidazolyl)、11 比0坐基（pyrazolyl)、二氫口比唾基、嗟唾咬基（thiazolidinyl)、異嗔°坐°定基、異曙°坐基 (isoxazolyl)、曙°坐咬基（oxazolidinyl)、曙二嗤基 (oxadiazolyl)、***基（triazolyl)、β 比啶基、二氫吼啶基、四氫π比咬基、六氫°比咬基、11比卩井基（pyraz i ny 1)、六氫 °比哄基、嘴咬基、四氫°密咬基、塔哄基（pyr i daz i ny 1)、嗎 11 318695 1378922 ’福琳基（morpholinyl)、氮辛基（azocinyl)、氮雜環庚基、吲哄基（i ndo 1 iz i ny 1)、苯并咪唑基、苯并***基、巧π朵基、異吲哚基、3Η-吲哚基、1Η-吲唑基（lH-indazolyl)、四嗤基、嘌吟基、喋咬基（pteridinyl)、4H-喹卩并基 (4H-quinolizinyl)、喹啉基（quinolyl)、二氫喹啉基、四氩喧蛛基、異喹琳基、二氫異啥琳基、四氫異啥琳基、二氳吹哄基（dihydrophthalazinyl)、萘咬基 (naphthyridinyl)、喧喏琳基（quinoxalinyl)、ofa坐琳基 • (quinazolinyl)、二氫喹唑啉基、二氫苯并噻哄基、二氫苯并曙哄基（dihydrobenzoxazinyl)、嗜嚇_基 (cinnolinyl)、咕噸基（xanthenyl)、咔唑（carbaz〇iyi)、万-咔啉基（/5-〇81*15〇111^1)、啡啶基（？1^肋111±1^(^1^1)、吖啶基（acridinyl)、5H-二氫-二苯并氮呼基 (5H-dihydro-dibenzazepinyl)與下式之螺雜環基，Regarding the compound (1) of the present invention, in the R group: Examples include 6: monocyclic or bicyclic aromatic = such as a benzyl or a decyl group. Wherein the preferred embodiment of the aryl group is a stupid group. In the case where RC or ring A) and R2 are heteroaryl A _ including 5 to 6 members of the oxygen-containing heteroaryl A: group, this heteroaryl group includes 5 to "two it f] such as fluorenyl or anthracene TM 1); a aryl group such as tMenyl or a 5 to 6 member containing 31S695 9 1378922. an azaaryl group such as a pyridyl group. Among them, an example of the heteroaryl group is preferably a thienyl group or a π-bite group. When the oxime is an aryl group and/or a heteroaryl group, the above ^ and ^ may be substituted by one to three groups selected from the group consisting of: (a) a halogen atom, a cyano group, and (c) one to three atomic atoms as needed. Substituted alkyl, (d) an alkyloxy group substituted with one to three halogen atoms, and (e) an aryl group, R, R3, R4, R5, R6, 8 or R9 Including 6 to 10 membered monocyclic or bicyclic aryl groups, such as phenyl, naphthyl and the like, wherein phenyl is preferred. Further, the aryl group may be substituted with one to three groups selected from the group consisting of: a halogen atom, (b) a hydroxyl group, (c) a cyano group, (d) a pendant oxy group, (a deficient alkyl group substituted with one to three halogen atoms, (f) an alkyloxyalkyl group, (g) Aminoalkyl, (h) cycloalkyl, (i) arylalkyl, (j An alkyloxy group substituted with one to three halogen atoms as needed, (k) an amine group substituted with one to two alkyl groups as desired, (1) an amine formazan group substituted with one to two alkyl groups as required, (ra) 酉 blood base, (η) thiol, (〇)alkyl sulfinyl, (p) thiol, (q) • amide sulfonyl substituted by one or two alkyl groups as needed (r) arylsulfonyl, (s) aryl 'the aryl group may optionally have one to three alkyl groups selected from a halogen atom, a cyano group, optionally substituted with one to three halogen atoms, an alkyloxy group. Substituted with a group of an alkanesulfonyl group, and (t) a heteroaryl group. In the case where R, R3, R4 'R5, R6, R8 or R9 are a saturated or unsaturated heterocyclic group, 'this heterocyclic group example includes ( a) saturated or unsaturated 4 to 7 membered hetero-singular groups. The heteromonocyclic group contains one to four heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms; (b) saturated or unsaturated 8 to 15 members Nitrobicyclo or tricyclic heterocyclyl 'the heterocyclic group fusing the aforementioned heteromonocyclic group with a 10 318 695 1378922, or two selected from C 3-8 cycloalkyl, 5 to 6 membered monocyclic aromatic Base and saturated or not full And other ring groups of 4 to 7 membered heteromonocyclic groups having from i to 4 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms: (C) saturated or unsaturated 8 to 11 members of the spir〇 heterocyclic group. R, R3, R4, R5, R6, R8 戎r9 Φ τ- & κf Examples of saturated or unsaturated heterocyclic groups are: (A) saturated or An unsaturated or sulfur-containing heterocyclic group selected from the group consisting of furyl, tetrahydrofuranyl, piperidyl, tetrahydropentanyl, thienyl, tetrahydrothiophenyl, thiopiperidyl, and tetra Hydrothiopiperidinyl, benzofuranyl, dihydrobenzoindole D, benzoyl, isochromanyl, chr〇many, heterochromyl, chromenyl, isochromene a benzopyranyl group and a benzodiazepine sigma group; or (yttrium) a saturated or unsaturated nitrogen-containing heterocyclic group selected from the group consisting of nitrogen azetidyl and pyridyl 17 Pyrrolidinyl,»»pyrrolinyl, imidazolidinyl, imidazolinyl 11^(1&2〇1111丫1), 11 azole bite base (0丫『& 2〇11(^1171), '» than "pyrazolinyl", pyrrolyl, 2H-pyrrole, imidazolyl, 11 to 0 pyrazolyl, dihydrogen to saliva, sputum (thiazolidinyl), isoindole, isobutylation, isoxazolyl, oxazolidinyl, oxadiazolyl, triazolyl, beta-pyridyl, Hydroziridinyl, tetrahydropi-bitergic, hexahydropyramine, 11-pyridylpyridyl (pyraz i ny 1), hexahydrogen thiol, mouth bite, tetrahydro-tense base, tower Pyridyl (pyr i daz i ny 1), 11 318695 1378922 'morpholinyl, azocinyl, azepanyl, fluorenyl (i ndo 1 iz i ny 1), benzene And imidazolyl, benzotriazolyl, cis-π-based, isodecyl, 3Η-fluorenyl, 1Η-carbazolyl (lH-indazolyl), tetradecyl, fluorenyl, pteridinyl , 4H-quinolizinyl, quinolyl, dihydroquinolyl, tetrahydrofuranyl, isoquinolinyl, dihydroisoindolyl, tetrahydroisoindole Base, two 氲哄 base (dihydrophthalaziny l), naphthyridinyl, quinoxalinyl, ofa quinazolinyl, dihydroquinazolinyl, dihydrobenzothianyl, dihydrobenzindole ( Dihydrobenzoxazinyl), cinnolinyl, xanthenyl, carbaz〇iyi, valino-porphyrin (/5-〇81*15〇111^1), morphinyl (? 1^rib 111±1^(^1^1), acridinyl, 5H-dihydro-dibenzazepinyl and a spiro heterocyclic group of the formula

式中，1^與rb相同或不同且為氫原子或烷基，而q與r為 1或2之整數。 R或R中餘和或不飽和雜當中，R、R3、R4、r5、r6、 %基之較佳實例，包括飽和或不飽和5至7員含氮、氧或硫之雜單環基，例如氮咀基、吡咯基、吡咯啶基、六氫吡啶基、吡啶基、六氫吡哄基、嘧啶基、吡卩井基、氮雜環庚基夫南基、四氫哌喃基、四氫硫代哌喃基、嗎福啉基、 318695 12 1378922 ，硫代嗎福琳基、β塞吩基、四氫β塞吩基、嘆tr坐基、異售cr坐基、噚。坐基、異Of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)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，（1；)烷基氧基烷基，（g)胺基烷基’（h)院亞續酿基烧基’（丨）院續酿基烧基，（]·)環院基， (k)芳基烷基，（1)視需要經一至三個鹵素原子取代之烷基氧基，（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)視需要經一至二個烷基取代之胺曱醯基，（Ρ)醯基，（q)烷基硫基，（r)烷亞磺醯基，（s)烷磺醯基，（t)視需要經一至二個烷基取代之胺磺醯基，芳磺醯基，（V)芳基，該芳基視需要可經一至三個選自鹵素原子、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—至三個選自視需要經—至三個自素原子取代之烷基、齒素原子與氰基之基團取代。 R R、R、R、R6、只8與R9中醯基之實例，包括由式 Rx-CO〇H [Ac-丨]之羧酸化合物移去羥基所構成之基團，換言之即式r-co-之基團，式中，RX為⑷氫原子，⑻視需要經-至三侧自鹵素原子、氰基與糾縣之基團取代之院基’⑷視需要經芳基取代之絲氧基，⑷環炫基， ⑹視需要經—至二個選自自素原子、氰基、_、三鹵素貌基與貌基氧基之基團取代之芳基，⑴視需要經—至二個 318695 13 -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、貌基與三鹵素烧基之基團取代之餘和或不飽和雜環基。此酿基之具體實例可為（al)f酿基，㈤）c卜道基—幾土一，如乙醯基、丙酿基等；三齒素_Ch烧基-幾基，例如一氟乙醯基等，或氰基_Ci 6烷基_羰基，例如氰乙醯基， (山(^6炫基氧基—裁基’例如甲氧幾基、乙氧幾基 '三級 :乳幾基等；或芳n道基氧基基，例如苯甲氧基 I叛f，（dl)C3-8環烷基-羰基，例如環丙基羰基、環戊基羰 1基等，（el)芳基-羰基，例如苯甲醯基；單或二鹵芳基一羰基，例如氯苯甲.酿基、氟苯甲醯基、二氟苯甲醯基等；氰 f芳基-羰基，例如氰苯甲醯基；三鹵素6烷基_芳基一 2基’、例如二氟甲基苯甲醯基；或三鹵素6烷基氧基_ 芳基幾基，例如二氟甲氧基苯甲酿基，（H)胺甲醯基、 N (Ch烷基）胺甲醯基，或（gl)呋喃甲醯基、噻吩甲醯基、廣°塞吩甲醯基、氛嗔吩甲醯基"比咬基幾基、氣n比咬基羰基、氰吡啶基羰基、三氟甲基吡啶基羰基或处畊基羰基。本發明之化合物[I ]當中’較佳之化合物實例包括化合物[I ]中， R與R相同或不同且為視需要經一至二個選自鹵素原子、氰基、二鹵素烷基、烷基氧基、烷基硫基、烷亞磺醯基與烷磺醯基之基團取代之苯基； R為（a)氫原子，（b)視需要經一至三個選自下列之基團取代之烷基：鹵素原子、氰基、烷基氧基、烷基硫基、醯基、胺基、醯胺基、胺曱醯基、烷基胺曱醯基胺基、烷 14 3]8695 1378922 %醯基胺基、二（烷基）胺磺醯基胺基與飽和或不飽和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烷基之基團取代），（c)視需要經一至二個烷基取代之胺磺醯基，或（d)飽和或不飽和5至6員雜環基（該雜環基視需要可經一至二個選自侧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-MH-之基團， Q為單鍵、氧原子或伸炫基， R4為（a)視需要經一至三個選自鹵素原子、氰基與烷磺醯基之基團取代之芳基，（〇環烷基，（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、視需要經一至三個鹵素原子取代之烷基、視需要經一至二個烷基取代之胺基、胺曱醯基與醯基，（d)式-N(R5)(R6)之基團，或（e)下式之螺雜環基：Wherein 1 is the same as or different from rb and is a hydrogen atom or an alkyl group, and q and r are integers of 1 or 2. Preferred examples of R, R3, R4, r5, r6, and % in the remainder or the unsaturated residue in R or R, including a saturated or unsaturated 5- to 7-membered heterocyclic group containing nitrogen, oxygen or sulfur, For example, a nitrogen-based group, a pyrrolyl group, a pyrrolidinyl group, a hexahydropyridyl group, a pyridyl group, a hexahydropyridinyl group, a pyrimidinyl group, a pyridinium group, an azepanyl group, a tetrahydropyranyl group, a tetrahydrogen group Thioppyranyl, morpholinyl, 318695 12 1378922, thiofenoflavinyl, beta-septenyl, tetrahydro-β-senoyl, sir-t-seat, iso-scr, sputum. Sit, iso-Ovazolyl, oxadiazolyl, tetrazolyl or acridinyl. Further, the above saturated or unsaturated nitrogen-containing heterocyclic group in 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) a hydroxyl group, (c) cyano '(d) pendant oxy group, (e) alkyl group substituted with one to three halogen atoms as desired, (1;) alkyloxyalkyl group, (g) aminoalkyl group' (h) The hospital is a continuation of the base of the kiln base (丨), the base of the base, (] ·) ring base, (k) arylalkyl, (1) alkyl substituted by one to three halogen atoms as needed An oxy group, (m) a carboxyl group, (n) an amine group optionally substituted with one or two groups selected from an alkyl group and a fluorenyl group, (0) an amine thiol group substituted with one to two alkyl groups as required, (Ρ) fluorenyl, (q) alkylthio, (r) alkylsulfinyl, (s) alkanesulfonyl, (t) optionally substituted with one to two alkyl sulfonyl groups, aromatic a sulfonyl group, (V) aryl group, which may optionally have one to three alkyl groups selected from a halogen atom, a cyano group, optionally substituted with one to three halogen atoms, an alkyloxy group and an alkanesulfonyl group. a group substituted, and (w) a heteroaryl group, the heteroaryl group as needed It may be - to three substituents selected from an optionally - substituted with from three to prime the alkyl group, substituted with a cyano atom tooth element group. Examples of RR, R, R, R6, only 8 and R9 in the fluorenyl group, including a group consisting of a carboxylic acid compound of the formula Rx-CO〇H [Ac-丨], wherein a group consisting of a hydroxyl group, in other words, an formula r-co a group wherein RX is (4) a hydrogen atom, (8) a group substituted by a halogen atom, a cyano group, and a group of a sulphate as needed - (4) a aryl group substituted with an aryl group as needed , (4) cyclodextrin, (6) as needed - to two aryl groups selected from the group consisting of a self-atomic atom, a cyano group, a _, a trihalogen group and a morphyl group, (1) as needed - to two 318695 13 -Alkyl-substituted amine group, or (g) a residual or unsaturated heterocyclic group substituted by one or two groups selected from the group consisting of a halogen atom, a cyano group, a top group and a trihalo group. Specific examples of the brewing base may be (al) f-bristing, (5)) c-channel----------------------------------- Or the like, or a cyano-Ci 6 alkyl-carbonyl group, such as a cyanoacetinyl group, (Mountainment, such as methoxyl group, ethoxy group, ethoxy group) Or an n-hydroxy group, such as benzyloxy I, f, (dl) C3-8 cycloalkyl-carbonyl, such as cyclopropylcarbonyl, cyclopentylcarbonyl 1 , etc., (el) aryl a carbonyl group, such as a benzylidene group; a mono or dihaloaryl-carbonyl group, such as a chlorobenzyl group, a fluorophenyl group, a fluorobenzhydryl group, a difluorobenzhydryl group, etc.; a cyanaryl-carbonyl group such as cyanide; Benzyl fluorenyl; trihalo 6 alkyl-aryl-2 yl, such as difluoromethyl benzhydryl; or trihalo 6 alkyloxy aryl group, such as difluoromethoxy benzoyl Stuffed base, (H) amine-methyl sulfhydryl, N (Ch alkyl) amine methyl sulfhydryl, or (gl) furanyl thiol, thiophenemethyl thiol, glucosylmethyl thiol, thiophenanthracene "Thank base, gas n ratio carbonyl, cyanopyridylcarbonyl, trifluoromethylpyridylcarbonyl Wherein the preferred compound of the compound [I] of the present invention includes the compound [I], R is the same as or different from R and is optionally selected from one or two selected from the group consisting of a halogen atom, a cyano group and a dihaloalkane. 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 (a), and (b) is optionally selected from one to three Substituted alkyl group: halogen atom, cyano group, alkyloxy group, alkylthio group, decyl group, amine group, decylamino group, amine fluorenyl group, alkyl amine decylamino group, alkane 14 3] 8695 1378922 % mercaptoamino group, di(alkyl)amine sulfonylamino group and saturated or unsaturated 5 to 6 membered heterocyclic group (the heterocyclic group may be optionally one to two selected from the group consisting of pendant oxy groups Substituted with an alkyl group), (c) an amine sulfonyl group substituted by one to two alkyl groups, or (d) a saturated or unsaturated 5 to 6 membered heterocyclic group (this heterocyclic group may be optionally used In the group of one or two selected from the group consisting of a pendant oxy group and an alkyl group; and wherein E is a group of the formula (i), Q1 is a single bond or a group of the formula -MH-, and Q is a single bond or an oxygen atom. Or dazzle a group, R4 is (a) an aryl group optionally substituted with one to three groups selected from a halogen atom, a cyano group and an alkanesulfonyl group, (cycloalkylene group, (c) optionally selected from one to two a saturated or unsaturated 5 to 7 membered heteromonocyclic group substituted by the following groups: a halogen atom, a pendant oxy group, a cyano group, an alkyl group optionally substituted with one to three halogen atoms, optionally substituted with one to two alkyl groups An amine group, an amine sulfhydryl group and a fluorenyl group, (d) a group of the formula -N(R5)(R6), or (e) a spiroheterocyclic group of the formula:

R為（1)視需要經一至三個選自齒素原子、胺基、烧基氧基、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)視需要經胺甲醯基取代之環烷基，（3)式 -N(R8)〇〇之基團，（4)醯基，（5)視需要經一至三個選自鹵素原子、氣基、二素烧基與烧基氧基之基團取代之芳 318695 15 1378922 -基，或（6)視需要經一至四個選自下列基團取代之飽和或不飽和5至7員雜單環基：_素原子、側氧基、視需要經一至二個鹵素原子取代之烷基、烷基氧基烷基、芳基烷基、視需要經一至三個鹵素原子取代之烷基氧基、醯基、羧基、胺甲lit基 '院y酿基、視需要經一至二個烧基取代之胺續醯基、芳磺醯基、視需要經一至二個選自烷基與醯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籲代之院基、鹵素原子與氰基之基團取代之雜芳基， R為虱原子，RB為烧基，9與1•為1之整數， R8為氫原子或烷基，及 R9為視需要經一至二個選自侧氧基、氰基與芳基之基團取代之烷基；醯基；芳基或雜芳基。此外，本發明之化合物[I ]當中，其他較佳化合物之實例包括：鲁（1)化合物[I]中，R1與R2相同或不同且為鹵素苯基；R3為炫基或院基氧基烧基；E為式（Π)之基團，式中，尺為（&) 視需要經一至三個鹵素原子取代之烷基，（b)烷基氧基烷基’（c)視需要經選自經基與烧基之基團取代之環烧基，（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（〇視需要經烷磺醯基、醯基或雜芳基取代之飽和或不飽和雜環基； (2)化合物[I]中，R1與R2相同或不同且為卤素苯基；R3為烧基或炫基氧基烧基；E為式（iii)之基團，式中，rai為胺 318695 16 1378922 .基或下式之基團：，让為3至4之整數； (3)化s物[I]_，r與R2相同或不同且為鹵素苯基；尺3為烷基或烷基氧基烷基；E為式（iv)之基團，式中，RAZ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。、” 鲁當中，更佳之化合物實例包括化合物[I]中， R1為經一至二個選自鹵素原子與三鹵素_Cl_4烷基之基團取代之苯基； R2為經一至二個鹵素原子取代之苯基； R3為視需要經一至三個鹵素原子取代之Ch烷基、Ch 烷基氧基-Ch烷基、氰基-Ch烷基氧基、胺基-Ch烷基（該基團之胺基部份可視需要經選自醯基、二（烷基）胺磺醯基鲁與Ch烷基-胺甲醢基之基團取代）、胺曱醯基-Ch烷基、噚唑基-Cw烷基（該基團之噚唑基部份可視需要經一至二個Cw烷基取代）、噻唑基-Ch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、胺曱醯基與Cl-4 烷基-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 17 318695 Ϊ378922 ' R為（a)Cl—4烷基，（b)視需要經胺甲醯基取代之c5_8 裱烷基，（c)視需要經一至二個鹵素原子取代之苯基，（幻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Cm烷基、視需要經一至二個鹵素原子取代之苯基、氰笨基、Cl_4烷基氧基_苯基、醯基、苯基烷基、羧基、視需要經一至二個選自Ci_4烷基與氰基之基團取代之胺基、胺甲醯基以及視需要經一至二個選自鹵素鲁原子、C"烷基與三鹵素—Ch烷基之基團取代之吡啶基，或（e)視需要經一至二個選自c,_4院基與。比咬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，R1與R2相同或不同且為鹵素苯基；只3為C,—4烷基、三鹵素-Cm烷基或c,_4烷基氧基吒^烷基； E為式（ii)之基團，式中，R為（a)視需要經一至三個鹵素鲁原子取代之Ci-4烧基，（b)視需要經選自羥基與Ch烷基之基團取代之C5-8 院基’（c)Ci-4烧基硫基，（d)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（e)視需要經選自Cl_4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； R為Ci-4烧基或Ci η烧基氧基-Ci-4炫基；E為式（iii)之基團，式中，RA1為胺基或下式之基團： 318695 18 1378922R is (1) an alkyl group substituted with one to three groups selected from a dentin atom, an amine group, a decyloxy group, an alkylthio group, an alkylsulfinyl group, an alkanesulfonyl group and an aryl group, as needed. '(2) a cycloalkyl group substituted with an amine mercapto group, (3) a group of the formula -N(R8) fluorene, (4) a fluorenyl group, and (5) optionally one to three selected from halogen a aryl 318695 15 1378922-based group substituted with an atom, a gas group, a dialkyl group and a decyloxy group, or (6) optionally substituted with one to four saturated or unsaturated groups selected from the following groups: 5 to 7 A heteromonocyclic group: an atom, a pendant oxy group, an alkyl group substituted with one to two halogen atoms, an alkyloxyalkyl group, an arylalkyl group, or an alkyl group substituted with one to three halogen atoms as needed a base group, a fluorenyl group, a carboxyl group, an amine group, an amine group which is substituted by one to two alkyl groups, an arylsulfonyl group, and optionally one or two groups selected from an alkyl group and An amine group substituted with a thiol group, an aryl group optionally substituted with one to two dentate atoms, and optionally one to two selected from the group consisting of: one to three halogen atoms as needed a heteroaryl group substituted with a halogen atom and a cyano group, R is a halogen atom, RB is an alkyl group, 9 and 1 are an integer of 1, R8 is a hydrogen atom or an alkyl group, and R9 is as desired. Two alkyl groups selected from the group consisting of pendant oxy, cyano and aryl; fluorenyl; aryl or heteroaryl. Further, among the compounds [I] of the present invention, examples of other preferred compounds include: Lu (1) In the compound [I], R1 and R2 are the same or different and are a halogen phenyl group; R3 is a leukoyl group or a siloxane group. a group of the formula (E) wherein, the ruler is (&) an alkyl group substituted with one to three halogen atoms as needed, and (b) an alkyloxyalkyl group (c) is optionally a cycloalkyl group substituted with a group selected from a group consisting of a group and a group, and (d) an alkylthio group '(e) optionally substituted with one or two aryl groups selected from a halogen atom and a cyano group, or (Suppose a saturated or unsaturated heterocyclic group which is substituted with an alkanesulfonyl group, a fluorenyl group or a heteroaryl group; (2) In the compound [I], R1 and R2 are the same or different and are a halogen phenyl group; Or a thioloxyalkyl group; E is a group of the formula (iii), wherein rai is an amine 318695 16 1378922. A group of the formula or the formula: let an integer of 3 to 4; (3) s [I]_, r is the same or different from R2 and is a halogen phenyl group; the rule 3 is an alkyl group or an alkyloxyalkyl group; and E is a group of the formula (iv), wherein RAZ is as needed 4 to 7 members substituted with pyrimidinyl or halopyrimidinyl In the case of the compound [I], R1 is a phenyl group substituted with one or two groups selected from a halogen atom and a trihalogen_Cl_4 alkyl group; R2 is a compound of the compound [I]; a phenyl group substituted with one to two halogen atoms; R3 is a Ch alkyl group substituted with one to three halogen atoms, a Ch alkyloxy-Ch alkyl group, a cyano-Ch alkyloxy group, an amine group-Ch Alkyl group (the amine moiety of the group may optionally be substituted with a group selected from the group consisting of a fluorenyl group, a di(alkyl)amine sulfonyl ruthenium group and a Ch alkyl-amine carbaryl group), an amine fluorenyl-Ch An alkyl group, a carbazolyl-Cw alkyl group (the carbazole moiety of the group may optionally be substituted with one to two Cw alkyl groups), a thiazolyl-Ch alkyl group; and E is a group of the formula (i), Q1 is a single bond, Q2 is a single bond or a Ch alkyl group, and R4 is saturated or not substituted with one to three groups selected from the group consisting of a pendant oxy group, an amine fluorenyl group and a Cl-4 alkyl-amino group. Saturated 5 to 6 membered heteromonocyclic groups, or a group of the formula -NH(R6), and 17 318695 Ϊ378922 'R is (a)Cl-4 alkyl, (b) optionally substituted with an amine mercapto group C5_8 decyl, (c) as needed A phenyl group substituted with one to two halogen atoms (a pseudo-saturated or unsaturated 5- to 7-membered heteromonocyclic group substituted with one to three groups selected from the group consisting of a halogen atom, a pendant oxy group, and optionally a Cm alkyl group substituted with three halogen atoms, optionally substituted with one to two halogen atoms, a phenyl group, a cyanyl group, a C 4 alkyloxy group, a phenyl group, a phenyl group, a carboxyl group, and optionally Two amine groups selected from the group consisting of a Ci_4 alkyl group and a cyano group, an amine carbenyl group, and optionally one or two groups selected from a halogen atom, a C" alkyl group and a trihalogen-Ch alkyl group; The pyridyl group, or (e) is optionally selected from one or two bases selected from the group consisting of c, _4. An amine group substituted with a group of a bite group. Examples of other preferred compounds include: (1) In the compound [I], R1 is the same as or different from R2 and is a halogen phenyl group; only 3 is C, -4 alkyl, trihalo-Cm alkyl or c, _4 Alkyloxy oxime alkyl; E is a group of the formula (ii), wherein R is (a) a Ci-4 alkyl group substituted by one to three halogen argon atoms, (b) as needed a C5-8-derived '(c)Ci-4 alkylthio group substituted with a group selected from a hydroxyl group and a Ch alkyl group, (d) optionally substituted with one or two groups selected from a halogen atom and a cyano group An aryl group, or (e) a saturated or unsaturated heterocyclic group substituted with a group selected from the group consisting of a Cl 4 alkanesulfonyl group, a fluorenyl group and a heteroaryl group; (2) In the compound [I], R 1 is the same as R 2 Or different and is a halogen phenyl group; R is a Ci-4 alkyl group or a Ci benzyloxy-Ci-4 succinyl group; E is a group of the formula (iii), wherein RA1 is an amine group or the following formula Group: 318695 18 1378922

，让為3至4之整數，·或 (/ )化5物[I ]中，R與R2相同或不同且為鹵素苯基； R為Ch烷基或Cl_4烷基氧基_Ci 4烷基；E為式（iv)之基團式中，R為視需要經°密咬基或三鹵素-Cl-4烧基-嘴咬基取代之4至7員脂肪族雜環基。當中’又更佳之化合物實例包括化合物[丨]中，籲R為經選自氯4子與三鹵素-〔!禮基之基團取代之苯基； ^為經一至二個選自氯原子或氟原子之基團取代之笨基； R為視需要經一至三個選自下列之基團取代之Cm烷基：氟原子、氰基、Ch烷基氧基、胺基-Ch烷基、Ci 3烷基一羰基胺基、Cl—3烷基-胺甲磺醯基胺基、Cl_3烷基_磺醯基胺基、一（Cl — 3烧基）胺績酿基胺基、^塞唾基與視需要經一至二個C]-3烷基取代之噚唑基；以及 φ E為式（i)之基團， Q1為單鍵， Q為單鍵或Cl-4伸院基， R4為視需要經一至二個選自侧氧基、Ci 3烷基胺基與胺甲疏基基團取代之飽和或不飽和5至6員雜單環基，咬為式-NH(R6)之基團，及 … R6為（a)Ci-3烷基’（b)視需要經胺曱醯基取代之C3 6 環烷基’（c)視需要經一至二個選自氣原子、氟原子、狀基與Cl-3统基氧基之基團取代之笨基’（d)視需要經一至三個 318695 19 1378922 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Cl_3烷基、二氟-Cl-3烷基-幾基、Cl-3燒基氧基-Cl—3烧基-羰基、氰基-Cm烷基-羰基、胺甲醯基、視需要經一至二個選自 C〗-3烷基、三氟-c,—3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、Ci3 烷基氧基與三氟-C!-3烷基之基團取代之苯甲醯基、羧基、苯曱基、視需要經一至二個選自氯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（e) 經一至二個選自Ch烷基與吡啶基之基團取代之胺基。當中，其他又更佳之化合物[丨]之實例包括： (1) 化3。物[I]中，R為氣苯基或三氟甲基苯基；r2為氯苯基；尺3為CH烧基；E為式（ii)之基團，式中三烷基；或 R2為氯苯基；R3為C,-3烷 RA1為5至6員脂肪族雜環 R2為氯苯基；R3為Ci_3烷 DA2為視需要經三氟-C,-3烷 (2) 化合物[I]中’ ri為氣苯基基；E為式（iii)之基團，式中基；或 (3) 化合物[I]中，ri為氣苯基基；E為式（iv)之基團，式中基密絲取代之5至6員軸族雜環’基本發明之化合物⑴當中，特別佳化合物之，選自下列所構成群組之化合物或其醫藥上可接受之 1 -（2-氯苯基）-5-(4_氯笨基） 1類· 4甲氧基~3-[Ν-(1-氮雜環 318695 20 1378922 -庚基）胺甲醯基]-1H_°比唑； 1-(2 -氯苯基）_5 -（4 -氣本基）-4-甲氧基- 3-[N-(4-四氫派喃基）胺甲醯基]-1H-°比唑； 1-(2-氯笨基）-5-(4-氯苯基）-4-乙氧基-3-[N-(N-嗎福啉基）胺曱醯基]-1H-吡唑；卜（2-氯苯基）-5-(4-氯苯基）-4-甲氧基-3-[N-(2, 2, 2-三氟乙基）胺甲醯基]-1H-吡唑； 1-(2-氯苯基）-5-(4-氯苯基）-4-甲氧基-3-[N-(N-六氫。比 •啶基）胺甲醯基]-1Η-吡唑； 1 -（2 -鼠苯基）- 5-（4 -氣本基）-4 -曱乳基- 3- [Ν -（Ν-嗎福琳基）胺甲醯基]-1Η-吡唑； 1-(2-氯苯基）-5-(4-氯苯基）-4-甲氧基-3-[N-(l-吼ρ各〇定基）胺甲醯基]-1Η_吡唑； 1-(2-氣苯基）-5-( 4-氯苯基）-4-乙氧基-3-[Ν-(Ν-六氫"比啶基）胺甲醯基]-1Η-吡唑；鲁1-(2-氯苯基）-5-(4-氯苯基）-4-(2-甲氧乙氧基）-3-[]^- (Ν-六氫σ比〇定基）胺甲醯基]-1Η-0比唾； 1-(2-氯苯基）-5-(4-氯苯基）-4-曱氧基-3-[l-(N-嗎福琳基）乙醯基]-1Η-吡唑； 1-(2, 4-二氯苯基）-5-(4-氣苯基）-4-甲氧基-3-[Ν-(Ν-六氫°比咬基）胺曱蕴基]-1 Η-η比唆； 1-(2, 4-二氯苯基）-5-(4-氣苯基）~4-曱氧基-3-[Ν-(1-«比咯啶基）胺曱醯基]-1Η-吡唑； 1-(2，4-·一氣本基）_5-(4 -鼠苯基）~4-曱氧基- 3- [Ν-(Ν -嗎 318695 21 1378922 -福琳基）胺曱醯基]-1 Η-0比0坐；卜（2, 4-二氯苯基）-5-(4-氯苯基）-4-曱氧基-3-[〇Γ，ΙΓ-二甲基肼基）羰基]-1H-吡唑； 1-（2-氯苯基）-5-(4-氯苯基）-4-曱氧基-3-(N-環戊基胺甲酿基）_1Η-π比。坐； 1-(2-氣苯基）-5-(4-氯苯基）-4-曱氧基-3-(N-異丙基胺曱酸基）~1Η-π比0坐； 1-(2, 4-二氯苯基）-5-(4-氣苯基）-4-二氟曱氧基 • -3-[N-( 1 比1»各σ定基）胺甲酸基]-1 Η-α比唾； 1-(2-氣-4-氟苯基）-5-(4-氯苯基）-4-曱氧基-3-[Ν-(Ν-嗎福啉基）胺甲醯基]-1Η-吡唑； 1-(2-氣苯基）-5-(4-三氟曱基苯基）-4-曱氧基-3-[(Ν' Ν' -二曱基肼基）羰基]-1Η-吡唑； 1 -（2-氣苯基）-5_(4-三氟甲基苯基）-4-甲氧基-3-[Ν-(1_ 〇比σ各咬基）胺甲醯基]-1 Η-σ比嗤；鲁1-(2-氯苯基）-5-(4-三It曱基苯基）-4-曱氧基-3-[Ν-(Ν_ 嗎福啉基）胺曱醯基]-1Η-吡唑； 1-(2-氯苯基）-5_(4_三氟曱基苯基）-4 -曱氧基-3-[Ν-(4- 四氫旅喃基）胺曱醯基]-1 Η-η比唾； 1-(2 -氣苯基）-5-(4 -氯苯基）-4 -甲氧基- 3-{Ν-[1-( 4-氟苯曱醯基）六氫吡哄-4-基]胺曱醯基丨-ΙΗ-吡唑； 1-(2-氯苯基）-5-(4-三氟曱基苯基）-4-二氟曱氧基_3_ [(N，N -二曱基骄基）徵基]-1Η-σΗ^σ坐； 1-(2-氯苯基）-5-(4-三氟曱基苯基）-4-二氟甲氧基_3-[N- 318695 22 1378922 (4-四氫哌喃基）胺甲醯基]-in-吡唑；卜（2-氯苯基）-5-(4-三氟f基笨基）_4_二i f氧基 (1-吡咯啶基）胺曱醯基]-1H-吡唑； (卜吡咯咬 1-(2-氯苯基）-5-(4-氯苯基）-4-曱氧基一基）胺甲醯基]-1H-吡唑； 1-(2-氯苯基）-5-(4-氯苯基）-4-曱氧基[恥（順一2 _ '^基_ N -嗎福嚇基）胺甲酿基]—1 η -〇比。坐，· 1-(2-氯苯基）-5-(4-氯苯基）-4-甲氧基-3-「μ~η • L1N~14, 4 -二氟 -N-六氫吼啶基）胺甲醯基]-in-吡唑； 1-(2-氯苯基）-5-(4-氯苯基）-4-甲氧基-3-[n~(4—二氟曱基-N-六氫吡啶基）胺曱醯基]— in-吡唑； 1-(2-氣苯基）-5-(4-氯苯基）-4-甲氧基一基肼基）羰基]-1H-吡唑； ’ 一甲 1 (2-氯本基）-5-(4-氣苯基）-4-乙氧基~3-f Γ/ΐ /*Let an integer of 3 to 4, or (or) 5 of the compound [I], R and R2 are the same or different and are a halogen phenyl group; R is a C alkyl group or a C 4 alkyloxy group _Ci 4 alkyl group Wherein E is a group of the formula (iv), and R is a 4 to 7 membered aliphatic heterocyclic group which is optionally substituted with a dimethyl group or a trihalogen-Cl-4 alkyl-mouth group. In the case of a 'better compound, including the compound [丨], R is a phenyl group substituted with a group selected from the group consisting of a chloro 4 and a trihalogen-[; a group of one or two selected from a chlorine atom or a styl group substituted with a group of a fluorine atom; R is a Cm alkyl group optionally substituted with one to three groups selected from the group consisting of a fluorine atom, a cyano group, a Ch alkyl group, an amino group-Ch alkyl group, and a Ci group. 3-alkyl-carbonylamino group, Cl-3 alkyl-amine mesosulfonylamino group, Cl_3 alkyl-sulfonylamino group, mono(Cl-3)alkylamine amine group, a carbazole group substituted with one to two C]-3 alkyl groups as desired; and φ E is a group of the formula (i), Q1 is a single bond, Q is a single bond or a Cl-4 stretching group, R4 a saturated or unsaturated 5 to 6 membered heteromonocyclic group substituted by one to two, optionally substituted with a pendant oxy group, a Ci 3 alkylamino group and an amine methylidyl group, as desired, the formula -NH(R6) a group, and ... R6 is (a) Ci-3 alkyl '(b) optionally substituted with an amine sulfhydryl group C3 6 cycloalkyl '(c) optionally one to two selected from a gas atom, a fluorine atom a stupid base substituted with a group of a C3-formyloxy group (d) as needed One to three 318695 19 1378922 saturated or unsaturated 5 to 7 membered heteromonocyclic groups substituted with a group selected from the group consisting of a fluorine atom, a pendant oxy group, a Cl_3 alkyl group optionally substituted with one to three fluorine atoms, and two Fluorine-Cl-3 alkyl-aryl, Cl-3alkyloxy-Cl-3 alkyl-carbonyl, cyano-Cm alkyl-carbonyl, aminemethanyl, optionally from one to two selected from C An amine group substituted with a group of -3 alkyl, trifluoro-c,-3 alkyl-carbonyl and benzhydryl, optionally one to two selected from a chlorine atom, a fluorine atom, a cyano group, a Ci3 alkyl group a benzyl group substituted with a group of an oxy group and a trifluoro-C!-3 alkyl group, a carboxyl group, a phenyl fluorenyl group, a phenyl group optionally substituted with one or two groups selected from a chlorine 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 (e) one to two selected from a C alkyl group and a pyridyl group The amine group substituted by the group. Examples of other and better compounds [丨] include: (1) Chemicals 3. In the compound [I], R is a gas phenyl or trifluoromethylphenyl group; r2 is a chlorophenyl group; the rule 3 is a CH alkyl group; and E is a group of the formula (ii), wherein a trialkyl group; or R2 Is a chlorophenyl group; R3 is C, -3 alkane RA1 is a 5- to 6-membered aliphatic heterocyclic ring R2 is a chlorophenyl group; R3 is a Ci_3 alkane DA2 as a trifluoro-C,-3 alkane (2) compound as needed [ Wherein 'ri is a gas phenyl group; E is a group of the formula (iii), a group of the formula; or (3) in the compound [I], ri is a gas phenyl group; and E is a group of the formula (iv) In the compound (1) of the basic invention, the compound of the invention is selected from the group consisting of the following compounds, and a compound selected from the group consisting of the following compounds or a pharmaceutically acceptable 1 - (2) -Chlorophenyl)-5-(4-chlorophenyl) 1 type·4methoxy~3-[Ν-(1-nitrogen heterocycle 318695 20 1378922-heptyl)aminemethanyl]-1H_° ratio Oxazole; 1-(2-chlorophenyl)_5-(4-carbomethoxy)-4-methoxy-3-(N-(4-tetrahydropyranyl)aminecarbamyl]-1H-° Butyrazole; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-ethoxy-3-[N-(N-morpholine)amine fluorenyl]-1H- Pyrazole; di(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-[N-(2, 2, 2-three Fluoroethyl)amine-mercapto]-1H-pyrazole; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-[N-(N-six Hydrogen. Bis-pyridyl)amine-methylmercapto]-1Η-pyrazole; 1 -(2 -murinephenyl)-5-(4-carbophenyl)-4-hydrazino- 3- [Ν-( Ν-moffinyl)amine-mercapto]-1Η-pyrazole; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-[N-( L-吼ρ 〇 ) ) ) ) ) ) ) ) ) ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; (Ν-hexahydro"pyridyl)aminemethanyl]-1Η-pyrazole; Lu 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-(2-methoxy Ethoxy)-3-[]^-(Ν-hexahydroσ 〇〇 ) ) ) ) ) ) ] ] ] ] ] 比 ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; 4-yloxy-3-[l-(N-moffinyl)ethinyl]-1Η-pyrazole; 1-(2,4-dichlorophenyl)-5-(4- Phenyl phenyl)-4-methoxy-3-[Ν-(Ν-hexahydroheptyl) amide group]-1 Η-η ratio 唆; 1-(2, 4-dichlorophenyl) -5-(4-Phenylphenyl)~4-decyloxy-3-[indole-(1-«pyrrolidyl)amine fluorenyl]-1Η-pyrazole; 1-(2,4- ·One gas base) _5-(4-Nopylphenyl)~4-曱oxy- 3- [Ν-(Ν - 318695 21 1378922 - Folinyl) Aminyl]-1 Η-0 to 0 sitting; Bu (2, 4-dichlorophenyl)-5-(4-chlorophenyl)-4-decyloxy -3-[〇Γ,ΙΓ-dimethylindolyl)carbonyl]-1H-pyrazole; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3 - (N-cyclopentylamine-based)_1Η-π ratio. Sitting; 1-(2-phenylphenyl)-5-(4-chlorophenyl)-4-decyloxy-3-(N-isopropylamine decanoate)~1Η-π ratio 0 sitting; 1 -(2,4-dichlorophenyl)-5-(4-phenylphenyl)-4-difluorodecyloxy; -3-[N-( 1 to 1» each sigma) carbamic acid group]- 1 Η-α is more than saliva; 1-(2-carb-4-fluorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-[Ν-(Ν-morpholinyl) Aminomethylidene]-1Η-pyrazole; 1-(2-phenylphenyl)-5-(4-trifluorodecylphenyl)-4-methoxy-3-[(Ν' Ν' - two曱肼 )) carbonyl]-1 Η-pyrazole; 1-(2-phenylphenyl)-5-(4-trifluoromethylphenyl)-4-methoxy-3-[Ν-(1_ 〇 ratio σ 咬 ) ) 胺 ) ) ) 胺胺胺 σ σ σ σ σ σ 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- [Ν-(Ν_ morpholino)amine fluorenyl]-1Η-pyrazole; 1-(2-chlorophenyl)-5-(4-trifluorodecylphenyl)-4-decyloxy-3 -[Ν-(4-tetrahydromethane) amidino]-1 Η-η than saliva; 1-(2-(phenylphenyl)-5-(4-chlorophenyl)-4-methoxy -3-{Ν-[1-(4-fluorophenylindenyl)hexahydropyridin-4-yl]amine-indenyl-indole-pyrazole; 1-(2-chlorophenyl)-5 -(4-trifluorodecylphenyl)-4-difluorodecyloxy_3_ [(N , N-dimercapto-based radix]-1Η-σΗ^σ sitting; 1-(2-chlorophenyl)-5-(4-trifluorodecylphenyl)-4-difluoromethoxy _3-[N- 318695 22 1378922 (4-tetrahydropyranyl)amine-methylmethyl]-in-pyrazole; Bu (2-chlorophenyl)-5-(4-trifluorof-phenyl) _4_Di-Isooxy(1-pyrrolidinyl)amine hydrazino]-1H-pyrazole; (Bipylate 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-曱oxy-yl)amine-methylmercapto]-1H-pyrazole; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-anthraceneoxy[Shame (Shun Yi 2 _ '^ Base _ N - 福吓 ) ) ) 胺胺胺胺 — — 。。。。。。。 Sit, 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-"μ~η • L1N~14, 4-difluoro-N-hexahydroindole Iridyl)amine-mercapto]-in-pyrazole; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-[n~(4-difluoro) Mercapto-N-hexahydropyridyl)amine fluorenyl]-in-pyrazole; 1-(2-phenylphenyl)-5-(4-chlorophenyl)-4-methoxy-yl fluorenyl )carbonyl]-1H-pyrazole; 'monomethyl 1 (2-chlorobenzyl)-5-(4-phenylphenyl)-4-ethoxy~3-f Γ/ΐ /*

LiN~L4~四氫派喃基）胺甲醯基]-1H-吡唑；籲卜（2-氣苯基）-5-(4-三氟甲基苯基）—4—乙氧基 ~一甲基耕基）幾基]_1Η-β比0坐； 1 (2-氣本基）-5-(4-氯苯基）-4-(2 -甲氧基乙氧基）— 3_[ν一 (4 -四氫旅喃基）胺甲醯基]_ifj-η比π坐； 1-(2-氣苯基）-5-(4-三氟甲基苯基）-4-(2-甲氧基乙氧基） -3-[Ν-(1-吡咯啶基）胺甲醯基]_ih-吡唑； 1-(2-氯苯基）-5-(4-三氟甲基苯基）-4-(2-甲氧基乙氧基） -3-[N-(N-嗎福啉基）胺曱醯基]_iff-吡唑； 1 (2氯本基）-5-(4-氯苯基）-4_甲氧基-3-[n~(i 1 一二側 318695 23 1378922 、氧基硫代嗎福啉基_4_基）胺曱醯基卜^—吡唑； 1-(2-氯苯基）_5_(4_氣苯基）_4_甲氧基_3_[n_(四氫呋喃 -3-基）胺曱醯基]一1H_吡唑； 1一（2:氯苯基）-5-(4-氯苯基）-4一甲氧基-3-[.(4-苯甲醯基六氫°比哄-1-基）胺曱醯基]_1H一吡唑；卜（2-氯苯基）-5_(4__氯苯基）-4_正丙氧一甲基肼基)魏基Hhh (，N~- 1-(2-氣苯基）-5 — (4_氯苯基）_4_曱氧基氯苯 _曱醯基）六氫吡哄—i—基]胺曱醯基卜1H_吡唑； 1-(2-氣苯基）-5一（4_氯苯基）_4_曱氧基_3_{n_[4^4一三氟曱基苯曱醯基）六氫吡畊-1-基]胺曱醯基丨-ΙΗ-吡唑； 1-(2-氣苯基）-5一（4_氯苯基）一4_曱氧基_3_{n_[4_(3一氟苯曱醯基）六氫吡哄-1一基]胺甲醯基卜1H_吡唑； 1-(2-氯苯基）-5-(4-氯苯基）—4_曱氧基_3_[(1，卜二側氧基硫代嗎福啉-4-基）乙醯基]-1H-吡唑；氯苯基）_5-(4_氯苯基）_4_二氟甲氧基一—吡 σ各啶基）胺甲醯基]-1H-吡唑；LiN~L4~tetrahydropyranyl)aminemethanyl]-1H-pyrazole; 吁(2-phenylphenyl)-5-(4-trifluoromethylphenyl)-4-ethoxy~ Monomethyl] kiln]_1Η-β is 0; 1 (2-carbyl)-5-(4-chlorophenyl)-4-(2-methoxyethoxy)-3_[ν 1-(4-tetrahydro-bromo-yl)aminomethane]_ifj-η is π-position; 1-(2-phenylphenyl)-5-(4-trifluoromethylphenyl)-4-(2- Methoxyethoxy)-3-[Ν-(1-pyrrolidinyl)aminecarboxylidene]-ih-pyrazole; 1-(2-chlorophenyl)-5-(4-trifluoromethylbenzene 4-(2-methoxyethoxy)-3-[N-(N-morpholino)amine fluorenyl]_iff-pyrazole; 1 (2 chlorophenyl)-5-( 4-chlorophenyl)-4_methoxy-3-[n~(i 1 a two-side 318695 23 1378922, oxythiomorpholinyl-4-yl) amidoxime-pyrazole ; 1-(2-chlorophenyl)_5_(4_gasphenyl)_4_methoxy_3_[n_(tetrahydrofuran-3-yl)amine fluorenyl]-1H_pyrazole; 1 (2: Chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-[.(4-benzylidene hexahydropyran-1-yl)amine thiol]_1H-pyridyl Oxazole; di(2-chlorophenyl)-5_(4__chlorophenyl)-4_n-propoxy-methylindolyl)weiki Hhh (, N~- 1-(2-phenylphenyl)-5-(4-chlorophenyl)_4_decyloxychlorophenyl-fluorenyl)hexahydropyridinium-i-yl]amine sulfhydryl 1H_pyrazole; 1-(2-phenylphenyl)-5-(4-chlorophenyl)_4_decyloxy_3_{n_[4^4-trifluoromethylphenyl) hexahydropyridyl Tung-1-yl]amine-indenyl-indole-pyrazole; 1-(2-phenylphenyl)-5-(4-chlorophenyl)-4-methoxyl_3_{n_[4_(3 Monofluoropyridinyl)hexahydropyridin-1-yl]amine-methylpyridyl 1H-pyrazole; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4_oxo Base_3_[(1, bis-oxothio oxafosolin-4-yl)ethinyl]-1H-pyrazole; chlorophenyl)_5-(4-chlorophenyl)_4_difluoromethyl Oxy-p-pyridinyl)amine-mercapto]-1H-pyrazole;

1-(2-氯苯基）—5_(4_氯苯基）_4_二氟曱氧基一3气（ν, 二甲基肼基）羰基]-1H-吡唑； 1-(2-氯苯基）_5-(4一氯苯基）_4_二氟甲氧基— (4—四氫〇底喃基）胺甲醯基]-1H-吡唑；卜（2-乳苯基）-5—(4_氯苯基）_4_乙氧基_3_{n〜私氟甲醯基）六氫吡畊_；1—基]胺曱醯基卜1H_吡唑； 1-(2-氯苯基）-5—(4_三氟曱基苯基）_4_乙氧基丨.Μ 一 318695 24 1378922 • (4一氣苯甲醯基）六氫吡畊-1-基]胺甲醯基}-111-吡唑； 1-(2-氯苯基）-5-(4-氣苯基卜4-二氟甲氧基-3-[Ν-(1，1_ 一側氧基硫代嗎福啉-4-基）胺甲醯基]-1H-吡唑； 1 -（2-氯苯基）-5_(4一氯苯基）_4一曱氧基_3_{N_[4-(3—氯苯甲酿基）六氫吼畊一 1-基]胺曱醯基丨-ΙΗ-吡唑； 1-(2-氯苯基）-5一（4一氯苯基）—4—曱氧基_3_{N_[4-(2_氯苯 ▼酸基）六氫°比畊~1-基]胺曱醯基}-1H-吡唑； 1-(2-氣笨基）_5一（4一氯苯基）一4_ 曱氧基_3_{N_[4_(3, 4_二氟苯甲醯基）六氫吡哄_丨_基]胺甲醯基卜1H_吡唑； 1 — (2-氣苯基）-5-(4-氯苯基）-4-曱氧基-3-{N-[4-(2, 4-二氣苯曱酿基）六氫吡啡一丨一基]胺曱醯基卜1H_吡唑； 1-(2-氯苯基）-5-(4-氯苯基）_4—曱氧基_3_{N_[4一（3, 5_二敦苯甲酿基）六氫吡哄-1-基]胺曱醯基丨-ΙΗ-吡唑； 1-(2-氣苯基）-5一（4_氯笨基）_4一甲氧基_3_[2_(1_曱磺醯基六氫吡啶-4-基）-1，,3,4-噚二唑-5-基]-1H-吡唑； • 1-(2, 4一二氯苯基）-5-(4-氯苯基）-4-曱氧基-3-[N-(4-氟苯基）胺甲醯基]一1H_吡唑； 1-(2-氯笨基）-5-(4-氯苯基）-4-甲氧基-3-ίΝ-[4-(4-氟苯基）六氫0比啡-1-基]胺曱醯基丨-ΙΗ-吡唑； 1-(2-氯笨基）_5-(4_氯苯基）一4—甲氧基_3_[Ν_(3_三氟甲基0比洛咬基）胺曱醯基]-1Η-吡唑； 1-(2, 4-二氣苯基）_5_(4_三氟甲基苯基）_4_甲氧基_3_ [〇Γ，ΙΤ-二曱基肼基）羰基]_1Η一吡唑； 1-(2’ 4一二氣苯基）-5-(4-三氟甲基苯基）-4-甲氧基_3-[Ν- 318695 25 (N〜嗎福啉基）胺曱醯基]-1H-吡唑；二氯苯基）_5 一（4_三氟甲基苯基）—4一曱氧基―3—[N. 一側氧基―2-四氫噻吩基）胺曱醯基]-1H-吡唑；虱氟笨基）_5_(4-三氟曱基苯基）一 4-甲氧基-3-U、四氫哌喃基）胺曱醯基]-1H-吡唑； | 氣-4-氟笨基）—5一（4一三氟曱基苯基）-4_曱氧基_3_ 嗎福啉基）胺甲醯基]_1H_吡唑；1-(2-chlorophenyl)-5-(4-chlorophenyl)_4-difluoromethoxy 3- gas (ν, dimethylindenyl)carbonyl]-1H-pyrazole; 1-(2- Chlorophenyl)_5-(4-chlorophenyl)_4_difluoromethoxy-(4-tetrahydroindolyl)amine-mercapto]-1H-pyrazole; Bu (2-lactylphenyl) -5-(4_chlorophenyl)_4_ethoxy_3_{n~ fluorocarbamyl)hexahydropyrazine_1-yl]amine sulfhydryl 1H_pyrazole; 1-(2 -Chlorophenyl)-5-(4-trifluorodecylphenyl)_4_ethoxy oxime. Μ 318695 24 1378922 • (4 acetophenoxy) hexahydropyrylene-1-yl]amine A Mercapto}-111-pyrazole; 1-(2-chlorophenyl)-5-(4-carbophenyl-4-difluoromethoxy-3-[indole-(1,1_ one-side oxysulfide) Defosolin-4-yl)amine-mercapto]-1H-pyrazole; 1-(2-chlorophenyl)-5-(4-chlorophenyl)_4-methoxy-_3_{N_[4- (3-chlorobenzyl) hexahydroindole-l-yl]amine-indenyl-indole-pyrazole; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4 —曱oxy_3_{N_[4-(2- chlorophenylh-acido) hexahydrogen ratio tiller~1-yl]amine sulfhydryl}-1H-pyrazole; 1-(2-gas base) _5-(4-chlorophenyl)- 4_ methoxy_3_{N_[4_(3, 4-difluorobenzene) Mercapto) hexahydropyridinium 丨基基 ] ] ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; -{N-[4-(2, 4-dibenzophenone) hexahydropyrimidin-yl]amine sulfhydryl 1H_pyrazole; 1-(2-chlorophenyl)-5- (4-chlorophenyl)_4-methoxyl_3_{N_[4,5,5-di-benzoyl)hexahydropyridin-1-yl]amine-indenyl-indole-pyrazole ; 1-(2-Phenylphenyl)-5-(4-chlorophenyl)_4-methoxy_3_[2_(1_oxasulfonylhexahydropyridin-4-yl)-1,,3, 4-oxadiazol-5-yl]-1H-pyrazole; • 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-[N -(4-fluorophenyl)aminemethanyl]- 1H-pyrazole; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-ίΝ-[ 4-(4-fluorophenyl)hexahydro 0-p-ment-1-yl]amine-indenyl-indole-pyrazole; 1-(2-chlorophenyl)_5-(4-chlorophenyl)-4 —methoxy_3_[Ν_(3_trifluoromethyl 0 洛基) amidino]-1Η-pyrazole; 1-(2, 4-diphenyl)_5_(4_trifluoro Methylphenyl)_4_methoxy_3_[〇Γ,ΙΤ-dimercaptoalkyl)carbonyl]_1Η-pyrazole; 1-(2' 4-diphenyl)-5-(4-tri Fluoromethyl ))-4-methoxy_3-[Ν- 318695 25 (N~morpholinyl)amine sulfhydryl]-1H-pyrazole; dichlorophenyl)_5-(4-trifluoromethylbenzene — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — Phenyl)- 4-methoxy-3-U, tetrahydropentanyl)amine hydrazino]-1H-pyrazole; | gas-4-fluorophenyl)-5-(tetrafluoroindenyl) Phenyl)-4_decyloxy_3_norfosolinyl)aminemethanyl]_1H_pyrazole;

氯笨基-（4-三氟曱基苯基）-4-甲氧基_3_[n_ L 1 —一側氧基-N-硫代嗎福啉基）胺曱醯基]_1H_吡唑； ^(2-氣笨基）-5-(4-氯苯基）-4-甲氧基-3-[N-(4-氟-N-六氫°比啶基）胺甲醯基]_1H_吡唑； 1-(2, 4_二氯苯基）一5-(4-氣苯基）-4-曱氧基-3-[n-(4-苯曱酿基六氫吡畊-1-基）胺甲醯基]-1H-吡唑； 1一（2, 4一二氣苯基）-5-(4-氯苯基）-4-曱氧基-3-{N-[4- (2’ 4-二氟苯曱醯基）六氫吡畊—卜基]胺曱醯基卜1H_吡唑; 鲁5-(4-氯苯基）一卜（2_氟苯基）_4_曱氧基_3_[N_(4,4一二氟 -N—六氫°比啶基）胺曱醯基]-1H-吡唑； 1-(2-氯苯基）-5-(4-三氟曱基苯基）-4-甲氧基-3-[N- (4, 4-二氟-N-六氫吡啶基）胺曱醯基]-1H_吡唑；卜（2’ 4一二氯苯基）-5-(4-三氟甲基苯基）-4-曱氧基-3-[N-(4, 4-二氟-N-六氳吡啶基）胺甲醯基]一1H_ 〇比σ坐； 5-(4-氯苯基）-卜（2_氟苯基）_4_曱氧基一3—{Ν_[3_(三氟甲基）°比咯啶-1·'基]胺甲醯基丨-ΙΗ-吡唑； 1-（2-氯苯基）-5_(4_氯苯基）_4_曱氧基一3_{Ν-[4_(5_氰基 26 318695 1378922 • 0比啶-2-基）六氫吡哄-卜基]胺曱醯基}_11}_吡唑； 1-(2-氣求基）-5-(4-氣笨基）-4-曱氧基-3-{N-[4-（5-二氟甲基〇比唆-2-基）六氫吼哄-1-基]胺曱醯基比0坐； 1-(2-氣苯基）-5-(4-氯苯基）-4-二氟曱氧基-3-[N_(4, 4-二氟-N-六氫吡啶基）胺甲醯基]_1H_吡唑； 1-(2-氣苯基）-5-(4-三氟甲基苯基）_4一甲氧基-3-[ δα, 2, 2-二氟乙基）_1， 3, 4-曙二嗤-2-基]-1H- 0比〇坐； 5-(4-氣苯基）-1-(2-氟苯基）一4_甲氧基_3_{N_[4-(4-氯苯鲁基）六氫吡明:-卜基]胺曱醯基卜1H_吡唑； 5-(4-氯苯基）-i —(2-氟苯基）_4一甲氧基_3_{n，-[4_(4-氟苯基）六氫吡哄-1-基]胺曱醯基丨-1H_吡唑； 4-胺甲醯基曱氧基-一氣苯基）__5_(4_氣苯基）_3一[ν-Ο-胺甲酿基-4-苯基-N-六氫。比啶基）胺曱醯基]_1Η_βΛ0坐； 4-(2-胺乙氧基）甲氧基―丨气卜氯笨基）—5_(4_氯苯基）一3_ [N-(吡咯啶-1-基）胺甲醯基]-1H-吡唑；籲4-[2-(乙醯基胺基）乙氧基]_卜（2 —氯苯基）_5_(4_氯苯基） -3-[Ν-(吡咯啶-ΐ_基）胺甲醯基]_1Η—吡唑； 1-(2-氯苯基）-5-(4-氣苯基）一4-[2-(甲磺醯基胺基）乙氧基]-3-[N-(吡咯啶-1-基）胺甲醯基]—1H_吡唑；以及 1-(2-氯苯基）-5-(4-氯苯基）-4-{2-[(m，N-二甲基胺磺醯基）胺基]乙氧基}-3-[N-(吡咯啶-i_基）胺曱醯基]_1{1_吡〇坐〇虽本發明之化合物[I ]於其分子中具有不對稱碳原子時’由於該不對稱碳原子而可存在有立體異構物（非鏡像異 318695 27 1378922 構物、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[I]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CB1受體轉介之疾病，例如精神，病包括精神***症、焦慮症、麼力、憂變症、瘤痛、神，’二退化症、脊髓小腦病症、認知失常、大腦創傷、恐慌發作、週邊神經病變、青光眼、偏頭痛、帕金森氏（Parkinson、) 症、阿兹海默（Alzheimer’s)症、杭丁頓氏症、雷諾氏（RaynaucT s)症候群、顫抖症、強迫症、健忘症、老人痴呆症、胸腺病症、妥瑞氏（Tourett^s)症候群、遲發性不自主運動、躁鬱症、癌症、藥物引發之不自主運動、肌張力不全、敗血性休克、出▲性休克、低也壓、失眠、免疫學疾病包括發炎、多發性硬化症、嘔吐、腹瀉、氣喘' 食慾疾病例如厭/暴食交替症、厭食症等、肥胖症、非胰島素依賴型糖尿病（NIDDM)、記憶障礙、泌尿疾病、心血管疾鲁病、***症、感染、與去髓鞘化有關之疾病、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病症（disorder) ° 此外，本發明化合物[I]可作為藥劑用於戒除慢性治療、酒精依賴或藥物濫用[例如’鴉片類藥物、巴比妥= (barbiturate)、***、古柯驗（***e)、*** (amphetamine)、天使塵（phencyclidine)、***、苯并二氛呼化合物等]。再者，本發明化合物[I ]可作為藥劑用於提高止痛藥物 318695 28 1378922 -或***物之止痛活性等；或作為戒煙（戒除依賴)藥劑。丁此外，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、高胰島素血症、尚脂血症、高膽固醇血症、高三酸甘油脂血症: :旨肪代謝病症、動脈硬化、高血壓、心血管疾病、冠心病、憂鬱症、焦慮症、藥物成癮與物質成瘾。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⑴之醫藥上可接受之鹽類包括：無機酸鹽，例如鹽酸鹽、硫酸鹽、磷酸鹽或氯漠酸趟. 有機酸鹽’例如乙酸鹽、反式丁烯二酸鹽、草酸鹽、；檬 =鹽、甲續酸鹽、苯確酸鹽、對f苯確酸鹽或順丁婦二酸 ^此外，當本發明化合物⑴於分子内具有㈣等時，該 j樂上可接受之鹽類之實例包括··與驗，例如驗金屬（例鈉鹽、卸鹽）或驗土金屬（例如，約鹽）所成之鹽類。或並Γί物[1]或其醫藥上可接受之鹽類包括其分子内鹽或』成物(顧tive)，以及其溶劑合物或其水合物。本發月化合物⑴或其醫藥上可接受之鹽類可口服或膠囊投：虫且能調配成慣用醫藥製劑，例如錠劑、顆粒、 >囊争刀末、注射劑或吸入劑。劑量合物⑴或其醫藥上可接受之鹽類所使用之了依據杈予途徑與患者年齡、體重、例如’投予注射製勒丨、s W，曰文毫方/八;常劑量範圍為約UQQ1至1.0 克/么斤/日，較佳為約Hu毫克/公斤/日。投 318695 29 1378922 予口服製劑時，通常劑量範圍為約〇〇〇1至1〇〇毫克/公斤 /日，較佳為約0.01至10毫克/公斤/日。本發明化合物[U亦可•作為上述越/病症治療之辅助、附加或補充之治療。該辅助、附加或補充之治療音指將本發明化合物伴隨地或依序地投予已接受、正接受或將接受用於病兄治療之-或多種附加治療劑，例如—或多種習知之抗憂鬱劑、抗精神病劑或抗焦慮劑之患者。Chlorophenyl-(4-trifluorodecylphenyl)-4-methoxy_3_[n_L 1 -oneoxy-N-thiomorpholinyl)amine thiol]_1H_pyrazole ;^(2-indolyl)-5-(4-chlorophenyl)-4-methoxy-3-[N-(4-fluoro-N-hexahydropyridyl)aminemethanyl] _1H_pyrazole; 1-(2,4-dichlorophenyl)-5-(4-phenylphenyl)-4-indolyl-3-[n-(4-benzoquinone-hexahydropyrazine -1-yl)amine-mercapto]-1H-pyrazole; 1-(2,4-dioxaphenyl)-5-(4-chlorophenyl)-4-decyloxy-3-{N- [4-(2' 4-difluorophenylhydrazolyl) hexahydropyrazine-bupropenyl] amidoxime 1H_pyrazole; Lu 5-(4-chlorophenyl)-b (2-fluorobenzene) )4_曱oxy_3_[N_(4,4-difluoro-N-hexahydropyridinyl)amine hydrazino]-1H-pyrazole; 1-(2-chlorophenyl)-5 -(4-trifluorodecylphenyl)-4-methoxy-3-[N-(4,4-difluoro-N-hexahydropyridinyl)amine fluorenyl]-1H-pyrazole; (2' 4 -Dichlorophenyl)-5-(4-trifluoromethylphenyl)-4-decyloxy-3-[N-(4,4-difluoro-N-hexafluoridyl) Aminomethyl hydrazide]-1H_ 〇 is more than σ; 5-(4-chlorophenyl)-bu(2_fluorophenyl)_4_methoxy-3-{Ν_[3_(trifluoromethyl)° ratio L-pyridine-1·' base] Mercaptopurine-hydrazine-pyrazole; 1-(2-chlorophenyl)-5-(4-chlorophenyl)_4_decyloxy-3_{Ν-[4_(5-cyano 26 318695 1378922 • 0 Bipyridin-2-yl)hexahydropyridinium-byl]amine sulfhydryl}_11}_pyrazole; 1-(2- gas base)-5-(4-adolyl)-4-oxo Base-3-{N-[4-(5-difluoromethylindol-2-yl)hexahydroindol-1-yl]amine fluorenyl is 0-position; 1-(2-phenylphenyl) -5-(4-chlorophenyl)-4-difluorodecyloxy-3-[N_(4,4-difluoro-N-hexahydropyridyl)aminemethanyl]_1H-pyrazole; -(2-Phenylphenyl)-5-(4-trifluoromethylphenyl)_4-methoxy-3-[ δα, 2, 2-difluoroethyl)_1, 3, 4-anthracene -2-yl]-1H- 0 is more than squat; 5-(4-phenylphenyl)-1-(2-fluorophenyl)- 4-methoxy-3-3_{N_[4-(4-chlorobenzene鲁基) hexahydropyridin:-buki]amine sulfhydryl 1H_pyrazole; 5-(4-chlorophenyl)-i-(2-fluorophenyl)_4-methoxy_3_{n ,-[4_(4-fluorophenyl)hexahydropyridin-1-yl]amine fluorenyl-1H-pyrazole; 4-amine-methyl fluorenyloxy-monophenyl)__5_(4_gas Phenyl)_3-[ν-Ο-amine-mercapto-4-phenyl-N-hexahydro.比 ) ) ) ] ] ] 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- -1-yl)amine-mercapto]-1H-pyrazole; 4-[2-(ethionylamino)ethoxy]-b (2-chlorophenyl)_5_(4-chlorophenyl) -3-[Ν-(pyrrolidinyl-fluorenyl)-carbamoyl]_1Η-pyrazole; 1-(2-chlorophenyl)-5-(4-phenylphenyl)-4-[2-( Methanesulfonylamino)ethoxy]-3-[N-(pyrrolidin-1-yl)aminemethanyl]-1H-pyrazole; and 1-(2-chlorophenyl)-5-( 4-chlorophenyl)-4-{2-[(m,N-dimethylaminesulfonyl)amino]ethoxy}-3-[N-(pyrrolidine-i-yl)amine oxime Base]_1{1_pyridinium oxime Although the compound [I] of the present invention has an asymmetric carbon atom in its molecule, a stereoisomer may exist due to the asymmetric carbon atom (non-mirror 318695 27 1378922) The construct, optical isomer), the invention also includes one of its stereoisomers and mixtures thereof. The compound [I] of the present invention has potent antagonistic activity against the CB1 receptor and can be used as a medicament for preventing and/or treating diseases referred to by the CB1 receptor, such as psychosis, diseases including schizophrenia, anxiety, dysfunction, and anxiety. Symptoms, tumor pain, god, 'two degenerative diseases, spinal cord cerebellar disorders, cognitive disorders, brain trauma, panic attacks, peripheral neuropathy, glaucoma, migraine, Parkinson's disease, Alzheimer's Symptoms, Huntington's disease, Raynauc's syndrome, trembling, obsessive-compulsive disorder, amnesia, Alzheimer's disease, thymic disorder, Tourett^s syndrome, delayed involuntary movement, depression Insufficiency, cancer, drug-induced involuntary movement, dystonia, septic shock, septic shock, low stress, insomnia, immunological diseases including inflammation, multiple sclerosis, vomiting, diarrhea, asthma, appetite diseases such as Anaerobic/albiary alternation, anorexia, obesity, non-insulin dependent diabetes mellitus (NIDDM), memory disorder, urinary disease, cardiovascular disease, infertility, infection, and Demyelination-related diseases, neuroinflammation, viral encephalitis, stroke, cirrhosis, or gastrointestinal diseases include intestinal transport disorders. In addition, the present compound [I] can be used as a medicament for quitting chronic treatment. Alcohol dependence or drug abuse [eg 'opioids, barbiturate, marijuana, ***e, amphetamine, phencyclidine, ecstasy, benzoquinone Compounds, etc.]. Further, the compound [I] of the present invention can be used as an agent for improving the analgesic activity of the analgesic drug 318695 28 1378922 - or an anesthetic drug; or as a smoking cessation (abdication-dependent) 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, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridate Ethanolemia: : Metabolic metabolic 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 (1) include: inorganic acid salts such as hydrochlorides, sulfates, phosphates or guanidinium chloride. Organic acid salts such as acetate, trans-butenedioate, oxalic acid Salt, lemon = salt, carboxylate, benzoate, p-benzoate or cis-butanyl acid. Further, when the compound (1) of the present invention has (four) in the molecule, the Examples of acceptable salts include, for example, tests involving metals (eg, sodium salts, salt removal) or soils (eg, about salts). Or a compound [1] or a pharmaceutically acceptable salt thereof includes an intramolecular salt or a hydrate thereof, and a solvate thereof or a hydrate thereof. The compound of the present invention (1) or a pharmaceutically acceptable salt thereof can be administered orally or in a capsule form: it can be formulated into a conventional pharmaceutical preparation such as a tablet, a granule, a capsule, an injection or an inhalant. The dosage form (1) or a pharmaceutically acceptable salt thereof is used according to the route of administration and the age, body weight of the patient, for example, 'injection of sputum, s W, 毫毫毫 / 八; About UQQ1 to 1.0 g/kg/day, preferably about Hu mg/kg/day. When administered to an oral preparation, it is usually administered in an amount ranging from about 1 to about 1 mg/kg/day, preferably from about 0.01 to 10 mg/kg/day. The compounds of the invention [U can also be used as adjunctive, additional or complementary treatments for the above-mentioned treatments. The auxiliary, additional or supplemental therapeutic sound refers to the concomitant or sequential administration of a compound of the invention to an acceptable therapeutic agent that has been accepted, is receiving or will be accepted for the treatment of a sick brother, for example - or a plurality of conventional antibiotics. A patient with a depression, antipsychotic or anti-anxiety agent.

本發明化合物[I]能以下列方式製備，惟不限於該等方法。The compound [I] of the present invention can be produced in the following manner, but is not limited to these methods.

方法AMethod A

[I-A] 式中’ Q21為單鍵或氧原子，而其他符號係、如以上所定義，能藉由以下方式製備： U)使式[II-A]之化合物與式[m_a]i醇類化合物反[IA] where Q21 is a single bond or an oxygen atom, and other symbol systems, as defined above, can be prepared by: U) bringing a compound of formula [II-A] with an alcohol of formula [m_a]i Compound anti

式中’ 1^為氫原子、烷基或苯曱基，所定義；而其他符號係如以上 318695 30 »41 1378922 式中，基，或 H0'R41 [III-a] 為環烷基或視需要經取代之飽和或不飽和雜環類或肼化合物 (2)使式[II-A]化合物與式[u卜b]之胺或其鹽類反應： hn(r42k〇 [IH_b]Wherein '1^ is a hydrogen atom, an alkyl group or a phenylhydrazine group, and the other symbols are as in the above 318695 30 » 41 1378922 wherein, the group, or H0'R41 [III-a] is a cycloalkyl group or a A substituted or unsaturated heterocyclic or anthracene compound (2) is required to react a compound of the formula [II-A] with an amine of the formula [ubb] or a salt thereof: hn(r42k〇[IH_b]

式中，R42與R43之一去A 者為虱原子或烷基，而另一者為需要經選自齒素原子、胺基石广為⑷視 * 土沉暴奴基、烷亞磺醯基'烷㈣基與視需要經取代之芳基之基團取代之燒基，（b)環燒基’（c)式-N(R8)(R9)之基團，⑷視需要經取代之芳美，或（e)視需要經取代之飽和或不飽和雜環基；或R42與^43 二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氮雜環基’其他符號係如以上所定義。Wherein one of R42 and R43 goes to A as a ruthenium atom or an alkyl group, and the other is required to be selected from a dentate atom, an amine sulphate (4), a soil, a sulfhydryl group, and a sulfinyl group. An alkyl (tetra) group substituted with a group optionally substituted with an aryl group, (b) a group of a cycloalkyl group 'c)-N(R8)(R9), (4) a substituted aromatic moiety, Or (e) a substituted or unsaturated heterocyclic group which is optionally substituted; or R42 and ^43 are bonded to each other at their terminals, and together with the adjacent nitrogen atom, form a saturated or unsaturated nitrogen atom which may be substituted as needed. The heterocyclic group 'other symbols' are as defined above.

Ra為氫原子時，上述反應（1)與反應（2)能在含縮合劑鲁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’例如二氯甲烷、三氯甲烧 (chloroform)、二甲基甲醯胺、二甲基乙醯胺、四氫呋喃、二曙烧（dioxane)、甲苯、苯、1,2-二氣乙烷、卜甲基吡咯 σ定酮、1，2 - —曱氣基乙院等。縮合劑可為例如：二環己基碳二亞胺（dicyclohexylcarbodiimide，DCC)、1-乙基-3- (3-二甲基胺基丙基）碳二亞胺鹽酸鹽（wsc HC1)、疊氮鱗酸二苯酉旨（diphenylphosphoryl azide，DPPA) ' 羰基二咪唑 (CDI)、鼠鱗酸·—乙酉曰（diethyl cyanophosphonate， 318695 31 1378922 -DEPC)、二異丙基碳二亞胺（DIpci)、六氟磷酸苯并*** _1 一基氧基參吼咯啶基鱗（PyBOP)、羰基二（***）、N-環己基碳二亞胺-Γ-丙基氧甲基、聚苯乙烯（ps-碳二亞胺）、N-乙氧羰基-2-乙氧基-1，2-二氫喹啉（EEDQ)、六氟磷酸2-(7-氮雜苯并***-1 —基）— I h 3, 3_四曱基脲鏽（2一（7_ azabenzotriazol-l-yl)-i，1，3, 3-tetramethyluroniiiffl hexaf luorophosphate，HATU)、六氟磷酸 2-(1Η-苯并*** -卜基）-1，1，3, 3-四甲基脲鑌（HBTU)、六氟磷酸溴參比咯肇σ定基鱗（PyBroP)、四氟硼酸2 — (ih-苯并***-卜基）-1，1， 3, 3-四甲基脲鑌（τβτυ)、六氯銻酸氯-1，1，3, 3-四曱基脲鎖（ACTU)等。活化劑之實例包括：卜羥基苯并***（H〇Bt)、 1-沒基琥珀醯亞胺（H〇Su)、二曱胺基吡啶（DMAP)、卜羥基氮雜苯并***（H〇At)、羥基呔醯亞胺（HOPht)、五氟酚 (Pfp-OH)、1-羥基苯并***_6_磺醯胺基曱基聚苯乙烯 (PS-HOBt)等。鹼包括例如：吡啶、三乙胺、二異丙基乙基籲胺、4-曱基嗎福啉、丨，8-二氮雜雙環[5, 4, 〇]_7 —十一烯（DBU) 等。上述製程中’化合物[Π—Α]之使用量為每一莫耳化合物[I ΙΙ-a]或化合物[ni-b]可使用〇· 33至1. 5莫耳，較佳為〇. 5至1. 2莫耳。縮合劑之使用量為每一莫耳化合物 [Π-A]、化合物[m_a]或化合可使用l 〇至& 〇莫耳較佳為1.0至1.2莫耳。驗之使用量為每一莫耳化 s物[II A]、化合物[iH-a]或化合物[ΙΙΙ-b]可使用1 〇至3. 0莫耳，較佳為1. 〇至1. 2莫耳。活化劑之使用量為 318695 32 1378922 每-莫耳化合物[H—A]、化合物[ni—a]或化合物⑴卜b] 可使用0.01至2.0莫耳，較#為n , 佐為〇至h〇莫耳。反應能在0至150 c進行，較佳為20至8〇〇c。化&物[11-幻之Ra為氫原子時，化合物[卜幻能藉由將化合物[Π-A]轉變成對應之反應性衍生物（例如，酸齒化物、混合酸酐）’然後在鹼存在下，於㈣中或無溶劑下使此反應性衍生物與化合物[⑴1]或化合物ΠΐΙ-b]反應而予以製備。籲合物[H-AkRa為烧基或苯甲基時，本方法a亦能藉由習知方式進行，例如以水解、使用鹽酸、〒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 hydrogen 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 dichloromethane, chloroform, dimethylformamide, dimethylacetamide, tetrahydrofuran, dioxane, toluene, benzene. 1,2-dioxaethane, methylpyrrolidone, 1,2 - 曱 gas base, etc. The condensing agent may be, for example, dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (wsc HC1), a stack Diphenylphosphoryl azide (DPPA) 'carbonyldiimidazole (CDI), diethyl cyanophosphonate (318695 31 1378922 -DEPC), diisopropylcarbodiimide (DIpci) , benzotriazole hexafluorophosphoric acid 1-pyridyl quinazolinyl scale (PyBOP), carbonyl bis(triazole), N-cyclohexylcarbodiimide-hydrazine-propyloxymethyl, polyphenylene Ethylene (ps-carbodiimide), N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), 2-(7-azabenzotriazole-1) hexafluorophosphate —基) — I h 3, 3_tetradecyl urea rust (2_(7_ azabenzotriazol-l-yl)-i, 1,3, 3-tetramethyluroniiiffl hexaf luorophosphate, HATU), hexafluorophosphate 2-(1Η- Benzotriazole-diyl-1,1,3,3-tetramethyluronium (HBTU), bromine hexafluorophosphate pyrrole sylate (PyBroP), tetrafluoroboric acid 2 - (ih-benzene And triazol-buki)-1,1,3,3-tetramethyluronium (τβτυ), six Antimonate chloro-1,1,3,3-four Yue urea lock (ACTU) and the like. Examples of the activator include: hydroxybenzotriazole (H〇Bt), 1-nonyl succinimide (H〇Su), diammonium pyridine (DMAP), and hydroxyazabenzotriazole ( H〇At), hydroxyquinone imine (HOPht), pentafluorophenol (Pfp-OH), 1-hydroxybenzotriazole_6_sulfonylamino decyl polystyrene (PS-HOBt), and the like. The base includes, for example, pyridine, triethylamine, diisopropylethylamine, 4-mercapto porphyrin, anthracene, 8-diazabicyclo[5,4, fluorene]-7-undecene (DBU) Wait. 5摩尔,优选为〇 5。 The compound [Π-Α] used in the above process is used per mole of the compound [I ΙΙ-a] or the compound [ni-b] can be used 〇 33 to 1.5 m, preferably 〇. 5 To 1. 2 moles. The condensing agent is used in an amount of from 1.0 to 1.2 moles per mole of the compound [Π-A], the compound [m_a] or the combination of 〇 to & 〇到1. The amount of use is 1 〇 to 3.0 mol, preferably 1. 〇 to 1. per mole of s [II A], compound [iH-a] or compound [ΙΙΙ-b]. 2 Mo Er. The amount of activator used is 318695 32 1378922 per-mole compound [H-A], compound [ni-a] or compound (1) b] can be used from 0.01 to 2.0 m, compared to #n, n is 〇 to h 〇莫耳. The reaction can be carried out at 0 to 150 c, preferably 20 to 8 〇〇c. When the compound [11-phantom Ra is a hydrogen atom, the compound [the phantom can be converted into a corresponding reactive derivative (for example, acid dentate, mixed acid anhydride) by the compound [Π-A]] This reactive derivative is prepared by reacting the reactive derivative with the compound [(1)1] or the compound ΠΐΙ-b in (4) or in the absence of a solvent. When the compound [H-AkRa is a pyridyl group or a benzyl group, the method a can also be carried out by a conventional method, for example, hydrolysis, hydrogenolysis or hydrogenation using hydrochloric acid, citric acid, trifluoroacetic acid or the like, The compound [Π_Α] is converted into a corresponding carboxylic acid compound of the formula [II-Aa]:

[Π-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[ΠΙ-a]或化合物[m-b]以如上述相同之方式反應而進行。[Π-Aa] wherein the symbol is as defined above, and then the carboxylic acid compound [n_Aa] is reacted with the compound [ΠΙ-a] or the compound [m-b] in the same manner as above.

方法B 本發明化合物[I ]中，E為式（i)之基團，Q2為伸燒基，且R為式-N(R42)(R43)基團之化合物，換言之，即下式[I—b] 之化合物： 318695 33 1378922Process B In the compound [I] of the present invention, E is a group of the formula (i), Q2 is a stretching group, and R is a compound of the formula -N(R42)(R43) group, in other words, the following formula [I] -b] Compound: 318695 33 1378922

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[111-b]或其鹽類反應來製備：Wherein Q22 is an alkylene group, and the other symbols are as defined above, and can be produced by reacting a compound of the following formula [II-B] with a compound [111-b] or a salt thereof:

[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[Iii-b]之反應能在含或不含鹼之溶劑中進行。溶劑之實例包括任何不影響反應之溶劑，例如二氣甲烷、三氣曱烷、二曱基曱醯胺、二曱基乙醯胺、—甲亞颯（dimethyl sulfoxide)、四氫呋喃、二噚烧甲本本1，2 - 一氯乙烧、1-曱基〇比。各咬酉同、ι，2 -二 _曱氧基乙烷等。鹼包括例如：吡啶、二基胺、-甲基嗎福琳、U-二氮雜雙;[= (DBU)、碳酸鉀等。上述製程中，化合物[Π卜b]之使用量為每一莫耳化物[Π_β]可使用U至莫耳，較佳為U至3.0莫3 =用量為每一莫耳化合物[⑴，或化合物[Η、” 至：莫耳’較佳為u至3.°莫耳。反應能在-至100 C進行，較佳為0至50°c。[Π.Β] where X is a halogen atom and the other symbols are as defined above. The reaction of the compound [II-B] with the compound [Iii-b] can be carried out in a solvent with or without a base. Examples of the solvent include any solvent which does not affect the reaction, such as dioxane, trioxane, dimethyl decylamine, dimercaptoacetamide, dimethyl sulfoxide, tetrahydrofuran, diterpenoid The book 1,2 - chloroethene, 1-mercaptopyrene ratio. Each bite is the same, i, 2, di-nonyloxyethane, and the like. The base includes, for example, pyridine, diamine, -methylmorphine, U-diazapine; [= (DBU), potassium carbonate, and the like. In the above process, the compound [Πbb] is used in an amount of U to Mo, preferably U to 3.0 Mo 3 per mole of oxime [Π_β] = amount per mole of compound [(1), or compound [Η," to: Moer' is preferably u to 3. ° mol. The reaction can be carried out at - to 100 C, preferably 0 to 50 ° c.

方法C 318695 34 1378922 本發明化合物[I]中，E為式（i)之基團，Q1為式 -N(R7)-之基團，q2為單鍵，且r4為式_n(r42)(r43)基團之化合物’換言之，即下式^ —⑺之化合物：Process C 318695 34 1378922 In the compound [I] of the present invention, E is a group of the formula (i), Q1 is a group of the formula -N(R7)-, q2 is a single bond, and r4 is a formula _n(r42) (r43) a compound of the group 'in other words, a compound of the following formula ^-(7):

式中’符號係如以上所定義，能藉由使下式[Π-C]之化合Where the 'symbols are as defined above, can be combined by the following formula [Π-C]

式中’付號係如以上所定義， r-co-r [a] 式中’W1與W2相同或不同，且為脫離基團。化合物[a ]中，W1與W2之實例包括：咪唾基、鹵素原鲁子與苯氧基。此化合物之具體實例包括：1, K羰基-二口米唾、光氣（phosgene)、三光氣等。反應所用溶劑之實例包括任何不影響反應之溶劑，例如乙腈、二氣曱烷、三氯曱烧、1，2 - 一氣乙院、四負^夫喃等。化合物之使用量為每一莫耳化合物[Π-C]可使用1.0至5.0莫耳，較佳為 1.0至1.2莫耳。化合物[a]之使用量為每一莫耳化合物 [Π-C]或化合物[Π i-b]可使用1· 〇至5. 〇莫耳，較佳為 1. 0至2. 0莫耳。反應能在-20至100°C進行，較佳為〇至 5(TC。 318695 35 1378922 (2)此外，化合物^-⑺亦能藉由使化合物[n_c]與化合物[a]反應而產生式[iv]之化合物：Wherein the 'note' is as defined above, r-co-r [a] where 'W1 is the same as or different from W2 and is a leaving group. In the compound [a ], examples of W1 and W2 include: a mercapto group, a halogen pros and a phenoxy group. Specific examples of the compound include: 1, K carbonyl - two mouth saliva, phosgene, triphosgene, and the like. Examples of the solvent used in the reaction include any solvent which does not affect the reaction, such as acetonitrile, dioxane, trichloroanthracene, 1,2 - one gas, and four negative. The amount of the compound used is 1.0 to 5.0 moles, preferably 1.0 to 1.2 moles per mole of the compound [Π-C]. The compound [a] is used in an amount of from 0 to 2. 0 moles per mole of the compound [Π-C] or the compound [Π i-b]. The reaction can be carried out at -20 to 100 ° C, preferably 〇 to 5 (TC. 318695 35 1378922 (2) Further, the compound ^-(7) can also be produced by reacting the compound [n_c] with the compound [a]. [iv] compounds:

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[ΙΠ-b]反應，或使化合物與化合物 [a ]反應產生式[v ]之化合物：Wherein the symbols are as defined above, and then the product or its reactive derivative is reacted with the compound [ΙΠ-b] or the compound is reacted with the compound [a] to give a compound of the formula [v]:

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]與峨曱烷反應而得到。化合物[11 -C ]或化合物[111 -b ]與化合物[a ]之反應能在溶劑t進行。溶劑之實例包括任何不影響反應之溶劑，例如乙腈、二氯曱烷、1，2-二氯乙烷、苯、曱苯、四氫呋喃、1,2-二甲氧基乙院等。化合物[a]之使用量為每一莫耳化合物[II-C]或化合物[ni-b]可使用1. 0至3. 0莫耳，較 36 318695 1378922 佳為1. 0至1. 2莫耳。本反應能在〇至15(rc進行，較佳為 20 至 80°C。土將化合物[IV]或化合物[V]轉變成其反應性衍生物之反應，能藉由例如使該化合物[IV]或化合物[v]與鹵化烷如碘甲烷在溶劑t反應來進行。本反應能在〇至15〇。〇進行，較佳為20至80°C。化合物[iv](或其反應性衍生物）與化合物之反應或化合物[V](或其反應性衍生物）與化合物⑴心之反應能在含驗之溶劑中進行。溶劑之實例包括任何不影塑反應之溶劑’例如二氯甲燒、三氯甲烷、二甲基甲酿胺、二甲基乙醯胺、二甲亞硬、四氫咳择、n甲苯、苯、1， ^氯乙炫、卜甲基氧基乙焼等。驗之貫例包括：吡啶、三乙胺、-昱兩苴一異丙基乙基胺、4-曱基嗎福啉、1，8-二氮雜雙環[5 4 Π1 7 衣L，4,〇J —十一烯（DBU)等。此等反應性衍生物之使用量為每一箪耳仆入 Γττ η1 旲耳化合物[ΠΙ-b]或化合物 [U—C]可使用㈣至3』莫耳，較佳為0.5^ 2莫耳。反應能在_30至10吖進行，較佳為〇至5(rc。·、換一⑶再^’化合物中’ R7為氫原子之化合物吕之即下式[I-Ca]之化合物：These reactive derivatives can be obtained by reacting a compound [V] having an imidazolyl group with decane. The reaction of the compound [11 -C ] or the compound [111 -b ] with the compound [a] can be carried out in a solvent t. Examples of the solvent include any solvent which does not affect the reaction, such as acetonitrile, dichlorodecane, 1,2-dichloroethane, benzene, toluene, tetrahydrofuran, 1,2-dimethoxyethane, and the like. 0至1. 2。 The compound [a] is used in an amount of 1. 0 to 3. 0 to 1. 0 to 1. 0 to 1. 0 to 1. 0 to 1. 2 to 0. Moor. The reaction can be carried out at a temperature of from 15 to rc, preferably from 20 to 80 ° C. The reaction of converting the compound [IV] or the compound [V] into its reactive derivative can be carried out, for example, by the compound [IV] Or the compound [v] is reacted with a halogenated alkane such as methyl iodide in a solvent t. The reaction can be carried out at a temperature of from 15 to 80 ° C. Compound [iv] (or its reactive derivative) The reaction with the compound or the reaction of the compound [V] (or its reactive derivative) with the compound (1) can be carried out in a solvent containing the test. Examples of the solvent include any solvent which does not affect the reaction, such as dichloroform. Burning, chloroform, dimethylamine, dimethylacetamide, dimethylene hard, tetrahydrogen cough, n-toluene, benzene, 1, chloroeththene, benzyloxyethyl hydrazine, etc. Examples of the pyridine include: pyridine, triethylamine, hydrazine, isopropyl isopropyl ethylamine, 4-mercapto phenanthroline, 1,8-diazabicyclo[5 4 Π1 7 clothing L, 4, 〇 J-undecene (DBU), etc. The amount of such reactive derivatives used is 箪ττ η1 旲 ear compound [ΠΙ-b] or compound [U-C] can be used (4) to 3 Mohr, preferably 0.5^2 mol. The reaction can be carried out at -30 to 10 Torr, preferably 〇 to 5 (rc.·, and (3) and then the compound of 'R7 is a hydrogen atom. That is, the compound of the following formula [I-Ca]:

[I-Ca] 式酸中，符號係如以上所定義，月b错由使下式[η I v 1 昱氰醋化合物與化合物[Π卜 J4再鹽類反應來製備： 318695 37 1378922In the formula [I-Ca], the symbol is as defined above, and the month b is prepared by reacting the following formula [η I v 1 昱 cyanide vinegar with a compound [Π J J4 re-salt: 318695 37 1378922

式中，符號係如以上所定義。本反應能在含鹼而含或不含活化劑之溶劑中進〜〜劑之實例包括任何不影響反應之溶劑，例二—仃。溶 V三氯甲院、二氣W二= 乙腈等。驗之貫例包括：三乙胺、二異内基乙基胺、基嗎福咐等。活化劑可為4-二甲基胺基吧力、4_π比洛σ定基吡啶等。化合物[iii—b]或其鹽類之使用量為每一莫耳物[XXIV]可使用1.0至5.0莫耳，較佳為1〇至2 〇莫耳。本反應能在-50至50°C進行，較佳為-丨〇至3(rc。Wherein the symbols are as defined above. Examples of the present reaction which can be used in a solvent containing a base with or without an activator include any solvent which does not affect the reaction, and Example 2 - hydrazine. Dissolved V trichloromethyl, two gas W two = acetonitrile. Examples of tests include: triethylamine, diisopropionylethylamine, kifafu and the like. The activator may be 4-dimethylamino-based bar, 4-π-pyrrolidine-based pyridine or the like. The compound [iii-b] or a salt thereof is used in an amount of 1.0 to 5.0 moles, preferably 1 to 2 moles per mole of [XXIV]. The reaction can be carried out at -50 to 50 ° C, preferably -丨〇 to 3 (rc.

方法D 本發明化合物[I]中，E為式（i)之基團，且Q2為單鍵或氧原子之化合物，換言之’即下式化合物：Process D In the compound [I] of the present invention, E is a group of the formula (i), and Q2 is a compound of a single bond or an oxygen atom, in other words, a compound of the formula:

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[i]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。Wherein the symbol is as defined above and can be prepared by reacting the compound [n_c] with the carboxylic acid compound [i] or a reactive derivative thereof: R4-Q21-C〇〇h [i] where Is as defined above. This reaction can be carried out in the same manner as in Process A.

E 38 318695 1378922 方法E-(〇 Ε為式（i i )基團之化合物，換言本發明化合物[I ]中，Ε 之，即下式[Ι-E]之化合物：E 38 318695 1378922 Method E-(〇 Ε is a compound of the formula (i i ), in other words, in the compound [I ] of the present invention, a compound of the formula [Ι-E]:

OR3 (N-OR3 (N-

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鹼之溶劑中反應來製備：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，例如二氣甲烷、三氯曱烷、四氫呋喃、二氣乙燒、曱苯、乙腈等。驗之實例包括：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-氣-1，3-φ —甲基咪唾鑌、五氯化構、聚鱗酸（p〇lyph〇Sph〇l iC acid)、填醯氯（phosphorus oxychloride)、亞硫醯氯 (thionyl chloride)等。本反應能在-10至80°C進行，較佳為10至50°C。方法E- (i i) 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Ε- (i i)來製備：反應式E_(ii) 39 318695 1378922 OR3 OR3The symbol in the formula is as defined above, and can be prepared by reacting a compound of the formula n_Ea] with a dehydrating agent in a solvent containing a base: wherein the symbol is as defined above. Examples of the solvent include any solvent which does not affect the reaction, such as di-methane, trichloromethane, tetrahydrofuran, di-oxygen bromide, toluene, acetonitrile and the like. Examples of the test include triethylamine, diisopropylethylamine, dimethylaminopyridine and the like. The dehydrating agent may be 2-oxo-1,3-φ-methylimidazolium chloride, pentachloride, polyfluoric acid (p〇lyph〇Sph〇l iC acid), phosphorous oxychloride, Thionyl chloride and the like. The reaction can be carried out at -10 to 80 ° C, preferably 10 to 50 ° C. Process E-(ii) In the compound [I] of the present invention, a compound wherein 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 Ε-(ii): Reaction Formula E_ (ii) 39 318695 1378922 OR3 OR3

步驟El-2 步驟El-1 --- R1Step El-2 Step El-1 --- R1

HzN^^NBoc SCH3 [2E] R2HzN^^NBoc SCH3 [2E] R2

NH2OH [5Ea] r2 或 H2N-NH2 [5Eb] 步驟El*4 , OR3 ,SCH3 [3E] NHBocNH2OH [5Ea] r2 or H2N-NH2 [5Eb] Steps El*4, OR3, SCH3 [3E] NHBoc

[4E] 步驟 El-3 ^^NHBoc w^-ccHjVw1 [6E][4E] Step El-3 ^^NHBoc w^-ccHjVw1 [6E]

上述反應式中，Boc為三級丁氧基羰基，w1()與W11為鹵素原子，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 :In the above reaction formula, Boc is a tertiary butoxycarbonyl group, w1() and W11 are a halogen atom, and ring A' is a 4 to 6 member nitrogen-containing heterocyclic group, and the other symbols are as defined above. Reaction step 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D 反應步驟E1 -2 : 一化合物[3E]與化合物[5Ea]或其鹽類之反應，能在含鹼 =岭J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、石異丙醇、四氫呋喃、二噚烷、N，N_二甲基甲醯胺 '二曱亞硬1二氣甲院、三氯曱院、苯、曱苯等。驗之實例包括：炭酉欠钾、兔酸氫鈉、碳酸鈉、填酸氫鈉、甲醇鈉、乙醇鈉二級丁醇鉀、三乙胺、°比咬等。此外，化合物[3E]與化合 318695 40 1378922 -物[5Eb]之反應亦能以如上述之方式進行。反應步驟E1-3 : 移除化合物[4E]之Boc基可依據習知方式（例如’酸處理）來進行。反應步驟E1-4 : 化合物U-EA1]與化合物[6E]之反應，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，例如乙腈、N，N-二甲基曱醯胺、四氫呋喃、二氯甲烷、三氯曱烷、鲁二氯乙烧、二鸣烷、二甲氧基乙烷等。鹼之實例包括：碳酸鉀、碳酸氫鈉、碳酸鈉、磷酸氫鈉、三乙胺、吡啶等。方法 E-(iii) 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)來製備：反應式E-(iii)The reaction of the compound [II-Ea] with the compound [2E] can be carried out in the same manner as the method A. The D reaction step E1-2: the reaction of a compound [3E] with the compound [5Ea] or a salt thereof can be carried out in the presence of a base = Conducted in Ridge J. 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, phenol isopropanol, tetrahydrofuran, dioxane, N,N-dimethylformamide, diterpene, hard, dioxane, trichloro Brothel, benzene, benzene, etc. Examples of tests include: anthrax under potassium, sodium hydrogen hydride, sodium carbonate, sodium hydrogen hydride, sodium methoxide, sodium ethoxide, potassium butoxide, triethylamine, and bite. Further, the reaction of the compound [3E] with the compound 318695 40 1378922 - the substance [5Eb] can also be carried out in the manner as described above. Reaction Step E1-3: Removal of the Boc group of the compound [4E] can be carried out in a conventional manner (e.g., 'acid treatment). Reaction Step E1-4: The reaction of the compound U-EA1] with the compound [6E] 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 acetonitrile, N,N-dimethylguanamine, tetrahydrofuran, dichloromethane, trichlorodecane, ruthenium dichloride, dioxane, dimethoxy. Ethane and the like. Examples of the base include potassium carbonate, sodium hydrogencarbonate, sodium carbonate, sodium hydrogen phosphate, triethylamine, pyridine, and the like. Process E-(iii) 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 (iv) can be produced, for example, according to the following reaction formula E-(iii): - (iii)

[HE] 步驟Ε2·4 R^COCl [12E][HE] Step Ε2·4 R^COCl [12E]

[I-EC] 41 318695 丄川922 ' 上述反應式中’符號係如以上所定義。反應步驟E2-1 : 化合物[II-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，例如曱魯苯二苯、二甲笨、四氫呋喃、二噚烷、二氯曱烷、三氣甲烷等。硫化劑之實例包括：拉威森氏（Lawess〇n,s)試劑、五硫化二磷等。片反應步驟E2-3 : 化合物[9E]與化合物[l〇E]或其鹽的反應能在含鹼之溶劑中進行。化合物[10E]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、四氫呋喃、二噚烷、二甲基甲醯胺、二甲亞砜、二氯甲烷、鲁氯仿、苯、甲苯等。鹼之實例包括碳酸鉀、碳酸氫鈉、碳酸鈉、磷酸氫鈉、甲醇鈉、乙醇鈉、第三丁醇鉀、三乙胺、 °比咬等。反應步驟E2-4 : 化合物[11E]與化合物[12E]之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，例如二氯甲炫、二甲基甲醯胺、四氫σ夫喃、二氯乙院、二曙院、二甲氧基乙炫等。驗之貫例包括··三乙胺、吼α定、碳酸钟、碳酸氫鈉、碳酸鈉、磷酸氫鈉等。 318695 42 1378922 本發明化合物[I]中，E為式（i)之基團，且Q2為伸乙基之化合物’換言之，即下式[I-F]之化合物：[I-EC] 41 318695 丄川922 'In the above reaction formula' symbol is as defined above. Reaction step E2-1: The reaction of the compound [II-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 ruthenium diphenyl, dimethyl benzene, tetrahydrofuran, dioxane, dichloromethane, trimethylmethane and the like. Examples of the vulcanizing agent include: Lawesson® (s) reagent, phosphorus pentasulfide, and the like. Sheet Reaction Step E2-3: The reaction of the compound [9E] with the compound [10〇E] or a salt thereof can be carried out in a solvent containing a base. The salt of the compound [10E] 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, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, benzene, toluene and the like. Examples of the base include potassium carbonate, sodium hydrogencarbonate, sodium carbonate, sodium hydrogen phosphate, sodium methoxide, sodium ethoxide, potassium t-butoxide, triethylamine, ° bite, and the like. Reaction Step E2-4: The reaction of the compound [11E] with the compound [12E] 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, dimethylformamide, tetrahydroindolyl, dichloroethane, diterpene, dimethoxyethyl and the like. Examples of tests include triethylamine, hydrazine, carbonic acid clock, sodium hydrogencarbonate, sodium carbonate, sodium hydrogen phosphate, and the like. 318695 42 1378922 In the compound [I] of the present invention, E is a group of the formula (i), and Q2 is a compound of the ethyl group. In other words, a compound of the following formula [I-F]:

式中，符號係如以上所定義，能藉由例如使下式[丨卜F ]之化合物與化合物[III-b]或其鹽類反應來製備： [Π-F] 式中，符號係如以上所定義。本反應能在含驗之溶劑中進打。溶劑之實例包括任何不影響反應之溶劑，例如乙醇、異丙醇〜四氫咳^二曙院^卜二甲基㈣胺、：石風等。鹼之實例包括：三乙胺、二異丙基乙基胺其嗎福琳等。化合MlII_b]或其鹽類之使用量為每土合物[II_F]可使用UH.O莫耳，較佳為以幻^匕耳。本反應能在20至？nrm * 、迦進仃’較佳為5()至職。且二1:月物Π]中，以式⑴之基團，Q2為單鍵，氧基取代之飽和…員含氮雜單物，換…即下式[卜G]之化合物： 318695 43 1378922Wherein the symbol is as defined above, and can be produced, for example, by reacting a compound of the formula [丨F] with a compound [III-b] or a salt thereof: [Π-F] wherein the symbol is As defined above. This reaction can be carried out in a solvent containing the test. Examples of the solvent include any solvent which does not affect the reaction, such as ethanol, isopropanol ~ tetrahydrocough ^ 曙曙 ^ ^ dimethyl (tetra) amine, : stone wind and the like. Examples of the base include triethylamine, diisopropylethylamine, and whallin. The compound MlII_b] or a salt thereof is used in an amount of UH.O mole per component [II_F], preferably in the form of a phantom. The reaction can be in 20 to? Nrm *, 嘉进仃' is preferably 5 () to the job. And in the 2: month material Π], the group of the formula (1), Q2 is a single bond, and the oxy group is substituted with a sulphur-substituted ... a nitrogen-containing mono-substrate, which is a compound of the following formula [Bu G]: 318695 43 1378922

式中，3至5之整數，而其他符號係如以上所定義，能藉由例如使T式[π-心合物與下式⑴]之化合物反應來製備：In the formula, an integer of 3 to 5, and the other symbols are as defined above, and can be produced, for example, by reacting a compound of the formula T [π-heart complex with the following formula (1)]:

[n-G] 式中，符號係如以上所定義， W ~(CH2)p~C〇-f6 [10] 式中，w5與r為鹵素原子，而其他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 =影響反應之溶劑，例如二氣甲院、三氯甲烧、乙猜、四氫呋喃、二噚烷、n，N-二曱基甲醯胺、乙醇等。鹼之實例 i包括·二乙胺、二異丙基乙基胺、甲基嗎福啉等。化合物[10]之使用量為每一莫耳化合物可使用丨.〇至。3. 0莫耳，較佳為丨.丨至2 〇莫耳。本反應能在_丨〇至工2〇 °C進行，較佳為30至80t：。本發明化合物[I]中，E為式（i)之基團，q2為單鍵，且R4為1，1-二側氧基-N-硫代嗎福啉基之化合物，換言之’即下式[I-H]之化合物： 318695 44 S02 [I-H] 式中，其他符號係如以上所定義，能藉由例如使上述化合射II-G]與二乙烯颯在含鹼之溶劑中反應來製備。貫例包括任何不影響反應之溶劑，例如乙醇、里 _ 甲苯、N，N—二甲基甲醒胺、二甲亞碼等：驗之實； J括：三乙胺、二異丙基乙基胺、"基嗎福琳、二甲胺 ^比，等。二乙_之使用量為每—莫耳化合物[π 使用1.0至3.0莫耳，較佳為12[n-G] wherein, the symbol is as defined above, W ~(CH2)p~C〇-f6 [10] where w5 and r are halogen atoms, and the other symbols are as defined above. This reaction can be carried out in a solvent containing a base. Examples of the solvent include any solvent which affects the reaction, such as digastric, trichloromethane, beta, tetrahydrofuran, dioxane, n,N-dimercaptocaramine, ethanol, and the like. Examples of the base i include diethylamine, diisopropylethylamine, methylmorpholine and the like. The amount of the compound [10] used is 丨.〇 to each mole compound. 3. 0 moles, preferably 丨. 丨 to 2 〇 Mo ears. The reaction can be carried out at a temperature of from 丨〇 to 2 ° C, preferably from 30 to 80 t:. In the compound [I] of the present invention, E is a group of the formula (i), q2 is a single bond, and R4 is a compound of 1,1-di-oxy-N-thiomorpholinyl group, in other words, Compound of the formula [IH]: 318695 44 S02 [IH] wherein the other symbols are as defined above, and can be produced, for example, by reacting the above-mentioned hydrazine II-G with divinyl hydrazine in a solvent containing a base. The examples include any solvent that does not affect the reaction, such as ethanol, lysine, toluene, N,N-dimethylmethamine, dimethyl methacrylate, etc.: test; J: triethylamine, diisopropyl Amine, " kiofronin, dimethylamine ^ ratio, and so on. The amount of diethyl _ used is 1.0 to 3.0 moles per mole of compound [π, preferably 12

在60至纖進行，較佳為⑽至⑽：^4耳。本反應能方法I 且物⑴中，Ε為式⑴之基團，以單鍵，飽和之5至7員含氮雜單環基取代之胺基，而該 3乳雜早％基復_氧基取代者，換言之之化合物：丨卜飞L丨1」It is carried out at 60 to fiber, preferably (10) to (10): ^4 ears. In the reaction method I and in the object (1), hydrazine is a group of the formula (1), a single bond, a saturated 5- to 7-membered aza-monocyclic group-substituted amine group, and the 3-milk-early-early group-reoxy group Substituted, in other words: 丨卜飞L丨1"

式中’z為醯基’ q為2至3之整數，r為i至2 而其他符號係如以上所定羞正 . 上所疋義此藉由例如使下式[丨-丨糾之化5物進行分子内環化反應來製備： 318695 45 1378922Where 'z is 醯 '' q is an integer from 2 to 3, r is i to 2 and the other symbols are as shamed as above. The above is defined by, for example, the following formula [丨-丨丨化化5 Preparation by intramolecular cyclization: 318695 45 1378922

式中，符號係如以上所定義。本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，例如二氣甲烷、亞颯、二甲基咪唑啶酮（dimethylimidaz〇lid〇ne)、乙腈、四氫呋喃、1，2-二曱氧基乙烷、丨，2-二氯乙烷等。鹼之貫例包括：氫化鈉、氫化鉀、碳酸鉀、碳酸鉋、乙醇鈉等。鹼之使用量為每一莫耳化合物[〗_Ia]可使用丨〇至5 〇莫耳，較佳為1.】至h5莫耳。本反應能在4〇至2〇〇£&進行，較佳為80至1201：。Wherein the symbols are as defined above. This reaction can be carried out in a solvent containing the test. Examples of the solvent include any solvent which does not affect the reaction, such as dihalomethane, hydrazine, dimethylimidaz〇lid〇ne, acetonitrile, tetrahydrofuran, 1,2-dimethoxyethane, hydrazine, 2-Dichloroethane, etc. Examples of the base include sodium hydride, potassium hydride, potassium carbonate, carbonic acid planing, sodium ethoxide and the like. The amount of base used is from 莫 to 5 莫 mol, preferably from 1. to h5 mol per mol compound [〗〖Ia]. The reaction can be carried out at 4 Torr to 2 Torr, preferably 80 to 1201:.

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

式中’符號係如以上所定義，能藉由例如使化合物[π 一 G] 與下式[Ac-Ι]之羧酸化合物或其反應性衍生物（例如，對應之酸鹵化物、酸酐）起反應來製備： r-COOH [Ac-1] 式中’符號係如以上所定義。本反應能以與上述方法A相同之方式進行。Wherein the symbol is as defined above, by, for example, the carboxylic acid compound of the compound [π-G] and the following formula [Ac-Ι] or a reactive derivative thereof (for example, the corresponding acid halide, acid anhydride) The reaction was prepared to: r-COOH [Ac-1] where the 'symbol' is as defined above. This reaction can be carried out in the same manner as in the above Process A.

方法K 本發明化合物[I]中，下式[I-K]之化合物： 318695 46 1378922Process K In the compound [I] of the present invention, the compound of the following formula [I-K]: 318695 46 1378922

[ΐ-κ] 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，能藉由例如使化合物[丨v] (r7=jj) 或其反應性衍生物與下式[11 ]之醇類化合物起反應來製備： R44-〇H [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。本發明之私的化合物[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（&)至（£)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Ri/R2為鹵素原子（或含鹵素之基團）之對應化合物[I]與氰化物（例如，氰化辞、氛化銅、氛化三甲基梦烧、氰化_等）在催化劑、驗與添加劑之存在或不存在下起反應而製得。驗之實例包括：三乙胺、N 一甲基六氫吼咬、二異丙基乙基胺等。催化劑之實例包括：妃催化劑’例如乙酸鈀、參（二苯亞甲基丙酮）二鈀、反式二氯雙（三環己膦）叙、肆（三笨膦）纪等，或錄催化劑，例如二漠苯麟）錄等。添加劑之實例包括：膦化合物，例如三苯膦、 1，1 -雙（二苯膦基）二（環戊二稀）鐵、消旋2,2、气二苯 318695 47 1378922 .膦基）-1，1、聯萘、2-(二-三級丁膦基）聯笨、2_(二環己膦基）聯苯、2-二環己膦基_Γ_(Ν，Ν-二甲胺基）聯笨或三一三級丁膦等。一一方法（b):具有烷基胺基或環烷基胺基（或含烷基胺基或環烷基胺基之基團）之化合物π]，能藉由使具齒二原^ 之對應化合物[I]與單或二烧基胺或環院基胺在催化劑、驗與添加劑之存在下起反應而製得。催化劑之實例可為用於方法（a)之鈀化合物與銅化合物等。添加劑之實例可為用於 =法（a)之膦化合物等。鹼之實例包括：乙酸鉀、碳酸鉀、碳酸絶、三級丁醇鉀等。方法（c):具有烷基氧基（或含烷基氧基之基團）之化合物[1]，能藉由使具經基（或含經基之基團）之對應化合物⑴ 與鹵化烷在溶劑中起反應；或使具羥基（或含烷基氧基之基團）之對應化合物[I]與醇類在含鹼（例如，碳酸鉀、碳酸鉋、氫化鈉等）或含活化劑（例如，偶氮二甲酸二乙酯等）鲁之洛劑中，在經三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（或含烷亞磺醯基或烷磺醯基之基團）之化合物[n，能藉由在溶劑中以氧化刎例如間氯過苯甲酸，處理具有烷基硫基（或含烷基硫基之基團）之對應化合物[门而製得。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π] 與醯化劑’例如缓酸化合物[Ac_n或反應性衍生物（例如，相應之酸i化物、對應之酸酐），反應而製得。本反應能 318695 48 1378922[ΐ-κ] wherein R44 is a saturated or unsaturated heteromonocyclic group which is optionally substituted, and the other symbols are as defined above, by, for example, making the compound [丨v] (r7=jj) or The reactive derivative is prepared by reacting with an alcohol compound of the following formula [11]: R44-〇H [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 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 (&) to (£). Process (a): The substituent [R] of RVR2 is a cyano group (or a group containing a cyano group), which can be made by making Ri/R2 a halogen atom (or a halogen-containing group) corresponding compound [ I] is prepared by reacting cyanide (for example, cyanide, copper, trimethylmethane, cyanide, etc.) in the presence or absence of a catalyst, an additive, and an additive. Examples of the test include triethylamine, N-methylhexahydroguanidine, diisopropylethylamine and the like. Examples of the catalyst include: a ruthenium catalyst such as palladium acetate, bis(diphenylmethyleneacetone) dipalladium, trans dichlorobis(tricyclohexylphosphine), hydrazine (triphenylphosphine), or the like, or a catalyst. For example, the second desert Benzin) recorded. Examples of the additive include: a phosphine compound such as triphenylphosphine, 1,1-bis(diphenylphosphino)bis(cyclopentadienyl)iron, racemic 2, 2, gas diphenyl 318695 47 1378922. phosphino)- 1, 1, binaphthyl, 2-(di-tri-tert-butylphosphino) phenyl, 2-(dicyclohexylphosphino)biphenyl, 2-dicyclohexylphosphino _ Γ Ν (Ν, Ν-dimethylamino) Stupid or three or three grades of butanol and so on. Method (b): a compound π] having an alkylamino group or a cycloalkylamino group (or a group containing an alkylamino group or a cycloalkylamino group), which can be obtained by The corresponding compound [I] is obtained by reacting a mono- or dialkylamine or a ring-based amine in the presence of a catalyst and an additive. Examples of the catalyst may be a palladium compound, a copper compound or the like used in the method (a). An example of the additive may be a phosphine compound or the like for the method (a). Examples of the base include potassium acetate, potassium carbonate, carbonic acid, potassium tert-butoxide, and the like. Process (c): a compound [1] having an alkyloxy group (or an alkyloxy group-containing group) capable of reacting a corresponding compound (1) having a trans group (or a group containing a radical) with an alkyl halide Reacting in a solvent; or reacting a corresponding compound [I] having a hydroxyl group (or an alkyloxy group-containing group) with an alcohol in a base (for example, potassium carbonate, carbonic acid planing, sodium hydride, etc.) or an activator (for example, diethyl azodicarboxylate, etc.) It is obtained by reacting in the presence of a trisubstituted phosphine in the ruthenium. 'Method (d) - a compound having an alkylsulfinyl group or an alkanesulfonyl group (or a group containing an alkylsulfinyl group or an alkanesulfonyl group) [n, which can be used as a ruthenium oxide in a solvent, for example Chloroperbenzoic acid is prepared by treating a corresponding compound 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), which can be obtained by using a corresponding compound π] having an amine group (or an amine group-containing group) For example, a slow acid compound [Ac_n or a reactive derivative (for example, a corresponding acid anhydride, a corresponding acid anhydride) is reacted. The reaction energy 318695 48 1378922

基氧基羰基之基團）之對應化合物π]而製得。一右有必要，前述製程所得之本發明化合物[丨]，能以習知方式轉變成其醫藥上可接受鹽類。鲁物之f偌〇本發明中間化合物中，Q1為單鍵或伸烷基之化合物 Π A] ’能以下列反應式A2或A3所述之方式來製備。反應式A1The corresponding compound π] of the group of the oxycarbonyl group) is obtained. As a matter of right, the compound of the present invention [丨] obtained by the above process can be converted into its pharmaceutically acceptable salt in a conventional manner. In the intermediate compound of the present invention, a compound wherein Q1 is a single bond or an alkylene group Π A] ' can be produced in the manner described in the following reaction formula A2 or A3. Reaction formula A1

m 反應步驟AM 分子内環化m reaction step AM intramolecular cyclization

反應式A2 318695 49 1378922 OR31 牛钡 OR31 >2，，'N oh [Π-Α11] 步驟I還原反應 A2-4Reaction formula A2 318695 49 1378922 OR31 Burdock OR31 >2,, 'N oh [Π-Α11] Step I reduction reaction A2-4

I ORJ1 [XUI ORJ1 [XU

[IX][IX]

[d][d]

反應式A3 步驟 A3-1 7 . 步驟Reaction Formula A3 Step A3-1 7 .

ZvO^^COORd A3^ [χνη X3-CH2-COORd [XIV] [XV]ZvO^^COORd A3^ [χνη X3-CH2-COORd [XIV] [XV]

去酯化反應上述反應式A1、A2與A3中，R11為視需要經取代之芳 50 318695 1378922 -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 為氫原子或烷基；Re為烷基；Rd為烷基或苯甲基；χι、χ2 與X3為鹵素原子；W3為反應性殘基；W4為反應性殘基，而其他付號係如以上所定義。反應步驟A1-1 : 自化合物[VI]產生化合物[VII]之反應能在含鹼之溶劑中進行。鹼之實例包括：乙酸納、乙酸卸、碳酸鈉、碳 Φ酸卸、碳酸氫鈉、碳酸氫卸、甲醇納、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、曱醇、二噚烷、二曱基甲醯胺、二曱基乙醯胺等。鹼之使用量為每一莫耳化合物[VI]可使用1.0至20莫耳，較佳為1.0 至3.0莫耳。本反應能在3〇至2〇(rc進行，較佳為6〇至 100〇C。反應步驟A1-2 : • 化合物[νπ]與化合物[VIII]之反應能在含鹼之溶劑中進行。鹼之實例包括：氫化鈉、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，例如一氣甲烷、苯、甲苯、四氫呋喃、二甲氧基乙烷、二噚烷、一甲基甲醯胺、二曱亞砜等。化合物[VIII]之使用量為每一莫耳化合物[VII]可使用1.0至1〇莫耳，較佳為1〇至 3. 〇莫耳。鹼之使用量為每一莫耳化合物[νπ]可使用丨.〇至20莫耳’較佳為1〇至5〇莫耳。本反應能在_3〇至1〇〇 318695 51 1378922 、C進行，較佳為2 0至6 〇。〇。同時，化合物[ΙΙ-Α]亦能在含活化劑（例如，偶氮二甲酸二乙酯）之溶劑中藉由使化合物[VII]與醇類化合物 [VlII-a]反應來製備： R3i-〇H [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、三氯甲烷、二甲基甲醯胺、鲁二甲基乙醯胺、二曱亞砜、四氫呋喃、二噚烷、甲苯、苯、 1，2-二氯乙烷、卜甲基吡咯啶酮、丨，2—二甲氧基乙烷等。反應步驟A2-1 : 以習知方式可使化合物[丨hA1丨]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欠鹵化物（化合物[IX ]中W3為鹵素原子）或相應之混合酸肝 (化合物[IX]中W3為烷基氧基羰基氧基等）。相應之酸鹵化物此藉由例如使化合物[11 _ a 11 ]與齒化劑（例如，亞硫醢鲁氯、磷醯氯、五氯化磷、草醯氯等）在含或不含催化劑量二曱基曱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-A11]與氯曱酸烷酯 (例如’氯甲酸乙酯等）在鹼（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溶劑，例如二氯曱烷、三氣甲烷、四氫呋喃、苯、曱苯等。本反應能在-60至lOOt進行，較佳為-40至8(TC。反應步驟A2-2 : 化合物[IX]轉變成化合物[X]能在含重氮甲烷化合物 52 318695 ^/8922 (例如，重氮甲烷、三甲基矽烷基重氮甲烷等）。溶劑之實 i括任饤不衫響反應之溶劑，例如乙越、二卩琴院、苯、尹苯等。重氮P烷化合物之使用量為每一莫耳化合物[Π] 可使用1 · 0至丨0莫耳，較佳為〗.〇至3· 〇莫耳。本反應能在~5〇至80 C進行，較佳為-10至5(TC。反應步騾A2-3 : 化合物[X]轉變成化合物[Π-Α12]之反應能在含或不含銀鹽之溶劑中加熱予以進行。溶劑之實例包括任何不影響f應之溶劑，例如水、醇（例如，甲醇、乙醇）等。銀鹽之實例包括：氧化銀、苯甲酸銀等。銀鹽之使用量為每Γ 莫耳化合物[X]使用丨刈至別莫耳’較佳為1〇至5 〇莫耳。本反應能在50至2〇(TC進行，較佳為別至15〇ΐ。、反應步驟A2-4 : 化合物[XI]能藉由在含還原組例如，氫化紹鐘等）之溶劑中還原化合物ΠΙ—Α11]而得到。溶劑之實例包括任何不影響反應之溶劑’例如乙⑽、四氫π夫喃等。還原劑之使用量為每—莫耳化合物[11仙]可使用1.0至20莫耳，較佳為2.0至5.G莫耳。本反應能在_5()至1()〇。^ 為-10 至 40°C。化合物[XI]亦能藉由還原Ra為烧基之化合物⑴一而製得。本反應能在含還原劑例如錢化鈉等之溶劑行。溶劑之實例包括任心影響反應之溶劑，例如喃與甲醇之混合物等。還原劑之使用量為每—莫耳化合物 [II-M]可使用1.0至20莫耳，較佳為2〇至5〇莫耳。 318695 53 1378922 本反應此在3 G至1 〇〇 °c進行，較佳為5 〇至8 〇。反應步驟A2-5 : 以白知方式可使化合物[χϊ]轉變成相應之反應性衍生化合物[XII])。例如，為鹵素原子或烷磺醯氧基之化合物[XII ]能藉由個別使用亞硫醯鹵例如亞硫醯氣，或鹵化烷磺醯例如甲磺醯氯來處理化合物[χι]而予以製備。反應步驟Α2-6 : 化合物[ΧΠ]與化合物[d]或其鹽類之反應能在含鹼之攀溶财進行。化合物[d]之鹽類實例包括：金屬鹽，例如卸鹽:溶劑之實例包括任何不影響反應之溶劑，例如乙鱗、四氫呋喃、苯、二甲基甲醯胺、二甲基乙醯胺、甲醇、乙醇等。驗實例包括：氫化鈉、氫化钟、甲醇納、乙醇鋼、二異丙胺基鋰、雙（三甲基矽烷基）胺基鋰等。化合物或其鹽類之使用量為每一莫耳化合物^丨丨]可使用1.0至 10. 〇莫耳，較佳為I 5至3· 〇莫耳。鹼之使用量為每一莫 #耳化合物[ΧΙΠ可使用^至10.0莫耳，較佳為15至3.'〇莫耳。本反應能在_2〇至2〇〇。(：進行，較佳為2〇至1〇(rc。若有需要，Q1為Cw伸烷基之化合物[Π_Α]能藉由例如將上述步驟Α2-3(或步驟Α2-6)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Λ2-卜Α2-2與Λ2-3(或步驟Α2_4、Α2_5與Α2_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[I丨_Α]能藉由例如使化合物 [Π-Ae]或化合物[Π-Af](參見以下反應步驟C1_4)進行 318695 54 1378922 -習知去自旨化反應而予以製備。反應步驟A 3 -1 : 化合物[XIV]與化合物[χν]之反應能在含鹼之溶劑中進行。驗之實例包括：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）胺基鐘、碳酸铯等。溶劑之實例包括任何不影響反應之溶劑’例如二氯甲烷、三氣曱烷、二曱基曱醯胺、二甲基乙醯胺、二甲亞颯、四氫呋喃、二噚烷、曱苯、苯、二Deesterification reaction In the above reaction formulas A1, A2 and A3, R11 is an optionally substituted aryl 50 318695 1378922-group or an optionally substituted heteroaryl group; R31 is optionally selected from a halogen atom, an amine group, a monoalkylamino group and a dialkylamino group substituted alkyl; Raa is a hydrogen atom or an alkyl group; Re is an alkyl group; Rd is an alkyl group or a benzyl group; χι, χ2 and X3 are halogen atoms; W3 Reactive residues; W4 is a reactive residue, while other symbols are as defined above. Reaction Step A1-1: The reaction of the compound [VII] from the compound [VI] can be carried out in an alkali-containing solvent. Examples of the base include sodium acetate, acetic acid unloading, sodium carbonate, carbon Φ acid unloading, sodium hydrogencarbonate, hydrogencarbonate unloading, sodium methoxide, sodium ethoxide, and the like. Examples of the solvent include any solvent which does not affect the reaction, such as water, ethanol, decyl alcohol, dioxane, dimethylformamide, dimercaptoacetamide and the like. The base is used in an amount of 1.0 to 20 moles, preferably 1.0 to 3.0 moles per mole of the compound [VI]. The reaction can be carried out at 3 Torr to 2 Torr (prc, preferably 6 Torr to 100 Torr C. Reaction Step A1-2: • The reaction of the compound [νπ] with the compound [VIII] 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, etc. Examples of the solvent include any a solvent which affects the reaction, such as monomethane, benzene, toluene, tetrahydrofuran, dimethoxyethane, dioxane, monomethylformamide, disulfoxide, etc. The compound [VIII] is used in an amount of The otic compound [VII] can be used in an amount of from 1.0 to 1 Torr, preferably from 1 Torr to 3. 〇 Moel. The amount of the base used is 每一.〇 to 20 摩尔's per mole of the compound [νπ] Preferably, the reaction can be carried out at _3〇 to 1〇〇318695 51 1378922, C, preferably 20 to 6 〇. 同时. At the same time, the compound [ΙΙ-Α] can also A solvent containing an activator (for example, diethyl azodicarboxylate) is prepared by reacting a compound [VII] with an alcohol compound [VlII-a]: R3i-〇H [VI In the formula, the symbols are as defined above. Examples of the solvent include any solvent which does not affect the reaction, such as dichloromethane, chloroform, dimethylformamide, lugethyleneamine, Disulfoxide, tetrahydrofuran, dioxane, toluene, benzene, 1,2-dichloroethane, methylpyrrolidone, anthracene, 2-dimethoxyethane, etc. Reaction Step A2-1: Known The compound [丨hA1丨] can be converted into the corresponding reactive derivative (compound [IX]). Examples of such reactive derivatives include the corresponding oxime halides (W3 in the compound [IX] is a halogen atom) or Corresponding mixed acid liver (W3 in the compound [IX] is an alkyloxycarbonyloxy group, etc.). The corresponding acid halide is obtained by, for example, the compound [11__11] and a toothing agent (for example, sulfoxide). The ruthenium chloride, the phosphonium chloride, the phosphorus pentachloride, the grass ruthenium chloride, etc. are prepared by reacting in a solvent with or without a catalyst amount of dimethyl decylamine or a solvent. Further, the corresponding mixed acid anhydride can be used by For example, the compound [II-A11] and an alkyl chloroantimonate (such as 'ethyl chloroformate, etc.) in a base (for example, 'triethylamine The reaction is carried out in the presence of diisopropylethylamine, etc. Examples of the solvent include any solvent which does not affect the reaction, such as dichlorosilane, trimethylmethane, tetrahydrofuran, benzene, toluene, etc. The reaction can be carried out at - 60 to 100 t, preferably -40 to 8 (TC. Reaction step A2-2: conversion of compound [IX] to compound [X] can be carried out in a diazomethane-containing compound 52 318695 ^/8922 (for example, diazomethane, Trimethyl decyl diazomethane, etc.) Solvents include solvents such as acetylene, diterpene, benzene, and phenyl. The diazo P-alkane compound is used in an amount of from 1 to 0 to 丨0 mol per mol of the compound [Π], preferably from 〇. to 3·mole. The reaction can be carried out at from -5 Torr to 80 C, preferably from -10 to 5 (TC. Reaction step A2-3: conversion of compound [X] to compound [Π-Α12] with or without silver The solvent of the salt is heated and heated. Examples of the solvent include any solvent which does not affect f, such as water, alcohol (for example, methanol, ethanol), etc. Examples of the silver salt include silver oxide, silver benzoate, etc. Silver salt The amount used is Γ 丨刈别化合物 ' X 较佳较佳较佳较佳较佳较佳较佳较佳较佳较佳较佳较佳较佳较佳较佳较佳较佳较佳较佳。。。本本本本本本本本本本本本本本本本本本Reaction Step A2-4: The compound [XI] can be obtained by reducing the compound ΠΙ-Α11] in a solvent containing a reducing group such as hydrogenation, etc. Examples of the solvent include any solvent which does not affect the reaction' B (10), tetrahydropyrene, etc. The reducing agent is used in an amount of 1.0 to 20 moles, preferably 2.0 to 5. G mole per mole of the compound [11 sen.] The reaction can be at _5. () to 1 () 〇. ^ is -10 to 40 ° C. The compound [XI] can also be obtained by reducing Ra as a calcining compound (1). The reaction can be carried out in the case of a reducing agent. Examples of the solvent include a solvent such as sodium hydride, etc. Examples of the solvent include a solvent which affects the reaction, such as a mixture of hexane and methanol, etc. The reducing agent is used in an amount of 1.0 to 20 moles per mole of the compound [II-M]. The ear is preferably 2 Torr to 5 Torr. 318695 53 1378922 The reaction is carried out at 3 G to 1 〇〇 °c, preferably 5 Torr to 8 Torr. Reaction Step A2-5: The compound [χϊ] is converted to the corresponding reactive derivative compound [XII]). For example, the compound [XII] which is a halogen atom or alkanesulfonyloxy group can be prepared by treating a compound [χι] with a sulfinium halide such as sulfinium gas or a halogenated alkanesulfonium chloride such as methylsulfonium chloride. . Reaction step Α2-6: The reaction of the compound [ΧΠ] with the compound [d] or its salt can be carried out in the presence of a base. Examples of the salt of the compound [d] include: a metal salt such as a salt-removing salt: examples of the solvent include any solvent which does not affect the reaction, such as ethylene scale, tetrahydrofuran, benzene, dimethylformamide, dimethylacetamide, Methanol, ethanol, etc. Examples include sodium hydride, hydrogenation clock, sodium methoxide, ethanol steel, lithium diisopropylamide, lithium bis(trimethyldecyl)amine, and the like. The compound or a salt thereof is used in an amount of from 1.0 to 10. Torr per mole of the molar compound, preferably from 1 to 3 hr. The amount of base used is each mole of compound [ΧΙΠ can be used to 10.0 moles, preferably 15 to 3." 莫 Mo Er. The reaction can range from _2 〇 to 2 〇〇. (: carried out, preferably 2 〇 to 1 〇 (rc. If necessary, Q1 is a compound of Cw alkyl group [Π_Α] can be obtained by, for example, the above steps Α2-3 (or steps Α2-6) The compound is converted into the corresponding carboxylic acid compound by deesterification reaction, and then the carboxylic acid compound is subjected to a series of reactions of steps Λ2-di-2-2 and Λ2-3 (or steps _2_4, Α2_5 and Α2_6), and the above process is repeated until The compound of the formula -N(R7)-[I丨_Α] can be carried out, for example, by subjecting the compound [Π-Ae] or the compound [Π-Af] (see the following reaction step C1_4). 318695 54 1378922 - It is conventionally prepared by a reaction. The reaction step A 3 -1 : The reaction of the compound [XIV] with the compound [χν] can be carried out in a solvent containing a base. Examples include: sodium carbonate, Potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydride, potassium hydride, lithium diisopropylamide, bis(tridecyldecylalkyl)amine clock, cesium carbonate, etc. Examples of the solvent include any solvent which does not affect the reaction' For example, dichloromethane, trioxane, dimethyl decylamine, dimethyl acetamide, dimethyl hydrazine, tetrahydrogen Furan, dioxane, toluene, benzene, two

^ * A J W 氣乙烷、1-曱基吡咯啶酮、丨，2_二曱氧基乙烷等。化合物 [χν]或其鹽類之使用量為每一莫耳化合物[xiv]可使用 1. 0至5· 0莫耳，較佳為丨.1至2· 〇莫耳。鹼之使用量為每一莫耳化合物[XIV]可使用；[.〇至5. 〇莫耳，較佳為1.丄至2. 0莫耳。本反應能在-10至lOOt：進行，較佳為20至 80°C。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σ物[XVII ]之分子内環化反應能在含鹵化劑及含或来3活化劑之〉谷劑中進行。鹵化劑之實例包括：亞硫醯氯、 '五氣化碟 '草si氣等。活化劑之實例包括：氣化鋁，化鐵（Π I )、三氯化硼、三氟化硼、四氯化鈦、四氯 =錫=。溶劑之實例包括任何不影響反應之溶劑，例如二瓜化妷、二氯甲烷、硝基曱烷、三氯曱烷、四氫呋喃、二 55 318695 Ϊ378922 、曙炫、甲苯、苯、硝基策、】？—备 , 令月岙本 U-—虱乙烷、l 2一二甲氧基乙烷等4化劑之使用量為每一莫耳化合物…⑴可使用 i.O至。5.G莫耳，較佳為L1至U莫耳。本反應能在⑽ 至200°C進行’較佳為8〇至i5〇〇c。反應步驟A3-4: .、化合物[XVIII]與化合物如]之反應能在含驗之溶劑中進行。鹼之實例包括：鹼金屬醇鹽，例如甲醇鈉，·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、甲醇、四氫吱唾、二嗜院、甲苯、苯、U —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 [ΧΠΙΙ]使用LO至3 0莫耳，較佳為1〇至15莫耳。鹼之使用量為每一莫耳化合物[XVIII]可使用1.0至5.0莫耳’較佳為1.1至3·〇莫耳。本反應能在_7〇至15〇t進行，較佳為-50至50°C。反應步驟A3-5: ^化合物[xx]與化合物[XXI]之反應能在含或不含鹼之冷劑中進行。鹼之實例包括：吡啶、三乙胺、二異丙基乙基胺、曱基嗎福啉、1，8-二氮雜雙環[5, 4, 0]十一烯等。 >谷劑之實例包括任何不影響反應之溶劑，例如乙醇、曱醇、 2虱呋喃、二噚烷、曱苯、苯、l 2_二曱氧基乙烷等。化合物[XXI]之使用量為每一莫耳化合物[χχ]可使用I 〇至莫耳，較佳為1· 1至丨.5莫耳。本反應能在_1Q至1〇〇 C進行’較佳為20至6(TC。 318695 56 1378922 ii)化合物[II-B]能藉由例如使用化合物[Π-Aa]或相應之二燒基醯胺化合物或相應之N-烷基-N-烷基氧基醯胺化合物依據下列反應式B來製備：^ * A J W ethane, 1-decylpyrrolidone, anthracene, 2_dimethoxyethane, and the like. The compound [χν] or a salt thereof is used in an amount of from 1.0 to 5.0 moles per mole of the compound [xiv], preferably from 1.1 to 2·〇. The amount of the base used is that each mole compound [XIV] can be used; [.〇 to 5. 〇莫耳, preferably 1. 丄 to 2. 0 mole. The reaction can be carried out at from -10 to 100 t: preferably from 20 to 80 °C. Reaction Step A3-2: | The deesterification reaction of the compound [XVI] can be carried out by subjecting the compound to a conventional hydrolysis reaction. Reaction step A3-3: • The intramolecular cyclization reaction of the yttrium compound [XVII] can be carried out in a gluten-containing agent containing a halogenating agent and an activator. Examples of the halogenating agent include: sulfinium chloride, 'five gasification dish' grass si gas, and the like. Examples of the activator include: vaporized aluminum, iron (Π I ), boron trichloride, boron trifluoride, titanium tetrachloride, tetrachloro = tin =. Examples of the solvent include any solvent which does not affect the reaction, such as ruthenium dichloride, dichloromethane, nitrodecane, trichlorodecane, tetrahydrofuran, 255, 318,695, Ϊ 922 378, 922, benzene, toluene, benzene, nitro, ? —, 岙令 U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U 5. G Mo, preferably L1 to U Mo. The reaction can be carried out at (10) to 200 ° C, preferably from 8 Torr to i5 〇〇 c. Reaction Step A3-4: The reaction of the compound [XVIII] with a compound such as] can be carried out in a solvent containing the test. Examples of the base include an alkali metal alkoxide such as sodium methoxide, an alkali metal amine such as lithium diisopropylamide, an alkali metal hydride such as sodium hydride or the like. Examples of the solvent include any solvent which does not affect the reaction, such as ethanol, methanol, tetrahydrofuran, dicholine, toluene, benzene, U-dimethoxyethane and the like. The compound [XIX] or a salt thereof is used in an amount of from LO to 30 moles, preferably from 1 to 15 moles per mole of the compound [ΧΠΙΙ]. The base is used in an amount of from 1.0 to 5.0 mols, preferably from 1.1 to 3 mol%, per mol of the compound [XVIII]. The reaction can be carried out at from -7 Torr to 15 Torr, preferably from -50 to 50 °C. Reaction Step A3-5: The reaction of the compound [xx] with the compound [XXI] can be carried out in a refrigerant containing or not containing a base. Examples of the base include pyridine, triethylamine, diisopropylethylamine, decylmorpholine, 1,8-diazabicyclo[5,4,0]undecene and the like. > Examples of the granules include any solvent which does not affect the reaction, such as ethanol, decyl alcohol, 2-furfuran, dioxane, toluene, benzene, l2-dimethoxyethane, and the like. The compound [XXI] is used in an amount of from 1 Torr to 1 mol per mol of the molar compound [χχ], preferably from 1.1 to 0.5 mol. The reaction can be carried out at _1Q to 1 〇〇C, preferably 20 to 6 (TC. 318695 56 1378922 ii), the compound [II-B] can be used, for example, by using the compound [Π-Aa] or the corresponding dialkyl group. The guanamine compound or the corresponding N-alkyl-N-alkyloxyguanamine compound is prepared according to the following reaction formula B:

反應式BReaction B

R1 /〇R 步驟Bl-l t OR3R1 /〇R Step Bl-l t OR3

Rc-Li [bl] ^-OH 或 L J R2 m 〇 Rc-Mg.Y [b2] W-Aa] [ΧΧΠ]Rc-Li [bl] ^-OH or L J R2 m 〇 Rc-Mg.Y [b2] W-Aa] [ΧΧΠ]

(TRC 步騾Bl-2(TRC Step Bl-2

H 鹵化劑H halogenating agent

Vq22^ [Π-Β] 上述反應式中，Rc為院基，γ為鹵素原子，而其他符號係如以上所定義。反應步驟B1-1 : φ 化合物[II-Aa]與化合物㈧1]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，例如***、四氫呋喃、二噚烷、二甲氧基乙烷、苯、甲苯等。化合物[bl]或化合物[b2]之使用量為每一莫耳化合物 [Π-Aa]可使用2·0至3.0莫耳，較佳為2〇至2·5莫耳。本反應能在-50至80°C進行’較佳為-ίο至。反應步驟B1-2 : 化合物[XXII]之由化反應能在溶劑中進行。齒化劑之實例包m溴琥賴亞胺、雙（二甲基乙醯胺）二漠 318695 57 1378922 例如溴馱等。溶劑之實例包括任何不影響反應之溶劑，i7g如乙鍵一氣甲院、1，2-二氯乙烷、三氯甲坑、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.〇至莫耳，較佳為1.〇至2 〇莫耳。本反應能在_10至5〇 c進行，較佳為〇至3(Tc。 111)化合物[11-C ]例如能以下列反應式C1所述之方式來製備：步驟 Cl-1Vq22^ [Π-Β] In the above reaction formula, Rc is a hospital group, γ is a halogen atom, and other symbols are as defined above. Reaction Step B1-1: φ The reaction of the compound [II-Aa] with the compound (VIII) 1] 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, toluene and the like. The compound [b1] or the compound [b2] is used in an amount of from 2.00 to 3.0 mol, preferably from 2 to 2.5 mol, per mole of the compound [Π-Aa]. The reaction can be carried out at -50 to 80 ° C, preferably - ίο. Reaction Step B1-2: The catalyzed reaction of the compound [XXII] can be carried out in a solvent. Examples of the toothing agent include m-bromosuccinimide, bis(dimethylacetamide), dimethyl 318695 57 1378922 such as bromine and the like. Examples of the solvent include any solvent which does not affect the reaction, i7g such as ethyl ketone, ketone, 1,2-dichloroethane, trichloromethane, carbon tetrachloride, and the like. The halogenating agent is used in an amount of from 丨.〇 to mol, preferably from 1.〇 to 2 〇mol, per mole of compound [χχπ]. The reaction can be carried out at _10 to 5 〇 c, preferably 〇 to 3 (Tc. 111). The compound [11-C] can be produced, for example, in the manner described in the following Reaction Scheme C1: Step Cl-1

C0N3 反應式C1 OR3 ι>2 疊氮化反應，厂 [II-Ac ] (azidation) Rz [xxjjjjC0N3 reaction formula C1 OR3 ι>2 azidation reaction, plant [II-Ac ] (azidation) Rz [xxjjjj

Rl>Y^y-co〇H 庫爾提斯（Curtius) 重排Rl>Y^y-co〇H Curtius rearrangement

N-N OR3N-N OR3

Rl^-NC0 Cl-3 [XXIV] 步驟睃處理 OR3 R2’ [II-Ca ] 步驟 Cl-4 • 烧化反應 OR3RlVv ,N-N R2 [Π-Cb ] 上述反應式中，R i為烷基，而其他符號係如以上所定義‘ 反應步驟C1-1 : 化合物[Π-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、曱苯、四氫呋喃、***等。疊氮化劑之實例包括：遇氯磷酸二苯酯（DPPA)、疊氮化鈉等。鹼之實例包括··吡啶登二乙胺、二異丙基乙基胺、4-甲基嗎福啉、〗，二气雜^隹環[5, 4’ 0]十一烯等。疊氮化劑之使用量為每一莫耳二人= 3U695 58 1378922 • [II-Ac]可使用1. 〇至5· 〇莫耳，較佳為（丨至2. 〇莫耳。 -鹼之使用量為每一莫耳化合物口卜^]可使用ι〇·至莫耳，較佳為1. 1至3.0莫耳。本反應能在行，較佳為-1。至1(TC。 5〇〇：進反應步驟C1-2 : 化合物[XXIV]能藉由在溶劑中加熱進行庫爾提斯 (Curtius)重排反應予以製備。溶劑之實例包括任何不影響反應之溶劑，例如苯、甲苯、n三氣曱燒等。本反 •應能在40至2G0t：進行，較佳為6〇至12〇〇c。反應步驟C1-3 : 化合物[XXIV]之酸處理能在有或無溶劑中進行。溶劑之實例包括任何不影響反應之溶劑，例如水等。酸之實例々包括：強酸，例如硫酸、鹽酸、硝酸、三氟乙酸、氫溴酸等。酸之使用量為每一莫耳化合物[χχιν]可使用2 〇至。1〇_ 〇莫耳，較佳為至5.0莫耳。本反應能在〇至2〇〇 # C進行，較佳為40至120°C。反應步驟C1-4 : 化合物[I I-Ca]之烷化反應能在溶劑中於下列丨）至3) $條件下進行’例如1}於鹼（例如，氫化鈉、碳酸鉀、吡疋二乙胺、二異丙基乙基胺、4-甲基嗎福啉、；[，8__二氮雜雙環[5, 4’ 0]十一烯等）以及式[χχν]之炫基齒化物存在下： R72-X4 [XXV] 式中，R為烷基，X4為鹵素原子；或2)於還原劑（例如， 318695 59 1378922 氫化铭經、棚氫化納鈉等）下：酸 ------ 一 (例如，乙酸、曱酸等）以及醛化合物[χχνι]存在 r73-CHO [XXVI] 式t，R73為烷基；或3)於活化劑（例如，偶氮一醋等）、經三取代之鱗（例如，三苯膊、三丁 = [XXVII]之醇化合物存在下： r74~〇H [XXVII] 式中，R74為烧基。溶劑之實例包括任何不影響反應之溶劑，例如二氣甲烷、三氣甲烷、二甲基甲醯胺、二甲基乙酿胺、二甲亞石風 '四氫吱口南、二嗜院、甲笨、苯、i ==、卜甲基料㈣、U—二甲氧基乙院等。本反應此在-20至l〇〇t：進行，較佳為〇至4〇它。义引5二:有义要’可在化合物[II~Ca]進行燒化反應刚，引入適當保護基（例 >，、炫基氧基幾基如2級基，方基烷基氧基羰基如苯 " 佴罐其处价“ 本7乳基▲基專）至3-胺基。此除。。土月呆護基種類，利用習知方式予以引入或去化合物⑴训亦能藉由在式[e]之醇化合物中·· ^e~〇H [e] m述相提斯重排反 2)“到下式[H-Aek化合物： 318695 60 1378922 r1 OR3 [Π-Ae ] :2XH^ 然後使此化合物[Π-Ae]與烷基鹵化物[xxv]或醇化合物 [XXVII]反應，產生式[Ii-Af]之化合物： , OR3 R71 [Π-Af] r>n^-or« 式中，符號係如以上所定義，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15〇Ό加熱處理；或（3)進行催化性氫化反應。化合物[11 - F ]能藉由使化合物[丨丨_ A a ]與化合物[b 1 ] (例如，烷基鋰如甲基鋰）在溶劑（例如，四氫呋喃）中反應，然後使產物與R。為乙烯基之化合物[b2](例如，溴化乙'婦基鎂）反應來製備。化合物[II-G]能藉由以如方法4所述之相同方式，使，合物Πΐ-Aa]與式[12]之肼化合物或其鹽類反應，然後自產物中移除醯基（Z)而製得·· H2N-NHZ [12] 式中，Z為醯基。严本發明之說明與申請專利範圍中，厂南素 =、蛾或漠原子。「絲」意指具有】至6個碳二， Λ 4個碳原子之直鏈或支鏈燒基。「環燒基」意指 318695 61 •具有3至8個碳原子，較 -炫基」意指具有…個；7個碳原子之環烷基。「伸之直鏈或支鏈伸烧基。子’較佳為1至3個碳原子實施例以更詳細地說明，但本發明化合物藉由以下實施例予不應解釋成將本發明限制於此。實施例1 ?’基嗎福嚇(147克)、水可溶碳二亞胺鹽酸鹽 (.克)與1，基笨并三唾水合物(2·21克)加至3_竣基 + (2-虱本基)-5_(4'氣苯基)+甲氧基*吡唑。5 克，參考例1⑻所得之化合物）之二氣甲院（1〇〇毫升）溶液中’於室溫攪拌混合物—夜。然後將碳酸氫鈉水溶液加至反應混合物中並祕，接著用三氯？科取。有機層以硫酸鎂乾燥後過濾。舰經真^濃縮後粗產物时朦管柱層析（溶劑：己烷/乙酸乙酯=40/60至2〇/8〇)進行純化，得到 1-(2-氯苯基）-5-(4-氯苯基）-4-甲氧基_3_[ν_(ν_嗎福啉基）胺曱醯基]-1Η-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 : 447/449fM+Hj + 實施例2 至溫下，將草醯氯（21微升）與一滴二甲基甲酿胺加至參考例1(6)所得化合物（73毫克）之二氯曱烷（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 1378922 • °比咯啶鹽酸鹽（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石夕膠管柱層析（Chromatorex NH-石夕膠，Fuji Si lie i aRl^-NC0 Cl-3 [XXIV] Step 睃Processing OR3 R2' [II-Ca ] Step Cl-4 • Burning reaction OR3RlVv, NN R2 [Π-Cb ] In the above reaction formula, R i is an alkyl group, and others The symbol is as defined above. 'Reaction step C1-1: The reaction of the compound [Π-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 and the like. Examples of the azidating agent include: diphenyl chlorophosphate (DPPA), sodium azide, and the like. Examples of the base include pyridine, diethylamine, diisopropylethylamine, 4-methylmorpholine, dimethylidene ring, [5, 4'0] undecene, and the like. The amount of azide used is 2 695 per person = 3 U695 58 1378922 • [II-Ac] can be used 1. 〇 to 5· 〇耳, preferably (丨 to 2. 〇耳 -. The amount of the compound used may be from 1 to 3.0 moles, preferably from 1.1 to 3.0 moles. The reaction can be carried out, preferably from -1 to 1 (TC. 5〇〇: Into the reaction step C1-2: The compound [XXIV] can be prepared by subjecting a Curtius rearrangement reaction by heating in a solvent. Examples of the solvent include any solvent which does not affect the reaction, such as benzene, Toluene, n gas, etc. This reaction should be carried out at 40 to 2 G0t: preferably 6 to 12 C. Reaction step C1-3: Acid treatment of compound [XXIV] with or without Examples of the solvent include any solvent which does not affect the reaction, such as water, etc. Examples of the acid include: a strong acid such as sulfuric acid, hydrochloric acid, nitric acid, trifluoroacetic acid, hydrobromic acid, etc. The amount of the acid used is The molar compound [χχιν] can be used in an amount of 2 〇 to 1 〇〇耳, preferably to 5.0 摩尔. The reaction can be carried out at 〇 to 2 〇〇 # C, preferably 40 To 120 ° C. Reaction Step C1-4: The alkylation reaction of the compound [I I-Ca] can be carried out in a solvent under the following conditions 3) to 3) $ for example [1] in a base (for example, sodium hydride, carbonic acid) Potassium, pyridinium diethylamine, diisopropylethylamine, 4-methylmorpholine, [,8__diazabicyclo[5,4'0]undecene, etc.) and formula [χχν] In the presence of a dentate dentate: R72-X4 [XXV] wherein R is an alkyl group and X4 is a halogen atom; or 2) is a reducing agent (for example, 318695 59 1378922 hydrogenation, sodium hydride, etc.) : acid ------ a (for example, acetic acid, citric acid, etc.) and an aldehyde compound [χχνι] in the presence of r73-CHO [XXVI] formula t, R73 is an alkyl group; or 3) in an activator (for example, azo a vinegar, etc., a three-substituted scale (for example, in the presence of an alcohol compound of triphenyl or tributyl = [XXVII]: r74~〇H [XXVII] wherein R74 is a burnt group. Examples of the solvent include any Solvents affecting the reaction, such as di-methane, tri-methane, dimethylformamide, dimethylacetamide, dimethyl sulphide 'tetrahydrofuran, south of the hospital, a stupid, benzene, i ==, MB (4), U Dimethoxy ethoxylate, etc. The reaction is carried out at -20 to l〇〇t: preferably 〇 to 4 。. 义引五二: 义义要' can be burned in the compound [II~Ca] Just after the reaction, a suitable protecting group is introduced (for example, a thioloxy group such as a 2-stage group, a arylalkyloxycarbonyl group such as benzene), a 佴其本本本本本本本本本本To 3-amino group. This is divided. . The type of soil-protecting base can be introduced or removed by a conventional method. (1) Training can also be performed by using the alcohol compound of the formula [e]·· ^e~〇H [e] m "To the following formula [H-Aek compound: 318695 60 1378922 r1 OR3 [Π-Ae ] : 2XH^] This compound [Π-Ae] is then reacted with an alkyl halide [xxv] or an alcohol compound [XXVII] to produce a compound of the formula [Ii-Af]: , OR3 R71 [Π-Af] r>n^-or« wherein, the symbol is as defined above, and then the formula Re〇c〇_醯 is removed and prepared The thiol moiety can be removed by treatment with (1) acid such as hydrochloric acid, trifluoroacetic acid, hydrobromic acid or the like; or (2) heat treatment at about 15 Torr; or (3) catalytic hydrogenation reaction. The compound [11 - F ] can be reacted with a compound [b 1 ] (for example, an alkyl lithium such as methyl lithium) in a solvent (for example, tetrahydrofuran), and then the product is reacted with R. is prepared by reacting a vinyl compound [b2] (for example, bromide bromide). The compound [II-G] can be obtained in the same manner as described in the method 4, Aa] and the formula [12] The compound or a salt thereof is reacted, and then the thiol group (Z) is removed from the product to obtain H2N-NHZ [12] wherein Z is a fluorenyl group. Prime =, moth or desert atom. "Silk" means a straight or branched alkyl group having from 4 carbon atoms to 4 carbon atoms. "Cycloalkyl" means 318695 61 • having 3 to 8 carbon atoms, and more than - stilbene means having a cycloalkyl group of 7 carbon atoms. The "stretched straight chain or branched chain extended group. The 'preferably 1 to 3 carbon atom examples are explained in more detail, but the compounds of the present invention should not be construed as limiting the present invention by the following examples. Example 1 ? 'Kifufu scare (147 g), water soluble carbodiimide hydrochloride (.g) and 1, stupid and trisalhydrate (2. 21 g) added to 3_竣Base + (2-oxime-based)-5-(4'-phenophenyl) + methoxy-pyrazole. 5 g, refer to the compound obtained in Example 1 (8) in a solution of the second gas (1 ml) The mixture was stirred at room temperature overnight. Then an aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and then secreted, followed by trichlorobenzene. The organic layer was dried over magnesium sulfate and then filtered. Purification by column chromatography (solvent: hexane / ethyl acetate = 40/60 to 2 〇 / 8 〇) to give 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methyl Oxy_3_[ν_(ν_morpholinyl)amine hydrazino]-1 Η-pyrazole (3.99 g, yield 81%) was obtained as a powder. Mass Spectrum (MS) Data: MS (atmospheric pressure chemical free, APCI) m/z : 447/449fM+Hj + Example 2 To the temperature, the grass is chlorine (21 To a solution of the compound obtained in Reference Example 1 (6) (73 mg) in dichloromethane (2 ml), and the mixture was stirred at the same temperature for one hour. The mixture was diluted with tetrahydrofuran (2 mL), then N-amine 318 695 62 1378922 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; IN HC1 solution (800 μl) and stirred. 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 to give a crude product. Shixi rubber column chromatography (Chromatorex NH-Shi Xijiao, Fuji Si lie ia

Chem.公司製造’溶劑：己烷/乙酸乙酯=5〇/5〇至3〇/7〇) 進行純化，得到1-(2-氯笨基）-5-(4-氣苯基）-4-甲氧基 -3-[N-U-吡咯啶基）胺甲醯基]-1H-吡唑（43毫克，產率籲50%)呈粉末。 MS(APCI)m/z ： 431/433[M+H]+ 實施例3 (1) 在0°C、氮氣環境下，將甲基鋰（丨.ο·***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3〇分鐘，然後室溫攪拌3小時。接著在冰冷卻下將水與乙酸籲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石夕膠管柱層析（溶劑：己烧/乙酸乙酯=9〇/1〇至85/15) 進行純化，得到3-乙醯基-1-(2-氯苯基）_5_(4_氣苯基） -4-甲氧基-1H-吡唑（1. 1克，產率43%)呈固體。 MS(APCI)ra/z ： 361/363[M+H]+ (2) 將溴（8· 5微升）逐滴加至上述步驟所得化合物 (60鼋克）之三氯曱院（3毫升）溶液中，室溫擾拌混合物3 小時。然後》辰备目反應混合物，殘留物以二甲基甲醯胺（3毫 318695 63 1378922 .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授掉。有機層用矽藻土管柱（CHEMELUTE，VARIAN公司製造）萃取。萃取液輕真空濃縮後所得粗產物用矽膠管桎層析（ch『⑽at〇rex NH-石夕膠，Fujl Silicia Chem.公司製造，溶劑·己以乙酸乙㈣20至65/35)進行純化，流出之區分液經真空濃縮。所得產物以三級丁醇溶解後進行冷;東乾燥，得到3_ [1-(N-嗎福啉基）乙醯基]—卜（2_氣苯基）_5 _ ·+甲氧基坐（26.8毫克，產率36%)呈粉末。土 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i i 3之—者中所述之相同方法處理，得到如下表1所示之化合物。Chem. Company's manufacture of 'solvent: hexane/ethyl acetate = 5〇/5〇 to 3〇/7〇) was purified to give 1-(2-chlorophenyl)-5-(4-phenylphenyl)- 4-Methoxy-3-[NU-pyrrolidinyl)aminemethanyl]-1H-pyrazole (43 mg, yield 50%) was obtained as a powder. MS (APCI) m/z : 431/433 [M+H] + Example 3 (1) Methyllithium (丨.ο········· A solution of the compound (2.5 g) obtained in the title compound (1) (m. 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 crude product was purified by chromatography eluting with EtOAc (solvent: hexane / ethyl acetate = 9 〇 /1 〇 to 85/15) to give 3-ethyl fluoren-1-(2- Chlorophenyl)_5_(4-hydroxyphenyl)-4-methoxy-1H-pyrazole (1.1 g, yield 43%) was obtained as a solid. MS (APCI)ra/z : 361/363[M+H]+ (2) bromine (8.5 μl) was added dropwise to the compound obtained in the above step (60 g) of trichloropurine (3 ml) In the solution, the mixture was spoiled at room temperature for 3 hours. Then the reaction mixture was prepared and the residue was diluted with dimethylformamide (3 s 318 695 63 1378922 liters). Add morphine (146 μl) and stir at room temperature for 2 hours. - Water and ethyl acetate were then added to the reaction mixture and allowed to pass. The organic layer was extracted with a diatomaceous earth pipe column (CHEMELUTE, manufactured by VARIAN Co., Ltd.). The crude product obtained by light vacuum concentration of the extract was purified by silica gel chromatography (ch "(10) at 〇rex NH-shixi gum, manufactured by Fujl Silicia Chem., solvent, ethyl acetate (tetra) 20 to 65/35), and eluted. The partition liquid was concentrated in vacuo. The obtained product is dissolved in tertiary butanol and then cooled; it is dried in the east to obtain 3_[1-(N-morpholineyl)ethenyl]-b (2-phenylphenyl)_5 _ ·+methoxy sit ( 26.8 mg, yield 36%) was in powder. Soil MS (APCI) m/z: 446/448 [M+H] + Examples 4 to 13 The corresponding starting materials were treated in the same manner as described in Example ii 3 to give the following Table 1 The compound shown.

318695 64 1378922 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]+ 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 / \—/ . 固體 MS(APCI): 461/463 [M+H]+318695 64 1378922 Table 1(1) Example No. R3 -N(R5)(R6) Physicochemical properties, etc. 4 ch3 H /N^CF3 Solid MS (APCI): 444/446 [M+H]+ 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 / \—/ . Solid MS (APCI): 461/463 [M+H]+

65 318695 1378922 表 1(2)65 318695 1378922 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-羥基苯并三峻水合物（184毫克）加至3 -叛基-1-(2 -氯苯基）-5-(4-氯苯基）-4-曱氧基-1H-η比唑（290毫克，參考例1(6)所得化 66 318695 1378922 •合物）之二氣甲烷/二曱基甲醯胺（6毫升/〇. 5毫升）之溶液 -中’室溫擾拌混合物一夜。然後將碳酸氫納水溶液加至反應混合物中並攪拌’接著用三氣甲烷萃取。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= 85/15至70/30)進行純化’得到ι_(2-氣苯基）-5-(4-氯苯基）-4-曱氧基-3-[N-(4-四氫硫代哌喃基）胺甲醯基]_1H_ 〇比唾（323宅克’產率87%)呈無色固體。 MS(APCI)m/z ： 462/464[M+H]+ •實施例15 在〇°C ’將三氟乙酸（77微升）加至實施例14所得化合物（116笔克）之二氯曱烷（4毫升）溶液中，室溫攪拌混合物 30分鐘。接著加入3-氣過苯曱酸（58毫克，水含量25%)，在相同溫度下攪拌1小時，室溫攪拌2小時。添加碳酸氫鈉水溶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—三氯曱烷/曱醇=1〇〇/〇至95/5) 進行純化，得到1-(2-氯苯基）—5_(4_氣苯基）_4-曱氧基 -3_{N-[4-(卜侧氧基四氫硫代哌喃基）]胺甲醯基卜1H_吡。坐（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-氯過苯曱酸係使用115毫克外，將實施例14所知化合物（116毫克）以如實施例丨5相同之方法處理，得到 1-（2-氯苯基）-5-(4_氣苯基）_4_甲氧基— 3_{Ν_[4_(ι，卜二 318695 67 1378922 -側氧基四氫硫代哌喃基）]胺曱醯基}_1{}_吡唑（69毫克，產 •率56%)呈無色固體。 MS(APCI)ra/z ： 494/496[M+H]+ 實施例17 將4-四氫硫代哌喃醇（61毫克）與4-二曱胺基吡啶（2〇毫克）加至參考例1(6)所得化合物（73毫克）之二氯甲烷（3 笔升）溶液中並撥拌混合物。然後在〇添加二環己基碳二亞胺（45毫克）至混合物中並室溫攪拌一夜。將碳酸氫鈉水籲溶液加至反應混合物中並攪拌，接著用三氯曱烷萃取。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=77/23至53/47)進行純化，得到ι_(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-吡唑（53毫克，產率59%)呈無色固體。 MS(APCI)m/z ： 447/449[M+H]+ 實施例18 % 在0 C、氮氣環境下’將疊氮磷酸二苯酯（47微升）與二乙胺（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，然後在8〇。〇攪拌混合物一夜。接著在冰冷卻下將4-四氫哌喃基胺（36毫克）與4_二曱胺基吡啶（2. 4毫克）加至反應混合物中，在8〇。〇搜拌一夜。接著加入；ε反酸氫鈉水溶液並攪拌，然後用矽藻土管柱（CH⑽ 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（溶劑：己烷/乙酸乙酯=6〇/4〇至 20/80)進行純化，得到丨气卜氣笨基）_5_(4_氣苯基）_4_羥 318695 68 1378922 -基- 3- [N -(4-四氫派喃基）腺基]-1Η-α比唾（i〇亳克，產率 -11%)呈無色固體。 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-胺基一1 _ 三級丁氧羰基氮咀以如實施例1所述之相同方法處理，得到1-(2，4- 一氯本基）_5_(4 -氣笨基）-4-曱氧基一 (1-三級丁氧羰基）氮咀基]胺甲醯基卜1H_吡唾（59〇毫鲁克，產率83%)呈固體。 MS(APCI)m/z : 551/553[M+H]+ (2) 將4NHH-乙酸乙酯（2毫升）加至上述步驟（1)所得化合物（590毫克）之三氣曱烷（5毫升）溶液中，室溫攪拌混合物一夜。然後真空濃縮反應混合物，添加乙酸乙酯與碳酸氫鈉水溶液至殘留物中並攪拌。有機層以硫酸鎂乾燥後過濾。濾液經真空濃縮後殘留物以二氣曱烷（2毫升）稀鲁釋。接著加入三乙胺（30毫升）與對氣苯曱醯氯（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' 濾液經真空濃縮後殘留物以二曱基曱醯胺（1毫升）稀釋。接著加入氫化鈉（4毫克）並在8(rc攪拌2日。冷卻至室溫後加入水與乙酸乙酯，有機層以乙酸乙酯萃取。萃取液二真空濃縮後所得粗產物用矽膠管柱層析（溶劑.：己烷/乙酸 =酯=〇/1〇〇)進行純化，得到卜^扣二氯苯基）_5_(4_氯苯基）-4-羥基-3-{N-[3-(4_氯苯甲醯基）氮。且基]胺甲醯基} 318695 69 1378922 -1H-吡唑（30毫克，產率52%)呈粉末。 MSCAPCI)m/z ： 589/591[M+H]+ 實施例20 (1)將1-三級丁氧羰基_3_胺基吡咯啶（279毫克）、水可溶碳二亞胺鹽酸鹽（288毫克）與卜經基笨并三唆水人物 ⑽毫克）加至3 —絲+⑶氯苯基）—5各氯苯基）二_ mu坐（363毫克，參考例1(6)所得化合物）之二氣甲烷（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，接著用三氯甲烷萃取。萃取液經真空濃縮後粗產物时膠管柱層析（溶劑：己烷/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_(卜三級丁氧羰基），咯啶基]胺甲醯基卜卜（2 一氣苯基）_5一（4—氣苯基氧基-1H-吼唑（516毫克，產率97%)呈無色粉末。 MS(APCI)m/z . 431/433[M+H-Boc] + (Boc :三級丁氧幾基） • (2)在〇°C，將4N HC卜二噚烷（3毫升）加至上述步驟 (1)所得化合物（425毫克）之二噚烷（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。接著將碳酸氫納水溶液加至反應混合物中進行鹼化。授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]-1H-吡唑（344毫克，產率100%)呈無色黏稠物。 MS(APCI)m/z ： 431/433[M+H]+ 318695 70 1378922 • (3)在0C ’將三乙胺（Π2微升）與三氟乙酸酐（56微 -升）加至上述步驟（2)所得化合物（86毫克）之曱醇（3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_並攪拌，然後用矽藻土管柱（CHEM ELlJTE， VAR IAN公司製造）萃取。萃取液經真空濃縮，得到ι_(2_ 氣苯基）-5-(4-氯笨基）-4-曱氧基-3-{N-[3-(1-三氟乙醯基）σ比p各咬基]胺曱酿基丨 — ΙΗ-吡唑（90毫克，產率86%)呈無色粉末。 ® MS(APCI)ra/z ： 527/529[M+H]+ 實施例21 (1)將N-三級丁氧羰基肼（297毫克）、水可溶碳二亞胺鹽酉文鹽（431笔克）與1-羥基苯并***水合物（345毫克）加至3羧基-1-(2-氣苯基）—5_(4_氯苯基）一4_甲氧基吼坐（3.5克，參考例1(6)所得化合物）之二氣甲烷（2〇毫升） /合液中’室皿授拌混合物4小時。然後將碳酸氫納水溶液鲁加至反應混合物中並攪拌，接著用三氣甲烷萃取。萃取液經真空濃縮後粗產物用石夕勝管柱層析（溶劑：己烧/乙酸乙酯别/20 i 60/40)進行純化，錢以三級丁醇溶解。溶液經冷束乾燥得到3-[ (IT-三級丁氧幾基肼基）胺甲驢基] 1 氯苯基一氯苯基）-4-甲氧基-1H-吼唑（722毫克，產率100%)無色粉末。 MSCAPCI)m/z : 477/479[M+H]+ (2)在〇°C，將4NHC卜二噚烷（25毫升）加至上述步驟 1)所得化合物（3. 43克）之二噚烷（1〇毫升）溶液令，然後 338695 71 1378922 在50 C麟混合物3日。冷卻後，將碳酸氫m容液與乙酸乙醋加至反應混合物巾。攪拌混合物後以乙酸乙酿萃取。有機層以琉酸鎂乾燥後過濾❶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_肼基羰基、 + (2-氣苯基）-5-(4-氣苯基）_4_甲氧基„坐（2 克’產率100%)淡黃色粉末。 MS(APCI)m/z ： 377/379[M+H]+Example 14 4-tetrahydrothiopipetanylamine (140 mg, compound obtained in Reference Example 12 (2)), water-soluble carbodiimide hydrochloride (230 mg) and 1-hydroxybenzotris Hydrate (184 mg) was added to 3-derived-1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-1H-η-pyrazole (290 mg, reference example) 1(6) A solution of the obtained gas of 66 318695 1378922 (dimer) of methane/dimercaptocarhamamine (6 ml / 〇. 5 ml) - in room temperature at room temperature. Aqueous sodium bicarbonate solution was then added to the reaction mixture and stirred' followed by extraction with tri-methane. The extract was concentrated in vacuo and the crude material was purified using silica gel column chromatography (solvent: hexane/ethyl acetate = 85/15 to 70/30) to afford ι_(2-phenylphenyl)-5-(4- Chlorophenyl)-4-decyloxy-3-[N-(4-tetrahydrothiopiperidyl)aminemethanyl]_1H_ 〇 is a colorless solid than saliva (323 house yield '87%). MS (APCI) m/z: 462 / 464 [M+H] + </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Add trifluoroacetic acid (77 microliters) to the dichloride of the compound obtained in Example 14 (116 grams). The mixture was stirred at room temperature for 30 minutes in decane (4 mL). Next, 3-gas perbenzoic acid (58 mg, water content 25%) was added, and the mixture was stirred at the same temperature for 1 hour and at room temperature for 2 hours. An aqueous solution of sodium hydrogencarbonate 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 on a silica gel column (solvent: hexane / _ ethyl acetate = 50 / 50 to 30 / 70 - trichloro decane / decyl alcohol = 1 〇〇 / 〇 to 95/5 Purification to give 1-(2-chlorophenyl)-5-(4-hydrophenyl)-4-pyreneoxy-3_{N-[4-(b-oxytetrahydrothiopiperidyl)] Aminomethylpyrazine 1H_pyridyl. Sitting (28.5 mg, yield 24%) was a colorless solid. MS (APCI) m/z: 478 / 480 [M+H] + Example 16 Compound (116 mg) of the compound of Example 14 was used in the same manner as in Example 3-1 except that 3-chloroperbenzoic acid was used. 5 The same method is used to obtain 1-(2-chlorophenyl)-5-(4-hydrophenyl)-4-methoxy-3_{Ν_[4_(ι, 卜二318695 67 1378922 - sideoxy four Hydrothiopyranyl)]aminoguanidino}_1{}_pyrazole (69 mg, yield 56%) was a colorless solid. MS (APCI)ra/z: 494/496 [M+H] + Example 17 4-tetrahydrothiopentanol (61 mg) and 4-diaminopyridylpyridine (2 mg) The compound obtained in Example 1 (6) (73 mg) was dissolved in dichloromethane (3 liters). Dicyclohexylcarbodiimide (45 mg) was then added to the mixture in hydrazine and stirred at room temperature overnight. A solution of sodium hydrogencarbonate was added to the reaction mixture and stirred, followed by extraction with trichloromethane. The extract was concentrated in vacuo and the crude material was purified using EtOAc EtOAc EtOAc EtOAc EtOAc Chlorophenyl)-4-methoxy-3-(4-tetrahydrothiopyranyloxy)carbonyl-1H-pyrazole (53 mg, yield 59%) was obtained as a colourless solid. MS (APCI) m/z : 447 / 449 [M+H] + Example 18 % 'Diphenyl azide (47 μL) and diethylamine (33 μL) at 0 C under nitrogen atmosphere The compound (73 mg) obtained in Reference Example 1 (6) was added to a solution of benzene (3 ml), and then at 8 Torr. The mixture was stirred overnight. Next, 4-tetrahydropyranylamine (36 mg) and 4-diaminopyridylpyridine (2.4 mg) were added to the reaction mixture under ice cooling at 8 Torr. 〇〇一。。. Then, an aqueous solution of sodium ε-acid hydrogenate was added and stirred, followed by extraction with a column of diatomaceous earth (manufactured by CH (10) ELUTE' VARIAN Co., Ltd.). The crude product obtained by concentration in vacuo was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 6 〇 / 4 〇 to 20 / 80) to give 丨卜卜 ) _ _ _ _ _ Gas phenyl)_4_hydroxy 318695 68 1378922 -yl-3- [N-(4-tetrahydropyranyl) gland]-1Η-α is colorless than saliva (i〇亳g, yield -11%) solid. MS (APCI) m/z: 461 / 463 [M+H] + Example 19 (1) The compound obtained in Reference Example 17 (513 mg) and 3-amino-1 - tri-butoxycarbonyl nitrogen Treatment in the same manner as described in Example 1 gave 1-(2,4-chlorobenzyl)_5-(4-oxaphenyl)-4-methoxyl-(1-tertiarybutoxycarbonyl)azide Aminomethionyl 1H_pyrazine (59 〇 milliuk, yield 83%) was solid. MS (APCI) m/z: 551 / 553 [M+H] + (2) 4NHH-ethyl acetate (2 ml) was added to the compound obtained in the above step (1) (590 mg) of trioxane (5) The solution was stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo, and ethyl acetate and aqueous sodium bicarbonate were added to the residue and stirred. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was crystallised eluted with di-hexane (2 mL). Then triethylamine (30 ml) and p-benzoquinone 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 EtOAc EtOAc EtOAc. Then, sodium hydride (4 mg) was added and stirred at 8 (rc for 2 days). After cooling to room temperature, water and ethyl acetate were added and the organic layer was extracted with ethyl acetate. Chromatography (solvent: hexane / acetic acid = ester = 〇 / 1 〇〇) was purified to give bis-dichlorophenyl)_5_(4-chlorophenyl)-4-hydroxy-3-{N-[ 3-(4-Chlorobenzylidene) nitrogen. And the hydrazinyl group 318695 69 1378922 -1H-pyrazole (30 mg, yield 52%) was a powder. MSCAPCI) m/z: 589/591 [M+H] + Example 20 (1) 1-tert-butoxycarbonyl-3-I-aminopyrrolidine (279 mg), water-soluble carbodiimide hydrochloride Salt (288 mg) and Bujingji stupid and Sanshui character (10) mg) added to 3 - silk + (3) chlorophenyl) - 5 chlorophenyl) di-mu sit (363 mg, reference compound 1 (6) The mixture was stirred in a solution of dioxane (5 mL) at room temperature overnight. Then, an aqueous sodium hydrogencarbonate solution was added to the reaction mixture and stirred, followed by extraction with chloroform. The extract was concentrated in vacuo and the crude product was purified by column chromatography (solvent: 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), pyridyl]amine-methylpyridinium (2-monophenyl)_5-(4-phenylphenyl-1H-indole) The azole (516 mg, yield 97%) was obtained as a colorless powder. MS (APCI) m/z. 431/433 [M+H-Boc] + (Boc: tris-butoxy). (2) in 〇° To a solution of the compound obtained in the above step (1) (425 mg) in dioxane (2 ml), the mixture was stirred at the same temperature for 2 hours, and stirred at room temperature 2 The aqueous solution of sodium hydrogencarbonate was then added to the reaction mixture for alkalization. The mixture was then extracted with a column of diatomaceous earth (CHEMELUTE, manufactured by VARIAN). The extract was concentrated in vacuo to give 1-(2-chlorophenyl). -5-(4-chlorophenyl)-4-methoxy-3-[N-(3-pyrrolidinyl)amine hydrazino]-1H-pyrazole (344 mg, yield 100%) Colorless viscous material MS (APCI) m/z : 431/433 [M+H]+ 318695 70 1378922 • (3) at 0C 'triethylamine (Π 2 μL) with trifluoroacetic anhydride (56 μ-liter Adding to the compound obtained in the above step (2) (86 mg) in methanol (3 ml) The mixture was stirred overnight at room temperature, and then aqueous sodium hydrogencarbonate solution was added to the reaction mixture _ and stirred, and then extracted with a celite column (CHEM ELlJTE, manufactured by VAR IAN). The extract was concentrated in vacuo to give ι_(2_ Phenyl phenyl)-5-(4-chlorophenyl)-4-decyloxy-3-{N-[3-(1-trifluoroethenyl) σ ratio p each bite] amine hydrazine — ΙΗ-pyrazole (90 mg, yield 86%) as a colorless powder. MS (APCI) / s: 527 / 529 [M + H] + Example 21 (1) N-tertiary butoxycarbonyl肼 (297 mg), water-soluble carbodiimide salt (431 g) and 1-hydroxybenzotriazole hydrate (345 mg) added to 3-carboxy-1-(2-phenylene) -5_(4_chlorophenyl)-4-methoxyl sitting (3.5 g, compound obtained in Reference Example 1 (6)) in di-methane (2 〇 ml) / in liquid mixture 'room mixing mixture 4 Then, the aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and stirred, followed by extraction with tri-gas methane. The extract was concentrated in vacuo and the crude product was chromatographed on a silica gel column (solvent: hexane/ethyl acetate) /20 i 60/40) for purification, the money is in the third grade The alcohol is dissolved. The solution is dried by cold drying to obtain 3-[(IT-tris-butoxymethylhydrazinyl)aminomethane] 1 chlorophenyl-chlorophenyl)-4-methoxy-1H-carbazole ( 722 mg, yield 100%) colorless powder. MSCAPCI)m/z: 477/479 [M+H] + (2) 44C, 4NHC dioxane (25 ml) was added to the compound of the above step 1) (3. 43 g) Alkane (1 〇 ml) solution was ordered, then 338695 71 1378922 in a 50 C lining mixture for 3 days. After cooling, a hydrogen carbonate m-containing solution and ethyl acetate were added to the reaction mixture. The mixture was stirred and extracted with acetic acid. The organic layer is dried with magnesium citrate, and the filtrate is filtered and concentrated in vacuo. The obtained crude product is dissolved in tris-butyl alcohol, and then lyophilized to give 3 - mercaptocarbonyl, + (2-phenylphenyl)-5-(4- Phenyl phenyl)_4_methoxy s sitting (2 g 'yield 100%) light yellow powder MS (APCI) m/z : 377/379 [M+H]+

(3)將1-曱磺醯基六氫吡啶一4_甲酸（62毫克）、水可容碳二亞胺鹽酸鹽（58毫克）與卜經基苯并三唾水合物（46毫克）加至上述步驟（2)所得化合物（76毫克）之二氯甲烷毫升）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攪拌’然後以三氯曱烷萃取。萃取液經真S I縮後所得粗產物时膠管柱層冑（溶冑：己燒/ 乙酉欠乙，92/8至9G/1Q)進行純化，得到卜（2_氯苯基） -5-(4-氣苯基）—3-({r—[(卜甲續酿基六氫吼咬_4_基）幾基]肼基}幾基）-4-甲氧基鲁吼峻（85.8毫克，產率76%) 呈無色粉末。 MS(APCI)m/z ： 566/568[M+H]1 實施例22 (1)將1-胺基-4-三級丁氧羰基六氫吼畊基（73〇毫 ^ >考例16(2)所得化合物）、水可溶碳二亞胺鹽酸鹽 αο克）、卜經基苯并三唾水合物（827毫a)與三乙胺⑽ 微升）加至3-叛基-卜（2_氣苯基）_5〜（4_氯苯基）_4—甲氧基一IH-t坐（1.96克，參考例1(6)所得化合物）之二氯甲烷 31S695 72 1378922 (20毫升）溶液中，室溫擾拌混合物一夜。然後將碟酸氯銷水溶液加至反應混合物中並攪拌，接著用三氯甲烷萃取。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=60/40至40/60)進行純化，得到3_[n_(4_三級丁氧羰基六氫呢畊-1-基）胺甲醯基]_丨_(2_氯苯基）_5_(4_ 氣苯基）-4-甲氧基-1H-吡唑（1.56克，產率79%)呈無色固體。 MS(APCI)m/z ： 546/548[M+H]+ (2) 在室溫，將4ΝΗΠ-二噚烷（2〇毫升）加至上述步驟 (1)所得化合物（1.56克）之二噚烷（1〇毫升）溶液中，然後在50 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進行鹼化。攪拌混合物然後以三氣曱烷萃取。萃取液以硫酸鎂乾燥後過濾。濾液經真空濃縮，付到1-(2-氯苯基）-5-(4-氯苯基）_4-甲氧基-3-[N-(六氫比哄-1-基）胺曱醯基]-1H-吡唑（1. 26克，產率99%)呈無色固體。 MS(APCI)m/z ： 446/448[M+H]+ (3) 將三乙胺（39微升）與苯甲醯氯（16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。萃取液經真空展縮後所得粗產物用矽膠管柱層析（溶劑··己烷/乙酸乙酯 -4〇/60至0/100)進行純化，得到3-[N-(4-苯曱醯基六氫吼哄-1-基）胺曱醯基;14-(2-氣苯基）一5_(4_氯苯基）_4_曱 318695 73 1378922 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23 在〇°C，將4Ν HC1-二吗烧（6毫升）加至實施例21(1) 所得化合物（95毫克）之二喝炫（5毫升）溶液中，然後在5〇 C授拌混合物2小時。冷卻後’將碳酸氫鋼水溶液加至反應混合物中進行驗化。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，得到3_肼基 _羰基-1-(2-氣苯基）-5-(4-氯苯基）-4-曱氧基-1H-吡唾 (1-26克，產率9 9%)粗產物。接著加入乙醇（2毫升）、三乙胺（28微升）與二乙細礙（24微升）’在氮氣環境下加熱避流混合物5小時。冷卻後，加水至反應混合物中並授摔。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膝管柱層析 (溶劑：三氯曱烷/曱醇=1〇〇/〇至96/4)與NH-石夕膠管柱層鲁析（Chromatorex 關-矽膠 ’ Fuji Silicia Chem.公司製造，溶劑：己烷/乙酸乙酯=40/60至20/80)進行純化，得到 (2 -氣苯基）-5-(4 -氣苯基）-3-[N-(1，1-二側氧基硫代 N-嗎福琳基）胺甲醯基]-4-曱氧基-ΐΗ-π比唾（43毫克，產率 50%)無色固體。 MS(APCI)m/z ： 495/497[M+H]+(3) Add 1-indolesulfonylhexahydropyridin-4-carboxylic acid (62 mg), water-capable carbodiimide hydrochloride (58 mg) and dipyridylbenzotrihydrate (46 mg) to A solution of the compound obtained in the above step (2) (76 mg) in dichloromethane (m.). Next, an aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and stirred, and then extracted with trichloromethane. When the crude product obtained by the actual SI shrinkage is purified, the column layer of ruthenium (solvent: calcined / acetonitrile, ethyl, 92/8 to 9G/1Q) is purified to obtain di(2-chlorophenyl)-5-( 4-Phenylphenyl)-3-({r-[( 甲续六六六 _ _ _ _ _ _ _ _ _ 4 } } } } } } } } } } } } } 8 8 8 8 8 8 8 8 8 8 8 8 Rate 76%) is a colorless powder. MS (APCI) m / z : 566 / 568 [M + H] 1 Example 22 (1) 1-amino-4-tert-butoxycarbonyl hexahydro hydrazine cultivating base (73 〇 milli ^ > 16(2) compound obtained), water-soluble carbodiimide hydrochloride αο克), p-benzotristrihydrate (827 mA) and triethylamine (10) liters) added to 3-rebel-b (2_Vetylphenyl)_5~(4-_Phenylphenyl)_4-methoxy-IH-t (1.96 g, compound obtained in Reference Example 1 (6)) dichloromethane 31S695 72 1378922 (20 ml) In the solution, the mixture was stirred overnight at room temperature. Then, an aqueous solution of the acid chloride pin was added to the reaction mixture and stirred, followed by extraction with chloroform. The extract was concentrated in vacuo and the crude product was purified using EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc Till-1-yl)amine-methylmercapto]-indole-(2-chlorophenyl)_5_(4-hydroxyphenyl)-4-methoxy-1H-pyrazole (1.56 g, yield 79%) was colorless solid. MS (APCI) m/z: 546 / 548 [M+H] + (2) THF (2 mM) was added to the compound obtained in the above step (1) (1.56 g) at room temperature The solution was stirred in decane (1 mL) and then stirred at 50 C overnight. After cooling to room temperature, an aqueous solution of sodium hydrogencarbonate was added to the reaction mixture for alkalization. The mixture was stirred and then extracted with trioxane. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 1-(2-chlorophenyl)-5-(4-chlorophenyl)- 4-methoxy-3-[N-(hexahydropyridin-1-yl)amine oxime The group -1H-pyrazole (1.26 g, yield 99%) was a colorless solid. MS (APCI) m/z: 446/448 [M+H] + (3) Triethylamine (39 μL) and benzamidine chloride (16 μL) were added to the compound obtained in the above step (2) (38) The solution was stirred at room temperature for one night in a solution of methylene chloride (1 ml). Next, an aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and stirred, followed by extraction with chloroform. The crude product obtained by vacuum stretching was purified by silica gel column chromatography (solvent·hexane/ethyl acetate-4〇/60 to 0/100) to obtain 3-[N-(4-benzoquinone). Mercaptohexahydroindol-1-yl)amine fluorenyl; 14-(2-phenylphenyl)-5-(4-chlorophenyl)_4_曱318695 73 1378922 oxy-1H-pyrazole (20 mg The yield was 53%) as a colorless solid. - MS (APCI) m/z: 550 / 552 [M+H] + Example 23 Ν 1- 1- 1- 1- 1- 1- 1- 1- 6 6 6 6 6 6 6 6 6 6 6 6 95 95 95 95 95 The second is in a dazzling (5 ml) solution, then the mixture is allowed to mix at 5 ° C for 2 hours. After cooling, an aqueous solution of hydrogencarbonate steel was added to the reaction mixture for verification. The organic layer was extracted with a diatomaceous earth pipe column (CHEM ELUTE, manufactured by VARIAN Co., Ltd.). The extract is concentrated in vacuo to give 3-mercapto-carbonyl-1-(2-phenylphenyl)-5-(4-chlorophenyl)-4-decyloxy-1H-pyrazine (1-26 g, Yield 9 9%) crude product. Then, ethanol (2 ml), triethylamine (28 μl) and diethyl bromide (24 μl) were added to heat the mixture for 5 hours under a nitrogen atmosphere. After cooling, water was added to the reaction mixture and allowed to fall. 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 subjected to columnar column chromatography (solvent: trichlorodecane / decyl alcohol = 1 〇〇 / 〇 to 96 / 4) and NH - Shixi rubber tube column layer (Chromatorex off - 矽 ' ' Fuji Purified by Silicia Chem., solvent: hexane/ethyl acetate = 40/60 to 20/80) to give (2-phenylphenyl)-5-(4-phenylene)-3-[N- (1,1-di-side oxythio N-moffufryl)amine carbaryl]-4-oxime-oxime-π than saliva (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）與卜經基苯并三唑水合物（35毫克）加至實施例22(2)所得化合物（67毫克） 318695 74 1378922 ·-之二氯甲烧（2毫升）溶液中’室溫攪拌混合物一夜。然後 -將碳酸氫納水溶液加至反應混合物中並授拌，接著用二氯曱烷萃取。萃取液經真空濃縮後粗產物用矽膠管桎層析（溶劑：己烷/乙酸乙酯=40/60至0/100)進行純化，得到3_{N_ [4-（5_溴-2-噻吩甲醯基）六氫吡啡-卜基]胺甲醯基}_卜 (2-氯苯基）-5-(4-氯苯基）-4-甲氧基-in-0比唑（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 butyl benzotriazole hydrate (35 mg) were added to the compound obtained in Example 22 (2) (67 mg) 318 695 74 1378922 The mixture was stirred at room temperature for one night in a solution of methylene chloride (2 ml). Then - an aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and stirred, followed by extraction with dichloromethane. The extract was concentrated in vacuo and the crude material was purified using silica gel chromatography (solvent: hexane/ethyl acetate=40/60 to 0/100) to afford 3_{N_[4-(5-bromo-2-thiophene) Mercapto) hexahydropyridinyl-diyl]aminocarbazide}-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-in-0-pyrazole (79 Mg, yield 79%) solid. MS (APCI) m/z : 634/636 [M+H]+

_實施例24B 將氰化鋅（6宅克）、參（二苯亞甲基丙g同）二免（ι.5毫克）與1，1 -雙（二苯膦基）二（環戊二烯）鐵（DPpf，1. 8毫克）加至貫施例2 4 A所得化合物（4 9毫克）之二曱基曱醯胺（1 毫升）溶液中’然後在微波反應器中於18 〇。〇授拌混合物J 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授拌。有機層用石夕藻土管柱（CHEM ELUTE，VARIAN公司鲁製造）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= 30/70至〇/1 〇〇)進行純化，得到 3-{N-[4-(5-氰基-2噻吩甲醯基）六氫吡畊_卜基]胺甲醯基}-1-（2-氯笨基）-5-(4-氣苯基）一4〜曱氧基一iH-η比唾（79 毫克，產率83%)無色固體。 MSCAPCDm/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 笔克）之二氯曱烷（3毫升）溶液中，室溫攪拌混合物j小 318695 75 1378922 時。然後真空濃縮反應混合物，殘留物以二甲基曱醯胺（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。搜摔後，β人物用矽藻土管柱（CHEM ELUTE，VARIAN公司製造）處理:^ 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^ 1-(2〜氣苯基）-5-(4-氯苯基）一4_曱氧基_3_[2_(n_嗎福I 基）乙酿基]-1Η - °比ϋ坐。 (2)將二曱基曱酷胺（3毫升）加至上述步驟g)所得化合物中，然後在0。(：加入氫化鈉（8. 8毫克）《>在氮氣環境下至溫攪拌混合物1小時。接著將碳酸氫鈉水溶液加至反應混合物中。攪拌後，混合物用上述之矽藻土管柱處理以萃取有機層。萃取液經真空濃縮’所得粗產物依序用石夕勝管柱層析（溶劑：己烧/乙酸乙酯=6〇/4〇至40/60)與凝勝渗透層析（管柱：JAIGEL-1H與2Η ’流動相：三氣甲烷）進行純籲化，得到1-(2-氯苯基）-5-(4-氯苯基）-4-曱氧基-3-[2- (Ν-嗎福琳基）丙酸基]一Ho比嗤（ίο. 3毫克，步驟（1)至（2) 總產率11«無色粉末。 MS(APCI)m/z ： 581/583[M+H]+ 實施例26 將參考例5(2)與1-胺基吡咯啶以如實施例1所述之相同方法處理，得到1-(2-氣苯基）-5-(4-氯苯基）-4-曱氧幾基甲氧基- 3- [Ν-(1-吼洛。定基）胺曱酿基]-1Η-π比唾（71. 3 毫克，產率73%)固體。 76 318695 1378922 .-MSCAPCI)m/z ： 489/491 [M+H] + - 實施例27 將6N氨-甲醇（1毫升）加至實施例26所得化合物（5〇毫克）之甲醇（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柱層析（溶劑：己烧/乙酸乙醋=50/50至30/70)進行純化，得到4_胺曱醯基曱氧基-l-(2-氯苯基）-5-(4-氯苯基）一3-[^1-吨籲咯啶基）胺曱醯基]-1H-吡唑（10. 2毫克，產率11%)淡黃色固體。、 MS(APCI)m/z ： 474/476[M+H]+ 實施例28 將氯化2-氣-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毫克）之二氯曱烧（2宅升）>谷液中’至溫授拌混合物一夜。然後將石炭酸鲁氣納水〉谷液加至反應合物中並擾掉，接著以三氣甲烧萃取。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1-(2_氯苯基）-5-(4-氯苯基）-4-曱氧基-3-[2-(l-甲磺醯基六氫吼啶 -4-基）-1，3, 4-卩萼二〇坐-5-基]-1Η-π比嗤（21. 8毫克，產率 26%)‘無色固體。 MS(APCI)ra/z ： 548/550 [M+H] + 實施例2 9 3-胺基-1-(2-氯苯基）-5-(4-氣笨基）-4-曱氧基-1H- 318695 77 1378922 .°比°坐（3 3宅克，參考例6所得化合物）與環己烧曱酸（12亳 -克）以如實施例1所述之相同方法處理，得到氯苯基） -5-(4-氣苯基）-3-環己羰基胺基_4_曱氧基_1Η_π比唑（28 .毫克，產率63%)固體。 MS(APCI)m/z : 444/446[Μ+Η]+ 實施例30 在〇c、氮氣環境下，將疊氮磷酸二苯酯（47微升）與二乙胺（33微升）加至參考例1 (6)所得化合物（了3毫克）之籲曱苯（3毫升）溶液中，並在相同溫度下攪拌混合物3〇分鐘，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4-二甲胺基咄啶（2. 4毫克）加至反應混合物中，然後在8〇1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 _=70/30至60/40)進行純化，得到丨-㈡-氯苯基）—5_(4 一氯苯基）-3-{[(四氫哌喃_4_基氧基）羰基]胺基卜4_曱氧基 -1H-比峻（16毫克，產率17%)無色固體。 MSCAPCDm/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，得到1，5-雙（4一氣苯基）_4_曱氧基_3_[N_(吡咯啶基）胺甲蕴基]-1H-吡唑（32毫克，產率74%)粉末。 MS(電灑游離，ESI)m/z : 431. 05[M+H] + 318695 78 1378922 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）之二氯甲烷（3毫升）溶液中，室溫檀掉混合物一夜。接著在〇°C將碳酸氫鈉水溶液加至反應忍合物中並攪拌’混合物用矽藻土管柱（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（溶劑：三氣曱烷/甲醇=1〇〇/〇至94/6)進行純化’得到1-(2-氣苯基）_5_(4_氯苯基）_4_曱氧基_3_ • [N-(l-乙醯基_3_吡咯啶基）胺曱醯基]_1H_吡唑（86毫克，產率91%)粉末。 MS(APCI)m/z ： 473/475[M+H]+ 實施例33 貝施例20 (2)所得化合物（8β毫克）與甲磺醯氯以如實施例32所述之相同方法處理，得到i_(2_氯苯基氯苯基）-4-甲氧基-3-[Ν-(1-甲磺醯基-3-吡咯啶基）胺甲籲醯基]-1H-吡唑（84毫克，產率83%)粉末。 MS(APCI)m/z : 509/511[M+H]+ 實施例34 實施例20(2)所得化合物（86毫克）與N，N_二曱基胺磺醯氯以如實施例32所述之相同方法處理，得到1-(2_氣苯基）-5-(4-氯苯基）-4-甲氧基-3-{n-[1-(n，N〜二甲基胺碏醯基）-3-吡咯啶基]胺曱醯基丨-iH—吡唑（62毫克，產率π%) 粉末。。 MSCAPCI)m/z · 538/540[M+H]+ 318695 79 1378922 ，實施例35 ’ 對應之起始物以如實施例25(1)所述之相同方法處理知到氣苯基）_5一（4_氯苯基）-4_曱氧基κ 1 (順_2,6 —二曱基N-六氫吡啶基）乙醯基]-1H-吡唑（46毫克’產率49%)固體。毛 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知到1-(2-氣苯基）-5-(4-氯苯基）-4-甲氧基[ 1 _ 1-二側氧基硫代N-嗎福啉基）乙醯基]-in-吡唑（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 HC1-二噚烷（3毫升）加至實施例21(1) 所得化合物（95毫克）之二曙烷（1亳升）溶液中，然後4〇艽鲁攪拌混合物2小時。冷卻至室溫後，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，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（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_3一 {N-[1-(2-侧氧基）六氫吡啶基]胺甲醯基卜1H_吡唑（57毫克，產率62%)無色固體。 MS(APCI)ra/z ： 459/461[M+H]+ 實施例3 8 318695 80 1378922 ·' 將嗎福琳（21微升）與三乙胺（28微升）加至參考例8 .所得化合物（75毫克）之p醇（2毫升）溶液中，然後加熱廻流混合物2小時。冷卻至室溫後，將水與乙酸乙酯加至反應混合物中並攪拌，混合物用矽藻土管柱（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管柱層析（溶劑：三氯甲烷/甲醇=1〇〇/〇至95/5)進行純化，得到1-(2-氯苯基）-5_(4-氣苯基）_4_甲氧基_3_ [3-(N-嗎福啉基）丙醯基]_ιΗ_吡唑（8〇. 5毫克，產率 •無色固體。 MS(APCI)m/z ： 460/462[M+H]+ 實施例39 在〇°C，將三乙胺（42微升）與三光氣（89毫克）加至參考例9(2)所得化合物（50毫克）之丨，2_二氣乙烷（3毫升）洛液中，然後601攪拌混合物2· 5小時。冷卻反應混合物至〇°C後將水加入並攪拌，接著以三氯甲烷萃取。萃取液鲁經真空濃縮後，殘留物以二氣曱烷稀釋。接著加入U一二氧化硫代嗎福啉（41毫克），室溫攪拌混合物4小時。然後將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=45/55至20/80)進行純化，得到1-(2-氯苯基）-5-(4-氯苯基）-3-[(1，卜二側氧基硫代 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 1378922 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) Ν45 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 ch3- 粉末 MS(APCI):465/467[M+H]+ 42 CHr /^ HN-N O 〆 \f 粉末 MS(APCI):481/483[M+H]+ 43 ch3- 粉末 MS(APCI):480/482[M+H]+ 44 ch3- -NH-N(CH3)2 粉末 MS(APCI):439/441 [M+H]+ 45 f2ch- /"V HN-N O / \^f 粉末 MS(APCI):517/519[M+H]+ 46 f2ch- 中-n〇粉末 MS(APCI):501/503[M+H]+ 82 318695 1378922 表 2(2) σχχτ&' clX5-ci r' 實施例號瑪 R3 -NCR5)^6) 物化性質等 47 cf3ch2- 甲-N〕粉末 MS(APCI):533/535[M+H]+ 48 CF3CH2- HN-N^O / \^f 粉末 MS(APCI):549/551 [M+H]+ 49 CF3CH2- 粉末 MS(APCI):548/550[M+H]+ 50 CF3CH2- KSi— 粉末 MS(APCI):547/549[M+H]+ 51 CF3CH2- -NH-N(CH3)2 粉末 MS(APCI):507/509[M+H]+ 52 ch3- H XT 固體 MS(APCI):540/542[M+H]+ 53 ch3_ ffiNi-^^-CF3 固體 MS(APCI):541/543[M+H]+ 54 ch3- t_hQ_cf3 固體 MS(APCI):490/492[M+H]+ 83 318695 1378922 表 2(3)_Example 24B Zinc cyanide (6 house gram), ginseng (diphenylmethylene propyl g) with two (1. 5 mg) and 1,1 - bis (diphenylphosphino) bis (cyclopentane) Ethyl) iron (DPpf, 1.8 mg) was added to a solution of the compound (4 9 mg) obtained from EtOAc (yield: EtOAc) 〇 Mix the mixture for 5 minutes. After cooling to room temperature, water and ethyl acetate were added to the reaction mixture and the mixture was stirred. The organic layer was extracted with a celite column (CHEM ELUTE, manufactured by VARIAN Co., Ltd.), and the extract was concentrated in vacuo. The obtained crude product was chromatographed on silica gel column (solvent: hexane/ethyl acetate = 30/70 to 〇/ Purification by 1 〇〇) to give 3-{N-[4-(5-cyano-2 thiophenemethyl) hexahydropyrazine-diyl]aminocarboxyl}-1-(2-chlorophenyl) -5-(4-Phenylphenyl)- 4~methoxy-iH-η is a colorless solid than saliva (79 mg, yield 83%). MSCAPCDm/z: 581/583 [M+H] + Example 25 (1) bromine (15 μL) was added dropwise to the solution of the compound obtained in Reference Example 7 (72 g) in dichloromethane (3 ml) Mix the mixture at room temperature at 318695 75 1378922. The reaction mixture was then concentrated in vacuo and EtOAcqqqqq The morphine (87 μl) was added and then stirred at room temperature for 2 hours. An aqueous solution of sodium hydrogencarbonate is then added to the reaction mixture. After the search, the β-human was treated with a diatomaceous earth pipe column (CHEM ELUTE, manufactured by VARIAN): an organic layer was taken. 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-diphenyl)-5- (4-Chlorophenyl)- 4-decyloxy_3_[2_(n_?? I) Erythryl]-1Η-° is more than ϋ. (2) Dimethyl hydrazine (3 ml) was added to the compound obtained in the above step g), and then at 0. (: sodium hydride (8.8 mg) was added. > The mixture was stirred under nitrogen for 1 hour. Then an aqueous solution of sodium hydrogencarbonate was added to the reaction mixture. After stirring, the mixture was treated with the above-mentioned celite column. The organic layer was extracted. The extract was concentrated in vacuo. The obtained crude product was chromatographed on EtOAc (solvent: hexane / ethyl acetate = 6 〇 / 4 〇 to 40 / 60). Column: JAIGEL-1H and 2Η 'mobile phase: tri-gas methane) were purely atomized to give 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3- [2-(Ν-?福琳基)propionic acid group]-Ho ratio ί(ίο. 3 mg, steps (1) to (2) total yield 11 «colorless powder. MS (APCI) m/z : 581 /583[M+H]+ Example 26 Reference Example 5(2) was treated with 1-aminopyrrolidine in the same manner as described in Example 1 to give 1-(2-phenylphenyl)-5- (4-chlorophenyl)-4-oxiranyl methoxy- 3- [Ν-(1-吼洛.定基)amine 曱 ]]-1Η-π than saliva (71. 3 mg, yield 73%) solid. 76 318695 1378922 .-MSCAPCI) m/z : 489/491 [M+H] + - Example 27 6N ammonia-methanol (1 ml) The compound obtained in Example 26 (5 mg) was evaporated from m. The crude product thus obtained is purified by silica gel column chromatography (solvent: hexanes / ethyl acetate = 50/50 to 30/70) to give 4-amino-decyloxy-l-(2-chlorophenyl) -5-(4-Chlorophenyl)-3-[^1-tono-r-hexyl)aminoindolyl]-1H-pyrazole (10.2 mg, yield 11%) as a pale yellow solid. MS (APCI) m/z: 474/476 [M+H] + Example 28 2-Chloro-1,3-dimethylimidazolium chloride (4 mg) and triethylamine (62 μL) The compound obtained in Example 21 (3) (884 mg) was added to the mixture of dichlorohydrazine (2 liters) > Then, the charcoal acid gas was added to the reaction mixture and scrambled, and then extracted by trigassene. The extract was concentrated in vacuo and the crude product was purified using EtOAc EtOAc EtOAc EtOAc EtOAc -Chlorophenyl)-4-decyloxy-3-[2-(l-methylsulfonylhexahydroacridin-4-yl)-1,3,4-anthracenequinone-5-yl] -1 Η-π ratio 21. (21. 8 mg, yield 26%) 'colorless solid. MS (APCI)ra/z: 548/550 [M+H] + Example 2 9 3-Amino-1-(2-chlorophenyl)-5-(4-indolyl)-4-indole Base-1H-318695 77 1378922. °°° (3 3 house grams, the compound obtained in Reference Example 6) and cyclohexanoic acid (12亳-g) were treated in the same manner as described in Example 1 to give chlorine. Phenyl)-5-(4-phenylphenyl)-3-cyclohexylcarbonylamino-4-yloxyl-indole-pyrazole (28 mg, yield 63%) solid. MS (APCI) m/z: 444/446 [Μ+Η]+ Example 30 Add diphenyl azide (47 μL) and diethylamine (33 μL) under 〇c, nitrogen atmosphere. To a solution of the obtained compound (3 mg) in EtOAc (3 ml), and the mixture was stirred at the same temperature for 3 hrs, then stirred at room temperature for 1 hour, and stirred at 801 for 2 hours. Next, 4-tetrahydropipetanol (37 mg) and 4-dimethylaminoacridine (2.4 mg) were added to the reaction mixture under ice-cooling, followed by stirring overnight at 8 °C. In the crucible, 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 (CHEMELUTE, manufactured by VARIAN Co., Ltd.). The crude product obtained by concentration in vacuo was purified by silica gel column chromatography (solvent: hexane/ethyl acetate _= 70/30 to 60/40) to give bis-(di)-chlorophenyl)-5-(4) Monochlorophenyl)-3-{[(tetrahydropyran-4-yloxy)carbonyl]amino-4-bromo-1H-pyrim (16 mg, yield 17%) as a colourless solid. MSCAPCDm/z: 462 / 464 [M+H] + Example 31 The corresponding starting material was treated in the same manner as described in Example 1 to give 1,5-bis(4-monophenyl)-4-inox. Base_3_[N_(pyrrolidinyl)amine-1-yl]-1H-pyrazole (32 mg, yield 74%) powder. MS (electrospray free, ESI) m/z: 431. 05 [M+H] + 318695 78 1378922 Example 32 - Triethylamine (112 μL) and acetonitrile (28 μL) was added to the Example (2) A solution of the obtained compound (m. Next, an aqueous solution of sodium hydrogencarbonate was added to the reaction mixture at 〇 ° C and stirred, and the mixture was extracted with a diatomaceous earth column (CHEM ELUTE, manufactured by VARIAN Co., Ltd.). The crude product obtained by concentration in vacuo was purified by silica gel column chromatography (solvent: trioxane / methanol = 1 / / / / / / / / / / / / / / / / / / / / / / / / 4_Chlorophenyl)_4_decyloxy_3_ • [N-(l-Ethyl-3-pyrrolidinyl)amine hydrazino]_1H-pyrazole (86 mg, yield 91%) powder. MS (APCI) m/z: 473 / 475 [M+H] + Example 33 (B) 20 (2) The obtained compound (8β mg) and methanesulfonyl chloride were treated in the same manner as described in Example 32, Obtaining i_(2_chlorophenylchlorophenyl)-4-methoxy-3-[indole-(1-methylsulfonyl-3-pyrrolidinyl)amine methyl sulfhydryl]-1H-pyrazole ( 84 mg, yield 83%) powder. MS (APCI) m/z: 509 / 511 [M+H] + </RTI> Example 34 The compound obtained from Example 20 (2) (86 mg) and N,N-didecylamine sulfonium chloride as in Example 32 Treated in the same manner to give 1-(2-hydroxyphenyl)-5-(4-chlorophenyl)-4-methoxy-3-{n-[1-(n,N~dimethylamine) Mercapto)-3-pyrrolidinyl]amine-indenyl-iH-pyrazole (62 mg, yield π%) powder. . MSCAPCI) m/z · 538/540 [M+H]+ 318695 79 1378922, Example 35' corresponding starting material was treated in the same manner as described in Example 25 (1) to give a phenyl group. (4-Chlorophenyl)-4_methoxy κ 1 (cis 2,6-didecyl N-hexahydropyridinyl)ethinyl]-1H-pyrazole (46 mg 'yield 49%) solid. Hair 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-phenylphenyl) -5-(4-chlorophenyl)-4-methoxy[ 1 _ 1-di- oxythio N-norfosolinyl)ethinyl]-in-pyrazole (73 mg, yield 74%) solid. MS (APCI) m/z: 472 / 474 [M+H] + <"&&&&&&&&&&&&&&&&&&&& In a dioxane (1 liter) solution, the mixture was stirred for 4 hours. After cooling to room temperature, an aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and stirred, and the mixture was extracted with a celite column (chem ELUTE, manufactured by VARIAN). 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)hexahydropyridyl]amine-methylpyridyl 1H-pyrazole (57 mg, yield 62%). MS (APCI)ra/z: 459/461 [M+H] + Example 3 8 318695 80 1378922 · ' Add whallin (21 μl) and triethylamine (28 μl) to Reference Example 8. A solution of the obtained compound (75 mg) in EtOAc (2 mL). After cooling to room temperature, water and ethyl acetate were added to the reaction mixture and stirred, and the mixture was extracted with a celite column (CHEM ELUtE, manufactured by VAR IAN). The crude product obtained by concentration in vacuo was purified by silica gel column chromatography (solvent: trichloromethane / methanol = 1 / / / / / / / / / / / / / / / / / / 4-Phenylphenyl)_4_methoxy_3_[3-(N-morpholinyl)propanyl]_ιΗ_pyrazole (8〇. 5 mg, yield • colorless solid. MS (APCI) m /z: 460/462 [M+H] + Example 39 To a solution of the compound obtained in Reference Example 9 (2) (50 mg) was added triethylamine (42 μL) and triphosgene (89 mg) at 〇 °C. Then, 2_di-ethane (3 ml) in a solution, then 601 the mixture was stirred for 2.5 hours. After cooling the reaction mixture to 〇 ° C, water was added and stirred, followed by extraction with chloroform. After concentration in vacuo, the residue was diluted with dioxane, then sulphuric acid, sulphonic acid (41 mg) was added, and the mixture was stirred at room temperature for 4 hours. Then an aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and stirred. The extract was extracted with trichloromethane. The crude product was purified by vacuum column chromatography (solvent: hexane/ethyl acetate=45/55 to 20/80) to afford 1-(2- Chlorophenyl)-5-(4-chlorophenyl)-3-[(1, bis-oxooxy N-norfosolinyl)carbonyl]amino-4-decyloxy_1H-pyrazole (23.4 mg, yield 31%) of colorless solid. MS (APCI) m/z: 495 / 497 [M+H] + 318 695 81 1378922 Examples 40 to 192 - corresponding starting materials as in Examples 1 to 3 Treatment in the same manner as described in one of them gave the compound shown in the following Table 2. Table 2 (1) Ν 45 Example No. R3 - N (R5) (R6) Physicochemical properties, etc. 40 ch3- Powder MS (APCI): 479 /481 [M+H]+ 41 ch3- Powder MS (APCI): 465/467[M+H]+ 42 CHr /^ HN-N O 〆\f Powder MS (APCI): 481/483 [M+H ]+ 43 ch3- Powder MS (APCI): 480/482 [M+H]+ 44 ch3- -NH-N(CH3)2 Powder MS (APCI): 439/441 [M+H]+ 45 f2ch- / "V HN-N O / \^f Powder MS (APCI): 517/519 [M+H]+ 46 f2ch- medium-n〇 powder MS (APCI): 501/503 [M+H]+ 82 318695 1378922 Table 2(2) σχχτ&' clX5-ci r' Example No. R3 - NCR5)^6) Physicochemical properties, etc. 47 cf3ch2-A-N] Powder MS (APCI): 533/535 [M+H]+ 48 CF3CH2- HN-N^O / \^f Powder MS (APCI): 549/551 [M+H]+ 49 CF3CH2- Powder MS (APCI): 548/550[M+H]+ 50 CF3CH 2- KSi—Powder MS (APCI): 547/549[M+H]+ 51 CF3CH2- -NH-N(CH3)2 Powder MS (APCI): 507/509[M+H]+ 52 ch3- H XT Solid MS (APCI): 540/542 [M+H]+ 53 ch3_ffiNi-^^-CF3 Solid MS (APCI): 541/543 [M+H]+ 54 ch3- t_hQ_cf3 Solid MS (APCI): 490/ 492[M+H]+ 83 318695 1378922 Table 2(3)

〜N、N"N_R5 Ο-Cl ^ 實施例號碼 R3 -N^XR6) 物化性質等 55 CHr ψ-〇粉末 MS(APCI):430/432[M+H]+ 56 CHr ECN-<I 粉末 MS(APCI):402/404[M+H]+ 57 ch3- ch3 粉末 MS(APCI):467/469[M+H]+ 58 ch3_ hn-^H3 7 ch3 粉末 MS(APCI):404/406[M+H]+ 59 CH3- TCH3 H CH3 粉末 MS(APCI):418/420[M+H]+ 60 ch3- 粉末 MS(APCI):452/454[M+H]+ 61 o ψ<2° 粉末 MS(APCI):517/519[M+H]+ 62 o 粉末 MS(APCI):501/503[M+H]+ 63 o 粉末 MS(APCI):515/517[M+H]+ 84 318695 1378922 表 2(4)~N, N"N_R5 Ο-Cl ^ Example number R3 -N^XR6) Physicochemical properties, etc. 55 CHr ψ-〇 powder MS (APCI): 430/432 [M+H]+ 56 CHr ECN-<I powder MS (APCI): 402/404 [M+H]+ 57 ch3-ch3 powder MS (APCI): 467/469 [M+H]+ 58 ch3_ hn-^H3 7 ch3 powder MS (APCI): 404/406 [M+H]+ 59 CH3- TCH3 H CH3 Powder MS (APCI): 418/420 [M+H]+ 60 ch3- Powder MS (APCI): 452/454 [M+H]+ 61 o ψ<2 ° Powder MS (APCI): 517/519 [M+H] + 62 o Powder MS (APCI): 501/503 [M+H] + 63 o Powder MS (APCI): 515/517 [M+H]+ 84 318695 1378922 Table 2 (4)

Ck ^v n-r5 Ο-Cl R' Boc:三級丁氧基羰基實施例號碼 R3 -N^XR6) 物化性質等 64 -(CH2)2SCH3 HN-N^O / V-—/ 粉末 MS(APCI):507/509[M+H]+ 65 ^C° hnh/^o / 粉末 MS(APCI):546/548[M+H]+ 66 粉末 MS(APCI):545/547[M+H]+ 67 -ch3 PDSr-N^-〇CH3 粉末 MS(APCI):475/477[M+H]+ 68 -ch3 HN-N^ VT)CH3 粉末 MS(APCI):461/463[M+H]+ 69 -ch3 HN-On-S02 7 ^ xc2h5 粉末 MS(APCI):537/539[M+H]+ 70 -ch3 hn-/~^sr-so2 7 N(CH3)2 粉末 MS(APCI):552/554[M+H]+ 71 -ch3 平-{二NHBoc 粉末 MS(APCI):545/547[M+H]+ 85 318695 1378922 表 2(5)Ck ^v n-r5 Ο-Cl R' Boc: tertiary butoxycarbonyl group number R3 -N^XR6) physicochemical properties, etc. 64 -(CH2)2SCH3 HN-N^O / V--/ Powder MS ( APCI): 507/509 [M+H]+ 65 ^C° hnh/^o / Powder MS (APCI): 546/548 [M+H]+ 66 Powder MS (APCI): 545/547 [M+H ]+ 67 -ch3 PDSr-N^-〇CH3 Powder MS (APCI): 475/477[M+H]+ 68 -ch3 HN-N^ VT)CH3 Powder MS (APCI):461/463[M+H ]+ 69 -ch3 HN-On-S02 7 ^ xc2h5 Powder MS (APCI): 537/539 [M+H]+ 70 -ch3 hn-/~^sr-so2 7 N(CH3)2 Powder MS (APCI) :552/554[M+H]+ 71 -ch3 ping-{two NHBoc powder MS(APCI):545/547[M+H]+ 85 318695 1378922 Table 2(5)

αχχτ&5 O^CI 〆實施例號瑪 R3 -N(R5)(R6) 物化性質等 72 ch3 粉末 MS(APCI):480/482[M+H]+ 73 ch3 ψ-〇粉末 MS(APCI):463/465[M+H]+ 74 ch3 / ^ ch3 粉末 MS(APCI):487/489[M+H]+ 75 ch3 H ch3 黏稠物 MS(APCI):449/451 [M+H]+ 76 ch3 h ch3 ，n、nV h3c^ 粉末 MS(APCI):473/475[M+H]+ 77 o i^hnQd 粉末 MS(APCI):533/535[M+H]+ 78 ch3 H ，Nv^sch3 黏稠物 MS(APCI):436/438[M+H]+ 79 ch3- ch3 固體 MS(APCI):468/470[M+H]+ 86 318695 1378922Χχ χχ & & 5 R R R R R R R R R R R R R R R R R R R R :463/465[M+H]+ 74 ch3 / ^ ch3 Powder MS (APCI): 487/489 [M+H]+ 75 ch3 H ch3 Viscous MS (APCI): 449/451 [M+H]+ 76 ch3 h ch3 , n, nV h3c^ powder MS (APCI): 473/475 [M+H] + 77 oi^hnQd powder MS (APCI): 533/535 [M+H]+ 78 ch3 H , Nv^ Sch3 Viscous MS (APCI): 436/438 [M+H]+ 79 ch3-ch3 Solid MS (APCI): 468/470 [M+H]+ 86 318695 1378922

表 2(6) αχχτ^。5 n-r5 O-ci ^ 實施例號碼 R3 -N^XR6) 物化性質等 80 ch3- ψ-^(02Η5)2 粉末， MS(APCI):433/435[M+H]+ 81 ch3- ch3 飞h3 粉末 MS(APCI):475/477[M+H]+ 82 ch3_ h3c 甲 r3c 粉末 MS(APCI):473/475[M+H]+ 83 ch3- ψ，3ζ 粉末 MS(APCI):481/483[M+H]+ 84 ch3_ mn/^ycF3 固體 MS(APCI):513/515[M+H]+ 85 C2H5- ψ-Ή(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 1378922 表 2(7)Table 2(6) αχχτ^. 5 n-r5 O-ci ^ Example No. R3 -N^XR6) Physicochemical properties, etc. 80 ch3- ψ-^(02Η5)2 powder, MS(APCI):433/435[M+H]+ 81 ch3-ch3 Fly h3 powder MS (APCI): 475 / 477 [M + H] + 82 ch3_ h3c A r3c powder MS (APCI): 473 / 475 [M + H] + 83 ch3- ψ, 3 ζ powder MS (APCI): 481 /483[M+H]+ 84 ch3_ mn/^ycF3 Solid MS (APCI): 513/515[M+H]+ 85 C2H5- ψ-Ή(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 1378922 Table 2 ( 7)

乏^5 實施例號碼 R3 -NO^XR6) 物化性質等 88 CH30(CH2)2- IBsT— 固體 MS(APCI):490/492[M+H]+ 89 ch3o(ch2)2- HN-N(CH3)2 粉末 MS(APCI):449/451[M+H]+ 90 ch3o(ch2)2· 粉末 MS(APCI):475/477[M+H3+ 91 ch3- 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. 〒-c〇固體 MS(APCI):474/476tM+H]+ 95 ch3- 平 -nCn_O 固體 MS(APCI):522/524[M+H]+ 96 ch3_ 固體 MS(APCI):523/525[M+H]+ 88 318695 1378922Lack ^5 Example number R3 -NO^XR6) Physical and chemical properties, etc. 88 CH30(CH2)2- IBsT- Solid MS (APCI): 490/492[M+H]+ 89 ch3o(ch2)2- HN-N( CH3)2 Powder MS (APCI): 449/451 [M+H]+ 90 ch3o(ch2)2· Powder MS (APCI): 475/477 [M+H3+ 91 ch3-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. 〒-c〇solid MS (APCI): 474/476tM+H]+ 95 ch3-ping-nCn_O solid MS (APCI): 522/524 [M+H ]+ 96 ch3_ Solid MS (APCI): 523/525 [M+H]+ 88 318695 1378922

表 2(8) N-R5 Οχι R6’ 實施例號碼 R3 -NCR5)^6) 物化性質等 97 ch3- HN,NX 1 一、och3 固體 MS(APCI):475/477[M+H]+ 98 ch3_ HN'N>^ 1 S)ch3 固體 MS(APCI):475/477[M+H]+ 99 ch3- 固體 MS(APCI):524/526[M+H]+ 100 ch3- 固體 MS(APCI):524/526[M+H]+ 101 CH3(CH2)2- 固體 MS(APCI):586/588[M+H]+ 102 f2ch- 甲-N〕固體 MS(APCI):467/469[M+H]+ 103 f2ch- 平-n(ch3)2 固體 MS(APCD：441/443[M+H]+ 104 CH30COCH2- ffi^-N(CH3)2 固體 MS(APCI):463/465[M+H]+ 105 f2ch- 甲〇固體 MS(APCI):482/484[M+H]+ 89 318695 1378922 表 2(9)Table 2(8) N-R5 Οχι R6' Example No. R3 - NCR5)^6) Physicochemical properties, etc. 97 ch3-HN, NX 1 I. och3 Solid MS (APCI): 475/477 [M+H]+ 98 Ch3_ HN'N>^ 1 S)ch3 Solid MS (APCI): 475/477 [M+H]+ 99 ch3-solid MS (APCI): 524/526 [M+H]+ 100 ch3-solid MS (APCI) ): 524/526[M+H]+ 101 CH3(CH2)2-solid MS (APCI): 586/588 [M+H]+ 102 f2ch-A-N] solid MS (APCI): 467/469 [ M+H]+ 103 f2ch-pin-n(ch3)2 solid MS (APCD: 441/443[M+H]+ 104 CH30COCH2-ffi^-N(CH3)2 solid MS (APCI): 463/465 [ M+H]+ 105 f2ch- formazan solid MS (APCI): 482/484 [M+H]+ 89 318695 1378922 Table 2 (9)

實施例號碼 R3 -NCR5)^6) 物化性質等 106 (CH3)2NS〇2· 平*^〇固體 MS(APCI):524/526[M+H]+ 107 (CH3)2NS〇2- 呼w(ch3)2 固體 MS(APCI):498/500[M+H]+ 108 (CH3>2NS〇2- ψ-〇> 固體 MS(APCI):539/541[M+H]+ 109 ch3- 固體 MS(APCI):540/542[M+H]+ 110 ch3- 甲oo^ 固體 MS(APCI):540/542[M+H]+ 111 ch3- ^<7cp3 固體 MS(APCI):499/501 [M+H]+ 112 /~Os ψ-Ν^Ι 固體 MS(APCI):514/516[M+H]+ 113 r^Os m<-^(CH3)2 固體 MS(APCI):488/490[M+H]+ 114 λΛΙ HN— 固體 MS(APCI):529/531 [M+H]+ 90 318695 1378922 表 2(10) αχκ^。 ν+5 OCcl R6’ 實施例號碟 R3 -N(R5)(R6) 物化性質等 115 ~V^ch3 h3c-^j HNT-N^] 固體 MS(APCI):526/528[M+H]+ 116 固體 MS(APCI):527/529[M+H]+ 117 ^V，CH3 h3c々 HN^(CU3)2 固體 MS(APCI):500/502[M+H]+ 118 ch3- 固體 MS(APCI):439/441 [M+H]+ 119 ch3- \ /=\ HN-^N 固體 MS(APCI):439/441 [M+H]+ 120 ch3· ^UrCN 固體 MS(APCI):463/465[M+H]+ 121 ch3- ，N"O^〇CH3 固體 MS(APCI):468/470[M+H]+ 91 318695 1378922Example No. R3 - NCR5)^6) Physicochemical properties, etc. 106 (CH3)2NS〇2· Flat*^〇 Solid MS (APCI): 524/526 [M+H]+ 107 (CH3)2NS〇2- 呼 w (ch3)2 Solid MS (APCI): 498/500 [M+H]+ 108 (CH3>2NS〇2-ψ-〇> Solid MS (APCI): 539/541 [M+H]+ 109 ch3- Solid MS (APCI): 540/542 [M+H]+ 110 ch3- oo^ solid MS (APCI): 540/542 [M+H]+ 111 ch3-^<7cp3 solid MS (APCI): 499 /501 [M+H]+ 112 /~Os ψ-Ν^Ι Solid MS (APCI): 514/516[M+H]+ 113 r^Os m<-^(CH3)2 Solid MS (APCI): 488/490[M+H]+ 114 λΛΙ HN—solid MS (APCI): 529/531 [M+H]+ 90 318695 1378922 Table 2(10) αχκ^. ν+5 OCcl R6' Example No. R3 -N(R5)(R6) Physicochemical properties, etc. 115 ~V^ch3 h3c-^j HNT-N^] Solid MS (APCI): 526/528 [M+H]+ 116 Solid MS (APCI): 527/529 [M+H]+ 117 ^V,CH3 h3c々HN^(CU3)2 Solid MS (APCI): 500/502[M+H]+ 118 ch3-solid MS (APCI): 439/441 [M+H ]+ 119 ch3- \ /=\ HN-^N Solid MS (APCI): 439/441 [M+H]+ 120 ch3· ^UrCN Solid MS (APCI): 463/465 [M+H]+ 121 ch3 - , N"O^〇CH3 Solid MS (APCI): 468/470[M+H]+ 91 318695 1378922

表 2(11) Rtx^ Ni5 O^ci R' 實施例號碼 R, -N(R5)(R6) 物化性質等 122 F 平-N〕粉末 MS(APCI):415/417[M+H]+ 123 F 粉末 MS(APGI):429/431 [M+H]+ 124 ch3o- 固體 MS(APCI):427/429[M+H]+ 125 ch3o- 平 - 固體 MS(APCI):441/443[M+H]+ 126 ch3o- HN-N^O / \f 固體 MS(APCI):443/445[M+H]+ 127 ch3o- 平-(Z)3 固體 MS(APCI):442/444[M+H]+ 128 NC- 固體 MS(APCI):422/424[M+H]+ 92 318695 1378922 表 2(12) C1n 〇〇 H3 n-r5 fAAci ^ 實施例號碼 -N^XR6) 物化性質等 129 ψ-Ν(ΟΗ3)2 / 粉末 MS(APCI):423/425[M+H]+ 130 ψ-N^j 粉末 MS(APCI):449/451 [M+H]+ 131 粉末 MS(APCI):463/465[M+H]+ 132 ΗΝΗ^ΓΛ) / \^f •粉末 MS(APGI):465/467[M+H]+ 133 ψ^Οο 粉末 MS(APCI):464/466[M+H]+ 93 318695 1378922 表 2(13)Table 2 (11) Rtx^ Ni5 O^ci R' Example number R, -N(R5)(R6) Physical and chemical properties, etc. 122 F flat-N] Powder MS (APCI): 415/417 [M+H]+ 123 F powder MS (APGI): 429/431 [M+H]+ 124 ch3o- solid MS (APCI): 427/429 [M+H]+ 125 ch3o- ping - solid MS (APCI): 441/443 [ M+H]+ 126 ch3o- HN-N^O / \f Solid MS (APCI): 443/445 [M+H]+ 127 ch3o- ping-(Z)3 Solid MS (APCI): 442/444 [ M+H]+ 128 NC-solid MS (APCI): 422/424 [M+H]+ 92 318695 1378922 Table 2(12) C1n 〇〇H3 n-r5 fAAci ^ Example No. -N^XR6) Physicochemical Properties Etc. 129 ψ-Ν(ΟΗ3)2 / Powder MS (APCI): 423/425 [M+H]+ 130 ψ-N^j Powder MS (APCI): 449/451 [M+H]+ 131 Powder MS ( APCI): 463/465[M+H]+ 132 ΗΝΗ^ΓΛ) / \^f • Powder MS (APGI): 465/467 [M+H]+ 133 ψ^Οο Powder MS (APCI): 464/466 [M+H]+ 93 318695 1378922 Table 2 (13)

F3C^UorV N-R5 R6 實施例號碼 R3 -N(R5)(R6) .物化性質等 134 ch3- m^N(CH3)2 固體 MS(APCI):439/441 [M+H]+ 135 ch3- m-N^j 固體 MS(APCI):465/467[M+H]+ 136 ch3_ 固體 MS(APCI):479/481 [M+H]+ 137 ch3- HN-N 0 / \f 固體 MS(APCI):481/483 [M+H]+ 138 ch3_ 固體 MS(APCI):480/482[M+H]+ 139 f2ch- ™-N(CH3)2 粉末 MS(APCI):475/477[M+H]+ 140 f2ch- HN—{^0 / N( 粉末 MS(APCI):516/518[M+H]+ 141 f2ch- 粉末 MS(APCI):501/503[M+H]+ 142 c2h5- ffisfHSr(CH3)2 固體 MS(APCI):453/455[M+H]+ 94 318695 1378922 表 2(14) F3C^ n-r5 (X, 實施例號碼 R3 -N^XR6) 物化性質等 143 c2h5- 固體 MS(APCI):479/481 [M+H]+ 144 c2h5- 平- 固體 MS(APCI):493/495[M+H]+ 145 C2H5- HN-N p 固體 MS(APCI):495/497[M+H]+ 146 C2H5- 固體 MS(APCI)494/496[M+H]+ 147 CH30(CH2)2- ψ谭 H3)2 粉末 MS(APCI):483/485[M+H]+ 148 CH30(CH2)2- 固體 MS(APCI):509/511 [M+H]+ 149 ch3o(ch2)2· ΗΝΤ-Ν^ 固體 MS(APCD：523/525[M+H]+ 150 CH30(CH2)2- r-\ HN-N 0 / \^f 固體. MS(APCI):525/527[M+H]+ 151 CH30(CH2)2- Hsr— 粉末 MS(APCI):524/526[M+H]+ 95 318695 1378922 表 2(15)F3C^UorV N-R5 R6 Example number R3 -N(R5)(R6) .Physicochemical properties, etc. 134 ch3- m^N(CH3)2 Solid MS (APCI): 439/441 [M+H]+ 135 ch3 - mN^j Solid MS (APCI): 465/467 [M+H]+ 136 ch3_ Solid MS (APCI): 479/481 [M+H]+ 137 ch3- HN-N 0 / \f Solid MS (APCI) ): 481/483 [M+H]+ 138 ch3_ Solid MS (APCI): 480/482 [M+H]+ 139 f2ch- TM-N(CH3)2 Powder MS (APCI): 475/477 [M+ H]+ 140 f2ch- HN—{^0 / N (Powder MS (APCI): 516/518 [M+H]+ 141 f2ch- Powder MS (APCI): 501/503 [M+H]+ 142 c2h5- ffisfHSr(CH3)2 Solid MS (APCI): 453/455 [M+H]+ 94 318695 1378922 Table 2(14) F3C^n-r5 (X, Example No. R3 -N^XR6) Physicochemical properties, etc. 143 c2h5 - Solid MS (APCI): 479/481 [M+H]+ 144 c2h5-Peace - Solid MS (APCI): 493/495 [M+H]+ 145 C2H5-HN-N p Solid MS (APCI): 495 /497[M+H]+ 146 C2H5- Solid MS (APCI) 494/496[M+H]+ 147 CH30(CH2)2- ψ Tan H3)2 Powder MS (APCI): 483/485 [M+H ]+ 148 CH30(CH2)2- Solid MS (APCI): 509/511 [M+H]+ 149 ch3o(ch2)2· ΗΝΤ-Ν^ Solid MS (APCD:523/525[M+H]+ 150 CH30(CH2)2- r-\ HN-N 0 / \^f Solid. MS(APCI):525/527[M+ H]+ 151 CH30(CH2)2- Hsr—powder MS (APCI): 524/526 [M+H]+ 95 318695 1378922 Table 2 (15)

αχ^。 N-R5 C^R" R6 實施例號瑪 R” -N^XR6) 物化性質等 152 CFr HN-N^] 固體 MS(APCI):465/467[M+H]+ 153 cf3_ 固體 MS(APCI):479/481 [M+H]+ 154 cf3- r~\ HN-^J 0 / y 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 HN^(CH3)2 粉末 MS(ESI):389.09[M+H]+ 158 F HN-N^] 粉末 MS(ESI):415.11[M+H]+ 159 F 甲-"(Z)0 粉末 MS(ESI):430.10[M+H]+ 96 318695 1378922 表 2(16)Αχ^. N-R5 C^R" R6 Example No. R"-N^XR6) Physical and chemical properties, etc. 152 CFr HN-N^] Solid MS (APCI): 465/467 [M+H]+ 153 cf3_ Solid MS (APCI) ):479/481 [M+H]+ 154 cf3- r~\ HN-^J 0 / y 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 HN^(CH3)2 powder MS (ESI): 389.09 [M+H]+ 158 F HN-N^] Powder MS (ESI): 415.11 [M+H]+ 159 F A-"(Z)0 powder MS (ESI): 430.10 [M+H]+ 96 318695 1378922 Table 2 (16)

F3Co^ n-r5 r"A^^c1 r6 實施例號码 R” -N(R5)(R6) 物化性質等 160 Cl 甲-Qd 粉末 MS(APCI):514/516[M+H]+ 161 Cl roi-N(CH3)2 粉末 MS(APCI):473/475[M+H]+ 162 Cl ψ<2° 粉末 MS(APCI):515/517[M+H]+ 163 Cl 粉末 MS(APCI):548/550[M+H]+ 164 Cl ch3 h/心粉末 MS(APCI):536/538[M+H]+ 165 F ψ-Cp 粉末 MS(APCI):498/500[M+H]+ 166 F m^-N(CH3)2 粉末 MS(APCI):457/459[M+H]+ 167 F 粉末 MS(APCI):499/501 [M+H]+ 168 F Ψ^ίο2 粉末 MS(APCI):532/534[M+H]+ 169 F ch3 粉末 MS(APCI):520/522[M+H]+ 97 318695 1378922 表 2(17)F3Co^ n-r5 r"A^^c1 r6 Example number R" -N(R5)(R6) Physicochemical properties, etc. 160 Cl A-Qd powder MS (APCI): 514/516 [M+H]+ 161 Cl roi-N(CH3)2 powder MS (APCI): 473/475 [M+H]+ 162 Cl ψ<2° powder MS (APCI): 515/517 [M+H]+ 163 Cl powder MS (APCI) ): 548/550 [M+H]+ 164 Cl ch3 h/heart powder MS (APCI): 536/538 [M+H]+ 165 F ψ-Cp powder MS (APCI): 498/500 [M+H ]+ 166 F m^-N(CH3)2 Powder MS (APCI): 457/459 [M+H]+ 167 F Powder MS (APCI): 499/501 [M+H]+ 168 F Ψ^ίο2 Powder MS (APCI): 532/534 [M+H] + 169 F ch3 powder MS (APCI): 520/522 [M+H] + 97 318695 1378922 Table 2 (17)

C1^〇 SF-R5 (X a 貫施例號碼 R3 -N(R5)(R6) 物化性質等 170 o 粉末 MS(APCI):516/518[M+H]+ 171 ch3 tO 粉末 MS(APCI):479/481 [M+H]+ 172 粉末 MS(APCI):532/534[M+H]+ 173 ch3 A H3C^〇^CH3 粉末 MS(APCI):460/462[M+H]+ 174 ch3 <x 固體 MS(APCI):466/468[M+H]+ 98 318695 1378922 表 2(18) r'^5 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 / N—/ 粉末 MS(APCI):431/433[M+H]+ 177 F H 粉末 MS(APCI):430/432[M+H]+ 178 CH3〇 H -NH-N(CH3)2 固體 MS(APGI):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 ™-〇固體 MS(APCI):490/492[M+H]+ 182 CN H -NH-N(CH3)2 / 固體 MS(APCI):396/398[M+H]+ 183 CN H 固體 MS(APCI):437/439[M+H]十 184 Cl Cl ^q_CF3 固體 MS(APCI):540/542[M+H]+ 99 318695 1378922 表 2(19) cko^ n-r5 (X” 士實施例號碼 R” -NCR5)^6) 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):401.09[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 粉末 MS(ESI):437.10[M+H]+ 100 318695 1378922 表 2(20) c，xVn〇實施例號碼 -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]+C1^〇SF-R5 (X a Example number R3 -N(R5)(R6) Physicochemical properties, etc. 170 o Powder MS (APCI): 516/518 [M+H]+ 171 ch3 tO Powder MS (APCI) :479/481 [M+H]+ 172 Powder MS (APCI): 532/534[M+H]+ 173 ch3 A H3C^〇^CH3 Powder MS (APCI): 460/462[M+H]+ 174 Ch3 <x solid MS (APCI): 466/468 [M+H] + 98 318695 1378922 Table 2 (18) r'^5 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 / N-/ Powder MS (APCI): 431 /433[M+H]+ 177 FH Powder MS (APCI): 430/432 [M+H]+ 178 CH3〇H -NH-N(CH3)2 Solid MS (APGI): 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 TM - 〇 solid MS (APCI): 490 / 492 [M + H] + 182 CN H - NH-N (CH3) 2 / solid MS (APCI): 396 / 398 [M + H] + 183 CN H solid MS ( APCI): 437/439 [M+H] 十184 Cl Cl ^q_CF3 Solid MS (APCI): 540/542 [M+H]+ 99 318695 1378922 Table 2 (19) cko^ n-r5 (X" implementation Example number R" -NCR5)^6) 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): 401.09 [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 powder MS (ESI): 437.10 [M+H]+ 100 318695 1378922 Table 2(20) c, xVn〇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]+

實施例193至218 對應之起始物以如實施例22(3)中所述之相同方法處理，得到如下表3所示化合物。The corresponding starting materials of Examples 193 to 218 were treated in the same manner as described in Example 22 (3) to give the compound shown in Table 3 below.

101 318695 1378922 表 3(1) c，xVn^ HN-N^N-RM, 實施例號码 RM 物化性質等 193 固體 MS(APCI):568/570[M+H]+ 194 固體 MS(APCD：576/578[M+H]+ 195 ；固體 MS(APCI):585/587[M+H]+ 196 ^Q-cn 固體 MS(APCI):575/577[M+H]+ 197 y〇-ci 固體 MS(ESI):583.99[M+H]+ 198 -c〇ch3 固體 MS(ESI):487.97[M+H]十 199 固體 MS(ESI):618.03[M+H]+ 200 F 粉末 MS(ESI):568.01[M+H]+ 201 K); 粉末 MS(ESI):539.98[M+H]+ 202 ^〇-〇ch3 MS(ESI):580.05[M+H]+ 102 318695 1378922 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 1378922 表 3(3) HN—N N-R,M h3c?~f 實施例號瑪 R”，物化性質等 210 >-〇固體 MS(APCI):578/580[M+H]+ 211 Q. /r\ 固體 MS(APCI):596/598[M+H]+ 表 3(4)101 318695 1378922 Table 3(1) c, xVn^ HN-N^N-RM, Example number RM Physicochemical properties, etc. 193 Solid MS (APCI): 568/570 [M+H] + 194 Solid MS (APCD: 576/578[M+H]+ 195 ; Solid MS (APCI): 585/587[M+H]+ 196^Q-cn Solid MS (APCI):575/577[M+H]+ 197 y〇- Ci solid MS (ESI): 583.99 [M+H] + 198 - s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s (ESI): 568.01 [M+H] + 201 K); powder MS (ESI): 539.98 [M+H] + 202 〇-〇ch3 MS (ESI): 580.05 [M+H] + 102 318695 1378922 3(2) Example No. R, R3 R", physicochemical properties, etc. 203 Cl ch3 powder MS (ESI): 542.04 [M+H] + 204 Cl ch3 powder MS (ESI): 551.00 [M+H] + 205 Cl Ch3 solid MS (ESI): 568.01 [M+H] + s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s Solid MS (APCI): 582/584 [M+H] + 209 cf3 c2h5 Solid MS (APCI): 616/618 [M+H] + 103 318695 1378922 Table 3 (3) HN-N NR, M h3c?~ f Example No. R", physicochemical properties, etc. 210 > - 〇 Solid MS (APCI): 578/580 [M+H] + 211 Q. /r\ Solid MS (APCI): 5 96/598[M+H]+ Table 3(4)

C1XX^ HN-N^JSHT 實施例號瑪 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 1378922 215 0 固體 ucF MS(APCI):586/588[M+H]+ ο 固體 MS(APCI):586/588[M+H]+ 216 ίαΡ 217 F 固體 MS(APCI):586/588[M+H]+ 218 固體 nT 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。C1XX^ HN-N^JSHT 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 1378922 215 0 Solid ucF MS (APCI): 586/588 [M+H]+ ο Solid MS (APCI): 586/588 [M+ H]+ 216 ίαΡ 217 F solid MS (APCI): 586/588 [M+H]+ 218 solid nT MS (APGI): 575/577 [M+H]+ Examples 219 to 224 Treatment with the same method as described in Example 1 or 22 (3) gave the compound shown in Table 4 below.

105 318695 1378922105 318695 1378922

表 oC； )CH3 6 HN-R6 實施例號碼 R6 物化性質等 219 J3〇K0 固體 MS(APCI):549/551 [M+H]+ 220 xy〇KaF 固體 MS(APCI):567/569[M+H]+ 221 粉末 ~ MS(APCI)535/537[M+H]+ 222 粉末 MS(APCI):553/555[M+H]+ .223 粉末 MS(APCI):553/555[M+H]+ 224 •<\CrCI 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28中所述之相同方法處 106 318695 1378922 -·理，得到如下表5所示化合物。 - 表5 於- 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):471/473[M+H]+ 228 固體 MS(APCI):574/576[M+H]+ 229 固體 MS(APCI):548/550[M+H]+ 230 -O-CN 固體 MS(APCI):488/490[M+H]+ 231 -〇固體 MS(APCI):463/465[M+H]+Table oC; )CH3 6 HN-R6 Example No. R6 Physicochemical properties, etc. 219 J3〇K0 Solid MS (APCI): 549/551 [M+H]+ 220 xy〇KaF Solid MS (APCI): 567/569 [M +H]+ 221 Powder ~ MS(APCI)535/537[M+H]+ 222 Powder MS (APCI): 553/555[M+H]+ .223 Powder MS (APCI): 553/555 [M+ H] + 224 • <\CrCI Powder MS (APCI): 569/571 [M+H] + Examples 225 to 231 Corresponding starting materials are in the same manner as described in Example 28 106 318695 1378922 - The compound shown in the following Table 5 was obtained. - Table 5 - 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): 471/473 [M+H] + 228 mp. MS (APCI): 574 / 576 [M+H] + 229 NMR MS (APCI): 548/550 [M+H] + 230 - O-CN solid MS (APCI): 488/490 [M+H] + 231 - 〇 solid 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 1378922 表6 r’^Kq HN—<^NHR.m RnX^^Cl 實施例號碼 R， R” R”，物化性質等 232 Cl Cl 粉末 MS(APCI):555/557[M+H]+ 233 Cl Cl V 粉末 MS(APCI):573/575[M+H]+ 234 Cl Cl 粉末 MS(APCI):573/575[M+H]+ 235 cf3 H 粉末 MS(APCI):555/557 [M+H]+ 236 cf3 H ^〇rF 粉末 MS(APCI):573/575[M+H]+ 237 cf3 H 粉末 MS(APCI):573/575[M+H]+ 238 cf3 H VQra 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 1378922 表 HN-N^^S02 R" Ο 實施例號瑪 R， R” R3 物化性質等 239 Cl H -C2H5 固體 MS(APCI):509/511ΓΜ+ΗΤ 240 Cl H -(CH2>2〇CH3 固體 MS(APCI):539/541 [Μ+Η]+ 241 Cl H -chf2 固體 MS(APCI):531/533[M+H]+ 242 Cl Cl -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):597/599rM+Hl+ 246 cf3 Cl •ch3 粉末 MS(APCI):563/565[M+H]+ 247 cf3 F -ch3 粉末 MS(APCI):547/549rM+H]+ 248 cf3 H -ch3 粉末 MS(APCI):529/531 ΓΜ+Hf 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 1378922The 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 Table 6 below. 107 318695 1378922 Table 6 r'^Kq HN—<^NHR.m RnX^^Cl Example number R, R” R”, physicochemical properties, etc. 232 Cl Cl Powder MS (APCI): 555/557 [M+H ]+ 233 Cl Cl V Powder MS (APCI): 573/575 [M+H]+ 234 Cl Cl Powder MS (APCI): 573/575 [M+H]+ 235 cf3 H Powder MS (APCI): 555/ 557 [M+H]+ 236 cf3 H ^〇rF Powder MS (APCI):573/575[M+H]+ 237 cf3 H Powder MS (APCI):573/575[M+H]+ 238 cf3 H VQra Powder MS (APCI): 589 / 591 [M + H] + The corresponding starting materials of Examples 239 to 248 were treated in the same manner as described in Example 23 to give the compound shown in Table 7 below. 108 318695 1378922 Table HN-N^^S02 R" 实施 Example No. R, R” R3 Physicochemical Properties, etc. 239 Cl H -C2H5 Solid MS (APCI): 509/511ΓΜ+ΗΤ 240 Cl H -(CH2>2〇 CH3 solid MS (APCI): 539/541 [Μ+Η]+ 241 Cl H -chf2 solid MS (APCI): 531/533 [M+H]+ 242 Cl Cl -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): 597/599rM+Hl+ 246 cf3 Cl • ch3 Powder MS (APCI): 563/565 [M+H]+ 247 cf3 F -ch3 Powder MS (APCI): 547/549rM+H]+ 248 cf3 H -ch3 Powder MS (APCI): 529/531 ΓΜ+Hf Examples 249 to 254 The corresponding starting materials were treated in the same manner as described in Example 30, and the following table was obtained. Compound shown in 8. 109 318695 1378922

表 r5 CC八實施例號瑪 -N(R5)(R6) 物化性質等 249 ?H3 固體 MS(APCI):449/451 [M+H]+ 250 -N 0 N^f 固體 MS(APCI):447/449[M+H]+ 251 -o 固體 MS(APCI):445/447[M+H]+ 252 -N(CH3)2 固體 MS(APCI):405/407[M+H]+ 253 〇^nh2 H 固體 MS(APCI):531/533 [M+H]+ 254 /~Λ 一ν^^ο2 固體 MS(APCI):495/497[M+H]+ 實施例255至260 對應之起始物以如實施例2 9中所述之相同方法處理，得到如下表9所示化合物。 110 318695 1378922 表 aXXj^ 〇CN严實施例號碼 R”，物化性質等 255 固體 MS(APCI):438/440[M+H]+ 256 固體 MS(APCI):463/465 [M+H]+ 257 固體 MS(APCI):439/441 [M+H]+ 258 固體 MS(APCI):464/466[M+H]+ 259 固體 MS(APCI):507/509[M+H]+ 260 ~Q^so2ch3 固體 MS(APCI):516/518[M+H]+Table r5 CC VIII Example No. M-N(R5)(R6) Physicochemical properties, etc. 249 ?H3 Solid MS (APCI): 449/451 [M+H]+ 250 -N 0 N^f Solid MS (APCI): 447/449[M+H]+ 251 -o Solid MS (APCI): 445/447[M+H]+ 252 -N(CH3)2 Solid MS (APCI): 405/407 [M+H]+ 253 〇^nh2 H Solid MS (APCI): 531/533 [M+H]+ 254 /~Λ ν^^ο2 Solid MS (APCI): 495/497 [M+H]+ Examples 255 to 260 The starting material was treated in the same manner as described in Example 29 to give the compound shown in Table 9 below. 110 318695 1378922 Table aXXj^ 〇CN strict example number R”, physicochemical properties, etc. 255 Solid MS (APCI): 438/440 [M+H]+ 256 Solid MS (APCI): 463/465 [M+H]+ 257 Solid MS (APCI): 439/441 [M+H]+ 258 Solid MS (APCI): 464/466 [M+H]+ 259 Solid MS (APCI): 507/509 [M+H]+ 260 ~ Q^so2ch3 Solid MS (APCI): 516/518 [M+H]+

實施例261至262 對應之起始物以如實施例37中所述之相同方法處理，得到如下表10所示化合物。 111 318695 1378922 表10 C1xx och3 心 N HN-N R6 G1 實施例號碼 -N(R5)(R6) 物化性質等 261 、P 固體 MS(APCI):445/447[M+H]+ 262 ,ch3 一N. O^CN 固體 MS(APCI):458/460[M+H]+ 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）之二氯曱烷（2毫升）溶液 φ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-(曱亞續酿基）乙氧基]定基）胺曱酿基]-坐（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 1378922 之相同方法處理，得到1-(2-氣苯基）-5-(4-氯苯基）-4-曱氧基-3-[(l-苯甲醯基六氫吡啶-4-基）羰基]胺基-in-吡唑 (40毫克，產率74%)固體。 MS(APCI)m/z ： 549/551[M+H]+ 實施例265 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1-(2-氣苯基）_5_(4_氯苯基）_4-U-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ι〇%)粉末。 MS(APCI)m/z ： 548/550[M+H]+ 實施例266 貫施例172所得化合物（16〇毫克）以如實施例16所述之相同方法處理，得到^(2—氣苯基）_5_(4_氯苯基）_4一 α 1-二側氧基—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（73毫克，產率45%)固體。 _MS(APCI)m/z : 564/566[M+H] + 實施例267 (1)參考例18所得化合物（155毫克）以如實施例1所述之相同方法處理，得到卜（2_氣苯基卜5 —(4'氯苯基）_4_ (4—四氫硫代哌°南基）氧基-3-[N-(N-嗎福啉基）胺曱醯基] -1H-吡唑（no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i5 所述之相同方法處理，得到卜（2 —氯苯基）n氣苯基） 318695 113 1378922 ·· -4-(1-側氧基-4-四氫硫代哌喃基）氧基unjn—嗎福啉 •基）胺甲醯基]-lH-nfca坐（97毫克，產率μ%)粉末。 MS(APCI)m/z ： 549/551[M+H]+ 實施例268 貫施例7 8所得化合物（6 5毫克）以如實施例15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-(甲亞磺醯基）乙基]胺甲醯基卜1H_吡唑（62 毫克，產率92%)粉末。籲MS(APCI)m/z : 452/454[M+H]+ 實施例269 貫施例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-氣苯基）-5-(4-氣苯基）-4-曱氧基-3-{N-[2-(曱磺醯基）乙基]胺甲醯基卜1H_吡唑（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-氣苯基）-4-曱氧基一3-(2 —吼啶基乙酿基）胺基-1H-吡唑（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）曱氧基-1-(2-氯苯基）-5〜（4〜氣苯1) [ΟΓ，Ν’-二甲肼基）羰基]-1H-吡唑（26 7奎古士土宅見，產率30%) 318695 114 1378922 ••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 (X, k6 實施例號碼 -N(R5)(R6) 物化性質等 272 、i^y-S02CH3 粉末 MS(APCI):509/511 [M+H]+ 273 一办固體 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 -氣苯基）-4 -甲氧基- 3- [N-(4 -苯甲基-4-乙氧羰基六氫吡啶-1-基）胺甲醯基]-1H-吡唑（152 毫克，產率83%)呈無色固體。 MS(APCI)m/z ： 607/609[M+H]+ 115 318695 1378922 .· ⑵將2N氫氧錢水溶液（250微升）加至上述步驟⑴ .所得化合物（150毫克）之乙醇（3毫升）溶液中然後於6〇 C «拌混合物-夜。接著再將2N氫氧錢水溶液⑼〇微升）加至反應混合物中’於9〇。〇㈣混合物2日。冷卻至室溫！ ’加入1N鹽酸水溶液並攪拌，混合物以三氯甲烷萃取。萃取液經真空濃縮後所得粗產物用石夕膠管柱層析（溶 j . 一氯曱烧/甲醇=98/2至95/5)與石夕膠薄層層析（溶劑：三氣甲烧/甲醇=95/5)進行純化，得到卜（2_氣苯基 (4-氯苯基）+甲氧基-3餐（4-苯甲基―4_誠六氫π比咬一1 一基）胺曱醯基]鲁。比唾⑸·5毫克，產率卿呈淡黃色固體。 MS(APCI)m/z ： 579/581[M+H]+ (3)將氣化毫克）、水可溶碳二亞胺鹽酸鹽（2〇毫克）、卜經基苯并三嗤水合物（16毫克）與三乙胺（2〇微升）加至上述步驟⑴所得化合物（29.4亳克）之二甲基甲酿胺 #(1毫升）溶液中，室溫擾拌混合物一夜。接著將碳酸氮納水溶液加至反應混合物中並_，混合物用三氯甲烧萃取。有機層用水清洗後經真空濃縮。所得粗產物用nh一矽膠管柱層析（ChromW NH-石夕膠，溶劑：己烧/乙酸乙酉旨 =35/65至0/100)進行純化’得到卜（2_氯苯基）_5_(4_氯苯基）-4-甲氧基-3-[N-(4_苯甲基+胺甲酿基六氫吼啶 -1-基）胺甲酿基]-1H-t坐⑵·6亳克，產率_呈體。 MS(APCI)m/z ： 578/580[M+H]+ 318695 116 1378922 ••實施例275 (1) 參考例1(6)所得化合物（545毫克）與參考例45(3) 所付化合物（2 9 2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-氣苯基）-4-甲氧基一 3 一 [N_ (4-曱氧羰基四氫硫代哌喃-4-基）胺曱醯基卜1H_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，將二氟乙酸（163微升）加至上述步驟（i) 所得化合物（275毫克）之二氣曱烷（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笨曱酸 (244毫克）加至反應混合物中，室溫攪拌混合物工小時。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15所述之相同方法萃取與純化，得到1-(2-氯苯基）-5-(4-氣苯基）-4-甲氧基_3_[n_ (4甲氧幾基-1，1-一側氧基四氫硫代α底喃一基）胺曱醯鲁基]-1Η-吡唑（272.1毫克，產率93%)之淡黃色固體。 MS(APCI)m/z ： 552/554[M+H]+ (3) 將2N氫氧化鈉水溶液（490微升）加至上述步驟所得化合物（270毫克）之乙醇（3毫升）溶液中，然後室溫攪拌混合物一夜。接著將2N鹽酸水溶液（5〇〇微升）加至反應混合物中並攪拌，混合物以三氯曱烷萃取。萃取液經真空濃縮後所得粗產物用矽膠管柱層析（溶劑：三氯甲烷/曱醇 = 99/1至90/10)進行純化，得到丨_(2_氣苯基）_5_(4_氯苯基）-4-甲氧基-3-[N-(4-羧基-1，1 —二側氧基四氫硫代哌喃 318695 117 1378922 ’ -4-基）胺甲醯基]-1H-n比。坐（224 7亳克，產率85%)呈淡普 •色固體。 ” MSCAPCI)m/z ： 538/540[M+H]+ 古⑷將氣化鍵（7.5亳克）、水可溶碳二亞胺鹽酸鹽（28 毫克）、卜Μ基笨并三唾水合物（21毫克）與三乙胺（29微升）加至上述步驟（3)所得化合物（38亳克）之二甲基甲醯胺（1 毫升）溶液中，室溫授拌混合物2日。接著將碳酸氫鈉水溶液加至反應混合物中並擾摔’混合物用三氯甲烧萃取。有籲機層用水清洗後經真空濃縮。所得粗產物用ΝΗ_石夕膠管柱層析（Chromatorex ΝΗ-矽膠，溶劑：己烷/乙酸乙酯=2〇/8〇至0/100)進行純化，得到丨_(2-氯苯基）_5_(4_氯苯基）一4_ 甲氧基-3-[N-(4-胺曱酿基一u一二側氧基四氮硫代^南 -4-基）胺曱醯基]-1H-吡唑（33.9毫克，產率85%)無色固體。 MS(APCI)m/z ： 537/539[M+H]+ 鲁實施例2 7 6 (1) 參考例5 ( 2 )所得化合物（16 8毫克）與參考例4 7 (2) 所得化合物（70毫克）以如實施例丨所述之相同方法處理，得到1-(2-氯本基）-5-( 4-氯苯基）-4-甲氧裁基甲氧基_3_ [N-(4-甲氧羰基-4-苯基六氫吡啶—1-基）胺曱醯基]_1H一吡哇（108.1毫克’產率5 7%)之無色固體。 MS(APCI)m/z ： 637/639[M+H]+ (2) 將2N鼠氣化納水溶液（336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8〇。〇 318695 118 1378922 .·=混合物2彳、時。接著再將2N氫氧化財溶液⑽微 •，）加至反應混合物中，10代_混合物i小時。添加四，呋喃（1毫升）至反應混合物中，1〇(rc攪拌3曰。冷卻至室溫後，加入2N鹽酸水溶液（500微升）並攪拌，混合物以三氯甲烧萃取。萃取液經真空濃縮後殘留物以二甲基甲酿胺（2毫升）稀釋。然後加入氯化銨（27毫克）、水可溶碳二亞胺鹽酸鹽（97毫克）、1-羥基苯并***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，混合物用三氣甲烷萃取。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（Chromatorex NH-矽膠，溶劑：己院/乙酸乙酯=20/80至0/100)進行純化，得到ι_(2-氯苯基）_5_(4_ 氯苯基）-4-胺曱醯基曱氧基-3-[N-(4-胺甲醯基一4-苯基六虱〇比〇定-1-基）胺甲醯基]-111-11比。坐（59.2毫克，產率58%) 呈無色固體。 ^MSCAPCDra/z ： 607/609[M+H] + 實施例277 (1)冰冷卻下，將二曱酸二-三級丁酯（21.82克）之四氫咬喃溶液（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-曱硫脲（18. 85克，產率 99%)呈白色固體。 119 318695 1378922 *' MS(APCI)m/z ： 191[M+H] + (2) 在室溫，將水可溶碳二亞胺鹽酸鹽（2. 86克）加至含參考例1 (6)所知化合物（3. 63克）、上述步驟（1)所得化合物（2. 85克）、1-沒基苯并三σ坐（2. 28克）與三乙胺（1. 51 克）之Ν, Ν-—曱基曱醯胺（1 〇〇毫升）溶液中，然後攪拌混合物一夜。接著將水加至反應混合物中，以過濾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1_(2_氣苯基）_5_(4_氣苯 _基）-4-甲氧基-3-(N-{[(三級丁氧羰基胺基）曱硫基]亞曱基}胺甲醯基）-111-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（20毫升）懸浮液中’然後8 0 C授掉混合物一夜。冷卻後，將水加至反應混合物中，混合物以三氯曱烷萃取。萃取液以硫酸鎂籲乾燥後經真空濃縮。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i-(2-氣苯基）-5-(4-氯苯基）-4-甲氧基-3-[5-(三級丁氧羰基胺基） -1，2, 4-***-3-基]-1H-吡唑（814毫克，產率81%)呈白色固體。 MSCAPCI)m/z ： 501/503[M+H]+ (4)在至溫’將4N HC1-二卩亏烧（2.0毫升）加至上述步驟（3)所得化合物（〇.go克）之f醇（1〇毫升）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， 3】8695 120 1378922 ••混合物用三氣曱烷萃取。萃取液以硫酸鎂乾燥後經真空濃 -縮，得到1-(2-氯苯基）-5-(4-氯苯基）-4-曱氧基-3_(5 一胺基-1，2,4-三。坐-3-基）-111-°比〇坐（390毫克’產率61%)呈白色固體。 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（1〇〇毫克）與碳酸鉀（276毫克）之乙猜（3 毫升）懸浮液中，然後使混合物在140°C微波反應器中授摔 _ 9 0分鐘。接著將水加至反應混合物中，混合物用乙酸乙酉旨萃取。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：三氯曱烷/甲醇=1〇〇/0至92/8)進行純化’得到1-(2-氯苯基）-5-(4-氯苯基）-4-甲氧基_3一 [5-(1-°比洛咬基）-1，2, 4-三°坐-3-基]-1Η-π比唾（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，80°C攪拌混合物一夜。冷卻後，將水加至反應混合物中，混合物用三氣甲烷萃取。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=80/20至60/40)進行純化，得到1-(2_氯苯基） -5-(4-氣苯基）-4-甲氧基-3-[3-(三級丁氧羰基胺基） -1，2,4-噚二唑-5-基]-111-吡唑（194毫克，產率19%)呈白 318695 121 1378922 •'色固體。 * MS(APCI)m/z ： 502/504[M+H]+ (2) 在室溫，將4N HC1-二Of烷（1.0毫升）加至上述步驟（1)所得化合物（0. 17克）之甲醇（5毫升）溶液中，搜拌混合物一夜。接著將碳酸氫鈉水溶液加至反應混合物中，混合物用三氯甲烧萃取。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-曱氧基-3-(3-胺基-1，2, 4-噚二唑-5-基）-1Η-啦唑（104毫克，產率76%)呈籲白色固體。 MS(APCI)m/z ： 402/404[M+H]+ (3) 在室溫，將1，4-二溴丁烷（1毫升）加至含上述步驟 (2)所得化合物（80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°C微波反應器中擾拌 210分鐘。接著將水加至反應混合物中，混合物用乙酸乙醋萃取。萃取液以硫酸鎂乾燥後經真空濃縮。所得粗產物鲁用矽膠管柱層析（溶劑：己烷/乙酸乙酯=95/5至〇/10〇)進行純化，得到1-(2-氯苯基）-5-(4-氯苯基）-4-甲氧基一3_ [3-(卜吡咯啶基）-1，2, 4-噚二唑-5-基]-1H-吡唑（8. i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氫氧化納水溶液（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，室溫攪拌混合物5小時。接著再將2N氫氧化鈉水溶液（5毫升）加至反 318695 122 1378922 * ••應混合物中，60°C攪拌混合物一夜。冷卻至室溫後力入 -⑽鹽酸水溶液（20毫升）並攪拌混合物。接著將=加至二= 物中並繼續擾拌混合物。所產生沉殿物以過遽法收集，然後乾燥’得到3-緩基-卜（2_氣苯基）_5_(4_氣苯基基-1Η-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，籲得到1-(2-氯苯基）-5-(4-氯苯基）-4-羥基-3-{[4-胺曱醯基4 (乙胺基）-N-六虱π比咬基]幾基丨比π坐（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 (1) 參考例1(6)所得化合物（145毫克）與參考例44所得化合物（77毫克）以如實施例1所述之相同方法處理，得鲁到卜（2-氣苯基）-5-（4-氯苯基）_4—曱氧基—3一[n_q-曱氧羰基環己烷-卜基）胺甲醯基]-1H-吡唑（175毫克，產率87%) 呈無色粉末。 MS(APCI)m/z ： 502/504[M+H]+ (2) 上述步驟（1)所得化合物（174毫克）以如實施例 275(3)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-(1-羧基環己烷-1-基）胺曱醯基] -1H-吡唑（171毫克，產率1〇〇%)呈無色固體。 MS(APCI)m/z ： 488/490[M+H]+ 123 318695 1378922 (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i_(2_氯苯基）_5_(4_氯苯基）-4-甲氧基-3-[Ν-(1-胺甲醯基環己烷一丨―基）胺曱醯基] -1H-吡唑（26.1毫克，產率77%)呈無色固體。 MS(APCI)in/z ： 487/489[M+H] + 實施例281 (1) 參考例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 ❿到1-(2-氣苯基）-5-（4-氯苯基）-4-f氧基-3_[n一（4_甲氧羰基四氫哌喃-4-基）胺甲醯基]—1H_吡唑（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i_(2_氯苯基）_5_(4_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 (4)所述之相同方法處理，得到丨_(2_氯苯基氯苯基）-4-曱氧基-3-[N-(4-胺甲酿基-四氫娘喃_4_基）胺甲醯基]-1H-吡唑（31毫克，產率9〇%)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（2〇〇毫克）以如實施例 318695 124 1378922 275(3)所述之相时法處理，得到卜（2〜氣笨苯基）_4—甲氧基，3餐㈣-四氫硫醯基]-1H-口比唾（146毫克，產率76%)呈無土）胺甲 MS(APCI)m/z : 506/508[M+H]+ ⑵上述步驟⑴所得化合物（35毫克） ⑷所述之相同方法處理，得歸-氣苯基)二基4-甲氧基-3^4_胺甲醯基_四氣硫代· 甲醒基]鲁❿坐（3ΐ·ι毫克，產率88%)呈固體南4基）胺 MS(APCI)m/z : 505/507[M+H]+ 實施例283 ⑴參考例i⑹所得化合物（1〇9毫克）與參考例* 得化合物（94毫克）以如實施例！所述之相同方法處理，得 =1-(2-氯苯基）—5_(4_氯苯基）—4_甲氧基一3，—（[甲氧羰基-4-苯基六氫吡啶―丨—基）胺甲醯基]_1H-吡唑（I". 8 毫克，產率82%)呈無色固體。 . 0MS(APCI)m/z ： 579/581 [M+H] + (2)將2N氫氧化鈉水溶液（25〇微升）加至上述步驟（ι) 所得化合物（140毫克）之乙醇（3毫升）溶液中，然後5(rc 攪拌混合物2小時。接著將四氫呋喃（2毫升）加至反應混合物中，8(TC攪拌混合物2日。冷卻至室溫後，加入⑽ π»·酉文水;谷液（250微升）並搜拌，混合物以三氯甲烧萃取。萃取液以硫酸鎂乾燥後過濾。濾液經真空濃縮，所得殘留物以一甲基甲酿胺（2毫升）稀釋。接著加入氯化録（18毫克）、水可溶碳二亞胺鹽酸鹽（65毫克）、丨_羥基苯并*** 125 318695 1378922 •水合物（52耄克）與三乙胺（95微升），室溫擾拌混合物一 •夜。然後將飽和碳酸氫鈉水溶液加至反應混合物中並搜拌，混合物用三氯曱烷萃取。有機層用水清洗後濃縮。所得粗產物用二異丙醚清洗，得到1-(2-氣苯基）-5-(4-氣苯基）-4_曱氧基-3-[N-(4-胺曱醯基-4-苯基六氫π比咬_卜基）胺曱醯基]-1H-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 鲁（1)冰冷卻下，將2· 2N偶氮二甲酸二乙酯-甲苯溶液 (4. 5毫升）逐滴加至含參考例1(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=80/20至60/40)進行純化，得到籲4-[2-(三級丁氧羰基胺基）乙氧基卜卜（2_氯苯基）_5_(4_ 氯苯基）-3-乙氧羰基-ΐΗ-η比唑（3. 37克，產率65%)呈固體。 MS(APCI)m/z ： 520/522[M+H]+ (2)將IN氫氧化鈉水溶液（15毫升）加至上述步驟（d 所得化合物（2. 60克）之乙醇（2〇毫升）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—；[_ (2-氯苯基）-5-(4-氣苯基）_1H_n比唑（2.47克，產率99%) 呈固體。 126 318695 1378922 MS(APCI)m/z ： 490/492[M+H]+ ' (3)在室温’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*** (1. 53克）與三乙胺（2 2〇克）之N，N_二甲基曱醯胺（5〇毫升） ’谷液中’然後擾拌混合物一夜。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）乙氧鲁基-1-(2-氣苯基）_5_(4_氯苯基各咬基）胺曱醯基]-1Η-吡唑（2. 07克，產率74%)呈固體。 MS(APCI)m/z ： 560/562[M+H]+ (4) 在室溫，將4N HC卜二卩琴烷加至上述步驟（3)所得化合物（1. 68克）之二噚烷（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***-乙醇清洗然後乾燥後，得到4-(2-胺基乙氧基）-卜（2-氯苯基鲁氯苯基）-3-[Ν-(1-吡咯啶基）胺曱醯基]-1H-吡唑鹽酸鹽 (1. 55克，產率97%)呈固體。 MS(APCI)m/z ： 460/462[M+H]+ (5) 上述步驟（4)所得化合物（100毫克）用NH-石夕膠管柱層析（溶劑：三氯曱烷/曱醇=1〇〇/〇至94/6)處理，得到 4-(2-胺基乙氧基）-1-(2-氣苯基）-5-(4-氣苯基 (1-β比各咬基）胺曱醯基]-1H-吼。坐（57毫克，產率66%)呈粉末。 MS(APCI)m/z ： 460/462[M+H]+ 318695 127 1378922 ••實施例285 將乙酿氣（79¾克）與三乙胺（151毫克）加至參考例 284(4)所得化合物（99毫克）之二氯甲烷（2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。所得粗產物用石夕膠管柱層析（溶劑：三氯曱烷/曱醇= 100/0至94/6)進行純化，得到4-[2-(乙醯基胺基）乙氧基]-1-(2-氣苯基）-5-(4-氯苯基）-3-[N-(i-〇比籲°各°定基）胺甲醯基]-1Η-%α坐（20毫克，產率20%)呈粉末。 MS(APCI)ra/z ： 502/504[Μ+Η]+ 實施例286 實施例284 (4)所得化合物（99毫克）與甲續醯氣（ία 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-(曱磺醯基胺基）乙氧基]_3_ [Ν-(1-σ比嘻咬基）胺甲醯基]-1Η-π比唑（83毫克，產率77%) |呈粉末。 MS(APCI)ra/z ： 538/540[Μ+Η]+ 實施例287 實施例284(4)所得化舍物（99毫克）與二甲基胺續醯氯（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-（二甲基胺績醯基）乙氧基]-3-[Ν-(1-πΛρ各咬基）胺甲醯基]-1{]-吼唾（71毫克，產率63%)呈粉末。 MS(APCI)m/z ： 567/569[M+H]+ 318695 128 1378922 •'實施例288 ' 實施例284(4)所得化合物（99毫克）與異氰酸乙醋毫克）以如實施例285所述之相同方法處理，得到卜^一氯笨基）-5-(4-氯苯基）-4-[2-(1^-乙基脲基）乙氧基]_3_[{^_ (1-吼咯啶基）胺曱醯基]-1H-吡唑（79毫克，產率74%)呈粉末。 MS(APCI)ra/z ： 531/533[M+H]+ 實施例289 馨（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）、 1-羥基苯并***（3. 06克）與三乙胺（1. 〇1克）之N，N_二曱基曱醯胺（100亳升）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***清洗後乾燥，得到1-(2-氯苯基氯苯基）籲-4-甲氧基-3-胺甲醯基-1H-吡唑（2. 04克，產率56%)呈固體。 MS(APCI)m/z ： 362/364[M+H]+ (2)將含上述步驟（！）所得化合物（i. 克）與拉威森氏试劑（2· 02克）之曱苯（1 〇毫升）溶液加熱題流擾拌2小時。冷卻後，將NH-矽膠（2克）加至反應混合物中然後過濾混合物。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1_(2一氯苯基）-5-(4-氣苯基）-4-甲氧基-3-硫代胺甲醯基_1Η_„比 318695 129 1378922 。坐（0. 69克，產率37%)呈固體。 MS(APCI)m/z ： 378/380[M+H]+The corresponding starting materials of Examples 261 to 262 were treated in the same manner as described in Example 37 to give the compound shown in Table 10 below. 111 318695 1378922 Table 10 C1xx och3 heart N HN-N R6 G1 Example number -N(R5)(R6) Physicochemical properties, etc. 261, P Solid MS (APCI): 445/447 [M+H]+ 262 ,ch3 N. O^CN solid MS (APCI): 458 / 460 [M+H] + Example 263. 3-chloroperbenzoic acid (90 mg, water content 25%) was added to Example 64 at 0 °C. The obtained compound (127 mg) was dissolved in EtOAc (2 mL), and then 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-(曱续 ))) ethoxy] aryl) Amine oxime]-sit (92 mg, yield 70%) powder. MS (APCI) m/z: </RTI> <RTI ID=0.0></RTI> </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> (2-Phenylphenyl)-5-(4-chlorophenyl)-4-decyloxy-3-[(l-benzylidinylhexahydropyridin-4-yl)carbonyl]amino-in-pyridyl Azole (40 mg, yield 74%) solid. MS (APCI) m/z: 549 / </RTI> <RTI ID=0.0></RTI> </RTI> </RTI> </RTI> <RTIgt; )_5_(4_chlorophenyl)_4-U-sideoxy-4-tetrahydrothiopiperidyl)oxy_3_[n_(4_tetrahydropyranyl)amine-methylmethyl]-1H- Pyrazole (15 mg, yield ι%) powder. MS (APCI) m/z: 548 / 550 [M+H] + </RTI> </RTI> </RTI> _5_(4_Chlorophenyl)_4-α 1-di-oxy-4-tetrahydrothiopiperidyl)oxy_3_[N_(4-tetrahydropyranyl)amine-methyl) -1H-pyrazole (73 mg, yield 45%) solid. _MS(APCI)m/z: 564/566 [M+H] + Example 267 (1) The compound obtained in Reference Example 18 (155 mg) was treated in the same manner as described in Example 1. Phenyl 5-(4'chlorophenyl)_4_(4-tetrahydrothiopiperazinyloxy-3-[N-(N-morpholineyl)amine fluorenyl]-1H-pyridyl Oxazole (no mg, yield 92%) powder. MS (APCI) m/z: 533 / 535 [M+H] + (2) Compound (152 mg) obtained in the above step (1) as described in Example i5 Treated in the same manner to obtain bis(2-chlorophenyl)n-phenyl) 318695 113 1378922 ··-4-(1-oxo-4-tetrahydrothiopyranyl)oxyunjn—who Phenanyl-aminocarbazinyl]-lH-nfca sitting (97 mg, yield μ%) powder. MS (APCI) m/z: 549 / 551 [M+H] + </RTI> </RTI> </RTI> Chlorophenyl)-5_(4-hydroxyphenyl)-4-methoxy-3-{N-[2-(methylsulfinyl)ethyl]amine-methylpyridyl 1H-pyrazole (62 mg , yield 92%) powder. MS (APCI) m/z: 452 / 454 [M+H] + Example 269 The compound obtained in Example 78 (65 mg) was treated in the same manner as described in Example 16 to give 1-(2- gas Phenyl)-5-(4-phenylphenyl)-4-decyloxy-3-{N-[2-(nonylsulfonyl)ethyl]amine-methylpyridyl 1H-pyrazole (68 mg, Yield 96%) powder. MS (APCI) m/z: 468 / 470 [M+H] + ?? -(4-Phenylphenyl)-4-methoxy-3-(2-anthranidylethyl)amino-1H-pyrazole (31 mg, yield 69%) powder. MS (APCI) m/z: 453 / 455 [M+H] + </ RTI> </ RTI> 271 The corresponding starting material was treated in the same manner as described in Example 27 to give 4-(amine fluorenyl) decyloxy group - 1-(2-chlorophenyl)-5~(4~gasbenzene 1) [ΟΓ,Ν'-dimethylhydrazino)carbonyl]-1H-pyrazole (26 7 Quaker's house, yield 30%) ) 318695 114 1378922 •• 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. Compound shown in 11. Table 11 hn-n (X, k6 Example No. -N(R5)(R6) Physicochemical Properties, etc. 272, i^y-S02CH3 Powder MS (APCI): 509/511 [M+H]+ 273 One Solid MS (APCI): 503 / 505 [M+H] + Example 274 (1) The compound (109 mg) of the compound of Reference Example (6) and the compound (105 mg) obtained in Reference Example 48 were the same as described in Example 1. Process to give 1-(2-chlorophenyl)-5-(4-cyclophenyl)-4-methoxy-3- [N-(4-benzyl-3- ethoxycarbonylhexahydropyridine) -1-yl)amine-mercapto]-1H-pyrazole (152 mg, yield 83%) as a colorless solid. MS (APCI) m/z: 607/609[M+H]+ 115 318695 1378922 . (2) A 2N aqueous solution of hydrogen peroxide (250 μl) was added to the above step (1). A solution of the obtained compound (150 mg) in ethanol (3 ml) was then taken at 6 〇C «mixed mixture - night. Then 2N oxyhydrogen Aqueous solution (9) 〇 microliters) was added to the reaction mixture at <9 Torr. 〇 (4) Mixture 2 days. Cool to room temperature! '1N aqueous hydrochloric acid was added and stirred, and the mixture was extracted with chloroform. The crude product obtained by vacuum concentration of the extract was chromatographed on a Shixi rubber column (solvent j. chlorohydrin/methanol = 98/2 to 95/5) and thin layer chromatography of Shixi gum (solvent: trimethyl ketone) /methanol=95/5) Purification to obtain b (2_gas phenyl (4-chlorophenyl) + methoxy-3 meal (4-benzylol-4_cheng hexahydro π ratio bite one 1 Amine thiol] Lu. Compared with saliva (5)·5 mg, the yield is a pale yellow solid. MS (APCI) m/z: 579/581 [M+H]+ (3) gasification of mg), Water-soluble carbodiimide hydrochloride (2 mg), p-perylene benzotriazine hydrate (16 mg) and triethylamine (2 〇 microliter) were added to the compound obtained in the above step (1) (29.4 g) In a solution of dimethyl ketoamine # (1 ml), the mixture was stirred overnight at room temperature. Next, an aqueous solution of sodium carbonate was added to the reaction mixture and the mixture was extracted with trichloromethane. The organic layer was washed with water and concentrated in vacuo. The obtained crude product was purified by nh-purine column chromatography (ChromW NH-shixi gum, solvent: hexane/acetic acid ethyl acetate = 35/65 to 0/100) to obtain bis(2-chlorophenyl)_5_( 4-(Chlorophenyl)-4-methoxy-3-[N-(4-phenylethyl+amine-methyl hexahydroacridin-1-yl)amine-branthyl]-1H-t(2)· 6 grams, yield _ body. MS (APCI) m/z: 578 / 580 [M+H] + 318 695 116 1378922 • • Example 275 (1) The compound obtained in Reference Example 1 (6) (545 mg) and the compound of Reference Example 45 (3) (2 9 2 mg) was treated in the same manner as described in Example 1 to give 1-(2-chlorophenyl)-5-(4-phenylphenyl)-4-methoxy-l-[N- ( 4-oxooxycarbonyltetrahydrothiopyran-4-yl)amine hydrazino 1H-pyrazole (48 mg, yield 92%) as a colorless solid. MS (APCI) m/z: 520/522 [M+H] + (2) difluoroacetic acid (163 μl) was added to the second gas of the compound (275 mg) obtained in the above step (i) under ice cooling. The mixture was stirred in a solution of hexane (5 mL) and then stirred at room temperature for 30 min. Then, m-chloroic acid (244 mg) was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for several hours. 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 15 to give 1-(2-chlorophenyl)-5-(4-phenylphenyl)-4-methoxy_3_[n_ (4A) Oxy-l-yl-1,1-one oxytetrahydrothioa- s-yl)amine sulphonyl]-1 oxime-pyrazole (272.1 mg, yield 93%) as a pale yellow solid. MS (APCI) m/z: 552 / 554 [M+H] + (3) EtOAc (3 EtOAc) The mixture was then stirred at room temperature overnight. Next, a 2N aqueous hydrochloric acid solution (5 liters of microliter) was added to the reaction mixture and stirred, and the mixture was extracted with trichloromethane. The crude product obtained by concentration in vacuo was purified by silica gel column chromatography (solvent: trichloromethane / decyl alcohol = 99/1 to 90/10) to give 丨_(2_ phenylphenyl)_5_(4_ Chlorophenyl)-4-methoxy-3-[N-(4-carboxy-1,1-di-tertiaryoxytetrahydrothiopyran 318695 117 1378922 '-4-yl)aminemethanyl]- 1H-n ratio. Sitting (224 7 g, yield 85%) was a pale color solid. MSCAPCI) m/z : 538/540[M+H]+ Ancient (4) will be gasified (7.5 gram), water soluble carbodiimide hydrochloride (28 mg), diphthyl and stupid Hydrate (21 mg) and triethylamine (29 μl) were added to a solution of the compound obtained in the above step (3) (38 g) in dimethylformamide (1 ml). Then, an aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and the mixture was shaken off. The mixture was extracted with trichloromethane. The organic layer was washed with water and concentrated in vacuo. The obtained crude product was chromatographed with ΝΗ_石夕胶柱柱 (Chromatorex ΝΗ Purification by hydrazine, solvent: hexane/ethyl acetate = 2 〇 / 8 Torr to 0/100, to give 丨-(2-chlorophenyl)-5-(4-chlorophenyl)- 4-methoxy-3 -[N-(4-Amine 基一 u u 氧基氧基氧基四四四 ] ] ] ] ] ] ] ] ] ] ] ] ] ] ( ( ( ( ( ( ( ( ( ( ( ( ( ( MS (APCI) m/z: 537/539 [M+H] + ruthenium Example 2 7 6 (1) Reference Example 5 (2) Compound (16 8 mg) and Reference Example 4 7 (2) (70 mg) was treated in the same manner as described in Example to give 1-(2-chloro 5-(4-chlorophenyl)-4-methoxyoxylmethoxy_3_[N-(4-methoxycarbonyl-4-phenylhexahydropyridin-1-yl)amine fluorenyl ]_1H-Pyva (108.1 mg 'yield 5 7%) of colorless solid. MS (APCI) m/z: 637/639 [M+H]+ (2) 2N mouse gasified sodium solution (336 μl Add to the solution of the above compound (107 mg) in ethanol (2 ml), and then at 8 〇〇 695 695 695 118 1378922 .· = mixture 2 彳, then 2N hydrogen hydroxide solution (10) •,)) added to the reaction mixture, 10 passages - mixture for 1 hour. Add four, furan (1 ml) to the reaction mixture, 1 〇 (rc stirred 3 曰. After cooling to room temperature, add 2N aqueous hydrochloric acid (500 micro ()) and stirred, the mixture was extracted with trichloromethane. The extract was concentrated in vacuo and the residue was diluted with dimethylamine (2 ml). then ammonium chloride (27 mg), water soluble carbon Amine hydrochloride (97 mg), 1-hydroxybenzotriazole hydrate (77 mg) and triethylamine (140 μL), and the mixture was stirred at room temperature for 4 hr. then aqueous sodium hydrogen carbonate solution was added to the reverse. The mixture was stirred and the mixture was extracted with tri-methane. The organic layer was washed with water and concentrated in vacuo. The obtained crude product was chromatographed with NH 矽矽 ( ( ( ( ( ( ( ( 己己己己己己己己己己己己己己0/100) Purification to give ι_(2-chlorophenyl)_5_(4- chlorophenyl)-4-amine fluorenyloxy-3-[N-(4-aminecarboxamidine-4-phenyl) The ratio of hexamethylpyrrolidine to -1-yl)amine carbaryl]-111-11. Sitting (59.2 mg, yield 58%) was a colorless solid. ^MSCAPCDra/z: 607/609 [M+H] + Example 277 (1) Dihydrogenate (20 ml) of di-tert-butyl phthalate (21.82 g) was added dropwise under ice cooling. It was added to a solution of water (300 ml) containing S-methylthiourea sulfate (15.31 g) and potassium carbonate (3. 4 g), and the mixture was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate. The extract was dried over MgSO.sub.4, then evaporated. 119 318695 1378922 *' MS(APCI)m/z : 191[M+H] + (2) Water soluble carbodiimide hydrochloride (2.86 g) was added to Reference Example 1 at room temperature (6) The compound (3.63 g), the compound obtained in the above step (1) (2.85 g), 1-diphenylbenzotriazine (2.28 g) and triethylamine (1. 51) After gram), a solution of hydrazine-hydrazinamide (1 ml) was stirred and the mixture was stirred overnight. Water was then added to the reaction mixture, and the resulting precipitate was collected by filtration and then dissolved with tri-methane. The solution is washed with water, dried over magnesium sulfate and concentrated in vacuo to give 1-[2-(2-phenylphenyl)-5-(4-phenylbenzene-yl)-4-methoxy-3-(N-{[( The carbonylamino) sulfonyl] fluorenyl] fluorenyl]-aminomethyl)-111-pyrazole (5.20 mg, 97% yield) was obtained as a white solid. MS (APCI) m/z: 535 / 537 [M+H] + (3) 肼 HCl (6.85 g) was added to the compound (1.07 g) obtained in the above step (2) and potassium carbonate at room temperature. (6. 91 g) of methanol (20 ml) in the suspension 'then 80 C was given the mixture overnight. 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 = 65/35 to 45/55) to give i-(2-phenylphenyl)-5-(4-chlorophenyl). 4-methoxy-3-[5-(tertiary butoxycarbonylamino)-1,2,4-triazol-3-yl]-1H-pyrazole (814 mg, yield 81%) White solid. MSCAPCI)m/z: 501/503[M+H]+ (4) Add 4N HCl-dioxin (2.0 ml) to the compound obtained in the above step (3) (〇.go) In a solution of f-alcohol (1 ml), the mixture was stirred overnight. Next, an aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, 3] 8965 120 1378922 • The mixture was extracted with trioxane. The extract was dried over magnesium sulfate and concentrated in vacuo to give 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4- methoxy-3-(5-amino-1,2 , 4-III. Sodium-3-yl)-111-° is squat (390 mg 'yield 61%) as 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 (1 〇〇mg) with potassium carbonate (276 mg) in a B (3 ml) suspension, then let the mixture drop in a 140 °C microwave reactor for _90 minutes. 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: trichloromethane / methanol = 1 / / / / / / / / / / / / / / / / / / / / / / / / / / ))-4-methoxy _3-[5-(1-° piroxime)-1,2,4-three-position -3-yl]-1Η-π than saliva (33. 4 mg, Yield 29%) was a pale yellow solid. MS (APCI) m/z: 455 / 457 [M+H] + </RTI> 278 (1) hydroxyamine hydrochloride (6.99 g) was added to the compound obtained in Example 277 (2) 1. 07 g) The mixture was stirred at 80 ° C overnight with a solution of potassium carbonate (6.91 g) in methanol (2 mL). After cooling, water was added to the reaction mixture, and the mixture was extracted with tri-gas methane. 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 1-(2-chlorophenyl)-5-(4-phenylphenyl) 4-methoxy-3-[3-(tertiary butoxycarbonylamino)-1,2,4-oxadiazol-5-yl]-111-pyrazole (194 mg, yield 19%) White 318695 121 1378922 • 'Color solid. * MS(APCI)m/z: 502 / 504 [M+H] + (2) 4N HCl-di-Ofane (1.0 ml) was added to the compound obtained in the above step (1) (0. 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 trichloromethane. The extract was dried over magnesium sulfate and concentrated in vacuo to give 1-(2-phenylphenyl)-5-(4-chlorophenyl)-4-decyloxy-3-(3-amino-1,2, 4-oxadiazol-5-yl)-1 oxime-lazole (104 mg, yield 76%) was obtained 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) (80 mg) With a suspension of potassium carbonate (276 mg) in acetonitrile (3 mL), the mixture was then stirred in a 14 ° C microwave reactor for 210 minutes. 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 column chromatography (solvent: hexane/ethyl acetate=95/5 to 〇/10 〇) to give 1-(2-chlorophenyl)-5-(4-chlorobenzene. ))-4-methoxy-3_[3-(pyrrolidinyl)-1,2,4-oxadiazol-5-yl]-1H-pyrazole (8. i mg, yield 9%) It is a white solid. MS (APCI) m/z: 456 / 458 [M+H] + Example 279 (1) A 2N aqueous sodium hydroxide solution (1 mL) was added to the compound obtained in Reference Example 1 (4) (3. 77 g) The mixture was stirred at room temperature for 5 hours in a solution of ethanol (30 mL). Then, 2N aqueous sodium hydroxide solution (5 ml) was added to the reverse 318695 122 1378922 *•• The mixture was stirred at 60 ° C overnight. After cooling to room temperature, a solution of -(10) aqueous hydrochloric acid (20 ml) was added and the mixture was stirred. Then add = to the second and continue to disturb the mixture. The resulting shoal was collected by the sputum method and then dried to obtain 3-sodium-di-(2- phenyl)-5-(4- phenylphenyl-1 Η-pyrazole (3.07 g, yield 88%) MS (APCI) m/z: 349 / 351 [M+H] + (2) Compound (52 mg) obtained in the above step (1) and the compound (34 mg) obtained in Reference Example 53 (3) Treated in the same manner as described in Example 吁, lending 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-hydroxy-3-{[4-aminoindenyl 4 (ethylamine) (N) m-z: 502/504 [M+H] is a pale yellow solid with a ratio of π (33. 7 mg, yield 45%). + Example 280 (1) The compound obtained in Reference Example 1 (6) (145 mg) and the compound obtained in Reference Example 44 (77 mg) were treated in the same manner as described in Example 1, to obtain a solvent. 5-(4-chlorophenyl)-4-indolyloxy-3-[n_q-indoleoxycarbonylcyclohexane-buyl)amine-mercapto]-1H-pyrazole (175 mg, yield 87 %) is a colorless powder. MS (APCI) m/z: 502 / 504 [M+H] + (2) The compound obtained in the above step (1) (174 mg) was treated in the same manner as described in Example 275 (3) to give 1-( 2-Chlorophenyl)-5-(4-chlorophenyl)-4-decyloxy-3_[N-(1-carboxycyclohexane-1-yl)amine fluorenyl]-1H-pyrazole ( 171 mg, yield 1% by weight) as a colorless solid. MS (APCI) m/z: 488 / 490 [M+H] + 123 318695 1378922 (3) The compound obtained in the above step (2) (34 mg) was treated in the same manner as described in Example 275 (4). Obtaining i_(2_chlorophenyl)_5_(4-chlorophenyl)-4-methoxy-3-[indole-(1-aminocarboxycyclohexane-yl)amine thiol]- 1H-pyrazole (26.1 mg, yield 77%) was obtained as a colorless solid. MS (APCI) in /z: 487 / 489 [M+H] + Example 281 (1) The compound (145 mg) of the compound of Reference Example (6) and the compound (78 mg) obtained in Reference Example 46 as in Example 1 The same method is used to obtain 1-(2-phenylphenyl)-5-(4-chlorophenyl)-4-foxy-3_[n-(4-methoxycarbonyltetrahydropyran). 4--4-Aminomethylmercapto]-1H-pyrazole (15 mg, yield 74%) was obtained as a colorless solid. MS (APCI) 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 i_( 2-(chlorophenyl)_5_(4-chlorophenyl)-4-methoxy-3-[N-(4-carboxy-tetrahydropyran-4-yl)aminecarboxamide-yl]-1H-pyridyl The azole (137. 3 mg, yield 93) was obtained as a colorless solid. MS (APCI) m/z: 490 / 492 [M+H] + (3) Compound (34 mg) obtained in the above step (2) (4) The same method as described, to obtain 丨_(2_chlorophenylchlorophenyl)-4-methoxy-3-[N-(4-amine-branyl-tetrahydro-n-yl_4_ Aminomethylmercapto]-1H-pyrazole (31 mg, yield 9%) was obtained as a solid. MS (APCI) m/z: 489 / 491 [M+H] + Example 282 (1) Example The compound obtained by 275(1) (2 mg) was treated as the phase described in Example 318695 124 1378922 275 (3) to give b (2~ phenophenyl)-4-methoxy, 3 (4) - tetrahydrothioindolyl]-1H-port than saliva (146 mg, yield 76%) is soilless) amine methyl MS (APCI) m / z: 506 / 508 [M + H] + (2) the above step (1) Compound (35 mg) (4) treated in the same manner as described above, Dikilyl 4-methoxy-3^4-aminocarbazide_tetraqi thio-methyl ketone base] ruthenium (3 ΐ·ι mg, yield 88%) APCI) m/z: 505 / 507 [M+H] + Example 283 (1) Compound (1 〇 9 mg) of Reference Example i (6) and Reference Example * Compound (94 mg) was obtained as in Example! The same method is used to obtain 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3,-([methoxycarbonyl-4-phenylhexahydropyridine]丨基基胺胺 ] ] ] ] ] ] ( ( ( ( ( ( ( ( ( ( ( ( ( ( 。。。。。。。。。。 0MS(APCI)m/z : 579/581 [M+H] + (2) A 2N aqueous sodium hydroxide solution (25 μL) was added to the above-mentioned compound (140 mg) of ethanol (3). ML) solution, then 5 (rc stir the mixture for 2 hours. Then add tetrahydrofuran (2 ml) to the reaction mixture, 8 (TC stir the mixture for 2 days. After cooling to room temperature, add (10) π»·酉文水; The broth (250 μl) was mixed and the mixture was extracted with trichloromethane. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue was diluted with methyleneamine (2 ml). Chloride (18 mg), water-soluble carbodiimide hydrochloride (65 mg), hydrazine-hydroxybenzotriazole 125 318695 1378922 • hydrate (52 g) and triethylamine (95 μl) The mixture was stirred at room temperature for one night. Then a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was applied, and the mixture was extracted with trichloromethane. The organic layer was washed with water and then concentrated. Washing to give 1-(2-phenylphenyl)-5-(4-phenylphenyl)-4_decyloxy-3-[N-(4-amine oxime) -4-Phenylhexahydropi-pyrene-pyridyl)-amino-yl-1H-pyrazole (25.5 mg, yield 19%) was obtained as a colorless solid. MS (APCI) m/z: 564/566 [M +H]+ Example 284 Lu (1) 2·2N diethyl azodicarboxylate-toluene solution (4.5 ml) was added dropwise to the compound containing Reference Example 1 (4) (3) 77 g), N-(2-hydroxyethyl)amine decanoic acid tert-butyl ester (1.61 g) and triphenylphosphine (2.62 g) in tetrahydrofuran (100 ml), the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. EtOAc EtOAc m. 40) Purification is carried out to give 4-[2-(tertiary butoxycarbonylamino)ethoxy bromide (2-chlorophenyl)-5-(4-chlorophenyl)-3-ethoxycarbonyl-indole-n The azole (3.37 g, yield 65%) was solid. MS (APCI) m/z: 520 / 522 [M+H] + (2) IN aqueous sodium hydroxide (15 ml) was added to the above steps (d The obtained compound (2.60 g) in ethanol (2 ml) was stirred at room temperature The precipitate was collected by filtration, washed with water-ethanol and dried to give 4-[2-(tertiary butoxycarbonylamino)ethoxy-3-yl-carboxyl group; [_ (2-chloro Phenyl)-5-(4-phenylphenyl)_1H_n-pyrazole (2.47 g, yield 99%) as a solid. 126 318695 1378922 MS (APCI) m/z: 490/492 [M+H]+ ' ( 3) Water-soluble carbodiimide hydrochloride (1.92 g) was added to the compound obtained in the above step (2) (2.77 g), 1-hydroxybenzotriazole (1. 53). g) with triethylamine (2 2 gram) of N,N-dimethyl decylamine (5 〇 ml) 'in the trough liquid' and then spoiled the mixture overnight. Water was then added to the reaction mixture to extract 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 thio- 1-(2-Phenylphenyl)-5-(4-chlorophenyl octa)aminoguanidino]-1 Η-pyrazole (2.07 g, yield 74%) was obtained as a solid. MS (APCI) m/z: 560 / 562 [M+H] + (4) 4N HCl dioxin was added to the compound (1.68 g) obtained in the above step (3) at room temperature. The mixture was stirred overnight (4 ml). After the reaction mixture was concentrated in vacuo, the residue was washed with diethyl ether-ethanol and then dried to give 4-(2-aminoethyloxy)-b (2-chlorophenyl chlorophenyl)-3-[ 1-Pyryryridinyl)aminoindenyl]-1H-pyrazole hydrochloride (1.55 g, yield 97%) was obtained as a solid. MS (APCI) m/z: 460 / 462 [M+H] + (5) Compound (100 mg) obtained in the above step (4) was chromatographed on NH-Dishite column (solvent: trichloromethane / decyl alcohol) =1〇〇/〇 to 94/6) to give 4-(2-aminoethoxy)-1-(2-phenylphenyl)-5-(4-phenylphenyl) Amino group]-1H-indole. Sit (57 mg, yield 66%) as a powder. MS (APCI) m/z: 460/462 [M+H]+ 318695 127 1378922 ••Example 285 A solution of the compound (99 mg) obtained from m. m. An aqueous solution of sodium hydrogencarbonate was added to the reaction mixture. The mixture was extracted with chloroform. The extract was dried over magnesium sulfate and concentrated in vacuo. The obtained crude product was chromatographed on silica gel column (solvent: trichloromethane / decyl alcohol = 100 Purification from /0 to 94/6) gave 4-[2-(ethylamino)ethoxy]-1-(2-phenylphenyl)-5-(4-chlorophenyl)-3- [N-(i-〇吁 ° ° ° ° °) Aminomethyl hydrazide]-1 Η-% α sitting (20 mg, yield 20%) in powder. MS (APCI)ra / z : 502 / 504 [Μ+Η]+ Example 286 Example 284 (4) The obtained compound (99 mg) and m. 5-(4-chlorophenyl)-4-[2-(nonylsulfonylamino)ethoxy]_3_ [Ν-(1-σ 嘻嘻)))] - π-biazole (83 mg, yield 77%) | as a powder. MS (APCI)ra/z: 538/540 [Μ + Η] + Example 287 Example 284 (4) obtained (99 mg) And dimethylamine hydrazine chloride (144 mg) was treated in the same manner as described in Example 285 to give 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-[2 -(dimethylamino)methyl ethoxy]-3-[Ν-(1-πΛρ each carbyl)amine carbhydryl]-1{]-吼吼 (71 mg, yield 63%) MS (APCI) m/z: 567 / 569 [M+H] + 318 695 128 1378922 • 'Example 288 ' The compound obtained in Example 284 (4) (99 mg) and acetoacetic acid Treated in the same manner as described in Example 285 to give the product: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 5-(4-chlorophenyl)-4-[2-(1^-ethylureido)ethoxy]_3_[{ ^_(1-Pyrridinyl)aminoindenyl]-1H-pyrazole (79 G, 74% yield) as a powder. MS (APCI)ra/z: 531/533 [M+H] + Example 289 (1) Water-soluble carbodiimide hydrochloride (3.83 g) was added at room temperature to include Reference Example 1 ( 6) N, N_2 of the obtained compound (3.66 g), 7N ammonia-methanol (6 ml), 1-hydroxybenzotriazole (3.66 g) and triethylamine (1. 〇1 g) In a solution of decylamine (100 liters), the mixture was then 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-chlorophenylchlorophenyl). %) is solid. MS (APCI) m / z : 362 / 364 [M + H] + (2) The compound (i. g) obtained with the above step (!) and the acetonide reagent (2.02 g) of benzene (1 〇 ml) solution heating problem flow mixing for 2 hours. After cooling, NH-gelatin (2 g) was added to the reaction mixture and the mixture was filtered. The filtrate was concentrated in vacuo to give a crude material which was purified using silica gel column chromatography (solvent: hexane/ethyl acetate=85/15 to 65/35) to give 1-(2-chlorophenyl)-5-(4- Phenyl)-4-methoxy-3-thiocarbamoyl-1Η_„ is 318695 129 1378922. Sit (0. 69 g, yield 37%) as a solid. 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025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。混合物以三氣甲烷萃取，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）之二氯甲烷 (2.5毫升）溶液中，加入卜“气三氟甲基）嘧啶基]六氫吡啶-4-羰基氯（293毫克），室溫攪拌混合物一夜。然後加入飽和碳酸氫鈉水溶液，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。所得粗產物用矽膠管柱層析 (溶劑：己烷/乙酸乙酯=50/50至30/7〇)進行純化，得^到卜（2-氯苯基）-5-(4-氯苯基）-4〜甲氧基一 3 一 {5_[W4_三氟甲基。密。定-2-基）吼口各唆-4-基***一 3_基}_1{1一吡唑（19毫克，產率12%)呈固體。 0MS(APCI)m/z ： 615/617[M+H] + 實施例290至308 之相同方法處理，得到相應物質以如實施例1中所述如下表12所示化合物。 318695 130 1378922(3) A solution containing the compound obtained in the above step (2) (7 mg) and ruthenium hydrate (025 mg) in ethanol (2.5 ml) was stirred and stirred for 2 hours. After cooling, the reaction mixture was concentrated in vacuo and then water was added to residue. The mixture was extracted with tri-gas methane, and the extract was dried over magnesium sulfate and concentrated in vacuo. Then, a solution of the obtained crude product and triethylamine (151 mg) in dichloromethane (2.5 ml) was added to the mixture of "trifluoromethyl)pyrimidinyl]hexahydropyridin-4-carbonyl chloride (293 mg). The mixture was stirred overnight. Then a saturated aqueous solution of sodium bicarbonate was added, and the mixture was extracted with chloroform. The extract was dried over magnesium sulfate and concentrated in vacuo. Purification by 50/50 to 30/7 〇) to give (2-chlorophenyl)-5-(4-chlorophenyl)-4~methoxy-3 to {5_[W4_trifluoromethyl 。。定基基基基基基基基基基基基基基基基基基基基基基基基基基 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 : 615/617 [M+H] + </ RTI> </ RTI> </ RTI> <RTI ID=0.0></RTI>

表 12(1) αχνη。5 N-R5 ULC1 R6’ 實施例號碼 -N(R5)(R6) 物化性質等 290 Γ 粉末 MS(APCI):481/483 [M+H]+ 291 F 粉末 MS(APCI):463/465 [M+H]+ 292 甲-N^~F 粉末 MS(APCI):463/465 [M+H]+ 293 N=v 粉末 MS(APCI):440/442 [M+H]+ 294 Η 〇2Η5 粉末 MS(APCI):456/458 [M+H]+ 295 Η 粉末 MS(APCI):454/456 [M+H]+ 131 318695 1378922 表 12(2)Table 12(1) αχνη. 5 N-R5 ULC1 R6' Example No. -N(R5)(R6) Physicochemical Properties, etc. 290 粉末 Powder MS (APCI): 481/483 [M+H]+ 291 F Powder MS (APCI): 463/465 [ M+H]+ 292 A-N^~F Powder MS (APCI): 463/465 [M+H]+ 293 N=v Powder MS (APCI): 440/442 [M+H]+ 294 Η 〇2Η5 Powder MS (APCI): 456/458 [M+H]+ 295 Η Powder MS (APCI): 454/456 [M+H]+ 131 318695 1378922 Table 12(2)

Cl、a WCH> N-R5 / 'LAr.. R6 實施例號碼 R” -N^XR6) 物化性質等 296 C1 粉末 MS(APCI):521/523 [M+H]+ 297 C1 ψ^Ο-Q 粉末 MS(APCI):522/524 [M+H]+ ΟΟί3 298 C1 och3 粉末 MS(APCI):500/502 [M+H]+ 299 C1 粉末 MS(APCI):443/445 [M+H]+ 300 F ，>crCF3 粉末 ’ MS(APCI):483/485 [M+H]+ 301 F ψ^Ο<1 固體 MS(APCI):465/467 [M+H]+ 132 318695 1378922 表 12(3) ^0；N 實施例號瑪 R, Rn Km 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]+Cl, a WCH> N-R5 / 'LAr.. R6 Example number R" -N^XR6) Physicochemical properties, etc. 296 C1 Powder MS (APCI): 521/523 [M+H]+ 297 C1 ψ^Ο- Q Powder MS (APCI): 522/524 [M+H]+ ΟΟί3 298 C1 och3 Powder MS (APCI): 500/502 [M+H]+ 299 C1 Powder MS (APCI): 443/445 [M+H ]+ 300 F ,>crCF3 powder 'MS(APCI): 483/485 [M+H]+ 301 F ψ^Ο<1 Solid MS (APCI): 465/467 [M+H]+ 132 318695 1378922 Table 12(3) ^0;N Example No. R, Rn Km 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]+

實施例309至324 133 318695 1378922 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)Examples 309 to 324 133 318695 1378922 The corresponding materials were treated in the same manner as described in Example 22 (3) to give the compound shown in Table 13 below. Table 13(1)

iX w rx R" 實施例號瑪 R” Rx/ 物化性質等 309 H \^CF3 粉末 MS(APCI): 556/558 [M+H]+ 310 H \^OCH3 粉末 MS(APCI): 518/520 [M+H]+ 311 H \xCN 粉末 MS(APCI): 513/515 [M+H]+ 312 Cl 粉末 MS(APCI): 584/586 [M+H]+ 313 Cl 粉末 MS(APCI): 620/622 [M+H]+ 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(APCD： 576/578 [M+H]+ 317 Cl \^cf3 粉末 MS(APCI): 590/592 [M+H]+ 134 318695 1378922 表 13(2) CCF w rx 實施例號碼 Rx 物化性質等 318 -O'01 粉末 MS(APCI): 568/570 [M+H]+ 319 众粉末 MS(APCI): 568/570 [M+H]+ 320 C1X) 粉末 MS(APCI): 568/570 [M+H]+ 321 -〇~F 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 _h〇_〇ch3 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 1378922 表 14(1) 實施例號碼 R 物化性質等 325 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 v^CH3 固體 MS(APCI): 503/505 [M+H]+ 329 ^〇H 固體 MS(APCI): 443/445 [M+H]+ 330 "XC1 H3CCH3 固體 MS(APCI): 463/465 [M+H]+ 331 \^SCH3 固體 MS(APCI): 433/435 [M+H]+ 136 318695 1378922 表 14(2) R" 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+H]+ 335 cf3 Cl 粉末 MS(APCI): 537/539 [M+H]+ 實施例336 (1)在氮氣環境下，將草醯氯（1. 92毫升）之二氯曱烷 (70毫升）溶液冷卻至-74°C，然後將二曱亞颯（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-hydroxyazet idine，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IN HC1水溶液（64毫升）。室 137 318695 1378922 溫攪拌混合物，然後分離水層。將1NHC1水溶液加至層並攪拌，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氫氧化鈉水溶液中和（pH9)，接^ = 7乙酸乙酉旨萃取。萃取液以鹽水清洗，以硫酸鎂乾燥後過遽。濾液經真空濃縮後所得粗產物用矽膠管桎層析（溶劑：己烷 /乙酸乙酯=100/0至90/10)進行純化，得到卜二苯1甲基^ 咀-3-酮（4. 57克，產率92%)呈白色固體。土大 MS(APCI)ra/z ： 238[M+H]+ # ⑵將二曱胺鹽酸鹽（4.89克）、乙酸（3·42毫升）與氰化鉀（3.92克）加至上述步驟（1)所得化合物（1〇.76克）之曱醇（110毫升）溶液中，55°C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，以硫酸鎂乾燥後過濾。濾液經真空濃縮後所得粗產物用矽膠管柱層籲析（溶劑：己烷/乙酸乙酯=5/1至4/1)進行純化，得到卜二苯甲基-4-氰基-4-二甲胺基氮哩（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1 〇分鐘之時間逐滴加至上述步驟（2)所得化合物（13. 5克）之二氯甲烧（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2Ν氫氧化納水溶液鹼化（ΡΗ11)。混合物以二氯f烷萃取，有機層】38 318695 1378922 以碳酸氫鈉水溶液清洗，以硫酸鎂乾燥後過濾。濾液經真空濃縮後殘留物以乙酸乙酯再結晶，得到卜二苯甲基胺甲醯基-4-二甲胺基氮哩（9. 47克，產率68〇%)呈無色固 MS(APCI)m/z ： 31〇[M+H]+ (4)將 IN HC1-二 Pf 烷（12. 8 毫升）與 10% 鈀-碳〇. 36iX w rx R" Example No. R" Rx/ Physicochemical Properties, etc. 309 H \^CF3 Powder MS (APCI): 556/558 [M+H]+ 310 H \^OCH3 Powder MS (APCI): 518/520 [M+H]+ 311 H \xCN Powder MS (APCI): 513/515 [M+H]+ 312 Cl Powder MS (APCI): 584/586 [M+H]+ 313 Cl Powder MS (APCI): 620/622 [M+H]+ 314 Cl OC; Powder MS (APCI): 620/622 [M+H]+ 315 Cl Powder MS (APCI): 627/629 [M+H]+ 316 Cl cf3 Powder MS (APCD: 576/578 [M+H]+ 317 Cl \^cf3 Powder MS (APCI): 590/592 [M+H]+ 134 318695 1378922 Table 13(2) CCF w rx Example No. Rx Physicochemical Properties, etc. 318 -O'01 Powder MS (APCI): 568/570 [M+H]+ 319 Powder MS (APCI): 568/570 [M+H]+ 320 C1X) Powder MS (APCI): 568/570 [ M+H]+ 321 -〇~F 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 _h〇_〇ch3 Powder MS (APCI): 564/566 [M+H]+ Examples 325 to 335 The corresponding materials were the same as described in Example 21. After treatment, the obtained product was treated in the same manner as described in Example 28 to give the following Table 14 135 318695 1378922 Table 14(1) Example No. R Physicochemical properties, etc. 325 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 v^CH3 Solid MS (APCI): 503/505 [M+H]+ 329 ^〇H Solid MS (APCI) : 443/445 [M+H]+ 330 "XC1 H3CCH3 Solid MS (APCI): 463/465 [M+H]+ 331 \^SCH3 Solid MS (APCI): 433/435 [M+H]+ 136 318695 1378922 Table 14(2) R" 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+H]+ 335 cf3 Cl powder MS (APCI): 537/539 [M+H]+ Example 336 (1) in a nitrogen atmosphere The solution of chloroform (1.252 ml) in dichloromethane (70 ml) was cooled to -74 ° C, then diterpenoid (3.22 ml) was added dropwise over 15 minutes. . The mixture was stirred at the same temperature for 20 minutes, then a solution of 1-benzhydryl-3-hydroxyazetidine (5 g) in dichlorohydrazine (25 ml) was taken over 45 minutes. The time is added dropwise. The mixture was stirred at the same 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. After the reaction mixture was warmed to 0 ° C, aqueous <RTI ID=0.0>#</RTI> Room 137 318695 1378922 The mixture was stirred while the aqueous layer was separated. An aqueous 1NHC1 solution was added to the layer and stirred, and then the aqueous layer was separated (the extraction step was repeated three times). The combined aqueous layers were neutralized (pH 9) with a 2N aqueous sodium hydroxide solution while stirring, and then extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and dried. The filtrate was concentrated in vacuo to give a crude material (yield: hexane/ethyl acetate = 100/0 to 90/10). 57 g, yield 92%) as a white solid. Soil MS (APCI)ra/z : 238[M+H]+ # (2) Add the guanamine hydrochloride (4.89 g), acetic acid (3.42 ml) and potassium cyanide (3.92 g) to the above steps. (1) A solution of the obtained compound (1 〇.76 g) in methanol (110 ml) was stirred at 55 ° C for 115 min. After cooling to room temperature, a saturated aqueous solution of sodium hydrogencarbonate (15 mL) was added to the mixture, and the mixture was stirred at room temperature for 45 minutes. The mixture was extracted with EtOAc. EtOAc was evaporated. The filtrate was concentrated in vacuo and the crude product was purified using EtOAc EtOAc EtOAc EtOAc Dimethylaminopurine (13.55 g, yield 1%) was 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) over a period of more than 1 minute ( 13. 5 g) of a solution of methylene chloride (275 ml) was stirred at room temperature for 41 hours. Then, the reaction mixture was dropwise added to ice-cooled water, followed by alkalization with a 2 Torr aqueous solution of hydrogen peroxide while stirring (ΡΗ11). The mixture was extracted with dichlorofane, and the organic layer was washed with aqueous sodium bicarbonate, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was crystallised from ethyl acetate (ethyl acetate) APCI) m/z : 31 〇 [M+H] + (4) IN HC1-di Pf alkane (12.8 ml) with 10% palladium-carbon ruthenium. 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***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4_胺曱醯基-4-二甲胺基氮咀鹽酸鹽（22〇克，產率96%)呈無色固 MS(APCI)m/z* 144[M+H]+ (5)將2N氫氧化鈉水溶液（5〇〇微升）加至上述步驟（4) 所得化D物（180笔克）之水（2毫升）溶液中，室溫攪拌混合丨物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〒醯基_4_二甲胺基-1-亞石肖基氮。且（137毫克，產率79%)呈淡黃色固體。 MS(APCI)m/z : 173[Μ+Η]+ (6)將氯化亞錫（ΙΙ)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 1378922 .加，廻流攪拌1曰。冷卻至室溫後，真空濃縮反應混合物。 -接著將三氯f烷加至殘留物_並攪拌，然後用矽藻土 (celite)過濾。濾液經真空濃縮後將殘留物溶解在N，卜二甲基甲醯胺（3毫升）中。接著加入參考例1(6)所得化合物 (145毫克），然後混合物以如實施例i中所述之相同方法處理，得到1-(2-氣苯基）一5 一（4_氯苯基）_4_甲氧基 [3-胺甲醯基-3-(二甲胺基）氮咀一丨一基]胺曱醯基卜1H一吡唑（化合物a ’ 4. 7毫克，產率2. 7%)呈淡黃色固體與氣笨基）-5-(4-氣苯基）-3-{[3-胺甲醯基-3 —(二甲胺基）氮吸-卜基]胺甲醯基卜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[Μ+ίίΓ 實施例337 (1)將碳酸鉀（3· 73克）與六氫吼哄（i. 16克）加至2, 5- 籲二氣。比咬（2克）二甲基甲醯胺（30毫升）之溶液中，然後於 11 〇 C擾拌混合物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得粗產物用ΝΗ-石夕膠管柱層析（Chromatorex ΝΗ-石夕膠，溶劑：三氯曱烷/曱醇=1〇〇/〇至99/1)進行純化，得到5-氯 -2-(1-六氫。比卩井基）吼啶（〇. 28克，產率1〇〇9〇呈淡黃色固體。 MS(APCI)m/z ： 198/200[M+H]+ 140 318695 1378922 ‘ （2)上述步驟（1)所得化合物（270毫克）以如實施例 -336(5)中所述之相同方法處理，得到5_氣_2_(4-亞硝基六氫0比卩井-1-基）〇比咬呈淡黃色固體。 (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，接著逐漸加入氫化鋁鋰（91毫克），攪拌混合物1小k。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―卜基） _ -5-氯σ比咬（276毫克）呈淡黃色固體。 MS(APCI)ra/z · 213/215[M+H]+ (4) 將參考例1(6)所得化合物（loo毫克）與上述步驟 (3)所得化合物（59毫克）以如實施例丨中所述之相同方法處理，得到1-(2-氣笨基）-5-(4-氯苯基）-3_{!^[4_(5_氯 °比°定-2-基）六氫°比哄-1-基]胺甲醯基卜4-甲氧基— 1JJ一n比唑 (96毫克，產率63%)呈無色粉末。 0MS(APCI)m/z ： 557/559[M+H] + 實施例3 3 8 將碳酸鉀（50毫克）與6-氯菸鹼腈 (6-chioronicotinnitrile，50 毫克）加至參考例 22(2)所得化合物（60毫克）二甲基甲醯胺（丨.2毫升）溶液中，然後在17 0 C微波加熱盗中授掉混合物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=5〇/5〇至 318695 141 1378922 30/70)進行純化’得到1-(2-氯苯基）-5-(4-氯苯基）-3-{N-[4-(5-氰基》比啶-2-基）六氫吡哄-1-基]胺甲醯基}-4-甲氧基-1H-吡唑（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）-3-{1^-[4-(5-二氣甲基11比啶-2-基）六氫吡畊-1-基]胺甲醯基}-4-甲氧基一1H_吡唑呈籲無色粉末。 MS(APCI)m/z ： 573/575[M+H]+ 實施例340至351 中所述之相同方法處理，得相應物質以如實施例337 到如下表15所示化合物。The mixture was added to a solution of the compound (3·95 g) obtained in the above step (3) in methanol (8 ml), and the mixture was stirred at room temperature for 3 hours under nitrogen atmosphere. 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 4-amine- s- </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; 144[M+H]+ (5) Add 2N aqueous sodium hydroxide solution (5 μL) to the solution of the obtained D (180 g) in water (2 ml) in the above step (4), room temperature The mixture was stirred for 30 minutes. 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. EtOAc m. Base 4 - dimethylamino-1-phenyl succinyl nitrogen. (137 mg, yield 79%) was obtained as a pale yellow solid. MS (APCI) m/z : 173 [Μ + Η] + (6) The stannous chloride (hydrazine) dihydrate (316 mg) was added to the compound obtained in the above step (5) (69 mg) of ethanol (2) In ML) solution, the mixture was 318695 139 1378922. Add, turbulently stir 1 曰. After cooling to room temperature, the reaction mixture was concentrated in vacuo. - Trichlorofane was then added to the residue _ and stirred, followed by filtration with celite. The filtrate was concentrated in vacuo and the residue was crystallisjjjjjjjj Next, the compound (145 mg) obtained in Reference Example 1 (6) was added, and then the mixture was treated in the same manner as described in Example i to give 1-(2-phenylphenyl)-5-(4-chlorophenyl). _4_methoxy[3-aminocarbamido-3-(dimethylamino)nitrogen hydrazide-yl]amine sulfhydryl 1H-pyrazole (Compound a ' 4. 7 mg, yield 2. 7%) light yellow solid with a gas base) -5-(4-phenylphenyl)-3-{[3-aminocarbamido-3((dimethylamino)azinyl-bu-]amine A醯基卜 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 [Μ+ίίΓ Example 337 (1) Potassium carbonate (3· 73 g) with hexahydroquinone (i. 16 g) added to 2, 5- 2 gas. In a solution of the bite (2 g) of dimethylformamide (30 ml), the mixture was then spoiled at 11 ° C for 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 chromatography on silica gel chromatography (Chromatorex 石-shixi gum, solvent: trichloromethane / decyl alcohol = 1 〇〇 / 〇 to 99 / 1) to give 5 -Chloro-2-(1-hexahydro. than 卩井基) acridine (〇. 28 g, yield 1〇〇9〇 as a pale yellow solid. MS (APCI) m/z: 198/200 [M+ H]+ 140 318695 1378922 ' (2) The compound obtained in the above step (1) (270 mg) was treated in the same manner as described in Example-336 (5) to give 5-?? Hexagonal hexanyl-1-pyrene-pyrene is a pale yellow solid. (3) The solution of the compound obtained in the above step (2) in tetrahydrofuran (4 ml) is cooled to 〇 ° C, then gradually added lithium aluminum hydride. (91 mg), the mixture was stirred for 1 k. Then, a saturated aqueous solution of sodium hydrogencarbonate was gradually added to the mixture, and the mixture was extracted with trichloromethane. The organic layer was dried over magnesium sulfate and filtered. (4-Amino hexahydropyridinium-diyl) _ -5-chloro σ ratio bite (276 mg) is a pale yellow solid. MS (APCI)ra/z · 213/215[M+H]+ (4) The compound obtained in Reference Example 1 (6) (loo mg) was treated with the compound obtained in the above step (3) (yield: 59 mg) in the same manner as described in the Example to give 1-(2-carboyl)-5-(4-chlorophenyl). -3_{!^[4_(5_chloro° ratio °-2-yl)hexahydropyran-1-1-yl]aminemethanyl 4-methoxy- 1JJ-n-biazole (96 mg, Yield 63%) as colorless powder. 0MS (APCI) m/z: 557/559 [M+H] + Example 3 3 8 Potassium carbonate (50 mg) and 6-chloronicotinonitrile (6-chioronicotinnitrile, 50 mg) was added to a solution of the compound obtained in Reference Example 22 (2) (60 mg) in dimethylformamide (2 ml), and then the mixture was allowed to stand for 1 hour in a microwave oven. The reaction mixture was cooled. After that, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sulphuric acid, and then filtered. The filtrate was concentrated in vacuo. /ethyl acetate = 5 〇 / 5 〇 to 318 695 141 1378922 30 / 70) Purification 'to give 1-(2-chlorophenyl)-5-(4-chlorophenyl)-3-{N-[4- (5-cyano)pyridin-2-yl)hexahydropyridin-1-yl]aminemethanyl}-4-methoxy- 1H-pyrazole (20. 8 mg, yield 28%) was obtained as a colorless powder. MS (APCI) m/z: 548 / 550 [M+H] + Example 339 The corresponding material as described in Example 338 Treated in the same manner to give 1-(2-chlorophenyl)-5-(4-chlorophenyl)-3-{1^-[4-(5-dimethylmethyl 11-pyridin-2-yl)hexa Hydropyridin-1-yl]amine-methylmethyl}-4-methoxy-1H-pyrazole is a colorless powder. MS (APCI) m/z: 573 / 575 [M+H] </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI>

318695 142 1378922 表 15(1)318695 142 1378922 Table 15(1)

N HN-N^^N一R，，" 實施例號碼 R” R”” 物化性質等 340 Cl ~0~CF3 粉末 MS(APCI): 591/593 [M+H]+ 341 F 粉末 MS(APCI): 540/542 [M+H]+ 342 F 粉末 MS(APCI): 540/542 [M+H]+ 343 F 粉末 MS(APCI): 540/542 [M+H]+ 344 F ;〇粉末 MS(APCI): 524/526 [M+H]+ 345 F 粉末 MS(APCI): 524/526 [M+H]+ 346 F 粉末 MS(APCI): 524/526 [M+H]+ 347 Cl 0¾ 粉末 MS(APCI): 556/558 [M+H]+ 143 318695 1378922 表 15(2) N HN-N N-R,m, 實施例號碼 R” R”” 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 ~0~CH3 粉末 MS(APCI): 537/539 [M+H]+ 實施例352 (1)在室溫，將1N氫氧化納水溶液（5毫升）加至參考例1(6)所得化合物（750毫克）之曱醇（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’ 混合物以三氯曱烷萃取。萃取液以硫酸鎂乾燥後經真空濃縮。所得粗產物以曱醇清洗’然後乾燥’得到3 -叛基-1- (2 -氯苯基）-5-(4-氣苯基）-4-羥基-1Η-π比唑（626毫克’產率 90%)呈固體。 MS(APCI)m/z ： 349/351[M+H]+ 144 318695 U/8922 a (2)在至溫’將水可溶碳二亞胺鹽酸鹽（570毫克）加至 3上述步驟（1)所得化合物（620毫克）、4-胺基四氫旅喃 (300毫克）、卜羥基笨并***（460毫克）與三乙胺（3()〇毫克）之N, N 一甲基曱醯胺（丨5毫升）溶液中，然後攪拌混合物夜。接著將飽和碳酸氫鈉水溶液加至反應混合物中，此δ物以一氣T烷萃取。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：己烧/乙酸乙酯= 75/25至0/100)進行純化，得到^(2—氯苯基）_5_(4_氣苯基）-4-羥基-3-[Ν-(4-四氫哌喃基）胺甲醯基]_1Η_吡唑 (272毫克，產率35%)呈固體。 MS(APCI)m/z ： 432/434[M+H]+ (3)在至溫，將溴乙腈（180毫升）加至上述步驟（？）所得化合物（129毫克）與碳酸鉋（163毫克）之N，N_:甲基甲醯胺（3毫升）懸浮液中，在相同溫度下攪拌混合物6小時。接著將水加至反應混合物中’混合物以乙酸乙醋萃取。萃籲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=60/40至40/60)進行純化，得到1-(2-氯苯基）-5-(4-氯苯基）-4-氰基甲氧基_3_[卜（4_ 四氫略°南基）胺甲醢基]-1Η-σ比峻（135毫克，產率π%)呈固體。 MSCAPCI)m/z ： 471/473[M+H]+ 實施例353至355 相應物質以如實施例23中所述之相同方法處理，得到如下表16所示化合物。 318695 145 1378922 表16 f3cN HN-N^^N-R,, " Example number R" R"" Physicochemical properties, etc. 340 Cl ~0~CF3 Powder MS (APCI): 591/593 [M+H]+ 341 F Powder MS ( APCI): 540/542 [M+H]+ 342 F Powder MS (APCI): 540/542 [M+H]+ 343 F Powder MS (APCI): 540/542 [M+H]+ 344 F ;〇 Powder MS (APCI): 524/526 [M+H]+ 345 F Powder MS (APCI): 524/526 [M+H]+ 346 F Powder MS (APCI): 524/526 [M+H]+ 347 Cl 03⁄4 Powder MS (APCI): 556/558 [M+H]+ 143 318695 1378922 Table 15(2) N HN-N NR,m, Example No. R" R"" Physicochemical Properties, 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 ~0~CH3 powder MS (APCI): 537 / 539 [M+H] + Example 352 (1) 1 N aqueous sodium hydroxide (5 ml) was added to the compound obtained in Reference Example 1 (6) at room temperature ( Stir the mixture overnight in a solution of 750 mg) in methanol (10 ml). A 2N aqueous HCl solution was then added to the reaction mixture. The mixture was extracted with trichloromethane. The extract was dried over magnesium sulfate and concentrated in vacuo. The crude product obtained was washed with decyl alcohol 'and then dried' to give 3 - thiol-1-(2-chlorophenyl)-5-(4-phenylphenyl)-4-hydroxy-1 Η-π-biazole (626 mg' The yield was 90%) as a solid. MS (APCI) m/z : 349/351 [M+H]+ 144 318695 U/8922 a (2) Add water-soluble carbodiimide hydrochloride (570 mg) to 3 at the temperature above. (1) The obtained compound (620 mg), 4-aminotetrahydro brigade (300 mg), hydroxy benzotriazole (460 mg) and triethylamine (3 () 〇 mg) of N, N-A In a solution of guanamine (丨 5 ml), the mixture was stirred overnight. A saturated aqueous solution of sodium hydrogencarbonate was then added to the reaction mixture which was extracted with mono- hexane. The extract was dried over MgSO.sub.4 and evaporated to dryness. _5_(4_Phenylphenyl)-4-hydroxy-3-[indole-(4-tetrahydropyranyl)aminemethanyl]_1Η-pyrazole (272 mg, yield 35%) was obtained as a solid. MS (APCI) m/z: 432 / 434 [M+H] + (3) bromoacetonitrile (180 ml) was added to the above step (?) compound (129 mg) and carbonated (163 mg). In a suspension of N,N_:methylmethionamine (3 ml), the mixture was stirred at the same temperature for 6 hours. Water was then 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 column chromatography (solvent: hexane / ethyl acetate = 60 / 40 to 40 / 60) to give 1-(2-chlorophenyl)-5-(4-chlorophenyl). 4-Cyanomethoxy-3-3_[Bu(4_tetrahydro)-carbamoyl]-1Η-σ ratio (135 mg, yield π%) was solid. MSCAPCI) m/z: 471 / 473 [M+H] + </ RTI> 353 to 355. 318695 145 1378922 Table 16 f3c

R” 實施例號碼 Rr 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。R" Example number Rr 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 The corresponding materials were treated in the same manner as described in Example 1 to give the compound shown in Table 17 below.

146 318695 1378922 表17 cl^Vn。 -Ν厂）~R，"’ 實施例號碼 R”” 物化性質等 356 Λη2 固體 MS(APCI): 488/490 [M+H]+ 357 Ο Η 固體 MS(APCI): 570/572 [M+H]+ 358 Λ) 固體 MS(APCI): 564/566 [M+H]+ 359 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 -曱乳基 -3-[Ν-(1-六氫吡哄基）胺甲醯基]-1H-0比唾（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 1378922 得到1-(2-氯苯基）-5-(4-氣笨基）_4_甲氧基_3_[N_[4- [2-(曱颯基）乙醯基]六氫吡啡一丨_基]胺甲醯基]_1H_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)所得化合物（129毫克）與碳酸鉋（163毫克）之N，N_二甲基曱醯胺（3毫升）懸浮液中，室溫攪拌混合物6小時。接鲁著將水加至反應混合物中，混合物以乙酸乙酯萃取。萃取液以硫酸鎮乾你後經真空濃縮。所得粗產物用發勝管柱層析（溶劑：己烷/乙酸乙酯=60/40至40/60)進行純化，得到 -氯苯基）-5-(4 -氯苯基）-4-(乙氧幾基）（二敗）甲氧基 -3-[N-(4-四氫哌喃基）胺曱醯基]-1H-吡唑（74毫克，產率 44%)呈粉末。 MS(APCI)m/z ： 554/556[M+H]+ 修實施例363至3β4 相應物質以如實施例279中所述之相同方法處理，得到如下表18所示化合物。 148 318695 1378922 表18146 318695 1378922 Table 17 cl^Vn. -Ν厂)~R,"'Example number R"" Physicochemical properties, etc. 356 Λη2 Solid MS (APCI): 488/490 [M+H]+ 357 Ο 固体 Solid MS (APCI): 570/572 [M +H]+ 358 Λ) Solid MS (APCI): 564/566 [M+H]+ 359 solid MS (APCI): 584/586 [M+H]+ Example 360 The corresponding material as in Example 22 (1) ) is treated in the same manner as described in 22(2) to give 5-(4-chlorophenyl)-1_(2,4-dichlorophenyl)-4-indolyl-3-[Ν-(1- Hexahydropyridinyl)amine carbaryl]-1H-0 is a powder compared to saliva (560 mg 'yield 81%). MS (APCI) m/z: 480 / 482 [M+H] + </ RTI> </ RTI> </ RTI> The corresponding material was treated in the same manner as described in Example 22 (3) 147 318 695 1378922 to give 1-(2-chlorophenyl) -5-(4-indolyl)_4_methoxy_3_[N_[4-[2-(indolyl)ethenyl]hexahydropyridinyl-yl]aminomethane]_1H _Pyrazole (28 mg, yield 63%) was in powder. MS (APCI) m/z: 566 / 568 [M+H] + </RTI> </RTI> </RTI> </RTI> The mixture was stirred at room temperature for 6 hours with a suspension of hexanes (163 mg) of N,N-dimethylamine (3 ml). Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract is dried with sulfuric acid and concentrated in vacuo. The obtained crude product was purified by flash chromatography (solvent: hexane/ethyl acetate = 60/40 to 40/60) to give -chlorophenyl)-5-(4-chlorophenyl)-4- (Ethoxycarbonyl) (dioxa) methoxy-3-[N-(4-tetrahydropyranyl)amine hydrazino]-1H-pyrazole (74 mg, yield 44%) was obtained as a powder. MS (APCI) m/z: 554 / 556 [M+H] + </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 148 318695 1378922 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 1378922 •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-氣苯基）-3-侧氧基丁酸乙酯（25克，產率 95%)呈液體。 MSCAPCI)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ι〇分鐘之時間逐滴加至含2_氯苯胺（13 3克）之2N 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，在相同溫度下攪拌混合物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_氣苯基）—2一 [(2-氯苯基）亞肼基]—3_側氧基丁酸乙酯（32· 3克，產率馨82%)呈粉末。 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1小時。反應混合物經真空濃縮，殘留物以***稀釋後以鹽水清洗。有機層以硫酸鎂乾燥後過滤。遽液經真空濃縮，得到 4-溴-4-(4-氣苯基）-2-[(2-氯苯基）亞肼基]側氧基f丁酸乙酯（39克，產率1〇〇%)呈固體。 318695 150 1378922 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毫升）溶液中，於9q°c擾拌混合物3小時。反應混合物濃縮後，將乙酸乙酯與水加至殘留物中並擾拌混合物。有機層以鹽水清洗，以硫酸錤乾燥後過濾。濾液經真空濃縮，所得固體物質以異丙醚及乙醇清洗，得到^(2-氯苯基）-5-(4-氣笨基）-3-乙氧羰基_4_ 羥基-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）之二曱基曱醯胺（15〇毫升）溶液中，在相同溫度下攪拌混合物30分鐘，接著在室溫攪拌丨小時。將埃甲娱> (4. 95毫升）加至反應混合物中，室溫授拌混合物1 小時。接著反應混合物中加入水與乙酸乙酯並攪拌混合物。有機層以鹽水清洗，以硫酸鎂乾燥後過濾。濾液經真籲空濃縮，所得固體物質以異丙醚清洗，得到氣苯基） -5-(4-氣苯基）-3-乙氧羰基一4-甲氧基一1H_吡唑（15. 7 克，產率7 6%)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2N HC1水溶液（3〇毫升）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質，以水清洗，得到3_羧基氯苯基）_5_(4_氣 318695 151 1378922 苯基）-4-曱氧基-1H-吼唑（14. 4克，產率99%)呈粉末。 MS(APCI)m/z ： 363/365[M+H]+ 參考例2Reference 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). 5小时。 The mixture was stirred at the same temperature for 1.5 hours. 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 149 318 695 13 y y y y y y y y y y y y y y Ethyl 3-oxobutanoate (25 g, 95% yield) was a liquid. MSCAPCI)m/z : 241/243 [M+H]+ (2) Under ice cooling, an aqueous solution of sodium nitrite (79 g) was added dropwise over 2 mM to 2-chloroaniline (13). In a 3 g) 2N HC1 solution, the mixture 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 stirred at a temperature of 3 Torr 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 hexanes and dried in vacuo to give 4-(4-phenylphenyl)-2-[(2-chlorophenyl)-indenyl]- 3 oxoxybutyric acid The ester (32. 3 g, yield 82%) was in powder. MS (APCI) m/z: 379 / 381 [M+H] + (3) bromine (4.33 ml) was added dropwise to the compound obtained in the above step (2) (32.2 g) of trichloromethane (500) The solution was stirred at room temperature for 1 hour in ML) solution. After additional bromine (1 ml) was added, the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The organic layer was dried over magnesium sulfate and filtered. The mash was concentrated in vacuo to give 4-bromo-4-(4- phenylphenyl)-2-[(2-chlorophenyl) fluorenyl] </RTI> 〇〇%) is solid. 318695 150 1378922 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) In a solution of /100 ml), the mixture was disrupted at 9 q ° c for 3 hours. After the reaction mixture was concentrated, ethyl acetate and water were added to the residue and mixture was stirred. The organic layer was washed with brine, dried over barium sulfate and filtered. The filtrate was concentrated in vacuo, and the obtained solid material was washed with diethyl ether and ethanol to give (2-chlorophenyl)-5-(4-carboyl)-3-ethoxycarbonyl-4-hydroxy-1H-pyrazole ( 26 g, yield 81%) was in powder. • MS (APCI) m/z: 377 / 379 [M+H] + (5) s s s s s s s s s s The mixture was stirred at the same temperature for 30 minutes in a solution of guanamine (15 ml), followed by stirring at room temperature for a few hours. Add Aegean > (4.95 ml) to the reaction mixture and mix the mixture for 1 hour at room temperature. Water and ethyl acetate were then 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 concentrated by vacuum, and the obtained solid material was washed with isopropyl ether to give phenylphenyl]- 5-(4-phenylphenyl)-3-ethoxycarbonyl- 4-methoxy-1H-pyrazole (15) 7 g, yield 7 6%) is a powder. MS (APCI) m/z: 391 / 393 [M+H] + (6) EtOAc (2. The mixture was stirred at room temperature overnight in a solution of ethanol (2 mL). A 2N aqueous HCl solution (3 mL) was added to the mixture, and the mixture was stirred and concentrated. The solid matter was collected by filtration, and washed with water to give 3-carboxy-chlorophenyl) _5_ (4 _ s s s s s s s s s s s s s s s s s s s s s s s %) is a powder. MS (APCI) m/z : 363/365 [M+H]+ Reference Example 2

將二笨膦（208毫克）與2-(N-嗎福琳基）乙醇（96微升）加至1-(2-氯苯基）-5-(4-氯苯基）-3-乙氧羰基_4_羥基 -1H-吡唑（200毫克，參考例1(4)所得化合物）之四氫呋喃 (4毫升）溶液中並攪拌。在〇〇c、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矽膠管柱層析（溶劑：己烷/乙酸乙酯=67/33至30/70)進行純化，得到氯苯基）-5-(4-氣苯基）-3-乙氧羰基-4-[2-(n-嗎福啉基）乙氧基]-1Η-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)中所述之相同籲方法處理，得到5-(4-氣苯基）-1-(2,4-二氣苯基）-3_乙氧幾基-4-經基-lH-nt唾（6. 2克）。 MS(APCI)m/z ： 411/413[M+H]+ (2) 在氮氣環境下，將氫化鈉（118毫克，6〇%礦油懸浮液）加至上述步驟（1)所得化合物（1.1克）之二曱基曱醯胺 (12毫升）溶液中，在相同溫度下攪拌混合物15分鐘。將三氟甲磺酸2, 2, 2-三氟乙酯（1.18毫升）加至反應混合物中’然後於6 0 C授拌混合物15分鐘。冷卻至室溫後，加入檸檬酸水溶液與乙酸乙酯。混合物以乙酸乙酯萃取，有 318695 152 1378922 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（Chr〇mat〇rex Njj-石夕朦，Fu“ si 1 icia Chem.公司製造，溶劑：己烧/乙酸乙酯=9 g/ίο至80/20) 進行純化，得到5-(4-氯苯基）4-(2,4-:氯苯基）_3_乙氧羰基-4-(2, 2, 2-三氟乙氧基）-ΐΗ-α比唑（1. 28克，產率97%) 呈無色固體。Add bisphosphonate (208 mg) and 2-(N-norfosyl)ethanol (96 μl) to 1-(2-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl A solution of oxycarbonyl-4-hydroxy-1H-pyrazole (200 mg, the compound obtained in Reference Example 1 (4)) in tetrahydrofuran (4 ml) was stirred. Diisopropyl azodicarboxylate (154 μl) was added dropwise under a nitrogen atmosphere, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and then purified and purified eluting eluting eluting elut elut 3-Ethoxycarbonyl-4-[2-(n-morpholino)ethoxy]-indole-pyrazole (463 mg, yield 100%) was obtained as 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) to give 5-(4-Phenylphenyl)-1-(2,4-diphenyl)-3-ethoxydolyl-4-yl-lH-nt saliva (6.2 g). MS (APCI) m/z: 411/413 [M+H] + (2) Sodium hydride (118 mg, 6 〇% mineral oil suspension) was added to the compound obtained in the above step (1) under a nitrogen atmosphere ( In a solution of 1.1 g) of decylguanamine (12 ml), the mixture was stirred at the same temperature for 15 minutes. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (1.18 ml) was added to the reaction mixture, and then the mixture was stirred at 60 C for 15 minutes. After cooling to room temperature, an aqueous citric acid solution and ethyl acetate were added. The mixture was extracted with ethyl acetate. 318 695 152 1378922. The filtrate was concentrated in vacuo and the crude product was purified eluting with EtOAc EtOAc EtOAc (EtOAc). /ίο to 80/20) Purification to give 5-(4-chlorophenyl)4-(2,4-:chlorophenyl)_3_ethoxycarbonyl-4-(2, 2, 2-trifluoroethyl) Oxy)-indole-α-pyrazole (1. 28 g, yield 97%) was obtained as a colorless solid.

MsCAPCI)m/z : 493/495[M+H]+ 參考例4 (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1-(2_氯苯基）_3_乙氧羰基_4_羥基—5_(4_ 二氟甲基苯基比峻（40克）。 MS(APCI)m/z ： 411/413[M+H]+ (2) 將氯二氟乙酸（ι· 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）之二甲基甲醯胺（1〇毫升）溶液中，然後於80°C攪拌混合物2日。冷卻至室溫後，將 φ稀釋之HC1水溶液加至反應混合物中。攪拌後，混合物以氣曱烧萃取，萃取液經真空濃縮。殘留物以甲醇（1 〇毫升）稀釋，然後在室溫加入1N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，混合物以三氯甲烷萃取，萃取液經真空濃縮。所得粗產物以甲醇清洗，乾燥後得到氯苯基）-4-二氟曱氧基-3-乙氧幾基一5_(4一三敦甲基苯基） -1H-吡唑（504毫克，產率58%)呈無色固體。 MS(APCI)m/z ： 433/435 [M+H] + 318695 153 1378922 ’參考例5 (1)在室溫’將氫化鈉（0.40克，6 0%礦油懸浮液）加至參考例1(4)所得化合物（丨·39克）之二甲基曱醯胺（1〇毫升）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。加入擰檬酸水溶液與乙酸乙酯至反應混合物中。攪拌後，混合物以=酸乙酯萃取，有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矽膠管柱層析（溶劑：己烷/乙酸乙 >酯=50/50至30/70)進行純化，得到丨气卜氯苯基）_5_(4一氯苯基）-3-乙氧羰基-4_氰基甲氧基_1Η_π比唑（1·28克，產率61%)呈白色粉末。 MS(APCI)m/z ： 416/418[M+H]+ (2)冰冷部下，將in氫氧化鈉水溶液（2毫升）加至上述步驟⑴所得化合物甲醇（5毫升）溶液巾，然後室溫授拌混合物2小時。將2NHC1水溶液（4毫升）加至反應混合物 •中’混合物以三氯甲烷萃取。有機層以硫酸鎂乾燥後過濾。真空濃縮濾液，3-羧基-1-(2-氯苯基）_卜（4_氯苯基）_4_ (甲氧幾基）甲氧基-1H-吼唾（431毫克，產率99%)呈白色粉末。 MSCAPCI)m/z ： 421/423[M+H]+ 參考例6 一在〇 C、氮軋兄下’將二苯基磷疊氮化物⑽微升）與三乙胺（Π0微升）加至參考例丨⑻所得化合物⑽毫克）在相同溫度下授掉混合物3〇 318695 154 丄378922 分鐘，於80C攪拌混合物2小時。接著將6N HC1水溶液 -加至反應混合物中，於10(rc攪拌混合物—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―丨气卜氯苯基）-5-(4-氯苯基）一4-甲氧基_1H_0比唑（43毫克，產率 50%)呈淡黃色固體。 ® MS(APCI)m/z ： 334/336[M+H]+ 參考例7 在〇 C、氮氣環境下，將甲基鋰（13· 9毫升，ι 〇指乙醚溶液）逐滴加至參考例1(6)所得化合物（2·5克）之四氫呋喃（100宅升）溶液中，並在相同溫度下攪拌混合物3〇分鐘，然後於室溫攪拌3小時。接著在冰冷卻下將水與乙酸乙S旨加至反應混合物中並㈣。有機層以碳酸氫納水溶液清洗’以·請乾燥後㈣。㈣經真空濃縮，所得粗產物用石夕膠管柱層析（溶劑：己燒am9〇/1〇至85/15) 進行純化，得到3~乙醯基-1-(2-氯苯基）-5-(4-氯苯基） —4-曱氧基-1H-他唾αΐ克，產率·呈淡黃色固體。 MS(APCI)m/z: 361/363[Μ+Η]+ 參考例8 在-78°C、氮氣環境下，將甲基鋰（2.9毫升，丨〇他乙隨液）逐滴加至3一絲+ (2-氯苯基）-5-(4-氯苯基） -4-甲氧基鲁吼。坐（1〇9克）之四氯咬喃（3〇毫升）溶液 318695 155 1378922MsCAPCI) 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 1 (1;) to 1 (4) to give 1- (2_Chlorophenyl)_3_ethoxycarbonyl_4_hydroxy-5-(4-difluoromethylphenyl ratio (40 g). MS (APCI) m/z: 411/413 [M+H]+ (2) To a solution of the compound obtained in the above step (1) (82 mg) of dimethylformamide (1 ml), with chlorodifluoroacetic acid (1·3 g) and potassium carbonate (2.66 g). In the solution, the mixture was then stirred at 80 ° C for 2 days. After cooling to room temperature, a φ diluted aqueous solution of HCl was added to the reaction mixture. After stirring, the mixture was extracted with a gas-purified mixture, and the extract was concentrated in vacuo. Methanol (1 mL) was diluted, then a 1N aqueous sodium hydroxide solution (4 mL) was added at room temperature, and the mixture was stirred overnight at the same temperature. The diluted aqueous solution of HCl was added to the reaction mixture. After stirring, the mixture was chloroform. The extract is concentrated in vacuo, and the obtained crude product is washed with methanol and dried to give chlorophenyl)-4-difluoromethoxy-3-ethoxyxyl-5-(4-tetradylmethylphenyl)- 1H-pyrazole (504 mg, yield 58%) was obtained as a colorless solid. MS (APCI) m/z: 433/435 [M+H] + 318695 153 1378922 'Reference Example 5 (1) Add sodium hydride (0.40 g, 60% mineral oil suspension) to the reference example at room temperature 1 (4) The obtained compound (丨·39 g) in dimethyl decylamine (1 mL) was stirred at the same temperature for 15 minutes. Bromoacetonitrile (1.2 g) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. An aqueous solution of citric acid and ethyl acetate were added to the reaction mixture. After stirring, the mixture was extracted with ethyl acetate. The filtrate was concentrated in vacuo and the crude product was purified by EtOAc EtOAc EtOAc EtOAc Phenyl)-3-ethoxycarbonyl-4-cyanomethoxy-1-indole-π-pyrazole (1·28 g, yield 61%) was obtained as a white powder. MS (APCI) m / z: 416 / 418 [M + H] + (2) Under ice cooling, a solution of sodium hydroxide in water (2 ml) was added to the solution of the compound obtained in the above step (1), methanol (5 ml), and then room The mixture was warmed for 2 hours. A 2 NHC1 aqueous solution (4 ml) was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo, 3-carboxy-l-(2-chlorophenyl)-b (4-dichlorophenyl)- 4-(methoxy) methoxy-1H-indole (431 mg, yield 99%) It is a white powder. MSCAPCI)m/z : 421/423[M+H]+ Reference Example 6 I added 'diphenylphosphorus azide (10) microliter) to triethylamine (Π0 μL) under 〇C, nitrogen rolling brother To the compound (10 mg) obtained in Reference Example (8), the mixture was subjected to 3 318 695 154 丄 378 922 sec at the same temperature, and the mixture was stirred at 80 C for 2 hours. Next, a 6N aqueous HCl solution was added to the reaction mixture, and the mixture was stirred at 10 (rc). 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. After drying over magnesium sulfate, the filtrate was concentrated in vacuo. EtOAc m. Chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-1H-0-r-azole (43 mg, yield 50%) was obtained as pale yellow solid. ® MS(APCI)m/z : 334/336[M+H]+ Reference Example 7 Add methyl lithium (13·9 ml, ι 〇 ether solution) to the reference under 〇C, nitrogen atmosphere. The compound obtained in Example 1 (6) (2.5 g) was dissolved in tetrahydrofuran (100 liters), and the mixture was stirred at the same temperature for 3 hrs, and then stirred at room temperature for 3 hr. Water and acetic acid were then added to the reaction mixture under ice cooling and (iv). The organic layer is washed with an aqueous solution of sodium hydrogencarbonate. (4) After concentration in vacuo, the obtained crude product was purified by chromatography on silica gel column (solvent: hexanes am9 〇/1 〇 to 85/15) to obtain 3-ethylamino-1-(2-chlorophenyl)- 5-(4-Chlorophenyl)-4-oxooxy-1H-tapropargyl, Yield·light yellow solid. MS (APCI) m/z: 361/363 [Μ+Η]+ Reference Example 8 Methyl lithium (2.9 ml, thiophanate) was added dropwise to 3 at -78 ° C under a nitrogen atmosphere. A trace of + (2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy ruthenium. Sit (1〇9g) of tetrachlorine (3〇ml) solution 318695 155 1378922

中’並在相同溫度下搜拌混合物3 〇分鐘。回溫至室溫後，將溴化（乙烯基）鎂（7. 7毫升’ 〇. 97M四氫呋喃溶液）逐滴加至反應混合物中，室溫攪拌混合物3小時。將水與1N HC1 水溶液加至反應混合物中。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。濾液經真空濃縮，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，得到卜（2_氯苯基）_5_(4_氯苯基）_4—甲氧基-3-乙烯羰基-1H-吡唑（780毫克，產率70%)呈無色固 MS(APCI)m/z ： 373/375[Μ+Η]+ 參考例9 (1)在o°c、氮氣環境下，將二苯基磷疊氮化物（2 37 毫升）與三乙胺（1.67毫升）加至3-羧基-1-(2-氣苯基）一5一 (4 -氣本基）-4 -曱氧基-in-nit〇i_(3.63克）之甲苯（3〇毫升）溶液中，然後在相同溫度下攪拌混合物30分鐘，於8(rc _攪拌混合物3小時。冷卻至〇°c後，將苯甲醇（1. 86毫升）與4-二曱胺基》比咬（61毫克）加至反應混合物中，於。〇攪拌混合物一夜。冷卻至室溫後，將碳酸氫鈉水溶液加至反應混合物中。擾摔後’混合物以乙酸乙醋萃取，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3-苯甲氧羰基胺基-1-(2-氣苯基）-5-(4-氣苯基） -4-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]+ 318695 156 1378922 (2)將10%把_碳（400毫克）加至上述步驟（！）所得化合物（4.1克）之曱醇（50毫升）溶液中，在氫氣環境下室溫攪拌混合物7小時。過濾反應混合物，濾液經真空濃縮。接著將三氯曱烧與碳酸氫鈉水溶液加至殘留物中。授摔後，混合物以三氯曱烷萃取，萃取液以硫酸鎂乾燥後過據。渡液經真空濃縮，所得粗產物以乙醇再結晶，然後過濾除去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=70/30至50/50)進行籲純化，得到3-胺基-1-(2-氯苯基）-5-(4-氣苯基）-4-曱氧基-1Η-β比峻（310毫克，產率11%)呈淡黃色固體。 MS(APCI)m/z ： 334/336[M+H]+ 參考例10 (1)冰冷卻下，將氫化鈉（360毫升）加至1-苯甲氧幾武 -4-羥基六氫吼啶（1. 3克）二甲基甲醯胺（1〇毫升）溶液中’在氮氣環境下室溫攪拌混合物1小時。冰冷卻丁，將籲埃甲烧（374微升）加至反應混合物中，在相同溫度下授掉混合物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，以硫酸鎮乾燥後過滤。濾液經真空濃縮，所得粗產物用石夕膠管柱声析（溶劑：己烧/乙酸乙酯=88/12至70/30)進行純化，得到 1-苯甲氧羰基-4-甲氧基六氫咣啶（622毫克，產率45%)呈淡黃色油狀物。 MS(APCI)m/z ： 250[M+H]+ (2)將10%鈀-碳（80 .毫克）加至上述步驟（！）所得化入 318695 157 1378922 物（620毫克）之曱醇（20毫升）溶液中，在氫氣環境下室溫攪拌混合物3小時。以膜過遽器過濾反應混合物，滤液經真空濃縮，得到4-曱氧基六氫吡啶（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（57.1克）之二氯甲烷（3〇〇毫升）溶鲁液中，室溫授拌混合物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。授拌混合物，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。濾液經真空濃縮，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_(三級丁氧羰基）胺基六氩吡啶（83· 2克，產率^呈淡黃色固體。鲁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f醇（350毫升）溶液中，在氫氣環境下室溫授拌混合物-夜。以膜過渡器過渡反應混合物，渡液經^ 空濃縮，得到4-(三級丁氧羰基）胺基六氫吡啶（48 3 了產率96%)呈淡黃色固體。 ·兄’ MS(APCI)m/z ： 201[M+H]+ 驟（2)所得化合接著在冰冷卻下 (3)將三乙胺（5. 23毫升）加至上述步物（5.0克）之一氯曱炫（5〇毫升）溶液中， 318695 158 1378922 加入乙續醯氯（2.36毫升）。在相同溫度下授拌混合物3〇分鐘。回溫至室溫後，真空濃縮反應混合物，將三氣甲广與碳酸氫納水溶液加至殘留物中。攪拌後，有㈣以^ 鎂乾燥，然後過濾。濾液經真空濃縮，所產生晶體以異醚再結晶，得到4-(三級丁氧羰基）胺基_丨_乙磺醯基六、= 吧啶（6. 99克，產率96%)呈淡黃色固體。土 ’、風 MS(APCI)m/z : 291[M+H]+ (4)將4NHC1-二鳄烧（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。將四气夫南與2 N鼠氧化納水浴液加至反應混合物中進行中和。力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-乙磺蕴基六氫吼啶（4. 20克，產率94%)呈淡紅色粉末。 ’ MS(APCI)m/z ： 193[M+H]+ 鲁參考例12 (1)在室溫’將乙酸納（3.28克）與經胺鹽酸鹽（1 μ 克）加至4-四氬硫代哌喃酮（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。反應混合物經真空濃縮，將乙酸乙S旨與碳酸氫納水溶液加至殘留物中。授拌後，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。辰喃肟（4-tetrahydrothiopyrane oxime)(2.53 克，產率 96%) 呈無色固體。 318695 159 1378922 ' MS(APCI)m/z : 132[M+H]+ . 冰冷卻下、氮氣環境中，將氫化鋁鋰（289毫克）加至上述步驟（1)所知化合物（5〇〇毫克）之乙驗（iq毫升）溶液中，在相同溫度下攪拌混合物30分鐘，接著在室溫攪拌 1小時。再將氫化鋁鋰（72毫克）加至反應混合物中，4〇t 攪拌混合物2小時。將水（1毫升）與2N氫氧化鈉水溶液（1 毫升）加至反應混合物中。攪拌後，用矽藻土（Celite)過濾混合物，濾液經真空濃縮，得到4-四氫硫代哌喃基胺（15〇響毫克，產率34%)呈黄色液體。 MS(APCI)m/z : 118[M+H]+ 參考例13 將20%三氯化鈦水溶液（413毫升）加至4_亞硝基硫代嗎福啉（17. 6克）之水（5毫升）溶液中，室溫攪拌混合物3. 5 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 φ水清洗，以硫酸鎂乾燥後過濾。濾液經真空濃縮，得到4_ 胺基硫代嗎福啉（10. 14克，產率64.5%)呈淡黄色黏稠物。在該產物（7. 57克）三氣甲烷（10毫升）溶液中，加入4Ν HC卜二曙烧（17. 6毫升）並擾拌。真空遭縮反應混合物，所產生晶體以異丙醚-己烷清洗，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)ra/z ： 119[M-HC1]+ 參考例14 (1)將2N氫氧化鈉水溶液（7.6亳升）加至4,4_二氟六 318695 160 1378922 :吡啶鹽酸鹽（2.0克）之水（32毫升）溶液中，室溫攪拌混 .合物1小時。冰冷卻下，將亞硝酸鈉（175克）加至反應混 =物中:然後加入乙酸（1.27毫升）。室溫攪拌混合物^小 4。接著加入碳酸氫鈉水溶液並攪拌，混合物以三氯甲烷萃取萃取液以硫酸錤乾燥，然後過濾。滤液經真空濃縮，所知粗產物用矽膠管柱層析（溶劑：己烷/乙酸乙酯=4/1) 進行純化，得到4,4-二氟-1-亞硝基六氫吡啶（1. 89克，產率9 9%)呈淡黃色固體。 _ MS(APCI)m/z : 151[M+H]+ (2)冰冷卻下，將氫化鋁鋰（837毫克）逐漸加至上述步驟（1)所得化合物（1.89克）之四氫呋喃溶液中，然後加熱廻流混合物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3〇分鐘。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曱烷加至殘留物中。攪拌後，有機層以硫酸鈉乾燥，然鲁後過濾。濾液經真空濃縮，得到丨_胺基_4,4_二氟六氫吡咬（500毫克’產率29%)呈淡黃色油狀物。 MS(APCI)m/z ： 137[M+H]+ 參考例15 將漠化氫水溶液（1〇毫升）加至參考例9(丨）所得化合物（1. 9克）之乙酸（1 〇毫升）溶液中，於8〇°c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’混合物以三氯曱烷萃取。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，所得 318695 161 1378922 粗產物用矽膠管柱層析（溶劑：己烷/乙酸乙酯=70/30至 0/100)與NH-矽膠管柱層析（chromatorex NH-石夕勝，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-氯笨基氣笨基）-4-甲氧基-1Η-η比唑（353毫克’產率26%)呈淡黃色固體。 MS(APCI)m/z ： 334/336[M+H]+ 參考例16 鲁（1)將亞硝酸二級丁 g旨（3. 5毫升）加至4 -三級丁氧幾基六氫《比畊（1.3克）之二氯甲烷（50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，所得粗產物用矽膠管柱層析（溶劑：己烷/乙酸乙酯=4/1至2/1)進行純化，付到4-二級丁氧幾基-1 _亞硝基六氫α比卩井（75§毫克，產率50°/〇呈黃色固體。 MS(APCI)m/z ： 216[M+H]+ # (2)在室溫，將鋅粉（l. 1克）加至上述步驟（i)所得化合物（730毫克）之曱醇（1〇毫升）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，混合物以二氣甲烷萃取》有機層以硫酸鈉乾燥，然後過;慮。濾液經真二/辰縮，彳于到1 _胺基_4_三級丁氧幾基六氫吡畊（730毫克，產率100%)呈淡黃色油狀物。火土參考例17 參考例3(1)所得化合物以如參考例1(5)至1(6)中所 318695 162 1378922 述之相同方法處理，得到3_羧基4-(2,4—二氯苯基）_5_ (4-氯苯基）-4-甲氧基-1H_吡唑（2.8克，產率89%)呈固體。 MS(APCI)m/z ： 397/399[M+H]+ 參考例18 參考例1(4)所得化合物（321毫克）與四氫硫代哌喃 4醇以如參考例2中所述之相同方法處理，得到^ — ^―氯苯基）-5普氯苯基）_3_乙氧隸+ (4_四氫硫代㈣基）氧基-1HH然後該產物以如參考例丨⑻中所述之相同方法處理，得到+ + + (4-四氫硫代㈣基）氧基鲁対（351毫克，呈固體。 MS(APCI)m/z ： 449/451[M+H]+ 參考例19 得相應起始物以如參考例1中 ,,r ^ 1 f所述之相同方法處理到1,5 -雙（4 -氯苯基）-4一甲蓮其ιυ 不土）4甲虱基-1H-吡唑一3一羧酸（3丨克，產率67%)呈固體。 MS(APCI)m/z ： 363/365[M+H]+ 參考例20至43 考' 中所述之相同方相應起始物以如參考例一法處理，得到如下表B1所示化合物 3J8695 163 1378922 表 Bl(l) R1 〇ch3 r2XHh 參考例號碼 R1 R2 物化性質等 20 Ί 〇c 固體 MS(APCI):347/349 [M+H]+ 21 ci-〇- 双固體 MS(APCI):381/383 [M+H]+ 22 h3co-^^~ 〇c 固體 MS(APCI):359/361 [M+H]+ 23 ci^Q- 〇ς 固體 MS(APCI):397/399 [M+H]+ 24 Cl—— a. 固體 MS(APCI):354/356 [M+H]+ 25 ci-〇- aF 固體 MS(APCI):347/349 [M+H]+ 26 nc~^3~ ίΧ 固體 MS(APCI):354/356 [M+H]+ 164 318695 1378922 表 Bl(2) 參考例號碼 R1 R2 物化性質等 27 F3CH〇- clJ〇C^j 固體 MS(ESI):429/431 [M-H]* 28 p3C-〇- 双固體 MS(ESI):413/415 [M-H]' 29 CX〇CH3 固體 MS(APCI):359/361 [M+H]+ 30 h3co2s-(^— acl 固體 MS(APCI):407/409 [M+H]+Medium and mix the mixture for 3 minutes at the same temperature. After warming to room temperature, brominated (vinyl)magnesium (7.7 ml of 〇. 97 M tetrahydrofuran solution) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 3 hr. Water and 1 N HCl aqueous solution were added to the reaction mixture. After stirring, the mixture was 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 purified by chromatography (solvent: hexane/ethyl acetate = 9 〇 /1 〇 to 85/15) to give bis(2-chlorophenyl)_5_(4_ Chlorophenyl)_4-methoxy-3-vinylcarbonyl-1H-pyrazole (780 mg, yield 70%) as colorless solid MS (APCI) m/z: 373/375 [Μ+Η]+ Reference Example 9 (1) Diphenylphosphorium azide (2 37 ml) and triethylamine (1.67 ml) were added to 3-carboxy-1-(2-phenylphenyl)-one under a nitrogen atmosphere. 5-(4-carboyl)-4-decyloxy-in-nit〇i_ (3.63 g) in toluene (3 mL) solution, then stir the mixture at the same temperature for 30 minutes at 8 (rc _ The mixture was stirred for 3 hours. After cooling to EtOAc, benzyl alcohol (1. <RTI ID=0.0></RTI> </RTI> <RTIgt; After room temperature, an aqueous solution of sodium hydrogencarbonate was added to the reaction mixture. After the mixture was removed, the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo. (solvent: already /ethyl acetate = 80/20 to 60/40) was purified to give 3-benzyloxycarbonylamino-1-(2-phenylphenyl)-5-(4-phenylphenyl)-4-methoxy Base-1H-pyrazole (4.15 g, yield 89%) is a pale yellow viscous material. MS (APCI) m/z: 468/470 [M+H]+ 318695 156 1378922 (2) 10% _ Carbon (400 mg) was added to a solution of EtOAc (EtOAc, m. Trichloropyrene and an aqueous solution of sodium hydrogencarbonate were added to the residue. After the dropping, the mixture was extracted with trichloromethane, and the extract was dried over magnesium sulfate, and then the mixture was concentrated in vacuo. Crystallization, followed by filtration to remove the resulting colorless precipitated material. The filtrate was concentrated in vacuo, and the obtained crude product was purified by column chromatography (solvent: hexane / ethyl acetate = 70 / 30 to 50 / 50) -Amino-1-(2-chlorophenyl)-5-(4-phenylphenyl)-4-oximeoxy-1 Η-β ratio (310 mg, yield 11%) as a pale yellow solid. (APCI)m/z : 334/336[M+H]+ Reference Example 10 (1) Sodium hydride (360 ml) was added to 1-benzyloxyzol-4-hydroxyhexahydroacridine (1.3 g) dimethylformamide (1 ml) under ice cooling. The mixture was stirred for 1 hour at room temperature under a nitrogen atmosphere. The mixture was ice-cooled, and the mixture 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 sulfuric acid and filtered. The filtrate was concentrated in vacuo, and the obtained crude product was purified by chromatography (solvent: hexane/ethyl acetate = 88/12 to 70/30) to give 1-benzyloxycarbonyl-4-methoxy Hydrogen acridine (622 mg, yield 45%) was obtained as a pale yellow oil. MS (APCI) m/z: 250 [M+H] + (2) 10% palladium-carbon (80 mg) was added to the above step (!) to obtain 318695 157 1378922 (620 mg) of sterol. The mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere (20 ml). The reaction mixture was filtered through a pad of EtOAc (EtOAc). MS (APCI) m/z: 116 [M+H] + Reference Example 11 (1) The dimethyl carboxylic acid tri-butyl ester (68.8 g) was added to the indolinyl-4-amino group under ice cooling. Hydrogen pyridine (57.1 g) in dichloromethane (3 ml) was dissolved in a solution, and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo and ethyl acetate and aqueous The mixture was stirred and the organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo, and the obtained crude crystals were washed with diethyl ether and then collected by filtration. The filtrate was concentrated in vacuo, and the obtained crude crystals were washed with diethyl ether and then collected by filtration. The collected crude crystals were combined, and dried to give the crystals of yt- syl- _ 4- (tris-butoxycarbonyl)-amino hexa- ar pyridine (83·2 g, yield = pale yellow solid. Lu MS (APCI) m/z: 291[M+H]+ (2) 20% palladium-carbon (17.5 g) was added to the above-mentioned step (丨) to obtain a solution of the character (72. 6 g) in the alcohol (350 ml) in hydrogen Under the environment, the mixture was stirred at room temperature. The reaction mixture was exchanged with a membrane transition vessel, and the mixture was concentrated to give 4-(tris-butoxycarbonyl)amine hexahydropyridine (48% yield: 96%). Light yellow solid. · Brother's MS (APCI) m/z: 201 [M+H] + (2) The resulting compound was then added to the above step under ice cooling (3) triethylamine (5.23 ml). One of the substances (5.0 g) in a solution of chlorhexidine (5 〇 ml), 318695 158 1378922 was added with chlorohydrazine (2.36 ml). The mixture was stirred at the same temperature for 3 minutes. After returning to room temperature, vacuum The reaction mixture was concentrated, and a mixture of trimethyl sulphate and aqueous sodium hydrogencarbonate was added to the residue. After stirring, (4) dried with magnesium and then filtered. The filtrate was concentrated in vacuo and 4-(tertiary butoxycarbonyl)amine-based oxime-ethylsulfonylamino-6, = baridine (6.99 g, yield 96%) was obtained as a pale yellow solid. /z: 291 [M+H] + (4) 4NHC1-dione (23.5 ml) and methanol (5 ml) were added to the compound obtained in the above step (3), and the mixture was stirred at room temperature overnight. Four air funan and 2 N sodium oxide water bath were added to the reaction mixture for neutralization. The mixture was saturated with potassium carbonate to extract the mixture, and the mixture was extracted with tetrahydrofuran. The extract was concentrated in vacuo, and the residue was dissolved in tri-butyl alcohol, then frozen. Drying gave 4-amino-1-ethylsulfonyl hexahydroacridine (4.20 g, yield 94%) as a pale red powder. ' MS (APCI) m/z : 193 [M+H]+ Lu Reference Example 12 (1) Adding sodium acetate (3.28 g) and amine hydrochloride (1 μg) to 4-tetrahydrothiopiperone (2.22 g) at room temperature (1) 〇〇ml)) The mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated in vacuo, and ethyl acetate was added to the residue with aqueous sodium hydrogen carbonate. After stirring, the mixture was extracted with ethyl acetate. The layers were washed with brine, dried over MgSO~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 'MS (APCI) m/z: 132 [M+H]+. Lithium aluminum hydride (289 mg) was added to the compound of the above-mentioned step (1) (5 mg) under ice cooling under a nitrogen atmosphere. In a test (iq ml) solution, the mixture was stirred at the same temperature for 30 minutes, followed by stirring at room temperature for 1 hour. Further, lithium aluminum hydride (72 mg) was added to the reaction mixture, and the mixture was stirred at 4 Torr for 2 hours. Water (1 ml) and 2N aqueous sodium hydroxide (1 mL) were added to the mixture. After stirring, the mixture was filtered with EtOAc (EtOAc)EtOAc. MS (APCI) m/z: 118 [M+H] + EMI37.1 </ RTI> A 20% aqueous solution of titanium trichloride (413 ml) was added to the water of 4-nitrosothio-morpholine (17.6 g). 5小时。 The mixture was stirred at room temperature for 3.5 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 φ water, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 4-amine thiophenoline (10. 14 g, yield: 64.5%) as pale yellow viscous. To a solution of the product (7. 57 g), m. m. The reaction mixture was vacuumed, and the crystals obtained were washed with isopropyl ether-hexane, and dried to give 4-amino thiophenoxaline hydrochloride (6.3 g, yield 63.6%) as a powder. MS (APCI)ra/z : 119 [M-HC1] + Reference Example 14 (1) 2N aqueous sodium hydroxide solution (7.6 liters) was added to 4,4-difluoro-6318695 160 1378922: pyridine hydrochloride ( In a solution of 2.0 g) of water (32 ml), the mixture was stirred at room temperature for 1 hour. Sodium nitrite (175 g) was added to the reaction mixture under ice cooling: then acetic acid (1.27 ml) was added. The mixture was stirred at room temperature ^4. Next, an aqueous solution of sodium hydrogencarbonate was added and stirred, and the mixture was extracted with chloroform to dryness with sulphate and then filtered. The filtrate was concentrated in vacuo, and the crude product was purified using silica gel column chromatography (solvent: hexane/ethyl acetate = 4/1) to give 4,4-difluoro-1-nitros hexahydropyridine (1) 89 g, yield 9 9%) was a pale yellow solid. _ MS(APCI) m/z: 151 [M+H] + (2) EtOAc (EtOAc, EtOAc) The turbulent mixture was then heated for 1 hour. Water was added to the reaction mixture under ice cooling, and then the turbulent mixture was heated for 3 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 stirring, the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to give EtOAc EtOAc EtOAc (EtOAc: EtOAc MS (APCI) m/z: 137 [M+H] + </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> In the solution, the mixture was stirred at 8 ° C for 2 hours. A 2N aqueous solution of sodium hydroxide (13 mL) was added to the mixture and the mixture was stirred and extracted with trichloromethane. The mixture was extracted with chloroform. The extract was dried over magnesium sulfate and then filtered. The filtrate was concentrated in vacuo to give 318 695 161 1378922 crude product using silica gel column chromatography (solvent: hexane/ethyl acetate = 70/30 to 0/100) and NH-purine column chromatography (chromatorex NH-Shi Xisheng) , manufactured by Fuji Silicia Chem., solvent: hexane / ethyl acetate = 7 〇 / 3 〇 to 60 / 40) Purification 'to give 3-amino-indole-(2-chlorophenyl) -Methoxy-1?-n-biazole (353 mg 'yield 26%) as a pale yellow solid. MS (APCI) m / z : 334 / 336 [M + H] + Reference Example 16 Lu (1) nitrous acid secondary butyl g (3.5 ml) was added to the 4 - 3 -butoxy-hexyl hexahydro In a solution of plough (1.3 g) in dichloromethane (50 ml), the mixture was then heated overnight. The reaction mixture was concentrated in vacuo, and the obtained crude product was purified by EtOAc EtOAc EtOAc EtOAc EtOAc Nitrohexahydro-α ratio 卩 well (75 § mg, yield 50 ° / 〇 yellow solid. MS (APCI) m / z: 216 [M + H] + # (2) at room temperature, zinc powder ( l. 1 g) was added to a solution of the compound obtained in the above step (i) (730 mg) in decyl alcohol (1 ml), and then, under ice cooling, acetic acid (10 ml) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and an aqueous solution of sodium hydrogencarbonate was added to the filtrate for alkalization. After stirring, the mixture was extracted with dioxane methane. The organic layer was dried over sodium sulfate and then passed over. To 1 -amino group - 4 - tertiary butoxyl hexahydropyrazine (730 mg, yield 100%) is a pale yellow oil. Fire soil reference example 17 Reference compound 3 (1) obtained as reference Treated in the same manner as described in Examples 1 (5) to 1 (6), 318695 162 1378922, to give 3-carboxyl 4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methoxy Base-1H_pyrazole (2.8 g, produced The yield was 89%) as a solid. MS (APCI) m/z: 397 / 399 [M+H] + Reference Example 18 The compound obtained in Reference Example 1 (4) (321 mg) and tetrahydrothiopentanol Treated in the same manner as described in Reference Example 2 to give 2-(chlorophenyl)-5-chlorophenyl)_3_ethoxyxane (4-tetrahydrothio(tetra)thio)oxy-1HH and then the product Treated in the same manner as described in Reference Example (8) to give + + + (4-tetrahydrothio(tetra)thio)oxy ruthenium (351 mg, as a solid. MS (APCI) m/z: 449/451 [M+H]+ Reference Example 19 The corresponding starting material was treated in the same manner as described in Reference Example 1, r ^ 1 f to 1,5-bis(4-chlorophenyl)-4-methyl Its υ υ ) ) 4 4 4 4 4 4 4 4 4 4 4 4 4 4 。。。。。。。。。。。。. MS (APCI) m / z : 363 / 365 [M + H] + Reference Examples 20 to 43 The same starting materials as described in the 'Record' were treated as in Reference Example 1, to give the compound 3J8695 shown in Table B1 below. 163 1378922 Table Bl(l) R1 〇ch3 r2XHh Reference example number R1 R2 Physicochemical properties, etc. 20 〇〇c Solid MS (APCI): 347/349 [M+H]+ 21 ci-〇- Double solid MS (APCI): 381/383 [M+H]+ 22 h3co-^^~ 〇c Solid MS (APCI): 359/361 [M+H]+ 23 ci^Q- 固体 Solid MS (APCI): 397/399 [M +H]+ 24 Cl—— a. Solid MS (APCI): 354/356 [M+H]+ 25 ci-〇- aF Solid MS (APCI): 347/349 [M+H]+ 26 nc~^ 3~ ίΧ Solid MS (APCI): 354/356 [M+H]+ 164 318695 1378922 Table Bl(2) Reference example number R1 R2 Physicochemical properties, etc. 27 F3CH〇- clJ〇C^j Solid MS (ESI): 429 /431 [MH]* 28 p3C-〇-Dual solid MS (ESI): 413/415 [MH]' 29 CX〇CH3 Solid MS (APCI): 359/361 [M+H]+ 30 h3co2s-(^— Acl solid MS (APCI): 407/409 [M+H]+

165 318695 1378922 表 Bl(3)165 318695 1378922 Table Bl(3)

R1 pR3 O-d 參考例號碼 R1 R3 物化性質等 31 Cl—— o 固體 MS(APCI):433/435 [M+H]+ 32 α分 -(CH2)2SCH3 粉末 MS(APCI):423/425 [M+H]+ 33 -chf2 粉末 MS(APCI):433/435 [M+H]+ 34 ci-〇- -c2h5 固體 MS(APCI):377/379 [M+H]+ 35 -C2H5 固體 MS(APCI):411/413 [M+H]+ 36 Qr -(CH2)2OCH3 固體 MS(APCI):407/409 [M+H]+ 37 -(CH2)2OCH3 固體 MS(APCI):441/443 [M+H]+ 38 ciH0^ -c3h7 固體 MS(APCI):391/393 [M+H]+ 166 318695 1378922R1 pR3 Od Reference example number R1 R3 Physical and chemical properties, etc. 31 Cl—— o Solid MS (APCI): 433/435 [M+H]+ 32 α-(CH2)2SCH3 Powder MS (APCI): 423/425 [M +H]+ 33 -chf2 powder MS (APCI): 433/435 [M+H]+ 34 ci-〇- -c2h5 solid MS (APCI): 377/379 [M+H]+ 35 -C2H5 solid MS ( APCI): 411/413 [M+H]+ 36 Qr -(CH2)2OCH3 Solid MS (APCI): 407/409 [M+H]+ 37 -(CH2)2OCH3 Solid MS (APCI):441/443 [ M+H]+ 38 ciH0^ -c3h7 Solid MS (APCI):391/393 [M+H]+ 166 318695 1378922

表 Bl(4) cl^ CAc 參考例號碼 R3 物化性質等 39 9 ,ch3 δΛ：Η3 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 -VvCH3 h3c^ 43 參考例44 冰冷卻下，攪拌1-胺基環己基羧酸（600毫克）之四氫 σ夫喃-曱醇溶液。然後逐滴加入（三曱基石夕烧基）重氮甲烧溶液（4. 2毫升）’攪拌混合物一夜。真空濃縮反應混合物，將***-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-甲氧幾·基環己烧。（423毫克’產率5 2%)呈白色粉末。 167 318695 1378922 MS(APCI)m/z : 158[M+H]+ 參考例4 5 (1) 將四氫硫代哌喃-4-酮（丨〇克）之甲醇（22毫升）溶液加至氰化钟（5. 6克）與氣化銨（5. 克）之水（17毫升）溶液中，然後混合物加熱廻流一夜。冷卻至室溫後.，將1Ν 氫氧化鈉水溶液加至反應混合物中。混合物以***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***溶液中加入4N HC1_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& 6克，產率88%)呈無色固體。 MS(ESI)m/z ： 143[M+H]+ (2) 使上述步驟（丨）所得化合物（1〇· 5克）之fjci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。 0MS(ESI)m/z ： 162[M+H] + (3) 將亞硫酿氯（5 · 7毫升）逐漸滴加至上述步驟（2)所得化合物（10. 6克）之甲醇（70毫升）溶液中，然後加熱過流混合物一夜。冷卻至室溫後，真空濃縮反應混合物。殘留物以乙酸乙酯-***清洗’然後加入1N氫氧化鈉水溶液。混合物以三氣曱烷萃取，有機層以硫酸鎂乾燥，然後過淚。遽液經真空濃縮’得到4-胺基-4-曱氧羰基四氫硫代派喃 (3. 83克，產率39%)呈棕色油狀物。 MS(ESI)m/z ： 176[M+H]+ 318695 168 1378922 (4)將間氯過苯曱酸（394毫克）逐漸加至上述步驟（ -所得化合物（100毫克）之二氣甲烷（4毫升）溶液中，室溫拌混合物30分鐘。將甲醇（4毫升）加至反應混合物中咖= 後，漸加入PL-HC〇3 MP(巨多孔性聚合物鍵結等當量Hc〇= 樹脂（〇· 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··己燒/ = 酸乙酯=30/70至〇/1〇〇)進行純化，得到4_胺基_4-甲1羰基-ι，ι-二側氧基四氫硫代哌喃（38毫克，產率32%) 攀固體。 …、巴 MS(ESI)m/z : 208[Μ+ΗΓ 參考例4 6 相應物質以如參考例45(1)至45(3)中所述之相同方法處理，仔到4-胺基-4-甲氧羰基四氫哌喃呈白色晶體。 MS(ESI)m/z : 16〇[Μ+Η]+ 參考例47 • 在室溫，將2Ν(三甲基矽烷基）重氮甲烷-***溶液 ^•8毫升）滴加至卜三級丁氧羰基_4_羧基_4_苯基六氫吡欠（1.53克）之四氫呋喃（2毫升）_甲醇（2毫升）溶液中，在相同溫度下授拌現合物3小時。將餘和碳酸氫鋼水溶液加至反應混合物中並授拌，混合物以三氯甲烧萃取。萃取液以硫酸，乾燥，然後過遽。濾液經真空濃縮，所得粗產物用石夕膠官柱層析（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。比°定（1. 31克，產率82%)呈無色固體。 318695 169 1378922 MSCAPCI)m/z ： 220[M+H]+ (2)將4N flC卜二Of烷（3毫升）加至上述步驟（u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 HC卜二卩f烷（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^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（172微升）加入殘留物中，室溫鲁攪拌混合物一夜。將飽和碳酸氫鈉水溶液加至反應混合物中並攪拌，混合物以三氣曱烷萃取。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。冰冷卻下，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，將飽和碳酸氫鋼水溶液加至濾液中。攪拌後，混合物以三氯曱烧萃取，籲萃取液以硫酸鎂乾燥，然後過濾。濾液經真空濃縮，得到 1-胺基-4-甲氧羰基-4-苯基六氫吡啶（389毫克，產率83%) 呈無色固體。 MS(APCI)m/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-4-苯曱基六氩。比啶（495毫克）之水（5毫升）溶液中，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攪拌混合物，混合物以三氯曱烷萃取。萃取液經真 170 318695 1378922 空漠縮，所得粗產物用石夕耀管柱層析（溶劑：己燒/乙酸乙醋-一關5至80/20)進行純化，然後乾燥，得到[乙氧幾基-4-苯甲基-卜亞破基六氫吼咬（565毫克，產率呈無色固體。冰冷卻下’將鋅粉（654毫克）加至該產物⑽ 毫克）之甲醇（3毫升）溶液中，然後加入乙酸（3毫升），室溫授拌混合物3小時。過敍應混合物，_經真空濃縮。將飽和碳酸氫納水溶液與三氣甲院加至殘留物中並授掉混合物’混合物以三氯甲院萃取。萃取液以硫酸鎮乾燥，然後過濾。濾液經真空濃縮，得到卜胺基_4_笨甲基_4—乙'氧羰基六氫吡啶（508毫克，產率97%)呈無色黏稠物。虱 MS(APCI)m/z ： 263[M+H]+ 參考例49 參考例4(1)所得化合物以如參考例丨（5)至丨（6)中戶述之相同方法處理，得到3-綾基—氯苯基）_5 —(^2 氟甲基苯基）-4-甲氧基-1H-吼唑（4. 1克，產率85%) 1 固體。 …、色 MS(APCI)m/z ： 397/399[M+H]+ 參考例50至52 相應物質以如參考例1(1)至1(4)中所述之相同處理，然後所得產物以如參考例4(2)中所述之相同 ^ 理，得到如下表B2所示化合物。 '、處 318695 171 1378922 表B2Table Bl(4) cl^ CAc Reference example number R3 Physicochemical properties, etc. 39 9 ,ch3 δΛ:Η3 Solid MS (APCI): 456/458 [M+H]+ 40 -chf2 In the following steps, each compound is used as a starting material. Used without further purification. 41 42 -VvCH3 h3c^ 43 Reference Example 44 A solution of 1-aminocyclohexylcarboxylic acid (600 mg) in tetrahydro sulphur-furanol was stirred under ice cooling. Then, a solution of triazolyl (dichlorocarbazide) (4.2 ml) was added dropwise, and the mixture was stirred overnight. The reaction mixture was concentrated in vacuo and diethyl ether-hexane (1/1). Then, 4 Μ of HC1-ethyl acetate (1. 05 ml) was added, and the precipitate was collected by filtration, and then dried to give 1-amino-1-methoxy- hexane. (423 mg' yield 52%) was a white powder. 167 318695 1378922 MS(APCI) m/z : 158 [M+H] + Reference Example 4 5 (1) A solution of tetrahydrothiopyran-4-one (methanol) in methanol (22 ml) Cyanide clock (5.6 g) and a solution of ammonium sulfate (5 g) in water (17 ml), then the mixture was heated and turbulent overnight. After cooling to room temperature, a 1 Torr 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 <RTI ID=0.0> The precipitate was collected by filtration to give 4-amino-4-cyanotetrahydrothiopyran hydrochloride (hexane & 6 g, yield 88%) as a colorless solid. MS (ESI) m/z: 143 [M+H] + (2) The obtained compound (1 〇·5 g) of fjci aqueous solution (500 ml) was heated under reflux for one night. 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. 0MS(ESI)m/z: 162 [M+H] + (3) A solution of the compound obtained in the above step (2) (10. 6 g) of methanol (70). In ML) solution, then heat the overcurrent mixture overnight. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was washed with ethyl acetate-diethyl ether. The mixture was extracted with trioxane, and the organic layer was dried over magnesium sulfate and then passed. The hydrazine was concentrated in vacuo to give 4-amino-4-indoleoxycarbonyltetrahydrothiopyran (3. 83 g, yield 39%) as a brown oil. MS (ESI) m / z: 176 [M+H] + 318 695 168 1378922 (4) Gradually added m-chloroperbenzoic acid (394 mg) to the above procedure (-the obtained compound (100 mg) of di- methane ( 4 ml) solution, mix the mixture for 30 minutes at room temperature. Add methanol (4 ml) to the reaction mixture, then add PL-HC〇3 MP (macroporous polymer bond equivalent Hc〇= resin) (〇·9 g), the mixture was stirred overnight. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The obtained crude product was chromatographed on a silica gel column (solvent·············· Purification was carried out to give 4-amino-4-methyl-1-carbonyl-m, i-di-oxytetrahydrothiopyran (38 mg, yield 32%) as a solid. ..., MS (ESI) m /z : 208 [Μ + ΗΓ Reference Example 4 6 The corresponding substance was treated in the same manner as described in Reference Examples 45(1) to 45(3), to 4-amino-4-methoxycarbonyltetrahydroperidine. The crystals were white crystals. MS (ESI) m/z: 16 〇 [Μ+Η]+ Reference Example 47 • 2 Ν (trimethyl decyl) diazomethane-diethyl ether solution (•8 ml) was dropped at room temperature Add to the third grade butoxycarbonyl _4_carboxy_4_phenylhexahydro In a solution of pyridinium (1.53 g) in tetrahydrofuran (2 ml)-methanol (2 ml), the mixture was stirred at the same temperature for 3 hours. The remaining aqueous solution of hydrogencarbonate was added to the reaction mixture and mixed. The extract was extracted with trichloromethane. The extract was dried with sulphuric acid, and then filtered. The filtrate was concentrated in vacuo and the crude product was chromatographed on EtOAc (solvent: hexane / ethyl acetate = 90/10 to 85 / 15) Purification was carried out to give tributyloxycarbonyl-4-methoxycarbonyl-4-phenylhexahydropyrene as a colorless solid (1. 31 g, yield 82%). 318 695 169 1378922 MSCAPCI) /z: 220 [M+H] + (2) To a solution of the obtained compound (dichlorohexane (2 ml). 4N HCl dioxane (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 trichloromethane. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and water (5 mL). Sodium nitrite (276 mg) and acetic acid (172 μl) were added to the residue, and the mixture was stirred overnight at room temperature. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and stirred, and the mixture was extracted with trioxane. After concentrating in vacuo, the obtained crude material was purified by EtOAc EtOAc EtOAc EtOAc Under ice cooling, zinc powder (654 mg) was added, followed by dropwise addition of acetic acid (3 ml), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered, and a saturated aqueous solution of hydrogen carbonate was added to the filtrate. After stirring, the mixture was extracted with trichlorosulfonium, and the extract was dried over magnesium sulfate and then filtered. The filtrate was concentrated in vacuo to give 1-amino-4-methoxycarbonyl-4-phenylhexahydropyridine (389 mg, yield: 83%) as a colourless solid. MS (APCI) m/z: 235 [M+H] +. s. 48. Sodium nitrite (276 s) and acetic acid (201 liters) were added to 4- ethoxycarbonyl-4-phenylhydrazinium hex argon. The mixture was stirred at room temperature overnight in a solution of pyridine (495 mg) in water (5 mL). A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and the mixture was stirred, and the mixture was extracted with dichloromethane. The extract was subjected to air shrinkage by the true 170 318695 1378922, and the obtained crude product was purified by Shi Xiyao column chromatography (solvent: hexane/acetic acid vinegar - 5 to 80/20), and then dried to obtain [ethoxy group]. Benzyl-4-benzyl-bupyridyl hexahydropurine (565 mg, yield as a colorless solid. EtOAc (3 mL). Into the solution, acetic acid (3 ml) was then added, and the mixture was stirred at room temperature for 3 hours. The mixture should be clarified, _ concentrated in vacuo. A saturated aqueous solution of sodium hydrogencarbonate and a trisole were added to the residue and the mixture mixture was subjected to extraction with trichloromethane. The extract was dried with sulfuric acid and then filtered. The filtrate was concentrated in vacuo to give the title compound: </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt;虱MS(APCI)m/z : 263 [M+H]+ Reference Example 49 The compound obtained in Reference Example 4 (1) was treated in the same manner as described in Reference Examples (5) to (6) to give 3 - mercapto-chlorophenyl)_5 - (^2 fluoromethylphenyl)-4-methoxy-1H-indazole (4.1 g, yield 85%) 1 solid. ..., color MS (APCI) m/z : 397/399 [M+H] + Reference Examples 50 to 52 The corresponding materials were treated in the same manner as described in Reference Examples 1 (1) to 1 (4), and then the obtained product The compound shown in the following Table B2 was obtained by the same procedure as described in Reference Example 4 (2). ', 318695 171 1378922 Table B2

參考例號碼 R1 R2 物化性質等 50 _〇ςι 白色固體 MS(APCI):399/401 [M+H]+ 51 白色固體 MS(APCI):467/469 [M+H]+ 52 F3C-0- 淡黃色固體 MS(APCI):451/453 [M+H]+ 參考例53 (1)冰冷卻下，將乙胺鹽酸鹽（2. 69克）之水（3毫升）擊溶浪滴加至卜笨曱基六氫吡啶-4-酮（5. 69克）之乙醇（4. 2 毫升）溶液中’然後滴加入氰化鉀（2. 〇4克）之水（7毫升）溶液，室溫攪拌混合物一夜。將異丙醇（丨〇毫升）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，授拌混合物然後萃取。有機層以二氣甲烷（30笔升）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（⑽毫升）加 =物。遽液經真空濃縮，得到卜苯甲基+氛基+ 土 n定（7.3克，產率99.7%)呈黃色油狀物。 318695 172 1378922 MS(APCI)m/z : 244[M+H]+ (2 )冰冷部下，以超過2 Q八户性 ^ 20刀鐘之恰間，將濃硫酸（4. 3 毫升）滴力口至上述步驟⑴所得化合物（1.38幻之二氯曱炫（4:8毫升）溶液中，室溫㈣混合物—夜。自反應混合物中萃取出有制，然後冰冷卻下，以超過丨小時之“時^，將28%氨水溶液滴加至有機層中。將水（12毫升）加至混合物中，混合物以二氣Ψ料取。有機層以鹽水清洗了以硫酸鎂乾燥後過濾。濾液經真空濃縮，得到卜苯曱基一4一胺甲醯基-4-(乙胺基）六氫吡啶（144克，產率97%)呈淡黃色固體。 ' MS(APCI)m/z ： 262[M+H]+ (3)將20%虱乳化Ιε -碳加至上述步驟（2)所得化合物 (1·4克）之甲醇（19毫升）溶液中，然後在氮氣環境下室溫授掉〉tt*合物一仪。用碎澡土過遽反應混合物，濾、液經直空 /辰細。將異丙_( 3 0毫升）加至濃縮液中，過濾收集所沉殿鲁晶體’乾燥後得到4-胺曱酿基-4-乙胺基六氫。比。定（〇. 84 克，產率91%)呈淡黃色固體。 MS(APCI)ra/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/CHO#C3(Euroscreen公司）培養基：F-12(GIBCO#1 1765-062) ’ 10%胎牛血清，抗 173 318695 1378922 • 生素[400微克，遺傳黴素（Geneticin) - (GIBCO#11811-〇31) 緩衝溶液A : 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）、％(：12(5毫莫耳濃度）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磷酸緩衝溶液 (x2)清洗，然後在冰冷卻或4ΐ：(以下步驟亦在相同溫度下 •進行）下添加緩衝溶液Α(2毫升）。用細胞到棒收集細胞，用微吸取官型超音波振盪器振盪20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（43GGG X g，60分鐘）。將產生之沉殺小粒懸浮在緩衝溶液A中，用波特氏^的优^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 φ材料：緩衝溶液B : 50毫莫耳濃度tris_HCI(pH7 5)，含有伸乙基二胺四乙酸（2.5毫莫耳濃度）、MgCM5毫莫耳 /辰度）與牛血清白蛋白（2毫克/亳升’無脂肪酸’ SIGMA-A7030) 缓衝溶液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）、MgCi2(5毫莫耳濃度）與牛血清白蛋白（2毫克/毫升，無㈣酸， SIGMA-A7906) 318695 174 1378922 ’ 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//z 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 )之每一格孔襄有緩衝溶液B(140微升）、每一試驗化合物二甲亞砜溶液 _ (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3(TC培養混合物90 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（；（2〇〇微升5(1〇)清洗女析盤，然後於50C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鲁（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ICso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。式驗化合物之1C5。值顯不在表C1。當中，表中符號定義如下： + : 100奈莫耳濃度<ic5〇<500奈莫耳濃度 + + : 10奈莫耳濃度<IC5t)<100奈莫耳濃度 + + + : IC5D<10奈莫耳濃度 318695 175 1378922 表Cl 試驗化合物 -一耳濃度）實施例4化合物 ++ 實施例3 6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13 4化合物 ------- ++ 實施例14 8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3 0 7化合物 +++ 實施例3 3 9化合物 ___ Ή 工業上應用媒介^ =，化合物⑴可用於治療及/或預防各種CB1受體 ^亦可m料純__症。本發明化合物 u J 7Γ 了用於戒除慢性治療本發明化合物π]可用：又、或樂物濫用。而且，劑。、作為止痛活性增強藥劑或戒煙藥 318695 176Reference example number R1 R2 Physicochemical properties, etc. 50 _〇ςι White solid MS (APCI): 399/401 [M+H]+ 51 White solid MS (APCI): 467/469 [M+H]+ 52 F3C-0- Light yellow solid MS (APCI): 451 / 453 [M+H] + Reference Example 53 (1) Under ice cooling, ethylamine hydrochloride (2.69 g) in water (3 ml) was applied dropwise. a solution of potassium cyanide (2. 4 g) in water (7 ml) was added dropwise to a solution of bromide hexahydropyridin-4-one (5.69 g) in ethanol (4.2 ml). The mixture was stirred at room temperature overnight. Isopropanol (丨〇 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 extracted. The organic layer was diluted with dioxane (30 liters), washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to add isopropanol ((10) mL). The mash was concentrated in vacuo to give the title compound: EtOAc (yield: 7.3 g, yield: 99.7%) as a yellow oil. 318695 172 1378922 MS(APCI)m/z : 244[M+H]+ (2) Under the icy part, the concentrated sulfuric acid (4.3 ml) was dropped with more than 2 Q eight households ^ 20 knives. Oral to the compound obtained in the above step (1) (1.38 phantom dichloropurine (4:8 ml) solution, room temperature (tetra) mixture - night. Extracted from the reaction mixture, and then cooled under ice for more than 丨 hours "When, a 28% aqueous ammonia solution was added dropwise to the organic layer. Water (12 ml) was added to the mixture, and the mixture was taken up in two portions. The organic layer was washed with brine, dried over magnesium sulfate and filtered. Concentration in vacuo gave phenylphenyl-tetramethylpyridin-4-(ethylamino) hexahydropyridine (144 g, yield 97%) as a pale yellow solid. < MS (APCI) m/z: 262 [M+H]+ (3) 20% hydrazine emulsified ε ε-carbon was added to a solution of the compound (1·4 g) obtained in the above step (2) in methanol (19 ml), and then allowed to stand at room temperature under nitrogen atmosphere. 〉 tt* compound one instrument. The reaction mixture was passed through a crushed bath, filtered, and the liquid was passed through a straight space/next. The isopropyl _ (30 ml) was added to the concentrate, and the crystal of the Shen Dianlu was collected by filtration. After drying, the 4-amine bromo-4-ethylamino hexahydro group was obtained as a pale yellow solid (yield: 84 g, yield 91%). MS (APCI) s / s: 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/CHO#C3 (Euroscreen) Medium: F-12 (GIBCO #1 1765) -062) '10% fetal bovine serum, anti-173 318695 1378922 • Biotin [400 μg, Geneticin - (GIBCO #11811-〇31) Buffer solution A: 50 millimolar concentration tris-HCl (pH7 5), containing ethylenediaminetetraacetic acid (2.5 millimolar concentration), % (: 12 (5 millimolar concentration) and sucrose (200 millimolar concentration) Step: Culture the receptor in the above medium The cells were washed with phosphate buffer solution (x2) and then added with buffer solution (2 ml) under ice cooling or 4: (the following steps were also performed at the same temperature.) Collect cells with cells to the rod, and use micro-absorbers The ultrasonic oscillator oscillates for 20 seconds (pulse on: 2 seconds, pulse off: 1 second) 'then centrifugation (500 xg, 15 minutes). Separate the supernatant, then leave (43GGG X g, 60 minutes). The resulting granules were suspended in buffer solution A and homogenized by a Boter's excellent homogenizer. An equal volume of 80% glycerol was added to the homogenate. And then in _8〇.〇Save. (2) CB1 receptor binding assay step φ material: buffer solution B: 50 millimolar concentration tris_HCI (pH 7 5), containing exoethyldiaminetetraacetic acid (2.5 millimoles) Concentration), MgCM5 mM/min) and bovine serum albumin (2 mg/μl 'no fatty acid' SIGMA-A7030) buffer solution C: 50 millimolar concentration tris-HCl (pH 7.5), containing Ethylenediaminetetraacetic acid (25 mM concentration), MgCi2 (5 mM concentration) and bovine serum albumin (2 mg/ml, no (tetra) acid, SIGMA-A7906) 318695 174 1378922 'coating solution : 3% ethylimine polymer - radioactive ligand: [3H]-CP55940 [30 nmer concentration (nM) / 7992 decay per minute / microliter (dpm / / z 1)] Buffer solution B was diluted with 8.3 micromolar concentration (#M) radioligand solution to prepare method: The assay plate (96 cells, Costar No. #3371) was buffered in each well. B (140 μl), each test compound dimethyl sulfoxide solution _ (20 μl, final concentration 〇. 1%), radioactive ligand (2 〇 microliter) and membrane preparation (20 μL, 〇. 5 μg / 20 μl), then 3 (TC culture mixture for 90 minutes to carry out the 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 female disc was washed with a buffer solution (; (2 〇〇 microliter 5 (1 〇)), then dried at 50 ° for 1 hour, and Microscinti 40 (40 μL) was added to each well. The radiolabel was combined to flash Counter Lu (TopCount NXT, manufactured by Packard) was quantified. The ICso value of each test compound for binding of the radioligand to the CB1 receptor was calculated using Graphpad Prism 3.02 based on the quantified radiolabel activity. (3) Results. The 1C5 value of the test compound is not shown in Table C1. Among them, the symbols in the table are defined as follows: + : 100 nanomolar concentration <ic5〇<500 nanomolar concentration + + : 10 nanomolar concentration <IC5t) <100 Nymol concentration + + + : IC5D < 10 Nymol concentration 318695 175 1378922 Table Cl Test compound - one ear concentration) Example 4 compound ++ Example 3 6 compound ++ Example 54 compound ++ Implementation Example 5 5 Compound ++ Example 18 Compound - _ _ + + Example 13 4 Compound ------- ++ Example 14 8 Compound Example 216 Compound _ ++ Example 276 Compound _ ++ Implementation Example 279 Compound ++ Example 288 Compound + Example 3 0 7 compound +++ Example 3 3 9 compound ___ Ή Industrial application Medium ^ =, compound (1) can be used for the treatment and / or prevention of various CB1 receptors ^ can also be pure __ disease. The compound of the present invention, u J 7 , is used to quit chronic treatment. The compound of the present invention π] is usable: or, or a substance abuse. Moreover, the agent. As an analgesic activity enhancer or smoking cessation drug 318695 176

Claims

13789221378922

、申請專利範圍：種式[I]之吡唑化合物或其醫藥上可接受第 095138705 獍4 101年6月27曰长 f·利申請案頁公告本Patent application scope: Pyrazole compound of the formula [I] or its medicinal acceptable No. 095138705 獍4 June 27, 2003 f long f·li application page Announcement

[I] 式中，In the formula [I],

R1為經一至二個選自鹵素原子與三鹵素-(：14烷基之基取代之苯基； _ 2 R為經一至二個_素原子取代之苯基； R為0-4烷基氧基-C!-4烷基或視需要經一至三個鹵素原子取代之烷基 E為下列式（i)之基團：R1 is a phenyl group substituted with one to two halogen atoms and a trihalo-(:14 alkyl group; _ 2 R is a phenyl group substituted with one to two _ atoms; R is 0-4 alkyl oxygen Alkyl-C!-4 alkyl or an alkyl group E optionally substituted with one to three halogen atoms is a group of the following formula (i):

Q為單鍵， Q2為單鍵或 Cl-4伸院基， R4為視需要經一至三個選自側氧基或式_NH(R6)所示基團之基取代之飽和或不飽和5至6員雜單環基， 318695 (修正本) R6為（i)視需要經一至三個選自下列者所構成之群組的基取代之飽和或不飽和5至7員雜單環基：鹵素原子、視需要經一至三個_素原子取代之Cl-4烷基、視需要、、及至二個函素原子取代之苯基與酿基，（ϋ)視需要、左至一個Cl-4炫基取代之胺基。 177 1378922 第09S1387〇5號專利申請案 Ο &由含主击| 1〇1年6月27曰修正替換頁' . 明專利範圍第1項之η比唑化合物或其醫藥上可接受之鹽類，其中， R為、-!選自氧原子與三氟_匕_3烧基之基取代之苯基； R2為經一至二個選自氯原子或氟原子之基取代之苯基； R3為視需要經一至三個選自氟原子或Ci 4烷基氧基之基取代之Ch烷基； R4為（i)視需要經一至二個側氧基取代之不飽和5 至6員雜單環基或（ii)式-NH(R6)之基團； R為（1)視需要經一至三個選自於下列基取代之飽和或不飽和5至6員雜單環基：（a)氟原子、（b)視需要經一至二個氟原子取代之_3烧基、（c)視需要經一至二個選自於氣原子與氟原子取代之苯曱醯基和（d)視需要經一至二個選自於氣原子與氟原子取代之苯基或（Η) 雙（Cm烷基）胺基。 3. —種選自下列所構成群組之化合物或其醫藥上可接受之鹽類： 1-(2-氯苯基）-5-(4-氯苯基）-4-甲氧基-3-[Ν-(1-氮雜環庚基）胺甲醯基]-1H-吡唑； 1-(2-氯苯基）-5-(4-氯苯基）-4-甲氧基-3-[N-(4-四氫哌喃基）胺甲醯基]-1H-吡唑； 1-（2-氣苯基）-5-(4-氣苯基）-4-乙氧基-3-[N-(N-嗎福啉基）胺曱醯基]-1H-吡唑； 318695 (修正本) 178 1378922 第095138705號專利申請案 1〇1年6月27曰修正替換頁 1-(2-氯苯基）-5-(4-氯苯基）-4-曱氧基-3-[N-(N-六氫 * 吡啶基）胺甲醯基]-1H-吡唑； 1-(2-氣苯基）-5-(4-氯苯基）-4-曱氧基-3-[N-(N-嗎福淋基）胺甲釀基]_1Η-π比嗤； 1-(2-氣苯基）-5-(4-氣笨基）-4-曱氧基-3-[Ν-(1-σ比咯咬基）胺曱酿基]-1Η-π比嗤； 1-(2-氯苯基）-5-(4-氣笨基）-4-乙氧基-3-[Ν-(Ν-六氫吡啶基）胺f醯基]-1Η-吡唑；Q is a single bond, Q2 is a single bond or a Cl-4 stretching base, and R4 is a saturated or unsaturated group which is optionally substituted with one to three groups selected from a pendant oxy group or a group represented by the formula _NH(R6). To 6 members of a heterocyclic ring group, 318695 (amendment) R6 is (i) a saturated or unsaturated 5 to 7 membered heteromonocyclic group substituted by one or three groups selected from the group consisting of: a halogen atom, a Cl-4 alkyl group substituted with one to three _ prime atoms, if necessary, and a phenyl group and a aryl group substituted with two atomic atoms, (ϋ) as needed, left to one Cl-4 Amine-substituted amine group. 177 1378922 Patent application No. 09S1387〇5 amp & by the main attack | 1 June 1st, 27th revised replacement page '. The patent scope of the first item of the η-biazole compound or its pharmaceutically acceptable salt And R is a phenyl group selected from the group consisting of an oxygen atom and a trifluoro-indole-3-alkyl group; R2 is a phenyl group substituted with one to two groups selected from a chlorine atom or a fluorine atom; R3 a C alkyl group substituted with one to three groups selected from a fluorine atom or a Ci 4 alkyloxy group as desired; R 4 is an unsaturated 5 to 6 member monomer which is (i) optionally substituted with one to two pendant oxy groups. a ring group or (ii) a group of the formula -NH(R6); R is (1) optionally one or three saturated or unsaturated 5 to 6 membered heteromonocyclic groups selected from the group consisting of: (a) a fluorine atom, (b) a _3 alkyl group substituted by one or two fluorine atoms as needed, (c) one to two phenyl fluorenyl groups selected from a gas atom and a fluorine atom, if necessary, and (d) as needed One to two phenyl or (Η) bis(Cm alkyl)amine groups selected from the group consisting of a gas atom and a fluorine atom. 3. A compound selected from the group consisting of pharmaceutically acceptable salts thereof: 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3 -[Ν-(1-azepanyl)amine-carbamoyl]-1H-pyrazole; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy- 3-[N-(4-tetrahydropiperidyl)aminemethanyl]-1H-pyrazole; 1-(2-phenylphenyl)-5-(4-phenylphenyl)-4-ethoxy -3-[N-(N-morpholinyl)amine hydrazino]-1H-pyrazole; 318695 (amendment) 178 1378922 Patent application No. 095138705 1〇1月627曰 Revision replacement page 1 -(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-[N-(N-hexahydro*pyridyl)aminemethanyl]-1H-pyrazole; 1-(2-Phenylphenyl)-5-(4-chlorophenyl)-4-indolyl-3-[N-(N-moffipyl)amine-based base]_1Η-π 嗤; 1-(2-Phenylphenyl)-5-(4-oxaphenyl)-4-decyloxy-3-[indole-(1-σ-rheptyl)amine oxime]-1Η-π ratio 1-(2-chlorophenyl)-5-(4-oxaphenyl)-4-ethoxy-3-[indole-(anthracene-hexahydropyridyl)amine f-yl]-1Η-pyridyl Azole

1-(2-氯苯基）-5-(4-氯苯基）-4-(2-甲氧乙氧基）-3- [N-(N-六氫吡啶基）胺曱醯基]吡唑； 1-(2-氣苯基）-5-(4-氣苯基）-4-甲氧基_3-[1-(^-嗎福嘴基）乙酿基]-1Η-β比坐； 1-(2, 4-二氯苯基）-5-(4-氣苯基）-4-甲氧基-3-[Ν-(Ν- 六氫吡啶基）胺甲醯基]-1Η-吡唑； 1-(2, 4-二氡苯基）-5-(4-氣苯基）-4-甲氧基-3-[Ν-(1- 吡咯啶基）胺曱醯基]-1Η-吡唑； 1-(2,4-二氱苯基）-5-(4-氣苯基）-4-甲氧基一3-[1^-(1^- 嗎福嚇基）胺曱酿基]-1H-d比唾； 1-(2, 4-二氣苯基）-5-(4-氯苯基）-4-甲氧基一3_[(N' N 一一甲拼基）幾基]-1Η-πϋ唾； 1-(2, 4-二氣苯基）-5-(4-氯苯基）-4-二氟甲氧基_3_ [N-(l-吡咯啶基）胺曱醯基]_1H -〇比唾； 1-(2-氯-4-氟苯基）-5-(4-氯苯基）一4-曱氧基—3一[N_ (N-嗎福啉基）胺曱醯基卜1H_吡唑； 318695 (修正本) 179 1378922 第095138705號專利申請案 101年6月27日修正替換頁 1-(2-氯苯基）-5-(4-三氣曱基笨基）-4-曱氧基-3-[(Ν' - Ν -二曱肼基）戴基]-1Η-°比嗅； . 1-(2-氯苯基）-5-(4-三氟曱基苯基）-4-曱氧基- 3-[Ν- U-吡咯啶基）胺曱醯基]-1Η-吡唑； 1-(2-氯苯基）-5-( 4-三氟甲基苯基）-4-甲氧基-3- [Ν- (N-嗎福啉基）胺甲醯基]-1H-吡唑； 1-(2-氣苯基）-5-(4-三氟甲基笨基）-4-曱氧基_3_[n_ (4 -四氫〇底喃基）胺曱趨基]-1Η-α比唾； _ 1一（2_ 氯苯基）-5-(4-氯苯基）-4-曱氧基氟苯甲醯基）六氫η比畊-4-基]胺甲醯基]-in-吡嗤； 1-(2-氯苯基）-5-(4-三氟曱基苯基）-4-二氟甲氧基_3_ [〇Γ，Ν、二曱肼基）羰基]-1H-吡唑； 1-(2-氯苯基）-5-(4-三氟曱基笨基）-4-二氟甲氧基一3— [N-(4-四氫哌喃基）胺甲醯基]-in—吡唑； 1-(2-氯苯基）-5-(4-三氟甲基苯基）-[二氟甲氧基一3_ • [N-(l-吡咯啶基）胺甲醯基]-1H-吡唑； 1-(2-氯苯基）-5-(4-氯苯基）-4-曱氧基-3-[N-(l-吼咯啶基）胺甲醯基]-1H-吡唑； 1 (2 -乳本基）-5-(4-氯苯基）-4 -甲氧基-3-[N-(順-2, 6 -二甲基嗎福啉基）胺甲醯基]一吡唑； 1-(2-氣苯基）-5-(4-氣苯基）~4-甲氧基-3-[N-(4, 4-二氟-N-六氫吡啶基）胺甲醯基吡唑； 1-(2-氯苯基）-5-(4-氯苯基）-4-甲氧基-3-[N-(4-三氟 318695 (修正本) 甲基-N-六氫吡啶基）胺甲醯基卜1H_吡唑； 180 1378922 第〇951387〇5號專利申請案 101年6月27日修正替換頁 1-(2 -氯苯基）-5-(4-氣苯基）-4-甲氧基—3-[(N'Nx-二曱肼基）羰基]-1H-吡唑； 1 -（2-氯苯基）-5-(4-氣苯基）-4-乙氧基-3-[N-(4-四氫哌喃基）胺曱醯基]-1H-吡唑； 1-(2-氯苯基）-5-(4-三氟甲基笨基）-4-乙氧基-3-[(1Γ， ΓΓ-二曱肼基）羰基]-1H-吡唑； 1-（2 -氯苯基）-5-( 4-氯苯基）-4-(2-甲氧乙氧基）-3- [N-(4-四氫哌喃基）胺甲醯基]-in_吡唑； 1 -（2-氯苯基）-5-(4-三氟曱基苯基）-4-(2-甲氧乙氧基） -3-[Ν-(1-吡咯啶基）胺甲醯基]-in-吡唑； 1-(2-氣苯基）-5-(4-三氟甲基苯基）-4-(2-甲氧乙氧基） -3-[N-(N-嗎福啉基）胺曱醯基]-1H-吡唑； 1-(2-氯苯基）-5-(4-氯苯基）-4-甲氧基-3-[N~(l，1-二側氧基硫代嗎福啉基-4-基）胺甲醯基]-1H -0比〇坐； 1-(2-氯苯基）-5-(4-氯苯基）_4-甲氧基-3-[N~(四氫咬喃-3-基）胺甲醯基]_ih-吡唑； 1~(2-氣苯基）-5-(4-氯苯基）-4-甲氧基-3-[N~(4-苯曱醯基六氫吡哄-1-基）胺曱醯基]-1H-吡唑； 1-（2-氯苯基）-5-(4-氯笨基）_4-(正丙氧基， N ~ —曱肼基）徵基]比嗤；卜（2-氯苯基）-5-(4-氯苯基）-4-曱氧基-3-[Ν-[4-(4- 氯笨曱醯基）六氫吡啡—卜基]胺甲醯.基]—1Η—吡唾； 318695 (修正本）卜（2-氣苯基）一5一（4_氯苯基）_4_曱氧基_3_[Ν_[4—(3_ 氟苯甲醯基）六氫吡哄―卜基]胺甲醯基]_1Η_吡唑； 181 1378922 • 第095138705號專利申請案 1〇1年6月27曰修正替換頁 1-(2-氯苯基）-5-(4-氯苯基）-4-甲氧基-3-[(1，1 -二側 - 乳基硫代嗎福琳-4_基）乙酿基]_1Η-α比唾； • 亂苯基）-5-(4-氯苯基）-4-二敗曱氧基-3-[N-(l- °比咯啶基）胺曱醯基]-1Η-吡唑； 1-(2-氯苯基）-5-(4-氯苯基）-4-二氟曱氧基-3-[ (1Τ， N _ —曱胖基）幾基]-1Η-πΛ唾； 1-(2-氣苯基）-5-(4-氣苯基）-4-二氟曱氧基-3-[Ν-(4- 擊四氫哌喃基）胺曱醯基]-1Η -Π比唾； 1-(2-氣苯基）-5-(4-氣笨基）—4-乙氧基-3-[Ν-[4-（4- 氟苯甲醯基）六氫吡D并—1-基]胺甲醯基]_1Η_吡唑； 1-(2-氣苯基）_5_(4一三氟甲基苯基）_4_乙氧基_3一[Ν_ [4一（4-氟苯甲醯基）六氫0比哄_卜基]胺甲醯基] 唑；1-(2-Chlorophenyl)-5-(4-chlorophenyl)-4-(2-methoxyethoxy)-3-[N-(N-hexahydropyridinyl)amine fluorenyl] Pyrazole; 1-(2-phenylphenyl)-5-(4-carbophenyl)-4-methoxy-3-(1-(^-?-fusphoryl)ethylidene]-1Η-β Ratio of 1-(2,4-dichlorophenyl)-5-(4-carbophenyl)-4-methoxy-3-[indole-(anthracene-hexahydropyridyl)amine-carbenyl] -1Η-pyrazole; 1-(2,4-diphenylene)-5-(4-phenylphenyl)-4-methoxy-3-[indole-(1-pyrrolidinyl)amine oxime ]]-Η-pyrazole; 1-(2,4-diphenylene)-5-(4-phenylphenyl)-4-methoxy-3-[1^-(1^- Alkyl aryl]-1H-d than saliva; 1-(2,4-diphenyl)-5-(4-chlorophenyl)-4-methoxy-3_[(N' N a group of 1] Η-πϋ saliva; 1-(2, 4-diphenyl)-5-(4-chlorophenyl)-4-difluoromethoxy_3_ [N-( L-pyrrolidinyl)amine hydrazino]_1H-indole ratio saliva; 1-(2-chloro-4-fluorophenyl)-5-(4-chlorophenyl)- 4-indolyloxy-3-[ N_(N-morpholino)amine sulfhydryl 1H_pyrazole; 318695 (amendment) 179 1378922 Patent Application No. 095138705 Revised on June 27, 2011 Replacement Page 1-(2-Chlorophenyl) -5-(4-trimethyl sulfhydryl)-4-decyloxy-3-[(Ν' - Ν-diinyl) Daigi]-1Η-° than olfactory; . 1-(2- Chlorophenyl)-5-(4-trifluorodecylphenyl)-4-decyloxy-3-[Ν-U-pyrrolidinyl)amine fluorenyl]-1Η-pyrazole; 1-(2 -Chlorophenyl)-5-(4-trifluoromethylphenyl)-4-methoxy-3-[indole-(N-morpholino)aminemethanyl]-1H-pyrazole; -(2-Phenylphenyl)-5-(4-trifluoromethylphenyl)-4-decyloxy_3_[n_(4-tetrahydroindolyl)amine fluorenyl]-1Η-α Specific saliva; _ 1 -(2_chlorophenyl)-5-(4-chlorophenyl)-4-decyloxyfluorobenzhydryl)hexahydron-rhenyl-4-amino]aminocarbazinyl]- In-pyridinium; 1-(2-chlorophenyl)-5-(4-trifluorodecylphenyl)-4-difluoromethoxy_3_[〇Γ,Ν,二曱肼yl)carbonyl] -1H-pyrazole; 1-(2-chlorophenyl)-5-(4-trifluoromethylphenyl)-4-difluoromethoxy-3-(N-(4-tetrahydropyranyl) Aminomethyl]-in-pyrazole; 1-(2-chlorophenyl)-5-(4-trifluoromethylphenyl)-[difluoromethoxy-3_ • [N-(l- Pyrrrolidinyl)aminomethane]-1H-pyrazole; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-[N-(l-吼Acridine Methotyl]-1H-pyrazole; 1 (2-lactyl)-5-(4-chlorophenyl)-4-methoxy-3-[N-(cis-2,6-dimethyl吗福olinyl)amine-mercapto]pyrazole; 1-(2-phenylphenyl)-5-(4-phenylphenyl)~4-methoxy-3-[N-(4, 4- Difluoro-N-hexahydropyridyl)amine-methylpyridylpyrazole; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-[N-(4 -Trifluorotribe 318695 (Revised) Methyl-N-hexahydropyridyl)amine-methylpyridyl 1H-pyrazole; 180 1378922 Patent Application No. 951,387, No. 5, June 27, 2011 Revision Replacement Page 1- (2-Chlorophenyl)-5-(4-phenylphenyl)-4-methoxy-3-([N'Nx-diindenyl)carbonyl]-1H-pyrazole; 1 -(2- Chlorophenyl)-5-(4-phenylphenyl)-4-ethoxy-3-[N-(4-tetrahydropyranyl)amine sulfhydryl]-1H-pyrazole; 1-(2 -chlorophenyl)-5-(4-trifluoromethylphenyl)-4-ethoxy-3-[(1Γ, ΓΓ-dimercapto)carbonyl]-1H-pyrazole; 1-(2 -Chlorophenyl)-5-(4-chlorophenyl)-4-(2-methoxyethoxy)-3-[N-(4-tetrahydropyranyl)aminecarbamyl]-in_ Pyrazole; 1-(2-chlorophenyl)-5-(4-trifluorodecylphenyl)-4-(2-methoxyethoxy)-3-[indolyl-(1-pyrrole) Aminomethyl]-in-pyrazole; 1-(2-phenylphenyl)-5-(4-trifluoromethylphenyl)-4-(2-methoxyethoxy)-3- [N-(N-morpholinyl)amine hydrazino]-1H-pyrazole; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3- [N~(l,1-di-oxythio-norfosfosyl-4-yl)amine-carbamoyl]-1H-0 is more than squat; 1-(2-chlorophenyl)-5-(4 -Chlorophenyl)_4-methoxy-3-[N~(tetrahydro-n-yl-3-yl)aminemethanyl]_ih-pyrazole; 1~(2-phenylphenyl)-5-(4 -chlorophenyl)-4-methoxy-3-[N~(4-benzofluorenylhexahydropyridin-1-yl)amine fluorenyl]-1H-pyrazole; 1-(2-chloro Phenyl)-5-(4-chlorophenyl)_4-(n-propoxy, N~-fluorenyl) levy] 嗤(2-chlorophenyl)-5-(4-chlorobenzene 4-yloxy-3-[indolyl-[4-(4-chloro)-hexahydropyridinyl-diyl]aminocarboxinyl]- 1Η-pyrazine; 318695 (amendment) ) (2-Phenylphenyl)-5-(4-chlorophenyl)_4_decyloxy_3_[Ν_[4-(3_fluorobenzhydryl)hexahydropyridinium-b-amino]aminoformamidine Base]_1Η_pyrazole; 181 1378922 • Patent Application No. 095138705 1/1 June 27 Revision Replacement Page 1-(2- Chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-[(1,1 -di-tert-milylthio-norfosolin-4_yl)-branyl]_1Η- Alpha ratio to saliva; • chaotic phenyl)-5-(4-chlorophenyl)-4-dioxadecyloxy-3-[N-(l-°pyrrolidyl)amine fluorenyl]-1Η- Pyrazole; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-difluorodecyloxy-3-[(1Τ, N _ 曱基) group]-1Η- ΛΛ; 1-(2-Phenylphenyl)-5-(4-phenylphenyl)-4-difluorodecyloxy-3-[indole-(4-tetrahydropyranyl)amine sulfhydryl ]-1Η -Π ratio saliva; 1-(2-phenylphenyl)-5-(4-indolyl)-4-ethoxy-3-[indole-[4-(4-fluorobenzhydryl) Hexahydropyrano D-l-yl]amine-carbamoyl]_1Η-pyrazole; 1-(2-phenylphenyl)_5_(4-trifluoromethylphenyl)_4_ethoxy_3-[ Ν_[4-(4-fluorobenzylidene) hexahydro 0 哄卜 ] ] ] ] ] ] ] ] ] ; ; ; ; ;

318695 (修正本) 1 一（2-氣苯基）-5-(4-氣笨基）_4_二氟曱氧基_3_[N-(1，1-二侧氧基硫代嗎福啉基）胺曱醯基卜1H_吡唑；氣苯基氣笨基）_4-曱氧基-3-[N-[4-(3-氯笨甲酿基）六氫D比哄基]胺甲醯基]Η_β比.嗤； Υ (2~氯苯基）_5_(4-氣苯基）一4-甲氧基-3-[Ν-[4-(2-氯笨甲醯基）六氫吡u并一丨_基]胺曱醯基]_1Η_吡唑； 1 (2—氯苯基）-5-(4-氯笨基）一4_甲氧基_3-[N-[4- ，一氟笨甲醯基）六氫吡[]井一1_基]胺甲醯基]-1H-吡〇坐； \(2-氯苯基一（4—氯苯基卜甲氧基_3_[n_[4_ (2’ 4 一氟笨甲醯基）六氫吡畊_1_基]胺甲醯基]_1H_0比 182 1378922 • 第095138705號專利申請案 101年6月27日修正替換頁' 唑； - 1_(2_ 氯苯基）-5-(4-氯苯基）-4- F 氧基-3-[N-[4- . (3, 5-二氟苯甲醯基）六氫吡π井-1-基]胺甲醯基]-in-吼唾； 1-( 2-氯苯基）-5-(4-氯苯基）-4- f 氧基-3-[N-[ 4-(4- 氟苯基）六氫吼哄-1-基]胺甲醯基]_1Η_β比唑； 1-(2-氣苯基）-5-(4-氯苯基）-4-曱氧基-3-[Ν-(3-三氟曱基吡咯啶-卜基）胺曱醯基]-1Η-吡唑；籲卜（2, 4 一二氯苯基）_5_(4-三氟甲基苯基）-4-甲氧基-3- [〇r，ir-二甲肼基）羰基]-1H-吡唑； 1-(2, 4-二氯苯基）-5-(4-三氟甲基苯基）-4-甲氧基-3- [N-(N-嗎福啉基）胺甲醯基]-in-吡唑； 1-(2, 4-二氣苯基）-5-(4-三氟曱基苯基）-4-曱氧基一3- [N-(l，1-二側氧基-2-四氫噻吩基）胺甲醯基]—1H_^ 唑； φ 1_(2_氯一 4-氟苯基）-5-（4-三氟甲基苯基）-4-甲氧基 -3 - [N-(4-四氫哌喃基）胺曱醯基]—η-吡唑； 1-(2-氯苯基）-5-(4-三氟曱基苯基）_4_曱氧基_3_[N_ (1，卜二側氧基N-硫代嗎福淋基）胺曱酿基]-1JJ-吡唑； 1-（2-氯苯基）-5-(4-氣苯基）-4-曱氧基-3-[1^-(4-氟 -N-六氣吡啶基）胺甲醯基]-1H-吡唑； 1-(2’ 二氣苯基）-5-(4-氣苯基）-4-甲氧基-3-[n-(4- 苯甲醯基六氫吡畊-1-基）胺甲醯基]_1H一吡唑； 1-(2’ 4-二氣苯基）-5-(4-氣苯基）-4-甲氧基-3-[n-[4- 318695 (修正本) 183 1378922 第095138705號專利t請案 101年6月27日修正替換頁 (2, 4-二氟苯甲醯基）六氫吡啡-卜基]胺甲醯基]_ΐΗ-α比 - 唾； ' 5_(4-氣苯基）-1-(2 -氟苯基）-4-曱氧基-3-[Ν-(4, 4-二氟-Ν-六氫比啶基）胺曱醯基]— Η一吡唑； 1-(2 -氣苯基）-5-( 4-三氟曱基笨基）-4-甲氧基-3-[Ν-(4,4-二氟-N-六氫吡啶基）胺甲醯基]-1H-吡唑； 1-(2, 4-二氯苯基）-5-(4-三氟甲基苯基）-4-甲氧基-3 — 鲁 [N-(4, 4-二氟-N-六氫吡啶基）胺甲醯基]-1H-吡唑； 5-（4-氣苯基）-i一（2-氟苯基）-4-曱氧基-3-[N-[3-(三氟曱基）吡咯啶-1-基]胺曱醯基]-1H-吡唑； 1 (2 -氣本基）-5-(4-氯苯基）-4-二氟甲氧基-3~[n~ (4, 4 -一氟-N -六氫π比咬基）胺甲酿基]— iH-n比嗤； 5 (4-氣本基）-i —(2-氟苯基）-4-曱氧基-3-[N-[4~d 氯苯基）六氫吨啡―丨―基]胺甲醯基]-i η -U比β坐； 5-(4-氣苯基氟笨基）_4一曱氧基一3一[ν_[4、（4、 # 氟苯基）六氫吡畊-1-基]胺曱醯基]-1Η-吡唑。 4· 一種包含式[I ]之吡唑化合物或其醫藥上可接受鹽_作為活性成分之醫藥組成物：318695 (amendment) 1 1-(2-phenylphenyl)-5-(4-indolyl)_4_difluorodecyloxy_3_[N-(1,1-di- oxythiomorpholine Amine oxime 1H_pyrazole; gas phenyl gas stupid) _4-methoxy-3-[N-[4-(3-chlorobenzyl) hexahydro D-indenyl]amine醯醯 Η β β β β 2 2 2 2 2 β 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 2 2 2 Hydropyrazine and hydrazino-yl]aminoindolyl]_1Η-pyrazole; 1 (2-chlorophenyl)-5-(4-chlorophenyl)- 4-methoxy-3-[N-[ 4-, monofluoro-p-methyl hydrazino) hexahydropyridinium [] well- 1_yl]-aminomethyl hydrazino]-1H-pyridinium; \(2-chlorophenyl-(4-chlorophenyl)methoxy Base_3_[n_[4_(2' 4 -Fluorobenzoyl)-hexahydropyrazine-1_yl]amine-methylidene]_1H_0 ratio 182 1378922 • Patent application No. 095138705 revised June 27, 101 Replacement page 'azole; - 1_(2_chlorophenyl)-5-(4-chlorophenyl)-4-Foxy-3-[N-[4-. (3, 5-difluorobenzhydryl) Hexahydropyridinium-1-yl]aminemethanyl]-in-吼 saliva; 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-foxy-3- [N-[ 4-(4-fluorophenyl)hexahydroindol-1-yl]amine formazan ]_1Η_β-biazole; 1-(2-phenylphenyl)-5-(4-chlorophenyl)-4-methoxy-3-[indole-(3-trifluorodecylpyrrolidinyl-bu)amine Mercapto]-1Η-pyrazole; 吁(2,4-dichlorophenyl)_5_(4-trifluoromethylphenyl)-4-methoxy-3-[〇r,ir-dimethyl Mercapto)carbonyl]-1H-pyrazole; 1-(2,4-dichlorophenyl)-5-(4-trifluoromethylphenyl)-4-methoxy-3-[N-(N -orfosfyl)amine-mercapto]-in-pyrazole; 1-(2,4-diphenyl)-5-(4-trifluorodecylphenyl)-4-methoxyl-3 - [N-(l,1-di-oxo-2-tetrahydrothienyl)aminecarboxylidene]-1H_^ oxazole; φ 1_(2_chloro-4-fluorophenyl)-5-(4- Trifluoromethylphenyl)-4-methoxy-3 -[N-(4-tetrahydropiperidyl)amine fluorenyl]-η-pyrazole; 1-(2-chlorophenyl)-5 -(4-trifluorodecylphenyl)_4_decyloxy_3_[N_(1, bis-oxo-N-thiofenofyl)amine oxime]-1JJ-pyrazole; 1- (2-Chlorophenyl)-5-(4-carbophenyl)-4-decyloxy-3-[1^-(4-fluoro-N-hexapyridinyl)aminemethanyl]-1H- Pyrazole; 1-(2'diphenyl)-5-(4-phenylphenyl)-4-methoxy-3-[n-(4-benzylidene hexahydropyrylene-1-yl )amine Methyl hydrazide]_1H-pyrazole; 1-(2' 4-diphenyl)-5-(4-phenylphenyl)-4-methoxy-3-[n-[4- 318695 (amendment) ) 183 1378922 Patent No. 095138705, t., June 27, 101, revised replacement page (2, 4-difluorobenzhydryl) hexahydropyridin-buyl]amine-methylglycolate]_ΐΗ-α ratio - saliva ; '5_(4-Phenylphenyl)-1-(2-fluorophenyl)-4-decyloxy-3-[indole-(4,4-difluoro-indole-hexahydropyridinyl)amine oxime Mercapto]- Η-pyrazole; 1-(2-(phenyl)-5-(4-trifluorodecyl)-4-methoxy-3-[indole-(4,4-difluoro) -N-hexahydropyridyl)amine-mercapto]-1H-pyrazole; 1-(2,4-dichlorophenyl)-5-(4-trifluoromethylphenyl)-4-methoxy -3 - Lu [N-(4,4-Difluoro-N-hexahydropyridyl)amine-carbamoyl]-1H-pyrazole; 5-(4-Phenylphenyl)-i-(2-fluorobenzene) 4-yloxy-3-[N-[3-(trifluoromethyl)pyrrolidin-1-yl]aminoindolyl]-1H-pyrazole; 1 (2-air group)- 5-(4-Chlorophenyl)-4-difluoromethoxy-3~[n~(4,4-fluoro-N-hexahydropyranyl) aminoglycol]-iH-n ratio嗤; 5 (4-gas phenyl)-i —(2-fluorophenyl)-4-decyloxy-3-[N-[4~d chlorophenyl)hexahydro tonate丨基基胺胺基 ] ] U U U U U U U U U U U U U 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- Lithium hexahydropyrylene-1-yl]amine hydrazino]-1 Η-pyrazole. 4. A pharmaceutical composition comprising the pyrazole compound of the formula [I] or a pharmaceutically acceptable salt thereof as an active ingredient:

式中， R1為經一至二個選自鹵素原子與三鹵素—Ci *境基之基取代之笨基； a 318695 (修正本） 184 ^/^922 第〇951387〇5號專利申請索 101年6月27曰修正替換頁 R2為經一至二個鹵素原子取代之苯基； R為Cl—4烷基氧基-Cl—4烷基或視需要經一至三個鹵素原子取代之烧基； E為下列式（i)之基團·· —Q1Wherein R1 is a stupid group substituted with one to two groups selected from a halogen atom and a trihalogen-Ci* group; a 318695 (amendment) 184 ^/^922 No. 951387〇5 Patent Application No. 101 Modified on June 27, R2 is a phenyl group substituted with one to two halogen atoms; R is a C 4 alkyloxy-Cl-4 alkyl group or an alkyl group substituted with one to three halogen atoms as needed; Is a group of the following formula (i) ···Q1

⑴ Q1為單鍵， Q為單鍵或Cl-4伸烧基， R4為視需要經一至三個選自側氧基或式-NH(R6)所不基團之基取代之飽和或不飽和5至6員雜單環基， R為（Ο視需要經一至三個選自於下列者之所構成之群組的基取代之飽和或不飽和5至7員雜單環基：鹵素原子、視需要經一至三個函素原子取代之烷基、視需要經一至二個鹵素原子取代之笨基與醯基，（ii)視需要經一至二個Cl-4燒基取代之胺基。 .如申請專利範圍第4項之醫藥組成物，該組成物係作為治療肥胖症之藥劑。 •如申請專利範圍第4項之醫藥組成物，該組成物係作為治療焦慮症或食慾疾病。 •如申請專利範圍第6項之醫藥組成物，該食慾疾病為暴食交替症或厭食症。 318695 (修正本） 185(1) Q1 is a single bond, Q is a single bond or a Cl-4 extension group, and R4 is a saturated or unsaturated group which is optionally substituted with one to three groups selected from a pendant oxy group or a group other than the group -NH(R6). a 5- to 6-membered heteromonocyclic group, R is a saturated or unsaturated 5 to 7 membered heteromonocyclic group which is substituted with a group of one to three selected from the group consisting of: a halogen atom, An alkyl group substituted with one to three functional atoms as desired, a stupid group and a fluorenyl group substituted with one to two halogen atoms, and (ii) an amine group substituted with one to two Cl-4 alkyl groups as needed. The pharmaceutical composition of claim 4 is a pharmaceutical composition for treating obesity. • A pharmaceutical composition as claimed in claim 4, which is used for treating anxiety or an appetite disease. The pharmaceutical composition of claim 6 of the patent scope, the appetite disease is binge eating disorder or anorexia. 318695 (amendment) 185