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TW201311664A - Substituted heteroaromatic pyrazole-containing carboxamide and urea derivatives as vanilloid receptor ligands - Google Patents

Substituted heteroaromatic pyrazole-containing carboxamide and urea derivatives as vanilloid receptor ligands Download PDF

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TW201311664A
TW201311664A TW101126709A TW101126709A TW201311664A TW 201311664 A TW201311664 A TW 201311664A TW 101126709 A TW101126709 A TW 101126709A TW 101126709 A TW101126709 A TW 101126709A TW 201311664 A TW201311664 A TW 201311664A
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Taiwan
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methyl
group
alkyl
pyrazol
trifluoromethyl
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TW101126709A
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Chinese (zh)
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Robert Frank
Gregor Bahrenberg
Thomas Christoph
Bernhard Lesch
Jee-Woo Lee
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Gruenenthal Gmbh
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Abstract

The invention relates to substituted heteroaromatic pyrazole-containing carboxamide and urea derivatives as vanilloid receptor ligands, to pharmaceutical compositions containing these compounds and also to these compounds for use in the treatment and/or prophylaxis of pain and further diseases and/or disorders.

Description

以含被取代吡唑芳環之羧醯胺與尿素衍生物做為類香草素受體之配位體 Using a carboxamide containing a substituted pyrazole ring and a urea derivative as a ligand for a vanilloid receptor

本發明係關於以含被取代吡唑芳環之羧醯胺及尿素衍生物做為類香草素受體之配位體，含此類化合物之藥物組合物，及使用此類化合物治療及/或預防疼痛及其它疾病/或失調。 The present invention relates to a pharmaceutical composition comprising such a compound as a ligand for a vanilloid receptor containing a substituted pyrazole ring and a urea derivative, and the use of such a compound for treatment and/or Prevent pain and other diseases and/or disorders.

疼痛治療，尤其係神經性疼痛，於醫學界極為重要。世界各地皆需要可有效地治療疼痛之方法。對慢性及非慢性疼痛患者處以以患者為中心及目標導向治療之迫切需求，被認為是可成功地且有效地治療患者疼痛之方式，其亦被記載於許多科學研究，並於近期出現於止痛藥應用或疼痛之基礎研究領域。 Pain management, especially neuropathic pain, is extremely important in the medical community. There is a need in the world for effective treatment of pain. The urgent need for patient-centered and goal-oriented treatment for patients with chronic and non-chronic pain is considered to be a successful and effective way to treat pain in patients. It is also documented in many scientific studies and has recently appeared in pain relief. Basic research areas for drug application or pain.

類香草素受體亞型1(VR1/TRPV1)，通常亦稱為辣椒素受體，係治療疼痛之一合適起始點，尤其是選自由急性疼痛、慢性疼痛、神經性疼痛與內臟疼痛構成之群組。尤其，該受體會被類香草素，如辣椒素、熱與質子激發，且於形成疼痛上扮演著核心角色。此外，該受體對許多其他生理與病理心理過程亦極為重要，且係一適用於治療許多其他疾病之標靶，例如偏頭痛、抑鬱症、神經退化性疾病、認知疾患、焦慮狀態、癲癇症、咳嗽、腹瀉、搔癢、炎症、心血管系統疾病、飲食異常、藥物依賴、藥物濫用及尿失禁。 The vanilloid receptor subtype 1 (VR1/TRPV1), also commonly known as the capsaicin receptor, is a suitable starting point for the treatment of pain, especially from acute pain, chronic pain, neuropathic pain and visceral pain. Group of. In particular, the receptor is stimulated by vanilloids such as capsaicin, heat and protons and plays a central role in the formation of pain. In addition, the receptor is extremely important for many other physiological and pathological processes, and is suitable for the treatment of many other diseases, such as migraine, depression, neurodegenerative diseases, cognitive disorders, anxiety, epilepsy Cough, diarrhea, itching, inflammation, cardiovascular disease, eating disorders, drug dependence, drug abuse, and urinary incontinence.

除了需要對類香草素受體1(VR1/TRPV1受體)具親和性之化合物本身(效力與療效)以外，亦需要其它具有可與其相較或具更佳性質之化合物。 In addition to the compounds themselves (potency and efficacy) that require affinity for the vanilloid receptor 1 (VR1/TRPV1 receptor), other compounds having comparable or better properties are also required.

因此，改善該化合物之代謝穩定性、於水性介質之可溶性或可透性有其優勢。這些因素有益於口服生物利用度，或可改變藥代動力學/藥效動力學(pharmacokinetic/pharmacodynamic，PK/PD) 之狀況；例如，其可導出更有利之效力期限。 Therefore, there is an advantage in improving the metabolic stability of the compound and the solubility or permeability of the aqueous medium. These factors contribute to oral bioavailability or may alter pharmacokinetic/pharmacodynamic (PK/PD) The condition; for example, it can lead to a more favorable period of effectiveness.

因此，本發明之目標係提供新穎化合物，以具有優於先前技術之特性較佳。尤其，該化合物須適合做為藥物組合物之藥理活性成分，以治療及/或預防至少部分地由類香草素受體1 VR1/TRPV1受體)介導之失調或疾病之藥物組合物較佳。 Accordingly, it is an object of the present invention to provide novel compounds which are preferred over the prior art. In particular, the compound is preferably suitable as a pharmacologically active ingredient of a pharmaceutical composition for the treatment and/or prevention of a pharmaceutical composition which is at least partially mediated by the vanilloid receptor 1 VR1/TRPV1 receptor. .

此目標已藉由本專利申請之標的物及此本文描述之標的物達成。 This object has been achieved by the subject matter of this patent application and the subject matter described herein.

意外地發現如下所示通式(I)之被取代化合物，對類香草素受體亞型1 VR1/TRPV1)具有相當強之親和性，因此特別地適合用於預防及/或治療至少部分地由類香草素受體1(VR1/TRPV1)介導之失調或疾病。 Surprisingly, it has been found that the substituted compound of the formula (I) as shown below has a relatively strong affinity for the vanilloid receptor subtype 1 VR1/TRPV1) and is therefore particularly suitable for the prevention and/or treatment at least partially A disorder or disease mediated by vanilloid receptor 1 (VR1/TRPV1).

因此本發明涉及通式(I)之被取代化合物， 其中，R0 代表一未被取代或被單取代或被多取代之C1-10脂族殘基、一C3-10環脂族殘基或一3至10構件雜環脂族殘基，其於各例中係未被取代或被單取代或被多取代，及於各例中選擇性地經由一C1-8脂族基橋接(bridge)，其進而可係未被取代或被單取代或被多取代，芳基或雜芳基，其於各例中係未被取代或被單取代或被多取代，及於各例中選擇性地經由一C1-8脂族基橋接，其進而可係未被取代或被單取代或被 多取代；R1 代表H、R0、C(=O)-R0、C(=O)-OH、C(=O)-OR0、C(=O)-NHR0、C(=O)-N(R0)2、OH、O-R0、SH、S-R0、S(=O)2-R0、S(=O)2-OR0、S(=O)2-NHR0、S(=O)2-N(R0)2、NH2、NHR0、N(R0)2、NH-S(=O)2-R0、N(R0)(S(=O)2-R0)或SCl3；R2 代表H、R0、F、Cl、Br、I、CN、NO2、OH、SH、CF3、CF2H、CFH2、CF2Cl、CFCl2、CH2CF3、OCF3、OCF2H、OCFH2、OCF2Cl、OCFCl2、SCF3、SCF2H、SCFH2、SCF2Cl、SCFCl2、S(=O)2-CF3、S(=O)2-CF2H、S(=O)2-CFH2或SF5；R3 代表H或一C1-10脂族殘基，其係未被取代或被單取代或被多取代；R3a 代表H或一C1-4脂族殘基，其係未被取代或被單取代或被多取代；n 代表0、1、2、3或4，以代表1、2、3或4較佳，以代表1、2或3更佳，以代表1或2又更佳，以代表1最佳；R4a 代表H或一C1-4脂族殘基，其係未被取代或被單取代或被多取代、一C3-6環脂族殘基，其係未被取代或被單取代或被多取代、或一芳基，其係未被取代或被單取代或被多取代；Y 代表O、S或N-CN，以代表O較佳；Z 代表N或C-R4b，R4b 代表H或一C1-4脂族殘基，其係未被取代或被單取代或被多取代；或R4a與R4b及將其連結之碳原子共同形成一C3-6環脂族殘基，其係未被取代或被單取代或被多取代； T1 代表N或C-R5，U1 代表N或C-R6，V 代表N或C-R7，U2 代表N或C-R8，T2 代表N或C-R9，附帶條件為T1、U1、V、U2及T2變量其中之1、2或3代表一氮原子，R5、R6、R7、R8及R9各自相互獨立地代表H、F、Cl、Br、I、NO2、CN、CF3、CF2H、CFH2、CF2Cl、CFCl2、R0、C(=O)H、C(=O)R0、CO2H、C(=O)OR0、CONH2、C(=O)NHR0、C(=O)N(R0)2、OH、OCF3、OCF2H、OCFH2、OCF2Cl、OCFCl2、OR0、O-C(=O)-R0、O-C(=O)-O-R0、O-(C=O)-NH-R0、O-C(=O)-N(R0)2、O-S(=O)2-R0、O-S(=O)2OH、O-S(=O)2OR0、O-S(=O)2NH2、O-S(=O)2NHR0、O-S(=O)2N(R0)2、NH2、NH-R0、N(R0)2、NH-C(=O)-R0、NH-C(=O)-O-R0、NH-C(=O)-NH2、NH-C(=O)-NH-R0、NH-C(=O)-N(R0)2、NR0-C(=O)-R0、NR0-C(=O)-O-R0、NR0-C(=O)-NH2、NR0-C(=O)-NH-R0、NR0-C(=O)-N(R0)2、NH-S(=O)2OH、NH-S(=O)2R0、NH-S(=O)2OR0、NH-S(=O)2NH2、NH-S(=O)2NHR0、NH-S(=O)2N(R0)2、NR0-S(=O)2OH、NR0-S(=O)2R0、NR0-S(=O)2OR0、NR0-S(=O)2NH2、NR0-S(=O)2NHR0、NR0-S(=O)2N(R0)2、SH、SCF3、SCF2H、SCFH2、SCF2Cl、SCFCl2、SR0、S(=O)R0、S(=O)2R0、S(=O)2OH、S(=O)2OR0、S(=O)2NH2、S(=O)2NHR0或S(=O)2N(R0)2；其「脂族(aliphatic group)」及「脂族殘基(aliphatic residue)」於各例中相互獨立地，可係支鏈或非支鏈，飽和或不飽和；其「環脂族殘基(cycloaliphatic residue)」及「雜環脂族殘基 (heterocycloaliphatic residue)」於各例中相互獨立地，可係支鏈或非支鏈，飽和或不飽和；其「脂族(aliphatic group)」、「脂族殘基(aliphatic residue)」、「環脂族殘基(cycloaliphatic residue)」及「雜環脂族殘基(heterocycloaliphatic residue)」之「被單取代或多取代(mono-or polysubstituted)」，係指其於各例中相互自獨立地於其相應之殘基或功能基上，有一或多個氫原子各自相互獨立地被以至少一選自由F、Cl、Br、I、NO2、CN、=O、=NH、=N(OH)、=C(NH2)2、CF3、CF2H、CFH2、CF2Cl、CFCl2、R0、C(=O)-H、C(=O)-R0、C(=O)-OH、C(=O)-OR0、CO-NH2、C(=O)-NHR0、C(=O)-N(R0)2、OH、OCF3、OCF2H、OCFH2、OCF2Cl、OCFCl2、OR0、O-C(=O)-R0、O-C(=O)-O-R0、O-(C=O)-NH-R0、O-C(=O)-N(R0)2、O-S(=O)2-R0、O-S(=O)2-OH、O-S(=O)2-OR0、O-S(=O)2-NH2、O-S(=O)2-NHR0、O-S(=O)2-N(R0)2、NH2、NH-R0、N(R0)2、NH-C(=O)-R0、NH-C(=O)-O-R0、NH-C(=O)-NH2、NH-C(=O)-NHR0、NH-C(=O)-N(R0)2、NR0-C(=O)-R0、NR0-C(=O)-O-R0、NR0-C(=O)-NH2、NR0-C(=O)-NHR0、NR0-C(=O)-N(R0)2、NH-S(=O)2-OH、NH-S(=O)2-R0、NH-S(=O)2-OR0、NH-S(=O)2-NH2、NH-S(=O)2-NHR0、NH-S(=O)2-N(R0)2、NR0-S(=O)2-OH、NR0-S(=O)2-R0、NR0-S(=O)2-OR0、NR0-S(=O)2-NH2、NR0-S(=O)2-NHR0、NR0-S(=O)2-N(R0)2、SH、SCF3、SCF2H、SCFH2、SCF2Cl、SCFCl2、SR0、S(=O)-R0、S(=O)2-R0、S(=O)2-OH、S(=O)2-OR0、S(=O)2-NH2、S(=O)2-NHR0與S(=O)2-N(R0)2等取代基組成之群組取代；其「芳基(aryl)」及「雜芳基(heteroaryl)」之「被單取代或多取代(mono-or polysubstituted)」，係指其於各例中相互自獨立地於其相應 之殘基上，有一或多個氫原子各自相互獨立地被以至少一選自由F、Cl、Br、I、NO2、CN、CF3、CF2H、CFH2、CF2Cl、CFCl2、R0、C(=O)-H、C(=O)-R0、C(=O)-OH、C(=O)-OR0、CO-NH2、C(=O)-NHR0、C(=O)-N(R0)2、OH、、、、、、、、、、OCF3、OCF2H、OCFH2、OCF2Cl、OCFCl2、OR0、O-C(=O)-R0、O-C(=O)-O-R0、O-(C=O)-NH-R0、O-C(=O)-N(R0)2、O-S(=O)2-R0、O-S(=O)2-OH、O-S(=O)2-OR0、O-S(=O)2-NH2、O-S(=O)2-NHR0、O-S(=O)2-N(R0)2、NH2、NHR0、N(R0)2、NH-C(=O)-R0、NH-C(=O)-O-R0、NH-C(=O)-NH2、NH-C(=O)-NH-R0、NH-C(=O)-N(R0)2、NR0-C(=O)-R0、NR0-C(=O)-O-R0、NR0-C(=O)-NH2、NR0-C(=O)-NH-R0、NR0-C(=O)-N(R0)2、NH-S(=O)2-OH、NH-S(=O)2-R0、NH-S(=O)2-OR0、NH-S(=O)2-NH2、NH-S(=O)2-NHR0、NH-S(=O)2-N(R0)2、NR0-S(=O)2-OH、NR0-S(=O)2R0、NR0-S(=O)2-OR0、NR0-S(=O)2-NH2、NR0-S(=O)2-NHR0、NR0-S(=O)2-N(R0)2、SH、SCF3、SCF2H、SCFH2、SCF2Cl、SCFCl2、SR0、S(=O)-R0、S(=O)2-R0、S(=O)2-OH、S(=O)2-OR0、S(=O)2-NH2、S(=O)2-NHR0與S(=O)2-N(R0)2等取代基組成之群組取代；選擇性地以單一立體異構物或立體異構物之混合物之形式、以自由化合物之形式及/或其生理上可接受之鹽或之形式溶劑化物之形式，尤其係其水合物。 The invention therefore relates to substituted compounds of the general formula (I), Wherein R 0 represents an unsubstituted or monosubstituted or polysubstituted C 1-10 aliphatic residue, a C 3-10 cycloaliphatic residue or a 3 to 10 membered heterocyclic aliphatic residue, In each case unsubstituted or monosubstituted or polysubstituted, and in each case selectively bridged via a C 1-8 aliphatic group, which in turn may be unsubstituted or monosubstituted or a polysubstituted, aryl or heteroaryl group which is unsubstituted or monosubstituted or polysubstituted in each case, and optionally bridged via a C 1-8 aliphatic group in each case, which in turn may be Unsubstituted or monosubstituted or polysubstituted; R 1 represents H, R 0 , C(=O)-R 0 , C(=O)-OH, C(=O)-OR 0 , C(=O) -NHR 0 , C(=O)-N(R 0 ) 2 , OH, OR 0 , SH, SR 0 , S(=O) 2 -R 0 , S(=O) 2 -OR 0 , S(= O) 2 -NHR 0 , S(=O) 2 -N(R 0 ) 2 , NH 2 , NHR 0 , N(R 0 ) 2 , NH-S(=O) 2 -R 0 , N(R 0 (S(=O) 2 -R 0 ) or SCl 3 ; R 2 represents H, R 0 , F, Cl, Br, I, CN, NO 2 , OH, SH, CF 3 , CF 2 H, CFH 2 , CF 2 Cl, CFCl 2 , CH 2 CF 3 , OCF 3 , OCF 2 H, OCFH 2 , OCF 2 Cl, OCFCl 2 , SCF 3 , SCF 2 H, SCFH 2 , SCF 2 Cl, SCFCl 2 , S(=O) 2 -CF 3 , S(=O) 2 -CF 2 H, S(=O) 2 -CFH 2 or SF 5 ; R 3 represents H or a C 1-10 aliphatic residue which is unsubstituted or monosubstituted or polysubstituted; R 3a represents H or a C 1-4 aliphatic residue which is unsubstituted or monosubstituted or Multi-substitution; n represents 0, 1, 2, 3 or 4 to represent 1, 2, 3 or 4, preferably to represent 1, 2 or 3, to represent 1 or 2, and more preferably to represent 1 R 4a represents H or a C 1-4 aliphatic residue which is unsubstituted or monosubstituted or polysubstituted, a C 3-6 cycloaliphatic residue which is unsubstituted or monosubstituted or Polysubstituted, or monoaryl, which is unsubstituted or monosubstituted or polysubstituted; Y represents O, S or N-CN, preferably represents O; Z represents N or CR 4b , and R 4b represents H or a C 1-4 aliphatic residue which is unsubstituted or monosubstituted or polysubstituted; or R 4a and R 4b together with the carbon atom to which they are bonded form a C 3-6 cycloaliphatic residue, based unsubstituted or mono- or polysubstituted; T 1 represents N or CR 5, U 1 represents N or CR 6, V represents N or CR 7, U 2 represents N or CR 8 T 2 represents N or CR 9, with the proviso that 1, 2 or 3 T 1, U 1, V , U 2 , and wherein the variable T 2 represents a nitrogen atom, R 5, R 6, R 7, R 8 , and R 9 each independently representing H, F, Cl, Br, I, NO 2 , CN, CF 3 , CF 2 H, CFH 2 , CF 2 Cl, CFCl 2 , R 0 , C(=O)H, C ( =O)R 0 , CO 2 H, C(=O)OR 0 , CONH 2 , C(=O)NHR 0 , C(=O)N(R 0 ) 2 , OH, OCF 3 , OCF 2 H, OCFH 2 , OCF 2 Cl, OCFCl 2 , OR 0 , OC(=O)-R 0 , OC(=O)-OR 0 , O-(C=O)-NH-R 0 , OC(=O)- N(R 0 ) 2 , OS(=O) 2 -R 0 , OS(=O) 2 OH, OS(=O) 2 OR 0 , OS(=O) 2 NH 2 , OS(=O) 2 NHR 0 , OS(=O) 2 N(R 0 ) 2 , NH 2 , NH-R 0 , N(R 0 ) 2 , NH-C(=O)-R 0 , NH-C(=O)-OR 0 , NH-C(=O)-NH 2 , NH-C(=O)-NH-R 0 , NH-C(=O)-N(R 0 ) 2 , NR 0 -C(=O)- R 0 , NR 0 -C(=O)-OR 0 , NR 0 -C(=O)-NH 2 , NR 0 -C(=O)-NH-R 0 , NR 0 -C(=O)- N(R 0 ) 2 , NH-S(=O) 2 OH, NH-S(=O) 2 R 0 , NH-S(=O) 2 OR 0 , NH-S(=O) 2 NH 2 , NH-S(=O) 2 NHR 0 , NH-S(=O) 2 N(R 0 ) 2 , NR 0 -S(=O) 2 OH, NR 0 -S(=O) 2 R 0 , NR 0 -S(=O) 2 OR 0 , NR 0 -S(=O) 2 NH 2 NR 0 -S(=O) 2 NHR 0 , NR 0 -S(=O) 2 N(R 0 ) 2 , SH, SCF 3 , SCF 2 H, SCFH 2 , SCF 2 Cl, SCFCl 2 , SR 0 , S(=O)R 0 , S(=O) 2 R 0 , S(=O) 2 OH, S(=O) 2 OR 0 , S(=O) 2 NH 2 , S(=O) 2 NHR 0 or S(=O) 2 N(R 0 ) 2 ; its "aliphatic group" and "aliphatic residue" are independent of each other in each case, and may be branched or not. Branched, saturated or unsaturated; its "cycloaliphatic residue" and "heterocycloaliphatic residue" are independent of each other in each case, and may be branched or unbranched. Saturated or unsaturated; its "aliphatic group", "aliphatic residue", "cycloaliphatic residue" and "heterocycloaliphatic residue""mono-orpolysubstituted" means that in each case, independently of each other, on its corresponding residue or functional group, one or more hydrogen atoms are each independently independent of each other. One selected from the group consisting of F, Cl, Br, I, NO 2 , CN, =O, =NH, =N(OH), =C(N H 2 ) 2 , CF 3 , CF 2 H, CFH 2 , CF 2 Cl, CFCl 2 , R 0 , C(=O)-H, C(=O)-R 0 , C(=O)-OH, C(=O)-OR 0 , CO-NH 2 , C(=O)-NHR 0 , C(=O)-N(R 0 ) 2 , OH, OCF 3 , OCF 2 H, OCFH 2 , OCF 2 Cl, OCFCl 2 , OR 0 , OC(=O)-R 0 , OC(=O)-OR 0 , O-(C=O)-NH-R 0 , OC(=O)-N(R 0 ) 2 , OS(=O) 2 -R 0 , OS(=O) 2 -OH, OS(=O) 2 -OR 0 , OS(=O) 2 -NH 2 , OS(=O) 2 -NHR 0 , OS(=O) 2 -N(R 0 ) 2 , NH 2 , NH-R 0 , N(R 0 ) 2 , NH-C(=O)-R 0 , NH-C(=O)-OR 0 , NH-C(=O)-NH 2 , NH-C(=O)-NHR 0 , NH-C(=O)-N(R 0 ) 2 , NR 0 -C(=O)-R 0 , NR 0 -C(=O)-OR 0 , NR 0 -C(=O)-NH 2 , NR 0 -C(=O)-NHR 0 , NR 0 -C(=O)-N(R 0 2 , NH-S(=O) 2 -OH, NH-S(=O) 2 -R 0 , NH-S(=O) 2 -OR 0 , NH-S(=O) 2 -NH 2 , NH-S(=O) 2 -NHR 0 , NH-S(=O) 2 -N(R 0 ) 2 , NR 0 -S(=O) 2 -OH, NR 0 -S(=O) 2 - R 0 , NR 0 -S(=O) 2 -OR 0 , NR 0 -S(=O) 2 -NH 2 , NR 0 -S(=O) 2 -NHR 0 , NR 0 -S(=O) 2 -N(R 0 ) 2 , SH, SCF 3 , SCF 2 H, SCFH 2 , SCF 2 Cl, SCFCl 2 , SR 0 , S(=O)-R 0 , S(=O) 2 -R 0 , S(=O) 2 -OH, S(=O) 2 -OR 0 , S(=O) 2 -NH 2 , S(=O) 2 -NHR 0 and group substitution of S(=O) 2 -N(R 0 ) 2 and other substituents; "(aryl)" and "heteroaryl" are "mono-or polysubstituted", meaning that they are independent of each other in their respective residues, one or more Each of the hydrogen atoms is independently selected from each other by at least one selected from the group consisting of F, Cl, Br, I, NO 2 , CN, CF 3 , CF 2 H, CFH 2 , CF 2 Cl, CFCl 2 , R 0 , C (=O). )-H, C(=O)-R 0 , C(=O)-OH, C(=O)-OR 0 , CO-NH 2 , C(=O)-NHR 0 , C(=O)- N(R 0 ) 2 , OH, , , , , , , , , , OCF 3 , OCF 2 H, OCFH 2 , OCF 2 Cl, OCFCl 2 , OR 0 , OC(=O)-R 0 , OC(=O)-OR 0 , O-(C=O)-NH-R 0 , OC(=O)-N(R 0 ) 2 , OS(=O) 2 -R 0 , OS(=O) 2 -OH, OS(=O) 2 -OR 0 , OS(=O) 2 -NH 2 , OS(=O) 2 -NHR 0 , OS(=O) 2 -N(R 0 ) 2 , NH 2 , NHR 0 , N(R 0 ) 2 , NH-C(=O)-R 0 , NH-C(=O)-OR 0 , NH-C(=O)-NH 2 , NH-C(=O)-NH-R 0 , NH-C(=O)-N(R 0 ) 2 , NR 0 -C(=O)-R 0 , NR 0 -C(=O)-OR 0 , NR 0 -C(=O)-NH 2 , NR 0 -C(=O)-NH-R 0 , NR 0 -C(=O)-N(R 0 ) 2 , NH-S(=O) 2 -OH, NH-S(=O) 2 -R 0 , NH-S(=O) 2 - OR 0 , NH-S(=O) 2 -NH 2 , NH-S(=O) 2 -NHR 0 , NH-S(=O) 2 -N(R 0 ) 2 , NR 0 -S(=O 2 -OH, NR 0 -S(=O) 2 R 0 , NR 0 -S(=O) 2 -OR 0 , NR 0 -S(=O) 2 -NH 2 , NR 0 -S(=O 2 -NHR 0 , NR 0 -S(=O) 2 -N(R 0 ) 2 , SH, SCF 3 , SCF 2 H, SCFH 2 , SCF 2 Cl, SCFCl 2 , SR 0 , S(=O) -R 0 , S(=O) 2 -R 0 , S(=O) 2 -OH, S(=O) 2 -OR 0 , S(=O) 2 -NH 2 , S(=O) 2 - NHR 0 and S (= O) 2 -N ( R 0) 2 and other substituents of the group consisting of substituted; selectively single stereoisomer or mixture of stereoisomers Form thereof, the form of the free compound of solvent and / or a physiologically acceptable salt form or the form of the composition, based in particular hydrates.

於本發明，「單一立體異構物(single stereoisomer)」一詞包含個別對映異構物或非對映異構物。於本發明，「立體異構物之混合 物(mixture of stereoisomers)」一詞包含消旋物與任何混合比例之對映異構物混合物及/或非對映異構物。 In the present invention, the term "single stereoisomer" encompasses individual enantiomers or diastereomers. In the present invention, "a mixture of stereoisomers The term "mixture of stereoisomers" includes mixtures of the racemates and enantiomers and/or diastereomers in any mixing ratio.

於本發明，「生理上可接受之鹽(physiologically acceptable salt)」一詞包含一種鹽類，其含至少一根據本發明之化合物及至少一生理上可接受之酸或鹼。 In the present invention, the term "physiologically acceptable salt" encompasses a salt comprising at least one compound according to the invention and at least one physiologically acceptable acid or base.

於本發明，「C1-10脂族殘基(C1-10 aliphatic residue)」、「C1-8脂族殘基(C1-8 aliphatic residue)」及「C1-4脂族殘基(C1-4 aliphatic residue)」等詞包含無環之飽和或不飽和脂族烴殘基，其可係支鏈或非支鏈，亦可係未被取代或被單取代或被多取代，其分別含有1至10、或1至8、或1至4個碳原子；即分別為C1-10烷基(C1-10alkanyls，C1-10 alkyls)、C2-10烯基與C2-10炔基，及C1-8烷基(C1-8 alkanyls，C1-8 alkyls)、C2-8烯基與C2-8炔基，及C1-4烷基(C1-4 alkanyls，C1-4 alkyls)、C2-4烯基及C2-4炔基。烯基含有至少一C-C雙鍵(一C=C-鍵)，炔基含有至少一C-C三鍵(一C≡C-鍵)。脂族殘基以選自由烷基(alkanyl，alkyl)及烯基殘基組成之群組較佳，以烷基(alkanyl，alkyl)殘基更佳。較佳之C1-10烷基殘基係選自由甲基、乙基、正丙基、2-丙基、正丁基、異丁基、二級丁基、三級丁基、正戊基、異戊基、新戊基、正己基、正庚基、正辛基、正壬基與正癸基組成之群組。較佳之C1-8烷基殘基係選自由甲基、乙基、正丙基、2-丙基、正丁基、異丁基、二級丁基、三級丁基、正戊基、異戊基、新戊基、正己基、正庚基與正辛基組成之群組。較佳之C1-4烷基殘基係選自由甲基、乙基、正丙基、2-丙基、正丁基、異丁基、二級丁基與三級丁基組成之群組。較佳之C2-10烯基殘基係選自由乙烯基(ethenyl，vinyl)、丙烯基(-CH2CH=CH2、-CH=CH-CH3、-C(=CH2)-CH3)、丁烯基、戊烯基、己烯基、庚烯基、辛烯基、壬烯基與癸烯基組成之群組。較佳之 C2-8烯基殘基係選自由乙烯基(ethenyl，vinyl)、丙烯基(-CH2CH=CH2、-CH=CH-CH3、-C(=CH2)-CH3)、丁烯基、戊烯基、己烯基、庚烯基與壬烯基組成之群組。較佳之C2-4烯基殘基係選自由乙烯基(ethenyl，vinyl)、丙烯基(-CH2CH=CH2、-CH=CH-CH3、-C(=CH2)-CH3)與丁烯基組成之群組。較佳之C2-10炔基殘基係選自由乙炔基、丙炔基(-CH2-C≡CH、-C≡C-CH3)、丁炔基、戊炔基、己炔基、庚炔基、辛炔基、壬炔基與癸炔基組成之群組。較佳之C2-8炔基殘基選自由乙炔基、丙炔基(-CH2-C≡CH、-C≡C-CH3)、丁炔基、戊炔基、己炔基、庚炔基與辛炔基組成之群組。較佳之C2-4炔基殘基係選自由乙炔基、丙炔基(-CH2-C≡CH、-C≡C-CH3)與丁炔基組成之群組。 In the present invention, "C 1-10 aliphatic residue (C 1-10 aliphatic residue)", "C 1-8 aliphatic residue (C 1-8 aliphatic residue)" and "C 1-4 aliphatic residue The term "C 1-4 aliphatic residue"" includes an acyclic saturated or unsaturated aliphatic hydrocarbon residue which may be branched or unbranched, or may be unsubstituted or monosubstituted or polysubstituted, It contains 1 to 10, or 1 to 8, or 1 to 4 carbon atoms, respectively; that is, C 1-10 alkyl (C 1-10 alkanyls, C 1-10 alkyls), C 2-10 alkenyl and C 2-10 alkynyl, and C 1-8 alkyl (C 1-8 alkanyls, C 1-8 alkyls), C 2-8 alkenyl and C 2-8 alkynyl, and C 1-4 alkyl ( C 1-4 alkanyls, C 1-4 alkyls), C 2-4 alkenyl and C 2-4 alkynyl. The alkenyl group contains at least one CC double bond (a C=C-bond) and the alkynyl group contains at least one CC triple bond (a C≡C- bond). The aliphatic residue is preferably selected from the group consisting of an alkyl group (alkanyl, alkyl) and an alkenyl residue, and an alkanyl (alkyl) residue is more preferred. Preferred C 1-10 alkyl residues are selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, secondary butyl, tert-butyl, n-pentyl, A group consisting of isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, n-decyl and n-decyl. Preferred C 1-8 alkyl residues are selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, secondary butyl, tert-butyl, n-pentyl, A group consisting of isopentyl, neopentyl, n-hexyl, n-heptyl and n-octyl. Preferred C 1-4 alkyl residues are selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, secondary butyl and tertiary butyl. Preferred C 2-10 alkenyl residues are selected from the group consisting of ethenyl, vinyl, propylene (-CH 2 CH=CH 2 , -CH=CH-CH 3 , -C(=CH 2 )-CH 3 a group consisting of butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl and decenyl. Preferred C 2-8 alkenyl residues are selected from the group consisting of ethenyl, vinyl, propenyl (-CH 2 CH=CH 2 , -CH=CH-CH 3 , -C(=CH 2 )-CH 3 a group consisting of butenyl, pentenyl, hexenyl, heptenyl and decenyl. Preferred C 2-4 alkenyl residues are selected from the group consisting of ethenyl, vinyl, propenyl (-CH 2 CH=CH 2 , -CH=CH-CH 3 , -C(=CH 2 )-CH 3 ) a group consisting of butenyl groups. Preferred C 2-10 alkynyl residues are selected from the group consisting of ethynyl, propynyl (-CH 2 -C≡CH, -C≡C-CH 3 ), butynyl, pentynyl, hexynyl, g. A group consisting of an alkynyl group, an octynyl group, a decynyl group and a decynyl group. Preferred C 2-8 alkynyl residues are selected from the group consisting of ethynyl, propynyl (-CH 2 -C≡CH, -C≡C-CH 3 ), butynyl, pentynyl, hexynyl, heptyne A group consisting of a base and an octynyl group. Preferably, the C 2-4 alkynyl residue is selected from the group consisting of ethynyl, propynyl (-CH 2 -C≡CH, -C≡C-CH 3 ) and butynyl.

於本發明之目的，「C3-6環脂族殘基(C3-6 cycloaliphatic residue)」與「C3-10環脂族殘基(C3-10 cycloaliphatic residue)」等詞分別係指含有3、4、5或6個碳原子，及含有3、4、5、6、7、8、9或10個碳原子之環狀脂族烴，其中，烴基於各例中可係飽和或不飽和(但非芳香族)、未被取代或被單取代或被多取代。該環脂族殘基可經環脂族殘基上任何所需要或可能之環構件，與相應之上級總體結構(superordinate general structure)鍵結。該環脂族殘基亦可與其它飽和、(部分地)不飽和、(雜)環、芳香族或芳環系統縮合，即與環脂族、雜環脂族、芳基或雜芳基殘基縮合，其於各例中可進而係未被取代或被單取代或被多取代。C3-10環脂族殘基可進一步係於單處或多處橋接，例如，於金剛烷基(adamantly)、雙環[2,2,1]庚基或雙環[2,2,2]辛基之情況。較佳之C3-10環脂族殘基係選自由環丙基、環丁基、環戊基、環己基、環庚基、環辛基、環壬基、環癸基、金 剛烷基、、、、、環戊烯基、環己烯基、環庚烯基與環壬烯基組成之群組。較佳之C3-6環脂族殘基係選自由環丙基、環丁基、環戊基、環己基、環戊烯基與環己烯基組成之群組。特佳之C3-10環脂族與C3-6環脂族殘基係C5-6環脂族殘基，如環戊基、環己基、環戊烯基與環己烯基。 For the purposes of the present invention, "C 3-6 cycloaliphatic residue (C 3-6 cycloaliphatic residue)" and "C 3-10 cycloaliphatic residue (C 3-10 cycloaliphatic residue)" means the meanings respectively a cyclic aliphatic hydrocarbon containing 3, 4, 5 or 6 carbon atoms and containing 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, wherein the hydrocarbons may be saturated or based on each case Unsaturated (but not aromatic), unsubstituted or monosubstituted or polysubstituted. The cycloaliphatic residue can be bonded to the corresponding superordinate general structure via any desired or possible ring member on the cycloaliphatic residue. The cycloaliphatic residue may also be condensed with other saturated, (partially) unsaturated, (hetero), aromatic or aromatic ring systems, ie, with cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl residues. The base condensation, which in each case may be unsubstituted or monosubstituted or polysubstituted. The C 3-10 cycloaliphatic residue may be further bridged in a single or multiple positions, for example, in adamantly, bicyclo[2,2,1]heptyl or bicyclo[2,2,2]octyl The situation of the base. Preferred C 3-10 cycloaliphatic residues are selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclodecyl, adamantyl, , , , a group consisting of a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group and a cyclodecenyl group. Preferred C 3-6 cycloaliphatic residues are selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl. Particularly preferred C 3-10 cycloaliphatic and C 3-6 cycloaliphatic residues are C 5-6 cycloaliphatic residues such as cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl.

於本發明之目的，「3至6構件雜環脂族殘基(3-6-membered heterocycloaliphatic residue)」與「3至10構件雜環脂族殘基(3-10-membered heterocycloaliphatic residue)」等詞分別指具有3至6，即3、4、5或6個環構件，與3至10，即3、4、5、6、7、8、9或10個環構件之飽和或不飽和(但非芳香族)雜環脂族殘基，其於各例中有至少一碳原子，若適當亦可係2或3個碳原子，被以相互獨立地選自由O、S、S(=O)2、N、NH與N(C1-8烷基)，例如N(CH3)，等雜原子或雜原子基團組成之群組取代，以被相互獨立地選自由O、S、N、NH與N(C1-8烷基)，例如N(CH3)，等雜原子或雜原子基團組成之群組取代較佳，其中，該環構件可係未被取代或被單取代或被多取代。若未註明，該雜環脂族殘基可經雜環脂族殘基上任何所需之或可能之環構件，與相應之上級總體結構鍵結。該雜環脂族殘基亦可與其它飽和、(部分地)不飽和(雜)環脂族或芳香族或芳環系統縮合，即與環脂族、雜環脂族、芳基或雜芳基殘基縮合，其各自可進而係未被取代或被單取代或被多取代。較佳之雜環脂族殘基係選自由氮雜環丁基(azetidinyl)、氮丙啶基(aziridinyl)、氮雜環庚烷基(azepanyl)、氮啃基(azocanyl)、二氮雜環庚烷基(diazepanyl)、二硫戊烷基(dithiolanyl)、二氫喹啉基(dihydroquinolinyl)、二氫咯基(dihydropyrrolyl)、二氧雜環己基 (dioxanyl)、二氧雜環戊烷基(dioxolanyl)、二氧雜環庚烷基(dioxepanyl)、二氫茚基(dihydroindenyl)、二氫啶基(dihydropyridinyl)、二氫呋喃基(dihydrofuranyl)、二氫異喹啉基(dihydroisoquinolinyl)、二氫吲哚基(dihydroindolinyl)、二氫異吲哚基(dihydroisoindolyl)、咪唑啶基(imidazolidinyl)、異噁唑烷啉(isoxazolidinyl)、嗎咻基(morpholinyl)、環氧乙基(oxiranyl)、氧雜環丁基(oxetanyl)、氧雜氮雜環庚烷基(oxazepanyl)、咯啶基(pyrrolidinyl)、哌嗪基(piperazinyl)、4-甲基哌嗪基(4-methylpiperazinyl)、哌啶基(piperidinyl)、吡唑啶基(pyrazolidinyl)、吡喃基(pyranyl)、四氫咯基(tetrahydropyrrolyl)、四氫吡喃基(tetrahydropyranyl)、四氫-2H-吡喃-4-基(tetrahydro-2H-pyran-4-yl)、四氫喹啉基(tetrahydroquinolinyl)、四氫異喹啉基(tetrahydroisoquinolinyl)、四氫吲哚基(tetrahydroindolinyl)、四氫呋喃基(tetrahydrofuranyl)、四氫啶基(tetrahydropyridinyl)、四氫苯硫基(tetrahydrothiophenyl)、四氫啶吲哚基(tetrahydropyridoindolyl)、四氫萘基(tetrahydronaphthyl)、四氫咔啉基(tetrahydrocarbolinyl)、四氫異噁唑基(tetrahydroisoxazololyl)、四氫啶基(tetrahydropyridinyl)、噻唑烷基(thiazolidinyl)與硫基嗎咻基(thiomorpholinyl)組成之群組。 For the purpose of the present invention, "3-6-membered heterocycloaliphatic residue" and "3-10-membered heterocycloaliphatic residue", etc. The words respectively mean that there are 3 to 6, ie 3, 4, 5 or 6 ring members, and 3 to 10, ie 3, 4, 5, 6, 7, 8, 9 or 10 ring members are saturated or unsaturated ( a non-aromatic heterocyclic aliphatic residue, which in each case has at least one carbon atom, if appropriate 2 or 3 carbon atoms, is independently selected from O, S, S (=O) 2 , N, NH and N (C 1-8 alkyl), such as N (CH 3 ), a group of heteroatoms or heteroatoms, such as groups, are substituted independently of each other from O, S, N a group substitution of NH and N (C 1-8 alkyl), such as N(CH 3 ), a hetero atom or a hetero atom group, wherein the ring member may be unsubstituted or monosubstituted or Being replaced by many. If not indicated, the heterocyclic aliphatic residue can be bonded to the corresponding superior overall structure via any desired or possible ring member on the heterocyclic aliphatic residue. The heterocyclic aliphatic residue may also be condensed with other saturated, (partially) unsaturated (hetero) cycloaliphatic or aromatic or aromatic ring systems, ie, with cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl The base residues are condensed, each of which may in turn be unsubstituted or monosubstituted or polysubstituted. Preferred heterocyclic aliphatic residues are selected from the group consisting of azetidinyl, aziridinyl, azepanyl, azocanyl, diazepine. Diazepanyl, dithiolanyl, dihydroquinolinyl, dihydropyrrolyl, dioxanyl, dioxolyl , dioxepanyl, dihydroindenyl, dihydropyridinyl, dihydrofuranyl, dihydroisoquinolinyl, dihydroanthracene Dihydroindolinyl, dihydroisoindolyl, imidazolidinyl, isoxazolidinyl, morpholinyl, oxiranyl, oxirane Oxetanyl, oxazepanyl, pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidinyl ), pyrazolidinyl, pyranyl, tetrahydropyrrolyl, tetrahydropyridyl Tetrahydropyranyl, tetrahydro-2H-pyran-4-yl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroanthracene Tetrahydroindolinyl, tetrahydrofuranyl, tetrahydropyridinyl, tetrahydrothiophenyl, tetrahydropyridoindolyl, tetrahydronaphthyl, tetrahydroanthracene A group consisting of tetrahydrocarbolinyl, tetrahydroisoxazololyl, tetrahydropyridinyl, thiazolidinyl and thiomorpholinyl.

於本發明之目的，「芳基(aryl)」一詞係指具有6至14個環構件，即6、7、8、9、10、11、12、13或14個環構件之芳香族烴基，以具有6至10個環構件，即6、7、8、9或10個環構件較佳，包括苯基與萘基。各芳基殘基可係未被取代或被單取代或被多取代，其中，芳基取代基可係相同或不同，及可於芳基殘基上任何需要或可能之位置。該芳基可經任何所需或可能之芳基殘基之環構件與上級結構鍵結。該芳基殘基亦可與其它飽和、(部分地)不飽 和、(雜)環脂族、芳香族或芳環系統縮合，即與環脂族、雜環脂族、芳基或雜芳基殘基縮合，其可進而係未被取代或被單取代或被多取代。被縮合之芳基殘基實例為苯並二氧雜環己基(benzodioxolanyl)與苯並二氧雜環己烷(benzodioxanyl)。芳基以選自由苯基、1-萘基、2-萘基、茀基與蒽基(anthracenyl)組成之群組較佳，其各自可分別係未被取代或被單取代或被多取代。一特佳之芳基係未被取代或被單取代或被多取代之苯基。 For the purposes of the present invention, the term "aryl" refers to an aromatic hydrocarbon radical having from 6 to 14 ring members, ie 6, 7, 8, 9, 9, 10, 11, 12, 13 or 14 ring members. Preferably, it has 6 to 10 ring members, that is, 6, 7, 8, 9 or 10 ring members, including a phenyl group and a naphthyl group. Each aryl residue may be unsubstituted or monosubstituted or polysubstituted, wherein the aryl substituents may be the same or different and may be at any desired or possible position on the aryl residue. The aryl group can be bonded to the superior structure via a ring member of any desired or possible aryl residue. The aryl residue may also be saturated with other, partially (not) Condensation with a (hetero)cycloaliphatic, aromatic or aromatic ring system, ie with a cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl residue, which may in turn be unsubstituted or monosubstituted or More substitution. Examples of condensed aryl residues are benzodioxolanyl and benzodioxanyl. The aryl group is preferably selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, anthracenyl and anthracenyl, each of which may be unsubstituted or monosubstituted or polysubstituted, respectively. A particularly preferred aryl group is a phenyl group which is unsubstituted or monosubstituted or polysubstituted.

於本發明之目的，「雜芳基(heteroaryl)」一詞係代表一含有至少一雜原子之5或6構件之環狀芳香族殘基，若適當亦可含2、3、4或5個雜原子，其中，該雜原子係各自相互獨立地選自由S、N與O組成之群組，及該雜芳基殘基可係未被取代或被單取代或被多取代；於雜芳基被取代之狀況下，其取代基可係相同或不同，且可於雜芳基上任何需要或可能之位置。若未註明，其可於雜芳基殘基上任何需要或可能之位置與上級總體結構鍵結。該雜芳基亦可係具有多達14個環構件之雙環或多環系統之一部分，其中，該環系統可由其他飽和、(部分地)不飽和、(雜)環脂族或芳香族或芳環所構成，即由環脂族、雜環脂族、芳基或雜芳基殘基構成，其可進而係未被取代或被單取代或被多取代。雜芳基殘基以選自由苯並呋喃基(benzofuranyl)、苯並咪唑基(benzoimidazolyl)、苯並吩基(benzothienyl)、苯並噻二唑基(benzothiadiazolyl)、苯並噻唑基(benzothiazolyl)、苯並三唑基(benzotriazolyl)、苯並噁唑基(benzooxazolyl)、苯並噁二唑基(benzooxadiazolyl)、喹唑啉基(quinazolinyl)、喹喔啉基(quinoxalinyl)、唑基(carbazolyl)、喹啉基(quinolinyl)、二苯並呋喃基(dibenzofuranyl)、二苯並吩基(dibenzothienyl)、呋喃基(furyl，furanyl)、咪唑基(imidazolyl)、咪唑噻唑基(imidazothiazolyl)、吲唑基(indazolyl)、吲哚嗪基 (indolizinyl)、吲哚基(indolyl)、異喹啉基(isoquinolinyl)、異噁唑(isoxazoyl)、異噻唑(isothiazolyl)、吲哚基、萘啶基(naphthyridinyl)、噁唑基、噁二唑基、吩嗪基(phenazinyl)、吩噻嗪基(phenothiazinyl)、酞嗪基(phthalazinyl)、吡唑基(pyrazolyl)、啶基(2-啶基、3-啶基、4-啶基)、咯基(pyrrolyl)、噠嗪基(pyridazinyl)、嘧啶基(pyrimidinyl)、吡嗪基(pyrazinyl)、嘌呤基(purinyl)、吩嗪基(phenazinyl)、吩基(苯硫基)(thienyl(thiophenyl))、三唑基(triazolyl)、四唑基(tetrazolyl)、噻唑基(thiazolyl)、噻二唑基(thiadiazolyl)與三嗪基(triazinyl)組成之群組較佳。 For the purposes of the present invention, the term "heteroaryl" refers to a cyclic aromatic residue containing 5 or 6 members of at least one hetero atom, and may suitably contain 2, 3, 4 or 5 if appropriate. a hetero atom, wherein the hetero atom is each independently selected from the group consisting of S, N and O, and the heteroaryl residue may be unsubstituted or monosubstituted or polysubstituted; the heteroaryl is In the case of substitution, the substituents may be the same or different and may be at any desired or possible position on the heteroaryl. If not stated, it can be bonded to the superior structure at any desired or possible position on the heteroaryl residue. The heteroaryl group can also be part of a bicyclic or polycyclic ring system having up to 14 ring members, wherein the ring system can be composed of other saturated, (partially) unsaturated, (hetero) cycloaliphatic or aromatic or aromatic The ring is composed of a cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl residue which may in turn be unsubstituted or monosubstituted or polysubstituted. The heteroaryl residue is selected from the group consisting of benzofuranyl, benzoimidazolyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, Benzotriazolyl, benzooxazolyl, benzooxadiazolyl, quinazolinyl, quinoxalinyl, carbazolyl, Quinolinyl, dibenzofuranyl, dibenzothienyl, furyl, furanyl, imidazolyl, imidazothiazolyl, carbazolyl Indazolyl), pyridazinyl (indolizinyl), indolyl, isoquinolinyl, isoxazoyl, isothiazolyl, sulfhydryl, naphthyridinyl, oxazolyl, oxadiazole Phenazinyl, phenothiazinyl, phthalazinyl, pyrazolyl, pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), Pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, purinyl, phenazinyl, thiophenyl (thiophenyl) The group consisting of triazolyl, tetrazolyl, thiazolyl, thiadiazolyl and triazinyl is preferred.

於本發明之目的，「經由一C1-4脂族基或經由一C1-8脂族基橋接(bridged via a C1-4 aliphatic group or via a C1-8 aliphatic group)」一詞於殘基，如芳基、雜芳基、雜環脂族殘基與環脂族殘基中，係指該殘基具有上述意義，及該殘基係分別經由一C1-4脂族基或經由一C1-8脂族基與相應之上級總體結構鍵結。該C1-4脂族基與該C1-8脂族基於所有狀況下，可係支鏈或非支鏈，未被取代或被單取代或被多取代。該C1-4脂族基於所有狀況下，可進而係飽和或不飽和，即其可係一C1-4伸烷基、一C2-4伸烯基或一C2-4亞炔基。C1-8脂族基亦是如此，即一C1-8脂族基於所有狀況下，可進而係飽和或不飽和，即其可係一C1-8伸烷基、一C2-8伸烯基或一C2-8亞炔基。較佳地，該C1-4-脂族基係一C1-4伸烷基或一C2-4伸烯基，以係一C1-4伸烷基更佳。較佳地，該C1-8脂族基係一C1-8伸烷基或一C2-8伸烯基，以係一C1-8伸烷基更佳。較佳之C1-4伸烷基係選自由-CH2-、-Ch2-CH2-、-CH(CH3)-、-CH2-CH2-CH2、-CH(CH3)-CH2-、-CH(CH2CH3)-、-CH2-(CH2)2-CH2-、-CH(CH3)-CH2-CH2-、-CH2-CH(CH3)-CH2-、-CH(CH3)-CH(CH3)-、-CH(CH2CH3)-CH2-、-C(CH3)2-CH2-、-CH(CH2CH2CH3)-與- C(CH3)(CH2CH3)-組成之群組。較佳之C2-4伸烯基係選自由-CH=CH-、-CH=CH-CH2-、-C(CH3)=CH2-、-CH=CH-CH2-CH2-、-CH2-CH=CH-CH2-、-CH=CH-CH=CH-、-C(CH3)=CH-CH2-、-CH=C(CH3)-CH2-、-C(CH3)=C(CH3)-與-C(CH2CH3)=CH-組成之群組。較佳之C2-4亞炔基係選自由-C≡C-、-C≡C-CH2-、-C≡C-CH2-CH2-、-C≡C-CH(CH3)-、-CH2-C≡C-CH2-與-C≡C-C≡C-組成之群組。較佳之C1-8伸烷基係選自由-CH2-、-CH2-CH2-、-CH(CH3)-、-CH2-CH2-CH2-、-CH(CH3)-CH2-、-CH(CH2CH3)-、-CH2-(CH2)2-CH2-、-CH(CH3)-CH2-CH2-、-CH2-CH(CH3)-CH2-、-CH(CH3)-CH(CH3)-、-CH(CH2CH3)-CH2-、-C(CH3)2-CH2-、-CH(CH2CH2CH3)-、-C(CH3)(CH2CH3)-、-CH2-(CH2)3-CH2-、-CH(CH3)-CH2-CH2-CH2-、-CH2-CH(CH3)-CH2-CH2-、-CH(CH3)-CH2-CH(CH3)-、-CH(CH3)-CH(CH3)-CH2-、-C(CH3)2-CH2-CH2-、-CH2-C(CH3)2-CH2-、-CH(CH2CH3)-CH2-CH2-、-CH2-CH(CH2CH3)-CH2-、-C(CH3)2-CH(CH3)-、-CH(CH2CH3)-CH(CH3)-、-C(CH3)(CH2CH3)-CH2-、-CH(CH2CH2CH3)-CH2-、-C(CH2CH2CH3)-CH2-、-CH(CH2CH2CH2CH3)-、-C(CH3)(CH2CH2CH3)-、-C(CH2CH3)2-與-CH2-(CH2)4-CH2-組成之群組。較佳之C2-8伸烯基係選自由-CH=CH-、-CH=CH-CH2-、-C(CH3)=CH2-、-CH=CH-CH2-CH2--CH2-CH=CH-CH2-、-CH=CH-CH=CH-、-C(CH3)=CH-CH2-、-CH=C(CH3)-CH2-、-C(CH3)=C(CH3)-、-C(CH2CH3)=CH-、-CH=CH-CH2-CH2-CH2-、-CH2-CH=CH2-CH2-CH2-、-CH=CH=CH-CH2-CH2-與-CH=CH2-CH-CH=CH2-組成之群組。較佳之C2-8亞炔基係選自由-C≡C-、-C≡C-CH2-、-C≡C-CH2-CH2-、-C≡C-CH(CH3)-、-CH2-C≡C-CH2-、-C≡C-C≡C-、-C≡C-C(CH3)2-、-C≡C-CH2-CH2-CH2-、-CH2-C≡C-CH2-CH2-、-C≡C-C≡C-CH2-與-C≡C-CH2-C≡C組成之群 組。 For the purposes of the present invention, the term "via a C 1-4 aliphatic group or via a C 1-8 aliphatic group bridge (bridged via a C 1-4 aliphatic group or via a C 1-8 aliphatic group) " In the case of a residue, such as an aryl group, a heteroaryl group, a heterocyclic aliphatic residue and a cycloaliphatic residue, it means that the residue has the above meaning, and the residue is via a C 1-4 aliphatic group, respectively. Or via a C 1-8 aliphatic group bonded to the corresponding upper level overall structure. The C 1-4 aliphatic group and the C 1-8 aliphatic group may be branched or unbranched, unsubstituted or monosubstituted or polysubstituted, based on all conditions. The C 1-4 aliphatic group may be saturated or unsaturated under all conditions, that is, it may be a C 1-4 alkylene group, a C 2-4 alkylene group or a C 2-4 alkynylene group. . The same is true for the C 1-8 aliphatic group, that is, a C 1-8 aliphatic group can be saturated or unsaturated based on all conditions, that is, it can be a C 1-8 alkylene group, a C 2-8 group. An alkenyl group or a C 2-8 alkynylene group. Preferably, the C 1-4 -aliphatic group is a C 1-4 alkylene group or a C 2-4 alkylene group, more preferably a C 1-4 alkylene group. Preferably, the C 1-8 aliphatic group is a C 1-8 alkylene group or a C 2-8 alkylene group, preferably a C 1-8 alkylene group. Preferably, the C 1-4 alkylene group is selected from the group consisting of -CH 2 -, -Ch 2 -CH 2 -, -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 , -CH(CH 3 )- CH 2 -, -CH(CH 2 CH 3 )-, -CH 2 -(CH 2 ) 2 -CH 2 -, -CH(CH 3 )-CH 2 -CH 2 -, -CH 2 -CH (CH 3 )-CH 2 -, -CH(CH 3 )-CH(CH 3 )-, -CH(CH 2 CH 3 )-CH 2 -, -C(CH 3 ) 2 -CH 2 -, -CH(CH 2 A group consisting of CH 2 CH 3 )- and - C(CH 3 )(CH 2 CH 3 )-. Preferably, the C 2-4 alkenyl group is selected from the group consisting of -CH=CH-, -CH=CH-CH 2 -, -C(CH 3 )=CH 2 -, -CH=CH-CH 2 -CH 2 -, -CH 2 -CH=CH-CH 2 -, -CH=CH-CH=CH-, -C(CH 3 )=CH-CH 2 -, -CH=C(CH 3 )-CH 2 -, -C (CH 3 )=Group of C(CH 3 )- and -C(CH 2 CH 3 )=CH-. Preferably, the C 2-4 alkynylene group is selected from the group consisting of -C≡C-, -C≡C-CH 2 -, -C≡C-CH 2 -CH 2 -, -C≡C-CH(CH 3 )- a group consisting of -CH 2 -C≡C-CH 2 - and -C≡CC≡C-. Preferably, the C 1-8 alkylene group is selected from the group consisting of -CH 2 -, -CH 2 -CH 2 -, -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -, -CH(CH 3 ) -CH 2 -, -CH(CH 2 CH 3 )-, -CH 2 -(CH 2 ) 2 -CH 2 -, -CH(CH 3 )-CH 2 -CH 2 -, -CH 2 -CH(CH 3 ) -CH 2 -, -CH(CH 3 )-CH(CH 3 )-, -CH(CH 2 CH 3 )-CH 2 -, -C(CH 3 ) 2 -CH 2 -, -CH(CH 2 CH 2 CH 3 )-, -C(CH 3 )(CH 2 CH 3 )-, -CH 2 -(CH 2 ) 3 -CH 2 -, -CH(CH 3 )-CH 2 -CH 2 -CH 2 -, -CH 2 -CH(CH 3 )-CH 2 -CH 2 -, -CH(CH 3 )-CH 2 -CH(CH 3 )-, -CH(CH 3 )-CH(CH 3 )- CH 2 -, -C(CH 3 ) 2 -CH 2 -CH 2 -, -CH 2 -C(CH 3 ) 2 -CH 2 -, -CH(CH 2 CH 3 )-CH 2 -CH 2 -, -CH 2 -CH(CH 2 CH 3 )-CH 2 -, -C(CH 3 ) 2 -CH(CH 3 )-, -CH(CH 2 CH 3 )-CH(CH 3 )-, -C( CH 3 )(CH 2 CH 3 )-CH 2 -, -CH(CH 2 CH 2 CH 3 )-CH 2 -, -C(CH 2 CH 2 CH 3 )-CH 2 -, -CH(CH 2 CH 2 CH 2 CH 3 )-, -C(CH 3 )(CH 2 CH 2 CH 3 )-, -C(CH 2 CH 3 ) 2 - and -CH 2 -(CH 2 ) 4 -CH 2 - Group. Preferably, the C 2-8 extended alkenyl group is selected from the group consisting of -CH=CH-, -CH=CH-CH 2 -, -C(CH 3 )=CH 2 -, -CH=CH-CH 2 -CH 2 -- CH 2 -CH=CH-CH 2 -, -CH=CH-CH=CH-, -C(CH 3 )=CH-CH 2 -, -CH=C(CH 3 )-CH 2 -, -C( CH 3 )=C(CH 3 )-, -C(CH 2 CH 3 )=CH-, -CH=CH-CH 2 -CH 2 -CH 2 -, -CH 2 -CH=CH 2 -CH 2 - A group consisting of CH 2 -, -CH=CH=CH-CH 2 -CH 2 - and -CH=CH 2 -CH-CH=CH 2 -. Preferably, the C 2-8 alkynylene group is selected from the group consisting of -C≡C-, -C≡C-CH 2 -, -C≡C-CH 2 -CH 2 -, -C≡C-CH(CH 3 )- , -CH 2 -C≡C-CH 2 -, -C≡CC≡C-, -C≡CC(CH 3 ) 2 -, -C≡C-CH 2 -CH 2 -CH 2 -, -CH 2 a group consisting of -C≡C-CH 2 -CH 2 -, -C≡CC≡C-CH 2 - and -C≡C-CH 2 -C≡C.

於本發明，與「脂族殘基(aliphatic residue)」、「脂族基(aliphatic group)」、「環脂族殘基(cycloaliphatic residue)」及「雜環脂族殘基(heterocycloaliphatic residue)」等詞相關之「被單取代或多取代(mono-or polysubstituted)」，係指分別與其相應與其相應之殘基或功能基上，有一或多個氫原子各自相互獨立地被至少一選自由F、Cl、Br、I、NO2、CN、=O、=NH、=N(OH)、=C(NH2)2、CF3、CF2H、CFH2、CF2Cl、CFCl2、R0、C(=O)-H、C(=O)-R0、C(=O)-OH、C(=O)-OR0、CO-NH2、C(=O)-NHR0、C(=O)-N(R0)2、OH、OCF3、OCF2H、OCFH2、OCF2Cl、OCFCl2、OR0、O-C(=O)-R0、O-C(=O)-O-R0、O-(C=O)-NH-R0、O-C(=O)-N(R0)2、O-S(=O)2-R0、O-S(=O)2-OH、O-S(=O)2-OR0、O-S(=O)2-NH2、O-S(=O)2-NHR0、O-S(=O)2-N(R0)2、NH2、NH-R0、N(R0)2、NH-C(=O)-R0、NH-C(=O)-O-R0、NH-C(=O)-NH2、NH-C(=O)-NHR0、NH-C(=O)-N(R0)2、NR0-C(=O)-R0、NR0-C(=O)-O-R0、NR0-C(=O)-NH2、NR0-C(=O)-NHR0、NR0-C(=O)-N(R0)2、NH-S(=O)2-OH、NH-S(=O)2-R0、NH-S(=O)2-OR0、NH-S(=O)2-NH2、NH-S(=O)2-NHR0、NH-S(=O)2-N(R0)2、NR0-S(=O)2-OH、NR0-S(=O)2-R0、NR0-S(=O)2-OR0、NR0-S(=O)2-NH2、NR0-S(=O)2-NHR0、NR0-S(=O)2-N(R0)2、SH、SCF3、SCF2H、SCFH2、SCF2Cl、SCFCl2、SR0、S(=O)-R0、S(=O)2-R0、S(=O)2-OH、S(=O)2-OR0、S(=O)2-NH2、S(=O)2-NHR0與S(=O)2-N(R0)2組成之群組單取代或多取代，例如二取代、三取代、四取代或五取代。「被多取代(polysubstituted)」一詞於被多取代之殘基與功能基之意義，包括這些殘基或功能基於不同或相同原子被多取代，例如於同一碳原子被三取代，如CF3、CH2CF3或1,1-二氟環己基之狀況， 或於不同位置被多取代，如CH(OH)-CH=CH-CHCl2或1-氯-3-氟環己基之狀況。若適當，取代基本身可進而被單取代或多取代。可以相同或不同之取代基進行多取代。 In the present invention, and "aliphatic residue", "aliphatic group", "cycloaliphatic residue" and "heterocycloaliphatic residue" The term "mono-or polysubstituted" as used herein, refers to a residue or a functional group corresponding thereto, respectively, wherein one or more hydrogen atoms are independently selected from each other by at least one selected from F, Cl, Br, I, NO 2 , CN, =O, =NH, =N(OH), =C(NH 2 ) 2 , CF 3 , CF 2 H, CFH 2 , CF 2 Cl, CFCl 2 , R 0 , C(=O)-H, C(=O)-R 0 , C(=O)-OH, C(=O)-OR 0 , CO-NH 2 , C(=O)-NHR 0 , C (=O)-N(R 0 ) 2 , OH, OCF 3 , OCF 2 H, OCFH 2 , OCF 2 Cl, OCFCl 2 , OR 0 , OC(=O)-R 0 , OC(=O)-OR 0 , O-(C=O)-NH-R 0 , OC(=O)-N(R 0 ) 2 , OS(=O) 2 -R 0 , OS(=O) 2 -OH, OS(= O) 2 -OR 0 , OS(=O) 2 -NH 2 , OS(=O) 2 -NHR 0 , OS(=O) 2 -N(R 0 ) 2 , NH 2 , NH-R 0 , N (R 0 ) 2 , NH-C(=O)-R 0 , NH-C(=O)-OR 0 , NH-C(=O)-NH 2 , NH-C(=O)-NHR 0 , NH-C(=O)-N(R 0 ) 2 , NR 0 -C(=O)-R 0 , NR 0 -C(=O )-OR 0 , NR 0 -C(=O)-NH 2 , NR 0 -C(=O)-NHR 0 , NR 0 -C(=O)-N(R 0 ) 2 , NH-S(= O) 2 -OH, NH-S(=O) 2 -R 0 , NH-S(=O) 2 -OR 0 , NH-S(=O) 2 -NH 2 , NH-S(=O) 2 -NHR 0 , NH-S(=O) 2 -N(R 0 ) 2 , NR 0 -S(=O) 2 -OH, NR 0 -S(=O) 2 -R 0 , NR 0 -S( =O) 2 -OR 0 , NR 0 -S(=O) 2 -NH 2 , NR 0 -S(=O) 2 -NHR 0 , NR 0 -S(=O) 2 -N(R 0 ) 2 , SH, SCF 3 , SCF 2 H, SCFH 2 , SCF 2 Cl, SCFCl 2 , SR 0 , S(=O)-R 0 , S(=O) 2 -R 0 , S(=O) 2 -OH , S(=O) 2 -OR 0 , S(=O) 2 -NH 2 , S(=O) 2 -NHR 0 and S(=O) 2 -N(R 0 ) 2 Or multiple substitutions, such as disubstituted, trisubstituted, tetrasubstituted or pentasubstituted. The term "polysubstituted" is used in the meaning of a polysubstituted residue and a functional group, including the substitution of these residues or functions based on different or identical atoms, for example, the same carbon atom is trisubstituted, such as CF 3 . , the condition of CH 2 CF 3 or 1,1-difluorocyclohexyl, or polysubstituted at different positions, such as the condition of CH(OH)-CH=CH-CHCl 2 or 1-chloro-3-fluorocyclohexyl. If appropriate, the substituting body may in turn be monosubstituted or substituted. Multiple substitutions can be made with the same or different substituents.

「脂族殘基(aliphatic residue)」與「脂族基(aliphatic group)」較佳之取代基係選自由F、Cl、Br、I、NO2、CF3、CN、=O、=NH、R0、(C1-8伸烷基)-OH、C(=O)(R0或H)、C(=O)O(R0或H)、C(=O)N(R0或H)2、OH、OR0、O-C(=O)-R0、O-(C1-8伸烷基)-OH、O-(C1-8伸烷基)-O-C1-8烷基、OCF3、N(R0或H)2、N(R0或H)-C(=O)-R0、N(R0或H)-S(=O)2-R0、N(R0或H)-C(=O)-N(R0或H)2、SH、SCF3、SR0、S(=O)2R0、S(=O)2O(R0或H)與S(=O)2-N(R0或H)2組成之群組。 Preferred substituents for "aliphatic residue" and "aliphatic group" are selected from the group consisting of F, Cl, Br, I, NO 2 , CF 3 , CN, =O, =NH, R 0 , (C 1-8 alkylene)-OH, C(=O)(R 0 or H), C(=O)O(R 0 or H), C(=O)N(R 0 or H 2 , OH, OR 0 , OC(=O)-R 0 , O-(C 1-8alkylene )-OH, O-(C 1-8alkylene )-OC 1-8 alkyl, OCF 3 , N(R 0 or H) 2 , N(R 0 or H)-C(=O)-R 0 , N(R 0 or H)-S(=O) 2 -R 0 , N(R 0 or H)-C(=O)-N(R 0 or H) 2 , SH, SCF 3 , SR 0 , S(=O) 2 R 0 , S(=O) 2 O(R 0 or H) A group consisting of S(=O) 2 -N(R 0 or H) 2 .

「脂族殘基(aliphatic residue)」與「脂族基(aliphatic group)」特佳之取代基係選自由F、Cl、Br、I、NO2、CF3、CN、=O、C1-8脂族殘基、經芳基、雜芳基、C3-6環脂族殘基、3至6構件雜環脂族殘基、經一C1-4脂族基橋接之芳基、雜芳基、C3-6環脂族殘基或3至6構件雜芳脂族，CHO、C(=O)-C1-8脂族殘基、C(=O)芳基、C(=O)雜芳基、CO2H、C(=O)O-C1-8脂族殘基、C(=O)O-芳基、C(=O)O-雜芳基、C(=O)-NH2、C(=O)NH-C1-8脂族殘基、C(=O)N(C1-8脂族殘基)2、C(=O)NH-芳基、C(=O)N(芳基)2、C(=O)NH-雜芳基、C(=O)N(雜芳基)2、C(=O)N(C1-8脂族殘基)(芳基)、C(=O)N(C1-8脂族殘基)(雜芳基)、C(=O)N(雜芳基)(芳基)、OH、O-C1-8脂族殘基、OCF3、O-(C1-8脂族殘基)-OH、O-(C1-8脂族基)-O-C1-8脂族殘基、O-苄基、O-芳基、O-雜芳基、O-C(=O)-C1-8脂族殘基、O-C(=O)芳基、O-C(=O)雜芳基、NH2、NH-C1-8脂族殘基、NH-(C1-8脂族基)-OH、N(C1-8脂族殘基)[(C1-8脂族基)-OH]、N(C1-8脂族殘基)2、NH-C(=O)-C1-8脂族殘基、NH-S(=O)2-C1-8脂族殘基、N(C1-8脂族殘基)[S(=O)2-C1-8脂族殘基]、NH-S(=O)2-NH2、NH-C(=O)-芳基、 NH-C(=O)-雜芳基、SH、S-C1-8脂族殘基、SCF3、S-苄基、S-芳基、S-雜芳基、S(=O)2-C1-8脂族殘基、S(=O)2芳基、S(=O)2雜芳基、S(=O)2OH、S(=O)2O-C1-8脂族殘基、S(=O)2O-芳基、S(=O)2O-雜芳基、S(=O)2-NH-C1-8脂族殘基、S(=O)2-NH-芳基與S(=O)2-NH-雜芳基組成之群組。 The preferred substituents of "aliphatic residue" and "aliphatic group" are selected from the group consisting of F, Cl, Br, I, NO 2 , CF 3 , CN, =O, C 1-8. An aliphatic residue, an aryl group, a heteroaryl group, a C 3-6 cycloaliphatic residue, a 3 to 6 membered heterocyclic aliphatic residue, an aryl group bridged by a C 1-4 aliphatic group, a heteroaryl group a C 3-6 cycloaliphatic residue or a 3 to 6 member heteroaromatic aliphatic group, CHO, C(=O)-C 1-8 aliphatic residue, C(=O)aryl, C(=O Heteroaryl, CO 2 H, C(=O)OC 1-8 aliphatic residue, C(=O)O-aryl, C(=O)O-heteroaryl, C(=O)- NH 2 , C(=O)NH-C 1-8 aliphatic residue, C(=O)N(C 1-8 aliphatic residue) 2 , C(=O)NH-aryl, C(= O) N(aryl) 2 , C(=O)NH-heteroaryl, C(=O)N(heteroaryl) 2 , C(=O)N(C 1-8 aliphatic residue) Aryl), C(=O)N(C 1-8 aliphatic residue) (heteroaryl), C(=O)N(heteroaryl)(aryl), OH, OC 1-8 aliphatic Residue, OCF 3 , O-(C 1-8 aliphatic residue)-OH, O-(C 1-8 aliphatic)-OC 1-8 aliphatic residue, O-benzyl, O-aryl Base, O-heteroaryl, OC(=O)-C 1-8 aliphatic residue, OC(=O)aryl, OC(=O)heteroaryl, NH 2 , NH-C 1-8 Family residues, NH-(C 1-8 aliphatic)-OH, N (C 1-8 aliphatic Residue) [(C 1-8 aliphatic)-OH], N (C 1-8 aliphatic residue) 2 , NH-C(=O)-C 1-8 aliphatic residue, NH-S (=O) 2 -C 1-8 aliphatic residue, N (C 1-8 aliphatic residue) [S(=O) 2 -C 1-8 aliphatic residue], NH-S (=O 2 -NH 2 , NH-C(=O)-aryl, NH-C(=O)-heteroaryl, SH, SC 1-8 aliphatic residue, SCF 3 , S-benzyl, S- Aryl, S-heteroaryl, S(=O) 2 -C 1-8 aliphatic residue, S(=O) 2 aryl, S(=O) 2 heteroaryl, S(=O) 2 OH, S(=O) 2 OC 1-8 aliphatic residue, S(=O) 2 O-aryl, S(=O) 2 O-heteroaryl, S(=O) 2 -NH-C A group consisting of 1-8 aliphatic residues, S(=O) 2 -NH-aryl groups and S(=O) 2 -NH-heteroaryl groups.

「脂族殘基(aliphatic residue)」與「脂族基(aliphatic group)」最佳之取代基係選自由F、Cl、Br、I、CF3、C(=O)-NH2、C(=O)NH-C1-8脂族殘基、C(=O)N(C1-8脂族殘基)2、OH、O-C1-8脂族殘基、O-(C1-8脂族殘基)-OH、O-(C1-8脂族基)-O-C1-8脂族殘基、NH2、NH-C1-8脂族殘基、N(C1-8脂族殘基)2、NH-(C1-8脂族基)-OH、N(C1-8脂族殘基)[(C1-8脂族基)-OH]、NH-C(=O)-C1-8脂族殘基、NH-S(=O)2-C1-8脂族殘基、N(C1-8脂族殘基)[S(=O)2-C1-8脂族殘基]、NH-S(=O)2-NH2、SH、S-C1-8脂族殘基、S(=O)2-C1-8脂族殘基與S(=O)2-NH-C1-8脂族殘基組成之群組。 The preferred substituents for "aliphatic residue" and "aliphatic group" are selected from the group consisting of F, Cl, Br, I, CF 3 , C(=O)-NH 2 , C ( =O) NH-C 1-8 aliphatic residue, C(=O)N (C 1-8 aliphatic residue) 2 , OH, OC 1-8 aliphatic residue, O-(C 1-8 Aliphatic residue) -OH, O-(C 1-8 aliphatic)-OC 1-8 aliphatic residue, NH 2 , NH-C 1-8 aliphatic residue, N (C 1-8 fat) Family residue) 2 , NH-(C 1-8 aliphatic)-OH, N (C 1-8 aliphatic residue) [(C 1-8 aliphatic)-OH], NH-C (= O)-C 1-8 aliphatic residue, NH-S(=O) 2 -C 1-8 aliphatic residue, N(C 1-8 aliphatic residue) [S(=O) 2 -C 1-8 aliphatic residue], NH-S(=O) 2 -NH 2 , SH, SC 1-8 aliphatic residue, S(=O) 2 -C 1-8 aliphatic residue and S ( =O) Group of 2 -NH-C 1-8 aliphatic residues.

「環脂族殘基(cycloaliphatic residue)」與「雜環脂族殘基(heterocycloaliphatic residue)」較佳之取代基係選自由F、Cl、Br、I、NO2、CF3、CN、=O、=NH、R0、C(=O)(R0或H)、C(=O)O(R0或H)、C(=O)N(R0或H)2、OH、OR0、O-C(=O)-R0、O-(C1-8烷基)-OH、O-(C1-8烷基)-O-C1-8烷基、OCF3、N(R0或H)2、N(R0或H)-C(=O)-R0、N(R0或H)-S(=O)2-R0、N(R0或H)-C(=O)-N(R0或H)2、SH、SCF3、SR0、S(=O)2R0、S(=O)2O(R0或H)與S(=O)2-N(R0或H)2組成之群組。 Preferred substituents for "cycloaliphatic residue" and "heterocycloaliphatic residue" are selected from the group consisting of F, Cl, Br, I, NO 2 , CF 3 , CN, =0, =NH, R 0 , C(=O)(R 0 or H), C(=O)O(R 0 or H), C(=O)N(R 0 or H) 2 , OH, OR 0 , OC(=O)-R 0 , O-(C 1-8 alkyl)-OH, O-(C 1-8 alkyl)-OC 1-8 alkyl, OCF 3 , N(R 0 or H) 2 , N(R 0 or H)-C(=O)-R 0 , N(R 0 or H)-S(=O) 2 -R 0 , N(R 0 or H)-C(=O) -N(R 0 or H) 2 , SH, SCF 3 , SR 0 , S(=O) 2 R 0 , S(=O) 2 O(R 0 or H) and S(=O) 2 -N( A group consisting of R 0 or H) 2 .

「環脂族殘基(cycloaliphatic residue)」與「雜環脂族殘基(heterocycloaliphatic residue)」特佳之取代基係選自由F、Cl、Br、I、NO2、CF3、CN、=O、C1-8脂族殘基、芳基、雜芳基、C3-6環脂族殘基、3至6構件雜環脂族殘基、經由一C1-4脂族基橋接之芳基、 雜芳基、C3-6環脂族殘基或3至6構件雜環脂族，CHO、C(=O)-C1-8脂族殘基、C(=O)芳基、C(=O)雜芳基、CO2H、C(=O)O-C1-8脂族殘基、C(=O)O-芳基、C(=O)O-雜芳基、CONH2、C(=O)NH-C1-8脂族殘基、C(=O)N(C1-8脂族殘基)2、C(=O)NH-芳基、C(=O)N(芳基)2、C(=O)NH-雜芳基、C(=O)N(雜芳基)2、C(=O)N(C1-8脂族殘基)(芳基)、C(=O)N(C1-8脂族殘基)(雜芳基)、C(=O)N(雜芳基)(芳基)、OH、O-C1-8脂族殘基、OCF3、O-(C1-8脂族基)-OH、O-(C1-8脂族基)-O-C1-8脂族殘基、O-苄基、O-芳基、O-雜芳基、O-C(=O)-C1-8脂族殘基、O-C(=O)芳基、O-C(=O)雜芳基、NH2、NH-C1-8脂族殘基、N(C1-8脂族殘基)2、NH-C(=O)-C1-8脂族殘基、NH-C(=O)-芳基、NH-C(=O)-雜芳基、SH、S-C1-8脂族殘基、SCF3、S-苄基、S-芳基、S-雜芳基、S(=O)2-C1-8脂族殘基、S(=O)2芳基、S(=O)2雜芳基、S(=O)2OH、S(=O)2O-C1-8脂族殘基、S(=O)2O-芳基、S(=O)2O-雜芳基、S(=O)2-NH-C1-8脂族殘基、S(=O)2-NH-芳基與S(=O)2-NH-雜芳基組成之群組。 The preferred substituents of "cycloaliphatic residue" and "heterocycloaliphatic residue" are selected from the group consisting of F, Cl, Br, I, NO 2 , CF 3 , CN, =O, a C 1-8 aliphatic residue, an aryl group, a heteroaryl group, a C 3-6 cycloaliphatic residue, a 3 to 6 membered heterocyclic aliphatic residue, an aryl group bridged via a C 1-4 aliphatic group , heteroaryl, C 3-6 cycloaliphatic residue or 3 to 6 membered heterocyclic aliphatic, CHO, C(=O)-C 1-8 aliphatic residue, C(=O)aryl, C (=O)heteroaryl, CO 2 H, C(=O)OC 1-8 aliphatic residue, C(=O)O-aryl, C(=O)O-heteroaryl, CONH 2 , C(=O)NH-C 1-8 aliphatic residue, C(=O)N(C 1-8 aliphatic residue) 2 , C(=O)NH-aryl, C(=O)N (aryl) 2 , C(=O)NH-heteroaryl, C(=O)N(heteroaryl) 2 , C(=O)N(C 1-8 aliphatic residue) (aryl) , C(=O)N (C 1-8 aliphatic residue) (heteroaryl), C(=O)N(heteroaryl)(aryl), OH, OC 1-8 aliphatic residue, OCF 3 , O-(C 1-8 aliphatic)-OH, O-(C 1-8 aliphatic)-OC 1-8 aliphatic residue, O-benzyl, O-aryl, O- Heteroaryl, OC(=O)-C 1-8 aliphatic residue, OC(=O)aryl, OC(=O)heteroaryl, NH 2 , NH-C 1-8 aliphatic residue, N (C 1-8 aliphatic Yl) 2, NH-C (= O) -C 1-8 aliphatic residue, NH-C (= O) - aryl, NH-C (= O) - heteroaryl, SH, SC 1-8 Aliphatic residue, SCF 3 , S-benzyl, S-aryl, S-heteroaryl, S(=O) 2 -C 1-8 aliphatic residue, S(=O) 2 aryl, S (= O) 2 heteroaryl, S (= O) 2 OH , S (= O) 2 OC 1-8 aliphatic residue, S (= O) 2 O- aryl, S (= O) 2 O - heteroaryl, S (= O) 2 -NH -C 1-8 aliphatic residue, S (= O) 2 -NH- aryl group S (= O) 2 -NH- group of heteroaryl groups group.

於本發明，與「芳基(aryl)」及「雜芳基(heteroaryl)」等詞相關之「被單取代或多取代(mono-or polysubstituted)」，係指分別與其相應之殘基或功能基上，一或多個氫原子各自相互獨立地被以至少一選自由F、Cl、Br、I、NO2、CN、CF3、CF2H、CFH2、CF2Cl、CFCl2、R0、C(=O)-H、C(=O)-R0、C(=O)-OH、C(=O)-OR0、CO-NH2、C(=O)-NHR0、C(=O)-N(R0)2、OH、、、、、、、、、、OCF3、OCF2H、OCFH2、OCF2Cl、OCFCl2、OR0、O-C(=O)-R0、O-C(=O)-O-R0、O-(C=O)-NH-R0、 O-C(=O)-N(R0)2、O-S(=O)2-R0、O-S(=O)2-OH、O-S(=O)2-OR0、O-S(=O)2-NH2、O-S(=O)2-NHR0、O-S(=O)2-N(R0)2、NH2、NHR0、N(R0)2、NH-C(=O)-R0、NH-C(=O)-O-R0、NH-C(=O)-NH2、NH-C(=O)-NH-R0、NH-C(=O)-N(R0)2、NR0-C(=O)-R0、NR0-C(=O)-O-R0、NR0-C(=O)-NH2、NR0-C(=O)-NH-R0、NR0-C(=O)-N(R0)2、NH-S(=O)2-OH、NH-S(=O)2-R0、NH-S(=O)2-OR0、NH-S(=O)2-NH2、NH-S(=O)2-NHR0、NH-S(=O)2-N(R0)2、NR0-S(=O)2-OH、NR0-S(=O)2R0、NR0-S(=O)2-OR0、NR0-S(=O)2-NH2、NR0-S(=O)2-NHR0、NR0-S(=O)2-N(R0)2、SH、SCF3、SCF2H、SCFH2、SCF2Cl、SCFCl2、SR0、S(=O)-R0、S(=O)2-R0、S(=O)2-OH、S(=O)2-OR0、S(=O)2-NH2、S(=O)2-NHR0與S(=O)2-N(R0)2等取代基組成之群組單取代或多取代，例如，二取代、三取代、四取代或五取代；「芳基(aryl)」與「雜芳基(heteroaryl)」較佳之取代基係選自由F、Cl、Br、I、NO2、CF3、CN、R0、C(=O)(R0或H)、C(=O)O(R0或H)、C(=O)N(R0或H)2、OH、OR0、、、、、、O-C(=O)-R0、O-(C1-8烷基)-O-C1-8烷基、OCF3、N(R0或H)2、N(R0或H)-C(=O)-R0、N(R0或H)-S(=O)2-R0、N(R0或H)-C(=O)-N(R0或H)2、SH、SCF3、SR0、S(=O)2R0、S(=O)2O(R0或H)與S(=O)2-N(R0或H)2等取代基組成之群組。 In the present invention, "mono-or polysubstituted" in relation to the words "aryl" and "heteroaryl" refers to a residue or a functional group corresponding thereto. The one or more hydrogen atoms are each independently selected from at least one selected from the group consisting of F, Cl, Br, I, NO 2 , CN, CF 3 , CF 2 H, CFH 2 , CF 2 Cl, CFCl 2 , R 0 . , C(=O)-H, C(=O)-R 0 , C(=O)-OH, C(=O)-OR 0 , CO-NH 2 , C(=O)-NHR 0 , C (=O)-N(R 0 ) 2 , OH, , , , , , , , , , OCF 3 , OCF 2 H, OCFH 2 , OCF 2 Cl, OCFCl 2 , OR 0 , OC(=O)-R 0 , OC(=O)-OR 0 , O-(C=O)-NH-R 0 , OC(=O)-N(R 0 ) 2 , OS(=O) 2 -R 0 , OS(=O) 2 -OH, OS(=O) 2 -OR 0 , OS(=O) 2 -NH 2 , OS(=O) 2 -NHR 0 , OS(=O) 2 -N(R 0 ) 2 , NH 2 , NHR 0 , N(R 0 ) 2 , NH-C(=O)-R 0 , NH-C(=O)-OR 0 , NH-C(=O)-NH 2 , NH-C(=O)-NH-R 0 , NH-C(=O)-N(R 0 ) 2 , NR 0 -C(=O)-R 0 , NR 0 -C(=O)-OR 0 , NR 0 -C(=O)-NH 2 , NR 0 -C(=O)-NH-R 0 , NR 0 -C(=O)-N(R 0 ) 2 , NH-S(=O) 2 -OH, NH-S(=O) 2 -R 0 , NH-S(=O) 2 - OR 0 , NH-S(=O) 2 -NH 2 , NH-S(=O) 2 -NHR 0 , NH-S(=O) 2 -N(R 0 ) 2 , NR 0 -S(=O 2 -OH, NR 0 -S(=O) 2 R 0 , NR 0 -S(=O) 2 -OR 0 , NR 0 -S(=O) 2 -NH 2 , NR 0 -S(=O 2 -NHR 0 , NR 0 -S(=O) 2 -N(R 0 ) 2 , SH, SCF 3 , SCF 2 H, SCFH 2 , SCF 2 Cl, SCFCl 2 , SR 0 , S(=O) -R 0 , S(=O) 2 -R 0 , S(=O) 2 -OH, S(=O) 2 -OR 0 , S(=O) 2 -NH 2 , S(=O) 2 - a group consisting of a substituent consisting of NHR 0 and S(=O) 2 -N(R 0 ) 2 , monosubstituted or polysubstituted, for example, disubstituted, trisubstituted, tetrasubstituted or Penta-substituted; "Aryl" and "heteroaryl" preferred substituents are selected from the group consisting of F, Cl, Br, I, NO 2 , CF 3 , CN, R 0 , C(=O) (R 0 or H), C(=O)O(R 0 or H), C(=O)N(R 0 or H) 2 , OH, OR 0 , , , , , , OC(=O)-R 0 , O-(C 1-8 alkyl)-OC 1-8 alkyl, OCF 3 , N(R 0 or H) 2 , N(R 0 or H)-C( =O)-R 0 , N(R 0 or H)-S(=O) 2 -R 0 , N(R 0 or H)-C(=O)-N(R 0 or H) 2 , SH, a group consisting of substituents such as SCF 3 , SR 0 , S(=O) 2 R 0 , S(=O) 2 O(R 0 or H) and S(=O) 2 -N(R 0 or H) 2 group.

「芳基(aryl)」與「雜芳基(heteroaryl)」特佳之取代基係選自由F、Cl、Br、I、NO2、CF3、CF2H、CFH2、CN、C1-8脂族殘基、芳基、雜芳基、C3-6環脂族殘基、3至6構件雜環脂族殘基、經由 一C1-4脂族基橋接之芳基、雜芳基，C3-6環脂族殘基或3至6構件雜環脂族、(C1-8脂族基)-O-C1-8脂族殘基、CHO、C(=O)-C1-8脂族殘基、C(=O)芳基、C(=O)雜芳基、CO2H、C(=O)O-C1-8脂族殘基、C(=O)O-芳基、C(=O)O-雜芳基、CONH2、C(=O)NH-C1-8脂族殘基、C(=O)N(C1-8脂族殘基)2、C(=O)NH-芳基、C(=O)N(芳基)2、C(=O)NH-雜芳基、C(=O)N(雜芳基)2、C(=O)N(C1-8脂族殘基)(芳基)、C(=O)N(C1-8脂族殘基)(雜芳基)、C(=O)N(雜芳基)(芳基)、OH、、、、、、O-C1-8脂族殘基、OCF3、O-(C1-8脂族基)-OH、O-(C1-8脂族基)-O-C1-8脂族殘基、O-苄基、O-芳基、O-雜芳基、O-C(=O)-C1-8脂族殘基、O-C(=O)芳基、O-C(=O)雜芳基、NH2、NH-C1-8脂族殘基、N(C1-8脂族殘基)2、NH-C(=O)-C1-8脂族殘基、NH-C(=O)-芳基、NH-C(=O)-雜芳基、SH、S-C1-8脂族殘基、SCF3、S-苄基、S-芳基、S-雜芳基、S(=O)2-C1-8脂族殘基、S(=O)2芳基、S(=O)2雜芳基、S(=O)2OH、S(=O)2O-C1-8脂族殘基、S(=O)2O-芳基、S(=O)2O-雜芳基、S(=O)2-NH-C1-8脂族殘基、S(=O)2-NH-芳基與S(=O)2-NH-雜芳基等取代基組成之群組。 The preferred substituents of "aryl" and "heteroaryl" are selected from the group consisting of F, Cl, Br, I, NO 2 , CF 3 , CF 2 H, CFH 2 , CN, C 1-8. Aliphatic residue, aryl, heteroaryl, C 3-6 cycloaliphatic residue, 3 to 6 membered heterocyclic aliphatic residue, aryl, heteroaryl bridged via a C 1-4 aliphatic group , C 3-6 cycloaliphatic residue or 3 to 6 membered heterocycloaliphatic, (C 1-8 aliphatic)-OC 1-8 aliphatic residue, CHO, C(=O)-C 1- 8 aliphatic residue, C(=O) aryl, C(=O)heteroaryl, CO 2 H, C(=O)OC 1-8 aliphatic residue, C(=O)O-aryl , C(=O)O-heteroaryl, CONH 2 , C(=O)NH-C 1-8 aliphatic residue, C(=O)N(C 1-8 aliphatic residue) 2 , C (=O)NH-aryl, C(=O)N(aryl) 2 , C(=O)NH-heteroaryl, C(=O)N(heteroaryl) 2 , C(=O) N (C 1-8 aliphatic residue) (aryl), C(=O)N (C 1-8 aliphatic residue) (heteroaryl), C(=O)N(heteroaryl) ( Aryl), OH, , , , , , OC 1-8 aliphatic residue, OCF 3 , O-(C 1-8 aliphatic)-OH, O-(C 1-8 aliphatic)-OC 1-8 aliphatic residue, O- Benzyl, O-aryl, O-heteroaryl, OC(=O)-C 1-8 aliphatic residue, OC(=O)aryl, OC(=O)heteroaryl, NH 2 , NH -C 1-8 aliphatic residue, N (C 1-8 aliphatic residue) 2 , NH-C(=O)-C 1-8 aliphatic residue, NH-C(=O)-aryl , NH-C(=O)-heteroaryl, SH, SC 1-8 aliphatic residue, SCF 3 , S-benzyl, S-aryl, S-heteroaryl, S(=O) 2 - C 1-8 aliphatic residue, S(=O) 2 aryl, S(=O) 2 heteroaryl, S(=O) 2 OH, S(=O) 2 OC 1-8 aliphatic residue , S(=O) 2 O-aryl, S(=O) 2 O-heteroaryl, S(=O) 2 -NH-C 1-8 aliphatic residue, S(=O) 2 -NH a group consisting of an aryl group and a substituent such as S(=O) 2 -NH-heteroaryl.

根據本發明之化合物係以取代基定義，例如以R1、R2及R3(第一代取代基)，若適當，其本身可被取代(第二代取代基)。取決於該定義，該取代基之取代基本身可被再取代(第三代取代基)。例如，若R1係一C1-10脂族殘基(第一代取代基)，則該C1-10脂族殘基本身可被取代，例如被以一NH-C1-10脂族殘基(第二代取代基)取代，而產生R1=(C1-10脂族殘基-NH-C1-10脂族殘基)此一功能基。該NH-C1-10脂族殘基本身身可再被取代，例如，被以氯(第三代取代基)再取代。整體而言，其產生R1=C1-10脂族殘基-NH-C1-10脂族 殘基此一功能基，其中，該NH-C1-10脂族殘基之C1-10脂族殘基係被氯取代。 The compounds according to the invention are defined by substituents, for example R 1 , R 2 and R 3 (first-generation substituents), which, if appropriate, may themselves be substituted (second-generation substituents). Depending on the definition, the substituent of the substituent can be resubstituted (the third generation substituent). For example, if R 1 is a C 1-10 aliphatic residue (first generation substituent), the C 1-10 aliphatic residue can be substituted, for example, as an NH-C 1-10 aliphatic The residue (second-generation substituent) is substituted to give R 1 = (C 1-10 aliphatic residue -NH-C 1-10 aliphatic residue) such a functional group. The NH-C 1-10 aliphatic residue can be further substituted, for example, by chlorine (third generation substituent). In general, it produces a functional group of R 1 =C 1-10 aliphatic residue -NH-C 1-10 aliphatic residue, wherein the NH-C 1-10 aliphatic residue is C 1- The 10 aliphatic residue is substituted with chlorine.

但於一較佳具體實施例中，其第三代取代基不可被再取代，即無第四代取代基。 However, in a preferred embodiment, the third generation substituents are not resubstituted, i.e., no fourth generation substituents.

於另一較佳具體實施例中，其第二代取代基不可被再取代，即其甚至無第三代取代基。換言之，於該具體實施例中，例如通式(I)之案例，若適當，R1至R9之功能基各自可被取代；但相應之取代基本身不可再被取代。 In another preferred embodiment, the second generation substituents are not resubstituted, i.e., they are even without third generation substituents. In other words, in this particular embodiment, for example, in the case of the general formula (I), the functional groups of R 1 to R 9 may each be substituted if appropriate; however, the corresponding substituents may no longer be substituted.

於部分狀況下，根據本發明之化合物係以取代基為芳基或雜芳基殘基者定義、或以取代基帶有芳基或雜芳基殘基者定義，其分別係未被取代或被多取代，或與將其連結之碳原子或雜原子共同成為一環構件或多個環構件，而形成一環狀結構，例如一芳基或雜芳基，其於各例中係未被取代或被單取代或被多取代。若適當，這些芳基或雜芳基殘基及以此方式產生之(雜)芳香環系統皆可與一環脂族縮合，以一C3-6環脂族殘基較佳，或與雜環脂族殘基縮合，以一C3-6環脂族殘基或雜環脂族殘基較佳，以一3至6構件雜環脂族殘基較佳，或與芳基或雜芳基縮合，例如與一C3-6環脂族殘基，如環戊基，或一3至6構件雜環脂族殘基，如嗎咻基，或一芳基，如苯基，或一雜芳基，如啶基，其中，以此方式縮合之環脂族或雜環脂族殘基、芳基或雜芳基殘基本身可分別係未被取代或被單取代或被多取代。 In some cases, the compounds according to the invention are defined as those wherein the substituent is an aryl or heteroaryl residue, or where the substituent carries an aryl or heteroaryl residue, which are each unsubstituted or Multiple substitutions, or a carbon atom or a hetero atom to which it is bonded, together form a ring member or a plurality of ring members to form a cyclic structure, such as an aryl or heteroaryl group, which is unsubstituted in each case or The sheet is replaced or replaced by a single. If appropriate, these aryl or heteroaryl residues and the (hetero) aromatic ring system produced in this manner may be condensed with a cycloaliphatic, preferably a C 3-6 cycloaliphatic residue, or a heterocyclic ring. The aliphatic residue is condensed, preferably a C 3-6 cycloaliphatic residue or a heterocyclic aliphatic residue, preferably a 3- to 6-membered heterocyclic aliphatic residue, or an aryl or heteroaryl group. Condensation, for example with a C 3-6 cycloaliphatic residue, such as a cyclopentyl group, or a 3 to 6 membered heterocyclic aliphatic residue, such as a fluorenyl group, or an aryl group, such as a phenyl group, or a hetero An aryl group, such as a pyridine group, wherein the cycloaliphatic or heterocyclic aliphatic residue, aryl or heteroaryl residue condensed in this manner can be unsubstituted or monosubstituted or polysubstituted, respectively.

於部分狀況下，根據本發明之化合物係以取代基為一環脂族殘基或一雜環脂族殘基者定義、或以取代基帶有一環脂族殘基或一雜環脂族殘基者定義，其於各狀況下分別係未被取代或被單取代或被多取代，或與將其連結之碳原子或雜原子共同成為一環構件或多個環構件，而形成一環狀結構，例如一環脂族或一雜環脂 族環系統。若適當，這些環脂族或雜環脂族環系統及以此方式產生之(雜)環脂族環系統皆可與一芳基或雜芳基縮合，以選自由苯基、啶基與吩基組成之群組較佳，或與一環脂族殘縮合，以一C3-6環脂族較佳，或與一雜環脂族殘基縮合，以一3至6構件雜環脂族殘較佳，例如與一芳基，如苯基，或一雜芳基，如啶基，或一環脂族殘基，如環己基，或一雜環脂族殘基，如嗎咻基，其中，以此方式縮合之芳基或雜芳基殘基或環脂族或雜環脂族殘基本身可係未被取代或被單取代或被多取代。 In some cases, the compounds according to the invention are those wherein the substituent is a cycloaliphatic residue or a heterocycloaliphatic residue, or the substituent has a cycloaliphatic residue or a heterocycloaliphatic residue. a definition, which in each case is unsubstituted or monosubstituted or polysubstituted, or together with a carbon atom or a hetero atom to which it is bonded, becomes a ring member or a plurality of ring members, thereby forming a ring structure, such as a ring. Aliphatic or heterocyclic aliphatic ring system. If appropriate, these cycloaliphatic or heterocyclic aliphatic ring systems and the (hetero)cycloaliphatic ring systems produced in this manner can be condensed with an aryl or heteroaryl group selected from the group consisting of phenyl, pyridine and pheno Preferably, the group of base groups is condensed with a cycloaliphatic residue, preferably a C 3-6 cycloaliphatic group, or condensed with a heterocycloaliphatic residue to form a 3 to 6 member heterocyclic aliphatic residue. Preferably, for example, an aryl group such as a phenyl group, or a heteroaryl group such as a pyridine group, or a cycloaliphatic residue such as a cyclohexyl group or a heterocyclic aliphatic residue such as a fluorenyl group, wherein The aryl or heteroaryl residue or cycloaliphatic or heterocyclic aliphatic residue condensed in this manner may be unsubstituted or monosubstituted or polysubstituted.

於本發明之範疇內，此用於化學式之符號，代表一相應之殘基與其上級總體結構連結。 Within the scope of the present invention, This symbol for the chemical formula represents a corresponding residue linked to its superior overall structure.

若一殘基多次地出現於一分子中，則該殘基可分別係具有不同意義之取代基：例如，若R1與R2兩者皆代表一3至10構件雜環脂族殘基，則該3至10構件雜環脂族殘基於R1可代表，例如嗎咻基，而於R2代表哌嗪基。 If a residue is present in a molecule multiple times, the residue may be a substituent having a different meaning: for example, if both R 1 and R 2 represent a 3 to 10 member heterocyclic aliphatic residue , the 3-10 member heterocyclic aliphatic residue R 1 may be on behalf of, for example, it shoop group, and in R 2 represents piperazinyl.

若一殘基多次地出現於一分子，如R0殘基之實例，則該殘基可分別係具有不同意義之取代基。 If a residue occurs multiple times in a molecule, such as an example of a R 0 residue, the residue may be a substituent having a different meaning.

「R0或H(R0 or H)」一詞於殘基中，係指R0與H可以任何可能之組合出現於該殘基。因此，例如，「N(R0或H)2(N(R0 or H)2)」此殘基可代表「NH2」、「NHR0」與「N(R0)2」。於「N(R0)2」之實例中，若R0多次地出現於一殘基中，則R0可分別具有相同或不同意義：於此「N(R0)2」實例中，例如，R0可代表芳基兩次，從而產生「N(芳基)2」此功能基，或R0可代表芳基一次，及C1-10脂族殘基一次，從而產生「N(芳基)(C1-10脂族殘基)」此功能基。 The term "R 0 or H(R 0 or H)" in the residue means that R 0 and H may be present in the residue in any possible combination. Thus, for example, "N(R 0 or H) 2 (N(R 0 or H) 2 )") may represent "NH 2 ", "NHR 0 ", and "N(R 0 ) 2 ". In the example of "N(R 0 ) 2 ", if R 0 appears in a residue multiple times, R 0 may have the same or different meanings respectively: in this "N(R 0 ) 2 " example, For example, R 0 may represent an aryl group twice, thereby producing a functional group of "N(aryl) 2 ", or R 0 may represent an aryl group once, and a C 1-10 aliphatic residue once, thereby producing "N ( Aryl) (C 1-10 aliphatic residue) "This functional group.

於本發明，「形成生理上相容之酸之鹽類(salt formed with a physiologically compatible acid)」一詞或「生理上可接受之酸之鹽類(salt of physiologically acceptable acids)」，係指分別含有無機酸 或有機酸活性成分之鹽類，其具生理相容性-特別係當用於人體及/或哺乳動物。生理上可接受之鹽之實例為：氫氯酸、氫溴酸、硫酸、甲基磺酸、對甲苯磺酸、碳酸、甲酸、醋酸、草酸、丁二酸、酒石酸、杏仁酸、丁烯酸、馬來酸、乳酸、檸檬酸、麩胺酸、糖質酸、單甲基癸二酸(monomethylsebacic acid)、5-氧脯氨酸(5-oxoproline)、己烷-1-磺酸、菸鹼酸、2-、3-或4-氨基苯酸、2,4,6-三甲基苯甲酸、α-硫辛酸、乙醯甘胺酸、馬尿酸、磷酸、天冬胺酸。以檸檬酸與氫氯酸為首選。 In the present invention, the term "salt formed with a physiologically compatible acid" or "salt of physiologically acceptable acids" means Containing inorganic acid Or a salt of an organic acid active ingredient, which is physiologically compatible - especially when used in humans and/or mammals. Examples of physiologically acceptable salts are: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, crotonic acid. , maleic acid, lactic acid, citric acid, glutamic acid, glycolic acid, monomethylsebacic acid, 5-oxoproline, hexane-1-sulfonic acid, tobacco Alkali acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, α-lipoic acid, acetylglycine, hippuric acid, phosphoric acid, aspartic acid. Citric acid and hydrochloric acid are preferred.

於本發明，「形成生理上相容之鹼之鹽類(salt formed with a physiologically compatible base)」一詞或「生理上可接受之鹼之鹽類(salt of physiologically acceptable bases)」，係指根據本發明各化合物之鹽類為一陰離子-例如，於一適當之功能基脫質子後-含有至少一陽離子或鹼-以含有至少一無機陽離子較佳-其具生理相容性-特別係用於人體及/或哺乳動物時。以鹼與鹼土金屬之鹽類特佳，尤其係(單-)或(二-)鈉、(單-)或(二-)鉀、鎂或鈣等鹽類，但亦可係銨鹽[NHxR4-x]+，其x=0、1、2、3或4，而R代表一支鏈或非支鏈C1-4脂族殘基。 In the present invention, the term "salt formed with a physiologically compatible base" or "salt of physiologically acceptable bases" means The salts of the compounds of the invention are an anion - for example, after a suitable functional group deprotonation - containing at least one cation or base - preferably containing at least one inorganic cation - which is physiologically compatible - especially for When the human body and / or mammals. It is particularly preferred as a salt of an alkali and an alkaline earth metal, especially a salt such as (mono-) or (di-) sodium, (mono-) or (di-) potassium, magnesium or calcium, but may also be an ammonium salt [NH x R 4-x ] + , where x = 0, 1, 2, 3 or 4, and R represents a branched or unbranched C 1-4 aliphatic residue.

根據本發明通式(I)化合物之更佳具體實施例含有通式(I-a)、(I-b)、(I-c)及/或(I-d)： More preferred embodiments of the compounds of formula (I) according to the invention contain formula (Ia), (Ib), (Ic) and/or (Id):

其中，特定之自由基、變量及指數具有本文上述關於根據本發明之化合物及其較佳具體實施例之涵義。 The specific free radicals, variables and indices herein have the meanings described above with respect to the compounds according to the invention and their preferred embodiments.

此外，根據本發明通式(I)之較佳具體實施例含有通式(I-e)、(I-f)、(I-g)、(I-h)、(I-i)及/或(I-j)： 其中，特定之自由基、變量及指數具有本文上述關於根據本發明之化合物及其較佳具體實施例之涵義。 Furthermore, preferred embodiments of the general formula (I) according to the invention contain the general formulae (Ie), (If), (Ig), (Ih), (Ii) and/or (Ij): The specific free radicals, variables and indices herein have the meanings described above with respect to the compounds according to the invention and their preferred embodiments.

此外，根據本發明通式(I)之較佳具體實施例含有通式(I-k)、(I-l)、(I-m)及/或(I-n)： 其中，特定之自由基、變量及指數具有本文上述關於根據本發明之化合物及其較佳具體實施例之涵義。 Furthermore, preferred embodiments of the general formula (I) according to the invention contain the general formulae (Ik), (Il), (Im) and/or (In): The specific free radicals, variables and indices herein have the meanings described above with respect to the compounds according to the invention and their preferred embodiments.

根據本發明通式(I)化合物之一特佳具體實施例含有通式(I-k)。 A particularly preferred embodiment of one of the compounds of the formula (I) according to the invention contains the formula (I-k).

通式(I-k)-、(I-l)、(I-m)與(I-n)之特佳具體實施例分別含有通式(I-k-1)、(I-l-1)、(I-m-1)與(I-n-1) 其中，特定之自由基、變量及指數具有本文上述關於根據本發明之化合物及其較佳具體實施例之涵義。 Particularly preferred embodiments of the general formulae (Ik)-, (Il), (Im) and (In) contain the general formulae (Ik-1), (Il-1), (Im-1) and (In-1), respectively. ) The specific free radicals, variables and indices herein have the meanings described above with respect to the compounds according to the invention and their preferred embodiments.

根據本發明通式(l-k-1)之化合物亦為首選，其含有通式(l-k2a)： 其中，Rk 代表苯基，其係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、CN、OH、O-CH3、CH3、CH(CH3)2、N(CH3)2、CF3、CHF2與三級丁基等取代基組成之群組單取代或多取代，苯基以被一或二個相互獨立地選自由F、Cl、Br、I、CN、OH、O-CH3、CH3、CH(CH3)2、N(CH3)2、CF3、CHF2與三級丁基等取代基組成 之群組單取代或二取代較佳，苯基以於間位被以一選自由F、Cl、Br、I、CN、OH、O-CH3、CH3、CH(CH3)2、N(CH3)2、CF3、CHF2與三級丁基等取代基組成之群組單取代更佳，及R2、R7與R8含有本文上述關於根據本發明之化合物及其較佳具體實施例之涵義。 The compound of the formula (lk-1) according to the invention is also preferred, which contains the formula (l-k2a): Wherein R k represents a phenyl group which is unsubstituted or is one or more independently selected from the group consisting of F, Cl, Br, I, CN, OH, O-CH 3 , CH 3 , CH (CH 3 ) 2, N (CH 3) 2, CF 3, CHF 2 with a tertiary butyl group substituents of the group consisting of mono- or polysubstituted phenyl in each is independently selected from one or two F, Cl, a group monosubstituted group of substituents such as Br, I, CN, OH, O-CH 3 , CH 3 , CH(CH 3 ) 2 , N(CH 3 ) 2 , CF 3 , CHF 2 and a tertiary butyl group or Preferably, the diphenyl group is selected from the group consisting of F, Cl, Br, I, CN, OH, O-CH 3 , CH 3 , CH(CH 3 ) 2 , N(CH 3 ) 2 , The group mono-substitution of the substituents such as CF 3 , CHF 2 and a tertiary butyl group is more preferred, and R 2 , R 7 and R 8 contain the meanings of the above-mentioned compounds according to the invention and their preferred embodiments.

根據本發明通式(l-k-1)之一化合物為首選，其含有通式(O-1)及/或(O-2)： 其中，R1 於各例中代表一或多個取代基，例如一或二個取代基，以一個取代基較佳，以一於苯基環間位之取代基更佳，該取代基以相互獨立地選自由F、Cl、Br、I、CN、OH、O-CH3、CH3、CH(CH3)2、N(CH3)2、CF3、CHF2與三級丁基組成之群組較佳，以選自由F、Cl、Br、I、OH、O-CH3、CH3、CF3、CHF2與三級丁基組成之群組更佳，以選自由F、Cl、Br、I、OH、O-CH3、CH3、CF3組成之群組再更佳，以選自由F、Cl、OH與O-CH3組成之群組又更佳，以選自由F與Cl組成之群組最佳，及R2、R7與R8含有本文上述關於根據本發明之化合物及其較佳具體實施例之涵義，其中，R2以代表CF3、環丙基或三級丁基較佳，以代表CF3或三級丁基更佳，以代表CF3又更佳。 其中，R8以代表F、Cl、CH3或H較佳，其中，R8以代表H更佳，其中，R7以選自由下列基團組成之群組較佳：CH3、C2H5、CH2-OH、C2H4-OH、CH(OH)-CH2-OH、CH2-O-CH3、C2H4-O-CH3、CH2-O-CH2-OH、CH2-O-C2H4-OH、CH2-O-CH2-O-CH3、CH2-O-C2H4-O-CH3、CH2-S(=O)2-CH3、C2H4-S(=O)2-CH3、CH2-NH-S(=O)2-CH3、CH2-NH-S(=O)2-NH2、CH2-NH-CH2-OH、CH2-NH-C2H4-OH、CH2-NH-C2H4-O-CH3、CH2-N(CH3)-C2H4-OH、CH2-N(CH3)-C2H4-O-CH3、O-CH3、O-C2H4-OH、O-C2H4-O-CH3、NH-CH3、N(CH3)2、NH-C2H4-OH、NH-C2H4-O-CH3、N(CH3)-[C2H4-OH]、N(CH3)-[C2H4-O-CH3]、NH-S(=O)2-CH3，環丙基、環丁基、環己基、O-環丙基、四氫吡喃基，以四氫-2H-吡喃-4-基、氮雜環丁基、哌啶基、嗎咻基或咯啶基較佳，其於各例中相互獨立地係未被取代，或被以一相互獨立地選自由F、Cl、Br、I、OH、O-CH3、NH2、N(CH3)2、CH3、C2H5與三級丁基等取代基組成之群組單取代，其中，R7以選自由CH2-OH、C2H4-OH、CH(OH)-CH2OH、CH2-O-C2H4-OH、CH2-NH-S(=O)2-CH3、CH2-NH-S(=O)2-NH2、CH2-S(=O)2-CH3、C2H4-S(=O)2-CH3、O-CH3、N(CH3)2、NH-C2H4-OH、NH-C2H4-O-CH3、N(CH3)-[C2H4-OH]、NH-S(=O)2-CH3、氮雜環丁基組成之群組更佳，其中，氮雜環丁基可係未被取代或被以OH單取代。 A compound of the formula (lk-1) according to the invention is preferred, which comprises the formula (O-1) and/or (O-2): Wherein R 1 represents one or more substituents in each of the examples, for example, one or two substituents, preferably a substituent, preferably a substituent at the meta position of the phenyl ring, the substituents being mutually Independently selected from the group consisting of F, Cl, Br, I, CN, OH, O-CH 3 , CH 3 , CH(CH 3 ) 2 , N(CH 3 ) 2 , CF 3 , CHF 2 and tertiary butyl Preferably, the group is selected from the group consisting of F, Cl, Br, I, OH, O-CH 3 , CH 3 , CF 3 , CHF 2 and tertiary butyl, selected from the group consisting of F, Cl, More preferably, the group consisting of Br, I, OH, O-CH 3 , CH 3 , and CF 3 is more preferably selected from the group consisting of F, Cl, OH, and O-CH 3 selected from the group consisting of F and The group of Cl compositions is optimal, and R 2 , R 7 and R 8 contain the above-mentioned meanings relating to the compounds according to the invention and their preferred embodiments, wherein R 2 represents CF 3 , cyclopropyl or tri The butyl group is preferred to represent CF 3 or a tertiary butyl group to better represent CF 3 . Wherein R 8 is preferably represented by F, Cl, CH 3 or H, wherein R 8 is more preferably represented by H, wherein R 7 is preferably selected from the group consisting of: CH 3 , C 2 H 5 , CH 2 -OH, C 2 H 4 -OH, CH(OH)-CH 2 -OH, CH 2 -O-CH 3 , C 2 H 4 -O-CH 3 , CH 2 -O-CH 2 - OH, CH 2 -OC 2 H 4 -OH, CH 2 -O-CH 2 -O-CH 3 , CH 2 -OC 2 H 4 -O-CH 3 , CH 2 -S(=O) 2 -CH 3 , C 2 H 4 -S(=O) 2 -CH 3 , CH 2 -NH-S(=O) 2 -CH 3 , CH 2 -NH-S(=O) 2 -NH 2 , CH 2 -NH -CH 2 -OH, CH 2 -NH-C 2 H 4 -OH, CH 2 -NH-C 2 H 4 -O-CH 3 , CH 2 -N(CH 3 )-C 2 H 4 -OH, CH 2 -N(CH 3 )-C 2 H 4 -O-CH 3 , O-CH 3 , OC 2 H 4 -OH, OC 2 H 4 -O-CH 3 , NH-CH 3 , N(CH 3 ) 2 , NH-C 2 H 4 -OH, NH-C 2 H 4 -O-CH 3 , N(CH 3 )-[C 2 H 4 -OH], N(CH 3 )-[C 2 H 4 - O-CH 3 ], NH-S(=O) 2 -CH 3 , cyclopropyl, cyclobutyl, cyclohexyl, O-cyclopropyl, tetrahydropyranyl, tetrahydro-2H-pyran- 4-Based, azetidinyl, piperidinyl, decyl or pyridyl is preferably unsubstituted in each case independently of each other, or independently selected from F, Cl, Br, I OH, O-CH 3, NH 2, N (CH 3) 2, CH 3, C 2 H 5 with a tertiary butyl group substituents of the group consisting of mono-substituted, wherein, R 7 selected from the group consisting of CH 2 -OH in , C 2 H 4 -OH, CH(OH)-CH 2 OH, CH 2 -OC 2 H 4 -OH, CH 2 -NH-S(=O) 2 -CH 3 , CH 2 -NH-S (= O) 2 -NH 2 , CH 2 -S(=O) 2 -CH 3 , C 2 H 4 -S(=O) 2 -CH 3 , O-CH 3 , N(CH 3 ) 2 , NH-C 2 H 4 -OH, NH-C 2 H 4 -O-CH 3 , N(CH 3 )-[C 2 H 4 -OH], NH-S(=O) 2 -CH 3 , azetidinyl More preferably, the group consisting of azacyclobutyl groups may be unsubstituted or monosubstituted with OH.

特佳之化合物為根據本發明通式(I-k-1)之一化合物，其含有通式(I-k-2)及/或通式(I-k-3)及/或通式(I-k-4)及/或通式(I-k-5)： 其中，R2、R7與R8含有本文上述關於根據本發明之化合物及其較佳具體實施例之涵義，其中，R2以代表CF3、環丙基或三級丁基較佳，以代表CF3或三級丁基更佳，以代表CF3又更佳，其中，R8以代表F、Cl、CH3或H較佳，其中，R8以代表H更佳，其中，R7以選自由下列基團組成之群組較佳：CH3、C2H5、CH2-OH、C2H4-OH、CH(OH)-CH2-OH、CH2-O-CH3、C2H4-O-CH3、CH2-O-CH2-OH、CH2-O-C2H4-OH、CH2-O-CH2-O-CH3、CH2-O-C2H4-O-CH3、CH2-S(=O)2-CH3、C2H4-S(=O)2-CH3、CH2-NH-S(=O)2-CH3、CH2-NH-S(=O)2-NH2、CH2-NH-CH2-OH、CH2-NH-C2H4-OH、CH2-NH-C2H4-O-CH3、CH2-N(CH3)-C2H4-OH、CH2-N(CH3)-C2H4-O-CH3、O-CH3、O-C2H4-OH、O-C2H4-O-CH3、NH-CH3、N(CH3)2、NH-C2H4-OH、NH-C2H4-O-CH3、N(CH3)-[C2H4-OH]、N(CH3)-[C2H4-O-CH3]、NH-S(=O)2-CH3，環丙基、環丁基、環戊基、環己基、O-環丙基、四氫吡喃基，以選自四氫-2H-吡喃-4-基、氮雜環丁基、哌啶基、嗎咻基或咯啶基 較佳，其於各例中相互獨立地係未被取代，或被以一相互獨立地選自由F、Cl、Br、I、OH、O-CH3、NH2、N(CH3)2、CH3、C2H5與三級丁基等取代基組成之群組單取代，其中，R7以選自由CH2-OH、C2H4-OH、CH(OH)-CH2OH、CH2-O-C2H4-OH、CH2-NH-S(=O)2-CH3、CH2-NH-S(=O)2-NH2、CH2-S(=O)2-CH3、C2H4-S(=O)2-CH3、O-CH3、N(CH3)2、NH-C2H4-OH、NH-C2H4-O-CH3、N(CH3)-[C2H4-OH]、NH-S(=O)2-CH3、氮雜環丁基組成之群組更佳，其中，氮雜環丁基可係未被取代，或被以OH單取代。 A particularly preferred compound is a compound of the formula (Ik-1) according to the invention which comprises the formula (Ik-2) and/or the formula (Ik-3) and/or the formula (Ik-4) and/or General formula (Ik-5): Wherein R 2 , R 7 and R 8 contain the above-mentioned meanings with respect to the compounds according to the invention and preferred embodiments thereof, wherein R 2 is preferably represented by CF 3 , cyclopropyl or tert-butyl, More preferably, CF 3 or a tertiary butyl group is preferred to represent CF 3 , wherein R 8 is preferably represented by F, Cl, CH 3 or H, wherein R 8 is more preferably represented by H, wherein R 7 Preferably, it is selected from the group consisting of CH 3 , C 2 H 5 , CH 2 -OH, C 2 H 4 -OH, CH(OH)-CH 2 -OH, CH 2 -O-CH 3 , C 2 H 4 -O-CH 3, CH 2 -O-CH 2 -OH, CH 2 -OC 2 H 4 -OH, CH 2 -O-CH 2 -O-CH 3, CH 2 -OC 2 H 4 -O-CH 3 , CH 2 -S(=O) 2 -CH 3 , C 2 H 4 -S(=O) 2 -CH 3 , CH 2 -NH-S(=O) 2 -CH 3 , CH 2 -NH-S(=O) 2 -NH 2 , CH 2 -NH-CH 2 -OH, CH 2 -NH-C 2 H 4 -OH, CH 2 -NH-C 2 H 4 -O-CH 3 , CH 2 -N(CH 3 )-C 2 H 4 -OH, CH 2 -N(CH 3 )-C 2 H 4 -O-CH 3 , O-CH 3 , OC 2 H 4 -OH, OC 2 H 4 -O-CH 3 , NH-CH 3 , N(CH 3 ) 2 , NH-C 2 H 4 -OH, NH-C 2 H 4 -O-CH 3 , N(CH 3 )-[C 2 H 4 -OH], N ( CH 3) - [C 2 H 4 -O-CH 3], NH-S (= O) 2 -CH 3, cyclopropyl, a group, a cyclopentyl group, a cyclohexyl group, an O-cyclopropyl group, a tetrahydropyranyl group, selected from tetrahydro-2H-pyran-4-yl, azetidinyl, piperidinyl, decyl or Preferred are pyridyl groups, which are independently unsubstituted in each case, or are independently selected from the group consisting of F, Cl, Br, I, OH, O-CH 3 , NH 2 , N (CH 3 ). ) 2, CH 3, C 2 H 5 with a tertiary butyl group substituents of the group consisting of mono-substituted, wherein, R 7 selected from the group consisting in CH 2 -OH, C 2 H 4 -OH, CH (OH) -CH 2 OH, CH 2 -OC 2 H 4 -OH, CH 2 -NH-S(=O) 2 -CH 3 , CH 2 -NH-S(=O) 2 -NH 2 , CH 2 -S(=O 2 -CH 3 , C 2 H 4 -S(=O) 2 -CH 3 , O-CH 3 , N(CH 3 ) 2 , NH-C 2 H 4 -OH, NH-C 2 H 4 -O -CH 3, N (CH 3) - [C 2 H 4 -OH], NH-S (= O) 2 -CH 3, azetidinyl group consisting of more preferably, wherein, azetidinyl It may be unsubstituted or monosubstituted with OH.

根據本發明之一較佳具體實施例中，通式(I)之R1≠H。 According to a preferred embodiment of the invention, R 1 ≠H of the formula (I).

根據本發明之另一較佳具體實施例中，通式(I)之化合物R1 代表H、一C1-10脂族殘基、一O-C1-10脂族殘基、一S-C1-10脂族殘基、一NH-C1-10脂族殘基、一N(C1-10脂族殘基)2、一C(=O)-C1-10脂族殘基、一C(=O)-NH-C1-10脂族殘基、一C(=O)-N(C1-10脂族殘基)2、一NH-C(=O)-C1-10脂族殘基、一NH-S(=O)2-C1-10脂族殘基、一N(C1-10脂族殘基)-S(=O)2-C1-10脂族殘基、一S(=O)2-C1-10脂族殘基、一S(=O)2-NH-C1-10脂族殘基、一S(=O)2-N(C1-10脂族殘基)2，其中，各上述殘基於各例中可選擇性地經由一C1-8脂族基橋接，其進而可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、=O、O-C1-4烷基、O-C1-4伸烷基-OH、OCF3、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基與SCF3等取代基組成之群組單取代或多取代，其中，該C1-10脂族殘基於各例中，相互獨立地可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、 NO2、CN、OH、=O、O-C1-4烷基、OCF3、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3、苯基與啶基等取代基組成之群組單取代或多取代，其中，苯基或啶基分別係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、C(=O)-OH、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3與S(=O)2OH等取代基組成之群組單取代或多取代；或代表一C3-10環脂族殘基、一C(=O)-C3-10環脂族殘基、一O-C3-10環脂族殘基、一O-(C1-8脂族基)-C3-10環脂族殘基、一S-C3-10環脂族殘基、一S-(C1-8脂族基)-C3-10環脂族殘基、一NH-C3-10環脂族殘基、一NH-(C1-8脂族基)-C3-10環脂族殘基、一N(C1-10脂族殘基)(C3-10環脂族殘基)、一3至10構件雜環脂族殘基、一C(=O)-(3至10構件雜環脂族殘基)、一O-(3至10構件雜環脂族殘基)、一O-(C1-8脂族基)-(3至10構件雜環脂族殘基)、一S-(3至10構件雜環脂族殘基)、一S-(C1-8脂族基)-(3至10構件雜環脂族殘基)、一NH-(3至10構件雜環脂族殘基)、NH-(C1-8脂族基)-(3至10構件雜環脂族殘基)、一N(C1-10脂族殘基)(3至10構件雜環脂族殘基)，其中，各上述殘基於各例中可選擇性地經由一C1-8脂族基橋接，其進而可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、=O、O-C1-4烷基、OCF3、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基與SCF3等取代基組成之群組單取代或多取代， 其中，該C1-10脂族殘基、該C1-8脂族基、該C3-10環脂族殘基與該3至10構件雜環脂族殘基於各例中相互獨立地，可分別係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、=O、O-C1-4烷基、OCF3、C1-4烷基、CF3、SH、S-C1-4烷基、SCF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、苯基與啶基等取代基組成之群組單取代或多取代，其中，苯基或啶基分別係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、C(=O)-OH、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3與S(=O)2OH等取代基組成之群組單取代或多取代，或代表芳基、C(=O)-芳基、O-芳基、一O-(C1-8脂族基)-芳基、S-芳基、一S-(C1-8脂族基)-芳基、一NH-芳基、NH-C(=O)-芳基、NH-S(=O)2-芳基、一NH-(C1-8脂族基)-芳基、一N(C1-10脂族殘基)(芳基)、雜芳基、C(=O)-雜芳基、O-雜芳基、O-(C1-8脂族基)-雜芳基、S-(雜芳基)、S-(C1-8脂族基)-(雜芳基)、NH-(雜芳基)、NH-C(=O)-雜芳基、NH-S(=O)2-雜芳基、NH-(C1-8脂族基)-(雜芳基)、N(C1-10脂族殘基)(雜芳基)，其中，各上述殘基於各例中可選擇性地經由一C1-8脂族基橋接，其進而可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、=O、O-C1-4烷基、OCF3、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基與SCF3等取代基組成之群組單取代或多取代，其中，各上述殘基之C1-10脂族殘基、C1-8脂族基、芳基 與雜芳基於各例中相互獨立地，可分別係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、、、、、、OH、O-C1-4烷基、O-C1-4伸烷基-O-C1-4烷基、OCF3、C1-4烷基、C1-4伸烷基-O-C1-4-烷基、CF3、CF2H、CHF2、SH、S-C1-4烷基、SCF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、苯基與啶基等取代基組成之群組單取代或多取代，其中，苯基或啶基分別可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、O-C1-4伸烷基-O-C1-4烷基、OCF3、C1-4烷基、C1-4伸烷基-O-C1-4-烷基、C(=O)-OH、CF3、CF2H、CHF2、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3與S(=O)2OH等取代基組成之群組單取代或多取代。 According to another preferred embodiment of the present invention, the compound R 1 of the formula (I) represents H, a C 1-10 aliphatic residue, an OC 1-10 aliphatic residue, an SC 1-10 An aliphatic residue, an NH-C 1-10 aliphatic residue, an N (C 1-10 aliphatic residue) 2 , a C(=O)-C 1-10 aliphatic residue, a C ( =O)-NH-C 1-10 aliphatic residue, a C(=O)-N(C 1-10 aliphatic residue) 2 , a NH-C(=O)-C 1-10 aliphatic Residue, one NH-S(=O) 2 -C 1-10 aliphatic residue, one N (C 1-10 aliphatic residue)-S(=O) 2 -C 1-10 aliphatic residue , an S(=O) 2 -C 1-10 aliphatic residue, an S(=O) 2 -NH-C 1-10 aliphatic residue, an S(=O) 2 -N (C 1- 10 aliphatic residue) 2 , wherein each of the above residues is selectively bridged via a C 1-8 aliphatic group, which may in turn be unsubstituted or independently of one another Free F, Cl, Br, I, NO 2 , CN, OH, =O, OC 1-4 alkyl, OC 1-4 alkyl-OH, OCF 3 , CF 3 , NH 2 , NH (C 1 a group of mono- or poly-substituents consisting of a substituent of -4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl and SCF 3 , wherein the C 1-10 aliphatic Residual based on each case, independently of each other, can be unsubstituted Or with one or more independently selected from the group consisting of F, Cl, Br, I, NO 2, CN, OH, = O, OC 1-4 alkyl, OCF 3, CF 3, NH 2, NH (C 1 -4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 , a group consisting of a substituent such as a phenyl group and a pyridine group, monosubstituted or polysubstituted, wherein benzene The yl or acyl group is unsubstituted, respectively, or is selected independently from one another by F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OCF 3 , C 1- 4 alkyl, C(=O)-OH, CF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 a group consisting of a mono- or poly-substitution of a substituent such as S(=O) 2 OH; or a C 3-10 cycloaliphatic residue, a C(=O)-C 3-10 cycloaliphatic residue , an OC 3-10 cycloaliphatic residue, an O-(C 1-8 aliphatic)-C 3-10 cycloaliphatic residue, an SC 3-10 cycloaliphatic residue, an S-( C 1-8 aliphatic)-C 3-10 cycloaliphatic residue, one NH-C 3-10 cycloaliphatic residue, one NH-(C 1-8 aliphatic)-C 3-10 ring An aliphatic residue, an N (C 1-10 aliphatic residue) (C 3-10 cycloaliphatic residue), a 3 to 10 membered heterocyclic aliphatic residue, a C(=O)-(3) To 10 component heterocyclic aliphatic residues a group of O-(3 to 10 component heterocyclic aliphatic residues), an O-(C 1-8 aliphatic group)-(3 to 10 component heterocyclic aliphatic residue), an S-(3) To a 10-membered heterocyclic aliphatic residue), an S-(C 1-8 aliphatic group)-(3 to 10 membered heterocyclic aliphatic residue), an NH- (3 to 10 membered heterocyclic aliphatic residue) Base), NH-(C 1-8 aliphatic group)-(3 to 10 component heterocyclic aliphatic residue), and one N (C 1-10 aliphatic residue) (3 to 10 member heterocyclic aliphatic residue) Each of the above residues may be selectively bridged via a C 1-8 aliphatic group, which may in turn be unsubstituted, or may be independently selected from F, Cl, in one or more , Br, I, NO 2 , CN, OH, =O, OC 1-4 alkyl, OCF 3 , CF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) a group consisting of SH, SC 1-4 alkyl and a group consisting of a substituent such as SCF 3 mono- or poly-substituted, wherein the C 1-10 aliphatic residue, the C 1-8 aliphatic group, the C 3 The -10 cycloaliphatic residue and the 3 to 10 component heterocyclic aliphatic residue are independently unsubstituted according to each of the examples, or are each independently selected from F, Cl, Br by one or more , I, NO 2, CN, OH, = O, OC 1-4 alkyl, OCF 3, C 1-4 alkyl , CF 3, SH, SC 1-4 alkyl, SCF 3, NH 2, NH (C 1-4 alkyl), N (C 1-4 alkyl) 2, phenyl and the like substituents piperidinyl group consisting of a group mono- or poly-substituted, wherein the phenyl or pyridine group is unsubstituted, respectively, or is selected from one or more independently from F, Cl, Br, I, NO 2 , CN, OH, OC 1 -4 alkyl, OCF 3 , C 1-4 alkyl, C(=O)-OH, CF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , a group consisting of SH, SC 1-4 alkyl, SCF 3 and S(=O) 2 OH, such as a mono- or poly-substituent, or an aryl group, a C(=O)-aryl group, an O-aryl group , O-(C 1-8 aliphatic)-aryl, S-aryl, an S-(C 1-8 aliphatic)-aryl, an NH-aryl, NH-C (=O )-aryl, NH-S(=O) 2 -aryl, mono-NH-(C 1-8 aliphatic)-aryl, one N (C 1-10 aliphatic residue) (aryl), Heteroaryl, C(=O)-heteroaryl, O-heteroaryl, O-(C 1-8 aliphatic)-heteroaryl, S-(heteroaryl), S-(C 1- 8 aliphatic group)-(heteroaryl), NH-(heteroaryl), NH-C(=O)-heteroaryl, NH-S(=O) 2 -heteroaryl, NH-(C 1 -8 aliphatic group)-(heteroaryl), N(C 1-10 aliphatic residue) (heteroaryl), wherein each of the above residues is based on each case Optionally, bridged via a C 1-8 aliphatic group, which in turn may be unsubstituted, or selected from one or more independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH , =O, OC 1-4 alkyl, OCF 3 , CF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl and a group consisting of a substituent such as SCF 3 which is mono- or poly-substituted, wherein the C 1-10 aliphatic residue, the C 1-8 aliphatic group, the aryl group and the heteroaryl group of each of the above residues are independent of each other based on each of the above examples. , may be unsubstituted, or one or more independently selected from F, Cl, Br, I, NO 2 , CN, , , , , , OH, OC 1-4 alkyl, OC 1-4 alkylene-OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, C 1-4 alkyl-OC 1-4 -alkyl , CF 3 , CF 2 H, CHF 2 , SH, SC 1-4 alkyl, SCF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , phenyl and a group consisting of a mono- or poly-substituent of a substituent such as a pyridine group, wherein the phenyl or pyridine group may be unsubstituted, respectively, or may be selected from F, Cl, Br, I, NO independently of one or more of each other. 2 , CN, OH, OC 1-4 alkyl, OC 1-4 alkylene-OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, C 1-4 alkylene-OC 1-4 -alkyl, C(=O)-OH, CF 3 , CF 2 H, CHF 2, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1 a group consisting of -4 alkyl, SCF 3 and a combination of substituents such as S(=O) 2 OH is mono- or poly-substituted.

於根據本發明通式(I)化合物之另一較佳具體實施例中，殘基R1代表(T1)子結構 其E 代表C(=O)、O、S、S(=O)2、NH-C(=O)或NR11，以代表O、S或NR11較佳，其中，R11代表H或一C1-4脂族殘基，其係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、OH、O-C1-4烷基、OCF3、NH2、NH-C1-4烷基與N(C1-4烷基)2 等取代基組成之群組單取代或多取代；o 代表0或1，以代表0較佳；R10a與R10b各自相互獨立地代表H、F、Cl、Br、I或一C1-4脂族殘基，其係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、OH、O-C1-4烷基、OCF3、NH2、NH-C1-4烷基與N(C1-4烷基)2等取代基組成之群組單取代或多取代；m 代表0、1、2、3或4，以代表0、1或2較佳，以代表0或1更佳；G 代表一C1-8脂族殘基，其係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、=O、O-C1-4烷基、O-C1-4伸烷基-OH、O-C1-4伸烷基-O-C1-4烷基、OCF3、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基與SCF3等取代基組成之群組單取代或多取代，或代表一C3-10環脂族殘基或一3至10構件雜環脂族殘基，其於各例中係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、=O、O-C1-4烷基、OCF3、C1-4烷基、CF3、SH、S-C1-4烷基、SCF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、苯基與啶基等取代基組成之群組單取代或多取代，其中，苯基或啶基分別係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、C(=O)-OH、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3與S(=O)2OH等取代基組成之群組單取代或多取代；或代表一芳基或雜芳基，其於各例中係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、 O-C1-4烷基、O-C1-4伸烷基-O-C1-4烷基、、、、、、OCF3、C1-4烷基、C1-4伸烷基-O-C1-4-烷基、CF3、CF2H、CFH2、SH、S-C1-4烷基、SCF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、苯基與啶基等取代基組成之群組單取代或多取代，其中，苯基或啶基分別係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、C(=O)-OH、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3與S(=O)2OH等取代基組成之群組單取代或多取代。 In another preferred embodiment of the compound of formula (I) according to the invention, residue R 1 represents a (T1) substructure Its E represents C(=O), O, S, S(=O) 2 , NH-C(=O) or NR 11 , preferably represents O, S or NR 11 , wherein R 11 represents H or a a C 1-4 aliphatic residue which is unsubstituted or which is selected from one or more independently from F, Cl, Br, I, OH, OC 1-4 alkyl, OCF 3 , NH 2 , a group consisting of a mono- or poly-substituent consisting of a substituent such as NH-C 1-4 alkyl and N(C 1-4 alkyl) 2 ; o represents 0 or 1, preferably represents 0; each of R 10a and R 10b Representing each other independently of H, F, Cl, Br, I or a C 1-4 aliphatic residue, which is unsubstituted or selected from one, more independently of one another from F, Cl, Br, I, a group mono- or poly-substituted with OH, OC 1-4 alkyl, OCF 3 , NH 2 , NH-C 1-4 alkyl and N(C 1-4 alkyl) 2 ; m represents 0 1, 2, 3 or 4, preferably 0, 1 or 2, preferably 0 or 1; G represents a C 1-8 aliphatic residue which is unsubstituted or is taken as an A plurality of mutually independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, =0, OC 1-4 alkyl, OC 1-4 alkyl-OH, OC 1-4 alkyl- OC 1-4 alkyl, OCF 3, CF 3, NH 2, NH (C 1-4 alkyl), N (C 1-4 Yl) 2, SH, SC 1-4 alkyl and SCF 3 consisting of a substituent group singly or multiply substituted, or represents a cyclic aliphatic C 3-10 residue or a 3- to 10-member heterocycloaliphatic a residue, which is unsubstituted in each case, or is selected from one or more independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, =0, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, CF 3 , SH, SC 1-4 alkyl, SCF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , benzene a group mono- or poly-substituted with a group consisting of a substituent such as a pyridine group, wherein the phenyl or pyridine group is unsubstituted, respectively, or is independently selected from F, Cl, Br, I, in one or more NO 2 , CN, OH, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, C(=O)-OH, CF 3 , NH 2 , NH(C 1-4 alkyl), N ( a group consisting of C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 and S(=O) 2 OH, such as a group consisting of a mono- or poly-substituent; or an aryl or heteroaryl group , in each case unsubstituted, or one or more independently selected from F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OC 1-4 Alkyl-OC 1-4 alkyl, , , , , , OCF 3 , C 1-4 alkyl, C 1-4 alkylene-OC 1-4 -alkyl, CF 3 , CF 2 H, CFH 2 , SH, SC 1-4 alkyl, SCF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , a group consisting of a substituent such as a phenyl group and a pyridine group, monosubstituted or polysubstituted, wherein the phenyl or pyridine group is respectively Unsubstituted, or selected from one or more of each other independently from F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, C ( =O)-OH, CF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 and S(=O) A group consisting of 2 OH and the like is mono- or poly-substituted.

於根據本發明通式(I)化合物之一特佳具體實施例中，殘基R1代表(T1)子結構，其中，o代表0。 In a particularly preferred embodiment of one of the compounds of the general formula (I) according to the invention, the residue R 1 represents a (T1) substructure, wherein o represents 0.

較佳地，殘基R1 代表(T1)子結構，其E 代表O、S或NR11，其中，R11代表H或一未被取代之C1-4脂族殘基，以選自由甲基、乙基、正丙基、異丙基、正丁基、二級丁基、三級丁基較佳；o 代表0或1，以代表0較佳；R10a與R10b各自相互獨立地代表H、F、Cl、Br、I或一未被取代之C1-4脂族殘基，以選自由甲基、乙基、正丙基、異丙基、正丁基、二級丁基、三級丁基較佳；m 代表0、1或2，以代表0或1較佳；G 代表一C1-8脂族殘基，其未被取代，或被以一或多個相互 獨立地選自由F、Cl、Br、I、OH、O-C1-4烷基、O-C1-4伸烷基-OH、O-C1-4伸烷基-O-C1-4烷基、OCF3、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基與SCF3等取代基組成之群組單取代或多取代；或代表一C3-10環脂族殘基或一3至10構件雜環脂族殘基，其於各例中係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、CF3、SCF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、苯基與啶基等取代基組成之群組單取代或多取代，其中，苯基或啶基分別係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基與SCF3等取代基組成之群組單取代或多取代；或代表一芳基或雜芳基，其於各例中係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、O-C1-4伸烷基-O-C1-4烷基、、、、、、OCF3、C1-4烷基、C1-4伸烷基-O-C1-4-烷基、CF3、CF2H、CFH2、SH、S-C1-4烷基、SCF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、苯基與啶基等取代基組成之群組單取代或多取代，其中，苯基或啶基分別係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基與SCF3等取代基組成之群組 單取代或多取代。 Preferably, residue R 1 represents a (T1) substructure, wherein E represents O, S or NR 11 , wherein R 11 represents H or an unsubstituted C 1-4 aliphatic residue selected from Base, ethyl, n-propyl, isopropyl, n-butyl, dibutyl, tert-butyl are preferred; o represents 0 or 1, preferably represents 0; R 10a and R 10b are each independently Represents H, F, Cl, Br, I or an unsubstituted C 1-4 aliphatic residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, and butyl , a tertiary butyl group is preferred; m represents 0, 1 or 2, preferably represents 0 or 1; G represents a C 1-8 aliphatic residue which is unsubstituted or is independently of one or more Selected from F, Cl, Br, I, OH, OC 1-4 alkyl, OC 1-4 alkyl-OH, OC 1-4 alkyl-OC 1-4 alkyl, OCF 3 , CF 3 a group monosubstituted or polysubstituted with a group consisting of a substituent such as NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl and SCF 3 ; Representing a C 3-10 cycloaliphatic residue or a 3 to 10 membered heterocyclic aliphatic residue, which is unsubstituted in each case, or selected from one or more independently selected from F, Cl, Br I, NO 2, CN, OH , OC 1-4 alkyl, OCF 3, C 1-4 alkyl, CF 3, SCF 3, NH 2, NH (C 1-4 alkyl), N (C 1- 4 alkyl) 2, phenyl and pyridyl substituent groups like the group consisting of mono- or polysubstituted, wherein the phenyl or pyridyl are based unsubstituted or substituted with one or more independently selected from the group consisting of F , Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, CF 3 , NH 2 , NH(C 1-4 alkyl), N(C a group of 1-4 alkyl) 2 , SH, SC 1-4 alkyl and a substituent such as SCF 3 ; a mono- or poly-substituent; or an aryl or heteroaryl group, which is not Substituted, or one or more independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OC 1-4 alkyl-OC 1-4 alkyl , , , , , , OCF 3 , C 1-4 alkyl, C 1-4 alkylene-OC 1-4 -alkyl, CF 3 , CF 2 H, CFH 2 , SH, SC 1-4 alkyl, SCF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , a group consisting of a substituent such as a phenyl group and a pyridine group, monosubstituted or polysubstituted, wherein the phenyl or pyridine group is respectively Unsubstituted, or selected from one or more independently of each other from F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, CF 3 a group consisting of NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl and a substituent such as SCF 3 is mono- or poly-substituted.

更佳地，殘基R1 代表(T1)子結構，其E 代表O、S或NR11，以代表O或S較佳，其中，R11代表H或選自由甲基、乙基、正丙基與異丙基組成之群組，o 代表0或1，以代表0較佳；R10a與R10b係相互獨立地選自由H、甲基、乙基、正丙基、異丙基、正丁基、二級丁基、三級丁基組成之群組；m 代表0、1或2，以代表0或1較佳；G 代表一C1-8脂族殘基，以代表甲基、乙基、正丙基、異丙基、正丁基、二級丁基、三級丁基、戊基、己基或較佳，其於各例中係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、OH、O-C1-4烷基、O-C1-4伸烷基-OH、O-C1-4伸烷基-O-C1-4烷基、CF3、NH2、NH(C1-4烷基)與N(C1-4烷基)2等取代基組成之群組單取代或多取代；或代表一C3-6環脂族殘基，以選自由環丙基、環丁基、環戊基與環己基較佳，或一3至6構件雜環脂族殘基、咯啶基、哌嗪基、4-甲基哌嗪基、哌啶基、嗎咻基、四氫咯基、四氫喹啉基、四氫異喹啉基、二氫喹啉基、二氫咯基、二氫啶基、二氫異喹啉基、四氫吡喃基，以代表四氫-2H-吡喃-4-基、四氫呋喃基、四氫啶基與與硫基嗎咻基較佳，其於各例中相互獨立地係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、CN、OH、O-C1-4烷基、C1-4烷基、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2與苯基等取代 基組成之群組單取代或多取代，其中，苯基可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2與SCF3等取代基組成之群組單取代或多取代；或代表一芳基，以表苯基較佳，或代表雜芳基，以啶基、呋喃基或吩基較佳，其於各例中係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、O-C1-4伸烷基-O-C1-4烷基、、、、、、OCF3、C1-4烷基、C1-4伸烷基-O-C1-4-烷基、CF3、CF2H、CFH2、SCF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2與苯基等取代基組成之群組單取代或多取代，其中，苯基係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2與SCF3等取代基組成之群組單取代或多取代。 More preferably, the residue R 1 represents a (T1) substructure, and E represents O, S or NR 11 to represent O or S, wherein R 11 represents H or is selected from methyl, ethyl or n-propyl. a group consisting of a group and an isopropyl group, o represents 0 or 1, preferably represents 0; and R 10a and R 10b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, and a group consisting of a butyl group, a secondary butyl group, and a tertiary butyl group; m represents 0, 1 or 2 to represent 0 or 1 is preferred; G represents a C 1-8 aliphatic residue to represent a methyl group, Ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tert-butyl, pentyl, hexyl or Preferably, it is unsubstituted in each case, or is selected from one or more independently selected from the group consisting of F, Cl, Br, I, OH, OC 1-4 alkyl, OC 1-4 alkyl- a group consisting of OH, OC 1-4 alkyl-OC 1-4 alkyl, CF 3 , NH 2 , NH(C 1-4 alkyl) and N(C 1-4 alkyl) 2 Monosubstituted or polysubstituted; or represents a C 3-6 cycloaliphatic residue selected from a cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl group, or a 3 to 6 member heterocyclic aliphatic residue Base, pyridyl, piperazinyl, 4-methylpiperazinyl, piperidinyl, decyl, tetrahydrorupyl, tetrahydroquinolyl, tetrahydroisoquinolinyl, dihydroquinolinyl, Dihydroryl, dihydropyridyl, dihydroisoquinolinyl, tetrahydropyranyl, to represent tetrahydro-2H-pyran-4-yl, tetrahydrofuranyl, tetrahydropyridyl and thiopyridinium Preferably, the substituents are unsubstituted independently of each other in each of the examples, or are independently selected from the group consisting of F, Cl, Br, I, CN, OH, OC 1-4 alkyl, C 1 a group of mono- or poly-substituents consisting of a substituent of -4 alkyl, CF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 and a phenyl group, wherein benzene Keke Unsubstituted or substituted with one or more independently selected from the group consisting of F, Cl, Br, I, CN, OH, OC 1-4 alkyl, OCF 3, C 1-4 alkyl, CF 3, NH 2 a group consisting of NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 and a substituent such as SCF 3 which is mono- or polysubstituted; or an aryl group, preferably a phenyl group, Or a heteroaryl group, preferably a pyridyl group, a furyl group or a phenyl group, which is unsubstituted in each case, or one or more independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OC 1-4 alkyl-OC 1-4 alkyl, , , , , , OCF 3 , C 1-4 alkyl, C 1-4 alkylene-OC 1-4 -alkyl, CF 3 , CF 2 H, CFH 2 , SCF 3 , NH 2 , NH (C 1-4 alkane yl), N (C 1-4 alkyl) 2 and phenyl group substituted with the group consisting of mono- or polysubstituted, wherein the phenyl-based unsubstituted or substituted with one or more independently selected from the group consisting of F, Cl, Br, I, CN, OH, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, CF 3 , NH 2 , NH(C 1-4 alkyl), N (C 1- The group consisting of 4 alkyl) 2 and a substituent such as SCF 3 is mono- or poly-substituted.

再更佳地，殘基R1 代表(T1)子結構，其E 代表O、S或NR11，以代表O或S較佳，其中，R11代表H或選自由甲基與乙基組成之群組，o 代表0或1，以代表0較佳；R10a與R10b係相互獨立地選自由H、甲基與乙基組成之群組，m 代表0、1或2，以代表0或1較佳；G 代表甲基、乙基、正丙基、異丙基、正丁基、二級丁基、 三級丁基、戊基、己基，其於各例中係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、OH、O-C1-4烷基、O-C1-4伸烷基-OH、與O-C1-4伸烷基-O-C1-4烷基等取代基組成之群組單取代或多取代，或代表，或代表環丙基、環丁基、環戊基、與環己基，或選自由咯啶基、哌嗪基、4-甲基哌嗪基、哌啶基、嗎咻基、四氫咯基、四氫喹啉基、四氫異喹啉基、四氫吡喃基組成之群組，以四氫-2H-吡喃-4-基、四氫呋喃基、四氫啶基與硫基嗎咻基較佳，其於各例中互獨立地係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、OH、O-C1-4烷基、C1-4烷基、NH2、NH(C1-4烷基)與N(C1-4烷基)2等取代基組成之群組單取代或多取代，或代表苯基、啶基、呋喃基或，其於各例中係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、O-C1-4伸烷基-O-C1-4烷基、、、、、、OCF3、C1-4烷基、C1-4伸烷基-O-C1-4-烷基、CF3、CF2H、CFH2、SCF3、NH2、NH(C1-4烷基)與N(C1-4烷基)2等取代基組成之群組單取代或多取代。 More preferably, the residue R 1 represents a (T1) substructure, and E represents O, S or NR 11 to represent O or S, wherein R 11 represents H or is selected from the group consisting of methyl and ethyl. Group, o represents 0 or 1, preferably represents 0; R 10a and R 10b are independently selected from the group consisting of H, methyl and ethyl, and m represents 0, 1 or 2 to represent 0 or 1 is preferred; G represents methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tert-butyl, pentyl, hexyl, which are unsubstituted in each case, or One or more independently selected from the group consisting of F, Cl, Br, I, OH, OC 1-4 alkyl, OC 1-4 alkyl-OH, and OC 1-4 alkyl-OC 1- a group consisting of a substituent such as a 4- alkyl group, mono- or poly-substituted, or represented Or on behalf of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, or selected from pyridyl, piperazinyl, 4-methylpiperazinyl, piperidinyl, decyl, tetrahydroyl a group consisting of tetrahydroquinolyl, tetrahydroisoquinolyl, and tetrahydropyranyl, tetrahydro-2H-pyran-4-yl, tetrahydrofuranyl, tetrahydropyridyl, and thiomethalin Preferably, they are independently unsubstituted in each case, or are selected from one or more independently selected from the group consisting of F, Cl, Br, I, OH, OC 1-4 alkyl, C 1-4 alkane. a group consisting of a substituent consisting of a substituent such as NH 2 , NH 2 (C 1-4 alkyl) and N(C 1-4 alkyl) 2 or a polysubstituted group, or a phenyl group, a pyridyl group, a furyl group or It is unsubstituted in each case, or is selected from one or more of each other independently from F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OC 1-4 alkylene base-OC 1-4 alkyl, , , , , , OCF 3 , C 1-4 alkyl, C 1-4 alkylene-OC 1-4 -alkyl, CF 3 , CF 2 H, CFH 2 , SCF 3 , NH 2 , NH (C 1-4 alkane The group consists of a mono- or poly-substitution of a group consisting of a substituent such as N(C 1-4 alkyl) 2 .

又更佳地，殘基R1 代表(T1)子結構，其E 代表O或S，o 代表0或1，以代表0較佳， R10a與R10b係相互獨立地選自由H、甲基與乙基組成之群組，以各自代表H較佳；m 代表0、1或2，以代表0或1較佳；G 代表甲基、乙基、正丙基、異丙基、正丁基、二級丁基、三級丁基、戊基、己基，或代表，或代表環丙基、環丁基、環戊基與環己基，或選自由哌啶基、嗎咻基、四氫咯基、四氫喹啉基、四氫異喹啉基、二氫喹啉基、二氫咯基、二氫啶基、二氫異喹啉基、四氫吡喃基組成之群組，以四氫-2H-吡喃-4-基、四氫呋喃基與四氫啶基較佳，其於各例中相互獨立地係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、OH、O-C1-4烷基、C1-4烷基、NH2、NH(C1-4烷基)與N(C1-4烷基)2等取代基組成之群組單取代或多取代，或代表呋喃基或吩基，其於各例中係未被取代，或代表苯基或啶基，其於各例中係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、O-C1-4伸烷基-O-C1-4烷基、、、、、、OCF3、C1-4烷基、C1-4伸烷基-O-C1-4-烷基、CF3、CF2H、CFH2、SCF3、NH2、NH(C1-4烷基)與N(C1-4烷基)2等取代基組成之群組單取代或多取代。 Still more preferably, the residue R 1 represents a (T1) substructure, wherein E represents O or S, o represents 0 or 1, preferably represents 0, and R 10a and R 10b are independently selected from H, methyl. The group consisting of ethyl groups, preferably each represents H; m represents 0, 1 or 2, preferably represents 0 or 1; G represents methyl, ethyl, n-propyl, isopropyl, n-butyl. , secondary butyl, tertiary butyl, pentyl, hexyl, or representative Or represents cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, or selected from piperidinyl, decyl, tetrahydrorupyl, tetrahydroquinolyl, tetrahydroisoquinolinyl, dihydroquine a group consisting of phenyl, dihydro, pyridyl, dihydroisoquinolinyl, tetrahydropyranyl, tetrahydro-2H-pyran-4-yl, tetrahydrofuranyl and tetrahydropyridyl Preferably, they are unsubstituted independently of each other in each case, or are selected from one or more independently selected from the group consisting of F, Cl, Br, I, OH, OC 1-4 alkyl, C 1-4 alkane. a group consisting of a group consisting of NH 2 , NH (C 1-4 alkyl) and N(C 1-4 alkyl) 2, such as a mono- or poly-substituent, or a furanyl or phenyl group, in each case The middle system is unsubstituted, or represents a phenyl or pyridine group, which is unsubstituted in each case, or is selected from F, Cl, Br, I, NO 2 , CN, OH independently of one or more. , OC 1-4 alkyl, OC 1-4 alkyl-OC 1-4 alkyl, , , , , , OCF 3 , C 1-4 alkyl, C 1-4 alkylene-OC 1-4 -alkyl, CF 3 , CF 2 H, CFH 2 , SCF 3 , NH 2 , NH (C 1-4 alkane The group consists of a mono- or poly-substitution of a group consisting of a substituent such as N(C 1-4 alkyl) 2 .

最佳地，R1 代表苯基，其係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、CN、OH、O-CH3、CH3、CH(CH3)2、N(CH3)2、CF3、CHF2與三級丁基等取代基組成之群組單取 代或多取代，苯基以被一或二個相互獨立地選自由F、Cl、Br、I、CN、OH、O-CH3、CH3、CH(CH3)2、N(CH3)2、CF3、CHF2與三級丁基等取代基組成之群組單取代或二取代較佳，苯基以於間位被以一選自由F、Cl、Br、I、CN、OH、O-CH3、CH3、CH(CH3)2、N(CH3)2、CF3、CHF2與三級丁基等取代基組成之群組單取代更佳。 Most preferably, R 1 represents a phenyl group which is unsubstituted or is selected independently from one another by F, Cl, Br, I, CN, OH, O-CH 3 , CH 3 , CH ( a group consisting of CH 3 ) 2 , N(CH 3 ) 2 , CF 3 , CHF 2 and a tertiary butyl group, such as a mono- or poly-substituent group, the phenyl group being independently selected from one or two by F, a group consisting of substituents such as Cl, Br, I, CN, OH, O-CH 3 , CH 3 , CH(CH 3 ) 2 , N(CH 3 ) 2 , CF 3 , CHF 2 and a tertiary butyl group Preferably, the phenyl group is selected from the group consisting of F, Cl, Br, I, CN, OH, O-CH 3 , CH 3 , CH(CH 3 ) 2 , N(CH 3 ) 2 , a combination of CF 3 , CHF 2 and a tertiary butyl group is preferably a group monosubstituted.

於根據本發明之一特佳具體實施例中，通式(I)之R2係≠H。 In a particularly preferred embodiment according to the invention, the R 2 of the formula (I) is ≠H.

於根據本發明通式(I)化合物之另一較佳具體實施例中，R2 代表H、F、Cl、Br、I、CN、NO2、CF3、CF2H、CFH2、CF2Cl、CFCl2、OH、OCF3、OCF2H、OCFH2、OCF2Cl、OCFCl2、SH、SCF3、SCF2H、SCFH2、SCF2Cl、SCFCl2，或一C1-10脂族殘基，其係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、=O、O-C1-4烷基、OCF3、C(=O)-OH、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3、S(=O)2OH、苄基、苯基、啶基與吩基等取代基組成之群組單取代或多取代，其中，苄基、苯基、啶基、吩基分別可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、C(=O)-OH、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3與S(=O)2OH等取代基組成之群組單取代或多取代；或一C3-10環脂族殘基或一3至10構件雜環脂族殘基，其於各例中係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、OH、=O、C1-4烷基、O-C1-4烷基、OCF3、C(=O)-OH與CF3等取代基組成之群組單取代或多取代；其中，各上述殘基，即C3-10環脂族殘基或3至10構件 雜環脂族殘基，於各例中可選擇性地經由一C1-8脂族基橋接，其進而可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、=O、O-C1-4烷基、OCF3、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基與SCF3等取代基組成之群組單取代或多取代，或芳基或雜芳基，其分別係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、C(=O)-OH、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-8烷基、SCF3、S(=O)2OH、苄基、苯基、啶基與吩基等取代基組成之群組單取代或多取代，其中，苄基、苯基、啶基、吩基可分別係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-8烷基、OCF3、C1-4烷基、C(=O)-OH、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3與S(=O)2OH等取代基組成之群組單取代或多取代；其中，各上述殘基，即芳基與雜芳基，於各例中可選擇性地經由一C1-8脂族基橋接，其進而可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、=O、O-C1-4烷基、OCF3、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基與SCF3等取代基組成之群組單取代或多取代。 In another preferred embodiment of the compound of formula (I) according to the invention, R 2 represents H, F, Cl, Br, I, CN, NO 2 , CF 3 , CF 2 H, CFH 2 , CF 2 Cl, CFCl 2 , OH, OCF 3 , OCF 2 H, OCFH 2 , OCF 2 Cl, OCFCl 2 , SH, SCF 3 , SCF 2 H, SCFH 2 , SCF 2 Cl, SCFCl 2 , or a C 1-10 fat a family residue which is unsubstituted or which is selected from one or more independently from F, Cl, Br, I, NO 2 , CN, OH, =0, OC 1-4 alkyl, OCF 3 , C(=O)-OH, CF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 , S(= O) a group of mono- or poly-substituents consisting of a substituent such as 2 OH, a benzyl group, a phenyl group, a pyridine group and a phenyl group, wherein the benzyl group, the phenyl group, the pyridine group and the phenyl group may be unsubstituted, respectively, or One or more independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, C(=O)-OH , CF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 and S(=O) 2 OH, etc. the group consisting of mono- or polysubstituted; or a C 3-10 cyclic aliphatic residue, or a 3 10 member heterocycloaliphatic residue, which is unsubstituted in the respective embodiments based, or with one or more independently selected from the group consisting of F, Cl, Br, I, OH, = O, C 1-4 alkyl a group of mono- or poly-substitutions consisting of a substituent such as OC 1-4 alkyl, OCF 3 , C(=O)-OH, and CF 3 ; wherein each of the above residues, ie, a C 3-10 cycloaliphatic residue a base or a 3 to 10 membered heterocyclic aliphatic residue, which in each case is optionally bridged via a C 1-8 aliphatic group, which in turn may be unsubstituted or independently of one or more Free F, Cl, Br, I, NO 2 , CN, OH, =O, OC 1-4 alkyl, OCF 3 , CF 3 , NH 2 , NH(C 1-4 alkyl), N (C 1 -4 alkyl) 2 , SH, SC 1-4 alkyl and a combination of SCF 3 and the like are mono- or poly-substituted, or aryl or heteroaryl, which are unsubstituted or respectively Or a plurality of mutually independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, C(=O)-OH, CF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-8 alkyl, SCF 3 , S(=O) 2 OH, benzyl, phenyl a group consisting of a substituent such as a pyridine group and a phenyl group a substitution or a substitution, wherein the benzyl group, the phenyl group, the pyridyl group, and the phenyl group are each unsubstituted, or are independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, OC 1-8 alkyl, OCF 3 , C 1-4 alkyl, C(=O)-OH, CF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkane a group of mono- or poly-substituents consisting of a substituent such as 2 , SH, SC 1-4 alkyl, SCF 3 and S(=O) 2 OH; wherein each of the above residues, ie, an aryl group and a heteroaryl group Optionally, in each case, bridged via a C 1-8 aliphatic group, which in turn may be unsubstituted, or selected from one or more independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, =O, OC 1-4 alkyl, OCF 3 , CF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1- The group consisting of a substituent of 4 alkyl and SCF 3 is mono- or poly-substituted.

較佳地，R2 代表F、Cl、Br、I、CN、NO2、CF3、CF2H、CFH2、CF2Cl、CFCl2、OH、OCF3、OCF2H、OCFH2、OCF2Cl、OCFCl2、SH、SCF3、SCF2H、SCFH2、SCF2Cl、SCFCl2， 或代表一C1-8脂族殘基，其係未被取代或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、=O、O-C1-4烷基、OCF3、C(=O)-OH、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3、S(=O)2OH等取代基組成之群組單取代或多取代，或代表一C3-6環脂族殘基或一3至6構件雜環脂族殘基，其於各例中係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、OH、=O、C1-4烷基、O-C1-4烷基、OCF3、C(=O)-OH與CF3等取代基組成之群組單取代或多取代；或代表苯基或啶基，其於各例中係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、C(=O)-OH、CF3、NH2、NH(C1-4烷基)與N(C1-4烷基)2等取代基組成之群組單取代或多取代。 Preferably, R 2 represents F, Cl, Br, I, CN, NO 2 , CF 3 , CF 2 H, CFH 2 , CF 2 Cl, CFCl 2 , OH, OCF 3 , OCF 2 H, OCFH 2 , OCF 2 Cl, OCFCl 2 , SH, SCF 3 , SCF 2 H, SCFH 2 , SCF 2 Cl, SCFCl 2 , or represents a C 1-8 aliphatic residue which is unsubstituted or is one or more Independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, =0, OC 1-4 alkyl, OCF 3 , C(=O)-OH, CF 3 , NH 2 , NH (C 1 Group of mono- or poly-substitutions of substituents such as -4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 , S(=O) 2 OH, or Represents a C 3-6 cycloaliphatic residue or a 3 to 6 membered heterocyclic aliphatic residue which is unsubstituted in each case or which is independently selected from F, Cl, in one or more a group mono- or poly-substituted with a group consisting of a substituent such as Br, I, OH, =O, C 1-4 alkyl, OC 1-4 alkyl, OCF 3 , C(=O)-OH, and CF 3 ; Represents a phenyl or pyridine group, which is unsubstituted in each case, or is selected from one or more independently of each other from F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl , OCF 3 , C 1-4 alkyl, C(=O)-OH, CF 3 a group consisting of a group consisting of NH 2 , NH(C 1-4 alkyl) and N(C 1-4 alkyl) 2 is mono- or poly-substituted.

更佳地，R2 代表一C1-8脂族殘基，其係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、=O、O-C1-4烷基、OCF3、C(=O)-OH、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3、S(=O)2OH等取代基組成之群組單取代或多取代，或代表一C3-6環脂族殘基或一3至6構件雜環脂族殘基，其於各例中係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、OH、=O、C1-4烷基、O-C1-4烷基、OCF3、C(=O)-OH與CF3等取代基組成之群組單取代或多取代。 More preferably, R 2 represents a C 1-8 aliphatic residue which is unsubstituted or is selected independently from one another by F, Cl, Br, I, NO 2 , CN, OH, =O, OC 1-4 alkyl, OCF 3 , C(=O)-OH, CF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, a group consisting of a group consisting of a substituent such as a C 1-4 alkyl group, an SCF 3 group, an S(=O) 2 OH group, a mono- or poly-substituent, or a C 3-6 cycloaliphatic residue or a 3- to 6-membered heterocyclic ring An aliphatic residue, which is unsubstituted in each case, or one or more independently selected from the group consisting of F, Cl, Br, I, OH, =0, C 1-4 alkyl, OC 1- A group consisting of a group consisting of a substituent of 4 alkyl, OCF 3 , C(=O)-OH and CF 3 is mono- or poly-substituted.

再更佳地，R2 代表一C1-4脂族殘基，其係未被取代，或被以一或多個相 互獨立地選自由F、Cl、Br、I與OH等取代基組成之群組單取代或多取代，或代表一C3-6環脂族殘基或一3至6構件雜環脂族殘基，其於各例中係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I與OH等取代基組成之群組單取代或多取代。 Even more preferably, R 2 represents a C 1-4 aliphatic residue which is unsubstituted or consists of one or more substituents independently selected from the group consisting of F, Cl, Br, I and OH. The group is mono- or polysubstituted, or represents a C 3-6 cycloaliphatic residue or a 3 to 6 membered heterocyclic aliphatic residue, which is unsubstituted in each case or is one or more They are independently selected from the group consisting of mono- or poly-substitutions consisting of substituents such as F, Cl, Br, I and OH.

又更佳地，R2 代表一C1-4脂族殘基，其係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I等取代基組成之群組單取代或多取代，或代表一C3-6環脂族殘基或一3至6構件雜環脂族殘基，以一C3-6環脂族殘基較佳，其於各例中係未被取代。 Still more preferably, R 2 represents a C 1-4 aliphatic residue which is unsubstituted or is grouped by one or more substituents independently selected from the group consisting of F, Cl, Br, I, and the like. Monosubstituted or polysubstituted, or represents a C 3-6 cycloaliphatic residue or a 3 to 6 membered heterocyclic aliphatic residue, preferably a C 3-6 cycloaliphatic residue, in each case The system is not replaced.

特佳地，R2 係選自由CF3、甲基、乙基、正丙基、異丙基、正丁基、二級丁基與三級丁基組成之群組，或係選自由環丙基、環丁基、環戊基與環己基組成之群組。 Particularly preferably, R 2 is selected from the group consisting of CF 3 , methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl and tertiary butyl, or selected from cyclopropyl A group consisting of a group consisting of a cyclobutyl group, a cyclopentyl group and a cyclohexyl group.

最佳地，R2係選自由三級丁基、CF3、環丙基、環丁基、環戊基與環己基組成之群組，以選自由三級丁基、CF3與環丙基組成之群組較佳，以選自由三級丁基與CF3組成之群組更佳。 Most preferably, the R 2 is selected from the group consisting of tertiary butyl, CF 3 , cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, selected from the group consisting of tertiary butyl, CF 3 and cyclopropyl. The group of compositions is preferably selected from the group consisting of tributyl and CF 3 .

於根據本發明通式(I)化合物之又另一較佳具體實施例中，R3 代表H或一C1-4脂族殘基，其係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、CN、OH、=O、O-C1-4烷基、OCF3、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基與SCF3等取代基組成之群組單取代或多取代。 In still another preferred embodiment of the compound of formula (I) according to the invention, R 3 represents H or a C 1-4 aliphatic residue which is unsubstituted or which is one or more Independently selected from the group consisting of F, Cl, Br, I, CN, OH, =0, OC 1-4 alkyl, OCF 3 , CF 3 , NH 2 , NH(C 1-4 alkyl), N (C 1- The group consisting of 4, alkyl, 2 , SH, SC 1-4 alkyl and a substituent such as SCF 3 is mono- or poly-substituted.

較佳地，R3 代表H或一C1-4脂族殘基，其係未被取代，或被以一或多 個相互獨立地選自由F、Cl、Br、I與OH等取代基組成之群組單取代或多取代。 Preferably, R 3 represents H or a C 1-4 aliphatic residue which is unsubstituted or consists of one or more substituents independently selected from the group consisting of F, Cl, Br, I and OH. The group is monosubstituted or multi-substituted.

更佳地，R3 代表H或一未被取代之C1-4脂族殘基，以選自由甲基、乙基、正丙基、異丙基、正丁基、二級丁基與三級丁基組成之群組較佳。 More preferably, R 3 represents H or an unsubstituted C 1-4 aliphatic residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, dibutyl and tri A group of butyl groups is preferred.

尤其，R3 係選自由H、甲基與乙基組成之群組，以代表H或甲基較佳，以代表H更佳。 In particular, R 3 is selected from the group consisting of H, methyl and ethyl to preferably represent H or methyl, preferably to represent H.

於根據本發明通式(I)化合物之一較佳具體實施例中，n 代表1、2、3或4，以代表1、2或3較佳，以代表1或2更佳，以代表1最佳。 In a preferred embodiment of the compound of the formula (I) according to the present invention, n represents 1, 2, 3 or 4 to represent 1, 2 or 3, preferably 1 or 2, to represent 1 optimal.

於根據本發明通式(I)化合物之又另一較佳具體實施例中，R3a 代表H或一C1-4脂族殘基，其係未被取代，或被以一或多個相互獨立地選自一F、Cl、Br、I、CN、OH、=O、O-C1-4烷基、OCF3、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基與SCF3等取代基組成之群組單取代或多取代。 In still another preferred embodiment of the compound of formula (I) according to the invention, R 3a represents H or a C 1-4 aliphatic residue which is unsubstituted or which is one or more Independently selected from the group consisting of F, Cl, Br, I, CN, OH, =0, OC 1-4 alkyl, OCF 3 , CF 3 , NH 2 , NH(C 1-4 alkyl), N (C 1 -4 alkyl) 2 , SH, SC 1-4 alkyl and a group consisting of a substituent such as SCF 3 are mono- or poly-substituted.

較佳地，R3a 代表H或一C1-4脂族殘基，其係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I與OH等取代基組成之群組單取代或多取代。 Preferably, R 3a represents H or a C 1-4 aliphatic residue which is unsubstituted or consists of one or more substituents independently selected from the group consisting of F, Cl, Br, I and OH. The group is monosubstituted or multi-substituted.

更佳地，R3a 代表H或一未被取代之C1-4脂族殘基，以選自由甲基、乙基、正丙基、異丙基、正丁基、二級丁基與三級丁基組成之群組較佳。 More preferably, R 3a represents H or an unsubstituted C 1-4 aliphatic residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, dibutyl and tri A group of butyl groups is preferred.

尤其， R3a 係選自由H、甲基與乙基組成之群組，以代表H或甲基較佳，以代表H更佳。 In particular, R 3a is selected from the group consisting of H, methyl and ethyl, preferably H or methyl, to better represent H.

於根據本發明通式(I)化合物之令一較佳具體實施例中，Y 代表O或S，以代表O較佳。 In a preferred embodiment of the compound of formula (I) according to the invention, Y represents O or S to represent O.

根據本發明通式(I)化合物之一具體實施例亦為首選，其中，R4a 代表H或一C1-4脂族殘基，其係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、=O、O-C1-4烷基、OCF3、C(=O)-OH、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3、S(=O)2OH、苄基、苯基、啶基與吩基等取代基組成之群組單取代或多取代，其中，苄基、苯基、啶基、吩基分別可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、C(=O)-OH、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3與S(=O)2OH等取代基組成之群組單取代或多取代，或代表一C3-6環脂族殘基，其係未被取代，或被以至少一選自由F、Cl、Br、I、NO2、CN、OH、=O、O-C1-4烷基、OCF3、C1-4烷基、C(=O)-OH、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3、S(=O)2OH、苄基、苯基、啶基與吩基等取代基組成之群組單取代或多取代，其中，苄基、苯基、啶基、吩基分別可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、C(=O)-OH、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3與S(=O)2OH等取代基組成之群組單取代或多取代。或代表一芳基，其係未被取代，或被以至少一選自由F、 Cl、Br、I、NO2、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、C(=O)-OH、CF3、CF2H、CFH2、CF2Cl、CFCl2、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3、S(=O)2OH與NH-S(=O)2-C1-4烷基等取代基組成之群組單取代或多取代，R4b 代表H或一C1-4脂族殘基，其係未被取代，或被以至少一選自由F、Cl、Br、I、NO2、CN、OH、=O、O-C1-4烷基、OCF3、C(=O)-OH、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3、S(=O)2OH、苄基、苯基、啶基與吩基等取代基組成之群組單取代或多取代，其中，苄基、苯基、啶基、吩基分別係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、C(=O)-OH、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3與S(=O)2OH等取代基組成之群組單取代或多取代，或R4a與R4b即將其連結之碳原子共同形成一C3-6環脂族殘基，其係未被取代，或被以至少一選自由F、Cl、Br、I、NO2、CN、OH、=O、O-C1-4烷基、OCF3、C1-4烷基、C(=O)-OH、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3、S(=O)2OH、苄基、苯基、啶基與吩基等取代基組成之群組單取代或多取代，其中，苄基、苯基、啶基、吩基分別可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、C(=O)-OH、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3與S(=O)2OH等取代基組成之群組單取代或多取代。 A particular embodiment of a compound of formula (I) according to the invention is also preferred, wherein R 4a represents H or a C 1-4 aliphatic residue which is unsubstituted or which is independent of one or more Selected from F, Cl, Br, I, NO 2 , CN, OH, =0, OC 1-4 alkyl, OCF 3 , C(=O)-OH, CF 3 , NH 2 , NH (C 1- Substituents such as 4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 , S(=O) 2 OH, benzyl, phenyl, pyridine and phenyl a group consisting of a mono- or poly-substitution in which a benzyl group, a phenyl group, a pyridyl group, or a phenyl group may be unsubstituted, respectively, or one or more independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, C(=O)-OH, CF 3 , NH 2 , NH(C 1-4 alkyl), N ( a group consisting of C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 and S(=O) 2 OH, such as a mono- or poly-substituted group, or a C 3-6 cycloaliphatic group a family residue which is unsubstituted or is selected from at least one selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, =0, OC 1-4 alkyl, OCF 3 , C 1-4 alkane Base, C(=O)-OH, CF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) a group consisting of SH, SC 1-4 alkyl, SCF 3 , S(=O) 2 OH, benzyl, phenyl, pyridine, and phenyl, etc., wherein the group consists of a mono- or poly-substituent, wherein the benzyl group , phenyl, pyridine, phenyl, respectively, may be unsubstituted, or one or more independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, C(=O)-OH, CF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1- A group consisting of a group consisting of a substituent of 4 alkyl, SCF 3 and S(=O) 2 OH, is mono- or poly-substituted. Or represents an aryl group which is unsubstituted or is selected from at least one selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl , C(=O)-OH, CF 3 , CF 2 H, CFH 2 , CF 2 Cl, CFCl 2 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , a group consisting of SH, SC 1-4 alkyl, SCF 3 , S(=O) 2 OH and a substituent such as NH-S(=O) 2 -C 1-4 alkyl, mono- or poly-substituted, R 4b Represents H or a C 1-4 aliphatic residue which is unsubstituted or is selected from at least one selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, =0, OC 1-4 alkyl , OCF 3 , C(=O)-OH, CF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 a group of mono- or poly-substituents consisting of a substituent such as S(=O) 2 OH, a benzyl group, a phenyl group, a pyridine group and a phenyl group, wherein the benzyl group, the phenyl group, the pyridine group and the phenyl group are not respectively Substituted, or selected from one or more independently of each other by F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, C(=O -OH, CF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 and S(=O) 2 OH Wait Group group consisting of mono- or polysubstituted, or R 4a and R 4b carbon atoms which is about to concatenate together form a C 3-6 cycloaliphatic residue, which system is unsubstituted or is at least one selected from the group consisting of F , Cl, Br, I, NO 2 , CN, OH, =O, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, C(=O)-OH, CF 3 , NH 2 , NH ( C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 , S(=O) 2 OH, benzyl, phenyl, pyridine and phenyl a group consisting of a mono- or poly-substituent of a group consisting of a benzyl group, a phenyl group, a pyridyl group, and a phenyl group, respectively, may be unsubstituted, or one or more independently selected from the group consisting of F, Cl, Br , I, NO 2 , CN, OH, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, C(=O)-OH, CF 3 , NH 2 , NH(C 1-4 alkyl) And a group consisting of N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 and S(=O) 2 OH, such as a mono- or poly-substituent.

較佳地，R4a 代表H或一C1-4脂族殘基，其係未被取代，或被以至少一選自由F、Cl、Br、I、NO2、CN、OH、=O、O-C1-4烷基、OCF3、C(=O)-OH、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3與S(=O)2OH等取代基組成之群組單取代或多取代，或代表一C3-6環脂族殘基，其係未被取代，或被以至少一選自由F、Cl、Br、I、NO2、CN、OH、=O、O-C1-4烷基、OCF3、C1-4烷基、C(=O)-OH、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3與S(=O)2OH等取代基組成之群組單取代或多取代，或代表一芳基，其係未被取代，或被以至少一選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、C(=O)-OH、CF3、CF2H、CFH2、CF2Cl、CFCl2、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3、S(=O)2OH與NH-S(=O)2-C1-4烷基等取代基組成之群組單取代或多取代，R4b 代表H或一C1-4脂族殘基，其係未被取代，或被以至少一選自由F、Cl、Br、I、NO2、CN、OH、=O、O-C1-4烷基、OCF3、C(=O)-OH、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3與S(=O)2OH等取代基組成之群組單取代或多取代，或R4a與R4b及將其連結之碳原子共同形成一C3-6環脂族殘基，其係未被取代，或被以至少一選自由F、Cl、Br、I、NO2、CN、OH、=O、O-C1-4烷基、OCF3、C1-4烷基、C(=O)-OH、CF3、NH2、NH(C1-4 烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3與S(=O)2OH等取代基組成之群組單取代或多取代。 Preferably, R 4a represents H or a C 1-4 aliphatic residue which is unsubstituted or is selected from at least one selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, =0, OC 1-4 alkyl, OCF 3 , C(=O)-OH, CF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1- a group consisting of a substituent consisting of a substituent such as a 4- alkyl group, an SCF 3 and an S(=O) 2 OH group, or a C 3-6 cycloaliphatic residue, which is unsubstituted or at least One selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, =0, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, C(=O)-OH, CF 3 , NH 2 , a group consisting of NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 and S(=O) 2 OH Substituted or substituted, or represented as an aryl group, which is unsubstituted, or at least one selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, C(=O)-OH, CF 3 , CF 2 H, CFH 2 , CF 2 Cl, CFCl 2 , NH 2 , NH(C 1-4 alkyl), N (C 1-4 a group of monosubstituted groups of alkyl, 2 , SH, SC 1-4 alkyl, SCF 3 , S(=O) 2 OH and NH-S(=O) 2 -C 1-4 alkyl polysubstituted, R 4b Table H or a C 1-4 aliphatic residue, which system is unsubstituted or is at least one selected from the group consisting of F, Cl, Br, I, NO 2, CN, OH, = O, OC 1-4 alkyl , OCF 3 , C(=O)-OH, CF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 a group consisting of a mono- or poly-substituent consisting of a substituent such as S(=O) 2 OH, or R 4a and R 4b and a carbon atom to which they are bonded form a C 3-6 cycloaliphatic residue, which is not Substituted, or at least one selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, =0, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, C(=O) -OH, CF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 and S(=O) 2 OH, etc. The group consisting of substituents is mono- or poly-substituted.

更佳地，R4a 代表H或一C1-4脂族殘基，其係未被取代，或被以至少一選自由F、Cl、Br、I、OH、=O、O-C1-4烷基、OCF3、CF3與SCF3等取代基組成之群組單取代或多取代。或代表一C3-6環脂族殘基，其係未被取代，或被以至少一選自由F、Cl、Br、I、OH、=O、O-C1-4烷基、OCF3、C1-4烷基、CF3與SCF3等取代基組成之群組單取代或多取代，或代表一芳基，以苯基較佳，其係未被取代，或被以至少一選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、C(=O)-OH、CF3、CF2H、CFH2、CF2Cl、CFCl2、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3、S(=O)2OH與NH-S(=O)2-C1-4烷基等取代基組成之群組單取代或多取代；R4b 代表H或一C1-4脂族殘基，其係未被取代，或被以至少一選自由F、Cl、Br、I、OH、=O、O-C1-4烷基、OCF3、CF3與SCF3等取代基組成之群組單取代或多取代，或R4a與R4b及將其連結之碳原子共同形成一C3-6環脂族殘基，其係未被取代，或被以至少一選自由F、Cl、Br、I、OH、=O、O-C1-4烷基、OCF3、C1-4烷基、CF3與SCF3等取代基組成之群組單取代或多取代。 More preferably, R 4a represents H or a C 1-4 aliphatic residue which is unsubstituted or is selected from at least one selected from the group consisting of F, Cl, Br, I, OH, =0, OC 1-4 alkane. The group consisting of a substituent such as a group, OCF 3 , CF 3 and SCF 3 is mono- or poly-substituted. Or represents a C 3-6 cycloaliphatic residue which is unsubstituted or is selected from at least one selected from the group consisting of F, Cl, Br, I, OH, =0, OC 1-4 alkyl, OCF 3 , C a group consisting of a group consisting of 1-4 alkyl, CF 3 and SCF 3, such as a mono- or poly-substituent, or an aryl group, preferably a phenyl group, which is unsubstituted or at least one selected from the group consisting of F , Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, C(=O)-OH, CF 3 , CF 2 H, CFH 2 , CF 2 Cl, CFCl 2 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 , S(=O) 2 OH and a group consisting of a mono- or poly-substituent of a substituent such as NH-S(=O) 2 -C 1-4 alkyl; R 4b represents an H or a C 1-4 aliphatic residue which is unsubstituted, or Monosubstituted or polysubstituted with at least one group selected from the group consisting of F, Cl, Br, I, OH, =0, OC 1-4 alkyl, OCF 3 , CF 3 and SCF 3 , or R 4a Together with R 4b and the carbon atom to which it is bonded, a C 3-6 cycloaliphatic residue which is unsubstituted or at least one selected from the group consisting of F, Cl, Br, I, OH, =0, OC 1-4 alkyl group, OCF 3 , C 1-4 alkyl group, CF 3 and SCF 3, etc. The group consisting of substituents is mono- or poly-substituted.

再更佳地，R4a 代表H或一未被取代之C1-4脂族殘基，以代表H較佳，或係選自由甲基、乙基、正丙基、異丙基、正丁基、二級丁 基與三級丁基組成之群組，或代表一未被取代之C3-6環脂族殘基，以選自由環丙基、環丁基、環戊基與環己基組成之群組較佳，或代表一苯基，其係未被取代，或被以至少一選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、C(=O)-OH、CF3、CF2H、CFH2、CF2Cl、CFCl2、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3、S(=O)2OH與NH-S(=O)2-C1-4烷基等取代基組成之群組單取代或多取代，R4b 代表H或一C1-4脂族殘基，其係未被取代，或被以至少一選自由F、Cl、Br、I、OH、=O、O-C1-4烷基、OCF3、CF3與SCF3等取代基組成之群組單取代或多取代，或R4a與R4b及將其連結之碳原子共同形成一C3-6環脂族殘基，以選自由環丙基、環丁基、環戊基與環己基組成之群組較佳，其係未被取代，或被以至少一選自由F、Cl、Br、I、OH、=O、O-C1-4烷基、OCF3、C1-4烷基、CF3與SCF3等取代基組成之群組單取代或多取代。 Even more preferably, R 4a represents H or an unsubstituted C 1-4 aliphatic residue, preferably represented by H, or selected from methyl, ethyl, n-propyl, isopropyl, n-butyl a group consisting of a base, a secondary butyl group and a tertiary butyl group, or an unsubstituted C 3-6 cycloaliphatic residue selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl Preferably, the group consisting of or representing a phenyl group is unsubstituted or at least one selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, C(=O)-OH, CF 3 , CF 2 H, CFH 2 , CF 2 Cl, CFCl 2 , NH 2 , NH(C 1-4 alkyl), N (C 1 a group consisting of -4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 , S(=O) 2 OH and NH-S(=O) 2 -C 1-4 alkyl Substituted or polysubstituted, R 4b represents H or a C 1-4 aliphatic residue which is unsubstituted or is selected from at least one selected from the group consisting of F, Cl, Br, I, OH, =0, OC 1-4 a group consisting of a group consisting of a substituent such as an alkyl group, OCF 3 , CF 3 and SCF 3 or a polysubstituted group, or R 4a and R 4b together with a carbon atom to which they are bonded form a C 3-6 cycloaliphatic residue, Selected from cyclopropyl, cyclo Group, cyclopentyl group and cyclohexyl group consisting of the preferred, which system is unsubstituted or is at least one selected from the group consisting of F, Cl, Br, I, OH, = O, OC 1-4 alkyl, OCF 3 a group consisting of a C 1-4 alkyl group, a CF 3 group, and a SCF 3 group, such as a mono- or poly-substitution.

又更佳地，R4a 代表H、甲基、乙基、環丙基、環丁基、環戊基、環己基或苯基，其中，苯基係未被取代，或被以1、2、3、4或5個相互獨立地選自由F、Cl、Br、I、NO2、CN、CF3、CF2H、CFH2、CF2Cl、CFCl2、OH、NH2、NH(C1-4烷基)與N(C1-4烷基)(C1-4烷基)、C1-4烷基與O-C1-4-烷基等取代基組成之群組取代；R4b代表H、甲基或乙基， 或R4a與R4b及將其連結之碳原子共同形成一環丙基、環丁基、環戊基或環己基環。 Still more preferably, R 4a represents H, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl, wherein the phenyl is unsubstituted or is 1, 2 3, 4 or 5 are independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, CF 3 , CF 2 H, CFH 2 , CF 2 Cl, CFCl 2 , OH, NH 2 , NH (C 1 -4 alkyl) is substituted with a group consisting of a substituent such as N(C 1-4 alkyl)(C 1-4 alkyl), C 1-4 alkyl and OC 1-4 -alkyl; R 4b represents H, methyl or ethyl, or R 4a and R 4b together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.

根據本發明通式(I)之一化合物為首選，其中，R4a代表H、甲基、乙基、環丙基、環丁基、環戊基、環己基或苯基，其中，苯基係未被取代，或被以1、2或3個相互獨立地選自由F、Cl、Br、CF3、甲基與甲氧基等取代基組成之群組取代；R4b代表H、甲基或乙基，或R4a與R4b及將及連結之碳原子共同形成環丙基、環丁基、環戊基或環己基環。 A compound according to the invention of the formula (I) is preferred, wherein R 4a represents H, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl, wherein the phenyl group Unsubstituted, or substituted by 1, 2 or 3 groups independently selected from the group consisting of substituents such as F, Cl, Br, CF 3 , methyl and methoxy; R 4b represents H, methyl or The ethyl group, or R 4a and R 4b , together with the carbon atom to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.

根據本發明通式(I)之化合物又更佳，其中，R4a代表H、甲基或乙基，R4b代表H、甲基或乙基，以代表H或甲基較佳，以代表H更佳，或R4a與R4b及將其連結之碳原子共同形成環丙基、環丁基、環戊基或環己基環。 Further preferred according to the invention is a compound of the formula (I) wherein R 4a represents H, methyl or ethyl, and R 4b represents H, methyl or ethyl, preferably H or methyl, to represent H. More preferably, R 4a and R 4b together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.

根據本發明通式(I)之一化合物為最佳，其中R4a代表H、甲基或乙基，以代表H或甲基較佳，R4b代表H、甲基或乙基，以代表H或甲基較佳，以代表H更佳。 The compound of the formula (I) according to the invention is most preferred, wherein R 4a represents H, methyl or ethyl, preferably represents H or methyl, and R 4b represents H, methyl or ethyl to represent H. Or a methyl group is preferred to represent H.

於根據本發明通式(I)化合物之另一較佳具體實施例中，R3a 係選自由H、甲基與乙基組成之群組，以代表H或甲基較佳，以代表H更佳；R4a 代表H、甲基、乙基、環丙基、環丁基、環戊基、環己基或苯基，其中，苯基係未被取代，或被以1、2、3、4或5個相互獨立地選自由F、Cl、Br、I、NO2、CN、CF3、CF2H、CFH2、CF2Cl、CFCl2、OH、NH2、NH(C1-4烷基)與N(C1-4烷基)(C1-4烷基)、C1-4烷基、與O-C1-4-烷基等取代基組成之群組取代； R4b 代表H、甲基或乙基，或R4a與R4b及將其連結之碳原子共同形成一環丙基、環丁基、環戊基或環己基環。 In another preferred embodiment of the compound of formula (I) according to the present invention, R 3a is selected from the group consisting of H, methyl and ethyl, preferably H or methyl, to represent H. Preferably, R 4a represents H, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl, wherein the phenyl is unsubstituted or is 1, 2, 3, 4 Or 5 independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, CF 3 , CF 2 H, CFH 2 , CF 2 Cl, CFCl 2 , OH, NH 2 , NH (C 1-4 alkane) And a group consisting of a substituent such as N(C 1-4 alkyl)(C 1-4 alkyl), C 1-4 alkyl, and OC 1-4 -alkyl; R 4b represents H, Methyl or ethyl, or R 4a and R 4b together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.

於根據本發明通式(I)化合物之又另一較佳具體實施例中，Z 代表N，及R4a代表H；或Z 代表CR4b，及R4a與R4b各自代表H；Z 代表CR4b，及R4a代表甲基，而R4b代表H。 In still another preferred embodiment of the compound of formula (I) according to the invention, Z represents N, and R 4a represents H; or Z represents CR 4b , and R 4a and R 4b each represent H; Z represents CR 4b , and R 4a represents a methyl group, and R 4b represents H.

於根據本發明通式(I)化合物之又另一較佳具體實施例中，Z 代表N，及R4a代表H；或Z 代表CR4b，及R4a與R4b各自代表H；或Z 代表CR4b，及R4a代表H而R4b代表甲基。 In still another preferred embodiment of the compound of formula (I) according to the invention, Z represents N, and R 4a represents H; or Z represents CR 4b , and R 4a and R 4b each represent H; or Z represents CR 4b , and R 4a represent H and R 4b represents a methyl group.

於根據本發明通式(I)之一較佳具體實施例中，T1、U1、V、U2與T2變量其中之1或2代表氮原子，以T1、U1、V、U2與T2變量其中僅有1個代表氮原子較佳，以T1、U1、V、U2與T2其中僅有U1代表氮原子更佳，即T1代表C-R5、V代表C-R7、U2代表C-R8而T2代表C-R9。 In a preferred embodiment of the general formula (I) according to the present invention, one or two of the T 1 , U 1 , V, U 2 and T 2 variables represent a nitrogen atom, and T 1 , U 1 , V, Of the U 2 and T 2 variables, only one of them represents a nitrogen atom, and T 1 , U 1 , V, U 2 and T 2 wherein only U 1 represents a nitrogen atom, that is, T 1 represents CR 5 , V. Representing CR 7 , U 2 represents CR 8 and T 2 represents CR 9 .

於根據本發明通式(I)化合物之另一較佳具體實施例中，通式(I)之(T2)子結構 代表一或多個子結構(T2-a)、(T2-b)、(T2-c)、(T2-d)、(T2-e)、(T2-f)、(T2-g)、(T2-h)、(T2-i)、(T2-j)、(T2-k)、(T2-l)、(T2-m)、(T2-n)、及/或(T2-o) 其R5、R6、R7、R8與R9於各例中相互獨立地含有上述意義其中一種意義，或具有本文上述關於根據本發明之化合物及其較佳具體實施例之涵義。 In another preferred embodiment of the compound of formula (I) according to the invention, the (T2) substructure of formula (I) Represents one or more substructures (T2-a), (T2-b), (T2-c), (T2-d), (T2-e), (T2-f), (T2-g), (T2) -h), (T2-i), (T2-j), (T2-k), (T2-l), (T2-m), (T2-n), and/or (T2-o) R 5 , R 6 , R 7 , R 8 and R 9 in each case independently of one another have the meaning of the above meaning, or have the meanings of the above-mentioned compounds according to the invention and their preferred embodiments.

較佳之(T2)子結構為(T2-a)、(T2-b)、(T2-c)、(T2-e)、(T2-f)、(T2-h)、(T2-i)與(T2-j)，更佳之(T2)子結構為(T2-a)、(T2-b)與 (T2-c)，一特佳之(T2)子結構為(T2-b)。 The preferred (T2) substructures are (T2-a), (T2-b), (T2-c), (T2-e), (T2-f), (T2-h), (T2-i) and (T2-j), the better (T2) substructure is (T2-a), (T2-b) and (T2-c), a particularly good (T2) substructure is (T2-b).

(T2-a)、(T2-b)及(T2-c)特佳之子結構分別為(T2-a-I)、(T2-b-I)與(T2-c-I)子結構 其R6、R7與R8於各例中相互獨立地含有上述意義，或具有本文描述述關於根據本發明之化合物及其較佳具體實施例之涵義。(T2-b-I)係最佳之子結構。 The substructures of (T2-a), (T2-b) and (T2-c) are (T2-aI), (T2-bI) and (T2-cI) substructures, respectively. R 6 , R 7 and R 8 have the above-mentioned meanings independently of each other in each case, or have the meanings described herein with respect to the compounds according to the invention and their preferred embodiments. (T2-bI) is the best substructure.

於根據本發明通式(I)化合物之又另一較佳具體實施例中，R5、R6、R7、R8與R9係相互獨立地選自由下列基團組成之群組H、F、Cl、Br、I、CN、NO2、CF3、CF2H、CFH2、CF2Cl、CFCl2、OH、OCF3、OCF2H、OCFH2、OCF2Cl、OCFCl2、SH、SCF3、SCF2H、SCFH2、SCF2Cl、SCFCl2、NH2、C(=O)-NH2、C(=O)-H、C(=O)-OH、S(=O)2-OH、S(=O)2-NH2，一C1-10脂族殘基、(C1-8脂族基)-OH、(C1-8脂族基)-O-C1-10脂族殘基、(C1-8脂族基)-O-(C1-8脂族基)-OH、(C1-8脂族基)-O-(C1-8脂族基)-O-C1-10脂族殘基、一(C1-8脂族基)-NH-C1-10脂族殘基、一(C1-8脂族基)-NH-(C1-8脂族殘基)-OH、一(C1-8脂族基)-N(C1-10脂族殘基)-(C1-8脂族殘基)-OH、一(C1-8脂族基)-NH-S(=O)2-C1-10脂族殘基、一(C1-8脂族基)-NH-S(=O)2-NH2、一(C1-8脂族基)-S(=O)2-C1-10脂族殘基、一C(=O)-C1-10脂族殘基、一C(=O)-NH-C1-10脂族殘基， 一O-C1-10脂族殘基、一O-(C1-8脂族基)-O-C1-10脂族殘基、O-(C1-8脂族基)-OH，一NH-C1-10脂族殘基、一N(C1-10脂族殘基)2、一NH-[(C1-8脂族基)-O-C1-10脂族殘基]、一NH-[(C1-8脂族基)-OH]、一N(C1-10脂族殘基)[(C1-8脂族基)-OH]、一N(C1-10脂族殘基)[(C1-8脂族基)-O-C1-10脂族殘基]、一NH-C(=O)-C1-10脂族殘基、一N(C1-10脂族殘基)[(C(=O)-C1-10脂族殘基)]、一N(C1-10脂族殘基)[(C1-8脂族基)-O-C1-10脂族殘基]、一N(C1-10脂族殘基)[(C1-8脂族基)-OH]、一NH-S(=O)2-C1-10脂族殘基、一N(C1-10脂族殘基)[S(=O)2-C1-10脂族殘基]，一S(=O)2-C1-10脂族殘基、一S(=O)2-NH-C1-10脂族殘基、一S(=O)2-N(C1-10脂族殘基)2、一S-C1-10脂族殘基，其中，各上述各C1-10脂族殘基與C1-8脂族基於各例中可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、=O、O-C1-4烷基、OCF3、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3、苯基或啶基等取代基組成之群組單取代或多取代，其中，苯基或啶基分別係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、C(=O)-OH、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3與S(=O)2OH等取代基組成之群組單取代或多取代，一C3-10環脂族殘基、一C(=O)-C3-10環脂族殘基、一C(=O)NH-C3-10環脂族殘基、一O-C3-10環脂族殘基、一O-(C1-8脂族基)-C3-10環脂族殘基、一S-C3-10環脂族殘基、一S-(C1-8脂族基)-C3-10環脂族殘基、一NH-C3-10環脂族殘 基、一NH-C(=O)-C3-10環脂族殘基、一NH-(C1-8脂族基)-C3-10環脂族殘基、一N(C1-10脂族殘基)(C3-10環脂族殘基)、一3至10構件雜環脂族殘基、一C(=O)-(3至10構件雜環脂族殘基)、一C(=O)-NH-(3至10構件雜環脂族殘基)、一O-(3至10構件雜環脂族殘基)、一O-(C1-8脂族基)-(3至10構件雜環脂族殘基)、一S-(3至10構件雜環脂族殘基)、一S-(C1-8脂族基)-(3至10構件雜環脂族殘基)、一NH-(3至10構件雜環脂族殘基)、一NH-C(=O)-(3至10構件雜環脂族殘基)、NH-(C1-8脂族基)-(3至10構件雜環脂族殘基)、一N(C1-10脂族殘基)(3至10構件雜環脂族殘基)，其中，各上述殘基於各例中可選擇性地經由一C1-8脂族基橋接，其中，該C1-10脂族殘基、該C1-8脂族基、該C3-10環脂族殘基與該3至10構件雜環脂族殘基於各例中，分別可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、C1-4烷基、C1-4伸烷基-OH、C1-4伸烷基-O-C1-4烷基、CF3、C(=O)-C1-4烷基、O-C1-4烷基、O-C1-4伸烷基-OH、O-C1-4伸烷基-O-C1-4烷基、=O、OCF3、OH、SH、S-C1-4烷基、SCF3、SO2-C1-4烷基、NH2、=NH、=N(OH)、NH-C1-4烷基、N(C1-4烷基)2、NH-SO2-C1-4烷基、NH-C(=O)-C1-4烷基、苯基與啶基等取代基組成之群組單取代或多取代，其中，苯基與啶基分別係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、C(=O)-OH、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3與S(=O)2OH等取代基組成之群組單取代或 多取代，芳基、C(=O)-芳基、C(=O)-NH-芳基、O-芳基、一O-(C1-8脂族基)-芳基、S-芳基、一S-(C1-8脂族基)-芳基、一NH-芳基、NH-C(=O)-芳基、NH-S(=O)2-芳基、一NH-(C1-8脂族基)-芳基、一N(C1-10脂族殘基)(芳基)、雜芳基、C(=O)-雜芳基、C(=O)-NH-雜芳基、O-雜芳基、O-(C1-8脂族基)-雜芳基、S-(雜芳基)、S-(C1-8脂族基)-(雜芳基)、NH-(雜芳基)、NH-C(=O)-雜芳基、NH-S(=O)2-雜芳基、NH-(C1-8脂族基)(雜芳基)、N(C1-10脂族殘基)(雜芳基)，其中，各上述殘基於各例中可選擇性地經由一C1-8脂族基橋接，其中，上述殘基之芳基與雜芳基於各例中相互獨立地，可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、O-C1-4伸烷基-O-C1-4烷基、O-C1-4伸烷基-OH、OCF3、C1-4烷基、C1-4伸烷基-O-C1-4-烷基、C1-4伸烷基-OH、C(=O)-C1-4烷基、CF3、CF2H、CHF2、SH、S-C1-4烷基、SCF3、SO2-C1-4烷基、NH2、NH(C1-4烷基)、N(C1-4烷基)2、NH-SO2-C1-4烷基、NH-C(=O)-C1-4烷基、苯基與啶基等取代基組成之群組單取代或多取代，其中，苯基或啶基分別係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、O-C1-4伸烷基-O-C1-4烷基OCF3、C1-4烷基、C1-4伸烷基-O-C1-4-烷基、C(=O)-OH、CF3、CF2H、CHF2、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3與S(=O)2OH等取代基組成之群組單取代或多取代， 其中，上述殘基之C1-10脂族殘基與C1-8脂族基於各例中相互獨立地，可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、=O、O-C1-4烷基、OCF3、C1-4烷基、CF3、SH、S-C1-4烷基、SCF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、苯基與啶基等取代基組成脂群組單取代或多取代，其中，苯基或啶基分別係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、C(=O)-OH、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3與S(=O)2OH等取代基組成之群組單取代或多取代。 In still another preferred embodiment of the compound of formula (I) according to the invention, R 5 , R 6 , R 7 , R 8 and R 9 are independently of each other selected from group H consisting of the following groups, F, Cl, Br, I, CN, NO 2 , CF 3 , CF 2 H, CFH 2 , CF 2 Cl, CFCl 2 , OH, OCF 3 , OCF 2 H, OCFH 2 , OCF 2 Cl, OCFCl 2 , SH , SCF 3 , SCF 2 H, SCFH 2 , SCF 2 Cl, SCFCl 2 , NH 2 , C(=O)-NH 2 , C(=O)-H, C(=O)-OH, S(=O 2 -OH, S(=O) 2 -NH 2 , a C 1-10 aliphatic residue, (C 1-8 aliphatic)-OH, (C 1-8 aliphatic)-OC 1- 10 aliphatic residue, (C 1-8 aliphatic)-O-(C 1-8 aliphatic)-OH, (C 1-8 aliphatic)-O-(C 1-8 aliphatic -OC 1-10 aliphatic residue, one (C 1-8 aliphatic)-NH-C 1-10 aliphatic residue, one (C 1-8 aliphatic)-NH-(C 1- 8 aliphatic residue) -OH, one (C 1-8 aliphatic)-N (C 1-10 aliphatic residue) - (C 1-8 aliphatic residue) -OH, one (C 1- 8 aliphatic group) -NH-S(=O) 2 -C 1-10 aliphatic residue, one (C 1-8 aliphatic)-NH-S(=O) 2 -NH 2 , one (C 1-8 aliphatic)-S(=O) 2 -C 1-10 aliphatic residue, a C(=O)-C 1-10 aliphatic residue, a C(=O)-NH-C 1-10 aliphatic residue, an aliphatic residue -OC 1-10 A O- (C 1-8 aliphatic) -OC 1-10 aliphatic residue, O- (C 1-8 aliphatic) -OH, an NH-C 1-10 aliphatic residue, a N (C 1-10 aliphatic residue) 2 , a NH-[(C 1-8 aliphatic)-OC 1-10 aliphatic residue], a NH-[(C 1-8 aliphatic)- OH], one N (C 1-10 aliphatic residue) [(C 1-8 aliphatic)-OH], one N (C 1-10 aliphatic residue) [(C 1-8 aliphatic group) ) - OC 1-10 aliphatic residue], one NH-C(=O)-C 1-10 aliphatic residue, one N (C 1-10 aliphatic residue) [(C(=O)- C 1-10 aliphatic residue)], one N (C 1-10 aliphatic residue) [(C 1-8 aliphatic)-OC 1-10 aliphatic residue], one N (C 1- 10 aliphatic residue) [(C 1-8 aliphatic)-OH], one NH-S(=O) 2 -C 1-10 aliphatic residue, one N (C 1-10 aliphatic residue) )[S(=O) 2 -C 1-10 aliphatic residue], an S(=O) 2 -C 1-10 aliphatic residue, an S(=O) 2 -NH-C 1-10 An aliphatic residue, an S(=O) 2 -N(C 1-10 aliphatic residue) 2 , an SC 1-10 aliphatic residue, wherein each of the above C 1-10 aliphatic residues The C 1-8 aliphatic group may be unsubstituted based on each of the examples, or may be independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, =0, OC 1-4 Alkyl, OCF 3 , CF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3, phenyl or pyridyl group and the like substituent group consisting of mono- or polysubstituted, wherein the phenyl or pyridyl are based unsubstituted or substituted with one or more independent Selected from F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, C(=O)-OH, CF 3 , NH 2 , NH a group consisting of (C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 and S(=O) 2 OH, etc. Substituted, a C 3-10 cycloaliphatic residue, a C(=O)-C 3-10 cycloaliphatic residue, a C(=O)NH-C 3-10 cycloaliphatic residue, an OC 3-10 cycloaliphatic residue, mono-O-(C 1-8 aliphatic)-C 3-10 cycloaliphatic residue, one SC 3-10 cycloaliphatic residue, one S-(C 1- 8 aliphatic group)-C 3-10 cycloaliphatic residue, one NH-C 3-10 cycloaliphatic residue, one NH-C(=O)-C 3-10 cycloaliphatic residue, one NH -(C 1-8 aliphatic)-C 3-10 cycloaliphatic residue, one N (C 1-10 aliphatic residue) (C 3-10 cycloaliphatic residue), a 3 to 10 building block a heterocyclic aliphatic residue, a C(=O)-(3 to 10 membered heterocyclic aliphatic residue), a C(=O)-NH- (3 to 10 membered heterocyclic aliphatic residue), O- (3 to 10 component heterocycloaliphatic residue), a O- (C 1-8 aliphatic Yl) - (3-10 member heterocyclic aliphatic residue), a -S- (3-10 member heterocyclic aliphatic residue), a S- (C 1-8 aliphatic) - (3-10 member Heterocyclic aliphatic residue), one NH-(3 to 10 membered heterocyclic aliphatic residue), one NH-C(=O)-(3 to 10 membered heterocyclic aliphatic residue), NH-(C) a 1-8 aliphatic group)-(3 to 10 member heterocyclic aliphatic residue), an N (C 1-10 aliphatic residue) (3 to 10 member heterocyclic aliphatic residue), wherein each of the above The residue is optionally bridged via a C 1-8 aliphatic group in each case, wherein the C 1-10 aliphatic residue, the C 1-8 aliphatic group, the C 3-10 cycloaliphatic residue The base and the 3 to 10 member heterocyclic aliphatic residue may be unsubstituted, respectively, or may be independently selected from the group consisting of F, Cl, Br, I, C 1-4 alkyl, respectively, in one or more , C 1-4 alkylene-OH, C 1-4 alkylene-OC 1-4 alkyl, CF 3 , C(=O)-C 1-4 alkyl, OC 1-4 alkyl, OC 1-4 alkylene-OH, OC 1-4 alkylene-OC 1-4 alkyl, =0, OCF 3 , OH, SH, SC 1-4 alkyl, SCF 3 , SO 2 -C 1- 4 alkyl, NH 2 , =NH, =N(OH), NH-C 1-4 alkyl, N(C 1-4 alkyl) 2 , NH-SO 2 -C 1-4 alkyl, NH- substituted with C (= O) -C 1-4 alkyl, phenyl, piperidinyl and the like The group consisting of substituted or unsubstituted mono, wherein phenyl and pyridyl are based unsubstituted or substituted with one or more independently selected from the group consisting of F, Cl, Br, I, NO 2, CN, OH, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, C(=O)-OH, CF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 and S (= O) 2 OH and other substituents composed of groups of mono- or poly-substituted, aryl, C (= O)-aryl, C (= O -NH-aryl, O-aryl, mono-O-(C 1-8 aliphatic)-aryl, S-aryl, mono-S-(C 1-8 aliphatic)-aryl, NH-aryl, NH-C(=O)-aryl, NH-S(=O) 2 -aryl, mono NH-(C 1-8 aliphatic)-aryl, one N (C 1- 10 aliphatic residues) (aryl), heteroaryl, C(=O)-heteroaryl, C(=O)-NH-heteroaryl, O-heteroaryl, O-(C 1-8 Aliphatic)-heteroaryl, S-(heteroaryl), S-(C 1-8 aliphatic)-(heteroaryl), NH-(heteroaryl), NH-C(=O) -heteroaryl, NH-S(=O) 2 -heteroaryl, NH-(C 1-8 aliphatic)(heteroaryl), N(C 1-10 aliphatic residue) (heteroaryl) ), wherein each of the above embodiments based on the respective residues optionally via a bridging C 1-8 aliphatic group, wherein the aryl group and the residue Aryl in each case based on independently of each other, it can be based unsubstituted or substituted with one or more independently selected from the group consisting of F, Cl, Br, I, NO 2, CN, OH, OC 1-4 alkyl, OC 1-4 alkyl-OC 1-4 alkyl, OC 1-4 alkyl-OH, OCF 3 , C 1-4 alkyl, C 1-4 alkyl-OC 1-4 -alkyl, C 1-4 alkylene-OH, C(=O)-C 1-4 alkyl, CF 3 , CF 2 H, CHF 2 , SH, SC 1-4 alkyl, SCF 3 , SO 2 -C 1 -4 alkyl, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , NH-SO 2 -C 1-4 alkyl, NH-C(=O)-C a group consisting of a mono- or poly-substituent consisting of a substituent such as an alkyl group, a phenyl group and a pyridine group, wherein the phenyl or pyridyl group is unsubstituted, respectively, or is independently selected from one or more , Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OC 1-4 alkylene-OC 1-4 alkyl OCF 3 , C 1-4 alkyl, C 1-4 Alkyl-OC 1-4 -alkyl, C(=O)-OH, CF 3 , CF 2 H, CHF 2, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl ) 2, SH, SC 1-4 alkyl, SCF 3 and S (= O) 2 OH group and the like substituent group consisting of mono- or polysubstituted, wherein the residue of C 1-10 aliphatic residues C 1-8 aliphatic based on each In the examples, independently of each other, may be unsubstituted or selected from one or more independently from F, Cl, Br, I, NO 2 , CN, OH, =0, OC 1-4 alkyl, OCF. 3 , C 1-4 alkyl, CF 3 , SH, SC 1-4 alkyl, SCF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , phenyl a mono- or poly-substituent of a group consisting of a substituent such as a pyridine group, wherein the phenyl or pyridine group is unsubstituted, respectively, or is selected independently from one another by F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, C(=O)-OH, CF 3 , NH 2 , NH(C 1-4 alkyl), N(C a group consisting of 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 and S(=O) 2 OH, such as a mono- or poly-substituent.

較佳地，R5、R6、R7、R8與R9係各自相互獨立地選自由下列基團組成之群組：H、F、Cl、Br、I、CN、NO2、CF3、CF2H、CFH2、CF2Cl、CFCl2、OH、OCF3、OCF2H、OCFH2、OCF2Cl、OCFCl2、SH、SCF3、SCF2H、SCFH2、SCF2Cl、SCFCl2、NH2、C(=O)-NH2、C(=O)-H、C(=O)-OH、S(=O)2-OH、S(=O)2-NH2，一C1-10脂族殘基、(C1-8脂族基)-OH、(C1-8脂族基)-O-C1-10脂族殘基、(C1-8脂族基)-O-(C1-8脂族基)-OH、(C1-8脂族基)-O-(C1-8脂族基)-O-C1-10脂族殘基、一(C1-8脂族基)-NH-C1-10脂族殘基、一(C1-8脂族基)-NH-(C1-8脂族殘基)-OH、一(C1-8脂族基)-N(C1-10脂族殘基)-(C1-8脂族殘基)-OH、一(C1-8脂族基)-NH-S(=O)2-C1-10脂族殘基、一(C1-8脂族基)-NH-S(=O)2-NH2、一(C1-8脂族基)-S(=O)2-C1-10脂族殘基、一C(=O)-C1-10脂族殘基、一C(=O)-NH-C1-10脂族殘 基，一O-C1-10脂族殘基、一O-(C1-8脂族基)-O-C1-10脂族殘基、O-(C1-8脂族基)-OH，一NH-C1-10脂族殘基、一N(C1-10脂族殘基)2、一NH-(C1-8脂族基)-O-C1-10脂族殘基、一NH-(C1-8脂族基)-OH、一N(C1-10脂族殘基)[(C1-8脂族基)-OH]、一N(C1-10脂族殘基)[(C1-8脂族基)-O-C1-10脂族殘基]、一NH-C(=O)-C1-10脂族殘基、一N(C1-10脂族殘基)[(C(=O)-C1-10脂族殘基)]、一N(C1-10脂族殘基)[(C1-8脂族基)-O-C1-10脂族殘基]、一N(C1-10脂族殘基)[(C1-8脂族基)-OH]、一NH-S(=O)2-C1-10脂族殘基、一N(C1-10脂族殘基)[S(=O)2-C1-10脂族殘基]，一S(=O)2-C1-10脂族殘基、一S(=O)2-NH-C1-10脂族殘基、一S(=O)2-N(C1-10脂族殘基)2、一S-C1-10脂族殘基，其中，各上述C1-10脂族殘基與C1-8脂族基於各例中可係未被取代，或被以OH單取代；一C3-10環脂族殘基、一C(=O)-C3-10環脂族殘基、一C(=O)NH-C3-10環脂族殘基、一O-C3-10環脂族殘基、一O-(C1-8脂族基)-C3-10環脂族殘基、一S-C3-10環脂族殘基、一S-(C1-8脂族基)-C3-10環脂族殘基、一NH-C3-10環脂族殘基、一NH-C(=O)-C3-10環脂族殘基、一NH-(C1-8脂族基)-C3-10環脂族殘基、一N(C1-10脂族殘基)(C3-10環脂族殘基)、一3至10構件雜環脂族殘基、一C(=O)-(3至10構件雜環脂族殘基)、一C(=O)-NH-(3至10構件雜環脂族殘基)、一O-(3至10構件雜環脂族殘基)、一O-(C1-8脂族基)-(3至10構件雜環脂族殘基)、一S-(3至10構件雜環脂族殘基)、一S-(C1-8脂族基)-(3至10構件雜環脂族殘基)、一NH-(3至10構件 雜環脂族殘基)、一NH-C(=O)-(3至10構件雜環脂族殘基)、NH-(C1-8脂族基)-(3至10構件雜環脂族殘基)、一N(C1-10脂族殘基)(3至10構件雜環脂族殘基)，其中，各上述殘基於各例中可選擇性地經由一C1-8脂族基橋接，其中，該C1-10脂族殘基與該C1-8脂族基於各例中，相互獨立地可係未被取代，或被以OH取代，其中，該C3-10環脂族殘基與該3至10構件雜環脂族殘基於各例中，分別可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、C1-4烷基、C1-4伸烷基-OH、C1-4伸烷基-O-C1-4烷基、CF3、C(=O)-C1-4烷基、O-C1-4烷基、O-C1-4伸烷基-OH、O-C1-4伸烷基-O-C1-4烷基、=O、OCF3、OH、SH、S-C1-4烷基、SCF3、SO2-C1-4烷基、NH2、=NH、=N(OH)、NH-C1-4烷基、N(C1-4烷基)2、NH-SO2-C1-4烷基、NH-C(=O)-C1-4烷基等取代基組成之群組單取代或多取代，芳基、C(=O)-芳基、C(=O)-NH-芳基、O-芳基、一O-(C1-8脂族基)-芳基、S-芳基、一S-(C1-8脂族基)-芳基、一NH-芳基、NH-C(=O)-芳基、NH-S(=O)2-芳基、一NH-(C1-8脂族基)-芳基、一N(C1-10脂族殘基)(芳基)、雜芳基、C(=O)-雜芳基、C(=O)-NH-雜芳基、O-雜芳基、O-(C1-8脂族基)-雜芳基、S-(雜芳基)、S-(C1-8脂族基)-(雜芳基)、NH-(雜芳基)、NH-C(=O)-雜芳基、NH-S(=O)2-雜芳基、NH-(C1-8脂族基)(雜芳基)、N(C1-10脂族殘基)(雜芳基)，其中，各上述殘基於各例中可選擇性地經由一C1-8脂族基橋接， 其中，各上述殘基之芳基與雜芳基於各例中相互獨立地可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、O-C1-4伸烷基-O-C1-4烷基、O-C1-4伸烷基-OH、OCF3、C1-4烷基、C1-4伸烷基-O-C1-4-烷基、C1-4伸烷基-OH、C(=O)-C1-4烷基、CF3、CF2H、CHF2、SH、S-C1-4烷基、SCF3、SO2-C1-4烷基、NH2、NH(C1-4烷基)、N(C1-4烷基)2、NH-SO2-C1-4烷基、NH-C(=O)-C1-4烷基、苯基與啶基等取代基組成之群組單取代或多取代，其中，苯基與啶基分別係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、O-C1-4伸烷基-O-C1-4烷基、OCF3、C1-4烷基、C1-4伸烷基-O-C1-4-烷基、C(=O)-OH、CF3、CF2H、CHF2、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3與S(=O)2OH等取代基組成之群組單取代或多取代，其中，上述殘基之C1-10脂族殘基與C1-8脂族基於各例中，可係未被取代，或被以OH單取代。 Preferably, R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from the group consisting of H, F, Cl, Br, I, CN, NO 2 , CF 3 , CF 2 H, CFH 2 , CF 2 Cl, CFCl 2 , OH, OCF 3 , OCF 2 H, OCFH 2 , OCF 2 Cl, OCFCl 2 , SH, SCF 3 , SCF 2 H, SCFH 2 , SCF 2 Cl, SCFCl 2 , NH 2 , C(=O)-NH 2 , C(=O)-H, C(=O)-OH, S(=O) 2 -OH, S(=O) 2 -NH 2 , a C 1-10 aliphatic residue, (C 1-8 aliphatic)-OH, (C 1-8 aliphatic)-OC 1-10 aliphatic residue, (C 1-8 aliphatic) -O-(C 1-8 aliphatic)-OH, (C 1-8 aliphatic)-O-(C 1-8 aliphatic)-OC 1-10 aliphatic residue, one (C 1 -8 aliphatic group)-NH-C 1-10 aliphatic residue, one (C 1-8 aliphatic group)-NH-(C 1-8 aliphatic residue)-OH, one (C 1-8) Aliphatic)-N (C 1-10 aliphatic residue)-(C 1-8 aliphatic residue)-OH, one (C 1-8 aliphatic)-NH-S(=O) 2 - C 1-10 aliphatic residue, one (C 1-8 aliphatic)-NH-S(=O) 2 -NH 2 , one (C 1-8 aliphatic)-S(=O) 2 - C 1-10 aliphatic residue, a C(=O)-C 1-10 aliphatic residue, a C(=O)-NH-C 1-10 aliphatic residue, an OC 1-10 aliphatic group residue, a O- (C 1-8 aliphatic) -OC 1-10 aliphatic residue, O- (C 1-8 Aromatic group) -OH, an NH-C 1-10 aliphatic residue, an N (C 1-10 aliphatic residue) 2, a NH- (C 1-8 aliphatic) -OC 1-10 aliphatic Family residue, mono NH-(C 1-8 aliphatic)-OH, one N (C 1-10 aliphatic residue) [(C 1-8 aliphatic)-OH], one N (C 1 -10 aliphatic residue) [(C 1-8 aliphatic)-OC 1-10 aliphatic residue], one NH-C(=O)-C 1-10 aliphatic residue, one N (C) 1-10 aliphatic residue) [(C(=O)-C 1-10 aliphatic residue)], a N (C 1-10 aliphatic residue) [(C 1-8 aliphatic group)- OC 1-10 aliphatic residue], one N (C 1-10 aliphatic residue) [(C 1-8 aliphatic)-OH], one NH-S(=O) 2 -C 1-10 Aliphatic residue, an N (C 1-10 aliphatic residue) [S(=O) 2 -C 1-10 aliphatic residue], an S(=O) 2 -C 1-10 aliphatic residue , S(=O) 2 -NH-C 1-10 aliphatic residue, one S(=O) 2 -N(C 1-10 aliphatic residue) 2 , one SC 1-10 aliphatic residue a group wherein each of the above C 1-10 aliphatic residues and C 1-8 aliphatic groups are unsubstituted or monosubstituted with OH; a C 3-10 cycloaliphatic residue, C(=O)-C 3-10 cycloaliphatic residue, a C(=O)NH-C 3-10 cycloaliphatic residue, an OC 3-10 cycloaliphatic residue, an O-(C 1-8 aliphatic group)-C 3-10 cycloaliphatic residue, one SC 3-10 cycloaliphatic residue, one S-(C 1-8 An aliphatic group - a C 3-10 cycloaliphatic residue, an NH-C 3-10 cycloaliphatic residue, an NH-C(=O)-C 3-10 cycloaliphatic residue, an NH- (C 1-8 aliphatic group)-C 3-10 cycloaliphatic residue, one N (C 1-10 aliphatic residue) (C 3-10 cycloaliphatic residue), a 3 to 10 building block a cycloaliphatic residue, a C(=O)-(3 to 10 membered heterocyclic aliphatic residue), a C(=O)-NH- (3 to 10 membered heterocyclic aliphatic residue), an O - (3 to 10 component heterocyclic aliphatic residues), one O-(C 1-8 aliphatic)-(3 to 10 component heterocyclic aliphatic residue), and one S-(3 to 10 member heterocyclic ring) An aliphatic residue), an S-(C 1-8 aliphatic group)-(3 to 10 membered heterocyclic aliphatic residue), an NH- (3 to 10 membered heterocyclic aliphatic residue), an NH -C(=O)-(3 to 10 component heterocyclic aliphatic residues), NH-(C 1-8 aliphatic)-(3 to 10 component heterocyclic aliphatic residues), one N (C 1 a -10 aliphatic residue) (3 to 10 membered heterocyclic aliphatic residues), wherein each of the above residues is selectively bridged via a C 1-8 aliphatic group, wherein the C 1 - The 10 aliphatic residue and the C 1-8 aliphatic group may be unsubstituted or independently substituted with each other based on each of the examples, wherein the C 3-10 cycloaliphatic residue and the 3 to 10 Component heterocyclic aliphatic residue based on each In the examples, they may be unsubstituted or respectively selected from one or more independently selected from the group consisting of F, Cl, Br, I, C 1-4 alkyl, C 1-4 alkyl-OH, C 1- 4- alkyl-OC 1-4 alkyl, CF 3 , C(=O)-C 1-4 alkyl, OC 1-4 alkyl, OC 1-4 alkyl-OH, OC 1-4 Alkyl-OC 1-4 alkyl, =0, OCF 3 , OH, SH, SC 1-4 alkyl, SCF 3 , SO 2 -C 1-4 alkyl, NH 2 , =NH, =N(OH , NH-C 1-4 alkyl, N(C 1-4 alkyl) 2 , NH-SO 2 -C 1-4 alkyl, NH-C(=O)-C 1-4 alkyl, etc. Group consisting of mono- or poly-substituted, aryl, C(=O)-aryl, C(=O)-NH-aryl, O-aryl, mono-O-(C 1-8 aliphatic) )-aryl, S-aryl, an S-(C 1-8 aliphatic)-aryl, an NH-aryl, NH-C(=O)-aryl, NH-S(=O) 2 -aryl, mono-NH-(C 1-8 aliphatic)-aryl, one N (C 1-10 aliphatic residue) (aryl), heteroaryl, C(=O)-heteroaryl , C(=O)-NH-heteroaryl, O-heteroaryl, O-(C 1-8 aliphatic)-heteroaryl, S-(heteroaryl), S-(C 1- 8 aliphatic group)-(heteroaryl), NH-(heteroaryl), NH-C(=O)-heteroaryl, NH-S(=O) 2 -heteroaryl, NH-(C 1 -8 aliphatic) (heteroaryl), N (C 1-10 aliphatic residue) (heteroaryl) Wherein each of the above embodiments based on the respective residues optionally bridged via a C 1-8 aliphatic group, wherein each of the aryl residue of the aryl and heteroaryl independently of one another based on the respective embodiments may be based unsubstituted, or One or more independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OC 1-4 alkyl-OC 1-4 alkyl, OC 1 -4 alkylene-OH, OCF 3 , C 1-4 alkyl, C 1-4 alkyl-OC 1-4 -alkyl, C 1-4 alkyl-OH, C(=O)- C 1-4 alkyl, CF 3 , CF 2 H, CHF 2 , SH, SC 1-4 alkyl, SCF 3 , SO 2 -C 1-4 alkyl, NH 2 , NH(C 1-4 alkyl , N(C 1-4 alkyl) 2 , NH-SO 2 -C 1-4 alkyl, NH-C(=O)-C 1-4 alkyl, a substituent such as a phenyl group and a pyridine group The group is mono- or polysubstituted, wherein the phenyl group and the pyridine group are unsubstituted, respectively, or are one or more independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, OC 1 -4 alkyl, OC 1-4 alkylene-OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, C 1-4 alkylene-OC 1-4 -alkyl, C(=O -OH, CF 3 , CF 2 H, CHF 2, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 and S(=O a group consisting of a substituent consisting of 2 OH, such as a mono- or poly-substitution, wherein the C 1-10 aliphatic residue of the above residue and the C 1-8 aliphatic group are either unsubstituted or Substituted with OH.

更佳地，R5、R6、R7、R8與R9係各自相互獨立地選自由下列基團組成之群組：H、F、Cl、Br、I、CN、NO2、CF3、CF2H、CFH2、CF2Cl、CFCl2、OH、OCF3、OCF2H、OCFH2、OCF2Cl、OCFCl2、SH、SCF3、SCF2H、SCFH2、SCF2Cl、SCFCl2、NH2、C(=O)-NH2、C(=O)-H、C(=O)-OH、S(=O)2-OH、S(=O)2-NH2；一C1-10脂族殘基、(C1-8脂族基)-OH、(C1-8脂族基)-O-C1-10脂族殘基、(C1-8脂族基)-O-(C1-8脂族基)-OH、(C1-8脂族 基)-O-(C1-8脂族基)-O-C1-10脂族殘基、一(C1-8脂族基)-NH-C1-10脂族殘基、一(C1-8脂族基)-NH-(C1-8脂族殘基)-OH、一(C1-8脂族基)-N(C1-10脂族殘基)-(C1-8脂族殘基)-OH、一(C1-8脂族基)-NH-S(=O)2-C1-10脂族殘基、一(C1-8脂族基)-NH-S(=O)2-NH2、一(C1-8脂族基)-S(=O)2-C1-10脂族殘基，一O-C1-10脂族殘基、一O-(C1-8脂族基)-O-C1-10脂族殘基、O-(C1-8脂族基)-OH，一NH-C1-10脂族殘基、一N(C1-10脂族殘基)2、一NH-(C1-8脂族基)-O-C1-10脂族殘基、一NH-(C1-8脂族基)-OH、一N(C1-10脂族殘基)[(C1-8脂族基)-O-C1-10脂族殘基]、一N(C1-10脂族殘基)[(C1-8脂族基)-OH]、一NH-S(=O)2-C1-10脂族殘基，其中，各上述C1-10脂族殘基與C1-8脂族基於各例中可係未被取代，或被以OH單取代；一C3-10環脂族殘基、一C(=O)-C3-10環脂族殘基、一C(=O)NH-C3-1環脂族殘基、一O-C3-10環脂族殘基、一NH-C3-10環脂族殘基、一NH-C(=O)-C3-10環脂族殘基、一3至10構件雜環脂族殘基、一C(=O)-(3至10構件雜環脂族殘基)、一C(=O)-NH-(3至10構件雜環脂族殘基)、一O-(3至10構件雜環脂族殘基)、一NH-(3至10構件雜環脂族殘基)、一NH-C(=O)-(3至10構件雜環脂族殘基)，其中，該C3-10環脂族殘基與該3至10構件雜環脂族殘基於各例中，分別相互獨立地可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、C1-4烷基、C1-4伸烷基-OH、C1-4伸烷基-O-C1-4烷基、CF3、C(=O)-C1-4烷基、O-C1-4烷基、O-C1-4伸烷基-OH、O-C1-4伸烷基 -O-C1-4烷基、OCF3、OH、SH、S-C1-4烷基、SCF3、SO2-C1-4烷基、NH2、NH-C1-4烷基、N(C1-4烷基)2、NH-SO2-C1-4烷基、NH-C(=O)-C1-4烷基等取代基組成之群組單取代或多取代；芳基、C(=O)-芳基、C(=O)-NH-芳基、NH-C(=O)-芳基、雜芳基、C(=O)-雜芳基、C(=O)-NH-雜芳基、NH-C(=O)-雜芳基，其中，上述殘基之芳基與雜芳基於各例中，相互獨立地可係未被取代或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、O-C1-4伸烷基-O-C1-4烷基、O-C1-4伸烷基-OH、OCF3、C1-4烷基、C1-4伸烷基-O-C1-4-烷基、C1-4伸烷基-OH、C(=O)-C1-4烷基、CF3、CF2H、CHF2、SH、S-C1-4烷基、SCF3、SO2-C1-4烷基、NH2、NH(C1-4烷基)、N(C1-4烷基)2、NH-SO2-C1-4烷基、NH-C(=O)-C1-4烷基、苯基與啶基等取代基組成之群組單取代或多取代，其中，苯基與啶基分別係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、O-C1-4伸烷基-O-C1-4烷基、OCF3、C1-4烷基、C1-4伸烷基-O-C1-4-烷基、C(=O)-OH、CF3、CF2H、CHF2、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3與S(=O)2OH等取代基組成之群組單取代或多取代。 More preferably, R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from the group consisting of H, F, Cl, Br, I, CN, NO 2 , CF 3 , CF 2 H, CFH 2 , CF 2 Cl, CFCl 2 , OH, OCF 3 , OCF 2 H, OCFH 2 , OCF 2 Cl, OCFCl 2 , SH, SCF 3 , SCF 2 H, SCFH 2 , SCF 2 Cl, SCFCl 2 , NH 2 , C(=O)-NH 2 , C(=O)-H, C(=O)-OH, S(=O) 2 -OH, S(=O) 2 -NH 2 ; a C 1-10 aliphatic residue, (C 1-8 aliphatic)-OH, (C 1-8 aliphatic)-OC 1-10 aliphatic residue, (C 1-8 aliphatic) -O-(C 1-8 aliphatic)-OH, (C 1-8 aliphatic)-O-(C 1-8 aliphatic)-OC 1-10 aliphatic residue, one (C 1 -8 aliphatic group)-NH-C 1-10 aliphatic residue, one (C 1-8 aliphatic group)-NH-(C 1-8 aliphatic residue)-OH, one (C 1-8) Aliphatic)-N (C 1-10 aliphatic residue)-(C 1-8 aliphatic residue)-OH, one (C 1-8 aliphatic)-NH-S(=O) 2 - C 1-10 aliphatic residue, one (C 1-8 aliphatic)-NH-S(=O) 2 -NH 2 , one (C 1-8 aliphatic)-S(=O) 2 - C 1-10 aliphatic residue, an OC 1-10 aliphatic residue, an O-(C 1-8 aliphatic)-OC 1-10 aliphatic residue, O-(C 1-8 aliphatic yl) -OH, an NH-C 1-10 aliphatic residue, an N (C 1-10 aliphatic residue ) 2, a NH- (C 1-8 aliphatic) -OC 1-10 aliphatic residue, an NH- (C 1-8 aliphatic) -OH, a N (C 1-10 aliphatic residue ()((C 1-8 aliphatic)-OC 1-10 aliphatic residue], one N (C 1-10 aliphatic residue) [(C 1-8 aliphatic)-OH], one NH-S(=O) 2 -C 1-10 aliphatic residue, wherein each of the above C 1-10 aliphatic residues and C 1-8 aliphatic groups are unsubstituted based on each of the examples, or OH monosubstituted; a C 3-10 cycloaliphatic residue, a C(=O)-C 3-10 cycloaliphatic residue, a C(=O)NH-C 3-1 cycloaliphatic residue, An OC 3-10 cycloaliphatic residue, an NH-C 3-10 cycloaliphatic residue, an NH-C(=O)-C 3-10 cycloaliphatic residue, a 3- to 10-membered heterocyclic ring An aliphatic residue, a C(=O)-(3 to 10 membered heterocyclic aliphatic residue), a C(=O)-NH- (3 to 10 membered heterocyclic aliphatic residue), an O- (3 to 10 component heterocyclic aliphatic residues), one NH-(3 to 10 component heterocyclic aliphatic residue), one NH-C(=O)-(3 to 10 component heterocyclic aliphatic residue) Wherein the C 3-10 cycloaliphatic residue and the 3 to 10 member heterocyclic aliphatic residue are independently unsubstituted independently of each other based on each of the examples, or are independently selected from each other by one or more Free F, Cl, Br, I, C 1-4 alkyl, C 1-4 alkyl - OH, C 1-4 alkylene-OC 1-4 alkyl, CF 3 , C(=O)-C 1-4 alkyl, OC 1-4 alkyl, OC 1-4 alkyl-OH, OC 1-4 alkylene-OC 1-4 alkyl, OCF 3 , OH, SH, SC 1-4 alkyl, SCF 3 , SO 2 -C 1-4 alkyl, NH 2 , NH-C 1- Group monosubstituted composition of substituents such as 4 alkyl, N(C 1-4 alkyl) 2 , NH-SO 2 -C 1-4 alkyl, NH-C(=O)-C 1-4 alkyl Or polysubstituted; aryl, C(=O)-aryl, C(=O)-NH-aryl, NH-C(=O)-aryl, heteroaryl, C(=O)-heteroaryl a C(=O)-NH-heteroaryl group, an NH-C(=O)-heteroaryl group, wherein the aryl group and the heteroaryl group of the above-mentioned residue are independently substituted independently of each other based on each of the examples. Or one or more independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OC 1-4 alkyl-OC 1-4 alkyl, OC 1-4 alkyl-OH, OCF 3 , C 1-4 alkyl, C 1-4 alkyl-OC 1-4 -alkyl, C 1-4 alkyl-OH, C (=O) -C 1-4 alkyl, CF 3 , CF 2 H, CHF 2 , SH, SC 1-4 alkyl, SCF 3 , SO 2 -C 1-4 alkyl, NH 2 , NH(C 1-4 alkane a group consisting of a substituent such as N(C 1-4 alkyl) 2 , NH-SO 2 -C 1-4 alkyl, NH-C(=O)-C 1-4 alkyl, phenyl and pyridine It The group is mono- or polysubstituted, wherein the phenyl group and the pyridine group are unsubstituted, respectively, or are one or more independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, OC 1 -4 alkyl, OC 1-4 alkylene-OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, C 1-4 alkylene-OC 1-4 -alkyl, C(=O -OH, CF 3 , CF 2 H, CHF 2 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 and A group consisting of a substituent such as S(=O) 2 OH is mono- or poly-substituted.

又更佳地，R5、R6、R7、R8與R9係相互獨立地選自由下列基團組成之群組：H、F、Cl、Br、I、CN、CF3、CF2H、CFH2、OH、OCF3、SH、SCF3、NH2、C(=O)-NH2、S(=O)2-OH、S(=O)2-NH2； 一C1-4脂族殘基、(C1-4脂族基)-OH、(C1-4脂族基)-O-C1-4脂族殘基、(C1-4脂族基)-O-(C1-4脂族基)-OH、(C1-4脂族基)-O-(C1-4脂族基)-O-C1-4脂族殘基、一(C1-4脂族基)-NH-C1-4脂族殘基、一(C1-4脂族基)-NH-(C1-4脂族殘基)-OH、一(C1-4脂族基)-N(C1-4脂族殘基)-(C1-4脂族殘基)-OH、一(C1-4脂族基)-NH-S(=O)2-C1-4脂族殘基、一(C1-4脂族基)-NH-S(=O)2-NH2、一(C1-4脂族基)-S(=O)2-C1-4脂族殘基，一O-C1-4脂族殘基、一O-(C1-4脂族基)-O-C1-4脂族殘基、O-(C1-4脂族基)-OH，一NH-C1-4脂族殘基、一N(C1-4脂族殘基)2、一NH-(C1-4脂族基)-O-C1-4脂族殘基、一NH-(C1-4脂族基)-OH、一N(C1-4脂族殘基)[(C1-4脂族基)-O-C1-4脂族殘基]、一N(C1-4脂族殘基)[(C1-4脂族基)-OH]、一NH-S(=O)2-C1-4脂族殘基，其中，上述C1-4脂族殘基與C1-4脂族基於各例中可係未被取代或被以OH單取代；一C3-6環脂族殘基、O-C3-6環脂族殘基、一3至6構件雜環脂族殘基、O-(3至6構件雜環脂族殘基)，其中，該C3-6環脂族殘基與該3至6構件雜環脂族殘基於各例中，分別相互獨立地可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、C1-4烷基、C1-4伸烷基-OH、C1-4伸烷基-O-C1-4烷基、CF3、C(=O)-C1-4烷基、O-C1-4烷基、O-C1-4伸烷基-OH、O-C1-4伸烷基-O-C1-4烷基、OH、SH、S-C1-4烷基、SO2-C1-4烷基、NH2、NH-C1-4烷基、N(C1-4烷基)2、NH-SO2-C1-4烷基與NH-C(=O)-C1-4烷基等取代基組成之群組單取代或多取 代，芳基、C(=O)-NH-芳基、NH-C(=O)-芳基、雜芳基、C(=O)-NH-雜芳基、NH-C(=O)-雜芳基，其中，上述殘基之芳基與雜芳基於各例中，分別可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、O-C1-4伸烷基-O-C1-4烷基、O-C1-4伸烷基-OH、OCF3、C1-4烷基、C1-4伸烷基-O-C1-4-烷基、C1-4伸烷基-OH、C(=O)-C1-4烷基、CF3、CF2H、CHF2、SH、S-C1-4烷基、SCF3、SO2-C1-4烷基、NH2、NH(C1-4烷基)、N(C1-4烷基)2、NH-SO2-C1-4烷基與NH-C(=O)-C1-4烷基等取代基組成之群組單取代或多取代。 Still more preferably, R 5 , R 6 , R 7 , R 8 and R 9 are independently of each other selected from the group consisting of H, F, Cl, Br, I, CN, CF 3 , CF 2 H, CFH 2, OH, OCF 3, SH, SCF 3, NH 2, C (= O) -NH 2, S (= O) 2 -OH, S (= O) 2 -NH 2; a C 1- 4 aliphatic residue, (C 1-4 aliphatic)-OH, (C 1-4 aliphatic)-OC 1-4 aliphatic residue, (C 1-4 aliphatic)-O- ( C 1-4 aliphatic)-OH, (C 1-4 aliphatic)-O-(C 1-4 aliphatic)-OC 1-4 aliphatic residue, one (C 1-4 aliphatic -NH-C 1-4 aliphatic residue, mono(C 1-4 aliphatic)-NH-(C 1-4 aliphatic residue)-OH, mono(C 1-4 aliphatic) -N(C 1-4 aliphatic residue)-(C 1-4 aliphatic residue)-OH, mono(C 1-4 aliphatic)-NH-S(=O) 2 -C 1-4 Aliphatic residue, mono(C 1-4 aliphatic)-NH-S(=O) 2 -NH 2 , mono(C 1-4 aliphatic)-S(=O) 2 -C 1-4 Aliphatic residue, an OC 1-4 aliphatic residue, an O-(C 1-4 aliphatic)-OC 1-4 aliphatic residue, O-(C 1-4 aliphatic)-OH , an NH-C 1-4 aliphatic residue, an N (C 1-4 aliphatic residue) 2 , an NH-(C 1-4 aliphatic)-OC 1-4 aliphatic residue, NH-(C 1-4 aliphatic)-OH, one N (C 1-4 aliphatic residue) [(C 1-4 aliphatic)-OC 1-4 aliphatic residue], one N(C 1-4 aliphatic residue) [(C 1-4 aliphatic)-OH], an NH-S(=O) 2 -C 1-4 aliphatic residue, wherein the above C 1- 4 aliphatic residues and C 1-4 aliphatic groups may be unsubstituted or monosubstituted with OH based on each of the examples; a C 3-6 cycloaliphatic residue, an OC 3-6 cycloaliphatic residue, a 3 to 6 membered heterocyclic aliphatic residue, O-(3 to 6 membered heterocyclic aliphatic residue), wherein the C 3-6 cycloaliphatic residue and the 3 to 6 membered heterocyclic aliphatic residue are based on In each case, they may be unsubstituted independently of each other, or may be independently selected from the group consisting of F, Cl, Br, I, C 1-4 alkyl, C 1-4 alkyl-OH. , C 1-4 alkylene-OC 1-4 alkyl, CF 3 , C(=O)-C 1-4 alkyl, OC 1-4 alkyl, OC 1-4 alkylene-OH, OC 1-4 alkylene-OC 1-4 alkyl, OH, SH, SC 1-4 alkyl, SO 2 -C 1-4 alkyl, NH 2 , NH-C 1-4 alkyl, N (C a group of 1-4 alkyl) 2 , NH-SO 2 -C 1-4 alkyl and a substituent such as NH-C(=O)-C 1-4 alkyl, mono- or poly-substituted, aryl, C(=O)-NH-aryl, NH-C(=O)-aryl, heteroaryl, C(=O)-NH-heteroaryl, NH-C(=O)-heteroaryl, Wherein the aryl group and the heteroaryl group of the above residue are each based on each of the examples, respectively Unsubstituted, or one or more independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OC 1-4 alkyl-OC 1-4 Alkyl, OC 1-4 alkylene-OH, OCF 3 , C 1-4 alkyl, C 1-4 alkylene-OC 1-4 -alkyl, C 1-4 alkylene-OH, C (=O)-C 1-4 alkyl, CF 3 , CF 2 H, CHF 2 , SH, SC 1-4 alkyl, SCF 3 , SO 2 -C 1-4 alkyl, NH 2 , NH(C a group consisting of a substituent such as 1-4 alkyl), N(C 1-4 alkyl) 2 , NH-SO 2 -C 1-4 alkyl and NH-C(=O)-C 1-4 alkyl Groups are monosubstituted or polysubstituted.

再更佳地，R5、R6、R7、R8與R9係相互獨立地選自由下列基團組成之群組：H、F、Cl、Br、I、CN、CF3、CF2H、CFH2、OH、OCF3、SH、SCF3、NH2、C(=O)-NH2、S(=O)2-OH、S(=O)2-NH2；C1-4烷基、C1-4伸烷基-OH、C1-4伸烷基-O-C1-4烷基、C1-4伸烷基-O-C1-4伸烷基-OH、C1-4伸烷基-O-C1-4伸烷基-O-C1-4烷基、C1-4伸烷基-S(=O)2-C1-4烷基、C1-4伸烷基-NH-S(=O)2-C1-4烷基、C1-4伸烷基-NH-S(=O)2-NH2、C1-4伸烷基-NH-C1-4伸烷基-OH、C1-4伸烷基-NH-C1-4伸烷基-O-C1-4烷基、C1-4伸烷基-N(C1-4烷基)-C1-4伸烷基-OH、C1-4伸烷基-N(C1-4烷基)-C1-4伸烷基-O-C1-4烷基、O-C1-4烷基、O-C1-4伸烷基-OH、O-C1-4伸烷基-O-C1-4烷基、NH-C1-4烷基、N(C1-4烷基)2、NH-C1-4伸烷基-OH、NH-C1-4伸烷基-O-C1-4烷基、N(C1-4烷基)-[C1-4伸烷基-OH]、N(C1-4烷基)-[C1-4伸烷基 -O-C1-4烷基]、NH-S(=O)2-C1-4烷基，其中，C1-4伸烷基於各例中可係未被取代，或被以OH單取代，一C3-6環脂族殘基、O-C3-6環脂族殘基、一3至6構件雜環脂族殘基，其中，該C3-6環脂族殘基以選自由環丙基、環丁基、環戊基、環己基組成之群組較佳，及其中，該3至6構件雜環脂族殘基以選自由四氫吡喃基組成之群組較佳，以四氫-2H-吡喃-4-基、氮雜環丁基、哌啶基、嗎咻基與咯啶基較佳，其中，該C3-6環脂族殘基與該3至6構件雜環脂族殘基分別可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、OH、O-C1-4烷基、NH2、NH(C1-4烷基)、與N(C1-4烷基)2等取代基組成之群組，及C1-4烷基單取代或多取代，苯基、C(=O)-NH-苯基、NH-C(=O)-苯基、雜芳基、C(=O)-NH-雜芳基、NH-C(=O)-雜芳基，以苯基、C(=O)-NH-苯基與NH-C(=O)-苯基較佳，其中，雜芳基以選自由啶基、呋喃基與吩基組成之群組較佳；其中，上述殘基之苯基與雜芳基於各例中，相互獨立地可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、OH、O-C1-4烷基、C1-4烷基與CF3等取代基組成之群組單取代或多取代。 Even more preferably, R 5 , R 6 , R 7 , R 8 and R 9 are independently of each other selected from the group consisting of H, F, Cl, Br, I, CN, CF 3 , CF 2 H, CFH 2 , OH, OCF 3 , SH, SCF 3 , NH 2 , C(=O)-NH 2 , S(=O) 2 -OH, S(=O) 2 -NH 2 ; C 1-4 Alkyl, C 1-4 alkylene-OH, C 1-4 alkylene-OC 1-4 alkyl, C 1-4 alkylene-OC 1-4 alkylene-OH, C 1-4 alkyl-OC 1-4 alkyl-OC 1-4 alkyl, C 1-4 alkyl-S(=O) 2 -C 1-4 alkyl, C 1-4 alkyl-NH -S(=O) 2 -C 1-4 alkyl, C 1-4 alkylene-NH-S(=O) 2 -NH 2 , C 1-4 alkylene-NH-C 1-4 Alkyl-OH, C 1-4 alkylene-NH-C 1-4 alkylene-OC 1-4 alkyl, C 1-4 alkylene-N(C 1-4 alkyl)-C 1 -4 alkylene-OH, C 1-4 alkylene-N(C 1-4 alkyl)-C 1-4 alkylene-OC 1-4 alkyl, OC 1-4 alkyl, OC 1 -4 alkylene-OH, OC 1-4 alkylene-OC 1-4 alkyl, NH-C 1-4 alkyl, N(C 1-4 alkyl) 2 , NH-C 1-4 Alkyl-OH, NH-C 1-4 alkylene-OC 1-4 alkyl, N(C 1-4 alkyl)-[C 1-4 alkylene-OH], N (C 1-4 Alkyl)-[C 1-4 alkylene-OC 1-4 alkyl], NH-S(=O) 2 -C 1-4 alkyl, wherein C 1-4 alkylene can be used in each case Is unsubstituted or monosubstituted with OH, a C 3-6 cycloaliphatic residue, an OC 3-6 cycloaliphatic residue, a 3 to 6 membered heterocyclic aliphatic residue, wherein the C 3 a -6 cycloaliphatic residue is preferably selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and wherein the 3 to 6 member heterocyclic aliphatic residue is selected from the group consisting of tetrahydrogen Preferably, the pyranyl group is preferably tetrahydro-2H-pyran-4-yl, azetidinyl, piperidinyl, decyl and pyridyl, wherein the C 3-6 The cycloaliphatic residue and the 3 to 6 membered heterocyclic aliphatic residue may be unsubstituted, respectively, or may be independently selected from the group consisting of F, Cl, Br, I, OH, OC 1-4 a group consisting of an alkyl group, NH 2 , NH(C 1-4 alkyl), a substituent such as N(C 1-4 alkyl) 2 , and a C 1-4 alkyl mono- or poly-substituted phenyl group , C(=O)-NH-phenyl, NH-C(=O)-phenyl, heteroaryl, C(=O)-NH-heteroaryl, NH-C(=O)-heteroaryl Preferably, the phenyl group, the C(=O)-NH-phenyl group and the NH-C(=O)-phenyl group, wherein the heteroaryl group is selected from the group consisting of a pyridine group, a furyl group and a pheno group. Preferably, wherein the phenyl group and the heteroaryl group of the above residue are based on each case , independently of each other, may be unsubstituted or substituted with one or more independently selected from the group consisting of F, Cl, Br, I, OH, OC 1-4 alkyl, C 1-4 alkyl and CF 3 , etc. Groups of base groups are monosubstituted or polysubstituted.

於根據本發明通式(I)化合物之又另一較佳具體實施例中，R5、R6、R8與R9係各自相互獨立地選自由下列基團組成之群組 H、F、Cl、Br、I、CN、NO2、CF3、CF2H、CFH2、CF2Cl、CFCl2、OH、OCF3、OCF2H、OCFH2、OCF2Cl、OCFCl2、SH、SCF3、SCF2H、SCFH2、SCF2Cl、SCFCl2、NH2、C(=O)-NH2、C(=O)-H、C(=O)-OH、S(=O)2-OH、S(=O)2-NH2、一C1-10脂族殘基、一NH-C1-10脂族殘基、一N(C1-10脂族殘基)2與一O-C1-10脂族殘基，其中，該C1-10脂族殘基於各例中可係未被取代，或被以OH單取代或二取代；及R7係選自由下列基團組成之群組H、F、Cl、Br、I、CN、NO2、CF3、CF2H、CFH2、CF2Cl、CFCl2、OH、OCF3、OCF2H、OCFH2、OCF2Cl、OCFCl2、SH、SCF3、SCF2H、SCFH2、SCF2Cl、SCFCl2、NH2、C(=O)-NH2、C(=O)-H、C(=O)-OH、S(=O)2-OH、S(=O)2-NH2，一C1-10脂族殘基、(C1-8脂族基)-OH、(C1-8脂族基)-O-C1-10脂族殘基、(C1-8脂族基)-O-(C1-8脂族基)-OH、(C1-8脂族基)-O-(C1-8脂族基)-O-C1-10脂族殘基、一(C1-8脂族基)-NH-C1-10脂族殘基、一(C1-8脂族基)-NH-(C1-8脂族殘基)-OH、一(C1-8脂族基)-N(C1-10脂族殘基)-(C1-8脂族殘基)-OH、一(C1-8脂族基)-NH-S(=O)2-C1-10脂族殘基、一(C1-8脂族基)-NH-S(=O)2-NH2、一(C1-8脂族基)-S(=O)2-C1-10脂族殘基、一C(=O)-C1-10脂族殘基、一C(=O)-NH-C1-10脂族殘基，一O-C1-10脂族殘基、一O-(C1-8脂族基)-O-C1-10脂族殘基、O-(C1-8脂族基)-OH，一NH-C1-10脂族殘基、一N(C1-10脂族殘基)2、一NH-[(C1-8脂族基)-O-C1-10脂族殘基]、一NH-[(C1-8脂族基)-OH]、一N(C1-10脂族殘基)[(C1-8脂族基)-OH]、一N(C1-10脂族殘 基)[(C1-8脂族基)-O-C1-10脂族殘基]、一NH-C(=O)-C1-10脂族殘基、一N(C1-10脂族殘基)[(C(=O)-C1-10脂族殘基)]、一N(C1-10脂族殘基)[(C1-8脂族基)-O-C1-10脂族殘基]、一N(C1-10脂族殘基)[(C1-8脂族基)-OH]、一NH-S(=O)2-C1-10脂族殘基、一N(C1-10脂族殘基)[S(=O)2-C1-10脂族殘基]，一S(=O)2-C1-10脂族殘基、一S(=O)2-NH-C1-10脂族殘基、一S(=O)2-N(C1-10脂族殘基)2、一S-C1-10脂族殘基，其中，各上述C1-10脂族殘基與C1-8脂族基於各例中，可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、=O、O-C1-4烷基、OCF3、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3、苯基與啶基等取代基組成之群組單取代或多取代，其中，苯基或啶基分別係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、C(=O)-OH、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3與S(=O)2OH等取代基組成之群組單取代或多取代，一C3-10環脂族殘基、一C(=O)-C3-10環脂族殘基、一C(=O)NH-C3-10環脂族殘基、一O-C3-10環脂族殘基、一O-(C1-8脂族基)-C3-10環脂族殘基、一S-C3-10環脂族殘基、一S-(C1-8脂族基)-C3-10環脂族殘基、一NH-C3-10環脂族殘基、一NH-C(=O)-C3-10環脂族殘基、一NH-(C1-8脂族基)-C3-10環脂族殘基、一N(C1-10脂族殘基)(C3-10環脂族殘基)、一3至10構件雜環脂族殘基、一C(=O)-(3至10構件雜環脂族殘基)、一C(=O)-NH-(3至10構件雜環脂族殘基)、一O-(3至10構件雜環脂族殘基)、一O-(C1-8脂族基)-(3至10構件 雜環脂族殘基)、一S-(3至10構件雜環脂族殘基)、一S-(C1-8脂族基)-(3至10構件雜環脂族殘基)、一NH-(3至10構件雜環脂族殘基)、一NH-C(=O)-(3至10構件雜環脂族殘基)、NH-(C1-8脂族基)-(3至10構件雜環脂族殘基)、一N(C1-10脂族殘基)(3至10構件雜環脂族殘基)，其中，各上述殘基於各例中可選擇性地經由一C1-8脂族基橋接，其中，該C1-10脂族殘基、該C1-8脂族基、該C3-10環脂族殘基與該3至10構件雜環脂族殘基於各例中，分別相互獨立地可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、C1-4烷基、C1-4伸烷基-OH、C1-4伸烷基-O-C1-4烷基、CF3、C(=O)-C1-4烷基、O-C1-4烷基、O-C1-4伸烷基-OH、O-C1-4伸烷基-O-C1-4烷基、=O、OCF3、OH、SH、S-C1-4烷基、SCF3、SO2-C1-4烷基、NH2、=NH、=N(OH)、NH-C1-4烷基、N(C1-4烷基)2、NH-SO2-C1-4烷基、NH-C(=O)-C1-4烷基、苯基與啶基等取代基組成之群組單取代或多取代，其中，苯基與啶基分別係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、C(=O)-OH、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3與S(=O)2OH等取代基組成之群組單取代或多取代，芳基、C(=O)-芳基、C(=O)-NH-芳基、O-芳基、一O-(C1-8脂族基)-芳基、S-芳基、一S-(C1-8脂族基)-芳基、一NH-芳基、NH-C(=O)-芳基、NH-S(=O)2-芳基、一NH-(C1-8脂族基)-芳基、一N(C1-10脂族殘基)(芳基)、雜芳基、C(=O)-雜芳基、 C(=O)-NH-雜芳基、O-雜芳基、O-(C1-8脂族基)-雜芳基、S-(雜芳基)、S-(C1-8脂族基)-(雜芳基)、NH-(雜芳基)、NH-C(=O)-雜芳基、NH-S(=O)2-雜芳基、NH-(C1-8脂族基)(雜芳基)、N(C1-10脂族殘基)(雜芳基)，其中，各上述殘基於各例中可選擇性地經由一C1-8脂族基橋接，其中，上述殘基之芳基與雜芳基於各例中，分別相互獨立地可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、O-C1-4伸烷基-O-C1-4烷基、O-C1-4伸烷基-OH、OCF3、C1-4烷基、C1-4伸烷基-O-C1-4-烷基、C1-4伸烷基-OH、C(=O)-C1-4烷基、CF3、CF2H、CHF2、SH、S-C1-4烷基、SCF3、SO2-C1-4烷基、NH2、NH(C1-4烷基)、N(C1-4烷基)2、NH-SO2-C1-4烷基、NH-C(=O)-C1-4烷基、苯基與啶基等取代基組成之群組單取代或多取代，其中，苯基或啶基分別係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、O-C1-4伸烷基-O-C1-4烷基OCF3、C1-4烷基、C1-4伸烷基-O-C1-4-烷基、C(=O)-OH、CF3、CF2H、CHF2、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3與S(=O)2OH等取代基組成之群組單取代或多取代，其中，上述殘基之C1-10脂族殘基與C1-8脂族基於各例中，分別相互獨立地可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、=O、O-C1-4烷基、OCF3、C1-4烷基、CF3、SH、S-C1-4烷基、SCF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、苯基與啶基 等取代基組成之群組單取代或多取代，其中，苯基或啶基分別係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、C(=O)-OH、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3與S(=O)2OH等取代基組成之群組單取代或多取代。 In still another preferred embodiment of the compound of formula (I) according to the invention, R 5 , R 6 , R 8 and R 9 are each independently selected from the group consisting of H, F, Cl, Br, I, CN, NO 2 , CF 3 , CF 2 H, CFH 2 , CF 2 Cl, CFCl 2 , OH, OCF 3 , OCF 2 H, OCFH 2 , OCF 2 Cl, OCFCl 2 , SH, SCF 3 , SCF 2 H, SCFH 2 , SCF 2 Cl, SCFCl 2 , NH 2 , C(=O)-NH 2 , C(=O)-H, C(=O)-OH, S(=O) 2 -OH, S(=O) 2 -NH 2 , a C 1-10 aliphatic residue, an NH-C 1-10 aliphatic residue, an N (C 1-10 aliphatic residue) 2 and a An OC 1-10 aliphatic residue, wherein the C 1-10 aliphatic residue is unsubstituted in each of the examples, or is mono- or disubstituted with OH; and R 7 is selected from the group consisting of Groups H, F, Cl, Br, I, CN, NO 2 , CF 3 , CF 2 H, CFH 2 , CF 2 Cl, CFCl 2 , OH, OCF 3 , OCF 2 H, OCFH 2 , OCF 2 Cl, OCFCl 2 , SH, SCF 3 , SCF 2 H, SCFH 2 , SCF 2 Cl, SCFCl 2 , NH 2 , C(=O)-NH 2 , C(=O)-H, C(=O)-OH, S (= O) 2 -OH, S (= O) 2 -NH 2, a C 1-10 aliphatic residue, (C 1-8 aliphatic) -OH, (C 1-8 aliphatic ) -OC 1-10 aliphatic residue, (C 1-8 aliphatic) -O- (C 1-8 aliphatic) -OH, (C 1-8 aliphatic) -O- (C 1 -8 aliphatic group)-OC 1-10 aliphatic residue, one (C 1-8 aliphatic group)-NH-C 1-10 aliphatic residue, one (C 1-8 aliphatic group)-NH -(C 1-8 aliphatic residue) -OH, mono (C 1-8 aliphatic)-N (C 1-10 aliphatic residue) - (C 1-8 aliphatic residue) -OH, One (C 1-8 aliphatic)-NH-S(=O) 2 -C 1-10 aliphatic residue, one (C 1-8 aliphatic)-NH-S(=O) 2 -NH 2 , one (C 1-8 aliphatic)-S(=O) 2 -C 1-10 aliphatic residue, a C(=O)-C 1-10 aliphatic residue, a C (=O -NH-C 1-10 aliphatic residue, an OC 1-10 aliphatic residue, an O-(C 1-8 aliphatic)-OC 1-10 aliphatic residue, O-(C 1 -8 aliphatic group)-OH, one NH-C 1-10 aliphatic residue, one N (C 1-10 aliphatic residue) 2 , one NH-[(C 1-8 aliphatic)-OC 1-10 aliphatic residue], one NH-[(C 1-8 aliphatic)-OH], one N (C 1-10 aliphatic residue) [(C 1-8 aliphatic)-OH ], a N (C 1-10 aliphatic residue) [(C 1-8 aliphatic)-OC 1-10 aliphatic residue], an NH-C(=O)-C 1-10 aliphatic Residue, one N (C 1-10 aliphatic residue) [(C(=O)-C 1-10 aliphatic residue)], one N (C 1-10 aliphatic residue) [(C 1 -8 aliphatic group) -OC 1-10 aliphatic residue], a N (C 1-10 aliphatic Yl) [(C 1-8 aliphatic) -OH], a NH-S (= O) 2 -C 1-10 aliphatic residue, an N (C 1-10 aliphatic residue) [S ( =O) 2 -C 1-10 aliphatic residue], an S(=O) 2 -C 1-10 aliphatic residue, an S(=O) 2 -NH-C 1 -10 aliphatic residue , an S(=O) 2 -N(C 1 -10 aliphatic residue) 2 , an SC 1-10 aliphatic residue, wherein each of the above C 1-10 aliphatic residues and a C 1-8 lipid Based on each of the examples, the group may be unsubstituted or selected from one or more independently from F, Cl, Br, I, NO 2 , CN, OH, =0, OC 1-4 alkyl, OCF. 3 , CF 3 , NH 2 , NH (C 1-4 alkyl), N (C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 , phenyl and pyridine group and other substituents The group is mono- or polysubstituted, wherein the phenyl or pyridine group is unsubstituted, respectively, or is selected from one or more independently from F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, C(=O)-OH, CF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 a group consisting of SH, SC 1-4 alkyl, SCF 3 and S(=O) 2 OH, such as a mono- or poly-substitution, a C 3-10 cycloaliphatic residue, a C (=O) -C 3-10 cycloaliphatic residue, a C(=O)NH-C 3-10 cycloaliphatic residue, an OC 3-10 cycloaliphatic residue, an O-(C 1-8 aliphatic)-C 3-10 cycloaliphatic residue, an SC 3-10 cycloaliphatic Family residue, an S-(C 1-8 aliphatic)-C 3-10 cycloaliphatic residue, an NH-C 3-10 cycloaliphatic residue, an NH-C(=O)-C 3-10 cycloaliphatic residue, one NH-(C 1-8 aliphatic)-C 3-10 cycloaliphatic residue, one N (C 1-10 aliphatic residue) (C 3-10 ring) An aliphatic residue), a 3 to 10 membered heterocyclic aliphatic residue, a C(=O)-(3 to 10 membered heterocyclic aliphatic residue), a C(=O)-NH-(3 to 10 member heterocyclic aliphatic residue), one O-(3 to 10 component heterocyclic aliphatic residue), one O-(C 1-8 aliphatic)-(3 to 10 component heterocyclic aliphatic residue) ), an S-(3 to 10 membered heterocyclic aliphatic residue), an S-(C 1-8 aliphatic group)-(3 to 10 membered heterocyclic aliphatic residue), an NH-(3 to 10 member heterocyclic aliphatic residue), one NH-C(=O)-(3 to 10 member heterocyclic aliphatic residue), NH-(C 1-8 aliphatic group)-(3 to 10 building block) a cycloaliphatic residue), an N (C 1-10 aliphatic residue) (3 to 10 membered heterocyclic aliphatic residues), wherein each of the above residues is selectively via a C 1- 8 aliphatic-based bridging, wherein the C 1-10 aliphatic residue, the C 1-8 aliphatic group, the C 3 The 10 cycloaliphatic residue and the 3 to 10 membered heterocyclic aliphatic residue may be unsubstituted independently of each other based on each of the examples, or may be independently selected from F, Cl, Br, in one or more I, C 1-4 alkyl, C 1-4 alkyl-OH, C 1-4 alkyl-OC 1-4 alkyl, CF 3 , C(=O)-C 1-4 alkyl, OC 1-4 alkyl, OC 1-4 alkyl-OH, OC 1-4 alkyl-OC 1-4 alkyl, =0, OCF 3 , OH, SH, SC 1-4 alkyl, SCF 3 , SO 2 -C 1-4 alkyl, NH 2 , =NH, =N(OH), NH-C 1-4 alkyl, N(C 1-4 alkyl) 2 , NH-SO 2 -C a group consisting of a mono- or poly-substituent consisting of a substituent such as an alkyl group, an NH-C(=O)-C 1-4 alkyl group, a phenyl group and a pyridine group, wherein the phenyl group and the pyridine group are respectively not Substituted, or selected from one or more independently of each other by F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, C(=O -OH, CF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 and S(=O) 2 OH A group consisting of a mono- or poly-substituted group of aryl, C(=O)-aryl, C(=O)-NH-aryl, O-aryl, O-(C 1-8 aliphatic) - aryl, S- aryl group, a S- (C 1-8 Aliphatic) - aryl group, an NH- aryl, NH-C (= O) - aryl, NH-S (= O) 2 - aryl group, a NH- (C 1-8 aliphatic) - aryl , N (C 1-10 aliphatic residue) (aryl), heteroaryl, C(=O)-heteroaryl, C(=O)-NH-heteroaryl, O-heteroaryl , O-(C 1-8 aliphatic)-heteroaryl, S-(heteroaryl), S-(C 1-8 aliphatic)-(heteroaryl), NH-(heteroaryl) , NH-C(=O)-heteroaryl, NH-S(=O) 2 -heteroaryl, NH-(C 1-8 aliphatic)(heteroaryl), N(C 1-10 ) a family residue) (heteroaryl), wherein each of the above residues is selectively bridged via a C 1-8 aliphatic group in each case, wherein the aryl group and the heteroaryl group of the above residue are based on each case, Independently independent of each other, may be unsubstituted or selected from one or more independently from F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OC 1-4 alkylene --OC 1-4 alkyl, OC 1-4 alkyl-OH, OCF 3 , C 1-4 alkyl, C 1-4 alkyl-OC 1-4 -alkyl, C 1-4 Alkyl-OH, C(=O)-C 1-4 alkyl, CF 3 , CF 2 H, CHF 2 , SH, SC 1-4 alkyl, SCF 3 , SO 2 -C 1-4 alkyl, NH 2, NH (C 1-4 alkyl), N (C 1-4 alkyl) 2, NH-SO 2 -C 1-4 alkyl, NH-C (= O) -C 1-4 a group consisting of a mono- or poly-substituent consisting of a substituent such as a phenyl group and a pyridine group, wherein the phenyl or pyridyl group is unsubstituted, respectively, or is selected independently from one another by F, Cl, Br , I, NO 2 , CN, OH, OC 1-4 alkyl, OC 1-4 alkyl-OC 1-4 alkyl OCF 3 , C 1-4 alkyl, C 1-4 alkyl-OC 1-4 -alkyl, C(=O)-OH, CF 3 , CF 2 H, CHF 2 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH a group of mono- or poly-substitutions consisting of a substituent such as SC 1-4 alkyl, SCF 3 and S(=O) 2 OH, wherein the C 1-10 aliphatic residue of the above residue is C 1-8 The aliphatic groups may be unsubstituted, independently of each other, or may be independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, =0, OC 1- 4 alkyl, OCF 3 , C 1-4 alkyl, CF 3 , SH, SC 1-4 alkyl, SCF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl ) 2, phenyl and pyridyl substituent groups like the group consisting of mono- or polysubstituted, wherein the phenyl or pyridyl are based unsubstituted or substituted with one or more independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkane Base, OCF 3 , C 1-4 alkyl, C(=O)-OH, CF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC A group consisting of a group of 1-4 alkyl, SCF 3 and a substituent such as S(=O) 2 OH is mono- or poly-substituted.

較佳地，R5、R6、R8與R9係相互獨立地選自由下列基團組成之群組H、F、Cl、Br、I、CN、NO2、CF3、CF2H、CFH2、OH、OCF3、OCF2Cl、OCFCl2、SH、SCF3、NH2、C(=O)-NH2、甲基、乙基、三級丁基、O-甲基、NH-甲基、N(甲基)2；及R7係選自由下列基團組成之群組H、F、Cl、Br、I、CN、NO2、CF3、CF2H、CFH2、CF2Cl、CFCl2、OH、OCF3、OCF2H、OCFH2、OCF2Cl、OCFCl2、SH、SCF3、SCF2H、SCFH2、SCF2Cl、SCFCl2、NH2、C(=O)-NH2、C(=O)-H、C(=O)-OH、S(=O)2-OH、S(=O)2-NH2，一C1-10脂族殘基、(C1-8脂族基)-OH、(C1-8脂族基)-O-C1-10脂族殘基、(C1-8脂族基)-O-(C1-8脂族基)-OH、(C1-8脂族基)-O-(C1-8脂族基)-O-C1-10脂族殘基、一(C1-8脂族基)-NH-C1-10脂族殘基、一(C1-8脂族基)-NH-(C1-8脂族殘基)-OH、一(C1-8脂族基)-N(C1-10脂族殘基)-(C1-8脂族殘基)-OH、一(C1-8脂族基)-NH-S(=O)2-C1-10脂族殘基、一(C1-8脂族基)-NH-S(=O)2-NH2、一(C1-8脂族基)-S(=O)2-C1-10脂族殘基、一C(=O)-C1-10脂族殘基、一C(=O)-NH-C1-10脂族殘基，一O-C1-10脂族殘基、一O-(C1-8脂族基)-O-C1-10脂族殘基、 O-(C1-8脂族基)-OH，一NH-C1-10脂族殘基、一N(C1-10脂族殘基)2、一NH-(C1-8脂族基)-O-C1-10脂族殘基、一NH-(C1-8脂族基)-OH、一N(C1-10脂族殘基)[(C1-8脂族基)-OH]、一N(C1-10脂族殘基)[(C1-8脂族基)-O-C1-10脂族殘基]、一NH-C(=O)-C1-10脂族殘基、一N(C1-10脂族殘基)[(C(=O)-C1-10脂族殘基)]、一N(C1-10脂族殘基)[(C1-8脂族基)-O-C1-10脂族殘基]、一N(C1-10脂族殘基)[(C1-8脂族基)-OH]、一NH-S(=O)2-C1-10脂族殘基、一N(C1-10脂族殘基)[S(=O)2-C1-10脂族殘基]，一S(=O)2-C1-10脂族殘基、一S(=O)2-NH-C1-10脂族殘基、一S(=O)2-N(C1-10脂族殘基)2、一S-C1-10脂族殘基，其中，各上述C1-10脂族殘基與C1-8脂族基於各例中，可係未被取代，或被以OH單取代；一C3-10環脂族殘基、一C(=O)-C3-10環脂族殘基、一C(=O)NH-C3-10環脂族殘基、一O-C3-10環脂族殘基、一O-(C1-8脂族基)-C3-10環脂族殘基、一S-C3-10環脂族殘基、一S-(C1-8脂族基)-C3-10環脂族殘基、一NH-C3-10環脂族殘基、一NH-C(=O)-C3-10環脂族殘基、一NH-(C1-8脂族基)-C3-10環脂族殘基、一N(C1-10脂族殘基)(C3-10環脂族殘基)、一3至10構件雜環脂族殘基、一C(=O)-(3至10構件雜環脂族殘基)、一C(=O)-NH-(3至10構件雜環脂族殘基)、一O-(3至10構件雜環脂族殘基)、一O-(C1-8脂族基)-(3至10構件雜環脂族殘基)、一S-(3至10構件雜環脂族殘基)、一S-(C1-8脂族基)-(3至10構件雜環脂族殘基)、一NH-(3至10構件雜環脂族殘基)、一NH-C(=O)-(3至10構件雜環脂族殘基)、NH-(C1-8脂族基)-(3至10構件雜環脂族殘基)、一N(C1-10 脂族殘基)(3至10構件雜環脂族殘基)，其中，各上述殘基於各例中可選擇性地經由一C1-8脂族基橋接，其中，該C1-10脂族殘基與該C1-8脂族基於各例中，各自相互獨立地可係未被取代，或被以OH單取代，其中，該C3-10環脂族殘基與該3至10構件雜環脂族殘基於各例中，相互獨立地可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、C1-4烷基、C1-4伸烷基-OH、C1-4伸烷基-O-C1-4烷基、CF3、C(=O)-C1-4烷基、O-C1-4烷基、O-C1-4伸烷基-OH、O-C1-4伸烷基-O-C1-4烷基、=O、OCF3、OH、SH、S-C1-4烷基、SCF3、SO2-C1-4烷基、NH2、=NH、=N(OH)、NH-C1-4烷基、N(C1-4烷基)2、NH-SO2-C1-4烷基、NH-C(=O)-C1-4烷基等取代基組成之群組單取代或多取代，芳基、C(=O)-芳基、C(=O)-NH-芳基、O-芳基、一O-(C1-8脂族基)-芳基、S-芳基、一S-(C1-8脂族基)-芳基、一NH-芳基、NH-C(=O)-芳基、NH-S(=O)2-芳基、一NH-(C1-8脂族基)-芳基、一N(C1-10脂族殘基)(芳基)、雜芳基、C(=O)-雜芳基、C(=O)-NH-雜芳基、O-雜芳基、O-(C1-8脂族基)-雜芳基、S-(雜芳基)、S-(C1-8脂族基)-(雜芳基)、NH-(雜芳基)、NH-C(=O)-雜芳基、NH-S(=O)2-雜芳基、NH-(C1-8脂族基)(雜芳基)、N(C1-10脂族殘基)(雜芳基)，其中，各上述殘基於各例中可選擇性地經由一C1-8脂族基橋接，其中，上述殘基之芳基與雜芳基於各例中，相互獨立地可係未被取代，或被以一或多個相互獨立地選自由F、 Cl、Br、I、NO2、CN、OH、O-C1-4烷基、O-C1-4伸烷基-O-C1-4烷基、O-C1-4伸烷基-OH、OCF3、C1-4烷基、C1-4伸烷基-O-C1-4-烷基、C1-4伸烷基-OH、C(=O)-C1-4烷基、CF3、CF2H、CHF2、SH、S-C1-4烷基、SCF3、SO2-C1-4烷基、NH2、NH(C1-4烷基)、N(C1-4烷基)2、NH-SO2-C1-4烷基、NH-C(=O)-C1-4烷基、苯基與啶基等取代基組成之群組單取代或多取代，其中，苯基或啶基分別係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、O-C1-4伸烷基-O-C1-4烷基OCF3、C1-4烷基、C1-4伸烷基-O-C1-4-烷基、C(=O)-OH、CF3、CF2H、CHF2、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3與S(=O)2OH等取代基組成之群組單取代或多取代，其中，上述殘基之C1-10脂族殘基與C1-8脂族基於各例中，可係未被取代，或被以OH單取代。 Preferably, R 5 , R 6 , R 8 and R 9 are independently of each other selected from the group consisting of H, F, Cl, Br, I, CN, NO 2 , CF 3 , CF 2 H, CFH 2 , OH, OCF 3 , OCF 2 Cl, OCFCl 2 , SH, SCF 3 , NH 2 , C(=O)-NH 2 , methyl, ethyl, tert-butyl, O-methyl, NH- Methyl, N(methyl) 2 ; and R 7 are selected from the group consisting of H, F, Cl, Br, I, CN, NO 2 , CF 3 , CF 2 H, CFH 2 , CF 2 Cl, CFCl 2 , OH, OCF 3 , OCF 2 H, OCFH 2 , OCF 2 Cl, OCFCl 2 , SH, SCF 3 , SCF 2 H, SCFH 2 , SCF 2 Cl, SCFCl 2 , NH 2 , C(=O -NH 2 , C(=O)-H, C(=O)-OH, S(=O) 2 -OH, S(=O) 2 -NH 2 , a C 1-10 aliphatic residue, (C 1-8 aliphatic)-OH, (C 1-8 aliphatic)-OC 1-10 aliphatic residue, (C 1-8 aliphatic)-O-(C 1-8 aliphatic -OH, (C 1-8 aliphatic)-O-(C 1-8 aliphatic)-OC 1-10 aliphatic residue, one (C 1-8 aliphatic)-NH-C 1-10 aliphatic residue, one (C 1-8 aliphatic)-NH-(C 1-8 aliphatic residue)-OH, one (C 1-8 aliphatic)-N (C 1- aliphatic residue 10) - (C 1-8 aliphatic residue) -OH, a (C 1-8 aliphatic) -NH-S (= O) 2 -C 1-10 aliphatic residue A (C 1-8 aliphatic) -NH-S (= O) 2 -NH 2, a (C 1-8 aliphatic) -S (= O) 2 -C 1-10 aliphatic residue, a C(=O)-C 1-10 aliphatic residue, a C(=O)-NH-C 1-10 aliphatic residue, an OC 1-10 aliphatic residue, an O-(C 1 -8 aliphatic group)-OC 1-10 aliphatic residue, O-(C 1-8 aliphatic group)-OH, one NH-C 1-10 aliphatic residue, one N (C 1-10 fat) Family residue) 2 , an NH-(C 1-8 aliphatic)-OC 1-10 aliphatic residue, an NH-(C 1-8 aliphatic)-OH, a N (C 1-10) Aliphatic residue) [(C 1-8 aliphatic)-OH], one N (C 1-10 aliphatic residue) [(C 1-8 aliphatic)-OC 1-10 aliphatic residue ], an NH-C(=O)-C 1-10 aliphatic residue, an N (C 1-10 aliphatic residue) [(C(=O)-C 1-10 aliphatic residue)] , an N (C 1-10 aliphatic residue) [(C 1-8 aliphatic)-OC 1-10 aliphatic residue], an N (C 1-10 aliphatic residue) [(C 1 -8 aliphatic group)-OH], one NH-S(=O) 2 -C 1-10 aliphatic residue, one N (C 1-10 aliphatic residue) [S(=O) 2 -C 1-10 aliphatic residue], an S(=O) 2 -C 1-10 aliphatic residue, an S(=O) 2 -NH-C 1-10 aliphatic residue, an S (=O a 2 -N (C 1-10 aliphatic residue) 2 , an SC 1-10 aliphatic residue, wherein each of the above C 1-10 aliphatic residues and a C 1-8 aliphatic group are based on each case, Can not be taken Or, substituted by OH; a C 3-10 cycloaliphatic residue, a C(=O)-C 3-10 cycloaliphatic residue, a C(=O)NH-C 3-10 ring An aliphatic residue, an OC 3-10 cycloaliphatic residue, an O-(C 1-8 aliphatic)-C 3-10 cycloaliphatic residue, an SC 3-10 cycloaliphatic residue, An S-(C 1-8 aliphatic)-C 3-10 cycloaliphatic residue, an NH-C 3-10 cycloaliphatic residue, an NH-C(=O)-C 3-10 ring Aliphatic residue, an NH-(C 1-8 aliphatic)-C 3-10 cycloaliphatic residue, an N (C 1-10 aliphatic residue) (C 3-10 cycloaliphatic residue) a 3- to 10-membered heterocyclic aliphatic residue, a C(=O)-(3 to 10 membered heterocyclic aliphatic residue), a C(=O)-NH- (3 to 10 membered heterocyclic ring) An aliphatic residue), an O-(3 to 10 membered heterocyclic aliphatic residue), an O-(C 1-8 aliphatic group)-(3 to 10 membered heterocyclic aliphatic residue), an S - (3 to 10 component heterocyclic aliphatic residues), one S-(C 1-8 aliphatic)-(3 to 10 component heterocyclic aliphatic residue), one NH- (3 to 10 member heterocyclic ring) Aliphatic residue), one NH-C(=O)-(3 to 10 component heterocyclic aliphatic residue), NH-(C 1-8 aliphatic group)-(3 to 10 member heterocyclic aliphatic residue a N (C 1-10 aliphatic residue) (3 to 10 member heterocyclic aliphatic residue), wherein each of the above residues is optional based on each Selectively bridged via a C 1-8 aliphatic group, wherein the C 1-10 aliphatic residue and the C 1-8 aliphatic group are each independently unsubstituted, or Monosubstituted with OH, wherein the C 3-10 cycloaliphatic residue and the 3 to 10 membered heterocyclic aliphatic residue are independently unsubstituted in each of the examples, or are one or more Independently selected from the group consisting of F, Cl, Br, I, C 1-4 alkyl, C 1-4 alkyl-OH, C 1-4 alkyl-OC 1-4 alkyl, CF 3 , C (= O)-C 1-4 alkyl, OC 1-4 alkyl, OC 1-4 alkyl-OH, OC 1-4 alkyl-OC 1-4 alkyl, =0, OCF 3 , OH, SH, SC 1-4 alkyl, SCF 3 , SO 2 -C 1-4 alkyl, NH 2 , =NH, =N(OH), NH-C 1-4 alkyl, N(C 1-4 alkane yl) 2, NH-SO 2 -C 1-4 alkyl, NH-C (= O) -C 1-4 alkyl substituent such as a group consisting of mono or poly-substituted, aryl, C (= O )-aryl, C(=O)-NH-aryl, O-aryl, mono-O-(C 1-8 aliphatic)-aryl, S-aryl, one S-(C 1-8 Aliphatic)-aryl, mono-NH-aryl, NH-C(=O)-aryl, NH-S(=O) 2 -aryl, mono NH-(C 1-8 aliphatic)- Aryl, an N (C 1-10 aliphatic residue) (aryl), heteroaryl, C(=O)- Heteroaryl, C(=O)-NH-heteroaryl, O-heteroaryl, O-(C 1-8 aliphatic)-heteroaryl, S-(heteroaryl), S-(C 1-8 aliphatic group)-(heteroaryl), NH-(heteroaryl), NH-C(=O)-heteroaryl, NH-S(=O) 2 -heteroaryl, NH-( a C 1-8 aliphatic group) (heteroaryl), N (C 1-10 aliphatic residue) (heteroaryl), wherein each of the above residues is selectively via a C 1-8 based on each of the examples An aliphatic group bridging, wherein the aryl group and the heteroaryl group of the above residue are independently unsubstituted in each of the examples, or are independently selected from F, Cl, Br, I, in one or more NO 2 , CN, OH, OC 1-4 alkyl, OC 1-4 alkylene-OC 1-4 alkyl, OC 1-4 alkylene-OH, OCF 3 , C 1-4 alkyl, C 1-4 alkyl-OC 1-4 -alkyl, C 1-4 alkyl-OH, C(=O)-C 1-4 alkyl, CF 3 , CF 2 H, CHF 2 , SH, SC 1-4 alkyl, SCF 3 , SO 2 -C 1-4 alkyl, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , NH-SO 2 -C a group of mono- or poly-substituents consisting of a substituent of 1-4 alkyl, NH-C(=O)-C 1-4 alkyl, phenyl and pyridine, wherein the phenyl or pyridine group is not Substituted, or selected from one or more independently of each other From F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OC 1-4 alkyl-OC 1-4 alkyl OCF 3 , C 1-4 alkyl, C 1- 4- alkyl-OC 1-4 -alkyl, C(=O)-OH, CF 3 , CF 2 H, CHF 2 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 a group of mono- or poly-substituents consisting of a substituent of alkyl, 2 , SH, SC 1-4 alkyl, SCF 3 and S(=O) 2 OH, wherein the C 1-10 aliphatic residue of the above residue The base and the C 1-8 aliphatic group may be unsubstituted or monosubstituted with OH, based on the respective examples.

更佳地，R5、R6、R8與R9係相互獨立地選自由下列基團組成之群組H、F、Cl、Br、I、CF3、CF2H、CFH2、OH、甲基與O-甲基；及R7係選自由下列基團組成之群組H、F、Cl、Br、I、CN、NO2、CF3、CF2H、CFH2、CF2Cl、CFCl2、OH、OCF3、OCF2H、OCFH2、OCF2Cl、OCFCl2、SH、SCF3、SCF2H、SCFH2、SCF2Cl、SCFCl2、NH2、C(=O)-NH2、C(=O)-H、C(=O)-OH、S(=O)2-OH、S(=O)2-NH2，一C1-10脂族殘基、(C1-8脂族基)-OH、(C1-8脂族基)-O-C1-10脂族殘基、(C1-8脂族基)-O-(C1-8脂族基)-OH、(C1-8脂族 基)-O-(C1-8脂族基)-O-C1-10脂族殘基、一(C1-8脂族基)-NH-C1-10脂族殘基、一(C1-8脂族基)-NH-(C1-8脂族殘基)-OH、一(C1-8脂族基)-N(C1-10脂族殘基)-(C1-8脂族殘基)-OH、一(C1-8脂族基)-NH-S(=O)2-C1-10脂族殘基、一(C1-8脂族基)-NH-S(=O)2-NH2、一(C1-8脂族基)-S(=O)2-C1-10脂族殘基，一O-C1-10脂族殘基、一O-(C1-8脂族基)-O-C1-10脂族殘基、O-(C1-8脂族基)-OH，一NH-C1-10脂族殘基、一N(C1-10脂族殘基)2、一NH-(C1-8脂族基)-O-C1-10脂族殘基、一NH-(C1-8脂族基)-OH、一N(C1-10脂族殘基)[(C1-8脂族基)-O-C1-10脂族殘基]、一N(C1-10脂族殘基)[(C1-8脂族基)-OH]、一NH-S(=O)2-C1-10脂族殘基，其中，各上述C1-10脂族殘基與C1-8脂族基於各例中可係未被取代，或被以OH單取代；一C3-10環脂族殘基、一C(=O)-C3-10環脂族殘基、一C(=O)NH-C3-10環脂族殘基、一O-C3-10環脂族殘基、一NH-C3-10環脂族殘基、一NH-C(=O)-C3-10環脂族殘基、一3至10構件雜環脂族殘基、一C(=O)-(3至10構件雜環脂族殘基)、一C(=O)-NH-(3至10構件雜環脂族殘基)、一O-(3至10構件雜環脂族殘基)、一NH-(3至10構件雜環脂族殘基)、一NH-C(=O)-(3至10構件雜環脂族殘基)，其中，該C3-10環脂族殘基與該3至10構件雜環脂族殘基於各例中分別相互獨立地，可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、C1-4烷基、C1-4伸烷基-OH、C1-4伸烷基-O-C1-4烷基、CF3、C(=O)-C1-4烷基、O-C1-4烷基、O-C1-4伸烷基-OH、O-C1-4伸烷基 -O-C1-4烷基、OCF3、OH、SH、S-C1-4烷基、SCF3、SO2-C1-4烷基、NH2、NH-C1-4烷基、N(C1-4烷基)2、NH-SO2-C1-4烷基、NH-C(=O)-C1-4烷基等取代基組成之群組單取代或多取代；芳基、C(=O)-芳基、C(=O)-NH-芳基、NH-C(=O)-芳基、雜芳基、C(=O)-雜芳基、C(=O)-NH-雜芳基、NH-C(=O)-雜芳基，其中，上述殘基之芳基與雜芳基於各例中分別相互獨立地，可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、O-C1-4伸烷基-O-C1-4烷基、O-C1-4伸烷基-OH、OCF3、C1-4烷基、C1-4伸烷基-O-C1-4-烷基、C1-4伸烷基-OH、C(=O)-C1-4烷基、CF3、CF2H、CHF2、SH、S-C1-4烷基、SCF3、SO2-C1-4烷基、NH2、NH(C1-4烷基)、N(C1-4烷基)2、NH-SO2-C1-4烷基、NH-C(=O)-C1-4烷基、苯基與啶基等取代基組成之群組單取代或多取代，其中，苯基或啶基分別係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、O-C1-4伸烷基-O-C1-4烷基OCF3、C1-4烷基、C1-4伸烷基-O-C1-4-烷基、C(=O)-OH、CF3、CF2H、CHF2、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3與S(=O)2OH等取代基組成之群組單取代或多取代。 More preferably, R 5 , R 6 , R 8 and R 9 are independently of each other selected from the group consisting of H, F, Cl, Br, I, CF 3 , CF 2 H, CFH 2 , OH, Methyl and O-methyl; and R 7 are selected from the group consisting of H, F, Cl, Br, I, CN, NO 2 , CF 3 , CF 2 H, CFH 2 , CF 2 Cl, CFCl 2 , OH, OCF 3 , OCF 2 H, OCFH 2 , OCF 2 Cl, OCFCl 2 , SH, SCF 3 , SCF 2 H, SCFH 2 , SCF 2 Cl, SCFCl 2 , NH 2 , C(=O)- NH 2 , C(=O)-H, C(=O)-OH, S(=O) 2 -OH, S(=O) 2 -NH 2 , a C 1-10 aliphatic residue, (C 1-8 aliphatic group) -OH, (C 1-8 aliphatic group)-OC 1-10 aliphatic residue, (C 1-8 aliphatic group)-O-(C 1-8 aliphatic group) -OH, (C 1-8 aliphatic)-O-(C 1-8 aliphatic)-OC 1-10 aliphatic residue, mono(C 1-8 aliphatic)-NH-C 1- 10 aliphatic residue, one (C 1-8 aliphatic)-NH-(C 1-8 aliphatic residue)-OH, one (C 1-8 aliphatic)-N (C 1-10 lipid Family residue)-(C 1-8 aliphatic residue)-OH, one (C 1-8 aliphatic)-NH-S(=O) 2 -C 1-10 aliphatic residue, one (C 1-8 aliphatic group)-NH-S(=O) 2 -NH 2 , one (C 1-8 aliphatic)-S(=O) 2 -C 1-10 aliphatic residue, an OC 1 -10 aliphatic residue, a O- (C 1-8 aliphatic Yl) -OC 1-10 aliphatic residue, O- (C 1-8 aliphatic) -OH, an NH-C 1-10 aliphatic residue, an N (C 1-10 aliphatic residue) 2 , an NH-(C 1-8 aliphatic)-OC 1-10 aliphatic residue, an NH-(C 1-8 aliphatic)-OH, an N (C 1-10 aliphatic residue) ) [(C 1-8 aliphatic)-OC 1-10 aliphatic residue], an N (C 1-10 aliphatic residue) [(C 1-8 aliphatic)-OH], an NH -S(=O) 2 -C 1-10 aliphatic residue, wherein each of the above C 1-10 aliphatic residues and C 1-8 aliphatic groups are unsubstituted or based on OH in each case Monosubstituted; a C 3-10 cycloaliphatic residue, a C(=O)-C 3-10 cycloaliphatic residue, a C(=O)NH-C 3-10 cycloaliphatic residue, OC 3-10 cycloaliphatic residue, an NH-C 3-10 cycloaliphatic residue, an NH-C(=O)-C 3-10 cycloaliphatic residue, a 3 to 10 membered heterocyclic ester Family residues, a C(=O)-(3 to 10 membered heterocyclic aliphatic residue), a C(=O)-NH- (3 to 10 membered heterocyclic aliphatic residue), an O-( 3 to 10 membered heterocyclic aliphatic residues), one NH-(3 to 10 membered heterocyclic aliphatic residue), one NH-C(=O)-(3 to 10 membered heterocyclic aliphatic residue), wherein the C 3-10 cycloaliphatic residues with the 3-10 member heterocyclic aliphatic residue based on the respective embodiments independently of one another, can be based not Substituents, or with one or more independently selected from the group consisting of F, Cl, Br, I, C 1-4 alkyl, C 1-4 alkylene -OH, C 1-4 alkylene -OC 1- 4- alkyl, CF 3 , C(=O)-C 1-4 alkyl, OC 1-4 alkyl, OC 1-4 alkyl-OH, OC 1-4 alkyl-OC 1-4 Base, OCF 3 , OH, SH, SC 1-4 alkyl, SCF 3 , SO 2 -C 1-4 alkyl, NH 2 , NH-C 1-4 alkyl, N(C 1-4 alkyl) 2 , NH-SO 2 -C 1-4 alkyl, NH-C (=O)-C 1-4 alkyl and other substituents composed of groups of mono- or poly-substituted; aryl, C (= O)- Aryl, C(=O)-NH-aryl, NH-C(=O)-aryl, heteroaryl, C(=O)-heteroaryl, C(=O)-NH-heteroaryl And an NH-C(=O)-heteroaryl group, wherein the aryl group and the heteroaryl group of the above-mentioned residue are independently of each other, may be unsubstituted, or may be independently selected one or more Free F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OC 1-4 alkyl-OC 1-4 alkyl, OC 1-4 alkyl-OH, OCF 3 , C 1-4 alkyl, C 1-4 alkyl-OC 1-4 -alkyl, C 1-4 alkyl-OH, C(=O)-C 1-4 alkyl, CF 3 , CF 2 H, CHF 2 , SH, SC 1-4 alkyl, SCF 3 , SO 2 -C 1-4 alkyl, NH 2 , NH (C 1-4 Alkyl), N(C 1-4 alkyl) 2 , NH-SO 2 -C 1-4 alkyl, NH-C(=O)-C 1-4 alkyl, substituents such as phenyl and pyridine a group consisting of a mono- or poly-substitution in which a phenyl or pyridyl group is unsubstituted, respectively, or one or more independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OC 1-4 alkylene-OC 1-4 alkyl OCF 3 , C 1-4 alkyl, C 1-4 alkylene-OC 1-4 -alkyl, C (= O)-OH, CF 3 , CF 2 H, CHF 2, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 A group consisting of a substituent consisting of a substituent such as S(=O) 2 OH is mono- or poly-substituted.

又更佳地，R5、R6、R8與R9係相互獨立地選自由下列基團組成之群組H、F、Cl、Br、I、CF3、OH、甲基與O-甲基；及R7係選自由下列基團組成之群組 H、F、Cl、Br、I、CN、CF3、CF2H、CFH2、OH、OCF3、SH、SCF3、NH2、C(=O)-NH2、S(=O)2-OH、S(=O)2-NH2，一C1-4脂族殘基、(C1-4脂族基)-OH、(C1-4脂族基)-O-C1-4脂族殘基、(C1-4脂族基)-O-(C1-4脂族基)-OH、(C1-4脂族基)-O-(C1-4脂族基)-O-C1-4脂族殘基、一(C1-4脂族基)-NH-C1-4脂族殘基、一(C1-4脂族基)-NH-(C1-4脂族殘基)-OH、一(C1-4脂族基)-N(C1-4脂族殘基)-(C1-4脂族殘基)-OH、一(C1-4脂族基)-NH-S(=O)2-C1-4脂族殘基、一(C1-4脂族基)-NH-S(=O)2-NH2、一(C1-4脂族基)-S(=O)2-C1-4脂族殘基，一O-C1-4脂族殘基、一O-(C1-4脂族基)-O-C1-4脂族殘基、O-(C1-4脂族基)-OH，一NH-C1-4脂族殘基、一N(C1-4脂族殘基)2、一NH-(C1-4脂族基)-O-C1-4脂族殘基、一NH-(C1-4脂族基)-OH、一N(C1-4脂族殘基)[(C1-4脂族基)-O-C1-4脂族殘基]、一N(C1-4脂族殘基)[(C1-4脂族基)-OH]、一NH-S(=O)2-C1-4脂族殘基，其中，各上述C1-4脂族殘基與C1-4脂族基於各例中可係未被取代，或被以OH單取代；一C3-6環脂族殘基、O-C3-6環脂族殘基、一3至6構件雜環脂族殘基、O-(3至6構件雜環脂族殘基)，其中，該C3-6環脂族殘基與該3至6構件雜環脂族殘基於各例中分別相互獨立地，可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、C1-4烷基、C1-4伸烷基-OH、C1-4伸烷基-O-C1-4烷基、CF3、C(=O)-C1-4烷基、O-C1-4烷基、O-C1-4伸烷基-OH、O-C1-4伸烷基-O-C1-4烷基、OH、SH、S-C1-4烷基、SO2-C1-4烷基、NH2、 NH-C1-4烷基、N(C1-4烷基)2、NH-SO2-C1-4烷基與NH-C(=O)-C1-4烷基等取代基組成之群組單取代或多取代，芳基、C(=O)-NH-芳基、NH-C(=O)-芳基、雜芳基、C(=O)-NH-雜芳基、NH-C(=O)-雜芳基，其中，上述殘基之芳基與雜芳基於各例中分別相互獨立地，可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、O-C1-4伸烷基-O-C1-4烷基、O-C1-4伸烷基-OH、OCF3、C1-4烷基、C1-4伸烷基-O-C1-4-烷基、C1-4伸烷基-OH、C(=O)-C1-4烷基、CF3、CF2H、CHF2、SH、S-C1-4烷基、SCF3、SO2-C1-4烷基、NH2、NH(C1-4烷基)、N(C1-4烷基)2、NH-SO2-C1-4烷基與NH-C(=O)-C1-4烷基等取代基組成之群組單取代或多取代。 Still more preferably, R 5 , R 6 , R 8 and R 9 are independently of each other selected from the group consisting of H, F, Cl, Br, I, CF 3 , OH, methyl and O-A And R 7 are selected from the group consisting of H, F, Cl, Br, I, CN, CF 3 , CF 2 H, CFH 2 , OH, OCF 3 , SH, SCF 3 , NH 2 , C(=O)-NH 2 , S(=O) 2 -OH, S(=O) 2 -NH 2 , a C 1-4 aliphatic residue, (C 1-4 aliphatic)-OH, (C 1-4 aliphatic)-OC 1-4 aliphatic residue, (C 1-4 aliphatic)-O-(C 1-4 aliphatic)-OH, (C 1-4 aliphatic ))-O-(C 1-4 aliphatic)-OC 1-4 aliphatic residue, one (C 1-4 aliphatic)-NH-C 1-4 aliphatic residue, one (C 1 -4 aliphatic group -NH-(C 1-4 aliphatic residue) -OH, mono(C 1-4 aliphatic)-N(C 1-4 aliphatic residue)-(C 1-4 Aliphatic residue) -OH, mono(C 1-4 aliphatic)-NH-S(=O) 2 -C 1-4 aliphatic residue, mono(C 1-4 aliphatic)-NH- S(=O) 2 -NH 2 , a (C 1-4 aliphatic)-S(=O) 2 -C 1-4 aliphatic residue, an OC 1-4 aliphatic residue, an O- (C 1-4 aliphatic)-OC 1-4 aliphatic residue, O-(C 1-4 aliphatic)-OH, one NH-C 1-4 aliphatic residue, one N (C 1 -4 aliphatic residue) 2 , an NH-(C 1-4 aliphatic)-OC 1-4 aliphatic residue, an NH -(C 1-4 aliphatic)-OH, one N (C 1-4 aliphatic residue) [(C 1-4 aliphatic)-OC 1-4 aliphatic residue], one N (C 1-4 aliphatic residue) [(C 1-4 aliphatic)-OH], an NH-S(=O) 2 -C 1-4 aliphatic residue, wherein each of the above C 1-4 fats The family residue and the C 1-4 aliphatic group may be unsubstituted or monosubstituted with OH in each case; a C 3-6 cycloaliphatic residue, an OC 3-6 cycloaliphatic residue, a 3 a 6-membered heterocyclic aliphatic residue, O-(3 to 6 membered heterocyclic aliphatic residue), wherein the C 3-6 cycloaliphatic residue and the 3 to 6 member heterocyclic aliphatic residue are each based on In the examples, independently of each other, they may be unsubstituted or selected from one or more independently from F, Cl, Br, I, C 1-4 alkyl, C 1-4 alkyl-OH, C 1-4 alkylene-OC 1 -4 alkyl, CF 3 , C(=O)-C 1-4 alkyl, OC 1-4 alkyl, OC 1-4 alkylene-OH, OC 1 -4 alkylene-OC 1-4 alkyl, OH, SH, SC 1-4 alkyl, SO 2 -C 1-4 alkyl, NH 2 , NH-C 1-4 alkyl, N (C 1 -4 alkyl) 2 , NH-SO 2 -C 1-4 alkyl group with a substituent such as NH-C(=O)-C 1-4 alkyl group, mono- or poly-substituted, aryl, C (=O)-NH-aryl, NH-C(=O)-aryl, heteroaryl, C(=O)-NH- a group, an NH-C(=O)-heteroaryl group, wherein the aryl group and the heteroaryl group of the above-mentioned residue are independently of each other, may be unsubstituted, or may be independently of one another Free choice of F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OC 1-4 alkyl-OC 1-4 alkyl, OC 1-4 alkyl-OH, OCF 3 , C 1-4 alkyl, C 1-4 alkyl-OC 1-4 -alkyl, C 1-4 alkyl-OH, C(=O)-C 1-4 alkyl, CF 3 , CF 2 H, CHF 2 , SH, SC 1-4 alkyl, SCF 3 , SO 2 -C 1-4 alkyl, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkane yl) 2, NH-SO 2 -C 1-4 alkyl and NH-C (= O) -C 1-4 alkyl substituent group like the group consisting of mono- or polysubstituted.

再更佳地，R5、R6、R8與R9係各自相互獨立地選自由下列基團組成之群組H、F、Cl、Br、I、CF3、OH、甲基、O-甲基；而R7係選自由下列基團組成之群組H、F、Cl、Br、I、CN、CF3、CF2H、CFH2、OH、OCF3、SH、SCF3、NH2、C(=O)-NH2、S(=O)2-OH、S(=O)2-NH2；C1-4烷基、C1-4伸烷基-OH、C1-4伸烷基-O-C1-4烷基、C1-4伸烷基-O-C1-4伸烷基-OH、C1-4伸烷基-O-C1-4伸烷基-O-C1-4烷基、C1-4伸烷基-S(=O)2-C1-4烷基、C1-4伸烷基-NH-S(=O)2-C1-4烷基、C1-4伸烷基-NH-S(=O)2-NH2、C1-4伸烷基-NH-C1-4伸烷基-OH、C1-4伸烷基-NH-C1-4伸烷基-O-C1-4烷基、C1-4伸烷基-N(C1-4烷基)-C1-4伸烷基-OH、C1-4伸烷基 -N(C1-4烷基)-C1-4伸烷基-O-C1-4烷基、O-C1-4烷基、O-C1-4伸烷基-OH、O-C1-4伸烷基-O-C1-4烷基、NH-C1-4烷基、N(C1-4烷基)2、NH-C1-4伸烷基-OH、NH-C1-4伸烷基-O-C1-4烷基、N(C1-4烷基)-[C1-4伸烷基-OH]、N(C1-4烷基)-[C1-4伸烷基-O-C1-4烷基]、NH-S(=O)2-C1-4烷基，其中，C1-4伸烷基於各例中可係未被取代，或被以OH單取代，一C3-6環脂族殘基、O-C3-6環脂族殘基、一3至6構件雜環脂族殘基，其中，該C3-6環脂族殘基以選自由環丙基、環丁基、環戊基、環己基組成之群組較佳，及其中，該3至6構件雜環脂族殘基以選自由四氫吡喃基組成之群組較佳，以四氫-2H-吡喃-4-基、氮雜環丁基、哌啶基、嗎咻基與咯啶基較佳，其中，該C3-6環脂族殘基與該3至6構件雜環脂族殘基分別可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、OH、O-C1-4烷基、NH2、NH(C1-4烷基)、與N(C1-4烷基)2等取代基組成之群組，及C1-4烷基單取代或多取代，苯基、C(=O)-NH-苯基、NH-C(=O)-苯基、雜芳基、C(=O)-NH-雜芳基、NH-C(=O)-雜芳基，以苯基、C(=O)-NH-苯基與NH-C(=O)-苯基較佳，其中，雜芳基以選自由啶基、呋喃基與吩基組成之群組較佳；其中，上述殘基之苯基與雜芳基於各例中分別相互獨立地，可係未被取代，或被以一或多個相互獨立地選自由 F、Cl、Br、I、OH、O-C1-4烷基、C1-4烷基與CF3等取代基組成之群組單取代或多取代。 Even more preferably, each of R 5 , R 6 , R 8 and R 9 is independently selected from the group consisting of H, F, Cl, Br, I, CF 3 , OH, methyl, O- Methyl; and R 7 is selected from the group consisting of H, F, Cl, Br, I, CN, CF 3 , CF 2 H, CFH 2 , OH, OCF 3 , SH, SCF 3 , NH 2 , C(=O)-NH 2 , S(=O) 2 -OH, S(=O) 2 -NH 2 ; C 1-4 alkyl, C 1-4 alkylene-OH, C 1-4 alkyl-OC 1-4 alkyl, C 1-4 alkyl-OC 1-4 alkyl-OH, C 1-4 alkyl-OC 1-4 alkyl-OC 1-4 Base, C 1-4 alkyl-S(=O) 2 -C 1-4 alkyl, C 1-4 alkyl-NH-S(=O) 2 -C 1-4 alkyl, C 1 -4 alkylene-NH-S(=O) 2 -NH 2 , C 1-4 alkylene-NH-C 1-4 alkylene-OH, C 1-4 alkylene-NH-C 1 -4 alkylene-OC 1-4 alkyl, C 1-4 alkylene-N(C 1-4 alkyl)-C 1-4 alkylene-OH, C 1-4 alkyl-N (C 1-4 alkyl)-C 1-4 alkylene-OC 1-4 alkyl, OC 1-4 alkyl, OC 1-4 alkyl-OH, OC 1-4 alkyl-OC 1-4 alkyl, NH-C 1-4 alkyl, N(C 1-4 alkyl) 2 , NH-C 1-4 alkylene-OH, NH-C 1-4 alkylene-OC 1 -4 alkyl, N(C 1-4 alkyl)-[C 1-4 alkylene-OH], N(C 1-4 alkyl)- [C 1-4 alkylene-OC 1-4 alkyl], NH-S(=O) 2 -C 1-4 alkyl, wherein the C 1-4 alkylene group may be unsubstituted in each case Or being monosubstituted with OH, a C 3-6 cycloaliphatic residue, an OC 3-6 cycloaliphatic residue, a 3 to 6 membered heterocyclic aliphatic residue, wherein the C 3-6 cycloaliphatic The group residue is preferably selected from the group consisting of a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group, and wherein the 3 to 6 member heterocyclic aliphatic residue is selected from the group consisting of tetrahydropyranyl groups. Preferably, the group is preferably tetrahydro-2H-pyran-4-yl, azetidinyl, piperidinyl, decyl and pyridyl, wherein the C 3-6 cycloaliphatic residue The base and the 3 to 6 member heterocyclic aliphatic residue may be unsubstituted, respectively, or may be independently selected from the group consisting of F, Cl, Br, I, OH, OC 1-4 alkyl, NH. 2 , NH(C 1-4 alkyl), a group consisting of a substituent such as N(C 1-4 alkyl) 2 , and a C 1-4 alkyl mono- or poly-substitution, phenyl, C (= O)-NH-phenyl, NH-C(=O)-phenyl, heteroaryl, C(=O)-NH-heteroaryl, NH-C(=O)-heteroaryl, phenyl , C(=O)-NH-phenyl and NH-C(=O)-phenyl are preferred, wherein the heteroaryl is selected from the group consisting of pyridine, Preferably, the group consisting of a furyl group and a phenyl group; wherein the phenyl group and the heteroaryl group of the above residue are independently of each other, may be unsubstituted, or may be independently selected from one or more A group consisting of a group consisting of a substituent such as F, Cl, Br, I, OH, OC 1-4 alkyl, C 1-4 alkyl and CF 3 is mono- or poly-substituted.

於根據本發明通式(I)化合物之一特佳具體實施例中，R5與R9係相互獨立地選自由下列基團組成之群組H、F、Cl、Br、I、CF3、OH、甲基、O-甲基，以兩者皆代表H較佳，R6與R8係相互獨立地選自由下列基團組成之群組H、F、Cl、Br、I、CF3、OH、甲基、O-甲基；及R7係選自由下列基團組成之群組H、F、Cl、Br、I、CN、CF3、CF2H、CFH2、OH、OCF3、SH、SCF3、NH2、C(=O)-NH2、S(=O)2-OH、S(=O)2-NH2；C1-4烷基、C1-4伸烷基-OH、C1-4伸烷基-O-C1-4烷基、C1-4伸烷基-O-C1-4伸烷基-OH、C1-4伸烷基-O-C1-4伸烷基-O-C1-4烷基、C1-4伸烷基-S(=O)2-C1-4烷基、C1-4伸烷基-NH-S(=O)2-C1-4烷基、C1-4伸烷基-NH-S(=O)2-NH2、C1-4伸烷基-NH-C1-4伸烷基-OH、C1-4伸烷基-NH-C1-4伸烷基-O-C1-4烷基、C1-4伸烷基-N(C1-4烷基)-C1-4伸烷基-OH、C1-4伸烷基-N(C1-4烷基)-C1-4伸烷基-O-C1-4烷基、O-C1-4烷基、O-C1-4伸烷基-OH、O-C1-4伸烷基-O-C1-4烷基、NH-C1-4烷基、N(C1-4烷基)2、NH-C1-4伸烷基-OH、NH-C1-4伸烷基-O-C1-4烷基、N(C1-4烷基)-[C1-4伸烷基-OH]、N(C1-4烷基)-[C1-4伸烷基-O-C1-4烷基]、NH-S(=O)2-C1-4烷基，其中，C1-4伸烷基於各例中可係未被取代，或被以OH單取代，一C3-6環脂族殘基、O-C3-6環脂族殘基、一3至6構件雜環脂族殘基， 其中，該C3-6環脂族殘基以選自由環丙基、環丁基、環戊基、環己基組成之群組較佳，及其中，該3至6構件雜環脂族殘基以選自由四氫吡喃基組成之群組較佳，以四氫-2H-吡喃-4-基、氮雜環丁基、哌啶基、嗎咻基與咯啶基較佳，其中，該C3-6環脂族殘基與該3至6構件雜環脂族殘基分別可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、OH、O-C1-4烷基、NH2、NH(C1-4烷基)、與N(C1-4烷基)2等取代基組成之群組，其C1-4烷基單取代或多取代，苯基、C(=O)-NH-苯基、NH-C(=O)-苯基、雜芳基、C(=O)-NH-雜芳基、NH-C(=O)-雜芳基，以苯基、C(=O)-NH-苯基與NH-C(=O)-苯基較佳，其中，雜芳基以選自由啶基、呋喃基與吩基組成之群組較佳；其中，上述殘基之苯基與雜芳基於各例中，相互獨立地可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、OH、O-C1-4烷基、C1-4烷基與CF3等取代基組成之群組單取代或多取代。 In a particularly preferred embodiment of one of the compounds of the general formula (I) according to the invention, R 5 and R 9 are independently of each other selected from the group consisting of H, F, Cl, Br, I, CF 3 , OH, methyl, O-methyl, preferably both represent H, and R 6 and R 8 are independently selected from the group consisting of H, F, Cl, Br, I, CF 3 , OH, methyl, O-methyl; and R 7 are selected from the group consisting of H, F, Cl, Br, I, CN, CF 3 , CF 2 H, CFH 2 , OH, OCF 3 , SH, SCF 3 , NH 2 , C(=O)-NH 2 , S(=O) 2 -OH, S(=O) 2 -NH 2 ; C 1-4 alkyl, C 1-4 alkylene -OH, C 1-4 alkylene-OC 1-4 alkyl, C 1-4 alkylene-OC 1-4 alkylene-OH, C 1-4 alkylene-OC 1-4 alkylene --OC 1-4 alkyl, C 1-4 alkylene-S(=O) 2 -C 1-4 alkyl, C 1-4 alkylene-NH-S(=O) 2 -C 1 -4 alkyl, C 1-4 alkylene-NH-S(=O) 2 -NH 2 , C 1-4 alkylene-NH-C 1-4 alkylene-OH, C 1-4 Alkyl-NH-C 1-4 alkylene-OC 1-4 alkyl, C 1-4 alkylene-N(C 1-4 alkyl)-C 1-4 alkylene-OH, C 1 -4 alkylene-N(C 1-4 alkyl)-C 1-4 alkylene-OC 1-4 alkyl, OC 1-4 alkyl, OC 1-4 alkyl-O H, OC 1-4 alkyl-OC 1-4 alkyl, NH-C 1-4 alkyl, N(C 1-4 alkyl) 2 , NH-C 1-4 alkyl-OH, NH -C 1-4 alkylene-OC 1-4 alkyl, N(C 1-4 alkyl)-[C 1-4 alkylene-OH], N(C 1-4 alkyl)-[C 1-4 alkyl-OC 1-4 alkyl], NH-S(=O) 2 -C 1-4 alkyl, wherein the C 1-4 alkyl group may be unsubstituted in each case, or Monosubstituted with OH, a C 3-6 cycloaliphatic residue, an OC 3-6 cycloaliphatic residue, a 3 to 6 membered heterocyclic aliphatic residue, wherein the C 3-6 cycloaliphatic residue Preferably, the group is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and wherein the 3 to 6 member heterocyclic aliphatic residue is selected from the group consisting of tetrahydropyranyl groups. Preferably, the group is preferably tetrahydro-2H-pyran-4-yl, azetidinyl, piperidinyl, decyl and pyridyl, wherein the C 3-6 cycloaliphatic residue The 3 to 6 membered heterocyclic aliphatic residues may be unsubstituted, respectively, or may be independently selected from the group consisting of F, Cl, Br, I, OH, OC 1-4 alkyl, NH 2 , a group consisting of a substituent of NH(C 1-4 alkyl) and N(C 1-4 alkyl) 2 , a C 1-4 alkyl group monosubstituted or polysubstituted, phenyl, C ( =O)-NH-phenyl, NH-C(=O)-phenyl, heteroaryl, C(=O)-NH-heteroaryl, NH-C(=O)-heteroaryl, with benzene a group, C(=O)-NH-phenyl and NH-C(=O)-phenyl are preferred, wherein the heteroaryl group is preferably selected from the group consisting of a pyridine group, a furyl group and a pheno group; The phenyl and heteroaryl groups of the above residues may be unsubstituted independently of each other based on each of the examples, or may be independently selected from the group consisting of F, Cl, Br, I, OH, OC 1-4 The group consisting of an alkyl group, a C 1-4 alkyl group and a substituent such as CF 3 is mono- or poly-substituted.

於根據本發明通式(I)化合物之令一較佳具體實施例中，R5與R9皆代表H，R6與R8係相互獨立地選自由下列基團組成之群組H、F、Cl、Br、I、CF3、OH、甲基、O-甲基；及R7係選自由下列基團組成之群組H、F、Cl、Br、I、CN、CF3、CF2H、CFH2、OH、OCF3、SH、SCF3、NH2、C(=O)-NH2、S(=O)2-OH、S(=O)2-NH2， CH3、C2H5、CH2-OH、C2H4-OH、CH2-CH(OH)-CH2-OH、CH2-O-CH3、C2H4-O-CH3、CH2-O-CH2-OH、CH2-O-C2H4-OH、CH2-O-CH2-O-CH3、CH2-O-C2H4-O-CH3、CH2-S(=O)2-CH3、C2H4-S(=O)2-CH3、CH2-NH-S(=O)2-CH3、CH2-NH-S(=O)2-NH2、CH2-NH-CH2-OH、CH2-NH-C2H4-OH、CH2-NH-C2H4-O-CH3、CH2-N(CH3)-C2H4-OH、CH2-N(CH3)-C2H4-O-CH3、O-CH3、O-C2H4-OH、O-C2H4-O-CH3、NH-CH3、N(CH3)2、NH-C2H4-OH、NH-C2H4-O-CH3、N(CH3)-[C2H4-OH]、N(CH3)-[C2H4-O-CH3]、NH-S(=O)2-CH3，環丙基、環丁基、環戊基、環己基、O-環丙基、四氫吡喃基，以四氫-2H-吡喃-4-基、氮雜環丁基、哌啶基、嗎咻基或咯啶基較佳，其於各例中係相互獨立地未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、OH、O-CH3、NH2、N(CH3)2、CH3、C2H5與三級丁基等取代基組成之群組單取代或多取代，苯基、C(=O)-NH-苯基或NH-C(=O)-苯基，其中，苯基於各例中，相互獨立地可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、OH、O-CH3、CH3、C2H5與CF3等取代基組成之群組單取代或多取代。 In a preferred embodiment of the compound of formula (I) according to the invention, both R 5 and R 9 represent H, and R 6 and R 8 are independently of each other selected from the group consisting of the following groups H, F , Cl, Br, I, CF 3 , OH, methyl, O-methyl; and R 7 are selected from the group consisting of H, F, Cl, Br, I, CN, CF 3 , CF 2 H, CFH 2 , OH, OCF 3 , SH, SCF 3 , NH 2 , C(=O)-NH 2 , S(=O) 2 -OH, S(=O) 2 -NH 2 , CH 3 , C 2 H 5 , CH 2 -OH, C 2 H 4 -OH, CH 2 -CH(OH)-CH 2 -OH, CH 2 -O-CH 3 , C 2 H 4 -O-CH 3 , CH 2 - O-CH 2 -OH, CH 2 -OC 2 H 4 -OH, CH 2 -O-CH 2 -O-CH 3 , CH 2 -OC 2 H 4 -O-CH 3 , CH 2 -S(=O 2 -CH 3 , C 2 H 4 -S(=O) 2 -CH 3 , CH 2 -NH-S(=O) 2 -CH 3 , CH 2 -NH-S(=O) 2 -NH 2 , CH 2 -NH-CH 2 -OH, CH 2 -NH-C 2 H 4 -OH, CH 2 -NH-C 2 H 4 -O-CH 3 , CH 2 -N(CH 3 )-C 2 H 4- OH, CH 2 -N(CH 3 )-C 2 H 4 -O-CH 3 , O-CH 3 , OC 2 H 4 -OH, OC 2 H 4 -O-CH 3 , NH-CH 3 , N(CH 3 ) 2 , NH-C 2 H 4 -OH, NH-C 2 H 4 -O-CH 3 , N(CH 3 )-[C 2 H 4 -OH], N(CH 3 )-[ C 2 H 4 -O-CH 3 ], NH-S(=O) 2 -CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, O-cyclopropyl, tetrahydropyranyl, tetrahydro-2H-pyran-4-yl, azetidinyl, piperidinyl Preferably, the fluorenyl or pyridyl group is unsubstituted independently of each other in each case, or is independently selected from the group consisting of F, Cl, Br, I, OH, O-CH 3 a group of mono- or poly-substituted groups of substituents such as NH 2 , N(CH 3 ) 2 , CH 3 , C 2 H 5 and a tertiary butyl group, phenyl, C(=O)-NH-phenyl or NH-C(=O)-phenyl, wherein the phenyl group, in each case, may be unsubstituted independently of each other, or may be independently selected from the group consisting of F, Cl, Br, I, OH, The group consisting of a substituent such as O-CH 3 , CH 3 , C 2 H 5 and CF 3 is mono- or poly-substituted.

R7之特佳殘基係選自由下列基團組成之群組H、F、Cl、Br、I、CN、CF3、CF2H、CFH2、OH、OCF3、SH、SCF3、NH2、C(=O)-NH2、S(=O)2-OH、S(=O)2-NH2，CH3、C2H5、CH2-OH、C2H4-OH、CH(OH)-CH2OH、CH2-CH(OH)-CH2-OH、CH2-O-CH3、C2H4-O-CH3、 CH2-O-CH2-OH、CH2-O-C2H4-OH、CH2-O-CH2-O-CH3、CH2-O-C2H4-O-CH3、CH2-S(=O)2-CH3、C2H4-S(=O)2-CH3、CH2-NH-S(=O)2-CH3、CH2-NH-S(=O)2-NH2、CH2-NH-CH2-OH、CH2-NH-C2H4-OH、CH2-NH-C2H4-O-CH3、CH2-N(CH3)-C2H4-OH、CH2-N(CH3)-C2H4-O-CH3、O-CH3、O-C2H4-OH、O-C2H4-O-CH3、NH-CH3、N(CH3)2、NH-C2H4-OH、NH-C2H4-O-CH3、N(CH3)-[C2H4-OH]、N(CH3)-[C2H4-O-CH3]、NH-S(=O)2-CH3，環丙基、環丁基、環戊基、環己基、O-環丙基、四氫吡喃基，以四氫-2H-吡喃-4-基、氮雜環丁基、哌啶基、嗎咻基或咯啶基較佳，其於各例中相互獨立地可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、OH、O-CH3、NH2、N(CH3)2、CH3、C2H5與三級丁基等取代基組成之群組單取代或多取代，苯基、C(=O)-NH-苯基或NH-C(=O)-苯基，其中，苯基於各例中相互獨立地可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、OH、O-CH3、CH3、C2H5與CF3組成之取代基群組單取代或多取代。 The particularly preferred residue of R 7 is selected from the group consisting of H, F, Cl, Br, I, CN, CF 3 , CF 2 H, CFH 2 , OH, OCF 3 , SH, SCF 3 , NH 2 , C(=O)-NH 2 , S(=O) 2 -OH, S(=O) 2 -NH 2 , CH 3 , C 2 H 5 , CH 2 -OH, C 2 H 4 -OH, CH(OH)-CH 2 OH, CH 2 -CH(OH)-CH 2 -OH, CH 2 -O-CH 3 , C 2 H 4 -O-CH 3 , CH 2 -O-CH 2 -OH, CH 2 -OC 2 H 4 -OH, CH 2 -O-CH 2 -O-CH 3 , CH 2 -OC 2 H 4 -O-CH 3 , CH 2 -S(=O) 2 -CH 3 , C 2 H 4 -S(=O) 2 -CH 3 , CH 2 -NH-S(=O) 2 -CH 3 , CH 2 -NH-S(=O) 2 -NH 2 , CH 2 -NH-CH 2 -OH, CH 2 -NH-C 2 H 4 -OH, CH 2 -NH-C 2 H 4 -O-CH 3 , CH 2 -N(CH 3 )-C 2 H 4 -OH, CH 2 - N(CH 3 )-C 2 H 4 -O-CH 3 , O-CH 3 , OC 2 H 4 -OH, OC 2 H 4 -O-CH 3 , NH-CH 3 , N(CH 3 ) 2 , NH-C 2 H 4 -OH, NH-C 2 H 4 -O-CH 3 , N(CH 3 )-[C 2 H 4 -OH], N(CH 3 )-[C 2 H 4 -O- CH 3 ], NH-S(=O) 2 -CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, O-cyclopropyl, tetrahydropyranyl, tetrahydro-2H-pyridyl Methyl-4-yl, azetidinyl, piperidinyl, decyl or pyridyl is preferred, each Independently of each other may be based unsubstituted or substituted with one or more independently selected from the group consisting of F, Cl, Br, I, OH, O-CH 3, NH 2, N (CH 3) 2, CH 3, a mono- or poly-substituted group consisting of a substituent such as C 2 H 5 and a tertiary butyl group, phenyl, C(=O)-NH-phenyl or NH-C(=O)-phenyl, wherein benzene Independently independent of each other in each case, or one or more independently selected from the group consisting of F, Cl, Br, I, OH, O-CH 3 , CH 3 , C 2 H 5 and CF 3 The group of substituents consisting is monosubstituted or polysubstituted.

R7之最佳殘基係選自由CH2-S(=O)2-CH3、C2H4-S(=O)2-CH3、CH2-O-C2H4-OH、CH2-OH、CH2-CH2-OH、CH(OH)-CH2OH、CH2-NH-S(=O)2-CH3、CH2-NH-S(=O)2-NH2、C2H4-OH、NH-CH2-CH2-OH、NH-CH2-CH2-OCH3與N(CH3)-CH2-CH2-OH組成之群組；尤其以C2H4-S(=O)2-CH3、CH2-O-C2H4-OH、CH2-OH、CH2-NH-S(=O)2-CH3與C2H4-OH為最佳。 The optimal residue for R 7 is selected from the group consisting of CH 2 -S(=O) 2 -CH 3 , C 2 H 4 -S(=O) 2 -CH 3 , CH 2 -OC 2 H 4 -OH, CH 2 -OH, CH 2 -CH 2 -OH, CH(OH)-CH 2 OH, CH 2 -NH-S(=O) 2 -CH 3 , CH 2 -NH-S(=O) 2 -NH 2 , a group consisting of C 2 H 4 —OH, NH—CH 2 —CH 2 —OH, NH—CH 2 —CH 2 —OCH 3 and N(CH 3 )—CH 2 —CH 2 —OH; especially C 2 H 4 -S(=O) 2 -CH 3 , CH 2 -OC 2 H 4 -OH, CH 2 -OH, CH 2 -NH-S(=O) 2 -CH 3 and C 2 H 4 -OH are optimal.

於根據本發明通式(I)化合物之另一較佳具體實施例中， R5與R9至少其中之一代表H，以R5與R9兩者皆代表H較佳。 In another preferred embodiment of the compound of formula (I) according to the invention, at least one of R 5 and R 9 represents H, and both R 5 and R 9 represent H preferably.

於根據本發明通式(I)化合物之又另一較佳具體實施例中，R6與R8至少其中之一代表H，以兩者皆代表H較佳。 In still another preferred embodiment of the compound of formula (I) according to the present invention, at least one of R 6 and R 8 represents H, and both represent H.

於根據本發明通式(I)化合物之又另一較佳具體實施例中，R6與R8兩者皆代表H。 In still another preferred embodiment of the compound of formula (I) according to the invention, both R 6 and R 8 represent H.

於根據本發明通式(I)化合物之又另一較佳具體實施例中，R5與R9至少其中之一代表H，以兩者皆代表H較佳及R6與R8至少其中之一代表H，以兩者皆代表H較佳或R6與R8兩者皆代表H。 In still another preferred embodiment of the compound of formula (I) according to the present invention, at least one of R 5 and R 9 represents H, both of which represent H is preferred and R 6 and R 8 are at least One represents H, both of which represent H or both R 6 and R 8 represent H.

本發明之一特佳具體實施例為一根據本發明通式(I)之一化合物，其中，R1代表(T1)子結構 其E 代表O或S，o 代表0或1，以代表0較佳，R10a與R10b係相互獨立地選自由H、甲基與乙基組成之群組，以各自代表H較佳；m 代表0、1或2，以代表0或1較佳；G 代表甲基、乙基、正丙基、異丙基、正丁基、二級丁基、三級丁基、戊基、己基，或代表，或代表環丙基、環丁基、環戊基與環己基，或選自由哌啶基、嗎咻基、四氫咯基、四氫喹啉基、四氫異喹啉基、二 氫喹啉基、二氫咯基、二氫啶基、二氫異喹啉基、四氫吡喃基組成之群組，以四氫-2H-吡喃-4-基、四氫呋喃基與四氫啶基較佳，其於各例中相互獨立地可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、OH、O-C1-4烷基、C1-4烷基、NH2、NH(C1-4烷基)與N(C1-4烷基)2等取代基組成之群組單取代或多取代，或代表呋喃基或吩基，其於各例中係未被取代，或代表苯基或啶基，其於各例中係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、O-C1-4伸烷基-O-C1-4烷基、、、、、、OCF3、C1-4烷基、C1-4伸烷基-O-C1-4-烷基、CF3、CF2H、CFH2、SCF3、NH2、NH(C1-4烷基)與N(C1-4烷基)2等取代基組成之群組單取代或多取代；R2 係選自由CF3、甲基、乙基、正丙基、異丙基、正丁基、二級丁基與三基丁基組成之群組，或係選自由環丙基、環丁基、環戊基與環己基組成之群組；R3 代表H或一未被取代之C1-4脂族殘基，以選自由甲基、乙基、正丙基、異丙基、正丁基、二級丁基與三級丁基組成之群組較佳；n 代表1、2或3，以代表1或2較佳，以代表1更佳，R3a 代表H、甲基或乙基，R4a 代表H、甲基或乙基，Y 代表O，Z 代表N或CR4b， 當R4a代表H時，以代表N較佳，或當R4a與R4b各自代表H時，以代表CR4b較佳，或當R4a代表甲基而R4b代表H時，以代表CR4b較佳，R4b 代表H、甲基或乙基，以代表H或甲基較佳，以代表H更佳；T1 代表N或C-R5，U1 代表N或C-R6，V 代表N或C-R7，U2 代表N或C-R8，T2 代表N或C-R9，附帶條件為T1、U1、V、U2及T2變量其中之1、2或3代表氮原子，R5與R9係相互獨立地選自由下列基團組成之群組H、F、Cl、Br、I、CF3、OH、甲基、O-甲基，以兩者皆代表H較佳，R6與R8係相互獨立地選自由下列基團組成之群組H、F、Cl、Br、I、CF3、OH、甲基、O-甲基；及R7係選自由下列基團組成之群組H、F、Cl、Br、I、CN、CF3、CF2H、CFH2、OH、OCF3、SH、SCF3、NH2、C(=O)-NH2、S(=O)2-OH、S(=O)2-NH2；C1-4烷基、C1-4伸烷基-OH、C1-4伸烷基-O-C1-4烷基、C1-4伸烷基-O-C1-4伸烷基-OH、C1-4伸烷基-O-C1-4伸烷基-O-C1-4烷基、C1-4伸烷基-S(=O)2-C1-4烷基、C1-4伸烷基-NH-S(=O)2-C1-4烷基、C1-4伸烷基-NH-S(=O)2-NH2、C1-4伸烷基-NH-C1-4伸烷基-OH、C1-4伸烷基-NH-C1-4伸烷基-O-C1-4烷基、C1-4伸烷基-N(C1-4烷基)-C1-4伸烷基-OH、C1-4伸烷基 -N(C1-4烷基)-C1-4伸烷基-O-C1-4烷基、O-C1-4烷基、O-C1-4伸烷基-OH、O-C1-4伸烷基-O-C1-4烷基、NH-C1-4烷基、N(C1-4烷基)2、NH-C1-4伸烷基-OH、NH-C1-4伸烷基-O-C1-4烷基、N(C1-4烷基)-[C1-4伸烷基-OH]、N(C1-4烷基)-[C1-4伸烷基-O-C1-4烷基]、NH-S(=O)2-C1-4烷基，其中，C1-4伸烷基於各例中可係未被取代，或被以OH單取代，一C3-6環脂族殘基、O-C3-6環脂族殘基、一3至6構件雜環脂族殘基，其中，該C3-6環脂族殘基以選自由環丙基、環丁基、環戊基、環己基組成之群組較佳，及其中，該3至6構件雜環脂族殘基以選自由四氫吡喃基組成之群組較佳，以四氫-2H-吡喃-4-基、氮雜環丁基、哌啶基、嗎咻基與咯啶基較佳，其中，該C3-6環脂族殘基與該3至6構件雜環脂族殘基分別可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、OH、O-C1-4烷基、NH2、NH(C1-4烷基)、與N(C1-4烷基)2組成之群組，及C1-4烷基單取代或多取代，苯基、C(=O)-NH-苯基、NH-C(=O)-苯基、雜芳基、C(=O)-NH-雜芳基、NH-C(=O)-雜芳基，以苯基、C(=O)-NH-苯基與-C(=O)-苯基較佳，其中，雜芳基以選自由啶基、呋喃基與吩基組成之群組較佳；其中，上述殘基之苯基與雜芳基於各例中分別相互獨立地，可係未被取代，或被以一或多個相互獨立地選自由 F、Cl、Br、I、OH、O-C1-4烷基、C1-4烷基與CF3等取代基組成之群組單取代或多取代，R7以選自由H、F、CH2-OH、C2H4-OH、CH(OH)-CH2OH、CH2-O-C2H4-OH、CH2-NH-S(=O)2-CH3、CH2-NH-S(=O)2-NH2、CH2-S(=O)2-CH3、C2H4-S(=O)2-CH3、O-CH3、N(CH3)2、NH-C2H4-OH、NH-C2H4-O-CH3、N(CH3)-[C2H4-OH]、NH-S(=O)2-CH3、氮雜環丁基組成之群組較佳，其中，氮雜環丁基可係未被取代，或被以OH單取代，R7以選自由H、F、CH2-OH、C2H4-OH、CH2-O-C2H4-OH、CH2-NH-S(=O)2-CH3、C2H4-S(=O)2-CH3、O-CH3、N(CH3)2、NH-C2H4-OH、NH-C2H4-O-CH3、N(CH3)-[C2H4-OH]、NH-S(=O)2-CH3、氮雜環丁基組成之群組更佳，其中，氮雜環丁基可係未被取代，或被以OH單取代，本發明之另一特佳具體實施例為一根據本發明通式(I)之一化合物，其中，R1 代表苯基，其係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、OH、O-CH3、CH3、CH(CH3)2、三級丁基與CF3等取代基組成之群組單取代或多取代，以被以一或多個相互獨立地選自由F、Cl、Br、I、O-CH3、CH3、CH(CH3)2、三級丁基與CF3等取代基組成之群組單取代或二取代較佳，已被一選自由F、Cl、Br與I等取代基組成之群組單取代更佳，R2 係選自由CF3、三級丁基與環丙基組成之群組，R3 代表H或甲基，以代表H較佳，n 代表l，R3a 代表H， R4a 代表H或甲基，Y 代表O，Z 代表N或CR4b，當R4a代表H時，以代表N較佳，或當R4a與R4b各自代表H時，以代表CR4b較佳，或當R4a代表甲基而R4b代表H時，以代表CR4b較佳，R4b 代表H或甲基，T1 代表C-R5，U1 代表N，V 代表C-R7，U2 代表N或C-R8，以代表C-R8較佳，T2 代表C-R9，R5與R9皆代表H，R8係選自由下列基團組成之群組H、F、Cl、Br、I、CF3、OH、甲基、O-甲基；及R7係選自由下列基團組成之群組H、F、Cl、Br、I、CN、CF3、CF2H、CFH2、OH、OCF3、SH、SCF3、NH2、C(=O)-NH2、S(=O)2-OH、S(=O)2-NH2，CH3、C2H5、CH2-OH、C2H4-OH、CH(OH)-CH2-OH、CH2-O-CH3、C2H4-O-CH3、CH2-O-CH2-OH、CH2-O-C2H4-OH、CH2-O-CH2-O-CH3、CH2-O-C2H4-O-CH3、CH2-S(=O)2-CH3、C2H4-S(=O)2-CH3、CH2-NH-S(=O)2-CH3、CH2-NH-S(=O)2-NH2、CH2-NH-CH2-OH、CH2-NH-C2H4-OH、CH2-NH-C2H4-O-CH3、CH2-N(CH3)-C2H4-OH、CH2-N(CH3)-C2H4-O-CH3、O-CH3、O-C2H4-OH、O-C2H4-O-CH3、NH-CH3、N(CH3)2、 NH-C2H4-OH、NH-C2H4-O-CH3、N(CH3)-[C2H4-OH]、N(CH3)-[C2H4-O-CH3]、NH-S(=O)2-CH3，環丙基、環丁基、環戊基、環基基、O-環丙基、四氫吡喃基，以四氫-2H-吡喃-4-基、氮雜環丁基、哌啶基、嗎咻基或咯啶基較佳，其於各例中相互獨立地可係未被取代或被以一或多個相互獨立地選自由F、Cl、Br、I、OH、O-CH3、NH2、N(CH3)2、CH3、C2H5與三級丁基等取代基組成之群組單取代或多取代，苯基、C(=O)-NH-苯基或NH-C(=O)-苯基，其中，苯基於各例中，相互獨立地可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、OH、O-CH3、CH3、C2H5與CF3等取代基組成之群組單取代或多取代，R7以選自由H、F、CH2-OH、C2H4-OH、CH(OH)-CH2OH、CH2-O-C2H4-OH、CH2-NH-S(=O)2-CH3、CH2-NH-S(=O)2-NH2、CH2-S(=O)2-CH3、C2H4-S(=O)2-CH3、O-CH3、N(CH3)2、NH-C2H4-OH、NH-C2H4-O-CH3、N(CH3)-[C2H4-OH]、NH-S(=O)2-CH3、氮雜環丁基組成之群組較佳，其中，氮雜環丁基可係未被取代，或被以OH單取代，以H、F、CH2-OH、C2H4-OH、CH2-O-C2H4-OH、CH2-NH-S(=O)2-CH3、C2H4-S(=O)2-CH3、O-CH3、N(CH3)2、NH-C2H4-OH、NH-C2H4-O-CH3、N(CH3)-[C2H4-OH]、NH-S(=O)2-CH3、氮雜環丁基較佳，其中，氮雜環丁基可係未被取代，或被以OH單取代，R7以選自由C2H4-S(=O)2-CH3、CH2-O-C2H4-OH、CH2-OH、CH2-NH-S(=O)2-CH3與C2H4-OH組成之群組更佳。 A particularly preferred embodiment of the invention is a compound of the formula (I) according to the invention, wherein R 1 represents a (T1) substructure Wherein E represents O or S, o represents 0 or 1, preferably represents 0, and R 10a and R 10b are independently selected from the group consisting of H, methyl and ethyl, each of which represents H is preferred; Representing 0, 1 or 2 to represent 0 or 1 is preferred; G represents methyl, ethyl, n-propyl, isopropyl, n-butyl, dibutyl, tert-butyl, pentyl, hexyl, Or on behalf of Or represents cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, or selected from piperidinyl, decyl, tetrahydrorupyl, tetrahydroquinolyl, tetrahydroisoquinolinyl, dihydroquine a group consisting of phenyl, dihydro, pyridyl, dihydroisoquinolinyl, tetrahydropyranyl, tetrahydro-2H-pyran-4-yl, tetrahydrofuranyl and tetrahydropyridyl Preferably, it may be unsubstituted independently of each other in each case, or may be selected from F, Cl, Br, I, OH, OC 1-4 alkyl, C 1-4 independently of one another. a group consisting of a group consisting of an alkyl group, NH 2 , NH(C 1-4 alkyl) and N(C 1-4 alkyl) 2, such as a mono- or poly-substituent, or a furanyl or phenyl group, In the examples, they are unsubstituted or represent a phenyl or pyridyl group, which is unsubstituted in each case, or is selected from F, Cl, Br, I, NO 2 , CN, independently of one or more. OH, OC 1-4 alkyl, OC 1-4 alkyl-OC 1-4 alkyl, , , , , , OCF 3 , C 1-4 alkyl, C 1-4 alkylene-OC 1-4 -alkyl, CF 3 , CF 2 H, CFH 2 , SCF 3 , NH 2 , NH (C 1-4 alkane a group consisting of a group consisting of a substituent such as N(C 1-4 alkyl) 2 is mono- or poly-substituted; R 2 is selected from the group consisting of CF 3 , methyl, ethyl, n-propyl, isopropyl, n-butyl a group consisting of a base, a secondary butyl group and a triyl butyl group, or selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; R 3 represents H or an unsubstituted C The 1-4 aliphatic residue is preferably selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, dibutyl and tert-butyl; n represents 1, 2 Or 3, preferably 1 or 2, preferably 1 is represented, R 3a represents H, methyl or ethyl, R 4a represents H, methyl or ethyl, Y represents O, and Z represents N or CR 4b , When R 4a represents H, preferably represents N, or when R 4a and R 4b each represent H, preferably represents CR 4b , or when R 4a represents a methyl group and R 4b represents H, to represent CR 4b. Preferably, R 4b represents H, methyl or ethyl to represent H or methyl, preferably to represent H; T 1 represents N or CR 5 and U 1 represents N or CR 6 , V Represents N or CR 7 , U 2 represents N or CR 8 , and T 2 represents N or CR 9 with the condition that the T 1 , U 1 , V, U 2 and T 2 variables, wherein 1, 2 or 3 represent a nitrogen atom, R 5 and R 9 are independently of each other selected from the group consisting of H, F, Cl, Br, I, CF 3 , OH, methyl, O-methyl, both of which represent H, preferably. R 6 and R 8 are independently of each other selected from the group consisting of H, F, Cl, Br, I, CF 3 , OH, methyl, O-methyl; and R 7 is selected from the group consisting of Groups H, F, Cl, Br, I, CN, CF 3 , CF 2 H, CFH 2 , OH, OCF 3 , SH, SCF 3 , NH 2 , C(=O)-NH 2 , S ( =O) 2 -OH, S(=O) 2 -NH 2 ; C 1-4 alkyl, C 1-4 alkylene-OH, C 1-4 alkylene-OC 1-4 alkyl, C 1-4 alkylene-OC 1-4 alkylene-OH, C 1-4 alkylene-OC 1-4 alkylene-OC 1-4 alkyl, C 1-4 alkyl-S ( =O) 2 -C 1-4 alkyl, C 1-4 alkylene-NH-S(=O) 2 -C 1-4 alkyl, C 1-4 alkylene-NH-S (=O 2 -NH 2 , C 1-4 alkylene-NH-C 1-4 alkylene-OH, C 1-4 alkylene-NH-C 1-4 alkylene-OC 1-4 alkyl , C 1-4 alkyl-N(C 1-4 alkyl)-C 1-4 alkylene-OH, C 1-4 alkyl-N ( C 1-4 alkyl)-C 1-4 alkylene-OC 1-4 alkyl, OC 1-4 alkyl, OC 1-4 alkyl-OH, OC 1-4 alkyl-OC 1 -4 alkyl, NH-C 1-4 alkyl, N(C 1-4 alkyl) 2 , NH-C 1-4 alkylene-OH, NH-C 1-4 alkylene-OC 1- 4- alkyl, N(C 1-4 alkyl)-[C 1-4 alkylene-OH], N(C 1-4 alkyl)-[C 1-4 alkylene-OC 1-4 alkane And NH-S(=O) 2 -C 1-4 alkyl, wherein the C 1-4 alkylene group may be unsubstituted in each case, or monosubstituted with OH, a C 3-6 ring An aliphatic residue, an OC 3-6 cycloaliphatic residue, a 3 to 6 membered heterocyclic aliphatic residue, wherein the C 3-6 cycloaliphatic residue is selected from the group consisting of cyclopropyl, cyclobutyl, A group consisting of a cyclopentyl group and a cyclohexyl group is preferred, and wherein the 3 to 6 member heterocyclic aliphatic residue is preferably selected from the group consisting of tetrahydropyranyl groups, and tetrahydro-2H-pyran. -4-yl, azetidinyl, piperidinyl, decyl and pyridyl are preferred, wherein the C 3-6 cycloaliphatic residue and the 3 to 6 member heterocyclic aliphatic residue are respectively May be unsubstituted or selected from one or more independently of each other from F, Cl, Br, I, OH, OC 1-4 alkyl, NH 2 , NH(C 1-4 alkyl), and N (C 1-4 alkyl) 2 group The groups, C 1-4 alkyl and mono- or polysubstituted phenyl, C (= O) -NH- phenyl, NH-C (= O) - phenyl, heteroaryl, C (= O -NH-heteroaryl, NH-C(=O)-heteroaryl, preferably phenyl, C(=O)-NH-phenyl and -C(=O)-phenyl, wherein The aryl group is preferably selected from the group consisting of a pyridyl group, a furyl group and a phenyl group; wherein the phenyl group and the heteroaryl group of the above residue are independently of each other, may be unsubstituted, or may be one Or a plurality of groups which are independently selected from the group consisting of F, Cl, Br, I, OH, OC 1-4 alkyl, C 1-4 alkyl and CF 3 , such as a mono- or poly-substitution, R 7 Free choice of H, F, CH 2 -OH, C 2 H 4 -OH, CH(OH)-CH 2 OH, CH 2 -OC 2 H 4 -OH, CH 2 -NH-S(=O) 2 -CH 3 , CH 2 -NH-S(=O) 2 -NH 2 , CH 2 -S(=O) 2 -CH 3 , C 2 H 4 -S(=O) 2 -CH 3 , O-CH 3 , N(CH 3 ) 2 , NH-C 2 H 4 -OH, NH-C 2 H 4 -O-CH 3 , N(CH 3 )-[C 2 H 4 -OH], NH-S(=O) A group of 2- CH 3 and azetidinyl groups is preferred, wherein the azetidinyl group may be unsubstituted or monosubstituted with OH, and R 7 is selected from the group consisting of H, F, CH 2 -OH , C 2 H 4 -OH, CH 2 -OC 2 H 4 - OH, CH 2 -NH-S(=O) 2 -CH 3 , C 2 H 4 -S(=O) 2 -CH 3 , O-CH 3 , N(CH 3 ) 2 , NH-C 2 H 4 a group consisting of -OH, NH-C 2 H 4 -O-CH 3 , N(CH 3 )-[C 2 H 4 -OH], NH-S(=O) 2 -CH 3 , azetidinyl More preferably, the azacyclobutyl group may be unsubstituted or monosubstituted with OH, and another particularly preferred embodiment of the present invention is a compound of the formula (I) according to the present invention, wherein R 1 represents a phenyl group which is unsubstituted or is independently selected from one or more selected from the group consisting of F, Cl, Br, I, OH, O-CH 3 , CH 3 , CH(CH 3 ) 2 , The group consisting of a butyl group and a substituent such as CF 3 is mono- or poly-substituted to be independently selected from one or more of F, Cl, Br, I, O-CH 3 , CH 3 , CH (CH) 3 ) 2 , a combination of a tertiary butyl group and a CF 3 group, such as a mono- or di-substituent, is preferably a mono-substitution group selected from the group consisting of substituents such as F, Cl, Br and I. R 2 is selected from the group consisting of CF 3 , a tertiary butyl group and a cyclopropyl group, R 3 represents H or a methyl group to represent H, and n represents 1, R 3a represents H, and R 4a represents H or A. Base, Y stands for O, Z Table N or CR 4b, when R 4a represents H, preferred to represent N, or when R 4a and R 4b each represent H, preferred to represent CR 4b, or when represents methyl and R 4a R 4b represents H when, preferred to represent CR 4b, R 4b represents H or methyl, T 1 representative of CR 5, U 1 Representative N, V Representative CR 7, U 2 represents N or CR 8, CR 8 to represent preferred, T 2 Representative CR 9 , R 5 and R 9 represent H, and R 8 is selected from the group consisting of H, F, Cl, Br, I, CF 3 , OH, methyl, O-methyl; 7 is selected from the group consisting of H, F, Cl, Br, I, CN, CF 3 , CF 2 H, CFH 2 , OH, OCF 3 , SH, SCF 3 , NH 2 , C (=O) )-NH 2 , S(=O) 2 -OH, S(=O) 2 -NH 2 , CH 3 , C 2 H 5 , CH 2 -OH, C 2 H 4 -OH, CH(OH)-CH 2 -OH, CH 2 -O-CH 3 , C 2 H 4 -O-CH 3 , CH 2 -O-CH 2 -OH, CH 2 -OC 2 H 4 -OH, CH 2 -O-CH 2 - O-CH 3 , CH 2 -OC 2 H 4 -O-CH 3 , CH 2 -S(=O) 2 -CH 3 , C 2 H 4 -S(=O) 2 -CH 3 , CH 2 -NH -S(=O) 2 -CH 3 , CH 2 -NH-S(=O) 2 -NH 2 , CH 2 -NH-CH 2 -OH, CH 2 -NH-C 2 H 4 -OH, CH 2 -NH-C 2 H 4 -O-CH 3 , CH 2 -N(CH 3 )-C 2 H 4 -OH, CH 2 -N(CH 3 )-C 2 H 4 -O-CH 3 , O-CH 3 , OC 2 H 4 -OH, OC 2 H 4 -O-CH 3 , NH-CH 3 , N(CH 3 ) 2 , NH-C 2 H 4 -OH, NH-C 2 H 4 -O-CH 3 , N(CH 3 )-[C 2 H 4 -OH], N(CH 3 )-[C 2 H 4 -O -CH 3 ], NH-S(=O) 2 -CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cycloalkyl, O-cyclopropyl, tetrahydropyranyl, tetrahydro-2H - pyran-4-yl, azetidinyl, piperidinyl, decyl or pyridyl, preferably independently of each other in each case, or independently of one or more Is selected from the group consisting of F, Cl, Br, I, OH, O-CH 3 , NH 2 , N(CH 3 ) 2 , CH 3 , C 2 H 5 and a tertiary butyl group, etc. a polysubstituted, phenyl, C(=O)-NH-phenyl or NH-C(=O)-phenyl group, wherein the phenyl group, in each case, may be unsubstituted independently of each other, or may be substituted by one or a plurality of groups which are independently selected from the group consisting of F, Cl, Br, I, OH, O-CH 3 , CH 3 , C 2 H 5 and CF 3 are mono- or poly-substituted, and R 7 is selected from H, F, CH 2 -OH, C 2 H 4 -OH, CH(OH)-CH 2 OH, CH 2 -OC 2 H 4 -OH, CH 2 -NH-S(=O) 2 -CH 3 , CH 2 -NH-S(=O) 2 -NH 2 , CH 2 -S(=O) 2 -CH 3 , C 2 H 4 -S(=O) 2 -CH 3 , O-CH 3 , N(CH 3 ) 2 , NH-C 2 H 4- OH, NH-C 2 H 4 -O-CH 3 , N(CH 3 )-[C 2 H 4 -OH], NH-S(=O) 2 -CH 3 , azetidinyl Preferably, the group is azacyclobutyl which may be unsubstituted or monosubstituted with OH, such as H, F, CH 2 -OH, C 2 H 4 -OH, CH 2 -OC 2 H 4 - OH, CH 2 -NH-S(=O) 2 -CH 3 , C 2 H 4 -S(=O) 2 -CH 3 , O-CH 3 , N(CH 3 ) 2 , NH-C 2 H 4 -OH, NH-C 2 H 4 -O-CH 3 , N(CH 3 )-[C 2 H 4 -OH], NH-S(=O) 2 -CH 3 , azetidinyl group is preferred, Wherein, the azacyclobutyl group may be unsubstituted or monosubstituted with OH, and R 7 is selected from C 2 H 4 -S(=O) 2 -CH 3 , CH 2 -OC 2 H 4 -OH, A group consisting of CH 2 -OH, CH 2 -NH-S(=O) 2 -CH 3 and C 2 H 4 -OH is more preferred.

本發明之另一特佳具體實施例為一根據本發明通式(I)之一化合物，其中， R1 代表苯基，其被以F、Cl或CH(CH3)2單取代，R2 代表CF3或三級丁基，R3 代表H，n 代表l，R3a 代表H，R4a 代表H或甲基，Y 代表O，Z 代表N或CR4b，當R4a代表H時，以代表N較佳，或當R4a與R4b各自代表H時，以代表CR4b較佳，或當R4a代表甲基而R4b代表H時，以代表CR4b較佳，R4b 代表H，T1 代表C-R5，U1 代表N，V 代表C-R7，U2 代表N或C-R8，T2 代表C-R9，R5與R9皆代表H，R8係選自由H、F、CH3、CF3、OH與O-甲基組成之群組，以H、F、CF3、OH與O-甲基較佳；及R7係選自由下列基團組成之群組H、F、CH2-OH、C2H4-OH、CH(OH)-CH2OH、CH2-O-C2H4-OH、CH2-NH-S(=O)2-CH3、CH2-NH-S(=O)2-NH2、CH2-S(=O)2-CH3、C2H4-S(=O)2-CH3、O-CH3、N(CH3)2、NH-C2H4-OH、NH-C2H4-O-CH3、N(CH3)-[C2H4-OH]、NH-S(=O)2-CH3、氮雜環丁基，其中， 氮雜環丁基可係未被取代，或被以OH單取代，以H、F、CH2-OH、C2H4-OH、CH2-O-C2H4-OH、CH2-NH-S(=O)2-CH3、C2H4-S(=O)2-CH3、O-CH3、N(CH3)2、NH-C2H4-OH、NH-C2H4-O-CH3、N(CH3)-[C2H4-OH]、NH-S(=O)2-CH3、氮雜環丁基較佳，其中，氮雜環丁基可係未被取代，被以OH單取代，其中，C(=O)-NH-苯基或NH-C(=O)-苯基於各例中，相互獨立地可係未被取代，或被以一或多個相互獨立地選自由F、Cl與CF3等取代基組成之群組單取代或多取代。 Another particularly preferred embodiment of the invention is a compound of the formula (I) according to the invention, wherein R 1 represents a phenyl group which is monosubstituted with F, Cl or CH(CH 3 ) 2 , R 2 Represents CF 3 or tertiary butyl, R 3 represents H, n represents l, R 3a represents H, R 4a represents H or methyl, Y represents O, Z represents N or CR 4b , and when R 4a represents H, Preferably, N is preferred, or when R 4a and R 4b each represent H, preferably represents CR 4b , or when R 4a represents methyl and R 4b represents H, preferably represents CR 4b , and R 4b represents H, T 1 represents CR 5 , U 1 represents N, V represents CR 7 , U 2 represents N or CR 8 , T 2 represents CR 9 , R 5 and R 9 both represent H, and R 8 is selected from H, F, CH 3 , CF 3, OH and O- group consisting of methyl, to H, F, CF 3, OH and O- preferred methyl; and R 7 group selected from the group consisting of H the group consisting of, F, CH 2 -OH, C 2 H 4 -OH, CH(OH)-CH 2 OH, CH 2 -OC 2 H 4 -OH, CH 2 -NH-S(=O) 2 -CH 3 , CH 2 -NH- S(=O) 2 -NH 2 , CH 2 -S(=O) 2 -CH 3 , C 2 H 4 -S(=O) 2 -CH 3 , O-CH 3 , N(CH 3 ) 2 , NH-C 2 H 4 -OH, NH-C 2 H 4 -O-CH 3, N (CH 3) - [C 2 H 4 -OH], NH-S (= O) 2 -CH 3 Azetidinyl, wherein azetidinyl system may be unsubstituted or substituted in the single OH to H, F, CH 2 -OH, C 2 H 4 -OH, CH 2 -OC 2 H 4 -OH, CH 2 -NH-S(=O) 2 -CH 3 , C 2 H 4 -S(=O) 2 -CH 3 , O-CH 3 , N(CH 3 ) 2 , NH-C 2 H 4- OH, NH-C 2 H 4 -O-CH 3 , N(CH 3 )-[C 2 H 4 -OH], NH-S(=O) 2 -CH 3 , azetidinyl group is preferred Wherein the azetidinyl group may be unsubstituted and monosubstituted with OH, wherein C(=O)-NH-phenyl or NH-C(=O)-phenyl is in each case independently of each other It may be unsubstituted or monosubstituted or polysubstituted with one or more groups independently selected from the group consisting of substituents such as F, Cl and CF 3 .

根據本發明之特佳化合物係選自下列群組1 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(啶-2-基)乙醯胺；2 N-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-2-(啶-2-基)丙醯胺；3 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(啶-2-基)丙醯胺；4 1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(啶-2-基)尿素；5 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(啶-2-基)尿素；6 N-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-2-(啶-3-基)乙醯胺；7 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(啶-3-基)乙醯胺；8 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(啶-3-基)丙醯胺； 9 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(啶-3-基)尿素；10 N-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-2-(啶-4-基)乙醯胺；11 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(啶-4-基)乙醯胺；12 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(啶-4-基)尿素；13 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(嘧啶-4-基)乙醯胺；14 1N-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-2-(吡嗪-2-基)乙醯胺；15 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(嗒-4-基)尿素；16 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(嘧啶-5-基)乙醯胺；17 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-氯啶-3-基)乙醯胺；18 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(5-氟啶-3-基)尿素；19 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(2-甲基嘧啶-5-基)尿素；20 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(1,3,5-三嗪-2-基)尿素；21 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-(甲磺醯基)乙基)啶-3-基)尿素； 22 1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(5-氟-6-(2-(甲磺醯基)乙基)啶-3-基)尿素；23 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(5-氟-6-(2-(甲磺醯基)乙基)啶-3-基)尿素；24 1-((1-(3-氯苯基)-3-環丙基-1H-吡唑-5-基)甲基)-3-(5-氟-6-(2-(甲磺醯基)乙基)啶-3-基)尿素；25 5-(3-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)脲基)啶醯胺；26 5-(3-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)脲基)啶醯胺；27 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-(甲基磺醯胺基甲基)啶-3-基)丙醯胺；28 N-((5-(3-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)脲基)啶-2-基)甲基)甲基磺醯胺；29 N-((5-(3-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)脲基)啶-2-基)甲基)硫醯二胺；30 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-(羥甲基)啶-3-基)丙醯胺；31 (E)-1-((1-(3,3-二甲基丁烯-1-基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素；32 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素；33 1-((1-(3-氟苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素；34 1-((1-(3-氟-4-甲苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素； 35 1-((1-(3-氟-4-甲氧苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素；36 1-(6-(羥甲基)啶-3-基)-3-((1-間-甲苯基-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；37 1-(6-(羥甲基)啶-3-基)-3-((1-(4-甲氧基-3-甲苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；38 1-(6-(羥甲基)啶-3-基)-3-((1-(3-異丙苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；39 1-((1-(3-三級丁基苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素；40 1-(6-(羥甲基)啶-3-基)-3-((1-(3-(甲氧基甲基)苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；41 1-((1-(3-(二氟甲基)苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素；42 1-((1-(3-苯腈)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素；43 1-((1-(3-(二甲胺基)苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素；44 1-((1-(5-氯啶-3-基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素；45 1-(6-(羥甲基)啶-3-基)-3-((1-(6-甲氧啶-3-基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；46 1-((1-(苯並[d][1,3]二氧環戊烯-5-基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素；47 1-((1-(1H-吲哚-6-基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素； 48 1-((1-(呋喃-3-基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素；49 1-(6-(羥甲基)啶-3-基)-3-((1-(噻吩-2-基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；50 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(5-氟-6-(羥甲基)啶-3-基)尿素；51 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-(2-羥乙基)啶-3-基)丙醯胺；52 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙基)啶-3-基)尿素；53 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-((2-羥乙氧)甲基)啶-3-基)丙醯胺；54 1-((1-(3-氟苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(四氫-2H-吡喃-4-基)啶-3-基)尿素；55 5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶醯胺；56 5-(1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶醯胺；57 5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)-N-苯基啶醯胺；58 5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)-N-(4-氟苯基)啶醯胺；59 5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)-N-(4-(三氟甲基)苯基)啶醯胺；60 5-(1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)-N-(4-氟苯基)啶醯胺； 61 5-(1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)-N-(4-(三氟甲基)苯基)啶醯胺；62 5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)-N-苯基嘧啶-2-羧醯胺；63 5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)-N-(4-氟苯基)嘧啶-2-羧醯胺；64 5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)-N-(4-(三氟甲基)苯基)嘧啶-2-羧醯胺；65 5-(1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)-N-苯基嘧啶-2-羧醯胺；66 5-(1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)-N-(4-氟苯基)嘧啶-2-羧醯胺；67 5-(1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)-N-(4-(三氟甲基)苯基)嘧啶-2-羧醯胺；68 1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(2-甲氧基乙胺)啶-3-基)尿素；69 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-甲氧基乙胺)啶-3-基)尿素；70 1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素；71 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素；72 1-((1-(3-氯苯基)-3-環丙基-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素；73 1-((1-(3-氯苯基)-4-甲基-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素； 74 1-(6-(2-羥乙胺)啶-3-基)-3-((1-戊基-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；75 1-((1-(環丙基甲基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素；76 1-((1-環己基-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素；77 1-(6-(2-羥乙胺)啶-3-基)-3-((1-(四氫-2H-吡喃-4-基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；78 1-((1-(3-氟苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素；79 1-((1-(3,4-二氟苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素；80 1-(6-(2-羥乙胺)啶-3-基)-3-((1-(3-甲氧苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；81 1-(6-(2-羥乙胺)啶-3-基)-3-((1-間-甲苯基-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；82 1-(6-(2-羥乙胺)啶-3-基)-3-((1-(3-異丙苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；83 1-((1-(3-三級丁基苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素；84 1-((3-三級丁基-1-(3-(三氟甲基)苯基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素；85 1-((3-三級丁基-1-(啶-2-基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素；86 1-(6-(2-羥乙胺)啶-3-基)-3-((1-(4-甲氧苄基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素； 87 1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-((2-羥乙基)(甲基)胺基)啶-3-基)尿素；88 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-((2-甲氧基乙基)(甲基)胺基)啶-3-基)丙醯胺；89 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-((2-甲氧基乙基)(甲基)胺基)啶-3-基)尿素；90 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-((2-羥乙基)(甲基)胺基)啶-3-基)尿素；91 N-(5-(1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)苯甲醯胺；92 N-(5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)苯甲醯胺；93 N-(5-(1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)-4-氟苯甲醯胺；94 N-(5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)-4-氟苯甲醯胺；95 N-(5-(1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)-4-氯苯甲醯胺；96 4-氯-N-(5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)苯甲醯胺；97 4-氯-N-(5-(1-氧代-1-((1-(啶-3-基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)丙烷-2-基)啶-2-基)苯甲醯胺；98 N-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-2-(6-(甲基磺醯胺)啶-3-基)丙醯胺；99 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-(甲基磺醯胺)啶-3-基)丙醯胺； 100 N-((1-(3-氟苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-(甲基磺醯胺)啶-3-基)丙醯胺；101 N-(5-(3-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)脲基)啶-2-基)甲基磺醯胺；102 N-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-2-(5-氟-6-(甲基磺醯胺)啶-3-基)丙醯胺；103 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(5-氟-6-(甲基磺醯胺)啶-3-基)丙醯胺；104 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(5-甲氧基-6-(甲基磺醯胺)啶-3-基)丙醯胺；105 N-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-2-(5-甲氧基-6-(甲基磺醯胺)啶-3-基)丙醯胺；106 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(二甲胺基)-5-(三氟甲基)啶-3-基)尿素；107 1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(二甲胺基)-5-(三氟甲基)啶-3-基)尿素；108 1-(6-(氮雜環丁-1-基)啶-3-基)-3-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)尿素；109 1-(6-(氮雜環丁-1-基)啶-3-基)-3-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；110 1-((3-三級丁基-1-(3-氟苯基)-1H-吡唑-5-基)甲基)-3-(6-(3-羥基氮雜環丁-1-基)啶-3-基)尿素；111 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(3-羥基氮雜環丁-1-基)啶-3-基)尿素；112 1-((1-(3-氟苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(3-羥基氮雜環丁-1-基)啶-3-基)尿素； 113 1-((1-(3-氯-4-氟苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(3-羥基氮雜環丁-1-基)啶-3-基)尿素；114 1-(6-(3-羥基氮雜環丁-1-基)啶-3-基)-3-((1-間-甲苯基-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；115 1-(6-(3-羥基氮雜環丁-1-基)啶-3-基)-3-((1-(3-異丙苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；116 1-((1-(3-三級丁基苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(3-羥基氮雜環丁-1-基)啶-3-基)尿素；117 1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(3-羥基氮雜環丁-1-基)啶-3-基)尿素；118 1-((1-(3-(二甲胺基)苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(3-羥基氮雜環丁-1-基)啶-3-基)尿素；119 1-(6-(3-羥基氮雜環丁-1-基)啶-3-基)-3-((1-(3-甲氧苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；120 1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(咯啶-1-基)啶-3-基)尿素；121 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(咯啶-1-基)啶-3-基)尿素；122 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(5-氟-6-(咯啶-1-基)啶-3-基)尿素；123 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(5-甲氧基-6-(咯啶-1-基)啶-3-基)尿素；124 (R)-1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(3-羥基咯啶-1-基)啶-3-基)尿素；125 (S)-1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(3-羥基咯啶-1-基)啶-3-基)尿素； 126 (R)-1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(3-羥基咯啶-1-基)啶-3-基)尿素；127 (S)-1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(3-羥基咯啶-1-基)啶-3-基)尿素；128 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-羥基啶-3-基)尿素；129 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-甲氧啶-3-基)丙醯胺；130 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(2-甲氧基嘧啶-5-基)尿素；131 1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(2-甲氧乙氧基)啶-3-基)尿素；132 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-甲氧乙氧基)啶-3-基)尿素；133 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙氧)啶-3-基)尿素；134 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-((2-羥乙胺)甲基)啶-3-基)尿素；135 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(((2-羥乙基)(甲基)胺基)甲基)啶-3-基)尿素；136 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-甲基啶-3-基)尿素；137 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(5-甲基啶-3-基)尿素；138 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(4,6-二甲基啶-3-基)尿素； 139 1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(5-(羥甲基)啶-2-基)尿素；140 1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(5-(羥甲基)啶-3-基)尿素；141 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)-2-甲基啶-3-基)尿素；142 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(5-氟-6-(羥甲基)啶-3-基)丙醯胺；143 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙基)-2-甲基啶-3-基)尿素；144 1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(1,2-二羥乙基)啶-3-基)尿素；145 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(1,2-二羥乙基)啶-3-基)尿素；146 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-(2-羥乙胺)啶-3-基)丙醯胺；147 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-(2-甲氧基乙胺)啶-3-基)丙醯胺；148 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-((2-羥乙基)(甲基)胺基)啶-3-基)丙醯胺；149 N-((1-(3-氯-4-氟苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-(2-羥乙基)啶-3-基)丙醯胺；150 N-((1-(3-氯苯基)-3-環丙基-1H-吡唑-5-基)甲基)-2-(6-(2-羥乙基)啶-3-基)丙醯胺；151 2-(6-(2-羥乙基)啶-3-基)-N-((1-間-甲苯基-3-(三氟甲基)-1H-吡唑-5-基)甲基)丙醯胺； 152 1-((3-三級丁基-1-(3-氟苯基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙基)啶-3-基)尿素；153 1-((3-三級丁基-1-(3-甲氧苯基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙基)啶-3-基)尿素；154 1-((3-三級丁基-1-(3-氟苯基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素；155 1-((1-(3,5-二氟苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素；156 1-((1-(4-氯-3-甲苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素；157 1-(6-(2-羥乙胺)啶-3-基)-3-((1-(4-甲氧基-3-甲苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；158 1-((1-(4-氟-3-甲苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素；159 1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(甲磺醯基甲基)啶-3-基)尿素；160 1-((3-三級丁基-1-(3-氟苯基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素；161 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-(2-(甲磺醯基)乙基)啶-3-基)丙醯胺；162 N-((5-(3-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)脲基)嘧啶-2-基)甲基)甲基磺醯胺；及163 1-((3-環丙基-1-(3-氟苯基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素；選擇性地，以單一立體異構物或一立體異構物混合物之形式，以自由化合物及/或其生理上可接受之鹽之形式。 A particularly preferred compound according to the invention is selected from the group 1 N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)- 2-(pyridin-2-yl)acetamide; 2 N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2- (pyridin-2-yl)propanamine; 3 N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2- (pyridin-2-yl)propanamide; 4 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(pyridine -2-yl) urea; 5 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(pyridine-2 -based) urea; 6 N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(pyridin-3-yl)ethyl Indoleamine; 7 N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(pyridin-3-yl)ethyl Indoleamine; 8 N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(pyridin-3-yl)propene Guanamine 9 1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(pyridin-3-yl)urea; 10 N -((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(pyridin-4-yl)acetamide; 11 N-( (1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(pyridin-4-yl)acetamide; 12 1-( (1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(pyridin-4-yl)urea; 13 N-((1) -(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(pyrimidin-4-yl)acetamide; 14 1N-((3) - Tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(pyrazin-2-yl)acetamide; 15 1-((1- (3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(indol-4-yl)urea; 16 N-((1-(3) -Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(pyrimidin-5-yl)acetamide; 17 N-((1-(3) -Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(6-chloropyridin-3-yl)acetamide; 18 1-((1 -(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(5-fluoropyridin-3-yl)urea; 19 1-(( 1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(2-methylpyrimidin-5-yl)urea; 20 1- ((1-( 3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(1,3,5-triazin-2-yl)urea; 21 1- ((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-(methylsulfonyl)ethyl) Pyridin-3-yl)urea; 22 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(5-fluoro-6-(2-(methylsulfonate) Mercapto)ethyl)pyridin-3-yl)urea; 23 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl) -3-(5-fluoro-6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)urea; 24 1-((1-(3-chlorophenyl)-3-cyclopropyl) -1H-pyrazol-5-yl)methyl)-3-(5-fluoro-6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)urea; 25 5-(3-( (3-tertiary butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)ureido)pyridinium; 26 5-(3-((1-(3- Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)ureido)pyridinium; 27 N-((1-(3-chlorophenyl)-3- (trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(6-(methylsulfonylamino)pyridin-3-yl)propanamine; 28 N-(( 5-(3-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)ureido)pyridin-2-yl)methyl) Methylsulfonamide; 29 N-((5-(3-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)urea Alkyl)-2-yl)methyl)thioindolediamine; 30 N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl) 2-(6-(hydroxymethyl)pyridin-3-yl)propanamine; 31 (E)-1-((1-(3,3-dimethylbuten-1-yl)- 3-( Fluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(hydroxymethyl)pyridin-3-yl)urea; 32 1-((1-(3-chlorophenyl)) -3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(hydroxymethyl)pyridin-3-yl)urea; 33 1-((1-(3) -fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(hydroxymethyl)pyridin-3-yl)urea; 34 1-( (1-(3-Fluoro-4-methyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(hydroxymethyl)pyridine-3- Base) urea 35 1-((1-(3-Fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(hydroxyl) Benzyl-3-yl)urea; 36 1-(6-(hydroxymethyl)pyridin-3-yl)-3-((1-m-tolyl-3-(trifluoromethyl)-1H- Pyrazol-5-yl)methyl)urea; 37 1-(6-(hydroxymethyl)pyridin-3-yl)-3-((1-(4-methoxy-3-methylphenyl)-3) -(trifluoromethyl)-1H-pyrazol-5-yl)methyl)urea; 38 1-(6-(hydroxymethyl)pyridin-3-yl)-3-((1-(3-) Propyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)urea; 39 1-((1-(3-tri-butylphenyl)-3-) Fluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(hydroxymethyl)pyridin-3-yl)urea; 40 1-(6-(hydroxymethyl)pyridine-3 -yl)-3-((1-(3-(methoxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)urea; 41 1- ((1-(3-(Difluoromethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(hydroxymethyl)pyridine -3-yl)urea; 42 1-((1-(3-benzonitrile)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(hydroxyl) Methyl)pyridin-3-yl)urea; 43 1-((1-(3-(dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)) 3-(6-(hydroxymethyl)pyridin-3-yl)urea; 44 1-((1-(5-chloropyridin-3-yl)-3-(trifluoromethyl)- 1H-pyrazol-5-yl)methyl)-3-(6-(hydroxymethyl)pyridin-3-yl)urea; 45 1-(6-(hydroxymethyl)pyridin-3-yl)-3 -((1-(6-methoxy-3-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)urea; 46 1-((1-(benzo) [d][1,3]dioxolcyclo-5-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(hydroxymethyl) Pyridin-3-yl)urea; 47 1-((1-(1H-indol-6-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3 -(6-(hydroxymethyl)pyridin-3-yl)urea; 48 1-((1-(Furan-3-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(hydroxymethyl)pyridin-3 -based) urea; 49 1-(6-(hydroxymethyl)pyridin-3-yl)-3-((1-(thiophen-2-yl)-3-(trifluoromethyl)-1H-pyrazole -5-yl)methyl)urea; 50 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-( 5-fluoro-6-(hydroxymethyl)pyridin-3-yl)urea; 51 N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5- Methyl)-2-(6-(2-hydroxyethyl)pyridin-3-yl)propanamine; 52 1-((1-(3-chlorophenyl)-3-(trifluoromethyl) -1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethyl)pyridin-3-yl)urea; 53 N-((1-(3-chlorophenyl)-) 3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(6-((2-hydroxyethoxy)methyl)pyridin-3-yl)propanamine; 54 1 -((1-(3-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(tetrahydro-2H-pyran-4) -yl)pyridin-3-yl)urea; 55 5-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino) )-1-oxopropan-2-yl)pyridiniumamine; 56 5-(1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)) Methylamino)-1-oxopropan-2-yl)pyridinium; 57 5-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole) -5-base) A Amino)-1-oxopropan-2-yl)-N-phenylpyridinium; 58 5-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl))- 1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-N-(4-fluorophenyl)pyridinium; 59 5-(1-((1-(3) -Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-N-(4-(trifluoromethyl) Phenyl) pyridinamine; 60 5-(1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methylamino)-1-oxyl Propane-2-yl)-N-(4-fluorophenyl)pyridinium; 61 5-(1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)- N-(4-(Trifluoromethyl)phenyl)pyridinium; 62 5-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole- 5-yl)methylamino)-1-oxopropan-2-yl)-N-phenylpyrimidine-2-carboxamide; 63 5-(1-((1-(3-chlorophenyl))- 3-(Trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-N-(4-fluorophenyl)pyrimidine-2-carboxamide ;64 5-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2- -N-(4-(trifluoromethyl)phenyl)pyrimidine-2-carboxamide; 65 5-(1-((3-tert-butyl-1-(3-chlorophenyl))- 1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-N-phenylpyrimidine-2-carboxamide; 66 5-(1-((3-tri-butyl) 1-(3-chlorophenyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-N-(4-fluorophenyl)pyrimidin-2- Carboxylamidine; 67 5-(1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropane-2 -yl)-N-(4-(trifluoromethyl)phenyl)pyrimidine-2-carboxamide; 68 1-((3-tert-butyl-1-(3-chlorophenyl)-1H- Pyrazol-5-yl)methyl)-3-(6-(2-methoxyethylamine)-3-yl)urea ;69 1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-methoxy B) Amine)-3-yl)urea; 70 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6- (2-hydroxyethylamine)pyridin-3-yl)urea; 71 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl -3-(6-(2-hydroxyethylamine)-3-yl)urea; 72 1-((1-(3-chlorophenyl)-3-cyclopropyl-1H-pyrazole-5- Methyl)-3-(6-(2-hydroxyethylamine)-3-yl)urea; 73 1-((1-(3-chlorophenyl)-4-methyl-3-(three) Fluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethylamine)-3-yl)urea; 74 1-(6-(2-Hydroxyethylamine)-3-yl)-3-((1-pentyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl) Urea; 75 1-((1-(cyclopropylmethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethylamine) Pyridin-3-yl)urea; 76 1-((1-cyclohexyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyl) Ethylamine)pyridin-3-yl)urea; 77 1-(6-(2-hydroxyethylamine)pyridin-3-yl)-3-((1-(tetrahydro-2H-pyran-4-yl)) -3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)urea; 78 1-((1-(3-fluorophenyl)-3-(trifluoromethyl)-1H- Pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethylamine)-3-yl)urea; 79 1-((1-(3,4-difluorophenyl)-3) -(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethylamine)-3-yl)urea; 80 1-(6-(2- Hydroxyethylamine)pyridin-3-yl)-3-((1-(3-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)urea; 81 1-(6-(2-hydroxyethylamine)-3-yl)-3-((1-m-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl Urea; 82 1-(6-(2-hydroxyethylamine)-3-yl)-3-((1-(3-isopropylphenyl)-3-(trifluoromethyl)-1H-pyridyl) Zyrid-5-yl)methyl)urea; 83 1-((1-(3-tert-butylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl) -3-( 6-(2-hydroxyethylamine)-3-yl)urea; 84 1-((3-tert-butyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazole-5 -yl)methyl)-3-(6-(2-hydroxyethylamine)-3-yl)urea; 85 1-((3-tert-butyl-1-(pyridin-2-yl)-1H) -pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethylamine)-3-yl)urea; 86 1-(6-(2-hydroxyethylamine)-3-yl --3-((1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)urea; 87 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-((2-hydroxyethyl)) Amino)pyridin-3-yl)urea; 88 N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)- 2-(6-((2-methoxyethyl)(methyl)amino)pyridin-3-yl)propanamine; 89 1-((1-(3-chlorophenyl)-3-) Trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-((2-methoxyethyl)(methyl)amino)pyridin-3-yl)urea; 1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-((2-hydroxyethyl)) Methyl)amino)pyridin-3-yl)urea; 91 N-(5-(1-((3-triphenyl)-1H-pyrazol-5-yl) Methylamino)-1-oxopropan-2-yl)pyridin-2-yl)benzamide; 92 N-(5-(1-((1-(3-chlorophenyl))-3-) (trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)pyridin-2-yl)benzamide; 93 N-(5-(1) -((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-2-yl) 4-fluorobenzamide; 94 N-(5-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamine) ))-1-oxopropan-2-yl)pyridin-2-yl)-4-fluorobenzamide; 95 N-(5-(1-((3-tert-butyl-1-(3)) - Phenyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)pyridin-2-yl)-4-chlorobenzamide; 96 4-chloro-N- (5-(1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl) Pyridin-2-yl)benzamide; 97 4-chloro-N-(5-(1-oxo-1-((1-(pyridin-3-yl)-3-(trifluoromethyl))) -1H-pyrazol-5-yl)methylamino)propan-2-yl)pyridin-2-yl)benzamide; 98 N-((3-tert-butyl-1-(3-chlorobenzene) -1H-pyrazol-5-yl)methyl)-2-(6-(methylsulfonamide)pyridin-3-yl)propanamine; 99 N-((1-(3-chlorobenzene) 3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(6-(methylsulfonamide)pyridin-3-yl)propanamine; 100 N-((1-(3-Fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(6-(methylsulfonamide) pyridine 3-yl)propanamine; 101 N-(5-(3-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl) Ureido)pyridin-2-yl)methylsulfonamide; 102 N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl) -2-(5-fluoro-6-(methylsulfonamide)-3-yl)propanamine; 103 N-((1-(3-chlorophenyl)-3-(trifluoromethyl)) -1H-pyrazol-5-yl)methyl)-2-(5-fluoro-6-(methylsulfonamide)-3-yl)propanamine; 104 N-((1-(3- Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(5-methoxy-6-(methylsulfonamide)-3-yl Propylamine; 105 N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(5-methoxy-6 -(methylsulfonamide)pyridin-3-yl)propanamine; 106 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-yl) )methyl)-3-(6-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl)urea; 107 1-((3-tertiary butyl-1-(3-) Chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl)urea; 108 1-( 6-(azetidin-1-yl)pyridin-3-yl)-3-((3-tert-butyl-1-(3-chlorophenyl)-1H- Zin-5-yl)methyl)urea; 109 1-(6-(azetidin-1-yl)pyridin-3-yl)-3-((1-(3-chlorophenyl)-3- (trifluoromethyl)-1H-pyrazol-5-yl)methyl)urea; 110 1-((3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazole-5- Methyl)-3-(6-(3-hydroxyazetidin-1-yl)pyridin-3-yl)urea; 111 1-((1-(3-chlorophenyl)-3-) Trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(3-hydroxyazetidin-1-yl)pyridin-3-yl)urea; 112 1-(( 1-(3-Fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(3-hydroxyazetidin-1-yl) Pyridin-3-yl)urea; 113 1-((1-(3-Chloro-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(3-hydroxyl) Azetidin-1-yl)pyridin-3-yl)urea; 114 1-(6-(3-hydroxyazetidin-1-yl)pyridin-3-yl)-3-((1-inter) -tolyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)urea; 115 1-(6-(3-hydroxyazetidin-1-yl)pyridine-3- 3-((1-(3-isopropylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)urea; 116 1-((1-(3) -Tris-butylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(3-hydroxyazetidin-1-yl)pyridine -3-yl)urea; 117 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(3- Hydroxyazetidin-1-yl)pyridin-3-yl)urea; 118 1-((1-(3-(dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyridyl) Zin-5-yl)methyl)-3-(6-(3-hydroxyazetidin-1-yl)pyridin-3-yl)urea; 119 1-(6-(3-hydroxyazetidine) -1-yl)pyridin-3-yl)-3-((1-(3-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)urea; 120 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(rhodin-1-yl)pyridine- 3-based) urea; 121 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole -5-yl)methyl)-3-(6-(l-pyridin-1-yl)pyridin-3-yl)urea; 122 1-((1-(3-chlorophenyl)-3-(trifluoro) Methyl)-1H-pyrazol-5-yl)methyl)-3-(5-fluoro-6-(rhodin-1-yl)pyridin-3-yl)urea; 123 1-((1-( 3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(5-methoxy-6-(rhodin-1-yl)pyridine- 3-yl) urea; 124 (R)-1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-( 6-(3-hydroxylpyridin-1-yl)pyridin-3-yl)urea; 125 (S)-1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H -pyrazol-5-yl)methyl)-3-(6-(3-hydroxylidine-1-yl)pyridin-3-yl)urea; 126 (R)-1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(3-hydroxyrrolidine) -1-yl)pyridin-3-yl)urea; 127 (S)-1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl --3-(6-(3-hydroxylidine-1-yl)pyridin-3-yl)urea; 128 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-) 1H-pyrazol-5-yl)methyl)-3-(6-hydroxypyridin-3-yl)urea; 129 N-((1-(3-chlorophenyl)-3-(trifluoromethyl)) -1H-pyrazol-5-yl)methyl)-2-(6-methoxy-3-yl)propanamine; 130 1-((1-(3-chlorophenyl)-3-) Fluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(2-methoxypyrimidin-5-yl)urea; 131 1-((3-tert-butyl-1-(3) -chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-methoxyethoxy)pyridin-3-yl)urea; 132 1-((1-(3 -Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-methoxyethoxy)pyridin-3-yl)urea; 133 1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethoxy)pyridine -3-yl)urea; 134 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-( (2-hydroxyethylamine)methyl)pyridin-3-yl)urea; 135 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5- )methyl)-3-(6-(((2-hydroxyethyl))(methyl)amino)methyl)pyridin-3-yl)urea; 136 1-((1-(3-chlorophenyl) --3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-methylpyridin-3-yl)urea; 137 1-((1-(3-chloro) Phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(5-methylpyridin-3-yl)urea; 138 1-((1-(3) -Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(4,6-dimethylidene-3-yl)urea; 139 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(5-(hydroxymethyl)pyridin-2-yl Urea; 140 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(5-(hydroxymethyl)pyridine- 3-yl)urea; 141 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(hydroxy Methyl)-2-methylpyridin-3-yl)urea; 142 N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)- 2-(5-fluoro-6-(hydroxymethyl)pyridin-3-yl)propanamine; 143 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)) -1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethyl)-2-methylpyridin-3-yl)urea; 144 1-((3-tert-butyl) 1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(1,2-dihydroxyethyl)pyridin-3-yl)urea; 145 1- ((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(1,2-dihydroxyethyl)pyridine -3-yl)urea; 146 N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(6-( 2-hydroxyethylamine)pyridin-3-yl)propanamine; 147 N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-yl)- 2-(6-(2-methoxyethylamine)pyridin-3-yl)propanamine; 148 N-((1-(3-chlorophenyl)-3-(trifluoromethyl)) -1H-pyridyl Zyrid-5-yl)methyl)-2-(6-((2-hydroxyethyl)(methyl)amino)pyridin-3-yl)propanamine; 149 N-((1-(3- Chloro-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(6-(2-hydroxyethyl)pyridin-3-yl)propan Indoleamine; 150 N-((1-(3-chlorophenyl)-3-cyclopropyl-1H-pyrazol-5-yl)methyl)-2-(6-(2-hydroxyethyl)pyridine 3-yl)propanamine; 151 2-(6-(2-hydroxyethyl)pyridin-3-yl)-N-((1-m-tolyl-3-(trifluoromethyl)-1H -pyrazol-5-yl)methyl)propanamide; 152 1-((3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethyl)pyridine-3 -base) urea; 153 1-((3-tert-butyl-1-(3-methoxyphenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyl) Ethyl)pyridin-3-yl)urea; 154 1-((3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6 -(2-hydroxyethylamine)pyridin-3-yl)urea; 155 1-((1-(3,5-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5- Methyl)-3-(6-(2-hydroxyethylamine)-3-yl)urea; 156 1-((1-(4-chloro-3-methylphenyl)-3-(trifluoromethyl) -1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethylamine)-3-yl)urea; 157 1-(6-(2-hydroxyethylamine)pyridine 3-yl)-3-((1-(4-methoxy-3-methyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)urea; 158 1 -((1-(4-Fluoro-3-methyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethylamine) Pyridin-3-yl)urea; 159 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(A) Sulfhydrylmethyl)pyridin-3-yl)urea; 160 1-((3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazol-5-yl)methyl)-3 -(6-(hydroxymethyl)pyridin-3-yl)urea; 161 N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5- )methyl)-2-(6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)propanamine; 162 N-((5-(3-((1-(3-)) Phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)ureido)pyrimidin-2-yl)methyl)methylsulfonamide; and 163 1-((3) -cyclopropyl-1-(3-fluorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(hydroxymethyl)pyridin-3-yl)urea; alternatively, In the form of a single stereoisomer or a mixture of stereoisomers, in the form of a free compound and/or a physiologically acceptable salt thereof.

此外，根據本發明化合物以可造成百分之50之辣椒素被取代較佳，其經螢光成像讀板儀(fluorescent imaging plate reader，FLIPR)檢定，以100 nM之濃度存在於CHO K1細胞中，該細胞係以小於2,000 nM之人類VR1基因轉染，以少於1,000 nM較佳，以少於300 nM更佳，以少於100 nM再更佳，以少於75 nM又更佳，以少於50 nM又更佳，以少於10 nM最佳。 Furthermore, it is preferred that the compound according to the present invention is substituted with 50% capsaicin, which is detected by a fluorescent imaging plate reader (FLIPR) and is present in CHO K1 cells at a concentration of 100 nM. The cell line is transfected with a human VR1 gene of less than 2,000 nM, preferably less than 1,000 nM, more preferably less than 300 nM, even more preferably less than 100 nM, more preferably less than 75 nM, Less than 50 nM is better, and less than 10 nM is optimal.

於此方法中，鈣離子量係於鈣離子敏感染料(Fluo-4型，Molecular Probes Europe BV，Leiden，荷蘭)之輔助下，以螢光成像讀板儀(fluorescent imaging plate reader，FLIPR，分子儀器(Molecular Devices)，Sunnyvale，美國)檢定，其描述如下。 In this method, the amount of calcium ions is supplemented by a calcium ion sensitive dye (Fluo-4 type, Molecular Probes Europe BV, Leiden, The Netherlands), with a fluorescent imaging plate reader (FLIPR, molecular instrument). (Molecular Devices), Sunnyvale, USA) assay, which is described below.

根據本發明上述通式(I)之被取代化合物、與其相應之立體異構物及與其相應之酸、鹼、鹽類與溶劑化物具毒理學安全性，因此，適合做為藥物組合物中之藥物活性成分。 According to the present invention, the substituted compound of the above formula (I), the corresponding stereoisomer thereof and the acid, base, salt and solvate thereof corresponding thereto are toxicologically safe, and therefore, suitable as a pharmaceutical composition The active ingredient of the drug.

因此本發明進一步涉及一種含有至少一種根據本發明上述化學式(I)之化合物之藥物組合物，若適當，其於各例中係純之立體異構物之形式，特別係對映異構物或非對映異構物，其消旋物或立體異構物混合物之形式，特別係對映異構物及/或非對映異構物，於任何所需之混合比例，或分別地為其相應之鹽之形式，或分別地為其相應之溶劑化物之形式，以及若適當，一或多種藥理相容之助劑。 The invention further relates to a pharmaceutical composition comprising at least one compound of the above formula (I) according to the invention, if appropriate in the form of a pure stereoisomer, in particular an enantiomer or a diastereomer, in the form of a racemate or a mixture of stereoisomers, especially an enantiomer and/or diastereomer, in any desired mixing ratio, or separately The corresponding salt forms, or separately in the form of their corresponding solvates, and, where appropriate, one or more pharmacologically compatible adjuvants.

根據本發明之藥物組合物特別適用於調控類香草素受體1-(VR1/TRPV1)，以用於抑制類香草素受體1(VR1/TRPV1)及/或用於激發類香草素受體1(VR1/TRPV1)較佳，即其具有催動或拮抗作用。 The pharmaceutical composition according to the present invention is particularly useful for regulating the vanilloid receptor 1-(VR1/TRPV1) for inhibiting vanilloid receptor 1 (VR1/TRPV1) and/or for eliciting vanilloid receptors 1 (VR1/TRPV1) is preferred, that is, it has a stimulating or antagonizing effect.

同樣地，根據本發明之藥物組合物特別適用於預防及/或治療至少部分地由類香草素受體1介導之失調或疾病。 Likewise, the pharmaceutical compositions according to the invention are particularly suitable for the prevention and/or treatment of disorders or diseases mediated at least in part by the vanilloid receptor 1 .

根據本發明之藥物組合物適合施用於成人與兒童，包括學齡前兒童及嬰幼兒。 The pharmaceutical composition according to the present invention is suitable for administration to adults and children, including preschool children and infants.

根據本發明之藥物組合物可係液體、半固體或固體藥物劑型，例如，注射液、滴劑、果汁、糖漿、噴霧劑、懸浮液、錠劑、貼布、膠囊、硬膏劑(plaster)、塞劑、軟膏、乳劑、乳液、凝膠、水乳液、氣膠(aerosol)或複粒形式，例如，丸狀或顆粒之形式，若適當，可壓製成錠劑、注入膠囊或懸浮於液體，並以此形式投藥。 The pharmaceutical composition according to the present invention may be in the form of a liquid, semi-solid or solid pharmaceutical dosage form, for example, an injection, a drop, a juice, a syrup, a spray, a suspension, a lozenge, a patch, a capsule, a plaster, Suppositories, ointments, creams, lotions, gels, aqueous emulsions, aerosols or complex forms, for example in the form of pellets or granules, if appropriate, can be compressed into tablets, infused into capsules or suspended in liquids, And in this form.

除上述化學式(I)之至少一被取代化合物之外，根據本發明之藥物組合物其傳統上含有其它生理上可接受之藥理助劑，例如，其可係選自由賦形劑、充填劑、溶媒、稀釋劑、表面活性物質、染料、防腐劑、噴離形劑(blasting agent)、助滑添加劑、潤滑劑、香料、及粘合劑組成之群組，若適當，以其純立體異構物之其中一種形式，特別是對映異構物或非對映異構物，其消旋物或立體異構物混合物之形式，特別是對映異構物或非對映異構物，於任何所需之混合比例，或若適當，於相應之鹽類或分別與其相應之溶劑化物之形式。 In addition to at least one substituted compound of the above formula (I), the pharmaceutical composition according to the invention conventionally contains other physiologically acceptable pharmacological adjuvants, for example, which may be selected from excipients, fillers, a group of solvents, diluents, surface active materials, dyes, preservatives, blasting agents, slip additives, lubricants, perfumes, and binders, if appropriate, in their pure stereoisomers One of the forms, especially the enantiomers or diastereomers, in the form of a racemate or a mixture of stereoisomers, especially enantiomers or diastereomers, Any desired mixing ratio, or if appropriate, in the form of the corresponding salt or the corresponding solvate.

生理上相容助劑之選擇及其使用劑量，取決於該藥物組合物是否經口服、皮下、非經口、靜脈內、腹膜內、皮內、肌肉內、鼻內、頰內(bucally)、經直腸或局部地投藥，例如，於治療皮膚、黏膜及眼睛感染。錠劑、糖衣藥九、膠囊、顆粒、九劑、滴劑、果汁與糖漿之製備，以適合口服應用較佳；溶液、懸浮液、易於復原之乾燥製劑及噴霧劑以適合非經口、局部性及吸入性應用較佳。用於根據本發明藥物組合物之根據本發明之被取代化合物，儲存於溶解形式或硬膏劑形式，係適合之經皮應用製劑，若適當可添加提升皮膚滲透之藥劑。口服或經皮應用製備形式可釋放根據本發明之各被取代化合物，其亦可以延緩釋放之方式被釋放。 The choice of physiologically compatible adjuvant and the dosage thereof to be used depend on whether the pharmaceutical composition is administered orally, subcutaneously, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, It is administered rectally or topically, for example, to treat skin, mucous membranes, and eye infections. Preparation of tablets, dragees, capsules, granules, nine doses, drops, juices and syrups, preferably for oral use; solutions, suspensions, easy-to-restore dry preparations and sprays for non-oral, topical Sexual and inhalation applications are preferred. The substituted compound according to the present invention for use in the pharmaceutical composition according to the present invention, which is stored in a dissolved form or in the form of a plaster, is suitable for a transdermal application, and if appropriate, an agent for enhancing skin penetration can be added. Orally or transdermally prepared forms can release the substituted compounds according to the invention, which can also be released in a manner that delays release.

根據本發明之藥物組合物係於所屬領域者已知之傳統方式、儀器、方法及製程之輔助下製備而成，例如「雷明頓之藥物科學」(“Remington’s Pharmaceutical Sciences”)，A.R.Gennaro(編輯)，第17版，麥克出版公司(Mack Publishing Company)，Easton，Pa，1985之描述，特別係第8部，第76至第93章。茲以引用及揭露方式介紹相關之描述。患者被給予之不同劑量之根據本發明上述通式(I)被取代化合物，投藥劑量係取決於，例如，患者之體重或年齡、應用方式、症狀失調嚴重度。劑量通常係0.001至100毫克/公斤，以0.05至75毫克/公斤較佳，以0.05至50毫克之至少一根據本發明之化合物相對於患者之體重(每公斤)特佳。 The pharmaceutical compositions according to the present invention are prepared with the aid of conventional means, apparatus, methods and processes known to those skilled in the art, such as "Remington's Pharmaceutical Sciences", ARGennaro (ed.) , 17th edition, described by Mack Publishing Company, Easton, Pa, 1985, in particular Part 8, Chapters 76-93. The relevant description is hereby incorporated by reference. The dose of the compound of the above formula (I) according to the present invention administered to a patient in varying doses depends on, for example, the weight or age of the patient, the mode of application, and the severity of the disorder. The dose is usually from 0.001 to 100 mg/kg, preferably from 0.05 to 75 mg/kg, and from 0.05 to 50 mg, at least one compound according to the invention is particularly preferred relative to the weight of the patient (per kg).

根據本發明之藥物組合物以適用於治療及/或預防選自由疼痛構成之一或多種失調及/或疾病較佳，以選自下列疼痛種類組成之群組較佳：急性疼痛、慢性疼痛、神經性疼痛、內臟疼痛與關節疼痛、痛覺過敏、異常性疼痛、灼痛、偏頭痛、抑鬱、緊張、軸索損傷、神經性退化疾病，以選自由多發性硬化症、阿茲海默症、帕金森氏症與亨丁頓舞蹈症組成之群組較佳，認知功能障礙，以認知缺陷較佳，尤其是記憶障礙、癲癇、呼吸系統疾病，以選自由氣喘、支氣管炎與肺部發炎組成之群組較佳，咳嗽、尿失禁、膀胱過動症(OAB)、胃腸道失調及/或損傷、十二指腸潰瘍、胃潰瘍、刺激性腸症後群、中風、眼睛刺激、皮膚刺激、神經過敏性皮膚疾病、過敏性皮膚疾病、乾癬、白斑症、單純皰疹、炎症，以腸道、眼睛、膀胱、皮膚或鼻腔黏膜發炎較佳，腹瀉、搔癢、骨質疏鬆症、關節炎、骨性關節炎、風濕性疾病、飲食異常，以選自由暴食症、惡病體質、厭食症與肥胖症組成之群組較佳，藥物依賴、藥物濫用、藥物依賴戒斷症狀、藥物耐受性之產生，以天然或合成類鴉片較佳，毒品(drug)依賴、毒品濫用、毒品依賴戒 斷症狀、酒精依賴、酒精濫用、與酒精依賴戒斷症狀、用於利尿、用於抑制尿鈉排泄、用於影響心血管系統、用於提升警覺性、用於治療傷口及/或灼傷、用於治療神經阻斷、用於提升性慾、用於調節運動活動、用於抗焦應、用於局部麻醉及/或抑制不良副作用，以選自由使用類香草素受體1(VR1/TRPV1受體)激動劑引發之發熱、高血壓與支氣管收縮組成之群組較佳，以選自由辣椒素、仙人掌毒素、奧伐尼(olvanil)、阿伐尼(arvanil)、SDZ-249665、SDZ-249482、紐伐尼(nuvanil)與卡薩伐尼(capsavanil)組成之群組較佳。 The pharmaceutical composition according to the present invention is preferably used in the treatment and/or prevention of one or more disorders and/or diseases selected from pain, preferably selected from the group consisting of acute pain, chronic pain, Neuropathic pain, visceral pain and joint pain, hyperalgesia, allodynia, burning pain, migraine, depression, nervousness, axonal injury, neurodegenerative diseases, selected from multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease group are better, cognitive dysfunction, better cognitive deficits, especially memory disorders, epilepsy, respiratory diseases, selected from asthma, bronchitis and inflammation of the lungs Groups are better, cough, urinary incontinence, overactive bladder (OAB), gastrointestinal disorders and/or injuries, duodenal ulcers, gastric ulcers, post-stimulation of pruritus, stroke, eye irritation, skin irritation, nervousness Skin diseases, allergic skin diseases, dryness, leukoplakia, herpes simplex, inflammation, inflammation of the intestines, eyes, bladder, skin or nasal mucosa, diarrhea, phlegm , osteoporosis, arthritis, osteoarthritis, rheumatic diseases, abnormal diet, selected from the group consisting of bulimia, cachexia, anorexia and obesity, drug dependence, drug abuse, drug dependence Withdrawal symptoms, drug tolerance, natural or synthetic opioids, drug dependence, drug abuse, drug dependence Symptoms, alcohol dependence, alcohol abuse, alcohol withdrawal symptoms, use in diuresis, use in inhibiting urinary sodium excretion, influencing the cardiovascular system, for alertness, for treating wounds and/or burns, For the treatment of neurological blockade, for lifting libido, for regulating motor activity, for anti-coking, for local anesthesia and/or for inhibiting adverse side effects, selected from the use of vanilloid receptor 1 (VR1/TRPV1 receptor) The group of agonist-induced fever, hypertension, and bronchoconstriction is preferably selected from the group consisting of capsaicin, cactus toxin, olvanil, arvanil, SDZ-249665, SDZ-249482, A group consisting of nuvanil and capsavanil is preferred.

根據本發明之藥物組合物適用於治療及/或預防選自由疼痛構成之一或多種失調及/或疾病，特別適用之疼痛係選自由下列疼痛組成之群組：急性疼痛、慢性疼痛、神經性疼痛、內臟疼痛與關節疼痛、偏頭痛、抑鬱、神經性退化疾病，以選自由多發性硬化症、阿茲海默症、帕金森氏症與亨丁頓舞蹈症組成之群組較佳，認知功能障礙，以認知缺陷較佳，尤其是記憶障礙，炎症，以腸道、眼睛、膀胱、皮膚或鼻腔黏膜發炎較佳，尿失禁、膀胱過動症、藥物依賴、藥物濫用、藥物依賴戒斷症狀、藥物耐受性之產生，以天然或合成類鴉片較佳，毒品依賴、毒品濫用、毒品依賴戒斷症狀、酒精依賴、酒精濫用與酒精依賴戒斷症狀。 The pharmaceutical composition according to the present invention is suitable for the treatment and/or prevention of one or more disorders and/or diseases selected from pain, and particularly suitable for pain selected from the group consisting of acute pain, chronic pain, neuropathy Pain, visceral pain and joint pain, migraine, depression, neurodegenerative diseases, selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease, cognitive Dysfunction, better cognitive deficits, especially memory impairment, inflammation, inflammation in the intestine, eyes, bladder, skin or nasal mucosa, urinary incontinence, overactive bladder, drug dependence, drug abuse, drug dependence withdrawal Symptoms, drug tolerance, natural or synthetic opioids, drug dependence, drug abuse, drug dependence withdrawal symptoms, alcohol dependence, alcohol abuse and alcohol dependence withdrawal symptoms.

根據本發明之藥物組合物適用於治療及/或預防選自由疼痛構成之一或多種失調及/或疾病，最適用之疼痛係選自由急性疼痛、慢性疼痛、神經性疼痛與內臟疼痛組成之群組。 The pharmaceutical composition according to the present invention is suitable for the treatment and/or prevention of one or more disorders and/or diseases selected from pain, and the most suitable pain is selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain. group.

本發明另涉及用於調控類香草素受體1(VR1/TRPV1)之一種根據通式(I)之被取代化合物，及若適當，一種根據通式(I)之被取代化合物及一或多種藥理可接受之助劑，以用於抑制類香草素受體1-(VR1/TRPV1)及/或激發類香草素受體1-(VR1/TRPV1)較佳。 The invention further relates to a substituted compound according to formula (I) for regulating vanilloid receptor 1 (VR1/TRPV1) and, if appropriate, a substituted compound according to formula (I) and one or more A pharmacologically acceptable adjuvant for inhibiting the vanilloid receptor 1-(VR1/TRPV1) and/or eliciting the vanilloid receptor 1-(VR1/TRPV1) is preferred.

因此，本發明另涉及用於預防及/或治療至少部分由類香草素受體1介導之失調及/或疾病之根據通式(I)之一被取代化合物，及若適當，一種根據通式(I)之被取代化合物及一或多種藥理可接受之助劑。 Accordingly, the present invention further relates to a compound according to one of the formula (I) for preventing and/or treating a disorder and/or a disease mediated at least in part by a vanilloid receptor 1 and, if appropriate, a A substituted compound of formula (I) and one or more pharmaceutically acceptable adjuvants.

本發明因此另涉及用於預防及/或治療選自由疼痛構成之失調及/或疾病之一種根據通式(I)之被取代化合物，及若適當，一種根據通式(I)之一被取代化合物及一或多種藥理可接受助劑，較適用之疼痛係選自由下列疼痛組成之群組：急性疼痛、慢性疼痛、神經性疼痛、內臟疼痛與關節疼痛、痛覺過敏、異常性疼痛、灼痛、偏頭痛、抑鬱、緊張、軸索損傷、神經性退化疾病，以選自由多發性硬化症、阿茲海默症、帕金森氏症與亨丁頓舞蹈症組成之群組較佳，認知功能障礙，以認知缺陷較佳，尤其是記憶障礙，癲癇、呼吸系統疾病，以選自由氣喘、支氣管炎與肺部發炎組成之群組較佳，咳嗽、尿失禁、膀胱過動症、胃腸道失調及/或損傷、十二指腸潰瘍、胃潰瘍、刺激性腸症後群、中風、眼睛刺激、皮膚刺激、神經過敏性皮膚疾病、過敏性皮膚疾病、乾癬、白斑症、單純皰疹、炎症，以腸道、眼睛、膀胱、皮膚或鼻腔黏膜發炎較佳，腹瀉、搔癢、骨質疏鬆症、關節炎、骨性關節炎、風濕性疾病、飲食異常，以選自由暴食症、惡病體質、厭食症與肥胖症組成之群組較佳，藥物依賴、藥物濫用、藥物依賴戒斷症狀、藥物耐受性之產生，以天然或合成類鴉片較佳，毒品依賴、毒品濫用、毒品依賴戒斷症狀、酒精依賴、酒精濫用、與酒精依賴戒斷症狀、用於利尿、用於抑制尿鈉排泄、用於影響心血管系統、用於提升警覺性、用於治療傷口及/或灼傷、用於治療神經阻斷、用於提升性慾、用於調節運動活動、用於抗焦慮、用於局部麻醉及/或抑制不良副作用，以選自由使用類香草素受體1(VR1/TRPV1受體)激 動劑引發之發熱、高血壓與支氣管收縮組成之群組較佳，以選自由辣椒素、仙人掌毒素、奧伐尼、阿伐尼、SDZ-249665、SDZ-249482、紐伐尼與卡薩伐尼組成之群組較佳。 The invention therefore further relates to a substituted compound according to formula (I) for use in the prevention and/or treatment of a disorder and/or disease selected from pain, and, if appropriate, a compound according to formula (I) The compound and one or more pharmacologically acceptable adjuvants, the more suitable pain is selected from the group consisting of acute pain, chronic pain, neuropathic pain, visceral pain and joint pain, hyperalgesia, allodynia, burning pain , migraine, depression, tension, axonal injury, neurodegenerative diseases, selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease, cognitive function Obstacles, better cognitive deficits, especially memory disorders, epilepsy, respiratory diseases, selected from the group consisting of asthma, bronchitis and lung inflammation, cough, urinary incontinence, overactive bladder, gastrointestinal disorders And/or injury, duodenal ulcer, gastric ulcer, irritating enteropathy, stroke, eye irritation, skin irritation, neuropathic skin disease, allergic skin disease, dryness, Spot, herpes simplex, inflammation, inflammation of the intestine, eyes, bladder, skin or nasal mucosa, diarrhea, itching, osteoporosis, arthritis, osteoarthritis, rheumatic diseases, abnormal diet, to choose The group consisting of free bulimia, cachexia, anorexia and obesity is better, drug dependence, drug abuse, drug dependence withdrawal symptoms, drug tolerance, natural or synthetic opioids, drug dependence , drug abuse, drug dependence withdrawal symptoms, alcohol dependence, alcohol abuse, alcohol withdrawal symptoms, use in diuresis, use in inhibiting urinary sodium excretion, influencing the cardiovascular system, for alertness, for treatment Wounds and/or burns, for the treatment of nerve blockage, for lifting libido, for regulating motor activity, for anxiolytic, for local anesthesia and/or for inhibiting adverse side effects, selected from the use of vanilloid receptor 1 (VR1/TRPV1 receptor) The group of fever, hypertension and bronchoconstriction caused by the agent is preferably selected from the group consisting of capsaicin, cactus toxin, ovanov, arva, SDZ-249665, SDZ-249482, Newvni and Kasava The group consisting of Nie is preferred.

最佳者為用於預防及/或治療疼痛之一種根據通式(I)之被取代化合物，及若適當，一種根據通式(I)之被取代化合物及一或多種藥理可接受之助劑，較適用之疼痛係選自由急性疼痛、慢性疼痛、神經性疼痛與內臟疼痛組成之群組。 Preferred is a substituted compound according to formula (I) for the prevention and/or treatment of pain and, if appropriate, a substituted compound according to formula (I) and one or more pharmaceutically acceptable adjuvants The more suitable pain is selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain.

本發明進一步涉及使用至少一種根據通式(I)之化合物，及若適當，一或多種藥理可接受之助劑於製備調節類香草素受體1(VR1/TRPV1)之藥物組合物，以抑制類香草素受體1(VR1/TRPV1)及/或激發類香草素受體1(VR1/TRPV1)較佳，及進一步用於預防及/或治療至少部分由類香草素受體1介導之失調及/或疾病，例如，選自由疼痛構成之失調及/或疾病，較適用之疼痛係選自由下列疼痛組成之群組：急性疼痛、慢性疼痛、神經性疼痛、內臟疼痛與關節疼痛、痛覺過敏、異常性疼痛、灼痛、偏頭痛、抑鬱、緊張、軸索損傷、神經性退化疾病，以選自由多發性硬化症、阿茲海默症、帕金森氏症與亨丁頓舞蹈症組成之群組較佳，認知功能障礙，以認知缺陷較佳，尤其是記憶障礙，癲癇、呼吸系統疾病，以選自由氣喘、支氣管炎與肺部發炎組成之群組較佳，咳嗽、尿失禁、膀胱過動症、胃腸道失調及/或損傷、十二指腸潰瘍、胃潰瘍、刺激性腸症後群、中風、眼睛刺激、皮膚刺激、神經過敏性皮膚疾病、過敏性皮膚疾病、乾癬、白斑症、單純皰疹、炎症，以腸道、眼睛、膀胱、皮膚或鼻腔黏膜發炎較佳，腹瀉、搔癢、骨質疏鬆症、關節炎、骨性關節炎、風濕性疾病、飲食異常，以選自由暴食症、惡病體質、厭食症與肥胖症組成之群組較佳，藥物依賴、藥物濫用、藥物依賴戒斷症狀、藥物耐受性之產生，以 天然或合成類鴉片較佳，毒品依賴、毒品濫用、毒品依賴戒斷症狀、酒精依賴、酒精濫用與酒精依賴戒斷症狀、用於利尿、用於抑制尿鈉排泄、用於影響心血管系統、用於提升警覺性、用於治療傷口及/或灼傷、用於治療神經阻斷、用於提升性慾、用於調節運動活動、用於抗焦應、用於局部麻醉及/或抑制不良副作用，以選自由使用類香草素受體1(VR1/TRPV1受體)激動劑引發之發熱、高血壓與支氣管收縮組成之群組較佳，以選自由辣椒素、仙人掌毒素、奧伐尼、阿伐尼、SDZ-249665、SDZ-249482、紐伐尼與卡薩伐尼組成之群組較佳。 The invention further relates to the use of at least one compound according to formula (I), and if appropriate one or more pharmaceutically acceptable adjuvants, for the preparation of a pharmaceutical composition for regulating vanilloid receptor 1 (VR1/TRPV1) for inhibition Vanilloid receptor 1 (VR1/TRPV1) and/or elicited vanilloid receptor 1 (VR1/TRPV1) is preferred, and is further useful for the prevention and/or treatment of at least in part by vanilloid receptor 1 Disorders and/or diseases, for example, selected from disorders and/or diseases consisting of pain, the more suitable pain being selected from the group consisting of acute pain, chronic pain, neuropathic pain, visceral pain and joint pain, pain sensation Allergies, allodynia, burning pain, migraine, depression, tension, axonal injury, neurodegenerative diseases, selected from multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease The group is better, cognitive dysfunction, better cognitive deficits, especially memory disorders, epilepsy, respiratory diseases, preferably selected from the group consisting of asthma, bronchitis and lung inflammation, cough, urinary incontinence, Bladder Symptoms, gastrointestinal disorders and/or injuries, duodenal ulcers, gastric ulcers, post-stimulation of irritation, stroke, eye irritation, skin irritation, neuropathic skin diseases, allergic skin diseases, dryness, leukoplakia, herpes simplex, Inflammation, inflammation of the mucous membranes of the intestines, eyes, bladder, skin or nasal cavity, diarrhea, itching, osteoporosis, arthritis, osteoarthritis, rheumatic diseases, abnormal diet, selected from bulimia nervosa, cachexia The group consisting of anorexia and obesity is better, drug dependence, drug abuse, drug dependence withdrawal symptoms, drug tolerance, Natural or synthetic opioids are better, drug dependence, drug abuse, drug dependence withdrawal symptoms, alcohol dependence, alcohol abuse and alcohol dependence withdrawal symptoms, use in diuresis, use in inhibiting urinary sodium excretion, affecting the cardiovascular system, Used for alertness, for treating wounds and/or burns, for treating nerve blockage, for lifting libido, for regulating motor activity, for anti-coking, for local anesthesia and/or for inhibiting adverse side effects, Preferably, the group consisting of fever, hypertension, and bronchoconstriction induced by the use of a vanilloid receptor 1 (VR1/TRPV1 receptor) agonist is selected from the group consisting of capsaicin, cactus toxin, ovanov, and arva The group consisting of Ni, SDZ-249665, SDZ-249482, Newvni and Kasavini is preferred.

本發明另一方面為調控類香草素受體1(VR1/TRPV1)之方法，以抑制類香草素受體1(VR1/TRPV1)及/或激發類香草素受體1(VR1/TRPV1)較佳，及一種治療及/或預防哺乳動物中，至少部分由類香草素受體1介導之失調及/或疾病之方法，以選自由疼痛構成之失調及/或疾病群組較佳，較適用之疼痛係選自由下列疼痛組成之群組：急性疼痛、慢性疼痛、神經性疼痛、內臟疼痛與關節疼痛、痛覺過敏、異常性疼痛、灼痛、偏頭痛、抑鬱、緊張、軸索損傷、神經性退化疾病，以選自由多發性硬化症、阿茲海默症、帕金森氏症與亨丁頓舞蹈症組成之群組較佳，認知功能障礙，以認知缺陷較佳，尤其是記憶障礙，癲癇、呼吸系統疾病，以選自由氣喘、支氣管炎與肺部發炎組成之群組較佳，咳嗽、尿失禁、膀胱過動症、胃腸道失調及/或損傷、十二指腸潰瘍、胃潰瘍、刺激性腸症後群、中風、眼睛刺激、皮膚刺激、神經過敏性皮膚疾病、過敏性皮膚疾病、乾癬、白斑症、單純皰疹、炎症，以腸道、眼睛、膀胱、皮膚或鼻腔黏膜發炎較佳，腹瀉、搔癢、骨質疏鬆症、關節炎、骨性關節炎、風濕性疾病、飲食異常，以選自由暴食症、惡病體質、厭食症與肥胖症組成之群組較佳，藥物依賴、 藥物濫用、藥物依賴戒斷症狀、藥物耐受性之產生，以天然或合成類鴉片較佳，毒品依賴、毒品濫用、毒品依賴戒斷症狀、酒精依賴、酒精濫用與酒精依賴戒斷症狀、用於利尿、用於抑制尿鈉排泄、用於影響心血管系統、用於提升警覺性、用於治療傷口及/或灼傷、用於治療神經阻斷、用於提升性慾、用於調節運動活動、用於抗焦慮、用於局部麻醉及/或抑制不良副作用，以選自由使用類香草素受體1(VR1/TRPV1受體)激動劑引發之發熱、高血壓與支氣管收縮組成之群組較佳，以選自由辣椒素、仙人掌毒素、奧伐尼、阿伐尼、SDZ-249665、SDZ-249482、紐伐尼與卡薩伐尼組成之群組較佳，其包含給予哺乳動物一有效劑量之根據通式(I)之至少一化合物。 Another aspect of the invention is a method for regulating vanilloid receptor 1 (VR1/TRPV1) to inhibit vanilloid receptor 1 (VR1/TRPV1) and/or to stimulate vanilloid receptor 1 (VR1/TRPV1). Preferably, and a method of treating and/or preventing a disorder, and/or disease mediated by at least a portion of the vanilloid receptor 1 in a mammal, preferably selected from the group consisting of disorders and/or diseases consisting of pain. Suitable pain is selected from the group consisting of acute pain, chronic pain, neuropathic pain, visceral pain and joint pain, hyperalgesia, allodynia, burning pain, migraine, depression, tension, axonal injury, Neurodegenerative disease, preferably selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease, cognitive dysfunction, better cognitive deficits, especially memory impairment , epilepsy, respiratory diseases, selected from the group consisting of asthma, bronchitis and inflammation of the lungs, cough, urinary incontinence, overactive bladder, gastrointestinal disorders and / or injuries, duodenal ulcer, gastric ulcer, irritation Post-intestinal group Stroke, eye irritation, skin irritation, neuropathic skin disease, allergic skin disease, dryness, leukoplakia, herpes simplex, inflammation, inflammation of the intestines, eyes, bladder, skin or nasal mucosa, diarrhea, itching, Osteoporosis, arthritis, osteoarthritis, rheumatic diseases, abnormal diet, preferably selected from the group consisting of bulimia, cachexia, anorexia and obesity, drug dependence, Drug abuse, drug dependence withdrawal symptoms, drug tolerance, natural or synthetic opioids, drug dependence, drug abuse, drug dependence withdrawal symptoms, alcohol dependence, alcohol abuse and alcohol dependence withdrawal symptoms, use Diuretic, for inhibiting urinary sodium excretion, for influencing the cardiovascular system, for alertness, for treating wounds and/or burns, for treating nerve block, for lifting libido, for regulating exercise, For anti-anxiety, for local anesthesia, and/or for inhibiting adverse side effects, preferably selected from the group consisting of fever, hypertension, and bronchoconstriction induced by the use of a vanilloid receptor 1 (VR1/TRPV1 receptor) agonist. Preferably, it is selected from the group consisting of capsaicin, cactus toxin, ovanovin, arsenic, SDZ-249665, SDZ-249482, novatin and casafani, which comprises administering to the mammal an effective dose. At least one compound according to formula (I).

對抗疼痛之效力如Bennett或Chung模式(Bennett or Chung model)(Bennett，G.J.及Xie,Y.K.，如見於人類之大鼠周圍單一神經病變引發之痛覺障礙(A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man)，疼痛期刊(Pain)1988,33(1),87-107；Kim,S.H.及Chung,J.M.，大鼠周圍神經病變模式之脊神經結扎實驗模式(An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat)，疼痛期刊(Pain)1992,50(3),355-363)之閃尾實驗(例如，根據D'Amour及Smith(藥理學與實驗治療學期刊(J.Pharm.Exp.Ther.)72,74 79(1941))，或福馬林測試(例如，根據D.Dubuisson et al.，疼痛期刊(Pain)1977,4,161-174)所示。 Bennett as the efficacy against pain or the Chung model (Bennett or Chung model) (Bennett , GJ and Xie, YK, pain disorders as seen around the human initiator of mononeuropathy in rat (A peripheral mononeuropathy in rat that produces disorders of pain sensation Like those seen in man), Pain 1988, 33(1), 87-107; Kim, SH and Chung, JM, an experimental model for peripheral neuropathy By segmental spinal nerve ligation in the rat, Pain 1992, 50 (3), 355-363) (eg, according to D'Amour and Smith (Journal of Pharmacology and Experimental Therapeutics (J. Pharm. Exp. Ther.) 72, 74 79 (1941)), or the formalin test (for example, according to D. Dubuisson et al., Pain 1977, 4, 161-174).

本發明進一步涉及製備上述本發明通式(I)化合物之方法。 The invention further relates to a process for the preparation of the abovementioned compounds of the general formula (I) according to the invention.

尤其，根據本發明通式(I)之化合物，可以根據通式(II)之至少一化合物製備而成， 其R1、R2、R3、R3a與n具有前述之意義，其係於一反應介質中，若適當，於至少一適合之偶合試劑存在之條件下，若適當，於至少一鹼基存在之條件下，與一通式(III)之化合物反應，其D=OH或Hal， 其Hal代表一鹵素，以代表溴或氯較佳，及R4a、Y、T1、U1、V、T2與U2各自具有前述意義其中一種意義，及Z代表C-R4b，其中，R4b具有前述意義其中一種意義，其於一反應介質中，若適當，於至少一適合之偶合試劑存在之條件下，若適當，於至少一鹼基存在之條件下，形成通式(I)之化合物， 其Z代表CR4b而R1、R2、R3、R3a、R4a、R4b、Y、T1、U1、V、T2與U2及n具有前述意義其中一種意義；或於至少一通式(II)之化合物中， 其R1、R2、R3、R3a與n具有前述意義其中一種意義，其經反應形成一通式(IV)之化合物 其R1、R2、R3、R3a與n具有前述意義其中一種意義，其於一反應介質中、於氯甲酸苯酯存在之條件下、若適當，於至少一鹼基及/或至少一偶合試劑存在之條件下，若適當，將該化合物純化及/或分離，並將一通式(IV)之化合物與一通式(V)之化合物進行反應， 其R4a、T1、U1、V、T2與U2具有前述意義其中一種意義，及Z代表N，於一反應介質中，若適當，於至少一適合之偶合試劑存在之條件下，若適當，於至少一鹼基存在之條件下，形成一通式(I)之化合物， 其Z代表N及R1、R2、R3、R3a、R4a、Y、T1、U1、V、T2與U2及具有前述意義其中一種意義。 In particular, the compound of the formula (I) according to the invention may be prepared according to at least one compound of the formula (II). R 1 , R 2 , R 3 , R 3a and n have the aforementioned meanings, which are in a reaction medium, if appropriate, in the presence of at least one suitable coupling reagent, if appropriate, at least one base In the presence of a reaction with a compound of formula (III), D = OH or Hal, Hal thereof represents a halogen to represent bromine or chlorine, and R 4a , Y, T 1 , U 1 , V, T 2 and U 2 each have one of the aforementioned meanings, and Z represents CR 4b , wherein R 4b has one of the above meanings, in a reaction medium, if appropriate, in the presence of at least one suitable coupling reagent, if appropriate, in the presence of at least one base, to form a formula (I) Compound, Z represents CR 4b and R 1 , R 2 , R 3 , R 3a , R 4a , R 4b , Y, T 1 , U 1 , V, T 2 and U 2 and n have one of the aforementioned meanings; In at least one compound of the formula (II), Its R 1 , R 2 , R 3 , R 3a and n have one of the aforementioned meanings, which are reacted to form a compound of the formula (IV) R 1 , R 2 , R 3 , R 3a and n have one of the aforementioned meanings, in a reaction medium, in the presence of phenyl chloroformate, if appropriate, at least one base and/or at least The compound is purified and/or isolated, if appropriate, in the presence of a coupling reagent, and a compound of the formula (IV) is reacted with a compound of the formula (V). And R 4a , T 1 , U 1 , V, T 2 and U 2 have one of the foregoing meanings, and Z represents N, in a reaction medium, if appropriate, in the presence of at least one suitable coupling reagent, If appropriate, a compound of the formula (I) is formed in the presence of at least one base, Z represents N and R 1 , R 2 , R 3 , R 3a , R 4a , Y, T 1 , U 1 , V, T 2 and U 2 and has one of the aforementioned meanings.

上述通式(II)與(V)之化合物與上述通式(III)之羧酸，特別是與D=OH，進行反應以產生上述通式(I)之化合物，該反應以於選自由二乙醚、四氫呋喃、乙腈、甲醇、乙醇、(1,2)-二氯乙烷、二甲基甲醯胺、二氯甲烷與相應之混合物組成之反應介質群組中進行進行較佳，若適當，於至少一偶合試劑之存在之條件下，以選自由1-苯並三唑基氧代-三-(二甲胺基)-六氟磷酸鹽(1-benzotriazolyloxy-tris-(dimethylamino)-phosphonium hexafluorophosphate，BOP)、二環己碳二醯亞胺(dicyclohexylcarbodiimide，DCC)、N’-(3-二甲胺基丙基)-N-乙基碘化二亞胺(N’-(3-dimethylaminopropyl)-N-ethylcarbodiimide，EDCI)、二異丙醚碳二醯亞胺(diisopropylcarbodiimide)、1,1’-羰基二咪唑(1,1’-carbonyldiimidazole，CDI)、N-[(二甲胺基)-1H-1,2,3-三唑並[4,5-b]啶並-1-基-甲烯]-N-甲基甲烷銨六氟磷酸鹽N-氧化物 (N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridino-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate N-oxide，HATU)、O-(苯並三唑-1-基)-N,N,N‘,N‘-四甲基脲六氟磷酸鹽(O-(benzotriazol-1-yl)-N,N,N‘,N‘-tetramethyluronium tetrafluoroborate，TBTU)、N-羥苯並三唑(N-hydroxybenzotriazole，HOBt)與1-羥基-7-氮雜苯並三氮唑(1-hydroxy-7-azabenzotriazole，HOAt)組成之群組較佳，若適當，於至少一有機鹼存在之條件下，以選自由三乙胺、啶基、二甲基胺基啶、N-甲基嗎啉基與二異丙醚乙胺組成之群組較佳，以介於-70℃至100℃之間之溫度中進行較佳。 The above compounds of the formulae (II) and (V) are reacted with a carboxylic acid of the above formula (III), in particular with D = OH, to give a compound of the above formula (I), the reaction being selected from the group consisting of Preferably, in the reaction medium group consisting of diethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, (1,2)-dichloroethane, dimethylformamide, dichloromethane and the corresponding mixture, if appropriate, 1-benzotriazolyloxy-tris-(dimethylamino)-phosphonium hexafluorophosphate is selected from the group consisting of 1-benzotriazolyloxy-tris-(dimethylamino)-phosphonium hexafluorophosphate in the presence of at least one coupling reagent , BOP), dicyclohexylcarbodiimide (DCC), N'-(3-dimethylaminopropyl)-N-ethyl iodide diimide (N'-(3-dimethylaminopropyl) -N-ethylcarbodiimide, EDCI), diisopropylcarbodiimide, 1,1'-carbonyldiimidazole (CDI), N-[(dimethylamino)- 1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-mene]-N-methylmethaneammonium hexafluorophosphate N-oxide (N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridino-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate N-oxide, HATU), O-(benzotriazole) Zin-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate,TBTU ), N-hydroxybenzotriazole (HOBt) and 1-hydroxy-7-azabenzotriazole (HOAt) are better grouped, if appropriate , in the presence of at least one organic base, preferably selected from the group consisting of triethylamine, pyridine, dimethylaminopyridine, N-methylmorpholinyl and diisopropyl ether ethylamine It is preferred to carry out a temperature between -70 ° C and 100 ° C.

或者，上述通式(II)與(V)之化合物與上述通式(III)中D=Hal之羧酸鹵化物進行反應，其Hal代表一做為脫離基之鹵素，以代表氯或溴原子較佳，以形成上述通式(I)之化合物，該反應係於一反應介質中進行，以選自由二乙醚、四氫呋喃、乙腈、甲醇、乙醇、二甲基甲醯胺、二氯甲烷與相應之混合物組成之群組較佳，若適當，於一有機鹼或無機鹼存在之條件下，以選自由三乙胺、二甲胺基啶、啶基與二異丙胺組成之群組較佳，以介於-70℃至100℃之間之溫度中進行較佳。 Alternatively, the above compounds of the formulae (II) and (V) are reacted with a carboxylic acid halide of D = Hal in the above formula (III), wherein Hal represents a halogen as a leaving group to represent a chlorine or bromine atom. Preferably, to form a compound of the above formula (I), the reaction is carried out in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, dimethylformamide, dichloromethane and corresponding Preferably, the group of the mixture is, if appropriate, in the presence of an organic base or an inorganic base, preferably selected from the group consisting of triethylamine, dimethylaminopyridine, pyridine and diisopropylamine. It is preferably carried out at a temperature between -70 ° C and 100 ° C.

上述通式(II)、(III)、(IV)與(V)之化合物分別可藉由商購取得，及/或以熟知此技術領域者已知之常規方法製備而成。尤其，製備該化合物之方法係例如WO 2010/127855-A2與WO 2010/127856-A2所揭露。該引證文件之相應部分於此視為揭露之一部分。 The above compounds of the formulae (II), (III), (IV) and (V) are each commercially available and/or prepared by conventional methods known to those skilled in the art. In particular, the process for the preparation of this compound is disclosed, for example, in WO 2010/127855-A2 and WO 2010/127856-A2. Corresponding parts of this reference document are hereby considered to be part of the disclosure.

所有可應用於合成根據本發明化合物之反應，可各自於熟知此技術領域者所知之常規條件進性，例如，關於壓力或添加化合物之順序。若適當，熟知此技術領域者可藉由進行初步測試，判 斷各條件之最佳程序。以本文描述之反應得到之中間及最終產物各自可被純化及/或分離，若需要及/或必要，可採用熟知此技術領域者已知之常規方法。適用之純化程序，例如萃取程序及層析法程序，係如管柱色層分析或製備色層分析。所有可應用於合成根據本發明化合物之反應順序之處理步驟，及相應之中間或最終產物之純化及/或分離，可部分地或完全地於惰性氣體氣氛中進行，以於氮氣氣氛下進行較佳。 All of the reactions which can be applied to the synthesis of the compounds according to the invention can each be carried out in conventional conditions well known to those skilled in the art, for example, with regard to pressure or the order in which the compounds are added. If appropriate, those skilled in the art can judge by doing preliminary tests. The best procedure for breaking each condition. The intermediate and final products obtained by the reactions described herein can each be purified and/or isolated, and if desired and/or necessary, conventional methods known to those skilled in the art can be employed. Suitable purification procedures, such as extraction procedures and chromatography procedures, such as column chromatography or preparative chromatography. All treatment steps which can be applied to the synthesis of the reaction sequence of the compounds according to the invention, and the purification and/or separation of the corresponding intermediate or final products, can be carried out partially or completely in an inert gas atmosphere for comparison under a nitrogen atmosphere. good.

根據本發明之被取代化合物可以其自由鹼、其自由基之兩種形式分離，亦可以與其相應之鹽類之形式分離，尤其是生理上相容之鹽類，即生理可接受之鹽類。 The substituted compound according to the present invention may be isolated in the form of a free base or a free radical thereof, or may be isolated from the form of its corresponding salt, especially a physiologically compatible salt, i.e., a physiologically acceptable salt.

與根據本發明之被取代化合物相應之自由鹼可被轉換為相應之鹽類，以生理上相容之鹽類較佳，例如，藉由將其與無機或有機酸反應，以氫氯酸、氫溴酸、硫酸、甲基磺酸、對甲苯磺酸、碳酸、甲酸、醋酸、草酸、丁二酸、酒石酸、杏仁酸、丁烯酸、馬來酸、乳酸、檸檬酸、麩胺酸、糖質酸、單甲基癸二酸、5-氧脯氨酸、己烷-1-磺酸、菸鹼酸、2-、3-或4-氨基苯酸、2,4,6-三甲基苯甲酸、α-硫辛酸、乙醯甘胺酸、馬尿酸、磷酸及/或天冬胺酸。上述通式(I)之各被取代化合物及相應異體異構物之自由鹼，同樣可藉由利用一自由酸或糖類添加劑之鹽類，例如，糖精、甜蜜素(cyclamate)或丁磺氨(acesulphame)，將其轉換為相應之生理上相容之鹽類。 The free base corresponding to the substituted compound according to the present invention can be converted into the corresponding salt, preferably a physiologically compatible salt, for example, by reacting it with an inorganic or organic acid, with hydrochloric acid, Hydrobromic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, crotonic acid, maleic acid, lactic acid, citric acid, glutamic acid, Glycolic acid, monomethyl sebacic acid, 5-oxoproline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethyl Benzoic acid, alpha-lipoic acid, acetaminoglycolic acid, hippuric acid, phosphoric acid and/or aspartic acid. The free radicals of the above-mentioned substituted compounds of the general formula (I) and the corresponding isomers can likewise be obtained by using a salt of a free acid or a sugar additive, for example, saccharin, cyclamate or sulfonamide ( Acesulphame), which is converted to the corresponding physiologically compatible salt.

同樣地，根據本發明被取代化合物之自由酸，可藉由與合適之鹼反應，而被轉換為相應之生理上相容之鹽類。實例包括鹼金屬鹽、鹼土金屬鹽或銨鹽類[NHxR4-x]+，其x=0、1、2、3或4，而R代表一支鏈或無支鏈C1-4脂族殘基。 Likewise, the free acid of the substituted compound according to the present invention can be converted to the corresponding physiologically compatible salt by reaction with a suitable base. Examples include alkali metal salts, alkaline earth metal salts or ammonium salts [NH x R 4-x ] + , where x = 0, 1, 2, 3 or 4, and R represents a chain or an unbranched C 1-4 Aliphatic residue.

根據本發明之被取代化合物及相應之立體異構物，若適當， 可如與該化合物相應之酸、相應之鹼或鹽類般，採用熟知此技術領域者已知之常規方法獲得其溶劑化物之形式，以其水合物之形式較佳。 Substituted compounds and corresponding stereoisomers according to the invention, if appropriate, The form of the solvate can be obtained in the form of a hydrate thereof by a conventional method known to those skilled in the art, such as an acid, a corresponding base or a salt corresponding to the compound.

於製備後，若所獲得之根據本發明之被取代化合物為立體異構物混合物之形式，以其消旋物或其它各種對映異構物及/或非對映異構物之形式較佳，可利用熟知此技術領域者已知之常規方法將其分離。實例包括色層分離法，特別是於正常壓力或較高壓力下使用液相色層分析法，以中壓色層分析法(MPLC)與高效能液相層析法(HPLC)較佳，亦可採用分離結晶法(fractional crystallisation)。所述之方法可使個別對映異構物彼此分離，例如以對掌性固定相高效能液相層析法，或以對掌性酸類結晶之方式形成之非對映異構物鹽類，如(+)-酒石酸、(-)-酒石酸或(+)-10-樟腦磺酸。 After preparation, if the substituted compound obtained according to the invention is in the form of a mixture of stereoisomers, it is preferably in the form of its racemate or other various enantiomers and/or diastereomers. It can be separated by conventional methods known to those skilled in the art. Examples include chromatographic separation methods, especially liquid chromatography based on normal pressure or higher pressure, preferably by medium pressure chromatography (MPLC) and high performance liquid chromatography (HPLC). Fractional crystallisation can be employed. The method allows the individual enantiomers to be separated from one another, for example, by high performance liquid chromatography for palmate stationary phase or by diastereomeric salts formed by crystallisation of palmitic acid. Such as (+)-tartaric acid, (-)-tartaric acid or (+)-10-camphorsulfonic acid.

用於如下描述之反應及方法之化學品及反應成分可藉由商購取得，或可分別以熟知此技術領域者已知之常規方法製備而成。 The chemicals and reaction components used in the reactions and methods described below are commercially available or can be prepared by conventional methods well known to those skilled in the art.

通用反應方案(方案1)：General Reaction Scheme (Scheme 1):

於步驟j01，可採用熟知此技術領域者所熟悉之方法，將酸性鹵化物J-0以甲醇酯化，其Hal以代表氯或溴較佳，以形成化合物J-I。 In step j01 , acid halide J-0 can be esterified with methanol using a method well known to those skilled in the art, and Hal is preferably represented by chlorine or bromine to form compound JI .

於步驟j02，可採用熟知此技術領域者所熟悉之方法，將二甲基丙酸甲酯(methyl pivalate)J-I轉化為氧代烷基腈J-II，例如使用烷基腈R3CH2-CN，若適當，於鹼基存在之情況下進行。 In step j02 , methyl pivalate JI can be converted to oxoalkyl nitrile J-II by methods well known to those skilled in the art, for example using alkyl nitrile R 3 CH 2 - CN, if appropriate, is carried out in the presence of a base.

於步驟j03，可採用熟知此技術領域者所熟悉之方法，將化合物J-II轉化為被以胺基取代之吡唑基衍生物J-III，較佳為氯化例如使用聯胺水合物進行環化作用。 In step j03 , the compound J-II can be converted to the pyrazolyl derivative J-III substituted with an amine group by a method well known to those skilled in the art, preferably by chlorination using, for example, a hydrazine hydrate. Cyclization.

於步驟j04，可採用熟知此技術領域者所熟悉之方法，先將胺基化合物J-III轉化為重氮鹽，例如使用亞硝酸，並可藉由使用氰化物將氮排除，以將重氮鹽轉化為被氰基取代之吡唑化合物J-IV，若適當，於一偶合試劑存在之條件下進行。 In step j04 , the amine compound J-III can be first converted to a diazonium salt by a method well known to those skilled in the art, for example, using nitrous acid, and the nitrogen can be removed by using cyanide to remove the diazonium salt. Conversion to a pyrazole compound J-IV substituted with a cyano group, if appropriate, in the presence of a coupling reagent.

於步驟j05，可採用熟知此技術領域者所熟悉之方法，於N位置對化合物J-IV進行取代，例如使用一鹵化物R1-Hal，若適當，於一鹼基或一偶合試劑存在之條件下進行，其中，Hal以代表氯、溴或碘較佳，或使用一硼酸B(OH)2R1或一相應之硼酸酯，若適當，於一偶合試劑及/或一鹼基存在之條件下進行，以此方法獲得化合物J-V。若R1係經由一雜原子與通式(I)連結(例如，若R1代表(T-1)子結構，其o代表1，及尤其E代表O、S、S(=O)2、NH-C(=O)或NR11)，則可使用熟知此技術領域者已知之方法進行取代，例如，於羥胺-O-磺酸之輔助下，隨即將其轉化為二級或三級胺，其中，E=NR11(例如WO 2010/127855-A2與WO 2010/127856-A2之描述)。於E=O之情況下，可採用熟知此技術領域者已知之方法進行取代，例如於過氧試劑之輔助下，隨即將其轉化為乙醚。於E =S(=O)2之情況下，例如，該取代反應可藉由將磺醯氯磺醯化進行。於E=S之情況下，例如，可將其與二硫化物反應或與亞磺醯氯或磺醯胺反應以進行製備，或以熟知此技術領域者已知之方法將其轉化為硫醇，隨後將其轉化為硫醚。 In step j05 , compound J-IV can be substituted at the N position by methods well known to those skilled in the art, for example using a monohalide R 1 -Hal, if appropriate, in the presence of a base or a coupling reagent. Under conditions, wherein Hal is preferably represented by chlorine, bromine or iodine, or a boronic acid B(OH) 2 R 1 or a corresponding boronic acid ester, if appropriate, in a coupling reagent and/or a base Under the conditions, the compound JV was obtained in this way. If R 1 is bonded to the formula (I) via a hetero atom (for example, if R 1 represents a (T-1) substructure, o represents 1 and especially E represents O, S, S(=O) 2 , NH-C(=O) or NR 11 ) can be substituted by methods known to those skilled in the art, for example, with the aid of hydroxylamine-O-sulfonic acid, which is subsequently converted to a secondary or tertiary amine. Wherein E = NR 11 (for example, the description of WO 2010/127855-A2 and WO 2010/127856-A2). In the case of E = O, substitution can be carried out by methods known to those skilled in the art, for example, with the aid of a peroxygen reagent, followed by conversion to diethyl ether. In the case of E = S(=O) 2 , for example, the substitution reaction can be carried out by deuteration of sulfonium chlorosulfonate. In the case of E = S, for example, it may be reacted with a disulfide or with sulfinium chloride or sulfoximine to prepare, or converted to a mercaptan by methods known to those skilled in the art. It is then converted to a thioether.

或者，可採用第二合成途徑，首先以熟知此技術領域者已知之方法，於步驟k01中將一酯基K-0還原成醛基K-I，例如使用適合之氫化試劑，例如金屬氫化物即適合用於製備化合物J-V。 Alternatively, a second synthetic route can be employed, first reducing the monoester K-0 to the aldehyde group KI in step k01 by methods known to those skilled in the art, for example using a suitable hydrogenating reagent, such as a metal hydride. Used to prepare compound JV .

於步驟k02，可採用熟知此技術領域者已知之方法，將醛基K-I與步驟k05所獲得之聯氨K-V，由一級胺K-IV開始反應，以熟知此技術領域者已知之方法將水排除，以產生聯氨K-II。 In step k02 , the aldehyde group KI can be reacted with the hydrazine KV obtained in step k05 by a method known to those skilled in the art, starting from the primary amine K-IV , and the water can be excluded by a method known to those skilled in the art. To produce hydrazine K-II .

於步驟k03，可以熟知此技術領域者已知之方法，於保持雙鍵完整之情況下，將聯氨K-II鹵化，較佳為氯化例如使用如以NCS之氯化試劑，即可獲得化合物K-III。 In step k03 , a method known to those skilled in the art can be well known, and the hydrazine K-II can be halogenated, preferably chlorinated, for example, using a chlorinating reagent such as NCS, while maintaining the double bond intact. K-III .

於步驟k04，可利用熟知此技術領域者已知之方法，將聯氨鹵化物(hydrazonoyl halide)K-III轉化為氰基取代化合物J-V，例如使用以鹵素取代腈基進行環化作用。 In step k04 , the hydrazonoyl halide K-III can be converted to the cyano substituted compound JV by methods well known to those skilled in the art, for example, by halogenation in place of a nitrile group for cyclization.

於步驟j06，可採用熟知此技術領域者已知之方法，將化合物J-V氫化，例如使用一適合之催化劑，如鈀/活性炭或使用適合之氫化試劑，即可以此方法獲得化合物(II)，其中，R3a係H。或者，於進行j07之前，可採用熟知此技術領域者已知之方法，將一未被取代，或被單取代或多取代之C1-4脂族殘基帶入胺(II)，其R3a≠H，例如一基胺脂單烷化。 In step j06 , compound JV can be hydrogenated by a method known to those skilled in the art, for example, using a suitable catalyst such as palladium/activated carbon or using a suitable hydrogenating reagent to obtain compound ( II ). R 3a is H. Alternatively, an unsubstituted, or monosubstituted or polysubstituted C 1-4 aliphatic residue can be introduced into the amine ( II ) prior to the completion of j07 by a method known to those skilled in the art, and R 3a ≠ H, for example a monoamine, is monoalkylated.

於步驟j07，可採用熟知此技術領域者已知之方法，將化合物(II)轉化為化合物(IV)，例如使用氯甲酸苯酯，若適當，於一偶合試劑及/或一鹼基存在之條件下進行。除本文所揭示、使用氯甲酸苯酯製備不對稱尿素之方法以外，亦可使用熟知此技術領域者所 熟悉之其它方法，若適當，基於使用活性碳酸衍生物或異氰酸鹽之方法。 In step j07 , compound ( II ) can be converted to compound ( IV ) by methods well known to those skilled in the art, for example, using phenyl chloroformate, if appropriate, in the presence of a coupling reagent and/or one base. Go on. In addition to the methods disclosed herein for the preparation of asymmetric urea using phenyl chloroformate, other methods well known to those skilled in the art can be used, if appropriate, based on the use of an active carbonic acid derivative or isocyanate.

於步驟j08，胺(V)可被轉化為尿素化合物(I)(其中，Z=N)。此項反應可藉由使用熟知此技術領域者所熟悉之方法，將其與(IV)進行反應而達成，若適當，於鹼基存在之條件下進行。 In step j08 , the amine ( V ) can be converted to the urea compound ( I ) (wherein Z = N). This reaction can be carried out by reacting it with ( IV ) using a method well known to those skilled in the art, and if appropriate, in the presence of a base.

於步驟j09，胺(II)可被轉化為醯胺(I)(其中，Z=C-R4b)。例如，此項反應可採用熟知此技術領域者所熟悉之方法，藉由將其與一酸鹵化物進行反應而達成，以化學式(III)之氯較佳，其D=Hal，若適當，於一鹼基存在之條件下進行，或藉由將其與一化學式(III)之酸進行反應，其D=OH，若適當，於一適合之偶合試劑存在之條件下進行，例如，N-[(二甲胺基)-1H-1,2,3-三唑並[4,5-b]啶並-1-基-甲烯]-N-甲基甲烷銨六氟磷酸鹽N-氧化物或1,1’-羰基二咪唑，若適當，可添加一鹼基。此外，可採熟知此技術領域者所熟悉之方法，藉由化合物(IIIa)之反應，將胺(II)轉化為醯胺(I)(其中，Z=C-R4b)，若適當，於一鹼基存在之條件下進行。 In step j09 , the amine ( II ) can be converted to the indoleamine ( I ) (wherein Z = CR 4b ). For example, the reaction can be carried out by reacting it with an acid halide using a method well known to those skilled in the art, preferably having a chlorine of the formula ( III ), D = Hal, if appropriate, Performing in the presence of one base, or by reacting it with an acid of formula ( III ), D = OH, if appropriate, in the presence of a suitable coupling reagent, for example, N-[ (dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-mene]-N-methylmethaneammonium hexafluorophosphate N-oxide Or 1,1 '-carbonyldiimidazole, if appropriate, one base may be added. In addition, the amine ( II ) can be converted to the guanamine ( I ) (wherein Z = CR 4b ) by the reaction of the compound ( IIIa ) by a method familiar to those skilled in the art, and if appropriate, a base The base is carried out under the conditions of existence.

根據通式(I)之化合物，其中，Z=N，可進一步以根據通用反應方案2之反應順序製備而成。 According to the compound of the formula ( I ), wherein Z = N, it can be further prepared in the reaction sequence according to the general reaction scheme 2.

通用反應方案(方案2)：General Reaction Scheme (Scheme 2):

於步驟v1，可採用熟知此技術領域者已知之方法，將化合物(V)轉化為化合物(Va)，例如使用氯甲酸苯酯，若適當，於一偶合試劑及/或一鹼基存在之條件下進行。除本文所揭示、使用氯甲酸苯酯製備不對成尿素之方法以外，亦可使用熟知此技術領域者所熟悉之其它方法，若適當，基於使用活性碳酸衍生物或異氰酸鹽之方法。 In step v1 , compound ( V ) can be converted to compound ( Va ) by methods well known in the art, for example using phenyl chloroformate, if appropriate, in the presence of a coupling reagent and/or one base. Go on. In addition to the methods disclosed herein for the preparation of non-formed urea using phenyl chloroformate, other methods well known to those skilled in the art can be used, if appropriate, based on the use of an active carbonic acid derivative or isocyanate.

於步驟v2，胺(II)可被轉化為尿素化合物(I)(其中，Z=N)。此項反應可採用熟知此技術領域者所熟悉之方法，將其與(Va)進行反應而達成，若適當，於一鹼基存在之條件下進行。 In step v2 , the amine ( II ) can be converted to the urea compound ( I ) (wherein Z = N). This reaction can be carried out by reacting it with ( Va ) by a method well known to those skilled in the art, and if appropriate, in the presence of one base.

可由有機化學標準工序，例如J.March之高等有機化學(Advanced Organic Chemistry)，Wiley & Sons，第六版，2007；F.A.Carey、R.J.Sundberg之高等有機化學(Advanced Organic Chemistry)，A部與B部，Springer，第五版，2007；作者團隊，有機合成方法概述(Compendium of Organic Synthetic Methods)，Wiley & Sons，推斷出熟知此技術領域者所熟悉之進行反應步驟j01至j09、k01至k05及v1與v2之方法。此外，其它方法及參 考文獻亦發布於常見之資料庫，例如愛思唯爾(Elsevier)之Reaxys®資料庫，荷蘭阿姆斯特丹，或美國化學學會之SciFinder®資料庫，美國華盛頓。 Standard procedures in organic chemistry, such as J. March, Advanced Organic Chemistry, Wiley & Sons, Sixth Edition, 2007; FA Carey, RJ Sundberg, Advanced Organic Chemistry, Part A and Part B, Springer , Fifth Edition, 2007; team of authors, the method outlined in organic synthesis (Compendium of organic synthetic methods), Wiley & Sons, inferred well known in the art are familiar with this technique of reacting step j01 to j09, k01 to k05 and v1 and v2 The method. In addition, other methods and references are also published in common databases such as Elsevier's Reaxys® database, Amsterdam, the Netherlands, or the American Chemical Society's SciFinder® database, Washington, USA.

藉由數個實例之輔助，本發明之描述如下。實例之用意僅於描述本發明，但本發明之整體概念不受限於實例之限定。 The invention is described below with the aid of several examples. The examples are intended to describe the invention only, but the overall concept of the invention is not limited by the examples.

【實施方式】 [Embodiment]

「等量(equivalents)(eq.或eq)」係指等量莫耳，「RT(room temperature)」係指室溫(23±7℃)，「M」係指以mol/l為單位之濃度，「aq.(aqueous)」係指水溶液，「sat.(saturated)」係指飽和，「sol.(solution)」係指溶液，「conc.(concentrated)」係指濃縮。 "Equivalents (eq. or eq)" means equivalent molars, "RT (room temperature)" means room temperature (23 ± 7 ° C), and "M" means mol/l. Concentration, "aq. (aqueous)" means an aqueous solution, "sat. (saturated)" means saturated, "sol. (solution)" means a solution, and "conc. (concentrated)" means concentrated.

其它縮寫： Other acronyms:

所製備化合物之產量皆未經優化。所有溫度皆未經校正。 The yield of the prepared compounds was not optimized. All temperatures are uncorrected.

所有未明確描述之起始原料若非經商購取得(供應商之詳細資料，如Acros、Avocado、Aldrich、Apollo、Bachem、Fluka、FluoroChem、Lancaster、Manchester Organics、MatrixScientific、Maybridge、Merck、Rovathin、Sigma、TCI、Oakwood等，可分別於MDL之Symyx®化學物品資料庫(Symyx® Available Chemicals Database of MDL)，San Ramon，美國，或ACS之SciFinder®資料庫，華盛頓DC，美國取得)，其合成方式即已精確地描述於專業文獻(例如，實驗指導方針可於愛思唯爾之Reaxys®資料庫，阿姆斯特，荷蘭丹查取)，或可利用熟知此技術領域者已知之常規方法製備而成。 All starting materials not expressly described are not commercially available (supplier details such as Acros, Avocado, Aldrich, Apollo, Bachem, Fluka, FluoroChem, Lancaster, Manchester Organics, Matrix Scientific, Maybridge, Merck, Rovathin, Sigma, TCI) Oakwood, etc., respectively, can be obtained from MDL's Symyx® Available Chemicals Database of MDL, San Ramon, USA, or ACS's SciFinder® database, Washington DC, USA. Precisely described in the professional literature (for example, experimental guidelines can be found in Elsevier's Reaxys® database, Armstrong, Holland), or can be prepared using conventional methods known to those skilled in the art. .

用於管柱色層分析之固定相為E.Merck，Darmstadt之矽膠60(0.04至0.063 mm)。 The stationary phase for column chromatography was E. Merck, Darmstadt's silicone 60 (0.04 to 0.063 mm).

溶媒、流動溶媒或溶析液之混合比例係以體積/體積比表示。 The mixing ratio of the solvent, flowing solvent or eluent is expressed in volume/volume ratio.

所有中間產物及示範性化合物係使用氫核磁共振光譜(1H-NMR spectroscopy)進行特點分析。此外，亦對所有示範性化合 物及精選之中間產物進行質譜測試(MS，[M+H]+之質荷比)。 All intermediates and exemplary compounds were characterized by hydrogen nuclear magnetic resonance spectroscopy ( 1 H-NMR spectroscopy). In addition, mass spectrometry tests (MS, [M+H] + mass-to-charge ratio) were also performed on all exemplary compounds and selected intermediates.

中間產物之合成：Synthesis of intermediates:

1. 3-三級丁基-1-甲基-1H-吡唑-5-基-甲胺之合成(步驟j01至j06) 1. Synthesis of 3-tert-butyl-1-methyl-1H-pyrazole-5-yl-methylamine (steps j01 to j06 )

步驟j01：於0℃，將三甲基乙醯氯(J-0)(1等量，60公克)於30分鐘內逐滴加入甲醇溶液中，並將該混合物於室溫攪拌1小時。於添加水(120毫升)後，將分離之有機相以水(120毫升)清洗，以硫酸鈉乾燥，並以二氯甲烷(150毫升)共蒸餾，即可獲得純度為99%之液態產物J-I(57公克)。 Step j01 : Trimethylacetamidine chloride ( J-0 ) (1 equivalent, 60 g) was added dropwise to the methanol solution over 30 minutes at 0 ° C, and the mixture was stirred at room temperature for 1 hour. After adding water (120 ml), the separated organic phase was washed with water (120 ml), dried over sodium sulfate, and then distilled with dichloromethane (150 ml) to obtain a liquid product JI having a purity of 99%. (57 grams).

步驟j02：將氫化鈉(50%，存在於石蠟油中)(1.2等量，4.6公克)以1,4-二氧陸圜(120毫升)溶解，並將該混合物攪拌數分鐘。於15分鐘內將乙腈(1.2等量，4.2公克)逐滴加入該混合物中，並攪拌30分鐘。於15分鐘內將二甲基丙酸甲酯(J-I)(1等量，10公克)逐滴加入該反應混合物中，並回流3小時。反應完成後，將該反應混合物置放於冰水中(200公克)，將其酸化至pH 4.5，並以二氯甲烷(12 x 250毫升)萃取。將合併有機相以硫酸鈉乾燥，蒸餾，並由正己烷(100毫升)再結晶後，可獲得5公克、褐色固狀之產物(J-II)(51%生產率)。 Step j02 : Sodium hydride (50% in paraffin oil) (1.2 equivalent, 4.6 g) was dissolved in 1,4-dioxane (120 ml), and the mixture was stirred for several minutes. Acetonitrile (1.2 equivalent, 4.2 g) was added dropwise to the mixture over 15 minutes and stirred for 30 minutes. Methyl dimethylpropionate ( JI ) (1 equivalent, 10 g) was added dropwise to the reaction mixture over 15 minutes and refluxed for 3 hours. After completion of the reaction, the reaction mixture was taken in ice water (200 g), which was acidified to pH 4.5 and extracted with dichloromethane (12 x 250 ml). The combined organic phases were dried over sodium sulfate, after distillation, by n-hexane (100 mL) was recrystallized obtained 5 g, of a tan solid form product (J-II) (51% productivity).

步驟j03：於室溫將4,4-二甲基-3-氧絡戊酮腈(4,4-dimethyl-3-oxopentanenitrile)(J-II)(1等量，5公克)以乙醇(100毫升)溶解，將其與聯胺水合物(2等量，4.42公克)混合，並回流3小時。將其蒸餾以去除乙醇，之後以水(100毫升)溶解所得之殘留物，再以醋酸乙酯(300毫升)萃取。將合併有機相以硫酸鈉乾燥，於真空狀態去除溶媒，由正己烷(200毫升)再結晶後，即可獲得淡紅色固體狀之產物(J-III)(5公克，89%生產率)。 Step j03 : 4,4-dimethyl-3-oxopentanenitrile ( J-II ) (1 equivalent, 5 g) in ethanol (100) at room temperature Dissolved in milliliters, mixed with hydrazine hydrate (2 equivalents, 4.42 grams) and refluxed for 3 hours. It was distilled to remove ethanol, and the residue was dissolved in water (100 ml), and ethyl acetate (300 ml). The combined organic phases were dried over sodium sulfate, the solvent is removed in vacuum, n-hexane recrystallization (200 mL), to obtain a pale red solid of the product was (J-III) (5 g, 89% productivity).

步驟j04：將3-三級丁基-1H-吡唑-5-胺(J-III)(1等量，40公克)以經稀釋之氯化氫(存在於120毫升之水之120毫升氯化氫)，並於30分鐘之時間，於0至5℃逐滴與亞硝酸鈉(1.03等量，25公克，溶於100毫升)混合。攪拌30分鐘後，將該反應混合物以碳酸鈉中和。於30分鐘內，將由氰化鉀(2.4等量，48公克)、水(120毫升)與氰化亞銅(CuCN)(1.12等量，31公克)反應所得之重氮鹽逐滴加入該反應混合物中，並將該混合物於75℃再度攪拌30分鐘。反應完成後，以醋酸乙酯(3 x 500毫升)萃取該反應混合物，並將合併有機相以硫酸鈉乾燥，再於真空狀態去除溶媒。將殘留物以管柱色層分析法(矽膠：100至200篩孔(mesh)，溶析液：20%之醋酸乙酯/正己烷)純化後，可獲得白色固體狀之產物(J-IV)(6.5公克，15%)。 Step j04 : 3-tert-butyl-1H-pyrazole-5-amine ( J-III ) (1 equivalent, 40 g) is diluted with hydrogen chloride (120 ml of hydrogen chloride in 120 ml of water), It was mixed with sodium nitrite (1.03 equivalent, 25 g, dissolved in 100 ml) dropwise at 0 to 5 ° C for 30 minutes. After stirring for 30 minutes, the reaction mixture was neutralized with sodium carbonate. The diazonium salt obtained by reacting potassium cyanide (2.4 equivalent, 48 g), water (120 ml) and cuprous cyanide (CuCN) (1.12 equivalent, 31 g) was added dropwise to the reaction over 30 minutes. The mixture was stirred at 75 ° C for another 30 minutes. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (3×500 ml), and the combined organic phases were dried over sodium sulfate and then evaporated. The residue was purified by column chromatography (methylene chloride: 100 to 200 mesh, eluting solvent: 20% ethyl acetate / n-hexane) to afford product ( J-IV) ) (6.5 grams, 15%).

步驟j05(方法1)： Step j05 ( method 1 ):

於室溫，將3-三級丁基-1H-吡唑-5-碳化腈(J-IV)(10毫莫耳)於攪拌同時加至以二甲基甲醯(20毫升)溶解之氫化鈉(60%，12.5毫莫耳)懸浮液中。攪拌15分鐘後，將甲基碘化物(37.5毫莫耳)於室溫逐滴加至該反應混合物中。於100℃攪拌30分鐘後，將該反應混合物與水(150毫升)混合，並以二氯甲烷(3 x 75毫升)萃取。以水(100毫升)及飽和氯化鈉溶液(100毫升)清洗合併有機相，並以硫酸鎂乾燥。將溶媒於真空狀態去除後，以管柱色層分析法(矽膠：100至200篩孔，溶析液：以各種醋酸乙酯與環己烷混合物做為流動溶媒)純化殘留物，即可獲得J至V之產物。 3-tert-butyl-1H-pyrazole-5-carbonitrile ( J-IV ) (10 mmol) was added to the hydrogenation dissolved in dimethylformamidine (20 ml) while stirring at room temperature. Sodium (60%, 12.5 mmol) in suspension. After stirring for 15 minutes, methyl iodide (37.5 mmol) was added dropwise to the reaction mixture at room temperature. After stirring at 100 ° C for 30 minutes, the reaction mixture was combined with water (150 ml The combined organic phases were washed with water (100 ml) and saturated sodium chloride (100 ml) and dried over magnesium sulfate. After the solvent is removed in a vacuum state, the residue is purified by column chromatography (silicone: 100 to 200 mesh, eluent: a mixture of various ethyl acetate and cyclohexane as a mobile solvent). The product of J to V.

步驟j06： Step j06 :

方法1：method 1:

將J至V與鈀碳(10%，500毫克)及濃氯化氫(3毫升)以甲醇(30毫升)溶解，並將其於室溫暴露於氫氣氣氛中6小時。將該反應混 合物以矽藻土過濾，並於真空狀態下濃縮。以快速色層分析法(flash chromatography)(矽膠：100至200篩孔，溶析液：醋酸乙酯)純化殘留物，即可獲得產物(II)。 J to V and palladium on carbon (10%, 500 mg) and concentrated hydrogen chloride (3 ml) were dissolved in methanol (30 ml), and the mixture was exposed to a hydrogen atmosphere at room temperature for 6 hours. The reaction mixture was filtered with celite and concentrated under vacuum. The product ( II ) can be obtained by flash chromatography (purine: 100 to 200 mesh, eluent: ethyl acetate) to purify the residue.

方法2：Method 2:

將J至V以四氫呋喃(10毫升)溶解，並於其中添加甲硼烷-甲硫醚複合物(2.0 M於四氫呋喃中，3毫升，3等量)。將該反應混合物加熱回流8小時，隨後添加2N之氯化氫水溶液，並再次將該反應混合物回流30分鐘。將該反應混合物與氫氧化鈉水溶液(2N)混合，並以醋酸乙酯清洗。將合併有機相以飽和氯化鈉水溶液清洗，並以硫酸鎂乾燥。於真空狀態下去除溶媒，並以管柱色層分析法(矽膠：100至200篩孔，溶析液：以各種二氯甲烷及甲醇混合物做為流動溶媒)純化殘留物，以獲得產物(II)(3-三級丁基-1-甲基-1H-吡唑-5-基)甲胺)。 J to V was dissolved in tetrahydrofuran (10 ml), and a borane-methyl sulfide complex (2.0 M in tetrahydrofuran, 3 ml, 3 equivalents) was added thereto. The reaction mixture was heated to reflux for 8 h then a 2N aqueous solution of hydrogen chloride was added and the mixture was again refluxed for 30 min. The reaction mixture was mixed with aqueous sodium hydroxide (2N) and washed with ethyl acetate. The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was removed under vacuum, and the residue was purified by column chromatography (tank: 100 to 200 mesh, eluent: mixture of various dichloromethane and methanol) to obtain a product ( II) (3-tert-butyl-1-methyl-1H-pyrazol-5-yl)methylamine).

2.下列其它中間產物係以類似上列1.所描述之方法合成： 2. The following other intermediates were synthesized in a manner similar to that described in 1 .

3.或者，亦可採用以下方法(方法2)進行步驟j05： 3. Alternatively, step j05 can also be performed using the following method ( method 2 ):

步驟j05(方法2)： Step j05 ( Method 2):

將一3-三級丁基-1H-吡唑-5-碳化腈(3-tert-butyl-1H-pyrazol-5-carbonitrile)(J-IV)(10毫莫耳)、一B(OH)2R1硼酸或相應之硼酸酯(20毫莫耳)及乙酸銅(15毫莫耳)之混合物放入二氯甲烷(200毫升)，於室溫將其與啶(20毫莫耳)邊攪拌邊混合，再將該混合物攪拌16小時。於真空狀態去除溶媒後，以管柱色層分析法(矽膠：100至200篩孔，溶析液：以各種醋酸乙酯與環己烷混合物做為流動溶媒)純化所得之殘留物，以獲得J-V 之產物。 3-tert-butyl-1H-pyrazol-5-carbonitrile ( J-IV ) (10 mmol), one B(OH) 2 R 1 boric acid or a mixture of the corresponding borate ester (20 mmol) and copper acetate (15 mmol) in dichloromethane (200 ml), which was combined with pyridine (20 mmol) at room temperature. The mixture was stirred while stirring, and the mixture was stirred for 16 hours. After the solvent is removed in a vacuum state, the residue obtained by column chromatography (powder: 100 to 200 mesh, eluent: a mixture of various ethyl acetate and cyclohexane) is used to obtain a residue. The product of JV .

4. 1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基-甲胺之合成(步驟k01至k05與j06) 4. 1- (3-chlorophenyl) -3- (trifluoromethyl) lH-pyrazol-5-yl - methylamine of (step k01 to k05 and J06)

步驟k01：於保護性氣體氣氛下，將氫化鋁鋰(LAlH，lithium aluminium hydride)(0.25等量，0.7公克)以無水二乙醚(30毫升)溶解，並於室溫攪拌2小時。以二乙醚(20毫升)溶解所產生之懸浮液。以無水二乙醚(20毫升)溶解乙基-2,2,2-三氟醋酸鹽(K-0)(1等量，10公克)，並於-78℃將其以1小時之時間逐滴加至懸浮液中。隨後，再度將該混合物於-78℃攪拌2小時。逐滴添加乙醇(95%，2.5毫升)，將該混合物加熱至室溫，再與濃硫酸(7.5毫升)一起置放於冰水中(30毫升)。將有機相分離並於真空狀態下濃縮，隨後立即將反應產物K-I用於下一反應步驟k02。 Step k01: under protective gas atmosphere, lithium aluminum hydride (LAlH, lithium aluminium hydride) ( 0.25 equivalent amount, 0.7 grams) in anhydrous diethyl ether (30 ml) was dissolved, and stirred at room temperature for 2 hours. The resulting suspension was dissolved in diethyl ether (20 mL). Ethyl-2,2,2-trifluoroacetate ( K-0 ) (1 eq, 10 g) was dissolved in anhydrous diethyl ether (20 mL), and was dropped at -78 °C over 1 hour. Add to the suspension. Subsequently, the mixture was again stirred at -78 ° C for 2 hours. Ethanol (95%, 2.5 ml) was added dropwise, and the mixture was warmed to room temperature and then placed with iced water (30 ml). The organic phase was separated and concentrated under vacuum, then the reaction product KI was used in the next reaction step k02 .

步驟k05：於-5至0℃，將3-氯苯胺(K-IV)(1等量，50公克)以氯化氫(300毫升)溶解，並攪拌10分鐘。於相同溫度，以3小時之時間逐滴添加一亞硝酸鈉(1.2等量，32.4公克)、水(30毫升)、二氯化錫‧2水(SnCl2‧2H2O)(2.2等量，70.6公克)與濃氯化氫(100毫升)混合物。於-5至0℃攪拌2小時後，以氫氧化鈉溶液將該反應混合物之酸鹼值調整為pH 9，並以醋酸乙酯(250毫升)萃取。將合併有機相以硫酸鎂乾燥，並於真空狀態去除溶媒。以管柱色層分析法(矽膠：100至200篩孔，溶析液：8%之醋酸乙酯/正己烷)進行純化，以獲得40公克(72%)褐色油狀之(3-氯苯基)聯氨(K-IV)。 Step k05 : 3-Chloroaniline ( K-IV ) (1 equivalent, 50 g) was dissolved in hydrogen chloride (300 ml) at -5 to 0 ° C and stirred for 10 min. At the same temperature, sodium nitrite (1.2 equivalent, 32.4 g), water (30 ml), tin dichloride ‧ water (SnCl 2 ‧2H 2 O) (2.2 equivalents) were added dropwise over a period of 3 hours , 70.6 g) and a mixture of concentrated hydrogen chloride (100 ml). After stirring at -5 to 0 ° C for 2 hours, the pH of the reaction mixture was adjusted to pH 9 with sodium hydroxide and extracted with ethyl acetate (250 ml). The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. Purification by column chromatography (tank: 100 to 200 mesh, eluent: 8% ethyl acetate / n-hexane) to obtain 40 g (72%) of brown oil (3-chlorobenzene) Base) hydrazine ( K-IV ).

步驟k02：將由k01獲得之醛基(K-I)(2等量，300毫升)及(3-氯苯基)聯氨(K-IV)(1等量，20公克)放入乙醇(200毫升)中，並回流5小時。於真空狀態去除溶媒，並以管柱色層分析法(矽膠：100至200篩孔，溶析液：正己烷)純化殘留物，以獲得褐色油狀物質之產物K-II(25克，72%)。 Step k02: by aldehyde (KI) k01 is obtained of (2 equivalent amount, 300 ml) and (3-chlorophenyl) hydrazine (K-IV) (1 equivalent amount, 20 grams) was placed in ethanol (200 ml) Medium and reflux for 5 hours. The solvent is removed in vacuum, and analysis by column chromatography (silica gel: 100-200 mesh, elution solution: n-hexane) to give the residue, to obtain the product as a brown oily substance K-II (25 g, 72 %).

步驟k03：將聯氨K-II(1等量，25公克)以二甲基甲醯胺(125毫升)溶解。於室溫，於15分鐘內分次添加N-氯代丁二醯亞胺(1.3等量，19.5克)，並攪拌3小時。以蒸餾法去除二甲基甲醯胺，並以醋酸乙酯溶解殘留物。於真空狀態除醋酸乙酯，並以管柱色層分析法(矽膠：100至200篩孔，溶析液：正己烷)純化殘留物，所得之產物K-III(26.5克，92%)為粉紅色油狀物質。 Step k03 : Hydrazine K-II (1 equivalent, 25 g) was dissolved in dimethylformamide (125 ml). N-chlorobutanediimine (1.3 equivalent, 19.5 g) was added portionwise over 15 minutes at room temperature and stirred for 3 hours. The dimethylformamide was removed by distillation and the residue was dissolved in ethyl acetate. The ethyl acetate was removed in a vacuum state, and the residue was purified by column chromatography (yield: 100 to 200 mesh, eluent: n-hexane) to give the product K-III (26.5 g, 92%). Pink oily substance.

步驟k04：於室溫，以甲苯(150毫升)溶解聯氨氯(hydrazonoyl chloride)K-III(1等量，10克)，並將其與2-氯丙烯腈(2等量，6.1毫升)及三乙胺(2等量，10.7毫升)混合。將該反應混合物於80℃攪拌20小時。隨後以水(200毫升)稀釋該混合物，並將相分離。將有機相以硫酸鎂乾燥，並於真空狀態去除溶媒。以管柱色層分析法(矽膠：100至200篩孔，溶析液：5%之醋酸乙酯/正己烷)純化殘留物，所得之產物(5.5公克，52%)呈白色固體狀J-V。 Step k04 : Dissolve hydrazonoyl chloride K-III (1 equivalent, 10 g) in toluene (150 ml) at room temperature and mix it with 2-chloroacrylonitrile (2 equivalent, 6.1 ml) And triethylamine (2 equal amount, 10.7 ml) was mixed. The reaction mixture was stirred at 80 ° C for 20 hours. The mixture was then diluted with water (200 mL) and the phases were separated. The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo. Analysis by column chromatography (silica gel: 100-200 mesh, elution solution: 5% ethyl acetate / hexane) to give the residue, the resulting product (5.5 g, 52%) as a white solid JV.

步驟j06(方法3)： Step j06 ( method 3 ):

將碳化腈J-V(1等量，1公克)以甲醇胺溶液(150毫升，1：1)溶解，並於氫氣立方體(H-cube)進行氫化(10巴，80℃，1毫升/分鐘，0.25莫耳/公升)。於真空狀態去除溶媒後即可獲得白色固體狀之(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺(II)(0.92公克，91%)。 The carbonized nitrile JV (1 equivalent, 1 gram) was dissolved in methanolic amine solution (150 ml, 1:1) and hydrogenated in a hydrogen cube (H-cube) (10 bar, 80 ° C, 1 ml/min, 0.25 Moor / liter). (1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamine ( II ) (0.92 g) was obtained as a white solid. , 91%).

5.下列其它中間產物係以類似上列4.所描述之方法合成： 5. The following other intermediates were synthesized in a manner similar to that described in 4 .

6.製備精選之通式(Va)或(IV)之胺甲酸苯酯(carbamate phenyl ester)及通式(IIIa)之苯酯 6. Preparation of a selected carbamate phenyl ester of the formula ( Va ) or ( IV ) and a phenyl ester of the formula ( IIIa )

6.1苯甲醚(3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)氨基甲酸甲酯之合成(例如，用於合成實例化合物no.2、4、6與10)6.1 Synthesis of methyl azide (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)carbamate (for example, for the synthesis of example compounds no. 2, 4) , 6 and 10)

步驟a：於一以二甲基甲醯胺(25毫升)溶解之(3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺(5克，18毫莫耳)溶液中添加碳酸鉀(9.16公克，66毫莫耳，3.5等量)，並將內容物冷卻至0℃。隨後於15分鐘之期間，逐滴添加氯甲酸苯酯(3.28公克(2.65毫升)，20毫莫耳，1.1等量)，並將整體反應混合物於0℃攪拌15分鐘。以薄層層析法(20%之醋酸乙酯-正己烷)監控反應過程。反應完成後，將反應物過濾，以冷水(100毫升)稀釋濾液，並以醋酸乙酯(3×25毫升)萃取產物。以飽和之氯化鈉溶液(100毫升)清洗合併有機層，以硫酸鈉乾燥，並於較低壓力將其濃縮。以管柱色層分析法(矽膠：100至200篩孔，溶析液：存在於正己烷之10%之醋酸乙酯)純化粗製產物，以獲得呈白色固體狀之所需產物(3.2公克，45%)。 Step a: (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methylamine (5 g) dissolved in dimethylformamide (25 ml) Potassium carbonate (9.16 grams, 66 millimolar, 3.5 equivalents) was added to the solution, and the contents were cooled to 0 °C. Subsequently, phenyl chloroformate (3.28 g (2.65 ml), 20 mmol, 1.1 equivalent) was added dropwise over a period of 15 min, and the whole reaction mixture was stirred at 0 ° C for 15 min. The course of the reaction was monitored by thin layer chromatography (20% ethyl acetate-n-hexane). After the reaction was completed, the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The combined organic layers were washed with aq. EtOAc (EtOAc)EtOAc. The crude product was purified by column chromatography (EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: 45%).

7.製備其它精選之根據通式(II)之吡唑衍生物 7. Preparation of other selected pyrazole derivatives according to formula ( II )

7.1(1-(3-氯苯基)-4-甲基-3-(三氟甲基)-1H-吡唑-5-基)甲胺之合成(用於合成實例化合物no.73)Synthesis of 7.1(1-(3-chlorophenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamine (for the synthesis of the example compound no.73)

步驟a：於-20℃，將正丁基鋰(1.6莫耳)(24.7公克(258.3毫升)，0.38莫耳，2.2等量)於2小時之期間，逐滴加至以四氫呋喃(400毫升)溶解之二異丙胺(40.8公克(57毫升)，0.404莫耳，2.3等量)溶液中，並將內容物於0℃攪拌30至45分鐘。將內容物冷卻至-75℃，並於2小時之期間，逐滴添加以四氫呋喃(200毫升)溶解之乙基2,2,2-三氟醋酸酯(25公克，0.17莫耳)溶液。先將該反應混合物於-75℃攪拌1小時，再於室溫攪拌1小時。以薄層層析法(存在於正己烷之50%之醋酸乙酯)監控反應過程。反應完成後，以冰水(700毫升)對反應物進行淬火反應，並將溶媒完全地蒸餾出。以二氯甲烷(3×300毫升)清洗殘留物，以30%之氯化氫溶液將內容物酸化，再以乙醚(3×400毫升)萃取產物。將合併有機層以硫酸鈉乾燥，於較低壓力濃縮，並於真空狀態蒸餾所得之粗製產物，以於35℃/0.1 mm之條件，獲得呈無色液態之產物(17公克，64%)。 Step a: n-Butyllithium (1.6 mol) (24.7 g (258.3 ml), 0.38 mol, 2.2 equivalent) was added dropwise at -20 ° C to tetrahydrofuran (400 ml) over a period of 2 h. The solution was dissolved in diisopropylamine (40.8 g (57 ml), 0.404 mol, 2.3 equivalent) and the contents were stirred at 0 ° C for 30 to 45 min. The contents were cooled to -75 ° C, and a solution of ethyl 2,2,2-trifluoroacetate (25 g, 0.17 mol) dissolved in tetrahydrofuran (200 ml) was added dropwise over a period of 2 h. The reaction mixture was stirred at -75 ° C for 1 hour and then at room temperature for 1 hour. The course of the reaction was monitored by thin layer chromatography (50% ethyl acetate in n-hexane). After completion of the reaction, the reactant was quenched in ice water (700 ml), and the solvent was completely distilled off. The residue was washed with dichloromethane (3.times.3 mL). EtOAc (EtOAc) The combined organic layers were dried with EtOAc (EtOAc m.)

步驟b：以乙醇氯化氫(300毫升)溶解步驟-a之產物(10公克，0.066莫耳)，並添加3-氯苯胼(9.43公克，0.066莫耳，1等量)。將該反應混合物加熱回流2小時。以薄層層析法(存在於正己烷之20%醋酸乙酯)監控反應過程。反應完成後，將反應內容物濃縮，並以水(200毫升)溶解殘留物。以1N之氫氧化鈉溶液將內容物鹼 化至酸鹼值呈約12，並將內容物過濾。以醋酸乙酯(200毫升)溶解所得之固體，將內容物以硫酸鈉乾燥並於較低壓力濃縮，以生產紅色固體狀之所需產物(12公克，65%)。 Step b: The product of step -a (10 g, 0.066 mol) was dissolved in ethanolic hydrogen chloride (300 mL) and 3-chlorophenylhydrazine (9.43 g, 0.066 mol, 1 equivalent) was added. The reaction mixture was heated to reflux for 2 h. The course of the reaction was monitored by thin layer chromatography (20% ethyl acetate in n-hexane). After completion of the reaction, the reaction contents were concentrated, and the residue was dissolved in water (200 ml). The contents were basified to a pH of about 12 with a 1N sodium hydroxide solution and the contents filtered. The resulting solid was dissolved in ethyl acetate (EtOAc) (EtOAc)

步驟c：以乙腈(176毫升)溶解二溴化銅(11.33公克，0.0511莫耳，1.2等量)，並將其加熱至150℃。隨後添加亞硝酸丁酯(6.59公克(7.47毫升)，0.063莫耳，1.5等量)，再於30分鐘之期間，於150℃逐滴添加以乙腈(176毫升)溶解之步驟-b產生之溶液(11.75公克，0.042莫耳)，並將其攪拌15分鐘。以薄層層析法(5%之醋酸乙酯/正己烷)監控反應過程。反應完成後，將乙腈蒸餾出，並以冰水(300毫升)溶解殘留物，再以醋酸乙酯(5×100毫升)萃取產物。將合併萃取物以硫酸鈉乾燥，並於較低壓力濃縮，再以管柱色層分析法(矽膠：100至200篩孔，溶析液：純正己烷)純化粗製產物。純產物未經分離，所得之混合物呈紅色液態狀(16公克，粗製產物)；該產物可於下一步驟使用。 Step c: Copper dibromide (11.33 g, 0.0511 mol, 1.2 equivalent) was dissolved in acetonitrile (176 mL) and heated to 150 °C. Subsequently, butyl nitrite (6.59 g (7.47 ml), 0.063 mol, 1.5 equivalent) was added, and then the solution of the step - b was added dropwise at 150 ° C in acetonitrile (176 ml) over a period of 30 minutes. (11.75 grams, 0.042 moles) and stir for 15 minutes. The progress of the reaction was monitored by thin layer chromatography (5% ethyl acetate / n-hexane). After the reaction was completed, the acetonitrile was evaporated, and the residue was crystallised eluted with EtOAc (EtOAc) The combined extracts were dried over sodium sulfate and concentrated at a lower pressure, and then the crude product was purified by column chromatography (yield: 100 to 200 mesh, eluent: pure n-hexane). The pure product was not isolated and the resulting mixture was taken in red liquid (16 g, crude product);

步驟d：於一以N-甲基-2-吡咯烷酮(130毫升)溶解之一步驟-c產生之溶液(13公克，0.038莫耳)中添加氰化銅(6.8公克，0.076莫耳，2等量)及碘化鈉(100毫克，催化物)。將該反應混合物置放於一預熱至180℃之油浴中，並攪拌8小時。以薄層層析法(存在於正己烷之5%醋酸乙酯)監控反應過程。反應完成後，以水(200毫升)稀釋反應內容物，並以醋酸乙酯(5×100毫升)萃取產物。將合併萃取物以冰水(5×50毫升)清洗，以硫酸鈉乾燥，並於較低壓力濃縮。以管柱色層分析法(矽膠：100至200篩孔，溶析液：存在於正己烷之2%醋酸乙酯)純化該粗製產物，以獲得淡黃色固體狀之所需產物(8公克)。 Step d: Add copper cyanide (6.8 g, 0.076 mol, 2, etc.) to a solution (13 g, 0.038 mol) dissolved in one step - c with N-methyl-2-pyrrolidone (130 ml). Amount) and sodium iodide (100 mg, catalyst). The reaction mixture was placed in an oil bath preheated to 180 ° C and stirred for 8 hours. The course of the reaction was monitored by thin layer chromatography (5% ethyl acetate in n-hexane). After the reaction was completed, the reaction mixture was diluted with water (200 ml), and the product was extracted with ethyl acetate (5×100 ml). The combined extracts were washed with ice water (5×50 mL) dried over sodium sulfate. The crude product was purified by column chromatography (EtOAc: EtOAc: EtOAc: EtOAc: EtOAc) .

步驟e：於30分鐘期間0至5℃，將以四氫呋喃(70毫升)溶解之硼烷-四氫呋喃逐滴加至以無水四氫呋喃(30毫升)溶解之一步驟 -d產生之溶液(5公克，0.017莫耳)中。將反應混合物緩慢地加熱至50℃，並攪拌12小時。以薄層層析法(75%之醋酸乙酯/正己烷)監控反應過程。反應完成後，以濃氯化氫將內容物於0℃至5℃酸化，並將內容物於室溫攪拌2小時。隨後將內容物以10%之氫氧化鈉溶液鹼化至酸鹼值呈約12，並以醋酸乙酯(5×50毫升)萃取產物。將合併萃取物以硫酸鈉乾燥，並於較低壓力濃縮。以10%之乙醚/正己烷清洗所得之固體，並將其乾燥，以獲得呈白色固體狀之所需產物(3公克，59%)。 Step e: borane-tetrahydrofuran dissolved in tetrahydrofuran (70 ml) was added dropwise to a solution of one of the steps - d dissolved in anhydrous tetrahydrofuran (30 ml) over a period of 30 minutes (5 g, 0.017) Moer). The reaction mixture was slowly heated to 50 ° C and stirred for 12 hours. The progress of the reaction was monitored by thin layer chromatography (75% ethyl acetate / n-hexane). After completion of the reaction, the contents were acidified with concentrated hydrogen chloride at 0 ° C to 5 ° C, and the mixture was stirred at room temperature for 2 hr. The contents were then basified to a pH of about 12 with a 10% sodium hydroxide solution and the product was extracted with ethyl acetate (5 x 50 mL). The combined extracts were dried over sodium sulfate and concentrated at lower pressure. The resulting solid was washed with EtOAc (EtOAc) elute

7.2(1-(3-氯苯基)-3-環丙基-1H-吡唑-5-基)甲胺鹽酸鹽之合成(例如，用於合成實例化合物no.24與72)Synthesis of 7.2 (1-(3-chlorophenyl)-3-cyclopropyl-1H-pyrazol-5-yl)methylamine hydrochloride (for example, for the synthesis of example compounds no. 24 and 72)

步驟a：於室溫，將草酸二乙酯(0.92毫升，6.85毫莫耳，1等量)加至一以乙醇鈉溶液(新鮮配製之以乙醇(30毫升)溶解之鈉(1公克，8.2毫莫耳，1.2等量))，隨後於0℃，逐滴添加環丙基甲基酮(0.74毫升，7.5毫莫耳，1.1等量)。將該反應混合物緩慢地加熱 至室溫，並攪拌3小時。添加冰水(10毫升)，並於較低壓力將乙醇蒸發。以2 N之氯化氫水溶液(15毫升)稀釋殘留之水層，並以二乙醚(2×25毫升)萃取。以飽和之氯化鈉溶液清洗有機層，以硫酸鈉乾燥，將其過濾，並濃縮，以獲得呈淡褐色液態之產物(400毫克，31%)。 Step a: At room temperature, diethyl oxalate (0.92 ml, 6.85 mmol, 1 equivalent) was added to a solution of sodium ethoxide (salted in ethanol (30 ml) dissolved in sodium (1 g, 8.2 Millol, 1.2 equivalent)), followed by dropwise addition of cyclopropylmethylketone (0.74 mL, 7.5 mmol, 1.1 equivalent) at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. Ice water (10 ml) was added and the ethanol was evaporated at a lower pressure. The residual aqueous layer was diluted with aq. EtOAc (EtOAc m. The organic layer was washed with EtOAc (EtOAc m.

步驟b：於室溫，將甲氧胺鹽酸鹽(溶於水之30%溶液，0.4毫升，0.651毫莫耳，1.2等量)加至一以乙醇(8毫升)溶解之於步驟-a獲得之產物(200毫克，0.543毫莫耳，1等量)溶液中，並將該反應混合物攪拌1小時。於較低壓力將乙醇蒸發，並以醋酸乙酯(15毫升)萃取殘留之水層。以水(10毫升)及飽和之氯化鈉溶液(10毫升)清洗有機層，以硫酸鈉乾燥，將其過濾，並於較低壓力濃縮，以獲得一淡黃色液體(180毫克，78%)。 Step b: methoxyamine hydrochloride (30% solution in water, 0.4 ml, 0.651 mmol, 1.2 equivalent) was added to a solution of ethanol (8 ml) at room temperature in a step - a The obtained product (200 mg, 0.543 mmol, 1 equivalent) was obtained and the mixture was stirred for 1 hour. Ethanol was evaporated at a lower pressure and the residual aqueous layer was extracted with ethyl acetate (15 mL). The organic layer was washed with EtOAc (EtOAc) (EtOAc)EtOAc. .

步驟c：以醋酸(20毫升)及2-甲氧基乙醇(10毫升)溶解一步驟-b產物(1.1公克，5.164毫莫耳，1等量)與3-氯苯基氫氯酸胼(1.84公克，10.27毫莫耳，2等量)之混合物，並將該反應混合物於105℃加熱3小時。將溶媒蒸發，並以醋酸乙酯(60毫升)萃取殘留物。以水(10毫升)及飽和之氯化鈉溶液(10毫升)清洗有機層，並以硫酸鈉乾燥，將其過濾，並於較低壓力濃縮，以獲得殘留物。以管柱色層分析法(矽膠：100至200篩孔，溶析液：醋酸乙酯-石油醚(4：96))將其純化，以獲得一淡褐色之半固體(1.15公克，77%)。 Step c: Dissolve one step - b product (1.1 g, 5.164 mmol, 1 equivalent) with 3-chlorophenylhydrochloride hydrate (acetic acid (20 ml) and 2-methoxyethanol (10 ml)) A mixture of 1.84 grams, 10.27 millimoles, 2 equivalents, and the reaction mixture was heated at 105 °C for 3 hours. The solvent was evaporated, and the residue was crystalljjjjjjj The organic layer was washed with water (10 ml) and sat. sodium chloride (10 ml) and dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford residue. It was purified by column chromatography (silicone: 100 to 200 mesh, eluent: ethyl acetate-petroleum ether (4:96)) to obtain a pale brown semi-solid (1.15 g, 77%). ).

步驟d：於0℃，將氫氧化鋰(1.08公克，25.71毫莫耳，3等量)加至以四氫呋喃(15毫升)-甲醇(9毫升)-水(3毫升)溶解之步驟-c產物(2.5公克，8.62毫莫耳，1等量)溶液中，並將該反應混合物於室溫攪拌2小時。將溶媒蒸發，並將殘留物之酸鹼值以2N之氯化氫水溶液(1.2毫升)調整為約3。以醋酸乙酯(2×60毫升)萃取酸性水層；以水(10毫升)及飽和之氯化鈉溶液(10毫升)清洗合併 有機層，以硫酸鈉乾燥，將其過濾，並於較低壓力濃縮，以獲得一白色固體(1.4公克，62%)。 Step d: at 0 deg.] C, lithium hydroxide (1.08 g, 25.71 mmol, 3 equivalents) was added to a tetrahydrofuran (15 mL) - methanol (9 ml) - water was dissolved step (3 mL) - c product (2.5 g, 8.62 mmol, 1 equivalent) in solution and the reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated, and the pH of the residue was adjusted to about 3 with 2N aqueous hydrogen chloride (1.2 mL). The acidic aqueous layer was extracted with ethyl acetate (2×60 mL). The combined organic layer was washed with water (10 ml) and saturated sodium chloride solution (10 ml), dried over sodium sulfate, filtered and The pressure was concentrated to give a white solid (1.4 g, 62%).

步驟e：於0℃，將啶(0.25毫升，3.2毫莫耳，0.6等量)及二碳酸三級丁酯(1.4毫升，6.37毫莫耳，1.2等量)加至以1,4-二氧陸圜(30毫升)溶解之步驟-d產物(1.4公克，5.34毫莫耳，1等量)溶液中，並將產生之混合物於相同溫度攪拌30分鐘。於0℃添加銨碳酸氫鹽(0.84公克，10.63毫莫耳，2等量)，並將該反應混合物於室溫攪拌過夜。以水(10毫升)稀釋該反應混合物，並以醋酸乙酯(2×30毫升)清洗水層。以2N之氯化氫(20毫升)、水(10毫升)及飽和之氯化鈉溶液(10毫升)清洗有機層，以硫酸鈉乾燥，將其過濾，並於較低壓力濃縮，以產生殘留物。以管柱色層分析法(矽膠：100至200篩孔，溶析液：醋酸乙酯-石油醚(16：84))進行純化，以獲得一白色固體(1公克，72%)。 Step e: Add pyridine (0.25 ml, 3.2 mmol, 0.6 equivalent) and butyl dicarbonate (1.4 mL, 6.37 mmol, 1.2 equivalent) to 1,4-two at 0 °C. Oxygen guanidine (30 ml) was dissolved in a solution of d- product (1.4 g, 5.34 mmol, 1 equivalent) and the resulting mixture was stirred at the same temperature for 30 minutes. Ammonium hydrogencarbonate (0.84 g, 10.63 mmol, 2 equivalents) was added at 0 ° C, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (10 mL) and brine was evaporated. The organic layer was washed with aq. EtOAc (EtOAc)EtOAc. Purification by column chromatography (tank: 100 to 200 mesh, eluent: ethyl acetate- petroleum ether (16: 84)) afforded white solid (1 g, 72%).

步驟f：於0℃，將甲硼烷-甲硫醚複合物(1.44毫升，15.32毫莫耳，2等量)加至以四氫呋喃(25毫升)溶解之步驟-e產物(2公克，7.66毫莫耳，1等量)溶液中，並將該反應混合物於70℃加熱3小時。將該反應混合物冷卻至0℃，添加甲醇(15毫升)，並將該反應混合物加熱回流1小時。令該反應混合物冷卻至室溫，並於較低壓力下將溶媒蒸發。將殘留物以乙醚(15毫升)溶解，將其冷卻至0℃，並添加溶於1,4-二氧陸圜(3毫升)之氯化氫溶液(該反應混合物之酸鹼值約為4)。將析出之固體過濾並以二乙醚(5毫升，三次)清洗，以獲得呈白色固體狀之氯化氫化合物(600毫克，28%)。 Step f: The borane-methyl sulfide complex (1.44 ml, 15.32 mmol, 2 equal amounts) was added to the step of dissolving in tetrahydrofuran (25 ml) at 0 ° C - e product (2 g, 7.66 m) Mohr, 1 equal amount) in solution, and the reaction mixture was heated at 70 ° C for 3 hours. The reaction mixture was cooled to 0.degree. C., MeOH (15 mL). The reaction mixture was allowed to cool to room temperature and the solvent was evaporated at a lower pressure. The residue was dissolved in diethyl ether (15 mL), cooled to 0 <RTI ID=0.0>>>>> The precipitated solid was filtered and washed with diethyl ether (5 mL, EtOAc)

7.3(3-三級丁基-1-(啶-2-基)-1H-吡唑-5-基)甲胺之合成(例如，用於合成實例化合物no.85)Synthesis of 7.3 (3-tertiary butyl-1-(pyridin-2-yl)-1H-pyrazol-5-yl)methylamine (for example, for the synthesis of the example compound no. 85)

步驟a：於一以乙醇(100毫升)溶解之2-氯啶(20公克，0.17莫耳)溶液中添加聯胺水合物(132毫升)，並將該反應混合物加熱回流15小時。以薄層層析法(40%之醋酸乙酯/正己烷)監控反應過程。若反應未完成，令其繼續回流15小時，並以薄層層析法監控。反應完成後，將氫氯酸胼於100℃完全地蒸餾出，以二氯甲烷(500毫升)溶解殘留物，並以飽和之碳酸鈉溶液(100毫升)清洗內容物。將合併有機層以硫酸鈉乾燥，並於較低壓力濃縮，以獲得一低熔點固態狀之產物(11公克，粗製產物)。所得之粗製產物可直接於下一步驟使用。 Step a: To a solution of 2-chloropyridine (20 g, 0.17 mol) dissolved in ethanol (100 ml) was added hydr. hydrate (132 mL). The progress of the reaction was monitored by thin layer chromatography (40% ethyl acetate / n-hexane). If the reaction is not complete, it is allowed to continue to reflux for 15 hours and monitored by thin layer chromatography. After completion of the reaction, the hydrazine hydride was completely distilled off at 100 ° C, the residue was dissolved in dichloromethane (500 ml), and the mixture was washed with saturated sodium carbonate (100 ml). The combined organic layers were dried with sodium sulfate and concentrated <RTI ID=0.0> The resulting crude product can be used directly in the next step.

步驟b：於一經攪拌、以乙醇溶解之步驟-a產物(11公克，粗製產物)溶液中，分次添加4,4-二甲基-3-氧絡戊酮腈(11.3公克，0.09莫耳，0.9等量)，隨後再添加催化量之氯化氫。將該反應混合物加熱至100℃並回流6小時。以薄層層析法(20%之醋酸乙酯/正己烷)監控反應過程。反應完成後，將乙醇蒸餾出，以水(200毫升)溶解殘留物，並以醋酸乙酯(2×100毫升)萃取產物。將合併萃取物以硫酸鈉乾燥，於較低壓力濃縮，並以管柱色層分析法(矽膠：100至200篩孔，溶析液：存在於正己烷之10%醋酸乙酯)進行純化，以獲得灰白色固體狀之所需產物(18公克)。 Step b: to a stirred, in the step of dissolving ethanol - a product (11 g, crude product) was added portionwise 4,4-dimethyl-3-pentanone envelope carbonitrile (11.3 g, 0.09 mole , 0.9 equal amount), followed by the addition of a catalytic amount of hydrogen chloride. The reaction mixture was heated to 100 ° C and refluxed for 6 hours. The course of the reaction was monitored by thin layer chromatography (20% ethyl acetate / n-hexane). After completion of the reaction, the ethanol was evaporated, and the residue was crystallisjjjjjjjjjjj The combined extracts were dried over sodium sulfate, concentrated at a lower pressure, and purified by column chromatography (p.: 100 to 200 mesh, eluent: 10% ethyl acetate in n-hexane). The desired product (18 g) was obtained as a white solid.

步驟c：於一以乙腈(80毫升)溶解之步驟-b產物(4公克，0.01莫耳)溶液中添加氯化銅(12.3公克，0.09莫耳，5等量)。於10分鐘之時間，逐滴添加以乙腈(40毫升(總共120毫升))溶解之亞硝酸叔丁酯(2.8(3.3毫升)，0.023莫耳，1.5等量)溶液，並將整體反應體積於室溫攪拌5小時。以薄層層析法(10%之醋酸乙酯/正己烷)監控反應過程。反應完成後，將乙腈蒸餾出，以水(100毫升)溶解殘留物，並以醋酸乙酯(2×200毫升)萃取。將合併萃取物以硫酸鈉乾燥，於較低壓力濃縮，並以管柱色層分析法(矽膠：100至200篩孔，溶析液：存在於正己烷之4%醋酸乙酯)純化該粗製產物，以獲得呈淡黃色液體狀之所需產物(2.1公克，48%)。 Step c: Copper chloride (12.3 grams, 0.09 moles, 5 equivalents) was added to a solution of the step- b product (4 grams, 0.01 mole) dissolved in acetonitrile (80 mL). A solution of tert-butyl nitrite (2.8 (3.3 ml), 0.023 mol, 1.5 equivalent) dissolved in acetonitrile (40 ml (120 ml total)) was added dropwise over 10 min. Stir at room temperature for 5 hours. The course of the reaction was monitored by thin layer chromatography (10% ethyl acetate / n-hexane). After the reaction was completed, EtOAc was evaporated. The combined extracts were dried over sodium sulfate, concentrated at a lower pressure, and purified by column chromatography (EtOAc: 100 to 200 mesh, eluent: 4% ethyl acetate in n-hexane). The product was obtained to give the desired product (2.1 g, 48%).

步驟d：於一經攪拌、以N-甲基-2-吡咯烷酮(21毫升)溶解之步驟-c產物(2.1公克，0.008莫耳)溶液中分次添加氰化銅(1.56公克，0.017莫耳，2等量)，隨後添加催化量之碘化鈉。將該反應混合物加熱至180℃，並於此溫度維持4小時。以薄層層析法(10%之醋酸乙酯/正己烷)監控反應過程。反應完成後，以醋酸乙酯稀釋反應內容物，將內容物以矽藻土床(celite bed)過濾，並以冷水(50毫升)清洗濾液。將有機層以硫酸鈉乾燥，於較低壓力濃縮，並以管柱色層分析法(矽膠：100至200篩孔，溶析液：存在於正己烷之6至8%醋酸乙酯)純化粗製產物，以獲得呈灰白色固體狀之產物(0.8公克，40%)。 Step d: stirred at once, to the step of N- methyl-2-pyrrolidone (21 ml) was dissolved the - c product (2.1 g, 0.008 mole) was added portionwise a solution of copper cyanide (1.56 g, 0.017 mole, 2 equal amount), followed by the addition of a catalytic amount of sodium iodide. The reaction mixture was heated to 180 ° C and maintained at this temperature for 4 hours. The course of the reaction was monitored by thin layer chromatography (10% ethyl acetate / n-hexane). After completion of the reaction, the reaction contents were diluted with ethyl acetate, and the mixture was filtered over celite bed, and the filtrate was washed with cold water (50 ml). The organic layer was dried over sodium sulfate, concentrated at a lower pressure, and purified by column chromatography (purine: 100 to 200 mesh, eluent: 6 to 8% ethyl acetate in n-hexane). The product was obtained as a white solid (0.8 g, 40%).

步驟e：於一以甲醇溶解之(20毫升)步驟-d產物(1.5公克，0.006莫耳)溶液中添加催化量之雷尼鎳。將該反應混合物於60 psi氫化1小時。以薄層層析法(15%之醋酸乙酯/正己烷)監控反應過程。起始原料消失後，將內容物以矽藻土床過濾，並以甲醇清洗。以管柱色層分析法(矽膠：100至200篩孔，溶析液：存在於正己烷之6%醋酸乙酯)純化濾液，以獲得呈乳白色油狀之目標產物(1.4 公克，97%)。 Step e: A catalytic amount of Raney nickel was added to a solution of methanol-dissolved (20 mL) step- d product (1.5 g, 0.006 mol). The reaction mixture was hydrogenated at 60 psi for 1 hour. The course of the reaction was monitored by thin layer chromatography (15% ethyl acetate / n-hexane). After the starting material disappeared, the contents were filtered through a bed of diatomaceous earth and washed with methanol. The filtrate was purified by column chromatography (EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc) .

7.4(1-(啶-3-基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺鹽酸鹽之合成(例如，用於合成實例化合物no.97)Synthesis of 7.4 (1-(pyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamine hydrochloride (for example, for the synthesis of the example compound no.97)

步驟a：於15分鐘之期間，將以水(40毫升)溶解之亞硝酸鈉(35.23公克，510.6毫莫耳)溶液逐滴加至0℃、以濃氯化氫(500毫升)溶解之冰冷啶-3-胺基(40公克，425.5毫莫耳)溶液中，於添加期間將溫度維持於0℃。添加完成後將該溶液攪拌20分鐘。隨後，於20分鐘之期間，逐滴添加以濃氯化氫(100毫升)溶解之二氯化錫(177.5公克，936.3毫莫耳)溶液，於添加期間將溫度維持於0℃，並將所產生之黃色溶液於0℃攪拌30分鐘。將所得之黃色固體過濾，以水(3×50毫升)清洗，並將其乾燥，以獲得黃色固體狀之產物(106.5公克，粗製產物)。 Step a : a solution of sodium nitrite (35.23 g, 510.6 mmol) dissolved in water (40 ml) was added dropwise to 0 ° C and dissolved in concentrated hydrogen chloride (500 ml). In a solution of 3-amino (40 g, 425.5 mmol), the temperature was maintained at 0 °C during the addition. The solution was stirred for 20 minutes after the addition was completed. Subsequently, a solution of tin dichloride (177.5 g, 936.3 mmol) dissolved in concentrated hydrogen chloride (100 ml) was added dropwise over a period of 20 minutes, and the temperature was maintained at 0 ° C during the addition, and the resulting The yellow solution was stirred at 0 ° C for 30 minutes. The resulting yellow solid was filtered, washed with EtOAc EtOAcjjjjjj

步驟b：於0℃，將乙腈(38.46毫升，731.7毫莫耳)加至以1,4-二氧陸圜(450毫升)溶解之冰冷氫化鈉(60%分散於油中，29.26公克，731.7毫莫耳)懸浮液中，並攪拌30分鐘。將該反應混合物冷 卻-5℃，緩慢地添加乙基2,2,2-三氟醋酸酯(83.12公克，585.36毫莫耳)，並將該反應混合物於室溫攪拌16小時。將該反應混合物冷卻至0℃，以甲醇(150毫升)進行淬火反應，以醋酸乙酯(300毫升)稀釋，並以經稀釋之氯化氫水溶液將酸鹼值調整為約4。將有機層分離，並以醋酸乙酯(2×250毫升)萃取水層。以水(250毫升)及飽和之氯化鈉溶液(200毫升)清洗合併醋酸乙酯層，以硫酸鈉乾燥，將其過濾，並於較低壓力濃縮，以獲得一褐色液體(57公克)。該粗製產物不需進一步純化即可使用。 Step b : Acetonitrile (38.46 ml, 731.7 mmol) was added to ice-cold sodium hydride (60% dissolving in oil, 29.26 g, 731.7) dissolved in 1,4-dioxane (450 ml) at 0 °C. Millions of the suspension and stir for 30 minutes. The reaction mixture was cooled to -5 ° C, ethyl 2,2,2-trifluoroacetate (83.12 g, 585.36 mmol) was slowly added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was cooled to 0 ° C, quenched with methanol (150 mL), diluted with ethyl acetate (300 ml), and adjusted to a pH of about 4 with diluted aqueous hydrogen chloride. The organic layer was separated and the aqueous layer was extracted ethyl acetate (2×250 mL). The combined ethyl acetate layer was washed with water (250 ml) and sat. sodium chloride (200 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford a brown liquid (57 g). This crude product was used without further purification.

步驟c：將以乙醇(650毫升)溶解之步驟-b產物(57公克，粗製產物；416.05毫莫耳)與步驟-a產物(60.5公克，416.05毫莫耳)攪拌回流3小時。將該反應混合物濃縮；以醋酸乙酯(2公升)稀釋所得之殘留物，以水(2×500毫升)及飽和之氯化鈉溶液(500毫升)清洗，以硫酸鈉乾燥，將其過濾，並於較低壓力濃縮，以獲得殘留物。以管柱色層分析法(矽膠：100至200篩孔，溶析液：存在於石油醚之30%醋酸乙酯)將其純化，以獲得一黃色固體(31.48公克)。 Step c : The step- b product (57 g, crude product; 416.05 mmol) dissolved in ethanol (650 mL) was stirred and refluxed for 3 hours with the step- a product (60.5 g, 416.05 mmol). The reaction mixture was concentrated. EtOAc (EtOAc m. It was concentrated at a lower pressure to obtain a residue. It was purified by column chromatography (tank: 100 to 200 mesh, eluent: 30% ethyl acetate in petroleum ether) to give a yellow solid (31.48 g).

步驟d：於0℃，將以乙腈(100毫升)溶解之步驟-c產物(23.5公克，103.07毫莫耳)溶液逐滴加至以無水乙腈(350毫升)溶解之冰冷碘化鉀(51.3公克，309.21毫莫耳)及亞硝酸異戊酯(41.16毫升，309.21毫莫耳)懸浮液中，並將該反應混合物於100℃攪拌20小時。將該反應混合物濃縮；以醋酸乙酯(1公升)稀釋所得之殘留物，以水(2×400毫升)及飽和之氯化鈉溶液(200毫升)清洗，以硫酸鈉乾燥，並將其過濾及濃縮，以獲得殘留物。以管柱色層分析法(矽膠：100至200篩孔，溶析液：存在於石油醚之30%醋酸乙酯)將其純化，以獲得一淡黃色固體(16.52公克，37%)。 Step d : A solution of the step-c product (23.5 g, 103.07 mmol) dissolved in acetonitrile (100 ml) was added dropwise to ice-cold potassium iodide (51.3 g, 309.21) dissolved in anhydrous acetonitrile (350 ml) at 0 °C. Millol) and isoamyl nitrite (41.16 ml, 309.21 mmol) were stirred and the reaction mixture was stirred at 100 ° C for 20 hours. The reaction mixture was concentrated; EtOAc (EtOAc) (EtOAc m. And concentrated to obtain a residue. It was purified by column chromatography (tank: 100 to 200 mesh, eluent: 30% ethyl acetate in petroleum ether) to afford a pale yellow solid (16.52 g, 37%).

步驟e：於一以無水N-甲基-2-吡咯烷酮(150毫升)溶解之步驟 -d產物(16.5公克，48.67毫莫耳)溶液中添加氰化亞銅(6.53公克，73.0毫莫耳)，並將該反應混合物於200℃攪拌2小時。將該反應混合物冷卻至室溫，以乙烯二胺(50毫升)進行淬火反應，再以醋酸乙酯(800毫升)稀釋。將所得之懸浮液以矽藻土床過濾，再以醋酸乙酯(2×100毫升)清洗。將合併濾液以水(2×300毫升)及飽和之氯化鈉溶液(250毫升)清洗，以硫酸鈉乾燥，將其過濾，並於較低壓力濃縮，以獲得殘留物。以管柱色層分析法(矽膠；100至200篩孔，溶析液：存在於石油醚之20至30%醋酸乙酯)將其純化，以獲得一黃色固體(5.12公克，44%)。 Step e : Add copper cyanide (6.53 g, 73.0 mmol) to a solution of the step- d product (16.5 g, 48.67 mmol) dissolved in anhydrous N-methyl-2-pyrrolidone (150 ml). The reaction mixture was stirred at 200 ° C for 2 hours. The reaction mixture was cooled to room temperature and then quenched with ethyldiamine (50 mL). The resulting suspension was filtered over a pad of celite and washed with ethyl acetate (2×100 mL). The combined filtrate was washed with water (2×300 ml) and sat. sodium chloride (250 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford residue. It was purified by column chromatography (tank: 100 to 200 mesh, eluent: 20 to 30% ethyl acetate in petroleum ether) to afford a yellow solid (5.12 g, 44%).

步驟f：於一以飽和之甲醇氨(methanolic NH3)(50毫升)溶解之步驟-e產物(4.5公克，18.9毫莫耳)溶液中添加雷尼鎳(3公克，濕重，以甲醇(4×5毫升)清洗)，並於室溫，將該混合物於一帕爾氫化器(Parr hydrogenator)，以40 Psi之壓力下氫化4小時。將該反應混合物以矽藻土床過濾，並將濾液於較低壓力濃縮。將所得之殘留物於以乙醚(50毫升)溶解之飽和氯化氫中攪拌2小時。將乙醚傾析，以乙醚(3×10毫升)清洗所得之固體，將其真空乾燥，以獲得呈淡褐色固體狀之化合物產物(1.2公克，23%)。 Step f : Add Raney nickel (3 g, wet weight to methanol) in a solution of the step-e product (4.5 g, 18.9 mmol) dissolved in saturated methanolic ( 3 ml) (50 ml). 4 x 5 ml) washed) and the mixture was hydrogenated at a temperature of 40 Psi for 4 hours at room temperature in a Parr hydrogenator. The reaction mixture was filtered through a pad of celite, and filtrate was concentrated at lower pressure. The residue obtained was stirred for 2 hours with saturated hydrogen chloride dissolved in diethyl ether (50 ml). The ether was decanted, EtOAc (EtOAc) (EtOAc)

7.5(1-(4-甲氧苄基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺之合成(例如，用於實例化合物no.86)Synthesis of 7.5 (1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamine (for example, for example compound no. 86)

步驟a：將4-二甲胺基啶(4.25公克，0.034莫耳，0.01等量)加至二氯甲烷(3公升)中，並將內容物冷卻至-10℃。於45分鐘之期間，依序於-10℃添加三氟醋酸酐(765公克(510毫升)，3.2莫耳，1.05等量)及乙基乙烯基醚(250公克，3.04莫耳)。隨後將整體反應混合物先於0℃攪拌8小時，再於室溫攪拌過夜。以薄層層析法(10%之醋酸乙酯/正己烷)監控反應過程。反應完成後，將內容物以飽和之碳酸氫鈉溶液(600毫升)進行淬火反應，以分離有機層。以二氯甲烷(2×500毫升)萃取水層。將合併有機層以水(2×1公升)清洗，以硫酸鈉乾燥，並於較低壓力濃縮，以獲得褐色液體狀之產物(450公克，粗製產物)。 Step a: 4-Dimethylaminopyridine (4.25 grams, 0.034 moles, 0.01 equivalent) was added to dichloromethane (3 liters) and the contents were cooled to -10. Trifluoroacetic anhydride (765 g (510 ml), 3.2 mol, 1.05 equivalent) and ethyl vinyl ether (250 g, 3.04 mol) were added at -10 °C over a period of 45 min. The whole reaction mixture was then stirred at 0 ° C for 8 hours and then at room temperature overnight. The course of the reaction was monitored by thin layer chromatography (10% ethyl acetate / n-hexane). After completion of the reaction, the contents were quenched with a saturated sodium hydrogen carbonate solution (600 ml) to separate organic layers. The aqueous layer was extracted with dichloromethane (2×500 mL). The combined organic layers were washed with water (2×1 liters), dried over sodium sulfate, and concentrated to afford a brown liquid (450 g, crude product).

步驟b：以乙醇(1.4公升)溶解二(氫氯酸)胼(225公克，2.14莫耳，1.6等量)，並將其徹底攪拌。於45分鐘之期間，於室溫逐滴添加三乙胺(135.4公克(185.4毫升)，1.34莫耳，1等量)。隨後，於室溫逐滴添加步驟-a之產物(225公克，粗製產物)，並將整體反應混合物回流過夜。以薄層層析法(20%之醋酸乙酯/正己烷)監控反 應過程。反應完成後，將乙醇完全地蒸餾出，以冰水(500毫升)溶解殘留物，並以醋酸乙酯(2×400毫升)萃取產物。將合併萃取物以冰水(300毫升)清洗，以硫酸鈉乾燥，並於較低壓力濃縮，以獲得灰白色固體狀之所需產物(195公克)。 Step b: Dissolve bis(hydrochloride) hydrazine (225 grams, 2.14 moles, 1.6 equivalents) in ethanol (1.4 liters) and stir thoroughly. Triethylamine (135.4 grams (185.4 ml), 1.34 moles, 1 equivalent) was added dropwise at room temperature over a 45 minute period. Subsequently, the product of step - a (225 g, crude product) was added dropwise at room temperature and the whole reaction mixture was refluxed overnight. The course of the reaction was monitored by thin layer chromatography (20% ethyl acetate / n-hexane). After completion of the reaction, the ethanol was completely distilled, and the residue was dissolved in ice water (500 ml). The combined extracts were washed with EtOAc (EtOAc m.

步驟c：將氫化鈉(33.08公克(19.85，60%)，1.5等量)加至小量之正己烷中，並徹底攪拌10分鐘。將正己烷傾析，於氮氣氣氛下逐滴添加無水二甲基甲醯胺(500毫升)，並將其徹底攪拌。於氮氣氣氛下，逐滴添加以二甲基甲醯胺(125毫升)溶解之步驟-b產物(75公克，0.55莫耳)溶液。隨後，逐滴添加以二甲基甲醯胺(125毫升)溶解之4-甲氧基苯甲醯氯(86.3公克，0.55莫耳，1等量)溶液，並將整體反應混合物於室溫攪拌12小時。以薄層層析法(存在於正己烷之10%醋酸乙酯)監控反應過程。反應完成後，將反應內容物倒入冰水(500毫升)中，並以醋酸乙酯(2×400毫升)萃取產物。隨後，將內容物以硫酸鈉乾燥，並於較低壓力濃縮，以獲得褐色液體狀之所需產物(125公克，88%)。 Step c: Sodium hydride (33.08 g (19.85, 60%), 1.5 equivalent) was added to a small amount of n-hexane and stirred thoroughly for 10 min. The n-hexane was decanted, anhydrous dimethylformamide (500 ml) was added dropwise under a nitrogen atmosphere, and stirred thoroughly. A solution of the step- b product (75 g, 0.55 mol) dissolved in dimethylformamide (125 ml) was added dropwise under a nitrogen atmosphere. Subsequently, a solution of 4-methoxybenzimid chloride (86.3 g, 0.55 mol, 1 equivalent) dissolved in dimethylformamide (125 ml) was added dropwise, and the whole reaction mixture was stirred at room temperature. 12 hours. The course of the reaction was monitored by thin layer chromatography (10% ethyl acetate in n-hexane). After completion of the reaction, the reaction mixture was poured into ice water (500 ml), Subsequently, the contents were dried over sodium sulfate and concentrated under reduced pressure to afford desired product (125 g, 88%).

步驟d：以四氫呋喃(500毫升)溶解二異丙胺(28.4公克(39.4毫升)，1.2等量)，將其徹底攪拌，並將內容物冷卻至0℃。於0℃，逐滴添加正丁基鋰(234.4毫升，1.5等量)，並將內容物冷卻至-78℃。於30分鐘之期間，逐滴添加以四氫呋喃(200毫升)溶解之步驟-c產物(62公克，0.24莫耳)，並將該內容物於-78℃再度攪拌30分鐘。隨後，將無水二氧化碳鼓泡通入該反應混合物1.5小時，並以薄層層析法(10%之醋酸乙酯/正己烷)監控反應過程。反應完成後，將反應內容物倒入冰水(300毫升)中，並於鹼性條件下，以醋酸乙酯(2×200毫升)萃取水層。將水層以20%之氯化氫溶液酸化，並以醋酸乙酯(2×200毫升)萃取。將合併有機層以硫酸鈉乾燥，並於較低壓力濃縮，以獲得灰白色固體狀之所需產物(42公克， 58%)。 Step d: Dissolve diisopropylamine (28.4 g (39.4 ml), 1.2 equivalent) in tetrahydrofuran (500 mL), stir thoroughly, and cool the contents to 0 °C. n-Butyllithium (234.4 mL, 1.5 equivalents) was added dropwise at 0 ° C and the contents were cooled to -78 °C. The product of step -c (62 g, 0.24 mol) dissolved in tetrahydrofuran (200 mL) was added dropwise over a period of 30 min and the mixture was stirred again at -78 °C for 30 min. Subsequently, anhydrous carbon dioxide was bubbled through the reaction mixture for 1.5 hours, and the reaction was monitored by thin layer chromatography (10% ethyl acetate / n-hexane). After completion of the reaction, the reaction mixture was poured into ice water (300 ml), and the aqueous layer was extracted with ethyl acetate (2×200 ml) under basic conditions. The aqueous layer was acidified with a 20% aqueous hydrogen chloride solution and extracted with ethyl acetate (2×200 mL). The combined organic layers were dried with EtOAc EtOAc (EtOAc)

步驟e：於一以二氯甲烷(750毫升)溶解之步驟-d產物(50公克，0.16莫耳)溶液中添加催化量之二甲基甲醯胺，並將其冷卻至0℃。於30分鐘之期間，於0℃逐滴添加亞硫醯氯(99.3公克(61毫升)，0.83莫耳，5等量)。將整體反應混合物緩慢地加熱至回流溫度並使其回流2小時。以薄層層析法(10%之醋酸乙酯/正己烷)監控反應過程。起始原料消失後，將二氯甲烷完全地蒸餾出。將以上製備之酸性氯以二氯甲烷(500毫升)溶解，並於0℃逐滴添加於氨水溶液(600至700毫升)中。將整體反應混合物攪拌1小時，並以薄層層析法(10%之醋酸乙酯/正己烷，Rf~0.7)監控反應過程。反應完成後，加入冰水(200毫升)，並以醋酸乙酯(2×200毫升)萃取產物。將合併有機層以硫酸鈉乾燥，並於較低壓力濃縮，以獲得灰白色固體重之所需產物(37公克，粗製產物)。所獲得之粗製產物可直接於下一步驟使用。 Step e: A catalytic amount of dimethylformamide was added to a solution of the step- d product (50 g, 0.16 mol) dissolved in dichloromethane (750 mL) and cooled to 0 °C. Thionium chloride (99.3 g (61 ml), 0.83 mol, 5 equivalent) was added dropwise at 0 °C over a period of 30 minutes. The whole reaction mixture was slowly heated to reflux temperature and allowed to reflux for 2 hours. The course of the reaction was monitored by thin layer chromatography (10% ethyl acetate / n-hexane). After the starting material disappeared, the dichloromethane was completely distilled off. The acidic chlorine prepared above was dissolved in dichloromethane (500 ml) and added dropwise to aqueous ammonia (600 to 700 ml) at 0 °C. The whole reaction mixture was stirred for 1 hour and the reaction was monitored by thin layer chromatography (10% ethyl acetate / n-hexane, Rf - 0.7). After the reaction was completed, ice water (200 ml) was added, and the product was extracted with ethyl acetate (2×200 ml). The combined organic layers were dried with EtOAc (EtOAc m. The crude product obtained can be used directly in the next step.

步驟f：將氫化鋁鋰(4.7公克，0.12莫耳，1等量)加至小量之正己烷中並徹底攪拌10分鐘。將正己烷傾析，並於低溫條件下將四氫呋喃(250毫升)加至氫化鋁鋰中。隨後於30分鐘之期間，於0℃逐滴添加以四氫呋喃(120毫升)溶解之步驟-e產物(37公克，0.12莫耳)溶液，並將該反應混合物加熱回流5小時。以薄層層析法(50%之醋酸乙酯/正己烷)監控反應過程。反應完全啟動後，添加氫化鋁鋰(2.3公克)，並再度回流4小時。此次令反應完成。之後，將反應內容物緩慢地加至飽和之硫酸鈉溶液(1公升)，並以醋酸乙酯(2×500毫升)萃取產物。將混合萃取物以硫酸鈉乾燥，並於較低壓力濃縮，以獲得灰白色固體狀之粗製產物(32.5公克)。所得之粗製產物可直接於下一步驟使用。 Step f: Lithium aluminum hydride (4.7 g, 0.12 mol, 1 equivalent) was added to a small amount of n-hexane and stirred thoroughly for 10 min. The n-hexane was decanted, and tetrahydrofuran (250 ml) was added to lithium aluminum hydride under low temperature. Then, a solution of the step-e product (37 g, 0.12 mol) dissolved in tetrahydrofuran (120 ml) was added dropwise at 0 ° C over 30 min, and the reaction mixture was heated to reflux for 5 hr. The course of the reaction was monitored by thin layer chromatography (50% ethyl acetate / n-hexane). After the reaction was completely started, lithium aluminum hydride (2.3 g) was added and refluxed for another 4 hours. The response was completed. Thereafter, the reaction contents were slowly added to a saturated sodium sulfate solution (1 liter), and the product was extracted with ethyl acetate (2×500 ml). The combined extracts were dried with EtOAc (EtOAc m. The resulting crude product can be used directly in the next step.

步驟g：於10分鐘之期間，將三乙胺(22.7公克(30.2毫升)， 0.026莫耳，0.8等量)逐滴加至冷卻至0℃、以二氯甲烷(600毫升)溶解之步驟-f產物((80公克，0.28莫耳)溶液中。隨後，於20至30分鐘之期間，於0℃逐滴添加以二氯甲烷(200毫升)溶解之二碳酸二叔丁酯(Boc anhydride)(61.2公克(62.5毫升)。將整體反應混合物先於0℃攪拌30分鐘，再於室溫攪拌30分鐘。以薄層層析法(20%之醋酸乙酯/正己烷)監控反應過程。反應完成後，將二氯甲烷完全地蒸餾出，以冰水(500毫升)溶解殘留物，並以醋酸乙酯(2×300毫升)萃取產物。將合併萃取物以硫酸鈉乾燥，並於較低壓力濃縮。將所得之粗製產物油正己烷(200毫升)重結晶，以獲得灰白色固體狀之所需產物(80公克，74%)。 Step g: During the course of 10 minutes, triethylamine (22.7 g (30.2 ml), 0.026 mol, 0.8 equivalent) was added dropwise to the step of cooling to 0 ° C and dissolving in dichloromethane (600 ml) - f product ((80 g, 0.28 mol) in solution. Subsequently, Boc anhydride dissolved in dichloromethane (200 ml) was added dropwise at 0 °C over a period of 20 to 30 minutes. (61.2 g (62.5 ml). The whole reaction mixture was stirred at 0 ° C for 30 minutes and then at room temperature for 30 minutes. The reaction was monitored by thin layer chromatography (20% ethyl acetate / n-hexane). After completion, the methylene chloride was completely distilled off, the residue was crystallised eluted with EtOAc (EtOAc) The resulting crude product was crystallised from EtOAc (EtOAc:EtOAc)

步驟h：以二氯甲烷(30毫升)溶解步驟-g產物(5公克，0.012莫耳)，並將其冷卻至0℃。於0℃，以氯化氫氣體鼓泡通入該反應混合物45分鐘。以薄層層析法(30%之醋酸乙酯/正己烷)監控反應過程。反應完成後，將二氯甲烷完全地蒸餾出。以冰水(200毫升)溶解殘留物，並以20%之醋酸乙酯/正己烷(2×100毫升)萃取產物。以2N之氫氧化鈉溶液將水層之酸鹼值鹼化至約10，並以醋酸乙酯(5×100毫升)萃取。將合併有機層以水(2×200毫升)清洗，以硫酸鈉乾燥，並於較低壓力濃縮，以獲得黃色液體狀之所需產物(2.4公克，64%)。 Step h : The step- g product (5 g, 0.012 mol) was dissolved in dichloromethane (30 mL) and cooled to 0. The reaction mixture was bubbled through hydrogen chloride gas at 0 ° C for 45 minutes. The progress of the reaction was monitored by thin layer chromatography (30% ethyl acetate / n-hexane). After the reaction was completed, the dichloromethane was completely distilled off. The residue was dissolved in ice water (200 mL) andEtOAc was evaporated The pH of the aqueous layer was basified to about 10 with a 2N sodium hydroxide solution and extracted with ethyl acetate (5×100 mL). The combined organic layers were washed with EtOAc EtOAc m.

示範性化合物之合成：Synthesis of exemplary compounds:

製備醯胺(Z=C-R 4b ) Preparation of decylamine (Z = CR 4b )

通式(II)之胺與通式(III)之羧酸或通式(III)之羧酸衍生物反應，以形成通式(I)化合物之大方向，其中，Z=C-R4b(醯胺)，如方案1(步驟j09)。 A carboxylic acid derivative of formula (II) with an amine of formula (III) or a carboxylic acid of formula (III), the form to formula (I) compounds of the general direction, wherein, Z = CR 4b (Amides ), as in scenario 1 (step j09 ).

方法A： Method A :

於室溫，將通式(III)之酸(1等量)、通式(II)之胺(1.2等量)及N-乙基-N‘-(3-二甲胺基丙基)碘化二亞胺氯化氫(1.2等量)加入二甲基甲醯胺(10毫莫耳之酸/20毫升)中攪拌12小時，隨後於其中添加水。以醋酸乙酯重複萃取該反應混合物，使水層所含之氯化鈉達到飽和，隨後以醋酸乙酯重新萃取。將合併有機相以1N之氯化氫及飽和之氯化鈉溶液清洗，以硫酸鎂乾燥，並於真空狀態下去除溶媒。以快速色層分析法(矽膠：100至200篩孔，溶析液：不同比例之醋酸乙酯/正己烷，例如1：2)純化殘留物，以此方法獲得產物(I)。 The acid of the formula ( III ) (1 equivalent), the amine of the formula ( II ) (1.2 equivalent) and N-ethyl-N'-(3-dimethylaminopropyl) iodine at room temperature Diimine hydrogen chloride (1.2 equivalent) was added to dimethylformamide (10 mmol of acid / 20 ml) and stirred for 12 hours, after which water was added. The reaction mixture was repeatedly extracted with ethyl acetate to saturate the sodium chloride contained in the aqueous layer, followed by re-extraction with ethyl acetate. The combined organic phases were washed with 1N hydrogen chloride and saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The product ( I ) is obtained by flash chromatography (purine: 100 to 200 mesh, eluent: different ratios of ethyl acetate/n-hexane, for example 1:2) to purify the residue.

方法B： Method B :

於0℃，將通式(III)之酸(1等量)與通式(II)之胺(1.1等量)以二氯甲烷(1毫莫耳酸於6毫升中)溶解，並將其與N-乙基-N‘-(3-二甲胺基丙基)碘化二亞胺氯化氫(1.5等量)、h1-羥基苯並三唑水合物(h1-hydroxybenzotriazolhydrate)(1.4等量)及三乙胺(3等量)混合。將該反應混合物於室溫攪拌20分鐘，並以管柱色層分析法(矽膠：100至200篩孔，溶析液：不同比例之正己烷/醋酸乙酯，例如2：1)純化粗製產物，以此方法獲得(I)。 The acid of the formula ( III ) (1 equivalent) and the amine of the formula ( II ) (1.1 equivalent) were dissolved in dichloromethane (1 mmol of a solution in 6 ml) at 0 ° C, and N-ethyl-N'-(3-dimethylaminopropyl) iodide diimine hydrogen chloride (1.5 equivalent), h1-hydroxybenzotriazolhydrate (1.4 equivalent) And triethylamine (3 equal amount) mixed. The reaction mixture was stirred at room temperature for 20 minutes, and the crude product was purified by column chromatography (gel: 100 to 200 mesh, eluent: different ratios of n-hexane / ethyl acetate, for example 2:1) In this way, ( I ) is obtained.

方法C： Method C :

首先將通式(III)、D=OH之酸(1等量)與氯化劑混合，以亞硫醯氯混合較佳，將以此方法所得之混合物煮沸回流，以此方法將酸(III)轉化為相應之D=Ha之酸性氯(III)。將通式(II)之胺(1.1等量)以二氯甲烷(1毫莫耳之酸於6毫升中)溶解，並於0℃與三乙胺(3等量)混合。將該反應混合物於室溫攪拌20小時，並以管柱色層分析法(矽膠：100至200篩孔，溶析液：不同比例之正己烷/醋酸乙酯，例如2：1)純化粗製產物，以此方法獲得(I)。 First, the acid of the general formula ( III ) and D=OH (1 equivalent amount) is mixed with a chlorinating agent, preferably mixed with sulfinium chloride, and the mixture obtained by the method is boiled and refluxed, thereby acid ( III). ) is converted to the corresponding acid chloride ( III ) of D = Ha. The amine of the general formula ( II ) (1.1 equivalent) was dissolved in dichloromethane (1 mmol of acid in 6 ml) and mixed with triethylamine (3 equivalent) at 0 °C. The reaction mixture was stirred at room temperature for 20 hours, and the crude product was purified by column chromatography (gel: 100 to 200 mesh, eluent: different ratios of n-hexane / ethyl acetate, for example 2:1) In this way, ( I ) is obtained.

方法D： Method D :

將所獲得之苯酯(IIIa)(1等量)與相應之胺(II)(1.1等量)以四氫呋喃(10毫莫耳之反應混合物於120毫升)溶解，並於添加1,8-二氮雜二環[5,4,0]十一碳-7-烯(1.5等量)後，於室溫攪拌16小時。於真空狀態去除溶媒後，再以快速色層分析法(矽膠：100至200篩孔，溶析液：不同比例之醋酸乙酯/正己烷例如1：1)純化所得之殘留物，以此方法獲得(I)。 The obtained phenyl ester ( IIIa ) (1 equivalent) and the corresponding amine ( II ) (1.1 equivalent) were dissolved in tetrahydrofuran (10 mmol reaction mixture in 120 ml), and 1,8-di was added thereto. After azabicyclo[5,4,0]undec-7-ene (1.5 equivalent), it was stirred at room temperature for 16 hours. After removing the solvent in a vacuum state, the residue obtained by the rapid color layer analysis method (silicone: 100 to 200 mesh, solution: different ratio of ethyl acetate/n-hexane, for example, 1:1) is purified. Obtain ( I ).

製備尿素(Z=N) Preparation of urea (Z = N)

通式(II)或(V)之胺與氯甲酸苯酯反應，以形成通式(IV)或(Va)之化合物(分別為步驟j07與步驟v1)，及後續通式(V)之化合物與通式(VI)之胺反映，或通式(VIa)之化合物與通式(II)之胺反應，以形成通式(I)之化合物之大方向，其中，A=N，如方案1a與1c(分別為步驟j08與步驟v2)： The amine of the formula ( II ) or ( V ) is reacted with phenyl chloroformate to form a compound of the formula ( IV ) or ( Va ) (steps j07 and v1 , respectively), and a compound of the formula ( V ) Reaction with an amine of the formula ( VI ), or a compound of the formula ( VIa ) with an amine of the formula ( II ) to form the general direction of the compound of the formula ( I ), wherein A = N, as in Scheme 1a With 1c (steps j08 and v2, respectively ):

步驟j07/步驟v1：將通式(II)或(V)之胺(1等量)置放於二氯甲烷(10毫莫耳之胺於70毫升)中，於室溫添加氯甲酸苯酯(1.1等量)，並將該混合物攪拌30分鐘。於真空狀態去除溶媒後，以快速色層分析法(矽膠：100至200篩孔，溶析液：不同比例之二乙醚/正己烷，例如1：2)純化殘留物，以此方法獲得(IV)或(Va)。 Step j07 / Step v1 : The amine of the formula ( II ) or ( V ) (1 equivalent) is placed in dichloromethane (10 mmol of amine in 70 ml), and phenyl chloroformate is added at room temperature. (1.1 equivalent) and the mixture was stirred for 30 minutes. After removal of the solvent in vacuum, rapid Chromatography (silica gel: 100-200 mesh, elution solution: different proportions of diethyl ether / n-hexane, e.g. 1: 2) to give the residue obtained in this way (IV ) or ( Va ).

步驟j08/步驟v2：將所獲得之胺基甲酸苯酯(IV)或(Va)(1等量)及相應之胺(V)或(II)(1.1等量)以四氫呋喃(10毫莫耳之反應混合物於120毫升)溶解，並於添加1,8-二氮雜二環[5,4,0]十一碳-7-烯(1.5等量)後於室溫攪拌16小時。於真空狀態去除溶媒後，以快速色層分析法(矽膠：100至200篩孔，溶析液：不同比例之醋酸乙酯/正己烷，例如1：1)純化所得之殘留物，以此方法獲得(I)。 Step j08 / step v2 : the obtained phenyl carbamate ( IV ) or ( Va ) (1 equivalent) and the corresponding amine ( V ) or ( II ) (1.1 equivalent) in tetrahydrofuran (10 mmol) The reaction mixture was dissolved in 120 ml) and stirred at room temperature for 16 hours after addition of 1,8-diazabicyclo[5,4,0]undec-7-ene (1.5 equivalent). After removing the solvent in a vacuum state, the residue obtained by the rapid color layer analysis method (silicone: 100 to 200 mesh, solution: different ratio of ethyl acetate/n-hexane, for example, 1:1) is purified. Obtain ( I ).

示範性化合物1至19、21至27、30、32、50至51、53至71、79、87至96、98至115、117、120至121、123-127與129至133，係以如上揭露之其中一種方法，及根據方案1與2獲得。示範性 化合物20、28-29、31、33至49、52、72-78、80至86、97、116、118至119、122、128與134至135可以如上揭露之其中一種方法獲得。熟知此技術領域者了解該使用何種方法獲得一特定示範性化合物。 Exemplary compounds 1 to 19, 21 to 27, 30, 32, 50 to 51, 53 to 71, 79, 87 to 96, 98 to 115, 117, 120 to 121, 123 to 127 and 129 to 133 are as above One of the methods disclosed, and obtained according to Schemes 1 and 2. Exemplary Compounds 20, 28-29, 31, 33 to 49, 52, 72-78, 80 to 86, 97, 116, 118 to 119, 122, 128 and 134 to 135 can be obtained by one of the methods as disclosed above. Those skilled in the art are aware of which method is used to obtain a particular exemplary compound.

精選示範性化合物之詳細合成方法Detailed synthesis of selected exemplary compounds

實例1之合成：Synthesis of Example 1:

N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(啶-2-基)乙醯胺 N-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(pyridin-2-yl)acetamide

步驟1：於0℃，將乙腈(20公克，487.5毫莫耳)逐滴加至冰冷、以1,4-二氧陸圜(300毫升)溶解之氫化鈉(60%分散於油中，19.5公克，487.5毫莫耳)懸浮液中，並攪拌30分鐘。將該反應混合物冷卻至-5℃，緩慢地添加三氟乙酯(A)(55公克，387.3毫莫耳)，並於室溫攪拌16小時，直氣相分層分析顯示至其被完全消耗。將該反應混合物冷卻至0℃，以甲醇(120毫升)進行淬火反應，以醋酸乙酯(200毫升)稀釋，並以經稀釋之氯化氫水溶液將酸鹼值調整為約4。將有機層分離，並以醋酸乙酯(2×250毫升)萃取水層。將合併醋酸乙酯層以水(250毫升)及飽和之氯化鈉溶液(200毫升)清洗，以硫酸鈉乾燥，將其過濾，並於較低壓力濃縮，以獲得4,4,4-三氟-3-氰基丙酮。該粗製產物不需進一步純化即可使用。此項反應係分為三批次(3×55公克)進行，以獲得褐色液體之4,4,4-三氟-3-氰基丙酮(B)粗製產物(75公克)。 Step 1: Acetonitrile (20 grams, 487.5 millimoles) was added dropwise to the ice-cold, sodium hydride dissolved in 1,4-dioxane (300 ml) at 60 ° C (60% dispersed in oil, 19.5) Grams, 487.5 mmoles in suspension, and stirred for 30 minutes. The reaction mixture was cooled to -5 ° C, trifluoroethyl ester (A) (55 g, 387.3 mmol) was slowly added, and stirred at room temperature for 16 hours, and analyzed by direct gas phase stratification until it was completely consumed. . The reaction mixture was cooled to 0 ° C, quenched with EtOAc (EtOAc) (EtOAc) The organic layer was separated and the aqueous layer was extracted ethyl acetate (2×250 mL). The combined ethyl acetate layer was washed with water (250 ml) and saturated sodium chloride solution (200 ml), dried over sodium sulfate, filtered and concentrated at lower pressure to obtain 4, 4, 4 Fluoro-3-cyanoacetone. This crude product was used without further purification. This reaction was carried out in three batches (3 x 55 g) to give a crude product of 4,4,4-trifluoro-3-cyanoacetone (B) (75 g) as a brown liquid.

步驟2：將以乙醇(1.1公升)溶解之4,4,4-三氟-3-氰基丙酮(B)(75.3公克，粗製產物，557毫莫耳(理論上))及3-氯苯胼(C)(99.87公克，557.7毫莫耳)攪拌回流3小時，直至薄層層析分析顯示其被完全消耗。將該反應混合物濃縮；將所得之殘留物以醋酸乙酯(1公升)稀釋，以水(2×250毫升)及飽和之氯化鈉溶液(200毫升)清洗，以硫酸鈉乾燥，將其過濾，並於較低壓力濃縮，以獲得殘留物。以管柱色層分析法(矽膠：100至200篩孔，溶析液：存在於石油醚之50至70%氯仿)進行純化，以獲得淡黃色固體狀之1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-胺(D)(30.32公克，10%，總和以上2步驟)。 Step 2: 4,4,4-Trifluoro-3-cyanoacetone (B) (75.3 g, crude product, 557 mmol (theoretical)) and 3-chlorobenzene dissolved in ethanol (1.1 liter)胼(C) (99.87 grams, 557.7 millimoles) was stirred under reflux for 3 hours until thin layer chromatography analysis showed complete consumption. The reaction mixture was concentrated; EtOAc EtOAc (EtOAc m. And concentrated at a lower pressure to obtain a residue. Purification by column chromatography (tank: 100 to 200 mesh, eluent: 50 to 70% chloroform in petroleum ether) to give 1-(3-chlorophenyl) as a pale yellow solid. -3-(Trifluoromethyl)-1H-pyrazole-5-amine (D) (30.32 g, 10%, sum 2 above).

步驟3：於0℃，將以乙腈(50毫升)溶解之1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-胺(D)(10公克，38.16毫莫耳)溶液逐滴加至冰冷、以無水乙腈(100毫升)溶解之碘化鉀(19.02公克，114.55毫莫 耳)及亞硝酸異戊酯(15.3毫升，114.55毫莫耳)溶液中，並將該反應混合物於100℃攪拌20分鐘，直至薄層層析分析顯示其被完全消耗。將該反應混合物濃縮；將所得之殘留物以醋酸乙酯(1公升)稀釋，以水(2×500毫升)及飽和之氯化鈉溶液(200毫升)清洗，以硫酸鈉乾燥，將其過濾並濃縮，以獲得殘留物。以管柱色層分析法(矽膠：100至200篩孔，溶析液：存在於石油醚之5%醋酸乙酯)將其純化，以獲得淡黃色固體狀之1-(3-氯苯基)-5-碘基-3-(三氟甲基)-1H-吡唑。此項反應係分為三批次(3×10公克)進行，以獲得黃色固體狀之1-(3-氯苯基)-5-碘基-3-(三氟甲基)-1H-吡唑(E)(20.12公克，合併純化，47%)。 Step 3: 1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-amine (D) (10 g, dissolved in acetonitrile (50 mL). 38.16 mmol) was added dropwise to a solution of potassium iodide (19.02 g, 114.55 mmol) and isoamyl nitrite (15.3 ml, 114.55 mmol) dissolved in anhydrous acetonitrile (100 mL). The reaction mixture was stirred at 100 ° C for 20 minutes until analysis by thin layer chromatography indicated that it was consumed completely. The reaction mixture was concentrated; the residue was purified ethyl acetate (1 liter), washed with water (2×500 ml) and saturated sodium chloride solution (200 ml), dried over sodium sulfate and filtered It was concentrated to obtain a residue. It was purified by column chromatography (tank: 100 to 200 mesh, eluent: 5% ethyl acetate in petroleum ether) to give 1-(3-chlorophenyl) as a pale yellow solid. -5-iodo-3-(trifluoromethyl)-1H-pyrazole. This reaction was carried out in three batches (3 x 10 g) to give 1-(3-chlorophenyl)-5-iodo-3-(trifluoromethyl)-1H-pyridin as a yellow solid. Oxazole (E) (20.12 g, combined purification, 47%).

步驟4：於一以無水N-甲基-2-吡咯啶酮(200毫升)溶解之1-(3-氯苯基)-5-碘基-3-(三氟甲基)-1H-吡唑(E)(20.12公克，54.06毫莫耳)溶液中添加氰化銅(I)(7.33公克，81.84毫莫耳)，並將該反應混合物於200℃攪拌2小時，直至薄層層析分析顯示其被完全消耗。將該反應混合物冷卻至室溫，以乙烯二胺(50毫升)進行淬火反應，並以醋酸乙酯(200毫升)稀釋。將所得之懸浮液以矽藻土床過濾，並以醋酸乙酯(2×50毫升)清洗。將合併濾液以水(100毫升)及飽和之氯化鈉溶液(100毫升)清洗，以硫酸鈉乾燥，將其過濾，並於較低壓力濃縮，以獲得殘留物。以管柱色層分析法(矽膠：100至200篩孔，溶析液：石油醚)進行純化，以獲得黃色固體狀之1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-碳化腈(F)(10.12公克、69%)。 Step 4: 1-(3-Chlorophenyl)-5-iodo-3-(trifluoromethyl)-1H-pyrene dissolved in anhydrous N-methyl-2-pyrrolidone (200 mL) Copper (I) cyanide (I) (7.33 g, 81.84 mmol) was added to the solution of azole (E) (20.12 g, 54.06 mmol), and the reaction mixture was stirred at 200 ° C for 2 hours until thin layer chromatography analysis Show that it is completely consumed. The reaction mixture was cooled to room temperature and then quenched with ethyldiamine (50 mL). The resulting suspension was filtered over a pad of celite and washed with ethyl acetate (2 <RTIgt; The combined filtrate was washed with water (100 ml) and sat. sodium chloride (100 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford residue. Purification by column chromatography (tank: 100 to 200 mesh, eluent: petroleum ether) to give 1-(3-chlorophenyl)-3-(trifluoromethyl) as a yellow solid. -1H-pyrazole-5-carbonitrile (F) (10.12 g, 69%).

步驟5：於0℃，將甲硼酸．甲硫醚(22.6毫升，241.35毫莫耳)加至以四氫呋喃(120毫升)溶解之1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-碳化腈(F)(10.12公克，37.13毫莫耳)溶液中，並將該反應混合物於室溫攪拌24小時，直至薄層層析分析顯示反應完成。將該反應混合物冷卻至室溫，緩慢地添加甲醇(50毫升)，並將所產 生之混合物加熱回流30分鐘。將溶媒蒸發，並將所得之殘留物於以二乙醚(50毫升)溶解之飽和氯化氫溶液中攪拌2小時。將固體過濾，以戊烷(2×20毫升)及5%之醋酸乙酯/石油醚(2×20毫升)清洗，並將其真空乾燥，以獲得白色固體狀之(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺氫氯化物(G)(3.1公克，27%)。 Step 5: At 0 ° C, borazoic acid. Methyl sulfide (22.6 ml, 241.35 mmol) was added to 1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carbonitrile dissolved in tetrahydrofuran (120 mL) (F) (10.12 g, 37.13 mmol) solution and the reaction mixture was stirred at room temperature for 24 hours until thin layer chromatography analysis indicated the reaction was completed. The reaction mixture was cooled to room temperature, methanol (50 mL) was slowly added, and the resulting mixture was heated to reflux for 30 min. The solvent was evaporated, and the residue was evaporated mjjjjjjjjjj The solid was filtered, washed with EtOAc (EtOAc (EtOAc) elute Phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamine hydrochloride (G) (3.1 g, 27%).

步驟6：於一經攪拌、以四氫呋喃(2.1毫升)溶解之(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺(G)(75毫克，0.275毫莫耳)及2-(啶-2-基)醋酸(47毫克，0.275毫莫耳)溶液中添加1-羥基苯並三唑水合物(0.037毫升，0.275毫莫耳)、O-(1H-苯並三唑-1-基)-N,N,N',N'-四甲基脲四氟硼酸酯(0.089公克，0.275毫莫耳)、N-二異丙基乙胺(0.14毫升，0.825毫莫耳)及二甲基甲醯胺(0.1毫升)。將該反應混合物攪拌40小時。將該反應混合物於較低壓力濃縮，以管柱色層分析法(矽膠：100至200篩孔，溶析液：醋酸乙酯/甲醇18：1)純化所得之固體，以獲得白色固體狀之N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(啶-2-基)乙醯胺(實例化合物1)(102毫克，94%)。 Step 6: (1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamine (G) (1) dissolved in tetrahydrofuran (2.1 mL) Add 1-hydroxybenzotriazole hydrate (0.037 ml, 0.275 mmol) to a solution of 75 mg, 0.275 mmol, and 2-(pyridin-2-yl)acetic acid (47 mg, 0.275 mmol). O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (0.089 g, 0.275 mmol), N-diisopropyl Ethylamine (0.14 mL, 0.825 mmol) and dimethylformamide (0.1 mL). The reaction mixture was stirred for 40 hours. The reaction mixture was concentrated at a lower pressure, and the obtained solid was purified by column chromatography (yield: 100 to 200 mesh, eluent: ethyl acetate / methanol 18:1) to give a white solid. N-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(pyridin-2-yl)acetamide (example) Compound 1) (102 mg, 94%).

實例6、7、10、11、13、14、16及17係以類似之方法，以商購取得之被取代啶/嘧啶製備而成。 Examples 6, 7, 10, 11, 13, 14, 16 and 17 were prepared in a similar manner using commercially available substituted pyridine/pyrimidine.

實例2之合成：Synthesis of Example 2:

N-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-2-(啶-2-基)丙醯胺 N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(pyridin-2-yl)propanamide

步驟1：於-78℃，將正丁基鋰(49毫升，2.04 M，0.10莫耳)加至經攪拌、以無水四氫呋喃(20毫升)溶解之二異丙胺(10.8公克，0.1莫耳)溶液中。將該反應混合物攪拌30分鐘。於該溶液逐滴添加以無水四氫呋喃(20毫升)溶解之2-甲基啶(A)(10公克，0.107莫耳)。將該反應混合物於-78℃攪拌1小時。於-78℃，將二碳酸三級丁酯(24公克，0.11莫耳)加入該混合物中，令其於2小時之期間回溫至室溫。將該反應混合物以飽和氯化銨溶液(50毫升)進行淬火反應，以水(60毫升)稀釋，並以醋酸乙酯(3 x 80毫升)萃取。將整體有機層以飽和之氯化鈉溶液(50毫升)清洗。將最終之有機層以硫酸鎂乾燥，並於較低壓力將其濃縮，以獲得粗製產物。 以管柱色層分析法(矽膠：100至200篩孔，溶析液：存在於正己烷之10%醋酸乙酯)純化該粗製產物，以獲得三級丁基2-(啶-2-基)乙酸酯(B1)(6公克，29%)。 Step 1: To a solution of diisopropylamine (10.8 g, 0.1 mol) dissolved in anhydrous tetrahydrofuran (20 ml) with n-butyllithium (49 ml, 2.04 M, 0.10 mol) at -78 °C in. The reaction mixture was stirred for 30 minutes. To the solution was added 2-methylpyridine (A) (10 g, 0.107 mol) dissolved in anhydrous tetrahydrofuran (20 ml). The reaction mixture was stirred at -78 °C for 1 hour. Tributyl phthalate (24 grams, 0.11 moles) was added to the mixture at -78 ° C and allowed to warm to room temperature over a period of 2 hours. The reaction mixture was quenched with EtOAc (EtOAc) (EtOAc) The whole organic layer was washed with saturated sodium chloride solution (50 mL). The final organic layer was dried over magnesium sulfate and concentrated at lower pressure to afford crude material. The crude product was purified by column chromatography (tank: 100 to 200 mesh, eluent: 10% ethyl acetate in n-hexane) to afford tris-butyl 2-(pyridine-2-yl) ) Acetate (B1) (6 g, 29%).

步驟2：於-78℃，將正丁基鋰(7.6毫升，2.04莫耳，15.55毫莫耳)加至以無水四氫呋喃(5毫升)溶解之二異丙胺(1.56公克，15.55毫莫耳)溶液中。將該反應混合物攪拌30分鐘。於該溶液中逐滴添加以無水四氫呋喃(5毫升)溶解之六甲基膦醯胺(2.78公克，15.55毫莫耳)及三級丁基2-(啶-2-基)乙酸酯(B1)(3公克，15.55毫莫耳)。將該反應混合物於-78℃攪拌1小時。於-78℃，將以5毫升之無水四氫呋喃溶解之硫酸二甲酯(1.95公克，15.55莫耳)加至該溶液中，令其於2小時之期間回溫至周圍溫度。將該反應混合物以飽和之氯化銨溶液(30毫升)進行淬火反應，以水(50毫升)稀釋，並以醋酸乙酯(2 x 50毫升)萃取。將整體有機層以飽和之氯化鈉溶液(50毫升)清洗。將最終之有機層以硫酸鎂乾燥，並於較低壓力濃縮，以獲得粗製化合物；以管柱色層分析法(矽膠：100至200篩孔，溶析液：存在於正己烷之5%醋酸乙酯)純化該粗製產物，以獲得三級丁基2-(啶-2-基)丙酸(C)(1.8公克，56%)。 Step 2: Add n-butyllithium (7.6 ml, 2.04 mol, 15.55 mmol) to diisopropylamine (1.56 g, 15.55 mmol) dissolved in anhydrous tetrahydrofuran (5 mL) at -78 °C. in. The reaction mixture was stirred for 30 minutes. To the solution was added dropwise hexamethylphosphoniumamine (2.78 g, 15.55 mmol) dissolved in anhydrous tetrahydrofuran (5 ml) and tributyl butyl 2-(pyridine-2-yl) acetate (B1 ) (3 grams, 15.55 millimoles). The reaction mixture was stirred at -78 °C for 1 hour. Dimethyl sulfate (1.95 g, 15.55 mol) dissolved in 5 ml of anhydrous tetrahydrofuran was added to the solution at -78 ° C, and allowed to warm to ambient temperature over a period of 2 hours. The reaction mixture was quenched with EtOAc (EtOAc) (EtOAc) The whole organic layer was washed with saturated sodium chloride solution (50 mL). The final organic layer was dried over magnesium sulfate and concentrated at a lower pressure to obtain a crude compound; by column chromatography (gel: 100 to 200 mesh, eluent: 5% acetic acid in n-hexane) Ethyl ester) The crude product was purified to give tri-butyl 2-(pyridin-2-yl)propanoic acid (C) (1.8 g, 56%).

步驟3：於三級丁基2-(啶-2-基)丙酸(C)(2.5公克，12.07毫莫耳)中添加6 N之氯化氫(65毫升)，並攪拌12小時。將該反應混合物於較低壓力濃縮，以獲得粗製化合物；將該粗製化合物與甲苯(3 x 10毫升)共蒸餾，以獲得2-(啶-2-基)丙酸(D)(1.6公克)。 Step 3: 6 N of hydrogen chloride (65 ml) was added to tributyl butyl 2-(pyridin-2-yl)propanoic acid (C) (2.5 g, 12.07 mmol) and stirred for 12 hours. The reaction mixture was concentrated at a lower pressure to give a crude compound; the crude compound was co-distilled with toluene (3 x 10 ml) to give 2-(pyridin-2-yl)propionic acid (D) (1.6 g) .

1H核磁共振(二甲亞碸-d6，400 MHz)：1.54(d，3H)；4.27(d，1H)；7.78(t，1H)；7.80(d，1H)；8.38(t，1H)；8.76(d，1H)。 1 H NMR (dimethyl sulfonium-d 6 , 400 MHz): 1.54 (d, 3H); 4.27 (d, 1H); 7.78 (t, 1H); 7.80 (d, 1H); 8.38 (t, 1H) ); 8.76 (d, 1H).

步驟4：於一經攪拌、以四氫呋喃(3.5毫升)溶解之2-(啶-2-基)丙酸(D)(0.097公克，0.648毫莫耳)及(3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺(0.114公克，0.432毫莫耳)溶液中添加1- 羥基苯並三唑水合物(0.06毫升，0.432毫莫耳)、O-(1H-苯並三唑-1-基)-N,N,N',N'-四甲基脲四氟硼酸酯(0.139公克，0.432毫莫耳)及N-二異丙基乙胺(0.22毫升，1.296毫莫耳)，以獲得一懸浮液。添加二甲基甲醯胺(1.3毫升)後，將該反應混合物攪拌36小時。將該反應混合物於較低壓力濃縮，以管柱色層分析法(矽膠：100至200篩孔，溶析液：醋酸乙酯/環己烷90：1)純化所得之固體，以獲得N-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-2-(啶-2-基)丙醯胺(實例化合物2)(31毫克，18%)。 Step 4: 2-(Acridin-2-yl)propionic acid (D) (0.097 g, 0.648 mmol) and (3-tert-butyl-1-) dissolved in tetrahydrofuran (3.5 mL) with stirring. 1-Hydroxybenzotriazole hydrate (0.06 ml, 0.432 mmol), O, 3-chlorophenyl)-1H-pyrazol-5-yl)methylamine (0.114 g, 0.432 mmol) -(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (0.139 g, 0.432 mmol) and N-diisopropyl B Amine (0.22 mL, 1.296 mmol) was obtained to give a suspension. After the addition of dimethylformamide (1.3 ml), the reaction mixture was stirred for 36 hours. The reaction mixture was concentrated at a lower pressure, and the obtained solid was purified by column chromatography (yield: 100 to 200 mesh, eluent: ethyl acetate / cyclohexane 90:1) to obtain N- ((3-tert-Butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(pyridin-2-yl)propanamide (Example Compound 2) ( 31 mg, 18%).

可以類似之方法，使用商購取得之相應被取代啶製備實例8。 Example 8 can be prepared in a similar manner using commercially available substituted pyridines.

實例3之合成：Synthesis of Example 3:

N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(啶-2-基)丙醯胺 N-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(pyridin-2-yl)propanamide

實例化合物3之反應步驟1至3係如實例化合物2所描述，隨後進行步驟4： The reaction steps 1 to 3 of Example Compound 3 are as described in Example Compound 2, followed by Step 4 :

步驟4：於一經攪拌、以四氫呋喃(2.5毫升)溶解之2-(啶-2-基)丙酸(0.075公克，0.496毫莫耳)及((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺(0.091公克，0.331毫莫耳)溶液中添加1-羥基苯並三唑水合物(0.045毫升，0.331毫莫耳)、O-(1H-苯並三唑-1-基)-N,N,N',N'-四甲基脲四氟硼酸酯(0.107公克，0.331毫莫耳)及N-二異丙基乙胺(0.169毫升，0.993毫莫耳)，以獲得一懸浮液。添加N,N-二甲基甲醯胺(1毫升)後，將該反應混合物攪拌36小時。將該反應混合物於較低壓力濃縮，並以管柱色層分析法(矽膠：100至200篩孔，溶析液：醋酸乙酯/二氯甲烷10：1)純化所獲得之固體，以獲得灰白色固體狀之N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(啶-2-基)丙醯胺(實例化合物3)(18毫克，13%)。 Step 4: 2-(Acridin-2-yl)propionic acid (0.075 g, 0.496 mmol) and ((1-(3-chlorophenyl)-3-) dissolved in tetrahydrofuran (2.5 mL). 1-Hydroxybenzotriazole hydrate (0.045 ml, 0.331 mmol), O was added to a solution of (trifluoromethyl)-1H-pyrazol-5-yl)methylamine (0.091 g, 0.331 mmol). -(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (0.107 g, 0.331 mmol) and N-diisopropyl B Amine (0.169 mL, 0.993 mmol) was obtained to give a suspension. After addition of N,N-dimethylformamide (1 mL), the reaction mixture was stirred for 36 hours. Concentrate and purify the obtained solid by column chromatography (p.: 100 to 200 mesh, eluent: ethyl acetate / dichloromethane 10:1) to afford N-(( 1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(pyridin-2-yl)propanamide (Example Compound 3) 18 mg, 13%).

實例4之合成：Synthesis of Example 4:

1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(啶-2-基)尿素 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(pyridin-2-yl)urea

步驟1：於室溫，於一以四氫呋喃與乙腈(3：4，50毫升)溶解之2-胺基啶(400毫克，4.25毫莫耳)溶液中緩慢地添加氯甲酸苯酯(0.8毫升，6.376毫莫耳)及啶(0.4毫升，5.525毫莫耳)。將該反應混合物攪拌3小時。薄層層析法顯示起始原料被完全消耗。添加水後，以醋酸乙酯萃取該混合物。將萃取物以硫酸鎂乾燥，並於較低壓力濃縮。以管柱色層分析法(矽膠：100至200篩孔，溶析液：正己烷/醋酸乙酯4：1)純化粗製殘留物，以獲得苯基吡啶-2-基胺甲酸酯(710毫克，78%)。 Step 1: Slowly add phenyl chloroformate (0.8 ml, in a solution of 2-aminopyridine (400 mg, 4.25 mmol) dissolved in tetrahydrofuran and acetonitrile (3:4, 50 mL). 6.376 millimoles) and pyridine (0.4 ml, 5.525 mmol). The reaction mixture was stirred for 3 hours. Thin layer chromatography showed complete consumption of the starting material. After adding water, the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated at lower pressure. The crude residue was purified by column chromatography (tane: 100 to 200 mesh, eluent: n-hexane / ethyl acetate 4:1) to afford phenylpyridin-2-ylamines. Mg, 78%).

步驟2：於室溫，於一以乙腈(20毫升)溶解之苯基吡啶-2-基胺甲酸酯(70毫克，0.327毫莫耳)溶液中添加4-二甲胺基啶(40毫克，0.327毫莫耳)及(3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺(112毫克，0.425毫莫耳)。將該反應混合物於50℃加熱15小時。薄層層析法顯示起始原料被完全消耗。將該反應混合物以水稀釋， 並以醋酸乙酯萃取。以水及飽和之氯化鈉溶液清洗有機部分。再將有機層以硫酸鎂乾燥，並於較低壓力濃縮。以管柱色層分析法(矽膠：100至200篩孔，溶析液：正己烷/醋酸乙酯1：1)純化粗製產物，以獲得1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(啶-2-基)尿素(實例化合物4)(62毫克，49%)。 Step 2: Add 4-dimethylamididine (40 mg) to a solution of phenylpyridin-2-ylcarbamate (70 mg, 0.327 mmol) dissolved in acetonitrile (20 mL) at rt. , 0.327 mmol, and (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine (112 mg, 0.425 mmol). The reaction mixture was heated at 50 °C for 15 hours. Thin layer chromatography showed complete consumption of the starting material. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic portion was washed with water and a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and concentrated at lower pressure. The crude product was purified by column chromatography (gel: 100 to 200 mesh, eluent: n-hexane / ethyl acetate 1:1) to obtain 1-((3-tris-butyl-1-) 3-Chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(pyridin-2-yl)urea (example compound 4) (62 mg, 49%).

1H核磁共振(300 MHz，CDCl3)：δ 8.11(dd，1H，J=5.13 Hz，Ar-H)；7.97(s，1H，Ar-NH)；7.59(m，1H，Ar-H)；7.56(m，1H，Ar-H)；7.36(m，3H，Ar-H)；6.89(dd，1H，J=5.1 Hz，Ar-H)；6.70(d，1H，J=8.25 Hz，Ar-H)；6.33(s，1H，Ar-H)；4.63(d，2H，J=5.67 Hz，Ar-CH2)；1.33(S，9H，Ar-(CH3)3)。 1 H NMR (300 MHz, CDCl3): δ 8.11 (dd, 1H, J = 5.13 Hz, Ar-H); 7.97 (s, 1H, Ar-NH); 7.59 (m, 1H, Ar-H); 7.56 (m, 1H, Ar-H); 7.36 (m, 3H, Ar-H); 6.89 (dd, 1H, J = 5.1 Hz, Ar-H); 6.70 (d, 1H, J = 8.25 Hz, Ar -H); 6.33 (s, 1H, Ar-H); 4.63 (d, 2H, J = 5.67 Hz, Ar-CH 2 ); 1.33 (S, 9H, Ar-(CH 3 ) 3 ).

實例9、12、15、18至19、54及136至138係以類似方法，以商購取得之被取代啶/嘧啶製備而成。可以類似方法製備實例20。 Examples 9, 12, 15, 18 to 19, 54 and 136 to 138 were prepared in a similar manner using commercially available substituted pyridine/pyrimidine. Example 20 can be prepared in a similar manner.

實例5之合成：Synthesis of Example 5:

1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(啶-2-基)尿素 1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(pyridin-2-yl)urea

實例化合物5之反應步驟1係如實例化合物4所描述，隨後進行步驟2： The reaction step 1 of Example Compound 5 is as described in Example Compound 4, followed by Step 2 :

步驟2：於室溫，於一以乙腈(20毫升)溶解之苯基吡啶-2-基胺甲酸酯(70毫克，0.327毫莫耳)溶液中添加4-二甲胺基啶(40毫克，0.327毫莫耳)與(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺 (117毫克，0.425毫莫耳)。將該反應混合物於50℃加熱15小時。薄層層析法顯示起始原料被完全消耗。將該反應混合物以水稀釋，並以醋酸乙酯萃取。以水及飽和之氯化鈉溶液清洗有機部分。將有機層以硫酸鎂乾燥，並於較低壓力濃縮。以管柱色層分析法(矽膠：100至200篩孔，溶析液：正己烷/醋酸乙酯1：1)純化粗製產物，以獲得1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(啶-2-基)尿素(實例化合物5)(61毫克，47%)。 Step 2: Add 4-dimethylamididine (40 mg) to a solution of phenylpyridin-2-ylcarbamate (70 mg, 0.327 mmol) dissolved in acetonitrile (20 mL) at rt. , (0.327 mmol) and (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamine (117 mg, 0.425 mmol). The reaction mixture was heated at 50 °C for 15 hours. Thin layer chromatography showed complete consumption of the starting material. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic portion was washed with water and a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and concentrated at lower pressure. The crude product was purified by column chromatography (gel: 100 to 200 mesh, eluent: n-hexane / ethyl acetate 1:1) to obtain 1-((3-tris-butyl-1-) 3-Chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(pyridin-2-yl)urea (example compound 5) (61 mg, 47%).

1H核磁共振(300 MHz，CDCl3)：δ 8.13(dd，1H，J=6.96 Hz，Ar-H)；7.62(m，1H，Ar-H)；7.56(m，1H，Ar-H)；7.45(m，3H，Ar-H)；6.93(dd，1H，J=6.6 Hz，Ar-H)；6.72(s，1H，Ar-NH)；6.64(d，1H，J=8.25 Hz，Ar-H)；4.63(d，2H，J=5.67 Hz，Ar-CH2)。 1 H NMR (300 MHz, CDCl3): δ 8.13 (dd, 1H, J = 6.96 Hz, Ar-H); 7.62 (m, 1H, Ar-H); 7.56 (m, 1H, Ar-H); 7.45 (m, 3H, Ar-H); 6.93 (dd, 1H, J = 6.6 Hz, Ar-H); 6.72 (s, 1H, Ar-NH); 6.64 (d, 1H, J = 8.25 Hz, Ar -H); 4.63 (d, 2H, J = 5.67 Hz, Ar-CH 2 ).

實例21之合成：Synthesis of Example 21:

1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)-甲基)-3-(6-(2-(甲磺醯基)乙基)啶-3-基)尿素 1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-methyl)-3-(6-(2-(methylsulfonyl) Ethyl)pyridin-3-yl)urea

步驟1：將五氯化磷(11.15公克，53.54毫莫耳)於以60℃加熱之同時分次加至經攪拌、以氧氯化磷(50毫升)溶解之5-硝基吡啶-2-醇(5公克，35.71毫莫耳)溶液中，並將該反應混合物於60℃攪拌過夜。薄層層析法顯示起始原料於16小時候被完全消耗。將 該反應混合物於較低壓力濃縮，以去除多餘之氧氯化磷。將殘留物倒入冰塊中，並以醋酸乙酯(3 x 100毫升)萃取。將合併有機層已飽和之氯化鈉溶液(50毫升)清洗。將有機層以無水硫酸鎂乾燥，並於較低壓力濃縮，以獲得固態之2-氯-5-硝基吡啶(5公克，89%)。 Step 1: Palladium pentachloride (11.15 g, 53.54 mmol) was added to the 5-nitropyridine-2- which was stirred and dissolved in phosphorus oxychloride (50 ml) while heating at 60 °C. A solution of alcohol (5 grams, 35.71 millimoles) was added and the reaction mixture was stirred at 60 ° C overnight. Thin layer chromatography indicated that the starting material was completely consumed at 16 hours. The reaction mixture was concentrated at a lower pressure to remove excess phosphorus oxychloride. The residue was poured into ice and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with saturated sodium chloride solution (50 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford solid 2-chloro-5-nitropyridine (5 g, 89%).

步驟2：於一經攪拌、以四氫呋喃(3毫升)溶解之三(二亞苄基丙酮)二鈀(144毫克，0.15毫莫耳)及三芳基膦(trifuryl phosphine)(73毫克，0.31毫莫耳)懸浮液中，依序添加以四氫呋喃(2毫升)溶解之2-氯-5-硝基吡啶(500毫克，3.16毫莫耳)及三丁基乙烯基錫(1.2公克，3.78毫莫耳)。將該反應混合物除氣，並緩慢地加熱至60℃，並於此溫度攪拌過夜。薄層層析法顯示起始原料被完全消耗。將該反應混合物冷卻至室溫並以水稀釋，隨後以醋酸乙酯(50毫升)萃取。將合併有機層以飽和之氯化鈉溶液(2 x 50毫升)清洗，並以無水硫酸鎂乾燥。將溶媒於較低壓力濃縮，以獲得粗製化合物。以管柱色層分析法(矽膠：100至200篩孔，溶析液：正己烷)純化該粗製化合物，以獲得5-硝基-2-乙烯吡啶(350毫克，74%)。 Step 2: Tris(dibenzylideneacetone)dipalladium (144 mg, 0.15 mmol) and trifuryl phosphine (73 mg, 0.31 mmol) dissolved in tetrahydrofuran (3 ml) with stirring. In the suspension, 2-chloro-5-nitropyridine (500 mg, 3.16 mmol) and tributylvinyltin (1.2 g, 3.78 mmol) dissolved in tetrahydrofuran (2 ml) were added in this order. . The reaction mixture was degassed and slowly heated to 60 ° C and stirred at this temperature overnight. Thin layer chromatography showed complete consumption of the starting material. The reaction mixture was cooled to room temperature and diluted with water then ethyl acetate (50 ml). The combined organic layers were washed with a saturated aqueous solution of sodium chloride (2 x 50 ml) and dried over anhydrous magnesium sulfate. The solvent was concentrated at a lower pressure to obtain a crude compound. The crude compound was purified by column chromatography (yield: 100 to 200 mesh, eluent: n-hexane) to afford 5-nitro-2-ethylpyridine (350 mg, 74%).

步驟3：於室溫，於一經攪拌、以乙醇(3.5毫升)溶解之5-硝基-2-乙烯吡啶(350毫克，2.33毫莫耳)溶液中，依序添加甲基磺酸鈉(2.37公克，23.21毫莫耳)與醋酸(140毫克，2.33毫莫耳)。將該反應混合物於60℃回流14小時。將該反應混合物冷卻至室溫，並於較低壓力濃縮，以獲得粗製化合物。將其以水(2 x 10毫升)清洗，並以垂熔漏斗過濾，以獲得2-(2-(甲磺醯基)乙基)-5-硝基吡啶(500毫克，92%)。 Step 3: Sodium methanesulfonate (2.37) was added sequentially to a solution of 5-nitro-2-vinylpyridine (350 mg, 2.33 mmol) dissolved in ethanol (3.5 ml) at room temperature. G, 23.21 mmol) with acetic acid (140 mg, 2.33 mmol). The reaction mixture was refluxed at 60 ° C for 14 hours. The reaction mixture was cooled to room temperature and concentrated at a lower pressure to give a crude compound. This was washed with water (2 x 10 mL) and filtered with EtOAc EtOAc (EtOAc)

步驟4：於一經攪拌、以乙醋酸乙酯(8毫升)溶解之2-(2-(甲磺醯基)乙基)-5-硝基吡啶(400毫克，1.73毫莫耳)溶液中添加10%之鈀碳(40毫克)。將該反應混合物於氫氣氣氛下攪拌6小時。薄層層析法顯示起始原料被完全消耗。將該反應混合物過濾，並將濾 液於較低壓力濃縮，以獲得固態化合物；將其以溶於正己烷之20%醋酸乙酯清洗，以獲得6-(2-(甲磺醯基)乙基)啶-3-胺(300毫克，86%)。 Step 4: Add to a solution of 2-(2-(methylsulfonyl)ethyl)-5-nitropyridine (400 mg, 1.73 mmol) dissolved in ethyl acetate (8 mL). 10% palladium on carbon (40 mg). The reaction mixture was stirred under a hydrogen atmosphere for 6 hours. Thin layer chromatography showed complete consumption of the starting material. The reaction mixture was filtered, and the filtrate was concentrated at a reduced pressure to give a solid compound which was washed with 20% ethyl acetate in n-hexane to obtain 6-(2-(methylsulfonyl)ethyl. Pyridine-3-amine (300 mg, 86%).

1H核磁共振(二甲亞碸-d6，400 MHz)：7.86(s，1H)；6.98(d，1H)；6.86(dd，1H)；5.16(s，2H)；3.40(t，2H)；2.95(m，5H)。 1 H NMR (dimethyl sulfonium-d 6 , 400 MHz): 7.86 (s, 1H); 6.98 (d, 1H); 6.86 (dd, 1H); 5.16 (s, 2H); 3.40 (t, 2H) ); 2.95 (m, 5H).

步驟5：於150℃，於一經攪拌、以四氫呋喃(3毫升)溶解之6-(2-(甲磺醯基)乙基)啶-3-胺(41毫克，0.203毫莫耳)溶液中，依序添加N-二異丙基乙胺(0.095毫升，0.551毫莫耳)及苯基(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)氨基甲酸甲酯(75毫克，0.19毫莫耳)，並於微波條件下(7巴)攪拌1小時。以管柱色層分析法(矽膠：100至200篩孔，溶析液：醋酸乙酯/甲醇9：1)純化經濃縮之反應混合物，以獲得白色固體狀之1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-(甲磺醯基)乙基)啶-3-基)尿素(實例化合物21)(44毫克，46%)。 Step 5: In a solution of 6-(2-(methylsulfonyl)ethyl)pyridin-3-amine (41 mg, 0.203 mmol) dissolved in tetrahydrofuran (3 ml) at 150 ° C, N-diisopropylethylamine (0.095 ml, 0.551 mmol) and phenyl(1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5- were added sequentially. Methyl carbamate (75 mg, 0.19 mmol) was stirred under microwave conditions (7 bar) for 1 hour. The concentrated reaction mixture was purified by column chromatography (EtOAc: 100 to 200 mesh, eluting solvent: ethyl acetate/methanol 9:1) to afford 1-((1-(3) -Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-(methylsulfonyl)ethyl)pyridin-3-yl Urea (Example Compound 21) (44 mg, 46%).

實例24之合成：Synthesis of Example 24:

1-((1-(3-氯苯基)-3-環丙基-1H-吡唑-5-基)甲基)-3-(5-氟-6-(2-(甲磺醯基)乙基)啶-3-基)尿素 1-((1-(3-Chlorophenyl)-3-cyclopropyl-1H-pyrazol-5-yl)methyl)-3-(5-fluoro-6-(2-(methylsulfonyl) Ethyl)pyridin-3-yl)urea

步驟1：於60℃，於一經攪拌、以氧氯化磷(15毫升)溶解之3-氟-5-硝基吡啶-2-醇(1.5公克，9.48毫莫耳)溶液中添加五氯化磷(2.96公克，14.22毫莫耳)。將該反應混合物於相同溫度攪拌10小時。將該反應混合物冷卻至室溫，將其倒入碎冰中，並以醋酸乙酯(3 x 20毫升)萃取。以飽和之碳酸鈉溶液(25毫升)清洗整體有機層。將清洗後之有機層以無水硫酸鎂乾燥，並於較低壓力濃縮，以獲得粗製化合物；以管柱色層分析法(矽膠：100至200篩孔，溶析液：存在於正己烷之5%醋酸乙酯)純化該粗製化合物，以獲得2-氯-3-氟-5-硝基吡啶(1.62公克，97%)。 Step 1: Adding pentachlorination at 60 ° C in a solution of 3-fluoro-5-nitropyridin-2-ol (1.5 g, 9.48 mmol) dissolved in phosphorus oxychloride (15 ml) at 60 ° C Phosphorus (2.96 grams, 14.22 millimoles). The reaction mixture was stirred at the same temperature for 10 hours. The reaction mixture was cooled to room temperature, poured into EtOAc (EtOAc) (EtOAc) The entire organic layer was washed with a saturated sodium carbonate solution (25 mL). The washed organic layer is dried over anhydrous magnesium sulfate and concentrated at a lower pressure to obtain a crude compound; by column chromatography (gel: 100 to 200 mesh, eluent: 5 in n-hexane) The crude compound was purified to give 2-chloro-3-fluoro-5-nitropyridine (1.62 g, 97%).

步驟2：於氮氣氣氛下，於一經攪拌、以四氫呋喃(16毫升) 溶解之2-氯-3-氟-5-硝基吡啶(1.6公克，9.0毫莫耳)溶液中添加三丁基乙烯基錫(3.42公克，10.8毫莫耳)、三(二亞苄基丙酮)二鈀(0.42公克，0.45毫莫耳)及三芳基膦(0.2公克，0.9毫莫耳)。將該反應混合物徹底地脫氧，並於600C加熱6小時。將該反應混合物以水(20毫升)稀釋，並以醋酸乙酯(3 x 25毫升)萃取。將合併有機層以飽和之氯化鈉溶液(25毫升)清洗，以無水硫酸鎂乾燥，並於較低壓力濃縮，以獲得粗製化合物。以管柱色層分析法(矽膠：100至200篩孔，溶析液：存在於正己烷之5%醋酸乙酯)純化該粗製化合物，以獲得3-氟-5-硝基-2-乙烯吡啶(1.5公克，96%)。 Step 2: Add tributylvinyl in a solution of 2-chloro-3-fluoro-5-nitropyridine (1.6 g, 9.0 mmol) dissolved in tetrahydrofuran (16 ml) under a nitrogen atmosphere. Tin (3.42 grams, 10.8 millimoles), tris(dibenzylideneacetone)dipalladium (0.42 grams, 0.45 millimoles) and triarylphosphine (0.2 grams, 0.9 millimoles). The reaction mixture was thoroughly deoxygenated and heated at 6006 C h. The reaction mixture was diluted with water (20 mL) andEtOAc. The combined organic layers were washed with EtOAc EtOAc (EtOAc) The crude compound was purified by column chromatography (tank: 100 to 200 mesh, eluent: 5% ethyl acetate in n-hexane) to afford 3-fluoro-5-nitro-2-ethyl Pyridine (1.5 g, 96%).

步驟3：於室溫，於一經攪拌、以乙醇(15毫升)溶解之3-氟-5-硝基-2-乙烯吡啶(1.5公克，8.92毫莫耳)溶液中添加甲烷亞磺酸鈉(9.1公克，89.3毫莫耳)及醋酸(0.53公克，8.92毫莫耳)。將該反應混合物於60℃加熱10小時。隨後將該反應混合物冷卻至室溫，並於較低壓力濃縮，並將其過濾，以獲得粗製產物。以水(25毫升)清洗所產生之固體，以獲得3-氟-2-(2-(甲磺醯基)乙基)-5-硝基吡啶(0.81公克，36%)。 Step 3: Add methane sulfinate (Sodium sulfinate) to a solution of 3-fluoro-5-nitro-2-vinylpyridine (1.5 g, 8.92 mmol) dissolved in ethanol (15 ml) at room temperature ( 9.1 grams, 89.3 millimoles) and acetic acid (0.53 grams, 8.92 millimoles). The reaction mixture was heated at 60 ° C for 10 hours. The reaction mixture was then cooled to room temperature and concentrated at a lower pressure and filtered to give a crude material. The resulting solid was washed with water (25 mL) to give 3-fluoro-2-(2-(methylsulfonyl)ethyl)-5-nitropyridine (0.81 g, 36%).

步驟4：於氬氣氣氛下，於一以醋酸乙酯(8毫升)溶解之3-氟-2-(2-(甲磺醯基)乙基)-5-硝基吡啶(0.8公克，3.22毫莫耳)中添加10%之鈀碳(80毫克)，將其於帕爾反應釜(Parr vessel)氫化，並將反應物持續攪拌2小時。將該反應混合物以矽藻土床過濾，以醋酸乙酯徹底清洗，並於較低壓力濃縮，以獲得5-氟-6-(2-(甲磺醯基)乙基)啶-3-胺(0.62公克，88%)。 Step 4: 3-Fluoro-2-(2-(methylsulfonyl)ethyl)-5-nitropyridine (0.8 g, 3.22) dissolved in ethyl acetate (8 mL) under argon. 10% palladium on carbon (80 mg) was added to the millimolar, which was hydrogenated in a Parr vessel and the reaction was stirred continuously for 2 hours. The reaction mixture was filtered over a pad of celite, washed thoroughly with ethyl acetate and concentrated at lower pressure to give 5-fluoro-6-(2-(methylsulfonyl)ethyl)pyridin-3-amine (0.62 grams, 88%).

1H核磁共振(二甲亞碸-d6，400 MHz)：δ 7.73(s，1H)；6.72(dd，1H)；5.55(s，2H)；3.41(t，2H)；2.98-3.02(m，5H)。 1 H NMR (dimethyl sulfonium-d 6 , 400 MHz): δ 7.73 (s, 1H); 6.72 (dd, 1H); 5.55 (s, 2H); 3.41 (t, 2H); 2.98-3.02 ( m, 5H).

步驟5：將5-氟-6-(2-(甲磺醯基)乙基)啶-3-胺(100毫克，0.458毫莫耳)以二氯甲烷(2.5毫升)溶解。添加三乙胺(0.076毫升，0.55 毫莫耳)及氯甲酸苯酯(0.065毫升，0.513毫莫耳)，並將該反應混合物於室溫攪拌12小時。以飽和之碳酸鈉溶液(10毫升)萃取該反應混合物。以二氯甲烷(2 x 20毫升)萃取水層。將合併有機層以無水硫酸鎂乾燥，並於較低壓力濃縮，以獲得粗製產物；以管柱色層分析法(矽膠：100至200篩孔，溶析液：醋酸乙酯/正環己烷3：1)純化該粗製產物，以獲得苯基5-氟-6-(2-(甲磺醯基)乙基)啶-3-基胺甲酸酯(62毫克，40%)。 Step 5: 5-Fluoro-6-(2-(methylsulfonyl)ethyl)pyridine-3-amine (100 mg, 0.458 mmol) was dissolved in dichloromethane (2.5 mL). Triethylamine (0.076 ml, 0.55 mmol) and phenyl chloroformate (0.065 mL, 0.513 mmol) were then weighed. The reaction mixture was extracted with a saturated sodium carbonate solution (10 mL). The aqueous layer was extracted with dichloromethane (2 x 20 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product. </ br></br> 3:1) The crude product was purified to give phenyl 5-fluoro-6-(2-(methylsulfonyl)ethyl)pyridin-3-ylcarbamate (62 mg, 40%).

步驟6：於150℃，於一經攪拌、以四氫呋喃(3毫升)溶解之(1-(3-氯苯基)-3-環丙基-1H-吡唑-5-基)甲胺(50毫克，0.204毫莫耳)溶液中，依序添加N-二異丙基乙胺(0.1毫升，0.592毫莫耳)及苯基5-氟-6-(2-(甲磺醯基)乙基)啶-3-基胺甲酸酯(76毫克，0.224毫莫耳)加至，並將其於微波條件下(7巴)攪拌1小時。以管柱色層分析法(矽膠：100至200篩孔，溶析液：醋酸乙酯/甲醇19：1)純化濃縮後之反應混合物，以獲得橘色固體狀之1-((1-(3-氯苯基)-3-環丙基-1H-吡唑-5-基)甲基)-3-(5-氟-6-(2-(甲磺醯基)乙基)啶-3-基)尿素(實例化合物24)(34毫克，34%)。 Step 6: (1-(3-Chlorophenyl)-3-cyclopropyl-1H-pyrazol-5-yl)methanamine (50 mg, dissolved in tetrahydrofuran (3 ml) at 150 ° C , 0.204 mmol), N-diisopropylethylamine (0.1 ml, 0.592 mmol) and phenyl 5-fluoro-6-(2-(methylsulfonyl)ethyl) were added sequentially. Pyridin-3-ylcarbamate (76 mg, 0.224 mmol) was added and stirred under microwave conditions (7 bar) for 1 hour. The concentrated reaction mixture was purified by column chromatography (tank: 100 to 200 mesh, eluent: ethyl acetate/methanol 19:1) to obtain 1-((1-) as an orange solid. 3-chlorophenyl)-3-cyclopropyl-1H-pyrazol-5-yl)methyl)-3-(5-fluoro-6-(2-(methylsulfonyl)ethyl)pyridine-3 -Base) Urea (Example Compound 24) (34 mg, 34%).

實例22及23係以類似方法製備而成。 Examples 22 and 23 were prepared in a similar manner.

實例25之合成：Synthesis of Example 25:

5-(3-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)脲基)啶醯胺 5-(3-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)ureido)pyridinium

步驟1：將5-胺基-2-氰砒啶(500毫克，4.20毫莫耳)以四氫呋喃及乙腈(1：1之比例)溶解。於該反應混合物中添加啶(0.37毫升，4.62毫莫耳，1.1等量)與氯甲酸苯酯(0.55毫升，4.41毫莫耳，1.05等量)，並於室溫攪拌2小時。將該反應混合物以水稀釋，並以醋酸乙酯萃取。以水及飽和之氯化鈉溶液清洗有機部分。將有機層以硫酸鎂乾燥，並於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得純苯基6-氰砒啶-3-基胺甲酸酯(880毫克，88%)。 Step 1: 5-Amino-2-cyanoacridine (500 mg, 4.20 mmol) was dissolved in tetrahydrofuran and acetonitrile (1:1 ratio). To the reaction mixture were added pyridine (0.37 ml, 4.62 mmol, 1.1 eq.) and phenyl chloroformate (0.55 ml, 4.41 mM, 1.05 eq.) and stirred at room temperature for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic portion was washed with water and a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and concentrated at lower pressure. The crude product was purified by column chromatography to afford pure phenyl 6- cyanacin-3-ylcarbamate (880 mg, 88%).

步驟2：於室溫，於一以乙腈溶解之苯基6-氰砒啶-3-基胺甲酸酯(150毫克，0.63毫莫耳，1.05等量)溶液中添加二甲胺基啶(80毫克，0.66毫莫耳，1.1等量)及(3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺(157毫克，0.60毫莫耳，1等量)。將該反應混合物於50℃加熱過夜。將該反應混合物以水稀釋，並以醋酸乙酯萃取。 以水及飽和之氯化鈉溶液清洗有機部分。將有機層以硫酸鎂乾燥，並於較低壓力濃縮。以管柱色層分析法純化該粗製產物，以獲得1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-氰砒啶-3-基)尿素(220毫克，90%)。 Step 2: Add dimethylaminopyridine to a solution of phenyl 6-cyanoacridin-3-ylcarbamate (150 mg, 0.63 mmol, 1.05 equivalent) dissolved in acetonitrile at room temperature. 80 mg, 0.66 mmol, 1.1 equivalent) and (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methylamine (157 mg, 0.60 mmol) , 1 equal amount). The reaction mixture was heated at 50 °C overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic portion was washed with water and a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and concentrated at lower pressure. The crude product was purified by column chromatography to give 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3- (6-Cyanoacridin-3-yl)urea (220 mg, 90%).

步驟3：將1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-氰砒啶-3-基)尿素(220毫克，0.54毫莫耳)以硫酸(2.9毫升)溶解。將該反應混合物於60℃攪拌2小時，隨後將其冷卻至室溫。將該反應混合物以冰水稀釋，並以2M之氫氧化鈉溶液中和(pH=7)。以醋酸乙酯萃取該混合物。將有機層以硫酸鎂乾燥，並於較低壓力濃縮。以管柱色層分析法純化該粗製產物，以獲得5-(3-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)脲基)啶醯胺(實例化合物25)(90毫克，39%)。 Step 3: 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-cyanacridin-3-yl) Urea (220 mg, 0.54 mmol) was dissolved in sulfuric acid (2.9 mL). The reaction mixture was stirred at 60 ° C for 2 hours and then cooled to room temperature. The reaction mixture was diluted with ice water and neutralized with a 2M sodium hydroxide solution (pH = 7). The mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated at lower pressure. The crude product was purified by column chromatography to give 5-(3-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl) Ureido) pyridine amine (example compound 25) (90 mg, 39%).

1H核磁共振(300 MHz，二甲亞碸-d6)：δ 9.11(br.s，NH)；8.59(m，1H，Ar-H)；7.94(m，3H，Ar-H)；7.52(m，5H，Ar-H)；6.92(m，NH)；6.33(s，1H，吡唑-H)；4.42(d，2H，J=5.67 Hz，Ar-CH2)；1.26(s，9H，t-butyl-H)。 1 H NMR (300 MHz, dimethyl hydrazine-d 6 ): δ 9.11 (br.s, NH); 8.59 (m, 1H, Ar-H); 7.94 (m, 3H, Ar-H); 7.52 (m, 5H, Ar-H); 6.92 (m, NH); 6.33 (s, 1H, pyrazole-H); 4.42 (d, 2H, J = 5.67 Hz, Ar-CH 2 ); 1.26 (s, 9H, t-butyl-H).

實例26之合成：Synthesis of Example 26:

5-(3-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)脲基)啶醯胺 5-(3-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)ureido)pyridinium

步驟1：將5-胺基-2-氰砒啶(500毫克，4.20毫莫耳)以四氫呋喃及乙腈(1：1之比例)溶解。於該反應混合物中添加啶(0.37毫升，4.62毫莫耳，1.1等量)與氯甲酸苯酯(0.55毫升，4.41毫莫耳，1.05等量)，並於室溫攪拌2小時。將該反應混合物以水稀釋，並以醋酸乙酯萃取。以水及飽和之氯化鈉溶液清洗有機部分。將有機層以硫酸鎂乾燥，並於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得苯基6-氰砒啶-3-基胺甲酸酯(880毫克，88%)。 Step 1: 5-Amino-2-cyanoacridine (500 mg, 4.20 mmol) was dissolved in tetrahydrofuran and acetonitrile (1:1 ratio). To the reaction mixture were added pyridine (0.37 ml, 4.62 mmol, 1.1 eq.) and phenyl chloroformate (0.55 ml, 4.41 mM, 1.05 eq.) and stirred at room temperature for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic portion was washed with water and a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and concentrated at lower pressure. The crude product was purified by column chromatography to afford phenyl 6- cyanacin-3-ylamine ( 880 mg, 88%).

步驟2：於室溫，於一以乙腈溶解之苯基6-氰砒啶-3-基胺甲酸酯(150毫克，0.63毫莫耳，1.05等量)溶液中添加4-二甲胺基啶(80毫克，0.66毫莫耳，1.1等量)及(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺(165毫克，0.60毫莫耳，1等量)。將該反應混合物於50℃加熱過夜。將該反應混合物以水稀釋，並以醋酸乙酯萃取。 以水及飽和之氯化鈉溶液清洗有機部分。將有機層以硫酸鎂乾燥，並於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-氰砒啶-3-基)尿素(220毫克，88%)。 Step 2: Add 4-dimethylamino group to a solution of phenyl 6-cyanoacridin-3-ylcarbamate (150 mg, 0.63 mmol, 1.05 equivalent) dissolved in acetonitrile at room temperature. Pyridine (80 mg, 0.66 mmol, 1.1 equivalent) and (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamine (165 mg, 0.60 millimoles, 1 equal amount). The reaction mixture was heated at 50 °C overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic portion was washed with water and a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and concentrated at lower pressure. The crude product was purified by column chromatography to give 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3 -(6-Cyanopyridin-3-yl)urea (220 mg, 88%).

步驟3：將1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-氰砒啶-3-基)尿素(220毫克，0.52毫莫耳)以硫酸(2.8毫升)溶解。將該反應混合物於60℃攪拌2小時，隨後將其冷卻至室溫。將該反應混合物以冰水稀釋，並以2M之氫氧化鈉溶液中和(pH=7)。以醋酸乙酯萃取該混合物。將有機層以硫酸鎂乾燥，並於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得5-(3-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)脲基)啶醯胺(實例化合物26)(80毫克，35%)。 Step 3: 1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-cyanacidine-3) -Base) Urea (220 mg, 0.52 mmol) was dissolved in sulfuric acid (2.8 mL). The reaction mixture was stirred at 60 ° C for 2 hours and then cooled to room temperature. The reaction mixture was diluted with ice water and neutralized with a 2M sodium hydroxide solution (pH = 7). The mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated at lower pressure. The crude product was purified by column chromatography to give 5-(3-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl Ureido) pyridine amine (example compound 26) (80 mg, 35%).

1H核磁共振(300 MHz，丙酮-d6)：δ 8.64(m，2H，Ar-H，NH)；8.10(m，1H，Ar-H)；8.01(m，1H，Ar-H)；7.73(m，2H，Ar-H)；7.63(m，3H，Ar-H)；6.86(s，1H，吡唑-H)；6.75(m，NH)；6.62(br.s，NH)；4.62(m，2H，Ar-CH2)。 1 H nuclear magnetic resonance (300 MHz, acetone-d 6 ): δ 8.64 (m, 2H, Ar-H, NH); 8.10 (m, 1H, Ar-H); 8.01 (m, 1H, Ar-H); 7.73 (m, 2H, Ar-H); 7.63 (m, 3H, Ar-H); 6.86 (s, 1H, pyrazole-H); 6.75 (m, NH); 6.62 (br.s, NH); 4.62 (m, 2H, Ar-CH 2 ).

實例27之合成：Synthesis of Example 27:

N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-(甲基磺醯胺基甲基)啶-3-基)丙醯胺 N-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(6-(methylsulfonylaminomethyl) Pyridin-3-yl)propanamide

步驟1：於室溫，於一以乙醇溶解之6-氯-3-啶基乙酸鹽酸(3.0公克，17.5毫莫耳)溶液中緩慢地添加硫酸(0.3毫升)。將該反應混合物以100℃加熱過夜。薄層層析法顯起始原料被完全消耗。將該反應混合物冷卻至室溫，並以碳酸氫鈉中和。以醋酸乙酯萃取該混合物，並以水及飽和之氯化鈉溶液清洗。將萃取物以硫酸鎂乾燥，並於較低壓力濃縮，以獲得所需之乙基2-(6-氯啶-3-基)乙酸 酯(3.0公克，86%)。 Step 1: Sulfuric acid (0.3 ml) was slowly added to a solution of 6-chloro-3-pyridine acetic acid hydrochloride (3.0 g, 17.5 mmol) dissolved in ethanol at room temperature. The reaction mixture was heated at 100 ° C overnight. Thin layer chromatography showed that the starting materials were completely consumed. The reaction mixture was cooled to room temperature and neutralized with sodium bicarbonate. The mixture was extracted with ethyl acetate and washed with water and a saturated sodium chloride solution. The extract was dried over magnesium sulfate and concentrated under reduced pressure to afford ethyl 2-(6-chloropyridin-3-yl)acetate (3.0 g, 86%).

步驟2：於0℃，於一以無水二甲基甲醯胺溶解之乙基2-(6-氯啶-3-基)乙酸酯(3.0公克，15.1毫莫耳)溶液中緩慢地添加60%之氫化鈉(664毫克，16.6毫莫耳，1.1等量)及碘代甲烷(1.0毫升，15.9毫莫耳，1.05等量)。將該反應混合物於氮氣氣氛下加熱至室溫45分鐘。薄層層析法顯示起始原料被完全消耗。於該反應混合物中添加水以進行淬火反應。將該混合物以醋酸乙酯萃取，並以水及飽和之氯化鈉溶液清洗。以硫酸鎂乾燥該萃取物，並於較低壓力將其濃縮，以獲得粗製產物；以管柱色層分析法純化該粗製產物，以獲得乙基2-(6-氯啶-3-基)丙酸(916毫克，28%)。 Step 2: Slowly add in a solution of ethyl 2-(6-chloropyridin-3-yl)acetate (3.0 g, 15.1 mmol) dissolved in anhydrous dimethylformamide at 0 °C. 60% sodium hydride (664 mg, 16.6 mmol, 1.1 equivalent) and methyl iodide (1.0 mL, 15.9 mmol, 1.05 equivalent). The reaction mixture was heated to room temperature for 45 minutes under a nitrogen atmosphere. Thin layer chromatography showed complete consumption of the starting material. Water is added to the reaction mixture to carry out a quenching reaction. The mixture was extracted with ethyl acetate and washed with water and a saturated sodium chloride solution. The extract was dried over magnesium sulfate and concentrated at a lower pressure to give a crude product. The crude product was purified by column chromatography to give ethyl 2-(6-chloropyridin-3-yl). Propionic acid (916 mg, 28%).

步驟3：於一以無水二甲基甲醯胺溶解之乙基2-(6-氯啶-3-基)丙酸(3.0公克，13.8毫莫耳)溶液中添加氰化鋅(2.3公克，19.9毫莫耳，1.5等量)及四(三苯基膦基)鈀(0)(1.5公克，1.32毫莫耳，0.1等量)。將該反應混合物於氮氣氣氛下回流過夜。薄層層析法顯示起始原料被完全消耗。以矽藻土墊將該混合物過濾，並於較低壓力將濾液濃縮，以獲得所需之化合物。以醋酸乙酯萃取該混合物，並以水及飽和之氯化鈉溶液清洗。將萃取物以硫酸鎂乾燥，並於較低壓力濃縮，以獲得粗製產物；以管柱色層分析法將其純化，以獲得乙基2-(6-氰砒啶-3-基)丙酸(1.3公克，45%)。 Step 3: Add zinc cyanide (2.3 g, in a solution of ethyl 2-(6-chloropyridin-3-yl)propionic acid (3.0 g, 13.8 mmol) dissolved in anhydrous dimethylformamide. 19.9 millimolar, 1.5 equivalents) and tetrakis(triphenylphosphino)palladium(0) (1.5 grams, 1.32 millimolar, 0.1 equivalent). The reaction mixture was refluxed overnight under a nitrogen atmosphere. Thin layer chromatography showed complete consumption of the starting material. The mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated at a lower pressure to give the desired compound. The mixture was extracted with ethyl acetate and washed with water and a saturated sodium chloride solution. The extract was dried over magnesium sulfate and concentrated at a lower pressure to give a crude product which was purified by column chromatography to give ethyl 2-(6-c-c- cyanoazin-3-yl)propanoic acid. (1.3 grams, 45%).

步驟4：將乙基2-(6-氰砒啶-3-基)丙酸(1.3公克，6.22毫莫耳)以四氫呋喃及水(1：1)溶解。於該反應混合物中添加以四氫呋喃及水(1：1)溶解之氫氧化鈉(622毫克，15.6毫莫耳，2.5等量)，並於氮氣氣氛下，將其於室溫攪拌4小時。薄層層析法顯示起始原料被完全消耗。將該混合物以水稀釋，並添加醋酸，直至其酸鹼值為3。隨後以二氯甲烷萃取該混合物。以水及飽和之氯化鈉溶液清洗有機部分。將有機層以硫酸鎂乾燥，並於較低壓力濃縮。以管 柱色層分析法純化粗製產物，以獲得2-(6-氰砒啶-3-基)丙酸(1.1公克，95%)。 Step 4: Ethyl 2-(6-cyanoacridin-3-yl)propanoic acid (1.3 g, 6.22 mmol) was dissolved in tetrahydrofuran and water (1:1). Sodium hydroxide (622 mg, 15.6 mmol, 2.5 equivalent) dissolved in tetrahydrofuran and water (1:1) was added to the reaction mixture, and the mixture was stirred at room temperature for 4 hr under nitrogen atmosphere. Thin layer chromatography showed complete consumption of the starting material. The mixture was diluted with water and acetic acid was added until it had a pH of 3. The mixture was then extracted with dichloromethane. The organic portion was washed with water and a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and concentrated at lower pressure. The crude product was purified by column chromatography to give 2-(6-c- cyanoazin-3-yl)propanoic acid (1.1 g, 95%).

步驟5：於室溫，於一以二甲基甲醯胺溶解之2-(6-氰砒啶-3-基)丙酸(364毫克，2.07毫莫耳)溶液中添加N-(3-二甲胺基丙基)-N’-乙基碘化二亞胺(594毫克，3.09毫莫耳，1.5等量)、N-羧苯並三唑(419毫克，3.09毫莫耳，1.5等量)、三乙胺(0.72毫升，5.17毫莫耳，2.5等量)及(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺(565毫克，2.07毫莫耳，1等量)，並將其攪拌過夜。薄層層析法顯示起始原料被完全消耗。將該反應混合物以水稀釋，並以醋酸乙酯萃取。以水及飽和之氯化鈉溶液清洗有機部分。將有機層以硫酸鎂乾燥，並於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-(氰砒啶)啶-3-基)丙醯胺(378毫克，42%)。 Step 5: Add N-(3-) to a solution of 2-(6-cyanoacridin-3-yl)propionic acid (364 mg, 2.07 mmol) dissolved in dimethylformamide at room temperature. Dimethylaminopropyl)-N'-ethyl iodide diimide (594 mg, 3.09 mmol, 1.5 equivalent), N-carboxybenzotriazole (419 mg, 3.09 mmol, 1.5, etc.) Amount, triethylamine (0.72 ml, 5.17 mmol, 2.5 equivalents) and (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl) Amine (565 mg, 2.07 mmol, 1 equivalent) and stirred overnight. Thin layer chromatography showed complete consumption of the starting material. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic portion was washed with water and a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and concentrated at lower pressure. The crude product was purified by column chromatography to give N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2 -(6-(Cyanopyridin-3-yl)propanamide (378 mg, 42%).

步驟6：將N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-(氰砒啶)啶-3-基)丙醯胺(372毫克，0.86毫莫耳)以甲醇溶解。將該混合物以冰浴冷卻，並緩慢地添加二碳酸三級丁酯(374毫克，1.72毫莫耳，2等量)、氯化鎳￭6水(NiCl2￭6H2O)(20毫克，0.09毫莫耳，0.1等量)及硼氫化鈉(227毫克，6.00毫莫耳，7等量)，並於攪拌1小時。1小時之後，於該混合物中添加二乙烯三胺(0.09毫升，0.86毫莫耳，1等量)，並於室溫攪拌1小時。薄層層析法顯示起始原料被完全消耗。將該反應混合物以水稀釋，並以醋酸乙酯萃取。以水及飽和之氯化鈉溶液清洗有機部分。將有機層以硫酸鎂乾燥，並於較低壓力濃縮。以管柱色層分析法純化該粗製產物，以獲得三級丁基(5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)氨基甲酸甲酯(166毫克，41%)。 Step 6: N-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(6-(cyanoacridine) Pyridin-3-yl)propanamide (372 mg, 0.86 mmol) was dissolved in methanol. The mixture was cooled in an ice bath, and butyl tricarbonate (374 mg, 1.72 mmol, 2 equivalents), nickel chloride ( 6 mL) (NiCl 2 ■ 6H 2 O) (20 mg, 0.09 mmol, 0.1 equivalents) and sodium borohydride (227 mg, 6.00 mmol, 7 equivalents) and stirred for 1 hour. After 1 hour, diethylenetriamine (0.09 ml, 0.86 mmol, 1 equivalent) was added to the mixture and stirred at room temperature for 1 hour. Thin layer chromatography showed complete consumption of the starting material. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic portion was washed with water and a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and concentrated at lower pressure. The crude product was purified by column chromatography to give tris-butyl(5-(1-(3-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole)- Methyl 5-amino)methylamino)-1-oxopropan-2-yl)pyridin-2-yl)carbamate (166 mg, 41%).

步驟7：將三級丁基(5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)氨基甲酸甲酯(166毫克，0.30毫莫耳)以二氯甲烷(4毫升)溶解。於該反應混合物中添加三氟醋酸(1毫升)，並於氮氣氣氛下，於室溫攪拌過夜。薄層層析法顯示起始原料被完全消耗。將該混合物以碳酸氫鈉溶液中和，並以二氯甲烷萃取。以水及飽和之氯化鈉溶液清洗有機部分。將有機層以硫酸鎂乾燥，並於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得2-(6-(胺甲基)啶-3-基)-N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)丙醯胺(75毫克，56%)。 Step 7: Tert-butyl butyl (5-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1 Methyl 2-oxopropan-2-yl)pyridin-2-yl)carbamate (166 mg, 0.30 mmol) was dissolved in dichloromethane (4 mL). Trifluoroacetic acid (1 ml) was added to the reaction mixture and stirred at room temperature overnight under nitrogen atmosphere. Thin layer chromatography showed complete consumption of the starting material. The mixture was neutralized with a sodium hydrogen carbonate solution and extracted with dichloromethane. The organic portion was washed with water and a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and concentrated at lower pressure. The crude product was purified by column chromatography to give 2-(6-(aminomethyl)pyridin-3-yl)-N-((1-(3-chlorophenyl)-3-(trifluoro) -1H-pyrazol-5-yl)methyl)propanamide (75 mg, 56%).

步驟8：於0℃，於一以二氯甲烷溶解之2-(6-(胺甲基)啶-3-基)-N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)丙醯胺(75毫克，0.17毫莫耳)溶液中添加甲磺醯氯(0.013毫升，0.17毫莫耳，1等量)及三乙胺(0.023毫升，0.17毫莫耳，1等量)加至。將該反應混合物攪拌30分鐘。薄層層析法顯示起始原料被完全消耗。將該混合物以醋酸乙酯萃取，並以水及飽和之氯化鈉溶液清洗。將萃取物以硫酸鎂乾燥，並於較低壓力將其濃縮。以管柱色層分析法純化粗製產物，以獲得N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-(甲基磺醯胺基甲基)啶-3-基)丙醯胺(實例化合物27)(45毫克，51%)。 Step 8: 2-(6-(Aminomethyl)pyridin-3-yl)-N-((1-(3-chlorophenyl)-3-(3)-dissolved in dichloromethane at 0 ° C Methylsulfonium chloride (0.013 ml, 0.17 mmol, 1 equivalent) was added to a solution of fluoromethyl)-1H-pyrazol-5-yl)methyl)propanamide (75 mg, 0.17 mmol) and Triethylamine (0.023 ml, 0.17 mmol, 1 equivalent) was added. The reaction mixture was stirred for 30 minutes. Thin layer chromatography showed complete consumption of the starting material. The mixture was extracted with ethyl acetate and washed with water and a saturated sodium chloride solution. The extract was dried over magnesium sulfate and concentrated at a lower pressure. The crude product was purified by column chromatography to give N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2 -(6-(Methylsulfonylamino)pyridin-3-yl)propanamide (Example Compound 27) (45 mg, 51%).

1H核磁共振(300 MHz，CDCl3)：δ 8.42(s，1H，Ar-H)；7.64(dd，1H，J=8.07Hz，2.22Hz，Ar-H)；7.43(m，3H，Ar-H)；7.32(m，2H，Ar-H)；6.46(s，1H，吡唑-H)；5.79(bs，1H，醯胺-H)；5.59(bs，1H，胺(Ms)-H)；4.51(d，2H，J=5.67Hz；吡唑-CH2)；4.43(d，2H，J=5.31Hz，Ar-CH2)；3.53(m，1H)；2.96(s，3H，Ms-CH3)；1.49(d，3H，J=6.96Hz)。 1 H NMR (300 MHz, CDCl 3 ): δ 8.42 (s, 1H, Ar-H); 7.64 (dd, 1H, J = 8.07 Hz, 2.22 Hz, Ar-H); 7.43 (m, 3H, Ar) -H); 7.32 (m, 2H, Ar-H); 6.46 (s, 1H, pyrazole-H); 5.79 (bs, 1H, decylamine-H); 5.59 (bs, 1H, amine (Ms)- H); 4.51 (d, 2H, J = 5.67 Hz; pyrazole-CH 2 ); 4.43 (d, 2H, J = 5.31 Hz, Ar-CH 2 ); 3.53 (m, 1H); 2.96 (s, 3H) , Ms-CH 3 ); 1.49 (d, 3H, J = 6.96 Hz).

實例50之合成：Synthesis of Example 50:

1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(5-氟-6-(羥甲基)啶-3-基)尿素 1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(5-fluoro-6-(hydroxymethyl) Pyridin-3-yl)urea

步驟1：於氮氣氣氛下，於硝酸鉀(16.6公克，164毫莫耳，2等量)中依序添加三氟醋酸(12.2毫升，164毫莫耳，18.7公克，2等量)及三氟醋酸酐(11.4毫升，17.2公克，82毫莫耳，1等量)。15分鐘後立即添加油狀之3-氟-2-氰吡啶(3-fluoropicolinonitrile)(10.0公克，82毫莫耳)。攪拌48小時之後，將其倒入飽和之碳酸氫鈉水溶液(400毫升)中，並以醋酸乙酯(3×300毫升)萃取該混合物。將合併有機層以硫酸鈉乾燥，並將其濃縮，以獲得黃色油狀物。根據H核磁共振，該粗製產物係由約20%之產物及起始原料所組成。使用二氯甲烷將油狀物吸附於至二氧化矽(100公克)。將吸附後之二氧化矽置放於一10公分之矽膠柱上方(約1公升)，以存在於庚烷之20%醋酸乙酯洗脫產物。將含有產物之部分集中，以獲得呈白色固體狀之3-氟-5-硝基2-氰吡啶 (3-fluoro-5-nitropicolinonitrile)(2.1公克，15%)。 Step 1: In a nitrogen atmosphere, add trifluoroacetic acid (12.2 ml, 164 mmol, 18.7 g, 2 equivalents) and trifluoride in potassium nitrate (16.6 g, 164 mmol, 2 equivalents). Acetic anhydride (11.4 ml, 17.2 g, 82 mmol, 1 equivalent). Immediately after 15 minutes, oily 3-fluoropicolinonitrile (10.0 g, 82 mmol) was added. After stirring for 48 hours, it was poured into a saturated aqueous solution of sodium bicarbonate (400 ml), and the mixture was extracted with ethyl acetate (3×300 ml). The combined organic layers were dried with sodium sulfate and evaporated According to H NMR, the crude product consisted of about 20% of the product and starting material. The oil was adsorbed to cerium oxide (100 g) using dichloromethane. The adsorbed cerium oxide was placed on top of a 10 cm ruthenium column (about 1 liter) and the product was eluted with 20% ethyl acetate in heptane. The fractions containing the product were concentrated to give 3-fluoro-5-nitropicolinonitrile (2.1 g, 15%) as a white solid.

步驟2：將以醋酸乙酯(10毫升)及醋酸(10毫升)溶解之3-氟-5-硝基-2-氰吡啶(2.1公克，12.6毫莫耳)加熱至約65℃，並添加鐵粉(542毫克，9.7毫莫耳，5等量)。30分鐘後即產生棕紅色懸浮液，將該懸浮液以矽藻土過濾並濃縮。將殘留物加至醋酸乙酯(200毫升)與飽和之碳酸氫鈉水溶液(200毫升)中。將以此產生之深褐色沉澱物以矽藻土過濾。將層相分離，以醋酸乙酯(3×200毫升)萃取水層。將合併有機層以硫酸鈉乾燥並濃縮，以獲得呈褐色固體狀之5-胺基-3-氟-2-氰吡啶(1.52公克)。 Step 2: 3-Fluoro-5-nitro-2-cyanopyridine (2.1 g, 12.6 mmol) dissolved in ethyl acetate (10 ml) and acetic acid (10 ml) was heated to about 65 ° C and added Iron powder (542 mg, 9.7 mmol, 5 equivalents). A brown-red suspension was produced after 30 minutes and the suspension was filtered over Celite and concentrated. The residue was taken up in ethyl acetate (EtOAc) (EtOAc) The dark brown precipitate thus produced was filtered with diatomaceous earth. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×200 mL). The combined organic layers were dried with EtOAc EtOAc (EtOAc)

步驟3+4：將以濃氯化氫水溶液(20毫升)溶解之5-胺基-3-氟-2-氰吡啶(1.52公克，11毫莫耳)溶液於80℃加熱過夜。將該混合物濃縮，以獲得紅色固體狀之粗製產物。添加甲醇(100毫升)，並將其於50℃旋轉蒸發。重複此流程3次，以將產物乾燥。隨後，添加甲醇(50毫升)及硫酸(1毫升)，並將該混合物回流過夜。待該混合物冷卻至室溫後，將其倒入碳酸氫鈉(100公克)中，並將其濃縮。添加水(300毫升)及醋酸乙酯(200毫升)，並分離層相。以醋酸乙酯萃取水層(2×200毫升)。將合併有機層以硫酸鈉乾燥，並將其濃縮，以獲得褐色殘留物；將所得之殘留物加至二氯甲烷(20毫升)中一起碾碎。將產生之固體過濾並乾燥，以獲得呈淡褐色固體狀之產物(860毫克，45%)。 Step 3+4: A solution of 5-amino-3-fluoro-2-cyanopyridine (1.52 g, 11 mmol) dissolved in concentrated aqueous hydrogen chloride (20 mL). The mixture was concentrated to give a crude product as a red solid. Methanol (100 mL) was added and it was evaporated at 50 °C. This procedure was repeated 3 times to dry the product. Subsequently, methanol (50 ml) and sulfuric acid (1 ml) were added, and the mixture was refluxed overnight. After the mixture was cooled to room temperature, it was poured into sodium hydrogencarbonate (100 g) and concentrated. Water (300 ml) and ethyl acetate (200 ml) were added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×200 mL). The combined organic layers were dried with EtOAc EtOAc (EtOAc) The resulting solid was filtered and dried to give crystals (yield: 860 mg, 45%).

步驟5：將以四氫呋喃(50毫升)溶解之甲基5-胺基-3-氟-2-氰吡啶(860毫克，5.0毫莫耳)溶液於冰塊或水浴中冷卻。添加氫鋁化鋰溶液(4N，溶於二乙醚)(3.75毫升，15毫莫耳，3等量)。於1小時後，將其倒入醋酸乙酯中(200毫升)。添加水(10毫升)及飽和之碳酸氫鈉水溶液(10毫升)，並將該混合物攪拌30分鐘。將溶液由白色沉澱物中傾析出，將其以飽和之氯化鈉溶液清洗，以硫酸 鈉乾燥，並將其濃縮，以獲得一褐色固體。將其以短矽膠柱(2公分)過濾，以獲得呈黃色固體狀之目標產物(522毫克，3.67毫莫耳，73%)。 Step 5: A solution of methyl 5-amino-3-fluoro-2-cyanopyridine (860 mg, 5.0 mmol) dissolved in tetrahydrofuran (50 mL) was cooled in ice or water. A lithium aluminum hydride solution (4N, dissolved in diethyl ether) (3.75 mL, 15 mmol, 3 equivalents) was added. After 1 hour, it was poured into ethyl acetate (200 mL). Water (10 ml) and saturated aqueous sodium bicarbonate (10 ml) were added and the mixture was stirred for 30 min. The solution was decanted from a white precipitate which was washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated to give a brown solid. It was filtered through a short EtOAc column (2 mL) to afford product (yield: 522 mg, 3.67 mmol, 73%) as a yellow solid.

步驟6：於150℃，於一經攪拌、以四氫呋喃(3毫升)溶解之(5-胺基-3-氟啶-2-基)甲醇(28毫克，0.202毫莫耳)溶液中依序添加N-二異丙基乙胺(0.093毫升，0.548毫莫耳)及苯基(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)氨基甲酸甲酯(74毫克，0.189毫莫耳)，並於微波條件下(7巴)攪拌1小時。將經濃縮之反應混合物以管柱色層分析法(矽膠：100至200篩孔，溶析液：醋酸乙酯/甲醇9：1)純化，以獲得白色固體狀之1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(5-氟-6-(羥甲基)啶-3-基)尿素(實例化合物50)(12毫克，14%)。 Step 6: Add N sequentially at 150 ° C in a solution of (5-amino-3-fluoropyridine-2-yl)methanol (28 mg, 0.202 mmol) dissolved in tetrahydrofuran (3 mL) -diisopropylethylamine (0.093 ml, 0.548 mmol) and phenyl(1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)carbamic acid Methyl ester (74 mg, 0.189 mmol) was stirred under microwave conditions (7 bar) for 1 hour. The concentrated reaction mixture was purified by column chromatography (EtOAc: 100 to 200 mesh, eluent: ethyl acetate / methanol 9:1) to afford 1-((1-) 3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(5-fluoro-6-(hydroxymethyl)pyridin-3-yl)urea (Example compound 50) (12 mg, 14%).

實例52之合成：Synthesis of Example 52:

1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙基)啶-3-基)尿素 1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethyl)pyridine- 3-base urea

步驟1：於一經攪拌、室溫狀態、以二甲基甲醯胺(50毫升)之丙二酸二乙酯(9.6毫升，63.25毫莫耳，2等量)溶液中添加碳酸鉀(12.8公克，93.09毫莫耳，3等量)及2-氯-5-硝基吡啶(5公克，31.23毫莫耳，1等量)，並於70℃攪拌16小時。將該反應混合物倒入冰水中，以醋酸乙酯(2 x 25毫升)萃取，以硫酸鈉乾燥，並使其蒸發，以獲得二乙基2-(5-硝基吡啶-2-基)丙二酸酯(5.7公克，68%)。 Step 1: Add potassium carbonate (12.8 g) to a solution of diethyl malonamide (50 ml) of diethyl malonate (9.6 ml, 63.25 mmol, 2 equivalents) at room temperature. , 93.09 mmol, 3 equivalents) and 2-chloro-5-nitropyridine (5 g, 31.23 mmol, 1 equivalent), and stirred at 70 ° C for 16 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate (2×25 ml), dried over sodium sulfate and evaporated to give diethyl 2-(5-nitropyridin-2-yl) Diester (5.7 g, 68%).

步驟2：於經攪拌、以二甲亞碸(15毫升)溶解之二乙基2-(5-硝基吡啶-2-基)丙二酸酯(1.0公克，3.5毫莫耳，1.0等量)溶液中添 加氯化鈉(0.21公克，3.5毫莫耳，1.0等量)及水(0.2毫升)，並將所產生之反應混合物於120℃攪拌2小時。將該反應混合物濃縮，並以醋酸乙酯(2 x 20毫升)萃取，以飽和之氯化鈉溶液(30毫升)清洗，以硫酸鈉乾燥，並將其濃縮。使用醋酸乙酯/石油醚(1：9)做為溶析液，以矽膠(100至200篩孔)管柱色層分析法純化該粗製產物，以獲得乙基2-(5-硝基吡啶-2-基)乙酸酯(0.41公克，55%)。 Step 2: Diethyl 2-(5-nitropyridin-2-yl)malonate (1.0 g, 3.5 mmol, 1.0 equivalent) dissolved in dimethyl hydrazine (15 ml) Sodium chloride (0.21 g, 3.5 mmol, 1.0 equivalent) and water (0.2 ml) were added to the solution, and the resulting reaction mixture was stirred at 120 ° C for 2 hours. The reaction mixture was concentrated with EtOAc EtOAc m. Ethyl acetate/petroleum ether (1:9) was used as the eluent, and the crude product was purified by silica gel chromatography (100 to 200 mesh) to obtain ethyl 2-(5-nitropyridine). -2-yl) acetate (0.41 g, 55%).

步驟3：於-78℃，於一經攪拌、以無水四氫呋喃溶解之乙基2-(5-硝基吡啶-2-基)乙酸酯(2.5公克，11.91毫莫耳，1.0等量)溶液中，逐滴添加二異丁基氫化鋁(23毫升，23.8毫莫耳)。將該反應混合物於-78℃攪拌2小時，隨後將該反應混合物以冰水進行淬火反應，以醋酸乙酯(30毫升)萃取，並於較低壓力蒸發。使用醋酸乙酯/石油醚(1：1)做為溶析液，以矽膠(100至200篩孔)管柱色層分析法純化粗製產物，以獲得2-(5-硝基吡啶-2-基)乙醇(0.5公克，25%)。 Step 3: Ethyl 2-(5-nitropyridin-2-yl)acetate (2.5 g, 11.91 mmol, 1.0 equivalent) dissolved in anhydrous tetrahydrofuran at -78 ° C Diisobutylaluminum hydride (23 ml, 23.8 mmol) was added dropwise. The reaction mixture was stirred at -78.degree. C. for 2 hr then EtOAc (EtOAc) Ethyl acetate/petroleum ether (1:1) was used as the eluent, and the crude product was purified by silica gel chromatography (100 to 200 mesh) to obtain 2-(5-nitropyridine-2- Base) Ethanol (0.5 g, 25%).

步驟4：於0℃，於一經攪拌、以二氯甲烷(20毫升)溶解之2-(5-硝基吡啶-2-基)乙醇(0.300公克，1.78毫莫耳，1.0等量)溶液中添加咪唑(0.182公克，2.6毫莫耳，1.5等量)及叔丁基二甲基氯矽烷(0.390公克，2.6毫莫耳)，並於室溫攪拌2小時。將該反應混合物以水(25毫升)進行淬火反應，並以二氯甲烷(2 x 15毫升)萃取。以飽和之氯化鈉溶液(30毫升)清洗有機層，將其以硫酸乾燥並濃縮。使用醋酸乙酯/石油醚(1：9)做為溶析液，以矽膠(100至200篩孔)管柱色層分析法純化粗製產物，以獲得2-(2-(三級丁基二甲基矽氧基三級丁基二甲基矽氧基)乙基)-5-硝基吡啶(0.42公克，84%)。 Step 4: In a solution of 2-(5-nitropyridin-2-yl)ethanol (0.300 g, 1.78 mmol, 1.0 equivalent) dissolved in dichloromethane (20 mL) at 0 ° C Imidazole (0.182 g, 2.6 mmol, 1.5 equivalent) and tert-butyldimethylchloromethane (0.390 g, 2.6 mmol) were added and stirred at room temperature for 2 h. The reaction mixture was quenched with water (25 mL). The organic layer was washed with a saturated aqueous solution of sodium chloride (30 ml), dried and evaporated. Ethyl acetate/petroleum ether (1:9) was used as the eluent, and the crude product was purified by silica gel column chromatography (100 to 200 mesh) to obtain 2-(2-(tri-butyl) Methyl decyloxy tert-butyl dimethyl methoxy) ethyl)-5-nitropyridine (0.42 g, 84%).

步驟5：於一經攪拌、以甲醇(10毫升)溶解之2-(2-(三級丁基二甲基矽氧基)乙基)-5-硝基吡啶(0.4公克，1.4毫莫耳，1.0等量)溶液中添加10%之鈀碳(0.1公克)，並於氫氣氣氛下，將其於室溫 攪拌2小時。將該反應混合物以矽藻土墊過濾，並將濾液於較低壓力濃縮。將粗製產物以二乙醚(20毫升)清洗，以獲得灰白色固體狀之6-(2-(三級丁基二甲基矽氧基)乙基)啶-3-胺(0.25公克，71%)。 Step 5: 2-(2-(tert-butyldimethyl methoxy)ethyl)-5-nitropyridine (0.4 g, 1.4 mmol) dissolved in methanol (10 mL). 1.0 equivalent of the solution was added with 10% palladium on carbon (0.1 g), and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated. The crude product was washed with diethyl ether (20 mL) to afford 6-(2-(tert-butyl dimethyl </RTI></RTI><RTIgt; .

步驟6：於0℃，於以丙酮(10毫升)溶解之6-(2-(三級丁基二甲基矽氧基)乙基)啶-3-胺(0.14公克，0.5毫莫耳，1.0等量)溶液中添加啶(0.08毫升，1.0毫莫耳，2等量)與氯甲酸苯酯(0.095公克，0.6毫莫耳，1.1等量)。隨後，將該反應混合物於室溫攪拌2小時。將該反應混合物濃縮，並以二氯甲烷(10毫升)稀釋，以水(20毫升)清洗，以硫酸鈉乾燥，並於較低壓力下濃縮，以獲得灰白色故體重之苯基6-(2-(三級丁基二甲基矽氧基)乙基)啶-3-基胺甲酸酯(0.195公克，94%)。 Step 6: 6-(2-(tert-butyldimethyl methoxy)ethyl)pyridine-3-amine (0.14 g, 0.5 mmol) dissolved in acetone (10 mL) at 0 °C. 1.0 aliquot of the solution was added pyridine (0.08 ml, 1.0 mmol, 2 equivalents) with phenyl chloroformate (0.095 g, 0.6 mmol, 1.1 equivalent). Subsequently, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, diluted with methylene chloride (10 mL), washed with water (20 ml), dried over sodium sulfate, and concentrated under reduced pressure to give phenyl 6-(2 -(Tributylbutyldimethyloxy)ethyl)pyridin-3-ylcarbamate (0.195 g, 94%).

步驟7：於一經攪拌、以二氯甲烷(10毫升)溶解之(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺(150毫克，0.48毫莫耳，1.0等量)溶液中添加三乙胺(0.3毫升，2.3毫莫耳，5.0等量)，並於室溫攪拌10分鐘；隨後再添加苯基6-(2-(三級丁基二甲基矽氧基)乙基)啶-3-基胺甲酸酯(180毫克，0.48毫莫耳，1.0等量)，並於室溫攪拌16小時。將該反應混合物濃縮；以矽膠管柱色層分析法(100至200篩孔)純化粗製產物，再以製備色層分析法純化，以獲得白色固體狀之1-(6-(2-(三級丁基二甲基矽氧基)乙基)啶-3-基)-3-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素(198毫克，76%)。 Step 7: (1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine (150) was dissolved in dichloromethane (10 mL). Add milliethylamine (0.3 ml, 2.3 mmol, 5.0 equivalent) to the solution in milligrams, 0.48 mmol, 1.0 equivalents, and stir at room temperature for 10 minutes; then add phenyl 6-(2-( Tributyl butyl dimethyl oxy) ethyl) pyridine-3-yl carbamate (180 mg, 0.48 mmol, 1.0 eq.) was stirred at room temperature for 16 h. The reaction mixture was concentrated; the crude product was purified by chrome column chromatography (100 to 200 mesh) and purified by preparative chromatography to give 1-(6-(2-(3) Butyl dimethyl methoxy oxy) ethyl) pyridine-3-yl)-3-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5- Base) methyl) urea (198 mg, 76%).

步驟8：於一經攪拌、以四氫呋喃(10毫升)溶解之1-(6-(2-(三級丁基二甲基矽氧基)乙基)啶-3-基)-3-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素(198毫克，0.35毫莫耳，1.0等量)溶液中添加2 N之氯化氫(1.5毫升)，並於室溫攪拌30分鐘。將該反 應混合物以飽和之碳酸氫鈉水溶液鹼化，並以醋酸乙酯(10毫升)萃取，以硫酸鈉乾燥，並將其蒸發，以獲得固體狀之1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙基)啶-3-基)尿素(實例化合物52)(98毫克，62%)。 Step 8: 1-(6-(2-(tert-butyldimethyl methoxy)ethyl)pyridin-3-yl)-3-((1), dissolved in tetrahydrofuran (10 ml) Add 2 N to the solution of (3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)urea (198 mg, 0.35 mmol, 1.0 equivalent) Hydrogen chloride (1.5 ml) was stirred at room temperature for 30 minutes. The reaction mixture was basified with EtOAc EtOAc (EtOAc m. Phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethyl)pyridin-3-yl)urea (example compound 52) (98 mg, 62%).

實例53之合成：Synthesis of Example 53:

N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-((2-羥乙氧)甲基)啶-3-基)丙醯胺 N-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(6-((2-hydroxyethoxy)) Pyridyl-3-yl)propanamide

步驟1：於一經攪拌、以四氫呋喃(450毫升)溶解之(5-溴吡啶-2-基)甲醇(19公克，101.1毫莫耳)溶液中，分次添加氫化鈉(3.636 公克，151.6毫莫耳)。於室溫攪拌20分鐘後，添加乙基2-溴乙酸酯(20.561公克，134.4毫莫耳，於45毫升之四氫呋喃中)。將該反應混合物於室溫攪拌5小時。以飽和之碳酸氫鈉溶液(200毫升)稀釋後，將該混合物於較低壓力濃縮，並以醋酸乙酯(3 x 200毫升)萃取。將合併有機層以水(150毫升)及飽和之氯化鈉溶液(150毫升)清洗，以硫酸鎂乾燥，並於真空狀態濃縮，以獲得粗製化合物。以管柱色層分析法(矽膠：100至200篩孔，溶析液：醋酸乙酯/石油醚1：1)純化該化合物，以獲得橘色油狀之甲基2-((5-溴吡啶-2-基)甲氧基)乙酸酯(19.39公克，84%)。 Step 1: Sodium hydride (3.636 g, 151.6 mmol) was added in portions with a solution of (5-bromopyridin-2-yl)methanol (19 g, 101.1 mmol) dissolved in tetrahydrofuran (450 mL). ear). After stirring at room temperature for 20 minutes, ethyl 2-bromoacetate (20.561 g, 134.4 mmol, in 45 ml of tetrahydrofuran) was added. The reaction mixture was stirred at room temperature for 5 hours. After diluting with a saturated aqueous solution of sodium bicarbonate (200 mL), the mixture was concentrated and evaporated. The combined organic layers were washed with water (150 ml) and sat. The compound was purified by column chromatography (tank: 100 to 200 mesh, eluent: ethyl acetate / petroleum ether 1:1) to obtain methyl 2-((5-bromo) Pyridin-2-yl)methoxy) acetate (19.39 g, 84%).

步驟2：將甲基2-((5-溴吡啶-2-基)甲氧基)乙酸酯(9公克，34.6毫莫耳)以乙醇(100毫升)溶解。分次添加硼氫化鈉(3.93公克，103.9毫莫耳)後，將該反應混合物於室溫攪拌3小時，將其以水(250毫升)稀釋，並以醋酸乙酯(3 x 150毫升)萃取。將合併有機層以硫酸鎂乾燥，於較低壓力濃縮，並以管柱色層分析法(矽膠：100至200篩孔，溶析液：醋酸乙酯/石油醚1：1)進行純化，以獲得黃色油狀之2-((5-溴吡啶-2-基)甲氧基)乙醇(5.25公克，65%)。 Step 2: Methyl 2-((5-bromopyridin-2-yl)methoxy)acetate (9 g, 34.6 mmol) was dissolved in ethanol (100 mL). After a portion of sodium borohydride (3.93 g, 103.9 mmol) was added, the reaction mixture was stirred at room temperature for 3 hr, diluted with water (250 ml) and extracted with ethyl acetate (3 x 150 ml) . The combined organic layers were dried over magnesium sulfate, concentrated at a lower pressure, and purified by column chromatography (p.: 100 to 200 mesh, eluent: ethyl acetate / petroleum ether 1:1) 2-((5-Bromopyridin-2-yl)methoxy)ethanol (5.25 g, 65%) was obtained as a yellow oil.

步驟3：將2-((5-溴吡啶-2-基)甲氧基)乙醇(5.25公克，22.6毫莫耳)以二甲基甲醯胺(40毫升)溶解，並添加叔丁基二甲基氯矽烷(4.432公克，29.4毫莫耳)及咪唑(3.08公克，45.2毫莫耳)。將該混合物攪拌2小時，以水(100毫升)稀釋，以醋酸乙酯(3 x 80毫升)萃取，以硫酸鎂乾燥，再以管柱色層分析法(矽膠：100至200篩孔，溶析液：醋酸乙酯/石油醚1：7)純化，以獲得黃色油狀之5-溴-2-((2-(三級丁基二甲基矽氧基)乙氧基)甲基)-啶(7.9公克，100%)。 Step 3: Dissolve 2-((5-bromopyridin-2-yl)methoxy)ethanol (5.25 g, 22.6 mmol) in dimethylformamide (40 mL) and add tert-butyl Methylchlorodecane (4.432 g, 29.4 mmol) and imidazole (3.08 g, 45.2 mmol). The mixture was stirred for 2 hours, diluted with water (100 ml), extracted with ethyl acetate (3 x 80 ml), dried over magnesium sulfate, and then chromatographed (column: 100 to 200 mesh, dissolved The liquid was purified by ethyl acetate/petroleum ether 1:7) to obtain 5-bromo-2-((2-(tert-butyldimethyl methoxy)ethoxy)methyl) as a yellow oil. - pyridine (7.9 grams, 100%).

步驟4a：催化劑C之合成：於一經攪拌、以無水四氫呋喃(15毫升)溶解之[1,1’-雙(二苯基膦基)二茂鐵]二氯鈀(II)溶液中添加1,1'-雙(二苯基膦基)二茂鐵(0.4公克，0.7218毫莫耳)，並逐滴添加 正丁基鋰(0.9毫升，1.4毫莫耳)，以獲得橘色懸浮液C。 Step 4a: Synthesis of Catalyst C: 1 is added to a solution of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dissolved in anhydrous tetrahydrofuran (15 ml). 1'-bis(diphenylphosphino)ferrocene (0.4 g, 0.7218 mmol), and n-butyllithium (0.9 ml, 1.4 mmol) was added dropwise to obtain an orange suspension C.

步驟4：將醋酸鉈(I)(7.6公克，28.9毫莫耳)以無水四氫呋喃(45毫升)溶解，並於氮氣逆流下添加C。將該混合物加熱至85℃。以無水四氫呋喃(15毫升)溶解5-溴-2-((2-(三級丁基二甲基矽氧基)乙氧基)甲基)-啶(4.98公克，14.4毫莫耳)，將其逐滴加至該反應混合物中，並將其於回流下攪拌2小時。將該反應混合物以水-醋酸乙酯(200毫升，1：1)稀釋，以矽藻土床過濾，以醋酸乙酯(2x50毫升)萃取，以硫酸鎂乾燥，再於真空狀態濃縮。以管柱色層分析法(矽膠：100至200篩孔，溶析液：醋酸乙酯/石油醚1：2)純化粗製化合物，以獲得黃色油狀之甲基2-(6-((2-(三級丁基二甲基矽氧基)乙氧基)甲基)啶-3-基)丙酸(4.05公克，80%)。 Step 4: Barium acetate (I) (7.6 g, 28.9 mmol) was dissolved in anhydrous tetrahydrofuran (45 mL) and C was added under reflux of nitrogen. The mixture was heated to 85 °C. Dissolve 5-bromo-2-((2-(tert-butyldimethyl methoxy)ethoxy)methyl)-pyridine (4.98 g, 14.4 mmol) in anhydrous tetrahydrofuran (15 mL). It was added dropwise to the reaction mixture, which was stirred under reflux for 2 hours. The reaction mixture was diluted with EtOAc EtOAc (EtOAc m. The crude compound was purified by column chromatography (pluton: 100 to 200 mesh, eluent: ethyl acetate / petroleum ether 1:2) to afford methyl 2-(6-((2) -(Tributylbutyldimethyloxy)ethoxy)methyl)pyridin-3-yl)propanoic acid (4.05 g, 80%).

步驟5：於氮氣氣氛及4℃之條件下，將甲基2-(6-((2-(三級丁基二甲基矽氧基)乙氧基)-甲基)啶-3-基)丙酸(4公克，11.3毫莫耳)置放於一圓底燒瓶中，並逐滴添加四正丁基氟化銨(13.6毫升，13.6毫莫耳)，再將其於室溫攪拌1小時。於添加二氧化矽(5公克)後，於較低壓力去除溶媒，並以管柱色層分析法(矽膠：100至200篩孔，溶析液：醋酸乙酯/石油醚2：1)純化所得之粗製產物，以獲得呈橘色油狀之甲基2-(6-((2-羥乙氧)甲基)啶-3-基)丙酸(2公克，74%)。 Step 5: Methyl 2-(6-((2-(tert-butyl dimethyl methoxy))ethoxy)-methyl) pyridine-3-yl group under nitrogen atmosphere at 4 ° C Propionic acid (4 g, 11.3 mmol) was placed in a round bottom flask, and tetra-n-butylammonium fluoride (13.6 ml, 13.6 mmol) was added dropwise, and then stirred at room temperature for 1 hour. . After the addition of cerium oxide (5 g), the solvent was removed at a lower pressure and purified by column chromatography (100-200 mesh, eluent: ethyl acetate/petroleum ether 2:1). The resulting crude product was obtained as a m. m.

步驟6：於以四氫呋喃(5毫升)溶解之2-(6-((2-羥乙氧)甲基)啶-3-基)丙酸中添加甲醇(10毫升)及1N之氫氧化鈉溶液(8.3毫升)。將該混合物於75℃攪拌1小時，將其於真空狀態濃縮，並以2 N之氯化氫稀釋，直至酸鹼值呈約6.5。將該混合物於較低壓力濃縮至2毫升之體積，將其置放於活性陽離子交換器上，並以管柱色層分析法(矽膠：100至200篩孔，溶析液：醋酸乙酯/甲醇1：1)將其純化，以獲得黃色油狀之2-(6-((2-羥乙氧)甲基)啶-3-基) 丙酸(405毫克，44%)。 Step 6: Add methanol (10 ml) and 1N sodium hydroxide solution to 2-(6-((2-hydroxyethoxy)methyl)pyridin-3-yl)propanoic acid dissolved in tetrahydrofuran (5 ml) (8.3 ml). The mixture was stirred at 75 ° C for 1 hour, concentrated under vacuum and diluted with 2N hydrogen chloride until a pH of about 6.5. The mixture was concentrated to a volume of 2 ml at a lower pressure, placed on an active cation exchanger, and analyzed by column chromatography (tank: 100 to 200 mesh, eluent: ethyl acetate / This was purified by EtOAc (EtOAc: EtOAc (EtOAc)

步驟7：於一以四氫呋喃(1.7毫升)溶解之2-(6-((2-羥乙氧)甲基)啶-3-基)丙酸(49毫克，0.221毫莫耳)溶液中添加1-羧苯並三唑(31毫克，0.221毫莫耳)、O-(1H-苯並三唑-1-基)-N,N,N',N'-四甲基脲四氟硼酸酯(71毫克，0.221毫莫耳)、N-二異丙基乙胺(0.113毫升，0.663毫莫耳)及(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺(60毫克，0.221毫莫耳)。將該反應混合物於室溫攪拌48小時。將該反應混合物以水稀釋並以醋酸乙酯萃取。將有機層以硫酸鎂乾燥，並於較低壓力濃縮。以管柱色層分析法(矽膠：100至200篩孔，溶析液：醋酸乙酯/甲醇9：1)純化粗製產物，以獲得白色固體狀之純N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-((2-羥乙氧)甲基)啶-3-基)丙醯胺(實例化合物53)(94毫克，88%)。 Step 7: Add 1 to a solution of 2-(6-((2-hydroxyethoxy)methyl)pyridin-3-yl)propanoic acid (49 mg, 0.221 mmol) dissolved in tetrahydrofuran (1.7 mL) -Carboxybenzotriazole (31 mg, 0.221 mmol), O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (71 mg, 0.221 mmol), N-diisopropylethylamine (0.113 ml, 0.663 mmol) and (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H- Pyrazol-5-yl)methylamine (60 mg, 0.221 mmol). The reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated at lower pressure. The crude product was purified by column chromatography (EtOAc: EtOAc:EtOAc:EtOAc:EtOAc Phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(6-((2-hydroxyethoxy)methyl)pyridin-3-yl)propanoid Amine (example compound 53) (94 mg, 88%).

可以類似方法製備實例161，而實例30、51、129、142及149至151係以類似方法製備而成。 Example 161 can be prepared in a similar manner, while Examples 30, 51, 129, 142, and 149 to 151 are prepared in a similar manner.

實例55之合成：Synthesis of Example 55:

5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶醯胺 5-(1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl) Pyridinamine

步驟1：於一以乙醇溶解之6-氯-3-吡啶醋酸(1公克，5.83毫莫耳)溶液中添加硫酸(1.6毫升)。將該混合物回流4小時，隨後將其冷卻至室溫，並濃縮。將殘留物以醋酸乙酯稀釋，並以飽和之碳酸氫鈉溶液清洗。將所得之混合物以硫酸鎂乾燥，並於較低壓力濃縮，以獲得粗製產物。以管柱色層分析法純化該產物，以獲得乙基2-(6-氯啶-3-基)乙酸酯(1.1公克，95%)。 Step 1: Sulfuric acid (1.6 ml) was added to a solution of 6-chloro-3-pyridineacetic acid (1 g, 5.83 mmol) dissolved in ethanol. The mixture was refluxed for 4 hours, then cooled to room temperature and concentrated. The residue was diluted with ethyl acetate and washed with a saturated sodium hydrogen carbonate solution. The resulting mixture was dried over magnesium sulfate and concentrated under reduced pressure to give crude material. The product was purified by column chromatography to give ethyl 2-(6-chloropyridin-3-yl)acetate (1.1 g, 95%).

步驟2：於0℃，於一以二甲基甲醯胺溶解之乙基2-(6-氯啶-3- 基)乙酸酯(1.1公克，5.51毫莫耳)溶液中，依序緩慢地添加氫化鈉(242毫克，6.06毫莫耳)，隨後再添加碘甲烷(821毫克，5.79毫莫耳)。將該混合物於相同溫度攪拌1小時，隨後以水進行淬火反應。將所產生之混合物以醋酸乙酯稀釋，並以水清洗。將有機層以硫酸鎂乾燥，並於較低壓力濃縮，以獲得粗製產物。以管柱色層分析法純化該粗製產物，以獲得乙基2-(6-氯啶-3-基)丙酸(790毫克，67%)。 Step 2: Slowly in a solution of ethyl 2-(6-chloropyridin-3-yl)acetate (1.1 g, 5.51 mmol) dissolved in dimethylformamide at 0 °C. Sodium hydride (242 mg, 6.06 mmol) was added followed by methyl iodide (821 mg, 5.79 mmol). The mixture was stirred at the same temperature for 1 hour, followed by quenching reaction with water. The resulting mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate and concentrated at lower pressure to afford crude material. The crude product was purified by column chromatography to give ethyl 2-(6-chloropyridin-3-yl)propanoic acid (790 mg, 67%).

步驟3：於一以二甲基甲醯胺溶解之乙基2-(6-氯啶-3-基)丙酸(790毫克，3.7毫莫耳)溶液中添加氰化鋅(434毫克，3.7毫莫耳)及四(三苯基膦基)鈀(0)(1.28公克，1.11毫莫耳)。將該反應混合物於100℃攪拌12小時，隨後將其冷卻至室溫。將該混合物以矽藻土塞過濾，並將其濃縮。以醋酸乙酯稀釋殘留物，並以10%之氯化氫溶液清洗。將有機層以硫酸鎂乾燥，並於較低壓力濃縮，以獲得粗製產物。以管柱色層分析法純化該粗製產物，以獲得乙基2-(6-氰砒啶-3-基)丙酸(420毫克，56%)。 Step 3: Add zinc cyanide (434 mg, 3.7) to a solution of ethyl 2-(6-chloropyridin-3-yl)propionic acid (790 mg, 3.7 mmol) dissolved in dimethylformamide. Millol) and tetrakis(triphenylphosphino)palladium(0) (1.28 g, 1.11 mmol). The reaction mixture was stirred at 100 ° C for 12 hours and then cooled to room temperature. The mixture was filtered through a pad of Celite and concentrated. The residue was diluted with ethyl acetate and washed with a 10% hydrogen chloride solution. The organic layer was dried over magnesium sulfate and concentrated at lower pressure to afford crude material. The crude product was purified by column chromatography to give ethyl 2-(6-c-c- </RTI><RTIgt;</RTI><RTIgt;

步驟4：於一以四氫呋喃及水溶解之乙基2-(6-氰砒啶-3-基)丙酸(420毫克，2.06毫莫耳)溶液中添加氫氧化鋰單一水合物(129毫克，3.08毫莫耳)。將該反應混合物於40℃攪拌2小時，隨後以10%之氯化氫溶液將其酸化。以醋酸乙酯萃取該混合物。將有機層以硫酸鎂乾燥，並於較低壓力濃縮，以獲得所需之2-(6-氰砒啶-3-基)丙酸(330毫克，94%)。 Step 4: Add a lithium hydroxide monohydrate (129 mg, in a solution of ethyl 2-(6-cyanacridin-3-yl)propanoic acid (420 mg, 2.06 mmol) dissolved in tetrahydrofuran and water. 3.08 millimoles). The reaction mixture was stirred at 40 ° C for 2 hours and then acidified with 10% hydrogen chloride solution. The mixture was extracted with ethyl acetate. The organic layer was dried with MgSO.sub.4.

步驟5：於一以乙腈溶解之2-(6-氰砒啶-3-基)丙酸(330毫克，1.87毫莫耳)溶液中添加1-羧苯並三唑(380毫克，2.81毫莫耳)、1-乙基-3-(3-二甲胺基丙基)碘化二亞胺(537毫克，2.81毫莫耳)及(1-(3-氯苯基)-3-(三氰甲基)-1H-吡唑-5-基)甲胺(543毫克，1.97毫莫耳)。將該反應混合物於室溫攪拌過夜。於該反應混合物中添加 水並以醋酸乙酯萃取。將有機層以硫酸鎂乾燥，並於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得純N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-氰砒啶-3-基)丙醯胺(440毫克，54%)。 Step 5: Add 1-carboxybenzotriazole (380 mg, 2.81 mmol) to a solution of 2-(6-cyanoacridin-3-yl)propionic acid (330 mg, 1.87 mmol) dissolved in acetonitrile. Ear), 1-ethyl-3-(3-dimethylaminopropyl) iodide diimide (537 mg, 2.81 mmol) and (1-(3-chlorophenyl)-3-(three) Cyanomethyl)-1H-pyrazol-5-yl)methylamine (543 mg, 1.97 mmol). The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated at lower pressure. The crude product was purified by column chromatography to give pure N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)- 2-(6-Cyanoacridin-3-yl)propanamide (440 mg, 54%).

步驟6：將起始原料N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-氰砒啶-3-基)丙醯胺(200毫克，0.46毫莫耳)以硫酸(2毫升)溶解。將該反應混合物於60℃攪拌2小時，隨後將其冷卻至室溫。以水稀釋該反應混合物，並以2M之氫氧化鈉溶液中和(pH=7)。以醋酸乙酯萃取該混合物。將有機層以硫酸鎂乾燥，並於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得純5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶醯胺(實例化合物55)(85毫克，41%)。 Step 6: Starting the starting material N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(6-cyanide) Pyridin-3-yl)propanamide (200 mg, 0.46 mmol) was dissolved in sulfuric acid (2 mL). The reaction mixture was stirred at 60 ° C for 2 hours and then cooled to room temperature. The reaction mixture was diluted with water and neutralized with a 2M sodium hydroxide solution (pH = 7). The mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated at lower pressure. The crude product was purified by column chromatography to obtain pure 5-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)) Amino)-1-oxopropan-2-yl)pyridiniumamine (Example Compound 55) (85 mg, 41%).

1H核磁共振(300 MHz，CDCl3)：δ 8.44(d，1H，J=2.01 Hz，啶-H)；8.10(d，1H，J=7.86 Hz，啶-H)；7.80(br.s，NH)；7.75(dd，1H，J=8.04，2.19 Hz，啶-H)；7.36(m，4H，Ar-H)；6.52(s，1H，吡唑-H)；5.88(m，NH)；5.64(br.s，NH)；4.52(m，2H，Ar-CH2)；3.59(四分體(quartet)，1H，J=7.14 Hz，醯胺-CH)；1.53(d，3H，J=7.14 Hz，醯胺-CH3)。 1 H NMR (300 MHz, CDCl 3 ): δ 8.44 (d, 1H, J = 2.01 Hz, pyridine-H); 8.10 (d, 1H, J = 7.86 Hz, pyridine-H); 7.80 (br.s , NH); 7.75 (dd, 1H, J = 8.04, 2.19 Hz, pyridine-H); 7.36 (m, 4H, Ar-H); 6.52 (s, 1H, pyrazole-H); 5.88 (m, NH) ; 5.64 (br.s, NH); 4.52 (m, 2H, Ar-CH 2 ); 3.59 (quartet, 1H, J = 7.14 Hz, decyl-CH); 1.53 (d, 3H) , J = 7.14 Hz, decylamine -CH 3 ).

實例56係以類似方式製備而成。 Example 56 was prepared in a similar manner.

實例57之合成：Synthesis of Example 57:

5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)-N-苯基啶醯胺 5-(1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl) -N-phenyl pyridine guanamine

步驟1：將甲苯(114毫升)冷卻至-78℃，於相同溫度逐滴添加正丁基鋰(79.7毫升，127毫莫耳)，隨後添加以甲苯(60毫升)溶解之2,5-二溴吡啶(30公克，120毫莫耳)，並攪拌2小時。於-78℃，以無水二氧化碳氣體鼓泡通入該反應混合物中1小時。以薄層層析法監控反應過程。反應完成後，將反應內容物回溫至室溫，並於較低壓力將甲苯蒸餾出。隨後於該反應混合物中添加水(200毫升)，並將其以矽藻土床過濾。以經稀釋之氯化氫溶液酸化濾液，將固體沉澱出，將其過濾，並以硫酸鈉乾燥，以獲得褐色固體狀 之5-溴吡啶羧酸(12公克，47%生產率)。 Step 1: Toluene (114 ml) was cooled to -78 ° C, n-butyllithium (79.7 ml, 127 mmol) was added dropwise at the same temperature, followed by the addition of 2,5-di dissolved in toluene (60 ml). Bromopyridine (30 g, 120 mmol) and stirred for 2 hours. The reaction mixture was bubbled through anhydrous carbon dioxide gas at -78 ° C for 1 hour. The reaction process was monitored by thin layer chromatography. After the reaction was completed, the reaction contents were warmed to room temperature, and toluene was distilled off at a lower pressure. Water (200 mL) was then added to the reaction mixture, which was filtered over celite. The filtrate was acidified with aq. EtOAc (EtOAc) (EtOAc).

步驟2：將以四氫呋喃(80毫升)溶解之5-溴吡啶羧酸(8公克，30毫莫耳)倒入一250毫升之燒瓶。於該反應混合物中添加苯胺(4.44公克，47毫莫耳)、O-(1H-苯並三唑-1-基)-N,N,N',N'-四甲基脲四氟硼酸酯(15.33公克，47毫莫耳)及三乙胺(6.43公克，63.6毫莫耳)。將整體反應物於室溫攪拌1小時。反應完成後，將四氫呋喃完全地蒸餾出。於該反應混合物中添加水(100毫升)，以飽和之碳酸鈉溶液將其鹼化，並醋酸乙酯(2×50毫升)萃取。將有機層於較低壓力濃縮，以獲得粗製產物。以管柱色層分析法(矽膠：100至200篩孔，溶析液：存在於正己烷之2%醋酸乙酯)純化該粗製產物，以獲得白色固體狀之5-溴-N-苯基啶醯胺(7.27公克，72%)。 Step 2: 5-Bromopyridinecarboxylic acid (8 g, 30 mmol) dissolved in tetrahydrofuran (80 mL) was poured into a 250 mL flask. An aniline (4.44 g, 47 mmol), O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate was added to the reaction mixture. Ester (15.33 grams, 47 millimoles) and triethylamine (6.43 grams, 63.6 millimoles). The whole reaction was stirred at room temperature for 1 hour. After the reaction was completed, tetrahydrofuran was completely distilled off. Water (100 ml) was added to the reaction mixture, which was crystallised with sat. The organic layer was concentrated at a lower pressure to give a crude product. The crude product was purified by column chromatography (EtOAc: 100 to 200 mesh, eluted: 2% ethyl acetate in n-hexane) to afford 5-bromo-N-phenyl as a white solid. Pyridinamine (7.27 grams, 72%).

步驟3：將以二甲基甲醯胺(109毫升)溶解之5-溴-N-苯基啶醯胺(7.2公克，26毫莫耳)及2-氯丙酸甲酯(9.64公克，79毫莫耳)以氮氣鼓泡10分鐘。於該反應混合物中添加錳(2.89公克，50毫莫耳)，並再以氮氣鼓泡10分鐘。添加溴化鎳聯吡啶(NiBr2 bipy)(0.97公克，1.8毫莫耳)，並再度以氮氣鼓泡10分鐘。隨後，於該反應混合物中添加催化量之三氟醋酸，並攪拌30分鐘。反應完成後，將反應內容物以水稀釋，並以矽藻土床過濾。以醋酸乙酯萃取濾液(3×50毫升)，將有機層於較低壓力濃縮，以獲得粗製產物。以管柱色層分析法(矽膠：100至200篩孔，溶析液：存在於正己烷之5%醋酸乙酯)純化該粗製產物，以獲得白色固體狀之甲基2-(6-(苯胺甲醯基)啶-3-基)丙酸(1.5公克，20%)。 Step 3: 5-Bromo-N-phenylpyridiniumamine (7.2 g, 26 mmol) and methyl 2-chloropropionate (9.64 g, 79) dissolved in dimethylformamide (109 ml). Millules were bubbled with nitrogen for 10 minutes. Manganese (2.89 grams, 50 millimoles) was added to the reaction mixture and bubbling with nitrogen for another 10 minutes. Nickel bromide bipyridine (NiBr 2 bipy) (0.97 g, 1.8 mmol) was added and bubbled again with nitrogen for 10 minutes. Subsequently, a catalytic amount of trifluoroacetic acid was added to the reaction mixture and stirred for 30 minutes. After the reaction was completed, the reaction contents were diluted with water and filtered through a bed of diatomaceous earth. The filtrate was extracted with ethyl acetate (3×50 mL) and the organic layer was concentrated at lower pressure to afford crude product. The crude product was purified by column chromatography (EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc Aniline-methyl)pyridin-3-yl)propionic acid (1.5 g, 20%).

步驟4：於一以四氫呋喃(18毫升)及水(18毫升)溶解之甲基2-(6-(苯胺甲醯基)啶-3-基)丙酸(1.8公克，6毫莫耳)溶液中添加氫氧化鋰單一水合物(0.3公克，12毫莫耳)，並於室溫攪拌1小時。反應完成後，將四氫呋喃完全地蒸餾出。隨後添加醋酸乙酯(100 毫升)，再將水層分離，以6 N之氯化氫溶液(5毫升)將其酸化，並以醋酸乙酯萃取(2×50毫升)。將合併有機層以硫酸鈉乾燥，並於較低壓力濃縮，以獲得白色固體狀之2-(6-(苯胺甲醯基)啶-3-基)丙酸(1.65公克，96%)。 Step 4: A solution of methyl 2-(6-(anilinecarbamidinyl)-3-yl)propanoic acid (1.8 g, 6 mmol) dissolved in tetrahydrofuran (18 mL) and water (18 mL) Lithium hydroxide monohydrate (0.3 g, 12 mmol) was added and stirred at room temperature for 1 hour. After the reaction was completed, tetrahydrofuran was completely distilled off. Ethyl acetate (100 mL) was then added and the aqueous layer was separated and evaporated with EtOAc (EtOAc) The combined organic layers were dried with sodium sulphate (EtOAc EtOAc EtOAc)

步驟5：於氮氣氣氛下，將2-(6-(苯胺甲醯基)啶-3-基)丙酸(61毫克，0.228毫莫耳)置放於一圓底燒瓶中，添加二氯甲烷(1.3毫升)及1-氯-N,N,2-三甲基丙烯胺(47毫升，0.355毫莫耳)，將其於室溫攪拌1小時。隨後添加(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺(50毫克，0.182毫莫耳)及三乙胺(107毫升，0.637毫莫耳)，並將該反應混合物於室溫攪拌48小時。將該反應混合物以二氯甲烷(10毫升)稀釋，以飽和之碳酸鈉容易清洗(2 x 10毫升)。以二氯甲烷(2 x 10毫升)萃取水層，將其合併，以硫酸鈉乾燥，並將其過濾。將溶媒蒸發，最後以管柱色層分析法(矽膠：100至200篩孔，溶析液：環己烷/醋酸乙酯1：2)進行純化，以獲得灰白色固體狀之5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)-N-苯基啶醯胺(實例化合物57)(12毫克，33%)。 Step 5: 2-(6-(anilinemethanyl)pyridin-3-yl)propanoic acid (61 mg, 0.228 mmol) was placed in a round bottom flask under nitrogen, and dichloromethane was added. 1.3 ml) and 1-chloro-N,N,2-trimethylpropenamine (47 ml, 0.355 mmol) were stirred at room temperature for 1 hour. Subsequent addition of (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamine (50 mg, 0.182 mmol) and triethylamine (107 mL, 0.637 mmol) and the reaction mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with dichloromethane (10 mL) and washed with saturated sodium carbonate (2 x 10 mL). The aqueous layer was extracted with dichloromethane (2×10 mL). The solvent was evaporated, and finally purified by column chromatography (silicone: 100 to 200 mesh, eluent: cyclohexane / ethyl acetate 1:2) to obtain 5-- ((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-N-phenyl Pyridinamine (example compound 57) (12 mg, 33%).

實例58、59及61係以類似方法製備而成。 Examples 58, 59 and 61 were prepared in a similar manner.

實例60之合成：Synthesis of Example 60:

5-(1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)-N-(4-氟苯基)啶醯胺 5-(1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-N -(4-fluorophenyl)pyridinium

步驟1：如實例57所述。 Step 1: As described in Example 57.

步驟2：將5-溴吡啶羧酸(7.5公克，30毫莫耳)及4-氟苯胺(4.97公克，40莫耳)倒入四氫呋喃(75毫升)。隨後添加O-(1H-苯並三唑-1-基)-N,N,N',N'-四甲基脲四氟硼酸酯(14.37公克，40毫莫耳)與三乙胺(6.02公克，50毫莫耳)，並將其於室溫攪拌1小時。以薄層層析法監控反應過程；反應完成後，於較低壓力將四氫呋喃蒸餾出，隨後於該反應混合物中添加碳酸鈉溶液，並以醋酸乙酯(2×50毫升)萃取。將合併有機層以硫酸鈉乾燥，並於較低壓力濃縮，以獲得粗製產物。以管柱色層分析法(矽膠：100至200篩孔，溶析液：存在於正己烷之2%醋酸乙酯)進行純化，以獲得黃色固體狀之5- 溴-N-(4-氟苯基)啶醯胺(7公克，67%)。 Step 2: 5-Bromopyridinecarboxylic acid (7.5 g, 30 mmol) and 4-fluoroaniline (4.97 g, 40 mol) were poured into tetrahydrofuran (75 mL). Subsequently, O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (14.37 g, 40 mmol) and triethylamine ( 6.02 g, 50 mmol, and allowed to stir at room temperature for 1 hour. The reaction was monitored by thin layer chromatography; after completion of the reaction, tetrahydrofuran was distilled off at a lower pressure, then sodium carbonate solution was added to the mixture, and ethyl acetate (2.times.50 ml). The combined organic layers were dried over sodium sulfate and concentrated at lower pressure to afford crude material. Purification by column chromatography (tank: 100 to 200 mesh, eluent: 2% ethyl acetate in n-hexane) to give 5-bromo-N-(4-fluoro) as a yellow solid Phenyl) pyridinamine (7 g, 67%).

步驟3：將以二甲基甲醯胺(105毫升)溶解之5-溴-N-(4-氟苯基)啶醯胺(7公克，23.8毫莫耳)、甲基2-氯丙酸(8.7公克，71毫莫耳)倒入一圓底燒瓶中，並以氮氣鼓泡30分鐘。於該反應混合物中添加錳(2.61公克，47.6毫莫耳)，並以氮氣鼓泡30分鐘。添加溴化鎳聯吡啶(0.97公克，1.8毫莫耳)，並再度於以氮氣鼓泡15分鐘。隨後添加催化量之三氟醋酸，並攪拌30分鐘。以薄層層析法監控反應過程。反應完成後，以水稀釋反應內容物，並以矽藻土床過濾。以醋酸乙酯(3×50毫升)萃取濾液，並於較低壓力將有機層濃縮，以獲得粗製產物。以管柱色層分析法(矽膠：100至200篩孔，溶析液：存在於正己烷之5%醋酸乙酯)將其純化，以獲得白色固體狀之甲基2-(6-(4-氟苯基甲醯胺基)啶-3-基)丙酸(1.5公克，22%)。 Step 3: 5-Bromo-N-(4-fluorophenyl)pyridiniumamine (7 g, 23.8 mmol) dissolved in dimethylformamide (105 ml), methyl 2-chloropropionic acid (8.7 g, 71 mmol) was poured into a round bottom flask and sparged with nitrogen for 30 minutes. Manganese (2.61 grams, 47.6 millimoles) was added to the reaction mixture and was bubbled with nitrogen for 30 minutes. Nickel bromide bipyridyl (0.97 grams, 1.8 millimolar) was added and again bubbling with nitrogen for 15 minutes. A catalytic amount of trifluoroacetic acid was then added and stirred for 30 minutes. The reaction process was monitored by thin layer chromatography. After completion of the reaction, the reaction contents were diluted with water and filtered through a bed of diatomaceous earth. The filtrate was extracted with ethyl acetate (3 x 50 mL) and the organic layer was concentrated at lower pressure to afford crude product. It was purified by column chromatography (silicone: 100 to 200 mesh, eluent: 5% ethyl acetate in n-hexane) to afford methyl 2-(6-(4) -Fluorophenylcarbamamino)pyridin-3-yl)propionic acid (1.5 g, 22%).

步驟4：將以四氫呋喃(10毫升)溶解之甲基2-(6-(4-氟苯基甲醯胺基)啶-3-基)丙酸(1.8公克，6毫莫耳)倒入一圓底燒瓶中。隨後添加水(10毫升)及氫氧化鋰(0.302公克，12毫莫耳)。將該反應混合物於室溫攪拌1小時。以薄層層析法監控反應過程。反應完成後，將四氫呋喃蒸餾出。以醋酸乙酯(2 x 20毫升)萃取水層，以經稀釋之氯化氫溶液(20毫升)將其酸化，再以醋酸乙酯(2×25毫升)萃取。將合併有機層以硫酸鈉乾燥，並於較低壓力濃縮，以獲得呈白色固體狀之所需2-(6-(4-氟苯基甲醯胺基)啶-3-基)丙酸(1.5公克，88%)。 Step 4: Pour methyl 2-(6-(4-fluorophenylcarbamimidyrridin-3-yl)propanoic acid (1.8 g, 6 mmol) dissolved in tetrahydrofuran (10 mL) into a circle In the bottom flask. Water (10 ml) and lithium hydroxide (0.302 g, 12 mmol) were then added. The reaction mixture was stirred at room temperature for 1 hour. The reaction process was monitored by thin layer chromatography. After the reaction was completed, tetrahydrofuran was distilled off. The aqueous layer was extracted with ethyl acetate (2×20 mL)EtOAc. The combined organic layers were dried with EtOAc (EtOAc EtOAc (EtOAc) 1.5 grams, 88%).

步驟5：於一以四氫呋喃(1.6毫升)溶解之2,2-(6-(4-氟苯基甲醯胺基)啶-3-基)丙酸(59毫克，0.208毫莫耳)溶液中添加1-羧苯並三唑(27毫克，0.208毫莫耳)、O-(1H-苯並三唑-1-基)-N,N,N',N'-四甲基脲四氟硼酸酯(67毫克，0.208毫莫耳)、三乙胺(0.07毫升， 0.416毫莫耳)及(3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺(55毫克，0.208毫莫耳)。將該反應混合物於室溫攪拌過夜。以水稀釋該混合物，並以醋酸乙酯萃取。將有機層以硫酸鎂乾燥，並於較低壓力濃縮。以管柱色層分析法(矽膠：100至200篩孔，溶析液：環丙烷/醋酸乙酯1：1)純化粗製產物，以獲得純5-(1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)-N-(4-氟苯基)啶醯胺(實例化合物60)(83毫克，75%)。 Step 5: Dissolve 2,2-(6-(4-fluorophenylcarbamimidyrridin-3-yl)propanoic acid (59 mg, 0.208 mmol) in tetrahydrofuran (1.6 mL) Add 1-carboxybenzotriazole (27 mg, 0.208 mmol), O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroboron Acid ester (67 mg, 0.208 mmol), triethylamine (0.07 mL, 0.416 mmol) and (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazole-5- Methylamine (55 mg, 0.208 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated at lower pressure. The crude product was purified by column chromatography (tank: 100 to 200 mesh, eluent: cyclopropane / ethyl acetate 1:1) to obtain pure 5-(1-((3-tert-butyl) 1-(3-Chlorophenyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-N-(4-fluorophenyl)pyridiniumamine (example) Compound 60) (83 mg, 75%).

實例63之合成：Synthesis of Example 63:

5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)-N-(4-氟苯基)嘧啶-2-羧醯胺 5-(1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl) -N-(4-fluorophenyl)pyrimidine-2-carboxamide

步驟1：於一250毫升之圓底燒瓶中，於一以甲苯(50毫升)溶解之5-溴嘧啶-2-羧酸(5公克，24.63毫莫耳)中添加亞硫醯氯(5.63毫升，73.89毫莫耳)。將該反應混合物於100℃回流2小時。隨後於較低壓力去除亞硫醯氯及甲苯。藉由以甲苯製造共沸液，將水去除。將殘留物以二氯甲烷(100毫升)溶解，並將其於氮氣氣氛下加至溶於二氯甲烷(100毫升)之4-氟苯胺(2.68公克，24.13毫莫耳)溶液中。將該反應混合物於室溫攪拌16小時。起始原料被完全消耗後，以二氯甲烷(50毫升)稀釋乾反應混合物，並依序以水(2 x 100毫升)、碳酸氫鈉溶液(2 x 100毫升)及飽和之氯化鈉溶液(100毫升)清洗。將有機層以硫酸鎂乾燥，並於較低壓力濃縮。以管柱色層分析法(矽膠：100至200篩孔，溶析液：存在於正己烷之20%醋酸乙酯)純化粗製產物，以獲得5-溴-N-(4-氟苯基)嘧啶-2-羧醯胺(5.6公克，78%)。 Step 1 : Add sulfoxide (5.63 ml) to a 5-bromopyrimidine-2-carboxylic acid (5 g, 24.63 mmol) dissolved in toluene (50 ml) in a 250 mL round bottom flask. , 73.89 millimoles). The reaction mixture was refluxed at 100 ° C for 2 hours. Subsulphonium chloride and toluene are then removed at a lower pressure. The water was removed by making an azeotrope with toluene. The residue was dissolved in dichloromethane (100 mL). EtOAc m. The reaction mixture was stirred at room temperature for 16 hours. After the starting material was completely consumed, the dry reaction mixture was diluted with dichloromethane (50 mL), followed by water (2 x 100 mL), sodium bicarbonate solution (2 x 100 mL) and saturated sodium chloride solution. (100 ml) for cleaning. The organic layer was dried over magnesium sulfate and concentrated at lower pressure. The crude product was purified by column chromatography (tank: 100 to 200 mesh, eluent: 20% ethyl acetate in n-hexane) to afford 5-bromo-N-(4-fluorophenyl) Pyrimidine-2-carboxyguanamine (5.6 g, 78%).

步驟2：將氫化鈉(60%，872毫克，21.81毫莫耳)置放於一250毫升之雙頭圓底燒瓶中，於氮氣氣氛下添加無水二甲基甲醯胺(25毫升)。於-5℃，於以二甲基甲醯胺溶解之氫化鈉懸浮液中添加以無水二甲基甲醯胺(30毫升)溶解之5-溴-N-(4-氟苯基)嘧啶-2-羧醯胺(5.4公克，18.24毫莫耳)溶液。將該反應混合物於相同溫度攪拌30分鐘。之後，維持相同溫度下，逐滴添加2-(三甲基矽基)乙氧甲基氯(4.52公克，27.36毫莫耳)。將該反應混合物於周圍溫度攪拌2小時。起始原料被完全消耗後，將該反應混合物以氯化銨溶液(150毫升)進行淬火反應，並以醋酸乙酯(3×100毫升)萃取。將合併有機層以硫酸鎂乾燥，並於較低壓力濃縮。以管柱色層分析法(矽膠：100至200篩孔，溶析液：存在於正己烷之20%醋酸乙酯)純化粗製產物，以獲得5-溴-N-(4-氟苯基)-N-((2-(三甲基矽基)乙氧基)甲基)嘧啶-2-羧醯胺(6.5公克，84%)。 Step 2: Sodium hydride (60%, 872 mg, 21.81 mmol) was placed in a 250 mL double-headed round bottom flask and anhydrous dimethylformamide (25 mL) was then evaporated. 5-Bromo-N-(4-fluorophenyl)pyrimidine dissolved in anhydrous dimethylformamide (30 ml) was added to a suspension of sodium hydride dissolved in dimethylformamide at -5 °C. 2-Carboxyguanamine (5.4 g, 18.24 mmol) solution. The reaction mixture was stirred at the same temperature for 30 minutes. Thereafter, 2-(trimethylsulfonyl)ethoxymethyl chloride (4.52 g, 27.36 mmol) was added dropwise while maintaining the same temperature. The reaction mixture was stirred at ambient temperature for 2 hours. After the starting material was completely consumed, the reaction mixture was quenched with ammonium chloride solution (150 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over magnesium sulfate and concentrated at lower pressure. The crude product was purified by column chromatography (tank: 100 to 200 mesh, eluent: 20% ethyl acetate in n-hexane) to afford 5-bromo-N-(4-fluorophenyl) -N-((2-(Trimethyldecyl)ethoxy)methyl)pyrimidine-2-carboxamide (6.5 g, 84%).

步驟3：將5-溴-N-(4-氟苯基)-N-((2-(三甲基矽基)乙氧基)甲基)嘧啶-2-羧醯胺(7.5公克，17.59毫莫耳)以1,4-二氧陸圜(86毫升)溶解，於氮氣氣氛下，依序添加4,4,4',4',5,5,5',5'-八甲基-2,2'-二-(1,3,2-二雜氧戊硼烷)(4.7公克，18.47毫莫耳)及醋酸鉀(5.2公克，52.77毫莫耳)。將該反應混合物攪拌5分鐘，並添加[1,1’-雙(二苯基膦基)二茂鐵]二氯鈀(II)(644毫克，0.87毫莫耳)。將該反應混合物回流16小時。起始原料被完全消耗後，將該反應混合物以水稀釋，並以醋酸乙酯(3×100毫升)萃取。將合併有機層以硫酸鎂乾燥，並於較低壓力濃縮。粗製產物N-(4-氟苯基)-5-(4,4,5,5-四甲基-1,3,2-二雜氧戊硼烷-2-基)-N-((2-(三甲基)-乙氧基)甲基)嘧啶-2-羧醯胺(9.0公克，粗製產物)不須經純化，即可於下一步驟使用。 Step 3 : 5-Bromo-N-(4-fluorophenyl)-N-((2-(trimethylmethyl)ethoxy)methyl)pyrimidine-2-carboxamide (7.5 g, 17.59) Dissolve in 1,4-dioxane (86 ml) and add 4,4,4',4',5,5,5',5'-octamethyl in sequence under a nitrogen atmosphere. -2,2'-di-(1,3,2-dioxaborolane) (4.7 g, 18.47 mmol) and potassium acetate (5.2 g, 52.77 mmol). The reaction mixture was stirred for 5 minutes and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (644 mg, 0.87 mmol) was added. The reaction mixture was refluxed for 16 hours. After the starting material was completely consumed, the reaction mixture was diluted with water and ethyl acetate (3×100 mL). The combined organic layers were dried over magnesium sulfate and concentrated at lower pressure. The crude product N-(4-fluorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(2 -(Trimethyl)-ethoxy)methyl)pyrimidine-2-carboxamide (9.0 g, crude product) was used in the next step without purification.

步驟4：將N-(4-氟苯基)-5-(4,4,5,5-四甲基-1,3,2-二雜氧戊硼烷-2-基)-N-((2-(三甲基)-乙氧基)甲基)嘧啶-2-羧醯胺(8.3公克，17.59毫莫耳)以甲苯(83毫升)溶解，並於氮氣氣氛下，依序添加甲基2-(三氟甲基磺醯基氧代)丙烯酸(4.94公克，21.12毫莫耳)及2M之碳酸鈉溶液(35毫升)。之後，再添加四(三苯基膦基)鈀(0)(1.02公克，0.87毫莫耳)。將該反應混合物回流16小時。起始原料被完全消耗後，以水稀釋該反應混合物，並以醋酸乙酯(3 x 100毫升)萃取。將合併有機層以硫酸鎂乾燥，並於較低壓力濃縮。以管柱色層分析法(100至200篩孔，矽膠，溶析液：存在於正己烷之10%醋酸乙酯)純化粗製產物，以獲得甲基2-(2-((4-氟苯基)((2-(三甲基矽基)乙氧基)甲基)胺甲醯基)嘧啶-5-基)丙烯酸(5公克，67%)。 Step 4: N-(4-Fluorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-( (2-(Trimethyl)-ethoxy)methyl)pyrimidine-2-carboxamide (8.3 g, 17.59 mmol) was dissolved in toluene (83 ml) and added sequentially under a nitrogen atmosphere. 2-(Trifluoromethylsulfonyloxy)acrylic acid (4.94 g, 21.12 mmol) and 2M sodium carbonate solution (35 mL). Thereafter, tetrakis(triphenylphosphino)palladium(0) (1.02 g, 0.87 mmol) was further added. The reaction mixture was refluxed for 16 hours. After the starting material was completely consumed, the reaction mixture was diluted with water and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over magnesium sulfate and concentrated at lower pressure. The crude product was purified by column chromatography (100 to 200 mesh, silica gel, solvent: 10% ethyl acetate in n-hexane) to afford methyl 2-(2-((4-fluorobenzene) ((2-(Trimethyldecyl)ethoxy)methyl)amine-mercapto)pyrimidin-5-yl)acrylic acid (5 g, 67%).

步驟5：於一500毫升之帕爾反應釜中，將甲基2-(2-((4-氟苯基)((2-(三甲基矽基)乙氧基)甲基)胺甲醯基)嘧啶-5-基)丙烯酸(5.0公克)以醋酸乙酯(50毫升)溶解，並於氮氣氣氛下添加10%之鈀碳。該反應釜係於50 Psi氫氣壓力下裝配至帕爾裝備。2小時之 後，薄層層析法顯示起始原料被完全消耗。以矽藻土床過濾該催化劑，並將濾液於較低壓力濃縮，以獲得甲基2-(2-((4-氟苯基)((2-(三甲基矽基)乙氧基)甲基)胺甲醯基)嘧啶-5-基)丙酸(5公克，定量)。 Step 5: In a 500 ml Parr reactor, methyl 2-(2-((4-fluorophenyl)((2-(trimethylsulfonyl))ethoxy)methyl)amine) Mercaptopyrimidin-5-yl)acrylic acid (5.0 g) was dissolved in ethyl acetate (50 ml) and 10% palladium carbon was added under a nitrogen atmosphere. The kettle was assembled to a Parr apparatus at 50 Psi hydrogen pressure. After 2 hours, thin layer chromatography showed the starting material was completely consumed. The catalyst was filtered through a bed of diatomaceous earth, and the filtrate was concentrated at a lower pressure to obtain methyl 2-(2-((4-fluorophenyl)((2-(trimethylmethyl))ethoxy)) Methyl)aminomethionylpyrimidin-5-yl)propionic acid (5 g, quantitative).

步驟6：將甲基2-(2-((4-氟苯基)((2-(三甲基矽基)乙氧基)甲基)胺甲醯基)嘧啶-5-基)丙酸(3.0公克，6.92毫莫耳)以乙醇(87毫升)溶解，並添加6 N之氯化氫(87毫升)。將該反應混合物於90℃回流2小時。於起始原料被完全轉化後，將乙醇於較低壓力蒸發，並以水稀釋殘留物，再以碳酸鈉溶液將其酸化。以醋酸乙酯清洗水層。之後將水層以6 N之氯化氫溶液酸化，再以醋酸乙酯(3 x 50毫升)萃取。將合併有機層以硫酸鎂乾燥，並於較低壓力濃縮，以獲得純2-(2-(4-氟苯基甲醯胺基)嘧啶-5-基)丙酸(700毫克，35%)。 Step 6: Methyl 2-(2-((4-fluorophenyl)((2-(trimethylsulfonyl)ethoxy)methyl))methionyl)pyrimidin-5-yl)propanoic acid (3.0 g, 6.92 mmol) was dissolved in ethanol (87 mL) and 6N hydrogen chloride (87 mL). The reaction mixture was refluxed at 90 ° C for 2 hours. After the starting material has been completely converted, the ethanol is evaporated at a lower pressure and the residue is diluted with water and acidified with a sodium carbonate solution. The aqueous layer was washed with ethyl acetate. The aqueous layer was then acidified with 6 N aqueous hydrogen chloride and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried with MgSO.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub. .

1H核磁共振(二甲亞碸-d6，400 MHz)：δ 12.82(1H，s)；10.80(1H，s)；8.94(2H，s)；7.91-7.88(2H，m)；7.20(2H，t)；3.96(1H，q)；1.52(3H，d)；液相層析法(M+H)：290；高效能液相層析法：97.71%。 1 H NMR (dimethyl sulfonium-d 6, 400 MHz): δ 12.82 (1H, s); 10.80 (1H, s); 8.94 (2H, s); 7.91-7.88 (2H, m); 7.20 ( 2H, t); 3.96 (1H, q); 1.52 (3H, d); liquid chromatography (M+H): 290; high-performance liquid chromatography: 97.71%.

步驟7：於一經攪拌、溶於四氫呋喃(2毫升)之(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺(0.06公克，0.218毫莫耳)與2-(2-(4-氟苯基胺甲醯基)嘧啶-5-基)丙酸(0.063公克，0.218毫莫耳)溶液中中添加1-羥基苯並三唑水合物(0.029毫升，0.218毫莫耳)、O-(1H-苯並三唑-1-基)-N,N,N',N'-四甲基脲四氟硼酸酯(0.07公克，0.218毫莫耳)及N-二異丙基乙胺(0.074毫升，0.436毫莫耳)，將該反應混合物攪拌48小時。將該反應混合物於較低壓力濃縮，以管柱色層分析法(矽膠：100至200篩孔，溶析液：醋酸乙酯/二乙醚2：1)純化所得之粗製固體，以獲得5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)-N-(4-氟苯基)嘧啶-2- 羧醯胺(實例化合物63)(39毫克，33%)。 Step 7: (1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine (0.06 g, dissolved in tetrahydrofuran (2 mL) Addition of 1-hydroxybenzotriazole to a solution of 2-(2-(4-fluorophenylaminomethyl)pyrimidin-5-yl)propanoic acid (0.063 g, 0.218 mmol) Hydrate (0.029 ml, 0.218 mmol), O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (0.07 g, 0.218 mmol and N-diisopropylethylamine (0.074 mL, 0.436 mmol). The reaction mixture was concentrated at a lower pressure, and the obtained crude solid was purified by column chromatography (yield: 100 to 200 mesh, eluent: ethyl acetate / diethyl ether 2:1) to obtain 5- (1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-N -(4-Fluorophenyl)pyrimidine-2-carboxamide (example compound 63) (39 mg, 33%).

實例62、64、66及67係以類似方法製備而成。 Examples 62, 64, 66 and 67 were prepared in a similar manner.

實例65之合成：Synthesis of Example 65:

5-(1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)-N-苯基嘧啶-2-羧醯胺 5-(1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-N -phenylpyrimidine-2-carboxyguanamine

步驟1：於一250毫升之圓底燒瓶中，將5-溴嘧啶-2-羧酸(5.22公克，24.63毫莫耳)以甲苯(100毫升)溶解，並添加亞硫醯氯(5.4毫升，73.89毫莫耳)。將該反應混合物於100℃回流2小時。之後，於較低壓力去除亞硫醯氯與甲苯。藉由以甲苯製造共沸液，將水去除。將殘留物以二氯甲烷(100毫升)溶解，於氮氣氣氛下，將其加至以二氯甲烷(100毫升)溶解之苯胺(2.27公克，24.42毫莫 耳)溶液中。將該反應混合物於周圍溫度攪拌16小時。起始原料完全消耗後，以二氯甲烷(50毫升)稀釋該反應混合物，依序以水(2×100毫升)、碳酸氫鈉溶液(2×100毫升)及飽和之氯化鈉溶液(100毫升)清洗。將有機層以硫酸鎂乾燥，並於較低壓力濃縮。以管柱色層分析法(矽膠：100至200篩孔，溶析液：存在於正己烷之20%醋酸乙酯)純化粗製化合物，以獲得5-溴-N-苯基嘧啶-2-羧醯胺(5.5公克，77%)。 Step 1 : Dissolve 5-bromopyrimidine-2-carboxylic acid (5.22 g, 24.63 mmol) in toluene (100 mL) in a 250 mL round bottom flask and add sulphur chloride (5.4 mL, 73.89 millimoles). The reaction mixture was refluxed at 100 ° C for 2 hours. Thereafter, sulphur sulphur chloride and toluene are removed at a lower pressure. The water was removed by making an azeotrope with toluene. The residue was dissolved in dichloromethane (100 mL) EtOAc (EtOAc) The reaction mixture was stirred at ambient temperature for 16 hours. After the starting material was completely consumed, the reaction mixture was diluted with dichloromethane (50 mL), then water (2×100 mL), sodium hydrogen carbonate solution (2×100 mL) and saturated sodium chloride solution (100) ML) cleaning. The organic layer was dried over magnesium sulfate and concentrated at lower pressure. The crude compound was purified by column chromatography (tank: 100 to 200 mesh, eluent: 20% ethyl acetate in n-hexane) to obtain 5-bromo-N-phenylpyrimidine-2-carboxylate. Guanamine (5.5 grams, 77%).

步驟2：將氫化鈉(950毫克，23.91毫莫耳)置放於一250毫升之雙頸圓底燒瓶中，並於氮氣氣氛下添加無水二甲基甲醯胺(20毫升)。於-5℃，於該以二甲基甲醯胺溶解之氫化鈉懸浮液中添加溶於無水二甲基甲醯胺(40毫升)之5-溴-N-苯基嘧啶-2-羧醯胺(5.5公克，19.92毫莫耳)溶液。將該反應混合物於相同溫度攪拌30分鐘。之後，於相同溫度，逐滴添加2-(三甲基矽基)乙氧甲基氯(4.98公克，29.89毫莫耳)。將該反應混合物於周圍溫度攪拌2小時。起始原料被完全消耗後，以氯化銨溶液(150毫升)對該反應混合物進行淬火反應並以醋酸乙酯(3×100毫升)萃取。將合併有機層以硫酸鎂乾燥，並於較低壓力將其濃縮。以管柱色層分析法(矽膠：100至200篩孔，溶析：存在於正己烷之20%醋酸乙酯)，以獲得純5-溴-N-苯基-N-((2-(三甲基矽基)乙氧基)甲基)嘧啶-2-羧醯胺(7.2公克，90%)。 Step 2: Sodium hydride (950 mg, 23.91 mmol) was placed in a 250 mL double-necked round bottom flask and anhydrous dimethylformamide (20 mL). 5-Bromo-N-phenylpyrimidine-2-carboxyindole dissolved in anhydrous dimethylformamide (40 ml) was added to the sodium hydride suspension dissolved in dimethylformamide at -5 °C. A solution of amine (5.5 g, 19.92 mmol). The reaction mixture was stirred at the same temperature for 30 minutes. Thereafter, 2-(trimethylsulfonyl)ethoxymethyl chloride (4.98 g, 29.89 mmol) was added dropwise at the same temperature. The reaction mixture was stirred at ambient temperature for 2 hours. After the starting material was completely consumed, the reaction mixture was quenched with ammonium chloride solution (150 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over magnesium sulfate and concentrated at lower pressure. By column chromatography (tank: 100 to 200 mesh, elution: 20% ethyl acetate present in n-hexane) to obtain pure 5-bromo-N-phenyl-N-((2-( Trimethyl indenyl)ethoxy)methyl)pyrimidine-2-carboxamide (7.2 g, 90%).

步驟3：將5-溴-N-苯基-N-((2-(三甲基矽基)乙氧基)甲基)嘧啶-2-羧醯胺(6.5公克，15.92毫莫耳)以1,4-二氧陸圜(80毫升)溶解，並於氮氣氣氛下，依序添加4,4,4',4',5,5,5',5'-八甲基-2,2'-Bi-(1,3,2-二雜氧戊硼烷)(4.24公克，16.7毫莫耳)及醋酸鉀(4.68公克，47.76毫莫耳)。將該反應混合物攪拌5分鐘，並添加[1,1‘-雙(二苯基膦基)二茂鐵]二氯鈀(II)(582毫克，0.79毫莫耳)。將該反應混合物回 流16小時。起始原料被完全溶解後，將該反應混合物以水稀釋，並以醋酸乙酯(3×100毫升)萃取。將合併有機層以硫酸鎂乾燥，並於較低壓力濃縮。該粗製產物N-苯基-5-(4,4,5,5-四甲基-1,3,2-二雜氧戊硼烷-2-基)-N-((2-(三甲基矽基)乙氧基)甲基)嘧啶-2-羧醯胺(8.0公克，粗製產物)不須純化即可於下一步驟使用。 Step 3: 5-bromo-N-phenyl-N-((2-(trimethyldecyl)ethoxy)methyl)pyrimidine-2-carboxamide (6.5 g, 15.92 mmol) 1,4-Dioxane (80 ml) was dissolved, and 4,4,4',4',5,5,5',5'-octamethyl-2,2 was added sequentially under a nitrogen atmosphere. '-Bi-(1,3,2-dioxaborolane) (4.24 g, 16.7 mmol) and potassium acetate (4.68 g, 47.76 mmol). The reaction mixture was stirred for 5 minutes and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (582 mg, 0.79 mmol) was added. The reaction mixture was refluxed for 16 hours. After the starting material was completely dissolved, the reaction mixture was diluted with water and ethyl acetate (3×100 mL). The combined organic layers were dried over magnesium sulfate and concentrated at lower pressure. The crude product N-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-((2-(tri-) Ethyl)ethyl)methyl)pyrimidine-2-carboxamide (8.0 g, crude product) was used in the next step without purification.

步驟4：將N-苯基-5-(4,4,5,5-四甲基-1,3,2-二雜氧戊硼烷-2-基)-N-((2-(三甲基矽基)乙氧基)甲基)嘧啶-2-羧醯胺(7.3公克，16.04毫莫耳)以甲苯(73毫升)溶解，並於氮氣氣氛下，依序添加甲基2-(三氟甲基磺醯基氧代)丙烯酸(4.5公克，19.25毫莫耳)及2M之碳酸鈉溶液(32毫升)。隨後再添加四(三苯基膦鈀)(0)(927毫克，0.80毫莫耳)。將該反應混合物回流16小時。起始原料被完全消耗後，將該反應混合物以水稀釋，並以醋酸乙酯(3 x 100毫升)萃取。將合併有機層以硫酸鎂乾燥，並於較低壓力濃縮。以管柱色層分析法(矽膠：100至200篩孔，溶析液：存在於正己烷之10%醋酸乙酯)純化粗製產液，以獲得純甲基2-(2-(苯基((2-(三甲基矽基)乙氧基)甲基)胺甲醯基)嘧啶-5-基)丙烯酸(4.3公克，65%)。 Step 4: N-Phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-((2-(3) Methyl decyl) ethoxy)methyl)pyrimidine-2-carboxamide (7.3 g, 16.04 mmol) was dissolved in toluene (73 ml), and methyl 2-(s) was added sequentially under a nitrogen atmosphere. Trifluoromethylsulfonyloxy)acrylic acid (4.5 g, 19.25 mmol) and 2M sodium carbonate solution (32 mL). Then tetrakis(triphenylphosphinepalladium) (0) (927 mg, 0.80 mmol) was added. The reaction mixture was refluxed for 16 hours. After the starting material was completely consumed, the reaction mixture was diluted with water and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over magnesium sulfate and concentrated at lower pressure. The crude product liquid was purified by column chromatography (tank: 100 to 200 mesh, eluent: 10% ethyl acetate in n-hexane) to obtain pure methyl 2-(2-(phenyl) (2-(Trimethyldecyl)ethoxy)methyl)amine-mercaptopyrimidin-5-yl)acrylic acid (4.3 g, 65%).

步驟5：於一250毫升之帕爾反應釜，將甲基2-(2-(苯基((2-(三甲基矽基)乙氧基)甲基)胺甲醯基)嘧啶-5-基)丙烯酸(4.3公克)以醋酸乙酯(43毫升)溶解，並於氮氣氣氛下添加10%之鈀碳(430毫克)。該反應釜係於50 psi氫氣壓力下裝配至帕爾裝備。2小時後，薄層層析法顯示起始原料被烷璇消耗。將催化劑以矽藻土床過濾，並將濾液於較低壓力濃縮，以獲得甲基2-(2-(苯基((2-(三甲基汐基)乙氧基)-甲基)胺甲醯基)嘧啶-5-基)丙酸(4.0公克，93%)。 Step 5: In a 250 ml Parr reactor, methyl 2-(2-(phenyl((2-(trimethylmethyl))ethoxy)methyl)amine)pyridyl)pyrimidine-5 Acrylic acid (4.3 g) was dissolved in ethyl acetate (43 ml), and 10% palladium carbon (430 mg) was added under a nitrogen atmosphere. The kettle was assembled to a Parr apparatus at 50 psi hydrogen pressure. After 2 hours, thin layer chromatography showed the starting material was consumed by the alkane. The catalyst was filtered through a bed of diatomaceous earth, and the filtrate was concentrated at a lower pressure to give methyl 2-(2-(phenyl((2-(trimethylmethyl) ethoxy)))) Methiol)pyrimidin-5-yl)propionic acid (4.0 g, 93%).

步驟6：將甲基2-(2-(苯基((2-(三甲基矽基)乙氧基)-甲基)胺甲醯基)嘧啶-5-基)丙酸(2.5公克，6.0毫莫耳)以乙醇(75.6毫升)溶解，並添加6 N之氯化氫(75.6毫升)。將該反應混合物於90℃回 流2小時。起始原料被完全轉化後，於較低壓力去除乙醇，將殘留物以水稀釋，並以碳酸鈉溶液鹼化。以醋酸乙酯清洗水層。之後，以6N之氯化氫將水層酸化，並以醋酸乙酯(3×50毫升)萃取。將合併有機層以硫酸鎂乾燥，並於較低壓力濃縮，以獲得純2-(2-(氟苯基胺甲醯基)嘧啶-5-基)丙酸(750毫克，47%)。 Step 6: methyl 2-(2-(phenyl((2-(methyl)methyl)ethoxy)-methyl)amine,carboxamido)pyrimidin-5-yl)propanoic acid (2.5 g, Dissolved in ethanol (75.6 ml) and added 6 N hydrogen chloride (75.6 mL). The reaction mixture was refluxed at 90 ° C for 2 hours. After the starting material was completely converted, the ethanol was removed at a lower pressure, and the residue was diluted with water and basified with a sodium carbonate solution. The aqueous layer was washed with ethyl acetate. The aqueous layer was then acidified with EtOAc (EtOAc) (EtOAc) The combined organic layers were dried with MgSO.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.

1H核磁共振(二甲亞碸-d6，400 MHz)：δ 12.87(1H，s)；δ 10.70(1H，s)；δ 8.97(2H，s)；δ 7.86(2H，d)；δ 7.37(2H，t)；δ 7.13(1H，t)；δ 3.97(1H，q)；δ 1.52(3H，d)；液相層析法(M+H)：272.0；高效能液相層析法：95.02%。 1 H NMR (dimethyl sulfonium-d 6 , 400 MHz): δ 12.87 (1H, s); δ 10.70 (1H, s); δ 8.97 (2H, s); δ 7.86 (2H, d); δ 7.37 (2H, t); δ 7.13 (1H, t); δ 3.97 (1H, q); δ 1.52 (3H, d); liquid chromatography (M+H): 272.0; high performance liquid chromatography Law: 95.02%.

步驟7：於一經攪拌、溶於四氫呋喃(1.7毫升)之(3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺(0.057公克，0.221毫莫耳)及2-(2-(氟苯基胺甲醯基)嘧啶-5-基)丙酸(0.06公克，0.221毫莫耳)溶液中添加1-羥基苯並三唑水合物(0.029毫升，0.221毫莫耳)、O-(1H-苯並三唑-1-基)-N,N,N',N'-四甲基脲四氟硼酸酯(0.071公克，0.221毫莫耳)及N-二異丙基乙胺(0.075毫升，0.442毫莫耳)，並將該反應混合物攪拌36小時。將該反應混合物於較低壓力濃縮，以管柱色層分析法(矽膠：100至200篩孔，溶析液：醋酸乙酯/環己烷5：1)純化所得之固體，以獲得5-(1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)-N-苯基嘧啶-2-羧醯胺(實例化合物65)(118毫克，99%)。 Step 7: (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine (0.057 g, 0.221 mmol) in tetrahydrofuran (1.7 mL). Add 1-hydroxybenzotriazole hydrate (0.029 ml) to a solution of 2-(2-(fluorophenylaminomethyl)pyrimidin-5-yl)propanoic acid (0.06 g, 0.221 mmol) , 0.221 mmol, O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (0.071 g, 0.221 mmol) N-diisopropylethylamine (0.075 mL, 0.442 mmol) was stirred and the mixture was stirred for 36h. The reaction mixture was concentrated at a lower pressure, and the obtained solid was purified by column chromatography (yield: 100 to 200 mesh, eluent: ethyl acetate / cyclohexane 5:1) to obtain 5- (1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-N-benzene Pyrimidine-2-carboxyguanamine (example compound 65) (118 mg, 99%).

實例68之合成：Synthesis of Example 68:

1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(2-甲氧基乙胺)啶-3-基)尿素 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-methoxyethylamine)pyridine- 3-base urea

步驟1至3：如實例69之描述。 Steps 1 to 3: as described in Example 69.

步驟4：於室溫，於一經攪拌、溶於乙腈(9毫升)之(3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺(105毫克，0.398毫莫耳)溶液中，依序添加三乙胺(0.22毫升，1.592毫莫耳)及苯基6-(2-甲氧基乙胺)啶-3-基胺甲酸酯(116毫克，0.406毫莫耳)，並將其回流攪拌過夜。將該反應混合物於較低壓力濃縮，以管柱色層分析法(矽膠：100至200篩孔，溶析液：醋酸乙酯)純化所得之固體，以獲得琥珀色固體狀之1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(2-甲氧基乙胺)啶-3-基)尿素(實例化合物68)(178毫克， 98%)。 Step 4: (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine (105) in acetonitrile (9 mL). Triethylamine (0.22 ml, 1.592 mmol) and phenyl 6-(2-methoxyethylamine)pyridine-3-ylcarbamate (116) were added in a solution of milligrams, 0.398 mmol. Mg, 0.406 mmol, and stirred at reflux overnight. The reaction mixture was concentrated at a lower pressure, and the obtained solid was purified by column chromatography (yield: 100 to 200 mesh, eluent: ethyl acetate) to obtain 1-(( 3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-methoxyethylamine)-3-yl) Urea (example compound 68) (178 mg, 98%).

實例69之合成：Synthesis of Example 69:

1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-甲氧基乙胺)啶-3-基)尿素 1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-methoxyethylamine) Pyridin-3-yl)urea

步驟1：將2-氯-5-硝基吡啶(4.0公克)與2-甲氧基乙胺(20毫升)於室溫攪拌1小時。將該反應混合物以水(30毫升)稀釋，以醋酸乙酯(2 x 50毫升)萃取，以飽和之氯化鈉溶液(20毫升)清洗，以硫酸鈉乾燥，並於真空狀態蒸發。以正戊烷(25毫升)清洗殘留物，以獲得黃色固體狀之N-(2-甲氧基乙基)-5-硝基吡啶-2-胺(4.8公克，87%)。 Step 1: 2-Chloro-5-nitropyridine (4.0 g) and 2-methoxyethylamine (20 mL) were stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The residue was washed with n-pentane (25 mL) to afford N-(2-methoxyethyl)-5-nitropyridin-2-amine (4.8 g, 87%).

步驟2：於一經攪拌、溶於醋酸乙酯(50毫升)之N-(2-甲氧基乙基)-5-硝基吡啶-2-胺(4.8公克，22.84毫莫耳)溶液中添加10%之 鈀碳(550毫克)，隨後於氫氣氣氛下，將其於室溫攪拌16小時。令該反應混合物通過矽藻土，並於較低壓力蒸發。以戊烷(20毫升)清洗以此產生之殘留物，以獲得N2-(2-甲氧基乙基)啶-2,5-二胺(3.51公克，87%)。 Step 2: Add to a solution of N-(2-methoxyethyl)-5-nitropyridin-2-amine (4.8 g, 22.84 mmol) dissolved in ethyl acetate (50 mL). 10% palladium on carbon (550 mg) was then stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction mixture was passed through diatomaceous earth and evaporated at a lower pressure. The residue thus obtained was washed with pentane (20 ml) to give N2-(2-methoxyethyl)pyridine-2,5-diamine (3.51 g, 87%).

步驟3：於0℃，於一經攪拌、溶於丙酮(35毫升)之N2-(2-甲氧基乙基)啶-2,5-二胺(3.8公克，22.75毫莫耳)溶液中，依序添加啶(5.5毫升，68.25毫莫耳)及氯甲酸苯酯(3.2毫升，25.025毫莫耳)，並於室溫攪拌1小時。將溶媒蒸發，將所得之殘留物以醋酸乙酯(150毫升)溶解，以水(50毫升)及飽和之氯化鈉溶液(50毫升)清洗，以硫酸鈉乾燥，並將其蒸發；將殘留物純化(矽膠：100至200篩孔，溶析液：甲醇/氯仿1：99)，以獲得白色固體狀之苯基6-(2-甲氧基乙胺)啶-3-基胺甲酸酯(3.1公克，47%)。 Step 3: in a solution of N2-(2-methoxyethyl)pyridine-2,5-diamine (3.8 g, 22.75 mmol) dissolved in acetone (35 mL) at 0 ° C. Pyridine (5.5 ml, 68.25 mmol) and phenyl chloroformate (3.2 ml, 25.025 mmol) were added sequentially and stirred at room temperature for 1 hour. The solvent was evaporated, and the residue was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Purification of phenyl 6-(2-methoxyethylamine)-3-ylaminocarbamic acid as a white solid (yield: 100 to 200 mesh, eluent: methanol / chloroform 1:99) Ester (3.1 grams, 47%).

步驟4：於室溫，於一經攪拌、溶於二氯甲烷(5毫升)之(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺鹽酸鹽(217毫克，0.696毫莫耳)溶液中，依序添加三乙胺(0.3毫升，2.088毫莫耳)及苯基6-(2-甲氧基乙胺)啶-3-基胺甲酸酯(200毫克，0.696毫莫耳)，並將其攪拌16小時。將該反應混合物以二氯甲烷(15毫升)稀釋，以水(10毫升)及飽和之氯化鈉溶液(5毫升)清洗，以硫酸鈉乾燥，並將其蒸發。以乙醚(5毫升)及二氯甲烷(10毫升)純化並清洗殘留物，以獲得灰白色固體狀之1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-甲氧基乙胺)啶-3-基)尿素(實例化合物69)(132毫克，40%)。 Step 4: (1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl) in dichloromethane (5 mL) In a solution of methylamine hydrochloride (217 mg, 0.696 mmol), triethylamine (0.3 ml, 2.008 mmol) and phenyl 6-(2-methoxyethylamine) pyridine-3- were added sequentially. The carbamate (200 mg, 0.696 mmol) was stirred for 16 hours. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. Purify and wash the residue in EtOAc (EtOAc) (EtOAc (EtOAc) Pyrazol-5-yl)methyl)-3-(6-(2-methoxyethylamine)-3-yl)urea (Example Compound 69) (132 mg, 40%).

實例70之合成：Synthesis of Example 70:

1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethylamine)pyridine-3- Urea

步驟1：將2-氯-5-硝基吡啶(4.0公克)與2-胺基乙醇(20毫升)於室溫攪拌1小時。將該反應混合物以水(30毫升)稀釋，以醋酸乙酯(2 x 50毫升)萃取，以飽和之氯化鈉溶液(20毫升)清洗，以硫酸鈉乾燥，並於真空狀態蒸發。以正戊烷清(25毫升)洗殘留物，以獲得黃色固體狀之2-(5-硝基吡啶-2-基胺基)乙醇(4.16公克，91%)。 Step 1: 2-Chloro-5-nitropyridine (4.0 g) and 2-aminoethanol (20 ml) were stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The residue was washed with EtOAc (EtOAc m.

步驟2：於一經攪拌、溶於四氫呋喃(50毫升)之2-(5-硝基吡啶-2-基胺基)乙醇(4.0g，21.85毫莫耳，1等量)溶液中添加10%之鈀碳(600毫克)，並於氫氣氣球壓力(balloon pressure)下，將其於室溫攪拌16小時。使該反應混合物通過矽藻土，將其蒸發，並以二乙醚(20毫升)清洗，以獲得2-(5-胺基吡啶-2-基胺基)乙醇(3.02公克，90%)。 Step 2: Add 10% to a solution of 2-(5-nitropyridin-2-ylamino)ethanol (4.0 g, 21.85 mmol, 1 equivalent) dissolved in tetrahydrofuran (50 ml) Palladium on carbon (600 mg) was stirred at room temperature for 16 hours under a balloon pressure. The reaction mixture was taken through EtOAc (EtOAc)EtOAcEtOAcEtOAc.

步驟3：於0℃，於一經攪拌、溶於丙酮(35毫升)之2-(5-胺基 吡啶-2-基胺基)乙醇(3.0公克，19.60毫莫耳，1等量)溶液中，依序添加啶(4.7毫升，58.82毫莫耳，3等量)及氯甲酸苯酯(2.7毫升，21.56毫莫耳，1.1等量)，並將其於室溫攪拌1小時。將溶媒蒸發，並將所得之殘留物以醋酸乙酯(150毫升)溶解，以水(50毫升)及飽和之氯化鈉溶液(50毫升)清洗，以硫酸鈉乾燥，並將其蒸發。將該殘留物純化(中性氧化鋁，以甲醇/三氯甲烷(1：49)做為溶析液)，以獲得粉紅色固體狀之苯基6-(2-羥乙胺)啶-3-基胺甲酸酯(0.80公克，19%)。 Step 3: in a solution of 2-(5-aminopyridin-2-ylamino)ethanol (3.0 g, 19.60 mmol, 1 equivalent) in acetone (35 mL) at 0 ° C. Pyridine (4.7 ml, 58.82 mmol, 3 equivalents) and phenyl chloroformate (2.7 ml, 21.56 mmol, 1.1 equivalent) were added sequentially and stirred at room temperature for 1 hour. The solvent was evaporated, and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The residue was purified (neutral alumina, using methanol/trichloromethane (1:49) as a solvent) to afford phenyl 6-(2-hydroxyethylamine) - carbamate (0.80 g, 19%).

步驟4：於一經攪拌、溶於乙腈(9毫升)之3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺(105毫克，0.398毫莫耳，1.0等量)溶液中，依序添加三乙胺(0.220毫升，1.59毫莫耳，4.0等量)及苯基6-(2-羥乙胺)啶-3-基胺甲酸酯(111毫克，0.406毫莫耳，1.02等量)將其回流攪拌16小時。將該反應混合物於真空狀態濃縮，並將殘留物純化(管柱色層分析法，矽膠，醋酸乙酯/甲醇(4：1)做為溶析液)，以獲得1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素(實例化合物70)(125毫克，71%)。 Step 4: 3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine (105 mg, 0.398 mmol) in acetonitrile (9 mL). In the solution of the ear, 1.0 equal amount), triethylamine (0.220 ml, 1.59 mmol, 4.0 equivalent) and phenyl 6-(2-hydroxyethylamine)-3-ylcarbamate ( 111 mg, 0.406 mmol, 1.02 equivalent) was stirred at reflux for 16 hours. The reaction mixture was concentrated under vacuum, and the residue was purified (p.p. chromatography, ethyl acetate, ethyl acetate/methanol (4:1) as solvent) to obtain 1-((3- 3-) Grade butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethylamine)-3-yl)urea (example compound 70 ) (125 mg, 71%).

實例72、78、80、81與154至158係以類似方法製備而成。可以類似方法製備實例73至77與82至86。 Examples 72, 78, 80, 81 and 154 to 158 were prepared in a similar manner. Examples 73 to 77 and 82 to 86 can be prepared in a similar manner.

實例71之合成：Synthesis of Example 71:

1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素 1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethylamine)pyridine- 3-base urea

步驟1至3：參照實例化合物70。 Steps 1 to 3: Refer to Example Compound 70.

步驟4：於室溫，於一經攪拌、溶於二氯甲烷(2.0毫升)之(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺(100毫克，0.318毫莫耳，1.0等量)溶液中，依序添加三乙胺(0.13毫升，0.95毫莫耳，3.0等量)及苯基6-(2-羥乙胺)啶-3-基胺甲酸酯(87毫克，0.318毫莫耳，1.0等量)，並將其攪拌16小時。將該反應混合物以水(5毫升)稀釋，以醋酸乙酯(10毫升)萃取，以飽和之氯化鈉溶液清洗，以硫酸鈉乾燥，再將其蒸發。以乙醚(5毫升)及二氯甲烷(10毫升)清洗並純化殘留物，以獲得淡粉紅色固體狀之1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素(實例化合物71)(77.7毫克，54%)。 Step 4: (1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl) in dichloromethane (2.0 mL) at rt. Triethylamine (0.13 ml, 0.95 mmol, 3.0 equivalent) and phenyl 6-(2-hydroxyethylamine) pyridine were added sequentially to a solution of methylamine (100 mg, 0.318 mmol, 1.0 equivalent). 3-Hydrylcarbamate (87 mg, 0.318 mmol, 1.0 equivalent) and stirred for 16 h. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The residue was washed with EtOAc (EtOAc) (EtOAc) -1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethylamine)-3-yl)urea (example compound 71) (77.7 mg, 54%).

實例79之合成：Synthesis of Example 79:

1-((1-(3,4-二氟苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素 1-((1-(3,4-Difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethylamine) Pyridin-3-yl)urea

步驟1：將2-氯-5-硝基吡啶(4.0公克)與2-胺基乙醇(20毫升)於室溫攪拌1小時。將該反應混合物以水(30毫升)稀釋，以醋酸乙酯(2 x 50毫升)萃取，以飽和之氯化鈉溶液(20毫升)清洗，以硫酸鈉乾燥，並於真空狀態蒸發。以正戊烷(25毫升)清洗殘留物，以獲得黃色固體狀之2-(5-硝基吡啶-2-基胺基)乙醇(4.16公克，91%)。 Step 1: 2-Chloro-5-nitropyridine (4.0 g) and 2-aminoethanol (20 ml) were stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The residue was washed with n-pentane (25 mL) toieldield

步驟2：於一經攪拌、溶於四氫呋喃(50毫升)之2-(5-硝基吡啶-2-基胺基)乙醇(4.0公克，21.85毫莫耳)溶液中添加10%之鈀碳(600毫克)，並於氫氣氣球壓力下，將其於室溫攪拌16小時。使 該反應混合物通過矽藻土，將其蒸發，以二乙醚(20毫升)清洗產生之殘留物，以獲得2-(5-胺基吡啶-2-基胺基)乙醇(3.02公克，90%)。 Step 2: Add 10% palladium on carbon (600 g) in a solution of 2-(5-nitropyridin-2-ylamino)ethanol (4.0 g, 21.85 mmol) dissolved in tetrahydrofuran (50 ml). (mg) and stirred at room temperature for 16 hours under a hydrogen balloon pressure. The reaction mixture was passed through celite, which was evaporated and evaporated to ethyl ether (20 ml) to afford to give 2-(5-aminopyridin-2-ylamino)ethanol (3.02 g, 90%) ).

步驟3：於0℃，於一經攪拌、溶於丙酮(35毫升)之2-(5-胺基吡啶-2-基胺基)乙醇(3.0公克，19.60毫莫耳)溶液中，依序添加啶(4.7毫升，58.82毫莫耳)及氯甲酸苯酯(2.7毫升，21.56毫莫耳)，並將其於室溫攪拌1小時。將溶媒蒸發，將殘留物以醋酸乙酯(150毫升)溶解，以水(50毫升)及飽和之氯化鈉溶液(50毫升)清洗，以硫酸鈉乾燥，並將其蒸發。將殘留物純化(中性氧化鋁，溶析液：甲醇/氯仿1：49)，以獲得粉紅色固狀之苯基6-(2-羥乙胺)啶-3-基胺甲酸酯(0.8公克，19%)。 Step 3: Add in a solution of 2-(5-aminopyridin-2-ylamino)ethanol (3.0 g, 19.60 mmol) dissolved in acetone (35 ml) at 0 ° C. Pyridine (4.7 ml, 58.82 mmol) and phenyl chloroformate (2.7 mL, 21.56 mmol) were stirred at room temperature for 1 hour. The solvent was evaporated, the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The residue was purified (neutral alumina, lysate: methanol / chloroform 1:49) to afford phenyl 6-(2-hydroxyethylamine) </RTI> 0.8 grams, 19%).

步驟4：於150℃，於一經攪拌、溶於四氫呋喃(5毫升)之(1-(3,4-二氟苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺鹽酸鹽(53毫克，0.170毫莫耳)溶液中，依序添加三乙胺(0.084毫升，0.493毫莫耳)及苯基6-(2-羥乙胺)啶-3-基胺甲酸酯(49毫克，0.182毫莫耳)，並將其於微波條件下(7巴)攪拌1.5小時。以管柱色層分析法(矽膠：100至200篩孔，溶析液：醋酸乙酯/甲醇10：1)純化經濃縮之反應混合物，以獲得白色固體狀之1-((1-(3,4-二氟苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素(實例化合物79)(46毫克，59%)。 Step 4: (1-(3,4-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl group in tetrahydrofuran (5 ml) at 150 ° C In a solution of methylamine hydrochloride (53 mg, 0.170 mmol), triethylamine (0.084 mL, 0.493 mmol) and phenyl 6-(2-hydroxyethylamine)-3-yl were added sequentially. The carbamate (49 mg, 0.182 mmol) was stirred under microwave conditions (7 bar) for 1.5 hours. The concentrated reaction mixture was purified by column chromatography (EtOAc: 100 to 200 mesh, eluting solvent: ethyl acetate / methanol 10:1) to afford 1-((1-(3) ,4-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethylamine)-3-yl)urea (Example Compound 79) (46 mg, 59%).

實例89之合成：Synthesis of Example 89:

1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-((2-甲氧基乙基)(甲基)胺基)啶-3-基)尿素 1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-((2-methoxyethyl) (methyl)amino)pyridin-3-yl)urea

步驟1：將2-氯-5-硝基吡啶(3.0公克)與2-甲氧基乙基甲基胺(10毫升)於室溫攪拌1小時。將該反應混合物以水(50毫升)稀釋，以醋酸乙酯(2 x 150毫升)萃取，以飽和之氯化鈉溶液(50毫升)清洗，以硫酸鈉乾燥，並將其濃縮，以獲得黃色固體狀之N-(2-甲氧基乙基)-N-甲基-5-硝基吡啶-2-胺(3.3公克，83%)。 Step 1: 2-Chloro-5-nitropyridine (3.0 g) and 2-methoxyethylmethylamine (10 ml) were stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. N-(2-methoxyethyl)-N-methyl-5-nitropyridin-2-amine (3.3 g, 83%) as a solid.

步驟2：於一經攪拌、溶於醋酸乙酯(35毫升)之N-(2-甲氧基乙基)-N-甲基-5-硝基吡啶-2-胺(3.3公克，15.63毫莫耳)溶液中添加10%之鈀碳(450毫克)，並於氫氣氣氛下，將其於室溫攪拌16小時。使該反應混合物通過矽藻土，並將其濃縮。以戊烷(20毫升) 清洗殘留物，以獲得N2-(2-甲氧基乙基)-N2-甲基啶-2,5-二胺(2.0公克，73%)。 Step 2: N-(2-methoxyethyl)-N-methyl-5-nitropyridin-2-amine (3.3 g, 15.63 mmol) dissolved in ethyl acetate (35 mL) To the solution, 10% palladium on carbon (450 mg) was added, and the mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction mixture was passed through celite and concentrated. The residue was washed with pentane (20 mL) to afford N2-(2- methoxyethyl)-N2-methyl pyridine-2,5-diamine (2.0 g, 73%).

步驟3：於0℃，於一經攪拌、溶於丙酮之N2-(2-甲氧基乙基)-N2-甲基啶-2,5-二胺(2.0公克，11.04毫莫耳)溶液中，依序添加啶(4.3毫升，33.12毫莫耳)及氯甲酸苯酯(2.46毫升，12.144毫莫耳)，並於室溫攪拌1小時。將該反應混合物及殘留物以醋酸乙酯(150毫升)溶解，以水(50毫升)及飽和之氯化鈉溶液(50毫升)清洗，以硫酸鈉乾燥，將其蒸發，並將殘留物純化(矽膠：100至200篩孔，溶析液：醋酸乙酯/石油醚2：3)，以獲得白色固體狀之苯基6-((2-甲氧基乙基)(甲基)胺基)啶-3-基胺甲酸酯(2.56公克，77%)。 Step 3: at 0 ° C in a solution of N2-(2-methoxyethyl)-N2-methylpyridine-2,5-diamine (2.0 g, 11.04 mmol) dissolved in acetone Pyridine (4.3 ml, 33.12 mmol) and phenyl chloroformate (2.46 ml, 12.144 mmol) were added sequentially and stirred at room temperature for 1 hour. The reaction mixture and the residue were crystall~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (silicone: 100 to 200 mesh, solution: ethyl acetate / petroleum ether 2:3) to obtain phenyl 6-((2-methoxyethyl)(methyl)amine group as a white solid Pyridin-3-ylcarbamate (2.56 g, 77%).

步驟4：於室溫，於一經攪拌、溶於二氯甲烷(5毫升)之(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺鹽酸鹽(105毫克，0.338毫莫耳)溶液中，依序添加三乙胺(0.15毫升，1.014毫莫耳)及苯基6-((2-甲氧基乙基)(甲基)胺基)啶-3-基胺甲酸酯(102毫克，0.338毫莫耳)，並攪拌16小時。將該反應混合物以二氯甲烷(15毫升)稀釋，以水(10毫升)及飽和之氯化鈉溶液(5毫升)清洗，以硫酸鈉乾燥，並將其蒸發。將殘留物純化(中性氧化鋁，溶析液：甲醇/氯仿1：49)，以獲得灰白色固體狀之1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-((2-甲氧基乙基)(甲基)胺基)啶-3-基)尿素(實例化合物89)(74.8毫克，49%)。 Step 4: (1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl) in dichloromethane (5 mL) In the solution of methylamine hydrochloride (105 mg, 0.338 mmol), triethylamine (0.15 ml, 1.014 mmol) and phenyl 6-((2-methoxyethyl) (methyl) were added sequentially. Amino)pyridin-3-ylcarbamate (102 mg, 0.338 mmol) and stirred for 16 hours. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The residue was purified (neutral alumina, EtOAc (MeOH: EtOAc: EtOAc) -1H-pyrazol-5-yl)methyl)-3-(6-((2-methoxyethyl)(methyl)amino)pyridin-3-yl)urea (Example Compound 89) (74.8 Mg, 49%).

實例90之合成：Synthesis of Example 90:

1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-((2-羥乙基)(甲基)胺基)啶-3-基)尿素 1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-((2-hydroxyethyl)) Methyl)amino)pyridin-3-yl)urea

步驟1：將2-氯-5-硝基吡啶(4.0公克)與2-甲基乙醇胺(20毫升)於室溫攪拌1小時。將該反應混合物以水(30毫升)稀釋，以醋酸乙酯(2 x 50毫升)萃取，以飽和之氯化鈉溶液(20毫升)清洗，以硫酸鈉乾燥，並於真空狀態下蒸發。將殘留物以正戊烷(25毫升)清洗，以獲得黃色固體狀之2-(甲基(5-硝基吡啶-2-基)胺基)乙醇(4.5公克，91%)。 Step 1: 2-Chloro-5-nitropyridine (4.0 g) and 2-methylethanolamine (20 ml) were stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc. The residue was washed with n-pentane (25 mL)EtOAcield

步驟2：於一經攪拌、以醋酸乙酯(50毫升)溶解之2-(甲基(5-硝基吡啶-2-基)胺基)乙醇(4.8公克，24.36毫莫耳)溶液中添加10%之鈀碳(550毫克)，並於氫氣氣氛下，將其於室溫攪拌16小時。使該反應混合物通過矽藻土，並於較低壓力下蒸發。將所得之殘 留物以二乙醚(20毫升)清洗，以獲得2-((5-胺基吡啶-2-基)(甲基)胺基)乙醇(3.3公克，81%)。 Step 2: Add 10 to a solution of 2-(methyl(5-nitropyridin-2-yl)amino)ethanol (4.8 g, 24.36 mmol) dissolved in ethyl acetate (50 ml). Palladium on carbon (550 mg) was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction mixture was passed through diatomaceous earth and evaporated under lower pressure. The residue obtained was washed with diethyl ether (20 ml) toield of 2-((5-aminopyridin-2-yl)(methyl)amino)ethanol (3.3 g, 81%).

步驟3：於0℃，於一經攪拌、以丙酮(40毫升)溶解之2-((5-胺基吡啶-2-基)(甲基)胺基)乙醇(3.3公克，16.75毫莫耳)溶液中，依序添加啶(4.0毫升，50.25毫莫耳)及氯甲酸苯酯(2.3毫升，18.425毫莫耳)，並於室溫攪拌1小時。將溶媒蒸發，並將殘留物乙醋酸乙酯(150毫升)溶解，以水(50毫升)及飽和之氯化鈉溶液(50毫升)清洗，以硫酸鈉乾燥，將其蒸發，並將殘留物純化(矽膠：100至200篩孔，溶析液：甲醇/氯仿1：19)，以獲得綠色固體狀之苯基6-((2-羥乙基)(甲基)胺基)啶-3-基胺甲酸酯(1.2公克，25%)。 Step 3: 2-((5-Aminopyridin-2-yl)(methyl)amino)ethanol (3.3 g, 16.75 mmol) dissolved in acetone (40 mL) at 0 °C. In the solution, pyridine (4.0 ml, 50.25 mmol) and phenyl chloroformate (2.3 ml, 18.425 mmol) were sequentially added and stirred at room temperature for 1 hour. The solvent was evaporated, and the residue EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Purification (tank: 100 to 200 mesh, solution: methanol/chloroform 1:19) to obtain phenyl 6-((2-hydroxyethyl)(methyl)amino)pyridine-3 as a green solid - carbamate (1.2 g, 25%).

步驟4：於室溫，於一經攪拌、溶於二氯甲烷(5毫升)之(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺氫氯鹽(108毫克，0.348毫莫耳)溶液中，依序添加三乙胺(0.15毫升，1.044毫莫耳)及苯基6-((2-羥乙基)(甲基)胺基)啶-3-基胺甲酸酯(100毫克，0.348毫莫耳)，並攪拌16小時。將該反應混合物以二氯甲烷(15毫升)稀釋，以水(10毫升)及飽和之氯化鈉溶液(5毫升)清洗，以硫酸鈉乾燥，並將其蒸發。將殘留物以乙醚(5毫升)及二氯甲烷(5毫升)清洗，以獲得灰白色固體狀之1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-((2-羥乙基)(甲基)胺基)啶-3-基)尿素(實例化合物90)(58毫克，36%)。 Step 4: (1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl) in dichloromethane (5 mL) Triethylamine (0.15 ml, 1.044 mmol) and phenyl 6-((2-hydroxyethyl)(methyl)amine were added sequentially to a solution of methylamine hydrochloride (108 mg, 0.348 mmol). Base pyridine-3-ylcarbamate (100 mg, 0.348 mmol) and stirred for 16 hours. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The residue was washed with diethyl ether (5 mL) elute Pyrazol-5-yl)methyl)-3-(6-((2-hydroxyethyl)(methyl)amino)pyridin-3-yl)urea (Example Compound 90) (58 mg, 36%) .

實例87係以類似方法製備而成。 Example 87 was prepared in a similar manner.

實例91之合成：Synthesis of Example 91:

N-(5-(1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)苯甲醯胺 N-(5-(1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl) Pyridin-2-yl)benzamide

步驟1至2：如實例55之描述。 Steps 1 to 2: as described in Example 55.

步驟3：將乙酸鈀(II)(78毫克，0.35毫莫耳)、2,2'-雙(二苯基膦基)-1,1'-聯萘(218毫克，0.35毫莫耳)及甲苯置放於一圓底燒瓶中。將該混合物於氮氣氣留下攪拌15分鐘，隨後添加乙基2-(6-氯啶-3-基)丙酸(370毫克，1.73毫莫耳)、苯甲醯胺(189毫克，1.56毫莫耳)及碳酸銫(2.258公克，6.93毫莫耳)。使該反應混合物回流過夜，隨後將其冷卻至室溫。以矽藻土塞過濾該混合物，並將其濃縮。將殘留物以醋酸乙酯稀釋，並以10%之氯化氫溶液清洗。將有機層以硫酸鎂乾燥，並於較低壓力濃縮，以獲得粗製產物。以管柱色層分析法純化該粗製產物，以獲得乙基2-(6-苄醯胺基啶-3-基)丙酸(295毫克，63%)。 Step 3: palladium (II) acetate (78 mg, 0.35 mmol), 2,2 ' -bis(diphenylphosphino)-1,1 ' -binaphthyl (218 mg, 0.35 mmol) and The toluene was placed in a round bottom flask. The mixture was stirred under nitrogen for 15 minutes, then ethyl 2-(6-chloropyridin-3-yl)propanoic acid (370 mg, 1.73 mmol), benzamide (189 mg, 1.56 m). Mohr) and strontium carbonate (2.258 grams, 6.93 millimoles). The reaction mixture was refluxed overnight then cooled to room temperature. The mixture was filtered through a pad of Celite and concentrated. The residue was diluted with ethyl acetate and washed with a 10% hydrogen chloride solution. The organic layer was dried over magnesium sulfate and concentrated at lower pressure to afford crude material. The crude product was purified by column chromatography to give ethyl 2-(6-benzylaminopyridin-3-yl)propanoic acid (295 mg, 63%).

步驟4：於一溶於四氫呋喃與水之乙基2-(6-苄醯胺基啶-3-基) 丙酸(295毫克，0.99毫莫耳)溶液中添加氫氧化鋰單一水合物(62毫克，1.48毫莫耳)。將該反應混合物於40℃攪拌2小時，隨後以10%之氯化氫溶液將其酸化。以醋酸乙酯萃取該混合物。將有機層以硫酸鎂乾燥，並於較低壓力濃縮，以獲得2-(6-苄醯胺基啶-3-基)丙酸(250毫克，94%)。 Step 4: Add lithium hydroxide monohydrate to a solution of ethyl 2-(6-benzylidinopyridin-3-yl)propionic acid (295 mg, 0.99 mmol) dissolved in tetrahydrofuran and water (62) Mg, 1.48 millimoles). The reaction mixture was stirred at 40 ° C for 2 hours and then acidified with 10% hydrogen chloride solution. The mixture was extracted with ethyl acetate. The organic layer was dried with MgSO.sub.sub.sub.sub.sub.sub.sub.sub.

步驟5：於一溶於二甲基甲醯胺之2-(6-苄醯胺基啶-3-基)丙酸(80毫克，0.30毫莫耳)溶液中添加1-羧苯並三唑(60毫克，0.44毫莫耳)、1-乙基-3-(3-二甲胺基丙基)碘化二亞胺(85毫克，0.44毫莫耳)、三乙胺(0.08毫升，0.59毫莫耳)及(3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺(78毫克，0.30毫莫耳)。將該反應混合物於室溫攪拌過夜。將該混合物以水稀釋，並以醋酸乙酯萃取。將有機層以硫酸鎂乾燥，並於較低壓力下濃縮。以管柱色層分析法純化該粗製產物，以獲得純N-(5-(1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)苯甲醯胺(實例化合物91)(105毫克，69%)。 Step 5: Add 1-carboxybenzotriazole to a solution of 2-(6-benzylidinopyridin-3-yl)propanoic acid (80 mg, 0.30 mmol) dissolved in dimethylformamide (60 mg, 0.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl) iodide diimide (85 mg, 0.44 mmol), triethylamine (0.08 mL, 0.59) Millol) and (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methylamine (78 mg, 0.30 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain pure N-(5-(1-((3-triphenyl)-1H-pyrazol-5-yl) Methylamino)-1-oxopropan-2-yl)pyridin-2-yl)benzamide (example compound 91) (105 mg, 69%).

1H核磁共振(400 MHz，CDCl3)：δ 8.53(br.s，NH)；8.34(d，1H，J=8.58 Hz，啶-H)；8.14(d，1H，J=2.09 Hz，啶-H)；7.90(m，2H，Ar-H)；7.63(dd，1H，J=8.61，2.29 Hz，啶-H)；7.54(m，3H，Ar-H)；7.40(m，1H，Ar-H)；7.27(m，3H，Ar-H)；6.06(s，1H，吡唑-H)；5.47(m，NH)；4.48(m，2H，Ar-CH2)；3.46(四分體，1H，J=7.14 Hz，醯胺-CH)，1.48(d，3H，J=7.17 Hz，醯胺-CH3)，1.28(s，9H，三級丁基-H)。 1 H NMR (400 MHz, CDCl 3 ): δ 8.53 (br.s, NH); 8.34 (d, 1H, J = 8.58 Hz, pyridine-H); 8.14 (d, 1H, J = 2.09 Hz, pyridine -H); 7.90 (m, 2H, Ar-H); 7.63 (dd, 1H, J = 8.61, 2.29 Hz, pyridine-H); 7.54 (m, 3H, Ar-H); 7.40 (m, 1H, Ar-H); 7.27 (m, 3H, Ar-H); 6.06 (s, 1H, pyrazole-H); 5.47 (m, NH); 4.48 (m, 2H, Ar-CH 2 ); 3.46 (four split, 1H, J = 7.14 Hz, Amides -CH), 1.48 (d, 3H , J = 7.17 Hz, Amides -CH 3), 1.28 (s, 9H, tert.butyl -H).

實例92之合成：Synthesis of Example 92:

N-(5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)苯甲醯胺 N-(5-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropane-2 -yl)pyridin-2-yl)benzamide

步驟1至4：如實例91之描述。 Steps 1 to 4: As described in Example 91.

步驟5：於一溶於二甲基甲醯胺之2-(6-苄醯胺基啶-3-基)丙酸(80毫克，0.30毫莫耳)溶液中添加1-羥苯並三唑(60毫克，0.44毫莫耳)、1-乙基-3-(3-二甲胺基丙基)碘化二亞胺(85毫克，0.44毫莫耳)、三乙胺(0.08毫升，0.59毫莫耳)及(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺(81毫克，0.30毫莫耳)。將該反應混合物於室溫攪拌過夜。將該混合物以水稀釋，並以醋酸乙酯萃取。將有機層以硫酸鎂乾燥，並於較低壓力濃縮。以管柱色層分析法純化該粗製產物，以獲得純N-(5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)苯甲醯胺(實例化合物92)(125毫克，80%)。 Step 5: Add 1-hydroxybenzotriazole to a solution of 2-(6-benzylguanidin-3-yl)propanoic acid (80 mg, 0.30 mmol) dissolved in dimethylformamide (60 mg, 0.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl) iodide diimide (85 mg, 0.44 mmol), triethylamine (0.08 mL, 0.59) Millol) and (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamine (81 mg, 0.30 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated at lower pressure. The crude product was purified by column chromatography to obtain pure N-(5-(1-((1-(3-chlorophenyl))-3-(trifluoromethyl)-1H-pyrazole-5) -yl)methylamino)-1-oxopropan-2-yl)pyridin-2-yl)benzamide (example compound 92) (125 mg, 80%).

1H核磁共振(400 MHz，CDCl3)：δ 8.54(br.s，NH)；8.34(d，1H，J=8.62 Hz，啶-H)；8.16(d，1H，J=2.04 Hz，啶-H)；7.90(m，2H，Ar-H)；7.64(m，1H，啶-H)；7.57(m，1H，Ar-H)；7.50(m，2H，Ar-H)；7.40(m，3H，Ar-H)；7.28(m，1H，Ar-H)；6.49(s， 1H，吡唑-H)；5.59(m，NH)；4.49(m，2H，Ar-CH2)；3.49(四分體，1H，J=7.12 Hz，醯胺-CH)；1.49(d，3H，J=7.14 Hz，醯胺-CH3)。 1 H NMR (400 MHz, CDCl 3 ): δ 8.54 (br.s, NH); 8.34 (d, 1H, J = 8.62 Hz, pyridine-H); 8.16 (d, 1H, J = 2.04 Hz, pyridine -H); 7.90 (m, 2H, Ar-H); 7.64 (m, 1H, pyridine-H); 7.57 (m, 1H, Ar-H); 7.50 (m, 2H, Ar-H); 7.40 ( m, 3H, Ar-H); 7.28 (m, 1H, Ar-H); 6.49 (s, 1H, pyrazole-H); 5.59 (m, NH); 4.49 (m, 2H, Ar-CH 2 ) ; 3.49 (tetrad, 1H, J = 7.12 Hz, decyl-CH); 1.49 (d, 3H, J = 7.14 Hz, decylamine -CH 3 ).

實例93之合成：Synthesis of Example 93:

N-(5-(1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)-4-氟苯甲醯胺 N-(5-(1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl) Pyridin-2-yl)-4-fluorobenzamide

步驟1至2：如實例55之描述。 Steps 1 to 2: as described in Example 55.

步驟3：將乙酸鈀(II)(42毫克，0.19毫莫耳)、2,2'-雙(二苯基膦基)-1,1'-聯萘(118毫克，0.19毫莫耳)及甲苯放入一圓底燒瓶中。將該混合物於氮氣氣流下攪拌15分鐘，隨後添加乙基2-(6-氯啶-3-基)丙酸(200毫克，0.94毫莫耳)、4-氟苯甲醯胺(130毫克，0.94毫莫耳)及碳酸銫(1.225公克，3.76毫莫耳)。將該反應混合物回流過夜，隨後將其冷卻至室溫。將該混合物以矽藻土塞過濾，並將其濃縮。將殘留物以醋酸乙酯稀釋，並以10%之氯化氫溶液清洗。將有機層以硫酸鎂乾燥，並於較低壓力濃縮，以獲得粗製 化合物。以管柱色層分析法將其純化，以獲得純乙基2-(6-(4-氟苯甲醯胺)啶-3-基)丙酸(160毫克，54%)。 Step 3: palladium (II) acetate (42 mg, 0.19 mmol), 2,2 ' -bis(diphenylphosphino)-1,1 ' -binaphthyl (118 mg, 0.19 mmol) and Toluene was placed in a round bottom flask. The mixture was stirred under a stream of nitrogen for 15 minutes, then ethyl 2-(6-chloropyridin-3-yl)propanoic acid (200 mg, 0.94 mmol), 4-fluorobenzamide (130 mg, 0.94 millimolar) and barium carbonate (1.225 grams, 3.76 millimolar). The reaction mixture was refluxed overnight then cooled to room temperature. The mixture was filtered through a pad of Celite and concentrated. The residue was diluted with ethyl acetate and washed with a 10% hydrogen chloride solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to afford crude compound. This was purified by column chromatography to give pure ethyl 2-(6-(4-fluorobenzamide)-3-yl)propanoic acid (160 mg, 54%).

步驟4：於一以四氫呋喃及水溶解之乙基2-(6-(4-氟苯甲醯胺)啶-3-基)丙酸(160毫克，0.51毫莫耳)溶液中添加氫氧化鋰單一水合物(32毫克，0.76毫莫耳)。將該反應混合物於40℃攪拌2小時，隨後以10%之氯化氫溶液將其酸化。以醋酸乙酯萃取該混合物。將有機層以硫酸鎂乾燥，並於較低壓力下濃縮，以獲得2-(6-(4-氟苯甲醯胺)啶-3-基)丙酸(150毫克，99%)。 Step 4: Add lithium hydroxide to a solution of ethyl 2-(6-(4-fluorobenzamide)-3-yl)propanoic acid (160 mg, 0.51 mmol) dissolved in tetrahydrofuran and water. Single hydrate (32 mg, 0.76 mmol). The reaction mixture was stirred at 40 ° C for 2 hours and then acidified with 10% hydrogen chloride solution. The mixture was extracted with ethyl acetate. The organic layer was dried with MgSO.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.

步驟5：於一溶於二甲基甲醯胺溶解之2-(6-(4-氟苯甲醯胺)啶-3-基)丙酸(50毫克，0.17毫莫耳)溶液中添加1-羥苯並三唑(35毫克，0.26毫莫耳)、1-乙基-3-(3-二甲胺基丙基)碘化二亞胺(50毫克，0.26毫莫耳)、三乙胺(0.05毫升，0.35毫莫耳)及(3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺(46毫克，0.17毫莫耳)。將該反應混合物於室溫攪拌過夜。將該混合物以水稀釋，並以醋酸乙酯萃取。將有機層以硫酸鎂乾燥，並於較低壓力下濃縮。以管柱色層分析法純化粗製產物，以獲得純N-(5-(1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)-4-氟苯甲醯胺(實例化合物93)(46毫克，50%)。 Step 5: Add 1 to a solution of 2-(6-(4-fluorobenzamide)-3-yl)propanoic acid (50 mg, 0.17 mmol) dissolved in dimethylformamide -Hydroxybenzotriazole (35 mg, 0.26 mmol), 1-ethyl-3-(3-dimethylaminopropyl) iodide diimide (50 mg, 0.26 mmol), triethyl Amine (0.05 ml, 0.35 mmol) and (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methylamine (46 mg, 0.17 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain pure N-(5-(1-((3-triphenyl)-1H-pyrazol-5-yl)) Methylamino)-1-oxopropan-2-yl)pyridin-2-yl)-4-fluorobenzamide (Example Compound 93) (46 mg, 50%).

1H核磁共振(300 MHz，CDCl3)：δ 8.56(br.s，NH)；8.32(d，1H，J=8.68 Hz，啶-H)；8.15(d，1H，J=2.41 Hz，啶-H)；7.94(m，2H，Ar-H)；7.66(dd，1H，J=8.43，2.39 Hz，啶-H)；7.39(m，1H，Ar-H)；7.24(m，5H，Ar-H)；6.08(s，1H，吡唑-H)；5.54(t，NH，J=5.42 Hz)；4.50(d，2H，J=5.41 Hz，Ar-CH2)；3.48(四分體，1H，J=7.21 Hz，醯胺-CH)，1.49(d，3H，J=7.19 Hz，醯胺-CH3)，1.30(s，9H，三級丁基-H)。 1 H NMR (300 MHz, CDCl 3 ): δ 8.56 (br.s, NH); 8.32 (d, 1H, J = 8.68 Hz, pyridine-H); 8.15 (d, 1H, J = 2.41 Hz, pyridine -H); 7.94 (m, 2H, Ar-H); 7.66 (dd, 1H, J = 8.43, 2.39 Hz, pyridine-H); 7.39 (m, 1H, Ar-H); 7.24 (m, 5H, Ar-H); 6.08 (s, 1H, pyrazole-H); 5.54 (t, NH, J = 5.42 Hz); 4.50 (d, 2H, J = 5.41 Hz, Ar-CH 2 ); 3.48 (four points) body, 1H, J = 7.21 Hz, Amides -CH), 1.49 (d, 3H , J = 7.19 Hz, Amides -CH 3), 1.30 (s, 9H, tert.butyl -H).

實例94之合成：Synthesis of Example 94:

N-(5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)-4-氟苯甲醯胺 N-(5-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropane-2 -yl)pyridin-2-yl)-4-fluorobenzamide

步驟1至4：如實例93之描述。 Steps 1 to 4: As described in Example 93.

步驟5：於一溶於二甲基甲醯胺之2-(6-(4-氟苯甲醯胺)啶-3-基)丙酸(50毫克，0.17毫莫耳)溶液中添加1-羧苯並三唑(35毫克，0.26毫莫耳)、1-乙基-3-(3-二甲胺基丙基)碘化二亞胺(50毫克，0.26毫莫耳)、三乙胺(0.05毫升，0.35毫莫耳)及(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺(48毫克，0.17毫莫耳)。將該反應混合物於室溫攪拌過夜。將該混合物以水稀釋，並以醋酸乙酯萃取。將有機層以硫酸鎂乾燥，並於較低壓力下濃縮。以管柱色層分析法純化粗製產物，以獲得純N-(5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)-4-氟苯甲醯胺(實例化合物94)(44毫克，46%)。 Step 5: Add 1- in a solution of 2-(6-(4-fluorobenzamide)-3-yl)propanoic acid (50 mg, 0.17 mmol) dissolved in dimethylformamide Carboxybenzotriazole (35 mg, 0.26 mmol), 1-ethyl-3-(3-dimethylaminopropyl) iodide diimide (50 mg, 0.26 mmol), triethylamine (0.05 ml, 0.35 mmol) and (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamine (48 mg, 0.17 mmol) . The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give pure N-(5-(1-((1-(3-chlorophenyl))-3-(trifluoromethyl)-1H-pyrazole-5- Methylamino)-1-oxopropan-2-yl)pyridin-2-yl)-4-fluorobenzamide (example compound 94) (44 mg, 46%).

1H核磁共振(400 MHz，CDCl3)：δ 8.48(br.s，NH)；8.31(d，1H，J=8.60 Hz，啶-H)；8.16(d，1H，J=2.10 Hz，啶-H)；7.92(m， 2H，Ar-H)；7.64(dd，1H，J=8.58，2.27 Hz，啶-H)；7.40(m，3H，Ar-H)；7.28(m，3H，Ar-H)；7.18(m，2H，Ar-H)；6.48(s，1H，吡唑-H)；5.58(m，NH)；4.49(m，2H，Ar-CH2)；3.48(四分體，1H，J=7.14 Hz，醯胺-CH)，1.49(d，3H，J=7.14 Hz，醯胺-CH3)。 1 H NMR (400 MHz, CDCl 3 ): δ 8.48 (br.s, NH); 8.31 (d, 1H, J = 8.60 Hz, pyridine-H); 8.16 (d, 1H, J = 2.10 Hz, pyridine -H); 7.92 (m, 2H, Ar-H); 7.64 (dd, 1H, J = 8.58, 2.27 Hz, pyridine-H); 7.40 (m, 3H, Ar-H); 7.28 (m, 3H, Ar-H); 7.18 (m, 2H, Ar-H); 6.48 (s, 1H, pyrazole-H); 5.58 (m, NH); 4.49 (m, 2H, Ar-CH 2 ); 3.48 (four split, 1H, J = 7.14 Hz, Amides -CH), 1.49 (d, 3H , J = 7.14 Hz, Amides -CH 3).

實例95之合成：Synthesis of Example 95:

N-(5-(1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)-4-氯苯甲醯胺 N-(5-(1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl) Pyridin-2-yl)-4-chlorobenzamide

步驟1至2：如實例55之描述。 Steps 1 to 2: as described in Example 55.

步驟3：將乙酸鈀(II)(84毫克，0.37毫莫耳)、2,2'-雙(二苯基膦基)-1,1'-聯萘(233毫克，0.37毫莫耳)與甲苯放入一圓底燒瓶中。將該混合物於氮氣氣流下攪拌15分鐘，隨後添加乙基2-(6-氯啶-3-基)丙酸(400毫克，1.87毫莫耳)、4-氯苯甲醯胺(291毫克，1.87毫莫耳)及碳酸銫(2.44公克，7.49毫莫耳)。將該反應混合物回流過夜，隨後將其冷卻至室溫。將該混合物以矽藻土塞於室溫過濾，並將其濃縮。以醋酸乙酯稀釋殘留物，並以10%之氯化氫 溶液清洗。將有機層以硫酸鎂乾燥，並於較低壓力下濃縮，以獲得粗製產物。以管柱色層分析法純化該粗製產物，以獲得乙基2-(6-(4-氯苯甲醯胺)啶-3-基)丙酸(360毫克，58%)。 Step 3: Palladium (II) acetate (84 mg, 0.37 mmol), 2,2 '- bis (diphenylphosphino) -1,1' - binaphthyl (233 mg, 0.37 mmol) and Toluene was placed in a round bottom flask. The mixture was stirred under a stream of nitrogen for 15 minutes, then ethyl 2-(6-chloropyridin-3-yl)propanoic acid (400 mg, 1.87 mmol), 4-chlorobenzamide (291 mg, 1.87 millimoles) and barium carbonate (2.44 grams, 7.49 millimoles). The reaction mixture was refluxed overnight then cooled to room temperature. The mixture was filtered with celite and filtered at room temperature and concentrated. The residue was diluted with ethyl acetate and washed with a 10% hydrogen chloride solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give crude material. The crude product was purified by column chromatography to give ethyl 2-(6-(4-chlorobenzamide) </RTI><RTIgt;

步驟4：於一溶於四氫呋喃之乙基2-(6-(4-氯苯甲醯胺)啶-3-基)丙酸(360毫克，1.08毫莫耳)溶液中添加氫氧化鋰單一水合物(68毫克，1.62毫莫耳)。將該反應混合物於40℃攪拌2小時，隨後以10%之氯化氫溶液將其酸化。以醋酸乙酯萃取該混合物。將有機層以硫酸鎂乾燥，並於較低壓力下濃縮，以獲得2-(6-(4-氯苯甲醯胺)啶-3-基)丙酸(300毫克，91%)。 Step 4: Adding lithium hydroxide monohydrate to a solution of ethyl 2-(6-(4-chlorobenzamide)-3-yl)propanoic acid (360 mg, 1.08 mmol) dissolved in tetrahydrofuran (68 mg, 1.62 mmol). The reaction mixture was stirred at 40 ° C for 2 hours and then acidified with 10% hydrogen chloride solution. The mixture was extracted with ethyl acetate. The organic layer was dried with MgSO.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.

步驟5：於一溶於二甲基甲醯胺之2-(6-(4-氯苯甲醯胺)啶-3-基)丙酸(70毫克，0.23毫莫耳)溶液中添加1-羧苯並三唑(46毫克，0.34毫莫耳)、1-乙基-3-(3-二甲胺基丙基)碘化二亞胺(66毫克，0.34毫莫耳)、三乙胺(0.06毫升，0.46毫莫耳)及(3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺(60毫克，0.23毫莫耳)。將該反應混合物於室溫攪拌過夜。以水稀釋該混合物，並以醋酸乙酯萃取。將有機層以硫酸鎂乾燥，並於較低壓力下濃縮。以管柱色層分析法純化粗製產物，以獲得純N-(5-(1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)-4-氯苯甲醯胺(實例化合物95)(70毫克，55%)。 Step 5: Add 1- in a solution of 2-(6-(4-chlorobenzamide)-3-yl)propanoic acid (70 mg, 0.23 mmol) dissolved in dimethylformamide Carboxybenzotriazole (46 mg, 0.34 mmol), 1-ethyl-3-(3-dimethylaminopropyl) iodide diimide (66 mg, 0.34 mmol), triethylamine (0.06 ml, 0.46 mmol) and (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methylamine (60 mg, 0.23 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain pure N-(5-(1-((3-triphenyl)-1H-pyrazol-5-yl)) Methylamino)-1-oxopropan-2-yl)pyridin-2-yl)-4-chlorobenzamide (Example Compound 95) (70 mg, 55%).

1H核磁共振(300 MHz，CDCl3)：δ 8.68(br.s，NH)；8.32(d，1H，J=8.62 Hz，啶-H)；8.12(d，1H，J=2.24 Hz，啶-H)；7.86(m，2H，Ar-H)；7.66(dd，1H，J=8.63，2.38 Hz，啶-H)；7.49(m，2H，Ar-H)；7.42(m，1H，Ar-H)；7.28(m，3H，Ar-H)；6.08(s，1H，吡唑-H)；5.60(t，NH，J=5.53 Hz)；4.50(d，2H，J=5.52 Hz，Ar-CH2)；3.47(四分體，1H，J=7.14 Hz，醯胺-CH)，1.48(d，3H，J=7.14 Hz，醯胺-CH3)，1.29(s，9H，三級丁基-H)。 1 H NMR (300 MHz, CDCl 3 ): δ 8.68 (br.s, NH); 8.32 (d, 1H, J = 8.62 Hz, pyridine-H); 8.12 (d, 1H, J = 2.24 Hz, pyridine -H); 7.86 (m, 2H, Ar-H); 7.66 (dd, 1H, J = 8.63, 2.38 Hz, pyridine-H); 7.49 (m, 2H, Ar-H); 7.42 (m, 1H, Ar-H); 7.28 (m, 3H, Ar-H); 6.08 (s, 1H, pyrazole-H); 5.60 (t, NH, J = 5.53 Hz); 4.50 (d, 2H, J = 5.52 Hz) , Ar-CH 2 ); 3.47 (tetrad, 1H, J = 7.14 Hz, decyl-CH), 1.48 (d, 3H, J = 7.14 Hz, decyl-CH 3 ), 1.29 (s, 9H, Tert-butyl-H).

實例96之合成：Synthesis of Example 96:

4-氯-N-(5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)苯甲醯胺 4-Chloro-N-(5-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxyl Propane-2-yl)pyridin-2-yl)benzamide

步驟1至4：如實例95之描述。 Steps 1 to 4: as described in Example 95.

步驟5：於一溶於二甲基甲醯胺之2-(6-(4-氯苯甲醯胺)啶-3-基)丙酸(70毫克，0.23毫莫耳)溶液中添加1-羧苯並三唑(46毫克，0.34毫莫耳)、1-乙基-3-(3-二甲胺基丙基)碘化二亞胺(66毫克，0.34毫莫耳)、三乙胺(0.06毫升，0.46毫莫耳)及(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺(63毫克，0.23毫莫耳)。將該反應混合物於室溫攪拌過夜。以水稀釋該混合物，並以醋酸乙酯萃取。將有機層以硫酸鎂乾燥，並於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得純4-氯-N-(5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)苯甲醯胺(實例化合物96)(81毫克，63%)。 Step 5: Add 1- in a solution of 2-(6-(4-chlorobenzamide)-3-yl)propanoic acid (70 mg, 0.23 mmol) dissolved in dimethylformamide Carboxybenzotriazole (46 mg, 0.34 mmol), 1-ethyl-3-(3-dimethylaminopropyl) iodide diimide (66 mg, 0.34 mmol), triethylamine (0.06 ml, 0.46 mmol) and (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamine (63 mg, 0.23 mmol) . The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated at lower pressure. The crude product was purified by column chromatography to give pure 4-chloro-N-(5-(1-((1-(3-chlorophenyl))-3-(trifluoromethyl)-1H-py Zyrid-5-yl)methylamino)-1-oxopropan-2-yl)pyridin-2-yl)benzamide (example compound 96) (81 mg, 63%).

1H核磁共振(300 MHz，CDCl3)：δ 8.56(br.s，NH)；8.32(d， 1H，J=8.77 Hz，啶-H)；8.16(d，1H，J=2.24 Hz，啶-H)；7.86(m，2H，Ar-H)；7.66(dd，1H，J=8.64，2.38 Hz，啶-H)；7.45(m，5H，Ar-H)；7.29(m，1H，Ar-H)；6.50(s，1H，吡唑-H)；5.67(m，NH)；4.51(m，2H，Ar-CH2)；3.50(四分體，1H，J=7.08 Hz，醯胺-CH)，1.51(d，3H，J=7.12 Hz，醯胺-CH3)。 1 H NMR (300 MHz, CDCl 3 ): δ 8.56 (br.s, NH); 8.32 (d, 1H, J = 8.77 Hz, pyridine-H); 8.16 (d, 1H, J = 2.24 Hz, pyridine -H); 7.86 (m, 2H, Ar-H); 7.66 (dd, 1H, J = 8.64, 2.38 Hz, pyridine-H); 7.45 (m, 5H, Ar-H); 7.29 (m, 1H, Ar-H); 6.50 (s, 1H, pyrazole-H); 5.67 (m, NH); 4.51 (m, 2H, Ar-CH 2 ); 3.50 (tetrad, 1H, J = 7.08 Hz, 醯amine -CH), 1.51 (d, 3H , J = 7.12 Hz, Amides -CH 3).

可以類似方法製備實例97。 Example 97 can be prepared in a similar manner.

實例102之合成：Synthesis of Example 102:

N-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-2-(5-氟-6-(甲基磺醯胺)啶-3-基)丙醯胺 N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(5-fluoro-6-(methylsulfonamide) Pyridin-3-yl)propanamide

步驟1：於氮氣氣氛下，將叔丁醇鉀(0.473公克，4221毫莫耳)放入一圓底燒瓶中，加入無水二甲基甲醯胺(5毫升)，並於室溫攪拌10分鐘。隨後將其冷卻至-20℃，添加2-硝基-3-氟啶(200毫克， 1.407毫莫耳)，再逐滴添加2-氯丙酸乙酯(0.273毫升，2.111莫耳)，並將其攪拌20分鐘。隨後加入經稀釋之氯化氫，並於室溫攪拌10分鐘。以醋酸乙至萃取，以水清洗，以硫酸鎂乾燥，將其過濾，並蒸發。最後以管柱色層分析法將其純化，以獲得乙基2-(5-氟-6-硝基吡啶-3-基)丙酸(153毫克，45%)。 Step 1: Potassium tert-butoxide (0.473 g, 4221 mmol) was placed in a round bottom flask under a nitrogen atmosphere, anhydrous dimethylformamide (5 ml) was added and stirred at room temperature for 10 min. Then it was cooled to -20 ° C, 2-nitro-3-fluoropyridine (200 mg, 1.407 mmol) was added, and ethyl 2-chloropropionate (0.273 ml, 2.111 mol) was added dropwise, and It was stirred for 20 minutes. Diluted hydrogen chloride was then added and stirred at room temperature for 10 minutes. Extracted with ethyl acetate to water, washed with water, dried over magnesium sulfate, filtered and evaporated. Finally, it was purified by column chromatography to give ethyl 2-(5-fluoro-6-nitropyridin-3-yl)propanoic acid (153 mg, 45%).

步驟2：將乙基2-(5-氟-6-硝基吡啶-3-基)丙酸(100毫克)放入一圓底燒瓶中，添加乙醇及鈀碳(20重量%)，並於氫氣存在之條件下於室溫攪拌2小時。隨後以矽藻土過濾，並將溶媒蒸發，以獲得乙基2-(6-胺基-5-氟啶-3-基)丙酸(69毫克，79%)。 Step 2: Ethyl 2-(5-fluoro-6-nitropyridin-3-yl)propanoic acid (100 mg) was placed in a round bottom flask, and ethanol and palladium on carbon (20% by weight) were added and Stir at room temperature for 2 hours under the conditions present. It was then filtered through celite, and the solvent was evaporated to give ethyl 2-(6-amino-5-fluoropyridin-3-yl)propanoic acid (69 mg, 79%).

步驟3：於氮氣氣氛下，將乙基2-(6-胺基-5-氟啶-3-基)丙酸(1.525公克，7.185毫莫耳)放入一圓底燒瓶中，加入無水四氫呋喃(14毫升)，並將其攪拌。隨後將其冷卻至0℃，依序添加三乙胺(2.181毫升，21.555毫莫耳)及甲基磺醯氯(0.837毫升，10.778毫莫耳)，並於室溫攪拌2小時。以醋酸乙酯萃取該反應混合物，以水清洗，以硫酸鎂乾燥，將其過濾，並將溶媒蒸發，最後以管柱色層分析法將其純化，以獲得乙基2-(5-氟-6-(甲基磺醯胺)啶-3-基)丙酸(1.39公克，67%)。 Step 3: Ethyl 2-(6-amino-5-fluoropyridin-3-yl)propanoic acid (1.525 g, 7.185 mmol) was placed in a round bottom flask under nitrogen atmosphere, and anhydrous tetrahydrofuran was added. 14 ml) and stir it. Then it was cooled to 0 ° C, and triethylamine (2.181 ml, 21.555 mmol) and methylsulfonium chloride (0.837 ml, 10.778 mmol) were sequentially added and stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered, and evaporated, and then purified by column chromatography to obtain ethyl 2-(5-fluoro- 6-(Methylsulfonamide)pyridin-3-yl)propanoic acid (1.39 g, 67%).

步驟4：將乙基2-(5-氟-6-(甲基磺醯胺)啶-3-基)丙酸(110毫克，0.378毫莫耳)及乙基酯放入一圓底燒瓶中，隨後添加四氫呋喃(5毫升)，並將其冷卻至0℃，逐滴添加溶於水(5毫升)之氫氧化鋰單一水合物(0.039公克，0.947毫莫耳)溶液，並於室溫攪拌2小時。隨後將該反應混合物以醋酸乙酯萃取，以水清洗，以經稀釋之氯化氫酸化水層，再以醋酸乙酯萃取，以水清洗，以硫酸鎂乾燥，將其過濾，並將溶媒蒸發，以獲得2-(5-氟-6-(甲基磺醯胺)啶-3-基)丙酸(59毫克，60%)。 Step 4: Put ethyl 2-(5-fluoro-6-(methylsulfonamide)-3-yl)propanoic acid (110 mg, 0.378 mmol) and ethyl ester in a round bottom flask. Subsequently, tetrahydrofuran (5 ml) was added, and it was cooled to 0 ° C, and a solution of lithium hydroxide monohydrate (0.039 g, 0.947 mmol) dissolved in water (5 ml) was added dropwise and stirred at room temperature 2 hour. The reaction mixture is then extracted with ethyl acetate, washed with water, and the aqueous layer is acidified with diluted aqueous hydrogen chloride, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and evaporated. 2-(5-Fluoro-6-(methylsulfonamide)-3-yl)propanoic acid (59 mg, 60%) was obtained.

步驟5：將2-(5-氟-6-(甲基磺醯胺)啶-3-基)丙酸(100毫克， 0.365毫莫耳)放入一圓底燒瓶中，於氮氣氣氛下依序添加二甲基甲醯胺(5毫升)、N-(3-二甲胺基丙基)-N’-乙基碘化二亞胺(104毫克，0.547毫莫耳)及N-羧苯並三唑(74毫克，0.547毫莫耳)；將該混合物攪拌1小時。之後，添加(3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺(96毫克，0.365毫莫耳)，並於室溫攪拌4小時。將該反應混合物以醋酸乙酯萃取，以水清洗，以硫酸鎂乾燥，將其過濾，並將溶媒蒸發。最後以管柱色層分析法純將其純化，以獲得白色固體狀之N-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-2-(5-氟-6-(甲基磺醯胺)啶-3-基)丙醯胺(實例化合物102，130毫克，67%)。 Step 5: 2-(5-Fluoro-6-(methylsulfonamide)pyridin-3-yl)propanoic acid (100 mg, 0.365 mmol) was placed in a round bottom flask and placed under nitrogen atmosphere. Add dimethylformamide (5 ml), N-(3-dimethylaminopropyl)-N'-ethyl iodide diimide (104 mg, 0.547 mmol) and N-carboxybenzophenone Triazole (74 mg, 0.547 mmol); the mixture was stirred for 1 hour. Thereafter, (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine (96 mg, 0.365 mmol) was added and stirred at room temperature for 4 hr. The reaction mixture was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and evaporated. Finally, it was purified by column chromatography to obtain N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl) A as a white solid. 2-(5-Fluoro-6-(methylsulfonamide)-3-yl)propanamide (example compound 102, 130 mg, 67%).

1H核磁共振(300 MHz，CDCl3)：δ 7.97(s，1H，Ar-H)，7.41(d，3H，J=1.5Hz，2HAr-H)；7.36(s，2H，Ar-H)；6.13(s，1H，Ar-H)；5.64(s，1H，R-NH)；4.50(d，2H，J=4.2Hz，Ar-CH2)；3.46(s，3H，ArSO2-CH3)；3.43(q，1H，J=6.9Hz，Ar-CH)；1.45(d，3H，J=6.9Hz，ArCH-CH3)；1.31(s，9H，R-C(CH3)3)。 1 H NMR (300 MHz, CDCl 3 ): δ 7.97 (s, 1H, Ar-H), 7.41 (d, 3H, J = 1.5 Hz, 2HAr-H); 7.36 (s, 2H, Ar-H) ; 6.13 (s, 1H, Ar-H); 5.64 (s, 1H, R-NH); 4.50 (d, 2H, J = 4.2 Hz, Ar-CH2); 3.46 (s, 3H, ArSO 2 -CH 3 3.43 (q, 1H, J = 6.9 Hz, Ar-CH); 1.45 (d, 3H, J = 6.9 Hz, ArCH-CH 3 ); 1.31 (s, 9H, RC(CH 3 ) 3 ).

實例98至100係以類似方法製備而成。 Examples 98 to 100 were prepared in a similar manner.

實例103之合成：Synthesis of Example 103:

N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(5-氟-6-(甲基磺醯胺)啶-3-基)丙醯胺 N-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(5-fluoro-6-(methylsulfonate) Amine)-3-yl)propanamide

步驟1至4：參照實例化合物102。 Steps 1 to 4: Refer to Example Compound 102.

步驟5：於氮氣氣氛下，將2-(5-氟-6-(甲基磺醯胺)啶-3-基)丙酸(100毫克，0.365毫莫耳)放入一圓底燒瓶中，並依序添加二甲基甲醯胺(5毫升)、N-(3-二甲胺基丙基)-N’-乙基碘化二亞胺(104毫克，0.547毫莫耳)及N-羧苯並三唑(74毫克，0.547毫莫耳)，並攪拌1小時。再添加(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺(99毫克，0.365毫莫耳)，並於室溫攪拌4小時。將該反應混合物以醋酸乙酯萃取，以水清洗，以硫酸鎂乾燥，將其過濾，並將溶媒蒸發。最後以管柱色層分析法將其純化，以獲得白色固體狀之N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(5-氟-6-(甲基磺醯胺)啶-3-基)丙醯胺(實例化合物103)(140毫克，71%)。 Step 5: 2-(5-Fluoro-6-(methylsulfonamide)-3-yl)propanoic acid (100 mg, 0.365 mmol) was placed in a round bottom flask under a nitrogen atmosphere. Add dimethylformamide (5 ml), N-(3-dimethylaminopropyl)-N'-ethyl iodide diimide (104 mg, 0.547 mmol) and N-carboxyl. Benzotriazole (74 mg, 0.547 mmol) and stirred for 1 hour. (1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine (99 mg, 0.365 mmol) was added and stirred at room temperature for 4 hours. . The reaction mixture was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and evaporated. Finally, it was purified by column chromatography to give N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl) as a white solid. Methyl)-2-(5-fluoro-6-(methylsulfonamide)-3-yl)propanamide (Example Compound 103) (140 mg, 71%).

1H核磁共振(300 MHz，CDCl3)：δ 7.98(s，1H，Ar-H)；7.41(d，2H，J=1.5Hz，2H，Ar-H)；7.40(s，2H，Ar-H)；7.33(m，1H，Ar-H)；6.52(s，1H，Ar-H)；5.80(s，1H，NH)；4.50(m，2H，Ar-CH2)；3.48(s，3H，ArSO2-CH3)；3.48(q，1H，J=11.91Hz，Ar-CH)；1.46(d，3H，J=6.9Hz，ArCH-CH3)。 1 H NMR (300 MHz, CDCl 3 ): δ 7.98 (s, 1H, Ar-H); 7.41 (d, 2H, J = 1.5 Hz, 2H, Ar-H); 7.40 (s, 2H, Ar-) H); 7.33 (m, 1H, Ar-H); 6.52 (s, 1H, Ar-H); 5.80 (s, 1H, NH); 4.50 (m, 2H, Ar-CH2); 3.48 (s, 3H) , ArSO 2 -CH 3 ); 3.48 (q, 1H, J = 11.91 Hz, Ar-CH); 1.46 (d, 3H, J = 6.9 Hz, ArCH-CH 3 ).

實例104之合成：Synthesis of Example 104:

N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(5-甲氧基-6-(甲基磺醯胺)啶-3-基)丙醯胺 N-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(5-methoxy-6-(methyl) Sulfonamide)-3-yl)propanamide

步驟1：於氮氣氣氛下，將叔丁醇鉀(146毫克，1.297毫莫耳)放入一圓底燒瓶中，添加二甲基甲醯胺(3毫升)後將其於室溫攪拌10分鐘，之後，將其冷卻至-40℃，隨後添加商購取得之2-硝基-3-甲氧啶(100毫克，0.648毫莫耳)及逐滴添加2-氯-丙酸乙基酯(0.0908毫升，0.712毫莫耳)；將該混合物攪拌20分鐘。隨後添加經稀釋之氯化氫，並於室溫攪拌10分鐘。以醋酸乙酯萃取，以水清洗，以硫酸鎂乾燥，將其過濾，並將溶媒蒸發。最後，以管柱色層分析法將其純化，以獲得2-(5-甲氧基-6-硝基-啶-3-基)-丙酸乙基酯(82毫克，50%)。 Step 1: Potassium tert-butoxide (146 mg, 1.297 mmol) was placed in a round bottom flask under nitrogen, dimethylformamide (3 mL) was added and stirred at room temperature for 10 min. Thereafter, it was cooled to -40 ° C, followed by the addition of commercially available 2-nitro-3-methoxypyridine (100 mg, 0.648 mmol) and dropwise addition of 2-chloro-propionic acid ethyl ester (0.0908). ML, 0.712 mmol; stir the mixture for 20 minutes. Diluted hydrogen chloride was then added and stirred at room temperature for 10 minutes. It was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and evaporated. Finally, it was purified by column chromatography to give 2-(5-methoxy-6-nitro-pyridin-3-yl)-propionic acid ethyl ester (82 mg, 50%).

步驟2：將2-(5-甲氧基-6-硝基-啶-3-基)-丙酸乙基酯(100毫克)放入一圓底燒瓶中，隨後添加乙醇及20%之鈀碳；於氫氣存在之條件下將該混合物於室溫攪拌2小時。隨後將其以矽藻土過濾， 並將溶媒蒸發，以獲得2-(6-胺基-5-甲氧基-啶-3-基)-丙酸乙基酯(68毫克，78%)。 Step 2: 2-(5-Methoxy-6-nitro-pyridin-3-yl)-propionic acid ethyl ester (100 mg) was placed in a round bottom flask followed by the addition of ethanol and 20% palladium on carbon The mixture was stirred at room temperature for 2 hours in the presence of hydrogen. It was then filtered over celite, and the solvent was evaporated to give ethyl 2-(6-amino-5-methoxy-pyridin-3-yl)-propanoate (68 mg, 78%).

步驟3：於氮氣氣氛下，將2-(6-胺基-5-甲氧基-啶-3-基)-丙酸乙基酯(200毫克，0.891毫莫耳)放入一圓底燒瓶中，添加四氫呋喃，並加以攪拌。隨後將其冷卻至0℃，依序添加三乙胺(0.137毫升，0.981毫莫耳)及甲基磺醯氯(0.076毫升，0.981毫莫耳)，並於室溫攪拌2小時。將該反應混合物以醋酸乙酯萃取，以水清洗，以硫酸鎂乾燥，將其過濾，並將溶媒蒸發。最後以管柱色層分析法將其純化，以獲得2-(6-甲磺醯氨基-5-甲氧基-啶-3-基)-丙酸乙基酯(180毫克，67%)。 Step 3: Put 2-(6-Amino-5-methoxy-pyridine-3-yl)-propionic acid ethyl ester (200 mg, 0.891 mmol) in a round bottom flask under a nitrogen atmosphere. Add tetrahydrofuran and stir. Then it was cooled to 0 ° C, and triethylamine (0.137 ml, 0.981 mmol) and methylsulfonium chloride (0.076 ml, 0.981 mmol) were sequentially added and stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and evaporated. Finally, it was purified by column chromatography to give 2-(6-methanesulfonylamino-5-methoxy-pyridin-3-yl)-propionic acid ethyl ester (180 mg, 67%).

步驟4：將2-(5-甲氧基-6-甲磺醯氨基-啶-3-基)-丙酸乙基酯(1.6公克，5.291毫莫耳)放入一圓底燒瓶中，添加四氫呋喃，並將其冷卻至0℃。逐滴添加溶於水(10毫升)之氫氧化鋰單一水合物(556毫克，13.229毫莫耳)溶液，並於室溫攪拌2小時。將該反應混合物以醋酸乙酯萃取，以水清洗，並以經稀釋之氯化氫將其酸化，再以醋酸乙酯萃取，以水清洗，以硫酸鎂乾燥，將其過濾，並將溶媒蒸發，以獲得2-(5-甲氧基-6-(甲基磺醯胺)啶-3-基)丙酸(870毫克，60%)。 Step 4: 2-(5-Methoxy-6-methylsulfonylamino-pyridin-3-yl)-propionic acid ethyl ester (1.6 g, 5.291 mmol) was placed in a round bottom flask and tetrahydrofuran was added. And cool it to 0 °C. A solution of lithium hydroxide monohydrate (556 mg, 13.229 mmol) in water (10 ml) was added dropwise and stirred at room temperature for 2 hours. The reaction mixture is extracted with ethyl acetate, washed with water, and then acidified with diluted hydrogen chloride, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered, and evaporated. 2-(5-Methoxy-6-(methylsulfonamide)-3-yl)propanoic acid (870 mg, 60%) was obtained.

步驟5：於氮氣氣氛下，將2-(5-甲氧基-6-(甲基磺醯胺)啶-3-基)丙酸(109毫克，0.362毫莫耳)放入一圓底燒瓶中，並添加二甲基甲醯胺(5毫升)。隨後添加1-乙基-3-(3-二甲胺基丙基)碘化二亞胺(104毫克，0.543毫莫耳)及1-羥苯並三唑(73毫克，0543毫莫耳)，並將其攪拌1小時。隨後添加(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺(100毫克，0.362毫莫耳)，並於室溫攪拌4小時。將該反應混合物以醋酸乙酯萃取，以水清洗，以硫酸鎂乾燥，將其過濾，並將溶媒蒸發。最後，以管柱色層分析法將其純化，以 獲得白色固體狀之N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(5-甲氧基-6-(甲基磺醯胺)啶-3-基)丙醯胺(實例化合物104)(145毫克，69%)。 Step 5: 2-(5-Methoxy-6-(methylsulfonamide)-3-yl)propanoic acid (109 mg, 0.362 mmol) was placed in a round bottom flask under a nitrogen atmosphere. And add dimethylformamide (5 ml). Subsequent addition of 1-ethyl-3-(3-dimethylaminopropyl) iodide diimide (104 mg, 0.543 mmol) and 1-hydroxybenzotriazole (73 mg, 0543 mmol) And stir it for 1 hour. Then (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamine (100 mg, 0.362 mmol) was added and stirred at room temperature for 4 hours. . The reaction mixture was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and evaporated. Finally, it was purified by column chromatography to give N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl) as a white solid. Methyl)-2-(5-methoxy-6-(methylsulfonamide)-3-yl)propanamide (Example Compound 104) (145 mg, 69%).

1H核磁共振(300 MHz，CDCl3)：δ 7.74(s，1H，Ar-H)；7.43(m，3H，Ar-H)；7.30(s，1H，Ar-H)；7.05(s，1H，Ar-H)；6.46(s，1H，Ar-H)；5.83(s，1H，R-NH)；4.47(d，2H，J=4.02 Hz，ArCH2)；3.86(s，3H，Ar-OCH3)；3.46(s，3H，RSO2-CH3)；3.46(q，1H，J=6.96 Hz，Ar-CH)；1.44(d，3H，J=7.14 Hz，ArCH-CH3)。 1 H NMR (300 MHz, CDCl 3 ): δ 7.74 (s, 1H, Ar-H); 7.43 (m, 3H, Ar-H); 7.30 (s, 1H, Ar-H); 7.05 (s, 1H, Ar-H); 6.46 (s, 1H, Ar-H); 5.83 (s, 1H, R-NH); 4.47 (d, 2H, J = 4.02 Hz, ArCH 2 ); 3.86 (s, 3H, Ar-OCH 3 ); 3.46 (s, 3H, RSO 2 -CH 3 ); 3.46 (q, 1H, J = 6.96 Hz, Ar-CH); 1.44 (d, 3H, J = 7.14 Hz, ArCH-CH 3 ).

實例105之合成：Synthesis of Example 105:

N-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-2-(5-甲氧基-6-(甲基磺醯胺)啶-3-基)丙醯胺 N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(5-methoxy-6-(methylsulfonate) Amine)-3-yl)propanamide

步驟1至4：如實例104之描述。 Steps 1 through 4: as described in Example 104.

步驟5：於氮氣氣氛下，將2-(5-甲氧基-6-(甲基磺醯胺)啶-3-基)丙酸(80毫克，0.292毫莫耳)放入一圓底燒瓶中，依序添加二甲 基甲醯胺(5毫升)、1-乙基-3-(3-二甲胺基丙基)碘化二亞胺(76毫克，0.397毫莫耳)及1-羥苯並三唑(53毫克，0.397毫莫耳)，並攪拌1小時。隨後添加(3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺(70毫克，0.265毫莫耳)，並於室溫攪拌4小時。將該反應混合物以醋酸乙酯萃取，以水清洗，以硫酸鎂乾燥，將其過濾，並將溶媒蒸發。最後，以管柱色層分析法將其純化，以獲得白色固體狀之N-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-2-(5-甲氧基-6-(甲基磺醯胺)啶-3-基)丙醯胺(實例化合物105)(121毫克，80%)。 Step 5: 2-(5-Methoxy-6-(methylsulfonamide)-3-yl)propanoic acid (80 mg, 0.292 mmol) was placed in a round bottom flask under a nitrogen atmosphere. , adding dimethylformamide (5 ml), 1-ethyl-3-(3-dimethylaminopropyl) iodide diimide (76 mg, 0.397 mmol) and 1-hydroxyl Benzotriazole (53 mg, 0.397 mmol) and stirred for 1 hour. Then (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine (70 mg, 0.265 mmol) was added and stirred at room temperature for 4 hr. The reaction mixture was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and evaporated. Finally, it was purified by column chromatography to obtain N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl) A as a white solid. 2-(5-Methoxy-6-(methylsulfonamide)-3-yl)propanamide (example compound 105) (121 mg, 80%).

1H核磁共振(300 MHz，CDCl3)：δ 7.75(s，1H，Ar-H)；7.33(m，2H，Ar-H)；7.10(s，1H，Ar-H)；6.08(s，1H，Ar-H)；4.47(m，2H，Ar-CH2)；3.86(s，3H，Ar-OCH3)；3.46(s，3H，ArSO2-CH3)；3.42(q，1H，J=11.01Hz，Ar-CH)；1.46(d，3H，J=7.14Hz，ArCH-CH3)；1.29(s，9H，R-C(CH3)3)。 1 H NMR (300 MHz, CDCl 3 ): δ 7.75 (s, 1H, Ar-H); 7.33 (m, 2H, Ar-H); 7.10 (s, 1H, Ar-H); 6.08 (s, 1H, Ar-H); 4.47 (m, 2H, Ar-CH 2 ); 3.86 (s, 3H, Ar-OCH 3 ); 3.46 (s, 3H, ArSO 2 -CH 3 ); 3.42 (q, 1H, J=11.01 Hz, Ar-CH); 1.46 (d, 3H, J = 7.14 Hz, ArCH-CH 3 ); 1.29 (s, 9H, RC(CH 3 ) 3 ).

可以類似方法製備實例28、29與實例162。 Examples 28, 29 and 162 can be prepared in a similar manner.

實例106之合成：Synthesis of Example 106:

1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(二甲胺基)-5-(三氟甲基)啶-3-基)尿素 1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(dimethylamino)-5- (trifluoromethyl)pyridin-3-yl)urea

步驟1：將溶於二甲基甲醯胺之2-氯-3-碘基-5-硝基吡啶(250毫克，0.88毫莫耳)、甲基2,2-二氟-2-(氟磺醯基)乙酸酯(0.06毫升，0.44毫莫耳)與碘化銅(I)(25毫克，0.13毫莫耳)混合物置放於一100毫升之圓底燒瓶中，於於氫氣氣氛下，將其於70℃加熱3小時。再添加0.03毫升之2,2-二氟-2-(氟磺醯基)乙酸酯，並將該混合物於70℃攪拌16小時。將該反應混合物冷卻至室溫，以水稀釋，並以醋酸乙酯萃取。將有機層於較低壓力下濃縮，以獲得粗製產物。以管柱色層分析法純化該粗製產物，以獲得2-氯-5-硝基-3-(三氟甲基)啶(41毫克，21%)。 Step 1: 2-Chloro-3-iodo-5-nitropyridine (250 mg, 0.88 mmol) dissolved in dimethylformamide, methyl 2,2-difluoro-2-(fluorine) A mixture of sulfonyl)acetate (0.06 mL, 0.44 mmol) and copper (I) iodide (25 mg, 0.13 mmol) was placed in a 100 mL round bottom flask under a hydrogen atmosphere. It was heated at 70 ° C for 3 hours. Further, 0.03 ml of 2,2-difluoro-2-(fluorosulfonyl)acetate was added, and the mixture was stirred at 70 ° C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water and ethyl acetate. The organic layer was concentrated under lower pressure to give a crude product. The crude product was purified by column chromatography to give 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (41 mg, 21%).

步驟2：將2-氯-5-硝基-3-(三氟甲基)啶(41毫克，0.18毫莫耳)、二甲胺鹽酸鹽(18毫克，0.22毫莫耳)、碳酸鉀(88毫克，0.63毫莫耳)及1,4,7,10,13,16-六氧雜環十八烷(10毫克)以乙腈溶解。使 該反應混合物回流12小時。將該反應混合物冷卻至室溫，隨後將其於較低壓力濃縮。以醋酸乙酯萃取該混合物，並以水清洗。將有機層於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得N,N-二甲基-5-硝基-3-(三氟甲基)啶-2-胺(36毫克，84%)。 Step 2: 2-Chloro-5-nitro-3-(trifluoromethyl)pyridine (41 mg, 0.18 mmol), dimethylamine hydrochloride (18 mg, 0.22 mmol), potassium carbonate (88 mg, 0.63 mmol) and 1,4,7,10,13,16-hexaoxacyclooctadecane (10 mg) were dissolved in acetonitrile. The reaction mixture was refluxed for 12 hours. The reaction mixture was cooled to room temperature and then concentrated at lower pressure. The mixture was extracted with ethyl acetate and washed with water. The organic layer was concentrated at lower pressure. The crude product was purified by column chromatography to give N,N-dimethyl-5-nitro-3-(trifluoromethyl)pyridin-2-amine (36 mg, 84%).

步驟3：將N,N-二甲基-5-硝基-3-(三氟甲基)啶-2-胺(200毫克，0.85毫莫耳)以甲醇溶解。於該混合物中添加10%之鈀碳(40毫克)。於氫氣氣氛下，將所產生之反應混合物於室溫攪拌1小時。以矽藻土床過濾該混合物，並將濾液於較低壓力濃縮，以獲得N2,N2-二甲基-3-(三氟甲基)啶-2,5-二胺(60毫克，34%)。 Step 3: N,N-Dimethyl-5-nitro-3-(trifluoromethyl)pyridine-2-amine (200 mg, 0.85 mmol) was dissolved in methanol. 10% palladium on carbon (40 mg) was added to the mixture. The resulting reaction mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The mixture was filtered through a pad of celite, and the filtrate was concentrated at lower pressure to afford N2,N2-dimethyl-3-(trifluoromethyl) pyridine-2,5-diamine (60 mg, 34% ).

步驟4：將N2,N2-二甲基-3-(三氟甲基)啶-2,5-二胺(60毫克，0.29毫莫耳)以乙腈溶解。於該反應混合物中分別添加啶(0.03毫升，0.35毫莫耳)及氯甲酸苯酯(0.04毫升，0.31毫莫耳)，將其於室溫攪拌1小時。以水稀釋該反應混合物，並以醋酸乙酯萃取。將有機層於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得苯基6-(二甲胺基)-5-(三氟甲基)啶-3-基胺甲酸酯(47毫克，49%)。 Step 4: N2,N2-Dimethyl-3-(trifluoromethyl)pyridine-2,5-diamine (60 mg, 0.29 mmol) was dissolved in acetonitrile. Pyridine (0.03 ml, 0.35 mmol) and phenyl chloroformate (0.04 ml, 0.31 mmol) were added to the mixture, which was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated at lower pressure. The crude product was purified by column chromatography to afford phenyl 6-(dimethylamino)-5-(trifluoromethyl)pyridin-3-ylcarbamate (47 mg, 49%).

步驟5：將苯基6-(二甲胺基)-5-(三氟甲基)啶-3-基胺甲酸酯(47毫克，0.14毫莫耳)與(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺(42毫克，0.15毫莫耳)以二甲亞碸溶解。隨後於該混合物中添加三乙胺(0.04毫升，0.29毫莫耳)。將該混合物於室溫攪拌過夜。將該反應混合物以水稀釋，並以醋酸乙酯萃取。將有機層於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(二甲胺基)-5-(三氟甲基)啶-3-基)尿素(實例化合物106)(52毫克，71%)。 Step 5: Phenyl 6-(dimethylamino)-5-(trifluoromethyl)pyridin-3-ylcarbamate (47 mg, 0.14 mmol) with (1-(3-chlorobenzene) 3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamine (42 mg, 0.15 mmol) was dissolved in dimethyl sulfoxide. Triethylamine (0.04 mL, 0.29 mmol) was then added to the mixture. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated at lower pressure. The crude product was purified by column chromatography to give 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3 -(6-(Dimethylamino)-5-(trifluoromethyl)pyridin-3-yl)urea (example compound 106) (52 mg, 71%).

1H核磁共振(300 MHz，CD3OD)：8.33(d，1H，J=2.58Hz，Ar-H)；8.07(d，1H，J=2.55Hz，Ar-H)；7.64(m，1H，Ar-H)； 7.57(m，3H，Ar-H)；6.77(s，1H，Ar-H)；4.48(s，2H，Ar-CH2)；2.85(s，6H，Ar-N(CH3)2)。 1 H NMR (300 MHz, CD 3 OD): 8.33 (d, 1H, J = 2.58 Hz, Ar-H); 8.07 (d, 1H, J = 2.55 Hz, Ar-H); 7.64 (m, 1H) , Ar-H); 7.57 (m, 3H, Ar-H); 6.77 (s, 1H, Ar-H); 4.48 (s, 2H, Ar-CH 2 ); 2.85 (s, 6H, Ar-N ( CH 3 ) 2 ).

實例107之合成：Synthesis of Example 107:

1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(二甲胺基)-5-(三氟甲基)啶-3-基)尿素 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(dimethylamino)-5-(three Fluoromethyl)pyridin-3-yl)urea

步驟1至4：如實例106之描述。 Steps 1 through 4: as described in Example 106.

步驟5：將苯基6-(二甲胺基)-5-(三氟甲基)啶-3-基胺甲酸酯(39毫克，0.12毫莫耳)及(3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺(34毫克，0.13毫莫耳)以二甲亞碸溶解。隨後添加三乙胺(0.03毫升，0.24毫莫耳)。將該混合物於室溫攪拌過夜。以水稀釋該混合物，並以醋酸乙酯萃取。將有機層於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(二甲胺基)-5-(三氟甲基)啶-3-基)尿素(實例 化合物107)(41毫克，69%)。 Step 5: Phenyl 6-(dimethylamino)-5-(trifluoromethyl)pyridin-3-ylamine formate (39 mg, 0.12 mmol) and (3-tri-butyl) 1-(3-Chlorophenyl)-1H-pyrazol-5-yl)methylamine (34 mg, 0.13 mmol) was dissolved in dimethyl sulfoxide. Triethylamine (0.03 mL, 0.24 mmol) was then added. The mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated at lower pressure. The crude product was purified by column chromatography to give 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-( 6-(Dimethylamino)-5-(trifluoromethyl)pyridin-3-yl)urea (example compound 107) (41 mg, 69%).

1H核磁共振(300 MHz，CD3OD)：δ 8.33(d，1H，J=2.73Hz，Ar-H)；8.08(d，1H，J=2.73Hz，Ar-H)；7.55(m，4H，Ar-H)；6.37(s，1H，Ar-H)；4.43(s，2H，Ar-CH2)；2.85(s，6H，Ar-N(CH3)2)；1.32(s，9H，Ar-C(CH3)3)。 1 H NMR (300 MHz, CD 3 OD): δ 8.33 (d, 1H, J = 2.73 Hz, Ar-H); 8.08 (d, 1H, J = 2.73 Hz, Ar-H); 7.55 (m, 4H, Ar-H); 6.37 (s, 1H, Ar-H); 4.43 (s, 2H, Ar-CH 2 ); 2.85 (s, 6H, Ar-N(CH 3 ) 2 ); 1.32 (s, 9H, Ar-C(CH 3 ) 3 ).

實例108之合成：Synthesis of Example 108:

1-(6-(氮雜環丁-1-基)啶-3-基)-3-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)尿素 1-(6-(azetidin-1-yl)pyridin-3-yl)-3-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazole-5- Methyl)urea

步驟1：將2-氯-5-硝基吡啶(300毫克，1.89毫莫耳)、氮雜環丁鹽酸鹽(212毫克，2.27毫莫耳)、碳酸鉀(915毫克，6.62毫莫耳)及1,4,7,10,13,16-六氧雜環十八烷(60毫克)以乙腈溶解。使該反應混合物回流過夜。將該反應混合物冷卻至室溫，隨後將其於較低壓力濃縮。以醋酸乙酯萃取該混合物，並以水清洗。將有機層於 較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得2-(氮雜環丁-1-基)-5-硝基吡啶(196毫克，58%)。 Step 1: 2-Chloro-5-nitropyridine (300 mg, 1.89 mmol), azetidin hydrochloride (212 mg, 2.27 mmol), potassium carbonate (915 mg, 6.62 mmol) And 1,4,7,10,13,16-hexaoxacyclooctadecane (60 mg) was dissolved in acetonitrile. The reaction mixture was refluxed overnight. The reaction mixture was cooled to room temperature and then concentrated at lower pressure. The mixture was extracted with ethyl acetate and washed with water. The organic layer was concentrated at lower pressure. The crude product was purified by column chromatography to give 2-(azetidin-1-yl)-5-nitropyridine (196 mg, 58%).

步驟2：將2-(氮雜環丁-1-基)-5-硝基吡啶(185毫克，1.03毫莫耳)以甲醇溶解。於該混合物中添加10%之鈀碳(37毫克)。於氫氣氣氛下，將以此產生之混合物於室溫攪拌1小時。將該混合物以矽藻土床過濾，並於較低壓力濃縮，以獲得6-(氮雜環丁-1-基)啶-3-胺(154毫克，99%)。 Step 2: 2-(Azetidin-1-yl)-5-nitropyridine (185 mg, 1.03 mmol) was dissolved in methanol. 10% palladium on carbon (37 mg) was added to the mixture. The mixture thus obtained was stirred at room temperature for 1 hour under a hydrogen atmosphere. The mixture was filtered through a pad of celite and concentrated at a reduced pressure to afford 6-(azetidin-l-yl)pyridin-3-amine (154 mg, 99%).

步驟3：將6-(氮雜環丁-1-基)啶-3-胺(154毫克，1.03毫莫耳)以乙腈溶解。於該反應混合物中分別添加啶(0.1毫升，1.24毫莫耳)及氯甲酸苯酯(0.14毫升，1.08毫莫耳)，並於室溫攪拌1小時。將該反應混合物以水稀釋，並以醋酸乙酯萃取。將有機層於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得苯基6-(氮雜環丁-1-基)啶-3-基胺甲酸酯(123毫克，44%)。 Step 3: 6-(Azetidin-1-yl)pyridine-3-amine (154 mg, 1.03 mmol) was dissolved in acetonitrile. Pyridine (0.1 ml, 1.24 mmol) and phenyl chloroformate (0.14 ml, 1.08 mmol) were added to the mixture and stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated at lower pressure. The crude product was purified by column chromatography to give phenyl 6-(azetidin-1-yl)pyridin-3-ylcarbamate (123 mg, 44%).

步驟4：將苯基6-(氮雜環丁-1-基)啶-3-基胺甲酸酯(60毫克，0.22毫莫耳)及(3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺(62毫克，0.23毫莫耳)以二甲亞碸溶解。隨後於該混合物中添加三乙胺(0.06毫升，0.45毫莫耳)。將該混合物於室溫攪拌過夜。將該混合物以水稀釋，並以醋酸乙酯萃取。將有機層於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得1-(6-(氮雜環丁-1-基)啶-3-基)-3-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)尿素(實例化合物108)(56毫克，57%)。 Step 4: Phenyl 6-(azetidin-1-yl)pyridin-3-ylcarbamate (60 mg, 0.22 mmol) and (3-tert-butyl-1-(3-) Chlorophenyl)-1H-pyrazol-5-yl)methylamine (62 mg, 0.23 mmol) was dissolved in dimethyl sulfoxide. Triethylamine (0.06 mL, 0.45 mmol) was then added to the mixture. The mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated at lower pressure. The crude product was purified by column chromatography to give 1-(6-(azetidin-1-yl)pyridin-3-yl)-3-((3-tert-butyl-1-(3) -Chlorophenyl)-1H-pyrazol-5-yl)methyl)urea (example compound 108) (56 mg, 57%).

1H核磁共振(300 MHz，CD3OD)：δ 7.94(d，1H，J=2.58Hz，Ar-H)；7.55(m，5H，Ar-H)；6.38(d，2H，J=7.14Hz，Ar-H)；4.40(s，2H，Ar-CH2)；4.00(m，4H，氮雜環丁-CH2)；2.42(m，2H，氮雜環丁-CH2)；1.32(s，9H，Ar-C(CH3)3)。 1 H NMR (300 MHz, CD 3 OD): δ 7.94 (d, 1H, J = 2.58 Hz, Ar-H); 7.55 (m, 5H, Ar-H); 6.38 (d, 2H, J = 7.14) Hz, Ar-H); 4.40 (s, 2H, Ar-CH 2 ); 4.00 (m, 4H, azetidin-CH 2 ); 2.42 (m, 2H, azetidin-CH 2 ); (s, 9H, Ar-C(CH 3 ) 3 ).

實例101係以類似方法製備而成。 Example 101 was prepared in a similar manner.

實例109之合成：Synthesis of Example 109:

1-(6-(氮雜環丁-1-基)啶-3-基)-3-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素 1-(6-(azetidin-1-yl)pyridin-3-yl)-3-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole- 5-based)methyl)urea

步驟1至3：如實例108之描述。 Steps 1 to 3: As described in Example 108.

步驟4：將苯基6-(氮雜環丁-1-基)啶-3-基胺甲酸酯(60毫克，0.22毫莫耳)及(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺(65毫克，0.23毫莫耳)以二甲亞碸溶解。隨後添加三乙胺(0.06毫升，0.45毫莫耳)。將該混合物於室溫攪拌過夜。以水稀釋該反應混合物，並以醋酸乙酯萃取。將有機層於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得1-(6-(氮雜環丁-1-基)啶-3-基)-3-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素(實例化合物109)(80毫克，80%)。 Step 4: Phenyl 6-(azetidin-1-yl)pyridin-3-ylcarbamate (60 mg, 0.22 mmol) and (1-(3-chlorophenyl)-3- (Trifluoromethyl)-1H-pyrazol-5-yl)methylamine (65 mg, 0.23 mmol) was dissolved in dimethyl sulfoxide. Triethylamine (0.06 mL, 0.45 mmol) was then added. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated at lower pressure. The crude product was purified by column chromatography to give 1-(6-(azetidin-1-yl)pyridin-3-yl)-3-((1-(3-chlorophenyl)-3) -(Trifluoromethyl)-1H-pyrazol-5-yl)methyl)urea (Example Compound 109) (80 mg, 80%).

1H核磁共振(300 MHz，CD3OD)：δ 7.94(d，1H，J=2.58Hz，Ar-H)；7.63(m，5H，Ar-H)；6.75(s，1H，Ar-H)；6.47(d，1H，J=8.79Hz，Ar-H)；4.45(s，2H，Ar-CH2)；4.00(m，4H，氮雜環丁-CH2)；2.42(m，2H，氮雜環丁-CH2)。 1 H NMR (300 MHz, CD 3 OD): δ 7.94 (d, 1H, J = 2.58 Hz, Ar-H); 7.63 (m, 5H, Ar-H); 6.75 (s, 1H, Ar-H) 6.47 (d, 1H, J = 8.79 Hz, Ar-H); 4.45 (s, 2H, Ar-CH 2 ); 4.00 (m, 4H, azetidin-CH 2 ); 2.42 (m, 2H) , azetidin-CH 2 ).

實例111之合成：Synthesis of Example 111:

1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(3-羥基氮雜環丁-1-基)啶-3-基)尿素 1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(3-hydroxyazetidine- 1-yl)pyridin-3-yl)urea

步驟1：於一經冷卻、溶於二甲基甲醯胺(7毫升)之2-氯-5-硝基吡啶(554毫克，3.50毫莫耳，1等量)及3-羥基氮雜環丁二烯氯(3-hydroxyazetidinium chloride)(459毫克，4.20毫莫耳，1.2等量)溶液中添加1.46毫升之三乙胺，將該混合物攪拌30分鐘後，以薄層層析法判斷反應是否已完成。將溶媒蒸發，以25毫升之水懸浮殘留物，並以醋酸乙酯萃取(3 x 25毫升)。將有機層合併，並以水(2 x 25毫升)及飽和之氯化鈉溶液(1 x 25毫升)清洗，以硫酸鎂乾 燥。將溶媒蒸發，並以管柱色層分析法(矽膠，以醋酸乙酯/正己烷1/2體積/體積比做為溶析液)純化殘留物，以獲得黃色固體狀之1-(5-硝基吡啶-2-基)氮雜環丁-3-醇(572毫克，84%)。 Step 1: 2-Chloro-5-nitropyridine (554 mg, 3.50 mmol, 1 equivalent) and 3-hydroxyazetidine dissolved in dimethylformamide (7 mL) upon cooling Add 1.46 ml of triethylamine to a solution of 3-hydroxyazetidinium chloride (459 mg, 4.20 mmol, 1.2 equivalent), stir the mixture for 30 minutes, and judge whether the reaction has been determined by thin layer chromatography. carry out. The solvent was evaporated, and the residue was crystallised eluted eluted eluted The organic layers were combined and washed with water (2×25 mL) and sat. The solvent was evaporated, and the residue was purified by column chromatography (yield eluted with ethyl acetate / n-hexane 1/2 volume / volume ratio) to obtain 1-(5- Nitropyridin-2-yl)azetidin-3-ol (572 mg, 84%).

步驟2：將1-(5-硝基吡啶-2-基)氮雜環丁-3-醇(570毫克，2.92毫莫耳，1等量)以乙醇(30毫升)溶解，並以10%之鈀碳將其於一氫氣立方體進行氫化(10巴之氫氣，1毫升/分鐘)。將該混合物蒸發，以獲得1-(5-胺基吡啶-2-基)氮雜環丁-3-醇(480毫克)，該產物不需進一步純化即可使用。 Step 2: Dissolve 1-(5-nitropyridin-2-yl)azetidin-3-ol (570 mg, 2.92 mmol, 1 equivalent) in ethanol (30 mL) with 10% The palladium on carbon was hydrogenated in a hydrogen cube (10 bar of hydrogen, 1 ml/min). The mixture was evaporated to give 1-(5-aminopyridin-2-yl)azetidin-3-ol (480 mg), which was used without further purification.

步驟3：於一經攪拌、溶於二氯甲烷(14毫升)之(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺(551毫克，2.00毫莫耳，1等量)溶液中添加氯甲酸苯酯(285 μL，2.24毫莫耳，1.12等量)及三乙胺(333 μL，2.4毫莫耳，1.2等量)，並將其於室溫攪拌過夜。以碳酸鈉(c=1莫耳/L，1x 20毫升)清洗該反應混合物，以二氯甲烷(2 x 10毫升)萃取水層，並以硫酸鎂將有機層乾燥。將溶媒蒸發，並以管柱色層分析法(矽膠，以醋酸乙酯/正己烷(1/4體積/體積比)做為溶析液)純化殘留物，以獲得2-(5-胺基吡啶-2-基氧基)乙醇，以獲得苯基(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)氨基甲酸甲酯(352毫克，44%)。 Step 3: (1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamine (551) was dissolved in dichloromethane (14 mL). mM, 2.00 mmol, 1 equivalent) of phenyl chloroformate (285 μL, 2.24 mmol, 1.12 equivalent) and triethylamine (333 μL, 2.4 mmol, 1.2 equivalent), and It was stirred at room temperature overnight. The reaction mixture was washed with EtOAc (EtOAc (EtOAc) The solvent was evaporated, and the residue was purified by column chromatography (yield, ethyl acetate / n-hexane (1/4 volume / volume ratio) as a solvent) to obtain 2-(5-amino group) Pyridin-2-yloxy)ethanol to obtain methyl phenyl(1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)carbamate (352 mg , 44%).

步驟4：於一經攪拌、溶於乙腈(6毫升)之苯基(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)氨基甲酸甲酯(87毫克，0.22毫莫耳，1.0等量)溶液中，依序添加三乙胺(90 μL，0.66毫莫耳，3.0等量)及1-(5-胺基吡啶-2-基)氮雜環丁-3-醇(38毫克，0.24毫莫耳，1.02等量)，並將其回流攪拌16小時。將該反應混合物於真空狀態濃縮，並將殘留物純化(管柱色層分析法，矽膠，以6/1體積/體積比之醋酸乙酯/甲醇做為溶析液)，以獲得1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(3-羥基氮雜環丁-1-基)啶-3-基) 尿素(實例化合物111)(56毫克，55%)。 Step 4: Phenyl (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)carbamate, dissolved in acetonitrile (6 mL) (87 mg, 0.22 mmol, 1.0 equivalent) of the solution, followed by the addition of triethylamine (90 μL, 0.66 mmol, 3.0 equivalent) and 1-(5-aminopyridin-2-yl) nitrogen Heterocyclic butan-3-ol (38 mg, 0.24 mmol, 1.02 equivalent) was stirred at reflux for 16 h. The reaction mixture was concentrated under vacuum, and the residue was purified (column chromatography, silica gel, eluted with ethyl acetate/methanol at a volume ratio of 6/1) to obtain 1-( (1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(3-hydroxyazetidin-1-yl) Pyridin-3-yl) Urea (Example Compound 111) (56 mg, 55%).

實例110、112至115及117係以類似方法製備而成。可以類似方法製備實例116及118至119。 Examples 110, 112 through 115, and 117 were prepared in a similar manner. Examples 116 and 118 to 119 can be prepared in a similar manner.

實例120之合成：Synthesis of Example 120:

1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(咯啶-1-基)啶-3-基)尿素 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(rhodin-1-yl)pyridin-3 -base) urea

步驟1：將2-氯-5-硝基吡啶(300毫克，1.89毫莫耳)、咯啶(0.19毫升，2.27毫莫耳)、碳酸鉀(785毫克，5.68毫莫耳)及1,4,7,10,13,16-六氧雜環十八烷(60毫克)以乙腈溶解。將該反應混合物回流過夜；之後，將該反應混合物冷卻至室溫，並較低壓力將其濃縮。以醋酸乙酯萃取該混合物，並以水清洗。將有機層於較低壓力濃縮。 以管柱色層分析法純化粗製產物，以獲得5-硝基-2-(咯啶-1-基)啶(317毫克，87%)。 Step 1: 2-Chloro-5-nitropyridine (300 mg, 1.89 mmol), pyridine (0.19 mL, 2.27 mmol), potassium carbonate (785 mg, 5.68 mmol) and 1,4 7,10,13,16-hexaoxacyclooctadecane (60 mg) was dissolved in acetonitrile. The reaction mixture was refluxed overnight; after that, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The mixture was extracted with ethyl acetate and washed with water. The organic layer was concentrated at lower pressure. The crude product was purified by column chromatography to afford 5-nitro-2-(l-l-l-l-yl)pyridine (317 mg, 87%).

步驟2：將5-硝基-2-(咯啶-1-基)啶(317毫克，1.65毫莫耳)以甲醇溶解，並添加10%之鈀碳(64毫克)。於氫氣氣氛下，將產生之混合物於室溫攪拌1小時。將該混合物以矽藻土床過濾，並將濾液於較低壓力濃縮，以獲得6-(咯啶-1-基)啶-3-胺(261毫克，97%)。 Step 2: 5-Nitro-2-(l-pyridin-1-yl)pyridine (317 mg, 1.65 mmol) was dissolved in methanol and 10% palladium carbon (64 mg) was added. The resulting mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The mixture was filtered over a pad of celite, and the filtrate was concentrated at a lower pressure to afford 6-(bryridin-1-yl)pyridin-3-amine (261 mg, 97%).

步驟3：將6-(咯啶-1-基)啶-3-胺(261毫克，1.6毫莫耳)以乙腈溶解。於該反應混合物中分別添加啶(0.16毫升，1.92毫莫耳)及氯甲酸苯酯(0.21毫升，1.68毫莫耳)，並於室溫攪拌1小時。以水稀釋該反應混合物，並以醋酸乙酯萃取。將有機層於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得苯基6-(咯啶-1-基)啶-3-基胺甲酸酯(218毫克，48%)。 Step 3: 6-(Bryn-1-yl)pyridin-3-amine (261 mg, 1.6 mmol) was dissolved in acetonitrile. Pyridine (0.16 ml, 1.92 mmol) and phenyl chloroformate (0.21 ml, 1.68 mmol) were added to the mixture and stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated at lower pressure. The crude product was purified by column chromatography to give phenyl 6-(bryridin-1-yl)pyridin-3-ylcarbamate (218 mg, 48%).

步驟4：將苯基6-(咯啶-1-基)啶-3-基胺甲酸酯(70毫克，0.25毫莫耳)及(3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺(69毫克，0.26毫莫耳)以二甲亞碸溶解。隨後於該混合物中添加三乙胺(0.07毫升，0.49毫莫耳)。將該混合物於室溫攪拌過夜。以水稀釋該反應混合物，並以醋酸乙酯萃取。將有機層於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(咯啶-1-基)啶-3-基)尿素(實例化合物120)(99毫克，88%)。 Step 4: Phenyl 6-(rhodin-1-yl)pyridin-3-ylcarbamate (70 mg, 0.25 mmol) and (3-tert-butyl-1-(3-chlorobenzene) The base-1H-pyrazol-5-yl)methylamine (69 mg, 0.26 mmol) was dissolved in dimethyl sulfoxide. Triethylamine (0.07 mL, 0.49 mmol) was then added to the mixture. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated at lower pressure. The crude product was purified by column chromatography to give 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-( 6-(Lyridine-1-yl)pyridin-3-yl)urea (example compound 120) (99 mg, 88%).

1H核磁共振(300 MHz，CD3OD)：δ 7.92(d，1H，J=2.37Hz，Ar-H)；7.56(m，5H，Ar-H)；6.47(d，1H，J=8.97Hz，Ar-H)；6.35(s，1H，Ar-H)；4.40(s，2H，Ar-CH2)；3.42(m，4H，咯啶-CH2)；2.04(m，4H，咯啶-CH2)；1.32(s，9H，Ar-C(CH3)3)。 1 H NMR (300 MHz, CD 3 OD): δ 7.92 (d, 1H, J = 2.37 Hz, Ar-H); 7.56 (m, 5H, Ar-H); 6.47 (d, 1H, J = 8.97) Hz, Ar-H); 6.35 (s, 1H, Ar-H); 4.40 (s, 2H, Ar-CH 2 ); 3.42 (m, 4H, pyridin-CH 2 ); 2.04 (m, 4H, pyridine-CH 2 ); 1.32 (s, 9H, Ar-C(CH 3 ) 3 ).

實例121之合成：Synthesis of Example 121:

1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(咯啶-1-基)啶-3-基)尿素 1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(rhodin-1-yl)pyridine -3-yl) urea

步驟1至3：如實例120之描述。 Steps 1 to 3: As described in Example 120.

步驟4：將苯基6-(咯啶-1-基)啶-3-基胺甲酸酯(70毫克，0.25毫莫耳)及(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺(72毫克，0.26毫莫耳)以二甲亞碸溶解，隨後於該混合物中添加三乙胺(0.07毫升，0.49毫莫耳)。將該混合物於室溫攪拌過夜。以水稀釋該反應混合物，並以醋酸乙酯萃取。將有機層於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(咯啶-1-基)啶-3-基)尿素(實例化合物121)(114毫克，99%)。 Step 4: Phenyl 6-(rhodin-1-yl)pyridin-3-ylcarbamate (70 mg, 0.25 mmol) and (1-(3-chlorophenyl)-3-(3) Fluoromethyl)-1H-pyrazol-5-yl)methylamine (72 mg, 0.26 mmol) was dissolved in dimethyl sulfoxide, followed by the addition of triethylamine (0.07 mL, 0.49 mmol). . The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated at lower pressure. The crude product was purified by column chromatography to give -((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3- (6-(Chlorin-1-yl)pyridin-3-yl)urea (example compound 121) (114 mg, 99%).

1H核磁共振(300 MHz，CD3OD)：δ 7.91(d，1H，J=2.19Hz，Ar-H)；7.63(s，1H，Ar-H)；7.57(m，4H，Ar-H)；6.74(s，1H， Ar-H)；6.47(d，1H，J=8.61Hz，Ar-H)；4.45(s，2H，Ar-CH2)；3.42(m，4H，咯啶-CH2)；2.03(m，4H，咯啶-CH2)。 1 H NMR (300 MHz, CD 3 OD): δ 7.91 (d, 1H, J = 2.19 Hz, Ar-H); 7.63 (s, 1H, Ar-H); 7.57 (m, 4H, Ar-H) 6.74 (s, 1H, Ar-H); 6.47 (d, 1H, J = 8.61 Hz, Ar-H); 4.45 (s, 2H, Ar-CH 2 ); 3.42 (m, 4H, pyridinium) CH 2 ); 2.03 (m, 4H, pyridin-CH 2 ).

可以類似分法製備實例122。 Example 122 can be prepared in a similar manner.

實例123之合成：Synthesis of Example 123:

1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(5-甲氧基-6-(咯啶-1-基)啶-3-基)尿素 1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(5-methoxy-6-(r-pyridine) -1-yl)pyridin-3-yl)urea

步驟1：於0℃，於一以硫酸(7.4毫升)溶解之3-甲氧啶-2-醇(925毫克，7.39毫莫耳)溶液中，緩慢地添加硝酸(60%)(0.64毫升，11.09毫莫耳)。添加硝酸後，將該反應混合物以40℃加熱3小時。 將該反應混合物冷卻至室溫，隨後添加碎冰。攪拌30分鐘後，將該溶液過濾，以獲得3-甲氧基-5-硝基吡啶-2-醇(1.043公克，83%)。 Step 1: slowly add nitric acid (60%) (0.64 ml, in a solution of 3-methoxy-2-ol (925 mg, 7.39 mmol) dissolved in sulfuric acid (7.4 mL) at 0 °C. 11.09 millimoles). After the addition of nitric acid, the reaction mixture was heated at 40 ° C for 3 hours. The reaction mixture was cooled to room temperature and then crushed ice was added. After stirring for 30 minutes, the solution was filtered to give 3-methoxy-5-nitropyridin-2-ol (1.043 g, 83%).

步驟2：將3-甲氧基-5-硝基吡啶-2-醇(1.043公克，6.13毫莫耳)及五氯化磷(0.638公克，3.07毫莫耳)以氯化磷醯(1.71毫升)溶解。將該反應混合物回流4小時。之後，將其冷卻至室溫，將該反應混合物倒入碎冰中，並攪拌30分鐘。隨後以碳酸鈉將該混合物鹼化至pH 7，再以醋酸乙酯萃取該溶液。將有機層於較低壓力濃縮，以獲得粗製產物。以管柱色層分析法將其純化，以獲得2-氯-3-甲氧基-5-硝基吡啶(920毫克，80%)。 Step 2: 3-methoxy-5-nitropyridin-2-ol (1.043 g, 6.13 mmol) and phosphorus pentachloride (0.638 g, 3.07 mmol) as phosphine chloride (1.71 ml) ) Dissolved. The reaction mixture was refluxed for 4 hours. Thereafter, it was cooled to room temperature, and the reaction mixture was poured into crushed ice and stirred for 30 minutes. The mixture was then basified to pH 7 with sodium carbonate and the solution was extracted with ethyl acetate. The organic layer was concentrated at a lower pressure to give a crude product. This was purified by column chromatography to give 2-chloro-3-methoxy-5-nitropyridine (920 mg, 80%).

步驟3：將2-氯-3-甲氧基-5-硝基吡啶(400毫克，2.12毫莫耳)、咯啶(0.21毫升，2.55毫莫耳)、碳酸鉀(880毫克，6.38毫莫耳)及1,4,7,10,13,16-六氧雜環十八烷(80毫克)以乙腈溶解。將該反應混合物回流過夜。將該反應混合物冷卻至室溫，隨後於較低壓力濃縮。再以醋酸乙酯萃取該混合物，並以水清洗。將有機層於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得3-甲氧基-5-硝基-2-(咯啶-1-基)啶(458毫克，97%)。 Step 3: 2-Chloro-3-methoxy-5-nitropyridine (400 mg, 2.12 mmol), pyridine (0.21 mL, 2.55 mmol), potassium carbonate (880 mg, 6.38 mmol) The ear) and 1,4,7,10,13,16-hexaoxacyclooctadecane (80 mg) were dissolved in acetonitrile. The reaction mixture was refluxed overnight. The reaction mixture was cooled to room temperature and then concentrated at lower pressure. The mixture was extracted with ethyl acetate and washed with water. The organic layer was concentrated at lower pressure. The crude product was purified by column chromatography to give 3-methoxy-5-nitro-2-(l-pyridin-1-yl)pyridine (458 mg, 97%).

步驟4：將3-甲氧基-5-硝基-2-(咯啶-1-基)啶(458毫克，2.05毫莫耳)以甲醇溶解，並添加10%之鈀碳(92毫克)。於氫氣氣氛下，將以此產生之混合物於室溫攪拌1小時。以矽藻土純過濾該混合物，並將濾液於較低壓力濃縮，以獲得5-甲氧基-6-(咯啶-1-基)啶-3-胺(396毫克，99%)。 Step 4: Dissolve 3-methoxy-5-nitro-2-(l-pyridin-1-yl)pyridine (458 mg, 2.05 mmol) in methanol and add 10% palladium on carbon (92 mg) . The mixture thus obtained was stirred at room temperature for 1 hour under a hydrogen atmosphere. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to afford 5-methoxy-6-(- </RTI><RTIgt;

步驟5：將5-甲氧基-6-(咯啶-1-基)啶-3-胺(396毫克，2.05毫莫耳)以乙腈溶解。於該反應混合物中分別添加啶(0.20毫升，2.46毫莫耳)及氯甲酸苯酯(0.27毫升，2.15毫莫耳)，並將其於室溫攪拌1小時。以水稀釋該反應混合物，並以醋酸乙酯萃取。將有機層於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得苯 基5-甲氧基-6-(咯啶-1-基)啶-3-基胺甲酸酯(364毫克，57%)。 Step 5: 5-Methoxy-6-(rhodin-1-yl)pyridin-3-amine (396 mg, 2.05 mmol) was dissolved in acetonitrile. Pyridine (0.20 ml, 2.46 mmol) and phenyl chloroformate (0.27 ml, 2.15 mmol) were added to the mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated at lower pressure. The crude product was purified by column chromatography to afford phenyl 5-methoxy-6-(l- </RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt;

步驟6：將苯基5-甲氧基-6-(咯啶-1-基)啶-3-基胺甲酸酯(186毫克，0.59毫莫耳)及(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺(172毫克，0.62毫莫耳)以二甲亞碸溶解。隨後於該混合物中添加三乙胺(0.17毫升，1.19毫莫耳)。將該混合物於室溫攪拌過夜。以水稀釋該反應混合物，並以醋酸乙酯萃取。將有機層於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(5-甲氧基-6-(咯啶-1-基)啶-3-基)尿素(實例化合物123)(186毫克，63%)。 Step 6: Phenyl 5-methoxy-6-(l-pyridin-1-yl)pyridin-3-ylcarbamate (186 mg, 0.59 mmol) and (1-(3-chlorophenyl) -3-(Trifluoromethyl)-1H-pyrazol-5-yl)methylamine (172 mg, 0.62 mmol) was dissolved in dimethyl sulfoxide. Triethylamine (0.17 mL, 1.19 mmol) was then added to the mixture. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated at lower pressure. The crude product was purified by column chromatography to give 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3 -(5-Methoxy-6-(rhodin-1-yl)pyridin-3-yl)urea (example compound 123) (186 mg, 63%).

1H核磁共振(300 MHz，CD3OD)：δ 7.63(s，1H，Ar-H)；7.56(m，4H，Ar-H)；7.24(s，1H，Ar-H)；6.75(s，1H，Ar-H)；4.45(s，2H，Ar-CH2)；3.78(s，3H，Ar-OCH3)；3.53(m，4H，咯啶-CH2)；1.90(m，4H，咯啶-CH2)。 1 H NMR (300 MHz, CD 3 OD): δ 7.63 (s, 1H, Ar-H); 7.56 (m, 4H, Ar-H); 7.24 (s, 1H, Ar-H); 6.75 (s , 1H, Ar-H); 4.45 (s, 2H, Ar-CH 2 ); 3.78 (s, 3H, Ar-OCH 3 ); 3.53 (m, 4H, pyridin-CH 2 ); 1.90 (m, 4H) , ralidine-CH 2 ).

實例124之合成：Synthesis of Example 124:

(R)-1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(3-羥咯啶-1-基)啶-3-基)尿素 (R)-1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(3-hydroxyl) Pyridin-1-yl)pyridin-3-yl)urea

步驟1：將2-氯-5-硝基吡啶(365毫克，2.30毫莫耳)、(R)-3-咯啶烷醇(241毫克，2.76毫莫耳)、碳酸鉀(955毫克，6.91毫莫耳)及1,4,7,10,13,16-六氧雜環十八烷(73毫克)以乙腈溶解。將該反應混合物回流過夜。將該反應混合物冷卻至室溫，並於較低壓力將其濃縮。隨後，以醋酸乙酯萃取該混合物，並以水清洗。將有機層於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得(R)-1-(5-硝基吡啶-2-基)咯啶-3-醇(452毫克，94%)。 Step 1: 2-Chloro-5-nitropyridine (365 mg, 2.30 mmol), (R)-3-rrolidine (241 mg, 2.76 mmol), potassium carbonate (955 mg, 6.91) Millol) and 1,4,7,10,13,16-hexaoxacyclooctadecane (73 mg) were dissolved in acetonitrile. The reaction mixture was refluxed overnight. The reaction mixture was cooled to room temperature and concentrated at a lower pressure. Subsequently, the mixture was extracted with ethyl acetate and washed with water. The organic layer was concentrated at lower pressure. The crude product was purified by column chromatography to give (R)-l-(5-nitropyridin-2-yl)-l-pyridin-3-ol (452 mg, 94%).

步驟2：將(R)-1-(5-硝基吡啶-2-基)咯啶-3-醇(452毫克，2.16 毫莫耳)以甲醇溶解，並添加10%之鈀碳(91毫克)。於氫氣氣氛下，將該反應混合物於室溫攪拌1小時。以矽藻土醇過濾該混合物，並於較低壓力濃縮濾液，以獲得(R)-1-(5-胺基吡啶-2-基)咯啶-3-醇(386毫克，99%)。 Step 2: Dissolve (R)-1-(5-nitropyridin-2-yl)rrolidine-3-ol (452 mg, 2.16 mmol) in methanol and add 10% palladium on carbon (91 mg) ). The reaction mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The mixture was filtered with celite, and the filtrate was concentrated at a lower pressure to afford (R)-l-(5-aminopyridin-2-yl)-l-pyridin-3-ol (386 mg, 99%).

步驟3：將(R)-1-(5-胺基吡啶-2-基)咯啶-3-醇(386毫克，2.16毫莫耳)以乙腈溶解。於該反應混合物中分別添加啶(0.21毫升，2.59毫莫耳)及氯甲酸苯酯(0.29毫升，2.26毫莫耳)，並將其於室溫攪拌1小時。以水稀釋該反應混合物，並以醋酸乙酯萃取。將有機層於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得(R)-苯基6-(3-羥基咯啶-1-基)啶-3-基胺甲酸酯(125毫克，19%)。 Step 3: (R)-1-(5-Aminopyridin-2-yl)pyridin-3-ol (386 mg, 2.16 mmol) was dissolved in acetonitrile. Pyridine (0.21 ml, 2.59 mmol) and phenyl chloroformate (0.29 ml, 2.26 mmol) were added to the mixture and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated at lower pressure. The crude product was purified by column chromatography to give (R)-phenyl 6-(3-hydroxyl-l-l-yl)pyridin-3-ylcarbamate (125 mg, 19%).

步驟4：將(R)-苯基6-(3-羥基咯啶-1-基)啶-3-基胺甲酸酯(60毫克，0.20毫莫耳)及(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺(58毫克，0.21毫莫耳)以二甲亞碸溶解。隨後於該混合物中添加三乙胺(0.06毫升，0.40毫莫耳)。將該混合物於室溫攪拌過夜。以水稀釋該反應混合物，並以醋酸乙酯萃取。將有機層於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得(R)-1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(3-羥基咯啶-1-基)啶-3-基)尿素(實例化合物124)(186毫克，64%)。 Step 4: (R)-Phenyl 6-(3-hydroxyrheptan-1-yl)pyridin-3-ylcarbamate (60 mg, 0.20 mmol) and (1-(3-chlorobenzene) 3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamine (58 mg, 0.21 mmol) was dissolved in dimethyl sulfoxide. Triethylamine (0.06 mL, 0.40 mmol) was then added to the mixture. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated at lower pressure. The crude product was purified by column chromatography to give (R)-1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl) 3-(6-(3-Hydroxypyridin-1-yl)pyridin-3-yl)urea (example compound 124) (186 mg, 64%).

1H核磁共振(300 MHz，CD3OD)：δ 7.92(d，1H，J=1.77Hz，Ar-H)；7.62(s，1H，Ar-H)；7.56(m，4H，Ar-H)；6.74(s，1H，Ar-H)；6.47(d，1H，J=6.75Hz，Ar-H)；4.50(m，1H，咯啶烷醇-CH)；4.44(s，2H，Ar-CH2)；3.56(m，4H，咯啶烷醇-CH2)；2.17(m，2H，咯啶烷醇-CH2)。 1 H NMR (300 MHz, CD 3 OD): δ 7.92 (d, 1H, J = 1.77 Hz, Ar-H); 7.62 (s, 1H, Ar-H); 7.56 (m, 4H, Ar-H) 6.74 (s, 1H, Ar-H); 6.47 (d, 1H, J = 6.75 Hz, Ar-H); 4.50 (m, 1H, pyridinol-CH); 4.44 (s, 2H, Ar) -CH 2 ); 3.56 (m, 4H, pyridinol-CH 2 ); 2.17 (m, 2H, pyridinol-CH 2 ).

實例125之合成：Synthesis of Example 125:

(S)-1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(3-羥基咯啶-1-基)啶-3-基)尿素 (S)-1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(3-hydroxy) Pyridin-1-yl)pyridin-3-yl)urea

步驟1：將2-氯-5-硝基吡啶(459毫克，2.90毫莫耳)、(S)-3-咯啶烷醇(303毫克，3.48毫莫耳)、碳酸鉀(1.202公克，8.70毫莫耳)及1,4,7,10,13,16-六氧雜環十八烷(92毫克)以乙腈溶解。將該反應混合物回流過夜。將該反應混合物冷卻至室溫，並於較低壓力濃縮。隨後以醋酸乙酯萃取該混合物，並以水清洗。將有機層於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得(S)-1-(5-硝基吡啶-2-基)咯啶-3-醇(574毫克，95%)。 Step 1: 2-Chloro-5-nitropyridine (459 mg, 2.90 mmol), (S)-3-rrolidine (303 mg, 3.48 mmol), potassium carbonate (1.202 g, 8.70) Millol) and 1,4,7,10,13,16-hexaoxacyclooctadecane (92 mg) were dissolved in acetonitrile. The reaction mixture was refluxed overnight. The reaction mixture was cooled to room temperature and concentrated at lower pressure. The mixture was then extracted with ethyl acetate and washed with water. The organic layer was concentrated at lower pressure. The crude product was purified by column chromatography to give (S)-l-(5-nitropyridin-2-yl)-l-pyridin-3-ol (574 mg, 95%).

步驟2：將(S)-1-(5-硝基吡啶-2-基)咯啶-3-醇(574毫克，2.74 毫莫耳)以甲醇溶解，並添加10%之鈀碳(115毫克)。於氫氣氣氛下，將所得之混合物於室溫攪拌1小時。以矽藻土醇過濾該混合物，並於較低壓力將其濃縮，以獲得(S)-1-(5-胺基吡啶-2-基)咯啶-3-醇(491毫克，99%)。 Step 2: Dissolve (S)-1-(5-nitropyridin-2-yl)pyridin-3-ol (574 mg, 2.74 mmol) in methanol and add 10% palladium on carbon (115 mg) ). The resulting mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The mixture was filtered over celite and concentrated at a reduced pressure to afford (S)-l-(5-aminopyridin-2-yl)-l-pyridin-3-ol (491 mg, 99%) .

步驟3：將(S)-1-(5-胺基吡啶-2-基)咯啶-3-醇(491毫克，2.74毫莫耳)以乙腈溶解。於該反應混合物中分別添加啶(0.27毫升，3.29毫莫耳)及氯甲酸苯酯(0.36毫升，2.88毫莫耳)，並將其於室溫攪拌1小時。以水稀釋該反應混合物，並以醋酸乙酯萃取。將有機層於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得(S)-苯基6-(3-羥基咯啶-1-基)啶-3-基胺甲酸酯(274毫克，33%)。 Step 3: (S)-1-(5-Aminopyridin-2-yl)pyridin-3-ol (491 mg, 2.74 mmol) was dissolved in acetonitrile. Pyridine (0.27 ml, 3.29 mmol) and phenyl chloroformate (0.36 ml, 2.88 mmol) were added to the mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated at lower pressure. The crude product was purified by column chromatography to give (S)-phenyl 6-(3-hydroxy-l-l-l-yl)pyridin-3-ylcarbamate (274 mg, 33%).

步驟4：將(S)-苯基6-(3-羥基咯啶-1-基)啶-3-基胺甲酸酯(138毫克，0.46毫莫耳)及(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺(133毫克，0.48毫莫耳)以二甲亞碸溶解。隨後於該混合物中添加三乙胺(0.13毫升，0.92毫莫耳)。將該混合物於室溫攪拌過夜。以水稀釋該反應混合物，並以醋酸乙酯萃取。將有機層於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得(S)-1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(3-羥基咯啶-1-基)啶-3-基)尿素(實例化合物125)(157毫克，71%)。 Step 4: (S)-Phenyl 6-(3-hydroxyrheptan-1-yl)pyridin-3-ylcarbamate (138 mg, 0.46 mmol) and (1-(3-chlorobenzene) 3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamine (133 mg, 0.48 mmol) was dissolved in dimethyl sulfoxide. Triethylamine (0.13 mL, 0.92 mmol) was then added to the mixture. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated at lower pressure. The crude product was purified by column chromatography to give (S)-1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl). 3-(6-(3-Hydroxypyridin-1-yl)pyridin-3-yl)urea (example compound 125) (157 mg, 71%).

1H核磁共振(300 MHz，CD3OD)：δ 7.93(d，1H，J=2.4Hz，Ar-H)；7.63(m，1H，Ar-H)；7.57(m，4H，Ar-H)；6.75(s，1H，Ar-H)；6.49(d，1H，J=9.3Hz，Ar-H)；4.51(m，1H，咯啶烷醇-CH)；4.45(s，2H，Ar-CH2)；3.59(m，4H，咯啶烷醇-CH2)；2.15(m，2H，咯啶烷醇-CH2)。 1 H NMR (300 MHz, CD 3 OD): δ 7.93 (d, 1H, J = 2.4 Hz, Ar-H); 7.63 (m, 1H, Ar-H); 7.57 (m, 4H, Ar-H) 6.75 (s, 1H, Ar-H); 6.49 (d, 1H, J = 9.3 Hz, Ar-H); 4.51 (m, 1H, pyridinol-CH); 4.45 (s, 2H, Ar) -CH 2 ); 3.59 (m, 4H, pyridinol-CH 2 ); 2.15 (m, 2H, pyridinol-CH 2 ).

實例131之合成：Synthesis of Example 131:

1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(2-甲氧基乙氧基)啶-3-基)尿素 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-methoxyethoxy)pyridine -3-yl) urea

步驟1：將2-氯-5-硝基吡啶(5.00公克，31.6毫莫耳，1等量)及2-甲氧基乙醇(2.52公克，33.1毫莫耳，1.05等量)以二甲基甲醯胺(32毫升)溶解，並將其冷卻至0℃。於該混合物中分次添加氫化鈉(60%(重量/重量比)於礦物油中，1.30毫克，32.5毫莫耳，1.03等量)，並使其回溫至室溫過夜。反應完成後(薄層層析法)，添加醋酸(5毫升)，並將溶媒蒸發。將殘留物懸浮於二乙醚(100毫升)中，並將其過濾。將過濾塊以二氯甲烷(2 x 50毫升)清洗，將濾液蒸發，並以管柱色層分析法(矽膠，以1/4體積/體積比之醋酸乙酯/正己烷做為溶析液)將其純化，以獲得黃色固體狀之2-(2-甲氧基乙氧基)-5-硝基吡啶(3.96公克，63%)。 Step 1: 2-Chloro-5-nitropyridine (5.00 g, 31.6 mmol, 1 equivalent) and 2-methoxyethanol (2.52 g, 33.1 mmol, 1.05 equivalent) as dimethyl Formamidine (32 ml) was dissolved and allowed to cool to 0 °C. Sodium hydride (60% (w/w ratio) in mineral oil, 1.30 mg, 32.5 mmol, 1.03 equivalent) was added portionwise to the mixture and allowed to warm to room temperature overnight. After completion of the reaction (thin layer chromatography), acetic acid (5 ml) was added, and the solvent was evaporated. The residue was suspended in diethyl ether (100 mL) and filtered. The filter block was washed with dichloromethane (2 x 50 ml), and the filtrate was evaporated and analyzed by column chromatography (tank, 1/4 volume/volume ratio of ethyl acetate/n-hexane). It was purified to give 2-(2-methoxyethoxy)-5-nitropyridine (3.96 g, 63%) as a yellow solid.

步驟2：將2-(2-甲氧基乙氧基)-5-硝基吡啶(3.95公克，19.9毫莫耳，1等量)以乙醇(180毫升)溶解，並以10%之鈀碳將其於氫氣立方體氫化。將該混合物蒸發，以獲得無色固體狀之6-(2-甲氧基乙氧基)啶-3-胺(3.30毫克，98%)，該產物不需進一步醇化即可使用。 Step 2: Dissolve 2-(2-methoxyethoxy)-5-nitropyridine (3.95 g, 19.9 mmol, 1 equivalent) in ethanol (180 mL) with 10% palladium on carbon It was hydrogenated in a hydrogen cube. The mixture was evaporated to give 6-(2-methoxyethoxy)pyridin-3-amine (3.30 mg, 98%) as a colourless solid.

步驟3：於0℃，於一經攪拌、溶於丙酮(10毫升)之6-(2-甲氧基乙氧基)啶-3-胺(501毫克，2.98毫莫耳，1等量)溶液中，依序添加啶(722 μL，8.94毫莫耳，3等量)及氯甲酸苯酯(489 μL，3.87毫莫耳，1.3等量)，並將其於室溫攪拌過夜。將該反應混合物蒸發，並以管柱色層分析法純化(矽膠，以1/1體積/體積比之甲基特丁基醚/甲醇做為溶析液)，以獲得2-(5-胺基吡啶-2-基氧代)乙醇，以獲得無色固體狀之苯基6-(2-甲氧基乙氧基)啶-3-基胺甲酸酯(686毫克，80%)。 Step 3: 6-(2-methoxyethoxy)pyridin-3-amine (501 mg, 2.98 mmol, 1 equivalent) in acetone (10 mL) at 0 ° C In the order, pyridine (722 μL, 8.94 mmol, 3 equivalents) and phenyl chloroformate (489 μL, 3.87 mmol, 1.3 equivalent) were added sequentially, and stirred at room temperature overnight. The reaction mixture was evaporated and purified by column chromatography (yellow gel, using methyl tert-butyl ether/methanol as a solvent in a ratio of 1/1 volume/volume) to obtain 2-(5-amine) Pyridin-2-yloxy)ethanol to give phenyl 6-(2-methoxyethoxy)pyridin-3-ylamine carboxate (686 mg, 80%).

步驟4：於一經攪拌、溶於丙酮(9毫升)之(3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)乙腈(102毫克，0.387毫莫耳，1.0等量)溶液中，依序添加三乙胺(0.214毫升，1.55毫莫耳，4.0等量)及苯基6-(2-甲氧基乙氧基)啶3-基胺甲酸酯(113毫克，0.395毫莫耳，1.02等量)，並將其回流攪拌16小時。將該反應混合物於真空狀態濃縮，並將殘留物純化(管柱色層分析法，矽膠，以4/1體積/體積比之醋酸乙酯/正己烷做為溶析液)，以獲得無色固體狀之1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(2-甲氧基乙氧基)啶-3-基)尿素(實例化合物131)(159毫克，90%)。 Step 4: (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)acetonitrile (102 mg, 0.387 mmol) dissolved in acetone (9 mL) In the solution of the ear, 1.0 equal amount), triethylamine (0.214 ml, 1.55 mmol, 4.0 equivalent) and phenyl 6-(2-methoxyethoxy)pyridine 3-ylaminocarboxylic acid were added sequentially. The ester (113 mg, 0.395 mmol, 1.02 equivalent) was stirred at reflux for 16 h. The reaction mixture was concentrated under vacuum, and the residue was purified (column chromatography, silica gel, eluting with ethyl acetate / n-hexane at a volume ratio of 4/1) to obtain a colorless solid. 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-methoxyethoxy) Pyridin-3-yl)urea (example compound 131) (159 mg, 90%).

實例128可以類似方法製備，實例130係以類似方法製備而成。 Example 128 can be prepared in a similar manner and Example 130 is prepared in a similar manner.

實例132之合成：Synthesis of Example 132:

1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-甲氧基乙氧基)啶-3-基)尿素 1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-methoxyethoxy) Pyridin-3-yl)urea

步驟1至3：參照實例化合物131。 Steps 1 to 3: Refer to Example Compound 131.

步驟4：於一經攪拌、溶於乙腈(9毫升)之(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺(108毫克，0.392毫莫耳，1.0等量)溶液中，依序添加三乙胺(0.216毫升，1.57毫莫耳，4.0等量)及苯基6-(2-甲氧基乙氧基)啶-3-基胺甲酸酯(114毫克，0.400毫莫耳，1.02等量)，並將其回流攪拌16小時。將該反應混合物於真空狀態濃縮，並將殘留物純化(管柱色層分析法，矽膠，以4/1體積/體積比之醋酸乙酯/正己烷做為溶析液)，以獲得無色固體狀之1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-甲氧基乙氧基)啶-3-基)尿素(實例化合物132)(156毫克，85%)。 Step 4: (1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine (108 mg, acetonitrile (9 mL) Triethylamine (0.216 ml, 1.57 mmol, 4.0 equivalent) and phenyl 6-(2-methoxyethoxy)pyridine-3- were added sequentially to a solution of 0.392 mmol, 1.0 eq. The carbamate (114 mg, 0.400 mmol, 1.02 equivalent) was stirred at reflux for 16 h. The reaction mixture was concentrated under vacuum, and the residue was purified (column chromatography, silica gel, eluting with ethyl acetate / n-hexane at a volume ratio of 4/1) to obtain a colorless solid. 1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-methoxy B) Oxypyridin-3-yl)urea (example compound 132) (156 mg, 85%).

實例133之合成： Synthesis of Example 133 :

1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙氧)啶-3-基)尿素 1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethoxy)pyridine- 3-base urea

步驟1：將2-氯-5-硝基吡啶(1.51公克，9.55毫莫耳，1等量)及2-(苯甲氧基)乙醇(1.53公克，10.0毫莫耳，1.05等量)以二甲基甲醯胺(9毫升)溶解，並將其冷卻至0℃。於該混合物中分次添加氫化鈉(60%(重量/重量比)於礦物油中，392毫克，9.84毫莫耳，1.03等量)，並使其於室溫回溫過夜。反應完成後(薄層層析法)，添加醋酸(1毫升)，並將溶媒蒸發。將殘留物懸浮於二乙醚(20毫升)，並將其過濾。以二氯甲烷(2 x 2毫升)清洗過濾塊，將濾液蒸發，並以管柱色層分析法(矽膠，以1/4體積/體積比之醋酸乙酯/正己烷做為溶析液)將其純化，以獲得黃色固體狀之2-(2-(苯甲氧基)乙氧基)-5-硝基吡啶(2.09公克，80%)。 Step 1: 2-Chloro-5-nitropyridine (1.51 g, 9.55 mmol, 1 equivalent) and 2-(benzyloxy)ethanol (1.53 g, 10.0 mmol, 1.05 equivalent) Dimethylformamide (9 ml) was dissolved and allowed to cool to 0 °C. Sodium hydride (60% (w/w ratio) in mineral oil, 392 mg, 9.84 mmol, 1.03 equivalent) was added portionwise to the mixture and allowed to warm overnight at room temperature. After completion of the reaction (thin layer chromatography), acetic acid (1 ml) was added, and the solvent was evaporated. The residue was suspended in diethyl ether (20 mL) and filtered. The filter block was washed with dichloromethane (2 x 2 ml), and the filtrate was evaporated and analyzed by column chromatography (tank, 1/4 volume/volume ratio of ethyl acetate/hexane). This was purified to give 2-(2-(benzyloxy)ethoxy)-5-nitropyridine (2.09 g, 80%) as a yellow solid.

步驟2：將2-(2-(苯甲氧基)乙氧基)-5-硝基吡啶(2.09公克，7.61毫莫耳，1等量)以乙醇(90毫升)溶解，並以10%之鈀碳將其於氫氣立方體氫化。將該混合物蒸發，並以管柱色層分析法(矽膠，以9/1體積比之甲基特丁基醚/甲醇最為溶析液)純化殘留物，以獲得無色固體狀之2-(5-胺基吡啶-2-基氧基)乙醇(209毫克，18%)。 Step 2: 2-(2-(Benzyloxy)ethoxy)-5-nitropyridine (2.09 g, 7.61 mmol, 1 equivalent) was dissolved in ethanol (90 mL) with 10% The palladium carbon hydrogenates it in a hydrogen cube. The mixture was evaporated, and the residue was purified by column chromatography (yield, EtOAc (yield: -Aminopyridin-2-yloxy)ethanol (209 mg, 18%).

步驟3：於0℃，於一經攪拌、溶於丙酮(5毫升)之2-(5-胺基吡啶-2-基氧基)乙醇(209毫克，1.36毫莫耳，1等量)溶液中，依序添加啶(329 μL，4.07毫莫耳，3等量)及氯甲酸苯酯(276 μL，1.76毫莫耳，1.3等量)，並將其於室溫攪拌過夜。將該反應混合物蒸發，並以管柱色層分析法純化(矽膠，以9/1體積/體積比之甲基特丁基醚/甲醇做為溶析液)，以獲得2-(5-胺基吡啶-2-基氧基)乙醇，以獲得無色固體狀之苯基6-(2-羥乙氧)啶-3-基胺甲酸酯(138毫克，37%)。 Step 3: In a solution of 2-(5-aminopyridin-2-yloxy)ethanol (209 mg, 1.36 mmol, 1 equivalent) dissolved in acetone (5 mL) at 0 ° C Pyridine (329 μL, 4.07 mmol, 3 equivalents) and phenyl chloroformate (276 μL, 1.76 mmol, 1.3 equivalent) were added sequentially and stirred at room temperature overnight. The reaction mixture was evaporated and purified by column chromatography (yellow gel, using 9/1 volume/volume ratio of methyl tert-butyl ether/methanol as a solvent) to obtain 2-(5-amine) Phenylpyridin-2-yloxy)ethanol to give phenyl 6-(2-hydroxyethoxy)pyridin-3-ylamine carboxate (138 mg, 37%).

步驟4：於一經攪拌、溶於乙腈(5毫升)之(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺(62毫克，0.23毫莫耳，1.0等量)溶液中，依序添加三乙胺(0.124毫升，0.90毫莫耳，4.0等量)及苯基6-(2-羥乙氧)啶-3-基胺甲酸酯(63毫克，0.23毫莫耳，1.02等量)，並將其回流攪拌16小時。將該反應混合物於真空狀態濃縮，並將殘留物純化(管柱色層分析法，矽膠，以4/1體積/體積比之醋酸乙酯/正己烷做為溶析液)，以獲得無色固體狀之1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙氧)啶-3-基)尿素(實例化合物133)(92毫克，90%)。 Step 4: (1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine (62 mg, acetonitrile (5 mL) In a solution of 0.23 millimolar, 1.0 equivalents, triethylamine (0.124 ml, 0.90 mmol, 4.0 equivalent) and phenyl 6-(2-hydroxyethoxy)-3-ylamine A were added sequentially. The ester (63 mg, 0.23 mmol, 1.02 equivalent) was stirred at reflux for 16 h. The reaction mixture was concentrated under vacuum, and the residue was purified (column chromatography, silica gel, eluting with ethyl acetate / n-hexane at a volume ratio of 4/1) to obtain a colorless solid. 1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethoxy) Pyridin-3-yl)urea (example compound 133) (92 mg, 90%).

實例134之合成： Synthesis of Example 134 :

1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-((2-羥乙胺)甲基)啶-3-基)尿素 1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-((2-hydroxyethylamine)) Pyridin-3-yl)urea

步驟1：於0℃，於一經攪拌、溶於二甲基甲醯胺(100毫升)之5-胺基2-氰吡啶(5-aminopicolinonitrile)(10公克，83.94毫莫耳，1.0等量)溶液中，分次添加氫化鈉(6.0公克，251.82毫莫耳，3.0等量)，隨後添加苯甲基溴化物，並將其於室溫攪拌3小時。將該反應混合物以水(200毫升)稀釋，以醋酸乙酯(2 x 150毫升)萃取，並以飽和之氯化鈉溶液(150毫升)清洗。將有機層以無水硫酸 鈉乾燥，並於真空狀態將其蒸發。使用醋酸乙酯/石油醚(3：7)，將粗製產物以矽膠管柱色層分析法純化，以獲得淡黃色固體狀之5-(二芐基胺基)-2-氰吡啶(17公克，68%)。 Step 1: 5-Aminopicolinonitrile (10 g, 83.94 mmol, 1.0 equivalent) dissolved in dimethylformamide (100 ml) at 0 ° C To the solution, sodium hydride (6.0 g, 251.82 mmol, 3.0 equivalent) was added in portions, followed by the addition of benzyl bromide, which was stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by silica gel column chromatography using ethyl acetate / petroleum ether (3: 7) to afford 5-(dibenzylamino)-2-cyanide as a pale yellow solid (17 g) , 68%).

步驟2：將一經攪拌、溶於四氫呋喃(100毫升)之5-(二芐基胺基)-2-氰吡啶(200毫克，0.668毫莫耳，1.0等量)溶液冷卻至-78℃，並緩慢地添加1 M、溶於甲苯(1.3毫升，1.337毫莫耳，2.0等量)之二異丁基氫化鋁，將該混合物於-78℃攪拌3小時。以水(150毫升)稀釋該反應混合物，以醋酸乙酯(70毫升x 2)萃取，以飽和之氯化鈉溶液(100毫升)清洗有機層，以硫酸鈉將其乾燥，並於真空狀態蒸發。使用醋酸乙酯/石油醚(2：3)，將粗製產物以矽膠管柱色層分析法(100至200篩孔)純化，以獲得固體狀之5-(二芐基胺基)-吡啶-2-甲醛(5-(dibenzylamino)picolinaldehyde)(100毫克，50%)。 Step 2: Cool a solution of 5-(dibenzylamino)-2-cyanopyridine (200 mg, 0.668 mmol, 1.0 equivalent) in tetrahydrofuran (100 mL) to -78 ° C with stirring. 1 M, diisobutylaluminum hydride in toluene (1.3 ml, 1.337 mmol, 2.0 equivalent) was slowly added, and the mixture was stirred at -78 °C for 3 hours. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc (EtOAc) . The crude product was purified by silica gel column chromatography (100 to 200 mesh) using ethyl acetate/petroleum ether (2:3) to give 5-(dibenzylamino)-pyridine as a solid. 2-(dibenzylaminopicolinaldehyde) (100 mg, 50%).

步驟3：於0℃，於一經攪拌、溶於四氫呋喃(30毫升)之5-(二芐基胺基)-吡啶-2-甲醛(50毫克，0.615毫莫耳，1.0等量)溶液中添加2-甲氧基胺(18.6毫克，0.248毫莫耳，1.5等量)、催化量之醋酸(1滴)及分次添加三乙醯氧基硼氫化鈉(140毫克，0.662毫莫耳，2.0等量)，並於室溫攪拌3小時。以碳酸氫鈉中和該反應混合物，以水(50毫升)將其稀釋，並以醋酸乙酯(2 x 60毫升)萃取。將有機層以飽和之氯化鈉溶液(50毫升)清洗，以硫酸鈉乾燥，並於真空狀態濃縮。以醋酸乙酯/石油醚(3：7)做為溶析液，將所得之殘留物以中性氧化鋁純化，以獲得白色固體狀之N,N-二苯基-6-((2-甲氧基乙胺)甲基)啶-3-胺(35毫克，58%)。 Step 3: Add at 0 ° C in a solution of 5-(dibenzylamino)-pyridine-2-carbaldehyde (50 mg, 0.615 mmol, 1.0 equivalent) dissolved in tetrahydrofuran (30 mL) 2-methoxylamine (18.6 mg, 0.248 mmol, 1.5 equivalent), catalytic amount of acetic acid (1 drop) and sodium triethyloxyborohydride (140 mg, 0.662 mmol, 2.0) Equivalent) and stirred at room temperature for 3 hours. The reaction mixture was neutralized with sodium bicarbonate, diluted with water (50 mL) andEtOAc. The organic layer was washed with EtOAc (EtOAc m. Ethyl acetate/petroleum ether (3:7) was used as the eluent, and the obtained residue was purified by neutral alumina to give N,N-diphenyl-6-(2- Methoxyethylamine)methyl)pyridin-3-amine (35 mg, 58%).

步驟4：將N,N-二苯基-6-((2-甲氧基乙胺)甲基)啶-3-胺(2公克，8.3毫莫耳，1.0等量)以濃硫酸(5毫升)溶解，將其於50℃加熱3小時。以2N之氫氧化納容易將該反應混合物之酸鹼值調整為約9，並以醋酸乙酯(2 x 100毫升)萃取。將有機層分離，以飽和之 氯化鈉溶液(2 x 10毫升)清洗，以硫酸鈉乾燥，並於真空狀態下蒸發，以獲得6-((2-甲氧基乙胺)甲基)啶-3-胺(550毫克，53%，褐色油狀)。 Step 4: N,N-diphenyl-6-((2-methoxyethylamine)methyl)pyridine-3-amine (2 g, 8.3 mmol, 1.0 equivalent) in concentrated sulfuric acid (5 Dissolve in ml) and heat it at 50 °C for 3 hours. The pH of the reaction mixture was adjusted to about 9 with 2N sodium hydroxide and extracted with ethyl acetate (2 x 100 mL). The organic layer was separated, washed with a saturated sodium chloride solution (2×10 ml), dried over sodium sulfate and evaporated in vacuo to give 6-((2-methoxyethylamine) 3-Amine (550 mg, 53%, brown oil).

步驟5：於0℃，於一經攪拌、溶於丙酮(10毫升)之6-((2-甲氧基乙胺)甲基)啶-3-胺(800毫克，4.4毫莫耳，1.0等量)溶液中添加啶(0.69毫升，8.8毫莫耳，2.0等量)及氯甲酸苯酯(55毫克，4.4毫莫耳，1.0等量)，並於室溫攪拌1小時。將該反應混合物以水(100毫升稀釋，以醋酸乙酯(150毫升x 2)萃取，並將合併有機層分離，以飽和之氯化鈉溶液(100毫升)清洗，以硫酸鈉乾燥，並於真空狀態下蒸發。使用醋酸乙酯/石油醚(1：4)做為溶析液，以矽膠色層分析法(100至200篩孔)純化殘留物，以獲得灰白色固體狀之苯機6-((2-甲氧基乙胺)甲基)啶-3-基胺甲酸酯(700毫克，47%)。 Step 5: 6-((2-methoxyethylamine)methyl)pyridin-3-amine (800 mg, 4.4 mmol, 1.0, etc.) dissolved in acetone (10 ml) at 0 ° C A solution of pyridine (0.69 ml, 8.8 mmol, 2.0 equivalent) and phenyl chloroformate (55 mg, 4.4 mmol, 1.0 equivalent) were added to the solution and stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc (EtOAc (EtOAc)EtOAc. Evaporation under vacuum. Ethyl acetate/petroleum ether (1:4) was used as the lysing solution, and the residue was purified by silica gel chromatography (100 to 200 mesh) to obtain a benzene machine 6- ((2-Methoxyethylamine)methyl)pyridin-3-ylcarbamate (700 mg, 47%).

步驟6：於0℃，於一經攪拌、溶於二氯甲烷(10毫升)之苯基6-((2-甲氧基乙胺)甲基)啶-3-基胺甲酸酯(700毫克，2.083毫莫耳，1.0等量)溶液中添加三乙胺(0.57毫升，4.166毫莫耳，2.0等量)及二碳酸三級丁酯(0.54毫升，2.499毫莫耳，1.2等量)，並於室溫攪拌1小時。以水(100毫升)稀釋該反應混合物，以醋酸乙酯(2 x 150毫升)萃取，將合併有機層分離，以飽和之氯化鈉溶液(100毫升)清洗，以硫酸鈉乾燥，並於真空狀態下將其蒸發。使用醋酸乙酯/石油醚(3：2)做為溶析液，以矽膠色層分析法純化殘留物，以獲得無色具黏性液體狀之6-((2-甲氧基乙基-N-叔丁氧基醯氨基)甲基)啶-3-基胺甲酸酯(650毫克，68%)。 Step 6: Phenyl 6-((2-methoxyethylamine)methyl)pyridin-3-ylcarbamate (700 mg) dissolved in dichloromethane (10 mL) at 0 ° C. , 2.083 millimolar, 1.0 equal amount) solution of triethylamine (0.57 ml, 4.166 mmol, 2.0 equivalent) and butyl dicarbonate (0.54 ml, 2.499 mmol, 1.2 equivalent), It was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc (EtOAc (EtOAc)EtOAc. Evaporate it in the state. Ethyl acetate/petroleum ether (3:2) was used as the eluent, and the residue was purified by silica gel chromatography to obtain 6-((2-methoxyethyl-N) as a colorless viscous liquid. - tert-Butoxyguanidinoamino)methyl)pyridin-3-ylcarbamate (650 mg, 68%).

步驟7：於室溫，於一經攪拌、溶於二氯甲烷(10毫升)之化合物6-((2-甲氧基乙基-N-三級丁氧基羰基-胺基)甲基)啶-3-基胺甲酸酯(150毫克，0.37毫莫耳，1.0等量)溶液中，依序添加三乙胺(0.1毫升，0.74毫莫耳，及2.0等量)及化合物(1-(3-氯苯基)-3-(三氟甲 基)-1H-吡唑-5-基)甲胺(117毫克，0.37毫莫耳，1.0等量)，並攪拌16小時。將二氯甲烷蒸發，將其以水(30毫升)稀釋，以醋酸乙酯(50毫升)萃取，以飽和之氯化鈉溶液(30毫升)清洗，以硫酸鈉乾燥，並於真空狀態蒸發。使用甲醇/三氯甲烷(1：19)做為溶析液，以矽膠色層分析法純化粗製產物，以獲得白色固體狀之三級丁基(5-(3-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)脲基)啶-2-基)甲基(2-甲氧基乙基)胺甲酸酯(200毫克，55%)。 Step 7: Compound 6-((2-methoxyethyl-N-tertiarybutoxycarbonyl-amino)methyl)pyridine at room temperature with stirring in dichloromethane (10 mL) In the solution of 3-aminocarbamate (150 mg, 0.37 mmol, 1.0 equivalent), triethylamine (0.1 ml, 0.74 mmol, and 2.0 equivalent) and compound (1-( 3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamine (117 mg, 0.37 mmol, 1.0 eq.) and stirred for 16 hr. The methylene chloride was evaporated, diluted with EtOAc EtOAc m. The crude product was purified by silica gel chromatography using methanol/trichloromethane (1:19) as a solvent to give a tri-butyl group as a white solid (5-(3-((1-(3-) Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)ureido)pyridin-2-yl)methyl(2-methoxyethyl)amine formate (200 mg, 55%).

步驟8：於一經攪拌、溶於二氯甲烷(10毫升)之三級丁基(5-(3-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)脲基)啶-2-基)甲基(2-甲氧基乙基)胺甲酸酯(200毫克，0.343毫莫耳，1.0等量)溶液中添加三溴化硼(0.68毫升，0.686毫莫耳，2.0等量)，並於-78℃攪拌3小時。以碳酸氫鈉溶液(10毫升)對該反應混合物進行淬火反應，以醋酸乙酯(2 x 30毫升)萃取，以飽和之氯化鈉溶液(15毫升)清洗，以無水硫酸鈉乾燥，並於真空狀態將其濃縮。使用甲醇/二氯甲烷/氨(1：4：0.5)做為溶析液，以中性氧化鋁管柱色層分析法純化粗製產物，以獲得灰白色固體狀之1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-((2-羥乙胺)甲基)啶-3-基)尿素(實例化合物134)(90毫克，56%)。 Step 8: Tert-butyl (5-(3-((1-(3-chlorophenyl))-3-(trifluoromethyl)-1H-) in dichloromethane (10 mL) Addylpyrazol-5-yl)methyl)ureido)pyridin-2-yl)methyl(2-methoxyethyl)amine formate (200 mg, 0.343 mmol, 1.0 equivalent) Boron tribromide (0.68 ml, 0.686 mmol, 2.0 equivalent) was stirred at -78 °C for 3 hours. The reaction mixture was quenched with sodium bicarbonate (10 mL), EtOAc (EtOAc m. It was concentrated under vacuum. The crude product was purified by neutral alumina column chromatography using methanol/dichloromethane/ammonia (1:4:0.5) as a solvent to afford 1-((1-(3) -Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-((2-hydroxyethylamine)methyl)pyridin-3-yl) Urea (example compound 134) (90 mg, 56%).

實例135之合成：Synthesis of Example 135:

1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(((2-羥乙基)(甲基)胺基)甲基)啶-3-基)尿素 1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(((2-hydroxyethyl))) (methyl)amino)methyl)pyridin-3-yl)urea

步驟1：於0℃，於一經攪拌、溶於二甲基甲醯胺(100毫升)之5-胺基2-氰吡啶(10公克，83.94毫莫耳，1.0等量)溶液中，分次添加氫化鈉(60%)(6.0公克，251.82毫莫耳，3.0等量)，隨後再添加苯甲基溴化物，並於室溫攪拌3小時。以水(200毫升)稀釋該反應混合物，以醋酸乙酯(2 x 150毫升)萃取，並以飽和之氯化鈉溶液(150毫升)清洗。將有機層以無水硫酸鈉乾燥，並於真空狀態蒸發。使用醋酸乙酯/石油醚(3：7)最為溶析液，以矽膠色層分析法(100至200篩孔)純化粗製產物，以獲得淡黃色固體狀之5-(二芐基胺基)-2-氰吡啶(17公克，68%)。 Step 1: At 0 ° C, in a solution of 5-amino-2-cyanopyridine (10 g, 83.94 mmol, 1.0 equivalent) dissolved in dimethylformamide (100 ml) at 0 ° C Sodium hydride (60%) (6.0 g, 251.82 mmol, 3.0 equivalents) was added followed by benzyl bromide and stirred at room temperature for 3 h. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by silica gel chromatography (100 to 200 mesh) using ethyl acetate/petroleum ether (3:7) eluting to give 5-(dibenzylamino) as a pale yellow solid. 2-cyanopyridine (17 grams, 68%).

步驟2：於一冷卻至-78℃、經攪拌、溶於四氫呋喃(100毫升)之5-(二芐基胺基)-2-氰吡啶(200毫克，0.668毫莫耳，1.0等量)溶 液中，緩慢地添加1M之溶於甲苯(1.3毫升，1.337毫莫耳，2.0等量)之異丁基氫化鋁，並於-78℃攪拌3小時。以水(150毫升)稀釋該反應混合物，以醋酸乙酯(2 x 70毫升)萃取，以飽和之氯化鈉溶液(100毫升)清洗有機層，以硫酸鈉乾燥，並於真空狀態將其蒸發。使用醋酸乙酯/石油醚(2：3)做為溶析液，以矽膠色層分析法(100至200篩孔)純化粗製產物，以獲得固體狀之5-(二芐基胺基)-吡啶-2-甲醛(100毫克，50%)。 Step 2: a solution of 5-(dibenzylamino)-2-cyanopyridine (200 mg, 0.668 mmol, 1.0 equivalent) dissolved in tetrahydrofuran (100 ml) with stirring to -78 ° C 1 M of isobutylaluminum hydride in toluene (1.3 ml, 1.337 mmol, 2.0 equivalent) was slowly added, and stirred at -78 °C for 3 hours. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc (EtOAc) . The crude product was purified by gelatin chromatography (100 to 200 mesh) using ethyl acetate/petroleum ether (2:3) as a solvent to give a solid 5-(dibenzylamino)- Pyridine-2-carbaldehyde (100 mg, 50%).

步驟3：於0℃，於一經攪拌、溶於四氫呋喃(10毫升)之5-(二芐基胺基)吡啶-2-甲醛(100毫克，0.33毫莫耳，1.0等量)溶液中，分次添加2-(甲胺基)乙醇(37毫克，0.49毫莫耳，1.5等量)、催化量之醋酸及三乙醯氧基硼氫化鈉(175毫克，0.827毫莫耳，2.5等量)，並於室溫攪拌3小時。將該反應混合物以碳酸氫鈉中和，以水(50毫升)稀釋，並以醋酸乙酯(2 x 60毫升)萃取。將有機層以飽和之氯化鈉溶液(50毫升)清洗，以硫酸鈉乾燥，並於真空狀態蒸發。使用醋酸乙酯/石油醚(1：4)做為溶析液，將所得之殘留物以中性氧化鋁純化，以獲得白色固體狀之2-(((5-(二芐基胺基)啶-2-基)甲基)(甲基)胺基)乙醇(50毫克，42%)。 Step 3: Dissolve in a solution of 5-(dibenzylamino)pyridine-2-carbaldehyde (100 mg, 0.33 mmol, 1.0 equivalent) in tetrahydrofuran (10 ml) at 0 ° C Add 2-(methylamino)ethanol (37 mg, 0.49 mmol, 1.5 equivalent), catalytic amount of acetic acid and sodium triethoxysulfonate (175 mg, 0.827 mmol, 2.5 equivalents) And stirred at room temperature for 3 hours. The reaction mixture was neutralized with sodium bicarbonate, diluted with water (50 mL) andEtOAc. The organic layer was washed with EtOAc (EtOAc)EtOAc. Ethyl acetate/petroleum ether (1:4) was used as the eluent, and the obtained residue was purified by neutral alumina to afford 2-(((5-(dibenzylamino)) as a white solid. Pyridin-2-yl)methyl)(methyl)amino)ethanol (50 mg, 42%).

步驟4：將2-(((5-(二芐基胺基)啶-2-基)甲基)(甲基)胺基)乙醇(3公克，8.31毫莫耳，1.0等量)以濃硫酸(10毫升)溶解，並於50℃加熱3小時。將該反應混合物冷卻，以2N之氫氧化納溶液將酸鹼值調整為約9，再以醋酸乙酯(2 x 100毫升)萃取。將有機層分離，並以飽和之氯化鈉溶液(2 x 10毫升)清洗，以硫酸鈉乾燥，並於真空狀態將其濃縮，以獲得褐色油狀之2-(((5-胺基吡啶-2-基)甲基)(甲基)胺基)乙醇(800毫克，53%)。分離出之化合物可直接於下一步驟使用。 Step 4: 2-(((5-(Dibenzylamino)pyridin-2-yl)methyl)(methyl)amino)ethanol (3 g, 8.31 mmol, 1.0 equivalent) Sulfuric acid (10 ml) was dissolved and heated at 50 ° C for 3 hours. The reaction mixture was cooled, and the pH was adjusted to about 9 with a 2N sodium hydroxide solution and then extracted with ethyl acetate (2 x 100 mL). The organic layer was separated and washed with aq. EtOAc (EtOAc (EtOAc) 2-yl)methyl)(methyl)amino)ethanol (800 mg, 53%). The isolated compound can be used directly in the next step.

步驟5：於0℃，於一經攪拌、溶於丙酮(10毫升)之2-(((5-胺 基吡啶-2-基)甲基)(甲基)胺基)乙醇(600毫克，3.30毫莫耳，1.0等量)溶液中添加啶(0.78毫升，9.90毫莫耳，3.0等量)及氯甲酸苯酯(0.41毫升，3.30毫莫耳，1.0等量)，並於室溫攪拌1小時。將該反應混合物以水(50毫升)稀釋，以醋酸乙酯(2 x 50毫升)萃取，將合併有機層分離，並以飽和之氯化鈉溶液(50毫升)清洗，以硫酸鈉乾燥，再於真空狀態蒸發。使用甲醇/三氯甲烷(1：19)做為溶析液，以矽膠色層分析法純化粗製產物，以獲得灰白色固體狀之化合物苯基6-(((2-羥乙基)(甲基)胺基)甲基)啶-3-基胺甲酸酯(300毫克，23%)。 Step 5: 2-(((5-Aminopyridin-2-yl)methyl)(methyl)amino)ethanol (600 mg, 3.30) at 0 ° C, dissolved in acetone (10 mL). Millenol, 1.0 equal amount) solution was added pyridine (0.78 ml, 9.90 mmol, 3.0 equivalent) and phenyl chloroformate (0.41 ml, 3.30 mmol, 1.0 equivalent), and stirred at room temperature 1 hour. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc. Evaporate in a vacuum. The crude product was purified by silica gel chromatography using methanol/trichloromethane (1:19) as the solvent to give the compound phenyl 6-(((2-hydroxyethyl)) Amino)methyl)pyridin-3-ylcarbamate (300 mg, 23%).

步驟6：於室溫，於一經攪拌、溶於二氯甲烷(5毫升)之(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺鹽酸鹽(103.4毫克，0.332毫莫耳，1.0等量)溶液中，依序添加三乙胺(0.13毫升，0.996毫莫耳，3.0等量)及苯基6-(((2-羥乙基)(甲基)胺基)甲基)啶-3-基胺甲酸酯(100毫克，0.332毫莫耳，1.0等量)，並將其攪拌過夜。將二氯甲烷蒸發，隨後以水稀釋該反應混合物，並以醋酸乙酯萃取。將合併有機層以飽和之氯化鈉溶液(5毫升)清洗，以無水硫酸鈉乾燥，並於真空狀態蒸發。使用甲醇/三氯甲烷(3：17)做為溶析液，以矽膠管柱色層分析法(100至200篩孔)純化粗製產物，以獲得白色固體狀之化合物1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(((2-羥乙基)(甲基)胺基)甲基)啶-3-基)尿素(實例化合物135)(70毫克，43%)。 Step 6: (1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl) in dichloromethane (5 mL) In the solution of methylamine hydrochloride (103.4 mg, 0.332 mmol, 1.0 equivalent), triethylamine (0.13 ml, 0.996 mmol, 3.0 equivalent) and phenyl 6-(((2- Hydroxyethyl)(methyl)amino)methyl)pyridin-3-ylcarbamate (100 mg, 0.332 mmol, 1.0 eq.) and stirred overnight. The dichloromethane was evaporated, then the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with EtOAc EtOAc m. The crude product was purified by silica gel column chromatography (100 to 200 mesh) using methanol/trichloromethane (3:17) as a solvent to afford compound 1-((1-( 3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(((2-hydroxyethyl))(methyl)amino)) Methyl)pyridin-3-yl)urea (example compound 135) (70 mg, 43%).

實例139之合成： Synthesis of Example 139 :

1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(5-(羥甲基)啶-2-基)尿素 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(5-(hydroxymethyl)pyridin-2-yl) Urea

步驟1：於0℃，於一經攪拌、溶於乙醇之6-胺基菸鹼酸(218毫克，1.58毫莫耳)溶液中，緩慢地添加亞硫醯氯(0.56毫升，4.74毫莫耳)。將該反應混合物回流攪拌過夜。隨後將該混合物冷卻至室溫，並將溶媒於真空狀態蒸發。將其以醋酸乙酯溶解，並以飽和之碳酸氫鈉溶液清洗。將有機層乾燥(硫酸鎂)並過濾。於真空狀態去除濾液。所得粗製狀態之6-胺基菸鹼酸乙基(200毫克，粗製產物)之生產率為76%。 Step 1: Slowly add sulfite chloride (0.56 ml, 4.74 mmol) at 0 ° C in a solution of 6-aminonicotinic acid (218 mg, 1.58 mmol) dissolved in ethanol. . The reaction mixture was stirred at reflux overnight. The mixture was then cooled to room temperature and the solvent was evaporated under vacuum. It was dissolved in ethyl acetate and washed with a saturated sodium hydrogen carbonate solution. The organic layer was dried (MgSO4) and filtered. The filtrate was removed under vacuum. The productivity of the obtained 6-aminonicotinic acid ethyl group (200 mg, crude product) in a crude state was 76%.

步驟2：於氮氣氣氛下，將6-胺基菸鹼酸乙基(200毫克，1.21毫莫耳)於0℃加至一經攪拌、溶於四氫呋喃之氫化鋁鋰(183毫 克，4.83毫莫耳)溶液中。將該反應混合物於0℃攪拌30分鐘，再於室溫攪拌3小時。於0℃，以1 N之氯化氫對該混合物進行淬火反應，直至其酸鹼值為3，隨後，以碳酸鈉溶液將其鹼化，直至其酸鹼值為7。以矽藻土過濾該混合物，以去除氫化鋁鋰殘留物，再將其以醋酸乙酯溶解，並以飽和之碳酸鈉溶液清洗。將有機層乾燥(硫酸鎂)並過濾。於真空狀態去除濾液。所得粗製狀態之(6-胺基吡啶-3-基)甲醇(55毫克，粗製產物)其生產率為75%。 Step 2: 6-Aminonicotinic acid ethyl (200 mg, 1.21 mmol) was added to a hydrogenated lithium aluminum hydride (183 mg, 4.83 mmol) dissolved in tetrahydrofuran at 0 ° C under a nitrogen atmosphere. ) in solution. The reaction mixture was stirred at 0 ° C for 30 minutes and then at room temperature for 3 hours. The mixture was quenched with 1 N of hydrogen chloride at 0 ° C until its pH was 3, and then it was basified with sodium carbonate solution until its pH was 7. The mixture was filtered with diatomaceous earth to remove the lithium aluminum hydride residue, which was dissolved in ethyl acetate and washed with a saturated sodium carbonate solution. The organic layer was dried (MgSO4) and filtered. The filtrate was removed under vacuum. The obtained crude (6-aminopyridin-3-yl)methanol (55 mg, crude product) had a productivity of 75%.

步驟3：於一經攪拌、溶於二甲基甲醯胺之(6-胺基吡啶-3-基)甲醇(55毫克，0.44毫莫耳)溶液中添加咪唑(60毫克，0.88毫莫耳)與叔丁基二甲基氯矽烷(66毫克，0.44毫莫耳)。將該反應混合物於室溫攪拌5小時。以醋酸乙酯萃取該混合物，並以水清洗數次。將有機層以硫酸鎂乾燥，並將其過濾。於真空狀態去除濾液。以管柱色層分析法純化粗製產物，以獲得5-((三級丁基二甲基矽氧基)甲基)啶-2-胺(44毫克)，其生產率為42%。 Step 3: Add imidazole (60 mg, 0.88 mmol) to a solution of (6-aminopyridin-3-yl)methanol (55 mg, 0.44 mmol) dissolved in dimethylformamide. With tert-butyldimethylchloromethane (66 mg, 0.44 mmol). The reaction mixture was stirred at room temperature for 5 hours. The mixture was extracted with ethyl acetate and washed several times with water. The organic layer was dried over magnesium sulfate and filtered. The filtrate was removed under vacuum. The crude product was purified by column chromatography to give 5-((tris-butyl dimethyl dimethyloxy)methyl) pyridine-2-amine (44 mg) with a yield of 42%.

步驟4：於一經攪拌、以四氫呋喃及乙腈做為共溶劑之5-((三級丁基二甲基矽氧基)甲基)啶-2-胺(44毫克，0.18毫莫耳)溶液中添加氯甲酸苯酯(0.03毫升，0.20毫莫耳)及啶(0.018毫升，0.22毫莫耳)。將該反應混合物於室溫攪拌1小時。將該混合物以醋酸乙酯溶解，並以水及飽和之氯化鈉溶液清洗。將有機層以硫酸鎂乾燥，並將其過濾。於真空狀態去除濾液。以純化粗製產物，以獲得苯基5-((三級丁基二甲基矽氧基)甲基)啶-2-基胺甲酸酯(52毫克)，其生產率為79%。 Step 4: 5-((tert-butyldimethyl methoxy)methyl)pyridin-2-amine (44 mg, 0.18 mmol) in a solution of tetrahydrofuran and acetonitrile as a cosolvent Phenyl chloroformate (0.03 ml, 0.20 mmol) and pyridine (0.018 mL, 0.22 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was dissolved in ethyl acetate and washed with water and a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and filtered. The filtrate was removed under vacuum. The crude product was purified to give phenyl 5-((tert-butyldimethyl methoxy)methyl)pyridin-2-ylcarbamate (52 mg) with a yield of 79%.

步驟5：於一經攪拌、溶於乙腈之苯基5-((三級丁基二甲基矽氧基)甲基)啶-2-基胺甲酸酯(50毫克，0.15毫莫耳)及(3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺(40毫克，0.15毫莫耳)溶液中添加4-二甲胺基啶(30毫克，0.15毫莫耳)。將該反應混合物於50℃ 攪拌過夜。以醋酸乙酯溶解該混合物，並以水及飽和之氯化鈉溶液清洗。將有機層以硫酸鎂乾燥，並將其過濾。於真空狀態去除濾液。以管柱色層分析法純化粗製產物，以獲得1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(5-((三級丁基二甲基矽氧基)甲基)啶-2-基)尿素(68毫克)，其生產率為86%。 Step 5: Phenyl 5-((tertiary butyldimethylamyloxy)methyl)pyridin-2-ylcarbamate (50 mg, 0.15 mmol) dissolved in acetonitrile with stirring 4-Dimethylaminopyridine (30) was added to a solution of (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methylamine (40 mg, 0.15 mmol) Mg, 0.15 millimoles). The reaction mixture was stirred at 50 ° C overnight. The mixture was dissolved in ethyl acetate and washed with water and a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and filtered. The filtrate was removed under vacuum. The crude product was purified by column chromatography to give 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-( 5-((tertiary butyldimethylammonio)methyl)pyridin-2-yl)urea (68 mg), which had a productivity of 86%.

步驟6：於一經攪拌、溶於四氫呋喃之1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(5-((三級丁基二甲基矽氧基)甲基)啶-2-基)尿素(68毫克，0.13毫莫耳)溶液中添加1M之四丁基氟化銨(0.26毫升，0.26毫莫耳)。將該反應混合物於室溫攪拌18小時。隨後添加另一部分之1M四丁基氟化銨(0.39毫升，0.39毫莫耳)，將該混合物再度攪拌4小時。以飽和之碳酸氫鈉溶液對該混合物進行淬火反應，隨後將其以醋酸乙酯溶解，並以水清洗。將有機層以硫酸鎂乾燥，並將其過濾。於真空狀態去除濾液。以管柱色層分析法純化粗製產物，以獲得1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(5-(羥甲基)啶-2-基)尿素(實例化合物139)(31毫克)，其生產率為56%。 Step 6: 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(5-) dissolved in tetrahydrofuran Add 1M tetrabutylammonium fluoride (0.26 ml, 0.26 mmol) to a solution of ((tert-butyl dimethyl dimethyloxy)methyl) pyridine-2-yl) urea (68 mg, 0.13 mmol) ear). The reaction mixture was stirred at room temperature for 18 h. Another portion of 1 M tetrabutylammonium fluoride (0.39 mL, 0.39 mmol) was then added and the mixture was stirred for a further 4 hours. The mixture was quenched with a saturated sodium hydrogen carbonate solution, which was then dissolved in ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate and filtered. The filtrate was removed under vacuum. The crude product was purified by column chromatography to give 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-( 5-(Hydroxymethyl)pyridin-2-yl)urea (example compound 139) (31 mg), which had a productivity of 56%.

1H核磁共振(300 MHz，CD3OD)：8.08(s，1H，Ar)；7.66(dd，1H，J=8.57 Hz，Ar)；7.52(m，1H，Ar)；7.44(br m，3H，J=7.42-7.47，Ar)；6.98(d，1H，J=8.43 Hz，Ar)；6.35(s，1H，吡唑)；4.55(s，2H，CH2)；4.53(s，2H，CH2)，1.31(s，9H，三級丁基)。 1 H NMR (300 MHz, CD 3 OD): 8.08 (s, 1H, Ar); 7.66 (dd, 1H, J = 8.57 Hz, Ar); 7.52 (m, 1H, Ar); 7.44 (br m, 3H, J=7.42-7.47, Ar); 6.98 (d, 1H, J=8.43 Hz, Ar); 6.35 (s, 1H, pyrazole); 4.55 (s, 2H, CH2); 4.53 (s, 2H, CH2), 1.31 (s, 9H, tert-butyl).

實例140之合成： Synthesis of Example 140 :

1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(5-(羥甲基)啶-3-基)尿素 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(5-(hydroxymethyl)pyridin-3-yl) Urea

步驟1：於0℃，於一經攪拌、溶於乙醇之5-胺基菸鹼酸(300毫克，2.17毫莫耳)溶液中，緩慢地添加亞硫醯氯(0.47毫升，6.51毫莫耳)。將該反應混合物回流攪拌過夜。隨後將該混合物冷卻至室溫，並於真空狀態去除溶媒。以醋酸乙酯將其溶解，並以飽和之碳酸氫鈉溶液清洗。將有機層乾燥(硫酸鎂)，並將其過濾。於真空狀態去除濾液。所得粗製狀態之5-胺基醃酸乙酯(315毫克，粗製產物)其生產率為89%。 Step 1: Slowly add sulphide chloride (0.47 ml, 6.51 mmol) at 0 ° C in a solution of 5-amino nicotinic acid (300 mg, 2.17 mmol) dissolved in ethanol. . The reaction mixture was stirred at reflux overnight. The mixture was then cooled to room temperature and the solvent was removed under vacuum. It was dissolved in ethyl acetate and washed with a saturated sodium hydrogen carbonate solution. The organic layer was dried (MgSO.sub.4) and filtered. The filtrate was removed under vacuum. The obtained 5-aminopicuric acid ethyl ester (315 mg, crude product) was found to have a productivity of 89%.

步驟2：於氮氣氣氛下，緩慢地將以四氫呋喃溶解之乙基5-胺基醃酸乙酯(223毫克，1.34毫莫耳)於0℃加至一經攪拌、溶於四氫呋喃之氫化鋁鋰(254毫克，5.36毫莫耳)溶液中。將該反應混 合物於0℃攪拌30分鐘，再於室溫攪拌3小時。於0℃，以1N之氯化氫對該混合物進行淬火反應，直至其酸鹼值為3,再將其以碳酸鈉溶液鹼化，直至酸鹼值為7。隨後以矽藻土過濾該混合物，以去除氫化鋁鋰，將其以醋酸乙酯溶解，並以飽和之碳酸鈉溶液清洗。將有機層以硫酸鎂乾燥，並將其過濾。於真空狀態去除濾液。所得粗製狀態之(5-胺基吡啶-3-基)甲醇(111毫克，粗製產物)其生產率為54%。 Step 2: Ethyl 5-amino-picryl ethyl ester (223 mg, 1.34 mmol) dissolved in tetrahydrofuran was slowly added to the aluminum hydride (aluminum hydride) dissolved in tetrahydrofuran at 0 ° C under a nitrogen atmosphere. 254 mg, 5.36 mmoles in solution. The reaction mixture was stirred at 0 ° C for 30 minutes and then at room temperature for 3 hours. The mixture was quenched with 1 N of hydrogen chloride at 0 ° C until it had a pH of 3 and then basified with sodium carbonate solution until a pH of 7. The mixture was then filtered with diatomaceous earth to remove lithium aluminum hydride, which was dissolved in ethyl acetate and washed with saturated sodium carbonate solution. The organic layer was dried over magnesium sulfate and filtered. The filtrate was removed under vacuum. The obtained crude product of (5-aminopyridin-3-yl)methanol (111 mg, crude product) had a yield of 54%.

步驟3：於一經攪拌、溶於二甲基甲醯胺之(5-胺基吡啶-3-基)甲醇(87毫克，0.89毫莫耳)溶液中添加咪唑(12毫克，1.77毫莫耳)及叔丁基二甲基氯矽烷(134毫克，0.89毫莫耳)。將該反應混合物於室溫攪拌5小時。以醋酸乙酯溶解該混合物，並以水清洗數次。將有機層以硫酸鎂乾燥，並將其過濾。於真空狀態去除濾液。以管柱色層分析法純化粗製產物，以獲得5-((三級丁基二甲基矽氧基)甲基)啶-3-胺(132毫克)，其生產率為50%。 Step 3: Add imidazole (12 mg, 1.77 mmol) to a solution of (5-aminopyridin-3-yl)methanol (87 mg, 0.89 mmol) dissolved in dimethylformamide. And tert-butyldimethylchloromethane (134 mg, 0.89 mmol). The reaction mixture was stirred at room temperature for 5 hours. The mixture was dissolved in ethyl acetate and washed several times with water. The organic layer was dried over magnesium sulfate and filtered. The filtrate was removed under vacuum. The crude product was purified by column chromatography to give 5-((tris-butyl dimethyl methoxy oxy)methyl) pyridine-3-amine (132 mg) with a yield of 50%.

步驟4：於一經攪拌、以四氫呋喃及乙腈做為共溶劑之5-((三級丁基二甲基矽氧基)甲基)啶-3-胺(132毫克，0.55毫莫耳)溶液中添加氯甲酸苯酯(0.073毫升，0.58毫莫耳)及啶(0.054毫升，0.66毫莫耳)。將該反應混合物於室溫攪拌1小時。以醋酸乙酯溶解該混合物，並以水及飽和之氯化鈉溶液清洗。將有機層乾燥(硫酸鎂)並過濾。於真空狀態去除濾液。以管柱色層分析法純化粗製產物，以獲得苯基5-((三級丁基二甲基矽氧基)甲基)啶-3-基胺甲酸酯(171毫克)，其生產率為86%。 Step 4: 5-((tert-butyldimethyl methoxy)methyl)pyridin-3-amine (132 mg, 0.55 mmol) in a solution of tetrahydrofuran and acetonitrile as a cosolvent Phenyl chloroformate (0.073 ml, 0.58 mmol) and pyridine (0.054 mL, 0.66 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was dissolved in ethyl acetate and washed with water and a saturated sodium chloride solution. The organic layer was dried (MgSO4) and filtered. The filtrate was removed under vacuum. The crude product was purified by column chromatography to give phenyl 5-((tert-butyldimethyl methoxy)methyl)pyridin-3-ylcarbamate (171 mg). 86%.

步驟5：於一經攪拌、溶於乙腈之苯基5-((三級丁基二甲基矽氧基)甲基)啶-3-基胺甲酸酯(80毫克，0.22毫莫耳)及(3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺(59毫克，0.22毫莫耳)之溶液中添加4-二甲胺基吡啶(27毫克，0.22毫莫耳)。將該反應混合物於 50℃攪拌過夜。將該混合物以醋酸乙酯溶解，並以水及飽和之氯化鈉溶液清洗。將有機層乾燥(硫酸鎂)並過濾。於真空狀態去除濾液。以管柱色層分析法純化粗製產物，以獲得1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(5-((三級丁基二甲基矽氧基)甲基)啶-3-基)尿素(86毫克)，其生產率為73%。 Step 5: Phenyl 5-((tertiary butyldimethylamyloxy)methyl)pyridin-3-ylcarbamate (80 mg, 0.22 mmol) dissolved in acetonitrile with stirring 4-Dimethylaminopyridine was added to a solution of (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methylamine (59 mg, 0.22 mmol). 27 mg, 0.22 mmol.) The reaction mixture was stirred at 50 ° C overnight. The mixture was dissolved in ethyl acetate and washed with water and a saturated sodium chloride solution. The organic layer was dried (MgSO4) and filtered. The filtrate was removed under vacuum. The crude product was purified by column chromatography to give 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-( 5-((tertiary butyldimethylammonio)methyl)pyridin-3-yl)urea (86 mg), which had a productivity of 73%.

步驟6：於一經攪拌、溶於四氫呋喃之1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(5-((三級丁基二甲基矽氧基)甲基)啶-3-基)尿素(86公克，0.16毫莫耳)溶液中添加1M之四丁基氟化銨(0.18毫升，0.18毫莫耳)。將該反應混合物於室溫攪拌18小時。隨後添加另一部分之1M之四丁基氟化銨(0.47毫升，0.47毫莫耳)，並將該混合物再度攪拌4小時。以飽和之碳酸氫鈉溶液對該混合物進行淬火反應，再以醋酸乙酯將其溶解，並以水清洗。將有機層乾燥(硫酸鎂)並過濾。於真空狀態去除濾液。以管柱色層分析法純化粗製產物，以獲得1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(5-((三級丁基二甲基矽氧基)甲基)啶-3-基)尿素(實例化合物140)(65毫克)，其生產率為96%。 Step 6: 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(5-) dissolved in tetrahydrofuran Add 1M tetrabutylammonium fluoride (0.18 ml, 0.18 mmol) to a solution of ((tert-butyl dimethyl dimethyloxy)methyl)pyridin-3-yl)urea (86 g, 0.16 mmol) ear). The reaction mixture was stirred at room temperature for 18 h. Another portion of 1 M tetrabutylammonium fluoride (0.47 mL, 0.47 mmol) was then added and the mixture was stirred for a further 4 hours. The mixture was quenched with saturated sodium bicarbonate solution, dissolved with ethyl acetate and washed with water. The organic layer was dried (MgSO4) and filtered. The filtrate was removed under vacuum. The crude product was purified by column chromatography to give 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-( 5-((tertiary butyldimethylammonio)methyl)pyridin-3-yl)urea (example compound 140) (65 mg), with a yield of 96%.

1H核磁共振(300 MHz，CD3OD)：8.43(d，1H，J=2.37 Hz，Ar)；8.13(s，1H，Ar)；7.91(s，1H，Ar)；7.56(t，1H，J=2.01 Hz，Ar)；7.48(br m，3H，7.43-7.54，Ar)；6.37(s，1H，吡唑)；4.62(s，2H，CH2)；4.44(s，2H，CH2)；1.32(m，9H，三級丁基)。 1 H NMR (300 MHz, CD 3 OD): 8.43 (d, 1H, J = 2.37 Hz, Ar); 8.13 (s, 1H, Ar); 7.91 (s, 1H, Ar); 7.56 (t, 1H) , J = 2.01 Hz, Ar); 7.48 (br m, 3H, 7.43 - 7.54, Ar); 6.37 (s, 1H, pyrazole); 4.62 (s, 2H, CH2); 4.44 (s, 2H, CH2) ; 1.32 (m, 9H, tertiary butyl).

實例141之合成： Synthesis of Example 141 :

1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)-2-甲基啶-3-基)尿素 1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(hydroxymethyl)-2-methyl Gyridin-3-yl)urea

步驟1：於一經攪拌、溶於1,4-二氧陸圜(20毫升)之2,6-二甲基-3-硝基吡啶(3公克，19.5毫莫耳，1.0等量)溶液中添加二氧化硒(2.625公克，28.80毫莫耳，1.2等量)，並將該反應混合物於100℃攪拌16小時。將該反應混合物以矽藻土床過濾，並於較低壓力將濾液濃縮，以獲得褐色液態狀之5,6-二甲基-吡啶-2-甲醛(3.0公克，95%)。 Step 1: In a solution of 2,6-dimethyl-3-nitropyridine (3 g, 19.5 mmol, 1.0 equivalent) dissolved in 1,4-dioxane (20 ml) Selenium dioxide (2.625 grams, 28.80 millimolar, 1.2 equivalents) was added and the reaction mixture was stirred at 100 ° C for 16 hours. The reaction mixture was filtered over a pad of celite, and the filtrate was concentrated at a lower pressure to afford 5,6-dimethyl-pyridine-2-carbaldehyde (3.0 g, 95%).

步驟2：於0℃，於一經攪拌、溶於甲醇(20毫升)之5,6-二甲基-吡啶-2-甲醛(3.0公克，18.2毫莫耳，1.0等量)之溶液中添加硼氫化鈉(720毫克，18.2毫莫耳，1等量)，並於0℃攪拌1小時。 將該反應混合物以冰水進行淬火反應，於較低壓力濃縮，以二氯甲烷(2 x 50毫升)萃取，再將其濃縮，以獲得(6-甲基-5-硝基吡啶-2-基)甲醇(2.4公克，約75%)。 Step 2: Add boron to a solution of 5,6-dimethyl-pyridine-2-carbaldehyde (3.0 g, 18.2 mmol, 1.0 equivalent) dissolved in methanol (20 ml) at 0 °C. Sodium hydride (720 mg, 18.2 mmol, 1 equivalent) was stirred at 0 °C for 1 hour. The reaction mixture was quenched with ice water, concentrated at lower pressure, extracted with dichloromethane (2×50 ml), and then concentrated to give (6-methyl-5-nitropyridine-2- Methanol) (2.4 g, about 75%).

步驟3：於0℃，於一溶於二氯甲烷(10毫升)之(6-甲基-5-硝基吡啶-2-基)甲醇(500毫克，3.01毫莫耳，1.0等量)溶液中，依序添加咪唑(410毫克，6.02毫莫耳，2等量)及叔丁基二甲基氯矽烷(500毫克，3.313毫莫耳，及1.1等量)，並於0℃攪拌1小時。以水(50毫升)稀釋該反應混合物，以二氯甲烷(2 x 50毫升)萃取，並將其濃縮，以獲得6-((三級丁基二甲基矽氧基)甲基)-2-甲基-3-硝基吡啶(800毫克，約94%)。 Step 3: a solution of (6-methyl-5-nitropyridin-2-yl)methanol (500 mg, 3.01 mmol, 1.0 equivalent) in dichloromethane (10 mL) at 0 ° C Imidazole (410 mg, 6.02 mmol, 2 equivalents) and tert-butyldimethylchloromethane (500 mg, 3.313 mmol, and 1.1 equivalent) were added sequentially and stirred at 0 ° C for 1 hour. . The reaction mixture was diluted with water (50 mL), extracted with dichloromethane (2 x 50 ml) and concentrated to give 6-((tris-butyl dimethyl methoxy oxy)methyl) -Methyl-3-nitropyridine (800 mg, about 94%).

步驟4：於一經攪拌、溶於甲醇(50毫升)之6-((三級丁基二甲基矽氧基)甲基)-2-甲基-3-硝基吡啶(800毫克，3.54毫莫耳，1.0等量)溶液中添加鈀碳(400毫克)，並於40 Psi之氫氣下攪拌16小時。使該反應混合物通過矽藻土，並將濾液於較低壓力濃縮，以獲得6-((三級丁基二甲基矽氧基)甲基)-2-甲基啶-3-胺(700毫克，95%)。 Step 4: 6-((tert-butyldimethyl methoxy)methyl)-2-methyl-3-nitropyridine (800 mg, 3.54 m) in methanol (50 mL). Palladium on carbon (400 mg) was added to the solution of Mohr, 1.0 equivalent, and stirred under 40 Psi of hydrogen for 16 hours. The reaction mixture was passed through diatomaceous earth and the filtrate was concentrated under reduced pressure to afford 6-((tris-butyl dimethyl methoxy oxy)methyl) Mg, 95%).

步驟5：於0℃，於一經攪拌、溶於丙酮(20毫升)之6-((三級丁基二甲基矽氧基)甲基)-2-甲基啶-3-胺(700毫克，2.7毫莫耳，1.0等量)溶液中添加啶(639毫克，8.1毫莫耳，3.0等量)及氯甲酸苯酯(422毫克，2.7毫莫耳，1.0等量)，並於0℃攪拌4小時。將丙酮蒸發，使用醋酸乙酯/石油醚(1：9)做為溶析液，以矽膠(100至200篩孔)管柱色層分析法純化殘留物，以獲得具黏性固體狀之苯基6-((三級丁基二甲基矽氧基)甲基)-2-甲基啶-3-基胺甲酸酯(1.0公克，90%)。 Step 5: 6-((tert-butyldimethyl methoxy)methyl)-2-methylpyridine-3-amine (700 mg) dissolved in acetone (20 mL) at 0 ° C , 2.7 millimolar, 1.0 equal amount) pyridine (639 mg, 8.1 mmol, 3.0 equivalent) and phenyl chloroformate (422 mg, 2.7 mmol, 1.0 equivalent) were added to the solution at 0 °C. Stir for 4 hours. The acetone was evaporated, and ethyl acetate/petroleum ether (1:9) was used as the eluent, and the residue was purified by silica gel chromatography (100 to 200 mesh) to obtain a benzene having a viscous solid. 6-((Tris-butyl dimethyl methoxy)methyl)-2-methyl pyridine-3-ylcarbamate (1.0 g, 90%).

步驟6：於0℃，於一溶於二氯甲烷(20毫升)之苯基6-((三級丁基二甲基矽氧基)甲基)-2-甲基啶-3-基胺甲酸酯(180毫克，0.48毫莫耳，1.0等量)溶液中添加三乙胺(154毫克，1.44毫莫耳，3等 量)及(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺鹽酸鹽(150毫克，0.48毫莫耳，1.0等量)加至一經攪拌、。將該反應混合物於室溫攪拌12小時。將該反應混合物以二氯甲烷稀釋，以水清洗，以二氯甲烷萃取，以硫酸鈉乾燥，並於較低壓力濃縮，以獲得白色固體狀之1-(6-((三級丁基二甲基矽氧基)甲基)-2-甲基啶-3-基)-3-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素(300毫克，約70%)。 Step 6: Phenyl 6-((tertiary butyldimethylmethyloxy)methyl)-2-methylpyridin-3-ylamine dissolved in dichloromethane (20 mL) at 0 ° C Triethylamine (154 mg, 1.44 mmol, 3 equivalents) and (1-(3-chlorophenyl)-3-() were added to the formate (180 mg, 0.48 mmol, 1.0 equivalent) solution. Trifluoromethyl)-1H-pyrazol-5-yl)methylamine hydrochloride (150 mg, 0.48 mmol, 1.0 eq.) was added and stirred. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc (EtOAc m. Methyl decyloxy)methyl)-2-methylpyridin-3-yl)-3-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5 -yl)methyl)urea (300 mg, about 70%).

步驟7：於0℃，於一經攪拌、溶於四氫呋喃(20毫升)之1-(6-((三級丁基二甲基矽氧基)甲基)-2-甲基啶-3-基)-3-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素(300毫克，0.541毫莫耳，1.0等量)溶液中添加2N之氯化氫(10毫升)。將該反應混合物於室溫攪拌3小時，並將四氫呋喃蒸發。將殘留物以醋酸乙酯稀釋，以水清洗，以硫酸鈉乾燥，並於較低壓力蒸發。使用甲醇/二氯甲烷(1：9)做為溶析液，以矽膠管柱色層分析法(100至200篩孔)純化粗製產物，以獲得灰白色固體狀之1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)-2-甲基啶-3-基)尿素(實例化合物141)(120毫克，約40%)。 Step 7: 1-(6-((tert-butyldimethyl methoxy)oxy)methyl)-2-methylpyridin-3-yl in 1-hydrofuran (20 mL) )-3-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)urea (300 mg, 0.541 mmol, 1.0 equivalent 2N hydrogen chloride (10 ml) was added to the solution. The reaction mixture was stirred at room temperature for 3 hr and THF evaporated. The residue was diluted with ethyl acetate, washed with water, dried over sodium sulfate and evaporated. The crude product was purified by silica gel column chromatography (100 to 200 mesh) using methanol/dichloromethane (1:9) as the solvent to afford 1-((1-(3) -Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(hydroxymethyl)-2-methylpyridin-3-yl)urea (Example compound 141) (120 mg, ca. 40%).

實例143之合成：Synthesis of Example 143:

1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙基)-2-甲基啶-3-基)尿素 1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethyl)-2 -methyl pyridine-3-yl) urea

步驟1：於室溫，於一經攪拌、溶於乙醇(10毫升)之2,6-二甲基-3-硝基吡啶(200毫克，1.3毫莫耳，1.0等量)溶液中，依序添加40%之甲醛水溶液(15毫升)及水(10毫升)，並於200℃攪拌48小時。將該水溶性溶媒蒸發，並使用醋酸乙酯/石油醚(2：8)做為溶析液，以矽膠管柱色層分析法(100至200篩孔)純化粗製產物，以獲得黃色液態狀之2-(6-甲基-5-硝基吡啶-2-基)乙醇(220毫克，55%)。 Step 1: at room temperature, in a solution of 2,6-dimethyl-3-nitropyridine (200 mg, 1.3 mmol, 1.0 equivalent) dissolved in ethanol (10 ml), sequentially A 40% aqueous formaldehyde solution (15 ml) and water (10 ml) were added and stirred at 200 ° C for 48 hours. The water-soluble solvent was evaporated, and ethyl acetate/petroleum ether (2:8) was used as an eluent, and the crude product was purified by silica gel column chromatography (100 to 200 mesh) to obtain a yellow liquid. 2-(6-Methyl-5-nitropyridin-2-yl)ethanol (220 mg, 55%).

步驟2：於0℃，於一經攪拌、溶於二氯甲烷(20毫升)之2-(6-甲基-5-硝基吡啶-2-基)乙醇(300毫克，1.6毫莫耳，1.0等量)溶液中，依序添加咪唑(217毫克，3.2毫莫耳，2等量)及叔丁基二甲基氯矽烷(264毫克，1.76毫莫耳，1.1等量)，並於0℃攪拌1小時。將該反應混合物以水(50毫升)稀釋，以二氯甲烷(2 x 50毫升)萃 取，並將其乾燥及濃縮，以獲得6-(2-(三級丁基二甲基矽氧基)乙基)-2-甲基-3-硝基吡啶(400毫克，82%)。 Step 2: 2-(6-methyl-5-nitropyridin-2-yl)ethanol (300 mg, 1.6 mmol, 1.0) in dichloromethane (20 mL). In an equal amount of the solution, imidazole (217 mg, 3.2 mmol, 2 equivalents) and tert-butyldimethylchloromethane (264 mg, 1.76 mmol, 1.1 equivalent) were added sequentially at 0 °C. Stir for 1 hour. The reaction mixture was diluted with water (50 mL), EtOAc (EtOAc (EtOAc) Ethyl)-2-methyl-3-nitropyridine (400 mg, 82%).

步驟3：於一經攪拌、溶於甲醇(50毫升)之6-(2-(三級丁基二甲基矽氧基)乙基)-2-甲基-3-硝基吡啶(400毫克，1.35毫莫耳，1.0等量)溶液中添加10%之鈀碳(150毫克)，並於40 Psi之氫氣氣氛下攪拌16小時。使該反應混合物通過矽藻土，並將濾液於較低壓力蒸發，以獲得6-(2-(三級丁基二甲基矽氧基)乙基)-2-甲基啶-3-胺(300毫克，83%)。 Step 3: 6-(2-(tert-butyldimethyl methoxy)ethyl)-2-methyl-3-nitropyridine (400 mg, dissolved in methanol (50 mL) To a solution of 1.35 mmol, 1.0 equivalent, 10% palladium on carbon (150 mg) was added and stirred under a hydrogen atmosphere of 40 Psi for 16 hours. The reaction mixture was passed through diatomaceous earth, and the filtrate was evaporated at a lower pressure to give 6-(2-(tert-butyldimethyl methoxy)ethyl)-2-methylpyridin-3-amine (300 mg, 83%).

步驟4：於0℃，於一經攪拌、溶於丙酮之6-(2-(三級丁基二甲基矽氧基)乙基)-2-甲基啶-3-胺(300毫克，1.12毫莫耳，1.0等量)溶液中添加啶(265毫克，3.36毫莫耳，3.0等量)及氯甲酸苯酯(176毫克，1.12毫莫耳，1.0等量)，並於0℃攪拌4小時。將丙酮蒸發，並使用醋酸乙酯/石油醚(1：9)做為溶析液，以矽膠(100至200篩孔)管柱色層分析法純化殘留物，以獲得具黏性固體狀之苯基6-(2-(三級丁基二甲基矽氧基)乙基)-2-甲基啶-3-基胺甲酸酯(213毫克，48%)。 Step 4: 6-(2-(tert-butyldimethyl methoxy)ethyl)-2-methylpyridine-3-amine (300 mg, 1.12) dissolved in acetone at 0 ° C Millenol, 1.0 equal amount) solution was charged with pyridine (265 mg, 3.36 mmol, 3.0 equivalent) and phenyl chloroformate (176 mg, 1.12 mmol, 1.0 equivalent), and stirred at 0 °C. hour. The acetone was evaporated, and ethyl acetate/petroleum ether (1:9) was used as the eluent, and the residue was purified by silica gel chromatography (100 to 200 mesh) to obtain a viscous solid. Phenyl 6-(2-(tert-butyl dimethyl dimethyloxy)ethyl)-2-methyl pyridine-3-ylcarbamate (213 mg, 48%).

步驟5：於0℃，於一經攪拌、溶於二氯甲烷(5毫升)之苯基6-(2-(三級丁基二甲基矽氧基)乙基)-2-甲基啶-3-基胺甲酸酯(213毫克，0.55毫莫耳，1.0等量)溶液中添加三乙胺(176毫克，1.65毫莫耳，3等量)及(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺鹽酸鹽(171毫克，0.55毫莫耳，1.0等量)。將該反應混合物於相同溫度攪拌12小時。隨後，將該反應混合物以二氯甲烷稀釋，以水清洗2次，以二氯甲烷萃取，以硫酸鈉乾燥，並於較低壓力濃縮，以獲得黃色液體狀之1-(6-(2-(三級丁基二甲基矽氧基)乙基)-2-甲基啶-3-基)-3-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素(300毫克，80%)。 Step 5: Phenyl 6-(2-(tert-butyldimethyl methoxy)ethyl)-2-methyl pyridine - dissolved in dichloromethane (5 mL) at 0 ° C. Add 3-ethylamine (176 mg, 1.65 mmol, 3 equivalents) and (1-(3-chlorophenyl) to a solution of 3-aminocarbamate (213 mg, 0.55 mmol, 1.0 equivalent) -3-(Trifluoromethyl)-1H-pyrazol-5-yl)methylamine hydrochloride (171 mg, 0.55 mmol, 1.0 equivalent). The reaction mixture was stirred at the same temperature for 12 hours. Subsequently, the reaction mixture was diluted with dichloromethane, washed twice with water, extracted with dichloromethane, dried over sodium sulfate, and concentrated at lower pressure to give 1-(6-(2-) (tertiary butyl dimethyl methoxy) ethyl)-2-methyl pyridine-3-yl)-3-((1-(3-chlorophenyl)-3-(trifluoromethyl)- 1H-pyrazol-5-yl)methyl)urea (300 mg, 80%).

步驟6：於0℃，於一經攪拌、溶於四氫呋喃(20毫升)之1-(6-(2-(三級丁基二甲基矽氧基)乙基)-2-甲基啶-3-基)-3-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素(300毫克，0.528毫莫耳，1.0等量)溶液中添加2 N之氯化氫(10毫升)。將該反應混合物於室溫攪拌4小時，將其濃縮，以醋酸乙酯(20毫升)稀釋，以水清洗2次，以硫酸鈉乾燥，並於較低壓力濃縮。使用甲醇/二氯甲烷(1：9)做為溶析液，以矽膠管柱色層分析法(100至200篩孔)純化粗製產物，以獲得白色固體狀之1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙基)-2-甲基啶-3-基)尿素(實例化合物143)(60毫克，25%)。 Step 6: 1-(6-(2-(tert-butyldimethyl methoxy)ethyl)-2-methylpyridine-3 in tetrahydrofuran (20 mL) at 0 ° C -yl)-3-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)urea (300 mg, 0.528 mmol, 1.0 Add 2 N of hydrogen chloride (10 ml) to the solution. The reaction mixture was stirred at rt EtOAc (EtOAc)EtOAc. The crude product was purified by silica gel column chromatography (100 to 200 mesh) using methanol/dichloromethane (1:9) as a solvent to afford 1-((1-(3) -Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethyl)-2-methylpyridine-3-yl Urea (example compound 143) (60 mg, 25%).

實例144之合成：Synthesis of Example 144:

1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(1,2-二羥乙基)啶-3-基)尿素 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(1,2-dihydroxyethyl)pyridine -3-yl) urea

步驟1：於室溫，於一溶於四氫呋喃之2-氯-4-硝基吡啶(500毫克，3.15毫莫耳)溶液中添加氯化鋰(936毫克，22.08毫莫耳，7等量)、四(三苯基膦基)鈀(0)(547毫克，0.47毫莫耳，0.15等量)及三丁基乙烯基錫(1.84毫升，6.31毫莫耳，2等量)。將該反應混合物於氮氣氣氛下回流過夜。薄層層析法顯示起始原料被完全消耗。將該反應混合物冷卻至室溫。以醋酸乙酯稀釋該混合物，以飽和之氟化鉀溶液清洗有機層，隨後以醋酸乙酯萃取。以飽和之氯化鈉溶液清洗有機部分。將有機層以硫酸鎂乾燥，並於較低壓力濃縮，以獲得粗製產物。以管柱色層分析法純化該粗製產物，以獲得5-硝基-2-乙烯吡啶(350毫克，74%)。 Step 1: Add lithium chloride (936 mg, 22.08 mmol, 7 equivalents) to a solution of 2-chloro-4-nitropyridine (500 mg, 3.15 mmol) dissolved in tetrahydrofuran at room temperature. Tetrakis(triphenylphosphino)palladium(0) (547 mg, 0.47 mmol, 0.15 equivalent) and tributylvinyltin (1.84 mL, 6.31 mmol, 2 equivalents). The reaction mixture was refluxed overnight under a nitrogen atmosphere. Thin layer chromatography showed complete consumption of the starting material. The reaction mixture was cooled to room temperature. The mixture was diluted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of potassium chloride and then extracted with ethyl acetate. The organic portion was washed with a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and concentrated at lower pressure to afford crude material. The crude product was purified by column chromatography to give 5-nitro-2-ethylpyridine (350 mg, 74%).

步驟2：於氮氣氣氛下，於以丙酮溶解之5-硝基-2-乙烯吡啶(350毫克，2.33毫莫耳)溶液中添加0.5%之四氧化鋨(溶於水)(2.36毫升，0.05毫莫耳，0.02等量)及50%之4-甲基嗎咻-N-氧化物(溶於水)(1.66毫升，6.99毫莫耳，3等量)。將該反應混合物於室溫攪拌4小時。薄層層析法顯示起始原料被完全消耗。以水稀釋，並以醋酸乙酯萃取該反應混合物。以飽和之氯化鈉溶液清洗有機部分。將有機層以硫酸鎂乾燥，並於較低壓力濃縮，以獲得粗製產物。以管柱色層分析法純化該粗製產物，以獲得1-(5-硝基吡啶-2-基)乙烷-1,2-二醇(368毫克，86%)。 Step 2: Add 0.5% osmium tetroxide (dissolved in water) to a solution of 5-nitro-2-vinylpyridine (350 mg, 2.33 mmol) dissolved in acetone under a nitrogen atmosphere (2.36 ml, 0.05). Millol, 0.02 equivalents) and 50% 4-methylindole-N-oxide (dissolved in water) (1.66 mL, 6.99 mmol, 3 equivalents). The reaction mixture was stirred at room temperature for 4 hours. Thin layer chromatography showed complete consumption of the starting material. It was diluted with water and the reaction mixture was extracted with ethyl acetate. The organic portion was washed with a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and concentrated at lower pressure to afford crude material. The crude product was purified by column chromatography to give 1-(5-nitropyridin-2-yl)ethane-1,2-diol (368 mg, 86%).

步驟3：將一溶於二氯甲烷之1-(5-硝基吡啶-2-基)乙烷-1,2-二醇(368毫克，2.00毫莫耳)溶液以四氯化鋯(47毫克，0.20毫莫耳，0.1等量)及2,2-甲氧基丙烷(0.3毫升，2.40毫莫耳，1.2等量)處理。將該混合物於室溫攪拌4小時。薄層層析法顯示起始原料被完全消耗。將該反應混合物以水稀釋，並以醋酸乙酯萃取。以飽和之氯化鈉溶液清洗有機部分。將有機層以硫酸鎂乾燥，並於較低壓力濃縮，以獲得粗製產物。以管柱色層分析法純化該粗製產物， 以獲得2-(2,2-二甲基-1,3-二氧戊環-4-基)-5-硝基吡啶(311毫克，69%)。 Step 3: A solution of 1-(5-nitropyridin-2-yl)ethane-1,2-diol (368 mg, 2.00 mmol) dissolved in dichloromethane as zirconium tetrachloride (47) Mg, 0.20 mmol, 0.1 equivalent) and 2,2-methoxypropane (0.3 mL, 2.40 mmol, 1.2 equivalent). The mixture was stirred at room temperature for 4 hours. Thin layer chromatography showed complete consumption of the starting material. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic portion was washed with a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and concentrated at lower pressure to afford crude material. The crude product was purified by column chromatography to give 2-(2,2-dimethyl-1,3-dioxolan-4-yl)-5-nitropyridine (311 mg, 69%) ).

步驟4：將2-(2,2-二甲基-1,3-二氧戊環-4-基)-5-硝基吡啶(311毫克，1.38毫莫耳)以甲醇及四氫呋喃(1：1，15毫升)溶解，並於該混合物中添加10%之鈀碳(31毫克，10%)。於氫氣氣氛下，將所得之混合物於室溫攪拌3小時。薄層層析法顯示起始原料被完全消耗。將該混合物以矽藻土床過濾，並將濾液於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得6-(2,2-二甲基-1,3-二氧戊環-4-基)啶-3-胺(201毫克，75%)。 Step 4: 2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-5-nitropyridine (311 mg, 1.38 mmol) in methanol and tetrahydrofuran (1: 1,15 ml) was dissolved, and 10% palladium on carbon (31 mg, 10%) was added to the mixture. The resulting mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. Thin layer chromatography showed complete consumption of the starting material. The mixture was filtered through a pad of celite and the filtrate was concentrated at lower pressure. The crude product was purified by column chromatography to give 6-(2,2-dimethyl-l,3-dioxolan-4-yl)pyridin-3-amine (201 mg, 75%).

步驟5：將6-(2,2-二甲基-1,3-二氧戊環-4-基)啶-3-胺(201毫克，1.04毫莫耳)以乙腈(3毫升)及四氫呋喃(4毫升)溶解。於該反應混合物中添加啶(0.10毫升，1.24毫莫耳，1.2等量)及氯甲酸苯酯(0.14毫升，1.09毫莫耳，1.05等量)，於氮氣氣氛下，將其於室溫攪拌3小時。薄層層析法顯示起始原料被完全消耗。將該反應混合物以水稀釋並以醋酸乙酯萃取。以水及飽和之氯化鈉溶液清洗有機部分。將有機層以硫酸鎂乾燥，並於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得苯基6-(2,2-二甲基-1,3-二氧戊環-4-基)啶-3-基胺甲酸酯(321毫克，99%)。 Step 5: 6-(2,2-Dimethyl-1,3-dioxolan-4-yl)pyridine-3-amine (201 mg, 1.04 mmol) in acetonitrile (3 mL) and THF (4 ml) dissolved. Add pyridine (0.10 ml, 1.24 mmol, 1.2 equivalent) and phenyl chloroformate (0.14 ml, 1.09 mmol, 1.05 equivalent) to the reaction mixture, and stir at room temperature under nitrogen atmosphere. 3 hours. Thin layer chromatography showed complete consumption of the starting material. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic portion was washed with water and a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and concentrated at lower pressure. The crude product was purified by column chromatography to give phenyl 6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-ylcarbamate (321 Mg, 99%).

步驟6：於室溫，於一溶於氰甲烷之苯基6-(2,2-二甲基-1,3-二氧戊環-4-基)啶-3-基胺甲酸酯(79毫克，0.251毫莫耳)溶液中添加4-二甲胺基啶(31毫克，0.251毫莫耳)及(3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺(66毫克，0.251毫莫耳)。將該反應混合物於50℃加熱過夜。薄層層析法顯示起始原料被完全消耗。將該反應混合物以水稀釋，並以醋酸乙酯萃取。將有機部分以水及飽和之氯化鈉溶液清洗。將有機層以硫酸鎂乾燥，並於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得1-((3-三級丁基 -1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(2,2-二甲基-1,3-二氧戊環-4-基)啶-3-基)尿素(111毫克，91%)。 Step 6: Phenyl 6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-ylcarbamate in cyanomethane at room temperature ( Add 4-dimethylamididine (31 mg, 0.251 mmol) and (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazole in a solution of 79 mg, 0.251 mmol. -5-yl)methylamine (66 mg, 0.251 mmol). The reaction mixture was heated at 50 °C overnight. Thin layer chromatography showed complete consumption of the starting material. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic portion was washed with water and a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and concentrated at lower pressure. The crude product was purified by column chromatography to give 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-( 6-(2,2-Dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)urea (111 mg, 91%).

步驟7：於室溫，於一溶於甲醇之1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(2,2-二甲基-1,3-二氧戊環-4-基)啶-3-基)尿素(111毫克，0.229毫莫耳)溶液中添加四氯化鋯(5毫克，0.0229毫莫耳)。將該反應混合物以35℃加熱過夜。薄層層析法顯示起始原料被完全消耗。將該反應混合物以水稀釋，並以醋酸乙酯萃取。將有機部分以水及飽和之氯化鈉溶液清洗。將有機層以硫酸鎂乾燥，並於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(1,2-二羥乙基)啶-3-基)尿素(實例化合物144)(21毫克，21%)。 Step 7: 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(1-tris-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3- Add zirconium tetrachloride (5 mg) to a solution of 6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)urea (111 mg, 0.229 mmol) , 0.0229 millimoles). The reaction mixture was heated at 35 °C overnight. Thin layer chromatography showed complete consumption of the starting material. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic portion was washed with water and a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and concentrated at lower pressure. The crude product was purified by column chromatography to give 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-( 6-(1,2-Dihydroxyethyl)pyridin-3-yl)urea (example compound 144) (21 mg, 21%).

1H核磁共振(300 MHz，二甲亞碸)：δ 8.79(br s，1H)；8.44(d，J=2.4 Hz，1H)；7.82(d，J=8.61 Hz，1H)；7.61(s，1H)；7.55-7.46(m，3H)；7.32(d，J=8.43 Hz，1H)；6.84(br t，1H)；6.32(s，1H)；5.27(d，J=4.74 Hz，1H)；4.65(t，J=5.7 Hz，1H)；4.49(m，1H)；4.40(d，J=5.67 Hz，2H)；3.61(m，1H)；1.96(d，J=9.87 Hz，1H)；1.27(s，9H)。 1 H NMR (300 MHz, dimethyl hydrazine): δ 8.79 (br s, 1H); 8.44 (d, J = 2.4 Hz, 1H); 7.82 (d, J = 8.61 Hz, 1H); 7.61 (s , 1H); 7.55-7.46 (m, 3H); 7.32 (d, J = 8.43 Hz, 1H); 6.84 (br t, 1H); 6.32 (s, 1H); 5.27 (d, J = 4.74 Hz, 1H) ); 4.65 (t, J = 5.7 Hz, 1H); 4.49 (m, 1H); 4.40 (d, J = 5.67 Hz, 2H); 3.61 (m, 1H); 1.96 (d, J = 9.87 Hz, 1H) ); 1.27 (s, 9H).

實例145之合成：Synthesis of Example 145:

1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(1,2-二羥乙基)啶-3-基)尿素 1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(1,2-dihydroxyethyl) Pyridin-3-yl)urea

步驟1至5：參照實例化合物102。 Steps 1 to 5: Refer to Example Compound 102.

步驟6：於室溫，於一溶於乙腈(3毫升)之苯基6-(2,2-二甲基-1,3-二氧戊環-4-基)啶-3-基胺甲酸酯(200毫克，0.64毫莫耳)溶液中添加4-二甲胺基啶(78毫克，0.64毫莫耳，1等量)及(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺(192毫克，0.70毫莫耳，1.1等量)。將該反應混合物以50℃加熱過夜。薄層層析法顯示起始原料被完全消耗。將該反應混合物以水稀釋，並以醋酸乙酯萃取。將有機部分以水及飽和之氯化鈉溶液清洗。將有機層以硫酸鎂乾燥，並於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2,2-二甲基-1,3-二氧戊環-4-基)啶-3-基)尿素(303毫克，96%)。 Step 6: Phenyl 6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-ylamine in acetonitrile (3 ml) at room temperature 4-dimethylaminopyridine (78 mg, 0.64 mmol, 1 equivalent) and (1-(3-chlorophenyl)-3-(3) were added to the solution of the acid ester (200 mg, 0.64 mmol). Fluoromethyl)-1H-pyrazol-5-yl)methylamine (192 mg, 0.70 mmol, 1.1 equivalent). The reaction mixture was heated at 50 °C overnight. Thin layer chromatography showed complete consumption of the starting material. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic portion was washed with water and a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and concentrated at lower pressure. The crude product was purified by column chromatography to give 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3 -(6-(2,2-Dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)urea (303 mg, 96%).

步驟7：於室溫，於一溶於甲醇之1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2,2-二甲基-1,3-二氧戊環-4-基)啶-3-基)尿素(303毫克，0.61毫莫耳)溶液中添加四氯化鋯(28毫克，0.12 毫莫耳，0.3等量)。將該反應混合物以35℃加熱過夜。薄層層析法顯示起始原料被完全消耗。將該反應混合物以水稀釋，並以醋酸乙酯萃取。將有機部分以水及飽和之氯化鈉溶液清洗。將有機層以硫酸鎂乾燥，並於較低壓力濃縮。以管柱色層分析法純化粗製產物，以獲得1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(1,2-二羥乙基)啶-3-基)尿素(實例化合145)(102毫克，37%)。 Step 7: 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3 in methanol at room temperature -(6-(2,2-Dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)urea (303 mg, 0.61 mmol) was added with zirconium tetrachloride ( 28 mg, 0.12 mmol, 0.3 equivalent). The reaction mixture was heated at 35 °C overnight. Thin layer chromatography showed complete consumption of the starting material. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic portion was washed with water and a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and concentrated at lower pressure. The crude product was purified by column chromatography to give 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3 -(6-(1,2-Dihydroxyethyl)pyridin-3-yl)urea (example compound 145) (102 mg, 37%).

1H核磁共振(400 MHz，CDCl3)：δ 8.45(d，1H，Ar)；7.86(dd，1H，J=2.1 Hz，8.5 Hz，Ar)；7.64(q，1H，Ar)；7.51-7.56(m，3H，Ar)；7.45(d，1H，J=8.4 Hz，Ar)；6.75(s，1H，吡唑)；4.69(m，1H，CH)；4.48(s，2H，CH2)；3.60-3.80(m，2H，CH2)。 1 H NMR (400 MHz, CDCl 3 ): δ 8.45 (d, 1H, Ar); 7.86 (dd, 1H, J = 2.1 Hz, 8.5 Hz, Ar); 7.64 (q, 1H, Ar); 7.56 (m, 3H, Ar); 7.45 (d, 1H, J = 8.4 Hz, Ar); 6.75 (s, 1H, pyrazole); 4.69 (m, 1H, CH); 4.48 (s, 2H, CH2) ; 3.60-3.80 (m, 2H, CH2).

實例146之合成：Synthesis of Example 146:

N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-(2-羥乙胺)啶-3-基)丙醯胺 N-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(6-(2-hydroxyethylamine)pyridine- 3-mercaptoamine

步驟1：於-78℃，於一經攪拌、溶於二氯甲烷(10毫升)之N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-(2-甲氧基乙胺)啶-3-基)丙醯胺(實例化合物147，300毫克，0.623毫莫耳，1.0等量)溶液中添加、溶於二氯甲烷之1M三溴化硼(1.87毫升，1.871毫莫耳，3.0等量)，將其於室溫攪拌3小時，並以碳酸氫鈉 將酸鹼值調整為約8，再以水(20毫升)將其稀釋。以醋酸乙酯(2 x 50毫升)萃取水層；將合併有機層分離，以飽和之氯化鈉溶液(50毫升)清洗，以硫酸鈉乾燥，並於真空狀態將其蒸發。使用甲醇/三氯甲烷(1：9)作為溶析液，以矽膠管柱(100至200篩孔)純化粗製產物，以獲得灰白色固體狀之N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-(2-羥乙胺)啶-3-基)丙醯胺(實例化合物146)(140毫克，48%)。 Step 1: N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole) was dissolved in dichloromethane (10 mL) at -78 °C. 5-yl)methyl)-2-(6-(2-methoxyethylamine)-3-yl)propanamide (example compound 147, 300 mg, 0.623 mmol, 1.0 equivalent) Add 1 M boron tribromide (1.87 ml, 1.871 mmol, 3.0 equivalents) in dichloromethane, stir at room temperature for 3 hours, and adjust the pH to about 8 with sodium bicarbonate. It was then diluted with water (20 ml). The aqueous layer was extracted with EtOAc (EtOAc)EtOAc. The crude product was purified using a methanol/trichloromethane (1:9) as a solvent eluting with a silica gel column (100 to 200 mesh) to afford N-((1-(3-chlorophenyl) -3-(Trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(6-(2-hydroxyethylamine)-3-yl)propanamide (example compound 146) 140 mg, 48%).

實例147之合成： Synthesis of Example 147 :

N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-(2-甲氧基乙胺)啶-3-基)丙醯胺 N-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(6-(2-methoxyethylamine) Pyridin-3-yl)propanamide

步驟1：於0℃，於一經攪拌、溶於乙醇(10毫升)之2-氯-5-(氯甲基)啶(1公克，6.17毫莫耳，1.0等量)溶液中，逐滴添加溶於水(10毫升)之氰化鈉(325毫克，6.79毫莫耳，1.1等量)溶液，隨後 將其於100℃攪拌3小時。將該反應混合物以水(50毫升)清洗，以醋酸乙酯(2 x 70毫升)萃取，並以飽和之氯化鈉溶液(20毫升)清洗。將有機層以無水硫酸鈉乾燥，並於真空狀態蒸發。使用醋酸乙酯/石油醚(3：7)作為溶析液，以矽膠色層分析法(100至200篩孔)純化粗製產物，以獲得黃色固體狀之2-(6-氯啶-3-基)乙腈(400毫克，63%)。 Step 1: Add dropwise at 0 ° C in a solution of 2-chloro-5-(chloromethyl)pyridine (1 g, 6.17 mmol, 1.0 equivalent) dissolved in ethanol (10 ml) A solution of sodium cyanide (325 mg, 6.79 mmol, 1.1 equivalent) dissolved in water (10 ml) was then stirred at 100 ° C for 3 hours. The reaction mixture was washed with EtOAc (EtOAc) (EtOAc) The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by silica gel chromatography (100 to 200 mesh) using ethyl acetate/petroleum ether (3:7) as eluent to afford 2-(6-chloropyridine-3- Base) acetonitrile (400 mg, 63%).

步驟2：於一經攪拌、溶於四氫呋喃(100毫升)之2-(6-氯啶-3-基)乙腈(10公克，65.7毫莫耳，1.0等量)溶液中，分次添加氫化鈉(1.578公克，65.7毫莫耳，1.0等量)，並將其於0℃攪拌10分鐘，隨後於該混合物中添加甲基碘化物(4.02毫升，65.7毫莫耳，1.0等量)。於0℃，將該反應混合物緩慢地以水(150毫升)稀釋，以醋酸乙酯(2 x 100毫升)及飽和之氯化鈉溶液(100毫升)萃取，以硫酸鈉乾燥，並於真空狀態蒸發。使用醋酸乙酯/石油醚(1：4)做為溶析液，以矽膠色層分析法(100至200篩孔)純化粗製產物，以獲得固體狀之2-(6-氯啶-3-基)丙腈(5公克，46%)。 Step 2: Sodium hydride was added in portions in a solution of 2-(6-chloropyridin-3-yl)acetonitrile (10 g, 65.7 mmol, 1.0 equivalent) dissolved in tetrahydrofuran (100 mL). 1.578 g, 65.7 mmol, 1.0 equivalent), and stirred at 0 °C for 10 minutes, then methyl iodide (4.02 mL, 65.7 mmol, 1.0 equivalent) was added to the mixture. The reaction mixture was slowly diluted with water (150 ml), EtOAc (EtOAc (EtOAc) evaporation. The crude product was purified by silica gel chromatography (100 to 200 mesh) using ethyl acetate/petroleum ether (1:4) as a solvent to give solid 2-(6-chloropyridine-3- Base) propionitrile (5 grams, 46%).

步驟3：於一經攪拌、溶於二甲亞碸(15毫升)之2-(6-氯啶-3-基)丙腈(2公克，12.04毫莫耳，1.0等量)溶液中添加三乙胺(3.34毫升，24.09毫莫耳，2.0等量)及N-(2-甲氧基乙基)甲基胺(1.8公克，24.09毫莫耳，2.0等量)。將該反應混合物以100℃加熱16小時。將該反應混合物以水(50毫升)稀釋，並以醋酸乙酯(2 x 60毫升)萃取。將有機層以飽和之氯化鈉溶液(50毫升)清洗，以硫酸鈉乾燥，並於真空狀態蒸發。使用醋酸乙酯/石油醚(3：7)做為溶析液，以中性氧化鋁純化所得之殘留物，以獲得白色固體狀之2-(6-(2-甲氧基乙胺)啶-3-基)丙腈(500毫克，40%)。 Step 3: Add triethyl bromide to a solution of 2-(6-chloropyridin-3-yl)propanenitrile (2 g, 12.04 mmol, 1.0 equivalent) dissolved in dimethyl hydrazine (15 ml) Amine (3.34 mL, 24.09 mmol, 2.0 equivalent) and N-(2-methoxyethyl)methylamine (1.8 g, 24.09 mmol, 2.0 equivalent). The reaction mixture was heated at 100 ° C for 16 hours. The reaction mixture was diluted with water (50 mL) andEtOAc. The organic layer was washed with EtOAc (EtOAc)EtOAc. The ethyl acetate/petroleum ether (3:7) was used as the eluent, and the residue obtained was purified from neutral alumina to give 2-(6-(2-methoxyethylamine) pyridine as a white solid. 3-yl)propanenitrile (500 mg, 40%).

步驟4：於一經攪拌、溶於甲醇(8毫升)之三甲基氯矽烷(TMSCl)(4.6毫升，20.4毫莫耳，3.0等量)溶液中添加2-(6-(2-甲 氧基乙胺)啶-3-基)丙腈(1.4公克，6.8毫莫耳，1.0等量)，並將其以60℃加熱5小時。將該反應混合物以水(50毫升)稀釋，以碳酸氫鈉(10毫升)將酸鹼值調整為約9，並以醋酸乙酯(2 x 100毫升)萃取。將有機層分離，並以飽和之氯化鈉溶液(50毫升)清洗，以硫酸鈉乾燥，並於真空狀態蒸發。使用醋酸乙酯/石油醚(1：1)做為溶析液，以矽膠管柱(100至200篩孔)純化殘留物，以獲得淡黃色液體狀之甲基2-(6-(2-甲氧基乙胺)啶-3-基)丙酸(1.2公克，73.5%)。 Step 4: Add 2-(6-(2-methoxy) to a solution of trimethylchloromethane (TMSCl) (4.6 mL, 20.4 mmol, 3.0 equivalent) dissolved in methanol (8 mL). Ethylamine)pyridin-3-yl)propanenitrile (1.4 g, 6.8 mmol, 1.0 equivalent) was heated at 60 °C for 5 hours. The reaction mixture was diluted with water (50 mL) EtOAc (EtOAc) The organic layer was separated, washed with EtOAc EtOAc m. Ethyl acetate/petroleum ether (1:1) was used as the eluent, and the residue was purified on a silica gel column (100 to 200 mesh) to obtain methyl 2-(6-(2-) Methoxyethylamine)pyridin-3-yl)propionic acid (1.2 g, 73.5%).

步驟5：於60℃，於一經攪拌、溶於四氫呋喃/水(5毫升+5毫升)之甲基2-(6-(2-甲氧基乙胺)啶-3-基)丙酸(200毫克，0.840毫莫耳，1.0等量)溶液中添加氫氧化鋰/水(104毫克，2.52毫莫耳，3.0等量)，並攪拌2小時。將該反應混合物以水(5毫升)稀釋，以1N之氯化氫酸化(pH約4)，隨後以醋酸乙酯(2 x 25毫升)萃取。將有機層以飽和之氯化鈉溶液(20毫升)清洗，以無水硫酸鈉乾燥，並於真空狀態蒸發，以獲得2-(6-(2-甲氧基乙胺)啶-3-基)丙酸(120毫克，64%)。該粗製產物不需進一步純化，即可直接於下一步驟使用。 Step 5: Methyl 2-(6-(2-methoxyethylamine)-3-yl)propanoic acid (200) dissolved in tetrahydrofuran/water (5 mL + 5 mL) at 60 ° C To the solution was added lithium hydroxide/water (104 mg, 2.52 mmol, 3.0 equivalent) in milligrams, 0.840 mmol, 1.0 equivalents, and stirred for 2 hours. The reaction mixture was diluted with water (5 mL) EtOAc (EtOAc)EtOAc. The organic layer was washed with saturated aqueous sodium chloride (20 ml), dried over anhydrous sodium sulfate and evaporated in vacuo to afford 2-(6-(2-methoxyethylamine) Propionic acid (120 mg, 64%). This crude product was used directly in the next step without further purification.

步驟6：於室溫，於一經攪拌、溶於二氯甲烷(5毫升)之2-(6-(2-甲氧基乙胺)啶-3-基)丙酸(224毫克，0.446毫莫耳，1.0等量)溶液中，依序添加N-(3-二甲胺基丙基)-N’-乙基碘化二亞胺.氯化氫(127毫克，0.669毫莫耳，1.5等量)、N-羧苯並三唑(75毫克，0.490毫莫耳，1.1等量)，N,N-二異丙基乙胺(DIPEA)(0.23毫升，1.338毫莫耳，3等量)及(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺(139毫克，0.446毫莫耳，1.0等量)，並攪拌3小時。將該反應混合物以水(10毫升)稀釋，並以醋酸乙酯萃取(2 x 25毫升)。將有機層以飽和之氯化鈉溶液(20毫升)清洗，以無水硫酸鈉乾燥，並於真空狀態蒸發。使用甲醇/三氯甲烷(1：19)做為溶析液，以管柱色層分析 法(100至200篩孔)純化粗製產物，以獲得灰白色固體狀之N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-(2-甲氧基乙胺)啶-3-基)丙醯胺(實例化合物147)(80毫克，37%)。 Step 6: 2-(6-(2-methoxyethylamine)pyridine-3-yl)propanoic acid (224 mg, 0.446 mmol) dissolved in dichloromethane (5 mL). N,(3-dimethylaminopropyl)-N'-ethyl iodide diimide. Hydrogen chloride (127 mg, 0.669 mmol, 1.5 equivalent) was added to the solution in an ear, 1.0 equivalent. , N-carboxybenzotriazole (75 mg, 0.490 mmol, 1.1 equivalent), N,N-diisopropylethylamine (DIPEA) (0.23 mL, 1.338 mmol, 3 equivalents) and 1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamine (139 mg, 0.446 mmol, 1.0 equivalent) and stirred for 3 hours. The reaction mixture was diluted with water (10 mL) andEtOAc. The organic layer was washed with EtOAc (EtOAc m. The crude product was purified by column chromatography (100 to 200 mesh) using methanol/trichloromethane (1:19) as a solvent to afford N-((1-(3-) Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(6-(2-methoxyethylamine)pyridin-3-yl)propanamide (Example compound 147) (80 mg, 37%).

可以類似方法製備實例88。 Example 88 can be prepared in a similar manner.

實例148之合成：Synthesis of Example 148:

N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-((2-羥乙基)(甲基)胺基)啶-3-基)丙醯胺 N-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(6-((2-hydroxyethyl)) Methyl)amino)pyridin-3-yl)propanamide

步驟1：於0℃，於一經攪拌、溶於乙醇之2-氯-5-(氯甲基)啶(1公克，6.17毫莫耳，1.0等量)溶液中，逐滴添加溶於水(10毫升) 之氰化鈉(325毫克，6.79毫莫耳，1.1等量)溶液，隨後將其於100℃攪拌3小時。將該反應混合物以水(50毫升)稀釋，並以醋酸乙酯(2 x 70毫升)萃取。將有機層以硫酸鈉乾燥。並於真空狀態蒸發。使用醋酸乙酯/石油醚(3：7)做為溶析液，以矽膠色層分析法(100至200篩孔)純化粗製產物，以獲得黃色固體狀之2-(6-氯啶-3-基)乙腈(400毫克，63%)。 Step 1: Dissolve in water at 0 ° C in a solution of 2-chloro-5-(chloromethyl)pyridine (1 g, 6.17 mmol, 1.0 equivalent) dissolved in ethanol. 10 ml) of sodium cyanide (325 mg, 6.79 mmol, 1.1 equivalent) solution, which was then stirred at 100 ° C for 3 hours. The reaction mixture was diluted with water (50 mL) andEtOAc. The organic layer was dried over sodium sulfate. And evaporated in a vacuum state. The crude product was purified by silica gel chromatography (100 to 200 mesh) using ethyl acetate/petroleum ether (3:7) as the eluent to give 2-(6-chloropyridine-3) as a yellow solid. -Base) Acetonitrile (400 mg, 63%).

步驟2：於一經攪拌、溶於四氫呋喃(100毫升)、冷卻至0℃之2-(6-氯啶-3-基)乙腈(10公克，65.7毫莫耳，1.0等量)溶液中，分次添加氫化鈉(1.578公克，65.7毫莫耳，1.0等量)，並攪拌10分鐘。於0℃添加碘甲烷(4.02毫升，65.7毫莫耳，1.0等量)。將該反應混合物以水(150毫升)稀釋，以醋酸乙酯(100毫升x2)及飽和之氯化鈉溶液(100毫升)萃取，以硫酸鈉乾燥，並於真空狀態蒸發。使用醋酸乙酯/石油醚(1：4)做為溶析液，以矽膠色層分析法(100至200篩孔)純化粗製產物，以獲得固體狀之2-(6-氯啶-3-基)丙腈(5公克，46%)。 Step 2: In a solution of 2-(6-chloropyridin-3-yl)acetonitrile (10 g, 65.7 mmol, 1.0 equivalent) dissolved in tetrahydrofuran (100 ml) and cooled to 0 ° C Sodium hydride (1.578 g, 65.7 mmol, 1.0 equivalent) was added in portions and stirred for 10 minutes. Methyl iodide (4.02 mL, 65.7 mmol, 1.0 equivalent) was added at 0 °C. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The crude product was purified by silica gel chromatography (100 to 200 mesh) using ethyl acetate/petroleum ether (1:4) as a solvent to give solid 2-(6-chloropyridine-3- Base) propionitrile (5 grams, 46%).

步驟3：於一經攪拌、溶於二甲亞碸(7毫升)之2-(6-氯啶-3-基)丙腈(1公克，6.02毫莫耳，1.0等量)溶液中添加三乙胺(1.67毫升，12.04毫莫耳，2.0等量)及N-(2-甲氧基乙基)甲基胺(1.07公克，12.04毫莫耳，2.0等量)。將該反應混合物於100℃加熱16小時。將該反應混合物以水(50毫升)稀釋，並以醋酸乙酯(2 x 60毫升)萃取。將有機層以飽和之氯化鈉溶液(50毫升)清洗，以硫酸鈉乾燥，並於真空狀態蒸發。使用酸乙酯/石油醚(1：4)做為溶析液，以中性氧化鋁純化所得之殘留物，以獲得白色固體狀之2-(6-((2-甲氧基乙基)(甲基)胺基)啶-3-基)丙腈(600毫克，45%)。 Step 3: Add triethyl bromide to a solution of 2-(6-chloropyridin-3-yl)propionitrile (1 g, 6.02 mmol, 1.0 equivalent) dissolved in dimethyl hydrazine (7 ml) Amine (1.67 ml, 12.04 mmol, 2.0 equivalent) and N-(2-methoxyethyl)methylamine (1.07 g, 12.04 mmol, 2.0 equivalent). The reaction mixture was heated at 100 ° C for 16 hours. The reaction mixture was diluted with water (50 mL) andEtOAc. The organic layer was washed with EtOAc (EtOAc)EtOAc. The residue obtained was purified by neutral alumina using ethyl acetate/petroleum ether (1:4) as a solvent to give 2-(6-((2-methoxyethyl)) as a white solid. (Methyl)amino)pyridin-3-yl)propanenitrile (600 mg, 45%).

步驟4：於一經攪拌之三甲基氯矽烷(3.0毫升，13.69毫莫耳，3.0等量)與甲醇(0.73毫升，22.8毫莫耳，5.0等量)溶液中添加 2-(6-((2-甲氧基乙基)(甲基)胺基)啶-3-基)丙腈(1公克，22.8毫莫耳，5.0等量)，並於60℃加熱5小時。將該反應混合物以水(50毫升)稀釋，以碳酸氫鈉(10毫升)將酸鹼值調整為約9，並以醋酸乙酯(2 x 60毫升)萃取。將有機層分離，以飽和之氯化鈉溶液(50毫升)清洗，以硫酸鈉乾燥，並於真空狀態蒸發。使用醋酸乙酯/石油醚(2：3)做為溶析液，以矽膠管柱(100至200篩孔)純化殘留物，以獲得淡黃色油狀之甲基2-(6-((2-甲氧基乙基)(甲基)胺基)啶-3-基)丙酸(700毫克，61%)。 Step 4: Add 2-(6-(()) to a stirred solution of trimethylchloromethane (3.0 ml, 13.69 mmol, 3.0 equivalent) and methanol (0.73 mL, 22.8 mmol, 5.0 equivalent). 2-Methoxyethyl)(methyl)amino)pyridin-3-yl)propanenitrile (1 g, 22.8 mmol, 5.0 equivalent) and heated at 60 °C for 5 hours. The reaction mixture was diluted with water (50 mL) EtOAc (EtOAc) The organic layer was separated, washed with EtOAc EtOAc m. Ethyl acetate/petroleum ether (2:3) was used as the eluent, and the residue was purified on a silica gel column (100 to 200 mesh) to obtain methyl 2-(6-((2) -Methoxyethyl)(methyl)amino)pyridin-3-yl)propanoic acid (700 mg, 61%).

步驟5：於60℃，於一經攪拌、溶於四氫呋喃：水(5毫升+5毫升)之甲基2-(6-((2-甲氧基乙基)(甲基)胺基)啶-3-基)丙酸(200毫克，0.793毫莫耳，1.0等量)溶液中添加氫氧化鋰．水(99毫克，2.380毫莫耳，3.0等量)，並攪拌2小時。將該反應混合物以水(5毫升)稀釋，以1N之氯化氫酸化，隨後以醋酸乙酯(2 x 25毫升)萃取。將有機層以水(20毫升)及飽和之氯化鈉溶液(20毫升)清洗，以無水硫酸鈉乾燥，並於真空狀態蒸發，以獲得2-(6-((2-甲氧基乙基)(甲基)胺基)啶-3-基)丙酸(150毫克，79%)。該粗製產物不需進一步純化，即可於下一步驟使用。 Step 5: methyl 2-(6-((2-methoxyethyl))(methyl)amino)pyridine at 60 ° C in tetrahydrofuran: water (5 mL + 5 mL) Add lithium hydroxide to a solution of 3-yl)propionic acid (200 mg, 0.793 mmol, 1.0 equivalent). Water (99 mg, 2.380 mmol, 3.0 equivalent) and stirred for 2 hours. The reaction mixture was diluted with water (5 mL) EtOAc. The organic layer was washed with water (20 ml) and sat. sodium chloride (20 ml), dried over anhydrous sodium sulfate and evaporated in vacuo to afford 2-(6-((2-methoxyethyl) (Methyl)amino)pyridin-3-yl)propanoic acid (150 mg, 79%). This crude product was used in the next step without further purification.

步驟6：於室溫，於一經攪拌、溶於二氯甲烷(10毫升)之2-(6-((2-甲氧基乙基)(甲基)胺基)啶-3-基)丙酸(150毫克，0.630毫莫耳，1.0等量)溶液中，依序添加N-(3-二甲胺基丙基)-N’-乙基碘化二亞胺．氯化氫(180毫克，0.945毫莫耳，1.5等量)、N-羧苯並三唑(106毫克，0.693毫莫耳，1.1等量)、N,N-二異丙基乙胺(0.3毫升，1.89毫莫耳，3等量)及(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺(173毫克，0.630毫莫耳，1.0等量)，並攪拌3小時。將二氯甲烷蒸發，將殘留物以水(10毫升)稀釋，並以醋酸乙酯(2 x 25毫升)萃取。將有機層以飽和之氯化鈉溶液(20毫升)清洗，以無 水硫酸鈉乾燥，並於真空狀態蒸發。使用甲醇/三氯甲烷(1：19)做為溶析液，以矽膠管柱色層分析法(100至200篩孔)純化粗製產物，以獲得N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-((2-甲氧基乙基)(甲基)胺基)啶-3-基)丙醯胺(140毫克，45%，淡黃色黏稠液體)。 Step 6: 2-(6-((2-methoxyethyl)(methyl)amino)pyridin-3-yl)propanol in dichloromethane (10 mL) N-(3-dimethylaminopropyl)-N'-ethyl iodide diimine was added sequentially to the solution of acid (150 mg, 0.630 mmol, 1.0 equivalent). Hydrogen chloride (180 mg, 0.945 mmol, 1.5 equivalents), N-carboxybenzotriazole (106 mg, 0.693 mmol, 1.1 equivalent), N,N-diisopropylethylamine (0.3 mL, 1.89 millimolar, 3 equal amounts) and (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamine (173 mg, 0.630 mmol, 1.0 equivalent) and stirred for 3 hours. The methylene chloride was evaporated, the~~~~~~~ The organic layer was washed with EtOAc (EtOAc m. The crude product was purified by column chromatography (100 to 200 mesh) using methanol/trichloromethane (1:19) as a solvent to obtain N-((1-(3-chlorophenyl)). --3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(6-((2-methoxyethyl)(methyl)amino)pyridine-3- Base) acrylamide (140 mg, 45%, pale yellow viscous liquid).

步驟7：於-78℃，於一經攪拌、溶於二氯甲烷(20毫升)之N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-((2-甲氧基乙基)(甲基)胺基)啶-3-基)丙醯胺(300毫克，0.606毫莫耳，1.0等量)溶液中添加溶於二氯甲烷之1M三溴化硼(0.9毫升，0.909毫莫耳，1.5等量)，並於室溫攪拌3小時。以碳酸氫鈉將該反應物之酸鹼值調整至約8，並以水(20毫升)稀釋。以醋酸乙酯(2 x 50毫升)萃取水層；將合併有機層分離，並以飽和之氯化鈉溶液(50毫升)清洗，以硫酸鈉乾燥，並於真空狀態下蒸發。使用甲醇/三氯甲烷(1：9)做為溶析液，以矽膠色層分析法(100至200篩孔)純化殘留物，以獲得黃色固體狀之N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-((2-羥乙基)(甲基)胺基)啶-3-基)丙醯胺(實例化合物148)(200毫克，68%)。 Step 7: N-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole---(-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole) was dissolved in dichloromethane (20 mL). 5-yl)methyl)-2-(6-((2-methoxyethyl)(methyl)amino)pyridin-3-yl)propanamide (300 mg, 0.606 mmol, 1.0, etc.) To the solution was added 1 M boron tribromide (0.9 ml, 0.909 mmol, 1.5 equivalent) dissolved in dichloromethane, and stirred at room temperature for 3 hours. The pH of the reaction was adjusted to ca. 8 with sodium bicarbonate and diluted with water (20 mL). The aqueous layer was extracted with EtOAc (EtOAc)EtOAc. The residue was purified by silica gel chromatography (100 to 200 mesh) using methanol/trichloromethane (1:9) as a solvent to afford N-((1-(3-chloro) Phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(6-((2-hydroxyethyl)(methyl)amino)pyridine-3- Propionamide (example compound 148) (200 mg, 68%).

實例152之合成：Synthesis of Example 152:

1-((3-三級丁基-1-(3-氟苯基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙基)啶-3-基)尿素 1-((3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethyl)pyridine-3- Urea

步驟1至6：參照實例化合物52。 Steps 1 to 6: Refer to Example Compound 52.

步驟7：於室溫，於一經攪拌、溶於二氯甲烷(10毫升)之(3-三級丁基-1-(3-氟苯基)-1H-吡唑-5-基)甲胺鹽酸鹽(150毫克，0.606毫莫耳，1.0等量)溶液中添加三乙胺(184毫克，2.326毫莫耳，3.0等量)加至，並攪拌10分鐘，隨後添加苯基6-(2-(三級丁基二甲基矽氧基)乙基)啶-3-基胺甲酸酯(226毫克，0.605毫莫耳，1.0等量)，再於室溫攪拌16小時。將該反應混合物蒸發，並以矽膠管柱色層分析法(60至120篩孔)純化所得之粗製產物，以獲得固體狀之1-((3-三級丁基-1-(3-氟苯基)-1H-吡唑-5-基)甲基)-3-(6-(2-(三級丁基二甲基矽氧基)乙基)啶-3-基)尿素(280毫克，88%)。 Step 7: (3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazol-5-yl)methanamine dissolved in dichloromethane (10 mL) at room temperature Add the triethylamine (184 mg, 2.326 mmol, 3.0 equivalent) to the solution of the hydrochloride (150 mg, 0.606 mmol, 1.0 equivalent) and stir for 10 minutes, then add phenyl 6-( 2-(tert-butyl dimethyl dimethyloxy)ethyl) pyridine-3-ylcarbamate (226 mg, 0.605 mmol, 1.0 eq.) was stirred at room temperature for 16 hours. The reaction mixture was evaporated, and the obtained crude product was purified by silica gel column chromatography (60 to 120 mesh) to obtain 1-((3-tris-butyl-1-) 3-fluoro Phenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-(tertiary butyldimethylamyloxy)ethyl)pyridin-3-yl)urea (280 mg) , 88%).

步驟8：於室溫，於一經攪拌、溶於四氫呋喃(3毫升)之1-((3-三級丁基-1-(3-氟苯基)-1H-吡唑-5-基)甲基)-3-(6-(2-(三級丁基二甲基矽氧基)乙基)啶-3-基)尿素(280毫克，0.5706毫莫耳，1.0等量) 溶液中添加2N之氯化氫(1.5毫升)，並攪拌2小時。將該反應混合物以碳酸氫鈉水溶液中和，以醋酸乙酯萃取，以硫酸鈉乾燥，並將其蒸發，已獲得固體狀之1-((3-三級丁基-1-(3-氟苯基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙基)啶-3-基)尿素(實例化合物152)(84毫克，35%)。 Step 8: 1-((3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazol-5-yl)-) in tetrahydrofuran (3 mL) 3-(6-(2-(tertiary butyldimethyl)oxy)ethyl)pyridin-3-yl)urea (280 mg, 0.5706 mmol, 1.0 equivalent) 2N added to solution Hydrogen chloride (1.5 ml) was stirred for 2 hours. The reaction mixture was neutralized with aqueous sodium hydrogencarbonate, extracted with ethyl acetate, dried over sodium sulfate and evaporated and evaporated. Phenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethyl)pyridin-3-yl)urea (example compound 152) (84 mg, 35%).

實例153之合成：Synthesis of Example 153:

1-((3-三級丁基-1-(3-甲氧苯基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙基)啶-3-基)尿素 1-((3-tert-butyl-1-(3-methoxyphenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethyl)pyridine-3 -base) urea

步驟1至6：參照實例化合物152。 Steps 1 to 6: Refer to Example Compound 152.

步驟7：於一經攪拌、溶於二氯甲烷(10毫升)之(3-三級丁基-1-(3-甲氧苯基)-1H-吡唑-5-基)甲胺鹽酸鹽(100毫克，0.3855毫莫耳，1.0等量)溶液中添加三乙胺(116毫克，1.1485毫莫耳，3.0等量)，並於室溫攪拌10分鐘，隨後添加苯基6-(2-(三級丁基二甲基矽氧基)乙基)啶-3-基胺甲酸酯(144毫克，0.386毫莫耳，1.0等量)，再於室溫攪拌16小時。將該反應混合物蒸發，以矽膠管柱色層分析法(60至120篩孔)純化所得之粗製產物，以獲得固體狀之1-((3-三級丁基-1-(3-甲氧苯基)-1H-吡唑-5-基)甲基)-3-(6-(2-(三級丁基 二甲基矽氧基)乙基)啶-3-基)尿素(180毫克，86%)。 Step 7: (3-tert-butyl-1-(3-methoxyphenyl)-1H-pyrazol-5-yl)methanamine hydrochloride dissolved in dichloromethane (10 mL) (100 mg, 0.3855 mmol, 1.0 equivalent) was added triethylamine (116 mg, 1.1485 mmol, 3.0 equivalent) and stirred at room temperature for 10 min, then phenyl 6-(2- (Tertiary butyl dimethyl methoxy) ethyl) pyridine-3-ylcarbamate (144 mg, 0.386 mmol, 1.0 eq.) and stirred at room temperature for 16 hr. The reaction mixture was evaporated, and the obtained crude product was purified by silica gel column chromatography (60 to 120 mesh) to obtain 1-((3-tris-butyl-1-(3-methoxy) as a solid. Phenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-(tertiary butyldimethylammonio)ethyl)pyridin-3-yl)urea (180 mg , 86%).

步驟8：於一經攪拌、溶於四氫呋喃(3毫升)之1-((3-三級丁基-1-(3-甲氧苯基)-1H-吡唑-5-基)甲基)-3-(6-(2-(三級丁基二甲基矽氧基)乙基)啶-3-基)尿素(180毫克，0.3347毫莫耳，1.0等量)溶液中添加2N之氯化氫(0.9毫升)，並於室溫攪拌2小時。將該反應混合物以碳酸氫鈉水溶液中和，以醋酸乙酯萃取，以硫酸鈉乾燥，並將其蒸發，以獲得固體狀之1-((3-三級丁基-1-(3-甲氧苯基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙基)啶-3-基)尿素(實例化合物153)(64毫克，45%)。 Step 8: 1-((3-tert-butyl-1-(3-methoxyphenyl)-1H-pyrazol-5-yl)methyl)-(4-tris-butyl-1-(3-methoxyphenyl)-1H-pyrazol-5-yl)methyl) Add 2N hydrogen chloride to a solution of 3-(6-(2-(tert-butyldimethyl methoxy)ethyl)pyridin-3-yl)urea (180 mg, 0.3347 mmol, 1.0 equivalent) 0.9 ml) and stirred at room temperature for 2 hours. The reaction mixture was neutralized with aq. sodium hydrogen sulfate solution, extracted with ethyl acetate, dried over sodium sulfate and evaporated to give 1--(3-tris-butyl-1-(3- 3- Oxyphenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethyl)pyridin-3-yl)urea (example compound 153) (64 mg, 45%).

實例159之合成：Synthesis of Example 159:

1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(甲磺醯基甲基)啶-3-基)尿素 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(methylsulfonylmethyl)pyridin-3 -base) urea

步驟1：於-78℃，於一經攪拌、溶於四氫呋喃(10毫升)之5- 溴-2-氰吡啶(0.5公克，2.732毫莫耳，1.0等量)溶液中添加二異丁基氫化鋁(4毫升，4.98毫莫耳，1.5等量)，並將該反應混合物於-78℃攪拌4小時。以薄層層析法監控該反應混合物，並以2N之氯化氫(2毫升)進行淬火反應，以二氯甲烷(10毫升)萃取，以硫酸鈉乾燥，並將其蒸發，以提供純度頗高之5-溴吡啶-2-甲醛(0.3公克，約60%)；該產物不需進一步純化，即可於下一階段使用。 Step 1: Add diisobutylaluminum hydride to a solution of 5-bromo-2-cyanopyridine (0.5 g, 2.732 mmol, 1.0 equivalent) dissolved in tetrahydrofuran (10 ml) at -78 °C. (4 mL, 4.98 mmol, 1.5 equivalent) and the reaction mixture was stirred at -78 °C for 4 h. The reaction mixture was monitored by EtOAc (EtOAc) eluted eluted eluted eluted 5-bromopyridine-2-carbaldehyde (0.3 g, ca. 60%); this product was used in the next stage without further purification.

步驟2：於一經攪拌、溶於甲醇(10毫升)之5-溴吡啶-2-甲醛(0.5公克，2.68毫莫耳，1.0等量)溶液中添加硼氫化鈉(0.18公克，5.37毫莫耳，2等量)，並於室溫攪拌4小時。將甲醇蒸發，並以醋酸乙酯(10毫升)稀釋，以水(15毫升)清洗，以硫酸鈉乾燥，並於較低壓力濃縮，以獲得粗製化合物。以矽膠管柱色層分析法(100至200篩孔，20%之醋酸乙酯-石油醚做為溶析液之系統)純化該粗製化合物，以獲得(5-溴吡啶-2-基)甲醇(0.2公克，50%)。 Step 2: Sodium borohydride (0.18 g, 5.37 mmol) was added to a solution of 5-bromopyridine-2-carbaldehyde (0.5 g, 2.68 mmol, 1.0 equivalent) dissolved in methanol (10 mL). , 2 equal amounts), and stirred at room temperature for 4 hours. The methanol was evaporated and diluted with ethyl acetate (EtOAc) (EtOAc)EtOAc. The crude compound was purified by a silica gel column chromatography (100 to 200 mesh, 20% ethyl acetate-petroleum ether as a solution) to obtain (5-bromopyridin-2-yl)methanol. (0.2 grams, 50%).

步驟3：於0℃，於一經攪拌、溶於二氯甲烷(5毫升)之(5-溴吡啶-2-基)甲醇(0.2公克，1.06毫莫耳，1.0等量)溶液中添加三苯基磷(0.4公克，1.59毫莫耳，1.5等量)及N-溴代丁二醯亞胺(N-bromosuccinimide)(0.3公克，1.59毫莫耳，1.5等量)，並於室溫攪拌1小時。將該反應混合物以水進行淬火反應，並以二氯甲烷(2 x 10毫升)萃取。將有機層以飽和之氯化鈉溶液(30毫升)清洗，以硫酸鈉乾燥，將其濃縮，並使用醋酸乙酯/石油醚(1：9)做為溶析液，以矽膠管柱色層分析法(100至200篩孔)純化粗製產物，以獲得5-溴-2-(溴甲基)啶(0.2公克，約77%)。 Step 3: Add triphenylbenzene at 0 ° C in a solution of (5-bromopyridin-2-yl)methanol (0.2 g, 1.06 mmol, 1.0 equivalent) dissolved in dichloromethane (5 mL) Phosphorus (0.4 g, 1.59 mmol, 1.5 equivalent) and N-bromosuccinimide (0.3 g, 1.59 mmol, 1.5 equivalent), and stirred at room temperature 1 hour. The reaction mixture was quenched with water and extracted with dichloromethane (2×10 mL). The organic layer was washed with a saturated sodium chloride solution (30 ml), dried over sodium sulfate, and concentrated, and ethyl acetate / petroleum ether (1:9) as a solvent. The crude product was purified by analytical method (100 to 200 mesh) to give 5-bromo-2-(bromomethyl)pyridine (0.2 g, about 77%).

步驟4：於一經攪拌、溶於異丙醇(15毫升)之5-溴-2-(溴甲基)啶溶液(1.0公克，4.29毫莫耳，1.0等量)中添加甲烷亞磺酸鈉(2.1公克，21.45毫莫耳，5.0等量)，並於70℃攪拌4小時。將該反應混合物濃縮，並以醋酸乙酯(30毫升)稀釋，以水(20毫升)清洗， 以硫酸鈉乾燥，並於較低壓力蒸發。以二乙醚(30毫升)清洗所得之粗製產物，以獲得5-溴-2-(甲磺醯基甲基)啶(0.8公克，80%)。 Step 4: Add sodium methane sulfinate to a solution of 5-bromo-2-(bromomethyl)pyridine (1.0 g, 4.29 mmol, 1.0 equivalent) dissolved in isopropanol (15 ml). (2.1 g, 21.45 mmol, 5.0 equivalent) and stirred at 70 ° C for 4 hours. The reaction mixture was concentrated with EtOAc EtOAc m. The obtained crude product was washed with diethyl ether (30 ml) to afford 5-bromo-2-(methylsulfonylmethyl)pyridine (0.8 g, 80%).

步驟5：於氮氣氣氛下，於一經攪拌、溶於甲苯(10毫升)之5-溴-2-(甲磺醯基甲基)啶(0.1公克，0.4毫莫耳，1.0等量)溶液中添加二苯基酮亞胺(0.086毫升，0.48毫莫耳，1.2等量)，隨後添加三(二亞苄基丙酮)二鈀(36毫克，0.4毫莫耳，0.1等量)及碳酸銫(0.2公克，0.6毫莫耳，1.5等量)。將該反應混合物回流5小時，以水(5毫升)稀釋，以醋酸乙酯(10毫升)萃取，以硫酸鈉乾燥，以獲得N-(二苯亞甲基)-6-(甲磺醯基甲基)啶-3-胺(90毫克，粗製產物)。 Step 5: Under a nitrogen atmosphere, in a solution of 5-bromo-2-(methylsulfonylmethyl)pyridine (0.1 g, 0.4 mmol, 1.0 equivalent) dissolved in toluene (10 ml) Diphenyl ketimine (0.086 ml, 0.48 mmol, 1.2 equivalent) was added followed by tris(dibenzylideneacetone)dipalladium (36 mg, 0.4 mmol, 0.1 equivalent) and cesium carbonate ( 0.2 grams, 0.6 millimolar, 1.5 equals). The reaction mixture was refluxed for 5 hrs, diluted with water (5 ml), ethyl acetate (10 ml), and dried over sodium sulfate to give N-(diphenylmethylene)-6-(methylsulfonyl) Methyl)pyridin-3-amine (90 mg, crude product).

步驟6：於一經攪拌、溶於甲醇之N-(二苯亞甲基)-6-(甲磺醯基甲基)啶-3-胺(90毫克)溶液中添加濃氯化氫(2毫升)，並於室溫攪拌30分鐘。將該反應混合物以水(5毫升)稀釋，以醋酸乙酯(10毫升)萃取，並於較低壓力蒸發。將所得之粗製產物以二乙醚(10毫升)清洗，以獲得6-(甲磺醯基甲基)啶-3-胺(30毫克，約52%)。 Step 6: Add concentrated hydrogen chloride (2 ml) to a solution of N-(dibenzylidene)-6-(methylsulfonylmethyl)pyridin-3-amine (90 mg) in methanol. Stir at room temperature for 30 minutes. The reaction mixture was diluted with water (5 mL)EtOAc. The obtained crude product was washed with diethyl ether (10 ml) to afford 6-(methylsulfonylmethyl)pyridin-3-amine (30 mg, about 52%).

步驟7：於0℃，於一經攪拌，溶於丙酮(10毫升)之6-(甲磺醯基甲基)啶-3-胺溶液(0.8公克，4.301毫莫耳，1.0等量)溶液中添加氯甲酸苯酯(0.5毫升，4.731毫莫耳，1.1等量)及啶(0.96毫升，12.90毫莫耳，3等量)。將該反應混合物於室溫攪拌1小時。將丙酮蒸發，並以二氯甲烷(15毫升)稀釋殘留物，以水(10毫升)清洗，以硫酸鈉乾燥，並於較低壓力濃縮。以二乙醚(10毫升)清洗該粗製產物，以獲得灰白色固體狀之苯基6-(甲磺醯基甲基)啶-3-基胺甲酸酯(0.8公克，約50%)。 Step 7: Dissolve in a solution of 6-(methylsulfonylmethyl)pyridin-3-amine (0.8 g, 4.301 mmol, 1.0 equivalent) in acetone (10 ml) at 0 ° C. Phenyl chloroformate (0.5 ml, 4.731 mmol, 1.1 equivalents) and pyridine (0.96 ml, 12.90 mmol, 3 equivalents) were added. The reaction mixture was stirred at room temperature for 1 hour. The residue was evaporated with EtOAc (EtOAc)EtOAc. The crude product was washed with diethyl ether (10 mL) to afford phenyl 6-(methanesulfonylmethyl)pyridin-3-ylcarbamate (0.8 g, about 50%).

步驟8：於一經攪拌，溶於二氯甲烷(10毫升)之6-(甲磺醯基甲基)啶-3-基胺甲酸酯(100毫克，0.31毫莫耳，1.0等量)溶液中添加三乙胺(0.2毫升，1.2毫莫耳，3.0等量)，並於室溫攪拌10分鐘。添加(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺鹽酸鹽(100毫 克，0.3毫莫耳)，並再度攪拌於室溫16小時。將該反應混合物濃縮，依序以矽膠管柱色層分析法(100至200篩孔)及製備色層分析法純化所得之粗製產物，以獲得灰白色固體狀之1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(甲磺醯基甲基)啶-3-基)尿素(實例化合物159)(110毫克，40%)。 Step 8: A solution of 6-(methylsulfonylmethyl)pyridin-3-ylcarbamate (100 mg, 0.31 mmol, 1.0 equivalent) dissolved in dichloromethane (10 mL). Triethylamine (0.2 ml, 1.2 mmol, 3.0 equivalent) was added and stirred at room temperature for 10 min. Add (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamine hydrochloride (100 mg, 0.3 mmol) and stir again in the chamber Warm for 16 hours. The reaction mixture was concentrated, and the obtained crude product was purified by chromatography chromatography (100 to 200 mesh) and preparative chromatographic analysis to obtain 1-((1-(3-) Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(methylsulfonylmethyl)pyridin-3-yl)urea (example compound 159) (110 mg, 40%).

實例160之合成：Synthesis of Example 160:

1-((3-三級丁基-1-(3-氟苯基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素 1-((3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(hydroxymethyl)pyridin-3-yl) Urea

步驟1：於室溫，於一經攪拌、溶於1,4-二氧陸圜(30毫升)之2-甲基-5-硝基吡啶(3.0公克，0.021莫耳，1等量)溶液中添加二氧 化硒(2.9公克，0.026莫耳，1.2等量)，並將其回流攪拌16小時。將該反應混合物過濾，蒸發，以醋酸乙酯(50毫升)稀釋，以水(50毫升)清洗，以硫酸鈉乾燥，以獲得5-硝基-吡啶-2-甲醛(3.12公克，94%)。 Step 1: at room temperature, in a solution of 2-methyl-5-nitropyridine (3.0 g, 0.021 mol, 1 equivalent) dissolved in 1,4-dioxane (30 ml) at room temperature Selenium dioxide (2.9 grams, 0.026 moles, 1.2 equivalents) was added and stirred at reflux for 16 hours. The reaction mixture was filtered, evaporated, evaporated with wlululujjjjjjjjjjjjjjjjjjjj .

步驟2：於0℃，於一經攪拌、溶於甲醇(10毫升)之5-硝基-吡啶-2-甲醛(350公克，2.3毫莫耳，1.0等量)溶液中添加硼氫化鈉(82毫克，2.3毫莫耳，1.0等量)，並將所得之反應混合物攪拌2小時。將該反應混合物蒸發，以醋酸乙酯(20毫升)溶解殘留物，以飽和之氯化鈉溶液(30毫升)清洗，以硫酸鈉乾燥，並將其蒸發，以獲得(5-硝基吡啶-2-基)甲醇(0.210公克，60%)。 Step 2: Sodium borohydride (82) was added to a solution of 5-nitro-pyridine-2-carbaldehyde (350 g, 2.3 mmol, 1.0 equivalent) dissolved in methanol (10 mL) at 0 ° C. Mg, 2.3 mmol, 1.0 equivalent), and the resulting reaction mixture was stirred for 2 hours. The reaction mixture was evaporated, the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 2-Base) Methanol (0.210 g, 60%).

步驟3：於0℃，，於一經攪拌、溶於二氯甲烷(10毫升)之(5-硝基吡啶-2-基)甲醇(570毫克，3.7毫莫耳，1.0等量)溶液中添加咪唑(377毫克，5.5毫莫耳，1.5等量)及叔丁基二甲基氯矽烷(832毫克，5.5毫莫耳，1.5等量)，並於室溫下攪拌2小時。將該反應混合物以水(20毫升)清洗，以硫酸鈉乾燥，將其蒸發，使用醋酸乙酯/石油醚(1：9)做為溶析液，以矽膠(100至200篩孔)管柱色層分析法將其純化，以獲得2-((三級丁基二甲基矽氧基)甲基)-5-硝基吡啶(753毫克，76%)。 Step 3: Add at 0 ° C, in a solution of (5-nitropyridin-2-yl)methanol (570 mg, 3.7 mmol, 1.0 equivalent) dissolved in dichloromethane (10 mL) Imidazole (377 mg, 5.5 mmol, 1.5 equivalents) and tert-butyldimethylchloromethane (832 mg, 5.5 mmol, 1.5 equivalent) were stirred at room temperature for 2 hours. The reaction mixture was washed with water (20 ml), dried over sodium sulfate and evaporated, and ethyl acetate / petroleum ether (1:9) as solvent This was purified by chromatography to give 2-((tris-butyldimethyl methoxy)methyl)-5-nitropyridine (753 mg, 76%).

步驟4：於一經攪拌、溶於甲醇(10毫升)之2-((三級丁基二甲基矽氧基)甲基)-5-硝基吡啶(400毫克，1.492毫莫耳，1.0等量)溶液中添加10%之鈀碳(100毫克)，於氫氣氣氛下，將其於室溫攪拌1小時。將該反應混合物以矽藻土塞過濾，並於較低壓力將濾液濃縮。以二乙醚(20毫升)清洗粗製產物，以獲得灰白色固體狀之6-((三級丁基二甲基矽氧基)甲基)啶-3-胺(269毫克，76%)。 Step 4: 2-((tert-butyldimethyl methoxy)methyl)-5-nitropyridine (400 mg, 1.492 mmol, 1.0, etc.) in methanol (10 ml) with stirring. 10% palladium on carbon (100 mg) was added to the solution, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The reaction mixture was filtered through a pad of Celite, and filtrate was concentrated at lower pressure. The crude product was washed with EtOAc (EtOAc) (EtOAcjjjjjj

步驟5：於0℃，於一經攪拌、溶於丙酮(10毫升)之6-((三級丁基二甲基矽氧基)甲基)啶-3-胺(400毫克，1.680毫莫耳，1.0等 量)溶液中添加啶(0.27毫升，3.20毫莫耳，2等量)及氯甲酸苯酯(0.2毫升，1.8毫莫耳，1.1等量)，並於室溫攪拌2小時。將該反應混合物濃縮，以二氯甲烷(20毫升)稀釋，以水(30毫升)清洗，以硫酸鈉乾燥，並於較低壓力蒸發。以二乙醚(5毫升)清洗所得之粗製產物，以獲得灰白色固體狀之苯基6-((三級丁基二甲基矽氧基)甲基)啶-3-基胺甲酸酯(517毫克，86%)。 Step 5: 6-((tert-butyldimethyl methoxy)methyl)pyridine-3-amine (400 mg, 1.680 mmol) dissolved in acetone (10 mL) at 0 ° C A solution of 1.0 (equal amount) of pyridine (0.27 ml, 3.20 mmol, 2 equivalents) and phenyl chloroformate (0.2 ml, 1.8 mmol, 1.1 equivalent) were stirred at room temperature for 2 hours. The reaction mixture was concentrated with EtOAc EtOAc m. The obtained crude product was washed with diethyl ether (5 ml) to afford phenyl 6-((tris-butyl dimethyl methoxy oxy)methyl) Mg, 86%).

步驟6：於一經攪拌、溶於二氯甲烷(10毫升)之(3-三級丁基-1-(3-氟苯基)-1H-吡唑-5-基)甲胺鹽酸鹽(82毫克，0.331毫莫耳，1.0等量)溶液中添加三乙胺(1.7毫升，1.33毫莫耳，4.0等量)，並於室溫攪拌10分鐘，再添加苯基6-((三級丁基二甲基矽氧基)甲基)啶-3-基胺甲酸酯(120毫克，0.335毫莫耳，1.0等量)，並於室溫攪拌16小時。將該反應混合物濃縮，依序以矽膠管柱色層分析法(100至200篩孔)及製備色層分析法純化所得之粗製產物，以獲得白色固體狀之1-((3-三級丁基-1-(3-氟苯基)-1H-吡唑-5-基)甲基)-3-(6-((三級丁基二甲基矽氧基)甲基)啶-3-基)尿素(119毫克，70%)。 Step 6: (3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazol-5-yl)methanamine hydrochloride (m.p.) Add 82 mg, 0.331 mmol, 1.0 equal amount) to the solution, add triethylamine (1.7 ml, 1.33 mmol, 4.0 equivalent), and stir at room temperature for 10 minutes, then add phenyl 6-((level 3) Butyldimethylmethyloxy)methyl)pyridin-3-ylcarbamate (120 mg, 0.335 mmol, 1.0 eq.) was stirred at room temperature for 16 h. The reaction mixture was concentrated, and the obtained crude product was purified by chrome column chromatography (100 to 200 mesh) and preparative chromatography to obtain 1-((3-tris) 1-(3-fluorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-((tertiary butyldimethylamyloxy)methyl)pyridine-3- Base) urea (119 mg, 70%).

步驟7：於一經攪拌、溶於四氫呋喃(10毫升)之1-((3-三級丁基-1-(3-氟苯基)-1H-吡唑-5-基)甲基)-3-(6-((三級丁基二甲基矽氧基)甲基)啶-3-基)尿素(119毫克，0.0.232毫莫耳，1.0等量)溶液中添加2N之氯化氫(1.5毫升)，並於室溫攪拌2小時。將該反應混合物以碳酸氫鈉水溶液鹼化，以醋酸乙酯(20毫升)萃取，以硫酸鈉乾燥，並將其蒸發，以獲得固體狀之化合物1-((3-三級丁基-1-(3-氟苯基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素(實例化合物160)(43毫克，47%)。 Step 7: 1-((3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazol-5-yl)methyl)-3 was dissolved in tetrahydrofuran (10 mL). Add 2N hydrogen chloride to a solution of (6-((tertiary butyldimethyl methoxy)methyl)pyridin-3-yl)urea (119 mg, 0.0.232 mmol, 1.0 equivalent) (ml) and stirred at room temperature for 2 hours. The reaction mixture was basified with EtOAc (EtOAc) (EtOAc) -(3-Fluorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(hydroxymethyl)pyridin-3-yl)urea (example compound 160) (43 mg, 47% ).

實例32、33及35至37係以類似方法製備而成。可採用類似方法製備實例31、34、36及38至49。 Examples 32, 33 and 35 to 37 were prepared in a similar manner. Examples 31, 34, 36 and 38 to 49 can be prepared in a similar manner.

質譜分析數據係以下列示範性化合物之實例(表1a及1b)引用於下文： Mass spectrometry data is quoted below using examples of the following exemplary compounds (Tables 1a and 1b):

藥理方法Pharmacological method

I.於類香草素受體1(VRI/TRPV1受體)進行之功能測試I. Functional testing at vanilloid receptor 1 (VRI/TRPV1 receptor)

可利用下列檢測判斷某物質對大鼠物種之類香草素受體1(VR1/TRPV1)之催動或拮抗影響。於此檢測中，鈣離子通過該受體通道之流量，係以於鈣離子敏感染料(Fluo-4型，Molecular Probes Europe BV，Leiden，荷蘭)之輔助下，以螢光成像讀板儀(FLIPR，分子儀器，Sunnyvale，美國)量化。 The following tests can be used to determine the stimulatory or antagonistic effects of a substance on vanilloid receptor 1 (VR1/TRPV1) in rat species. In this assay, the flow of calcium ions through the receptor channel is complemented by a calcium ion sensitive dye (Fluo-4, Molecular Probes Europe BV, Leiden, The Netherlands) with a fluorescence imaging plate reader (FLIPR). , Molecular Instruments, Sunnyvale, USA) Quantification.

方法：method:

完全培養基：50毫升之HAMS F12營養混合物(Gibco Invitrogen GmbH，Karlsruhe，德國)，其含有10%以體積計之胎牛血清(FCS)(foetal calf serum，Gibco Invitrogen GmbH，Karlsruche，德國，經熱滅活)、2 mM之L-麩醯胺(Sigma，Munich，德國)、1%以重量計之抗生素/抗黴菌(AA)溶液(antibiotic/antimyotic solution，PAA，Pasching，奧地利)，及25 ng/毫升之神經生長因子(NGF)培養基(2.5 S，Gibco Invitrogen GmbH，Karlsruhe，德國)。 Complete medium: 50 ml of HAMS F12 nutrient mixture (Gibco Invitrogen GmbH, Karlsruhe, Germany) containing 10% by volume of fetal bovine serum (FCS) (foetal calf serum, Gibco Invitrogen GmbH, Karlsruche, Germany, heat-killed Live), 2 mM L-glutamate (Sigma, Munich, Germany), 1% by weight antibiotic/antimytic solution (PAA, Pasching, Austria), and 25 ng/ Million of nerve growth factor (NGF) medium (2.5 S, Gibco Invitrogen GmbH, Karlsruhe, Germany).

細胞培養板：將以多聚賴氨酸塗覆、具有透明底座之黑色96孔板(96-孔黑色/透明板，BD Biosciences，Heidelberg，德國)，另行以層黏蛋白(laminin)(Gibco Invitrogen GmbH，Karlsruhe，德國)塗覆；將該層黏蛋白之濃度以磷酸鹽溶液(不含鈣與鎂之磷酸鹽，Gibco Invitrogen GmbH，Karlsruhe，德國)稀釋為100 μg/毫升。將濃度為100 μg/毫升之層黏蛋白等分試樣分裝，並儲存於-20℃。以1：10之比例，將該等分式樣以磷酸鹽溶液稀釋為10 μg/毫升之層黏蛋白，並將50 μL之該溶液吸移至細胞培養板之凹處。將細胞培養板於37℃溫育至少2小時，將多餘之溶液抽吸出，並以磷酸 鹽溶液清洗各凹處兩次。將塗覆後之細胞培養板儲存於大量之磷酸鹽溶液中，直至培養細胞前再將其移除。 Cell culture plate: black 96-well plate (96-well black/transparent plate, BD Biosciences, Heidelberg, Germany) coated with polylysine, with a transparent base, separately with laminin (Gibco Invitrogen) GmbH, Karlsruhe, Germany) Coating; the concentration of this layer of mucin was diluted to 100 μg/ml with a phosphate solution (free of calcium and magnesium phosphate, Gibco Invitrogen GmbH, Karlsruhe, Germany). An aliquot of laminin at a concentration of 100 μg/ml was dispensed and stored at -20 °C. The aliquot was diluted to a 10 μg/ml layer of mucin with a phosphate solution at a ratio of 1:10, and 50 μL of this solution was pipetted into the recess of the cell culture plate. Incubate the cell culture plate at 37 ° C for at least 2 hours, pump out the excess solution, and use phosphoric acid The salt solution is washed twice in each recess. The coated cell culture plate is stored in a large amount of phosphate solution until it is removed before culturing the cells.

細胞之製備：Preparation of cells:

將被斷頭犧牲之大鼠之脊柱移除，並立即將其置放於冰冷之漢克平衡鹽溶液(Hank’s buffered saline solution，Gibco Invitrogen GmbH，Karlsruhe，德國)，即將平衡鹽溶液置放於冰浴中，並與1%以重量計(體積百分比)之抗生素/抗黴菌溶液(PAA，Pasching，奧地利)混合。將脊柱沿縱向切開，並將其與筋膜共同從脊椎管移除。隨後，移除背根神經節(dorsal root ganglia，DRG)，並同樣將其存放於冰冷、與1%以體積計之抗生素/抗黴菌溶液混合之漢克平衡鹽溶液。將所有殘存之血液及脊髓神經由背根神經節移除，並將其各自置放於500 μL之冰冷2型膠原酶(PAA，Pasching，奧地利)，並於37℃溫育35分鐘。添加2.5%以重量計之胰蛋白(PAA，Pasching，奧地利)後，繼續於37℃溫育10分鐘。溫育完成後，小心地將含酶溶液以移液管移除，並於各殘留之背根神經節中添加500 μL之完全培養基。將各背根神經節懸浮數次，以注射器使其通過No.1、No.12及No.16套管，並移放至裝有15毫升完全培養基之50毫升尖底離心管(Falcon tube)。將各尖底離心管之內容物分別以70 μm之Falcon濾心過濾，並於室溫，以1,200 rpm離心10分鐘。將所得之細胞團懸浮於250 μL之完全培養基，並判讀細胞數。 The spine of the rat that was sacrificed by the decapitation was removed and immediately placed in an ice-cold brine solution (Hank's buffered saline solution, Gibco Invitrogen GmbH, Karlsruhe, Germany), placing the balanced salt solution in an ice bath Medium and mixed with 1% by weight (by volume) antibiotic/antimycotic solution (PAA, Pasching, Austria). The spine is cut longitudinally and removed from the spinal canal with the fascia. Subsequently, the dorsal root ganglia (DRG) was removed and stored in ice-cold, Hank's balanced salt solution mixed with 1% by volume antibiotic/antimycotic solution. All remaining blood and spinal nerves were removed from the dorsal root ganglia and placed in 500 μL of ice-cold type 2 collagenase (PAA, Pasching, Austria) and incubated at 37 ° C for 35 minutes. After adding 2.5% by weight of trypsin (PAA, Pasching, Austria), incubation was continued for 10 minutes at 37 °C. After the incubation was completed, the enzyme-containing solution was carefully removed by pipette, and 500 μL of complete medium was added to each of the remaining dorsal root ganglia. Each dorsal root ganglion was suspended several times, passed through a No. 1, No. 12 and No. 16 cannula with a syringe, and transferred to a 50 ml Falcon tube containing 15 ml of complete medium. . The contents of each sharp-bottomed centrifuge tube were separately filtered through a 70 μm Falcon filter and centrifuged at 1,200 rpm for 10 minutes at room temperature. The resulting cell pellet was suspended in 250 μL of complete medium and the number of cells was determined.

將懸浮液之細胞數設為每毫升3 x 105顆細胞，並將150 μL之各懸浮液，置入上述經塗覆之細胞培養板之凹處。將培養板置放於培養箱2至3天，該培養箱之條件為37℃、5%以體積計之二氧化碳及95%之相對溼度。隨後，將細胞放入存在於含有2 μM之 Fluo-4及0.01%以體積計之Pluronic F127(Molecular Probes Europe BV，Leiden，荷蘭)之漢克平衡鹽溶液(Gibco Invitrogen GmbH，Karlsruhe，德國)，並於37℃培養30分鐘，再以漢克平衡鹽溶液清洗3次；之後，於室溫溫育15分鐘，以供螢光成像讀板測量鈣離子所用。此例中，鈣離子-依賴螢光係於添加物質之前與之後測量(λex=488 nm，λem=540 nm)。其係藉由隨時間變化之最強螢光強度(螢光計數，fluorescence counts，FC)進行量化。 The number of cells in the suspension was set to 3 x 10 5 cells per ml, and 150 μL of each suspension was placed in a recess of the above coated cell culture plate. The plate was placed in an incubator for 2 to 3 days at 37 ° C, 5% by volume of carbon dioxide and 95% relative humidity. Subsequently, the cells were placed in a Hank's balanced salt solution (Gibco Invitrogen GmbH, Karlsruhe, Germany) present in 2 μM of Fluo-4 and 0.01% by volume of Pluronic F127 (Molecular Probes Europe BV, Leiden, The Netherlands). The cells were incubated at 37 ° C for 30 minutes and then washed 3 times with Hank's balanced salt solution; after that, they were incubated at room temperature for 15 minutes for measurement of calcium ions by fluorescent imaging plates. In this case, the calcium ion-dependent fluorescence was measured before and after the addition of the substance (λex = 488 nm, λem = 540 nm). It is quantified by the strongest fluorescence intensity (fluorescence counts, FC) as a function of time.

螢光成像讀板檢驗：Fluorescence imaging reading board inspection:

螢光成像讀板儀規程包含添加兩種物質。第一，將欲測試之化合物(10 μM)以移液管轉移至細胞上，並將其鈣離子流入量與對照組(10 μM之辣椒素)比較。此項比較提供添加10 μM之辣椒素(CP)後，基於鈣離子信號之活性百分比結果。於5分鐘之溫育後，添加100 nM之辣椒素，並判讀鈣離子之流入量。 The Fluorescence Imaging Plate Reader protocol includes the addition of two substances. First, the compound to be tested (10 μM) was pipetted onto the cells, and the amount of calcium ion influx was compared with the control group (10 μM capsaicin). This comparison provides a percentage of activity based on calcium ion signal after addition of 10 μM capsaicin (CP). After 5 minutes of incubation, 100 nM capsaicin was added and the influx of calcium ions was interpreted.

激動劑及拮抗劑減敏會導致鈣離子流入。抑制百分比之計算，係藉由將其與10 μM之抗辣椒鹼可達到之最大抑制效果進行比較。 Desensitization of agonists and antagonists leads to calcium influx. The percent inhibition was calculated by comparing it to the maximum inhibitory effect achieved by 10 μM anti-capsaicin.

進行三重分析(n=3)，並重複獨立實驗至少3次(N=4)。 A triple analysis (n=3) was performed and independent experiments were repeated at least 3 times (N=4).

從因不同濃度之欲測試之通式(I)化合物所造成之百分比位移開始，計算造成50%位移之辣椒素之IC50抑制濃度。測試物質之Ki值係以Cheng-Prusoff方程式(Cheng，Prusoff；Biochem.Pharmacol.22,3099-3108,1973)之方式轉換而得。 From the percentage displacement by different concentrations of the compound to be tested of formula (I) resulting from the beginning, 50% of capsaicin caused calculated displacements inhibitory concentration IC 50. The K i value of the test substance was converted in the manner of the Cheng-Prusoff equation (Cheng, Prusoff; Biochem. Pharmacol. 22, 3099-3108, 1973).

藥理學數據：Pharmacological data:

根據本發明之化合物對類香草素受體1(VR1/TRPV1受體)之親和性，係以上述方法判定。 The affinity of the compound according to the present invention for the vanilloid receptor 1 (VR1/TRPV1 receptor) was determined by the above method.

根據本發明之化合物對VR1/TRPV1受體具有極強之之親和性(表2a及表2b)。 The compounds according to the invention have a strong affinity for the VR1/TRPV1 receptor (Table 2a and Table 2b).

表2a及表2b中之縮寫具有下列意義：Cap=辣椒素 The abbreviations in Table 2a and Table 2b have the following meanings: Cap = Capsaicin

AG=激動劑 AG = agonist

NE=無影響 NE=no effect

pAG=部分激動劑 pAG = partial agonist

「@」符號後之值，係代表判定各抑制(以百分比表示)發生時之濃度。 The value after the "@" symbol is the concentration at which the occurrence of each inhibition (expressed as a percentage) is determined.

Claims (15)

一種通式(I)之被取代化合物， 其中，R0 代表一C1-10脂族殘基，其係未被取代，或被單取代或多取代、一C3-10環脂族殘基或一3至10構件雜環脂族殘基，其於各例中係未被取代，或被單取代或多取代，及於各例中選擇性地經由一C1-8脂族基橋接，其進而可係未被取代，或被單取代或多取代、芳基或雜芳基，其於各例中係未被取代，或被單取代或多取代，及於各例中選擇性地經由一C1-8脂族基橋接，其進而可係未被取代，或被單取代或多取代；R1 代表H、R0、C(=O)-R0、C(=O)-OH、C(=O)-OR0、C(=O)-NHR0、C(=O)-N(R0)2、OH、O-R0、SH、S-R0、S(=O)2-R0、S(=O)2-OR0、S(=O)2-NHR0、S(=O)2-N(R0)2、NH2、NHR0、N(R0)2、NH-S(=O)2-R0、N(R0)(S(=O)2-R0)、或SCl3；R2 代表H、R0、F、Cl、Br、I、CN、NO2、OH、SH、CF3、CF2H、CFH2、CF2Cl、CFCl2、CH2CF3、OCF3、OCF2H、OCFH2、OCF2Cl、OCFCl2、SCF3、SCF2H、SCFH2、SCF2Cl、SCFCl2、S(=O)2-CF3、S(=O)2-CF2H、S(=O)2-CFH2或SF5；R3 代表H或一C1-10脂族殘基，其係未被取代，或被單取 代或多取代；n 代表1、2、3或4；R3a 代表H或一C1-4脂族殘基，其係未被取代，或被單取代或多取代；R4a 代表H或一C1-4脂族殘基，其係未被取代，或被單取代或多取代、一C3-6環脂族殘基，其係未被取代，或被單取代或多取代、或一芳基，其係未被取代，或被單取代或多取代；Y 代表O、S或N-CN；Z 代表N或C-R4b；R4b 代表H或一C1-4脂族殘基，其係未被取代，或被單取代或多取代；或R4a與R4b與將其連結之碳原子共同形成一C3-6環脂族殘基，其係未被取代，或被單取代或多取代；T1 代表N或C-R5；U1 代表N或C-R6；V 代表N或C-R7；U2 代表N或C-R8；T2 代表N或C-R9；附帶條件為T1、U1、V、U2與T2變量之1、2或3代表氮原子；R5、R6、R7、R8與R9相互獨立地代表H、F、Cl、Br、I、NO2、CN、CF3、CF2H、CFH2、CF2Cl、CFCl2、R0、C(=O)H、C(=O)R0、CO2H、C(=O)OR0、CONH2、C(=O)NHR0、C(=O)N(R0)2、OH、OCF3、OCF2H、OCFH2、OCF2Cl、OCFCl2、OR0、O-C(=O)-R0、 O-C(=O)-O-R0、O-(C=O)-NH-R0、O-C(=O)-N(R0)2、O-S(=O)2-R0、O-S(=O)2OH、O-S(=O)2OR0、O-S(=O)2NH2、O-S(=O)2NHR0、O-S(=O)2N(R0)2、NH2、NH-R0、N(R0)2、NH-C(=O)-R0、NH-C(=O)-O-R0、NH-C(=O)-NH2、NH-C(=O)-NH-R0、NH-C(=O)-N(R0)2、NR0-C(=O)-R0、NR0-C(=O)-O-R0、NR0-C(=O)-NH2、NR0-C(=O)-NH-R0、NR0-C(=O)-N(R0)2、NH-S(=O)2OH、NH-S(=O)2R0、NH-S(=O)2OR0、NH-S(=O)2NH2、NH-S(=O)2NHR0、NH-S(=O)2N(R0)2、NR0-S(=O)2OH、NR0-S(=O)2R0、NR0-S(=O)2OR0、NR0-S(=O)2NH2、NR0-S(=O)2NHR0、NR0-S(=O)2N(R0)2、SH、SCF3、SCF2H、SCFH2、SCF2Cl、SCFCl2、SR0、S(=O)R0、S(=O)2R0、S(=O)2OH、S(=O)2OR0、S(=O)2NH2、S(=O)2NHR0或S(=O)2N(R0)2；其「脂族基」與「脂族殘基」於各例中，相互獨立地可係支鏈或非支鏈，飽和或不飽和；其「環脂族殘基」與「雜環脂族殘基」於各例中，相互獨立地可係飽和或不飽和；其「脂族基」、「脂族殘基」、「環脂族殘基」與「雜環脂族殘基」之「被單取代或被多取代」，係關於其於各例中，相互自獨立地於其相應之殘基或功能基中，有一或多個氫原子各自相互獨立地被以至少一選自由F、Cl、Br、I、NO2、CN、=O、=NH、=N(OH)、=C(NH2)2、CF3、CF2H、CFH2、CF2Cl、CFCl2、R0、C(=O)-H、C(=O)-R0、C(=O)-OH、C(=O)-OR0、CO-NH2、C(=O)-NHR0、C(=O)-N(R0)2、OH、OCF3、OCF2H、OCFH2、OCF2Cl、OCFCl2、OR0、O-C(=O)-R0、O-C(=O)-O-R0、O-(C=O)-NH-R0、O-C(=O)-N(R0)2、O-S(=O)2-R0、O-S(=O)2-OH、 O-S(=O)2-OR0、O-S(=O)2-NH2、O-S(=O)2-NHR0、O-S(=O)2-N(R0)2、NH2、NH-R0、N(R0)2、NH-C(=O)-R0、NH-C(=O)-O-R0、NH-C(=O)-NH2、NH-C(=O)-NHR0、NH-C(=O)-N(R0)2、NR0-C(=O)-R0、NR0-C(=O)-O-R0、NR0-C(=O)-NH2、NR0-C(=O)-NHR0、NR0-C(=O)-N(R0)2、NH-S(=O)2-OH、NH-S(=O)2-R0、NH-S(=O)2-OR0、NH-S(=O)2-NH2、NH-S(=O)2-NHR0、NH-S(=O)2-N(R0)2、NR0-S(=O)2-OH、NR0-S(=O)2-R0、NR0-S(=O)2-OR0、NR0-S(=O)2-NH2、NR0-S(=O)2-NHR0、NR0-S(=O)2-N(R0)2、SH、SCF3、SCF2H、SCFH2、SCF2Cl、SCFCl2、SR0、S(=O)-R0、S(=O)2-R0、S(=O)2-OH、S(=O)2-OR0、S(=O)2-NH2、S(=O)2-NHR0與S(=O)2-N(R0)2等取代基組成之群組單取代或多取代；其「芳基」與「雜芳基」之「被單取代或被多取代」，係關於其於各例中，相互自獨立地於其相應之殘基中，有一或多個氫原子各自相互獨立地被以至少一選自由F、Cl、Br、I、NO2、CN、CF3、CF2H、CFH2、CF2Cl、CFCl2、R0、C(=O)-H、C(=O)-R0、C(=O)-OH、C(=O)-OR0、CO-NH2、C(=O)-NHR0、C(=O)-N(R0)2、OH、、、、、、、、、、OCF3、OCF2H、OCFH2、OCF2Cl、OCFCl2、OR0、O-C(=O)-R0、O-C(=O)-O-R0、O-(C=O)-NH-R0、O-C(=O)-N(R0)2、O-S(=O)2-R0、O-S(=O)2-OH、O-S(=O)2-OR0、O-S(=O)2-NH2、O-S(=O)2-NHR0、O-S(=O)2-N(R0)2、NH2、NHR0、N(R0)2、NH-C(=O)-R0、NH-C(=O)-O-R0、NH-C(=O)-NH2、 NH-C(=O)-NH-R0、NH-C(=O)-N(R0)2、NR0-C(=O)-R0、NR0-C(=O)-O-R0、NR0-C(=O)-NH2、NR0-C(=O)-NH-R0、NR0-C(=O)-N(R0)2、NH-S(=O)2-OH、NH-S(=O)2-R0、NH-S(=O)2-OR0、NH-S(=O)2-NH2、NH-S(=O)2-NHR0、NH-S(=O)2-N(R0)2、NR0-S(=O)2-OH、NR0-S(=O)2R0、NR0-S(=O)2-OR0、NR0-S(=O)2-NH2、NR0-S(=O)2-NHR0、NR0-S(=O)2-N(R0)2、SH、SCF3、SCF2H、SCFH2、SCF2Cl、SCFCl2、SR0、S(=O)-R0、S(=O)2-R0、S(=O)2-OH、S(=O)2-OR0、S(=O)2-NH2、S(=O)2-NHR0與S(=O)2-N(R0)2等取代基組成之群組單取代或多取代；選擇性地於單一立體異構物或立體異構物之混合物之形式、以自由化合物之形式及/或其生理上可接受之鹽之形式。 a substituted compound of the formula (I), Wherein R 0 represents a C 1-10 aliphatic residue which is unsubstituted or monosubstituted or polysubstituted, a C 3-10 cycloaliphatic residue or a 3 to 10 membered heterocyclic aliphatic residue , in each case unsubstituted, or mono- or poly-substituted, and optionally bridged via a C 1-8 aliphatic group in each case, which in turn may be unsubstituted or monosubstituted or a substituted, aryl or heteroaryl group which is unsubstituted in each case, or mono- or polysubstituted, and optionally bridged via a C 1-8 aliphatic group in each case, which in turn may Substituted, or mono- or poly-substituted; R 1 represents H, R 0 , C(=O)-R 0 , C(=O)-OH, C(=O)-OR 0 , C(=O)- NHR 0 , C(=O)-N(R 0 ) 2 , OH, OR 0 , SH, SR 0 , S(=O) 2 -R 0 , S(=O) 2 -OR 0 , S(=O 2 -NHR 0 , S(=O) 2 -N(R 0 ) 2 , NH 2 , NHR 0 , N(R 0 ) 2 , NH-S(=O) 2 -R 0 , N(R 0 ) (S(=O) 2 -R 0 ), or SCl 3 ; R 2 represents H, R 0 , F, Cl, Br, I, CN, NO 2 , OH, SH, CF 3 , CF 2 H, CFH 2 , CF 2 Cl, CFCl 2 , CH 2 CF 3 , OCF 3 , OCF 2 H, OCFH 2 , OCF 2 Cl, OCFCl 2 , SCF 3 , SC F 2 H, SCFH 2 , SCF 2 Cl, SCFCl 2 , S(=O) 2 -CF 3 , S(=O) 2 -CF 2 H, S(=O) 2 -CFH 2 or SF 5 ; R 3 Represents H or a C 1-10 aliphatic residue which is unsubstituted or monosubstituted or polysubstituted; n represents 1, 2, 3 or 4; R 3a represents H or a C 1-4 aliphatic residue , which is unsubstituted or monosubstituted or polysubstituted; R 4a represents H or a C 1-4 aliphatic residue which is unsubstituted or monosubstituted or polysubstituted, a C 3-6 cycloaliphatic a residue which is unsubstituted or monosubstituted or polysubstituted, or an aryl group which is unsubstituted or monosubstituted or polysubstituted; Y represents O, S or N-CN; Z represents N or CR 4b R 4b represents H or a C 1-4 aliphatic residue which is unsubstituted or monosubstituted or polysubstituted; or R 4a and R 4b together with the carbon atom to which they are bonded form a C 3-6 ring An aliphatic residue which is unsubstituted or monosubstituted or polysubstituted; T 1 represents N or CR 5 ; U 1 represents N or CR 6 ; V represents N or CR 7 ; U 2 represents N or CR 8 ; 2 represents N or CR 9; with the proviso that T 1, U 1, V, U 2 with 1, 2 or 3 T 2 represents a nitrogen atom variables; R 5, R 6, R 7, R 8 R 9 independently of one another represent H, F, Cl, Br, I, NO 2, CN, CF 3, CF 2 H, CFH 2, CF 2 Cl, CFCl 2, R 0, C (= O) H, C ( =O)R 0 , CO 2 H, C(=O)OR 0 , CONH 2 , C(=O)NHR 0 , C(=O)N(R 0 ) 2 , OH, OCF 3 , OCF 2 H, OCFH 2 , OCF 2 Cl, OCFCl 2 , OR 0 , OC(=O)-R 0 , OC(=O)-OR 0 , O-(C=O)-NH-R 0 , OC(=O)- N(R 0 ) 2 , OS(=O) 2 -R 0 , OS(=O) 2 OH, OS(=O) 2 OR 0 , OS(=O) 2 NH 2 , OS(=O) 2 NHR 0 , OS(=O) 2 N(R 0 ) 2 , NH 2 , NH-R 0 , N(R 0 ) 2 , NH-C(=O)-R 0 , NH-C(=O)-OR 0 , NH-C(=O)-NH 2 , NH-C(=O)-NH-R 0 , NH-C(=O)-N(R 0 ) 2 , NR 0 -C(=O)- R 0 , NR 0 -C(=O)-OR 0 , NR 0 -C(=O)-NH 2 , NR 0 -C(=O)-NH-R 0 , NR 0 -C(=O)- N(R 0 ) 2 , NH-S(=O) 2 OH, NH-S(=O) 2 R 0 , NH-S(=O) 2 OR 0 , NH-S(=O) 2 NH 2 , NH-S(=O) 2 NHR 0 , NH-S(=O) 2 N(R 0 ) 2 , NR 0 -S(=O) 2 OH, NR 0 -S(=O) 2 R 0 , NR 0 -S(=O) 2 OR 0 , NR 0 -S(=O) 2 NH 2 , NR 0 -S(=O) 2 NHR 0 , NR 0 -S(=O) 2 N(R 0 ) 2 , SH, SCF 3 , SCF 2 H, SCFH 2 , SCF 2 Cl, SCFCl 2 , SR 0 , S(=O)R 0 , S(=O) 2 R 0 , S(=O) 2 OH, S(=O) 2 OR 0 , S(=O) 2 NH 2 , S(=O) 2 NHR 0 or S(=O) 2 N(R 0 ) 2 ; The "aliphatic group" and "aliphatic residue" in each case may be branched or unbranched, saturated or unsaturated, independently of each other; "cycloaliphatic residues" and "heterocyclic aliphatic residues" In each case, it may be saturated or unsaturated independently of each other; the "aliphatic group", "aliphatic residue", "cycloaliphatic residue" and "heterocyclic aliphatic residue" Substituted or polysubstituted, in each case, independently of each other in its corresponding residue or functional group, one or more hydrogen atoms are each independently selected from at least one selected from the group consisting of F, Cl, Br, I, NO 2 , CN, =O, =NH, =N(OH), =C(NH 2 ) 2 , CF 3 , CF 2 H, CFH 2 , CF 2 Cl, CFCl 2 , R 0 , C (=O)-H, C(=O)-R 0 , C(=O)-OH, C(=O)-OR 0 , CO-NH 2 , C(=O)-NHR 0 , C(= O)-N(R 0 ) 2 , OH, OCF 3 , OCF 2 H, OCFH 2 , OCF 2 Cl, OCFCl 2 , OR 0 , OC(=O)-R 0 , OC(=O)-OR 0 , O-(C=O)-NH-R 0 , OC(=O)-N(R 0 ) 2 , OS(=O) 2 -R 0 , OS(=O) 2 -OH, OS(=O) 2 -OR 0 , OS(=O) 2 -NH 2 , OS(=O) 2 -NHR 0 , OS(=O) 2 -N(R 0 ) 2 , NH 2 , NH-R 0 , N(R 0 ) 2 , NH-C(=O)-R 0 , NH-C(=O)-OR 0 , NH-C(=O)-NH 2 , NH-C(=O)-NHR 0 , NH-C(=O)-N(R 0 ) 2 , NR 0 -C(=O)-R 0 , NR 0 -C(=O)-OR 0 , NR 0 -C(=O)-NH 2 , NR 0 -C(=O)-NHR 0 , NR 0 -C(=O)-N(R 0 ) 2 , NH-S(=O) 2 -OH, NH-S(=O) 2 -R 0 , NH-S(=O) 2 -OR 0 , NH -S(=O) 2 -NH 2 , NH-S(=O) 2 -NHR 0 , NH-S(=O) 2 -N(R 0 ) 2 , NR 0 -S(=O) 2 -OH NR 0 -S(=O) 2 -R 0 , NR 0 -S(=O) 2 -OR 0 , NR 0 -S(=O) 2 -NH 2 , NR 0 -S(=O) 2 - NHR 0 , NR 0 -S(=O) 2 -N(R 0 ) 2 , SH, SCF 3 , SCF 2 H, SCFH 2 , SCF 2 Cl, SCFCl 2 , SR 0 , S(=O)-R 0 , S(=O) 2 -R 0 , S(=O) 2 -OH, S(=O) 2 -OR 0 , S(=O) 2 -NH 2 , S(=O) 2 -NHR 0 and a group consisting of a mono- or poly-substitution of a substituent such as S(=O) 2 -N(R 0 ) 2 ; the "aryl" or "heteroaryl" is either mono- or polysubstituted, in each of the embodiments, since each independently of their respective residues, one or more hydrogen atoms are each independently substituted with at least one selected from the group consisting of F, Cl, Br, I, NO 2 CN, CF 3, CF 2 H , CFH 2, CF 2 Cl, CFCl 2, R 0, C (= O) -H, C (= O) -R 0, C (= O) -OH, C (= O)-OR 0 , CO-NH 2 , C(=O)-NHR 0 , C(=O)-N(R 0 ) 2 , OH, , , , , , , , , , OCF 3 , OCF 2 H, OCFH 2 , OCF 2 Cl, OCFCl 2 , OR 0 , OC(=O)-R 0 , OC(=O)-OR 0 , O-(C=O)-NH-R 0 , OC(=O)-N(R 0 ) 2 , OS(=O) 2 -R 0 , OS(=O) 2 -OH, OS(=O) 2 -OR 0 , OS(=O) 2 -NH 2 , OS(=O) 2 -NHR 0 , OS(=O) 2 -N(R 0 ) 2 , NH 2 , NHR 0 , N(R 0 ) 2 , NH-C(=O)-R 0 , NH-C(=O)-OR 0 , NH-C(=O)-NH 2 , NH-C(=O)-NH-R 0 , NH-C(=O)-N(R 0 ) 2 , NR 0 -C(=O)-R 0 , NR 0 -C(=O)-OR 0 , NR 0 -C(=O)-NH 2 , NR 0 -C(=O)-NH-R 0 , NR 0 -C(=O)-N(R 0 ) 2 , NH-S(=O) 2 -OH, NH-S(=O) 2 -R 0 , NH-S(=O) 2 - OR 0 , NH-S(=O) 2 -NH 2 , NH-S(=O) 2 -NHR 0 , NH-S(=O) 2 -N(R 0 ) 2 , NR 0 -S(=O 2 -OH, NR 0 -S(=O) 2 R 0 , NR 0 -S(=O) 2 -OR 0 , NR 0 -S(=O) 2 -NH 2 , NR 0 -S(=O 2 -NHR 0 , NR 0 -S(=O) 2 -N(R 0 ) 2 , SH, SCF 3 , SCF 2 H, SCFH 2 , SCF 2 Cl, SCFCl 2 , SR 0 , S(=O) -R 0 , S(=O) 2 -R 0 , S(=O) 2 -OH, S(=O) 2 -OR 0 , S(=O) 2 -NH 2 , S(=O) 2 - a group consisting of a substituent consisting of NHR 0 and S(=O) 2 -N(R 0 ) 2 , monosubstituted or polysubstituted; optionally in a single stereoisomer or stereo The mixture of isomers is in the form of a free compound and/or a physiologically acceptable salt thereof. 根據申請專利範圍第1項所述之被取代化合物，其特徵為n代表1。 A substituted compound according to claim 1 of the patent application, characterized in that n represents 1. 根據申請專利範圍第1項或第2項所述之被取代化合物，其特徵為Y代表O。 A substituted compound according to claim 1 or 2, wherein Y represents O. 根據前述申請專利範圍中任何一項所述之被取代化合物，其特徵為R1 代表(T1)子結構，其 E 代表O、S或NR11，其中，R11代表H或一未被取代之C1-4脂族殘基；o 代表0或1； R10a與R10b各自相互獨立地代表H、F、Cl、Br、I或一未被取代之C1-4脂族殘基，m 代表0、1或2；G 代表一C1-8脂族殘基，其係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、OH、O-C1-4烷基、O-C1-4伸烷基-OH、O-C1-4伸烷基-O-C1-4烷基、OCF3、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基與SCF3等取代基組成之群組單取代或多取代；或代表一C3-10環脂族殘基或一3至10構件雜環脂族殘基，其於各例中係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、CF3、SCF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、苯基與啶基等取代基組成之群組單取代或多取代，其中，苯基或啶基分別係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基與SCF3等取代基組成之群組單取代或多取代；或代表一芳基或雜芳基，其於各例中係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、O-C1-4伸烷基-O-C1-4烷基、、、、、、OCF3、C1-4烷基、C1-4伸烷基-O-C1-4-烷基、CF3、CF2H、CFH2、SH、S-C1-4烷基、SCF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、苯基與啶基 等取代基組成之群組單取代或多取代，其中，苯基或啶基分別係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、CF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基與SCF3等取代基組成之群組單取代或多取代。 A substituted compound according to any one of the preceding claims, wherein R 1 represents a (T1) substructure, E represents O, S or NR 11 , wherein R 11 represents H or an unsubstituted C 1-4 aliphatic residue; o represents 0 or 1; R 10a and R 10b each independently represent H, F, Cl, Br, I or an unsubstituted C 1-4 aliphatic residue, m represents 0, 1 or 2; G represents a C 1-8 aliphatic residue which is unsubstituted or is Or a plurality of mutually independently selected from the group consisting of F, Cl, Br, I, OH, OC 1-4 alkyl, OC 1-4 alkyl-OH, OC 1-4 alkyl-OC 1-4 alkyl, Group monosubstituted composition of substituents such as OCF 3 , CF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl and SCF 3 Or polysubstituted; or represents a C 3-10 cycloaliphatic residue or a 3 to 10 membered heterocyclic aliphatic residue, which is unsubstituted in each case, or selected independently of one or more Free F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, CF 3 , SCF 3 , NH 2 , NH (C 1-4 alkyl a group of mono- or poly-substituents consisting of a substituent such as N(C 1-4 alkyl) 2 , a phenyl group and a pyridine group, wherein the phenyl or pyridine group is unsubstituted or is one or more Independently selected from F, C l, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, CF 3 , NH 2 , NH(C 1-4 alkyl), N (C 1 -4 alkyl) 2 , SH, SC 1-4 alkyl and a group consisting of a substituent such as SCF 3 are mono- or polysubstituted; or represent an aryl or heteroaryl group, which is unsubstituted in each case Or one or more independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OC 1-4 alkyl-OC 1-4 alkyl, , , , , , OCF 3 , C 1-4 alkyl, C 1-4 alkylene-OC 1-4 -alkyl, CF 3 , CF 2 H, CFH 2 , SH, SC 1-4 alkyl, SCF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , a group consisting of a substituent such as a phenyl group and a pyridine group, monosubstituted or polysubstituted, wherein the phenyl or pyridine group is respectively Unsubstituted, or selected from one or more independently of each other from F, Cl, Br, I, NO 2 , CN, OH, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, CF 3 a group consisting of NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl and a substituent such as SCF 3 is mono- or poly-substituted. 根據前述申請專利範圍中任何一項所述之被取代化合物，其特徵為R2 代表一C1-4脂族殘基，其係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I等取代基組成之群組單取代或多取代，或代表一未被取代之C3-6環脂族殘基。 A substituted compound according to any one of the preceding claims, wherein R 2 represents a C 1-4 aliphatic residue which is unsubstituted or is selected independently from one another by one or more The group consisting of substituents such as F, Cl, Br, and I is mono- or poly-substituted, or represents an unsubstituted C 3-6 cycloaliphatic residue. 根據前述申請專利範圍中任何一項所述之被取代化合物，其特徵為R3 係選自由H、甲基與乙基組成之群組。 A substituted compound according to any one of the preceding claims, characterized in that R 3 is selected from the group consisting of H, methyl and ethyl. 根據前述申請專利範圍中任何一項所述之被取代化合物，其特徵為R3a 係選自由H、甲基與乙基組成之群組，R4a 代表H、甲基、乙基、環丙基、環丁基、環戊基、環己基或苯，其中，苯基係未被取代，或被以1、2、3、4或5個相互獨立地選自由F、Cl、Br、I、NO2、CN、CF3、CF2H、CFH2、CF2Cl、CFCl2、OH、NH2、NH(C1-4烷基)與N(C1-4烷基)(C1-4烷基)、C1-4烷基及O-C1-4-烷基等取代基組成之群組取代；R4b 代表H、甲基或乙基，或R4a與R4b與將其連結之碳原子共同形成一環丙基、環丁基 環戊基或環己基環。 A substituted compound according to any one of the preceding claims, wherein R 3a is selected from the group consisting of H, methyl and ethyl, and R 4a represents H, methyl, ethyl, cyclopropyl. , cyclobutyl, cyclopentyl, cyclohexyl or benzene, wherein the phenyl is unsubstituted or is independently selected from 1, 2, 3, 4 or 5 from F, Cl, Br, I, NO 2 , CN, CF 3 , CF 2 H, CFH 2 , CF 2 Cl, CFCl 2 , OH, NH 2 , NH(C 1-4 alkyl) and N(C 1-4 alkyl) (C 1-4 a group substitution of a substituent such as an alkyl group, a C 1-4 alkyl group, and an OC 1-4 -alkyl group; R 4b represents H, a methyl group or an ethyl group, or R 4a and R 4b and a carbon to which it is bonded The atoms together form a cyclopropyl, cyclobutylcyclopentyl or cyclohexyl ring. 根據前述申請專利範圍中任何一項所述之被取代化合物，其特徵為Z 代表N，及R4a代表H；或Z 代表CR4b及R4a與R4b各自代表H；或Z 代表CR4b及R4a代表甲基而R4b代表H。 A substituted compound according to any one of the preceding claims, wherein Z represents N and R 4a represents H; or Z represents CR 4b and R 4a and R 4b each represent H; or Z represents CR 4b and R 4a represents a methyl group and R 4b represents H. 根據前述申請專利範圍中任何一項所述之被取代化合物，其特徵為通式(I)之(T2)子結構 代表一或多個子結構(T2-a)、(T2-b)、(T2-c)、(T2-d)、(T2-e)、(T2-f)、(T2-g)、(T2-h)、(T2-i)、(T2-j)、(T2-k)、(T2-l)、(T2-m)、(T2-n)及/或(T2-o) A substituted compound according to any one of the preceding claims, which is characterized by a (T2) substructure of the formula (I) Represents one or more substructures (T2-a), (T2-b), (T2-c), (T2-d), (T2-e), (T2-f), (T2-g), (T2) -h), (T2-i), (T2-j), (T2-k), (T2-l), (T2-m), (T2-n), and/or (T2-o) 根據前述申請專利範圍中任何一項所述之被取代化合物，其特徵為R5與R9係相互獨立地選自由H、F、Cl、Br、I、CN、NO2、CF3、CF2H、CFH2、OH、OCF3、OCF2Cl、OCFCl2、SH、SCF3、NH2、C(=O)-NH2、甲基、乙基、三級丁基、O-甲基、NH-甲基與N(甲基)2組成之群組； R6與R8係相互獨立地選自由H、F、Cl、Br、I、CN、NO2、CF3、CF2H、CFH2、OH、OCF3、OCF2Cl、OCFCl2、SH、SCF3、NH2、C(=O)-NH2、甲基、乙基、三級丁基、O-甲基、NH-甲基與N(甲基)2組成之群組；及R7係選自由H、F、Cl、Br、I、CN、NO2、CF3、CF2H、CFH2、CF2Cl、CFCl2、OH、OCF3、OCF2H、OCFH2、OCF2Cl、OCFCl2、SH、SCF3、SCF2H、SCFH2、SCF2Cl、SCFCl2、NH2、C(=O)-NH2組成之群組；一C1-10脂族殘基、(C1-8脂族基)-OH、(C1-8脂族基)-O-C1-10脂族殘基、(C1-8脂族基)-O-(C1-8脂族基)-OH、(C1-8脂族基)-O-(C1-8脂族基)-O-C1-10脂族殘基、一(C1-8脂族基)-NH-C1-10脂族殘基、一(C1-8脂族基)-NH-(C1-8脂族殘基)-OH、一(C1-8脂族基)-N(C1-10脂族殘基)-(C1-8脂族殘基)-OH、一(C1-8脂族基)-NH-S(=O)2-C1-10脂族殘基、一(C1-8脂族基)-NH-S(=O)2-NH2、(C1-8脂族基)-S(=O)2-C1-10脂族殘基、一C(=O)-C1-10脂族殘基、一C(=O)-NH-C1-10脂族殘基，一O-C1-10脂族殘基、一O-(C1-8脂族基)-O-C1-10脂族殘基、O-(C1-8脂族基)-OH，一NH-C1-10脂族殘基、一N(C1-10脂族殘基)2、一NH-(C1-8脂族基)-O-C1-10脂族殘基、一NH-(C1-8脂族基)-OH、一NH-C(=O)-C1-10脂族殘基、一N(C1-10脂族殘基)(C(=O)-C1-10脂族殘基)、一N(C1-10脂族殘基)[(C1-8脂族基)-O-C1-10脂族殘基]、一N(C1-10脂族殘基)[(C1-8脂族基)-OH]、一NH-S(=O)2-C1-10脂族殘基、一N(C1-10脂族殘基)[S(=O)2-C1-10脂族殘基]，一S(=O)2-C1-10脂族殘基、一S(=O)2-NH-C1-10脂族殘基、一 S(=O)2-N(C1-10脂族殘基)2、一S-C1-10脂族殘基，其中，各上述之C1-10脂族殘基與C1-8脂族基於各例中，可係未被取代，或被以OH單取代；一C3-10環脂族殘基、一C(=O)-C3-10環脂族殘基、一C(=O)NH-C3-10環脂族殘基、一O-C3-10環脂族殘基、一O-(C1-8脂族基)-C3-10環脂族殘基、一S-C3-10環脂族殘基、一S-(C1-8脂族基)-C3-10環脂族殘基、一NH-C3-10環脂族殘基、一NH-C(=O)-C3-10環脂族殘基、一NH-(C1-8脂族基)-C3-10環脂族殘基、一N(C1-10脂族殘基)(C3-10環脂族殘基)、一3至10構件雜環脂族殘基、一C(=O)-(3至10構件雜環脂族殘基)、一C(=O)-NH-(3至10構件雜環脂族殘基)、一O-(3至10構件雜環脂族殘基)、一O-(C1-8脂族基)-(3至10構件雜環脂族殘基)、一S-(3至10構件雜環脂族殘基)、一S-(C1-8脂族基)-(3至10構件雜環脂族殘基)、一NH-(3至10構件雜環脂族殘基)、一NH-C(=O)-(3至10構件雜環脂族殘基)、NH-(C1-8脂族基)-(3至10構件雜環脂族殘基)、一N(C1-10脂族殘基)(3至10構件雜環脂族殘基)，其中，各上述殘基可選擇性地經由一C1-8脂族基橋接，其中，該C1-10脂族殘基與該C1-8脂族基於各例中，相互獨立地可係未被取代，或被以OH單取代，其中，該C3-10環脂族殘基與該3至10構件雜環脂族殘基分別可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、=O、O-C1-4烷基、OCF3、C1-4烷基、CF3、SH、S-C1-4烷基、SCF3、NH2、NH(C1-4烷基)與N(C1-4烷基)2等取代基組成之群組單取代或多取代， 芳基、C(=O)-芳基、C(=O)-NH-芳基、O-芳基、一O-(C1-8脂族基)-芳基、S-芳基、一S-(C1-8脂族基)-芳基、一NH-芳基、NH-C(=O)-芳基、NH-S(=O)2-芳基、一NH-(C1-8脂族基)-芳基、一N(C1-10脂族殘基)(芳基)、雜芳基、C(=O)-雜芳基、C(=O)-NH-雜芳基、O-雜芳基、O-(C1-8脂族基)-雜芳基、S-(雜芳基)、S-(C1-8脂族基)-(雜芳基)、NH-(雜芳基)、NH-C(=O)-雜芳基、NH-S(=O)2-雜芳基、NH-(C1-8脂族基)(雜芳基)、N(C1-10脂族殘基)(雜芳基)，其中，各上述殘基於各例中，可選擇性地經由一C1-8脂族基橋接，其中，各上述殘基之C1-10脂族殘基與C1-8脂族基於各例中，相互獨立地可係未被取代，或被以OH單取代，其中，上述殘基之芳基與雜芳基於各例中，分別相互獨立地，可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、O-C1-4伸烷基-O-C1-4烷基、OCF3、C1-4烷基、C1-4伸烷基-O-C1-4烷基、CF3、CF2H、CHF2、SH、S-C1-4烷基、SCF3、NH2、NH(C1-4烷基)、N(C1-4烷基)2、苯基與啶基等取代基組成之群組單取代或多取代，其中，苯基或啶基分別係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、O-C1-4伸烷基-O-C1-4烷基OCF3、C1-4烷基、C1-4伸烷基-O-C1-4烷基、C(=O)-OH、CF3、CF2H、CHF2、NH2、NH(C1-4烷基)、N(C1-4烷基)2、SH、S-C1-4烷基、SCF3與S(=O)2OH等取代基組成之群組單取代或多取代。 A substituted compound according to any one of the preceding claims, wherein R 5 and R 9 are independently selected from the group consisting of H, F, Cl, Br, I, CN, NO 2 , CF 3 , CF 2 H, CFH 2 , OH, OCF 3 , OCF 2 Cl, OCFCl 2 , SH, SCF 3 , NH 2 , C(=O)-NH 2 , methyl, ethyl, tert-butyl, O-methyl, a group consisting of NH-methyl and N(methyl) 2 ; R 6 and R 8 are independently selected from H, F, Cl, Br, I, CN, NO 2 , CF 3 , CF 2 H, CFH 2 , OH, OCF 3 , OCF 2 Cl, OCFCl 2 , SH, SCF 3 , NH 2 , C(=O)-NH 2 , methyl, ethyl, tert-butyl, O-methyl, NH- a group consisting of a group of N(methyl) 2 ; and R 7 is selected from the group consisting of H, F, Cl, Br, I, CN, NO 2 , CF 3 , CF 2 H, CFH 2 , CF 2 Cl, CFCl 2 , OH, OCF 3 , OCF 2 H, OCFH 2 , OCF 2 Cl, OCFCl 2 , SH, SCF 3 , SCF 2 H, SCFH 2 , SCF 2 Cl, SCFCl 2 , NH 2 , C(=O)-NH 2 a group consisting of a C 1-10 aliphatic residue, (C 1-8 aliphatic)-OH, (C 1-8 aliphatic)-OC 1-10 aliphatic residue, (C 1- 8 aliphatic group) -O-(C 1-8 aliphatic)-OH, (C 1-8 aliphatic)-O-(C 1-8 aliphatic -OC 1-10 aliphatic residue, one (C 1-8 aliphatic)-NH-C 1-10 aliphatic residue, one (C 1-8 aliphatic)-NH- (C 1 -8 aliphatic residue) -OH, mono(C 1-8 aliphatic)-N (C 1-10 aliphatic residue) - (C 1-8 aliphatic residue) -OH, one (C 1 -8 aliphatic group)-NH-S(=O) 2 -C 1-10 aliphatic residue, one (C 1-8 aliphatic)-NH-S(=O) 2 -NH 2 , (C 1-8 aliphatic)-S(=O) 2 -C 1-10 aliphatic residue, a C(=O)-C 1-10 aliphatic residue, a C(=O)-NH-C 1-10 aliphatic residue, an OC 1-10 aliphatic residue, an O-(C 1-8 aliphatic)-OC 1-10 aliphatic residue, and an O-(C 1-8 aliphatic group) )-OH, an NH-C 1-10 aliphatic residue, an N (C 1-10 aliphatic residue) 2 , an NH-(C 1-8 aliphatic)-OC 1-10 aliphatic residue a group, an NH-(C 1-8 aliphatic)-OH, an NH-C(=O)-C 1-10 aliphatic residue, an N (C 1-10 aliphatic residue) (C( =O)-C 1-10 aliphatic residue), one N (C 1-10 aliphatic residue) [(C 1-8 aliphatic)-OC 1-10 aliphatic residue], one N ( C 1-10 aliphatic residue) [(C 1-8 aliphatic)-OH], one NH-S(=O) 2 -C 1-10 aliphatic residue, one N (C 1-10 lipid) Family residue) [S(=O) 2 -C 1-10 aliphatic residue], an S(=O) 2 -C 1-10 aliphatic residue, a S(=O) 2 -NH-C 1-10 aliphatic residue, an S (= O) 2 -N ( C 1-10 aliphatic Yl) 2, a SC 1-10 aliphatic residue, wherein each of the aforementioned C 1-10 aliphatic residue with aliphatic C 1-8 based on the respective embodiments, the system may be unsubstituted or mono to OH Substituted; a C 3-10 cycloaliphatic residue, a C(=O)-C 3-10 cycloaliphatic residue, a C(=O)NH-C 3-10 cycloaliphatic residue, an OC 3-10 cycloaliphatic residue, mono-O-(C 1-8 aliphatic)-C 3-10 cycloaliphatic residue, one SC 3-10 cycloaliphatic residue, one S-(C 1- 8 aliphatic group)-C 3-10 cycloaliphatic residue, one NH-C 3-10 cycloaliphatic residue, one NH-C(=O)-C 3-10 cycloaliphatic residue, one NH -(C 1-8 aliphatic)-C 3-10 cycloaliphatic residue, one N (C 1-10 aliphatic residue) (C 3-10 cycloaliphatic residue), a 3 to 10 building block a heterocyclic aliphatic residue, a C(=O)-(3 to 10 membered heterocyclic aliphatic residue), a C(=O)-NH- (3 to 10 membered heterocyclic aliphatic residue), O-(3 to 10 component heterocyclic aliphatic residue), 1-O-(C 1-8 aliphatic)-(3 to 10 component heterocyclic aliphatic residue), and one S-(3 to 10 component hetero a cycloaliphatic residue), an S-(C 1-8 aliphatic group)-(3 to 10 membered heterocyclic aliphatic residue), an NH-(3 to 10 membered heterocyclic aliphatic residue), NH-C (= O) - (3 to 10 component heterocycloaliphatic residue), NH- (C 1-8 aliphatic) - (3-10 member Cycloaliphatic residues), a N (C 1-10 aliphatic residue) (3-10 member heterocyclic aliphatic residue), wherein each of the residues optionally via a C 1-8 aliphatic a bridge, wherein the C 1-10 aliphatic residue and the C 1-8 aliphatic group are independently unsubstituted in each of the examples, or are monosubstituted with OH, wherein the C 3-10 The cycloaliphatic residue and the 3 to 10 membered heterocyclic aliphatic residue may be unsubstituted, respectively, or may be independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH. , =O, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, CF 3 , SH, SC 1-4 alkyl, SCF 3 , NH 2 , NH(C 1-4 alkyl) and N a group consisting of a mono- or poly-substituted group of (C 1-4 alkyl) 2 and the like, an aryl group, a C(=O)-aryl group, a C(=O)-NH-aryl group, an O-aryl group, O-(C 1-8 aliphatic)-aryl, S-aryl, an S-(C 1-8 aliphatic)-aryl, an NH-aryl, NH-C(=O) -aryl, NH-S(=O) 2 -aryl, mono NH-(C 1-8 aliphatic)-aryl, one N (C 1-10 aliphatic residue) (aryl), hetero Aryl, C(=O)-heteroaryl, C(=O)-NH-heteroaryl, O-heteroaryl, O-(C 1-8 aliphatic)-heteroaryl, S-( heteroaryl), S- (C 1-8 aliphatic ) - (heteroaryl), NH- (heteroaryl), NH-C (= O ) - heteroaryl, NH-S (= O) 2 - heteroaryl, NH- (C 1-8 aliphatic (heteroaryl), N (C 1-10 aliphatic residue) (heteroaryl), wherein each of the above residues is selectively bridged via a C 1-8 aliphatic group, based on each instance, Wherein, the C 1-10 aliphatic residue and the C 1-8 aliphatic group of each of the above residues may be unsubstituted independently of each other or may be monosubstituted by OH, wherein the residue is aromatic The base and heteroaryl are, based on each of the examples, independently of each other, may be unsubstituted, or may be independently selected from one or more independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, OC 1- 4- alkyl, OC 1-4 alkylene-OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, C 1-4 alkylene-OC 1-4 alkyl, CF 3 , CF 2 H And CHF 2 , SH, SC 1-4 alkyl, SCF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , a substituent such as a phenyl group and a pyridine group a group mono- or poly-substituted, wherein the phenyl or pyridine group is unsubstituted, respectively, or is selected from one or more independently from F, Cl, Br, I, NO 2 , CN, OH, OC 1 -4 alkyl, OC 1-4 alkylene-OC 1-4 alkyl OCF 3 , C 1-4 alkyl, C 1-4 alkylene-OC 1-4 alkyl, C(=O)-OH, CF 3 , CF 2 H, CHF 2, NH 2 , NH(C 1-4 alkane A group consisting of a group consisting of N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 and S(=O) 2 OH, such as a mono- or poly-substituent. 根據前述申請專利範圍中任何一項所述之被取代化合物，其特 徵為R1 代表(T1)子結構 其E 代表O或S，o 代表0或1，R10a與R10b係相互獨立地選自由H、甲基與乙基組成之群組；m 代表0、1或2；G 代表甲基、乙基、正丙基、異丙基、正丁基、二級丁基、三級丁基、戊基、己基，或代表，或代表環丙基、環丁基、環戊基與環己基，或係選自由哌啶基、嗎咻基、四氫咯基、四氫喹啉基、四氫異喹啉基、二氫喹啉基、二氫咯基、二氫啶基、二氫異喹啉基、四氫吡喃基組成之群組，以四氫-2H-吡喃-4-基、四氫呋喃基與四氫啶基較佳，其於各例中相互獨立地係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、OH、O-C1-4烷基、C1-4烷基、NH2、NH(C1-4烷基)與N(C1-4烷基)2等取代基組成之群組單取代或多取代，或代表呋喃基或吩基，其於各例中係未被取代，或代表苯基或啶基，其於各例中係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、NO2、 CN、OH、O-C1-4烷基、O-C1-4伸烷基-O-C1-4烷基、、、、、、OCF3、C1-4烷基、C1-4伸烷基-O-C1-4-烷基、CF3、CF2H、CFH2、SCF3、NH2、NH(C1-4烷基)與N(C1-4烷基)2等取代基組成之群組單取代或多取代；R2 係選自由CF3、甲基、乙基、正丙基、異丙基、正丁基、二級丁基與三級丁基組成之群組，或係選自由環丙基、環丁基、環戊基與環己基組成之群組；R3 代表H或一未被取代之C1-4脂族殘基；n 代表1、2或3，以代表1或2較佳，以代表1更佳，R3a 代表H、甲基或乙基，R4a 代表H、甲基或乙基，Y 代表O，Z 代表N或CR4b，R4b 代表H、甲基或乙基，T1 代表N或C-R5，U1 代表N或C-R6，V 代表N或C-R7，U2 代表N或C-R8，T2 代表N或C-R9，附帶條件為T1、U1、V、U2與T2變量之1、2或3代表一氮原子；R5與R9係相互獨立地選自由H、F、Cl、Br、I、CF3、OH、 甲基與O-甲基組成之群組；R6與R8係相互獨立地選自由H、F、Cl、Br、I、CF3、OH、甲基與O-甲基組成之群組；及R7係選自由下列基團組成之群組H、F、Cl、Br、I、CN、CF3、CF2H、CFH2、OH、OCF3、SH、SCF3、NH2、C(=O)-NH2、S(=O)2-OH、S(=O)2-NH2；C1-4烷基、C1-4伸烷基-OH、C1-4伸烷基-O-C1-4烷基、C1-4伸烷基-O-C1-4伸烷基-OH、C1-4伸烷基-O-C1-4伸烷基-O-C1-4烷基、C1-4伸烷基-S(=O)2-C1-4烷基、C1-4伸烷基-NH-S(=O)2-C1-4烷基、C1-4伸烷基-NH-S(=O)2-NH2、C1-4伸烷基-NH-C1-4伸烷基-OH、C1-4伸烷基-NH-C1-4伸烷基-O-C1-4烷基、C1-4伸烷基-N(C1-4烷基)-C1-4伸烷基-OH、C1-4伸烷基-N(C1-4烷基)-C1-4伸烷基-O-C1-4烷基、O-C1-4烷基、O-C1-4伸烷基-OH、O-C1-4伸烷基-O-C1-4烷基、NH-C1-4烷基、N(C1-4烷基)2、NH-C1-4伸烷基-OH、NH-C1-4伸烷基-O-C1-4烷基、N(C1-4烷基)-[C1-4伸烷基-OH]、N(C1-4烷基)-[C1-4伸烷基-O-C1-4烷基]、NH-S(=O)2-C1-4烷基，其中，C1-4伸烷基於各例中，可係未被取代，或被以OH單取代，一C3-6環脂族殘基、O-C3-6環脂族殘基、一3至6構件雜環脂族殘基，其中，該C3-6環脂族殘基與該3至6構件雜環脂族殘基分別可係未被取代，或被一或多個相互獨立地選自由F、Cl、Br、I、OH、O-C1-4烷基、NH2、NH(C1-4烷基)、與N(C1-4烷基)2、與C1-4烷基等取代基組成之群組單取代或多取代， 苯基、C(=O)-NH-苯基、NH-C(=O)-苯基、雜芳基、C(=O)-NH-雜芳基、NH-C(=O)-雜芳基，其中，上述殘基之苯基與雜芳基於各例中，分別可係未被取代，或被以一或多個相互獨立地選自由F、Cl、Br、I、OH、O-C1-4烷基、C1-4烷基與CF3等取代基組成之群組單取代或多取代。 A substituted compound according to any one of the preceding claims, characterized in that R 1 represents a (T1) substructure Its E represents O or S, and o represents 0 or 1, and R 10a and R 10b are independently selected from the group consisting of H, methyl and ethyl; m represents 0, 1 or 2; G represents methyl, B. Base, n-propyl, isopropyl, n-butyl, secondary butyl, tert-butyl, pentyl, hexyl, or Or represents cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, or is selected from the group consisting of piperidinyl, decyl, tetrahydrorupyl, tetrahydroquinolyl, tetrahydroisoquinolinyl, dihydrogen a group consisting of quinolyl, dihydror-yl, dihydropyridyl, dihydroisoquinolinyl, tetrahydropyranyl, tetrahydro-2H-pyran-4-yl, tetrahydrofuranyl and tetrahydropyridine Preferably, the substituents are unsubstituted independently of each other in each case, or are independently selected from the group consisting of F, Cl, Br, I, OH, OC 1-4 alkyl, C 1-4 a group consisting of a group consisting of an alkyl group, NH 2 , NH(C 1-4 alkyl) and N(C 1-4 alkyl) 2, such as a mono- or poly-substituent, or a furanyl or phenyl group, In the examples, they are unsubstituted or represent a phenyl or pyridine group, which is unsubstituted in each case, or is selected from F, Cl, Br, I, NO 2 , CN, independently of one or more. OH, OC 1-4 alkyl, OC 1-4 alkyl-OC 1-4 alkyl, , , , , , OCF 3 , C 1-4 alkyl, C 1-4 alkylene-OC 1-4 -alkyl, CF 3 , CF 2 H, CFH 2 , SCF 3 , NH 2 , NH (C 1-4 alkane a group consisting of a group consisting of a substituent such as N(C 1-4 alkyl) 2 is mono- or poly-substituted; R 2 is selected from the group consisting of CF 3 , methyl, ethyl, n-propyl, isopropyl, n-butyl a group consisting of a base, a secondary butyl group and a tertiary butyl group, or selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; R 3 represents H or an unsubstituted C 1-4 aliphatic residue; n represents 1, 2 or 3, preferably 1 or 2, preferably 1 is preferred, R 3a represents H, methyl or ethyl, and R 4a represents H, methyl or B. Base, Y represents O, Z represents N or CR 4b , R 4b represents H, methyl or ethyl, T 1 represents N or CR 5 , U 1 represents N or CR 6 , V represents N or CR 7 , and U 2 represents N or CR 8 , T 2 represents N or CR 9 , with the condition that 1 , 2 or 3 of the T 1 , U 1 , V, U 2 and T 2 variables represent a nitrogen atom; R 5 and R 9 are independent of each other Selected from the group consisting of H, F, Cl, Br, I, CF 3 , OH, methyl and O-methyl; R 6 and R 8 are independently selected from H, F, Cl, Br, I, CF 3 , OH, methyl and a group of O-methyl groups; and R 7 is selected from the group consisting of H, F, Cl, Br, I, CN, CF 3 , CF 2 H, CFH 2 , OH, OCF 3 , SH , SCF 3 , NH 2 , C(=O)-NH 2 , S(=O) 2 -OH, S(=O) 2 -NH 2 ; C 1-4 alkyl, C 1-4 alkylene- OH, C 1-4 alkyl-OC 1-4 alkyl, C 1-4 alkyl-OC 1-4 alkyl-OH, C 1-4 alkyl-OC 1-4 alkyl -OC 1-4 alkyl, C 1-4 alkylene-S(=O) 2 -C 1-4 alkyl, C 1-4 alkylene-NH-S(=O) 2 -C 1- 4- alkyl, C 1-4 alkylene-NH-S(=O) 2 -NH 2 , C 1-4 alkylene-NH-C 1-4 alkylene-OH, C 1-4 alkylene --NH-C 1-4 alkylene-OC 1-4 alkyl, C 1-4 alkylene-N(C 1-4 alkyl)-C 1-4 alkylene-OH, C 1- 4- alkyl-N(C 1-4 alkyl)-C 1-4 alkylene-OC 1-4 alkyl, OC 1-4 alkyl, OC 1-4 alkyl-OH, OC 1- 4- alkyl-OC 1-4 alkyl, NH-C 1-4 alkyl, N(C 1-4 alkyl) 2 , NH-C 1-4 alkyl-OH, NH-C 1-4 alkyl-OC 1-4 alkyl, N(C 1-4 alkyl)-[C 1-4 alkyl-OH], N(C 1-4 alkyl)-[C 1-4 alkylene --OC 1-4 alkyl], NH-S(=O) 2 -C 1-4 alkyl, wherein C 1-4 alkyl is in each case, may be unsubstituted, or may be O H monosubstituted, a C 3-6 cycloaliphatic residue, an OC 3-6 cycloaliphatic residue, a 3 to 6 membered heterocyclic aliphatic residue, wherein the C 3-6 cycloaliphatic residue The 3 to 6 membered heterocyclic aliphatic residues may be unsubstituted, respectively, or may be independently selected from the group consisting of F, Cl, Br, I, OH, OC 1-4 alkyl, NH 2 , NH. (C 1-4 alkyl), a group consisting of a substituent such as N(C 1-4 alkyl) 2 , and a C 1-4 alkyl group, mono- or poly-substituted, phenyl, C(=O)- NH-phenyl, NH-C(=O)-phenyl, heteroaryl, C(=O)-NH-heteroaryl, NH-C(=O)-heteroaryl, wherein the above residues Phenyl and heteroaryl, respectively, may be unsubstituted, or one or more independently selected from the group consisting of F, Cl, Br, I, OH, OC 1-4 alkyl, C 1-4 The group consisting of an alkyl group and a substituent such as CF 3 is mono- or poly-substituted. 根據前述申請專利範圍中任何一項所述之被取代化合物，其選自下列基團1 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(啶-2-基)乙醯胺；2 N-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-2-(啶-2-基)丙醯胺；3 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(啶-2-基)丙醯胺；4 1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(啶-2-基)尿素；5 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(啶-2-基)尿素；6 N-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-2-(啶-3-基)乙醯胺；7 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(啶-3-基)乙醯胺；8 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(啶-3-基)丙醯胺；9 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(啶-3-基)尿素； 10 N-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-2-(啶-4-基)乙醯胺；11 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(啶-4-基)乙醯胺；12 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(啶-4-基)尿素；13 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(嘧啶-4-基)乙醯胺；14 1N-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-2-(吡嗪-2-基)乙醯胺；15 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(嗒-4-基)尿素；16 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(嘧啶-5-基)乙醯胺；17 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-氯啶-3-基)乙醯胺；18 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(5-氟啶-3-基)尿素；19 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(2-甲基嘧啶-5-基)尿素；20 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(1,3,5-三嗪-2-基)尿素；21 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-(甲磺醯基)乙基)啶-3-基)尿素；22 1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(5-氟-6-(2-(甲磺醯基)乙基)啶-3-基)尿素； 23 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(5-氟-6-(2-(甲磺醯基)乙基)啶-3-基)尿素；24 1-((1-(3-氯苯基)-3-環丙基-1H-吡唑-5-基)甲基)-3-(5-氟-6-(2-(甲磺醯基)乙基)啶-3-基)尿素；25 5-(3-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)脲基)啶醯胺；26 5-(3-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)脲基)啶醯胺；27 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-(甲基磺醯胺基甲基)啶-3-基)丙醯胺；28 N-((5-(3-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)脲基)啶-2-基)甲基)甲基磺醯胺；29 N-((5-(3-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)脲基)啶-2-基)甲基)硫醯二胺；30 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-(羥甲基)啶-3-基)丙醯胺；31 (E)-1-((1-(3,3-二甲基丁烯-1-基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素；32 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素；33 1-((1-(3-氟苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素；34 1-((1-(3-氟-4-甲苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素；35 1-((1-(3-氟-4-甲氧苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素； 36 1-(6-(羥甲基)啶-3-基)-3-((1-間-甲苯基-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；37 1-(6-(羥甲基)啶-3-基)-3-((1-(4-甲氧基-3-甲苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；38 1-(6-(羥甲基)啶-3-基)-3-((1-(3-異丙苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；39 1-((1-(3-三級丁基苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素；40 1-(6-(羥甲基)啶-3-基)-3-((1-(3-(甲氧基甲基)苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；41 1-((1-(3-(二氟甲基)苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素；42 1-((1-(3-苯腈)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素；43 1-((1-(3-(二甲胺基)苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素；44 1-((1-(5-氯啶-3-基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素；45 1-(6-(羥甲基)啶-3-基)-3-((1-(6-甲氧啶-3-基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；46 1-((1-(苯並[d][1,3]二氧環戊烯-5-基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素；47 1-((1-(1H-吲哚-6-基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素；48 1-((1-(呋喃-3-基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素； 49 1-(6-(羥甲基)啶-3-基)-3-((1-(噻吩-2-基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；50 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(5-氟-6-(羥甲基)啶-3-基)尿素；51 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-(2-羥乙基)啶-3-基)丙醯胺；52 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙基)啶-3-基)尿素；53 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-((2-羥乙氧)甲基)啶-3-基)丙醯胺；54 1-((1-(3-氟苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(四氫-2H-吡喃-4-基)啶-3-基)尿素；55 5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶醯胺；56 5-(1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶醯胺；57 5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)-N-苯基啶醯胺；58 5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)-N-(4-氟苯基)啶醯胺；59 5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)-N-(4-(三氟甲基)苯基)啶醯胺；60 5-(1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)-N-(4-氟苯基)啶醯胺；61 5-(1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)-N-(4-(三氟甲基)苯基)啶醯胺； 62 5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)-N-苯基嘧啶-2-羧醯胺；63 5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)-N-(4-氟苯基)嘧啶-2-羧醯胺；64 5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)-N-(4-(三氟甲基)苯基)嘧啶-2-羧醯胺；65 5-(1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)-N-苯基嘧啶-2-羧醯胺；66 5-(1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)-N-(4-氟苯基)嘧啶-2-羧醯胺；67 5-(1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)-N-(4-(三氟甲基)苯基)嘧啶-2-羧醯胺；68 1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(2-甲氧基乙胺)啶-3-基)尿素；69 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-甲氧基乙胺)啶-3-基)尿素；70 1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素；71 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素；72 1-((1-(3-氯苯基)-3-環丙基-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素；73 1-((1-(3-氯苯基)-4-甲基-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素； 74 1-(6-(2-羥乙胺)啶-3-基)-3-((1-戊基-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；75 1-((1-(環丙基甲基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素；76 1-((1-環己基-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素；77 1-(6-(2-羥乙胺)啶-3-基)-3-((1-(四氫-2H-吡喃-4-基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；78 1-((1-(3-氟苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素；79 1-((1-(3,4-二氟苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素；80 1-(6-(2-羥乙胺)啶-3-基)-3-((1-(3-甲氧苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；81 1-(6-(2-羥乙胺)啶-3-基)-3-((1-間-甲苯基-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；82 1-(6-(2-羥乙胺)啶-3-基)-3-((1-(3-異丙苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；83 1-((1-(3-三級丁基苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素；84 1-((3-三級丁基-1-(3-(三氟甲基)苯基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素；85 1-((3-三級丁基-1-(啶-2-基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素；86 1-(6-(2-羥乙胺)啶-3-基)-3-((1-(4-甲氧苄基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素； 87 1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-((2-羥乙基)(甲基)胺基)啶-3-基)尿素；88 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-((2-甲氧基乙基)(甲基)胺基)啶-3-基)丙醯胺；89 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-((2-甲氧基乙基)(甲基)胺基)啶-3-基)尿素；90 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-((2-羥乙基)(甲基)胺基)啶-3-基)尿素；91 N-(5-(1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)苯甲醯胺；92 N-(5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)苯甲醯胺；93 N-(5-(1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)-4-氟苯甲醯胺；94 N-(5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)-4-氟苯甲醯胺；95 N-(5-(1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)-4-氯苯甲醯胺；96 4-氯-N-(5-(1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)苯甲醯胺；97 4-氯-N-(5-(1-氧代-1-((1-(啶-3-基)-3-(三氟甲基)-1H-吡唑-5-基)甲胺基)丙烷-2-基)啶-2-基)苯甲醯胺；98 N-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-2-(6-(甲基磺醯胺)啶-3-基)丙醯胺；99 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-(甲基磺醯胺)啶-3-基)丙醯胺； 100 N-((1-(3-氟苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-(甲基磺醯胺)啶-3-基)丙醯胺；101 N-(5-(3-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)脲基)啶-2-基)甲基磺醯胺；102 N-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-2-(5-氟-6-(甲基磺醯胺)啶-3-基)丙醯胺；103 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(5-氟-6-(甲基磺醯胺)啶-3-基)丙醯胺；104 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(5-甲氧基-6-(甲基磺醯胺)啶-3-基)丙醯胺；105 N-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-2-(5-甲氧基-6-(甲基磺醯胺)啶-3-基)丙醯胺；106 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(二甲胺基)-5-(三氟甲基)啶-3-基)尿素；107 1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(二甲胺基)-5-(三氟甲基)啶-3-基)尿素；108 1-(6-(氮雜環丁-1-基)啶-3-基)-3-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)尿素；109 1-(6-(氮雜環丁-1-基)啶-3-基)-3-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；110 1-((3-三級丁基-1-(3-氟苯基)-1H-吡唑-5-基)甲基)-3-(6-(3-羥基氮雜環丁-1-基)啶-3-基)尿素；111 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(3-羥基氮雜環丁-1-基)啶-3-基)尿素；112 1-((1-(3-氟苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(3-羥基氮雜環丁-1-基)啶-3-基)尿素； 113 1-((1-(3-氯-4-氟苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(3-羥基氮雜環丁-1-基)啶-3-基)尿素；114 1-(6-(3-羥基氮雜環丁-1-基)啶-3-基)-3-((1-間-甲苯基-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；115 1-(6-(3-羥基氮雜環丁-1-基)啶-3-基)-3-((1-(3-異丙苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；116 1-((1-(3-三級丁基苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(3-羥基氮雜環丁-1-基)啶-3-基)尿素；117 1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(3-羥基氮雜環丁-1-基)啶-3-基)尿素；118 1-((1-(3-(二甲胺基)苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(3-羥基氮雜環丁-1-基)啶-3-基)尿素；119 1-(6-(3-羥基氮雜環丁-1-基)啶-3-基)-3-((1-(3-甲氧苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；120 1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(咯啶-1-基)啶-3-基)尿素；121 1-((1-3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(咯啶-1-基)啶-3-基)尿素；122 1-((1-3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(5-(氟-6-(咯啶-1-基)啶-3-基)尿素；123 1-((1-3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(5-(甲氧基-6-(咯啶-1-基)啶-3-基)尿素；124 (R)-1-((1-3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(3-羥基咯啶-1-基)啶-3-基)尿素；125 (S)-1-((1-3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(3-羥基咯啶-1-基)啶-3-基)尿素； 126 (R)-1-((1-3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(3-羥基咯啶-1-基)啶-3-基)尿素；127 (S)-1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(3-羥基咯啶-1-基)啶-3-基)尿素；128 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-羥基啶-3-基)尿素；129 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-甲氧啶-3-基)丙醯胺；130 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(2-甲氧基嘧啶-5-基)尿素；131 1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(2-甲氧乙氧基)啶-3-基)尿素；132 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-甲氧乙氧基)啶-3-基)尿素；133 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙氧)啶-3-基)尿素；134 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-((2-羥乙胺)甲基)啶-3-基)尿素；135 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(((2-羥乙基)(甲基)胺基)甲基)啶-3-基)尿素；136 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-甲基啶-3-基)尿素；137 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(5-甲基啶-3-基)尿素；138 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(4,6-二甲基啶-3-基)尿素； 139 1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(5-(羥甲基)啶-2-基)尿素；140 1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(5-(羥甲基)啶-3-基)尿素；141 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)-2-甲基啶-3-基)尿素；142 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(5-氟-6-(羥甲基)啶-3-基)丙醯胺；143 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙基)-2-甲基啶-3-基)尿素；144 1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(1,2-二羥乙基)啶-3-基)尿素；145 1-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(1,2-二羥乙基)啶-3-基)尿素；146 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-(2-羥乙胺)啶-3-基)丙醯胺；147 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-(2-甲氧基乙胺)啶-3-基)丙醯胺；148 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-((2-羥乙基)(甲基)胺基)啶-3-基)丙醯胺；149 N-((1-(3-氯-4-氟苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-(2-羥乙基)啶-3-基)丙醯胺；150 N-((1-(3-氯苯基)-3-環丙基-1H-吡唑-5-基)甲基)-2-(6-(2-羥乙基)啶-3-基)丙醯胺；151 2-(6-(2-羥乙基)啶-3-基)-N-((1-間-甲苯基-3-(三氟甲基)-1H-吡唑-5-基)甲基)丙醯胺； 152 1-((3-三級丁基-1-(3-氟苯基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙基)啶-3-基)尿素；153 1-((3-三級丁基-1-(3-甲氧苯基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙基)啶-3-基)尿素；154 1-((3-三級丁基-1-(3-氟苯基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素；155 1-((1-(3,5-二氟苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素；156 1-((1-(4-氯-3-甲苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素；157 1-(6-(2-羥乙胺)啶-3-基)-3-((1-(4-甲氧基-3-甲苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)尿素；158 1-((1-(4-氟-3-甲苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素；159 1-((3-三級丁基-1-(3-氯苯基)-1H-吡唑-5-基)甲基)-3-(6-(甲磺醯基甲基)啶-3-基)尿素；160 1-((3-三級丁基-1-(3-氟苯基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素；161 N-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)-2-(6-(2-(甲磺醯基)乙基)啶-3-基)丙醯胺；162 N-((5-(3-((1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)甲基)脲基)嘧啶-2-基)甲基)甲基磺醯胺；及163 1-((3-環丙基-1-(3-氟苯基)-1H-吡唑-5-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素；選擇性地選擇性地以單一立體異構物或立體異構物之混合物之形式、以自由化合物之形式及/或其生理上可接受之鹽或之形 式。 A substituted compound according to any one of the preceding claims, which is selected from the group consisting of 1 N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole -5-yl)methyl)-2-(pyridin-2-yl)acetamide; 2 N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazole-5 -yl)methyl)-2-(pyridin-2-yl)propanamine; 3 N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5 -yl)methyl)-2-(pyridin-2-yl)propanamide; 4 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl) )methyl)-3-(pyridin-2-yl)urea; 5 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)) Benzyl-3-(pyridin-2-yl)urea; 6 N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2 -(pyridin-3-yl)acetamide; 7 N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2 -(pyridin-3-yl)acetamide; 8 N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2 -(pyridin-3-yl)propanamine; 9 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3 -(pyridin-3-yl)urea; 10 N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(pyridin-4-yl)acetamide; 11 N -((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(pyridin-4-yl)acetamide; 12 1 -((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(pyridin-4-yl)urea; 13 N-( (1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(pyrimidin-4-yl)acetamide; 14 1N-( (3-tertiary butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(pyrazin-2-yl)acetamide; 15 1-(( 1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(indol-4-yl)urea; 16 N-((1- (3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(pyrimidin-5-yl)acetamide; 17 N-((1- (3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(6-chloropyridin-3-yl)acetamide; 18 1-( (1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(5-fluoropyridin-3-yl)urea; 19 1- ((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(2-methylpyrimidin-5-yl)urea; 20 1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(1,3,5-triazine-2- Base) urea 21 1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-(methylsulfonyl) Ethyl)pyridin-3-yl)urea; 22 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-( 5-fluoro-6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)urea; 23 1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(5-fluoro-6-(2-( Methanesulfonyl)ethyl)pyridin-3-yl)urea; 24 1-((1-(3-chlorophenyl)-3-cyclopropyl-1H-pyrazol-5-yl)methyl)- 3-(5-fluoro-6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)urea; 25 5-(3-((3-tert-butyl-1-(3-chloro)) Phenyl)-1H-pyrazol-5-yl)methyl)ureido)pyridinium; 26 5-(3-((1-(3-chlorophenyl)-3-(trifluoromethyl))- 1H-pyrazol-5-yl)methyl)ureido)pyridinium; 27 N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5- Methyl)-2-(6-(methylsulfonylamino)pyridin-3-yl)propanamine; 28 N-((5-(3-((1-(3-chlorobenzene)) 3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)ureido)pyridin-2-yl)methyl)methylsulfonamide; 29 N-((5-( 3-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)ureido)pyridin-2-yl)methyl)thiolane Amine; 30 N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(6-(hydroxymethyl)pyridine 3-yl)propanamine; 31 (E)-1-((1-(3,3-dimethylbuten-1-yl)-3-(trifluoromethyl)-1H-pyrazole- 5-yl)methyl)-3-(6-(hydroxymethyl)pyridin-3-yl)urea; 32 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-) 1H- Zyrid-5-yl)methyl)-3-(6-(hydroxymethyl)pyridin-3-yl)urea; 33 1-((1-(3-fluorophenyl)-3-(trifluoromethyl) -1H-pyrazol-5-yl)methyl)-3-(6-(hydroxymethyl)pyridin-3-yl)urea; 34 1-((1-(3-fluoro-4-tolyl)) -3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(hydroxymethyl)pyridin-3-yl)urea; 35 1-((1-(3) -fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(hydroxymethyl)pyridin-3-yl)urea ; 36 1-(6-(Hydroxymethyl)pyridin-3-yl)-3-((1-m-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl) Urea; 37 1-(6-(hydroxymethyl)pyridin-3-yl)-3-((1-(4-methoxy-3-methylphenyl)-3-(trifluoromethyl)-1H- Pyrazol-5-yl)methyl)urea; 38 1-(6-(hydroxymethyl)pyridin-3-yl)-3-((1-(3-isopropylphenyl)-3-(trifluoro) Methyl)-1H-pyrazol-5-yl)methyl)urea; 39 1-((1-(3-tert-butylphenyl)-3-(trifluoromethyl)-1H-pyrazole- 5-yl)methyl)-3-(6-(hydroxymethyl)pyridin-3-yl)urea; 40 1-(6-(hydroxymethyl)pyridin-3-yl)-3-((1- (3-(Methoxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)urea; 41 1-((1-(3-(difluoro)) Methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(hydroxymethyl)pyridin-3-yl)urea; 42 1- ((1-(3-Benzonitrile)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(hydroxymethyl)pyridin-3-yl)urea ;43 1-((1-(3-(Dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(hydroxy Methyl)pyridin-3-yl)urea; 44 1-((1-(5-chloropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl) -3-(6-(hydroxymethyl)pyridin-3-yl)urea; 45 1-(6-(hydroxymethyl)pyridin-3-yl)-3-((1-(6-methoxy)- 3-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)urea; 46 1-((1-(benzo[d][1,3]dioxolane) Alkene-5-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(hydroxymethyl)pyridin-3-yl)urea; 47 1- ((1-(1H-吲哚-6-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(hydroxymethyl)pyridine-3 -base) urea; 48 1-((1-(furan-3-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(hydroxyl) Pyridyl-3-yl)urea; 49 1-(6-(Hydroxymethyl)pyridin-3-yl)-3-((1-(thiophen-2-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl) Methyl)urea; 50 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(5-fluoro-6 -(hydroxymethyl)pyridin-3-yl)urea; 51 N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl) 2-(6-(2-hydroxyethyl)pyridin-3-yl)propanamine; 52 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyridyl) Zyrid-5-yl)methyl)-3-(6-(2-hydroxyethyl)pyridin-3-yl)urea; 53 N-((1-(3-chlorophenyl)-3-(trifluoro) Methyl)-1H-pyrazol-5-yl)methyl)-2-(6-((2-hydroxyethoxy)methyl)pyridin-3-yl)propanamine; 54 1-((1- (3-Fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(tetrahydro-2H-pyran-4-yl)pyridine- 3-based) urea; 55 5-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxyl Propane-2-yl)pyridinium; 56 5-(1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methylamino)- 1-oxopropan-2-yl)pyridinium; 57 5-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl) Methylamino)-1-oxopropan-2-yl)-N-phenylpyridiniumamine; 58 5-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl))) -1H-pyridyl -5-yl)methylamino)-1-oxopropan-2-yl)-N-(4-fluorophenyl)pyridinium; 59 5-(1-((1-(3-chlorophenyl) --3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-N-(4-(trifluoromethyl)phenyl) Pyridinamine; 60 5-(1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropane-2 -yl)-N-(4-fluorophenyl)pyridiniumamine; 61 5-(1-((3-triphenyl)-1-H-pyrazol-5-yl) Methylamino)-1-oxopropan-2-yl)-N-(4-(trifluoromethyl)phenyl)pyridinium; 62 5-(1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl -N-phenylpyrimidine-2-carboxamide; 63 5-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)) Methylamino)-1-oxopropan-2-yl)-N-(4-fluorophenyl)pyrimidine-2-carboxamide; 64 5-(1-((1-(3-chlorophenyl))) -3-(Trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-N-(4-(trifluoromethyl)phenyl)pyrimidine -2-carboxyguanamine; 65 5-(1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methylamino)-1-oxo Propane-2-yl)-N-phenylpyrimidine-2-carboxamide; 66 5-(1-((3-tert-butyl)-1-(3-chlorophenyl)-1H-pyrazole-5 -yl)methylamino)-1-oxopropan-2-yl)-N-(4-fluorophenyl)pyrimidine-2-carboxamide; 67 5-(1-((3-tertiary butyl) 1-(3-chlorophenyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-N-(4-(trifluoromethyl)phenyl) Pyrimidine-2-carboxyguanamine; 68 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2) -methoxyethylamine)pyridin-3-yl)urea; 69 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl )-3-(6-(2-methoxyethylamine)-3-yl)urea; 70 1-((3-tri-butyl) 1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethylamine)-3-yl)urea; 71 1-(( 1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethylamine)-3-yl) Urea; 72 1-((1-(3-chlorophenyl)-3-cyclopropyl-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethylamine)pyridine- 3-yl)urea; 73 1-((1-(3-chlorophenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3- (6-(2-hydroxyethylamine)-3-yl) urea; 74 1-(6-(2-Hydroxyethylamine)-3-yl)-3-((1-pentyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl) Urea; 75 1-((1-(cyclopropylmethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethylamine) Pyridin-3-yl)urea; 76 1-((1-cyclohexyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyl) Ethylamine)pyridin-3-yl)urea; 77 1-(6-(2-hydroxyethylamine)pyridin-3-yl)-3-((1-(tetrahydro-2H-pyran-4-yl)) -3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)urea; 78 1-((1-(3-fluorophenyl)-3-(trifluoromethyl)-1H- Pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethylamine)-3-yl)urea; 79 1-((1-(3,4-difluorophenyl)-3) -(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethylamine)-3-yl)urea; 80 1-(6-(2- Hydroxyethylamine)pyridin-3-yl)-3-((1-(3-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)urea; 81 1-(6-(2-hydroxyethylamine)-3-yl)-3-((1-m-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl Urea; 82 1-(6-(2-hydroxyethylamine)-3-yl)-3-((1-(3-isopropylphenyl)-3-(trifluoromethyl)-1H-pyridyl) Zyrid-5-yl)methyl)urea; 83 1-((1-(3-tert-butylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl) -3-( 6-(2-hydroxyethylamine)-3-yl)urea; 84 1-((3-tert-butyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazole-5 -yl)methyl)-3-(6-(2-hydroxyethylamine)-3-yl)urea; 85 1-((3-tert-butyl-1-(pyridin-2-yl)-1H) -pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethylamine)-3-yl)urea; 86 1-(6-(2-hydroxyethylamine)-3-yl --3-((1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)urea; 87 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-((2-hydroxyethyl)) Amino)pyridin-3-yl)urea; 88 N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)- 2-(6-((2-methoxyethyl)(methyl)amino)pyridin-3-yl)propanamine; 89 1-((1-(3-chlorophenyl)-3-) Trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-((2-methoxyethyl)(methyl)amino)pyridin-3-yl)urea; 1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-((2-hydroxyethyl)) Methyl)amino)pyridin-3-yl)urea; 91 N-(5-(1-((3-triphenyl)-1H-pyrazol-5-yl) Methylamino)-1-oxopropan-2-yl)pyridin-2-yl)benzamide; 92 N-(5-(1-((1-(3-chlorophenyl))-3-) (trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)pyridin-2-yl)benzamide; 93 N-(5-(1) -((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-2-yl) 4-fluorobenzamide; 94 N-(5-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamine) ))-1-oxopropan-2-yl)pyridin-2-yl)-4-fluorobenzamide; 95 N-(5-(1-((3-tert-butyl-1-(3)) - Phenyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)pyridin-2-yl)-4-chlorobenzamide; 96 4-chloro-N- (5-(1-((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl) Pyridin-2-yl)benzamide; 97 4-chloro-N-(5-(1-oxo-1-((1-(pyridin-3-yl)-3-(trifluoromethyl))) -1H-pyrazol-5-yl)methylamino)propan-2-yl)pyridin-2-yl)benzamide; 98 N-((3-tert-butyl-1-(3-chlorobenzene) -1H-pyrazol-5-yl)methyl)-2-(6-(methylsulfonamide)pyridin-3-yl)propanamine; 99 N-((1-(3-chlorobenzene) 3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(6-(methylsulfonamide)pyridin-3-yl)propanamine; 100 N-((1-(3-Fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(6-(methylsulfonamide) pyridine 3-yl)propanamine; 101 N-(5-(3-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl) Ureido)pyridin-2-yl)methylsulfonamide; 102 N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl) -2-(5-fluoro-6-(methylsulfonamide)-3-yl)propanamine; 103 N-((1-(3-chlorophenyl)-3-(trifluoromethyl)) -1H-pyrazol-5-yl)methyl)-2-(5-fluoro-6-(methylsulfonamide)-3-yl)propanamine; 104 N-((1-(3- Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(5-methoxy-6-(methylsulfonamide)-3-yl Propylamine; 105 N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(5-methoxy-6 -(methylsulfonamide)pyridin-3-yl)propanamine; 106 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-yl) )methyl)-3-(6-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl)urea; 107 1-((3-tertiary butyl-1-(3-) Chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl)urea; 108 1-( 6-(azetidin-1-yl)pyridin-3-yl)-3-((3-tert-butyl-1-(3-chlorophenyl)-1H- Zin-5-yl)methyl)urea; 109 1-(6-(azetidin-1-yl)pyridin-3-yl)-3-((1-(3-chlorophenyl)-3- (trifluoromethyl)-1H-pyrazol-5-yl)methyl)urea; 110 1-((3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazole-5- Methyl)-3-(6-(3-hydroxyazetidin-1-yl)pyridin-3-yl)urea; 111 1-((1-(3-chlorophenyl)-3-) Trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(3-hydroxyazetidin-1-yl)pyridin-3-yl)urea; 112 1-(( 1-(3-Fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(3-hydroxyazetidin-1-yl) Pyridin-3-yl)urea; 113 1-((1-(3-Chloro-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(3-hydroxyl) Azetidin-1-yl)pyridin-3-yl)urea; 114 1-(6-(3-hydroxyazetidin-1-yl)pyridin-3-yl)-3-((1-inter) -tolyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)urea; 115 1-(6-(3-hydroxyazetidin-1-yl)pyridine-3- 3-((1-(3-isopropylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)urea; 116 1-((1-(3) -Tris-butylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(3-hydroxyazetidin-1-yl)pyridine -3-yl)urea; 117 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(3- Hydroxyazetidin-1-yl)pyridin-3-yl)urea; 118 1-((1-(3-(dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyridyl) Zin-5-yl)methyl)-3-(6-(3-hydroxyazetidin-1-yl)pyridin-3-yl)urea; 119 1-(6-(3-hydroxyazetidine) -1-yl)pyridin-3-yl)-3-((1-(3-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)urea; 120 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(rhodin-1-yl)pyridine- 3-based) urea; 121 1-((1-3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole- 5-yl)methyl)-3-(6-(rhodin-1-yl)pyridin-3-yl)urea; 122 1-((1-3-chlorophenyl)-3-(trifluoromethyl) -1H-pyrazol-5-yl)methyl)-3-(5-(fluoro-6-(rhodin-1-yl)pyridin-3-yl)urea; 123 1-((1-3- Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(5-(methoxy-6-(rhodin-1-yl)pyridin-3 -base) urea; 124 (R)-1-((1-3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6- (3-hydroxyrheptan-1-yl)pyridin-3-yl)urea; 125 (S)-1-((1-3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole -5-yl)methyl)-3-(6-(3-hydroxylidine-1-yl)pyridin-3-yl)urea; 126 (R)-1-((1-3-Tris-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(3-hydroxyl) [rhodin-1-yl)pyridin-3-yl)urea; 127 (S)-1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl) Methyl)-3-(6-(3-hydroxylidine-1-yl)pyridin-3-yl)urea; 128 1-((1-(3-chlorophenyl)-3-(trifluoromethyl) -1H-pyrazol-5-yl)methyl)-3-(6-hydroxypyridin-3-yl)urea; 129 N-((1-(3-chlorophenyl)-3-(trifluoromethyl) -1H-pyrazol-5-yl)methyl)-2-(6-methoxy-3-yl)propanamine; 130 1-((1-(3-chlorophenyl)-3- (trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(2-methoxypyrimidin-5-yl)urea; 131 1-((3-tert-butyl-1-) (3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-methoxyethoxy)pyridine-3-yl)urea; 132 1-((1- (3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-methoxyethoxy)pyridin-3-yl) Urea; 133 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethoxy) Pyridin-3-yl)urea; 134 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6 -((2-hydroxyethylamine)methyl)pyridin-3-yl)urea; 135 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5 -yl)methyl)-3-(6-(((2-hydroxyethyl))(methyl)amino)methyl)pyridin-3-yl)urea; 136 1-((1-(3-chloro) Phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-methylpyridin-3-yl)urea; 137 1-((1-(3) -chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(5-methylpyridin-3-yl)urea; 138 1-((1- (3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(4,6-dimethylidene-3-yl)urea; 139 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(5-(hydroxymethyl)pyridin-2-yl Urea; 140 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(5-(hydroxymethyl)pyridine- 3-yl)urea; 141 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(hydroxy Methyl)-2-methylpyridin-3-yl)urea; 142 N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)- 2-(5-fluoro-6-(hydroxymethyl)pyridin-3-yl)propanamine; 143 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)) -1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethyl)-2-methylpyridin-3-yl)urea; 144 1-((3-tert-butyl) 1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(1,2-dihydroxyethyl)pyridin-3-yl)urea; 145 1- ((1-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(1,2-dihydroxyethyl)pyridine -3-yl)urea; 146 N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(6-( 2-hydroxyethylamine)pyridin-3-yl)propanamine; 147 N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-yl)- 2-(6-(2-methoxyethylamine)pyridin-3-yl)propanamine; 148 N-((1-(3-chlorophenyl)-3-(trifluoromethyl)) -1H-pyridyl Zyrid-5-yl)methyl)-2-(6-((2-hydroxyethyl)(methyl)amino)pyridin-3-yl)propanamine; 149 N-((1-(3- Chloro-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(6-(2-hydroxyethyl)pyridin-3-yl)propan Indoleamine; 150 N-((1-(3-chlorophenyl)-3-cyclopropyl-1H-pyrazol-5-yl)methyl)-2-(6-(2-hydroxyethyl)pyridine 3-yl)propanamine; 151 2-(6-(2-hydroxyethyl)pyridin-3-yl)-N-((1-m-tolyl-3-(trifluoromethyl)-1H -pyrazol-5-yl)methyl)propanamide; 152 1-((3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethyl)pyridine-3 -base) urea; 153 1-((3-tert-butyl-1-(3-methoxyphenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyl) Ethyl)pyridin-3-yl)urea; 154 1-((3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6 -(2-hydroxyethylamine)pyridin-3-yl)urea; 155 1-((1-(3,5-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5- Methyl)-3-(6-(2-hydroxyethylamine)-3-yl)urea; 156 1-((1-(4-chloro-3-methylphenyl)-3-(trifluoromethyl) -1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethylamine)-3-yl)urea; 157 1-(6-(2-hydroxyethylamine)pyridine 3-yl)-3-((1-(4-methoxy-3-methyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)urea; 158 1 -((1-(4-Fluoro-3-methyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(6-(2-hydroxyethylamine) Pyridin-3-yl)urea; 159 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(A) Sulfhydrylmethyl)pyridin-3-yl)urea; 160 1-((3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazol-5-yl)methyl)-3 -(6-(hydroxymethyl)pyridin-3-yl)urea; 161 N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5- )methyl)-2-(6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)propanamine; 162 N-((5-(3-((1-(3-)) Phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)ureido)pyrimidin-2-yl)methyl)methylsulfonamide; and 163 1-((3) -cyclopropyl-1-(3-fluorophenyl)-1H-pyrazol-5-yl)methyl)-3-(6-(hydroxymethyl)pyridin-3-yl)urea; selective selection Sexually in the form of a single stereoisomer or a mixture of stereoisomers, in the form of a free compound and/or a physiologically acceptable salt or form thereof formula. 一種藥物組合物，其含有至少一種根據申請專利範圍第1項至第12項中任何一項所述之被取代化合物。 A pharmaceutical composition comprising at least one substituted compound according to any one of claims 1 to 12. 一種根據申請專利範圍第1項至第12項中任何一項所述之被取代化合物，其用於治療及/或預防一或多種由疼痛構成之疾病及/或失調，以選自由下列疼痛構成之群組較佳：急性疼痛、慢性疼痛、神經性疼痛、內臟疼痛與關節疼、痛覺過敏、異常性疼痛、灼痛、偏頭痛、抑鬱、緊張、軸索損傷、神經性退化疾病，以選自由多發性硬化症、阿茲海默症、帕金森氏症與亨丁頓舞蹈症組成之群組較佳，認知功能障礙，以認知缺陷較佳，尤其係記憶障礙，癲癇、呼吸系統疾病，以選自由氣喘、支氣管炎與肺部發炎組成之群組較佳，咳嗽、尿失禁、膀胱過動症、胃腸道失調及/或損傷、十二指腸潰瘍、胃潰瘍、刺激性腸症後群、中風、眼睛刺激、皮膚刺激、神經過敏性皮膚疾病、過敏性皮膚疾病、乾癬、白斑症、單純皰疹、炎症，以腸道、眼睛、膀胱、皮膚或鼻腔黏膜發炎較佳，腹瀉、搔癢、骨質疏鬆症、關節炎、骨性關節炎、風濕性疾病、飲食異常，以選自由暴食症、惡病體質、厭食症與肥胖症組成之群組較佳，藥物依賴、藥物濫用、藥物依賴戒斷症狀、藥物耐受性之產生，以天然或合成類鴉片較佳，毒品依賴、毒品濫用、毒品依賴戒斷症狀、酒精依賴、酒精濫用、與酒精依賴戒斷症狀、用於利尿、用於抑制尿鈉排泄、用於影響心血管系統、用於提升警覺性、用於治療傷口及/或灼傷、用於治療神經阻斷、用於提升性慾、用於調節運動活動、用於抗焦慮、用於局部麻醉及/或抑制不良副作用，以選自由因使用類香草素受體1(VR1/TRPV1受體)激動劑引發之發熱、高血壓與支氣管收縮組成之群組較佳，以選自由 辣椒素、仙人掌毒素、奧伐尼、阿伐尼、SDZ-249665、SDZ-249482、紐伐尼與卡薩伐尼組成之群組較佳。 A substituted compound according to any one of claims 1 to 12 for use in the treatment and/or prevention of one or more diseases and/or disorders constituting pain, selected from the group consisting of the following pains The group is better: acute pain, chronic pain, neuropathic pain, visceral pain and joint pain, hyperalgesia, allodynia, burning pain, migraine, depression, nervousness, axonal injury, neurodegenerative diseases, Free multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease group are better, cognitive dysfunction, better cognitive deficits, especially memory impairment, epilepsy, respiratory diseases, Preferably, it is selected from the group consisting of asthma, bronchitis and inflammation of the lungs, cough, urinary incontinence, overactive bladder, gastrointestinal disorders and/or injuries, duodenal ulcer, gastric ulcer, irritating enteropathy, stroke, stroke, Eye irritation, skin irritation, neuropathic skin disease, allergic skin disease, dryness, leukoplakia, herpes simplex, inflammation, intestines, eyes, bladder, skin or nasal cavity Membrane inflammation is better, diarrhea, itching, osteoporosis, arthritis, osteoarthritis, rheumatic diseases, abnormal diet, preferably selected from the group consisting of bulimia, cachexia, anorexia and obesity. Drug dependence, drug abuse, drug dependence withdrawal symptoms, drug tolerance, natural or synthetic opioids, drug dependence, drug abuse, drug dependence withdrawal symptoms, alcohol dependence, alcohol abuse, and alcohol dependence Symptoms, for diuresis, for inhibiting urinary sodium excretion, for influencing the cardiovascular system, for alertness, for treating wounds and/or burns, for treating nerve block, for lifting libido, for Regulates motor activity, is used for anxiolytics, is used for local anesthesia, and/or inhibits adverse side effects, and is selected from the group consisting of fever, hypertension, and bronchoconstriction induced by the use of a vanilloid receptor 1 (VR1/TRPV1 receptor) agonist. Group is preferred to be selected from A group consisting of capsaicin, cactus toxin, ovanov, arva, SDZ-249665, SDZ-249482, novva and casafani is preferred. 一種治療及/或預防由疼痛構成之失調及/或疾病之方法，其包含給予哺乳類動物依有效劑量之至少一種根據申請專利範圍第1項至第12項中任何一項所述之被取代化合物；疼痛以選自由下列群疼痛構成之群組較佳：急性疼痛、慢性疼痛、神經性疼痛、內臟疼痛與關節疼痛、痛覺過敏、異常性疼痛、灼痛、偏頭痛、抑鬱、緊張、軸索損傷、神經性退化疾病，以選自由多發性硬化症、阿茲海默症、帕金森氏症與亨丁頓舞蹈症組成之群組較佳，認知功能障礙，以認知缺陷較佳，尤其係記憶障礙，癲癇、呼吸系統疾病，以選自由氣喘、支氣管炎與肺部發炎組成之群組較佳，咳嗽、尿失禁、膀胱過動症、胃腸道失調及/或損傷、十二指腸潰瘍、胃潰瘍、刺激性腸症後群、中風、眼睛刺激、皮膚刺激、神經過敏性皮膚疾病、過敏性皮膚疾病、乾癬、白斑症、單純皰疹、炎症，以腸道、眼睛、膀胱、皮膚或鼻腔黏膜發炎較佳，腹瀉、搔癢、骨質疏鬆症、關節炎、骨性關節炎、風濕性疾病、飲食異常，以選自由暴食症、惡病體質、厭食症與肥胖症組成之群組較佳，藥物依賴、藥物濫用、藥物依賴戒斷症狀、藥物耐受性之產生，以天然或合成類鴉片較佳、毒品依賴、毒品濫用、毒品依賴戒斷症狀、酒精依賴、酒精濫用、與酒精依賴戒斷症狀、用於利尿、用於抑制尿鈉排泄、用於影響心血管系統、用於提升警覺性、用於治療傷口及/或灼傷、用於治療神經阻斷、用於提升性慾、用於調節運動活動、用於抗焦慮、用於局部麻醉及/或抑制不良副作用，以選自由因使用類香草素受體1(VR1/TRPV1受體)激動劑引發之發熱、高血壓與支氣管收縮組成之群組較佳，以選自由辣椒素、 仙人掌毒素、奧伐尼、阿伐尼、SDZ-249665、SDZ-249482、紐伐尼與卡薩伐尼組成之群組較佳。 A method for treating and/or preventing a disorder and/or a disease caused by pain, comprising administering to a mammal an effective amount of at least one of the substituted compounds according to any one of claims 1 to 12 Pain is preferably selected from the group consisting of acute pain, chronic pain, neuropathic pain, visceral pain and joint pain, hyperalgesia, allodynia, burning pain, migraine, depression, tension, axonal Injury, neurodegenerative diseases, selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease, cognitive dysfunction, better cognitive deficits, especially Memory disorders, epilepsy, respiratory diseases, preferably selected from the group consisting of asthma, bronchitis, and inflammation of the lungs, cough, urinary incontinence, overactive bladder, gastrointestinal disorders and/or injuries, duodenal ulcers, gastric ulcers, After irritating bowel syndrome, stroke, eye irritation, skin irritation, neuropathic skin disease, allergic skin disease, dryness, leukoplakia, simple blisters Inflammation, inflammation of the mucous membranes of the intestines, eyes, bladder, skin or nasal cavity, diarrhea, itching, osteoporosis, arthritis, osteoarthritis, rheumatic diseases, abnormal diet, selected from bulimia nervosa, cachexia The group consisting of constitution, anorexia and obesity is better, drug dependence, drug abuse, drug dependence withdrawal symptoms, drug tolerance, natural or synthetic opioids, drug dependence, drug abuse, drug dependence Withdrawal symptoms, alcohol dependence, alcohol abuse, alcohol-dependent withdrawal symptoms, use in diuresis, use in inhibiting urinary sodium excretion, influencing the cardiovascular system, for alertness, for treating wounds and/or burns, For the treatment of nerve block, for lifting libido, for regulating motor activity, for anxiolytic, for local anesthesia and/or for inhibiting adverse side effects, selected from the use of vanilloid receptor 1 (VR1/TRPV1) a group of agonist-induced fever, hypertension, and bronchoconstriction, preferably selected from capsaicin, The group consisting of cactus toxin, ovanov, arva, SDZ-249665, SDZ-249482, novva and casafani is preferred.
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