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TW201311665A - Substituted heterocyclic aza derivatives - Google Patents

Substituted heterocyclic aza derivatives Download PDF

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Publication number
TW201311665A
TW201311665A TW101126710A TW101126710A TW201311665A TW 201311665 A TW201311665 A TW 201311665A TW 101126710 A TW101126710 A TW 101126710A TW 101126710 A TW101126710 A TW 101126710A TW 201311665 A TW201311665 A TW 201311665A
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Taiwan
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alkyl
pyridin
group
methyl
aliphatic
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TW101126710A
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Chinese (zh)
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Robert Frank
Thomas Christoph
Bernhard Lesch
Jee-Woo Lee
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Gruenenthal Gmbh
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Abstract

The invention relates to heterocyclic aza 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

被取代氮雜環衍生物 Substituted nitrogen heterocyclic derivative

本發明係關於以氮雜環衍生物(heterocyclic aza derivatives)做為類香草素受體受體、含此化合物之醫藥組合物及使用此化合物治療及/或預防疼痛及更多之疾病及/或失調。 The present invention relates to a pharmaceutical composition comprising a compound having a heterocyclic aza derivative as a vanilloid receptor, and the use of the compound for treating and/or preventing pain and more diseases and/or Disorder.

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，被認為是成功且理想之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 a successful and ideal way to treat pain in patients. It is also documented in many scientific studies and recently appeared in painkillers. Or the basic research area of 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、神經疼痛與內臟疼痛構成之群組。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. 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通透性有其優勢。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, it is advantageous to improve the metabolic stability of the compound, solubility or permeability in an aqueous medium. These factors are beneficial for oral bioavailability, or can alter the condition of pharmacokinetic/pharmacodynamic (PK/PD); for example, it can lead to a more favorable potency period.

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 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) disorder or disease. good.

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。 It has been unexpectedly found that the substituted compound of the formula (I) 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 of at least a part. 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， The invention therefore relates to substituted compounds of the general formula (I),

其中，n代表0、1、2、3或4；以代表1、2、3或4較佳；X代表N或CH；Y代表O、S或N-CN；Z代表N或C-R4b；A1代表N或CR5；A2代表N或CR6； A3代表N或CR7；A4代表N或CR8；A5代表N或CR9；附帶條件為A1、A2、A3、A4與A5變量其中之1、2或3代表一氮原子；R0代表一C1-10脂族殘基，其係未被取代或被單取代或被多取代、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(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，進而可係未被取代或被單取代或被多取代；R1代表一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單取代或被多取代；R2代表R0、OR0、SR0、NH2、NHR0或N(R0)2；R3代表H或一C1-4脂族殘基，其未被取代或被單取代或被多取代；R4a代表H、一未被取代或被單取代或被多取代之C1-4脂族殘基、一未被取代或被單取代或被多取代之C3-6環脂族殘基、或未被取代或被單取代或被多取代之芳基；R4b代表H、或一未被取代或被單取代或被多取代之C1-4脂族殘基；或R4a與R4b及將其連結之碳原子共同形成一未被取代或被單取代或被多取代之C3-6環脂族殘基；R5、R6、R7、R8與R9各自相互獨立地代表H、F、Cl、Br、I、 CN、CF3、CF2H、CFH2、CF2Cl、CFCl2、NO2、R0、C(=O)-H、C(=O)-R0、C(=O)-OH、C(=O)-OR0、C(=O)-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)-NHR0、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)-NH-R0、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或S(=O)2-N(R0)2；其「脂族基(aliphatic group)」與「脂族殘基(aliphatic residue)」於各例中，可相互獨立地為支鏈或非支鏈，飽和或不飽和；其「環脂族殘基(cycloaliphatic residue)」與「雜環脂族殘基(heterocycloaliphatic residue)」於各例中，可相互獨立地為支鏈或非支鏈，飽和或不飽和；其「脂族基(aliphatic group)」、「脂族殘基(aliphatic residue)」、「環脂族殘基(cycloaliphatic residue)」與「雜環脂族殘基(heterocycloaliphatic residue)」之「被單取代或被多取代(mono-or polysubstituted)」，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等取代基組成之群組取代；其「芳基(aryl)」與「雜芳基(heteroaryl)」之「被單取代或被多取代(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之形式。 Wherein n represents 0, 1, 2, 3 or 4; preferably 1, 2, 3 or 4; X represents N or CH; Y represents O, S or N-CN; Z represents N or CR 4b ; 1 represents N or CR 5 ; A 2 represents N or CR 6 ; A 3 represents N or CR 7 ; A 4 represents N or CR 8 ; A 5 represents N or CR 9 ; conditions are A 1 , A 2 , A 3 1, 2 or 3 of the A 4 and A 5 variables represent a nitrogen atom; R 0 represents a C 1-10 aliphatic residue which is unsubstituted or monosubstituted or polysubstituted, a C 3-10 a cycloaliphatic residue or a 3 to 10 membered heterocyclic aliphatic residue which is unsubstituted in each case, or mono- or polysubstituted, and optionally via a C 1-8 lipid in each case a family-based bridge, which in turn may be unsubstituted or monosubstituted or polysubstituted; aryl or heteroaryl, which in each case is unsubstituted or monosubstituted or polysubstituted, and in each case Optionally, bridged via a C 1-8 aliphatic group, which in turn may be unsubstituted or monosubstituted or polysubstituted; R 1 represents a C 1-4 aliphatic residue which is unsubstituted or monosubstituted or polysubstituted, a C 3-6 cycloaliphatic residue or a 3 to 6 member heterocyclic aliphatic residue Which is unsubstituted or monosubstituted to each embodiment based or polysubstituted; R 2 represents R 0, OR 0, SR 0 , NH 2, NHR 0 or N (R 0) 2; R 3 represents H or a C 1 a -4 aliphatic residue which is unsubstituted or monosubstituted or polysubstituted; R 4a represents H, an unsubstituted or monosubstituted or polysubstituted C 1-4 aliphatic residue, an unsubstituted or a C 3-6 cycloaliphatic residue which is mono- or polysubstituted, or an aryl group which is unsubstituted or monosubstituted or polysubstituted; R 4b represents H, or is unsubstituted or monosubstituted or polysubstituted a C 1-4 aliphatic residue; or R 4a and R 4b together with the carbon atom to which they are bonded form an unsubstituted or monosubstituted or polysubstituted C 3-6 cycloaliphatic residue; R 5 , R 6. R 7 , R 8 and R 9 each independently represent H, F, Cl, Br, I, CN, CF 3 , CF 2 H, CFH 2 , CF 2 Cl, CFCl 2 , NO 2 , R 0 , C(=O)-H, C(=O)-R 0 , C(=O)-OH, C(=O)-OR 0 , C(=O)-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) -NHR 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)-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 or S(=O) 2 -N(R 0 2 ; its "aliphatic group" and "aliphatic residue" in each case, independently or branched or unbranched, saturated or unsaturated; Cycloaliphatic residue and heterocyclic aliphatic In each case, a heterocycloaliphic residue may be branched or unbranched, saturated or unsaturated, and "aliphatic group" or "aliphatic residue", "cycloaliphatic residue" and "heterocycloaliphatic residue" are "mono-or polysubstituted", in respect of each of them, Independently on 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 is substituted with a group consisting of a substituent such as S(=O) 2 -N(R 0 ) 2 ; its "aryl" and "heteroaryl" are either substituted or multiple "mono-or polysubstituted" means that in each case, independently of each other on its corresponding residue, 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 -NHR 0 and S (= O) 2 -N ( R 0) 2 , etc. The group consisting of a substituted substituent; selectively as a mixture of stereoisomers or a single stereoisomer thereof, the form of the free compound and / or in the form of a physiologically acceptable salt of.

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, the term "mixture of stereoisomers" encompasses mixtures and/or diastereomers of the racemate with 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)」與「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1至10、1至8、或1至4個碳原子，即分別為C1-10烷基(alkanyls)(C1-10烷基(alkyls))、C2-10烯基與C2-10炔基，以及C1-8烷基(C1-8烷基)、C2-8烯基與C2-8炔基，以及C1-4烷基(alkanyls)(C1-4烷基(alkyls))、 C2-4烯基與C2-4炔基。烯基含有至少一C-C雙鍵(一C=C-鍵)，及炔基含有至少一C-C三鍵(一C≡C-鍵)。脂族殘基以選自由烷基(alkanyls)(alkyls)與烯基殘基組成之群組較佳，以烷基(alkanyls)(alkyls)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、正已基、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、正已基、正庚基與正辛基組成之群組。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、正已基、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、與辛烯基組成之群組。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、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, 1 to 8, or 1 to 4 carbon atoms, respectively, which are respectively C 1-10 alkyl (alkanyls) (C 1-10 alkyls), C 2-10 alkenyl groups and C 2-10 alkynyl, and C 1-8 alkyl (C 1-8 alkyl), C 2-8 alkenyl and C 2-8 alkynyl, and C 1-4 alkyl (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 alkanyls (alkyls) and alkenyl residues, and more preferably alkanyls (alkyls) residues. 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 1-8 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. Preferably, the C 2-10 alkenyl residue is 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. Preferably, the preferred C 2-8 alkenyl residue is selected from the group consisting of ethenyl, vinyl, propylene (-CH 2 CH=CH 2 , -CH=CH-CH 3 , -C(=CH 2 )- A group consisting of CH 3 ), butenyl, pentenyl, hexenyl, heptenyl, and octenyl. 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. Preferably, the C 2-10 alkynyl residue is selected from the group consisting of ethynyl, propynyl, (-CH 2 -C≡CH, -C≡C-CH 3 ), butynyl, pentynyl, hexynyl, A group consisting of heptynyl, octynyl, decynyl, and decynyl. 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, g. a group consisting of an alkynyl group 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(C3-10cycloaliphatic residue)」等詞，分別係指含3、4、5或6個碳原子及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。該環脂族殘基可分別經環脂族殘基之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、環庚烯基與環辛烯基組成之群組。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)," the words, respectively, based a cycloaliphatic hydrocarbon containing 3, 4, 5 or 6 carbon atoms and 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 of the cycloaliphatic residue, respectively. 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 in turn be unsubstituted or monosubstituted or polysubstituted. The C 3-10 cycloaliphatic residue can be further bridged in a single or multiple positions, for example, in the case of adamantly, bicyclo [2.2.1] heptyl or bicyclo [2.2.2] octyl. 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 cyclooctenyl 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，分別係指具有 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，相互獨立地被以選自由O、S、S(=O)2、N、NH與N(C1-8烷基)，如N(CH3)等雜原子或雜原子基團組成之群組取代，以被各自相互獨立地選自由O、S、N、NH與N(C1-8烷基)，如N(CH3)，組成之群組之一雜原子或雜原子群組取代較佳，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)、二氧雜環己烷(dioxanyl)、二氧雜環己基(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. Words, respectively, means having 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 saturated or not a saturated (but non-aromatic) heterocyclic aliphatic residue, which in each case has at least one carbon atom, if appropriate 2 or 3 carbon atoms, independently selected from O, S, S (=O) 2 , N, NH and N (C 1-8 alkyl), such as N (CH 3 ) and other hetero atom or hetero atom group group substitution, to be independently selected from each other by O, S, N, NH and N (C 1-8 alkyl), such as N(CH 3 ), one of the group consisting of a hetero atom or a hetero atom group is preferably substituted, wherein the ring member can be unsubstituted Or replaced by a single or replaced. If not indicated, the heterocyclic aliphatic residue can be bonded to the corresponding superior overall structure via a heterocyclic aliphatic residue, any desired or possibly ring member. 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, dioxolanyl , dioxepanyl, dihydroindenyl, dihydropyridinyl, dihydrofuranyl, dihydroisoquinolinyl, dihydroanthracene Dihydroindolinyl, dihydroisoindolyl, imidazolidinyl, isoxazolidinyl, morpholinyl, oxiranyl, oxetane Oxetanyl, oxazepanyl, pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidinyl , pyrazolidinyl, pyranyl, tetrahydropyrrolyl, tetrahydropyran 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 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 residue is condensed, which in turn may be unsubstituted or monosubstituted or polysubstituted. 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形成，即由環脂族、雜環脂族、芳基或雜芳基殘基形成，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、二苯並吩基、呋喃基(furyl，furanyl)、咪唑基、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)、三唑基、四唑基、噻唑基、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 Multiple substitution; in the case of a heteroaryl 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 formed, ie, formed from 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, dibenzophenyl, furyl, furanyl, imidazolyl, imidazothiazolyl, indazolyl, indolizinyl ), indolyl, isoquinolinyl, isoxazoyl, isothiazolyl, sulfhydryl, naphthyridinyl, oxazolyl, oxadiazolyl, Phenazinyl, phenothiazinyl, phthalazinyl, pyrazolyl, pyridine (2-pyridyl, 3-pyridyl, 4-pyridyl), aryl (pyrrolyl), pyridazinyl, pyrimidinyl, pyrazinyl, purinyl, Piperazinyl group consisting of (phenazinyl), thienyl (thiophenyl), triazolyl, tetrazolyl, thiazolyl, thiadiazolyl (thiadiazolyl) and triazinyl (triazinyl) 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橋接。於該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，或係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，進而可係飽和或不飽和，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，進而可係飽和或不飽和，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 bridging with a corresponding super-level overall structure via a C 1-8 aliphatic group. The C 1-4 aliphatic group and the C 1-8 aliphatic group may be branched or unbranched based on all conditions, or unsubstituted or monosubstituted or polysubstituted. The C 1-4 aliphatic group is based on all conditions and may be saturated or unsaturated, 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 is 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 CH 2 CH 3 )- and -C(CH 3 )(CH 2 CH 3 )-groups. 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 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)」等詞，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，一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 word "mono-or polysubstituted" as used herein, and the corresponding residue or functional group, respectively, 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 are group mono- or poly-substituted, for example 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, a substituent can then 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 "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 1-8 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) A group of 2 -N(R 0 or H) 2 components.

「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、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、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脂族殘基)-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. Aliphatic, heteroaryl, 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, 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 residue)-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, 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 a group of -C 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脂族殘基)-OH、O-(C1-8脂族殘基)-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 heterocycloaliphatic, 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 residue)-OH, O-(C 1-8 aliphatic residue)-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 group, 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- aryl group S (= O) 2 -NH- heteroaryl groups Group of.

於本發明，於「芳基(aryl)」及「雜芳基(heteroaryl)」等詞方面，「被單取代或多取代(mono-or polysubstituted)」等詞，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組成之群組。 In the present invention, in the terms of "aryl" and "heteroaryl", the words "mono-or polysubstituted" refer to their respective residues or Functionally, 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 -NHR 0 and S(=O) 2 -N(R 0 ) 2 are group mono- or poly-substituted, for example Disubstituted, trisubstituted, tetrasubstituted or pentasubstituted; preferred substituents for "aryl" and "heteroaryl" 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, SCF 3 , A group consisting of 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 .

「芳基(aryl)」與「雜芳基(heteroaryl)」特佳之取代基係選自由F、Cl、B、I、NO、CF3、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環脂族基殘基或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脂族殘基)-OH、O-(C1-8脂族殘基)-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 "aryl" and "heteroaryl" are selected from the group consisting of F, Cl, B, I, NO, CF 3 , CN, C 1-8 aliphatic residues, aryl groups, 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, a heteroaryl group, a C 3-6 cycloaliphatic group Base residue or 3 to 6 member heterocycloaliphatic, 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)Nheteroaryl) 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 residue) -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 an S(=O) 2 -NH-heteroaryl group.

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)。依此定義，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C1-4脂族殘基(第一代取代基)，則該C1-4脂族殘基本身可被取代，例如被一NH-C1-4脂族殘基(第二代取代基)取代。其產生 R1=(C1-4脂族殘基-NH-C1-4脂族殘基)此一功能基。該NH-C1-4脂族殘基本身身可再被取代，例如，以氯(第三代取代基)取代。整體而言，其產生R1=C1-4脂族殘基-NH-C1-4脂族殘基此一功能基，其中，該NH-C1-4脂族殘基之C1-4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). By definition, the substituent of the substituent can be resubstituted (the third generation substituent). For example, if R 1 is a C 1-4 aliphatic residue (first generation substituent), the C 1-4 aliphatic residue can be substituted, for example, by an NH-C 1-4 aliphatic residue. Substituent (second generation substituent) substitution. It produces this functional group of R 1 =(C 1-4 aliphatic residue -NH-C 1-4 aliphatic residue). The NH-C 1-4 aliphatic residue can be further substituted, for example, by chlorine (third generation substituent). In general, it produces a functional group of an R 1 =C 1-4 aliphatic residue -NH-C 1-4 aliphatic residue, wherein the NH-C 1-4 aliphatic residue is C 1- The 4 aliphatic residue is substituted with chlorine.

但於一較佳具體實施例中，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., have 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取代，即其甚至無第三代取代基。換言之，於該具體實施例中，通式(I)之案例，例如若適當，R1至R9之功能基可各自被取代；但相應之取代基本身不可被取代。 In another preferred embodiment, the second generation substituents are not substituted, i.e., they are even without third generation substituents. In other words, in this particular embodiment, in the case of the general formula (I), for example, if appropriate, the functional groups of R 1 to R 9 may each be substituted; however, the corresponding substituents may not 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，或其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，其各自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 they are attached, together form a ring member or a plurality of ring members, forming a cyclic structure, such as an aryl or heteroaryl group, each unsubstituted or monosubstituted or Being replaced by many. 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 3- to 6-membered heterocyclic aliphatic residue, or condensed with an aryl or heteroaryl group, 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 heteroaryl group, such as a pyridine group, wherein the cycloaliphatic or heterocyclic ring condensed in this manner The residue, aryl or heteroaryl residue may 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6構件雜環脂族殘基，則該3至6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 appears 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 6 member heterocyclic aliphatic residue Then, the 3 to 6 member heterocyclic aliphatic residue may be represented by R 1 based on, for example, a fluorenyl group, and R 2 represents a piperazinyl group.

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 "physiologically acceptable acid salt" "Salt of physiologically acceptable acids" means salts containing inorganic or organic acid active ingredients, respectively, which are 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，但亦可為銨鹽[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, particularly 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.

於一根據本發明通式(I)化合物之具體實施例中，A1、A2、A3、A4與A5變量其中之1或2代表一氮原子。 In a particular embodiment of the compound of formula (I) according to the invention, one or two of the A 1 , A 2 , A 3 , A 4 and A 5 variables represent a nitrogen atom.

於根據本發明通式(I)化合物之另一具體實施例中，A1、A2、A3、A4與A5變量其中之1代表一氮原子。 In another embodiment of the compound of formula (I) according to the invention, one of the A 1 , A 2 , A 3 , A 4 and A 5 variables represents a nitrogen atom.

於根據本發明通式(I)化合物之又另一具體實施例中，A2代表一氮原子，A1代表C-R5，A3代表C-R7，A4代表C-R8及A5代表C-R9。 In still another embodiment of the compound of formula (I) according to the invention, A 2 represents a nitrogen atom, A 1 represents CR 5 , A 3 represents CR 7 , A 4 represents CR 8 and A 5 represents CR 9 .

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 formula (I) according to the invention, n represents 1, 2, 3 or 4, preferably 1 or 2 or 3, preferably 1 or 2, to represent 1 is optimal.

於根據本發明之化合物中，Y以代表O或S較佳，以代表O更佳。 In the compound according to the present invention, Y is preferably represented by O or S to represent O.

於根據本發明通式(I)化合物之一更佳具體實施例中，X代表N。 In a more preferred embodiment of one of the compounds of formula (I) according to the invention, X represents N.

於根據本發明通式(I)化合物之另一較佳具體實施例中，X代表CH。 In another preferred embodiment of the compound of formula (I) according to the invention, X represents CH.

於根據本發明通式(I)化合物之另一較佳具體實施例中，R1 代表一C1-4脂族殘基，其係未被取代，或被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、SCF3S(=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、啶基與吩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、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被多取代，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。 In another preferred embodiment of the compound of formula (I) according to the invention, R 1 represents a C 1-4 aliphatic residue which is unsubstituted or which is independently selected from one or more 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 a group consisting of a substituent such as N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 S(=O) 2 OH, benzyl, phenyl, pyridine, and phenyl a mono- or poly-substitution wherein the benzyl, phenyl, pyridine and phenyl groups, 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 alkane a group consisting of a substituent of 2 , SH, SC 1-4 alkyl, SCF 3 and S(=O) 2 OH, monosubstituted or polysubstituted, or representing a C 3-6 cycloaliphatic residue or a 3 to 6 membered heterocyclic aliphatic residue, which in each case is unsubstituted or is independently selected from one or more selected from the group consisting of F, Cl, Br, I, OH, =O, C 1- Substituted by 4- alkyl, OC 1-4 alkyl, OCF 3 , C(=O)-OH and CF 3 Groups of base groups are monosubstituted or polysubstituted.

較佳地，R1 代表一C1-4脂族殘基，其係未被取代，或被一或多個相互 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、SCF3等取代基組成之群組單取代或多取代，或代表一C3-6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與CF3等取代基組成之群組單取代或多取代。 Preferably, R 1 represents a C 1-4 aliphatic residue which is unsubstituted or is selected independently from one another by F, Cl, Br, I, CN, OH, =0, OC Substituents such as 1-4 alkyl group, OCF 3 , CF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 The group consisting of mono- or poly-substituted, or representing a C 3-6 aliphatic residue, or a 3- to 6-membered heterocyclic aliphatic residue, which is unsubstituted in each case, or is one or more Groups mono- or polysubstituted independently of one another consisting of substituents such as F, Cl, Br, I, OH, =0, C 1-4 alkyl, OC 1-4 alkyl, OCF 3 and CF 3 .

更佳地，R1 代表一C1-4脂族殘基，其係未被取代，或被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。 More preferably, R 1 represents a C 1-4 aliphatic residue which is unsubstituted or is grouped by one or more groups independently selected from the group consisting of substituents such as F, Cl, Br, I and OH. Monosubstituted 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 independently of one or more The group consisting of a substituent such as F, Cl, Br, I and OH is mono- or poly-substituted.

再更佳地，R1 代表一C1-4脂族殘基，其係未被取代，或被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，其於各例中係未被取代。 Even more preferably, R 1 represents a C 1-4 aliphatic residue which is unsubstituted or is grouped by one or more groups independently selected from the group consisting of substituents such as F, Cl, Br, and I. Substituted 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.

又更佳地，R1 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。 Still more preferably, R 1 is selected from the group consisting of CF 3 , methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl and tertiary butyl, or is selected from the group consisting of A group consisting of propyl, cyclobutyl, cyclopentyl and cyclohexyl.

特佳地，R1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更佳，以選自由三級丁基與CF3組成之群組又更佳。 Particularly preferably, R 1 is selected from the group consisting of tributyl, CF 3 , cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, selected from the group consisting of tertiary butyl, CF 3 and cyclopropyl. The composition group is more preferably selected from the group consisting of a tertiary butyl group and a CF 3 group.

於根據本發明通式(I)化合物之又一更佳具體實施例中，R2 代表一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，其中，該C1-10脂族殘基於各例中，互獨立地可係未被取代，或被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，苯基或啶基各自係未被取代，或被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；其中，上述各殘基於各例中，可選擇性地經一C1-8脂族殘基橋接，其進而可係未被取代，或被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，或代表一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、O-(3至10構件雜環脂族殘基)、O-(C1-8脂族基)-(3至10構件雜 環脂族殘基)、S-(3至10構件雜環脂族殘基)、S-(C1-8脂族基)-(3至10構件雜環脂族殘基)、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)、N(C1-10脂族殘基)(3至10構件雜環脂族殘基)，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，相互獨立地可係未被取代，或被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，其中，上述殘基於各例中，可選擇性地經一C1-8脂族基橋接，其進而可係未被取代，或被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，或代表芳基、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、一NH-(C1-8脂族基)-芳基、一N(C1-10脂族殘基)(芳基)、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-(C1-8脂族基)-(雜芳基)、N(C1-10脂族殘 基)(雜芳基)，其中，該C1-10脂族殘基、該C1-8脂族基、芳基與雜芳基於各例中，相互獨立地可係未被取代，或被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，其中，各上述殘基於各例中，可選擇性地經一C1-8脂族基橋接，其進而可係未被取代，或被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 still another more specific embodiment of the compound of formula (I) according to the present invention, R 2 represents a C 1-10 aliphatic residue, an OC 1-10 aliphatic residue, an SC 1-10 aliphatic group. a residue, an NH-C 1-10 aliphatic residue, an N (C 1-10 aliphatic residue) 2 , wherein the C 1-10 aliphatic residue is independently based on each other Substituted, or 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 , CF 3 , NH 2 , NH ( a group mono- or poly-substituted with a group consisting of a substituent such as C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 , phenyl and pyridine; , phenyl or pyridine are each 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 1-4 alkyl, SCF a group consisting of a mono- or poly-substitution of a substituent such as S(=O) 2 OH; wherein each of the above residues is selectively bridged via a C 1-8 aliphatic residue, respectively, Can be unsubstituted or be one or more Mutually independently selected from 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 are mono- or poly-substituted, or represent a C 3-10 cycloaliphatic residue, an OC 3 a -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 An aliphatic group - a C 3-10 cycloaliphatic residue, an NH-C 3-10 cycloaliphatic 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, O-(3 to 10 membered heterocyclic aliphatic residue) ), O-(C 1-8 aliphatic)-(3 to 10 component heterocyclic aliphatic residue), S-(3 to 10 component heterocyclic aliphatic residue), S-(C 1-8 aliphatic) Group of bases - (3 to 10 component heterocyclic aliphatic residues), NH- (3 to 10 component heterocyclic aliphatic residues), NH-(C 1-8 aliphatic) - (3 to 10 building blocks) a cycloaliphatic residue), N(C 1-10 aliphatic residue) (3 to 10 membered heterocyclic aliphatic residue), wherein the C 1-10 aliphatic residue, the C 1-8 aliphatic group, the C 3-10 cycloaliphatic residues with the 3-10 member heterocycloaliphatic Residues based on the respective embodiments, the system may be independently unsubstituted or substituted 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 , 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 , 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 pyridine 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, OCF 3 , C 1-4 alkyl, C(=O)-OH, CF 3 , NH 2 , NH(C 1-4 alkyl), N ( a group mono- or poly-substituted with a group consisting of a substituent such as C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 and S(=O) 2 OH, wherein the above residue is based on each case, Optionally, it may be bridged via a C 1-8 aliphatic group, which in turn may be unsubstituted, or 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 SCF 3 a group consisting of a group of mono- or poly-substitutions, or generations Epiaryl, O-aryl, mono-O-(C 1-8 aliphatic)-aryl, S-aryl, an S-(C 1-8 aliphatic)-aryl, an NH-aryl , an NH-(C 1-8 aliphatic)-aryl group, an N (C 1-10 aliphatic residue) (aryl), a heteroaryl group, an O-heteroaryl group, an O-(C 1 -8 aliphatic)-heteroaryl, S-(heteroaryl), S-(C 1-8 aliphatic)-(heteroaryl), NH-(heteroaryl), NH-(C 1 -8 aliphatic)-(heteroaryl), N(C 1-10 aliphatic residue) (heteroaryl), wherein the C 1-10 aliphatic residue, the C 1-8 aliphatic group The aryl group and the heteroaryl group 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, 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 alkyl, OCF 3 , C 1-4 alkyl, C(=O)-OH, CF 3 , NH 2 , NH(C 1-4 alkane Base), N(C 1-4 alkyl) 2 , SH, SC 1 a group of mono- or poly-substituents consisting of a substituent such as -4 alkyl, SCF 3 and S(=O) 2 OH, wherein each of the above residues is selectively subjected to a C 1-8 aliphatic group based on each of the examples. a bridge, which in turn may be unsubstituted, or 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 , Group mono- or poly-substitution consisting of substituents such as CF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl and SCF 3 .

於根據本發明通式(I)化合物之一更佳具體實施例中，R2代表(T1)子結構 其E 代表O、S或NR11，其中，R11代表H或一C1-4脂族殘基，其係未被取代，或被 一或多個相互獨立地選自由F、Cl、Br、I、OH、O-C1-4烷基、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；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C1-4脂族殘基，其係未被取代，或被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-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，其係未被取代，或被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、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 a more preferred embodiment of the compound of formula (I) according to the invention, R 2 represents a (T1) substructure Its E represents O, S or NR 11 , wherein R 11 represents H or a C 1-4 aliphatic residue which is unsubstituted or is independently selected from F, Cl, Br, by one or more a mono- or poly-substitution group consisting of a substituent such as I, OH, OC 1-4 alkyl, OCF 3 , NH 2 , NH-C 1-4 alkyl and N(C 1-4 alkyl) 2 ; Representing 0 or 1; R 10a and R 10b each independently represent H, F, Cl, Br, I or a C 1-4 aliphatic residue, which are unsubstituted or independently of one or more a group consisting of substituents such as F, Cl, Br, I, OH, OC 1-4 alkyl, OCF 3 , NH 2 , NH-C 1-4 alkyl and N(C 1-4 alkyl) 2 The group is mono- or polysubstituted; m represents 0, 1, 2, 3 or 4, preferably 0, 1 or 2, preferably 0 or 1; G represents a C 1-4 aliphatic residue, Unsubstituted, or one or more independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, =0, OC 1-4 alkyl, OC 1-4 alkyl-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 a group consisting of a substituent such as a pyridine group, monosubstituted or polysubstituted, , Phenyl or piperidinyl each 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 a group consisting of a mono- or poly-substituent of a group consisting of a substituent such as S(=O) 2 OH; or a C 3-10 cycloaliphatic residue or a 3 to 10 membered heterocyclic aliphatic residue, In the case of being unsubstituted, or 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 Substituents such as 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 pyridine a group consisting of a mono- or poly-substitution in which a phenyl or pyridine 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, 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 group and the like substituent group consisting of mono- or polysubstituted by Generation; represents an aryl or heteroaryl group or an aryl group, which system is 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, CF 3 , 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 mono- or poly-substituent consisting of a substituent such as a phenyl group and a pyridine group, wherein the phenyl or pyridine 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, OCF 3 , C 1-4 alkyl, C(=O)-OH, CF 3 , NH 2 , NH(C 1-4 alkyl), N ( A group consisting of a C 1-4 alkyl) 2 , SH, SC 1-4 alkyl group, a group consisting of a substituent such as SCF 3 and S(=O) 2 OH 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R2 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、二級丁基與三級丁基組成之群組較佳；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，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；m 代表0、1或2，以代表0或1較佳； G 代表一C1-4脂族殘基，其係未被取代，或被一或多個相互獨立地選自由F、Cl、Br、I、OH、O-C1-4烷基、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構件雜環脂族殘基於各例中，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、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，其係未被取代，或被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、CF3、SH、S-C1-4烷基、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。 Preferably, the residue R 2 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 the group consisting of The group consisting of ethyl, ethyl, n-propyl, isopropyl, n-butyl, dibutyl and tert-butyl is preferred; 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 selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, dibutyl and tri Preferably, the group of butyl groups is preferred; m represents 0, 1 or 2 to represent 0 or 1 is preferred; G represents a C 1-4 aliphatic residue which is unsubstituted or is one or more Independently selected from F, Cl, Br, I, OH, OC 1-4 alkyl, OC 1-4 alkyl-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, a group monosubstituted or polysubstituted with a substituent such as SCF 3 ; or a C 3-10 ring An aliphatic residue or a 3- to 10-membered heterocyclic aliphatic residue is unsubstituted, or one or more independently selected from the group consisting of F, Cl, Br, I, OH, 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 alkyl, OCF 3 , C 1-4 alkyl, C(=O)-OH, CF 3 , NH 2 , NH(C 1-4 a group of mono- or poly-substituents consisting of a substituent such as an alkyl group, N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 and S(=O) 2 OH; or a representative An aryl or heteroaryl group which is 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 , CF 3 , SH, SC 1-4 alkyl, C 1-4 alkyl, SCF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , phenyl and pyridine a group consisting of a group consisting of a mono- or poly-substitution in which the phenyl or pyridine 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, OCF 3 , C 1-4 alkyl, C(=O)-OH, C Substituents such as F 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 The group is monosubstituted or multi-substituted.

較佳地，該殘基R2 代表(T1)子結構，其 E 代表O、S或NR11，其中，R11代表H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；o 代表0或1；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、二級丁基與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 代表甲基、乙基、正丙基、異丙基、正丁基、二級丁基或三級丁基，其於各例中係未被取代，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，或一3至6構件雜環脂族殘基，以選自由咯啶基、哌嗪基、4-甲基哌嗪基、哌啶基、嗎咻基、四氫咯基、四氫吡喃基、四氫-2H-吡喃-4-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、四氫啶基與硫代嗎咻基組成之群組較佳，其於各例中係未被取代，或被一或多個相互獨立地選自由F、Cl、Br、I、OH、O-C1-4烷基、OCF3、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，以苯基或啶基較佳，其於各例中係未被取代，或被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、SH、S-C1-4烷基、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，苯基可係未被取代，或被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與SCF3等取代基組成之群組單取代或多取代。 Preferably, the residue R 2 represents a (T1) substructure, wherein E represents O, S or NR 11 , wherein R 11 represents H or is selected from methyl, ethyl, n-propyl, isopropyl, a group consisting of n-butyl, secondary butyl and tertiary butyl; o represents 0 or 1; R 10a and R 10b are independently selected from H, methyl, ethyl, n-propyl, isopropyl a group consisting of n-butyl, a secondary butyl and a tertiary butyl group; m represents 0, 1 or 2, preferably 0 or 1; G represents methyl, ethyl, n-propyl, isopropyl , n-butyl, secondary butyl or tert-butyl, 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 a group consisting of a mono- or poly-substituent consisting of a substituent such as OC 1-4 alkyl-OC 1-4 alkyl; or a C 3-6 cycloaliphatic residue selected from a cyclopropyl group, Preferably, the group consisting of a cyclobutyl group, a cyclopentyl group and a cyclohexyl group, or a 3- to 6-membered heterocyclic aliphatic residue is selected from the group consisting of a pyridyl group, a piperazinyl group, a 4-methylpiperazinyl group, and a piperidine group. Pyridyl, decyl, tetrahydrorupyl, tetrahydropyranyl, tetrahydro-2H-pyran-4-yl, tetrahydroquinoline a group consisting of tetrahydroisoquinolyl, dihydroquinolyl, dihydroropenyl, dihydropyridyl, dihydroisoquinolyl, tetrahydropyridyl and thioxanthyl groups, preferably In each case, unsubstituted or one or more independently selected from F, Cl, Br, I, 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 phenyl group, such as a mono- or poly-substituent, wherein the phenyl group may be unsubstituted or One or more mutually independent 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 and SCF 3 The group is mono- or polysubstituted; or represents an aryl or heteroaryl group, preferably a phenyl or pyridyl 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, OCF 3 , C 1-4 alkyl, CF 3 , SH, SC 1-4 alkyl, SCF 3 , NH 2 , NH a group of mono- or poly-substituents consisting of a substituent of (C 1-4 alkyl), N(C 1-4 alkyl) 2 and a phenyl group, wherein the phenyl group may be unsubstituted or One or more mutually independent 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 and SCF 3 The group is monosubstituted or multi-substituted.

再更佳地，殘基R2 代表(T1)子結構，其E 代表O、S或NR11；其中，R11代表H或選自由甲基、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，o 代表0或1；R10a與R10b係各自相互獨立地選自由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、或三級丁基，其於各例中皆未被取代；或係選自由環丙基、環丁基、環戊基與環己基組成之群組，或係選自由咯啶基、哌嗪基、4-甲基哌嗪基、哌啶基、四氫吡喃基、四氫-2H-吡喃-4-基、嗎咻基與硫代嗎咻基組成之群組，其於各例中係未被取代，或被一或多個相互獨立地選自由F、Cl、Br、I、OH、C1-4烷基、O-C1-4烷基、OCF3、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，以苯基或啶基較佳，其於各例中係未被取代，或被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、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，苯基可係未被取代，或被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、與SCF3等取代基組成之群組單取代或多取代。 More preferably, the residue R 2 represents a (T1) substructure, wherein E represents O, S or NR 11 ; wherein R 11 represents H or is selected from methyl, ethyl, n-propyl, isopropyl, or a group consisting of butyl, secondary butyl and tertiary butyl, o represents 0 or 1; R 10a and R 10b are each independently selected from the group consisting of H, methyl and ethyl, and m represents 0. , 1 or 2, preferably represents 0 or 1; G represents methyl, ethyl, n-propyl, isopropyl, n-butyl, dibutyl or tert-butyl, which is in each case Unsubstituted; or selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, or selected from the group consisting of pyridyl, piperazinyl, 4-methylpiperazinyl, piperidinyl a group consisting of tetrahydropyranyl, tetrahydro-2H-pyran-4-yl, fluorenyl and thio-indenyl, which are unsubstituted in each case or are one or more Independently selected from the group consisting of F, Cl, Br, I, OH, C 1-4 alkyl, OC 1-4 alkyl, OCF 3 , CF 3 , NH 2 , NH(C 1-4 alkyl), N (C) 4alkyl) 2 and the substituent group consisting of phenyl group mono- or polysubstituted, wherein the phenyl-based unsubstituted, or One or more groups 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 and SCF 3 Mono- or poly-substituted; or represents an aryl or heteroaryl group, preferably a phenyl or pyridyl group, which is unsubstituted in each case, or one or more independently selected from F, Cl, Br, I, 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 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 a group consisting of OH, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, CF 3 , and a group consisting of a substituent such as SCF 3 is mono- or poly-substituted.

最佳地，R2 代表苯基，其係未被取代，或被一或多個相互獨立地選自由F、Cl、Br、I、OH、O-CH3、CH3、CH(CH3)2、N(CH3)2、三級丁基與CF3等取代基組成之群組單取代或多取代，苯基以被以一或二個相互獨立地選自由F、Cl、Br、I、O-CH3、CH3、CH(CH3)2、N(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，苯基以於間位被一選自由F、Cl、CH3、OCH3、CH(CH3)2與N(CH3)2等取代基組成之群組單取代更佳。 Most preferably, R 2 represents a phenyl group which is unsubstituted or one or more independently selected from the group consisting of F, Cl, Br, I, OH, O-CH 3 , CH 3 , CH(CH 3 ) a group consisting of a group consisting of N(CH 3 ) 2 , a tertiary butyl group and a CF 3 group, such as a mono- or poly-substituent, the phenyl group being independently selected from F, Cl, Br, I by one or two Preferably, the group consisting of O-CH 3 , CH 3 , CH(CH 3 ) 2 , N(CH 3 ) 2 , a tertiary butyl group and a CF 3 group is preferably mono- or di-substituted, and the phenyl group is The position is preferably monosubstituted by a group selected from the group consisting of F, Cl, CH 3 , OCH 3 , CH(CH 3 ) 2 and N(CH 3 ) 2 .

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 independently of one or more Selected from 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 A group consisting of a group consisting of 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. Groups are single or multiple 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.

根據本發明通式(I)化合物之另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、SCF3S(=O)2OH、苄基、苯基、啶基與噻吩基等取代基組成之群組單取代或多取代，其中，苄基、苯基、啶基與噻吩基可分別係未被取代，或被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脂族殘基，其係未被取代或被至少一選自由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、SCF3S(=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、啶基與吩基可分別係未被取代，或被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、SCF3S(=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、啶基與吩基可分別係未被取代，或被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、SCF3S(=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、啶基與吩基可分別係未被取代，或被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。 Another embodiment of the 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 at least one selected from the group consisting of F and 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 S(=O) 2 OH, benzyl, phenyl, pyridine and thienyl groups, etc. a multiple substitution wherein the benzyl, phenyl, pyridine and thienyl groups are unsubstituted, respectively, or are 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 a group consisting of SH, SC 1-4 alkyl, SCF 3 and S(=O) 2 OH, such as a mono- or poly-substituent, or a C 3-6 aliphatic 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 , 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 group, such as a group of mono- or poly-substitution, wherein benzyl, phenyl, pyridine and phenyl can be respectively Substituted, 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 A group consisting of a substituent consisting of a mono- or poly-substituent, or 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 alkane Base, 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), Composition of N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 , S(=O) 2 OH and NH-S(=O) 2 -C 1-4 alkyl The group is mono- or polysubstituted, R 4b represents H or a C 1-4 aliphatic residue, which is unsubstituted or 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 S(=O) 2 OH, benzyl, phenyl, pyridine and phenyl, and the like, a group consisting of a mono- or poly-substituent, wherein benzyl, benzene The 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 a group consisting of a substituent consisting of a substituent such as SCF 3 and S(=O) 2 OH, or a combination of R 4a and R 4b and a carbon atom to which they are bonded form a C 3-6 cycloaliphatic residue, It 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 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 S(=O) 2 OH, a group of mono- or poly-substituents consisting of a substituent such as a benzyl group, a phenyl group, a pyridine group or a phenyl group, wherein the benzyl group, the phenyl group, the pyridine group and the phenyl group may be unsubstituted or one or more, respectively. 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-substitution.

較佳地，R4a 代表H或一C1-4脂族殘基，其係未被取代或被至少一選自由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，其係未被取代或被至少一選自由F、Cl、Br、I、NO2、CN、OH、=O、O-C1-4烷基、OCF3、C(=O)-OH、C1-4烷基、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環脂族殘基，其係未被取代或被至少一選自由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 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 alkane a group consisting of a group consisting of a substituent such as SCF 3 and S(=O) 2 OH, mono- or poly-substituted, or a C 3-6 cycloaliphatic residue, which is unsubstituted or at least one selected from F , Cl, Br, I, NO 2 , CN, OH, =O, OC 1-4 alkyl, OCF 3 , C(=O)-OH, C 1-4 alkyl, CF 3 , NH 2 , NH ( Group mono- or poly-substitution consisting of a substituent such as C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 and S(=O) 2 OH Or represents 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 alkyl) 2 , SH a group consisting of a group consisting of a substituent such as SC 1-4 alkyl, SCF 3 , S(=O) 2 OH and NH-S(=O) 2 -C 1-4 alkyl, and R 4b represents H or a C 1-4 Aliphatic residue, which is unsubstituted or substituted with at least one system 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 and S(=O) 2 OH a group consisting of a single or multiple substitution, or R 4a and R 4b together with the carbon atom to which they are attached form a C 3-6 cycloaliphatic residue which is unsubstituted or at least one selected from 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 a group of 1-4 alkyl), 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.

更佳地，R4a 代表H或一C1-4脂族殘基，其係未被取代或被至少一選自由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 at least one selected from the group consisting of F, Cl, Br, I, OH, =0, OC 1-4 alkyl, a group consisting of a substituent consisting of OCF 3 , CF 3 and SCF 3 is mono- or poly-substituted, or represents a C 3-6 cycloaliphatic residue which is unsubstituted or at least one selected from the group consisting of F, Cl, Br a group consisting of a substituent consisting of a substituent such as I, OH, =O, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl, CF 3 and SCF 3 , or a mono- or Preferably, the 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 1-4 alkyl) 2 , SH, SC a group consisting of a group consisting of 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, and R 4b represents H or a C 1-4 aliphatic residue which is unsubstituted or at least one selected from the group consisting of F, Cl, Br, I, OH, =0, OC 1-4 alkyl, OCF 3 , CF 3 and SCF 3 a group consisting of a substituent consisting of a single or multiple substitution, or R 4a and R 4b The linked carbon atoms together form 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, 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.

再更佳地，R4a 代表H或一未被取代之C1-4環脂族殘基，以代表H或選自由甲基、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，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環脂族殘基，其係未被取代或被至少一選自由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及R4b與將其連結之碳原子共同形成-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，其未被取代或被至少一選自由F、Cl、Bt、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 cycloaliphatic residue to represent H or selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, di Preferably, the group consisting of a butyl group and a tertiary butyl group, or an unsubstituted C 3-6 cycloaliphatic residue, is selected from the group consisting of a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group. Preferably, or a group of phenyl groups which are 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 alkane a group consisting of 2 , SH, SC 1-4 alkyl, SCF 3 , S(=O) 2 OH and a group consisting of a substituent such as NH-S(=O) 2 -C 1-4 alkyl Substituted, R 4b represents H or a C 1-4 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, OCF 3 , a group consisting of a substituent such as CF 3 and SCF 3 is mono- or poly-substituted, 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 the ring Propyl, cyclobutyl, cyclopentane Preferably, the group consisting of a group and a cyclohexyl group is unsubstituted or at least one selected from the group consisting of F, Cl, Bt, I, OH, =0, OC 1-4 alkyl, OCF 3 , C 1-4 alkyl And a group consisting of a substituent such as CF 3 and SCF 3 is mono- or poly-substituted.

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1、2、3、4或5個相互獨立地選自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-烷基之取代基取代； R4b代表H、甲基或乙基，或R4a及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。 Still more preferably, R 4a represents H, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl, wherein the phenyl is unsubstituted or 1, 2, 3, 4 or 5 independently of each other 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 substituent of N(C 1-4 alkyl)(C 1-4 alkyl), C 1-4 alkyl and OC 1-4 -alkyl; R 4b represents H, methyl or B The 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)之一特佳化合物，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F、Cl、Br、CF3、甲基與甲氧基之取代組取代；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環丙基、環丁基、環戊基或環己基環。 A particularly preferred compound of the formula (I) according to the invention, wherein R 4a represents H, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl, wherein phenyl is Unsubstituted or substituted with 1, 2 or 3 substituent groups independently selected from the group consisting of F, Cl, Br, CF 3 , methyl and methoxy; R 4b represents H, methyl or ethyl, or R 4a and R 4b together with the carbon atom to which they are bonded form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.

根據本發明通式(I)之一又更佳之化合物，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 represents H or methyl, to represent More preferably, H or R 4a and R 4b together form a carbon atom to form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl ring.

根據本發明通式(I)之一最佳之化合物，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。 A preferred compound according to the invention of the formula (I), 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 methyl is preferred.

於根據本發明化合物之另一較佳具體實施例中，其結構之一部分 代表一選自 之基團，其中，取代基R5、R6、R7、R8與R9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。 In another preferred embodiment of the compound according to the invention, a part of its structure Representative one selected from A group wherein the substituents R 5 , R 6 , R 7 , R 8 and R 9 contain the above-mentioned meanings with respect to the compounds according to the invention and their preferred embodiments.

一特佳之結構部分係。 a particularly good structural part .

另一特佳之結構部分係。 Another excellent structural part .

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係各自相互獨立地選自由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、C(=O)-H、C(=O)-OH、S(=O)2-OH與S(=O)2-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、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，各上述之C1-10脂族殘基與C1-8脂族基於各例中，可各自係未被取代，或被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)3OH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，相互獨立地可係未被取代，或被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 each independently selected from 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 and S (=O) Group of 2 -NH 2 groups; a C 1-10 aliphatic residue, (C 1-8 aliphatic)-OH, (C 1-8 aliphatic)-OC 1-10 lipid Family 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 lipid Family residue) -OH, mono(C 1-8 aliphatic)-N (C 1-10 aliphatic residue) - (C 1-8 aliphatic residue) -OH, one (C 1-8 fat) 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 group)-S(=O) 2 -C 1-10 aliphatic residue, a C(=O)-C 1-10 aliphatic residue, a C(=O)-NH-C 1- 10 aliphatic residues, an OC 1-10 aliphatic residue, an O-(C 1-8 aliphatic)-OC 1-10 aliphatic residue, O-(C 1-8 aliphatic)-OH, one NH-C 1-10 aliphatic residue, one N (C 1-10 Aliphatic residue) 2 , an NH-[(C 1-8 aliphatic)-OC 1-10 aliphatic residue], a 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 residues], one NH-C(=O)-C 1-10 aliphatic residue, one N (C 1-10 aliphatic residue) [(C(=O)-C 1-10 lipid Family residues)], 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 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, each may be unsubstituted or 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 , CF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC a group of mono- or poly-substituents consisting of a substituent such as a 1-4 alkyl group, an SCF 3 group, a phenyl group and a pyridine group, wherein the phenyl group or the pyridine group are unsubstituted, respectively, or are independently selected from one or more Free 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 a group of 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 and S(=O) 3 OH, such as a mono- or poly-substituent, 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 lipid) Family-based)-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)-C 3-10 cycloaliphatic residue, one N (C 1-10 aliphatic) (C 3-10 cycloaliphatic residue), a 3 to 10 membered heterocyclic ester Family 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 member heterocycloaliphatic residue), a O- (C 1-8 aliphatic) - (3 10 member heterocycloaliphatic residue), a -S- (3-10 member heterocyclic aliphatic residue), a S- (C 1-8 aliphatic) - (3-10 member heterocyclic aliphatic residue ), an NH-(3 to 10 component heterocyclic aliphatic residue), an NH-C(=O)-(3 to 10 component heterocyclic aliphatic residue), NH-(C 1-8 aliphatic group) a (3 to 10 member heterocyclic aliphatic residue), an N (C 1-10 aliphatic residue) (3 to 10 membered heterocyclic aliphatic residue), wherein each of the above residues is based on each case, Optionally being bridged via a C 1-8 aliphatic group, wherein the C 1-10 aliphatic residue, the C 1-8 aliphatic group, the C 3-10 cycloaliphatic residue and the 3 to The 10 member heterocyclic aliphatic residue 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, 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 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-C (=O substituted) -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 a group consisting of SH, SC 1-4 alkyl, SCF 3 and S(=O) 2 OH, such as a mono- or poly-substituted group, 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 Group-)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 residue and the heteroaryl Based on each example, the system may be independently 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 1- 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 group and the pyridine group are 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 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 a group of mono- or poly-substitutions consisting of a substituent such as SH, 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 aliphatic based on each case Independently from each other, unsubstituted or 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 , phenyl and pyridine a group consisting of a group consisting of a mono- or poly-substitution in which the phenyl or pyridine 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, 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 consisting of a group consisting of 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、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脂族殘基)-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，各上述脂殘基於各例中，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，可相互獨立地係未被取代或被以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，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。 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 group; one 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)-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 An 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, O- (C 1-8 aliphatic) -OC 1-10 aliphatic residue, O- (C 1-8 aliphatic) -OH, 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 group) -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)], one N (C 1-10 aliphatic residue) [(C 1-8 aliphatic residue)-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 aliphatic residue, an S(=O) 2 -N(C 1-10 aliphatic residue) 2 , an SC 1-10 aliphatic residue, wherein each The C 1-10 aliphatic residue and the C 1-8 aliphatic group may be unsubstituted or monosubstituted with OH based on each case; 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 yl) -C 3-10 cyclic aliphatic residue, a SC 3-10 cyclic aliphatic residue, a S- (C 1-8 aliphatic ) -C 3-10 cycloaliphatic residue, an NH-C 3-10 cycloaliphatic residue, an NH-C (= O) -C 3-10 cyclic aliphatic residue, a 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 member heterocyclic aliphatic group 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 a 10-membered heterocyclic aliphatic residue), an O-(C 1-8 aliphatic group)-(3 to 10 membered heterocyclic aliphatic residue), and an S-(3 to 10 membered heterocyclic aliphatic residue) a), an S-(C 1-8 aliphatic group)-(3 to 10 component heterocyclic aliphatic residue), an NH- (3 to 10 component 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), and one N (C 1-10 lipid) a family residue) (3 to 10 member heterocyclic aliphatic residues), wherein each of the above-mentioned lipid residues is selectively bridged via a C 1-8 aliphatic group, wherein the C 1-10 The 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 member are based on each of the examples. Heterocyclic aliphatic residues , The system may be independently unsubstituted or substituted 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- 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) (hetero Yl), wherein each of the above embodiments based on the respective residues, optionally via a bridging C 1-8 aliphatic group, wherein the aryl residue and the heteroaryl based on the respective embodiments, the system may not be independent of each other 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 , 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, phenyl and pyridine a group consisting of a mono- or poly-substitution in which the phenyl or pyridine groups are 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 With S(=O) a group consisting of a substituent such as OH, which is mono- or poly-substituted, wherein each of the above C 1-10 aliphatic residues and C 1-8 aliphatic groups may be unsubstituted or OH-based. Replace.

更佳地，R5、R6、R7、R8與R9係各自相互獨立地選自由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、C(=O)-H、C(=O)-OH、S(=O)2-OH、S(=O)2-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、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，上述之各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，相互獨立地可係未被取代，或被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，上述殘基之各芳基與雜芳基於各例中，可係未被取代，或被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; the 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)-O- (C 1-8 aliphatic)-OH, (C 1-8 aliphatic)-O-(C 1-8 aliphatic)-OC 1-10 aliphatic residue, one (C 1-8 fat) Group-)NH-C 1-10 aliphatic residue, mono(C 1-8 aliphatic)-NH-(C 1-8 aliphatic residue)-OH, one (C 1-8 aliphatic group) )-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)- OH, an NH-C 1-10 aliphatic residue, an N (C 1-10 aliphatic residue) 2 , a N H-(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)-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 or monosubstituted with OH, based on each of the examples. 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 a -10 cycloaliphatic residue, an NH-C 3-10 cycloaliphatic residue, an NH-C(=O)-C 3-10 cycloaliphatic residue, a 3 to 10 member heterocyclic aliphatic residue a group, 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 a 10-membered heterocyclic aliphatic residue), an NH-(3 to 10 membered heterocyclic aliphatic residue), an NH-C(=O)-(3 to 10 membered heterocyclic aliphatic residue), wherein The C 3-10 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, by one or more br, I, C 1-4 alkyl, C 1-4 alkylene -OH, C 1-4 alkoxy stretch -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, 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- Group of monoalkyl or polysubstituted groups of 4 alkyl) 2 , NH-SO 2 -C 1-4 alkyl, NH-C(=O)-C 1-4 alkyl, etc.; aryl, C ( =O)-aryl, C(=O)-NH-aryl, NH-C(=O)-aryl, heteroaryl, C(=O)-heteroaryl, C(=O)-NH a heteroaryl group, an NH-C(=O)-heteroaryl group, wherein each aryl group and heteroaryl group of the above residue may be unsubstituted or may be independently selected from 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, phenyl and pyridyl substituent groups like the group consisting of mono- or polysubstituted by 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, 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, SC 1-4 alkyl, SCF 3 and S(=O) 2 OH, etc. The group consisting is monosubstituted or multi-substituted.

更佳地，R5、R6、R7、R8與R9係各自相互獨立地選自由以下功能基組成之群組：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，上述各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，相互獨立地可係未被取代，或被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曲代或多取代，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，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。 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, 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, a N (C 1-4 aliphatic residue) [(C 1-4 aliphatic) -OC 1-4 aliphatic residue] A N (C 1-4 aliphatic residue) [(C 1-4 aliphatic) -OH], a NH-S (= O) 2 -C 1-4 aliphatic residue, wherein each of the C 1-4 aliphatic residues and C 1-4 aliphatic groups may be unsubstituted or monosubstituted with OH based on each case; a C 3-6 cycloaliphatic residue, 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 ester The family 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, 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, OH, SH, SC 1-4 alkyl, SO 2 -C 1-4 alkyl, NH 2 , NH-C 1-4 alkyl, N ( a group consisting of a C 1-4 alkyl) 2 , a NH—SO 2 —C 1-4 alkyl group and a substituent such as NH—C(=O)—C 1-4 alkyl group; , C(=O)-NH-aryl, NH-C(=O)-aryl, heteroaryl, C(=O)-NH-heteroaryl, NH-C(=O)-heteroaryl a base in which the aryl group and the heteroaryl group of each of the above residues are based on each other, Based site can be 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 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 Composition of (C 1-4 alkyl), N(C 1-4 alkyl) 2 , NH-SO 2 -C 1-4 alkyl and NH-C(=O)-C 1-4 alkyl The group is monosubstituted or multi-substituted.

又更佳地，R5、R6、R7、R8與R9係各自相互獨立地選自由以下功能基組成之群組：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、環戊基與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)、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，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。 Still 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, 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 alkyl-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 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 alkyl-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-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 alkylene in Embodiment, the system may be unsubstituted or substituted in the single OH, a C 3-6 cycloaliphatic residue, OC 3-6 cycloaliphatic residue, a 3 to 6 member heterocyclic aliphatic residue, wherein The C 3-6 cycloaliphatic residue is preferably selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and wherein the 3 to 6 member heterocyclic aliphatic residue is selected Preferably, the group of free tetrahydropyranyl groups is preferably tetrahydro-2H-pyran-4-yl, azetidinyl, piperidinyl, decyl and pyridyl, wherein the C The 3-6 cycloaliphatic residue and the 3 to 6 member heterocyclic aliphatic residue may be unsubstituted, respectively, or may be independently selected from F, Cl, Br, I, OH, OC 1 by one or more. -4 alkyl, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , a group monosubstituted or polysubstituted with a substituent such as a C 1-4 alkyl group, benzene Base, C(=O)-NH-phenyl, NH-C(=O)-phenyl, heteroaryl, C(=O)-NH-heteroaryl, NH-C(=O)-heteroaryl a group, preferably a phenyl group, a C(=O)-NH-phenyl group, and a NH-C(=O)-phenyl group, wherein the heteroaryl group is selected from the group consisting of a pyridine group, a furyl group and a phenyl group. Preferably, wherein the phenyl group and the hetero aryl group of the above residue are each In the examples, they may be unsubstituted independently of one another, or may be independently selected from the group consisting of F, Cl, Br, I, OH, OC 1-4 alkyl, C 1-4 alkyl and CF 3 , etc. The group consisting of substituents is mono- or poly-substituted.

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以下功能基組成之群組：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；而R7係選自由以下功能基組成之群組：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，可係未被取代，或被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、SO3-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，苯基與啶基係分別地未被取代或被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，上述殘基之各芳基與雜芳基於各例中，可相互獨立地係未被取代，或被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，苯基與啶基分別地係未被取代，或被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 the following functional 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, an NH-C 1-10 aliphatic residue, an N (C 1-10 aliphatic residue) 2 and An OC 1-10 aliphatic residue, wherein the C 1-10 aliphatic residue is unsubstituted or monosubstituted or disubstituted with OH, and R 7 is selected from the following functional groups. 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 group)-OC 1-10 aliphatic residue, (C 1-8 aliphatic group)-O-(C 1-8 aliphatic group)-OH, (C 1-8 aliphatic group) -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)-NH-S(=O) 2 -C 1-10 aliphatic residue, one (C 1-8 aliphatic)-NH-S ( =O) 2 -NH 2 , mono(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)-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], 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)], one N (C 1-10 aliphatic residue) Base) [(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 a -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 the C 1-8 aliphatic group may be unsubstituted, or 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 , 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 a group consisting of a group consisting of a mono- or poly-substituent in which the phenyl or pyridine 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, OCF 3 , C 1-4 alkyl, C(=O)-OH, CF 3 , NH 2 , NH(C 1-4 alkyl), N (C 1-4 a group of mono- or poly-substituted, a C 3-10 cycloaliphatic residue, a C consisting of a substituent such as an alkyl group 2 , SH, SC 1-4 alkyl, SCF 3 and S(=O) 2 OH; (=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 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- a 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 aliphatic residues), one O-(3 to 10 membered heterocyclic aliphatic residue), one O-(C 1-8 aliphatic)-(3 to 10 membered 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 membered heterocyclic aliphatic residues), one NH-C(=O)-(3 to 10 membered heterocyclic aliphatic residues), NH-(C 1-8 aliphatic)-(3 to 10) a heterocyclic aliphatic residue), an N(C 1-10 aliphatic) (3 to 10 membered heterocyclic aliphatic residue), wherein each of the above residues is selectively via a C based on each 1-8 aliphatic group bridged, wherein the C 1-10 aliphatic residue, the C 1-8 aliphatic group, the C The 3-10 cycloaliphatic residue and the 3 to 10 membered heterocyclic aliphatic residue may be unsubstituted or may be independently selected from the group consisting of F, Cl, Br, I, C, based on each of the examples. 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, =O, OCF 3 , OH, SH, SC 1-4 alkyl, SCF 3 , SO 3- 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 a group of mono- or poly-substituents consisting of a substituent of an alkyl group, 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 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, Substituents such as 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 Group of mono- or polysubstituted, 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) Family 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 a group, NH-S(=O) 2 -heteroaryl, NH-(C 1-8 aliphatic)(heteroaryl), N(C 1-10 aliphatic residue) (heteroaryl), wherein Each of the above residues may be selectively bridged via a C 1-8 aliphatic group, wherein each of the aryl groups and heteroaryl groups of the above residues may be independently substituted independently of each other based on the respective 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 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, phenyl, piperidinyl and the like take The group consisting of a substituted or mono-substituted group, 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, 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 mono- or poly-substitution group consisting of a substituent such as S(=O) 2 OH, wherein the C 1-10 aliphatic residue of the above residue and the C 1-8 aliphatic group are independently of each other based on each case May be unsubstituted or 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 alkane Substituents such as CF, CF 3 , SH, SC 1-4 alkyl, SCF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , phenyl and pyridine 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, OCF 3 , C 1-4 alkyl, C(=O)-OH, C Substituents such as F 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 The group is monosubstituted or multi-substituted.

較佳地，R5、R6、R8與R9係相互獨立地選自由以下功能基組成之群組：H、F、Cl、Br、I、CN、NO2、CF3、CF2H、CFH2、OH、OCF3、OCF2Cl、OCFCl2、SH、SCF3、NH2、C(=O)-NH2、CH2OH、甲基、乙基、三級丁基、O-甲基、NH-甲基、N(甲基)2；以選自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較佳；而R7係選自由以下功能基組成之群組：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，相互獨立地可經由一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 , CH 2 OH, methyl, ethyl, tert-butyl, O- Methyl, NH-methyl, N(methyl) 2 ; selected from the group consisting of 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 are preferred; 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 , 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)-OC 1-10 aliphatic residue, (C 1-8 aliphatic)-O-(C 1-8 aliphatic)-OH, (C 1- aliphatic 8-yl) -O- (C 1-8 aliphatic ) -OC 1-10 aliphatic residue, a (C 1-8 aliphatic) -NH-C 1-10 aliphatic residue, a (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 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 Base, an NH-(C 1-8 aliphatic)-OH, a 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], 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)-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 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 , may be unsubstituted or monosubstituted with OH; 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 membered heterocyclic aliphatic residues), one NH-C(=O)-(3 to 10 membered heterocyclic aliphatic residues), NH-(C 1-8 aliphatic)-(3 to 10) a heterocyclic aliphatic residue), an N (C 1-10 aliphatic residue) (3 to 10 membered heterocyclic aliphatic residue), wherein each of the above residues is optionally via one a C 1-8 aliphatic group bridge wherein the C 1-10 aliphatic residue and the C 1-8 aliphatic group are independently unsubstituted or independently substituted with OH, based on each of the examples, wherein The C 3-10 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 by one or more ,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 alkane Base, 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 a group consisting of a substituent consisting of 2 -C 1-4 alkyl, NH-C(=O)-C 1-4 alkyl, etc., mono- or poly-substituted, aryl, C(=O)-aryl, C ( =O)-NH- Group, O- aryl group, a O- (C 1-8 aliphatic) - aryl, S- aryl group, a S- (C 1-8 aliphatic) - aryl group, an NH- aryl group, 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)-(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 The above residues may be bridged independently of each other via a C 1-8 aliphatic group, wherein the aryl group and the heteroaryl group of the above residue may be unsubstituted or independently based on each of the examples. Or a plurality of mutually 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 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 1- 4 alkyl), N(C 1-4 alkyl) 2 , NH-SO 2 -C 1-4 alkyl, NH-C(=O)-C 1-4 alkyl, phenyl and pyridine a group consisting of a mono- or poly-substitution in which the phenyl or pyridine groups are 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 mono- or poly-substitution group consisting of a substituent such as S(=O) 2 OH, wherein each C 1-10 aliphatic residue of the above residue and the C 1-8 aliphatic group are based on each case, Not substituted, or replaced by OH.

更佳地，R5、R6、R8與R9係各自相互獨立地選自由以下功能基組成之群組：H、F、Cl、Br、I、CF3、CF2H、CFH2、OH、CH2OH、甲基與O-甲基；以選自H、F、Cl、Br、I、CF3、CF2H、CFH2、OH、甲基與O-甲基較佳；而R7係選自由以下功能基組成之群組：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)、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構件雜環脂族殘於各例中，相互獨立地可係未被取代，或被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，苯基或啶基分別地係未被取代，或被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 each independently selected from the group consisting of H, F, Cl, Br, I, CF 3 , CF 2 H, CFH 2 , OH, CH 2 OH, methyl and O-methyl; preferably selected from the group consisting of H, F, Cl, Br, I, CF 3 , CF 2 H, CFH 2 , OH, methyl and O-methyl; 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 , 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, mono(C 1-8 aliphatic)-N(C 1-10 aliphatic residue)-(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 Yl) -NH-S (= O) 2 -NH 2, a (C 1-8 aliphatic) -S (= O) 2 -C 1-10 aliphatic residue, an aliphatic residue OC 1-10 a group, an O-(C 1-8 aliphatic)-OC 1-10 aliphatic residue, an O-(C 1-8 aliphatic)-OH, an NH-C 1-10 aliphatic residue, N (C 1-10 aliphatic residue) 2 , mono NH-(C 1-8 aliphatic)-OC 1-10 aliphatic residue, mono 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 group)-OH], an NH-S(=O) 2 -C 1-10 aliphatic residue, wherein each of the above C 1-10 aliphatic residues is based on a C 1-8 aliphatic group In each case, it may be unsubstituted or monosubstituted with OH; 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 NH-C 3-10 cycloaliphatic residue, an NH-C(=O)-C 3-10 a 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 member heterocyclic aliphatic residue), one O-(3 to 10 member heterocyclic aliphatic residue), one NH-(3 to 10 member heterocyclic aliphatic residue), one NH-C(=O)- (3 to 10 member heterocyclic aliphatic residues) ), Wherein the C 3-10 cycloaliphatic residues with the 3-10 member heterocyclic aliphatic residue in each example, the system may be independently unsubstituted or substituted with 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, OCF 3 , OH, SH, SC 1-4 alkane a group, 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, a mono- or poly-substituted group of substituents such as NH-C(=O)-C 1-4 alkyl, aryl, C(=O)-aryl, C(=O)-NH-aryl, NH-C(=O)-aryl, heteroaryl, C(=O)-heteroaryl, C(=O)-NH-heteroaryl, NH-C(=O)-heteroaryl, wherein The aryl group and the heteroaryl group of the above residue 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, 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 Group, 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 a group of 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; a multiple substitution wherein the phenyl or pyridine 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 and S(=O) 2 A group consisting of a substituent such as OH is mono- or poly-substituted.

再更佳地，R5、R6、R8與R9係各自相互獨立地選自由以下功能基組成之群組：H、F、Cl、Br、I、CF3、OH、CH2OH、甲基與O-甲基，以選自H、F、Cl、Br、I、CF3、OH、甲基與O-甲基更佳；而R7係選自由以下功能基組成之群組：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，上述之各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，相互獨立地可係未被取代，或被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，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。 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, CH 2 OH, The methyl group and the O-methyl group are preferably selected from the group consisting of H, F, Cl, Br, I, CF 3 , OH, methyl and O-methyl; and R 7 is selected from the group consisting of the following functional 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 , a C 1-4 aliphatic residue, (C 1-4 aliphatic)-OH, (C 1-4 aliphatic)-OC 1-4 lipid Family 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)-NH-(C 1-4 lipid Family residue) -OH, mono(C 1-4 aliphatic)-N (C 1-4 aliphatic residue)-(C 1-4 aliphatic residue)-OH, one (C 1-4 lipid) Group-)NH-S(=O) 2 -C 1-4 aliphatic residue, mono(C 1-4 aliphatic)-NH-S(=O) 2 -NH 2 , one (C 1- 4 aliphatic group)-S(=O) 2 -C 1-4 aliphatic residue, an OC 1-4 aliphatic residue, an O-(C 1-4 aliphatic)-OC 1-4 lipid Family residue, O-(C 1-4 aliphatic)-OH, one NH -C 1-4 aliphatic residue, one N (C 1-4 aliphatic residue) 2 , one NH-(C 1-4 aliphatic)-OC 1-4 aliphatic residue, one 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 aliphatic The residue and the C 1-4 aliphatic group 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 a 6-membered heterocyclic aliphatic residue, O-(3 to 6 membered heterocyclic residue), wherein the C 3-6 cycloaliphatic residue and the 3 to 6 member heterocyclic aliphatic residue are based on each case , independently of each other, may be unsubstituted or 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, OH, SH, SC 1-4 alkyl, 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 such as a group consisting of a single Alternate or polysubstituted, aryl, C(=O)-NH-aryl, NH-C(=O)-aryl, heteroaryl, C(=O)-NH-heteroaryl, NH-C ( =O)-heteroaryl, wherein the aryl and heteroaryl of each of the above residues are independently unsubstituted, independently of one another, 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, OC 1-4 alkylene-OH, OCF 3 , C 1-4 alkane , 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 1-4 alkyl), N(C 1-4 alkyl) 2 , NH-SO 2 -C 1-4 alkyl and NH-C (= O) -C 1-4 alkyl substituent such as a group consisting of mono- or polysubstituted.

又更佳地，R5、R6、R8與R9係各自相互獨立地選自由以下功能基族成之群組：H、F、Cl、Br、I、CF3、OH、CH2OH、甲基、O-甲基，以H、F、Cl、Br、I、CF3、OH、甲基與O-甲基較佳；而R7係選自由以下功能基族成之群組：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構件雜環脂族殘以選自由四氫吡喃基組成之群組較佳，以選自由四氫-2H-吡喃-4-基、氮雜環丁基、哌啶基、嗎咻基與咯啶基更佳，其中，該C3-6環脂族殘與該3至6構件雜環脂族殘，分別地可係未被取代，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，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，各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，或被一或多個各自相互獨立地選自由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。 Still more preferably, R 5 , R 6 , R 8 and R 9 are each independently selected from the group consisting of H, F, Cl, Br, I, CF 3 , OH, CH 2 OH , methyl, O-methyl, preferably H, F, Cl, Br, I, CF 3 , OH, methyl and O-methyl; and R 7 is selected from the group consisting of the following functional 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 Alkyl-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 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 alkyl -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 group -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 C 1-4 alkyl is in each case, and may be unsubstituted 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 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and wherein the 3 to 6 member heterocyclic aliphatic residue is selected from the group consisting of tetrahydropyranyl. Preferably, the group is selected from the group consisting of tetrahydro-2H-pyran-4-yl, azetidinyl, piperidinyl, decyl and pyridyl, wherein the C 3-6 cycloaliphatic Residues and the 3 to 6 member heterocyclic aliphatic residues, respectively, may be unsubstituted or one or more independently selected from the group consisting of F, Cl, Br, I, OH, OC 1-4 alkyl, NH 2 , a group consisting of NH(C 1-4 alkyl) and N(C 1-4 alkyl) 2 and a C 1-4 alkyl group, such as a mono- or poly-substitution, phenyl, C (= O) -NH-phenyl, NH-C(=O)-phenyl, heteroaryl, C(=O)-NH-heteroaryl, NH-C(=O)-heteroaryl, with benzene And 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 phenyl group; The phenyl and heteroaryl groups of each 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)化合物之一特佳具體實施例中，R5與R9係各自相互獨立地選自由以下功能基組成之群組：H、F、Cl、Br、I、CF3、OH、CH2OH、甲基、O-甲基，以選自H、F、Cl、Br、I、CF3、OH、甲基、O-甲基較佳，以兩者皆代表H更佳；R6與R8係各自相互獨立地選自由以下功能基組成之群組：H、F、Cl、Br、I、CF3、OH、CH2OH、甲基、O-甲基，以選自H、F、Cl、Br、I、CF3、OH、甲基、O-甲基較佳；而R7係選自由以下功能基組成之群組： 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，各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，以選自四氫-2H-吡喃-4-基、氮雜環丁基、哌啶基、嗎咻基與咯啶基更佳，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地，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，上述殘基之各苯基與雜芳基於各例中，相互獨立地可係未被取代，或被一或多個相互獨立地選自由F、Cl、Br、I、OH、O-C1-4烷基、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 formula (I) according to the invention, the R 5 and R 9 systems are each independently selected from the group consisting of H, F, Cl, Br, I, CF 3 , OH, CH 2 OH, methyl, O-methyl, preferably selected from the group consisting of H, F, Cl, Br, I, CF 3 , OH, methyl, O-methyl, both of which represent H More preferably; each of R 6 and R 8 is independently selected from the group consisting of H, F, Cl, Br, I, CF 3 , OH, CH 2 OH, methyl, O-methyl, Preferably, it is 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 alkylene-OC 1-4 alkyl, C 1-4 alkylene-OC 1-4 Alkyl-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 group -NH-C 1-4 alkylene group -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 alkyl -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 alkyl-OH], N(C 1 - 4 alkyl)-[ C 1-4 alkyl-OC 1-4 alkyl], NH-S(=O) 2 -C 1-4 alkyl, wherein each C 1-4 alkyl group is in each case, may be Substituted, 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 ring The aliphatic residue is preferably selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and wherein the 3 to 6 membered heterocyclic aliphatic residue is selected from the group consisting of tetrahydropyranyl. Preferably, the group consisting of tetrahydro-2H-pyran-4-yl, azetidinyl, piperidinyl, decyl and pyridyl is preferred, wherein the C 3-6 ring The aliphatic residue and the 3 to 6 member heterocyclic aliphatic residue, respectively, may be unsubstituted Or one or more independently selected from the group consisting of F, Cl, Br, I, OH, OC 1-4 alkyl, NH 2 , NH(C 1-4 alkyl) and N (C 1-4 alkyl) a group consisting of 2 substituents, 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)-benzene Preferably, the heteroaryl group is preferably selected from the group consisting of a pyridine group, a furyl group and a phenyl group; wherein each of the phenyl groups and heteroaryl groups of the above residues are independently of each other based on the respective examples. Substituted or monosubstituted by one or more groups independently selected from the group consisting of F, Cl, Br, I, OH, OC 1-4 alkyl, C 1-4 alkyl, and CF 3 More substitution.

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 present invention, at least one of R 5 and R 9 represents H, and both R 5 and R 9 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至少其中之一代表H，以其中之一代表H較佳。 In still another preferred embodiment of the compound of the formula (I) according to the present invention, at least one of R 6 and R 8 represents H, and one of them represents H is preferred.

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R5與R9兩者皆代表H較佳，及R6與R8至少其中之一代表H，以其中之一代表H較佳，或R6與R8兩者皆代表H。 According to yet another compound of formula (I) of the present invention, preferred embodiments, R 5 and wherein at least one of R 9 represents H, both of R 5 and R 9 represents H are preferred, and R 6 At least one of R 8 and R represents H, and one of them represents H, or both R 6 and R 8 represent H.

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皆代表H，或R5與R9其中之一代表H，而R5與R9之另一個之殘基代表CH2OH；以R5與R9兩者皆代表H較佳，R6與R8係各自相互獨立地選自由以下功能基組成之群組： H、F、Cl、Br、I、CF3、OH、CH2OH、甲基、O-甲基，以選自H、F、Cl、Br、I、CF3、OH、甲基、O-甲基較佳；而R7係選自由以下功能基組成之群組：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，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-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，自相互獨立地可係未被取代，或被一或多個相互獨立地選自由F、Cl、Br、I、OH、O-CH3、CH3、C2H5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 formula (I) according to the invention, both R 5 and R 9 represent H, or one of R 5 and R 9 represents H, and the other of R 5 and R 9 The residue represents CH 2 OH; it is preferred that both R 5 and R 9 represent H, and each of R 6 and R 8 is independently selected from the group consisting of the following functional groups: H, F, Cl, Br, I , CF 3 , OH, CH 2 OH, methyl, O-methyl, preferably selected from the group consisting of H, F, Cl, Br, I, CF 3 , OH, methyl, O-methyl; and R 7 Select the group consisting of the following functional 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 , 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, preferably tetrahydro-2H-pyran-4-yl, azetidinyl, piperidinyl, decyl or pyridyl, which is independent of each other in each case Substituted, or 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 , C 2 H 5 and tertiary a group consisting of a group consisting of a mono- or poly-substituent, phenyl, C(=O)-NH-phenyl or NH-C(=O)-phenyl, wherein the phenyl group is independent of each other in each case The ground may be unsubstituted or grouped by one or more substituents independently selected from the group consisting of F, Cl, Br, I, OH, O-CH 3 , CH 3 , C 2 H 5 and CF 3 Single or multiple substitution.

R7之特佳殘基係選自由以下功能基組成之群組：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-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。 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- Pyran-4-yl, azetidinyl, piperidinyl, decyl or pyridyl is preferred, Each of the examples is independently unsubstituted, or 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 In each case, independently of each other, unsubstituted 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 consisting of such substituents is mono- or poly-substituted.

根據本發明通式(I)之較佳化合物，其中， n代表1；X代表N或CH；Y代表O；Z代表N或C-R4b；A1代表N或CR5；A2代表N或CR6；A3代表N或CR7；A4代表N或CR8；A5代表N或CR9；附帶條件為A1、A2、A3、A4與A5變量之1、2或3代表一氮原子；R1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；R2代表(T1)子結構 其E 代表O、S或NR11，其中，R11代表H或一C1-4脂族殘基，其係未被取代，或被一或多個相互獨立地選自由F、Cl、Br、I、OH、O-C1-4烷基、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C1-4脂族殘基，其係未被取代，或被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-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環脂族殘基或一3至10構件雜脂族殘基，其於各例中係未被取代，或被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，其係未被取代，或被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、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成之取代基群組單取代或多取代；R3係選自由H、甲基與乙基組成之群組。 Preferred compounds of the formula (I) according to the invention, wherein n represents 1; X represents N or CH; Y represents O; Z represents N or CR 4b ; A 1 represents N or CR 5 ; A 2 represents N or CR 6 ; A 3 represents N or CR 7 ; A 4 represents N or CR 8 ; A 5 represents N or CR 9 ; conditional is 1 , 2 or 3 of A 1 , A 2 , A 3 , A 4 and A 5 variables Represents a nitrogen atom; R 1 is selected from the group consisting of tertiary butyl, CF 3 , cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; R 2 represents a (T1) substructure Its E represents O, S or NR 11 , wherein R 11 represents H or a C 1-4 aliphatic residue which is unsubstituted or is independently selected from F, Cl, Br, by one or more a mono- or poly-substitution group consisting of a substituent such as I, OH, OC 1-4 alkyl, OCF 3 , NH 2 , NH-C 1-4 alkyl and N(C 1-4 alkyl) 2 ; Representative 0 or 1; preferably 0, R 10a and R 10b each independently represent H, F, Cl, Br, I or a C 1-4 aliphatic residue, which is unsubstituted or Or a plurality of mutually independently selected from the group consisting of F, Cl, Br, I, OH, OC 1-4 alkyl, OCF 3 , NH 2 , NH-C 1-4 alkyl and N(C 1-4 alkyl) 2 The group consisting of a substituent is mono- or polysubstituted; m represents 0, 1, 2, 3 or 4, preferably 0, 1 or 2, preferably 0 or 1; G represents a C 1-4 An aliphatic residue which is unsubstituted or one or more independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, =0, OC 1-4 alkyl, OC 1- 4- alkyl-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 pyridyl substituent groups like the group consisting of monosubstituted Or substituted, 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, 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 mono- or poly-substituent consisting of a substituent such as an alkyl group, an SCF 3 and an S(=O) 2 OH group; or a C 3-10 cycloaliphatic residue or a 3 to 10 component heteroaliphatic residue , in each case unsubstituted, or 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 , phenyl and pyridine a group consisting of a group consisting of a mono- or poly-substituent in which the phenyl or pyridine 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, OCF 3 , C 1-4 alkyl, C(=O)-OH, CF 3 , NH 2 , NH(C 1-4 alkyl), N (C 1-4 a group consisting of alkyl, 2 , SH, SC 1-4 alkyl, SCF 3 and S(=O) 2 OH Monosubstituted or polysubstituted; or represents an aryl or heteroaryl group which is unsubstituted or which is independently selected from F, Cl, Br, I, NO 2 , CN, OH, 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 alkane yl) 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, 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 group of substituents mono- or poly-substituted; R 3 is selected from H a group consisting of a methyl group and an ethyl group.

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F、Cl、Br、I、NO2、CN、CF3、CF2H、CFH2、CF2Cl、CFCl2、OH、NH2、NH(C1-4烷基)與(C1-4烷基)(C1-4烷基)、C1-4烷基、與O-C1-4-烷基之取代基取代；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環丙基、環丁基、環戊基、或環己基環；R5、R6、R7、R8與R9各自係相互獨立地選自由以下功能基組成之群組：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，相互獨立地可係未被取代，或被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，各上述殘基之芳基與雜芳基於各例中，可係未被取代，或被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。 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 alkyl) and (C 1-4 alkyl)(C 1-4 alkyl), C 1-4 alkyl, substituted with a substituent of OC 1-4 -alkyl; R 4b represents H, methyl or ethyl; R 4a and R 4b together with the carbon atom to which they are bonded form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring; R 5 , R 6 , R 7 , R 8 and R 9 are each independently of each other Select from the following group of functional 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 Yl) -O- (C 1-8 aliphatic group -OC 1-10 aliphatic residue, a (C 1-8 aliphatic) -NH-C 1-10 aliphatic residue, a (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 fat Family 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)-OH, one NH-C 1-10 aliphatic residue, one N (C 1- 10 aliphatic residues) 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)-OC 1-10 aliphatic residue], one 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 the C 1-8 aliphatic group are based on each case, Substituted or monosubstituted with OH; a C 3-10 cycloaliphatic residue, a C(=O)-C 3-10 cycloaliphatic residue, a C(=O)NH-C 3-10 ring Aliphatic residue, an OC 3-10 cycloaliphatic residue, an NH-C 3-10 cycloaliphatic residue, an NH-C(=O)-C 3-10 a 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 member heterocyclic aliphatic residue), one O-(3 to 10 member heterocyclic aliphatic residue), one NH-(3 to 10 member heterocyclic aliphatic residue), one NH-C (=O) a (3 to 10 membered heterocyclic aliphatic residue), wherein the C 3-10 cycloaliphatic residue and the 3 to 10 membered heterocyclic aliphatic 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, C 1-4 alkyl, C 1-4 alkyl-OH, C 1-4 alkyl-OC 1-4 a group, 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, 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 , a group of mono- or poly-substituted groups of substituents such as NH-SO 2 -C 1-4 alkyl, NH-C(=O)-C 1-4 alkyl; aryl, C(=O)-aryl , C(=O)-NH-aryl, NH-C(=O)-aryl, heteroaryl, C(=O)-heteroaryl, C(=O)-NH-heteroaryl, NH -C(=O)-heteroaryl, wherein the aryl and heteroaryl of each of the above residues are based on each case , 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, 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 1-4 alkyl), N(C 1-4 alkyl) 2 , NH-SO 2 -C 1-4 alkyl, NH-C(=O)-C 1-4 alkyl, phenyl a group mono- or poly-substituted with a substituent such as a pyridine group, wherein the phenyl or pyridine 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 -alkane Base, 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 A group consisting of a group consisting of an alkyl group, an SCF 3 and a substituent such as S(=O) 2 OH is mono- or poly-substituted.

本發明之另一較佳具體實施例係依根據通式(I)之化合物，其中，R1 係選自由CF3、三級丁基與環丙基組成之群組，R2 代表苯基，其係未被取代，或被一或多個相互獨立地選自由F、Cl、Br、I、OH、O-CH3、CH3、CH(CH3)2、N(CH3)2、三級丁基與CF3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、O-CH3、CH3、CH(CH3)2、N(CH3)2、三級丁基與CF3組成之取代基單取代或二取代較佳，苯基以於間位被一選自由F、Cl、CH3、OCH3、CH(CH3)2與N(CH3)2組成之群組之取代基單取代更佳，或代表4-甲基哌啶基，R3 代表H，n 代表1，X 代表CH或N，以代表N較佳，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，A1 代表C-R5，A2 代表N，A3 代表C-R7，A4 代表N或C-R8，以代表CR8較佳，A5 代表C-R9，R5與R9皆代表H，或R5與R9其中之一代表H而剩餘之R5與R9之殘基代表CH2OH；以R5與R9皆代表H較更佳，R6與R8係各自相互獨立地選自由以下功能基組成之群組：H、F、Cl、Br、I、CF3、OH、CH2OH、甲基、O-甲基，以 選自H、F、Cl、Br、I、CF3、OH、甲基、O-甲基較佳；而R7係選自由以下功能基組成之群組：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-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-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C2H4-S(=O)2-CH3、CH2-O-C2H4-OH、CH2-OH、CH2-NH-S(=O)2-CH3、CH(OH)-CH2OH與C2H4-OH組成之群組較 佳，以選自由由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。 Another preferred embodiment of the present invention is the compound according to formula (I) wherein R 1 is selected from the group consisting of CF 3 , a tertiary butyl group and a cyclopropyl group, and R 2 represents a phenyl group. It is unsubstituted or is one or more independently selected from the group consisting of F, Cl, Br, I, OH, O-CH 3 , CH 3 , CH(CH 3 ) 2 , N(CH 3 ) 2 , The group consisting of a butyl group and a substituent such as CF 3 is mono- or poly-substituted, and the phenyl group is selected from F, Cl, Br, I, O-CH 3 , CH 3 , CH independently of one or two. Preferably, the substituent consisting of CH 3 ) 2 , N(CH 3 ) 2 , a tertiary butyl group and a CF 3 group is mono- or di-substituted, and the phenyl group is at a meta position selected from the group consisting of F, Cl, CH 3 and OCH 3 . The substituent of the group consisting of CH(CH 3 ) 2 and N(CH 3 ) 2 is preferably monosubstituted, or represents 4-methylpiperidinyl, R 3 represents H, n represents 1, and X represents CH or N. Preferably, N is represented, R 4a represents H or methyl, Y represents O, Z represents N or CR 4b , when R 4a represents H, preferably represents N, or when R 4a and R 4b each represent H to represent the preferred CR 4b, or represents methyl when R 4a and R 4b represents H, preferred to represent CR 4b, R 4b Representative H Methyl, A 1 representative of CR 5, A 2 on behalf of N, A 3 Representative CR 7, A 4 represents N or CR 8, CR 8 to represent preferred, A 5 on behalf of CR 9, R 5 and R 9 both represent H, Or one of R 5 and R 9 represents H and the remaining residues of R 5 and R 9 represent CH 2 OH; it is more preferred that R 5 and R 9 represent H, and R 6 and R 8 are each independently of each other. Selected from the group consisting of H, F, Cl, Br, I, CF 3 , OH, CH 2 OH, methyl, O-methyl, selected from H, F, Cl, Br, I, CF 3 , OH, methyl, O-methyl are preferred; 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 , 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, cyclohexyl , O-cyclopropyl, tetrahydropyranyl, tetrahydro-2H-pyran-4-yl, azetidinyl, piperidinyl, decyl or pyridyl is preferred, in each case Independently, independently of one another, selected from the group consisting of F, Cl, Br, I, OH, O-CH 3 , NH 2 , N(CH 3 ) 2 , CH 3 , C 2 a group consisting of a substituent consisting of a substituent such as H 3 and a tertiary butyl group, monosubstituted or polysubstituted, phenyl, C(=O)-NH-phenyl or NH-C(=O)-phenyl, wherein phenyl is each In the examples, independently of each other, may be unsubstituted or substituted by one or more independently selected from F, Cl, Br, I, OH, O-CH 3 , CH 3 , C 2 H 5 and CF 3 , etc. The group consisting of a mono- or poly-substitution, R 7 is selected from 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 CH (OH) -CH 2 OH and C 2 H 4 -OH group consisting of Preferably, in a selected from the group consisting of C 2 H 4 -S (= O ) 2 -CH 3, CH 2 -OC 2 H 4 -OH The group consisting of CH 2 -OH, CH 2 -NH-S(=O) 2 -CH 3 and C 2 H 4 -OH is more preferred.

根據本發明化合物之其他具體實施例，係以如下所示之通式A1至A14代表： Other specific embodiments of the compounds according to the invention are represented by the general formulae A1 to A14 shown below:

其中，該特定之自由基、變量與指數具有本文所述、根據本發明之化合物，及其較佳具體實施例之意義。 Wherein the particular free radical, variable and index have the meanings of the compounds described herein, according to the invention, and preferred embodiments thereof.

根據本發明之特佳化合物如下： Particularly preferred compounds according to the invention are as follows:

1. N-((2-戊基-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺 1. N-((2-pentyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-2-yl)acetamide

2. N-((2-環戊基-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺 2. N-((2-Cyclopentyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-2-yl)acetamide

3. 1-(啶-2-基)-3-((2-(四氫-2H-吡喃-4-基)-6-(三氟甲基)啶-3-基)甲基)尿素 3. 1-(Acridin-2-yl)-3-((2-(tetrahydro-2H-pyran-4-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea

4. N-((2-(環己基甲基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺 4. N-((2-(Cyclohexylmethyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-2-yl)acetamide

5. N-((2-(3-氯苯基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺 5. N-((2-(3-Chlorophenyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-2-yl)acetamide

6. N-((2-(3-氯-4-氟苯基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺 6. N-((2-(3-Chloro-4-fluorophenyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-2-yl)acetamide

7. 2-(啶-2-基)-N-((2-間-甲苯基-6-(三氟甲基)啶-3-基)甲基)乙醯胺 7. 2-(Acridin-2-yl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide

8. N-((2-(3-甲氧苯基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺 8. N-((2-(3-Methoxyphenyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-2-yl)acetamide

9. N-((2-(丁胺基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺 9. N-((2-(butylamino)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-2-yl)acetamide

10. 2-(啶-2-基)-N-((2-(咯啶基-1-基)-6-(三氟甲基)啶-3-基)甲基)乙醯胺 10. 2-(Acridin-2-yl)-N-((2-(rhodidyl-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide

11. N-(2-(4-甲基哌啶-1-基)-4-(三氟甲基)苄基)-2-(啶-2-基)乙醯胺 11. N-(2-(4-Methylpiperidin-1-yl)-4-(trifluoromethyl)benzyl)-2-(pyridin-2-yl)acetamide

12. N-((6-三級丁基-2-(4-甲基哌啶-1-基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺 12. N-((6-Tris-butyl-2-(4-methylpiperidin-1-yl)pyridin-3-yl)methyl)-2-(pyridin-2-yl)acetamide

13. N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺 13. N-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-2-yl)acetamidine amine

14. N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)丙醯胺 14. N-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-2-yl)propanoid amine

15. 2-甲基-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)丙醯胺 15. 2-Methyl-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridine-2 -base propylamine

16. N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-1-(啶-2-基)環丙醯胺 16. N-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-1-(pyridin-2-yl)cyclopropane Guanamine

17. 2-環己基-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺 17. 2-Cyclohexyl-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridine-2 -yl)acetamide

18. N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)-2-間-甲苯乙醯胺 18. N-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-2-yl)-2 -m-toluene

19. 1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-3-(啶-2-基)尿素 19. 1-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(pyridin-2-yl)urea

20. 1-甲基-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-1-(啶-2-基)尿素 20. 1-Methyl-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-1-(pyridine-2 -base) urea

21. 1-甲基-1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-3-(啶-2-基)尿素 21. 1-Methyl-1-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(pyridine-2 -base) urea

22. N-((2-嗎啉基-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺 22. N-((2-Morpholinyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-2-yl)acetamide

23. 1-((2-(4-(二甲胺基)哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-3-(啶-2-基)尿素 23. 1-((2-(4-(Dimethylamino)piperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(pyridine-2- Urea

24. N-((2-((2-甲氧乙氧)甲基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺 24. N-((2-((2-methoxyethoxy))methyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-2-yl)acetamidine amine

25. N-((2-丁氧基-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺 25. N-((2-Butoxy-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-2-yl)acetamide

26. N-((2-(環丁基甲氧基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺 26. N-((2-(Cyclobutylmethoxy)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-2-yl)acetamide

27. N-((2-(環己氧基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺 27. N-((2-(Cyclohexyloxy)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-2-yl)acetamide

28. N-(4-三級丁基-2-(環己基硫代)苄基)-2-(啶-2-基)乙醯胺 28. N-(4-tert-butyl-2-(cyclohexylthio)benzyl)-2-(pyridin-2-yl)acetamide

29. N-(2-(環己基硫代)-4-(三氟甲基)苄基)-2-(啶-2-基)乙醯胺 29. N-(2-(Cyclohexylthio)-4-(trifluoromethyl)benzyl)-2-(pyridin-2-yl)acetamide

30. N-((6-環丙基-2-(4-甲基哌啶-1-基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺 30. N-((6-Cyclopropyl-2-(4-methylpiperidin-1-yl)pyridin-3-yl)methyl)-2-(pyridin-2-yl)acetamide

31. N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-3-基)乙醯胺 31. N-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-3-yl)acetamidine amine

32. N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-3-基)丙醯胺 32. N-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-3-yl)propanoid amine

33. N-(4-三級丁基-2-(4-甲基哌啶-1-基)苄基)-2-(啶-3-基)乙醯胺 33. N-(4-tert-butyl-2-(4-methylpiperidin-1-yl)benzyl)-2-(pyridin-3-yl)acetamide

34. N-((2-(環己基硫代)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-3-基)乙醯胺 34. N-((2-(Cyclohexylthio)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-3-yl)acetamide

35. 1-((2-(3-氯苯基)-6-(三氟甲基)啶-3-基)甲基)-3-(啶-3-基)尿素 35. 1-((2-(3-Chlorophenyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(pyridin-3-yl)urea

36. 1-(啶-3-基)-3-((2-間-甲苯基-6-(三氟甲基)啶-3-基)甲基)尿素 36. 1-(Acridin-3-yl)-3-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)urea

37. 1-((2-(3-甲氧苯基)-6-(三氟甲基)啶-3-基)甲基)-3-(啶-3-基)尿素 37. 1-((2-(3-Methoxyphenyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(pyridin-3-yl)urea

38. N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-4-基)乙醯胺 38. N-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-4-yl)acetamidine amine

39. N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-2-(嘧啶-4-基)乙醯胺 39. N-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyrimidin-4-yl)acetamidine amine

40. N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-2-(吡嗪-2-基)乙醯胺 40. N-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyrazin-2-yl)ethyl Guanamine

41. N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-2-(嘧啶-2-基)乙醯胺 41. N-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyrimidin-2-yl)acetamidine amine

42. 1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-3-(噠嗪-4-基)尿素 42. 1-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(pyridazin-4-yl)urea

43. 1-(2-(4-甲基哌啶-1-基)-4-(三氟甲基)苄基)-3-(噠嗪-4-基)尿素 43. 1-(2-(4-Methylpiperidin-1-yl)-4-(trifluoromethyl)benzyl)-3-(pyridazin-4-yl)urea

44. 1-(4-三級丁基-2-(環己基硫代)苄基)-3-(噠嗪-4-基)尿素 44. 1-(4-Tributyl -2-(cyclohexylthio)benzyl)-3-(pyridazin-4-yl)urea

45. 1-((2-(3-氟苯基)-6-(三氟甲基)啶-3-基)甲基)-3-(噠嗪-4-基)尿素 45. 1-((2-(3-Fluorophenyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(pyridazin-4-yl)urea

46. 1-((2-(3-氯-4-氟苯基)-6-(三氟甲基)啶-3-基)甲基)-3-(噠嗪-4-基)尿素 46. 1-((2-(3-Chloro-4-fluorophenyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(pyridazin-4-yl)urea

47. N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-2-(嘧啶-5-基)乙醯胺 47. N-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyrimidin-5-yl)acetamidine amine

48. 1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-3-(1,3,5-三嗪-2-基)尿素 48. 1-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(1,3,5-triazine -2-yl) urea

49. 2-(6-氯啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺 49. 2-(6-Chloro-3-yl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl Propylamine

50. 2-(5-氟啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)乙醯胺 50. 2-(5-Fluoropyridin-3-yl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl Ethylamine

51. 1-(5-氟啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 51. 1-(5-Fluoropyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl Urea

52. 1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-3-(2-甲基嘧啶-5-基)尿素 52. 1-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(2-methylpyrimidine-5- Urea

53. 2-(6-(羥甲基)啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺 53. 2-(6-(Hydroxymethyl)pyridin-3-yl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine-3- Methyl)propanamide

54. N-((2-(3-氟苯基)-6-(三氟甲基)啶-3-基)甲基)-2-(6-(羥甲基)啶-3-基)丙醯胺 54. N-((2-(3-Fluorophenyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(6-(hydroxymethyl)pyridin-3-yl) Propylamine

55. 1-(6-(羥甲基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 55. 1-(6-(Hydroxymethyl)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine-3- Methyl)urea

56. 1-(6-(羥甲基)啶-3-基)-3-((2-戊基-6-(三氟甲基)啶-3-基)甲 基)尿素 56. 1-(6-(Hydroxymethyl)pyridin-3-yl)-3-((2-pentyl-6-(trifluoromethyl)pyridin-3-yl)methyl Urea

57. 1-((2-(3-氟苯基)-6-(三氟甲基)啶-3-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素 57. 1-((2-(3-Fluorophenyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(6-(hydroxymethyl)pyridin-3-yl) Urea

58. 1-(6-(羥甲基)啶-3-基)-3-((2-間-甲苯基-6-(三氟甲基)啶-3-基)甲基)尿素 58. 1-(6-(Hydroxymethyl)pyridin-3-yl)-3-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)urea

59. 1-(6-(羥甲基)啶-3-基)-3-((2-(3-異丙苯基)-6-(三氟甲基)啶-3-基)甲基)尿素 59. 1-(6-(Hydroxymethyl)pyridin-3-yl)-3-((2-(3-isopropylphenyl)-6-(trifluoromethyl)pyridin-3-yl)methyl Urea

60. 1-((2-(3-(二甲胺基)苯基)-6-(三氟甲基)啶-3-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素 60. 1-((2-(3-(Dimethylamino)phenyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(6-(hydroxymethyl)pyridine -3-yl) urea

61. 1-(5-氯-6-(羥甲基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 61. 1-(5-Chloro-6-(hydroxymethyl)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl) Pyridin-3-yl)methyl)urea

62. 2-(6-(2-烴乙基)啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺 62. 2-(6-(2-Carboethyl)pyridin-3-yl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine- 3-yl)methyl)propanamide

63. 1-(6-(2-烴乙基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 63. 1-(6-(2-Carboethyl)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine- 3-yl)methyl)urea

64. 2-(6-((2-烴乙基)甲基)啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺 64. 2-(6-((2-Hydroxyethyl)methyl)pyridin-3-yl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl) Pyridin-3-yl)methyl)propanamide

65. 1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-3-(6-(甲基磺醯基甲基)啶-3-基)尿素 65. 1-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(6-(methylsulfonyl) Methyl)pyridin-3-yl)urea

66. 1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-3-(6-(2-(甲基磺醯基)乙基)啶-3-基)尿素 66. 1-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(6-(2-(methyl) Sulfhydryl)ethyl)pyridin-3-yl)urea

67. 1-(5-氟-6-(2-(甲基磺醯基)乙基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 67. 1-(5-Fluoro-6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)- 6-(trifluoromethyl)pyridin-3-yl)methyl)urea

68. 1-((6-環丙基-2-(4-甲基哌啶-1-基)啶-3-基)甲基)-3-(5-氟-6-(2-(甲基磺醯基)乙基)啶-3-基)尿素 68. 1-((6-Cyclopropyl-2-(4-methylpiperidin-1-yl)pyridin-3-yl)methyl)-3-(5-fluoro-6-(2-(A) Sulfosyl)ethyl)pyridin-3-yl)urea

69. 1-(5-氟-6-(2-(甲基磺醯基)乙基)啶-3-基)-3-((2-(3-氟苯 基)-6-(三氟甲基)啶-3-基)甲基)尿素 69. 1-(5-Fluoro-6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)-3-((2-(3-fluorobenzene) -6-(trifluoromethyl)pyridin-3-yl)methyl)urea

70. N-((5-(3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)脲基)啶-2-基)甲基)甲基磺醯胺 70. N-((5-(3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)ureido)pyridine- 2-yl)methyl)methylsulfonamide

71. N-((5-(3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)脲基)啶-2-基)甲基)硫醯二胺 71. N-((5-(3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)ureido)pyridine- 2-yl)methyl)thioindole

72. N-((5-(3-(2-(環己氧基)-4-(三氟甲基)苄基)脲基)啶-2-基)甲基)硫醯二胺 72. N-((5-(3-(2-(Cyclohexyloxy)-4-(trifluoromethyl)benzyl)ureido)pyridin-2-yl)methyl)thioindolediamine

73. N-((5-(3-((2-間-甲苯基-6-(三氟甲基)啶-3-基)甲基)脲基)啶-2-基)甲基)硫醯二胺 73. N-((5-(3-((2-m-tolyl-6-(trifluoromethyl))-3-yl)methyl)ureido)pyridin-2-yl)methyl)sulfide Decane diamine

74. 5-(1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺基)-1-氧代丙烷-2-基)吡啶醯胺 74. 5-(1-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methylamino)-1-oxopropane-2 -based pyridylamine

75. 5-(1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺基)-1-氧代丙烷-2-基)-N-苯基吡啶醯胺 75. 5-(1-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methylamino)-1-oxopropane-2 -yl)-N-phenylpyridinium

76. 5-(1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺基)-1-氧代丙烷-2-基)-N-苯基嘧啶-2-羧醯胺 76. 5-(1-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methylamino)-1-oxopropane-2 -yl)-N-phenylpyrimidine-2-carboxamide

77. 5-(1-((2-(乙胺)-6-(三氟甲基)啶-3-基)甲胺基)-1-氧代丙烷-2-基)-N-(4-氟苯基)嘧啶-2-羧醯胺 77. 5-(1-((2-(ethylamine)-6-(trifluoromethyl))-3-yl)methylamino)-1-oxopropan-2-yl)-N-(4) -fluorophenyl)pyrimidine-2-carboxamide

78. N-(4-氟苯基)-5-(1-氧代-1-((2-(咯啶-1-基)-6-(三氟甲基)啶-3-基)甲胺基)丙烷-2-基)嘧啶-2-羧醯胺 78. N-(4-Fluorophenyl)-5-(1-oxo-1-((2-(rhodindin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)) Amino)propan-2-ylpyrimidine-2-carboxamide

79. N-(4-氟苯基)-5-(1-氧代-1-((2-(哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺基)丙烷-2-基)嘧啶-2-羧醯胺 79. N-(4-Fluorophenyl)-5-(1-oxo-1-((2-(piperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)) Amino)propan-2-ylpyrimidine-2-carboxamide

80. N-(4-氟苯基)-5-(1-((2-嗎啉基-6-(三氟甲基)啶-3-基)甲胺基)-1-氧代丙烷-2-基)嘧啶-2-羧醯胺 80. N-(4-Fluorophenyl)-5-(1-((2-morpholinyl-6-(trifluoromethyl)pyridin-3-yl)methylamino)-1-oxopropane- 2-yl)pyrimidine-2-carboxamide

81. N-(4-氟苯基)-5-(1-氧代-1-((2-間-甲苯基-6-(三氟甲基)啶-3-基)甲胺基)丙烷-2-基)嘧啶-2-羧醯胺 81. N-(4-Fluorophenyl)-5-(1-oxo-1-((2-m-tolyl-6-(trifluoromethyl))-3-yl)methylamino)propane -2-yl)pyrimidine-2-carboxamide

82. 5-(1-氧代-1-((2-(哌啶-1-基甲基)-6-(三氟甲基)啶-3-基)甲胺 基)丙烷-2-基)-N-(4-(三氟甲基)苯基)嘧啶-2-羧醯胺 82. 5-(1-Oxo-1-((2-(piperidin-1-ylmethyl)-6-(trifluoromethyl))-3-yl)methylamine Propyl-2-yl)-N-(4-(trifluoromethyl)phenyl)pyrimidine-2-carboxamide

83. 1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-3-(6-(四氫-2H-吡喃-4-基)啶-3-基)尿素 83. 1-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(6-(tetrahydro-2H- Pyran-4-yl)pyridin-3-yl)urea

84. 2-(5-胺基-6-溴啶-2-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺 84. 2-(5-Amino-6-bromodin-2-yl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine-3 -yl)methyl)propanamide

85. 2-(6-(2-羥乙胺)啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺 85. 2-(6-(2-Hydroxyethylamine)-3-yl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine- 3-yl)methyl)propanamide

86. 1-(6-(2-羥乙胺)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 86. 1-(6-(2-Hydroxyethylamine)-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine- 3-yl)methyl)urea

87. 2-(6-(2-甲氧基乙胺)啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺 87. 2-(6-(2-Methoxyethylamine)pyridin-3-yl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl) Pyridin-3-yl)methyl)propanamide

88. 1-(6-(2-甲氧基乙胺)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 88. 1-(6-(2-Methoxyethylamine)-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl) Pyridin-3-yl)methyl)urea

89. 2-(6-((2-烴乙基)(甲基)胺)啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺 89. 2-(6-((2-Hydroxyethyl)(methyl)amine)pyridin-3-yl)-N-((2-(4-methylpiperidin-1-yl)-6-( Trifluoromethyl)pyridin-3-yl)methyl)propanamide

90. 1-(6-((2-烴乙基)(甲基)胺)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 90. 1-(6-((2-Hydroxyethyl)(methyl)amine)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-() Trifluoromethyl)pyridin-3-yl)methyl)urea

91. 1-(6-((2-甲氧基乙基)(甲基)胺)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 91. 1-(6-((2-Methoxyethyl)(methyl)amine)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6 -(trifluoromethyl)pyridin-3-yl)methyl)urea

92. N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-2-(6-(甲基磺醯胺)啶-3-基)丙醯胺 92. N-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(6-(methylsulfonamide) Pyridin-3-yl)propanamide

93. N-(5-(3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)脲基)啶-2-基)甲基磺醯胺 93. N-(5-(3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)ureido)pyridine-2 -yl)methylsulfonamide

94. N-(5-(3-((6-環丙基-2-(4-甲基哌啶-1-基)啶-3-基)甲基)脲基)啶-2-基)甲基磺醯胺 94. N-(5-(3-((6-Cyclopropyl-2-(4-methylpiperidin-1-yl))-3-yl)methyl)ureido)-2-yl) Methionamide

95. 2-(6-(甲基磺醯胺)啶-3-基)-N-((2-嗎啉基-6-(三氟甲基)啶-3- 基)甲基)丙醯胺 95. 2-(6-(Methylsulfonamide)-3-yl)-N-((2-morpholinyl-6-(trifluoromethyl)pyridine-3- Methyl)propanamide

96. 2-(5-氟-6-(甲基磺醯胺)啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺 96. 2-(5-Fluoro-6-(methylsulfonamide)-3-yl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl) Pyridin-3-yl)methyl)propanamide

97. 2-(5-甲氧基-6-(甲基磺醯胺)啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺 97. 2-(5-Methoxy-6-(methylsulfonamide)-3-yl)-N-((2-(4-methylpiperidin-1-yl)-6-(III Fluoromethyl)pyridin-3-yl)methyl)propanamide

98. N-(5-(1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)苯甲醯胺 98. N-(5-(1-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methylamino)-1-oxo Propane-2-yl)pyridin-2-yl)benzamide

99. 4-氯-N-(5-(1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)苯甲醯胺 99. 4-Chloro-N-(5-(1-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl))-3-yl)methylamino)- 1-oxopropan-2-yl)pyridin-2-yl)benzamide

100. 4-氯-N-(5-(1-(2-(4-甲基哌啶-1-基)-4-(三氟甲基)苄基胺基)-1-氧代丙烷-2-基)啶-2-基)苯甲醯胺 100. 4-Chloro-N-(5-(1-(2-(4-methylpiperidin-1-yl)-4-(trifluoromethyl)benzylamino)-1-oxopropane- 2-yl)pyridin-2-yl)benzamide

101. 4-氯-N-(5-(1-(2-(環己基硫代)-4-(三氟甲基)苄基胺基)-1-氧代丙烷-2-基)啶-2-基)苯甲醯胺 101. 4-Chloro-N-(5-(1-(2-(cyclohexylthio)-4-(trifluoromethyl)benzylamino)-1-oxopropan-2-yl)pyridine- 2-yl)benzamide

102. N-(5-(1-(4-三級丁基-2-(環己基硫代)苄基胺基)-1-氧代丙烷-2-基)啶-2-基)-4-氯苯甲醯胺 102. N-(5-(1-(4-Tributyl butyl-2-(cyclohexylthio)benzylamino)-1-oxopropan-2-yl)pyridin-2-yl)-4 Chlorobenzylamine

103. 4-氯-N-(5-(1-(2-(環戊基氧基)-4-(三氟甲基)苄基胺基)-1-氧代丙烷-2-基)啶-2-基)苯甲醯胺 103. 4-Chloro-N-(5-(1-(2-(cyclopentyloxy)-4-(trifluoromethyl)benzylamino)-1-oxopropan-2-yl)pyridine -2-yl)benzamide

104. 1-(6-(二甲胺基)-5-(三氟甲基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 104. 1-(6-(Dimethylamino)-5-(trifluoromethyl)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6- (trifluoromethyl)pyridin-3-yl)methyl)urea

105. 1-(6-(氮雜環丁烷-1-基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 105. 1-(6-(Azetidin-1-yl)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl) Pyridin-3-yl)methyl)urea

106. 1-(6-(氮雜環丁烷-1-基)-5-氟啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 106. 1-(6-(Azetidin-1-yl)-5-fluoropyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6- (trifluoromethyl)pyridin-3-yl)methyl)urea

107. 1-(6-(氮雜環丁烷-1-基)-5-甲氧啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 107. 1-(6-(Azetidin-1-yl)-5-methoxy-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6 -(trifluoromethyl)pyridin-3-yl)methyl)urea

108. 1-(6-(3-羥基氮雜環丁烷-1-基)啶-3-基)-3-((2-(4-甲基哌啶 -1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 108. 1-(6-(3-Hydroxyazetidin-1-yl)pyridin-3-yl)-3-((2-(4-methylpiperidine) -1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea

109. 1-(6-(3-羥基氮雜環丁烷-1-基)啶-3-基)-3-((2-戊基-6-(三氟甲基)啶-3-基)甲基)尿素 109. 1-(6-(3-Hydroxyazetidin-1-yl)pyridin-3-yl)-3-((2-pentyl-6-(trifluoromethyl))-3-yl Methyl) urea

110. 1-(6-(3-羥基氮雜環丁烷-1-基)啶-3-基)-3-((2-間-甲苯基-6-(三氟甲基)啶-3-基)甲基)尿素 110. 1-(6-(3-Hydroxyazetidin-1-yl)pyridin-3-yl)-3-((2-m-tolyl-6-(trifluoromethyl)pyridine-3 -based)methyl)urea

111. 1-(6-(3-羥基氮雜環丁烷-1-基)啶-3-基)-3-((2-甲氧基-6-(三氟甲基)啶-3-基)甲基)尿素 111. 1-(6-(3-Hydroxyazetidin-1-yl)pyridin-3-yl)-3-((2-methoxy-6-(trifluoromethyl)pyridine-3- Methyl)urea

112. 1-(6-(3-羥基氮雜環丁烷-1-基)啶-3-基)-3-((2-異丁氧基-6-(三氟甲基)啶-3-基)甲基)尿素 112. 1-(6-(3-Hydroxyazetidin-1-yl)pyridin-3-yl)-3-((2-isobutoxy-6-(trifluoromethyl)pyridine-3 -based)methyl)urea

113. 1-((2-(環丁基甲氧基)-6-(三氟甲基)啶-3-基)甲基)-3-(6-(3-羥基氮雜環丁烷-1-基)啶-3-基)尿素 113. 1-((2-(Cyclobutylmethoxy)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(6-(3-hydroxyazetidin-1- Pyridin-3-yl)urea

114. 1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-3-(6-(咯啶基-1-基)啶-3-基)尿素 114. 1-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(6-(pyridyl)-1 -yl)pyridin-3-yl)urea

115. 1-(5-氟-6-(咯啶-1-基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 115. 1-(5-Fluoro-6-(l-pyridin-1-yl)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoro) Methyl)pyridin-3-yl)methyl)urea

116. 1-(5-甲氧基-6-(咯啶-1-基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 116. 1-(5-Methoxy-6-(l-pyridin-1-yl)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-( Trifluoromethyl)pyridin-3-yl)methyl)urea

117.(S)-1-(6-(3-羥基咯啶-1-基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 117. (S)-1-(6-(3-Hydroxypyridin-1-yl)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6- (trifluoromethyl)pyridin-3-yl)methyl)urea

118.(R)-1-(6-(3-羥基咯啶-1-基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 118. (R)-1-(6-(3-Hydroxylpyridin-1-yl)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-) (trifluoromethyl)pyridin-3-yl)methyl)urea

119. 1-(6-羥基啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 119. 1-(6-Hydroxypyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl Urea

120. 2-(6-甲氧基啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺 120. 2-(6-Methoxypyridine-3-yl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl) Methyl) acrylamide

121. 1-(2-甲氧基嘧啶-5-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲 基)啶-3-基)甲基)尿素 121. 1-(2-Methoxypyrimidin-5-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl) Pyridin-3-yl)methyl)urea

122. 1-(2-環丁氧嘧啶-5-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 122. 1-(2-Cyclobutoxypyrimidin-5-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl) Methyl) urea

123. 1-(6-(2-羥基乙氧基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 123. 1-(6-(2-Hydroxyethoxy)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine -3-yl)methyl)urea

124. 1-(6-(2-甲氧乙氧基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 124. 1-(6-(2-Methoxyethoxy)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl) Pyridin-3-yl)methyl)urea

125. 1-(6-(2-羥基乙氧基)啶-3-基)-3-((2-間-甲苯基-6-(三氟甲基)啶-3-基)甲基)尿素 125. 1-(6-(2-Hydroxyethoxy)pyridin-3-yl)-3-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl) Urea

126. 1-(5-(羥甲基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 126. 1-(5-(Hydroxymethyl)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine-3- Methyl)urea

127. 1-(5-(羥甲基)啶-2-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 127. 1-(5-(Hydroxymethyl)pyridin-2-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine-3- Methyl)urea

128. 1-(3-(羥甲基)啶-4-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 128. 1-(3-(Hydroxymethyl)pyridin-4-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine-3- Methyl)urea

129. 1-(6-(1,2-二烴乙基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 129. 1-(6-(1,2-Dihydroethylethyl)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl) Pyridin-3-yl)methyl)urea

130. 1-((2-(3-氟苯基)-6-(三氟甲基)啶-3-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素，及 130. 1-((2-(3-Fluorophenyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(6-(2-hydroxyethylamine)pyridine-3- Base) urea, and

131. 1-((5'-氯-6-(三氟甲基)-2,3'-雙啶-3-基)甲基)-3-(6-(2-羥乙胺)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。 131. 1-((5'-Chloro-6-(trifluoromethyl)-2,3'-bispyridin-3-yl)methyl)-3-(6-(2-hydroxyethylamine)pyridine- 3-base urea Optionally, 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。 Further, according to the compound of the present invention, it is preferred to cause 50% of capsaicin to be substituted, which is detected by a fluorescent imaging plate reader (FLIPR) and is present in CHO K1 cells at a concentration of 100 nM. Medium cell line 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 Even better, with less than 10 nM.

於此方法中，鈣離子流入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 calcium ion influx 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). Instrumentation (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，則壓製成錠劑、注入膠囊或懸浮於液體，並以此形式投藥。 The pharmaceutical composition according to the invention may be a liquid, semi-solid or solid pharmaceutical agent Type, for example, injection, drops, juice, syrup, spray, suspension, lozenge, patch, capsule, plaster, stopper, ointment, emulsion, lotion, gel, water emulsion, gas The aerosol or the compound form, for example, in the form of pellets or granules, if appropriate, is compressed into a tablet, injected into a capsule or suspended in a liquid, and administered 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、糖衣藥丸、膠囊、顆粒、丸劑、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, pills, drops, juices and syrups, preferably for oral use; solutions, suspensions, easy-to-restore dry preparations and sprays for non-oral, topical 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 mg/kg，以0.05至75 mg/kg較佳，以0.05至50 mg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。 According to a conventional manner medicament of the present invention compositions are known in the in art who belongs, with the aid of instruments, methods and processes of the preparation from, e.g., Remington's Pharmaceutical Sciences (Remington's Pharmaceutical Sciences), ARGennaro ( ed.), 17th Edition, 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 particularly preferably from 0.05 to 50 mg of the compound according to the invention relative to the body weight of the patient (per kilogram).

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，較適用之疼痛係選自由急性疼痛、慢性疼痛、神經性疼痛、內臟疼痛與關節疼痛組成之群組、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(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 for the treatment and/or prevention of one or more disorders and/or diseases selected from pain, and the more suitable pain is selected from acute pain, chronic pain, neuropathic pain, visceral pain. Groups with joint pain, hyperalgesia, allodynia, burning pain, migraine, depression, nervousness, axonal injury, neurodegenerative diseases, selected from multiple sclerosis, Alzheimer's disease, Parkinson's disease The group consisting of Hunter's disease and Huntington's disease is better, cognitive dysfunction, better cognitive deficits, especially memory disorders, epilepsy, respiratory diseases, selected from the group consisting of asthma, bronchitis and inflammation of the lungs. Better group, cough, urinary incontinence, overactive bladder (OAB), gastrointestinal disorders and / or injury, duodenal ulcer, gastric ulcer, irritating intestinal syndrome, stroke, eye irritation, skin irritation, neuropathic skin disease , allergic skin diseases, dryness, leukoplakia, herpes simplex, inflammation, inflammation of the intestines, eyes, bladder, skin or nasal mucosa, diarrhea, itching, Osteoporosis, arthritis, osteoarthritis, rheumatic diseases, abnormal diet, selected from the group consisting of bulimia, cachexia, anorexia and obesity, drug dependence, drug abuse, drug dependence Symptoms, drug tolerance, natural or synthetic opioids, drug dependence, drug abuse, drug dependence withdrawal symptoms, alcohol dependence, alcohol abuse, alcohol dependence withdrawal symptoms, for diuresis For inhibiting urinary sodium excretion, for influencing the cardiovascular system, for alertness, for treating wounds and/or burns, for treating nerve blockage, for lifting sexual desire, for regulating athletic activity, For anti-anxiety, for local anesthesia and/or inhibition of adverse side effects, 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, olvanil, arvanil, SDZ-249665, SDZ-249482, nuvanil and capsavanil. The group 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急性疼痛、慢性疼痛、神經性疼痛、內臟疼痛與關節疼痛組成之群組、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 the particularly suitable pain is selected from the group consisting of acute pain, chronic pain, neuropathic pain, visceral pain and joint pain. Groups, migraine, depression, neurodegenerative diseases, selected from a group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease, cognitive dysfunction, Better cognitive impairment, especially memory impairment, inflammation, inflammation of the intestine, eyes, bladder, skin or nasal mucosa, urinary incontinence, overactive bladder, drug dependence, drug abuse, drug dependence withdrawal symptoms, drugs Tolerance is produced by 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.

尤其，本發明因此另又涉及用於預防及/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急性疼痛、慢性疼痛、神經性疼痛、內臟疼痛與關節疼痛組成之群組、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(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。 In particular, the invention therefore relates to a substituted compound according to formula (I) for use in the prevention and/or treatment of disorders and/or diseases selected from pain, and, if appropriate, a compound according to formula (I) A substituted 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 disease, selected from a 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, post-stimulation group, stroke, eye irritation, skin irritation, neuropathic skin disease, allergic skin disease, dryness, white Symptoms, herpes simplex, inflammation, inflammation of the intestines, eyes, bladder, skin or nasal mucosa, diarrhea, itching, osteoporosis, arthritis, osteoarthritis, rheumatic diseases, abnormal diet, selected from Groups of bulimia, cachexia, anorexia and obesity are 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 treating wounds And/or burns, for the treatment of neurological blockade, for the promotion of libido, for the regulation of motor activity, for anxiolytics, for local anesthesia and/or for the inhibition of adverse side effects, selected from the use of vanilloid receptors 1 (VR1/TRPV1 receptor) agonist-induced fever, hypertension, and bronchoconstriction are preferably selected from the group consisting of capsaicin, cactus toxin, olvanil, and arva (ar) A group consisting of vanil), SDZ-249665, SDZ-249482, nuvanil and capsavanil 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急性疼痛、慢性疼痛、神經性疼痛、內臟疼痛與關節疼痛組成之群組、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(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 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) Inhibition of vanilloid receptor 1-(VR1/TRPV1) and/or eliciting vanilloid receptor 1-(VR1/TRPV1) is preferred, and further for preventing and/or treating at least in part by vanilloid receptor 1 The mediated disorder and/or disease, for example, selected from disorders and/or diseases consisting of pain, the more suitable pain is 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 defects, especially memory disorders, epilepsy, respiratory diseases, selected from the group consisting of asthma, bronchitis and lung inflammation, cough, urinary incontinence, Overactive bladder, stomach Disorders and/or injuries, duodenal ulcers, gastric ulcers, post-stimulation of pruritus, stroke, eye irritation, skin irritation, neuropathic skin diseases, allergic skin diseases, dryness, leukoplakia, herpes simplex, inflammation, Intestinal, eye, bladder, skin or nasal mucosa inflammation, diarrhea, itching, osteoporosis, arthritis, osteoarthritis, rheumatic diseases, abnormal diet, selected from bulimia, cachexia, anorexia Better with 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, for diuresis, for inhibition of urinary sodium excretion, for influencing the cardiovascular system, for alertness, for treatment Treating wounds and/or burns, for treating 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 The group consisting of VR1/TRPV1 receptor agonist-induced fever, hypertension, and bronchoconstriction is preferably selected from the group consisting of capsaicin, cactus toxin, olvanil, arvanil, A group consisting of SDZ-249665, SDZ-249482, nuvanil and capsavanil 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以選自由急性疼痛、慢性疼痛、神經性疼痛、內臟疼痛與關節疼痛組成之群組、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，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 modulating the vanilloid receptor 1-(VR1/TRPV1) to inhibit the vanilloid receptor 1-(VR1/TRPV1) and/or to stimulate the vanilloid receptor 1 (VR1/TRPV1) Preferably, and a method of treating and/or preventing a disorder and/or disease mediated by at least in part of the vanilloid receptor 1 in a mammal, preferably selected from the group consisting of disorders of pain and/or disease. 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 dysfunction, better cognitive deficits, especially Memory disorders, 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 ulcers, gastric ulcers, Post-stimulation 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, selected from the group consisting of bulimia, cachexia, anorexia and obesity, drug dependence, drug abuse, drug dependence Symptoms, drug tolerance, natural or synthetic opioids, drug dependence, drug abuse, drug dependence withdrawal symptoms, alcohol Dependence, alcohol abuse and alcohol dependence withdrawal symptoms, for diuresis, for inhibition of urinary sodium excretion, for affecting the cardiovascular system, for alertness, for treating wounds and/or burns, for treating nerve blockage For raising libido, for regulating motor activity, for anxiolytic, for local anesthesia and/or for inhibiting adverse side effects, selected from fever caused by the use of a vanilloid receptor 1 (VR1/TRPV1 receptor) agonist The group consisting of hypertension and bronchoconstriction is preferably selected from the group consisting of capsaicin, cactus toxin, olvanil, arvanil, SDZ-249665, SDZ-249482, nuvanil. Preferably, the group consisting of capsavanil comprises at least one compound according to formula (I) administered to the mammal in an effective amount.

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紮實驗模式(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， (II)其X、R1、R2、R3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，R4a、Y、A1、A2、A3、A4與A5各自具有前述意義其中一種意義，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X、R1、R2、R3、R4a、R4b、Y、A1、A2、A3、A4與A5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X、R1、R2、R3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X、R1、R2、R3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、A1、A2、A3、A4與A5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而X、R1、R2、R3、R4a、Y、A1、A2、A3、A4與A5及n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). (II) wherein X, R 1 , R 2 , R 3 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 Reaction with a compound of the formula (III) in the presence of a base, D = OH or Hal, Hal thereof represents a halogen to represent bromine or chlorine, and R 4a , Y, A 1 , A 2 , A 3 , A 4 and A 5 each have one of the aforementioned meanings, and Z represents CR 4b , wherein R 4b Having one of the foregoing 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 compound of formula (I) , Z represents CR 4b and X, R 1 , R 2 , R 3 , R 4a , R 4b , Y, A 1 , A 2 , A 3 , A 4 and A 5 and n have one of the aforementioned meanings; In at least one compound of the formula (II), Its X, R 1 , R 2 , R 3 and n have one of the aforementioned meanings, which are reacted to form a compound of the formula (IV) X, R 1 , R 2 , R 3 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 one 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 , A 1 , A 2 , A 3 , A 4 and A 5 have one of the aforementioned meanings, and Z represents N in a reaction medium, if appropriate, in the presence of at least one suitable coupling reagent Forming a compound of the formula (I), if appropriate, in the presence of at least one base, Z represents N and X, R 1 , R 2 , R 3 , R 4a , Y, A 1 , A 2 , A 3 , A 4 and A 5 and n have one of the aforementioned meanings.

上述通式(II)與(V)之化合物與上述通式(III)之羧酸進行反應，特別是與D=OH，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’-(3-二甲基胺基丙基)-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-基)-N,N,N‘,N‘-tetramethyluronium tetrafluoroborate)(TBTU)、N-羧苯並三唑(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-[(II) Methylamino)-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-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (O- (benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate) (TBTU), N-hydroxybenzotriazole Preferably, the group of (HOBt) and 1-hydroxy-7-azabenzotriazole (HOAt) is, if appropriate, in the presence of at least one organic base, Preferably, the group consisting of triethylamine, pyridine, dimethylaminopyridine, N-methylmorpholinyl and diisopropyl ether ethylamine is preferably at a temperature between -70 ° C and 100 ° C. Better in the middle.

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、二甲基胺基啶、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, preferably selected from the group consisting of triethylamine, dimethylaminopyridine, pyridine and diisopropylamine in the presence of an organic or inorganic base. Preferably, it is 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 2007/045462-A2、WO 2008/125342-A2與WO 2008/125337-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 method of preparing the compound is disclosed, for example, in WO 2007/045462-A2, WO 2008/125342-A2 and WO 2008/125337-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。 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 determine the optimal procedure for each condition by conducting a preliminary test. 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 processing steps applicable to the synthesis of the reaction sequence of the compounds according to the invention, and corresponding intermediate or final production Purification and/or separation of the material may be carried out partially or completely in an inert gas atmosphere.

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，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 a corresponding salt, preferably a physiologically compatible salt, for example, 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-oxoargonium Acid, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, α-lipoic acid, acetylglycine, horse Uric 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。 The substituted compounds according to the present invention and the corresponding stereoisomers, if appropriate, can be obtained by conventional methods known to those skilled in the art, such as the corresponding acid, corresponding base or salt of the compound. The form is preferably in the form of its hydrate.

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 methods, especially at normal or higher pressures The liquid chromatography method is preferably carried out by medium pressure chromatography (MPLC) and high performance liquid chromatography (HPLC), and fractional crystallisation may also 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j1，可利用熟知此技術領域者已知之方式，若適當，於一偶合試劑及/或鹼存在之條件下，將化合物(II)轉換為化合物 (IV)，例如使用氯甲酸苯酯。除本文所揭露之以氯甲酸苯酯製備非對稱尿素之方法外，若適當，亦可使用其它熟知此技術領域者熟悉、基於使用活性碳酸衍生物或異氰酸酯基之方法。 In step j1 , compound (II) can be converted to compound (IV), for example, using phenyl chloroformate, in a manner known to those skilled in the art, if appropriate, in the presence of a coupling reagent and/or base. In addition to the methods of preparing asymmetric ureas with phenyl chloroformate disclosed herein, other methods well known to those skilled in the art, based on the use of reactive carbonic acid derivatives or isocyanate groups, may be used as appropriate.

步驟j2中，可將胺轉換為尿素化合物(I)(其中，Z=N)。可藉由熟知此技術領域者熟悉之方法，將其與(IV)進行反應而達成，若適當，於一鹼基存在之條件條件進行。 In step j2 , the amine can be converted to the urea compound (I) (where Z = N). This can be achieved by reacting it with (IV) by methods well known to those skilled in the art, and if appropriate, under conditions in which one base is present.

於步驟j3中，可將胺(II)轉換為醯胺(I)(其中，A=C-R4b)。例如，可藉由熟知此技術領域者熟悉之方法，將其與通式(III)之酸性鹵化物(D=Hal)，以氯較佳，進行反應而達成，若適當，於一鹼基存在之條件下進行；或藉由將其與一通式(III)之酸(D=OH)進行反應而達成，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(HATU)或1,1’-羰基二咪唑(CDI)，若適當，可添加一鹼基。此外，可藉由熟知此技術領域者熟悉之方法，將胺(II)與化合物(IIIa) 進行反應，而將其將轉換為醯胺(I)(其中，Z=C-R4b)，若適當，於一鹼基存在之條件進行反應。 In step j3 , the amine (II) can be converted to the guanamine (I) (wherein A = CR 4b ). For example, it can be achieved by reacting it with an acid halide of the formula (III) (D=Hal), preferably by chlorine, by a method well known to those skilled in the art, and if appropriate, in one base. To be carried out under the conditions; or by reacting it with an acid of the formula (III) (D=OH), if appropriate, in the presence of a suitable coupling reagent, for example, N-[(2) Methylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-mene]-N-methylmethaneammonium hexafluorophosphate N-oxide (HATU Or 1,1 '-carbonyldiimidazole (CDI), if appropriate, one base may be added. In addition, the amine (II) and the compound (IIIa) can be obtained by methods well known to those skilled in the art. The reaction is carried out, and it is converted into the guanamine (I) (wherein, Z = CR 4b ), and if appropriate, the reaction is carried out in the presence of one base.

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

根據通式(I)之化合物，其中，Z=N，可進一步根據通用反應 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 according to the reaction sequence of the general reaction scheme 2:

於步驟j4，可藉由熟知此技術領域者熟悉之方法，將化合物(V)轉換為化合物(Va)，其中，Z=N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。除本文所揭露之以氯甲酸苯酯製備非對稱尿素之方法外，若適當，亦可使用其它熟知此技術領域者熟悉、基於使用活性碳酸衍生物或異氰酸酯基之方法。 In step j4 , compound (V) can be converted to compound (Va) by methods well known to those skilled in the art, wherein Z = N, for example, using phenyl chloroformate, if appropriate, in a coupling reagent and/or It is carried out under the condition that one base is present. In addition to the methods of preparing asymmetric ureas with phenyl chloroformate disclosed herein, other methods well known to those skilled in the art, based on the use of reactive carbonic acid derivatives or isocyanate groups, may be used as appropriate.

於步驟j5，可將胺(II)轉換為尿素化合物(I)(其中，Z=N)。其可藉由熟知此技術領域者熟悉之方法，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 j5 , the amine (II) can be converted to the urea compound (I) (where Z = N). This can be achieved by reacting it with (Va) by methods 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進行反應步驟j1至j5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; The author's team, Compendium of Organic Synthetic Methods, Wiley & Sons, infers a method well known to those skilled in the art for performing reaction steps j1 to j5 . 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.

實例Instance

「等量(equivalents)(eq)」係指等量莫耳，「RT(room temperature)」係指室溫，「M」與「N」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)" means the same amount of moles, "RT (room temperature)" means room temperature, "M" and "N" means the concentration in mol/l, "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。 The yield of the prepared compounds was not optimized.

所有溫度皆未經校正。 All temperatures are uncorrected.

所有未明確描述之起始原料若非商購取得(供應商之詳細資料，如Acros、Avocado、Aldrich、Bachem、Fluka、Lancaster、Maybridge、Merck、Sigma、TCI、Oakwood等，可於MDL之Symyx®化學物品資料庫(Symyx® Available Chemicals Database of MDL)，San Ramon，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，荷蘭阿姆斯特丹查取)，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 explicitly described are commercially available (Supplier details such as Acros, Avocado, Aldrich, Bachem, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI, Oakwood, etc., available in MDL's Symyx® Chemistry) The Synjx® Available Chemicals Database of MDL, obtained from San Ramon, USA, has been accurately described in the professional literature (for example, experimental guidelines are available from Elsevier's Reaxys® database). It is available in Amsterdam, the Netherlands, or can be prepared by 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(0.0-0-0.063 mm)。薄層層析測試係使用E.Merck，Darmstadt之高效薄膜層析預塗層板，矽膠60 F 254進行。 The stationary phase for column chromatography was E. Merck, Darmstadt's silicone 60 (0.0-0-0.063 mm). The TLC test was performed using a high performance thin film chromatography precoated plate from E. Merck, Darmstadt, Silicone 60 F 254.

溶媒、流動溶媒或層析測試之混合比例分別係以體積/體積表示。 The mixing ratios of the vehicle, flow solvent or chromatographic test are expressed in volume/volume, respectively.

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

示範性化合物5至10、13、14、19、22、24、31、32、38、39至42、47、49、55、67、74至81、84至92、95至99、104至105、107至108、114、116至118、120、123至124與126-131係以本文描述之方法製備而成。其它示範性化合物係以類似方法製備而成。熟知此技術領域者明白獲得一特定示範性化合物需使用之方法及材料。 Exemplary Compounds 5 to 10, 13, 14, 19, 22, 24, 31, 32, 38, 39 to 42, 47, 49, 55, 67, 74 to 81, 84 to 92, 95 to 99, 104 to 105 107 to 108, 114, 116 to 118, 120, 123 to 124 and 126-131 are prepared in the manner described herein. Other exemplary compounds were prepared in a similar manner. Those skilled in the art are aware of the methods and materials needed to obtain a particular exemplary compound.

實例6之合成：Synthesis of Example 6:

N-((2-(3-氯-4-氟苯基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺 N-((2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-2-yl)acetamide

步驟1：於-10℃，將乙基乙烯基醚(7.5g，1 mol)逐滴加至經攪拌、以二氯甲烷(75 mL)溶解之4-二甲基胺基啶(0.1g，1.0 mmol)及三氟乙酸酐(23.2g，1.1 mol)溶液。將該反應混合物於0℃攪拌16小時，隨後將其加溫至25至30℃。薄層層析法顯示起始原料被完全消耗。隨後以水(2 x 60 mL)及碳酸氫鈉溶液(2 x 25 mL)，及最後以飽和之氟化鈉溶液(1 x 30 mL)清洗有機層。將清洗後之有機層以無水硫酸鎂乾燥，並於較低壓力下濃縮，以獲得深褐色之油性殘留物。最後，將該殘留物蒸餾出，以獲得一無色液態化合物(14.5 g，82%)。 Step 1: Ethyl vinyl ether (7.5 g, 1 mol) was added dropwise at -10 °C to 4-dimethylamididine (0.1 g, dissolved in dichloromethane (75 mL). 1.0 mmol) and a solution of trifluoroacetic anhydride (23.2 g, 1.1 mol). The reaction mixture was stirred at 0 °C for 16 hours and then allowed to warm to 25 to 30 °C. Thin layer chromatography showed complete consumption of the starting material. The organic layer was then washed with water (2 x 60 mL) and sodium bicarbonate solution (2 x 25 mL) and finally with saturated sodium fluoride solution (1 x 30 mL). The washed organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a dark brown oily residue. Finally, the residue was distilled to give a colorless liquid compound (14.5 g, 82%).

步驟2：於10至15℃，將氫化鈉(4.12 g，60%，0.13 mol)分次加至以1,4-二氧陸圜(70 mL)溶解之2-氰基乙醯胺(7.25 g，0.086 mol)溶液中。添加後，將其於周圍溫度攪拌30分鐘。將以1,4-二 氧陸圜(70 mL)溶解之(E)-4-乙氧基-1,1,1-三氟-3-丁烯-2-酮(14.5 g，0.086 mol)溶液逐滴加入該混合物。添加完成後，將產生之溶液平緩地回流22小時。一固體即會於該混合物中分離出。將該混合物冷卻至周圍溫度，並以垂熔漏斗過濾。以2 L之1,4-二氧陸圜清洗該殘留物。將清洗後之固體以水溶解，並將其以4N之鹽酸(200 mL)酸化。以醋酸乙酯(3 x 75 mL)萃取該混合物。以飽和之氯化鈉溶液(75 mL)清洗整個醋酸乙酯層，最後以硫酸鎂乾燥。於較低壓力移除有機溶媒後，即可得到黃色固體(11 g，68%)。 Step 2: Sodium hydride (4.12 g, 60%, 0.13 mol) was added in portions to 2-cyanoacetamide (7.25) dissolved in 1,4-dioxane (70 mL) at 10 to 15 °C. g, 0.086 mol) in solution. After the addition, it was stirred at ambient temperature for 30 minutes. (E)-4-Ethoxy-1,1,1-trifluoro-3-buten-2-one (14.5 g, 0.086 mol) dissolved in 1,4-dioxane (70 mL) The solution was added dropwise to the mixture. After the addition was completed, the resulting solution was gently refluxed for 22 hours. A solid will separate out of the mixture. The mixture was cooled to ambient temperature and filtered through a funnel. The residue was washed with 2 L of 1,4-dioxane. The washed solid was dissolved in water and acidified with 4N hydrochloric acid (200 mL). The mixture was extracted with ethyl acetate (3 x 75 mL). The entire ethyl acetate layer was washed with a saturated sodium chloride solution (75 mL) and dried over magnesium sulfate. After removal of the organic solvent at lower pressure, a yellow solid (11 g, 68%) was obtained.

步驟3：將經攪拌、以二氯甲烷(50 mL)溶解之2-羥基-6-(三氟甲基)菸鹼甲腈(10 g，53.19 mmol)溶液冷卻至0至5℃。於該溶液中添加三乙胺(11 mL，79.78 mmol)，並於0至5℃攪拌30分鐘。於0至5℃將三氟甲磺酸酐(19 mL，106.38 mmol)逐滴加入該混合物，並將該混合物於室溫攪拌16小時。薄層層析法顯示起始原料被完全消耗。將該反應混合物以二氯甲烷稀釋，並以水(2 x 250 mL)清洗有機部分。將清洗後之有機層以無水硫酸鎂乾燥，並於較低壓力濃縮，以獲得粗製產物；以管柱色層分析法(矽膠：100至200網目(mesh)；溶析液：存在於正己烷之10%醋酸乙酯)純化該粗製產物，以獲得純3-氰基-6-(三氟甲基)啶-2-基三氟甲磺酸(12.5 g，73%)。 Step 3: A solution of 2-hydroxy-6-(trifluoromethyl)nicotinonitrile (10 g, 53.19 mmol) dissolved in dichloromethane (50 mL) was cooled to 0 to 5 °C. Triethylamine (11 mL, 79.78 mmol) was added to this solution and stirred at 0 to 5 ° C for 30 min. Trifluoromethanesulfonic anhydride (19 mL, 106.38 mmol) was added dropwise to the mixture at 0 to 5 ° C, and the mixture was stirred at room temperature for 16 hr. Thin layer chromatography showed complete consumption of the starting material. The reaction mixture was diluted with dichloromethane and the organic portion was washed with water (2×250 mL). The washed organic layer is dried over anhydrous magnesium sulfate and concentrated at a lower pressure to obtain a crude product; by column chromatography (gel: 100 to 200 mesh; eluent: present in n-hexane The crude product was purified by 10% ethyl acetate to afford pure 3-cyano-6-(trifluoromethyl)pyridin-2-yltrifluoromethanesulfonic acid (12.5 g, 73%).

步驟4：於一500 mL之圓底燒瓶中，將3-氰基-6-(三氟甲基)啶-2-基三氟甲磺酸(12 g，37.48 mmol)以甲苯(70 mL)溶解，並添加4-氟-3-氯硼酸(7.48 g，44.97 mmol)、碳酸鈉水溶液(2M，75 mL)及四(三苯基膦基)鈀(0)(2.16 g，1.87 mmol)，最後以氮氣沖洗該系統。將反應混合物加熱至100℃，並於該溫度攪拌4小時。薄層層析法顯示起始原料被完全消耗。將該反應混合物冷卻，以水(300 mL)稀釋，並以存在於正己烷之20%醋酸乙酯(2 x 200 mL)萃取。 以水(200 mL)及飽和之氯化鈉溶液(200 mL)清洗該混合有機層。以無水硫酸鎂將其乾燥，並於較低壓力濃縮。以管柱色層分析法(矽膠1：100至200網目；溶析液：存在於正己烷之5%醋酸乙酯)純化此粗製產物，以獲得2-(3-氯-4-氟苯基)-6-(三氟甲基)菸鹼甲腈(9.2 g，82%)。 Step 4: 3-cyano-6-(trifluoromethyl)pyridin-2-yltrifluoromethanesulfonic acid (12 g, 37.48 mmol) in toluene (70 mL) in a 500 mL round bottom flask Dissolved and added 4-fluoro-3-chloroboric acid (7.48 g, 44.97 mmol), aqueous sodium carbonate (2M, 75 mL) and tetrakis(triphenylphosphino)palladium(0) (2.16 g, 1.87 mmol). Finally the system was flushed with nitrogen. The reaction mixture was heated to 100 ° C and stirred at this temperature for 4 hours. Thin layer chromatography showed complete consumption of the starting material. The reaction mixture was cooled, diluted with water (300 mL) andEtOAcEtOAc The mixed organic layer was washed with water (200 mL) and saturated sodium chloride solution (200 mL). It was dried over anhydrous magnesium sulfate and concentrated at a lower pressure. The crude product was purified by column chromatography (p. 1 : 100 to 200 mesh; eluent: 5% ethyl acetate in n-hexane) to afford 2-(3-chloro-4-fluorophenyl). - 6-(Trifluoromethyl)nicotinonitrile (9.2 g, 82%).

步驟5：將2-(3-氯-4-氟苯基)-6-(三氟甲基)菸鹼甲腈(7.1 g，23.66 mmol)以無水四氫呋喃(70 mL)溶解並將其冷卻，於0至5℃之氮氣氣氛下添加甲硼烷-二甲硫(3.41 mL，35.44 mmol)。隨後將該反應混合物回流20小時。於低溫狀態以甲醇(6 mL)對多餘之甲硼烷-二甲硫進行淬火反應，隨後添加二碳酸酯二叔丁酯(10.86 mL，47.32 mmol)，並於周圍溫度攪拌1小時。薄層層析法顯示起始原料被完全消耗。將有機揮發物濃縮，以獲得粗製產物；以管柱色層分析法(矽膠：100至200網目；溶析液：存在於正己烷之5%醋酸乙酯)純化產物，以獲得一白色固體(5.27 g，55%)。 Step 5: Dissolve 2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)nicotinonitrile (7.1 g, 23.66 mmol) in anhydrous tetrahydrofuran (70 mL) and cool. Borane-dimethyl sulfide (3.41 mL, 35.44 mmol) was added under a nitrogen atmosphere at 0 to 5 °C. The reaction mixture was then refluxed for 20 hours. The excess borane-dimethyl sulfide was quenched with methanol (6 mL) at low temperature, followed by the addition of di-tert-butyl dicarbonate (10.86 mL, 47.32 mmol) and stirred at ambient temperature for 1 hour. Thin layer chromatography showed complete consumption of the starting material. The organic volatiles were concentrated to give a crude product; the product was purified by column chromatography (eluent: 100 to 200 mesh; eluent: 5% ethyl acetate in n-hexane) to afford a white solid ( 5.27 g, 55%).

步驟6：於低溫狀態，將1,4-二氧陸圜-氯化氫(10 mL)加至經攪拌、溶解於1,4-二氧陸圜(5 mL)之三級丁基(2-(3-氯-4-氟苯基)-6-(三氟甲基)啶-3-基)氨基甲酸甲酯(5.27 g，13.04 mmol)溶液，並將該反應混合物攪拌12小時。將該反應混合物於較低壓力濃縮，並以甲醇共同蒸餾三次，將所得之固體以垂熔漏斗過濾，再以存在於正己烷之10%醋酸乙酯清洗，以獲得純(2-(3-氯-4-氟苯基)-6-(三氟甲基)啶-3-基)甲胺鹽酸鹽(4.14 g，93%)。 Step 6: Add 1,4-dioxane-hydrogen chloride (10 mL) to the tertiary butyl group (2-() ((()), stirred and dissolved in 1,4-dioxane (5 mL) at low temperature. A solution of methyl 3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyridin-3-yl)carbamate (5.27 g, 13.04 mmol). The reaction mixture was concentrated at a reduced pressure and then distilled three times with methanol. The obtained solid was filtered on a funnel and washed with 10% ethyl acetate in n-hexane to obtain pure (2-(3- Chloro-4-fluorophenyl)-6-(trifluoromethyl)pyridin-3-yl)methylamine hydrochloride (4.14 g, 93%).

1H NMR(二甲亞碸-d6，400 MHz)：δ 8.70(s，3H)；8.49(d，1H)；8.11(d，1H)；7.83(d，1H)；7.60(t，2H)；4.16(s，2H)。 1 H NMR (dimethyl sulfonium-d 6 , 400 MHz): δ 8.70 (s, 3H); 8.49 (d, 1H); 8.11 (d, 1H); 7.83 (d, 1H); 7.60 (t, 2H) ); 4.16 (s, 2H).

步驟7：將1-羥基苯並三唑水合物(0.0447 mL，0.329 mmol)、O-(1H-苯並三唑基-1-基)-N,N,N',N'-四甲基脲六氟磷酸鹽(0.106 g，0.329 mmol)及N-二異丙基乙胺(0.124 mL，0.658 mmol)加至經 攪拌、以四氫呋喃(2.5 mL)溶解之(2-(3-氯-4-氟苯基)-6-(三氟甲基)啶-3-基)甲胺鹽酸鹽(0.1 g，0.329 mmol)及2-(啶-2-基)醋酸(0.057 g，0.329 mmol)溶液中，並將該反應混合物攪拌24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網目；溶析液：存在於醋酸乙酯之10%甲醇)純化所得之固體，以獲得一白色固體(81 mg，58%)。 Step 7: 1-Hydroxybenzotriazole hydrate (0.0447 mL, 0.329 mmol), O-(1H-benzotriazolyl-1-yl)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (0.106 g, 0.329 mmol) and N-diisopropylethylamine (0.124 mL, 0.658 mmol) were added to the mixture (2-(3-chloro-4) dissolved in tetrahydrofuran (2.5 mL) -fluorophenyl)-6-(trifluoromethyl)pyridin-3-yl)methylamine hydrochloride (0.1 g, 0.329 mmol) and 2-(pyridin-2-yl)acetic acid (0.057 g, 0.329 mmol) In the solution, the reaction mixture was stirred for 24 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: 10% methanol in ethyl acetate) to obtain a white solid. (81 mg, 58%).

示範性化合物7至10、13、22與24係以相似之方式製備而成，示範性化合物25至27可以類似之方式製備而成。 Exemplary compounds 7 to 10, 13, 22 and 24 are prepared in a similar manner, and exemplary compounds 25 to 27 can be prepared in a similar manner.

實例14之合成：Synthesis of Example 14:

N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-3-基)丙醯胺 N-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-3-yl)propanamide

步驟1：於-78℃，將正丁基鋰(49 mL，2.04M，0.10 mol)加至經攪拌、以無水四氫呋喃(20 mL)溶解之二異丙胺(10.8 g，0.1 mol)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(20 mL)溶解之2-甲基啶(10 g，0.107 mol)。將該反應混合物於-78℃攪拌1小時。於-78℃，將二碳酸二叔丁酯(24 g，0.11 mol)加至該混合物中，並使其回溫至室溫2小時。以飽和銨 氯化物(50 mL)對該反應混合物進行淬火反應，將其以水稀釋(60 mL)，並以醋酸乙酯(3 x 80 mL)萃取。以飽和之氯化鈉溶液(50 mL)清洗整體有機層。以無水硫酸鎂將最終之有機層乾燥，並將其於較低壓力濃縮，以獲得粗製化合物；以管柱色層分析法(矽膠：100至200網目；溶析液：存在於正己烷之10%醋酸乙酯)將其純化，以獲得三級丁基2-(啶-2-基)乙酸鹽(6 g，29%)。 Step 1: To a solution of diisopropylamine (10.8 g, 0.1 mol) dissolved in anhydrous tetrahydrofuran (20 mL) was added to a solution of n-butyllithium (49 mL, 2.04 M, 0.10 mol). The reaction mixture was stirred for 30 minutes. To the solution was added dropwise 2-methylpyridine (10 g, 0.107 mol) dissolved in anhydrous tetrahydrofuran (20 mL). The reaction mixture was stirred at -78 °C for 1 hour. Di-tert-butyl dicarbonate (24 g, 0.11 mol) was added to the mixture at -78 ° C and allowed to warm to room temperature for 2 h. The reaction mixture was quenched with EtOAc (EtOAc) (EtOAc) The entire organic layer was washed with a saturated sodium chloride solution (50 mL). The final organic layer was dried over anhydrous magnesium sulfate and concentrated at a lower pressure to give a crude compound. </ RTI></RTI></RTI></RTI></RTI><RTIgt; It was purified by ethyl acetate (ethyl acetate) to give tributyl butyl 2-(pyridin-2-yl)acetate (6 g, 29%).

步驟2：於-78℃，將正丁基鋰(7.6 mL，2.04 M，15.55 mmol)加至經攪拌、以無水四氫呋喃(5 mL)溶解之二異丙胺(1.56 g，15.55 mmol)溶液中。將該溶液攪拌30分鐘。於該溶液中逐滴添加六甲基磷醯胺(2.78 g，15.55 mmol)及以無水四氫呋喃(5 mL)溶解之三級丁基2-(啶-2-基)乙酸鹽(3 g，15.55 mmol)。將該反應混合物於-78℃攪拌1小時。於-78℃，將以無水四氫呋喃(5 ml)溶解之硫酸二甲酯(1.95 g，15.55 mol)加至該溶液，並使其回溫至周圍溫度2小時。以飽和氯化銨溶液(30 mL)對該反應混合物進行淬火反應，將其以水(50 mL)稀釋，並以醋酸乙酯(2 x 50 mL)萃取。以飽和之氯化鈉溶液(50 mL)清洗整體有機層。將最終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；再以管柱色層分析法(矽膠：100至200網目；溶析液：存在於正己烷之5%醋酸乙酯)純化該粗製化合物，以獲得三級丁基2-(啶-2-基)丙酸(1.8 g，56%)。 Step 2: To a solution of diisopropylamine (1.56 g, 15.55 mmol), which was dissolved in anhydrous tetrahydrofuran (5 mL). The solution was stirred for 30 minutes. To the solution, hexamethylphosphoniumamine (2.78 g, 15.55 mmol) and tributyl butyl 2-(pyridine-2-yl)acetate (3 g, 15.55) dissolved in anhydrous tetrahydrofuran (5 mL) were added dropwise. Mm). The reaction mixture was stirred at -78 °C for 1 hour. Dimethyl sulfate (1.95 g, 15.55 mol) dissolved in anhydrous tetrahydrofuran (5 ml) was added to the solution at -78 ° C and allowed to warm to ambient temperature for 2 hours. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (30 mL), which was diluted with water (50 mL) and ethyl acetate (2 x 50 mL). The entire organic layer was washed with a saturated sodium chloride solution (50 mL). The final organic layer was dried over anhydrous magnesium sulfate and concentrated at a lower pressure to obtain a crude compound; and then subjected to column chromatography (gel: 100 to 200 mesh; eluent: 5% acetic acid in n-hexane) The crude compound was purified to give tributyl butyl 2-(pyridin-2-yl)propanoic acid (1.8 g, 56%).

步驟3：將6N之鹽酸(65 mL)加至三級丁基2-(啶-2-基)丙酸(2.5 g，12.07 mmol)，並攪拌12小時。將該反應混合物於較低壓力濃縮，以獲得粗製產物，再將其以甲苯(3 x 10 mL)共蒸餾，以獲得2-(啶-2-基)丙酸(1.6 g)。 Step 3: 6N Hydrochloric acid (65 mL) was added to tris-butyl 2-(pyridin-2-yl)propanoic acid (2.5 g, 12.07 mmol) and stirred for 12 hours. The reaction mixture was concentrated at a reduced pressure to give a crude product which was then co-distilled with toluene (3 x 10 mL) to give 2-(pyridin-2-yl)propanoic acid (1.6 g).

1H NMR(二甲亞碸-d6，400MHz)：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 sulfoxide -d 6, 400MHz): 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：將1-羥基苯並三唑水合物(0.045 mL，0.331 mmol)、 O-(1H-苯並三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸鹽(0.107 g，0.331 mmol)與N-二異丙基乙胺(0.128 mL，0.993 mmol)加至一經攪拌、以四氫呋喃(2.5 mL)溶解之2-(啶-2-基)丙酸(0.093 g，0.496 mmol)與(2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺(0.09 g，0.331 mmol)溶液中，以產生一懸浮液。於添加N,N-二甲基甲醯胺(0.1 mL)後，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，並以管柱色層分析法(矽膠：100至200網目；溶析液：醋酸乙酯)純化所得之固體，以獲得N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)丙醯胺(35 mg，26%)。 Step 4: 1-Hydroxybenzotriazole hydrate (0.045 mL, 0.331 mmol), O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethylurea Hexafluorophosphate (0.107 g, 0.331 mmol) and N-diisopropylethylamine (0.128 mL, 0.993 mmol) were added to 2-(pyridine-2-yl)propane dissolved in tetrahydrofuran (2.5 mL) Acid (0.093 g, 0.496 mmol) in (2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methanamine (0.09 g, 0.331 mmol) To produce a suspension. After the addition of N,N-dimethylformamide (0.1 mL), the reaction mixture was stirred for 48 hr. 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 N-((2-(4-) Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-2-yl)propanamide (35 mg, 26%).

實例19之合成：Synthesis of Example 19:

1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-3-(啶-2-基)尿素 1-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(pyridin-2-yl)urea

步驟1：於室溫，將氯甲酸苯酯(0.8 mL，6.376 mmol)與啶(0.4 mL，5.525 mmol)緩慢地加至一以四氫呋喃與乙腈(50 mL，3：4)溶解之2-胺基啶(400 mg，4.25 mmol)溶液。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。於添加水後，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網目；溶析液：正己烷-醋酸乙酯，4：1)純化該粗製產物，以獲得苯基啶-2-基胺甲酸酯(710 mg，78%)。 Step 1: Slowly add phenyl chloroformate (0.8 mL, 6.376 mmol) and pyridine (0.4 mL, 5.525 mmol) to a 2-amine dissolved in tetrahydrofuran and acetonitrile (50 mL, 3:4). A solution of pyridine (400 mg, 4.25 mmol). The reaction mixture was stirred for 3 hours. Thin layer chromatography showed complete consumption of the starting material. After the addition of water, the mixture was extracted with ethyl acetate. The extract 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, 4:1) to afford phenylpyridin-2-ylamine. Mg, 78%).

步驟2：於室溫，將4-二甲基胺基啶(40 mg，0.327 mmol，1等量)及(2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺(116 mg，0.425 mmol，1.3等量)加至一以乙腈(20 mL)溶解之苯基啶-2-基胺甲酸酯(70 mg，0.327 mmol)溶液。將該反應混合物於50℃加熱12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網目；溶析液：正己烷-醋酸乙酯，1：1)純化該粗製產物，以獲得1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-3-(啶-2-基)尿素(58 mg，45%)。 Step 2: 4-dimethylaminopyridine (40 mg, 0.327 mmol, 1 equivalent) and (2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl) at room temperature Phenyl-3-yl)methanamine (116 mg, 0.425 mmol, 1.3 eq.) was added to phenyl pyridine-2-ylcarbamate (70 mg, 0.327 mmol) dissolved in acetonitrile (20 mL) Solution. The reaction mixture was heated at 50 °C for 12 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 (pluton: 100 to 200 mesh; eluent: n-hexane-ethyl acetate, 1:1) to obtain 1-((2-(4-methylpiperidine). 1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(pyridin-2-yl)urea (58 mg, 45%).

1H NMR(300 MHz，氘代氯仿)：δ 8.27(S，1H，Ar-NH)；8.12(dd，1H，J=4.05Hz，Ar-H)；7.78(d，1H，J=7.5 Hz，Ar-H)；7.59(M，1H，Ar-H)；7.22(d，1H，J=7.68 Hz，Ar-H)；6.88(m，1H，Ar-H)；6.75(d，1H，J=8.22 Hz，Ar-H)；4.63(d，2H，J=5.85 Hz，Ar-CH2)；3.47(d，2H，J=12.81 Hz，六氫嘧啶-H)；2.90(m，2H，六氫嘧啶-H)；1.76(m，2H，六氫嘧啶-H)；1.40(m，2H，六氫嘧啶-H)；1.00(d，3H，J=6.39 Hz，六氫嘧啶-CH3)。 1 H NMR (300 MHz, deuterated chloroform): δ 8.27 (S, 1H, Ar-NH); 8.12 (dd, 1H, J = 4.05 Hz, Ar-H); 7.78 (d, 1H, J = 7.5 Hz) , Ar-H); 7.59 (M, 1H, Ar-H); 7.22 (d, 1H, J = 7.68 Hz, Ar-H); 6.88 (m, 1H, Ar-H); 6.75 (d, 1H, J = 8.22 Hz, Ar-H); 4.63 (d, 2H, J = 5.85 Hz, Ar-CH 2 ); 3.47 (d, 2H, J = 12.81 Hz, hexahydropyrimidine-H); 2.90 (m, 2H) , hexahydropyrimidine-H); 1.76 (m, 2H, hexahydropyrimidine-H); 1.40 (m, 2H, hexahydropyrimidine-H); 1.00 (d, 3H, J = 6.39 Hz, hexahydropyrimidine-CH 3 ).

示範性化合物23可以類似之方式製備而成，示範性化合物35至37，43至46與48可以類似方法製備而成。示範性化合物42已以類似方法製備而成。 Exemplary compound 23 can be prepared in a similar manner, and exemplary compounds 35 to 37, 43 to 46 and 48 can be prepared in a similar manner. Exemplary compound 42 has been prepared in a similar manner.

實例55之合成：Synthesis of Example 55:

1-(6-(羥甲基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 1-(6-(Hydroxymethyl)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl) Methyl) urea

步驟1：於室溫，將BH3SMe2(2 M，溶於四氫呋喃中)(4.34 mL，8.69 mmol，3等量)加至經攪拌、以四氫呋喃溶解溶解之5-胺基砒啶甲酸(400 mg，2.90 mmol)溶液。將該反應混合物回流過夜。薄層層析法顯示起始原料被完全消耗。以水對該反應混合物進行淬火反應，並以乙基醋酸進行萃取。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，並於較低之壓力將其濃縮，以獲得粗製產物；以管柱色層分析純化該粗製產物，以獲得(5-胺基啶-2-基)甲醇(136 mg，36%)。 Step 1: BH 3 SMe 2 (2 M in tetrahydrofuran) (4.34 mL, 8.69 mmol, 3 eq.) was added to a solution of 5-aminopyridinic acid dissolved in tetrahydrofuran (dissolved in tetrahydrofuran). 400 mg, 2.90 mmol) solution. The reaction mixture was refluxed overnight. Thin layer chromatography showed complete consumption of the starting material. The reaction mixture was quenched 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 under reduced pressure to afford crude material. Mg, 36%).

步驟2：將(5-胺基啶-2-基)甲醇(118 mg，0.95 mmol)以乙腈(3 mL)及四氫呋喃(4 mL)溶解。於該反應混合物中添加啶(0.09 mL，1.14 mmol，1.2等量)及氯甲酸苯酯(0.12 mL，0.98 mmol，1.03等量)，並於氮氣氣氛及室溫之條件下攪拌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，並以乙基醋酸萃取。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，並將其於較低壓力濃縮。以管柱色層分析法純化所得之粗製產物，以獲得6-(羥甲基)啶-3-基胺甲酸酯(191 mg，82%)。 Step 2: (5-Aminopyridine-2-yl)methanol (118 mg, 0.95 mmol) was dissolved in acetonitrile (3 mL) and THF (4 mL). Pyridine (0.09 mL, 1.14 mmol, 1.2 equivalent) and phenyl chloroformate (0.12 mL, 0.98 mmol, 1.03 equivalent) were added to the reaction mixture, and stirred under nitrogen atmosphere and room temperature for 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 a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and concentrated at lower pressure. The obtained crude product was purified by column chromatography to give 6-(hydroxymethyl)pyridin-3-ylcarbamate (191 mg, 82%).

步驟3：於室溫，將三乙胺(0.11 mL，0.77 mmol，3等量)及(2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺(70 mg，0.26 mmol，1等量)加入一以二氯甲烷溶解之苯基6-(羥甲基)啶-3-基胺甲酸酯(63 mg，0.26 mmol)溶液。將該反應混合物攪拌過夜。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，並以乙基醋酸萃取。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，並於較低之壓力濃縮。以管柱色層分析法純化粗製產物，以獲得1-(6-(羥甲基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素(73 mg，67%)。 Step 3: Triethylamine (0.11 mL, 0.77 mmol, 3 equivalents) and (2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine- 3 at room temperature Methylamine (70 mg, 0.26 mmol, 1 equivalent) was added to a solution of phenyl 6-(hydroxymethyl)pyridin-3-ylcarbamate (63 mg, 0.26 mmol) dissolved in dichloromethane. . The reaction mixture was 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 is washed with water and a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give 1-(6-(hydroxymethyl)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6 -(Trifluoromethyl)pyridin-3-yl)methyl)urea (73 mg, 67%).

示範性化合物56至60可以類似方法製備而成。 Exemplary compounds 56 to 60 can be prepared in a similar manner.

實例67之合成：Synthesis of Example 67:

1-(5-氟-6-(2-(甲基磺醯基)乙基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 1-(5-Fluoro-6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-) (trifluoromethyl)pyridin-3-yl)methyl)urea

步驟1：於60℃，將五氯化磷(2.96 g，14.22 mmol)加至經攪拌、以氧氯化磷(15 mL)溶解之3-氟-5-硝基啶-2-醇(1.5 g，9.48 mmol)溶液。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周圍溫度，將其倒入碎冰中，並以醋酸乙酯(3 x 20 mL)萃取。以飽和碳酸鈉溶液(25 mL)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(100至200網目；存在於己烷之5%醋酸乙酯)純化該粗製化合物，以獲得2-氯-3-氟-5-硝基啶(1.62 g，97%)。 Step 1: Phosphorus pentachloride (2.96 g, 14.22 mmol) was added to 3-fluoro-5-nitropyridin-2-ol (1.5) dissolved in phosphorus oxychloride (15 mL) at 60 °C. g, 9.48 mmol) solution. The reaction mixture was stirred at the same temperature for 10 hours. The reaction mixture was cooled to ambient temperature, poured into crushed ice and extracted with ethyl acetate (3 x 20 mL). The entire organic layer was washed with saturated sodium carbonate solution (25 mL). The washed organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by column chromatography (100 to 200 mesh; 5% ethyl acetate in hexane) The compound was crude to give 2-chloro-3-fluoro-5-nitropyridine (1.62 g, 97%).

步驟2：於氮氣氣氛下，將三丁基乙烯基錫(tributylvinyltin)(3.42 g，10.8 mmol)與三(二亞苄基丙酮)二鈀(Pd2(dba)3)(0.42 g，0.45 mmol)及三呋喃基雜環戊二烯(trifuryl phosphene)(0.2 g，0.9 mmol)加至經攪拌、以四氫呋喃(16 mL)溶解之2-氯-3-氟-5-硝基啶(1.6 g，9.0 mmol)溶液。將該反應混合物徹底地脫氧，並於60℃加熱至6小時。以水(20 mL)稀釋該反應混合物，並以醋酸乙酯(3 x 25 mL)萃取。以飽和之氯化鈉溶液(25 mL)清洗混合有機層，並以無水硫酸鎂乾燥，再將其於較低之壓力濃縮，以獲得粗製化合物。以管柱色層分析法(矽膠：100至200網目；溶析液：存在己烷之5%醋酸乙酯)純化該粗製化合物，以獲得3-氟-5-硝基-2-乙烯啶(1.5 g，96%)。 Step 2: Tributylvinyltin (3.42 g, 10.8 mmol) and tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ) (0.42 g, 0.45 mmol) under a nitrogen atmosphere And trifuryl phosphene (0.2 g, 0.9 mmol) was added to 2-chloro-3-fluoro-5-nitropyridine (1.6 g) dissolved in tetrahydrofuran (16 mL) , 9.0 mmol) solution. The reaction mixture was thoroughly deoxygenated and heated to 60 ° C for 6 hours. The reaction mixture was diluted with water (20 mL) andEtOAcEtOAc The organic layer was washed with a saturated sodium chloride solution (25 mL) and dried over anhydrous magnesium sulfate. The crude compound was purified by column chromatography (tank: 100 to 200 mesh; eluent: 5% ethyl acetate in the presence of hexane) to afford 3-fluoro-5-nitro-2-vinylpyridine ( 1.5 g, 96%).

步驟3：於周圍溫度，將甲基並磺酸鈉(sodium methane sulfinate)(9.1 g，89.3 mmol)及醋酸(0.53 g，8.92 mmol)加至經攪拌、以乙醇(15 mL)溶解之3-氟-5-硝基-2-乙烯啶(1.5 g，8.92 mmol)溶液。將該反應混合物於60℃加熱10小時。令該反應混合物冷卻至周圍溫度，並將其於較低壓力濃縮，以獲得粗製化合物；將該粗製化合物過濾，並將所獲得之固體以水(25 mL)清洗，以獲得3-氟-2-(2-(甲基磺醯基)乙基)-5-硝基啶)(0.81 g，36%)。 Step 3: Sodium methane sulfinate (9.1 g, 89.3 mmol) and acetic acid (0.53 g, 8.92 mmol) were added to the mixture at ambient temperature and dissolved in ethanol (15 mL). A solution of fluoro-5-nitro-2-vinylpyridine (1.5 g, 8.92 mmol). The reaction mixture was heated at 60 ° C for 10 hours. The reaction mixture was allowed to cool to ambient temperature and concentrated at a lower pressure to give a crude compound; the crude compound was filtered, and the obtained 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，將鈀碳(palladium on charcoal)(80 mg)加至以醋酸乙酯(8 mL)溶解之3-氟-2-(2-(甲基磺醯基)乙基)-5-硝基啶(0.8 g，3.22 mmol)溶液，並使其於帕爾反應釜(Parr vessel)氫化；令反應於攪拌下持續2小時。將該反應混合物以矽藻土床(celite bed)過濾，以醋酸乙酯徹底地清洗，並於較低壓力濃縮，以獲得5-氟-6-(2-(甲基磺醯基)乙基)啶-3-胺(0.62 g，88%)。 Step 4: Palladium on charcoal (80 mg) was added to 3-fluoro-2-(2-(methylsulfonyl) B dissolved in ethyl acetate (8 mL) under an argon atmosphere. A solution of 5-aminopyridine (0.8 g, 3.22 mmol) was hydrogenated in a Parr vessel; the reaction was stirred for 2 hours. The reaction mixture was filtered over celite bed, washed thoroughly with ethyl acetate and concentrated at lower pressure to afford 5-fluoro-6-(2-(methylsulfonyl)ethyl Pyridine-3-amine (0.62 g, 88%).

步驟5：將5-氟-6-(2-(甲基磺醯基)乙基)啶-3-胺(99 mg，0.454 mmol)以丙酮/二甲基甲醯胺溶解(1.5 mL+0.63 mL)。於0℃、將啶(0.11 mL，1.36 mmol)於逐滴加入該反應混合物中，再加入氯甲酸苯酯(0.075 mL，0.59 mmol)。將該混合物於室溫攪拌2小時。將該反應混合物於較低壓力濃縮，並以二氯甲烷稀釋，及以碳酸氫鈉溶液(1 x 15 mL)清洗。以二氯甲烷(2 x 20 mL)萃取水層。將有機層以硫酸鎂乾燥，並將其於較低壓力濃縮，以獲得苯基5-氟-6-(2-(甲基磺醯基)乙基)啶-3-基胺甲酸酯(249 mg)。 Step 5: Dissolve 5-fluoro-6-(2-(methylsulfonyl)ethyl)pyridine-3-amine (99 mg, 0.454 mmol) in acetone/dimethylformamide (1.5 mL+0.63) mL). Pyridine (0.11 mL, 1.36 mmol) was added dropwise to the reaction mixture at 0 ° C and then phenyl chloroacetate (0.075 mL, 0.59 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated at lower pressure and diluted with dichloromethane and washed with sodium bicarbonate (1 x 15 mL). The aqueous layer was extracted with dichloromethane (2 x 20 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to afford phenyl 5-fluoro-6-(2-(methylsulfonyl)ethyl)pyridin-3-ylamine. 249 mg).

步驟6：將苯基5-氟-6-(2-(甲基磺醯基)乙基)啶-3-基胺甲酸酯(80 mg，0.237 mmol)及(2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺鹽酸鹽(73 mg，0.237 mmol)以四氫呋喃(3.6 mL)溶解。隨後添加N-二異丙基乙胺(0.157 mL，0.924 mmol)。將該混合物以微波(7巴)，於150℃攪拌1小時。完成後，將該混合物於較低壓力濃縮，以獲得粗製化合物。以醋酸乙酯-甲醇(4：1)做為溶溶析液，利用管柱色層分析法純化該粗製化合物，以獲得1-(5-氟-6-(2-(甲基磺醯基)乙基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素(40 mg，33%)。 Step 6: Phenyl 5-fluoro-6-(2-(methylsulfonyl)ethyl)pyridin-3-ylcarbamate (80 mg, 0.237 mmol) and (2-(4-methyl) Piperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methylamine hydrochloride (73 mg, 0.237 mmol) was dissolved in tetrahydrofurane (3.6 mL). Then N-diisopropylethylamine (0.157 mL, 0.924 mmol) was added. The mixture was stirred in a microwave (7 bar) at 150 ° C for 1 hour. After completion, the mixture was concentrated at a lower pressure to obtain a crude compound. The crude compound was purified by column chromatography using ethyl acetate-methanol (4:1) as the solvent to obtain 1-(5-fluoro-6-(2-(methylsulfonyl)) Ethyl)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea (40 mg , 33%).

可以相似之方法製備示範性化合物68及69。 Exemplary compounds 68 and 69 can be prepared in a similar manner.

實例74之合成：Synthesis of Example 74:

5-(1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺基)-1-氧代丙烷-2-基)啶醯胺 5-(1-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methylamino)-1-oxopropan-2-yl) Pyridoxamine

步驟1：將硫酸(1.6 mL)加至一以乙醇溶解之6-氯-3-啶乙酸(1 g，5.83 mmol)溶液。將該混合物回流4小時，隨後將其冷卻至室溫，並將其濃縮。將殘留物以醋酸乙酯稀釋，並以飽和碳酸氫鈉溶液清洗。將產生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粗製產物法，以獲得乙基2-(6-氯啶-3-基)乙酸酯(1.1 g，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 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). Acetate (1.1 g, 95%).

步驟2：於0℃，將氫化納(242 mg，6.06 mmol)緩慢地加至以二甲基甲醯胺溶解之乙基2-(6-氯啶-3-基)乙酸酯(1.1 g，5.51 mmol)溶液，隨後添加碘甲烷(821 mg，5.79 mmol)。將該混合物於相同溫度攪拌1小時，再以水對其進行淬火反應。將所得之混合物以醋酸乙酯稀釋，再以水清洗。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 mg，67%)。 Step 2: Slowly add sodium hydride (242 mg, 6.06 mmol) to ethyl 2-(6-chloropyridin-3-yl)acetate (1.1 g) dissolved in dimethylformamide at 0 °C. , 5.51 mmol) solution followed by methyl iodide (821 mg, 5.79 mmol). The mixture was stirred at the same temperature for 1 hour and then quenched 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 a reduced pressure to afford crude product; the crude product was purified by column chromatography to give ethyl 2-(6-chloropyridin-3-yl)propanoic acid. (790 mg, 67%).

步驟3：將氰化鋅(434 mg，3.7 mmol)與四(三苯基膦基)鈀(0)(1280 mg，1.11 mmol)加至以二甲基甲醯胺溶解之乙基2-(6-氯啶-3-基)丙酸(790 mg，3.7 mmol)溶液。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(plug of celite)過濾，並將其濃縮。以醋酸乙酯稀釋殘留物，並以10%之鹽酸清洗。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-氰啶-3-基)丙酸(420 mg，56%)。 Step 3: Zinc cyanide (434 mg, 3.7 mmol) and tetrakis(triphenylphosphino)palladium(0) (1280 mg, 1.11 mmol) were added to ethyl 2-(() dissolved in dimethylformamide A solution of 6-chloropyridine-3-yl)propionic acid (790 mg, 3.7 mmol). The reaction mixture was stirred at 100 ° C for 12 hours and then cooled to room temperature. The mixture was filtered through a plug of celite and concentrated. The residue was diluted with ethyl acetate and washed with 10% hydrochloric acid. The organic layer was dried over magnesium sulfate and concentrated at a reduced pressure to afford crude product; the crude product was purified by column chromatography to give ethyl 2-(6-cyandin-3-yl)propanoic acid. (420 mg, 56%).

步驟4：將氫氧化鋰單水合物(129 mg，3.08 mmmol)加至以四氫呋喃與水溶解之乙基2-(6-氰啶-3-基)丙酸(420 mg，2.06 mmol)溶液。將該反應混合物於40℃攪拌2小時，隨後以10%之鹽酸將其酸化。以醋酸乙酯萃取該混合物。將有機層以以硫酸鎂乾燥，並於較低壓力將其濃縮，以獲得所需之2-(6-氰啶-3-基)丙酸(330 mg，94%)。 Step 4: Lithium hydroxide monohydrate (129 mg, 3.08 mmol) was added to a solution of ethyl 2-(6-cyanidin-3-yl)propanoic acid (420 mg, 2.06 mmol) dissolved in tetrahydrofuran and water. The reaction mixture was stirred at 40 ° C for 2 hours and then acidified with 10% hydrochloric acid. 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：將1-羧苯並三唑(380 mg，2.81 mmol)、1-乙基-3-(3-二甲基胺基丙基)碳二醯亞胺(537 mg，2.81 mmol)與(2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺(537 mg，1.97 mmol)加至以乙腈溶解之2-(6-氰啶-3-基)丙酸(330 mg，1.87 mmol)溶液。將該反應混合物於室溫攪拌12小時。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該粗製產物，以獲得純2-(6-氰啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺(500 mg，62%)。 Step 5: 1-Carboxybenzotriazole (380 mg, 2.81 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (537 mg, 2.81 mmol) and (2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methanamine (537 mg, 1.97 mmol) was added to 2-(6- A solution of cyanidin-3-yl)propionic acid (330 mg, 1.87 mmol). The reaction mixture was stirred at room temperature for 12 hours. 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 2-(6-cyandin-3-yl)-N-((2-(4-methylpiperidin-1-yl)-6- ( Trifluoromethyl)pyridin-3-yl)methyl)propanamide (500 mg, 62%).

步驟6：將起始原料2-(6-氰啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺(140 mg，0.33 mmol)以硫酸(1.7 mL)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。以冰水稀釋該反應混合物，並以2 M之氫氧化鈉溶液 將其中和(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，以獲得純5-(1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺基)-1-氧代丙烷-2-基)啶醯胺(40 mg，27%)。 Step 6: Starting the starting material 2-(6-cyanidin-3-yl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine-3 -Methyl)propanamide (140 mg, 0.33 mmol) was dissolved in sulfuric acid (1.7 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 2 M 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 pure 5-(1-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl))-3-yl Methylamino)-1-oxopropan-2-yl)pyridiniumamine (40 mg, 27%).

1H NMR(300MHz，氘代氯仿)：δ 8.52(d，1H，J=2.01 Hz，啶-H)；8.15(d，1H，J=8.14 Hz，啶-H)；7.85(dd，1H，J=8.09，2.21 Hz，啶-H)；7.80(br.s，NH)；7.50(d，1H，J=7.73 Hz)；7.21(d，1H，J=7.73 Hz，Ar-H)；6.55(m，NH)；5.78(br.s，NH)；4.50(m，2H，Ar-CH2)；3.67(四分體(quartet)；1H，J=6.96 Hz，醯胺-CH)；3.31(m，2H，六氫嘧啶-H)；2.82(m，2H，六氫嘧啶-H)；1.72(m，2H，六氫嘧啶-H)；1.56(m，4H，醯胺-CH3，六氫嘧啶-H)；1.19(m，2H，六氫嘧啶-H)；0.97(d，3H，J=6.39 Hz，六氫嘧啶-CH3)。 1 H NMR (300MHz, deuteriochloroform): δ 8.52 (d, 1H , J = 2.01 Hz, pyridine -H); 8.15 (d, 1H , J = 8.14 Hz, pyridine -H); 7.85 (dd, 1H , J = 8.09, 2.21 Hz, pyridine-H); 7.80 (br.s, NH); 7.50 (d, 1H, J = 7.73 Hz); 7.21 (d, 1H, J = 7.73 Hz, Ar-H); (m, NH); 5.78 (br.s, NH); 4.50 (m, 2H, Ar-CH 2 ); 3.67 (quartet; 1H, J = 6.96 Hz, decyl-CH); (m, 2H, hexahydropyrimidine -H); 2.82 (m, 2H , hexahydropyrimidine -H); 1.72 (m, 2H , hexahydropyrimidine -H); 1.56 (m, 4H , Amides -CH 3, hexahydropyrimidine -H); 1.19 (m, 2H , hexahydropyrimidine -H); 0.97 (d, 3H , J = 6.39 Hz, hexahydropyrimidine -CH 3).

實例75之合成：Synthesis of Example 75:

5-(1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺基)-1-氧代丙烷-2-基)-N-苯基啶醯胺 5-(1-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methylamino)-1-oxopropan-2-yl) )-N-phenyl pyridine guanamine

步驟1至5：如實例74之描述。 Steps 1 to 5: as described in Example 74.

步驟6：將2-(6-氰啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺(200 mg，0.46 mmol)懸浮於乙醇，並添加2M之氫氧化鈉(2.3 mL，4.64 mmol)，將該混合物回流20小時。使該混合物冷卻至室溫，並將其濃縮。將該混合物以醋酸乙酯稀釋，並以1M之鹽酸溶液將其酸化。以醋酸乙酯萃取該混合物。將有機層以以硫酸鎂乾燥，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5-(1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺基)-1-氧代丙烷-2-基)砒啶甲酸(180 mg，78%)。 Step 6: 2-(6-Cyanidin-3-yl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl) Methyl)propanamide (200 mg, 0.46 mmol) was suspended in ethanol, and 2M sodium hydroxide (2.3 mL, 4.46 mmol) was added and the mixture was refluxed for 20 hr. The mixture was allowed to cool to room temperature and concentrated. The mixture was diluted with ethyl acetate and acidified with a 1M aqueous solution of hydrochloric acid. 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 pure 5-(1-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl))-3-yl Methylamino)-1-oxopropan-2-yl)acridinecarboxylic acid (180 mg, 78%).

步驟7：將亞硫醯二氯(0.14 mL，2 mmol)加至以氯甲烷溶解之5-(1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺基)-1-氧代丙烷-2-基)砒啶甲酸(180 mg，0.4 mmol)溶液。將該反應混合物回流2 小時，隨後於較低壓力移除亞硫醯二氯。以氯甲烷溶解殘留物，再將其加至以氯甲烷溶解之苯胺(0.037 mL，0.4 mmol)與三乙胺(0.08 mL，0.6 mmol)溶液中。將該反應混合物於室溫攪拌2小時，隨後添加水，再以氯甲烷萃取。將有機層以硫酸鎂乾燥，並於較低壓力將其濃縮。以管柱色層分析法純化該粗製產物，以獲得5-(1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺基)-1-氧代丙烷-2-基)-N-苯基啶甲醯胺(50 mg，25%)。 Step 7: Add sulfite dichloride (0.14 mL, 2 mmol) to 5-(1-((2-methyl)piperidin-1-yl)-6-(trifluoro) A solution of methyl)pyridin-3-yl)methylamino)-1-oxopropan-2-yl)pyridinic acid (180 mg, 0.4 mmol). The reaction mixture was refluxed for 2 hours, then sulphur dichloride was removed at a lower pressure. The residue was dissolved in chloromethane and then taken to a solution of phenylamine (0.037 mL, 0.4 mmol) and triethylamine (0.08 mL, 0.6 mmol). The reaction mixture was stirred at room temperature for 2 hr then water was added and then extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated at lower pressure. The crude product was purified by column chromatography to give 5-(1-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl) Methylamino)-1-oxopropan-2-yl)-N-phenylpyridinecarboxamide (50 mg, 25%).

1H NMR(300MHz，氘代氯仿)：δ 9.94(br.s，1H，NH)；8.56(d，1H，J=2.01 Hz，啶-H)；8.26(d，1H，J=8.04 Hz，啶-H)；7.89(dd，1H，J=8.11，2.04 Hz，啶-H)；7.76(d，2H，J=7.75 Hz，Ar-H)；7.51(d，1H，J=7.52 Hz，Ar-H)；7.40(m，2H，Ar-H)；7.18(m，2H，Ar-H)；6.51(br.s，1H，NH)；4.51(m，2H，Ar-CH2)；3.68(四分體，1H，J=7.04 Hz，醯胺-CH)；3.32(m，2H，六氫嘧啶-H)；2.83(m，2H，六氫嘧啶-H)；1.71(m，2H，六氫嘧啶-H)；1.60(m，4H，醯胺-CH3，六氫嘧啶-H)；1.23(m，2H，六氫嘧啶-H)；0.96(d，3H，J=6.41 Hz，六氫嘧啶-CH3)。 1 H NMR (300MHz, deuteriochloroform): δ 9.94 (br.s, 1H , NH); 8.56 (d, 1H, J = 2.01 Hz, pyridine -H); 8.26 (d, 1H , J = 8.04 Hz, pyridine-H); 7.89 (dd, 1H, J = 8.11, 2.04 Hz, pyridine-H); 7.76 (d, 2H, J = 7.75 Hz, Ar-H); 7.51 (d, 1H, J = 7.52 Hz, Ar-H); 7.40 (m, 2H, Ar-H); 7.18 (m, 2H, Ar-H); 6.51 (br.s, 1H, NH); 4.51 (m, 2H, Ar-CH 2 ); 3.68 (tetrad, 1H, J = 7.04 Hz, decylamine-CH); 3.32 (m, 2H, hexahydropyrimidine-H); 2.83 (m, 2H, hexahydropyrimidine-H); 1.71 (m, 2H) , hexahydropyrimidine-H); 1.60 (m, 4H, decyl-CH 3 , hexahydropyrimidine-H); 1.23 (m, 2H, hexahydropyrimidine-H); 0.96 (d, 3H, J = 6.41 Hz) , hexahydropyrimidine-CH 3 ).

實例76之合成：Synthesis of Example 76:

5-(1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺基)-1-氧代丙烷-2-基)-N-苯基嘧啶-2-羧醯胺 5-(1-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methylamino)-1-oxopropan-2-yl) )-N-phenylpyrimidine-2-carboxamide

步驟1：於一250 mL之圓底燒瓶中，將亞硫醯二氯(5.4 mL，73.89 mmol)加至以苯(100 mL)溶解之5-溴嘧啶-2-羧酸(5.22 g，24.63 mmol)。將該反應混合物於100℃回流2小時。之後，於較低壓力移除亞硫醯二氯及苯。使用甲苯製造共沸物，以將水移除。將殘留物以二氯甲烷(100 mL)溶解，並於氮氣氣氛下，將其加至存在於二氯甲烷(100 mL)之苯胺溶液(2.27 g，24.42 mmol)。將該反應混合物於周圍溫度攪拌16小時。於起始原料被完全消耗後，以二氯甲烷(50 mL)稀釋該反應混合物，並依序以水(2×100 mL)、碳酸氫鈉溶液(2×100 mL)及飽和之氯化鈉溶液(100 mL)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網目；溶析液：存在於正己烷之20%醋酸乙酯)純化該粗製化合物，以獲得5-溴-N-苯基嘧啶-2-羧醯胺(5.5 g，77%)。 Step 1: In a 250 mL round bottom flask, add sulfoxide dichloride (5.4 mL, 73.89 mmol) to 5-bromopyrimidine-2-carboxylic acid (5.22 g, 24.63) dissolved in benzene (100 mL). Mm). The reaction mixture was refluxed at 100 ° C for 2 hours. Thereafter, sulphur dichloride and benzene are removed at a lower pressure. An azeotrope was made using toluene to remove water. 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), followed by water (2×100 mL), sodium bicarbonate (2×100 mL) and saturated sodium chloride. Wash the solution (100 mL). 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 give 5-bromo-N-phenylpyrimidine-2-carboxylate. Indoleamine (5.5 g, 77%).

步驟2：將氫化鈉(950 mg，23.91 mmol)置放於一250 mL之圓底雙頸燒瓶中，並於氮氣氣氛下添加無水二甲基甲醯胺(20 mL)。於-5℃，將以無水二甲基甲醯胺(39.76 mL)溶解之5-溴基-N-苯基嘧啶-2-羧醯胺(5.5g，19.92 mmol)溶液加至該以二甲基甲醯胺溶解之氫化鈉懸浮液。將該反應混合物於同樣溫度攪拌30分鐘。之後，於維持相同溫度下，逐滴添加2-(三甲基矽基)乙氧甲基氯(4.98 g，29.89 mmol)。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 mL)對該反應混合物進行淬火反應，並醋酸乙酯(3×100 mL)萃取。將該混合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網目；溶析液：存在於正己烷之20%醋酸乙酯)純化該粗製化合物，以獲得純5-溴基-N-苯基-N-((2-(三甲基矽基)乙氧基)甲基)嘧啶-2-羧醯胺(7.2 g，90%)。 Step 2: Sodium hydride (950 mg, 23.91 mmol) was placed in a 250 mL round bottom double-necked flask and anhydrous dimethylformamide (20 mL) was then evaporated. To a solution of 5-bromo-N-phenylpyrimidine-2-carboxamide (5.5 g, 19.92 mmol) dissolved in anhydrous dimethylformamide (39.76 mL) at -5 °C A suspension of sodium methamine dissolved sodium hydride. 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 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 ethyl acetate (3×100 mL). The combined organic layers were 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 afford pure 5-bromo-N-phenyl-N- ((2-(Trimethyldecyl)ethoxy)methyl)pyrimidine-2-carboxamide (7.2 g, 90%).

步驟3：將5-溴基-N-苯基-N-((2-(三甲基矽基)乙氧基)甲基)嘧啶-2-羧醯胺(6.5 g，15.92 mmol)以1,4-二氧陸圜(80 mL)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'-雙-(1,3,2-二氧硼戊環)(4.24 g，16.7 mmol)及乙酸鉀(4.68 g，47.76 mmol)。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 mg，0.79 mmol)。將該反應混合物回流16小時。於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(3×100 mL)萃取。將該混合有機層以硫酸鎂乾燥，並於較低壓力下濃縮。N-苯基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-N-((2-(三甲基矽基)乙氧基)-甲基)嘧啶-2-甲醯胺粗製產物不須經純化(8.0 g，粗製產物)即可供下一步驟使用。 Step 3: 5-bromo-N-phenyl-N-((2-(trimethylmethyl)ethoxy)methyl)pyrimidine-2-carboxamide (6.5 g, 15.92 mmol) as 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. Bis-(1,3,2-dioxaborolan) (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 consumed, the reaction mixture was diluted with water and extracted with ethyl acetate (3×100 mL). The combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure. N-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-((2-(trimethyldecyl)) The crude product of ethoxy)-methyl)pyrimidine-2-carboxamide can be used in the next step without purification (8.0 g, crude product).

步驟4：將N-苯基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-N-((2-(三甲基矽基)乙氧基)-甲基)嘧啶-2-羧醯胺(7.3 g，16.04 mmol)以甲苯(73 mL)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 g，19.25 mmol)及2M之碳酸鈉溶液(32 mL)。之後再添加四(三苯基膦基)鈀(0)(927 mg，0.80 mmol)。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，再以醋酸乙酯(3 x 100 mL)萃取。將該混合有機層以硫酸鎂乾燥，並於較低壓力濃縮。以管柱色層分析(矽膠：100至200網目；溶析液：存在於正己烷之10%醋酸乙酯)純化該粗製產物，以獲得純甲基2-(2-(苯基((2-(三甲基矽基)乙氧基)甲基)胺基甲醯基)嘧啶-5-基)丙烯酸(4.3 g，65%)。 Step 4: N-Phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-((2-(tri-) Ethyl)ethyl)pyrimidine-2-carboxamide (7.3 g, 16.04 mmol) was dissolved in toluene (73 mL), and methyl 2-(trifluoromethyl) was added sequentially under a nitrogen atmosphere. Alkylsulfonyloxy)acrylic acid (4.5 g, 19.25 mmol) and 2M sodium carbonate solution (32 mL). Tetrakis(triphenylphosphino)palladium(0) (927 mg, 0.80 mmol) was then 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 (gel: 100 to 200 mesh; eluent: 10% ethyl acetate in n-hexane) to afford pure methyl 2-(2-(phenyl). -(Trimethyldecyl)ethoxy)methyl)aminocarboxamidopyrimidin-5-yl)acrylic acid (4.3 g, 65%).

步驟5：於一250 mL之帕爾反應釜中，將甲基2-(2-(苯基((2-(三甲基矽基)乙氧基)甲基)胺基甲醯基)嘧啶-5-基)丙烯酸(4.3 g)以醋酸乙酯(43 mL)溶解，並於氮氣氣氛下添加鈀活性炭(palladium on activated charcoal)(10% Pd，430 mg)。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完全消耗。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-(三甲基矽基)乙氧基)甲基)胺基甲醯基)嘧啶-5-基)丙酸(4.0 g，93%)。 Step 5: In a 250 mL Parr reactor, methyl 2-(2-(phenyl((2-(trimethylmethyl))ethoxy)methyl)aminomethyl)pyrimidine -5-yl)acrylic acid (4.3 g) was dissolved in ethyl acetate (43 mL) and palladium on activated charcoal (10% Pd, 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 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-(phenyl((2-(trimethylmethyl))) oxy)methyl) Methylidene)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)胺基甲醯基)嘧啶-5-基)丙酸(2.5 g，6.0 mmol)以乙醇(76 mL)溶解，並添加6N之鹽酸(76 mL)。將該反應混合物於90℃回流2小時。起始原料被完全消耗後，於較低壓力將乙醇蒸發，並以水稀釋殘留物，再以碳酸鈉溶液將其鹼化。以醋酸乙酯清洗水層。再以6N之鹽酸將該水層酸化，並以醋酸乙酯萃取(3×50 mL)。將該混合有機層以硫酸鎂乾燥，並於較低壓力濃縮，以獲得純2-(2-(苯基胺基甲醯基)嘧啶-5-基)丙酸(750 mg，47%)。 Step 6: Methyl 2-(2-(phenyl((2-(methyl)methyl)ethoxy)methyl)aminocarbamoyl)pyrimidin-5-yl)propanoic acid (2.5 g, 6.0 mmol) was dissolved in ethanol (76 mL) and 6N hydrochloric acid (76 mL) was added. The reaction mixture was refluxed at 90 ° C for 2 hours. After the starting material was completely consumed, the ethanol was evaporated at a lower pressure, and the residue was diluted with water and then alkalized with a sodium carbonate solution. The aqueous layer was washed with ethyl acetate. The aqueous layer was 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 NMR(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)；LCMS(M+H)：272.0；HPLC：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); LCMS (M+H): 272.0; HPLC: 95.02%.

步驟7：將1-羥基苯並三唑水合物(0.034 mL，0.256 mmol)、O-(1H-苯並三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸鹽(0.082 g，0.256 mmol)及N-二異丙基乙胺(0.066 mL，0.512 mmol)加至經攪拌、以四氫呋喃(2 mL)溶解之(2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺(0.07 g，0.256 mmol)及2-(2-(苯基胺基甲醯基)嘧啶-5-基)丙酸(0.069 g，0.256 mmol)溶液，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，並以管柱色層分析法(矽膠：100至200網目；溶析液：醋酸乙酯)純化所得之固體，以獲得5-(1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺基)-1-氧代丙烷-2-基)-N-苯基嘧啶-2-羧醯胺(35 mg，26%)。 Step 7: 1-Hydroxybenzotriazole hydrate (0.034 mL, 0.256 mmol), O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethylurea Hexafluorophosphate (0.082 g, 0.256 mmol) and N-diisopropylethylamine (0.066 mL, 0.512 mmol) were added to the mixture (2-(4-methylpiperidine) dissolved in tetrahydrofuran (2 mL) 1-yl)-6-(trifluoromethyl)pyridin-3-yl)methylamine (0.07 g, 0.256 mmol) and 2-(2-(phenylaminomethylindenyl)pyrimidin-5-yl) A solution of propionic acid (0.069 g, 0.256 mmol) was added and the mixture was stirred for 36 h. 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 5-(1-((2-) (4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methylamino)-1-oxopropan-2-yl)-N-phenylpyrimidine-2 Carboxylamamine (35 mg, 26%).

實例77之合成：Synthesis of Example 77:

5-(1-((2-(乙胺基)-6-(三氟甲基)啶-3-基)甲胺基)-1-氧代丙烷-2-基)-N-(4-氟苯基)嘧啶-2-羧醯胺 5-(1-((2-(ethylamino))-6-(trifluoromethyl)pyridin-3-yl)methylamino)-1-oxopropan-2-yl)-N-(4- Fluorophenyl)pyrimidine-2-carboxamide

步驟1：於一250 mL圓底燒瓶中，將5-溴嘧啶-2-羧酸(5 g，24.63 mmol)以苯(50 mL)溶解，並添加亞硫醯二氯(5.63 mL，73.89 mmol)。將該反應混合物於100℃回流2小時。之後，於較低壓力下，將亞硫醯二氯與苯移除。使用甲苯製造共沸物，以將水移除。將殘留物以二氯甲烷(100 mL)溶解，隨後於氮氣氣氛下，將其加至以二氯甲烷(100 mL)溶解之4-氟苯胺(2.68 g，24.13 mmol)溶液。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 mL)稀釋該反應混合物，並依序以水(2 x 100 mL)、碳酸氫鈉溶液(2 x 100 mL)及飽和之氯化鈉溶液(100 mL)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網目；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-溴基-N-(4-氟苯基)嘧啶-2-羧醯胺(5.6 g，78%)。 Step 1: Dissolve 5-bromopyrimidine-2-carboxylic acid (5 g, 24.63 mmol) in benzene (50 mL) in a 250 mL round bottom flask and add sulfoxide dichloride (5.63 mL, 73.89 mmol) ). The reaction mixture was refluxed at 100 ° C for 2 hours. Thereafter, sulfite dichloride and benzene are removed at a lower pressure. An azeotrope was made using toluene to remove water. The residue was dissolved in dichloromethane (100 mL) then EtOAc (EtOAc) The reaction mixture was stirred at room temperature for 16 hours. After the starting material was completely consumed, the 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 give 5-bromo-N-(4-fluorophenyl) Pyrimidine-2-carboxyguanamine (5.6 g, 78%).

步驟2：將氫化鈉(60%，872 mg，21.81 mmol)置放於一250 mL之圓底雙頸燒瓶，並於氮氣氣氛下添加二甲基甲醯胺(25 mL)。於-5℃，將以無水二甲基甲醯胺(30 mL)溶解之5-溴基-N-(4-氟苯基)嘧啶-2-羧醯胺(5.4 g，18.24 mmol)溶液加至以二甲基甲醯胺溶解之氫化鈉懸浮液。將該反應混合物於相同溫度攪拌30分鐘。之後，於維持相同溫度下，逐滴添加2-(三甲基矽基)乙氧甲基氯(4.52 g，27.36 mmol)。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 mL)對該反應混合物進行淬火反應，並以醋酸乙酯(3×100 mL)萃取。將混合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網目；溶析液：存在於正己烷之20%醋酸乙酯)純化所得之粗製化合物，以獲得5-溴基-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 g，84%)。 Step 2: Sodium hydride (60%, 872 mg, 21.81 mmol) was placed in a 250 mL round bottom two-necked flask and dimethylformamide (25 mL) was added under a nitrogen atmosphere. Add 5-bromo-N-(4-fluorophenyl)pyrimidine-2-carboxamide (5.4 g, 18.24 mmol) in anhydrous dimethylformamide (30 mL) at -5 °C. To a suspension of sodium hydride dissolved in dimethylformamide. 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 obtained crude compound was purified by column chromatography (tank: 100 to 200 mesh; eluent: 20% ethyl acetate in n-hexane) to obtain 5-bromo-N-(4-fluorobenzene). -N-((2-(Trimethyldecyl)ethoxy)methyl)pyrimidine-2-carboxamide (6.5 g, 84%).

步驟3：將5-溴基-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 g，17.59 mmol)以1,4-二氧陸圜(86 mL)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'-雙-(1,3,2-二氧硼戊環)(4.7g，18.47 mmol)及乙酸鉀(5.2 g，52.77 mmol)。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)(Pd(dppf)2Cl2)(644 mg，0.87 mmol)。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(3×100 mL)萃取。將混合有機層以硫酸鎂乾燥，並於較低壓力濃縮。N-(4-氟苯基)-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-N-((2-(三甲基矽基)乙氧基)-甲基)嘧啶-2-羧醯胺粗製產物不須純化(9.0 g，粗製產物)，即可供下一步驟使用。 Step 3: 5-bromo-N-(4-fluorophenyl)-N-((2-(trimethylsulfonyl)ethoxy)methyl)pyrimidine-2-carboxamide (7.5 g, 17.59 mmol) was dissolved in 1,4-dioxane (86 mL) and added 4,4,4',4',5,5,5',5'-octamethyl in sequence under a nitrogen atmosphere. -2,2'-bis-(1,3,2-dioxaborolan) (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) (Pd(dppf) 2 Cl 2 ) (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 extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over magnesium sulfate and concentrated at lower pressure. N-(4-fluorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-((2-(3) The crude product of methylmercapto)ethoxy)-methyl)pyrimidine-2-carboxamide does not require purification (9.0 g, crude product), which can be used in the next step.

步驟4：將N-(4-氟苯基)-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-N-((2-(三甲基矽基)-乙氧基)甲基)嘧啶-2-羧醯胺(8.3 g， 17.59 mmol)以甲苯(83 mL)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 g，21.12 mmol)及2 M之碳酸鈉溶液(35.2 mL)。之後，添加四(三苯基膦基)鈀(0)(1.02 g，0.87 mmol)。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 mL)萃取。將混合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網目；溶析液：存在於正己烷之10%醋酸乙酯)純化所得之粗製化合物，以獲得甲基2-(2-((4-氟苯基)((2-(三甲基矽基)乙氧基)甲基)胺基甲醯基)嘧啶-5-基)丙烯酸(5 g，67%)。 Step 4: N-(4-Fluorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(( 2-(Trimethylsulfonyl)-ethoxy)methyl)pyrimidine-2-carboxamide (8.3 g, 17.59 mmol) was dissolved in toluene (83 mL), and then added methyl 2-(Trifluoromethylsulfonyloxy)acrylic acid (4.94 g, 21.12 mmol) and 2 M sodium carbonate solution (35.2 mL). Thereafter, tetrakis(triphenylphosphino)palladium(0) (1.02 g, 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 extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over magnesium sulfate and concentrated at lower pressure. The obtained crude compound was purified by column chromatography (tank: 100 to 200 mesh; eluent: 10% ethyl acetate in n-hexane) to obtain methyl 2-(2-((4-fluoro)) Phenyl)((2-(trimethylindenyl)ethoxy)methyl)aminomethylmercapto)pyrimidin-5-yl)acrylic acid (5 g, 67%).

步驟5：於一500 mL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)胺基甲醯基)-嘧啶-5-基)丙烯酸(5.0 g)以醋酸乙酯(50 mL)溶解，並於氮氣氣氛下添加鈀活性炭(10%之鈀，500 mg)。該反應釜係於50 psi氫氣壓力下裝配至帕爾裝備。2小時候，薄層層析顯示起始原料被完全消耗。將該催化劑以矽藻土床過濾，並於較低壓力濃縮，以獲得甲基2-(2-((4-氟苯基)((2-(三甲基矽基)乙氧基)甲基)胺基甲醯基)嘧啶-5-基)丙酸(5 g，定量分析)。 Step 5: In a 500 mL Parr reactor, methyl 2-(2-((4-fluorophenyl)((2-(trimethylmethyl))ethoxy)methyl)amino) Methylmercapto)-pyrimidin-5-yl)acrylic acid (5.0 g) was dissolved in ethyl acetate (50 mL), and palladium activated carbon (10% palladium, 500 mg) was added under a nitrogen atmosphere. The kettle was assembled to a Parr apparatus at 50 psi hydrogen pressure. At 2 hours, thin layer chromatography showed that the starting material was completely consumed. The catalyst was filtered through a bed of diatomaceous earth and concentrated at a lower pressure to obtain methyl 2-(2-((4-fluorophenyl)((2-(trimethylmethyl))ethoxy)) Aminomethylmercaptopyrimidin-5-yl)propionic acid (5 g, quantitative analysis).

步驟6：將甲基2-(2-((4-氟苯基)((2-(三甲基矽基)乙氧基)甲基)胺基甲醯基)-嘧啶-5-基)丙酸(3.0 g，6.92 mmol)以乙醇(87 mL)溶解，並添加6N之鹽酸(87 mL)。將該反應混合物於90℃回流2小時。起始原料被完全消耗後，於較低壓力將乙醇蒸發，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，以6N之鹽酸將水層酸化，再以醋酸乙酯(3 x 50 mL)萃取。將混合有機層以硫酸鎂乾燥，並於較低壓力濃縮，以獲得純2-(2-(4-氟苯基胺基甲醯基)嘧啶-5-基)丙酸(700 mg，35%)。 Step 6: Methyl 2-(2-((4-fluorophenyl)((2-(trimethylmethyl)ethoxy)methyl)aminomethyl)pyrimidin-5-yl) Propionic acid (3.0 g, 6.92 mmol) was dissolved in ethanol (87 mL) and 6N hydrochloric acid (EtOAc) The reaction mixture was refluxed at 90 ° C for 2 hours. After the starting material was completely consumed, the ethanol was evaporated at a lower pressure, and the residue was diluted with water and acidified with a sodium carbonate solution. The aqueous layer was washed with ethyl acetate. Thereafter, the aqueous layer was acidified with 6N hydrochloric acid and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over magnesium sulfate and concentrated at lower pressure to afford pure 2-(2-(4-fluorophenylaminomethylmethyl)pyrimidin-5-yl)propanoic acid (700 mg, 35%) ).

1H NMR(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)；LCMS(M+H)：290；HPLC：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); LCMS (M+H): 290; HPLC: 97.71%.

步驟7：將1-羥基苯並三唑水合物(0.034 mL，0.251 mmol)、O-(1H-苯並三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸鹽(0.082 g，0.251 mmol)及N-二異丙基乙胺(0.034 mL，0.251 mmol)加至經攪拌、以四氫呋喃(2 mL)溶解之3-(銨甲基)-N-乙基-6-(三氟甲基)啶-2-胺(0.055 g，0.251 mmol)與2-(2-(4-氟苯基胺基甲醯基)嘧啶-5-基)丙酸(0.072 g，0.251 mmol)溶液，並將該反應混合物攪拌24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網目；溶析液：存在於醋酸乙酯之5%甲醇)純化所得之固體，以獲得5-(5-(2-(乙胺)-6-(三氟甲基)啶-3-基)-3-氧代戊烷-2-基)-N-(4-氟苯基)嘧啶-2-羧醯胺(74 mg，60%)。 Step 7: 1-Hydroxybenzotriazole hydrate (0.034 mL, 0.251 mmol), O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethylurea Hexafluorophosphate (0.082 g, 0.251 mmol) and N-diisopropylethylamine (0.034 mL, 0.251 mmol) were added to 3-(ammoniummethyl)-N- which was dissolved in tetrahydrofuran (2 mL). Ethyl-6-(trifluoromethyl)pyridin-2-amine (0.055 g, 0.251 mmol) and 2-(2-(4-fluorophenylaminocarbamimidyl)pyrimidin-5-yl)propanoic acid ( 0.072 g, 0.251 mmol) solution and the reaction mixture was stirred for 24 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: 5% methanol in ethyl acetate) to obtain 5- ( 5-(2-(ethylamine)-6-(trifluoromethyl)pyridin-3-yl)-3-oxopentan-2-yl)-N-(4-fluorophenyl)pyrimidin-2- Carboxylamamine (74 mg, 60%).

示範性化合物78至81係以類似方法製備而成。 Exemplary compounds 78 to 81 were prepared in a similar manner.

實例84之合成：Synthesis of Example 84:

2-(5-胺基-6-溴啶-2-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺 2-(5-Amino-6-bromodin-2-yl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl Methyl)propanamide

步驟1：將碘化亞銅(0.28 g，1.476 mmol)、碳酸銫(7 g，22.2 mmol)及砒啶甲酸(0.182 g，1.478 mmol)加至以1,4-二氧陸圜溶解之2-溴-5-硝基啶(1.5 g，7.4 mmol)及丙二酸二乙酯溶液。將該混合物回流。於混合物中添加水，並以醋酸乙酯萃取。將有機層以硫酸鎂乾燥，並將其過濾及濃縮。以管柱色層分析法純化殘留物，以獲得二乙基2-(5-硝基啶-2-基)丙二酸(2.9 g，99%)。 Step 1: Copper (II) iodide (0.28 g, 1.476 mmol), cesium carbonate (7 g, 22.2 mmol) and acridinecarboxylic acid (0.182 g, 1.478 mmol) were added to dissolve in 1,4-dioxane. -Bromo-5-nitropyridine (1.5 g, 7.4 mmol) and diethyl malonate solution. The mixture was refluxed. Water was added to the mixture and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered and concentrated. The residue was purified by column chromatography to give diethyl 2-(5-nitropyridin-2-yl)malonic acid (2.9 g, 99%).

步驟2：於0℃，將氫化鈉(0.4 g，15.4 mmol)及碘甲烷(0.6 mL，15.4 mmol)加至以二甲基甲醯胺溶解之二乙基2-(5-硝基啶-2-基)丙二酸(2.9 g，10.27 mmol)溶液。於該混合物添加水，並以醋酸乙酯萃取。將有機層以硫酸鎂乾燥，並將其過濾及濃縮。以管柱色層分析法純化殘留物，以獲得二乙基2-甲基-2-(5-硝基啶-2-基)丙二酸(0.956 g，32%)。 Step 2: Sodium hydride (0.4 g, 15.4 mmol) and methyl iodide (0.6 mL, 15.4 mmol) were added to diethyl 2-(5-nitropyridine) dissolved in dimethylformamide at 0 °C. 2-Base) malonic acid (2.9 g, 10.27 mmol) solution. Water was added to the mixture and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered and concentrated. The residue was purified by column chromatography to give diethyl 2-methyl-2-(5-nitropyridin-2-yl)malonic acid (0.956 g, 32%).

步驟3：將鐵(0.901 g，10.5 mmol)加至以醋酸溶解之二甲基2-甲基-2-(5-硝基啶-2-基)丙二酸(0.956 g，3.23 mmol)溶液。於該混 合物添加水，並以醋酸乙酯萃取。將有機層以硫酸鎂乾燥，並將其過濾及濃縮。以管柱色層分析法純化殘留物，以獲得二乙基2-(5-胺基啶-2-基)-2-甲基丙二酸(0.85 g，99%)。 Step 3: Add iron (0.901 g, 10.5 mmol) to a solution of dimethyl 2-methyl-2-(5-nitropyridin-2-yl)malonic acid (0.956 g, 3.23 mmol) dissolved in acetic acid . Water was added to the mixture and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered and concentrated. The residue was purified by column chromatography to give diethyl 2-(5-aminopyridin-2-yl)-2-methylmalonic acid (0.85 g, 99%).

步驟4：將溴化鈉(0.133 g，1.9 mmol)及過硫酸氫(oxone)(1.29 g，1.9 mmol)加至以水與丙酮溶解之二乙基2-(5-胺基啶-2-基)-2-甲基丙二酸(0.5 g，1.9 mmol)溶液。將該反應混合物於室溫攪拌3分鐘。於該混合物添加水，並以醋酸乙酯萃取。將有機層以硫酸鎂乾燥，並將其過濾及濃縮。以管柱色層分析法純化殘留物，以獲得二乙基2-(5-胺基-6-溴啶-2-基)-2-甲基丙二酸(0.36 g，41%)。 Step 4: Sodium bromide (0.133 g, 1.9 mmol) and oxone (1.29 g, 1.9 mmol) were added to diethyl 2-(5-aminopyridine-2- dissolved in water and acetone A solution of 2-methylmalonic acid (0.5 g, 1.9 mmol). The reaction mixture was stirred at room temperature for 3 minutes. Water was added to the mixture and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered and concentrated. The residue was purified by column chromatography to give diethyl 2-(5-amino-6-bromodin-2-yl)-2-methylmalonic acid (0.36 g, 41%).

步驟5：於0℃，將甲磺醯氯(0.1 mL，1.8 mmol)加至以啶溶解之二乙基2-(5-胺基-6-溴啶-2-基)-2-甲基丙二酸溶液。將該混合物於0℃攪拌30分鐘，再於室溫攪拌3小時。於該混合物添加水，並以醋酸乙酯萃取。將有機層以硫酸鎂乾燥，並將其過濾及濃縮。以管柱色層分析法純化殘留物，以獲得二乙基2-(6-溴-5-(甲基磺醯胺)啶-2-基)-2-甲基丙二酸(0.37 g，99%)。 Step 5: Add methanesulfonium chloride (0.1 mL, 1.8 mmol) to diethyl 2-(5-amino-6-bromodin-2-yl)-2-methyl dissolved in pyridine at 0 °C Malonic acid solution. The mixture was stirred at 0 ° C for 30 minutes and then at room temperature for 3 hours. Water was added to the mixture and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered and concentrated. The residue was purified by column chromatography to give diethyl 2-(6-bromo-5-(methylsulfonamide)-2-yl)-2-methylmalonic acid (0.37 g, 99%).

步驟6：將氫氧化鈉(0.042 g，1 mmol)加至以四氫呋喃溶解之二乙基2-(6-溴-5-(甲基磺醯胺)啶-2-基)-2-甲基丙二酸(0.215 g，0.5 mmol)溶液。將該混合物回流，隨後添加水，並將其以醋酸酸化。以二氯甲烷萃取該混合物。將有機層以硫酸鎂乾燥，並將其過濾及濃縮。以管柱色層分析法純化殘留物，以獲得2-(5-胺基-6-溴啶-2-基)丙酸(0.238 g，99%)。 Step 6: Add sodium hydroxide (0.042 g, 1 mmol) to diethyl 2-(6-bromo-5-(methylsulfonamide)-2-yl)-2-methyl dissolved in tetrahydrofuran A solution of malonic acid (0.215 g, 0.5 mmol). The mixture was refluxed, then water was added and it was acidified with acetic acid. The mixture was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and filtered and concentrated. The residue was purified by column chromatography to give 2-(5-amino-6-bromodin-2-yl)propanoic acid (0.238 g, 99%).

步驟7：於室溫，將1-乙基-3-(3-二甲基胺基丙基)碳二醯亞胺)(0.226 g，1.184 mmol)、1-羧苯並三唑(0.16 g，1.184mmol)及三乙胺(0.008 g，0.67 mmol)加至以1,4-二氧陸圜溶解之2-(5-胺基-6-溴啶-2-基)丙酸(0.238 g，0.74 mmol)及(2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺(0.201 g，0.74 mmol)。將該反應混合物於室溫 攪拌15小時，並添加水，再以醋酸乙酯萃取。將有機層以硫酸鎂乾燥，並將其過濾及濃縮。以管柱色層分析法純化殘留物，以獲得2-(5-胺基-6-溴啶-2-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺(0.2 g，54%)。 Step 7: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.226 g, 1.184 mmol), 1-carboxybenzotriazole (0.16 g) at room temperature , 1.184 mmol) and triethylamine (0.008 g, 0.67 mmol) were added to 2-(5-amino-6-bromodin-2-yl)propanoic acid (0.238 g) dissolved in 1,4-dioxane. , 0.74 mmol) and (2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methylamine (0.201 g, 0.74 mmol). The reaction mixture was stirred at room temperature for 15 hr and water was added and then ethyl acetate. The organic layer was dried over magnesium sulfate and filtered and concentrated. The residue was purified by column chromatography to give 2-(5-amino-6-bromodin-2-yl)-N-((2-(4-methylpiperidin-1-yl)- 6-(Trifluoromethyl)pyridin-3-yl)methyl)propanamide (0.2 g, 54%).

1H NMR(300 MHz，氘代氯仿)：δ 7.53(d，1H，J=7.68Hz，Ar-H)；7.20(d，1H，J=7.71Hz，Ar-H)；7.08(d，1H，J=8.04Hz，Ar-H)；6.09(m，2H，Ar-H及CO-NH)；4.47(m，2H，Ar-CH2)；4.10(br.s，2H，Ar-NH2)；3.69(q，1H，J=7.3Hz，Ar-CH)；3.37(m，2H，六氫嘧啶-H)；2.83(m，2H，六氫嘧啶-H)；1.72(m，2H，六氫嘧啶-H)；1.55(d，3H，J=7.14Hz，ArCH-CH3)；1.39(m，3H，六氫嘧啶-H與2H)；0.96(d，3H，J=7.3 Hz，六氫嘧啶-CH3)。 1 H NMR (300 MHz, deuterated chloroform): δ 7.53 (d, 1H, J = 7.68 Hz, Ar-H); 7.20 (d, 1H, J = 7.71 Hz, Ar-H); 7.08 (d, 1H) , J = 8.04 Hz, Ar-H); 6.09 (m, 2H, Ar-H and CO-NH); 4.47 (m, 2H, Ar-CH 2 ); 4.10 (br.s, 2H, Ar-NH 2 3.69 (q, 1H, J = 7.3 Hz, Ar-CH); 3.37 (m, 2H, hexahydropyrimidine-H); 2.83 (m, 2H, hexahydropyrimidine-H); 1.72 (m, 2H, Hexahydropyrimidine-H); 1.55 (d, 3H, J = 7.14 Hz, ArCH-CH 3 ); 1.39 (m, 3H, hexahydropyrimidine-H and 2H); 0.96 (d, 3H, J = 7.3 Hz, Hexahydropyrimidine-CH 3 ).

實例85之合成：Synthesis of Example 85:

2-(6-(2-羥乙胺)啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺 2-(6-(2-hydroxyethylamine)-3-yl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine-3- Methyl)propanamide

步驟1：於0℃，將以水(10 mL)溶解之氰化鈉(325 mg，6.79 mmol，1.1等量)溶液逐滴加至經攪拌、以乙醇(10 mL)溶解之2-氯-5-(氯甲基)啶(1 g，6.17 mmol，1.0等量)溶液，並於100℃攪拌3小時。將該反應混合物以水(50ml)稀釋，並以醋酸乙酯(70mLx2)萃取，以飽和之氯化鈉溶液(20mL)清洗，再以無水硫酸鈉乾燥，並於真空狀態將其蒸發。使用矽膠層析法(100至200網目)，以醋酸乙酯/石油醚(3：7)純化粗製產物，以獲得呈黃色固體狀之2-(6-氯啶-3-基)乙腈(400 mg，63%)。 Step 1: At 0 ° C, a solution of sodium cyanide (325 mg, 6.79 mmol, 1.1 equivalent) dissolved in water (10 mL) was added dropwise to 2-chloro-dissolved in ethanol (10 mL). A solution of 5-(chloromethyl)pyridine (1 g, 6.17 mmol, 1.0 eq.) was stirred at 100 ° C for 3 h. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. The crude product was purified using EtOAc (EtOAc (EtOAc) (EtOAc) Mg, 63%).

步驟2：將氫化鈉(1.578 g，65.7 mmol，1.0等量)分次加入經攪拌、冷卻至0℃、以四氫呋喃(100 mL)溶解之2-(6-氯啶-3-基)乙腈(10 g，65.7 mmol，1.0等量)溶液，並攪拌10分鐘。於0℃添加碘甲烷(4.02 mL，65.7 mmol，1.0等量)。以水(150ml)稀釋該反應混合物，以醋酸乙酯(100mLx2)及飽和之氯化鈉溶液(100 mL)萃取；以硫酸鈉將其乾燥，再將其於真空狀態蒸發。使用矽膠層析法(100至200網目)，以醋酸乙酯/石油醚(1：4)純化粗製產物，以獲得固體狀之2-(6-氯啶-3-基)丙腈(5 g，46%)。 Step 2: Sodium hydride (1.578 g, 65.7 mmol, 1.0 eq.) was added in portions with 2-(6-chloropyridin-3-yl)acetonitrile dissolved in THF (100 mL). 10 g, 65.7 mmol, 1.0 equal amount) solution 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 water (150 mL),EtOAcEtOAcEtOAc. The crude product was purified using ethyl acetate / petroleum ether (1:4) using silica gel chromatography (100 to 200 mesh) to give 2-(6-chloropyridin-3-yl)propionitrile as a solid (5 g , 46%).

步驟3：將TEA(3.34 mL，24.09 mmol，2.0等量)與N(2-甲氧基乙基)甲胺(1.8 g，24.09 mmol，2.0等量)加至經攪拌、以二甲亞碸(15 mL)溶解之2-(6-氯啶-3-基)丙腈(2 g，12.04 mmol，1.0等量)溶液，並將其於100℃加熱16小時。將該反應混合物以水(50mL)稀釋，並以醋酸乙酯(60 mL x 2)萃取。以飽和之氯化鈉溶液(50 mL)清洗有機層，以硫酸鈉乾燥，並於真空環境蒸發。以醋酸乙酯/石油醚(3：7)做為溶析液將殘留物純化，以獲得固體狀之2-(6-(2-甲氧基乙胺)啶-3-基)丙腈(500 mg，40%)。 Step 3: Add TEA (3.34 mL, 24.09 mmol, 2.0 equivalents) to N(2-methoxyethyl)methylamine (1.8 g, 24.09 mmol, 2.0 equivalent) to the stirred, dimethyl hydrazine (15 mL) a solution of 2-(6-chloropyridin-3-yl)propanenitrile (2 g, 12.04 mmol, 1.0 eq.) dissolved and heated at 100 ° C for 16 h. The reaction mixture was diluted with water (50 mL) andEtOAcEtOAc The organic layer was washed with a saturated aqueous solution of sodium chloride (50 mL), dried over sodium sulfate and evaporated. The residue was purified by using ethyl acetate / petroleum ether (3:7) as a solvent to give 2-(6-(2-methoxyethylamine)pyridin-3-yl)propanonitrile as a solid. 500 mg, 40%).

步驟4：將2-(6-(2-甲氧基乙胺)啶-3-基)丙腈(1.4 g，6.8 mmol，1.0等量)加至經攪拌、以甲醇(8 mL)溶解之三甲基氯矽烷(TMSCl)(4.6 mL，20.4 mmol，3.0等量)溶液，並於60℃加熱至5小時。將該反應混合物以水(50 mL)稀釋，並以碳酸氫鈉(10 mL)將其酸鹼值調整為pH9，再以醋酸乙酯(2 x 100mL)萃取。將有機層分離，並以飽和之氯化鈉溶液(50 mL)清洗，以硫酸鈉乾燥，並於真空狀態將其蒸發。以醋酸乙酯/石油醚(1：1)做為溶析液，將殘留物以矽凝膠管柱層析(100至200網目)純化，以獲得呈淡黃色液態之甲基2-(6-(2-甲氧基乙胺)啶-3-基)丙酸(1.2 g，74%)。 Step 4: 2-(6-(2-Methoxyethylamine) pyridine-3-yl)propanenitrile (1.4 g, 6.8 mmol, 1.0 eq.) was then stirred and dissolved in methanol (8 mL) A solution of trimethylchlorodecane (TMSCl) (4.6 mL, 20.4 mmol, 3.0 equivalent) was heated to 60 ° C for 5 hours. The reaction mixture was diluted with water (50 mL) and the pH was adjusted to pH with sodium bicarbonate (10 mL) 9, and extracted with ethyl acetate (2 x 100 mL). The organic layer was separated and washed with aq. EtOAc (EtOAc)EtOAc. Ethyl acetate/petroleum ether (1:1) was used as the eluent, and the residue was purified by hydrazine gel column chromatography (100 to 200 mesh) to obtain methyl 2-(6) in pale yellow liquid. -(2-Methoxyethylamine)pyridin-3-yl)propanoic acid (1.2 g, 74%).

步驟5：於-78℃，將化合物三溴化硼(BBr3)(9.4 mL，9.4 mmol，1.5等量)加至經攪拌、以二氯甲烷(20 mL)溶解之甲基2-(6-(2-甲氧基乙胺)啶-3-基)丙酸(1.5 g，6.3 mmol，1.0等量)溶液，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為約8，以水(100 mL)稀釋，再以醋酸乙酯萃取(150 mL x 2)。將混合有機層分離，以飽和之氯化鈉溶液清洗(100mL)，以硫酸鈉乾燥，再於真空狀態將其蒸發。以甲醇/氯仿(1：9)做為溶析液，將殘留物以矽凝膠管柱層析(100至200網目)純化，以獲得呈淡黃色之油性甲基2-(6-(2-羥乙胺)啶-3-基)丙酸(300 mg，21%)。 Step 5: Add the compound boron tribromide (BBr 3 ) (9.4 mL, 9.4 mmol, 1.5 equivalent) to the methyl 2-(6) dissolved in dichloromethane (20 mL) at -78 °C. A solution of (2-methoxyethylamine)pyridin-3-yl)propanoic acid (1.5 g, 6.3 mmol, 1.0 eq.) was stirred at room temperature for 3 hr. The pH of the reaction was adjusted to ca. 8 with sodium bicarbonate, diluted with water (100 mL) and ethyl acetate (150 mL x 2). The combined organic layers were separated, washed with a saturated sodium chloride solution (100 mL), dried over sodium sulfate and evaporated. Methanol/chloroform (1:9) was used as the eluent, and the residue was purified by hydrazine gel column chromatography (100 to 200 mesh) to obtain a pale yellow oily methyl 2-(6-(2) - hydroxyethylamine)pyridin-3-yl)propanoic acid (300 mg, 21%).

步驟6：於60℃，將氫氧化鋰(LiOH.H2O)(100 mg，4.33 mmol，3.0等量)加至經攪拌、以四氫呋喃/水(9 mL/9 mL)溶解之2-(6-(2-羥乙胺)啶-3-基)丙酸(324 mg，1.45 mmol，1.0等量)溶液，並攪拌16小時。將四氫呋喃蒸餾出，將該反應混合物以乙醚(10 mL)萃取，以1N之鹽酸將其酸化(pH 3-4)，再將溶媒蒸發。將殘留物懸浮於甲醇(10 mL)，並以超聲波處理15分鐘。將該混合物過濾，以無水Mg2SO4乾燥，並於真空狀態蒸發，以獲得2-(6-(2-羥乙胺)啶-3-基)丙酸(662 mg)；該產物不需進一步純化即可使用。 Step 6: Lithium hydroxide (LiOH.H 2 O) (100 mg, 4.33 mmol, 3.0 equivalent) was added to 2-(2) dissolved in tetrahydrofuran/water (9 mL/9 mL) at 60 °C. A solution of 6-(2-hydroxyethylamine)-3-yl)propanoic acid (324 mg, 1.45 mmol, 1.0 eq.) was stirred for 16 h. The tetrahydrofuran was distilled off, the reaction mixture was extracted with diethyl ether (10 mL), acidified (pH 3-4) with 1N hydrochloric acid, and the solvent was evaporated. The residue was suspended in methanol (10 mL) and sonicated for 15 min. The mixture was filtered, dried over anhydrous Mg 2 SO 4, and evaporated in vacuum to obtain 2- (6- (2-hydroxyethylamino) piperidin-3-yl) propanoic acid (662 mg); which was used without Further purification can be used.

步驟7：將亨氏鹼(Hünig′s base)(0.193 mL，1.14 mmol，4等 量)、1-羧苯並三唑(39 mg，0.29 mmol，1等量)及O-(苯並三唑-1-基)-N,N,N‘,N‘-四甲基脲六氟磷酸鹽(92 mg，0.29 mmol，1等量)加至經攪拌、以四氫呋喃/N,N-二甲基甲醯胺(2 mL/0.1 mL)溶解之2-(6-(2-羥乙胺)啶-3-基)丙酸(59 mg，0.29 mmol，1.0等量)溶液，再添加(2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺(77 mg，0.29 mmol，1等量)，並將該混合物於室溫攪拌16小時。將溶媒蒸發，並將殘留物以20 mL之醋酸乙酯溶解，再以20 mL之水萃取。將水層以3x20 mL之醋酸乙酯萃取，將有機相以Mg2SO4乾燥，將溶媒蒸發，並以線性梯度(以100%之醋酸乙酯開始，以醋酸乙酯/甲醇(80/20)結束；15管柱體(column voluminas))做為溶析液，將殘留物以管柱色層分析法純化，以獲得黃色油性之2-(6-(2-羥乙胺)啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺(化合物實例85，30 mg；23%)。 Step 7: Hünig's base (0.193 mL, 1.14 mmol, 4 equivalents), 1-carboxybenzotriazole (39 mg, 0.29 mmol, 1 equivalent) and O-(benzotriazole) -1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (92 mg, 0.29 mmol, 1 equivalent) added to the stirred, tetrahydrofuran/N,N-dimethyl A solution of 2-(6-(2-hydroxyethylamine)-3-yl)propanoic acid (59 mg, 0.29 mmol, 1.0 equivalent) dissolved in formamide (2 mL / 0.1 mL), then added (2- (4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methanamine (77 mg, 0.29 mmol, 1 eq.). hour. The solvent was evaporated, and the residue was dissolved in ethyl acetate (20 mL). The aqueous layer was extracted with 3x20 mL of ethyl acetate, the organic phase was dried Mg 2 SO 4, the solvent was evaporated, and (starting with 100% linear gradient of ethyl acetate to ethyl acetate / methanol (80/20 End; 15 column (column voluminas) as the eluent, the residue was purified by column chromatography to obtain yellow oily 2-(6-(2-hydroxyethylamine)pyridine-3 -yl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (Compound Example 85, 30 mg ;twenty three%).

實例86之合成：Synthesis of Example 86:

1-(6-(2-羥乙胺)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 1-(6-(2-hydroxyethylamine)-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine-3- Methyl)urea

步驟1：將2-氯-5-硝基啶(4.0 g)與2-胺乙醇(20 mL)於室溫一起攪拌1小時。將該反應化合物以水(30 mL)稀釋，並以醋酸乙酯(50 mL x 2)萃取，以飽和之氯化鈉溶液(20 mL)清洗，再以硫酸鈉乾燥，並於真空狀態蒸發。以正戊烷(25 mL)清洗殘留物，以獲得2-(5-硝基啶-2-基胺基)乙醇(4.16 g，91%，黃色固體)。薄層層析系統：甲醇/氯仿(1：19)；Rf：0.2。 Step 1: 2-Chloro-5-nitropyridine (4.0 g) was stirred with 2-amine ethanol (20 mL) 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 2-(5-nitropyridin-2-ylamino)ethanol (4.16 g, 91%, yellow solid). Thin layer chromatography system: methanol / chloroform (1:19); R f : 0.2.

步驟2：將10%之鈀碳(600 mg)加至經攪拌、以四氫呋喃(50 mL)溶解之2-(5-硝基啶-2-基胺基)乙醇(4.0g，21.85 mmol，1等量)溶液，並於氫氣氣球壓力(balloon pressure)下，於室溫攪拌16小時。使該反應混合物通過矽藻土，將其蒸發，並以以二乙醚(20 mL)清洗所獲得之殘留物，以獲得2-(5-胺基啶-2-基胺基)乙醇(3.02 g，90%)。薄層層析系統：甲醇/氯仿(3：17)；Rf：0.5。 Step 2: 10% palladium on carbon (600 mg) was added to 2-(5-nitropyridin-2-ylamino)ethanol (4.0 g, 21.85 mmol, 1), which was dissolved in tetrahydrofuran (50 mL). The solution was equilibrated and stirred at room temperature for 16 hours under a balloon pressure. The reaction mixture was passed through celite, evaporated, and the residue obtained was washed with diethyl ether (20 mL) to give 2-(5-aminopyridin-2-ylamino)ethanol (3.02 g) , 90%). Thin layer chromatography system: methanol/chloroform (3:17); Rf : 0.5.

步驟3：於0℃，依序將啶(4.7 mL，58.82 mmol，3等量)及氯甲酸苯酯(2.7 mL，21.56 mmol，1.1等量)加至經攪拌、以丙酮(35 mL)溶解之2-(5-胺基啶-2-基胺基)乙醇(3.0 g，19.60 mmol，1等量)溶液，並於室溫攪拌1小時。將溶媒蒸發，並將所得之殘留物以醋酸乙酯(150 mL)溶解，以水(50 mL)及飽和之氯化鈉溶液(50 mL)清洗並乾燥(硫酸鈉)；將該殘留物純化(以中性氧化鋁，甲醇/氯仿(1：49)做為溶析液)，以獲得苯基6-(2-羥乙胺)啶-3-基胺甲酸酯(0.80 g，19%，粉紅色固體)。薄層層析系統：甲醇/氯仿(1：9)；Rf：0.5。 Step 3: pyridine (4.7 mL, 58.82 mmol, 3 equivalents) and phenyl chloroformate (2.7 mL, 21.56 mmol, 1.1 equivalents) were added to the mixture at 0 ° C and dissolved in acetone (35 mL). A solution of 2-(5-aminopyridine-2-ylamino)ethanol (3.0 g, 19.60 mmol, 1 eq.) was stirred at room temperature for 1 hour. The solvent was evaporated, and the obtained residue was crystallised from ethyl acetate (150 mL), washed with water (50 mL) (Neutral alumina, methanol/chloroform (1:49) as the eluent) to obtain phenyl 6-(2-hydroxyethylamine)-3-ylcarbamate (0.80 g, 19%) , pink solid). Thin layer chromatography system: methanol / chloroform (1:9); R f : 0.5.

步驟4：依序將三乙胺(0.204 mL，1.47 mmol，4.0等量)及苯基6-(2-羥乙胺)啶-3-基胺甲酸酯(102 mg，0.375 mmol，1.02等量)加至經攪拌、以乙腈(9 mL)溶解之(2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基甲胺(100 mg，0.368 mmol，1.0等量)溶液，將其於回流下攪拌16小時。將該反應混合物於真空狀態濃縮，並純化殘留物 (管柱色層分析法，矽膠，以醋酸乙酯/甲醇(20：1)做為溶析液)，以獲得1-(6-(2-羥乙胺)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素(化合物實例86，mg；17%)。 Step 4: sequentially triethylamine (0.204 mL, 1.47 mmol, 4.0 equivalent) and phenyl 6-(2-hydroxyethylamine)-3-ylcarbamate (102 mg, 0.375 mmol, 1.02, etc.) (2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-ylmethylamine (100 mg, dissolved in acetonitrile (9 mL) A solution of 0.368 mmol, 1.0 eq.) was stirred under reflux for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified (p.p. 1) as a solution to obtain 1-(6-(2-hydroxyethylamine)-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6 -(Trifluoromethyl)pyridin-3-yl)methyl)urea (Compound Example 86, mg; 17%).

示範性化合物130與131係以類似方法製備而成。 Exemplary compounds 130 and 131 were prepared in a similar manner.

實例87之合成：Synthesis of Example 87:

2-(6-(2-甲氧基乙胺)啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺 2-(6-(2-Methoxyethylamine)pyridin-3-yl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine- 3-yl)methyl)propanamide

步驟1：於0℃，將以水(10 mL)溶解之氰化鈉(325 mg，6.79 mmol，1.1等量)溶液逐滴加至經攪拌、以乙醇(10 mL)溶解之2-氯-5-(氯甲基)啶(1 g，6.17 mmol，1.0等量)溶液，並於100℃攪拌3小時。將該反應混合物以水(50 mL)稀釋，以醋酸乙酯(70mL x 2)萃取，以飽和之氯化鈉溶液(20 mL)清洗，再以無水硫酸鈉乾燥，並於真空狀態蒸發。使用醋酸乙酯/石油醚(3：7)，以矽膠層析法(100至200網目)純化粗製產物，以獲得呈黃色固體狀之2-(6-氯啶-3- 基)乙腈(400 mg，63%)。薄層層析系統：醋酸乙酯/石油醚(2：3)；Rf：0.30。 Step 1: At 0 ° C, a solution of sodium cyanide (325 mg, 6.79 mmol, 1.1 equivalent) dissolved in water (10 mL) was added dropwise to 2-chloro-dissolved in ethanol (10 mL). A solution of 5-(chloromethyl)pyridine (1 g, 6.17 mmol, 1.0 eq.) was stirred at 100 ° C for 3 h. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. The crude product was purified using EtOAc (EtOAc (EtOAc) (EtOAc) Mg, 63%). Thin layer chromatography system: ethyl acetate / petroleum ether (2:3); Rf : 0.30.

步驟2：將氫化鈉(1.578 g，65.7 mmol，1.0等量)分次加至經攪拌、冷卻至0℃、以四氫呋喃(100 mL)溶解之2-(6-氯啶-3-基)乙腈(10 g，65.7 mmol，1.0等量)溶液，並攪拌10分鐘。於0℃添加碘甲烷(4.02 mL，65.7 mmol，1.0等量)。將該反應混合物以水(150 mL)稀釋，以醋酸乙酯(100 mL x 2)及飽和之氯化鈉溶液(100 mL)萃取，以硫酸鈉乾燥，再於真空狀態蒸發。使用醋酸乙酯/石油醚(1：4)，以矽膠層析法(100至200網目)純化粗製產物，以獲得固體狀之2-(6-氯啶-3-基)丙腈(5 g，46%)。薄層層析系統：醋酸乙酯/石油醚(3：7)；Rf：0.4。 Step 2: Sodium hydride (1.578 g, 65.7 mmol, 1.0 eq.) was added in portions to 2-(6-chloropyridin-3-yl)acetonitrile which was stirred and cooled to 0 ° C and dissolved in tetrahydrofuran (100 mL) (10 g, 65.7 mmol, 1.0 equivalent) solution and stir 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)EtOAc. The crude product was purified by silica gel chromatography (100 to 200 mesh) using ethyl acetate / petroleum ether (1: 4) to give 2-(6-chloropyridin-3-yl)propionitrile as a solid (5 g , 46%). Thin layer chromatography system: ethyl acetate / petroleum ether (3:7); Rf : 0.4.

步驟3：將TEA(3.34 mL，24.09 mmol，2.0等量)及N(2-甲氧基乙基)甲胺(1.8 g，24.09 mmol，2.0等量)加至經攪拌、以二甲亞碸(15 mL)溶解之2-(6-氯啶-3-基)丙腈(2 g，12.04 mmol，1.0等量)溶液，並於100℃加熱16小時。將該反應混合物以水(50 mL)稀釋，並以醋酸乙酯(60 mL x 2)萃取。以飽和之氯化鈉溶液(50mL)清洗有機層，以硫酸鈉乾燥，再於真空狀態將其蒸發。使用醋酸乙酯/石油醚(3：7)做為溶析液，以矽膠層析法(100至200網目)純化殘留物，以獲得呈白色固體狀之2-(6-(2-甲氧基乙胺)啶-3-基)丙腈(500 mg，40%)。薄層層析系統：醋酸乙酯/石油醚(4：1)；Rf：0.2。 Step 3: Add TEA (3.34 mL, 24.09 mmol, 2.0 equivalents) and N(2-methoxyethyl)methylamine (1.8 g, 24.09 mmol, 2.0 equivalents) to the stirred dimethyl hydrazine (15 mL) a solution of 2-(6-chloropyridin-3-yl)propanenitrile (2 g, 12.04 mmol, 1.0 eq.) dissolved and heated at 100 ° C for 16 h. The reaction mixture was diluted with water (50 mL) andEtOAcEtOAc The organic layer was washed with a saturated sodium chloride solution (50 mL), dried over sodium sulfate and evaporated. Ethyl acetate/petroleum ether (3:7) was used as the eluent, and the residue was purified by silica gel chromatography (100 to 200 mesh) to give 2-(6-(2-methoxy) as a white solid. Ethylamine)pyridin-3-yl)propanenitrile (500 mg, 40%). Thin layer chromatography system: ethyl acetate/petroleum ether (4:1); Rf : 0.2.

步驟4：將2-(6-(2-甲氧基乙胺)啶-3-基)丙腈(1.4 g，6.8 mmol，1.0等量)加至經攪拌、以甲醇(8 mL)溶解之三甲基氯矽烷(4.6 mL，20.4 mmol，3.0等量)溶液，並60℃於加熱5小時。將該反應混合物以水(50 mL)稀釋，並以碳酸氫鈉(10mL)將酸鹼值調整為約9，再以醋酸乙酯萃取(100mLx2)。將有機層分離，以飽和之氯化鈉溶液(50mL)清洗，以硫酸鈉乾燥，再於真空狀態蒸發。 使用醋酸乙酯/石油醚(1：1)做為溶析液，以矽膠層析法(100至200網目)純化殘留物，以獲得呈淡黃色液體狀之甲基2-(6-(2-甲氧基乙胺)啶-3-基)丙酸(1.2 g，74%)。薄層層析系統：醋酸乙酯/石油醚(3：2)；Rf：0.3。 Step 4: 2-(6-(2-Methoxyethylamine) pyridine-3-yl)propanenitrile (1.4 g, 6.8 mmol, 1.0 eq.) was then stirred and dissolved in methanol (8 mL) A solution of trimethylchlorodecane (4.6 mL, 20.4 mmol, 3.0 equivalent) was heated at 60 ° C for 5 hours. The reaction mixture was diluted with water (50 mL) and EtOAc (EtOAc) The organic layer was separated, washed with a saturated aqueous Ethyl acetate/petroleum ether (1:1) was used as the eluent, and the residue was purified by silica gel chromatography (100 to 200 mesh) to obtain methyl 2-(6-(2) as a pale yellow liquid. -Methoxyethylamine)pyridin-3-yl)propanoic acid (1.2 g, 74%). Thin layer chromatography system: ethyl acetate / petroleum ether (3:2); Rf : 0.3.

步驟5：於60℃，將氫氧化鋰-水(LiOH.H2O)(24 mg，1.0 mmol，3.0等量)加至將攪拌、以四氫呋喃/水(2 mL+2 mL)溶解之甲基2-(6-(2-甲氧基乙胺)啶-3-基)丙酸(83 mg，0.35 mmol，1.0等量)溶液，並攪拌16小時。將該反應混合物以水(1.5 mL)稀釋，以1N之鹽酸酸化(pH 3至4)，並將溶媒蒸發。將殘留物懸浮於醋酸乙酯/甲醇(6 mL+6 mL)，並以超聲波處理15分鐘。將該混合物過濾，以無水Mg2SO4乾燥，再於真空狀態蒸發，以獲得2-(6-(2-甲氧基乙胺)啶-3-基)丙酸(240 mg)，該產物不須進一步純化即可使用。 Step 5: Add lithium hydroxide-water (LiOH.H 2 O) (24 mg, 1.0 mmol, 3.0 equivalent) to the stirred, tetrahydrofuran/water (2 mL + 2 mL) solution at 60 ° C. A solution of 2-(6-(2-methoxyethylamine)-3-yl)propanoic acid (83 mg, 0.35 mmol, 1.0 eq.) was stirred and stirred for 16 hr. The reaction mixture was diluted with water (1.5 mL), acidified with 1N hydrochloric acid (pH 3 to 4) and evaporated. The residue was suspended in ethyl acetate / methanol (6 mL + 6 mL) and sonicated for 15 min. The mixture was filtered, dried with anhydrous Mg 2 SO 4, and evaporated in vacuum to obtain 2- (6- (2-methoxyethylamine) piperidin-3-yl) propanoic acid (240 mg), which was It can be used without further purification.

步驟6：將亨氏鹼(0.187 mL，1.10 mmol，4等量)、1-羧苯並三唑(37 mg，0.28 mmol，1等量)及O-(苯並三唑-1-基)-N,N,N‘,N‘-四甲基脲六氟磷酸鹽(89 mg，0.28 mmol，1等量)加至(2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺(75 mg，0.28 mmol，1等量)加至經攪拌、以四氫呋喃/N,N-二甲基甲醯胺(2 mL/0.1 mL)溶解之2-(6-(2-甲氧基乙胺)啶-3-基)丙酸(62 mg，0.28 mmol，1.0等量)溶液，再添加(2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺(75 mg，0.28 mmol，1等量)，並將該混合物於室溫攪拌3天。將溶媒蒸發，將殘留物以20 mL之醋酸乙酯溶解，並以20 mL之水萃取。以3x20 mL之醋酸乙酯萃取水層，將有機層以Mg2SO4乾燥，並將溶媒蒸發；用醋酸乙酯/環己烷(3：2)做為溶析液，以管柱色層分析法純化殘留物，以獲得無色油性之2-(6-(2-甲氧基乙胺)啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺(化 合物實例87，42 mg；32%)。 Step 6: Heinzine (0.187 mL, 1.10 mmol, 4 equivalents), 1-carboxybenzotriazole (37 mg, 0.28 mmol, 1 equivalent) and O-(benzotriazol-1-yl)- N,N,N',N'-tetramethylurea hexafluorophosphate (89 mg, 0.28 mmol, 1 equivalent) is added to (2-(4-methylpiperidin-1-yl)-6- ( Trifluoromethyl)pyridin-3-yl)methanamine (75 mg, 0.28 mmol, 1 equivalent) was added and stirred, dissolved in tetrahydrofuran/N,N-dimethylformamide (2 mL / 0.1 mL) a solution of 2-(6-(2-methoxyethylamine)-3-yl)propanoic acid (62 mg, 0.28 mmol, 1.0 eq.), followed by (2-(4-methylpiperidine-1) -yl)-6-(trifluoromethyl)pyridin-3-yl)methanamine (75 mg, 0.28 mmol, 1 eq.), and the mixture was stirred at room temperature for 3 days. The solvent was evaporated, and the residue was dissolved in ethyl acetate (20 mL) The aqueous layer was extracted with 3×20 mL of ethyl acetate, the organic layer was dried over Mg 2 SO 4 and the solvent was evaporated; ethyl acetate/cyclohexane (3:2) was used as the eluent to the column chromatography The residue was purified by analytical methods to give 2-(6-(2-methoxyethylamine)pyridin-3-yl)-N-((2-(4-methylpiperidin-1-yl) as a colorless oil. -6-(Trifluoromethyl)pyridin-3-yl)methyl)propanamide (Compound Example 87, 42 mg; 32%).

實例88之合成：Synthesis of Example 88:

1-(6-(2-甲氧基乙胺)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 1-(6-(2-Methoxyethylamine)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine- 3-yl)methyl)urea

步驟1：將2-氯-5-硝基啶(4.0 g)與2-甲氧基乙基胺(20 mL)於室溫攪拌1小時。將該反應混合物以水(30 mL)稀釋，以醋酸乙酯(50 mL x 2)萃取，以飽和之氯化鈉溶液(20 mL)清洗，再以硫酸鈉乾燥，並於真空狀態將其蒸發。以正戊烷(25 mL)清洗殘留物，以獲得N-(2-甲氧基乙基)-5-基啶-2-胺(4.8 g，87%，黃色固體)。 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 water (30 mL), EtOAc (EtOAc) (EtOAc) . The residue was washed with n-pentane (25 mL) to afford N-(2-methoxyethyl)-5-ylpyridin-2-amine (4.8 g, 87%, yellow solid).

步驟2：將10%之鈀碳(550 mg)加至經攪拌、以醋酸乙酯(50 mL)溶解之N-(2-甲氧基乙基)-5-硝基啶-2-胺(4.8g，22.84 mmol，1等量)溶液，隨後將其於氫氣氣球壓力下，於室溫攪拌16小時。使該反應混合物通過矽藻土，並於較低壓力蒸發。將所得之殘留物以戊烷(20 mL)清洗，以獲得N2-(2-甲氧基乙基)啶-2,5-二胺(3.51 g，87%)。 Step 2: 10% palladium on carbon (550 mg) was added to N-(2-methoxyethyl)-5-nitropyridin-2-amine (supplemented with ethyl acetate (50 mL). A solution of 4.8 g, 22.84 mmol, 1 equivalent) was then stirred at room temperature for 16 hours under a hydrogen balloon pressure. The reaction mixture was passed through diatomaceous earth and evaporated at a lower pressure. The residue obtained was washed with pentane (20 mL) to afford N2-(2-methoxyethyl)pyridine-2,5-diamine (3.51 g, 87%).

步驟3：於0℃，依序將啶(5.5 mL，68.25 mmol，3等量)與氯甲酸苯酯(3.2 mL，25.025 mmol，1.1等量)加至經攪拌、以丙酮(35 mL)溶解之N2-(2-甲氧基乙基)啶-2,5-二胺(3.8 g，22.75 mmol，1等量)溶液，並於室溫攪拌1小時。將溶媒蒸發，並將所得之殘留物以醋酸乙酯(150 mL)溶解，以水(50 mL)及飽和之氯化鈉溶液(50 mL)清洗、乾燥(硫酸鈉)及蒸發；將殘留物純化(矽膠；100至200網目；以甲醇/氯仿(1：99)做為溶析液)，以獲得苯基6-(2-甲氧基乙胺)啶-3-基胺甲酸酯(3.1 g，47%，白色固體)。 Step 3: sequentially add pyridine (5.5 mL, 68.25 mmol, 3 equivalents) to phenyl chloroformate (3.2 mL, 25.025 mmol, 1.1 equivalent) at 0 ° C until stirred and dissolved in acetone (35 mL) A solution of N2-(2-methoxyethyl)pyridine-2,5-diamine (3.8 g, 22.75 mmol, 1 equivalent) was stirred at room temperature for 1 hour. The solvent was evaporated, and the obtained residue was taken ethyl acetate (150 mL), washed with water (50 mL) and saturated sodium chloride solution (50 mL), dried (sodium sulfate) and evaporated; Purification (gelatin; 100 to 200 mesh; methanol/chloroform (1:99) as the eluent) to obtain phenyl 6-(2-methoxyethylamine)pyridine-3-ylcarbamate ( 3.1 g, 47%, white solid).

步驟4：依序將三乙胺(0.195 mL，1.41 mmol，4.0等量)及苯基-6-(2-甲氧基乙胺)啶-3-基胺甲酸酯(102 mg，0.359 mmol，1.02等量)加至經攪拌、以乙腈(8 mL)溶解之(2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺(96 mg，0.352 mmol，1.0等量)溶液，並將其於回流下攪拌16小時。將該反應混合物於真空狀態濃縮，再將殘留物純化(以管柱色層分析法，矽膠，以醋酸乙酯/甲醇(10：1)做為溶析液)，以獲得1-(6-(2-羥乙胺)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素(化合物實例89，mg；44%)。 Step 4: Triethylamine (0.195 mL, 1.41 mmol, 4.0 equivalent) and phenyl-6-(2-methoxyethylamine) pyridine-3-ylcarbamate (102 mg, 0.359 mmol) (1.02 equivalent) was added to (2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methylamine dissolved in acetonitrile (8 mL) (96 mg, 0.352 mmol, 1.0 eq.) solution was stirred at reflux for 16 h. The reaction mixture was concentrated under vacuum, and the residue was purified (by column chromatography, silica gel, ethyl acetate/methanol (10:1) as solvent) to obtain 1-(6- (2-Hydroxyethylamine)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl) Urea (Compound Example 89, mg; 44%).

實例89之合成：Synthesis of Example 89:

2-(6-((2-烴乙基)(甲基)胺基)啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺 2-(6-((2-hydrocarbylethyl)(methyl)amino)pyridin-3-yl)-N-((2-(4-methylpiperidin-1-yl)-6-) Fluoromethyl)pyridin-3-yl)methyl)propanamide

步驟1：於0℃，將以水(10 mL)溶解之氰化鈉(325 mg，6.79 mmol，1.1等量)溶液逐滴加至經攪拌、以乙醇溶解之氰化鈉(325 mg，6.79 mmol，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 mL)稀釋，並以醋酸乙酯(70mL x 2)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)，以矽膠層析法(100至200網目)純化粗製產物，以獲得呈黃色固體之2-(6-氯啶-3-基)乙腈(400 mg，63%)。薄層層析系統：醋酸乙酯/石油醚(2：3)；Rf：0.30。 Step 1: At 0 ° C, a solution of sodium cyanide (325 mg, 6.79 mmol, 1.1 equivalent) dissolved in water (10 mL) was added dropwise to the sodium cyanide dissolved in ethanol (325 mg, 6.79). A solution of mmol, 1.1 equivalents) was then stirred at 100 ° C for 3 hours. The reaction mixture was diluted with water (50 mL) andEtOAcEtOAc The organic layer was dried over 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) to afford 2-(6-chloropyridin-3-yl)acetonitrile as a yellow solid (400 mg , 63%). Thin layer chromatography system: ethyl acetate / petroleum ether (2:3); Rf : 0.30.

步驟2：於0℃，將氫化鈉(1.578 g，65.7 mmol，1.0等量)分次加至經攪拌、以四氫呋喃(100 mL)溶解之2-(6-氯啶-3-基)乙腈(10 g，65.7 mmol，1.0等量)溶液，並將其攪拌10分鐘，隨後於0℃添加碘甲烷(4.02 mL，65.7 mmol，1.0等量)，並於室溫攪拌5小時。將該反應混合物以水(150 mL)稀釋，以醋酸乙酯(100mL x 2)及飽和之氯化鈉溶液(100 mL)萃取，以硫酸鈉乾燥，再於真空狀態蒸發。使用醋酸乙酯/石油醚(1：4)做為溶析液，以矽膠層析法(100至200網目)純化該粗製產物，以獲得固體狀之2-(6-氯啶-3-基)丙 腈(5 g，46%)。薄層層析系統：醋酸乙酯/石油醚(3：7)；Rf：0.4。 Step 2: Sodium hydride (1.578 g, 65.7 mmol, 1.0 eq.) was added in portions to 2-(6-chloropyridin-3-yl)acetonitrile which was dissolved in tetrahydrofuran (100 mL). 10 g, 65.7 mmol, 1.0 eq.) solution was stirred for 10 min then iodomethane (4.02 mL, 65.7 mmol, 1.0 equivalent) was added at 0 ° C and stirred at room temperature for 5 h. The reaction mixture was diluted with EtOAc (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-chloropyridin-3-yl) ) Propionitrile (5 g, 46%). Thin layer chromatography system: ethyl acetate / petroleum ether (3:7); Rf : 0.4.

步驟3：依序將TEA(1.67 mL，12.04 mmol，2.0等量)及N(2-甲氧基乙基)甲胺(1.07 g，12.04 mmol，2.0等量)加至經攪拌、以二甲亞碸(7 mL)溶解之2-(6-氯啶-3-基)丙腈(1 g，6.02 mmol，1.0等量)溶液。將該混合物於100℃攪拌16小時，以水(50mL)稀釋，再以醋酸乙酯(60 mL x 2)萃取。以飽和之氯化鈉溶液(50mL)清洗有機層，將其以硫酸鈉乾燥，並於真空狀態蒸發。使用醋酸乙酯/石油醚(1：4)做為溶析液，以中性氧化鋁純化所得之殘留物，以獲得呈白色固體狀之2-(6-((2-甲氧基乙基)(甲基)胺基)啶-3-基)丙腈(600 mg，45%)。薄層層析系統：醋酸乙酯/石油醚(2：3)；Rf：0.3。 Step 3: Add TEA (1.67 mL, 12.04 mmol, 2.0 equivalent) and N(2-methoxyethyl)methylamine (1.07 g, 12.04 mmol, 2.0 equivalent) to the stirred, dimethyl A solution of 2-(6-chloropyridin-3-yl)propanenitrile (1 g, 6.02 mmol, 1.0 equivalent) dissolved in hydrazine (7 mL). The mixture was stirred at 100 &lt;0&gt;C for 16 h, diluted with water (50 mL) andEtOAc. The organic layer was washed with a saturated sodium chloride solution (50 mL). Ethyl acetate/petroleum ether (1:4) was used as the eluent, and the residue obtained was purified to purified crystals to afford 2-(6-(2-methoxyethyl) as a white solid. (Methyl)amino)pyridin-3-yl)propanenitrile (600 mg, 45%). Thin layer chromatography system: ethyl acetate / petroleum ether (2:3); Rf : 0.3.

步驟4：將2-(6-((2-甲氧基乙基)(甲基)胺基)啶-3-基)丙腈(1 g，22.8 mmol，5.0等量)加至經攪拌、以甲醇(0.73 mL，22.8 mmol，5.0等量)溶解之三甲基氯矽烷(3.0 mL，13.69 mmol，3.0等量)溶液，將其於60℃加熱5小時。將該反應混合物以水(50 mL)稀釋，並以碳酸氫鈉(10 mL)將酸鹼值調整至約9，再以醋酸乙酯(60 mL x 2)萃取。將有機層分離，並以飽和之氯化鈉溶液(50mL)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，以矽膠管柱色層分析法(100至200網目)純化殘留物，以獲得淡黃色油性之甲基2-(6-((2-甲氧基乙基)(甲基)胺基)啶-3-基)丙酸(700 mg，61%)。薄層層析系統：醋酸乙酯/石油醚(2：3)；Rf：0.3。 Step 4: Add 2-(6-((2-methoxyethyl)(methyl)amino)pyridin-3-yl)propanenitrile (1 g, 22.8 mmol, 5.0 equivalent) to stirring, A solution of trimethylchloromethane (3.0 mL, 13.69 mmol, 3.0 eq.) dissolved in methanol (0.73 mL, 22.8 mmol, 5.0 eq.) was heated at 60 ° C for 5 hours. The reaction mixture was diluted with water (50 mL) and EtOAc (EtOAc) (EtOAc) The organic layer was separated and washed with aq. EtOAc (EtOAc) Ethyl acetate/petroleum ether (2:3) was used as the eluent, and the residue was purified by silica gel column chromatography (100 to 200 mesh) to obtain pale yellow oily methyl 2-(6-( (2-Methoxyethyl)(methyl)amino)pyridin-3-yl)propanoic acid (700 mg, 61%). Thin layer chromatography system: ethyl acetate / petroleum ether (2:3); Rf : 0.3.

步驟5：於-78℃，將化合物三溴化硼(1.61 mL，16.8 mmol，2.0等量)加至經攪拌、以二氯甲烷(20 mL)溶解之甲基2-(6-((2-甲氧基乙基)(甲基)胺基)啶-3-基)丙酸(2.0 g，7.93 mmol，1.0等量)溶液，將其於室溫攪拌3小時，並以碳酸氫鈉將酸鹼值調整至約8，再以水(100 mL)稀釋。以醋酸乙酯(150mL x 2)萃取水層，將混合有機層分離，並以飽和之氯化鈉溶液(100mL)清洗，以硫酸鈉乾 燥，並於真空狀態蒸發。以醋酸乙酯/石油醚(7：3)做為溶析液，以矽膠管柱色層分析法(100至200網目)純化殘留物，以獲得呈淡黃色油性之甲基2-(6-((2-烴乙基)(甲基)胺基)啶-3-基)丙酸(800 mg，42%)。薄層層析系統：醋酸乙酯/石油醚(4：1)；Rf：0.15。 Step 5: Add the compound boron tribromide (1.61 mL, 16.8 mmol, 2.0 equivalent) to the methyl 2-(6-(2) dissolved in dichloromethane (20 mL) at -78 °C. a solution of (methoxyethyl)(methyl)amino)pyridin-3-yl)propanoic acid (2.0 g, 7.93 mmol, 1.0 eq.), which was stirred at room temperature for 3 h and then sodium bicarbonate The pH was adjusted to about 8, and then diluted with water (100 mL). The aqueous layer was extracted with EtOAc (EtOAc) (EtOAc) Ethyl acetate/petroleum ether (7:3) was used as the eluent, and the residue was purified by silica gel column chromatography (100 to 200 mesh) to obtain a pale yellow oily methyl 2-(6- ((2-Hydroxyethyl)(methyl)amino)pyridin-3-yl)propanoic acid (800 mg, 42%). Thin layer chromatography system: ethyl acetate / petroleum ether (4:1); Rf : 0.15.

步驟6：於60℃，將氫氧化鋰-水(LiOH.H2O)(24 mg，1.0 mmol，3.0等量)加至經攪拌、以四氫呋喃/水(2 mL+2 mL)溶解之甲基2-(6-((2-烴乙基)(甲基)胺基)啶-3-基)丙酸(83 mg，0.35 mmol，1.0等量)溶液，並攪拌16小時。將該反應混合物以水(1.5 mL)稀釋，以1N之鹽酸酸化(pH 3至4)，並將溶媒蒸發。將殘留物懸浮於醋酸乙酯/甲醇(6 mL+6 mL)，並以超聲波處理15分鐘。將該混合物過濾，以無水Mg2SO4乾燥，並於真空狀態蒸發，以獲得2-(6-((2-烴乙基)(甲基)胺基)啶-3-基)丙酸(138 mg)，該產物不需進一步純化即可使用。 Step 6: Add lithium hydroxide-water (LiOH.H 2 O) (24 mg, 1.0 mmol, 3.0 equivalent) to the stirred solution in tetrahydrofuran/water (2 mL + 2 mL) at 60 °C. A solution of 2-(6-((2-hydrocarbyl))(methyl)amino)pyridin-3-yl)propanoic acid (83 mg, 0.35 mmol, 1.0 eq.) was stirred for 16 h. The reaction mixture was diluted with water (1.5 mL), acidified with 1N hydrochloric acid (pH 3 to 4) and evaporated. The residue was suspended in ethyl acetate / methanol (6 mL + 6 mL) and sonicated for 15 min. The mixture was filtered, dried over anhydrous Mg 2 SO 4 and evaporated in vacuo to afford 2-(6-((2-(ethyl)ethyl))) 138 mg), the product was used without further purification.

步驟7：將亨氏鹼(0.186 mL，1.10 mmol，4等量)、1-羧苯並三唑(37 mg，0.28 mmol，1等量)及O-(苯並三唑-1-基)-N,N,N‘,N‘-四甲基脲六氟磷酸鹽(89 mg，0.28 mmol，1等量)加至經攪拌、以四氫呋喃/N,N-二甲基甲醯胺(2 mL/0.1 mL)溶解之2-(6-((2-烴乙基)(甲基)胺基)啶-3-基)丙酸(61 mg，0.28 mmol，1.0等量)溶液，再添加(2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺(74 mg，0.28 mmol，1等量)；將該混合物於室溫攪拌16小時。將溶媒蒸發，並將殘留物以20 mL之醋酸乙酯溶解，再以20 mL之水萃取。以3x20 mL之醋酸乙酯萃取水層，將有機相以Mg2SO4乾燥，並將溶媒蒸發；以線性梯度(以100%之醋酸乙酯開始，以醋酸乙酯/乙醇(95/5)結束；10管柱體)做為溶析液，以管柱色層分析法純化殘留物，以獲得黃色油性之2-(6-((2-烴乙基)(甲基)胺基)啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺(化 合物實例89，49 mg；37%)。 Step 7: Heinzine base (0.186 mL, 1.10 mmol, 4 equivalents), 1-carboxybenzotriazole (37 mg, 0.28 mmol, 1 equivalent) and O-(benzotriazol-1-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (89 mg, 0.28 mmol, 1 equivalent) was added to the stirred, tetrahydrofuran/N,N-dimethylformamide (2 mL) /0.1 mL) dissolved 2-(6-((2-hydrocarbyl))(methyl)amino)pyridin-3-yl)propanoic acid (61 mg, 0.28 mmol, 1.0 equivalent) solution, then added ( 2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methanamine (74 mg, 0.28 mmol, 1 eq.); 16 hours. The solvent was evaporated, and the residue was dissolved in ethyl acetate (20 mL). The aqueous layer was extracted with 3×20 mL of ethyl acetate. The organic phase was dried over Mg 2 SO 4 and solvent evaporated. A gradient gradient starting with 100% ethyl acetate with ethyl acetate/ethanol (95/5) The residue is purified by column chromatography to obtain a yellow oily 2-(6-((2-hydrocarbylethyl)(methyl)amino)pyridine. 3-yl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (Compound Example 89, 49 mg; 37%).

實例90之合成：Synthesis of Example 90:

1-(6-((2-烴乙基)(甲基)胺基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 1-(6-((2-hydrocarbylethyl)(methyl)amino)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(3- Fluoromethyl)pyridin-3-yl)methyl)urea

步驟1：將2-氯-5-硝基啶(4.0 g)與2-甲基胺乙醇(20 mL)於室溫攪拌1小時。將該反應混合物以水(30 mL)稀釋，以醋酸乙酯(50 mL x 2)萃取，以飽和之氯化鈉溶液(20 mL)清洗，再以硫酸鈉乾燥，並於真空狀態蒸發。以正戊烷(25 mL)清洗殘留物，以獲得2-(甲基(5-硝基啶-2-基)胺基)乙醇(4.5 g，91%，黃色固體)。薄層層析系統：甲醇/氯仿(1：19)；Rf：0.4。 Step 1: 2-Chloro-5-nitropyridine (4.0 g) and 2-methylamine ethanol (20 mL) were stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. The residue was washed with n-pentane (25 mL) to give 2-(methyl(5-nitropyridin-2-yl)amino)ethanol (4.5 g, 91%, yellow solid). Thin layer chromatography system: methanol / chloroform (1:19); R f : 0.4.

步驟2：將10%之鈀碳(550 mg)加至經攪拌、以醋酸乙酯(50 mL)溶解之2-(甲基(5-硝基啶-2-基)胺基)乙醇(4.8 g，24.36 mmol，1等量)溶液，並於氫氣氣球壓力下，於室溫攪拌16小時。使該反應混合物通過矽藻土，並於較低壓力蒸發。將所得之殘留物以二乙醚(20 mL)清洗，以獲得2-((5-胺基啶-2-基)(甲基)胺基)乙醇(3.3 g，8%)。薄層層析系統：甲醇/氯仿(1：9)；Rf：0.4。 Step 2: 10% palladium on carbon (550 mg) was added to 2-(methyl(5-nitropyridin-2-yl)amino)ethanol (4.8) dissolved in ethyl acetate (50 mL). g, 24.36 mmol, 1 equivalent) solution, and stirred at room temperature for 16 hours under hydrogen balloon pressure. The reaction mixture was passed through diatomaceous earth and evaporated at a lower pressure. The residue obtained was washed with diethyl ether (20 mL) to afford 2-((5-aminopyridin-2-yl)(methyl)amino)ethanol (3.3 g, 8%). Thin layer chromatography system: methanol / chloroform (1:9); R f : 0.4.

步驟3：於0℃，依序將啶(4.0 mL，50.25 mmol，3等量)與氯甲酸苯酯)(2.3 mL，18.425 mmol，1.1等量)加至經攪拌、以丙酮(40 mL)溶解之2-((5-胺基啶-2-基)(甲基)胺基)乙醇(3.3 g，16.75 mmol，1等量)溶液，並於室溫攪拌1小時。將溶媒蒸發，並將殘留物以醋酸乙酯(150 mL)溶解，以水(50 mL)及飽和之氯化鈉溶液(50 mL)清洗，將其乾燥(硫酸鈉)，並純化(矽膠，100至200網目；以甲醇/氯仿(1：19)做為溶析液)，以獲得苯基6-((2-烴乙基)(甲基)胺基)啶-3-基胺甲酸酯(1.2 g，25%，綠色固體)。薄層層析系統：甲醇/氯仿(1：19)；Rf：0.4。 Step 3: sequentially add pyridine (4.0 mL, 50.25 mmol, 3 equivalents) to phenyl chloroformate (2.3 mL, 18.425 mmol, 1.1 equivalent) to 0 ° C, stirring to acetone (40 mL) A solution of 2-((5-aminopyridin-2-yl)(methyl)amino)ethanol (3.3 g, 16.75 mmol, 1 equivalent) was dissolved and stirred at room temperature for 1 hour. The solvent was evaporated, and the residue was purified ethyl acetate (150 mL). 100 to 200 mesh; methanol/chloroform (1:19) as the eluent) to obtain phenyl 6-((2-hydrocarbyl)(methyl)amino)pyridin-3-ylaminecarboxylic acid Ester (1.2 g, 25%, green solid). Thin layer chromatography system: methanol / chloroform (1:19); R f : 0.4.

步驟4：依序將三乙胺(0.193 mL，1.41 mmol，4.0等量)及苯基6-((2-烴乙基)(甲基)胺基)啶-3-基胺甲酸酯(102 mg，0.355 mmol，1.02等量)加至經攪拌、以乙腈(8 mL)溶解之(2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺(95 mg，0.35 mmol，1.0等量)溶液，將其於回流下攪拌16小時。於真空狀態下將該反應混合物濃縮，並純化殘留物(管柱色層分析法，矽膠，以醋酸乙酯/環己烷(9：1)做為溶析液)，以獲得1-(6-((2-烴乙基)(甲基)胺基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素(化合物實例90，59 mg，36%)。 Step 4: sequentially triethylamine (0.193 mL, 1.41 mmol, 4.0 equivalent) and phenyl 6-((2-hydrocarbyl)(methyl)amino)pyridin-3-ylcarbamate ( 102 mg, 0.355 mmol, 1.02 eq.) (2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine-3 was dissolved in acetonitrile (8 mL). A solution of methylamine (95 mg, 0.35 mmol, 1.0 eq.) was stirred at reflux for 16 h. The reaction mixture was concentrated under vacuum, and the residue was purified (column chromatography, silica gel, ethyl acetate / cyclohexane (9:1) as solvent) to obtain 1-(6) -((2-hydrocarbylethyl)(methyl)amino)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl) Pyridin-3-yl)methyl)urea (Compound Example 90, 59 mg, 36%).

實例91之合成：Synthesis of Example 91:

1-(6-((2-甲氧基乙基)(甲基)胺基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 1-(6-((2-methoxyethyl)(methyl)amino)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6- (trifluoromethyl)pyridin-3-yl)methyl)urea

步驟1：將2-氯-5-硝基啶(3.0 g)與2-甲氧基乙基甲基胺(10 mL)於室溫攪拌1小時。將該反應混合物以水(50 mL)稀釋，以醋酸乙酯(150 mL x 2)萃取，以飽和之氯化鈉溶液(50 mL)清洗，以硫酸鈉乾燥，並將其濃縮，以獲得N-(2-甲氧基乙基)-N-甲基-5-硝基啶-2-胺(3.3 g，83%，黃色固體)。薄層層析系統：醋酸乙酯/石油醚(1：1)；Rf：0.40。 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) -(2-Methoxyethyl)-N-methyl-5-nitropyridin-2-amine (3.3 g, 83%, yellow solid). Thin layer chromatography system: ethyl acetate / petroleum ether (1:1); R f : 0.40.

步驟2：將10%之鈀碳(450 mg)加至經攪拌、以醋酸乙酯(35 mL)溶解之N-(2-甲氧基乙基)-N-甲基-5-硝基啶-2-胺(3.3g，15.63 mmol，1等量)溶液，於氫氣氣球壓力下，將其於室溫攪拌16小時。隨後使該反應混合物通過矽藻土並將其濃縮。以戊烷(20 mL)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 g，73%)。薄層層析系統：甲醇/氯仿(1：19)；Rf：0.6。 Step 2: 10% palladium on carbon (450 mg) was added to N-(2-methoxyethyl)-N-methyl-5-nitropyridine dissolved in ethyl acetate (35 mL). A solution of 2-amine (3.3 g, 15.63 mmol, 1 eq.) was stirred at room temperature for 16 hr under hydrogen balloon pressure. The reaction mixture was then passed through celite and concentrated. The residue was washed with pentane (20 mL) to afford N2-(2-methoxyethyl)-N2-methyl <RTIgt; Thin layer chromatography system: methanol / chloroform (1:19); R f : 0.6.

步驟3：於0℃，依序將啶(4.3 mL，33.12 mmol，3等量)及氯甲酸苯酯(2.46 mL，12.144 mmol，1.1等量)加至經攪拌、以丙酮(30 mL)溶解之N2-(2-甲氧基乙基)-N2-甲基啶-2,5-二胺(2.0 g，11.04 mmol，1等量)溶液，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 mL)溶解，以水(50 mL)及飽和之氯化鈉溶液 (50 mL)清洗，將其乾燥(硫酸鈉)並蒸發，隨後將殘留物純化(矽膠：100至200網目；以醋酸乙酯/石油醚(2：3)做為溶析液)，以獲得苯基6-((2-甲氧基乙基)(甲基)胺基)啶-3-基胺甲酸酯(2.56 g，77%，白色固體)。薄層層析系統：甲醇/氯仿(1：49)；Rf：0.5。 Step 3: pyridine (4.3 mL, 33.12 mmol, 3 equivalents) and phenyl chloroformate (2.46 mL, 12.144 mmol, 1.1 equivalents) were added to the mixture at 0 ° C and dissolved in acetone (30 mL). A solution of N2-(2-methoxyethyl)-N2-methylpyridine-2,5-diamine (2.0 g, 11.04 mmol, 1 equivalent) was stirred at room temperature for 1 hour. The reaction mixture and the residue were dissolved in ethyl acetate (150 mL), washed with water (50 mL) and saturated sodium chloride solution (50 mL), dried (sodium sulfate) and evaporated Purification (tank: 100 to 200 mesh; ethyl acetate/petroleum ether (2:3) as the eluent) to obtain phenyl 6-((2-methoxyethyl)(methyl)amine Pyridin-3-ylcarbamate (2.56 g, 77%, white solid). Thin layer chromatography system: methanol / chloroform (1:49); R f : 0.5.

步驟4：依序將三乙胺(0.264 mL，1.90 mmol，4.0等量)及苯基6-((2-甲氧基)(甲基)胺基)啶-3-基胺甲酸酯(146 mg，0.486 mmol，1.02等量)加至經攪拌、以乙腈(9 mL)溶解之(2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺(130 mg，0.476 mmol，1.0等量)溶液，將其於回流下攪拌16小時。於真空狀態將該反應混合物濃縮，並將殘留物純化(管柱色層分析法：矽膠，以醋酸乙酯/環己烷(4：1)做為溶析液)，以獲得1-(6-((2-甲氧基乙基)(甲基)胺基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素(化合物實例91，89 mg；39%)。 Step 4: sequentially triethylamine (0.264 mL, 1.90 mmol, 4.0 equivalent) and phenyl 6-((2-methoxy)(methyl)amino)pyridin-3-ylcarbamate ( 146 mg, 0.486 mmol, 1.02 eq.) (2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine-3 was dissolved in acetonitrile (9 mL). A solution of methylamine (130 mg, 0.476 mmol, 1.0 eq.) was stirred at reflux for 16 h. The reaction mixture was concentrated under vacuum and the residue was purified (p.p. chromatography: EtOAc (EtOAc: EtOAc) -((2-methoxyethyl)(methyl)amino)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl) Base pyridine-3-yl)methyl)urea (Compound Example 91, 89 mg; 39%).

實例96之合成：Synthesis of Example 96:

2-(5-氟-6-(甲基磺醯胺)啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺 2-(5-Fluoro-6-(methylsulfonamide)pyridin-3-yl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl) Pyridin-3-yl)methyl)propanamide

步驟1：於氮氣氣氛下，於一圓底燒瓶中，加入以無水二甲基甲醯胺(5 mL)溶解之叔丁醇鉀(0.473 g，4221 mmol)，並於室溫攪拌10分鐘。隨後，將其冷卻至-20℃，並添加3-氟-2-硝基啶(200 mg，1.407 mmol)，再逐滴添加2-氯-丙酮酸乙酯(0.273 mL，2.111 mol)，並攪拌20分鐘。隨後，添加經稀釋之鹽酸，並於室溫攪拌10分鐘。以醋酸乙酯萃取，以水清洗，以硫酸鎂乾燥並過濾，再將溶媒蒸發，最後，以管柱色層分析法純化，以獲得2-(5-氟-6-硝基-啶-3-基)-丙酮酸乙酯(153 mg，45%)。 Step 1: Potassium tert-butoxide (0.473 g, 4221 mmol) dissolved in anhydrous dimethylformamide (5 mL) was added to a EtOAc. Subsequently, it was cooled to -20 ° C, and 3-fluoro-2-nitropyridine (200 mg, 1.407 mmol) was added, followed by dropwise addition of ethyl 2-chloro-pyruvate (0.273 mL, 2.11 mol). Stir for 20 minutes. Subsequently, diluted hydrochloric acid was added and stirred at room temperature for 10 minutes. Extracted with ethyl acetate, washed with water, dried over magnesium sulfate and filtered, and then evaporated, and finally purified by column chromatography to obtain 2-(5-fluoro-6-nitro-pyridine-3 -yl)-ethyl pyruvate (153 mg, 45%).

步驟2：將2-(5-氟-6-硝基-啶-3-基)-丙酮酸乙酯(100 mg)置放於一圓底燒瓶中，並依序添加乙醇及鈀碳(20 wt%)，再於氫氣存在之條件下，於室溫攪拌2小時。隨後，將其以矽藻土床過濾，並將溶媒蒸發，以獲得2-(6-胺基-5-氟-啶-3-基)-丙酮酸乙酯(69 mg，79%)。 Step 2: Ethyl 2-(5-fluoro-6-nitro-pyridin-3-yl)-pyruvate (100 mg) was placed in a round bottom flask, and ethanol and palladium on carbon (20 wt. %), and stirred at room temperature for 2 hours in the presence of hydrogen. Subsequently, it was filtered over a pad of celite, and the solvent was evaporated to give ethyl 2-(6-amino-5-fluoro-pyridin-3-yl)-pyruvate (69 mg, 79%).

步驟3：於氮氣氣氛下，將2-(6-胺基-5-氟-啶-3-基)-丙酮酸乙酯(1.525 g，7.185 mmol)置放於一圓體燒瓶中，添加無水四氫呋喃 (14 mL)並將其攪拌。隨後將其冷卻至0℃，並依序添加三乙胺(2.181 mL，21.555 mmol)及甲磺醯氯(0.837 mL，10.778 mmol)，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2-(5-氟基-6-甲烷磺醯胺基-啶-3-基)-丙酮酸乙酯(1.39 g，67%)。 Step 3: Ethyl 2-(6-amino-5-fluoro-pyridine-3-yl)-pyruvate (1.525 g, 7.185 mmol) was placed in a round flask under anhydrous nitrogen, 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 methanesulfonium chloride (0.837 mL, 10.778 mmol) were added sequentially 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 2-(5-fluoro- 6-Methanesulfonylamino-pyridin-3-yl)-pyruvate ethyl ester (1.39 g, 67%).

步驟4：將2-(5-氟基-6-甲烷磺醯胺基-啶-3-基)-丙酸(110 mg，0.378 mmol)乙基酯置放於一圓底燒瓶中，隨後添加四氫呋喃(5 mL)，並將其冷卻至0℃，隨後逐滴添加以水(5 mL)溶解之氫氧化鋰單水化物(0.039 g，0.947 mmol)溶液，再於室溫攪拌2小時。隨後以醋酸乙酯萃取該反應混合物，以水清洗，並以經稀釋之鹽酸將水層酸化，再次以醋酸乙酯萃取，並以水清洗，以硫酸鎂乾燥，將其過濾，並將溶媒蒸發，以獲得2-(5-氟基-6-(甲基磺醯胺)啶-3-基)丙酸(59 mg，60%)。 Step 4: 2-(5-Fluoro-6-methanesulfonylamino-pyridin-3-yl)-propionic acid (110 mg, 0.378 mmol) ethyl ester was placed in a round bottom flask, followed by the addition of tetrahydrofuran (5 mL), and cooled to 0 ° C, then a solution of lithium hydroxide monohydrate (0.039 g, 0.947 mmol) dissolved in water (5 mL) was added dropwise, and then stirred at room temperature for 2 hours. The reaction mixture was then extracted with ethyl acetate, washed with water, and the aqueous layer was acidified with diluted hydrochloric acid, extracted again with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and evaporated To give 2-(5-fluoro-6-(methylsulfonamide)-3-yl)propanoic acid (59 mg, 60%).

步驟5：將2-(5-氟基-6-(甲基磺醯胺)啶-3-基)丙酸(100 mg，0.365 mmol)置放於一圓底燒瓶中，並於氮氣氣氛下添加二甲基甲醯胺(5 mL)。隨後，添加1-乙基-3-(3-二甲基胺基丙基)碳二醯亞胺)(104 mg，0.547 mmol)及1-羧苯並三唑(74 mg，0.547 mmol)，並攪拌1小時。再添加(2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺(96 mg，0.365 mmol)，並於室溫攪拌4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，再以管柱色層分析法進行純化，以獲得白色固體狀之2-(5-氟基-6-(甲基磺醯胺)啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺(144 mg，73%)。 Step 5: 2-(5-Fluoro-6-(methylsulfonamide)-3-yl)propanoic acid (100 mg, 0.365 mmol) was placed in a round bottom flask and was added under nitrogen. Dimethylformamide (5 mL). Subsequently, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) (104 mg, 0.547 mmol) and 1-carboxybenzotriazole (74 mg, 0.547 mmol) were added. Stir for 1 hour. (2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methanamine (96 mg, 0.365 mmol). 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 2-(5-fluoro) as a white solid. 5--6-(methylsulfonamide)pyridin-3-yl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl )methyl)propanamide (144 mg, 73%).

1H NMR(300MHz，氘代氯仿)：δ 8.04(s，1H，Ar-H)；7.53(dd，2H，Ar-H，J=2.01Hz)；7.24(d，1H，Ar-H，J=7.68Hz)；6.43(s， 1H，R-NH)；4.51(m，2H，Ar-CH2)；3.56(q，1H，J=6.6 Hz，Ar-CH)；3.47(s，1H，Ar-MS)；3.33(t，2H，J=11.34 Hz，六氫嘧啶-H)；1.73(br.s，2H，六氫嘧啶-H)；1.54(d，3H，J=7.14 Hz，ArCH-CH3)；1.26(m，2H，六氫嘧啶-H)；1.00(d，3H，J=6.6 Hz，六氫嘧啶-CH3)。 1 H NMR (300MHz, deuteriochloroform): δ 8.04 (s, 1H , Ar-H); 7.53 (dd, 2H, Ar-H, J = 2.01Hz); 7.24 (d, 1H, Ar-H, J = 7.68 Hz); 6.43 (s, 1H, R-NH); 4.51 (m, 2H, Ar-CH 2 ); 3.56 (q, 1H, J = 6.6 Hz, Ar-CH); 3.47 (s, 1H, Ar-MS); 3.33 (t, 2H, J = 11.34 Hz, hexahydropyrimidine-H); 1.73 (br.s, 2H, hexahydropyrimidine-H); 1.54 (d, 3H, J = 7.14 Hz, ArCH -CH 3 ); 1.26 (m, 2H, hexahydropyrimidine-H); 1.00 (d, 3H, J = 6.6 Hz, hexahydropyrimidine-CH 3 ).

實例97之合成：Synthesis of Example 97:

2-(5-甲氧基-6-(甲基磺醯胺)啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺 2-(5-Methoxy-6-(methylsulfonamide)pyridin-3-yl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl) Pyridin-3-yl)methyl)propanamide

步驟1：於氮氣氣氛下，將叔丁醇鉀(146 mg，1.297 mmol)置放於一圓底燒瓶中，並添加無水二甲基甲醯胺(3 mL)，再於室溫攪拌10分鐘。隨後，將其冷卻至-40℃，並添加2-硝基-3-甲氧基啶(100 mg，0.648 mmol)，及逐滴添加2-氯-丙酮酸乙酯(0.0908 mL，0.712 mmol)，再將其攪拌20分鐘。隨後，添加經稀釋之鹽酸，並於室溫攪拌10分鐘。將其以醋酸乙酯萃取，以水清洗，以硫酸鎂 乾燥，過濾，並將溶媒蒸發；最後再以管柱色層分析法進行純化，以獲得2-(5-甲氧基-6-硝基-啶-3-基)-丙酮酸乙酯(82 mg，50%)。 Step 1: Potassium tert-butoxide (146 mg, 1.297 mmol) was placed in a round-bottomed flask, and anhydrous dimethylformamide (3 mL) was added and stirred at room temperature for 10 min. Subsequently, it was cooled to -40 ° C, and 2-nitro-3-methoxypyridine (100 mg, 0.648 mmol) was added, and 2-chloro-pyruvate ethyl ester (0.0908 mL, 0.712 mmol) was added dropwise. Then stir it for 20 minutes. Subsequently, diluted hydrochloric acid was added and stirred at room temperature for 10 minutes. It is extracted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered, and the solvent is evaporated; and finally purified by column chromatography to obtain 2-(5-methoxy-6-nitrate Ethyl-pyridin-3-yl)-pyruvate ethyl ester (82 mg, 50%).

步驟2：將2-(5-甲氧基-6-硝基-啶-3-基)-丙酮酸乙酯(100 mg)置放於一圓體燒瓶中，隨後添加乙醇及鈀碳(20 wt%)，並於氮氣存在之條件下於室溫攪拌2小時。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)-丙酮酸乙酯(68 mg，78%)。 Step 2: Ethyl 2-(5-methoxy-6-nitro-pyridin-3-yl)-pyruvate (100 mg) was placed in a round flask, followed by the addition of ethanol and palladium on carbon (20 wt %) and stirred at room temperature for 2 hours in the presence of nitrogen. Filtration over celite and evaporation of solvent to give ethyl 2-(6-amino-5-methoxy-pyridin-3-yl)-pyruvate (68 mg, 78%).

步驟3：於氮氣氣氛下，將2-(6-胺基-5-甲氧基-啶-3-基)-丙酮酸乙酯(200 mg，0.891 mmol)置放於一圓體燒瓶中，添加無水四氫呋喃，並加以攪拌。隨後將其冷卻至0℃，並添加三乙胺(0.137 mL，0.981 mmol)。隨後添加甲磺醯氯(0.076 mL，0.981 mmol)，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；最後再以管柱色層分析法進行純化，以獲得2-(6-甲磺醯胺基-5-甲氧基-啶-3-基)-丙酮酸乙酯(180 mg，67%)。 Step 3: Ethyl 2-(6-amino-5-methoxy-pyridin-3-yl)-pyruvate (200 mg, 0.891 mmol) was placed in a round flask under nitrogen atmosphere. Anhydrous tetrahydrofuran was dried and stirred. It was then cooled to 0 ° C and triethylamine (0.137 mL, 0.981 mmol) was added. Methanesulfonium chloride (0.076 mL, 0.981 mmol) was then added and stirred at room temperature for 2 h. 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 2-(6-methanesulfonamide Ethyl 5-methoxy-pyridine-3-yl)-pyruvate (180 mg, 67%).

步驟4：將2-(5-甲氧基-6-甲磺醯胺基-啶-3-基)-丙酮酸乙酯(1.6 g，5.291 mmol)置放於一圓底燒瓶中，隨後添加四氫呋喃，並將其冷卻至0℃。逐滴添加以水(10 mL)溶解之氫氧化鋰單水化物(556 mg，13.229 mmol)溶液，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，並以經稀釋之鹽酸將水層酸化，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 mg，60%)。 Step 4: Ethyl 2-(5-methoxy-6-methanesulfonylamino-pyridin-3-yl)-pyruvate (1.6 g, 5.291 mmol) was placed in a round bottom flask followed by tetrahydrofuran And cool it to 0 °C. A solution of lithium hydroxide monohydrate (556 mg, 13.229 mmol) dissolved in water (10 mL) was added dropwise and stirred at room temperature for 2 h. The reaction mixture was extracted with ethyl acetate, washed with water, and the aqueous layer was acidified with diluted hydrochloric acid, and then 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(77 mg，0.282 mmol)置放於一圓底燒瓶中，並添加二甲基甲醯胺(5 mL)。隨後添加1-乙基-3-(3-二甲基胺基丙基)碳二醯亞胺)(74 mg，0.384 mmol)及1-羧苯並三唑(52 mg，0.384 mmol)，並攪 拌1小時。添加(2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺(70 mg，0.256 mmol)，並於室溫攪拌4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，最後再以管柱色層分析法進行純化，以獲得白色固體狀之2-(5-甲氧基-6-(甲基磺醯胺)啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺(115 mg，78%)。 Step 5: 2-(5-Methoxy-6-(methylsulfonamide)-3-yl)propanoic acid (77 mg, 0.282 mmol) was placed in a round bottom flask under a nitrogen atmosphere. And dimethylformamide (5 mL) was added. Subsequently added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) (74 mg, 0.384 mmol) and 1-carboxybenzotriazole (52 mg, 0.384 mmol), and Stir for 1 hour. (2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methanamine (70 mg, 0.256 mmol). 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 2-(5- Methoxy-6-(methylsulfonamide)pyridin-3-yl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine-3 -yl)methyl)propanamide (115 mg, 78%).

1H NMR(300MHz，氘代氯仿)：δ 7.82(s，1H，Ar-H)；7.64(d，1H，J=7.53 Hz，Ar-H)；7.36(s，1H，Ar-H)；7.26(d，1H，J=3.6 Hz，Ar-H)；7.10(s，1H，Ar-H)；6.34(s，1H，R-NH)；4.50(m，2H，Ar-CH2)；3.84(s，3H，Ar-OCH3)；3.57(m，1H，Ar-CH)；3.34(s，3H，Ar-MS)3.36(t，2H，J=14.82 Hz，六氫嘧啶-H)；2.82(t，2H，J=12.63 Hz，六氫嘧啶-H)；1.74(br.s，2H，六氫嘧啶-H)；1.30(d，3H，J=8.43 Hz，ArCH-CH3)；1.18(m，2H，六氫嘧啶-Hs)；1.01(d，3H，J=6.6 Hz，六氫嘧啶-CH3)。 1 H NMR (300MHz, deuteriochloroform): δ 7.82 (s, 1H , Ar-H); 7.64 (d, 1H, J = 7.53 Hz, Ar-H); 7.36 (s, 1H, Ar-H); 7.26 (d, 1H, J = 3.6 Hz, Ar-H); 7.10 (s, 1H, Ar-H); 6.34 (s, 1H, R-NH); 4.50 (m, 2H, Ar-CH 2 ); 3.84 (s, 3H, Ar-OCH 3 ); 3.57 (m, 1H, Ar-CH); 3.34 (s, 3H, Ar-MS) 3.36 (t, 2H, J = 14.82 Hz, hexahydropyrimidine-H) ; 2.82 (t, 2H, J = 12.63 Hz, hexahydropyrimidine-H); 1.74 (br.s, 2H, hexahydropyrimidine-H); 1.30 (d, 3H, J = 8.43 Hz, ArCH-CH 3 ) ; 1.18 (m, 2H, hexahydropyrimidine-Hs); 1.01 (d, 3H, J = 6.6 Hz, hexahydropyrimidine-CH 3 ).

實例98之合成：Synthesis of Example 98:

N-(5-(1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)苯甲醯胺 N-(5-(1-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methylamino)-1-oxopropane- 2-yl)pyridin-2-yl)benzamide

步驟1至2：如例74所述。 Steps 1 to 2: as described in Example 74.

步驟3：將乙酸鈀(II)(78 mg，0.35 mmol)、2,2'-雙二苯膦基-1,1'-聯萘(218 mg，0.35 mmol)及甲苯置放於一圓底燒瓶中。於氮氣氣流下，將該混合物攪拌15分鐘，隨後添加乙基2-(6-氯啶-3-基)丙酸(370 mg，1.73 mmol)，苯甲醯胺(189 mg，1.56 mmol)及碳酸銫(2258 mg，6.93 mmol)。將該反應混合物回流過夜，隨後將起冷卻至室溫。將該混合物以矽藻土塞過濾並濃縮。以醋酸乙酯稀釋殘留物並以10%之鹽酸溶液清洗。將有機層以硫酸鎂乾燥，於較低壓力濃縮，以獲得粗製產物；再以管柱色層分析純化該粗製產物，以獲得純乙基2-(6-苯甲醯胺啶-3-基)丙酸(295 mg，63%)。 Step 3: Palladium(II) acetate (78 mg, 0.35 mmol), 2,2'-bisdiphenylphosphino-1,1'-binaphthyl (218 mg, 0.35 mmol) and toluene were placed in a round bottom flask. in. The mixture was stirred for 15 minutes under a stream of nitrogen, then ethyl 2-(6-chloropyridin-3-yl)propanoic acid (370 mg, 1.73 mmol), benzamide (189 mg, 1.56 mmol) Barium carbonate (2258 mg, 6.93 mmol). The reaction mixture was refluxed overnight 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% aqueous solution of hydrochloric acid. The organic layer was dried over magnesium sulfate and concentrated at a reduced pressure to afford crude product. The crude product was purified by column chromatography to obtain pure ethyl 2-(6-benzidin-3-yl) Propionic acid (295 mg, 63%).

步驟4：將氫氧化鋰單水合物(62 mg，1.48 mmmol)加至以四氫呋喃及水溶解之乙基2-(6-苯甲醯胺啶-3-基)丙酸(295 mg，0.99 mmol)溶液。將該反應混合物於40℃攪拌2小時，隨後以10%之鹽酸溶液將其酸化。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-苯甲醯胺啶-3-基) 丙酸(250 mg，94%)。 Step 4: Add lithium hydroxide monohydrate (62 mg, 1.48 mmmol) to ethyl 2-(6-benzimididine-3-yl)propanoic acid (295 mg, 0.99 mmol) dissolved in tetrahydrofuran and water. ) solution. The reaction mixture was stirred at 40 ° C for 2 hours and then acidified with a 10% aqueous solution of hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was dried with MgSO.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.

步驟5：將1-羧苯並三唑(75 mg，0.55 mmol)、1-乙基-3-(3-二甲基胺基丙基)碳二醯亞胺)(106 mg，0.55 mmol)、三乙胺(0.1 mL，0.74 mmol)及(2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺(106 mg，0.39 mmol)加至以二甲基甲醯胺溶解之2-(6-苯甲醯胺啶-3-基)丙酸(100 mg，0.37 mmol)溶液。將該反應混合物於室溫攪拌12小時。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，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-(5-(1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)苯甲醯胺(100 mg，51%)。 Step 5: 1-Carboxybenzotriazole (75 mg, 0.55 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (106 mg, 0.55 mmol) , triethylamine (0.1 mL, 0.74 mmol) and (2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methanamine (106 mg, 0.39 mmol Add to a solution of 2-(6-benzimidazin-3-yl)propionic acid (100 mg, 0.37 mmol) dissolved in dimethylformamide. The reaction mixture was stirred at room temperature for 12 hours. 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 N-(5-(1-((2-(4-methyl)piperidin-1-yl)-6-(trifluoromethyl)pyridine-3 -yl)methylamino)-1-oxopropan-2-yl)pyridin-2-yl)benzamide (100 mg, 51%).

1H NMR(300MHz，氘代氯仿)：δ 9.03(br.s，NH)；8.35(d，1H，J=8.62 Hz，啶-H)；8.13(d，1H，J=2.02 Hz，啶-H)；7.90(m，2H，Ar-H)；7.75(dd，1H，J=8.63，2.21 Hz，啶-H)；7.57(m，1H，Ar-H)；7.48(m，3H，Ar-H)；7.18(d，1H，J=7.71 Hz，Ar-H)；6.53(t，NH，J=5.51 Hz)；4.46(m，2H，Ar-CH2)；3.57(四分體，1H，J=7.14 Hz，醯胺-CH)；3.31(m，2H，六氫嘧啶-H)；2.80(m，2H，六氫嘧啶-H)；1.70(m，2H，六氫嘧啶-H)；1.55(m，4H，醯胺-CH3，六氫嘧啶-H)；1.22(m，2H，六氫嘧啶-H)；0.95(d，3H，J=6.43 Hz，六氫嘧啶-CH3)。 1 H NMR (300MHz, deuteriochloroform): δ 9.03 (br.s, NH ); 8.35 (d, 1H, J = 8.62 Hz, pyridine -H); 8.13 (d, 1H , J = 2.02 Hz, piperidin - H); 7.90 (m, 2H, Ar-H); 7.75 (dd, 1H, J = 8.63, 2.21 Hz, pyridine-H); 7.57 (m, 1H, Ar-H); 7.48 (m, 3H, Ar) -H); 7.18 (d, 1H, J = 7.71 Hz, Ar-H); 6.53 (t, NH, J = 5.51 Hz); 4.46 (m, 2H, Ar-CH 2 ); 3.57 (tetrad, 1H, J=7.14 Hz, decylamine-CH); 3.31 (m, 2H, hexahydropyrimidine-H); 2.80 (m, 2H, hexahydropyrimidine-H); 1.70 (m, 2H, hexahydropyrimidine-H) 1.55 (m, 4H, decyl-CH 3 , hexahydropyrimidine-H); 1.22 (m, 2H, hexahydropyrimidine-H); 0.95 (d, 3H, J = 6.43 Hz, hexahydropyrimidine-CH) 3 ).

示範性化合物99係以相似方式製備而成，示範性化合物100至103亦係以相似方式製備而成。 Exemplary compound 99 was prepared in a similar manner and exemplary compounds 100 through 103 were also prepared in a similar manner.

實例104之合成：Synthesis of Example 104:

1-(6-(二甲胺基)-5-(三氟甲基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 1-(6-(Dimethylamino)-5-(trifluoromethyl)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(III Fluoromethyl)pyridin-3-yl)methyl)urea

步驟1：於一100 mL之圓底燒瓶中，將以二甲基甲醯胺溶解之2-氯-3-碘-5-硝基啶(250 mg，0.88 mmol)、甲基2,2-二氟-2-(氟磺醯基)醋酸(0.06 mL，0.44 mmol)及碘化亞銅(25 mg，0.13 mmol)混合物於氫氣氣氛下，以70℃加熱3小時。另將0.03 mL之甲基2,2-二氟-2-(氟磺醯基)醋酸加至該混合物，並於70℃加熱16小時。將該反應混合物冷卻至室溫，並以水稀釋，以醋酸乙酯萃取。將有機層於較低壓力濃縮，以獲得粗製產物；再將該粗製產物以管柱色層分析法純化，以獲得2-氯-5-硝基-3-(三氟甲基)啶(41 mg，21%)。 Step 1: 2-Chloro-3-iodo-5-nitropyridine (250 mg, 0.88 mmol), methyl 2,2- dissolved in dimethylformamide in a 100 mL round bottom flask A mixture of difluoro-2-(fluorosulfonyl)acetic acid (0.06 mL, 0.44 mmol) and cuprous iodide (25 mg, 0.13 mmol) was heated at 70 ° C for 3 hours under a hydrogen atmosphere. Further, 0.03 mL of methyl 2,2-difluoro-2-(fluorosulfonyl)acetic acid was added to the mixture, and the mixture was heated at 70 ° C for 16 hours. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was concentrated at a lower pressure to give a crude product; the crude product was purified by column chromatography to give 2-chloro-5-nitro-3-(trifluoromethyl) pyridine. Mg, 21%).

步驟2：將2-氯-5-硝基-3-(三氟甲基)啶(41 mg，0.18 mmol)、二甲胺鹽酸鹽(18 mg，0.22 mmol)、碳酸鉀(88 mg，0.63 mmol)及1,4,7,10,13,16-六氧雜環十八烷(10 mg)以乙腈溶解。將該反應混合物回流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 mg，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 mg，0.85 mmol)以甲醇溶解；並添加10%鈀碳(40 mg)。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N2,N2-二甲基-3-(三氟甲基)啶-2,5-二胺(60 mg，34%)。 Step 3: Dissolve N,N-dimethyl-5-nitro-3-(trifluoromethyl)pyridine-2-amine (200 mg, 0.85 mmol) in methanol; add 10% palladium on carbon (40 mg ). 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 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 mg，0.29 mmol)以乙腈溶解。分別將添加啶(0.03 mL，0.35 mmol)及氯甲酸苯酯(0.04 mL，0.31 mmol)加至該反應混合物中，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-(二胺基)-5-(三氟甲基)啶-3-基胺甲酸酯(47 mg，49%)。 Step 4: N2,N2-Dimethyl-3-(trifluoromethyl)pyridine-2,5-diamine (60 mg, 0.29 mmol) was dissolved in EtOAc. Pyridine (0.03 mL, 0.35 mmol) and phenyl chloroformate (0.04 mL, 0.31 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-(diamino)-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(40 mg，0.12 mmol)及(2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺(36 mg，0.13 mmol)以二甲基亞碸溶解。隨後添加三乙胺(0.03 mL，0.25 mmol)。將該混合物於室溫攪拌過夜。將該反應混合物以水稀釋，再以醋酸乙酯萃取。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，以獲得所需之1-(6-(二甲胺基)-5-(三氟甲基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素(45 mg，73%)。 Step 5: Phenyl 6-(dimethylamino)-5-(trifluoromethyl)pyridin-3-ylcarbamate (40 mg, 0.12 mmol) and (2-(4-methylpiperidine) 1-yl)-6-(trifluoromethyl)pyridin-3-yl)methanamine (36 mg, 0.13 mmol) was dissolved in dimethyl hydrazine. Triethylamine (0.03 mL, 0.25 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 the desired 1-(6-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl)-3-((2- 4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea (45 mg, 73%).

1H NMR(300 MHz，CD3OD)：δ 8.39(d，1H，J=2.73Hz，Ar-H)；8.14(d，1H，J=2.76Hz，Ar-H)；7.82(d，1H，J=7.5Hz，Ar-H)；7.34(d，1H，J=7.5Hz，Ar-H)；4.45(s，1H，Ar-CH2)；3.47(m，2H，六氫嘧啶-CH2)；2.91(m，8H，六氫嘧啶-CH2與Ar-N(CH3)2)； 1.78(m，2H，六氫嘧啶-CH2)；1.58(m，1H，六氫嘧啶-CH)；1.45(m，2H，六氫嘧啶-CH2)；1.02(d，3H，J=6.42Hz，六氫嘧啶-CH3)。 1 H NMR (300 MHz, CD 3 OD): δ 8.39 (d, 1H, J = 2.73 Hz, Ar-H); 8.14 (d, 1H, J = 2.76 Hz, Ar-H); 7.82 (d, 1H) , J = 7.5 Hz, Ar-H); 7.34 (d, 1H, J = 7.5 Hz, Ar-H); 4.45 (s, 1H, Ar-CH 2 ); 3.47 (m, 2H, hexahydropyrimidine-CH 2 ); 2.91 (m, 8H, hexahydropyrimidine-CH 2 and Ar-N(CH 3 ) 2 ); 1.78 (m, 2H, hexahydropyrimidine-CH 2 ); 1.58 (m, 1H, hexahydropyrimidine - CH); 1.45 (m, 2H, hexahydropyrimidine-CH 2 ); 1.02 (d, 3H, J = 6.42 Hz, hexahydropyrimidine-CH 3 ).

實例105之合成：Synthesis of Example 105:

1-(6-(氮雜環丁基-1-基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 1-(6-(azetidin-1-yl)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl) Pyridin-3-yl)methyl)urea

步驟1：將2-氯-5-硝基啶(300 mg，1.89 mmol)、氮雜環丁烷鹽酸鹽(212 mg，2.27 mmol)、碳酸鉀(915 mg，6.62 mmol)及1,4,7,10,13,16-六氧雜環十八烷(60 mg)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。再以管柱色層分析法純化粗製產物，以獲得2-(氮雜環丁基-1-基)-5-硝基啶(196 mg，58%)。 Step 1: 2-Chloro-5-nitropyridine (300 mg, 1.89 mmol), azetidine 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-(氮雜環丁基-1-基)-5-硝基啶(185 mg，1.03 mmol)以甲醇溶解，並添加10%鈀碳(37 mg)。於氫氣氣氛，將所得之混合物於室溫攪拌1小時。以矽藻土床過濾該混合物，並於較低壓力將濾液濃縮，以獲得6-(氮雜環丁基-1-基)啶-3-胺(154 mg，99%)。 Step 2: 2-(Azetidinyl-1-yl)-5-nitropyridine (185 mg, 1.03 mmol) was dissolved in methanol and 10% palladium carbon (37 mg). The resulting 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 a lower pressure to give 6-(azetidin-l-yl)pyridin-3-amine (154 mg, 99%).

步驟3：將6-(氮雜環丁基-1-基)啶-3-胺(154 mg，1.03 mmol)以乙腈溶解。於該反應混合物中分別添加啶(0.1 mL，1.24 mmol)及氯甲酸苯酯(0.14 mL，1.08 mmol)，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。於較低壓力將有機層濃縮。以管柱色層分析法純化該粗製產物，以獲得苯基6-(氮雜環丁基-1-基)啶-3-基胺甲酸酯(123 mg，44%)。 Step 3: 6-(Azetidinyl-1-yl)pyridine-3-amine (154 mg, 1.03 mmol) was dissolved in EtOAc. 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 a lower pressure. The crude product was purified by column chromatography to give phenyl 6-(azetidin-l-yl)pyridin-3-ylcarbamate (123 mg, 44%).

步驟4：將苯基6-(氮雜環丁基-1-基)啶-3-基胺甲酸酯(70 mg，0.26 mmol)及(2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺(75 mg，0.27 mmol)以二甲基亞碸溶解。隨後添加三乙胺(0.07 mL，0.52 mmol)。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。於較低壓力將有機層濃縮；並以管柱色層分析法純化粗製產物，以獲得所需之化合物1-(6-(氮雜環丁基-1-基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)-啶-3-基)甲基)尿素(66 mg，56%)。 Step 4: Phenyl 6-(azetidin-1-yl)pyridin-3-ylcarbamate (70 mg, 0.26 mmol) and (2-(4-methylpiperidin-1-yl) - 6-(Trifluoromethyl)pyridin-3-yl)methanamine (75 mg, 0.27 mmol) was dissolved in dimethyl hydrazine. Triethylamine (0.07 mL, 0.52 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 a lower pressure; and the crude product was purified by column chromatography to give the desired compound 1-(6-(azetidin-1-yl)pyridin-3-yl)- 3-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)-pyridin-3-yl)methyl)urea (66 mg, 56%).

1H NMR(300 MHz，CD3OD)：δ 7.99(d，1H，J=2.01Hz，Ar-H)；7.81(d，1H，J=7.32Hz，Ar-H)；7.61(dd，1H，J=8.79Hz，2.55Hz，Ar-H)；7.34(d，1H，J=7.71Hz，Ar-H)；6.39(d，1H，J=8.97Hz，Ar-H)；4.43(s，1H，Ar-CH2)；4.019(m，4H，氮雜環丁基-CH2)；3.46(m，2H，六氫嘧啶-CH2)；2.89(m，2H，六氫嘧啶-CH2)；2.43(m，2H，氮雜環丁基-CH2)；1.77(m，2H，六氫嘧啶-CH2)；1.57(m，1H，六氫嘧啶-CH)；1.43(m，2H，六氫嘧啶-CH2)；1.02(d，3H，J=6.39Hz，六氫嘧啶-CH3)。 1 H NMR (300 MHz, CD 3 OD): δ 7.99 (d, 1H, J = 2.01 Hz, Ar-H); 7.81 (d, 1H, J = 7.32 Hz, Ar-H); 7.61 (dd, 1H) , J = 8.79 Hz, 2.55 Hz, Ar-H); 7.34 (d, 1H, J = 7.71 Hz, Ar-H); 6.39 (d, 1H, J = 8.97 Hz, Ar-H); 4.43 (s, 1H, Ar-CH 2 ); 4.019 (m, 4H, azetidinyl-CH 2 ); 3.46 (m, 2H, hexahydropyrimidine-CH 2 ); 2.89 (m, 2H, hexahydropyrimidine-CH 2 ) ; 2.43 (m, 2H, azetidinyl-CH 2 ); 1.77 (m, 2H, hexahydropyrimidine-CH 2 ); 1.57 (m, 1H, hexahydropyrimidine-CH); 1.43 (m, 2H) , hexahydropyrimidine-CH 2 ); 1.02 (d, 3H, J = 6.39 Hz, hexahydropyrimidine-CH 3 ).

實例114之合成：Synthesis of Example 114:

1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-3-(6-(咯啶基-1-基)啶-3-基)尿素 1-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(6-(pyridinyl-1-yl) Pyridin-3-yl)urea

步驟1：將2-氯-5-硝基啶(300 mg，1.89 mmol)、吡咯啶(0.19 mL，2.27 mmol)、碳酸鉀(785 mg，5.68 mmol)及1,4,7,10,13,16-六氧雜環十八烷(60 mg)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。於較低壓力將有機層濃縮。以管柱色層分析法純化粗製產物，以獲得5-硝基-2-(咯啶基-1-基)啶(317 mg，87%)。 Step 1: 2-Chloro-5-nitropyridine (300 mg, 1.89 mmol), pyrrolidine (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. 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 a lower pressure. The crude product was purified by column chromatography to give 5-nitro-2-(pyridinyl-1-yl)pyridine (317 mg, 87%).

步驟2：將5-硝基-2-(咯啶基-1-基)啶(317 mg，1.65 mmol)以甲醇溶解，並添加10%鈀碳(64 mg)。於氫氣氣氛下，將所得之混合 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-(咯啶基-1-基)啶-3-胺(261 mg，97%)。 Step 2: 5-Nitro-2-(l-pyridinyl-1-yl)pyridine (317 mg, 1.65 mmol) was dissolved in methanol and 10% palladium carbon (64 mg). The resulting 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 a lower pressure to afford 6-(- </RTI><RTIgt;</RTI><RTIgt;

步驟3：將6-(咯啶基-1-基)啶-3-胺(261 mg，1.6 mmol)以乙腈溶解。於該反應混合物中分別添加啶(0.16 mL，1.92 mmol)及氯甲酸苯酯(0.21 mL，1.68 mmol)，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-(咯啶基-1-基)啶-3-基胺甲酸酯(218 mg，48%)。 Step 3: 6-(Brynidin-1-yl)pyridin-3-amine (261 mg, 1.6 mmol) was dissolved in EtOAc. 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 afford phenyl 6-( &lt;RTI ID=0.0&gt;&gt;&gt;

步驟4：將苯基6-(咯啶基-1-基)啶-3-基胺甲酸酯(70 mg，0.25 mmol)及(2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺(71 mg，0.26 mmol)以二甲基亞碸溶解；隨後添加三乙胺(0.07 mL，0.49 mmol)。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；再以管柱色層分析法純化粗製產物，以獲得所需之1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-3-(6-(咯啶基-1-基)啶-3-基)尿素(90 mg，79%)。 Step 4: Phenyl 6-(pyridinyl-1-yl)pyridin-3-ylcarbamate (70 mg, 0.25 mmol) and (2-(4-methylpiperidin-1-yl)- 6-(Trifluoromethyl)pyridin-3-yl)methanamine (71 mg, 0.26 mmol) was dissolved in dimethyl hydrazine; then 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 a lower pressure; the crude product was purified by column chromatography to give desired 1-((2-(4-methylpiperidin-1-yl)-6-(trifluoro) Methyl)pyridin-3-yl)methyl)-3-(6-(pyridinyl-1-yl)pyridin-3-yl)urea (90 mg, 79%).

1H NMR(300 MHz，CD3OD)：δ 7.97(d，1H，J=2.73Hz，Ar-H)；7.82(d，1H，J=7.68Hz，Ar-H)；7.57(dd，1H，J=8.97Hz，2.55Hz，Ar-H)；7.34(d，1H，J=7.68Hz，Ar-H)；6.49(d，1H，J=9.15Hz，Ar-H)；4.43(s，2H，Ar-CH2)；3.46(m，6H，咯啶-CH2與六氫嘧啶-CH2)；2.89(m，2H，六氫嘧啶-CH2)；2.04(m，4H，六氫嘧啶-CH2)；1.77(m，2H，哌啶-CH2)；1.57(m，1H，六氫嘧啶-CH)；1.43(m，2H，六氫嘧啶-CH2)；1.01(d，3H，J=6.39Hz，六氫嘧啶-CH3)。 1 H NMR (300 MHz, CD 3 OD): δ 7.97 (d, 1H, J = 2.73 Hz, Ar-H); 7.82 (d, 1H, J = 7.68 Hz, Ar-H); 7.57 (dd, 1H) , J = 8.97 Hz, 2.55 Hz, Ar-H); 7.34 (d, 1H, J = 7.68 Hz, Ar-H); 6.49 (d, 1H, J = 9.15 Hz, Ar-H); 4.43 (s, 2H, Ar-CH 2 ); 3.46 (m, 6H, pyridin-CH 2 and hexahydropyrimidine-CH 2 ); 2.89 (m, 2H, hexahydropyrimidine-CH 2 ); 2.04 (m, 4H, hexahydro) Pyrimidine-CH 2 ); 1.77 (m, 2H, piperidine-CH 2 ); 1.57 (m, 1H, hexahydropyrimidine-CH); 1.43 (m, 2H, hexahydropyrimidine-CH 2 ); 1.01 (d, 3H, J = 6.39 Hz, hexahydropyrimidine-CH 3 ).

實例123之合成：Synthesis of Example 123:

1-(6-(2-羥乙氧基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲 基)啶-3-基)甲基)尿素 1-(6-(2-hydroxyethoxy)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl) Pyridin-3-yl)methyl)urea

步驟1：將2-氯-5-硝基啶(1.51 g，9.55 mmol，1等量)及2-(苯甲氧基)乙醇(1.53 g，10.0 mmol，1.05等量)以N,N-二甲基甲醯胺(9 mL)溶解，並將其冷卻至0℃。分次添加氫化鈉(溶於60% w/w礦物油，392 mg，9.84 mmol，1.03等量)，並使該混合物回溫至室溫過夜。反應完成後(薄層層析法)，添加醋酸(1 mL)，並將溶媒蒸發。將殘留物懸浮於乙醚(20 mL)，並將其過濾。將過濾塊以二氯甲烷(2 x 2 mL)清洗，將濾液蒸發，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)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-硝基啶(2.09 g，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) as N,N- Dimethylformamide (9 mL) was dissolved and allowed to cool to 0 °C. Sodium hydride (dissolved in 60% w/w mineral oil, 392 mg, 9.84 mmol, 1.03 equivalent) was added in portions and the mixture was warmed to room temperature overnight. 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 (sand gel, ethyl acetate / n-hexane 1/4 (vol/vol) as the eluent It 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-硝基啶(2.09 g，7.61 mmol，1等量)以乙醇(90 m)溶解，並使用10%鈀碳將其於氫氣立方體(H-cube)上進行氫化反應。將該混合物蒸發，並以管柱色層分析法(矽膠，以甲基叔丁基醚/甲醇(9/1，體積/體積)做為溶析液)純化殘留物，以獲得無色固體狀之2-(5-胺基啶-2-基氧基)乙醇(209 mg，18%)。 Step 2: 2-(2-(Benzyloxy)ethoxy)-5-nitropyridine (2.09 g, 7.61 mmol, 1 equivalent) was dissolved in ethanol (90 m) using 10% palladium carbon This was hydrogenated on a hydrogen cube (H-cube). The mixture was evaporated and the residue was purified by column chromatography chromatography eluting eluting eluting eluting 2-(5-Aminopyridine-2-yloxy)ethanol (209 mg, 18%).

步驟3：於0℃，依序將啶(329 μL，4.07 mmol，3等量)及氯甲酸苯酯)(276 μL，1.76 mmol，1.3等量)加至經攪拌、以丙酮(5 mL)溶解之2-(5-胺基啶-2-基氧基)乙醇(209 mg，1.36 mmol，1等量)溶液，並於室溫攪拌過夜。將該反應混合物蒸發，並以管柱色層分析法(矽膠，以甲基叔丁基醚/甲醇(9/1，體積/體積)做為溶析液)純化，以獲得無色固體狀之苯基6-(2-羥乙氧基)啶-3-基胺甲酸酯(138 mg，37%)。 Step 3: sequentially add pyridine (329 μL, 4.07 mmol, 3 equivalents) and phenyl chloroformate (276 μL, 1.76 mmol, 1.3 equivalent) to the stirred, acetone (5 mL) at 0 °C. A solution of 2-(5-aminopyridine-2-yloxy)ethanol (209 mg, 1.36 mmol, 1 eq.) was dissolved and stirred at room temperature overnight. The reaction mixture was evaporated and purified by column chromatography (yield eluting with methyl tert-butyl ether/methanol (9/1, vol/vol) as solvent) to afford benzene as a colorless solid. 6-(2-Hydroxyethoxy)pyridin-3-ylcarbamate (138 mg, 37%).

步驟4：依序將三乙胺(0.193 mL，1.39 mmol，4.0等量)及苯基6-(2-羥乙氧基)啶-3-基胺甲酸酯(97 mg，0.36 mmol，1.02等量)加至經攪拌、以乙腈(8 mL)溶解之2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺(95 mg，0.35 mmol，1.0等量)溶液，並在回流下攪拌16小時。將該反應混合物於真空狀態濃縮，並以管柱色層分析法(矽膠，以醋酸乙酯/環己烷(9/1，體積/體積)做為(溶析液)純化殘留物，以獲得無色固體狀之1-(6-(2-羥乙氧基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素(化合物實例92，119 mg；75%)。 Step 4: Triethylamine (0.193 mL, 1.39 mmol, 4.0 equivalent) and phenyl 6-(2-hydroxyethoxy)pyridin-3-ylcarbamate (97 mg, 0.36 mmol, 1.02) Addition to 2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methanamine (95 mg, dissolved in acetonitrile (8 mL) , 0.35 mmol, 1.0 equal amount) solution, and stirred under reflux for 16 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography (yield, ethyl acetate / cyclohexane (9/1, vol/vol) as solvent. 1-(6-(2-hydroxyethoxy)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl) as a colorless solid Pyridin-3-yl)methyl)urea (Compound Example 92, 119 mg; 75%).

實例124之合成：Synthesis of Example 124:

1-(6-(2-甲氧基乙氧基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 1-(6-(2-methoxyethoxy)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine -3-yl)methyl)urea

步驟1：將2-氯-5-硝基啶(5.00 g，31.6 mmol，1等量)及2-甲氧基乙醇(2.52 g，33.1 mmol，1.05等量)以N,N-二甲基甲醯胺(32 mL)溶解，並將其冷卻至0℃。分次添加氫化鈉(溶於60% w/w之礦物油，1.30 mg，32.5 mmol，1.03等量)，並將該混合物冷卻至室溫過夜。反應完成(薄層層析法)後，添加醋酸(5 mL)，並將溶媒蒸發。將殘留物懸浮於乙醚(100 mL)，並將其過濾。以二氯甲烷(2 x 50 mL)清洗過濾塊，將濾液蒸發，再以管柱色層分析法(矽膠，以醋酸乙酯/正己烷(1/4，體積/體積)做為溶析液)純化，以獲得黃色固體狀之2-(2-甲氧基乙氧基)-5-硝基啶(3.96 g，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 N,N-dimethyl Formamidine (32 mL) was dissolved and allowed to cool to 0 °C. Sodium hydride (dissolved in 60% w/w mineral oil, 1.30 mg, 32.5 mmol, 1.03 equivalent) was added portionwise and the mixture was cooled 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), the filtrate was evaporated, and then subjected to column chromatography (gelatin, ethyl acetate/n-hexane (1/4, vol/vol) as the lysate. Purified to give 2-(2-methoxyethoxy)-5-nitropyridine (3.96 g, 63%).

步驟2：將2-(2-甲氧基乙氧基)-5-硝基啶(3.95 g，19.9 mmol，1等量)以乙醇(180 mL)溶解，並使用10%鈀碳將其於氫氣立方體上進行氫化反應。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 mg，98%)，該產物不需進一步純化即可使用。 Step 2: Dissolve 2-(2-methoxyethoxy)-5-nitropyridine (3.95 g, 19.9 mmol, 1 equivalent) in ethanol (180 mL) and use 10% palladium on carbon The hydrogenation reaction is carried out on a hydrogen cube. The mixture was evaporated to give 6-(2-methoxyethoxy)pyridin-3-amine (3.30 mg, 98%).

步驟3：於0℃，依序將啶(722 μL，8.94 mmol，3等量)及氯甲酸苯酯(489 μL，3.87 mmol，1.3等量)加至經攪拌、以丙酮(10 mL)溶解之6-(2-甲氧基乙氧基)啶-3-胺(501 mg，2.98 mmol，1等量) 溶液，並於室溫攪拌過夜。將該反應混合物蒸發，並以管柱色層分析法(矽膠，以甲基叔丁基醚/甲醇(1/1，體積/體積)做為溶析液)純化，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 mg，80%)。 Step 3: Add pyridine (722 μL, 8.94 mmol, 3 equivalents) and phenyl chloroformate (489 μL, 3.87 mmol, 1.3 equivalents) to 0 ° C, and stir to dissolve in acetone (10 mL). A solution of 6-(2-methoxyethoxy)pyridin-3-amine (501 mg, 2.98 mmol, 1 eq.) was stirred at room temperature overnight. The reaction mixture was evaporated and purified by column chromatography (yield eluted with methyl tert-butyl ether/methanol (1/1, vol/vol) as solvent) to afford benzene as colorless solid. 6-(2-Methoxyethoxy)pyridin-3-ylcarbamate (686 mg, 80%).

步驟4：依序將三乙胺(0.193 mL，1.39 mmol，4.0等量)及苯基6-(2-甲氧基乙氧基)啶-3-基胺甲酸酯(102 mg，0.355 mmol，1.02等量)加至經攪拌、以乙腈(8 mL)溶解之(2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺(95 mg，0.35 mmol，1.0等量)溶液，並於回流下攪拌16小時。將該反應混合物於真空狀態濃縮，並以管柱色層分析法(矽膠，以醋酸乙酯/環己烷(2/1，體積/體積)做為溶析液)純化殘留物，以獲得無色固體狀之1-(6-(2-甲氧基乙氧基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素(化合物實例93，136 mg；84%)。 Step 4: Triethylamine (0.193 mL, 1.39 mmol, 4.0 eq.) and phenyl 6-(2-methoxyethoxy)pyridin-3-ylcarbamate (102 mg, 0.355 mmol). (1.02 equivalent) was added to (2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methylamine dissolved in acetonitrile (8 mL) (95 mg, 0.35 mmol, 1.0 eq.) solution was stirred at reflux for 16 h. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography (EtOAc, ethyl acetate/hexane (2/1, volume/volume) as solvent) to obtain colorless. Solid 1-(6-(2-methoxyethoxy)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl) Base pyridine-3-yl)methyl)urea (Compound Example 93, 136 mg; 84%).

實例126之合成：Synthesis of Example 126:

1-(5-(羥甲基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 1-(5-(Hydroxymethyl)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl) Methyl) urea

步驟1：於0℃，緩慢地將亞硫醯二氯加至經攪拌、以乙醇溶解之5-氨基菸鹼酸(300 mg，2.17 mmol)。將該反應混合物於回流下攪拌過夜。隨後將其冷卻至室溫，並於真空狀態移除溶媒。再將其以乙基醋酸溶解，並以飽和碳酸氫鈉溶液清洗。將有機層以硫酸鎂乾燥，並過濾。將濾液於真空狀態移除，以獲得粗製狀態之5-氨基菸鹼酸乙酯(315 mg，89%)。 Step 1: Slowly add sulphur dichloride to the stirred, ethanol-dissolved 5-aminonicotinic acid (300 mg, 2.17 mmol) at 0 °C. The reaction mixture was stirred at reflux overnight. It 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 over magnesium sulfate and filtered. The filtrate was removed in vacuo to give ethyl 5-aminonicotinate (315 mg, 89%) as crude.

步驟2：於0℃、氮氣氣氛下，緩慢地將以四氫呋喃之溶解5-氨基菸鹼酸乙酯加至經攪拌、以四氫呋喃溶解之氫鋁化鋰(254 mg，5.36 mmol)。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之鹽酸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，直至其酸鹼值為7。隨後以矽藻土過濾該混合物，以移除氫鋁化鋰殘留物，並將其以乙基醋酸溶解，以飽和碳酸鈉溶液清洗。將有機層以硫酸鎂乾燥並過濾。將濾液於真空狀態移除，以獲得粗製狀態之(5-胺基啶-3-基) 甲醇(111 mg，粗製產物)，其生產率為54%。 Step 2: Ethyl 5-aminonicotinate added in tetrahydrofuran was slowly added to lithium aluminohydride (254 mg, 5.36 mmol) dissolved in tetrahydrofuran under stirring at 0 °C. 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 hydrochloric acid at 0 ° C until its pH was 3, which was then basified with sodium carbonate solution until its pH was 7. The mixture was then filtered with diatomaceous earth to remove the lithium aluminum hydride residue, 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 in vacuo to give (5-aminopyridin-3-yl)methanol (111 mg, crude product) as a crude material.

步驟3：將咪唑(12 mg，1.77 mmol)及三級丁基二甲基氯矽烷(tert-butyldimethylchlorosilane)(134 mg，0.89 mmol)加至經攪拌、以二甲基甲醯胺溶解之(5-胺基啶-3-基)甲醇(87 mg，0.89 mmol)溶液。將該反應混合物於室溫攪拌5小時。將該混合物溶解於以基醋酸，並以水清洗數次。將有機層以硫酸鎂乾燥，並將其過濾。將濾液於真空狀態移除。以管柱色層分析法純化粗製產物，以獲得5-((三級丁基二甲基矽雜氧基)甲基)啶-3-胺(5-((tert-Butyldimethylsilyloxy)methyl)pyridin-3-amine)(132 mg)，其生產率為50%。 Step 3: Imidazole (12 mg, 1.77 mmol) and tert-butyldimethylchlorosilane (134 mg, 0.89 mmol) were added to the mixture and dissolved in dimethylformamide (5) -Aminopyridin-3-yl)methanol (87 mg, 0.89 mmol). The reaction mixture was stirred at room temperature for 5 hours. The mixture was dissolved in acetic acid 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-((tert-Butyldimethylsilyloxy)methyl)pyridin- 5-((tert-Butyldimethylsilyloxy)methyl)pyridin- 3-amine) (132 mg) with a productivity of 50%.

步驟4：將氯甲酸苯酯(0.073 mL，0.58 mmol)及啶(0.054 mL，0.66 mmol)加至經攪拌、以四氫呋喃及乙腈做為共溶劑之5-((三級丁基二甲基矽雜氧基)甲基)啶-3-胺(132 mg，0.55 mmol)溶液。將該反應混合物於室溫攪拌1小時。將該混合物以乙基醋酸溶解，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。將濾液於真空狀態移除。以管柱色層分析法純化該粗製產物，以獲得苯基5-((三級丁基二甲基矽雜氧基)甲基)啶-3-基胺甲酸酯(171 mg)，其生產率為86%。 Step 4: Add phenyl chloroformate (0.073 mL, 0.58 mmol) and pyridine (0.054 mL, 0.66 mmol) to 5-((tert-butyl dimethyl hydrazide) with stirring, tetrahydrofuran and acetonitrile as cosolvent A solution of a heteroxy)methyl)pyridin-3-amine (132 mg, 0.55 mmol). 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 by column chromatography to give phenyl 5-((tris-butyl dimethyl decyloxy)methyl)pyridin-3-ylcarbamate (171 mg). Productivity is 86%.

步驟5：將二甲基胺基啶(27 mg，0.28 mmol)加至經攪拌、以乙腈溶解之苯基5-((三級丁基二甲基矽雜氧基)甲基)啶-3-基胺甲酸酯(100 mg，0.28 mmol)及(2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺(61 mg，0.28 mmol)溶液。將該反應混合物於50℃攪拌過夜。將該混合物以乙基醋酸溶解，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。將濾液於真空狀態移除。以管柱色層分析法純化粗製產物，以獲得2-(5-((三級丁基二甲基矽雜氧基)甲基)啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟 甲基)啶-3-基)甲基)乙醯胺(107 mg)，其生產率為89%。 Step 5: Add dimethylaminopyridine (27 mg, 0.28 mmol) to phenyl 5-((tertiary butyl dimethyl decyloxy)methyl) pyridine-3 dissolved in acetonitrile with stirring. - carbamates (100 mg, 0.28 mmol) and (2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine-3-yl)methylamine (61 mg, 0.28 mmol) solution. 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 2-(5-((tert-butyl dimethyl decyloxy)methyl)pyridin-3-yl)-N-((2-(4) Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide (107 mg), which had a productivity of 89%.

步驟6：將1M之四-正丁基氟化銨(tetra-n-butylammoniumfluoride)(0.22 mL，0.22 mmol)加至經攪拌、以四氫呋喃溶解之2-(5-((三級丁基二甲基矽雜氧基)甲基)啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)乙醯胺(107 g，0.20 mmol)溶液。將該反應混合物於室溫攪拌18小時。隨後添加另一部分1M之四-正丁基氟化銨(0.78 mL，0.78 mmol)，再將該混合物攪拌4小時。以飽和碳酸氫鈉溶液對該混合物進行淬火反應，隨後將其以乙基醋酸溶解，並以水清洗。將有機層以硫酸鎂乾燥，並將其過濾。將濾液於真空狀態移除。以管柱色層分析法純化粗製產物，以獲得2-(5-(羥甲基)啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)乙醯胺(77 mg)，其生產率為92%。 Step 6: Add 1 M tetra-n-butylammonium fluoride (0.22 mL, 0.22 mmol) to 2-(5-((tri-tert-butyl dimethyl)) with stirring and dissolved in tetrahydrofuran Hexyloxy)methyl)pyridin-3-yl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl) A solution of acetamide (107 g, 0.20 mmol). The reaction mixture was stirred at room temperature for 18 h. Another portion of 1 M tetra-n-butylammonium fluoride (0.78 mL, 0.78 mmol) was then added and the mixture was stirred for 4 h. 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 2-(5-(hydroxymethyl)pyridin-3-yl)-N-((2-(4-methylpiperidin-1-yl)-6 -(Trifluoromethyl)pyridin-3-yl)methyl)acetamide (77 mg), which had a productivity of 92%.

實例127之合成：Synthesis of Example 127:

1-(5-(羥甲基)啶-2-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 1-(5-(Hydroxymethyl)pyridin-2-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl) Methyl) urea

步驟1：於0℃，緩慢地將亞硫醯二氯(0.55 mL，4.34 mmol)加至經攪拌、以乙醇溶解之6-氨基菸鹼酸(300 mg，2.51 mmol)溶液。將該反應混合物於回流下攪拌過夜。隨後，將該混合物冷卻至室溫，並於真空狀態移除溶媒。再將其以乙基醋酸溶解，並以飽和碳酸氫鈉溶液清洗。將有機層以硫酸鎂乾燥，並將其過濾。將濾液於真空狀態移除，以獲得粗製狀態之6-氨基菸鹼酸乙酯，其生產率為76%。 Step 1: Slowly add sulfoxide dichloride (0.55 mL, 4.34 mmol) to a stirred solution of 6-aminonicotinic acid (300 mg, 2.51 mmol) dissolved in ethanol at 0 °C. The reaction mixture was stirred at reflux overnight. Subsequently, the mixture was 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 over magnesium sulfate and filtered. The filtrate was removed in a vacuum to obtain a crude ethyl 6-aminonicotinate, which had a productivity of 76%.

步驟2：於氮氣氣氛、0℃之條件下，緩慢地將以四氫呋喃溶解之6-氨基菸鹼酸乙酯(80 mg，0.48 mmol)溶液加至經攪拌、以四氫呋喃溶解之氫鋁化鋰(73 mg，1.93 mmol)。將該反應混合物於0℃攪拌30分鐘，再於室溫攪拌3小時。將該混合物於0℃以1N之氯化氫進行淬火反應，直至其酸鹼值為3，再以碳酸鈉溶液將其鹼化，直至其酸鹼值為7。隨後，以矽藻土將該混合物過濾以移除氫鋁化鋰，並將其以乙基醋酸溶解，並以飽和談酸鈉溶液清洗。將 有機層以乾燥，並將其過濾。將濾液於真空狀態移除，以獲得粗製狀態之(6-胺基啶-3-基)甲醇(30 mg，粗製產物)，其生產率為50%。 Step 2: Slowly add a solution of 6-aminonicotinic acid ethyl ester (80 mg, 0.48 mmol) dissolved in tetrahydrofuran to a stirred lithium tetrahydrofuran dissolved in tetrahydrofuran under a nitrogen atmosphere at 0 °C ( 73 mg, 1.93 mmol). 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 hydrogen chloride at 0 ° C until its pH was 3, and it was basified with a sodium carbonate solution until its pH was 7. Subsequently, the mixture was filtered with diatomaceous earth to remove lithium aluminum hydride, which was dissolved in ethyl acetate and washed with a saturated sodium solution. The organic layer was dried and filtered. The filtrate was removed in vacuo to give (6-aminopyridin-3-yl)methanol (30 mg, crude product) as a crude product with a 50% yield.

步驟3：將咪唑(33 mg，0.48 mmol)及三級丁基二甲機氯矽烷(36 mg，0.24 mmol)加至經攪拌、以二甲基甲醯胺溶解之(6-胺基啶-3-基)甲醇(30 mg，0.24 mmol)溶液。將該反應混合物於室溫攪拌5小時。將該混合物以乙基醋酸溶解，並以水清洗數次，以移除二甲基甲醯胺殘留物。將有機層以硫酸鎂乾燥，並將其過濾。將濾液於真空狀態移除。以管柱色層分析法純化粗製產物，以獲得5-((三級丁基二甲基矽雜氧基)甲基)啶-2-胺(35 mg)，其生產率為35%。 Step 3: Add imidazole (33 mg, 0.48 mmol) and tert-butyl dimethyl chlorodecane (36 mg, 0.24 mmol) to the stirred solution of 6-aminopyridine in dimethylformamide. A solution of 3-yl)methanol (30 mg, 0.24 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 to remove the dimethylformamide residue. 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-decyloxy)methyl)pyridin-2-amine (35 mg) with a yield of 35%.

步驟4：將氯甲酸苯酯(0.018 mL，0.15 mmol)及啶(0.015 mL，0.18 mmol)加至經攪拌、以四氫呋喃及乙腈做為共溶劑之5-((三級丁基二甲基矽雜氧基)甲基)啶-2-胺(35 mg，0.15 mmol)溶液。將該反應混合物於室溫攪拌1小時。將該混合物以乙基醋酸溶液解，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。將濾液於真空狀態移除。以管柱色層分析法純化粗製產物，以獲得苯基5-((三級丁基二甲基矽雜氧基)甲基)啶-2-基胺甲酸酯(75 mg)；其生產率為99%。 Step 4: Add phenyl chloroformate (0.018 mL, 0.15 mmol) and pyridine (0.015 mL, 0.18 mmol) to 5-((tert-butyl dimethyl hydrazide) with stirring, tetrahydrofuran and acetonitrile as cosolvent A solution of a heterooxy)methyl)pyridine-2-amine (35 mg, 0.15 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was solutioned with ethyl acetate and washed with water and 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 phenyl 5-((tertiary butyldimethylammonium)methyl)pyridin-2-ylcarbamate (75 mg); It is 99%.

步驟5：將二甲基胺基啶)(24 mg，0.21 mmol)加至經攪拌、以乙腈溶解之苯基5-((三級丁基二甲基矽雜氧基)甲基)啶-2-基胺甲酸酯(75 mg，0.21 mmol)及(2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺(58 mg，0.21 mmol)溶液。將該反應混合物於50℃攪拌過夜。將該混合物以乙基醋酸溶解，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。將濾液於真空狀態移除。以管柱色層分析法純化粗製產物，以獲得1-(5-((三級丁基二 甲基矽雜氧基)甲基)啶-2-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素(93 mg)；其生產率為82%。 Step 5: Add dimethylaminopyridine (24 mg, 0.21 mmol) to phenyl 5-((tertiary butyl dimethyl decyloxy)methyl) pyridine - stirred in acetonitrile - 2-Base carbamate (75 mg, 0.21 mmol) and (2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine-3-yl)methylamine (58 mg , 0.21 mmol) solution. 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-(5-((tertiary butyl dimethyl decyloxy)methyl)pyridin-2-yl)-3-((2-(4) -Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea (93 mg); its productivity was 82%.

步驟6：將1M之四-正丁基氟化銨(0.26 mL，0.26 mmol)加至經攪拌、以四氫呋喃溶解之1-(5-((三級丁基二甲基矽雜氧基)甲基)啶-2-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素(93 g，0.17 mmol)溶液。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-正丁基氟化銨(0.39 mL，0.39 mmol)，並再將該混合物攪拌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，將其以乙基醋酸溶解，並以水清洗。將有機層以硫酸鎂乾燥，並將其過濾。將濾液於真空狀態移除。以管柱色層分析法純化粗製產物，以獲得1-(5-(羥甲基)啶-2-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素(24 mg)；其生產率為33%。 Step 6: Add 1 M tetra-n-butylammonium fluoride (0.26 mL, 0.26 mmol) to 1-(5-((tert-butyl dimethyl dimethyl decyloxy)), which was dissolved in tetrahydrofuran. Pyridyl-2-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea (93 g, 0.17 mmol) solution. The reaction mixture was stirred at room temperature for 18 h. Another portion of 1 M tetra-n-butylammonium fluoride (0.39 mL, 0.39 mmol) was then added and the mixture was stirred for further 4 hours. The mixture was quenched with a saturated sodium hydrogencarbonate 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-(5-(hydroxymethyl)pyridin-2-yl)-3-((2-(4-methylpiperidin-1-yl)-6 -(Trifluoromethyl)pyridin-3-yl)methyl)urea (24 mg); its productivity was 33%.

實例128之合成：Synthesis of Example 128:

1-(3-(羥甲基)啶-4-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 1-(3-(Hydroxymethyl)pyridin-4-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl) Methyl) urea

步驟1：將以二氯甲烷溶解之三甲基乙醯氯(423 mg，3.51 mmol，1.1等量)溶液緩慢地加至冰冷、以三乙胺(0.56 mL，3.98 mmol，1.25等量)及二氯甲烷溶解之啶-4-胺(300 mg，3.19 mmol)溶液。將該反應混合物於冰浴中攪拌15分鐘，隨後於室溫攪拌2小時，並倒入水。將該反應混合物以碳酸氫鈉稀釋，並以硫酸鈉乾燥，再將其蒸發。以管柱色層分析法純化粗製產物，以獲得N-(啶-4-基)棕櫚醯胺(377 mg，66%)。 Step 1: Slowly add a solution of trimethyl ethane chloride (423 mg, 3.51 mmol, 1.1 equivalent) dissolved in dichloromethane to ice-cold, triethylamine (0.56 mL, 3.98 mmol, 1.25 equivalent) and A solution of pyridine-4-amine (300 mg, 3.19 mmol) dissolved in dichloromethane. The reaction mixture was stirred in an ice bath for 15 min, then stirred at room temperature for 2 h and poured water. The reaction mixture was diluted with sodium bicarbonate and dried over sodium sulfate and evaporated. The crude product was purified by column chromatography to give N-(pyridin-4-yl) palmamine (377 mg, 66%).

步驟2：於惰性氣氛下，將N-(啶-4-基)棕櫚醯胺(377 mg，2.12 mmol)以無水四氫呋喃溶解，並將其冷卻至-78℃。於一小時內，逐滴添加以己烷溶解之1.6 M之丁基鋰(3.3 mL，5.29 mmol，2.5等量)溶液。隨後，將該反應混合物加溫至0℃，並攪拌3小時。 再添加以無水四氫呋喃溶解之無水二甲基甲醯胺(0.5 mL，6.35 mmol，3等量)。隨後，將該溶液回溫至室溫，並再度攪拌45分鐘。將該混合物倒入6N之鹽酸(5 mL)與冰(5 g)之混合物中。攪拌5分鐘後，將該溶液以碳酸鉀(3.3 g)中和，並以二乙醚萃取。將有機層以硫酸鎂乾燥，並將溶媒於真空狀態移除。以管柱色層分析法純化殘留物，以獲得N-(3-甲醯基啶-4-基)棕櫚醯胺(258 mg，59%)。 Step 2: N-(pyridin-4-yl)palmitoside (377 mg, 2.12 mmol) was dissolved in dry THF (m.). A 1.6 M solution of butyl lithium (3.3 mL, 5.29 mmol, 2.5 equivalents) dissolved in hexane was added dropwise over one hour. Subsequently, the reaction mixture was warmed to 0 ° C and stirred for 3 hours. Anhydrous dimethylformamide (0.5 mL, 6.35 mmol, 3 equivalents) dissolved in anhydrous tetrahydrofuran was added. Subsequently, the solution was warmed to room temperature and stirred for another 45 minutes. The mixture was poured into a mixture of 6N hydrochloric acid (5 mL) and ice (5 g). After stirring for 5 minutes, the solution was neutralized with potassium carbonate (3.3 g) and extracted with diethyl ether. The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by column chromatography to give N-(3-carbamidin-4-yl) palmamine (258 mg, 59%).

步驟3：將N-(3-甲醯基啶-4-基)棕櫚醯胺(245 mg，1.20 mmol)以3 N之鹽酸(2.47 mL)溶解，並將其加熱並回流8小時。薄層層析顯示起始原料被完全消耗。以二乙醚萃取該混合物。使用碳酸鉀將水層鹼化，並以氯仿萃取。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4-胺基菸鹼醛(4-aminonicotinaldehyde)(57 mg，40%)。 Step 3: N-(3-Methylpyridin-4-yl)palmitoleamine (245 mg, 1.20 mmol) was dissolved in 3N hydrochloric acid (2. Thin layer chromatography showed the starting material was completely consumed. The mixture was extracted with diethyl ether. The aqueous layer was basified with potassium carbonate and extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated at lower pressure. The crude product was purified by column chromatography to give 4-aminonicotinaldehyde (57 mg, 40%).

步驟4：將以四氫呋喃溶解之4-胺基菸鹼醛(57 mg，0.47 mmol)溶液於冰浴中冷卻，並添加氫鋁化鋰(27 mg，0.70 mmol，1.5等量)。將冰浴移除，並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。以水(1 mL)對該反應混合物進行淬火反應，並添加1 N之鹽酸(2 mL)，再以乙基醋酸萃取。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。該殘留物(60 mg，99%)可於粗製狀態供下一反應使用。 Step 4: A solution of 4-aminonicotinaldehyde (57 mg, 0.47 mmol) dissolved in tetrahydrofuran was cooled in an ice bath and lithium hydride (27 mg, 0.70 mmol, 1.5 equivalents) was added. The ice bath was removed and the reaction mixture was stirred for 30 min. Thin layer chromatography showed complete consumption of the starting material. The reaction mixture was quenched with water (1 mL), and 1N hydrochloric acid (2 mL) was then evaporated. 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 residue (60 mg, 99%) was used in the crude state for the next reaction.

步驟5：將咪唑(219 mg，3.22 mmol，2等量)及三級丁基二甲基氯矽烷(267 mg，1.77 mmol，1.1等量)加至經攪拌、以二甲基甲醯胺溶解之(4-胺基啶-3-基)甲醇(200 mg，1.61 mmol)溶液。將該反應混合物於室溫攪拌5小時。將該混合物以乙基醋酸溶解，並以水清洗數次。將有機層以硫酸鎂乾燥，並將其過濾。將濾液於真空狀態移除。以管柱色層分析法純化粗製產物，以獲得3-((三級 丁基二甲基矽雜氧基)甲基)啶-4-胺(325 mg，85%)。 Step 5: Add imidazole (219 mg, 3.22 mmol, 2 equivalents) and tertiary butyl dimethyl chlorodecane (267 mg, 1.77 mmol, 1.1 equivalent) to the mixture and dissolve with dimethylformamide A solution of (4-aminopyridine-3-yl)methanol (200 mg, 1.61 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 afford 3-((tris-butyl dimethyl </RTI></RTI><RTIgt;

步驟6：將3-((三級丁基二甲基矽雜氧基)甲基)啶-4-胺(325 mg，1.36 mmol)以乙腈(3 mL)及四氫呋喃(4 mL)溶解。於該反應混合物中添加啶(0.13 mL，1.64 mmol，1.2等量)及氯甲酸苯酯(0.18 mL，1.43 mmol，1.05等量)，並於氮氣氣氛下，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，並以乙基醋酸萃取。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3-((三級丁基二甲基矽雜氧基)甲基)啶-4-基胺甲酸酯(151 mg，46%)。 Step 6: 3-((Tri-tert-butyldimethyl-nonyloxy)methyl)pyridin-4-amine (325 mg, 1.36 mmol) was dissolved in EtOAc (3 mL) and THF (4 mL). Pyridine (0.13 mL, 1.64 mmol, 1.2 equivalent) and phenyl chloroformate (0.18 mL, 1.43 mmol, 1.05 eq.) were added to the mixture and the mixture was stirred at room temperature for 3 hr. 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 pure phenyl 3-((tris-butyl dimethyl decyloxy)methyl)pyridin-4-ylcarbamate (151 mg, 46% ).

步驟7：於室溫，將二甲基胺基啶(26 mg，0.21 mmol，1等量)及(2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺(63 mg，0.23 mmol，1.1等量)加至以乙腈(3 mL)溶解之苯基3-((三級丁基二甲基矽雜氧基)甲基)啶-4-基胺甲酸酯(75 mg，0.21 mmol)溶液。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，並以乙基醋酸萃取。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1-(3-((三級丁基二甲基矽雜氧基)甲基)啶-4-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素(103 mg，92%)。 Step 7: dimethylaminopyridine (26 mg, 0.21 mmol, 1 equivalent) and (2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl) at room temperature Pyridin-3-yl)methanamine (63 mg, 0.23 mmol, 1.1 equivalent) was added to phenyl 3-((tertiary butyl dimethyl decyloxy)methyl) dissolved in acetonitrile (3 mL) A solution of pyridine-4-ylcarbamate (75 mg, 0.21 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 pure 1-(3-((tris-butyl dimethyl decyloxy)methyl)pyridin-4-yl)-3-((2-) 4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea (103 mg, 92%).

步驟8：將1 M之四-正丁基氟化銨(0.38 mL，0.38 mmol，2等量)加至經攪拌、以四氫呋喃溶解之1-(3-((三級丁基二甲基矽雜氧基)甲基)啶-4-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素(103 mg，0.19 mmol)溶液。將該反應混合物於室溫攪拌18小時。以飽和碳酸氫鈉溶液對該混合物進行淬火反應，隨後將其以乙基醋酸溶解，並以水清洗。將有機層以硫酸鎂乾燥並過濾。 將濾液於真空狀態移除。以管柱色層分析法純化粗製產物，以獲得1-(3-(羥甲基)啶-4-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素(45 mg，55%)。 Step 8: Add 1 M of tetra-n-butylammonium fluoride (0.38 mL, 0.38 mmol, 2 equivalents) to 1-(3-((tri-butyl dimethyl hydrazide) dissolved in tetrahydrofuran) Hepoxy)methyl)pyridin-4-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl) Urea (103 mg, 0.19 mmol) solution. The reaction mixture was stirred at room temperature for 18 h. 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-(hydroxymethyl)pyridin-4-yl)-3-((2-(4-methylpiperidin-1-yl)-6 -(Trifluoromethyl)pyridin-3-yl)methyl)urea (45 mg, 55%).

實例129之合成：Synthesis of Example 129:

1-(6-(1,2-二烴乙基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素 1-(6-(1,2-Dihydroethylethyl)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine -3-yl)methyl)urea

步驟1：於室溫，將氯化鋰(936 mg，22.08 mmol，7等量)、四(三苯基膦基)鈀(0)(547 mg，0.47 mmol，0.15等量)及三丁基乙烯基錫(1.84 mL，6.31 mmol，2等量)加至以四氫呋喃溶解之2-氯-4-硝基啶(500 mg，3.15 mmol)溶液。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。將該混合物以乙基醋酸稀釋，並將有機層以飽和氟化鉀溶液清洗，隨後以乙基醋酸萃取。以飽和氯化鈉溶液清 洗有機部分。將有機層以乾燥並於較低壓力濃縮，以管柱色層分析純化該粗製產物，以獲得5-硝基-2-乙烯啶(350 mg，74%)。 Step 1: Lithium chloride (936 mg, 22.08 mmol, 7 equivalents), tetrakis(triphenylphosphino)palladium(0) (547 mg, 0.47 mmol, 0.15 equivalent) and tributyl at room temperature Vinyltin (1.84 mL, 6.31 mmol, 2 equivalents) was added to a solution of 2-chloro-4-nitropyridine (500 mg, 3.15 mmol) dissolved in tetrahydrofuran. 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 potassium fluoride solution and then extracted with ethyl acetate. The organic portion was washed with a saturated sodium chloride solution. The organic layer was dried and concentrated under reduced pressure and purified to afford purified crystals.

步驟2：於氮氣氣氛下，將0.5%之四氧化鋨(溶於水)(2.36 mL，0.05 mmol，0.02等量)及50%之N-甲基嗎啉基-N-氧化物(溶於水)(1.66 mL，6.99 mmol，3等量)加至以丙酮溶解之5-硝基-2-乙烯啶(350 mg，2.33 mmol)溶液。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。將該反應混合物以水稀釋，並以乙基醋酸萃取。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。以管柱色層分析純化該粗製產物，以獲得1-(5-硝基啶-2-基)乙烷-1,2-二醇(368 mg，86%)。 Step 2: 0.5% osmium tetroxide (dissolved in water) (2.36 mL, 0.05 mmol, 0.02 equivalent) and 50% N -methylmorpholinyl- N -oxide (dissolved in a nitrogen atmosphere) Water) (1.66 mL, 6.99 mmol, 3 equivalents) was added to a solution of 5-nitro-2-vinylpyridine (350 mg, 2.33 mmol) dissolved in acetone. The reaction 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 1-(5-nitropyridin-2-yl)ethane-1,2-diol (368 mg, 86%).

步驟3：以四氯化鋯(47 mg，0.20 mmol，0.1等量)及2,2-甲氧丙烷(0.3 mL，2.40 mmol，1.2等量)處理以二氯甲烷溶解之1-(5-硝基啶-2-基)乙烷-1,2-二醇(368 mg，2.00 mmol)溶液。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，並以乙基醋酸萃取。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；再以管柱色層分析純化該粗製產物，以獲得2-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)-5-硝基啶(311 mg，69%)。 Step 3: Treatment with zirconium tetrachloride (47 mg, 0.20 mmol, 0.1 equivalent) and 2,2-methoxypropane (0.3 mL, 2.40 mmol, 1.2 equivalent) in 1-(5- A solution of nitropyridin-2-yl)ethane-1,2-diol (368 mg, 2.00 mmol). 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 under reduced pressure to give a crude product. The crude product was purified by column chromatography to give 2-(2,2-dimethyl-l-II) Oxolan-4-yl)-5-nitropyridine (311 mg, 69%).

步驟4：將2-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)-5-硝基啶(311 mg，1.38 mmol)以甲醇及四氫呋喃(1：1，15 mL)溶解；並添加10%之鈀碳(31 mg，10%)。於氫氣下，將該反應混合物於室溫攪拌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，並於較低壓力濃縮。以管柱色層分析純化該粗製產物，以獲得6-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)啶-3-胺(201 mg，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. The reaction mixture was stirred at room temperature for 3 hours under hydrogen. Thin layer chromatography showed complete consumption of the starting material. The mixture was filtered through a pad of celite and concentrated at lower pressure. The crude product was purified by column chromatography to give 6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine (201 mg, 75%) ).

步驟5：將6-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)啶-3-胺(201 mg，1.04 mmol)以乙腈(3 mL)及四氫呋喃(4 mL)溶解。於該反應混合物中添加啶(0.10 mL，1.24 mmol，1.2等量)及氯甲酸苯酯(0.14 mL，1.09 mmol，1.05等量)，並於氮氣氣氛下，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，並以乙基醋酸萃取。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。以管柱色層分析純化該粗製產物，以獲得苯基6-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)啶-3-基胺甲酸酯(321 mg，99%)。 Step 5: 6-(2,2-Dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine (201 mg, 1.04 mmol) in acetonitrile (3 mL) and THF (4 mL) dissolved. Pyridine (0.10 mL, 1.24 mmol, 1.2 equivalent) and phenyl chloroformate (0.14 mL, 1.09 mmol, 1.05 eq.) were added to the mixture and the mixture was stirred at room temperature for 3 hr. 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-ylamine carbamate. (321 mg, 99%).

步驟6：於室溫，將4-二甲基胺基啶(41 mg，0.33 mmol，1等量)及(2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺(100 mg，0.37 mmol，1.1等量)加至以乙腈(3 mL)溶解之苯基6-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)啶-3-基胺甲酸酯(105 mg，0.33 mmol)。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，並以乙基醋酸萃取。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。以管柱色層分析純化該粗製產物，以獲得1-(6-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素(149 mg，90%)。 Step 6: 4-dimethylaminopyridine (41 mg, 0.33 mmol, 1 equivalent) and (2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl) at room temperature Benzyl-3-yl)methanamine (100 mg, 0.37 mmol, 1.1 equivalent) was added to phenyl 6-(2,2-dimethyl-1,3-dioxonate dissolved in acetonitrile (3 mL) Heterocyclic pentan-4-yl)pyridin-3-ylcarbamate (105 mg, 0.33 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-(6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-3 -((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea (149 mg, 90%).

步驟7：於室溫，將四氯化鋯(22mg，0.09 mmol，0.3等量)加至以甲醇溶解之1-(6-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素(149 mg，0.31 mmol)溶液。機該反應混合物於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，並以乙基醋酸萃取。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。以管柱色層分析純化該粗 製產物，以獲得1-(6-(1,2-二烴乙基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素(44 mg，32%)。 Step 7: Add zirconium tetrachloride (22 mg, 0.09 mmol, 0.3 equivalent) to 1-(6-(2,2-dimethyl-1,3-dioxo) dissolved in methanol at room temperature. Pent-4-yl)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl) Urea (149 mg, 0.31 mmol) solution. 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-(6-(1,2-dihydroethylethyl)pyridin-3-yl)-3-((2-(4-methylpiperidine-1) -yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea (44 mg, 32%).

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 mL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/mL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 calf Serum (FCS) (foetal calf serum, Gibco Invitrogen GmbH, Karlsruche, Germany, heat inactivated), 2 mM L-glutamate (Sigma, Munich, Germany), 1% by weight antibiotics / anti-fungal ( AA) solution (antibiotic/antimyotic solution, PAA, Pasching, Austria), and 25 ng/mL nerve growth factor (NGF) medium (2.5 S, Gibco Invitrogen GmbH, Karlsruhe, Germany).

細胞培養板：將經多聚賴氨酸塗覆、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/mL。將濃度為100 μg/mL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/mL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: a 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) Coated by GmbH, Karlsruhe, Germany; 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. The cell culture plates were incubated at 37 ° C for at least 2 hours, the excess solution was aspirated, and the recesses were washed twice with a phosphate solution. 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。將脊柱依縱向切開，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 mL完全培養基之50 mL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. Remove all remaining blood and spinal nerves from the dorsal root ganglion, Each was 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 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) containing 2 μM Fluo-4 and 0.01% by volume of Pluronic F127 (Molecular Probes Europe BV, Leiden, The Netherlands). Incubate at 37 ° C for 30 minutes, then wash 3 times with Hank's balanced salt solution; then, incubate for 15 minutes at room temperature for fluorescence imaging to measure calcium ions. 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 the addition of 10 μM capsaicin (CP), based on the percentage of activity of the calcium ion signal. 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受體之親和性如以下表2及表3所示。於該表中，Cap代表辣椒素，AG代表激動劑。 The affinity of the compounds according to the invention for the VR1/TRPV1 receptor is shown in Tables 2 and 3 below. In the table, Cap represents capsaicin and AG represents an 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，n代表1、2、3或4；X代表N或CH；Y代表O、S或N-CN；Z代表N或C-R4b；A1代表N或CR5；A2代表N或CR6；A3代表N或CR7；A4代表N或CR8；A5代表N或CR9；附帶條件為A1、A2、A3、A4與A5變量之1、2或3代表一氮原子；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，進而可能係未被取代或被單取代或被多取代；芳基或雜芳基，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，進 而可能係未被取代或被單取代或被多取代；R1代表一未被取代或被單取代或被多取代之C1-4脂族殘基、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單取代或被多取代；R2代表R0、OR0、SR0、NH2、NHR0或N(R0)2；R3代表H或C1-4脂族殘基，其係未被取代或被單取代或被多取代；R4a代表H、一未被取代或被單取代或被多取代之C1-4脂族殘基、一未被取代或被單取代或被多取代之C3-6環脂族殘基、或未被取代或被單取代或被多取代之芳基；R4b 代表H或一未被取代或被單取代或被多取代之C1-4脂族殘基；或R4a與R4b及將其連結之碳原子共同形成一未被取代或被單取代或被多取代之C3-6環脂族殘基；R5、R6、R7、R8與R9各自相互獨立地代表H、F、Cl、Br、I、CN、CF3、CF2H、CFH2、CF2Cl、CFCl2、NO2、R0、C(=O)-H、C(=O)-R0、C(=O)-OH、C(=O)-OR0、C(=O)-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)-NHR0、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)-NH-R0、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、或S(=O)2-N(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，相互獨立地可係支鏈或非支鏈，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」與「雜芳基」之「被單取代或被多取代」，係於各例中，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 n represents 1, 2, 3 or 4; X represents N or CH; Y represents O, S or N-CN; Z represents N or CR 4b ; A 1 represents N or CR 5 ; A 2 represents N or CR 6 A 3 represents N or CR 7 ; A 4 represents N or CR 8 ; A 5 represents N or CR 9 ; with the condition that 1 , 2 or 3 of the A 1 , A 2 , A 3 , A 4 and A 5 variables represent a nitrogen atom; 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 multiple Substituted; aryl or heteroaryl, unsubstituted or monosubstituted or polysubstituted in each case, and optionally bridged via a C 1-8 aliphatic group in each case, which may be unsubstituted Or monosubstituted or polysubstituted; R 1 represents an unsubstituted or monosubstituted or polysubstituted C 1-4 aliphatic residue, a C 3-6 cycloaliphatic residue or a 3 to 6 member heterocyclic ring An aliphatic residue which is unsubstituted or monosubstituted or taken in each case R 2 represents R 0 , OR 0 , SR 0 , NH 2 , NHR 0 or N(R 0 ) 2 ; R 3 represents an H or C 1-4 aliphatic residue which is unsubstituted or monosubstituted or Polysubstituted; R 4a represents H, an unsubstituted or monosubstituted or polysubstituted C 1-4 aliphatic residue, an unsubstituted or monosubstituted or polysubstituted C 3-6 cycloaliphatic residue An aryl group which is unsubstituted or monosubstituted or polysubstituted; R 4b represents H or an unsubstituted or monosubstituted or polysubstituted C 1-4 aliphatic residue; or R 4a and R 4b and The carbon atoms to which they are bonded together form an unsubstituted or monosubstituted or polysubstituted C 3-6 cycloaliphatic residue; R 5 , R 6 , R 7 , R 8 and R 9 each independently represent H , F, Cl, Br, I, CN, CF 3 , CF 2 H, CFH 2 , CF 2 Cl, CFCl 2 , NO 2 , R 0 , C(=O)-H, C(=O)-R 0 , C(=O)-OH, C(=O)-OR 0 , C(=O)-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)-NHR 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)-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 , or S(=O) 2 -N(R 0 ) 2 ; its "aliphatic group" and "aliphatic residue" in each case, independently of each other, may be branched or unbranched, saturated or not Saturated; "cycloaliphatic residue" and "heterocyclic aliphatic residue" in each case, independently or independently branched or unbranched, saturated or unsaturated; "aliphatic", "fat" Family "Substituted or polysubstituted" of "cycloaliphatic residue" and "heterocyclic aliphatic residue", as used in each case, independently of each other in its corresponding residue or functional group Wherein 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 S(=O) 2 -N(R 0 ) 2 and other substituents of the group consisting of a substituted group; the "aryl" and "heteroaryl group" of the "mono- or polysubstituted", based on the respective embodiments, since each independently of their respective residues, 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 -NHR 0 and S(=O) 2 -N(R 0 ) 2 Substituting a group of such substituents; optionally 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. 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。 A substituted compound according to any one of the preceding claims, characterized in that R 1 is selected from the group consisting of CF 3 , methyl, ethyl, n-propyl, isopropyl, n-butyl, butyl and The group consisting of tertiary butyl groups, or selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. 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(T1)子結構，其 E 代表O、S或NR11，其中，R11代表H或一未被取代或被一或多個各自相互獨立地選自由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C1-4脂族殘基，其係未被取代，或被一或多個各自相互獨立地選自由 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C1-4脂族殘基，其係未被取代，或被一或多個各自相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、=O、O-C1-4烷基、O-C1-4伸烷基-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，或被一或多個各自相互獨立地選自由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，或被一或多個各自相互獨立地選自由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，或被一或多個各自相互獨立地選自由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，其係未被取代，或被一或多個各自相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、CF3、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，或被一或多個各自相互獨立地選自由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 substituted compound according to any one of the preceding claims, wherein R 2 represents a (T1) substructure, E represents O, S or NR 11 , wherein R 11 represents H or an unsubstituted or one or more are each independently selected from F, Cl, Br, I, OH, OC 1-4 alkyl, OCF a group of mono- or poly-substituted C 1-4 aliphatic residues consisting of NH 2 , NH-C 1-4 alkyl and N(C 1-4 alkyl) 2 ; o represents 0 or 1; R 10a and R 10b each independently represent H, F, Cl, Br, I or a C 1-4 aliphatic residue, which are unsubstituted or independently selected from one or more of each other by Groups consisting of substituents such as F, Cl, Br, I, OH, OC 1-4 alkyl, OCF 3 , NH 2 , NH-C 1-4 alkyl and N(C 1-4 alkyl) 2 Substituted or polysubstituted; m represents 0, 1, 2, 3 or 4, preferably 0, 1 or 2, preferably 0 or 1; G represents a C 1-4 aliphatic residue, which is not Substituted, or one or more of each independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, =0, OC 1-4 alkyl, OC 1-4 alkyl-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 Group mono- or poly-substitution of substituents such as pyridine Wherein the phenyl or based piperidinyl are unsubstituted or substituted with one or more substituents each 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 a group consisting of SCF 3 and S(=O) 2 OH, such as a mono- or poly-substituent; or a C 3-10 cycloaliphatic residue or a 3 to 10 membered heterocyclic aliphatic residue, In each case, unsubstituted, or one or more independently selected from each other by 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 pyridine a group consisting of a mono- or poly-substituent of a group consisting of a phenyl or pyridine group, respectively, or unsubstituted, or one or more of each 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 group and the like substituent composition Group mono- or polysubstituted; represents an aryl or heteroaryl group or an aryl group, which system is unsubstituted, or one or more are each independently selected from F, Cl, Br, I, NO 2, CN, OH , 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 are each 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 a group of mono- or poly-substituents consisting of a substituent such as -4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 and S(=O) 2 OH. 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個各自相互獨立地選自由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)等取代基組成之群組、C1-4烷基及O-C1-4-烷基取代；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環丙基、環丁基、環戊基或環己基環。 The substituted compound according to any one of the preceding claims, wherein R 4a represents H, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl, wherein The phenyl group is unsubstituted or selected from 1, 2 , 3 , 4 or 5 independently of each other from F, Cl, Br, I, NO 2 , CN, CF 3 , CF 2 H, CFH 2 , CF 2 a group consisting of a substituent such as Cl, CFCl 2 , OH, NH 2 , NH(C 1-4 alkyl) and N(C 1-4 alkyl)(C 1-4 alkyl), C 1-4 alkane And OC 1-4 -alkyl substituted; 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 ring Hexyl 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，其特徵為此部分結構 代表一選自由下列基團組成之群組 。 A substituted compound according to any one of the preceding claims, which is characterized by a partial structure Representing a group selected from the group consisting of the following groups . 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、R6、R7、R8與R9各自相互獨立地代表H、F、Cl、Br、I、CN、NO2、CF3、CF2H、CFH2、CF2Cl、CFCl2、OH、OCF3、OCF2H、OCFH2、OCF2Cl、OCFCl2、SH、SCF3、SCF2H、SCFH2、SCF2Cl、SCFCl2、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，上述之C1-10脂族殘基與C1-8脂族基於各例中係未被取代；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，上述之殘基於各例中可選擇性地可經由一C1-8脂族基橋接，其中，C1-10脂族殘基與C1-8脂族基於各例中相互獨立地未被取代，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各自相互獨立地選自由F、Cl、Br、I、C1-4烷基、C1-4烷基-OH、CF3、C(=O)-C1-4烷基、O-C1-4烷基、O-C1-4烷基-OH、O-C1-4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，上述之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，或被以一或多個各自相互獨立地選自由F、Cl、Br、I、C1-4烷基、C1-4烷基-OH、CF3、C(=O)-C1-4烷基、O-C1-4烷基、O-C1-4烷基-OH、O-C1-4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、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，或被一或多個各自相互獨立地選自由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脂族基於各例中係未被取代。 The substituted compound according to any one of the preceding claims, wherein R 5 , R 6 , R 7 , R 8 and R 9 each independently represent 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 1-10 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, one O-(C 1-8 fat Family group)-OC 1-10 aliphatic residue, O-(C 1-8 aliphatic)-OH, one NH-C 1-10 aliphatic residue, one 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, 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], 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 fat) Family 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) 2 - N (C 1-10 aliphatic residue) 2 , an SC 1-10 aliphatic residue, wherein the above C 1-10 aliphatic residue and the C 1-8 aliphatic group are unsubstituted based on each case 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 a -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 Cycloaliphatic 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 building block) a cycloaliphatic residue), an O-(3 to 10 membered heterocyclic aliphatic residue), an O-(C 1-8 aliphatic group)-(3 to 10 membered heterocyclic aliphatic residue), S-(3 to 10 component heterocyclic aliphatic residue), an S-(C 1-8 aliphatic group)-(3 to 10 member heterocyclic aliphatic residue), and one NH-(3 to 10 building block) a cycloaliphatic residue), an NH-C(=O)-(3 to 10 membered heterocyclic aliphatic residue), NH-(C 1-8 aliphatic)-(3 to 10 membered heterocyclic aliphatic Residue), an N (C 1-10 aliphatic residue) (3 to 10 membered heterocyclic aliphatic residue), wherein the above residue is optionally via a C 1-8 lipid based on each of the examples a group-based bridge wherein the C 1-10 aliphatic residue and the C 1-8 aliphatic group are unsubstituted independently of each other based on each of the examples, wherein the C 3-10 cycloaliphatic residue and the 3 to 10 member Heterocyclic aliphatic residues based on each case, mutual Based site can be unsubstituted or substituted with one or more substituents each independently selected from the group consisting of F, Cl, Br, I, C 1-4 alkyl, C 1-4 alkyl -OH, 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, =O, 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 a group consisting of a substituent such as NH-SO 2 -C 1-4 alkyl, NH-C(=O)-C 1-4 alkyl, mono- or poly-substituted, aryl, C(=O)-aryl Base, C(=O)-NH-aryl, O-aryl, mono-O-(C 1-8 aliphatic)-aryl, S-aryl, mono-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, 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 aliphatic residue Base) (heteroaryl), wherein the above residue is optional based on each case Selectively bridged via a C 1-8 aliphatic group, wherein the aryl and heteroaryl groups of the above residues are independently unsubstituted in each case, or independently of one another Optional free F, Cl, Br, I, C 1-4 alkyl, C 1-4 alkyl-OH, 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, 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, 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 one or more of each 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 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) 2 OH group and the like substituent group consisting of a substituted or mono-substituted, wherein the residue of C 1-10 aliphatic residue with C 1-8 aliphatic Based on the respective embodiments based unsubstituted. 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n代表1；X代表N或CH；Y代表O；Z代表N或C-R4b；A1代表N或CR5；A2代表N或CR6；A3代表N或CR7；A4代表N或CR8；A5代表N或CR9； 附帶條件為A1、A2、A3、A4與A5變量之1、2或3代表一氮原子；R1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；R2 代表(T1)子結構 其E 代表O、S或NR11，其中，R11代表H或一C1-4脂族殘基，其係未被取代，或被一或多個各自相互獨立地選自由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；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，或被一或多個各自相互獨立地選自由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C1-4脂族殘基，其係未被取代，或被一或多個各自相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、=O、O-C1-4烷基、O-C1-4伸烷基-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，或被一或多個各自相互獨立地選自由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，或被一或多個各自相互獨立地選自由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，苯基或啶基係未被取代，或被一或多個各自相互獨立地選自由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；或代表芳基或雜芳基，其係未被取代，或被一或多個各自相互獨立地選自由F、Cl、Br、I、NO2、CN、OH、O-C1-4烷基、OCF3、C1-4烷基、CF3、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，苯基或啶基係未被取代，或被一或多個各自相互獨立地選自由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；R3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)組成之群組、C1-4烷基與O-C1-4-烷基之取代基取代；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環丙基、環丁基、環戊基、或環己基環；R5、R6、R7、R8與R9係各自相互獨立地選自由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、C(=O)-H、C(=O)-OH、S(=O)2-OH、S(=O)2-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、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，上述之C1-10脂族殘基與C1-8脂族基於各例中係未被取代或被以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，相自獨立地可係未被取代，或被一或多個各自相互獨立地選自由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，或被以一或多個各自相互獨立地選自由 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，或被一或多個各自相互獨立地選自由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。 The scope of the patent is substituted with any one of said compounds, wherein n represents 1; X represents N or CH; Y Representative O; Z represents N or CR 4b; A 1 represents N or CR 5; A 2 Represents N or CR 6 ; A 3 represents N or CR 7 ; A 4 represents N or CR 8 ; A 5 represents N or CR 9 ; conditional is 1 of A 1 , A 2 , A 3 , A 4 and A 5 variables 2 or 3 represents a nitrogen atom; R 1 is selected from the group consisting of a tertiary butyl group, a CF 3 group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group; and R 2 represents a (T1) substructure. Its E represents O, S or NR 11 , wherein R 11 represents H or a C 1-4 aliphatic residue which is unsubstituted or is selected independently from one another by F, Cl, Br a group of mono- or poly-substituents consisting of a substituent such as I, OH, OC 1-4 alkyl, OCF 3 , NH 2 , NH-C 1-4 alkyl and N(C 1-4 alkyl) 2 ; o represents 0 or 1; R 10a and R 10b each independently represent H, F, Cl, Br, I or a C 1-4 aliphatic residue, which are unsubstituted or are each one or more Independently selected from the group consisting of F, Cl, Br, I, OH, OC 1-4 alkyl, OCF 3 , NH 2 , NH-C 1-4 alkyl and N(C 1-4 alkyl) 2 The group is mono- or polysubstituted; m represents 0, 1, 2, 3 or 4, preferably 0, 1 or 2, preferably 0 or 1; G represents a C 1-4 aliphatic residue. , which are unsubstituted or one or more independently selected from each other by F, Cl, Br, I, NO 2 , CN, OH, =0, OC 1-4 alkyl, OC 1-4 alkylene --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 single substitution of a group consisting of a substituent such as a phenyl group and a pyridine group Multi-substituted, wherein each phenyl or pyridyl is unsubstituted system, or one or more are each independently 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(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; or represents a cyclic aliphatic C 3-10 residue or a 3-10 member heterocyclic aliphatic residue a group, which is unsubstituted in each case, or one or more of each 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 a mono- or poly-substitution group consisting of a substituent such as a pyridyl group, wherein the phenyl or pyridyl group is unsubstituted or one or more of each 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 group and the like substituent Into the group of mono- or polysubstituted; or represents aryl or heteroaryl, which system is unsubstituted, or one or more are each independently selected from F, Cl, Br, I, NO 2, CN, OH, 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, phenyl or piperidinyl based unsubstituted or substituted with one or more are each independently 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 (C 1 a group of mono- or poly-substituted groups of -4 alkyl), N(C 1-4 alkyl) 2 , SH, SC 1-4 alkyl, SCF 3 and S(=O) 2 OH; 3 is selected from the group consisting of H, methyl and ethyl; R 4a represents H, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl, wherein phenyl is Unsubstituted, or selected from 1, 2 , 3 , 4 or 5 independently of each other by F, Cl, Br, I, NO 2 , CN, CF 3 , CF 2 H, CFH 2 , CF 2 Cl, CFCl 2 , OH, NH 2 , NH (C a group consisting of 1-4 alkyl) and N(C 1-4 alkyl)(C 1-4 alkyl), a substituent of a C 1-4 alkyl group and an OC 1-4 -alkyl group; R 4b Representing H, methyl or ethyl, or R 4a and R 4b together with the carbon atom to which they are bonded form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring; R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from 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)- a group consisting of 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, 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 aliphatic residue)- (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 Yl) -NH-S (= O) 2 -NH 2, a (C 1-8 aliphatic) -S (= O) 2 -C 1-10 aliphatic residue, an aliphatic residue OC 1-10 a group, an O-(C 1-8 aliphatic)-OC 1-10 aliphatic residue, O-(C 1-8 aliphatic)-OH, an NH-C 1-10 aliphatic residue, N (C 1-10 aliphatic residue) 2 , mono NH-(C 1-8 aliphatic)-OC 1-10 aliphatic residue, mono 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 group)-OH], an NH-S(=O) 2 -C 1-10 aliphatic residue, wherein the above C 1-10 aliphatic residue and the C 1-8 aliphatic group are each based on In the case of being unsubstituted or monosubstituted with OH; 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 NH-C 3-10 cycloaliphatic residue, an NH-C(=O)-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 NH- (3 to 10 membered heterocyclic aliphatic residue), an NH-C(=O)-(3 to 10 member heterocyclic aliphatic residue), The C 3-10 cycloaliphatic residues with the 3-10 member heterocyclic aliphatic residue based on the respective embodiments, the phase can be independent from the system unsubstituted or substituted with one or more are each independently selected from 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, 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 a group consisting of a mono- or poly-substituent of a substituent such as -C(=O)-C 1-4 alkyl; aryl, C(=O)-aryl, C(=O)-NH-aryl, NH -C(=O)-aryl, heteroaryl, C(=O)-heteroaryl, C(=O)-NH-heteroaryl, NH-C(=O)-heteroaryl, wherein The aryl group and the heteroaryl group of the above-mentioned residue may be unsubstituted independently of each other based on each of the examples, or may be selected from F, Cl, Br, I, NO 2 , CN, OH independently of one or more of each other. , 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 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 1-4 alkyl, substituents such as phenyl and pyridine a group consisting of a mono- or poly-substitution wherein the phenyl or pyridine groups are unsubstituted, respectively, or one or more are each 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. 根據前述申請專利範圍中任何一項或多項所述之被取代化合物，其特徵為R5與R9係各自相互獨立地選自由H、F、Cl、Br、I、CF3、OH、CH2OH、甲基、O-甲基組成之群組；R6與R8係各自相互獨立地選自由H、F、Cl、Br、I、CF3、OH、CH2OH、甲基、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哌喃基組成之群組較佳，以四氫-2H-哌喃-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，或被以一或多個各自相互獨立地選自由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，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，或被一或多個各自相互獨立地選自由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 or more of the preceding claims, wherein the R 5 and R 9 systems are each independently selected from the group consisting of H, F, Cl, Br, I, CF 3 , OH, CH 2 a group consisting of OH, methyl, and O-methyl; each of R 6 and R 8 is independently selected from the group consisting of H, F, Cl, Br, I, CF 3 , OH, CH 2 OH, methyl, O- a group of 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 alkyl-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 alkane Base, 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 stretch Group -OH, OC 1-4 alkylene -OC 1-4 alkyl, NH-C 1-4 alkyl, N (C 1-4 alkyl) 2, NH-C 1-4 alkylene group -OH , NH-C 1-4 alkylene-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 the C 1-4 alkylene group may be unsubstituted in each case Or monosubstituted by 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 group The residue is preferably selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and wherein the 3 to 6 membered heterocyclic aliphatic residue is selected from the group consisting of tetrahydropyranyl. Preferably, the group is preferably tetrahydro-2H-piperidin-4-yl, azetidinyl, piperidinyl, decyl and pyridyl, wherein the C 3-6 cycloaliphatic residue And the 3 to 6 member heterocyclic aliphatic residue may be unsubstituted, respectively, or may be selected from F, Cl, Br, I, OH, OC 1-4 alkyl, NH, independently of each other. 2, NH2 (C 1-4 alkyl) and N (C 1-4 alkyl) 2 group like the group consisting of substituted and unsubstituted C 1-4 alkyl or mono-substituted, benzene , C(=O)-NH-phenyl, NH-C(=O)-phenyl, heteroaryl, C(=O)-NH-heteroaryl, NH-C(=O)-heteroaryl Wherein the phenyl group and the heteroaryl group of the above-mentioned residue are independently unsubstituted in each of the examples, or are independently selected from the group consisting of F, Cl, Br, I, OH, OC 1 A group consisting of a monoalkyl group, a C 1-4 alkyl group, and a substituent such as CF 3 may be 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，係選自下列群組1. N-((2-戊基-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺2. N-((2-環戊基-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺3. 1-(啶-2-基)-3-((2-(四氫-2H-吡喃-4-基)-6-(三氟甲基)啶-3-基)甲基)尿素4. N-((2-(環己基甲基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺5. N-((2-(3-氯苯基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺6. N-((2-(3-氯-4-氟苯基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺7. 2-(啶-2-基)-N-((2-間-甲苯基-6-(三氟甲基)啶-3-基)甲基)乙醯胺8. N-((2-(3-甲氧苯基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺9. N-((2-(丁胺基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺10. 2-(啶-2-基)-N-((2-(咯啶基-1-基)-6-(三氟甲基)啶-3-基)甲基)乙醯胺11. N-(2-(4-甲基哌啶-1-基)-4-(三氟甲基)苄基)-2-(啶-2-基)乙醯胺12. N-((6-三級丁基-2-(4-甲基哌啶-1-基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺13. N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺 14. N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)丙醯胺15. 2-甲基-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)丙醯胺16. N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-1-(啶-2-基)環丙醯胺17. 2-環己基-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺18. N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)-2-間-甲苯乙醯胺19. 1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-3-(啶-2-基)尿素20. 1-甲基-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-1-(啶-2-基)尿素21. 1-甲基-1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-3-(啶-2-基)尿素22. N-((2-嗎啉基-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺23. 1-((2-(4-(二甲胺基)哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-3-(啶-2-基)尿素24. N-((2-((2-甲氧乙氧)甲基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺25. N-((2-丁氧基-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺26. N-((2-(環丁基甲氧基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺 27. N-((2-(環己氧基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺28. N-(4-三級丁基-2-(環己基硫代)苄基)-2-(啶-2-基)乙醯胺29. N-(2-(環己基硫代)-4-(三氟甲基)苄基)-2-(啶-2-基)乙醯胺30. N-((6-環丙基-2-(4-甲基哌啶-1-基)啶-3-基)甲基)-2-(啶-2-基)乙醯胺31. N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-3-基)乙醯胺32. N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-3-基)丙醯胺33. N-(4-三級丁基-2-(4-甲基哌啶-1-基)苄基)-2-(啶-3-基)乙醯胺34. N-((2-(環己基硫代)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-3-基)乙醯胺35. 1-((2-(3-氯苯基)-6-(三氟甲基)啶-3-基)甲基)-3-(啶-3-基)尿素36. 1-(啶-3-基)-3-((2-間-甲苯基-6-(三氟甲基)啶-3-基)甲基)尿素37. 1-((2-(3-甲氧苯基)-6-(三氟甲基)啶-3-基)甲基)-3-(啶-3-基)尿素38. N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-2-(啶-4-基)乙醯胺39. N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-2-(嘧啶-4-基)乙醯胺40. N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-2-(吡嗪-2-基)乙醯胺 41. N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-2-(嘧啶-2-基)乙醯胺42. 1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-3-(噠嗪-4-基)尿素43. 1-(2-(4-甲基哌啶-1-基)-4-(三氟甲基)苄基)-3-(噠嗪-4-基)尿素44. 1-(4-三級丁基-2-(環己基硫代)苄基)-3-(噠嗪-4-基)尿素45. 1-((2-(3-氟苯基)-6-(三氟甲基)啶-3-基)甲基)-3-(噠嗪-4-基)尿素46. 1-((2-(3-氯-4-氟苯基)-6-(三氟甲基)啶-3-基)甲基)-3-(噠嗪-4-基)尿素47. N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-2-(嘧啶-5-基)乙醯胺48. 1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-3-(1,3,5-三嗪-2-基)尿素49. 2-(6-氯啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺50. 2-(5-氟啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)乙醯胺51. 1-(5-氟啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素52. 1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-3-(2-甲基嘧啶-5-基)尿素53. 2-(6-(羥甲基)啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺54. N-((2-(3-氟苯基)-6-(三氟甲基)啶-3-基)甲基)-2-(6-(羥甲基) 啶-3-基)丙醯胺55. 1-(6-(羥甲基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素56. 1-(6-(羥甲基)啶-3-基)-3-((2-戊基-6-(三氟甲基)啶-3-基)甲基)尿素57. 1-((2-(3-氟苯基)-6-(三氟甲基)啶-3-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素58. 1-(6-(羥甲基)啶-3-基)-3-((2-間-甲苯基-6-(三氟甲基)啶-3-基)甲基)尿素59. 1-(6-(羥甲基)啶-3-基)-3-((2-(3-異丙苯基)-6-(三氟甲基)啶-3-基)甲基)尿素60. 1-((2-(3-(二甲胺基)苯基)-6-(三氟甲基)啶-3-基)甲基)-3-(6-(羥甲基)啶-3-基)尿素61. 1-(5-氯-6-(羥甲基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素62. 2-(6-(2-烴乙基)啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺63. 1-(6-(2-烴乙基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素64. 2-(6-((2-烴乙基)甲基)啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺65. 1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-3-(6-(甲基磺醯基甲基)啶-3-基)尿素66. 1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-3-(6-(2-(甲基磺醯基)乙基)啶-3-基)尿素67. 1-(5-氟-6-(2-(甲基磺醯基)乙基)啶-3-基)-3-((2-(4-甲基哌啶 -1-基)-6-(三氟甲基)啶-3-基)甲基)尿素68. 1-((6-環丙基-2-(4-甲基哌啶-1-基)啶-3-基)甲基)-3-(5-氟-6-(2-(甲基磺醯基)乙基)啶-3-基)尿素69. 1-(5-氟-6-(2-(甲基磺醯基)乙基)啶-3-基)-3-((2-(3-氟苯基)-6-(三氟甲基)啶-3-基)甲基)尿素70. N-((5-(3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)脲基)啶-2-基)甲基)甲基磺醯胺71. N-((5-(3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)脲基)啶-2-基)甲基)硫醯二胺72. N-((5-(3-(2-(環己氧基)-4-(三氟甲基)苄基)脲基)啶-2-基)甲基)硫醯二胺73. N-((5-(3-((2-間-甲苯基-6-(三氟甲基)啶-3-基)甲基)脲基)啶-2-基)甲基)硫醯二胺74. 5-(1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺基)-1-氧代丙烷-2-基)吡啶醯胺75. 5-(1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺基)-1-氧代丙烷-2-基)-N-苯基吡啶醯胺76. 5-(1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺基)-1-氧代丙烷-2-基)-N-苯基嘧啶-2-羧醯胺77. 5-(1-((2-(乙胺)-6-(三氟甲基)啶-3-基)甲胺基)-1-氧代丙烷-2-基)-N-(4-氟苯基)嘧啶-2-羧醯胺78. N-(4-氟苯基)-5-(1-氧代-1-((2-(咯啶-1-基)-6-(三氟甲基)啶-3-基)甲胺基)丙烷-2-基)嘧啶-2-羧醯胺79. N-(4-氟苯基)-5-(1-氧代-1-((2-(哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺基)丙烷-2-基)嘧啶-2-羧醯胺80. N-(4-氟苯基)-5-(1-((2-嗎啉基-6-(三氟甲基)啶-3-基)甲胺 基)-1-氧代丙烷-2-基)嘧啶-2-羧醯胺81. N-(4-氟苯基)-5-(1-氧代-1-((2-間-甲苯基-6-(三氟甲基)啶-3-基)甲胺基)丙烷-2-基)嘧啶-2-羧醯胺82. 5-(1-氧代-1-((2-(哌啶-1-基甲基)-6-(三氟甲基)啶-3-基)甲胺基)丙烷-2-基)-N-(4-(三氟甲基)苯基)嘧啶-2-羧醯胺83. 1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-3-(6-(四氫-2H-吡喃-4-基)啶-3-基)尿素84. 2-(5-胺基-6-溴啶-2-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺85. 2-(6-(2-羥乙胺)啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺86. 1-(6-(2-羥乙胺)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素87. 2-(6-(2-甲氧基乙胺)啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺88. 1-(6-(2-甲氧基乙胺)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素89. 2-(6-((2-烴乙基)(甲基)胺)啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺90. 1-(6-((2-烴乙基)(甲基)胺)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素91. 1-(6-((2-甲氧基乙基)(甲基)胺)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素92. N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-2-(6-(甲基磺醯胺)啶-3-基)丙醯胺93. N-(5-(3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基) 脲基)啶-2-基)甲基磺醯胺94. N-(5-(3-((6-環丙基-2-(4-甲基哌啶-1-基)啶-3-基)甲基)脲基)啶-2-基)甲基磺醯胺95. 2-(6-(甲基磺醯胺)啶-3-基)-N-((2-嗎啉基-6-(三氟甲基)啶-3-基)甲基)丙醯胺96. 2-(5-氟-6-(甲基磺醯胺)啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺97. 2-(5-甲氧基-6-(甲基磺醯胺)啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺98. N-(5-(1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)苯甲醯胺99. 4-氯-N-(5-(1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲胺基)-1-氧代丙烷-2-基)啶-2-基)苯甲醯胺100. 4-氯-N-(5-(1-(2-(4-甲基哌啶-1-基)-4-(三氟甲基)苄基胺基)-1-氧代丙烷-2-基)啶-2-基)苯甲醯胺101. 4-氯-N-(5-(1-(2-(環己基硫代)-4-(三氟甲基)苄基胺基)-1-氧代丙烷-2-基)啶-2-基)苯甲醯胺102. N-(5-(1-(4-三級丁基-2-(環己基硫代)苄基胺基)-1-氧代丙烷-2-基)啶-2-基)-4-氯苯甲醯胺103. 4-氯-N-(5-(1-(2-(環戊基氧基)-4-(三氟甲基)苄基胺基)-1-氧代丙烷-2-基)啶-2-基)苯甲醯胺104. 1-(6-(二甲胺基)-5-(三氟甲基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素105. 1-(6-(氮雜環丁烷-1-基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素106. 1-(6-(氮雜環丁烷-1-基)-5-氟啶-3-基)-3-((2-(4-甲基哌啶-1- 基)-6-(三氟甲基)啶-3-基)甲基)尿素107. 1-(6-(氮雜環丁烷-1-基)-5-甲氧啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素108. 1-(6-(3-羥基氮雜環丁烷-1-基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素109. 1-(6-(3-羥基氮雜環丁烷-1-基)啶-3-基)-3-((2-戊基-6-(三氟甲基)啶-3-基)甲基)尿素110. 1-(6-(3-羥基氮雜環丁烷-1-基)啶-3-基)-3-((2-間-甲苯基-6-(三氟甲基)啶-3-基)甲基)尿素111. 1-(6-(3-羥基氮雜環丁烷-1-基)啶-3-基)-3-((2-甲氧基-6-(三氟甲基)啶-3-基)甲基)尿素112. 1-(6-(3-羥基氮雜環丁烷-1-基)啶-3-基)-3-((2-異丁氧基-6-(三氟甲基)啶-3-基)甲基)尿素113. 1-((2-(環丁基甲氧基)-6-(三氟甲基)啶-3-基)甲基)-3-(6-(3-羥基氮雜環丁烷-1-基)啶-3-基)尿素114. 1-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)-3-(6-(咯啶基-1-基)啶-3-基)尿素115. 1-(5-氟-6-(咯啶-1-基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素116. 1-(5-甲氧基-6-(咯啶-1-基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素117.(S)-1-(6-(3-羥基咯啶-1-基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素118.(R)-1-(6-(3-羥基咯啶-1-基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素119. 1-(6-羥基啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶 -3-基)甲基)尿素120. 2-(6-甲氧基啶-3-基)-N-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)丙醯胺121. 1-(2-甲氧基嘧啶-5-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素122. 1-(2-環丁氧嘧啶-5-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素123. 1-(6-(2-羥基乙氧基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素124. 1-(6-(2-甲氧乙氧基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素125. 1-(6-(2-羥基乙氧基)啶-3-基)-3-((2-間-甲苯基-6-(三氟甲基)啶-3-基)甲基)尿素126. 1-(5-(羥甲基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素127. 1-(5-(羥甲基)啶-2-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素128. 1-(3-(羥甲基)啶-4-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素129. 1-(6-(1,2-二烴乙基)啶-3-基)-3-((2-(4-甲基哌啶-1-基)-6-(三氟甲基)啶-3-基)甲基)尿素130. 1-((2-(3-氟苯基)-6-(三氟甲基)啶-3-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素，及131. 1-((5'-氯-6-(三氟甲基)-2,3'-雙啶-3-基)甲基)-3-(6-(2-羥乙胺)啶-3-基)尿素，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之形式。 The substituted compound according to any one of the preceding claims is selected from the group consisting of 1. N-((2-pentyl-6-(trifluoromethyl)pyridin-3-yl)methyl) -2-(pyridin-2-yl)acetamide 2. N-((2-cyclopentyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridine-2- Acetylamine 3. 1-(pyridin-2-yl)-3-((2-(tetrahydro-2H-pyran-4-yl)-6-(trifluoromethyl)pyridin-3-yl Methyl)urea 4. N-((2-(cyclohexylmethyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-2-yl)acetamide 5. N-((2-(3-Chlorophenyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-2-yl)acetamide 6. N- ((2-(3-Chloro-4-fluorophenyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-2-yl)acetamide 7. 2- (pyridin-2-yl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide 8. N-((2-(3- Methoxyphenyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-2-yl)acetamide 9. N-((2-(butylamino)- 6-(Trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-2-yl)acetamide 10. 2-(pyridine-2-yl)-N-((2-() N-(2-(4-methylpiperidin-1-yl)-4-)pyridyl-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide (Trifluoromethyl)benzyl)-2-(pyridin-2-yl)acetamide 12. N-((6-tertiary butyl- 2-(4-Methylpiperidin-1-yl)pyridin-3-yl)methyl)-2-(pyridin-2-yl)acetamide 13. N-((2-(4-methyl) Pyridin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-2-yl)acetamide 14. N-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-2-yl)propanoid Amine 15. 2-Methyl-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridine- 2-yl)propanamide 16. N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-1-(pyridine -2-yl)cyclopropanamide 17. 2-cyclohexyl-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)- 2-(2-yl-2-piperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl) Methyl)-2-(pyridin-2-yl)-2-m-tolylacetamide 19. 1-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl) Pyridin-3-yl)methyl)-3-(pyridin-2-yl)urea 20. 1-methyl-3-((2-(4-methylpiperidin-1-yl)-6-() Trifluoromethyl)pyridin-3-yl)methyl)-1-(pyridin-2-yl)urea 21. 1-methyl-1-((2-(4-methylpiperidin-1-yl)) -6-(Trifluoromethyl)pyridin-3-yl)methyl)-3-(pyridin-2-yl)urea 22. N-((2-morpholinyl-6-(trifluoromethyl)pyridine -3-yl)methyl)-2-(pyridin-2-yl)acetamide 23. 1-((2-(4-(dimethylamino)piperidin-1-yl)-6-(three Fluoromethyl)pyridin-3-yl)methyl)-3-(pyridin-2-yl)urea 24. N-((2-((2-methoxyethoxy))methyl)-6-(trifluoro) Methyl)pyridin-3-yl)methyl)-2-(啶-2-yl)acetamide 25. N-((2-butoxy-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-2-yl)acetamidine Amine 26. N-((2-(cyclobutylmethoxy)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-2-yl)acetamide 27. N-((2-(Cyclohexyloxy)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-2-yl)acetamide 28. N-( 4-tert-butyl-2-(cyclohexylthio)benzyl)-2-(pyridin-2-yl)acetamide 29. N-(2-(cyclohexylthio)-4-(trifluoro) Methyl)benzyl)-2-(pyridin-2-yl)acetamide 30. N-((6-cyclopropyl-2-(4-methylpiperidin-1-yl))-3-yl Methyl)-2-(pyridin-2-yl)acetamide 31. N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine-3- Methyl)-2-(pyridin-3-yl)acetamide 32. N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine-3 -yl)methyl)-2-(pyridin-3-yl)propanamide 33. N-(4-tert-butyl-2-(4-methylpiperidin-1-yl)benzyl)-2 -(pyridin-3-yl)acetamide 34. N-((2-(cyclohexylthio)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridine-3 -yl)acetamide 35. 1-((2-(3-Chlorophenyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(pyridin-3-yl)urea 36. 1-(Acridin-3-yl)-3-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)urea 37. 1-((2- 3-methoxyphenyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(pyridin-3-yl)urea 38. N-((2-(4-methyl)啶-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyridin-4-yl)acetamide 39. N-((2-(4-methyl) Piperidine-1- -6-(Trifluoromethyl)pyridin-3-yl)methyl)-2-(pyrimidin-4-yl)acetamide 40. N-((2-(4-methylpiperidin-1-) 6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyrazin-2-yl)acetamide 41. N-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(pyrimidin-2-yl)acetamidine Amine 42. 1-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(pyridazin-4-yl) Urea 43. 1-(2-(4-Methylpiperidin-1-yl)-4-(trifluoromethyl)benzyl)-3-(pyridazin-4-yl)urea 44. 1-(4 - Tert-butyl-2-(cyclohexylthio)benzyl)-3-(pyridazin-4-yl)urea 45. 1-((2-(3-fluorophenyl)-6-(trifluoro) Methyl)pyridin-3-yl)methyl)-3-(pyridazin-4-yl)urea 46. 1-((2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl) N-((2-methyl-4-piperidin-1-yl)-6-(trifluoromethyl) Benzyl-3-yl)methyl)-2-(pyrimidin-5-yl)acetamide 48. 1-((2-(4-methylpiperidin-1-yl)-6-(trifluoro) Methyl)pyridin-3-yl)methyl)-3-(1,3,5-triazin-2-yl)urea 49. 2-(6-chloropyridin-3-yl)-N-(2 -(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide 50. 2-(5-fluoropyridine-3-yl)-N -((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide 51. 1-(5-fluoropyridine-3- 3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea 52. 1-((2-(4 -methylpiperidin-1-yl)-6-( Fluoromethyl)pyridin-3-yl)methyl)-3-(2-methylpyrimidin-5-yl)urea 53. 2-(6-(Hydroxymethyl)pyridin-3-yl)-N-( (2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamine 54. N-((2-(3-fluorophenyl) )-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(6-(hydroxymethyl) Pyridin-3-yl)propanamide 55. 1-(6-(Hydroxymethyl)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-( Trifluoromethyl)pyridin-3-yl)methyl)urea 56. 1-(6-(Hydroxymethyl)pyridin-3-yl)-3-((2-pentyl-6-(trifluoromethyl) Pyridin-3-yl)methyl)urea 57. 1-((2-(3-fluorophenyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(6- (hydroxymethyl)pyridin-3-yl)urea 58. 1-(6-(hydroxymethyl)pyridin-3-yl)-3-((2-m-tolyl-6-(trifluoromethyl)) Pyridin-3-yl)methyl)urea 59. 1-(6-(hydroxymethyl)pyridin-3-yl)-3-((2-(3-isopropylphenyl)-6-(trifluoromethyl) ))-3-yl)methyl)urea 60. 1-((2-(3-(Dimethylamino)phenyl)-6-(trifluoromethyl)pyridin-3-yl)methyl) -3-(6-(hydroxymethyl)pyridin-3-yl)urea 61. 1-(5-chloro-6-(hydroxymethyl)pyridin-3-yl)-3-((2-(4- Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea 62. 2-(6-(2-hydrocarbylethyl)pyridin-3-yl)-N -((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamine 63. 1-(6-(2-hydrocarbon B Benzyl-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea 64. 2- (6-((2-Hydroxyethyl)methyl)pyridin-3-yl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine- 3-yl)methyl)propanamide 65. 1-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(6-(methylsulfonylmethyl) Pyridin-3-yl)urea 66. 1-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-( 6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)urea 67. 1-(5-fluoro-6-(2-(methylsulfonyl)ethyl)pyridine-3- Benzyl-3-((2-(4-methylpiperidine) -1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea 68. 1-((6-cyclopropyl-2-(4-methylpiperidin-1-yl)) Pyridin-3-yl)methyl)-3-(5-fluoro-6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)urea 69. 1-(5-fluoro-6- (2-(Methylsulfonyl)ethyl)pyridin-3-yl)-3-((2-(3-fluorophenyl)-6-(trifluoromethyl)pyridin-3-yl)methyl Urea 70. N-((5-(3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)ureido) Pyridin-2-yl)methyl)methylsulfonamide 71. N-((5-(3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl))) Acridine-3-yl)methyl)ureido)pyridin-2-yl)methyl)thioindolediamine 72. N-((5-(3-(2-(cyclohexyloxy))-4-) Fluoromethyl)benzyl)ureido)pyridin-2-yl)methyl)thioindolediamine 73. N-((5-(3-((2-)-tolyl-6-(trifluoromethyl) Pyridin-3-yl)methyl)ureido)pyridin-2-yl)methyl)thioindolediamine 74. 5-(1-((2-(4-methylpiperidin-1-yl))- 5-(1-((2-(4-methylpiperidine)) 5-(1-((2-(4-methylpiperidine)) 5-(1-((2-(4-methylpiperidine)) -1-yl)-6-(trifluoromethyl)pyridin-3-yl)methylamino)-1-oxopropan-2-yl)-N-phenylpyridinium amide 76. 5-(1- ((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methylamino)-1-oxopropan-2-yl -N-phenylpyrimidine-2-carboxyguanamine 77. 5-(1-((2-(ethylamine)-6-(trifluoromethyl))-3-yl)methylamino)-1- Oxopropan-2-yl)-N-(4-fluorophenyl)pyrimidine-2-carboxamide 7878. N-(4-fluorophenyl)-5-(1-oxo-1-(2) -(rrolidine-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methylamino)propan-2-ylpyrimidine-2-carboxamide 59. N-(4-fluorobenzene 5-(1-oxo-1-((2-(piperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methylamino)propan-2-yl) Pyrimidine-2-carboxyguanamine 80. N-(4-fluorophenyl)-5-(1-((2-morpholinyl-6-(trifluoromethyl))-3-yl)methylamine N-(4-fluorophenyl)-5-(1-oxo-1-((2-m-tolyl)). 5-(1-trifluoromethyl)pyridin-3-yl)methylamino)propan-2-ylpyrimidine-2-carboxyindole 82. 5-(1-oxo-1-((2-) Pyridin-1-ylmethyl)-6-(trifluoromethyl)pyridin-3-yl)methylamino)propan-2-yl)-N-(4-(trifluoromethyl)phenyl)pyrimidine- 2-carboxyguanamine 83. 1-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(6-( Tetrahydro-2H-pyran-4-yl)pyridin-3-yl)urea 84. 2-(5-Amino-6-bromodin-2-yl)-N-((2-(4-methyl) Piperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamine 85. 2-(6-(2-hydroxyethylamine)-3-yl)-N -((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamine 86. 1-(6-(2-hydroxyethyl) Amine)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea 87. 2- (6-(2-Methoxyethylamine)pyridin-3-yl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine-3- Methyl)propanamide 88. 1-(6-(2-methoxyethylamine)pyridine-3-yl)-3-((2-(4-methylpiperidin-1-yl)- 6-(Trifluoromethyl)pyridin-3-yl)methyl)urea 89. 2-(6-((2-Hydroxyethyl)(methyl)amine))-3-yl)-N-(( 2-(4-methyl 1-(6-((2-hydrocarbyl))(methyl)amino)pyridinium 3-(3-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea 91. 1-(6-( (2-methoxyethyl)(methyl)amine)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine -3-yl)methyl)urea 92. N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2- (6-(Methylsulfonamide)-3-yl)propanamine 93. N-(5-(3-((2-(4-methylpiperidin-1-yl)-6-) Fluoromethyl)pyridin-3-yl)methyl) Ureido)pyridin-2-yl)methylsulfonamide 94. N-(5-(3-((6-cyclopropyl-2-(4-methylpiperidin-1-yl))-3- 2-(6-(methylsulfonamide)pyridin-3-yl)-N-((2-morpholinyl-) 6-(Trifluoromethyl)pyridin-3-yl)methyl)propanamine 96. 2-(5-Fluoro-6-(methylsulfonamide)-3-yl)-N-(2 -(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamine 97. 2-(5-Methoxy-6-(methyl) Sulfonamide)pyridin-3-yl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide 98. N-(5-(1-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methylamino)-1-oxo Propane-2-yl)pyridin-2-yl)benzamide 99. 4-Chloro-N-(5-(1-((2-(4-methylpiperidin-1-yl)-6-) Trifluoromethyl)pyridin-3-yl)methylamino)-1-oxopropan-2-yl)pyridin-2-yl)benzamide 100. 4-Chloro-N-(5-(1- (2-(4-Methylpiperidin-1-yl)-4-(trifluoromethyl)benzylamino)-1-oxopropan-2-yl)pyridin-2-yl)benzamide 101. 4-Chloro-N-(5-(1-(2-(cyclohexylthio)-4-(trifluoromethyl)benzylamino)-1-oxopropan-2-yl)pyridine- 2-yl)benzamide 102102. N-(5-(1-(4-tri-butyl-2-(cyclohexylthio)benzylamino)-1- Propane-2-yl)pyridin-2-yl)-4-chlorobenzamide 103. 4-Chloro-N-(5-(1-(2-(cyclopentyloxy)-4-) Fluoromethyl)benzylamino)-1-oxopropan-2-yl)pyridin-2-yl)benzamide 10.. 1-(6-(dimethylamino)-5-(trifluoromethyl) Alkyl)-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea 105. 1- (6-(azetidin-1-yl)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine- 3-yl)methyl)urea 106. 1-(6-(azetidin-1-yl)-5-fluoropyridin-3-yl)-3-((2-(4-methylpiperidine) -1- 6-(3-trifluoromethyl)pyridin-3-yl)methyl)urea 107. 1-(6-(azetidin-1-yl)-5-methoxy-3-yl) 3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea 108. 1-(6-(3-hydroxy nitrogen) Heterocyclobutan-1-yl)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)- Urea 109. 1-(6-(3-Hydroxyazetidin-1-yl)pyridin-3-yl)-3-((2-pentyl-6-(trifluoromethyl)pyridine- 3-yl)methyl)urea 110. 1-(6-(3-hydroxyazetidin-1-yl)pyridin-3-yl)-3-((2-m-tolyl-6-() Trifluoromethyl)pyridin-3-yl)methyl)urea 111. 1-(6-(3-hydroxyazetidin-1-yl)pyridin-3-yl)-3-((2-A) Oxy-6-(trifluoromethyl)pyridin-3-yl)methyl)urea 112. 1-(6-(3-hydroxyazetidin-1-yl)pyridin-3-yl)-3 -((2-Isobutoxy-6-(trifluoromethyl)pyridin-3-yl)methyl)urea 113. 1-((2-(cyclobutylmethoxy)-6-(trifluoromethyl) Pyridin-3-yl)methyl)-3-(6-(3-hydroxyazetidin-1-yl)pyridin-3-yl)urea 114. 1-((2-(4-methyl) Piperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(6-(pyridinyl-1-yl)pyridin-3-yl)urea 115. 1 -(5-fluoro-6-(l-pyridin-1-yl)pyridin-3-yl)-3-((2-(4-methyl) Iridin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea 116. 1-(5-Methoxy-6-(rhodin-1-yl)pyridine-3- 3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea 117. (S)-1-(6 -(3-hydroxylpyridin-1-yl)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridine-3- ())methyl)urea 118.(R)-1-(6-(3-hydroxylidine-1-yl)pyridin-3-yl)-3-((2-(4-methylpiperidine-1) -yl-6-(trifluoromethyl)pyridin-3-yl)methyl)urea 119. 1-(6-Hydroxypyridin-3-yl)-3-((2-(4-methylpiperidine) -1-yl)-6-(trifluoromethyl)pyridine -3-yl)methyl)urea 120. 2-(6-Methoxypyridine-3-yl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoro) Methyl)pyridin-3-yl)methyl)propanamine 121. 1-(2-Methoxypyrimidin-5-yl)-3-((2-(4-methylpiperidin-1-yl)) -6-(Trifluoromethyl)pyridin-3-yl)methyl)urea 122. 1-(2-Cyclobutoxypyrimidin-5-yl)-3-((2-(4-methylpiperidine)- 1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea 123. 1-(6-(2-hydroxyethoxy)pyridin-3-yl)-3-(2 -(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea 124. 1-(6-(2-methoxyethoxy)pyridine- 3-(3-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea 125. 1-(6-( 2-hydroxyethoxy)pyridin-3-yl)-3-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)urea 126. 1-(5- (Hydroxymethyl)pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea 127 1-(5-(Hydroxymethyl)pyridin-2-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl))-3-yl )methyl)urea 128. 1-(3-(Hydroxymethyl)pyridin-4-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl) Pyridin-3-yl)methyl)urea 129. 1-(6-(1,2-Dihydrocarbyl)pyridin-3-yl)-3-((2-(4-methylpiperidine-1) -yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea 130. 1-((2-(3-fluorophenyl)-6-(trifluoromethyl)pyridine-3- Methyl)-3-(6-(2-hydroxyethylamine)-3-yl)urea, and 131. 1-((5'-chloro-6-(trifluoromethyl)-2,3 '-Bisridin-3-yl)methyl)-3-(6-(2-hydroxyethylamine)-3-yl)urea, optionally as a single stereoisomer or a mixture of stereoisomers Form The form of the free compound and/or the form of its physiologically acceptable salt. 一種醫藥組成物，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，疼痛以選自由急性疼痛、慢性疼痛、神經性疼痛、內臟疼痛與關節疼痛組成之群組較佳、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 caused by pain, selected from acute pain , chronic pain, neuropathic pain, visceral pain and joint pain, a group of better, hyperalgesia, allodynia, burning pain, migraine, depression, nervousness, axonal injury, neurodegenerative diseases, selected from multiple Sex 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, Free asthma, bronchitis, and inflammation of the lungs, cough, urinary incontinence, overactive bladder, gastrointestinal disorders and/or injuries, duodenal ulcers, gastric ulcers, post-stimulation of irritation, stroke, eye irritation , skin irritation, neuropathic skin disease, allergic skin disease, dryness, leukoplakia, herpes simplex, inflammation, intestines, eyes, bladder, skin or nasal mucosa Better inflammation, diarrhea, itching, osteoporosis, arthritis, osteoarthritis, rheumatic diseases, abnormal diet, selected from the group consisting of bulimia, cachexia, anorexia and obesity, drugs 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, 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 conditioning Exercise, for anti-anxiety, for local anesthesia and/or inhibition of adverse side effects, 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 peppers A group consisting of a sucrose, a cactus toxin, an ovanovin, an arsenic, an SDZ-249665, an SDZ-249482, a novva and a valvavir 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，疼痛以選自由急性疼痛、慢性疼痛、神經性疼痛、內臟疼痛與關節疼痛組成之群組較佳、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，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。 A method of treating and/or preventing disorders and/or diseases caused by pain, the pain being selected from the group consisting of acute pain, chronic pain, neuropathic pain, visceral pain and joint pain, hyperalgesia, allodynia , burning, migraine, depression, nervousness, 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 lung inflammation, cough, urinary incontinence, overactive bladder, Gastrointestinal disorders and/or injuries, duodenal ulcers, gastric ulcers, irritating intestinal disorders, stroke, eye irritation, skin irritation, neuropathic skin diseases, allergic skin diseases, dryness, leukoplakia, herpes simplex, inflammation, Inflammation of the intestine, eyes, bladder, skin or nasal mucosa, diarrhea, itching, osteoporosis, arthritis, osteoarthritis, rheumatic diseases, Abnormal food, 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 Better, drug dependence, drug abuse, drug dependence withdrawal symptoms, alcohol dependence, alcohol abuse, alcohol withdrawal symptoms, use in diuresis, use in inhibiting urinary sodium excretion, affecting the cardiovascular system, and alerting Sex, for treating wounds and/or burns, for treating nerve block, for lifting libido, for regulating motor activity, for anxiolytic, for local anesthesia and/or for inhibiting adverse side effects, selected from A group of fever, hypertension, and bronchoconstriction evoked by a vanilloid receptor 1 (VR1/TRPV1 receptor) agonist is preferred, selected from the group consisting of capsaicin, cactus toxin, ovanov, arva, SDZ- A group consisting of 249665, SDZ-249482, Newvni and Casafaini is preferred, which comprises administering an effective dose to a mammal. There is one less compound to be substituted according to any one of claims 1 to 12.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108675954A (en) * 2018-04-03 2018-10-19 爱斯特（成都）生物制药股份有限公司 A kind of preparation method of 2- amino -3- hydroxymethylpyridines

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