TW201336840A - Triazine-oxadiazoles - Google Patents

Triazine-oxadiazoles Download PDF

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TW201336840A
TW201336840A TW101108521A TW101108521A TW201336840A TW 201336840 A TW201336840 A TW 201336840A TW 101108521 A TW101108521 A TW 101108521A TW 101108521 A TW101108521 A TW 101108521A TW 201336840 A TW201336840 A TW 201336840A
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Taiwan
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alkyl
methyl
amino
alkoxy
halo
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TW101108521A
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Chinese (zh)
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Oliver Barker
Jonathan Mark Bentley
Mark Gary Bock
Thomas Cain
Praful Chovatia
Jennifer Ruth Dod
Florence Eustache
Laura Gleave
Jonathan Hargrave
Alexander Heifetz
Richard Law
Ali Raoof
David Willows
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Novartis Ag
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Abstract

The invention relates to new derivatives of formula (I), wherein the substituents are as defined in the specification; to processes for the preparation of such derivatives; pharmaceutical compositions comprising such derivatives; such derivatives as a medicament; such derivatives for the treatment of chronic pain.

Description

三 - 二唑Tri-oxadiazole

本發明係關於新三-二唑；製備該等三-二唑之方法；包括該等三-二唑視情況與一或多種其他醫藥活性化合物之組合之醫藥組合物；作為藥劑之該等三-二唑視情況與一或多種其他醫藥活性化合物之組合；用於治療慢性疼痛(例如慢性疼痛之陽性症狀，例如感覺異常、感覺遲鈍、痛覺過敏、觸感痛及自發性疼痛)之該等三-二唑視情況與一或多種其他醫藥活性化合物之組合(亦包含治療哺乳動物、尤其人類之該等疾病之方法)；及該等三-二唑在製備用於治療慢性疼痛(例如慢性疼痛之陽性症狀(例如感覺異常、感覺遲鈍、痛覺過敏、觸感痛及自發性疼痛)以及陰性症狀(例如失去感覺))之醫藥組合物(藥劑)中之用途。 The present invention relates to the new three - Diazole; preparation of the three - Method of oxadiazole; including these three - a pharmaceutical composition wherein the oxadiazole is combined with one or more other pharmaceutically active compounds; - a combination of oxadiazole and one or more other pharmaceutically active compounds; for treating chronic pain (eg, positive symptoms of chronic pain, such as paresthesia, dysesthesia, hyperalgesia, tactile pain, and spontaneous pain) - a combination of oxadiazole and one or more other pharmaceutically active compounds (including methods for treating such diseases in mammals, especially humans); and - A pharmaceutical composition (pharmaceutical) for the preparation of a oxadiazole for the treatment of chronic pain, such as positive symptoms of chronic pain (eg, paresthesia, dysesthesia, hyperalgesia, tactile pain, and spontaneous pain) and negative symptoms (eg, loss of sensation) ) for use.

本發明化合物係鈉通道阻斷劑，尤其係涉及疼痛之電壓閘控式鈉通道1.7(Nav1.7)之選擇性抑制劑。因其他鈉通道亞型涉及不同之基本生理學過程(例如心臟活性(Nav1.5)、肌肉收縮(Nav1.4)及CNS神經傳遞(Nav1.1、1.2及1.6))，故認為對於Nav1.7之選擇性與副作用之潛在消除有關。 The compounds of the invention are sodium channel blockers, particularly selective inhibitors of voltage-gated sodium channel 1.7 (Nav1.7) involving pain. Because other sodium channel subtypes involve different basic physiological processes (eg, cardiac activity (Nav1.5), muscle contraction (Nav1.4), and CNS neurotransmission (Nav1.1, 1.2, and 1.6)), it is considered for Nav1. The selectivity of 7 is related to the potential elimination of side effects.

闡述若干Nav1.7阻斷劑：狼蛛毒液肽Pro-TX-II係Nav1.7之有效抑制劑(Schmalhofer等人，Molecular Pharmacology 2008,74,1476-1484)。闡述一系列苯并氮雜卓Nav1.7阻斷 劑以展示在疼痛之臨床前藥理學模型中之活性(Williams等人，Biochemistry,2007,46(50),14693-14703；McGowan等人，Anesth Analg,2009,109,951-958)。可將胺基-噻唑及胺基-吡啶闡述為Nav1.7抑制劑(WO 2007109324)且將異唑闡述為Nav1.7抑制劑(WO 2009010784)。 Several Nav1.7 blockers are described: potent inhibitors of the Wolf Spider Venom Pro-TX-II line Nav1.7 (Schmalhofer et al, Molecular Pharmacology 2008, 74, 1476-1484). A series of benzodiazepine Nav1.7 blockers are described to demonstrate activity in preclinical pharmacology models of pain (Williams et al, Biochemistry, 2007, 46(50), 14693-14703; McGowan et al., Anesth Analg, 2009, 109, 951-958). Amino-thiazole and amino-pyridine can be described as Nav1.7 inhibitors (WO 2007109324) and will vary Azole is described as a Nav1.7 inhibitor (WO 2009010784).

SCN9A(編碼Nav1.7之基因)中之無義突變似乎與先天性對痛無感症(CIP)有關(Cox等人，Nature,2006,444(7121),894-898)。患有CIP之患者基本上對於在大部分個體中引起疼痛之感覺(例如骨折、燒傷、牙膿腫、闌尾炎及分娩)完全沒有感覺。同時，其能夠辨別其他感覺，例如熱覺(熱/冷)及觸覺(靈敏/遲鈍)刺激(Goldberg等人，Clinical Genetics,2007,71(4),311-319)。 Nonsense mutations in SCN9A (the gene encoding Nav1.7) appear to be associated with congenital painlessness (CIP) (Cox et al, Nature, 2006, 444 (7121), 894-898). Patients with CIP are essentially completely devoid of feelings that cause pain in most individuals (eg, fractures, burns, tooth abscesses, appendicitis, and childbirth). At the same time, it is able to discern other sensations such as thermal (hot/cold) and tactile (sensitive/slow) stimuli (Goldberg et al., Clinical Genetics, 2007, 71(4), 311-319).

最近臨床報導表明，人類Nav1.7之功能突變之獲得通常與嚴重病理學病狀有關。原發性紅熱肢痛症與Nav1.7中之突變T2573A及T2543C有關(Yang等人，Journal of Medical Genetics,2004,41(3),171-4)。將陣發性劇痛症闡述為與位於Nav1.7之非活化型閘門區域中之突變M1627K、T1464I及I1461T有關(Fertleman等人，Neuron,2006,52(5),767-774)。 Recent clinical reports have shown that the acquisition of functional mutations in human Nav1.7 is often associated with severe pathological conditions. Primary red hot limb pain is associated with mutations T2573A and T2543C in Nav1.7 (Yang et al, Journal of Medical Genetics, 2004, 41(3), 171-4). Paroxysmal pain was described as related to mutations M1627K, T1464I and I1461T located in the non-activated gate region of Nav1.7 (Fertleman et al, Neuron, 2006, 52(5), 767-774).

因此，Nav1.7通道之選擇性抑制可提供全面性止痛。 Therefore, selective inhibition of the Nav1.7 channel provides comprehensive analgesia.

因此，持續需要可用於治療及預防對於Nav1.7之抑制具有反應之病症或疾病之化合物，尤其係具有改良之效能、耐受性及/或選擇性之化合物。 Thus, there is a continuing need for compounds that are useful in the treatment and prevention of conditions or diseases responsive to inhibition of Nav 1.7, particularly compounds having improved potency, tolerance and/or selectivity.

已報導相關但在結構上有所不同之三，例如用作激酶 抑制劑(Janssen(WO 2004009562))；用作整合素抑制劑(Biochem Pharma(WO 2000075129))。 Has been reported to be related but structurally different For example, as a kinase inhibitor (Janssen (WO 2004009562)); as an integrin inhibitor (Biochem Pharma (WO 2000075129)).

在第一態樣中，本發明係關於式(I)之三-二唑及/或其醫藥上可接受之鹽及/或溶劑合物， 其中R1係選自氫-鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-；R2係選自氫-C1-C7-烷基-鹵代-C2-C7-烷基-胺基-C2-C7-烷基-N-C1-C7-烷基-胺基-C2-C7-烷基-N,N-二-C1-C7-烷基-胺基-C2-C7-烷基-羥基-C2-C7-烷基- C1-C7-烷氧基-C2-C7-烷基-C3-C10-環烷基-C1-C7-烷基-氰基-C2-C7-烷基-；或R1及R2與其所附接之原子一起形成4-7員飽和或部分飽和之雜環，該雜環未經取代或經1-3個選自以下之取代基取代：C1-C7-烷基-鹵代-C1-C7-烷基-胺基-C1-C7-烷基-N-C1-C7-烷基-胺基-C1-C7-烷基-N,N-二-C1-C7-烷基-胺基-C1-C7-烷基-羥基-C1-C7-烷基-C1-C7-烷氧基-C1-C7-烷基-C3-C10-環烷基-C1-C7-烷基-氰基-C1-C7-烷基-；R係選自鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-C1-C7-烷氧基-氰基-鹵代-C1-C7-烷氧基-硝基； -C(O)-O-R'，其中R'係選自氫、C1-C7-烷基、C3-C10-環烷基、C1-C7-烷氧基、鹵代-C1-C7-烷基芳基、芳基-C1-7-烷基-、雜芳基、雜芳基C1-C7-烷基-、雜環基；-S(=O)2-C1-C7-烷基；-S(=O)2-C3-C10-環烷基；-S(=O)2-C1-C7-烷氧基；R3係選自(a)-L-Y，其中-L-係選自直接鍵結、-(CH2)p-、-C(O)-、-NR7-、-NR7-C(O)-或-C(O)-NR7-，其中p係選自1、2或3R7係選自氫及C1-C7-烷基Y係選自環烷基、芳基、雜芳基、雜環基、螺環基，其未經取代或經1-3個選自以下之取代基取代：鹵素-；C1-C7-烷基-；鹵代-C1-C7-烷基-；鹵代-C1-C7-烷基-氧基-C1-C7-烷基；鹵代-C1-C7-烷基-氧基-C1-C7-烷基-氧基；C1-C7-烷氧基-；C1-C7-烷氧基-C1-C7-烷氧基-；NC-C1-C7-烷氧基-；C1-C7-烷氧基-C1-C7-烷基-；C3-C10-環烷基-氧基-C1-C7-烷基-；C3-C10-環烷基-C1-C7-烷基-氧基-；C3-C10-環烷基-氧基-； C3-C10-環烷基-NR7'-C1-C7-烷基-，其中R7'係選自氫及C1-C7-烷基；C3-C10-環烷基-C1-C7-烷氧基-C1-C7-烷基-；C2-C7-烯基；鹵代-C2-C7-烯基；羥基-；羥基-C1-C7-烷基-；鹵代-C1-C7-烷基-氧基-；胺基-；N-C1-C7-烷基-胺基-；N-鹵代-C1-C7-烷基-胺基-；N-雜環基-胺基-、N-C3-C10-環烷基-胺基-，其中該等雜環基及環烷基視情況經鹵代-C1-C7-烷基-氧基、C1-C7-烷基、C3-C10-環烷基及C1-C7-烷氧基取代；N-C3-C10-環烷基-C1-C7-烷基-胺基-；N,N-二-C1-C7-烷基-胺基-；N,N-二-鹵代-C1-C7-烷基-胺基-；N,N-二-雜環基-胺基-、N,N-二-C3-C10-環烷基-胺基-，其中該等雜環基及環烷基視情況經鹵代-C1-C7-烷基-氧基、C1-C7-烷基、C3-C10-環烷基及C1-C7-烷氧基取代；氰基-；側氧基；C1-C7-烷氧基-羰基-；C1-C7-烷氧基-C1-C7-烷氧基-C1-C7-烷基-；芳基；芳基-C1-C7-烷基-；芳基-氧基； 雜環基；雜環基-C1-C7-烷基-；雜環基-氧基-；雜環基-氧基-C1-C7-烷基-；芳基-氧基-C1-C7-烷基-；雜芳基-氧基-C1-C7-烷基-；羥基-羰基-；-S-鹵代-C1-C7-烷基；-S-C1-C7-烷基；-S-芳基；鹵代-C1-C7-烷基-S-C1-C7-烷基；C1-C7-烷基-S-C1-C7-烷基；-S(=O)2-C1-C7-烷基；-S(=O)2-鹵代-C1-C7-烷基；-S(=O)2-芳基；-S(=O)2-雜芳基；-S(=O)2-NR4'R4；-S(=O)2-雜環基；鹵代-C1-C7-烷基-S(=O)2-C1-C7-烷基；C1-C7-烷基-S(=O)2-C1-C7-烷基；-S(=O)-C1-C7-烷基；-S(=O)-鹵代-C1-C7-烷基；-S(=O)-C1-C7-烷氧基；-S(=O)-C3-C10-環烷基；-C(O)-C1-C7-烷基；-C(O)-鹵代-C1-C7-烷基；-C(O)-C1-C7-烷氧基；-C(O)-C3-C10環烷基；-C(O)O-C1-C7-烷基；-C(O)O-C3-C10-環烷基；-C(O)O-鹵代-C1-C7-烷基；-C(O)O-C1-C7-烷氧基；-C(O)-NR4'R4或-NHC(O)-R4，其中R4係選自氫、C1-C7-烷基、鹵代-C1-C7-烷基、C3-C10-環烷基、C3-C10-環烷基-C1-C7-烷基及C1-C7-烷氧基；R4'係選自氫；或R4及R4'與其所附接之氮原子一起形成4-7員飽和 或部分飽和之單環雜環，該雜環視情況含有選自N、O或S之另一雜原子，且其中該雜環視情況經芳基、芳基-氧基-、C1-C7-烷基、鹵代-C1-C7-烷基或C1-C7-烷氧基取代，且該芳基視情況經鹵素、C1-C7-烷基、鹵代-C1-C7-烷基或C1-C7-烷氧基取代。或(b)-C(O)-NR5'R5或-C(O)-O-R5，其中R5及R5'係選自氫、C1-C7-烷基、C3-C10-環烷基、C1-C7-烷氧基、鹵代-C1-C7-烷基芳基、芳基-C1-C7-烷基-、芳基、雜芳基、雜芳基C1-C7-烷基-、雜環基、二氫化茚，或R5及R5'與其所附接之氮原子一起形成4-9員飽和或部分飽和之單環或雙環雜環，該單環或雙環雜環視情況含有選自N、O或S之另一雜原子；其中該等C3-C10-環烷基、芳基、雜芳基、雜環基及二氫化茚視情況經1至3個選自以下之取代基取代：C1-C7-烷基、鹵代-C1-C7-烷基、C1-C7-烷氧基、鹵代-C1-C7-烷基-氧基-、鹵代-C1-C7-烷基-氧基-C1-C7-烷基、C1-C7-烷基-氧基-C1-C7-烷基及羥基-C1-C7-烷基；或(c)-NR6'R6，其中R6係選自氫、C1-C7-烷基，R6'係選自氫、C1-C7-烷基、C1-C7-烷基羰基-、C3-C10-環烷基；或R6及R6'與其所附接之氮原子一起形成4-7員飽和或部 分飽和之單環或7-12員飽和或部分飽和之雙環雜環，該雜環視情況含有選自N、O或S之另一雜原子；該單環及雙環雜環未經取代或經1-3個選自以下之取代基取代：C1-C7-烷基-、鹵代-C1-C7-烷基-、C1-C7-烷氧基-、鹵代-C1-C7-烷氧基-、鹵代-C1-C7-烷氧基-C1-C7-烷基-、羥基-及C1-C7-烷氧基-羰基-；(d)-NR5'-C(O)-R5，其中R5係選自氫、C1-C7-烷基、C3-C10-環烷基、C1-C7-烷氧基、鹵代-C1-C7-烷基、芳基、芳基-C1-C7-烷基-、雜芳基、雜芳基-C1-C7-烷基-、雜環基；R5'係選自氫、C1-C7-烷基；m為0-1；且n為0-2；R8為氫且R9係選自氫、C1-C7-烷氧基-C1-C7-烷基-、C1-C7-烷基、C1-C7-烷氧基及鹵代-C1-C7-烷基；其中C1-C7-烷基、C1-C7-烷氧基、雜環基、芳基、雜芳基視情況經芳基、雜芳基、雜環基、C1-C7-烷基、C1-C7-烷氧基、鹵代-C1-C7-烷基、OH取代；前提係不包含6-[5-(2-呋喃基)-1,2,4-二唑-3-基]-N2-甲基-N2-苯基-1,3,5-三-2,4-二胺及6-[5-(2-呋喃基)-1,2,4-二唑-3-基]-N,N,N'-甲基-N'-苯基-1,3,5-三-2,4-二胺。6-[5-(2-呋喃基)-1,2,4-二唑-3-基]-N2-甲基-N2-苯基-1,3,5-三-2,4-二胺(CAS-899373-19-4)及6-[5-(2-呋喃 基)-1,2,4-二唑-3-基]-N,N,N'-甲基-N'-苯基-1,3,5-三-2,4-二胺(CAS-899373-21-8)係來自化學文庫之化合物。 In the first aspect, the invention relates to the third formula (I) - An oxadiazole and/or a pharmaceutically acceptable salt and/or solvate thereof, Wherein R 1 is selected from hydrogen-halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-; R 2 is selected from hydrogen-C 1 -C 7 -alkyl-halo -C 2 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-NC 1 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-N,N-di-C 1- C 7 -Alkyl-amino-C 2 -C 7 -alkyl-hydroxy-C 2 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 2 -C 7 -alkyl- C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkyl-cyano-C 2 -C 7 -alkyl-; or R 1 and R 2 together with the attached atom form a 4-7 member a saturated or partially saturated heterocyclic ring which is unsubstituted or substituted with from 1 to 3 substituents selected from C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-amine -C 1 -C 7 -alkyl-NC 1 -C 7 -alkyl-amino-C 1 -C 7 -alkyl-N,N-di-C 1 -C 7 -alkyl-amino group- C 1 -C 7 -alkyl-hydroxy-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-C 3 -C 10 -cycloalkyl-C 1- C 7 -alkyl-cyano-C 1 -C 7 -alkyl-; R is selected from halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-cyano-halo-C 1 -C 7 -alkoxy-nitro; -C(O)-O-R', wherein R' is selected from hydrogen, C 1 -C 7-- alkyl, C 3 -C 10 - cycloalkyl Group, C 1 -C 7 - alkoxy, halo -C 1 -C 7 - alkyl aryl, aryl -C 1 - 7 - alkyl -, heteroaryl, heteroaryl-C 1 -C 7 -alkyl-,heterocyclyl;-S(=O) 2 -C 1 -C 7 -alkyl;-S(=O) 2 -C 3 -C 10 -cycloalkyl;-S(=O) 2 -C 1 -C 7 -alkoxy; R 3 is selected from (a)-LY, wherein -L- is selected from direct bonding, -(CH 2 ) p -, -C(O)-, - NR 7 -, -NR7-C(O)- or -C(O)-NR 7 -, wherein p is selected from 1, 2 or 3R 7 is selected from the group consisting of hydrogen and C 1 -C 7 -alkyl Y a cycloalkyl, aryl, heteroaryl, heterocyclyl, spiro group which is unsubstituted or substituted with from 1 to 3 substituents selected from halogen-; C 1 -C 7 -alkyl- Halogen-C 1 -C 7 -alkyl-;halo-C 1 -C 7 -alkyl-oxy-C 1 -C 7 -alkyl;halo-C 1 -C 7 -alkyl- group -C 1 -C 7 - alkyl - group; C 1 -C 7 - alkoxy -; C 1 -C 7 - alkoxy, -C 1 -C 7 - alkoxy -; NC-C 1- C 7 -alkoxy-;C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-;C 3 -C 10 -cycloalkyl-oxy-C 1 -C 7 -alkane -C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkyl-oxy-; C 3 -C 10 -cycloalkyl-oxy-; C 3 -C 10 -cycloalkyl- NR 7 '-C 1 -C 7 - Group - where R 7 'is selected from hydrogen and C 1 -C 7 - alkyl; C 3 -C 10 - cycloalkyl, -C 1 -C 7 - alkoxy, -C 1 -C 7 - alkyl - C 2 -C 7 -alkenyl;halo-C 2 -C 7 -alkenyl;hydroxy-;hydroxy-C 1 -C 7 -alkyl-;halo-C 1 -C 7 -alkyl-oxygen -Amino-;NC 1 -C 7 -alkyl-amino-;N-halo-C 1 -C 7 -alkyl-amino-;N-heterocyclyl-amino-, NC 3 -C 10 -cycloalkyl-amino-, wherein the heterocyclic and cycloalkyl groups are optionally halogenated -C 1 -C 7 -alkyl-oxy, C 1 -C 7 -alkyl, C 3- C 10 -cycloalkyl and C 1 -C 7 -alkoxy substituted; NC 3 -C 10 -cycloalkyl-C 1 -C 7 -alkyl-amino-;N,N-di-C 1- C 7 -alkyl-amino-;N,N-di-halo-C 1 -C 7 -alkyl-amino-;N,N-di-heterocyclyl-amino-, N, N-di-C 3 -C 10 -cycloalkyl-amino-, wherein the heterocyclic and cycloalkyl groups are optionally halogenated-C 1 -C 7 -alkyl-oxy, C 1 -C 7 -alkyl, C 3 -C 10 -cycloalkyl and C 1 -C 7 -alkoxy substituted; cyano-; pendant oxy; C 1 -C 7 -alkoxy-carbonyl-; C 1 - C 7 - alkoxy, -C 1 -C 7 - alkoxy, -C 1 -C 7 - alkyl -; aryl; aryl -C 1 -C 7 - alkyl -; aryl - group; heterocyclyl; heterocyclyl -C 1 -C 7 - alkyl -; heterocyclyl - oxy -; heterocyclyl - oxy -C 1 -C 7 - alkyl -; aryl - Oxy-C 1 -C 7 -alkyl-;heteroaryl-oxy-C 1 -C 7 -alkyl-;hydroxy-carbonyl-;-S-halo-C 1 -C 7 -alkyl; -SC 1 -C 7 -alkyl;-S-aryl;halo-C 1 -C 7 -alkyl-SC 1 -C 7 -alkyl; C 1 -C 7 -alkyl-SC 1 -C 7 -alkyl;-S(=O) 2 -C 1 -C 7 -alkyl;-S(=O) 2 -halo-C 1 -C7-alkyl;-S(=O)2-aryl -S(=O) 2 -heteroaryl; -S(=O) 2 -NR 4 'R 4 ;-S(=O) 2 -heterocyclyl;halo-C 1 -C 7 -alkane -S(=O) 2 -C 1 -C 7 -alkyl; C 1 -C 7 -alkyl-S(=O) 2 -C 1 -C 7 -alkyl;-S(=O)- C 1 -C 7 -alkyl; -S(=O)-halo-C 1 -C 7 -alkyl; -S(=O)-C 1 -C 7 -alkoxy;-S(=O -C 3 -C 10 -cycloalkyl; -C(O)-C 1 -C 7 -alkyl; -C(O)-halo-C 1 -C 7 -alkyl; -C(O) -C 1 -C 7 -alkoxy;-C(O)-C 3 -C 10 cycloalkyl; -C(O)OC 1 -C 7 -alkyl; -C(O)OC 3 -C 10 -cycloalkyl; -C(O)O-halo-C 1 -C 7 -alkyl; -C(O)OC 1 -C 7 -alkoxy;-C(O)-NR 4' R 4 or -NHC (O) -R 4, wherein R 4 is selected from hydrogen, C 1 -C 7 - Yl, halo -C 1 -C 7 - alkyl, C 3 -C 10 - cycloalkyl, C 3 -C 10 - cycloalkyl, -C 1 -C 7 - alkyl and C 1 -C 7 - alkoxy An oxy group; R 4 ' is selected from hydrogen; or R 4 and R 4 ' together with the nitrogen atom to which it is attached form a 4-7 membered saturated or partially saturated monocyclic heterocyclic ring optionally containing N, Another hetero atom of O or S, and wherein the heterocyclic ring is optionally aryl, aryl-oxy-, C 1 -C 7 -alkyl, halo-C 1 -C 7 -alkyl or C 1 - C 7 -alkoxy is substituted, and the aryl group is optionally substituted by halogen, C 1 -C 7 -alkyl, halo-C 1 -C 7 -alkyl or C 1 -C 7 -alkoxy. Or (b)-C(O)-NR 5' R 5 or -C(O)-OR 5 , wherein R 5 and R 5 ' are selected from hydrogen, C 1 -C 7 -alkyl, C 3 -C 10 -cycloalkyl, C 1 -C 7 -alkoxy, halo-C 1 -C 7 -alkylaryl, aryl-C 1 -C 7 -alkyl-, aryl, heteroaryl, Heteroaryl C 1 -C 7 -alkyl-, heterocyclyl, indane, or R 5 and R 5 ' together with the nitrogen atom to which they are attached form a 4-9 membered saturated or partially saturated monocyclic or bicyclic ring a heterocyclic ring, the monocyclic or bicyclic heterocyclic ring optionally containing another hetero atom selected from N, O or S; wherein the C 3 -C 10 -cycloalkyl, aryl, heteroaryl, heterocyclic and The hydrogenation sterol is substituted with 1 to 3 substituents selected from the group consisting of C 1 -C 7 -alkyl, halo-C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy, halogenated -C 1 -C 7 -alkyl-oxy-, halo-C 1 -C 7 -alkyl-oxy-C 1 -C 7 -alkyl, C 1 -C 7 -alkyl-oxy- C 1 -C 7 -alkyl and hydroxy-C 1 -C 7 -alkyl; or (c)-NR 6' R 6 , wherein R 6 is selected from hydrogen, C 1 -C 7 -alkyl, R 6 ' is selected from hydrogen, C 1 -C 7 -alkyl, C 1 -C 7 -alkylcarbonyl-, C 3 -C 10 -cycloalkyl; or R 6 and R 6 ' and the nitrogen atom to which it is attached together a 4-7 member saturated or partially saturated monocyclic or 7-12 membered saturated or partially saturated bicyclic heterocyclic ring containing optionally another hetero atom selected from N, O or S; the monocyclic and bicyclic The ring is unsubstituted or substituted with from 1 to 3 substituents selected from C 1 -C 7 -alkyl-, halo-C 1 -C 7 -alkyl-, C 1 -C 7 -alkoxy -, halo-C 1 -C 7 -alkoxy-, halo-C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-, hydroxy- and C 1 -C 7 -alkoxy -carbonyl-;(d)-NR 5' -C(O)-R 5 , wherein R 5 is selected from the group consisting of hydrogen, C 1 -C 7 -alkyl, C 3 -C 10 -cycloalkyl, C 1 -C 7 -alkoxy, halo-C 1 -C 7 -alkyl, aryl, aryl-C 1 -C 7 -alkyl-, heteroaryl, heteroaryl-C 1 -C 7 - An alkyl-, heterocyclic group; R 5 ' is selected from hydrogen, C 1 -C 7 -alkyl; m is 0-1; and n is 0-2; R 8 is hydrogen and R 9 is selected from hydrogen, C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-, C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy and halo-C 1 -C 7 -alkyl Wherein C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy, heterocyclyl, aryl,heteroaryl, optionally, aryl, heteroaryl, heterocyclyl, C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy , halo-C 1 -C 7 -alkyl, OH substituted; the premise does not contain 6-[5-(2-furyl)-1,2,4- Diazol-3-yl]-N2-methyl-N2-phenyl-1,3,5-three -2,4-diamine and 6-[5-(2-furyl)-1,2,4- Diazol-3-yl]-N,N,N'-methyl-N'-phenyl-1,3,5-three -2,4-diamine. 6-[5-(2-furyl)-1,2,4- Diazol-3-yl]-N2-methyl-N2-phenyl-1,3,5-three -2,4-diamine (CAS-899373-19-4) and 6-[5-(2-furyl)-1,2,4- Diazol-3-yl]-N,N,N'-methyl-N'-phenyl-1,3,5-three -2,4-Diamine (CAS-899373-21-8) is a compound from a chemical library.

在另一態樣中，本發明係關於式(I)之三-二唑及/或其醫藥上可接受之鹽及/或溶劑合物， 其中R1係選自氫-鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-；R2係選自氫-C1-C7-烷基-鹵代-C2-C7-烷基-胺基-C2-C7-烷基-N-C1-C7-烷基-胺基-C2-C7-烷基-N,N-二-C1-C7-烷基-胺基-C2-C7-烷基-羥基-C2-C7-烷基- C1-C7-烷氧基-C2-C7-烷基-C3-C10-環烷基-C1-C7-烷基-氰基-C2-C7-烷基-；或R1及R2與其所附接之原子一起形成4-7員飽和或部分飽和之雜環，該雜環未經取代或經1-3個選自以下之取代基取代：C1-C7-烷基-鹵代-C1-C7-烷基-胺基-C1-C7-烷基-N-C1-C7-烷基-胺基-C1-C7-烷基-N,N-二-C1-C7-烷基-胺基-C1-C7-烷基-羥基-C1-C7-烷基-C1-C7-烷氧基-C1-C7-烷基-C3-C10-環烷基-C1-C7-烷基-氰基-C1-C7-烷基-；R係選自鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-C1-C7-烷氧基-氰基-鹵代-C1-C7-烷氧基-硝基； R3係選自(a)-L-Y，其中-L-係選自直接鍵結、-(CH2)p-、-C(O)-、-NR7-、-NR7-C(O)-或-C(O)-NR7-，其中p係選自1、2或3R7係選自氫、C1-C7-烷基Y係選自環烷基、芳基、雜芳基、雜環基，其未經取代或經1-3個選自以下之取代基取代：鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-C1-C7-烷氧基-C3-C10-環烷基-氧基-羥基-鹵代-C1-C7-烷基-氧基-胺基-N-C1-C7-烷基-胺基-N,N-二-C1-C7-烷基-胺基-氰基-C1-C7-烷氧基-羰基-羥基-羰基--C(O)-NR4'R4，其中R4係選自氫、C1-C7-烷基；R4'係選自氫， 或R4及R4'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環雜環，該單環雜環視情況含有選自N、O或S之另一雜原子；或(b)-C(O)-NR5'R5或-C(O)-O-R5，其中R5及R5'係選自氫、C1-C7-烷基；或(c)-NR6'R6，其中R6係選自氫、C1-C7-烷基，R6'係選自氫、C1-C7-烷基、C1-C7-烷基羰基-，m為0-1；且n為0-2；前提係不包含6-[5-(2-呋喃基)-1,2,4-二唑-3-基]-N2-甲基-N2-苯基-1,3,5-三-2,4-二胺。 In another aspect, the invention relates to the third formula (I) - An oxadiazole and/or a pharmaceutically acceptable salt and/or solvate thereof, Wherein R 1 is selected from hydrogen-halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-; R 2 is selected from hydrogen-C 1 -C 7 -alkyl-halo -C 2 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-NC 1 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-N,N-di-C 1- C 7 -Alkyl-amino-C 2 -C 7 -alkyl-hydroxy-C 2 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 2 -C 7 -alkyl- C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkyl-cyano-C 2 -C 7 -alkyl-; or R 1 and R 2 together with the attached atom form a 4-7 member a saturated or partially saturated heterocyclic ring which is unsubstituted or substituted with from 1 to 3 substituents selected from C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-amine -C 1 -C 7 -alkyl-NC 1 -C 7 -alkyl-amino-C 1 -C 7 -alkyl-N,N-di-C 1 -C 7 -alkyl-amino group- C 1 -C 7 -alkyl-hydroxy-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-C 3 -C 10 -cycloalkyl-C 1- C 7 -alkyl-cyano-C 1 -C 7 -alkyl-; R is selected from halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-cyano-halo-C 1 -C 7 -alkoxy-nitro; R 3 is selected from (a)-LY, wherein -L- is selected from direct bonding, - (CH 2 ) p -, -C (O)-, -NR 7 -, -NR 7 -C(O)- or -C(O)-NR 7 -, wherein p is selected from 1, 2 or 3R 7 is selected from hydrogen, C 1 -C 7 -alkyl Y is selected from cycloalkyl, aryl, heteroaryl, heterocyclyl, which is unsubstituted or substituted with from 1 to 3 substituents selected from halogen-C 1 -C 7 -alkane -halo-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 3 -C 10 -cycloalkyl-oxy-hydroxy-halo-C 1 -C 7 -alkyl -oxy-amino-NC 1 -C 7 -alkyl-amino-N,N-di-C 1 -C 7 -alkyl-amino-cyano-C 1 -C 7 -alkoxy- carbonyl-hydroxy-carbonyl-C(O)-NR 4' R 4 , wherein R 4 is selected from hydrogen, C 1 -C 7 -alkyl; R 4 ' is selected from hydrogen, or R 4 and R 4' Forming a 4-7 membered saturated or partially saturated monocyclic heterocycle together with the nitrogen atom to which it is attached, the monocyclic heterocycle optionally containing another heteroatom selected from N, O or S; or (b)-C ( O)-NR 5' R 5 or -C(O)-OR 5 , wherein R 5 and R 5 ' are selected from hydrogen, C 1 -C 7 -alkyl; or (c)-NR 6' R 6 , Wherein R 6 is selected from the group consisting of hydrogen, C 1 -C 7 -alkyl, and R 6 ' is selected from hydrogen, C 1 -C 7 -alkyl, C 1 -C 7 -alkylcarbonyl-, m is 0-1 ; and n is 0-2; the premise does not contain 6-[5-(2-furyl)-1,2,4- Diazol-3-yl]-N2-methyl-N2-phenyl-1,3,5-three -2,4-diamine.

6-[5-(2-呋喃基)-1,2,4-二唑-3-基]-N2-甲基-N2-苯基-1,3,5-三-2,4-二胺(CAS-899373-19-4)係來自化學文庫之化合物。 6-[5-(2-furyl)-1,2,4- Diazol-3-yl]-N2-methyl-N2-phenyl-1,3,5-three -2,4-Diamine (CAS-899373-19-4) is a compound from a chemical library.

在第二態樣中，本發明係關於式(I)之三-二唑及/或其醫藥上可接受之鹽及/或溶劑合物之用途， 其中R1係選自氫-鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-；R2係選自氫-C1-C7-烷基-鹵代-C2-C7-烷基-胺基-C2-C7-烷基-N-C1-C7-烷基-胺基-C2-C7-烷基-N,N-二-C1-C7-烷基-胺基-C2-C7-烷基-羥基-C2-C7-烷基-C1-C7-烷氧基-C2-C7-烷基-C3-C10-環烷基-C1-C7-烷基-氰基-C2-C7-烷基-；或R1及R2與其所附接之原子一起形成4-7員飽和或部分飽和之雜環，該雜環未經取代或經1-3個選自以下之取代基取代：C1-C7-烷基-鹵代-C1-C7-烷基-胺基-C1-C7-烷基- N-C1-C7-烷基-胺基-C1-C7-烷基-N,N-二-C1-C7-烷基-胺基-C1-C7-烷基-羥基-C1-C7-烷基-C1-C7-烷氧基-C1-C7-烷基-C3-C10-環烷基-C1-C7-烷基-氰基-C1-C7-烷基-；R係選自鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-C1-C7-烷氧基-氰基-鹵代-C1-C7-烷氧基-硝基；R3係選自(a)-(CH2)p-Y，其中p係選自0、1、2或3，且Y係選自芳基、雜芳基、雜環基，其未經取代或經1-3個選自以下之取代基取代：鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-C1-C7-烷氧基-C3-C10-環烷基-氧基- 羥基-鹵代-C1-C7-烷基-氧基-胺基-N-C1-C7-烷基-胺基-N,N-二-C1-C7-烷基-胺基-氰基-C1-C7-烷氧基-羰基-羥基-羰基--C(O)-NR4'R4，其中R4係選自氫、C1-C7-烷基；R4'係選自氫，或R4及R4'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環雜環，該單環雜環視情況含有選自N、O或S之另一雜原子；或(b)-C(O)-NR5'R5或-C(O)-O-R5，其中R5係選自氫、苄基、二氫茚基、四氫呋喃基、四氫吡喃基、環氧乙烷基、C3-C10-環烷基、C1-C7-烷基；R5'係選自氫、C1-C7-烷基，或R5及R5'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環或雙環雜環，該雜環視情況含有選自N、O或S之另一雜原子；或(c)-NR6'R6，其中 R6係選自氫、苄基、C3-C10-環烷基、C1-C7-烷基，R6'係選自氫、C1-C7-烷基、C1-C7-烷基羰基-，或R6及R6'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環或7-12員飽和或部分飽和之雙環雜環，該雜環視情況含有選自N、O或S之另一雜原子；其未經取代或經1-3個選自以下之取代基取代：C1-C7-烷基-羥基-C1-C7-烷氧基-羰基-或(d)-NR5'-C(O)-R5，其中R5係選自C3-C10-環烷基；R5'係選自氫、C1-C7-烷基；m為0-1；且n為0-1；前提係不包含6-[5-(2-呋喃基)-1,2,4-二唑-3-基]-N2-甲基-N2-苯基-1,3,5-三-2,4-二胺。 In the second aspect, the invention relates to the third formula (I) - The use of oxadiazole and/or its pharmaceutically acceptable salts and/or solvates, Wherein R 1 is selected from hydrogen-halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-; R 2 is selected from hydrogen-C 1 -C 7 -alkyl-halo -C 2 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-NC 1 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-N,N-di-C 1- C 7 -alkyl-amino-C 2 -C 7 -alkyl-hydroxy-C 2 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 2 -C 7 -alkyl- C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkyl-cyano-C 2 -C 7 -alkyl-; or R 1 and R 2 together with the attached atom form a 4-7 member a saturated or partially saturated heterocyclic ring which is unsubstituted or substituted with from 1 to 3 substituents selected from C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-amine group -C 1 -C 7 - alkyl - NC 1 -C 7 - alkyl - group -C 1 -C 7 - alkyl -N, N- two -C 1 -C 7 - alkyl - amino - C 1 -C 7 -alkyl-hydroxy-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-C 3 -C 10 -cycloalkyl-C 1- C 7 -alkyl-cyano-C 1 -C 7 -alkyl-; R is selected from halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-cyano-halo-C 1 -C 7 -alkoxy-nitro; R 3 is selected from (a)-(CH 2 ) p -Y, wherein p is selected from 0 , 1, 2 or 3, and Y system From aryl, heteroaryl, a heterocyclic group, which is unsubstituted or substituted with 1-3 substituents selected from the group: halogen -C 1 -C 7 - alkyl - halo -C 1 -C 7 - Alkyl-C 1 -C 7 -alkoxy-C 3 -C 10 -cycloalkyl-oxy-hydroxy-halo-C 1 -C 7 -alkyl-oxy-amino-NC 1 -C 7 -Alkyl-amino-N,N-di-C 1 -C 7 -alkyl-amino-cyano-C 1 -C 7 -alkoxy-carbonyl-hydroxy-carbonyl--C(O) -NR 4' R 4 , wherein R 4 is selected from hydrogen, C 1 -C 7 -alkyl; R 4 ' is selected from hydrogen, or R 4 and R 4' together with the nitrogen atom to which they are attached form 4- a 7-membered saturated or partially saturated monocyclic heterocyclic ring optionally containing another hetero atom selected from N, O or S; or (b) -C(O)-NR 5' R 5 or -C (O)-OR 5 , wherein R 5 is selected from the group consisting of hydrogen, benzyl, indanyl, tetrahydrofuranyl, tetrahydropyranyl, oxiranyl, C 3 -C 10 -cycloalkyl, C 1 -C 7 - alkyl; R 5 'is selected from hydrogen, C 1 -C 7 - alkyl, or R 5 and R 5' appended thereto form a 4-7 membered saturated or partially saturated with the bonding of a nitrogen atom mono a cyclic or bicyclic heterocyclic ring which optionally contains another hetero atom selected from N, O or S; or (c)-NR 6' R 6 wherein R 6 is selected from the group consisting of hydrogen, benzyl, C 3 -C 10 -cycloalkyl, C 1 -C 7 -alkyl, and R 6 ' is selected from hydrogen, C 1 -C 7 -alkyl, C 1 -C 7 -Alkylcarbonyl-, or R 6 and R 6 ' together with the nitrogen atom to which they are attached form a 4-7 membered saturated or partially saturated monocyclic or 7-12 membered saturated or partially saturated bicyclic heterocycle, which Circulatingly containing another hetero atom selected from N, O or S; unsubstituted or substituted with from 1 to 3 substituents selected from C 1 -C 7 -alkyl-hydroxy-C 1 -C 7 - alkoxy-carbonyl- or (d)-NR 5' -C(O)-R 5 , wherein R 5 is selected from C 3 -C 10 -cycloalkyl; R 5 ' is selected from hydrogen, C 1 -C 7 -alkyl; m is 0-1; and n is 0-1; the premise does not contain 6-[5-(2-furyl)-1,2,4- Diazol-3-yl]-N2-methyl-N2-phenyl-1,3,5-three -2,4-diamine.

不論在何處提及式(I)之一或多種化合物，此提及進一步亦意欲包含該等化合物之N-氧化物、其互變異構體及/或其(較佳地，醫藥上可接受之)鹽。 Wherever reference is made to one or more compounds of formula (I), this reference is further intended to include N-oxides, tautomers thereof and/or (preferably, pharmaceutically acceptable) of such compounds Salt).

出於闡釋本說明書之目的，將應用下列定義且若適宜，以單數使用之術語亦包含複數形式且反之亦然。 For the purposes of the present specification, the following definitions are applied and, where appropriate, the terms used in the singular also include the plural and vice versa.

除非另有所述，否則術語「鹵素」在本文中用於闡述選 自氟(fluoro、fluorine)、氯(chloro、chlorine)、溴(bromo、bromine)或碘(iodo、iodine)之群。 Unless otherwise stated, the term "halogen" is used herein to describe From the group of fluorine (fluorine, fluorine), chlorine (chloro, chlorine), bromine (bromo, bromine) or iodine (iodo, iodine).

如本文所使用，術語「烷基」係指具有至多20個碳原子之完全飽和之具支鏈(包含單一或多個支鏈)或無支鏈烴部分。除非另外提供，否則烷基係指具有1至16個碳原子、1至10個碳原子、1至7個碳原子或1至4個碳原子之烴部分。烷基之代表性實例包含但不限於甲基、乙基、正丙基、異丙基、正丁基、第二丁基、異丁基、第三丁基、正戊基、異戊基、新戊基、正己基、3-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、正庚基、正辛基、正壬基、正癸基及諸如此類。通常，烷基具有1-7個、更佳地1-4個碳。 As used herein, the term "alkyl" refers to a branched (including single or multiple branched) or unbranched hydrocarbon moiety having a complete saturation of up to 20 carbon atoms. Unless otherwise provided, alkyl refers to a hydrocarbon moiety having from 1 to 16 carbon atoms, from 1 to 10 carbon atoms, from 1 to 7 carbon atoms, or from 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, Neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-decyl, n-decyl and the like . Typically, the alkyl group has from 1 to 7, more preferably from 1 to 4 carbons.

如本文所使用，術語「鹵代烷基」係指經一或多個本文所定義鹵基取代之本文所定義烷基。鹵代-烷基可為單-鹵代-烷基、二-鹵代-烷基或多-鹵代-烷基(包含全-鹵代-烷基)。單-鹵代-烷基可在烷基內具有一個碘、溴、氯或氟。二-鹵代-烷基及多-鹵代-烷基可在烷基內具有兩個或更多個相同鹵素原子或不同鹵基之組合。通常，多-鹵代-烷基含有至多12或10或8或6或4或3或2個鹵基。鹵代-烷基之非限制性實例包含氟-甲基、二-氟-甲基、三-氟-甲基、氯-甲基、二-氯-甲基、三-氯-甲基、五-氟-乙基、七-氟-丙基、二-氟-氯-甲基、二-氯-氟-甲基、二-氟-乙基、二-氟-丙基、二-氯-乙基及二氯-丙基。全-鹵代-烷基係指所有氫原子皆由鹵素原子代替之烷基。 As used herein, the term "haloalkyl" refers to an alkyl group, as defined herein, substituted by one or more halo groups as defined herein. Halo-alkyl groups can be mono-halo-alkyl, di-halo-alkyl or poly-halo-alkyl (including per-halo-alkyl). The mono-halo-alkyl group may have one iodine, bromine, chlorine or fluorine in the alkyl group. The di-halo-alkyl and poly-halo-alkyl groups may have two or more of the same halogen atoms or a combination of different halo groups in the alkyl group. Typically, the poly-halo-alkyl group contains up to 12 or 10 or 8 or 6 or 4 or 3 or 2 halo groups. Non-limiting examples of halo-alkyl groups include fluoro-methyl, di-fluoro-methyl, tri-fluoro-methyl, chloro-methyl, di-chloro-methyl, tri-chloro-methyl, five -fluoro-ethyl, hepta-fluoro-propyl, di-fluoro-chloro-methyl, di-chloro-fluoro-methyl, di-fluoro-ethyl, di-fluoro-propyl, di-chloro-B Base and dichloro-propyl. The all-halo-alkyl group means an alkyl group in which all hydrogen atoms are replaced by a halogen atom.

如本文所使用，術語「環烷基」係指具有3-12個碳原子 之飽和或部分不飽和之單環、雙環或三環烴基團。除非另外提供，否則環烷基係指具有3至10個環碳原子或3至7個環碳原子之環狀烴基團。實例性單環烴基團包含但不限於環丙基、環丁基、環戊基、環戊烯基、環己基及環己烯基。實例性雙環烴基團包含八氫吲哚基、十氫萘基、雙環[2.1.1]己基、雙環[2.2.1]庚基、雙環[2.2.1]庚烯基、6,6-二甲基雙環[3.1.1]庚基、2,6,6-三甲基雙環[3.1.1]庚基、雙環[2.2.2]辛基。實例性三環烴基團包含金剛烷基。如本文所使用，術語「環烷基」較佳地係指環丙基、環戊基或環己基。 As used herein, the term "cycloalkyl" refers to having from 3 to 12 carbon atoms. A saturated or partially unsaturated monocyclic, bicyclic or tricyclic hydrocarbon group. Unless otherwise provided, a cycloalkyl group means a cyclic hydrocarbon group having 3 to 10 ring carbon atoms or 3 to 7 ring carbon atoms. Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl. Exemplary bicyclic hydrocarbon groups include octahydrofluorenyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethyl Bicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl. An exemplary tricyclic hydrocarbon group comprises an adamantyl group. As used herein, the term "cycloalkyl" preferably refers to cyclopropyl, cyclopentyl or cyclohexyl.

如本文所使用，術語「C2-C7-烯基」係指含有2至5個碳原子且含有至少一個碳碳雙鍵之直連或具支鏈烴基團。該等基團之實例包含乙烯基、丙烯基、丁烯基及戊烯基。除非指定特定結構，否則術語丁烯基及戊烯基等包含所有可能之E及Z異構體。 As used herein, the term "C 2 -C 7 - alkenyl" means containing from 2 to 5 carbon atoms and containing at least one direct carbon-carbon double bond or a branched hydrocarbon radical. Examples of such groups include ethenyl, propenyl, butenyl and pentenyl. Unless specified for a particular structure, the terms butenyl, pentenyl and the like encompass all possible E and Z isomers.

如本文所使用，術語「芳基」係指6碳單環、10碳雙環、14碳三環芳族環系統。「芳基」之實例係苯基及萘基。 As used herein, the term "aryl" refers to a 6 carbon monocyclic, 10 carbon bicyclic, 14 carbon tricyclic aromatic ring system. Examples of "aryl" are phenyl and naphthyl.

如本文所使用，術語「芳基」較佳地係指苯基。 As used herein, the term "aryl" preferably refers to phenyl.

如本文所使用，術語「雜芳基」係指4-、5-、6-或7員單環、7-、8-、9-、10-、11-或12員雙環或10-、11-、12-、13-、14-或15員三環不飽和環或環系統，其在環中攜帶有最高可能數量之共軛雙鍵，且含有至少一個選自N、O及S之雜原子，其中N及S亦可視情況氧化成各種氧化態。「雜 芳基」可附接至雜原子或碳原子。「雜芳基」可包含稠合或橋接環以及螺環。雜芳基之實例包含吡啶基、喹啉基、異喹啉基、噠基、嘧啶基、吡基、喹喔啉基、呋喃基、苯并呋喃基、二苯并呋喃基、苯硫基、苯并噻吩基、吡咯基、吲哚基、吡唑基、吲唑基、唑基、異唑基、噻唑基、異噻唑基、咪唑基、苯并咪唑基、二唑基(例如1,2,5-二唑基、1,2,4-二唑基、1,2,3-二唑基、1,3,4-二唑基)、噻二唑基(例如1,2,5-噻二唑基、1,2,4-噻二唑基、1,2,3-噻二唑基、1,3,4-噻二唑基)、三唑基(例如1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基)、三基-(例如1,2,3-三基、1,2,4-三基及1,3,5-三基)、四唑基。如本文所使用，術語「雜芳基」較佳地係指呋喃基、苯硫基、吡啶基、噻唑基、吡唑基、異唑基、咪唑基、吡咯基、苯并呋喃基、嘧啶基、唑基。 As used herein, the term "heteroaryl" refers to a 4-, 5-, 6- or 7-membered monocyclic, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring or 10-, 11 a -, 12-, 13-, 14- or 15 membered tricyclic unsaturated ring or ring system carrying the highest possible number of conjugated double bonds in the ring and containing at least one selected from the group consisting of N, O and S Atoms, where N and S can also be oxidized to various oxidation states as appropriate. "Heteroaryl" can be attached to a hetero atom or a carbon atom. "Heteroaryl" may include fused or bridged rings as well as spiro rings. Examples of heteroaryl groups include pyridyl, quinolyl, isoquinolinyl, anthracene Base, pyrimidinyl, pyridyl , quinoxalinyl, furyl, benzofuranyl, dibenzofuranyl, phenylthio, benzothienyl, pyrrolyl, indolyl, pyrazolyl, carbazolyl, Azolyl, different Azyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, Diazolyl (eg 1,2,5- Diazolyl, 1,2,4- Diazolyl, 1,2,3- Diazolyl, 1,3,4- Diazolyl), thiadiazolyl (eg 1,2,5-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,3,4- Thiadiazolyl), triazolyl (eg 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl), three Base - (for example 1, 2, 3-three Base, 1, 2, 4-three Base and 1,3,5-three Base), tetrazolyl. As used herein, the term "heteroaryl" preferably refers to furanyl, phenylthio, pyridyl, thiazolyl, pyrazolyl, isomeric Azyl, imidazolyl, pyrrolyl, benzofuranyl, pyrimidinyl, Azolyl.

如本文所使用，術語「雜環基」係指4-、5-、6-、7-或8員單環、7-、8-、9-、10-、11-或12員雙環狀或10-、11-、12-、13-、14-或15員三環飽和或部分不飽和之環系統且含有至少一個選自N、O及S之雜原子，其中N及S亦可視情況氧化成各種氧化態。「雜環基」可附接至雜原子或碳原子。「雜環基」可包含稠合或橋接環以及螺環。雜環基之實例包含二氧戊環基、咪唑啉基、咪唑啶基、異噻唑啶基、異唑啶基、嗎啉基、唑啶基、六氫吡啶基、六氫吡基、吡咯啶基、吡唑啶基、噻唑啶基、四氫呋喃基、三噻烷基、四氫吡喃基、硫嗎啉基以及「雜芳基」之二- 、四-、六-、八-或十氫衍生物。如本文所使用，術語「雜環基」較佳地係指嗎啉基、六氫吡啶基、四氫呋喃基、四氫吡喃基、吡咯啶基、二氫苯并呋喃基。如本文所使用，在Y之背景下，術語「雜環基」較佳地係指四氫呋喃基、四氫吡喃基、二氫苯并呋喃基。 As used herein, the term "heterocyclyl" refers to a 4-, 5-, 6-, 7- or 8-membered monocyclic, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring. Or a 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic saturated or partially unsaturated ring system and containing at least one hetero atom selected from N, O and S, wherein N and S may also be used. Oxidation to various oxidation states. "Heterocyclyl" can be attached to a hetero atom or a carbon atom. "Heterocyclyl" may include fused or bridged rings as well as spiro rings. Examples of heterocyclic groups include dioxolane, imidazolinyl, imidazolidinyl, isothiazolidinyl, and iso Zyridinyl, morpholinyl, Zyridinyl, hexahydropyridyl, hexahydropyridyl Base, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropyranyl, thiomorpholinyl and "heteroaryl" two-, four-, six-, eight - or a decahydro derivative. As used herein, the term "heterocyclyl" preferably refers to morpholinyl, hexahydropyridyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, dihydrobenzofuranyl. As used herein, in the context of Y, the term "heterocyclyl" preferably refers to tetrahydrofuranyl, tetrahydropyranyl, dihydrobenzofuranyl.

如本文所使用，在由R4及R4'以及其所附接之氮原子或由R5及R5'以及其所附接之氮原子或由R6及R6'以及其所附接之氮原子所形成雜環的背景下，術語「雜環基」較佳地係指嗎啉基、六氫吡啶基、吡咯啶基。 As used herein, a nitrogen atom consisting of R 4 and R 4 ' and its attachment or by R 5 and R 5 ' and the nitrogen atom to which it is attached or by R 6 and R 6' In the context of a heterocycle formed by a nitrogen atom, the term "heterocyclyl" preferably refers to morpholinyl, hexahydropyridyl, pyrrolidinyl.

如本文所使用，術語「螺環基」係指經由一個單一原子稠合至第二3至6員飽和環之如前文所定義之「4至7員單環雜環基」，且其中該第二環含有0、1或2個獨立地選自氧、氮及硫之雜原子。 As used herein, the term "spirocyclyl" refers to a "4 to 7 membered monocyclic heterocyclic group" as defined above, fused to a second 3 to 6 membered saturated ring via a single atom, and wherein the The bicyclic ring contains 0, 1 or 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur.

如本文所使用，術語「氧基」係指-O-連接基團。 As used herein, the term "oxy" refers to an -O- linking group.

本文所用之術語「側氧基」係指二價氧取代基，亦即=O。 The term "sideoxy" as used herein refers to a divalent oxygen substituent, ie, =0.

如本文所使用，所有取代基皆係以展示構成其之一或多個官能基之順序之方式寫出。官能基如上文所定義。視情況，使用連字符(-)或等號(=)指出其附接點。 As used herein, all substituents are written in a manner that exhibits the order in which one or more of the functional groups are formed. The functional groups are as defined above. Use a hyphen (-) or an equal sign (=) to indicate its attachment point, as appropriate.

在一實施例中，本發明提供式(I)化合物及/或其醫藥上可接受之鹽及/或溶劑合物，其中 其中R1係選自氫-鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-；R2係選自氫-C1-C7-烷基-鹵代-C2-C7-烷基-胺基-C2-C7-烷基-N-C1-C7-烷基-胺基-C2-C7-烷基-N,N-二-C1-C7-烷基-胺基-C2-C7-烷基-羥基-C2-C7-烷基-C1-C7-烷氧基-C2-C7-烷基-C3-C10-環烷基-C1-C7-烷基-氰基-C2-C7-烷基-；或R1及R2與其所附接之原子一起形成4-7員飽和或部分飽和 之雜環，該雜環未經取代或經1-3個選自以下之取代基取代：C1-C7-烷基-鹵代-C1-C7-烷基-胺基-C1-C7-烷基-N-C1-C7-烷基-胺基-C1-C7-烷基-N,N-二-C1-C7-烷基-胺基-C1-C7-烷基-羥基-C1-C7-烷基-C1-C7-烷氧基-C1-C7-烷基-C3-C10-環烷基-C1-C7-烷基-氰基-C1-C7-烷基-；R係選自鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-C1-C7-烷氧基-氰基-鹵代-C1-C7-烷氧基-硝基；R3係選自(a)-(CH2)p-Y，其中p係選自0、1、2或3，且Y係選自芳基、雜芳基、雜環基，其未經取代或經1-3個選自以下之取代基取代： 鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-C1-C7-烷氧基-C3-C10-環烷基-氧基-羥基-鹵代-C1-C7-烷基-氧基-胺基-N-C1-C7-烷基-胺基-N,N-二-C1-C7-烷基-胺基-氰基-C1-C7-烷氧基-羰基-羥基-羰基--C(O)-NR4'R4，其中R4係選自氫、C1-C7-烷基；R4'係選自氫，或R4及R4'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環雜環，該單環雜環視情況含有選自N、O或S之另一雜原子；或(b)-C(O)-NR5'R5或-C(O)-O-R5，其中R5係選自氫、苄基、二氫茚基、四氫呋喃基、四氫吡喃基、環氧乙烷基、C3-C10-環烷基、C1-C7-烷基；R5'係選自氫、C1-C7-烷基， 或R5及R5'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環或雙環雜環，該雜環視情況含有選自N、O或S之另一雜原子；或(c)-NR6'R6，其中R6係選自氫、苄基、C3-C10-環烷基、C1-C7-烷基，R6'係選自氫、C1-C7-烷基、C1-C7-烷基羰基-，或R6及R6'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環或7-12員飽和或部分飽和之雙環雜環，該雜環視情況含有選自N、O或S之另一雜原子；其未經取代或經1-3個選自以下之取代基取代：C1-C7-烷基-羥基-C1-C7-烷氧基-羰基-或(d)-NR5'-C(O)-R5，其中R5係選自C3-C10-環烷基；R5'係選自氫、C1-C7-烷基；m為0-1；且n為0-1；前提係不包含6-[5-(2-呋喃基)-1,2,4-二唑-3-基]-N2-甲基-N2-苯基-1,3,5-三-2,4-二胺。 In one embodiment, the present invention provides a compound of formula (I) and/or a pharmaceutically acceptable salt and/or solvate thereof, wherein Wherein R 1 is selected from hydrogen-halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-; R 2 is selected from hydrogen-C 1 -C 7 -alkyl-halo -C 2 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-NC 1 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-N,N-di-C 1- C 7 -alkyl-amino-C 2 -C 7 -alkyl-hydroxy-C 2 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 2 -C 7 -alkyl- C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkyl-cyano-C 2 -C 7 -alkyl-; or R 1 and R 2 together with the attached atom form a 4-7 member a saturated or partially saturated heterocyclic ring which is unsubstituted or substituted with from 1 to 3 substituents selected from C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-amine -C 1 -C 7 -alkyl-NC 1 -C 7 -alkyl-amino-C 1 -C 7 -alkyl-N,N-di-C 1 -C 7 -alkyl-amino group- C 1 -C 7 -alkyl-hydroxy-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-C 3 -C 10 -cycloalkyl-C 1- C 7 -alkyl-cyano-C 1 -C 7 -alkyl-; R is selected from halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-cyano-halo-C 1 -C 7 -alkoxy-nitro; R 3 is selected from (a)-(CH 2 ) p -Y, wherein p is selected from 0 1, 2 or 3, and Y selection An aryl group, a heteroaryl group, a heterocyclic group which is unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of: halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 - Alkyl-C 1 -C 7 -alkoxy-C3-C 10 -cycloalkyl-oxy-hydroxy-halo-C 1 -C 7 -alkyl-oxy-amino-NC 1 -C 7 -alkyl-amino-N,N-di-C 1 -C 7 -alkyl-amino-cyano-C 1 -C 7 -alkoxy-carbonyl-hydroxy-carbonyl--C(O)- NR 4' R 4 , wherein R 4 is selected from hydrogen, C 1 -C 7 -alkyl; R 4 ' is selected from hydrogen, or R 4 and R 4 ' together with the nitrogen atom to which they are attached form 4-7 a saturated or partially saturated monocyclic heterocyclic ring optionally containing another hetero atom selected from N, O or S; or (b) -C(O)-NR 5' R 5 or -C ( O)-OR 5 , wherein R 5 is selected from the group consisting of hydrogen, benzyl, indanyl, tetrahydrofuranyl, tetrahydropyranyl, oxiranyl, C 3 -C 10 -cycloalkyl, C 1 - C 7 -alkyl; R 5 ' is selected from hydrogen, C 1 -C 7 -alkyl, or R 5 and R 5 ' together with the nitrogen atom to which they are attached form a 4-7 member saturated or partially saturated monocyclic ring. Or a bicyclic heterocycle which optionally contains another hetero atom selected from N, O or S; or (c) -NR 6' R 6 wherein R 6 is selected from the group consisting of hydrogen, benzyl, C 3 -C 10 -cycloalkyl, C 1 -C 7 -alkyl, and R 6 ' is selected from hydrogen, C 1 -C 7 -alkyl, C 1 -C 7 -Alkylcarbonyl-, or R 6 and R 6 ' together with the nitrogen atom to which they are attached form a 4-7 membered saturated or partially saturated monocyclic or 7-12 membered saturated or partially saturated bicyclic heterocycle, which The case contains another hetero atom selected from N, O or S; it is unsubstituted or substituted with from 1 to 3 substituents selected from C 1 -C 7 -alkyl-hydroxy-C 1 -C 7 - Alkoxy-carbonyl- or (d)-NR 5' -C(O)-R 5 , wherein R 5 is selected from C 3 -C 10 -cycloalkyl; R 5 ' is selected from hydrogen, C 1 - C 7 -alkyl; m is 0-1; and n is 0-1; the premise does not contain 6-[5-(2-furyl)-1,2,4- Diazol-3-yl]-N2-methyl-N2-phenyl-1,3,5-three -2,4-diamine.

6-[5-(2-呋喃基)-1,2,4-二唑-3-基]-N2-甲基-N2-苯基-1,3,5-三-2,4-二胺(CAS-899373-19-4)係來自化學文庫之 化合物。 6-[5-(2-furyl)-1,2,4- Diazol-3-yl]-N2-methyl-N2-phenyl-1,3,5-three -2,4-Diamine (CAS-899373-19-4) is a compound from a chemical library.

在另一實施例中，本發明提供式(I)化合物及/或其醫藥上可接受之鹽及/或溶劑合物，其中R1係選自氫-鹵素-C1-C4-烷基-鹵代-C1-C4-烷基-。 In another embodiment, the present invention provides a compound of formula (I) and/or a pharmaceutically acceptable salt and/or solvate thereof, wherein R 1 is selected from hydrogen-halogen-C 1 -C 4 -alkyl -halo-C 1 -C 4 -alkyl-.

在另一實施例中，本發明提供式(I)化合物及/或其醫藥上可接受之鹽及/或溶劑合物，其中R1係選自氫-氯-氟-甲基-。 In another embodiment, the present invention provides compounds of Formula (I) compound and / or a pharmaceutically acceptable salt thereof and / or solvate thereof, in which R 1 is selected from hydrogen - chloro - fluoro - methyl -.

在另一實施例中，本發明提供式(I)化合物及/或其醫藥上可接受之鹽及/或溶劑合物，其中R1係選自氫-氟-。 In another embodiment, the present invention provides compounds of Formula (I) compound and / or a pharmaceutically acceptable salt thereof and / or solvate thereof, in which R 1 is selected from hydrogen - fluoro -.

在另一實施例中，本發明提供式(I)化合物及/或其醫藥上可接受之鹽及/或溶劑合物，其中R2係選自氫- C1-C4-烷基-鹵代-C2-C4-烷基-N,N-二-C1-C2-烷基-胺基-C2-C4-烷基-羥基-C2-C4-烷基-C1-C2-烷氧基-C2-C4-烷基-C3-C6-環烷基-C1-C7-烷基-。 In another embodiment, the present invention provides a compound of formula (I) and/or a pharmaceutically acceptable salt and/or solvate thereof, wherein R 2 is selected from hydrogen-C 1 -C 4 -alkyl-halogen -C 2 -C 4 -alkyl-N,N-di-C 1 -C 2 -alkyl-amino-C 2 -C 4 -alkyl-hydroxy-C 2 -C 4 -alkyl-C 1- C 2 -alkoxy-C 2 -C 4 -alkyl-C 3 -C 6 -cycloalkyl-C 1 -C 7 -alkyl-.

在另一實施例中，本發明提供式(I)化合物及/或其醫藥上可接受之鹽及/或溶劑合物，其中R2係選自氫-甲基-乙基-異丙基-2,2,2-三氟-乙基-N,N-二-甲基-胺基-乙基-羥基-乙基-甲氧基-乙基-環丙基-甲基-。 In another embodiment, the present invention provides a compound of formula (I) and/or a pharmaceutically acceptable salt and/or solvate thereof, wherein R 2 is selected from hydrogen-methyl-ethyl-isopropyl- 2,2,2-Trifluoro-ethyl-N,N-di-methyl-amino-ethyl-hydroxy-ethyl-methoxy-ethyl-cyclopropyl-methyl-.

在另一實施例中，本發明提供式(I)化合物及/或其醫藥上可接受之鹽及/或溶劑合物，其中R2係選自氫-甲基-乙基- 2,2,2-三氟-乙基-。 In another embodiment, the present invention provides a compound of formula (I) and/or a pharmaceutically acceptable salt and/or solvate thereof, wherein R 2 is selected from the group consisting of hydrogen-methyl-ethyl-2,2, 2-Trifluoro-ethyl-.

在另一實施例中，本發明提供式(I)化合物及/或其醫藥上可接受之鹽及/或溶劑合物，其中R1及R2一起選自-CH2-CH2-、-CH2-CH2-CH2-、-CH=CH-、-CH=CH-CH2-或-CH2-CH=CH-。 In another embodiment, the present invention provides a compound of formula (I) and/or a pharmaceutically acceptable salt and/or solvate thereof, wherein R 1 and R 2 are taken together from -CH 2 -CH 2 -, - CH 2 -CH 2 -CH 2 -, -CH=CH-, -CH=CH-CH 2 - or -CH 2 -CH=CH-.

在另一實施例中，本發明提供式(I)化合物及/或其醫藥上可接受之鹽及/或溶劑合物，其中R1及R2一起選自-CH2-CH2-或-CH2-CH2-CH2-。 In another embodiment, the present invention provides a compound of formula (I) and/or a pharmaceutically acceptable salt and/or solvate thereof, wherein R 1 and R 2 are taken together from -CH 2 -CH 2 - or - CH 2 -CH 2 -CH 2 -.

在另一實施例中，本發明提供式(I)化合物及/或其醫藥上可接受之鹽及/或溶劑合物，其中R1係選自氫-氯-氟-甲基-；R2係選自氫-C1-C4-烷基-鹵代-C2-C4-烷基-N,N-二-C1-C2-烷基-胺基-C2-C4-烷基-羥基-C2-C4-烷基-C1-C2-烷氧基-C2-C4-烷基- C3-C6-環烷基-C1-C7-烷基-。 In another embodiment, the present invention provides a compound of formula (I) and/or a pharmaceutically acceptable salt and/or solvate thereof, wherein R 1 is selected from the group consisting of hydrogen-chloro-fluoro-methyl-; R 2 Is selected from hydrogen-C 1 -C 4 -alkyl-halo-C 2 -C 4 -alkyl-N,N-di-C 1 -C 2 -alkyl-amino-C 2 -C 4 - Alkyl-hydroxy-C 2 -C 4 -alkyl-C 1 -C 2 -alkoxy-C 2 -C 4 -alkyl-C 3 -C 6 -cycloalkyl-C 1 -C 7 -alkane base-.

在另一實施例中，本發明提供式(I)化合物及/或其醫藥上可接受之鹽及/或溶劑合物，其中R係選自鹵素-C1-C4-烷基-鹵代-C1-C4-烷基-C1-C4-烷氧基-氰基-。 In another embodiment, the present invention provides a compound of formula (I) and/or a pharmaceutically acceptable salt and/or solvate thereof, wherein R is selected from halogen-C 1 -C 4 -alkyl-halo -C 1 -C 4 -alkyl-C 1 -C 4 -alkoxy-cyano-.

在另一實施例中，本發明提供式(I)化合物及/或其醫藥上可接受之鹽及/或溶劑合物，其中R係選自氯-氟-甲基-三氟甲基-甲氧基-氰基-。 In another embodiment, the present invention provides a compound of formula (I) and/or a pharmaceutically acceptable salt and/or solvate thereof, wherein R is selected from the group consisting of chloro-fluoro-methyl-trifluoromethyl- Oxy-cyano-.

在另一實施例中，本發明提供式(I)化合物及/或其醫藥上可接受之鹽及/或溶劑合物，其中R3係選自-(CH2)p-Y，其中p係選自0、1、2或3，且Y係選自芳基、雜芳基、雜環基，其未經取代或經1-3 個選自以下之取代基取代：鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-C1-C7-烷氧基-C3-C10-環烷基-氧基-羥基-鹵代-C1-C7-烷基-氧基-胺基-N-C1-C7-烷基-胺基-N,N-二-C1-C7-烷基-胺基-氰基-C1-C7-烷氧基-羰基-羥基-羰基--C(O)-NR4'R4，其中R4係選自氫、C1-C7-烷基；R4'係選自氫，或R4及R4'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環雜環，該單環雜環視情況含有選自N、O或S之另一雜原子。 In another embodiment, the present invention provides a compound of formula (I) and/or a pharmaceutically acceptable salt and/or solvate thereof, wherein R 3 is selected from the group consisting of —(CH 2 ) p —Y, wherein p is Selected from 0, 1, 2 or 3, and Y is selected from aryl, heteroaryl, heterocyclyl, which is unsubstituted or substituted with from 1 to 3 substituents selected from halogen-C 1 -C 7 -Alkyl-halo-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 3 -C 10 -cycloalkyl-oxy-hydroxy-halo-C 1 -C 7 -alkyl-oxy-amino-NC 1 -C 7 -alkyl-amino-N,N-di-C 1 -C 7 -alkyl-amino-cyano-C 1 -C 7 -alkane Oxy-carbonyl-hydroxy-carbonyl-C(O)-NR 4' R 4 , wherein R 4 is selected from hydrogen, C 1 -C 7 -alkyl; R 4 ' is selected from hydrogen, or R 4 and R 4 ' together with the nitrogen atom to which it is attached forms a 4-7 membered saturated or partially saturated monocyclic heterocyclic ring which optionally contains another hetero atom selected from N, O or S.

在另一實施例中，本發明提供式(I)化合物及/或其醫藥上可接受之鹽及/或溶劑合物，其中R3係選自-Y，其中 Y係選自芳基、雜芳基、雜環基，其未經取代或經1-2個選自以下之取代基取代：鹵素-C1-C4-烷基-鹵代-C1-C4-烷基-C1-C4-烷氧基-C3-C7-環烷基-氧基-羥基-鹵代-C1-C4-烷基-氧基-胺基-氰基-C1-C4-烷氧基-羰基-羥基-羰基--C(O)-NR4'R4，其中R4係選自氫、C1-C4-烷基；R4'係選自氫，或R4及R4'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環雜環，該單環雜環視情況含有選自N、O或S之另一雜原子。 In another embodiment, the present invention provides a compound of formula (I) and/or a pharmaceutically acceptable salt and/or solvate thereof, wherein R 3 is selected from the group consisting of -Y, wherein Y is selected from the group consisting of aryl and hetero An aryl group or a heterocyclic group which is unsubstituted or substituted with 1-2 substituents selected from halogen-C 1 -C 4 -alkyl-halo-C 1 -C 4 -alkyl-C 1 -C 4 -alkoxy-C 3 -C 7 -cycloalkyl-oxy-hydroxy-halo-C 1 -C 4 -alkyl-oxy-amino-cyano-C 1 -C 4 - alkoxy-carbonyl-hydroxy-carbonyl-C(O)-NR 4' R 4 , wherein R 4 is selected from hydrogen, C 1 -C 4 -alkyl; R 4 ' is selected from hydrogen, or R 4 And R 4 ' together with the nitrogen atom to which it is attached form a 4-7 membered saturated or partially saturated monocyclic heterocyclic ring which optionally contains another hetero atom selected from N, O or S.

在另一實施例中，本發明提供式(I)化合物及/或其醫藥上可接受之鹽及/或溶劑合物，其中R3係選自苯基、呋喃基、苯硫基、吡啶基、噻唑基、吡唑基、異唑基、咪唑基、吡咯基、苯并呋喃基、嘧啶基、唑 基、嗎啉基、六氫吡啶基、四氫呋喃基、四氫吡喃基、吡咯啶基、二氫苯并呋喃基，其未經取代或經1-2個選自以下之取代基取代：鹵素-C1-C4-烷基-鹵代-C1-C4-烷基-C1-C4-烷氧基-C3-C7-環烷基-氧基-羥基-鹵代-C1-C4-烷基-氧基-胺基-氰基-C1-C4-烷氧基-羰基--C(O)-NR4'R4，其中R4係選自氫、C1-C4-烷基；R4'係選自氫，或R4及R4'與其所附接之氮原子一起形成嗎啉基、六氫吡啶基、吡咯啶基。 In another embodiment, the present invention provides a compound of formula (I) and/or a pharmaceutically acceptable salt and/or solvate thereof, wherein R 3 is selected from the group consisting of phenyl, furyl, phenylthio, pyridyl , thiazolyl, pyrazolyl, different Azyl, imidazolyl, pyrrolyl, benzofuranyl, pyrimidinyl, An azolyl, morpholinyl, hexahydropyridyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, dihydrobenzofuranyl group which is unsubstituted or substituted with from 1-2 substituents selected from the group consisting of: Halogen-C 1 -C 4 -alkyl-halo-C 1 -C 4 -alkyl-C 1 -C 4 -alkoxy-C 3 -C 7 -cycloalkyl-oxy-hydroxy-halo -C 1 -C 4 -alkyl-oxy-amino-cyano-C 1 -C 4 -alkoxy-carbonyl-C(O)-NR 4' R 4 , wherein R 4 is selected from hydrogen And C 1 -C 4 -alkyl; R 4 ' is selected from hydrogen, or R 4 and R 4 ' together with the nitrogen atom to which they are attached form a morpholinyl group, a hexahydropyridyl group, a pyrrolidinyl group.

在另一實施例中，本發明提供式(I)化合物及/或其醫藥上可接受之鹽及/或溶劑合物，其中R3係選自苯基、呋喃基、苯硫基、吡啶基、噻唑基、吡唑基、異唑基、咪唑基、吡咯基、苯并呋喃基、嘧啶基、唑基、嗎啉基、六氫吡啶基、四氫呋喃基、四氫吡喃基、 吡咯啶基、二氫苯并呋喃基，其未經取代或經1-2個選自以下之取代基取代：氯-溴-氟-甲基-三氟甲基-2,2,2-三氟-乙基-甲氧基-環戊基-氧基-三氟甲基-氧基-2,2,2-三氟-乙基-氧基-胺基-氰基-甲氧基-羰基--C(O)-NR4'R4，其中R4係選自氫、甲基；R4'係選自氫，或R4及R4'與其所附接之氮原子一起形成嗎啉基、六氫吡啶基、吡咯啶基。 In another embodiment, the present invention provides a compound of formula (I) and/or a pharmaceutically acceptable salt and/or solvate thereof, wherein R 3 is selected from the group consisting of phenyl, furyl, phenylthio, pyridyl , thiazolyl, pyrazolyl, different Azyl, imidazolyl, pyrrolyl, benzofuranyl, pyrimidinyl, An azolyl, morpholinyl, hexahydropyridyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, dihydrobenzofuranyl group which is unsubstituted or substituted with from 1-2 substituents selected from the group consisting of: Chloro-bromo-fluoro-methyl-trifluoromethyl-2,2,2-trifluoro-ethyl-methoxy-cyclopentyl-oxy-trifluoromethyl-oxy-2,2,2 -Trifluoro-ethyl-oxy-amino-cyano-methoxy-carbonyl-C(O)-NR 4' R 4 , wherein R 4 is selected from hydrogen, methyl; R 4 ' is selected From hydrogen, or R 4 and R 4 ' together with the nitrogen atom to which they are attached form a morpholinyl group, a hexahydropyridyl group, a pyrrolidinyl group.

在另一實施例中，本發明提供式(I)化合物及/或其醫藥上可接受之鹽及/或溶劑合物，其中R3係選自-C(O)-NR5'R5或-C(O)-O-R5，其中 R5係選自氫、苄基、二氫茚基、四氫呋喃基、四氫吡喃基、環氧乙烷基、C3-C10-環烷基、C1-C7-烷基；R5'係選自氫、C1-C7-烷基，或R5及R5'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環或雙環雜環，該雜環視情況含有選自N、O或S之另一雜原子。 In another embodiment, the present invention provides compounds of Formula (I) compound and / or a pharmaceutically acceptable salt thereof and / or solvate thereof, wherein R 3 is selected from -C (O) -NR 5 'R 5 or -C(O)-OR 5 , wherein R 5 is selected from the group consisting of hydrogen, benzyl, indanyl, tetrahydrofuranyl, tetrahydropyranyl, oxiranyl, C 3 -C 10 -cycloalkyl, C 1 -C 7 -alkyl; R 5 ' is selected from hydrogen, C 1 -C 7 -alkyl, or R 5 and R 5 ' together with the nitrogen atom to which they are attached form a 4-7 member saturated or partially saturated A monocyclic or bicyclic heterocyclic ring which optionally contains another hetero atom selected from N, O or S.

在另一實施例中，本發明提供式(I)化合物及/或其醫藥上可接受之鹽及/或溶劑合物，其中R3係選自-NR6'R6，其中R6係選自氫、苄基、C3-C10-環烷基、C1-C7-烷基，R6'係選自氫、C1-C7-烷基、C1-C7-烷基羰基-，或R6及R6'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環或7-12員飽和或部分飽和之雙環雜環，該雜環視情況含有選自N、O或S之另一雜原子；其未經取代或經1-3個選自以下之取代基取代：C1-C7-烷基-羥基-C1-C7-烷氧基-羰基-。 In another embodiment, the present invention provides a compound of formula (I) and/or a pharmaceutically acceptable salt and/or solvate thereof, wherein R 3 is selected from -NR 6 ' R 6 , wherein R 6 is selected From hydrogen, benzyl, C 3 -C 10 -cycloalkyl, C 1 -C 7 -alkyl, R 6 ' is selected from hydrogen, C 1 -C 7 -alkyl, C 1 -C 7 -alkyl The carbonyl-, or R 6 and R 6 ' together with the nitrogen atom to which they are attached form a 4-7 membered saturated or partially saturated monocyclic or 7-12 membered saturated or partially saturated bicyclic heterocycle which optionally comprises Another hetero atom from N, O or S; which is unsubstituted or substituted with from 1 to 3 substituents selected from C 1 -C 7 -alkyl-hydroxy-C 1 -C 7 -alkoxy -carbonyl-.

在另一實施例中，本發明提供式(I)化合物及/或其醫藥上可接受之鹽及/或溶劑合物，其中R3係選自-NR5'-C(O)-R5，其中R5係選自C3-C10-環烷基； R5'係選自氫、C1-C7-烷基。 In another embodiment, the present invention provides a compound of formula (I) and/or a pharmaceutically acceptable salt and/or solvate thereof, wherein R 3 is selected from -NR 5 ' -C(O)-R 5 Wherein R 5 is selected from the group consisting of C 3 -C 10 -cycloalkyl; R 5 ' is selected from hydrogen, C 1 -C 7 -alkyl.

在另一實施例中，本發明提供式(I)化合物及/或其醫藥上可接受之鹽及/或溶劑合物，其中其中m為0。 In another embodiment, the present invention provides a compound of formula (I) and/or a pharmaceutically acceptable salt and/or solvate thereof, wherein m is 0.

在另一實施例中，本發明提供式(I)化合物及/或其醫藥上可接受之鹽及/或溶劑合物，其中R1係選自氫-氟-；R2係選自氫-C1-C4-烷基-鹵代-C2-C4-烷基-N,N-二-C1-C2-烷基-胺基-C2-C4-烷基-羥基-C2-C4-烷基-C1-C2-烷氧基-C2-C4-烷基-C3-C6-環烷基-C1-C7-烷基-；或R1及R2一起選自-CH2-CH2-或-CH2-CH2-CH2-；R係選自鹵素-C1-C4-烷基- 鹵代-C1-C4-烷基-C1-C4-烷氧基-氰基-；且R3係選自-(CH2)p-Y，其中p係選自0、1、2或3，且Y係選自芳基、雜芳基、雜環基，其未經取代或經1-3個選自以下之取代基取代：鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-C1-C7-烷氧基-C3-C10-環烷基-氧基-羥基-鹵代-C1-C7-烷基-氧基-胺基-N-C1-C7-烷基-胺基-N,N-二-C1-C7-烷基-胺基-氰基-C1-C7-烷氧基-羰基--C(O)-NR4'R4，其中R4係選自氫、C1-C7-烷基；R4'係選自氫，或R4及R4'與其所附接之氮原子一起形成4-7員飽 和或部分飽和之單環雜環，該單環雜環視情況含有選自N、O或S之另一雜原子，m為0；且n為0-1。 In another embodiment, the present invention provides a compound of formula (I) and/or a pharmaceutically acceptable salt and/or solvate thereof, wherein R 1 is selected from hydrogen-fluoro-; R 2 is selected from hydrogen- C 1 -C 4 -alkyl-halo-C 2 -C 4 -alkyl-N,N-di-C 1 -C 2 -alkyl-amino-C 2 -C 4 -alkyl-hydroxy- C 2 -C 4 -alkyl-C 1 -C 2 -alkoxy-C 2 -C 4 -alkyl-C 3 -C 6 -cycloalkyl-C 1 -C 7 -alkyl-; or R 1 and R 2 are together selected from -CH 2 -CH 2 - or -CH 2 -CH 2 -CH 2 -; R is selected from halogen-C 1 -C 4 -alkyl-halo-C 1 -C 4 - alkyl-C 1 -C 4 -alkoxy-cyano-; and R 3 is selected from -(CH 2 ) p -Y, wherein p is selected from 0, 1, 2 or 3, and Y is selected from An aryl, heteroaryl, heterocyclyl group which is unsubstituted or substituted with from 1 to 3 substituents selected from halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkane -C 1 -C 7 -alkoxy-C 3 -C 10 -cycloalkyl-oxy-hydroxy-halo-C 1 -C 7 -alkyl-oxy-amino-NC 1 -C 7 -alkyl-amino-N,N-di-C 1 -C 7 -alkyl-amino-cyano-C 1 -C 7 -alkoxy-carbonyl--C(O)-NR 4' R 4, wherein R 4 is selected from hydrogen, C 1 -C 7 - alkyl; R 4 'is selected from hydrogen, or R 4 and R 4' thereto The attached nitrogen atoms together form a 4-7 membered saturated or partially saturated monocyclic heterocycle which optionally contains another heteroatom selected from N, O or S, m is 0; and n is 0- 1.

在另一實施例中，本發明提供式(I)化合物及/或其醫藥上可接受之鹽及/或溶劑合物，其中R1係選自氫-氟-；R2係選自氫-C1-C4-烷基-鹵代-C2-C4-烷基-N,N-二-C1-C2-烷基-胺基-C2-C4-烷基-羥基-C2-C4-烷基-C1-C2-烷氧基-C2-C4-烷基-C3-C6-環烷基-C1-C7-烷基-；或R1及R2一起選自-CH2-CH2-或-CH2-CH2-CH2-；R係選自鹵素-C1-C4-烷基-鹵代-C1-C4-烷基- C1-C4-烷氧基-氰基-；且R3係選自苯基、呋喃基、苯硫基、吡啶基、噻唑基、吡唑基、異唑基、咪唑基、吡咯基、苯并呋喃基、嘧啶基、唑基、嗎啉基、六氫吡啶基、四氫呋喃基、四氫吡喃基、吡咯啶基、二氫苯并呋喃基，其未經取代或經1-2個選自以下之取代基取代：鹵素-C1-C4-烷基-鹵代-C1-C4-烷基-C1-C4-烷氧基-C3-C7-環烷基-氧基-羥基-鹵代-C1-C4-烷基-氧基-胺基-氰基-C1-C4-烷氧基-羰基--C(O)-NR4'R4，其中R4係選自氫、C1-C4-烷基；R4'係選自氫，或R4及R4'與其所附接之氮原子一起形成嗎啉基、六氫吡啶基、吡咯啶基，m為0；且 n為0-1。 In another embodiment, the present invention provides a compound of formula (I) and/or a pharmaceutically acceptable salt and/or solvate thereof, wherein R 1 is selected from hydrogen-fluoro-; R 2 is selected from hydrogen- C 1 -C 4 -alkyl-halo-C 2 -C 4 -alkyl-N,N-di-C 1 -C 2 -alkyl-amino-C 2 -C 4 -alkyl-hydroxy- C 2 -C 4 -alkyl-C 1 -C 2 -alkoxy-C 2 -C 4 -alkyl-C 3 -C 6 -cycloalkyl-C 1 -C 7 -alkyl-; or R 1 and R 2 are together selected from -CH 2 -CH 2 - or -CH 2 -CH 2 -CH 2 -; R is selected from halogen-C 1 -C 4 -alkyl-halo-C 1 -C 4 - alkyl - C 1 -C4- alkoxy - cyano -; and R 3 is selected from phenyl, furanyl, thiophenyl, pyridyl, thiazolyl, pyrazolyl, iso Azyl, imidazolyl, pyrrolyl, benzofuranyl, pyrimidinyl, An azolyl, morpholinyl, hexahydropyridyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, dihydrobenzofuranyl group which is unsubstituted or substituted with from 1-2 substituents selected from the group consisting of: Halogen-C 1 -C 4 -alkyl-halo-C 1 -C 4 -alkyl-C 1 -C 4 -alkoxy-C 3 -C 7 -cycloalkyl-oxy-hydroxy-halo -C 1 -C 4 -alkyl-oxy-amino-cyano-C 1 -C 4 -alkoxy-carbonyl-C(O)-NR 4' R 4 , wherein R 4 is selected from hydrogen , C 1 -C 4 -alkyl; R 4 ' is selected from hydrogen, or R 4 and R 4 ' together with the nitrogen atom to which they are attached form morpholinyl, hexahydropyridyl, pyrrolidinyl, m is 0 ; and n is 0-1.

在另一實施例中，本發明提供選自以下之式(I)化合物：6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-N-甲基-N-苯基-[1,3,5]三-2,4-二胺，6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-N-苯基-[1,3,5]三-2,4-二胺，6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-N-甲基-N-(3-甲基苯基)-[1,3,5]三-2,4-二胺，6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-N-甲基-N-(4-甲基苯基)-[1,3,5]三-2,4-二胺，6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-N-甲基-N-(3-甲氧基苯基)-[1,3,5]三-2,4-二胺，6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-N-甲基-N-(4-甲氧基苯基)-[1,3,5]三-2,4-二胺，6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-N-甲基-N-(3-氯苯基)-[1,3,5]三-2,4-二胺，6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-N-甲基-N-(4-氯苯基)-[1,3,5]三-2,4-二胺，N-甲基-N-苯基-6-(5-吡啶-2-基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺，N-甲基-N-苯基-6-(5-苯基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺，N-甲基-N-苯基-6-(5-噻吩-2-基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺， N-甲基-6-[5-(5-氯-噻吩-2-基)-[1,2,4]二唑-3-基]-N-苯基-[1,3,5]三-2,4-二胺，6-[5-(6-環戊氧基-吡啶-3-基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺，N-(2-氟-苯基)-6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-N-甲基-[1,3,5]三-2,4-二胺，N-(3-氟-苯基)-6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-N-甲基-[1,3,5]三-2,4-二胺，N-(4-氟-苯基)-6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-N-甲基-[1,3,5]三-2,4-二胺，N-(2-氯-苯基)-6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-N-甲基-[1,3,5]三-2,4-二胺，6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-N-甲基-N-鄰甲苯基-[1,3,5]三-2,4-二胺，N-甲基-6-[5-(5-甲基-呋喃-2-基)-[1,2,4]二唑-3-基]-N-苯基-[1,3,5]三-2,4-二胺，N-苄基-6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-N-甲基-[1,3,5]三-2,4-二胺，N-乙基-6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-N-苯基-[1,3,5]三-2,4-二胺，4-(2,3-二氫-吲哚-1-基)-6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-[1,3,5]三-2-基胺，6-[5-(2-氯-苯基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺， 6-[5-(3-甲氧基-苯基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺，6-[5-(2-甲氧基-苯基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺，6-[5-(4-甲氧基-苯基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺，N-甲基-N-苯基-6-(5-鄰甲苯基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺，N-甲基-N-苯基-6-5-間甲苯基-[12,4]二唑-3-基)-[1,3,5]三-2,4-二胺，N-甲基-N-苯基-6-(5-對甲苯基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺，6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-N-異丙基-N-苯基-[1,3,5]三-2,4-二胺，6-(5-苄基-[1,2,4]二唑-3-基)-N-甲基-N-苯基-[1,3,5]三-2,4-二胺，N-(3-氯-苯基)-6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺，N-(3-氯-苯基)-6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺，6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-N-甲基-N-(2,3-二氟苯基)-[1,3,5]三-2,4-二胺，6-[5-(3-氯-苯基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺， 6-[5-(4-氯-苯基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺，6-(5-呋喃-3-基-[1,2,4]二唑-3-基)-N-甲基-N-苯基-[1,3,5]三-2,4-二胺，N-乙基-N-苯基-6-(5-噻唑-2-基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺，N-苯基-6-(吡啶-2-基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺，N-苯基-6-[5-(1H-吡唑-3-基)-[1,2,4]二唑-3-基]-[1,3,5]三-2,4-二胺，N-苯基-6-{5-[6-(2,2,2-三氟-乙氧基)-吡啶-3-基]-[1,2,4]二唑-3-基}-[1,3,5]三-2,4-二胺，N-甲基-N-苯基-6-{5-[3-(2,2,2-三氟-乙氧基)-吡啶-2-基]-[1,2,4]二唑-3-基}-[1,3,5]三-2,4-二胺，6-[5-(3-溴吡啶-2-基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺，N-甲基-6-[5-(5-甲基-異唑-3-基)-[1,2,4]二唑-3-基]-N-苯基-[1,3,5]三-2,4-二胺，N-甲基-6-(5-嗎啉-4-基-[1,2,4]二唑-3-基)-N-苯基-[1,3,5]三-2,4-二胺，N-甲基-N-苯基-6-(5-六氫吡啶-1-基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺，6-[5-(6-甲氧基-吡啶-3-基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺， 6-[5-(6-甲氧基-吡啶-3-基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺，6-[5-(4,5-二甲基-呋喃-2-基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺，6-[5-(3-胺基-吡啶-2-基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺，6-[5-(3-胺基-吡啶-2-基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺，N-甲基-N-苯基-6-(5-噻唑-5-基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺，6-[5-(2-胺基-吡啶-3-基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺，6-[5-(5-胺基-吡啶-3-基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺，6-[5-(6-胺基-吡啶-3-基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺，N-甲基-N-苯基-6-[5-(四氫-吡喃-2-基)-[1,2,4]二唑-3-基]-[1,3,5]三-2,4-二胺，N-甲基-N-苯基-6-[5-(四氫-吡喃-4-基)-[1,2,4]二唑-3-基]-[1,3,5]三-2,4-二胺，N-甲基-6-[5-(5-甲基-1H-吡唑-3-基)-[1,2,4]二唑-3-基]-N-苯基-[1,3,5]三-2,4-二胺，6-[5-(1H-咪唑-4-基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺， N-甲基-N-苯基-6-[5-(1H-吡咯-2-基)-[1,2,4]二唑-3-基]-[1,3,5]三-2,4-二胺，N-甲基-N-苯基-6-[5-(2H-吡唑-3-基)-[1,2,4]二唑-3-基]-[1,3,5]三-2,4-二胺，N-甲基-6-[5-(5-甲基-噻吩-2-基)-[1,2,4]二唑-3-基]-N-苯基-[1,3,5]三-2,4-二胺，6-[5-(2,3-二氫-苯并呋喃-7-基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺，6-(5-苯并呋喃-2-基-[1,2,4]二唑-3-基)-N-甲基-N-苯基-[1,3,5]三-2,4-二胺，6-(5-咪唑-2-基-[1,2,4]二唑-3-基)-N-甲基-N-苯基-[1,3,5]三-2,4-二胺，N-甲基-N-苯基-6-[5-(四氫-呋喃-2-基)-[1,2,4]二唑-3-基]-[1,3,5]三-2,4-二胺，N-甲基-N-苯基-6-{5-[6-(2,2,2-三氟乙氧基)-吡啶-3-基]-[1,2,4]二唑-3-基}-[1,3,5]三-2,4-二胺，6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-N-苯基-N-(2,2,2-三氟-乙基)-[1,3,5]三-2,4-二胺，N-(2-二甲基胺基-乙基)-6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-N-苯基-[1,3,5]三-2,4-二胺，2-{[4-胺基-6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-[1,3,5]三-2-基]-苯基-胺基}-乙醇，3-[4-胺基-6-(甲基-苯基-胺基)-[1,3,5]三-2-基]-[1,2,4]二唑-5-甲酸苄基醯胺， 3-[4-胺基-6-(甲基-苯基-胺基)-[1,3,5]三-2-基]-[1,2,4]二唑-5-甲酸環戊基醯胺，3-[4-胺基-6-(甲基-苯基-胺基)-[1,3,5]三-2-基]-[1,2,4]二唑-5-甲酸乙酯，6-[5-(3-甲氧基-噻吩-2-基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺，5-{3-[4-胺基-6-(甲基-苯基-胺基)-[1,3,5]三-2-基]-[1,2,4]二唑-5-基}-噻吩-2-甲酸甲基醯胺，6-[5-(2-甲氧基-吡啶-3-基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺，6-[5-(2,4-二甲氧基-苯基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺，5-{3-[4-胺基-6-(甲基-苯基-胺基)-[1,3,5]三-2-基]-[1,2,4]二唑-5-基}-吡啶-2-甲腈，(5-{3-[4-胺基-6-(甲基-苯基-胺基)-[1,3,5]三-2-基]-[1,2,4]二唑-5-基}-噻吩-2-基)-嗎啉-4-基-甲酮，2-{3-[4-胺基-6-(甲基-苯基-胺基)-[1,3,5]三-2-基]-[1,2,4]二唑-5-基}-苯甲腈，6-[5-(2-氟-6-甲氧基-苯基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺，5-{3-[4-胺基-6-(甲基-苯基-胺基)-[1,3,5]三-2-基]-[1,2,4]二唑-5-基}-噻吩-2-甲酸甲酯，N-(3-氯-苯基)-6-[5-(3-甲氧基-苯基)-[1,2,4]二唑-3-基]-N-甲基-[1,3,5]三-2,4-二胺， N-(3-氯-苯基)-6-[5-(2-氯-苯基)-[1,2,4]二唑-3-基]-N-甲基-[1,3,5]三-2,4-二胺，N-(3-氟-苯基)-6-[5-(3-甲氧基-苯基)-[1,2,4]二唑-3-基]-N-甲基-[1,3,5]三-2,4-二胺，6-[5-(2-氯-苯基)-[1,2,4]二唑-3-基]-N-(3-氟-苯基)-N-甲基-[1,3,5]三-2,4-二胺，N-(3-氟-苯基)-N-甲基-6-[5-(5-甲基-呋喃-2-基)-[1,2,4]二唑-3-基]-[1,3,5]三-2,4-二胺，N-(2-氟-苯基)-6-[5-(3-甲氧基-苯基)-[1,2,4]二唑-3-基]-N-甲基-[1,3,5]三-2,4-二胺，N-(2-氟-苯基)-6-[5-(2-甲氧基-苯基)-[1,2,4]二唑-3-基]-N-甲基-[1,3,5]三-2,4-二胺，N-(2-氟-苯基)-N-甲基-6-(5-噻吩-2-基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺，N-(2-氟-苯基)-N-甲基-6-[5-(5-甲基-呋喃-2-基)-[1,2,4]二唑-3-基]-[1,3,5]三-2,4-二胺，6-[5-(2-甲氧基-苯基)-[1,2,4]二唑-3-基]-N-甲基-N-間甲苯基-[1,3,5]三-2,4-二胺，N-甲基-6-(5-噻吩-2-基-[1,2,4]二唑-3-基)-N-間甲苯基-[1,3,5]三-2,4-二胺，N-乙基-6-[5-(3-甲氧基-苯基)-[1,2,4]二唑-3-基]-N-苯基-[1,3,5]三-2,4-二胺，N-乙基-6-[5-(2-甲氧基-苯基)-[1,2,4]二唑-3-基]-N-苯基-[1,3,5]三-2,4-二胺， N-乙基-N-苯基-6-(5-噻吩-2-基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺，N-乙基-6-[5-(5-甲基-呋喃-2-基)-[1,2,4]二唑-3-基]-N-苯基-[1,3,5]三-2,4-二胺，N-(3-氟-苯基)-6-[5-(2-甲氧基-苯基)-[1,2,4]二唑-3-基]-N-甲基-[1,3,5]三-2,4-二胺，N-(3-氟-苯基)-N-甲基-6-(5-噻吩-2-基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺，N-(3-氯-苯基)-6-[5-(2-甲氧基-苯基)-[1,2,4]二唑-3-基]-N-甲基-[1,3,5]三-2,4-二胺，N-(3-氯苯基)-N-甲基-6-(5-噻吩-2-基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺，N-(3-氯-苯基)-N-甲基-6-[5-(5-甲基-呋喃-2-基)-[1,2,4]二唑-3-基]-[1,3,5]三-2,4-二胺，N-(5-氯-2-氟-苯基)-6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-N-甲基-[1,3,5]三-2,4-二胺，N-(2,5-二氟-苯基)-6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-N-甲基-[1,3,5]三-2,4-二胺，N-(2-氟-5-甲基-苯基)-6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-N-甲基-[1,3,5]三-2,4-二胺，N-(3-氯-2-氟-苯基)-6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-N-甲基-[1,3,5]三-2,4-二胺，N-(2-氟-3-甲基-苯基)-6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-N-甲基-[1,3,5]三-2,4-二胺， N-(5-氯-2-氟-苯基)-6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺，N-(2,5-二氟-苯基)-6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺，N-(2-氟-3-甲基-苯基)-6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺，N-(3-氯-2-氟-苯基)-6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺，N-(2-氟-3-甲基-苯基)-6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺，N-(2,3-二氟-苯基)-6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺，N-甲基-N-苯基-6-(5-吡啶-4-基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺，N-甲基-N-苯基-6-(5-吡啶-3-基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺，4-(3,4-二氫喹啉-1-基)-6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-[1,3,5]三-2-胺，N-(3-氟苯基)-6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺，6-[5-(5-甲氧基-吡啶-2-基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺，6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-N-(2-甲氧基-乙基)-N-苯基-[1,3,5]三-2,4-二胺， N-甲基-N-苯基-6-(5-嘧啶-4-基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺，N-環丙基甲基-6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-N-苯基-[1,3,5]三-2,4-二胺，6-[5-(4-氟-苯基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺，6-[5-(3-氟-苯基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺，6-[5-(2-氟-苯基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺，N-甲基-N-苯基-6-(5-噻唑-2-基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺，N-甲基-6-[5-(3-甲基-噻吩-2-基)-[1,2,4]二唑-3-基]-N-苯基-[1,3,5]三-2,4-二胺，N-甲基-6-(5-唑-5-基-[1,2,4]二唑-3-基)-N-苯基-[1,3,5]三-2,4-二胺，N-甲基-6-(5-唑-2-基-[1,2,4]二唑-3-基)-N-苯基-[1,3,5]三-2,4-二胺，N-甲基-6-[5-(5-甲基-噻吩-2-基)-[1,2,4]二唑-3-基]-N-苯基-[1,3,5]三-2,4-二胺，N-苯基-6-(5-噻唑-2-基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺，N-甲基-N-苯基-6-(5-吡咯啶-1-基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺， 6-[5-(3-甲氧基-2-吡啶基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[6-(三氟甲氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；6-{5-[6-(環丙基甲氧基)吡啶-3-基]-1,2,4-二唑-3-基}-2-N-(2-氟苯基)-2-N-甲基-1,3,5-三-2,4-二胺；6-{5-[6-(環丙基甲氧基)吡啶-3-基]-1,2,4-二唑-3-基}-2-N-(3-氟苯基)-2-N-甲基-1,3,5-三-2,4-二胺；6-{5-[6-(環丙基甲氧基)吡啶-3-基]-1,2,4-二唑-3-基}-2-N-(3-氟苯基)-1,3,5-三-2,4-二胺；6-(5-{[3-(4-氟苯氧基)氮雜環丁-1-基]羰基}-1,2,4-二唑-3-基)-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；6-{5-[6-(環丙基甲氧基)吡啶-3-基]-1,2,4-二唑-3-基}-2-N-(2-氟苯基)-1,3,5-三-2,4-二胺；6-{5-[6-(環丙基甲氧基)吡啶-3-基]-1,2,4-二唑-3-基}-2-N-(2,3-二氟苯基)-1,3,5-三-2,4-二胺；6-{5-[6-(環丙基甲氧基)吡啶-3-基]-1,2,4-二唑-3-基}-2-N-(2,3-二氟苯基)-2-N-甲基-1,3,5-三-2,4-二胺；2-N-甲基-6-{5-[6-(氧雜環戊烷-3-基氧基)吡啶-3-基]-1,2,4-二唑-3-基}-2-N-苯基-1,3,5-三-2,4-二胺；6-{5-[2-氯-6-(三氟甲基)吡啶-3-基]-1,2,4-二唑-3-基}-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；6-(5-{6-[(2-甲氧基乙氧基)甲基]吡啶-3-基}-1,2,4-二唑-3-基)-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺； 2-N-甲基-6-(5-{6-[(氧雜環戊烷-3-基氧基)甲基]吡啶-3-基}-1,2,4-二唑-3-基)-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[(1R,5S)-8-(3,3,3-三氟丙基)-8-氮雜雙環[3.2.1]辛烷-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；6-{5-[6-(環丙基甲氧基)吡啶-3-基]-1,2,4-二唑-3-基}-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-乙基-2-N-苯基-6-{5-[6-(2,2,2-三氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；6-[5-(6-乙氧基吡啶-3-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[6-(丙烷-2-基氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-苯基-6-{5-[6-(2,2,2-三氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-2-N-(2,2,2-三氟乙基)-1,3,5-三-2,4-二胺；2-N-苯基-6-{5-[6-(2,2,2-三氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-4-N-(2,2,2-三氟乙基)-1,3,5-三-2,4-二胺；2-N-甲基-6-[5-(3-甲基吡啶-2-基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺；6-[5-(5-氟吡啶-2-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；6-[5-(4,6-二甲基吡啶-3-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[6-(2,2,2-三氟乙氧基)吡啶-2-基]- 1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-(2-甲氧基乙基)-2-N-苯基-6-{5-[6-(2,2,2-三氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-(2-甲氧基乙基)-4-N-苯基-6-{5-[6-(2,2,2-三氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；6-[5-(6-氟吡啶-3-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；1-[4-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)六氫吡啶-1-基]-2,2,2-三氟乙烷-1-酮；6-[5-(1-甲烷磺醯基六氫吡啶-4-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；1-[4-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)六氫吡啶-1-基]-2-甲基丙烷-1-酮；1-[4-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)六氫吡啶-1-基]乙烷-1-酮；2-N-甲基-2-N-苯基-6-{5-[1-(3,3,3-三氟丙基)六氫吡啶-4-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；1-[4-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)六氫吡啶-1-基]-3,3,3-三氟丙烷-1-酮；6-{5-[4-(甲氧基甲基)六氫吡啶-1-基]-1,2,4-二唑-3-基}-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-6-{5-[4-(苯氧基甲基)六氫吡啶-1-基]-1,2,4-二唑-3-基}-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{4-[(2,2,2-三氟乙氧基)甲基]六氫 吡啶-1-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[1-(丙烷-1-磺醯基)六氫吡啶-4-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{1-[(2,2,2-三氟乙烷)磺醯基]六氫吡啶-4-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；6-{5-[1-(乙烷磺醯基)六氫吡啶-4-基]-1,2,4-二唑-3-基}-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[1-(丙烷-2-磺醯基)六氫吡啶-4-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；6-{5-[1-(苯磺醯基)六氫吡啶-4-基]-1,2,4-二唑-3-基}-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；6-[5-(1-苄基六氫吡啶-4-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-苯基-6-(5-{4-[(2,2,2-三氟乙氧基)甲基]六氫吡啶-1-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-[5-(4-{[(2,2,2-三氟乙基)硫基]甲基}六氫吡啶-1-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{4-[(苯基硫基)甲基]六氫吡啶-1-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{4-[(丙烷-2-基硫基)甲基]六氫吡啶-1-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-[5-(4-{[(2,2,2-三氟乙烷)磺醯基]甲基}六氫吡啶-1-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺； 6-(5-{4-[(苯磺醯基)甲基]六氫吡啶-1-基}-1,2,4-二唑-3-基)-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{4-[(丙烷-2-亞磺醯基)甲基]六氫吡啶-1-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{4-[(丙烷-2-磺醯基)甲基]六氫吡啶-1-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；3-[(4-胺基-6-{5-[6-(2,2,2-三氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2-基)胺基]苯甲酸甲酯；6-[5-(2-乙氧基苯基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-(3-甲基苯基)-1,3,5-三-2,4-二胺；6-[5-(4-甲氧基苯基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-(3-甲基苯基)-1,3,5-三-2,4-二胺；6-[5-(2-氟-6-甲氧基苯基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-(3-甲基苯基)-1,3,5-三-2,4-二胺；6-[5-(5-氟-2-甲氧基苯基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-(3-甲基苯基)-1,3,5-三-2,4-二胺；6-[5-(4-氟-2-甲氧基苯基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-(3-甲基苯基)-1,3,5-三-2,4-二胺；6-[5-(2,4-二甲氧基苯基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-(3-甲基苯基)-1,3,5-三-2,4-二胺；2-N-(3-甲烷磺醯基苯基)-6-{5-[6-(2,2,2-三氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-乙基-6-[5-(4-甲氧基苯基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺； 2-N-乙基-6-[5-(2-氟-6-甲氧基苯基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺；6-[5-(2-氯苯基)-1,2,4-二唑-3-基]-2-N-乙基-2-N-苯基-1,3,5-三-2,4-二胺；6-[5-(2-氯-4-氟苯基)-1,2,4-二唑-3-基]-2-N-乙基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-(3-甲基苯基)-6-{5-[2-(三氟甲氧基)苯基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；6-[5-(2-氯苯基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-(3-甲基苯基)-1,3,5-三-2,4-二胺；6-[5-(2-乙氧基苯基)-1,2,4-二唑-3-基]-2-N-乙基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-乙基-6-[5-(5-氟-2-甲氧基苯基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺；2-N-乙基-2-N-苯基-6-{5-[2-(三氟甲氧基)苯基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；6-{5-[(2-甲氧基苯基)甲基]-1,2,4-二唑-3-基}-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[1-(丙烷-1-磺醯基)吡咯啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[1-(丙烷-2-磺醯基)吡咯啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{1-[(2,2,2-三氟乙烷)磺醯基]吡咯啶-3-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺； 6-{5-[1-(苯磺醯基)吡咯啶-3-基]-1,2,4-二唑-3-基}-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[1-(3,3,3-三氟丙基)吡咯啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[1-(4,4,4-三氟丁烷-2-基)吡咯啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-[5-(6-{[(1,1,1-三氟丙烷-2-基)氧基]甲基}吡啶-3-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺；6-[5-(1-苄基吡咯啶-3-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；6-(5-{6-[(環丙基甲氧基)甲基]吡啶-3-基}-1,2,4-二唑-3-基)-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{6-[1-(2,2,2-三氟乙氧基)乙基]吡啶-3-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-苯基-6-[5-(6-{[(1,1,1-三氟丙烷-2-基)氧基]甲基}吡啶-3-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺；6-(5-{6-[(環丙基甲氧基)甲基]吡啶-3-基}-1,2,4-二唑-3-基)-2-N-苯基-1,3,5-三-2,4-二胺；2-N-苯基-6-(5-{6-[1-(2,2,2-三氟乙氧基)乙基]吡啶-3-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；6-{5-[6-(環丁氧基甲基)吡啶-3-基]-1,2,4-二唑-3-基}-2-N-苯基-1,3,5-三-2,4-二胺；6-(5-{4-[(環丙基甲氧基)甲基]六氫吡啶-1-基}-1,2,4-二 唑-3-基)-2-N-苯基-1,3,5-三-2,4-二胺；6-{5-[4-(環丁氧基甲基)六氫吡啶-1-基]-1,2,4-二唑-3-基}-2-N-苯基-1,3,5-三-2,4-二胺；6-(5-{4-[(環丙基甲氧基)甲基]六氫吡啶-1-基}-1,2,4-二唑-3-基)-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；6-{5-[4-(環丁氧基甲基)六氫吡啶-1-基]-1,2,4-二唑-3-基}-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；3-[4-胺基-6-(苯基胺基)-1,3,5-三-2-基]-N-環戊基-1,2,4-二唑-5-甲醯胺；3-{4-胺基-6-[(3-氟苯基)胺基]-1,3,5-三-2-基}-N-環戊基-1,2,4-二唑-5-甲醯胺；2-N-苯基-6-{5-[(吡咯啶-1-基)羰基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-苯基-6-[5-(六氫吡啶-1-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺；3-[4-胺基-6-(苯基胺基)-1,3,5-三-2-基]-1,2,4-二唑-5-甲醯胺；3-{4-胺基-6-[(3-氟苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-甲醯胺；3-{4-胺基-6-[(3-氟苯基)胺基]-1,3,5-三-2-基}-N-環丁基-1,2,4-二唑-5-甲醯胺；3-{4-胺基-6-[(3-氟苯基)胺基]-1,3,5-三-2-基}-N-(2,3-二氫-1H-茚-2-基)-1,2,4-二唑-5-甲醯胺；3-{4-胺基-6-[(3-氟苯基)胺基]-1,3,5-三-2-基}-N-(2,3-二 氫-1H-茚-1-基)-1,2,4-二唑-5-甲醯胺；2-N-(3-氟苯基)-6-{5-[(吡咯啶-1-基)羰基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；3-[4-胺基-6-(苯基胺基)-1,3,5-三-2-基]-N-環丁基-1,2,4-二唑-5-甲醯胺；3-[4-胺基-6-(苯基胺基)-1,3,5-三-2-基]-N-(2,3-二氫-1H-茚-2-基)-1,2,4-二唑-5-甲醯胺；6-{5-[(2,3-二氫-1H-異吲哚-2-基)羰基]-1,2,4-二唑-3-基}-2-N-苯基-1,3,5-三-2,4-二胺；6-[5-(環戊基胺基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺；2-N-(3-氟苯基)-6-{5-[(嗎啉-4-基)羰基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；3-{4-胺基-6-[(3-氟苯基)胺基]-1,3,5-三-2-基}-N-[(3R)-氧雜環戊烷-3-基]-1,2,4-二唑-5-甲醯胺；3-{4-胺基-6-[(3-氟苯基)胺基]-1,3,5-三-2-基}-N-(丙烷-2-基)-1,2,4-二唑-5-甲醯胺；6-[5-(環戊基胺基)-1,2,4-二唑-3-基]-2-N-(3-氟苯基)-1,3,5-三-2,4-二胺；2-N-(3-氟苯基)-6-[5-(六氫吡啶-1-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺；2-N-(3-氟苯基)-6-[5-(4-甲氧基六氫吡啶-1-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺；6-[5-(4-甲氧基六氫吡啶-1-基)-1,2,4-二唑-3-基]-2-N-苯 基-1,3,5-三-2,4-二胺；6-[5-(2-甲氧基吡啶-4-基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺；2-N-(3-氟苯基)-6-[5-(3-氟吡啶-2-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺；2-N-(4-氟苯基)-6-[5-(1,3-噻唑-2-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺；6-[5-(環己基胺基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺；6-[5-(4-甲基六氫吡啶-1-基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺；3-[4-胺基-6-(苯基胺基)-1,3,5-三-2-基]-N-(2,3-二氫-1H-茚-1-基)-1,2,4-二唑-5-甲醯胺；2-N-(3-氟苯基)-6-[5-(4-甲基六氫吡啶-1-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺；6-(5-{2-氧雜-7-氮雜螺[3.5]壬烷-7-基}-1,2,4-二唑-3-基)-2-N-苯基-1,3,5-三-2,4-二胺；6-[5-(2-甲氧基苯基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺；2-N-(3-氟苯基)-6-[5-(2-甲氧基苯基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺；6-[5-(5-胺基吡啶-2-基)-1,2,4-二唑-3-基]-2-N-(3-氟苯基)-1,3,5-三-2,4-二胺；3-{4-胺基-6-[(3-氟苯基)胺基]-1,3,5-三-2-基}-N-(氧雜環 丁-3-基)-1,2,4-二唑-5-甲醯胺；6-[5-(4-溴-1H-吡唑-3-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-6-[5-(1-甲基-1H-吡唑-3-基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-6-[5-(1-甲基-1H-吡唑-5-基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺；6-[5-(4-氯-1H-吡唑-3-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[5-(三氟甲基)-1H-吡唑-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[1-(2,2,2-三氟乙基)-1H-吡唑-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[1-(2,2,2-三氟乙基)-1H-吡唑-5-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-N-(6-甲氧基吡啶-3-基)-1,2,4-二唑-5-甲醯胺；3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-N-{[6-(2,2,2-三氟乙氧基)吡啶-3-基]甲基}-1,2,4-二唑-5-甲醯胺；3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-N-[(6-甲氧基吡啶-3-基)甲基]-1,2,4-二唑-5-甲醯胺；2-N-甲基-6-[5-(3-苯氧基環丁基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺； 2-N-甲基-2-N-苯基-6-(5-{[4-(2,2,2-三氟乙氧基)六氫吡啶-1-基]羰基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-N-[6-(三氟甲基)吡啶-3-基]-1,2,4-二唑-5-甲醯胺；2-N-(3-氯-2-氟苯基)-6-[5-(吡啶-2-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺；2-N-(3-氯苯基)-6-[5-(吡啶-2-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺；6-(5-環己基-1,2,4-二唑-3-基)-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺2-N-甲基-2-N-苯基-6-{5-[6-(三氟甲基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-6-[5-(2-甲基吡啶-3-基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺；2-N-苯基-6-[5-(1,3-噻唑-2-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺；2-N-甲基-6-{5-[6-(嗎啉-4-基)吡啶-2-基]-1,2,4-二唑-3-基}-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-6-[5-(6-甲基吡啶-2-基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺；2-N-(3-氯苯基)-6-[5-(3-氟吡啶-2-基)-1,2,4-二唑-3-基]-2-N-甲基-1,3,5-三-2,4-二胺；6-[5-(3-氯吡啶-2-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺； N-[1-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)六氫吡啶-4-基]-2,2,2-三氟乙醯胺；6-[5-(2-氯吡啶-3-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[(吡咯啶-1-基)羰基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[(六氫吡啶-1-基)羰基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-[5-(嘧啶-2-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺；5-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-甲酸甲酯；5-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)-N-(2,2,2-三氟乙基)吡啶-2-甲醯胺；6-[5-(3,5-二氟吡啶-2-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；6-[5-(3,5-二甲氧基吡啶-2-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-6-[5-(6-甲基吡啶-3-基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺；5-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-甲醯胺；6-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-3-甲酸甲酯； 5-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)-N-環丁基吡啶-2-甲醯胺；5-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)-N-環丙基吡啶-2-甲醯胺；5-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)-N-(環丙基甲基)吡啶-2-甲醯胺；5-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-甲酸丙烷-2-基酯；5-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-甲酸環戊基酯；2-N-甲基-2-N-苯基-6-(5-{6-[(2,2,2-三氟乙氧基)甲基]吡啶-3-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；6-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)-N-(2,2,2-三氟乙基)吡啶-3-甲醯胺；2-N-甲基-2-N-苯基-6-{5-[6-(吡咯啶-1-基甲基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{5-[1-(吡咯啶-1-基)乙基]吡啶-2-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；[5-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-基]甲醇；1-[6-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-3-基]乙烷-1-酮；5-{3-[4-胺基-6-(苯基胺基)-1,3,5-三-2-基]-1,2,4-二唑-5-基}吡啶-2-甲酸甲酯； 2-N-甲基-2-N-苯基-6-(5-{6-[(2,2,2-三氟乙氧基)甲基]吡啶-3-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-甲基-6-{5-[6-(嗎啉-4-基甲基)吡啶-3-基]-1,2,4-二唑-3-基}-2-N-苯基-1,3,5-三-2,4-二胺；6-(5-{6-[(環丁基胺基)甲基]吡啶-3-基}-1,2,4-二唑-3-基)-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{2-[(2,2,2-三氟乙氧基)甲基]吡啶-3-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{3-[(2,2,2-三氟乙氧基)甲基]吡啶-2-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-苯基-6-(5-{6-[(2,2,2-三氟乙氧基)甲基]吡啶-3-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；1-[5-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-基]乙烷-1-酮；6-[5-(4-乙烯基苯基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；6-[5-(1,3-二氫-2-苯并呋喃-5-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[1-(丙烷-1-磺醯基)氮雜環丁-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[1-(丙烷-2-磺醯基)氮雜環丁-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；6-{5-[1-(乙烷磺醯基)氮雜環丁-3-基]-1,2,4-二唑-3-基}-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺； 2-N-甲基-2-N-苯基-6-(5-{1-[(2,2,2-三氟乙烷)磺醯基]氮雜環丁-3-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；5-(3-{4-胺基-6-[(2-甲氧基乙基)(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-甲酸甲酯；2-N-(2-甲氧基乙基)-2-N-苯基-6-(5-{6-[(2,2,2-三氟乙氧基)甲基]吡啶-3-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；6-{5-[1-(苯磺醯基)氮雜環丁-3-基]-1,2,4-二唑-3-基}-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[1-(2,2,2-三氟乙基)氮雜環丁-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[6-(3,3,3-三氟丙基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-[5-(6-{[(2,2,2-三氟乙基)硫基]甲基}吡啶-3-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-[5-(6-{[(2,2,2-三氟乙烷)亞磺醯基]甲基}吡啶-3-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{6-[(2,2,2-三氟乙基)硫基]吡啶-3-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-苯基-6-{5-[6-(3,3,3-三氟丙基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{6-[(2,2,2-三氟乙烷)亞磺醯基]吡啶-3-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺； 2-N-甲基-2-N-苯基-6-[5-(6-{[(2,2,2-三氟乙烷)磺醯基]甲基}吡啶-3-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{[4-(3,3,3-三氟亞丙基)六氫吡啶-1-基]羰基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{5H,6H,7H-吡咯并[3,4-d]嘧啶-6-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[4-(3,3,3-三氟亞丙基)六氫吡啶-1-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-(5-氯-2-氟苯基)-6-[5-(吡啶-2-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺；6-{5-[5-(環丙基甲氧基)吡啶-2-基]-1,2,4-二唑-3-基}-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{6-[(2,2,2-三氟乙基)胺基]吡啶-3-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-甲基-6-(5-{6-[(氧雜環戊烷-3-基)胺基]吡啶-3-基}-1,2,4-二唑-3-基)-2-N-苯基-1,3,5-三-2,4-二胺；6-{5-[6-(2-甲氧基乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-{[5-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-基]氧基}乙腈；6-[5-(6-環丁氧基吡啶-3-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{6-[(丙烷-2-基)胺基]吡啶-3-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺； 6-(5-{6-[(環丙基甲基)胺基]吡啶-3-基}-1,2,4-二唑-3-基)-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；5-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)-1,2-二氫吡啶-2-酮；2-N-甲基-2-N-苯基-6-{5-[4-(2,2,2-三氟乙氧基)六氫吡啶-1-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-6-[5-(4-苯氧基六氫吡啶-1-基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{[(1r,4r)-4-(2,2,2-三氟乙氧基)環己基]胺基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；6-{5-[4-(苄氧基)六氫吡啶-1-基]-1,2,4-二唑-3-基}-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；6-[5-(2,3-二氫-1-苯并呋喃-5-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[5-(2,2,2-三氟乙氧基)吡啶-2-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-6-[5-(4-甲基-1,3-噻唑-2-基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-6-[5-(5-甲基-1,3-噻唑-2-基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺；2-N-(2,5-二氟苯基)-6-{5-[6-(2,2,2-三氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-6-{5-[(4-甲基六氫吡-1-基)羰基]-1,2,4-二唑-3-基}-2-N-苯基-1,3,5-三-2,4-二胺； 2-N-甲基-2-N-苯基-6-{5-[4-(三氟甲基)-1,3-噻唑-2-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；6-[5-(3-氟吡啶-2-基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺；1-[4-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)六氫吡-1-基]-2,2,2-三氟乙烷-1-酮；2-N-甲基-2-N-苯基-6-{5-[3-(三氟甲基)吡啶-2-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{5-[(2,2,2-三氟乙氧基)甲基]吡啶-2-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-苯基-6-(5-{5-[(2,2,2-三氟乙氧基)甲基]吡啶-2-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{4-[(2,2,2-三氟乙氧基)甲基]苯基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-[5-(4-苯基六氫吡啶-1-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺；(2R)-2-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡咯啶-1-甲酸第三丁基酯；2-N-甲基-2-N-苯基-6-{5-[4-(吡啶-2-基氧基)六氫吡啶-1-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；1-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)-4-苯基六氫吡啶-4-醇；6-{5-[6-(環己基氧基)吡啶-3-基]-1,2,4-二唑-3-基}-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺； 2-N-甲基-2-N-苯基-6-(5-{6-[(1,1,1-三氟丙烷-2-基)氧基]吡啶-3-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{5-[1-(2,2,2-三氟乙氧基)乙基]吡啶-2-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[6-(3,3,3-三氟丙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；6-[5-(4-甲氧基-4-苯基六氫吡啶-1-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-6-{5-[6-(環氧乙烷-4-基氧基)吡啶-3-基]-1,2,4-二唑-3-基}-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{4-[(2,2,2-三氟乙基)硫基]六氫吡啶-1-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-苯基-6-{5-[6-(3,3,3-三氟丙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-6-(5-{6-[(1-甲基吡咯啶-3-基)氧基]吡啶-3-基}-1,2,4-二唑-3-基)-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{4-[(2,2,2-三氟乙烷)磺醯基]六氫吡啶-1-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{6-[2-(2,2,2-三氟乙氧基)乙氧基]吡啶-3-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[4-(丙烷-2-基硫基)六氫吡啶-1-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[4-(丙烷-2-亞磺醯基)六氫吡啶-1-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺； 2-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)-N-(環丙基甲基)吡啶-3-甲醯胺；3-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)-N-(環丙基甲基)吡啶-2-甲醯胺；2-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)-N-環丁基吡啶-3-甲醯胺；6-{5-[6-(2,2-二氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；3-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)-N-環丙基吡啶-2-甲醯胺；3-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)-N-環丁基吡啶-2-甲醯胺；3-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)-N-(2,2,2-三氟乙基)吡啶-2-甲醯胺；2-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)-N-環丙基吡啶-3-甲醯胺；2-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-3-甲酸環丙基甲基酯；3-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-甲酸環丙基甲基酯；2-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-3-甲酸環戊基酯；3-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-甲酸環戊基酯； 2-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)-N-(2,2,2-三氟乙基)吡啶-3-甲醯胺；3-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)氮雜環丁烷-1-甲酸第三丁基酯；6-[5-(1-苄基氮雜環丁-3-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；1-[3-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)氮雜環丁-1-基]乙烷-1-酮；2-N-甲基-2-N-苯基-6-{5-[1-(3,3,3-三氟丙基)氮雜環丁-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；6-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)-3-苄基-3-氮雜雙環[3.1.0]己烷-2,4-二酮；2-N-甲基-2-N-苯基-6-{5-[6-[(2,2,2-三氟乙氧基)甲基]-3-氮雜雙環[3.1.0]己烷-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；4-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)-N,N-二甲基六氫吡-1-苯磺醯胺；2-N-甲基-2-N-苯基-6-(5-{4-[(2,2,2-三氟乙烷)磺醯基]六氫吡-1-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-苯基-6-{5-[6-[(2,2,2-三氟乙氧基)甲基]-3-氮雜雙環[3.1.0]己烷-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-6-{5-[6-(苯氧基甲基)-3-氮雜雙環[3.1.0]己烷-3-基]-1,2,4-二唑-3-基}-2-N-苯基-1,3,5-三-2,4-二胺； 6-{5-[6-(苯氧基甲基)-3-氮雜雙環[3.1.0]己烷-3-基]-1,2,4-二唑-3-基}-2-N-苯基-1,3,5-三-2,4-二胺；6-{5-[6-[(環丙基甲氧基)甲基]-3-氮雜雙環[3.1.0]己烷-3-基]-1,2,4-二唑-3-基}-2-N-苯基-1,3,5-三-2,4-二胺；2-N-苯基-6-{5-[6-[(3,3,3-三氟丙氧基)甲基]-3-氮雜雙環[3.1.0]己烷-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；6-{5-[6-[(環丙基甲氧基)甲基]-3-氮雜雙環[3.1.0]己烷-3-基]-1,2,4-二唑-3-基}-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[6-[(3,3,3-三氟丙氧基)甲基]-3-氮雜雙環[3.1.0]己烷-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[6-[(丙烷-2-基氧基)甲基]-3-氮雜雙環[3.1.0]己烷-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-苯基-6-{5-[(R,5S,6S)-6-[(丙烷-2-基氧基)甲基]-3-氮雜雙環[3.1.0]己烷-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；6-{5-[6-[(環戊基氧基)甲基]-3-氮雜雙環[3.1.0]己烷-3-基]-1,2,4-二唑-3-基}-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；6-{5-[6-[(環戊基氧基)甲基]-3-氮雜雙環[3.1.0]己烷-3-基]-1,2,4-二唑-3-基}-2-N-苯基-1,3,5-三-2,4-二胺； 2-N-甲基-2-N-苯基-6-{5-[(4-{[(2,2,2-三氟乙基)硫基]甲基}六氫吡啶-1-基)羰基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{[-6-[(2,2,2-三氟乙氧基)甲基]-3-氮雜雙環[3.1.0]己烷-3-基]羰基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{[-6-[(3,3,3-三氟丙氧基)甲基]-3-氮雜雙環[3.1.0]己烷-3-基]羰基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；6-(5-{[-6-[(環丙基甲氧基)甲基]-3-氮雜雙環[3.1.0]己烷-3-基]羰基}-1,2,4-二唑-3-基)-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；6-(5-{[-6-[(環戊基氧基)甲基]-3-氮雜雙環[3.1.0]己烷-3-基]羰基}-1,2,4-二唑-3-基)-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-6-(5-{[-6-(苯氧基甲基)-3-氮雜雙環[3.1.0]己烷-3-基]羰基}-1,2,4-二唑-3-基)-2-N-苯基-1,3,5-三-2,4-二胺；2-N-(3-氟苯基)-2-N-甲基-6-{5-[6-(2,2,2-三氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-(2-氟苯基)-2-N-甲基-6-{5-[6-(2,2,2-三氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-(3-氯苯基)-2-N-甲基-6-{5-[6-(2,2,2-三氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺； 2-N-(4-氟苯基)-2-N-甲基-6-{5-[6-(2,2,2-三氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-(2,3-二氟苯基)-2-N-甲基-6-{5-[6-(2,2,2-三氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-2-N-(3-甲基苯基)-6-{5-[6-(2,2,2-三氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-(3-氯-4-氟苯基)-6-{5-[6-(2,2,2-三氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-(3-氯-4-氟苯基)-2-N-甲基-6-{5-[6-(2,2,2-三氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；6-[5-(6-甲氧基吡啶-2-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-(3,4-二氟苯基)-6-{5-[6-(2,2,2-三氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-(2,4-二氟苯基)-2-N-甲基-6-{5-[6-(2,2,2-三氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；6-[5-(6-氯吡啶-3-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；6-[5-(2-乙氧基吡啶-3-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[5-(三氟甲基)吡啶-2-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；6-[5-(4-甲烷磺醯基苯基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺； 6-[5-(4-胺基環己基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；N-[4-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)環己基]胺基甲酸第三丁基酯；4-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)環己烷-1-醇；N-[4-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)環己基]-2-甲基丙醯胺；N-[4-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)環己基]-2-環丙基乙醯胺；N-[4-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)環己基]-3,3,3-三氟丙醯胺；N-[4-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)環己基]-2,2,2-三氟乙醯胺；2-N-甲基-6-[5-(4-苯氧基環己基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺；2-N-苯基-6-{5-[3-(三氟甲基)吡啶-2-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；6-[5-(3-氯吡啶-2-基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺；2-N-(6-氟吡啶-3-基)-2-N-甲基-6-{5-[6-(2,2,2-三氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-6-{5-[(3S)-3-苯氧基吡咯啶-1-基]-1,2,4-二唑-3-基}-2-N-苯基-1,3,5-三-2,4-二胺； 2-N-甲基-6-{5-[(3R)-3-苯氧基吡咯啶-1-基]-1,2,4-二唑-3-基}-2-N-苯基-1,3,5-三-2,4-二胺；2-N-(2-甲氧基乙基)-2-N-苯基-6-{5-[6-(2,2,2-三氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-(2-甲氧基乙基)-6-[5-(3-苯氧基氮雜環丁-1-基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺；6-[5-(2-氟-6-甲氧基苯基)-1,2,4-二唑-3-基]-2-N-(2-甲氧基乙基)-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[(2S)-吡咯啶-2-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺鹽酸鹽；2-N-甲基-2-N-苯基-6-{5-[(2R)-吡咯啶-2-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺鹽酸鹽；(2S)-2-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡咯啶-1-甲酸第三丁基酯；2-N-甲基-2-N-苯基-6-{5-[(2S)-1-(3,3,3-三氟丙基)吡咯啶-2-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[(2R)-1-(3,3,3-三氟丙基)吡咯啶-2-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[(3R)-3-(2,2,2-三氟乙氧基)吡咯啶-1-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；6-{5-[(2R)-2-(甲氧基甲基)吡咯啶-1-基]-1,2,4-二唑-3-基}-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[(3S)-3-(2,2,2-三氟乙氧基)吡咯啶-1-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺； 6-{5-[(2S)-2-(甲氧基甲基)吡咯啶-1-基]-1,2,4-二唑-3-基}-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-6-{5-[(2R)-1-[(2-甲基丙烷磺醯基]吡咯啶-2-基]-1,2,4-二唑-3-基}-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[(2R)-1-[(2,2,2-三氟乙烷)磺醯基]吡咯啶-2-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；1-[(2R)-2-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡咯啶-1-基]-2-環丙基乙烷-1-酮；1-[(2S)-2-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡咯啶-1-基]-2-環丙基乙烷-1-酮；1-[(2S)-2-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡咯啶-1-基]-3,3,3-三氟丙烷-1-酮；6-(5-{6-[(環丙基甲基)硫基]吡啶-3-基}-1,2,4-二唑-3-基)-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{6-[(3,3,3-三氟丙基)硫基]吡啶-3-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{6-[(3,3,3-三氟丙烷磺醯基]吡啶-3-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{6-[(3,3,3-三氟丙烷亞磺醯基]吡啶-3-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；6-{5-[6-(環丙基甲烷)亞磺醯基吡啶-3-基]-1,2,4-二唑-3-基}-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-苯基-6-(5-{[4-(2,2,2-三氟乙氧基)六氫吡啶-1-基]羰 基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；6-{5-[(4-乙氧基六氫吡啶-1-基)羰基]-1,2,4-二唑-3-基}-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；6-[5-({4-[(環丙基甲氧基)甲基]六氫吡啶-1-基}羰基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-[5-({4-[(2,2,2-三氟乙氧基)甲基]六氫吡啶-1-基}羰基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺；2-N-苯基-6-[5-({4-[(2,2,2-三氟乙氧基)甲基]六氫吡啶-1-基}羰基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺；6-(5-{[4-(環丙基甲氧基)六氫吡啶-1-基]羰基}-1,2,4-二唑-3-基)-2-N-苯基-1,3,5-三-2,4-二胺；6-[5-({4-[(環丙基甲氧基)甲基]六氫吡啶-1-基}羰基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-[5-({4-[(3,3,3-三氟丙氧基)甲基]六氫吡啶-1-基}羰基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-[5-({4-[(2,2,2-三氟乙基)硫基]六氫吡啶-1-基}羰基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺；2-N-苯基-6-[5-({4-[(2,2,2-三氟乙基)硫基]六氫吡啶-1-基}羰基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺；2-N-甲基-6-[5-(2-甲基嘧啶-5-基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺； 2-N-甲基-2-N-苯基-6-[5-(六氫吡-2-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-[5-(噠-4-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺；6-[5-(2-甲氧基吡啶-4-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{5-[(2,2,2-三氟乙基)胺基]吡啶-2-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[2-(2,2,2-三氟乙氧基)吡啶-4-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[6-(六氫吡啶-1-基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-(4-氟苯基)-6-[5-(3-氟吡啶-2-基)-1,2,4-二唑-3-基]-2-N-甲基-1,3,5-三-2,4-二胺；2-N-(2-氟苯基)-6-[5-(3-氟吡啶-2-基)-1,2,4-二唑-3-基]-2-N-甲基-1,3,5-三-2,4-二胺；2-N-(3-氟苯基)-6-[5-(3-氟吡啶-2-基)-1,2,4-二唑-3-基]-2-N-甲基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[2-(2,2,2-三氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；5-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)-N,N-二甲基吡啶-2-甲醯胺；2-N-甲基-2-N-苯基-6-[5-(噠-3-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺； 6-[5-(3-乙氧基吡啶-2-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；6-{5-[3-(環丙基胺基)吡啶-2-基]-1,2,4-二唑-3-基}-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；6-[5-(3-氟吡啶-2-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；6-{5-[3-(2-甲氧基乙氧基)吡啶-2-基]-1,2,4-二唑-3-基}-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[3-(丙烷-2-基氧基)吡啶-2-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；6-[5-(3-甲氧基吡啶-2-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[3-(2,2,2-三氟乙氧基)吡啶-2-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；6-(5-{3-[(環丙基甲基)胺基]吡啶-2-基}-1,2,4-二唑-3-基)-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；6-{5-[3-(環丁基胺基)吡啶-2-基]-1,2,4-二唑-3-基}-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-6-[5-(3-苯氧基氮雜環丁-1-基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-6-{5-[3-(嗎啉-4-基)吡啶-2-基]-1,2,4-二唑-3-基}-2-N-苯基-1,3,5-三-2,4-二胺；6-[5-(3-環丁氧基吡啶-2-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺； 2-N-甲基-2-N-苯基-6-{5-[3-(丙烷-2-基氧基)氮雜環丁-1-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；6-[5-(3-甲氧基氮雜環丁-1-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[3-(2,2,2-三氟乙氧基)氮雜環丁-1-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-6-{5-[3-(苯氧基甲基)氮雜環丁-1-基]-1,2,4-二唑-3-基}-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{3-[(3,3,3-三氟丙氧基)甲基]氮雜環丁-1-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{5-[(2,2,2-三氟乙氧基)甲基]呋喃-2-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；6-{5-[3-(環丙基甲氧基)氮雜環丁-1-基]-1,2,4-二唑-3-基}-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[3-(吡啶-2-基氧基)氮雜環丁-1-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-6-(5-{-8-氧雜-3-氮雜雙環[3.2.1]辛烷-3-基}-1,2,4-二唑-3-基)-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{4-[(3,3,3-三氟丙氧基)甲基]六氫吡啶-1-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-苯基-6-{5-[2-(2,2,2-三氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；6-[5-(3-苯氧基氮雜環丁-1-基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺； 2-N-甲基-2-N-苯基-6-{5-[4-(丙烷-2-磺醯基)六氫吡-1-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；4-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)六氫吡啶-1-甲酸第三丁基酯；6-{5-[1-(環丙烷磺醯基)六氫吡啶-4-基]-1,2,4-二唑-3-基}-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-6-(5-{1-[(2-甲基丙烷磺醯基]六氫吡啶-4-基}-1,2,4-二唑-3-基)-2-N-苯基-1,3,5-三-2,4-二胺；6-{5-[1-(丁烷-2-磺醯基)六氫吡啶-4-基]-1,2,4-二唑-3-基}-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；6-{5-[1-(環戊烷磺醯基)六氫吡啶-4-基]-1,2,4-二唑-3-基}-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-6-{5-[1-(2-甲基丙基)六氫吡啶-4-基]-1,2,4-二唑-3-基}-2-N-苯基-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[1-(丙烷-2-磺醯基)六氫吡啶-4-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；4-{3-[4-胺基-6-(苯基胺基)-1,3,5-三-2-基]-1,2,4-二唑-5-基}六氫吡啶-1-甲酸第三丁基酯；6-{5-[1-(環丙烷磺醯基)六氫吡啶-4-基]-1,2,4-二唑-3-基}-2-N-苯基-1,3,5-三-2,4-二胺；6-{5-[1-(丁烷-2-磺醯基)六氫吡啶-4-基]-1,2,4-二唑-3-基}-2-N-苯基-1,3,5-三-2,4-二胺；2-N-苯基-6-{5-[1-(丙烷-2-磺醯基)六氫吡啶-4-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺； 6-{5-[1-(環戊烷磺醯基)六氫吡啶-4-基]-1,2,4-二唑-3-基}-2-N-苯基-1,3,5-三-2,4-二胺；及4-{3-[4-胺基-6-(苯基胺基)-1,3,5-三-2-基]-1,2,4-二唑-5-基}-N,N-二甲基六氫吡啶-1-苯磺醯胺；或其醫藥上可接受之鹽。 In another embodiment, the invention provides a compound of formula (I) selected from the group consisting of 6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, 6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-N-phenyl-[1,3,5] -2,4-diamine, 6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-N-methyl-N-(3-methylphenyl)-[1,3,5] -2,4-diamine, 6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-N-methyl-N-(4-methylphenyl)-[1,3,5] -2,4-diamine, 6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-N-methyl-N-(3-methoxyphenyl)-[1,3,5] -2,4-diamine, 6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-N-methyl-N-(4-methoxyphenyl)-[1,3,5] -2,4-diamine, 6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-N-methyl-N-(3-chlorophenyl)-[1,3,5] -2,4-diamine, 6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-N-methyl-N-(4-chlorophenyl)-[1,3,5] -2,4-diamine, N-methyl-N-phenyl-6-(5-pyridin-2-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine, N-methyl-N-phenyl-6-(5-phenyl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine, N-methyl-N-phenyl-6-(5-thiophen-2-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine, N-methyl-6-[5-(5-chloro-thiophen-2-yl)-[1,2,4] Diazol-3-yl]-N-phenyl-[1,3,5] -2,4-diamine, 6-[5-(6-cyclopentyloxy-pyridin-3-yl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, N-(2-fluoro-phenyl)-6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-N-methyl-[1,3,5]3 -2,4-diamine, N-(3-fluoro-phenyl)-6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-N-methyl-[1,3,5]3 -2,4-diamine, N-(4-fluoro-phenyl)-6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-N-methyl-[1,3,5]3 -2,4-diamine, N-(2-chloro-phenyl)-6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-N-methyl-[1,3,5]3 -2,4-diamine, 6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-N-methyl-N-o-tolyl-[1,3,5] -2,4-diamine, N-methyl-6-[5-(5-methyl-furan-2-yl)-[1,2,4] Diazol-3-yl]-N-phenyl-[1,3,5] -2,4-diamine, N-benzyl-6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-N-methyl-[1,3,5]3 -2,4-diamine, N-ethyl-6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-N-phenyl-[1,3,5] -2,4-diamine, 4-(2,3-dihydro-indol-1-yl)-6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2-ylamine, 6-[5-(2-chloro-phenyl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, 6-[5-(3-methoxy-phenyl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, 6-[5-(2-methoxy-phenyl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, 6-[5-(4-methoxy-phenyl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, N-methyl-N-phenyl-6-(5-o-tolyl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine, N-methyl-N-phenyl-6-5-m-tolyl-[12,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine, N-methyl-N-phenyl-6-(5-p-tolyl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine, 6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-N-isopropyl-N-phenyl-[1,3,5] -2,4-diamine, 6-(5-benzyl-[1,2,4] Diazol-3-yl)-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, N-(3-chloro-phenyl)-6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine, N-(3-chloro-phenyl)-6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine, 6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-N-methyl-N-(2,3-difluorophenyl)-[1,3,5] -2,4-diamine, 6-[5-(3-chloro-phenyl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, 6-[5-(4-chloro-phenyl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, 6-(5-furan-3-yl-[1,2,4] Diazol-3-yl)-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, N-ethyl-N-phenyl-6-(5-thiazol-2-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine, N-phenyl-6-(pyridin-2-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine, N-phenyl-6-[5-(1H-pyrazol-3-yl)-[1,2,4] Diazol-3-yl]-[1,3,5] -2,4-diamine, N-phenyl-6-{5-[6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-[1,2,4] Diazol-3-yl}-[1,3,5]3 -2,4-diamine, N-methyl-N-phenyl-6-{5-[3-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-[1 , 2, 4] Diazol-3-yl}-[1,3,5]3 -2,4-diamine, 6-[5-(3-bromopyridin-2-yl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, N-methyl-6-[5-(5-methyl-iso Zin-3-yl)-[1,2,4] Diazol-3-yl]-N-phenyl-[1,3,5] -2,4-diamine, N-methyl-6-(5-morpholin-4-yl-[1,2,4] Diazol-3-yl)-N-phenyl-[1,3,5] -2,4-diamine, N-methyl-N-phenyl-6-(5-hexahydropyridin-1-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine, 6-[5-(6-methoxy-pyridin-3-yl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, 6-[5-(6-methoxy-pyridin-3-yl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, 6-[5-(4,5-dimethyl-furan-2-yl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, 6-[5-(3-amino-pyridin-2-yl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, 6-[5-(3-amino-pyridin-2-yl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, N-methyl-N-phenyl-6-(5-thiazol-5-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine, 6-[5-(2-amino-pyridin-3-yl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, 6-[5-(5-amino-pyridin-3-yl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, 6-[5-(6-amino-pyridin-3-yl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, N-methyl-N-phenyl-6-[5-(tetrahydro-pyran-2-yl)-[1,2,4] Diazol-3-yl]-[1,3,5] -2,4-diamine, N-methyl-N-phenyl-6-[5-(tetrahydro-pyran-4-yl)-[1,2,4] Diazol-3-yl]-[1,3,5] -2,4-diamine, N-methyl-6-[5-(5-methyl-1H-pyrazol-3-yl)-[1,2,4] Diazol-3-yl]-N-phenyl-[1,3,5] -2,4-diamine, 6-[5-(1H-imidazol-4-yl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, N-methyl-N-phenyl-6-[5-(1H-pyrrol-2-yl)-[1,2,4] Diazol-3-yl]-[1,3,5] -2,4-diamine, N-methyl-N-phenyl-6-[5-(2H-pyrazol-3-yl)-[1,2,4] Diazol-3-yl]-[1,3,5] -2,4-diamine, N-methyl-6-[5-(5-methyl-thiophen-2-yl)-[1,2,4] Diazol-3-yl]-N-phenyl-[1,3,5] -2,4-diamine, 6-[5-(2,3-dihydro-benzofuran-7-yl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, 6-(5-benzofuran-2-yl-[1,2,4] Diazol-3-yl)-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, 6-(5-imidazol-2-yl-[1,2,4] Diazol-3-yl)-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, N-methyl-N-phenyl-6-[5-(tetrahydro-furan-2-yl)-[1,2,4] Diazol-3-yl]-[1,3,5] -2,4-diamine, N-methyl-N-phenyl-6-{5-[6-(2,2,2-trifluoroethoxy)-pyridin-3-yl]-[1, 2,4] Diazol-3-yl}-[1,3,5]3 -2,4-diamine, 6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-N-phenyl-N-(2,2,2-trifluoro-ethyl)-[1,3,5] -2,4-diamine, N-(2-dimethylamino-ethyl)-6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-N-phenyl-[1,3,5] -2,4-diamine, 2-{[4-amino-6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 2-yl]-phenyl-amino}-ethanol, 3-[4-amino-6-(methyl-phenyl-amino)-[1,3,5]3 -2-base]-[1,2,4] Oxazol-5-formic acid benzylguanamine, 3-[4-amino-6-(methyl-phenyl-amino)-[1,3,5]3 -2-base]-[1,2,4] Diazol-5-carboxylic acid cyclopentyl decylamine, 3-[4-amino-6-(methyl-phenyl-amino)-[1,3,5] -2-base]-[1,2,4] Ethyl oxazol-5-carboxylate, 6-[5-(3-methoxy-thiophen-2-yl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, 5-{3-[4-amino-6-(methyl-phenyl-amino)-[1,3,5]3 -2-base]-[1,2,4] Oxazol-5-yl}-thiophene-2-carboxylic acid methyl decylamine, 6-[5-(2-methoxy-pyridin-3-yl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, 6-[5-(2,4-dimethoxy-phenyl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, 5-{3-[4-amino-6-(methyl-phenyl-amino)-[1,3,5]3 -2-base]-[1,2,4] Oxazol-5-yl}-pyridine-2-carbonitrile, (5-{3-[4-amino-6-(methyl-phenyl-amino)-[1,3,5]3 -2-base]-[1,2,4] Diazol-5-yl}-thiophen-2-yl)-morpholin-4-yl-methanone, 2-{3-[4-amino-6-(methyl-phenyl-amino)-[ 1,3,5]three -2-base]-[1,2,4] Diazol-5-yl}-benzonitrile, 6-[5-(2-fluoro-6-methoxy-phenyl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, 5-{3-[4-amino-6-(methyl-phenyl-amino)-[1,3,5]3 -2-base]-[1,2,4] Methyl oxazol-5-yl}-thiophene-2-carboxylate, N-(3-chloro-phenyl)-6-[5-(3-methoxy-phenyl)-[1,2,4] Diazol-3-yl]-N-methyl-[1,3,5] -2,4-diamine, N-(3-chloro-phenyl)-6-[5-(2-chloro-phenyl)-[1,2,4] Diazol-3-yl]-N-methyl-[1,3,5] -2,4-diamine, N-(3-fluoro-phenyl)-6-[5-(3-methoxy-phenyl)-[1,2,4] Diazol-3-yl]-N-methyl-[1,3,5] -2,4-diamine, 6-[5-(2-chloro-phenyl)-[1,2,4] Diazol-3-yl]-N-(3-fluoro-phenyl)-N-methyl-[1,3,5] -2,4-diamine, N-(3-fluoro-phenyl)-N-methyl-6-[5-(5-methyl-furan-2-yl)-[1,2,4] Diazol-3-yl]-[1,3,5] -2,4-diamine, N-(2-fluoro-phenyl)-6-[5-(3-methoxy-phenyl)-[1,2,4] Diazol-3-yl]-N-methyl-[1,3,5] -2,4-diamine, N-(2-fluoro-phenyl)-6-[5-(2-methoxy-phenyl)-[1,2,4] Diazol-3-yl]-N-methyl-[1,3,5] -2,4-diamine, N-(2-fluoro-phenyl)-N-methyl-6-(5-thiophen-2-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine, N-(2-fluoro-phenyl)-N-methyl-6-[5-(5-methyl-furan-2-yl)-[1,2,4] Diazol-3-yl]-[1,3,5] -2,4-diamine, 6-[5-(2-methoxy-phenyl)-[1,2,4] Diazol-3-yl]-N-methyl-N-m-tolyl-[1,3,5] -2,4-diamine, N-methyl-6-(5-thiophen-2-yl-[1,2,4] Diazol-3-yl)-N-m-tolyl-[1,3,5] -2,4-diamine, N-ethyl-6-[5-(3-methoxy-phenyl)-[1,2,4] Diazol-3-yl]-N-phenyl-[1,3,5] -2,4-diamine, N-ethyl-6-[5-(2-methoxy-phenyl)-[1,2,4] Diazol-3-yl]-N-phenyl-[1,3,5] -2,4-diamine, N-ethyl-N-phenyl-6-(5-thiophen-2-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine, N-ethyl-6-[5-(5-methyl-furan-2-yl)-[1,2,4] Diazol-3-yl]-N-phenyl-[1,3,5] -2,4-diamine, N-(3-fluoro-phenyl)-6-[5-(2-methoxy-phenyl)-[1,2,4] Diazol-3-yl]-N-methyl-[1,3,5] -2,4-diamine, N-(3-fluoro-phenyl)-N-methyl-6-(5-thiophen-2-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine, N-(3-chloro-phenyl)-6-[5-(2-methoxy-phenyl)-[1,2,4] Diazol-3-yl]-N-methyl-[1,3,5] -2,4-diamine, N-(3-chlorophenyl)-N-methyl-6-(5-thiophen-2-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine, N-(3-chloro-phenyl)-N-methyl-6-[5-(5-methyl-furan-2-yl)-[1,2,4] Diazol-3-yl]-[1,3,5] -2,4-diamine, N-(5-chloro-2-fluoro-phenyl)-6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-N-methyl-[1,3,5]3 -2,4-diamine, N-(2,5-difluoro-phenyl)-6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-N-methyl-[1,3,5]3 -2,4-diamine, N-(2-fluoro-5-methyl-phenyl)-6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-N-methyl-[1,3,5]3 -2,4-diamine, N-(3-chloro-2-fluoro-phenyl)-6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-N-methyl-[1,3,5]3 -2,4-diamine, N-(2-fluoro-3-methyl-phenyl)-6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-N-methyl-[1,3,5]3 -2,4-diamine, N-(5-chloro-2-fluoro-phenyl)-6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine, N-(2,5-difluoro-phenyl)-6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine, N-(2-fluoro-3-methyl-phenyl)-6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine, N-(3-chloro-2-fluoro-phenyl)-6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine, N-(2-fluoro-3-methyl-phenyl)-6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine, N-(2,3-difluoro-phenyl)-6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine, N-methyl-N-phenyl-6-(5-pyridin-4-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine, N-methyl-N-phenyl-6-(5-pyridin-3-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine, 4-(3,4-dihydroquinolin-1-yl)-6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 2-amine, N-(3-fluorophenyl)-6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine, 6-[5-(5-methoxy-pyridin-2-yl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, 6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-N-(2-methoxy-ethyl)-N-phenyl-[1,3,5] -2,4-diamine, N-methyl-N-phenyl-6-(5-pyrimidin-4-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine, N-cyclopropylmethyl-6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-N-phenyl-[1,3,5] -2,4-diamine, 6-[5-(4-fluoro-phenyl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, 6-[5-(3-fluoro-phenyl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, 6-[5-(2-fluoro-phenyl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine, N-methyl-N-phenyl-6-(5-thiazol-2-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine, N-methyl-6-[5-(3-methyl-thiophen-2-yl)-[1,2,4] Diazol-3-yl]-N-phenyl-[1,3,5] -2,4-diamine, N-methyl-6-(5- Azole-5-yl-[1,2,4] Diazol-3-yl)-N-phenyl-[1,3,5] -2,4-diamine, N-methyl-6-(5- Zin-2-yl-[1,2,4] Diazol-3-yl)-N-phenyl-[1,3,5] -2,4-diamine, N-methyl-6-[5-(5-methyl-thiophen-2-yl)-[1,2,4] Diazol-3-yl]-N-phenyl-[1,3,5] -2,4-diamine, N-phenyl-6-(5-thiazol-2-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine, N-methyl-N-phenyl-6-(5-pyrrolidin-1-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine, 6-[5-(3-methoxy-2-pyridyl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[6-(trifluoromethoxy)pyridin-3-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 6-{5-[6-(cyclopropylmethoxy)pyridin-3-yl]-1,2,4- Diazol-3-yl}-2-N-(2-fluorophenyl)-2-N-methyl-1,3,5-tri -2,4-diamine; 6-{5-[6-(cyclopropylmethoxy)pyridin-3-yl]-1,2,4- Diazol-3-yl}-2-N-(3-fluorophenyl)-2-N-methyl-1,3,5-tri -2,4-diamine; 6-{5-[6-(cyclopropylmethoxy)pyridin-3-yl]-1,2,4- Diazol-3-yl}-2-N-(3-fluorophenyl)-1,3,5-three -2,4-diamine; 6-(5-{[3-(4-fluorophenoxy)azetidin-1-yl]carbonyl}-1,2,4- Diazol-3-yl)-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 6-{5-[6-(cyclopropylmethoxy)pyridin-3-yl]-1,2,4- Diazol-3-yl}-2-N-(2-fluorophenyl)-1,3,5-three -2,4-diamine; 6-{5-[6-(cyclopropylmethoxy)pyridin-3-yl]-1,2,4- Diazol-3-yl}-2-N-(2,3-difluorophenyl)-1,3,5-three -2,4-diamine; 6-{5-[6-(cyclopropylmethoxy)pyridin-3-yl]-1,2,4- Diazol-3-yl}-2-N-(2,3-difluorophenyl)-2-N-methyl-1,3,5-tri -2,4-diamine; 2-N-methyl-6-{5-[6-(oxetan-3-yloxy)pyridin-3-yl]-1,2,4- Diazol-3-yl}-2-N-phenyl-1,3,5-three -2,4-diamine; 6-{5-[2-chloro-6-(trifluoromethyl)pyridin-3-yl]-1,2,4- Diazol-3-yl}-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 6-(5-{6-[(2-methoxyethoxy)methyl]pyridin-3-yl}-1,2,4- Diazol-3-yl)-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-6-(5-{6-[(oxacyclo-3-yloxy)methyl]pyridin-3-yl}-1,2 , 4- Diazol-3-yl)-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[(1R,5S)-8-(3,3,3-trifluoropropyl)-8 -azabicyclo[3.2.1]octane-3-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 6-{5-[6-(cyclopropylmethoxy)pyridin-3-yl]-1,2,4- Diazol-3-yl}-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-ethyl-2-N-phenyl-6-{5-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]- 1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 6-[5-(6-ethoxypyridin-3-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[6-(propan-2-yloxy)pyridin-3-yl]-1,2, 4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-phenyl-6-{5-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,2,4- Diazol-3-yl}-2-N-(2,2,2-trifluoroethyl)-1,3,5-three -2,4-diamine; 2-N-phenyl-6-{5-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,2,4- Diazol-3-yl}-4-N-(2,2,2-trifluoroethyl)-1,3,5-three -2,4-diamine; 2-N-methyl-6-[5-(3-methylpyridin-2-yl)-1,2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine; 6-[5-(5-fluoropyridin-2-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 6-[5-(4,6-dimethylpyridin-3-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[6-(2,2,2-trifluoroethoxy)pyridin-2-yl]- 1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-(2-methoxyethyl)-2-N-phenyl-6-{5-[6-(2,2,2-trifluoroethoxy) Pyridin-3-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-(2-methoxyethyl)-4-N-phenyl-6-{5-[6-(2,2,2-trifluoroethoxy) Pyridin-3-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 6-[5-(6-fluoropyridin-3-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 1-[4-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)hexahydropyridin-1-yl]-2,2,2-trifluoroethane-1-one; 6-[5-(1-methanesulfonylhexahydropyridin-4-yl) )-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 1-[4-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)hexahydropyridin-1-yl]-2-methylpropan-1-one; 1-[4-(3-{4-amino-6-[methyl(phenyl)amine) Base]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)hexahydropyridin-1-yl]ethane-1-one; 2-N-methyl-2-N-phenyl-6-{5-[1-(3,3,3 -trifluoropropyl)hexahydropyridin-4-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 1-[4-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)hexahydropyridin-1-yl]-3,3,3-trifluoropropan-1-one; 6-{5-[4-(methoxymethyl)hexahydropyridine-1 -base]-1,2,4- Diazol-3-yl}-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-6-{5-[4-(phenoxymethyl)hexahydropyridin-1-yl]-1,2,4- Diazol-3-yl}-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{4-[(2,2,2-trifluoroethoxy)methyl]hexahydropyridine -1-yl}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[1-(propan-1-sulfonyl)hexahydropyridin-4-yl]-1, 2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{1-[(2,2,2-trifluoroethane)sulfonyl]hexahydropyridine -4-yl}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 6-{5-[1-(ethanesulfonyl)hexahydropyridin-4-yl]-1,2,4- Diazol-3-yl}-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[1-(propane-2-sulfonyl)hexahydropyridin-4-yl]-1, 2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 6-{5-[1-(phenylsulfonyl)hexahydropyridin-4-yl]-1,2,4- Diazol-3-yl}-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 6-[5-(1-benzylhexahydropyridin-4-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-phenyl-6-(5-{4-[(2,2,2-trifluoroethoxy)methyl]hexahydropyridin-1-yl}-1 , 2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-[5-(4-{[(2,2,2-trifluoroethyl)thio]methyl} Hexahydropyridin-1-yl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{4-[(phenylthio)methyl]hexahydropyridin-1-yl}-1 , 2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{4-[(propan-2-ylthio)methyl]hexahydropyridin-1-yl }-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-[5-(4-{[(2,2,2-trifluoroethane)sulfonyl]methyl }hexahydropyridin-1-yl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine; 6-(5-{4-[(phenylsulfonyl)methyl]hexahydropyridin-1-yl}-1,2,4- Diazol-3-yl)-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{4-[(propane-2-sulfinyl)methyl]hexahydropyridine-1- Base}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{4-[(propane-2-sulfonyl)methyl]hexahydropyridin-1-yl }-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 3-[(4-amino-6-{5-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,2,4 - Diazol-3-yl}-1,3,5-three -2-yl)amino]benzoic acid methyl ester; 6-[5-(2-ethoxyphenyl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-(3-methylphenyl)-1,3,5-tri -2,4-diamine; 6-[5-(4-methoxyphenyl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-(3-methylphenyl)-1,3,5-tri -2,4-diamine; 6-[5-(2-fluoro-6-methoxyphenyl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-(3-methylphenyl)-1,3,5-tri -2,4-diamine; 6-[5-(5-fluoro-2-methoxyphenyl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-(3-methylphenyl)-1,3,5-tri -2,4-diamine; 6-[5-(4-fluoro-2-methoxyphenyl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-(3-methylphenyl)-1,3,5-tri -2,4-diamine; 6-[5-(2,4-dimethoxyphenyl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-(3-methylphenyl)-1,3,5-tri -2,4-diamine; 2-N-(3-methanesulfonylphenyl)-6-{5-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl] -1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-ethyl-6-[5-(4-methoxyphenyl)-1,2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-ethyl-6-[5-(2-fluoro-6-methoxyphenyl)-1,2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine; 6-[5-(2-chlorophenyl)-1,2,4- Diazol-3-yl]-2-N-ethyl-2-N-phenyl-1,3,5-three -2,4-diamine; 6-[5-(2-chloro-4-fluorophenyl)-1,2,4- Diazol-3-yl]-2-N-ethyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-(3-methylphenyl)-6-{5-[2-(trifluoromethoxy)phenyl]-1,2 , 4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 6-[5-(2-chlorophenyl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-(3-methylphenyl)-1,3,5-tri -2,4-diamine; 6-[5-(2-ethoxyphenyl)-1,2,4- Diazol-3-yl]-2-N-ethyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-ethyl-6-[5-(5-fluoro-2-methoxyphenyl)-1,2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-ethyl-2-N-phenyl-6-{5-[2-(trifluoromethoxy)phenyl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 6-{5-[(2-methoxyphenyl)methyl]-1,2,4- Diazol-3-yl}-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[1-(propan-1-sulfonyl)pyrrolidin-3-yl]-1,2 , 4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[1-(propan-2-sulfonyl)pyrrolidin-3-yl]-1,2 , 4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{1-[(2,2,2-trifluoroethane)sulfonyl]pyrrolidine- 3-base}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 6-{5-[1-(phenylsulfonyl)pyrrolidin-3-yl]-1,2,4- Diazol-3-yl}-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[1-(3,3,3-trifluoropropyl)pyrrolidin-3-yl]- 1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[1-(4,4,4-trifluorobutan-2-yl)pyrrolidine-3 -base]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-[5-(6-{[(1,1,1-trifluoropropan-2-yl)oxy] Methyl}pyridin-3-yl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine; 6-[5-(1-benzylpyrrolidin-3-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 6-(5-{6-[(cyclopropylmethoxy)methyl]pyridin-3-yl}-1,2,4- Diazol-3-yl)-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{6-[1-(2,2,2-trifluoroethoxy)ethyl]pyridine -3-yl}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-phenyl-6-[5-(6-{[(1,1,1-trifluoropropan-2-yl)oxy]methyl}pyridine-3- Base)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine; 6-(5-{6-[(cyclopropylmethoxy)methyl]pyridin-3-yl}-1,2,4- Diazol-3-yl)-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-phenyl-6-(5-{6-[1-(2,2,2-trifluoroethoxy)ethyl]pyridin-3-yl}-1 , 2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 6-{5-[6-(cyclobutoxymethyl)pyridin-3-yl]-1,2,4- Diazol-3-yl}-2-N-phenyl-1,3,5-three -2,4-diamine; 6-(5-{4-[(cyclopropylmethoxy)methyl]hexahydropyridin-1-yl}-1,2,4- Diazol-3-yl)-2-N-phenyl-1,3,5-three -2,4-diamine; 6-{5-[4-(cyclobutoxymethyl)hexahydropyridin-1-yl]-1,2,4- Diazol-3-yl}-2-N-phenyl-1,3,5-three -2,4-diamine; 6-(5-{4-[(cyclopropylmethoxy)methyl]hexahydropyridin-1-yl}-1,2,4- Diazol-3-yl)-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 6-{5-[4-(cyclobutoxymethyl)hexahydropyridin-1-yl]-1,2,4- Diazol-3-yl}-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 3-[4-amino-6-(phenylamino)-1,3,5-three -2-yl]-N-cyclopentyl-1,2,4- Oxazole-5-carbamamine; 3-{4-amino-6-[(3-fluorophenyl)amino]-1,3,5-three -2-yl}-N-cyclopentyl-1,2,4- Diazol-5-formamide; 2-N-phenyl-6-{5-[(pyrrolidin-1-yl)carbonyl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-phenyl-6-[5-(hexahydropyridin-1-yl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine; 3-[4-amino-6-(phenylamino)-1,3,5-three -2-yl]-1,2,4- Oxazole-5-carbamamine; 3-{4-amino-6-[(3-fluorophenyl)amino]-1,3,5-three -2-yl}-1,2,4- Oxazole-5-carbamamine; 3-{4-amino-6-[(3-fluorophenyl)amino]-1,3,5-three -2-yl}-N-cyclobutyl-1,2,4- Oxazole-5-carbamamine; 3-{4-amino-6-[(3-fluorophenyl)amino]-1,3,5-three -2-yl}-N-(2,3-dihydro-1H-indol-2-yl)-1,2,4- Oxazole-5-carbamamine; 3-{4-amino-6-[(3-fluorophenyl)amino]-1,3,5-three -2-yl}-N-(2,3-dihydro-1H-indol-1-yl)-1,2,4- Oxazol-5-formamide; 2-N-(3-fluorophenyl)-6-{5-[(pyrrolidin-1-yl)carbonyl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 3-[4-amino-6-(phenylamino)-1,3,5-three -2-yl]-N-cyclobutyl-1,2,4- Diazol-5-carbamide; 3-[4-amino-6-(phenylamino)-1,3,5-three -2-yl]-N-(2,3-dihydro-1H-indol-2-yl)-1,2,4- Diazol-5-carbamamine; 6-{5-[(2,3-dihydro-1H-isoindol-2-yl)carbonyl]-1,2,4- Diazol-3-yl}-2-N-phenyl-1,3,5-three -2,4-diamine; 6-[5-(cyclopentylamino)-1,2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-(3-fluorophenyl)-6-{5-[(morpholin-4-yl)carbonyl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 3-{4-amino-6-[(3-fluorophenyl)amino]-1,3,5-three -2-yl}-N-[(3R)-oxetan-3-yl]-1,2,4- Oxazole-5-carbamamine; 3-{4-amino-6-[(3-fluorophenyl)amino]-1,3,5-three -2-yl}-N-(propan-2-yl)-1,2,4- Diazol-5-formamide; 6-[5-(cyclopentylamino)-1,2,4- Diazol-3-yl]-2-N-(3-fluorophenyl)-1,3,5-three -2,4-diamine; 2-N-(3-fluorophenyl)-6-[5-(hexahydropyridin-1-yl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine; 2-N-(3-fluorophenyl)-6-[5-(4-methoxyhexahydropyridin-1-yl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine; 6-[5-(4-methoxyhexahydropyridin-1-yl)-1,2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine; 6-[5-(2-methoxypyridin-4-yl)-1,2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-(3-fluorophenyl)-6-[5-(3-fluoropyridin-2-yl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine; 2-N-(4-fluorophenyl)-6-[5-(1,3-thiazol-2-yl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine; 6-[5-(cyclohexylamino)-1,2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine; 6-[5-(4-methylhexahydropyridin-1-yl)-1,2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine; 3-[4-amino-6-(phenylamino)-1,3,5-three -2-yl]-N-(2,3-dihydro-1H-indol-1-yl)-1,2,4- Oxazol-5-formamide; 2-N-(3-fluorophenyl)-6-[5-(4-methylhexahydropyridin-1-yl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine; 6-(5-{2-oxa-7-azaspiro[3.5]decane-7-yl}-1,2,4- Diazol-3-yl)-2-N-phenyl-1,3,5-three -2,4-diamine; 6-[5-(2-methoxyphenyl)-1,2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-(3-fluorophenyl)-6-[5-(2-methoxyphenyl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine; 6-[5-(5-aminopyridin-2-yl)-1,2,4- Diazol-3-yl]-2-N-(3-fluorophenyl)-1,3,5-three -2,4-diamine; 3-{4-amino-6-[(3-fluorophenyl)amino]-1,3,5-three -2-yl}-N-(oxetan-3-yl)-1,2,4- Diazol-5-carbamide; 6-[5-(4-bromo-1H-pyrazol-3-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-6-[5-(1-methyl-1H-pyrazol-3-yl)-1,2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-6-[5-(1-methyl-1H-pyrazol-5-yl)-1,2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine; 6-[5-(4-chloro-1H-pyrazol-3-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[5-(trifluoromethyl)-1H-pyrazol-3-yl]-1,2 , 4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[1-(2,2,2-trifluoroethyl)-1H-pyrazole-3- Base]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[1-(2,2,2-trifluoroethyl)-1H-pyrazole-5- Base]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-N-(6-methoxypyridin-3-yl)-1,2,4- Diazol-5-carbamide; 3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-N-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]methyl}-1,2,4- Diazol-5-carbamide; 3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-N-[(6-methoxypyridin-3-yl)methyl]-1,2,4- Diazol-5-formamide; 2-N-methyl-6-[5-(3-phenoxycyclobutyl)-1,2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{[4-(2,2,2-trifluoroethoxy)hexahydropyridine-1- Base]carbonyl}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-N-[6-(trifluoromethyl)pyridin-3-yl]-1,2,4- Oxazol-5-formamide; 2-N-(3-chloro-2-fluorophenyl)-6-[5-(pyridin-2-yl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine; 2-N-(3-chlorophenyl)-6-[5-(pyridin-2-yl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine; 6-(5-cyclohexyl-1,2,4- Diazol-3-yl)-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine 2-N-methyl-2-N-phenyl-6-{5-[6-(trifluoromethyl)pyridin-3-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-6-[5-(2-methylpyridin-3-yl)-1,2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-phenyl-6-[5-(1,3-thiazol-2-yl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine; 2-N-methyl-6-{5-[6-(morpholin-4-yl)pyridin-2-yl]-1,2,4- Diazol-3-yl}-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-6-[5-(6-methylpyridin-2-yl)-1,2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-(3-chlorophenyl)-6-[5-(3-fluoropyridin-2-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-1,3,5-three -2,4-diamine; 6-[5-(3-chloropyridin-2-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; N-[1-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Oxazol-5-yl)hexahydropyridin-4-yl]-2,2,2-trifluoroacetamide; 6-[5-(2-chloropyridin-3-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[(pyrrolidin-1-yl)carbonyl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[(hexahydropyridin-1-yl)carbonyl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-[5-(pyrimidin-2-yl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine; 5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Methyl oxazol-5-yl)pyridine-2-carboxylate; 5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)-N-(2,2,2-trifluoroethyl)pyridine-2-carboxamide; 6-[5-(3,5-difluoropyridin-2-yl)-1 , 2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 6-[5-(3,5-dimethoxypyridin-2-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-6-[5-(6-methylpyridin-3-yl)-1,2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine; 5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Oxazol-5-yl)pyridine-2-carboxamide; 6-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Methyl oxazol-5-yl)pyridine-3-carboxylate; 5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-tri -2-yl}-1,2,4- Oxazol-5-yl)-N-cyclobutylpyridine-2-carboxamide; 5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5 -three -2-yl}-1,2,4- Oxazol-5-yl)-N-cyclopropylpyridine-2-carboxamide; 5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5 -three -2-yl}-1,2,4- Oxazol-5-yl)-N-(cyclopropylmethyl)pyridine-2-carboxamide; 5-(3-{4-amino-6-[methyl(phenyl)amino]-1 , 3,5-three -2-yl}-1,2,4- Diazol-5-yl)pyridine-2-carboxylic acid propan-2-yl ester; 5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Cyclobutyryl-5-yl)pyridine-2-carboxylic acid cyclopentyl ester; 2-N-methyl-2-N-phenyl-6-(5-{6-[(2,2,2-trifluoroethyl) Oxy)methyl]pyridin-3-yl}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 6-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)-N-(2,2,2-trifluoroethyl)pyridine-3-carboxamide; 2-N-methyl-2-N-phenyl-6-{5-[ 6-(pyrrolidin-1-ylmethyl)pyridin-3-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{5-[1-(pyrrolidin-1-yl)ethyl]pyridin-2-yl} -1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; [5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)pyridin-2-yl]methanol; 1-[6-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)pyridin-3-yl]ethane-1-one; 5-{3-[4-amino-6-(phenylamino)-1,3,5-tri -2-yl]-1,2,4- Methyl oxazol-5-yl}pyridine-2-carboxylate; 2-N-methyl-2-N-phenyl-6-(5-{6-[(2,2,2-trifluoroethoxy) )methyl]pyridin-3-yl}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-methyl-6-{5-[6-(morpholin-4-ylmethyl)pyridin-3-yl]-1,2,4- Diazol-3-yl}-2-N-phenyl-1,3,5-three -2,4-diamine; 6-(5-{6-[(cyclobutylamino)methyl]pyridin-3-yl}-1,2,4- Diazol-3-yl)-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{2-[(2,2,2-trifluoroethoxy)methyl]pyridine-3 -base}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{3-[(2,2,2-trifluoroethoxy)methyl]pyridine-2 -base}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-phenyl-6-(5-{6-[(2,2,2-trifluoroethoxy)methyl]pyridin-3-yl}-1,2 , 4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 1-[5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)pyridin-2-yl]ethane-1-one; 6-[5-(4-vinylphenyl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 6-[5-(1,3-dihydro-2-benzofuran-5-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[1-(propan-1-sulfonyl)azetidin-3-yl]-1 , 2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[1-(propan-2-sulfonyl)azetidin-3-yl]-1 , 2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 6-{5-[1-(ethanesulfonyl)azetidin-3-yl]-1,2,4- Diazol-3-yl}-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{1-[(2,2,2-trifluoroethane)sulfonyl]azacyclocycle But-3-yl}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 5-(3-{4-amino-6-[(2-methoxyethyl)(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Methyl oxazol-5-yl)pyridine-2-carboxylate; 2-N-(2-methoxyethyl)-2-N-phenyl-6-(5-{6-[(2,2, 2-trifluoroethoxy)methyl]pyridin-3-yl}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 6-{5-[1-(phenylsulfonyl)azetidin-3-yl]-1,2,4- Diazol-3-yl}-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[1-(2,2,2-trifluoroethyl)azetidin-3-yl ]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[6-(3,3,3-trifluoropropyl)pyridin-3-yl]-1 , 2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-[5-(6-{[(2,2,2-trifluoroethyl)thio]methyl} Pyridin-3-yl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-[5-(6-{[(2,2,2-trifluoroethane)sulfinyl]A }}pyridin-3-yl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{6-[(2,2,2-trifluoroethyl)thio]pyridine-3- Base}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-phenyl-6-{5-[6-(3,3,3-trifluoropropyl)pyridin-3-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{6-[(2,2,2-trifluoroethane)sulfinyl]pyridine- 3-base}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-[5-(6-{[(2,2,2-trifluoroethane)sulfonyl]methyl }pyridin-3-yl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{[4-(3,3,3-trifluoropropylene)hexahydropyridine-1- Base]carbonyl}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{5H,6H,7H-pyrrolo[3,4-d]pyrimidin-6-yl}- 1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[4-(3,3,3-trifluoropropylene)hexahydropyridin-1-yl ]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-(5-chloro-2-fluorophenyl)-6-[5-(pyridin-2-yl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine; 6-{5-[5-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4- Diazol-3-yl}-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{6-[(2,2,2-trifluoroethyl)amino]pyridine-3- Base}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-methyl-6-(5-{6-[(oxetan-3-yl)amino]pyridin-3-yl}-1,2,4 - Diazol-3-yl)-2-N-phenyl-1,3,5-three -2,4-diamine; 6-{5-[6-(2-methoxyethoxy)pyridin-3-yl]-1,2,4- Diazol-3-yl}-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-{[5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Oxazol-5-yl)pyridin-2-yl]oxy}acetonitrile; 6-[5-(6-cyclobutoxypyridine-3-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{6-[(propan-2-yl)amino]pyridin-3-yl}-1, 2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 6-(5-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-1,2,4- Diazol-3-yl)-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)-1,2-dihydropyridin-2-one; 2-N-methyl-2-N-phenyl-6-{5-[4-(2,2,2-three Fluoroethoxy)hexahydropyridin-1-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-6-[5-(4-phenoxyhexahydropyridin-1-yl)-1,2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{[(1r,4r)-4-(2,2,2-trifluoroethoxy) Cyclohexyl]amino}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 6-{5-[4-(benzyloxy)hexahydropyridin-1-yl]-1,2,4- Diazol-3-yl}-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 6-[5-(2,3-dihydro-1-benzofuran-5-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]- 1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-6-[5-(4-methyl-1,3-thiazol-2-yl)-1,2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-6-[5-(5-methyl-1,3-thiazol-2-yl)-1,2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-(2,5-difluorophenyl)-6-{5-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl] -1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-6-{5-[(4-methylhexahydropyridyl) -1-yl)carbonyl]-1,2,4- Diazol-3-yl}-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[4-(trifluoromethyl)-1,3-thiazol-2-yl]-1, 2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 6-[5-(3-fluoropyridin-2-yl)-1,2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine; 1-[4-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)hexahydropyridyl -1-yl]-2,2,2-trifluoroethane-1-one; 2-N-methyl-2-N-phenyl-6-{5-[3-(trifluoromethyl)pyridine -2-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{5-[(2,2,2-trifluoroethoxy)methyl]pyridine-2 -base}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-phenyl-6-(5-{5-[(2,2,2-trifluoroethoxy)methyl]pyridin-2-yl}-1,2 , 4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{4-[(2,2,2-trifluoroethoxy)methyl]phenyl} -1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-[5-(4-phenylhexahydropyridin-1-yl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine; (2R)-2-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Tert-butyl-5-yl)pyrrolidine-1-carboxylic acid tert-butyl ester; 2-N-methyl-2-N-phenyl-6-{5-[4-(pyridin-2-yloxy) Hexahydropyridin-1-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 1-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Oxazol-5-yl)-4-phenylhexahydropyridin-4-ol; 6-{5-[6-(cyclohexyloxy)pyridin-3-yl]-1,2,4- Diazol-3-yl}-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{6-[(1,1,1-trifluoropropan-2-yl)oxy]pyridine -3-yl}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{5-[1-(2,2,2-trifluoroethoxy)ethyl]pyridine -2-yl}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[6-(3,3,3-trifluoropropoxy)pyridin-3-yl]- 1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 6-[5-(4-methoxy-4-phenylhexahydropyridin-1-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-6-{5-[6-(oxiran-4-yloxy)pyridin-3-yl]-1,2,4- Diazol-3-yl}-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{4-[(2,2,2-trifluoroethyl)thio]hexahydropyridine- 1-base}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-phenyl-6-{5-[6-(3,3,3-trifluoropropoxy)pyridin-3-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-6-(5-{6-[(1-methylpyrrolidin-3-yl)oxy]pyridin-3-yl}-1,2, 4- Diazol-3-yl)-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{4-[(2,2,2-trifluoroethane)sulfonyl]hexahydropyridine -1-yl}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{6-[2-(2,2,2-trifluoroethoxy)ethoxy] Pyridin-3-yl}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[4-(propan-2-ylthio)hexahydropyridin-1-yl]-1, 2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[4-(propane-2-sulfinyl)hexahydropyridin-1-yl]-1 , 2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Oxazol-5-yl)-N-(cyclopropylmethyl)pyridine-3-carboxamide; 3-(3-{4-amino-6-[methyl(phenyl)amino]-1 , 3,5-three -2-yl}-1,2,4- Oxazol-5-yl)-N-(cyclopropylmethyl)pyridine-2-carboxamide; 2-(3-{4-amino-6-[methyl(phenyl)amino]-1 , 3,5-three -2-yl}-1,2,4- Oxazol-5-yl)-N-cyclobutylpyridine-3-carboxamide; 6-{5-[6-(2,2-difluoroethoxy)pyridin-3-yl]-1,2 , 4- Diazol-3-yl}-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 3-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Oxazol-5-yl)-N-cyclopropylpyridine-2-carboxamide; 3-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5 -three -2-yl}-1,2,4- Oxazol-5-yl)-N-cyclobutylpyridine-2-carboxamide; 3-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5 -three -2-yl}-1,2,4- Diazol-5-yl)-N-(2,2,2-trifluoroethyl)pyridine-2-carboxamide; 2-(3-{4-amino-6-[methyl(phenyl)) Amino]-1,3,5-three -2-yl}-1,2,4- Oxazol-5-yl)-N-cyclopropylpyridine-3-carboxamide; 2-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5 -three -2-yl}-1,2,4- Diazol-5-yl)pyridine-3-carboxylic acid cyclopropylmethyl ester; 3-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Cycloazol-5-yl)pyridine-2-carboxylic acid cyclopropylmethyl ester; 2-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Cycloazol-5-yl)pyridine-3-carboxylic acid cyclopentyl ester; 3-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Cyclobutyryl-5-yl)pyridine-2-carboxylic acid cyclopentyl ester; 2-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Oxazol-5-yl)-N-(2,2,2-trifluoroethyl)pyridine-3-carboxamide; 3-(3-{4-amino-6-[methyl(phenyl)) Amino]-1,3,5-three -2-yl}-1,2,4- Tert-butyl-5-yl)azetidin-1-carboxylic acid tert-butyl ester; 6-[5-(1-benzylazetidin-3-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 1-[3-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Oxazol-5-yl)azetidin-1-yl]ethane-1-one; 2-N-methyl-2-N-phenyl-6-{5-[1-(3,3, 3-trifluoropropyl)azetidin-3-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 6-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)-3-benzyl-3-azabicyclo[3.1.0]hexane-2,4-dione; 2-N-methyl-2-N-phenyl-6-{ 5-[6-[(2,2,2-trifluoroethoxy)methyl]-3-azabicyclo[3.1.0]hexane-3-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 4-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)-N,N-dimethylhexahydropyridyl 1-phenylsulfonamide; 2-N-methyl-2-N-phenyl-6-(5-{4-[(2,2,2-trifluoroethane)sulfonyl]hexahydropyridyl -1-yl}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-phenyl-6-{5-[6-[(2,2,2-trifluoroethoxy)methyl]-3-azabicyclo[3.1.0 ]Hex-3-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-6-{5-[6-(phenoxymethyl)-3-azabicyclo[3.1.0]hexane-3-yl]-1 , 2,4- Diazol-3-yl}-2-N-phenyl-1,3,5-three -2,4-diamine; 6-{5-[6-(phenoxymethyl)-3-azabicyclo[3.1.0]hexane-3-yl]-1,2,4- Diazol-3-yl}-2-N-phenyl-1,3,5-three -2,4-diamine; 6-{5-[6-[(cyclopropylmethoxy)methyl]-3-azabicyclo[3.1.0]hexane-3-yl]-1,2 , 4- Diazol-3-yl}-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-phenyl-6-{5-[6-[(3,3,3-trifluoropropoxy)methyl]-3-azabicyclo[3.1.0 ]Hex-3-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 6-{5-[6-[(cyclopropylmethoxy)methyl]-3-azabicyclo[3.1.0]hexane-3-yl]-1,2 , 4- Diazol-3-yl}-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[6-[(3,3,3-trifluoropropoxy)methyl]-3- Azabicyclo[3.1.0]hexane-3-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[6-[(propan-2-yloxy)methyl]-3-azabicyclo[ 3.1.0]Hex-3-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-phenyl-6-{5-[(R,5S,6S)-6-[(propan-2-yloxy)methyl]-3-azabicyclo [3.1.0]Hex-3-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 6-{5-[6-[(cyclopentyloxy)methyl]-3-azabicyclo[3.1.0]hexane-3-yl]-1,2, 4- Diazol-3-yl}-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 6-{5-[6-[(cyclopentyloxy)methyl]-3-azabicyclo[3.1.0]hexane-3-yl]-1,2, 4- Diazol-3-yl}-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[(4-{[(2,2,2-trifluoroethyl)thio]methyl) }hexahydropyridin-1-yl)carbonyl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{[-6-[(2,2,2-trifluoroethoxy)methyl]-) 3-azabicyclo[3.1.0]hexane-3-yl]carbonyl}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{[-6-[(3,3,3-trifluoropropoxy)methyl]- 3-azabicyclo[3.1.0]hexane-3-yl]carbonyl}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 6-(5-{[-6-[(cyclopropylmethoxy)methyl]-3-azabicyclo[3.1.0]hexane-3-yl]carbonyl} -1,2,4- Diazol-3-yl)-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 6-(5-{[-6-[(cyclopentyloxy)methyl]-3-azabicyclo[3.1.0]hexane-3-yl]carbonyl}- 1,2,4- Diazol-3-yl)-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-6-(5-{[-6-(phenoxymethyl)-3-azabicyclo[3.1.0]hexane-3-yl] Carbonyl}-1,2,4- Diazol-3-yl)-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-(3-fluorophenyl)-2-N-methyl-6-{5-[6-(2,2,2-trifluoroethoxy)pyridine- 3-base]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-(2-fluorophenyl)-2-N-methyl-6-{5-[6-(2,2,2-trifluoroethoxy)pyridine- 3-base]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-(3-chlorophenyl)-2-N-methyl-6-{5-[6-(2,2,2-trifluoroethoxy)pyridine- 3-base]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-(4-fluorophenyl)-2-N-methyl-6-{5-[6-(2,2,2-trifluoroethoxy)pyridine- 3-base]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-(2,3-difluorophenyl)-2-N-methyl-6-{5-[6-(2,2,2-trifluoroethoxy) Pyridin-3-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-(3-methylphenyl)-6-{5-[6-(2,2,2-trifluoroethoxy)pyridine -3-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-(3-chloro-4-fluorophenyl)-6-{5-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl ]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-(3-chloro-4-fluorophenyl)-2-N-methyl-6-{5-[6-(2,2,2-trifluoroethoxy Pyridin-3-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 6-[5-(6-methoxypyridin-2-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-(3,4-difluorophenyl)-6-{5-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl] -1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-(2,4-difluorophenyl)-2-N-methyl-6-{5-[6-(2,2,2-trifluoroethoxy) Pyridin-3-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 6-[5-(6-chloropyridin-3-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 6-[5-(2-ethoxypyridin-3-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[5-(trifluoromethyl)pyridin-2-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 6-[5-(4-methanesulfonylphenyl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 6-[5-(4-aminocyclohexyl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; N-[4-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Tert-butyl-5-yl)cyclohexyl]carbamic acid tert-butyl ester; 4-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-tri -2-yl}-1,2,4- Oxazol-5-yl)cyclohexane-1-ol; N-[4-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Oxazol-5-yl)cyclohexyl]-2-methylpropionamide; N-[4-(3-{4-amino-6-[methyl(phenyl)amino]-1,3, 5-three -2-yl}-1,2,4- Diazol-5-yl)cyclohexyl]-2-cyclopropylacetamide; N-[4-(3-{4-amino-6-[methyl(phenyl)amino]-1,3 , 5-three -2-yl}-1,2,4- Diazol-5-yl)cyclohexyl]-3,3,3-trifluoropropionamide; N-[4-(3-{4-amino-6-[methyl(phenyl)amino]- 1,3,5-three -2-yl}-1,2,4- Oxazol-5-yl)cyclohexyl]-2,2,2-trifluoroacetamide; 2-N-methyl-6-[5-(4-phenoxycyclohexyl)-1,2,4 - Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-phenyl-6-{5-[3-(trifluoromethyl)pyridin-2-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 6-[5-(3-chloropyridin-2-yl)-1,2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-(6-fluoropyridin-3-yl)-2-N-methyl-6-{5-[6-(2,2,2-trifluoroethoxy) Pyridin-3-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-6-{5-[(3S)-3-phenoxypyrrolidin-1-yl]-1,2,4- Diazol-3-yl}-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-6-{5-[(3R)-3-phenoxypyrrolidin-1-yl]-1,2,4- Diazol-3-yl}-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-(2-methoxyethyl)-2-N-phenyl-6-{5-[6-(2,2,2-trifluoroethoxy) Pyridin-3-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-(2-methoxyethyl)-6-[5-(3-phenoxyazetidin-1-yl)-1,2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine; 6-[5-(2-fluoro-6-methoxyphenyl)-1,2,4- Diazol-3-yl]-2-N-(2-methoxyethyl)-2-N-phenyl-1,3,5-tri -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[(2S)-pyrrolidin-2-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine hydrochloride; 2-N-methyl-2-N-phenyl-6-{5-[(2R)-pyrrolidin-2-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine hydrochloride; (2S)-2-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Tert-butyl-5-yl)pyrrolidine-1-carboxylic acid tert-butyl ester; 2-N-methyl-2-N-phenyl-6-{5-[(2S)-1-(3,3, 3-trifluoropropyl)pyrrolidin-2-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[(2R)-1-(3,3,3-trifluoropropyl)pyrrolidine-2 -base]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[(3R)-3-(2,2,2-trifluoroethoxy)pyrrolidine- 1-base]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 6-{5-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]-1,2,4- Diazol-3-yl}-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[(3S)-3-(2,2,2-trifluoroethoxy)pyrrolidine- 1-base]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 6-{5-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]-1,2,4- Diazol-3-yl}-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-6-{5-[(2R)-1-[(2-methylpropanesulfonyl)pyrrolidin-2-yl]-1,2, 4- Diazol-3-yl}-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[(2R)-1-[(2,2,2-trifluoroethane)sulfonyl) Pyrrolidin-2-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 1-[(2R)-2-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)pyrrolidin-1-yl]-2-cyclopropylethane-1-one; 1-[(2S)-2-(3-{4-amino-6-[methyl (phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)pyrrolidin-1-yl]-2-cyclopropylethane-1-one; 1-[(2S)-2-(3-{4-amino-6-[methyl (phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)pyrrolidin-1-yl]-3,3,3-trifluoropropan-1-one; 6-(5-{6-[(cyclopropylmethyl)thio]pyridine- 3-base}-1,2,4- Diazol-3-yl)-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{6-[(3,3,3-trifluoropropyl)thio]pyridine-3- Base}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{6-[(3,3,3-trifluoropropanesulfonyl)pyridin-3-yl }-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{6-[(3,3,3-trifluoropropanesulfinyl)pyridine-3- Base}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 6-{5-[6-(cyclopropylmethane)sulfinothrazin-3-yl]-1,2,4- Diazol-3-yl}-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-phenyl-6-(5-{[4-(2,2,2-trifluoroethoxy)hexahydropyridin-1-yl]carbonyl}-1, 2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 6-{5-[(4-ethoxyhexahydropyridin-1-yl)carbonyl]-1,2,4- Diazol-3-yl}-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 6-[5-({4-[(cyclopropylmethoxy)methyl]hexahydropyridin-1-yl}carbonyl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-[5-({4-[(2,2,2-trifluoroethoxy)methyl]hexahydro) Pyridin-1-yl}carbonyl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine; 2-N-phenyl-6-[5-({4-[(2,2,2-trifluoroethoxy)methyl]hexahydropyridin-1-yl}carbonyl) )-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine; 6-(5-{[4-(cyclopropylmethoxy)hexahydropyridin-1-yl]carbonyl}-1,2,4- Diazol-3-yl)-2-N-phenyl-1,3,5-three -2,4-diamine; 6-[5-({4-[(cyclopropylmethoxy)methyl]hexahydropyridin-1-yl}carbonyl)-1,2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-[5-({4-[(3,3,3-trifluoropropoxy)methyl]hexahydro) Pyridin-1-yl}carbonyl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-[5-({4-[(2,2,2-trifluoroethyl)thio]hexahydropyridine -1-yl}carbonyl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine; 2-N-phenyl-6-[5-({4-[(2,2,2-trifluoroethyl)thio]hexahydropyridin-1-yl}carbonyl) -1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine; 2-N-methyl-6-[5-(2-methylpyrimidin-5-yl)-1,2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-[5-(hexahydropyridyl) -2-yl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-[5-(哒 -4-base)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine; 6-[5-(2-methoxypyridin-4-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{5-[(2,2,2-trifluoroethyl)amino]pyridine-2- Base}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[2-(2,2,2-trifluoroethoxy)pyridin-4-yl]- 1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[6-(hexahydropyridin-1-yl)pyridin-3-yl]-1,2, 4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-(4-fluorophenyl)-6-[5-(3-fluoropyridin-2-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-1,3,5-three -2,4-diamine; 2-N-(2-fluorophenyl)-6-[5-(3-fluoropyridin-2-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-1,3,5-three -2,4-diamine; 2-N-(3-fluorophenyl)-6-[5-(3-fluoropyridin-2-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[2-(2,2,2-trifluoroethoxy)pyridin-3-yl]- 1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)-N,N-dimethylpyridine-2-carboxamide; 2-N-methyl-2-N-phenyl-6-[5-(哒 -3-yl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine; 6-[5-(3-ethoxypyridin-2-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 6-{5-[3-(cyclopropylamino)pyridin-2-yl]-1,2,4- Diazol-3-yl}-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 6-[5-(3-fluoropyridin-2-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 6-{5-[3-(2-methoxyethoxy)pyridin-2-yl]-1,2,4- Diazol-3-yl}-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[3-(propan-2-yloxy)pyridin-2-yl]-1,2, 4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 6-[5-(3-methoxypyridin-2-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[3-(2,2,2-trifluoroethoxy)pyridin-2-yl]- 1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 6-(5-{3-[(cyclopropylmethyl)amino]pyridin-2-yl}-1,2,4- Diazol-3-yl)-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 6-{5-[3-(cyclobutylamino)pyridin-2-yl]-1,2,4- Diazol-3-yl}-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-6-[5-(3-phenoxyazetidin-1-yl)-1,2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-6-{5-[3-(morpholin-4-yl)pyridin-2-yl]-1,2,4- Diazol-3-yl}-2-N-phenyl-1,3,5-three -2,4-diamine; 6-[5-(3-cyclobutoxypyridin-2-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[3-(propan-2-yloxy)azetidin-1-yl]-1 , 2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 6-[5-(3-methoxyazetidin-1-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[3-(2,2,2-trifluoroethoxy)azetidin-1- Base]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-6-{5-[3-(phenoxymethyl)azetidin-1-yl]-1,2,4- Diazol-3-yl}-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{3-[(3,3,3-trifluoropropoxy)methyl]azacyclocycle Butyl-1-yl}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{5-[(2,2,2-trifluoroethoxy)methyl]furan-2 -base}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 6-{5-[3-(cyclopropylmethoxy)azetidin-1-yl]-1,2,4- Diazol-3-yl}-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[3-(pyridin-2-yloxy)azetidin-1-yl]-1 , 2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-6-(5-{-8-oxa-3-azabicyclo[3.2.1]octane-3-yl}-1,2,4 - Diazol-3-yl)-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{4-[(3,3,3-trifluoropropoxy)methyl]hexahydropyridine -1-yl}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-phenyl-6-{5-[2-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 6-[5-(3-phenoxyazetidin-1-yl)-1,2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[4-(propane-2-sulfonyl)hexahydropyridyl -1-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 4-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Tert-butyl-5-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester; 6-{5-[1-(cyclopropanesulfonyl)hexahydropyridin-4-yl]-1,2,4- Diazol-3-yl}-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-6-(5-{1-[(2-methylpropanesulfonyl)hexahydropyridin-4-yl}-1,2,4- Diazol-3-yl)-2-N-phenyl-1,3,5-three -2,4-diamine; 6-{5-[1-(butane-2-sulfonyl)hexahydropyridin-4-yl]-1,2,4- Diazol-3-yl}-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 6-{5-[1-(cyclopentanesulfonyl)hexahydropyridin-4-yl]-1,2,4- Diazol-3-yl}-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-6-{5-[1-(2-methylpropyl)hexahydropyridin-4-yl]-1,2,4- Diazol-3-yl}-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[1-(propane-2-sulfonyl)hexahydropyridin-4-yl]-1, 2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 4-{3-[4-amino-6-(phenylamino)-1,3,5-three -2-yl]-1,2,4- Tert-butyl-5-yl}hexahydropyridine-1-carboxylic acid tert-butyl ester; 6-{5-[1-(cyclopropanesulfonyl)hexahydropyridin-4-yl]-1,2,4- Diazol-3-yl}-2-N-phenyl-1,3,5-three -2,4-diamine; 6-{5-[1-(butane-2-sulfonyl)hexahydropyridin-4-yl]-1,2,4- Diazol-3-yl}-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-phenyl-6-{5-[1-(propane-2-sulfonyl)hexahydropyridin-4-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 6-{5-[1-(cyclopentanesulfonyl)hexahydropyridin-4-yl]-1,2,4- Diazol-3-yl}-2-N-phenyl-1,3,5-three -2,4-diamine; and 4-{3-[4-amino-6-(phenylamino)-1,3,5-three -2-yl]-1,2,4- Azoxa-5-yl}-N,N-dimethylhexahydropyridine-1-benzenesulfonamide; or a pharmaceutically acceptable salt thereof.

式(I)化合物可具有不同異構體形式。如本文所使用，術語「光學異構體」或「立體異構體」係指本發明給定化合物中可存在之各種立體異構體構型中之任一者且包含幾何異構體。應理解，取代基可附接至碳原子之對掌性中心。因此，本發明包含化合物之對映異構體、非對映異構體、旋轉異構體、阻轉異構體或外消旋物。「對映異構體」係彼此為不可疊合鏡像之立體異構體對。對映異構體對之1：1混合物為「外消旋」混合物。若適宜，該術語可用於指示外消旋混合物。「非對映異構體」係具有至少兩個不對稱原子但彼此並非鏡像之立體異構體。根據Cahn-lngold-Prelog R-S體系來詳細說明絕對立體化學。當化合物係純淨對映異構體時，每一對掌性碳之立體化學可指定為R或S。絕對構型未知之拆分化合物可端視其在鈉D線波長下旋轉平面偏振光之方向(右旋或左旋)而指定為(+)或(-)。本文所述之某些化合物含有一或多個不對稱中心或軸且可由此產生對映異構體、非對映異構體及其他立體異構體形式，該等形式可根據絕對立體化學定義為(R)-或(S)-。本發明意欲包含所有該等可能之異構體，包含外消旋混合物、光學純形式及中間體混合物。可使用對掌性合成子或 對掌性試劑來製備光活性(R)-及(S)-異構體或使用習用技術來進行拆分。若化合物含有雙鍵，則取代基可為E或Z構型。若化合物含有二取代之環烷基，則環烷基取代基可具有順-或反構型。若化合物含有對掌性軸，則其可以阻轉異構體形式存在，該等阻轉異構體係構象異構體，其中圍繞單鍵之旋轉受限。可將阻轉異構體指定為(Ra)-或(Sa)-對映異構體。本發明亦欲包含所有旋轉異構體形式。本發明亦欲包含所有互變異構體形式。 The compounds of formula (I) may have different isomeric forms. As used herein, the term "optical isomer" or "stereoisomer" refers to any of the various stereoisomeric configurations that may be present in a given compound of the invention and includes geometric isomers. It will be understood that the substituents may be attached to the palm center of the carbon atom. Accordingly, the invention encompasses enantiomers, diastereomers, rotamers, atropisomers or racemates of the compounds. "Enantiomers" are stereoisomer pairs that are non-superimposable mirror images of each other. The 1:1 mixture of enantiomers is a "racemic" mixture. The term can be used to indicate a racemic mixture, if appropriate. A "diastereomer" is a stereoisomer that has at least two asymmetric atoms but is not mirror images of each other. The absolute stereochemistry is detailed in accordance with the Cahn-lngold-Prelog RS system. When the compound is a pure enantiomer, the stereochemistry of each pair of palmitic carbon can be designated as R or S. A resolved compound of unknown absolute configuration may be designated as (+) or (-) depending on its direction of rotation of the plane polarized light (right-handed or left-handed) at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers or axes and may thereby give rise to enantiomers, diastereomers, and other stereoisomeric forms which may be defined according to absolute stereochemistry Is (R)- or (S)-. The present invention is intended to include all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. The photoactive (R)- and (S)-isomers can be prepared using a palmitic synthon or a palmitic reagent or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent can have a cis- or anti-configuration. If the compound contains a pair of palmar axes, it can block the presence of isomers, such atropisomer conformational isomers, where rotation around a single bond is limited. The atropisomer can be designated as the (R a )- or (S a )-enantiomer. The invention also intends to encompass all rotamer forms. The invention also intends to encompass all tautomeric forms.

如本文所使用，術語「醫藥上可接受之鹽」係指保留有本發明化合物之生物有效性及性質之鹽且其通常在生物上或在其他方面係期望的。在許多情形下，本發明化合物藉助存在胺基及/或羧基或相似基團能夠形成酸性及/或鹼性鹽。 As used herein, the term "pharmaceutically acceptable salts" refers to salts which retain the biological effectiveness and properties of the compounds of the invention and which are generally biologically or otherwise desirable. In many cases, the compounds of the invention are capable of forming acidic and/or basic salts by the presence of amine groups and/or carboxyl groups or similar groups.

可使用無機酸及有機酸來形成醫藥上可接受之酸加成鹽，例如，乙酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、溴化物/氫溴酸鹽、碳酸氫鹽/碳酸鹽、硫酸氫鹽/硫酸鹽、樟腦磺酸鹽、氯化物/鹽酸鹽、氯茶鹼、檸檬酸鹽、乙二磺酸鹽、富馬酸鹽、葡庚糖酸鹽、葡萄糖酸鹽、葡糖醛酸鹽、馬尿酸鹽、氫碘酸鹽/碘化物、羥乙磺酸鹽、乳酸鹽、乳糖酸鹽、月桂基硫酸鹽、蘋果酸鹽、馬來酸鹽、丙二酸鹽、扁桃酸鹽、甲磺酸鹽、甲基硫酸鹽、萘酸鹽、萘磺酸鹽、菸鹼酸鹽、硝酸鹽、十八烷酸鹽、油酸鹽、草酸鹽、棕櫚酸鹽、巴莫酸鹽、磷酸鹽/磷酸氫鹽/磷酸二氫鹽、聚半乳糖醛酸鹽、丙酸鹽、硬脂酸鹽、琥珀酸鹽、磺 基水楊酸鹽、酒石酸鹽、甲苯磺酸鹽及三氟乙酸鹽。 Inorganic acids and organic acids can be used to form pharmaceutically acceptable acid addition salts, for example, acetate, aspartate, benzoate, besylate, bromide/hydrobromide, hydrogencarbonate Salt/carbonate, hydrogen sulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorophylline, citrate, ethanedisulfonate, fumarate, glucoheptonate, glucose Acid salt, glucuronate, horse urate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, propylene Acid salt, mandelic acid salt, methanesulfonate, methyl sulfate, naphthate, naphthalene sulfonate, nicotinic acid salt, nitrate, octadecanoate, oleate, oxalate, palmitic acid Salt, bamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfonate Salicylate, tartrate, tosylate and trifluoroacetate.

可自其衍生鹽之無機酸包含(例如)鹽酸、氫溴酸、硫酸、硝酸、磷酸及諸如此類。 The inorganic acid from which the salt can be derived includes, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

可自其衍生鹽之有機酸包含(例如)乙酸、丙酸、羥乙酸、草酸、馬來酸、丙二酸、琥珀酸、富馬酸、酒石酸、檸檬酸、苯甲酸、扁桃酸、甲烷磺酸、乙烷磺酸、甲苯磺酸、磺基水楊酸及諸如此類。可使用無機鹼及有機鹼來形成醫藥上可接受之鹼加成鹽。 Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonate Acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like. Inorganic bases and organic bases can be used to form pharmaceutically acceptable base addition salts.

可自其衍生鹽之無機鹼包含例如銨鹽及週期表之第1至12行之金屬鹽。在某些實施例中，該等鹽衍生自鈉、鉀、銨、鈣、鎂、鐵、銀、鋅及銅；尤其適宜之鹽包含銨、鉀、鈉、鈣及鎂鹽。 The inorganic base from which the salt can be derived contains, for example, an ammonium salt and a metal salt of the first to twelfth rows of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

可自其衍生鹽之有機鹼可包含(例如)一級胺、二級胺及三級胺、包含天然存在之經取代胺之經取代胺、環狀胺、鹼離子交換樹脂及諸如此類。某些有機胺包含異丙基胺、苄星、膽鹼鹽、二乙醇胺、二乙胺、離胺酸、葡甲胺、六氫吡及胺丁三醇。 The organic base from which the salt can be derived may include, for example, a primary amine, a secondary amine, and a tertiary amine, a substituted amine comprising a naturally occurring substituted amine, a cyclic amine, an alkali ion exchange resin, and the like. Certain organic amines include isopropylamine, benzathine, choline salt, diethanolamine, diethylamine, lysine, meglumine, hexahydropyridyl And tromethamine.

本發明之醫藥上可接受之鹽可藉由習用化學方法自母體化合物(具有鹼性或酸性部分)來合成。通常，該等鹽可藉由使游離酸形式之該等化合物與化學計量量之適當鹼(諸如Na、Ca、Mg或K之氫氧化物、碳酸鹽、碳酸氫鹽或諸如此類)反應來製備，或藉由使游離鹼形式之該等化合物與化學計量量之適當酸反應來製備。該等反應通常係在水或有機溶劑或二者之混合物中實施。通常，若可行，期望使 用非水性介質，例如乙醚、乙酸乙酯、乙醇、異丙醇或乙腈。可在(例如)「Remington's Pharmaceutical Sciences」，第20版，Mack Publishing公司，Easton,Pa.,(1985)；及「Handbook of Pharmaceutical Salts：Properties,Selection,and Use」，Stahl及Wermuth(Wiley-VCH,Weinheim，德國，2002)中發現其他適宜鹽之列表。 The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound (having a basic or acidic moiety) by conventional chemical methods. Generally, such salts can be prepared by reacting the compounds in the free acid form with a stoichiometric amount of a suitable base such as a hydroxide, carbonate, bicarbonate or the like of Na, Ca, Mg or K, Alternatively, it can be prepared by reacting the free base form of the compound with a stoichiometric amount of the appropriate acid. These reactions are usually carried out in water or an organic solvent or a mixture of the two. Usually, if feasible, expect to make Use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Available, for example, in "Remington's Pharmaceutical Sciences", 20th Edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH) A list of other suitable salts found in Weinheim, Germany, 2002).

出於分離或純化目的，亦可使用醫藥上不可接受之鹽，例如苦味酸鹽或高氯酸鹽。對於治療性應用而言，僅採用醫藥上可接受之鹽或游離化合物。 Pharmaceutically unacceptable salts such as picrate or perchlorate may also be employed for isolation or purification purposes. For therapeutic applications, only pharmaceutically acceptable salts or free compounds are employed.

鑒於呈游離形式之式(I)新穎化合物及彼等呈其鹽形式者(包含彼等可用作(例如)新穎化合物之純化或鑑別中之中間體之鹽)間之密切關係，在前文及後文中對於一或多種式(I)化合物之任何提及應理解為提及呈游離形式之化合物及/或亦提及一或多種其鹽(視情況及方便)，且提及一或多種溶劑合物(例如水合物)。 In view of the close relationship between the novel compounds of formula (I) in free form and those in their salt form, including those which can be used, for example, as intermediates in the purification or identification of novel compounds, Any reference to one or more compounds of formula (I) hereinafter is to be understood as referring to compounds in free form and/or also to one or more of their salts (as appropriate and convenient), and to mention one or more solvents Compound (eg hydrate).

本文所給出之任一式亦意欲代表未標記形式以及經同位素標記形式之化合物。經同位素標記之化合物具有由本文所給出式所示之結構，只是一或多個原子由具有所選原子質量或質量數之原子代替。可納入本發明化合物中之同位素的實例包含氫、碳、氮、氧、磷、氟及氯之同位素，例如分別為2H、3H、11C、13C、14C、15N、18F、31P、32P、35S、36Cl、125I。本發明包含各種如本文所定義之經同位素標記之化合物，例如彼等存在諸如3H及14C等放射性同位素者或彼等存在諸如13C等非放射性同位素者。該等經 同位素標記之化合物可用於代謝研究(14C)、反應動力學研究(例如，2H或3H)、檢測或顯像技術(諸如正電子發射斷層掃描術(PET)或單光子發射電腦斷層掃描術(SPECT)，包含藥物或基質組織分佈檢驗)或患者之放射性治療。特定而言，18F或經標記化合物可為PET或SPECT研究尤其需要。經同位素標記之本發明化合物及其前藥通常可藉由實施在反應圖中或在下文所述實例及製備中所揭示程序藉由使用易於獲得之經同位素標記之試劑取代未經同位素標記之試劑來製備。 Any of the formulae given herein are also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. An isotopically labeled compound has a structure as shown by the formula given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes which may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, respectively. , 31 P, 32 P, 35 S, 36 Cl, 125 I. The invention encompasses various isotopically-labeled compounds as defined herein, for example, those in which a radioisotope such as 3 H and 14 C is present or in which a non-radioactive isotope such as 13 C is present. Such isotopically labeled compounds can be used in metabolic studies ( 14 C), reaction kinetic studies (eg, 2 H or 3 H), detection or imaging techniques (such as positron emission tomography (PET) or single photon emission). Computed tomography (SPECT), which includes a drug or matrix tissue distribution test) or patient's radiotherapy. In particular, 18 F or labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the invention and prodrugs thereof can generally be substituted for unisotopically labeled reagents by the use of readily available isotope-labeled reagents by procedures disclosed in the reaction schemes or in the examples and preparations described below. To prepare.

另外，較重同位素、尤其氘(亦即，2H或D)取代可提供某些治療優點，此歸因於較大代謝穩定性，例如，活體內半表期增加或劑量需求減少或治療指數改良。應理解，此背景中之氘可視為式(I)化合物之取代基。此一較重同位素(尤其氘)之濃度可藉由同位素富集因子來定義。本文所用之術語「同位素富集因子」意指指定同位素之同位素豐度與天然豐度間之比率。若本發明化合物之取代基指明為氘，則該化合物之每一指定氘原子之同位素富集因子為至少3500(在每一指定氘原子處納入52.5%氘)、至少4000(納入60%氘)、至少4500(納入67.5%氘)、至少5000(納入75%氘)、至少5500(納入82.5%氘)、至少6000(納入90%氘)、至少6333.3(納入95%氘)、至少6466.7(納入97%氘)、至少6600(納入99%氘)或至少6633.3(納入99.5%氘)。 In addition, heavier isotopes, especially guanidine (i.e., 2 H or D) substitutions may provide certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-stage or reduced dose requirements or therapeutic index. Improvement. It should be understood that the oxime in this context can be considered as a substituent of the compound of formula (I). The concentration of this heavier isotope (especially helium) can be defined by the isotope enrichment factor. As used herein, the term "isotopic enrichment factor" means the ratio between the isotope abundance of a given isotope and the natural abundance. If the substituent of the compound of the invention is designated as hydrazine, the isotope enrichment factor for each of the specified ruthenium atoms of the compound is at least 3500 (52.5% 氘 at each designated 氘 atom), at least 4000 (60% 纳入 included) , at least 4500 (incorporated with 67.5% 氘), at least 5,000 (incorporating 75% 氘), at least 5,500 (incorporating 82.5% 氘), at least 6,000 (incorporating 90% 氘), at least 6333.3 (incorporating 95% 氘), at least 6466.7 (incorporated 97% 氘), at least 6600 (incorporating 99% 氘) or at least 6633.3 (including 99.5% 氘).

經同位素標記之式(I)化合物通常可藉由彼等熟習此項技術者熟知之習用技術來製備，或可藉由與彼等闡述於隨附 實例及製備中者類似之方法使用適當經同位素標記之試劑代替先前採用之未標記試劑來製備。 Isotopically labeled compounds of formula (I) are generally prepared by conventional techniques well known to those skilled in the art, or may be as described in connection with them. Similar methods in the examples and preparations were prepared using appropriately isotopically labeled reagents in place of the previously employed unlabeled reagents.

本發明之醫藥上可接受之溶劑合物包含彼等結晶化溶劑可經同位素取代者，例如，D2O、d6-丙酮、d6-DMSO。 The pharmaceutically acceptable solvates of the present invention comprise those in which the crystallization solvent can be substituted by an isotope, for example, D 2 O, d 6 -acetone, d 6 -DMSO.

含有能夠起氫鍵之供體及/或受體作用之基團之本發明化合物(亦即式(I)化合物)可能夠利用適宜共晶體形成劑形成共晶體。該等共晶體可藉由已知共晶體形成程序自式(I)化合物製備。該等程序包含在結晶條件下在式I化合物之溶液中與共晶體形成劑一起研磨、加熱、共昇華、共熔化或接觸並分離由此形成之共晶體。適宜共晶體形成劑包含彼等闡述於WO 2004/078163中者。因此，本發明進一步提供包括式(I)化合物之共晶體。 Compounds of the invention (i.e., compounds of formula (I)) containing a group capable of functioning as a donor and/or acceptor for hydrogen bonding may be capable of forming a co-crystal using a suitable co-crystal former. Such co-crystals can be prepared from compounds of formula (I) by known co-crystal formation procedures. The procedures comprise grinding, heating, co-liming, co-melting or contacting and separating the co-crystals thus formed from the solution of the compound of formula I in a solution of the compound of formula I under crystallization conditions. Suitable co-crystal formers include those described in WO 2004/078163. Accordingly, the present invention further provides a cocrystal comprising a compound of formula (I).

如本文所使用，術語「醫藥上可接受之載劑」包含如彼等熟習此項技術者已知之任一及所有溶劑、分散介質、包衣、表面活性劑、抗氧化劑、防腐劑(例如，抗細菌劑、抗真菌劑)、等滲劑、吸收延遲劑、鹽、防腐劑、藥物、藥物穩定劑、黏合劑、賦形劑、崩解劑、潤滑劑、甜味劑、矯味劑、染料及諸如此類及其組合(例如，Remington's Pharmaceutical Sciences，第18版，Mack Printing公司，1990，第1289-1329頁)。除任何與活性成份不相容之習用載劑之外，本發明涵蓋其於治療或醫藥組合物中之應用。 As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives known to those skilled in the art (eg, Antibacterial agent, antifungal agent), isotonic agent, absorption delaying agent, salt, preservative, drug, drug stabilizer, binder, excipient, disintegrator, lubricant, sweetener, flavoring agent, dye And the like and combinations thereof (for example, Remington's Pharmaceutical Sciences, 18th Edition, Mack Printing, 1990, pp. 1289-1329). In addition to any conventional carrier that is incompatible with the active ingredient, the invention encompasses its use in therapeutic or pharmaceutical compositions.

「組合」意指呈一劑量單元形式之固定組合或用於組合投與之成份的套組，其中式(I)化合物與組合成份可同時單 獨投與或在時間間隔內分開投與，此尤其使該等組合成份展示共同(例如協同)效應。 "Combination" means a fixed combination in the form of a dosage unit or a combination of components for administration, wherein the compound of formula (I) and the combination may be simultaneously Exclusively administered or separately administered over time intervals, in particular, allows the combined components to exhibit a common (e.g., synergistic) effect.

術語「治療有效量」之本發明化合物係指可使個體產生生物或醫學反應(例如，減小或抑制酶或蛋白質活性)或改善症狀、減輕病狀、減緩或延遲疾病進展或預防疾病等之本發明化合物的量。在一項非限制性實施例中，術語「治療有效量」係指當投與個體時對以下各項有效之本發明化合物的量：(1)至少部分減輕、抑制、預防及/或改善如下病狀或病症或疾病：(i)選自慢性疼痛(例如慢性疼痛之陽性症狀(例如感覺異常、感覺遲鈍、痛覺過敏、觸感痛及自發性疼痛)以及陰性症狀(例如失去感覺))，或(ii)由Nav1.7失調介導，或(iii)與Nav1.7失調有關，或(iv)特徵在於Nav1.7失調；或(2)減小或抑制Nav1.7活性。 The term "therapeutically effective amount" of a compound of the invention means that the individual is allowed to produce a biological or medical response (eg, to reduce or inhibit enzyme or protein activity) or to ameliorate symptoms, alleviate the condition, slow or delay disease progression, or prevent disease, and the like. The amount of the compound of the invention. In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the invention that is effective when administered to an individual: (1) at least partially alleviated, inhibited, prevented, and/or ameliorated as follows Condition or condition or disease: (i) selected from chronic pain (eg, positive symptoms of chronic pain (eg, paresthesia, dysesthesia, hyperalgesia, tactile pain, and spontaneous pain) and negative symptoms (eg, loss of sensation), Or (ii) mediated by Nav1.7 dysregulation, or (iii) associated with Nav1.7 dysregulation, or (iv) characterized by Nav1.7 dysregulation; or (2) reduced or inhibited Nav1.7 activity.

在另一非限制性實施例中，術語「治療性有效量」係指在投與細胞或組織或非細胞生物材料或介質時至少部分有效減小或抑制Nav1.7之本發明化合物之量。 In another non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the invention that is at least partially effective to reduce or inhibit Nav1.7 when administered to a cell or tissue or non-cellular biomaterial or medium.

如本文所使用，術語「個體」係指動物。通常，動物係哺乳動物。舉例而言，個體亦係指靈長類動物(例如，人類)、牛、綿羊、山羊、馬、狗、貓、兔、大鼠、小鼠、魚、鳥及諸如此類。在某些實施例中，個體為靈長類動物。在其他實施例中，個體為人類。 As used herein, the term "individual" refers to an animal. Typically, the animal is a mammal. For example, an individual also refers to a primate (eg, human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, and the like. In certain embodiments, the individual is a primate. In other embodiments, the individual is a human.

如本文所使用，術語「抑制」(inhibit、inhibition或inhibiting)係指減輕或阻抑指定病狀、症狀或病症或疾病，或顯著降低生物活性或過程之基線活性。 The term "inhibiting, inhibiting, or inhibiting" as used herein refers to alleviating or suppressing a specified condition, symptom or condition or disease, or significantly reducing the baseline activity of a biological activity or process.

在一實施例中，如本文所使用，術語「治療」(treat、treating或treatment)任一疾病或病症係指改善該疾病或病症(亦即，減緩或阻止或降低該疾病或其至少一種臨床症狀之進展)。在另一實施例中，「治療」(treat、treating或treatment)係指減輕或改善包括彼等患者不能感受到之物理參數中之至少一個物理參數。在又一實施例中，「治療」(treat、treating或treatment)係指在物理方面調節疾病或病症(例如，穩定可感受到之症狀)或在生理學方面調節疾病或病症(例如，穩定物理參數)或二者皆有。在再一實施例中，「治療」(treat、treating或treatment)係指預防或延遲疾病或病症之發作或發展或進展。 In one embodiment, the term "treat, treating, or treating" as used herein refers to amelioration of the disease or condition (ie, slowing or preventing or reducing the disease or at least one of its clinical conditions). Progress of symptoms). In another embodiment, "treat, treating, or treating" refers to alleviating or ameliorating at least one of the physical parameters including physical parameters that are incomprehensible to the patient. In still another embodiment, "treat, treating, or treating" refers to physically modulating a disease or condition (eg, stabilizing a sensible symptom) or physiologically modulating a disease or condition (eg, stabilizing physics) Parameter) or both. In still another embodiment, "treat, treating, or treating" refers to preventing or delaying the onset or progression or progression of a disease or condition.

如本文所使用，若個體在生物上、醫學上或在生活品質上自治療獲益，則該個體「需要」該治療。 As used herein, an individual "needs" the treatment if it benefits from treatment biologically, medically, or in quality of life.

除非本文另外指明或上下文明顯矛盾，否則如本文所使用，在本發明上下文(尤其在申請專利範圍之上下文)中使用之術語「一」(a、an)、「該」(the)及類似術語皆理解為涵蓋單數及複數二者。 The terms "a", "an", "the", and the like, are used in the context of the present invention (especially in the context of the claims), as used herein, unless otherwise indicated herein. It is understood to cover both singular and plural.

除非本文另外指明或上下文明顯矛盾，否則，本文所述之所有方法皆可以任何適宜順序實施。除非另外聲明，否則，本文所提供任何及所有實例或實例性語言(例如，「諸如」)僅意欲用於更好地闡釋本發明且並非對本發明範圍加以限制。 All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by the context. The use of any and all examples or example language (e.g., "such as") is intended to be illustrative of the invention and is not intended to limit the scope of the invention.

本發明化合物可以游離形式、其鹽形式或其前藥衍生物形式獲得。 The compounds of the invention may be obtained in free form, in the form of their salts or as a prodrug derivative thereof.

當鹼基團及酸基團二者存於同一分子中時，本發明化合物亦可形成內鹽，例如兩性離子分子。 When both the base group and the acid group are present in the same molecule, the compounds of the invention may also form internal salts, such as zwitterionic molecules.

本發明亦提供在活體內轉化成本發明化合物之本發明化合物的前藥。前藥係活性或非活性化合物，在將前藥投與個體後其經由活體內生理作用(例如水解、代謝及諸如此類)化學修飾轉變成本發明化合物。與製備及使用前藥相關之適用性及技術已為彼等熟習此項技術者所熟知。前藥可在概念上分成兩種非排他性種類：生物前體前藥及載劑前藥。參見The Practice of Medicinal Chemistry,Ch.31-32(由Wermuth編輯，Academic Press,San Diego,Calif.,2001)。通常，生物前體前藥係較相應活性藥物化合物為非活性或活性較低之化合物，其含有一個或多個保護基團且可藉由代謝或溶劑分解轉化成活性形式。活性藥物形式及任何釋放之代謝產物二者皆應具有可接受之低毒性。 The invention also provides prodrugs of the compounds of the invention which are converted in vivo to the compounds of the invention. Prodrugs are active or inactive compounds which, upon administration of the prodrug to an individual, are converted to the compounds of the invention by chemical modification via in vivo physiological action (e.g., hydrolysis, metabolism, and the like). The applicability and techniques associated with the preparation and use of prodrugs are well known to those skilled in the art. Prodrugs can be conceptually divided into two non-exclusive categories: bioprecursor prodrugs and carrier prodrugs. See The Practice of Medicinal Chemistry, Ch. 31-32 (edited by Wermuth, Academic Press, San Diego, Calif., 2001). Generally, a pro-precursor prodrug is a compound that is inactive or less active than the corresponding active pharmaceutical compound, which contains one or more protecting groups and can be converted to the active form by metabolism or solvolysis. Both the active drug form and any released metabolites should have acceptable low toxicity.

載劑前藥係含有輸送部分(例如，改良攝取及/或對作用位點之局部遞送的部分)之藥物化合物。在此一載劑前藥中期望藥物部分與輸送部分間之鏈接為共價鍵，前藥與藥物化合物相比為非活性或活性較低，且任一釋放之輸送部分係可接受性地無毒。對於輸送部分意欲增強攝取之前藥而言，輸送部分之釋放通常應較為迅速。在其他情形下，期望利用可提供慢釋放之部分(例如，某些聚合物)或其他部分(諸如，環糊精)。舉例而言，載劑前藥可用於改良一或多種下列性質：增加親脂性、增加藥理學效應之持久性、增加位點特異性、降低毒性及副反應及/或改良藥物 調配物(例如，穩定性、水溶性、抑制不期望之感官或生理化學性質)。舉例而言，可藉由(a)羥基與親脂羧酸(例如，具有至少一個親脂部分之羧酸)之酯化或(b)羧酸基團與親脂醇(例如，具有至少一個親脂部分之醇，例如脂肪醇)之酯化來增加親脂性。 The carrier prodrug is a pharmaceutical compound that contains a delivery moiety (e.g., a portion that improves uptake and/or local delivery to the site of action). In this carrier prodrug, it is desirable that the linkage between the drug moiety and the delivery moiety is a covalent bond, the prodrug is inactive or less active than the drug compound, and any delivered delivery moiety is acceptably non-toxic. . For delivery of a drug that is intended to enhance ingestion, the delivery of the delivery portion should generally be relatively rapid. In other situations, it may be desirable to utilize portions that provide slow release (eg, certain polymers) or other moieties (such as cyclodextrins). For example, carrier prodrugs can be used to modify one or more of the following properties: increased lipophilicity, increased persistence of pharmacological effects, increased site specificity, reduced toxicity and side effects, and/or improved drugs. Formulations (eg, stability, water solubility, inhibition of undesirable sensory or physiochemical properties). For example, by (a) esterification of a hydroxyl group with a lipophilic carboxylic acid (eg, a carboxylic acid having at least one lipophilic moiety) or (b) a carboxylic acid group with a lipophilic alcohol (eg, having at least one Esterification of the lipophilic moiety of an alcohol, such as a fatty alcohol, to increase lipophilicity.

實例性前藥係(例如)游離羧酸與硫醇之S-醯基衍生物及醇或酚之O-醯基衍生物的酯，其中醯基具有如本文所定義之含義。適宜前藥通常係在生理學條件下可藉由溶劑分解轉化成母體羧酸之醫藥上可接受之酯衍生物，例如，低碳烷基酯、環烷基酯、低碳烯基酯、苄基酯、單-或二取代低碳烷基酯(例如ω-(胺基、單-或二低碳烷基胺基、羧基、低碳烷氧基羰基)-低碳烷基酯、α-(低碳烷醯氧基、低碳烷氧基羰基或二-低碳烷基胺基羰基)-低碳烷基酯(例如新戊醯基氧基甲基酯))及習用於此項技術之類似物。此外，將胺掩蔽為經芳基羰氧基甲基取代之衍生物，其在活體內可藉由酯酶發生解離從而釋放游離藥物及甲醛(Bundgaard,J.Med.Chem.2503(1989))。另外，使用N-醯氧基甲基來掩蔽含有酸性NH基團(諸如咪唑、醯亞胺、吲哚及諸如此類)之藥物(Bundgaard,Design of Prodrugs,Elsevier(1985))。將羥基掩蔽為酯及醚。EP 039,051(Sloan及Little)揭示了曼尼希鹼(Mannich-base)異羥肟酸前藥、其製備及用途。 Exemplary prodrugs are, for example, esters of a free carboxylic acid with a S-mercapto derivative of a thiol and an O-mercapto derivative of an alcohol or phenol, wherein the fluorenyl group has the meaning as defined herein. Suitable prodrugs are usually pharmaceutically acceptable ester derivatives which can be converted to the parent carboxylic acid by solvolysis under physiological conditions, for example, lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters. a base ester, a mono- or disubstituted lower alkyl ester (for example, ω-(amino, mono- or di-lower alkylamino, carboxyl, lower alkoxycarbonyl)-lower alkyl ester, α- (lower alkyl alkoxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl ester (eg, neopentyloxymethyl ester) and used in the art Analogs. Further, the amine is masked as a derivative substituted with an arylcarbonyloxymethyl group which can be dissociated by an esterase in vivo to release free drug and formaldehyde (Bundgaard, J. Med. Chem. 2503 (1989)) . In addition, N-methoxymethyl is used to mask drugs containing acidic NH groups such as imidazole, quinone imine, guanidine, and the like (Bundgaard, Design of Prodrugs, Elsevier (1985)). The hydroxyl groups are masked as esters and ethers. EP 039,051 (Sloan and Little) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.

另外，本發明化合物(包含其鹽)亦可以其水合物形式來獲得或包含其他用於其結晶之溶劑。 Further, the compound of the present invention (including a salt thereof) may also be obtained in the form of its hydrate or contain other solvents for its crystallization.

在第三態樣中，本發明係關於製造如上所述之式(I)化合 物。 In a third aspect, the invention relates to the manufacture of a compound of formula (I) as described above Things.

根據本身已知之方法來製備式(I)化合物或其鹽，例如已報導4,6-二取代2-(5-烷基-1,2,4-二唑-3-基)-1,3,5-三之合成及結構(Russian Chemical Bulletin,2005,54(8),1900-1906)，但先前並未闡述用於製造式(I)化合物。 The compound of the formula (I) or a salt thereof is prepared according to a method known per se, for example, 4,6-disubstituted 2-(5-alkyl-1,2,4- has been reported. Diazol-3-yl)-1,3,5-three Synthesis and structure (Russian Chemical Bulletin, 2005, 54(8), 1900-1906), but has not previously been described for the manufacture of compounds of formula (I).

可根據反應圖1至4來製備式(I)化合物。 The compound of the formula (I) can be produced according to the reaction schemes 1 to 4.

一般反應方法：General reaction method:

在一實施例(方法I)中，本發明係關於製造式(I)化合物之方法，其包括步驟a)：使式(IV)化合物 (其中取代基如上文所定義)與式(III)之醯化劑 (其中取代基如上文所定義)在鹼(例如吡啶)存在下、適宜地在一或多種稀釋劑、尤其溶劑(例如甲苯)存在下進行反應；隨後脫水以引起環化(通常藉由加熱進行誘導)。用於醯化及脫水之典型反應條件在此項技術領域中已眾所周知且可應用於本方法中。式(III,X=Cl)之許多化合物市面有 售，另一選擇為，其可使用(例如)草醯氯、磷醯氯或亞硫醯氯在適宜溶劑(例如二氯甲烷或二氯乙烷)存在下視情況在催化性DMF存在下在介於室溫至回流溫度之溫度下自式(III,X=OH)之相應羧酸製得。 In one embodiment (Method I), the invention relates to a process for the manufacture of a compound of formula (I) which comprises the step a) of bringing a compound of formula (IV) (wherein the substituent is as defined above) and the oximation agent of formula (III) (wherein the substituent is as defined above) is carried out in the presence of a base such as pyridine, suitably in the presence of one or more diluents, especially a solvent such as toluene; followed by dehydration to cause cyclization (usually by heating) Induction). Typical reaction conditions for deuteration and dehydration are well known in the art and can be applied to the process. Many of the compounds of formula (III, X = Cl) are commercially available, and alternatively, they may be used, for example, of grass chloro, phosphonium chloride or sulfoxide chloride in a suitable solvent (for example dichloromethane or dichloroethane). The presence of alkane) is prepared from the corresponding carboxylic acid of formula (III, X = OH) in the presence of catalytic DMF at temperatures between room temperature and reflux temperature.

獲得式(IV)化合物，其包括步驟b)：使式(V)化合物 (其中取代基如上文所定義)與羥基胺在適宜溶劑(例如乙醇及水)存在下、視情況使用鹼(例如碳酸氫鈉)、視情況在加熱下(例如加熱至回流)進行反應。用於此反應之典型反應條件在此項技術領域中已眾所周知且可應用至本反應步驟中。 Obtaining a compound of formula (IV) comprising the step b) of bringing a compound of formula (V) (wherein the substituents are as defined above) and the hydroxylamine are reacted in the presence of a suitable solvent (for example ethanol and water), optionally with a base (for example sodium hydrogencarbonate), optionally with heating (for example heating to reflux). Typical reaction conditions for this reaction are well known in the art and can be applied to this reaction step.

獲得式(V)化合物，其包括步驟c)：使式(VI)化合物 (其中取代基如上文所定義)與諸如氰化鉀或氰化鈉等試劑在適宜溶劑(例如DMF或DMSO)中視情況在加熱下(例如加熱至120℃)；另一選擇為，可在50℃之溫度下視情況在共 試劑(例如氮雜雙環辛烷)存在下使用存於溶劑(例如乙腈)中之諸如四丁基氰化銨等試劑。用於此反應之典型反應條件在此項技術領域中已眾所周知且可應用至本反應步驟中。 Obtaining a compound of formula (V) comprising the step c) of bringing a compound of formula (VI) (wherein the substituent is as defined above) and an agent such as potassium cyanide or sodium cyanide in a suitable solvent (for example DMF or DMSO), as appropriate under heating (for example to 120 ° C); alternatively, at 50 At a temperature of ° C, an agent such as tetrabutylammonium cyanide in a solvent such as acetonitrile is optionally used in the presence of a co-reagent such as azabicyclooctane. Typical reaction conditions for this reaction are well known in the art and can be applied to this reaction step.

R2=烷基之式(V)化合物可藉由使R2=H之式(V)化合物與烷基化劑(例如碘甲烷)在鹼(例如碳酸鉀)存在下於適宜溶劑(例如DMF)中進行反應來製備。 A compound of formula (V) wherein R 2 =alkyl can be obtained by reacting a compound of formula (V) wherein R 2 = H with an alkylating agent such as methyl iodide in the presence of a base such as potassium carbonate in a suitable solvent such as DMF The reaction is carried out to prepare.

獲得式(VI)化合物，其包括步驟d)：使式(VII)化合物 (其中取代基如上文所定義)首先與氰尿醯氯(VIII)在0℃至室溫下進行反應，隨後使用存於適宜溶劑(例如THF)中之水性氨進行處理。典型反應條件在此項技術領域中已眾所周知且可應用至本反應步驟中。式(VII)之胺市面有售，或可根據彼等熟習此項技術者已知之標準方法製得。 Obtaining a compound of formula (VI) comprising the step d): bringing a compound of formula (VII) (wherein the substituents are as defined above) are first reacted with cyanuric chloride (VIII) at 0 ° C to room temperature and subsequently treated with aqueous ammonia in a suitable solvent such as THF. Typical reaction conditions are well known in the art and can be applied to this reaction step. Amines of formula (VII) are commercially available or may be prepared according to standard methods known to those skilled in the art.

在另一實施例(方法II)中，本發明係關於製造式(I)化合物之方法，其包括步驟a)及b)，其中獲得式(V)化合物，其包括步驟c')：使式(VII)化合物 (其中取代基如上文所定義)與氯三(IX)在適宜溶劑(例如 DMF或DMSO)中在適宜鹼(例如DIPEA)存在下、視情況在加熱至(例如)90℃下進行反應。典型反應條件在此項技術領域中已眾所周知且可應用至本反應步驟中。 In another embodiment (Method II), the invention relates to a process for the manufacture of a compound of formula (I), which comprises steps a) and b), wherein a compound of formula (V) is obtained which comprises step c'): (VII) compound (wherein the substituent is as defined above) and chlorine three (IX) The reaction is carried out in a suitable solvent (for example DMF or DMSO) in the presence of a suitable base (for example DIPEA), optionally with heating to, for example, 90 °C. Typical reaction conditions are well known in the art and can be applied to this reaction step.

獲得氯三(IX)，其包括步驟d')：使用氯化試劑(例如磷醯氯)在回流下處理6-胺基-4,5-二氫-4-側氧基-1,3,5-三-2甲腈(X)(J.Am.Chem.Soc.,1961,83,1261-2)。典型氯化條件在此項技術領域中已眾所周知且可應用至本反應步驟中。 Obtain chlorine three (IX), which comprises the step d'): treatment of 6-amino-4,5-dihydro-4-oxo-1,3,5-three with a chlorinating reagent (for example, phosphonium chloride) under reflux -2 carbonitrile (X) (J. Am. Chem. Soc., 1961, 83, 1261-2). Typical chlorination conditions are well known in the art and can be applied to this reaction step.

在另一實施例(方法2)中，本發明係關於製造式(I)化合物之方法，其包括步驟a)：使式(IX)之酯 與式(X)之胺或式(XI)之醇視情況在例如三甲基鋁二氮雜雙環-辛烷複合物(對於胺(X)而言)或酸或鹼等試劑存在下進行反應。 In another embodiment (Method 2), the invention relates to a process for the manufacture of a compound of formula (I) which comprises the step a) of making an ester of formula (IX) The reaction with an amine of the formula (X) or an alcohol of the formula (XI) is carried out, for example, in the presence of a reagent such as a trimethylaluminum diazabicyclo-octane complex (for the amine (X)) or an acid or a base. .

典型醯胺或轉酯化條件在此項技術領域中已眾所周知且可應用至本反應步驟中。式(X)及(XI)之胺及醇市面有售， 或可根據彼等熟習此項技術者已知之標準方法製得。 Typical guanamine or transesterification conditions are well known in the art and can be applied to this reaction step. Amines and alcohols of formula (X) and (XI) are commercially available. They may be prepared according to standard methods known to those skilled in the art.

在步驟b)中藉由使式(IV)化合物與乙基草醯氯進行反應來製備式(IX)之酯。 The ester of formula (IX) is prepared in step b) by reacting a compound of formula (IV) with ethyloxalyl chloride.

在另一實施例(方法3)中，本發明係關於製造式(I)化合物之方法，其包括步驟a)：使式(XII)化合物 與式(XIII)之胺在適宜鹼(例如碳酸鉀)存在下於適宜溶劑(例如DMF)中、視情況在加熱下進行反應。式(XIII)之胺市面有售，或可根據彼等熟習此項技術者已知之標準方法製得。 In another embodiment (Method 3), the invention relates to a process for the manufacture of a compound of formula (I) which comprises the step a) of bringing a compound of formula (XII) The reaction with an amine of formula (XIII) is carried out in the presence of a suitable base such as potassium carbonate in a suitable solvent such as DMF, optionally with heating. Amines of formula (XIII) are commercially available or may be prepared according to standard methods known to those skilled in the art.

在步驟b)中藉由使式(IV)化合物與三氯乙酸酐進行反應來製備式(XIII)化合物。 The compound of formula (XIII) is prepared in step b) by reacting a compound of formula (IV) with trichloroacetic anhydride.

本發明進一步包含本發明方法之任何變化形式，其中使用可在其任一階段獲得之中間體產物作為起始材料且實施剩餘步驟，或其中起始材料係在反應條件下原位形成，或其中反應組份係以其鹽或光學純對映體形式使用。 The invention further comprises any variant of the process of the invention, wherein an intermediate product obtainable at any stage thereof is used as a starting material and the remaining steps are carried out, or wherein the starting material is formed in situ under the reaction conditions, or wherein The reaction components are used in the form of their salts or optically pure enantiomers.

本發明化合物及中間體亦可根據彼等熟習此項技術者通常習知之方法彼此轉化。 The compounds of the present invention and intermediates can also be converted into each other according to methods generally known to those skilled in the art.

可根據標準方法(例如，使用層析方法、分佈方法、(重)結晶及諸如此類)對中間體及最終產物實施處理及/或純化。 The intermediates and final products can be treated and/or purified according to standard methods (e.g., using chromatographic methods, distribution methods, (heavy) crystallization, and the like).

一般而言，下列內容適用於上文及下文所述之所有過程。 In general, the following applies to all processes described above and below.

所有上述過程步驟皆可在彼等熟習此項技術者習知之反應條件下實施，該等條件包含彼等具體所述者：於溶劑或稀釋劑不存在時或(習慣上)存在時，該等溶劑或稀釋劑包含(例如)對所用試劑呈惰性並使其溶解之溶劑或稀釋劑；於觸媒、縮合劑或中和劑(例如離子交換劑，例如陽離子 交換劑，例如，呈H+形式，此端視反應及/或反應物之性質而定)不存在時或存在時；在低溫、常溫或高溫下(例如溫度介於約-100℃至約190℃之間，包含(例如)約-80℃至約150℃，例如在-80℃至-60℃下，在室溫下，在-20℃至40℃下或在回流溫度下)；在常壓下或在密閉器皿中，若需要，該器皿係在壓力下及/或在惰性氣氛中，例如在氬或氮氣氛中。 All of the above process steps can be carried out under the reaction conditions known to those skilled in the art, including those specifically mentioned: in the absence or (habitual) presence of a solvent or diluent, such The solvent or diluent comprises, for example, a solvent or diluent which is inert to the reagents used and which is soluble; a catalyst, a condensing agent or a neutralizing agent (for example an ion exchanger such as a cation) The exchanger, for example, in the form of H+, depending on the nature of the reaction and/or reactants, is absent or present; at low temperature, normal temperature or elevated temperature (eg, at a temperature of from about -100 ° C to about 190 ° C) Between, for example, about -80 ° C to about 150 ° C, for example, at -80 ° C to -60 ° C, at room temperature, at -20 ° C to 40 ° C or at reflux temperature); at atmospheric pressure Below or in a closed vessel, if desired, the vessel is under pressure and/or in an inert atmosphere, such as in an argon or nitrogen atmosphere.

在該等反應之所有階段，可將所形成異構體之混合物分離成個別異構體(例如，非對映異構體或對映異構體)或分離成任何期望之異構體混合物(例如，非對映異構體之混合物或外消旋物)，舉例而言，以與上述方法類似之方式加以分離。 The mixture of isomers formed may be separated into individual isomers (e.g., diastereomers or enantiomers) or separated into any desired mixture of isomers at all stages of the reaction ( For example, a mixture of diastereomers or a racemate), for example, is isolated in a manner similar to that described above.

除非在闡述該等過程時另外指定，否則可自其選擇彼等適用於任一特定反應之溶劑的溶劑包含彼等具體所述者，或(例如)水、酯(例如低碳烷基-低碳鏈烷酸酯，例如乙酸乙酯)、醚(例如脂肪族醚，例如二乙醚)或環醚(例如四氫呋喃或二烷)、液體芳族烴(例如苯或甲苯)、醇(例如甲醇、乙醇或1-丙醇或2-丙醇)、腈(例如乙腈)、鹵代烴(例如二氯甲烷或氯仿)、醯醯胺(例如二甲基甲醯胺或二甲基乙醯胺)、鹼(例如雜環狀氮鹼，例如吡啶或N-甲基吡咯啶-2-酮)、羧酸酐(例如低碳鏈烷酸酐，例如，乙酸酐)、環狀直鏈或具支鏈烴(例如環己烷、己烷或異戊烷、甲基環己烷)或彼等溶劑之混合物(例如水溶液)。該等溶劑混合物亦可藉由(例如)層析或分配用於處理中。 Unless otherwise specified in the description of such processes, solvents from which they may be selected for use in the solvent of any particular reaction include those specifically described, or, for example, water, esters (eg, lower alkyl-low) a carbon alkanoate such as ethyl acetate), an ether (such as an aliphatic ether such as diethyl ether) or a cyclic ether (such as tetrahydrofuran or two Alkane), a liquid aromatic hydrocarbon (such as benzene or toluene), an alcohol (such as methanol, ethanol or 1-propanol or 2-propanol), a nitrile (such as acetonitrile), a halogenated hydrocarbon (such as dichloromethane or chloroform), Amidoxime (such as dimethylformamide or dimethylacetamide), a base (such as a heterocyclic nitrogen base such as pyridine or N-methylpyrrolidin-2-one), a carboxylic anhydride (such as low carbon) An alkanoic anhydride, for example, acetic anhydride), a cyclic linear or branched hydrocarbon (such as cyclohexane, hexane or isopentane, methylcyclohexane) or a mixture of such solvents (for example, an aqueous solution). The solvent mixtures can also be used in the treatment by, for example, chromatography or partitioning.

化合物(包含其鹽)亦可以水合物形式獲得，或其晶體可(例如)包含用於結晶之溶劑。可存在不同之晶型。 The compound (including a salt thereof) can also be obtained in the form of a hydrate, or the crystal thereof can, for example, comprise a solvent for crystallization. Different crystal forms may exist.

本發明亦係關於下列過程之彼等形式：其中在該過程任一階段作為中間體獲得之化合物係用作起始材料並實施其餘過程步驟，或其中起始材料係在反應條件下形成或以衍生物形式(例如以受保護形式或以鹽形式)使用，或藉由本發明方法獲得之化合物係在過程條件下產生並進一步經受原位處理。 The invention also relates to such forms as those in which the compound obtained as an intermediate at any stage of the process is used as a starting material and the remaining process steps are carried out, or wherein the starting material is formed under the reaction conditions or The form of the derivative (for example, in protected form or in the form of a salt), or the compound obtained by the process of the invention, is produced under process conditions and further subjected to in situ treatment.

用於合成本發明化合物之所有起始材料、結構單元、試劑、酸、鹼、脫水劑、溶劑及觸媒皆市面有售，或可藉由熟習此項技術者已知之有機合成方法產生。 All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts useful in the synthesis of the compounds of the present invention are commercially available or can be produced by organic synthetic methods known to those skilled in the art.

在上述方法中，視情況，存在於起始材料中且並不意欲參與反應之官能基係以受保護形式存在，且解離存在之保護基團，藉此該等起始化合物亦可以鹽形式存在，前提係存在成鹽基團且可以鹽形式發生反應。在視情況實施之其他過程步驟中，不應參與反應之起始化合物之官能基可以未經保護形式存在或可(例如)由一或多個保護基團保護。然後根據已知方法中之一者整體或部分地去除保護基團。保護基團及其引入及去除方式闡述於(例如)以下文獻中：「Protective Groups in Organic Chemistry」,Plenum Press,London,New York 1973及「Methoden der Organischen Chemie」,Houben-Weyl，第4版，第15/1卷，Georg-Thieme-Verlag,Stuttgart 1974及Theodora W.Greene，「Protective Groups in Organic Synthesis」,John Wiley & Sons,New York 1981。保護基團之特性在於其可易於(例如)藉由溶劑分解、還原、光解或另一選擇為在生理學條件下去除，亦即並不發生不期望之二級反應。 In the above methods, the functional groups present in the starting material and not intended to participate in the reaction, as the case may be, exist in protected form and dissociate the protecting groups present, whereby the starting compounds may also exist in the form of a salt. The premise is the presence of a salt-forming group and can react in the form of a salt. In other process steps carried out as appropriate, the functional groups of the starting compound which should not participate in the reaction may be present in unprotected form or may be protected, for example, by one or more protecting groups. The protecting group is then removed, in whole or in part, according to one of the known methods. Protecting groups and their introduction and removal are described, for example, in "Protective Groups in Organic Chemistry", Plenum Press, London, New York 1973 and "Methoden der Organischen Chemie", Houben-Weyl, 4th edition, Volume 15/1, Georg-Thieme-Verlag, Stuttgart 1974 and Theodora W. Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York 1981. A protective group is characterized in that it can be easily removed under physiological conditions, for example by solvolysis, reduction, photolysis or another option, i.e., no undesirable secondary reactions occur.

在第四態樣中，本發明係關於本發明化合物作為藥物之用途。特定而已，式(I)化合物具有有價值之藥理學性質，如上文及下文所述。本發明由此提供：▪一種如本文所定義之式(I)化合物，其作為藥物/用作藥物；▪一種如本文所定義之式(I)化合物，其作為藥劑/用作藥劑；▪一種如本文所定義之式(I)化合物，其用於治療(for the treatment of/for use in the treatment of)慢性疼痛；▪一種如本文所定義之式(I)化合物，其用於治療(for the treatment of/for use in the treatment of)選自慢性疼痛之病症或疾病，該慢性疼痛係(例如)慢性疼痛之陽性症狀(例如感覺異常、感覺遲鈍、痛覺過敏、觸感痛及自發性疼痛)以及陰性症狀(例如失去感覺)；▪一種如本文所定義之式(I)化合物，其用於治療(for the treatment of/for use in the treatment of)一或多種Nav 1.7介導之病症或疾病；▪一種如本文所定義之式(I)化合物之用途，其用於製造用於治療慢性疼痛之藥劑；▪一種如本文所定義之式(I)化合物之用途，其用於製造用於治療選自慢性疼痛之病症或疾病之藥劑，該慢性疼痛 係(例如)慢性疼痛之陽性症狀(例如感覺異常、感覺遲鈍、痛覺過敏、觸感痛及自發性疼痛)以及陰性症狀(例如失去感覺)；一種如本文所定義之式(I)化合物之用途，其用於製造用於治療一或多種Nav 1.7介導之病症或疾病之藥劑；▪一種如本文所定義之式(I)化合物之用途，其用於治療一或多種Nav 1.7介導之病症或疾病；▪一種如本文所定義之式(I)化合物之用途，其用於治療慢性疼痛；▪一種如本文所定義之式(I)化合物之用途，其用於治療選自慢性疼痛之病症或疾病，該慢性疼痛係(例如)慢性疼痛之陽性症狀(例如感覺異常、感覺遲鈍、痛覺過敏、觸感痛及自發性疼痛)以及陰性症狀(例如失去感覺)；▪一種如本文所定義之式(I)化合物之用途，其用於抑制Nav 1.7；▪一種如本文所定義之式(I)化合物之用途，其用於治療一或多種Nav 1.7介導之病症或疾病；▪一種如本文所定義之式(I)化合物之用途，其用於治療慢性疼痛；▪一種如本文所定義之式(I)化合物之用途，其用於治療選自慢性疼痛之病症或疾病，該慢性疼痛係(例如)慢性疼痛之陽性症狀(例如感覺異常、感覺遲鈍、痛覺過敏、觸感痛及自發性疼痛)以及陰性症狀(例如失去感覺)；▪一種用於治療選自慢性疼痛之病症或疾病之方法，該慢 性疼痛係(例如)慢性疼痛之陽性症狀(例如感覺異常、感覺遲鈍、痛覺過敏、觸感痛及自發性疼痛)以及陰性症狀(例如失去感覺)，該方法包括以下步驟：向個體投與治療有效量之如本文所定義之式(I)化合物；▪一種調節個體中之Nav 1.7活性之方法，其包括向個體投與治療有效量之如本文所定義之式(I)化合物之步驟；▪一種治療Nav 1.7介導之病症或疾病之方法，其包括向個體投與治療有效量之如本文所定義之式(I)化合物之步驟；▪一種抑制細胞中之Nav 1.7之方法，其包括使該細胞與有效量之如本文所定義之式(I)化合物接觸。 In a fourth aspect, the invention relates to the use of a compound of the invention as a medicament. Specifically, the compounds of formula (I) have valuable pharmacological properties, as described above and below. The invention thus provides: a compound of formula (I) as defined herein as a medicament/for use as a medicament; a compound of formula (I) as defined herein as a medicament/agent; a compound of formula (I) as defined herein for use in the treatment of/for use in the treatment of chronic pain; a compound of formula (I) as defined herein for use in therapy (for The treatment of/for use in the treatment of a condition or a disease selected from chronic pain, for example, a positive symptom of chronic pain (eg, paresthesia, dysesthesia, hyperalgesia, tactile pain, and spontaneous pain) And a negative symptom (eg, loss of sensation); a compound of formula (I) as defined herein for use in the treatment of/for use in the treatment of one or more Nav 1.7 mediated disorders or Disease; a use of a compound of formula (I) as defined herein for the manufacture of a medicament for the treatment of chronic pain; the use of a compound of formula (I) as defined herein for the manufacture of Treatment selected from chronic Of pain disorders or diseases agent, the chronic pain For example, positive symptoms of chronic pain (eg, paresthesia, dysesthesia, hyperalgesia, tactile pain, and spontaneous pain) and negative symptoms (eg, loss of sensation); use of a compound of formula (I) as defined herein For use in the manufacture of a medicament for the treatment of one or more Nav 1.7 mediated disorders or diseases; a use of a compound of formula (I) as defined herein for the treatment of one or more Nav 1.7 mediated disorders Or disease; a use of a compound of formula (I) as defined herein for the treatment of chronic pain; a use of a compound of formula (I) as defined herein for the treatment of a condition selected from chronic pain Or disease, the chronic pain is, for example, a positive symptom of chronic pain (eg, paresthesia, dysesthesia, hyperalgesia, tactile pain, and spontaneous pain) and negative symptoms (eg, loss of sensation); a type as defined herein Use of a compound of formula (I) for inhibiting Nav 1.7; a use of a compound of formula (I) as defined herein for the treatment of one or more Nav 1.7 mediated disorders or diseases; Use of a compound of formula (I) as defined herein for the treatment of chronic pain; a use of a compound of formula (I) as defined herein for the treatment of a condition or disease selected from chronic pain Such as, for example, positive symptoms of chronic pain (such as paresthesia, dysesthesia, hyperalgesia, tactile pain, and spontaneous pain) and negative symptoms (such as loss of sensation); a condition for treating a condition or disease selected from chronic pain Method, the slow Sexual pain is, for example, a positive symptom of chronic pain (eg, paresthesia, dysesthesia, hyperalgesia, tactile pain, and spontaneous pain) and negative symptoms (eg, loss of sensation), the method comprising the steps of: administering to the individual An effective amount of a compound of formula (I) as defined herein; a method of modulating Nav 1.7 activity in an individual comprising the step of administering to the individual a therapeutically effective amount of a compound of formula (I) as defined herein; A method of treating a Nav 1.7 mediated disorder or disease comprising the step of administering to a subject a therapeutically effective amount of a compound of formula (I) as defined herein; a method of inhibiting Nav 1.7 in a cell comprising: The cell is contacted with an effective amount of a compound of formula (I) as defined herein.

在第五態樣中，本發明係關於包括本發明化合物之醫藥組合物。醫藥組合物可經調配用於特定投與途徑，例如，經口投與、非經腸投與及直腸投與等。此外，本發明之醫藥組合物可以固體形式(包含但不限於膠囊、錠劑、丸劑、微粒、粉劑或栓劑)或以液體形式(包含但不限於溶液、懸浮液或乳液)製得。醫藥組合物可經受習用醫藥操作(諸如殺菌)及/或可含有習用惰性稀釋劑、潤滑劑或緩衝劑、以及佐劑(例如防腐劑、穩定劑、潤濕劑、乳化劑及緩衝劑等)。 In a fifth aspect, the invention is directed to a pharmaceutical composition comprising a compound of the invention. The pharmaceutical compositions can be formulated for specific routes of administration, for example, oral administration, parenteral administration, and rectal administration. Furthermore, the pharmaceutical compositions of the present invention can be prepared in solid form, including but not limited to capsules, troches, pills, microparticles, powders or suppositories, or in liquid form, including but not limited to solutions, suspensions or emulsions. The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional inert diluents, lubricants or buffers, and adjuvants such as preservatives, stabilizers, wetting agents, emulsifying agents and buffers, and the like. .

通常，醫藥組合物係包括活性成份以及以下物質之錠劑或明膠膠囊：a)稀釋劑，例如乳糖、右旋醣、蔗糖、甘露糖醇、山梨糖醇、纖維素及/或甘胺酸； b)潤滑劑，例如二氧化矽、滑石粉、硬脂酸、其鎂或鈣鹽及/或聚乙二醇；對於錠劑而言，亦包含c)黏合劑，例如矽酸鎂鋁、澱粉膏糊、明膠、黃蓍膠、甲基纖維素、羧甲基纖維素鈉及/或聚乙烯吡咯啶酮；若需要包含d)崩解劑，例如澱粉、瓊脂、海藻酸或其鈉鹽或泡騰合劑；及/或e)吸收劑、著色劑、矯味劑及甜味劑。 In general, pharmaceutical compositions include lozenges or gelatin capsules of the active ingredient together with: a) diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants such as cerium oxide, talc, stearic acid, magnesium or calcium salts thereof and/or polyethylene glycol; for tablets, c) binders such as magnesium aluminum silicate, starch Paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if necessary, d) a disintegrant such as starch, agar, alginic acid or its sodium salt or An effervescent mixture; and/or e) an absorbent, a coloring agent, a flavoring agent, and a sweetener.

錠劑可根據業內已知方法經膜包衣或腸包衣。 Tablets can be film coated or enteric coated according to methods known in the art.

適用於經口投與之組合物包含有效量之呈錠劑、菱形錠劑、水性或油性懸浮液、可分散粉劑或微粒、乳液、硬或軟膠囊或糖漿或酏劑形式的本發明化合物。意欲口服使用之組合物可根據業內已知用於製造醫藥組合物之任一方法來製備，且該等組合物可含有一或多種選自由甜味劑、矯味劑、著色劑及防腐劑組成之群之試劑以提供醫藥上美觀且可口之製劑。錠劑可含有活性成份與適於製造錠劑且在醫藥上可接受之無毒賦形劑的混合物。舉例而言，該等賦形劑為：惰性稀釋劑，例如，碳酸鈣、碳酸鈉、乳糖、磷酸鈣或磷酸鈉；造粒劑及崩解劑，例如，玉米澱粉或海藻酸；黏合劑，例如，澱粉、明膠或阿拉伯膠；及潤滑劑，例如，硬脂酸鎂、硬脂酸或滑石粉。該等錠劑係無包衣或藉由已知技術包衣以延遲在胃腸道中之崩解及吸收並藉此提供較長時間之持續作用。舉例而言，可採用諸如甘油單硬脂酸酯或甘油二硬脂酸酯等延時材料。用於口服使用之 調配物可呈現為硬明膠膠囊形式，其中將活性成份與惰性固體稀釋劑(例如，碳酸鈣、磷酸鈣或高嶺土)混合；或可呈現為軟明膠膠囊形式，其中將活性成份與水或油介質(例如，花生油、液體石蠟或橄欖油)混合。 Compositions suitable for oral administration comprise an effective amount of a compound of the invention in the form of a lozenge, a lozenge, an aqueous or oily suspension, a dispersible powder or microparticles, an emulsion, a hard or soft capsule or a syrup or elixir. Compositions intended for oral use can be prepared according to any of the methods known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives. Group of reagents to provide a pharmaceutically elegant and palatable preparation. Tablets may contain a mixture of the active ingredient in admixture with a pharmaceutically acceptable pharmaceutically acceptable excipient. For example, the excipients are: an inert diluent such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; a granulating agent and a disintegrating agent, for example, corn starch or alginic acid; a binder, For example, starch, gelatin or gum arabic; and a lubricant such as magnesium stearate, stearic acid or talc. Such tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. For oral use The formulation may take the form of a hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent (for example, calcium carbonate, calcium phosphate or kaolin) or may be in the form of a soft gelatin capsule in which the active ingredient is combined with a water or oil medium (for example, peanut oil, liquid paraffin or olive oil) mixed.

某些可注射組合物係等滲水溶液或懸浮液，且栓劑較佳係自脂肪乳液或懸浮液製備。該等組合物可進行滅菌及/或含有佐劑，諸如防腐劑、穩定劑、潤濕劑或乳化劑、溶解促進劑、調節滲透壓之鹽及/或緩衝劑。此外，其亦可含有其他治療上有價值之物質。該等組合物係分別根據習用混和、造粒或包衣方法來製備且含有約0.1-75%或含有約1-50%之活性成份。 Certain injectable compositions are isotonic aqueous solutions or suspensions, and suppositories are preferably prepared from fatty emulsions or suspensions. The compositions may be sterilized and/or contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, dissolution promoters, salts for regulating osmotic pressure, and/or buffers. In addition, it may also contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulating or coating methods and contain from about 0.1% to about 75% or from about 1% to about 50% by weight of active ingredient.

適於經皮施加之組合物包含有效量之本發明化合物與適宜載劑。適於經皮遞送之載劑包含可吸收性藥理上可接受之溶劑以助於穿過宿主皮膚。舉例而言，經皮裝置係呈繃帶形式，其包括背襯構件；含有該化合物(視情況具有載劑)之儲存器；視情況包含速度控制障壁以便以受控之預定速度長時間遞送化合物至宿主皮膚；及將裝置固定至皮膚上之部件。 Compositions suitable for transdermal administration comprise an effective amount of a compound of the invention and a suitable carrier. Carriers suitable for transdermal delivery comprise an absorbable pharmaceutically acceptable solvent to aid passage through the skin of the host. By way of example, the transdermal device is in the form of a bandage comprising a backing member; a reservoir containing the compound, optionally with a carrier; optionally a speed control barrier to deliver the compound to the controlled predetermined rate for a prolonged period of time to Host skin; and components that secure the device to the skin.

適用於局部施加(例如，施加至皮膚及眼睛)之組合物包含水溶液、懸浮液、軟膏、乳霜、凝膠或(例如)藉由氣溶膠遞送之可噴霧調配物或諸如此類。該等局部遞送系統尤其適用於表皮施加以(例如)治療皮膚癌、用以(例如)防曬霜、洗劑、噴霧劑及諸如此類之預防用途。因此，其尤其適用於局部施加，包含業內熟知之化妝品用調配物。該等 調配物可含有增溶劑、穩定劑、增滲劑、緩衝劑及防腐劑。 Compositions suitable for topical application (e.g., to the skin and eyes) comprise an aqueous solution, suspension, ointment, cream, gel, or sprayable formulation delivered, for example, by aerosol or the like. Such topical delivery systems are particularly useful for topical application to, for example, the treatment of skin cancer, for prophylactic use, for example, sunscreens, lotions, sprays, and the like. Therefore, it is especially suitable for topical application, including cosmetic formulations well known in the art. Such The formulation may contain solubilizers, stabilizers, penetration enhancers, buffers, and preservatives.

如本文所使用，局部施加亦可涉及吸入或鼻內施加。其可在使用或未使用適宜推進劑下以乾燥粉末形式(單獨、呈(例如)乾燥摻合物與乳糖之混合物或與(例如)磷脂之混合組份顆粒形式)自乾燥粉末吸入器或以氣溶膠噴霧投遞形式自加壓容器、幫浦、噴射器、霧化器或噴霧器方便地遞送。 As used herein, topical application can also involve inhalation or intranasal application. It may be in the form of a dry powder (either alone, in the form of a mixture of dry blends with lactose or mixed component particles with, for example, phospholipids) from a dry powder inhaler or with a suitable propellant, or with a suitable propellant. Aerosol spray delivery forms are conveniently delivered from pressurized containers, pumps, ejector, nebulizers or nebulizers.

本發明進一步提供包括作為活性成份之本發明化合物的無水醫藥組合物及劑型，此乃因水可促進某些化合物降解。 The invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the invention as active ingredients, as water promotes the degradation of certain compounds.

可使用無水或含低水分之成份在低水分或低濕度條件下製備本發明之無水醫藥組合物及劑型。無水醫藥組合物可製備並儲存以維持其無水性質。因此，使用已知材料包裝無水組合物以防止暴露於水中從而其可包含於適宜配方套組中。適宜包裝之實例包含但不限於氣密性密封箔、塑膠、單位劑量容器(例如，小瓶)、泡罩包裝及條帶包裝。 The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low moisture containing ingredients under conditions of low moisture or low humidity. Anhydrous pharmaceutical compositions can be prepared and stored to maintain their anhydrous character. Thus, the anhydrous composition is packaged using known materials to prevent exposure to water so that it can be included in a suitable formulation kit. Examples of suitable packaging include, but are not limited to, hermetic sealing foils, plastics, unit dose containers (eg, vials), blister packs, and strip packs.

本發明進一步提供包括一種或多種可減小作為活性成份之本發明化合物分解速率之試劑的醫藥組合物及劑型。本文稱作「穩定劑」之該等試劑包含但不限於抗氧化劑(例如，抗壞血酸)、pH緩衝劑或鹽緩衝劑等。 The invention further provides pharmaceutical compositions and dosage forms that comprise one or more agents that reduce the rate of decomposition of the compounds of the invention as the active ingredient. Such agents referred to herein as "stabilizers" include, but are not limited to, antioxidants (e.g., ascorbic acid), pH buffers or salt buffers, and the like.

本發明由此提供▪一種醫藥組合物，其包括(亦即含有或由其組成)如本文所定義之式(I)化合物及一或多種載劑/賦形劑； ▪一種醫藥組合物，其包括治療有效量之如本文所定義之式(I)化合物及一或多種醫藥上可接受之載劑/賦形劑。 The invention thus provides a pharmaceutical composition comprising (ie, comprising or consisting of) a compound of formula (I) as defined herein and one or more carriers/excipients; A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as defined herein and one or more pharmaceutically acceptable carriers/excipients.

在第六態樣中，本發明係關於包括式(I)化合物與一或多種其他活性成份之組合。本發明由此提供▪一種組合、尤其醫藥組合，其包括治療有效量之式(I)化合物及一或多種治療活性劑、尤其止痛劑；▪一種組合醫藥組合物，其適用於同時或依序投與且包括治療有效量之如本文所定義之式(I)化合物、治療有效量之一或多種組合成份、尤其止痛劑；一或多種醫藥上可接受之賦形劑；▪一種如本文所定義之組合醫藥組合物，其(i)用作藥物，(ii)用於治療Nav1.7介導之疾病，(iii)用於Nav1.7介導之疾病之治療方法中。 In a sixth aspect, the invention relates to a combination comprising a compound of formula (I) and one or more other active ingredients. The invention thus provides a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of a compound of formula (I) and one or more therapeutically active agents, especially an analgesic; a combination pharmaceutical composition suitable for simultaneous or sequential use Administering and comprising a therapeutically effective amount of a compound of formula (I) as defined herein, a therapeutically effective amount of one or more combination ingredients, especially an analgesic; one or more pharmaceutically acceptable excipients; A combination pharmaceutical composition as defined, (i) for use as a medicament, (ii) for the treatment of a Nav1.7 mediated disease, and (iii) for the treatment of a Nav1.7 mediated disease.

如本文所定義之疼痛治療可以單一療法形式施加，或除本發明化合物外亦可涉及投與其他鎮痛藥或輔助療法。該療法可(例如)包含本發明化合物與一或多種下列種類之減痛成份之組合：a)類鴉片鎮痛藥，例如嗎啡(morphine)、酚派丙酮(ketobemidone)或芬太尼(fentanyl)；b)NSAID或COX-1/2類鎮痛藥，例如布洛芬(ibuprofen)、萘普生(naproxen)、塞來昔布(celecoxib)或乙醯基水楊酸及含有一氧化氮供應基團之其類似物；c)鎮痛性佐劑，例如阿米替林(amitriptyline)、丙米嗪(imipramine)、杜洛西汀(duloxetine)或美西律(mexiletine)；d)NMDA拮抗劑，例如氯胺酮(ketamine)或 右美沙芬(dextrometorfan)；e)鈉通道阻斷劑，例如利多卡因(lidocaine)；f)抗痙攣劑，例如卡馬西平(carbamazepine)、托吡酯(topiramate)或拉莫三(lamotrigine)；g)抗痙攣劑/鎮痛胺基酸，例如加巴噴丁(gabapentin)或普加巴林(pregabalin)；h)大麻素。 Pain management as defined herein may be applied as a monotherapy or may involve administration of other analgesics or adjuvant therapies in addition to the compounds of the invention. The therapy can, for example, comprise a combination of a compound of the invention and one or more of the following classes of pain reducing ingredients: a) an opioid analgesic, such as morphine, ketobemidone or fentanyl; b) NSAID or COX-1/2 analgesics, such as ibuprofen, naproxen, celecoxib or acetylsalicylic acid, and a nitric oxide-containing supply group An analog thereof; c) an analgesic adjuvant, such as amitriptyline, imipramine, duloxetine or mexiletine; d) an NMDA antagonist, for example Ketamine or dextromethorphan; e) sodium channel blockers, such as lidocaine; f) anticonvulsants, such as carbamazepine, topiramate or lamot (lamotrigine); g) an anti-caries agent/analgesic amino acid, such as gabapentin or pregabalin; h) cannabinoids.

該等藉由編號、通用名或商品名來鑑別之活性劑之結構可自標準綱要「默克索引(The Merck Index)」之現行版本或自諸如國際專利(Patents International)(例如IMS World Publications)等數據庫獲得。 The structure of the active agents identified by number, generic or trade name may be from the current version of the standard "The Merck Index" or from, for example, the International Patent (Patents International) (eg IMS World Publications) Wait for the database to get.

上述可與式(I)化合物組合使用之化合物可如此項技術中(例如上文所引用文件)中所述來製備及投與。 The above compounds which can be used in combination with the compounds of formula (I) can be prepared and administered as described in the art (for example, the documents cited above).

在另一實施例中，其他活性成份係激素醫藥。 In another embodiment, the other active ingredient is a hormonal medicine.

實驗experiment 實例：Example:

下列實例用於闡釋本發明而並不限制其範圍。所用縮寫係彼等業內習用者。 The following examples are intended to illustrate the invention without limiting its scope. The abbreviations used are those of the industry.

在下列程序中，在每一起始材料之後，通常提供參考說明。此僅提供用於幫助熟習此項技術之化學家。起始材料可能無需自所提及之批料製得。 In the following procedures, a reference is usually provided after each starting material. This is only available to chemists who are familiar with the technology. The starting materials may not need to be made from the batches mentioned.

NMR方法NMR method

使用Bruker DPX 250 MHz NMR或Bruker DRX 500 MHz NMR來測定NMR光譜。以位移(ppm)形式來報告所測值，其中零對應於作為內部標準之四甲基甲矽烷。以ppm形式([δ])來報告化學位移。將分裂圖案設計為：s，單峰；d， 雙重峰；t，三重峰；q，四重峰；m，多重峰；b，寬峰。在介於25℃至90℃之間之溫度下記錄NMR光譜。在檢測一個以上之構象異構體時，報告最豐富者之化學位移。 NMR spectra were determined using Bruker DPX 250 MHz NMR or Bruker DRX 500 MHz NMR. The measured value is reported in displacement (ppm), where zero corresponds to tetramethylformane as an internal standard. Chemical shifts are reported in ppm form ([δ]). Design the split pattern as: s, single peak; d, Double peak; t, triplet; q, quartet; m, multiplet; b, broad. The NMR spectrum was recorded at a temperature between 25 ° C and 90 ° C. When more than one conformer is detected, the chemical shift of the most abundant is reported.

分析型HPLC-MSAnalytical HPLC-MS 方法AMethod A

管柱：Waters Atlantis dC18(2.1×100 mm，3 um管柱) Column: Waters Atlantis dC18 (2.1 × 100 mm, 3 um column)

流速：0.6 ml/min Flow rate: 0.6 ml/min

溶劑A：0.1%甲酸/水 Solvent A: 0.1% formic acid / water

溶劑B：0.1%甲酸/乙腈 Solvent B: 0.1% formic acid / acetonitrile

注入體積：3 μl Injection volume: 3 μl

管柱溫度：40℃ Column temperature: 40 ° C

UV檢測波長：215 nm UV detection wavelength: 215 nm

洗脫劑：0 min至5 min，恆定梯度：95%溶劑A+5%溶劑B至100%溶劑B；5 min至5.4 min，100%溶劑B；5.4 min至5.42 min，恆定梯度：100%溶劑B至95%溶劑A+5%溶劑B；5.42 min至7.00 min，95%溶劑A+5%溶劑B Eluent: 0 min to 5 min, constant gradient: 95% solvent A + 5% solvent B to 100% solvent B; 5 min to 5.4 min, 100% solvent B; 5.4 min to 5.42 min, constant gradient: 100% Solvent B to 95% solvent A + 5% solvent B; 5.42 min to 7.00 min, 95% solvent A + 5% solvent B

方法BMethod B

管柱：Waters Atlantis dC18(2.1×50 mm，3 um) Column: Waters Atlantis dC18 (2.1 × 50 mm, 3 um)

溶劑A=0.1%甲酸(水溶液) Solvent A = 0.1% formic acid (aqueous solution)

溶劑B=0.1%甲酸(乙腈) Solvent B = 0.1% formic acid (acetonitrile)

流速：1 ml/min Flow rate: 1 ml/min

注入體積：3 ul Injection volume: 3 ul

UV檢測波長：215 nm UV detection wavelength: 215 nm

洗脫劑：0至2.5分鐘，恆定梯度：95%溶劑A+5%溶劑B至 100%溶劑B；2.5分鐘至2.7分鐘，100%溶劑B；2.71至3.0分鐘，95%溶劑A+5%溶劑B。 Eluent: 0 to 2.5 minutes, constant gradient: 95% solvent A + 5% solvent B to 100% solvent B; 2.5 minutes to 2.7 minutes, 100% solvent B; 2.71 to 3.0 minutes, 95% solvent A + 5% solvent B.

方法CMethod C

管柱：Waters Atlantis dC18(2.1×30 mm，3 um管柱) Column: Waters Atlantis dC18 (2.1 × 30 mm, 3 um column)

流速：1 ml/min Flow rate: 1 ml/min

溶劑A：0.1%甲酸/水 Solvent A: 0.1% formic acid / water

溶劑B：0.1%甲酸/乙腈 Solvent B: 0.1% formic acid / acetonitrile

注入體積：3 ul Injection volume: 3 ul

UV檢測波長：215 nm UV detection wavelength: 215 nm

洗脫劑：0 min至1.5 min，恆定梯度：95%溶劑A+5%溶劑B至100%溶劑B；1.5 min至1.6 min，100%溶劑B；1.60 min至1.61 min，恆定梯度：100%溶劑B至95%溶劑A+5%溶劑B；1.61 min至2.00 min，95%溶劑A+5%溶劑B。 Eluent: 0 min to 1.5 min, constant gradient: 95% solvent A + 5% solvent B to 100% solvent B; 1.5 min to 1.6 min, 100% solvent B; 1.60 min to 1.61 min, constant gradient: 100% Solvent B to 95% solvent A + 5% solvent B; 1.61 min to 2.00 min, 95% solvent A + 5% solvent B.

方法DMethod D

管柱：Waters Atlantis dC18(3.0×50 mm,3 um) Column: Waters Atlantis dC18 (3.0 × 50 mm, 3 um)

流速：1.2 ml/min Flow rate: 1.2 ml/min

溶劑A=0.1%甲酸(水溶液) Solvent A = 0.1% formic acid (aqueous solution)

溶劑B=0.1%甲酸(乙腈) Solvent B = 0.1% formic acid (acetonitrile)

注入體積：5 ul Injection volume: 5 ul

UV檢測波長：215 nm UV detection wavelength: 215 nm

洗脫劑：0至3.5分鐘，恆定梯度：95%溶劑A+5%溶劑B至100%溶劑B；3.5分鐘至3.8分鐘，100%溶劑B；3.9至4.5分鐘，95%溶劑A+5%溶劑B。 Eluent: 0 to 3.5 minutes, constant gradient: 95% solvent A + 5% solvent B to 100% solvent B; 3.5 minutes to 3.8 minutes, 100% solvent B; 3.9 to 4.5 minutes, 95% solvent A + 5% Solvent B.

方法EMethod E

管柱：Waters Atlantis dC18(2.1×50 mm，5 um) Column: Waters Atlantis dC18 (2.1 × 50 mm, 5 um)

流速：1.0 ml/min Flow rate: 1.0 ml/min

溶劑A=0.1%甲酸(水溶液) Solvent A = 0.1% formic acid (aqueous solution)

溶劑B=0.1%甲酸(乙腈) Solvent B = 0.1% formic acid (acetonitrile)

注入體積：15 ul Injection volume: 15 ul

UV檢測波長：215 nm UV detection wavelength: 215 nm

洗脫劑：0至2.5分鐘，恆定梯度：95%溶劑A+5%溶劑B至100%溶劑B；2.5分鐘至2.7分鐘，100%溶劑B；2.71至3.5分鐘，95%溶劑A+5%溶劑B。 Eluent: 0 to 2.5 minutes, constant gradient: 95% solvent A + 5% solvent B to 100% solvent B; 2.5 minutes to 2.7 minutes, 100% solvent B; 2.71 to 3.5 minutes, 95% solvent A + 5% Solvent B.

MS檢測，使用Waters LCT或LCT Premier或ZQ或ZMD MS detection using Waters LCT or LCT Premier or ZQ or ZMD

UV檢測，使用Waters 2996光電二極體陣列或Waters 2787 UV或Waters 2788 UV UV detection using Waters 2996 Photodiode Array or Waters 2787 UV or Waters 2788 UV

製備型HPLC-MSPreparative HPLC-MS 方法AMethod A

管柱：Waters SunFire製備型C18 OBD(5 um 19×100 mm) Column: Waters SunFire Preparative C18 OBD (5 um 19×100 mm)

流速：26 ml/min Flow rate: 26 ml/min

溶劑A：0.1% TFA/水 Solvent A: 0.1% TFA / water

溶劑B：0.1% TFA/乙腈 Solvent B: 0.1% TFA / acetonitrile

注入體積：1000 μl Injection volume: 1000 μl

管柱溫度：室溫 Column temperature: room temperature

檢測：質量指導 Testing: quality guidance

洗脫劑：0 min至1分鐘，90%溶劑A+10%溶劑B；1分鐘至7.5 min，恆定梯度：90%溶劑A+10%溶劑B至100%溶劑B；7.5 min至9 min，100%溶劑B；9 min至9.1 min，恆定 梯度：100%溶劑B至90%溶劑A+10%溶劑B；9.1 min至10 min，90%溶劑A+10%溶劑B。 Eluent: 0 min to 1 min, 90% solvent A + 10% solvent B; 1 min to 7.5 min, constant gradient: 90% solvent A + 10% solvent B to 100% solvent B; 7.5 min to 9 min, 100% solvent B; 9 min to 9.1 min, constant Gradient: 100% solvent B to 90% solvent A + 10% solvent B; 9.1 min to 10 min, 90% solvent A + 10% solvent B.

Waters Micromass Platform LCZ單四極質譜儀 Waters Micromass Platform LCZ Single Quadrupole Mass Spectrometer

Waters 600溶劑遞送模組 Waters 600 solvent delivery module

Waters 515輔助幫浦 Waters 515 auxiliary pump

Waters 2487 UV檢測器 Waters 2487 UV Detector

Gilson 215自動取樣器及流份收集器 Gilson 215 Autosampler and Fraction Collector

方法BMethod B

管柱：Waters XBridge製備型C18 OBD(5 μm 19×100 mm) Column: Waters XBridge preparative C18 OBD (5 μm 19×100 mm)

溶劑A：0.2%氫氧化銨/水 Solvent A: 0.2% ammonium hydroxide / water

溶劑B：0.2%氫氧化銨/乙腈 Solvent B: 0.2% ammonium hydroxide / acetonitrile

注入體積：1000 μl Injection volume: 1000 μl

管柱溫度：室溫 Column temperature: room temperature

檢測：UV指導 Detection: UV guidance

洗脫劑：0 min至2.5 min，90%溶劑A+10%溶劑B；2.5 min至14.5 min，恆定梯度：90%溶劑A+10%溶劑B至100%溶劑B；14.5 min至16.5 min，100%溶劑B；16.5 min至16.1 min，100%溶劑B至90%溶劑A+10%溶劑B；16.1 min至17 min，90%溶劑A+10%溶劑B。 Eluent: 0 min to 2.5 min, 90% solvent A + 10% solvent B; 2.5 min to 14.5 min, constant gradient: 90% solvent A + 10% solvent B to 100% solvent B; 14.5 min to 16.5 min, 100% solvent B; 16.5 min to 16.1 min, 100% solvent B to 90% solvent A + 10% solvent B; 16.1 min to 17 min, 90% solvent A + 10% solvent B.

Gilson 119 UV/VIS檢測器 Gilson 119 UV/VIS detector

Gilson 306幫浦 Gilson 306 pump

Gilson 215自動取樣器及流份收集器 Gilson 215 Autosampler and Fraction Collector

方法CMethod C

管柱：Waters Sunfire製備型C18 OBD(5 μm 19×100 mm) Column: Waters Sunfire Preparative C18 OBD (5 μm 19×100 mm)

溶劑A：100%水(milli-Q級，18.2兆歐姆) Solvent A: 100% water (milli-Q grade, 18.2 megaohms)

溶劑B：乙腈，100% HPLC級 Solvent B: acetonitrile, 100% HPLC grade

注入體積：至多1500 μl Injection volume: up to 1500 μl

管柱溫度：室溫 Column temperature: room temperature

檢測：UV指導 Detection: UV guidance

洗脫劑：0 min至2.0 min，95%溶劑A+5%溶劑B；2.0-2.5 min，90%溶劑A+10%溶劑B；2.5 min至14.5 min，梯度：90%溶劑A+10%溶劑B至100%溶劑B；14.5 min至16.5 min，保持100%溶劑B梯度；16.5 min至16.7 min，100%溶劑B至95%溶劑A+5%溶劑B；16.1 min至17.2 min，95%溶劑A+5%溶劑B。 Eluent: 0 min to 2.0 min, 95% solvent A + 5% solvent B; 2.0-2.5 min, 90% solvent A + 10% solvent B; 2.5 min to 14.5 min, gradient: 90% solvent A + 10% Solvent B to 100% solvent B; 14.5 min to 16.5 min, 100% solvent B gradient; 16.5 min to 16.7 min, 100% solvent B to 95% solvent A + 5% solvent B; 16.1 min to 17.2 min, 95% Solvent A + 5% Solvent B.

Gilson 119 UV/VIS檢測器 Gilson 119 UV/VIS detector

Gilson 306幫浦 Gilson 306 pump

Gilson 215自動取樣器及流份收集器 Gilson 215 Autosampler and Fraction Collector

方法DMethod D

管柱：Waters SunFire製備型C18 OBD(5 um 19×100 mm) Column: Waters SunFire Preparative C18 OBD (5 um 19×100 mm)

流速：26 ml/min Flow rate: 26 ml/min

溶劑A：0.1%甲酸/水 Solvent A: 0.1% formic acid / water

溶劑B：0.1%甲酸/乙腈 Solvent B: 0.1% formic acid / acetonitrile

注入體積：1000 μl Injection volume: 1000 μl

管柱溫度：室溫 Column temperature: room temperature

檢測：質量指導 Testing: quality guidance

洗脫劑：0 min至1分鐘，90%溶劑A+10%溶劑B；1分鐘至7.5 min，恆定梯度：90%溶劑A+10%溶劑B至100%溶劑 B；7.5 min至9 min，100%溶劑B；9 min至9.1 min，恆定梯度：100%溶劑B至90%溶劑A+10%溶劑B；9.1 min至10 min，90%溶劑A+10%溶劑B。 Eluent: 0 min to 1 min, 90% solvent A + 10% solvent B; 1 min to 7.5 min, constant gradient: 90% solvent A + 10% solvent B to 100% solvent B; 7.5 min to 9 min, 100% solvent B; 9 min to 9.1 min, constant gradient: 100% solvent B to 90% solvent A + 10% solvent B; 9.1 min to 10 min, 90% solvent A + 10% Solvent B.

Waters Micromass Platform LCZ單四極質譜儀 Waters Micromass Platform LCZ Single Quadrupole Mass Spectrometer

Waters 600溶劑遞送模組 Waters 600 solvent delivery module

Waters 515輔助幫浦 Waters 515 auxiliary pump

Waters 2487 UV檢測器 Waters 2487 UV Detector

Gilson 215自動取樣器及流份收集器 Gilson 215 Autosampler and Fraction Collector

化合物命名Compound naming

使用ACD Labs 10.0命名軟體及ChemAxon Marvin sketch 5.5.1.0命名工具(其符合IUPAC命名方案)或藉由與熟習此項技術者所熟知之習用命名法類似之方法來對所有化合物進行命名。以TFA鹽形式來分離一些化合物，此並未由化學名稱反映。在本發明之含義內，化學名稱代表中性形式以及其TFA鹽或任一其他鹽、尤其醫藥上可接受之鹽(若適宜)形式之化合物。 All compounds were named using the ACD Labs 10.0 naming software and the ChemAxon Marvin sketch 5.5.1.0 naming tool (which conforms to the IUPAC naming scheme) or by methods similar to the conventional nomenclature well known to those skilled in the art. Some compounds were isolated as TFA salts, which were not reflected by chemical names. Within the meaning of the present invention, the chemical name represents a neutral form as well as a compound of its TFA salt or any other salt, especially a pharmaceutically acceptable salt, if appropriate.

在230-400網目矽膠上或在預填充二氧化矽柱上實施急驟矽膠層析。 Flash gel chromatography was performed on 230-400 mesh gel or on a pre-packed ceria column.

縮寫abbreviation

所使用之所有醯氯皆市面有售或根據下列一般方法製得：將4-氯苯甲酸(67 mg，425 μmol)、DCM(2 ml)及DMF(1滴)在氮下裝填至RBF中。將混合物冷卻至0℃，然後在攪拌的同時使用草醯氯(70 μL,811 μmol)進行處理。將混合物升溫至室溫並攪拌1 h。在真空下濃縮混合物且未經進一步純化即使用。 All of the ruthenium chloride used is commercially available or prepared according to the following general procedure: 4-chlorobenzoic acid (67 mg, 425 μmol), DCM (2 ml) and DMF (1 drop) are loaded into the RBF under nitrogen. . The mixture was cooled to 0 ° C and then treated with hydrazine chloride (70 μL, 811 μmol) while stirring. The mixture was warmed to room temperature and stirred for 1 h. The mixture was concentrated under vacuum and used without further purification.

實例1：6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-N-甲基-N-苯基-[1,3,5]三-2,4-二胺 Example 1 : 6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-N-methyl-N-phenyl-[1,3,5] -2,4-diamine

6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-N-甲基-N-苯基-[1,3,5]三-2,4-二胺市面有售((CAS-899373-19-4)例如Ambinter，Aurora Fine Chemicals，Tim Tec公司，Interchim)。另一選擇為，其可根據下列程序製得(方法1)：在0℃及氮氣氛下於密封管中，向存於無水甲苯(3 mL)及無水吡啶(1 mL)中之4-胺基-N-羥基-6-(甲基-苯基-胺基)-[1,3,5]三-2-甲脒(中間體，1,95 mg，0.37 mmol)之懸浮液中添加存於無水甲苯(3 mL)溶液中之2-呋喃甲醯氯(53 mg，0.41 mmol)。將混合物在室溫下攪拌2 h。在此時間之後，將混合物在115℃下加熱18 h，冷卻至室溫並在減壓下濃縮。使用DCM(10 mL)稀釋粗產物，使用水(5 mL)萃取並藉由無水硫酸鈉乾燥。在減壓下濃縮之後，藉由製 備型HPLC之方法A來純化粗產物以得到實例1(62 mg，50%)。 6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-N-methyl-N-phenyl-[1,3,5] -2,4-Diamine is commercially available ((CAS-899373-19-4) such as Ambinter, Aurora Fine Chemicals, Tim Tec, Interchim). Alternatively, it can be prepared according to the following procedure ( Method 1 ): 4-amine in anhydrous toluene (3 mL) and anhydrous pyridine (1 mL) in a sealed tube at 0 ° C under a nitrogen atmosphere. --N-hydroxy-6-(methyl-phenyl-amino)-[1,3,5] three To a suspension of 2-formamidine (intermediate, 1,95 mg, 0.37 mmol) was added 2-furoylpyridinium chloride (53 mg, 0.41 mmol) in anhydrous toluene (3 mL). The mixture was stirred at room temperature for 2 h. After this time, the mixture was heated at 115 ° C for 18 h, cooled to room temperature and concentrated under reduced pressure. The crude product was diluted with EtOAc (EtOAc)EtOAc. After concentration under reduced pressure, the crude material was purified by m.

實例39：N-苯基-6-(吡啶-2-基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺(方法2) Example 39 : N-phenyl-6-(pyridin-2-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine ( method 2 )

將存於吡啶(1 ml)中之吡啶甲酸(90 mg，0.73 mmol)與羰基二-咪唑(0.12 g，0.73 mmol)之混合物攪拌2 h。添加N-苯基-6-(5-噻唑-2-基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺(以與中間體4類似之方式製得，100 mg，0.41 mmol)且將所得混合物加熱至100℃並攪拌24 h。在單獨器皿中，將存於吡啶(1 ml)中之吡啶甲酸(90 mg，0.73 mmol)與羰基二-咪唑(0.12 g，0.73 mmol)之第二混合物攪拌90分鐘並添加至第一混合物中，在100℃下再攪拌24 h。將混合物冷卻至室溫，在真空下濃縮並懸浮於碳酸氫鈉水溶液中。過濾掉固體，使用水、乙酸乙酯及甲醇洗滌並在真空下乾燥以得到標題化合物(73 mg，54%)。 A mixture of picolinic acid (90 mg, 0.73 mmol) and carbonyldi-imidazole (0.12 g, 0.73 mmol) in pyridine (1 ml) was stirred for 2 h. Add N-phenyl-6-(5-thiazol-2-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-Diamine (prepared in a similar manner to Intermediate 4, 100 mg, 0.41 mmol) and the mixture was heated to 100 ° C and stirred for 24 h. A second mixture of picolinic acid (90 mg, 0.73 mmol) in pyridine (1 ml) and carbonyldi-imidazole (0.12 g, 0.73 mmol) was stirred in a separate vessel for 90 min and added to the first mixture. Stir at 24 ° C for another 24 h. The mixture was cooled to room temperature, concentrated under vacuum and suspended in aqueous sodium bicarbonate. The solid was filtered, washed with EtOAc EtOAcqqqqq

實例42：N-甲基-N-苯基-6-{5-[3-(2,2,2-三氟-乙氧基)-吡啶-2-基]-[1,2,4]二唑-3-基}-[1,3,5]三-2,4-二胺(方法3) Example 42 : N-Methyl-N-phenyl-6-{5-[3-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-[1,2,4] Diazol-3-yl}-[1,3,5]3 -2,4-diamine ( method 3 )

向存於DMSO(5 mL)中之2-{3-[4-胺基-6-(甲基-苯基-胺基)-[1,3,5]三-2-基]-[1,2,4]二唑-5-基}-吡啶-3-醇(以與中間體58類似之方式製得，85 mg，0.23 mmol)之溶液中添加氫氧化鉀(77 mg，138 μmol)及1,1,1-三氟-2-碘-乙烷(159 mg，760 μmol)。將所得溶液在120℃下加熱12 h，冷卻至室溫，使用乙酸乙酯(10 mL)稀釋並使用鹽水(3×10 mL)洗滌。藉由無水硫酸鈉乾燥有機層，過濾並在減壓下 濃縮。藉由製備型HPLC(方法A)純化粗產物以得到奶油色固體形式之標題化合物(58 mg，57%)。 2-{3-[4-Amino-6-(methyl-phenyl-amino)-[1,3,5]3 in DMSO (5 mL) -2-base]-[1,2,4] Potassium hydroxide (77 mg, 138 μmol) and 1,1 were added to a solution of oxazol-5-yl}-pyridin-3-ol (prepared in a similar manner to Intermediate 58, 85 mg, 0.23 mmol). 1-Trifluoro-2-iodo-ethane (159 mg, 760 μmol). The resulting solution was heated at 120 <0>C for 12 h then cooled to EtOAc EtOAc (EtOAc) The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by preparative EtOAc (EtOAc)

實例46：N-甲基-N-苯基-6-(5-六氫吡啶-1-基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺(方法4) Example 46 : N-Methyl-N-phenyl-6-(5-hexahydropyridin-1-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine ( method 4 )

在氮下，將六氫吡啶(51 μL,518 μmol)添加至存於無水DMF(1 mL)中之N-甲基-N-苯基-6-(5-三氯甲基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺(中間體60，100 mg，259 μmol)(先前已裝填至RBF中)中。將混合物在室溫下攪拌18 h。然後使用35 mL EtOAc稀釋混合物。然後使用氟化銨飽和水溶液(3×6 ml)、鹽水(6 mL)萃取溶液，藉由硫酸鈉乾燥，並在真空中濃縮。藉由製備型HPLC(方法A)純化且隨後使用碳酸氫鈉飽和水溶液實施游離鹽基化(free basing)之後，獲得標題化合物(17 mg，19%)。 Hexahydropyridine (51 μL, 518 μmol) was added to N-methyl-N-phenyl-6-(5-trichloromethyl-[1, in anhydrous DMF (1 mL). 2,4] Diazol-3-yl)-[1,3,5]3 -2,4-Diamine (intermediate 60, 100 mg, 259 μmol) (previously filled into RBF). The mixture was stirred at room temperature for 18 h. The mixture was then diluted with 35 mL EtOAc. The solution was then extracted with aq. aq. EtOAc (3.sub.3 mL), brine (EtOAc) The title compound (17 mg, 19%) was obtained after purified by preparative HPLC (Method A).

實例67：N-甲基-N-苯基-6-{5-[6-(2,2,2-三氟乙氧基)-吡啶-3-基]-[1,2,4]二唑-3-基}-[1,3,5]三-2,4-二胺 Example 67 : N-Methyl-N-phenyl-6-{5-[6-(2,2,2-trifluoroethoxy)-pyridin-3-yl]-[1,2,4] Diazol-3-yl}-[1,3,5]3 -2,4-diamine

在氮下，將4-胺基-N-羥基-6-(甲基-3-甲基苯基-胺基)-[1,3,5]三-2-甲脒(中間體1，100 mg，380 μmol)置於密封管中。然後，依次添加5 mL無水吡啶及6-(2,2,2-三氟乙氧基)-菸醯氯(以與中間體57類似之方式製得，91 mg，380 μmol)。將混合物在室溫下攪拌48 hr。在此時間之後，將混合物在115℃下加熱18 h，冷卻並在真空中濃縮。將粗製殘餘物裝載於存於最小量DCM中之2 g isolute二氧化矽管柱上並使用乙酸乙酯-庚烷(20-50%)洗脫以得到標題化合物(54 mg，32%)。 4-Amino-N-hydroxy-6-(methyl-3-methylphenyl-amino)-[1,3,5]3 under nitrogen -2-carboxamidine (intermediate 1, 100 mg, 380 μmol) was placed in a sealed tube. Then, 5 mL of anhydrous pyridine and 6-(2,2,2-trifluoroethoxy)-sodium chloride (prepared in a similar manner to the intermediate 57, 91 mg, 380 μmol) were sequentially added. The mixture was stirred at room temperature for 48 hr. After this time, the mixture was heated at 115 ° C for 18 h, cooled and concentrated in vacuo. The crude residue was taken on EtOAc EtOAc EtOAc (EtOAc)

實例70：2-{[4-胺基-6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-[1,3,5]三-2-基]-苯基-胺基}-乙醇(方法5) Example 70 : 2-{[4-Amino-6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2-yl]-phenyl-amino}-ethanol ( Method 5 )

將6-(5-呋喃-2-基-[1,2,4]二唑-3-基)-N-苯基-[1,3,5]三-2,4-二胺(以與實例2類似之方式製得，100 mg，310 μmol)及碳酸鉀(86 mg，620 μmol)在密封管中於DMF(5 ml)中一起攪拌。添加2-溴乙醇(26 μL,310 μmol)且將反應液在110℃下加熱18 h。添加碳酸鉀(43 mg，310 μmol)及2-溴乙醇(26 μL,310 μmol)並將反應液在110℃下再攪拌18 h。在冷卻並蒸發溶劑之後，將粗製殘餘物溶於水(30 mL)中並使用DCM(30 mL)萃取兩次。使用鹽水(30 mL)洗滌合併之有機萃取物，藉由無水硫酸鈉乾燥並在真空下濃縮。使用製備型HPLC(方法B)純化粗製殘餘物以得到期望標題化合物(14 mg，12%)。 6-(5-furan-2-yl-[1,2,4] Diazol-3-yl)-N-phenyl-[1,3,5] -2,4-Diamine (prepared in a similar manner to Example 2, 100 mg, 310 μmol) and potassium carbonate (86 mg, 620 μmol) were stirred together in DMF (5 ml) in a sealed tube. 2-Bromoethanol (26 μL, 310 μmol) was added and the reaction was heated at 110 ° C for 18 h. Potassium carbonate (43 mg, 310 μmol) and 2-bromoethanol (26 μL, 310 μmol) were added and the reaction was stirred at 110 ° C for an additional 18 h. After cooling and evaporation of the solvent, EtOAc EtOAc m. The combined organic extracts were washed with brine (30 mL) dry The crude residue was purified using EtOAcqqqqqqq

實例71：3-[4-胺基-6-(甲基-苯基-胺基)-[1,3,5]三-2-基]-[1,2,4]二唑-5-甲酸苄基醯胺(方法6) Example 71 : 3-[4-Amino-6-(methyl-phenyl-amino)-[1,3,5]3 -2-base]-[1,2,4] Diazol-5-formic acid benzylguanamine ( Method 6 )

將3-[4-胺基-6-(甲基-苯基-胺基)-[1,3,5]三-2-基]-[1,2,4]二唑-5-甲酸乙酯(以與實例73類似之方式製得，80 mg，230 μmol)、苄基胺(50 μL，230 μmol)及乙醇(4 mL)在回流下加熱4 h。在蒸發溶劑之後，將粗製殘餘物裝載於存於最小量DCM中之5 g isolute預填充二氧化矽管柱上並使用10-30%乙酸乙酯-庚烷洗脫以得到標題化合物(79 mg，85%)。 3-[4-Amino-6-(methyl-phenyl-amino)-[1,3,5]3 -2-base]-[1,2,4] Ethyl azole-5-carboxylate (80 mg, 230 μmol in a similar manner to Example 73), benzylamine (50 μL, 230 μmol) and ethanol (4 mL) were heated under reflux for 4 h. After evaporating the solvent, the crude residue was taken on a 5 g of yolute pre-filled ruthenium dioxide column in a minimum amount of DCM and eluted with 10-30% ethyl acetate-heptane to give the title compound (79 mg , 85%).

實例75：5-{3-[4-胺基-6-(甲基-苯基-胺基)-[1,3,5]三-2-基]-[1,2,4]二唑-5-基}-噻吩-2-甲酸甲基醯胺 Example 75 : 5-{3-[4-Amino-6-(methyl-phenyl-amino)-[1,3,5]3 -2-base]-[1,2,4] Diazol-5-yl}-thiophene-2-carboxylic acid methyl guanamine

向存於無水DMF(4 mL)中之5-{3-[4-胺基-6-(甲基-苯基-胺基)-[1,3,5]三-2-基]-[1,2,4]二唑-5-基}-噻吩-2-甲酸(中間體62，316 mg，0.80 mmol)中添加CDI(190 mg，1.17 mmol)。將混合物攪拌2 h且然後在50℃下加熱3 h。在此時間之後，添加額外CDI(190 mg，1.17 mmol)並將混合物在65℃下加熱18 h。在冷卻至室溫之後，添加甲胺(2 M，存於THF中，3.5 mL，7 mmol)並將混合物在室溫下攪拌1 hr。然後使用DCM(20 mL)稀釋反應混合物，使用氫氧化鈉水溶液(1 M，20 mL)、飽和鹽水(20 mL)萃取並藉由硫酸鈉乾燥。蒸發溶劑以得到橙色膠，藉由製備型HPLC(方法A)進行純化且然後藉由層析在使用4% MeOH-DCM洗脫之二氧化矽上進行純化以得到標題化合物(27 mg，8%)。 5-{3-[4-Amino-6-(methyl-phenyl-amino)-[1,3,5]3 in anhydrous DMF (4 mL) -2-base]-[1,2,4] CDI (190 mg, 1.17 mmol) was added to the oxazol-5-yl}-thiophene-2-carboxylic acid ( Intermediate 62, 316 mg, 0.80 mmol). The mixture was stirred for 2 h and then heated at 50 °C for 3 h. After this time, additional CDI (190 mg, 1.17 mmol) was added and the mixture was heated at 65 °C for 18 h. After cooling to room temperature, methylamine (2M in THF, 3.5 mL, 7 mmol) was added and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) The solvent was evaporated to give the title compound (27 mg, 8%). ).

實例76：6-[5-(2-甲氧基-吡啶-3-基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺 Example 76 : 6-[5-(2-Methoxy-pyridin-3-yl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine

向3-{3-[4-胺基-6-(甲基-苯基-胺基)-[1,3,5]三-2-基]-[1,2,4]二唑-5-基}-吡啶-2-醇(中間體63，0.31 mmol)中添加DMF(2 mL)、碳酸鉀(85 mg，0.52 mmol)及碘甲烷(19 μL,0.31 mmol)。將所得混合物攪拌2h，然後添加額外碘甲烷(40 μL,0.62 mmol)。將反應液再攪拌1.5 h，然後添加額外碘甲烷(60 μL,0.93 mmol)。重複此順序兩次以上，然後起始材料已耗盡。使用乙酸乙酯(10 mL)稀釋粗製混合物，使用水(5 mL)萃取並藉由無水硫酸鈉乾燥。在減壓下濃縮之後，藉由層析在使用2%至6% MeOH-DCM梯度洗脫之二氧化矽上純化粗產物，且然後藉由使用熱甲醇(2 mL) 研磨來純化粗產物以得到標題化合物(44 mg，38%) To 3-{3-[4-amino-6-(methyl-phenyl-amino)-[1,3,5] three -2-base]-[1,2,4] To a solution of oxazol-5-yl}-pyridin-2-ol (Intermediate 63, 0.31 mmol), DMF (2 mL), EtOAc (EtOAc) The resulting mixture was stirred for 2 h then additional methyl iodide (40 uL, 0.62 mmol) was then added. The reaction was stirred for a further 1.5 h then additional methyl iodide (60 uL, 0.93 mmol). Repeat this sequence more than twice, then the starting material is exhausted. The crude mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. After concentrating under reduced pressure, the crude material was purified by chromatography eluting with EtOAc EtOAc (EtOAc) The title compound was obtained (44 mg, 38%)

實例79：(5-{3-[4-胺基-6-(甲基-苯基-胺基)-[1,3,5]三-2-基]-[1,2,4]二唑-5-基}-噻吩-2-基)-嗎啉-4-基-甲酮 Example 79 : (5-{3-[4-Amino-6-(methyl-phenyl-amino)-[1,3,5]3 -2-base]-[1,2,4] Diazol-5-yl}-thiophen-2-yl)-morpholin-4-yl-ketone

向存於無水DMF(0.5 mL)中之5-{3-[4-胺基-6-(甲基-苯基-胺基)-[1,3,5]三-2-基]-[1,2,4]二唑-5-基}-噻吩-2-甲酸(以與中間體62類似之方式製得，24 mg，61 μmol)中添加(3-二甲基胺基-丙基)-乙基-碳化二亞胺鹽酸鹽(17 mg，73 μmol)、HOAt(4.1 mg，31 μmol)及嗎啉(10 μL,92 μmol)。將反應混合物攪拌2 h，添加額外嗎啉(10 μL,92 μmol)及(3-二甲基胺基-丙基)-乙基-碳化二亞胺鹽酸鹽(9 mg，39 μmol)。將混合物再攪拌2 h，然後使用乙酸乙酯(5 mL)稀釋並使用檸檬酸水溶液(1 M，5 mL)、1 M NaOH(5 mL)、飽和鹽水(5 mL)萃取並藉由硫酸鈉乾燥。去除溶劑以得到膠，在使用乙酸乙酯-10%庚烷洗脫之二氧化矽上純化以得到標題化合物(20 mg，71%)。 5-{3-[4-Amino-6-(methyl-phenyl-amino)-[1,3,5]3 in anhydrous DMF (0.5 mL) -2-base]-[1,2,4] Addition of (3-dimethylamino-propyl)-ethyl-carbonization to oxazol-5-yl}-thiophene-2-carboxylic acid (prepared in a similar manner to intermediate 62, 24 mg, 61 μmol) Diimine hydrochloride (17 mg, 73 μmol), HOAt (4.1 mg, 31 μmol) and morpholine (10 μL, 92 μmol). The reaction mixture was stirred for 2 h and additional morpholine (10 uL, <RTI ID=0.0>>&&&&&&&&&&&&&&& The mixture was stirred for additional 2 h, then diluted with EtOAc (5 mL) and EtOAc (1 M, 5 mL), 1 M NaOH (5 mL) dry. The solvent was removed to give the title compound (20 mg, 71%).

實例137：{3-[4-胺基-6-(甲基-苯基-胺基)-[1,3,5]三-2-基]-[1,2,4]二唑-5-基}-[3-(4-氟-苯基)-氮雜環丁-1-基]-甲酮 Example 137 : {3-[4-Amino-6-(methyl-phenyl-amino)-[1,3,5]3 -2-base]-[1,2,4] Diazol-5-yl}-[3-(4-fluoro-phenyl)-azetidin-1-yl]-methanone

向N-甲基-N-苯基-6-(5-三氯甲基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺(以與中間體60類似之方式製得，63 mg，0.16 mmol)中添加3-(4-氟-苯基)-氮雜環丁烷鹽酸鹽(中間體122，39 mg，0.19 mmol)。添加二異丙基乙胺(42 μL)及二烷(1 mL)並將混合物在70℃下加熱4 h。使用1 M檸檬酸稀釋混合物以得到沈澱物，過濾該沈澱物。使用1 M碳酸氫鈉水溶液(2 mL)、水(2 mL)洗滌墊，且然後將 固體在MeOH(2 mL)中製成漿液以得到標題化合物(48 mg，65%)。 To N-methyl-N-phenyl-6-(5-trichloromethyl-[1,2,4] Diazol-3-yl)-[1,3,5]3 2-(4-Fluoro-phenyl)-azetidine hydrochloride (Intermediate 122) was added to the 2,4-diamine (prepared in a similar manner to the intermediate 60, 63 mg, 0.16 mmol). , 39 mg, 0.19 mmol). Add diisopropylethylamine (42 μL) and two Alkane (1 mL) and the mixture was heated at 70 ° C for 4 h. The mixture was diluted with 1 M citric acid to give a precipitate which was filtered. The pad was washed with aq. EtOAc (2 mL) (EtOAc)

實例143：6-{5-[6-(2-甲氧基-乙氧基甲基)-吡啶-3-基]-[1,2,4]二唑-3-基}-N-甲基-N-苯基-[1,3,5]三-2,4-二胺(方法7) Example 143 : 6-{5-[6-(2-Methoxy-ethoxymethyl)-pyridin-3-yl]-[1,2,4] Diazol-3-yl}-N-methyl-N-phenyl-[1,3,5] -2,4-diamine ( method 7 )

在氮氣氛下，向無水THF(2 mL)中添加2-甲氧基乙醇(20 mg，0.26 mmol)，隨後添加氫化鈉(存於礦物油中之60%分散液，10 mg，0.26 mmol)。將混合物在室溫下攪拌10 min，然後添加甲烷磺酸5-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-基]甲酯(中間體128，78 mg，0.17 mmol)。混合物變黑且將其在室溫下攪拌18 h。使用DCM(5 mL)稀釋混合物且使用1 M碳酸氫鈉水溶液(5 mL)、飽和鹽水(5 mL)洗滌並藉由硫酸鈉乾燥。蒸發溶劑以得到膠，藉由HPLC(方法A)純化該膠以得到標題化合物(6.8 mg，8%)。 2-methoxyethanol (20 mg, 0.26 mmol) was added to dry THF (2 mL), then sodium hydride (60% dispersion in mineral oil, 10 mg, 0.26 mmol) . The mixture was stirred at room temperature for 10 min, then 5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three methanesulfonate was added. -2-yl}-1,2,4- Diazol-5-yl)pyridin-2-yl]methyl ester (Intermediate 128, 78 mg, 0.17 mmol). The mixture turned black and was stirred at room temperature for 18 h. The mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. The solvent was evaporated to give the title compound (mjjjjjjj

實例144：N-甲基-N-苯基-6-{5-[6-(四氫-呋喃-3-基氧基甲基)-吡啶-3-基]-[1,2,4]二唑-3-基}-[1,3,5]三-2,4-二胺 Example 144 : N-Methyl-N-phenyl-6-{5-[6-(tetrahydro-furan-3-yloxymethyl)-pyridin-3-yl]-[1,2,4] Diazol-3-yl}-[1,3,5]3 -2,4-diamine

向存於3-羥基四氫呋喃(0.15 mL)中之乙酸釕(3 mg，0.007 mmol)、三乙胺(15 μL,0.11 mmol)之溶液中添加6-[5-(6-N-甲苯磺醯基-亞肼基甲基-吡啶-3-基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺(中間體100，30 mg，0.55 mmol)。將混合物在90℃下加熱2.5 h。在冷卻至室溫之後，使用DCM(2 mL)稀釋混合物，使用1 M碳酸氫鈉水溶液(2 mL)萃取並藉由無水硫酸鈉乾燥。蒸 發溶劑以得到紅色膠，藉由HPLC(方法C)純化該紅色膠以得到標題化合物(2.3 mg，9.4%)。 Add 6-[5-(6-N-toluenesulfonate) to a solution of cesium acetate (3 mg, 0.007 mmol) and triethylamine (15 μL, 0.11 mmol) in 3-hydroxytetrahydrofuran (0.15 mL). Base-indolylmethyl-pyridin-3-yl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-Diamine (intermediate 100, 30 mg, 0.55 mmol). The mixture was heated at 90 ° C for 2.5 h. After cooling to room temperature, the mixture was diluted with EtOAc EtOAc. The solvent was evaporated to give the title compound (2.3 mg, 9.4%).

實例145：外消旋N-甲基-N-苯基-6-{5-[(1R,3R,5S)-8-(3,3,3-三氟-丙基)-8-氮雜-雙環[3.2.1]辛-3-基]-[1,2,4]二唑-3-基}-[1,3,5]三-2,4-二胺(方法8) Example 145 : Racemic N-methyl-N-phenyl-6-{5-[(1R,3R,5S)-8-(3,3,3-trifluoro-propyl)-8-aza -bicyclo[3.2.1]oct-3-yl]-[1,2,4] Diazol-3-yl}-[1,3,5]3 -2,4-diamine ( method 8 )

向外消旋6-[(1R,3R,5S)-5-(8-氮雜-雙環[3.2.1]辛-3-基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺(中間體101，30 mg，0.08 mmol)中添加DCE(1 mL)、冰乙酸(14 mg)、氰基硼氫化鈉(8 mg，0.12 mmol)及3,3,3-三氟丙醛(13 mg，0.1 mmol)。將混合物攪拌2 h，然後添加額外氰基硼氫化鈉(8 mg，0.12 mmol)及3,3,3-三氟丙醛(13 mg，0.1 mmol)並將混合物在室溫下攪拌18 h。然後添加額外氰基硼氫化鈉(16 mg，0.24 mmol)及3,3,3-三氟丙醛(26 mg，0.2 mmol)並將混合物在室溫下攪拌2 h。然後使用DCM(3 mL)稀釋反應液，使用1 M碳酸氫鈉水溶液(5 mL)萃取並藉由硫酸鈉乾燥。蒸發以得到淺黃色固體，藉由HPLC(方法A)純化該淺黃色固體以得到標題化合物(20 mg，53%)。 Racemic 6-[(1R,3R,5S)-5-(8-aza-bicyclo[3.2.1]oct-3-yl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-Diamine (Intermediate 101, 30 mg, 0.08 mmol) with DCE (1 mL), glacial acetic acid (14 mg), sodium cyanoborohydride (8 mg, 0.12 mmol) and 3,3, 3-Trifluoropropanal (13 mg, 0.1 mmol). The mixture was stirred for 2 h then additional sodium cyanoborohydride (8 mg, 0.12 mmol) and 3,3,3-trifluoropropanal (13 mg, 0.1 mmol) was added and the mixture was stirred at room temperature for 18 h. Additional sodium cyanoborohydride (16 mg, 0.24 mmol) and 3,3,3-trifluoropropanal (26 mg, 0.2 mmol) were then added and the mixture was stirred at room temperature for 2 h. The reaction was then diluted with EtOAc (EtOAc)EtOAc. The title compound (20 mg, 53%) was obtained.

實例156：2-N-(2-甲氧基乙基)-2-N-苯基-6-{5-[6-(2,2,2-三氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺 Example 156 : 2-N-(2-Methoxyethyl)-2-N-phenyl-6-{5-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl ]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine

在室溫下，將2-N-苯基-6-{5-[6-(2,2,2-三氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺(以與實例41類似之方式製得，0.100 g，0.232 mmol)添加至存於 DMF(3 mL)中之碳酸銫(0.151 g，0.465 mmol)中，隨後添加1-溴-2-甲氧基乙烷(22 μL，0.232 mmol)。將反應混合物在室溫下攪拌1 h且然後加熱至50℃保持18 h。將反應混合物冷卻至室溫並在減壓下濃縮。將殘留物溶於EtOAc中並使用水洗滌。藉由無水硫酸鈉乾燥有機層，過濾並在減壓下濃縮以獲得褐色固體。藉由製備型HPLC(方法A)純化固體以得到標題化合物(2.8 mg，2.5%)。 2-N-Phenyl-6-{5-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,2,4- at room temperature Diazol-3-yl}-1,3,5-three -2,4-Diamine (prepared in a similar manner to Example 41, 0.100 g, 0.232 mmol) was added to cesium carbonate (0.151 g, 0.465 mmol) in DMF (3 mL). Bromo-2-methoxyethane (22 μL, 0.232 mmol). The reaction mixture was stirred at room temperature for 1 h and then heated to 50 ° C for 18 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with water. The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated The solid was purified by preparative EtOAc (EtOAc)

實例157：2-N-(2-甲氧基乙基)-4-N-苯基-6-{5-[6-(2,2,2-三氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺 Example 157 : 2-N-(2-Methoxyethyl)-4-N-phenyl-6-{5-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl ]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine

根據針對實例156所述之方法自2-N-苯基-6-{5-[6-(2,2,2-三氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺(以與實例41類似之方式製得，0.100 g，0.232 mmol)來製備2-N-(2-甲氧基乙基)-4-N-苯基-6-{5-[6-(2,2,2-三氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺。藉由製備型HPLC(方法A)純化粗製化合物以得到標題化合物(1.6 mg，1.4%)。 According to the method described for Example 156, from 2-N-phenyl-6-{5-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,2,4- Diazol-3-yl}-1,3,5-three 2-2,4-Diamine (prepared in a similar manner to Example 41, 0.100 g, 0.232 mmol) to give 2-N-(2-methoxyethyl)-4-N-phenyl-6-{ 5-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine. The crude compound was purified by preparative EtOAc (EtOAc)

實例159：1-[4-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)六氫吡啶-1-基]-2,2,2-三氟乙烷-1-酮(方法9) Example 159 : 1-[4-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)hexahydropyridin-1-yl]-2,2,2-trifluoroethane-1-one ( Method 9 )

向存於DCM(5 mL)中之2-N-甲基-2-N-苯基-6-[5-(六氫吡啶-4-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺鹽酸鹽(中間體105，0.050 g，0.129 mmol)中添加三乙胺(44.8 μL，0.321 mmol)且將反應混合物在室溫下攪拌10 min。添 加三氟乙酸酐(24 μL，0.257 mmol)且將混合物在室溫下攪拌36 h。使用DCM稀釋混合物並使用碳酸氫鈉飽和水溶液洗滌。藉由無水硫酸鈉乾燥有機層，過濾並在減壓下濃縮。藉由使用庚烷研磨來純化粗製化合物並藉由在真空下過濾來收集沈澱物以得到標題化合物(2.4 mg，4.2%)。 2-N-methyl-2-N-phenyl-6-[5-(hexahydropyridin-4-yl)-1,2,4- in DCM (5 mL) Diazol-3-yl]-1,3,5-three To the 2,4-diamine hydrochloride (Intermediate 105, 0.050 g, 0.129 mmol), triethylamine (44.8 <RTIgt; Trifluoroacetic anhydride (24 μL, 0.257 mmol) was added and the mixture was stirred at room temperature for 36 h. The mixture was diluted with DCM and washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The crude compound was purified by EtOAc EtOAc (EtOAc)

實例161：1-[4-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)六氫吡啶-1-基]-2-甲基丙烷-1-酮 Example 161 : 1-[4-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)hexahydropyridin-1-yl]-2-methylpropan-1-one

在室溫下，向存於DMF(5 mL)中之2-甲基丙酸(27.0 μL，0.299 mmol)中添加DIPEA(109 μL，0.624 mmol)且將混合物攪拌5 min。向反應混合物中添加六氟磷酸(1H-苯并三唑-1-基氧基)[叁(二甲基胺基)]鏻(0.121 g，0.274 mmol)並攪拌5 min。添加2-N-甲基-2-N-苯基-6-[5-(六氫吡啶-4-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺鹽酸鹽(中間體105，0.100 g，0.249 mmol)且將混合物在室溫下攪拌18 h。使用水稀釋反應混合物，使用EtOAc萃取並使用鹽水洗滌有機層。藉由無水硫酸鈉乾燥合併之有機萃取物，過濾並在減壓下濃縮。藉由FCC(DCM：MeOH 90：10)純化粗製化合物以得到標題化合物(96 mg，88%)。 DIPEA (109 μL, 0.624 mmol) was added to 2-methylpropionic acid (27.0 μL, 0.299 mmol) in DMF (5 mL) and the mixture was stirred for 5 min. To the reaction mixture was added hexafluorophosphoric acid (1H-benzotriazol-1-yloxy)[indole (dimethylamino)]indole (0.121 g, 0.274 mmol) and stirred for 5 min. Add 2-N-methyl-2-N-phenyl-6-[5-(hexahydropyridin-4-yl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-Diamine hydrochloride (Intermediate 105, 0.100 g, 0.249 mmol). The reaction mixture was diluted with water, extracted with EtOAc and brine brine. The combined organic extracts were dried with anhydrous sodium sulfate, filtered and evaporated. The crude compound was purified by EtOAcqqqqqqq

實例167：2-N-甲基-2-N-苯基-6-(5-{4-[(2,2,2-三氟乙氧基)甲基]六氫吡啶-1-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺 Example 167 : 2-N-Methyl-2-N-phenyl-6-(5-{4-[(2,2,2-trifluoroethoxy)methyl]hexahydropyridin-1-yl} -1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine

在室溫下，將2-N-甲基-2-N-苯基-6-[5-(三氯甲基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺(以與中間體60類似之方式製得，0.110 g，0.285 mmol)添加至存於DMF(2 mL)中之 碳酸鉀(0.071 g，0.518 mmol)之混合物中且將混合物攪拌5 min。向反應混合物中添加4-[(2,2,2-三氟乙氧基)甲基]六氫吡啶鹽酸鹽(中間體179，0.060 g，0.259 mmol)並在室溫下攪拌2 h。在減壓下濃縮反應混合物，溶於水中並使用EtOAc萃取。藉由無水硫酸鈉乾燥合併之有機萃取物，過濾並在減壓下濃縮。藉由FCC(EtOAc：庚烷，1：1)及製備型HPLC(方法A)純化粗製化合物以得到標題化合物(22.1 mg，18%)。 2-N-methyl-2-N-phenyl-6-[5-(trichloromethyl)-1,2,4- at room temperature Diazol-3-yl]-1,3,5-three -2,4-Diamine (prepared in a similar manner to the intermediate 60, 0.110 g, 0.285 mmol) was added to a mixture of potassium carbonate (0.071 g, 0.518 mmol) in DMF (2 mL) The mixture was stirred for 5 min. 4-[(2,2,2-Trifluoroethoxy)methyl]hexahydropyridine hydrochloride (Intermediate 179, 0.060 g, 0.259 mmol) was added to the mixture and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, dissolved in water andEtOAc. The combined organic extracts were dried with anhydrous sodium sulfate, filtered and evaporated. The crude compound was purified by EtOAc EtOAcjjjjjjj

實例173：6-[5-(1-苄基六氫吡啶-4-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺 Example 173 : 6-[5-(1-Benzylhexahydropyridin-4-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine

在0℃下，向存於DMF(2 mL)中之2-N-甲基-2-N-苯基-6-[5-(六氫吡啶-4-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺鹽酸鹽(中間體105，0.100 g，0.257 mmol)中添加氫化鈉(存於礦物油中之60%分散液，0.012 g，0.309 mmol)並攪拌5 min。添加苄基溴(30.6 μL，0.257 mmol)，將反應混合物升溫至室溫並攪拌18 h。然後將混合物在45℃下加熱18 h並使用苄基溴(30.6 μL，0.257 mmol)再處理。然後將混合物在50℃下加熱18 h並在室溫下攪拌72 h。使用DCM稀釋反應混合物且然後使用碳酸氫鈉飽和水溶液及鹽水洗滌。藉由無水硫酸鈉乾燥有機層，過濾並在減壓下濃縮。藉由製備型HPLC(方法A)純化粗製化合物以得到標題化合物(2.2 mg，1.9%)。 2-N-methyl-2-N-phenyl-6-[5-(hexahydropyridin-4-yl)-1,2,4- in DMF (2 mL) at 0 °C Diazol-3-yl]-1,3,5-three To the 2,4-diamine hydrochloride (Intermediate 105, 0.100 g, 0.257 mmol), sodium hydride (60% dispersion in mineral oil, 0.012 g, 0.309 mmol) was added and stirred for 5 min. Benzyl bromide (30.6 μL, 0.257 mmol) was added and the mixture was warmed to room temperature and stirred for 18 h. The mixture was then heated at 45 &lt;0&gt;C for 18 h and treated with benzyl bromide (30.6 [mu]L, 0.257 mmol). The mixture was then heated at 50 ° C for 18 h and at room temperature for 72 h. The reaction mixture was diluted with DCM and then washed with a saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The crude compound was purified by preparative EtOAc (EtOAc)

實例174：2-N-苯基-6-(5-{4-[(2,2,2-三氟乙氧基)甲基]六氫吡啶-1-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺 Example 174 : 2-N-Phenyl-6-(5-{4-[(2,2,2-trifluoroethoxy)methyl]hexahydropyridin-1-yl}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine

向存於DMF(2 mL)中之2-N-苯基-6-[5-(三氯甲基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺(中間體134，0.100 g，0.268 mmol)中添加DIPEA(93.6 μL，0.537 mmol)且將混合物在室溫下攪拌5 min。添加4-[(2,2,2-三氟乙氧基)甲基]六氫吡啶鹽酸鹽(中間體179，0.063 g，0.268 mmol)且將混合物在室溫下攪拌18 h。然後將反應混合物加熱至50℃保持18 h並加熱至70℃保持36 h。在減壓下濃縮反應混合物，溶於EtOAc中並使用水洗滌。藉由無水硫酸鈉乾燥有機層，過濾並在減壓下濃縮。藉由製備型HPLC(方法C)純化粗製化合物以得到標題化合物(10.8 mg，8.9%)。 2-N-phenyl-6-[5-(trichloromethyl)-1,2,4- in DMF (2 mL) Diazol-3-yl]-1,3,5-three To the 2,4-diamine (Intermediate 134, 0.100 g, 0.268 mmol) was added DIPEA (9. 4-[(2,2,2-Trifluoroethoxy)methyl]hexahydropyridine hydrochloride (Intermediate 179, 0.063 g, 0.268 mmol) was added and the mixture was stirred at room temperature for 18 h. The reaction mixture was then heated to 50 ° C for 18 h and heated to 70 ° C for 36 h. The reaction mixture was concentrated under reduced vacuolqqq elut elut elut The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The crude compound was purified by EtOAcqqqqqqq

實例178：2-N-甲基-2-N-苯基-6-[5-(4-{[(2,2,2-三氟乙烷)磺醯基]甲基}六氫吡啶-1-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺(方法10) Example 178 : 2-N-Methyl-2-N-phenyl-6-[5-(4-{[(2,2,2-trifluoroethane)sulfonyl]methyl}hexahydropyridine- 1-base)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine ( method 10 )

在0℃下，向存於DCM(2 mL)中之2-N-甲基-2-N-苯基-6-[5-(4-{[(2,2,2-三氟乙基)硫基]甲基}六氫吡啶-1-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺(批次1：來自實例175，36.8 mg，0.077 mmol)添加3-氯過氧苯甲酸(13.22 mg，0.077 mmol)。將反應混合物在0℃下攪拌1 h且然後在室溫下攪拌1 h。使用3-氯過氧苯甲酸(13.22 mg，0.077 mmol)再處理反應混合物並在室溫下攪拌1 h。使用5%硫代硫酸鈉水溶液及碳酸氫鈉飽和水溶液洗滌反應混合物。藉由無水硫酸鈉乾燥有機層，過濾並在減壓下濃縮。藉由製備型HPLC(方法A)純化粗製化合物以得到標題化合物(6.2 mg，16%)。 2-N-methyl-2-N-phenyl-6-[5-(4-{[(2,2,2-trifluoroethyl) in DCM (2 mL) at 0 °C )thio]methyl}hexahydropyridin-1-yl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-Diamine (batch 1: from Example 175, 36.8 mg, 0.077 mmol) was added 3-chloroperoxybenzoic acid (13.22 mg, 0.077 mmol). The reaction mixture was stirred at 0 °C for 1 h and then at room temperature for 1 h. The reaction mixture was re-treated with 3-chloroperoxybenzoic acid (13.22 mg, 0.077 mmol) and stirred at room temperature for 1 h. The reaction mixture was washed with a 5% aqueous sodium thiosulfate solution and a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The crude compound was purified by EtOAc (EtOAc)

實例216：6-(5-{4-[(環丙基甲氧基)甲基]六氫吡啶-1-基}-1,2,4-二唑-3-基)-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺 Example 216 : 6-(5-{4-[(cyclopropylmethoxy)methyl]hexahydropyridin-1-yl}-1,2,4- Diazol-3-yl)-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine

在室溫下，將碳酸鉀(0.107 g，0.776 mmol)及2-N-甲基-2-N-苯基-6-[5-(三氯甲基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺(以與中間體60類似之方式製得，0.150 g，0.388 mmol)添加至存於DMF(5 mL)中之4-[(環丙基甲氧基)甲基]六氫吡啶鹽酸鹽(中間體198，0.160 g，0.776 mmol)之溶液中。將反應混合物在室溫下攪拌18 h且然後在真空下蒸發以去除DMF。將粗製殘餘物溶於EtOAc(5 mL)中並使用水(3×3 mL)洗滌。合併水性洗滌液，使用EtOAc(2×3 mL)再萃取。合併有機萃取物，藉由硫酸鈉乾燥，過濾並蒸發以提供粗製褐色殘餘物，藉由製備型HPLC(方法B)純化該粗製褐色殘餘物以得到灰白色固體形式之標題化合物(28 mg，16%)。 Potassium carbonate (0.107 g, 0.776 mmol) and 2-N-methyl-2-N-phenyl-6-[5-(trichloromethyl)-1,2,4- at room temperature Diazol-3-yl]-1,3,5-three -2,4-Diamine (prepared in a similar manner to Intermediate 60, 0.150 g, 0.388 mmol) was added to 4-[(cyclopropylmethoxy)methyl] in DMF (5 mL) A solution of the hexahydropyridine hydrochloride (Intermediate 198, 0.160 g, 0.776 mmol). The reaction mixture was stirred at room temperature for 18 h and then evaporated under vacuum to remove DMF. The crude residue was taken into EtOAc (5 mL)EtOAc. The aqueous washes were combined and extracted with EtOAc (2×3 mL). The combined organic extracts were dried with EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH ).

實例221：2-N-苯基-6-[5-(六氫吡啶-1-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺(方法11) Example 221 : 2-N-phenyl-6-[5-(hexahydropyridin-1-yl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine ( Method 11 )

在室溫下，將六氫吡啶(0.483 mL，4.902 mmol)添加至存於二烷(4 mL)中之2-N-苯基-6-[5-(三氯甲基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺(以與中間體134類似之方式製得，0.913 g，2.451 mmol)之溶液中。將反應混合物在室溫下攪拌兩天，然後濃縮。將所得殘餘物溶於EtOAc及水中，並依次使用1 M HCl水溶液及鹽水洗滌。藉由硫酸鈉乾燥有機相，過濾並濃縮。藉由急驟層析(庚烷：EtOAc 3：2)純化粗製化合物以得到標題化合物(100 mg，26%)。 Add hexahydropyridine (0.483 mL, 4.902 mmol) to the second at room temperature 2-N-phenyl-6-[5-(trichloromethyl)-1,2,4- in alkane (4 mL) Diazol-3-yl]-1,3,5-three -2,4-Diamine (prepared in a similar manner to Intermediate 134, 0.913 g, 2.451 mmol). The reaction mixture was stirred at room temperature for two days and then concentrated. The residue was dissolved in EtOAc and EtOAc (EtOAc)EtOAc. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude compound was purified by EtOAc EtOAcjjjjjjj

實例256：2-N-甲基-2-N-苯基-6-{5-[1-(2,2,2-三氟乙基)-1H-吡唑-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺(方法12) Example 256 : 2-N-methyl-2-N-phenyl-6-{5-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]-1, 2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine ( method 12 )

將1-(2,2,2-三氟乙基)-1H-吡唑-3-甲酸甲酯(中間體204，0.312 g，1.5 mmol)溶於THF(2 mL)、MeOH(2 mL)及水(1 mL)之混合物中；添加氫氧化鋰(0.188 g，4.5 mmol)且將混合物在室溫下攪拌16 h。濃縮混合物，將殘餘物溶於水(1 mL)中且中和混合物。使用EtOAc(2×10 mL)萃取此混合物，藉由硫酸鈉乾燥有機萃取物並在真空下濃縮。使用戊烷(2×10 mL)洗滌粗製材料以得到1-(2,2,2-三氟乙基)-1H-吡唑-3-甲酸(0.200 g，69%)。然後根據針對實例251所述之方法自1-(2,2,2-三氟乙基)-1H-吡唑-3-甲酸(0.159 g，0.820 mmol)及4-胺基-N-羥基-6-[甲基(苯基)胺基]-1,3,5-三-2-甲脒(以與中間體1類似之方式製得，0.125 g，0.483 mmol)來製備2-N-甲基-2-N-苯基-6-{5-[1-(2,2,2-三氟乙基)-1H-吡唑-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺以得到標題化合物(0.110 g，55%)。 Methyl 1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxylate (Intermediate 204, 0.312 g, 1.5 mmol) eluted In a mixture of water (1 mL); lithium hydroxide (0.188 g, 4.5 mmol) was added and the mixture was stirred at room temperature for 16 h. The mixture was concentrated and the residue dissolved in water (1 mL) The mixture was extracted with EtOAc (2×10 mL)EtOAc. The crude material was washed with pentane (2×10 mL) to give 1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxylic acid (0.200 g, 69%). Then from 1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxylic acid (0.159 g, 0.820 mmol) and 4-amino-N-hydroxy- 6-[Methyl(phenyl)amino]-1,3,5-three 2-N-methylindole (prepared in a similar manner to Intermediate 1, 0.125 g, 0.483 mmol) to give 2-N-methyl-2-N-phenyl-6-{5-[1-(2, 2,2-trifluoroethyl)-1H-pyrazol-3-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-Diamine to give the title compound (0.110 g, 55%).

實例258：3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-N-(6-甲氧基吡啶-3-基)-1,2,4-二唑-5-甲醯胺(方法13) Example 258 : 3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-N-(6-methoxypyridin-3-yl)-1,2,4- Diazol-5-formamide ( Method 13 )

在0℃下，經5 min時段向存於甲苯(10 mL)中之3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-甲酸乙酯(以與實例73類似之方式製得，0.2 g，0.58 mmol)之溶液中添加三甲基鋁(2 M，存於甲苯中，0.88 mL，1.7 mmol)且然後將混合物在室溫下攪拌2 h。添加6-甲氧基吡啶-3-胺(0.21 g，1.7 mmol)且將混合物加熱至60℃保持15 h。將混合物冷卻至室溫並使用冰水驟冷。使用EtOAc(3×20 mL)萃取混合物且在真空下濃縮有機層。將殘餘物在乙腈中經30 min製成漿液且過濾掉所得沈澱物以得到標題化合物(0.100 g，43%)。 3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three in toluene (10 mL) at 0 °C over 5 min -2-yl}-1,2,4- To a solution of oxazol-5-carboxylate (prepared in a similar manner to Example 73, 0.2 g, 0.58 mmol) was added trimethylaluminum (2 M in toluene, 0.88 mL, 1.7 mmol) and then The mixture was stirred at room temperature for 2 h. 6-Methoxypyridin-3-amine (0.21 g, 1.7 mmol) was added and the mixture was heated to 60 ° C for 15 h. The mixture was cooled to room temperature and quenched with ice water. The mixture was extracted with EtOAc (3×20 mL)EtOAc. The residue was slurried in EtOAc (30 min).

實例261：2-N-甲基-6-[5-(3-苯氧基環丁基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺 Example 261 : 2-N-Methyl-6-[5-(3-phenoxycyclobutyl)-1,2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine

將三乙胺(2 mL，14.04 mmol)及苄基溴(1.2 mL，10.0 mmol)添加至存於THF(10 mL)中之3-側氧基環丁烷-1-甲酸(1.0 g，8.77 mmol)之溶液中且將混合物在室溫下攪拌2 h。添加EtOAc(10 mL)且使用水洗滌混合物，隨後使用1 M鹽酸洗滌且然後使用鹽水洗滌。藉由硫酸鈉乾燥有機層並在真空下濃縮。藉由FCC(使用存於己烷中之0-15% EtOAc之梯度洗脫)純化殘餘物以得到3-側氧基環丁烷-1-甲酸苄基酯(0.938 g，53%)。將一部分3-側氧基環丁烷-1-甲酸苄基酯(0.800 g，3.92 mmol)溶於THF(2.5 mL)與水(2.5 mL)之混合物中並冷卻至0℃。添加硼氫化鈉(0.051 g，1.96 mmol)且將混合物在室溫下攪拌1 h。在真空下濃縮混合物且添加EtOAc(10 mL)。使用水洗滌此混合物且然後使用鹽水洗滌，且然後藉由硫酸鈉乾燥有機層並濃縮。藉由FCC(使用存於己烷中之0-10% EtOAc之梯度洗脫)純化殘餘物以得到3-羥基環丁烷-1-甲酸苄基酯(0.715 g，88%)。將一部分3-羥基環丁烷-1-甲酸苄基酯(0.400 g，1.94 mmol) 溶於THF(10 mL)中且添加苯酚(0.547 g，5.83 mmol)及三苯基膦(0.662 g，2.52 mmol)。逐漸添加偶氮二甲酸二乙基酯(0.4 mL，2.52 mmol)且將混合物在室溫下攪拌24 h。蒸發混合物且然後使用EtOAc(3×10 mL)萃取。使用鹽水洗滌有機層並在真空下濃縮。藉由FCC(使用存於己烷中之0-15% EtOAc之梯度洗脫)純化殘餘物以得到3-苯氧基環丁烷-1-甲酸苄基酯(0.450 g，82%)。將一部分3-苯氧基環丁烷-1-甲酸苄基酯(0.400 g，1.42 mmol)溶於EtOH(10 mL)中且添加10%碳載鈀(0.010 g)。將混合物在氫氣氛及室溫下攪拌2 h。過濾混合物且蒸發濾液。藉由FCC(使用存於己烷中之0-10% EtOAc之梯度洗脫)純化殘餘物以得到3-苯氧基環丁烷-1-甲酸(0.245 g，95%)。然後根據針對實例209所述之方法自3-苯氧基環丁烷-1-甲酸(0.190 g，0.985 mmol)及4-胺基-N-羥基-6-[甲基(苯基)胺基]-1,3,5-三-2-甲脒(以與中間體1類似之方式製得，0.150 g，0.579 mmol)來製備2-N-甲基-6-[5-(3-苯氧基環丁基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺。藉由FCC(使用存於己烷中之10% MeOH洗脫)純化殘餘物以得到異構體混合物形式之標題化合物(0.095 g，42%)。 Add triethylamine (2 mL, 14.04 mmol) and benzyl bromide (1.2 mL, 10.0 mmol) to 3-oxocyclobutane-1-carboxylic acid (1.0 g, 8.77) in THF (10 mL) The solution was stirred at room temperature for 2 h. EtOAc (10 mL) was added and the mixture was washed with water then washed with 1 M hydrochloric acid and then brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified with EtOAc EtOAc EtOAc EtOAc (EtOAc A portion of 3-oxocyclobutane-1-carboxylic acid benzyl ester (0.800 g, 3.92 mmol) was dissolved in a mixture of THF (2.5 mL) and water (2.5 mL) and cooled to 0. Sodium borohydride (0.051 g, 1.96 mmol) was added and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and EtOAc (10 mL). This mixture was washed with water and then washed with brine, and then the organic layer was dried over sodium sulfate and concentrated. The residue was purified by EtOAcqqqqqqqq A portion of 3-hydroxycyclobutane-l-carboxylic acid benzyl ester (0.400 g, 1.94 mmol) was dissolved in THF (10 mL) and phenol (0.547 g, 5.83 mmol) and triphenylphosphine (0.662 g, 2.52) Mm). Diethyl azodicarboxylate (0.4 mL, 2.52 mmol) was gradually added and the mixture was stirred at room temperature for 24 h. The mixture was evaporated and then extracted with EtOAc (3×10 mL). The organic layer was washed with brine and concentrated under vacuum. The residue was purified with EtOAc EtOAc EtOAc EtOAc (EtOAc A portion of benzyl 3-phenoxycyclobutane-1-carboxylate (0.400 g, 1.42 mmol) was dissolved in EtOH (10 mL) and 10% palladium on carbon (0.010 g). The mixture was stirred under a hydrogen atmosphere at room temperature for 2 h. The mixture was filtered and the filtrate was evaporated. The residue was purified by EtOAc EtOAc EtOAc EtOAc Then from 3-phenoxycyclobutane-1-carboxylic acid (0.190 g, 0.985 mmol) and 4-amino-N-hydroxy-6-[methyl(phenyl)amino group according to the procedure described for Example 209. ]-1,3,5-three 2-N-methyl-6-[5-(3-phenoxycyclobutyl)-1, prepared in a similar manner to Intermediate 1, 0.150 g, 0.579 mmol, 2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine. The residue was purified with EtOAc EtOAcjjjjjjj

實例264：2-N-(3-氯-2-氟苯基)-6-[5-(吡啶-2-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺(方法14) Example 264 : 2-N-(3-Chloro-2-fluorophenyl)-6-[5-(pyridin-2-yl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine ( method 14 )

將三乙胺(1.10 mL，7.58 mmol)及1H-苯并三唑-1-醇(0.77 g，5.05 mmol)添加至存於DMF(10 mL)中之N-[3-(二甲基胺基)丙基]-N'-乙基碳化二亞胺鹽酸鹽(0.97 g，5.05 mmol)之溶液中且將混合物在室溫下攪拌20 min。添加吡啶甲酸(0.62 g，5.05 mmol)且在室溫下將混合物攪拌30 min。添加4-胺基-6-[(3-氯-2-氟苯基)胺基]-N'-羥基-1,3,5-三-2-甲脒(以與中間體73類似之方式製得，1.50 g，5.05 mmol)且將混合物在室溫下攪拌過夜，然後加熱至85℃保持約24 h。藉由Ambersep樹脂純化粗製化合物但使雜質留下。然後依次使用EtOAc、丙酮及MeOH及(最終)熱MeOH洗滌殘餘物以得到標題化合物(330 mg，17%)。 Add triethylamine (1.10 mL, 7.58 mmol) and 1H-benzotriazol-1-ol (0.77 g, 5.05 mmol) to N-[3-(dimethylamine) in DMF (10 mL) A solution of propyl]-N'-ethylcarbodiimide hydrochloride (0.97 g, 5.05 mmol) was added and the mixture was stirred at room temperature for 20 min. Pyridinecarboxylic acid (0.62 g, 5.05 mmol) was added and the mixture was stirred at room temperature for 30 min. Add 4-amino-6-[(3-chloro-2-fluorophenyl)amino]-N'-hydroxy-1,3,5-three 2-Methyl hydrazine (prepared in a similar manner to Intermediate 73, 1.50 g, 5.05 mmol) and the mixture was stirred at room temperature overnight and then warmed to 85 ° C for about 24 h. The crude compound was purified by Ambersp resin but the impurities were left behind. The residue was washed with EtOAc EtOAc (EtOAc)

實例279：(5-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-甲酸甲酯) Example 279 : (5-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Methyl oxazol-5-yl)pyridine-2-carboxylate)

在惰性氣氛下，將草醯氯(91 μL，1078 μmol)添加至存於DCM(3 mL)及DMF(0.3 mL)中之吡啶-2,5-二甲酸2-甲酯(91 mg，501 μmol)之溶液中。將溶液在室溫下攪拌1 h且然後蒸發至乾燥。將所得固體懸浮於無水吡啶(10 mL)中且添加4-胺基-N-羥基-6-(甲基-苯基-胺基)-[1,3,5]三-2-甲脒(以與中間體1類似之方式製得，100 mg，385 μmol)。將所得溶液在室溫及氮下攪拌16 h。在形成酯中間體後，藉由LCMS進行檢測，將反應混合物加熱至100℃再保持4 h且然後冷卻至室溫。然後將反應混合物傾倒至水中並使用DCM(3×25 mL)萃取。藉由硫酸鎂乾燥合併之有機物並蒸發至乾燥。藉由在熱MeOH中重結晶進一步純化所得殘餘物以得到淺褐色固體形式之標題化合物(59 mg，38%)。方法A HPLC-MS：MH+要求m/z=405；實驗值：m/z=405.1，Rt=3.72 min(96%)。1H NMR(500 MHz,DMSO-d6)δ ppm 9.39(1H,s),8.69(1H,d),8.29(1H,d),7..52(1H,s),7.42(4H,m),7.28(2H,d),3.94(3H,s)及3.48(3H,s)。 Add oxalic acid chloride (91 μL, 1078 μmol) to pyridine-2,5-dicarboxylic acid 2-methyl ester (91 mg, 501) in DCM (3 mL) and DMF (0.3 mL). In a solution of μmol). The solution was stirred at room temperature for 1 h and then evaporated to dryness. The obtained solid was suspended in anhydrous pyridine (10 mL) and 4-amino-N-hydroxy-6-(methyl-phenyl-amino)-[1,3,5] was added. 2-Methylformamide (prepared in a similar manner to Intermediate 1, 100 mg, 385 μmol). The resulting solution was stirred at room temperature under nitrogen for 16 h. After formation of the ester intermediate, the reaction mixture was heated to 100 ° C for 4 h and then cooled to room temperature by LCMS. The reaction mixture was then poured into water and extracted with DCM (3×25 mL). The combined organics were dried over magnesium sulfate and evaporated to dryness. The residue was purified by EtOAcqqqqqqq Method A HPLC-MS: MH+ requires m/z = 405. Found: m/z = 405.1, Rt = 3.72 min (96%). 1H NMR (500 MHz, DMSO-d6) δ ppm 9.39 (1H, s), 8.69 (1H, d), 8.29 (1H, d), 7..52 (1H, s), 7.42 (4H, m), 7.28 (2H, d), 3.94 (3H, s) and 3.48 (3H, s).

實例280：(5-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)-N-(2,2,2-三氟乙基)吡啶-2-甲醯胺) Example 280 : (5-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)-N-(2,2,2-trifluoroethyl)pyridine-2-carboxamide

向存於無水甲苯(3 mL)中之2,2,2-三氟-乙胺(39 mg，395 μmol)之懸浮液中添加雙(三甲基鋁)-1,4-二氮雜雙環[2.2.2]-辛烷(DABAL-Me3)(101 mg，395 μmol)。將所得溶液在40℃下攪拌1 h。然後向溶液中添加5-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-甲酸甲酯(以與實例279類似之方式製得，80 mg，197 μmol)且將反應混合物在80℃下再攪拌16 h。使用1 M HCl(1 mL)將反應混合物驟冷，蒸發至乾燥並再溶於DCM中。使用水(3×25 mL)洗滌有機溶液，藉由硫酸鎂乾燥，蒸發並藉由二氧化矽層析(50：50 EtOAc：庚烷)純化以得到白色固體形式之標題化合物(40 mg，43%)。 Add bis(trimethylaluminum)-1,4-diazabicyclo ring to a suspension of 2,2,2-trifluoro-ethylamine (39 mg, 395 μmol) in anhydrous toluene (3 mL) [2.2.2]-octane (DABAL-Me 3 ) (101 mg, 395 μmol). The resulting solution was stirred at 40 ° C for 1 h. Then add 5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three to the solution. -2-yl}-1,2,4- Methyl oxazol-5-yl)pyridine-2-carboxylate (prepared in a similar manner to Example 279, 80 mg, 197 μmol) and the mixture was stirred at 80 ° C for an additional 16 h. The reaction mixture was quenched with 1 M EtOAc (1 mL)EtOAc. The organic solution was washed with EtOAc (EtOAc) (EtOAc (EtOAc) %).

實例282：6-[5-(3,5-二甲氧基吡啶-2-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺 Example 282 : 6-[5-(3,5-Dimethoxypyridin-2-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine

藉由將2-N-甲基-2-N-苯基-6-[5-(嘧啶-2-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺(實例281，20 mg，52.3 μmol)及碳酸銫(20 mg，61.3 μmol)溶於MeOH(1 mL)中來製備6-[5-(3,5-二氟吡啶-2-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺。將所得混合物蒸發至乾燥，懸浮於熱水中並過濾。使用蒸餾水進一步洗滌所收集之白色固體並在真空下乾燥以得到白色固體形式之標題化 合物(13 mg，62%)。 By 2-N-methyl-2-N-phenyl-6-[5-(pyrimidin-2-yl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-Diamine (Example 281, 20 mg, 52.3 μmol) and cesium carbonate (20 mg, 61.3 μmol) dissolved in MeOH (1 mL) to give 6-[5-(3,5-difluoropyridine) -2-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine. The resulting mixture was evaporated to dryness, suspended in hot water and filtered. The collected white solid was further washed with EtOAc (EtOAc)EtOAc.

實例284：5-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-甲醯胺(方法15) Example 284 : 5-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)pyridine-2-carboxamide ( Method 15 )

向存於DCE(10 mL)及DMF(100 μL)中之5-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-甲酸(中間體124，50 mg，128 μmol)之溶液中添加草醯氯(22 μL,256 μmol)。將所得溶液在室溫下攪拌2 h，蒸發至乾燥並再懸浮於存於二烷(7 N，10 mL)中之氨溶液中。將反應混合物在室溫下攪拌過夜且然後傾倒至水(50 mL)中。使用DCM(3×50 mL)萃取混合物且乾燥合併之有機物並在真空下濃縮以得到粗製黃色固體。將粗製材料懸浮於MeOH中，過濾並使用額外MeOH洗滌。使所得固體在二烷及水中重結晶以得到白色固體形式之標題化合物(15 mg，30%)。 5-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three in DCE (10 mL) and DMF (100 μL) -2-yl}-1,2,4- Add a solution of oxazolidine chloride (22 μL, 256 μmol) to a solution of oxazol-5-yl)pyridine-2-carboxylic acid (Intermediate 124, 50 mg, 128 μmol). The resulting solution was stirred at room temperature for 2 h, evaporated to dryness and resuspended in two. Ammonia solution in alkane (7 N, 10 mL). The reaction mixture was stirred at room temperature overnight and then poured into water (50 mL). The mixture was extracted with EtOAc (EtOAc) (EtOAc) The crude material was suspended in MeOH, filtered and washed with additional MeOH. The resulting solid is in two The title compound (15 mg, 30%) was obtained.

實例291：2-N-甲基-2-N-苯基-6-(5-{6-[(2,2,2-三氟乙氧基)甲基]吡啶-3-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺 Example 291 : 2-N-Methyl-2-N-phenyl-6-(5-{6-[(2,2,2-trifluoroethoxy)methyl]pyridin-3-yl}-1 , 2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine

向存於無水THF(10 mL)中之[5-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-基]甲醇(實例295，30 mg，79 μmol)之溶液中添加三氟甲烷磺酸2,2,2-三氟-乙酯(56 mg，239 μmol)。將溶液冷卻至0℃且在惰性氣氛下添加氫化鈉(存於礦物油中之60%分散液，7 mg，159 μmol)，且將混合物在室溫下攪拌24 h。然後使用三氟甲烷磺酸2,2,2-三氟-乙酯(56 mg，239 μmol)及氫化鈉(存於礦物油中之60%分散液，7 mg，159 μmol)再處理 反應混合物並在室溫下再攪拌48 h。使用水(20 mL)將反應混合物驟冷並萃取至EtOAc(3×25 mL)中。藉由硫酸鎂乾燥合併之有機物並蒸發至乾燥。藉由二氧化矽層析(存於DCM中之3% MeOH)純化粗產物且然後藉由製備型HPLC-MS(方法B)再純化以得到灰白色固體形式之標題化合物(5.6 mg，15%)。 [5-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three in anhydrous THF (10 mL) -2-yl}-1,2,4- Add 2,2,2-trifluoro-ethyl trifluoromethanesulfonate (56 mg, 239 μmol) to a solution of oxazol-5-yl)pyridin-2-yl]methanol (Example 295, 30 mg, 79 μmol) ). The solution was cooled to 0 ° C and sodium hydride (60% dispersion in mineral oil, 7 mg, 159 μmol) was added under an inert atmosphere, and the mixture was stirred at room temperature for 24 h. The reaction mixture was then treated with 2,2,2-trifluoro-ethyl trifluoromethanesulfonate (56 mg, 239 μmol) and sodium hydride (60% dispersion in mineral oil, 7 mg, 159 μmol) Stir at room temperature for another 48 h. The reaction mixture was quenched with water (20 mL)EtOAc. The combined organics were dried over magnesium sulfate and evaporated to dryness. The crude product was purified by EtOAc (EtOAc EtOAc) .

實例293：2-N-甲基-2-N-苯基-6-{5-[6-(吡咯啶-1-基甲基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺(方法16) Example 293 : 2-N-Methyl-2-N-phenyl-6-{5-[6-(pyrrolidin-1-ylmethyl)pyridin-3-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine ( Method 16 )

向存於DCM(10 mL)中之[5-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-基]甲醇(中間體125，50 mg，132 μmol)之溶液中添加甲磺醯氯(11 μL,139 μmol)及三乙胺(20 μL,145 μmol)。將反應混合物在室溫及惰性氣氛下攪拌90 min且然後蒸發至乾燥。將所得固體溶於DCM(10 mL)、吡咯啶(24 μL,333 μmol)及三乙胺(46 μL,333 μmol)中並在室溫下再攪拌3 h。觀察到反應不完全，因此將反應液在35℃下再加熱16 h。然後使用水(3×25 mL)洗滌反應混合物且藉由硫酸鎂乾燥合併之有機物並蒸發至乾燥。藉由二氧化矽層析(存於DCM中之5% MeOH)純化所得粗產物以得到淺褐色固體形式之標題化合物(25 mg，45%)。 [5-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three in DCM (10 mL) -2-yl}-1,2,4- Add methanesulfonate chloride (11 μL, 139 μmol) and triethylamine (20 μL, 145 μmol) to a solution of oxazol-5-yl)pyridin-2-yl]methanol (intermediate 125, 50 mg, 132 μmol) ). The reaction mixture was stirred at room temperature under an inert atmosphere for 90 min and then evaporated to dryness. The obtained solid was dissolved in DCM (10 mL), pyrridine (24 μL, 333 μmol) and triethylamine (46 μL, 333 μmol) and stirred at room temperature for further 3 h. The reaction was observed to be incomplete, so the reaction was heated at 35 ° C for an additional 16 h. The reaction mixture was then washed with water (3.times.25 mL) and the combined organics dried over magnesium sulfate and evaporated. The crude product was purified by EtOAc EtOAc EtOAc EtOAc

實例294：2-N-甲基-2-N-苯基-6-(5-{5-[1-(吡咯啶-1-基)乙基]吡啶-2-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺 Example 294 : 2-N-Methyl-2-N-phenyl-6-(5-{5-[1-(pyrrolidin-1-yl)ethyl]pyridin-2-yl}-1,2, 4- Diazol-3-yl)-1,3,5-three -2,4-diamine

在0℃及氮下，向存於無水THF(5 mL)中之1-[6-(3-{4-胺 基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-3-基]乙烷-1-酮(以與實例296類似之方式製得，100 mg，257 μmol)及吡咯啶(53 μL,643 μmol)之溶液中逐滴添加異丙氧基鈦(183 mg，643 μmmol)。將反應混合物升溫至室溫並攪拌過夜。然後將反應混合物冷卻至0℃且添加硼氫化鈉(29 mg，771 μmmol)。將反應混合物在室溫下攪拌3 h且然後使用水(10 mL)驟冷並萃取至EtOAc(3×25 mL)中。藉由硫酸鎂乾燥合併之有機物，蒸發並藉由二氧化矽層析(存於DCM中之2% MeOH)純化粗產物以得到淺褐色固體形式之標題化合物(13 mg，12%)。 1-[6-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5 in anhydrous THF (5 mL) at 0 ° C under nitrogen -three -2-yl}-1,2,4- A solution of oxazol-5-yl)pyridin-3-yl]ethane-1-one (prepared in a similar manner to Example 296, 100 mg, 257 μmol) and pyrrolidine (53 μL, 643 μmol) Titanium isopropoxide (183 mg, 643 μmmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was then cooled to 0.degree. C. and sodium borohydride (29 mg, 771. The reaction mixture was stirred at rt EtOAc (3 mL) The combined organics were dried with EtOAc EtOAc EtOAcjjjjjjjj

實例295：[5-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-基]甲醇 Example 295 : [5-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)pyridin-2-yl]methanol

在0℃及氮下，向存於無水THF(50 mL)中之5-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-甲酸甲酯(以與實例279類似之方式製得，500 mg，1.23 mmol)之溶液中逐份添加硼氫化鈉(95 mg，2.46 mmol)。對所得溶液簡單地進行超音波處理並在40℃下攪拌1 h。然後將反應混合物在室溫下再攪拌16 h。使用水(25 mL)將反應液驟冷並使用EtOAc(3×25 mL)萃取。藉由硫酸鎂乾燥合併之有機物並蒸發至乾燥以得到黃色固體形式之粗產物。使用MeOH研磨固體，過濾並使用二乙醚(100 mL)進一步洗滌以得到橙紅色固體形式之標題化合物(305 mg，67%)。 5-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three in anhydrous THF (50 mL) at 0 ° C under nitrogen -2-yl}-1,2,4- Sodium borohydride (95 mg, 2.46 mmol) was added portionwise to a solution of methyl oxazol-5-yl)pyridine-2-carboxylate (prepared in a similar manner to Example 279, 500 mg, 1.23 mmol). The resulting solution was simply subjected to ultrasonic treatment and stirred at 40 ° C for 1 h. The reaction mixture was then stirred at room temperature for a further 16 h. The reaction was quenched with water (25 mL)EtOAc. The combined organics were dried with MgSO.sub. The solid was triturated with EtOAc (EtOAc)EtOAc.

實例304：1-[5-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三- 2-基}-1,2,4-二唑-5-基)吡啶-2-基]乙烷-1-酮 Example 304 : 1-[5-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three - 2-base}-1,2,4- Diazol-5-yl)pyridin-2-yl]ethane-1-one

在-78℃及惰性氣氛下，向存於無水THF(30 mL)中之5-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-甲酸甲酯(以與實例279類似之方式製得，1.00 g，2.47 mmol)之溶液中逐滴添加甲基溴化鎂(存於乙醚中之3 M溶液，907 μL，2.72 mmol)。將所得溶液在-78℃下攪拌1 h且然後升溫至室溫並再繼續攪拌1 h。再次冷卻反應混合物並使用丙酮(1 mL)及10%檸檬酸水溶液(5 mL)驟冷。使用EtOAc(3×50 mL)萃取反應混合物並使用鹽水(25 mL)洗滌所得有機物，藉由硫酸鎂乾燥並蒸發至乾燥。藉由製備型HPLC-MS(方法C)純化50毫克所得粗製材料以得到灰白色固體形式之標題化合物(21 mg)。 5-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5- in anhydrous THF (30 mL) at -78 ° C under an inert atmosphere three -2-yl}-1,2,4- Methyl carbazide-5-yl)pyridine-2-carboxylate (prepared in a similar manner to Example 279, 1.00 g, 2.47 mmol) was added dropwise methyl magnesium bromide (3 M in diethyl ether) Solution, 907 μL, 2.72 mmol). The resulting solution was stirred at -78 °C for 1 h and then warmed to room temperature and stirring was continued for further 1 h. The reaction mixture was again cooled and quenched with acetone (1 mL) and 10% aqueous citric acid (5 mL). The reaction mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The title compound (21 mg) was obtained from m.

實例312：2-N-(2-甲氧基乙基)-2-N-苯基-6-(5-{6-[(2,2,2-三氟乙氧基)甲基]吡啶-3-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺(方法17) Example 312 : 2-N-(2-Methoxyethyl)-2-N-phenyl-6-(5-{6-[(2,2,2-trifluoroethoxy)methyl]pyridine -3-yl}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine ( Method 17 )

向存於DCM(40 mL)中之[5-(3-{4-胺基-6-[(2-甲氧基-乙基)-苯基-胺基]-[1,3,5]三-2-基}-[1,2,4]二唑-5-基)-吡啶-2-基]-甲醇(中間體130，185 mg，0.44 mmol)之溶液中逐滴添加甲磺醯氯(48 μL,0.61 mmol)，隨後添加三乙胺(92 μL,0.66 mmol)。將所得溶液在惰性氣氛下攪拌3 h。觀察到反應不完全，因此添加額外甲磺醯氯(9 μL,0.10 mmol)及三乙胺(16 μL,0.11 mmol)並繼續攪拌1 h。使用水(2×50 mL)洗滌反應混合物並藉由硫酸鎂乾燥有機相並蒸發至乾燥以得到甲烷磺酸5-(3-{4-胺基-6-[(2-甲氧基-乙 基)-苯基-胺基]-[1,3,5]三-2-基}-[1,2,4]二唑-5-基)-吡啶-2-基甲酯中間體。在單獨烷瓶中，在0℃及氮下，將2,2,2-三氟-乙醇(190 μL,2.64 mmol)逐滴添加至存於無水THF(30 mL)中之氫化鈉(存於礦物油中之60%分散液，97 mg，2.42 mmol)之懸浮液中。將所得溶液在0℃下攪拌30 min且然後在0℃下經由套管逐滴轉移至存於無水THF(30 mL)中之甲烷磺酸5-(3-{4-胺基-6-[(2-甲氧基-乙基)-苯基-胺基]-[1,3,5]三-2-基}-[1,2,4]二唑-5-基)-吡啶-2-基甲酯中間體(220 mg，0.44 mmol)之溶液中。將反應混合物在室溫下攪拌18 h。使用飽和氯化銨水溶液(5 mL)將反應液驟冷並使用EtOAc(3×50 mL)萃取。使用鹽水(25 mL)洗滌合併之有機物，藉由硫酸鎂乾燥並蒸發至乾燥。藉由二氧化矽層析(存於DCM中之2% MeOH)純化粗產物且然後進一步藉由製備型HPLC-MS(方法C)進行純化以得到灰白色固體形式之標題化合物(21 mg，10%)。 [5-(3-{4-Amino-6-[(2-methoxy-ethyl)-phenyl-amino]-[1,3,5] in DCM (40 mL) three -2-base}-[1,2,4] Methylsulfonium chloride (48 μL, 0.61 mmol) was added dropwise to a solution of oxazol-5-yl)-pyridin-2-yl]-methanol (intermediate 130, 185 mg, 0.44 mmol), followed by triethylamine (92 μL, 0.66 mmol). The resulting solution was stirred under an inert atmosphere for 3 h. The reaction was observed to be incomplete, so additional methanesulfonium chloride (9 μL, 0.10 mmol) and triethylamine (16 μL, 0.11 mmol) were added and stirring was continued for 1 h. The reaction mixture was washed with water (2×50 mL) and dried over magnesium sulfate and evaporated to dryness to afford methanesulfonic acid 5-(3-{4-amino-6-[(2-methoxy-B) Base)-phenyl-amino]-[1,3,5] -2-base}-[1,2,4] Azoxa-5-yl)-pyridin-2-ylmethyl ester intermediate. In a separate alkane flask, 2,2,2-trifluoro-ethanol (190 μL, 2.64 mmol) was added dropwise to sodium hydride in anhydrous THF (30 mL) at 0 ° C under nitrogen. In a suspension of 60% dispersion in mineral oil, 97 mg, 2.42 mmol). The resulting solution was stirred at 0 ° C for 30 min and then transferred via cannula at 0 ° C to methanesulfonic acid 5-(3-{4-amino-6-[] in anhydrous THF (30 mL). (2-methoxy-ethyl)-phenyl-amino]-[1,3,5]3 -2-base}-[1,2,4] A solution of the oxazol-5-yl)-pyridin-2-ylmethyl ester intermediate (220 mg, 0.44 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction was quenched with EtOAc EtOAc (EtOAc) The combined organics were washed with brine (25 mL) dried over magnesium sulfate and evaporated. The crude product was purified by EtOAc (EtOAc) elute ).

實例314：2-N-甲基-2-N-苯基-6-{5-[1-(2,2,2-三氟乙基)氮雜環丁-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺 Example 314 : 2-N-Methyl-2-N-phenyl-6-{5-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]-1,2 , 4- Diazol-3-yl}-1,3,5-three -2,4-diamine

在0℃及氮下，向存於無水DMF(20 mL)中之氫化鈉(存於礦物油中之60%分散液，16 mg，0.41 mmol)之溶液中添加6-[5-(氮雜環丁-3-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺鹽酸鹽(中間體129，50 mg，0.138 mmol)及三氟甲烷磺酸2,2,2-三氟-乙酯(160 mg，0.69 mmol)。將反應混合物在室溫下攪拌16 h且然後使用飽和氯化銨水溶液(10 mL)驟冷並蒸發至乾燥。將所獲得 固體溶於EtOAc(20 mL)中，使用水(2×25 mL)洗滌，藉由硫酸鎂乾燥並蒸發至乾燥。藉由二氧化矽層析(存於DCM中之2% MeOH)純化所得粗產物且然後進一步藉由製備型HPLC-MS(方法B)進行純化以得到白色固體形式之標題化合物(5 mg，9%)。 Add 6-[5-(aza) to a solution of sodium hydride (60% dispersion in mineral oil, 16 mg, 0.41 mmol) in anhydrous DMF (20 mL) at 0 ° C under nitrogen Cyclobut-3-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-Diamine hydrochloride (Intermediate 129, 50 mg, 0.138 mmol) and 2,2,2-trifluoro-ethyl trifluoromethanesulfonate (160 mg, 0.69 mmol). The reaction mixture was stirred at room temperature for 16 h and then quenched with aq. The obtained solid was dissolved in EtOAc (EtOAc)EtOAc. The crude product was purified by EtOAc (EtOAc) elute elute %).

實例317：2-N-甲基-2-N-苯基-6-[5-(6-{[(2,2,2-三氟乙烷)亞磺醯基]甲基}吡啶-3-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺(方法18) Example 317 : 2-N-Methyl-2-N-phenyl-6-[5-(6-{[(2,2,2-trifluoroethane)sulfinyl]methyl}pyridine-3 -base)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine ( Method 18 )

向存於THF(2.5 mL)及丙酮(2.5 mL)中之2-N-甲基-2-N-苯基-6-[5-(6-{[(2,2,2-三氟乙基)硫基]甲基}吡啶-3-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺(實例316，75 mg，0.158 mmol)之溶液中添加過硫酸氫鉀製劑(202 mg，0.328 mmol)及飽和碳酸氫鈉水溶液(2 mL)。將所得懸浮液在室溫下攪拌4 h並在30℃下攪拌16 h。向反應混合物中添加額外過硫酸氫鉀製劑(97 mg，0.158 mmol)並在35℃下再繼續攪拌12 h。將溶液冷卻至室溫，使用EtOAc(50 mL)稀釋並使用水(2×25 mL)及鹽水(25 mL)洗滌。藉由硫酸鎂乾燥合併之有機物，蒸發至乾燥並藉由製備型HPLC-MS(方法C)純化以得到白色固體形式之標題化合物(16 mg，21%)。 2-N-methyl-2-N-phenyl-6-[5-(6-{[(2,2,2-trifluoroethyl) in THF (2.5 mL) and acetone (2.5 mL) Thio]methyl}pyridin-3-yl)-1,2,4- Diazol-3-yl]-1,3,5-three To a solution of the 2,4-diamine (Example 316, 75 mg, 0.158 mmol) was added potassium hydrogensulphate (202 mg, 0.328 mmol) and saturated aqueous sodium bicarbonate (2 mL). The resulting suspension was stirred at room temperature for 4 h and at 30 ° C for 16 h. An additional potassium persulfate formulation (97 mg, 0.158 mmol) was added to the reaction mixture and stirring was continued for a further 12 h at 35 °C. The solution was cooled to room temperature, diluted with EtOAc (50 mL) andEtOAc. The combined organics were dried with EtOAc EtOAc EtOAcjjjjjjj

實例323：2-N-甲基-2-N-苯基-6-(5-{5H,6H,7H-吡咯并[3,4-d]嘧啶-6-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺 Example 323 : 2-N-Methyl-2-N-phenyl-6-(5-{5H,6H,7H-pyrrolo[3,4-d]pyrimidin-6-yl}-1,2,4 - Diazol-3-yl)-1,3,5-three -2,4-diamine

在室溫下，向存於無水THF(3 mL)中之6,7-二氫-5H-吡咯并[3,4-d]嘧啶鹽酸鹽(38 mg，0.231mmol)之溶液中添加 DABAL-Me3(雙(三甲基鋁)-1,4-二氮雜雙環[2.2.2]-辛烷)(57 mg，0.231 mmol)。將溶液在氮及40℃下加熱3 h且添加N-甲基-N-苯基-6-(5-三氯甲基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺(中間體60，60 mg，0.155 mmol)。將所得反應混合物在80℃下加熱5 h且然後使用水(2 mL)逐滴進行驟冷。將溶液萃取至EtOAc(3×25 mL)中並使用1 M HCl水溶液(20 mL)、鹽水(20 mL)洗滌合併之有機物，藉由硫酸鎂乾燥，蒸發至乾燥並藉由製備型HPLC-MS(方法B)純化以得到白色固體形式之標題化合物(5 mg，8%)。 Add DABAL to a solution of 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine hydrochloride (38 mg, 0.231 mmol) in dry THF (3 mL). -Me 3 (bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]-octane) (57 mg, 0.231 mmol). The solution was heated at 40 ° C for 3 h and N-methyl-N-phenyl-6-(5-trichloromethyl-[1,2,4] was added. Diazol-3-yl)-[1,3,5]3 -2,4-Diamine (Intermediate 60, 60 mg, 0.155 mmol). The resulting reaction mixture was heated at 80 &lt;0&gt;C for 5 h and then quenched with water (2 mL). The solution was extracted into EtOAc (3.times.25 mL) and EtOAc (EtOAc)EtOAc. (Method B) Purified to give the title compound (5 mg, EtOAc)

實例324：2-N-甲基-2-N-苯基-6-{5-[4-(3,3,3-三氟亞丙基)六氫吡啶-1-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺 Example 324 : 2-N-Methyl-2-N-phenyl-6-{5-[4-(3,3,3-trifluoropropyl)hexahydropyridin-1-yl]-1,2 , 4- Diazol-3-yl}-1,3,5-three -2,4-diamine

在0℃及氮下，向存於無水二烷(10 mL)中之碘化三苯基-(3,3,3-三氟-丙基)-鏻(146 mg，0.30 mmol)之溶液中逐份添加第三丁醇鉀(34 mg，0.3 mmol)。將懸浮液在0℃下攪拌10 min且然後逐滴添加至存於無水二烷(10 mL)中之1-{3-[4-胺基-6-(甲基-苯基-胺基)-[1,3,5]三-2-基]-[1,2,4]二唑-5-基}-六氫吡啶-4-酮(中間體131，55 mg，0.150 mmol)之溶液中。將所得反應混合物在室溫下攪拌16 h並蒸發至乾燥。將所獲得固體溶於DCM(25 mL)中並使用水(25 mL)、飽和氯化銨水溶液(25 mL)及鹽水(25 mL)洗滌。藉由硫酸鎂乾燥有機相，蒸發至乾燥並藉由製備型HPLC-MS(方法B)純化以得到灰白色固體形式之標題化合物(8 mg，12%)。 Under 0 ° C and nitrogen, Potassium tert-butoxide (34 mg) was added portionwise to a solution of triphenyl-(3,3,3-trifluoro-propyl)-indole (146 mg, 0.30 mmol) in hexane (10 mL). 0.3 mmol). The suspension was stirred at 0 ° C for 10 min and then added dropwise to the remaining two 1-{3-[4-Amino-6-(methyl-phenyl-amino)-[1,3,5]3 in alkane (10 mL) -2-base]-[1,2,4] A solution of oxazol-5-yl}-hexahydropyridin-4-one (Intermediate 131, 55 mg, 0.150 mmol). The resulting reaction mixture was stirred at room temperature for 16 h and evaporated to dryness. The obtained solid was dissolved in DCM (25 mL) and washed with water (25 mL), sat. The title compound (8 mg, 12%) was obtained eluted elute

實例327：2-N-甲基-2-N-苯基-6-(5-{6-[(2,2,2-三氟乙基)胺 基]吡啶-3-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺(方法19) Example 327 : 2-N-Methyl-2-N-phenyl-6-(5-{6-[(2,2,2-trifluoroethyl)amino]pyridin-3-yl}-1, 2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine ( method 19 )

在氮及室溫下，將DavePhos(2-二環己基膦基-2'-(N,N-二甲基胺基)聯苯，0.023 g，0.058 mmol)及叁(二亞苄基丙酮)二鈀(0)(0.024 g，0.026 mmol)添加至存於THF(1 mL)中之6-[5-(6-氯吡啶-3-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺(中間體135，0.100 g，0.263 mmol)及2,2,2-三氟乙烷-1-胺(0.084 mL，1.050 mmol)之混合物中。藉由氮鼓泡將反應混合物脫氣且在室溫下逐滴添加存於THF(2.10 mL，2.10 mmol)中之1 M LiHMDS溶液。在攪拌的同時，將反應混合物在微波條件下(200W，T=120℃)加熱40 min(20 min斜坡變化，20 min保持於120℃)。在室溫下，使用EtOAc稀釋反應混合物並過濾。將所收集固體吸收於MeOH中，過濾並使用大量MeOH洗滌，且藉由製備型HPLC進一步純化以得到標題化合物(7 mg，6%)。 DavePhos (2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 0.023 g, 0.058 mmol) and hydrazine (dibenzylideneacetone) at room temperature and nitrogen Palladium(0) (0.024 g, 0.026 mmol) was added to 6-[5-(6-chloropyridin-3-yl)-1,2,4- in THF (1 mL) Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three a mixture of 2,4-diamine (intermediate 135, 0.100 g, 0.263 mmol) and 2,2,2-trifluoroethane-l-amine (0.084 mL, 1.050 mmol). The reaction mixture was degassed by bubbling nitrogen and a 1 M LiHMDS solution in THF (2.10 mL, 2.10 mmol) was added dropwise at room temperature. While stirring, the reaction mixture was heated under microwave conditions (200 W, T = 120 ° C) for 40 min (20 min ramp change, 20 min at 120 ° C). The reaction mixture was diluted with EtOAc at rt and filtered. The collected solids were taken up in EtOAc (EtOAc) elute

實例330：2-{[5-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-基]氧基}乙腈 Example 330 : 2-{[5-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)pyridin-2-yl]oxy}acetonitrile

將存於DMF(2 mL)中之5-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-醇(中間體136，0.150 g，0.414 mmol)、2-碘乙腈(0.036 mL，0.497 mmol)、碳酸銫(0.270 g，0.827 mmol)之混合物在90℃下於壓力管中攪拌18 h。添加額外之0.6當量2-碘乙腈且將混合物在90℃下攪拌過夜。將反應混合物冷卻至室溫，使用 水稀釋，藉由過濾收集沈澱物，使用水洗滌並在真空下乾燥。藉由製備型HPLC純化所得固體以得到標題化合物(3 mg，2%)。 5-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three in DMF (2 mL) -2-yl}-1,2,4- a mixture of oxazol-5-yl)pyridin-2-ol (Intermediate 136, 0.150 g, 0.414 mmol), 2-iodoacetonitrile (0.036 mL, 0.497 mmol), cesium carbonate (0.270 g, 0.827 mmol) at 90 ° C Stir in the pressure tube for 18 h. An additional 0.6 equivalent of 2-iodoacetonitrile was added and the mixture was stirred at 90 ° C overnight. The reaction mixture was cooled to room temperature, diluted with water, and the precipitate was collected by filtration, washed with water and dried under vacuum. The obtained solid was purified by preparative HPLC to afford title compound (3 mg, 2%).

實例332：2-N-甲基-2-N-苯基-6-(5-{6-[(丙烷-2-基)胺基]吡啶-3-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺(方法20) Example 332 : 2-N-Methyl-2-N-phenyl-6-(5-{6-[(propan-2-yl)amino]pyridin-3-yl}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine ( Method 20 )

將存於EtOH(1 mL)中之6-[5-(6-氯吡啶-3-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺(中間體135，0.100 g，0.263 mmol)、異丙胺(0.087 mL，1.052 mmol)、DIPEA(0.091 mL，0.525 mmol)之混合物在微波條件下加熱3次(第一處理：100W，130℃，40 min；第二處理：100W，130℃，45 min；第三處理：100W，130℃，45 min)。將反應混合物冷卻並在真空下濃縮。藉由製備型HPLC純化所得深色油狀物以得到標題化合物(29 mg，27%)。 6-[5-(6-chloropyridin-3-yl)-1,2,4- in EtOH (1 mL) Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three a mixture of 2,4-diamine (intermediate 135, 0.100 g, 0.263 mmol), isopropylamine (0.087 mL, 1.052 mmol), DIPEA (0.091 mL, 0.525 mmol). : 100 W, 130 ° C, 40 min; second treatment: 100 W, 130 ° C, 45 min; third treatment: 100 W, 130 ° C, 45 min). The reaction mixture was cooled and concentrated under vacuum. The resulting dark oil was purified by EtOAcqqqqqq

實例346：6-[5-(3-氟吡啶-2-基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺 Example 346 : 6-[5-(3-Fluoropyridin-2-yl)-1,2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine

將3-氟吡啶-2-甲酸(1.75 g，12.38 mmol)溶於吡啶(15 mL)中且添加N-(3-二甲基胺基丙基)-N'-乙基碳化二亞胺鹽酸鹽(2.74 g，14.28 mmol)。將混合物在室溫下攪拌2 h。添加4-胺基-N'-羥基-6-(苯基胺基)-1,3,5-三-2-甲脒(以與中間體4類似之方式製得，2.33 g，9.52 mmol)並混合物在室溫下攪拌16 h。LCMS展示轉化不完全，因此添加額外N-(3-二甲基胺基丙基)-N'-乙基碳化二亞胺鹽酸鹽(1.30 g，6.8 mmol)並將混合物在室溫下攪拌3 h，然後在氮下加 熱至60℃保持16 h。在真空下去除吡啶且向殘餘物中添加水(100 mL)。使用EtOAc(100 mL)萃取混合物，且添加鹽水(100 mL)以有助於分離乳液。然後使用DCM(100 mL)萃取水相，此亦形成乳液。在分離之後，過濾水相以去除不溶性膠。然後使用DCM(2×100 mL)進一步萃取水相。藉由硫酸鈉乾燥合併之DCM及EtOAc層並在真空下濃縮以得到淺橙色固體。藉由FCC使用存於DCM中之0-8% MeOH之梯度進行純化。藉由使用DCM研磨進一步純化粗產物以得到白色固體形式之標題化合物(0.425 g，13%)。 3-Fluoropyridine-2-carboxylic acid (1.75 g, 12.38 mmol) was dissolved in pyridine (15 mL) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide salt was added. Acid salt (2.74 g, 14.28 mmol). The mixture was stirred at room temperature for 2 h. Add 4-amino-N'-hydroxy-6-(phenylamino)-1,3,5-three 2-Methylhydrazine (prepared in a similar manner to Intermediate 4, 2.33 g, 9.52 mmol) and mixture was stirred at room temperature for 16 h. LCMS showed incomplete conversion, so additional N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.30 g, 6.8 mmol) was added and the mixture was stirred at room temperature 3 h, then heated to 60 ° C under nitrogen for 16 h. The pyridine was removed under vacuum and water (100 mL) was added to the residue. The mixture was extracted with EtOAc (100 mL) and brine (100 mL) was added to help isolate the emulsion. The aqueous phase was then extracted using DCM (100 mL) which also formed an emulsion. After separation, the aqueous phase is filtered to remove the insoluble gum. The aqueous phase was then further extracted using DCM (2 x 100 mL). The combined DCM and EtOAc layers were dried <RTI ID=0.0> Purification was carried out by FCC using a gradient of 0-8% MeOH in DCM. The crude product was purified by EtOAc (EtOAc)

實例358：2-N-甲基-2-N-苯基-6-(5-{5-[1-(2,2,2-三氟乙氧基)乙基]吡啶-2-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺 Example 358 : 2-N-Methyl-2-N-phenyl-6-(5-{5-[1-(2,2,2-trifluoroethoxy)ethyl]pyridin-2-yl} -1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine

將2,2,2-三氯乙醯亞胺酸1-[6-(3-{4-胺基-6-[甲基(苯基)胺基}1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-3-基]乙酯(中間體139，0.497 g，0.93 mmol)懸浮於DCE(8 mL)中。添加2,2,2-三氟乙醇(0.669 mL，9.29 mmol)及四氟硼酸二乙醚複合物(0.025 mL，0.19 mmol)且將混合物在室溫下攪拌7 h。LCMS展示轉化不完全，因此添加額外四氟硼酸二乙醚複合物(0.125 mL，0.93 mmol)並將混合物在室溫下攪拌21 h。添加DCM(100 mL)及碳酸氫鈉飽和水溶液(50 mL)。分離有機層，使用鹽水(30 mL)洗滌，藉由硫酸鈉乾燥並在真空下濃縮以得到褐色固體，藉由FCC使用存於DCM中之0-5% MeOH之梯度進行純化。然後藉由製備型HPLC(方法D)純化粗產物以得到灰白色固體。藉由FCC使用存於DCM中之0-3% MeOH之梯度進一步純化以得到灰白 色固體形式之標題化合物(0.022 g，5%)。 2,2,2-trichloroacetamido acid 1-[6-(3-{4-amino-6-[methyl(phenyl)amino}1,3,5-three -2-yl}-1,2,4- The oxazol-5-yl)pyridin-3-yl]ethyl ester (Intermediate 139, 0.497 g, 0.93 mmol) was suspended in DCM (8 mL). 2,2,2-Trifluoroethanol (0.669 mL, 9.29 mmol) and tetrafluoroboric acid diethyl ether complex (0.025 mL, 0.19 mmol) were added and the mixture was stirred at room temperature for 7 h. LCMS showed incomplete conversion, so additional THF (diethyldifluoroborate) complex (0.125 mL, 0.93 mmol) was added and the mixture was stirred at room temperature for 21 h. DCM (100 mL) and saturated aqueous sodium bicarbonate (50 mL) were added. The organic layer was separated, washed with EtOAc EtOAc m. The crude product was then purified by preparative HPLC (Method D) to give an off white solid. The title compound (0.022 g, 5%) was obtained eluted eluting eluting

實例366：2-N-甲基-2-N-苯基-6-(5-{6-[2-(2,2,2-三氟乙氧基)乙氧基]吡啶-3-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺 Example 366 : 2-N-Methyl-2-N-phenyl-6-(5-{6-[2-(2,2,2-trifluoroethoxy)ethoxy]pyridin-3-yl }-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine

在吡啶(3 mL)中合併6-[2-(2,2,2-三氟乙氧基)乙氧基]吡啶-3-甲酸(中間體242，0.133 g，0.50 mmol)及1,1'-羰基二咪唑(0.081 g，0.50 mmol)並在室溫下攪拌3 h。添加4-胺基-N-羥基-6-[甲基(苯基)胺基]-1,3,5-三-2-甲脒(以與中間體1類似之方式製得，0.100 g，0.39 mmol)並將混合物在室溫下攪拌4 h，然後加熱至80℃保持16 h。在真空下去除吡啶且將殘餘物分配於EtOAc(20 mL)與水(20 mL)之間。藉由硫酸鈉乾燥有機層並濃縮以得到橙色固體。藉由FCC使用存於庚烷中之30-70% EtOAc之梯度進行純化以得到白色固體形式之標題化合物(0.116 g，61%)。方法A HPLC-MS：MH+要求m/z=489，實驗值：m/z=489，Rt=4.58 min(100%)。1H NMR(500MHZ,CDCl3)δ ppm 9.06(1H,s),8.41(1H,d),7.47(2H,m),7.34(3H,m),6.96(1H,d),5.34(2H,br s),4.64(2H,t),4.04(2H,t),3.97(2H,q)及3.65(3H,s)。 6-[2-(2,2,2-Trifluoroethoxy)ethoxy]pyridine-3-carboxylic acid (intermediate 242, 0.133 g, 0.50 mmol) and 1,1 were combined in pyridine (3 mL) '-Carbonyldiimidazole (0.081 g, 0.50 mmol) and stirred at room temperature for 3 h. Add 4-amino-N-hydroxy-6-[methyl(phenyl)amino]-1,3,5-three 2-Methyl hydrazine (prepared in a similar manner to Intermediate 1, 0.100 g, 0.39 mmol) and the mixture was stirred at room temperature for 4 h then heated to 80 ° C for 16 h. The pyridine was removed in vacuo and EtOAcqqqqqqqq The organic layer was dried over sodium sulfate and concentrated to give an orange solid. The title compound (0.116 g, 61%) elute Method A HPLC-MS: MH+ requires m/z = 489, found: m/z = 489, Rt = 4.58 min (100%). 1H NMR (500MHZ, CDCl 3) δ ppm 9.06 (1H, s), 8.41 (1H, d), 7.47 (2H, m), 7.34 (3H, m), 6.96 (1H, d), 5.34 (2H, br s), 4.64 (2H, t), 4.04 (2H, t), 3.97 (2H, q) and 3.65 (3H, s).

實例384：1-[3-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)氮雜環丁-1-基]乙烷-1-酮 Example 384 : 1-[3-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)azetidin-1-yl]ethane-1-one

在DCE(5 mL)中合併6-[5-(氮雜環丁-3-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺(中間體149，85 mg，0.26 mmol)、3,3,3-三氟丙醛(32 μL,0.28 mmol)及乙酸(45 μL,0.78 mmol)並在室溫下攪拌3 h。添加三乙醯氧基硼氫化鈉(83 mg，0.39 mmol)且將混合物加熱至70℃保持5 h。在室溫下冷卻反應混合物，在真空下濃縮並藉由製備型HPLC(方法C)純化以得到白色固體形式之標題化合物(25 mg，26%)。 6-[5-(azetidin-3-yl)-1,2,4- in DCE (5 mL) Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine (intermediate 149, 85 mg, 0.26 mmol), 3,3,3-trifluoropropanal (32 μL, 0.28 mmol) and acetic acid (45 μL, 0.78 mmol) at room temperature Stir for 3 h. Sodium triethoxysulfonate (83 mg, 0.39 mmol) was added and the mixture was heated to 70 ° C for 5 h. The reaction mixture was cooled with EtOAc EtOAc m.

實例386：(1R,5S,6S)-6-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)-3-苄基-3-氮雜雙環[3.1.0]己烷-2,4-二酮) Example 386 : (1R,5S,6S)-6-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)-3-benzyl-3-azabicyclo[3.1.0]hexane-2,4-dione)

將(1R,5S,6S)-3-苄基-2,4-二側氧基-3-氮雜雙環[3.1.0]己烷-6-甲酸乙酯(中間體254，0.300 g，1.098 mmol)溶於THF(9 mL)及水(3 mL)中且添加氫氧化鋰(32 mg，1.31 mmol)，且將混合物在室溫下攪拌3 h。然後添加額外之1當量氫氧化鋰且將混合物在室溫下攪拌2 h以得到(1S,5R,6S)-3-苄基-2,4-二側氧基-3-氮雜雙環[3.1.0]己烷-6-甲酸。將一部分此酸(0.090 g，0.367 mmol)溶於吡啶(2 mL)中且添加1,1'-羰基二咪唑(0.089 g，0.551 mmol)，且將混合物在室溫下攪拌3 h。添加4-胺基-N-羥基-6-[甲基(苯基)胺基]-1,3,5-三-2-甲脒(以與中間體1類似之方式製得，0.095 g，0.367 mmol)且將混合物加熱至90℃過夜。然後添加額外之0.5當量已使用1,1'-羰基二咪唑活化之酸並將混合物在90℃下攪拌約1 h。然後添加額外之0.5當量已使用1,1'-羰基二咪唑活化之酸並將混合物在100℃下攪拌約3 h。在真空下濃縮反應混合物且使用MeOH研磨殘餘物。然後藉由製備型HPLC(方法C)純化粗製材料以得到灰 白色固體形式之標題化合物(0.085 g，49%)。 (1R,5S,6S)-3-Benzyl-2,4-di-oxy-3-azabicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester (Intermediate 254, 0.300 g, 1.098 Ethyl acetate was dissolved in THF (9 mL) and water (3 mL). An additional 1 equivalent of lithium hydroxide was then added and the mixture was stirred at room temperature for 2 h to give (1S,5R,6S)-3-benzyl-2,4-di-oxy-3-azabicyclo[3.1 .0] Hexane-6-formic acid. A portion of this acid (0.090 g, <RTI ID=0.0></RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt; Add 4-amino-N-hydroxy-6-[methyl(phenyl)amino]-1,3,5-three 2-Methylhydrazine (prepared in a similar manner to Intermediate 1, 0.095 g, 0.367 mmol) and the mixture was heated to 90 ° C overnight. An additional 0.5 equivalent of acid which had been activated with 1,1 '-carbonyldiimidazole was then added and the mixture was stirred at 90 ° C for about 1 h. An additional 0.5 equivalent of acid which had been activated with 1,1 '-carbonyldiimidazole was then added and the mixture was stirred at 100 ° C for about 3 h. The reaction mixture was concentrated in vacuo and the residue was purified eluting with MeOH. The crude material was purified by preparative EtOAc (EtOAc)

實例401：2-N-甲基-2-N-苯基-6-{5-[(4-{[(2,2,2-三氟乙基)硫基]甲基}六氫吡啶-1-基)羰基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺(方法21) Example 401 : 2-N-Methyl-2-N-phenyl-6-{5-[(4-{[(2,2,2-trifluoroethyl)thio]methyl}hexahydropyridine- 1-yl)carbonyl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine ( Method 21 )

在室溫下於密封管中，將雙(三甲基鋁)-1,4-二氮雜雙環[2.2.2]辛烷加合物(225 mg，0.88 mmol)添加至存於無水THF(6 mL)中之4-{[(2,2,2-三氟乙基)硫基]甲基}六氫吡啶鹽酸鹽(中間體267，219 mg，0.88 mmol)中。將反應混合物在40℃下攪拌2 h。在40℃下添加3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-甲酸乙酯(以與實例73類似之方式製得，200 mg，0.58 mmol)。將反應液在80℃下加熱2 h，然後在真空下濃縮。將殘餘物吸收於DMSO(6 mL)中且過濾掉無機殘餘物。藉由製備型HPLC(方法C)純化濾液以提供兩批標題化合物(批次1：33 mg，11%)。自製備型HPLC純化回收一些不純產物，濃縮此材料，使用水(50 mL)稀釋，使用1N HCl水溶液酸化(至pH 4)並使用EtOAc(3×50 mL)萃取。使用鹽水(50 mL)洗滌合併之有機層且藉由硫酸鎂乾燥。然後藉由製備型HPLC(方法C)純化此粗製材料以提供標題化合物(批次2：83 mg，28%)。 Bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane adduct (225 mg, 0.88 mmol) was added to dry THF in a sealed tube at room temperature. 4-{[(2,2,2-Trifluoroethyl)thio]methyl}hexahydropyridine hydrochloride (Intermediate 267, 219 mg, 0.88 mmol) in 6 mL). The reaction mixture was stirred at 40 ° C for 2 h. Add 3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three at 40 °C -2-yl}-1,2,4- Ethyl oxazol-5-carboxylate (prepared in a similar manner to Example 73, 200 mg, 0.58 mmol). The reaction was heated at 80 °C for 2 h then concentrated in vacuo. The residue was taken up in DMSO (6 mL) and the residue was filtered. The filtrate was purified by preparative HPLC (Method C) to provide two crops of the title compound (1:33 mg, 11%). Some of the impure product was purified by preparative HPLC purification, EtOAc (EtOAc) (EtOAc) The combined organic layers were washed with brine (50 mL) and dried over magnesium sulfate. This crude material was then purified by preparative HPLC (Method C) to afford the title compound (b. 2: 83 mg, 28%).

實例414：2-N-(3-氯-4-氟苯基)-2-N-甲基-6-{5-[6-(2,2,2-三氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺 Example 414 : 2-N-(3-Chloro-4-fluorophenyl)-2-N-methyl-6-{5-[6-(2,2,2-trifluoroethoxy)pyridine-3 -base]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine

向存於DMF(1 mL)中之2-N-(3-氯-4-氟苯基)-6-{5-[6- (2,2,2-三氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺(實例413，0.049 g，0.101 mmol)之溶液中添加碳酸鉀(0.028 g，0.028 mmol)及碘甲烷(0.021 g，0.152 mmol)。將反應混合物在室溫下攪拌14 h，然後添加額外碘甲烷(0.042 g，0.304 mmol)且將混合物在室溫下攪拌56 h。LCMS表明轉化不完全，因此添加額外碘甲烷(0.014 g，0.105 mmol)且將混合物加熱至50℃保持12 h。在此時間之後，添加碳酸銫(0.032 g，0.105 mmol)且將混合物加熱至50℃保持1 h。添加額外碘甲烷(0.021 g，0.152 mmol)及碳酸銫(0.064 g，0.201 mmol)且將混合物加熱至50℃保持14 h。添加氫化鈉(存於礦物油中之60%分散液，0.004 g，0.105 mmol)及額外碘甲烷(0.042 g，0.304 mmol)並在50℃下將混合物攪拌1h。使用水/氨/MeOH(1 mL)將混合物驟冷並使用EtOAc萃取。使用水洗滌有機層，藉由硫酸鈉乾燥並在真空下濃縮。將固體溶於DMF(0.5 mL)中且添加氫化鈉(存於礦物油中之60%分散液，0.006 g，0.152 mmol)及碘甲烷(0.042 g，0.304 mmol)。將反應混合物在室溫下攪拌2 h。使用水/氨/MeOH(1 mL)將反應混合物驟冷並使用EtOAc萃取。使用水洗滌有機層，藉由硫酸鈉乾燥並在真空下濃縮。藉由HPLC(方法B)純化殘留物以得到標題化合物(0.004 g，8%)。 2-N-(3-Chloro-4-fluorophenyl)-6-{5-[6-(2,2,2-trifluoroethoxy)pyridine-3 in DMF (1 mL) -base]-1,2,4- Diazol-3-yl}-1,3,5-three Potassium carbonate (0.028 g, 0.028 mmol) and methyl iodide (0.021 g, 0.152 mmol) were added to a solution of &lt;RTI ID=0.0&gt;&gt; The reaction mixture was stirred at room temperature for 14 h then additional EtOAc (EtOAc &lt LCMS indicated incomplete conversion, so additional methyl iodide (0.014 g, 0.105 mmol) was added and the mixture was heated to 50 °C for 12 h. After this time, cesium carbonate (0.032 g, 0.105 mmol) was added and the mixture was heated to 50 ° C for 1 h. Additional methyl iodide (0.021 g, 0.152 mmol) and cesium carbonate (0.064 g, 0.201 mmol) were added and the mixture was heated to 50 ° C for 14 h. Sodium hydride (60% dispersion in mineral oil, 0.004 g, 0.105 mmol) and additional methyl iodide (0.042 g, 0.304 mmol) were added and the mixture was stirred at 50 ° C for 1 h. The mixture was quenched with water / ammonia / MeOH (1 mL) andEtOAc. The organic layer was washed with water, dried over sodium sulfate and evaporated. The solid was dissolved in DMF (0.5 mL) and sodium hydride (60% dispersion in mineral oil, 0.006 g, 0.152 The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water / EtOAc / EtOAc (EtOAc) The organic layer was washed with water, dried over sodium sulfate and evaporated. The residue was purified by EtOAc (EtOAc)

實例422：6-[5-(4-胺基環己基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺(方法23) Example 422 : 6-[5-(4-Aminocyclohexyl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine ( Method 23 )

向N-[4-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2- 基}-1,2,4-二唑-5-基)環己基]胺基甲酸第三丁基酯(實例423，2.349 g，5.035 mmol)中添加氯化氫溶液(4 M，存於1,4-二烷中，10 mL，40 mmol)且將混合物在室溫下攪拌4 h。在真空下濃縮混合物，添加水且使用碳酸氫鈉飽和水溶液將水溶液中和至pH 7。藉由過濾收集所得沈澱物以得到白色固體形式之標題化合物(0.877 g，48%)。 To N-[4-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three -2- base}-1,2,4- Addition of hydrogen chloride solution (4 M, stored in 1,4-two) to the tert-butyl-5-yl)cyclohexyl]carbamic acid tert-butyl ester (Example 423, 2.349 g, 5.035 mmol) Acetone, 10 mL, 40 mmol) and the mixture was stirred at room temperature for 4 h. The mixture was concentrated under vacuum, water was added and the aqueous solution was neutralized to pH 7 using saturated aqueous sodium hydrogen carbonate. The obtained precipitate was collected to give the title compound (yield: </RTI>

實例425：N-[4-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)環己基]-2-甲基丙醯胺(方法22) Example 425 : N-[4-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)cyclohexyl]-2-methylpropanamide ( Method 22 )

向存於DMF(5 mL)中之2-甲基丙酸(0.03 g，0.327 mmol)之溶液中添加DIPEA(0.122 mL，0.682 mmol)，隨後添加六氟磷酸(1H-苯并三唑-1-基氧基)[叁(二甲基胺基)]鏻(0.13 g，0.3 mmol)。將反應混合物在室溫下攪拌5 min且添加6-[5-(4-胺基環己基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺(批次1：來自實例422，0.1 g，0.273 mmol)。將反應混合物在室溫下攪拌16 h且然後濃縮，使用EtOAc萃取，使用水洗滌，藉由硫酸鈉乾燥並濃縮。藉由使用存於DCM中之0-10% MeOH洗脫之FCC純化殘餘物。將粗產物溶於EtOAc中，使用碳酸氫鈉飽和水溶液洗滌，藉由硫酸鈉乾燥並在真空下濃縮以得到標題化合物(0.0255 g，21%)。 DIPEA (0.122 mL, 0.682 mmol) was added to a solution of 2-methylpropionic acid (0.03 g, 0.327 mmol) in DMF (5 mL), followed by hexafluorophosphoric acid (1H-benzotriazole-1) -yloxy)[indole (dimethylamino)]indole (0.13 g, 0.3 mmol). The reaction mixture was stirred at room temperature for 5 min and 6-[5-(4-aminocyclohexyl)-1,2,4- was added. Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-Diamine (batch 1: from example 422, 0.1 g, 0.273 mmol). The reaction mixture was stirred at rt EtOAc (EtOAc)EtOAc. The residue was purified by FCC eluting with 0-10% MeOH in DCM. The crude product was taken from EtOAc EtOAc EtOAc.

實例429：2-N-甲基-6-[5-(4-苯氧基環己基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺 Example 429 : 2-N-Methyl-6-[5-(4-phenoxycyclohexyl)-1,2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine

向存於THF(4 mL)中之4-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)環己烷-1-醇(實例 424，0.1 g，0.272 mmol)之溶液中添加苯酚(0.03 g，0.272 mmol)、三苯基膦(0.09 g，0.327 mmol)及N-{[(第三丁氧基)羰基]亞胺基}(第三丁氧基)甲醯胺(0.08 g，0.327 mmol)。將反應混合物在室溫下攪拌16 h。然後濃縮混合物並藉由製備型HPLC方法D純化以得到標題化合物(0.010 g，8%)。 4-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three in THF (4 mL) -2-yl}-1,2,4- Phenol (0.03 g, 0.272 mmol), triphenylphosphine (0.09 g, 0.327 mmol) and N were added to a solution of oxazol-5-yl)cyclohexane-1-ol (Example 424, 0.1 g, 0.272 mmol). -{[(Tertidinoxy)carbonyl]imino}(t-butoxy)carbamidine (0.08 g, 0.327 mmol). The reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated and purified by preparative EtOAc EtOAc EtOAc.

實例432：2-N-(6-氟吡啶-3-基)-2-N-甲基-6-{5-[6-(2,2,2-三氟乙氧基)吡啶-3-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺 Example 432 : 2-N-(6-Fluoropyridin-3-yl)-2-N-methyl-6-{5-[6-(2,2,2-trifluoroethoxy)pyridine-3- Base]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine

將6-(2,2,2-三氟乙氧基)吡啶-3-甲酸(以與中間體206類似之方式製得，0.216 g，0.051 mmol)添加至存於吡啶(1 ml)中之N-(3-二甲基胺基丙基)-N'-乙基碳化二亞胺鹽酸鹽(0.049 g，0.252 mmol)之溶液中且將混合物在室溫下攪拌16 h。添加額外N-(3-二甲基胺基丙基)-N'-乙基碳化二亞胺鹽酸鹽(0.0255 g，0.1 mmol)且將混合物在50℃下攪拌4 h。添加4-胺基-6-[(6-氟吡啶-3-基)(甲基)胺基]-N'-羥基-1,3,5-三-2-甲脒(中間體156，0.05 g，0.18 mmol)及N-(3-二甲基胺基丙基)-N'-乙基碳化二亞胺鹽酸鹽(0.0163 g，0.09 mmol)且將混合物在50℃下攪拌16 h且然後在60℃下攪拌5 h。將混合物溶於EtOAc中並使用水洗滌，且然後使用氯化銨飽和水溶液、碳酸氫鈉飽和水溶液洗滌，且然後使用鹽水洗滌。藉由硫酸鈉乾燥有機層並在真空下濃縮。藉由製備型HPLC(方法B)純化殘餘物以得到標題化合物(0.002 g，3%)。 6-(2,2,2-Trifluoroethoxy)pyridine-3-carboxylic acid (prepared in a similar manner to intermediate 206, 0.216 g, 0.051 mmol) was added to pyridine (1 ml) A solution of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.049 g, 0.252 mmol). Additional N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.0255 g, 0.1 mmol) was added and the mixture was stirred at 50 ° C for 4 h. Add 4-amino-6-[(6-fluoropyridin-3-yl)(methyl)amino]-N'-hydroxy-1,3,5-three 2-carboxamidine (Intermediate 156, 0.05 g, 0.18 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.0163 g, 0.09 mmol) The mixture was stirred at 50 ° C for 16 h and then at 60 ° C for 5 h. The mixture was dissolved in EtOAc and washed with water and then washed with a saturated aqueous solution of sodium chloride and saturated aqueous sodium hydrogen carbonate, and then washed with brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by EtOAcqqqqqq

實例436：2-N-(2-甲氧基乙基)-6-[5-(3-苯氧基氮雜環丁-1-基)-1,2,4-二唑-3-基]-2-N-苯基-1,3,5-三-2,4-二胺 Example 436 : 2-N-(2-Methoxyethyl)-6-[5-(3-phenoxyazetidin-1-yl)-1,2,4- Diazol-3-yl]-2-N-phenyl-1,3,5-three -2,4-diamine

將三氯乙酸酐(0.181 mL，0.989 mmol)添加至存於甲苯(10 mL)中之4-胺基-N'-羥基-6-[(2甲氧基乙基)(苯基)胺基]-1,3,5-三-2-甲脒(中間體160，0.250 g，0.824 mmol)中並在室溫下攪拌5 min。添加吡啶(3 mL)且將混合物加熱至85℃保持1 h。在真空下濃縮混合物並將殘餘物溶於EtOAc中。使用水、碳酸氫鈉飽和水溶液洗滌，且然後使用鹽水洗滌。藉由硫酸鈉乾燥有機層並濃縮。將殘餘物溶於DMF(2 mL)中且添加3-苯氧基氮雜環丁烷鹽酸鹽(0.13 g，0.685 mmol)及DIPEA(0.499 mL，1.370 mmol)。將混合物在室溫下攪拌13 h且然後在真空下濃縮。使用EtOAc(30 mL)萃取混合物，使用水、碳酸氫鈉飽和水溶液洗滌，且然後使用鹽水洗滌。藉由硫酸鈉乾燥有機層並在真空下濃縮。藉由使用存於DCM中之0-2% MeOH洗脫之FCC純化殘餘物。藉由FCC(使用存於庚烷中之50% EtOAc洗脫，然後使用存於DCM中之0-2% MeOH洗脫)進一步純化粗製材料以得到標題化合物(0.091 g，29%)。 Trichloroacetic anhydride (0.181 mL, 0.989 mmol) was added to 4-amino-N'-hydroxy-6-[(2methoxyethyl)(phenyl)amino group in toluene (10 mL) ]-1,3,5-three 2-Methylformamide (Intermediate 160, 0.250 g, 0.824 mmol) was stirred at room temperature for 5 min. Pyridine (3 mL) was added and the mixture was heated to 85 ° C for 1 h. The mixture was concentrated in vacuo and the residue was crystallised from EtOAc. It was washed with water, a saturated aqueous solution of sodium hydrogencarbonate, and then washed with brine. The organic layer was dried over sodium sulfate and concentrated. The residue was dissolved in DMF (2 mL) EtOAc (EtOAc:EtOAc: The mixture was stirred at room temperature for 13 h and then concentrated under vacuum. The mixture was extracted with EtOAc (30 mL), washed with water, sat. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by FCC eluting with 0-2% MeOH in DCM. The crude material was purified further EtOAc EtOAcqqqqq

實例441：2-N-甲基-2-N-苯基-6-{5-[(2S)-1-(3,3,3-三氟丙基)吡咯啶-2-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺(方法24) Example 441 : 2-N-Methyl-2-N-phenyl-6-{5-[(2S)-1-(3,3,3-trifluoropropyl)pyrrolidin-2-yl]-1 , 2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine ( Method 24 )

向存於DCE(5 mL)中之2-N-甲基-2-N-苯基-6-{5-[(2S)-吡咯啶-2-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺鹽酸鹽(實例438，0.2 g，0.535 mmol)之溶液中添加乙酸鈉 (0.07 g，0.8 mmol)及3,3,3-三氟丙醛(0.12 g，1.070 mmol)且將混合物在室溫下攪拌1 h。添加三乙醯氧基硼氫化鈉(0.17 g，0.8 mmol)且在室溫下將反應混合物攪拌2 h。添加DCM且使用碳酸氫鈉飽和水溶液洗滌混合物，且然後使用鹽水洗滌。藉由硫酸鈉乾燥有機層並在真空下濃縮。藉由使用存於庚烷中之20-100% EtOAc洗脫之FCC純化殘餘物以得到標題化合物(0.045 g，19%)。 2-N-methyl-2-N-phenyl-6-{5-[(2S)-pyrrolidin-2-yl]-1,2,4- in DCE (5 mL) Diazol-3-yl}-1,3,5-three Sodium acetate (0.07 g, 0.8 mmol) and 3,3,3-trifluoropropanal (0.12 g, 1.070 mmol) were added to a solution of 2,4-diamine hydrochloride (Example 438, 0.2 g, 0.535 mmol). And the mixture was stirred at room temperature for 1 h. Sodium triethoxysulfonate (0.17 g, 0.8 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. DCM was added and the mixture was washed with a saturated aqueous solution of sodium bicarbonate and then washed with brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified with EtOAc EtOAcjjjjjj

實例445：2-N-甲基-2-N-苯基-6-{5-[(3S)-3-(2,2,2-三氟乙氧基)吡咯啶-1-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺 Example 445 : 2-N-Methyl-2-N-phenyl-6-{5-[(3S)-3-(2,2,2-trifluoroethoxy)pyrrolidin-1-yl]- 1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine

將偶氮二甲酸二-第三丁基酯(2.96 g，12.83 mmol)添加至存於THF(24 mL)中之(3R)-3-羥基吡咯啶-1-甲酸第三丁基酯(2.00 g，10.70 mmol)、2,2,2-三氟乙醇(10.70 g，106.95 mmol)及三苯基膦(3.37 g，12.83 mmol)之冰冷卻混合物中。將混合物在70℃下攪拌18 h。在真空下濃縮混合物且藉由使用存於庚烷中之EtOAc之梯度洗脫之FCC純化殘餘物以得到(3S)-3-(2,2,2-三氟乙氧基)吡咯啶-1-甲酸第三丁基酯(0.393 g，14%)。將此產物溶於氯化氫溶液(4 M，存於1,4-二烷中，3 mL，12 mmol)中且將混合物攪拌2 h。濃縮混合物以得到(3S)-3-(2,2,2-三氟乙氧基)吡咯啶鹽酸鹽(0.203 g，產率為68%)。將此產物與存於DMF(2 mL)中之2-N-甲基-2-N-苯基-6-[5-(三氯甲基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺(以與中間體60類似之方式製得，0.1 g，0.259 mmol)及碳酸鉀(0.13 g，0.952 mmol)合併且將反應混合物在室溫下攪拌16 h。然後濃縮混合物並 將殘餘物溶於EtOAc中。使用碳酸氫鈉飽和水溶液洗滌，隨後使用鹽水洗滌，然後藉由硫酸鈉乾燥並在真空下濃縮。藉由製備型HPLC(方法D)純化殘餘物以得到標題化合物(0.006 g，6%)。 Di-t-butyl azodicarboxylate (2.96 g, 12.83 mmol) was added to (3R)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (2.00) in THF (24 mL). g, 10.70 mmol), 2,2,2-trifluoroethanol (10.70 g, 106.95 mmol) and triphenylphosphine (3.37 g, 12.83 mmol) in ice-cooled mixture. The mixture was stirred at 70 ° C for 18 h. The mixture was concentrated in vacuo and the residue was purified eluting eluting elut elut - Tert-butyl formate (0.393 g, 14%). This product is dissolved in hydrogen chloride solution (4 M, stored in 1,4-two The mixture was stirred for 2 h in hexanes (3 mL, 12 mmol). The mixture was concentrated to give (3S)-3-(2,2,2-trifluoroethoxy)pyrrolidine hydrochloride (0.203 g, yield 68%). This product was combined with 2-N-methyl-2-N-phenyl-6-[5-(trichloromethyl)-1,2,4- in DMF (2 mL) Diazol-3-yl]-1,3,5-three -2,4-Diamine (prepared in a similar manner to Intermediate 60, 0.1 g, 0.259 mmol) and potassium carbonate (0.13 g, 0.952 mmol) and the mixture was stirred at room temperature for 16 h. The mixture was then concentrated and the residue dissolved in EtOAc. It was washed with a saturated aqueous solution of sodium bicarbonate, then brine, then dried over sodium sulfate and evaporated. The residue was purified by EtOAcqqqqqq

實例464：2-N-甲基-2-N-苯基-6-[5-({4-[(3,3,3-三氟丙氧基)甲基]六氫吡啶-1-基}羰基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺 Example 464 : 2-N-Methyl-2-N-phenyl-6-[5-({4-[(3,3,3-trifluoropropoxy)methyl]hexahydropyridin-1-yl }carbonyl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine

將4-[(3,3,3-三氟丙氧基)甲基]六氫吡啶-1-甲酸第三丁基酯(中間體291，0.256 g，0.82 mmol)溶於存於二烷中之4 M HCl溶液中，將混合物在室溫下攪拌2 h，然後濃縮並使用甲苯共沸兩次。使用一部分所得殘餘物([(3,3,3-三氟丙氧基)甲基]六氫吡啶鹽酸鹽)(97 mg，0.39 mmol)及3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-甲酸乙酯(以與實例73類似之方式製得，90 mg，0.26 mmol)根據針對實例463所述之方法來製備標題化合物。藉由製備型HPLC(方法C)純化粗製殘餘物以得到標題化合物(36 mg，27%)。 4-[(3,3,3-Trifluoropropoxy)methyl]hexahydropyridine-1-carboxylic acid tert-butyl ester (intermediate 291, 0.256 g, 0.82 mmol) was dissolved in two The mixture was stirred at room temperature for 2 h in aq. A portion of the residue obtained ([(3,3,3-trifluoropropoxy)methyl]hexahydropyridine hydrochloride) (97 mg, 0.39 mmol) and 3-{4-amino-6-[ (phenyl)amino]-1,3,5-three -2-yl}-1,2,4- The title compound was prepared according to the procedure described for Example 463. The crude residue was purified by EtOAcqqqqqq

實例478：5-{3-[4-胺基-6-(甲基-苯基-胺基)-[1,3,5]三-2-基]-[1,2,4]二唑-5-基}-吡啶-2-甲酸二甲基醯胺 Example 478 : 5-{3-[4-Amino-6-(methyl-phenyl-amino)-[1,3,5]3 -2-base]-[1,2,4] Diazol-5-yl}-pyridine-2-carboxylic acid dimethyl decylamine

在40℃及氮下，將二甲胺(248 μL，0.495 mmol)及雙(三甲基鋁)-1,4-二氮雜雙環[2.2.2]-辛烷(128 mg，0.495 mmol)在無水甲苯(2 mL)中一起攪拌1 h。添加5-{3-[4-胺基-6-(甲基-苯基-胺基)-[1,3,5]三-2-基]-[1,2,4]二唑-5-基}-吡啶-2-甲酸甲酯(以與實例279類似之方式製得，80 mg， 0.198 mmol)並將反應液在80℃下攪拌約18 h。然後將混合物冷卻至室溫並使用EtOAc(20 mL)稀釋。然後使用2 M HCl(2×6 mL)、碳酸氫鈉飽和水溶液(2×6 mL)洗滌溶液，藉由硫酸鈉乾燥並在真空下蒸發。藉由急驟層析(存於DCM中之0-3% MeOH)純化粗製殘餘物且然後藉由急驟層析(存於庚烷中之0-80% EtOAc)進一步純化所獲得材料以得到標題化合物(10 mg，12%)。 Dimethylamine (248 μL, 0.495 mmol) and bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]-octane (128 mg, 0.495 mmol) at 40 ° C under nitrogen Stir together for 1 h in dry toluene (2 mL). Add 5-{3-[4-amino-6-(methyl-phenyl-amino)-[1,3,5] three -2-base]-[1,2,4] Methyl oxazol-5-yl}-pyridine-2-carboxylate (prepared in a similar manner to Example 279, 80 mg, 0.198 mmol) and the reaction mixture was stirred at 80 ° C for about 18 h. The mixture was then cooled to room temperature and diluted with EtOAc (20 mL). The solution was then washed with 2 M HCl (2×6 mL) EtOAc. The crude residue was purified by flash chromatography eluting eluting elut elut elut elut elut elut elut elut (10 mg, 12%).

實例481：6-{5-[3-(環丙基胺基)吡啶-2-基]-1,2,4-二唑-3-基}-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺 Example 481 : 6-{5-[3-(cyclopropylamino)pyridin-2-yl]-1,2,4- Diazol-3-yl}-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine

在室溫下於密封管中，將1,1'-羰基二咪唑(62 mg，0.380 mmol)添加至存於無水吡啶(1 mL)中之3-氟吡啶-2-甲酸(50 mg，0.354 mmol)之溶液中且將混合物攪拌1 h。添加4-胺基-N-羥基-6-(甲基-3-甲基苯基-胺基)-[1,3,5]三-2-甲脒(以與中間體1類似之方式製得，66 mg，0.253 mmol)且將混合物在室溫下攪拌60 min且然後在90℃下攪拌約18 h。然後使用環丙胺(300 μL，4.32 mmol)處理混合物並在80℃下攪拌7 h。然後使用EtOAc(35 mL)稀釋混合物並使用水(10 mL)、氯化銨飽和水溶液(2×6 mL)及2 M鹽酸(3×5 mL)洗滌。使用DCM(2×6 mL)洗滌合併之鹽酸萃取液且然後藉由添加2 M氫氧化鈉水溶液達到鹼性。使用DCM(4×7 mL)萃取所得溶液，使用鹽水(10 mL)洗滌合併之有機萃取液，藉由硫酸鈉乾燥並在真空下蒸發。藉由急驟層析(存於DCM中之0-3% MeOH)純化粗製殘餘物以得到標題化合物(17 mg，17%)。 Add 1,1'-carbonyldiimidazole (62 mg, 0.380 mmol) to 3-fluoropyridine-2-carboxylic acid (50 mg, 0.354) in anhydrous pyridine (1 mL) at room temperature. The mixture was stirred for 1 h. Add 4-amino-N-hydroxy-6-(methyl-3-methylphenyl-amino)-[1,3,5] three 2-Methylhydrazine (prepared in a similar manner to Intermediate 1, 66 mg, 0.253 mmol) and the mixture was stirred at room temperature for 60 min and then at 90 ° C for about 18 h. The mixture was then treated with cyclopropylamine (300 μL, 4.32 mmol) and stirred at 80 ° C for 7 h. The mixture was then diluted with EtOAc (35 mL) and washed with water (10 mL) The combined hydrochloric acid extracts were washed with DCM (2×6 mL) and then made basic with aq. The resulting solution was extracted with EtOAc (EtOAc) (EtOAc) The crude residue was purified by EtOAcjjjjjjjj

實例482：6-[5-(3-氟吡啶-2-基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺(方法26) Example 482 : 6-[5-(3-Fluoropyridin-2-yl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine ( Method 26 )

在室溫及氮下於密封管中，將N-[3-(二甲基胺基)丙基]-N'-乙基碳化二亞胺鹽酸鹽(633 mg，3.3 mmol)添加至存於無水吡啶(6 mL)中之3-氟吡啶-2-甲酸(400 mg，2.83 mmol)之溶液中。將反應混合物在室溫下攪拌1 h。添加4-胺基-N-羥基-6-(甲基-3-甲基苯基-胺基)-[1,3,5]三-2-甲脒(以與中間體1類似之方式製得，611 mg，2.36 mmol)且將混合物在室溫下攪拌約18 h。添加存於無水吡啶(1 mL)中之N-[3-(二甲基胺基)丙基]-N'-乙基碳化二亞胺鹽酸鹽(315 mg，1.15 mmol)之溶液且將混合物攪拌2 h。然後添加額外N-[3-(二甲基胺基)丙基]-N'-乙基碳化二亞胺鹽酸鹽(100 mg，0.52 mmol)及3-氟吡啶-2-甲酸(70 mg，0.5 mmol)且將混合物在室溫下攪拌1 h且然後在60℃下攪拌約18 h。然後使用EtOAc(75 mL)稀釋混合物並使用氯化銨飽和水溶液(4×15 mL)洗滌，然後使用碳酸氫鈉飽和水溶液(3×15 mL)及鹽水(15 mL)洗滌。藉由硫酸鈉乾燥有機層並在真空下蒸發。藉由急驟層析(存於DCM中之0-2% MeOH)純化粗製殘餘物以得到標題化合物(220 mg)。將20 mg此材料溶於熱DMSO(0.3 mL)及MeOH(0.5 mL)中且然後添加1：1 MeCN：水(1 mL)。過濾所得沈澱物，使用水(2×1 mL)洗滌固體且然後在真空下乾燥以得到白色固體形式之標題化合物(14 mg，2%)。 N-[3-(Dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride (633 mg, 3.3 mmol) was added to the sealed tube at room temperature under nitrogen. A solution of 3-fluoropyridine-2-carboxylic acid (400 mg, 2.83 mmol) in anhydrous pyridine (6 mL). The reaction mixture was stirred at room temperature for 1 h. Add 4-amino-N-hydroxy-6-(methyl-3-methylphenyl-amino)-[1,3,5] three 2-Methyl hydrazine (prepared in a similar manner to Intermediate 1, 611 mg, 2.36 mmol) and the mixture was stirred at room temperature for about 18 h. Add a solution of N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride (315 mg, 1.15 mmol) in anhydrous pyridine (1 mL) and The mixture was stirred for 2 h. Then add additional N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmol) and 3-fluoropyridine-2-carboxylic acid (70 mg) 0.5 mmol) and the mixture was stirred at room temperature for 1 h and then at 60 ° C for about 18 h. The mixture was then diluted with EtOAc (75 mL) EtOAc (EtOAc)EtOAc. The organic layer was dried over sodium sulfate and evaporated in vacuo. The crude residue was purified by EtOAcqqqqqq 20 mg of this material was dissolved in hot DMSO (0.3 mL) and MeOH (0.5 mL) and then 1:1 MeCN: water (1 mL). The resulting precipitate was filtered, washed with EtOAcqqqqqqqqq

實例487：6-{5-[3-(環丙基甲基胺基)-吡啶-2-基]-[1,2,4] 二唑-3-基}-N-甲基-N-苯基-[1,3,5]三-2,4-二胺(方法25) Example 487 : 6-{5-[3-(Cyclopropylmethylamino)-pyridin-2-yl]-[1,2,4] Diazol-3-yl}-N-methyl-N-phenyl-[1,3,5] -2,4-diamine ( Method 25 )

在室溫及氮下於密封管中，將6-[5-(3-氟吡啶-2-基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺(以與實例482類似之方式製得，50 mg，0.137 mmol)、1-環丙基甲胺(24 μL，0.274 mmol)及碳酸鉀(57 mg，0.411 mmol)懸浮於無水DMF(2 mL)中。將反應混合物在90℃下攪拌3 h且然後在100℃下攪拌18 h。使用DCM(10 mL)稀釋混合物且然後使用氯化銨飽和水溶液(3×5 mL)洗滌，且然後使用鹽水(5 mL)洗滌。藉由硫酸鈉乾燥有機層並在真空下蒸發。藉由急驟層析(存於DCM中之0-1%(存於MeOH中之7M氨))純化粗製殘餘物以得到標題化合物(25 mg，44%)。 6-[5-(3-Fluoropyridin-2-yl)-[1,2,4] in a sealed tube at room temperature under nitrogen Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-Diamine (prepared in a similar manner to Example 482, 50 mg, 0.137 mmol), 1-cyclopropylmethylamine (24 μL, 0.274 mmol) and potassium carbonate (57 mg, 0.411 mmol). In anhydrous DMF (2 mL). The reaction mixture was stirred at 90 ° C for 3 h and then at 100 ° C for 18 h. The mixture was diluted with DCM (10 mL) and then washed with a saturated aqueous solution of ammonium chloride (3×5 mL) and then washed with brine (5 mL). The organic layer was dried over sodium sulfate and evaporated in vacuo. The crude residue was purified by EtOAc EtOAc EtOAc EtOAc

實例492：6-[5-(3-異丙氧基氮雜環丁-1-基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺(方法27) Example 492 : 6-[5-(3-Isopropoxyazetidin-1-yl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine ( Method 27 )

在0℃及氮下，將氫化鈉(存於礦物油中之60%分散液，9 mg，0.22 mmol)添加至存於無水DMF(0.5 mL)中之1-{3-[4-胺基-6-(甲基-苯基-胺基)-[1,3,5]三-2-基]-[1,2,4]二唑-5-基}-氮雜環丁-3-醇(中間體166，50 mg，0.147 mol)之溶液中且將混合物攪拌10 min。然後添加存於無水DMF(0.5 mL)中之甲烷磺酸丙烷-2-基酯(26.7 μL，0.221 mmol)之溶液且將混合物在室溫下攪拌18 h。然後添加額外氫化鈉(存於礦物油中之60%分散液，9 mg，0.22 mmol)及甲烷磺酸丙烷-2-基酯(26.7 μL，0.221 mmol)且將混合物在室溫下攪拌4 h。使用EtOAc(10 mL)稀釋混合物然後使用碳酸鈉飽 和水溶液(4×5 mL)、鹽水(5 mL)洗滌並在真空下蒸發。藉由急驟層析(存於DCM中之0-2%(存於MeOH中之7 M氨))純化粗製殘餘物以得到淺黃色玻璃狀物形式之標題化合物(22 mg，39%)。 Sodium hydride (60% dispersion in mineral oil, 9 mg, 0.22 mmol) was added to 1-{3-[4-amino group in anhydrous DMF (0.5 mL). -6-(methyl-phenyl-amino)-[1,3,5] three -2-base]-[1,2,4] A solution of oxazol-5-yl}-azetidin-3-ol (Intermediate 166, 50 mg, 0.147 mol) was stirred for 10 min. A solution of propane-2-yl methanesulfonate (26.7 μL, 0.221 mmol) in dry DMF (0.5 mL) was then added and the mixture was stirred at room temperature for 18 h. Then additional sodium hydride (60% dispersion in mineral oil, 9 mg, 0.22 mmol) and propan-2-yl methanesulfonate (26.7 μL, 0.221 mmol) were added and the mixture was stirred at room temperature for 4 h . The mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. The crude residue was purified by flash chromatography eluting elut elut elut elut elut elut elut

實例495：N-甲基-6-[5-(3-苯氧基甲基氮雜環丁-1-基)-[1,2,4]二唑-3-基]-N-苯基-[1,3,5]三-2,4-二胺(方法28) Example 495 : N-Methyl-6-[5-(3-phenoxymethylazetidin-1-yl)-[1,2,4] Diazol-3-yl]-N-phenyl-[1,3,5] -2,4-diamine ( Method 28 )

將3-苯氧基甲基-氮雜環丁烷-1-甲酸第三丁基酯(中間體166，50 mg，0.189 mmol)在室溫下於DCM(1 mL)與三氟乙酸(0.25 mL)之混合物中攪拌30 min。在真空下蒸發混合物且將殘餘物溶於無水DMF(0.5 mL)中。添加DIPEA(165 μL，0.945 mmol)，隨後添加存於DMF(1.5 mL)中之N-甲基-N-苯基-6-(5-三氯甲基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺(以與中間體60類似之方式製得，37 mg，0.095 mmol)之溶液。將反應液在室溫下攪拌約42 h。使用EtOAc(15 mL)稀釋混合物然後使用氯化銨飽和水溶液(3×5 mL)、碳酸鈉飽和水溶液(3×5 mL)、鹽水(5 mL)洗滌，藉由硫酸鈉乾燥並在真空下蒸發。藉由急驟層析(存於DCM中之0-2% MeOH)純化粗製殘餘物且然後藉由製備型HPLC(方法D)進一步純化以得到標題化合物(6 mg，7%)。 3-Phenoxymethyl-azetidin-1-carboxylic acid tert-butyl ester (Intermediate 166, 50 mg, 0.189 mmol) in DCM (1 mL) and trifluoroacetic acid (0.25) The mixture was stirred for 30 min in mL). The mixture was evaporated in vacuo and the residue was takenjjjjjjjjj Add DIPEA (165 μL, 0.945 mmol) followed by N-methyl-N-phenyl-6-(5-trichloromethyl-[1,2,4] in DMF (1.5 mL) Diazol-3-yl)-[1,3,5]3 A solution of 2,4-diamine (prepared in a similar manner to intermediate 60, 37 mg, 0.095 mmol). The reaction was stirred at room temperature for about 42 h. The mixture was diluted with EtOAc (15 mL) and brine (EtOAc) . The crude residue was purified by flash chromatography eluting elut elut elut elut elut elut elut elut

實例之表格Example table

根據在第三欄中所示之方法(M)來製備表格中之下列實例。 The following examples in the table were prepared according to the method (M) shown in the third column.

在使用方法4時，端視實例，鹼(例如二異丙基乙胺或碳酸鉀)之存在係可選的。 When using Method 4, depending on the example, the presence of a base such as diisopropylethylamine or potassium carbonate is optional.

a. IonWork Quattro數據，b=人工膜片箝製數據，c=自動膜片箝製數據 a. IonWork Quattro data, b = artificial patch clamp data, c = automatic patch clamp data

M=方法 M=method

實例269、實例298、實例435、實例485及實例511並不存在。 Example 269, instance 298, instance 435, instance 485, and instance 511 do not exist.

中間體1：4-胺基-N-羥基-6-(甲基-苯基-胺基)-[1,3,5]三-2-甲脒 Intermediate 1 : 4-amino-N-hydroxy-6-(methyl-phenyl-amino)-[1,3,5] -2-甲脒

將存於EtOH(4 mL)中之4-胺基-6-(甲基-苯基-胺基)-[1,3,5]三-2甲腈(中間體2，138 mg，0.6 mmol)之溶液添加至羥基胺鹽酸鹽(51 mg，0.7 mmol)及碳酸氫鈉(61 mg，0.73 mmol)之水溶液(2 mL)中。將混合物在70℃下加熱2 h，冷卻至室溫並蒸發溶劑。使用水(4 mL)將粗製固體殘餘物製成漿液，然後在減壓下過濾以得到中間體1(95 mg，60%)。方法C HPLC-MS：MH+要求m/z=260；實驗 值：m/z=260，Rt=0.88 min(98%)。 4-Amino-6-(methyl-phenyl-amino)-[1,3,5]3 in EtOH (4 mL) A solution of -2 carbonitrile (intermediate 2, 138 mg, 0.6 mmol) was added to aq. EtOAc (EtOAc) The mixture was heated at 70 ° C for 2 h, cooled to room temperature and evaporated. The crude solid residue was slurried with water (4 mL) then filtered under reduced pressure to afford Intermediate 1 (95 mg, 60%). Method C HPLC-MS: MH+ requires m/z = 260; found: m/z = 260, Rt = 0.88 min (98%).

以與中間體1類似之方式來製備下列N-羥基-甲脒中間體。 The following N-hydroxy-carbamidine intermediate was prepared in a similar manner to Intermediate 1.

中間體2：4-胺基-6-(甲基-苯基-胺基)-[1,3,5]三-2甲腈 Intermediate 2 : 4-amino-6-(methyl-phenyl-amino)-[1,3,5]3 -2 carbonitrile

向2-胺基-4-氯-6-氰基-[1,3,5]三(中間體3，243 mg，1.6 mmol)中添加無水DMF(5 mL)、二異丙基乙胺(0.54 mL，3.1 mmol)及N-甲基-苯胺(184 mg，1.7 mmol)。將混合物在90℃下於壓力管中加熱18 h，然後冷卻至室溫。使用EtOAc(20 mL)稀釋反應混合物，使用水(2×10 mL)洗滌且藉由無水硫酸鈉乾燥有機層並在減壓下濃縮以提供期望產物，該期望產物未經進一步純化即直接使用(138 mg， 39%)。方法C HPLC-MS：MH+要求m/z=227；實驗值：m/z=227，Rt=1.20 min(93%)。 To 2-amino-4-chloro-6-cyano-[1,3,5] Anhydrous DMF (5 mL), diisopropylethylamine (0.54 mL, 3.1 mmol) and N-methyl-aniline (184 mg, 1.7 mmol). The mixture was heated in a pressure tube at 90 ° C for 18 h and then cooled to room temperature. The reaction mixture was diluted with EtOAc (EtOAc EtOAc (EtOAc) 138 mg, 39%). Method C HPLC-MS: MH+ requires m/z = 227. Found: m/z = 227, Rt = 1.20 min (93%).

根據與中間體2類似之程序來製備下列甲腈。 The following carbonitrile was prepared according to a procedure similar to Intermediate 2.

另一選擇為，根據下列方法來製備4-胺基-6-(甲基-苯基-胺基)-[1,3,5]三-2甲腈：向存於DMF(25 ml)中之6-氯-N-甲基-N-苯基-[1,3,5]三-2,4-二胺(中間體41，360 mg，2.67 mmol)之攪拌溶液中添加氰化鉀(435 mg，6.68 mmol)。將反應液在120℃及氮下攪拌2 h。使用EtOAc(80 ml)稀釋反應混合物；然後使 用5%碳酸氫鈉水溶液(2×20 mL)及飽和鹽水(2×5 mL)萃取溶液。蒸發溶劑之後，藉由FCC在矽膠(使用庚烷：EtOAc(1：0至8：2至6：4)洗脫)上純化粗製殘餘物以提供期望產物(380 mg，63%)。方法C HPLC-MS：MH+要求m/z=227；實驗值：m/z=227，Rt=1.24 min(95%)。 Alternatively, 4-amino-6-(methyl-phenyl-amino)-[1,3,5]3 can be prepared according to the following method. -2 carbonitrile: 6-chloro-N-methyl-N-phenyl-[1,3,5]3 in DMF (25 ml) Potassium cyanide (435 mg, 6.68 mmol) was added to a stirred solution of the 2,4-diamine (Intermediate 41, 360 mg, 2.67 mmol). The reaction solution was stirred at 120 ° C for 2 h under nitrogen. The reaction mixture was diluted with EtOAc (80 mL); EtOAc (EtOAc) After evaporating the solvent, the crude residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Method C HPLC-MS: MH+ requires m/z = 227. Found: m/z = 227, Rt = 1.24 min (95%).

根據與中間體2類似之程序來製備下列甲腈。 The following carbonitrile was prepared according to a procedure similar to Intermediate 2.

中間體3：2-胺基-4-氯-6-氰基-[1,3,5]三 Intermediate 3 : 2-Amino-4-chloro-6-cyano-[1,3,5]3

向2-胺基-4-氰基-6-側氧基-1,3,5-三(J.Am.Chem.Soc.,1961,83,1261-2,2.30 g，16.8 mmol)中添加三氯化磷醯(50 mL，547 mmol)並將混合物在90℃下加熱2 h。將反應混合物冷卻至室溫，然後傾倒於冰-水(250 mL)上並使用固體碳酸鈉鹼化至pH 8。然後將混合物萃取至DCM(3×250 mL)中且藉由無水硫酸鈉乾燥合併之有機物並在減壓下濃縮以得到期望化合物，該期望化合物未經進一步純化即使用其粗製物(343 mg，13%)。方法C HPLC-MS：2 MH+要求m/z=311；實驗值：m/z=311，Rt=0.74 min(100%)。 To 2-amino-4-cyano-6-sideoxy-1,3,5-three (J. Am. Chem. Soc., 1961, 83, 1261-2, 2.30 g, 16.8 mmol) was added bisphosphonium trichloride (50 mL, 547 mmol) and the mixture was heated at 90 ° C for 2 h. The reaction mixture was cooled to room temperature then poured onto ice-water (250 mL) and basified to pH 8 using solid sodium carbonate. The mixture was then extracted into EtOAc (3×250 mL)EtOAc. 13%). Method C HPLC-MS: 2 MH+ requires m/z = 311. Found: m/z = 311, Rt = 0.74 min (100%).

中間體7：4-氰基-N-甲基-N-3-甲基苯基-[1,3,5]三-2,6-二胺 Intermediate 7 : 4-cyano-N-methyl-N-3-methylphenyl-[1,3,5]3 -2,6-diamine

向2-胺基-4-氯-6-氰基-[1,3,5]三(以與中間體3類似之方式製得，46 mg，296 μmol)中添加1 mL無水DMSO、二異丙基乙胺(77 μL,444 μmol)及N-甲基-間甲苯胺(40 mg， 326 μmol)。將混合物在90℃下加熱2 h，冷卻並使用10 mL乙酸乙酯稀釋。然後使用水(10 mL)、0.5 M HCl(3×10 mL)、水(10 mL)及飽和鹽水(10 mL)萃取混合物。藉由無水硫酸鈉進一步乾燥有機層並蒸發以得到期望產物，該期望產物未經進一步純化或表徵即直接使用(42 mg，59%)。 To 2-amino-4-chloro-6-cyano-[1,3,5] (1 mg of anhydrous DMSO, diisopropylethylamine (77 μL, 444 μmol) and N-methyl-m-toluidine (40 mg, prepared in a similar manner to Intermediate 3, 46 mg, 296 μmol) , 326 μmol). The mixture was heated at 90 &lt;0&gt;C for 2 h, cooled and diluted with 10 mL EtOAc. The mixture was then extracted with water (10 mL), 0.5 M HCl (3×10 mL), water (10 mL) and saturated brine (10 mL). The organic layer was further dried over anhydrous sodium sulphate and evaporated to give the desired product which was used directly (42 mg, 59%).

根據與中間體7類似之程序來製備下列甲腈。 The following carbonitrile was prepared according to a procedure similar to Intermediate 7.

中間體18：吡啶-2-羰基氯 Intermediate 18 : Pyridine-2-carbonyl chloride

市面有售。 Available in the market.

中間體19：5-氯-噻吩-2-羰基氯 Intermediate 19 : 5-chloro-thiophene-2-carbonyl chloride

市面有售。 Available in the market.

中間體20：6-環戊氧基菸醯氟 Intermediate 20 : 6-cyclopentyloxyxanthene fluoride

在氮氣氛下，向6-環戊氧基菸酸(中間體21,74 mg，358 μmol)中添加2 mL DCE及草醯氯(63 μL,716 μmol)。將混合物在80℃下加熱1 h且在冷卻至室溫之後蒸發以得到澄清油狀物(81 mg，100%)。方法B HPLC-MS(在MeOH中，鑑別甲酯)：MH+要求m/z=222；實驗值：m/z=222， Rt=2.19 min(94%)。 To a solution of 6-cyclopentyloxynicotinic acid (intermediate 21, 74 mg, 358 μmol) was added 2 mL of DCE and chloroform (63 μL, 716 μmol) under a nitrogen atmosphere. The mixture was heated at 80 &lt;0&gt;C for 1 h and evaporated to EtOAc (EtOAc). Method B HPLC-MS (Methyl ester identified in MeOH): MH+ requires m/z = 222; Rt = 2.19 min (94%).

以與中間體20類似之方式來製備下列醯氯。 The following ruthenium chloride was prepared in a similar manner to the intermediate 20.

中間體21：6-環戊氧基菸酸 Intermediate 21 : 6-cyclopentyloxynicotinic acid

市面有售。 Available in the market.

中間體33：4-胺基-6-(苄基-甲基-胺基)-[1,3,5]三-2甲腈 Intermediate 33 : 4-amino-6-(benzyl-methyl-amino)-[1,3,5]3 -2 carbonitrile

向N-苄基-6-氯-N-甲基-[1,3,5]三-2,4-二胺(中間體34，350 mg，1.40 mmol)中添加四正丁基氰化銨(1.15 g，4.28 mmol)及無水乙腈(15 mL)。將反應混合物在50℃下攪拌1 h，使用EtOAc(20 mL)稀釋，使用水(2×10 mL)萃取，藉由無水硫酸鈉乾燥並在減壓下濃縮以提供期望產物，該期望產物未經進一步純化即直接使用(327 mg，97%)。方法C HPLC-MS：MH+要求m/z=241；實驗值：m/z=241，Rt=1.29 min(86%)。 To N-benzyl-6-chloro-N-methyl-[1,3,5] three To a 2,4-diamine (intermediate 34, 350 mg, 1.40 mmol) was added tetra-n-butylammonium cyanide (1.15 g, 4.28 mmol) and anhydrous acetonitrile (15 mL). The reaction mixture was stirred at 50 ° C for 1 h, diluted with EtOAc EtOAc (EtOAc) It was used directly after further purification (327 mg, 97%). Method C HPLC-MS: MH+ requires m/z = 241. Found: m/z = 241, Rt = 1.29 min (86%).

以與中間體33類似之方式來製備下列甲腈。 The following carbonitrile was prepared in a similar manner to the intermediate 33.

中間體34：N-苄基-6-氯-N-甲基-[1,3,5]三-2,4-二胺 Intermediate 34 : N-benzyl-6-chloro-N-methyl-[1,3,5]3 -2,4-diamine

向氰尿醯氯(250 mg，1.4 mmol)中添加無水THF(10 mL)、二異丙基乙胺(0.36 mL，2.0 mmol)及N-甲基苄基胺(164 mg,1.4 mmol)。將混合物在0℃下攪拌0.5 h且然後攪拌並升溫至室溫再保持1.5 h。使用濃氨(d=0.88,0.4 mL，6.2 mmol)處理反應混合物並在室溫下攪拌18 h。蒸發溶劑且使用EtOAc(10 mL)稀釋反應混合物並使用1 M HCl水溶液(5 mL)及飽和氯化鈉(5 mL)洗滌。藉由無水硫酸鈉乾燥有機層並在減壓下濃縮以提供期望產物，該期望產物未經進一步純化即直接使用(350 mg，103%)。方法C HPLC-MS：MH+要求m/z=250；實驗值：m/z=250，Rt=1.25 min(95%)。 Anhydrous THF (10 mL), diisopropylethylamine (0.36 mL, 2.0 mmol), and N-methylbenzylamine (164 mg, 1.4 mmol) were added to cyanide chloride (250 mg, 1.4 mmol). The mixture was stirred at 0 ° C for 0.5 h and then stirred and warmed to room temperature for a further 1.5 h. The reaction mixture was treated with concentrated ammonia (d = 0.88, 0.4 mL, 6.2 mmol) and stirred at room temperature for 18 h. The solvent was evaporated and EtOAc (EtOAc) (EtOAc) The organic layer was dried <RTI ID=0.0>(~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Method C HPLC-MS: MH+ requires m/z = 250; found: m/z = 250, Rt = 1.25 min (95%).

以與中間體34類似之方式來製備下列三-二胺。 The following three were prepared in a similar manner to the intermediate 34 - Diamine.

中間體36：4-胺基-6-(乙基-苯基-胺基)-[1,3,5]三-2甲腈 Intermediate 36 : 4-Amino-6-(ethyl-phenyl-amino)-[1,3,5]3 -2 carbonitrile

將6-氯-N-乙基-N-苯基-[1,3,5]三-2,4-二胺(中間體37，400 mg，1.60 mmol)溶於無水DMSO(5 mL)中，然後添加氰化鉀(200 mg，3.07 mmol)。將反應混合物在120℃下於壓力管中攪拌2 h，然後冷卻至室溫。使用EtOAc(20 mL)稀釋產物混合物，使用水(2×10 mL)、飽和氯化鈉(5 mL)萃取，藉由無水硫酸鈉乾燥並在減壓下濃縮。獲得期望產物且未經進一步純化即直接使用(300 mg，78%)。方法C HPLC-MS：MH+要求m/z=241；實驗值：m/z=241，Rt=1.27 min(89%)。 6-chloro-N-ethyl-N-phenyl-[1,3,5] three -2,4-Diamine (intermediate 37, 400 mg, 1.60 mmol) was dissolved in anhydrous DMSO (5 mL) then potassium cyanide (200 mg, 3.07 mmol). The reaction mixture was stirred at 120 ° C for 2 h in a pressure tube and then cooled to room temperature. The product mixture was diluted with EtOAc (20 mL)EtOAc. The desired product was obtained and used directly (300 mg, 78%) without further purification. Method C HPLC-MS: MH+ requires m/z = 241. Found: m/z = 241, Rt = 1.27 min (89%).

以與中間體36類似之方式來製備下列腈。 The following nitriles were prepared in a similar manner to intermediate 36.

中間體39：4-胺基-6-(2,3-二氫-吲哚-1-基)-[1,3,5]三-2甲腈 Intermediate 39 : 4-Amino-6-(2,3-dihydro-indol-1-yl)-[1,3,5]3 -2 carbonitrile

將4-氯-6-(2,3-二氫-吲哚-1-基)-[1,3,5]三-2-基胺(中間體40，680 mg，2.48 mmol)、氰化鉀(323 mg，4.96 mmol) 及18-冠-6(328 mg，1.24 mmol)裝填至圓底燒瓶中然後吸收於DMF(12 mL)中。將所得混合物降至預加熱至110℃之加熱塊中並在氮下攪拌2 h且然後在室溫下攪拌56 h。然後使用EtOAc(60 ml)稀釋反應液且使用5%碳酸鈉水溶液(2×10 ml)、鹽水(10 ml)萃取並藉由無水硫酸鎂進一步乾燥。在蒸發溶劑之後，藉由FCC在矽膠(使用1：0至8：2至1：1至0：1之庚烷：EtOAc洗脫)及管柱(使用THF沖洗)上純化粗製殘餘物以得到標題化合物(155 mg，26%)。方法B HPLC-MS：MH+要求m/z=239；實驗值：m/z=239，Rt=1.36 min(75%)。 4-chloro-6-(2,3-dihydro-indol-1-yl)-[1,3,5] 2-ylamine (intermediate 40, 680 mg, 2.48 mmol), potassium cyanide (323 mg, 4.96 mmol) and 18-crown-6 (328 mg, 1.24 mmol) were loaded into a round bottom flask and then taken up in DMF (12 mL). The resulting mixture was cooled to a heating block preheated to 110 ° C and stirred under nitrogen for 2 h and then stirred at room temperature for 56 h. The reaction was then diluted with EtOAc (EtOAc) (EtOAc)EtOAc. After evaporating the solvent, the crude residue was purified by FCC eluting with EtOAc (EtOAc:EtOAc:EtOAc:EtOAc The title compound (155 mg, 26%). Method B HPLC-MS: MH+ requires m/z = 239. Found: m/z = 239, Rt = 1.36 min (75%).

中間體41：6-氯-N-甲基-N-苯基-[1,3,5]三-2,4-二胺 Intermediate 41 : 6-chloro-N-methyl-N-phenyl-[1,3,5]3 -2,4-diamine

向存於THF(45 ml)中之(4,6-二氯-[1,3,5]三-2-基)-甲基-苯基-胺(中間體42，2.7 g，10.58 mmol)之攪拌溶液中添加濃氨水溶液(3 ml,52.91 mmol)之溶液。將反應液在室溫下攪拌1 h，然後使用THF(50 ml)稀釋反應液，使用濃氨水溶液(1 ml,17.64 mmol)處理並攪拌18 h。在真空下濃縮反應液並吸收於DCM(150 ml)中；然後使用2 M HCl水溶液(2×50 mL)及飽和鹽水(20 mL)萃取溶液並藉由無水硫酸鈉進一步乾燥。將有機相蒸發至乾燥以提供灰白色固體產物(2.743 g，110%)。方法B HPLC-MS：MH+要求m/z=236；實驗值：m/z=236，Rt=1.76 min(88%)。1H NMR(500 MHz,CDCl3)δ ppm 7.09-7.44(5H,m),5.21-5.65(2H,m),3.40(3H,s)。 (4,6-Dichloro-[1,3,5]3 in THF (45 ml) A stirred solution of 2-amino)-methyl-phenyl-amine (Intermediate 42, 2.7 g, 10.58 mmol) was added to a solution of concentrated aqueous ammonia (3 ml, 52.91 mmol). The reaction was stirred at room temperature for 1 h then diluted with EtOAc EtOAc EtOAc (EtOAc) The reaction mixture was concentrated under EtOAc (EtOAc)EtOAc. The organic phase was evaporated to dryness to give a white solid material (2.743 g, 110%). Method B HPLC-MS: MH+ requires m/z = 236. Found: m/z = 236, Rt = 1.76 min (88%). 1H NMR (500 MHz, CDCl3) δ ppm 7.09-7.44 (5H, m), 5.21-5.65 (2H, m), 3.40 (3H, s).

中間體42：(4,6-二氯-[1,3,5]三-2-基)-甲基-苯基-胺 Intermediate 42 : (4,6-Dichloro-[1,3,5]3 -2-yl)-methyl-phenyl-amine

在0-5℃下，向存於DCM(40 ml)中之氰尿醯氯(2 g，10.84 mmol)之攪拌溶液中逐滴添加存於DCM(30 ml)中之N-甲基苯胺(1.16 ml,10.84 mmol)及DIPEA(2.08 ml,12.26 mmol)之溶液。將所得混合物升溫至室溫並攪拌48 h。使用DCM(40 ml)稀釋反應混合物，然後使用2 M HCl水溶液(2×40 mL)及飽和鹽水(30 mL)萃取溶液並藉由無水硫酸鈉進一步乾燥。將有機相蒸發至乾燥以提供灰白色固體形式之標題化合物(2.726 g，99%)。方法C HPLC-MS：MH+要求m/z=255；實驗值：m/z=255，Rt=1.48 min(100%)。1H NMR(500 MHz,CDCl3)δ ppm 7.35-7.42(2H,m),7.29(1H,d),7.15-7.21(3H,m),3.48(3H,s)。 N-methylaniline in DCM (30 ml) was added dropwise to a stirred solution of cyanuric chloride (2 g, 10.84 mmol) in DCM (40 ml). A solution of 1.16 ml, 10.84 mmol) and DIPEA (2.08 ml, 12.26 mmol). The resulting mixture was warmed to room temperature and stirred for 48 h. The reaction mixture was diluted with DCM (40 mL), and then the mixture was extracted with 2 M aqueous HCl (2×40 mL) and saturated brine (30 mL) and dried over anhydrous sodium sulfate. The organic phase was evaporated to dryness to crystallite crystals Method C HPLC-MS: MH+ requires m/z = 255; found: m/z = 255, Rt = 1.48 min (100%). 1H NMR (500 MHz, CDCl3) δ ppm 7.35-7.42 (2H, m), 7.29 (1H, d), 7.15-7.21 (3H, m), 3.48 (3H, s).

中間體53：2-胺基-4-氰基-6-(2,3-二氟苯基-N-甲基胺基)-[1,3,5]三 Intermediate 53 : 2-Amino-4-cyano-6-(2,3-difluorophenyl-N-methylamino)-[1,3,5]

向2-胺基-4氰基-6-(2,3-二氟苯基胺基)-[1,3,5]三(中間體54，332 mg，1.34 mmol)中添加碳酸鉀(203 mg，1.46 mmol)、碘甲烷(83 μL,1.34 mmol)及無水DMF(3 mL)。將混合物在室溫下攪拌1 h且然後使用1M檸檬酸水溶液(10 mL)稀釋。使用乙酸乙酯(2×10 mL)萃取所得混合物並使用水(4×10 mL)、飽和鹽水(10 mL)洗滌合併之萃取物並藉由無水硫酸鈉進一步乾燥。蒸發溶劑以得到膠，將該膠裝載於二氧化矽管柱上並使用庚烷-30%乙酸乙酯洗脫以得到期望化合物(320 mg，91%)。方法B HPLC-MS：MH+要求m/z=262；實驗值：m/z=262，Rt=1.76 min(98%)。 To 2-amino-4cyano-6-(2,3-difluorophenylamino)-[1,3,5]tri Potassium carbonate (203 mg, 1.46 mmol), methyl iodide (83 μL, 1.34 mmol) and anhydrous DMF (3 mL) were added. The mixture was stirred at room temperature for 1 h and then diluted with 1M aqueous citric acid (10 mL). The resulting mixture was extracted with ethyl acetate (2×10 mL), and the combined extracts were washed with water (4×10 mL) and saturated brine (10 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated to give a gum, which was applied to a silica gel column and eluted with heptane-30% ethyl acetate to give the desired compound (320 mg, 91%). Method B HPLC-MS: MH+ requires m/z = 262. Found: m/z = 262, Rt = 1.76 min (98%).

中間體54：2-胺基-4氰基-6-(2,3-二氟苯基胺基)-[1,3,5]三 Intermediate 54 : 2-Amino-4cyano-6-(2,3-difluorophenylamino)-[1,3,5]3

向2-胺基-4-氯-6-(2,3-二氟苯基胺基)-[1,3,5]三(中間體55，1.0 g，3.89 mmol)中添加DABCO(540 mg，4.67 mmol)、四正丁基氰化銨(1.15 g，4.28 mmol)及無水乙腈(15 mL)。將反應混合物在50℃下攪拌1 h，使用50 mL乙酸乙酯稀釋，使用1 M檸檬酸水溶液(2×50 mL)、水(2×50 mL)、飽和鹽水(50 mL)萃取並藉由無水硫酸鈉進一步乾燥。蒸發溶劑以得到紅色膠，藉由管柱層析在二氧化矽(使用DCM-2%乙酸乙酯洗脫)上純化該紅色膠以得到期望化合物(429 mg，69%)。方法B HPLC-MS：MH+要求m/z=249；實驗值：m/z=249，Rt=1.64 min(91%)。 To 2-amino-4-chloro-6-(2,3-difluorophenylamino)-[1,3,5] (Intermediate 55, 1.0 g, 3.89 mmol) was added DABCO (540 mg, 4.67 mmol), tetra-n-butyl ammonium cyanide (1.15 g, 4.28 mmol) and anhydrous acetonitrile (15 mL). The reaction mixture was stirred at 50 ° C for 1 h, diluted with 50 mL EtOAc EtOAc (EtOAc) The anhydrous sodium sulfate was further dried. The solvent was evaporated to give a red gum, which was purified eluting with EtOAc EtOAc EtOAc Method B HPLC-MS: MH+ requires m/z = 249; found: m/z = 249, Rt = 1.64 min (91%).

以與中間體54類似之方式來製備下列腈。 The following nitriles were prepared in a similar manner to intermediate 54.

根據方法2來製備下列二唑。 Prepare the following according to Method 2 Diazole.

中間體57：6-(2,2,2-三氟-乙氧基)-菸醯氟 Intermediate 57 : 6-(2,2,2-trifluoro-ethoxy)-sodium fluoride

在氮氣氛下，向6-(2,2,2-三氟-乙氧基)-菸酸(100 mg，0.45 mmol)中添加DCE(5 mL)及草醯氯(60 ul,0.68 mmol)。將混合物在室溫下攪拌1.5 h然後在80℃下加熱2 h且在冷卻至室溫之後，蒸發以得到淺黃色油狀物形式之標題化合物(110 mg，100%)。方法C HPLC-MS(在MeOH中，鑑別甲酯)：MH+要求m/z=236；實驗值：m/z=236，Rt=1.41 min(95%)。 To a solution of 6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (100 mg, 0.45 mmol), DCE (5 mL) and chlorobenzene (60 ul, 0.68 mmol) . The mixture was stirred at room temperature for 1.5 h then EtOAc (EtOAc)EtOAc. Method C HPLC-MS (m.p. MeOH): MH+: m/z = 236;

中間體60：N-甲基-N-苯基-6-(5-三氯甲基-[1,2,4]二唑-3-基)-[1,3,5]三-2,4-二胺 Intermediate 60 : N-methyl-N-phenyl-6-(5-trichloromethyl-[1,2,4] Diazol-3-yl)-[1,3,5]3 -2,4-diamine

在氮下，向存於無水甲苯(2.5 mL)中之4-胺基-N-羥基-6-(甲基-3-甲基苯基-胺基)-[1,3,5]三-2-甲脒(根據與中間體1類似之方法製得，1 g，3.86 mmol)添加三氯乙酸酐(845 μL,4.63 mmol)。將混合物在室溫下攪拌1h，此時添加無水吡啶(2.5 mL)並將混合物攪拌45 min。然後添加無水吡啶(10 mL)及三氯乙酸酐(300 μL,1.64 mmol)並將混合物在室溫下攪拌30 min然後加熱至85℃保持35 min。使用 EtOAc(100 mL)稀釋反應混合物，且使用碳酸氫鈉飽和水溶液(3×50 ml)、鹽水(50 mL)萃取溶液並藉由無水硫酸鈉乾燥。獲得褐色固體形式之標題化合物(1.22 g，82%)。方法B HPLC-MS：MH+要求m/z=386；實驗值：m/z=386，Rt=2.20 min(77%)。 4-Amino-N-hydroxy-6-(methyl-3-methylphenyl-amino)-[1,3,5]3 in anhydrous toluene (2.5 mL) under nitrogen 2-Methylhydrazine (prepared according to a procedure similar to Intermediate 1 , 1 g, 3.86 mmol) was added trichloroacetic anhydride (845 μL, 4.63 mmol). The mixture was stirred at room temperature for 1 h at which time anhydrous pyridine (2.5 mL) was evaporated and the mixture was stirred for 45 min. Anhydrous pyridine (10 mL) and trichloroacetic anhydride (300 μL, 1.64 mmol) were then added and the mixture was stirred at room temperature for 30 min then heated to 85 ° C for 35 min. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) The title compound (1.22 g, 82%). Method B HPLC-MS: MH+ requires m/z = 386. Found: m/z = 386, Rt = 2.20 min (77%).

中間體61：6-甲氧基-菸酸 Intermediate 61 : 6-methoxy-nicotinic acid

在氮下於RBF中，將第三丁醇鉀(323 mg，2.88 mmol)及甲醇(64 μL,1.58 mmol)吸收於無水THF(6 mL)中，將混合物攪拌10 min，此時緩慢添加存於無水THF(2 mL)中之6-氯吡啶-3甲腈(200 mg，1.44 mmol)之溶液。將混合物在室溫下攪拌18 h。使用甲醇(6 μL,0.148 mmol)處理反應液，攪拌2 h，然後使用甲醇(20 μL,0.494 mmol)處理，攪拌2 h，然後使用第三丁醇鉀(50 mg，0.446 mmol)處理並攪拌18 h。然後在真空中濃縮混合物，懸浮於碳酸氫鈉飽和水溶液中並使用EtOAc(5×10 mL)萃取。使用鹽水(10 mL)洗滌合併之萃取物並在真空中濃縮以得到標題化合物(80 mg，36%)。1H NMR(500 MHz,CDCl3)δ ppm 8.94(1 H,s),8.22(1 H,dd,J=8.4,1.8 Hz),6.82(1 H,d,J=8.7 Hz),4.03(3 H,s)。 Potassium tert-butoxide (323 mg, 2.88 mmol) and methanol (64 μL, 1.58 mmol) were taken up in anhydrous THF (6 mL) under nitrogen, and the mixture was stirred for 10 min. A solution of 6-chloropyridine-3carbonitrile (200 mg, 1.44 mmol) in dry THF (2 mL). The mixture was stirred at room temperature for 18 h. The reaction was treated with methanol (6 μL, 0.148 mmol), stirred for 2 h, then treated with methanol (20 μL, 0.494 mmol), stirred for 2 h, then treated with potassium butoxide (50 mg, 0.446 mmol) and stirred. 18 h. The mixture was then concentrated in vacuo, EtOAcqqqqqqqq The combined extract was washed with EtOAc (EtOAc) 1H NMR (500 MHz, CDCl3) δ ppm 8.94 (1 H, s), 8.22 (1 H, dd, J = 8.4, 1.8 Hz), 6.82 (1 H, d, J = 8.7 Hz), 4.03 (3 H) , s).

中間體62：5-{3-[4-胺基-6-(甲基-苯基-胺基)-[1,3,5]三-2-基][1,2,4]二唑-5-基}-噻吩-2-甲酸 Intermediate 62 : 5-{3-[4-Amino-6-(methyl-phenyl-amino)-[1,3,5]3 -2-base][1,2,4] Diazol-5-yl}-thiophene-2-carboxylic acid

向存於甲醇(5 mL)中之5-{3-[4-胺基-6-(甲基-苯基-胺基)-[1,3,5]三-2-基]-[1,2,4]二唑-5-基}-噻吩-2-甲酸甲酯(實例82，1.02 g，2.45 mmol)之攪拌溶液中添加氫氧化 鈉水溶液(2 M,5 mL)。將混合物攪拌18 h，然後使用鹽酸(1 M,10 mL)酸化。過濾掉所形成沈澱物並在50℃下於真空中乾燥2 h以得到標題化合物(450 mg，46%)。方法B HPLC-MS：MH+要求m/z=396；實驗值：m/z=396，Rt=1.84 min(68%)。 5-{3-[4-Amino-6-(methyl-phenyl-amino)-[1,3,5]3 in methanol (5 mL) -2-base]-[1,2,4] To a stirred solution of methyl oxazol-5-yl}-thiophene-2-carboxylate (Example 82, 1.02 g, 2.45 mmol) was added aqueous sodium hydroxide (2 M, 5 mL). The mixture was stirred for 18 h then acidified with HCl (1 M, 10 mL). The precipitate formed was filtered off and dried in vacuo to give title title compound (450 mg, 46%). Method B HPLC-MS: MH+ requires m/z = 396. Found: m/z = 396, Rt = 1.84 min (68%).

中間體90：4-胺基-6-[(2-甲氧基-乙基)-苯基-胺基]-[1,3,5]三-2甲腈 Intermediate 90 : 4-Amino-6-[(2-methoxy-ethyl)-phenyl-amino]-[1,3,5]3 -2 carbonitrile

將存於DMF(5 mL)中之4-胺基-6-苯基胺基-[1,3,5]三-2甲腈(以與中間體5類似之方式製得，100 mg，470 μmol)、1-溴-2-甲氧基乙烷(50 μl,0.52 mmol)及碳酸鉀(130 mg，0.94 mmol)之混合物加熱至100℃並攪拌3 h。將混合物冷卻至室溫，使用乙酸乙酯稀釋，使用水洗滌，藉由硫酸鈉乾燥並在真空下濃縮以得到粗產物，該粗產物未經進一步純化即使用(400 mg，>100%，含有DMF)。方法C HPLC-MS：MH+要求m/z=271；實驗值：m/z=271，Rt=1.23 min(52%)。 4-Amino-6-phenylamino-[1,3,5]3 in DMF (5 mL) -2 carbonitrile (prepared in a similar manner to intermediate 5, 100 mg, 470 μmol), 1-bromo-2-methoxyethane (50 μl, 0.52 mmol) and potassium carbonate (130 mg, 0.94 mmol) The mixture was heated to 100 ° C and stirred for 3 h. The mixture was cooled to room temperature, diluted with EtOAc EtOAc EtOAc EtOAc (EtOAc) DMF). Method C HPLC-MS: MH+ requires m/z = 271. Found: m/z = 271, Rt = 1.23 min (52%).

中間體92：4-胺基-6-(環丙基甲基-苯基-胺基)-[1,3,5]三-2甲腈 Intermediate 92 : 4-Amino-6-(cyclopropylmethyl-phenyl-amino)-[1,3,5]3 -2 carbonitrile

向存於DMF(6 mL)中之4-胺基-6-苯基胺基-[1,3,5]三-2甲腈(以與中間體5類似之方式製得，160 mg，0.75 mmol)之溶液中添加碳酸鉀(207 mg，150 μmol)，隨後添加溴甲基-環丙烷(111 mg，830 μmol)。將混合物在120℃下加熱3 h，冷卻至室溫，然後萃取至乙酸乙酯(10 mL)中並使用水(3×10 mL)洗滌。藉由無水硫酸鈉乾燥有機層，過濾並在 減壓下濃縮以得到標題化合物，該標題化合物未經進一步純化即使用(300 mg，>100%)。方法C HPLC-MS：MH+要求m/z=267；實驗值：m/z=267，Rt=1.38 min(43%)。 4-Amino-6-phenylamino-[1,3,5]3 in DMF (6 mL) Potassium carbonate (207 mg, 150 μmol) was added to a solution of 2-carbonitrile (prepared in a similar manner to Intermediate 5, 160 mg, 0.75 mmol) followed by bromomethyl-cyclopropane (111 mg, 830 μmol) ). The mixture was heated at 120 &lt;0&gt;C for 3 h, cooled to rt then extracted ethyl EtOAc (EtOAc) (EtOAc) The organic layer was dried with EtOAc EtOAcjjjjjjjj Method C HPLC-MS: MH+ requires m/z = 267. Found: m/z = 267, Rt = 1.38 min (43%).

中間體93：3-甲氧基吡啶-2-羰基氯 Intermediate 93 : 3-methoxypyridine-2-carbonyl chloride

在0℃(冰浴)下，向存於二氯甲烷(10 ml)及吡啶(5 ml)中之3-甲氧基吡啶-2-甲酸鈉(中間體94，約3.3 mmol)之攪拌懸浮液中逐滴添加草醯氯(0.58 ml,6.6 mmol)。將混合物攪拌10分鐘，然後添加DMF(1滴)。將混合物升溫至室溫並攪拌2 h，然後在真空下濃縮。將殘餘物溶於二氯甲烷(10 ml)中並經由脫脂棉塞過濾。在真空下濃縮濾液以得到褐色油狀物形式之標題化合物(0.16 g)，該標題化合物未經進一步純化或表徵即使用。 Stirred suspension of sodium 3-methoxypyridine-2-carboxylate (intermediate 94, approx. 3.3 mmol) in dichloromethane (10 ml) and pyridine (5 ml). Grass chloroform (0.58 ml, 6.6 mmol) was added dropwise. The mixture was stirred for 10 minutes and then DMF (1 drop) was added. The mixture was warmed to room temperature and stirred for 2 h then concentrated in vacuo. The residue was dissolved in dichloromethane (10 ml) and filtered thru a pad. The filtrate was concentrated in vacuo to give title crystalljjjjjjjjj

中間體94：3-甲氧基吡啶-2-甲酸鈉 Intermediate 94 : sodium 3-methoxypyridine-2-carboxylate

向存於甲醇(10 ml)中之3-甲氧基吡啶-2-甲酸甲酯(中間體95，0.55 g，3.3 mmol)之攪拌溶液中逐滴添加氫氧化鈉水溶液(1 M，4 ml,4 mmol)。將混合物靜置過夜。在真空下濃縮混合物以得到白色固體，該白色固體未經進一步純化或表徵即使用。 Aqueous sodium hydroxide solution (1 M, 4 ml) was added dropwise to a stirred solution of methyl 3-methoxypyridine-2-carboxylate (intermediate 95, 0.55 g, 3.3 mmol) in methanol (10 ml) , 4 mmol). The mixture was allowed to stand overnight. The mixture was concentrated under vacuum to give a white solid which was used without further purification.

中間體95：3-甲氧基吡啶-2-甲酸甲酯 Intermediate 95 : Methyl 3-methoxypyridine-2-carboxylate

將3-羥基吡啶-2-甲酸甲酯(中間體96，1.2 g，7.8 mmol)、碳酸鉀(1.2 g，8.7 mmol)、碘甲烷(0.63 ml,1.0 mmol)及DMF(10 ml)之混合物攪拌過夜。使用水(20 ml)稀釋混合物並使用乙酸乙酯(2×20 ml)萃取。使用水洗滌合併之有機萃取物並在真空下濃縮。藉由急驟管柱層析(5 g二 氧化矽；庚烷-乙酸乙酯，1：0-5：1-2：1)純化殘餘物(0.82 g)以得到澄清油狀物形式之標題化合物(0.58 g，45%)。方法C HPLC-MS：MH+要求m/z=168；實驗值：m/z=168，Rt=0.76 min(100%)。 a mixture of methyl 3-hydroxypyridine-2-carboxylate (intermediate 96, 1.2 g, 7.8 mmol), potassium carbonate (1.2 g, 8.7 mmol), methyl iodide (0.63 ml, 1.0 mmol) and DMF (10 ml) Stir overnight. The mixture was diluted with water (20 ml) and extracted with ethyl acetate (2×20 ml). The combined organic extracts were washed with water and concentrated under vacuum. By flash column chromatography (5 g two The title compound (0.58 g, 45%) was obtained from m. Method C HPLC-MS: MH+ requires m/z = 168. Found: m/z = 168, Rt = 0.76 min (100%).

中間體96：3-羥基吡啶-2-甲酸甲酯 Intermediate 96 : Methyl 3-hydroxypyridine-2-carboxylate

將3-羥基吡啶-2-甲酸(2.0 g，14.4 mmol)、濃硫酸(0.5 ml)及甲醇(100 ml)之混合物加熱至回流並攪拌48小時。將混合物冷卻至室溫並攪拌60小時然後在真空下濃縮。將殘餘物溶於水(20 ml)中，使用固體碳酸鈉鹼化至pH 8(注意：氣體逸出！)並使用乙酸乙酯(3×20 ml)萃取。使用水洗滌合併之有機萃取物並在真空下濃縮以得到白色固體形式之標題化合物(1.22 g，55%)。方法C HPLC-MS：MH+要求m/z=154；實驗值：m/z=154，Rt=0.78 min(100%)。 A mixture of 3-hydroxypyridine-2-carboxylic acid (2.0 g, 14.4 mmol), concentrated sulfuric acid (0.5 ml) and methanol (100 ml) was warmed to reflux and stirred for 48 hr. The mixture was cooled to room temperature and stirred for 60 hours then concentrated under vacuum. The residue was dissolved in water (20 ml), basified to pH 8 using solid sodium carbonate (yield: gas evolution!) and extracted with ethyl acetate (3 x 20 ml). The combined organic extracts were washed with EtOAcqqqqm Method C HPLC-MS: MH+ requires m/z = 154; found: m/z = 154, Rt = 0.78 min (100%).

中間體100：6-[5-(6-N-甲苯磺醯基-亞肼基甲基-吡啶-3-基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺 Intermediate 100 : 6-[5-(6-N-toluenesulfonyl-arylenemethyl-pyridin-3-yl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine

向存於DCM(5 mL)中之(5-{3-[4-胺基-6-(甲基-苯基-胺基)-[1,3,5]三-2-基]-[1,2,4]二唑-5-基}-吡啶-2-基)-甲醇(以與實例297類似之方式製得，150 mg，0.40 mmol)添加戴斯-馬丁過碘烷(Dess-Martin periodinane)(185 mg，0.44 mmol)並將混合物在室溫下攪拌1h。蒸發反應混合物並向粗製殘餘物中添加對甲苯磺醯基醯肼(74 mg，0.40 mmol)及冰乙酸(4 mL)。將混合物在50℃下加熱2 h且然後蒸發。將殘餘物吸收於DCM(5 mL)中，使用1 M碳酸氫鈉水溶液(5 mL)萃取並藉由無水硫酸鈉乾燥以得到268 mg粗製固 體。然後使用EtOH(4×3 mL)研磨固體以得到標題化合物(104 mg，535)方法B HPLC-MS：MH+要求m/z=543；實驗值：m/z=543，Rt=1.99 min(64%)。 (5-{3-[4-Amino-6-(methyl-phenyl-amino)-[1,3,5]3 in DCM (5 mL) -2-base]-[1,2,4] Diazol-5-yl}-pyridin-2-yl)-methanol (prepared in a similar manner to Example 297, 150 mg, 0.40 mmol) was added with Dess-Martin periodinane (185 mg) , 0.44 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated and p-toluenesulfonyl hydrazide (74 mg, 0.40 mmol) and EtOAc (4 mL). The mixture was heated at 50 °C for 2 h and then evaporated. The residue was taken up in EtOAc EtOAc EtOAc. The solid was then triturated with EtOAc (4.times.3 mL) to give the title compound (104 mg, 353). %).

中間體101：外消旋6-[(1R,3R,5S)-5-(8-氮雜-雙環[3.2.1]辛-3-基)-[1,2,4]二唑-3-基]-N-甲基-N-苯基-[1,3,5]三-2,4-二胺 Intermediate 101 : racemic 6-[(1R,3R,5S)-5-(8-aza-bicyclo[3.2.1]oct-3-yl)-[1,2,4] Diazol-3-yl]-N-methyl-N-phenyl-[1,3,5] -2,4-diamine

向3-{3-[4-胺基-6-(甲基-苯基-胺基)-[1,3,5]三-2-基]-[1,2,4]二唑-5-基}-8-氮雜-雙環[3.2.1]辛烷-8-甲酸第三丁基酯(中間體102，125 mg，0.37 mmol)中添加DCM(3 mL)及三氟乙酸(3 mL)。將混合物在室溫下攪拌1 h且然後蒸發。將殘餘物吸收於DCM(5 mL)中且使用1 M碳酸氫鈉溶液(5 mL)、飽和鹽水(5 mL)洗滌並藉由硫酸鈉乾燥，蒸發以得到標題化合物，該標題化合物直接用於下一階段(74 mg，53%)。方法B HPLC-MS：MH+要求m/z=379；實驗值：m/z=379，Rt=1.37 min(95%)。 To 3-{3-[4-amino-6-(methyl-phenyl-amino)-[1,3,5] three -2-base]-[1,2,4] Addition of DCM (3 mL) and three to oxazol-5-yl}-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (Intermediate 102, 125 mg, 0.37 mmol) Fluoroacetic acid (3 mL). The mixture was stirred at room temperature for 1 h and then evaporated. The residue was taken up in EtOAc EtOAc EtOAc (EtOAc m. The next stage (74 mg, 53%). Method B HPLC-MS: MH+ requires m/z = 379. Found: m/z = 379, Rt = 1.37 min (95%).

中間體103：8-氮雜-雙環[3.2.1]辛烷-3,8-二甲酸8-第三丁基酯 Intermediate 103 : 8-aza-bicyclo[3.2.1]octane-3,8-dicarboxylic acid 8-t-butyl ester

向3-氰基-8-氮雜-雙環[3.2.1]辛烷-8-甲酸第三丁基酯(中間體104，190 mg，0.81 mmol)中添加氫氧化鉀(270 mg，4.83 mmol)、EtOH(3 mL)及水(1 mL)。將混合物在95℃下加熱4 h，冷卻並使用1 M檸檬酸水溶液酸化至pH=2。然後使用EtOAc(2×5 mL)萃取混合物並使用飽和鹽水(10 mL)洗滌合併之萃取物，並藉由無水硫酸鈉乾燥。蒸發以得到粗製標題化合物，該粗製標題化合物未經進一步純化即直接 使用(190 mg，94%)。方法B HPLC-MS：MH+要求m/z=255；實驗值：m/z=200(MH-tBu)，Rt=1.68 min(76%)。 Add potassium hydroxide (270 mg, 4.83 mmol) to 3-cyano-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (Intermediate 104, 190 mg, 0.81 mmol). ), EtOH (3 mL) and water (1 mL). The mixture was heated at 95 &lt;0&gt;C for 4 h, cooled and acidified to pH = 2 using 1 M aqueous EtOAc. The mixture was extracted with EtOAc (2×5 mL) andEtOAc. Evaporation to give the crude title compound. Method B HPLC-MS: MH + requires m / z = 255; Found: m / z = 200 (MH- t Bu), Rt = 1.68 min (76%).

中間體104：3-氰基-8-氮雜-雙環[3.2.1]辛烷-8-甲酸第三丁基酯 Intermediate 104 : 3-Cyano-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

向3-側氧基-8-氮雜-雙環[3.2.1]辛烷-8-甲酸第三丁基酯(300 mg，1.33 mmol)中添加DME(9 mL)及EtOH(0.2 mL)。將混合物冷卻至0℃，此時添加TOSMIC(530 mg，2.65 mmol)及第三丁醇鉀(609 mg，5.2 mmol)。將混合物攪拌至室溫且然後在50℃下加熱18 h。在此時間之後，蒸發反應液且裝載於二氧化矽管柱上並使用庚烷-10%至30%乙酸乙酯洗脫以得到標題化合物(216 mg，69%)。方法B HPLC-MS：MH+要求m/z=237；實驗值：m/z=237，Rt=1.35 min(86%)。 To a 3-tert-oxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (300 mg, 1.33 mmol) was added DME (9 mL) and EtOH (0.2 mL). The mixture was cooled to 0 ° C at which time TOSMIC (530 mg, 2.65 mmol) and potassium butoxide (609 mg, 5.2 mmol). The mixture was stirred to room temperature and then heated at 50 ° C for 18 h. After the time, the reaction mixture was evaporated and evaporated eluting elut elut elut elut elut elut elut elut Method B HPLC-MS: MH+ requires m/z = 237. Found: m/z = 237, Rt = 1.35 min (86%).

中間體105：2-N-甲基-2-N-苯基-6-[5-(六氫吡啶-4-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺鹽酸鹽 Intermediate 105 : 2-N-methyl-2-N-phenyl-6-[5-(hexahydropyridin-4-yl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine hydrochloride

將存於1,4-二烷(5 mL)中之4-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)六氫吡啶-1-甲酸第三丁基酯(中間體106，934 mg，2.06 mmol)及4 M氯化氫在0℃下於DCM(5 mL)中合併。將反應液升溫至室溫並攪拌18 h。在減壓下濃縮混合物以得到黃色固體形式之標題化合物(832 mg)。方法B HPLC-MS：MH+要求m/z=352實驗值：m/z=353，Rt=1.23 min(100%)。 Will be stored in 1,4-two 4-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three in alkane (5 mL) -2-yl}-1,2,4- The oxazol-5-yl) hexahydropyridine-1-carboxylic acid tert-butyl ester (Intermediate 106, 934 mg, 2.06 mmol) and 4 M hydrogen chloride were combined in DCM (5 mL). The reaction was warmed to room temperature and stirred for 18 h. The mixture was concentrated under reduced pressure to give title crystall Method B HPLC-MS: MH+ requires m/z = 352. Found: m/z = 353, Rt = 1.23 min (100%).

中間體109：3-[(4-胺基-6-氯-1,3,5-三-2-基)胺基]苯甲酸甲酯 Intermediate 109 : 3-[(4-Amino-6-chloro-1,3,5-three Methyl-2-amino)benzoate

在0℃下，將3-胺基苯甲酸甲酯(0.69 g，4.55 mmol)及1 N NaOH水溶液(0.91 mL，0.91 mmol)添加至存於1：1 MeCN/水混合物(40 mL)中之4,6-二氯-1,3,5-三-2-胺(0.75 g，4.55 mmol)之溶液中。將混合物在0℃下攪拌1 h並在室溫下攪拌3天。在真空下去除乙腈且過濾所得白色固體之水溶液並在真空下乾燥以提供標題化合物(1.1 g，87%)。方法B HPLC-MS：MH+要求m/z=280/282實驗值：m/z=280/282，Rt=1.69 min(95%)。 Methyl 3-aminobenzoate (0.69 g, 4.55 mmol) and 1 N aqueous NaOH (0.91 mL, 0.91 mmol) were then applied to 1:1 MeCN/water mixture (40 mL) 4,6-dichloro-1,3,5-three A solution of 2-amine (0.75 g, 4.55 mmol). The mixture was stirred at 0 ° C for 1 h and at room temperature for 3 days. The acetonitrile was removed in vacuo <RTI ID=0.0> Method B HPLC-MS: MH+ requires m/z = 280 / 282. Found: m/z = 280/282, Rt = 1.69 min (95%).

中間體113：2-N-甲基-2-N-苯基-6-[5-(吡咯啶-3-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺鹽酸鹽 Intermediate 113 : 2-N-methyl-2-N-phenyl-6-[5-(pyrrolidin-3-yl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine hydrochloride

在室溫下，將存於二烷(7 mL，28.2 mmol)中之4 N HCl溶液緩慢添加至存於二烷(15 mL)中之3-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡咯啶-1-甲酸第三丁基酯(中間體114，1.24 g，2.82 mmol)之溶液中。將反應混合物在室溫下攪拌18 h。在真空下濃縮反應混合物以得到黃色固體形式之標題化合物(1.05 g，100%)。方法B HPLC-MS：MH+(基於游離形式)理論值m/z=339實驗值：m/z=339，Rt=1.20 min(96%)。 At room temperature, it will be stored in two 4 N HCl solution in alkane (7 mL, 28.2 mmol) was slowly added to the residue 3-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three in alkane (15 mL) -2-yl}-1,2,4- A solution of oxazol-5-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (Intermediate 114, 1.24 g, 2.82 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo to give title crystall Method B HPLC-MS: MH+ (m.).

中間體115：3-{4-胺基-6-[(3-氟苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-甲酸乙酯 Intermediate 115 : 3-{4-Amino-6-[(3-fluorophenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-carboxylic acid ethyl ester

在室溫下，將氯側氧基乙酸乙酯(0.12 g，0.84 mmol)添加至存於吡啶(0.12 mL)及甲苯(4 mL)中之(4-胺基-6-[(3-氟苯基)胺基]-N-羥基-1,3,5-三-2-甲脒(以與中間體97類似之方式製得，0.20 g，0.76 mmol)之混合物中。將反應混 合物在室溫下攪拌1 h並在110℃下攪拌3 h。然後在室溫下冷卻混合物；添加DCM(20 mL)及1 M HCl水溶液(50 mL)。分離各相且使用DCM(2×20 mL)萃取水相。合併有機萃取物，藉由硫酸鈉乾燥，並濃縮。使用二乙醚洗滌粗製殘餘物。濃縮有機濾液並藉由急驟層析純化以得到黃色固體形式之標題化合物(45 mg，17%)。方法D HPLC-MS：MH+要求m/z=346實驗值：m/z=346，Rt=2.70 min(40%)。 Ethyl chloroacetate (0.12 g, 0.84 mmol) was added to pyridine (0.12 mL) and toluene (4 mL) at room temperature (4-amino-6-[(3-fluoro) Phenyl)amino]-N-hydroxy-1,3,5-three 2-Methylformamide (prepared in a similar manner to Intermediate 97, 0.20 g, 0.76 mmol). The reaction mixture was stirred at room temperature for 1 h and at 110 ° C for 3 h. The mixture was then cooled at room temperature; DCM (20 mL) and 1 M aqueous HCI (50 mL). The phases were separated and the aqueous phase was extracted with DCM (2×20 mL). The organic extracts were combined, dried over sodium sulfate and evaporated. The crude residue was washed with diethyl ether. The organic filtrate was concentrated and purified by flash chromatography eluting elut Method D HPLC-MS: MH+ requires m/z = 346. Found: m/z = 346, Rt = 2.70 min (40%).

中間體116：2-N-(3-氟苯基)-6-[5-(三氯甲基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺 Intermediate 116 : 2-N-(3-fluorophenyl)-6-[5-(trichloromethyl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine

在0℃下，將三氯乙酸酐(2.61 mL，14.3 mmol)添加至存於二烷(60 mL)(含有分子篩(3匙))中之4-胺基-6-[(3-氟苯基)胺基]-N-羥基-1,3,5-三-2-甲脒(以與中間體97類似之方式製得，3.13 g，11.9 mmol)之溶液中。將反應混合物在室溫下攪拌3.5 h，在100℃下攪拌30 min並在110℃下攪拌30 min。濃縮反應混合物；將所得殘餘物溶於EtOAc(100 mL)中並依次使用1 M HCl水溶液及碳酸氫鈉飽和水溶液洗滌。濃縮有機相以得到標題化合物(4.2 g，91%)，該標題化合物未經進一步純化即用於隨後步驟。 Add trichloroacetic anhydride (2.61 mL, 14.3 mmol) to the residue at 0 °C 4-Amino-6-[(3-fluorophenyl)amino]-N-hydroxy-1,3,5-three in alkane (60 mL) containing molecular sieves (3 tablespoons) 2-methylhydrazine (prepared in a similar manner to intermediate 97, 3.13 g, 11.9 mmol). The reaction mixture was stirred at room temperature for 3.5 h, at 100 ° C for 30 min and at 110 ° C for 30 min. The reaction mixture was concentrated. EtOAc EtOAc m. The organic phase was concentrated to give the title compound (jjjjjjjj

根據方法4來製備下列胺基-二唑。 The following amine groups were prepared according to Method 4 - Diazole.

中間體122：3-(4-氟苯氧基)氮雜環丁烷鹽酸鹽 Intermediate 122 : 3-(4-Fluorophenoxy)azetidine hydrochloride

向存於DCE(20 ml)中之1-(二苯基甲基)-3-(4-氟苯氧基)氮雜環丁烷(中間體123，3.2 g，9.6 mmol)之攪拌溶液中逐滴添加氯甲酸1-氯乙基酯(1.6 ml，1.5當量)。將混合物攪拌10 min，然後加熱至回流保持6 h。添加額外氯甲酸1-氯乙基酯(1.6 ml)且繼續加熱3 h。將混合物冷卻至室溫並在真空下濃縮。將殘餘物溶於MeOH(20 mL)中並靜置過夜。將混合物在回流下加熱並攪拌1 h，然後冷卻至室溫並在真空下濃縮。使殘餘物在二乙醚下結晶；使用刮勺將固體打碎，過濾-使用二乙醚洗滌-並在真空下乾燥以得到奶油色固體形式之標題化合物(1.78 g，91%)。方法B HPLC-MS：MH+要求m/z=168實驗值：m/z=168，Rt=0.69 min(92%)。1H NMR(250MHZ,DMSO-d6)δ ppm 9.50(2H,br s),7.15(2H,t),6.89(2H,dd),5.03(1H,m),4.39(2H,m)及3.93(2H,m)。 To a stirred solution of 1-(diphenylmethyl)-3-(4-fluorophenoxy)azetidine (intermediate 123, 3.2 g, 9.6 mmol) in DCM (20 mL) 1-Chloroethyl chloroformate (1.6 ml, 1.5 eq.) was added dropwise. The mixture was stirred for 10 min and then heated to reflux for 6 h. Additional 1-chloroethyl chloroformate (1.6 ml) was added and heating was continued for 3 h. The mixture was cooled to room temperature and concentrated under vacuum. The residue was dissolved in MeOH (20 mL) andEtOAc The mixture was heated under reflux and stirred for 1 h then cooled to rt and concentrated in vacuo. The residue was crystallized from EtOAc (EtOAc m. Method B HPLC-MS: MH+ requires m/z = 168. Found: m/z = 168, Rt = 0.69 min (92%). 1H NMR (250MHZ, DMSO-d6) δ ppm 9.50 (2H, br s), 7.15 (2H, t), 6.89 (2H, dd), 5.03 (1H, m), 4.39 (2H, m) and 3.93 (2H) , m).

中間體123：1-(二苯基甲基)-3-(4-氟苯氧基)氮雜環丁烷 Intermediate 123 : 1-(Diphenylmethyl)-3-(4-fluorophenoxy)azetidine

在氮下，向存於無水DMF(10 ml)中之氫化鈉(存於礦物油中之60%分散液，0.80 g，20 mmol)之攪拌懸浮液中逐滴添加存於DMF(10 ml)中之1-二苯甲基-氮雜環丁-3-醇(3.5 g，15 mmol)之溶液-注意：氫氣體逸出！在氣體停止逸出之後將混合物攪拌30 min，然後逐滴添加1,4-二氟苯(1.8 mL，18 mmol)。將混合物加熱至100℃並攪拌12 h，然後冷卻至室溫並傾倒至碳酸氫鈉水溶液(50 ml)中並使用EtOAc(2×50 ml)萃取兩次。使用水洗滌合併之有機層，在真空下濃縮並藉由急驟管柱層析(25 g矽膠；庚烷-EtOAc：1：0-9：1)純化。合併含有產物之部分，在真空下濃縮，使用庚烷洗滌並在真空下乾燥以得到標題化合物(3.256 g，67%)。方法B HPLC-MS：MH+要求m/z=334實驗值：m/z=334，Rt=1.69 min(89%)。1H NMR(250MHz,CDCl3)δ ppm 7.48-7.39(4H,m),7.39-7.12(6H,m),6.94(2H,t),6.71(2H,dd),4.75(1H,m),4.46(1H,s),3.78-3.65(2H,m)及3.20-3.07(2H,m)。 Add to DMF (10 ml) in a stirred suspension of sodium hydride (60% dispersion in mineral oil, 0.80 g, 20 mmol) in anhydrous DMF (10 ml). A solution of 1-diphenylmethyl-azetidin-3-ol (3.5 g, 15 mmol) - Note: hydrogen gas escapes! After the gas ceased to escape, the mixture was stirred for 30 min, then 1,4-difluorobenzene (1.8 mL, 18 mmol) was added dropwise. The mixture was heated to 100 &lt;0&gt;C and stirred for 12 h then cooled to EtOAc EtOAc (EtOAc) The combined organic layers were washed with EtOAc (EtOAc)EtOAc. The product was combined with EtOAc (EtOAc m. Method B HPLC-MS: MH+ requires m/z = 342. Found: m/z = 334, Rt = 1.69 min (89%). 1H NMR (250MHz, CDCl 3) δ ppm 7.48-7.39 (4H, m), 7.39-7.12 (6H, m), 6.94 (2H, t), 6.71 (2H, dd), 4.75 (1H, m), 4.46 (1H, s), 3.78-3.65 (2H, m) and 3.20-3.07 (2H, m).

中間體124：5-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-甲酸 Intermediate 124 : 5-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)pyridine-2-carboxylic acid

向存於MeOH(20 mL)中之(5-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-甲酸甲酯)(以與實例279類似之方式製得，500 mg，1.23 mmol)之溶液中添加1 M氫氧化鈉水溶液(1.85 mL，1.85 mmol)。將溶液在室溫下攪拌過夜並蒸發至乾燥。將所得固體溶於水(20 mL)中並使用1 M HCl水溶液將溶液酸化至pH 3。過 濾所得固體並乾燥以得到淺褐色固體形式之期望產物(418 mg，87%)。方法C HPLC-MS：MH+要求m/z=391；實驗值：m/z=390.9，Rt=1.16 min(95%)。 (5-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three in MeOH (20 mL) -2-yl}-1,2,4- A solution of methyl oxazol-5-yl)pyridine-2-carboxylate (prepared in a similar manner to Example 279, 500 mg, 1.23 mmol) was added 1 M aqueous sodium hydroxide (1.85 mL, 1.85 mmol). The solution was stirred at room temperature overnight and evaporated to dryness. The resulting solid was dissolved in water (20 mL) and the solution was acidified to pH 3 using 1 M aqueous HCI. The resulting solid was filtered and dried to give the desired crystals (yield: Method C HPLC-MS: MH+ requires m/z = 391. Found: m/z = 390.9, Rt = 1.16 min (95%).

中間體126：甲烷磺酸[2-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-3-基]甲酯、甲烷磺酸[3-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-基]甲酯及[2-(3-{4-甲烷磺酸胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-3-基]甲酯、甲烷磺酸[3-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-基]甲酯(區域異構體之混合物) Intermediate 126 : methanesulfonic acid [2-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Oxazol-5-yl)pyridin-3-yl]methyl ester, methanesulfonic acid [3-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5- three -2-yl}-1,2,4- Oxazol-5-yl)pyridin-2-yl]methyl ester and [2-(3-{4-methanesulfonateamino-6-[methyl(phenyl)amino]-1,3,5- three -2-yl}-1,2,4- Oxazol-5-yl)pyridin-3-yl]methyl ester, methanesulfonic acid [3-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5- three -2-yl}-1,2,4- Oxazol-5-yl)pyridin-2-yl]methyl ester (mixture of regioisomers)

在氮下，向存於DCM(25 mL)中之[2-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-3-基]甲醇及[3-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-基]甲醇(中間體127-區域異構體之混合物，300 mg，0.797 mmol)之溶液中添加甲磺醯氯(93 μL,1.19 mmol)及三乙胺(177 μL,1.27 mmol)。將反應混合物在室溫下攪拌4 h且然後使用水(3×25 ml)洗滌。藉由硫酸鎂乾燥有機相並蒸發至乾燥以得到標題化合物，該標題化合物未經進一步純化即使用(312 mg，86%)。方法C HPLC-MS：MH+要求m/z=455；實驗值：m/z=455，Rt=1.25 min(70%)。 [2-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three in DCM (25 mL) under nitrogen -2-yl}-1,2,4- Oxazol-5-yl)pyridin-3-yl]methanol and [3-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Addition of methanesulfonate chloride (93 μL, 1.19 mmol) and triethyl to a solution of oxazol-5-yl)pyridin-2-yl]methanol (mixture of intermediate 127-regioisomer, 300 mg, 0.797 mmol) Amine (177 μL, 1.27 mmol). The reaction mixture was stirred at room temperature for 4 h and then washed with water (3×25 ml). The organic phase was dried (MgSO4) Method C HPLC-MS: MH+ requires m/z = 455. Found: m/z = 455, Rt = 1.25 min (70%).

根據針對中間體126所述之程序來製備下列甲磺酸酯。 The following mesylate was prepared according to the procedure described for Intermediate 126.

中間體127：[2-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-3-基]甲醇及[3-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三2-基}-1,2,4-二唑-5-基)吡啶-2-基]甲醇(區域異構體之混合物) Intermediate 127 : [2-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Oxazol-5-yl)pyridin-3-yl]methanol and [3-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three 2-base}-1,2,4- Diazol-5-yl)pyridin-2-yl]methanol (mixture of regioisomers)

在氮及0℃下，向存於無水THF(75 mL)中之3-{3-[4-胺基-6-(甲基-苯基-胺基)-[1,3,5]三-2-基]-[1,2,4]二唑-5-基}-吡啶-2-甲酸甲酯及2-{3-[4-胺基-6-(甲基-苯基-胺基)-[1,3,5]三-2-基]-[1,2,4]二唑-5-基}-菸酸甲酯(中間體 147-區域異構體之混合物，800 mg，1.98 mmol)之溶液中逐份添加硼氫化鈉(187 mg，4.95 mmol)。將溶液升溫至室溫並再攪拌16 h。使用水(10 mL)將反應混合物驟冷並萃取至EtOAc(3×50 mL)中。使用鹽水洗滌合併之有機物，藉由硫酸鎂乾燥，蒸發至乾燥並使用二乙醚研磨。在真空下乾燥分離之淺黃色固體以得到標題化合物(540 mg，73%)。方法A HPLC-MS：MH+要求m/z=377；實驗值：m/z=377，Rt=3.40 min(64%)。 3-{3-[4-Amino-6-(methyl-phenyl-amino)-[1,3,5]3 in anhydrous THF (75 mL) at 0 ° C -2-base]-[1,2,4] Methyl oxazol-5-yl}-pyridine-2-carboxylate and 2-{3-[4-amino-6-(methyl-phenyl-amino)-[1,3,5] -2-base]-[1,2,4] Sodium borohydride (187 mg, 4.95 mmol) was added portionwise to a solution of oxazol-5-yl}-nicotinic acid methyl ester (intermediate 147 - mixture of regioisomers, 800 mg, 1.98 mmol). The solution was warmed to room temperature and stirred for a further 16 h. The reaction mixture was quenched with water (10 mL)EtOAcEtOAc The combined organics were washed with brine, dried over magnesium sulfate, evaporated and evaporated. The isolated pale yellow solid was dried <RTI ID=0.0> Method A HPLC-MS: MH+ requires m/z = 377; found: m/z = 377, Rt = 3.40 min (64%).

中間體130：[5-(3-{4-胺基-6-[(2-甲氧基乙基)(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-基]甲醇 Intermediate 130 : [5-(3-{4-Amino-6-[(2-methoxyethyl)(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)pyridin-2-yl]methanol

在0℃及氮下，向存於無水THF(50 mL)中之5-(3-{4-胺基-6-[(2-甲氧基乙基)(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-甲酸甲酯(實例311，212 mg，0.472 mmol)之溶液中逐份添加硼氫化鈉(45 mg，1.18 mmol)。將所得反應混合物在室溫下攪拌16 h且然後使用飽和氯化銨水溶液(10 mL)驟冷。將溶液萃取至EtOAc(3×25 mL)中並使用鹽水洗滌合併之有機物，藉由硫酸鎂乾燥並蒸發至乾燥以得到黃色固體形式之標題化合物(186 mg，94%)。方法C HPLC-MS：MH+要求m/z=421；實驗值：m/z=421，Rt=1.19 min(73%)。 5-(3-{4-Amino-6-[(2-methoxyethyl)(phenyl)amino]-1 in anhydrous THF (50 mL) at 0 ° C under nitrogen , 3,5-three -2-yl}-1,2,4- Sodium borohydride (45 mg, 1.18 mmol) was added portionwise to a solution of methyl oxazol-5-yl)pyridine-2-carboxylate (Example 311, 212 mg, 0.472 mmol). The resulting reaction mixture was stirred at room temperature for 16 h and then quenched with saturated aqueous ammonium chloride (10 mL). The solution was extracted into EtOAc (EtOAc (EtOAc)EtOAc. Method C HPLC-MS: MH+ requires m/z = 421. Found: m/z = 421, Rt = 1.19 min (73%).

中間體131：1-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)六氫吡啶-4-酮 Intermediate 131 : 1-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)hexahydropyridin-4-one

在0℃下，向存於DCM(20 mL)中之1-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)六氫吡啶- 4-醇(中間體132，120 mg，0.325 mmol)之溶液中添加戴斯-馬丁過碘烷(138 mg，0.325 mmol)。將所得反應混合物在室溫下攪拌2 h且然後添加額外戴斯-馬丁過碘烷(138 mg，0.325 mmol)。將反應混合物在室溫下再攪拌16 h且然後使用飽和碳酸氫鈉水溶液(10 mL)驟冷。分離所得雙層並使用1 M HCl水溶液(10 mL)進一步洗滌有機物。藉由硫酸鎂乾燥有機物，蒸發至乾燥並藉由二氧化矽層析(存於DCM中之0至3% MeOH)純化以得到灰白色固體形式之標題化合物(亦存在戴斯-馬丁過碘烷雜質(17%))(179 mg，150%)。方法C HPLC-MS：MH+要求m/z=367；實驗值：m/z=367，Rt=1.14 min(74%)。 1-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three in DCM (20 mL) at 0 °C -2-yl}-1,2,4- Dess-Martin periodinane (138 mg, 0.325 mmol) was added to a solution of the oxazol-5-yl)hexahydropyridin-4-ol (Intermediate 132, 120 mg, 0.325 mmol). The resulting reaction mixture was stirred at room temperature for 2 h and then additional Dess-Martin periodinane (138 mg, 0.325 mmol). The reaction mixture was stirred at room temperature for additional 16 h then quenched with saturated aqueous sodium hydrogen sulfate (10 mL). The resulting bilayer was separated and the organics were further washed with 1 M aqueous HCl (10 mL). The organics were dried <RTI ID=0.0></RTI><RTIID=0.0></RTI> (17%)) (179 mg, 150%). Method C HPLC-MS: MH+ requires m/z = 367; found: m/z = 367, Rt = 1.14 min (74%).

中間體133：3-[4-胺基-6-(苯基胺基)-1,3,5-三-2-基]-1,2,4-二唑-5-甲酸乙酯 Intermediate 133 : 3-[4-Amino-6-(phenylamino)-1,3,5-three -2-yl]-1,2,4- Diazol-5-carboxylic acid ethyl ester

在0℃下，將草醯氯單乙酯(0.396 mL，3.55 mmol)添加至存於甲苯及吡啶(40 mL)之1：1混合物中之(Z)-4-胺基-N'-羥基-6-(苯基胺基)-1,3,5-三-2-甲脒(以與中間體4類似之方式製得，0.792 g，3.23 mmol)之溶液中。將混合物升溫至室溫並在50℃下加熱2 h。將混合物冷卻至室溫，並在真空下濃縮。使用水稀釋殘餘物且藉由過濾收集所得固體並在真空下乾燥以得到黃色固體形式之標題化合物(0.923 g)，該標題化合物並未進一步純化。方法B HPLC-MS：MH+要求m/z=328；實驗值：m/z=328，Rt=1.77 min(42%)。 Add oxalic acid monoethyl ester (0.396 mL, 3.55 mmol) to (Z)-4-amino-N'-hydroxyl group in a 1:1 mixture of toluene and pyridine (40 mL) at 0 °C -6-(phenylamino)-1,3,5-three 2-methylhydrazine (prepared in a similar manner to intermediate 4, 0.792 g, 3.23 mmol). The mixture was warmed to room temperature and heated at 50 °C for 2 h. The mixture was cooled to room temperature and concentrated under vacuum. The residue was diluted with EtOAc (EtOAc m.) Method B HPLC-MS: MH+ requires m/z = 328. Found: m/z = 328, Rt = 1.77 min (42%).

中間體134：2-N-苯基-6-[5-(三氯甲基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺 Intermediate 134 : 2-N-phenyl-6-[5-(trichloromethyl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine

在0℃下，將2,2,2-三氯乙酸三氯乙醯基酯(0.875 mL，4.90 mmol)緩慢添加至存於甲苯(20 mL)中之(Z)-4-胺基-N'-羥基-6-(苯基胺基)-1,3,5-三-2-甲脒(以與中間體4類似之方式製得，1.00 g，4.08 mmol)之懸浮液中。在0℃下添加吡啶(0.62 mL)且將混合物在室溫下攪拌45 min，然後在65℃下加熱45 min。然後將混合物冷卻至室溫，且進一步添加0.6當量之2,2,2-三氯乙酸三氯乙醯基酯。將反應混合物在室溫下攪拌10 min並在65℃下攪拌40 min。在真空下濃縮混合物。將所得殘餘物溶於EtOAc(60 mL)中，使用碳酸氫鈉飽和水溶液(3×20 mL)洗滌，藉由硫酸鈉乾燥，過濾並在真空下濃縮以得到淺褐色固體形式之標題化合物(1.445 g，95%)。方法B HPLC-MS：MH+要求m/z=372/374；實驗值：m/z=372/374，Rt=1.41 min(72%)。 3,2,2-trichloroacetic acid trichloroethenyl ester (0.875 mL, 4.90 mmol) was slowly added to (Z)-4-amino-N in toluene (20 mL) at 0 °C '-Hydroxy-6-(phenylamino)-1,3,5-three A suspension of 2-formamidine (prepared in a similar manner to Intermediate 4, 1.00 g, 4.08 mmol). Pyridine (0.62 mL) was added at 0 ° C and the mixture was stirred at room temperature for 45 min then heated at 65 ° C for 45 min. The mixture was then cooled to room temperature, and 0.6 equivalent of trichloroethenyl 2,2,2-trichloroacetate was further added. The reaction mixture was stirred at room temperature for 10 min and at 65 ° C for 40 min. The mixture was concentrated under vacuum. The residue was taken from EtOAc EtOAc EtOAc. g, 95%). Method B HPLC-MS: MH+ requires m/z = 372 / 374. Found: m/z = 372/374, Rt = 1.41 min (72%).

中間體135：6-[5-(6-氯吡啶-3-基)-1,2,4-二唑-3-基]-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺 Intermediate 135 : 6-[5-(6-chloropyridin-3-yl)-1,2,4- Diazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine

將6-氯吡啶-3-甲酸(1 g，6.35 mmol)及亞硫醯氯(10 mL，138 mmol)加熱至回流保持2小時。在真空下濃縮混合物且使用二乙醚將殘餘物共沸並蒸發。然後將一部分此醯氯(0.75 g，4.26 mmol)添加至存於吡啶(12 mL)中之4-胺基-N-羥基-6-[甲基(苯基)胺基]-1,3,5-三-2-甲脒(以與中間體1類似之方式製得，0.920 g，3.55 mmol)之溶液中，且將混合物在室溫下攪拌過夜然後加熱至70℃保持3 h。將混合物冷卻至室溫並在真空下濃縮。添加水且將混合物攪拌30 min。過濾固體並使用額外之水洗滌。然後使用甲苯將固 體共沸並在真空下乾燥以得到標題化合物，該標題化合物未經純化即用於下一步驟中。方法B HPLC-MS：MH+要求m/z=381實驗值：m/z=381，Rt=1.99 min(35%)。 6-Chloropyridine-3-carboxylic acid (1 g, 6.35 mmol) and sulfinium chloride (10 mL, 138 mmol) were heated to reflux for 2 h. The mixture was concentrated under vacuum and the residue was evaporated and evaporated with diethyl ether. A portion of this ruthenium chloride (0.75 g, 4.26 mmol) was then added to 4-amino-N-hydroxy-6-[methyl(phenyl)amino]-1,3 in pyridine (12 mL). 5-three A solution of 2-methylindole (prepared in a similar manner to Intermediate 1, 0.920 g, 3.55 mmol), and the mixture was stirred at room temperature overnight and then heated to 70 ° C for 3 h. The mixture was cooled to room temperature and concentrated under vacuum. Water was added and the mixture was stirred for 30 min. The solid was filtered and washed with additional water. The solid was then azeotroped with toluene and dried in vacuo to give the title compound. Method B HPLC-MS: MH+ requires m/z = 381. Found: m/z = 381, Rt = 1.99 min (35%).

中間體136：5-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-醇 Intermediate 136 : 5-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)pyridin-2-ol

根據上文針對中間體135所述之方法自6-羥基吡啶-3-甲酸(0.556 g，4 mmol)、亞硫醯氯(1.2 mL，16 mmol)及4-胺基-N-羥基-6-[甲基(苯基)胺基]-1,3,5-三-2-甲脒(以與中間體1類似之方式製得，0.52 g，2 mmol)來製備。方法B HPLC-MS：MH+要求m/z=363實驗值：m/z=363，Rt=1.52 min(87%)。 From 6-hydroxypyridine-3-carboxylic acid (0.556 g, 4 mmol), sulfinium chloride (1.2 mL, 16 mmol) and 4-amino-N-hydroxy-6 according to the procedure described above for Intermediate 135 -[Methyl(phenyl)amino]-1,3,5-three 2-Methyl hydrazine (prepared in a similar manner to Intermediate 1, 0.52 g, 2 mmol) was prepared. Method B HPLC-MS: MH+ requires m/z = 363. Found: m/z = 363, Rt = 1.52 min (87%).

中間體139：2,2,2-三氯乙醯亞胺酸1-[6-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-3-基]乙酯 Intermediate 139 : 2,2,2-trichloroacetamido acid 1-[6-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5- three -2-yl}-1,2,4- Diazol-5-yl)pyridin-3-yl]ethyl ester

將1-[6-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-3-基]乙烷-1-醇(中間體140，0.400 g，1.02 mmol)懸浮於DCM中。添加三氯乙腈(0.123 mL，1.22 mmol)及1,8-二氮雜雙環十一-7-烯(數滴)且將混合物在室溫下攪拌19 h。添加DCM(30 mL)及水(30 mL)，分離有機層並使用鹽水(30 mL)洗滌，然後藉由硫酸鈉乾燥並在真空下濃縮以得到金褐色固體形式之標題化合物(0.497 g，91%)，該標題化合物未經進一步純化即用於下一步驟中。方法C HPLC-MS：MH+要求m/z=534實驗值：m/z=534，Rt=1.55 min(57%)。 1-[6-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- The oxazol-5-yl)pyridin-3-yl]ethane-1-ol (Intermediate 140, 0.400 g, 1.02 mmol) was suspended in DCM. Trichloroacetonitrile (0.123 mL, 1.22 mmol) and 1,8-diazabicycloundec-7-ene (a few drops) were added and the mixture was stirred at room temperature for 19 h. The title compound (0.497 g, 91) was obtained eluted eluted eluted eluted eluted The title compound was used in the next step without further purification. Method C HPLC-MS: MH+ requires m/z = 534. Found: m/z = 534, Rt = 1.55 min (57%).

中間體140：1-[6-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-3-基]乙烷-1-醇 Intermediate 140 : 1-[6-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)pyridin-3-yl]ethane-1-ol

1-[6-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-3-基]乙烷-1-醇 1-[6-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)pyridin-3-yl]ethane-1-ol

將1-[6-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-3-基]乙烷-1-酮(中間體141，0.934 g，2.40 mmol)懸浮於THF(60 mL)中，添加硼氫化鈉(0.227 g，6.01 mmol)並將混合物在室溫下攪拌2 h。添加EtOAc(50 mL)及水(100 mL)並分離有機層。使用1 M鹽酸水溶液中和水層並使用EtOAc(3×30 mL)萃取。藉由硫酸鈉乾燥合併之有機層並在真空下濃縮以得到淺黃色固體形式之標題化合物(1.0 g)，該標題化合物未經進一步純化即用於下一步驟中。方法C HPLC-MS：MH+要求m/z=391實驗值：m/z=391，Rt=1.18 min(84%)。 1-[6-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- The oxazol-5-yl)pyridin-3-yl]ethane-1-one (Intermediate 141, 0.934 g, 2.40 mmol) was suspended in THF (60 mL) and sodium borohydride (0.227 g, 6.01 mmol) The mixture was stirred at room temperature for 2 h. Add EtOAc (50 mL) and water (100 mL) andEtOAc. The aqueous layer was neutralized with aq. EtOAc (EtOAc) The combined organic layer was dried with EtOAc EtOAcjjjjjjjjj Method C HPLC-MS: MH+ requires m/z = 391. Found: m/z = 391, Rt = 1.18 min (84%).

中間體142：2-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-3-甲酸與3-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-甲酸之1：1混合物 Intermediate 142 : 2-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Oxazol-5-yl)pyridine-3-carboxylic acid with 3-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- a 1:1 mixture of oxazol-5-yl)pyridine-2-carboxylic acid

將存於吡啶(10 mL)中之4-胺基-N'-羥基-6-[甲基(苯基)胺基]-1,3,5-三-2-甲脒(以與中間體1類似之方式製得，500 mg，1.93 mmol)及2,3-吡啶二甲酸酐(290 mg，1.92 mmol)在80℃下攪拌18 h且然後添加額外之1當量2,3-吡啶二甲酸酐，且將混合物進一步在80℃下加熱12 h。將反應混合物冷卻至室溫，在減壓下濃縮並藉由製備型HPLC(方法C)純 化以提供標題化合物之1：1混合物(135 mg，18%)。方法B HPLC-MS：MH+要求m/z=392；實驗值：m/z=392，Rt=1.52及1.58 min(45%及53%)。 4-Amino-N'-hydroxy-6-[methyl(phenyl)amino]-1,3,5-three in pyridine (10 mL) 2-carbamidine (prepared in a similar manner to intermediate 1, 500 mg, 1.93 mmol) and 2,3-pyridinedicarboxylic anhydride (290 mg, 1.92 mmol) were stirred at 80 ° C for 18 h and then added additional One equivalent of 2,3-pyridinedicarboxylic anhydride was added and the mixture was further heated at 80 ° C for 12 h. The reaction mixture was cooled to EtOAc EtOAc (EtOAc) Method B HPLC-MS: MH+ requires m/z = 392; found: m/z = 392, Rt = 1.52 and 1.58 min (45% and 53%).

中間體143：2-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-3-甲酸 Intermediate 143 : 2-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)pyridine-3-carboxylic acid

使用1 N HCl水溶液酸化來自中間體147之製備之水層並使用EtOAc萃取(3×100 mL)。使用鹽水(50 mL)洗滌合併之有機層，藉由硫酸鎂乾燥並在減壓下濃縮以提供酸異構體之粗製.混合物，藉由製備型HPLC(方法C)純化以提供標題化合物(120 mg，3%)。方法B HPLC-MS：MH+要求m/z=391；實驗值：m/z=391，Rt=1.62(100%)。 The aqueous layer from the intermediate 147 was acidified using EtOAc EtOAc (EtOAc) The combined organic layers were washed with EtOAc EtOAc (EtOAc) Mg, 3%). Method B HPLC-MS: MH+ requires m/z = 391. Found: m/z = 391, Rt = 1.62 (100%).

中間體144：3-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-甲酸 Intermediate 144 : 3-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Diazol-5-yl)pyridine-2-carboxylic acid

自與中間體143中所述相同之混合物來製備3-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-甲酸並藉由製備型HPLC(方法C)純化以提供標題化合物(160 mg，4%)。方法B HPLC-MS：MH+要求m/z=391；實驗值：m/z=391 1.55(100%)。 Preparation of 3-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three from the same mixture as described in Intermediate 143 -2-yl}-1,2,4- The oxazol-5-yl)pyridine-2-carboxylic acid was purified by preparative HPLC (Method C) to give the title compound (160 mg, 4%). Method B HPLC-MS: MH+ requires m/z = 391. Found: m/z = 391 1.55 (100%).

中間體145：3-(甲氧基羰基)吡啶-2-甲酸與2-(甲氧基羰基)吡啶-3-甲酸之(3：1)混合物 Intermediate 145 : (3:1) mixture of 3-(methoxycarbonyl)pyridine-2-carboxylic acid and 2-(methoxycarbonyl)pyridine-3-carboxylic acid

將2,3-吡啶二甲酸酐(5 g，33.11 mmol)溶於MeOH(25 mL)中且將混合物在80℃下加熱4 h。將反應混合物冷卻至室溫，在減壓下濃縮以提供白色固體形式之標題混合物(6 g，定量)。方法B HPLC-MS：MH+要求m/z=182；實驗 值：m/z=182，Rt=0.75 min(94%)。 2,3-Dipyridic acid anhydride (5 g, 33.11 mmol) was dissolved in MeOH (25 mL) and the mixture was evaporated. The reaction mixture was cooled to rt EtOAc (EtOAc) Method B HPLC-MS: MH+ requires m/z = 182; experiment Value: m/z = 182, Rt = 0.75 min (94%).

中間體146：2-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-3-甲酸與3-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-甲酸之(1：1.25)混合物 Intermediate 146 : 2-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Oxazol-5-yl)pyridine-3-carboxylic acid with 3-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- (1:1.25) mixture of oxazol-5-yl)pyridine-2-carboxylic acid

將2-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-3-甲酸甲酯與3-(3-{4-胺基-6-[甲基(苯基)胺基]-1,3,5-三-2-基}-1,2,4-二唑-5-基)吡啶-2-甲酸甲酯(中間體147，1.4 g，3.46 mmol)之3：1混合物溶於MeOH：THF(40 mL)之1：1混合物中，且然後添加2 M氫氧化鈉水溶液(14 mL)並將混合物攪拌14 h。在減壓下濃縮反應混合物且使用1 N HCl水溶液(pH 1-2)酸化並使用EtOAc(4×50 mL)萃取。使用水(50 mL)洗滌合併之有機層然後使用鹽水(50 mL)洗滌並在減壓下濃縮。藉由製備型HPLC(方法C)純化殘餘物以提供標題混合物(135 mg)。方法B HPLC-MS：MH+要求m/z=391；實驗值：m/z=391，Rt=1.51及1.56 min(59%及41%)。 2-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- Methyl oxazol-5-yl)pyridine-3-carboxylate with 3-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-three -2-yl}-1,2,4- A 3:1 mixture of methyl oxazol-5-yl)pyridine-2-carboxylate (Intermediate 147, 1.4 g, 3.46 mmol) was dissolved in a 1:1 mixture of MeOH: THF (40 mL) and then 2 M aqueous sodium hydroxide (14 mL) and the mixture was stirred for 14 h. The reaction mixture was concentrated with EtOAc (EtOAc) (EtOAc) The combined organic layers were washed with water (50 mL) then brine brine The residue was purified by preparative EtOAc (EtOAc) Method B HPLC-MS: MH+ requires m/z = 391. Found: m/z = 391, Rt = 1.51 and 1.56 min (59% & 41%).

中間體158：6-氯-2-N-(6-氟吡啶-3-基)-2-N-甲基-1,3,5-三-2,4-二胺 Intermediate 158 : 6-chloro-2-N-(6-fluoropyridin-3-yl)-2-N-methyl-1,3,5-tri -2,4-diamine

在0℃及氮下，向存於DMF(1 mL)中之6-氯-2-N-(6-氟吡啶-3-基)-1,3,5-三-2,4-二胺(中間體159，0.52 g，2.17 mmol)之溶液中逐份添加氫化鈉(存於礦物油中之60%分散液，0.0869 g，2.17 mmol)。將混合物攪拌5 min，然後添加碘甲烷(0.3 g，2.17 mmol)且將混合物加熱至50℃保持16 h。添加EtOAc且使用碳酸氫鈉飽和水溶液洗滌有機層，藉由硫酸鈉乾燥並濃縮。藉由FCC(使用存於庚烷中之10-50% EtOAc洗脫)純化殘餘物以得到標題化合物(0.089 g，產率為16%)。方法B HPLC-MS：MH+要求m/z=255實驗值：m/z=255，Rt=1.52 min(74%)。 6-Chloro-2-N-(6-fluoropyridin-3-yl)-1,3,5-three in DMF (1 mL) at 0 ° C under nitrogen Sodium hydride (60% dispersion in mineral oil, 0.0869 g, 2.17 mmol) was added portionwise to a solution of 2,4-diamine (intermediate 159, 0.52 g, 2.17 mmol). The mixture was stirred for 5 min then iodomethane (0.3 g, 2.17 mmol) was added and mixture was warmed to 50 &lt;0&gt;C for 16 h. The organic layer was washed with EtOAc (EtOAc)EtOAc. The residue was purified with EtOAc EtOAcjjjjjjj Method B HPLC-MS: MH+ requires m/z = 255. Found: m/z = 255, Rt = 1.52 min (74%).

中間體163：N-(2-甲氧基乙基)苯胺 Intermediate 163 : N-(2-methoxyethyl)aniline

向存於DCM(50 mL)中之苯基硼酸(5 g，41.0 mmol)中添加乙酸銅(II)(0.78 g，4.1 mmol)且將混合物在室溫下攪拌5 min。添加2-甲氧基乙胺(3.08 g，41.0 mmol)且將混合物在40℃下攪拌19 h。然後將混合物通過二氧化矽塞且然後藉由FCC(使用存於庚烷中之10% EtOAc洗脫)純化以得到標題化合物(1.065 g，產率為17%)。方法B HPLC-MS：MH+要求m/z=152實驗值：m/z=152，Rt=1.08 min(87%)。 To the phenylboric acid (5 g, 41.0 mmol) in DCM (50 mL), EtOAc (EtOAc) (EtOAc) 2-Methoxyethylamine (3.08 g, 41.0 mmol) was added and the mixture was stirred at 40 ° C for 19 h. The mixture was then purified by EtOAc (EtOAc) elute elute Method B HPLC-MS: MH+ requires m/z = 152 found: m/z = 152, Rt = 1.08 min (87%).

中間體168：5-胺基吡啶-2-甲酸甲酯 Intermediate 168 : methyl 5-aminopyridine-2-carboxylate

將5-胺基吡啶-2-甲酸(1.60 g，11.6 mmol)溶於MeOH(100 mL)中並添加濃硫酸(1.7 mL，12.8 mmol)且將混合物加熱至80℃保持5小時。在真空下濃縮反應混合物，藉由添加1 M碳酸氫鈉水溶液進行中和並使用EtOAc萃取。藉由硫酸鈉乾燥有機層並在真空下濃縮以得到淺黃色固體形式之標題化合物(1.813 g，定量)。方法B HPLC-MS：MH+要求m/z=153實驗值：m/z=153，Rt=0.35 min(藉由MS)。 5-Aminopyridine-2-carboxylic acid (1.60 g, 11.6 mmol) was dissolved in MeOH (100 mL) and concentrated sulfuric acid (1.7 mL, 12.8 mmol) was then added The reaction mixture was concentrated in vacuo and purified with EtOAc EtOAc. The title compound (1.813 g, EtOAc) was obtained eluted Method B HPLC-MS: MH+ requires m/z = 153 found: m/z = 153, Rt = 0.35 min (MS).

中間體169：5-(三氟甲氧基)吡啶-2-羰基氯 Intermediate 169 : 5-(Trifluoromethoxy)pyridine-2-carbonyl chloride

將存於5：1 MeOH：水混合物(3 mL)中之5-(三氟甲氧基)吡啶-2-甲酸甲酯(0.313 g，1.41 mmol)、氫氧化鉀(0.076 g， 1.35 mmol)之混合物在室溫下攪拌1 h。添加額外氫氧化鉀(0.015 g，0.267 mmol)之水溶液(0.2 mL)且將混合物在室溫下攪拌1 h。將反應混合物蒸發至乾燥並使用甲苯共沸兩次以得到5-(三氟甲氧基)吡啶-2-甲酸鉀中間體(404 mg 100%)。將一部分此中間體(0.173 g，0.706 mmol)溶於草醯氯(4 mL)中且將混合物在室溫下攪拌2 h，然後蒸發至乾燥且未經進一步純化即用於下一步驟中。 Methyl 5-(trifluoromethoxy)pyridine-2-carboxylate (0.313 g, 1.41 mmol), potassium hydroxide (0.076 g, EtOAc) The mixture of 1.35 mmol) was stirred at room temperature for 1 h. An additional aqueous solution of potassium hydroxide (0.015 g, 0.267 mmol) (0.2 mL) was added and the mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated to dryness and aq. EtOAc (EtOAc) A portion of this intermediate (0.173 g, <RTI ID=0.0>, </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt;

中間體171：6-(四氫-呋喃-3-基氧基)-菸酸 Intermediate 171 : 6-(tetrahydro-furan-3-yloxy)-nicotinic acid

向6-氯-菸酸(415 mg，2.59 mmol)中添加3-羥基四氫呋喃(468 mg，5.16 mmol)、氫氧化鉀(579 mg，10.3 mmol)及DMSO(5 mL)。將混合物在120℃下加熱24 h。添加額外氫氧化鉀(579 mg)及3-羥基四氫呋喃(468 mg)並將混合物在120℃下加熱24 h。將反應液冷卻至室溫，使用2 M HCl水溶液(13 mL)酸化至pH=1-2並萃取至EtOAc(3×5 mL)中。使用水(5×20 mL)、飽和鹽水(2×20 mL)洗滌合併之萃取物並藉由無水硫酸鈉乾燥。蒸發溶劑以得到橙色固體形式之標題化合物，在高真空下乾燥以去除痕量溶劑(209 mg，39%)。方法B HPLC-MS：MH+要求m/z=210；實驗值：m/z=210，Rt=1.32 min(100%)。 To 6-chloro-nicotinic acid (415 mg, 2.59 mmol) was added 3-hydroxytetrahydrofuran (468 mg, 5.16 mmol), potassium hydroxide (579 mg, 10.3 mmol) and DMSO (5 mL). The mixture was heated at 120 ° C for 24 h. Additional potassium hydroxide (579 mg) and 3-hydroxytetrahydrofuran (468 mg) were added and the mixture was heated at 120 °C for 24 h. The reaction was cooled to room EtOAc then EtOAc (EtOAc)EtOAc. The combined extracts were washed with water (5×20 mL), brine (2×20 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated to give the title compound, m. Method B HPLC-MS: MH+ requires m/z = 210; found: m/z = 210, Rt = 1.32 min (100%).

中間體173：6-(環丙基甲氧基)吡啶-3-甲酸 Intermediate 173 : 6-(cyclopropylmethoxy)pyridine-3-carboxylic acid

將6-氯吡啶-3-甲酸(1.00 g，6.347 mmol)、環丙基甲醇(0.759 mL，9.520 mmol)及氫氧化鉀(1.424 g，25.39 mmol)溶於DMSO(25 mL)中並在100℃下加熱18 h。將反應混合物冷卻至室溫；添加水並使用1 M鹽酸酸化至pH 4-5。在 真空下過濾掉所得沈澱物以得到標題化合物(1.079 g，88%)。方法B HPLC-MS：MH+要求m/z=193實驗值：m/z=194，Rt=1.95 min(96%)。 6-Chloropyridine-3-carboxylic acid (1.00 g, 6.347 mmol), cyclopropylmethanol (0.759 mL, 9.520 mmol) and potassium hydroxide (1.424 g, 25.39 mmol) were dissolved in DMSO (25 mL) at 100 Heat at °C for 18 h. The reaction mixture was cooled to room temperature; water was added and acidified to pH 4-5 using 1 M hydrochloric acid. in The resulting precipitate was filtered to give the title compound (l. Method B HPLC-MS: MH+ requires m/z = 193: m/z = 194, Rt = 1.95 min (96%).

中間體174：6-(2,2,2-三氟乙氧基)吡啶-2-甲酸 Intermediate 174 : 6-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid

將6-氯吡啶-2-甲酸(1.00 g，6.347 mmol)、2,2,2-三氟乙烷-1-醇(0.683 mL，9.520 mmol)及氫氧化鉀(1.424 g，25.387 mmol)溶於DMSO(25 mL)中並在100℃下加熱18 h。使用氫氧化鉀(0.356 g，6.347 mmol)再處理反應混合物並在100℃下加熱18 h。然後使用2,2,2-三氟乙烷-1-醇(1.367 mL，19.040 mmol)及氫氧化鉀(0.356 g，6.347 mmol)再處理反應混合物並在110℃下加熱18 h。然後使用氫氧化鉀(0.356 g，6.347 mmol)及2,2,2-三氟乙烷-1-醇(0.683 mL，9.520 mmol)進一步再處理反應混合物且將混合物在室溫下攪拌72 h。添加水(10 mL)並使用1 M鹽酸酸化至pH 1。使用EtOAc(3×15 mL)萃取水層且使用鹽水(15 mL)洗滌有機層。藉由無水硫酸鈉乾燥，過濾並在減壓下濃縮以得到褐色膠。藉由FCC(DCM：MeOH 90：10)純化粗製材料以得到黃色固體形式之標題化合物(1.26 g，90%)。方法B HPLC-MS：MH+要求m/z=222實驗值：m/z=222，Rt=1.71 min(79%)。 6-Chloropyridine-2-carboxylic acid (1.00 g, 6.347 mmol), 2,2,2-trifluoroethane-1-ol (0.683 mL, 9.520 mmol) and potassium hydroxide (1.424 g, 25.387 mmol) It was heated in DMSO (25 mL) at 100 ° C for 18 h. The reaction mixture was re-treated with potassium hydroxide (0.356 g, 6.347 mmol) and heated at 100 ° C for 18 h. The reaction mixture was then re-treated with 2,2,2-trifluoroethane-1-ol (1.367 mL, 19.040 mmol) and potassium hydroxide (0.356 g, 6.347 mmol) and heated at 110 ° C for 18 h. The reaction mixture was then further treated with potassium hydroxide (0.356 g, 6.347 mmol) and 2,2,2-trifluoroethane-l-ol (0.683 mL, 9.520 mmol) and the mixture was stirred at room temperature for 72 h. Water (10 mL) was added and acidified to pH 1 using 1 M hydrochloric acid. The aqueous layer was extracted with EtOAc (3×15 mL) and brine. It was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give brown gum. The crude material was purified by EtOAc EtOAcjjjjjj Method B HPLC-MS: MH+ requires m/z = 422. Found: m/z = 222, Rt = 1.71 min (79%).

中間體175：4-(甲氧基甲基)六氫吡啶鹽酸鹽 Intermediate 175 : 4-(Methoxymethyl)hexahydropyridine hydrochloride

將存於1,4-二烷中之4 M氯化氫溶液(807 μL，3.23 mmol)添加至4-(甲氧基甲基)六氫吡啶-1-甲酸第三丁基酯(中間體176，74 mg，0.323 mmol)中且將混合物在室溫下 攪拌18 h，然後蒸發至乾燥以提供標題化合物(47.7 mg，89%)。方法B HPLC-MS：MH+要求m/z=130實驗值：m/z=130，Rt=0.24 min。 Will be stored in 1,4-two 4 M hydrogen chloride solution (807 μL, 3.23 mmol) in alkane was added to 4-(methoxymethyl)hexahydropyridine-1-carboxylic acid tert-butyl ester (Intermediate 176, 74 mg, 0.323 mmol). The mixture was stirred at rt EtOAc (EtOAc) Method B HPLC-MS: MH+ requires m/z = 130 found: m/z = 130, Rt = 0.24 min.

根據針對中間體175所述之方法來製備下列中間體。 The following intermediates were prepared according to the procedure described for Intermediate 175.

中間體176：4-(甲氧基甲基)六氫吡啶-1-甲酸第三丁基酯 Intermediate 176 : 4-(methoxymethyl)hexahydropyridine-1-carboxylic acid tert-butyl ester

在0℃下，將存於DMF(2.5 mL)中之4-(羥甲基)六氫吡啶-1-甲酸第三丁基酯(0.300 g，1.395 mmol)之溶液逐滴添加至存於無水DMF(2.5 mL)中之氫化鈉(存於礦物油中之60%分散液，0.067 g，1.674 mmol)之懸浮液中。將反應混合物在0℃下攪拌10 min，隨後逐滴添加碘甲烷(86 μL，1.395 mmol)。將混合物升溫至室溫並攪拌18 h。使用氫化鈉(存於礦物油中之60%分散液，0.067 g，1.674 mmol)及碘甲烷(86 μL，1.395 mmol)再處理反應混合物並在室溫下攪拌18 h。在減壓下蒸發反應混合物，溶於DCM中並使用碳酸氫鈉飽和水溶液洗滌。合併有機萃取物，藉由無水硫酸鈉乾燥，過濾並在減壓下濃縮。藉由FCC(EtOAc：庚烷，1：1)純化粗製材料以得到標題化合物(0.074 g，23%)。方法B HPLC-MS：MH+要求m/z=229實驗值：m/z=174(MH+-tBu)Rt=1.98 min(99%)。 A solution of 4-(hydroxymethyl)hexahydropyridine-1-carboxylic acid tert-butyl ester (0.300 g, 1.395 mmol) in DMF (2.5 mL) was added dropwise at 0 ° C. A suspension of sodium hydride (60% dispersion in mineral oil, 0.067 g, 1.674 mmol) in DMF (2.5 mL). The reaction mixture was stirred at 0 &lt;0&gt;C for 10 min then EtOAc (EtOAc &lt The mixture was warmed to room temperature and stirred for 18 h. The reaction mixture was re-treated with sodium hydride (60% dispersion in mineral oil, 0.067 g, 1.674 mmol) and io The reaction mixture was evaporated under reduced pressure. The combined organic extracts were dried with anhydrous sodium sulfate, filtered and evaporated. The crude material was purified by EtOAc EtOAcjjjjjj Method B HPLC-MS: MH+ requires m/z = 229. Found: m/z = 174 (MH+-tBu) Rt = 1.98 min (99%).

以與中間體176類似之方式來製備下列醚。 The following ethers were prepared in a similar manner to intermediate 176.

中間體178：4-(苯氧基甲基)六氫吡啶-1-甲酸第三丁基酯 Intermediate 178 : 4-(phenoxymethyl)hexahydropyridine-1-carboxylic acid tert-butyl ester

將4-(羥甲基)六氫吡啶-1-甲酸第三丁基酯(0.300 g，1.393 mmol)、苯酚(0.122 mL，1.393 mmol)、三苯基膦(0.440 g，1.672 mmol)及N-{[(第三丁氧基)羰基]亞胺基}(第三丁氧基)甲醯胺(0.390 g，1.672 mmol)在THF(4 mL)中合併並在室溫下攪拌18 h。在減壓下濃縮反應混合物並藉由FCC(EtOAc：庚烷，1：1)純化以得到白色固體。藉由使用二乙醚進行研磨來進一步純化以得到標題化合物(0.289 g，71%)。方法B HPLC-MS：MH+要求m/z=292實驗值：m/z=235(MH+-tBu)，Rt=2.44 min(71%)。 4-(Hydroxymethyl)hexahydropyridine-1-carboxylic acid tert-butyl ester (0.300 g, 1.393 mmol), phenol (0.122 mL, 1.393 mmol), triphenylphosphine (0.440 g, 1.672 mmol) and N -{[(Tertidinoxy)carbonyl]imino}(t-butoxy)carbamide (0.390 g, 1.672 mmol) was combined in THF (4 mL). The reaction mixture was concentrated with EtOAc EtOAc m. Further purification by trituration with diethyl ether gave the title compound (0.289 g, 71%). Method B HPLC-MS: MH+ requires m/z = 292. Found: m/z = 235 (MH+-tBu), Rt = 2.44 min (71%).

中間體179：4-[(2,2,2-三氟乙氧基)甲基]六氫吡啶鹽酸鹽 Intermediate 179 : 4-[(2,2,2-Trifluoroethoxy)methyl]hexahydropyridine hydrochloride

將存於1,4-二烷(2.48 mL，9.93 mmol)中之4 M氯化氫溶液添加至4-[(2,2,2-三氟乙氧基)甲基]六氫吡啶-1-甲酸第三丁基酯(中間體180，0.289 g，0.993 mmol)中且將混合物在室溫下攪拌18 h，然後蒸發至乾燥以提供標題化合物(0.136 g，59%)。方法B HPLC-MS：MH+(HCl鹽)理論值 m/z=198實驗值：m/z=198，Rt=0.72 min。 Will be stored in 1,4-two Add 4 M hydrogen chloride solution in alkane (2.48 mL, 9.93 mmol) to 4-[(2,2,2-trifluoroethoxy)methyl]hexahydropyridine-1-carboxylic acid tert-butyl ester (intermediate) The title compound (0.136 g, 59%) was obtained. Method B HPLC-MS: MH+ ( HCl salt). m.s.

中間體180：4-[(2,2,2-三氟乙氧基)甲基]六氫吡啶-1-甲酸第三丁基酯 Intermediate 180 : 4-[(2,2,2-trifluoroethoxy)methyl]hexahydropyridine-1-carboxylic acid tert-butyl ester

將4-(羥甲基)六氫吡啶-1-甲酸第三丁基酯(0.300 g，1.393 mmol)、2,2,2-三氟乙烷-1-醇(1.00 mL，13.935 mmol)、三苯基膦(0.440 g，1.672 mmol)及N-{[(第三丁氧基)羰基]亞胺基}(第三丁氧基)甲醯胺(0.390 g，1.672 mmol)在THF(10 mL)中合併並在室溫下攪拌36 h，然後加熱至75℃保持18 h。在減壓下濃縮反應混合物並藉由FCC(EtOAc：庚烷，1：1)純化以得到標題化合物(0.192 g，50%)。方法B HPLC-MS：MH+要求m/z=297實驗值：m/z=242(MH+-tBu)，Rt=2.25 min(100%)。 4-(hydroxymethyl)hexahydropyridine-1-carboxylic acid tert-butyl ester (0.300 g, 1.393 mmol), 2,2,2-trifluoroethane-1-ol (1.00 mL, 13.935 mmol), Triphenylphosphine (0.440 g, 1.672 mmol) and N-{[(t-butoxy)carbonyl]imino}(t-butoxy)carbamamine (0.390 g, 1.672 mmol) in THF (10) They were combined in mL) and stirred at room temperature for 36 h, then heated to 75 ° C for 18 h. The reaction mixture was concentrated with EtOAc EtOAcjjjjjjjj Method B HPLC-MS: MH+ requires m/z = 297. Found: m/z = 242 (MH+-tBu), Rt = 2.25 min (100%).

以與中間體180類似之方式來製備下列三氟乙氧基醚。 The following trifluoroethoxy ether was prepared in a similar manner to Intermediate 180.

中間體183：4-{[(2,2,2-三氟乙基)硫基]甲基}六氫吡啶-1-甲酸第三丁基酯 Intermediate 183 : 4-{[(2,2,2-trifluoroethyl)thio]methyl}hexahydropyridine-1-carboxylic acid tert-butyl ester

在0℃下，將2,2,2-三氟乙烷-1-硫醇(0.151 mL，1.636 mmol)逐滴添加至存於無水DMF(3 mL)中之氫化鈉(存於礦物油中之60%分散液，0.065 g，1.636 mmol)之懸浮液中。然後逐滴添加存於DMF(4 mL)中之4-[(甲烷磺醯基氧基)甲 基]六氫吡啶-1-甲酸第三丁基酯(中間體181，0.320 g，1.091 mmol)之溶液且將反應混合物在室溫下攪拌4 h。使用EtOAc(30 mL)稀釋混合物並使用碳酸氫鈉飽和水溶液(10 mL)洗滌，隨後使用鹽水(10 mL)洗滌。藉由無水硫酸鈉乾燥有機層，過濾並在減壓下蒸發。藉由FCC(EtOAc：庚烷，20：80)純化粗製材料以提供無色油狀物形式之標題化合物(0.288 g，82%)。方法B HPLC-MS：MH+要求m/z=313實驗值：m/z=257(M-第三丁基)，Rt=2.28 min(97%)。 Add 2,2,2-trifluoroethane-1-thiol (0.151 mL, 1.636 mmol) dropwise to sodium hydride (in mineral oil) in anhydrous DMF (3 mL) at 0 °C In a 60% dispersion, 0.065 g, 1.636 mmol) suspension. Then add 4-[(methanesulfonyloxy) A in DMF (4 mL) A solution of the hexahydropyridine-1-carboxylic acid tert-butyl ester (Intermediate 181, 0.320 g, 1.091 mmol) and the mixture was stirred at room temperature for 4 h. The mixture was diluted with EtOAc (30 mL) andEtOAc. The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The crude material was purified by EtOAc EtOAcjjjjjjj Method B HPLC-MS: MH+ requires m/z = 313. Found: m/z = 257 (M-t-butyl), Rt = 2.28 min (97%).

中間體185：4-[(苯基硫基)甲基]六氫吡啶-1-甲酸第三丁基酯 Intermediate 185 : 4-[(phenylthio)methyl]hexahydropyridine-1-carboxylic acid tert-butyl ester

根據針對中間體183所述之方法自4-(羥甲基)六氫吡啶-1-甲酸第三丁基酯(中間體181，0.320 g，1.091 mmol)及硫代苯酚(0.117 mL，1.145 mmol)來製備4-[(苯基硫基)甲基]六氫吡啶-1-甲酸第三丁基酯以得到標題化合物(0.483 g)。1H NMR(250 MHz,CDCl3)δ ppm 7.22(5H,m),4.10(2H,m),2.83(2H d),2.64(2H,t),1.84(2H,d),1.63(1H,m),1.44(9H,s)及1.17(2H,m)。 From 4-(hydroxymethyl)hexahydropyridine-1-carboxylic acid tert-butyl ester (Intermediate 181, 0.320 g, 1.091 mmol) and thiophenol (0.117 mL, 1.145 mmol) according to the procedure described for Intermediate 183 Preparation of 4-[(phenylthio)methyl]hexahydropyridine-1-carboxylic acid tert-butyl ester gave the title compound (0.483 g). 1H NMR (250 MHz, CDCl 3 ) δ ppm 7.22 (5H, m), 4.10 (2H, m), 2.83 (2H d), 2.64 (2H, t), 1.84 (2H, d), 1.63 (1H, m ), 1.44 (9H, s) and 1.17 (2H, m).

中間體187：4-[(丙烷-2-基硫基)甲基]六氫吡啶-1-甲酸第三丁基酯 Intermediate 187 : 4-[(propan-2-ylthio)methyl]hexahydropyridine-1-carboxylic acid tert-butyl ester

根據針對中間體183所述之方法自4-(羥甲基)六氫吡啶-1-甲酸第三丁基酯(中間體181，0.320 g，1.091 mmol)及丙烷硫醇鈉(0.161 g，1.636 mmol)來製備4-[(丙烷-2-基硫基)甲基]六氫吡啶-1-甲酸第三丁基酯以得到標題化合物(0.180 g，60%)。方法B HPLC-MS：MH+要求m/z=274實 驗值：m/z=218(M-第三丁基)，Rt=2.51 min。 From (4-(hydroxymethyl)hexahydropyridine-1-carboxylic acid tert-butyl ester (intermediate 181, 0.320 g, 1.091 mmol) and sodium propane thiolate (0.161 g, 1.636) according to the procedure described for Intermediate 183 To a solution of the title compound (0.180 g, 60%). Method B HPLC-MS: MH+ requires m/z = 274 Found: m/z = 218 (M-tert-butyl), Rt = 2.51 min.

中間體188：6-{[(1,1,1-三氟丙烷-2-基)氧基]甲基}吡啶-3-甲酸 Intermediate 188 : 6-{[(1,1,1-Trifluoropropan-2-yl)oxy]methyl}pyridine-3-carboxylic acid

在0℃下，將1,1,1-三氟丙烷-2-醇(0.406 mL，4.483 mmol)逐滴添加至存於無水THF(20 mL)中之氫化鈉(60%，存於礦物油中)(0.239 g，5.977 mmol)之懸浮液中。將混合物在0℃下攪拌15分鐘。逐滴添加存於THF(10 mL)中之6-(甲烷磺醯基氧基)甲基]吡啶-3-甲酸甲酯(中間體189，0.733 g，2.989 mmol)之溶液。將反應混合物在0℃下攪拌30分鐘並在室溫下攪拌3天。使用水(10 mL)將反應混合物驟冷並使用EtOAc(30 mL)稀釋。分離各相，且使用碳酸氫鈉飽和水溶液(3×15 mL)萃取有機相。合併水性萃取物，使用EtOAc(1×10 mL)洗滌。拋棄有機相且使用2 N HCl將水相酸化至pH 4並使用EtOAc(3×30 mL)萃取。合併有機萃取物，藉由硫酸鈉乾燥，過濾並蒸發以提供褐色粗製殘餘物。藉由急驟層析(DCM：MeOH 98：2)純化粗製材料以得到淺褐色固體形式之標題化合物(0.345 g，46%)。方法B HPLC-MS：MH+要求m/z=250實驗值：m/z=250，Rt=1.61 min(89%)。 1,1,1-Trifluoropropan-2-ol (0.406 mL, 4.438 mmol) was added dropwise at 0 ° C to sodium hydride (60% in anhydrous THF (20 mL). Medium) (0.239 g, 5.977 mmol) in suspension. The mixture was stirred at 0 ° C for 15 minutes. A solution of 6-(methanesulfonyloxy)methyl]pyridine-3-carboxylic acid methyl ester (Intermediate 189, 0.733 g, 2.289 mmol) in THF (10 mL). The reaction mixture was stirred at 0 ° C for 30 minutes and at room temperature for 3 days. The reaction mixture was quenched with water (10 mL) The phases were separated and the organic phase was extracted using a saturated aqueous solution of sodium bicarbonate (3×15 mL). The combined aqueous extracts were washed with EtOAc (1×10 mL). The organic phase was discarded and the aqueous was acidified to pH 4 using EtOAc (EtOAc) The combined organic extracts were dried with sodium sulfate, filtered and evaporated The crude material was purified by flash chromatography eluting elut elut elut elut Method B HPLC-MS: MH+ requires m/z = 250 found: m/z = 250, Rt = 1.61 min (89%).

以與中間體188類似之方式來製備下列醚，其中視情況加熱至高達80℃。 The following ethers were prepared in a similar manner to Intermediate 188, which was heated up to 80 °C as appropriate.

中間體190：6-(羥甲基)吡啶-3-甲酸甲酯 Intermediate 190 : methyl 6-(hydroxymethyl)pyridine-3-carboxylate

將氯化鈣(22.7 g，204.9 mmol)添加至存於1：2 THF：MeOH混合物(300 mL)中之吡啶-2,5-二甲酸二甲基酯(10.0 g，51.2 mmol)之懸浮液中。在0℃下冷卻混合物，逐份添加硼氫化鈉(4.85 g，128.1 mmol)。將反應混合物緩慢升溫至室溫並攪拌18 h。添加額外之2.5當量硼氫化鈉且將反應混合物在室溫下攪拌2天。添加額外THF(100 mL)及MeOH(100 mL)且將混合物攪拌約15 h。添加額外之2.5當量硼氫化鈉(較新批次)且將反應混合物在室溫下攪拌15 h。將混合物緩慢傾倒於冰-水上並使用EtOAc(約200 mL)稀釋。過濾白色固體並拋棄。分離來自濾液之各相，使用水(3×100 mL)洗滌有機相。合併水性洗滌液並使用EtOAc(2×100 mL)再萃取。合併有機萃取物，藉由硫酸鈉乾燥，過濾並在真空下濃縮以得到灰白色固體形式之標題化合物(5.8 g，73%)。方法B HPLC-MS：MH+要求m/z=168實驗值：m/z=168，Rt=0.91 min(100%)。 Calcium chloride (22.7 g, 204.9 mmol) was added to a suspension of pyridine-2,5-dicarboxylic acid dimethyl ester (10.0 g, 51.2 mmol) in a 1:2 THF:MeOH mixture (300 mL) in. The mixture was cooled at 0 ° C and sodium borohydride (4.85 g, 128.1 mmol) was added portionwise. The reaction mixture was slowly warmed to room temperature and stirred for 18 h. An additional 2.5 equivalents of sodium borohydride were added and the reaction mixture was stirred at room temperature for 2 days. Additional THF (100 mL) and MeOH (100 mL) were added and the mixture was stirred for about 15 h. An additional 2.5 equivalents of sodium borohydride (newer batch) was added and the reaction mixture was stirred at room temperature for 15 h. The mixture was poured slowly onto ice-water and diluted with EtOAc (~ 200 mL). The white solid was filtered and discarded. The phases from the filtrate were separated and the organic phase was washed with water (3 x 100 mL). The aqueous washes were combined and extracted with EtOAc (2×100 mL). The combined organic extracts were dried with EtOAc EtOAcjjjjjjjj Method B HPLC-MS: MH+ requires m/z = 168: m/z = 168, Rt = 0.91 min (100%).

中間體194：6-(1-羥基乙基)吡啶-3-甲酸甲酯 Intermediate 194 : Methyl 6-(1-hydroxyethyl)pyridine-3-carboxylate

在-78℃下，將甲基溴化鎂(1 M，存於THF中)(3.03 mL，3.03 mmol)之溶液逐滴添加至存於THF(20 mL)中之6-甲醯基吡啶-3-甲酸甲酯(中間體195，0.50 g，3.03 mmol)之溶液中。將反應混合物在-78℃下攪拌1h且添加水(20 mL)。將混合物升溫至室溫並使用EtOAc(3×20 mL)萃取。 合併有機萃取物，藉由硫酸鈉乾燥，過濾並在真空下濃縮以提供灰白色固體形式之標題化合物(0.407 g，74%)。方法B HPLC-MS：MH+要求m/z=182實驗值：m/z=182，Rt=1.11 min(98%)。 A solution of methylmagnesium bromide (1 M in THF) (3.03 mL, 3.03 mmol) was added dropwise to a solution of 6-methylpyridylpyridine in THF (20 mL) at -78. A solution of methyl 3-formate (Intermediate 195, 0.50 g, 3.03 mmol). The reaction mixture was stirred at -78.degree. C. for 1 h and water (20 mL). The mixture was warmed to room temperature and extracted with EtOAc (3×20 mL). The combined organic extracts were dried with EtOAc EtOAcjjjjjjj Method B HPLC-MS: MH+ requires m/z = 182. Found: m/z = 182, Rt = 1.11 min (98%).

中間體195：6-甲醯基吡啶-3-甲酸甲酯 Intermediate 195 : Methyl 6-methylpyridyl-3-carboxylate

在室溫下，將戴斯-馬丁過碘烷(2.54 g，5.98 mmol)添加至存於DCM(75 mL)中之6-(羥甲基)吡啶-3-甲酸甲酯(中間體190，1.00 g，5.98 mmol)之溶液中。將反應混合物在室溫下攪拌24 hr，然後使用DCM(50 mL)稀釋，使用碳酸氫鈉飽和水溶液與硫代硫酸鈉之1：1混合物(3×75 mL)洗滌。藉由硫酸鈉乾燥有機相，過濾並在真空下蒸發以提供標題化合物(1.02 g，105%)。方法B HPLC-MS：MH+要求m/z=166實驗值：m/z=166，Rt=1.44 min(62%)。 Add Dess-Martin periodinane (2.54 g, 5.98 mmol) to methyl 6-(hydroxymethyl)pyridine-3-carboxylate (Intermediate 190, in DCM (75 mL). 1.00 g, 5.98 mmol) in solution. The reaction mixture was stirred at room temperature for 24 hr then diluted with EtOAc EtOAc. The organic phase was dried <RTI ID=0.0> Method B HPLC-MS: MH+ requires m/z = 166. Found: m/z = 166, Rt = 1.44 min (62%).

中間體198：4-[(環丙基甲氧基)甲基]六氫吡啶鹽酸鹽 Intermediate 198 : 4-[(cyclopropylmethoxy)methyl]hexahydropyridine hydrochloride

在室溫下，將存於二烷中之4 N HCl溶液(5 mL，20.0 mmol)添加至存於二烷(3 mL)中之4-[(環丙基甲氧基)甲基]六氫吡啶-1-甲酸第三丁基酯(中間體199，0.75 g，2.77 mmol)之溶液中。將反應混合物在室溫下攪拌3 h，然後蒸發至乾燥以提供淺粉紅色黏性固體形式之標題化合物(0.7 g，125%)。方法B HPLC-MS：MH+(基於游離形式)理論值m/z=170實驗值：m/z=170，Rt=0.87 min。 At room temperature, it will be stored in two 4 N HCl solution (5 mL, 20.0 mmol) in alkane was added to A solution of 4-[(cyclopropylmethoxy)methyl]hexahydropyridine-1-carboxylic acid tert-butyl ester (Intermediate 199, 0.75 g, 2.77 mmol) in EtOAc (3 mL). The reaction mixture was stirred at rt EtOAc (EtOAc) Method B HPLC-MS: MH+ (based on free form) Theory m/z = 170. Found: m/z = 170, Rt = 0.77 min.

中間體199：4-[(環丙基甲氧基)甲基]六氫吡啶-1-甲酸第三丁基酯 Intermediate 199 : 4-[(cyclopropylmethoxy)methyl]hexahydropyridine-1-carboxylic acid tert-butyl ester

在0℃下，將存於DMF(10 mL)中之N-boc-4-六氫吡啶甲 醇(0.500 g，2.322 mmol)之溶液逐滴添加至存於無水DMF(15 mL)中之氫化鈉(60%，存於礦物油中)(0.186 g，4.645 mmol)之懸浮液中。將混合物在0℃下攪拌15分鐘並在室溫下攪拌10分鐘，然後再次冷卻且逐滴添加(溴甲基)環丙烷(0.227 mL，2.322 mmol)。將反應混合物在0℃下攪拌10分鐘，在室溫下攪拌1 h並在80℃下攪拌4h。使用EtOAc(60 mL)稀釋反應混合物並使用水(3×20 mL)洗滌。合併水性洗滌液並使用EtOAc(3×20 mL)再萃取。合併有機萃取物，藉由硫酸鈉乾燥，過濾並蒸發以提供無色油狀物形式之標題化合物(0.614 g，98%)。方法B HPLC-MS：MH+要求m/z=270實驗值：m/z=214(MH+-tBu)，Rt=2.33 min(83%)。 N-boc-4-hexahydropyridine in DMF (10 mL) at 0 °C A solution of the alcohol (0.500 g, 2.322 mmol) was added dropwise to a suspension of sodium hydride (60% in mineral oil) (0.186 g, 4.465 mmol) in anhydrous DMF (15 mL). The mixture was stirred at 0 °C for 15 minutes and at room temperature for 10 minutes then cooled again and (bromomethyl)cyclopropane (0.227 mL, 2.322 mmol). The reaction mixture was stirred at 0 ° C for 10 min, at rt for 1 h and at 80 ° C for 4 h. The reaction mixture was diluted with EtOAc (60 mL) andEtOAc. The aqueous washes were combined and extracted with EtOAc (3×20 mL). The combined organic extracts were dried with EtOAc EtOAcjjjjjjj Method B HPLC-MS: MH+ requires m/z = 270: m/z = 214 (MH+-tBu), Rt = 2.33 min (83%).

中間體202：4-(2,2,2-三氟乙氧基)六氫吡啶 Intermediate 202 : 4-(2,2,2-trifluoroethoxy)hexahydropyridine

在室溫下，將三氟乙酸(1.15 mL)逐滴添加至存於(10 mL)DCM中之4-(2,2,2-三氟乙氧基)六氫吡啶-1-甲酸第三丁基酯(以與中間體203類似之方式製得，1.14 g，4.0 mmol)之溶液中。將反應混合物在室溫下攪拌16 h。然後在真空下濃縮混合物，將粗製殘餘物溶於水中且使用二乙醚(2次)萃取產物。使用固體碳酸鉀將水相鹼化至pH 10並使用DCM(4次)萃取。合併有機萃取物，藉由硫酸鈉乾燥並在真空下濃縮以得到標題化合物(610 mg，83%)。1H NMR(300 MHz,CDCl3)δ ppm 3.84(2H,q),3.53(1H,m),3.10(2H,m),2.61(2H,m),1.76(2H,m)及1.54(2H,s)。 Trifluoroacetic acid (1.15 mL) was added dropwise to 4-(2,2,2-trifluoroethoxy)hexahydropyridine-1-carboxylic acid in (10 mL) DCM. A solution of butyl ester (prepared in a similar manner to intermediate 203, 1.14 g, 4.0 mmol). The reaction mixture was stirred at room temperature for 16 h. The mixture was then concentrated under vacuum, the crude residue was taken in water and the product was taken with diethyl ether (2times). The aqueous phase was basified to pH 10 using solid potassium carbonate and extracted with DCM (4 times). The combined organic extracts were dried with EtOAc EtOAc EtOAc 1H NMR (300 MHz, CDCl 3 ) δ ppm 3.84 (2H, q), 3.53 (1H, m), 3.10 (2H, m), 2.61 (2H, m), 1.76 (2H, m) and 1.54 (2H, s).

中間體204：1-(2,2,2-三氟乙基)-1H-吡唑-3-甲酸甲酯 Intermediate 204 : methyl 1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxylate

將1H-吡唑-3-甲酸甲酯(1.0 g，7.94 mmol)溶於DMF(25 mL)中且添加碳酸銫(12.9 g，39.7 mmol)。將混合物冷卻至0℃且逐漸添加甲烷磺酸2,2,2-三氟乙基酯(2.4 mL，19.8 mmol)。將混合物升溫至室溫並攪拌16 h。添加水且使用EtOAc(3×25 mL)萃取混合物。使用鹽水(3×10 mL)洗滌合併之有機萃取物並在真空下濃縮。藉由FCC(使用己烷洗脫，隨後使用存於DCM中之0.5% MeOH洗脫)純化殘餘物以得到黃色油狀物形式之標題化合物(0.312 g，19%)。方法D HPLC-MS：MH+要求m/z=209實驗值：m/z=209，Rt=2.08 min(98%)。 Methyl 1H-pyrazole-3-carboxylate (1.0 g, 7.94 mmol) was dissolved in DMF (25 mL) and EtOAc (12.9 g, 39.7 mmol). The mixture was cooled to 0 ° C and 2,2,2-trifluoroethyl methanesulfonate (2.4 mL, 19.8 mmol) was gradually added. The mixture was warmed to room temperature and stirred for 16 h. Water was added and the mixture was extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (3×10 mL) and concentrated in vacuo. The residue was purified by EtOAc EtOAcjjjjjj Method D HPLC-MS: MH+ requires m/z = 209.

中間體205：1-(2,2,2-三氟乙基)-1H-吡唑-5-甲酸甲酯 Intermediate 205 : methyl 1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxylate

自與針對中間體204所述相同之混合物來製備1-(2,2,2-三氟乙基)-1H-吡唑-5-甲酸甲酯以得到黃色油狀物形式之標題化合物(0.063 g，4%)。方法D HPLC-MS：MH+要求m/z=209實驗值：m/z=209，Rt=1.26 min(96%)。 Methyl 1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxylate was obtained as the title compound (0.063) g, 4%). Method D HPLC-MS: MH+ requires m/z = 209.

中間體206：6-(2,2,2-三氟乙氧基)吡啶-3-甲酸 Intermediate 206 : 6-(2,2,2-trifluoroethoxy)pyridine-3-carboxylic acid

將存於DMSO(50 mL)中之6-氯吡啶-3-甲酸(6.0 g，38.1 mmol)、2,2,2-三氟乙醇(8.2 mL，114.2 mmol)及氫氧化鉀(10.7 g，190.4 mmol)之混合物在120℃下攪拌18 h並在室溫下靜置2天。添加額外之2當量氫氧化鉀及1.5當量2,2,2-三氟乙醇且將反應混合物在120℃下攪拌18 h。使用濃HCl水溶液酸化混合物直至出現奶油色沈澱物為止。藉由過濾收集沈澱物，使用1 N HCl水溶液洗滌，然後溶於EtOAc中，使用1 N HCl水溶液洗滌3次並使用鹽水洗滌3次。藉 由硫酸鈉乾燥有機相，過濾並在真空下濃縮以得到奶油色固體形式之標題化合物(6.9 g，82%)。方法C HPLC-MS：MH+要求m/z=222實驗值：m/z=222，Rt=1.24 min(98%)。 6-chloropyridine-3-carboxylic acid (6.0 g, 38.1 mmol), 2,2,2-trifluoroethanol (8.2 mL, 114.2 mmol) and potassium hydroxide (10.7 g) in DMSO (50 mL) The mixture of 190.4 mmol) was stirred at 120 ° C for 18 h and allowed to stand at room temperature for 2 days. An additional 2 equivalents of potassium hydroxide and 1.5 equivalents of 2,2,2-trifluoroethanol were added and the reaction mixture was stirred at 120 ° C for 18 h. The mixture was acidified using concentrated aqueous HCl until a creamy precipitate appeared. The precipitate was collected by filtration, washed with 1N aqueous HCI, then EtOAc. borrow The organic phase was dried <RTI ID=0.0> Method C HPLC-MS: MH+ requires m/z = 222. Found: m/z = 222, Rt = 1.24 min (98%).

中間體207：6-(3,3,3-三氟丙基)吡啶-3-甲酸 Intermediate 207 : 6-(3,3,3-trifluoropropyl)pyridine-3-carboxylic acid

向存於EtOH(20 mL)中之6-(3,3,3-三氟丙基)吡啶-3甲腈(中間體208，189 mg，0.945 mmol)之溶液中添加氫氧化鉀(265 mg，4.72 mmol)。將溶液在100℃下加熱6 h且然後添加額外氫氧化鉀(53 mg，0.94 mmol)。在105℃下再攪拌3 h之後，將反應混合物冷卻至室溫，蒸發至乾燥並再溶於水(20 mL)中。使用1 M HCl水溶液將溶液酸化至pH 3並使用EtOAc(3×25 mL)萃取。藉由硫酸鎂乾燥合併之有機物並蒸發至乾燥以得到淺褐色固體形式之標題化合物(183 mg，89%)。方法C HPLC-MS：MH+要求m/z=220；實驗值：m/z=220，Rt=1.12 min(91%)。 Add potassium hydroxide (265 mg) to a solution of 6-(3,3,3-trifluoropropyl)pyridine-3-carbonitrile (intermediate 208, 189 mg, 0.945 mmol) in EtOH (20 mL) , 4.72 mmol). The solution was heated at 100 °C for 6 h and then additional potassium hydroxide (53 mg, 0.94 mmol) was added. After stirring at 105 ° C for an additional 3 h, the reaction mixture was cooled to room EtOAc then evaporated to dryness The solution was acidified to pH 3 using 1 M aq. EtOAc and EtOAc (EtOAc) The combined organics were dried with EtOAc EtOAcjjjjjjj Method C HPLC-MS: MH+ requires m/z = 220; found: m/z = 220, Rt = 1.12 min (91%).

中間體208：6-(3,3,3-三氟丙基)吡啶-3甲腈 Intermediate 208 : 6-(3,3,3-trifluoropropyl)pyridine-3-carbonitrile

在-78℃及氮下，向存於無水THF(20 mL)中之6-甲基-菸甲腈(118 mg，1.0 mmol)之溶液中逐滴添加二異丙基胺鋰(存於THF/庚烷/乙基苯中之2 M溶液，550 μL，1.1 mmol)。將所得溶液升溫至室溫保持5 min且然後冷卻回-78℃。然後向溶液中逐滴添加1,1,1-三氟-2-碘-乙烷(524 mg，2.5 mmol)且將反應混合物升溫至室溫並在此溫度下攪拌2 h。在0℃下冷卻反應混合物並使用水驟冷；使用EtOAc(3×25 mL)萃取所得溶液。使用鹽水(25 mL)洗滌合併之有機物，藉由硫酸鎂乾燥並藉由二氧化矽層析(存於 庚烷中之25% EtOAc)純化以得到淺黃色油狀物形式之標題化合物(191 mg，95%)。方法C HPLC-MS：MH+要求m/z=201；實驗值：m/z=201，Rt=1.22 min(86%)。 To a solution of 6-methyl-nicotinic carbonitrile (118 mg, 1.0 mmol) in dry THF (20 mL). 2 M solution in /heptane/ethylbenzene, 550 μL, 1.1 mmol). The resulting solution was warmed to room temperature for 5 min and then cooled back to -78 °C. Then 1,1,1-trifluoro-2-iodo-ethane (524 mg, 2.5 mmol) was added dropwise to the solution and the mixture was warmed to room temperature and stirred at this temperature for 2 h. The reaction mixture was cooled at 0&lt;0&gt;C and quenched with water; EtOAc (3 <RTIgt; The combined organics were washed with brine (25 mL) dried over magnesium sulfate and filtered The title compound (191 mg, 95%) eluted Method C HPLC-MS: MH+ requires m/z = 201; found: m/z = 201, Rt = 1.22 min (86%).

中間體209：6-[(2,2,2-三氟乙基)硫基]吡啶-3-甲酸 Intermediate 209 : 6-[(2,2,2-trifluoroethyl)thio]pyridine-3-carboxylic acid

向存於MeOH(10 mL)中之6-[(2,2,2-三氟乙基)硫基]吡啶-3-甲酸甲酯(中間體210，345 mg，1.37 mmol)之溶液中添加2 M氫氧化鈉水溶液(1.37 mL，2.74 mmol)。將所得反應混合物在室溫下攪拌4 h且然後蒸發至乾燥。將剩餘殘餘物溶於水(20 mL)中，使用1 M HCl水溶液酸化至pH 4.5並使用DCM(3×25 mL)萃取。藉由硫酸鎂乾燥合併之有機物並蒸發至乾燥以得到白色固體形式之標題化合物(300 mg，93%)。方法C HPLC-MS：MH+要求m/z=238；實驗值：m/z=238，Rt=1.35 min(98%)。 Add to a solution of methyl 6-[(2,2,2-trifluoroethyl)thio]pyridine-3-carboxylate (Intermediate 210, 345 mg, 1.37 mmol) in MeOH (10 mL) 2 M aqueous sodium hydroxide (1.37 mL, 2.74 mmol). The resulting reaction mixture was stirred at room temperature for 4 h and then evaporated to dryness. The residue was taken up in water (20 mL)EtOAc. The combined organics were dried with EtOAc EtOAc EtOAc EtOAc Method C HPLC-MS: MH+ requires m/z = 238; found: m/z = 238, Rt = 1.35 min (98%).

中間體210：6-[(2,2,2-三氟乙基)硫基]吡啶-3-甲酸甲酯 Intermediate 210 : Methyl 6-[(2,2,2-trifluoroethyl)thio]pyridine-3-carboxylate

在0℃及氮下，向存於無水THF(40 mL)中之氫化鈉(存於礦物油中之60%分散液，90 mg，2.25 mmol)之溶液中逐滴添加2,2,2-三氟-乙烷硫醇(200 μL,2.25 mmol)。將所得溶液攪拌15 min並在0℃下逐滴添加至存於無水THF(40 mL)中之6-氯-菸酸甲酯(257 mg，1.5 mmol)之溶液中。將反應混合物升溫至室溫並再繼續攪拌3 h。使用水在0℃下將溶液驟冷並萃取至EtOAc(3×50 mL)中。使用鹽水(20 mL)洗滌合併之有機物，藉由硫酸鎂乾燥，蒸發至乾燥並藉由二氧化矽層析(存於庚烷中之25% EtOAc)純化以得到無色油狀物形式之標題化合物(370 mg，98%)。方法C HPLC- MS：MH+要求m/z=252；實驗值：m/z=252，Rt=1.41 min(94%)。 2,2,2- was added dropwise to a solution of sodium hydride (60% dispersion in mineral oil, 90 mg, 2.25 mmol) in anhydrous THF (40 mL) at 0 ° C under nitrogen. Trifluoro-ethanethiol (200 μL, 2.25 mmol). The resulting solution was stirred for 15 min and added dropwise to a solution of &lt;RTI ID=0.0&gt;&gt; The reaction mixture was warmed to room temperature and stirring was continued for additional 3 h. The solution was quenched with water at 0&lt;0&gt;C and extracted into EtOAc (3.times.50 mL). The combined organics were washed with EtOAc (EtOAc (EtOAc) (370 mg, 98%). Method C HPLC- MS: MH+ requires m/z = 252; found: m/z = 252, Rt = 1.41 min (94%).

中間體212：4-(3,3,3-三氟亞丙基)六氫吡啶-1-甲酸第三丁基酯 Intermediate 212 : 4-(3,3,3-trifluoropropylene)hexahydropyridine-1-carboxylic acid tert-butyl ester

在0℃及氮下，向存於THF(20 mL)中之三苯基(3,3,3-三氟丙基)溴化鏻(中間體213，972 mg，2 mmol)之溶液中添加第三丁醇鉀(235 mg，2.1 mmol)。將所得反應混合物在0℃下攪拌15 min且然後添加存於THF(5 mL)中之4-側氧基-六氫吡啶-1-甲酸第三丁基酯(398 mg，2 mmol)之溶液。將溶液在0℃下再攪拌1 h且然後蒸發至乾燥。將所得殘留物溶於EtOAc(25 mL)中並使用水(2×25 mL)洗滌。使用鹽水洗滌合併之有機物，藉由硫酸鎂乾燥並蒸發至乾燥。將粗製固體溶於二乙醚(50 mL)中且然後過濾以去除不溶性雜質。將濾液蒸發至乾燥以得到4-(3,3,3-三氟亞丙基)六氫吡啶-1-甲酸第三丁基酯(中間體212，0.99 g，檢測到三苯基膦雜質)，4-(3,3,3-三氟亞丙基)六氫吡啶-1-甲酸第三丁基酯未經進一步純化即使用。 Add to a solution of triphenyl(3,3,3-trifluoropropyl)phosphonium bromide (intermediate 213, 972 mg, 2 mmol) in THF (20 mL). Potassium tert-butoxide (235 mg, 2.1 mmol). The resulting reaction mixture was stirred at 0&lt;0&gt;C for 15 min then EtOAc (EtOAc &lt . The solution was stirred at 0 ° C for an additional 1 h and then evaporated to dryness. The residue was dissolved in EtOAc (25 mL)EtOAcEtOAc. The combined organics were washed with brine, dried over magnesium sulfate and evaporated to dry. The crude solid was dissolved in diethyl ether (50 mL) and then filtered to remove insoluble impurities. The filtrate was evaporated to dryness to give 4-(3,3,3-trifluoropropyl)hexahydropyridine-l-carboxylic acid tert-butyl ester (intermediate 212, 0.99 g, triphenylphosphine impurity detected) 4-(3,3,3-trifluoropropylene)hexahydropyridine-1-carboxylic acid tert-butyl ester was used without further purification.

中間體213：三苯基(3,3,3-三氟丙基)溴化鏻 Intermediate 213 : Triphenyl (3,3,3-trifluoropropyl)phosphonium bromide

向存於甲苯(20 mL)中之1,1,1-三氟-3-碘-丙烷(3 g，0.0133 mol)之溶液中添加三苯基膦(3.51 g，0.0133 mol)。將所得懸浮液在90℃下加熱28 h且然後冷卻至室溫。將反應混合物蒸發至乾燥並在二乙醚(100 mL)中實施5 min之超音波處理。過濾所得白色沈澱物，使用額外二乙醚洗滌並在真空下乾燥以得到白色結晶固體形式之標題化合物(3.89 g，60%)。方法C HPLC-MS：MH+要求m/z=359(游離鹽)；實驗值：m/z=359，Rt=1.06 min(100%)。 Triphenylphosphine (3.51 g, 0.0133 mol) was added to a solution of 1,1,1-trifluoro-3-iodo-propane (3 g, 0.0133 mol) in toluene (20 mL). The resulting suspension was heated at 90 °C for 28 h and then cooled to room temperature. The reaction mixture was evaporated to dryness and then applied to EtOAc (EtOAc) The resulting white precipitate was filtered, washed with EtOAc EtOAc EtOAc g, 60%). Method C HPLC-MS: MH+ requires m/z = 359 ( free salt); mp.

中間體214：5-(環丙基甲氧基)吡啶-2-甲酸 Intermediate 214 : 5-(cyclopropylmethoxy)pyridine-2-carboxylic acid

將5-(環丙基甲氧基)吡啶-2甲腈(中間體215，0.12 g，0.622 mmol)溶於EtOH(2 mL)中且添加氫氧化鈉(35% w/w)(2 mL)之水溶液。將混合物在90℃下攪拌3 h並在室溫下靜置2天。在真空下去除EtOH。藉由過濾收集所得白色沈澱物，在真空下乾燥且使用甲苯共沸並在高真空下乾燥6 h以得到標題化合物(120 mg，90%)。方法B HPLC-MS：MH+要求m/z=193；實驗值：m/z=193，Rt=1.21 min(98%)。 5-(Cyclopropylmethoxy)pyridine-2-carbonitrile (Intermediate 215, 0.12 g, 0.622 mmol) was dissolved in EtOH (2 mL) and sodium hydroxide (35% w/w) (2 mL) An aqueous solution. The mixture was stirred at 90 ° C for 3 h and allowed to stand at room temperature for 2 days. The EtOH was removed under vacuum. The resulting white precipitate was collected by EtOAcqqqqm Method B HPLC-MS: MH+ requires m/z = 193. Found: m/z = 193, Rt = 1.21 min (98%).

中間體215：5-(環丙基甲氧基)吡啶-2甲腈 Intermediate 215 : 5-(cyclopropylmethoxy)pyridine-2carbonitrile

在室溫下，將環丙基甲醇(0.120 mL，1.504 mmol)添加至存於DMF(4 mL)中之氫化鈉(60%，存於礦物油中)(0.072 g，1.805 mmol)之懸浮液中。將混合物在室溫下攪拌30 min，添加4-氯苯甲腈(0.139 g，1.002 mmol)。將反應混合物在室溫下攪拌18 h。使用水稀釋混合物並使用EtOAc(3次)萃取。合併有機萃取物，使用水(2次)、鹽水(2次)洗滌，乾燥並在真空下蒸發。藉由急驟層析(己烷：EtOAc，9：1至85：15)純化粗製殘餘物以得到標題化合物(0.120 g，69%)。方法B HPLC-MS：MH+要求m/z=175；實驗值：m/z=175，Rt=1.73 min(100%)。 Add cyclopropylmethanol (0.120 mL, 1.504 mmol) to a suspension of sodium hydride (60% in mineral oil) (0.072 g, 1.805 mmol) in DMF (4 mL) in. The mixture was stirred at room temperature for 30 min and 4-chlorobenzonitrile (0.139 g, 1. The reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were washed with water (2x), brine (2), dried and evaporated. The crude residue was purified by EtOAc EtOAcjjjjj Method B HPLC-MS: MH+ requires m/z = 175; found: m/z = 175, Rt = 1.73 min (100%).

中間體216：6-乙氧基吡啶-3-甲酸 Intermediate 216 : 6-ethoxypyridine-3-carboxylic acid

在室溫下，將氫氧化鉀粉末(0.373 g，12.005 mmol)及EtOH(0.3 mL，6.002 mmol)添加至存於DMSO(12 mL)中 之6-氯吡啶-3-甲酸(0.473 g，3.001 mmol)之溶液中。將反應混合物在100℃下加熱21 h，並冷卻至室溫。添加1 M HCl水溶液。藉由過濾收集所得沈澱物，使用水洗滌並在真空下乾燥以得到標題化合物(356 mg，71%)。方法B HPLC-MS：MH+要求m/z=168；實驗值：m/z=168，Rt=1.50 min(95%)。 Potassium hydroxide powder (0.373 g, 12.005 mmol) and EtOH (0.3 mL, 6.002 mmol) were added to DMSO (12 mL) at room temperature A solution of 6-chloropyridine-3-carboxylic acid (0.473 g, 3.001 mmol). The reaction mixture was heated at 100 ° C for 21 h and cooled to room temperature. Add 1 M aqueous HCl solution. The resulting precipitate was collected by EtOAcqqq elut elut elut Method B HPLC-MS: MH+ requires m/z = 168. Found: m/z = 168, Rt = 1.50 min (95%).

以與中間體216類似之方式來製備下列烷氧基吡啶。 The following alkoxypyridines were prepared in a similar manner to intermediate 216.

中間體222：5-(2,2,2-三氟乙氧基)吡啶-2-甲酸 Intermediate 222 : 5-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid

將5-(2,2,2-三氟乙氧基)吡啶-2-甲酸甲酯(中間體223，0.650 g，2.77 mmol)溶於MeOH(10 mL)中，添加2 M氫氧化鈉水溶液(3.46 mL，6.93 mmol)並將混合物在室溫下攪拌2 h。在真空下去除MeOH並藉由添加2 M鹽酸水溶液(3.5 mL)來中和水性懸浮液。過濾所得沈澱物，使用二乙醚洗滌並在真空下乾燥以得到白色固體形式之標題化合物(0.179 mg，29%)。1H NMR(500MHZ,MeOH-d4)δ ppm 8.41(1H,d),8.15(1H,d),7.59(1H,dd)及4.77(2H,q)。 Methyl 5-(2,2,2-trifluoroethoxy)pyridine-2-carboxylate (Intermediate 223, 0.650 g, 2.77 mmol) was dissolved in MeOH (10 mL). (3.46 mL, 6.93 mmol) and the mixture was stirred at room temperature for 2 h. The MeOH was removed under vacuum and the aqueous suspension was neutralized by adding 2 M aqueous hydrochloric acid (3.5 mL). The resulting precipitate was filtered, washed with EtOAcjjjjjjjj 1H NMR (500 MHZ, MeOH-d4) δ δ </ RTI> 8.41 (1H, d), 8.15 (1H, d), 7.59 (1H, dd) and 4.77 (2H, q).

中間體223：5-(2,2,2-三氟乙氧基)吡啶-2-甲酸甲酯 Intermediate 223 : methyl 5-(2,2,2-trifluoroethoxy)pyridine-2-carboxylate

將5-羥基吡啶-2-甲酸甲酯(中間體224，0.610 g，3.59 mmol)溶於DMF(5 mL)中，添加碳酸銫(1.40 g，4.31 mmol)及三氟甲烷磺酸2,2,2-三氟乙基酯(1.0 g，4.31 mmol)並將混合物在室溫下攪拌18 h。將混合物分配於EtOAc(50 mL)與水(15 mL)之間並使用額外EtOAc(2×20 mL)萃取水層。藉由硫酸鈉乾燥合併之有機層並在真空下濃縮。藉由FCC(使用存於庚烷中之0-50% EtOAc之梯度洗脫)純化粗製材料以得到白色固體形式之標題化合物(0.652 g，77%)。1H NMR(500MHZ,CDCl3)δ ppm 8.40(1H,d),8.09(1H,d),7.27(1H,dd),4.41(2H,q)及3.93(3H,s)。 Methyl 5-hydroxypyridine-2-carboxylate (Intermediate 224, 0.610 g, 3.59 mmol) was dissolved in DMF (5 mL). 2-Trifluoroethyl ester (1.0 g, 4.31 mmol) and the mixture was stirred at room temperature for 18 h. The mixture was partitioned between EtOAc (50 mL)EtOAc. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude material was purified by EtOAc EtOAcjjjjjjj 1H NMR (500MHZ, CDCl 3) δ ppm 8.40 (1H, d), 8.09 (1H, d), 7.27 (1H, dd), 4.41 (2H, q) and 3.93 (3H, s).

中間體224：5-羥基吡啶-2-甲酸甲酯 Intermediate 224 : Methyl 5-hydroxypyridine-2-carboxylate

將6-羥基吡啶甲酸(0.500 g，3.59 mmol)溶於MeOH(20 mL)中並在氮下冷卻至0℃。逐滴添加亞硫醯氯(0.651 mL，8.98 mmol)，將混合物升溫至室溫並攪拌2 h。TLC表明並無反應，因此添加額外亞硫醯氯(0.781 mL，10.77 mmol)並將混合物加熱至75℃保持8 h。在真空下濃縮混合物以得到白色固體形式之標題化合物(0.685 g)，該標題化合物未經進一步純化即用於下一步驟中。NMR展示約25%之未反應之5-羥基吡啶甲酸。1H NMR(500MHZ,MeOH-d4)δ ppm 8.44(1H,d),8.39(1H,d),8.02(1H,dd)及4.09(3H,s)。 6-Hydroxypicolinic acid (0.500 g, 3.59 mmol) was dissolved in MeOH (20 mL) and cooled to EtOAc. Thionite chloride (0.651 mL, 8.98 mmol) was added dropwise, the mixture was warmed to room temperature and stirred for 2 h. TLC showed no reaction, so additional sulfinium chloride (0.781 mL, 10.77 mmol) was added and the mixture was heated to 75 ° C for 8 h. The mixture was concentrated under EtOAc EtOAc EtOAc. NMR showed about 25% unreacted 5-hydroxypicolinic acid. 1H NMR (500 MHZ, MeOH-d4) δ </ RTI> </ RTI> </ RTI> 8.44 (1H, d), 8.39 (1H, d), 8.02 (1H, dd) and 4.09 (3H, s).

中間體225：5-[(2,2,2-三氟乙氧基)甲基]吡啶-2-甲酸 Intermediate 225 : 5-[(2,2,2-trifluoroethoxy)methyl]pyridine-2-carboxylic acid

將粉末狀氫氧化鉀(0.331 g，5.90 mmol)溶於EtOH(2 mL)中並添加至5-[(2,2,2-三氟乙氧基)甲基]吡啶-2甲腈(中 間體226，0.255 g，1.18 mmol)中。將混合物加熱至110℃保持16 h。在冷卻之後，將殘餘物溶於水(3 mL)中，藉由添加10%鹽酸水溶液酸化至pH 1並使用EtOAc(3×20 mL)萃取。藉由硫酸鈉乾燥合併之有機層並濃縮以得到褐色膠形式之標題化合物(0.252 g，91%)，該標題化合物未經進一步純化即用於下一步驟中。方法C HPLC-MS：MH+要求m/z=236實驗值：m/z=236，Rt=0.83 min(82%)。 Powdered potassium hydroxide (0.331 g, 5.90 mmol) was dissolved in EtOH (2 mL) and added to 5-[(2,2,2-trifluoroethoxy)methyl]pyridine-2carbonitrile Interstitial 226, 0.255 g, 1.18 mmol). The mixture was heated to 110 ° C for 16 h. After cooling, the residue was taken-up~~~~~~~~~~~~~~~~~~~~~~ The combined organic layer was dried with EtOAc EtOAcjjjjjjjjj Method C HPLC-MS: MH+ requires m/z = 236. Found: m/z = 236.

中間體226：5-[(2,2,2-三氟乙氧基)甲基]吡啶-2甲腈 Intermediate 226 : 5-[(2,2,2-trifluoroethoxy)methyl]pyridine-2carbonitrile

將2-氯-5-[(2,2,2-三氟乙氧基)甲基]吡啶(中間體227，0.537 g，2.38 mmol)溶於DMF(6 mL)中且添加氰化鋅(0.279 g，2.38 mmol)。藉由在氮流下攪拌10 min來將混合物脫氣。添加四(三苯基膦)鈀(0)(0.275 g，0.24 mmol)及額外DMF(2 mL)並將混合物在密封管中加熱至100℃保持6 h。將混合物分配於EtOAc(50 mL)與水(50 mL)之間並使用額外水(2×50 mL)洗滌有機層。藉由硫酸鈉乾燥有機層並濃縮以得到橙色油狀物。藉由FCC(使用存於庚烷中之0-30% EtOAc之梯度洗脫)純化以得到無色油狀物形式之標題化合物(0.255 g，50%)。1H NMR(500MHZ,CDCl3)δ ppm 8.62(1H,d),7.79(1H,dd),7.66(1H,d),4.72(2H,s)及3.89(2H,q)。 2-Chloro-5-[(2,2,2-trifluoroethoxy)methyl]pyridine (Intermediate 227, 0.537 g, 2.38 mmol) was dissolved in DMF (6 mL) and zinc cyanide was added ( 0.279 g, 2.38 mmol). The mixture was degassed by stirring for 10 min under a stream of nitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.275 g, 0.24 mmol) and additional DMF (2 mL) were added and the mixture was heated to 100 ° C in a sealed tube for 6 h. The mixture was partitioned between EtOAc (50 mL) and water (EtOAc) The organic layer was dried over sodium sulfate and concentrated to give an orange oil. The title compound (0.255 g, 50%) eluted elut elut elut elut elut elut 1H NMR (500MHZ, CDCl 3) δ ppm 8.62 (1H, d), 7.79 (1H, dd), 7.66 (1H, d), 4.72 (2H, s) and 3.89 (2H, q).

中間體227：2-氯-5-[(2,2,2-三氟乙氧基)甲基]吡啶 Intermediate 227 : 2-chloro-5-[(2,2,2-trifluoroethoxy)methyl]pyridine

將(6-氯吡啶-3-基)甲醇(1.0 g，6.97 mmol)溶於THF(20 mL)中，添加第三丁醇鉀(0.860 g，7.66 mmol)並在室溫下攪拌混合物。在冰冷卻下逐滴添加三氟甲烷磺酸2,2,2-三 氟乙基酯(1.78 g，7.66 mmol)且然後將混合物在室溫下攪拌2 h。添加EtOAc(50 mL)及水(50 mL)，分離有機層並將水層中和至pH 6。然後使用EtOAc(3×20 mL)進一步萃取水層，藉由硫酸鈉乾燥合併之有機層並濃縮以得到黃色固體。藉由FCC(使用存於庚烷中之0-50% EtOAc之梯度洗脫)純化以得到無色油狀物形式之標題化合物(0.537 g，34%)。1H NMR(500MHZ,CDCl3)δ ppm 8.30(1H,d),7.61(1H,dd),7.30(1H,d),4.61(2H,s)及3.82(2H,q)。 (6-Chloropyridin-3-yl)methanol (1.0 g, 6.97 mmol) was dissolved in THF (20 mL). 2,2,2-Trifluoroethyl trifluoromethanesulfonate (1.78 g, 7.66 mmol) was added dropwise with ice-cooling and then the mixture was stirred at room temperature for 2 h. EtOAc (50 mL) and water (50 mL) were evaporated. The aqueous layer was further extracted with EtOAc (3×20 mL)EtOAc. Purification by FCC (EtOAc EtOAc (EtOAc) 1H NMR (500MHZ, CDCl 3) δ ppm 8.30 (1H, d), 7.61 (1H, dd), 7.30 (1H, d), 4.61 (2H, s) and 3.82 (2H, q).

中間體228：6-(環己基氧基)吡啶-3-甲酸 Intermediate 228 : 6-(cyclohexyloxy)pyridine-3-carboxylic acid

將6-氯菸酸(0.500 g，3.17 mmol)、粉末狀氫氧化鉀(0.712 g，12.69 mmol)及環己醇(0.636 g，6.35 mmol)在DMSO(12 mL)中合併並在密封管中加熱至100℃保持18 h且然後加熱至120℃保持21 h。藉由添加2 M鹽酸將混合物酸化至pH 1。然後將混合物在室溫下靜置過夜並過濾掉所得沈澱物，使用水洗滌並在真空下乾燥以得到奶油色固體形式之標題化合物(0.389 g，55%)。1H NMR(500MHZ,MeOH-d4)δ ppm 8.76(1H,d),8.19(1H,dd),6.79(1H,d),5.11(1H,m),2.03(2H,m),1.83(2H,m),1.64(1H,m),1.56(2H,m),1.47(2H,m)及1.38(1H,m)。 6-chloronicotinic acid (0.500 g, 3.17 mmol), powdered potassium hydroxide (0.712 g, 12.69 mmol) and cyclohexanol (0.636 g, 6.35 mmol) were combined in DMSO (12 mL) and placed in a sealed tube Heat to 100 ° C for 18 h and then heat to 120 ° C for 21 h. The mixture was acidified to pH 1 by the addition of 2 M hydrochloric acid. The mixture was then allowed to stand at room temperature overnight, and the obtained residue was filtered, washed with water and evaporated to give the title compound (0.389 g, 55%). 1H NMR (500 MHZ, MeOH-d4) δ δ 8.76 (1H, d), 8.19 (1H, dd), 6.79 (1H, d), 5.11 (1H, m), 2.03 (2H, m), 1.83 (2H, m), 1.64 (1H, m), 1.56 (2H, m), 1.47 (2H, m) and 1.38 (1H, m).

中間體229：6-[(1,1,1-三氟丙烷-2-基)氧基]吡啶-3-甲酸 Intermediate 229 : 6-[(1,1,1-Trifluoropropan-2-yl)oxy]pyridine-3-carboxylic acid

將6-氯菸酸(0.500 g，3.17 mmol)、粉末狀氫氧化鉀(0.712 g，12.69 mmol)及1,1,1-三氟丙烷-2-醇(0.724 g，6.35 mmol)在DMSO(12 mL)中合併並在密封管中加熱至100℃保持18 h。藉由添加2 M鹽酸將混合物酸化至pH 1。 然後將混合物在室溫下靜置過夜並過濾掉所得沈澱物，使用水洗滌並在真空下乾燥以得到奶油色固體形式之標題化合物(0.527 g，71%)。1H NMR(500MHZ,MeOH-d4)δ ppm 8.82(1H,d),8.29(1H,dd),6.94(1H,d),5.96(1H,m)及1.52(3H,d)。 6-chloronicotinic acid (0.500 g, 3.17 mmol), powdered potassium hydroxide (0.712 g, 12.69 mmol) and 1,1,1-trifluoropropan-2-ol (0.724 g, 6.35 mmol) in DMSO ( Combined in 12 mL) and heated to 100 ° C in a sealed tube for 18 h. The mixture was acidified to pH 1 by the addition of 2 M hydrochloric acid. After the mixture was allowed to stand at room temperature overnight, the obtained residue was filtered, washed with water and evaporated 1H NMR (500 MHZ, MeOH-d4) δ δ δ 8.82 (1H, d), 8.29 (1H, dd), 6.94 (1H, d), 5.96 (1H, m) and 1.52 (3H, d).

中間體230：6-(3,3,3-三氟丙氧基)吡啶-3-甲酸 Intermediate 230 : 6-(3,3,3-trifluoropropoxy)pyridine-3-carboxylic acid

將6-(3,3,3-三氟丙氧基)吡啶-3-甲酸甲酯(中間體231，0.240 g，0.91 mmol)溶於EtOH(7.5 mL)中且添加2 M氫氧化鈉水溶液(1.37 mL，2.74 mmol)。將混合物在室溫下攪拌3 h。然後將混合物濃縮至最小體積並藉由添加2 M鹽酸進行酸化。使用DCM萃取混合物，分離有機層並在真空下濃縮以得到白色固體形式之標題化合物(0.102 g，48%)。1H NMR(250MHZ,MeOH-d4)δ ppm 8.76(1H,d),8.20(1H,dd),6.80(1H,d),4.61(2H,t)及2.71(2H,m)。 Methyl 6-(3,3,3-trifluoropropoxy)pyridine-3-carboxylate (Intermediate 231, 0.240 g, 0.91 mmol) was dissolved in EtOH (7.5 mL). (1.37 mL, 2.74 mmol). The mixture was stirred at room temperature for 3 h. The mixture was then concentrated to a minimum volume and acidified by the addition of 2 M hydrochloric acid. The mixture was extracted with EtOAc (EtOAc m. 1H NMR (250 MHZ, MeOH-d4) δ δ </ RTI> </ RTI> 8.76 (1H, d), 8.20 (1H, dd), 6.80 (1H, d), 4.61 (2H, t) and 2.71 (2H, m).

中間體231：6-(3,3,3-三氟丙氧基)吡啶-3-甲酸乙酯 Intermediate 231 : ethyl 6-(3,3,3-trifluoropropoxy)pyridine-3-carboxylate

將3,3,3-三氟丙醇(0.338 g，2.96 mmol)溶於THF(5 mL)中並在氮下冷卻至0℃。添加第三丁醇鉀(0.332 g，2.96 mmol)並將混合物攪拌5 min。添加6-氯菸酸乙酯(0.500 g，2.69 mmol)，將混合物升溫至室溫並攪拌3 h。添加鹽水(10 mL)並使用EtOAc(3×10 mL)萃取混合物。藉由硫酸鈉乾燥合併之有機層並濃縮以得到黃色油狀物。藉由FCC(使用存於庚烷中之0-10% EtOAc之梯度洗脫)純化以得到無色油狀物形式之標題化合物(0.240 g，34%)，該標題化合物未經進一步純化即用於下一步驟中。NMR展示約 15%之未反應之6-氯菸酸乙酯。1H NMR(500MHZ,MeOH-d4)δ ppm 8.75(1H,d),8.11(1H,dd),6.71(1H,d),4.55(2H,t),4.31(2H,q),2.57(2H,m)及1.33(3H,t)。 3,3,3-Trifluoropropanol (0.338 g, 2.96 mmol) was dissolved in THF (5 mL) and cooled to EtOAc. Potassium tert-butoxide (0.332 g, 2.96 mmol) was added and the mixture was stirred for 5 min. Ethyl 6-chloronicotinate (0.500 g, 2.69 mmol) was added and the mixture was warmed to room temperature and stirred for 3 h. Brine (10 mL) was added and the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were dried with sodium sulfate and evaporated Purification by FCC (EtOAc EtOAc (EtOAc) In the next step. NMR display 15% unreacted ethyl 6-chloronicotinate. 1H NMR (500 MHZ, MeOH-d4) δ ppm 8.75 (1H, d), 8.11 (1H, dd), 6.71 (1H, d), 4.55 (2H, t), 4.31 (2H, q), 2.57 (2H, m) and 1.33 (3H, t).

中間體234：4-羥基-4-苯基六氫吡啶-1-甲酸第三丁基酯 Intermediate 234 : 4-Hydroxy-4-phenylhexahydropyridine-1-carboxylic acid tert-butyl ester

將4-羥基-4-苯基六氫吡啶(1.0 g，5.64 mmol)及二碳酸二-第三丁基酯(1.35 g，6.21 mmol)在DCM(30 mL)中合併並在室溫下攪拌3 h。使用DCM(100 mL)稀釋混合物並使用碳酸氫鈉飽和水溶液(3×30 mL)洗滌。藉由硫酸鈉乾燥有機層並濃縮以得到淺黃色油狀物形式之標題化合物(1.759 g)，該標題化合物未經進一步純化即用於下一步驟中。1H NMR(500MHZ,CDCl3)：7.50(2H,d),7.40(2H,t),7.31(1H,t),4.06(2H,br s),3.27(2H,br s),2.03(2H,br s),1.73(2H,d)及1.51(9H,s)。 4-Hydroxy-4-phenylhexahydropyridine (1.0 g, 5.64 mmol) and di-tert-butyl dicarbonate (1.35 g, 6.21 mmol) were combined in DCM (30 mL) 3 h. The mixture was diluted with DCM (100 mL) and washed with aq. The org. br. 1H NMR (500MHZ, CDCl 3) : 7.50 (2H, d), 7.40 (2H, t), 7.31 (1H, t), 4.06 (2H, br s), 3.27 (2H, br s), 2.03 (2H, Br s), 1.73 (2H, d) and 1.51 (9H, s).

中間體235：6-(環氧乙烷-4-基氧基)吡啶-3-甲酸 Intermediate 235 : 6-(oxiran-4-yloxy)pyridine-3-carboxylic acid

將6-(環氧乙烷-4-基氧基)吡啶-3-甲酸乙酯(中間體236，0.239 g，0.95 mmol)溶於EtOH(5 mL)中，添加2 M氫氧化鈉水溶液(1.43 mL，2.85 mmol)且將混合物在室溫下攪拌4 h。在真空下濃縮混合物並藉由添加2 M鹽酸水溶液將殘餘物酸化至pH 6。然後使用DCM萃取混合物，隨後使用氯仿/異丙醇萃取。使用疏水性玻璃料分離有機層並在真空下濃縮以得到白色固體形式之標題化合物(0.162 g，47%)，該標題化合物未經進一步純化即直接用於下一步驟中。方法C HPLC-MS：MH+要求m/z=224實驗值：m/z=224，Rt=1.06 min(91%)。 Ethyl 6-(oxirane-4-yloxy)pyridine-3-carboxylate (Intermediate 236, 0.239 g, 0.95 mmol) was dissolved in EtOH (5 mL). 1.43 mL, 2.85 mmol) and the mixture was stirred at room temperature for 4 h. The mixture was concentrated under vacuum and the residue was acidified to pH 6 with 2M aqueous hydrochloric acid. The mixture was then extracted using DCM followed by extraction with chloroform / isopropyl alcohol. The organic layer was separated with EtOAc EtOAc m. Method C HPLC-MS: MH+ requires m/z = 224. Found: m/z = 224, Rt = 1.06 min (91%).

中間體236：6-(環氧乙烷-4-基氧基)吡啶-3-甲酸乙酯 Intermediate 236 : Ethyl 6-(oxirane-4-yloxy)pyridine-3-carboxylate

將環氧乙烷-4-醇(0.302 g，2.96 mmol)溶於THF(5 mL)中並在氮下冷卻至0℃。添加第三丁醇鉀(0.332 g，2.96 mmol)並將混合物攪拌5 min。添加6-氯菸酸乙酯(0.500 g，2.69 mmol)，將混合物升溫至室溫並攪拌3 h。添加水(5 mL)並使用EtOAc(2×10 mL)萃取混合物。藉由硫酸鈉乾燥有機層並在真空下濃縮。藉由FCC(使用存於庚烷中之5-20% EtOAc之梯度洗脫)純化殘餘物以得到無色油狀物形式之標題化合物(0.239 g，35%)。1H NMR(250MHZ,CDCl3)δ ppm 8.80(1H,dd),8.14(1H,m),6.73(1H,dd),5.25(1H,m),4.39(2H,dq),3.96(2H,m),3.60(2H,m),2.05(2H,m),1.81(2H,m)及1.40(3H,dt)。 Ethylene oxide-4-ol (0.302 g, 2.96 mmol) was dissolved in THF (5 mL) and cooled to EtOAc. Potassium tert-butoxide (0.332 g, 2.96 mmol) was added and the mixture was stirred for 5 min. Ethyl 6-chloronicotinate (0.500 g, 2.69 mmol) was added and the mixture was warmed to room temperature and stirred for 3 h. Water (5 mL) was added and the mixture was extracted with EtOAc (2×10 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified with EtOAc EtOAcjjjjjj 1H NMR (250MHZ, CDCl 3) δ ppm 8.80 (1H, dd), 8.14 (1H, m), 6.73 (1H, dd), 5.25 (1H, m), 4.39 (2H, dq), 3.96 (2H, m ), 3.60 (2H, m), 2.05 (2H, m), 1.81 (2H, m) and 1.40 (3H, dt).

中間體238：4-[(2,2,2-三氟乙基)硫基]六氫吡啶-1-甲酸第三丁基酯 Intermediate 238 : 4-[(2,2,2-trifluoroethyl)thio]hexahydropyridine-1-carboxylic acid tert-butyl ester

將2,2,2-三氟乙醇(0.133 mL，1.49 mmol)溶於DMF中並在氮下冷卻至0℃。添加氫化鈉(存於礦物油中之60%分散液，0.060 g，1.49 mmol)並將混合物攪拌10 min。添加4-(甲烷磺醯基氧基)六氫吡啶-1-甲酸第三丁基酯(中間體239，0.320 g，1.15 mmol)且將混合物在室溫下攪拌18 h。然後使用EtOAc(30 mL)稀釋混合物並使用水(10 mL)洗滌，隨後使用碳酸氫鈉飽和水溶液(10 mL)及鹽水(10 mL)洗滌。藉由硫酸鈉乾燥有機層並在真空下濃縮以得到淺黃色油狀物。藉由FCC(使用存於庚烷中之0-20% EtOAc之梯度洗脫)純化以得到無色油狀物形式之標題化合物(0.197 g，57%)。1H NMR(500MHZ,CDCl3)δ ppm 4.02(2H,br s),3.14(2H,q),2.98(3H,m),1.97(2H,d),1.52(2H,m)及1.48(9H,s)。 2,2,2-Trifluoroethanol (0.133 mL, 1.49 mmol) was dissolved in DMF and cooled to 0 ° C under nitrogen. Sodium hydride (60% dispersion in mineral oil, 0.060 g, 1.49 mmol) was added and the mixture was stirred for 10 min. 4-(Methanesulfonyloxy)hexahydropyridine-1-carboxylic acid tert-butyl ester (Intermediate 239, 0.320 g, 1.15 mmol) was added and the mixture was stirred at room temperature for 18 h. The mixture was then diluted with EtOAc (30 mL) and washed with water (10 mL) and then brine. The organic layer was dried with sodium sulfate and evaporated Purification by FCC (EtOAc EtOAc (EtOAc) 1H NMR (500MHZ, CDCl 3) δ ppm 4.02 (2H, br s), 3.14 (2H, q), 2.98 (3H, m), 1.97 (2H, d), 1.52 (2H, m) and 1.48 (9H, s).

中間體240：6-[(1-甲基吡咯啶-3-基)氧基]吡啶-3-甲酸 Intermediate 240 : 6-[(1-Methylpyrrolidin-3-yl)oxy]pyridine-3-carboxylic acid

將6-[(1-甲基吡咯啶-3-基)氧基]吡啶-3-甲酸乙酯(中間體241，0.089 g，0.36 mmol)溶於EtOH(2 mL)中，添加2 M氫氧化鈉水溶液(0.53 mL，1.07 mmol)且將混合物在室溫下攪拌4 h。在真空下濃縮混合物並藉由添加2 M鹽酸將殘餘物酸化至pH 6。然後濃縮混合物並在真空下乾燥以得到奶油色固體形式之標題化合物(0.136 g)，該標題化合物未經進一步純化即直接用於下一步驟中。方法C HPLC-MS：MH+要求m/z=223實驗值：m/z=223，Rt=0.38 min(17%，藉由ELS)。 Ethyl 6-[(1-methylpyrrolidin-3-yl)oxy]pyridine-3-carboxylate (Intermediate 241, 0.089 g, 0.36 mmol) was dissolved in EtOH (2 mL). A solution of sodium sulphate (0.53 mL, 1.07 mmol) and mixture was stirred at room temperature for 4 h. The mixture was concentrated under vacuum and the residue was acidified to pH 6 with 2M hydrochloric acid. The mixture was then concentrated and dried <RTI ID=0.0> Method C HPLC-MS: MH+ requires m/z = 223: m/z = 223, Rt = 0.38 min (17% by ELS).

中間體241：6-[(1-甲基吡咯啶-3-基)氧基]吡啶-3-甲酸乙酯 Intermediate 241 : Ethyl 6-[(1-methylpyrrolidin-3-yl)oxy]pyridine-3-carboxylate

根據針對中間體236所述之方法自1-甲基吡咯啶-3-醇(0.161 g，1.59 mmol)及6-氯菸酸乙酯(0.269 g，1.45 mmol)來製備6-[(1-甲基吡咯啶-3-基)氧基]吡啶-3-甲酸乙酯。藉由FCC(使用存於EtOAc中之0-20% MeOH之梯度洗脫)純化粗製材料以得到無色油狀物形式之標題化合物(0.089 g，25%)。1H NMR(250MHZ,CDCl3)δ ppm 8.82(1H,m),8.13(1H,dt),6.74(1H,m),5.43(1H,m),4.39(2H,dq),2.82(3H,m),2.40(3H,s),2.39(2H,m),2.04(1H,m)及1.40(3H,dt)。 6-[(1-) was prepared from 1-methylpyrrolidin-3-ol (0.161 g, 1.59 mmol) and ethyl 6-chloronicotinate (0.269 g, 1.45 mmol) according to the procedure described for intermediate 236. Ethyl methyl pyrrolidin-3-yl)oxy]pyridine-3-carboxylate. The crude material was purified with EtOAc EtOAcjjjjjj 1H NMR (250MHZ, CDCl 3) δ ppm 8.82 (1H, m), 8.13 (1H, dt), 6.74 (1H, m), 5.43 (1H, m), 4.39 (2H, dq), 2.82 (3H, m ), 2.40 (3H, s), 2.39 (2H, m), 2.04 (1H, m) and 1.40 (3H, dt).

中間體242：6-[2-(2,2,2-三氟乙氧基)乙氧基]吡啶-3-甲酸 Intermediate 242 : 6-[2-(2,2,2-trifluoroethoxy)ethoxy]pyridine-3-carboxylic acid

將6-[2-(2,2,2-三氟乙氧基)乙氧基]吡啶-3-甲酸甲酯(中間體243，0.453 g，1.62 mmol)溶於MeOH(5 mL)中，添加2 M氫氧化鈉水溶液(1.62 mL，3.24 mmol)且將混合物在室溫下攪拌1 h。然後在真空下濃縮混合物並使用2 M鹽酸酸化。過濾掉所得沈澱物並在真空下乾燥以得到白色固體形式之標題化合物(0.245 g，57%)。1H NMR(500MHZ,MeOH-d4)δ ppm 8.79(1H,d),8.23(1H,dd),6.90(1H,d),4.55(2H,dd),4.03(2H,q)及4.01(2H,dd)。 Methyl 6-[2-(2,2,2-trifluoroethoxy)ethoxy]pyridine-3-carboxylate (Intermediate 243, 0.45 g, 1.62 mmol) 2 M aqueous sodium hydroxide (1.62 mL, 3.24 mmol) was added and the mixture was stirred at room temperature for 1 h. The mixture was then concentrated under vacuum and acidified using 2M hydrochloric acid. The resulting precipitate was filtered and dried <jjjjjjjjj 1H NMR (500MHZ, MeOH-d4) δ ppm 8.79 (1H, d), 8.23 (1H, dd), 6.90 (1H, d), 4.55 (2H, dd), 4.03 (2H, q) and 4.01 (2H, Dd).

中間體243：6-[2-(2,2,2-三氟乙氧基)乙氧基]吡啶-3-甲酸甲酯 Intermediate 243 : Methyl 6-[2-(2,2,2-trifluoroethoxy)ethoxy]pyridine-3-carboxylate

將2-(2,2,2-三氟乙氧基)乙醇(0.462 g，3.21 mmol)溶於THF(5 mL)中並冷卻至0℃。添加第三丁醇鉀(0.360 g，3.21 mmol)，將混合物攪拌5 min且添加6-氯菸酸甲酯(0.500 g，2.91 mmol)。將混合物升溫至室溫並攪拌3 h。添加鹽水(10 mL)且使用EtOAc(3×20 mL)萃取混合物。藉由硫酸鈉乾燥合併之有機層並濃縮以得到黃色油狀物，藉由FCC純化以得到無色油狀物形式之標題化合物(0.453 g，56%)。1H NMR(500MHZ,CDCl3)δ ppm 8.73(1H,d),8.10(1H,dd),6.74(1H,d),4.50(2H,t),3.93(2H,t),3.87(2H,q)及3.84(3H,s)。 2-(2,2,2-Trifluoroethoxy)ethanol (0.462 g, 3.21 mmol) was dissolved in THF (5 mL) and cooled to EtOAc. Potassium tert-butoxide (0.360 g, 3.21 mmol) was added, the mixture was stirred for 5 min and methyl 6-chloronicotinate (0.500 g, 2.91 mmol). The mixture was warmed to room temperature and stirred for 3 h. Brine (10 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined organics were dried with EtOAc EtOAcjjjjjjjj 1H NMR (500MHZ, CDCl 3) δ ppm 8.73 (1H, d), 8.10 (1H, dd), 6.74 (1H, d), 4.50 (2H, t), 3.93 (2H, t), 3.87 (2H, q ) and 3.84 (3H, s).

中間體245：4-(丙烷-2-基硫基)六氫吡啶-1-甲酸第三丁基酯 Intermediate 245 : 4-(propan-2-ylthio)hexahydropyridine-1-carboxylic acid tert-butyl ester

將4-(甲烷磺醯基氧基)六氫吡啶-1-甲酸第三丁基酯(中間體239，0.320 g，1.15 mmol)及2-丙烷硫醇鈉(0.147 g，1.50 mmol)在DMF(3 mL)中合併並在室溫下攪拌18 h。然 後使用EtOAc(30 mL)稀釋混合物並使用水(3×10 mL)洗滌。藉由硫酸鈉乾燥有機層並濃縮以得到黃色油狀物。藉由FCC(使用存於庚烷中之0-20% EtOAc之梯度洗脫)純化以得到無色油狀物形式之標題化合物(0.179 g，60%)。1H NMR(500MHZ,CDCl3)δ ppm 3.88(2H,br s),2.94(1H,m),2.86(2H,m),2.77(1H,m),1.83(2H,d),1.42(2H,m),1.38(9H,s)及1.20(6H,d)。 4-(Methanesulfonyloxy)hexahydropyridine-1-carboxylic acid tert-butyl ester (Intermediate 239, 0.320 g, 1.15 mmol) and 2-propanethiol sodium (0.147 g, 1.50 mmol) in DMF (3 mL) was combined and stirred at room temperature for 18 h. The mixture was then diluted with EtOAc (30 mL) and washed with water (3.times.10 mL). The organic layer was dried with sodium sulfate and concentrated to give a yellow oil. Purification by FCC (EtOAc EtOAc (EtOAc) 1H NMR (500MHZ, CDCl 3) δ ppm 3.88 (2H, br s), 2.94 (1H, m), 2.86 (2H, m), 2.77 (1H, m), 1.83 (2H, d), 1.42 (2H, m), 1.38 (9H, s) and 1.20 (6H, d).

中間體247：4-(丙烷-2-亞磺醯基)六氫吡啶-1-甲酸第三丁基酯 Intermediate 247 : 4-(propane-2-sulfinyl) hexahydropyridine-1-carboxylic acid tert-butyl ester

將4-(丙烷-2-基硫基)六氫吡啶-1-甲酸第三丁基酯(以與中間體245類似之方式製得，0.160 g，0.62 mmol)溶於DCM(3 mL)中並冷卻至0℃。添加間氯過苯甲酸(0.138 g，0.62 mmol)，將混合物升溫至室溫並攪拌17 h。添加額外間氯過苯甲酸(0.040 g，0.18 mmol)且將混合物在室溫下攪拌3 h。然後使用DCM(10 mL)稀釋混合物並使用硫代硫酸鈉飽和水溶液(10 mL)洗滌。分離有機層並藉由FCC(使用存於庚烷中之50-100% EtOAc洗脫，隨後使用存於EtOAc中之10% MeOH洗脫)純化以得到無色油狀物形式之標題化合物(0.124 g，73%)。方法C HPLC-MS：MH+要求m/z=276實驗值：m/z=298(M+Na)，Rt=1.14 min(100%)。 4-(propan-2-ylthio)hexahydropyridine-1-carboxylic acid tert-butyl ester (prepared in a similar manner to intermediate 245, 0.160 g, 0.62 mmol) was dissolved in DCM (3 mL) And cooled to 0 °C. m-Chloroperbenzoic acid (0.138 g, 0.62 mmol) was added and the mixture was warmed to room temperature and stirred for 17 h. Additional m-chloroperbenzoic acid (0.040 g, 0.18 mmol) was added and the mixture was stirred at room temperature for 3 h. The mixture was then diluted with DCM (10 mL) and washed with aq. The organic layer was separated and purified with EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH , 73%). Method C HPLC-MS: MH+ requires m/z = 276. Found: m/z = 298 (M+Na), Rt = 1.14 min (100%).

中間體248：4-[(2,2,2-三氟乙氧基)甲基]苯甲酸 Intermediate 248 : 4-[(2,2,2-Trifluoroethoxy)methyl]benzoic acid

將4-[(2,2,2-三氟乙氧基)甲基]苯甲酸甲酯(中間體249，1.05 g，4.23 mmol)溶於MeOH(10 mL)中，添加2 M氫氧化鈉水溶液(6.4 mL，12.69 mmol)且將混合物在室溫下攪拌3 h。然後添加THF(2 mL)並將混合物在室溫下攪拌整個週末。然後在真空下濃縮混合物並藉由添加2 M鹽酸酸化殘餘物。使用少量水稀釋混合物並使用DCM(3×20 mL)萃取。藉由硫酸鈉乾燥合併之有機層並在真空下濃縮以得到白色固體形式之標題化合物(0.974 g，98%)。1H NMR(500MHZ,CDCl3)δ ppm 8.14(2H,d),7.49(2H,d),4.79(2H,s)及3.91(2H,q)。 Methyl 4-[(2,2,2-trifluoroethoxy)methyl]benzoate (Intermediate 249, 1.05 g, 4.23 mmol) was dissolved in MeOH (10 mL). Aqueous solution (6.4 mL, 12.69 mmol) and mixture was stirred at room temperature for 3 h. Then THF (2 mL) was added and the mixture was stirred at room temperature over the weekend. The mixture was then concentrated under vacuum and the residue was acidified with 2M hydrochloric acid. The mixture was diluted with a small amount of water and extracted with DCM (3×20 mL). The combined organic layer was dried with EtOAc EtOAcjjjjjjj 1H NMR (500MHZ, CDCl 3) δ ppm 8.14 (2H, d), 7.49 (2H, d), 4.79 (2H, s) and 3.91 (2H, q).

中間體249：4-[(2,2,2-三氟乙氧基)甲基]苯甲酸甲酯 Intermediate 249 : Methyl 4-[(2,2,2-trifluoroethoxy)methyl]benzoate

將2,2,2-三氟乙醇(0.35 mL，4.80 mmol)溶於THF(2 mL)中並在氮下冷卻至0℃。逐份添加氫化鈉(存於礦物油中之60%分散液，0.192 g，4.80 mmol)並將混合物攪拌10 min。添加存於THF(3 mL)中之4-(溴甲基)苯甲酸甲酯之溶液，將混合物升溫至室溫且然後加熱至50℃保持3 h。然後使用水(15 mL)及EtOAc(20 mL)稀釋混合物。分離有機層並使用1 M鹽酸中和水層。使用EtOAc(2×20 mL)進一步萃取水層。藉由硫酸鈉乾燥合併之有機層並在真空下濃縮以得到無色油性殘餘物形式之標題化合物(1.05 g，97%)。1H NMR(500MHZ,CDCl3)δ ppm 7.95(2H,d),7.33(2H,d),4.64(2H,s),3.83(3H,s)及3.77(2H,q)。 2,2,2-Trifluoroethanol (0.35 mL, 4.80 mmol) was dissolved in THF (2 mL) and cooled to EtOAc. Sodium hydride (60% dispersion in mineral oil, 0.192 g, 4.80 mmol) was added portionwise and the mixture was stirred for 10 min. A solution of methyl 4-(bromomethyl)benzoate in THF (3 mL) was added and the mixture was warmed to room temperature and then warmed to 50 ° C for 3 h. The mixture was then diluted with water (15 mL) and EtOAc (20 mL). The organic layer was separated and the aqueous layer was neutralized using 1 M hydrochloric acid. The aqueous layer was further extracted with EtOAc (2×20 mL). The combined organic layer was dried with EtOAc EtOAcjjjjjjj 1H NMR (500MHZ, CDCl 3) δ ppm 7.95 (2H, d), 7.33 (2H, d), 4.64 (2H, s), 3.83 (3H, s) and 3.77 (2H, q).

中間體250：6-(2,2-二氟乙氧基)吡啶-3-甲酸 Intermediate 250 : 6-(2,2-difluoroethoxy)pyridine-3-carboxylic acid

將粉末狀氫氧化鉀(712 mg，12.7 mmol)添加至存於DMSO(15 mL)中之6-氯菸酸(500 mg，3.17 mmol)及2,2-二氟乙醇(520 mg，6.35 mmol)之混合物中且將混合物在120℃下攪拌14 h。添加額外之二當量2,2-二氟乙醇及氫氧 化鉀且將混合物加熱24 h。將混合物冷卻至室溫，使用水(5 mL)稀釋，使用1 N HCl水溶液酸化(至pH 1)並使用EtOAc(3×50 mL)萃取。使用水(2×25 mL)洗滌合併之有機層，然後使用鹽水(50 mL)洗滌，並在減壓下濃縮以提供淺褐色固體形式之標題化合物(620 mg，96%)。方法B HPLC-MS：MH+要求m/z=204；實驗值：m/z=204，Rt=1.54 min(90%)。 Potassium hydroxide (712 mg, 12.7 mmol) was added to 6-chloronicotinic acid (500 mg, 3.17 mmol) and 2,2-difluoroethanol (520 mg, 6.35 mmol) in DMSO (15 mL). The mixture was stirred and the mixture was stirred at 120 ° C for 14 h. Add two additional equivalents of 2,2-difluoroethanol and hydrogen Potassium was added and the mixture was heated for 24 h. The mixture was cooled to room temperature, diluted with EtOAc EtOAc (EtOAc) The combined organic layers were washed with EtOAc EtOAc m. Method B HPLC-MS: MH+ requires m/z = 204; found: m/z = 204, Rt = 1.54 min (90%).

中間體251：(1R,5S,6S)-6-[(2,2,2-三氟乙氧基)甲基]-3-氮雜雙環[3.1.0]己烷 Intermediate 251 : (1R,5S,6S)-6-[(2,2,2-trifluoroethoxy)methyl]-3-azabicyclo[3.1.0]hexane

將(1R,5S,6S)-3-苄基-6-[(2,2,2-三氟乙氧基)甲基]-3-氮雜雙環[3.1.0]己烷(中間體252，360 mg，1.26 mmol)及碳載氫氧化鈀(20 wt.%,108 mg，0.15 mmol)在EtOH(95 mL)中合併且將混合物在4巴氫氣氛下加熱至50℃保持18 h。經由矽藻土(celite)過濾混合物，向濾液中添加新鮮觸媒且將混合物在4巴氫氣氛下加熱至60℃保持14 h。經由矽藻土過濾混合物並在減壓下濃縮以得到油狀物形式之標題化合物(203 mg，82%)。方法B HPLC-MS：MH+要求m/z=196；實驗值：m/z=196，Rt=0.23 min(藉由MS)。 (1R,5S,6S)-3-benzyl-6-[(2,2,2-trifluoroethoxy)methyl]-3-azabicyclo[3.1.0]hexane (Intermediate 252 , 360 mg, 1.26 mmol) and palladium hydroxide on carbon (20 wt.%, 108 mg, 0.15 mmol) were combined in EtOH (95 mL) and the mixture was heated to 50 ° C under a hydrogen atmosphere of 4 bar for 18 h. The mixture was filtered through celite, fresh catalyst was added to the filtrate and the mixture was heated to 60 ° C under a hydrogen atmosphere of 4 bar for 14 h. The mixture was filtered through EtOAc (EtOAc)EtOAc. Method B HPLC-MS: MH+ requires m/z = 196. Found: m/z = 196, Rt = 0.23 min (MS).

以與中間體251類似之方式來製備下列中間體。 The following intermediates were prepared in a similar manner to the intermediate 251.

中間體252：(1R,5S,6S)-3-苄基-6-[(2,2,2-三氟乙氧基)甲基]-3-氮雜雙環[3.1.0]己烷 Intermediate 252 : (1R,5S,6S)-3-benzyl-6-[(2,2,2-trifluoroethoxy)methyl]-3-azabicyclo[3.1.0]hexane

在室溫下，將甲磺醯氯(320 μL,4.13 mmol)添加至存於DCM(20 mL)中之[(1R,5S,6S)-3-苄基-3-氮雜雙環[3.1.0]己烷-6-基]甲醇(中間體253，600 mg，2.95 mmol)及三乙胺(620 μL,4.43 mmol)之溶液中。將混合物攪拌3 h且然後添加氯化銨飽和水溶液(20 mL)。使用DCM(3×20 mL)洗滌混合物。使用水(20 mL)洗滌合併之有機層，然後使用鹽水(20 mL)洗滌並在減壓下濃縮以提供期望甲磺酸鹽中間體。將存於DMF(3 mL)中之2,2,2-三氟乙醇(255 μL,3.54 mmol)及氫化鈉(存於礦物油中之60%分散液，141 mg，3.54 mmol)之混合物在0℃下攪拌30分鐘且然後在0℃下添加至存於DMF(5 mL)中之甲磺酸鹽中間體之溶液中。將所得混合物在室溫下攪拌14 h。添加氯化銨飽和水溶液(20 mL)且使用EtOAc(4×50 mL)萃取混合物。使用水(3×20 mL)洗滌合併之有機層，然後使用鹽水(20 mL)洗滌，在減壓下濃縮並藉由急驟層析(40% EtOAc：庚烷)純化以提供淺黃色固體形式之標題化合物(360 mg，42%)。方法B HPLC- MS：MH+要求m/z=286；實驗值：m/z=286，Rt=1.24 min(73%)。 Methanesulfonium chloride (320 μL, 4.13 mmol) was added to [(1R,5S,6S)-3-benzyl-3-azabicyclo[3.1.] in DCM (20 mL). 0] Hexane-6-yl]methanol (intermediate 253, 600 mg, 2.95 mmol) and triethylamine (620 uL, 4.43 mmol). The mixture was stirred for 3 h and then aqueous ammonium chloride (20 mL) was added. The mixture was washed with DCM (3 x 20 mL). The combined organic layers were washed with water (20 mL) then brine (20 mL). a mixture of 2,2,2-trifluoroethanol (255 μL, 3.54 mmol) and sodium hydride (60% dispersion in mineral oil, 141 mg, 3.54 mmol) in DMF (3 mL) Stir at 0 °C for 30 minutes and then add to a solution of the mesylate intermediate in DMF (5 mL) at 0 °C. The resulting mixture was stirred at room temperature for 14 h. A saturated aqueous solution of ammonium chloride (20 mL) was added and the mixture was extracted with EtOAc (4×50 mL). The combined organics were washed with EtOAc (EtOAc (EtOAc)EtOAc. The title compound (360 mg, 42%). Method B HPLC- MS: MH+ requires m/z = 286; found: m/z = 286, Rt = 1.24 min (73%).

中間體253：[(1R,5S,6S)-3-苄基-3-氮雜雙環[3.1.0]己烷-6-基]甲醇 Intermediate 253 : [(1R,5S,6S)-3-benzyl-3-azabicyclo[3.1.0]hexane-6-yl]methanol

在0℃下，將存於無水THF(50 mL)中之氫化鋰鋁(5.6 g，147.5 mmol)之溶液逐滴添加至(1R,5S,6S)-3-苄基-2,4-二側氧基-3-氮雜雙環[3.1.0]己烷-6-甲酸乙酯(中間體254，10 g，36.6 mmol)之溶液中，將混合物升溫至室溫並在70℃下加熱18 h。將混合物冷卻至室溫並使用氯化銨飽和水溶液(5 mL)驟冷，隨後使用水(1 mL)驟冷並攪拌1 h。過濾掉殘餘物並使用EtOAc洗滌。藉由硫酸鎂乾燥濾液並在減壓下濃縮以得到黃色油狀物形式之標題化合物(7.7 g，定量)。方法B HPLC-MS：MH+要求m/z=204；實驗值：m/z=204，Rt=0.67 min(60%)。 A solution of lithium aluminum hydride (5.6 g, 147.5 mmol) in anhydrous THF (50 mL) was added dropwise to (1R,5S,6S)-3-benzyl-2,4-di. In a solution of ethyloxy-3-azabicyclo[3.1.0]hexane-6-carboxylate (intermediate 254, 10 g, 36.6 mmol), the mixture was warmed to room temperature and heated at 70 ° C. h. The mixture was cooled to room temperature and quenched with a saturated aqueous solution of ammonium chloride (5 mL) and then quenched with water (1 mL) and stirred for 1 h. The residue was filtered and washed with EtOAc. The filtrate was dried with EtOAc (EtOAc m. Method B HPLC-MS: MH+ requires m/z = 204; found: m/z = 204, Rt = 0.67 min (60%).

中間體254：(1R,5S,6S)-3-苄基-2,4-二側氧基-3-氮雜雙環[3.1.0]己烷-6-甲酸乙酯 Intermediate 254 : (1R,5S,6S)-3-benzyl-2,4-di-oxo-3-azabicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester

將5-苄基-4,6-二側氧基-1H,3aH,4H,5H,6H,6aH-吡咯并[3,4-c]吡唑-3-甲酸乙酯(中間體255，40 g，132.9 mmol)在190℃下於500 mL燒瓶中加熱。在逸出氮之後，逐份添加額外5-苄基-4,6-二側氧基-1H,3aH,4H,5H,6H,6aH-吡咯并[3,4-c]吡唑-3-甲酸乙酯(3 x10 g)且將混合物加熱30 min直至氣體停止逸出為止。將混合物冷卻至室溫且使用二乙醚稀釋並在室溫下攪拌1 h。將混合物冷卻至-30℃並攪拌30 min。過濾混合物並使用冷二乙醚洗滌以提供灰白色固體 形式之標題化合物(26.1 g，40%)。方法B HPLC-MS：MH+要求m/z=274；實驗值：m/z=274，Rt=1.96 min(82%)。 5-Benzyl-4,6-di-oxy-1H, 3aH, 4H, 5H, 6H, 6aH-pyrrolo[3,4-c]pyrazole-3-carboxylic acid ethyl ester (intermediate 255, 40 g, 132.9 mmol) was heated in a 500 mL flask at 190 °C. After the nitrogen evolution, additional 5-benzyl-4,6-di-oxy-1H, 3aH, 4H, 5H, 6H, 6aH-pyrrolo[3,4-c]pyrazole-3- was added in portions. Ethyl formate (3 x 10 g) and the mixture was heated for 30 min until the gas ceased to escape. The mixture was cooled to room temperature and diluted with diethyl ether and stirred at room temperature for 1 h. The mixture was cooled to -30 ° C and stirred for 30 min. The mixture was filtered and washed with cold diethyl ether to give an off-white solid The title compound of the form (26.1 g, 40%). Method B HPLC-MS: MH+ requires m/z = 274. Found: m/z = 274, Rt = 1.96 min (82%).

中間體255：5-苄基-4,6-二側氧基-1H,3aH,4H,5H,6H,6aH-吡咯并[3,4-c]吡唑-3-甲酸乙酯 Intermediate 255 : 5-benzyl-4,6-di-oxy-1H, 3aH, 4H, 5H, 6H, 6aH-pyrrolo[3,4-c]pyrazole-3-carboxylic acid ethyl ester

經30 min時段將重氮乙酸乙酯(30.3 mL，288.5 mmol)逐滴添加至存於二乙醚(300 mL)中之N-苄基馬來醯亞胺(49.5 g，264.7 mmol)之溶液中且將混合物在室溫下攪拌4天。過濾掉所得沈澱物，使用二乙醚(100 mL)洗滌並在真空下乾燥以提供白色固體形式之標題化合物(72 g，90%)。方法B HPLC-MS：MH+要求m/z=302；實驗值：m/z=302，Rt=1.74 min(83%)。 Ethyl diazoacetate (30.3 mL, 288.5 mmol) was added dropwise to a solution of N-benzylmaleimide (49.5 g, 264.7 mmol) in diethyl ether (300 mL) over 30 min. The mixture was stirred at room temperature for 4 days. The resulting precipitate was filtered, washed with EtOAc EtOAcjjjjjjj Method B HPLC-MS: MH+ requires m/z = 302; mp.: m/z = 302, Rt = 1.74 min (83%).

中間體268：4-{[(2,2,2-三氟乙基)硫基]甲基}六氫吡啶-1-甲酸第三丁基酯 Intermediate 268 : 4-{[(2,2,2-trifluoroethyl)thio]methyl}hexahydropyridine-1-carboxylic acid tert-butyl ester

在0℃下，將2,2,2-三氟乙烷-1-硫醇(471 μL,3.41 mmol)逐滴添加至存於無水DMF(10 mL)中之氫化鈉(存於礦物油中之60%分散液，0.065 g，1.636 mmol)之懸浮液中且將混合物攪拌15 min。逐滴添加存於DMF(5 mL)中之4-[(甲烷磺醯基氧基)甲基]六氫吡啶-1-甲酸第三丁基酯(以與中間體181類似之方式製得，1 g，3.41 mmol)之溶液且將混合物在室溫下攪拌5 h。使用水(50 mL)稀釋反應混合物並使用EtOAc(3×50 mL)萃取。使用碳酸氫鈉飽和水溶液(25 mL)洗滌合併之有機層然後使用鹽水(25 mL)洗滌，藉由硫酸鎂乾燥並在減壓下濃縮以提供淺黃色油狀物形式之標題化合物(1.13 g，定量)。方法B HPLC-MS：MH+要求 m/z=314實驗值：m/z=258(MH+-tBu)，Rt=2.39 min(98%)。 2,2,2-Trifluoroethane-1-thiol (471 μL, 3.41 mmol) was added dropwise at 0 ° C to sodium hydride (in mineral oil) in anhydrous DMF (10 mL) A suspension of 60% dispersion, 0.065 g, 1.636 mmol) and the mixture was stirred for 15 min. 4-[(Methanesulfonyloxy)methyl]hexahydropyridine-1-carboxylic acid tert-butyl ester (produced in a similar manner to Intermediate 181) was added dropwise in DMF (5 mL). A solution of 1 g, 3.41 mmol) and the mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with water (50 mL) andEtOAc. The combined organic layer was washed with EtOAcqqqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Quantitative). Method B HPLC-MS: MH+ Requirements m/z = 314. Found: m/z = 258 (MH+-tBu), Rt = 2.39 min (98%).

中間體270：(3S)-3-苯氧基吡咯啶-1-甲酸第三丁基酯 Intermediate 270 : (3S)-3-phenoxypyrrolidine-1-carboxylic acid tert-butyl ester

將偶氮二甲酸二異丙基酯(1.19 g，5.87 mmol)添加至存於THF(14 mL)中之(3R)-3-羥基吡咯啶-1-甲酸第三丁基酯(1 g，5.34 mmol)、苯酚(0.5 g，5.34 mmol)及三苯基膦(1.5 g，5.8 mmol)之冰冷卻混合物中。將混合物在室溫下攪拌20 h。然後在真空下濃縮混合物且使用二乙醚將殘餘物研磨兩次。過濾掉所得固體並拋棄。使用1 M氫氧化鈉水溶液洗滌濾液，藉由硫酸鈉乾燥並濃縮。藉由FCC(使用存於庚烷中之10% EtOAc洗脫)純化殘餘物以得到標題化合物(0.893 g，63%)。方法B HPLC-MS：MH+要求m/z=208實驗值：m/z=208，Rt=2.20 min(91%)。 Add diisopropyl azodicarboxylate (1.19 g, 5.87 mmol) to (3R)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (1 g, in THF (14 mL) 5.34 mmol), phenol (0.5 g, 5.34 mmol) and triphenylphosphine (1.5 g, 5.8 mmol) in ice-cooled mixture. The mixture was stirred at room temperature for 20 h. The mixture was then concentrated under vacuum and the residue was triturated twice with diethyl ether. The resulting solid was filtered off and discarded. The filtrate was washed with 1 M aqueous sodium hydroxide, dried over sodium sulfate and evaporated. The residue was purified with EtOAc EtOAcjjjjjj Method B HPLC-MS: MH+ requires m/z = 208. Found: m/z = 208, Rt = 2.20 min (91%).

中間體272：(3R)-3-苯氧基吡咯啶-1-甲酸第三丁基酯 Intermediate 272 : (3R)-3-phenoxypyrrolidine-1-carboxylic acid tert-butyl ester

根據針對中間體270所述之方法自(3S)-3-羥基吡咯啶-1-甲酸第三丁基酯(0.43 g，2.286 mmol)來製備(3R)-3-苯氧基吡咯啶-1-甲酸第三丁基酯以得到標題化合物(0.312 g，產率為51%)。方法B HPLC-MS：MH+要求m/z=208實驗值：m/z=208，Rt=2.20 min(100%)。 Preparation of (3R)-3-phenoxypyrrolidin-1 from (3S)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (0.43 g, 2.286 mmol) according to the procedure described for Intermediate 270 -T-butyl formate to give the title compound (0.312 g, yield 51%). Method B HPLC-MS: MH+ requires m/z = 208: m/z = 208, Rt = 2.20 min (100%).

中間體274：(3R)-3-(2,2,2-三氟乙氧基)吡咯啶-1-甲酸第三丁基酯 Intermediate 274 : (3R)-3-(2,2,2-trifluoroethoxy)pyrrolidine-1-carboxylic acid tert-butyl ester

將偶氮二甲酸二-第三丁基酯(2.96 g，12.83 mmol)添加至存於THF(24 mL)中之(3S)-3-羥基吡咯啶-1-甲酸第三丁基酯(2 g，10.70 mmol)、2,2,2-三氟乙醇(10.70 g，106.95 mmol)及三苯基膦(3.37 g，12.83 mmol)之冰冷卻混合物 中。將混合物在70℃下攪拌16 h。在真空下濃縮混合物且藉由FCC(使用存於庚烷中之EtOAc之梯度洗脫)純化殘餘物。使用庚烷洗滌所收集白色固體且濃縮濾液以得到標題化合物(1.263 g，44%)，該標題化合物未經進一步純化即使用。方法B HPLC-MS：MH+要求m/z=270實驗值：m/z=214(M-第三丁基)，Rt=2.02 min(82%)。 Di-tert-butyl azodicarboxylate (2.96 g, 12.83 mmol) was added to (3S)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (2) in THF (24 mL). Ice-cooled mixture of g, 10.70 mmol), 2,2,2-trifluoroethanol (10.70 g, 106.95 mmol) and triphenylphosphine (3.37 g, 12.83 mmol) in. The mixture was stirred at 70 ° C for 16 h. The mixture was concentrated under EtOAc (EtOAc m. The white solid was collected with EtOAc (EtOAc)EtOAc. Method B HPLC-MS: MH+ requires m/z = 270. Found: m/z = 214 (M-t-butyl), Rt = 2.02 min (82%).

中間體275：6-[(環丙基甲基)硫基]吡啶-3-甲酸 Intermediate 275 : 6-[(cyclopropylmethyl)thio]pyridine-3-carboxylic acid

根據針對中間體276所述之方法自6-硫基吡啶-3-甲酸(0.5 g，3.22 mmol)及(溴甲基)環丙烷(0.44 g，3.22 mmol)來製備6-[(環丙基甲基)硫基]吡啶-3-甲酸以得到標題化合物(0.521 g，61%)。方法B HPLC-MS：MH+要求m/z=210實驗值：m/z=210，Rt=1.77 min(79%)。 Preparation of 6-[(cyclopropyl) from 6-thiopyridine-3-carboxylic acid (0.5 g, 3.22 mmol) and (bromomethyl)cyclopropane (0.44 g, 3.22 mmol) according to the procedure described for Intermediate 276 Methyl)thio]pyridine-3-carboxylic acid gave the title compound (0.521 g, 61%). Method B HPLC-MS: MH+ requires m/z = 210 found: m/z = 210, Rt = 1.77 min (79%).

中間體276：6-[(3,3,3-三氟丙基)硫基]吡啶-3-甲酸 Intermediate 276 : 6-[(3,3,3-trifluoropropyl)thio]pyridine-3-carboxylic acid

在0℃下，向存於EtOH(50 mL)中之6-硫基吡啶-3-甲酸(0.5 g，3.22 mmol)之攪拌溶液中添加乙酸鈉(0.26 g，3.22 mmol)及1,1,1-三氟-3-碘丙烷(0.72 g，3.22 mmol)且將混合物在80℃下加熱24 h。在真空下濃縮混合物，添加水且使用乙酸將混合物酸化至pH 4。藉由過濾收集所得黃色沈澱物並藉由FCC(使用存於DCM中之2% MeOH洗脫)純化以得到標題化合物(0.459 g，57%)。方法B HPLC-MS：MH+要求m/z=252實驗值：m/z=252，Rt=1.84 min(91%)。 Sodium acetate (0.26 g, 3.22 mmol) and 1,1 were added to a stirred solution of 6-thiopyridine-3-carboxylic acid (0.5 g, 3.22 mmol) in EtOH (50 mL). 1-Trifluoro-3-iodopropane (0.72 g, 3.22 mmol) and the mixture was heated at 80 ° C for 24 h. The mixture was concentrated under vacuum, water was added and the mixture was acidified to pH 4 using acetic acid. The resulting yellow precipitate was purified by EtOAc EtOAcjjjjjjj Method B HPLC-MS: MH+ requires m/z = 252 found: m/z = 252, Rt = 1.84 min (91%).

中間體279：5-(2,2,2-三氟乙胺基)-吡啶-2-甲酸 Intermediate 279 : 5-(2,2,2-Trifluoroethylamino)-pyridine-2-carboxylic acid

將5-(2,2,2-三氟乙胺基)-吡啶-2-甲酸甲酯(中間體280，75 mg，0.320 mmol)溶於THF(0.75 mL)與水(0.25 mL)之混 合物中，且添加氫氧化物單水合鋰(27 mg，0.640 mmol)。將混合物在室溫下攪拌18 h。使用水(5 mL)稀釋混合物，藉由添加1 M HCl達到約pH 4，然後使用DCM(4×9 mL)萃取。使用鹽水(5 mL)洗滌合併之有機萃取物，藉由硫酸鈉乾燥並在真空下蒸發以得到白色固體形式之標題化合物(51 mg，72%)。方法B HPLC-MS：MH+要求m/z=221；實驗值：m/z=221，Rt=1.30 min(100%)。 Mixing methyl 5-(2,2,2-trifluoroethylamino)-pyridine-2-carboxylate (Intermediate 280, 75 mg, 0.320 mmol) in THF (0.75 mL) and water (0.25 mL) In the mixture, lithium hydroxide monohydrate (27 mg, 0.640 mmol) was added. The mixture was stirred at room temperature for 18 h. The mixture was diluted with water (5 mL), mp EtOAc (m.) The combined organic extracts were washed with EtOAc EtOAc m. Method B HPLC-MS: MH+ requires m/z = 221; found: m/z = 221, Rt = 1.30 min (100%).

中間體280：5-(2,2,2-三氟-乙基胺基)-吡啶-2-甲酸甲酯 Intermediate 280 : methyl 5-(2,2,2-trifluoro-ethylamino)-pyridine-2-carboxylate

將5-胺基吡啶-2-甲酸甲酯(中間體168，200 mg，1.31 mmol)及碳酸銫(642 mg，1.97 mmol)溶於無水DMF(2 mL)中並在氮下攪拌10 min。添加三氟甲烷磺酸2,2,2-三氟乙基酯(246 μL,1.70 mmol)且將混合物在室溫下攪拌18 h。添加額外碳酸銫(642 mg，1.97 mmol)及三氟甲烷磺酸2,2,2-三氟乙基酯(246 μL,1.70 mmol)且將混合物在85℃下攪拌6 h。使用EtOAc(50 mL)稀釋混合物並使用水(3×20 mL)洗滌，然後使用鹽水(20 mL)洗滌且然後藉由硫酸鈉乾燥並在真空下蒸發。藉由急驟層析(存於庚烷中之0-10% EtOAc)純化粗製殘餘物以得到白色固體形式之標題化合物(75 mg，24%)。方法B HPLC-MS：MH+要求m/z=235；實驗值：m/z=235，Rt=1.76 min(84%)。 Methyl 5-aminopyridine-2-carboxylate (Intermediate 168, 200 mg, 1.31 mmol) and EtOAc (EtOAc, EtOAc, EtOAc) 2,2,2-Trifluoroethyl trifluoromethanesulfonate (246 μL, 1.70 mmol) was added and the mixture was stirred at room temperature for 18 h. Additional cesium carbonate (642 mg, 1.97 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (246 μL, 1.70 mmol) were added and the mixture was stirred at 85 ° C for 6 h. The mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. The crude residue was purified by EtOAcjjjjjjjj Method B HPLC-MS: MH+ requires m/z = 235; found: m/z = 235, Rt = 1.76 min (84%).

中間體281：2-(2,2,2-三氟乙氧基)吡啶-4-甲酸 Intermediate 281 : 2-(2,2,2-trifluoroethoxy)pyridine-4-carboxylic acid

在氮下，將2-氯吡啶-4-甲酸(200 mg，1.27 mmol)、第三丁醇鉀(381 mg，3.81 mmol)及2,2,2-三氟乙醇(2.6 mL)裝填至密封管中並在170℃下攪拌3 h。添加2,2,2-三氟乙醇(1 mL)並將反應液在170℃下攪拌17 h。在真空下蒸發混合物且將殘餘物溶於水(5 mL)中。添加2 M HCl以使溶液達到pH 5且使用DCM(3×10 mL)萃取混合物。然後向水層中添加2 M HCl以使溶液達到pH 3且使用DCM(4×6 mL)萃取混合物。使用鹽水(5 mL)洗滌合併之有機萃取液，藉由硫酸鈉乾燥並在真空下蒸發以得到白色固體形式之標題化合物(210 mg，75%)。方法C HPLC-MS：MH+要求m/z=222；實驗值：m/z=222，Rt=1.26 min(95%)。 2-Chloropyridine-4-carboxylic acid (200 mg, 1.27 mmol), potassium butoxide (381 mg, 3.81 mmol) and 2,2,2-trifluoroethanol (2.6 mL) were packed in a sealed atmosphere under nitrogen. The tube was stirred at 170 ° C for 3 h. Add 2,2,2-trifluoroethanol (1 (mL) and the reaction was stirred at 170 ° C for 17 h. The mixture was evaporated under vacuum and the residue was takenEtOAcjjjjjjjj 2 M HCl was added to bring the solution to pH 5 and the mixture was extracted with DCM (3×10 mL). 2 M HCl was then added to the aqueous layer to bring the solution to pH 3 and the mixture was extracted using DCM (4×6 mL). The combined organic extracts were washed with EtOAc EtOAc m. Method C HPLC-MS: MH+ requires m/z = 222. Found: m/z = 222, Rt = 1.26 min (95%).

中間體282：2-(2,2,2-三氟乙氧基)菸酸 Intermediate 282 : 2-(2,2,2-trifluoroethoxy)nicotinic acid

將2-氟吡啶-3-甲酸(200 mg，1.42 mmol)溶於2,2,2-三氟乙醇(2 mL)中且添加第三丁醇鉀(477 mg，4.25 mmol)。然後將混合物加熱至90℃保持4 h。使用水(4 mL)稀釋混合物，添加2 M HCl以使溶液達到pH 4且使用DCM(3×4 mL)萃取混合物。向水層中添加2 M HCl以使溶液達到pH 3且使用DCM(4×5 mL)萃取混合物。藉由硫酸鈉乾燥合併之有機萃取液並在真空下蒸發以得到標題化合物(100 mg，32%)。方法C HPLC-MS：MH+要求m/z=222；實驗值：m/z=222，Rt=1.17 min(100%)。 2-Fluoropyridine-3-carboxylic acid (200 mg, 1.42 mmol) was dissolved in 2,2,2-trifluoroethanol (2 mL) and potassium t-butoxide (477 mg, 4.25 mmol). The mixture was then heated to 90 ° C for 4 h. The mixture was diluted with water (4 mL), 2 M HCl was added to bring the solution to pH 4 and mixture was extracted with DCM (3×4 mL). 2 M HCl was added to the aqueous layer to bring the solution to pH 3 and the mixture was extracted with DCM (4×5 mL). The combined organic extracts were dried with EtOAc EtOAc EtOAc Method C HPLC-MS: MH+ requires m/z = 222. Found: m/z = 222, Rt = 1.17 min (100%).

中間體283：3-(2-甲氧基乙氧基)-吡啶-2-甲酸 Intermediate 283 : 3-(2-methoxyethoxy)-pyridine-2-carboxylic acid

在氮下，將3-氟吡啶-2-甲酸(150 mg，1.06 mol)、2-甲氧基乙醇(1.5 mL)及第三丁醇鉀(356 mg，3.18 mmol)裝填至密封管中，然後在100℃下攪拌18 h。然後使用水(3 mL)稀釋混合物，添加1 M HCl以使溶液達到pH 5且使用DCM(2×5 mL)萃取混合物。向水層中添加1 M HCl以使溶 液達到pH 3且使用DCM(2×5 mL)萃取混合物。藉由硫酸鈉乾燥合併之有機萃取液並在真空下蒸發以得到褐色膠形式之標題化合物(54 mg，26%)。方法C HPLC-MS：MH+要求m/z=198；實驗值：m/z=198，Rt=0.29 min。 3-Fluoropyridine-2-carboxylic acid (150 mg, 1.06 mol), 2-methoxyethanol (1.5 mL) and potassium butoxide (356 mg, 3.18 mmol) were charged to a sealed tube under nitrogen. It was then stirred at 100 ° C for 18 h. The mixture was then diluted with water (3 mL), 1 M HCl was added to bring the solution to pH 5 and mixture was extracted with DCM (2 x 5 mL). Add 1 M HCl to the aqueous layer to dissolve The solution reached pH 3 and the mixture was extracted with DCM (2×5 mL). The combined organic extracts were dried with EtOAc EtOAcjjjjjjj Method C HPLC-MS: MH+ requires m/z = 198. Found: m/z = 198, Rt = 0.229 min.

中間體285：3-(2,2,2-三氟乙氧基)-吡啶-2-甲酸 Intermediate 285 : 3-(2,2,2-trifluoroethoxy)-pyridine-2-carboxylic acid

將第三丁醇鉀(954 mg，8.51 mmol)裝填至含有2,2,2-三氟乙醇(4 mL)及3-氟吡啶-2-甲酸(400 mg，2.84 mmol)之密封管中且將混合物加熱至130℃保持26 h，然後加熱至150℃保持4 h，且然後在120℃下保持約18 h。使用水(6 mL)稀釋混合物並使用DCM(2×4 mL)洗滌，然後拋棄。添加1 M HCl以使溶液達到pH 7且使用DCM(2×4 mL)萃取水溶液。如上所述在pH 5、pH 4及pH 3下重複萃取過程。藉由硫酸鈉乾燥合併之有機萃取液並在真空下蒸發以得到白色固體形式之標題化合物(305 mg，49%)。方法B HPLC-MS：MH+要求m/z=222；實驗值：m/z=222，Rt=0.73 min(100%)。 Potassium tert-butoxide (954 mg, 8.51 mmol) was loaded into a sealed tube containing 2,2,2-trifluoroethanol (4 mL) and 3-fluoropyridine-2-carboxylic acid (400 mg, 2.84 mmol). The mixture was heated to 130 ° C for 26 h, then heated to 150 ° C for 4 h, and then held at 120 ° C for about 18 h. The mixture was diluted with water (6 mL) and washed with DCM (2×4 mL) and then discarded. 1 M HCl was added to bring the solution to pH 7 and the aqueous solution was extracted with DCM (2×4 mL). The extraction process was repeated at pH 5, pH 4 and pH 3 as described above. The combined organic extracts were dried with EtOAcjjjjjjjjj Method B HPLC-MS: MH+ requires m/z = 222; found: m/z = 222, Rt = 0.73 min (100%).

中間體286：3-環丁氧基-吡啶-2-甲酸 Intermediate 286 : 3-cyclobutoxy-pyridine-2-carboxylic acid

將第三丁醇鉀(358 mg，3.19 mmol)懸浮於環丁醇(0.5 mL)中，添加3-氟吡啶-2-甲酸(150 mg，1.06 mmol)且將反應液在100℃下攪拌18 h。在真空下蒸發混合物以得到標題化合物(假定轉化100%)，該標題化合物未經進一步純化即用於下一步驟中。方法C HPLC-MS：MH+要求m/z=194；實驗值：m/z=194，Rt=0.83 min(100%)。 Potassium tert-butoxide (358 mg, 3.19 mmol) was suspended in cyclobutanol (0.5 mL), 3-fluoropyridine-2-carboxylic acid (150 mg, 1.06 mmol) was added and the reaction was stirred at 100 ° C 18 h. The mixture was evaporated in vacuo to give title crystall Method C HPLC-MS: MH+ requires m/z = 194; found: m/z = 194, Rt = 0.83 min (100%).

中間體290：5-(2,2,2-三氟乙氧基甲基)-呋喃-2-甲酸 Intermediate 290 : 5-(2,2,2-trifluoroethoxymethyl)-furan-2-carboxylic acid

將氫化鈉(存於礦物油中之60%分散液，60 mg，1.50 mmol)添加至存於無水DMF(1 mL)中之2,2,2-三氟乙醇(99 μL,1.38 mmol)中且將混合物在氮下攪拌20 min。然後添加5-氯甲基呋喃-2-甲酸甲酯(200 mg，1.15 mmol)且將混合物在室溫下攪拌18 h，然後在60℃下攪拌3 h，然後在100℃下攪拌3 h。在氮下添加氫化鈉(存於礦物油中之60%分散液，30 mg，0.75 mmol)且將反應混合物在室溫下攪拌18 h。添加氫化鈉(存於礦物油中之60%分散液，30 mg，0.75 mmol)且將混合物在室溫下攪拌3 h。使用EtOAc(30 mL)稀釋反應混合物然後使用碳酸氫鈉飽和水溶液(4×6 mL)、氯化銨飽和水溶液(2×6 mL)洗滌且然後使用鹽水(6 mL)洗滌。合併水性萃取液並藉由添加2 M HCl達到pH 1且然後使用DCM(5 mL)萃取。使用水洗滌(3×6 mL)合併之有機萃取液，然後使用鹽水(6 mL)洗滌且然後藉由硫酸鈉乾燥並在真空下蒸發以得到標題化合物(123 mg，48%)，該標題化合物未經進一步純化即使用。方法C HPLC-MS：(MH+)理論值m/z=225；實驗值：m/z=252，Rt=1.15 min(97%)。 Add sodium hydride (60% dispersion in mineral oil, 60 mg, 1.50 mmol) to 2,2,2-trifluoroethanol (99 μL, 1.38 mmol) in dry DMF (1 mL) The mixture was stirred under nitrogen for 20 min. Then methyl 5-chloromethylfuran-2-carboxylate (200 mg, 1.15 mmol) was added and the mixture was stirred at room temperature for 18 h, then stirred at 60 ° C for 3 h and then at 100 ° C for 3 h. Sodium hydride (60% dispersion in mineral oil, 30 mg, 0.75 mmol) was added under nitrogen and the mixture was stirred at room temperature for 18 h. Sodium hydride (60% dispersion in mineral oil, 30 mg, 0.75 mmol) was added and the mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with EtOAc (30 mL)EtOAcEtOAc. The aqueous extracts were combined and taken to pH 1 with 2 M HCl and then extracted with DCM (5 mL). The title compound (123 mg, 48%) was obtained eluted eluted eluted eluted eluted Used without further purification. Method C HPLC-MS: (MH+), m.

中間體125、中間體148、中間體165及中間體284並不存在。 Intermediate 125, intermediate 148, intermediate 165 and intermediate 284 were not present.

生物學數據Biological data 全細胞電壓箝位電生理學分析Whole-cell voltage clamp electrophysiological analysis

膜片箝製電生理學已被視為用於研究離子通道功能及藥理學之黃金標準技術。使用此方法，可在穩定(或瞬時)表 現所關注鈉通道亞型之細胞中量測鈉通道電流。在該等實驗期間施加化合物時，會提供關於影響所關注離子通道之化合物之活性及功效之功能量度。 Patch clamp electrophysiology has been recognized as the gold standard technique for studying ion channel function and pharmacology. Use this method to stabilize (or instantaneous) the table Sodium channel currents were measured in cells of the sodium channel subtype. When a compound is applied during such experiments, a measure of the function of the activity and efficacy of the compound affecting the ion channel of interest is provided.

可使用自動或人工膜片箝製技術實施電生理學研究。適用於此工作之自動膜片箝製儀器包含Ion Works HT(MDS)、Ion Works Quattro(MDS)、PatchLiner(Nanion technologies)、Port-A-Patch(Nanion technologies)、QPatch(Sophion)或任一其他適宜平臺。 Electrophysiological studies can be performed using automated or manual patch clamp techniques. Automatic patch clamp instruments suitable for this job include Ion Works HT (MDS), Ion Works Quattro (MDS), PatchLiner (Nanion technologies), Port-A-Patch (Nanion technologies), QPatch (Sophion) or any other Suitable platform.

為在自動膜片箝製儀器中進行記錄，將表現所關注電壓閘控式鈉通道亞型之細胞分配於製造商所提供之適當晶片(具有一個以上記錄格之板，每一記錄格皆含有一或多個孔隙以產生全細胞膜片)中。通常，使用全細胞多孔膜片組態來探測鈉通道上自動膜片箝製電生理學中化合物之藥理學。根據參考文獻或根據由儀器製造商所提供之說明書來製備用於該等實驗之細胞外及細胞內緩衝液。藉由通常整合至自動機器中之移液系統將含有欲測試化合物之測試溶液施加至表現所關注鈉通道之細胞中。 For recording in an automated patch clamp instrument, cells representing the voltage-gated sodium channel subtype of interest are dispensed to the appropriate wafer provided by the manufacturer (a plate with more than one recording grid, each containing One or more pores to produce a whole cell membrane). Typically, a whole cell porous membrane configuration is used to detect the pharmacology of the compound in the automatic patch-clamp electrophysiology on the sodium channel. Extracellular and intracellular buffers for such experiments were prepared according to references or according to instructions provided by the instrument manufacturer. The test solution containing the compound to be tested is applied to cells expressing the sodium channel of interest by a pipetting system typically integrated into an automated machine.

亦可使用如參考文獻(例如Pflugers Arch.,1981,391(2),85-100)中所述之標準人工膜片箝製技術之全細胞組態來實施電生理學研究。在此分析中，藉由習用微灌流系統或藉由自製灌流系統，將表現所關注電壓閘控式鈉通道蛋白質之細胞暴露於藥物中。使用適宜電壓刺激方案來活化電壓閘控式鈉通道。 Electrophysiological studies can also be performed using a full cell configuration of standard artificial patch clamp techniques as described in the references (eg, Pflugers Arch., 1981, 391(2), 85-100). In this analysis, cells expressing the voltage-gated sodium channel protein of interest are exposed to the drug by conventional micro-perfusion systems or by a self-made perfusion system. A voltage-controlled sodium channel is activated using a suitable voltage stimulation protocol.

使用適宜電壓刺激方案來活化所關注電壓閘控式鈉通道 蛋白。典型刺激方案可由連續電壓脈衝之掃掠組成，該等連續電壓脈衝始於保持電位(亦即-65 mV)，變至正性更高且去極化之測試脈衝電位(亦即-10 mV)，且最後變至負性更高且超極化之電位(亦即-100 mV)。根據所關注電壓閘控式離子通道之生物物理學及對通道組態之關注，脈衝之電壓及持續時間以及所施加掃掠之總頻率可有所變化。因此，設計刺激方案來評價化合物，此乃因化合物可能主要在鈍化狀態中阻斷NaV1.7通道。藉由反映通道之原始功能(亦即心率或神經元激活)之方案來評價相對於其他電壓閘控式鈉通道成員之選擇性。 Use a suitable voltage stimulation scheme to activate the voltage-gated sodium channel of interest protein. A typical stimulation scheme consists of a sweep of continuous voltage pulses that start at a holding potential (ie, -65 mV) and change to a more positive and depolarized test pulse potential (ie, -10 mV). And finally to a more negative and hyperpolarized potential (ie -100 mV). Depending on the biophysics of the voltage-gated ion channel of interest and the concern for channel configuration, the voltage and duration of the pulse and the total frequency of the applied sweep may vary. Therefore, a stimulation protocol was designed to evaluate the compound, as the compound may block the NaV1.7 channel primarily in the passivated state. The selectivity relative to other voltage-gated sodium channel members is evaluated by a scheme that reflects the original function of the channel (ie, heart rate or neuronal activation).

亦可使用如參考文獻(例如Pflugers Arch.,1981,391(2),85-100)中所述之標準人工膜片箝製技術之全細胞組態來實施電生理學研究。在此分析中，藉由習用微灌流系統或藉由自製灌流系統將表現人類目標電壓閘控式鈉通道蛋白之細胞暴露於藥物中。使用適宜電壓刺激方案來活化電壓閘控式鈉通道。適宜電壓刺激方案可由來自保持電位之連續電壓脈衝組成，每一電壓脈衝首先使細胞超極化，然後在短時間內將通道去極化。尤其適宜之保持電位可為使一部分通道保持鈍化狀態之電壓，例如-60 mV。適宜超極化電壓及持續時間可為-120 mV及100 ms，且去極化電壓及持續時間可為-20 mV及25 ms，且適宜脈衝頻率可為0.1 Hz，但亦可具有其他參數。因此，設計刺激方案來評價化合物，此乃因化合物可能主要在鈍化狀態中阻斷NaV1.7通道。藉由反映通道之原始功能(亦即心率或神經元激活)之 方案來評價相對於其他電壓閘控式鈉通道成員之選擇性。 Electrophysiological studies can also be performed using a full cell configuration of standard artificial patch clamp techniques as described in the references (eg, Pflugers Arch., 1981, 391(2), 85-100). In this analysis, cells expressing human target voltage-gated sodium channel proteins are exposed to the drug by conventional micro-perfusion systems or by self-contained perfusion systems. A voltage-controlled sodium channel is activated using a suitable voltage stimulation protocol. A suitable voltage stimulation scheme can consist of continuous voltage pulses from a holding potential, each voltage pulse first hyperpolarizing the cells and then depolarizing the channels in a short time. Particularly suitable to maintain the potential can be a voltage that keeps a portion of the channel passivated, for example -60 mV. The suitable hyperpolarization voltage and duration can be -120 mV and 100 ms, and the depolarization voltage and duration can be -20 mV and 25 ms, and the suitable pulse frequency can be 0.1 Hz, but other parameters can also be used. Therefore, a stimulation protocol was designed to evaluate the compound, as the compound may block the NaV1.7 channel primarily in the passivated state. By reflecting the original function of the channel (ie heart rate or neuron activation) Protocol to evaluate selectivity relative to other voltage-gated sodium channel members.

式(I)化合物對於Nav1.5之抑制，如使用QPatch所量測 Inhibition of Nav1.5 by a compound of formula (I), as measured using QPatch

式(I)化合物對於Nav1.5之抑制，如使用人工膜片箝製所量測 Inhibition of Nav1.5 by a compound of formula (I), as measured using artificial patch clamp

藥理學模型Pharmacological model

式(I)化合物可在大鼠之FCA(弗羅因德氏完全佐劑(Freund's Complete Adjuvant))測試中展示鎮痛活性，此測試係藉由足蹠注射弗羅因德氏完全佐劑誘導之發炎性疼痛模型(Stein等人，Pharmac.Biochem.Behav.,1988,31,445-451)。可在並不產生導致神經纖維發生傳導阻斷之組織濃度之劑量下獲得該模型中之鎮痛效應。因此，局部麻醉效應並不掩蓋化合物之鎮痛性質(Scott等人，British Journal of Anaesthesia,1988,61,165-8)。實例125及130展示其有 效劑量為1mg/kg(口服)且實例67展示其有效劑量為3 mg/kg(口服)。所有化合物皆係在FCA注射後72 h時進行測試。 The compound of formula (I) can exhibit analgesic activity in a FCA (Freund's Complete Adjuvant) test in rats, which is induced by injection of Freund's complete adjuvant in athlete's foot. Inflammatory Pain Model (Stein et al, Pharmac. Biochem. Behav., 1988, 31, 445-451). The analgesic effect in this model can be obtained at a dose that does not produce a tissue concentration that causes conduction blockage of the nerve fibers. Thus, the local anesthetic effect does not mask the analgesic properties of the compound (Scott et al, British Journal of Anaesthesia, 1988, 61, 165-8). Examples 125 and 130 show that they have The effective dose was 1 mg/kg (oral) and Example 67 showed an effective dose of 3 mg/kg (oral). All compounds were tested 72 h after FCA injection.

實施例：Example:

實施例1：一種式(I)化合物或其醫藥上可接受之鹽， 其中R1係選自氫-鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-；R2係選自氫-C1-C7-烷基-鹵代-C2-C7-烷基-胺基-C2-C7-烷基-N-C1-C7-烷基-胺基-C2-C7-烷基-N,N-二-C1-C7-烷基-胺基-C2-C7-烷基- 羥基-C2-C7-烷基-C1-C7-烷氧基-C2-C7-烷基-C3-C10-環烷基-C1-C7-烷基-氰基-C2-C7-烷基-；或R1及R2與其所附接之原子一起形成4-7員飽和或部分飽和之雜環，該雜環未經取代或經1-3個選自以下之取代基取代：C1-C7-烷基-鹵代-C1-C7-烷基-胺基-C1-C7-烷基-N-C1-C7-烷基-胺基-C1-C7-烷基-N,N-二-C1-C7-烷基-胺基-C1-C7-烷基-羥基-C1-C7-烷基-C1-C7-烷氧基-C1-C7-烷基-C3-C10-環烷基-C1-C7-烷基-氰基-C1-C7-烷基-；R係選自鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-C1-C7-烷氧基-氰基-鹵代-C1-C7-烷氧基- 硝基；-C(O)-O-R'，其中R'係選自氫、C1-C7-烷基、C3-C10-環烷基、C1-C7-烷氧基、鹵代-C1-C7-烷基芳基、芳基-C1-C7-烷基-、雜芳基及雜芳基C1-C7-烷基-、雜環基；-S(=O)2-C1-C7-烷基；-S(=O)2-C3-C10-環烷基；-S(=O)2-C1-C7-烷氧基；R3係選自(a)-L-Y，其中-L-係選自直接鍵結、-(CH2)p-、-C(O)-、-NR7-、-NR7-C(O)-或-C(O)-NR7-，其中p係選自1、2或3 R7係選自氫及C1-C7-烷基Y係選自環烷基、芳基、雜芳基、雜環基、螺環基，其未經取代或經1-3個選自以下之取代基取代：鹵素-；C1-C7-烷基-；鹵代-C1-C7-烷基-；鹵代-C1-C7-烷基-氧基-C1-C7-烷基；鹵代-C1-C7-烷基-氧基-C1-C7-烷基-氧基；C1-C7-烷氧基-；C1-C7-烷氧基-C1-C7-烷氧基-；NC-C1-C7-烷氧基-；C1-C7-烷氧基-C1-C7-烷基-；C3-C10-環烷基-氧基-C1-C7-烷基-；C3-C10-環烷基-C1-C7-烷基-氧基-； C3-C10-環烷基-氧基-；C3-C10-環烷基-NR7'-C1-C7-烷基-，其中R7'係選自氫及C1-C7-烷基；C3-C10-環烷基-C1-C7-烷氧基-C1-C7-烷基-；C2-C7-烯基；鹵代-C2-C7-烯基；羥基-；羥基-C1-C7-烷基-；鹵代-C1-C7-烷基-氧基-；胺基-；N-C1-C7-烷基-胺基-；N-鹵代-C1-C7-烷基-胺基-；N-雜環基-胺基-、N-C3-C10-環烷基-胺基-，其中該等雜環基及環烷基視情況經鹵代-C1-C7-烷基-氧基、C1-C7-烷基、C3-C10-環烷基及C1-C7-烷氧基取代；N-C3-C10-環烷基-C1-C7-烷基-胺基-；N,N-二-C1-C7-烷基-胺基-；N,N-二-鹵代-C1-C7-烷基-胺基-；N,N-二-雜環基-胺基-、N,N-二-C3-C10-環烷基-胺基-，其中該等雜環基及環烷基視情況經鹵代-C1-C7-烷基-氧基、C1-C7-烷基、C3-C10-環烷基及C1-C7-烷氧基取代；氰基-；側氧基；C1-C7-烷氧基-羰基-；C1-C7-烷氧基-C1-C7-烷氧基-C1-C7-烷基-； 芳基；芳基-C1-C7-烷基-；芳基-氧基；雜環基；雜環基-C1-C7-烷基-；雜環基-氧基-；雜環基-氧基-C1-C7-烷基-；芳基-氧基-C1-C7-烷基-；雜芳基-氧基-C1-C7-烷基-；羥基-羰基-；-S-鹵代-C1-C7-烷基；-S-C1-C7-烷基；-S-芳基；鹵代-C1-C7-烷基-S-C1-C7-烷基；C1-C7-烷基-S-C1-C7-烷基；-S(=O)2-C1-C7-烷基；-S(=O)2-鹵代-C1-C7-烷基；-S(=O)2-芳基；-S(=O)2-雜芳基；-S(=O)2-NR4'R4；-S(=O)2-雜環基；鹵代-C1-C7-烷基-S(=O)2-C1-C7-烷基；C1-C7-烷基-S(=O)2-C1-C7-烷基；-S(=O)-C1-C7-烷基；-S(=O)-鹵代-C1-C7-烷基；-S(=O)-C1-C7-烷氧基；-S(=O)-C3-C10-環烷基；-C(O)-C1-C7-烷基；-C(O)-鹵代-C1-C7-烷基；-C(O)-C1-C7-烷氧基；-C(O)-C3-C10環烷基；-C(O)O-C1-C7-烷基；-C(O)O-C3-C10-環烷基；-C(O)O-鹵代-C1-C7-烷基；-C(O)O-C1-C7-烷氧基；-C(O)-NR4'R4或-NHC(O)-R4，其中R4係選自氫、C1-C7-烷基、鹵代-C1-C7-烷基、C3-C10-環烷基、C3-C10-環烷基-C1-C7-烷基及C1-C7-烷氧基； R4'係選自氫；或R4及R4'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環雜環，該雜環視情況含有選自N、O或S之另一雜原子，且其中該雜環視情況經芳基、芳基-氧基-、C1-C7-烷基、鹵代-C1-C7-烷基或C1-C7-烷氧基取代，且該芳基視情況經鹵素、C1-C7-烷基、鹵代-C1-C7-烷基或C1-C7-烷氧基取代。或(b)-C(O)-NR5'R5或-C(O)-O-R5，其中R5及R5'係選自氫、C1-C7-烷基、C3-C10-環烷基、C1-C7-烷氧基、鹵代-C1-C7-烷基芳基、芳基-C1-C7-烷基-、芳基、雜芳基、雜芳基C1-C7-烷基-、雜環基、二氫化茚，或R5及R5'與其所附接之氮原子一起形成4-9員飽和或部分飽和之單環或雙環雜環，該單環或雙環雜環視情況含有選自N、O或S之另一雜原子；其中該等C3-C10-環烷基、芳基、雜芳基、雜環基及二氫化茚視情況經1至3個選自以下之取代基取代：C1-C7-烷基、鹵代-C1-C7-烷基、C1-C7-烷氧基、鹵代-C1-C7-烷基-氧基-、鹵代-C1-C7-烷基-氧基-C1-C7-烷基、C1-C7-烷基-氧基-C1-C7-烷基及羥基-C1-C7-烷基；或(c)-NR6'R6，其中R6係選自氫、C1-C7-烷基， R6'係選自氫、C1-C7-烷基、C1-C7-烷基羰基-、C3-C10-環烷基；或R6及R6'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環或7-12員飽和或部分飽和之雙環雜環，該雜環視情況含有選自N、O或S之另一雜原子；該單環及雙環雜環未經取代或經1-3個選自以下之取代基取代：C1-C7-烷基-、鹵代-C1-C7-烷基-、C1-C7-烷氧基-、鹵代-C1-C7-烷氧基-、鹵代-C1-C7-烷氧基-C1-C7-烷基-、羥基-及C1-C7-烷氧基-羰基-；(d)-NR5'-C(O)-R5，其中R5係選自氫、C1-C7-烷基、C3-C10-環烷基、C1-C7-烷氧基、鹵代-C1-C7-烷基、芳基、芳基-C1-C7-烷基-、雜芳基、雜芳基-C1-C7-烷基-、雜環基；R5'係選自氫、C1-C7-烷基；m為0-1；且n為0-2；R8為氫且R9係選自氫、C1-C7-烷氧基-C1-C7-烷基-、C1-C7-烷基、C1-C7-烷氧基及鹵代-C1-C7-烷基；其中C1-C7-烷基、C1-C7-烷氧基、雜環基、芳基、雜芳基視情況經芳基、雜芳基、雜環基、C1-C7-烷基、C1-C7-烷氧基、鹵代-C1-C7-烷基、OH取代；前提係不包含6-[5-(2-呋喃基)-1,2,4-二唑-3-基]-N2-甲基-N2-苯基-1,3,5-三-2,4-二胺及6-[5-(2-呋喃基)-1,2,4- 二唑-3-基]-N,N,N'-甲基-N'-苯基-1,3,5-三-2,4-二胺。 Embodiment 1: A compound of formula (I) or a pharmaceutically acceptable salt thereof, Wherein R 1 is selected from hydrogen-halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-; R 2 is selected from hydrogen-C 1 -C 7 -alkyl-halo -C 2 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-NC 1 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-N,N-di-C 1- C 7 -Alkyl-amino-C 2 -C 7 -alkyl-hydroxy-C 2 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 2 -C 7 -alkyl- C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkyl-cyano-C 2 -C 7 -alkyl-; or R 1 and R 2 together with the attached atom form a 4-7 member a saturated or partially saturated heterocyclic ring which is unsubstituted or substituted with from 1 to 3 substituents selected from C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-amine -C 1 -C 7 -alkyl-NC 1 -C 7 -alkyl-amino-C 1 -C 7 -alkyl-N,N-di-C 1 -C 7 -alkyl-amino group- C 1 -C 7 -alkyl-hydroxy-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-C 3 -C 10 -cycloalkyl-C 1- C 7 -alkyl-cyano-C 1 -C 7 -alkyl-; R is selected from halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-cyano-halo-C 1 -C 7 -alkoxy-nitro;-C(O)-O-R', wherein R' is selected from hydrogen, C 1 -C 7-- alkyl, C 3 -C 10 - cycloalkyl Group, C 1 -C 7 - alkoxy, halo -C 1 -C 7 - alkyl aryl, aryl -C 1 -C 7 - alkyl -, heteroaryl and heteroaryl-C 1 -C 7 -alkyl-, heterocyclic; -S(=O) 2 -C 1 -C 7 -alkyl; -S(=O) 2 -C 3 -C 10 -cycloalkyl; -S(=O 2 -C 1 -C 7 -alkoxy; R 3 is selected from (a)-LY, wherein -L- is selected from direct bonding, -(CH 2 ) p -, -C(O)-, -NR 7 -, -NR 7 -C(O)- or -C(O)-NR 7 -, wherein p is selected from 1, 2 or 3 R 7 is selected from hydrogen and C 1 -C 7 -alkyl Y is selected from the group consisting of cycloalkyl, aryl, heteroaryl, heterocyclyl, spiro, which is unsubstituted or substituted with from 1 to 3 substituents selected from halogen: C 1 -C 7 - Alkyl-;halo-C 1 -C 7 -alkyl-;halo-C 1 -C 7 -alkyl-oxy-C 1 -C 7 -alkyl;halo-C 1 -C 7 - alkyl - oxy -C 1 -C 7 - alkyl - group; C 1 -C 7 - alkoxy -; C 1 -C 7 - alkoxy, -C 1 -C 7 - alkoxy -; NC-C 1 -C 7 -alkoxy-;C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-;C 3 -C 10 -cycloalkyl-oxy-C 1 -C 7 -alkyl-; C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkyl-oxy-; C 3 -C 10 -cycloalkyl-oxy-; C 3 -C 10 - ring alkyl-NR 7' -C 1 -C 7 -alkyl-, wherein R 7 ' is selected from hydrogen and C 1 -C 7 -alkyl; C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkoxy-C 1 -C 7 -alkane -C 2 -C 7 -alkenyl;halo-C 2 -C 7 -alkenyl;hydroxy-;hydroxy-C 1 -C 7 -alkyl-;halo-C 1 -C 7 -alkyl -oxy-;amino-;NC 1 -C 7 -alkyl-amino-;N-halo-C 1 -C 7 -alkyl-amino-;N-heterocyclyl-amino-, NC 3 -C 10 -cycloalkyl-amino-, wherein the heterocyclic and cycloalkyl groups are optionally halo-C 1 -C 7 -alkyl-oxy, C 1 -C 7 -alkyl , C 3 -C 10 -cycloalkyl and C 1 -C 7 -alkoxy substituted; NC 3 -C 10 -cycloalkyl-C 1 -C 7 -alkyl-amino-;N,N- -C 1 -C 7 -alkyl-amino-;N,N-di-halo-C 1 -C 7 -alkyl-amino-;N,N-di-heterocyclyl-amino-, N,N-di-C 3 -C 10 -cycloalkyl-amino-, wherein the heterocyclic and cycloalkyl groups are optionally halogenated-C 1 -C 7 -alkyl-oxy, C 1 -C 7 -alkyl, C 3 -C 10 -cycloalkyl and C 1 -C 7 -alkoxy substituted; cyano-; pendant oxy; C 1 -C 7 -alkoxy-carbonyl-;C 1 -C 7 - alkoxy, -C 1 -C 7 - alkoxy, -C 1 -C 7 - alkyl -; aryl; aryl -C 1 -C 7 - alkyl -; Yl - oxy; heterocyclyl; heterocyclyl -C 1 -C 7 - alkyl -; heterocyclyl - oxy -; heterocyclyl - oxy -C 1 -C 7 - alkyl -; aryl -oxy-C 1 -C 7 -alkyl-;heteroaryl-oxy-C 1 -C 7 -alkyl-;hydroxy-carbonyl-;-S-halo-C 1 -C 7 -alkyl ;-SC 1 -C 7 -alkyl;-S-aryl;halo-C 1 -C 7 -alkyl-SC 1 -C 7 -alkyl; C 1 -C 7 -alkyl-SC 1 - C 7 -alkyl; -S(=O) 2 -C 1 -C 7 -alkyl;-S(=O) 2 -halo-C 1 -C 7 -alkyl;-S(=O) 2 -aryl; -S(=O) 2 -heteroaryl; -S(=O) 2 -NR 4' R 4 ;-S(=O) 2 -heterocyclyl;halo-C 1 -C 7 -alkyl-S(=O) 2 -C 1 -C 7 -alkyl; C 1 -C 7 -alkyl-S(=O) 2 -C 1 -C 7 -alkyl;-S(=O -C 1 -C 7 -alkyl; -S(=O)-halo-C 1 -C 7 -alkyl; -S(=O)-C 1 -C 7 -alkoxy;-S( =O)-C 3 -C 10 -cycloalkyl;-C(O)-C 1 -C 7 -alkyl;-C(O)-halo-C 1 -C 7 -alkyl;-C( O)-C 1 -C 7 -alkoxy;-C(O)-C 3 -C 10 cycloalkyl;-C(O)OC 1 -C 7 -alkyl;-C(O)OC 3 - C 10 -cycloalkyl; -C(O)O-halo-C 1 -C 7 -alkyl; -C(O)OC 1 -C 7 -alkoxy;-C(O)-NR 4' R 4 or -NHC(O)-R 4 , wherein R 4 is selected from hydrogen, C 1 - C 7 -alkyl, halo-C 1 -C 7 -alkyl, C 3 -C 10 -cycloalkyl, C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkyl and C 1 - a C 7 -alkoxy group; R 4 ' is selected from hydrogen; or R 4 and R 4 ' together with the nitrogen atom to which it is attached form a 4-7 membered saturated or partially saturated monocyclic heterocyclic ring, which heterocyclic ring contains Another hetero atom selected from N, O or S, and wherein the heterocyclic ring is optionally aryl, aryl-oxy-, C 1 -C 7 -alkyl, halo-C 1 -C 7 -alkyl Or a C 1 -C 7 -alkoxy group, and the aryl group optionally is halogen, C 1 -C 7 -alkyl, halo-C 1 -C 7 -alkyl or C 1 -C 7 -alkoxy Substituted. Or (b)-C(O)-NR 5' R 5 or -C(O)-OR 5 , wherein R 5 and R 5 ' are selected from hydrogen, C 1 -C 7 -alkyl, C 3 -C 10 -cycloalkyl, C 1 -C 7 -alkoxy, halo-C 1 -C 7 -alkylaryl, aryl-C 1 -C 7 -alkyl-, aryl, heteroaryl, Heteroaryl C 1 -C 7 -alkyl-, heterocyclyl, indane, or R 5 and R 5 ' together with the nitrogen atom to which they are attached form a 4-9 membered saturated or partially saturated monocyclic or bicyclic ring a heterocyclic ring, the monocyclic or bicyclic heterocyclic ring optionally containing another hetero atom selected from N, O or S; wherein the C 3 -C 10 -cycloalkyl, aryl, heteroaryl, heterocyclic and The hydrogenation sterol is substituted with 1 to 3 substituents selected from the group consisting of C 1 -C 7 -alkyl, halo-C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy, halogenated -C 1 -C 7 -alkyl-oxy-, halo-C 1 -C 7 -alkyl-oxy-C 1 -C 7 -alkyl, C 1 -C 7 -alkyl-oxy- C 1 -C 7 -alkyl and hydroxy-C 1 -C 7 -alkyl; or (c)-NR 6' R 6 , wherein R 6 is selected from hydrogen, C 1 -C 7 -alkyl, R 6 ' is selected from hydrogen, C 1 -C 7 -alkyl, C 1 -C 7 -alkylcarbonyl-, C 3 -C 10 -cycloalkyl; or R 6 and R 6 ' and the nitrogen atom to which it is attached together Forming a 4-7 membered saturated or partially saturated monocyclic or 7-12 membered saturated or partially saturated bicyclic heterocycle optionally containing another heteroatom selected from N, O or S; the monocyclic and bicyclic The ring is unsubstituted or substituted with from 1 to 3 substituents selected from C 1 -C 7 -alkyl-, halo-C 1 -C 7 -alkyl-, C 1 -C 7 -alkoxy -, halo-C 1 -C 7 -alkoxy-, halo-C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-, hydroxy- and C 1 -C 7 -alkoxy -carbonyl-;(d)-NR 5' -C(O)-R 5 , wherein R 5 is selected from the group consisting of hydrogen, C 1 -C 7 -alkyl, C 3 -C 10 -cycloalkyl, C 1 -C 7 -alkoxy, halo-C 1 -C 7 -alkyl, aryl, aryl-C 1 -C 7 -alkyl-, heteroaryl, heteroaryl-C 1 -C 7 - An alkyl-, heterocyclic group; R 5 ' is selected from hydrogen, C 1 -C 7 -alkyl; m is 0-1; and n is 0-2; R 8 is hydrogen and R 9 is selected from hydrogen, C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-, C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy and halo-C 1 -C 7 -alkyl Wherein C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy, heterocyclyl, aryl,heteroaryl, optionally, aryl, heteroaryl, heterocyclyl, C 1 -C 7 - alkyl, C 1 -C 7 - alkoxy Yl, halo -C 1 -C 7 - alkyl, OH substituents; provided that lines do not contain 6- [5- (2-furyl) -1,2,4 Diazol-3-yl]-N2-methyl-N2-phenyl-1,3,5-three -2,4-diamine and 6-[5-(2-furyl)-1,2,4- Diazol-3-yl]-N,N,N'-methyl-N'-phenyl-1,3,5-three -2,4-diamine.

實施例2：如實施例1之化合物，其中 其中R1係選自氫-鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-；R2係選自氫-C1-C7-烷基-鹵代-C2-C7-烷基-胺基-C2-C7-烷基-N-C1-C7-烷基-胺基-C2-C7-烷基-N,N-二-C1-C7-烷基-胺基-C2-C7-烷基-羥基-C2-C7-烷基-C1-C7-烷氧基-C2-C7-烷基-C3-C10-環烷基-C1-C7-烷基- 氰基-C2-C7-烷基-；或R1及R2與其所附接之原子一起形成4-7員飽和或部分飽和之雜環，該雜環未經取代或經1-3個選自以下之取代基取代：C1-C7-烷基-鹵代-C1-C7-烷基-胺基-C1-C7-烷基-N-C1-C7-烷基-胺基-C1-C7-烷基-N,N-二-C1-C7-烷基-胺基-C1-C7-烷基-羥基-C1-C7-烷基-C1-C7-烷氧基-C1-C7-烷基-C3-C10-環烷基-C1-C7-烷基-氰基-C1-C7-烷基-；R係選自鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-C1-C7-烷氧基-氰基-鹵代-C1-C7-烷氧基-硝基；R3係選自(a)-L-Y，其中 -L-係選自直接鍵結、-(CH2)p-、-C(O)-、-NR7-、-NR7-C(O)-或-C(O)-NR7-，其中p係選自1、2或3 R7係選自氫、C1-C7-烷基Y係選自環烷基、芳基、雜芳基、雜環基，其未經取代或經1-3個選自以下之取代基取代：鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-C1-C7-烷氧基-C3-C10-環烷基-氧基-羥基-鹵代-C1-C7-烷基-氧基-胺基-N-C1-C7-烷基-胺基-N,N-二-C1-C7-烷基-胺基-氰基-C1-C7-烷氧基-羰基-羥基-羰基--C(O)-NR4'R4，其中R4係選自氫、C1-C7-烷基；R4'係選自氫，或R4及R4'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環雜環，該單環雜環視情況含有選 自N、O或S之另一雜原子；或(b)-C(O)-NR5'R5或-C(O)-O-R5，其中R5及R5'係選自氫、C1-C7-烷基；或(c)-NR6'R6，其中R6係選自氫、C1-C7-烷基，R6'係選自氫、C1-C7-烷基、C1-C7-烷基羰基-，m為0-1；且n為0-2；前提係不包含6-[5-(2-呋喃基)-1,2,4-二唑-3-基]-N2-甲基-N2-苯基-1,3,5-三-2,4-二胺。 Embodiment 2: A compound as in Example 1, wherein Wherein R 1 is selected from hydrogen-halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-; R 2 is selected from hydrogen-C 1 -C 7 -alkyl-halo -C 2 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-NC 1 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-N,N-di-C 1- C 7 -alkyl-amino-C 2 -C 7 -alkyl-hydroxy-C 2 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 2 -C 7 -alkyl- C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkyl-cyano-C 2 -C 7 -alkyl-; or R 1 and R 2 together with the atom to which they are attached form a 4-7 member a saturated or partially saturated heterocyclic ring which is unsubstituted or substituted with from 1 to 3 substituents selected from C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-amine -C 1 -C 7 -alkyl-NC 1 -C 7 -alkyl-amino-C 1 -C 7 -alkyl-N,N-di-C 1 -C 7 -alkyl-amino group- C 1 -C 7 -alkyl-hydroxy-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-C 3 -C 10 -cycloalkyl-C 1- C 7 -alkyl-cyano-C 1 -C 7 -alkyl-; R is selected from halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-cyano-halo-C 1 -C 7 -alkoxy-nitro; R 3 is selected from (a)-LY, wherein -L- is selected from direct bonding, - (CH 2 ) p -, -C( O)-, -NR 7 -, -NR 7 -C(O)- or -C(O)-NR 7 -, wherein p is selected from 1, 2 or 3 R 7 is selected from hydrogen, C 1 -C 7 -alkyl Y is selected from cycloalkyl, aryl, heteroaryl, heterocyclyl, which is unsubstituted or substituted with from 1 to 3 substituents selected from halogen-C 1 -C 7 -alkane -halo-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 3 -C 10 -cycloalkyl-oxy-hydroxy-halo-C 1 -C 7 -alkyl -oxy-amino-NC 1 -C 7 -alkyl-amino-N,N-di-C 1 -C 7 -alkyl-amino-cyano-C 1 -C 7 -alkoxy- carbonyl-hydroxy-carbonyl-C(O)-NR 4' R 4 , wherein R 4 is selected from hydrogen, C 1 -C 7 -alkyl; R 4 ' is selected from hydrogen, or R 4 and R 4' Forming a 4-7 membered saturated or partially saturated monocyclic heterocycle together with the nitrogen atom to which it is attached, the monocyclic heterocycle optionally containing another heteroatom selected from N, O or S; or (b)-C ( O)-NR 5' R 5 or -C(O)-OR 5 , wherein R 5 and R 5 ' are selected from hydrogen, C 1 -C 7 -alkyl; or (c)-NR 6' R 6 , Wherein R 6 is selected from the group consisting of hydrogen, C 1 -C 7 -alkyl, and R 6 ' is selected from hydrogen, C 1 -C 7 -alkyl, C 1 -C 7 -alkylcarbonyl-, m is 0-1 ; and n is 0-2; the premise does not contain 6-[5-(2-furyl)-1,2,4- Diazol-3-yl]-N2-methyl-N2-phenyl-1,3,5-three -2,4-diamine.

實施例3：如實施例1或2之化合物，其中 其中R1係選自氫-鹵素-C1-C7-烷基- 鹵代-C1-C7-烷基-；R2係選自氫-C1-C7-烷基-鹵代-C2-C7-烷基-胺基-C2-C7-烷基-N-C1-C7-烷基-胺基-C2-C7-烷基-N,N-二-C1-C7-烷基-胺基-C2-C7-烷基-羥基-C2-C7-烷基-C1-C7-烷氧基-C2-C7-烷基-C3-C10-環烷基-C1-C7-烷基-氰基-C2-C7-烷基-；或R1及R2與其所附接之原子一起形成4-7員飽和或部分飽和之雜環，該雜環未經取代或經1-3個選自以下之取代基取代：C1-C7-烷基-鹵代-C1-C7-烷基-胺基-C1-C7-烷基-N-C1-C7-烷基-胺基-C1-C7-烷基-N,N-二-C1-C7-烷基-胺基-C1-C7-烷基-羥基-C1-C7-烷基-C1-C7-烷氧基-C1-C7-烷基-C3-C10-環烷基-C1-C7-烷基- 氰基-C1-C7-烷基-；R係選自鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-C1-C7-烷氧基-氰基-鹵代-C1-C7-烷氧基-硝基；R3係選自(a)-(CH2)p-Y，其中p係選自0、1、2或3，且Y係選自芳基、雜芳基、雜環基，其未經取代或經1-3個選自以下之取代基取代：鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-C1-C7-烷氧基-C3-C10-環烷基-氧基-羥基-鹵代-C1-C7-烷基-氧基-胺基-N-C1-C7-烷基-胺基-N,N-二-C1-C7-烷基-胺基- 氰基-C1-C7-烷氧基-羰基-羥基-羰基--C(O)-NR4'R4，其中R4係選自氫、C1-C7-烷基；R4'係選自氫，或R4及R4'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環雜環，該單環雜環視情況含有選自N、O或S之另一雜原子；或(b)-C(O)-NR5'R5或-C(O)-O-R5，其中R5係選自氫、苄基、二氫茚基、四氫呋喃基、四氫吡喃基、環氧乙烷基、C3-C10-環烷基、C1-C7-烷基；R5'係選自氫、C1-C7-烷基，或R5及R5'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環或雙環雜環，該雜環視情況含有選自N、O或S之另一雜原子；或(c)-NR6'R6，其中R6係選自氫、苄基、C3-C10-環烷基、C1-C7-烷基，R6'係選自氫、C1-C7-烷基、C1-C7-烷基羰基-，或R6及R6'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環或7-12員飽和或部分飽和之雙環雜環，該雜環視情況含有選自N、O或S之另一雜原子； 其未經取代或經1-3個選自以下之取代基取代：C1-C7-烷基-羥基-C1-C7-烷氧基-羰基-或(d)-NR5'-C(O)-R5，其中R5係選自C3-C10-環烷基；R5'係選自氫、C1-C7-烷基；m為0-1；且n為0-1；前提係不包含6-[5-(2-呋喃基)-1,2,4-二唑-3-基]-N2-甲基-N2-苯基-1,3,5-三-2,4-二胺。 Embodiment 3: The compound of Embodiment 1 or 2, wherein Wherein R 1 is selected from the group consisting of hydrogen-halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-; R 2 is selected from hydrogen-C 1 -C 7 -alkyl-halo -C 2 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-NC 1 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-N,N-di-C 1- C 7 -alkyl-amino-C 2 -C 7 -alkyl-hydroxy-C 2 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 2 -C 7 -alkyl- C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkyl-cyano-C 2 -C 7 -alkyl-; or R 1 and R 2 together with the attached atom form a 4-7 member a saturated or partially saturated heterocyclic ring which is unsubstituted or substituted with from 1 to 3 substituents selected from C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-amine -C 1 -C 7 -alkyl-NC 1 -C 7 -alkyl-amino-C 1 -C 7 -alkyl-N,N-di-C 1 -C 7 -alkyl-amino group- C 1 -C 7 -alkyl-hydroxy-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-C 3 -C 10 -cycloalkyl-C 1- C 7 -alkyl-cyano-C 1 -C 7 -alkyl-; R is selected from halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-cyano-halo-C 1 -C 7 -alkoxy-nitro; R 3 is selected from (a)-(CH 2 ) p -Y, wherein p is selected from 0 , 1, 2 or 3, and Y system From aryl, heteroaryl, a heterocyclic group, which is unsubstituted or substituted with 1-3 substituents selected from the group: halogen -C 1 -C 7 - alkyl - halo -C 1 -C 7 - Alkyl-C 1 -C 7 -alkoxy-C 3 -C 10 -cycloalkyl-oxy-hydroxy-halo-C 1 -C 7 -alkyl-oxy-amino-NC 1 -C 7 -Alkyl-amino-N,N-di-C 1 -C 7 -alkyl-amino-cyano-C 1 -C 7 -alkoxy-carbonyl-hydroxy-carbonyl--C(O) -NR 4' R 4 , wherein R 4 is selected from hydrogen, C 1 -C 7 -alkyl; R 4 ' is selected from hydrogen, or R 4 and R 4' together with the nitrogen atom to which they are attached form 4- a 7-membered saturated or partially saturated monocyclic heterocyclic ring optionally containing another hetero atom selected from N, O or S; or (b) -C(O)-NR 5' R 5 or -C (O)-OR 5 , wherein R 5 is selected from the group consisting of hydrogen, benzyl, indanyl, tetrahydrofuranyl, tetrahydropyranyl, oxiranyl, C 3 -C 10 -cycloalkyl, C 1 -C 7 -alkyl; R 5 ' is selected from hydrogen, C 1 -C 7 -alkyl, or R 5 and R 5' together with the nitrogen atom to which they are attached form a 4-7 member saturated or partially saturated single or a bicyclic heterocyclic ring, which ring optionally contains a heteroatom selected from N, O, or S of another hetero atom; or (c) -NR 6 'R 6 , which R 6 is selected from hydrogen, benzyl, C 3 -C 10 - cycloalkyl, C 1 -C 7 - alkyl, R 6 'is selected from hydrogen, C 1 -C 7 - alkyl, C 1 -C 7 -Alkylcarbonyl-, or R 6 and R 6 ' together with the nitrogen atom to which they are attached form a 4-7 membered saturated or partially saturated monocyclic or 7-12 membered saturated or partially saturated bicyclic heterocycle, which Circulatingly containing another hetero atom selected from N, O or S; unsubstituted or substituted with from 1 to 3 substituents selected from C 1 -C 7 -alkyl-hydroxy-C 1 -C 7 - alkoxy-carbonyl- or (d)-NR 5' -C(O)-R 5 , wherein R 5 is selected from C 3 -C 10 -cycloalkyl; R 5 ' is selected from hydrogen, C 1 -C 7 -alkyl; m is 0-1; and n is 0-1; the premise does not contain 6-[5-(2-furyl)-1,2,4- Diazol-3-yl]-N2-methyl-N2-phenyl-1,3,5-three -2,4-diamine.

實施例4：如實施例1至3中任一項之化合物，其中 R1係選自氫-鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-； R2係選自氫-C1-C7-烷基-鹵代-C2-C7-烷基-胺基-C2-C7-烷基-N-C1-C7-烷基-胺基-C2-C7-烷基-N,N-二-C1-C7-烷基-胺基-C2-C7-烷基-羥基-C2-C7-烷基-C1-C7-烷氧基-C2-C7-烷基-C3-C10-環烷基-C1-C7-烷基-氰基-C2-C7-烷基-；或R1及R2與其所附接之原子一起形成4-7員飽和或部分飽和之雜環，該雜環未經取代或經1-3個選自以下之取代基取代：C1-C7-烷基-鹵代-C1-C7-烷基-胺基-C1-C7-烷基-N-C1-C7-烷基-胺基-C1-C7-烷基-N,N-二-C1-C7-烷基-胺基-C1-C7-烷基-羥基-C1-C7-烷基-C1-C7-烷氧基-C1-C7-烷基-C3-C10-環烷基-C1-C7-烷基-氰基-C1-C7-烷基-； R係選自鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-C1-C7-烷氧基-氰基-鹵代-C1-C7-烷氧基-硝基；R3係選自(a)-(CH2)p-Y，其中p係選自0、1、2或3，且Y係選自芳基、雜芳基、雜環基，其未經取代或經1-3個選自以下之取代基取代：鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-C1-C7-烷氧基-C3-C10-環烷基-氧基-羥基-鹵代-C1-C7-烷基-氧基-胺基-N-C1-C7-烷基-胺基-N,N-二-C1-C7-烷基-胺基-氰基- C1-C7-烷氧基-羰基-羥基-羰基--C(O)-NR4'R4，其中R4係選自氫、C1-C7-烷基；R4'係選自氫，或R4及R4'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環雜環，該雜環視情況含有選自N、O或S之另一雜原子；或(b)-C(O)-NR5'R5或-C(O)-O-R5，其中R5係選自氫、苄基、二氫茚基、四氫呋喃基、四氫吡喃基、環氧乙烷基、C3-C10-環烷基、C1-C7-烷基；R5'係選自氫、C1-C7-烷基，或R5及R5'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環或雙環雜環，該雜環視情況含有選自N、O或S之另一雜原子；或(c)-NR6'R6，其中R6係選自氫、苄基、C3-C10-環烷基、C1-C7-烷基，R6'係選自氫、C1-C7-烷基、C1-C7-烷基羰基-，或R6及R6'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環或7-12員飽和或部分飽和之雙環雜環，該雜環視情況含有選自N、O或S之另一雜原子；其未經取代或經1-3個選自以下之取代基取代： C1-C7-烷基-羥基-C1-C7-烷氧基-羰基-或(d)-NR5'-C(O)-R5，其中R5係選自C3-C10-環烷基；R5'係選自氫、C1-C7-烷基；m為0-1；且n為0-1；前提係不包含6-[5-(2-呋喃基)-1,2,4-二唑-3-基]-N2-甲基-N2-苯基-1,3,5-三-2,4-二胺。 The compound of any one of embodiments 1 to 3, wherein R 1 is selected from hydrogen-halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-; R 2 is selected from hydrogen-C 1 -C 7 -alkyl-halo- C 2 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-NC 1 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-N,N-di-C 1 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-hydroxy-C 2 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 2 -C 7 -alkyl-C 3- C 10 -cycloalkyl-C 1 -C 7 -alkyl-cyano-C 2 -C 7 -alkyl-; or R 1 and R 2 together with the atoms to which they are attached form a 4-7 member saturation Or a partially saturated heterocyclic ring which is unsubstituted or substituted with from 1 to 3 substituents selected from C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-amino -C 1 -C 7 -alkyl-NC 1 -C 7 -alkyl-amino-C 1 -C 7 -alkyl-N,N-di-C 1 -C 7 -alkyl-amino-C 1- C 7 -alkyl-hydroxy-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkyl-cyano-C 1 -C 7 -alkyl-; R is selected from halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-C 1 - C 7 -alkoxy-cyano-halo-C 1 -C 7 -alkoxy-nitro; R 3 is selected from (a)-(CH 2 ) p -Y, wherein p is selected from 0, 1, 2 or 3, and Y is selected from Group, a heteroaryl group, a heterocyclic group, which is unsubstituted or substituted with 1-3 substituents selected from the group: halogen -C 1 -C 7 - alkyl - halo -C 1 -C 7 - alkyl -C 1 -C 7 -alkoxy-C 3 -C 10 -cycloalkyl-oxy-hydroxy-halo-C 1 -C 7 -alkyl-oxy-amino-NC 1 -C 7 - Alkyl-amino-N,N-di-C 1 -C 7 -alkyl-amino-cyano-C 1 -C 7 -alkoxy-carbonyl-hydroxy-carbonyl--C(O)-NR 4' R 4 , wherein R 4 is selected from hydrogen, C 1 -C 7 -alkyl; R 4 ' is selected from hydrogen, or R 4 and R 4 ' together with the nitrogen atom to which they are attached form a 4-7 member a saturated or partially saturated monocyclic heterocyclic ring optionally containing another hetero atom selected from N, O or S; or (b) -C(O)-NR 5' R 5 or -C(O)- OR 5 , wherein R 5 is selected from the group consisting of hydrogen, benzyl, indanyl, tetrahydrofuranyl, tetrahydropyranyl, oxiranyl, C 3 -C 10 -cycloalkyl, C 1 -C 7 - An alkyl group; R 5 ' is selected from hydrogen, C 1 -C 7 -alkyl, or R 5 and R 5 ' together with the nitrogen atom to which they are attached form a 4-7 membered saturated or partially saturated monocyclic or bicyclic hetero ring, said ring optionally containing heteroatoms selected from N, O, or S of another hetero atom; or (c) -NR 6 'R 6 , wherein R 6 is selected from the group Hydrogen, benzyl, C 3 -C 10 - cycloalkyl, C 1 -C 7 - alkyl, R 6 'is selected from hydrogen, C 1 -C 7 - alkyl, C 1 -C 7 - alkyl carbonyl -, or R 6 and R 6' together with the nitrogen atom to which they are attached form a 4-7 membered saturated or partially saturated monocyclic or 7-12 membered saturated or partially saturated bicyclic heterocycle optionally containing Another hetero atom of N, O or S; which is unsubstituted or substituted with from 1 to 3 substituents selected from C 1 -C 7 -alkyl-hydroxy-C 1 -C 7 -alkoxy- Carbonyl- or (d)-NR 5' -C(O)-R 5 , wherein R 5 is selected from C 3 -C 10 -cycloalkyl; R 5 ' is selected from hydrogen, C 1 -C 7 -alkane Base; m is 0-1; and n is 0-1; the premise does not contain 6-[5-(2-furyl)-1,2,4- Diazol-3-yl]-N2-methyl-N2-phenyl-1,3,5-three -2,4-diamine.

實施例5：如實施例1至3中任一項之化合物，其中R1係選自氫-鹵素-C1-C4-烷基-鹵代-C1-C4-烷基-。 The compound of any one of embodiments 1 to 3, wherein R 1 is selected from the group consisting of hydrogen-halogen-C 1 -C 4 -alkyl-halo-C 1 -C 4 -alkyl-.

實施例6：如實施例1至5中任一項之化合物，其中R1係選自氫-、氯-、氟-及甲基-。 The compound of any one of embodiments 1 to 5, wherein R 1 is selected from the group consisting of hydrogen-, chloro-, fluoro-, and methyl-.

實施例7：如實施例1至6中任一項之化合物，其中R1係選自氫-及氟-。 The compound of any one of embodiments 1 to 6, wherein R 1 is selected from the group consisting of hydrogen- and fluorine-.

實施例8：如實施例1至7中任一項之化合物，其中R2係選自氫- C1-C4-烷基-鹵代-C2-C4-烷基-N,N-二-C1-C2-烷基-胺基-C2-C4-烷基-羥基-C2-C4-烷基-C1-C2-烷氧基-C2-C4-烷基-C3-C6-環烷基-C1-C7-烷基-。 The compound of any one of embodiments 1 to 7, wherein the R 2 is selected from the group consisting of hydrogen - C 1 -C 4 -alkyl-halo-C 2 -C 4 -alkyl-N,N- Di-C 1 -C 2 -alkyl-amino-C 2 -C 4 -alkyl-hydroxy-C 2 -C 4 -alkyl-C 1 -C 2 -alkoxy-C 2 -C 4 - Alkyl-C 3 -C 6 -cycloalkyl-C 1 -C 7 -alkyl-.

實施例9：如實施例1至8中任一項之化合物，其中R2係選自氫-甲基-乙基-異丙基-2,2,2-三氟-乙基-N,N-二-甲基-胺基-乙基-羥基-乙基-甲氧基-乙基-環丙基-甲基-。 The compound of any one of embodiments 1 to 8, wherein the R 2 is selected from the group consisting of hydrogen-methyl-ethyl-isopropyl-2,2,2-trifluoro-ethyl-N,N -Dimethyl-amino-ethyl-hydroxy-ethyl-methoxy-ethyl-cyclopropyl-methyl-.

實施例10：如實施例1至9中任一項之化合物，其中R2係選自氫-甲基-乙基-2,2,2-三氟-乙基-。 The compound of any one of embodiments 1 to 9, wherein the R 2 is selected from the group consisting of hydrogen-methyl-ethyl-2,2,2-trifluoro-ethyl-.

實施例11：如實施例1至4中任一項之化合物，其中 R1及R2一起選自-CH2-CH2-、-CH2-CH2-CH2-、-CH=CH-、-CH=CH-CH2-或-CH2-CH=CH-。 The compound of any one of embodiments 1 to 4, wherein R 1 and R 2 are together selected from the group consisting of -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH=CH- , -CH=CH-CH 2 - or -CH 2 -CH=CH-.

實施例12：如實施例11中任一項之化合物，其中R1及R2一起選自-CH2-CH2-或-CH2-CH2-CH2-。 The compound of any one of embodiments 11, wherein R 1 and R 2 are together selected from -CH 2 -CH 2 - or -CH 2 -CH 2 -CH 2 -.

實施例13：如實施例1至4中任一項之化合物，其中R1係選自氫-氯-氟-甲基-；R2係選自氫-C1-C4-烷基-鹵代-C2-C4-烷基-N,N-二-C1-C2-烷基-胺基-C2-C4-烷基-羥基-C2-C4-烷基-C1-C2-烷氧基-C2-C4-烷基-C3-C6-環烷基-C1-C7-烷基-。 The compound of any one of embodiments 1 to 4, wherein R 1 is selected from the group consisting of hydrogen-chloro-fluoro-methyl-; and R 2 is selected from hydrogen-C 1 -C 4 -alkyl-halogen -C 2 -C 4 -alkyl-N,N-di-C 1 -C 2 -alkyl-amino-C 2 -C 4 -alkyl-hydroxy-C 2 -C 4 -alkyl-C 1- C 2 -alkoxy-C 2 -C 4 -alkyl-C 3 -C 6 -cycloalkyl-C 1 -C 7 -alkyl-.

實施例14：如實施例1至13中任一項之化合物，其中R係選自鹵素-C1-C4-烷基-鹵代-C1-C4-烷基-C1-C4-烷氧基- 氰基-。 The compound of any one of embodiments 1 to 13, wherein the R is selected from the group consisting of halogen-C 1 -C 4 -alkyl-halo-C 1 -C 4 -alkyl-C 1 -C 4 - alkoxy-cyano-.

實施例15：如實施例1至14中任一項之化合物，其中R係選自氯-氟-甲基-三氟甲基-甲氧基-氰基-。 The compound of any one of embodiments 1 to 14, wherein the R is selected from the group consisting of chloro-fluoro-methyl-trifluoromethyl-methoxy-cyano-.

實施例16：如實施例1至15中任一項之化合物，其中R3係選自-(CH2)p-Y，其中p係選自0、1、2或3，且Y係選自芳基、雜芳基、雜環基，其未經取代或經1-3個選自以下之取代基取代：鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-C1-C7-烷氧基-C3-C10-環烷基-氧基-羥基-鹵代-C1-C7-烷基-氧基-胺基-N-C1-C7-烷基-胺基- N,N-二-C1-C7-烷基-胺基--S(=O)2-C1-C7-烷基；-S(=O)2-鹵代-C1-C7-烷基；-S(=O)-C1-C7-烷基；-S(=O)-鹵代-C1-C7-烷基；C3-C10-環烷基-C1-C7-烷氧基-C1-C7-烷基-；氰基-C1-C7-烷氧基-羰基-羥基-羰基--C(O)-NR4'R4，其中R4係選自氫、C1-C7-烷基；R4'係選自氫，或R4及R4'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環雜環，該單環雜環視情況含有選自N、O或S之另一雜原子。 The compound of any one of embodiments 1 to 15, wherein the R 3 is selected from the group consisting of -(CH 2 ) p -Y, wherein the p is selected from 0, 1, 2 or 3, and the Y is selected from the group consisting of An aryl, heteroaryl, heterocyclyl group which is unsubstituted or substituted with from 1 to 3 substituents selected from halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkane -C 1 -C 7 -alkoxy-C 3 -C 10 -cycloalkyl-oxy-hydroxy-halo-C 1 -C 7 -alkyl-oxy-amino-NC 1 -C 7 -alkyl-amino-N,N-di-C 1 -C 7 -alkyl-amino--S(=O) 2 -C 1 -C 7 -alkyl;-S(=O) 2 - Halo-C 1 -C 7 -alkyl; -S(=O)-C 1 -C 7 -alkyl; -S(=O)-halo-C 1 -C 7 -alkyl; C 3 - C 10 -cycloalkyl-C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-; cyano-C 1 -C 7 -alkoxy-carbonyl-hydroxy-carbonyl--C(O -NR 4' R 4 , wherein R 4 is selected from hydrogen, C 1 -C 7 -alkyl; R 4 ' is selected from hydrogen, or R 4 and R 4 ' together with the nitrogen atom to which they are attached form 4 A -7 member saturated or partially saturated monocyclic heterocyclic ring optionally containing another hetero atom selected from N, O or S.

實施例17：如實施例1至16中任一項之化合物，其中R3係選自-Y，其中Y係選自芳基、雜芳基、雜環基，其未經取代或經1-2個選自以下之取代基取代：鹵素-C1-C4-烷基-鹵代-C1-C4-烷基-C1-C4-烷氧基-C3-C7-環烷基-氧基-羥基- 鹵代-C1-C4-烷基-氧基-胺基-氰基-C1-C4-烷氧基-羰基-羥基-羰基--S(=O)2-C1-C7-烷基；-S(=O)2-鹵代-C1-C7-烷基；-S(=O)-C1-C7-烷基；-S(=O)-鹵代-C1-C7-烷基C3-C10-環烷基-C1-C7-烷氧基-C1-C7-烷基-；-C(O)-NR4'R4，其中R4係選自氫、C1-C4-烷基；R4'係選自氫，或R4及R4'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環雜環，該單環雜環視情況含有選自N、O或S之另一雜原子。 The compound of any one of embodiments 1 to 16, wherein the R 3 is selected from the group consisting of -Y, wherein the Y is selected from the group consisting of an aryl group, a heteroaryl group, a heterocyclic group, which is unsubstituted or 1- Substituted by two substituents selected from the group consisting of: halogen-C 1 -C 4 -alkyl-halo-C 1 -C 4 -alkyl-C 1 -C 4 -alkoxy-C 3 -C 7 - ring Alkyl-oxy-hydroxy-halo-C 1 -C 4 -alkyl-oxy-amino-cyano-C 1 -C 4 -alkoxy-carbonyl-hydroxy-carbonyl--S(=O 2 -C 1 -C 7 -alkyl; -S(=O) 2 -halo-C 1 -C 7 -alkyl; -S(=O)-C 1 -C 7 -alkyl;-S (=O)-halo-C 1 -C 7 -alkyl C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-;-C(O -NR 4' R 4 , wherein R 4 is selected from hydrogen, C 1 -C 4 -alkyl; R 4 ' is selected from hydrogen, or R 4 and R 4' together with the nitrogen atom to which they are attached form 4 A -7 member saturated or partially saturated monocyclic heterocyclic ring optionally containing another hetero atom selected from N, O or S.

實施例18：如實施例1至17中任一項之化合物，其中R3係選自-Y，其中Y係選自芳基、雜芳基、雜環基，其未經取代或經1-2個選自以下之取代基取代：鹵素-C1-C4-烷基-鹵代-C1-C4-烷基-C1-C4-烷氧基-C3-C7-環烷基-氧基- 羥基-鹵代-C1-C4-烷基-氧基-胺基-氰基-C1-C4-烷氧基-羰基-羥基-羰基--C(O)-NR4'R4，其中R4係選自氫、C1-C4-烷基；R4'係選自氫，或R4及R4'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環雜環，該單環雜環視情況含有選自N、O或S之另一雜原子。 The compound of any one of embodiments 1 to 17, wherein the R 3 is selected from the group consisting of -Y, wherein the Y is selected from the group consisting of an aryl group, a heteroaryl group, a heterocyclic group, which is unsubstituted or 1- Substituted by two substituents selected from the group consisting of: halogen-C 1 -C 4 -alkyl-halo-C 1 -C 4 -alkyl-C 1 -C 4 -alkoxy-C 3 -C 7 - ring Alkyl-oxy-hydroxy-halo-C 1 -C 4 -alkyl-oxy-amino-cyano-C 1 -C 4 -alkoxy-carbonyl-hydroxy-carbonyl--C(O) -NR 4' R 4 , wherein R 4 is selected from hydrogen, C 1 -C 4 -alkyl; R 4 ' is selected from hydrogen, or R 4 and R 4' together with the nitrogen atom to which they are attached form 4- A 7-membered saturated or partially saturated monocyclic heterocyclic ring optionally containing another hetero atom selected from N, O or S.

實施例19：如實施例1至17中任一項之化合物，其中R3係選自苯基、呋喃基、苯硫基、吡啶基、噻唑基、吡唑基、異唑基、咪唑基、吡咯基、苯并呋喃基、嘧啶基、唑基、嗎啉基、六氫吡啶基、四氫呋喃基、四氫吡喃基、吡咯啶基、二氫苯并呋喃基，其未經取代或經1-2個選自以下之取代基取代：鹵素-C1-C4-烷基-鹵代-C1-C4-烷基-C1-C4-烷氧基-C3-C7-環烷基-氧基- 羥基-鹵代-C1-C4-烷基-氧基-胺基-氰基-C1-C4-烷氧基-羰基--S(=O)2-C1-C7-烷基；-S(=O)2-鹵代-C1-C7-烷基；-S(=O)-C1-C7-烷基；-S(=O)-鹵代-C1-C7-烷基C3-C10-環烷基-C1-C7-烷氧基-C1-C7-烷基-；-C(O)-NR4'R4，其中R4係選自氫、C1-C4-烷基；R4'係選自氫，或R4及R4'與其所附接之氮原子一起形成嗎啉基、六氫吡啶基、吡咯啶基。 The compound of any one of embodiments 1 to 17, wherein R 3 is selected from the group consisting of phenyl, furyl, phenylthio, pyridyl, thiazolyl, pyrazolyl, iso Azyl, imidazolyl, pyrrolyl, benzofuranyl, pyrimidinyl, An azolyl, morpholinyl, hexahydropyridyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, dihydrobenzofuranyl group which is unsubstituted or substituted with from 1-2 substituents selected from the group consisting of: Halogen-C 1 -C 4 -alkyl-halo-C 1 -C 4 -alkyl-C 1 -C 4 -alkoxy-C 3 -C 7 -cycloalkyl-oxy-hydroxy-halo -C 1 -C 4 -alkyl-oxy-amino-cyano-C 1 -C 4 -alkoxy-carbonyl--S(=O) 2 -C 1 -C 7 -alkyl;-S (=O) 2 -halo-C 1 -C 7 -alkyl;-S(=O)-C 1 -C 7 -alkyl;-S(=O)-halo-C 1 -C 7 - Alkyl C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-;-C(O)-NR 4' R 4 , wherein R 4 is selected from Hydrogen, C 1 -C 4 -alkyl; R 4 ' is selected from hydrogen, or R 4 and R 4 ' together with the nitrogen atom to which they are attached form a morpholinyl group, a hexahydropyridyl group, a pyrrolidinyl group.

實施例20：如實施例1至18中任一項之化合物，其中R3係選自苯基、呋喃基、苯硫基、吡啶基、噻唑基、吡唑基、異唑基、咪唑基、吡咯基、苯并呋喃基、嘧啶基、唑基、嗎啉基、六氫吡啶基、四氫呋喃基、四氫吡喃基、吡咯啶基、二氫苯并呋喃基，其未經取代或經1-2個選自以下之取代基取代：氯-溴-氟-甲基- 三氟甲基-2,2,2-三氟-乙基-2,2,2-三氟-乙基-氧基-甲基-環丙基-甲氧基-甲基--S(=O)2-2,2,2-三氟-乙基-；-S(=O)2-丙基；-S(=O)-3,3,3-三氟-丙基；3,3,3-三氟-丙基-氧基-甲基-；甲氧基-環戊基-氧基-三氟甲基-氧基-2,2,2-三氟-乙基-氧基-胺基-氰基-甲氧基-羰基--C(O)-NR4'R4，其中R4係選自氫、甲基；R4'係選自氫，或R4及R4'與其所附接之氮原子一起形成嗎啉基、六氫吡啶基、吡咯啶基。 The compound of any one of embodiments 1 to 18, wherein R 3 is selected from the group consisting of phenyl, furyl, phenylthio, pyridyl, thiazolyl, pyrazolyl, iso Azyl, imidazolyl, pyrrolyl, benzofuranyl, pyrimidinyl, An azolyl, morpholinyl, hexahydropyridyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, dihydrobenzofuranyl group which is unsubstituted or substituted with from 1-2 substituents selected from the group consisting of: Chloro-bromo-fluoro-methyl-trifluoromethyl-2,2,2-trifluoro-ethyl-2,2,2-trifluoro-ethyl-oxy-methyl-cyclopropyl-methoxy -methyl--S(=O) 2 -2,2,2-trifluoro-ethyl-;-S(=O) 2 -propyl;-S(=O)-3,3,3- Trifluoro-propyl; 3,3,3-trifluoro-propyl-oxy-methyl-; methoxy-cyclopentyl-oxy-trifluoromethyl-oxy-2,2,2- Trifluoro-ethyl-oxy-amino-cyano-methoxy-carbonyl-C(O)-NR 4' R 4 , wherein R 4 is selected from hydrogen, methyl; R 4 ' is selected from Hydrogen, or R 4 and R 4 ' together with the nitrogen atom to which they are attached, form a morpholinyl group, a hexahydropyridyl group, a pyrrolidinyl group.

實施例21：如實施例1至18中任一項之化合物，其中R3係選自苯基、呋喃基、苯硫基、吡啶基、噻唑基、吡唑基、異唑基、咪唑基、吡咯基、苯并呋喃基、嘧啶基、唑 基、嗎啉基、六氫吡啶基、四氫呋喃基、四氫吡喃基、吡咯啶基、二氫苯并呋喃基，其未經取代或經1-2個選自以下之取代基取代：氯-溴-氟-甲基-三氟甲基-2,2,2-三氟-乙基-環丙基-甲氧基-甲基-甲氧基-環戊基-氧基-三氟甲基-氧基-2,2,2-三氟-乙基-氧基-胺基-氰基-甲氧基-羰基--C(O)-NR4'R4，其中R4係選自氫、甲基；R4'係選自氫，或R4及R4'與其所附接之氮原子一起形成嗎啉基、六氫吡啶基、吡咯啶基。 The compound of any one of embodiments 1 to 18, wherein R 3 is selected from the group consisting of phenyl, furyl, phenylthio, pyridyl, thiazolyl, pyrazolyl, iso Azyl, imidazolyl, pyrrolyl, benzofuranyl, pyrimidinyl, An azolyl, morpholinyl, hexahydropyridyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, dihydrobenzofuranyl group which is unsubstituted or substituted with from 1-2 substituents selected from the group consisting of: Chloro-bromo-fluoro-methyl-trifluoromethyl-2,2,2-trifluoro-ethyl-cyclopropyl-methoxy-methyl-methoxy-cyclopentyl-oxy-trifluoro Methyl-oxy-2,2,2-trifluoro-ethyl-oxy-amino-cyano-methoxy-carbonyl-C(O)-NR 4' R 4 , wherein R 4 is selected From hydrogen, methyl; R 4 ' is selected from hydrogen, or R 4 and R 4 ' together with the nitrogen atom to which it is attached form a morpholinyl group, a hexahydropyridyl group, a pyrrolidinyl group.

實施例22：如實施例1至21中任一項之化合物，其中R3係選自 -C(O)-NR5'R5或-C(O)-O-R5，其中R5係選自氫、苄基、二氫茚基、四氫呋喃基、四氫吡喃基、環氧乙烷基、C3-C10-環烷基、C1-C7-烷基；R5'係選自氫、C1-C7-烷基，或R5及R5'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環或雙環雜環，該雜環視情況含有選自N、O或S之另一雜原子。 The compound of any one of embodiments 1 to 21, wherein R 3 is selected from the group consisting of -C(O)-NR 5' R 5 or -C(O)-OR 5 , wherein R 5 is selected from Hydrogen, benzyl, indanyl, tetrahydrofuranyl, tetrahydropyranyl, oxiranyl, C 3 -C 10 -cycloalkyl, C 1 -C 7 -alkyl; R 5 ' is selected from Hydrogen, C 1 -C 7 -alkyl, or R 5 and R 5 ' together with the nitrogen atom to which they are attached form a 4-7 membered saturated or partially saturated monocyclic or bicyclic heterocyclic ring optionally containing Another hetero atom of N, O or S.

實施例23：如實施例1至22中任一項之化合物，其中R3係選自-NR6'R6，其中R6係選自氫、苄基、C3-C10-環烷基、C1-C7-烷基，R6'係選自氫、C1-C7-烷基、C1-C7-烷基羰基-，或R6及R6'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環或7-12員飽和或部分飽和之雙環雜環，該雜環視情況含有選自N、O或S之另一雜原子；其未經取代或經1-3個選自以下之取代基取代：C1-C7-烷基-羥基-C1-C7-烷氧基-羰基-。 The compound of any one of embodiments 1 to 22, wherein R 3 is selected from the group consisting of -NR 6 ' R 6 , wherein R 6 is selected from the group consisting of hydrogen, benzyl, C 3 -C 10 -cycloalkyl , C 1 -C 7 -alkyl, R 6 ' is selected from hydrogen, C 1 -C 7 -alkyl, C 1 -C 7 -alkylcarbonyl-, or R 6 and R 6' are attached thereto The nitrogen atoms together form a 4-7 membered saturated or partially saturated monocyclic or 7-12 membered saturated or partially saturated bicyclic heterocycle which optionally contains another heteroatom selected from N, O or S; Substituted or substituted with 1-3 substituents selected from C 1 -C 7 -alkyl-hydroxy-C 1 -C 7 -alkoxy-carbonyl-.

實施例24：如實施例1至23中任一項之化合物，其中R3係選自-NR5'-C(O)-R5，其中R5係選自C3-C10-環烷基；R5'係選自氫、C1-C7-烷基。 The compound of any one of embodiments 1 to 23, wherein R 3 is selected from the group consisting of -NR 5 ' -C(O)-R 5 , wherein R 5 is selected from C 3 -C 10 -cycloalkane R 5 ' is selected from the group consisting of hydrogen and C 1 -C 7 -alkyl.

實施例25：如實施例1至24中任一項之化合物，其中m為0。 The compound of any one of embodiments 1 to 24, wherein m is 0.

實施例26：如實施例1至25中任一項之化合物，其中n為0或1，尤其為0。 The compound of any one of embodiments 1 to 25, wherein n is 0 or 1, especially 0.

實施例27：如實施例1之化合物，其中R1係選自氫-氟-；R2係選自氫-C1-C4-烷基-鹵代-C2-C4-烷基-N,N-二-C1-C2-烷基-胺基-C2-C4-烷基-羥基-C2-C4-烷基-C1-C2-烷氧基-C2-C4-烷基-C3-C6-環烷基-C1-C7-烷基-；或R1及R2一起選自-CH2-CH2-或-CH2-CH2-CH2-；R係選自鹵素-C1-C4-烷基-鹵代-C1-C4-烷基-C1-C4-烷氧基- 氰基-；且R3係選自-(CH2)p-Y，其中p係選自0、1、2或3，且Y係選自芳基、雜芳基、雜環基，其未經取代或經1-3個選自以下之取代基取代：鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-C1-C7-烷氧基-C3-C10-環烷基-氧基-羥基-鹵代-C1-C7-烷基-氧基-胺基-N-C1-C7-烷基-胺基-N,N-二-C1-C7-烷基-胺基-氰基-C1-C7-烷氧基-羰基--S(=O)2-C1-C7-烷基；-S(=O)2-鹵代-C1-C7-烷基；-S(=O)-C1-C7-烷基；-S(=O)-鹵代-C1-C7-烷基C3-C10-環烷基-C1-C7-烷氧基-C1-C7-烷基-；-C(O)-NR4'R4，其中R4係選自氫、C1-C7-烷基；R4'係選自氫， 或R4及R4'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環雜環，該單環雜環視情況含有選自N、O或S之另一雜原子，m為0；且n為0-1。 Embodiment 27. The compound of Embodiment 1, wherein R 1 is selected from the group consisting of hydrogen-fluoro-; and R 2 is selected from the group consisting of hydrogen-C 1 -C 4 -alkyl-halo-C 2 -C 4 -alkyl- N,N-di-C 1 -C 2 -alkyl-amino-C 2 -C 4 -alkyl-hydroxy-C 2 -C 4 -alkyl-C 1 -C 2 -alkoxy-C 2 -C 4 -alkyl-C 3 -C 6 -cycloalkyl-C 1 -C 7 -alkyl-; or R 1 and R 2 are taken together from -CH 2 -CH 2 - or -CH 2 -CH 2 -CH 2 -; R is selected from halogen-C 1 -C 4 -alkyl-halo-C 1 -C 4 -alkyl-C 1 -C 4 -alkoxy-cyano-; and R 3 Selected from -(CH 2 ) p -Y, wherein p is selected from 0, 1, 2 or 3, and Y is selected from aryl, heteroaryl, heterocyclic, unsubstituted or via 1-3 Substituted by a substituent selected from: halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 3 -C 10 -cycloalkyl -oxy-hydroxy-halo-C 1 -C 7 -alkyl-oxy-amino-NC 1 -C 7 -alkyl-amino-N,N-di-C 1 -C 7 -alkyl -amino-cyano-C 1 -C 7 -alkoxy-carbonyl--S(=O) 2 -C 1 -C 7 -alkyl;-S(=O) 2 -halo-C 1 - C 7 -alkyl;-S(=O)-C 1 -C 7 -alkyl;-S(=O)-halo-C 1 -C 7 -alkyl C 3 -C 10 -cycloalkyl- C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-;-C(O)-NR 4' R 4 , wherein R 4 is selected from hydrogen, C 1 -C 7 -alkyl; R 4 ' is selected from hydrogen, or R 4 and R 4' The attached nitrogen atoms together form a 4-7 membered saturated or partially saturated monocyclic heterocycle which optionally contains another heteroatom selected from N, O or S, m is 0; and n is 0 -1.

實施例28：如實施例1之化合物，其中R1係選自氫-氟-；R2係選自氫-C1-C4-烷基-鹵代-C2-C4-烷基-N,N-二-C1-C2-烷基-胺基-C2-C4-烷基-羥基-C2-C4-烷基-C1-C2-烷氧基-C2-C4-烷基-C3-C6-環烷基-C1-C7-烷基-；或R1及R2一起選自-CH2-CH2-或-CH2-CH2-CH2-；R係選自鹵素-C1-C4-烷基-鹵代-C1-C4-烷基- C1-C4-烷氧基-氰基-；且R3係選自苯基、呋喃基、苯硫基、吡啶基、噻唑基、吡唑基、異唑基、咪唑基、吡咯基、苯并呋喃基、嘧啶基、唑基、嗎啉基、六氫吡啶基、四氫呋喃基、四氫吡喃基、吡咯啶基、二氫苯并呋喃基，其未經取代或經1-2個選自以下之取代基取代：鹵素-C1-C4-烷基-鹵代-C1-C4-烷基-C1-C4-烷氧基-C3-C7-環烷基-氧基-羥基-鹵代-C1-C4-烷基-氧基-胺基-氰基-C1-C4-烷氧基-羰基--S(=O)2-C1-C7-烷基；-S(=O)2-鹵代-C1-C7-烷基；-S(=O)-C1-C7-烷基；-S(=O)-鹵代-C1-C7-烷基C3-C10-環烷基-C1-C7-烷氧基-C1-C7-烷基-；-C(O)-NR4'R4，其中R4係選自氫、C1-C4-烷基；R4'係選自氫， 或R4及R4'與其所附接之氮原子一起形成嗎啉基、六氫吡啶基、吡咯啶基，m為0；且n為0-1。 Embodiment 28: A compound of Embodiment 1, wherein R 1 is selected from hydrogen-fluoro-; R 2 is selected from hydrogen-C 1 -C 4 -alkyl-halo-C 2 -C 4 -alkyl- N,N-di-C 1 -C 2 -alkyl-amino-C 2 -C 4 -alkyl-hydroxy-C 2 -C 4 -alkyl-C 1 -C 2 -alkoxy-C 2 -C 4 -alkyl-C 3 -C 6 -cycloalkyl-C 1 -C 7 -alkyl-; or R 1 and R 2 are taken together from -CH 2 -CH 2 - or -CH 2 -CH 2 -CH 2 -; R is selected from halogen-C 1 -C 4 -alkyl-halo-C 1 -C 4 -alkyl-C 1 -C 4 -alkoxy-cyano-; and R 3 Selected from phenyl, furyl, phenylthio, pyridyl, thiazolyl, pyrazolyl, iso Azyl, imidazolyl, pyrrolyl, benzofuranyl, pyrimidinyl, An azolyl, morpholinyl, hexahydropyridyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, dihydrobenzofuranyl group which is unsubstituted or substituted with from 1-2 substituents selected from the group consisting of: Halogen-C 1 -C 4 -alkyl-halo-C 1 -C 4 -alkyl-C 1 -C 4 -alkoxy-C 3 -C 7 -cycloalkyl-oxy-hydroxy-halo -C 1 -C 4 -alkyl-oxy-amino-cyano-C 1 -C 4 -alkoxy-carbonyl--S(=O) 2 -C 1 -C 7 -alkyl;-S (=O) 2 -halo-C 1 -C 7 -alkyl;-S(=O)-C 1 -C 7 -alkyl;-S(=O)-halo-C 1 -C 7 - Alkyl C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-;-C(O)-NR 4' R 4 , wherein R 4 is selected from Hydrogen, C 1 -C 4 -alkyl; R 4 ' is selected from hydrogen, or R 4 and R 4 ' together with the nitrogen atom to which they are attached form morpholinyl, hexahydropyridyl, pyrrolidinyl, m is 0; and n is 0-1.

實施例29：一種式(I)化合物或其醫藥上可接受之鹽，其用於醫藥中， 其中R1係選自氫-鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-；R2係選自氫-C1-C7-烷基-鹵代-C2-C7-烷基-胺基-C2-C7-烷基-N-C1-C7-烷基-胺基-C2-C7-烷基- N,N-二-C1-C7-烷基-胺基-C2-C7-烷基-羥基-C2-C7-烷基-C1-C7-烷氧基-C2-C7-烷基-C3-C10-環烷基-C1-C7-烷基-氰基-C2-C7-烷基-；或R1及R2與其所附接之原子一起形成4-7員飽和或部分飽和之雜環，該雜環未經取代或經1-3個選自以下之取代基取代：C1-C7-烷基-鹵代-C1-C7-烷基-胺基-C1-C7-烷基-N-C1-C7-烷基-胺基-C1-C7-烷基-N,N-二-C1-C7-烷基-胺基-C1-C7-烷基-羥基-C1-C7-烷基-C1-C7-烷氧基-C1-C7-烷基-C3-C10-環烷基-C1-C7-烷基-氰基-C1-C7-烷基-；R係選自鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-C1-C7-烷氧基-氰基- 鹵代-C1-C7-烷氧基-硝基；-C(O)-O-R'，其中R'係選自氫、C1-C7-烷基、C3-C10-環烷基、C1-C7-烷氧基、鹵代-C1-C7-烷基芳基、芳基-C1-C7-烷基-、雜芳基、雜芳基C1-C7-烷基-、雜環基；-S(=O)2-C1-C7-烷基；-S(=O)2-C3-C10-環烷基；-S(=O)2-C1-C7-烷氧基；R3係選自(a)-L-Y，其中-L-係選自直接鍵結、-(CH2)p-、-C(O)-、-NR7-、-NR7-C(O)-或-C(O)-NR7-，其中p係選自1、2或3 R7係選自氫及C1-C7-烷基Y係選自環烷基、芳基、雜芳基、雜環基、螺環基，其未經取代或經1-3個選自以下之取代基取代：鹵素-；C1-C7-烷基-；鹵代-C1-C7-烷基-；鹵代-C1-C7-烷基-氧基-C1-C7-烷基；鹵代-C1-C7-烷基-氧基-C1-C7-烷基-氧基；C1-C7-烷氧基-；C1-C7-烷氧基-C1-C7-烷氧基-；NC-C1-C7-烷氧基-；C1-C7-烷氧基-C1-C7-烷基-；C3-C10-環烷基-氧基-C1-C7-烷基-； C3-C10-環烷基-C1-C7-烷基-氧基-；C3-C10-環烷基-氧基-；C3-C10-環烷基-NR7'-C1-C7-烷基-，其中R7'係選自氫及C1-C7-烷基；C3-C10-環烷基-C1-C7-烷氧基-C1-C7-烷基-；C2-C7-烯基；鹵代-C2-C7-烯基；羥基-；羥基-C1-C7-烷基-；鹵代-C1-C7-烷基-氧基-；胺基-；N-C1-C7-烷基-胺基-；N-鹵代-C1-C7-烷基-胺基-；N-雜環基-胺基-、N-C3-C10-環烷基-胺基-，其中該等雜環基及環烷基視情況經鹵代-C1-C7-烷基-氧基、C1-C7-烷基、C3-C10-環烷基及C1-C7-烷氧基取代；N-C3-C10-環烷基-C1-C7-烷基-胺基-；N,N-二-C1-C7-烷基-胺基-；N,N-二-鹵代-C1-C7-烷基-胺基-；N,N-二-雜環基-胺基-、N,N-二-C3-C10-環烷基-胺基-，其中該等雜環基及環烷基視情況經鹵代-C1-C7-烷基-氧基、C1-C7-烷基、C3-C10-環烷基及C1-C7-烷氧基取代；氰基-；側氧基；C1-C7-烷氧基-羰基-； C1-C7-烷氧基-C1-C7-烷氧基-C1-C7-烷基-；芳基；芳基-C1-C7-烷基-；芳基-氧基；雜環基；雜環基-C1-C7-烷基-；雜環基-氧基-；雜環基-氧基-C1-C7-烷基-；芳基-氧基-C1-C7-烷基-；雜芳基-氧基-C1-C7-烷基-；羥基-羰基-；-S-鹵代-C1-C7-烷基；-S-C1-C7-烷基；-S-芳基；鹵代-C1-C7-烷基-S-C1-C7-烷基；C1-C7-烷基-S-C1-C7-烷基；-S(=O)2-C1-C7-烷基；-S(=O)2-鹵代-C1-C7-烷基；-S(=O)2-芳基；-S(=O)2-雜芳基；-S(=O)2-NR4'R4；-S(=O)2-雜環基；鹵代-C1-C7-烷基-S(=O)2-C1-C7-烷基；C1-C7-烷基-S(=O)2-C1-C7-烷基；-S(=O)-C1-C7-烷基；-S(=O)-鹵代-C1-C7-烷基；-S(=O)-C1-C7-烷氧基；-S(=O)-C3-C10-環烷基；-C(O)-C1-C7-烷基；-C(O)-鹵代-C1-C7-烷基；-C(O)-C1-C7-烷氧基；-C(O)-C3-C10環烷基；-C(O)O-C1-C7-烷基；-C(O)O-C3-C10-環烷基；-C(O)O-鹵代-C1-C7-烷基；-C(O)O-C1-C7-烷氧基；-C(O)-NR4'R4或-NHC(O)-R4，其中R4係選自氫、C1-C7-烷基、鹵代-C1-C7-烷基、C3-C10-環烷基、C3-C10-環烷基-C1-C7-烷基及C1-C7- 烷氧基；R4'係選自氫；或R4及R4'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環雜環，該雜環視情況含有選自N、O或S之另一雜原子，且其中該雜環視情況經芳基、芳基-氧基-、C1-C7-烷基、鹵代-C1-C7-烷基或C1-C7-烷氧基取代，且該芳基視情況經鹵素、C1-C7-烷基、鹵代-C1-C7-烷基或C1-C7-烷氧基取代。或(b)-C(O)-NR5'R5或-C(O)-O-R5，其中R5及R5'係選自氫、C1-C7-烷基、C3-C10-環烷基、C1-C7-烷氧基、鹵代-C1-C7-烷基芳基、芳基-C1-C7-烷基-、芳基、雜芳基、雜芳基C1-C7-烷基-、雜環基、二氫化茚，或R5及R5'與其所附接之氮原子一起形成4-9員飽和或部分飽和之單環或雙環雜環，該單環或雙環雜環視情況含有選自N、O或S之另一雜原子；其中該等C3-C10-環烷基、芳基、雜芳基、雜環基及二氫化茚視情況經1至3個選自以下之取代基取代：C1-C7-烷基、鹵代-C1-C7-烷基、C1-C7-烷氧基、鹵代-C1-C7-烷基-氧基-及羥基-C1-C7-烷基；或(c)-NR6'R6，其中R6係選自氫、C1-C7-烷基，R6'係選自氫、C1-C7-烷基、C1-C7-烷基羰基-、C3-C10-環 烷基；或R6及R6'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環或7-12員飽和或部分飽和之雙環雜環，該雜環視情況含有選自N、O或S之另一雜原子；該單環及雙環雜環未經取代或經1-3個選自以下之取代基取代：C1-C7-烷基-、鹵代-C1-C7-烷基-、C1-C7-烷氧基-、羥基-及C1-C7-烷氧基-羰基-；(d)-NR5'-C(O)-R5，其中R5係選自氫、C1-C7-烷基、C3-C10-環烷基、C1-C7-烷氧基、鹵代-C1-C7-烷基、芳基、芳基-C1-C7-烷基-、雜芳基、雜芳基-C1-C7-烷基-、雜環基；R5'係選自氫、C1-C7-烷基；m為0-1；且n為0-2；R8為氫且R9係選自氫、鹵代-C1-C7-烷基、C1-C7-烷氧基-C1-C7-烷基-、C1-C7-烷基、C1-C7-烷氧基及鹵代-C1-C7-烷基；其中C1-C7-烷基、C1-C7-烷氧基、雜環基、芳基、雜芳基視情況經芳基、雜芳基、雜環基、C1-C7-烷基、C1-C7-烷氧基、鹵代-C1-C7-烷基、OH取代。 Embodiment 29: A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in medicine, Wherein R 1 is selected from hydrogen-halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-; R 2 is selected from hydrogen-C 1 -C 7 -alkyl-halo -C 2 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-NC 1 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-N,N-di-C 1- C 7 -alkyl-amino-C 2 -C 7 -alkyl-hydroxy-C 2 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 2 -C 7 -alkyl- C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkyl-cyano-C 2 -C 7 -alkyl-; or R 1 and R 2 together with the attached atom form a 4-7 member a saturated or partially saturated heterocyclic ring which is unsubstituted or substituted with from 1 to 3 substituents selected from C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-amine -C 1 -C 7 -alkyl-NC 1 -C 7 -alkyl-amino-C 1 -C 7 -alkyl-N,N-di-C 1 -C 7 -alkyl-amino group- C 1 -C 7 -alkyl-hydroxy-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-C 3 -C 10 -cycloalkyl-C 1- C 7 -alkyl-cyano-C 1 -C 7 -alkyl-; R is selected from halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-cyano-halo-C 1 -C 7 -alkoxy-nitro;-C(O)-O-R', wherein R' is selected from hydrogen, C 1 -C 7-- alkyl, C 3 -C 10 - cycloalkyl Group, C 1 -C 7 - alkoxy, halo -C 1 -C 7 - alkyl aryl, aryl -C 1 -C 7 - alkyl -, heteroaryl, heteroaryl-C 1 -C 7 -alkyl-, heterocyclic; -S(=O) 2 -C 1 -C 7 -alkyl; -S(=O) 2 -C 3 -C 10 -cycloalkyl; -S(=O 2 -C 1 -C 7 -alkoxy; R 3 is selected from (a)-LY, wherein -L- is selected from direct bonding, -(CH 2 ) p -, -C(O)-, -NR 7 -, -NR 7 -C(O)- or -C(O)-NR 7 -, wherein p is selected from 1, 2 or 3 R 7 is selected from hydrogen and C 1 -C 7 -alkyl Y is selected from the group consisting of cycloalkyl, aryl, heteroaryl, heterocyclyl, spiro, which is unsubstituted or substituted with from 1 to 3 substituents selected from halogen: C 1 -C 7 - Alkyl-;halo-C 1 -C 7 -alkyl-;halo-C 1 -C 7 -alkyl-oxy-C 1 -C 7 -alkyl;halo-C 1 -C 7 - alkyl - oxy -C 1 -C 7 - alkyl - group; C 1 -C 7 - alkoxy -; C 1 -C 7 - alkoxy, -C 1 -C 7 - alkoxy -; NC-C 1 -C 7 -alkoxy-;C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-;C 3 -C 10 -cycloalkyl-oxy-C 1 -C 7 -alkyl-; C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkyl-oxy-; C 3 -C 10 -cycloalkyl-oxy-; C 3 -C 10 - ring alkyl-NR 7' -C 1 -C 7 -alkyl-, wherein R 7 ' is selected from hydrogen and C 1 -C 7 -alkyl; C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkoxy-C 1 -C 7 -alkane -C 2 -C 7 -alkenyl;halo-C 2 -C 7 -alkenyl;hydroxy-;hydroxy-C 1 -C 7 -alkyl-;halo-C 1 -C 7 -alkyl -oxy-;amino-;NC 1 -C 7 -alkyl-amino-;N-halo-C 1 -C 7 -alkyl-amino-;N-heterocyclyl-amino-, NC 3 -C 10 -cycloalkyl-amino-, wherein the heterocyclic and cycloalkyl groups are optionally halo-C 1 -C 7 -alkyl-oxy, C 1 -C 7 -alkyl , C 3 -C 10 -cycloalkyl and C 1 -C 7 -alkoxy substituted; NC 3 -C 10 -cycloalkyl-C 1 -C 7 -alkyl-amino-;N,N- -C 1 -C 7 -alkyl-amino-;N,N-di-halo-C 1 -C 7 -alkyl-amino-;N,N-di-heterocyclyl-amino-, N,N-di-C 3 -C 10 -cycloalkyl-amino-, wherein the heterocyclic and cycloalkyl groups are optionally halogenated-C 1 -C 7 -alkyl-oxy, C 1 -C 7 -alkyl, C 3 -C 10 -cycloalkyl and C 1 -C 7 -alkoxy substituted; cyano-; pendant oxy; C 1 -C 7 -alkoxy-carbonyl-; C 1 -C 7 - alkoxy, -C 1 -C 7 - alkoxy, -C 1 -C 7 - alkyl -; aryl; aryl -C 1 -C 7 - alkyl -; Yl - oxy; heterocyclyl; heterocyclyl -C 1 -C 7 - alkyl -; heterocyclyl - oxy -; heterocyclyl - oxy -C 1 -C 7 - alkyl -; aryl -oxy-C 1 -C 7 -alkyl-;heteroaryl-oxy-C 1 -C 7 -alkyl-;hydroxy-carbonyl-;-S-halo-C 1 -C 7 -alkyl ;-SC 1 -C 7 -alkyl;-S-aryl;halo-C 1 -C 7 -alkyl-SC 1 -C 7 -alkyl; C 1 -C 7 -alkyl-SC 1 - C 7 -alkyl; -S(=O) 2 -C 1 -C 7 -alkyl;-S(=O) 2 -halo-C 1 -C 7 -alkyl;-S(=O) 2 -aryl; -S(=O) 2 -heteroaryl; -S(=O) 2 -NR 4' R 4 ;-S(=O) 2 -heterocyclyl;halo-C 1 -C 7 -alkyl-S(=O) 2 -C 1 -C 7 -alkyl; C 1 -C 7 -alkyl-S(=O) 2 -C 1 -C 7 -alkyl;-S(=O -C 1 -C 7 -alkyl; -S(=O)-halo-C 1 -C 7 -alkyl; -S(=O)-C 1 -C 7 -alkoxy;-S( =O)-C 3 -C 10 -cycloalkyl;-C(O)-C 1 -C 7 -alkyl;-C(O)-halo-C 1 -C 7 -alkyl;-C( O)-C 1 -C 7 -alkoxy;-C(O)-C 3 -C 10 cycloalkyl;-C(O)OC 1 -C 7 -alkyl;-C(O)OC 3 - C 10 -cycloalkyl; -C(O)O-halo-C 1 -C 7 -alkyl; -C(O)OC 1 -C 7 -alkoxy;-C(O)-NR 4' R 4 or -NHC(O)-R 4 , wherein R 4 is selected from hydrogen, C 1 - C 7 -alkyl, halo-C 1 -C 7 -alkyl, C 3 -C 10 -cycloalkyl, C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkyl and C 1 - C 7 -alkoxy; R 4 ' is selected from hydrogen; or R 4 and R 4 ' together with the nitrogen atom to which they are attached form a 4-7 membered saturated or partially saturated monocyclic heterocycle, which heterocycle optionally contains Another hetero atom selected from N, O or S, and wherein the heterocyclic ring is optionally aryl, aryl-oxy-, C 1 -C 7 -alkyl, halo-C 1 -C 7 -alkyl Or a C 1 -C 7 -alkoxy group, and the aryl group optionally is halogen, C 1 -C 7 -alkyl, halo-C 1 -C 7 -alkyl or C 1 -C 7 -alkoxy Substituted. Or (b)-C(O)-NR 5' R 5 or -C(O)-OR 5 , wherein R 5 and R 5 ' are selected from hydrogen, C 1 -C 7 -alkyl, C 3 -C 10 -cycloalkyl, C 1 -C 7 -alkoxy, halo-C 1 -C 7 -alkylaryl, aryl-C 1 -C 7 -alkyl-, aryl, heteroaryl, Heteroaryl C 1 -C 7 -alkyl-, heterocyclyl, indane, or R 5 and R 5 ' together with the nitrogen atom to which they are attached form a 4-9 membered saturated or partially saturated monocyclic or bicyclic ring a heterocyclic ring, the monocyclic or bicyclic heterocyclic ring optionally containing another hetero atom selected from N, O or S; wherein the C 3 -C 10 -cycloalkyl, aryl, heteroaryl, heterocyclic and The hydrogenation sterol is substituted with 1 to 3 substituents selected from the group consisting of C 1 -C 7 -alkyl, halo-C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy, halogenated -C 1 -C 7 -alkyl-oxy- and hydroxy-C 1 -C 7 -alkyl; or (c)-NR 6' R 6 , wherein R 6 is selected from hydrogen, C 1 -C 7 - An alkyl group, R 6 ' is selected from the group consisting of hydrogen, C 1 -C 7 -alkyl, C 1 -C 7 -alkylcarbonyl-, C 3 -C 10 -cycloalkyl; or R 6 and R 6' The attached nitrogen atoms together form a 4-7 membered saturated or partially saturated monocyclic or 7-12 membered saturated or partially saturated bicyclic heterocycle, The heterocyclic ring optionally contains another hetero atom selected from N, O or S; the monocyclic and bicyclic heterocyclic ring is unsubstituted or substituted with from 1 to 3 substituents selected from C 1 -C 7 -alkyl- , halogenated-C 1 -C 7 -alkyl-, C 1 -C 7 -alkoxy-, hydroxy- and C 1 -C 7 -alkoxy-carbonyl-; (d)-NR 5' -C (O)-R 5 , wherein R 5 is selected from the group consisting of hydrogen, C 1 -C 7 -alkyl, C 3 -C 10 -cycloalkyl, C 1 -C 7 -alkoxy, halo-C 1 - C 7 -alkyl, aryl, aryl-C 1 -C 7 -alkyl-, heteroaryl, heteroaryl-C 1 -C 7 -alkyl-, heterocyclic; R 5 ' is selected from Hydrogen, C 1 -C 7 -alkyl; m is 0-1; and n is 0-2; R 8 is hydrogen and R 9 is selected from hydrogen, halo-C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-, C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy and halo-C 1 -C 7 -alkyl; C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy, heterocyclyl, aryl,heteroaryl optionally with aryl, heteroaryl, heterocyclyl, C 1 -C 7 -alkane a group, a C 1 -C 7 -alkoxy group, a halogeno-C 1 -C 7 -alkyl group, or an OH group.

實施例30：如實施例29之化合物，其中 其中R1係選自氫-鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-；R2係選自氫-C1-C7-烷基-鹵代-C2-C7-烷基-胺基-C2-C7-烷基-N-C1-C7-烷基-胺基-C2-C7-烷基-N,N-二-C1-C7-烷基-胺基-C2-C7-烷基-羥基-C2-C7-烷基-C1-C7-烷氧基-C2-C7-烷基-C3-C10-環烷基-C1-C7-烷基-氰基-C2-C7-烷基-；或R1及R2與其所附接之原子一起形成4-7員飽和或部分飽和 之雜環，該雜環未經取代或經1-3個選自以下之取代基取代：C1-C7-烷基-鹵代-C1-C7-烷基-胺基-C1-C7-烷基-N-C1-C7-烷基-胺基-C1-C7-烷基-N,N-二-C1-C7-烷基-胺基-C1-C7-烷基-羥基-C1-C7-烷基-C1-C7-烷氧基-C1-C7-烷基-C3-C10-環烷基-C1-C7-烷基-氰基-C1-C7-烷基-；R係選自鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-C1-C7-烷氧基-氰基-鹵代-C1-C7-烷氧基-硝基；R3係選自(a)-L-Y，其中-L-係選自直接鍵結、-(CH2)p-、-C(O)-、-NR7-、-NR7-C(O)-或-C(O)-NR7-，其中p係選自1、2或3 R7係選自氫、C1-C7-烷基Y係選自環烷基、芳基、雜芳基、雜環基，其未經取代或經1-3個選自以下之取代基取代：鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-C1-C7-烷氧基-C3-C10-環烷基-氧基-羥基-鹵代-C1-C7-烷基-氧基-胺基-N-C1-C7-烷基-胺基-N,N-二-C1-C7-烷基-胺基-氰基-C1-C7-烷氧基-羰基-羥基-羰基--C(O)-NR4'R4，其中R4係選自氫、C1-C7-烷基；R4'係選自氫，或R4及R4'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環雜環，該雜環視情況含有選自N、O或S之另一雜原子；或(b)-C(O)-NR5'R5或-C(O)-O-R5，其中 R5及R5'係選自氫、C1-C7-烷基；或(c)-NR6'R6，其中R6係選自氫、C1-C7-烷基，R6'係選自氫、C1-C7-烷基、C1-C7-烷基羰基-，m為0-1；且n為0-2。 Embodiment 30: The compound of Embodiment 29, wherein Wherein R 1 is selected from hydrogen-halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-; R 2 is selected from hydrogen-C 1 -C 7 -alkyl-halo -C 2 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-NC 1 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-N,N-di-C 1- C 7 -alkyl-amino-C 2 -C 7 -alkyl-hydroxy-C 2 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 2 -C 7 -alkyl- C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkyl-cyano-C 2 -C 7 -alkyl-; or R 1 and R 2 together with the attached atom form a 4-7 member a saturated or partially saturated heterocyclic ring which is unsubstituted or substituted with from 1 to 3 substituents selected from C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-amine -C 1 -C 7 -alkyl-NC 1 -C 7 -alkyl-amino-C 1 -C 7 -alkyl-N,N-di-C 1 -C 7 -alkyl-amino group- C 1 -C 7 -alkyl-hydroxy-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-C 3 -C 10 -cycloalkyl-C 1- C 7 -alkyl-cyano-C 1 -C 7 -alkyl-; R is selected from halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-cyano-halo-C 1 -C 7 -alkoxy-nitro; R 3 is selected from (a)-LY, wherein -L- is selected from direct bonding, - (CH 2 ) p -, -C(O -, -NR 7 -, -NR 7 -C(O)- or -C(O)-NR 7 -, wherein p is selected from 1, 2 or 3 R 7 is selected from hydrogen, C 1 -C 7 -alkyl Y is selected from cycloalkyl, aryl, heteroaryl, heterocyclyl, which is unsubstituted or substituted with from 1 to 3 substituents selected from halogen-C 1 -C 7 -alkyl -halo-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 3 -C 10 -cycloalkyl-oxy-hydroxy-halo-C 1 -C 7 -alkyl- oxy-amino-NC 1 -C 7 -alkyl-amino-N,N-di-C 1 -C 7 -alkyl-amino-cyano-C 1 -C 7 -alkoxy-carbonyl -hydroxy-carbonyl-C(O)-NR 4' R 4 , wherein R 4 is selected from hydrogen, C 1 -C 7 -alkyl; R 4 ' is selected from hydrogen, or R 4 and R 4' The attached nitrogen atoms together form a 4-7 membered saturated or partially saturated monocyclic heterocycle which optionally contains another heteroatom selected from N, O or S; or (b)-C(O)- NR 5' R 5 or -C(O)-OR 5 , wherein R 5 and R 5 ' are selected from hydrogen, C 1 -C 7 -alkyl; or (c)-NR 6' R 6 , wherein R 6 Is selected from hydrogen, C 1 -C 7 -alkyl, R 6 ' is selected from hydrogen, C 1 -C 7 -alkyl, C 1 -C 7 -alkylcarbonyl-, m is 0-1; and n It is 0-2.

實施例31：如實施例29或30之化合物，其中 其中R1係選自氫-鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-；R2係選自氫-C1-C7-烷基-鹵代-C2-C7-烷基- 胺基-C2-C7-烷基-N-C1-C7-烷基-胺基-C2-C7-烷基-N,N-二-C1-C7-烷基-胺基-C2-C7-烷基-羥基-C2-C7-烷基-C1-C7-烷氧基-C2-C7-烷基-C3-C10-環烷基-C1-C7-烷基-氰基-C2-C7-烷基-；或R1及R2與其所附接之原子一起形成4-7員飽和或部分飽和之雜環，該雜環未經取代或經1-3個選自以下之取代基取代：C1-C7-烷基-鹵代-C1-C7-烷基-胺基-C1-C7-烷基-N-C1-C7-烷基-胺基-C1-C7-烷基-N,N-二-C1-C7-烷基-胺基-C1-C7-烷基-羥基-C1-C7-烷基-C1-C7-烷氧基-C1-C7-烷基-C3-C10-環烷基-C1-C7-烷基-氰基-C1-C7-烷基-；R係選自鹵素-C1-C7-烷基-鹵代-C1-C7-烷基- C1-C7-烷氧基-氰基-鹵代-C1-C7-烷氧基-硝基；R3係選自(a)-(CH2)p-Y，其中p係選自0、1、2或3，且Y係選自芳基、雜芳基、雜環基，其未經取代或經1-3個選自以下之取代基取代：鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-C1-C7-烷氧基-C3-C10-環烷基-氧基-羥基-鹵代-C1-C7-烷基-氧基-胺基-N-C1-C7-烷基-胺基-N,N-二-C1-C7-烷基-胺基-氰基-C1-C7-烷氧基-羰基-羥基-羰基--C(O)-NR4'R4，其中R4係選自氫、C1-C7-烷基； R4'係選自氫，或R4及R4'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環雜環，該雜環視情況含有選自N、O或S之另一雜原子；或(b)-C(O)-NR5'R5或-C(O)-O-R5，其中R5係選自氫、苄基、二氫茚基、四氫呋喃基、四氫吡喃基、環氧乙烷基、C3-C10-環烷基、C1-C7-烷基；R5'係選自氫、C1-C7-烷基，或R5及R5'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環或雙環雜環，該雜環視情況含有選自N、O或S之另一雜原子；或(c)-NR6'R6，其中R6係選自氫、苄基、C3-C10-環烷基、C1-C7-烷基，R6'係選自氫、C1-C7-烷基、C1-C7-烷基羰基-，或R6及R6'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環或7-12員飽和或部分飽和之雙環雜環，該雜環視情況含有選自N、O或S之另一雜原子；其未經取代或經1-3個選自以下之取代基取代：C1-C7-烷基-羥基-C1-C7-烷氧基-羰基-或 (d)-NR5'-C(O)-R5，其中R5係選自C3-C10-環烷基；R5'係選自氫、C1-C7-烷基；m為0-1；且n為0-1。 Embodiment 31: A compound of Embodiment 29 or 30, wherein Wherein R 1 is selected from hydrogen-halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-; R 2 is selected from hydrogen-C 1 -C 7 -alkyl-halo -C 2 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-NC 1 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-N,N-di-C 1- C 7 -alkyl-amino-C 2 -C 7 -alkyl-hydroxy-C 2 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 2 -C 7 -alkyl- C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkyl-cyano-C 2 -C 7 -alkyl-; or R 1 and R 2 together with the attached atom form a 4-7 member a saturated or partially saturated heterocyclic ring which is unsubstituted or substituted with from 1 to 3 substituents selected from C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-amine -C 1 -C 7 -alkyl-NC 1 -C 7 -alkyl-amino-C 1 -C 7 -alkyl-N,N-di-C 1 -C 7 -alkyl-amino group- C 1 -C 7 -alkyl-hydroxy-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-C 3 -C 10 -cycloalkyl-C 1- C 7 -alkyl-cyano-C 1 -C 7 -alkyl-; R is selected from halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-cyano-halo-C 1 -C 7 -alkoxy-nitro; R 3 is selected from (a)-(CH 2 ) p -Y, wherein p is selected from 0 , 1, 2 or 3, and Y system From aryl, heteroaryl, a heterocyclic group, which is unsubstituted or substituted with 1-3 substituents selected from the group: halogen -C 1 -C 7 - alkyl - halo -C 1 -C 7 - Alkyl-C 1 -C 7 -alkoxy-C 3 -C 10 -cycloalkyl-oxy-hydroxy-halo-C 1 -C 7 -alkyl-oxy-amino-NC 1 -C 7 -Alkyl-amino-N,N-di-C 1 -C 7 -alkyl-amino-cyano-C 1 -C 7 -alkoxy-carbonyl-hydroxy-carbonyl--C(O) -NR 4' R 4 , wherein R 4 is selected from hydrogen, C 1 -C 7 -alkyl; R 4 ' is selected from hydrogen, or R 4 and R 4' together with the nitrogen atom to which they are attached form 4- a 7-membered saturated or partially saturated monocyclic heterocyclic ring optionally containing another hetero atom selected from N, O or S; or (b) -C(O)-NR 5' R 5 or -C(O And -OR 5 , wherein R 5 is selected from the group consisting of hydrogen, benzyl, indanyl, tetrahydrofuranyl, tetrahydropyranyl, oxiranyl, C 3 -C 10 -cycloalkyl, C 1 -C 7 -alkyl; R 5 ' is selected from hydrogen, C 1 -C 7 -alkyl, or R 5 and R 5 ' together with the nitrogen atom to which they are attached form a 4-7 member saturated or partially saturated monocyclic ring or bicyclic heterocyclic ring, which ring optionally containing a further heteroatom selected from N, O or S heteroatoms of; or (c) -NR 6 'R 6 , wherein R 6 Is selected from hydrogen, benzyl, C 3 -C 10 - cycloalkyl, C 1 -C 7 - alkyl, R 6 'is selected from hydrogen, C 1 -C 7 - alkyl, C 1 -C 7 - alkoxy Alkylcarbonyl-, or R 6 and R 6 ' together with the nitrogen atom to which they are attached form a 4-7 membered saturated or partially saturated monocyclic or 7-12 membered saturated or partially saturated bicyclic heterocyclic ring, optionally containing Another hetero atom selected from N, O or S; which is unsubstituted or substituted with from 1 to 3 substituents selected from C 1 -C 7 -alkyl-hydroxy-C 1 -C 7 -alkoxy -carbonyl- or (d)-NR 5' -C(O)-R 5 , wherein R 5 is selected from C 3 -C 10 -cycloalkyl; R 5 ' is selected from hydrogen, C 1 -C 7 -alkyl; m is 0-1; and n is 0-1.

實施例32：如實施例29至31中任一項之化合物，其中 R1係選自氫-鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-；R2係選自氫-C1-C7-烷基-鹵代-C2-C7-烷基-胺基-C2-C7-烷基-N-C1-C7-烷基-胺基-C2-C7-烷基-N,N-二-C1-C7-烷基-胺基-C2-C7-烷基- 羥基-C2-C7-烷基-C1-C7-烷氧基-C2-C7-烷基-C3-C10-環烷基-C1-C7-烷基-氰基-C2-C7-烷基-；或R1及R2與其所附接之原子一起形成4-7員飽和或部分飽和之雜環，該雜環未經取代或經1-3個選自以下之取代基取代：C1-C7-烷基-鹵代-C1-C7-烷基-胺基-C1-C7-烷基-N-C1-C7-烷基-胺基-C1-C7-烷基-N,N-二-C1-C7-烷基-胺基-C1-C7-烷基-羥基-C1-C7-烷基-C1-C7-烷氧基-C1-C7-烷基-C3-C10-環烷基-C1-C7-烷基-氰基-C1-C7-烷基-；R係選自鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-C1-C7-烷氧基-氰基-鹵代-C1-C7-烷氧基- 硝基；R3係選自(a)-(CH2)p-Y，其中p係選自0、1、2或3，且Y係選自芳基、雜芳基、雜環基，其未經取代或經1-3個選自以下之取代基取代：鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-C1-C7-烷氧基-C3-C10-環烷基-氧基-羥基-鹵代-C1-C7-烷基-氧基-胺基-N-C1-C7-烷基-胺基-N,N-二-C1-C7-烷基-胺基-氰基-C1-C7-烷氧基-羰基-羥基-羰基--C(O)-NR4'R4，其中R4係選自氫、C1-C7-烷基；R4'係選自氫，或R4及R4'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環雜環，該雜環視情況含有選自 N、O或S之另一雜原子；或(b)-C(O)-NR5'R5或-C(O)-O-R5，其中R5係選自氫、苄基、二氫茚基、四氫呋喃基、四氫吡喃基、環氧乙烷基、C3-C10-環烷基、C1-C7-烷基；R5'係選自氫、C1-C7-烷基，或R5及R5'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環或雙環雜環，該雜環視情況含有選自N、O或S之另一雜原子；或(c)-NR6'R6，其中R6係選自氫、苄基、C3-C10-環烷基、C1-C7-烷基，R6'係選自氫、C1-C7-烷基、C1-C7-烷基羰基-，或R6及R6'與其所附接之氮原子一起形成4-7員飽和或部分飽和之單環或7-12員飽和或部分飽和之雙環雜環，該雜環視情況含有選自N、O或S之另一雜原子；其未經取代或經1-3個選自以下之取代基取代：C1-C7-烷基-羥基-C1-C7-烷氧基-羰基-或(d)-NR5'-C(O)-R5，其中R5係選自C3-C10-環烷基；R5'係選自氫、C1-C7-烷基； m為0-1；且n為0-1。 The compound of any one of embodiments 29 to 31, wherein R 1 is selected from hydrogen-halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-; R 2 is selected from hydrogen-C 1 -C 7 -alkyl-halo- C 2 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-NC 1 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-N,N-di-C 1 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-hydroxy-C 2 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 2 -C 7 -alkyl-C 3- C 10 -cycloalkyl-C 1 -C 7 -alkyl-cyano-C 2 -C 7 -alkyl-; or R 1 and R 2 together with the atoms to which they are attached form a 4-7 member saturation Or a partially saturated heterocyclic ring which is unsubstituted or substituted with from 1 to 3 substituents selected from C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-amino -C 1 -C 7 -alkyl-NC 1 -C 7 -alkyl-amino-C 1 -C 7 -alkyl-N,N-di-C 1 -C 7 -alkyl-amino-C 1- C 7 -alkyl-hydroxy-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkyl-cyano-C 1 -C 7 -alkyl-; R is selected from halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-C 1 - C 7 -alkoxy-cyano-halo-C 1 -C 7 -alkoxy-nitro; R 3 is selected from (a)-(CH 2 ) p -Y, wherein p is selected from 0, 1, 2 or 3, and Y is selected from Group, a heteroaryl group, a heterocyclic group, which is unsubstituted or substituted with 1-3 substituents selected from the group: halogen -C 1 -C 7 - alkyl - halo -C 1 -C 7 - alkyl -C 1 -C 7 -alkoxy-C 3 -C 10 -cycloalkyl-oxy-hydroxy-halo-C 1 -C 7 -alkyl-oxy-amino-NC 1 -C 7 - Alkyl-amino-N,N-di-C 1 -C 7 -alkyl-amino-cyano-C 1 -C 7 -alkoxy-carbonyl-hydroxy-carbonyl--C(O)-NR 4' R 4 , wherein R 4 is selected from hydrogen, C 1 -C 7 -alkyl; R 4 ' is selected from hydrogen, or R 4 and R 4' together with the nitrogen atom to which they are attached form a 4-7 member a saturated or partially saturated monocyclic heterocyclic ring optionally containing another hetero atom selected from N, O or S; or (b) -C(O)-NR 5' R 5 or -C(O)- OR 5 , wherein R 5 is selected from the group consisting of hydrogen, benzyl, indanyl, tetrahydrofuranyl, tetrahydropyranyl, oxiranyl, C 3 -C 10 -cycloalkyl, C 1 -C 7 - An alkyl group; R 5 ' is selected from hydrogen, C 1 -C 7 -alkyl, or R 5 and R 5 ' together with the nitrogen atom to which they are attached form a 4-7 membered saturated or partially saturated monocyclic or bicyclic hetero a ring which optionally contains another hetero atom selected from N, O or S; or (c) -NR 6' R 6 wherein R 6 is selected from Hydrogen, benzyl, C 3 -C 10 -cycloalkyl, C 1 -C 7 -alkyl, R 6 ' is selected from hydrogen, C 1 -C 7 -alkyl, C 1 -C 7 -alkylcarbonyl -, or R 6 and R 6' together with the nitrogen atom to which they are attached form a 4-7 membered saturated or partially saturated monocyclic or 7-12 membered saturated or partially saturated bicyclic heterocycle optionally containing Another hetero atom of N, O or S; which is unsubstituted or substituted with from 1 to 3 substituents selected from C 1 -C 7 -alkyl-hydroxy-C 1 -C 7 -alkoxy- Carbonyl- or (d)-NR 5' -C(O)-R 5 , wherein R 5 is selected from C 3 -C 10 -cycloalkyl; R 5 ' is selected from hydrogen, C 1 -C 7 -alkane Base; m is 0-1; and n is 0-1.

實施例33：一種醫藥組合物，其包括治療有效量之如實施例1至28中任一項之式(I)化合物及一或多種醫藥上可接受之載劑/賦形劑。 Embodiment 33: A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to any one of embodiments 1 to 28 and one or more pharmaceutically acceptable carriers/excipients.

實施例34：一種組合、尤其醫藥組合，其包括治療有效量之如實施例1至28中任一項之式(I)化合物及一或多種治療活性劑、尤其止痛劑。 Embodiment 34: A combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of a compound of formula (I) according to any one of embodiments 1 to 28 and one or more therapeutically active agents, especially an analgesic.

實施例35：一種如實施例1至28中任一項之式(I)化合物之用途，其用於製造用於治療慢性疼痛之藥劑。 Embodiment 35: Use of a compound of formula (I) according to any one of embodiments 1 to 28 for the manufacture of a medicament for the treatment of chronic pain.

實施例36：一種如實施例1至28中任一項之式(I)化合物之用途，其用於製造用於治療一或多種Nav 1.7介導之病症或疾病之藥劑。 Embodiment 36: Use of a compound of Formula (I) according to any one of embodiments 1 to 28 for the manufacture of a medicament for the treatment of one or more Nav 1.7 mediated disorders or diseases.

實施例37：一種如實施例1至28中任一項之式(I)化合物之用途，其用於用於治療一或多種Nav 1.7介導之病症或疾病。 Embodiment 37: Use of a compound of formula (I) according to any one of embodiments 1 to 28 for the treatment of one or more Nav 1.7 mediated disorders or diseases.

實施例38：一種如實施例1至28中任一項之式(I)化合物之用途，其用於治療慢性疼痛。 Embodiment 38: Use of a compound of formula (I) according to any one of embodiments 1 to 28 for the treatment of chronic pain.

實施例39：如實施例37之用途，其用於治療選自慢性疼痛之病症或疾病，該慢性疼痛係(例如)慢性疼痛之陽性症狀(例如感覺異常、感覺遲鈍、痛覺過敏、觸感痛及自發性疼痛)以及陰性症狀(例如失去感覺)。 Embodiment 39: The use of Embodiment 37, for treating a condition or disease selected from the group consisting of chronic pain, for example, a positive symptom of chronic pain (eg, paresthesia, dysesthesia, hyperalgesia, tactile pain) And spontaneous pain) and negative symptoms (such as loss of sensation).

實施例40：一種治療慢性疼痛之方法，其包括向個體投與治療有效量之如實施例1至28中任一項之式(I)化合物之步 驟。 Embodiment 40: A method of treating chronic pain comprising administering to a subject a therapeutically effective amount of a compound of formula (I) according to any one of embodiments 1 to 28 Step.

實施例41：如實施例40之方法，其中該病症或疾病係選自慢性疼痛，該慢性疼痛係(例如)慢性疼痛之陽性症狀(例如感覺異常、感覺遲鈍、痛覺過敏、觸感痛及自發性疼痛)以及陰性症狀(例如失去感覺)。 Embodiment 41: The method of Embodiment 40, wherein the condition or disease is selected from the group consisting of chronic pain, such as positive symptoms of chronic pain (eg, paresthesia, dysesthesia, hyperalgesia, tactile pain, and spontaneous) Sexual pain) and negative symptoms (such as loss of sensation).

實施例42：一種調節個體中之Nav 1.7活性之方法，其包括向個體投與治療有效量之如實施例1至28中任一項之式(I)化合物之步驟。 Embodiment 42: A method of modulating Nav 1.7 activity in an individual comprising the step of administering to the subject a therapeutically effective amount of a compound of formula (I) according to any one of embodiments 1 to 28.

實施例43：如實施例1之化合物或其醫藥上可接受之鹽，其選自實例1至517。 Embodiment 43: A compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of Examples 1 to 517.

實施例44：如實施例43之化合物，其中該化合物係選自2-N-甲基-2-N-苯基-6-(5-{4-[(2,2,2-三氟乙氧基)甲基]六氫吡啶-1-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[1-(丙烷-2-磺醯基)六氫吡啶-4-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；6-(5-{4-[(環丙基甲氧基)甲基]六氫吡啶-1-基}-1,2,4-二唑-3-基)-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-(3-氟苯基)-6-[5-(3-氟吡啶-2-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{6-[2-(2,2,2-三氟乙氧基)乙氧基]吡啶-3-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[(2R)-1-[(2,2,2-三氟乙烷)磺醯基]吡咯啶-2-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{6-[(3,3,3-三氟丙烷)亞磺醯基]吡 啶-3-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{4-[(3,3,3-三氟丙氧基)甲基]六氫吡啶-1-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[1-(丙烷-2-磺醯基)六氫吡啶-4-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；及N-甲基-N-苯基-6-{5-[6-(2,2,2-三氟乙氧基)-吡啶-3-基]-[1,2,4]二唑-3-基}-[1,3,5]三-2,4-二胺；或其醫藥上可接受之鹽。 Embodiment 44: A compound of Embodiment 43, wherein the compound is selected from the group consisting of 2-N-methyl-2-N-phenyl-6-(5-{4-[(2,2,2-trifluoroethyl) Oxy)methyl]hexahydropyridin-1-yl}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[1-(propane-2-sulfonyl)hexahydropyridin-4-yl]-1, 2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 6-(5-{4-[(cyclopropylmethoxy)methyl]hexahydropyridin-1-yl}-1,2,4- Diazol-3-yl)-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-(3-fluorophenyl)-6-[5-(3-fluoropyridin-2-yl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{6-[2-(2,2,2-trifluoroethoxy)ethoxy] Pyridin-3-yl}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[(2R)-1-[(2,2,2-trifluoroethane)sulfonyl) Pyrrolidin-2-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{6-[(3,3,3-trifluoropropane)sulfinyl]pyridine-3 -base}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{4-[(3,3,3-trifluoropropoxy)methyl]hexahydropyridine -1-yl}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[1-(propane-2-sulfonyl)hexahydropyridin-4-yl]-1, 2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; and N-methyl-N-phenyl-6-{5-[6-(2,2,2-trifluoroethoxy)-pyridin-3-yl]-[1 , 2, 4] Diazol-3-yl}-[1,3,5]3 a 2,4-diamine; or a pharmaceutically acceptable salt thereof.

Claims (17)

一種式(I)化合物或其醫藥上可接受之鹽， 其中R1係選自氫-鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-；R2係選自氫-C1-C7-烷基-鹵代-C2-C7-烷基-胺基-C2-C7-烷基-N-C1-C7-烷基-胺基-C2-C7-烷基-N,N-二-C1-C7-烷基-胺基-C2-C7-烷基-羥基-C2-C7-烷基-C1-C7-烷氧基-C2-C7-烷基-C3-C10-環烷基-C1-C7-烷基- 氰基-C2-C7-烷基-；或R1及R2與其所附接之原子一起形成4至7員飽和或部分飽和之雜環，該雜環未經取代或經1至3個選自以下之取代基取代：C1-C7-烷基-鹵代-C1-C7-烷基-胺基-C1-C7-烷基-N-C1-C7-烷基-胺基-C1-C7-烷基-N,N-二-C1-C7-烷基-胺基-C1-C7-烷基-羥基-C1-C7-烷基-C1-C7-烷氧基-C1-C7-烷基-C3-C10-環烷基-C1-C7-烷基-氰基-C1-C7-烷基-；R係選自鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-C1-C7-烷氧基-氰基-鹵代-C1-C7-烷氧基-硝基；-C(O)-O-R'，其中R'係選自氫、C1-C7-烷基、C3-C10-環烷基、C1-C7-烷氧基、鹵代-C1-C7-烷基芳基、芳 基-C1-C7-烷基-、雜芳基、雜芳基C1-C7-烷基-、雜環基；-S(=O)2-C1-C7-烷基；-S(=O)2-C3-C10-環烷基；-S(=O)2-C1-C7-烷氧基；R3係選自(a)-L-Y，其中-L-係選自直接鍵結、-(CH2)p-、-C(O)-、-NR7-、-NR7-C(O)-或-C(O)-NR7-，其中p係選自1、2或3 R7係選自氫及C1-C7-烷基Y係選自環烷基、芳基、雜芳基、雜環基、螺環基，其未經取代或經1至3個選自以下之取代基取代：鹵素-；C1-C7-烷基-；鹵代-C1-C7-烷基-；鹵代-C1-C7-烷基-氧基-C1-C7-烷基；鹵代-C1-C7-烷基-氧基-C1-C7-烷基-氧基；C1-C7-烷氧基-；C1-C7-烷氧基-C1-C7-烷氧基-；NC-C1-C7-烷氧基-；C1-C7-烷氧基-C1-C7-烷基-；C3-C10-環烷基-氧基-C1-C7-烷基-；C3-C10-環烷基-C1-C7-烷基-氧基-；C3-C10-環烷基-氧基-；C3-C10-環烷基-NR7'-C1-C7-烷基-，其中R7'係選自氫 及C1-C7-烷基；C3-C10-環烷基-C1-C7-烷氧基-C1-C7-烷基-；C2-C7-烯基；鹵代-C2-C7-烯基；羥基-；羥基-C1-C7-烷基-；鹵代-C1-C7-烷基-氧基-；胺基-；N-C1-C7-烷基-胺基-；N-鹵代-C1-C7-烷基-胺基-；N-雜環基-胺基-、N-C3-C10-環烷基-胺基-，其中該等雜環基及環烷基視情況經鹵代-C1-C7-烷基-氧基、C1-C7-烷基、C3-C10-環烷基及C1-C7-烷氧基取代；N-C3-C10-環烷基-C1-C7-烷基-胺基-；N,N-二-C1-C7-烷基-胺基-；N,N-二-鹵代-C1-C7-烷基-胺基-；N,N-二-雜環基-胺基-、N,N-二-C3-C10-環烷基-胺基-，其中該等雜環基及環烷基視情況經鹵代-C1-C7-烷基-氧基、C1-C7-烷基、C3-C10-環烷基及C1-C7-烷氧基取代；氰基-；側氧基；C1-C7-烷氧基-羰基-；C1-C7-烷氧基-C1-C7-烷氧基-C1-C7-烷基-；芳基；芳基-C1-C7-烷基-；芳基-氧基； 雜環基；雜環基-C1-C7-烷基-；雜環基-氧基-；雜環基-氧基-C1-C7-烷基-；芳基-氧基-C1-C7-烷基-；雜芳基-氧基-C1-C7-烷基-；羥基-羰基-；-S-鹵代-C1-C7-烷基；-S-C1-C7-烷基；-S-芳基；鹵代-C1-C7-烷基-S-C1-C7-烷基；C1-C7-烷基-S-C1-C7-烷基；-S(=O)2-C1-C7-烷基；-S(=O)2-鹵代-C1-C7-烷基；-S(=O)2-芳基；-S(=O)2-雜芳基；-S(=O)2-NR4'R4；-S(=O)2-雜環基；鹵代-C1-C7-烷基-S(=O)2-C1-C7-烷基；C1-C7-烷基-S(=O)2-C1-C7-烷基；-S(=O)-C1-C7-烷基；-S(=O)-鹵代-C1-C7-烷基；-S(=O)-C1-C7-烷氧基；-S(=O)-C3-C10-環烷基；-C(O)-C1-C7-烷基；-C(O)-鹵代-C1-C7-烷基；-C(O)-C1-C7-烷氧基；-C(O)-C3-C10環烷基；-C(O)O-C1-C7-烷基；-C(O)O-C3-C10-環烷基；-C(O)O-鹵代-C1-C7-烷基；-C(O)O-C1-C7-烷氧基；-C(O)-NR4'R4或-NHC(O)-R4，其中R4係選自氫、C1-C7-烷基、鹵代-C1-C7-烷基、C3-C10-環烷基、C3-C10-環烷基-C1-C7-烷基及C1-C7-烷氧基；R4'係選自氫； 或R4及R4'與其所附接之氮原子一起形成4至7員飽和或部分飽和之單環雜環，該雜環視情況含有選自N、O或S之另一雜原子，且其中該雜環視情況經芳基、芳基-氧基-、C1-C7-烷基、鹵代-C1-C7-烷基或C1-C7-烷氧基取代，且該芳基視情況經鹵素、C1-C7-烷基、鹵代-C1-C7-烷基或C1-C7-烷氧基取代；或(b)-C(O)-NR5'R5或-C(O)-O-R5，其中R5及R5'係選自氫、C1-C7-烷基、C3-C10-環烷基、C1-C7-烷氧基、鹵代-C1-C7-烷基芳基、芳基-C1-C7-烷基-、芳基、雜芳基、雜芳基C1-C7-烷基-、雜環基、二氫化茚，或R5及R5'與其所附接之氮原子一起形成4至9員飽和或部分飽和之單環或雙環雜環，該單環或雙環雜環視情況含有選自N、O或S之另一雜原子；其中該等C3-C10-環烷基、芳基、雜芳基、雜環基及二氫化茚視情況經1至3個選自以下之取代基取代：C1-C7-烷基、鹵代-C1-C7-烷基、C1-C7-烷氧基、鹵代-C1-C7-烷基-氧基-、鹵代-C1-C7-烷基-氧基-C1-C7-烷基、C1-C7-烷基-氧基-C1-C7-烷基及羥基-C1-C7-烷基；或(c)-NR6'R6，其中R6係選自氫、C1-C7-烷基，R6'係選自氫、C1-C7-烷基、C1-C7-烷基羰基-、C3-C10- 環烷基；或R6及R6'與其所附接之氮原子一起形成4至7員飽和或部分飽和之單環或7至12員飽和或部分飽和之雙環雜環，該雜環視情況含有選自N、O或S之另一雜原子；該單環及雙環雜環未經取代或經1至3個選自以下之取代基取代：C1-C7-烷基-、鹵代-C1-C7-烷基-、C1-C7-烷氧基-、鹵代-C1-C7-烷氧基-、鹵代-C1-C7-烷氧基-C1-C7-烷基-、羥基-及C1-C7-烷氧基-羰基-；(d)-NR5'-C(O)-R5，其中R5係選自氫、C1-C7-烷基、C3-C10-環烷基、C1-C7-烷氧基、鹵代-C1-C7-烷基、芳基、芳基-C1-C7-烷基-、雜芳基、雜芳基-C1-C7-烷基-、雜環基；R5'係選自氫、C1-C7-烷基；m為0至1；且n為0至2；R8為氫且R9係選自氫、C1-C7-烷氧基-C1-C7-烷基-、C1-C7-烷基、C1-C7-烷氧基及鹵代-C1-C7-烷基；其中C1-C7-烷基、C1-C7-烷氧基、雜環基、芳基、雜芳基視情況經芳基、雜芳基、雜環基、C1-C7-烷基、C1-C7-烷氧基、鹵代-C1-C7-烷基、OH取代；前提係不包含6-[5-(2-呋喃基)-1,2,4-二唑-3-基]-N2-甲基-N2-苯基-1,3,5-三-2,4-二胺及6-[5-(2-呋喃基)-1,2,4-二唑-3-基]-N,N,N'-甲基-N'-苯基-1,3,5-三-2,4-二 胺。 a compound of formula (I) or a pharmaceutically acceptable salt thereof, Wherein R 1 is selected from hydrogen-halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-; R 2 is selected from hydrogen-C 1 -C 7 -alkyl-halo -C 2 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-NC 1 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-N,N-di-C 1- C 7 -alkyl-amino-C 2 -C 7 -alkyl-hydroxy-C 2 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 2 -C 7 -alkyl- C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkyl-cyano-C 2 -C 7 -alkyl-; or R 1 and R 2 together with the atoms to which they are attached form 4 to 7 members a saturated or partially saturated heterocyclic ring which is unsubstituted or substituted with 1 to 3 substituents selected from C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-amine -C 1 -C 7 -alkyl-NC 1 -C 7 -alkyl-amino-C 1 -C 7 -alkyl-N,N-di-C 1 -C 7 -alkyl-amino group- C 1 -C 7 -alkyl-hydroxy-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-C 3 -C 10 -cycloalkyl-C 1- C 7 -alkyl-cyano-C 1 -C 7 -alkyl-; R is selected from halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-cyano-halo-C 1 -C 7 -alkoxy-nitro;-C(O)-O-R', wherein R' is selected from hydrogen, C 1 -C 7-- alkyl, C 3 -C 10 - Alkyl group, C 1 -C 7 - alkoxy, halo -C 1 -C 7 - alkyl aryl, aryl -C 1 -C 7 - alkyl -, heteroaryl, heteroaryl-C 1 - C 7 -alkyl-,heterocyclyl;-S(=O) 2 -C 1 -C 7 -alkyl;-S(=O) 2 -C 3 -C 10 -cycloalkyl;-S(= O) 2 -C 1 -C 7 -alkoxy; R 3 is selected from (a)-LY, wherein -L- is selected from direct bonding, -(CH 2 ) p -, -C(O)- , -NR 7 -, -NR 7 -C(O)- or -C(O)-NR 7 -, wherein p is selected from 1, 2 or 3 R 7 is selected from the group consisting of hydrogen and C 1 -C 7 -alkane The group Y is selected from the group consisting of a cycloalkyl group, an aryl group, a heteroaryl group, a heterocyclic group, a spiro group, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen-; C 1 -C 7 -alkyl-;halo-C 1 -C 7 -alkyl-;halo-C 1 -C 7 -alkyl-oxy-C 1 -C 7 -alkyl;halo-C 1 -C 7 - alkyl - group -C 1 -C 7 - alkyl - group; C 1 -C 7 - alkoxy -; C 1 -C 7 - alkoxy, -C 1 -C 7 - alkoxy - ;NC-C 1 -C 7 -alkoxy-;C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-;C 3 -C 10 -cycloalkyl-oxy-C 1 - C 7 -alkyl-; C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkyl-oxy-; C 3 -C 10 -cycloalkyl-oxy-; C 3 -C 10 - Cycloalkyl-NR 7' -C 1 -C 7 -alkyl-, wherein R 7 ' is selected from hydrogen and C 1 -C 7 -alkyl; C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-; C 2 -C 7 -alkenyl; halo-C 2 -C 7 -alkenyl; hydroxy-; hydroxy-C 1 -C 7 -alkyl-;halo-C 1 -C 7 -alkyl-oxy-;amino-;NC 1 -C 7 -alkyl-amino-;N-halo-C 1 -C 7 -alkyl-amino-;N-heterocyclyl-amine Base-, NC 3 -C 10 -cycloalkyl-amino-, wherein the heterocyclic and cycloalkyl groups are optionally halogenated -C 1 -C 7 -alkyl-oxy, C 1 -C 7 -alkyl, C 3 -C 10 -cycloalkyl and C 1 -C 7 -alkoxy substituted; NC 3 -C 10 -cycloalkyl-C 1 -C 7 -alkyl-amino-;N, N-di-C 1 -C 7 -alkyl-amino-;N,N-di-halo-C 1 -C 7 -alkyl-amino-;N,N-di-heterocyclyl-amine Base-, N,N-di-C 3 -C 10 -cycloalkyl-amino-, wherein the heterocyclic group and cycloalkyl group are optionally halogenated-C 1 -C 7 -alkyl-oxy , C 1 -C 7 -alkyl, C 3 -C 10 -cycloalkyl and C 1 -C 7 -alkoxy substituted; cyano-; pendant oxy; C 1 -C 7 -alkoxy-carbonyl -; C 1 -C 7 - alkoxy, -C 1 -C 7 - alkoxy, -C 1 -C 7 - alkyl -; aryl; aryl -C 1 -C 7 - alkyl - Aryl - group; heterocyclyl; heterocyclyl -C 1 -C 7 - alkyl -; heterocyclyl - oxy -; heterocyclyl - oxy -C 1 -C 7 - alkyl -; aryl -oxy-C 1 -C 7 -alkyl-;heteroaryl-oxy-C 1 -C 7 -alkyl-;hydroxy-carbonyl-;-S-halo-C 1 -C 7 -alkane -SC 1 -C 7 -alkyl;-S-aryl;halo-C 1 -C 7 -alkyl-SC 1 -C 7 -alkyl; C 1 -C 7 -alkyl-SC 1 -C 7 -alkyl;-S(=O) 2 -C 1 -C 7 -alkyl;-S(=O) 2 -halo-C 1 -C 7 -alkyl;-S(=O) 2 -aryl;-S(=O) 2 -heteroaryl; -S(=O) 2 -NR 4' R 4 ;-S(=O) 2 -heterocyclyl;halo-C 1 -C 7 -alkyl-S(=O) 2 -C 1 -C 7 -alkyl; C 1 -C 7 -alkyl-S(=O) 2 -C 1 -C 7 -alkyl;-S(= O)-C 1 -C 7 -alkyl;-S(=O)-halo-C 1 -C 7 -alkyl;-S(=O)-C 1 -C 7 -alkoxy;-S (=O)-C 3 -C 10 -cycloalkyl;-C(O)-C 1 -C 7 -alkyl;-C(O)-halo-C 1 -C 7 -alkyl;-C (O)-C 1 -C 7 -alkoxy;-C(O)-C 3 -C 10 cycloalkyl; -C(O)OC 1 -C 7 -alkyl; -C(O)OC 3 -C 10 -cycloalkyl; -C(O)O-halo-C 1 -C 7 -alkyl; -C(O)OC 1 -C 7 -alkoxy;-C(O)-NR 4 ' R 4 or -NHC(O)-R 4 , wherein R 4 is selected from hydrogen, C 1- C 7 -alkyl, halo-C 1 -C 7 -alkyl, C 3 -C 10 -cycloalkyl, C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkyl and C 1 -C 7 -alkoxy; R 4 ' is selected from hydrogen; or R 4 and R 4' together with the nitrogen atom to which they are attached form a 4 to 7 membered saturated or partially saturated monocyclic heterocyclic ring. Wherein the case contains another hetero atom selected from N, O or S, and wherein the heterocyclic ring is optionally aryl, aryl-oxy-, C 1 -C 7 -alkyl, halo-C 1 -C 7 - Alkylic or C 1 -C 7 -alkoxy substituted, and the aryl group optionally is halogen, C 1 -C 7 -alkyl, halo-C 1 -C 7 -alkyl or C 1 -C 7 - Alkoxy substituted; or (b)-C(O)-NR 5' R 5 or -C(O)-OR 5 , wherein R 5 and R 5 ' are selected from hydrogen, C 1 -C 7 -alkyl , C 3 -C 10 -cycloalkyl, C 1 -C 7 -alkoxy, halo-C 1 -C 7 -alkylaryl, aryl-C 1 -C 7 -alkyl-, aryl , heteroaryl, heteroaryl C 1 -C 7 -alkyl-, heterocyclyl, indane, or R 5 and R 5 ' together with the nitrogen atom to which they are attached form a 4 to 9 member saturated or partially saturated a monocyclic or bicyclic heterocyclic ring which optionally contains another hetero atom selected from N, O or S; Such C 3 -C 10 - cycloalkyl, aryl, heteroaryl, heterocyclyl and indane optionally 1 to 3 substituents selected from the substituents: C 1 -C 7 - alkyl, Halo-C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy, halo-C 1 -C 7 -alkyl-oxy-, halo-C 1 -C 7 -alkyl- Oxy-C 1 -C 7 -alkyl, C 1 -C 7 -alkyl-oxy-C 1 -C 7 -alkyl and hydroxy-C 1 -C 7 -alkyl; or (c)-NR 6' R 6 , wherein R 6 is selected from hydrogen, C 1 -C 7 -alkyl, and R 6 ' is selected from hydrogen, C 1 -C 7 -alkyl, C 1 -C 7 -alkylcarbonyl-, C 3 -C 10 -cycloalkyl; or R 6 and R 6 ' together with the nitrogen atom to which they are attached form a 4 to 7 membered saturated or partially saturated monocyclic or 7 to 12 membered saturated or partially saturated bicyclic heterocyclic ring. And the heterocyclic ring optionally contains another hetero atom selected from N, O or S; the monocyclic and bicyclic heterocyclic ring is unsubstituted or substituted with 1 to 3 substituents selected from C 1 -C 7 -alkane -halo-C 1 -C 7 -alkyl-, C 1 -C 7 -alkoxy-,halo-C 1 -C 7 -alkoxy-,halo-C 1 -C 7 - alkoxy-C 1 -C 7 -alkyl-, hydroxy- and C 1 -C 7 -alkoxy-carbonyl-; (d)-NR 5' -C(O)-R 5 , wherein R 5 is selected from the group consisting of hydrogen, C 1 -C 7 -alkyl, C 3 -C 10 -cycloalkyl, C 1 -C 7 -alkoxy, halo-C 1 -C 7 -alkyl, aryl, Aryl-C 1 -C 7 -alkyl-,heteroaryl,heteroaryl-C 1 -C 7 -alkyl-,heterocyclyl; R 5 ' is selected from hydrogen, C 1 -C 7 -alkane m; m is 0 to 1; and n is 0 to 2; R 8 is hydrogen and R 9 is selected from hydrogen, C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-, C 1 - C 7 -alkyl, C 1 -C 7 -alkoxy and halo-C 1 -C 7 -alkyl; wherein C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy, heterocyclic The aryl group, the aryl group and the heteroaryl group are optionally aryl, heteroaryl, heterocyclic, C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy, halo-C 1 -C 7 - Alkyl, OH substituted; the premise does not contain 6-[5-(2-furyl)-1,2,4- Diazol-3-yl]-N2-methyl-N2-phenyl-1,3,5-three -2,4-diamine and 6-[5-(2-furyl)-1,2,4- Diazol-3-yl]-N,N,N'-methyl-N'-phenyl-1,3,5-three -2,4-diamine. 如請求項1之化合物，其具有式(I) 其中R1係選自氫-鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-；R2係選自氫-C1-C7-烷基-鹵代-C2-C7-烷基-胺基-C2-C7-烷基-N-C1-C7-烷基-胺基-C2-C7-烷基-N,N-二-C1-C7-烷基-胺基-C2-C7-烷基-羥基-C2-C7-烷基-C1-C7-烷氧基-C2-C7-烷基-C3-C10-環烷基-C1-C7-烷基- 氰基-C2-C7-烷基-；或R1及R2與其所附接之原子一起形成4至7員飽和或部分飽和之雜環，該雜環未經取代或經1至3個選自以下之取代基取代：C1-C7-烷基-鹵代-C1-C7-烷基-胺基-C1-C7-烷基-N-C1-C7-烷基-胺基-C1-C7-烷基-N,N-二-C1-C7-烷基-胺基-C1-C7-烷基-羥基-C1-C7-烷基-C1-C7-烷氧基-C1-C7-烷基-C3-C10-環烷基-C1-C7-烷基-氰基-C1-C7-烷基-；R係選自鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-C1-C7-烷氧基-氰基-鹵代-C1-C7-烷氧基-硝基；R3係選自(a)-(CH2)p-Y，其中 p係選自0、1、2或3，且Y係選自芳基、雜芳基、雜環基，其未經取代或經1至3個選自以下之取代基取代：鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-C1-C7-烷氧基-C3-C10-環烷基-氧基-羥基-鹵代-C1-C7-烷基-氧基-胺基-N-C1-C7-烷基-胺基-N,N-二-C1-C7-烷基-胺基-氰基-C1-C7-烷氧基-羰基-羥基-羰基--C(O)-NR4'R4，其中R4係選自氫、C1-C7-烷基；R4'係選自氫，或R4及R4'與其所附接之氮原子一起形成4至7員飽和或部分飽和之單環雜環，該雜環視情況含有選自N、O或S之另一雜原子；或(b)-C(O)-NR5'R5或-C(O)-O-R5，其中 R5係選自氫、苄基、二氫茚基、四氫呋喃基、四氫吡喃基、環氧乙烷基、C3-C10-環烷基、C1-C7-烷基；R5'係選自氫、C1-C7-烷基，或R5及R5'與其所附接之氮原子一起形成4至7員飽和或部分飽和之單環或雙環雜環，該雜環視情況含有選自N、O或S之另一雜原子；或(c)-NR6'R6，其中R6係選自氫、苄基、C3-C10-環烷基、C1-C7-烷基，R6'係選自氫、C1-C7-烷基、C1-C7-烷基羰基-，或R6及R6'與其所附接之氮原子一起形成4至7員飽和或部分飽和之單環或7至12員飽和或部分飽和之雙環雜環，該雜環視情況含有選自N、O或S之另一雜原子；其未經取代或經1至3個選自以下之取代基取代：C1-C7-烷基-羥基-C1-C7-烷氧基-羰基-或(d)-NR5'-C(O)-R5，其中R5係選自C3-C10-環烷基；R5'係選自氫、C1-C7-烷基；m為0至1；且n為0至1；前提係不包含6-[5-(2-呋喃基)-1,2,4-二唑-3-基]-N2-甲 基-N2-苯基-1,3,5-三-2,4-二胺。 The compound of claim 1, which has the formula (I) Wherein R 1 is selected from hydrogen-halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-; R 2 is selected from hydrogen-C 1 -C 7 -alkyl-halo -C 2 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-NC 1 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-N,N-di-C 1- C 7 -alkyl-amino-C 2 -C 7 -alkyl-hydroxy-C 2 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 2 -C 7 -alkyl- C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkyl-cyano-C 2 -C 7 -alkyl-; or R 1 and R 2 together with the atoms to which they are attached form 4 to 7 members a saturated or partially saturated heterocyclic ring which is unsubstituted or substituted with 1 to 3 substituents selected from C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-amine -C 1 -C 7 -alkyl-NC 1 -C 7 -alkyl-amino-C 1 -C 7 -alkyl-N,N-di-C 1 -C 7 -alkyl-amino group- C 1 -C 7 -alkyl-hydroxy-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-C 3 -C 10 -cycloalkyl-C 1- C 7 -alkyl-cyano-C 1 -C 7 -alkyl-; R is selected from halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-cyano-halo-C 1 -C 7 -alkoxy-nitro; R 3 is selected from (a)-(CH 2 ) p -Y, wherein p is selected from 0 , 1, 2 or 3, and Y Selected from aryl, heteroaryl, a heterocyclic group, which is unsubstituted or substituted with 1 to 3 substituents selected from the group: halogen -C 1 -C 7 - alkyl - halo -C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 3 -C 10 -cycloalkyl-oxy-hydroxy-halo-C 1 -C 7 -alkyl-oxy-amino-NC 1 - C 7 -alkyl-amino-N,N-di-C 1 -C 7 -alkyl-amino-cyano-C 1 -C 7 -alkoxy-carbonyl-hydroxy-carbonyl--C(O -NR 4' R 4 , wherein R 4 is selected from hydrogen, C 1 -C 7 -alkyl; R 4 ' is selected from hydrogen, or R 4 and R 4 ' together with the nitrogen atom to which they are attached form 4 a 7-membered saturated or partially saturated monocyclic heterocyclic ring optionally containing another hetero atom selected from N, O or S; or (b) -C(O)-NR 5' R 5 or -C ( O)-OR 5 , wherein R 5 is selected from the group consisting of hydrogen, benzyl, indanyl, tetrahydrofuranyl, tetrahydropyranyl, oxiranyl, C 3 -C 10 -cycloalkyl, C 1 - C 7 -alkyl; R 5 ' is selected from hydrogen, C 1 -C 7 -alkyl, or R 5 and R 5 ' together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated or partially saturated monocyclic ring. Or a bicyclic heterocycle which optionally contains another hetero atom selected from N, O or S; or (c) -NR 6' R 6 , The R 6 is selected from the group consisting of hydrogen, benzyl, C 3 -C 10 -cycloalkyl, C 1 -C 7 -alkyl, and R 6 ' is selected from hydrogen, C 1 -C 7 -alkyl, C 1 - C 7 -alkylcarbonyl-, or R 6 and R 6 ' together with the nitrogen atom to which they are attached form a 4 to 7 membered saturated or partially saturated monocyclic or 7 to 12 membered saturated or partially saturated bicyclic heterocyclic ring, The heterocyclic ring optionally contains another hetero atom selected from N, O or S; it is unsubstituted or substituted with 1 to 3 substituents selected from C 1 -C 7 -alkyl-hydroxy-C 1 -C 7 - alkoxy-carbonyl- or (d)-NR 5' -C(O)-R 5 , wherein R 5 is selected from C 3 -C 10 -cycloalkyl; R 5 ' is selected from hydrogen, C 1 -C 7 -alkyl; m is 0 to 1; and n is 0 to 1; the premise does not contain 6-[5-(2-furyl)-1,2,4- Diazol-3-yl]-N2-methyl-N2-phenyl-1,3,5-three -2,4-diamine. 如請求項1之化合物，其中R1係選自氫-氯-氟-甲基-；R2係選自氫-C1-C4-烷基-鹵代-C2-C4-烷基-N,N-二-C1-C2-烷基-胺基-C2-C4-烷基-羥基-C2-C4-烷基-C1-C2-烷氧基-C2-C4-烷基-C3-C6-環烷基-C1-C7-烷基-。 The compound of claim 1, wherein R 1 is selected from the group consisting of hydrogen-chloro-fluoro-methyl-; and R 2 is selected from hydrogen-C 1 -C 4 -alkyl-halo-C 2 -C 4 -alkyl -N,N-di-C 1 -C 2 -alkyl-amino-C 2 -C 4 -alkyl-hydroxy-C 2 -C 4 -alkyl-C 1 -C 2 -alkoxy-C 2- C 4 -alkyl-C 3 -C 6 -cycloalkyl-C 1 -C 7 -alkyl-. 如請求項1或2之化合物，其中R3係選自-(CH2)p-Y，其中p係選自0、1、2或3，且Y係選自芳基、雜芳基、雜環基，其未經取代或經1至3個選自以下之取代基取代：鹵素-C1-C7-烷基- 鹵代-C1-C7-烷基-C1-C7-烷氧基-C3-C10-環烷基-氧基-羥基-鹵代-C1-C7-烷基-氧基-胺基-N-C1-C7-烷基-胺基-N,N-二-C1-C7-烷基-胺基--S(=O)2-C1-C7-烷基；-S(=O)2-鹵代-C1-C7-烷基；-S(=O)-C1-C7-烷基；-S(=O)-鹵代-C1-C7-烷基C3-C10-環烷基-C1-C7-烷氧基-C1-C7-烷基-；氰基-C1-C7-烷氧基-羰基-羥基-羰基--C(O)-NR4'R4，其中R4係選自氫、C1-C7-烷基；R4'係選自氫，或R4及R4'與其所附接之氮原子一起形成4至7員飽和或部分飽和之單環雜環，該單環雜環視情況含有選自N、O或S之另一雜原子。 The compound of claim 1 or 2, wherein R 3 is selected from the group consisting of -(CH 2 ) p -Y, wherein p is selected from 0, 1, 2 or 3, and Y is selected from the group consisting of aryl, heteroaryl, hetero a cyclic group which is unsubstituted or substituted with 1 to 3 substituents selected from halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-C 1 -C 7 - Alkoxy-C 3 -C 10 -cycloalkyl-oxy-hydroxy-halo-C 1 -C 7 -alkyl-oxy-amino-NC 1 -C 7 -alkyl-amino-N ,N-di-C 1 -C 7 -alkyl-amino-S(=O) 2 -C 1 -C 7 -alkyl;-S(=O) 2 -halo-C 1 -C 7 -alkyl;-S(=O)-C 1 -C 7 -alkyl;-S(=O)-halo-C 1 -C 7 -alkyl C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-; cyano-C 1 -C 7 -alkoxy-carbonyl-hydroxy-carbonyl-C(O)-NR 4' R 4 , wherein R 4 is selected from hydrogen, C 1 -C 7 -alkyl; R 4 ' is selected from hydrogen, or R 4 and R 4' together with the nitrogen atom to which they are attached form a 4 to 7 member saturated or partially saturated single A cyclic heterocyclic ring which optionally contains another hetero atom selected from N, O or S. 如請求項1或2之化合物，其中R3係選自-(CH2)p-Y，其中p係選自0、1、2或3，且 Y係選自芳基、雜芳基、雜環基，其未經取代或經1至3個選自以下之取代基取代：鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-C1-C7-烷氧基-C3-C10-環烷基-氧基-羥基-鹵代-C1-C7-烷基-氧基-胺基-N-C1-C7-烷基-胺基-N,N-二-C1-C7-烷基-胺基-氰基-C1-C7-烷氧基-羰基-羥基-羰基--C(O)-NR4'R4，其中R4係選自氫、C1-C7-烷基；R4'係選自氫，或R4及R4'與其所附接之氮原子一起形成4至7員飽和或部分飽和之單環雜環，該單環雜環視情況含有選自N、O或S之另一雜原子。 The compound of claim 1 or 2, wherein R 3 is selected from the group consisting of -(CH 2 ) p -Y, wherein p is selected from 0, 1, 2 or 3, and Y is selected from the group consisting of aryl, heteroaryl, hetero a cyclic group which is unsubstituted or substituted with 1 to 3 substituents selected from halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-C 1 -C 7 - Alkoxy-C 3 -C 10 -cycloalkyl-oxy-hydroxy-halo-C 1 -C 7 -alkyl-oxy-amino-NC 1 -C 7 -alkyl-amino-N ,N-di-C 1 -C 7 -alkyl-amino-cyano-C 1 -C 7 -alkoxy-carbonyl-hydroxy-carbonyl--C(O)-NR 4' R 4 , wherein R 4 is selected from the group consisting of hydrogen, C 1 -C 7 -alkyl; R 4 ' is selected from hydrogen, or R 4 and R 4 ' together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated or partially saturated monocyclic ring. A heterocyclic ring, which optionally contains another hetero atom selected from N, O or S. 如請求項1或2之化合物，其中R3係選自(b)-C(O)-NR5'R5或-C(O)-O-R5，其中 R5係選自氫、苄基、二氫茚基、四氫呋喃基、四氫吡喃基、環氧乙烷基、C3-C10-環烷基、C1-C7-烷基；R5'係選自氫、C1-C7-烷基，或R5及R5'與其所附接之氮原子一起形成4至7員飽和或部分飽和之單環或雙環雜環，該雜環視情況含有選自N、O或S之另一雜原子；或(c)-NR6'R6，其中R6係選自氫、苄基、C3-C10-環烷基、C1-C7-烷基，R6'係選自氫、C1-C7-烷基、C1-C7-烷基羰基-，或R6及R6'與其所附接之氮原子一起形成4至7員飽和或部分飽和之單環或7至12員飽和或部分飽和之雙環雜環，該雜環視情況含有選自N、O或S之另一雜原子；其未經取代或經1至3個選自以下之取代基取代：C1-C7-烷基-羥基-C1-C7-烷氧基-羰基-或(d)-NR5'-C(O)-R5，其中R5係選自C3-C10-環烷基；R5'係選自氫、C1-C7-烷基。 The compound of claim 1 or 2, wherein R 3 is selected from the group consisting of (b)-C(O)-NR 5' R 5 or -C(O)-OR 5 , wherein R 5 is selected from the group consisting of hydrogen, benzyl, Indoline, tetrahydrofuranyl, tetrahydropyranyl, oxiranyl, C 3 -C 10 -cycloalkyl, C 1 -C 7 -alkyl; R 5 ' is selected from hydrogen, C 1 - C 7 -alkyl, or R 5 and R 5 ' together with the nitrogen atom to which they are attached form a 4 to 7 membered saturated or partially saturated monocyclic or bicyclic heterocyclic ring optionally containing N, O or S Another hetero atom; or (c)-NR 6' R 6 , wherein R 6 is selected from the group consisting of hydrogen, benzyl, C 3 -C 10 -cycloalkyl, C 1 -C 7 -alkyl, R 6' Is selected from hydrogen, C 1 -C 7 -alkyl, C 1 -C 7 -alkylcarbonyl-, or R 6 and R 6' together with the nitrogen atom to which they are attached form a 4 to 7 member saturated or partially saturated Monocyclic or 7 to 12 membered saturated or partially saturated bicyclic heterocyclic ring containing optionally another hetero atom selected from N, O or S; unsubstituted or substituted with 1 to 3 substituents selected from Substituted: C 1 -C 7 -alkyl-hydroxy-C 1 -C 7 -alkoxy-carbonyl- or (d)-NR 5' -C(O)-R 5 , wherein R 5 is selected from C 3 -C 10 -cycloalkyl; R 5 ' is selected from hydrogen, C 1 -C 7 -alkyl. 如請求項1至3中任一項之化合物，其中m為0。 The compound of any one of claims 1 to 3, wherein m is 0. 如請求項1之化合物，其中 R1係選自氫-氟-；R2係選自氫-C1-C4-烷基-鹵代-C2-C4-烷基-N,N-二-C1-C2-烷基-胺基-C2-C4-烷基-羥基-C2-C4-烷基-C1-C2-烷氧基-C2-C4-烷基-C3-C6-環烷基-C1-C7-烷基-；或R1及R2一起選自-CH2-CH2-或-CH2-CH2-CH2-；R係選自鹵素-C1-C4-烷基-鹵代-C1-C4-烷基-C1-C4-烷氧基-氰基-；且R3係選自-(CH2)p-Y，其中p係選自0、1、2或3，且Y係選自芳基、雜芳基、雜環基，其未經取代或經1至 3個選自以下之取代基取代：鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-C1-C7-烷氧基-C3-C10-環烷基-氧基-羥基-鹵代-C1-C7-烷基-氧基-胺基-N-C1-C7-烷基-胺基-N,N-二-C1-C7-烷基-胺基-氰基-C1-C7-烷氧基-羰基--C(O)-NR4'R4，其中R4係選自氫、C1-C7-烷基；R4'係選自氫，或R4及R4'與其所附接之氮原子一起形成4至7員飽和或部分飽和之單環雜環，該單環雜環視情況含有選自N、O或S之另一雜原子，m為0；且n為0至1。 The compound of claim 1, wherein R 1 is selected from hydrogen-fluoro-; R 2 is selected from hydrogen-C 1 -C 4 -alkyl-halo-C 2 -C 4 -alkyl-N,N- Di-C 1 -C 2 -alkyl-amino-C 2 -C 4 -alkyl-hydroxy-C 2 -C 4 -alkyl-C 1 -C 2 -alkoxy-C 2 -C 4 - Alkyl-C 3 -C 6 -cycloalkyl-C 1 -C 7 -alkyl-; or R 1 and R 2 are taken together from -CH 2 -CH 2 - or -CH 2 -CH 2 -CH 2 - ; R is selected from the group consisting of halogen-C 1 -C 4 -alkyl-halo-C 1 -C 4 -alkyl-C 1 -C 4 -alkoxy-cyano-; and R 3 is selected from -( CH 2 ) p -Y, wherein p is selected from 0, 1, 2 or 3, and Y is selected from aryl, heteroaryl, heterocyclic, unsubstituted or 1 to 3 selected from the group consisting of Substituent substitution: halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 3 -C 10 -cycloalkyl-oxy- Hydroxy-halo-C 1 -C 7 -alkyl-oxy-amino-NC 1 -C 7 -alkyl-amino-N,N-di-C 1 -C 7 -alkyl-amino group- cyano-C 1 -C 7 -alkoxy-carbonyl-C(O)-NR 4' R 4 , wherein R 4 is selected from hydrogen, C 1 -C 7 -alkyl; R 4 ' is selected from Hydrogen, or R 4 and R 4 ' together with the nitrogen atom to which they are attached form a 4 to 7 membered saturated or partially saturated monocyclic heterocycle, The monocyclic heterocyclic ring optionally contains another hetero atom selected from N, O or S, m is 0; and n is 0 to 1. 如請求項1之化合物或其醫藥上可接受之鹽，其選自實例1至517。 A compound of claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of Examples 1 to 517. 如請求項9之化合物，其中該化合物係選自 2-N-甲基-2-N-苯基-6-(5-{4-[(2,2,2-三氟乙氧基)甲基]六氫吡啶-1-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[1-(丙烷-2-磺醯基)六氫吡啶-4-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；6-(5-{4-[(環丙基甲氧基)甲基]六氫吡啶-1-基}-1,2,4-二唑-3-基)-2-N-甲基-2-N-苯基-1,3,5-三-2,4-二胺；2-N-(3-氟苯基)-6-[5-(3-氟吡啶-2-基)-1,2,4-二唑-3-基]-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{6-[2-(2,2,2-三氟乙氧基)乙氧基]吡啶-3-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[(2R)-1-[(2,2,2-三氟乙烷)磺醯基]吡咯啶-2-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{6-[(3,3,3-三氟丙烷)亞磺醯基]吡啶-3-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-(5-{4-[(3,3,3-三氟丙氧基)甲基]六氫吡啶-1-基}-1,2,4-二唑-3-基)-1,3,5-三-2,4-二胺；2-N-甲基-2-N-苯基-6-{5-[1-(丙烷-2-磺醯基)六氫吡啶-4-基]-1,2,4-二唑-3-基}-1,3,5-三-2,4-二胺；及N-甲基-N-苯基-6-{5-[6-(2,2,2-三氟乙氧基)-吡啶-3-基]-[1,2,4]二唑-3-基}-[1,3,5]三-2,4-二胺；或其醫藥上可接受之鹽。 The compound of claim 9, wherein the compound is selected from the group consisting of 2-N-methyl-2-N-phenyl-6-(5-{4-[(2,2,2-trifluoroethoxy)) Hexahydropyridin-1-yl}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[1-(propane-2-sulfonyl)hexahydropyridin-4-yl]-1, 2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 6-(5-{4-[(cyclopropylmethoxy)methyl]hexahydropyridin-1-yl}-1,2,4- Diazol-3-yl)-2-N-methyl-2-N-phenyl-1,3,5-three -2,4-diamine; 2-N-(3-fluorophenyl)-6-[5-(3-fluoropyridin-2-yl)-1,2,4- Diazol-3-yl]-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{6-[2-(2,2,2-trifluoroethoxy)ethoxy] Pyridin-3-yl}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[(2R)-1-[(2,2,2-trifluoroethane)sulfonyl) Pyrrolidin-2-yl]-1,2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{6-[(3,3,3-trifluoropropane)sulfinyl]pyridine-3 -base}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-(5-{4-[(3,3,3-trifluoropropoxy)methyl]hexahydropyridine -1-yl}-1,2,4- Diazol-3-yl)-1,3,5-three -2,4-diamine; 2-N-methyl-2-N-phenyl-6-{5-[1-(propane-2-sulfonyl)hexahydropyridin-4-yl]-1, 2,4- Diazol-3-yl}-1,3,5-three -2,4-diamine; and N-methyl-N-phenyl-6-{5-[6-(2,2,2-trifluoroethoxy)-pyridin-3-yl]-[1 , 2, 4] Diazol-3-yl}-[1,3,5]3 a 2,4-diamine; or a pharmaceutically acceptable salt thereof. 一種式(I)化合物或其醫藥上可接受之鹽， 其中R1係選自氫-鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-；R2係選自氫-C1-C7-烷基-鹵代-C2-C7-烷基-胺基-C2-C7-烷基-N-C1-C7-烷基-胺基-C2-C7-烷基-N,N-二-C1-C7-烷基-胺基-C2-C7-烷基-羥基-C2-C7-烷基-C1-C7-烷氧基-C2-C7-烷基-C3-C10-環烷基-C1-C7-烷基-氰基-C2-C7-烷基-；或R1及R2與其所附接之原子一起形成4至7員飽和或部分飽 和之雜環，該雜環未經取代或經1至3個選自以下之取代基取代：C1-C7-烷基-鹵代-C1-C7-烷基-胺基-C1-C7-烷基-N-C1-C7-烷基-胺基-C1-C7-烷基-N,N-二-C1-C7-烷基-胺基-C1-C7-烷基-羥基-C1-C7-烷基-C1-C7-烷氧基-C1-C7-烷基-C3-C10-環烷基-C1-C7-烷基-氰基-C1-C7-烷基-；R係選自鹵素-C1-C7-烷基-鹵代-C1-C7-烷基-C1-C7-烷氧基-氰基-鹵代-C1-C7-烷氧基-硝基；-C(O)-O-R'，其中R'係選自氫、C1-C7-烷基、C3-C10-環烷基、C1-C7-烷氧基、鹵代-C1-C7-烷基芳基、芳基-C1-C7-烷基-、雜芳基、雜芳基C1-C7-烷基-、雜環基；-S(=O)2-C1-C7-烷基；-S(=O)2-C3-C10-環烷基；-S(=O)2-C1-C7- 烷氧基；R3係選自(a)-L-Y，其中-L-係選自直接鍵結、-(CH2)p-、-C(O)-、-NR7-、-NR7-C(O)-或-C(O)-NR7-，其中p係選自1、2或3 R7係選自氫及C1-C7-烷基Y係選自環烷基、芳基、雜芳基、雜環基、螺環基，其未經取代或經1至3個選自以下之取代基取代：鹵素-；C1-C7-烷基-；鹵代-C1-C7-烷基-；鹵代-C1-C7-烷基-氧基-C1-C7-烷基；鹵代-C1-C7-烷基-氧基-C1-C7-烷基-氧基；C1-C7-烷氧基-；C1-C7-烷氧基-C1-C7-烷氧基-；NC-C1-C7-烷氧基-；C1-C7-烷氧基-C1-C7-烷基-；C3-C10-環烷基-氧基-C1-C7-烷基-；C3-C10-環烷基-C1-C7-烷基-氧基-；C3-C10-環烷基-氧基-；C3-C10-環烷基-NR7'-C1-C7-烷基-，其中R7'係選自氫及C1-C7-烷基；C3-C10-環烷基-C1-C7-烷氧基-C1-C7-烷基-；C2-C7-烯基；鹵代-C2-C7-烯基； 羥基-；羥基-C1-C7-烷基-；鹵代-C1-C7-烷基-氧基-；胺基-；N-C1-C7-烷基-胺基-；N-鹵代-C1-C7-烷基-胺基-；N-雜環基-胺基-、N-C3-C10-環烷基-胺基-，其中該等雜環基及環烷基視情況經鹵代-C1-C7-烷基-氧基、C1-C7-烷基、C3-C10-環烷基及C1-C7-烷氧基取代；N-C3-C10-環烷基-C1-C7-烷基-胺基-；N,N-二-C1-C7-烷基-胺基-；N,N-二-鹵代-C1-C7-烷基-胺基-；N,N-二-雜環基-胺基-、N,N-二-C3-C10-環烷基-胺基-，其中該等雜環基及環烷基視情況經鹵代-C1-C7-烷基-氧基、C1-C7-烷基、C3-C10-環烷基及C1-C7-烷氧基取代；氰基-；側氧基；C1-C7-烷氧基-羰基-；C1-C7-烷氧基-C1-C7-烷氧基-C1-C7-烷基-；芳基；芳基-C1-C7-烷基-；芳基-氧基；雜環基；雜環基-C1-C7-烷基-；雜環基-氧基-；雜環基-氧基-C1-C7-烷基-；芳基-氧基-C1-C7-烷基- ；雜芳基-氧基-C1-C7-烷基-；羥基-羰基-；-S-鹵代-C1-C7-烷基；-S-C1-C7-烷基；-S-芳基；鹵代-C1-C7-烷基-S-C1-C7-烷基；C1-C7-烷基-S-C1-C7-烷基；-S(=O)2-C1-C7-烷基；-S(=O)2-鹵代-C1-C7-烷基；-S(=O)2-芳基；-S(=O)2-雜芳基；-S(=O)2-NR4'R4；-S(=O)2-雜環基；鹵代-C1-C7-烷基-S(=O)2-C1-C7-烷基；C1-C7-烷基-S(=O)2-C1-C7-烷基；-S(=O)-C1-C7-烷基；-S(=O)-鹵代-C1-C7-烷基；-S(=O)-C1-C7-烷氧基；-S(=O)-C3-C10-環烷基；-C(O)-C1-C7-烷基；-C(O)-鹵代-C1-C7-烷基；-C(O)-C1-C7-烷氧基；-C(O)-C3-C10環烷基；-C(O)O-C1-C7-烷基；-C(O)O-C3-C10-環烷基；-C(O)O-鹵代-C1-C7-烷基；-C(O)O-C1-C7-烷氧基；-C(O)-NR4'R4或-NHC(O)-R4，其中R4係選自氫、C1-C7-烷基、鹵代-C1-C7-烷基、C3-C10-環烷基、C3-C10-環烷基-C1-C7-烷基及C1-C7-烷氧基；R4'係選自氫；或R4及R4'與其所附接之氮原子一起形成4至7員飽和或部分飽和之單環雜環，該雜環視情況含有選自N、O或S之另一雜原子，且其中該雜環視情況 經芳基、芳基-氧基-、C1-C7-烷基、鹵代-C1-C7-烷基或C1-C7-烷氧基取代，且該芳基視情況經鹵素、C1-C7-烷基、鹵代-C1-C7-烷基或C1-C7-烷氧基取代；或(b)-C(O)-NR5'R5或-C(O)-O-R5，其中R5及R5'係選自氫、C1-C7-烷基、C3-C10-環烷基、C1-C7-烷氧基、鹵代-C1-C7-烷基芳基、芳基-C1-C7-烷基-、芳基、雜芳基、雜芳基C1-C7-烷基-、雜環基、二氫化茚，或R5及R5'與其所附接之氮原子一起形成4至9員飽和或部分飽和之單環或雙環雜環，該單環或雙環雜環視情況含有選自N、O或S之另一雜原子；其中該等C3-C10-環烷基、芳基、雜芳基、雜環基及二氫化茚視情況經1至3個選自以下之取代基取代：C1-C7-烷基、鹵代-C1-C7-烷基、C1-C7-烷氧基、鹵代-C1-C7-烷基-氧基-及羥基-C1-C7-烷基；或(c)-NR6'R6，其中R6係選自氫、C1-C7-烷基，R6'係選自氫、C1-C7-烷基、C1-C7-烷基羰基-、C3-C10-環烷基；或R6及R6'與其所附接之氮原子一起形成4至7員飽和或部分飽和之單環或7至12員飽和或部分飽和之雙環雜環，該雜環視情況含有選自N、O或S之另一雜原子； 該單環及雙環雜環未經取代或經1至3個選自以下之取代基取代：C1-C7-烷基-、鹵代-C1-C7-烷基-、C1-C7-烷氧基-、羥基-及C1-C7-烷氧基-羰基-；(d)-NR5'-C(O)-R5，其中R5係選自氫、C1-C7-烷基、C3-C10-環烷基、C1-C7-烷氧基、鹵代-C1-C7-烷基、芳基、芳基-C1-C7-烷基-、雜芳基、雜芳基-C1-C7-烷基-、雜環基；R5'係選自氫、C1-C7-烷基；m為0至1；且n為0至2；R8為氫且R9係選自氫、C1-C7-烷氧基-C1-C7-烷基-、C1-C7-烷基、C1-C7-烷氧基及鹵代-C1-C7-烷基；其中C1-C7-烷基、C1-C7-烷氧基、雜環基、芳基、雜芳基視情況經芳基、雜芳基、雜環基、C1-C7-烷基、C1-C7-烷氧基、鹵代-C1-C7-烷基、OH取代；其用作藥劑。 a compound of formula (I) or a pharmaceutically acceptable salt thereof, Wherein R 1 is selected from hydrogen-halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-; R 2 is selected from hydrogen-C 1 -C 7 -alkyl-halo -C 2 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-NC 1 -C 7 -alkyl-amino-C 2 -C 7 -alkyl-N,N-di-C 1- C 7 -alkyl-amino-C 2 -C 7 -alkyl-hydroxy-C 2 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 2 -C 7 -alkyl- C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkyl-cyano-C 2 -C 7 -alkyl-; or R 1 and R 2 together with the atoms to which they are attached form 4 to 7 members a saturated or partially saturated heterocyclic ring which is unsubstituted or substituted with 1 to 3 substituents selected from C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-amine -C 1 -C 7 -alkyl-NC 1 -C 7 -alkyl-amino-C 1 -C 7 -alkyl-N,N-di-C 1 -C 7 -alkyl-amino group- C 1 -C 7 -alkyl-hydroxy-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-C 3 -C 10 -cycloalkyl-C 1- C 7 -alkyl-cyano-C 1 -C 7 -alkyl-; R is selected from halogen-C 1 -C 7 -alkyl-halo-C 1 -C 7 -alkyl-C 1 -C 7 -alkoxy-cyano-halo-C 1 -C 7 -alkoxy-nitro;-C(O)-O-R', wherein R' is selected from hydrogen, C 1 -C 7 -alkyl, C 3 -C 10 - ring Alkyl, C 1 -C 7 -alkoxy, halo-C 1 -C 7 -alkylaryl, aryl-C 1 -C 7 -alkyl-,heteroaryl,heteroaryl C 1 - C 7 -alkyl-,heterocyclyl;-S(=O) 2 -C 1 -C 7 -alkyl;-S(=O) 2 -C 3 -C 10 -cycloalkyl;-S(= O) 2 -C 1 -C 7 - alkoxy; R 3 is selected from (a)-LY, wherein -L- is selected from direct bonding, -(CH 2 ) p -, -C(O)- , -NR 7 -, -NR 7 -C(O)- or -C(O)-NR 7 -, wherein p is selected from 1, 2 or 3 R 7 is selected from the group consisting of hydrogen and C 1 -C 7 -alkane The group Y is selected from the group consisting of a cycloalkyl group, an aryl group, a heteroaryl group, a heterocyclic group, a spiro group, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen-; C 1 -C 7 -alkyl-;halo-C 1 -C 7 -alkyl-;halo-C 1 -C 7 -alkyl-oxy-C 1 -C 7 -alkyl;halo-C 1 -C 7 - alkyl - group -C 1 -C 7 - alkyl - group; C 1 -C 7 - alkoxy -; C 1 -C 7 - alkoxy, -C 1 -C 7 - alkoxy - ;NC-C 1 -C 7 -alkoxy-;C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-;C 3 -C 10 -cycloalkyl-oxy-C 1 - C 7 -alkyl-; C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkyl-oxy-; C 3 -C 10 -cycloalkyl-oxy-; C 3 -C 10 - Cycloalkyl-NR 7' -C 1 -C 7 -alkyl-, wherein R 7 ' is selected from hydrogen and C 1 -C 7 -alkyl; C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-; C 2 -C 7 -alkenyl; halo-C 2 -C 7 -alkenyl; hydroxy-; hydroxy-C 1 -C 7 -alkyl-;halo-C 1 -C 7 -alkyl-oxy-;amino-;NC 1 -C 7 -alkyl-amino-;N-halo-C 1 -C 7 -alkyl-amino-;N-heterocyclyl-amine Base-, NC 3 -C 10 -cycloalkyl-amino-, wherein the heterocyclic and cycloalkyl groups are optionally halogenated -C 1 -C 7 -alkyl-oxy, C 1 -C 7 -alkyl, C 3 -C 10 -cycloalkyl and C 1 -C 7 -alkoxy substituted; NC 3 -C 10 -cycloalkyl-C 1 -C 7 -alkyl-amino-;N, N-di-C 1 -C 7 -alkyl-amino-;N,N-di-halo-C 1 -C 7 -alkyl-amino-;N,N-di-heterocyclyl-amine Base-, N,N-di-C 3 -C 10 -cycloalkyl-amino-, wherein the heterocyclic group and cycloalkyl group are optionally halogenated-C 1 -C 7 -alkyl-oxy , C 1 -C 7 -alkyl, C 3 -C 10 -cycloalkyl and C 1 -C 7 -alkoxy substituted; cyano-; pendant oxy; C 1 -C 7 -alkoxy-carbonyl -; C 1 -C 7 - alkoxy, -C 1 -C 7 - alkoxy, -C 1 -C 7 - alkyl -; aryl; aryl -C 1 -C 7 - alkyl - ; aryl-oxy; heterocyclic; heterocyclyl-C 1 -C 7 -alkyl-;heterocyclyl-oxy-;heterocyclyl-oxy-C 1 -C 7 -alkyl-; Aryl-oxy-C 1 -C 7 -alkyl-;heteroaryl-oxy-C 1 -C 7 -alkyl-;hydroxy-carbonyl-;-S-halo-C 1 -C 7 - Alkyl; -SC 1 -C 7 -alkyl; -S-aryl; halo-C 1 -C 7 -alkyl-SC 1 -C 7 -alkyl; C 1 -C 7 -alkyl-SC 1- C 7 -alkyl;-S(=O) 2 -C 1 -C 7 -alkyl;-S(=O) 2 -halo-C 1 -C 7 -alkyl;-S(=O 2 - aryl; -S(=O) 2 -heteroaryl; -S(=O) 2 -NR 4' R 4 ;-S(=O) 2 -heterocyclyl;halo-C 1 - C 7 -alkyl-S(=O) 2 -C 1 -C 7 -alkyl; C 1 -C 7 -alkyl-S(=O) 2 -C 1 -C 7 -alkyl;-S( =O)-C 1 -C 7 -alkyl;-S(=O)-halo-C 1 -C 7 -alkyl;-S(=O)-C 1 -C 7 -alkoxy;- S(=O)-C 3 -C 10 -cycloalkyl; -C(O)-C 1 -C 7 -alkyl; -C(O)-halo-C 1 -C 7 -alkyl;- C(O)-C 1 -C 7 -alkoxy; -C(O)-C 3 -C 10 cycloalkyl; -C(O)OC 1 -C 7 -alkyl; -C(O)OC 3 -C 10 - cycloalkyl; -C (O) O- halo -C 1 -C 7 - alkyl; -C (O) OC 1 -C 7 - alkoxy; -C (O) -NR 4' R 4 or -NHC(O)-R 4 , wherein R 4 is selected from hydrogen, C 1 -C 7 -alkyl, halo-C 1 -C 7 -alkyl, C 3 -C 10 -cycloalkyl, C 3 -C 10 -cycloalkyl-C 1 -C 7 -alkyl and C 1 -C 7 -alkoxy; R 4 ' is selected from hydrogen; or R 4 and R 4 ' together with the nitrogen atom to which they are attached form a 4 to 7 membered saturated or partially saturated monocyclic heterocyclic ring. Circulatingly containing another hetero atom selected from N, O or S, and wherein the heterocyclic ring is optionally aryl, aryl-oxy-, C 1 -C 7 -alkyl, halo-C 1 -C 7 -alkyl or C 1 -C 7 -alkoxy substituted, and the aryl group optionally is halogen, C 1 -C 7 -alkyl, halo-C 1 -C 7 -alkyl or C 1 -C 7 - alkoxy substituted; or (b) -C(O)-NR 5' R 5 or -C(O)-OR 5 , wherein R 5 and R 5 ' are selected from hydrogen, C 1 -C 7 -alkane , C 3 -C 10 -cycloalkyl, C 1 -C 7 -alkoxy, halo-C 1 -C 7 -alkylaryl, aryl-C 1 -C 7 -alkyl-, aryl a heteroaryl, heteroaryl C 1 -C 7 -alkyl-, heterocyclyl, indane, or R 5 and R 5 ' together with the nitrogen atom to which they are attached form a 4 to 9 member saturation or moiety a saturated monocyclic or bicyclic heterocyclic ring which optionally contains another hetero atom selected from N, O or S; Such C 3 -C 10 - cycloalkyl, aryl, heteroaryl, heterocyclyl and indane optionally 1 to 3 substituents selected from the substituents: C 1 -C 7 - alkyl, Halogen-C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy, halo-C 1 -C 7 -alkyl-oxy- and hydroxy-C 1 -C 7 -alkyl; (c) -NR 6' R 6 , wherein R 6 is selected from hydrogen, C 1 -C 7 -alkyl, and R 6 ' is selected from hydrogen, C 1 -C 7 -alkyl, C 1 -C 7 - Alkylcarbonyl-, C 3 -C 10 -cycloalkyl; or R 6 and R 6 ' together with the nitrogen atom to which they are attached form a 4 to 7 membered saturated or partially saturated monocyclic or 7 to 12 membered saturated or partially a saturated bicyclic heterocycle which optionally contains another hetero atom selected from N, O or S; the monocyclic and bicyclic heterocycles are unsubstituted or substituted with from 1 to 3 substituents selected from C 1 -C 7 -alkyl-,halo-C 1 -C 7 -alkyl-, C 1 -C 7 -alkoxy-, hydroxy- and C 1 -C 7 -alkoxy-carbonyl-; -NR 5' -C(O)-R 5 , wherein R 5 is selected from hydrogen, C 1 -C 7 -alkyl, C 3 -C 10 -cycloalkyl, C 1 -C 7 -alkoxy , halogenated-C 1 -C 7 -alkyl, aryl, aryl-C 1 -C 7 -alkyl-, heteroaryl, heteroaryl-C 1 - C 7 -alkyl-, heterocyclic group; R 5 ' is selected from hydrogen, C 1 -C 7 -alkyl; m is 0 to 1; and n is 0 to 2; R 8 is hydrogen and R 9 is selected From hydrogen, C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-, C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy and halo-C 1 -C 7 -alkyl; wherein C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy, heterocyclyl, aryl,heteroaryl optionally, aryl, heteroaryl, heterocyclyl, C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy, halo-C 1 -C 7 -alkyl, OH substituted; used as a pharmaceutical. 一種醫藥組合物，其包括治療有效量之如請求項1至11中任一項之式(I)化合物及一或多種醫藥上可接受之載劑/賦形劑。 A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 11 and one or more pharmaceutically acceptable carriers/excipients. 一種組合，特定言之醫藥組合，其包括治療有效量之如請求項1至11中任一項之式(I)化合物及一或多種治療活性劑，特定言之止痛劑。 A combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 11 and one or more therapeutically active agents, in particular an analgesic. 一種如請求項1至11中任一項之式(I)化合物之用途，其用於製造用於治療慢性疼痛之藥劑。 Use of a compound of formula (I) according to any one of claims 1 to 11 for the manufacture of a medicament for the treatment of chronic pain. 一種如請求項1至11中任一項之式(I)化合物之用途，其用於製造用於治療一或多種Nav 1.7介導之病症或疾病之藥劑。 Use of a compound of formula (I) according to any one of claims 1 to 11 for the manufacture of a medicament for the treatment of one or more Nav 1.7 mediated conditions or diseases. 如請求項14之用途，其中該藥劑用於治療選自慢性疼痛之病症或疾病，該慢性疼痛係例如慢性疼痛之陽性症狀，例如感覺異常、感覺遲鈍、痛覺過敏、觸感痛及自發性疼痛；以及陰性症狀，例如失去感覺。 The use of claim 14, wherein the agent is for treating a condition or disease selected from the group consisting of chronic pain, such as a positive symptom of chronic pain, such as paresthesia, dysesthesia, hyperalgesia, tactile pain, and spontaneous pain. And negative symptoms, such as loss of sensation. 一種如請求項1至11中任一項之式(I)化合物之用途，其用於製造用於調節個體中之Nav 1.7活性之藥劑。 Use of a compound of formula (I) according to any one of claims 1 to 11 for the manufacture of a medicament for modulating Nav 1.7 activity in an individual.
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